AMINO IMSTC 2021 Vol 1 (Scientific Paper)

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AMINO AMSA-Indonesia Competition Archive

Academic Competition IMSTC 2021: Vol 1


All the works publicized here are the works of AMSA-Indonesia’s member who participated in Indonesian Medical Students’ Training and Competition 2021





AMINO | IMSTC 2021

TABLE OF CONTENTS Scientific Paper ● First Winner Larvicidal Activity Against Anopheles sp. and Ecotoxicological Evaluation of Green-synthesized Silver Nanoparticles as A Promising Vector Control Agent to Halt Mosquito-borne Disease in Rural Countries: A Systematic Review ● Second Winner Comparing Different Medications in Combating Strongyloides stercoralis Infection : A Systematic Review and Meta-Analysis

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● Third Winner The Curative Innovation of Novel Triple-Drug Compared to Double-Drug Regimen in 39 Lymphatic Filariasis: A Systematic Review ● Finalists ■ The Correlation between School’s Hygiene Level, Environmental Sanitation, and Soil Contamination towards Intestinal Worm Infection Prevalence in Public Elementary School Students at Kedungkandang, Malang ■ Assessment of The Effectiveness of the Point-Of-Care Circulating Cathodic Antigen Test as A Diagnostic Tool for Schistosomiasis Infection in Children Under the Age of Six: A Systematic Review ■ Mapping of Soil-Transmitted Helminth Infection Prevalence and Its Relationship with Students’ Knowledge, Soil Contamination at Home and School in Public Elementary School Kedungkandang, Malang ■ Association Of Leprosy-Related Burden To Mental Health Problems Of Leprosy Patients For Better Management Of Leprosy: A Systematic Review ■ Comparing the Effectiveness of Vaccine and Gene Recombination of Anopheles sp. in Preventing Malaria: A Review of Literature ■ Proposed Mechanism for Wolbachia-mediated DENV Blocking in Ae. aegypti: A Systematic Review

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AMINO | IMSTC 2021 ● Entries ■ Determination of the Drug of Choice for Mass Drug Administration and Suppression of Growth Impairment in Children with Helminthiasis: A Systematic Review and Meta-Analysis ■ A Systematic Review of the Efficacy and Safety of Triple Drug Therapy (Diethylcarbamazine, Ivermectin, Albendazole) for Lymphatic Filariasis ■ The Efficiency and Safety of the Vaccine M72/AS01 as a Mean to Prevent Active Pulmonary Tuberculosis For M. Tuberculosis-Infected Adults That Are Tested HIV Positive and Negative: A Systematic Review ■ The Role of Molecular Quantitative PCR as An Alternative Tool to Increase Sensitivity and Prevalence in Diagnosis of Soil-Transmitted Helminthiasis Compared to Microscopy-based Kato-Katz Technique in Low Prevalence Settings in Asia-Africa Regions: A Systematic Review ■ Anaemia and Hepatomegaly Associated with Mortality Rate in Patients with Malaria : A Literature Review ■ The Assessment of The Safeness, Effectiveness, and Efficacy of Carica Papaya Leaf Extract Consumption as A Comprehensive Alternative Thrombocytopenia Therapeutic Application to Reduce Mortality Caused by Dengue Haemorrhagic Fever with Thrombocytopenia In Tropical States : A Systematic Review of Randomized Controlled Studies ■ Effectiveness of Using Recombinant Antigen for Pig Vaccination as a Potential Method for Controlling Taenia Solium Transmission to Humans in Cysticercosis: A Systematic Review ■ Effectiveness of Amikacin with Combination of Other Antibiotics as Treatment for Actinomycetoma: A Systematic Review ■ Systematic Review of the Impact of Mass Drug Administration for the Elimination of Lymphatic Filariasis in Endemic Areas ■ Assessment of the Bacillus Calmette Guerin (BCG) Vaccine Effectiveness in Mycobacterium Leprae Infection As Consideration for Leprosy Immunoprophylaxis Targeted to Close Contacts of Leprosy Patients: A Systematic Review ■ The Use Of Calamansi As A Spray To Overcome The Dengue Fever Caused By Larva Proliferation ■ The Effectiveness of Corticosteroids as a Means of Treatment for Nerve Function Impairment in Patients Diagnosed with Leprosy: A Systematic Review ■ The Effectiveness of Chimeric Yellow Fever Dengue - Tetravalent Dengue Vaccine (CYD-TDV) as An Efficacious Prevention for Dengue Fever in Asian and American Countries: A Systematic Review of Randomized Control Trial Studies

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AMINO | IMSTC 2021 ■ The Role of T-Cell Immunoglobulin and Mucin Domain 3 (TIM3) Blockade Signalling Enhances Cell Mediated Immunity Against Malaria : Systematic Review ■ Biochemical Analysis on Mycobacterium tuberculosis Diagnosis: A Systematic Review ■ The Performance of Serological Tests of Anti-PGL1, Anti-NDO-LID, and Anti-MMP-II for Early Detection in Individuals with Household Contact with Leprosy in Indonesia: A Literature Review ■ Observation on: "One Health Approach in Tackling Tropical Diseases and Future Pandemics" ■ Thymoquine in Nigella Sativa as A Treatment in Leprosy Patients to Prevent Erythema Nodusum Leprosum (ENL) Reaction: A Literature Review ■ The Use of Digital Health in Enhancing Medical Adherence and Reducing Stigma of Leprosy Patients ■ Development of Indonesia Public Health System to Overcome Filariasis Holistically by Preventive, Curative, and Rehabilitative Ways in The Medical Field ■ mRNA Vaccine For Covid-19 With Terpenes Peptide As An Inhibitor And Nanoparticle As A Protein Delivery ■ Ways to Ameliorate Unending Leprosy Cases in Indonesia: A Literature Review ■ What is Wrong Filariasis Control and Prevention In Indonesia? A Literature Review ■ Analysis Of Indonesia Prevention And Control Program Towards Rabies, What’s Wrong In The Implementation? A Literature Review ■ Ocimum Sanctum Linn. (Holy Basil Or Tulsi) As A Potential Natural Anthelmintics Remedy For Strongyloidiasis: A Literature Review ■ Peptide-Based Non Structural Protein 1 Inhibitor Potential in Inhibiting Dengue Virus Production: A Literature Review ■ Preventive, Curative, Rehabilitative Measures, And Activities To Raise Awareness Of The Indonesian People Towards Neglected Tropical Diseases, Especially Filariasis ■ Epidemiology of Dengue Haemorrhagic Fever In Aceh in the Last 5 years : A Literature Review

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SCIENTIFIC PAPER


TESTIMONY




AMINO | IMSTC 2021

Rivaldi Ruby AMSA-Universitas Katolik Indonesia Atma Jaya 3rd Winner of Scientific Paper Category IMSTC has wide options of competitions and training for us to participate in. This annual AMSA national event also aims to provide provisions, knowledge, skills, abilities and motivation to us members to make scientific papers along with promoting certain health topics to increase society's awareness through social platforms. Some tips and tricks while making a scientific paper is to be able to know the right and efficient way to filter necessary information and to divide tasks with other teammates during the initial data screening. One experience that we've learned throughout the process of this competition is to pay close attention to the academic guidelines provided to prevent any misunderstandings on the paper requirements. Having teammates that share the same perspective is also one important factor to ensure the work goes smoothly. It is also recommended to read different types of journals to get used to skimming as well as improving our reading skills.


MASTERPIECE


Larvicidal Activity Against Anopheles sp. and Ecotoxicological Evaluation of Greensynthesized Silver Nanoparticles as A Promising Vector Control Agent to Halt Mosquitoborne Disease in Rural Countries: A Systematic Review 1

Muhammad Afif Naufal1a, Nathaniel Gilbert Dyson1, Aldithya Fakhri1 Second Year Medical Student, Faculty of Medicine, Universitas Indonesia Asian Medical Students’ Association Indonesia a afifnaufal2001@gmail.com

Abstract Introduction: Mosquitoes still represent major threat for millions of people worldwide due to their contribution as a vector of mosquito-borne diseases, namely malaria and lymphatic filariasis, which are caused by Anopheles sp. bite. Killing mosquitoes at its larval stage is the most effective way to control them. Recently, accumulating evidences have shown the high potency of green synthesized silver nanoparticles (AgNPs) as larvicidal agent against several mosquito species, including Anopheles sp. Objectives: This systematic review aims to evaluate the potency of green synthesized AgNPs as promising larvicidal agent candidate against Anopheles sp. Materials and Method: We systematically searched through PubMed, EBSCOhost, ScienceDirect, Scopus, and ProQuest for peer-reviewed studies published up to 7 December 2020. Critical appraisal of included studies was performed using the ROBINS-I to assess the quality of the studies. Results: Fourteen eligible studies are included in this systematic review, published between 2015 and 2020. The compiled studies then assessed for risk of bias by using ROBINS-I. The results shown relatively low bias throughout the studies. Discussion: Based on included literatures, AgNPs have shown high potency at eradicating Anopheles sp. larvae. The larvicidal activity is attributed to particles size and phytochemicals cap, smaller particles and more polar reduced form of phytochemicals resulted in higher larvicidal activity although no significant increase is expected, thus plant extracts serve as a good regaent at AgNPs synthesis. Plant extract-synthesized AgNPs were found safe to non-target organisms Diplonychus indicus, Anisops bouvieri, and Gambusia affinis, with respective LC50 and LC90 values ranging from 517,86 µg/ml to 32.192,8 µg/ml and from 1.006,83 µg/ml to 61.796,55 µg/ml, respectively. Conclusion: Green synthesized AgNPs is a promising vector control agent due to its strong, stable larvicidal activity and low ecotoxicological effects. However, further studies in natural environment settings are needed to confirm its potency and safety. Keywords : Silver Nanoparticles, Plant Extracts, Anopheles sp., Larvicidal activity

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Larvicidal Activity Against Anopheles sp. And Ecotoxicological Evaluation of Greensynthesized Silver Nanoparticles as A Promising Vector Control Agent to Halt Mosquitoborne Disease in Rural Countries: A Systematic Review Scientific Paper

Author : Muhammad Afif Naufal Nathaniel Gilbert Dyson Aldithya Fakhri

Faculty of Medicine Universitas Indonesia Asian Medical Students’ Association Indonesia 2020

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Introduction Mosquitoes represent a major threat for millions of people around the world due to their contribution as vectors of devastating parasites and pathogens, including malaria, filariasis, yellow fever, dengue, chikungunya, and zika. This leads to reduced productivity and even death.1–3 Among the others, Anopheles sp. is one of the most important species, which serves as a vector for malaria and filariasis transmission in many rural countries, including Indonesia.4 According to the World Health Organizations (WHO), malaria causes an estimated 219 million cases globally, and results in 400,000 deaths annually.5 On the other hand, 893 million people in 49 countries worldwide are at high risk of lymphatic filariasis, which can also be caused by Anopheles sp. bite. Ironically, this disease has not gained much attention and therefore called neglected tropical diseases.6 Recently, the occurrence of mosquito-borne diseases increased due to favorable environment caused by global warming, high relative humidity, uneven rainfall, and sanitation facility all over the world.7 However, development of vaccines against this vector proved to be ineffective due to its high cost and long trial process required. Killing mosquitoes at larval stages is the only effective measure for controlling this vector-borne disease.8 Chemically synthesized insecticides, which are still used until today, have many major drawbacks, as they are expensive, non-selective and harmful to other organisms in the environment.9 In addition, some studies report the increasing resistance and high operational costs.10 Thus, eco-friendly control tools are urgently needed to obtain better efficacy with much less toxicity to the environment. Nanoparticles have increasingly attracted global attention through it’s various biomedical applications these days. Noble metal nanoparticles such as gold, silver, titanium, and platinum, are widely developed to support nanomedical field.11 Contrary to the chemical insecticides, biologically synthesized nanoparticles have proved to exhibit strong larvicidal activity against various mosquito vectors, including Anopheles sp.12,13 Furthermore, among other biological materials, plants possess a broad variety of metabolites that can aid in the biosynthesis, reduction and capping of metal ions. This can be utilized to stabilize the nanoparticles in order to provide more impact on its larvicidal activity.14 On the other hand, the use of plants for the fabrication of nanoparticles is a rapid, low cost, ecofriendly and single step method for biosynthesis process.15

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Recently, accumulating evidences have shown that green synthesized AgNPs as an ecofriendly, high potential candidate of larvicidal agent. However, to our knowledge, there has not been a systematic review made to evaluate and compare the utility of those different plant extracts in regards of its effectiveness and safety. Therefore, we decided to conduct a systematic review to evaluate and conclude the potency of green synthesized AgNPs as larvicidal agent. Materials and Methods Search method For this study, the authors performed a literature search based on the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA). To retrieve relevant studies, we applied the following keywords “green synthesis” OR “plant extract” OR “phytochemical”) AND “silver nanoparticle” AND “larvicidal “ AND “anopheles” AND (“toxicity” OR “non-target”). This search method was applied in 5 databases, namely PubMed, EBSCOhost, ScienceDirect, Scopus, and ProQuest, for peer-reviewed studies published up to 7 December 2020. Inclusion and exclusion criteria In creating this review, the authors applied some inclusion and exclusion criteria. The inclusion criteria were such follows: (1) study design mainly experimental studies; (2) study use AgNPs synthesized from plant extracts; (3) study outcomes consisted of LC50 and LC90 of larvae exposed to plant extract-synthesized silver nanoparticle; (4) study assessed ecotoxicological effect to another aquatic organism; (5) study using exposure time to the sample for 24 hours. The exclusion criteria that were applied are (1) unsuitable types of articles, such as commentaries, conference (2) inaccessible studies; (3) studies published in languages other than English or Bahasa Indonesia; (4) study without a control group. Study outcomes The main outcomes of interest observed in this review were larvicidal activity and ecotoxicological outcomes: (1) The larvicidal activity outcomes include lethal concentration 50 and 90 (LC50 and LC 90) of plant extract-synthesized silver nanoparticle to Anopheles sp. larva (2) The ecotoxicological effect of plant extract-synthesized AgNPs measured in LC50 and LC90 to another aquatic organisms that live where larvae usually found (3) Physicochemical characteristics of synthesized AgNPs, including particle size and colloidal stability.

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Risk of bias assessment ROBINS-I (Risk Of Bias In Non-randomised Studies-of Interventions) was utilized in evaluating the risk of bias in estimates of the effectiveness or safety (benefit or harm) of intervention from studies that did not use randomization to allocate interventions. The ROBINS-I tool consists of 7 main domains. The first two domains covering confounding and selection of participants into the study address issues before starting the interventions that are to be compared. The third domain addresses classification of the interventions themselves. The other four domains address issues after the start of interventions: biases due to deviations from intended interventions, missing data, measurement of outcomes, and selection of the reported result. The assessment was performed by three independent and blinded investigators, with conflicts being resolved through all authors’ consensus. Results and Discussion Search results After conducting searches in international databases using the aforementioned keyword, we acquired 215 studies which were then screened based on its title relevancy, eliminating 122 studies. Furthermore, duplicate titles were removed and evaluated based on its abstract, yielding 28 studies. Lastly, full-text screening were conducted, a total of 14 studies which consist of 3 study with ineligible study design, 4 studies without ecotoxicological assessment, and 7 studies that measured by other than LC value. The result of the study selection process is shown in Figure 1.

Figure 1. PRISMA flow chart of search strategies

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Characteristics of included studies After rigorous screening and rechecking to maintain uniformity and relevancy to inclusion and exclusion criteria, a total of 14 non-randomized controlled studies are included. The included studies are shown in Table 1.16–29 All 14 study were conducted in India, published between 2015 until 2020, and predominantly were authored by Govindarajan et al. Due to the objective of this review being assessing larvicidal activity and ecotoxicological effect of silver nanoparticles, subject of the studies include Anopheles sp. larvae (3rd and 4th instar) and various non-target aquatic animals that live in the same habitat as said larvae, namely Diplonychus indicus, Anisops bouvieri, Gambusia affinis, Daphnia magna, Oryzias latipes, Chilocorus circumdatus, and Poecilia reticulata, though the majority of studies used the first three species as the subject. The included studies were reviewed using ROBINS-I. A total of 11 of the studies are low risk of bias, while the rest are moderate. The justification of the assessment is attached as Appendix 2. Effectiveness of Silver Nanoparticle Synthesized by Plant Extract All the studies included have shown high larvicidal potency of green synthesized silver nanoparticles (AgNPs). Based on the average of LC90 values, green synthesized AgNPs can eradicate 90% of larvae (LC90) after 24 h of exposure to a concentration as little as ±24 mg/liter. The concentration is on par with the conventional larvicidal agents, namely Bacillus thuringiensis israeli, while remaining stable for at least 8 weeks before agglomerating and precipitating, thus exerting long, constant larvicidal activity while the latter depends on higher concentration to maintain an eradication rate that lasts no longer than 35 days.21,30 The larvicidal activity of AgNPs might be attributed to its physicochemical characteristics. A study conducted by Karthiga et al, suggest that the particle size is important as smaller particles can enter the larvae through the cuticle. Inside, AgNPs enter individual cells, inducing degradation of DNA, destruction of organelles, and apoptosis, leading to disturbance of normal phsyiology.17,31 Another characteristics, phytochemicals cap, are cosynthesized as a result of reduction of Ag+ ion in the process of making AgNPs. Throughout the studies, we observed no significant difference between the data, indicated by relatively small standard deviation of the AgNPs LC50 and 90. However, the smallest LC value, mentioned in Govindarajan et al29, as in contrast to the theory, it exhibit the smallest LC while having a moderate particle size of 44 nm. The study showed phytochemicals involved in the synthesis were flavones, quinones, and organic acids that are

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present in C. spinarum leaf. Possible explanation of this phenomenon is that these classes of molecules have low molecular weight and high polarity due to oxygen atom inside the molecules, thus oxidation produce polar groups of carbonyl within the molecules, which then favour higher agglomeration and concentration (dipole force).32–34 This conjecture is supported by lower-thanmean LC of AgNPs synthesized using similar extract phytochemicals constituent by Govindarajan et alc-d and Azarudeen et al.23-25 This proposed mechanism appears to be validated by the largest LC value observed by Benelli et al18, as the particle depicted to have smaller size than those of previously mentioned, while having the largest LC value. The phytochemicals involved in the synthesis were non to weakly polar and rather high in molecular weight, namely tannins. Tannins which are semi polar, contains high phenol content and are relatively “bulkier” and heavier.10 The phenol then will undergo oxidation, yielding quinone which is less polar, as a result, weakly attracted to other molecules, thus leading to less concentrated phytochemical cap surrounding the AgNPs, although Govindarajan et alh, observed lower-than-mean which we speculated that Clerodendrum chinense extract contain less tannin. In conclusion, compounds with high content of reduced oxygen atoms and small molecular weight, are highly recommended to maximize the efficacy of AgNPs although no striking difference is projected to be happened, thus plant extract serve as an excellent reducing agent. Biotoxicity on non-target aquatic organisms In recent years, mosquito larval control using chemical-based synthetic pesticides is wellthought-out as a major factor in dengue and malaria control strategies. Such a control strategy causes drastic effects on human and animal health and seriously contaminates the environment. Therefore, researchers looked at natural products as effective alternatives to conventional pesticides. The plant extract-synthesized AgNPs’ environmental toxicity was tested against nontarget mosquito predators, such as Diplonychus indicus, Gambusia affinis, and Anisops bouvieri. The effects of the plant extract-synthesized AgNPs on insects and fish were assessed using a standard method described by Sivagnaname and Kalyanasundaram (2004).22,35 From 17 studies that provide a quality assessment of our inclusion and exclusion criteria, we have LC50 and LC 90 values of non-target organisms ranged from 517,86 µg/ml to 32.192,8 µg/ml and from 1.006,83 µg/ml to 61.796,55 µg/ml, respectively. These results suggested that the plant extract-synthesized

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AgNPs are safe and environment friendly. We used several statistical analyses to assess the significance of plant extract-synthesized AgNPs toxicity against target and non-target organisms. The results showed that for both LC50 and LC90 of Anopheles sp. larva and non-target aquatic organisms differ significantly. Taken together, the data presented here provide evidence that LC50 and LC90 of Anopheles sp. larva and non-target aquatic organisms were higher than all of the non-target aquatic organisms. The observed low toxicity effect may be attributed to the specific interaction between silver nanoparticles and the larval extracellular lipoprotein matrix. This interaction increases the permeability of the plasma membrane of cells and finally causes the loss of cellular function and cell death.2 This mechanism cannot occur in other non-target aquatic organisms because of these specific interactions only to mosquito larvae. This review highlighted that plant extract-synthesized AgNPs could be employed at low dosages to strongly reduce populations of vector mosquitoes of medical importance without detrimental effects on predation rates of non-target aquatic organisms. Current challenges regarding mosquito control Given the availability of various chemically synthesized insecticides, to summarize, two main problems are commonly faced, namely (1) effectivity due to developed resistance, and (2) high toxicity to the environment.9 For the first issue, the use of green synthesized silver nanoparticles, as discussed previously, has been proved effective, indicated by its high toxicity (low LC50 and LC90 value) against Anopheles sp. larvae. Furthermore, for the second issue, this systematic review has compared the differences of toxicity to Anopheles sp. larvae and non-target aquatic organisms, and the results have been proved to be highly significant. Therefore, it can be concluded that green synthesized silver nanoparticles have much less toxicity to the environment, especially for other organisms found near the target’s habitat (Diplonychus indicus, Gambusia affinis, and Anisops bouvieri). Applicability of green synthesized silver nanoparticles in Indonesia Despite commendable effort by the government to speed up elimination of these diseases, especially in Indonesia, there still need to be a novel breakthrough in terminating the threat.36 Considering all the included studies in this systematic review, we then conclude that this innovation is very potential to be applied in Indonesia based on three major reasons. Firstly, the

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rearing conditions of Anopheles sp. used in all of the studies relatively able to represent Indonesia’s climate (in term of temperature and humidity). Second reason is due to the quite similar species of mosquitoes circulating both in India and Indonesia, except for several species such as Anopheles sundaicus and Anopheles balabacensis which are not tested in the studies. Furthermore, the technologies and methods used to synthesize silver nanoparticles are relatively cheap and simple, as reported by all included studies. Therefore, we believe that this innovation is highly feasible to be applied in Indonesia. Strength and limitation of the review We acknowledged that this review has its own strengths and limitations. First of all, to our knowledge, this is the first systematic review regarding the potency of green synthesized AgNPs as larvicidal agent. The other strength of this review lies on its homogenity of study design and results. The uniformity allows the reviewer to easily compare relations between variables, namely LC values of AgNPs (both on target and non-target organisms), size, and

phytochemical

substituents. Moreover, all of the included studies are no later than 2015, indicating the novelty and relevance of this idea, while maintaining mostly low risk of bias evaluated by ROBINS-I assessment. On the other hand, we realize that all of the included studies were still done in laboratory settings, hence its applicability in natural environment remains unknown. In laboratory settings, all of the rearing conditions, including the temperature, humidity, and growth medium, were kept under tight supervision, while these are not likely to happen in natural environment. Conclusion and Recommendation In conclusion, green synthesized silver nanoparticles are easy to produced, stable over time, and can be employed at low dosage to strongly exhibit larvicidal activity against Anopheles sp., which acts as a vector of various mosquito-borne diseases, without any significant ecotoxicological effect, while still yielding constant results from any plant extracts used, hence indicating its high applicability in Indonesia. Nevertheless, we also recommend further studies assessing applicability of green synthesized AgNPs in natural environment settings to ensure its potency and safety.

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Sivagnaname N, Kalyanasundaram M. Laboratory evaluation of methanolic extract of Atlantia monophylla (Family: Rutaceae) against immature stages of mosquitoes and nontarget organisms. Mem Inst Oswaldo Cruz. 2004;

36.

Meliyanie G, Andiarsa D. Program Eliminasi Lymphatic Filariasis di Indonesia. J Heal Epidemiol Commun Dis. 2019;

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Appendix 1. Study characteristics Intervention characteristics

Study outcome

Phytochemical characteristics No.

Author

Subject condition (Larvae stage, temperature, humidity) rd 3 Instar Larvae, NA, NA

Species

Silver Nanoparticles Characteristics Colloidal Stability

LC50 (µg/ml)

Detected Phytochemicals

LC50 (LCLUCL) (µg/ml)

LC90 (LCLUCL) (µg/ml)

Size

Alstonia venenata

NA

103.41 (91.65113.82)

203.61 (188.81223.06)

30-40 nm

Stable

Non-target exposure time 48 h

Larvae (LCLUCL)

Non-target (LCLUCL)

LC90 (µg/ml) Larvae (LCLUCL)

1.

Esan et al, 202016

2.

Govindarajan et al, 2016a[17]

3rd Instar Larvae, 28±2°C, 70-85%

Adiantum raddianum

NA

143.22 (126.35158.04)

285.74 (264.80313.31)

9.69-13.9 nm

Stable

48 h

10.33 (9.1411.39)

3.

Govindarajan et al,2016b[22]

3rd Instar Larvae, 28±2°C 70-85%

Quisqualis indica

NA

185.98 (164.65204.82)

367.39 (340.67402.51)

1-30 nm

Stable

48 h

12.52 (11.1513.74)

4.

Govindarajan et al, 2016c[23]

3rd Instar Larvae, 28±2°C, 70-85%

Nicandra physalodes

Flavones, Quinones, and Organic Acids

202.82 (178.79223.91)

404.85 (375.19443.88)

22-44 nm

Stable

48 h

12.39 (10.9913.62)

5.

Govindarajan et al, 2016d[24]

3rd Instar Larvae, 28±2°C, 70-85%

Ormocarpum cochinchinense

Flavones, Quinones, and Organic Acids

164.72 (145.92181.35)

324.33 (300.85355.14)

18-35 nm

Stable

48 h

10.43 (9.2411.48)

D.indicus 8100.21 (7157.01-8930.85) G.affinis 10597.53 (9397.21-11660.85)

20.62 (19.1122.59)

6.

Azarudeen et al, 201725

3rd Instar Larvae, 28±2°C, 70-85%

Naregamia alata

Flavones, Quinones, and Organic Acids

165.15 (146.72181.50)

321.56 (298.52351.71)

5-35 nm

Stable

48 h

12.40 (11.0213.63)

24.20 (22.4626.49)

7.

Govindarajan et al, 201726

3rd Instar Larvae, 28±2°C, 70-85%

Hugonia mystax

Flavonoids and Trepenoids

162.66 (143.23179.69)

326.16 (302.17357.79)

40-90 nm

Stable

48 h

14.45 (12.8415.88)

8.

Govindarajan et al, 2016e[27]

3rd Instar Larvae, 28±2°C, 70-85%

Zornia diphylla

Citronellol, Geraniol, and Flavones

61.23 (54.1267.49)

121.21 (112.40132.77)

30-60 nm

Stable

48 h

12.53 (11.1813.73)

A.bouvieri 629.58 (561.45-690.39) D.indicus 1058.31 (948.12-1157.48) G.affinis 2111.34 (1883.65-2314.64) G.affinis 32192.80 (28794.52-35240.89) D.indicus 14756.43 (13094.32-16230.74) A.bouvieri 12251.72 (10819.31-13512.43) C.circumdatus 613.11 (544.08-674.24) A.bouvieri 1100.73 (982.46-1206.59) G.affinis 1583.87 (1406.58-1742.00)"

14

12.28 (10.8613.54)

A. bouvieri 734.73 (655.27-805.69) D.indicus 1057.86 (938.29-1163.79) G.affinis 2107.7 (1850.63-2331.46) D.indicus 517.86 (460.60-568.80) G. affinis 635.98 (563.63 - 700.02) A. bouvieri 653.05 (581.17-717.15) D.indicus 860.94 (768.53-943.57) G.affinis 2181.16 (1947.40-2393.99) D.indicus 1032.81 (916.83-1135.66)

24.36 (22.5826.71)

20.51 (19.0122.48) 24.21 (22.4826.47)

24.24 (22.49 26.52)

28.11 (26.0930.76)

24.02 (22.3226.23)

Non-target (LCLUCL)

A.bouvieri 1418.27 (1316.82-1551.17) D.indicus 2089.53 (1937.41-2289.80) G.affinis 4317.84 (3991.25-4752.97) D.indicus 1006.83 (934.37-1101.83) G. affinis 1261.72 (1169.29-1383.67) A.bouvieri 1287.88 (1192.73-1413.54) D.indicus 1667.36 (1547.53-1824.82) G.affinis 4263.53 (3953.14-4673.35) D.indicus 2020.73 (1874.652212.49) D.indicus 16030.01 (14861.38-17566.47) G.affinis 20975.84 (19443.3422995.98) A.bouvieri 1214.95 (1128.14-1328.66) D.indicus 2011.14 (1869.25-2196.24) G.affinis 4073.07 (3782.26-4454.01) G.affinis 61796.55 (57392.75-67567.76) D.indicus 29116.24 (26987.41-31924.09) A.bouvieri 24358.07 (22574.93-26706.32) C.circumdatus 1195.27 (1109.48-1307.54) A.bouvieri 2147.85 (1991.91-2353.52) G.affinis 3189.47 (2945.86-3516.56)


9.

Alyahya et al, 201828

3rd Instar Larvae, 28±2°C, 70-85%

Holostemma adakodien

NA

185.79 (163.78205.14)

373.47 (345.78410.08)

NA

Stable

48 h

12.18 (10.7413.45)

D. indicus 623.48 (555.55-684.03)

24.33 (22.5526.68)

10.

Govindarajan et al, 2016f[29]

3rd Instar Larvae, 24-30°C, 85%

Carissa spinarum

Flavones, Quinones, and Organic Acids

104.24 (92.62114.55)

203.55 (188.91222.74)

44 nm

Stable

48 h

8.37 (7.449.19)

16.25 (15.0917.77)

11.

Benelli et al, 201718

3rd Instar Larvae, 28±2 °C, 70-85%

Acacia caesia

Tannins, Flavonoids, Alkaloids, Steroids and Glycosides

125.09 (111.45137.25)

241.68 (224.43264.25)

20-46 nm

Stable

24 h

18.66 (16.4520.61)

12.

Aarthi, et al., 201719

3rd Instar Larvae, 25-28 °C, NA

Habenaria plantaginea

NA

102.51 (90.72112.90)

202.16 (187.49221.45)

37.8 nm

Stable

48 h

12.23 (10.8313.46)

13.

Govindarajan, et al., 2016g[20]

3rd Instar Larvae, 28 ± 2 ◦ C, 70-85%

Ichnocarpus frutescens

Flavones, Quinones, and Organic Acids

185.83 (164.69204.52)

365.22 (338.85399.78)

37 nm

Stable

48 h

14.22 (12.5615.69)

14.

Govindarajan, et al., 2015h[21]

3rd Instar Larvae, 28 ± 2 °C, 70-85%

Clerodendrum chinense

Alkaloids, Flavonoids, Tannins, Terpenoids, Steroids, Glycosides and Benzenoids

61.74 (54.5368.07)

122.84 (113.85134.68)

25-30 nm

Stable

48 h

10.23 (9.0511.28)

D. indicus 4145.60 (3682.52-4556.55) A. bouvieri 4475.16 (4002.47-4900.26) G. affinis 6402.68 (5656.98-7060.43) D. indicus 11,063.27 (9961.10-12,062.30) A. bouvieri 9012.19 (8164.27-9789.24) G. affinis 27,277.05 (18,642.73-33,820.03) A. bouvieri, 831.82 (741.73-912.24) D. indicus, 1286.90 (1148.64-1410.52) P. reticulata, 3102.22 (2745.75-3417.22) G. affinis, 3486.10 (3133.90-3806.23) G. affinis 2098.61(1852.442315.26) D. indicus 873.25 (775.30-960.31) A. bouvieri 636.61 (567.11-698.59) G. affinis 1145.36 (1027.23-1252.13) D. indicus 647.05 (578.99-708.18) A. bouvieri 889.45 (792.20-976.30)

37.58 (34.7841.29)

24.02 (22.2826.29)

28.23 (26.1630.93)

20.23 (18.7622.16)

D. indicus 1203.33 (1117.431315.73) D. indicus 8095.36 (7511.21-8862.07) A. bouvieri 8713.45 (8077.78-9554.02) G. affinis 12883.05 (11924.53-14154.19) D. indicus 20,815.73 (19,359.76-22,716.20) A. bouvieri 16,581.63 (15,445.22-18,058.18) G. affinis 51,065.76 (42,854.16-69,001.45) A. bouvieri, 1601.37 (1487.37-1750.37) D. indicus, 2489.26 (2311.35-2722.37) P. reticulata, 6141.95 (5693.83-6731.49) G. affinis 6717.78 (6228.99-7364.49) G. affinis 4217.40 (3903.72-4633.45) D. indicus 1738.96 (1609.49-1911.22) A. bouvieri 1238.99 (1149.59-1356.59) G. affinis 2216.73 (2056.04-2428.89) D. indicus 1242.33 (1153.76-1358.38) A. bouvieri 1756.82 (1627.08-1928.99)

Titles: a. One-pot and eco-friendly synthesis of silver nanocrystals using Adiantum raddianum: Toxicity against mosquito vectors of medical and veterinary importance; b. One-pot biogenic fabrication of silver nanocrystals using Quisqualis indica: Effectiveness on malaria and Zika virus mosquito vectors, and impact on non-target aquatic organisms; c. One-pot fabrication of silver nanocrystals using Nicandra physalodes: A novel route for mosquito vector control with moderate toxicity on nontarget water bugs; d. One-pot fabrication of silver nanocrystals using Ormocarpum cochinchinense: Biophysical characterization of a potent mosquitocidal and toxicity on non-target mosquito predators; e. Single-step biosynthesis and characterization of silver nanoparticles using Zornia diphylla leaves: A potent eco-friendly tool against malaria and arbovirus vectors; f. Bio-physical Characterization of poly-dispersed Silver Nanocrystals Fabricated Using Carissa spinarum: a potent tool against mosquito vectors; g. Facile fabrication of eco-friendly nano-mosquitocides: Biophysicalcharacterization and effectiveness on neglected tropical mosquito vectors; h. Clerodendrum chinense-mediated biofabrication of silver nanoparticles: Mosquitocidal potential and acute toxicity against non-target aquatic organisms

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Appendix 2. ROBINS-I Risk of Bias Assessment

16


Y : Yes; PY : Probably Yes; N : No; PN : Probably No; NA : Not Available; NI : Not Indicated

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Comparing Different Medications in Combating Strongyloides stercoralis Infection : A Systematic Review and Meta-Analysis Aurielle Annalicia Setiawan 1a , William Wiradinata 1 , Nathanael Ibot David1 1Undergraduate

Medical Program, Faculty of Medicine, Brawijaya University 1a aurielle.annalicia@yahoo.com

ABSTRACT Introduction : Strongyloides stercoralis infection is the most neglected yet dangerous NTD, able to cause endogenous autoinfection, hyperinfection in immunosuppressed patients, malnutrition, and stunting in children. Its non-specific symptoms and lack of effective diagnostic methods leads to underestimation of case numbers. Pharmacological interventions are crucial to control infection, therefore an analysis is necessary to determine the best mass-drug therapy regimen. Materials & Methods : Data was collected from PubMed, ScienceDirect, Google Scholar, Researchgate, and Cochrane and assessed using PRISMA flow diagram, resulting in 13 studies for qualitative analysis and 8 studies for quantitative analysis. Risk of bias was assessed using Cochrane Risk of Bias tool, and meta analysis was conducted using Review Manager 5.4. Results and Discussion : Ivermectin is shown to be significantly more effective (based on cure rate (CR)) compared to other pharmacological treatments (albendazole, thiabendazole, tribendimidine, pyrvinium pamoate, moxidectin) in curing the infection of S.stercoralis (odds ratio (OR) = 3.48, 95% confidence intervals (CI) 1.79 to 6.80, P = 0.0003). Single-dose ivermectin is also shown to have higher efficacy based on cure rate (CR) compared to multiple dose ivermectin (odds ratio (OR) = 0.97, 95% confidence intervals (CI) 0.46 to 2.04, P = 0.94). Ivermectin is also shown to have the fewest adverse effects compared to other medications, and single-dose ivermectin does not significantly cause more adverse effects compared to multiple-doseaivermectin. Single-dose ivermectin is more effective than other treatments mentioned and also causes fewer adverse effects compared to other treatments. Further cost-effectiveness analysis is needed to evaluate the economical aspect of the result of this study.

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Conclusion : Single-dose ivermectin is more effective than other treatments mentioned and also causes fewer adverse effects compared to other treatments. Further cost-effectiveness analysis is needed to compare the cost-effectiveness of these medications.

Keywords: Strongyloides stercoralis, strongyloidiasis, treatment, efficacy, adverse effects

19


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INTRODUCTION Strongyloides stercoralis is the fourth most important intestinal nematode [1], with 200370 million people estimated to be infected[2]. However, strongyloidiasis is also the most neglected of the neglected tropical diseases to exist. It is considered as the most difficult NTD to diagnose, with only 50% of cases considered symptomatic[1]. Lack of sensitivity in diagnostic methods have also caused underestimation of case numbers[3]. South-East Asia, Africa, and Western Pacific Regions are reported to account for 76.1% of the global infections[4]. Infection presents with non-specific symptoms such as fever, cough, and urticaria, making it more difficult to detect. On the other hand, S. stercoralis infection can be dangerous in immunosuppressed patients, causing hyperinfection syndrome and dissemination to other internal organs[5]. Additionally, the special ability of this helminth to cause endogenous autoinfection can result in persistent infection and chronic strongyloidiasis which can last up to 75 years[6]. Other significant health problems that can occur in this infection are malnutrition and stunting which are caused by clinical manifestations in this disease such as nausea, vomiting, diarrhea, etc. S.stercoralis infection was found in Bangladesh to be the most common in children aged 7-10 year old with 18% prevalence and also infected 1-6 year olds with 10% prevalence. These age ranges represent the most vulnerable population to be affected by stunting and morbidity, even mortality caused by malnutrition[1]. S.stercoralis can be found worldwide, most prevalently in warm, underdeveloped areas with poor sanitation[2]. Infection occurs by penetration of intact skin by L3 larvae, which will then travel to the circulatory system and the respiratory system, including pharynx, where the larvae is then swallowed and travels to the small intestine where they reside to become adults and reproduce. Rhabditiform larvae is then excreted through faeces and develop to be L3 larvae, infecting another host[7]. Pharmacological means are apparently important in controlling strongyloidiasis, as reported in a study. Treatments were very effective, and control was possible with pharmacological means alone[8]. Previously, thiabendazole was the drug of choice for this disease, but unpleasant side effects have led to search for other alternatives. Albendazole is also reported to be effective[9]. Ivermectin is currently the treatment of choice for this disease, but there are only a few studies that compare different regimens for strongyloidiasis at the same time. This systematic review aims to summarize evidence on the efficacy of a number of

21


strongyloidiasis treatments in order to present the latest and comprehensive evidence for the best treatment of choice.

MATERIALS & METHODS This review was conducted according to PRISMA’s flow diagram. Items considered necessary for transparent reporting of a systematic review such as title, introduction, methods, result, and discussion were included in the checklist.

1. Eligibility Criteria for Human Clinical Trials a. Types of participants This review included all studies involving male and female participants aged 3-86 year old diagnosed with S. stercoralis infection. Diagnosis was established by either faecal tests or IFAT titre. b. Types of interventions Interventions included in this review were any antihelminthic drugs such as ivermectin, albendazole, thiabendazole, tribendimidine, pyrvinium pamoate, and moxidectin administered at any dose, by any route, and for any duration. c. Types of outcome measures Outcomes included the efficacy of the drugs in (1) eliminating S.stercoralis infection in participants, measured in cure rate (CR) and (2) the adverse effect of the drugs used (AE).

2. Search Strategy This research has been conducted according to the PRISMA guidelines and flowchart which is shown in. References were gathered from various sources such as PubMed, ScienceDirect, Google Scholar, Researchgate, and Cochrane. Only studies in English ranging from 1990-2020 are included in this systematic review. Keywords used were: (“Strongyloides stercoralis treatment efficacy” OR “strongyloidiasis”), AND (“Treatment”), AND (“efficacy”), AND (“ivermectin*” OR “thiabendazole*” OR “albendazole*” OR ”tribendimidine*” OR “moxidectin*” OR “pyrvinium pamoate*”) Wildcard term was used to increase sensitivity of the search. Studies included were original researches that evaluated the efficacy of various treatment on treatment of Strongyloides stercoralis infection or strongyloidiasis. Three reviewers listed above reviewed the studies and any disagreements were resolved by discussion.

22


3. Data extraction and analysis Studies deemed eligible were reviewed independently by the three authors listed above and the following data was extracted: author, publication year, country, study design, intervention, study population, sample characteristics, and results. The data was then analyzed and outcomes were summarized with emphasis on statistical results of the studies included. 4. Risk of Bias assessment Risk of bias assessment was done according to the Cochrane risk of bias tool which included selection bias, measurement of exposure, confounding variables, blinding of participants and personnel, incomplete outcome data, and reporting bias. Any disagreements by the authors were resolved through discussion. 5. Statistical analysis Meta analysis was conducted using Review Manager 5.4. Data across studies were evaluated based on cure rate (CR) and adverse effect (AE). Mantel-Haenszel method were utilized as the statistical method with 95% confidence intervals (CI). Random-effects models were used and P ≤ 0.05 was considered statistically significant. Bias in studies used in the metaanalysis were visually evaluated using a funnel plot.

RESULTS AND DISCUSSION

1. RESULTS 1.1. Study Identification and Selection Our search through the various databases mentioned above has resulted in a total of 5224 studies. After screening for duplicates, 275 studies were left and screening for other criteria excluded 222 records. A total of 40 studies were excluded due to limited presentations of findings and weak methodology., and finally, a total of 13 human studies were included in the qualitative analysis[9,11-22]. Eight studies were included in the quantitative analysis (metaanalysis)[9, 11-13, 15,18-19, 22] (see Figure 1).

1.2. Risk of Bias Assessment The studies acquired were examined with the Cochrane Risk of Bias tool. The risk for bias in both human and animal studies are mostly in the low and unclear risk of bias category, and some are classified as having high risk of bias (see Table 1).

1.3. Study Characteristics

23


Characteristics and properties of each study included were examined and listed (see Table 2).

1.4. Meta-analysis a. Cure Rate (CR) against Strongyloides stercoralis An analysis comparing the efficacy of ivermectin to other pharmacological treatment based on the cure rate (CR) of each medication on S.stercoralis infection was conducted. Data obtained from meta-analysis)[9, 11-13, 15,18-19, 22] indicate that ivermectin is significantly more effective compared to other pharmacological treatments in curing the infection of S.stercoralis (odds ratio (OR) = 3.48, 95% confidence intervals (CI) 1.79 to 6.80, P = 0.0003; see Figure 2.1). Tests for heterogeneity showed considerable heterogeneity (I2 = 83%). Qualitative observations based on the funnel plot resulted showed that the data collected has a low to moderate risk of reporting bias (see Figure 2.2). Based on the data obtained from meta-analysis, ivermectin is also shown to be significantly more effective compared to thiabendazole in curing the infection of S.stercoralis[11,13,18] (odds ratio (OR) = 1.44, 95% confidence intervals (CI) 1.05 to 1.98, P = 0.02; see Figure 3.1). Tests for heterogeneity indicated low heterogeneity (I2 = 0%). Qualitative observations based on the funnel plot resulted showed that the data collected has a low risk of reporting bias (see Figure 3.2). Data from meta-analysis also indicate that ivermectin is significantly more effective compared to albendazole in curing the infection of S.stercoralis[9,15,19,22](odds ratio (OR) = 6.76, 95% confidence intervals (CI) 4.29 to 10.66, P = <0.00001; see Figure 4.1). Heterogeneity testing showed low heterogeneity (I2 = 0%). Qualitative observations based on the funnel plot resulted showed that the data collected has a low risk of reporting bias (see Figure 4.2). Based on the data obtained from 3 studies, authors analyzed the efficacy of single dose ivermectin compared to multiple doses of ivermectin based on the cure rate (CR) of each medication on S.stercoralis infection. Data obtained from meta-analysis indicate that multiple dose of ivermectin is not significantly more effective compared to single dose ivermectin in curing the infection of S.stercoralis[9,14,18] (odds ratio (OR) = 0.97, 95% confidence intervals (CI) 0.46 to 2.04, P = 0.94; see Figure 5.1). Tests for heterogeneity showed moderate heterogeneity (I2 = 39%). Qualitative observations based on the funnel plot resulted showed that the data collected has a low risk of reporting bias (see Figure 5.2).

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b. Adverse effect An analysis comparing the adverse effect of ivermectin to thiabendazole based on the number of patients experiencing any adverse effect during medication was conducted. Data obtained from meta-analysis indicate that thiabendazole significantly causes more adverse effect compared to ivermectin[11,13,18] (odds ratio (OR) = 0.17, 95% confidence intervals (CI) 0.08 to 0.37, P = <0.00001; see Figure 6.1). Tests for heterogeneity showed substantial heterogeneity (I2 = 63%). Qualitative observations based on the funnel plot resulted showed that data collected has a low risk of reporting bias (see Figure 6.2). Data obtained from meta-analysis also indicate that albendazole does not significantly cause more adverse effect compared to ivermectin[9,15,19] (odds ratio (OR) = 0.73, 95% confidence intervals (CI) 0.46 to 1.15, P = 0.17; see Figure 7.1). Tests for heterogeneity showed low heterogeneity (I2 = 0%). Qualitative observations based on the funnel plot resulted showed that data collected has a low risk of reporting bias (see Figure 7.2). It is also indicated that multiple dose ivermectin does not significantly cause more adverse effect compared to single dose ivermectin[9,14,18] (odds ratio (OR) = 1.51, 95% confidence intervals (CI) 0.14 to 15.80, P = 0.73; see Figure 8.1). Tests for heterogeneity showed substantial heterogeneity (I2 = 62%). Qualitative observations based on the funnel plot resulted showed that data collected has a low risk of reporting bias (see Figure 8.2).

2. DISCUSSION

Strongyloides stercoralis infection, as the most neglected of the NTDs, demands our attention as it poses great threat to children with its effects in malnutrition and stunting, which can lead to negative impacts in children’s learning capacity. This is a serious issue in tropical, underdeveloped countries, where S.stercoralis infection is prevalent. Therefore a drug suited for mass-therapy is needed to fight off this disease, and an analysis on the efficacy, adverse effects, and cost-effectiveness of various drugs is needed to decide on the best option. Based on the data obtained from various publication, ivermectin is currently the most popular treatment used, followed by thiabendazole and albendazole. Data obtained through meta-analysis comparing the efficacy of ivermectin to other medications including thiabendazole, albendazole, moxidectin, tribendimidine, and pyrivinium pamoate [9, 11-13, 15,1819, 22]

shows that ivermectin is significantly more effective in treating S.stercoralis infection

based on cure rate. The same result is also found when comparing ivermectin to thiabendazole and albendazole[9,11,13,15,18,19,22]. Other treatments such as moxidectin displayed favorable cure

25


rate (93.6%), however the difference is not statistically significant when compared to ivermectin[12] (odds ratio (OR) = 1.33, 95% confidence intervals (CI) 0.29 to 6.22, P = 0.71). As for tribendimidine[21] (CR = 54.5%) and pyrvinium pamoate[22] (CR = 23.3%), the cure rate simply is not high enough to be considered viable. The superiority of ivermectin based on aforementioned analysis poses the question for comparing single dose to multiple doses of ivermectin. Based on the data obtained from 4 studies, the difference is miniscule and is not statistically significant[9,14,18] (odds ratio (OR) = 0.97, 95% confidence intervals (CI) 0.46 to 2.04, P = 0.94; see Figure 5.1). Therefore, based on cure rate, single dose ivermectin is more effective compared to other treatments. Analysis of adverse effects cannot be left behind in examining drug effects, therefore analyses and comparison of the adverse affects of ivermectin, albendazole, thiabendazole, single-dose ivermectin and multiple dose ivermectin were conducted. Data obtained through meta-analysis shows that thiabendazole resulted in significantly more adverse effects [11,13,18] but albendazole did not show a statistically significant difference[9,15,19]. There is no statistically significant difference between single dose and multiple doses of ivermectin[9,14,18]. Therefore it is safe to state that single-dose ivermectin has the fewest adverse effect compared to other drugs in this comparison. Cost-effectiveness is also an important aspect to be considered in determining a mass therapy regimen. Compared to albendazole, ivermectin is shown to more cost-effective in treating S.stercoralis infection[10], but no information has been found on the comparison the cost-effectiveness between ivermectin and thiabendazole to treat this disease. Further studies are needed to determine the cost-effectiveness of these three medications.

CONCLUSION

Strongyloides stercoralis infection is the most neglected of the NTDs, yet it is able to cause serious complications, such as malnutrition and stunting in children[1]. Pharmacological treatment is shown to be very effective to control infection, even without any other measures[8]. Based on the analysis above, single-dose ivermectin is shown to have the highest efficacy of the other medications (albendazole, thiabendazole, tribendimidine, pyrvinium pamoate, moxidectin, multiple dose ivermectin). Single-dose ivermectin is also shown to have generally fewer adverse effects than other medications. Further studies are needed to compare the costeffectiveness of these medications.

26


REFERENCES 1. Stephenson LS, Latham MC, Ottesen EA. Malnutrition and parasitic helminth infections. Parasitology. 2000 Oct;121(S1):S23-38. 2. Forrer A, Khieu V, Schär F, Hattendorf J, Marti H, Neumayr A, Char MC, Hatz C, Muth S, Odermatt P. Strongyloides stercoralis is associated with significant morbidity in rural Cambodia, including stunting in children. PLoS neglected tropical diseases. 2017 Oct 23;11(10):e0005685. 3. Buonfrate D, Formenti F, Perandin F, Bisoffi Z. Novel approaches to the diagnosis of Strongyloides stercoralis infection. Clinical Microbiology and Infection. 2015 Jun 1;21(6):543-52. 4. Buonfrate D, Bisanzio D, Giorli G, Odermatt P, Fürst T, Greenaway C, French M, Reithinger R, Gobbi F, Montresor A, Bisoffi Z. The Global Prevalence of Strongyloides stercoralis Infection. Pathogens. 2020 Jun;9(6):468. 5. Olsen A, van Lieshout L, Marti H, Polderman T, Polman K, Steinmann P, Stothard R, Thybo S, Verweij JJ, Magnussen P. Strongyloidiasis–the most neglected of the neglected tropical diseases?. Transactions of the Royal Society of Tropical Medicine and Hygiene. 2009 Oct 1;103(10):967-72. 6. Prendki V, Fenaux P, Durand R, Thellier M, Bouchaud O. Strongyloidiasis in man 75 years after initial exposure. Emerging infectious diseases. 2011 May;17(5):931. 7. Schär F, Trostdorf U, Giardina F, Khieu V, Muth S, Marti H, Vounatsou P, Odermatt P. Strongyloides stercoralis: global distribution and risk factors. PLoS Negl Trop Dis. 2013 Jul 11;7(7):e2288. 8. Hays R, Esterman A, McDermott R. Control of chronic Strongyloides stercoralis infection in an endemic community may be possible by pharmacological means alone: Results of a three-year cohort study. PLoS neglected tropical diseases. 2017 Jul 31;11(7):e0005825. 9. Suputtamongkol Y, Premasathian N, Bhumimuang K, Waywa D, Nilganuwong S, Karuphong E, Anekthananon T, Wanachiwanawin D, Silpasakorn S. Efficacy and safety of single and double doses of ivermectin versus 7-day high dose albendazole for chronic strongyloidiasis. PLoS Negl Trop Dis. 2011 May 10;5(5):e1044. 10. Muennig P, Pallin D, Challah C, Khan K. The cost-effectiveness of ivermectin vs. albendazole in the presumptive treatment of strongyloidiasis in immigrants to the United States. Epidemiology & Infection. 2004 Dec;132(6):1055-63.

27


11. Adenusi AA, Oke AO, Adenusi AO. Comparison of ivermectin and thiabendazole in the treatment of uncomplicated human Strongyloides stercoralis infection. African Journal of Biotechnology. 2003;2(11):465-9. 12. Barda B, Sayasone S, Phongluxa K, Xayavong S, Keoduangsy K, Odermatt P, Puchkov M, Huwyler J, Hattendorf J, Keiser J. Efficacy of moxidectin versus ivermectin against Strongyloides stercoralis infections: a randomized, controlled noninferiority trial. Clinical Infectious Diseases. 2017 Jul 15;65(2):276-81. 13. Bisoffi Z, Buonfrate D, Angheben A, Boscolo M, Anselmi M, Marocco S, Monteiro G, Gobbo M, Bisoffi G, Gobbi F. Randomized clinical trial on ivermectin versus thiabendazole for the treatment of strongyloidiasis. PLoS Negl Trop Dis. 2011 Jul 26;5(7):e1254. 14. Buonfrate D, Salas-Coronas J, Muñoz J, Maruri BT, Rodari P, Castelli F, Zammarchi L, Bianchi L, Gobbi F, Cabezas-Fernández T, Requena-Mendez A. Multiple-dose versus single-dose ivermectin for Strongyloides stercoralis infection (Strong Treat 1 to 4): a multicentre, open-label, phase 3, randomised controlled superiority trial. The Lancet Infectious Diseases. 2019 Nov 1;19(11):1181-90. 15. Datry A, Hilmarsdottir I, Mayorga-Sagastume R, Lyagoubi M, Gaxotte P, Biligui S, Chodakewitz J, Neu D, Danis M, Gentilini M. Treatment of Strongyloides stercoralis infection with ivermectin compared with albendazole: results of an open study of 60 cases. Transactions of the Royal Society of Tropical medicine and Hygiene. 1994 May 1;88(3):344-5. 16. Forrer A, Khieu V, Schindler C, Schär F, Marti H, Char MC, Muth S, Odermatt P. Ivermectin treatment and sanitation effectively reduce Strongyloides stercoralis infection risk in rural communities in Cambodia. PLoS neglected tropical diseases. 2016 Aug 22;10(8):e0004909. 17. Hailu T, Nibret E, Amor A, Munshea A, Anegagrie M. Efficacy of Single Dose Ivermectin Against Strongyloides stercoralis Infection Among Primary School Children in Amhara National Regional State. Infectious Diseases: Research and Treatment. 2020 Jun;13:1178633720932544. 18. Igual-Adell R, Oltra-Alcaraz C, Soler-Company E, Sánchez-Sánchez P, Matogo-Oyana J, Rodríguez-Calabuig D. Efficacy and safety of ivermectin and thiabendazole in the treatment of strongyloidiasis. Expert opinion on pharmacotherapy. 2004 Dec 1;5(12):2615-9.

28


19. Marti H, Haji HJ, Savioli L, Chwaya HM, Mgeni AF, Ameir JS, Hatz C. A comparative trial of a single-dose ivermectin versus three days of albendazole for treatment of Strongyloides stercoralis and other soil-transmitted helminth infections in children. The American journal of tropical medicine and hygiene. 1996 Nov 1;55(5):477-81. 20. Singthong S, Intapan PM, Wongsaroj T, Maleewong W. Randomized comparative trial of two high-dose albendazole regimens for uncomplicated human strongyloidiasis. Southeast Asian journal of tropical medicine and public health. 2006;37:32. 21. Steinmann P, Zhou XN, Du ZW, Jiang JY, Xiao SH, Wu ZX, Zhou H, Utzinger J. Tribendimidine and albendazole for treating soil-transmitted helminths, Strongyloides stercoralis and Taenia spp.: open-label randomized trial. PLoS Negl Trop Dis. 2008 Oct 15;2(10):e322. 22. Toma H, Sato Y, Shiroma Y, Kobayashi J, Shimabukuro I, Takara M. Comparative studies on the efficacy of three anthelmintics on treatment of human strongyloidiasis in Okinawa, Japan. Southeast Asian Journal of Tropical Medicine and Public Health. 2000 Mar;31(1):147-51.

29


Identification Screening

Records identified through database searching (PubMed = 256, Google Scholar = 2033, ResearchGate = 599, ScienceDirect = 1568, Cochrane = 768) (n = 5224 )

Records after duplicates removed and screened on the basis of titles and abstracts (n = 275 )

Records excluded (n = 222): Non-English journal (70) Abstract only (109) Does not include human studies (43)

Full-text articles assessed for eligibility (n = 53 )

Eligibility

Screening

Identification

TABLES & FIGURES

Included

Included

Studies included in qualitative synthesis (n = 13 )

Studies included in quantitative synthesis (meta-analysis) (n = 8)

Figure 1. Flowchart of study identification and selection based on PRISMA.

30

Full-text articles excluded (n= 40) Weak methodology (n = 23) Limited presentation of findings (n = 27)


Blinding of participants Selection Measurement Confounding and bias of exposure variables personnel

No Studies

Incomplete Reporting data bias

Adenusi et al., 1 2003

Low risk Low risk of bias of bias

Low risk of bias

Barda et al., 2 2017

Low risk Low risk of bias of bias

High risk of bias

Low risk of bias

Low risk of bias

Low risk of bias

Bisoffi et al., 3 2011

Low risk Low risk of bias of bias

Low risk of bias

Low risk of bias

Low risk of bias

Low risk of bias

Buonfrate et al., 4 2019

Low risk Low risk of bias of bias

Low risk of bias

Low risk of bias

Low risk of bias

Low risk of bias

5 Datry et al., 1994

Low risk Low risk of bias of bias

Low risk of bias

Unclear risk of Low risk of bias bias

Low risk of bias

Forrer et al., 6 2016

Low risk Low risk of bias of bias

Low risk of bias

Unclear risk of Low risk of bias bias

Low risk of bias

7 Hailu et al., 2020

Low risk Low risk of bias of bias

High risk of bias

Igual-Adell R et 8 al., 2004

Low risk Low risk of bias of bias

Low risk of bias

9 Marti et al., 1996

Low risk Low risk of bias of bias

Low risk of bias

Singthong et al., 10 2006

Low risk Low risk of bias of bias

Low risk of bias

Steinmann et 11 al.,2008

Low risk Low risk of bias of bias

High risk of bias

Suputtamongkol 12 et al., 2011

Low risk Low risk of bias of bias

Toma et al., 13 2000

Low risk Low risk of bias of bias

Unclear risk of Low risk of bias bias

Low risk of bias

Low risk of bias

Low risk of bias

Low risk of bias

Unclear risk of Low risk of bias bias

Low risk of bias

Low risk of bias

Low risk of bias

Low risk of bias

Unclear risk of Low risk of bias bias

Low risk of bias

Low risk of bias

Low risk of bias

Low risk of bias

High risk of bias

Unclear risk of Low risk of bias bias

Low risk of bias

High risk of bias

Unclear risk of Low risk of bias bias

Low risk of bias

211

38-86 y.o

HTLV-1 infection in 29.4% patients (62/211)

-

PP 14/60 (23.3%); ALB 65/84 (77.4%) ; IVM 65/67 (95.7.0%)

-

RCT

PP (5 mg/kg for 3 days) / ALB (400 mg for 3 days) / IVM (6 mg single dose)

-

Japan

IVM (200 μg/kg single dose) / IVM (200 μg/kg 2 doses, 2 weeks apart) / ALB (800 mg/day for 7 days)

-

96

>18 y.o

All had concomittant disease except 1 participant

-

RCT

ALB 19/30 (63.3%); IVM single dose 30/31 (96.8%); 2 dose IVM 27/29 (93.1%)

No serious adverse event

12

Toma et al., 2000

Suputtamongkol et al., 2011 Thailand

13

Table 1. Risk of bias assessment.

31


32

206 >2 y.o -

-

IVM 199/206 (96.6%)

-

5-70 y.o

-

-

IVM 24/ 29 (83%); ALB 9/ 24 (38%).

IVM 1/29 (3.4%) ; ALB 2/24 (8.3%)

IVM (200 μg/kg single dose)

IVM (150-200 μg/kg single dose) / ALB (400 mg/day for 3 days)

53

Cohort

RCT

face-to-face education on worm infections and hygiene

Cambodia

France

-

Forrer et al., 2016

6

Datry et al., 1994

5

-

IVM 87/92 (94.6%)

Living for the last 1 month in the region

-

6 -14 y.o

TBZ 5/31(16%); IVM single dose 2/22 (9%)

TBZ 25/31 (78%); IVM single dose 17/22 (77%), IVM for 2 days 35/35 (100%)

-

-

15-80+ y.o

88

-

Instruction to wear shoes appropriately and forbidden to get involved in irrigation activities for 2 weeks

92

IVM (200 μg/kg single dose) / IVM (200 μg/kg for 2 days) / TBZ (25 mg/kg/12 hour for 3 days )

RCT

Igual-Adell R et al., 2004 Spain

8

IVM (200 μg/kg single dose)

RCT

Ethiopia

Hailu et al., 2020

7

IVM 48/163 (29.4%) ; ALB 61/170 (35.9%)

IVM 126/152 (82.9%), ALB 67/149 (45.0%)

-

primary school (>=10 y.o ) -

301

-

IVM (200 μg/kg single dose) / ALB (400 mg for 3 days)

RCT

Tanzania

Marti et al., 1996

9

ALB for 3 days 5/58 (8.6%); ALB for 5 days 5/57 (8.8%)

ALB for 3 days 51/58 (87.9%); ALB for 5 days 51/57 (89.5%)

-

-

>10 y.o

115

-

ALB (800 mg/day for 3 days) / ALB (800 mg/day for 5 days), both treatment repeated once 7 days later

RCT

Thailand

Singthong et al., 2006

10

-

TBN 6/11 (54.5%) ; ALB 4/11 (36.4%)

-

Coinfection with other helminths (Taenia spp., A. lumbricoides, T.trichiura, hookworm)

5-14 y.o

22

-

TBN (200 mg single dose for age 5 to 14 years, 400 mg for >=15 years) / ALB (200 mg single dose for age 5 to 14 years, 400 mg for >=15 years)

RCT (open label)

People’s Republic of China

Steinmann et al.,2008

11


Table 2. Table summary of studies collected. Note: IVM = ivermectin, TBZ = thiabendazole, ALB = albendazole, TBN = tribendimidine, PP = pyrvinium pamoate, MOX = moxidectin.

33 Adverse event (AE)

IVM: 38/122 (31.15%); TBZ 74/109 (67.89%)

Day 7: IVM 107/122 (87.7%), TBZ 85/109 (77.98%); day 21: IVM 98/116 (84.48%) , TBZ 81/105 (77.14%); day 30: IVM 95/113 (84.07%), TBZ 81/103 (78.64%)

Cure rate (CR)

Results

-

Others

5-66 y.o

216

-

Sample characteristics

Study population

-

Medical conditions

Age

Others

None

MOX 59/63 (93.6%); IVM 59/62 (95.1%)

-

104 had coinfections with Opisthorchis viverrini, 72 had coinfections with hookworms.

>=12 y.o

125

-

IVM (200 μg/kg single dose) / MOX (8 mg single dose)

IVM (200 μg/kg single dose) / TBZ (50 mg/kg/day) for 3 days

Pharmacological

Interventions

RCT

RCT

Study design

3

IVM 24/115 (20.9%); TBZ 79/108 (73.1%)

>15 kg, currently living in a non-endemic area; have not planned travel to endemic countries before follow-up IVM 60/106 (56.6%), TBZ 48/92 (52.2%)

Diagnosis of strongyloidiasis by IFAT

>5 y.o

198

-

IVM (200 μg/kg single dose) / TBZ (2 daily doses of 25 mg/kg for 2 days)

RCT (open label)

Italy

Lao People’s Democratic Republic

Nigeria

Country

Bisoffi et al., 2011

Barda et al., 2017

2

Adenusi et al., 2003

1

Author, publication year

No

Single dose IVM 41/155 (26.45%), 4 dose IVM 54/154 (35.06%)

6 months: singledose IVM 107/128 (84%), 4 dose IVM 108/131 (82%); 12 months: single dose IVM 102/118 (86%), 4 dose IVM 96/113 (85%)

>15 kg, currently living in a non-endemic area

Positive faecal tests for S. stercoralis and positive serology at any titre / a positive serological test at high titre (regardless of the faecal test result)

>5 y.o

231

-

IVM (200 μg/kg single dose) / IVM (200 μg/kg on day 1, 2, 15, 16)

RCT (open-label)

Italy, Spain, UK

Buonfrate et al., 2019

4


Figure 2.1. Meta-analysis of ivermectin efficacy compared to other anti-helminthic medications (forest plot).

Figure 2.2. Meta-analysis of ivermectin efficacy compared to other anti-helminthic medications (funnel plot).

Figure 3.1. Meta-analysis of ivermectin efficacy compared to thiabendazole (forest plot).

34


Figure 3.2. Meta-analysis of ivermectin efficacy compared to thiabendazole (funnel plot).

Figure 4.1. Meta-analysis of ivermectin efficacy compared to albendazole (forest plot).

Figure 4.2. Meta-analysis of ivermectin efficacy compared to albendazole (funnel plot).

35


Figure 5.1. Meta-analysis of single dose ivermectin efficacy compared to multiple dose ivermectin treatment (forest plot).

Figure 5.2. Meta-analysis of single dose ivermectin efficacy compared to multiple dose ivermectin treatment (funnel plot).

Figure 6.1. Meta-analysis of ivermectin adverse effects compared to thiabendazole (forest plot).

Figure 6.2. Meta-analysis of ivermectin adverse effects compared to thiabendazole (funnel plot).

36


Figure 7.1. Meta-analysis of ivermectin adverse effects compared to albendazole (forest plot).

Figure 7.2. Meta-analysis of ivermectin adverse effects compared to albendazole (funnel plot).

Figure 8.1. Meta-analysis of single dose ivermectin adverse effects compared to multiple dose ivermectin treatment (forest plot).

37


Figure 8.2. Meta-analysis of single dose ivermectin adverse effects compared to multiple dose ivermectin treatment (funnel plot).

38


The Curative Innovation of Novel Triple-Drug Compared to Double-Drug Regimen in Lymphatic Filariasis: A Systematic Review Rivaldi Ruby1, Erlangga Saputra Arifin2, Charens3 1. 3rd Year Medical Student, aldiruby@gmail.com 2. 3rd Year Medical Student, arifinerlangga@gmail.com 3. 2nd Year Medical Student, charens91@gmail.com Abstract Introduction: The World Health Organization has established a global program aiming for the elimination of lymphatic filariasis by 2020; recent data has shown an impracticable result to accomplish it. Objectives: To identify whether a triple-drug (DEC, ALB, IVM) or double-drug (DEC & ALB / IVM & ALB) regimen is superior to the other in efficacy and safety for lymphatic filariasis treatment. Materials and Methods: A systematic review was conducted with Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement guidelines. The literature search was done using five databases: PubMed, ProQuest, ScienceDirect, EBSCO, and CENTRAL

with

“lymphatic

filariasis,”

“Ivermectin,”

“Albendazole,”

and

“Diethylcarbamazine” as the main keywords until December 3, 2020. Data collection was done by three independent reviewers and entered into a predesigned data extraction form. Cochrane risk of bias tool 2.0 was utilized in the quality assessment of the studies which covers seven domains of risk. Results and Discussion: Search strategies identified 209 studies. Three relevant full-text articles met our inclusion criteria. Overall studies had low risk of bias based on the authors’ judgement. The main findings from available data are as follows: (a) Administration of single dose of triple-drug regimen resulted in a total elimination of microfilaria 12 months after treatment whilst 91% participants given with double-drug remained microfilaremic (p=0.002); (b) In larger samples (n=182), triple drug cleared microfilaremia in 96% of the participants and only 32% of the participants receiving double drug regimen after 12 months observation; (c) Statistically, although no serious adverse events occurred, the triple-drug safety has a lower degree than the double-drug regimen (p=0.02).

39


Conclusion: The triple-drug has a better efficacy compared to the double-drug regimen in treating lymphatic filariasis. Furthermore, both regimens are proven safe with no serious adverse events elicited. Keywords: Albendazole; Diethylcarbamazine; Lymphatic Filariasis; Ivermectin; Systematic Review.

40


The Curative Innovation of Novel Triple-Drug Compared to Double-Drug Regimen in Lymphatic Filariasis: A Systematic Review

AUTHORS:

Rivaldi Ruby Erlangga Saputra Arifin Charens

Asian Medical Students’ Association AMSA-Indonesia 2020

41


I.

Introduction Lymphatic filariasis (LF) is a severe manifestation caused by a parasitic infection of

worms belonging to the genus Wuchereria and Brugia, that is transmissible by means of a mosquito vector.1 This infection does not kill its host but significantly reduces their quality of life.2 Latest data reported from the World Health Organization (WHO), which is in the year 2000, recorded over 120 million people were infected and about 40 million disfigured.3 In Indonesia alone, the ministry of health reported over 14,000 people suffered from chronic filariasis (elephantiasis) in the year 2014.4 There is still an estimate of 893 million people worldwide remain at risk of getting LF.3 Thus, this spectrum of disease is considered globally as one of the many neglected tropical diseases (NTD) requiring further interventions. The Global Programme to Eliminate Lymphatic Filariasis (GPELF) was initially established by the World Health Organization (WHO) in 2000 with the aim to achieve global elimination of LF by 2020.5 The proposed strategy includes the interruption LF transmission using mass drug administration as well as managing morbidity and preventing disability (MMPD) by providing access to primary recommended care. Latest reported data in 2019 on the progress of this program concluded a total of 37.3% are still at risk worldwide, which discourages the previous statement of it being completed in the year 2020.6 Nevertheless, it is best to focus on the treatment rather than the prevention in order to minimize the damage being done in the meantime. Currently, there are several regimens to treat LF. The well-known single-drug therapy is using Diethylcarbamazine (DEC) with a dosage of 6 mg/kg. Other drugs, such as Ivermectin (IVM) or Albendazole (ALB), rose to amplify the efficacy of DEC when combined.7 However, some research found flaws in this double-drug therapy - a detection of microfilaria at one year posttreatment. A systematic review on the combination of ALB with DEC also yielded little or even no differences compared to using single-drug.8 In 2015, a pilot randomized controlled trial (RCT) was done with the hypothesis that a triple-drug combination of DEC, ALB, and IVM might manifest a better result and coverage compared to only using two drugs. 9 The downside is that in accordance with medical scientific theory, more drug consumption is equivalent to more adverse events (AEs). Through this hypothesis, the objective of our systematic review is to analyze the efficacy and safety between a triple-drug and double-drug regimen in LF curative management qualitatively.

42


II.

Materials and Methods A systematic review was conducted with Preferred Reporting Items for Systematic

Reviews and Meta-analysis (PRISMA) statement guidelines to identify the efficacy and safety between a triple-drug and double-drug lymphatic filariasis treatment.10 Population, Intervention, Comparison, and Outcomes (PICO) questions were also used to formulate the inclusion criteria of this systematic review. The answer of those questions consecutively: Patients confirmed suffering from LF with no prior antifilarial treatment; Intervention with a triple-drug regimen consisting of DEC, ALB, and IVM; Comparison with a double-drug regimen consisting of DEC and ALB or IVM and ALB; Outcomes measured are efficacy and safety of both regimens. Differences between regimen doses and duration will be analyzed qualitatively based on the outcomes. The other inclusion criteria for this study is the study design and full-text availability. The study design had to be a RCT with participants confirmed as LF patients, and all included studies must have full text. The literature search was done using five databases: PubMed, ProQuest, ScienceDirect, EBSCO, and CENTRAL with “lymphatic filariasis,” “Ivermectin,” “Albendazole,” and “Diethylcarbamazine” as the main keywords until December 3, 2020. No language restrictions were imposed. The complete keywords are listed in Table 1 in the appendix. The result of the search was then imported to EndNote X9, and the duplicates were removed. All authors participated through each phase of the review independently by screening the titles and abstracts, assessing the full text for eligibility criteria, then including the relevant studies. Data collection was done by three independent reviewers (RR, EA, and C) and entered into a predesigned data extraction form. Differences arising between the three reviewers regarding study eligibility were resolved by consensus. Cochrane risk of bias tool 2.0 was utilized in the quality assessment of the studies which covers the following seven domains of risk. Included study quality will be classified as low, unclear, or high risk of bias.11 Disagreements arising in the process of the evaluation were all resolved by discussion among the review team.

43


III.

Result

Search Results A literature search from electronic databases yielded 287 studies. After removing the duplicates, 209 remaining studies. Screening through the titles and abstracts, the authors excluded studies with eight other studies that met the inclusion criteria. The result showed that three studies matched the criteria for inclusion.9,12,13 Search flowchart and selection method was summarized in Fig 1. Study Characteristics All of the included studies were done using the RCT design. Inclusion and exclusion criteria across studies showed similarities. Most of the study populations included were from Papua New Guinea9,12 and Côte d’Ivoire in West Africa13 that showed small sample varieties. The regimen dosage and duration has slight differences amongst studies with efficacy and safety analysis. Detailed characteristics of the included studies were summarized in Table 2. Quality Assessment There were unclear risks for all studies from the domain of selection and reporting bias. Concealment of the randomization done between the control and interventional group was unexplained.9,12,13 Also, two studies excluded incomplete data from the statistical testing; thus can alter the results.9,13 Two studies have an unclear risk in detection bias resulting from inadequate data.9,12 Overall studies had a low risk of bias based on the author's judgement. Risk of bias based on authors’ judgments was summarized in Fig 2. Efficacy in Clearing of Microfilaremia The pilot study done by Thomsen et al. included 24 participants with no chronic illnesses or prior LF infection. Participants also have not got the MDA prophylaxis. Included participants divided into two parallel groups with every 12 participants that received the tripledrug (DEC + ALB + IVM) or the double-drug regimen (DEC + ALB). The study yielded higher efficacy in the triple-drug regimen with total eradication until 12 months follow-up than the double-drug regimen still resulting in 10 of 11 participants having positive microfilaremia (p=0.002). After two years of follow-up, both regimens showed complete eradication of microfilaremia.9

44


In 2018, another comparison of a RCT study done by King et al. is conducted to evaluate also to test the efficacy of a single dose of triple-drug regimen in sustaining clearance being higher than a single dose of double-drug regimen for LF. A total of 182 participants were included, 60 of which were assigned to receive the triple-drug regimen administered once, and 61 for each double-drug regimen administered once and once a year for three years. Among 182 participants, 172 (95%) were evaluated at 12 months, 165 (91%) at 24 months, and 158 (87%) at 36 months after trial initiation – several were excluded for similar reasons, including a withdrawal, moved from the area, died, took a second dose by mistake or merely lost to follow-up. However, despite the decrease of the number of participants, the outcome of tripledrug regimen still result in significantly greater microfilarial clearance at 36 months than a single dose of the double-drug regimen, with a p-value lower than 0.025 (p=0.02), and was non-inferior to that with the double-drug regimen administered once a year for three years, with a one-sided P value for noninferiority lower than 0.025 (P=0.004).12 The most recent study was done in 2020 by Bjerum et al. consisting of 97 participants and using a similar triple-drug regimen but a somewhat different double-drug regimen consisting of IVM and ALB. The triple-drug group (45 participants) was given a single dose at the beginning of the research, while the double-drug group (52 participants) was given annually for three years. Results measured were the clearance of microfilaremia at 6, 12, 24, and 36 months posttreatment. The triple-drug regimen was significantly better compared to the double-drug regimen in clearing microfilaremia at 6 and 12 months (both with the value of p<0.001). However, superiority is the exact opposite in the 36 months (p=0.045). At the 24 months posttreatment, triple-drug regimen was still better but with an insignificant value (p=0.53). This concludes that although the triple-drug group was only given once at the beginning of the study, it can maintain a better clearance up to 24 months posttreatment.13 Safety Regarding the Adverse Events A potent and useful drug not only measured by its effectivity and efficacy, but also by its safety and harmlessness. All three studies reported that triple-drug therapy resulted in a much more AE compared to double-drug therapy. This is supported by the basic medical lessons that more drugs are equal to greater side effects. However, the AEs reported are mild to moderate AEs like fever, myalgias, headache, nausea, and the like. There are no serious or severe (e.g. grade 3) AEs reported.9,12,13

45


IV.

Discussion This systematic review concludes a similar result found in all three studies.9,12,13 All

things considered, the triple-drug regimen was revealed for being the more effective option compared to the double-drug regimen in treating LF. The clearance of microfilaremia measures this effectiveness at their given posttreatment, follow-up time. Study by Bjerum et al., however, showed that the double-drug regimen was significantly superior at 36 months posttreatment.13 Another important aspect is the therapy’s safety, which is measured by listing all AEs elicited after drug consumption. Both regimens are considered safe by means of no serious or severe AEs obtained. Mild to moderate AEs like fever, nausea, headache, and the like are more commonly found in patients treated with the triple-drug compared to the double-drug regimen.9,12,13 Differences in Various Aspects of the Regimen Although there are many similarities in the three included RCTs, their differences are a requirement to be discussed. Differences arise across studies yielded hazy analyzes in the overall results. The main distinguishable factor is the inconsistency in the drug combinations used. Bjerum et al. use a different double-drug combination, which includes ALB and IVM, compared with two other studies that used DEC and ALB.13 A clinical trial in Ghana using a combination of ALB and IVM showed the same efficacy and safety with a controlled group (DEC and ALB) but statistically incomparable.14 Moreover, a model-analysis results in the same efficacy between both kinds of double-drug regimen (IVM and ALB / DEC and ALB).15 Our analysis also considers IVM mechanisms of action that can be the main reason for DEC substitution in LF. Ivermectin causes paralysis and death of parasites by interacting with its chloride channel in the cell membrane leading to hyperpolarization.16 Although there are differences among the double-drug regimens, it can be concluded that both showed the same efficacy and safety that can be compared with triple-drug based on the data analyzes and each authors’ judgments. Another difference comes from the regimen frequency in which the double-drug regimen is not only given once. This difference can be ignored since a higher frequency of the double-drug regimen still shows inferior outcomes compared to the triple-drug regimen.17 Moreover, a study showed that the double-drug regimen has minor to none efficacious effect

46


even with more frequency.18 However, in some studies, it can affect the effectivity outcome on the last day of the treatment follow-up.13 In the safety objectives, a longer duration of follow up showed an extension of the safety observation. Although there are no serious AEs, the triple-drug regimen contains more chemical agents compound which can cause more AEs when compared to the double-drug regimen.19 Risk vs benefit will be the primary consideration when it comes to LF treatment.8 The highest benefits, besides the side effects, can be found by using the triple-drug regimen. However, in public situations, the doctor’s explanations about the triple-drug regimen’s potent benefits must be performed to prevent the misunderstanding of its AEs. Strength and Limitation of Each Study Included studies also shared some strengths and limitations. By referring to the risk of bias assessment, strengths such as the inclusion of using a random component had been performed, concluding a low risk of bias for random sequence generation, followed by the blinding of participants and the personnel or trial staff, specifically those who assessed the adverse events in the studies done by King et al. and Bjerum et al.12,13 However, the blinding of outcome assessment was only low risk in the study done by Bjerum et al. since it was specified that although it was an open-label trial, the investigators and staff who evaluated the examinations were masked with respect to treatment arm assignments.13 Meanwhile, the study done by King et al. gained the upper hand in incomplete outcome data, by conducting a sensitivity analysis (chi-squared analysis) to evaluate the potential effect of the missing data on the primary outcome at 36 months.12 There were also no other biases present. Several inherent limitations are the questionable allocation concealment, as these three studies did not indicate the method to conceal the possibility of foreseeing the assignments. As mentioned before, blinding of outcome assessment is also unclear in the studies done by Thomsen et al. and King et al.9,12 Another important caveat is the removal of participants which are lost to follow-up without performing a further analysis for the potential effects in the Thomsen et al. and Bjerum et al.’s study.9,13 Thomsen et al.’s study has also emphasized its limitations when assessing adverse events in the first 10 hours of follow-up since participants may have been aware of the treatment group assignments.9 Although, the subsequent follow-up of the participants in their communities was performed in a blinded manner by different trial staff. Also, the detection of

47


microfilaremia at follow-up could have been due to reinfection. On the other hand, the limitations from Bjerum et al.’s study include the unreliable outcome of higher infection rate in males due to its higher number of participants.13 This study is also involved in the retreatment of Mf-positive individuals after 24 months following a single dose of triple-drug therapy; however, this number was later considered as a failure. The authors acknowledge that this concept is without no obstacles. First and foremost, Indonesia happened to be the world’s largest island nation, consisting of approximately 17,000 islands. Therefore some difficulties may arise for the government to provide medicine to remote populations.20 Secondly, and probably the most crucial is the availability of the regimen used. Up to recently, the drug IVM is not yet officially approved and widely distributed in Indonesia. Lastly, the triple-drug regimen for LF interventions still requires further studies to be applied in public. V.

Conclusion The objective of this systematic review leads to the conclusion that the triple-drug

regimen is superior in terms of efficacy, but resulted in the sacrifice of its safety. One of the downsides in these three studies is the small geographic variety in the included respondents. It is crucial that future studies consider and involve a wide variety of people in order for this research to be generalized. To conclude, the authors believe that the presence of a triple-drug regimen can really aid in improving the course of lymphatic filariasis; thus, leading to much better outcomes. VI.

Conflict of Interest

The authors declare that there are no competing interests in this study.

48


REFERENCES 1. CDC

-

Lymphatic

Filariasis.

Cdc.gov.

https://www.cdc.gov/parasites/lymphaticfilariasis/index.html. Published 2020. Accessed December 14, 2020. 2. WHO | Understanding the community impact of lymphatic filariasis: a review of the sociocultural

literature.

Who.int.

https://www.who.int/bulletin/volumes/85/6/06-

031047/en/. Published 2020. Accessed December 14, 2020. 3. Lymphatic

Filariasis.

https://www.who.int/news-room/fact-sheets/detail/lymphatic-

filariasis. Published 2020. Accessed December 14, 2020. 4. InfoDATIN: Situasi Filariasis di Indonesia. Pusat Data dan Informasi Kementerian Kesehatan RI; 2019. 5. Ichimori K, King JD, Engels D, et al. Global programme to eliminate lymphatic filariasis: the processes underlying programme success. PLoS Negl Trop Dis. 2014;8(12):e3328. Published 2014 Dec 11. doi:10.1371/journal.pntd.0003328 6. Global programme to eliminate lymphatic filariasis: progress report, 2019. Who.int. https://www.who.int/publications-detail-redirect/who-wer9543. Published 2019. Accessed December 14, 2020. 7. Lourens GB, Ferrell DK. Lymphatic Filariasis. Nurs Clin North Am. 2019;54(2):181-192. doi:10.1016/j.cnur.2019.02.007 8. Macfarlane CL, Budhathoki SS, Johnson S, Richardson M, Garner P. Albendazole alone or in combination with microfilaricidal drugs for lymphatic filariasis. Cochrane Database Syst Rev. 2019;1(1):CD003753. Published 2019 Jan 8. doi:10.1002/14651858.CD003753.pub4 9. Thomsen EK, Sanuku N, Baea M, et al. Efficacy, Safety, and Pharmacokinetics of Coadministered Diethylcarbamazine, Albendazole, and Ivermectin for Treatment of Bancroftian Filariasis. Clin Infect Dis. 2015;62(3):334-341. doi:10.1093/cid/civ882 10. Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(7): e1000097. doi:10.1371/journal.pmed1000097 11. Sterne JAC, Savović J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366:l4898. Published 2019 Aug 28. doi:10.1136/bmj.l4898 12. King CL, Suamani J, Sanuku N, et al. A Trial of a Triple-Drug Treatment for Lymphatic Filariasis. N Engl J Med. 2018;379(19):1801-1810. doi:10.1056/NEJMoa1706854

49


13. Bjerum CM, Ouattara AF, Aboulaye M, et al. Efficacy and Safety of a Single Dose of Ivermectin, Diethylcarbamazine, and Albendazole for Treatment of Lymphatic Filariasis in Côte d'Ivoire: An Open-label Randomized Controlled Trial. Clin Infect Dis. 2020;71(7):e68-e75. doi:10.1093/cid/ciz1050 14. Dunyo SK, Simonsen PE. Ivermectin and albendazole alone and in combination for the treatment of lymphatic filariasis in Ghana: follow-up after re-treatment with the combination. Trans R Soc Trop Med Hyg. 2002;96(2):189-192. doi:10.1016/s00359203(02)90300-7 15. de Kraker ME, Stolk WA, van Oortmarssen GJ, Habbema JD. Model-based analysis of trial data: microfilaria and worm-productivity loss after diethylcarbamazine-albendazole or ivermectin-albendazole combination therapy against Wuchereria bancrofti. Trop Med Int Health. 2006;11(5):718-728. doi:10.1111/j.1365-3156.2006.01606.x 16. Laing R, Gillan V, Devaney E. Ivermectin - Old Drug, New Tricks?. Trends Parasitol. 2017;33(6):463-472. doi:10.1016/j.pt.2017.02.004 17. Dubray CL, Sircar AD, Beau de Rochars VM, et al. Safety and efficacy of co-administered diethylcarbamazine, albendazole and ivermectin during mass drug administration for lymphatic filariasis in Haiti: Results from a two-armed, open-label, cluster-randomized, community study. PLoS Negl Trop Dis. 2020;14(6):e0008298. Published 2020 Jun 8. doi:10.1371/journal.pntd.0008298 18. Edi C, Bjerum CM, Ouattara AF, et al. Pharmacokinetics, safety, and efficacy of a single co-administered dose of diethylcarbamazine, albendazole and ivermectin in adults with and without Wuchereria bancrofti infection in Côte d'Ivoire. PLoS Negl Trop Dis. 2019;13(5):e0007325. Published 2019 May 20. doi:10.1371/journal.pntd.0007325 19. Sankari T, Subramanian S, Hoti SL, Pani SP, Jambulingam P, Das PK. Heterogeneous response of Wuchereria bancrofti-infected persons to diethylcarbamazine (DEC) and its implications for the Global Programme to Eliminate Lymphatic Filariasis (GPELF) [published online ahead of print, 2020 Nov 4]. Parasitol Res. 2020;10.1007/s00436-02006950-7. doi:10.1007/s00436-020-06950-7 20. WHO | Indonesia firmly committed to eliminating lymphatic filariasis as a public health problem.

Who.int.

https://www.who.int/news/item/29-04-2020-indonesia-firmly-

committed-to-eliminating-lymphatic-filariasis-as-a-public-health-problem. Published 2020. Accessed December 14, 2020.

50


APPENDICES Table 1. Search Keywords Databases

Keywords

Articles

(((((((((Elephantiasis, PubMed

(Elephantiasis,

Filarial[MeSH

Filarial[Title/Abstract]))

Terms]) OR

OR

(Lymphatic

Filariasis[Title/Abstract]))

OR

(Lymphatic

Filariases[Title/Abstract]))

OR

(Bancroftian

Filariasis[Title/Abstract]))

OR

105

(Malayi

Filariasis[Title/Abstract])) OR (Elephantiasis[Title/Abstract])) AND

((((Ivermectin[MeSH

Terms])

OR

(Ivermectin[Title/Abstract])) OR (Ivomec[Title/Abstract])) OR (IVM[Title/Abstract]))) AND ((((albendazole[MeSH Terms])) OR (albendazole[Title/Abstract])) OR (ALB[Title/Abstract]))) AND

(((Diethylcarbamazine[MeSH

Terms])

(Diethylcarbamazine[Title/Abstract]))

OR OR

("Diethylcarbamazine Citrate"[Title/Abstract]))

ProQuest

(ab(Elephantiasis, Filarial OR Lymphatic Filariasis OR 44 Lymphatic Filariases OR Bancroftian Filariasis OR Malayi Filariasis OR Elephantiasis) OR ti(Elephantiasis, Filarial OR Lymphatic Filariasis OR Lymphatic Filariases OR Bancroftian Filariasis OR Malayi Filariasis OR Elephantiasis)) AND (ab(Ivermectin OR Ivomec OR IVM) OR ti(Ivermectin OR Ivomec OR IVM)) AND (ab(albendazole OR ALB) OR ti(albendazole OR ALB)) AND (ab(Diethylcarbamazine OR Diethylcarbamazine Citrate) OR ti(Diethylcarbamazine OR Diethylcarbamazine Citrate))

ScienceDirect

(Elephantiasis, Filarial OR Lymphatic Filariasis OR Lymphatic 27 Filariases OR Bancroftian Filariasis OR Elephantiasis) AND

51


Ivermectin AND albendazole AND (Diethylcarbamazine OR Diethylcarbamazine Citrate)

EBSCO

(ab(Elephantiasis, Filarial OR Lymphatic Filariasis OR 98 Lymphatic Filariases OR Bancroftian Filariasis OR Malayi Filariasis OR Elephantiasis) OR ti(Elephantiasis, Filarial OR Lymphatic Filariasis OR Lymphatic Filariases OR Bancroftian Filariasis OR Malayi Filariasis OR Elephantiasis)) AND (ab(Ivermectin OR Ivomec OR IVM) OR ti(Ivermectin OR Ivomec OR IVM)) AND (ab(albendazole OR ALB) OR ti(albendazole OR ALB) ) AND (ab(Diethylcarbamazine OR Diethylcarbamazine Citrate) OR ti(Diethylcarbamazine OR Diethylcarbamazine Citrate))

Elephantiasis, Filarial[MeSH Terms] AND Ivermectin[MeSH CENTRAL

Terms]

AND

albendazole[MeSH

Diethylcarbamazine[MeSH Terms]

52

Terms]

AND

13


Identification

Records identified through database searching (n=287)

Additional records identified through other sources (n=0)

PubMed (n=105) ScienceDirect (n=27) EBSCOhost (n=98) ProQuest (n=44) CENTRAL (n=13)

Eligibility

Screening

Records after duplicates removed (n=209)

Records screened (n=8)

Full-text articles assessed for eligibility (n=3) Full-text articles excluded with reasons (n=5)

Studies included in qualitative synthesis (n=3)

Included

Records excluded by title and abstract screening based on inclusion and exclusion criteria (n=201)

Reviews (n=2) Gyapong, et al. 2018; Fischer, et al. 2017. Letter to Editor (n=1) King, et al. 2020 Cohort Studies (n=2) Edi C, et al. 2019; Constant, et al. 2019

Studies included in quantitative synthesis (n=0)

Fig 1. PRISMA flow diagram of the identification and selection of studies included in the analysis

53


Table 2. Characteristics of the Included Studies Interventions Author

Study Design

Inclusion Criteria

Exclusion Criteria

Duration of Follow-up

Samples Triple drug

King et al. 2018

Thomse n et al. 2015

Bjerum et al. 2020

Double drug

Randomiz ed Controlled Trial

- Age 18-65 years - 50 or more mf/ml - never receive treatment with ALB or DEC

- recent history of illness - pregnant - clinically significant biochemical or hematologic abnormalities, proteinuria, hematuria, glucosuria

N=182

DEC + ALB + IVM

DEC + ALB

This includes a total of 60 patients assigned IVM+DEC+ALB administered once, 61 to DEC+ALB administered once, and 61 to DEC+ALB once a year for 3 years

IVM 200 μg/kg plus DEC 6mg/kg plus ALB 400mg administered once at trial initiation

DEC 6 mg/kg plus ALB 400mg administered once at trial initiation

Randomiz ed Controlled Trial Single blinded parallelgroup

- Aged 18-60 years ->100 microfilaria/mL no prior antifilarial medications - free from any acute or chronic illnesses

N/A

N=24

DEC + ALB + IVM

DEC + ALB

This includes a total of 12 patients assigned to DEC + ALB group and 12 patients assigned to DEC + ALB + IVM groups

Single dose IVM 200 μg/kg; ALB 400 mg; DEC 6 mg/kg

Single dose DEC 6 mg/kg; ALB 400 mg

- Age 18-70 years - 50 or more Mf/mL but otherwise healthy - No treatment with ALB or IVM within past 5 years

- Positive pregnancy test - History of chronic kidney or liver disease - Serum ALT, AST, or creatinine level >1.5 times the upper limit of normal - Severe anemia (Hb <7g/dL) Patients with onchocerciasis

N=97

DEC + ALB + IVM

IVM + ALB

This includes a total of 52 patients assigned to IVM+ALB group and 45 patients assigned to IVM+DEC+ALB group.

IVM 200 μg/kg and ALB 400 mg plus DEC 6 mg/kg were given only once at the beginning of the study.

IVM 200 μg/ kg and ALB 400 mg were given in a 3 annual dose.

Randomiz ed Controlled Trial

Result

Effectivity

Adverse events

Follow-up was done at 12, 24 and 36 months after trial initiation

triple-drug regimen cleared microfilaremia in 55 (96%), 52 (96%) and 55 participants (96%) at 12, 24 and 36 months respectively. A single dose of double-drug regimen cleared microfilaremia in 18 (32%), 31 (56%), 43 (83%) participants at 12,24 and 36 months respectively.

Moderate AEs after the initial treatment were more frequent with the triple-drug regimen than with the double-drug regimen.

Follow up was done until 2 years posttreatment

Triple-drug regimen resulting total elimination of microfilaria after 36 h and 7 days treatments and remain so at 12 months posttreatment, than the double-drug regimen 10 of 11 participants remained microfilaremic at 12 months follow-up

No serious AE was found in both treatment groups. Most common AEs elicited were fever, myalgia, pruritus, and proteinuria/hematuria.

At 12 months triple-drug vs doubledrug regimen p=0.002

54

Follow-up was done at 6, 12, 24, and 36 months posttreatment .

Triple-drug regimen resulted in a Mf complete clearance of 89%, 71%, 61%, and 55% at a follow-up time of 6, 12, 24, and 36 months, respectively. While double-drug regimen resulted in a Mf complete clearance of 34%, 26%, 54%, and 79% at similar follow-up time, respectively.

Adverse events were more on the triple-drug groups compared to the double-drug groups (83% and 50%, respectively; p=0.02).

Both groups resulted in similar AEs, which are none in the severe (grade 3) category and a similar one at the mild (grade 1) category. However, triple-drug therapy elicited more moderate (grade 2) AEs compared to double-drug therapy.


Abbreviation: AE : Adverse Events ALB : Albendazole ALT : Alanine Transferase AST : Aspartate Transferase DEC : Diethylcarbamazine dl : Deciliter g : Gram IVM : Ivermectin kg : Kilogram mf : Microfilaria mg : Milligram ml : Milliliter μg : Microgram N : Number of Participants N/A : Not Available

55


Fig 2. Risk of bias summary: review authors’ judgements about each risk of bias item for each included study

56


The Correlation between School’s Hygiene Level, Enviromental Sanitation, and Soil Contamination towards Intestinal Worm Infection Prevalence in Public Elementary School Students at Kedungkandang, Malang Vincentius Mario Yusuf1*, Amandus Michael Martin1, Brenda Kristi1 1

Undergraduate student, Faculty of Medicine, Universitas Brawijaya, Malang, East Java, Indonesia *vincentiusmarioyusuf@gmail.com

ABSTRACT (Introduction) The high prevalence of intestinal worm infection (35,3%) is still being a health problem in Indonesia for all of the age groups. Elementary school students are vulnerable toward the intestinal worm infection with a prevalence of 60-80%. Poor hygiene habit, sanitation, and soil contamination are some of the risk factors. This purpose of this study is to find out the epidemiology data and examine the relationship between school’s hygiene level, enviromental sanitation, and soil contamination towards intestinal worm infection prevalence in several public elementary school students at Kedungkandang, Malang (Methods) The populations of this study were 3th to 5th grade students from 12 elementary schools in Kedungkandang Subdistrict. Total sample of this study were 757 students. The data was collected through school sanitation questionnaire, school hygiene questionnaire, soil examination using Suzuki Floatation method, and feces examination using Kato Thick smear method. Statistical analysis was carried out by using Pearson and Spearman's correlation test. (Results) This study reveals that the prevalence rate of intestinal worm infection among elementary school students in Kedungkandang Subdistrict was 4,6%. The most common infective worm was Ascaris lumbricoides (80%). The analysis results showed that intestinal worm infection prevalence had a significant correlation with school’s sanitation (p=0.001) and insignificant correlation with school’s hygiene level (p=0,977) and soil contamination level (p=0,790). (Conclusion) The prevalence of intestinal worm infection among elementary school low due to high levels of sanitation and low levels of soil contamination. There is also a relationship between school’s hygiene level, sanitation, and soil contamination towards the intestinal worm infection incidence in several public elementary school at Kedungkandang, Malang. Promoting school activities such as Unit Kesehatan Sekolah (UKS) and health education to improve health behaviour is essential to prevent the intestinal worm infection. Keyword: intestinal worm infection, hygiene, sanitation, soil contamination

57


The Correlation between School’s Hygiene Level, Enviromental Sanitation, and Soil Contamination towards Intestinal Worm Infection Prevalence in Public Elementary School Students at Kedungkandang, Malang

Authors : Vincentius Mario Yusuf Amandus Michael Martin Brenda Kristi

Faculty of Medicine Universitas Brawijaya Asian Medical Students’ Association Indonesia 2020

58


INTRODUCTION

sanitation, hygiene, and soil contamination.

Indonesia still faces the high prevalence

One form of inadequate school sanitation is

of infectious diseases, especially those

the absence of a proper latrine with proper

related to poor hygiene and environmental

drainage,

sanitation. One of the diseases with a high

Inadequate

incidence is intestinal worm infection,

contamination which will become the

which is an environmentally based disease1.

media of worms transmission.

Ascaris lumbricoides, Trichuris trichiura, Ancylostoma americanus

duodenale, are

some

and of

latrine

in

a

septic

tank.

will

cause

soil

Poor hygiene such as defecation habits

Necator the

namely

in open waterways and around the house,

Soil

rarely cutting nails, eating without washing

Transmitted Helminths which are often

hands, and playing in the soil contaminated

found2.

with worms’ eggs or larvae without

The prevalence of intestinal worm

wearing footwear also increase the risk factors for intestinal worm infection6.

infection in Indonesia is still high, arround 60-80% among elementary school students.

Moist and warm soil with an optimum

Most infections occur in elementary school

temperature about 25 °C-30 ° C is a suitable

students because they have the most contact

place for the eggs of Ascaris lumbricoides

with soil3.

and Trichiuris trichiura to grow. Warm

In the report of a survey in 10 provinces

area with high humidity and poor sanitation

on the prevalence of worm infection in

are very beneficial for Strongyloides

2002 with a target age of primary school

stercoralis. Good soil for the growth of

students varied greatly from 4.8% to

Strongyloides stercoralis larvae is loose,

83.0%, with the highest prevalence in West

sandy, and humus, while hookworm larvae

Nusa Tenggara Province, while those in

need loose humus mixed sand, protected

East Java4.

from direct sunlight with an optimum

Elementary school children are expected

temperature of 23 ° C -32 ° C. This

to grow into potential human resources in

conditions are the characteristics of regions

the future. They need to be considered and

in Indonesia7.

prepared to be able to grow perfectly both

The last survey conducted in Malang

physically and intellectually5.

were in 1987 in Mulyorejo elementary

The occurrence of intestinal worm

school and Kedungkandang regions which

infections in elementary school children is

showed a high prevalence of more than

actually influenced by several supporting

60%8. Since that time until now there has

factors such as school environmental

59


been no official data on the incidence of

RESULT

worm infections in Malang.

This research began with counseling to

Based on the problems above, this

12 elementary schools in Kedungkandang

research aims to find out the epidemiology

District, Malang City. Of the 1552 students

data and the relationship between school’s

who attended the counseling, students who

hygiene level, enviromental sanitation, and

were willing to collect their stools for

soil contamination towards intestinal worm

examination were 757 students, coverage

infection prevalence in several public

(the number of pots divided by the number

elementary

of

school

students

at

pots

distributed)

was

48.78%.

Kedungkandang, Malang due to its high

Tlogowaru 1 elementary school was the

prevalence based on previous study so that

school that had the highest coverage, which

the government can take more action to

was 75%. The collected stool was then

control this disease.

examined at the Parasitology Laboratory at

MATERIAL AND METHODS

Faculty of Medicine Universitas Brawijaya

Research Design

to be examined using the Kato Thick Smear

This research was an analytical study

method to determine the status and the type

with cross sectional design.

of intestinal worm infections. Table 1. The Prevalence of Intestinal Worm

Population and Sample

Infection

The population in this research were 1552 students from grades 3, 4, and 5 at 12 elementary schools in Kedungkandang, Malang. The collected stool samples were 757 samples. Data Collection Data were collected by examining feces using the Kato Thick Smear method, soil examination using the Suzuki method

Table 1 shows that after examination,

validated questionnaire to asses the level of

there were 35 cases of intestinal worm

hygiene in the school environment, and

infection (4.6%), with the highest number

observation of school sanitation.

of

Data Analysis

cases

found

at

Arjowinangun

2

elementary school (11 cases) while the

Statistical analysis was performed using

fewest

the Pearson and Spearman Correlation test.

cases

Sawojajar6,

60

found

at

Sawojajar1,

and

Cemorokandang


elementary school (0 cases). The type of

Table 3. The Results of the School Hygiene

worm that infected the most was Ascaris

Level Based on the Questionnaire Assessment

lumbricoides with 28 cases (80%).

Figure 1. Ascaris lumbricoides Decorticated Eggs with 10x Magnification

The results of hygiene level by using

Table 2. Observation Results of School

questionnaire

showed

that

only

4

Environmental Sanitation Level Based on

elementary schools were met the criteria for

Questionnaire Assessment

high level of school hygiene, which were Sawojajar 6, Mergosono 4, Bumiayu 4 and Lesanpuro4 elementary school. Statistical data of the results of measuring the level of school hygiene in Kedungkandang District based on the questionnaire assessment can be seen in Table 3. Table 4. The Results of Soil Contamination in School

The results showed that all elementary schools in Kedungkandang had used Water seal type latrine, ceramic floor, and all schools had feces disposal in septic tanks.

To determine the corellation between

The water source used by most elementary

soil contamination and the incidence of

schools was PDAM water, however, there

worm infection, soil samples were taken

are 4 schools used well water as a water

from

source.

Kedungkandang District. Soil samples

61

12

elementary

schools

in


were taken from the same 5 locations in

The total number of pots distributed was

each school, namely: plant pots, sandbox,

1552 and 757 pots returned (coverage of

canteen, around the toilet, and in front of

48.78%). This coverage figure is lower than

the gate. Each location was taken 5 points

the case study conducted by Chadijah in

by eroding the soil surface so that all 300

Palu City in 2014 was 70% 9.

soil samples were obtained. The collected

Based on the results of the examination

soil samples were then examined at the

using the Kato Thick Smear method, it was

Parasitology Laboratory at Faculty of

found that the prevalence of intestinal

Medicine Universitas Brawijaya using the

worm infection was 4.6%. A survey

Suzuki method to determine whether the

conducted by the province of East Java in

soil was contaminated with worm eggs /

2008 - 2010 found an average worm

larvae or not.

infection prevalence rate of 7.95%

10

.

Table 4 shows that after inspection, 11

Research about intestinal worm infections

soil samples were found contaminated with

conducted in 2012 in Minahasa showed a

worm eggs (3.7%). The most type of worm

prevalence of 12.2% 11. A similar study was

that contaminated the soil was Ascaris

also conducted in the city of Palu in 2014

lumbricoides, which was 6 samples (55%).

and found that the prevalence of intestinal

Data Analysis

worm infections was 31.6% 9. This showed

Table 5. Analysis Results with Pearson and

that the prevalence of intestinal worm

Spearman Correlation

infection

in

Kedungkandang

District,

Malang City was low. The most common type of intestinal worms found in fecal examination in this study was Ascaris lumbricoides, which was 28 cases (80%). Data from WHO reports

From Table 5, it can be concluded that

that 800 million people are infected with

intestinal worm infections had significant

Ascaris lumbricoides, 600 million people

correlation with school’s sanitation and

are infected with Trichuris trichiura, and

insignificant correlation with school’s

600 million people are infected with

hygiene level and soil contamination.

Hookworm12. The results of research

Discussion

conducted

The Prevalence of Intestinal Worm

in

Tombariri

Subdistrict,

Minahasa Regency also showed that the

Infection

prevalence of Ascaris lumbricoides in elementary school students was the highest

62


compared to other worms, namely 36.4%

The results of the Environmental Health

13

. The same thing happened in a study

Risk Assessment (EHRA) study also

conducted in Palu which showed that the

mentioned about the clean water sources of

prevalence of Ascaris lumbricoides was

residents in Malang City, residents using

9

83.34%

. This explains that Ascaris

unprotected wells in Mergosono Village,

lumbricoides is still the type of worm that

Kedungkandang District (25%)14.

mostly

School Hygiene Level

infects

humans,

especially

elementary school students.

In this study, the level of school hygiene

School Sanitation

is a representation of the level of individual

Good sanitation is one of the preventive

hygiene of elementary school students as

measures that can be done to break the

assessed from 7 components, namely hand

chain of worm infection. The creation of

washing habits, habit of not eating raw

good sanitation can be seen from 4 factors,

food, bathing habits, defecating habits, nail

namely the availability of water sources,

hygiene, use of footwear, and deworming

types of latrines, types of floors, and

habits. Of the 742 respondents who

disposal of feces. Based on the research

represented 12 schools, only 4 schools had

results, it can be seen that all elementary

good hygiene levels and 8 schools had poor

schools

District,

hygiene levels. The lowest level of hygiene

Malang City have a good level of school

is Tlogowaru elementary school at 95.23%

environmental sanitation with values that

and the highest level of school hygiene is

do not differ much. A good level of school

Sawojajar 6, Mergosono 4, Bumiayu 4 and

sanitation

the

Lesanpuro 4 elementary school at 100%.

Kedungkandang area does not have rural

Study on the level of school hygiene has

characteristics that should have a lack of

never been done before, so data on previous

sanitation.

research is not available.

In

in

Kedungkandang

indicates

Permenkes

No.416

that

of

1990

The difference in the level of school

concerning Requirements and Supervision

hygiene is probably due to differences in

of Water Quality, it is stated that the

other factors that also affect the incidence

requirements for physical quality water are

of worms, such as tropical climate,

odorless, tasteless, colorless, and low levels

environmental

of turbidity. In the observations made,

residence, socio-economic conditions, and

differences in color and level of turbidity

population density15.

were found between schools that used PDAM water and those using well water.

63

sanitation,

place

of


School Soil Contamination

soil can also be carried away by the wind

Soil contamination is a condition where

and stick to food. Students who eat food

the soil contains worm eggs or larvae.

contaminated by worm eggs can develop

Based on the research results, it was found

intestinal worms5.

that

Correlation of Intestinal Worm Infection

the

prevalence

of

school

soil

contamination was 3.7%. The types of

Prevalence and School Hygiene

worm eggs found in soil samples were

Based on the Pearson correlation test,

Ascaris lumbricoides, Hookworm, and

that there was no significant corellation

Toxocara sp. The type of worm eggs that

between the level of school hygiene and the

contaminated the soil the most was Ascaris

incidence of worms in elementary school

lumbricoides, which was 6 samples (55%).

students in Kedungkandang District. This

In their life cycle, Ascaris lumbricoides

shows that the level of hygiene in schools is

eggs require soil media to develop into an

quite good and there are factors that are

infective form, the optimum temperature

more influential on the incidence of worms.

required is around 25˚C5. Malang City has

Although statistically there was no

cool air with an average temperature of

significant

corellation

between

these

25.13 ° C. This shows that Malang City has

variables, it does not mean that the level of

a suitable temperature for the development

school hygiene does not affect the

of Ascaris lumbricoides eggs. 5

incidence of worms in elementary school

Based on the results of the study, it was

students. Based on research conducted on

found that the location where the most

elementary school students in Barrang

worm eggs were found was in the sandbox

Lompo Island, Makassar, the incidence of

with 5 positive samples (45.5%). Loose

intestinal worm infection is influenced by

sand is a good medium for worms to breed.

individual

The sand in the sandbox is also not clear

students, such as the habit of washing hands

where it comes from. This proves that the

with soap, wearing footwear when leaving

soil in the sandbox can be a medium for

the house, cutting nails, and defecating in

worm infection in elementary school

proper place16. The low incidence of

students. Elementary school students also

intestinal

have the habit of buying snacks in front of

Kedungkandang District is also one of the

the school gate, even though in that area

factors that influence the correlation

there is a lot of soil. Dust from the soil can

between variables. So the relationship

be carried away by the wind and

between worms and the level of school

contaminate food. Worm eggs found in the

hygiene leads to an associative relationship

64

hygiene

worm

practices

infection

among

in


(risk factors), not a causative relationship

relationship

(etiological factors).

environment and worm infection17. This

Correlation between Intestinal Worm

shows that sanitation in the school

Infection

environment has a significant effect on the

Prevalence

and

Soil

Contamination

was

the

school

incidence of intestinal worm infection.

Based on the Spearman correlation test, there

between

no

significant

Intestinal

correlation

worm

infection

is

an

environment-based disease caused by poor conditions8.

between school soil contamination and the

environmental

incidence of intestinal worm infection in

adequate sanitation causes the environment

elementary

in

to be contaminated by feces containing

Although

eggs worms. Unhealthy waste disposal

statistically there was no significant

causes worm eggs to easily spread to the

relationship, it does not mean that soil

environment. Therefore we need an effort

pollution has no effect on the intestinal

to clean and sanitize the environment

worm

(sanitation) which can prevent the breeding

school

Kedungkandang

infection

students

District.

rate.

The

highest

Lack

percentage of worms was found in

and spread of these worms in humans.

Bumiayu 4 elementary school (7.69%) and

Study Limitation

of

the highest percentage of soil pollution was

The results of this study could not

also found in Bumiayu 4 elementary school

represent the prevalence of intestinal worm

(20%). This showed that soil pollution had

infection

an effect on worm disease rates. High levels

because it was only done in 12 public

of soil contamination will increase the

elementary schools and also could not

incidence of intestinal worm infection.

represent the prevalence of intestinal worm

Correlation

infections in Malang because it was only

between

the

Intestinal

in

Kedungkandang

Worms Infection Prevalence and School

done in 1 district.

Environmental Sanitation

CONCLUSION

District

Based on the results, it is known that

It can be concluded that the prevalence

there is a significant correlation between

of intestinal worm infection in 12 public

school environmental sanitation and the

elementary schools in Kedungkandang,

incidence of intestinal worm infections in

Malang is low (4.6%) due to high levels of

elementary

sanitation

school

Kedungkandang

students

District.

in

and

low

levels

of

soil

Research

contamination. There is also a relationship

conducted by Salbiah in Medan Belawang

between school’s hygiene level, sanitation,

Subdistrict also showed a significant

and

65

soil

contamination

towards

the


intestinal worm infection incidence in

Veteriner: Edisi Revisi. Universitas

several

Brawijaya Press, 2020.

public

elementary

school

at

Kedungkandang, Malang.

3.

Martila, Martila, Semuel Sandy, and

RECOMMENDATION

Nopita

1. It is necessary to improve Unit

Higiene Perorangan dengan Kejadian

Kesehatan Sekolah (UKS) activities so

Kecacingan pada Murid SD Negeri

that it can facilitate health activities in

Abe Pantai Jayapura." Plasma: Jurnal

schools, such as education about

Kesehatan 1.2 (2015): 87-96.

intestinal worm infection disease and

4.

2. Giving a longer time, approximately 3 so

that

respondents

sanitasi

kelurahan panggung kota Tegal tahun

have

2010.

3. It is necessary to carry out further

Diss.

Universitas

Negeri

Semarang, 2010. 5.

research in private elementary schools

Suriani, Endang, Nuzulia Irawati, and

in addition to public elementary schools

Yuniar

so that the results of the research can

Penyebab Kejadian Kecacingan pada

present one Kedungkandang District or

Anak Sekolah Dasar di Wilayah Kerja

can expand this study to 5 sub-districts

Puskesmas

in Malang so that the results can be

Tahun

more present the condition in Malang.

Andalas 8.4 (2020).

4. It is necessary to collaborate between

6.

Lestari.

"Analisis

Lubuk

Buaya

2017." Jurnal

Veridiana,

Ni

Faktor

Padang

Kesehatan

Nyoman,

Phetisya

schools and local health officials to

Pamela Frederika Sumolang, and Sitti

provide education about worms and

Chadijah. "Hubungan pengetahuan,

preventive measures to prevent worms

perilaku,

Resnhaleksmana

E.

nematoda

golongan

transmitted

dan

sanitasi

lingkungan

dengan angka kecacingan pada anak

REFERENCES

usus

sekolah dasar di kota Palu." Media

Prevalensi

helminthes

Penelitian

soil

dan

Pengembangan

Kesehatan 24.1 (2014): 20695.

(Intestinal 7.

Worm) pada peternak di lingkungan

2.

Silvia. Hubungan

cacingan pada balita di RW 03

sufficient time to collect stool samples.

1.

Altiara,

"Hubungan

lingkungan rumah dengan kejadian

the factors that influence it.

days,

Paembonan.

Lalangpuling, Indra Elisabet, and Elsa

Gatep Kelurahan Ampenan Selatan.

Herdiana. "Hubungan Infeksi Soil

Media Bina Ilmiah. Agustus 2014;8(5)

Transmitted Helminths (STH) Dengan

Sardjono,

Status Gizi Dan Anemia Pada Balita Di

Teguh

al. Helmintologi

Wahju,

Kedokteran

et

Puskesmas

dan

66

Kokar

Kabupaten


Alor." PROSIDING Seminar Nasional

8.

13. BPS Kota Malang. Kesejahteraan;

Tahun 2018 ISBN: 2549-0931. Vol. 1.

Pendidikan;

No. 3. 2018.

http://keckedungkandang.malangkota.

Putra, Rizky N. Hubungan kebiasaan

go.id/kesejahteraan-pendidikan-

mencuci

kesehatan/

tangan

sebelum

makan

dengan kejadian infeksi cacing pada anak

9.

SDN

14. Hairani, Budi. "Keberadaan telur dan larva cacing tambang pada tanah di

Surabayaun. Diss. Wijaya Kusuma

lingkungan Desa Sepunggur dan Desa

Surabaya University, 2019.

Gunung Tinggi Kabupaten Tanah

Ni

Kupang

2011.

V

Veridiana,

Dukuh

Kesehatan.

Nyoman,

Phetisya

Bumbu Kalimantan Selatan tahun

Pamela Frederika Sumolang, and Sitti

2014." Jurnal

Chadijah. "Hubungan pengetahuan,

(2015): 15-20.

perilaku,

dan

sanitasi

lingkungan

15. Kompas.

Vektor

2011.

Penyakit 9.1

http://

www.

dengan angka kecacingan pada anak

sanitasi.or.id/index.php?option=com_

sekolah dasar di kota Palu." Media

content&view=article&id=599:sanitas

Penelitian

idikotamalangmemprihatinkan&catid

dan

Pengembangan

Kesehatan 24.1 (2014): 20695. 10. Kemenkes,

R.

pengendalian Diretorat

I.

=53:kliping&Itemid=124/.

"Pedoman

16. Sumanto, D. Faktor Resiko Infeksi

kecacingan." Jakarta:

Cacing Tambang pada Anak Sekolah.

Jendral

PP

dan

PL,

Program Studi Magister Epidemiologi

Kemenkes (2012). 11. Kundaian,

Pasca Sarjana Universitas Diponerogo.

Friscasari,

Jootje

ML

2010.

Umboh, and Billy J. Kepel. "Hubungan

17. Kudji D. Faktor Yang Mempengaruhi

Antara Sanitasi Lingkungan dengan

Kecacingan

Infestasi Cacing pada Murid Sekolah

Beberapa

Dasar di Desa Teling Kecamatan

Indonesia (Poltekkes

Tombariri

Kupang).2020.

Kabupaten

Minahasa." Kesmas 1.1 (2012): 21-27. 12. World

Health

Organization. WHO

Technical Report of The TDR Disease Reference

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67

Pada

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Di Di

Kemenkes


Assessment of The Effectiveness of the Point-Of-Care Circulating Cathodic Antigen Test as A Diagnostic Tool for Schistosomiasis Infection in Children Under the Age of Six: A Systematic Review Darlene Asafia, Ester Elita Sumbayak, Nadia K. Heryadi

ABSTRACT Introduction: Schistosomiasis, also known as bilharzia, is a parasitic infection caused by the Schistosoma family. This parasite is commonly found around water sources that have been contaminated and polluted, thus allowing the Schistosoma worms to prevail. ³ This disease affects the rural areas due to their dependence on water sources and the lack of education surrounding the disease which includes its cause, transmission and prevention contributes to a high prevalence in schistosomiasis. Even though data show high prevalence of schistosomiasis, there were only a few studies conducted around pediatric schistosomiasis transmission and also the accuracy of its diagnostic tool, especially in infants and preschool-aged children, thus to control such transmission of infections, an alternative method called The Point Of Care Circulating Cathodic Antigen test (POC-CCA) was developed and we wanted to evaluate its sensitivity and specificity in diagnosing schistosomiasis infection in infants and preschool-aged children. ⁵ Materials and Method: In this systematic review that we conducted, we collected our data from an online journal which includes the PubMed and Google Scholar. The systematic analysis or method used in this study, as an example, the PICO method. Result and Discussion: By using the inclusion and exclusion criteria that we have set, we have found 4 relevant articles which consisted of articles conducted by Figueiredo et al, Coulibaly et al, Sassa et al and Armoo et al. These studies showed high sensitivity and specificity given by POCCCA when using it as a diagnostic tool in schistosomiasis infection in children. Conclusion: POC-CCA is an effective diagnostic tool, although more studies must be conducted towards preschool-aged children (PSAC) to further reassure its effectiveness. Keywords: Schistosomiasis, CCA, infants, preschool-aged children

68


Assessment of The Effectiveness of the Point-Of-Care Circulating Cathodic Antigen Test as A Diagnostic Tool for Schistosomiasis Infection in Children Under the Age of Six: A Systematic Review Darlene Asafia, Ester Elita Sumbayak, Nadia K. Heryadi

69


Introduction Schistosomiasis are included in the list of Neglected Tropical Diseases (NTDs) which infects approximately 207 million people. It is a disease caused by the infection of parasites in the Schistosoma family and is usually water-based or water transmitted. Schistosoma worms mainly reside in the bloodstream of the host. The two major types of schistosomiasis are the Schistosoma mansoni, Schistosoma japonicum and Schistosoma meongi caused, which is intestinal schistosomiasis and the urogenital schistosomiasis. ³ Schistosomiasis is a water-based disease, it affects primarily rural areas as they depend on water sources that have a high possibility to be polluted and contaminated, allowing schistosome worms to prevail. Lack of education of the disease including transmissions as well as a hygiene-deprived community also contributes to a high schistosomiasis prevalence. Many studies have been conducted about schistosomiasis, however limited studies about schistosomiasis in children under six years of age were found. Transmission of pediatric schistosomiasis is still in investigation as these children and infants are under strict observation of their guardians. Several hypotheses have been made, including the possible transmission from their mother or guardian in the form of breastmilk or bathing them in contaminated bath water. To control schistosomiasis infections, a reliable diagnostic tool is needed, the standard diagnostic tool is the Kato-Katz technique, however several studies have reported of its lack of efficacy as it underestimates low positivity rates in low parasite burden individuals. An alternative method, which displays high sensitivity and specificity the POC-CCA method was developed. ⁵ The point-of-care circulating cathodic antigen test or the POC-CCA has been deemed as a highly effective diagnostic tool in low endemic areas. POC-CCA uses urine or serum samples and detects antigens for worms, the anodic antigen (CAA) and circulating cathodic antigen (CCA) specifically. This method is easy and simple to use, it does not require a trained or certified individual to conduct it, therefore it is useful in endemic areas. A study has found that the presence of schistosomiasis in children with an age group lower than 10 years old are only diagnosed by the POC-CCA technique whereas it is not detected by the Kato-Katz technique, however in the same study, the Kato-Katz technique diagnosed more positive cases of schistosomiasis in adults 21-40 years of age. POC-CCA scored higher in the sensitivity test. ⁶ These findings lead us to a

70


hypothesis that POC-CCA is a highly effective tool in diagnosing schistosomiasis in children under six years of age. A better understanding of the efficacy of the POC-CCA could lead to a better control and diagnosis of the disease, thus we conducted a systematic review to determine the efficacy of POC-CCA as a schistosomiasis diagnostic tool for children. Methods For our systematic review, we used and collected our data from an online journal which are the Pubmed and Google Scholar, the approach we used on this systematic review are the PICO method and MeSH terminology. For the People or Population (P) we used “Children aged 0-6 years”. For intervention (I) we used the terminology “Circulating Cathodic Antigen or CCA”. For Outcome (O) we used “effective”. The hypothesis in this systematic review is “Is POC-CCA sensitive and specific enough to be an effective diagnostic tool in diagnosing schistosomiasis infection in children age 0-5 years old?”. The inclusion criteria used in this systematic review are cohort study, cross-sectional study, schistosomiasis infection, POC-CCA, children aged 0-6 years old as population. Exclusion criteria are systematic review, meta-analysis, animal study, adult population. Result and Discussion Using the PICO method, we have gathered and thoroughly selected 4 articles that were relevant to be analyzed. The diagram below shows the process of selection

71


Author

Study

Year

Subject

Results

Figueiredo et al.

Retrospective

October/Novem

Children <6

Of the three

1

cohort study

ber 2009; follow

years old in

diagnostic tools,

up

Africa (Sub-

the POC-CCA test

October/Novem

Saharan areas)

displaying a

ber 2010

sensitivity of 66.9%

72


Coulibaly et al. 2

Cohort study

August and

Preschool-aged

POC-CCA

November 2011

children with

displayed a higher

age range 2 -5.5

sensitivity and is

years old in Cote deemed a suitable d’Ivoire

test for rapid diagnosis of schistosomiasis in preschool aged children

Sassa et al.3

Cross-sectional

18 September -

Children of

Out of the 305

study

26 November

Mbita, Western

children, 11 was

2018

Kenya

found positive by the Kato-Katz technique and 276 children was found positive with schistosomiasis by the POC-CCA test.

Armoo et al.4

Cohort study

Second quarter

Children with

CCA assays

of 2017

age range 1-5

displays a higher

years old in

sensitivity due to

Southern Ghana

its ability to detect low CCA antigen levels.

A study by Figueiredo et al.1 took a sample of 925 children below 6 years of age, in Africa around the Sub-saharan areas, with a mean age of 2.8 years and upon follow up out of the initial 925 children, 735 children were recovered.The study compared three diagnostic-tool, the ELISA test which is considered to be a gold standard of diagnosis, the POC-CCA test and faecal

73


microscopy. POC-CCA test has the sensitivity and specificity of 52.5%-63.2% and 57.7%-75.6% whilst the faecal microscopy has a specificity of >87% but the sensitivity of 16.7%, especially in low transmission areas. SEA-ELISA has the specificity of 73.5% and the sensitivity of 78.5%. POC-CCA is deemed as a suitable alternative for the diagnosis of schistosomiasis in pre-school children in low transmission areas as it is a much faster, cost-saving and easy-to-use method without the need of a special laboratory tool such as a microscope and a special training. The results also show POC-CCA is more reliable and more sensitive than the fecal microscopy as a diagnostic tool and especially in mapping initiatives. The study concluded that the POC-CCA test was effective in diagnosing schistosomiasis in children. Coulibaly et al2 investigates the accuracy of the POC-CCA in diagnosing schistosomiasis on 367 preschool-aged children, but complete parasitological data before praziquantel treatment were available for 242 children and three weeks after the treatment or administration of praziquantel, only 86 out of the 242 children had complete parasitological data. The method was done by collecting 2 samples of stool and urine which were obtained before and after given praziquantel treatment. The widely used technique, the Kato-Katz method was found to have a much lower sensitivity than the POC-CCA diagnostic test. This was further proven by the results obtained as quadruplicate Kato-Katz thick smears identified 56 positive children and a single POCCCA identified 83 positive findings of schistosomiasis infections before praziquantel treatments. After the praziquantel treatment the Kato-Katz technique identified 22 positive cases and the POCCCA identified 34 positive infections. The study reached to a conclusion that the Kato-Katz technique has the sensitivity of 28.3% before praziquantel treatment and dropped all the way to 4% after the treatment whilst the POC-CCA test has the sensitivity of 69.7% before the treatment and increases all the way to 80% after the treatment in preschool children. Sassa et al.3 conducted a study with a sample of 305 children under two years of age with an average age of 16.7 months and a higher percentage (51.2%) of the male gender. The children were tested using two diagnostic tools, the Kato-Katz and the POC-CCA where it results in 11 positive outcomes using the Kato-Katz technique and the POC-CCA diagnosed 276 positive schistosomiasis cases, all of the Kato-Katz positive cases were also tested or found to be positive by the POC-CCA test. Samples were collected after obtaining informed consent, the trained research assistants visited the parents or main care-givers with pre-labelled specimen containers

74


and pediatric urine collection bags. Both of the Kato-Katz and POC-CCA methods have a low agreement, with a kappa index of 0.0078 (see Fig.1). A high prevalence percentage of 90.5% was found using the POC-CCA test, however the results obtained could have been the results of a false positive, in which there is a possibility of a cross-reactivity in a POC-CCA test as there are a higher positive case in younger, breastfeeding children. These outcomes could be the results of antigens found in the breast milk; however further studies should be conducted as there are no antigen nor metabolites with a possible reactivity reaction found in these children.

Fig.1 Results using Kato-Katz and POC-CCA technique towards 305 children According to Armoo et al4, with children from ages 1 to 5 years classified as PSAC, there are 190 PSAC from three sampling areas around Weija dam, Southern Ghana. This study was conducted as Cohort study within endemic communities.

The sample areas are Tomefa,

Torgahkope, and Manheam. Weija Dam is the main water source for more than half of 2 million people of Ghana. Each of 190 PSAC were delivers single urine and stool samples. From Tomefa, 63 samples were screened both using Kato-Katz and POC-CCA, 50 were screened using TaqMan qPCR. From Torgahkope/Adakope 69 samples were processed with both Kato-Katz and POCCCA, 60 were screened with TaqMan qPCR. Lastly, there are 58 samples from Manheam that are checked using Kato-Katz and POC-CCA, 50 people screened with TaqMan qPCR. From the samples, POC-CCA was identified as the largest number of positives. In Tomefa, when light/trace are counted, POC-CCA have prevalence 90,5% and when light/trace not included, the prevalence is 57,1%. Based on this study, POC-CCA (with trace result) has the highest prevalence of Schistosomiasis infection. Then, without the trace result POC-CCA can be identical to the result from Kato-Katz and real time PCR. The sensitivity of the urine CCA assay with trace included is 84,1% (95% CI = 72.7–92.1), and 36.5% (95% CI = 24.7–49.6). The specificity for the CCA test was 12.9% (95% CI = 6.6–22) and 76.5% (95% CI = 66–85) when faint/trace bands were included and excluded. Among PSAC 0-1 years old, CCA Assay has the highest number of positives. This study also confirmed CCA assay has a significantly higher diagnostic sensitivity than real-time

75


PCR TaqMan assay and also confirmed that urine CCA assay is able to determine more samples as positive compared to Kato-Katz. Urine CCA assay have high prevalence because this test able to detect low density of CCA antigen that has been released by active adult fluke infections. In conclusion,

CCA

assay

is

more

sensitive

than

the

other

three

assays.

Conclusion Based on the 4 studies that we have analyzed; all of their results show that POC-CCA test have high sensitivity and effectiveness on the diagnosis of schistosomiasis infection in children aged 1-5 years old. However, due to the fact that there are limited studies surrounding the issue of POC-CCA as a diagnostic tool in identifying schistosomiasis infection in children, this raises an urgency of how we still need further study about POC-CCA test on children with preschool age to keep on reassuring its effectiveness and accuracy in diagnosing schistosomiasis infection. References 1.

Sousa-Figueiredo JC, Betson M, Kabatereine NB, Stothard JR. The Urine Circulating Cathodic Antigen (CCA) Dipstick: A Valid Substitute for Microscopy for Mapping and Point-Of-Care Diagnosis of Intestinal Schistosomiasis. PLoS Negl Trop Dis. 2013;7(1).

2.

Coulibaly JT, N’Gbesso YK, Knopp S, N’Guessan NA, Silué KD, van Dam GJ, et al. Accuracy of Urine Circulating Cathodic Antigen Test for the Diagnosis of Schistosoma mansoni in Preschool-Aged Children before and after Treatment. PLoS Negl Trop Dis. 2013;7(3).

3.

Sassa M, Chadeka EA, Cheruiyot NB, Tanaka M, Moriyasu T, Kaneko S, et al. Prevalence and risk factors of schistosoma mansoni infection among children under two years of age in Mbita, Western Kenya. PLoS Negl Trop Dis [Internet]. 2020;14(8):1–17. Available from: http://dx.doi.org/10.1371/journal.pntd.0008473

4.

Armoo S, Cunningham LJ, Campbell SJ, Aboagye FT, Boampong FK, Hamidu BA, et al. Detecting Schistosoma mansoni infections among pre-school-aged children in southern Ghana: A diagnostic comparison of urine-CCA, real-time PCR and Kato-Katz assays. BMC Infect Dis. 2020;20(1):1–10.

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5.

Ekpo UF, Oluwole AS, Abe EM, Etta HE, Olamiju F, Mafiana CF. Schistosomiasis in infants and pre-school-aged children in sub-Saharan Africa: implication for control. 2012;

6.

Rodrigo S, Sousa M De, Helena I, Dias L, Luan Á, Fonseca S, et al. Concordance of the point-of-care circulating cathodic antigen test for the diagnosis of intestinal schistosomiasis in a low endemicity area. Infect Dis Poverty. 2019;7:1–9.

77


Mapping of Soil-Transmitted Helminth Infection Prevalence and Its Relationship with Students’ Knowledge, Soil Contamination at Home and School in Public Elementary School Kedungkandang, Malang Brenda Kristi1*, Amandus Michael Martin1, Vincentius Mario Yusuf1 1

Undergraduate student, Faculty of Medicine, Universitas Brawijaya, Malang, East Java, Indonesia *brendakristi2000@gmail.com

ABSTRACT (Introduction)Soil-transmitted helminth(STH) infection is still one of the health problem in Indonesia dominated by primary school children group with its high prevalence between 6080%. However STH infection is still considered as neglected disease even though it can lead to serious conditions. Moreover the data about STH infection is still lacking especially in Malang. Knowledge about STH infection and soil contamination are some of its risk factors. This study aims to find out the epidemiology data and the relationship between students’ knowledge, soil contamination at home and school toward the STH infection incidence in several public elementary school at Kedungkandang, Malang. (Methods)This research was a descriptive and analytical study with cross sectional design from June-December 2019. Subjects were 110 students from 12 public elementary school at Kedungkandang, Malang obtained by using systematic random sampling technique based on the inclusion and exclusion criteria. Questionnaire containing questions was used to assess students’ knowledge regarding STH infection. It had been tested for its validity and reliability. Stool examination was done by using Kato thick smear method while soil at home and school examination was done by using modification of Suzuki method. (Results)Univariate analysis had shown 29% positive STH infection incidence with the types of worms found were A. lumbricoides(80%), Hookworm, T. trichiura, and H. nana. Students’ knowledge(p=0.031) and soil contamination at home(p=0.039) had a significant relationship with the STH infection incidence. Meanwhile, soil contamination at school had insignificant relationship with the STH infection incidence(p=0.259). Students' knowledge, soil contamination at home and school had a positive and significant relationship with STH infection incidence(r=0.395,p=0.036) around 15.6%. (Conclusion)The prevalence of STH infection among elementary school is still quite high. There is also a relationship between student knowledge, soil contamination at home and school environment towards the STH infection incidence in several public elementary school at Kedungkandang, Malang. Keyword: STH infection, students’ knowledge, soil contamination

78


Mapping of Soil-Transmitted Helminth Infection Prevalence and Its Relationship with Students’ Knowledge, Soil Contamination at Home and School in Elementary School Kedungkandang, Malang

Authors : Brenda Kristi Amandus Michael Martin Vincentius Mario Yusuf

Faculty of Medicine Universitas Brawijaya Asian Medical Students’ Association Indonesia 2020

79


home yard[4]. Approximately 5.6% Ascaris

INTRODUCTION World Health Organization (WHO)

lumbricoides eggs were also found in the

stated that there are approximately 1.5

yard at the Paseh District, Bandung[4]. From

billion people infected with soil-transmitted

the results of soil examination around

helminth (STH) worldwide. The number of

houses at 3 RT in Patemon Village,

STH in Indonesia is still quite high, around

Semarang, 46.15% STH eggs were found[4].

60-80% of total population, which is

Soil contamination in Samosir Island,

dominated by elementary school students

North Sumatra by Ascaris lumbricoides

and people with low economic profile. The

eggs was 30.24%[4]. Study in Suka Village,

high prevalence of this disease is not taken

Tanah Karo Regency found that 45.8% of

seriously, so that it is known as chronic

Ascaris lumbricoides eggs exposed to the

neglected disease with effects ranging from

soil before being given treatment and after

mild to severe such as nausea, decreased

1 year of treatment, it decreased to 10.4%[4].

appetite, diarrhea, anal itching, anemia,

The behavior of children who tend to

impairment of cognitive function, growth,

buy unhygienic snack, frequent contact

and development, intestinal obstruction,

with the soil, walk with barefoot, defecate

malnutrition and Loeffler syndrome[1].

inappropriately, and uncontrolled hygiene

STH infection is strongly influenced by

cause rapid spread of STH infection. The

the environment condition due to its

study in Waiheru village, Ambon city,

transmission

soil

showed that 76.3% STH was found in the

contaminated by feces. There are 5 types of

feces of farmers (106 respondents) with

Soil Transmitted Helminth (STH), such as

100% type of Ancylostoma duodenale with

Ascaris

Ancylostoma

the highest eggs number of 6 -10 (36%), the

americanus,

level of farmers' knowledge is still low

Strongyloides stercoralis, and Trichuris

54.7%, negative attitudes 55.4%, and

trichiura[3]. Fertilized eggs under favorable

unfavorable actions 64.7%. There is a

environmental conditions will develop into

tendency for the lower knowledge, negative

infective eggs within a certain period of

attitudes and unfavorable actions, the

time. Humans can become infected by

greater the number of eggs found[5].

duodenale,

mainly

lumbricoides, Necator

through

infective eggs through direct contact with

Knowledge about STH infection is very

the hands and fecal-oral transmission[4].

important because it can influence attitude

Study conducted in Pisangan Baru

and behavior to prevent it. This study aims

Village, East Jakarta, which found 18.0% of

to find out the epidemiology data and the

Ascaris lumbricoides eggs in villagers’

relationship between students’ knowledge,

80


soil contamination at home and school

This study was conducted for 6 months

toward the STH infection incidence in

from June-December 2019 at Parasitology

several

at

laboratory, Faculty of Medicine Universitas

Kedungkandang, Malang due to its high

Brawijaya Malang and several public

prevalence based on previous study. so that

elementary school at

the government can take more action to

Malang.

control this disease.

Procedure

MATERIALS AND METHODS

1. Questionnaire containing questions was

public

elementary

school

Kedungkandang,

used to assess students’ knowledge

Research Design This research was a descriptive and

regarding signs and symptoms of STH

analytical study with cross sectional design.

infection, ways of transmission and

Population dan Sample

prevention, types of worms that infect

The population in this study were all

humans, and the proper hand washing

students in 12 public elementary school at

technique. Body weight and height were

Kedungkandang,

study

also measured. The questionnaire had

samples were 110 students obtained by

been tested for its validity and reliability

using

(see appendix 2).

Malang.

systematic

The

random

sampling

technique based on the inclusion and

2. Qualitative Laboratory Examination

exclusion criteria. The inclusion criteria

• Kato thick Smear method for stool

were students who were willing to be study

examination[6].

subjects and submitting their feces, parents

Cellophane tape (3x6 cm) was soaked in

of students and schools willing to have their

Malatchite-green solution for at least 24

land sampled and examined. The exclusion

hours. Stool (± 5 gr) was placed on oiled

criteria

samples,

paper, gauze was placed on top of the

respondents who changed their address, and

stool, then pressed, filtering the stool

were not in Malang for a significant amount

through the gauze. The preparation was

of time. School selection was done by

left at room temperature for 30 minutes.

Public Health Department and Education

Lastly, the cellophane tape was examined

Department

using

were

in

damaged

Malang.

Furthermore,

microscope

with

400x

randomization was carried out to obtain the

magnification to see the presence of

interval number. Then samples were

worms. • Modification of Suzuki Method for Soil

determined based on multiples of the

Inspection[4].

interval number obtained (see appendix 1). Location and Time

81


Soil samples at home were taken from 4

Study Data Analysis

locations outside the house (right, left,

Software SPSS 22.0 was used to analyze

front, back) and inside the house, as well

data. All data were served as mean ± SD

as from the school which were taken

and analyzed using univariate analysis, Chi

from plant pots, sandbox, canteen, and in

Square, Multiple Correlation Test. Result

front of the school gate. The surface of

was considered statistically significant if

the soil then was scrapped and put into

p<0.05.

different plastic bags according to the

RESULTS AND DISCUSSION

location and labeled. Soil samples were

Basic Characteristic

cleaned from gravel and leaves. Then 5

The age of the study respondents ranged

grams of soil were taken and put into

from 8-12 years. Most of the respondents

centrifuge

30%

were 9 years old, as many as 43 students

(Ca(ClO)2) hypochlorite solution was

(39%). While 12 years olds were the least

added into the tube and stirred with a

respondents, as many as 7 students (6%).

steering rod then left for one hour.

Male

Centrifuge at the speed of 2000 rpm was

(48,18%) and female respondents were 57

done for about 2 minutes for 2 times then

students (51,82%). Most of the respondents

the supernatant liquid was discarded. The

came from grade 3 and 4, as many as 40

sample was stirred again using steering

students

rod

respondents came from grade 5, as many as

and

tube.

MgSO4

20

ml

was

of

added

to

respondents

were

(36,4%),

while

53

students

the

approximately ¾ of the tube volume.

30 students (27,2%). (see appendix 3).

Next the centrifuge was done at a speed

Univariate Analysis

least

The results of the univariate analysis can

of 2500 rpm for 5 minutes. MgSO4

be seen in tables 1,2,3,4.

solution with BJ 1.260 was added to the

Table 1. Frequency Distribution of STH

centrifuge tube until the tube surface was

infection incidence

slightly inflated then left for a few minutes. Sample was covered using cover glass for 30 minutes. Cover glass was put on the object glass. Eosin was added as a colorant if necessary. The preparation was then examined under a

Types of worm eggs found were A.

microscope and the eggs/larvae of

lumbricoides

intestinal worms were identified.

(80%),

Hookworm,

T.

trichiura, and H. nana. These results were

82


supported by previous study in Indonesia

Bivariate Analysis

which stated that the prevalence of STH

The results of the bivariate analysis can

infection was dominated by elementary

be seen in tables 5, 6, and 7. Table 5. Cross Tabulation between Students'

school students and poor people with the types

of

worms

lumbricoides,

T.

found

were

trichiura,

Knowledge with The Incidence of STH Infection

A. and

Hookworm[2,7]. Table 2. Frequency Distribution of Student Knowledge

Chi Square Test results (see appendix 4) showed low students’ knowledge can Table 3. Frequency Distribution of Soil

significantly increase the incidence of STH

Contamination at Home

infection (p=0.031). These findings were not in accordance with previous study in Palu which stated that there was no significant relationship between knowledge and STH infection because the majority of the sample did not know about STH infection with 31% infected[8]. Meanwhile,

Only 54 houses met the inclusion

our study showed that 102 out of 110

criteria, with the highest number of eggs

samples

found were A. lumbricoides with a total of

had

understood

about

STH

infection and how to prevent it, with 29%

11 eggs. (44%).

of students infected.

Table 4. Frequency Distribution of Soil

Based on the logistic regression test, the

Contamination at School

contribution of the relationship between student knowledge and the incidence of STH infection was 4.2%. The factors that influence knowledge, including education, exposure to the mass media, and socioeconomics. Preventive behavior based on

From the 12 schools, 5 eggs were found

knowledge and awareness needs to be

in the sandbox (45.5%) which were used for

repeated in order to form a habit[9].

sports and playing.

83


Table 6. Cross Tabulation between Soil

in the incidence of STH infection (p =

Contamination at Home with the Incidence of

0.255). This could happen because not all

STH Infection

students had direct contact at the sampling site whereas prevention can be done by the use of footwear, good habits and knowledge of worm infections. Based on the logistic regression test, the contribution of the relationship between

Chi Square Test results (see appendix 5)

soil contamination at home and the

showed positive soil contamination at home

incidence of STH infection was 1.2%.

can cause a significant increase in the

Multivariate Analysis

incidence of STH infection (p = 0.038).

The results of the multivariate analysis

This is similar to previous study in South Kalimantan

where

the

rate

of

could be seen in tables 8, 9, 10, 11, 12, 13,

soil

and 14. The descriptive statistic can be seen

contamination at home by A. lumbricoides

in appendix 7.

eggs reached more than 70%.

Table 8. Double Correlation between Students’

Based on the logistic regression test, the

Knowledge and Soil Contamination at Home

contribution of the relationship between

toward STH Infection

soil contamination at home and the incidence of STH infection was 7.9%. This was due to the high knowledge of students which

can

influence

the

preventive

behavior of egg transmission. Table 7. Cross Tabulation between Soil Contamination at Schools with The Incidence of STH infection

From 2-tailed correlation, it was proven that students’ knowledge had significant relationship to the STH infection (sig.[2tailed] = 0.031). 2-tailed correlation of soil contamination at home with the STH

Chi Square Test results (see appendix 6)

infection incidence also had significant

showed positive soil contamination in

relationship (sig. [2-tailed] = 0.039).

schools can cause an insignificant increase

84


Table 9. Contribution of Students’ Knowledge

From 2-tailed correlation, it was proven

and Soil Contamination at Home toward STH

that students’ knowledge had significant

Infection Incidence

R

R Square

relationship to the STH infection (sig.[2-

Sig. F

tailed] = 0.031). 2-tailed correlation of soil

Change 0,384

0,148

Students'

knowledge

contamination at school with the STH

0,017

infection incidence didn’t have significant soil

and

relationship (sig. [2-tailed] = 0.259).

contamination at home had a positive and

Table 11. Contribution of Students’ Knowledge

significant relationship with STH infection

and Soil Contamination at School towards STH

incidence (r = 0.384, p = 0.017) around

Infection Incidence

14.8%.

This

occurred

due

to

R

high

R Square

Sig. F Change

knowledge and awareness in maintaining health from contaminated environment.

0,222

0,049

This result were not in accordance with the

Students'

knowledge

0,068 and

soil

previous study which stated that there was

contamination at school had a positive and

no significant relationship between the

insignificant

prevalence

of

with

STH

infection

with

infection incidence (r = 0.222, p = 0.068)

and

the

around 4.9%. This occurred due to high

environment[3].This occurred due to 75% of

students' knowledge about STH infections

students with high knowledge were in a

without awareness of prevention. Good

contaminated environment, whereas this

personal hygiene habits could prevent

study found that only 31.5% of students

transmission despite low knowledge about

with

STH infections.

knowledge

STH

relationship

level

high

knowledge

were

in

a

contaminated environment.

Table 12. Double Correlation between Soil

Table 10. Double Correlation between Students’

Contamination at Home and School toward

Knowledge and Soil Contamination at School

STH Infection

toward STH Infection

85


Soil

contamination

significant

relationship

at to

home

had

the

STH

with soil. Study Limitation

infection incidence (sig.[2-tailed] = 0.039).

This research was only conducted on

Meanwhile, contamination of soil at school

three risk factors that caused the STH

had no significant relationship with the

infection incidence which were students'

STH infection incidence (sig.[2-tailed] =

knowledge, soil contamination at home and

0.259).

school so that researcher could not analyze

Table 13. Contribution of Soil Contamination at

the relationship with the STH infection

Home and School towards STH Infection

incidence as a whole.

Incidence

R

R Square

CONCLUSION Sig. F

The prevalence of STH infection among

Change 0,310

0,096

elementary school is still quite high. There

0,077

is also a relationship between student

Soil contamination at home and school

knowledge, soil contamination at home and

had a positive and insignificant relationship

school environment towards the STH

with STH infection incidence (r = 0.310, p

infection incidence in several public

= 0.077) around 9.6%. This occurred due to

elementary school at Kedungkandang,

students which infected with STH from

Malang.

other playgrounds or infected students

RECOMMENDATION

which did not contaminate their home

Cooperation between Public Health

environment with feces containing eggs.

Office

Table 14. Contribution of Students’ Knowledge,

preventing

Soil Contamination at Home and School

0,395

R Square

0,156

school the

is

important

transmission

of

in

STH

infection. The STH infection-free program

towards STH Infection Incidence

R

and

includes

Sig. F

comprehensive

and

periodic

Change

socialization and inspection, maintaining

0,036

hygienicity of food and beverages, “Jamban

Students' knowledge, soil contamination

Sehat” program, and waste management. In

at home and school had a positive and

addition, it is necessary to conduct further

significant relationship with STH infection

research on other risk factors that can

incidence (r = 0.395, p = 0.036) around

contribute to STH infection. Hopefully, this

15.6%. This occurred due to high students'

can reduce the prevalence of this neglected

knowledge about STH infections that could

tropical infectious disease.

reduce bad habits such as direct contact

86


REFERENCES 1. WHO.

6.

Soil-transmitted

Helminth

parasit usus pada anak sekolah dasar di

Infections (https://www.who.int/news-

pesisir

room/fact-sheets/detail/soil-transmitted-

Kabupaten Minahasa Utara. eBiomedik.

helminth-infections). 2020

2016;4(1).

2. Kundaian F, Umboh JM, Kepel BJ.

7.

Wori

Sandy S, Irmanto M. Analisis model

dengan Infestasi Cacing pada Murid

(Ascaris lumbricoides) pada murid SD

Sekolah

di Distrik Arso Kabupaten Keerom

Dasar

di

Desa

Kecamatan

Tombariri

Minahasa.

Kesmas.

Teling

Kabupaten 2012

Papua. Jurnal Buski. 2014;5(1):21398.

Jan

8.

Sumolang PP, Chadijah S. Hubungan

31;1(1):21-7.Diktat

Parasitologi

pengetahuan, perilaku, dan sanitasi

Laboratorium

Kedokteran

lingkungan dengan angka kecacingan

Sardjono,

Fakultas

pada anak sekolah dasar di kota Palu.

T.W.,

and

Baskoro,

Nugraha,

2020. Helmintologi

A.D.,

Media Penelitian dan Pengembangan Kesehatan. 2014 Mar;24(1):20695.

R.Y.B.,

Arisandi D, Sohy SR, Nadifah F.

dan

Identification of Malaria Parasites in

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Chasan Boesoirie General Hospital

Brawijaya Press.

Ternate East Nusa Tenggara. Journal of

Dewi,

Kedokteran

9.

N.L.G.D.R.

and

Laksmi,

Health (JoH). 2016 Jan 31;3(1):39-

D.A.A.S., 2017. Hubungan Perilaku

44.Veridiana NN.

Higienitas Diri Dan Sanitasi Sekolah Dengan

Infeksi

Soil

Transmitted

Helminths Pada Siswa Kelas III-VI Sekolah Dasar Negeri No. 5 Delod Peken Tabanan Tahun 2014. E-Jurnal Medika Udayana, 6(5). 5.

Kecamatan

faktor risiko infeksi cacing gelang

Endharti, A.T., Fitri, L.E., Poeranto, S.

4.

pantai

Hubungan Antara Sanitasi Lingkungan

Brawijaya. 2011. 3.

Tangel F, Tuda JS, Pijoh VD. Infeksi

Selomo M, Ruslan JA. Gambaran Parasit Soil Transmitted Helminths dan Tingkat

Pengetahuan,

Sikap

serta

Tindakan Petani Sayur di Desa Waiheru Kecamatan

Baguala

Kota

Ambon.

Makassar: Universitas Hasanudin. 2013.

87


APPENDICES Appendix 1. Number of Control Groups for Each School (n=78)

Number of Case Groups for Each School (n=32)

Appendix 2. Validity Questionnare Number

r count

r table

Keputusan

No.1

,444

>0,666

Valid

No.2

,367

>0,666

Valid

No.3

,333

>0,666

Valid

No.4

,509

>0,666

Valid

No.5

,473

>0,666

Valid

No.6

,580

>0,666

Valid

No.7

,567

>0,666

Valid

No.8

,425

>0,666

Valid

No.9

,362

>0,666

Valid

No.10

,516

>0,666

Valid

No.11

,386

>0,666

Valid

No.12

,449

>0,666

Valid

No.13

,477

>0,666

Valid

No.14

,409

>0,666

Valid

No.15

,413

>0,666

Valid

No.16

,498

>0,666

Valid

No.17

,359

>0,666

Valid

88


No.18

,402

>0,666

Valid

No.19

,477

>0,666

Valid

No.20

,281

>0,666

Valid

Reliability Statistics

Part 1

Cronbach's Alpha

Value

,757

N of Items

10a

Value

,721

Part 2 N of Items

10b 20

Total N of Items

,698

Correlation Between Forms Spearman-Brown

Equal Length

Coefficient Guttman

Unequal Length

,822 ,822 ,821

Split-Half Coefficient a. The items are: no.1, no.2, no.3, no.4, no.5, no.6, no.7, no.8, no.9, no.10. b. The items are: no.11, no.12, no.13, no.14, no.15, no.16, no.17, no.18, no.19, no.20.

Appendix 3. Distribution of Study Subjects by Age Respondents

Amount of

Percentage

Age(Year)

Respondents

8

12

11 %

9

43

39%

10

25

22%

11

25

22%

12

7

6%

Total

110

100 %

Distribution of Study Subjects by Gender Gender

Amount of

Percentage

Respondents Male

53

48,18 %

Female

57

51,82 %

Total

110

100 %

89


Distribution of Study Subjects by Grade Grade

Amount of

Percentage

Respondents 3

40

36,4 %

4

40

36,4 %

5

30

27,2 %

Total

110

100 %

Appendix 4. Chi Square Test of Students' Knowledge and Incidence of STH Infection Asy mp. Sig. Exact Sig. Value Pearson Chi-Square Continuity Correction Likelihood Ratio

a

df

(2-sided)

4.668b

1

.031

3.085

1

.079

4.171

1

.041

Fisher's Exact Test Linear-by-Linear

4.626

1

Exact Sig.

(2-sided)

(1-sided)

.045

.045

.031

Association N of Valid Cases

110

Appendix 5. Chi Square Test of Soil Pollution at Home and Incidence of STH Infection Value

Pearson Chi-Square

df

Asymp. Sig.

Exact Sig.

Exact Sig.

(2-sided)

(2-sided)

(1-sided)

4,293a

1

,038

Continuity Correctionb

3,101

1

,078

Likelihood Ratio

4,181

1

,041

Fisher's Exact Test

,061

Linear-by-Linear Association N of Valid Cases

4,213

1

54

90

,040

,040


Appendix 6. Chi Square Test of Soil Pollution at School and Incidence of STH Infection

Value Pearson Chi-Square Continuity Correction

df

Asy mp. Sig.

Exact Sig.

Exact Sig.

(2-sided)

(2-sided)

(1-sided)

.297

.177

1.294b

1

.255

.861

1

.354

1.301

1

.254

a

Likelihood Ratio Fisher's Exact Test Linear-by-Linear

1.282

1

.257

Association N of Valid Cases

110

Appendix 7. Statistic Descriptive Analysis of Students’ Knowledge, Soil Contamination at Home and School towards STH infection incidence Mean

SD

N

Students’ knowledge

0.93

0.261

110

Soil contamination at home

0.31

0.469

54

Soil contamination at school

0.49

0.502

110

STH infection incidence

0.29

0.456

110

Appendix 8. Questionnare KUISIONER PENELITIAN TERKAIT DENGAN KEJADIAN KECACINGAN PADA SISWA SEKOLAH DASAR NEGERI KECAMATAN KEDUNGKANDANG KOTA MALANG TAHUN 2019 Oleh : Mahasiswa Pendidikan Dokter 2018 Fakultas Kedokteran Universitas Brawijaya Petunjuk pengisian : Isilah titik-titik dan pilihlah jawaban yang benar dengan tanda silang (X) A. IDENTITAS RESPONDEN 1.

Nomor Responden

: ……………………………………………

2.

Nama Siswa

: ……………………………………...…….

3.

Sekolah

: ……………………………………………

91


4.

Kelas

: ……………………………………………

5.

Usia Siswa

: ……………………………………………

6.

Nama Ibu

: ……………………………………………

Usia

: ……………………………………………

Pendidikan

:a. Tidak tamat SD b. Tamat SD c. Tamat SLTP/ se-derajat d. Tamat SLTA/ se-derajat e. Tamat perguruan tinggi

Pekerjaan 7.

Nama Ayah

: …………………………………………… : ……………………………………………

Usia

: ………………………………………..….

Pendidikan

: a. Tidak tamat SD b. Tamat SD c. Tamat SLTP/ se-derajat d. Tamat SLTA/ se-derajat e. Tamat perguruan tinggi

Pekerjaan

: ……………………………………………

8.

Jumlah anak

: ……………………………………………

9.

Alamat

: ……………………………………………

10. Nomor Telpon

: ……………………………………………

11. Luas rumah

: ……………………………………………

12. Jumlah penghuni rumah

: …………………………………………...

B. PENGETAHUAN SISWA (filled by student) Jawablah pernyataan dibawah ini sesuai dengan pengetahuan adik 1.

Seseorang dapat terinfeksi kecacingan:

92


a. Benar 2.

b. Salah

Telur cacing atau cacing tidak dapat masuk melalui tangan/ kaki: a. Benar

3.

b. Salah

Bibit penyakit cacing/ telur cacing dapat masuk melalui makanan yang dimakan: a. Benar

4.

b. Salah

Kecacingan bisa disebabkan karena tangan yang kotor: a. Benar

5.

b. Salah

Bermain ditanah tanpa sandal tidak akan menyebabkan terkena penyakit kecacingan: a. Benar

6.

b. Salah

Kecacingan bisa disebabkan karena memakan makanan yang kotor: a. Benar

7.

b. Salah

Kecacingan bisa disebabkan karena lingkungan yang kotor: a. Benar

8.

b. Salah

Bermain disungai tidak akan menyebabkan seseorang terkena penyakit kecacingan: a. Benar

9.

b. Salah

Kecacingan bisa menyebabkan seseorang mengalami kekurangan darah: a. Benar

b. Salah

10. Kecacingan bisa menyebabkan seseorang mengalami kekurangan gizi: a. Benar

b. Salah

11. Penyakit kecacingan tidak akan mengurangi selera makan seseorang: a. Benar

b. Salah

12. Kecacingan bisa menyebabkan seseorang menjadi malas, bodoh dan kurus: a. Benar

b. Salah

13. Makan-makanan yang bersih dan matang dapat mencegah kecacingan: a. Benar

b. Salah

14. Kebiasaan seseorang untuk mandi, tidak ada hubungannya dengan pencegahan kecacingan:

93


a. Benar

b. Salah

15. Buang air besar di WC dapat mencegah kecacingan: a. Benar

b. Salah

16. Cuci tangan sebelum makan dapat mencegah kecacingan: a. Benar

b. Salah

17. Cuci tangan hanya dengan air tanpa menggunakan sabun sudah cukup untuk mencegah kecacingan: a. Benar

b. Salah

18. Memakai sandal bila keluar rumah/WC dapat mencegah kecacingan: a. Benar

b. Salah

19. Memotong kuku satu minggu sekali dapat mencegah kecacingan: a. Benar

b. Salah

20. Mengonsumsi obat cacing sekali seumur hidup, dapat mencegah kecacingan: a.Benar

b. Salah

94


Informed Consent LEMBAR PERNYATAAN KESEDIAAN SEBAGAI SUBYEK PENELITIAN Dengan ini saya menyatakan bersedia menjadi subyek penelitian terkait dengan kejadian kecacingan pada siswa sekolah dasar negeri Kecamatan Kedungkandang Kota Malang tahun 2019. No. Subyek: 1.

Saya telah membaca Lembar Informasi penelitian ini dan telah menerima latar belakang, tujuan, jangka waktu beserta risiko penelitian serta peranan saya dalam penelitian ini

2.

Saya telah mengambil waktu untuk memikirkan keikutsertaan saya. Pertanyaan saya telah dijawab dengan memuaskan dan saya telah menerima satu kopi Lembar Informasi

3.

Saya mengerti bahwa keikutsertaan saya bersifat sukarela, atas pilihan saya sendiri dan saya dapat menolak atau mengundurkan diri dari penelitian ini setiap saat dan tidak akan memengaruhi kesehatan saya

4.

Saya akan segera menghubungi peneliti bila saya mengalami suatu gejala yang tidak biasa atau tidak diharapkan selama penelitian. Saya juga memahami bila ada informasi lain yang dapat memengaruhi keikutsertaan saya dalam penelitian ini akan segera disampaikan kepada saya

5.

Saya menyadari bahwa bila saya tidak bekerja sama penuh sesuai permintaan dan petunjuk peneliti, saya akan menerima risikonya

Malang, Peneliti

Yang membuat pernyataan

NIM. Saksi I,

Saksi II,

95


IMSTC 2021

ASSOCIATION OF LEPROSY-RELATED BURDEN TO MENTAL HEALTH PROBLEMS OF LEPROSY PATIENTS FOR BETTER MANAGEMENT OF LEPROSY: A SYSTEMATIC REVIEW

Authors: Rizqiko Pandai Hamukti

(21286)

Ketut Shri Satya Wiwekananda (21269) Ketut Shri Satya Yogananda

(21270)

AMSA-UNIVERSITAS GADJAH MADA 2020

97


ABSTRACT Introduction Leprosy is a chronic infectious disease caused by Mycobacterium leprae. Indonesia is the country with the third largest leprosy case in the world. Leprosy management guideline by the Ministry of Health Republic Indonesia still do not pay attention to the mental health problems of leprosy patients. Meanwhile, leprosy patients experience serious illness, disabilities, get a bad stigma, being discriminated, rejected from society, and also get a problem at work, which may affect their mental health. Therefore, this paper aimed to systematically review the association between leprosy-related burden with mental health problems of leprosy patient. Materials & Method This systematic review was based on PRISMA statement’s flow diagram and checklist to enhance the report quality and only included cross-sectional studies. This systematic review was conducted on 4 databases. The keywords used are: (depression OR "mental health" OR anxiety) AND (leprosy OR "Hansen disease" OR "lepra disease"). Result & Discussion A total of 10 articles were obtained, all of which showed a strong association between leprosy-related burden and mental health problems of leprosy patients. Mental health problems that often arise are depression, anxiety, suicidal thought, and poor mental wellbeing. Factors that can cause mental health problems from leprosy patients are disability, neuropathic pain, stigma and discrimination, unemployment, and also gender. There are still few studies intervention on this area. Based on previous intervention, reminiscence therapy has been shown to reduce stress, while community education has been shown to reduce discrimination in leprosy patients. Conclusion It was concluded that leprosy-related burden was significantly associated with mental health problems. There are few primary studies related to interventions aimed at the mental health of leprosy patients. Therefore, primary studies that discuss mental health-related interventions in leprosy patients are needed. For practice, comprehensive leprosy management must ensure psychological wellbeing for better management of leprosy.

98


IMSTC 2021

ASSOCIATION OF LEPROSY-RELATED BURDEN TO MENTAL HEALTH PROBLEMS OF LEPROSY PATIENTS FOR BETTER MANAGEMENT OF LEPROSY: A SYSTEMATIC REVIEW

Authors: Rizqiko Pandai Hamukti

(21286)

Ketut Shri Satya Wiwekananda (21269) Ketut Shri Satya Yogananda

(21270)

AMSA-UNIVERSITAS GADJAH MADA 2020

99


INTRODUCTION Leprosy is a chronic infectious disease caused by Mycobacterium leprae, also known as Hansen's disease. The disease primarily affects the skin, and also the peripheral nerves, the upper respiratory tract's mucosal surfaces, and the eyes. It is understood that leprosy occurs at all ages, from early childhood to very old age. Leprosy is curable and disability can be avoided by therapy in the early stages1. World Health Organization (WHO) data showed a prevalence of leprosy of 2 per 100,000 people, with 208,619 new cases occurring in 20182. Leprosy cases in Indonesia rank third in the world after India and Brazil, with the number of new leprosy sufferers in 2017 reaching 15,910 people, the discovery rate of new leprosy sufferers is 6.07 per 100,000 population. Based on Regulation of the Health Ministry of the Republic of Indonesia Number 11 of 2019, leprosy prevention serves to reduce the number of morbidities and break the chain of leprosy transmission. Article 6 paragraph (2), states that the prevention and control of leprosy include health promotion, surveillance, chemoprophylaxis, and management of leprosy sufferers3. In this guideline, the management of leprosy treatment in Indonesia still does not pay attention to the mental disorder experienced by leprosy sufferers, whereas health is not only about physical health but also mental health. The fact is, leprosy patients experience serious illness, disabilities, get a bad stigma, being discriminated, rejected from society, and also get a problem at work, which may affect their mental health4. The association between leprosy and the patient’s mental health was not clear yet. For this reason, the authors systematically review studies addressing the association between leprosy and the patient's mental health. Hence in the future can be used as the basis for better leprosy management.

MATERIALS & METHOD Author carried out systematic review based on PRISMA statement’s flow diagram and checklist to enhance the report quality. PRISMA statement consists of 27 items checklist and four-phases flow diagram5. The item of checklist was considered vital for transparent of systematic review reporting. A. Data Collection Technique Search Strategy The systematic review was conducted on 4 databases, e.g., PubMed, Scopus, Cochrane Library, and EBSCOhost. A set of keywords were used to find articles that

100


discuss the impact of leprosy on depression experienced by patients, for instance: (depression OR "mental health" OR anxiety) AND (leprosy OR "Hansen disease" OR "lepra disease"). Study Selection The included studies fulfilled several inclusion criteria. Authors used PICO model for inclusion criteria. The participants of studies must be leprosy patients; the intervention or exposure must be about mental health screening; the context must be in community or in hospitals; and the aim of the research should be related to mental health problems experienced by the patients. The author only includes cross-sectional method, because this method explains the relationship between exposure to study participants (leprosy-related burden on lepers) and outcome (mental health problems of lepers) which corresponding with the purpose of this study6. The study would be excluded if the studies are not written in English; was inaccessible; and published before 2010. The authors applied a considerable time limit to find the most relevant studies. In addition, review papers were also excluded. Risk of Bias Assessment This review assigned two reviewers to evaluate all included studies independently. This method was considered as reviewer triangulation, to avoid reviewer bias7. Both reviewers also evaluate the journals using a critical appraisal checklist from the Joanna Briggs Institute's critical appraisal tools, a validated quality appraisal tool that consist of 8 criteria8. If in the journals there was an explanation of the criteria requested from the appraisal tools and these criteria are fulfilled, then 1 point is added for each of these criteria. When the total point was ≥ 6 points, it was assessed as high quality and then the journal was included in data extraction and synthesis. B. Data Analysis Data from included studies were then extracted to obtain data about the impact of leprosy toward the patient’s depression. Eligible studies were reviewed and the following data were extracted: author’s name, year of publication, method, sample size, mean age, valid tools used, leprosy-related burden and measured outcome. Subsequently, obtained data were analyzed using descriptive statistical methods and summarized the findings of these studies. C. Literature Search Timeframe The literature search was conducted from November 2020 to December 2020.

101


RESULT & DISCUSSION RESULT A. Study Search Result

Figure 1. PRISMA Flow Chart Diagram The literature search and selection process are illustrated in Figure 1. A total of 221 articles were retrieved from four databases, 173 articles were screened based on inclusion and exclusion criteria after the duplicate had been removed. Subsequently, 32 full-text articles were screened for eligibility. Finally, 10 studies were included and analyzed in this paper, which met all of the inclusion criteria.

102


B. Risk of Bias Assessment A total of 10 studies were collected using a cross-sectional method. The assessment of each study was carried out using appropriate appraisal tools for each research method. The results of the study assessment show that all studies are included as high quality. Table 1. shows critical appraisal results on studies using Joanna Briggs Institute's Critical assessment tools. C. Characteristic of Cross-Sectional Studies There were 1,228 participants from the 10 articles of cross-sectional study that had been obtained. The mean age range of the participants was 30-59 years. All studies addressed the relationship between leprosy-related burden and the mental health of leprosy patients. The characteristics of each cross-sectional studies are described in Table 2. D. Outcome & Data Analysis The results of each study indicate a significant relationship between leprosyrelated burden and the mental health problems experienced by leprosy patients. In a study conducted by Giesel et al., it was found that 71% of leprosy patients in their study suffered from depression9. Research conducted by Ali et al. also supports the existence of depression in leprosy patients with 47% of leprosy patients suffering from depression, and even found that 12.4% of leprosy patients had suicidal intentions10. Dorst et al. reported that there was significant prevalence of depression (24.6%), poor mental wellbeing (38%), and suicidal thoughts (50%) in leprosy patients11. Bakare et al. also supported the tendency for depression in leprosy patients (14% moderate depression and 19% major depression) accompanied by anxiety disorder as much as 19.2%12. A study conducted by Garbin et al. reported a 67% depression in leprosy patients associated with perceived stigma and patient disabilities4. The study conducted by Haroun et al. (2012) also support the existence of depression in leprosy patients up to 85% of patients, where 65% of these depressed patients complain of pain, while 35% do not, this shows that depression in leprosy patients is not only caused by the pain they feel13. Three studies showed that psychological morbidity was associated with neuropathic pain14,15,16, one study showed that psychological morbidity was associated with the severity of leprosy16. Overall, these ten articles show that the burdens caused by leprosy are associated with mental-health problems felt by leprosy patients ranging from anxiety to suicidal intention, so that mental-health problems in leprosy patients should be considered in the management of leprosy patients.

103


DISCUSSION From the results of the studies obtained, all of them showed a significant relationship between leprosy related burden and mental health problems, but the specific causes that significantly affect mental health problems in leprosy sufferers are multifactorial. Furthermore, these specific factors need to be discussed in more depth discussion so that handling in overcoming mental health problems can be directed to the right target. A. Disability The one of the main fears of leprosy sufferers after being diagnosed with leprosy is disability, which people with leprosy showing a disability show a more significant level of depression4, 10,11. Disability causes the patient to have difficulty carrying out daily activities and participating in social activities in their environment17,18. In addition, disability also makes it difficult for patients to do or even get a job which results in the disappearance of income sources19. B. Neuropathic Pain Leprosy can cause clinical manifestations of neuropathic pain in the peripheral nerves. This is significantly related to psychological morbidity experienced by leprosy patients16,13. Pain intensity of perceived pain have a significant positive correlation with the patient's psychological stress15. Neuropathic pain can continue to be chronic and have an impact in disruption of the circadian rhythm

12,20,21

. This significantly causes

disruption of daily activities resulting in daily activity limitations20. C. Stigma and Discrimination Many patients with leprosy experience stigmatization and prejudice in addition to their physical impairment. This causes the sufferer to experience social rejection which leads to hatred, humiliation, unsympathetic reactions, even discrimination, so that social rejection was one of the most feared effect by leprosy patients4,11,17. Discrimination complicates life for leprosy patients, which predominantly occurs in schools, findings jobs, then when seeking health care22. Stigma and discrimination also have a big impact on difficulty of finding a mate and work17. The level of stigma significantly was positively associated with the depression score and negatively associated with the mental wellbeing score (p = 0.011)11. This means that higher levels of stigma will lead to increased levels of depression and decreased mental wellbeing of leprosy patients. Discrimination predominantly occurs in schools, findings jobs, then when seeking health care22. It is proven that not only the patient of leprosy got a stigma but also a whole community around patients whether the community members did not

104


have leprosy23. Therefore, stigma and discrimination can be more important for the leprosy patient and their family than physical impairment24. D. Ability to Work and Unemployment The unemployment of leprosy patients is largely due to deformities in leprosy patients25. Based on the study by Garbin et al., most leprosy patients were dissatisfied with their ability to work and experienced problems in their work, in the form of being dismissed from work, and experienced prejudices within the work environment4. In addition, some leprosy sufferers also experience discrimination when looking for jobs related to unemployment leading to moderate depressive episode12,17. The potential impact of unemployment on leprosy patients may be reduced through policies regulating the implementation of productive activities in their rehabilitation areas. E. Gender The prevalence of generated psychiatric disorders was significantly higher in females than males12. Results showed that stigma experienced by females significantly associated with the higher levels or depression than man (p = 0.011). In general, women have more attention to beauty and aesthetic standards than men. Appearance that is not in accordance with society's expectations creates stigma and prejudice from both the community and their self26. This is in line with a recent review describing the inferior position of women with leprosy, who often face more stigmatization, concealment, treatment delay, difficulties with marriage and social rejection resulting in lower quality of life and higher mental burden11.

Previous Intervention Addressed to the Mental Health of Leprosy Patients There are still very few researches on psychological disorders interventions in leprosy patients. Intervention using application of reminiscence therapy to treat 51 elderly leprosy patients in Taiwan has been shown to significantly reduce depression in leprosy patients referring to the GDS-SF score27. An 5 years approach for leprosy elimination in Indonesia called: ‘The Leprosy Friendly Village Approach’ (LFV) which was conducted by delivering education about leprosy consistently to the health workers and the community involving influencers to promote positive attitude toward leprosy, has a significant result in the better knowledge, involvement, and positive attitudes among health workers; less of discrimination and fear among community; and also decreasing the annual leprosy new cases after 5 years28. In other study it is suggested that meaningful and balanced counseling by the counselors is needed for leprosy-affected people, especially in

105


coping with enacted stigma; the need for education and psychological supportive; and client-oriented counseling so that patients feel free to tell their stories29,30.

Strengths and Limitation of The Study Systematic reviews on the relationship between mental health and leprosy were still minimum in number. Hence, the authors made this systematic review using the latest published articles in the last 10 years to maintain the relevance of the data obtained to the real facts. In addition, the authors also discussed specific factors that can affect the mental health of leprosy patients. The limitation of this study was that there were still few primary research articles that can be reviewed in the past 10 years. Therefore, the authors only included 10 articles using the cross-sectional study method. Hence, studies with more rigorous methods such as randomized controlled trials still need to be carried out in this area.

CONCLUSION After reviewing ten articles, it was concluded that leprosy-related burden was significantly associated with mental health problems experienced by leprosy patients, such as: depression, anxiety, poor mental wellbeing, and suicidal intention. Those mental health problems have aggravating factors, such as: disabilities, neuropathic pain, gender, stigma and discrimination, decrease ability to work and unemployment. In addition, there are very few primary studies related to interventions aimed at the mental health of leprosy patients. For future research, primary studies that discuss mental health-related interventions in leprosy patients are needed. The interventions carried out could be based on the factors that influence mental health problems in leprosy patients that have been discussed in this study. For practice, the authors also recommend that comprehensive health care for leprosy patients must also ensure psychological wellbeing. Thus, better management of leprosy patients can be achieved.

ACKNOWLEDGEMENT Authors thanks to dr. Prattama Santoso Utomo, MHPEd (Gadjah Mada University) for the willingness to give us suggestions and review our study. This study did not receive specific grants from funding agencies in the public sector, commercial, or non-profit sector.

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28.

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29.

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30.

Rai SS, Syurina E V., Peters RMH, Irwanto I, Naniche D, Zweekhorst MBM. Assessing the prospect of a common health-related stigma reduction response: Cross-perspectives of people living with stigmatised health conditions in Indonesia. Glob Public Health [Internet].

2020;0(0):1–14.

https://doi.org/10.1080/17441692.2020.1850834

109

Available

from:


TABLE AND FIGURES Table 1. Risk of Bias Assessment Ali

Haro

Dors

Haro

Reis

Baka Eyan Gies

Garb

Lasry-

et

un et

t et

un et

et

re et

oer,

el et

in et

Levy

al.,

al.,

al.,

al.,

al.,

al.,

2018

al.,

al.,

et al.,

2020

2019

2020

2012

2014

2015

2018

2015

2011

Were the criteria for inclusion in the sample clearly defined?

1

1

1

1

1

1

1

1

1

1

Were the study subjects and the setting described in detail?

1

1

1

1

1

1

1

1

1

1

Was the exposure measured in a valid and reliable way?

1

1

1

1

1

1

1

1

1

1

Were objective, standard criteria used for measurement of the

1

1

1

1

1

1

1

1

1

1

Were confounding factors identified?

1

1

1

1

1

1

1

1

1

1

Were strategies to deal with confounding factors stated?

1

1

1

1

0

1

0

0

0

0

Were the outcomes measured in a valid and reliable way?

1

1

1

1

1

1

1

1

1

1

Was appropriate statistical analysis used?

1

1

1

1

1

1

1

0

1

1

Total (borderline score = 6)

8

8

8

8

7

8

7

6

7

7

condition?

110


Table 2. Characteristics of Cross-sectional Studies Study

Bakare et al.,

Sample

Mean age

size (n)

(years)

235

50,9

2015

Leprosy-related burden (and tools used)

Mental health measured outcome (tools used)

Duration of illness

Anxiety & depression (CIDI)

Treatment status

Psychiatric morbidity (GHQ-28)

Unemployment Haroun et al.,

107

34

2012 Reis et al.,

Psychological comorbidity (GHQ-12)

Intensity of pain (BPI) 21

47,7

2014 Dorst et al.,

Neuropathic pain (DN4 & LANSS)

142

56,8

2020

Pain intensity (VAS)

Psychological comorbidity (GHQ-12

Neuropathic pain (DN4 questionnaire)

Quality of life WHOQOL-bref

Level of stigma (5-QSI-AP)

Level of depression (PHQ-9)

Level of impairment (WHO three-grade

Mental wellbeing status (WEMWBS)

system) Haroun et al.,

135

30

2019 Ali et al., 2020

Intensity of pain (BPI-short form)

Psychological comorbidity (GHQ-12)

Neuropathy pain (DFNS QST protocol) 251

51.9

Disability (the 12-item WHODAS

Depression and quality of life (PHQ-9 &

version 2.0)

DLQI) Suicidal ideation (CIDI scale)

111

Relationship


Garbin et al.,

94

55.1

2015

Pain intensity (validated questionnaire)

Patient self-esteem (validated

Patient believe in stigma and prejudice

questionnaire)

(validated questionnaire)

Patient quality of life (validated

Problem at work (validated

questionnaire)

questionnaire) Eyanoer., 2018

Giesel et al.,

100

42

51.6

47.5

Neuropathic pain (validated

Discrimination (validated questionnaire)

questionnaire)

Quality of life (validated questionnaire)

Pain intensity (VAS-INT)

Depressive symptoms (DN4 & HAMD

2018 Lasry-Levy et al., 2011

scale) 101

39.34

Disability (WHO disability criteria) Neuropathic pain (DN4)

112

Psychological morbidity: (GHQ-12)


Comparing the Effectiveness of Vaccine and Gene Recombination of Anopheles sp. in Preventing Malaria: A Review of Literature Angela S. Yahono and Vania Sasias

INTRODUCTION Tropical diseases have conquered the world for a long time. Malaria is one of the most prevalent of those. These parasites are contacted through the Anopheles mosquito species. There are several ways to admonish them, such as vaccine and genetic modification of its vector. Each has its own advantages and disadvantages. Thus, this paper is made to compare both works, to discuss which way is more effective and efficient in eradicating this parasite. MATERIALS AND METHODS The review method used in this literature review is the search engine NCBI, Science Direct, ClinicalKey, and SAGE Journals to find journals with 2 keywords; the first keywords were malaria AND vaccine; the second keywords were malaria AND gene AND (remodeling OR drive OR recombination) AND (Plasmodium OR Anopheles). The criteria we decided is published maximum around ten years ago. Afterward, the articles will be evaluated for their correlation with the topic to support the analysis in this literature review. RESULTS AND DISCUSSION A vaccine for malaria was never settled due to the variety. Latest clinical trials have involved several types of vaccines: pre-erythrocytic, erythrocytic, transmission-blocking, and mosquitocidal vaccines. Each type has its own successes and failures. On the other hand, scientists look into gene drives to create mosquitos that reject the Plasmodium. Unfortunately, gene recombination is incredibly risky and difficult to test. CONCLUSION Both techniques seem to still not well prepared to be released to society. However, it seems that the idea of vaccine presents more assurance compared to gene recombination due to the amount of information available. Despite that, gene remodeling has the potential for a better solution. Nevertheless, we urge extensive studies of both these solutions to gain a more certain answer.

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Comparing the Effectiveness of Vaccine and Gene Recombination of Anopheles sp. in Preventing Malaria: A Literature Review

Angela S. Yahono and Vania Sasias

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INTRODUCTION Tropical diseases have conquered the world for a long time. Malaria is one of the most prevalent of those, with around 229 million malaria cases worldwide in 2019. According to WHO, children under five years old are the most vulnerable group, and they make up 67% of the deaths caused by this parasite in 2019 - around 274,000 children, making it the largest killer of children.1,3 Although the number of malaria incidence has been substantially reduced, the progress has slowed down this past years, and without any strategic change, the Global technical strategy for malaria 2016–2030 (GTS) target to reduce the global malaria incidence and mortality rates by at least 90% will not be achieved.2,3 The six species of those plasmodia that cause this disease are Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale wallickeri, Plasmodium ovale curtisi, and Plasmodium knowlesi.1,5 WHO indicates that two of those - P. falciparum and P. vivax pose the biggest threat to humanity.2 These parasites are contacted through the Anopheles mosquito species. As of now, the strategy to reduce malarial infection is among preventing bites and for tourists to take antimalarial tablets.6 Although bite prevention is successful and can be used for the general population, malarial tablets cannot benefit those living in the endemic malaria area, as there are a lot of adverse effects and also a risk of resistance.7 Scientists, however, have concurred with some ways to admonish this parasite. Some of them include the production of vaccines and genetic modification of the Anopheles sp. Vaccine for malaria, although it has not existed yet, is deemed feasible by scientists. The thought is attributed to the rise in immunity in endemic malaria populations. The amount of antibodies against it increases along with age, providing confidence that the human body will produce such antibodies.9 Obstacle in the making of the vaccine includes the characteristic of this parasite, where after they infect the host, the parasite migrates into the bloodstream and conceal itself in the liver where it will multiply, safe away from the immune system, one of the reasons it is difficult to produce a vaccine for malaria.4 On the other hand, recombination of the Anopheles sp. gene presented a more complex solution. It relies on its gene drive. This modification is hoped to eliminate the possibility of the species becoming a vector for Plasmodium.6 This idea has been done in small amounts in a lab as an experiment. It is hypothesized that if enough modified mosquitos are released, it would reduce malaria vectors and hopefully reduce and possibly eradicate the infectious disease. Unfortunately, gene remodeling is quite controversial in the medical world as this means that humans will be able to change a living organism. Despite that, this technique may present a chance to eliminate one of the world’s most dangerous tropical diseases.

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Both of these techniques have the ability to admonish malaria. However, they both each have their advantages and disadvantages. Genetic remodeling is still a brand new idea while the vaccine has been used for a long time. On the other hand, creating a vaccine for malaria proved to be a difficult task to accomplish. Therefore, this study aimed to compare and discuss the effectiveness of vaccine and gene recombination in eradicating this parasite. MATERIALS & METHODE The review method used in this literature review is the search engine NCBI, Science Direct, ClinicalKey, and SAGE Journals to find journals with 2 keywords; the first keywords were malaria AND vaccine; the second keywords were malaria AND gene AND (remodeling OR drive OR recombination) AND (Plasmodium OR Anopheles). The criteria for the journals we chose is published a maximum of around ten years ago. Afterward, the articles will be evaluated for the correlation of the keywords with the topic to support the analysis in this literature review (Figure 1.1). RESULTS AND DISCUSSION From numerous articles, we were able to narrow it down to 8 articles, 4 articles regarding the effectiveness of vaccine and 4 regarding the effectiveness of gene recombination. Several articles also presented several examples of the latter and each their own pros and cons. Effectiveness of Vaccines Although the production of vaccines has many obstacles, it has been researched for quite a long time. Because of that, there is much information earned from all those years of research. With the vast development of technology, new information can be obtained, and old information can be combined to produce an effective solution to malaria. For instance, technologies are being utilized recently to capture the diverse data of infection using simian and human malaria parasites. Scientists were able to acquire supporting biology-based antigen systems and biochemical pathway discovery pipelines using these results.8 These are crucial for on-going research. Effectiveness of Gene Recombination On the other hand, gene remodeling has been done by humans for quite a while now. One quite popular is genetically modified organisms or GMO. This technique has also been done on mosquitos, particularly the Anopheles mosquito. Scientists looked at the gene drive of this unique animal in order to genetically modify it to reject the Plasmodium parasite. Gene drive has several mechanisms – meiotic drive, homing endonucleases, and transposable elements. These mechanisms cause several traits to spread rapidly, with a rate of 50% higher

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than traditional Mendelian principles.10 By remodeling this gene into an antimalarial gene, scientists were able to create non-infectious mosquitos. Types of Vaccine and Its Pros & Cons Because of the variety of the Plasmodium, it has taken a toll on vaccine production, and it may also be an obstacle to gene recombination. Based on a study by Salinas, et al., Plasmodium drug resistance phenotypes that play a key role in its transmission. These include the genes dhfr, dhps, Pfcrt, Pfmdr-1, and Pfg377, also IC50 values of AS. These variables have demonstrated that parasite genetic diversity is multifactorial, and a multi-pronged approach needs to be done.4 These factors can prevent drug resistance of Plasmodium, making it a potential for Malaria vaccine. Other components that can be used as a vaccine are antigens from Plasmodium. There have been several types of vaccines; pre-erythrocytic, erythrocytic, and transmission-blocking vaccines that have recently been in clinical trials. Pre-erythrocytic malaria vaccines target Plasmodium during its sporozoite and liver stages, thus preventing its development to the blood-stage.13 The most successful candidate is RTS, S, reaching phase 3 in the clinical trial.8 This is made of the antigen CPS (circumsporozoite protein), a P. falciparum sporozoite surface protein. The phase 3 trial for this vaccine was conducted in several countries around Africa, with infants and children as the subjects. Protection against malaria in 46% of the children and 27% of the infants was observed after 18 months. However, the protection given was not predictive. This result also showed that the immune responses against less immunodominant antigens are much more crucial than antigens. This contradicts the usual principles of vaccinology. Some erythrocytic vaccines have also been on a clinical trial. One of them is GMZ2 and MSP-3 fusion. The two components have been tested beforehand in phase 1 trials using Montanide ISA720 or Alum as adjuvants. The findings were the induction of cytophilic antibodies that were able to suppress in vitro parasite growth and functional antibodies.8 The diversity of Plasmodium antigens can be transcended by this vaccine. Meanwhile, transmission-blocking vaccines target pre-fertilization antigens expressed by gametocytes or post-fertilization antigens expressed by zygotes.8 This vaccine works by preventing the infection of the vector. For instance, the P. falciparum Pfs25 post-fertilization antigen is used to identify the parasite and attach itself to the mosquito midgut. At the same time, the monoclonal and polyclonal antibodies block it from infecting.8 Although these vaccines were poorly immunogenic, scientists have found a way to increase their immunogenicity.

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Another idea for the vaccine is a mosquitocidal vaccine. This vaccine gives immune control against the mosquito vector instead of the Plasmodium itself.12 Mosquitos ingest the immune components of the host along with blood. These immune components are able to stay active in the mosquito for 24 hours, possibly killing the mosquito. Therefore, some studies have considered this to be an interesting candidate for the malaria vaccine. However, mosquitocidal vaccines are considered unfeasible, and its research unacceptable. Gene Recombination and Its Pros & Cons The research concluded that engineered under dominance constructs are the safest gene drive strategy for transgenic containment.15 It was predicted that this system would not work unless the release proportion is more than ∼27% of the wild population. However, this system is not very invasive; even with a large parameterization, it requires at least 3% of a consistent migration rate per generation to advance into other populations. Another technology, TEs, and HEGs, in contrast, are much more capable of outspreading between subpopulations. However, TE is more than 50% likely to persist escapes greater than ten, and HEG persist homozygote escape greater than five. Hence, TE and HEG have the risk of subsequent after an accidental release. Another drive system, the meiotic system, also has risks following an accidental release. The meiotic drive system uses a Y-linked meiotic drive gene to drive an X-linked response allele into the population.15 While the Y-linked can disperse following an accidental release; the X-linked requires population growth. Concerning the unknown effects on the mosquito population, this gene drive would have a greater risk of coming out unsuccessful due to the more than 50% likelihood of it persisting for escapes of more than two mosquitos carrying it.15 On the other hand, another gene drive strategy, Medea and Wolbachia, presents a compromise between invasiveness (for intentional release) and containment (for accidental release).15 Wolbachia, unlike Medea, needs a more restrictive condition to spread, particularly due to its imperfect maternal transmission. Despite it, there is a risk of both systems to persist in an accidental release. Medea allele, however, is more likely to persist for homozygote escape sizes greater than 27 while Wolbachia greater than 74. What is concerning is the uncertain existence of a fitness advantage under natural conditions since it would not be known until experiments have been done. The most recent gene drive technology is CRISPR-Cas9, a tool that allowed the researchers to build gene drives and modify genomes at a population level using the nonMendelian inheritance principle.11 This technology sets itself apart from the other gene modification techniques because of its ease, although it is still quite new, founded in 1987. Its rapid development introduced a nuclease that is not difficult to engineer (unlike HEGs) or have

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poor repair substrates (unlike TALENs).14 One successful experiment regarding CRISPR-Cas9 is the 17-kbp synthetic construct in Anopheles stephensi. Furthermore, scientists found that a type of gene drive, site-specific nuclease-based systems, were strong enough and brisk at moving a gene into an unstructured cage population.14 The use of CRISPR-Cas9 for this system ensured that it is incredibly flexible and reusable. However, a ban on gene drive usage has been proposed in the United Nations Biodiversity Convention, but governments largely rejected the idea.10 This is due to the imbalance it can cause to the environment, particularly the food chain. Furthermore, transgenes can also respond differently than expected to migrate into other non-target organisms and mosquitos. Gene drive does not come without challenges, particularly in genetic engineering, epidemiology, and ecology.14 Genetic engineering presents challenges such as the sufficient drive mechanism needed to overcome costs, also the need to work rapidly, adaptable, reusable, and retain linkage to any cargo. On the other hand, epidemiology presents the possibility of producing another pathogen or illness due to a potential alteration in the organism's actions. Moreover, ecology presents the possibility of the gene drive affecting non-target organisms. In addition to that, CRISPR technology requires only a few individuals to commence an irreversible alteration of a population.14 Considering that a field test would pose a threat to the balance of the ecosystem. However, based on the simple reproductive number (R0) model for a vector-borne pathogen, the chance of a mosquito lasting another day (p) is the most sensitive part of the formula since minor variations in the survival of a vector will dramatically affect the number of transmissions. (Figure 1.2).12 CONCLUSION Both vaccine and genetic modification have their advantages and disadvantages. Vaccines have a vast amount of research done hence more information due to the years spent studying it while the genetic modification is relatively novel compared to vaccine. Vaccines have many different types, with each has its own successes and failures. The testing for vaccines is still proven to be lacking effectiveness. On the other hand, gene recombination has only been determined hypothetically of its effectiveness, fearing the risks of accidental release. Both techniques seem to still not well prepared to be released to society. However, based on the review we have conducted, it seems like, with the amount of knowledge available, the concept of vaccines provides more certainty than gene recombination. Despite that, gene remodeling may be a potential for a better solution to this issue. Nevertheless, we urge extensive studies of both these solutions to gain a clearer understanding of both the risks and the potential to gain a more certain answer.

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REFERENCE 1. Fact Sheet about Malaria [Internet]. Who.int. 2020 [cited 6 December 2020]. Available from: https://www.who.int/news-room/fact-sheets/detail/malaria 2. The "World malaria report 2019" at a glance [Internet]. Who.int. 2019 [cited 10 December

2020].

Available

from:

https://www.who.int/news-room/feature-

stories/detail/world-malaria-report-2019#:~:text=Malaria%20cases,In%202018%2C%20an&text=Nineteen%20countries%20in%20sub%2DSaharan,Nig er%20(4%25%20each). 3. Global technical strategy for malaria, 2016-2030. WHO; 2015. 4. Salinas N, Tang W, Tolia N. Blood-Stage Malaria Parasite Antigens: Structure, Function, and Vaccine Potential. Journal of Molecular Biology. 2019;431(21):42594280. 5. Milner D. Malaria Pathogenesis. Cold Spring Harbor Perspectives in Medicine. 2017;8(1):a025569. 6. Malaria - Prevention [Internet]. nhs.uk. 2018 [cited 11 December 2020]. Available from: https://www.nhs.uk/conditions/malaria/prevention/#:~:text=Bite%20prevention%20– %20avoid%20mosquito%20bites,dose%2C%20and%20finish%20the%20course. 7. AlKadi H. Antimalarial Drug Toxicity: A Review. Chemotherapy. 2007;53(6):385-391. 8. Moreno A, Joyner C. Malaria Vaccine Clinical Trials: What's on the Horizon. Current Opinion in Immunology. 2015; 35:98-106. 9. Kelsey A, Stillinger D, Pham T, Murphy J, Firth S, Carballar-Lejarazú R. Global Governing Bodies: A Pathway for Gene Drive Governance for Vector Mosquito Control. The American Journal of Tropical Medicine and Hygiene. 2020;103(3):976985. 10. Heitman E, Sawyer K, Collins J. Gene Drives on the Horizon. Applied Biosafety. 2016;21(4):173-176. 11. CDC - Malaria - About Malaria - Biology [Internet]. Cdc.gov. 2020 [cited 6 December 2020]. Available from: https://www.cdc.gov/malaria/about/biology/index.html 12. Billingsley P, Foy B, Rasgon J. Mosquitocidal Vaccines: A Neglected Addition to Malaria and Dengue Control Strategies. Trends in Parasitology. 2008;24(9):396-400. 13. Duffy P, Sahu T, Akue A, Milman N, Anderson C. Pre-erythrocytic malaria vaccines: identifying the targets. Expert Review of Vaccines. 2012;11(10):1261-1280. 14. Adelman Z, Tu Z. Control of Mosquito-Borne Infectious Diseases: Sex and Gene Drive. Trends in Parasitology. 2016;32(3):219-229.

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15. Marshall J. The Effect of Gene Drive on Containment of Transgenic Mosquitoes. Journal of Theoretical Biology. 2009;258(2):250-265. TABLE & FIGURES Figure 1.1 Graph of methods

Figure 1.2 The basic reproductive number (R0).

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Proposed Mechanism for Wolbachia-mediated DENV Blocking in Ae. aegypti: A Systematic Review Robby Soetedjo, Venna Bella Sabatina, Jacky Klemens Owen Abstract Introduction: Dengue fever is an infectious disease caused by the dengue virus (DENV). There are four serotypes of this virus; they are DENV-1, DENV-2, DENV-3, and DENV-4. This virus spreads through the bite of infected Aedes aegypti or Aedes albopictus, which many are found in various countries, mainly tropical countries. One of the control agents for DENV in Ae. aegypti is Wolbachia. Several strains of Wolbachia, especially wMel, can significantly reduce and inhibit DENV infection in various Ae. aegypti organs. Objective: In this study, we identify Wolbachia-mediated blocking mechanisms and factors that affect Wolbachia's effectiveness (wMel, wMelCS, wMelPop, or wMelPop-CLA) against DENV in Ae. aegypti mosquito. Method: It was carried out with the PRISMA statement guidelines. The literature search was done using four databases: PubMed, ProQuest, ScienceDirect, and EBSCOhost with "Wolbachia," "Aedes," and "Dengue" as the main keywords. Risk of bias assessed using OHAT risk of bias rating tool. Result and Discussion: Some of the factors that can affect the Wolbachia-mosquito-DENV

include gene expression and other proteins (AeVago1, AeCHD7, Pelo, and AaArgM3), mosquito metabolism, how the mosquito's innate immunity reacts to Wolbachia infection. We hypothesize gene expression factors play a big part in the underlying mechanism of DENV blocking by manipulating several processes in Ae. aegypti. Additionally, superinfection (a combination of Wolbachia strains) still needs more research to unravel its potential. Conclusion: In conclusion, Wolbachia could be one of the alternatives for controlling the DENV in Ae. aegypti mosquitoes potentially to be the key to eradicating dengue. Keyword: Wolbachia, Aedes, Dengue Virus, Systematic Review, and Biocontrol Agent

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Proposed Mechanism for ​Wolbachia​-mediated DENV Blocking in Ae. aegypti​: A Systematic Review

AUTHORS:

Robby Soetedjo Venna Bella Sabatina Jacky Klemens Owen

Asian Medical Students’ Association-Indonesia 2020

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Abstract Introduction: ​Dengue fever is an infectious disease caused by the dengue virus (DENV). There are four serotypes of this virus; they are DENV-1, DENV-2, DENV-3, and DENV-4. This virus spreads through the bite of infected ​Aedes aegypti ​or ​Aedes albopictus​, which many are found in various countries, mainly tropical countries. One of the control agents for DENV in ​Ae. aegypti is ​Wolbachia​. Several strains of ​Wolbachia​, especially ​w​Mel, can significantly reduce and inhibit DENV infection in various ​Ae. aegypti​ organs.

Objective​: In this study, we identify ​Wolbachia​-mediated blocking mechanisms and factors

that affect ​Wolbachia's effectiveness (​w​Mel, ​w​MelCS, ​w​MelPop, or w​MelPop-CLA) against DENV in ​Ae. aegypti ​mosquito.

Method​: It was carried out with the PRISMA statement guidelines. The literature search was done using four databases: PubMed, ProQuest, ScienceDirect, and EBSCOhost with "​Wolbachia​," "​Aedes​," and "Dengue" as the main keywords. Risk of bias assessed using OHAT risk of bias rating tool.

Result and Discussion: ​Some of the factors that can affect the ​Wolbachia​-mosquito-DENV

include gene expression and other proteins (AeVago1, AeCHD7, Pelo, and AaArgM3), mosquito metabolism, how the mosquito's innate immunity reacts to ​Wolbachia infection. We hypothesize gene expression factors play a big part in the underlying mechanism of DENV blocking by manipulating several processes in ​Ae. aegypti​. Additionally, superinfection (a

combination of ​Wolbachia​ strains) still needs more research to unravel it​s​ potential.

Conclusion​: In conclusion​, Wolbachia could be one of the alternatives for controlling the DENV in ​Ae. aegypti​ mosquitoes potentially to be the key to eradicating dengue. Keyword​: ​Wolbachia, Aedes, Dengue Virus, Systematic Review, and Biocontrol Agent

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Introduction Dengue is a mosquito-borne viral disease which is a Flaviviridae family. Dengue virus (DENV) has four similar serotypes: DENV-1, DENV-2, DENV-3, and DENV-4. Dengue can cause a broad spectrum of diseases, from subclinical disease to severe flu-like symptoms. Dengue is also capable of causing complications such as heavy bleeding, organ damage, and even death. Because it has four serotypes, at least a person must be exposed to all the viral serotypes to have lifelong immunity.​1 Dengue virus spreads through the bite of infected ​Aedes aegypti or ​Aedes albopictus​, and many are found in various countries, mainly tropical countries. Three billion people, around 40% of the world's population, live in areas with a high risk of dengue. Every year 400 million people get infected with dengue. As a tropical country, Indonesia has had an increased incidence of dengue hemorrhagic fever over the past 50 years, but the incidence that was previously large in Java has now moved to Bali and Kalimantan. Thus, dengue is one of the neglected tropical diseases ​that must be considered essential and the best

alternative is needed to be found.​2

Wolbachia is a gram-negative bacteria that usually resides in arthropods. These bacteria can be used to increase the immune system against viruses and reduce arthropods' reproductive capacity.​3 Therefore, ​Wolbachia has begun to be used as an alternative in controlling various viruses, especially DENV in mosquitoes where one of the common vectors is ​Ae. aegypti​. ​Wolbachia​'s advantages over conventional methods are the ability to make vectors resistant to DENV and can spread quickly to uninfected populations.​4,5 To determine the underlying mechanism of ​Wolbachia​-mediated blocking and

Wolbachia's effectiveness as a biocontrol agent for ​Ae. aegypti and found the, we conducted a systematic review from various studies. Several studies have shown that ​Wolbachia is an effective biological agent in controlling the development of this virus using several

mechanisms inducing oxidative reactions to prevent virus development and regulating various proteins that also influence viral development.​6-8 Method The systematic review was conducted with Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement guideline to identify ​Wolbachia​-mediated blocking mechanisms and factors that affect ​Wolbachia effectiveness in DENV blocking in Ae. aegypti​.9​ The literature search was done using four databases: PubMed, ProQuest,

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ScienceDirect, and EBSCOhost with "​Wolbachia​," "​Aedes​," and "Dengue" as the main

keywords. The last search date was 15 November 2020. No language and time restrictions were applied. The complete keywords are listed in Supplemental Table 1 in the appendices. The result of the search was then imported to EndNote X9, and the duplicates were removed. All authors participated through each phase of the review independently by screening the titles and abstracts, assessing the full text for eligibility criteria, then including the relevant studies. The eligibility criteria used for this study include the study design, participants, and relevant interventions as well as outcomes according to PICO questions. Eligible studies met the following criteria: (1) The study design had to be an animal study; (2) The sample that studies used was ​Ae. aegypti and intervened using ​Wolbachia ​strain ​w​Mel, ​w​MelCS, w​MelPop, or ​w​MelPop-CLA; (3) The study assesses the effectiveness of ​Wolbachia ​for DENV blocking in ​Ae. aegypti​.

The OHAT Risk of Bias Rating tool was utilized in the studies' quality assessment, which covers the following six domains of bias.​10 Included study quality will be classified as definitely low risk, probably low risk, probably high risk, or definitely high risk of bias. Disagreements arising in the process of the evaluation were all resolved by discussion among the review team. Result Search Results A literature search from electronic databases yielded 248 studies. After removing the duplicates, 168 studies remained. We were screening through titles and abstracts excluded 115 studies with 53 other studies that met the inclusion criteria. The result showed 18 studies that matched the criteria of inclusion. The search flowchart and selection method were summarized in Fig 1. Study Characteristics All studies were animal studies in ​Ae. aegypti bodies that measure viral load of DENV after ​Wolbachia intervention. The studies had common inclusion criteria that were

conducted in ​Ae. aegypti​. Mosquito intervened either using the ​Wolbachia ​strain ​w​Mel,

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w​MelCS, ​w​MelPop, or ​w​MelPop-CLA. There were no restrictions on the DENV strain that was used in the studies. Detailed study characteristics were summarized in Supplemental Table 2. Quality Assessment Based on the OHAT Risk of Bias Rating Tool, quality assessment results showed the mixed risk of bias ranging from definitely high risk to definitely low risk. Most studies have not reported the selection bias because there are no explanations about the randomization and allocation mechanism that the study used. In Performance bias, we found almost all studies use identical conditions in each experiment, so we conclude definitely low risk in many studies, but the author cannot be sure the personnel is blinded because it is not reported in many studies. Loss of the subject is insufficiently reported in multiple studies. For the three last domains, namely detection bias, selective reporting bias, and other bias, the author decided there is definitely low risk of bias in all studies. The risk of bias summary and graph were summarized in supplemental Table 3. Wolbachia​-mediated Blocking Numerous studies have researched ​Wolbachia​-mediated blocking to DENV. Some

strains of ​Wolbachia​, especially ​w​Mel, could reduce and inhibit DENV infection in various

organs of the ​Ae. aegypti​, all studies show a significant reduction of DENV load in ​Ae.

aegypti infected with ​Wolbachia​. ​The first study by Pearce et al. found that ​no DENV RNA was amplified from any ​w​Mel-carrying mosquito sample compared to control that having a

positive infection of DENV.​11 Next study by ​Etiene et al. showed a significant decrease of

DENV load in the ovaries of mosquitoes with infected ​Wolbachia ​strain ​w​Mel. The result

shows there is a correlation between bacterial density and the viral blocking effect of Wolbachia​ in the ovaries, which is useful to prevent vertical transmission of DENV.​12 DENV has the capability to disseminate to the head of the ​Ae. aegypti​. Fraser et al.

found that mosquitoes with ​Wolbachia ​strain ​w​Mel and ​w​MelCS have significantly reduced

viral RNA copies in the head compared to control .​7 Similar study shows that mosquitoes with ​w​Mel had no DENV disseminated to the heads, compared to 72% of control.​13

Representing the ability of ​Wolbachia to suppress DENV dissemination to the head of ​Ae.

aegypti​.

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Wolbachia also inhibits DENV infection in the body of the mosquitoes, according to several studies. It shows in the body of mosquitoes there are no DENV infections in ​w​Mel carrying mosquitoes.​13-15 In related studies by Walker et al. also show the result that w​MelPop-CLA mosquitos have even lower DENV loads in the abdomen than ​w​Mel carrying

mosquitoes.​14 ​The concentration of DENV in the saliva of the ​Ae. aegypti represents its ability

to transmit the pathogen. Most studies found that ​Wolbachia strain ​w​Mel is able to suppress

DENV in the saliva of the ​Ae. aegypti significantly​.13,15 ​ Additionally, ​Wolbachia can eradicate

all DENV in the saliva of the mosquitos.​14 With the eradication of DENV in saliva, the author believed ​Ae. aegypti​ will become unable to transmit DENV. In a study done by Audsley et al., they gave antibiotics to eradicate microbiomes in Ae. aegypti ​to see its effect on DENV replication. These shows a correlation that Infection

rates in the ​w​Mel line were much lower compared to control. There was no effect of

antibiotic treatment, but the effect for ​Wolbachia infection still significantly decreased DENV

load.​16 Other findings by Amuzu and McGraw found out that the ​Wolbachia b​ locking

mechanism is not tissue-specific, meaning the mechanism underlying the viral blocking is the same in all body parts of mosquitoes. They also found ​Wolbachia​'s density not affecting the

capability of DENV blocking as opposed to several studies before​.17 ​ Gene regulation​ Factor Plays a Major Role in DENV Blocking

Gene regulation that was influenced by ​Wolbachia could manipulate some mechanism

in ​Ae. aegypti and produce proteins that can induce DENV blocking. One example of

Wolbachia manipulation, such as cadherin genes, is typically used to mediate either enter, exit, or move within cells; with ​Wolbachia manipulation, it possible to alter that mechanism and contribute to DENV blocking.​18 Besides that, some proteins and antivirals can also play a role, for example, AeVago1, an antiviral protein in ​Ae. aegypti, ​which may function as a host

factor to suppress DENV replication in the mosquito.​19 Some proteins that also affect the

effectiveness of DENV and its life cycle against ​Wolbachia​, such as Pelo protein, which

interferes with replication and DENV suppression in ​Wolbachia's ​presence by suppressing AaDnmt2 gene that promotes dengue replication.​6,19 Likewise, AeCHD7 is an enzyme that works by downregulating the replication of DENV.​20 However, it is slightly different in the AaArgM3 protein, which plays an essential role in the maintenance of ​Wolbachia infection in mosquito cells but has no effect on DENV replication.​21 Overall, manipulating gene

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expression and protein, resulting in a combination of suppressing entry and replication of DENV​ ​involved in a majority of ​Wolbachia​ mechanisms of blocking. Metabolism Factor Still Poorly Understood and May Play a Minor Role We found the role of ​Ae. aegypti metabolism is still poorly understood because there is still no direct evidence of how it would influence DENV blocking. First, a study by Koh et al. that assess lipid influence on DENV blocking. There is limited evidence in that study Wolbachia and DENV antagonize each other for host lipid.​22 ​Next study by Amuzu et al., that repeated blood-feeding does not contribute to DENV blocking and does not increase

Wolbachia density.​23 Interestingly, low carbohydrate administration could reduce the induction of ROS in ​Wolbachia-​ infected mosquitoes instead of higher supplementation of carbohydrates that induce ROS.​11 Based on these findings, metabolism factors may play a minor role in DENV blocking. Innate immune Factor not Associated with DENV Blocking According to an assessment by Johanna et al., there are some immune components including cecropin D, cecropin E, defensin, C-type lectin, and transferrin in mosquito carrying ​Wolbachia​. Among those, ​w​MelPop had an increased level of each component compared to control, the smallest increase in C-type lectin (10-fold increase) and the biggest

is for Defensin C (250x). However, the ​w​Mel mosquito had a significant increase in cecropin

E and defensin C, but lesser than ​w​MelPop. Interestingly, C-type lectin decreased in all

strains except in ​w​MelPop.​13 These results show that the immune response is not associated with DENV blocking. In ​Wolbachia​-mediated DENV, blocking was not affected by altered microbiome

composition that is part of the innate immune system in ​Ae. aegypti​ .​16 At first, Pearce et al.

thought that the diet of ​Wolbachia infected mosquitoes would affect the mosquito's immune

system because in their experiment about the relationship between diet and the DENV load stated that there is a correlation. However, in ​Wolbachia ​infected mosquitoes, dietary changes

did not significantly affect immune system expression.​11 Innate immune in ​Ae. aegypti ​does not take part in DENV blocking but may act as defense against another pathogen.

Comparison Between ​Wolbachia​ Strains

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In a study comparing each strain's effectiveness, the ​w​MelCS strain had a better effect

on inhibiting DENV replication compared to ​the w​Mel strain.​24 Another strategy used by

Joubert et al. combines the two ​Wolbachia ​strains, ​w​Mel and ​w​AlbB, which can be called superinfection and proven to be more effective than a single infection.​25 Because the total

Wolbachia ​density in the ​w​Mel and ​w​AlbB line was higher than in either parental line and

comparable to the virulent ​wM ​ elPop-CLA strain. Discussion

Conventional vector control strategies perceive the mosquito as a foe to eliminate. However, The main aim of ​Wolbachia ​intervention is to block DENV infection in mosquitoes

to reduce the transmission.​4 Next advantage created by ​Wolbachia is cytoplasmic

incompatibility (CI) which happens when uninfected females mate with infected males, it will become sterile. This allows ​Wolbachia to ​spread quickly to uninfected populations.​5

Based on the studies included in this systematic review, we found ​Wolbachia block

DENV ​in several parts in ​Ae. aegypti such as ovary, head, body, and saliva. ​Wolbachia has many factors that affect its DENV blocking ability. The author categorizes these as three categories: gene regulation factor, metabolism factor, and innate immune factor. ​Wolbachia

can change some processes in ​Ae. aegypti​. The first one is ​Cadherin gene which plays a role

in cell-cell adhesion, cytoskeleton, and the intracellular signal.​18 DENV relies on cytoskeleton host to internal replication and moving inside the cell.​18 ​Wolbachia ​also has some

gene-manipulating effect on cell-cell adhesion, which could explain ​Wolbachia's ​connection and its DENV blocking ability.​18 AeVago is an insect-specific antiviral protein that is

upregulated upon infection of ​Wolbachia, possibly through the activated immune response of

the mosquitos; meanwhile, it is not produced after DENV infection, suggesting another mechanism in which ​Wolbachia can block DENV.​18 ​Wolbachia also affects the

downregulation of enzyme ​AeCHD7,​ which can interrupt the virus-host interaction and therefore play roles in DENV blocking.​20

Another factor is the metabolism factor, but the exact mechanism of DENV blocking is still unknown. Several factors are the host lipid competition between ​Wolbachia and DENV, repeated blood-feeding of DENV, and carbohydrate nutrients, resulting in ROS.​23 However, these factors are not significantly correlated to the DENV blocking effect of Wolbachia​ ​in ​Ae. aegypti​ which is also essential regarding the DENV load in the mosquito. Some immune components, like Cecropin D, cecropin E, defensin, C-type lectin, and transferrin are upregulated in ​Wolbachia carrying ​Ae. aegypti​, but these elevated immune 130


response is not associated with the appropriate DENV load in ​Ae. aegypti​.13 ​ Microbiome in

Ae. aegypti c​ omposition can also affect ​Wolbachia and DENV in the mosquito, which could

possibly affect the mechanism of blocking.​16 However, in the study, there is no correlation between microbiome and DENV infection in​ Ae. aegypti​.

Recently, ​Wolbachia has been utilized as a biocontrol agent in many countries such as

Australia, Indonesia, and Singapore.​26-28 Five years' effect of ​Wolbachia ​intervention in Australia has been demonstrated by Peter et al., the incidence of dengue has been reduced by 96% in the treated population.​26 If we are able to optimize many factors that could enhance DENV blocking, we hypothesize that ​Wolbachia ​may effectively reduce the incidence of dengue in the shorter term. The authors also acknowledge there is some limitation in this systematic review. First, we include animal studies in laboratory settings to measure DENV blocking; this may have resulted in different field outcomes. Second, we include several different strains of Wolbachia ​and DENV that might affect each study's result. On the bright side, the author believes a laboratory setting is the best method to homogenize data and mitigate external factors that may influence outcomes. Conclusion Dengue is spread by the bite of ​Ae. aegypti​. Controlling the vector is the key to

eradicate this disease. We believe ​Wolbachia ​has the potential to reduce transmission and

make ​Ae. aegypti resistant to DENV. ​Wolbachia ​have been proven to reduce DENV load in the ovary, head, body, and saliva. These processes are affected by two main factors, gene

expression factor and metabolism factor. ​Wolbachia superinfection is an interesting strategy

that is quite effective in DENV blocking but needs more research to unravel its potential. Overall, ​Wolbachia ​is an effective biocontrol agent and there are already several ongoing

field trials in many countries. We hope ​Wolbachia ​can immediately be applied to endemic areas and eradicate dengue. Conflict of Interest The author declares that there are no competing interests in this study.

References

131


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4. Dorigatti I, McCormack C, Nedjati-Gilani G, et al. Using Wolbachia for Dengue Control: Insights from Modelling. Trends Parasitol 2018; 34: 102–113. 5. Hoffmann AA, Montgomery B, Popovici J, et al. Successful establishment of Wolbachia in Aedes populations to suppress dengue transmission. Nature 2011; 476: 454–457. 6. Asad S, Hussain M, Hugo L, et al. Suppression of the pelo protein by Wolbachia and its effect on dengue virus in Aedes aegypti. ​PLoS Negl Trop Dis​ 2018; 12: e0006405–e0006405. 7. Fraser JE, De Bruyne JT, Iturbe-Ormaetxe I, et al. Novel Wolbachia-transinfected Aedes aegypti mosquitoes possess diverse fitness and vector competence phenotypes. PLoS Pathog​ 2017; 13: e1006751–e1006751. 8. King JG, Souto-Maior C, Sartori LM, et al. Variation in Wolbachia effects on Aedes mosquitoes as a determinant of invasiveness and vectorial capacity. ​Nat Commun 2018; 9: 1483–1483.

9. David Moher, Larissa Shamseer, Mike Clarke, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev. 2015 1 January;4:1. 10. OHAT (Office of Health Assessment and Translation) OHAT risk of bias rating tool for human and animal studies. 2015. 11. Caragata EP, Rezende FO, Simões TC, et al. Diet-Induced Nutritional Stress and Pathogen Interference in Wolbachia-Infected Aedes aegypti. ​PLoS Negl Trop Dis 2016; 10: e0005158–e0005158. 12. Pacidônio EC, Caragata EP, Alves DM, et al. The impact of Wolbachia infection on the rate of vertical transmission of dengue virus in Brazilian Aedes aegypti. ​Parasit Vectors​ 2017; 10: 296–296.1.

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13. Fraser JE, O’Donnell TB, Duyvestyn JM, et al. Novel phenotype of Wolbachia strain wPip in Aedes aegypti challenges assumptions on mechanisms of Wolbachia-mediated dengue virus inhibition. ​PLoS Pathog​ 2020; 16: e1008410–e1008410.1.

14. Walker T, Johnson PH, Moreira LA, et al. The wMel Wolbachia strain blocks dengue and invades caged Aedes aegypti populations. ​Nature​ 2011; 476: 450–453.1.

15. Ferguson NM, Kien DTH, Clapham H, et al. Modeling the impact on virus

transmission of Wolbachia-mediated blocking of dengue virus infection of Aedes aegypti. ​Sci Transl Med​ 2015; 7: 279ra37-279ra37.1. 16. Audsley MD, Ye YH, McGraw EA. The microbiome composition of Aedes aegypti is not critical for Wolbachia-mediated inhibition of dengue virus. PLoS Negl Trop Dis 2017; 11: e0005426. 17. Amuzu HE, McGraw EA. Wolbachia-Based Dengue Virus Inhibition Is Not Tissue-Specific in Aedes aegypti. PLoS Negl Trop Dis 2016; 10: e0005145.1. 18. Ford SA, Allen SL, Ohm JR, Sigle LT, Sebastian A, Albert I, et al. Selection on Aedes aegypti alters Wolbachia-mediated dengue virus blocking and fitness. Nature Microbiology. 2019 Nov 1;4(11):1832–9. 19. Zhang G, Hussain M, O’Neill SL, et al. Wolbachia uses a host microRNA to regulate transcripts of a methyltransferase, contributing to dengue virus inhibition in Aedes aegypti. Proceedings of the National Academy of Sciences 2013; 110: 10276–10281.1. 20. Asad S, Hall-Mendelin S, Asgari S. Downregulation of Aedes aegypti chromodomain helicase DNA binding protein 7/Kismet by Wolbachia and its effect on dengue virus replication. ​Sci Rep​ 2016; 6: 36850–36850. 21. Zhang G, Hussain M, Asgari S. Regulation of arginine methyltransferase 3 by a Wolbachia-induced microRNA in Aedes aegypti and its effect on Wolbachia and dengue virus replication. ​Insect Biochemistry and Molecular Biology​ 2014; 53: 81–88. 22. Koh C, Islam MN, Ye YH, et al. Dengue virus dominates lipid metabolism modulations in Wolbachia-coinfected Aedes aegypti. Commun Biol 2020; 3: 518.1. 23. Amuzu HE, Simmons CP, McGraw EA. Effect of repeat human blood feeding on Wolbachia density and dengue virus infection in Aedes aegypti. ​Parasites Vectors 2015; 8: 246.

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24. Flores HA, Taneja de Bruyne J, O’Donnell TB, et al. Multiple Wolbachia strains provide comparative levels of protection against dengue virus infection in Aedes aegypti. ​PLoS Pathog​ 2020; 16: e1008433–e1008433.1.

25. Joubert DA, Walker T, Carrington LB, et al. Establishment of a Wolbachia Superinfection in Aedes aegypti Mosquitoes as a Potential Approach for Future Resistance Management. ​PLoS Pathog​ 2016; 12: e1005434–e1005434.

26. Tantowijoyo W, Andari B, Arguni E, et al. Stable establishment of wMel Wolbachia in Aedes aegypti populations in Yogyakarta, Indonesia. PLoS Negl Trop Dis 2020; 14: e0008157–e0008157. 27. Sim S, Ng LC, Lindsay SW, et al. A greener vision for vector control: The example of the Singapore dengue control programme. PLoS Negl Trop Dis 2020; 14: e0008428–e0008428. 28. Ryan PA, Turley AP, Wilson G, et al. Establishment of wMel Wolbachia in Aedes aegypti mosquitoes and reduction of local dengue transmission in Cairns and surrounding locations in northern Queensland, Australia. Gates open research; 3.

134


Appendices Supplemental Table 1. Search Keyword Databases

PubMed

Keywords

Articles

("Aedes"[Mesh] OR aedes[Title/Abstract] OR aede[Title/Abstract]) AND ("​Wolbachia"​ [Mesh] OR

138

Wolbachia​[Title/Abstract]) AND ("Dengue Virus"[Mesh] OR "Dengue Virus"[Title/Abstract] OR "Dengue Viruses"[Title/Abstract] OR "Breakbone Fever Virus"[Title/Abstract] OR "Breakbone Fever Viruses"[Title/Abstract])

ProQuest

ab(aedes OR aede) AND ab(​Wolbachia​) AND ab("dengue

viruses" OR "dengue virus" OR "breakbone fever virus" OR

67

"breakbone fever viruses")

ScienceDirect

(Aedes OR aede) AND ​Wolbachia​ AND (dengue virus OR

dengue viruses OR Breakbone Fever Virus OR Breakbone Fever

26

Viruses)

EBSCO

AB (aedes OR aede) AND ("​Wolbachia​" OR ​Wolbachia)​ AND

("Dengue Viruses" OR "Breakbone Fever Virus" OR "Breakbone Fever Viruses"))

135

17


Supplemental Table 2. Table Characteristic of the Included Study Author

Study

Mosquit

Wolbach

Dengue

design

o species

ia​ strain

strain

Amuzu

Animal

Ae.

and

Study

aegypti

w​Mel

DENV 3

Outcomes

Correlation between Wolbachia​ density and

McGraw,

DENV load in individual

2016

tissues

Result

Wolbachia​ tissue densities in the

mosquito are not linear predictors of DENV load DENV inhibition is unlikely to be explained by tissue specific mechanisms

Zhang et

Animal

Ae.

al., 2013

Study

aegypti

w​MelPop

NR

-CLA

The impact of ​Wolbachia

Aae-miR-2940 plays an

and up-regulation

important role in the maintenance

of aae-miR-2940 on

of ​Wolbachia​ infection.

AaDnmt2 and possible

in mosquito cells and contributes

impact of regulation of the

to the resistance to DENV

target gene on DENV

infection in mosquito cells

replication Amuzu et

Animal

Ae.

al., 2015

Study

aegypti

w​Mel

DENV 2

Relationship between

Repeat feeding does not lead to

human blood feeding,

subsequent increases in ​Wolbachia

Wolbachia ​densities and

Koh et al.,

Animal

Ae.

2020

Study

aegypti

Audsley et

Animal

Ae.

al., 2017

Study

aegypti

Asad et

Animal

Ae.

al., 2018

Study

aegypti

w​Mel

w​Mel

w​MelPop

DENV 3

DENV 2

DENV-2

density nor increases effectiveness

DENV blocking.

of DENV blocking

Lipids involvement with

limited evidence for competition

Wolbachia​ mediated

between DENV3 and ​Wolbachia

viral blocking.

for the same host lipids.

Assess involvement of

Alteration in the

mosquito microbiota in

microbiome composition

Wolbachia​-mediated

did not affect DENV blocking by

blocking

w​Mel

Explored the involvement

Pelo is positively involved in

of the pelo protein, in

DENV replication, and its

Wolbachia​-mediated

suppression in the presence of

antiviral response and

Wolbachia​ may contribute to virus

mosquito-DENV

blocking.

interaction. Asad et

Animal

Ae.

al., 2016

Study

aegypti

w​MelPop -CLA

DENV2

AeCHD7​ effect in

Wolbachia​-DENV

136

AeCHD7​ is important for DENV replication, and ​Wolbachia


replication,

downregulates it, which may contribute towards the mechanism(s) of limiting DENV replication

Ford et al.,

Animal

Ae.

2019

Study

aegypti

w​Mel

DENV 3

To know the mechanism

There are some factors that can

and the factors involved in

involve ​Wolbachia​ mechanism

Wolbachia ​to reduce

Asad et

Animal

Ae.

sl., 2017

Study

aegypti

w​MelPop

DENV-2

including high-blocking genotypes

dengue virus in ​Ae. aegypti

and cadherin gene

Role of AeVago1, in

The ​Wolbachia​-induced AeVago1

Wolbachia​-mosquito-DEN V interactions.

in ​Ae. aegypti​ may function as a host factor to suppress DENV replication in the mosquito

Zhang et

Animal

Ae.

al., 2014

Study

aegypti

w​MelPop

DENV-2

AaArgM3 roles in

AaArgM3 plays an important role

Wolbachia ​infection in

in the maintenance of ​Wolbachia

V interactions

no effect on DENV replication.

The role of diet-induced

The change in diet did not

nutritional stress on

significantly affect immune

interference against DENV

expression, but low carbohydrate

and the avian malarial

levels led to a loss of ROS

parasite ​Plasmodium

induction in ​Wolbachia​-infected

Wolbachia-​infected ​Ae.​

host nutrition may not influence

Wolbachia​-mosquito-DEN

Pearce et

Animal

Ae.

al., 2016

Study

aegypti

w​Mel

DENV- 3

gallinaceum​ in

aegypti​, and on

physiological processes

infection in mosquito cells but has

mosquitoes.

DENV interference for Wolbachia​-infected mosquitoes

linked to the phenotype Flores et

Animal

Ae.

w​MelCS

DENV

Compare ​Ae​. ​aegypti

al., 2020

Study

aegypti

or

1-4

mosquitoes infected with

w​Mel,​w

w​MelCS or ​w​AlbB to the widely used ​w​Mel

AIbB

Wolbachia​ strain

Blocking of DENV replication was greatest by ​w​MelCS, but no

difference was observed between w​Mel-infected mosquitoes from each background suggesting that Wolbahia​ may override any underlying variation in DENV transmission potential

Joubert et

Animal

Ae.

w​Mel

al., 2016

study

aegypti

Fraser et

Animal

Ae.

al., 2017

Study

aegypti

To know the ​ Wolbachia

Wolbachia​ superinfections are

and

superinfection effectivity in

more effective at blocking dengue

w​AlbB

controlling dengue virus

than single infections.

Restriction of DENV-3

w​MelCS significantly reduces

w​MelCS, w​Ri,

DENV-2

DENV-3

replication

137

DENV RNA levels in mosquito


w​Pip Etiene et

Animal

Ae.

al., 2017

Study

aegypti

w​Mel

bodies and heads DENV-4,

DENV load in the ovaries

Wolbachia​ strain ​w​Mel

DENV

significantly decrease DENV load

-1,

in the ovaries of the mosquito

DENV -3 Johanna et

Animal

Ae.

al., 2020

Study

Aegypti

w​Mel

DENV-3

DENV Replication effect of Wolbachia​ strain ​w​Mel.

w​Mel significantlyl restricted DENV replication compared to its matched control line in the bodies,

Wolbachia ​density and its

head, and saliva of the mosquito

viral inhibition effect Innate immune response of the Wolbachia​-mediated

mosquito does not affect the

antiviral protection and

DENV replication in​ Wolbachia

innate immune response

infected mosquito

pathways and viral inhibition

High ​Wolbachia​ density is not required for viral inhibition

Walker et

Animal

Ae.

al.,2011

Study

aegypti

w​Mel

DENV-2

DENV load in mosquito

Total DENV-2 levels in

bodies upon ​Wolbachia

w​Mel-infected MGYP2.OUT

infection

females (whole bodies) were markedly reduced by ​Wolbachia

Ferguson

Animal

Ae.

et al.,

Study

aegypti

2015

w​Mel

DENV 1-4

DENV concentration in

compared to control

saliva of the Mosquito

Complete blockage of DENV-2

following ​Wolbachia

transmission in the saliva of the

infection

mosquito

Wolbachia​ strains ​w​Mel

w​MelPop has strong resistance to

and ​w​MelPop effects on

DENV load in the mosquito

DENV infection of mosquito abdomen tissue and largely prevented disseminated infection.

DENV salivary concentration in w​MelPop-infected mosquitos

w​MelPop mosquito has significantly lower DENV virus in saliva compared to control Abdomen infections were significantly lower in ​w​Mel compared to wild type

138


w​Mel reduce the basic

reproduction number, ​R​0​, of DENV transmission by 66–75%

DENV : Dengue virus NR

: Not reported

139


Supplemental table 3. ​Risk of bias summary: review authors’ judgements about each risk of bias item for each included study

Author

Selection Bias

Performance Bias

Attrition/

Detection Bias

Selective

Exclusion

Reporting

Bias

Bias

Other Bias

Was

Was

Were

Were the

Were

Can we

Can we

Were all

Were there no

administered

allocation to

experiment

research

outcome data

be

be

measured

other potential

dose or

study groups

al

personnel and

complete

confiden

confide

outcomes

threats to

exposure level

adequately

conditions

human subjects

without

t in the

nt in the

reported?

internal validity?

adequately

concealed?

identical

blinded to the

attrition or

exposure

outcom

across study

study group

exclusion

characte

e

groups?

during the

from

rization?

assessm

study?

analysis?

randomized?

Amuzu and McGraw, 2016 Zhang et al., 2013

Amuzu et al., 2015

Koh et al., 2020

Audsley et al., 2017

Asad et al., 2018

Asad et al., 2016

Ford et al., 2019

Asad et sl., 2017

Zhang et al., 2014

140

ent?


Pearce et al., 2016

Flores et al., 2020

Joubert et al., 2016

Fraser et al, 2017

Etiene et al., 2017

Johanna et al., 2020

Walker et al.,2011

Ferguson et al., 2015

Definitely low risk of bias

Probably low risk of bias

Probably high risk of bias

Definitely high risk of bias

141


Fig 1. ​PRISMA flow diagram of the identification and selection of studies included in the analysis

142


Determination of the Drug of Choice for Mass Drug Administration and Suppresion of Growth Impairment in Children with Helminthiasis: A Systematic Review and MetaAnalysis Actualization of the 2030 Targets for Soil-Transmitted Helminthiases Control Program Ivena Leonita 1*, Nathanael Ibot David 1, William Wiradinata 1 1

Faculty of Medicine, Brawijaya University, Malang, Indonesia *leonita.ivena@gmail.com; +62 81233099463

Introduction: Soil transmitted helminths (STH) infections are common infectious disease that affect

people

worldwide.

Three

species

categorized

as

STH

are

Ascaris

lumbricoides (roundworm), Necator americanus and Ancylostoma duodenale (hookworm), and Trichuris trichiura (whipworm). Being the most impacted group, children may experience growth disturbance due to the infections. Mass Drug Administration (MDA) using albendazole or mebendazole monotherapy is one of the world’s effort to eradicate STH infections. Material and Methods: This review is conducted based on PRISMA guidelines. Studies were searched using electronic databases, with the keywords “Soil Transmitted Helminths”, “Albendazole”, “Mebendazole”, and “Efficacy”, ranging from 2011-2020. Studies selected evaluated the efficacy of STH treatment on children. Cochrane-risk-of-bias tool was used to assess bias among studies. Mantel-Haenzel method and random effects model were used to generate the statistical analysis. Results and Discussion: Albendazole and mebendazole was evaluated as monotherapy and combination of therapies. Both drug as monotherapy was effective against Ascaris lumbricoides, quite effective against hookworm, and not effective against Trichuris trichiura. Combination of therapies showed higher efficacy against STH infections, compared to monotherapy. This suggests that current MDA regimen, which uses monotherapy, may not have the desired outcome. Also, nutrition profile increases along with the decrease of infection in children. Hence, choosing the right MDA regimen is beneficial in curing the disease and improving nutrition in children. Conclusions: Albendazole and mebendazole monotherapy only works for Ascaris lumbricoides and hookworm, and does not work in curing Trichuris trichiura. Changing the regimen administered as MDA into combination of therapies instead of monotherapy may improve the efficacy against STH infections and nutrition profile in children. Keywords: Soil-transmitted helminths, mass drug administration, albendazole, mebendazole

143


144


INTRODUCTION

America. Among such poverty-ridden

Soil-Transmitted Helminths (STH)

communities, pediatric helminth infections

infections are among the most common

also cost severe social repercussions [5].

infectious disease in children worldwide,

The manifestation of the disease burden in

yet STH infection is still classified as a

children is mainly shown as nutritional

Neglected

Disease

stress, poor appetite, food indigestion,

STH

malabsorption (manifested as vitamin A

(roundworm),

and iron deficiency), impaired growth, and

Necator americanus and Ancylostoma

anemia. The risk of infection also increases

duodenale (hookworm), and Trichuris

in children with malnutrition; therefore, it

tichiura

also

I.

Tropical

(NTD). Species are Ascaris

included

lumbricoides

(whipworm).

in

The

highest

increases

morbidity

in

these

prevalence is in developing countries.

individuals with STH. Impaired growth,

According to WHO, 24% of the world’s

especially in preschool-age children, is

population

billion

manifested as stunting and wasting [6, 7]. A

people) suffer from STH infection, and the

study conducted in China shows that

most affected age groups are preschool-age

children with STH infections have worse

and school-age children [1]. In Indonesia,

cognitive ability and school performance

the prevalence can range from 45%-65%,

than their fellow peers that are not infected

and it can reach 80% in areas with poor

[8].

(approximately 1.5

sanitation and hygiene [2]. Due to the high

When compared, STH deworming

number of pediatric cases globally, this has

is less expensive than its diagnosis, and it is

become special attention towards the STH

also safe. Hence in 2017, WHO published a

eradication target in 2030, which was

guideline

proclaimed by WHO and agreed upon by

chemotherapy, also known as Mass Drug

the international community [3].

Administration (MDA), to control STH

Few factors contribute to STH transmission,

including

regarding

preventive

infections in at-risk population groups,

socioeconomic

using

benzimidazole group of drugs

status, hygiene, sanitation, shoe-wearing

(Albendazole,

habit, clean water supply, and waste

Therefore, evidence gathering to prove and

disposal system [4]. It is indisputable that

search for the most potent drug for MDA is

various STH cases still can be found in

needed to improve the likelihood of

impoverished

lowering

communities,

even

in

or

Mebendazole)

even

[5,

eradicating

9].

STH

countries with adequate socioeconomic

infections. This systematic review aims to

conditions such as the United States of

assess

145

albendazole

and

mebendazole


medication's efficacy in the form of

and mebendazole, albendazole and oxantel

monotherapy

pamoate, albendazole and praziquantel,

or

combination

therapy

against STH infections.

mebendazole

I.

MATERIAL AND METHODS

albendazole and pyrantel pamoate and

The

this

oxantel pamoate, mebendazole and pyrantel

the

pamoate and oxantel pamoate. Intervention

PRISMA statement’s flow diagram and

is administered at any dose, by any route,

checklist to assure the quality of this review

and for any duration.

systematic

[10].

authors review

Matters

conducted according

considered

to

crucial

for

and

pyrantel

pamoate,

c. Type of outcome measures

transparent reporting of a systematic review

Outcomes of interest included (1)

such as title, introduction, methods, result,

determining anthelminthic drug with the

and discussion were included in the

best efficacy for the implementation of

checklist.

Mass Drug Administration (MDA) based

1. Eligibility

Criteria

for

on its STH etiology, and (2) determining

Human

the form of treatment administration

Clinical Trials

(monotherapy or combination therapy) with

a. Types of participants Studies

included

in

this

review

the best efficacy for the implementation of

involves preschool-age and school-age

Mass Drug Administration (MDA) based

children, ranging from 4 to 18 years old,

on its STH etiology.

with a soil-transmitted helminths infection.

2. Search Strategy

Studies that included patients above the age

Authors

searched

electronic

of 18 or other types of helminths infection

literature using search engines such as

were excluded.

Google Scholar, PubMed, ScienceDirect, Cochrane, and ResearchGate from 2011-

b. Type of interventions

2020.

The intervention was chosen to be

Keywords

used

were:

(“Soil-

included any anthelminthic drugs from the

transmitted helminths” OR “STH” OR

benzimidazole group, such as albendazole

“Ascaris

and

“Hookworm*” OR “Trichuris trichiura*”)

mebendazole.

Both

drugs

are

monotherapy

or

administered

as

combination

therapy

AND

lumbricoides*” (“Treatment”)

OR AND

other

(“Albendazole*” OR “Mebendazole*” OR

anthelminthic drugs (the combination of

“Ivermectin*” OR “Oxantel Pamoate*”)

two or three therapies and multiple-dose

AND (“Efficacy”) AND (“Randomized

therapy). The combinations used are

Controlled Trial*” OR “RCT*”). Wildcard

albendazole and ivermectin, albendazole

term was used to improve the sensitivity of

with

146


the search strategy. Studies included were

95%

original research that assessed the efficacy

random-effects model was used because of

of anthelminthic drugs on children with

the variance in substance used across

STH infection. All of the authors evaluated

studies. P ≤

the journals individually and differences of

statistically significant. Bias in studies used

opinion between the authors were discussed

in

and eventually resolved.

visually using a funnel plot.

3. Data Extraction and Analysis

II.

Data extracted from studies found to

confidence

the

intervals

0.05

meta-analysis

was

were

(CI).

The

considered

evaluated

RESULTS

1. Study Identification and Selection

be eligible are: author’s name, year of

After a thorough search for studies in

publication, place where the study was

numerous databases, 214 studies were

performed,

found. A total of 39 studies were excluded

study design,

samples,

sample

interventions

forms,

number

of

characteristics, and

due

to

its

weak

presentations

and

measured

methodology. Another 27 that involved

outcomes. The authors examined and

adults as participants were also excluded,

summarized the study's outcomes and

leaving nine eligible studies to be included

emphasized the statistical results.

in qualitative and quantitative analysis. All

4. Risk of Bias Assessment

authors agreed on all of the studies being

The quality of this study was

included in this review.

evaluated by three reviewers with an equal

2. Risk of Bias Assessment

portion by using the Cochrane-risk-of-bias

Authors assessed the studies included

tool. Bias assessed include selection bias,

in this review for risk of bias using the

measurement of exposure, confounding

Cochrane Risk do Bias Tool. The risk of

variables, blinding, missing data, and

bias is mostly low and unclear (see Table

reporting bias. Differences between authors

2).

were resolved by discussion.

3. Study Characteristics Summary of characteristics of the

5. Statistical Analysis Meta-analysis was created using

studies included are presented in Table 1.

Review Manager 5.4. Data gathered from

4. Meta-analysis of Primary Outcome

studies

were

dichotomized

into

two

Based on the studies' data, the efficacy

categories. The evaluation was based on

of albendazole and mebendazole as an

cure rate (CR) and dichotomized into cured

anthelminthic

and uncured. The mantel-Haenzel method

lumbricoides, hookworm, and Trichuris

were used as the statistical method with

trichiura was evaluated. Meta-analysis was

147

drug

against Ascaris


appraised from the number of people cured

Based on six studies that were assessed

and uncured at the end of treatment.

[11-16], albendazole was found to be

a. Efficacy against Ascaris lumbricoides

significantly inefficacious to treat Trichuris

Based on six studies that were

trichiura infection (see Figure 6). The

evaluated [11-16], albendazole was found

same thing with mebendazole, after five

to

studies were evaluated [13,15-19], it was

be

significant

in

curing Ascaris

lumbricoides infection (see Figure 2). A

discovered

similar thing can be found in the evaluation

significantly ineffective (see Figure 7).

of five studies regarding the efficacy of

Test for heterogeneity showed significant

mebendazole against Ascaris lumbricoides

conditions for all evaluations. A funnel plot

[13,15,17-19],

was

created for qualitative observations for both

in

albendazole and mebendazole exhibited

curing Ascaris lumbricoides infection (see

that data gathered has a risk of reporting

Figure 3). Test for heterogeneity showed

bias.

discovered

mebendazole to

be

significant

significant conditions for all evaluations. A funnel

plot

created

for

that

mebendazole

5. Meta-analysis

qualitative

of

was

Secondary

Outcome

observations for albendazole showed that

Based on the studies' data, the efficacy

data gathered has a low risk of reporting

of

albendazole

and

mebendazole

as

bias, while funnel plot for mebendazole

monotherapy and combination therapy

showed risk of reporting bias.

against Ascaris lumbricoides, hookworm,

b. Efficacy against Hookworm

and Trichuris trichiura infection was

Based on six studies that were assessed

evaluated. Meta-analysis was appraised

[11-16], albendazole was found to be

from the number of people cured and

significant in curing hookworm infection

uncured at the end of treatment.

(see Figure 4). Nonetheless, an evaluation

a. Efficacy

of

of five studies found that mebendazole

Monotherapy

usage was significantly ineffective (see

Therapy

Figure

lumbricoides

5)

heterogeneity

[13,15-18]. showed

Test

for

significant

Two

studies

Albendazole and

as

Combination

against

[11-12]

Ascaris

conveyed,

conditions for all evaluations. A funnel plot

albendazole as monotherapy is significant

created for qualitative observations for both

in curing Ascaris lumbricoides. It is also

albendazole and mebendazole showed that

significantly efficacious as a combination

data collected has a risk of reporting bias.

of two therapies, assessed from four studies

c. Efficacy against Trichuris trichiura

[13-16]. Test for heterogeneity showed

148


significant

conditions

for

both

monotherapy and combination of two

monotherapy and combination of two

therapies. In the other hand, evaluated from

therapies

Furthermore,

one study, the combination of three

combination of three therapies is also

therapies is significantly effective [13].

significant in curing the infection [13]. Test

However, test for heterogeneity was not

for heterogeneity was not applicable (see

applicable (see Figure 4).

evaluation.

Figure 2).

d. Efficacy

b. Efficacy

of

Mebendazole

Monotherapy

and

as

Monotherapy

Combination

studies

mebendazole

[15,17-19]

as

and

as

Combination

Based on four studies evaluated,

showed,

monotherapy

Mebendazole

Therapy against Hookworm

Therapy against Ascaris lumbricoides Four

of

mebendazole

as

monotherapy

is

is

significantly ineffective against hookworm

for Ascaris

[15-18], and test for heterogeneity showed

heterogeneity

significant conditions. Nevertheless, it is

showed significant conditions. It is also

significantly efficacious as a multiple-dose

significant in curing the infection as a

therapy, assessed from one study [17].

combination of two therapies [19]. On the

Evaluated from one study, the combination

contrary, the combination of three therapies

of three therapies is also significantly

is significantly ineffective [13]. In addition,

effective [13]. Test for heterogeneity was

a multiple-dose therapy is significantly

not applicable for evaluations that only

effective

included one study (see Figure 5).

significantly

therapeutic

lumbricoides.

Test

[17].

for

However,

test

for

heterogeneity was not applicable for

e. Efficacy

of

Albendazole

evaluations that only included one study

Monotherapy

(see Figure 3).

Therapy against Trichuris trichiura

c. Efficacy

of

Monotherapy

Albendazole and

Two

as

studies

indicated

Combination

revealed

[11-12],

albendazole as monotherapy is significantly

Combination

ineffective against Trichiuris trichiura, and

Therapy against Hookworm Two

studies

and

as

[11-12],

test for heterogeneity showed significant

albendazole as monotherapy is significant

conditions. As a combination of two

in curing hookworm. It is also significantly

therapies, it is also significantly ineffective,

efficacious as a combination of two

assessed from four studies [13-16], and test

therapies, assessed from four studies [13-

for

16]. Moreover, test for heterogeneity

conditions. However, evaluated from one

showed significant conditions for both

study [13], the combination of three

149

heterogeneity

showed

significant


therapies is significantly effective. Test for

infections [2, 4]. WHO recommends Mass

heterogeneity was not applicable (see

Drug Administration (MDA) using of

Figure 6).

albendazole

f. Efficacy

of

and

mebendazole

to

be

as

administered to young children, preschool

Combination

and school-age children, which they

Mebendazole

Monotherapy

or

Therapy against Trichuris trichiura

recommend annual or biannual single-dose

According to the evaluation of five

albendazole (400 mg) or mebendazole (500

studies

[15-19],

mebendazole

as

mg) for all young children (12–23 months

monotherapy is significantly inefficacious

of age), preschool (24–59 months of age)

against

for

and school-age children living in areas

significant

where the baseline prevalence for any STH

significantly

is 20% or higher among children. This

inefficacious as a multiple-dose therapy,

regimen is strongly recommended by WHO

assessed from one study [17]. Nonetheless,

despite its low quality of evidence [9].

Thichuris trichiura.

heterogeneity conditions.

showed It

is

also

Test

as a combination of two therapies it is

After evaluating eight studies that

significantly effective, assessed from one

conducted trials of various combination of

study [19]. Evaluated from one study, the

albendazole and mebendazole treatment,

combination of three therapies is also

authors concluded that albendazole (risk

significantly effective

for

difference (RD) = 0.89, P < 0.00001) is

heterogeneity was not applicable for

superior than mebendazole (risk difference

evaluation that only included one study (see

(RD) = 0.65, P < 0.00001) in curing Ascaris

Figure 7).

lumbricoides infection.

III.

DISCUSSION

mebendazole also showed efficacy that is

Soil-transmitted helminths (STH)

quite high, even though it is lower than

comprise

of Ascaris

hookworm

(Necator

[13].

Test

lumbricoides,

albendazole. All types of administration of

and

albendazole are very efficacious, but it is

Ancylostoma duodenale), and Trichuris

best to be administered as a combination of

trichiura. Infections caused by STH are

two therapies (risk difference (RD) =

spread across the world, with higher

0.96, P < 0.00001). As a monotherapy, both

prevalence can be found in areas with poor

albendazole and mebendazole exhibited a

hygiene,

very high efficacy. This proves that the use

poverty,

americanus

Nonetheless,

and

overcrowded.

Children are the most affected group, and

of

numerous aspects of children's growth and

mebendazole

development

currently being used as a Mass Drug

are

impacted

by

these

150

albendazole

monotherapy

monotherapy

that

or are


Administration (MDA) to treat Ascaris

efficacy and the best chance of curing

lumbricoides might

hookworm infection.

be

appropriate,

although albendazole as combination of

Based on nine studies assessed, this

two therapies is preferred. According

studies

infection to cure. Both albendazole (risk

evaluated, albendazole (risk difference

difference (RD) = -0.08, P < 0.00001) and

(RD) = 0.60, P < 0.00001) is found to be

mebendazole (risk difference (RD) = -

more effective against hookworm than

0.52, P < 0.00001) do not show efficacy

mebendazole. In fact, mebendazole (risk

against Trichuris trichiura. However, when

difference (RD) = -0.06, P < 0.00001) was

both are compared, albendazole is more

discovered to be ineffective. Albendazole

effective despite the poor overall result.

as a monotherapy (risk difference (RD) =

According to the forest plot, albendazole as

0.78, P < 0.00001) is shown to be the most

a combination of three therapies favored to

efficacious compared to the other type of

cured and exhibited the best efficacy among

administration. Contrary to its effect

other types of administration. As a

on Ascaris lumbricoides, albendazole as a

monotherapy (risk difference (RD) = -

combination

0.09, P < 0.00001), albendazole is close to

of

to

species was by far the hardest STH

two

eight

therapies

(risk

difference (RD) = 0.18, P < 0.00001) has

being

the poorest outcome against hookworm. On

trichiura infection. On the other hand,

the

a

mebendazole as a monotherapy (risk

monotherapy (risk difference (RD) = -

difference (RD) = -0.78, P < 0.00001) has

0.61, P < 0.00001) showed the worst

the poorest efficacy. Nevertheless, efficacy

outcome. This finding was a complete

of mebendazole as a combination of two

opposite of WHO recommendation, which

(risk difference (RD) = 0.82, P < 0.00001)

was

as

and three (risk difference (RD) = 0.77, P <

monotherapy for MDA. The use of

0.00001) therapies are quite high. As a drug

mebendazole as a monotherapy to treat

that are being administered for MDA, it is

STH should be an important matter to be

doubtful

reconsidered,

of

monotherapy or mebendazole monotherapy

albendazole is already appropriate. Suppose

will have a positive impact on Trichuris

that mebendazole is still being used, it

trichiura infection. After further analysis,

might be wise to administer it as a multiple-

the authors found that most of the drugs

dose therapy (risk difference (RD) =

combination

0.96, P < 0.00001), since it has the best

against Trichuris trichiura consist of either

other

the

hand,

use

mebendazole

of

whereas

as

mebendazole

the

use

151

able

to

that

cure Trichuris

either

that

are

albendazole

efficacious


albendazole or mebendazole and oxantel

efficacious when combined [23,24]. Same

pamoate. Oxantel pamoate might be a

thing

suitable candidate to replace previous

combination of therapies shows better

treatment

outcome than monotherapy. Based on a

against

combination

Perhaps,

STH

species,

the

study conducted in Southwest Sumba,

mebendazole with oxantel pamoate could

Indonesia, deworming using triple dose of

be

albendazole increases nutritional status in

solution

albendazole

other

or

the

of

STH.

with

to

treat Trichuris

trichiura more effectively.

children. The number of good nutritional

Studies conducted in few countries

status increases, along with the fall of

show that MDA decreases the number of

number of underweight children [25]. This

STH infections and increases school

finding could be used as a consideration to

enrolment and attendance in school-age

change the monotherapy regimen to

children. Moreover, there are benefits in the

combination therapy or

long run. Individuals who receive MDA in

therapies, which has shown to be superior

their childhood show increased cognitive

in curing STH infections and improves

scores almost a decade later, higher income

nutrition profile in children.

and work hours, improved literacy, and

V. CONCLUSIONS

multiple-dose

higher living standards [20-22]. This shows

Albendazole and mebendazole are

that getting the right regimen for MDA is

drugs that are currently being used as Mass

essential. Based on the authors’ analysis,

Drug

albendazole and mebendazole administered

monotherapy, they are only effective in

as a monotherapy could not cure all species

curing Ascaris

of STH infection. They are only efficacious

hookworm,

for Ascaris lumbricoides and hookworm,

responds well to albendazole. Trichuris

although albendazole is only effective

trichiura is trickier, unable to be cured by

against hookworm. Authors also found

albendazole or mebendazole monotherapy,

that Trichuris trichiura is the most difficult

and needs combination therapy to be fully

to cure and responds better to combined

cured. Overall, combination therapy shows

medication than monotherapy. This has

better outcomes than monotherapy in

also been proven by research conducted in

curing STH infections. Hence, further

Uganda and Tanzania, where they also

consideration needs to be made to establish

found that albendazole and mebendazole as

the

a monotherapy are ineffective in curing

administered as MDA to combat STH

Trichuris

infections.

trichiura,

but

nonetheless

152

Administration

most

(MDA).

As

a

lumbricoides and though

effective

hookworm

regimen

only

to

be


among schoolchildren in government

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156


TABLES AND FIGURES

Figure 1. Flowchart of study identification and selection based on PRISMA

157


Table 1. Table of data synthesized

158


Table 1 (cont.). Table of data synthesized

159


Table 1 (cont.). Table of data synthesized

160


Table 1 (cont.). Table of data synthesize

161


Table 2. Table of risk of bias (authors’ judgements of studies regarding each risk of bias item)

162


A. Forest Plot

B. Funnel Plot

Figure 2. Meta-analysis of cure rate of albendazole against Ascaris lumbricoides

163


A. Forest Plot

B. Funnel Plot

Figure 3. Meta-analysis of cure rate of mebendazole against Ascaris lumbricoides

164


A. Forest Plot

B. Funnel Plot

Figure 4. Meta-analysis of cure rate of albendazole against hookworm

165


A. Forest Plot

B. Funnel Plot

Figure 5. Meta-analysis of cure rate of mebendazole against hookworm

166


A. Forest Plot

B. Funnel Plot

Figure 6. Meta-analysis of cure rate of albendazole against Trichuris trichiura

167


A. Forest Plot

B. Funnel Plot

Figure 7. Meta-analysis of cure rate of mebendazole against Trichuris trichiura

168


A Systematic Review of the Efficacy and Safety of Triple Drug Therapy (Diethylcarbamazine, Ivermetin, Albendazole) for Lymphatic Filariasis Clarissa Jasmine Aurelia1,Gabriella Hilary Tumiwa1

ABSTRACT Introduction: Lymphatic Filariasis is a neglected tropical disease caused by the infection of nematode parasites, namely Wuchereria bancrofti, Brugia malayi, and Brugia timori carried by mosqitoes. Since 2005, the elimination of this NTD has been a national priority and done by conducting mass drug administration. New evidence and guidelines have recommended the use of the triple drug therapy (Diethylcarbamazine, Ivermetin, Albendazole). Thus, this systematic review aims to assess the efficacy and safety of the triple drug therapy to potentially accelerate the elimination of lymphatic filariasis.

Materials and Methods: Online databases including NCBI, Research Gate, Science Direct, and Google Scholar was used for data collection. PICO analysis and MeSH terminology was used for our systematic review.

Results and Discussion: There were 6 relevant studies found after being sorted using the inclusion and exclusion criteria. These includes studies conducted by Thomsen et. al, Weil et.al., Bjerum et al., Edi et al., King et al., and Dubray et al., which all indicated high efficacy of the triple drug therapy. All indicated adverse events did occur, but none were severe and was manageable.

Conclusion: This systematic analysis demonstrates that Ivermectin, Diethylcarbamazine, and Albendazole (IDA) as three drug regimen is efficacious and safe for Lymphatic Filariasis treatment, indicated by the decreased of microfilariae levels over a longer time period and the tolerable adverse events.

Keyword: Efficacy, Safety, Lymphatic Filariasis, Diethylcarbamazine, Ivermectin, Albendazole

169


A Systematic Review of the Efficacy and Safety of Triple Drug Therapy (Diethylcarbamazine, Ivermetin, Albendazole) for Lymphatic Filariasis

Clarissa Jasmine Aurelia1,Gabriella Hilary Tumiwa1

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A Systematic Review of the Efficacy and Safety of Triple Drug Therapy (Diethylcarbamazine, Ivermetin, Albendazole) for Lymphatic Filariasis Clarissa Jasmine Aurelia1,Gabriella Hilary Tumiwa1

Introduction: Lymphatic Filariasis is a neglected tropical disease caused by the infection of nematode parasites, namely Wuchereria bancrofti, Brugia malayi, and Brugia timori carried by mosqitoes. Since 2005, the elimination of this NTD has been a national priority and done by conducting mass drug administration. New evidence and guidelines have recommended the use of the triple drug therapy (Diethylcarbamazine, Ivermetin, Albendazole). Thus, this systematic review aims to assess the efficacy and safety of the triple drug therapy to potentially accelerate the elimination of lymphatic filariasis.

Materials and Methods: Online databases including NCBI, Research Gate, Science Direct, and Google Scholar was used for data collection. PICO analysis and MeSH terminology was used for our systematic review.

Results and Discussion: There were 6 relevant studies found after being sorted using the inclusion and exclusion criteria. These includes studies conducted by Thomsen et. al, Weil et.al., Bjerum et al., Edi et al., King et al., and Dubray et al., which all indicated high efficacy of the triple drug therapy. All indicated adverse events did occur, but none were severe and was manageable.

Conclusion: This systematic analysis demonstrates that Ivermectin, Diethylcarbamazine, and Albendazole (IDA) as three drug regimen is efficacious and safe for Lymphatic Filariasis treatment, indicated by the decreased of microfilariae levels over a longer time period and the tolerable adverse events.

Keyword: Efficacy, Safety, Lymphatic Filariasis, Diethylcarbamazine, Ivermectin, Albendazole

171


A Systematic Review of the Efficacy and Safety of Triple Drug Therapy (Diethylcarbamazine, Ivermetin, Albendazole) for Lymphatic Filariasis Clarissa Jasmine Aurelia1,Gabriella Hilary Tumiwa1

Introduction According to WHO, Neglected Tropical Diseases (NTD) are “communicable diseases that prevail in tropical and subtropical countries and affect more than one billion people”. Lymphatic filariasis, or also known as elephantiasis, is considered as an NTD affecting 893 million people in 49 countries in 2018.1 Lymphatic Filariasis is caused by the infection of nematode parasites, namely Wuchereria bancrofti, Brugia malayi, and Brugia timori, which are carried into humans as its primary reservoir by vectors. These vectors are mosquitoes particularly the species: Aedes, Anopheles, Culex, Mansonia, and Ochlerotatus2. In mosquitoes, microfilariae mature to infective larvae into a human’s bloodstream. The nematodes will then invade into blood vessels and mature into adult worms. This may lead to the blockage of lymphatic vessels, subsequently causing edema of peripheral parts of the body. Furthermore, this may also lead to adaptive changes of the connective tissues (hyperplasia) and increased risk of infection. This leads to morphological changes, like the skin of an elephant, of arms, legs, and other body parts3.

In Indonesia, the elimination of lymphatic filariasis was set as a public health national priority since 2005 by the World Health Organization’s Global Program to Eliminate Lymphatic Filariasis (GPELF) strategy for its annual large scale treatment (i.e. mass drug administration MDA) at high risk districts (which has been done since 1970)4. As reported in 2014, drug Regimen used for Indonesia’s MDA is diethylcarbamazine citrate (DEC) and albendazole4,5. New evidence has emerged regarding the high efficacy of the triple drug therapy (diethylcarbamazine, ivermectin, and albendazole – DEC, IVM, ALB) for lymphatic filariasis. This systematic review aims to review the efficacy and safety of the triple drug therapy (IDA) to accelerate elimination of lymphatic filariasis in Indonesia.

Methods

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All data for this systematic review were collected from online resources which includes NCBI, Research Gate, Science Direct, and Google Scholar. PICO Analysis and MeSH Terminology were used for this study as systematic analysis approaches. MeSH Terminology for P (Population) is “Patients with Lymphatic Filariasis”, I (Intervention) is “Three Drug Regimen (IDA) for Filariasis”, C (Comparison) is N/A, and O (Outcome) is “Efficacy and Safety of Three Drug Regimen”. The hypothesis question for this systematic review is “How efficacious and safe is the Three Drug Regimen for lymphatic filariasis patients?”. Inclusion criteria for this study includes “three drug regimen”, 5-year publication date (2015-2020), primary data, and research articles. Simultaneously, the exclusion criteria are books, encyclopaedias, discussions, short communications, mini reviews, correspondence, review articles, and literature reviews. In an attempt to avoid bias, the validity of the studies will be examined to fulfil the inclusion and exclusion criteria. After verifying its validity, the data will be analysed.

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Results and Discussion Using PICO Analysis and MeSH Terminology by searching through online database, 6 articles are acquired to be analysed. The process of data selection is shown in the diagram below. ((("Elephantiasis, Filarial"[Mesh]) AND "Ivermectin"[Mesh]) AND "Diethylcarbamazine"[Mesh]) AND "Albendazole"[Mesh]

NCBI (49)

Research Gate (17)

Science Direct (111)

Google Scholar (11) Inclusion criteria: - Three drug regimen - 5-year publication date (2015-2020) - Primary data - Research articles

5

6

0

11

0

Exclusion criteria: - Books - Encyclopaedias - Discussions - Short communications - Mini reviews - Correspondence - Review articles - Literature reviews.

Filtering double literature

9 Relevant study 6

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Authors

Study

Year

Subject Wuchereria

Thomsen et

al.6

Cohort

2016

bancrofti-infected Papua New Guineans adults Filariasis-infected

Weil et al.7

Cohort

2019

participants in endemic populations Filariasis- infected

Bjerum et al.8

Cohort

2020

participants in Cote d’Ivoire Adults with and

Edi et al.9

Cohort

2019

Results 100% individuals with IDA negative for MF after one year; 11/12 individuals positive with IA positive after one year. No serious AE observed.

AE rates are higher after IDA administration in comparison to DA. IDA compared to IA: lower efficacy at 36 months, higher at 6 and 12 months, equivalent at 24 months. IDA generally superior, well tolerated with no serious AE observed. There were no severe or serious adverse events. All LF

without Wuchereria

positive participants were amicrofilaremic at 7 days

bancrofti infection in

posttreatment and 27 of 31 (87%) remained

Coˆte d’Ivoire.

amicrofilaremic 12 months after treatment The three-drug regimen cleared microfilaremia in 55 of 57

Adults from Papua

Randomized King et

al.10

Controlled

2018

Trial

New Guinea with Wuchereria bancrofti microfilaremia

participants (96%) at 12 months, in 52 of 54 participants (96%) at 24 months, and in 55 of 57 participants (96%) at 36 months. Moderate adverse events were more common in the group that received the three-drug regimen than in the combined two-drug–regimen groups (27% vs. 5%, P<0.001), with no serious adverse events.

Two-armed, Open-label, Dubray et al.11

ClusterRandomized, Community

2016 2017

LF-endemic area in northern Haiti

Study Note: IDA – Ivermectin, Diethylcarbamazine, Albendazole (triple drug therapy) IA

– Ivermectin and Albendazole

DA – Diethylcarbamazine and Albendazole MF – Microfilariae AE – Adverse events MDA – Mass Drug Administration

175

MDA with IDA was at least as well tolerated and significantly more effective for clearing Mf compared to the standard DA regimen in this study.


In a study conducted by Thomsen et al., a total of 24 filariasis-infected people in Papua New Guinea was observed, with 12 treated with IDA and 12 with DA. Participants receiving DIA had total elimination at 36 hours and 7 days, great decrease in filarial antigen levels and Mf(-) at 12 and 24 months. In contrast, people who received DA at a single dose had less reductions of antigen level at 36 hours and 7 days. 10 out of 11 participants remained Mf(+) at 12 months. Participants from both groups tested antigen positive at 12 months and 2 years. Mild-moderate AES was observed in both groups – nausea, headache, arthralgia, pruritus, mild inguinal tenderness, and fever at 4-12 hours after treatment. Hematuria and proteinuria at 24-48 hours were observed but resolved after 7 days. Individuals who took DIA had more AEs 83% individuals with median of 4.5, in comparison to DA participants 50% (P =.19) with median of 2.5 (P = .021). 6

Wein et al. observed 11.262 out of 11,786 people (95,55%) with Mf(-) after DA Regimen was given, in comparison to 13,617 out of 14,229 people (95,70%) with Mf(-) after IDA. AEs in 26,836 filariasis-infected participants (12,280 participants after being administered with DA and 14,556 with IDA) in 5 different countries (Papua New Guinea, Indnesia, India, Haiti, and Fiji). AE rates after IDA administration is 29.4% higher than DA of 25.6% (P <0.001). However, after both drug therapies, only grade 1 (mild/moderate) AEs are observed such as headache, fever, muscle aches, fatigue, and gastrointestinal problems. Scrotal AEs are more common after DA (0.6% in comparison to 0.2%, P <0.001) with grade 1 severity (92.2%) and three grade 2 scrotal AE (two after DA, one after IDA).7

According to Bjerum et al., 45 participants assigned to a single dose of IDA showed 89%, 71%, and 55% elimination of microfilariae (Mf) at 6, 12, 24, and 36 months respectively. 52 participants which were assigned to IA administered once a year for three consecutive years showed 34%, 26%, 54%, and 79% Mf elimination at the same respective timeframe. Overall, the cumulative Mf burden of the administration of triple drug therapy (IDA) over 24 months (36th month could not be included, due to treatment done at 24th month for Mf positive participants), has 7.2 Mf/mL in comparison to 27.4 Mf/mL when IA is administered. This indicates that Mf levels drops 3.8 folds lower during administration of IDA. Bjerum et al.’s study also showed no severe adverse effects (SAE), 5 participants having grade 2 AE (which resolved in 2-3 days), and several participants having grade 1 adverse effects (e.g. headache, joint pain, fatigue, nausea) after

176


administration of IDA. After IA administration there were none with SAE, 1 participant with grade 2 AE, and several participants with grade 1 AE.8

Edi et al., discovered an open-label cohort study of treatment naïve Wuchereria bancroftiinfected (n = 32) and uninfected (n = 24) adults occupying in the Agboville district of Coˆte d’Ivoire, which is endemic for LF and non-endemic for onchocerciasis. At 39 hours and 7 days post-treatment, all LF-infected participants were Mf negative, and 27 of 31 (87%) were Mf negative 1 year after treatment. Among 14 men who had worm nests at baseline, 11 had no detectable worm nests at one year (79% reduction, p <0.001). FTS (Filariasis Test Strip) scores decreased significantly after treatment (P<0,001), and 6 of 31 (19%) participants were FTS negative. Every participant had at least one AE. With respect to objective AEs, 16 of 32 (50%) LF-infected subjects had fevers versus 4 of 24 (17%) uninfected participants post-treatment (P = 0.01). Fevers occurred most commonly between 18 and 42 hours. All fevers resolved by 72 hours after treatment. Scrotal swelling and pain occurred in 6 of the 20 (30%) LF- infected men, but this was not observed in uninfected men (P = 0.04). The onset of scrotal swelling and pain occurred from 48 to 96 hours post-treatment. Hematuria (based on urine dipstick, but not by microscopy) was detected in 10 of 32 (31%) LF- infected individuals, compared to 3 of 24 (13%) uninfected participants (P = 0.1). Hematuria was predominantly seen at 24 and 48 hours and was resolved by day 7. 9

Based on King et al. study, the three-drug regimen cleared microfilaremia in 55 participants (96%) at 12 months, in 52 (96%) at 24 months, and in 55 (96%) at 36 months after trial initiation. By contrast, a single dose of the two-drug regimen cleared microfilaremia in 18 participants (32%) at 12 months, in 31 (56%) at 24 months, and in 43 (83%) at 36 months. The three-drug regimen was more effective in reducing microfilarial counts at 12, 24, and 36 months after trial initiation than the two-drug regimen administered once (P = 0.007, respectively). Objective findings of fever (defined as an auricular temperature >37.5°C) and hemodynamic changes after initial treatment tended to be more common in the group that received the three-drug regimen than in the combined two-drug–regimen groups; however, these between-group differences were not significant. 10

177


According to Dubray et al., one year after treatment, significantly more participants who were Mf positive at baseline became Mf negative after IDA (94.4%, 34/36) compared to after DA (75.9%, 44/58) (P = 0.02). The two participants who remained Mf positive after IDA had Mf counts of 3,050 Mf/mL and 1383 Mf/mL at baseline. One year after treatment, the Mf counts in both participants were 33/mL. One year after treatment, the FTS score of the first participant was 3 and the Mf count was 6,667 Mf/mL; the FTS score of the second participant was 1 and the Mf count was 50Mf/mL. More participants receiving DA (17.3%, 491/2,844) reported an AE compared to participants who received IDA (11.0%, 321/2917). Most AEs reported were mild, 88.7% (436/491) of all AEs in the DA arm and 93.4%, (300/321) of all AEs in the IDA arm. 11

Conclusion This systematic analysis demonstrates that Ivermectin, Diethylcarbamazine, and Albendazole (IDA) as three drug regimen is efficacious and safe for Lymphatic Filariasis treatment, indicated by the decreased of microfilariae levels over a longer time period and the tolerable adverse events. All of the studies which had been analysed states that IDA as three-drug regimen is recommended for Lymphatic Filariasis treatment.

178


REFERENCES

1. WHO. Lymphatic filariasis [Internet]. Who.int. 2020 [cited 27 November 2020]. Available from: https://www.who.int/news-room/fact-sheets/detail/lymphatic-filariasis 2. Newman T, Juergens A. Filariasis. [Internet]. 2020 [cited 27 November 2020];. Available from: https://www.ncbi.nlm.nih.gov/books/NBK556012/ 3. Tada I. Pathogenesis and Treatment of Chronic Symptoms with Emphasis on Chyluria and Elephantiasis. Trop Med Health [Internet]. 2011 [cited 27 November 2020];39 (1 Suppl 2):37-50. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3153157/ 4. WHO. Indonesia firmly committed to eliminating lymphatic filariasis as a public health problem [Internet]. Who.int. 2020 [cited 27 November 2020]. Available from: https://www.who.int/news/item/29-04-2020-indonesia-firmly-committed-to-eliminatinglymphatic-filariasis-as-a-public-health-problem 5. Ambarita L, Taviv Y, Sitorus H, Pahlepi R, Kasnodihardjo K. Perilaku masyarakat terkait penyakit kaki gajah dan program pengobatan massal di kecamatan pemayung keabupaten Batanghari, Jambi. Media Penelitian dan Pengembangan Kesehatan. 2015;24(4). 6. Thomsen E, Sanuku N, Baea M, Satofan S, Maki E, Lombore B et al. Efficacy, Safety, and Pharmacokinetics of Coadministered Diethylcarbamazine, Albendazole, and Ivermectin for Treatment of Bancroftian Filariasis. Clinical Infectious Diseases. 2015;62(3):334-341. 7. Weil G, Bogus J, Christian M, Dubray C, Djuardi Y, Fischer P et al. The safety of double- and triple-drug community mass drug administration for lymphatic filariasis: A multicenter, open-label, cluster-randomized study. PLOS Medicine. 2019;16(6):e1002839. 8. Bjerum C, Ouattara A, Aboulaye M, Kouadio O, Marius V, Andersen B et al. Efficacy and Safety of a Single Dose of Ivermectin, Diethylcarbamazine, and Albendazole for Treatment of Lymphatic Filariasis in Côte d’Ivoire: An Open-label Randomized Controlled Trial. Clinical Infectious Diseases. 2019;71(7):e68-e75. 9. Edi C, Bjerum C, Ouattara A, Chhonker Y, Penali L, Méité A et al. Pharmacokinetics, safety, and efficacy of a single co-administered dose of diethylcarbamazine, albendazole and ivermectin in adults with and without Wuchereria bancrofti infection in Côte d’Ivoire. PLOS Neglected Tropical Diseases. 2019;13(5):e0007325. 10. King C, Suamani J, Sanuku N, Cheng Y, Satofan S, Mancuso B et al. A Trial of a TripleDrug Treatment for Lymphatic Filariasis. New England Journal of Medicine. 2018;379(19):1801-1810.

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11. Dubray C, Sircar A, Beau de Rochars V, Bogus J, Direny A, Ernest J et al. Safety and efficacy of co-administered diethylcarbamazine, albendazole and ivermectin during mass drug administration for lymphatic filariasis in Haiti: Results from a two-armed, openlabel, cluster-randomized, community study. PLOS Neglected Tropical Diseases. 2020;14(6):e0008298.

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Tables and Figures

Table 1. Comparison of microfilaria level at pre-treatment, 36 hours, 7 days, and one year posttreatment of IDA and DA (Thomsen et al.).6

Table 2. Adverse Effects (AE) of patients after given DA and DIA Regimens (Thomsen et al.).6

181


Table 3. Mf Results and Adverse Effects AE of patients after DA and IDA administration (Weil et al.).7

Table 4. Microfilaremia Clearance after Triple-Drug Regimen and Two-Drug Regimen Administration (Bjerum et al.).8

182


Table 5. Adverse Events after Triple-Drug Regimen and Two-Drug Regimen Administration (Bjerum et al.).8

183


Table 6. The efficacy of a single co-administered dose of the triple-drug regimen before and after treatment with respect to (A) Mf counts, (B) circulating filarial antigen levels as determined by mean filarial test strip (FTS) scores at 1 year after treatment, and (C) the number of active worm nests at one-year follow-up. Significance was determined by using the Mann Whitney test for FTS and worm nests (*** <0.001). (Edi et al.).9

Table 7. Adverse events (AEs) following treatment with a single dose of IVM, DEC, and ALB. (Edi et al.).9

184


Table 8. Clearance of Microfilaremia after Treatment for Lymphatic Filariasis ( Kings et al.).10

185


Table 9. Adverse Events after Initial Treatment for Lymphatic Filariasis ( King et al.).10

186


Table 10. Comparison of AE in the DA arm with AE in the IDA arm ( Dubray et al.).11

Table 11. Microfilaremia reduction 12 months after treatment by type of treatment (Dubray et al.). 11

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The Efficiency and Safety of the Vaccine M72/AS01 as a Mean to Prevent Active Pulmonary Tuberculosis For M. Tuberculosis-Infected Adults That are Tested HIV Positive and Negative: A Systematic Review Ida Bagus Ram K.P.M, Dion Ravinder Theodeus S, Elisheva Marcelyn Budiono Introduction: Tuberculosis (TB) is a disease caused by Mycobacterium tuberculosis complex (MTBC), infected almost one-third of the human population and became one of the top 10 causes of death worldwide. M72/AS01 is a candidate vaccine to protect the human body against TB disease. The initial development of this vaccine started with the adjuvanted Mtb72F vaccine, composed by Mtb72F antigen with one or two different Adjuvant Systems. Many researches were done to prove the immunogenicity of the candidate tuberculosis vaccine M72/AS01. However, there are only several studies on the efficiency and safety of this vaccine in M. tuberculosisinfected adults. Therefore, this systematic review has been done to evaluate the vaccine M72/AS01 in adults. Materials and Methods: Utilizing Pubmed and science directly as our source for collecting data and using Systematic review methods such as PICO to analyze data that we gathered. Our hypothesis is “Is The Vaccine M72/AS01 Efficient and Safe to Prevent Active Pulmonary Tuberculosis For M. Tuberculosis-Infected Adults That Are Tested HIV Positive and Negative?”. with the inclusion criteria in this Systematic review are Vaccine M72/AS01, Active Pulmonary Tuberculosis, HIV, Clinical Trials, Randomized Controlled Trials and Adult population. Exclusion Criteria are Systematic review, Meta-Analyses, Literature review, Children population. Results and Discussion: Using the inclusion and exclusion criteria, we found 5 relevant articles. D. Tait, O. Van Der Meeren, N. Kumarasamy, N. Kumarasamy (2018) states that the vaccine was efficient and was well tolerated with no severe side effects. A study conducted by P. Gillard found a strong hypersensitivity reaction during the controlled trial with it’s efficiency needing to be explored further. Conclusion: After reviewing 5 relevant journals, it was revealed that 3 of them showed an efficiency of the M72/AS01 Vaccine with no safety concern. With the other 2 journal showing small side effects as well as a severe hypersensitivity reaction. Therefore, we can conclude that the vaccine is quite efficient and is relatively safe to use. Keyword: Active Pulmonary Tuberculosis, Vaccine M72/AS01, Adults

188


The Efficiency and Safety of The Vaccine M72/AS01 as a Mean to Prevent Active Pulmonary Tuberculosis for M. Tuberculosis-Infected Adults That are Tested HIV Positive and Negative: A Systematic Review

Ida Bagus Ram K.P.M, Dion Ravinder Theodeus S, Elisheva Marcelyn Budiono

189


The Efficiency and Safety of The Vaccine M72/AS01 as Mean to Prevent Active Pulmonary Tuberculosis for M. Tuberculosis-Infected Adults That are Tested HIV Positive and Negative: A Systematic Review

Ida Bagus Ram K.P.M, Dion Ravinder Theodeus S, Elisheva Marcelyn Budiono

Introduction Tuberculosis (TB) is a disease caused by Mycobacterium tuberculosis complex (MTBC). This infectious disease infected almost one-third of the human population and became one of the top 10 causes of death worldwide with approximately 1.3 million cases of TB-related death in 2016. However, only 10% of individuals infected by M. tuberculosis may develop an active disease stage, while the clinical manifestations will increase in HIVcoinfected patients1,2. Human immunodeficiency virus (HIV) is a retrovirus that attacks the CD4+ T-cell, leading to cell death which results in immunodeficiency, where the immune system’s ability to fight off infections and malignancies is compromised. HIV is transmitted through blood or genital fluids from one person to another and also during the birth process and through breastfeeding. Without immediate treatment, patients that are infected by this virus have a high chance of developing acquired immunodeficiency syndrome (AIDS)3,4. M72/AS01 is a candidate vaccine to protect the human body against TB disease. The initial development of this vaccine started with the adjuvanted Mtb72F vaccine, composed by Mtb72F antigen with one or two different Adjuvant Systems. Mtb72F is a recombinant fusion protein derived from two immunogenic Mtb antigens, which are Mtb32A and Mtb39A. The Adjuvant Systems used in the development of this vaccine is liposome-based AS01 or oil-inwater emulsion-based AS02, where both act as a T-helper cell 1 (Th1)-type response inducer. Clinical study shows that both candidate vaccines were equally tolerated in Purified Protein Derivative (PPD)-negative adults along with the induced production of M72-specific humoral and CD4+ T-cell responses to persist until 3 years. However, the response of CD4+ T-cell in vaccine M72/AS01 was significantly more immunogenic than M72/AS025. Many researches have been done to prove the immunogenicity of the candidate tuberculosis vaccine M72/AS01. However, there are only several studies on the efficiency and

190


safety of this vaccine in M. tuberculosis-infected adults. Therefore, this systematic review has been done to evaluate the vaccine M72/AS01 in adults that are both HIV-positive and negative.

Methods The data we use in the systematic reviews are collected from Pubmed and Science direct. Systematic analysis approach is used in this study such as the PICO method and was used, P (Population) is used for “M. Tuberculosis-Infected adults with or without HIV'', I (intervention) is used for “Vaccine M72/AS01”, C (comparison) is used for N/A, O (Outcome) is used for “Vaccine M72/AS01 Efficiency and Safety on Preventing Active Pulmonary Tuberculosis”. The research questions in our systematic review are “Is The Vaccine M72/AS01 Efficient and Safe to Prevent Active Pulmonary Tuberculosis For M. Tuberculosis-Infected Adults That are Tested HIV Positive and Negative”. The inclusion criteria in this Systematic review are Vaccine M72/AS01, Active Pulmonary Tuberculosis, HIV, Clinical Trials, Randomized Controlled Trials and Adult population. Exclusion Criteria are Systematic review, MetaAnalyses, Literature review, Children population.

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Result and Discussion

Using the PICO method without applying the interventions, we have acquired 5 articles that will be analyzed. The diagram below shows the selection process of the articles.

(((“Pulmonary tuberculosis”) AND Vaccine M72/AS01) AND adults) NOT children

PubMED (15)

Inclusion Criteria: • Pulmonary Tuberculosis • Vaccine M72/AS01 • Clinical Trials • Randomized Controlled Trials • Population : Adult, adult with HIV+

Science direct (253)

10

Exclusion Criteria: • Systemic Review • Meta-analyses • Literature review • Population : Children

67

77

Filtering double literature 13 Relevant Study 6

Figure. 1 Information flowchart through the different phases of the systematic review

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Table. 1 Summary of studies of efficiency and safety of the vaccine M72/AS01 as a mean of prevent active pulmonary tuberculosis for M. Tuberculosis-infected adults Authors

Study

Year

Subject

Result The vaccine can induced cellular

N.

Randomized

Kumarasamy

Controlled

et al.6

Trials

2018

India adult with

and humoral immune respone in

HIV-positive and -

HIV+ and HIV- until 3rd year

negative

and no significant adverse effect related to the vaccine

N.

Randomized

Kumarasamy

Controlled

et al.7

Trials

P. Gillard et al.8

India adult with 2016

The vaccine was immunogenic

naive, and HIV-

and well-tolerated in India adults

negative

Randomized Controlled

ART-stable, ART-

2016

Trials

Adults with

Vaccine was immunogenic in

tuberculosis-naive,

adults previously or currently

previously treated

treated for tuberculosis, but

for tuberculosis and further analyses are needed for completed the

adults undergoing tuberculosis

intensive phase of

treatment. General adverse

tuberculosis

effects were recorded during

treatment

follow-up M72/AS01 vaccine provide

O. Van Der Meeren et al.9

Adult with HIV-

Randomized Controlled

2018

Trials

negative and latent M.tuberculosis infection

protection for M. tuberculosisinfected adults against active tuberculosis pulmonary tuberculosis disease and no significant adverse effect because of the vaccine

Adult with D. Tait et al.10

Randomized Controlled Trials

M.tuberculosis 2019

infection without active tuberculosis disease

193

The vaccine provided protection against progression to pulmonary tuberculosis disease for at least 3 years and no significant fatality caused by the vaccine


Note : HIV = Human Immunodeficiency Virus ART = Antiretroviral Therapy

According to Dereck R. Tait, M.B., Ch.B Final Analysis trial that enrolled over 3575 adults 18 to 50 years of age with M. tuberculosis infection (defined by positive results on interferon-γ release assay) without evidence of active tuberculosis disease at centers in Kenya, South Africa, and Zambia. The study aims to evaluate the efficacy of M72/AS01E to prevent active pulmonary tuberculosis disease according to the first case definition (bacteriologically confirmed pulmonary tuberculosis not associated with HIV infection and diagnosed with sputum obtained before initiation of treatment for tuberculosis). Regarding efficiency study, all participants in the M72/AS01E group were seropositive by month 2 and remained positive until month 36. All 95% confidence intervals overlap between groups, with the exception of the geometric mean concentration of anti-M72 IgG antibodies among participants in South Africa (670.9 ELISA units per milliliter; 95% CI, 527.9 to 852.5) and Kenya (440.4 ELISA units per milliliter; 95% CI, 375.2 to 516.8) at month 2. Administration of placebo at any time point. No CD8+ T-cell responses could be detected in either group. Therefore, this study concluded that the vaccine M72/AS01 provided approximately 50% protection against progression to active pulmonary tuberculosis for 3 years in M. tuberculosis–infected, HIV-negative adults. Regarding safety, it reported that two serious adverse events were considered by the investigators to be related to the trial regimen: one case of pyrexia in the M72/AS01E group (with onset on the day of dose 2) and one case of hypertensive encephalopathy in the placebo group (with onset on the day of dose 1). There were 47 deaths during the trial period: 19 deaths among 1786 participants (1.1%) in the M72/AS01E group and 28 among 1787 participants (1.6%) in the placebo group (relative risk, 0.68; 95% CI, 0.36 to 1.26; P=0.24) however, none of these deaths were determined by the investigators to be related to the trial regimen with the most common cause of death was trauma (in 28 participants). This indicates that the vaccine is relatively safe to use. In a randomized control study conducted by Nagalingeswaran Kumarasamy, MBBS, PhD which aims to assess the long term safety of M72/AS01 candidate vaccine in patients with infected tuberculosis as well human immunodeficiency virus (HIV)-positive (HIV+) and HIVnegative (HIV−). The control study was conducted in YRG CARE Medical Centre, in Chennai, India, between January 2011 and June 2015. Three cohorts were randomised (1:1) to receive 2

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doses of M72/AS01E (M72/AS01E groups) or saline (control groups) 1 month apart and were followed up toY3. Latent TB infection was then assessed at screening using an interferongamma (IFN-γ) release assay (IGRA). With a total of 240 participants enrolled in the study and 214 finishing the study. The result concludes that vaccination causes persistent humoral response against M72 with the lowest humoral immune response in the HIV+ART- cohort. In M72/AS01E recipient, no decrease in frequency was noted for specific CD4+ T-Cell expression immune markers among interleukin-2 (IL-2), IFN-γ, tumour necrosis factor alpha (TNF-α) and CD40 ligand (CD40L) was observed at Y3 post-vaccination. Which therefore concludes that the cellular and humoral immune responses induced by M72/AS01E in HIV+ and HIV− adults persisted up to Y3 post-vaccination with no safety concern. Olivier Van Der Meeren conducted a randomized double blinded placebo-controlled, phase 2b trial of the M72/AS01E tuberculosis vaccine in Kenya, South Africa, and Zambia. Human immunodeficiency virus (HIV)-negative adults 18 to 50 years of age with latent M. tuberculosis infection. The trial involves 3575 participants who underwent randomization, 3573 received at least one dose of M72/AS01E or placebo from August 2014 through November 2015, and 3330 received both doses. A total of 1786 participants received M72/AS01E and 1787 received placebo. The vaccine efficacy was 54.0% (90% confidence interval [CI], 13.9 to 75.4; 95% CI, 2.9 to 78.2; P=0.04). Results for the total vaccinated efficacy cohort were similar (vaccine efficacy, 57.0%; 90% CI, 19.9 to 76.9; 95% CI, 9.7 to 79.5; P=0.03). The result of this double blinded placebo-controlled trial provides approximately 54.0% protection for M. tuberculosis–infected adults against active pulmonary tuberculosis disease, without evident safety concerns. Adam Penn-Nicholson also conducted a cohort study which aims to look at the efficiency as well as safety of M72/AS01 vaccine in adults. There was three cohort study with three samples ; adults with smear- or culture-confirmed pulmonary TB disease who had completed the intensive phase of treatment, i.e. had documented treatment for pulmonary TB disease ongoing for 2–4 months prior to vaccination (TB-treatment cohort); adults (18-24 years old) with previous history of successfully treated pulmonary TB disease at least one year prior to vaccination and with no active pulmonary disease on chest X-ray (TB-treated cohort); and adults who had no active pulmonary disease as indicated by chest X-ray, no signs and symptoms of TB disease, and no history of chemoprophylaxis or treatment for TB (TB-naïve cohort). In this study, 71 adults were vaccinated with the M72/AS01E vaccine and 71 adults received the saline placebo. A total of 80 adults were included in the TB-naïve cohort, 49 in the TB-treated cohort, and 13 in the TB-treatment cohort. However, in this study it is stated

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that there is an increase of hypersensitivity reaction amongst the test subject. Out of 71 one adults vaccinated a total of 31 participants showed symptoms of local redness and swelling in the injection site which results in the study ending prematurely because of this high incidence. However, further test is required No additional clinically relevant AEs were observed, except one possibly vaccine-related SAE (hypersensitivity in TB-treated-M72/AS01E). Lastly, in accordance to Nagalingeswaran Kumarasamy Randomized, controlled observer-blind trial in which there was 240 adults who are either assigned antiretroviral therapy M72/AS01 or a placebo following a 0, 1-month schedule and followed for 12 month. The study was conducted in India at YRG CARE clinic. Participants is aged 18 to 59 years and has no past or current TB disease, no evidence of pulmonary pathology (active and/or acute or chronic pulmonary disease as confirmed by chest X-ray), no history of extra-pulmonary TB or chemotherapy for TB based on medical history, and clinical laboratory values that were considered acceptable by the investigator. Regarding safety for patients with HIV Positive, there are Solicited local (injection-site pain, swelling) present and general (fever [temperature ≥37.5 °C], headache, fatigue, malaise, myalgia, and gastrointestinal symptoms) AEs were recorded for 7 days after each vaccination. However, there is no other safety concern regarding the vaccine that may indicate red flags. For efficiency, the subjects that are HIV-positive can mount cell-mediated and humoral responses to two M72/AS01 doses, which persist at 1 year post-vaccination.

Conclusion From the systematic review, it can be concluded that the Vaccine M72/AS01 is considered effective with a mean effective rate of 50-55 percent in 3 years life span. Furthermore, the vaccine has no safety concern aside from general fever and headache in some cases in HIV test subjects and no other safety concern for Non-HIV test subjects. From the 5 journals reviewed, 4 journals revealed an efficiency in the vaccine with a mean effective rate 50-55 percent, and 1 journal having to end prematurely because of a high incidence in hypersensitive reaction. Regarding safety indications, 3 journal indicate that there are no concerning side effects for the vaccine, 1 showing an intense hypersensitivity reaction and 1 journal showing mild effects such as headaches and malaise in HIV patients. Overall however, we can conclude that the vaccine is efficient and safe to use to prevent active pulmonary tuberculosis in infected adults tested both positive and negative for HIV.

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Harries AD, Dye C. Tuberculosis [Internet]. Vol. 100, Annals of Tropical Medicine and Parasitology. Maney Publishing; 2006 [cited 2020 Dec 9]. p. 415–31. Available from: https://pubmed.ncbi.nlm.nih.gov/16899146/

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Gong W, Liang Y, Wu X. The current status, challenges, and future developments of new tuberculosis vaccines [Internet]. Vol. 14, Human Vaccines and Immunotherapeutics. Taylor and Francis Inc.; 2018 [cited 2020 Dec 9]. p. 1697–716. Available from: /pmc/articles/PMC6067889/?report=abstract

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Levy JA. Pathogenesis of human immunodeficiency virus infection [Internet]. Vol. 57, Microbiological Reviews. American Society for Microbiology (ASM); 1993 [cited 2020 Dec 9]. p. 183–289. Available from: /pmc/articles/PMC372905/?report=abstract

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Waymack JR, Sundareshan V. Acquired Immune Deficiency Syndrome [Internet]. StatPearls. StatPearls Publishing; 2020 [cited 2020 Dec 9]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/30725978

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Montoya J, Solon JA, Cunanan SRC, Acosta L, Bollaerts A, Moris P, et al. A randomized, controlled dose-finding Phase II study of the M72/AS01 candidate tuberculosis vaccine in healthy PPD-positive adults. J Clin Immunol [Internet]. 2013 Nov [cited 2020 Dec 9];33(8):1360–75. Available from: /pmc/articles/PMC3825318/?report=abstract

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Kumarasamy N, Poongulali S, Beulah FE, Akite EJ, Ayuk LN, Bollaerts A, et al. Long-term safety and immunogenicity of the M72/AS01E candidate tuberculosis vaccine in HIV-positive and -negative Indian adults Results from a phase II randomized controlled trial. Med (United States) [Internet]. 2018 Nov 1 [cited 2020 Dec 8];97(45). Available from: /pmc/articles/PMC6250513/?report=abstract

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Kumarasamy N, Poongulali S, Bollaerts A, Moris P, Beulah FE, Ayuk LN, et al. A randomized, controlled safety, and immunogenicity trial of the M72/AS01 candidate tuberculosis vaccine in HIV-positive indian adults. Med (United States) [Internet]. 2016 [cited 2020 Dec 8];95(3). Available from: /pmc/articles/PMC4998253/?report=abstract

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Gillard P, Yang PC, Danilovits M, Su WJ, Cheng SL, Pehme L, et al. Safety and immunogenicity of the M72/AS01E candidate tuberculosis vaccine in adults with tuberculosis: A phase II randomised study. Tuberculosis. 2016 Sep 1;100:118–27.

9.

Van Der Meeren O, Hatherill M, Nduba V, Wilkinson RJ, Muyoyeta M, Van Brakel E, et al. Phase 2b Controlled Trial of M72/AS01 E Vaccine to Prevent Tuberculosis . N Engl J Med [Internet]. 2018 Oct 25 [cited 2020 Dec 8];379(17):1621–34. Available from: /pmc/articles/PMC6151253/?report=abstract

10.

Tait DR, Hatherill M, Van Der Meeren O, Ginsberg AM, Van Brakel E, Salaun B, et al. Final Analysis of a Trial of M72/AS01 E Vaccine to Prevent Tuberculosis . N Engl J Med [Internet]. 2019 Dec 19 [cited 2020 Dec 8];381(25):2429–39. Available from: https://www.nejm.org/doi/10.1056/NEJMoa1909953

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The Role of Molecular Quantitative PCR as An Alternative Tool to Increase Sensitivity and Prevalence in Diagnosis of Soil-Transmitted Helminthiasis Compared to Microscopy-based Kato-Katz Technique in Low Prevalence Settings in Asia-Africa Regions: A Systematic Review. Tiara Julianti, Satria B. Nugraha, Michele Indrawan Introduction: STH was considered as a neglected tropical disease because of three primary highlights which are higher prevalence in underdeveloped nations, an ongoing disease, and inability to evaluate the impact of the infections on monetary and education sector. Early and accurate diagnosis of the infections is a major approach to control the morbidity caused by STH. The Kato-Katz Technique is the WHO “Gold Standard” that is very recommended to assess the prevalence of STH. However in the present day, PCR-based technique, such as qPCR, are progressively utilized to diagnose STH infections, as its molecular approach can recognize very little quantities of DNA even in low infections intensity which exhibit high sensitivity. Hence, this systematic review means to evaluate whether qPCR has higher sensitivity and prevalence compared with the Kato-Katz technique for diagnosis of Soil-Transmitted Helminthiasis. Methodology: Systematic analysis using MeSH terminology and PICO methods were utilized for data extraction of online database, such as PubMed, Google Scholar, and Cochrane Library. Results and Discussion: In total, 7 studies were finally used after being filtered through our inclusion and exclusion criteria. All of the studies came in an agreement that qPCR have higher sensitivity and prevalence compared to Kato-Katz technique in low prevalence settings, though few studies may suggest that Kato-Katz have higher prevalence for a specific species of STH. Conclusion: This systematic review concludes that qPCR is a more efficient tool than Kato-Katz technique in diagnosis of Soil-Transmitted Helminthiasis in low intensity settings. Kato-Katz is more likely to miss positive samples as it requires visual identification of small number of eggs which may degrade. qPCR, however, is more precise and sensitive as it can identify very little amount of STH DNA which is less likely to degrade.

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Keywords: STH, Soil-Transmitted Helminths, qPCR, Kato-Katz, Diagnostic tools

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The Role of Molecular Quantitative PCR as An Alternative Tool to Increase Sensitivity and Prevalence in Diagnosis of Soil-Transmitted Helminthiasis Compared to Microscopy-based Kato-Katz Technique in Low Prevalence Settings in Asia-Africa Regions: A Systematic Review. Tiara Julianti, Satria B. Nugraha, Michele Indrawan

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INTRODUCTION Soil-transmitted helminths (STH) are distributed worldwide mostly in tropical and subtropical regions. STH was considered as a neglected tropical disease due to three main features which are higher prevalence in underdeveloped nations, an ongoing disease, and inability to evaluate the impact of the infections on monetary and education sector. Infections of STH mainly caused by roundworm (​Ascaris lumbricoides​), whipworm (​Trichuris trichiura​), and

hookworm (​Necator americanus ​and ​Ancylostoma duodenale​). ​Ascaris ​and ​Trichuris affect mostly children while hookworm affects both children and young adults. It causes iron deficiency anemia, protein energy malnutrition, and stunted growth. Untreated infections lead to intestinal obstructions and gangrene. STH mainly occurred in areas with poverty, overcrowding, and poor sanitation. The prevalence is more in rural areas compared to urban areas. Approximately, 1.7 billion people are infected with one or more STH. According to a 2003 survey, the global prevalence of ​Ascaris lumbricoides is more than 1.2 billion, which >50% of cases are seen in China. ​Trichuris trichiura ​prevalence was 795 million, whereas hookworm prevalence was estimated to be 740

million. Sub-Saharan Africa and China contribute nearly 50% of hookworm prevalence. 2010 survey showed the prevalence rate of ​A. lumbricoides ​was 819 million and ​T. trichiura ​was 464 million and hookworm was 439 million in which >50% of cases were seen in South Asia and Sub-Saharan Africa. Asia contributes 67% of the global prevalence of STH and in Asia; India has the highest prevalence (21%) followed by China (18%)¹. Major approaches to control and reduce morbidity caused by STH infections include the periodic deworming of pre-school and school-aged children with antihelminthic drugs. Population-based studies and individual patient management including interventional studies can be accomplished when accurate diagnostic techniques are used. The Kato-Katz technique is the WHO “gold standard” that is widely recommended to assess the prevalence and infection intensity of STHs. Kato-Katz technique uses feces as the sample which is placed on a glass slide. A piece of cellophane soaked in glycerol covered the preparation. Subsequently, the slide is inverted and gently pressed down resulting in a thin smear. Glycerol serves to ‘clear’ the fecal material (fat) from the eggs around. Hookworm eggs require about 30 minutes, whereas other species require 1 to 24 hours to perform the counted eggs per gram of feces under the microscope². Polymerase chain reaction (PCR)-based techniques are increasingly used to

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diagnose STH infections. PCR as a molecular approach detects very small quantities of DNA which demonstrate high sensitivity. Real-time quantitative PCR (qPCR) techniques can also be used to provide quantitative measures of infection intensity³. Kato-Katz is commonly used to identify STH eggs in stools where infection intensity is low, this method frequently misses positive samples because it requires visual identification of a small number of eggs, and hookworm eggs may degrade prior to visualization. qPCR may detect more low intensity infections than Kato-Katz because it identifies STH DNA in stool. DNA can be detected in very small quantities. Appropriate diagnostic techniques are crucial to global soil-transmitted helminth (STH) control efforts. The recommended Kato-Katz method shows limited sensitivity for detecting light intensity infection whereas qPCR is a highly sensitive alternative diagnostic option. On that account, this systematic review was carried out to evaluate the accuracy between both diagnostic tools by their sensitivity and effectivity for detecting STH infections⁴.

MATERIALS AND METHODS This systematic review utilized data from several studies published in online sources, specifically PubMed and Google Scholar. These studies were gathered on November 2020 by utilizing the following keywords: ("Helminth Infection" OR "Soil Transmitted Helminth" OR "Helminthiasis") AND (“Diagnosis”) AND ("Kato-Katz" OR "Kato Technique") AND ("q-PCR" OR "Quantitative Polymerase Chain Reaction"). The search was limited based on studies in English as a primary language. A systematic analysis using MeSH terminology and PICO method was used for data extraction. For the PICO method, we used “Adult infected with Soil-transmitted helminth” for the People or Population (P). For the Intervention (I), we used “Kato-Katz” or “Kato technique” as a recommended method of helminthiasis diagnostic tool by the World Health Organization. For Comparison (C), we compare Kato-Katz to another diagnostic tool using “q-PCR” or “Quantitative Polymerase Chain Reaction”. Lastly, for the Outcome (O), we used “Effectivity and Sensitivity of q-PCR compared to Kato-Katz in low intensity setting”. Subsequently, several studies were gathered and reviewed by two reviewers using a standardized form. The data were further evaluated by other reviewers to reduce risk of error.

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Our study aims to assess whether molecular diagnostic tools such as q-PCR are more effective and sensitive in low intensity helminthiasis. In view of our theory in the introduction, our hypothesis is that q-PCR is more effective and sensitive compared to KK methods as a diagnostic tool in low intensity Soil-transmitted helminth infected patients. RESULT AND DISCUSSION Study selection Through PICO method and MeSH terminology, we obtained 7 eligible studies to be analyzed and reviewed. The graph below shows the process of selection of the articles.

Study characteristics and outcome Overall, a total of 8,063 participants were included in this review. All 7 studies included were either randomized controlled trials or cross-sectional which varied across Asia and Africa. Outcomes were a higher sensitivity and value of Quantitative Polymerase Chain Reaction in

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determining prevalence of soil-transmitted helminthiasis, as well as its efficacy in low prevalence settings. Result and Analysis of the study In a study conducted by ​Adisakwattana et al.⁵, stool samples (n=567) from fourteen

villages in Thailand borders were included in an in-field microscopic examination (Kato-Katz)

and molecular analysis compromising three multiplex qPCR assays. Overall data ​highlight the higher value of molecular diagnostic tools in determining the prevalence of helminthiasis compared to microscopic KK technique. ​Independent KK analysis showed a lower overall prevalence of any helminth infection compared to qPCR when used independently (17.99% (95% CI: 14.82-21.16%) vs ​(24.51%; 95% CI: 20.96–28.07%) ​(Table 1)​. Kappa analysis showed the best agreement between the qPCR and KK methods for ​A. lumbricoides (κ = 0.91​),

indicating concordance of STH diagnosis between the two approaches (Table 2)​. As STH are endemic in Thailand, improved detection was not significant using qPCR. However, there was a moderate concordance ​(κ = 0.54​) for ​O. viverrini​. The qPCR identified twice as many positive

samples as the KK, accounting for the lack of agreement. Furthermore, the GMEPG (prevalence and intensity) for ​O. viverrini was a relatively low 65.49 indicating that the KK missed low-grade infections that were subsequently identified by qPCR. A study from ​Dunn et al.⁶​, Parasites & Vectors collected stool samples of 648 participants from two villages in the delta region in Myanmar June 2016. Individual qPCR results were compared to KK results from the same stool sample to compare the prevalence, intensity of infection, and sensitivity between both diagnostic tools. The prevalence of any STH infection was found to be higher when using qPCR (45.06%) as diagnostic tools compared to KK (20.68%) and the result refers to ​Table 3​. The assessment of intensity showed that out of 623 KK negative ​A. lumbricoides results, 32 (5.14%) were confirmed positive by qPCR. This increased to 78 samples out of 566 (13.78%) for ​T. trichiura and 42 out of 606 (20.46%) for hookworm. These results represent that the infections missed by KK were predominately in

lower intensity of infection scores in the sample. Comparing Kato-Katz and qPCR results, the sensitivity to detect ​A. lumbricoides was 45.45% and 100% respectively, and for ​T. trichiura​, 52.30% and 91.61% respectively. Hookworm sensitivity was 25.30% for KK and 100% for qPCR.

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As indicated by a study carried out by ​Benjamin-Chung et al.⁴​, effectiveness of qPCR

and Double-slide Kato-Katz as a comprehensive diagnostic tool was compared in stool samples

of children age 2–12 years (n = 2,799) in a setting in rural Bangladesh with low STH intensity. According to the study, the noticed prevalence was higher for qPCR than Double-slide Kato-Katz for hookworm and ​T. trichiura yet lower for ​A. lumbricoides​. The observed STH

prevalence for both qPCR and double-slide Kato-Katz can be observed at ​Table 4​. ​Conformity

between Kato-Katz and qPCR was significantly higher for hookworm and ​T. trichiura than for ​A. lumbricoides with kappa measurement of ​κ ​= 0.42, ​κ ​= 0.58, and ​κ ​= 0.13 respectively (​Table 5)​.

Approximately 6-14% negative Double-slide Kato-Katz samples for various species were classified as positive by qPCR method. In addition, all Kato-Katz positive samples for ​A. lumbricoides that were tested negative by qPCR examination, also failed to generate a positive result when tested with the ITS-targeting assay. This study shows not only Kato-Katz had low sensitivity, but also possessed low specificity for ​A​. ​lumbricoides​. Though the cause of ​A​. lumbricoides misclassification cannot be determined. Utilizing the Bayesian latent class models,

sensitivity of double-slide Kato-Katz and qPCR separately for any species was evaluated at Table 6​. A trial design conducted by ​Keller et al.⁷​, was aimed to compare the performance of the microscopic Kato-Katz method and the molecular qPCR method for diagnosis of soil-transmitted helminthiasis. The stool samples were collected from the participants who were found positive for STH infection in at least two slides of quadruple Kato-Katz with an infection intensity of at least 100 eggs per gram of stool. The samples analyzed in this study were collected between September 2018 and December 2018 on Pemba Island, United Republic of Tanzania. Based on the trial, detection of STH infection was pointed out with most tests positive for qPCR and negative for Kato-Katz, these results refer to ​Table 7​. Overall comparisons between the two methods, the sensitivity of qPCR in detecting positive samples was higher than Kato-Katz

method. The sensitivity of qPCR relative to Kato-Katz was 93.7% for ​T. trichiura​, 84.4% for ​A. lumbricoides and 88.4% for hookworm, while the sensitivity of Kato-Katz relative to qPCR was

79.5%, 30.4%, and 35.9% for ​T. trichiura, A. lumbricoides​, and hookworm, respectively. The results are shown in Table 8​. Diagnostic method variability between samples was explained using Cohen’s Kappa that is shown in ​Table 9​. The results highlight that qPCR has higher sensitivity in assessing low infection intensities rather than Kato-Katz method.

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In a study by ​Barda et al.​⁸​, sensitivity of single real-time PCR is compared to

quadruplicate microscopic Kato-Katz as an alternative tool for helminth detection in 320 stool samples. Sensitivity of the two methods was calculated first for baseline and later for follow-up. Follow-up studies aimed to improve the DNA extraction by applying longer lysing time needed to improve release of nucleic acid. ​The limitation of this study is that combined KK at follow-up will generate 100% sensitivity as only subjects positive (>24 EPG) for ​T. trichiura by KK were

enrolled. This study concluded if baseline and follow-up results were combined, PCR is as sensitive as KK for ​T. trichiura and ​A. lumbricoides​, but more sensitive for hookworm. If

baseline and follow-up were considered separately, PCR is more sensitive than KK for all STHs at follow-up ​(Table 10)​. In order to evaluate the concordance of the two studies, Cohen’s Kappa measured the agreement on intensity categories of KK EPG (eggs per gram) and PCR DNA copy numbers. Result showed a poor agreement for ​T. trichiura (κ = 0.33) at baseline, and a moderate one for the other parasites. At follow-up a moderate agreement was reached for hookworm (κ = 0.47) and a good one for the other parasites (κ > 0.6) ​(Table 11)​. A study from ​Werkman et al.​⁹​, was conducted to quantify the impact of using qPCR on measured prevalence of STH infection as compared to KK. This study was performed in five villages in Western Kenya and was aimed to measure the sensitivity of qPCR to examine the intensity of infection and prevalence of STH and to compare this with standard KK method. Total samples taken were 1884 samples from 796 people with measurements by both KK and qPCR. The results showed that for ​Ascaris​, 54 individuals were found positive with both methods, 74 were found positive with qPCR and negative with KK, and 3 individuals were negative with qPCR and positive with KK. For hookworm, 42 individuals were found positive with both methods, 145 were found negative with qPCR and negative with KK, and 3 individuals were negative with qPCR and positive with KK. The threshold prevalence of ​Ascaris ​infection was 6% and 12% for KK and qPCR respectively. In hookworm infection, threshold values were

0.5% and 2% respectively. This study concluded that qPCR has higher sensitivity to make it very valuable as a diagnostic tool towards the elimination of STH species. Overall results refer to Figure 1​. According to ​Mationg et al.​10​, huge disparity in the prevalence from the samples (n = 263) were observed between the two methods of one type STH infection ​(33.8% by KK vs.

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78.3% by qPCR), ​Trichuris trichiura (23.6% by KK vs. 38.8% by qPCR) and ​Ascaris lumbricoides (20.5% by KK vs. 60.8% by qPCR) (​Table 12​). It can be seen that right around triple times the quantity of ​A. lumbricoides infections and 1.6 times the quantity of ​T. trichiura

infections were dictated by the qPCR procedure contrasted with the three slide KK technique. ​S. stercoralis, N. americanus and ​Ancylostoma spp​. were identified utilizing the qPCR however not by KK. The quantity of tests that tried negative by the KK was three-overlay higher than the number testing negative by qPCR. CONCLUSION Based on 7 studies that we have analyzed, we concluded that Quantitative Polymerase Chain Reaction (qPCR) is a better tool in diagnosis of Soil-Transmitted Helminthiasis compared to Kato-Katz method. When the infection intensities were low, Kato-Katz frequently misses positive samples because it requires visual identification of small numbers of eggs and hookworm eggs which may degrade prior to visualization. In comparison, qPCR may detect more in low intensity settings because it can identify and detect very small STH DNA in stool samples and is less likely to degrade than STH ova, which concludes that qPCR is more likely to be more precise and more sensitive than Kato-Katz.⁴ Thus, the greater sensitivity and precision of qPCR relative to Kato-Katz, the more promising it is as an alternative tool in diagnosis of STH infection. We hope this systematic review can enhance attention in selection of STH diagnostic tools and bring more interest in future studies to prove qPCR as a better STH diagnostic tool compared to Kato-Katz.

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APPENDIX Author

Year

Study

Population

Object

Result

Adisakwattana et al.⁵

2020

Cross-sectional

Stool samples from participants age 1.5 88 years (n=567); Fourteen villages in Thailand border regions.

STH (A.lumbricoides, T.trichiura, Hookworm), O.viverrini, Taenia. sp.

Higher sensitivity of independent qPCR (24.51%; 95% CI: 20.96–28.07%) compared to KK (17.99% (95% CI: 14.82-21.16%).

Dunn et al.⁶

2020

Cross-sectional

Stool samples from participants age 2-40+ years (n=648); Two villages in the delta region in Myanmar.

STH (A.lumbricoides, T.trichiura, Hookworm), Ancylostome ceylanium

Higher prevalence of any STH by qPCR (45.06%) compared to KK (20.68%) with p value (< 0.0001)

Benjamin-Chu ng et al.​⁴

2020

Cross-sectional

Stool samples from participants aged 2-12 years (n=2799); Gazipur, Mymensingh, Tangail and Kishoreganj districts of Bangladesh.

STH (​T.trichiura, Hookworm​ (incl. A. ceylanicum, A. duodenale, N. americanus and S. stercoralis) and A. lumbricoides)

The monitored prevalence was higher for qPCR contrasted to double-slide KK for hookworms and ​T. trichiura​ but lower for A. lumbricoides

Keller et al.⁷

2020

Randomized controlled trial

Stool sample (n=1636) from Pemba Island, United Republic of Tanzania.

STH (A.lumbricoides, T.trichiura, Hookworm)

Higher sensitivity of qPCR in low infection intensities compared to KK for any STH.

Barda et al.⁸

2020

Randomized controlled trial

School age adolescents age 12-19 years (n=320); Pemba Island, United Republic of Tanzania

STH (​T.trichiura, Hookworm​ (incl. A. duodenale, N. americanus and S. stercoralis) and A. lumbricoides)

A single real-time PCR is as sensitive as quadruplicate KK for T. trichiura​ and ​A. lumbricoides​ but more sensitive for hookworm. Baseline​: 77.5% (qPCR) to 70.4% (KK) Follow-up​: 72.7% (qPCR) to 43.0% (KK)

2018

Cross-sectional

Stool samples from 796 people (n=1884); Five villages in Western Kenya.

STH (​A. lumbricoides​ and hookworm)

Higher threshold prevalence of ​Ascaris and hookworm infection values in

Werkman al.⁹

et

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qPCR compared to KK. 6% (KK) and 12% (qPCR) for Ascaris​. 0.5% (KK) and 2% (qPCR) for hookworm. Mationg et al. 10 ​

2017

Cross-sectional

Stool samples from 263 schoolchildren; Laguna province in Philippines

Note: STH: Soil-transmitted Helminths KK: Kato-Katz or Kato technique qPCR: Quantitative Polymerase Chain Reaction

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STH (​T.trichiura, Hookworm​ (incl. N. americanus, Ancylostoma spp., E. vermicularis, and S. stercoralis) and A. lumbricoides)

Higher prevalence of at least one STH infection by qPCR compared to three-slide KK technique ​(78.3% by qPCR vs. 33.8% by KK).


REFERENCES 1. Parija SC, Chidambaram M, Mandal J. Epidemiology and clinical features of soil-transmitted helminths. Tropical Parasitology. 2017;7(2):81-85. 2. Mbong Ngwese M, Prince Manouana G, Nguema Moure PA, Ramharter M, Esen M, Adégnika AA. Diagnostic Techniques of Soil-Transmitted Helminths: Impact on Control Measures. TropicalMed. 2020;5(2):93. 3. Clarke NE, Richardson A, McCarthy J, Traub RJ, Nery SV, Llewellyn S. Quantitative Polymerase Chain Reaction for Diagnosis of Soil-Transmitted Helminth Infections: A Comparison with a Flotation-Based Technique and an Investigation of Variability in DNA Detection. The American Journal of Tropical Medicine and Hygiene. 2018;99(4):1033–40. 4. Benjamin-Chung J, Pilotte N, Ercumen A, Grant JR, Maasch JRMA, Gonzalez AM, et al. Comparison of multi-parallel qPCR and double-slide Kato-Katz for detection of soil-transmitted helminth infection among children in rural Bangladesh. Freeman MC, editor. PLoS Negl Trop Dis. 2020;14(4):e0008087. 5. Adisakwattana P, Yoonuan T, Phuphisut O, Poodeepiyasawat A, Homsuwan N, Gordon CA, et al. Clinical helminthiases in Thailand border regions show elevated prevalence levels using qPCR diagnostics combined with traditional microscopic methods. Parasites Vectors. 2020;13(1): 416. 6. Dunn JC, Papaiakovou M, Han KT, Chooneea D, Bettis AA, Wyine NY, et al. The increased sensitivity of qPCR in comparison to Kato-Katz is required for the accurate assessment of the prevalence of soil-transmitted helminth infection in settings that have received multiple rounds of mass drug administration. Parasites Vectors. 2020;13(1): 324.

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7. Keller L, Patel C, Welsche S, Schindler T, Hürlimann E, Keiser J. Performance of the Kato-Katz method and real time polymerase chain reaction for the diagnosis of soil-transmitted helminthiasis in the framework of a randomised controlled trial: treatment efficacy and day-to-day variation. Parasites Vectors. 2020;13(1). 8. Barda B, Schindler C, Wampfler R, Ame S, Ali SM, Keiser J. Comparison of real-time PCR and the Kato-Katz method for the diagnosis of soil-transmitted helminthiasis and assessment of cure in a randomized controlled trial. BMC Microbiol. 2020;20(1). 9. Werkman M, Wright J, Truscott J, Easton A, Oliveira R, Toor J et al. Testing for soil-transmitted helminth transmission elimination: Analysing the impact of the sensitivity of different diagnostic tools. PLOS Neglected Tropical Disease. 2018;. 10. Mationg M, Gordon C, Tallo V, Olveda R, Alday P, Reñosa A et al. Status of soil-transmitted helminth infections in schoolchildren in Laguna Province, the Philippines: Determined by parasitological and molecular diagnostic techniques. PLOS Neglected Tropical Disease. 2017;11(11).

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TABLE AND FIGURES

Table 1​ - Assessment of stool sample using in-field microscopic Kato-Katz analysis compared to qPCR. (Adisakwattana et al.⁵)

Table 2​ - Kappa analysis for agreement of the qPCR ​vs​ Kato-Katz methods. (Adisakwattana et al.⁵)

213


Table 3​ - Number of positive samples (n), prevalence (%) and 95% confidence intervals (95% CI) for Kato-Katz and qPCR diagnostic. (Dunn et al.⁶)

Table 4​ - Observed soil-transmitted helminth prevalence, Double-Slide Kato-Katz eggs per gram, and qPCR Cq values (N = 2,799). (Benjamin-Chung et al.⁴)

214


Table 5​ - Classification of qPCR and Double-Slide Kato-Katz for each type of STH (N = 2,799) (Benjamin-Chung et al.⁴)

Table 6​ - Estimated sensitivity, and specificity of each diagnostic method using Bayesian latent class models. (Benjamin-Chung et al.⁴)

215


Table 7 ​- Positivity agreement according to Kato-Katz and qPCR for all four-examination time points pooled (n=1636) for ​T. trichiura, A. lumbricoides​, and hookworm. (Keller et al.⁷)

Table 8​ - Mutual sensitivities calculated for combined Kato-Katz and combined qPCR for ​T. trichiura, A. lumbricoides, ​and hookworm at baseline and 14-21 days follow up. (Keller et al.⁷)

Table 9​ - Cohen’s Kappa for positivity of qPCR resp. Kato-Katz between baseline day 1 and day 2 and between follow-up day 1 and day 2. (Keller et al.⁷)

216


Table 10 - ​Sensitivity calculated for 2 days of Kato-Katz (KK) and one PCR sample for ​T. trichiura,​ hookworms (incl. ​A. duodenale, N. americanus​ and ​S. stercoralis) and A. lumbricoides. ​(Barda et al.⁸)

Table 11 - ​Agreement calculated with Cohen’s kappa between intensity categories based on EPG and frequency matched categories for PCR DNA copy numbers. (Brada et al.​⁸​)

217


Figure 1​ - Correlation of the mean qPCR results and mean egg count (+1) results for ​Ascaris​ (A) and hookworm (B) data. (Werkman et al.​⁹​)

Table 12​ - Prevalence of helminth infections in 263 schoolchildren in Laguna province, Philippines, stratified by diagnostic approach. (Mationg et al.​10​)

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Anemia and Hepatomegaly Associated with Mortality Rate in Patients with Malaria : A Literature Review Andreas Sihombing* Gabriel Justin Darmajaya* Jonathan Vincent Lee*

ABSTRACT

Malaria is a parasite infection transmitted by the Plasmodium that leads to acute life-threatening disease and poses a significant global health threat. Plasmodium consume hemoglobin and develops from immature trophozoites (ring stage) to either mature trophozoites or gametocytes. Mature trophozoites replicate, forming schizonts, disrupting erythrocyte cell membrane integrity, that causes anemia. In uncomplicated malaria, the patients will present elevated temperatures, perspiration, weakness, enlarged spleen, mild jaundice, enlargement of the liver, increased respiratory rate. Therefore we want to study the association between anemia, hepatomegaly and mortality rate in patients with malaria. Our search is done in PubMed Central using “Malaria, Falciparum”, “Anemia”, “Hepatomegaly”, and “Survival Rate” keywords, resulting in a total of 180 journals. The journals are further excluded according to year, research types, and exclusion criteria leaving only 2 journals. From a total of 611 patients, patients with anemia not increasing the total mortality rate of malaria. There is no direct association between hepatomegaly and malaria to increase mortality rate.

Keywords : Malaria, Anemia, Hepatomegaly, Survival Rate.

219


Anemia and Hepatomegaly Associated with Mortality Rate in Patients With Malaria : A Literature Review Scientific Paper

Author(s): Andreas Sihombing Gabriel Justin Darmajaya Jonathan Vincent Lee

220


Anemia and Hepatomegaly Associated with Mortality Rate in Patients with Malaria : A Literature Review Andreas Sihombing* Gabriel Justin Darmajaya* Jonathan Vincent Lee* INTRODUCTION Malaria Malaria is a parasite infection transmitted by the ​Anopheles mosquito that leads to acute life-threatening disease and poses a significant global health threat. Two billion people risk contracting malaria every year, including those in 90 endemic countries and 125 million travelers.​1 The female ​anopheles ​ingests gametes during a blood meal, which form sporozoites

that replicate in the gut. During subsequent blood meals, saliva containing sporozoites gets released into a human host’s bloodstream. Within 60 minutes, sporozoites reach the liver,

invade hepatocytes, and then rapidly divide, forming merozoites. In an active infection, organisms reenter the bloodstream and invade erythrocytes. Within erythrocytes, ​Plasmodium consume hemoglobin and develop from immature trophozoites (ring stage) to either mature trophozoites or gametocytes. Mature trophozoites replicate, forming schizonts, disrupting erythrocyte cell membrane integrity, and leading to capillary endothelial adherence and cell lysis. ​P. vivax and ​P. ovale infections may display "dormant schizogony," where inactive intrahepatic parasites (hypnozoites) remain until reactivation months to years in the future.​1 The incubation period varies by species: 8 to 11 days for ​P. falciparum, 8 to 17 days

for ​P. vivax​, 10 to 17 days for ​P. ovale​, 18 to 40 days for ​P. malariae​, and 9 to 12 days for ​P. knowlesi​. The periodicity of the ​Plasmodium

life cycle creates the classic “malarial

paroxysm” of rigors, followed by several hours of fever, followed by diaphoresis and drop to normal body temperature.​1 In uncomplicated malaria, the patients will present with fever, chills, sweats, headaches, nausea and vomiting, body aches, general malaise. Physical examination will find elevated temperatures, perspiration, weakness, enlarged spleen, mild jaundice, enlargement of the liver, increased respiratory rate. In severe malaria, the patient will present with cerebral malaria, severe anemia, hemoglobinuria, acute respiratory distress syndrome, coagulopathy, metabolic acidosis, and hypoglycemia.​2 The disease can be confirmed by clinical diagnosis based on symptoms and physical finding followed by microscopic diagnosis with Giemsa stain. Other test can be used like rapid diagnostic test to detect antigen, polymerase chain reaction to confirm the species of

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malarial parasite after diagnosis by smear microscopy, serologic test to detect antibodies against malaria parasites.​3 Treatment for patients diagnosed with malaria includes schizonticidal medications, supportive care, and hospitalization for high-risk patients. Treatment involves combination therapy targeting both the hepatic and erythrocytic forms. The chief antimalarials are chloroquine, hydroxychloroquine, primaquine, artemisinin-based combination therapy (ACT), and atovaquone-proguanil.​1 Anemia Anemia is an extremely common disease affecting up to one-third of the global population. In many cases, it is mild and asymptomatic and requires no management. The prevalence increases with age and is more common in women of reproductive age, pregnant women, and the elderly. The prevalence is more than 20% of individuals who are older than the age of 85. The incidence of anemia is 50%-60% in the nursing home population. In the elderly, approximately one-third of patients have a nutritional deficiency as the cause of anemia, such as iron, folate, and vitamin B12 deficiency.​4 Anemia is described as a reduction in the proportion of the red blood cells. The etiology of anemia depends on whether the anemia is hypoproliferative (corrected reticulocyte count <2%) or hyperproliferative (corrected reticulocyte count >2%). Hypoproliferative anemia divided by the mean corpuscular volume into microcytic anemia (MCV<80 fl), normocytic anemia (MCV 80-100 fl), and macrocytic anemia (MCV>100 fl). Hemolytic anemia divided into extravascular hemolysis where red cells are prematurely removed from the circulation by the liver and spleen and intravascular hemolysis where red cells lyse within the circulation.​4 Mechanisms that cause anemia are increased red blood cells destruction (blood loss and hemolysis) and deficient/defective erythropoiesis. Patients will present with weakness, tiredness, lethargy, shortness of breath, chest pain, reduced exercise tolerance, cool skin, tachypnea, hypotension, pallor of the conjunctiva. Management depends primarily on treating the underlying cause.​4 Hepatomegaly Hepatomegaly is an abnormal enlargement of liver size and is inherently defined by a volumetric change. Hepatic size has been an important biomarker for assessing disorders and

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surgical planning. Predictably, hepatic size estimates by physicians using palpation and percussion are approximate and adequate for diagnosing only massive hepatomegaly cases.​5 Liver involvement is often observed in hematological disorders, resulting in abnormal liver function tests, abnormalities in liver imaging, or clinical symptoms presenting with hepatic manifestations. In hemolytic anemia, jaundice and hepatosplenomegaly are often seen imitating liver diseases. In hematologic malignancies, malignant cells often infiltrate the liver and

may

demonstrate

abnormal

liver

function

test

results

accompanied

by

hepatosplenomegaly or formation of multiple nodules in the liver or spleen.​6 MATERIAL AND METHODS Search is done in PubMed Central using “Malaria, Falciparum”, “Anemia”, “Hepatomegaly”, and “Survival Rate” keywords, resulting in 180 journals. The journals are further excluded according to year, research types, and exclusion criteria leaving only 2 journals. RESULTS AND DISCUSSION One research done by Mathews et.al, in which 150 patients were included in prospective study, 57 patients severe malaria and 17 patients with uncomplicated malaria present with hepatomegaly. ​The median hemoglobin in the study population was 11.6 g/dl and 4 (6,3%) cases suffered from severe anemia (hemoglobin <7 g/dl). Mortality rates for severe anemia were 0 (0%). In a prospective study done by Kumar et.al, which included 511 patients. 389 patients classified as non-severe cases and 122 patients classified as severe cases. Among non-severe patients, 67 patients present with hepatomegaly. Among severe patients, 39 patients present with hepatomegaly. From severe malaria patients, 6 patients present with severe anemia (hemoglobin <7 g/dl). 3 patients with only severe anemia (no complication) survived. From a total of 611 patients, patients with anemia not increasing the total mortality rate. In this journal there is no direct association between patients with hepatomegaly and malaria. Patients with hepatomegaly can increase the mortality rate if there is another comorbid such as hyperbilirubinemia, metabolic acidosis, ARDS. It goes the same with anemia, it can increase the mortality rate if there is another comorbid such as metabolic acidosis, hyperbilirubinemia, Shock (Circulatory collapse), ARDS.

223


CONCLUSION Research from two journals show that anemia and hepatomegaly were not associated with increased mortality rate in malaria patients. Therefore, further research with specified goals, method, and outcome is needed to have a definitive conclusion.

224


REFERENCES 1. Buck E, Finnigan NA. Malaria [Internet]. StatPearls. StatPearls Publishing; 2020 [cited 2020 Dec 8]. Available from: ​http://www.ncbi.nlm.nih.gov/pubmed/31869175 2. CDC - Malaria - About Malaria - Disease [Internet]. [cited 2020 Dec 8]. Available from: ​https://www.cdc.gov/malaria/about/disease.html

3. CDC - Malaria - Diagnosis & Treatment (United States) - Diagnosis (U.S.) [Internet]. [cited

2020

Dec

8].

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https://www.cdc.gov/malaria/diagnosis_treatment/diagnosis.html 4. Anemia - StatPearls - NCBI Bookshelf [Internet]. [cited 2020 Dec 8]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK499994/ 5. Assessing Hepatomegaly: Automated Volumetric Analysis of the Liver [Internet]. [cited

2020

Dec

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3319283/ 6. Murakami J, Shimizu Y. Hepatic Manifestations in Hematological Disorders. International Journal of Hepatology [Internet]. 2013 [cited 2020 Dec 8];2013:1–13. Available from: /pmc/articles/PMC3626309/?report=abstract 7. Mathews SE, Bhagwati MM, Agnihotri V. Clinical spectrum of Plasmodium vivax infection, from benign to severe malaria: A tertiary care prospective study in adults from Delhi, India. Tropical Parasitology [Internet]. 2019 Jul 1 [cited 2020 Dec 8];9(2):88–92. Available from: /pmc/articles/PMC6767802/?report=abstract 8. Kumar R, Saravu K. Severe vivax malaria: a prospective exploration at a tertiary healthcare centre in Southwestern India. Pathogens and Global Health [Internet]. 2017 Apr

3

[cited

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8];111(3):148–60.

/pmc/articles/PMC5445641/?report=abstract

225

Available

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The Assessment of The Safeness, Effectiveness, and Efficacy of Carica Papaya Leaf Extract Consumption as A Comprehensive Alternative Thrombocytopenia Therapeutic Application to Reduce Mortality Caused by Dengue Hemorrhagic Fever with Thrombocytopenia In Tropical States : A Systematic Review of Randomized Controlled Studies Christina Valeria Sie, Raesha Fachira Isfianto, Johan Wibowo Introduction: Dengue Hemorrhagic Fever (DHF) is a disease caused by dengue viruses, a type of virus that is classified as arbovirus (Arthropod-borne viruses). DHF gives clinical manifestations of fever, muscle pain, and joint pain accompanied with leukopenia, rashes, lymphadenopathy, thrombocytopenia, and hemorrhagic diathesis. Global implication shows morbidity and mortality which are found almost throughout tropical countries especially Indonesia. The lack of effective therapeutic interventions for DHF leading to increased mortality. ​Carica papaya as one of the alternative, natural, herbal, and economical choices for DHF management. Thus, we made our systematic review to evaluate the effectiveness of Carica papaya as an effective alternative therapy for patients with DHF. Materials and Methods: The work of our systematic review is made by collecting data from online resources including Pubmed and Google Scholars. PICO analysis and MeSH terminology were used in the Systematic Analysis approaches in this study. Results and Discussion: Inclusion and exclusion criteria were used and we found 5 relevant studies to be analysed. Srikanth et al., Kasture et al., Gadhwal et al., Shetty et al. had defined that ​Carica papaya specifically ​Carica papaya leaves extract (CPLE) syrup increases platelet count of patients associated with dengue fever. In contrast, only one study conducted by Asghar et al. had stated that there is no significant difference on platelet count between patients who were given CPLE extract and patients who were in intravenous hydration. Conclusion: Based on our systematic review, we conclude that ​Carica papaya leaves extract

increases platelet count and may be an effective therapy of DHF. Exclusively, only 1 out of 5 studies specifies that there is no significant difference in platelet count between patients with CPLE therapy and patients with intravenous hydration

Keyword:​ Dengue hemorrhagic fever, ​Carica papaya​, therapy 226


The Assessment of The Safeness, Effectiveness, and Efficacy of Carica Papaya Leaf Extract Consumption as A Comprehensive Alternative Thrombocytopenia Therapeutic Application to Reduce Mortality Caused by Dengue Hemorrhagic Fever with Thrombocytopenia In Tropical States : A Systematic Review of Randomized Controlled Studies Christina Valeria Sie, Raesha Fachira Isfianto, Johan Wibowo

227


Introduction Dengue Hemorrhagic Fever (DHF) is a disease caused by dengue viruses, a type of virus that classified as arbovirus (Arthropod-borne viruses), which means viruses that are transmitted through the bite of arthropods, such as ​Aedes albopictus or female ​Aedes aegypti

mosquito as primary vector also ​Aedes polynesiensis​, ​Aedes scutellaris and ​Aedes niveus as secondary vector.​11 Dengue Hemorrhagic Fever also gives clinical manifestations of fever, muscle pain and joint pain accompanied by leukopenia, rashes, lymphadenopathy, thrombocytopenia and hemorrhagic diathesis.​9 The number of cases reported in 2015 was 129,650 with 1,701 number of deaths.​10 In addition, in 2018, there are still 65,602 cases of DHF occurred in Indonesia.​12 With a global implication, resulting in morbidity and mortality which are found almost throughout Indonesia. For more than 50 years DHF occurred in Indonesia, DHF still ended up as a serious issue in Indonesia. DENV is an arthropod-borne flavivirus that is highly associated with hemorrhagic fever and hemorrhagic shock. There are widely known Dengue Virus (DENV) serotypes, DENV-1, DENV-2, DENV-3 and DENV-4. Currently there is no specific treatment for DENV. DHF is characterized by the acute onset high fever sometimes followed by febrile phase. There are common haemorrhagic diathesis such as positive tourniquet test (TT), petechiae, easy bruising and or Gastrointestinal haemorrhage in severe state. By the end of the febrile phase, there is a tendency to develop hypovolemic shock (dengue shock syndrome) due to plasma leakage.​13 ​Abnormal haemostasis and plasma leakage are the main pathophysiologic hallmarks of DHF. Recent hopeful DHF vaccine candidates have just been deemed ineffective and there is still no prediction of complete vector control. Immunosuppression, in the form of corticosteroids​14 or immunoglobulins also has not shown any benefit.​15 The lack of effective therapeutic interventions for DHF leading to innovative alternative therapies, such as natural and herbal remedies for DHF. ​Carica papaya is one of the alternative, natural and herbal

choices that has already been an issue as DHF management also has been used in some countries for DHF treatment. ​Carica Papaya is a member of Caricaceae family that belongs

to polygamous, dicotyledonous, and diploid species.​16 ​Carica papaya leaves have been used

in ayurvedic medicine for many years. It is used as an anti-inflammatory agent for wound-healing,​17​ antitumor as well as immune modulatory effects,​18​ and as an antioxidant.​19 Indonesia is a tropical country with a diverse range of flora. Papaya (​Carica papaya L.), a plant originated native to Mexico and South America is one of the examples of flora diversity in Indonesia. The leaves of Carica papaya contain several biologically compounds, 1 228


such as caricain, chymopapain, papain, and glycine endopeptidase that have been shown to improve the acidity of pH, and leading to degradation of pepsin. Carica papaya also contains lipase, which is bound to the water-insoluble component of papain.​20 In addition, it also works as an anti-viral with haematological effects which might have pathophysiological implications as it is used as treatment for DHF, such as antioxidant properties.​21 The flavonoids of Carica papaya leaf extract also proved successfully inhibit a protease involved in viral assembly.​22 The intense polemic gradually continues to criticize the therapeutic efficacy and safety of Carica papaya as treatment of DHF. This systematic review aims to critically analyze the availability of clinical evidence from prospective controlled clinical trials on the efficacy and safety of Carica Papaya extract in the treatment of Dengue Haemorrhagic Fever infection. Material and Methods For our systematic review, we collect and use our data from several randomized control trial studies published in online sources including PubMed, GScholar, and Science Direct. The randomized clinical trial that we used were published within 2016 – 2020. The data were accessed in November 2020 using the following keyword or terms : (“Dengue Hemorrhagic Fever” OR “DHF”) AND “Thrombocytopenia” AND (“Carica Papaya” OR “Carica Papaya Leaves Extract” OR “CPLE”) AND (“Treatment” OR “Therapy”) AND (“Randomized Controlled Study” OR “Randomized Controlled Trial” OR “RCT”). A systematic analysis, such as PICO analysis and MeSH terminology, was also used in this study. For PICO analysis, we used “All age” for People or Population (P) . For the Intervention (I), we used “Carica Papaya for Dengue Hemorrhagic Fever Therapy”. For the Comparison (C), we compared the data from the population that did not get a CPLE therapy or as we called it, the control group. Lastly, the Outcome (O) we used “Thrombocytopenia in Dengue Hemorrhagic Fever”. The inclusion criteria used in this systematic review are a Randomized Control Trial, Patients with CPLE therapy and thrombocytopenia, and we used all age for our subject. While the exclusion criteria are meta analysis, literature review, case report, systematic review, and animal study. Results and Discussion We used the PICO method and MeSH terminology and obtained five randomized controlled studies that will be analyzed and reviewed. The initial search yielded 17 results from Google Scholar and 5 results from PubMed. The PRISMA flow chart is shown in Fig. 1, 2 229


depicting the process of choosing studies for the systematic review. After pairing with the inclusion and exclusion criteria, we eliminated 3 results from PubMed and 10 results from Google Scholar, filtering double literature also done and carried out five full text articles that were relevant for our quantitative analysis. A summary of all studies is provided in table 1. In brief, there are 4 studies conducted in India and one study conducted in Pakistan. All studies were mentioned as randomized and recruited adult DHF patients except two which included only pediatric patients (aged range 1-12 years and 1-16 years old).

Figure 1​ Flow chart with information of different selection phases of randomized controlled studies

3 230


Table 1​ Summary of studies on the effectiveness of​ Carica Papaya​ as therapy for dengue hemorrhagic fever with thrombocytopenia

Authors

Study

Year

Subject

Results

Srikanth et al ​⁴.

Randomized Controlled Study

2019

147 Children aged 112 years having thrombocytopenia associated with DF (NS-1 antigen positive) or DHF grades I and II

CPLE syrup increased the platelet count significantly to the control group

Kasture et al ⁵.

Randomized Controlled Study

2016

300 patients across 5 medical centres.

CPLE increased platelet count significantly with fewer side effects and good tolerability

Gadhwal et al ⁶.

Randomized Controlled Study

2016

Subjects were given CPLE capsule 500 mg and routine supportive treatment for five consecutive days

CPLE increased the platelet count in DF without any side effects and prevent the complications of thrombocytopenia

Shetty et al ⁷.

Randomized Controlled Study

2019

Children aged 1 - 16 were given a CPLE tablets with various doses depending on the age

CPLE has no side effect and coincided with the natural increase in platelet in the recovery phase

Asghar et al ⁸.

Randomized Controlled Study

2020

All patients with a diagnosis of dengue infection who had evidence of decreased platelets and febrile illness.

No significant difference in the course of patients who were given CPLE extract versus patients who were in intravenous hydration

Note: DF : Dengue Fever DHF : Dengue Hemorrhagic Fever CPLE : Carica Papaya Leaf Extract

In a prospective, open-label randomized controlled study conducted by Srikanth et al. from India, where the effect of Carica papaya extract on platelet counts was conducted in 285 subjects aged between 1 and 12 years ​that having thrombocytopenia associated with dengue fever (NS-1 antigen positive) or DHF grades I and II. Information to measure minimize bias was limited. There are two outcome measures, the primary was the mean increase in platelet count and the secondary outcome measures are changes in the Red White Cells (RBCs) and White Blood Cells (WBCs). The platelet count in the intervention group increased from day 3 onward and resulting in significantly increased platelet count compared to the control group. While the changes of mean RBCs count increased statistically significant on day 5 and mean 4 231


WBCs count increased statistically significant on day 3.There were just two children excluded and complained of nausea in the intervention group.​4 Efficacy and safety of ​Carica papaya leaf extract (CPLE) as empirical therapy for

thrombocytopenia associated with Dengue Fever (DF) also evaluated by a multicentric, double blind, placebo controlled, randomized, prospective study by Kasture et al. that is conducted in 300 DF patients across 5 centres. The subjects were randomized into two groups. The intervention group received a CPLE tablet three times daily for five days. The result indicates changes in red blood cells and white blood cells count, hematocrit, also platelet count. The intermediate measure of the platelet counts in the Carica papaya group on the third until fifth day were 88.897 × 10​9​/l, 102.579 × 10​9​/L and 155.886 × 10​9​/L, otherwise

the

control

group

counts were 55.633 × 10​9​/L, 64.582 × 10​9​/L and

70.528 × 10​9​/L. White blood cells count is also higher in the Carica Papaya group but the hematocrit and red blood cells count between two groups are similar. This study confirmed the significantly increased platelet count in patients with thrombocytopenia that is associated with DHF.​5 Another randomized control trial study by Gadhwal et al. that was held in India also showed that Carica papaya leaf extract can increase the platelet count in dengue fever without any side effects and also can prevent the compilation of thrombocytopenia. The number of samples taken didn’t mention clearly but all of the samples were randomised into two groups, the study group that was given a Carica papaya leaf extract capsule of 500 mg once daily and routine supportive treatment within 5 days and the control group that was given only routine supportive treatment. On the third day, the platelet count in the study group was 82.96±16.72 thousand which is significantly higher than the control group (66.45±17.36 thousands) with p value below 0.01. On the fourth and fifth day, the platelet count of the study group was 122.43±19.36 thousand showing the significantly higher than control group that was 112.47±17.49 thousand. The average platelet transfusion requirement in the study group was significantly less than the control group.​6 The single centre, comparative study conducted by Shetty et al. which were held in India with the sample among 30 children aged 1 to 16 years old with dengue and platelets ranged ≤1.5x105perμL and ≥50x 103perμL were included and assigned to either control group or test group the results show that the mean test group

platelet count was

143.27x103perμL, which was comparable with 148.20 x103perμL among control group and the difference was not statistically significant. On the third day, the test group mean platelet count had fallen up to 86.13 x103 perμL. On the fifth day, mean platelet count showed an 5 232


increase in the test group which was however not statistically significant. This result conclude that there is no side effect in children with dengue fever and low platelet count, this result could be affected by the day since onset of fever and starting platfast and repeat dengue viral infection that didn’t be considered also children with platelet count below 50,000/uL that were not included in the study.​7 The observational, comparative study conducted by Asghar et al. at the Department of Medicine at Dow University Hospital Karachi, Pakistan using sample included patients diagnosed dengue infection via serology and exclude all patients who were transfused with platelets during hospital stay or having chronic or autoimmune thrombocytopenic illness and admitted in ICU. All of the samples are divided into two groups (A and B), group A only receiving intravenous hydration and B group receiving papaya extract and intravenous hydration. In the first day, the mean platelet count was 27.85 ± 12.38 for group A and 35.29 ± 21.54 for group B. In the fourth day, the mean of platelet count in group A (83.79 ± 31.88) and B (80.70 ± 35.09) increasing. And the seventh day, the mean platelet count of group A was 217.23 ± 92.10 and the mean platelet count of group B was 231.64 ± 102.92. This result show no clinical significant role of papaya extracts in improving platelet counts supported by the mean days of hospital stay between A group and B group that not much different, 4.07 ± 1.17 for group A and 4.02 ± 1.14 for group B. At the end of this study, the author also declared there is no Conflict of Interest.​8 Several studies that have been reviewed and done have a distinct variation due to the inclusion and exclusion criteria of the sample, how the patients categorizations, the doses of Carica papaya that have been used and also measurements that were used to determine the platelet count. The parameters through which bias can be evaluated were not reported in some study, therefore the results obtained cannot be considered free of bias. But as far as many studies have been done, there is no evidence that Carica papaya is a toxic substance and there are no adverse events as evidence upon. The study that has been analyzed also didn’t report any significant side effects with Carica papaya extract. The absence of study that examined the physiological impact from Carica papaya to repair and help to increase the platelets count in DHF patients so on, the large scale randomized double blind placebo controlled trial are essentially needed to know the effectiveness and the safety of Carica papaya as a treatment for Dengue Hemorrhagic Fever.

6 233


Conclusion Therapy of dengue hemorrhagic fever with thrombocytopenia using carica papaya leaves extract has been increasing the platelet count significantly. This conclusion is confirmed by findings of 5 recent reviews which shows an effectiveness of carica papaya leaves extract, where various subjects from different age groups were given ​Carica papaya

leaf extract with different doses and period of time. Some of the studies said that ​Carica papaya significantly raises platelet, RBCs, and WBCs count significantly while other studies

said that ​Carica papaya did not raise the platelet, RBCs, and WBCs count significantly. Further studies are needed in order to find more evidence regarding the effectiveness of Carica papaya for therapy of Dengue Hemorrhagic Fever with thrombocytopenia. In the near future, if Carica papaya has proven to be effective for therapy of DHF it can be one of alternative herbal medicine with lower costs, which will also improve in reducing complications caused by thrombocytopenia and in enhancing the quality of life.

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International.

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Effectiveness of Using Recombinant Antigen for Pig Vaccination as a Potential Method for Controlling Taenia Solium Transmission to Humans in Cysticercosis: A Systematic Review Bhumika Raisinghani, Timothy Andhieka Nathanael Hartono, Yong Yee Wen

ABSTRACT Introduction: Cysticercosis, commonly known as Pork Tapeworm Infection, is a neglected zoonotic parasitic infection caused by the transmission of larval cysts of Taenia Solium tapeworm to human tissues from pigs as an intermediate host. The symptoms vary depending on the number, size and location of the cysticerci, as well as the intensity of the host’s immune response. The most severe form of infected human is neurocysticercosis (NCC). To prevent such an event, the use of vaccinations in pigs aims to prevent the disease near its source. Vaccines using recombinant T. Solium antigens have been front-runners in the protection of pigs against future challenges by T. Solium eggs. We wanted to evaluate the effectiveness of using recombinant antigens for DNA vaccination, to prevent further transmission of T. Solium cysticercosis. Materials and Methods: In our systematic review, we collected data from online resources which includes Pubmed, Science Direct, NCBI, and Publishers. Systematic Analysis approaches were used in this study, for example, using combinations of keywords related to population, intervention, and outcome. Results and Discussion: Using the inclusion and exclusion criteria, we have found 5 articles that are relevant for this review. Gauci et al., Kabululu et al., Lightowlers et al., Jayashi et al., and Assana et al., have all published in their studies the efficacy of using the vaccine to prevent the development of T. Solium cysticercosis in pigs. Conclusion: In conclusion, the use of recombinant antigen in vaccines is an effective method to combat the transmission of Taenia Solium cysticercosis.

Keyword: Pig, recombinant antigen, vaccine, cysticercosis, prevention

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Effectiveness of Using Recombinant Antigen for Pig Vaccination as a Potential Method for Controlling Taenia Solium Transmission to Humans in Cysticercosis: A Systematic Review Bhumika Raisinghani, Timothy Andhieka Nathanael Hartono, Yong Yee Wen

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Introduction Cysticercosis, commonly known as Pork Tapeworm Infection, is a neglected zoonotic parasitic infection caused by the transmission of larval cysts of Taenia Solium (T. Solium) tapeworm to human tissues from pigs as an indispensable intermediate host. In the worldwide scale, T. solium was identified to have been the highest public health concern amongst the foodborne parasites. It is a significant parasitic disease that truly and regularly influences human wellbeing and the economy in undeveloped nations. This disease is associated with low standards of living and poor sanitation, which may occur in countries with lower socio-economic status. T. Solium can be transmitted to humans through the consumption of raw or undercooked infected pork products (Taeniasis) or contaminated water. Direct contact with infected surfaces or substances may also increase the risk of someone developing the disease. In addition to pig-tohuman transmission, the parasite can also be transmitted from humans to pigs (Porcine Cysticercosis), by the ingestion of T. Solium eggs from infected human feces. The symptoms which occur in individuals with cysticercosis varies from case to case depending on the number, size and location of the cysticerci, as well as the intensity of the host’s immune response. It is often found in skeletal and heart muscle, skin, subcutaneous tissues, the lungs, and other tissues. The most severe form of infected human is neurocysticercosis (NCC). Neurocysticercosis is a state or condition where humans start to experience neurological disorders, which may later provoke epileptic manifestations or even death, as the parasite attacks the brain. To prevent such an event, the use of vaccinations in pigs aims to prevent the disease near its source. Vaccines using recombinant T. Solium antigens have been front-runners in the protection of pigs against future challenges by T. Solium eggs. The vaccine is produced by expression in Escherichia coli and is fused with glutathione S-transferase (GST) protein. Through polymerase chain reaction and the truncation of amino acids, T. Solium antigens recombinant antigens can be assembled as a vaccine. Previous studies on the effectiveness of recombinant antigens were incomplete and fragmented. Thus, through this systematic review, we wanted to evaluate the effectiveness of using recombinant antigens for DNA vaccination, to prevent further transmission of T. Solium cysticercosis.

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Methods In this Systematic Review, data was collected from various online journal platforms; PubMed, NCBI, ScienceDirect and Publisher. The PICO Method and MeSH terminology were among various Systematic Analysis approaches that have been used in this study. “Pig” was used as the Population or Subjects (P), while “Recombinant Antigen” or “Vaccination” was used for Intervention (I). For Outcome, we used the terms “Prevention” and “Cysticercosis”. The hypothesis opted for this systematic review is “Recombinant Antigen is effective for controlling Taenia Solium transmission to humans in cysticercosis”. In this Systematic Review, the inclusion criteria used are Randomized Clinical Trial, Taenia Solium, Cysticercosis, Recombinant Antigen, DNA Vaccine and a population of pigs. The exclusion criteria used are Meta-analysis, Literature Review, Case Report, and Children.

Results and Discussion Using the PICO approach, searching was done through an online database, and we acquired 5 articles that would be analyzed. The selection process is shown in the diagram below.

Figure 1. Information flow chart through the different phases of the systematic review

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Table 1. Summary of studies on recombinant antigen for pig vaccination

According to the study by Gauci et al, conducted in 4 groups of pigs with 5 pigs in each group (as shown on the table below). 5 pigs which are vaccinated with glutathione S-transferase (GST) and maltose-binding protein (MBP). Cysticerci was found in each of the 5 pigs which are vaccinated, ranging from 22–3831 cysts per animal (mean = 961). However, from the group of pigs immunized with TSOL 16, 2 pigs contained no cysts, 2 pigs contained 1 cyst each and the last pig contained 6 cysts (range = 0-6, mean = 2). The data shows that pigs the TSOL16 vaccine is more effective than the GST/MBP vaccine (99.8% protection, P = 0.008). Pigs vaccinated with TSOL45-1A were all infected and contained cysticerci ranging from 1-63 per animal (mean = 20), which represents the reduction in the mean number of parasites found in the control pigs (961) by 97.9%. However, the group immunized with TSOL45-1A and the controls can’t be said to be significantly different by its statistical comparison (P = 0.087, Mann–Whitney U test). The last group of pigs vaccinated with TSOL45-1B showed no statistical difference compared with the control group and contained cysticerci between 18-2912 per animal (mean = 780, P > 0.99).

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The comes about of the vaccine trial in which pigs were immunized with the TSOL16 recombinant antigen illustrates that the antigen is able to bestow high levels of protection against challenge disease with T. solium. Group (Antigen)

Number of cysts in individual pigs

Mean

P valuea

Protectionb (%)

Control

22, 31, 34, 889, 3831

961

-

-

TSOL16

0, 0, 1, 1, 6

2

0.008

99.8

TSOL45-1A

1, 5, 5, 25, 63

20

0.087

97.9

TSOL45-1B

18, 93, 127, 750, 2912

780

>0.99

18.8

Table 2. Number of T. solium cysticerci in pigs immunized with recombinant antigens and challenged with T. solium.

Kabululu ML et al conducted their study in rural districts of Tanzania by administering two groups of pigs with different given treatments, T1 (Oxfendazole / OFZ treatment alone [30 mg/kg, Paranthic 10%]) and T2 (TSOL18 [1 mL, Cysvax] and OFZ). TSOL18 vaccine is known for the prevention of T. Solium infection in pigs, meanwhile OFZ is for killing cysticerci in pig tissues which may present an opportunity for effective control of the disease. Both treated pig groups were initially necropsied to determine the prevalence of viable T. Solium cysticerci in different organs and muscle groups. Interventions for both T1 (n=36) and T2 (n=90) were given in three rounds at four months intervals. Then, carcase dissections were done to compare the presence, viability, and number of the cysticerci. The cysticerci were classified as viable if it was a translucent vesicle with a visible scolex inside. This study has shown differences of T2 group’s baseline and endline, compared to those in T1 group. The baseline and endline prevalence for T1 consecutively were 25.5% (Confidence Interval [CI] = 13.9, 40.3%) and 2.8% (CI = 0.1, 14.5%), which was convincing (p = 0.005). On the other hand, the significant baseline and endline prevalence for T2 (p = 0.001) consecutively were 12% (CI = 6.4, 20.0% ; p = 0.001) and 0% (CI = 0, 4.7%). The usage of TSOL18 with the help of OFZ has been conducted in several previous studies and proved to be consistent, since TSOL18 alone could only prevent new infections and did not clear the existing cysticerci. In the study conducted by Lightowlers et al, fifty Landrace-Petran cross pigs, approximately 12 weeks of age, were dispensed randomly to five equal treatment groups, T1 to T5. All groups were vaccinated with a TSOL18 maltose-binding protein fusion and Anti-

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TSOL18-specific IgG titers were analyzed, since TSOL18 was produced from the cloning of T. Solium oncospheres. However, the interval of given injections were differentiated for each pig group, which may provide the comparison of the antibody titers. Anti-TSOL18-specific IgG titres in T3 group, who received the treatment in the interval of 12 weeks, had the highest amount of antibody (Mean = 10,290 ; Median = 8500). In this trial, it was stated that the association between the peak IgG antibody titre raised to TSOL18 and the level of protection observed in individual pigs was unclear, but the antibody response induced in pigs which were vaccinated with the 3 months interval of the primary and secondary immunization, were proven to have protected pigs against T. Solium infection. In a study by Jayashi et al. 274 pigs were involved, where 220 were necropsied and the rest 54 were lost or died during the course of the trial (19.7%). Of the 220 euthanized, 107 were assigned to the control group and multiple cysticerci were found in 18 infected control animals (prevalence = 16.8%, total number of cysticerci = 34,081, mean = 1893.4); number of degenerated cysts found were 665 (2.0%). The rest 113 pigs were assigned to the treatment group and received the TSOL16-TSOL18 vaccine, where 106 (93.8%) pigs were found to be free of the infection and 80 of the 83 cysts found were degenerated (96.4%). Using the Wilcoxon signed-rank test (p<0.01), there was a significant 99.7% reduction in the total number of cysts (total number of cysticerci = 83, mean = 11.9), and a 99.9% reduction in the number of viable cysts found in the vaccinated group as compared to the control group. Degenerated cysts represented 96.5% of the final total cyst count in the treatment group as compared to 2% in the control group. Using Fisher’s exact test (p<0.001) we know that the degenerated:viable ratios were significantly different where in the control group, for every 50 viable cysts there was 1 degenerated cyst (degenerated:viable ratio = 0.02 [665/33,416]), while in the treatment group for every viable cyst, 27 degenerated cysts were found (degenerated:viable ratio = 26.67 [83/3])). Animals in the control group had a risk more than 12 times of acquiring viable cysts when compared to the treatment group; viable cysts are the only type that can develop to the adult Taenia Solium. On the McNemar-chi2 test (p<0.05), a significant difference in the incidence of infection between the treatment and control group was detected, when the pigs were analyzed in pairs. When a multivariate analysis was utilized after adjusting for regression by house, village and sex, the risk of finding an animal with viable cysts was 11.53 (95% CI 1.73–21.34) and with muscle viable cysts was 12.61 (95% CI 2.79-22.45) times more in the control than the vaccinated group,

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respectively. Out of the 7 infected pigs in the vaccinated group, 5 had degenerated cysts while 2 had viable cysticerci; one with 2 viable brain cysts and the other had one viable muscle cyst. Similar patterns of cyst localization were found in both groups where 53.0% (vaccinated) and 54.3% (control) were localized in the limbs, and the rest in tongue, heart and spinal, intercostal and head muscles. The use of vaccines in natural conditions reflect similar effectiveness as has been shown with other studies that use controlled conditions (>99%). Although the exact duration of immunity conferred by the vaccine is unknown, necropsies in this study was done 7 months after initial administration. Assana et al. stated in their study that out of their 102 animals in the control group, 20 were infected (prevalence = 19.6%, range = 3 to 37,000 cysticerci) and all had viable cysts, where 98% of the cysts were viable (mean no. of viable cysts = 7142). 13 animals had >1000 cysticerci, 3 had non-viable cysts, 15 had cysticerci in both the brain and muscle, and 3 had both viable and non-viable cysts in the brain; all animals with brain cysts had viable cysts with 97% of the brain cysts being viable. During necropsy of the animals in the vaccinated group, no cysticerci were found anywhere, for both the group which had a paired control necropsied as well and also for the 13 vaccinated pigs whose paired control was not available for necropsy. A statistically significant reduction in vaccinated animals with total cysts (P < 0.0001), viable cysts in muscles (P < 0.0001), total cysts in the brain (P = 0.0002) and viable cysts in the brain (P = 0.0002) was detected where the pairs of control and vaccinated were compared. Furthermore, the prevalence of infection dropped from 19.6% (19/97) in paired control pigs to 0% (0/97) in paired vaccinated pigs (P < 0.0001). After assessing the association between the total number of cysts in the muscles and the brain, the Spearman’s correlation coefficient was found to be 0.89 (95% Confidence Interval (CI) 0.84 to 0.92, P < 0.0001, n = 102). For the 20 pigs with cysts in the muscles, the correlation was 0.92 (95% CI 0.81 to 0.97, P < 0.0001). It was also reported that cysts in the brain only occurred when there were at least 479 cysts in the muscles. Conclusion Based on this review, we can conclude from the 5 studies that we have analyzed that the use of recombinant antigen in vaccines is an effective method to combat the transmission of Taenia Solium cysticercosis.

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References: 1. INFECTION WITH TAENIA SOLIUM (PORCINE CYSTICERCOSIS). In: Terrestrial Animal Health Code [Internet]. 28th ed. World Organisation of Human Health; 2019 [cited 2020Dec8]. Available from: https://www.oie.int/fileadmin/Home/eng/Health_standards/tahc/current/chapitre_taenia_soli um.pdf 2. CDC - DPDx - Cysticercosis [Internet]. 2020 [cited 2020 Dec 8]. Available from: https://www.cdc.gov/dpdx/cysticercosis/index.html 3. Cysticercosis - NORD (National Organization for Rare Disorders) [Internet]. NORD (National Organization for Rare Disorders). NORD; 2019 [cited 2020 Dec 8]. Available from: https://rarediseases.org/rare-diseases/cysticercosis/ 4. Garcia HH, Nash TE, Del Brutto OH. Clinical symptoms, diagnosis, and treatment of neurocysticercosis [Internet]. The Lancet. Neurology. U.S. National Library of Medicine; 2014 [cited 2020Dec8]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6108081/ 5. Gauci CG, Jayashi CM, Gonzalez AE, Lackenby J, Lightowlers MW. Protection of pigs against Taenia solium cysticercosis by immunization with novel recombinant antigens [Internet]. Vaccine. Elsevier; 2012 [cited 2020Dec8]. Available from: https://www.sciencedirect.com/science/article/pii/S0264410X12005415 6. Kabululu ML, Ngowi HA, Mlangwa JED, Mkupasi EM, Braae UC, Colston A, et al. TSOL18 vaccine and oxfendazole for control of Taenia solium cysticercosis in pigs: A field trial in endemic areas of Tanzania [Internet]. PLoS neglected tropical diseases. Public Library of Science; 2020 [cited 2020Dec6]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588121/ 7. Lightowlers MW;Donadeu M;Elaiyaraja M;Maithal K;Kumar KA;Gauci CG;Firestone SM;Sarasola P;Rowan TG; Anamnestic responses in pigs to the Taenia solium TSOL18 vaccine and implications for control strategies [Internet]. Parasitology. U.S. National

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Library of Medicine; 2016 [cited 2020Dec8]. Available from: https://pubmed.ncbi.nlm.nih.gov/26892239/ 8. Jayashi CM;Kyngdon CT;Gauci CG;Gonzalez AE;Lightowlers MW. Successful immunization of naturally reared pigs against porcine cysticercosis with a recombinant oncosphere antigen vaccine. Veterinary parasitology [Internet]. 2012 [cited 2020 Dec 7];188(3–4). Available from: https://pubmed.ncbi.nlm.nih.gov/22541797/ 9. Assana E, Kyngdon CT, Gauci CG, Geerts S, Dorny P, De Deken R, et al. Elimination of Taenia solium transmission to pigs in a field trial of the TSOL18 vaccine in Cameroon. International Journal for Parasitology [Internet]. 2010 Apr [cited 2020 Dec 7];40(5):515–9. Available from: https://pubmed.ncbi.nlm.nih.gov/20138046/ 10. Maganira J. Transmission biology of porcine cysticercosis in eastern-central Tanzania [Internet]. Available from: https://pub.epsilon.slu.se/16802/11/maganira_j_200330.pdf 11. Gauci C, Jayashi C, Lightowlers MW. Vaccine development against the Taenia solium parasite. Bioengineered [Internet]. 2013 Sep [cited 2020 Dec 8];4(5):343–7. Available from: https://pubmed.ncbi.nlm.nih.gov/23196744/

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Effectiveness of Amikacin with Combination of Other Antibiotics as Treatment for Actinomycetoma: A Systematic Review Putu Jason Christian Chendana, Juneca Prettycia Dharsono, Michael Santoso Abstract Introduction Mycetoma is a neglected tropical disease (NTD) characterized by scars, and abscesses. Mycetoma can be found worldwide, but it is endemic in tropical and subtropical countries, mostly between the latitudes 15º south and 30º north, known as the mycetoma belt. The endemic areas are characterized with short rainy seasons with little daily temperature fluctuations, followed by long dry seasons. ​Actinomycetoma is a type of mycetoma that is caused by bacterial infection, and more commonly found in South and Central America. Microorganisms that cause

the disease are found in the soil. This disease can affect all age groups, and men are more likely to be affected than women, with male to female ratio of 4:1 Amikacin is used in combination with other antibiotics. The usage of other antibiotics is for avoiding the antibiotic resistance in the patient. This systematic review is carried to further evaluate the effectiveness of having Amikacin in treating actinomycetoma. Materials and Methods The data are collected from ​Online Sources ​that have an ​Open Access, such as PubMed,

Google Scholar ​and Science Direct, using the combination of keywords related to patient population, intervention, and outcomes (PICO). Studies that fulfill the inclusion and exclusion criteria will be analyzed. Result and Discussion After using the inclusion and exclusion criteria, we found 6 relevant studies conducted by Welsh et al, Ameen et al, Bonifaz et al, Cárdenas et al, Agarwal et al, and Damle et al. Conclusion Among all of the studies that we have analyzed, we have found that the usage of amikacin with combination of other antibiotics like trimethoprim and sulfamethoxazole is effective as treatment for actinomycetoma. Keyword: ​Actimycetoma, amikacin, therapy

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Effectiveness of Amikacin With Combination of Other Antibiotics as Treatment for Actinomycetoma: A Systematic Review Putu Jason Christian Chendana, Juneca Prettycia Dharsono, Michael Santoso

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Introduction Mycetoma is a neglected tropical disease (NTD) characterized by scars, abscesses, nodules, and fistulae that drain serous or purulent material containing the etiological agent. Mycetoma can be found worldwide, but it is endemic in tropical and subtropical countries, mostly between the latitudes 15º south and 30º north, known as the mycetoma belt. The endemic areas are characterized with short rainy seasons with little daily temperature fluctuations, followed by long dry seasons. ​Actinomycetoma is a type of mycetoma that is caused by bacterial infection, and more commonly found in South and Central America. Microorganisms that cause the disease are found in the soil, and may enter the body through a break in the skin.​[1] This disease can affect all age groups, and men are more likely to be affected than women, with male to female ratio of 4:1.​[2] ​Mycetoma commonly affects young men aged between 20 and 40 years with low socioeconomic status, particularly farmers and herdsmen.​[3]

Amikacin used to treat severe or serious bacterial infections. Amikacin is used in combination with other antibiotics. The usage of other antibiotics is for avoiding the antibiotic resistance in the patient. In treating mycetoma, patients may be totally cured, and also may show improvement. This systematic review is carried to further evaluate the effectiveness of having Amikacin in the treatment of actinomycetoma. Methods For our systematic review, we collected data from online sources which includes PubMed​, ​Google Scholar​, and ​Science Direct​. Systematic analysis is done using PICO. MeSH terminology for P (Population) is “People with actinomycetoma” or “Actinomycetoma''. MeSH terminology for I (Intervention) is “Amikacin” or “Combination with amikacin”. MeSH terminology for C (Comparison) is N/A. MeSH terminology for O (Outcome) is “Healing” or “Effect” or “Result”. In this systematic review, the main question is: “Does the usage of amikacin help in treating actinomycetoma?”. Inclusion criteria are: prognostic studies, actinomycetoma cases. Exclusion criteria are: literature review, systematic review, case report, meta-analysis, animal study. In order to reduce bias, we check for the validity of each study that fulfills the inclusion and exclusion criteria, then the data will be analyzed.

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Results and Discussion Using PICO method, searching is done through an online database, and we have gathered 6 articles that will be analysed. The selection process is shown in the chart below.

Figure 1 ​Information flowchart through the different phases of the systematic review

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Table 1 ​Summary of studies on amikacin usage on actinomycetoma

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According to the study conducted by ​Welsh et al​[4] ​has shown that in 15 patients, 13

patients were given the combination of amikacin with trimethoprim-sulfamethaxazole

(TMP/SMX) and the other two were given amikacin only, has shown remission in all of the patients. “Its (amikacin) addition

to trimethoprim-sulfamethoxazole in the treatment of

actinomycotic mycetoma showed an impressive remission in all thirteen patients. This combination being quite superior to other medications and to amikacin alone gives the possibility of a better therapeutic response in a shorter period of time and offers an alternative to patients who do not respond to the traditional antibiotics and chemotherapeutic agents, or to those in whom the location or activity of the disease makes imperative a more aggressive treatment.” Ameen et al​[5] conducted a study using 19 confirmed cases of actinomycetomas treated since 1995 at a tertiary center for mycology to seek the effectiveness of imipenem either monotherapy or combination therapy with amikacin in treating severe refractory diseases. Selection of combination therapy;

Amikacin

with

sulfonamides;

intended for those at risk of dissemination to adjacent organs and treat severe infection refractory to other therapies. In recent studies, this kind of combination has greater than 95% cure. As stated in this study, 3 out of 8 cases previously treated with combination therapy failed due to inefficacy of renal impairment before given imipenem. Hereby, the effectiveness of imipenem both as monotherapy and in combination with amikacin is proven able to overcome severe refractory disease and patients at risk of or with established visceral disease. According to ​Bonifaz et al​[6]​, cases selected in this study had previously been treated

using several drugs; trimethoprim-sulfamethoxazole (co-trimoxazole), dapsone, and amikacin,

either alone or combined show no clinical and microbiological cure within 8 months is considered a failure. All 21 patients who had previously failed various treatments received

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amoxicillin-clavulanate (co-amoxiclav) as an alternative treatment with varying duration 4 to months, 4 out of 21 cases failed and others responded well to therapy. Treatment failures mentioned in recent studies that some may acquire resistance. According to study from ​Cárdenas et al​[7]​, 31 patients with a diagnosis of bacterial actinomycetoma attending a tertiary care hospital in northeast Mexico, with different causative agents such as N. brasiliensis, A. madurae, A. pelletieri, Nocardia spp., treated with different combination of Antibiotics including TMP/SMX alone (12.9% of patient) TMP/SMX + Amikacin (35.5% of patients) TMP/SMX + amoxicillin/clavulanic acid (19.4% of patient) TMP/SMX + amoxicillin/clavulanic acid + Amikacin (12.9% of patient) TMP/SMX + amikacin + moxifloxacin (6.5% of patient) and 4 patient with Recalcitrant cases. Each treatment have a different duration of treatment. The result is 3 out of 4 patients that get treated with TMP/SMX alone are cured, 10 out of 11 patients are cured (90.9%) for patient that get treated with TMP/SMX + Amikacin, for the combination of TMP/SMX + amoxicillin/clavulanic acid 6 out of 6 patients (100%) are cured, 3 out of 4 patient that get treated with triple combination (TMP/SMX + amoxicillin/clavulanic acid + Amikacin), the last combination of TMP/SMX + amikacin + moxifloxacin resulting 2 out of 2 patients cured. Total treatment duration ranged from 1 to 57 months (median 10, IQR: 7). Twenty-eight (90.3%) patients had complete resolution of the infection. Three patients (9.7%) were lost to follow-up. Patients refractory or resistant to previous treatment and/or with involvement of underlying organs or bone improved substantially with the combination of amikacin and TMP/SMX. A triple combination with amikacin was employed when patients did not respond to previous amoxicillin/clavulanate + TMP/SMX. Based on a study from ​Agarwal at el​[8]​, ​Ten patients (eight males, two females) aged

from 9 to 55 years (mean 29.6 years) were included in this study. Patients were treated with different treatment regimens, such as, Ramam regimen, modified Ramam regimen, Welsh regimen and its modification. 8 patients treated with Ramam regimen, One patient with our modified Welsh regimen and One patient with modified Ramam regimen. For the combination of the regimens can be seen on the table.

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Actinomycetoma shows response to a wide range of antibiotics, it is much better to use a Acombination of drugs to treat mycetoma rather than relying on a single drug to avoid resistance. Welsh regimen is a well-established landmark in the treatment of actinomycetoma for the last 35 years, which is based on use of amikacin and shows more than 90% efficacy in actinomycetoma treatment in many previous studies. Modified Welsh regimen rifampicin was added to this successful combination of amikacin and cotrimoxazole to further increase the effectiveness of the treatment. The outstanding feature of amikacin is that it is resistant to bacterial aminoglycoside inactivating enzymes so it is active against organism resistant to other aminoglycosides. Amikacin has been proved to be an effective inhibitor of Nocardia strain. Based on a study by ​Damle et al​[9]​, ​included 18 patients with a confirmed diagnosis of actinomycotic mycetoma, with The Actinomadura spp. was the causative organism in 14 cases while Nocardia spp. was found in 4 cases, all of the patients had a history of receiving treatment either in the form of monotherapy (dapsone, cotrimoxazole) or combination therapy (co-trimoxazole and streptomycin) with negligible response. With the history of patients demonstrating a failure to benefit from the use of an aminoglycoside (streptomycin) and cotrimoxazole, the authors decided to initiate the study with 3 drugs viz. Amikacin, Cotrimoxazole, and Rifampicin. Out of 18 patients, only 2 were lost to follow up, all 16 patients who completed the therapy attained remission Out of these 16 patients achieving remission, 10 patients showed significant response after 3 cycles of amikacin and remaining 6 patients required

255


4 cycles of amikacin. All patients tolerated the drugs quite well with no adverse effects or drug-drug interactions. The follow-up period has ranged between 12 to 18 months with no evidence of recurrence demonstrated in any of the treated cases. with the lack of adverse effects, absence of drug-drug interaction, shorter duration of overall therapy, and hospitalization of patients for amikacin cycles helped ensure good compliance. From these results, it can be inferred that this triple-drug combination could prove to be an useful option for treatment of resistant cases of actinomycetoma.

Conclusion In conclusion of our study, we have found that amikacin works well for treating actinomycetoma with combination of other antibiotics like TMP/SMX and DDS. Amikacin is a better therapeutic response in a shorter period of time, and also offered as an alternative treatment for patients who do not respond well to traditional antibiotics, and need more aggressive treatment.

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References 1. Mycetoma | Fungal Diseases | CDC [Internet]. Cdc.gov. 2020 [cited 5 December 2020]. Available from: ​https://www.cdc.gov/fungal/diseases/mycetoma/ 2. Reis C, Reis-Filho E. Mycetomas: an epidemiological, etiological, clinical, laboratory and therapeutic review [Internet]. 2020 [cited 5 December 2020]. Available from: https://pubmed.ncbi.nlm.nih.gov/29641691/ 3. Vongphoumy I, Dance D, Dittrich S, Logan J, Davong V, Rattanavong S et al. Case Report: Actinomycetoma Caused by Nocardia aobensis from Lao PDR with Favourable Outcome after Short-Term Antibiotic Treatment [Internet]. 2020 [cited 5 December 2020]. Available from: ​https://pubmed.ncbi.nlm.nih.gov/25879445/

4. Welsh O, Sauceda E, Gonzalez J, Ocampo J. Amikacin alone and in combination with trimethoprim-sulfamethoxazole in the treatment of actinomycotic mycetoma [Internet]. 1987

[cited

3

December

2020].

Available

from:

https://www.sciencedirect.com/science/article/abs/pii/S0190962287702278 5. Ameen M, Arenas R, Vásquez del Mercado E, Fernández R, Torres E, Zacarias R. Efficacy of imipenem therapy for Nocardia actinomycetomas refractory to sulfonamides [Internet].

2010

[cited

5

December

2020].

Available

from:

https://pubmed.ncbi.nlm.nih.gov/20005007/ 6. Bonifaz A, Flores P, Saúl A, Carrasco-Gerard E, Ponce R. Treatment of actinomycetoma due to Nocardia spp. with amoxicillin?clavulanate [Internet]. 2006 [cited 4 December 2020]. Available from: ​https://www.ncbi.nlm.nih.gov/pubmed/17223871 7. Cárdenas-de la Garza J, Welsh O, Cuéllar-Barboza A, Suarez-Sánchez K, De la Cruz-Valadez E, Cruz-Gómez L et al. Clinical characteristics and treatment of actinomycetoma in northeast Mexico: A case series [Internet]. 2020 [cited 5 December 2020]. Available from: ​https://pubmed.ncbi.nlm.nih.gov/32097417

8. Agarwal U. Treatment of actinomycetoma foot--our experience with ten patients. [Internet]. Reference.medscape.com. 2013 [cited 3 December 2020]. Available from: https://reference.medscape.com/medline/abstract/23181630 9. Damle D, Mahajan P, Pradhan S, Belgaumkar V. Modified Welsh regimen: a promising therapy for actinomycetoma. [Internet]. Reference.medscape.com. 2008 [cited 6

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258

from:


Systematic Review of the Impact of Mass Drug Administration for the Elimination of Lymphatic Filariasis in Endemic Areas Raissa Almirah Sujana, Maria Gabrielle Vanessa, Arvissya Athalla Amanda

Introduction : Lymphatic filariasis (LF) is a vector-borne neglected tropical disease which is transmitted between humans by mosquitoes. Mass drug administration (MDA) is a costeffective approach that could reduce the occurrence, extent, and severity of LF, and also might result in a sustained reduction in disease transmission. MDA is implemented throughout the entire at-risk population areas. In Indonesia, LF is considered a significant public health concern. Therefore, this systematic review was carried out to analyze how other countries have successfully eliminated or disrupted the transmission of LF. Materials and methods : For our systematic review, we collected our data from online resources which include PubMed and Google Scholar. Systematic analysis is done using PICO. Results and discussion : Using the inclusion and exclusion criteria, we found 6 relevant articles. Ojha et al., Khieu et al., Supali et al., Simonsen et al., Kanamitie et al., stated that increasing the number of MDA rounds is necessary before stopping the MDA program to ensure that the total transmission interruption status continues to be sustained even after the MDA is completed. Only 1 study by Jones et al that was unable to make a recommendation to stop MDA. Moreover, all studies stated that increasing MDA rounds is also necessary in areas with higher baseline endemicity for LF. Conclusion : We can conclude that MDA is effective in eliminating LF in endemic areas. Also, increasing MDA rounds is necessary in areas with higher baseline endemicity of LF.

Keyword : Mass drug administration, lymphatic filariasis, endemic areas.

259


Systematic Review of the Impact of Mass Drug Administration for the Elimination of Lymphatic Filariasis in Endemic Areas Raissa Almirah Sujana, Maria Gabrielle Vanessa, Arvissya Athalla Amanda

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Systematic Review of the Impact of Mass Drug Administration for the Elimination of Lymphatic Filariasis in Endemic Areas Raissa Almirah Sujana, Maria Gabrielle Vanessa, Arvissya Athalla Amanda

Introduction : Lymphatic filariasis (LF) is a vector-borne neglected tropical disease, which is caused by three parasites : Wuchereria bancrofti, Brugia malayi, and Brugia timori - all of which are endemic in Indonesia and are transmitted between humans by mosquitoes. Elephantiasis, the late manifestation of LF, may cause swollen limbs or thickening of the skin which typically inhibits mobility. Beyond the pain and disability that they are facing, people who are affected by LF are often ostracized by their communities as they are usually unable to work and eventually sink into poverty.¹ MDA is a strategy used to administer NTD medicines to the entire at-risk population of an area, most commonly a district. This strategy takes different forms in different countries, but usually consists of a campaign-style approach to deliver medications to all eligible people in at-risk communities, usually once or twice per year depending on the specific, targeted NTDs.² Mass drug administration (MDA) is a cost-effective approach that could reduce the occurrence, extent, and severity of LF, and also might result in a sustained reduction in disease transmission, where populations or sub-populations are offered treatment without individual diagnosis.³ In Indonesia, LF is considered a significant public health concern. Indonesia has faced tremendous challenges including program coordination in the many inhabited islands, conducting information, education and awareness programs, lack of capacity and insufficient medicines. For this reason, we carried out our systematic review to analyze how other countries have successfully eliminated or disrupted the transmission of LF.⁴

Materials and methods : For our systematic review, we collected our data from 2 online resources which include PubMed and Google Scholar. The studies that we used were published within 2010-2020. All

261


of the data were accessed using the following keywords or terms : ((“Lymphatic Filariasis”) AND (“Mass Drug Administration”) AND (“Endemic Areas”)). We only used English as the primary language to this systematic review. Systematic analysis is done using PICO. We used “Lymphatic Filariasis” for the P (Problem), “Mass Drug Administration” for the I (Intervention), and “The impact of MDA” for the O (Outcome). No comparison (C) was done in our systematic review. The research question for this systematic review is: “What is the impact of mass drug administration for the elimination of lymphatic filariasis in endemic areas?” The inclusion criteria used in this systematic review are : cohort study, repeated cross-sectional surveys, longitudinal study, LF, endemic areas, and outcome : impact of MDA. Exclusion criteria are : literature review, case report, systematic review, meta-analysis, and animal study. To reduce bias, we will check for the validity of the studies that fulfill the inclusion and exclusion criteria. After ensuring the validity of the studies, the data then will be analyzed.

Results and discussion : Using PICO approach, searching is done through online database. We acquired a total of 6 articles that will be analyzed. The selection process is shown in the diagram below.

Figure 1 Information flow chart through the different phases of the systematic review

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Table 1. Summary of studies of the impact of mass drug administration for elimination of lymphatic filariasis in endemic areas

Authors

Ojha et al

Study

Year

Subject

Results

Cohort

2017

Ten districts in

LF transmission was successfully disrupted in 6 out of 10 districts.

Nepal

However, some districts required additional MDA rounds to achieve LF transmission interruption.

Khieu et al

Cohort

2018

Endemic provinces

Elimination of LF was achieved in Cambodia due to the

in Cambodia

commitment of the government and effective implementation of MDA, monitoring, evaluation, and surveillance activities. For this reason, Cambodia was also validated by the WHO.

Supali et al

Cohort

2019

Paga, Lewomada,

Annual MDA was sufficient to reduce microfilariae prevalence in

and Pruda villages

areas with low to moderate baseline prevalence. Semiannual MDA

in Sikka district

was useful for rapidly reducing Mf prevalence in an area with higher baseline endemicitiy.

Simonsen et al

Repeated

2014

Rural areas (8

LF in the coastal areas was still widespread in many parts of Tanga

cross

districts) of Tanga

Region after 8 rounds of MDA. More strengthened efforts are

sectional

Region in north-

needed to increase the MDA treatment coverage, further support

surveys

eastern Tanzania

and advocacy for use of bed nets, and more male focus in health dissemination.

Kanamitie et

Longitudinal

2017

al

Jones et al

Cohort

2018

Two communities

Twice-yearly MDA programs may help accelerate LF elimination

in Ghana

and improve prospects for global elimination of LF by 2020.

Five villages in the

There was a substantial decline in the prevalence of LF when

Rufiji District,

compared with baseline values before the start of MDA. It is

southeastern

recommended for a formal TAS to be conducted to make an

Tanzania

informed decision on whether MDA can be stopped in Rufiji District.

Note : MDA : Mass Drug Administration Mf : Microfilariae LF : Lymphatic Filariasis TAS : Transmission Assessment Survey

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In a cohort study by Ojha et al with their subject being ten districts in Nepal, LF prevalence was shown to be reduced in 10 districts that underwent at least five MDA rounds with DEC and ALB. Six out of ten districts showed decreased LF Ag in pre-TAS compared to baseline. In five of the six districts, indicates that the transmission was interrupted; this shows that MDA coverage of 50% may be sufficient to interrupt LF transmission in urban populations. However, 5 rounds of MDA were not sufficient to disrupt the transmission cycle in some districts; this is due to their baseline for LF prevalence was comparatively higher thus required additional MDA rounds to achieve LF transmission interruption.⁵ In a cohort study conducted by Khieu et al, 5 rounds of MDA were implemented consecutively from 2005 to 2009. A sample of 60-120 households in each sentinel and spot check sites were selected to be assessed for LF infection. Baseline of microfilariae prevalence ranged from 0.00% to 1.8% in 6 implementation units and fell to 0% after two rounds of MDA in all implement units. TAS 2 and TAS 3 surveillance surveys were later conducted in children after stopping the MDA for 2-3 years and 4-6 years respectively. TAS 2 sample 1575 to 1805 children from 6 implementation untis, none were positive for antigenemia and the antigenemia prevalence was 0%. TAS 3 was conducted the same way and all children were found negative for this antigen. Results of TAS has proven the effectiveness of MDA shown by the total transmission interruption status continues to be sustained. ⁶

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A study conducted by Supali et al, Paga and Lewomada received annual MDA treatment while Pruda village received twice-yearly treatments both done over a period of 24 months. Pre- MDA baseline prevalence in Paga and Lewomada had a Mf prevalence of 3.9% and 5.0% respectively. The Mf prevalence in Pruda was 14.2%. After 3 rounds of MDA (annual MDA), Mf prevalence decreased to zero in Paga and to 0.3% in Lewomada. While after 5 rounds of MDA (semi-annual MDA), the Mf prevalence in Pruda decreased to 1.2%. Overall effect for semiannual MDA had 3.9 times higher odds (P < 0.001) of having Mf, compared with subjects receiving annual MDA. Therefore annual MDA was already sufficient to reduce Mf prevalence to less than 1% in areas with low to moderate baseline prevalence while semiannual MDA was useful for rapidly reducing Mf prevalence in areas with higher baseline endemicity. ⁷

According to Simonsen et al., through repeated human cross sectional surveys in communities and schools, the prevalence levels for both Mf and CFA (circulating filarial antigen) in 2013 were still well above those recommended for stopping MDA. There are other factors contributed although there can be little doubt that the major cause of the decrease was the MDAs. The study showed that LF still is widespread in many parts of Tanga Region after 8 rounds of MDA. The MDA activity needs to be strengthened to ensure higher treatment coverage.⁸ Based on a study by Kanamitie et al., three months after treatment of positive individuals, there was a significant decrease (p < 0.05) in Mf intensity and the prevalence rates gradually increased by the 6th and 9th months after treatment. However, a decrease in Mf prevalence was observed at the 12th month. The follow-up revealed that the participants reported receiving treatment that explains the

265


fall in ICT (immunochromatographic test) and Mf prevalence after month 9. In addition, supporting the modeling result that twice-yearly MDA programmes could accelerate LF elimination and improve prospects for global elimination of LF by 2020.⁹ According to Jones et al., In Rufiji District, twelve rounds of annual MDA were completed between 2002 and 2014 using stratified random sampling. Since the start of MDA intervention in 2002, there has been a progressive decline in LF prevalence and transmission after 12 rounds of ivermectin and albendazole MDA in the Rufiji District. The study showed that the prevalence of hydrocele and elephantiasis was lower than that reported before MDA. In comparison to the baseline values before MDA, our study recorded a progressive and substantial decline in LF prevalence in the study areas. However, it was not possible to make a recommendation to stop MDA because the current study methods did not follow the WHOapproved TAS.10

Conclusion: From the 6 studies that we have analyzed, we can conclude that MDA is effective in eliminating LF in endemic areas. According to 5 studies out of 6, increasing the number of MDA rounds is necessary before stopping the MDA program especially in areas with higher baseline endemicity of LF, in order to ensure that the total transmission interruption status continues to be sustained even after the MDA is completed. Only 1 study was unable to make a recommendation to stop MDA due to their study methods not following the WHO-approved TAS.

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References : 1. Indonesia launches final round of Mass Drugs Administration (MDA) Campaign to eliminate Lymphatic Filariasis [Internet]. World Health Organization. World Health Organization; 2019 [cited 2020Dec9]. Available from: https://www.who.int/indonesia/news/detail/22-10-2019-indonesia-launches-finalround-of-mass-drugs-administration-(mda)-campaign-to-eliminate-lymphaticfilariasis 2. USAID. Mass Drug Administration [Internet]. Neglected Tropical Disease Program. 2020 [cited 2020Dec9]. Available from: https://www.neglecteddiseases.gov/about/what-we-do/mass-drug-administration/ 3. Webster JP, Molyneux DH, Hotez PJ, Fenwick A. The contribution of mass drug administration to global health: past, present and future [Internet]. 2014 [cited 2020Dec9]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4024227/ 4. Indonesia firmly committed to eliminating lymphatic filariasis as a public health problem [Internet]. World Health Organization. World Health Organization; [cited 2020Dec9]. Available from: https://www.who.int/news/item/29-04-2020-indonesiafirmly-committed-to-eliminating-lymphatic-filariasis-as-a-public-health-problem 5. Ojha CR, Joshi B, KC KP, Dumre SP, Yogi KK, Bhatta B, et al. Impact of mass drug administration for elimination of lymphatic filariasis in Nepal. Reithinger R, editor. PLoS Negl Trop Dis. 2017;11(7):e0005788. 6. Khieu V, Or V, Tep C, Odermatt P, Tsuyuoka R, Char MC, et al. How elimination of lymphatic filariasis as a public health problem in the Kingdom of Cambodia was achieved. Infect Dis Poverty 7. Supali T, Djuardi Y, Lomiga A, Nur Linda S, Iskandar E, Goss CW, et al. Comparison of the Impact of Annual and Semiannual Mass Drug Administration on Lymphatic Filariasis Prevalence in Flores Island, Indonesia. The American Journal of Tropical Medicine and Hygiene 8. Simonsen PE, Derua YA, Magesa SM, Pedersen EM, Stensgaard A-S, Malecela MN, et al. Lymphatic filariasis control in Tanga Region, Tanzania: status after eight rounds of mass drug administration. Parasites Vectors 9. Kanamitie JN, Ahorlu CS, Otchere J, Aboagye-Antwi F, Kwansa-Bentum B, Boakye DA, et al. Twelve-month longitudinal parasitological assessment of lymphatic

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filariasis-positive individuals: impact of a biannual treatment with ivermectin and albendazole. Trop Med Int Health 10. Jones C, Ngasala B, Derua YA, Tarimo D, Reimer L, Bockarie M, et al. Lymphatic filariasis transmission in Rufiji District, southeastern Tanzania: infection status of the human population and mosquito vectors after twelve rounds of mass drug administration. Parasites Vectors

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Assessment of the Bacillus Calmette Guerin (BCG) Vaccine Effectiveness in Mycobacterium Leprae Infection As Consideration for Leprosy Immunoprophylaxis Targeted to Close Contacts of Leprosy Patients: A Systematic Review Cindy Prianto, Jovanicha Putri Setiawan, Jonathan Juniard Anurantha ABSTRACT Introduction: ​Leprosy, or also known as Hansen’s Disease, is a chronic infectious disease

caused by bacteria called ​Mycobacterium leprae and ​Mycobacterium lepromatosis which affects the skin and peripheral nerves. Leprosy is an endemic disease in tropical countries,

mainly found in underdeveloped or developing countries. According to WHO, the prevention of leprosy can be obtained through chemoprophylaxis and vaccines. Bacillus Calmette-Guérin (BCG) is a live attenuated vaccine form of ​Mycobacterium Bovis that has been used to prevent tuberculosis and other mycobacterial infections. Aim​: Our aim in this study is to evaluate the protective effect of the BCG vaccine as a consideration for leprosy immunoprophylaxis. Methods: ​We collected our data from an online journal which includes Pubmed and Google Scholar. Systematic Analysis approaches were used in this study.

Result and Discussion: By using the inclusion and exclusion criteria, we have found 6 relevant studies conducted by Cunha et al, Karonga Prevention Trial Group, Stanley et al, Gupte et al, Bagshawe et al, and Lwin et al. Conclusion: ​In conclusion for our study, we found a mixed result between each journal however we concluded that BCG Vaccine might have a protective effect against leprosy. BCG Vaccine should be considered as an immunoprophylaxis measurement against mycobacterium leprae infection Keyword​: ​Leprosy, BCG Vaccination, Immunoprophylaxis, Systematic Review

269


Assessment of the Bacillus Calmette Guerin (BCG) Vaccine Effectiveness in Mycobacterium Leprae Infection As Consideration for Leprosy Immunoprophylaxis Targeted to Close Contacts of Leprosy Patients : A Systematic Review

Author: Cindy Prianto Jovanicha Putri Setiawan Jonathan Juniard Anurantha

Asian Medical Students’ Association Indonesia 2020

270


Introduction Leprosy, or also known as Hansen’s Disease, is a chronic infectious disease caused by bacteria called ​Mycobacterium leprae and ​Mycobacterium lepromatosis which affects the skin

and peripheral nerves [1]. Contrary to most beliefs, leprosy is not highly contagious and the mechanism of transmission of leprosy includes prolonged close contact with untreated leprosy patients. Transmission can also occur through inhalation of droplets containing the bacteria which spread through sneezes or coughs [2]. Leprosy is an endemic disease in tropical countries, mainly found in underdeveloped or developing countries. Based on the data retrieved by the World Health Organization (WHO) from 127 countries, a total of 208,619 new cases were reported in 2018. The Southeast Asia Region contributed to 71% of the total global cases with 2 countries, India and Indonesia, contributing to 92% of the cases in the region. 120,334 and 17,017 cases were reported in India and Indonesia, respectively. Based on WHO’s Region of the Americas, Brazil remained the country that reported the high case level, with 28,660 cases representing 93% of the cases in the region. Brazil, India, and Indonesia are responsible for 79.6% of the total new cases reported globally and are classified as endemic countries for leprosy [3]. M. leprae is a gram-positive, acid-fast bacilli of ​Mycobacterium leprae complex, which

consists of ​M. leprae and ​M. lepromatosis​. ​M. leprae is a straight or slightly curved rod with rounded ends. It is typically slower to multiply compared to ​M. lepromatosis​, about 12-14 days by binary fission. The optimal temperature required by ​M. leprae for survival and proliferation is

between 27​o​C and 30​o​C which explains its tendency to spread on cooler surface areas, such as skin, peripheral nerves, testicles, and upper airways [2]. ​M. leprae mainly infects the Schwann cells of the peripheral nerve which causes demyelination and loss of axonal conductance. This explains the clinical manifestations of numbness in leprosy patients [1]. WHO established a classification based purely on the clinical symptoms due to the difficulties of microscopy examination of skin smear in several regions. According to this classification, leprosy is divided into paucibacillary (PB) and multibacillary (MB). Patients with up to five skin lesions and/or only one nerve trunk involved are categorized as PB whereas patients with more than five skin lesions and/or more than one nerve trunk involved fall into the MB category. If microscopy examination of skin smear is available, positive results are considered MB, regardless of the number of lesions [2].

272


Common findings on evaluation of leprosy using laboratory tests are elevated leukocyte, decreased hemoglobin, low hematocrit, increased liver function tests, and the presence of elevated serum C-reactive protein [1]. Leprosy is often diagnosed through clinical manifestations and confirmed with skin biopsy and acid-fast staining. In the MB form of leprosy, large numbers of foam cells are present. Foam cells are macrophages that have phagocytized the ​M. leprae bacteria but unable to destroy the bacteria and instead transport it throughout the body and cause the multiple lesions that appear in many parts of the body in MB leprosy patients. The presence of acid-fast bacilli in acid-fast staining using the Ziehl-Neelsen method confirms the diagnosis of leprosy. Some serological tests for leprosy have been developed but are not recommended due to the lack of sensitivity and specificity ​[4]. The treatment of leprosy consists of multiple drug therapy (MDT) to prevent drug resistance. The WHO recommended the use of dapsone and rifampicin as a treatment for tuberculoid leprosy and a combination with clofazimine for the lepromatous disease [1]. According to WHO, the prevention of leprosy can be obtained through chemoprophylaxis and vaccines. However, the effectiveness of single-dose rifampicin (SDR) for chemoprophylaxis and the development of vaccines still need further research [5]. Bacillus Calmette-Guérin (BCG) is a live attenuated vaccine form of ​Mycobacterium Bovis that has been used to prevent tuberculosis and other mycobacterial infections. The vaccine was first administered to human beings in 1921 and has continued to be the most widely administered vaccine worldwide as the only vaccine against tuberculosis. BCG vaccine is usually a part of routine newborn immunization in most countries. BCG vaccine can be given intracutaneously or intradermally. The vaccine works by presenting the BCG antigens to the dendritic cells in our body that initiate the production of antibodies and produce memory cells to fight future infection. BCG vaccine has been known to afford a protective effect on several other diseases besides tuberculosis, such as lymphadenitis due to ​Mycobacterium Avium [6]. In this study, we will evaluate whether BCG vaccination offers a protective effect against leprosy.

273


Methods In this systematic review, online journals were used to collect the data for the analysis, which include journals from google scholar and PubMed. A systematic analysis approach was used to process the data, such as PICO methods. For People or Population (P), “people from tropical countries” were used. For Intervention, “BCG vaccination” was used, with a control group which was not given the BCG vaccination as a comparison (C) to see the difference in the outcome. The “incidence of leprosy case” was used as the outcome (O). The Hypothesis for this systematic review is “can BCG vaccination give protection against Leprosy?”. This systematic review used clinical trials as an inclusion criteria which focuses on these factors: Leprosy/ Hansen disease, BCG vaccination, immunoprophylaxis, and people from tropical countries. The methods that were excluded from this review are meta-analysis, literature review, case-control study, and systematic review. Animal study was also excluded from the analysis. Result and Discussion Using the PICO method or approach, we have gathered and selected 6 studies to be analyzed. The diagram below shows the process of selecting studies that fit.

Figure. 1.1 ​Information on the flow chart through the different phases of the systematic review.

274


Author

Study Design Yea

Subject

Results

99,770 Schoolchildren aged

There is no evidence of protection of the

7-14 years with 1 BCG scar

second dose of BCG against all forms of

r Cunha et al​⁷

Clinical Trial

2008

leprosy within 6 years and 8 months of follow-up. Karonga

Total of 121,020 eligible

Their study indicated that secondary BCG

Prevention

Clinical Trial

1996

Malawi Population who was

vaccination shows a protective effect

Trial Group​⁸

assessed by the LCAs

against leprosy infection and that killed M. Leprae have no evidence of the added protection against leprosy

Stanley

et

Clinical Trial

1981

al​⁹

A total of 19,200 children

This study shows a sustained protective

and

effect of BCG vaccination against early

1,976

subsidiary

samples who have contacts or

relatives known

tuberculoid leprosy in children

with

leprosy and are all free of visible leprosy lesions in Uganda. Gupte et al

Clinical Trial

1998

¹⁰

171,400 volunteers in South

The protective effect of BCG vaccine

India.

against leprosy is 28.7% on the first survey and 34.1% on the second resurvey.

Bagshawe et

Clinical Trial

1989

al ​¹¹

Lwin et al ​¹²

Clinical Trial

1985

5,356 eligible subjects in

The overall protective effect of BCG

Karimui, Papua New Guinea

vaccine against leprosy is 48% with

- an isolated island with a

greater protection on subjects vaccinated

high prevalence of leprosy.

under the age of 15 years.

26,000 Children aged 0-14

BCG vaccination provides a very modest

years in the area with high

level of protection and is not likely to be

leprosy endemicity who had

an important solution for leprosy control.

not been vaccinated. BCG: ​ Bacillus Calmette Guerin Vaccine

LCAs: ​Paramedical Leprosy Control Assistants M. Leprae: ​Mycobacterium Leprae

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In a study conducted by ​Cunha et al [7], ​it was concluded that a second vaccination dose

of BCG does not provide protection against leprosy. In 1998, a cluster randomized community trial was conducted, with 6 years and 8 months follow up in the following years. The subject of the research were children aged 7-14 in a leprosy-endemic area in Brazil. Originally, the purpose

of this research was to find out the effect of the BCG vaccination involving those with no or one BCG scar against Leprosy. But midway, they changed course. Instead, they only include children with 1 BCG scar to be a part of the analysis to see the effect of second vaccination against leprosy. There were 99,770 school children with neonatal BCG (aged 7–14 years at baseline) participating, of whom 42,662 were in the intervention arm (receive revaccination), while the rest were in a control group which did not receive a placebo. In the following years after the intervention, the incidence rate ratio of leprosy in the intervention over the control arm within the follow-up, in schoolchildren with neonatal BCG, controlled for potential confounders and adjusted for clustering, was 0.99 (95% confidence interval: 0.68 to 1.45). Resulting in their conclusion that there was no evidence of protection conferred by the second dose of BCG vaccination in school children against leprosy during the trial follow-up. But the author also mentioned the possibility of the inaccuracy of the data. They provide possible causes that might distort the data such as selection bias. A clinical trial conducted by ​Karonga Prevention Trial Group [8] in northern Malawi

between 1986-1989 with a total of eligible 121,020 samples. Individuals are randomly assigned to each group depends on the lack of BCG scar during the first administration into the patient

without BCG scar and with BCG scar, a patient without BCG scar will then further get randomized with the administration of only BCG (27,904) or BCG plus killed ​M. Leprae (38,251) and the patient with BCG scar were allocated to placebo (23,307), a second BCG (23,456) and BCG plus killed ​M.Leprae ​(8,102) and are followed up for 5-9 years with the follow-up rates of 64%. By the end of this study 139 cases of leprosy had been identified and among the scar-positive samples, the second BCG vaccination shows a protective effect against leprosy when compared with the placebo, the rate ratio was 0.51 (95% CI 0.25–1.03, p=0.05). Their study indicated that secondary BCG vaccination shows a protective effect against leprosy infection and that killed ​M. Leprae​ has no evidence of the added protection against leprosy.

276


A study conducted by ​Stanley et al [9] ​with a total sample of 19,200 children who have

contacts or relatives known with leprosy and are all free of visible leprosy lesions in Uganda

between 1960 and 1964 followed on average for at least 8 years. At the end of the follow up, there are a total of 12,749 patients which gives 74% of follow-up rates and a total of 258 cases of leprosy of the main intake cases, 201 were from the control group, 41 had been from BCG-Vaccinated

Group

and

16

were

from

initially

strong

tuberculin-positive

group(unvaccinated). The data shows a significant decrease in the incidence of leprosy from 28.8 per 1000 among negative children, to 10.6 per 100 among those with Grade IV positive reaction (X² = 9.41; d.f. = 1; P < 0.01). Overall the study shows a sustained protective effect of BCG vaccination against early tuberculoid leprosy in children in Uganda. Gupte et al [10]​, conducted a study in South India with 171,400 volunteers in 1991 to compare the protective effect of a combination of BCG and killed M. leprae vaccine, Indian Cancer Research Centre (ICRC) vaccine, Mycobacterium w (Mw), BCG vaccine, and normal saline as placebo. Two surveys were conducted. The first survey immediately after vaccination showed the percentage of protective efficacy was 7.6% with BCG and killed M. leprae vaccine, 6.9% with ICRC vaccine, 11.5% with Mw vaccine, and 28.7% with BCG vaccine. The second resurvey revealed BCG and killed M. leprae provided 64% protection (CI 50.4-73.9), ICRC provided 65.5% protection (CI 48.0-77.0), Mw gave 25.7% protection (CI 1.9-43.8) and BCG gave 34.1% protection (CI 13.5-49.8). Both of the surveys showed the protective effect of BCG against leprosy. A study conducted by ​Bagshawe et al [11]. consists of 5,356 eligible subjects in

Karimui, Papua New Guinea, an isolated island with a high prevalence of leprosy (6.1% of 1,114

examined). The subjects were randomized either to receive BCG vaccine through intradermal injection (2,707) or to act as a control and receive saline (2,649). Subjects randomized to receive BCG were revaccinated annually in March from 1964 to 1966. The study population was first examined for leprosy before being vaccinated in March 1964, then in September 1966, November 1967, and annually thereafter in December until 1979. Suspected lesions were biopsied in London for a confirmed diagnosis. The data taken was when the first lesions were suspected. Between 1963 and 1975, 931 subjects died with slightly higher numbers of deaths on controls (489) compared to vaccinated (442) subjects. The highest mortality was in children under five years. However, there was not a significant difference among control and vaccinated

277


children in this age group. 92% of subjects were still in the study in 1975 which was the last survey. By the end of the survey, 202 cases of leprosy were identified in the vaccinated group and 364 cases were confirmed in the control group. The overall protective effect of BCG against clinical leprosy was 48%, with 95% confidence intervals between 34% and 59%. Protection was greater in subjects vaccinated under the age of 15 years (54%) than in those vaccinated at 15 years or older (34%). Protection was apparent at 12 months in all vaccinated subjects except the subjects under five years old. A trial conducted by ​Lwin et al [12]​. stated that BCG provides only a very modest level

of protection and that BCG vaccination is not likely to be an important solution for leprosy control. The research started in 1964 where some 26,000 children from a high leprosy-endemic

area who had not been vaccinated were admitted into the trial, whom 13,066 received BCG and 13,176 served as the control group. The children were divided into 2 categories, those with less than 10 mm reaction to the tuberculin test and those with 10 mm or more. And each of the categories were separated into 3 groups: (a) infants under one year of age; (b) children aged 1-14 years who were household contacts of a leprosy patient at the time of the first total population survey; and (c) children aged 1-14 years from households without a case of leprosy at the first survey. There were 6 groups in total. And then the children were examined for Leprosy annually until 14 years after the first examination. The results showed that the 2 groups (vaccinated and control) were very similar statistically. There were differences between batches and groups, but not much between the control and intervention. Conclusions In conclusion for our study, we found a mixed result between each journal however we concluded that BCG Vaccine might have a protective effect against leprosy. BCG Vaccine should be considered as an immunoprophylaxis measurement against mycobacterium leprae infection as we haven’t found a severe adverse reaction to BCG Vaccine except in immunocompromised patient as well as the other benefits of BCG Vaccine in other mycobacterial infection. However, our study has some limitations such as the lack of newer studies to assess the efficacy of the BCG Vaccine against leprosy that forces us to use older studies. Therefore more studies are needed to be conducted to assess the effectiveness of BCG in Leprosy.

278


Reference 1. Bhandari J, Awais M, Robbins BA, et al. Leprosy. [Updated 2020 Oct 5]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK559307/ 2. Lastória J, Abreu M. Leprosy: review of the epidemiological, clinical, and etiopathogenic aspects - Part 1. Anais Brasileiros de Dermatologia. 2014;89(2):205-218. 3. Leprosy: new data show steady decline in new cases [Internet]. World Health Organization.

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https://www.who.int/neglected_diseases/news/Leprosy-new-data-show-steady-decline-innew-cases/en/ 4. Laboratory Diagnostics | Hansen's Disease (Leprosy) | CDC [Internet]. Cdc.gov. 2020 [cited

1

December

2020].

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from:

https://www.cdc.gov/leprosy/health-care-workers/laboratory-diagnostics.html 5. Guidelines for the diagnosis, treatment and prevention of leprosy [Internet]. World Health Organization. World Health Organization; 1970 [cited 2020Nov27]. Available from: https://apps.who.int/iris/handle/10665/274127 6. Okafor CN, Rewane A, Momodu II. Bacillus Calmette Guerin. [Updated 2020 Jul 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: ​https://www.ncbi.nlm.nih.gov/books/NBK538185/ 7. Cunha SS, Alexander N, Barreto ML, Pereira ES, Dourado I, et al. (2008) BCG Revaccination Does Not Protect Against Leprosy in the Brazilian Amazon: A Cluster Randomised

Trial.

PLOS

Neglected

Tropical

Diseases

2(2):

e167.

https://doi.org/10.1371/journal.pntd.0000167 8. Randomised controlled trial of single BCG, repeated BCG, or combined BCG and killed Mycobacterium leprae vaccine for prevention of leprosy and tuberculosis in Malawi. The Lancet. 1996;348(9019):17–24. 9. Stanley SJ, Howland CM, Stone Mundefined, Sutherland Iundefined. BCG vaccination of children against leprosy in Uganda: final results [Internet]. The Journal of hygiene. U.S. National

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2020Nov21].

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10. MD; G. South India immunoprophylaxis trial against leprosy: relevance of findings in the context of leprosy trends [Internet]. International journal of leprosy and other mycobacterial diseases : official organ of the International Leprosy Association. U.S. National

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https://pubmed.ncbi.nlm.nih.gov/11757173/ 11. Bagshawe A, Scott GC, Russell DA, Wigley SC, Merianos A, Berry G. BCG vaccination in leprosy: final results of the trial in Karimui, Papua New Guinea, 1963-79 [Internet]. Bulletin of the World Health Organization. World Health Organization; 1989 [cited 2020Nov23]. Available from: ​https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2491274/ 12. Lwin K, Sundaresan T, Gyi MM, Bechelli LM, Tamondong C, Garbajosa PG, et al. BCG vaccination of children against leprosy: fourteen-year findings of the trial in Burma [Internet]. Bulletin of the World Health Organization. U.S. National Library of Medicine; 1985

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PEMANFAATAN JERUK KALAMANSI SEBAGAI SPRAY UNTUK PENGHAMBAT PERKEMBANGBIAKAN JENTIK NYAMUK PENYEBAB PENYAKIT DEMAM BERDARAH DENGUE Participate in IMSTC 2021 By AMSA-Indonesia

Disusun Oleh Nataniel Armando Pelmelay

281


THE USE OF CALAMANSI AS A SPRAY TO OVERCOME THE DENGUE FEVER CAUSED BY LARVA PROLIFERATION Nataniel Armando Pelmelay

ABSTRAK This scientific paper was motivated by the news of death caused by the spread of dengue hemorrhagic fever. This disease is transmitted through the bite of an Aedes agypti mosquito that has been infected with the Dengue virus. Thus, vector control is often carried out using chemicals that cause side effects to human health. Therefore, this study aims to seek and find simple non-chemical alternative materials to avoid the side effects of using chemicals, namely by using Calamansi. The method we use in this research is a descriptive approach based on the results of a literature review. We also do a mini research using the sample we used, namely mosquito larvae found in used bottles containing water reservoirs. This sample was tested using calamansi which had been squeezed and drained for use as an inhibitor for mosquito larvae reproduction. In this study, we made a comparison between the first container containing 300 ml of water mixed with water from the juice of 1 kalamansi orange. And for the second container which contains 100 ml of air mixed with the juice of half of Kalamansi oranges. The results of this study, it was found that after 24 hours in the first container the number of dead larvae was less than the live larvae, while in the second container the dead larvae were more than the live larvae. From these results, it can be concluded that the use calamansi juice must be adjusted to the volume of water available. In addition, the use calamansi juice is also very useful to inhibit the reproduction of mosquito larvae.

Keyword: Dengue Hemorrhagic Fever, Aedes aegypti, Calamansi

282


PENDAHULUAN Indonesia merupakan daerah tropis dan menjadi tempat perkembangbiakan beberapa jenis nyamuk yang membahayakan kesehatan manusia dan salah satu nyamuk yang berkembang biak, yaitu nyamuk Aedes aegypti yang berperan sebagai vektor penyakit demam berdarah dengue (DBD). Demam Berdarah Dengue (DBD) merupakan suatu penyakit menular akut yang banyak ditemukan di daerah tropis dan sub-tropis. Penyebaran penyakit ini sangat cepat dan sering menimbulkan wabah yang luar biasa, sehingga menyebabkan banyak kesakitan bahkan kematian. Salah satu provinsi yang telah terjangkit DBD adalah Maluku. Bahkan dapat dikatakan Maluku merupakan daerah endemis DBD. Nyamuk Aedes aegypti menyebarkan penyakit Virus Dengue dari genus flavivirus, family Flaviviridae. ke manusia melalui gigitannya. Virus Dengue penyebab Demam Berdarah Dengue (DBD) termasuk dalam kelompok B Arthropod Virus (Arbovirosis) yang sekarang dikenal sebagai genus Flavivirus, family Flaviviridae dan mempunyai 4 jenis serotipe, yaitu Den1, Den-2, Den-3, Den-4 (Adimidjaja 2007; Djunaedi, 2006) Nyamuk Aedes aegypti menggigit manusia pada pagi sampai sore hari, biasanya pukul 08.00 – 12.00 dan 15.00 – 17.00. Manifestasi atau gejala klinisnya tidak selalu terlihat jelas bahkan bisa tanpa gejala. Masa inkubasi virus dengue dalam tubuh manusia (inkubasi intrinsik) berkisar antara 3-14 hari sebelum gejala muncul. Gejala klinis rata-rata muncul pada hari ke-4 sampai hari ke-7, sedangkan masa inkubasi ekstrinsik (di dalam tubuh nyamuk) berlangsung sekitar 8-10 hari. Tetapi gejala umumnya seperti, demam mendadak, sakit kepala, nyeri belakang bola mata, mual dan manifestasi pendarahan seperti mimisan atau gusi berdarah serta adanya kemerahan di bagian permukaan tubuh pada penderita. Nyamuk Aedes aegypti hidup di tempat yang dingin dan terlindung dari matahari. Nyamuk ini mempunyai habitat pada tempat-tempat penampungan air seperti bak,drum air, tempayan, ember, kaleng bekas, vas bunga, botol bekas, potongan bambu, pangkal daun, dan lubang-lubang batu yang berisi air jernih. Dalam upaya penanganan terhadap masalah DBD, terdapat beberapa cara yang dilakukan salah satunya, yaitu melalui fogging (Pengasapan). Tetapi, pemberantasan nyamuk Aedes aegypti dengan metode ini hanya bertujuan untuk membunuh nyamuk dewasa yang di dalam tubuhnya

285


telah mengandung virus dengue tetapi tidak bias membunuh jentiknya, sehingga tindakan pengasapan ini kurang efektif dalam memberantas penyakit DBD. Adapun cara lain penanganan nyamuk Aedes aegypti menggunakan bahan kimia, yaitu dengan penggunaan Abate. Abate (Temephos) adalah insektisida organophosphorus nonsistemik yang digunakan sebagai larvasida untuk mengendalikan nyamuk pada lingkungan, termasuk wadah air rumah tangga. Meskipun demikian, Abate memiliki efek samping yang ditimbulkan seperti, efek terhadap penglihatan yang dapat berupa penglihatan yang kabur/keremangan, miosis dan otot siliaris kaku, hilangnya daya akomodasi mata, dan nyeri pada mata. Sedangkan efek pada sistem pernapasan dapat berupa hidung meler dan sensasi sesak di dada yang umum tejadi setelah paparan inhalasi. Dikarenakan banyaknya obat yang diproduksi dengan bahan dasar kimiawi yang mana pada saat yang bersamaan dapat menimbulkan efek samping bagi kesehatan manusia, maka perlu dicarikan bahan lain yang bersifat non-kimiawi sebagai alternatif pengganti bahan kimia dan ramah lingkungan, salah satunya adalah jeruk kalamansi yang memiliki minyak atsiri yang merupakan bahan aktif yang tidak disukai dan sangat dihindari serangga, termasuk nyamuk sehingga penggunaan bahan-bahan ini sangat bermanfaat sebagai bahan pengusir nyamuk (Sastrohamidjojo, 2004; Yunus, 2008)

METODE PENELITIAN Berdasarkan latar belakang masalah, perumusan masalah, dan tujuan yang hendak dicapai dalam penelitian, maka tahapan yang dilakukan dalam penelitian ini adalah sebagai berikut:

Tahap Pertama : Studi Literatur Studi Literatur merupakan tahap awal untuk mengetahui tentang penyakit Demam Berdarah Dengue, nyamuk Aedes aegypti, serta pengendalian vector menggunakan bahan kimia dan alami.

Tahap Kedua : Penelitian a. Alat dan Bahan Alat:

- 1 Pisau - 1 Botol Plastik bekas yang sudah dipotong

286


- 1 Sendok Plastik - 1 Buah Gelas Plastik Bahan:

- 2 Buah Jeruk Kalamansi - Jentik Nyamuk

b. Langkah-langkah penelitian 1. Siapkan alat dan bahan 2. Ambilah jentik nyamuk yang sudah disediakan secukupnya menggunakan gelas plastik dan masukan ke dalam 2 wadah/botol plastik. 1.1.Wadah pertama Masukan hasil perasan 1 buah jeruk kalamansi dan tuangkan ke dalam wadah/botol yang telah terisi air dengan volume + 300ml 1.2.Wadah kedua Masukan hasil perasan ½ buah jeruk nipis dan tuangkan ke dalam wadah/botol yang telah terisi air dengan volume + 100ml c. Cara Pengamatan / Pengukuran Sesuai tujuan penelitian ini yakni mengamati dampak bahan jeruk terhadap perkembangbiakan jentik, maka

setelah tahapan atau langkah penelitian ke-2

pengamatan akan dilakukan sesuai perubahan-perubahan waktu yang direncanakan. Pengamatan dilakukan terhadap pergerakan jentik di dalam wadah pengamatan per satuan waktu yang ditetapkan. Selanjutnya dihitung jumlah jentik yang masih hidup, tidak aktif dan yang sudah mati. Dari pengamatan ini, diharapakn dapat diperoleh besarnya dampak yang ditimbulkan oleh bahan jeruk sesuai komposisi yang ditentukan terhadap perkembangbiakan jentik-jentik nyamuk.

HASIL DAN PEMBAHASAN Cara pemberantasan nyamuk Aedes aegypti yang dilakukan secara alami Hasil yang diperoleh dari penelitian tentang pengaruh jeruk kalamansi terhadap perkembangbiakan jentik nyamuk, bahwa ada pengaruh yang ditimbulkan oleh perasan jeruk kalamansi yang mempengaruhi perkembangan jentik-jentik.

287


Untuk wadah yang pertama dengan volume air sebesar 300 ml yang kemiudia dicampur dengan perasan 1 ( satu ) buah jeruk kalamansi yang kemudia dilakukan pengamatan selama 24 jam, diperoleh hasil sebagaimana terlihat pada Tabel 1, berikut ini.

Tabel 1. Hasil Pengamatan Pada Wadah 1. Waktu Pengamatan ( jam )

Wadah 1

1

4

8

12

16

20

24

Aktif

10

10

9

8

4

2

2

Pasif

0

0

1

1

2

3

1

Mati

0

0

0

1

4

5

7

Dalam empat jam pertama, masih terlihat belum adanya pengaruh yang signifikan terhadap jentik-jentik yang ada di dalam wadah. Hal ini ditunjukan dengan 10 (sepuluh) jentik nyamuk yang diamati masih terlihat bergerak secara aktif di dalam wadah. Pada jam ke delapan, terlihat satu jentik yang tidak aktif. Jam ke duabelas 1 jentik mati, 1 tidak aktif dan pada jam ke enambelas terjadi perubahan yang cukup signifikan, dimana hanya tersisa 4 jentik yang aktif, sedangkan yang lainnya 2 jentik tidak aktif dan 4 jentik mati. Pada empat jam setelahnya bertambah menjadi 5 jentik yang mati dan 3 yang tidak aktif. Selanjutnya pada jam ke dua puluh empat , bertambah 2 jentik yang mati sehingga sampai jam ke duapuluh empat, dari 10 jentik yang diamati, didapati 8 jentik mengalami dampak perasan air jeruk atau 80% yakni 7 mati dan 1 tidak aktif. Secara grafis, dampak perasan air jeruk kalamansi dapat dilihat pada gambar berikut :

Jumlah Jentik

Dampak Jeruk Kalamansi Terhadap Perkembangbiakan Jentik 10 5 0 1

4

8

12

16

20

Jam Pengamatan Aktif

Pasif

Mati

Grafik 1. Hasil Pengamatan di wadah 1.

288

24


Untuk wadah yang kedua, dengan volume air sebesar 200 ml yang kemudian dicampur dengan perasan ½ (setengah ) buah jeruk kalamansi dan dilakukan pengamatan selama 24 jam terhadap 18 jentik, diperoleh hasil sebagaimana terlihat pada Tabel 2, berikut ini.

Tabel 2. Hasil Pengamatan Pada Wadah 2. Waktu Pengamatan ( jam )

Wadah 2 1

4

8

12

16

20

24

Aktif

18

18

12

10

6

6

6

Pasif

0

0

3

3

4

4

2

Mati

0

0

3

5

8

8

10

Dalam empat jam pertama, masih terlihat belum adanya pengaruh yang signifikan terhadap jentik-jentik yang ada di dalam wadah. Hal ini ditunjukan dengan 18 (delapan belas) jentik nyamuk yang diamati masih terlihat bergerak secara aktif di dalam wadah. Pada empat jam kemudian terlihat 3 ( tiga ) jentik yang tidak aktif dan 3 jentik sudah mengalami kematian. Jam ke duabelas didapati 5 jentik mati, 3 tidak aktif dan pada jam ke enambelas terjadi perubahan yang cukup signifikan, dimana hanya tersisa 6 jentik yang aktif, sedangkan yang lainnya 4 jentik tidak aktif dan 8 jentik mati. Pada empat jam setelahnya masih tetap sama. Selanjutnya pada jam ke dua puluh empat , bertambah 2 jentik yang mati sehingga sampai jam ke duapuluh empat, dari delapan belas jentik yang diamati 12 ( dua belas ) mengalami dampak perasan air jeruk atau 66,6 % yakni 10 mati dan 2 tidak aktif. Secara grafis, dampak perasan air jeruk kalamansi dapat dilihat pada gambar berikut :

Jumlah Jentik

Dampak Jeruk Kalamansi Terhadap Perkembangbiakan Jentik 20 15 10 5 0 1

4

8

12

16

Jam Pengamatan Aktif

Pasif

289

Mati

20

24


KESIMPULAN Dari hasil pengamatan, dapat disimpulkan beberapa hal sebagai berikut : a. Perasan air jeruk dapat digunakan sebagai bahan penghambat perkembangbiakan jentik-jentik nyamuk penyebab DBD b. Makin banyak komposisi air jeruk dalam wadah tempat berkembangnya jentik-jentik, makin cepat pengaruhnya terhadap jentik-jentik. c. Air hasil perasan jeruk kalamansi memberikan pengaruh yang cukup signifikan setelah enam belas jam setelah air perasan dimasukan

290


REFERENSI Dinas Kesehatan Kabupaten Cirebon. 2015. BAHAYA FOGGING. Kabupaten Cirebon. Bulletin Kewaspadaan dan Respons Early Warning Alert and Response system (EWARS). Djakaria S. 2004. PENDAHULUAN ENTOMOLOGI. PARASITOLOGI KEDOKTERAN EDISI KE-3. Fakultas Kedokteran Universitas Indonesia. Jakarta p60-61 Heni Prasetyowati dkk. 2016. STATUS RESISTENSI Aedes agypti (Linn.) TERHADAP ORGANOFOSFAT DI TIGA KOTAMADYA DKI JAKARTA. Jakarta Barat, Jakarta Timur, dan Jakarta Selatan. BALABA Vol. 12 No. 1 Juni : 23-30 Jayadi. 2011. BUDIDAYA TANAMAN JERUK. Kanisius. Yogyakarta Joni Hendri dkk. 2010. TEMPAT PERKEMBANGBIAKAN NYAMUK Aedes spp. DI PASAR WISATA PENGANDARAN. Pasar Wisata Pengandaran. Aspirator Vol. 2 No. 1 Muhammad Surya Rahman dan Liena Sofiana. 2016. PERBEDAAN STATUS KERENTANAN NYAMUK Aedes aegypti TERHADAP MALATHION DI KABUPATEN BANTUL YOGYAKARTA. Desa Panggungharjo dan Dlingo Bantul Yogyakarta. Jurnal Kesehatan Masyarakat. KEMAS 11 (2) Yuli Kusumawati dkk. 2007. UPAYA PEMBERANTASAN NYAMUK Aedes aegypti DENGAN PENGASAPAN (FOGGING) DALAM RANGKA MENCEGAH PENINGKATAN KASUS DEMAM BERDARA. WARTA, Vol.10, No. 1, Maret: 01 – 09 Yusuf Firmanta. 2008. DETEKSI RESISTENSI NYAMUK Aedes aegypti YANG BERASAL DARI DAERAH ENDEMIS DENGUE DI KOTA JAMBI BERDASARKAN AKTIVITAS ENZIM ESTERASE NON SPESIFIK TERHADAP INSEKTISIDA GOLONGAN PIRETROI. Kota Jambi.

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The Effectiveness of Corticosteroids as a Means of Treatment for Nerve Function Impairment in Patients Diagnosed with Leprosy: A Systematic Review

Chandni Kumar, Ida Bagus Ram K.P.M Introduction: Leprosy, also known as Hansen’s Disease, is a chronic granulomatous infection often affecting the skin and/or peripheral nerves. It is commonly caused by M. laprae, which targets Schwann cells in peripheral nerves, leading to nerve injury, demyelination and can potentially cause disability or Nerve Function Impairment (NFI). Corticosteroids, when used as therapy, have shown strong anti-inflammatory properties however there has been little research on its effect on NFI in leprosy. Therefore this systematic review has been conducted to evaluate the effectiveness of corticosteroids on treating/improving/restoring nerve function in leprosy.

Methods: Data for this systematic review has been obtained from online databases comprising PubMed and ScienceDirect. Analysis approaches used in this study are Pico Analysis and MeSH terminology.

Results and discussion: With the inclusion criteria, we found 5 relevant papers, 4 papers which were made by G.Dolly Capadia, I.Wagenaar, S. M Lambert, S. L Walker states that there was no relevant effect of corticosteroids in preventing as well treat neural function impairment. With one paper by V. S Chaitayana which states that cortisol can prevent some nerve damage and deformities in leprosy.

Conclusion: After reviewing the articles we can conclude that corticosteroids is not a good treatment nor prevention for neural function impairment as 4 journals indicate that there was no relevant effect and 1 jornal saying there is an effect. However, further studies needs to be conducted.

Keyword: Leprosy, Neural Function Impairment, Corticosteroids, Steroids.

292


The Effectiveness of Corticosteroids as a Means of Treatment for Nerve Function Impairment in Patients Diagnosed with Leprosy: A Systematic Review Chandni Kumar, Ida Bagus Ram K.P.M

293


Introduction Leprosy, or also known as Hansen’s Disease, is a chronic infection, granulomatous in nature, often affecting the skin and/or peripheral nerves. The common etiologic agent of leprosy is

Mycobacterium leprae.​1 Although the method of transmission is not fully

understood, studies have led to the belief that transmission occurs via respiratory means, through inhalation of bacilli in nasal secretions of an infected individual. Less common methods of transmission include skin erosions, vertical transmission, blood contact, breast milk as well as insect bites.​2 According to data from World Health Organization (WHO), there were as many as 208 619 new cases registered globally in 2018 from 159 countries, with 184 212 cases at the end of the year, resulting in a prevalence rate of 0.2/10 000.​3 Clinical manifestations of leprosy include skin lesions in the face or nerve trunk, numbness or loss of nerve function and erythema of skin lesions.​1 The clinical classification method established by WHO in 1988 divides leprosy into paucibacillary (PB) and multibacillary (MB). PB patients are those with upto 5 skin lesions and/or 1 nerve trunk involved, while MB patients would be those with >5 skin lesions and/or >1 nerve trunk involved. However in 1998, 3 classification groups were established: PB with single lesion, PB with 2-5 lesions andMB with more than 5 lesions.​4 Schwann Cells (SC) present as a major target for infection by M. leprae, consequently leading to nerve injury and demyelination, eventually leading to disability. It has been shown that M. leprae can invade SCs by a specific laminin-binding protein of 21 kDa in addition to PGL-1.​5 ​The main electrophysiological finding of leprosy neuropathy include asymmetrical involvement of the sensory or sensory and motor peripheral nerves, however, sensory loss is the cardinal symptom of leprosy neuropathy.​6 Leprosy reactions are generally divided into 2: type 1 reaction (or reversal reaction,) which results from cell immunity activation leading to classic symptoms of leprosy, and type 2 reaction (or erythema nodosum leprosum, ENL) which are systemic processes that involve multiple pro-inflammatory cytokines. In treatment of leprosy, especially RR type, corticosteroids are used usually to treat neuropathies that occur as a result of the disease. Corticosteroids have shown to be useful in improving symptoms, in reducing edema as well as post-inflammatory scarring, however there still exists a debate on its effectiveness in improving and restoring neural function after a patient has suffered Nerve Function Impairment (NFI) consequent to leprosy. Without appropriate treatment and management of NFI in leprosy, the infected individual may end up with irreversible deformity or disability.​7

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Previous studies conducted on the effectiveness of corticosteroids as treatment for NFI are fragmented and rather incomplete, and do not investigate enough into cases of NFI with leprosy as an underlying cause. Thus, we have conducted this systematic review in order to evaluate the effectiveness of corticosteroids as treatment for NFI in leprosy. Methods Data for this systematic review was obtained from online resources and databases, comprising Pubmed and ScienceDirect. Pico Analysis and MeSH terminology were used in the analysis approach for this study. MeSH terminology for Population (P) was N/A, MeSH terminology for Intervention (I) was “Corticosteroid OR Steroid'', while for Comparison (C), MeSH terminology was also N/A. For Outcome (O), the MeSH terminology used was “Improved Nerve Function OR Restored Nerve Function”. The underlying hypothesis question of this study is “Can corticosteroids treat and restore nerve function in patients with Nerve Function Impairment due to leprosy?”. Inclusion criteria are Randomized Controlled Trials (RCT), Clinical Trials, Neural Function Impairment, Leprosy, intervention: corticosteroid, outcome: restored neural function. Exclusion criteria are systematic review, literature review and meta-analyses. Each study will be screened for fulfilment of the given inclusion and exclusion criteria to ensure validity of each study as well as to reduce bias, after which data from each study will be analysed.

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Results and Discussion Using the PICO method without applying the interventions, we have acquired 5 articles that will be analyzed. The diagram below shows the selection process of the articles

Figure. 1 ​Information flow chart through the different phases of the systematic review

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Table. 1 ​Summary of studies of effectiveness of corticosteroids as treatment and prevention for neural function impairment in leprosy

Authors

Study

G.Dolly Capadia Prospective et al. 8​

Year

Subject

Result

2010

Newly detected,

Nerve damage continues

untreated leprosy

to occur even after the

aged 12 to 60 year

initiation of MDT with

defined as MB

only a small portion of

patients.

nerves having

Cohort Study

improvements. Further studies need to be conducted I.Wagenaar al.​9

et Randomized

2017

Leprosy patients

The proportion of

Controlled

who had recently

patients with improved

Trials

developed clinical

or restored nerve

NFI.

function does not differ significantly with the controlled group.

S. M Lambert et Randomized al. ​10

2016

Seventy three

Adverse event rates were

Controlled

leprosy patients

similar in both study,

Trials

with new T1R.

both quality group quality of life was also similar.

S. L Walker et Randomized al. ​11

2011

Individuals that

Corticosteroid treatment

Controlled

are diagnosed as

for T1R and NFI is

Trials

having leprosy

sub-optimal even when

with clinical

given in large doses for

evidence of TIR

16 weeks.

or new NFI.

297


V. S Chaitanya Randomized 12

2013

49 newly

Cortisol can prevent

Controlled

diagnosed

some nerve damage and

Trials

untreated leprosy

deformities in leprosy.

cases in T1R and 51 cases not in reaction (NR). Note : T1R = Type 1 Reaction NFI = Nerve function impairment . Gospi Dolly Capadia conducted a prospective cohort study which aims to to determine the extent of nerve involvement and to study the effect of corticosteroids combined with multidrug therapy on nerve damage in leprosy patients using sensory and motor nerve conduction studies. This study involved over 365 untreated multibacillary leprosy patients which is then monitored for a couple of months after one group is given 12-week regimen of corticosteroids for reaction and/or neuritis or silent neuropathy of 6 months duration along with 12-month multidrug therapy (group A),while the other group without reaction were treated with multidrug therapy only (group B). Notably at 18 months, in both groups, improvement was seen in a very small proportion of sensory and motor nerves (9%) with a marked change being toward deterioration (23%) (P 0.001), suggesting corticosteroids in combination with 12-month MDT failed to arrest or bring about any significant improvement/reversal of nerve functions. In the end, it is concluded that almost all the study patients showed impairment of one or more nerves at registration regardless of reaction, indicating that nerve damage in leprosy is more widespread. Both groups showed improvement during the 18 months, however it is said to only be a small amount with data showing higher percentages showing nerve deterioration in both groups. Despite the reports of corticosteroid being able to prevent and control nerve damage in patients with leprosy, the search for drugs for appropriate regimen of prevention and reversal should still be continued. This claim is also backed up by Inge Waegenaar, conducting a randomized controlled study which aims to look at the effects of prednisolone for treatments of Early Neuropathy in Leprosy. This study tries to evaluate whether a 32-week prednisolone course is more effective than a 20-week course in restoring and improving nerve function. Using a

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multi-centre, triple-blind, randomized controlled trial, leprosy patients who had recently developed clinical NFI (<6 months) were allocated to a prednisolone treatment regimen of either 20 weeks or 32 weeks. Prednisolone was started at either 45 or 60 mg/day, depending on the patient’s body weight, and was then tapered. Throughout follow up, NFI was assessed by voluntary muscle testing and monofilament testing. The result of this controlled trial was that the proportion of patients with improved or restored nerve function did not differ significantly between the groups. Indicating that there is no clear nerve function improvement if given corticosteroid in an increased amount of both dosage and time. Further research needs to be done. Another research done by Saba M Lambert who created a randomized control trial which seeks to uncover whether cyclosporine or prednisolone is the best management of leprosy patients with new type 1 reaction. In which seventy three patients new T1R were randomized to receive CnP or P for 20 weeks. Their improvement in nerve function, both new and old (sensory and motor) is then monitored . The result however indicates that there isn't a significant difference in both groups. Both groups' neural functions manage to improve in the range of 40-60 percent with only a difference in 20 percent improvement. In conclusion, ciclosporin could be a safe alternative second-line drug for patients with T1R who are not improving with prednisolone or are experiencing adverse events related to prednisolone. This study illustrates the difficulty in switching off leprosy inflammation. Better treatment agents for leprosy patients with reactions and nerve damage are needed. In Stephen L Walker randomized clinical trial tries to assess the safety and tolerability of high dose MP when given to patients with leprosy T1Rs and patients with leprosy associated acute neuritis with nerve function impairment in Nepal as well as to assess the effect of high dose MP on the clinical outcome of leprosy T1Rs and leprosy associated acute neuritis with nerve function impairment. The result of this experiment is that corticosteroid treatment for T1R and NFI is sub-optimal even when given in large doses for 16 weeks. Lastly, a study conducted by V. S Chaitanya concluded that cortisol can prevent some nerve damage and deformities in leprosy. The experiment conducted was a randomized controlled trial with a total of 49 leprosy cases in T1R and 51 leprosy cases without any reaction (NR) (controls) were enrolled in the study. Conclusion Based on the systematic review, it can be concluded that corticosteroids effectiveness as a means for treatment and prevention of neural function impairment is unclear with a lot of

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jornal indicating that the treatment is not effective. The topic still needs further research as out of the 5 journals found, 4 journals state that the effects of corticosteroids when compared to controlled groups does not significantly differ. The dosage as well as duration of the treatment does not play a significant role as well. However, all four studies also advised further discussion as well as research for the topic, while one study concluded that corticosteroid helps treat and prevent neural function impairment.

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References 1. Bhandari J, Awais M, Robbins BA, Gupta V. Leprosy. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2020. 2. Lastória JC, Abreu MAMM de. Leprosy: review of the epidemiological, clinical, and etiopathogenic aspects - part 1. An Bras Dermatol. 2014;89(2):205–18. 3. Leprosy [Internet]. Who.int. [cited 2020 Dec 8]. Available from: https://www.who.int/news-room/fact-sheets/detail/leprosy 4. Who.int. [cited 2020 Dec 8]. Available from: https://www.who.int/neglected_diseases/mediacentre/WHA_66.12_Eng.pdf?ua=1 5. Bhat RM, Prakash C. Leprosy: an overview of pathophysiology. Interdiscip Perspect Infect Dis. 2012;2012:181089. 6. Marques W. Chapter 12 Leprosy neuropathy. In: Advances in Clinical Neurophysiology, XV International Congress of Clinical Neurophysiology. Elsevier; 2002. p. 91–6. 7. Nery JA da C, Bernardes Filho F, Quintanilha J, Machado AM, Oliveira S de SC, Sales AM. Understanding the type 1 reactional state for early diagnosis and treatment: a way to avoid disability in leprosy. An Bras Dermatol. 2013;88(5):787–92. 8. Capadia GD, Shetty VP, Khambati FA, Ghate SD. Effect of corticosteroid usage combined with multidrug therapy on nerve damage assessed using nerve conduction studies: a prospective cohort study of 365 untreated multibacillary leprosy patients. J Clin Neurophysiol. 2010;27(1):38–47. 9. Wagenaar I, Post E, Brandsma W, Bowers B, Alam K, Shetty V, et al. Effectiveness of 32 versus 20 weeks of prednisolone in leprosy patients with recent nerve function impairment: A randomized controlled trial. PLoS Negl Trop Dis. 2017;11(10):e0005952. 10. Lambert SM, Alembo DT, Nigusse SD, Yamuah LK, Walker SL, Lockwood DNJ. A randomized controlled double blind trial of ciclosporin versus prednisolone in the management of leprosy patients with new Type 1 reaction, in Ethiopia. PLoS Negl Trop Dis. 2016;10(4):e0004502. 11. Chaitanya VS, Lavania M, Nigam A, Turankar RP, Singh I, Horo I, et al. Cortisol and proinflammatory cytokine profiles in type 1 (reversal) reactions of leprosy. Immunol Lett. 2013;156(1–2):159–67. 12. Walker SL, Nicholls PG, Dhakal S, Hawksworth RA, Macdonald M, Mahat K, et al. A phase two randomised controlled double blind trial of high dose intravenous methylprednisolone and oral prednisolone versus intravenous normal saline and oral prednisolone in individuals with leprosy type 1 reactions and/or nerve function impairment. PLoS Negl Trop Dis. 2011;5(4):e1041.

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The Effectiveness of ​Chimeric Yellow Fever Dengue - ​Tetravalent Dengue Vaccine

(CYD-TDV) as An Efficacious Prevention for Dengue Fever in Asian and American Countries: A Systematic Review of Randomized Control Trial Studies Reylinge Relia Margouw, Emmanuela Wilhelmina Mokalu, Jonathan Abdiel Caesar Nainggolan Introduction: Dengue fever is a vector-borne disease transmitted to humans by mosquitoes, especially by the ​Aedes species. Clinical manifestations of dengue such as extreme headache, muscle and joint pain, nausea, swollen glands, rash, and high fever. Dengue fever infects

many people and causes deaths every year, especially in countries around the equator. Although mosquito control and improved care have helped to reduce dengue fever’s impact, a vaccine is needed. New scientific discoveries have opened ways for the development of new vaccines to raise the population’s immunity. The CYD-TDV is one example of a newly developed type of vaccine established by Sanofi Pasteur. This vaccine, however, is also a controversial one. Thus, we made our systematic review to evaluate the effectiveness of CYD-TDV as an efficacious prevention for dengue fever. Materials and Methods: We gathered our data from online resources, including Pubmed, Google Scholar, and NCBI, in our systematic analysis. In this research, systematic analysis methods, including the PICO method and MeSH terminology, were used. Results and Discussion: We have done inclusion and exclusion criteria, and were left to 6 relevant studies for it to be analysed. From the studies conducted by Coronel et al., Dubey et al., Park et al., and Arredondo-García, et al. They stated that after giving the CYD-TDV, there are significant differences between both groups, proving that CYD-TDV is satisfactory to prevent dengue fever. ​As opposed to, ​Villar, et al. and Kirstein, et al., who stated that there is no significant difference between the CYD-TDV group and the placebo group. Conclusion: Based on our systematic review, 2 out of 6 studies stated that there were no significant differences between the CYD-TDV group and placebo group post-immunization. Therefore, we conclude that CYD-TDV may be an effective prevention of dengue fever.

Keyword:​ Dengue fever, CYD-TDV, prevention, vaccine

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The Effectiveness of ​Chimeric Yellow Fever Dengue - ​Tetravalent Dengue Vaccine (CYD-TDV) as An Efficacious Prevention for Dengue Fever in Asian and American Countries: A Systematic Review of Randomized Control Trial Studies Reylinge Relia Margouw, Emmanuela Wilhelmina Mokalu, Jonathan Abdiel Caesar Nainggolan

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Introduction Tropical countries have experienced many diseases from mild to extreme over the years. Among these diseases, the dengue fever is the most common, and yet, dengue is still one of the most neglected but severe infections, as nearly half of the world's population is estimated to be at risk of dengue infection, and dengue disease, especially severe dengue fever, is not adequately handled. Dengue is a viral infection spread by mosquitoes. Female mosquitoes transmit the dengue virus primarily from the species ​Aedes aegypti and, to a lesser extent, ​Ae. Albopictus​. Up to 400 million individuals get infected with dengue per year.

Around 100 million people get sick with infection, and 22,000 die from serious dengue fever.​[1] Severe dengue affects most countries in Asia and Latin America and has become a

leading cause of hospitalization and death in these regions among children and adults. Dengue is caused by the ​Flaviviridae ​family virus and there are four distinct but closely related dengue-causing serotypes of the virus (DENV-1, DENV-2, DENV-3 and DENV-4). Infection by one serotype results in lifelong immunity to that serotype but not to others. Over the last two decades, the number of dengue cases registered to the WHO has risen more than 8 fold, from 505,430 cases in 2000 to over 2,4 million in 2010 and 4,2 million in 2019. Reported deaths rose from 960 to 4032 between the years 2000 and 2015.​[2] Transmission of dengue fever can be through mosquito-to-human transmission, human-to-mosquito transmission, and other modes of transmission. The World Health Organization categorizes dengue into two major categories: dengue and severe dengue. Dengue should be suspected when extreme headache, pain behind the eyes, muscle and joint pain, nausea, vomiting, swollen glands, rash, are followed by high fever (40 °C/104 °F). Owing to plasma leakage, fluid retention, respiratory failure, significant bleeding, or organ impairment, severe dengue is a potentially fatal complication.​[2] Because of the severity of muscle spasms and joint pain, dandy fever, or seven-day fever due to the usual duration of symptoms, dengue is also known as breakbone fever. Untreated severe dengue fever can have a 10 percent to 20 percent mortality rate . The mortality rate is reduced to approximately percent by adequate supportive treatment.​[4] CYD-TDV is a tetravalent, live attenuated, chimeric dengue vaccine in a yellow fever 17D backbone developed by Sanofi Pasteur.​[3] Established by Sanofi Pasteur, Dengvaxia® (CYD-TDV) was licensed in December 2015 and has now been approved by regulatory authorities in around 20 countries. In November 2017, the findings of an additional study were published for the retrospectively determined serostatus at the time of vaccination were released. In those who undergo their first natural dengue infection after vaccination, however 1 304


it brings an increased risk of serious dengue (those who were seronegative at the time of vaccination).​[2] Thus, we conducted our systematic review to evaluate the effectiveness of the CYD Tetravalent Dengue Vaccine in dengue fever prevention. Method In our systematic review, we collected our data from an online resources which includes Pubmed, Google Scholar, and NCBI. Systematic Analysis approaches were used in this study including the PICO method and MeSH terminology. For the Problem (P) we used “dengue fever”. For intervention (I) the terminology “CYD-TDV vaccine” was used. For Comparison (C) we used the terminology “placebo”. For the outcome (O), we used “effectiveness in preventing dengue”. Hypothesis question for this systematic review is “Is CYD TDV vaccine effective for preventing dengue?”. The inclusion criteria used in this systematic review are a randomized controlled trial, CYD-TYD vaccine, placebo-controlled, publication for the last 5 years. The exclusion criteria are meta-analysis, a systematic review, animal study, literature review, case report. We will then verify the validity of the studies that meet the requirements for inclusion and exclusion. After ensuring the validity of the studies, the data will be analysed. Results and Discussion Using the PICO approach, we have gathered and selected 6 articles to be analyzed. The diagram below shows the process of selection.

Figure 1 ​Information flow chart through the different phases of the systematic review

2 305


Table 1.​ Summary of studies on the effectiveness of CYD-TDV on dengue fever prevention Authors

Study

Year

Subject

Coronel et al 5​​ .

Randomized

2019

251

Controlled Trial

Dubey et al 6​​ .

Randomized

Results healthy

After 28 days post-booster injection,

and

the booster dose provides a great

adults 15–23 years of

GMTRs increase in participants who

age

were dengue-seronegative.

189 participants of

For both dengue seropositive and

healthy Indian adults

dengue seronegative Indian adults,

adolescents

2016

Controlled Trial

the overall immunogenicity and protection profile of CYD-TDV administered at 0, 6, and 12 months was satisfactory. Park et al 7​​ .

Randomized

2019

Controlled Trial

118 participants who

At 28 days post booster injection,

had received all three

the GMTs of participants who were

CYD28 doses, aged

seronegative at baseline increased.

9–45 years Arredondo-García, et 8​

al ​ .

Villar, et al 9​​ .

Randomized

2018

Controlled Trial

Randomized

2015

Controlled Trial

35.123

participants

The study shows that the overall

that were stratified by

benefit-risk ratio of CYD-TDV was

age

positive.

20.869 children aged

The study shows a positive efficacy

9-16

of CYD-TDV and that the safety of CYD-TDV vaccine was similar to that of placebo.

Kirstein, et al 10 ​

Randomized

2018

Controlled Trial

390

healthy

participants 18–45-year-olds

aged

The study shows live attenuated CYD-TDV

vaccine given in a

compressed schedule in a place where the disease is non-endemic obtains similar antibody responses to the licensed vaccine schedule.

Note : CYD : ​Chimeric Yellow Fever-Dengue TDV : Tetravalent Dengue Vaccine GMT : Geometric mean titer GMTR : Geometric mean post-/pre-vaccination titer ratio

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According to the study by Dubey et al, conducted in 189 subjects which were assigned randomly to the CYD-TDV group (n=128) and placebo group (n=61). The study shows that in both dengue seropositive and dengue seronegative Indian adults, the overall immunogenicity and protection profile of CYD-TDV administered at 0, 6 and 12 months was satisfactory. During the analysis, no immediate unsolicited AEs were registered. In the CYD-TDV group, higher numbers of participants (9.5% and 19.0% respectively) were recorded in the solicited injection site reactions and solicited systemic reactions compared with the placebo group (4.9% and 6.6%, respectively). In both the CYD-TDV group (8/126 [6.3%]) and the placebo group (3/61 [4.9%]), pain that occurred within 3 days of the first injection and healed spontaneously was the only recorded injection site response after the first injection. Similarly, after the second injection in the CYD-TDV and placebo groups (2/117 [1.7%] vs 2/58 [3.4% respectively) and after the third injection in the CYD-TDV group (3/115 [2.6%]), pain was the only recorded injection site response. Erythema and swelling were not reported within 7 days after any injection. A slightly higher proportion of participants in the CYD-TDV group (9.4%) have registered unsolicited AEs within 28 days of any injection compared to the placebo group (6.6%). In either the CYD-TDV or the placebo group, there were no immediate unsolicited AEs. In both groups, all unsolicited AEs were considered as non-serious. During the study, no unsolicited adverse reactions, no deaths and no virologically confirmed cases of dengue were identified.​[6] According to the study by Coronel et al, conducted in 251 healthy adolescents and adults between the age of 15 to 23 which were randomly assigned to the CYD-TDV group (n=187) and placebo group (n=64). Among these, 250 participants remained in the study (n=186 and n=64 in CYD-TDV group and placebo groups, respectively) and 249 participants provided a blood sample (n=185 and n=64 in CYD-TDV group and placebo groups, respectively). The per-protocol analysis set included 177 participants out of 185 CYD-TDV participants. At the baseline (pre-vaccination), 136 participants in the CYD-TDV group were dengue-seropositive and 41 were seronegative while in the placebo group, 46 participants were dengue-seropositive and 18 were seronegative. Those who were dengue-seronegative pre-vaccination had lower GMTs pre-booster injection compared to those who were dengue-seropositive.

Post-booster

injection,

the

GMTs

remained

the

same

in

dengue-seropositive and seronegative but, after 28 days post-booster injection, the booster dose provides a great GMTRs increase in participants who were dengue-seronegative. During the study, the most frequently reported solicited injection site reaction in both groups was injection site pain (24.6% and 18.8% in the CYD-TDV and placebo groups, respectively) and 4 307


the most frequently reported solicited systemic reaction was headache [87 (46.5%) and 22 (34.4%) participants in the two groups, respectively]. One SAE was reported but it was considered not related to vaccination. No AEs or SAEs that lead to discontinuation were reported and also no deaths and dengue cases were reported 28 days post-booster injection.​[5] In the study conducted by Park et al, a total of 118 participants who had received all three CYD28 doses, aged 9–45 years were randomly assigned to the CYD-TDV group (n=89) and placebo group (n=29). Among these participants, one participant from each group was discontinued because they did not provide a post-dose blood sample. 116 participants (98.3%) completed the study and 103 participants (87.3%) were included in the per-protocol analysis set (PPAS; CYD-TDV group, n=75 [84.3%]; placebo group, n=28 [96.6%]). In the baseline (day 0 of CYD28 study), 19 participants from the CYD-TDV group were dengue seropositive (25.3%) and 56 were seronegative (74.7%) while in the placebo group, 10 participants were dengue seropositive (35.7%) and 18 were seronegative (64.3%). In the previous studies of CYD28, the majority of participants (93.1%) remained dengue seropositive (50% plaque reduction neutralization test [PRNT50] titer ≥10). The study shows that the GMTs pre and post-booster injection remains the same in participants who were seropositive at baseline. At 28 days post booster injection, the GMTs of participants who were seronegative at baseline increased. Overall, this study shows that booster injection could restore anti-dengue antibody titers to levels identical to those initially observed after three-dose CYD28. In this study, there were no safety concerns with the booster and it was well tolerated. There were no deaths, no AEs leading to discontinuation, no serious AESIs, and no dengue cases reported.​[7] In the study conducted by Arredondo-GarciÌa et al, a total of 35.123 children at the age of 2-16 years were assigned randomly to the CYD-TDV group (n=23 429) and placebo group (n=11 694). Each group was divided into two groups based on their age, <9 years and ≥9 years. The study shows that the overall benefit-risk ratio of CYD-TDV was positive. The results shows that 4 years after given the first dose of CYD-TDV, 233 and 228 participants had been hospitalized for virologically confirmed dengue (VCD) at least once in the CYD-TDV group (n=22 603) and placebo group (n=11 301), respectively (RR = 0.511, 95% CI 0.42-0.62). Out of those participants, cases that are classified as clinically severe were 48 and 47 cases, respectively. Overall, the CYD-TDV group showed a reduction in the number of hospitalized VCD cases. In children aged 9-16 years, the hospitalized VCD reduces 68% while in children aged 2-8 years, the rate of hospitalized VCD was low in year 1, 2, and 4 and

5 308


high in year 3. During the study, no participants withdrew from the trials and all VCD participants recovered completely.​[8] In a study conducted by Villar et al, 20.869 children from several Latin American countries aged between 9 and 16 years regardless of their sex were randomly assigned to receive either the CYD-TDV (n=13.920) or placebo (n=6949). Among these children, 2000 of these were then assigned to the reactogenicity and immunogenicity subgroups: 1334 into the vaccine group and 666 into the control group. At the baseline, 79,4% of the immunogenicity subgroup of 1944 children shows a seropositive status for one or more dengue stereotypes. In the per-protocol population, there were 176 virologically confirmed dengue (VCD) cases, with 11.973 person-years at risk in the vaccine group and 221 VCD cases with 5809 person-years at risk in the control group, for a vaccine efficacy of 60.8% (95% confidence interval, 52.0 to 68.0). In the population that were intended to be treated, or the intention-to-treat (who received at least one injection), the efficacy of the vaccine was 64.7% (95% CI, 58.7 to 69.8). On the other hand, serotype-specific vaccine efficacy was 50.3% for serotype 1, 42.3% for serotype 2, 74.0% for serotype 3, and 77.7% for serotype 4. Among the severe VCD cases, 1 of 12 was in the vaccine group, for an intention-to-treat vaccine efficacy of 95.5%. Vaccine efficacy against hospitalization for dengue was 80.3%. Both were observed over a 25 month period. The safety profile for the CYD-TDV vaccine was similar to that of placebo, with no significant and marked difference in rates of adverse events. During the study, there are no deaths among the children.​[9] According to Kirstein et al, she and her team tries to compare immune responses of dengue fever in endemic and non-endemic countries of the disease. Live attenuated tetravalent hemorrhagic vaccine such as CYD-DTV is licensed using a 0-, 6-, 12 month schedule in endemic areas, a question then arises, what if the scheduling implications for dengue fever endemic countries are carried out in non-endemic countries? An effective, shorter schedule may provide a more rapid, optimal protection of the targeted populations during vaccination campaigns in endemic countries. The team also analyzes the impact of Yellow fever (YF) co-administration. The study consisted of 390 healthy participants consisting of 18-45 year olds in the USA with no prior exposure to dengue. The participants were randomised to four treatment groups (4:4:4:1) stratified by their prior YF vaccination status. Group 1 with the standard 0-6-12 month schedule; Group 2 with the accelerated CYD-TDV 0-2-6 months schedule; Group 3 with CYD-TDV accelerated schedule along with YF co-administered (dose 1); Group 4 is only given YF vaccination. During this test, neutralising antibody GMTs and percentages of seropositive participants were measured 6 309


against each dengue serotype using 50% plaque reduction neutralisation test. The results of the RCT shows that on D28 post CYD-TDV dose 3 that there are no marked differences of seropositivity rates and GMTs between Group 1 and Group 2. In Groups 1 and 2, GMTs measured 6 months after the third dose decreased against all serotypes, except for a small increase in GMT for serotype 4 in Group 1. In addition, dengue seropositivity still remains above 70% for serotypes 2, 3, and 4 in group 1 and 2. Co-administration of YF turns out to not affect antibody responses against dengue and YF, or even impact vaccine safety following the completion of the schedule, compared to dengue or YF vaccine alone. The phase II study of healthy adults in a non-endemic area shows that an accelerated 0–2–6-month CYD-TDV vaccination schedule elicits a similar immune response to the licensed 0–6–12-month schedule. More rapid protection would be beneficial in the setting of public health programmes where a shorter schedule may allow potentially better compliance in dengue-endemic populations. Three participants reported SAEs, but none are considered related to the vaccination. During the trial, 13 participants experienced SAEs: 4 in Groups 1 and 2, and 5 in Group 3. One SAE was reported by the investigator as related to vaccination: a blighted ovum was detected 7 weeks after inadvertent vaccination of a woman during early pregnancy. Three non-serious AESIs were reported by three participants within 7 days following the first injection; two were assessed as related to vaccination. No AEs led to discontinuation in any group after 28 days of injection in this study.​[10] Conclusion From the 6 studies that we have analyzed, we conclude that ​Chimeric Yellow Fever

Dengue - ​Tetravalent Dengue Vaccine (CYD-TDV) is somewhat efficient in preventing dengue fever. Though from our systematic review, we found that people who have been vaccinated for dengue in the past may give positive effect to CYD-TDV performance that it may help improve the population's immunity to dengue. But in the end, there is still a need for further research to produce such concrete evidence.

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References 1. About Dengue: What You Need to Know | Dengue | CDC [Internet]. Cdc.gov. 2020

[cited

5

December

2020].

Available

from:

https://www.cdc.gov/dengue/about/index.html 2. Dengue and severe dengue [Internet]. Who.int. 2020 [cited 5 December 2020]. Available

from:

https://www.who.int/news-room/fact-sheets/detail/dengue-and-severe-dengue 3. WHO | Safety of CYD-TDV dengue vaccine [Internet]. Who.int. 2020 [cited 5 December

2020].

Available

from:

https://www.who.int/vaccine_safety/committee/topics/dengue/Aug_2015/en/ 4. Schaefer T, Panda P, Wolford R. Dengue Fever [Internet]. Ncbi.nlm.nih.gov. 2020

[cited

5

December

2020].

Available

from:

https://www.ncbi.nlm.nih.gov/books/NBK430732/ 5. Coronel D, García-Rivera E, Rivera M, Arredondo-García J, Dietze R, Perroud A et al. Dengue Vaccine Booster in Healthy Adolescents and Adults in Latin America: Evaluation 4-5 Years After a Primary 3-Dose Schedule [Internet]. Pubmed.ncbi.nlm.nih.gov. 2020. cited 6 December 2020]. Available from: ​https://pubmed.ncbi.nlm.nih.gov/30986790/ 6. Immunogenicity and safety of a tetravalent dengue vaccine in healthy adults in India: A randomized, observer-blind, placebo-controlled phase II trial [Internet]. Taylor & Francis. 2020 [cited 6 December 2020]. Available from: https://www.tandfonline.com/doi/full/10.1080/21645515.2015.1076598 7. Immunogenicity and safety of a dengue vaccine given as a booster in Singapore: a randomized Phase II, placebo-controlled trial evaluating its effects 5–6 years after completion of the primary series [Internet]. Taylor & Francis.

2020

[cited

6

December

2020].

Available

from:

https://www.tandfonline.com/doi/full/10.1080/21645515.2019.1661204

8. Arredondo-García J, Hadinegoro S, Reynales H, Chua M, Rivera Medina D, Chotpitayasunondh et al. Four-year safety follow-up of the tetravalent dengue vaccine efficacy randomized controlled trials in Asia and Latin America [Internet]. pubmed.ncbi.nlm.nih.gov. 2020 [cited 6 December 2020]. Available from: ​https://pubmed.ncbi.nlm.nih.gov/29408333/ 8 311


9. Villar L, Dayan GH, Arredondo-García JL, Rivera DM, Cunha R, Deseda C, Reynales H, Costa MS, Morales-Ramírez JO, Carrasquilla G, Rey LC, Dietze R, Luz K, Rivas E, Miranda Montoya MC, Cortés Supelano M, Zambrano B, Langevin E, Boaz M, Tornieporth N, Saville M, Noriega F; CYD15 Study Group. Efficacy of a tetravalent dengue vaccine in children in Latin America. [Internet] N Engl J Med. 2015 [cited 6 December 2020]. Available from: https://pubmed.ncbi.nlm.nih.gov/25365753/ 10. Kirstein, J., Douglas, W., Thakur, M., Boaz, M., Papa, T., Skipetrova, A., & Plennevaux, E. (2018). Immunogenicity of the CYD tetravalent dengue vaccine using an accelerated schedule: randomised phase II study in US adults. BMC Infectious Diseases, 18(1) [cited 9 December 2020]. Available from: https://doi.org/10.1186/s12879-018-3389-x

9 312


The Role of T-Cell Immunoglobulin and Mucin Domain 3 (TIM3) Blockade Signaling Enhances Cell Mediated Immunity Against Malaria : Systematic Review Marlin, Kinanthi Prima Astari, Nyimas Halimah Afifah

ABSTRACT Introduction : T cell immunoglobulin and mucin domain conaining molecule 3 (TIM3) has been appeared to be an important immunomodulatory particle and regulatory factor in both adaptive and innate immunity amid the past decade, but TIM 3 expression can influence different functions in the innate and adaptive immunity, and also different on the type of cells. This handle plays basic parts in many disease including malaria. So, the authors are going to take a comprehensive look at the accessible literature about the role of TIM 3 enhances cell mediated immunity against malaria. Material and Methods : This systematic review is reported following the PRISMA protocol. Literature search is carried out from PubMed, ScienceDirect, and ProQuest, pulished from 2016 until 2020, those which are evaluating the role TIM 3 mediated cell immunity against in all manifestations of malaria, and the outcomes of studies involved in during malaria infection including in early phase, in asymptomatic phase, in acute phase, in complicated and uncomplicated phase. Result and Discussion : From the search, 1240 studies were identified and finally obtained 7 studies that fulfill the criteria of this systematic review. Studies show that TIM 3 blockade signaling enhances cell mediated immunity and facilitates parasite clearance against Plasmodium infection. And TIM 3 also play a protective role during malarial infection and can prevent immunopathology in malaria infection. Conclusion : T cell immunoglobulin and mucin domain 3 (TIM 3) is one of co-inhibitory receptors that express cell mediated immunity (CD4+, CD8+, αβ T cells, and yδT-cells). TIM3 blockade signaling enhances sterile immunity and accelerates parasit clearance that can reduce clinical incidence risk and may prevent immunopathology in acute infections and severe inflammation during malaria.

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The Role of T-Cell Immunoglobulin and Mucin Domain 3 (TIM3) Blockade Signaling Enhances Cell Mediated Immunity Against Malaria : Systematic Review Participate in Indonesian Medical Students Training and Competition (IMSTC) 2021 By AMSA-Indonesia

Arranged by :

Marlin Kinanthi Prima Astari Nyimas Halimah Afifah

Asian Medical Students’ Association-Indonesia 2020

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INTRODUCTION Malaria is a life-threatening disease and the most severe parasitic disease in the world. WHO estimated that 2 billion people are at risk for malaria. Each year, malaria causes more than 300 million clinical cases and over 2 million deaths. In 2019, WHO estimated 229 million cases of malaria in the world. The calculable range of malaria deaths stood at 409.000 in 2019.1 Malaria transmission happens in additional than 100 countries. The highest transmission is found in Africa South of the Sahara and parts of Oceania (such as Papua New Guinea). In several temperate areas, such as United states, and therefore Western Europe, public health evaluates have succeeded in eliminating malaria. However, mst of those areas have arthropod genus mosquitoes which will transmit malaria, and presentation of the unwellness may be a constant risk.2 Malaria remains one among the foremost serious public health problems in lower and middle income countries in the world, so prevention is high priorities inside endemic region. Therefore it is clear that extra control devices will be required to ensure worlwide malaria eradication, and it has been also captured in World Health Organization’s worldwide technical strategy for prevention malaria from 2016 to 2030. 3 Malaria infection actuates strong innate immunity reactions in the host, which are essential to initiate protective acquired immunity and to result in direct antiparasitic effects. 4 In most cases, immunity protection has been related with the accessibility and action of CD4+ T cells of both T-helper type 1 (Th1) and Th2,8 cytotoxic CD8+ T cells and yδ T cells that can react to the stage of Plasmodium infection, 5 and be it’s responsible for controlling the asymptomatic liver stage and the symptomatic blood stage,8 and these immune responses may indeed hold the key for advancement of a profoundly solid vaccine against malaria.6,7 T cell immunoglobulin and mucin domain containing molecule 3 (Tim 3) has been appeared to be an important immunomodulatory particle4 and regulatory factor in both adaptive and innate immunity8 amid the past decade. Although, Tim 3 was at first distinguished as a layer marker particular for CD4+ Th1, 4 and CD8+ T-cytotoxic type 1 cells,8 its expression was before long affirmed in other immune cells, such as natural killer cells, dendritic cells, monocytes, and macrophages, interacts with galectin-9. In general, TIM 3 is demonstrated to act as a negative regulator pathway, but TIM 3 expression can influence different functions in the innate and adaptive immunity, and also different on the type of

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cells. This handle plays basic parts in many diseases, such as autoimmunity, allergy, viral disease, transplant tolerance, and indeed parasitic infection including malaria. In this systematic review, the authors are going to take a comprehensive look at the accessible literature about the role of T cell immunoglobulin and mucin domain 3 (Tim 3) enhances cell mediated immunity against malaria. MATERIAL AND METHODS This systematic review is reported following the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) protocol.10 Literature search is carried out with multiple electronic databases, such as PubMed, ScienceDirect, and ProQuest with keyword “T cell immunoglobulin”, “Mucin domain 3”, “TIM 3”, “Cell Mediated Immunity”, and “Prevention of Malaria”, and only literature pulished from 2016 until 2020 which are included. Randomized- controlled trials, cross sectional, cohort studies, laboratories and non human studies are also included. Review, case report, case series, and conference abstracts, book sections, commentaries/ editorials are excluded. Lastly, articles with unavailable full text, languages other than English, and irrelevant topics are also omitted. The eligible studies were : 1) those which are evaluating the role of T cell immunoglobulin and mucin domain 3 (Tim 3) mediated cell immunity against malaria in all manifestations of malaria, 2) the outcomes of studies involved in during malaria infection including in early phase, in asymptomatic phase, in acute phase, in complicated and uncomplicated phase. Studies were identified using the keywords described above. After removing duplicates using EndNote program, retrieved articles are screened based on their titles and abstracts. Thereafter, potentially eligible full text articles are throughly assessed using the eligibility criteria described above. Any emerging discrepancies will be resolved by consensus among the review team. The literature selections were summarized in Figure 1. RESULT From 1240 published papers from Pubmed, ScienceDirect, and ProQuest databases, we include studies because the other studies are not published in English and published below 2016. Of those, we finally include 7 eligible and valid studies because of other studies discussing other topics besides the evaluation of effectiveness T cell immunoglobulin and

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mucin domain 3 (Tim3) blockade signaling enhances cell mediated immunity in preventing malaria, unsuitable study design, studies are not found, and study duplication. The final eligible and valid studies (n=7) then were reviewed here and the results were summarized in Table 1. Interpretation of Table 1 : According to the table above, the study design from seven studies, two studies use in vitro experimental design, two studies use in vivo studies using the animal model, two studies use in vivo and in vitro assays, and one study use cross sectional with ex vivo analyzed. There was literature investigated T cell immunoglobulin and mucin domain 3 (Tim 3) in healthy individuals and in patients of malaria. 4,8,13 There were three studies, two of theme from China,4,8 and one from West Africa.13 There was one study focus on individuals in high risk of malaria (living in endemic malaria area) from Australia, 12 and also one study focus on acute malaria from German.11 The other two studies use the mice as sample size from China and UK9,14. The main outcomes were in during malaria infection (in the early stage, in asymptomatic phase, and in acute phase), 8,11,12,14 in plasmodium infection,4,9 and in complicated and uncomplicated malaria.13 According to the conclusion of seven studies, it found that Tim 3 blockade signaling enhances cell mediated immunity

and facilitates

parasite clearance against Plasmodium infection. And Tim 3 also play a protective role during malarial infection and can prevent immunopathology in malaria infection. DISCUSSION Malaria is a condition when our immune systems must obtain a cautious stability among inflammatory and anti-inflammatory responses to successfully fight the infection without inflicting damage to the host. Study has investigated the role of CD4+ T cell response and regulation11, and it was important factor affecting the clinical outcome of malaria. 13 From this sudy, we identified that the important process to control the action of CD4 + T cell (including spesific regulation or the expression) is the induction of co-inhibitory receptors (such as CTLA4, PD111, LAG3 and TIM 3)13, which can inhibit the inflammatory response. 11 In additional, the expression pattern of co-inhibitory molecules involved in regulative capability on CD4+ T cell with some manifestation of malaria (complicated/uncomplicated malaria, asymptomatic malaria, and healthy individual). 13 Those reseptors blockade signaling increased the effector response. Brief induction of regulatory T cells effector can be an important process which can control T cell responses and even can prevent severe

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inflammation in malaria.11 Beside of that, CD4+ T cell was related to protection of severe and clinical malaria.13 Co-inhibitory also have a major role to control Th1 response in blood stage malaria. The dominan co-inhibitory receptor is PD1 that can limit T cell responses. Study from Dookie et al investigated that the combined roles between TIM 3 and PD1 in regulating the antigen spesific CD4+ T cell, which the antigen express Tim 3 in high levels only during blood stage of malaria. This study investigated that combination TIM 3 blockade and PD1, caused to decrease in Th1 OT-II cells on day 15 of P yoelli NL-OVA infection was unforeseen, given the imperative regulatory action of Tim 3 in controlling effector T cell responses.14 Hou et al have also investigated that Tim 3 is expressed by CD4 + T cell in the high level only on day 5 of P berghei ANKA infection before being afterwards downregulated as infection advances.9 Moreover, TIM 3 is not only express CD4+, but it also express CD8+, αβ T cells which were shown in patients during acute P vivax infection but undetected teraphy. Even in recent study reported that TIM 3 expression turn into upregulated on yδT-cells during an infectious disease setting with continous exposure to malaria, this mechanism is controlled by the host immune response. IFN-ƴ, TNF-α and cytotoxic interest were not found in TIM3 + yδT-cells after re-stimulation with malaria antigens, and if the frequency of this cell increases so it was related to reduced risk of malaria manifestations. But, the amount of TIM 3 upregulation was different depending on the infected species (P. Falciparum or P. Vivax). Furthermore, TIM3 expression renders cells practically disabled, which is related with decreased risk of clinical malaria.12 In the recent study, we observed that TIM 3 changed into predominately expressed through CD 16+ TEMRA yδT-cells. It can be identified that TIM3 has a role as potential receptor that responsible for yδT-cells impairment related with malaria infection. Nevertheless signaling through CD16+ consequences in pyrogenic cytokine, which is TNF-α. As we know, TNF-α drastically contributes towards febrile in malaria, it means that if CD16+ TEMRA yδT-cells were inhibited may be essential to restrict the mechanism of immunopathogenesis within the host. Study from Schofield et al especially identified that TIM3 + CD16 + TEMRA yδT-cells was related to decreased clinical incidence risk, in additional the concept that regulation of noticeably specialised subsets is vital to decreased

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the symptoms of malaria. Accordingly, increased TIM 3 expression was related to reduce risk of febrile in malaria and asymptomatic infection. 12 Study from Hou et al also reported that Tim 3 blockade signaling could protected lymphocytes from exaustion from plasmodium infection. 4 Tim 3 blockade signaling reestablished lymphocyte action and resulted in expedited parasit clearance, and may play defensive part during malaria infection.8 Hence, the strategy of anti-Tim 3 antibodies effectively increased phagocytosis process and encouraged TNF-α and NO production in murine splenic machrophages both in vivo and in vitro, 4 without increasing serum of TNF-α and NO levels. It was indicated that Tim 3 upregulation can be responsible for lymphocyte loss all through malaria infection. So, the strategy of anti-Tim 3 may repair cell mediated immunity against Plasmodium infection, and prepare new approaches for malaria. 8 In additional, blocking Tim 3 pathway by utilizing an counter acting agent or a suloble Tim 3 immunoglobulin combination protein or repeal of Tim 3 signaling by RNA impendances may move forward insusceptibility in these disease, showing the potential value of Tim 3 signaling blockade in immune therapy based approaches. 8 There were some limitations to this review. First, the outcome criteria was not uniformed in the spesific phase of malaria due to different spesific types of cell mediated immunity. Second, the eligible participants vary among studies based on inclusion and exclusion criteria and there was still no study conducted in Indonesia, which is one of the main aims in this review implementation. The application of TIM 3 must be first validated to the health system in Indonesia. The studies we found still in low-level evidence for Indonesia. So, further study needs to be conducted in Indonesia setting. From this study, the authors hope that we can develope better solutions to help the government through biomolecular applications to reduce prevalence of malaria in the future with further research by medical students and medical professionals that will be useful to improve the quality of life of Indonesia’s society. CONCLUSION In general, this review conclude that T cell immunoglobulin and mucin domain 3 (TIM 3) is one of co-inhibitory receptors that express cell mediated immunity (CD4 +, CD8+, αβ T cells, and yδT-cells). TIM 3 blockade signaling enhances sterile immunity and accelerates parasit clearance that can reduce clinical incidence risk and may prevent immunopathology in acute infections and severe inflammation during malaria.

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REFERENCES 1. World Health Organization. Malaria [Internet]. 2020 [Cited 2020 Nov 28] Available from : https://www.who.int/news-room/fact-sheets/detail/malaria. 2. Centers for Disease Control and Prevention. Malaria [Internet]. 2020 [Cited 2020 Nov 28] Available from :https://www.cdc.gov/malaria/about/distribution.html. 3. World Health Organization. The Global technical Strategy for malaria [Internet]. 2019 [Cited

2020

Nov

28]

Available

from

:https://www.who.int/malaria/areas/global_target/en. 4. Hou N, Jiang N, ou Y, Piao X, Liu S, Li S, Chen Q. Down Regulation of Tim 3 in Monocytes and Macrophages in plasmodium infection and its Associatuion with Parasite Clearance. Front Microbiology. 2017; 2(8): 1431. 5. Kurup SP, Butler NS, Harty JT. T cell-mediated immunity to malaria. Nat Rev Immuology 19. 2019: 457-471. 6. Lyke KE, Ishizuka AS, Berry AA, et al. Attenuated PfSPZ Vaccine induces strain transcending T cells and durable protection against heterologous controlled human malaria infection. Proc Natl Acad Sci USA 2017; 114 (10): 2711-6. 7. Li X, Huang J, Zhang M, et al. Human CD8+ T cells mediate protective immunity induced by a human malaria vaccine in human system mice. Vaccine 2016; 34(38):4501-6. 8. Hou N, Zou Y, Piao X, Liu S, wang L, Li S, et al. T-cell immunoglobulin and mucindomain-containing molecule 3 (Tim3) signalling blockade improves cell mediated immunity against malaria. J infect. 2016; 24: 1547-1556. 9. Zhang Y, Jiang N, Zhang T, et al. Tim 3 signalling blockade with α-lactose induces compensatory TIGIT expression in Plasmodium berghei ANKA-infected mice. Paracites vectors. 2019;12: 534. 10. Salameh, Jean-Paul, et al. Preferred reporting items for systematic review and metaanalyses of diagnostic test accuracy studies (PRISMA-DTA_ : explanation, elaboration, and checklist. 2020:370. 11. Mackroth MS, et al. Acute malaria induces PD1+CTL4+ effector T cells with cellextrinsic supressor function.PloS pathogens. 2016;12(11). 12. Schofield L, et al. Synergistic effect of L-12 and 1L-18 induces TIM 3 regulation of yδ T cell function and decreases the risk of clinical malaria in children living in Papua New Guinea. BMC medicine. 2017;15(1):1-15.

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13. Abel A, et al. Differential expression pattern of co-inhibitory molecules on CD4+ T cells in uncomplicated versus complicated malaria. Sci Rep. 2018;8. 14. Dookie RS, et al. Combinatorial Tim 3 and PD 1 activity sustains antigen spesific Th1 cell numbers during blood stage malaria. Parasite Immunology. 2020;42(9).

TABLE AND FIGURE Figure 1. Diagram flow of study search and selection criteria

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Table 1. Summary of Studies Evaluating the Role of TIM3 Blockade Signaling Enhances Cell Mediated Immunity In Preventing Malaria Author

Year

Hou N 2016

Country

China

et al8

Sample Size

Study

Study

Main

Location

Design

Outcome

Human

At

peripheral blood

Friendship

and

samples from 21

Hospital,

vitro

patients

Capital

assays

with

falciparum

Beijing In

vivo During in malaria infection

Conclusion

Tim 3 on immune cells negatively

regulates

cell

mediated

immunity

Medical

against

Plasmodium infection

malaria and 21 University,

and blocking Tim 3

healthy

from March to

signaling

individuals

June 2016

sterile immunity and

enhances

may play a protective role during malarial parasite infection Mackr

2016

German

oth

25 patients with

At university In

acute malaria

hospital

vitro Acute

experimen

PD1+ CTLA4+ T cells

malaria

plays a crucial role in

infection

the immune regulation

MS et

Eppendorf in tal design

al11

Hamburg

and

between

common

March

2013

could

be

a

autoregulatory

and

mechanism that serves

September

to

2014

overwhelming

control Th1

responses and prevent immunopathology

in

acute

of

infections

malaria Schofi eld

L

et al12

2017

Australi

Human

a

samples 132

blood

In clinical trial In

from in 5 villages children

endemic

studies

Papua

of animal New model

areas Guinea

TIM 3 represents an

matic and important

in East Sepik using the Acute

aged 5-10 years Province living in malaria

vivo Asympto

Guinea

322

cell

regulatory component

malaria

involved

infection

minimizing symptoms

of Papua New

yδT

in malaria


Hou N 2017

China

et al4

Human

At

peripheral blood

Friendship

and

Hospital

plasma

Beijing In

vitro Early

experimen at tal design

stage

Tim

3

constricts

of monocytes/

Plasmodi

macrophages activity,

samples from 21

Capital

um

and

patients

medical

infection

treatment

facilitates

parasite

clearance,

suffering

from University

falciparum

from

March

anti

Tim

3

especially in the early

malaria and 16 2015-August

stage of Plasmodium

healthy

infection

2016

individuals Abel A

2018 et

At Jachie D/A Cross

In

The quality of CD4+ T

from 82 healthy,

Primary

uncompli

cell response is an

afebrile children

school and St with

between

Michael’s

vivo

complicat influencing the clinical

years old and 66

Catholic

analyzed

ed

outcome of malaria,

children

hospital,

malaria

and spesific clusters of

West

Blood

Africa

al13

samples

5-11

with

sectional ex

cated and important

acute,

Pramso

CTLA-4+ PD-1+ CD4+

symptomatic

between June-

T

malaria between

August 2015

associated

1-12 years old. Zhang Y

2019

China

et

al9

factor

Serum

which

are with

malaria complication

of

Key

In

Female BALB/c

laboratory of and

mice

livestock

vitro

phenotype (6-8

infectious

assays

weeks old)

diseases

of

cells

N

vivo Plasmodi in um infection

Tim 3 on lymphocytes negatively

regulates

cell

mediated

immunity

in

against

plasmodium infection

northeast China Dooki e

RS

et al14

2020

UK

Samples from P

At

Leiden In

vivo The early Tim

3

plays

yoelii NL-OVA medical center

studies

infected male 7

using the blood

combinatorial

week

old

animal

stage

with

mice

model

malaria

promoting

C57BL/6

an

phase of unexpected

PD-1

role in and

and female 6-7

sustaining a Th1 cell

week old OF1

response during the

mice

early phase of blood stage malaria

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Biochemical Analysis on Mycobacterium tuberculosis diagnosis: a systematic review Robert Kristianto1, Dewa Vighneswara1, Anastasia Bella Christophila1 Asian Medical Student Association1, Batch 2018 and 2019 ABSTRACT Introduction : Bacteria are included in cellular microbes which are divided into two, namely prokaryotic cells and eukaryotic cells. Bacteria with prokaryotic cells have special properties, namely that they do not have a nuclear membrane and an organelle membrane, while eukaryotic cells have a nuclear membrane and a nuclear membrane. Bacteria have several forms, including bacillus, coccus, and spiral. One of the bacteria that has bacilliform is Mycobacterium Tuberculosis. Mycobacterium Tuberculosis is mycobacteria or aerobic bacteria which do not form spores. Mycobacterium Tuberculosis is called acid-resistant bacillus bacteria, and Mycobacterium Tuberculosis causes tuberculosis and is a significant pathogen in humans. There are several techniques to confirm and diagnose tuberculosis patients, namely the Ziehl-Neelsen stain technique, culture on Lowenstein Jensen media, PCR, biochemical tests, serological tests. Material and Method : This type of research uses a systematic review with observation and biochemical analysis related to the diagnosis of tuberculosis. Data collection in this study was obtained from several journals published on Researchgate, Pubmed, and Google Scholar. We use the keyword "Mycobacterium tuberculosis, the diagnosis of mycobacterium tuberculosis, biochemical analysis of mycobacterium tuberculosis". From the research results of journal data, we then selected several journals with discussions to fit the topic of our scientific paper. Result and Discussion : From the analysis of several journals that have been obtained, the data required for tuberculosis examination requires a subject in the form of age, gender, duration of treatment and clinical symptoms, personal history of habits, so that an examination is carried out in the form of Ziehl Neelsen's staining examination, culture and GeneXpert examination method culture. In patients who are resistant to the antibiotic Rifampin, it turns out that they can also be resistant

to

INH

antibiotics.

Conclusion : The results of examinations using Lowenstein Jensen media showed resistance to Rifampin and Isoniazid antibiotics .

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Biochemical Analysis on Mycobacterium tuberculosis diagnosis: a systematic review Participate in IMSTC 2021 By AMSA-Indonesia

Arranged by : Robert Kristianto

1961050009

Dewa Vighneswara

1961050116

Anastasia Bella Christophila

1861050063

Faculty of Medicine Christian University of Indonesia Batch 2018 and 2019

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INTRODUCTION Bacteria are included in cellular microbes which can be divided into two, namely prokaryotic cells and eukaryotic cells.[1] Bacteria with prokaryotic cells have specific characters, namely, they do not have a nuclear membrane and an organelle membrane, while eukaryotic cells have a nuclear membrane and a nuclear membrane. [1] The structure of each prokaryotic cell and eukaryotic cell, namely prokaryotic cells with capsules, cell walls, pili, fimbriae, flagella, cell membranes, ribosomes, and nucleoid, all of which are present in a fluid called cytoplasm and eukaryotic cells have mitochondria, chloroplasts, endoplasmic reticulum and Golgi bodies, vacuoles, granules, cytoskeleton, alternative forms of cells (spores and conidia, as well as cysts).[1] Live bacteria are used as heterotrophs and parasites. [1] Bacteria classified into two, namely gram-positive bacteria and gram-negative bacteria.[1] Bacteria have several forms, including bacillus, coccus, and spiral.[1] Bacteria that have a bacilliform, one of which is Mycobacterium Tuberculosis. [2,3] Mycobacterium Tuberculosis is mycobacteria or aerobic bacteria that don't form spores. [2,3] Mycobacterium Tuberculosis is called acid-resistant bacillus bacteria, and Mycobacterium Tuberculosis causes tuberculosis and is a significant pathogen in humans. [2,3] There are several techniques to confirm and diagnose a patient with tuberculosis, namely the Ziehl-Neelsen staining technique, culture on Lowenstein Jensen media, PCR, biochemical tests, serology tests.[2,3] Tuberculosis is a disease caused by Mycobacterium Tuberculosis which is one of the oldest diseases that infect humans and is one of the infectious diseases.[3,4] According to data from the World Health Organization (WHO), the one-by third of the world's total population has contracted tuberculosis.[3,4]

Each year an estimated 9 million new cases occur and about 2

million of them die.[3,4] Deaths from tuberculosis infection were higher than those from AIDS and malaria. Children suffer from tuberculosis with the highest proportion of adults. [3,4] Children get infected by adults who have been infected with tuberculosis. [3,4] This disease is the biggest problem today with the prevalence rate that continues to increase.[3,4] The risk factors for infection from tuberculosis, among others, are children infected with active tuberculosis infection, tuberculosis endemic areas, low economy, unhygienic

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environment.[4,5] A baby whose mother is smear-positive for sputum has a high risk of being infected with TB.[4,5]

The closer the baby is to the mother, the more likely the baby is to be

infected with tuberculosis. Children infected with tuberculosis rarely pass it on to each other or adults.[4,5]

Then another factor is the lowest body immunity, including HIV / AIDS infection

and malnutrition, namely the commitment to the role of policymakers and not including access to tuberculosis services so that diagnosis and therapy can be carried out optimally.[4,5] Tuberculosis is highly contagious and is transmitted from person to person through airborne droplets.[4,5] In immunocompetent individuals, microorganisms are usually present in the inflammatory and immune response systems.[4,5] This is known as latent TB infection (LTBI) and there is no clinical evidence of disease.[4,5] When bacilli are inhaled it settles in the periphery of the lung, is often found at the apex of the lung or usually in the superior lobe, and causes nonspecific pneumonitis (pulmonary inflammation).[4,5] Some bacilli travel through the lymph flow and eventually settle in the lymph nodes, where they encounter lymphocytes, initiating an immune response. [4,5] The pulmonary inflammatory process will cause the activation of alveoli macrophages and neutrophils.

[4,5]

The phagocytes engulf the bacilli and initiate the process by

which the body's defense mechanisms isolate the bacilli, preventing the bacilli from spreading.[4,5] However, the bacteria managed to survive because it was able to survive and multiply in macrophages and fight the lysosomes that kill them, which form granulomatous lesions called tubercles.[4,5] The infected tissue in the tubercles then dies, forming a cheese-like material called caseous necrosis.[4,5] Collagen scar tissue then forms around the tubercles, completing the isolation of the bacilli.[4,5] The immune response is complete within ten days, preventing further multiplication of the bacilli.[4,5] When bacilli are isolated in tubercles and the immune system improves, tuberculosis is still alive but in a dormant state.[4,5] The lung is the port d'entrée for more than 98% of cases of TB infection. [4,5] Because of its very small size, the tuberculosis germs in the droplet nuclei are inhaled, can reach the alveolus.[4,5] The entry of tuberculosis germs will be immediately overcome by non-specific immunological mechanisms.[4,5] Alveolar macrophages will phagocyte TB germs and are usually able to destroy most of the TB germs. However, in a minority of cases, macrophages are not able to destroy TB germs and the germs will replicate in macrophages.[4,5] TB germs in macrophages

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that continue to multiply, eventually will form colonies in that place. The first site of the TB germ colony in lung tissue is called GOHN Primary Focus.[4,5] From the primary focus, TB germs spread through the lymph channels to regional lymph nodes, namely lymph nodes that have lymph channels to the primary focus location.[6,9] This spread causes inflammation in the lymph ducts (lymphangitis) and the affected lymph nodes (lymphadenitis). [6,9] If the primary focus is located in the lower or middle lung lobe, the lymph nodes that will be involved are the severe lymph nodes, whereas if the primary focus is located at the apex of the lung, the paratracheal glands will be involved.[6,9] The primary complex is a combination of the primary focus, enlarged regional lymph nodes (lymphadenitis), and inflamed lymph channels (lymphangitis). [6,9] The time taken from the entry of TB germs to the formation of a complete primary complex is known as the TB incubation period. [6,9] This differs from the understanding of the incubation period in other infectious processes, namely the time it takes from the entry of germs to the onset of disease symptoms.[6,9] The incubation period for TB usually lasts 4-8 weeks with a span of 2-12 weeks.[6,9] During this incubation period, germs grow to some 10,000-100,000, which is enough to stimulate a cellular immune response.[6,9] Clinical manifestations of tuberculosis include fatigue, weight loss, later, anorexia (decreased appetite), suffers and which usually occurs in the afternoon. [1,10] Cough with purulent sputum that slowly and more frequently over the course of weeks or months. Night sweats and anxiety sometimes occur.[1,10] Shortness of breath, chest pain, and coughing up blood can occur in advanced disease. [1,10] Examination of Mycobacterium Tuberculosis in sputum can be done by microscopic examination techniques, bacterial culture, PCR, biochemical tests, serology tests. [11,12] Sputum examination is carried out during, morning, during (SPS).[11,12] Sputum testing is a quick, easy, inexpensive, and efficient test that can be performed in almost any microbiology laboratory. [11,12] MATERIAL AND METHODS This type of research uses a systematic review with observation and biochemical analysis related to the diagnosis of tuberculosis. Data collection in this study was obtained from several journals published on Researchgate, Pubmed, and Google Scholar. We use the keyword

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"Mycobacterium tuberculosis, the diagnosis of mycobacterium tuberculosis, biochemical analysis of mycobacterium tuberculosis". From the research results of journal data, we then selected several journals with discussions to fit the topic of our scientific paper.

RESULT From the analysis of several journals that have been obtained, the data required for tuberculosis examination requires a subject in the form of age, gender, duration of treatment and clinical symptoms, personal history of habits, so that an examination is carried out in the form of Ziehl Neelsen's staining examination, culture and GeneXpert examination method culture. MTB / RIF[5,6]. After the culture examination and resistance test were carried out, some specimens grew in the media and specimens that did not grow in the culture media. Some samples were stated as Mycobacteria other than tuberculosis (MOTT), MDR-TB, non-MDR-TB. PCR GeneXpert MTB / RIF examination performed on the study sample showed a negative result of M. tuberculosis and several positive M. tuberculosis samples, from these positive results it was found that M. tuberculosis was sensitive to Rifampin.[5,6]

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Information : MDR-TB = multidrug resistant tuberculosis, BTA = batang tahan asam, ZN = ziehl neelsen, MOTT = mycobacteria other than tuberculosis, MTB = Mycobacterium tuberculosis, PCR = polymerase chain reaction DISCUSSION In patients who are resistant to the antibiotic Rifampicin, it turns out that they can also be resistant to INH antibiotics based on the results of the sensitivity test using the culture method with Lowenstein Jensen media as the gold standard in the examination.[5] Several samples showed sensitivity to the antibiotic Rifampicin on the PCR examination of GeneXpert MTB / RIF, but showed resistance to Rifampicin and INH antibiotics in the culture method sensitivity test, this is called a false negative on the results of the GeneXpert MTB / RIF PCR examination.[5] The GeneXpert MTB / RIF PCR examination assesses mutations in the hot spot region of the rpoB gene that indicate resistance to the antibiotic Rifampicin.[5] Several studies stated that 95% of M. tuberculosis mutated in the hot spot region of the rpoB gene which would cause resistance to the antibiotic Rifampicin, but it is estimated that as much as 5% of M. tuberculosis that is resistant to the antibiotic Rifampicin mutates outside the hot spot region of the rpoB gene.[5] The false negatives that are obtained may be due to mutations outside the hot spot region of the rpoB gene, so further research is needed to prove the cause of this false negative. [5] Another cause of low specificity is the large number of samples that do not grow on Lowenstein Jensen culture media.[5] There were several samples which on the PCR examination of GeneXpert MTB / RIF showed positive M. tuberculosis but did not grow at the time of culture, so they could not be analyzed.[5] Samples that do not grow on this culture media can be caused by the patient with suspected MDR-TB who is undergoing TB therapy which causes the viability of M. tuberculosis to decrease so that it cannot grow in Lowenstein Jensen culture media.[5] Mycobacteria other than tuberculosis or MOTT in 3 of 54 samples grown in Lowenstein Jensen culture media.[5] This may be due to mixed infection with M. tuberculosis complex and

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MOTT, but because MOTT grows faster than that of M. tuberculosis complex, so that the culture results are more MOTT than M. tuberculosis complex.[5] To be able to determine the MOTT, a niacin test was carried out, and the results were negative. Another thing that can cause MOTT is contamination because MOTT can be found in environments such as water, soil, and can colonize normal skin. Based on the validity test above, the examination of the PCR GeneXpert MTB / RIF method used a sputum examination material which had high validity against the gold standard with a sensitivity test of the culture method with Lowestein Jensen media. [5] This method can be used as a screening tool because it has a high sensitivity.[5] CONCLUSION The results of examinations using Lowenstein Jensen media showed resistance to Rifampicin and Isoniazid antibiotics.[5,6] M. tuberculosis bacteria resistant to Rifampicin antibiotics have mutations in the rpoB gene. If there are more sensitive M. tuberculosis, Rifampicin resistance can not be detected.[5,6] REFERENCES 1.

Rahman SA, Singh Y, Kohli S, Ahmed J, Ehtesham NZ, Tyagi AK, et al. Comparative Analyses of Nonpathogenic, Opportunistic, and Totally Pathogenic Mycobacteria Reveal Genomic and Biochemical Variabilities and Highlight the Survival Attributes of Mycobacterium tuberculosis. mBio. 2014;5:1-9.

2.

Kurniati A, Dewi DNSS, Purwani NN. Deteksi cepat dan spesifik Mycobacterium tuberculosis menggunakan Polymerase Chain Reaction. Journal of Vocational Health Studies. 2019;03:83-88.

3.

Susanti D, Kountul C, Buntuan V. Pemeriksaan Basil Tahan Asam (BTA) pada sputum penderita batuk ≥ 2 minggu di poliklinik penyakit dalam BLU RSUP. Prof. Dr. R.D Kandou Manado. Jurnal eCL. 2013;1:1-5.

4.

Endahyani SN, Adi K, Anam C. Histogram dan nilai derajat keabuan citra thoraks Computed Radiography (CR) untuk penderita Tuberculosis (TB) Paru-paru. JSM. 2010;18:118.

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5.

Ramadhan R, Fitria E, Rosdiana. Deteksi Mycobacterium tuberculosis dengan pemeriksaan mikroskopis dan Teknik PCR pada penderita Tuberkulosis Paru di Puskesmas Darul Imarah. SEL Jurnal Penelitian Kesehatan. 2017;4:73-80.

6.

Delogu G, Sali M, Fadda G. The biology of Mycobacterium tuberculosis infection. Mediterr J Hematol Infect Dis. 2013;5.

7.

Smith I. Mycobacterium tuberculosis pathogenesis and molecular determinants of virulence. Clin Microbiol Rev. 2003;16:463-496.

8.

Sakamoto K. The pathology of Mycobacterium tuberculosis infection. Veterinary Pathology. 2012;49:423-439.

9.

Huether SE, McCance KL. Buku Ajar Patofisiologi. Edisi 6. Elsevier. 2019

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Wilburn KM, Fieweger RA, VanderVen BC. Cholesterol and fatty acids grease the wheels of Mycobacterium tuberculosis pathogenesis. Pathogens and Disease. 2018;76:1-14.

11.

Dalberto PF, Junior VR, Falcao VCA, Pinto AFM, Abbadi BL, Bizzaro CV, et al. Assessing the role of deoD gene in Mycobacterium tuberculosis in vitro growth and macrophage infection. Microbial Pathogenesis. 2018;119:60-64.

12.

Rao M, Ippolito G, Mfinanga S, Ntoumi F, Manu DY, Vilaplana C, et al. Latent TB Infection (LTBI) - Mycobacterium tuberculosis pathogenesis and the dynamics of the granuloma battleground. International Journal of Infectious Disease. 2019;80:558561.

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The Performance of Serological Tests of Anti-PGL1, Anti-NDO-LID, and Anti-MMP-II for Early Detection in Individuals with Household Contact with Leprosy in Indonesia: A Literature Review Author: Graceanne Sheridan

(22010118120010)

Naily Fairuz Salma El Milla

(22010119140106)

Prudence Lucianus

(22010119130112) ABSTRACT

Introduction Leprosy, or Morbus Hansen’s disease, is a tropical disease caused by Mycobacterium leprae. Indonesia is the third country with the most leprosy cases after Brazil and India. WHO recommends clinical evaluation of leprosy household contacts, health education, case diagnosis, and treatment as part of the disease control strategy to break the transmission chain so that leprosy elimination will happen naturally over time. The easiest method to detect new cases is by serological testing, but the best antigen(s) for such a test is still unclear. Therefore, it is necessary to employ more sensitive serological parameters in order to investigate Mycobacterium leprae infection among household contacts in Indonesia.

Materials and Method The literature review was conducted by acquiring sources from scientific databases such as Google Scholar, PubMed, ScienceDirect, ResearchGate using keywords: “Serological Test Anti-PGL-1” AND “Leprosy Detection”; “Serological Test Anti-NDO-LID” AND “Leprosy Detection”; “Serological Test Anti-MMP-II” AND “Leprosy Detection”; “Serological Test for Early Detection of Leprosy in Household Contact”; “Serological Test” AND “ELISA”. The studies are included if they are published in English between the year 2000-2020, correlated to the aim of this study, and do not meet certain exclusion criteria.

Result and Discussion Early detection of infection by M. leprae, followed by effective treatment, is critical to reduce disease progression. Sensitive and specific tools for early detection of infection are critical for an effective leprosy elimination campaign. PGL-1, MMP-II, and NDO-LID each have

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their own advantages and limitations, yet the best antigen(s) for such a test is still unclear. A combination among these antibodies is proven to be more accurate in detecting leprosy.

Conclusion We strongly suggest a combination of anti-PGL1 salivary IgA/IgM and serum IgG/IgM, anti-NDO-LID serum IgG, and anti-MMP-II serum IgG/IgM measurements to be used for early detection of leprosy patients and their household contacts in Indonesia.

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The Performance of Serological Tests of Anti-PGL1, Anti-NDO-LID, and Anti-MMP-II for Early Detection in Individuals with Household Contact with Leprosy in Indonesia: A Literature Review

Author: Graceanne Sheridan

22010118120010

Naily Fairuz Salma El Milla

22010119140106

Prudence Lucianus

22010119130112

Asian Medical Students’ Association Indonesia (AMSA-Indonesia) 2020

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I. Introduction A. Background Leprosy, or Morbus Hansen’s disease is a tropical disease caused by Mycobacterium leprae, transmitted through close and prolonged contact through nasal mucosa.1 The clinical and histopathological manifestation of leprosy could vary, due to the various cellular immune responses of the host. The human immunity against leprosy is still inefficient as the cellular immunity might contribute to lesion onset, while humoral immunity does not provide enough protection against the antigen. Leprosy control by multidrug therapy (MDT) and BCG vaccination of household contacts (HHCs) had greatly decreased the number of leprosy cases, yet not completely.1,2 Every year, more than 200,000 new leprosy cases are registered globally. This stable number over the past 8 years indicates slow progress towards complete elimination of leprosy.3 Indonesia is the third country with the most leprosy cases after Brazil and India. Based on Peraturan Menteri Kesehatan Republik Indonesia Nomor 11 Tahun 2019, there are still hundreds of cities where leprosy have not been eliminated completely. Since the use of MDT, the number of leprosy cases have decreased drastically from 5.2 for every 10,000 citizens in 1981 to 0.9 for every 10,000 citizens in 2001.5 The World Health Organization (WHO) has set a target to interrupt leprosy transmission globally by 2020, with the leprosy elimination standard of 1 for every 10,000 citizens.4 However, since 2001, leprosy cases in Indonesia have been increasing again with 15,910 cases of leprosy found in 2017.5 This might be caused by low awareness of leprosy cases, stigma and discrimination towards leprosy, health centers lacking the capacity to make early diagnosis and treatment, and the lack of attention given to leprosy cases due to the resolving of other diseases, such as tuberculosis and HIV. Leprosy household contacts (HHCs) are at high risk of developing the disease, as MB patients are thought to be the principle source of infection.6 Early detection and MDT are crucial to achieve WHO’s goal of zero transmission. However, this is difficult to do because it is impossible to cultivate M. leprae in vitro, and the clinical forms vary. Physical examination does not identify the early

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stages of the disease when clinical manifestations are rarely present, and there is no gold standard method to guide clinicians.2,6,7 Therefore, it is necessary to employ more sensitive tools in order to investigate M. leprae infection among household contacts. Serological rapid tests were used to aid clinical diagnosis because they are easy to perform, cheaper than molecular tests, and do not require special equipment. Simple lateral flow test and dipstick assays are used to classify leprosy patients and identify contacts with risk of developing leprosy. Phenolic Glycolipid-I (PGL-I) is a Mycobacterium leprae-specific antigen responsible for its immunological specificity, with serum anti-PGL1 IgM as the most studied antibody.2 Major Membrane Protein-II (MMP-II) and Natural Disaccharide OctylLeprosy IDRI Diagnostic rapid tests (NDO-LID) are species-specific antigens used for leprosy serodiagnosis. MMP-II from M. leprae cell membrane, is one of the antigenic molecules capable of activating APCs and T cells, while NDO-LID is a semi-synthetic antigen using disaccharide (ND) attached to the octyl (O) radical, which mimics PGL-1, conjugated to form the LID, capable of recognizing IgM and IgG antibodies against M. leprae.7 In this study, we compare the performance of anti-PGL1, anti-NDO-LID, and anti-MMP-II in detecting M. leprae in leprosy household contacts and their index cases. B. Objective The aim of this study is to compare Mycobacterium leprae subclinical infection detection in household contacts (HHCs) group through serological parameters of Anti-PGL1 salivary IgA/IgM, serum IgG/IgM, Anti-NDO-LID serum IgG, and anti-MMP-II serum IgG/IgM.

II.

Materials and Methods The literature review was conducted by acquiring sources from Google Scholar, PubMed, ScienceDirect, and ResearchGate. Keywords, such as “Serological Test AntiPGL-1” AND “Leprosy Detection”; “Serological Test Anti-NDO-LID” AND “Leprosy Detection”; “Serological Test Anti-MMP-II” AND “Leprosy Detection”; “Serological Test for Early Detection of Leprosy in Household Contact”; were used to search the

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literatures. The literatures are included if they meet certain criteria: (1) written in English, (2) published in between the year 2000-2020, and (3) examine the early detection of leprosy using serological tests of Anti-PGL1 salivary IgA/IgM, or serum IgG/IgM, or Anti-NDO-LID serum IgG, or anti-MMP-II serum IgG/IgM. In addition, the studies are excluded: (1) by the abstract if older than 2000, incompatible language, or irrelevant, or (2) due to duplication, or (3) not correlated to the aim of this study (this study conducted in purpose of early detection in household contact and not intervention).

Figure 1. Flow diagram of study selection

III.

Results and Discussion Besides the use of multidrug therapy to patients and BCG vaccination for household contacts (HHCs), clinical evaluation of leprosy HHCs or patients’ early detection and health education are recommended to break the transmission chain until leprosy elimination happens naturally. Contact with MB patients is accepted to be responsible for bacilli transmission.2,6,7 A survey for new cases is needed to control the disease spread. The easiest method is by serological tests, but the best antigen(s) for such a test is still unclear.

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No.

1

2

3

4

5

6

7

Author

Year

E Cabral PB, et al.2

Richardus RA, et al.9

Fabri AC, et al .12

Method

Result

Conclusion

Salivary anti-PGL-1 IgA and IgM and serum anti-PGL-1 IgG showed good correlation ofs Serum anti-PGL1 IgG/IgM and salivary anticontacts and index cases (p < 0.01, p < 0.005, PGL1 IgA/IgM was investigated using an and p < 0.0001, respectively). This was not It was strongly suggested that ELISA, and nasal carriage of M. leprae for serum anti-PGL1 IgM (p > 0.05). A high serum IgG/IgM and salivary antiDNA was detected by PCR, in leprosy 2013 frequency of anti-PGL1 IgM positivity was PGL1 IgA/IgM measurements are household contacts of paucibacillary (PB) found in IgG-negative samples (p < 0.0001), used to follow leprosy household and multibacillary (MB) household leprosy where IgM antibodies were also positive in contacts. patients, their index cases, and in persons most of the samples. No volunteers in a low living in a low endemic city. endemic city had seropositivity IgG; but, two showed positivity for anti-PGL1 IgM. Between 2002 and 2009, fingerstick blood Anti-PGL-I Ab levels at intake did not from leprosy patients' contacts without significantly differ between contacts who clinical signs in Bangladesh were collected. developed leprosy during the study and those Analysis of anti-PGL-I Ab levels for 25 2017 who stayed healthy. Moreover, anti-PGL-I contacts who developed leprosy during follow-up and 199 contacts not diagnosed serology was unlikely in this population as no correlation was found between anti-PGL-I Ab with leprosy, was performed by ELISA levels at intake and the onset of leprosy. after bloodspots elusion from filter paper. (Clinical Trial) A higher proportion of seropositivity for all antigens was observed in MB leprosy patients Enzyme-linked immunosorbent assays and their HHCs compared with PB leprosy (ELISA) were used to analyze the antigenpatients and their HHCs. Anti-PGL-1 tests specific antibody responses of 94 leprosy were more frequently positive than anti-NDOcases, 104 household contacts of cases and HSA tests. The LID-1 and NDO-LID antigens 2.494 individuals from the general showed greater capacity to identify HHCs and population. individuals from the general population infected with M. leprae .

In Bangladesh, an endemic area, no association was observed between anti-PGL-I Ab levels and onset of disease, urging the need for a more specific biomarker for early detection of leprosy in this area. Tests that measure Ab against LID1, NDO-LID, NDO-HSA and PGL1 were effective for MB leprosy detection. Anti-LID-1 and antiNDO-LID were more effective than anti-NDO-HSA to identify subclinical infection. NDO-LID is important for the surveillance of HHC and the general population.

Jian L, et al. 16

The ability of antigens NDO-BSA and LID- Antigens detected by sera from MB patients 1 (ML0405 and ML2331) and the conjugate had sensitivities of 97.3%, 97.3% and 98.6% of those, NDO-LID, was evaluated to detect for NDO-BSA, LID-1 and NDO-LID, 2019 antibodies in the sera of 113 leprosy respectively. Among PB patients, antigens patients and 166 control individuals in detected antibodies in 74.4%, 56.4% and Yunnan province in southwest China. 69.2% of serum samples, respectively. (Diagnostic Test) Detection with NDO-LID most efficient.

Kai M, et al. 15

The results showed that 85% of MB patients The effectiveness of the enzyme-linked and 48% of PB patients were positive by immunosorbent assay (ELISA) was The epidemiological study MMP-II. Positivity rates for leprosy patients evaluated, by using the MMP-II antigen for conducted in Vietnam suggests that were higher with MMP-II than with PGL-I. 2008 detecting antibodies in leprosy patients and serological testing with MMP-II HHCs showed low positivity rates, but patients’ contacts in the mid-region of would be beneficial in detecting medical staff members showed high positivity Vietnam and compared to the results to leprosy. rates, with MMP-II. This shows that MMP-II those for the PGL-I method. is a better index marker than PGL-I.

Wang H, et al. 14

Antibodies to PGL-I and MMP-II were evaluated for serodiagnosis of leprosy in 2015 Southwest China, and the role in predicting the occurrence of the disease in household contacts of leprosy was examined.

13

Sera from patients and healthy individuals were collected with informed consent and the anti-MMP-II antibody levels of the sera were measured by ELISA. The study was 2009 conducted at South Sulawesi and Bali. The study population included 40 each of multibacillary leprosy and paucibacillary leprosy patients, 30 tuberculosis and 16 patients with typhoid. (Diagnostic Test)

Hatta M, et al

Using PGL-I, 94.9% of MB leprosy and 38.9% PB leprosy could be detected, while using MMP-II, 88.1% of MB and 61.1% of PB patients were positive. By combining the 2 tests, 100% of MB patients and 72.2% of PB patients were test-positive. Among HHCs, 28.3% and 30% had positive levels of PGL-I and MMP-II Abs, respectively. 7 out of 21 HHCs, developed leprosy during a 3 year follow-up. Anti-MMP-II antibody levels in Indonesian individuals were evaluated. The cut-off value was determined from ROC curve as 0.124 using the O.D. titers for patients with MB leprosy, so that the sensitivity of the test was 97.5% and the specificity of healthy individuals as control was 98.4%. With the determined cut-off values, 98% of MB leprosy and 48% of PB leprosy patients had positive levels of anti-MMP-II antibodies, 13% of patients with typhoid and 22% of the HHCs of MB leprosy had positive levels of antiMMP-II antibodies.

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The results indicated the use of NDO-LID in assisting in the diagnosis of PB and MB leprosy patients and that those antibody detection assays represent powerful diagnostic tools.

Measuring anti-PGL-I and antiMMP-II antibodies could facilitate early detection of leprosy. The combination of NDO-BSA and MMP-II is able to detect and monitor leprosy patients and HHCs. It could enhance surveillance and would be important in trials of new interventions and treatments.

The results suggested that measuring anti-MMP-II antibody levels could facilitate the detection of leprosy in endemic countries.


8

9

10

Marçal PH, et al. 17

Sera from healthy controls, paucibacillary (PB) and multibacillary (MB) leprosy patients, and their respective household contacts, were evaluated for the presence of antigen-specific IgM, IgG, and IgG subclass 2018 antibodies by enzyme-linked immunosorbent assay (ELISA). The sensitivity and specificity of each ELISA were evaluated by receiver operating characteristic (ROC) curve analysis (Diagnostic Test).

Serum IgM Abs against NDO-HAS, IgG Abs against LID-1, and IgG/M Abs against NDOLID are increased in MB patients. There is a It was indicate that serological selective increase in IgG1 and IgG3 tests based on the detection of antibodies against LID-1 and NDO-LID in antigen-specific IgG1 antibodies MB patients, showing that these antibody are a useful tool to differentiate isotypes are suitable for differentiating MB MB from PB patients, and indicate and PB patients. ROC curve shows an the enhanced performance of the improved capacity for diagnosing MB leprosy LID-1 and NDO-LID antigens in patients using the detection of IgG antibodies, the serodiagnosis of leprosy. particularly the IgG1 isotype, specific to LID1 and NDO-LID over the performance levels attained with NDO-HSA.

Serrano-Coll H, et al.18

An observational cross-sectional study was conducted involving sampling from 82 children and adolescents who had household contact with leprosy patients diagnosed in the last 5 years. Data were analyzed through bivariate analysis made by 2019 applying a Pearson x2 test for qualitative variables, while quantitative variables, were analyzed using a Student’s t-test or MannWhitney U test. Multivariate analysis used a multiple regression and binomial logistic approach.

Bivariate analysis demonstrated that antibody titers against NDO-LID were greater in M. leprae transmission persists children and adolescents with a low among young Colombians, and this socioeconomic status that had: lived in is associated with social and vulnerable areas of the UAChR region; eaten environmental conditions. An armadillo meat; exposed over 10 years to an intensification of efforts to identify index case and not received BCG new leprosy cases in vulnerable immunization. Moreover, a multivariate and forgotten populations where analysis showed that residing in the UAChR M. leprae transmission continues region has a strong association with a greater therefore appears necessary. possibility of M. leprae infection.

Wang L, et al. 19

Epidemiology of leprosy in southwest China is analyzed (Retrospective Study) to understand the transmission pattern and improve control programs. From 207 2018 countries, 2,353 new cases of leprosy were interviewed. A total of 53 from 6643 HHCs developed leprosy, and the incidence rate of leprosy in the HHCs was 364/100,000 person-years.

NDO-BSA have higher positive rates than MMP-II and LID-1. By combining antigens, 88.4% of MB leprosy and 59.9% in PB leprosy were detected. Combining NDO-BSA and MMP-II could detect 79.8% MB patients and 47.6% of PB patients. Combining NDOBSA and LID-1 was more effective to detect leprosy patients with 86.3% MB and 56.5% PB. This shows that combining different antigens could help in the diagnosis and monitoring of leprosy.

Combining NDO-LID and MMP-II could detect the most leprosy patients. Serological tests detecting Abs against multiple antigens is recommended. Emphasis should be on HHCs within leprosy patients to provide early diagnosis and treatment, disrupt transmission of M. leprae and provide control of the leprosy situation.

In post-treatment reactions, patients with positive PGL-I serology when released from treatment showed a greater chance of developing reactions compared to those with negative serology. A study conducted in Brazil observed a significant association between patients who had seropositive anti-PGL-I and a higher risk of relapse.8 In addition, patients with more anti-PGL-1 IgM at the onset of treatment have a higher risk of developing reactions, thus identifying patients for monitoring and early treatment may reduce nerve damage and disability. It is strongly recommended that serum anti-PGL-1 and salivary anti-PGL-1 measurements be used to follow up leprosy HHCs.2 Anti-PGL-1 in HHCs can identify preclinical-stage leprosy. There are more leprosy contacts in the group with positive anti-PGL-1 levels than in the test-negative group; however, only few actually developed leprosy. A study in Bangladesh analyzing the antiPGL-I Ab levels in leprosy patient contacts shows no association between anti-PGL-1 antibody levels and onset of disease.9 The salivary anti-PGL-1 antibodies might indicate infection, but not the disease. A study in Brazil found that 24 out of 45 HHCs positive for salivary antibodies did not have serum antibodies (they were infected with M. leprae

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but might not acquire the disease), while 64 out of 90 HHCs negative for salivary antiPGL-1 antibodies had serum antibodies. The maintenance of long-term immunological memory in the mucosal surfaces is difficult, since the bacteria can move into the systemic circulation, reducing the bacteria in the nose, so that secretory antibodies will decrease and serum antibody levels will increase.2 Unfortunately, diagnosing only on anti-PGL-I seropositivity would have more than half of the new leprosy cases undetected. A study in Brazil and the Philippines showed that anti-PGL-1 seropositive contacts have a higher risk of developing leprosy compared to seronegative contacts. However, of those that developed leprosy, half remained seronegative. These show that only measuring anti-PGL-1 antibodies is not enough to predict the development of leprosy.10 A study found that the detection of anti-NDO-LID antibodies appears to be better than other serological tests, such as those tests detecting antibodies against PGL-1.11 A study conducted by Leturiondo AL, et al. in 2019 found that while PGL-1 showed higher sensitivity in detecting MB leprosy patient, NDO-LID test showed higher specificity and accuracy compared to PGL-1. Relative to the PGL-1 antigen, the NDO-LID conjugate demonstrated a greater potential to identify infected HHC and individuals from the general population who were infected with M. leprae.12 Although the capacity of serological tests in the diagnosis of leprosy is limited, both anti-PGL 1 and anti-NDOLID are still important to aid clinical diagnosis as they could exclude leprosy as a possible cause of a skin lesion from a negative result of LID-1 or NDO-LID test, especially in endemic areas where other common dermatological conditions are often detected.7 MMP-II is a M. leprae component capable of stimulating CD4+ and CD8+T cells. The sera from leprosy patients have higher IgG titer to MMP-II. The measurement of both anti-PGL-1 and anti-MMP-II antibodies could facilitate early detection of leprosy. However, the positivity rate of anti-MMP-II was higher than PGL-1 with significant difference in detecting both MB and PB leprosy.13 A study compared the sera among Japanese and Indonesian leprosy patients showed that MMP-II is superior to PGL-I. Indonesians had higher positive rates due to their highly active disease state and that sera were collected before the start of chemotherapy. In contrary, a study in Vietnam showed

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that PGL-1 is superior to MMP-II. This is probably due to healthy Vietnamese having high anti-PGL-I antibody titers. PGL-I is a glycolipid component retained in infected cells for a long time after initial exposure, causing healthy individuals in endemic areas to have high anti-PGL-I antibody titers. In individuals who have been exposed to M. leprae but have not developed leprosy, antigen-presenting cells expressing MMP-II might be eliminated from the body by immune cells and thus lack the ability to produce antiMMP-II antibodies. By combining the 2 tests and considering either test positive as positive, 100% of MB patients and 72.2% of PB patients were found to test positive.13 ELISA tests are generally sensitive and specific with a suitable immunogenic antigen. In leprosy-endemic countries, simpler tests like the dip-stick test are necessary, yet still not as sensitive since detection is not feasible with low antibody level. HHCs should be carefully monitored serologically and for other clinical signs in order to initiate chemotherapy. Attention should also be given to patients who are HIV-positive or immunocompromised, since their immune system may not produce enough antibodies for detection. The development of sensitive, user-friendly tools for the detection of antiMMP-II antibodies, may further contribute to early detection of leprosy.13,14 The combination of anti-PGL-1 and anti-MMP-II is useful for detection and monitoring of leprosy patients and their HHCs. If both MMP-II and PGL-I antibodies could be measured simultaneously, the sensitivity of the assay system could be increased. PGL-I is a sugar antigen (IgM Ab) and MMP-II is a protein antigen (IgG Ab); a combination of these antibodies could lead to more accurate detection of leprosy.13,14,15

IV.

Conclusion One type of serodiagnosis is not enough to detect leprosy cases. A combination of anti-PGL-1 and anti-MMP-II could detect and monitor leprosy patients and their HHCs. Anti-NDO-LID antibodies could be used to detect the neurological condition of patients. The capacity of serological tests in the diagnosis of leprosy is limited, yet they are still important to aid clinical diagnosis. We strongly suggest a combination of anti-PGL1 salivary IgA/IgM and serum IgG/IgM, anti-NDO-LID serum IgG, and anti-MMP-II serum IgG/IgM measurements to be used for early detection of leprosy patients and their household contacts in Indonesia.

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PGL-I serology in contacts of leprosy patients in Bangladesh. PLoS neglected tropical diseases. 2017 Dec 11; 11(12): e0006083. 11. Serrano-Coll H, Muñoz M, Camilo Beltrán J, Duthie MS, Cardona-Castro N. Anti-natural octyl disaccharide-leprosy IDRI diagnostic (NDO-LID) antibodies as indicators of leprosy reactions and neuritis. Transactions of The Royal Society of Tropical Medicine and Hygiene. 2017 Mar 1; 111(3): 125-31. 12. Fabri AD, Carvalho AP, Araujo S, Goulart LR, de Mattos AM, Teixeira HC, Goulart IM, Duthie MS, Correa-Oliveira R, Lana FC. Antigen-specific assessment of the immunological status of various groups in a leprosy endemic region. BMC infectious diseases. 2015 Dec; 15(1): 1-9. 13. Hatta M, Makino M, Sabir M, Tandirogang N, Rusyati LM, Kai M, Fukutomi Y, Miyamoto Y, Mukai T, Maeda Y. Detection of serum antibodies to M. leprae major membrane protein-II in leprosy patients from Indonesia. Leprosy review. 2009 Dec 1; 80(4): 402. 14. Wang H, Liu W, Jin Y, Yu M, Jiang H, Tamura T, Maeda Y, Makino M. Detection of antibodies to both M. leprae PGL-I and MMP-II to recognize leprosy patients at an early stage of disease progression. Diagnostic microbiology and infectious disease. 2015 Nov 1; 83(3): 274-7. 15. Kai M, Phuc NH, Thi TH, Nguyen AH, Fukutomi Y, Maeda Y, Miyamoto Y, Mukai T, Fujiwara T, Nguyen TT, Makino M. Serological diagnosis of leprosy in patients in Vietnam by enzyme-linked immunosorbent assay with Mycobacterium leprae-derived major membrane protein II. Clinical and Vaccine Immunology. 2008 Dec 1; 15(12): 1755-9. 16. Jian L, Xiujian S, Yuangang Y, Yan X, Lianchao Y, Duthie MS, Yan W. Evaluation of antibody detection against the NDO-BSA, LID-1 and NDO-LID antigens as confirmatory tests to support the diagnosis of leprosy in Yunnan province, southwest China. Transactions of The Royal Society of Tropical Medicine and Hygiene. 2020 Feb 7; 114(3): 193-9. 17. Marçal PH, Fraga LA, Mattos AM, Menegati L, Coelho AD, Pinheiro RO, Sarno EN, Duthie MS, Teixeira HC. Utility of immunoglobulin isotypes against LID-1 and NDO-

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LID for, particularly IgG1, confirming the diagnosis of multibacillary leprosy. Memórias do Instituto Oswaldo Cruz. 2018; 113(5). 18. Serrano-Coll H, Mora HR, Beltrán JC, Duthie MS, Cardona-Castro N. Social and environmental conditions related to Mycobacterium leprae infection in children and adolescents from three leprosy endemic regions of Colombia. BMC infectious diseases. 2019 Dec 1; 19(1): 520. 19. Le W, Haiqin J, Danfeng H, Ying S, Wenyue Z, Jun Y, Li X, Tiejun S, Limei S, Jie L, De W. Monitoring and detection of leprosy patients in Southwest China: A retrospective study, 2010–2014. Scientific reports. 2018 Jul 30; 8(1): 1-8.

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Observation on: "One Health Approach in Tackling Tropical Diseases and Future Pandemics"

Rezky Ainun Ihsan, Chairul Fikri, Alifyah Alza A. Latuconsina

Faculty of Medicine, Indonesian Muslim University, Makassar, Indonesia

Abstract Neglected tropical diseases (NTDs) have long been overlooked in the global health agenda. They are intimately related to poverty, cause important local burdens of disease, but individually do not represent global priorities. Yet, NTDs were estimated to affect close to 2 billion people at the turn of the millennium, with a collective burden equivalent to HIV/AIDS, tuberculosis, or malaria. A global response was therefore warranted. The global response to neglected tropical diseases has been mounted to expressly help the poor and pull their poverty-related health problems out of neglect. Driven by novel thinking and boosted by strong public-private partnership the effort has taken proportions that are unmatched in scope today.Yet there is no room for complacency. All neglect has not been resolved, and despite unprecedented progress the job is not finished. It is hoped that during the coming decade the global response will further be able to build on successes achieved today, align with the new global health and development frameworks while keeping very focused attention on the development of novel products, the filling of knowledge gaps associated with implementation, and the generation of evidence-based science from field and laboratory for NTDs that are still lagging behind. It is also hoped that at the renewal of the London Declaration commitment, enough resources can be mobilized to see this global response in all its aspects through to its projected end in 2030. Keywords: Neglected tropical diseases, HIV/AIDS, tuberculosis, malaria

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manage the scaling up and Introduction

sustainment of NTD interventions

The World Health Organization

globally, and develop novel products

(WHO) conceived an innovative

and implementation strategies for

strategy in the early 2000s to combat

NTDs that are still lagging behind.

NTDs as a group of diseases, based on a combination of five public health

The combination of the WHO NTD

interventions. Access to essential

roadmap and the London Declaration,

NTD medicines has hugely improved

together with enhanced commitment

thanks to strong public-private

by endemic countries has been game-

partnership involving the

changing for the scaling up of NTD

pharmaceutical sector. The

interventions. In 2012, 700 million

combination of a WHO NTD roadmap

people were reached with NTD

with clear targets to be achieved by

treatments, representing less than

2020 and game-changing partner

37% of the 1.9 billion at risk. By

commitments endorsed in the London

2015, the number of people reached

Declaration on Neglected Tropical

had increased to 980 million, with the

Diseases, have led to unprecedented

one billion effectively being crossed

progress in the implementation of

as of 2016 onwards, for three years in

large-scale preventive treatment, case

a row. In 2018, 1.12 billion people

management and care of NTDs. The

were reached representing close to

coming decade will see as challenges

65% of those at risk, at which yearly

the mainstreaming of these NTD

calculation of populations and

interventions into Universal Health

coverages have taken into account the

Coverage and the coordination with

ongoing population expansion in age

other sectors to get to the roots of

groups eligible for treatment.

poverty and scale up transmissionbreaking interventions. Chinese

After several years of high coverage

expertise with the elimination of

with preventive treatment, NTDs

multiple NTDs, together with poverty

such as lymphatic filariasis, blinding

reduction and intersectoral action

trachoma and onchocerciasis are

piloted by municipalities and local

being eliminated. This has led to

governments, can serve as a model for

already 400 million people being

the latter. The international

freed of those diseases and not

community will also need to keep a

requiring preventive treatments

specific focus on NTDs in order to further steer this global response,

anymore. As a result, 31 countries 348

have eliminated at least one NTD


since 2012, as compared to only 13

systematic data collection and

during the entire pre-London

monitoring of progress has allowed to

Declaration period.

know where the worlds neediest are, to track equitable access to preventive

Considerable progress has also been

treatments, and to hold countries

made with mapping of NTDs, which

accountable. As an example, a recent

brought up the number of people at

collaborative initiative between

risk from 1.5 billion in 2016 to 1.75

Uniting to Combat NTDs, the WHO

billion in 2018. Mapping efforts

including ESPEN, and the

included the largest infectious

Organization of African Unity

disease survey in history – the global

(OAU), like the Africa Leaders’

trachoma mapping project. It

Malaria Alliance, has introduced a

collected data from

combined coverage score for the five

2.6 million people across 29

most prevalent NTDs. This aggregate

countries and, in turn, served as a

coverage figure that reflects a

model for region-wide mapping of

country’s performance in

the other four most prevalent NTDs

implementing large scale preventive

(lymphatic filariasis, onchocerciasis,

treatment is reviewed every year by

soil- transmitted helminthiasis,

African Heads of State at the OAU

schistosomiasis and trachoma) in

General Assembly. In the three years

Africa by the Expanded Special

for which the NTD score has been

Project for the Elimination of

calculated, 2015, 2016 and 2017,

Neglected Tropical Diseases

great progress has been achieved,

(ESPEN). ESPEN was established

with 15 OAU member countries

in 2016, following the closure of the

having achieved the WHO

African Programme for

recommended coverage of 75% or

Onchocerciasis Control, in the spirit

more for all five NTDs in 2017, as

of public-private partnership

compared to only 3 in 2015. The

between the WHO Regional Office

number of countries having achieved

for Africa, endemic countries and

between 25 and 74% coverage

NTD partners in an effort to

increased from 11 to 14 over the

mobilize political, technical and

period 2015–2017, while the number

financial resources to accelerate the

of countries with coverage below

elimination of Neglected Tropical

25% decreased from 34 to 2o.

Diseases in sub-Saharan Africa. The innovative and intensified Expanded disease mapping,

349

disease management (IDM) diseases,


such as African sleeping sickness,

novel treatments such as NECT

Buruli ulcer, Chagas disease, leprosy

(nifurtimox-eflornithine combination

and leishmaniasis, are NTDs for

treatment, merging two already

which cost-effective control tools did

existing drugs), and later oral

not exist and large-scale use of

fexinidazole. Complex but well-

existing tools could not be envisaged.

organized logistics have ensured

These diseases need to be managed

distribution of medicines down to

within the primary health-care

peripheral health care facilities. As a

system. Yet, the recent history of

result, the number of reported cases

strong public-private partnership

has decreased to 977 cases in 2018, a

driven by novel thinking has proven

more than 95% case reduction since

that these complex diseases can be

2000. This was accompanied by a

lifted out of neglect, and ultimately

substantial decrease in the number of

even be eliminated as public health

people at high or moderate risk of

problems. A prime example of the

contracting sleeping sickness in

former is Buruli ulcer, for which a

previously highly endemic areas. The

good decade ago management

2018 figures are already well below

consisted solely of aggressive

what was targeted by the WHO NTD

surgery and for which now an early

roadmap in terms of “elimination a

diagnostic and oral treatment are

public health problem” by the year

available

2020. The ongoing development of oral acoziborole that potentially could

The latter is illustrated by the

be given as a single-dose treatment

unprecedented progress made with

opens perspectives to interrupt

sleeping sickness elimination.

transmission of sleeping sickness in

Because of a breakdown of systematic

the coming decade.

control programmes, the disease had resurged from below 5000 reported

Three high-burden countries —

cases per year in the early 1960s to

Bangladesh, India and Nepal — have

close to 40.000 cases per year, mostly

teamed up to eliminate this deadly

late- stage disease, by the late 1990s.

disease as a public health problem by

Partnering between WHO, the

2020. This initiative has been built

pharmaceutical sector, endemic

on robust involvement of national

countries, nongovernmental

health services and strong

organizations and newly established

international collaboration, having

PDPs has led to transformative action in fast-tracking the development of

350

taken to scale a combination of early diagnosis and systematic treatment


with donated liposomal amphotericin

‘medical’ NTD interventions into

B (AmbisomeR) and vector control.

primary health care and making sure

Even though some challenges

they are part of the Universal Health

remain, the perspective for

Coverage (UHC) package in

elimination has become real.

poverty-stricken areas; and (ii) coordinating with other sectors to

Materials and Methods

scale up transmission-breaking interventions. NTDs are diseases of

From MDGs to SDGs: new

poverty and efforts to eliminate them

challenges and opportunities for

need to get to the roots of that

NTDs. Even though NTDs were not

poverty NTDs can therefore be used

specifically mentioned in the

as an indicator to attract

Millennium Development Goals

development to where it is most

(MDGs), the successful scaling up of

needed and will have most impact.

‘medical’ NTD interventions was

This perspective was strongly voiced

very much in line with progress

during The Second Global Partners

achieved for HIV/AIDS, tuberculosis

Meeting on NTDs in WHO and

and malaria. Sustained

WHO’s Fourth Report on Neglected

implementation and pivotal

Tropical Diseases.

combination with interventions impacting transmission, as already

Countries that have made major

strongly recommended by WHO in

strides against poverty during the

2005, have highlighted the potential

MDG era, such as China, have used

for large scale elimination of NTDs.

this approach since the early 2000s. Best documented for the elimination

The international commitment, in

of schistosomiasis, a disease that has

2015, towards a broader

had high political priority since the

development agenda (the Sustainable

founding of the People’s Republic of

Development Goals, SDGs) with a

China in 1949, such integrated,

strong focus on equity (leaving no

multidisciplinary approach to disease

one behind), provided new

control combined environmental

opportunities for NTDs to promote

improvements with industrial,

cross-sectoral action and thus

agricultural and water resource

fundamentally prevent transmission.

development projects to reduce

The road towards 2030 therefore

disease transmission while boosting

presents two major challenges for NTDs: (i) mainstreaming the

local economic development. Key 351

elements of success have been: (i)


strong national policies in favour of

trematodiasis, rabies, scabies and

multidisciplinary disease control; (ii)

taeniasis/cysticercosis. Some NTDs

intersectoral action for health and

such as cutaneous leishmaniasis,

development, piloted by

mycetoma and deep mycoses still

municipalities and local

have no first line, oral medicines

governments; and (iii) a strong

hampering widespread access to early

emphasis on equity and poverty

treatment and care. Snakebite

reduction in areas where it was most

envenoming would require a vigorous

needed. Lessons can and should be

transformational investment in the

learned from the Chinese experience

development of heat- stable,

in eliminating NTDs, including its

polyvalent antivenoms to make them

concern for continuously updating

fully accessible in resource-poor

strategies and interventions, and

peripheral settings.

maintaining surveillance-response systems at all levels, if one wishes to

In the current global health

achieve sustainable elimination of

environment, with NTDs not having

NTDs in the next decade.

a “focused” funding mechanism such as GAVI (The Global Alliance for

While it is expected that domestic

Vaccines and Immunisation) or the

funding for NTDs will increase and

Global Fund Against HIV/AIDS,

approach the levels required to cope

Tuberculosis and Malaria, and with

with the residual burden of NTDs

international donors tending to move

towards 2030, some earmarked

away from earmarked funding, the

funding for NTDs will remain crucial

risk is that local priorities of poverty

over the coming decade to further

such as NTDs may slide back into

scale up implementation, to build

neglect, as has been the case during

widespread NTD capacity, and to take

the “Health for All by the year 2000”

care of required innovation and

era.

product development. And the needs for the latter can’t be underestimated.

Result

While there is a recognized need for novel diagnostics across the NTD spectrum, there is also a need to further improve large scale access to medicines or commodities — for human or animal use — for diseases such as echinococcosis, foodborne

352


While the new NTD roadmap will

Environmental measures to limit

need to build further on the potential

transmission sources of

for elimination with current

schistosomiasis and soil-

interventions and an anticipated 90%

transmitted helminthiasis in China

fewer people requiring NTD

(a. Environmental modification

interventions by 2030, as specified

performed by cementing along

in the SDGs indicator of NTDs, it

both sides of a canal where was the

will also need to steer the integration

habitat of Oncomelania snails; b.

of NTD interventions into national

Safe water provided to each

systems. NTD interventions will

household by subsidy programmes

only become an integral part of UHC

from local government; c. This

when it is recognized that they are

new village latrine was built in a

local priorities of poverty and that

hyper-endemic village of

the health system needs to be

schistosomiasis; d. New irrigation

responsive to them. This requires

system being built in farmland that

sound technical and managerial

was the habitat of Oncomelania

knowledge of NTDs at all levels of

snails; e .The diagram of bio-gas

the health system, that currently still

chambers for faecal fermentation

largely needs to be built.

to eliminate eggs of schistosomes; f. A housewife is cooking a meal

Another challenge is for the health

in her kitchen room with the

system, under strong national

energy supplied by bio-gas

directives, to link up with

transferred by a tube connected to

municipalities and local

the faecal fermentation chambers)

governments to solicit cross-

Discussion

sectoral action — for basic water

The year 2020 will be crucial for the

supply, adequate sanitary

future of the global response to

infrastructure and improved

NTDs. Progress against the 2020

housing, for an integrated vector

NTD roadmap targets will be

control response, for the

assessed, a new 2021–2030 NTD

coordination of interventions with

roadmap will be launched by WHO

agriculture and livestock

— now for the 20 NTDs in its

management — to sustain

portfolio, and the London

achievements and alleviate the

Declaration commitments will need

underlying socio-economic

to be renewed.

353

determinants of NTDs. All this will


require adequate resources and

London Declaration commitment,

innovative financing mechanisms

enough resources can be mobilized to

that will need to be thought of,

see this global response in all its

such as leveraging broader

aspects through to its projected end in

investments in development with

2030.

small incremental NTD-specific

Reference:

components.

1. WHO. Working to overcome the global impact of neglected tropical diseases. First WHO report on neglected tropical diseases. Word Health Organization, Geneva,

Conclusions The global response to neglected

https://www.who.int/neglected_ diseases/resources/97892415640 90/en/

tropical diseases has been mounted to expressly help the poor and pull their

2010. Accessed 14 Dec 2019. 2. Neglected tropical diseases.

poverty-related health problems out of

https://www.who.int/neglecteddiseases/ diseases/en/. Accessed 18 Dec 2019.

neglect. Driven by novel thinking and boosted by strong public-private

3. World Health Organisaction. Metrics: Disability-Adjusted Life Year (DALY). https://www.who.int/healthinfo/gl obal_burden_disease/metrics_daly/

partnership the effort has taken proportions that are unmatched in scope today.

en/. Accessed 14 Dec 2019.

4. Fitzpatrick CNU, Lenk U, de Vlas SJ, Bundy DAP. An Investment Case for Ending

Yet there is no room for complacency. All neglect has not been resolved, and

Neglected Tropical Diseases. In: Disease Control Priorities (third edition), vol. 6. Washington (DC): The International Bank for Reconstruction and Development / The World Bank; 2017.

despite unprecedented progress the job is not finished. It is hoped that during the coming decade the global response

5. Hotez PJ, Molyneux DH, Fenwick A, Kumaresan J, Sachs SE, Sachs JD, et al. Control of neglected tropical diseases. N Engl J Med. 2007;357(10):1018

will further be able to build on successes achieved today, align with the new global health and development frameworks while

https://doi.org/10.1056/NEJMra06 4142.

keeping very focused attention on the

6. Neglected tropical diseases, five public-health interventions.

development of novel products, the

https://www.who.int/neglected_dise ases/5_strategies/en/. Accessed 18 Dec 2019.

filling of knowledge gaps associated with implementation, and the generation of evidence-based science from field and laboratory for NTDs that are still lagging behind. It is also hoped that at the renewal of the

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7. Rees CA, Hotez PJ, Monuteaux MC, Niescierenko M, Bourgeois FT. Neglected tropical diseases in children: an assessment of gaps in research prioritization. PLoS NeglTroDis.2019;13(1):e000711


1.https://doi.org/10.1371/journal. pntd.0007111. 8. Strategic and technical meeting on intensified control of neglected tropical diseases. A renewed effort to combat entrenched communicable diseases of the poor. Report of an international workshop in Berlin, 18-20 April 2005. Geneva: Word Health Organization; 2006.

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Thymoquine in Nigella Sativa as A Treatment in Leprosy Patients to Prevent Erythrema Nodusum Leprosum (ENL) Reaction: A Literature Review 1

Fatima Az Zahra, 1Yuniarhiza Srikandi Fiandini

1

Asian Medical Student Association, Batch 2019

ABSTRACT Introduction: Leprosy is an infectious disease caused by Mycobacterium leprae, that affects skin and peripheral nerves. The number of global leprosy case is still high, especially in Indonesia (the highest leprosy case in South-East Asian Regions). Management of leprosy is multidrug therapy (MDT). Nonetheless, these 2 complication reactions of MDT: Reversal Reaction and Erythema Nodusum Leprosum (ENL). Both reaction, leading cause of nerve damage in leprosy and may lead to permanent disability. High doses of oral corticosteroid is required for ENL treatment, especially thalidomide. However, many centres do not employ it in outpatient settings due to adverse effects and teratogenicity risk. It is also needed an antiinflammatory ingredient which can induce cytokine activity. Thymoquinone is the major bioactive ingredient found in Nigella sativa seed. Thymoquinone can suppress the production of TNF – α, the major cytokine produce during ENL reaction. Material and Methods: Literature searching was conducted using online databases obtained through search engines such as Google Scholar, PubMed, ResearchGate, ScienceDirect and NCBI with criterion paper published later than 2005. Two groups of keywords are used in the search field : (1) TNF-a in leprosy with erythema nodosum leprae reaction, (2) antiinflammatory effects of thymoquinone in Nigella sativa. Result and Discussion: From the search, 116 studies were identified and finally obtained 12 studies that fulfill the criterion of this literature review. According to the studies, Thymoquinone (2-isopropyl-5-methyl-1,4-benzoquinone) is one of the major chemical compounds in Nigella Sativa that are known to have anti-inflammatory that has been shown to decrease the the production of cytokines that are pro-inflammatory agents. Conclusion: Thymoquinone can suppress TNF-a production, it can be said that thymoquinone can prevent ENL which can worsen leprosy patient.

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Thymoquine in Nigella Sativa as A Treatment in Leprosy Patients to Prevent Erythrema Nodosum Leprosum (ENL) Reaction: A Literature Review Participate in IMSTC 2021 by AMSA-Indonesia

Arranged by:

1. Fatima Az Zahra

22010119120033

2. Yuniarhiza Srikandi F

22010119120013

FACULTY OF MEDICINE 2020

357


INTRODUCTION Leprosy is an infectious disease caused by Mycobacterium leprae. It mainly causes skin lesion and neuropathy and late diagnosis of the leprosy related with the various complications and disabilities 1. Clinical findings of leprosy based on the cellular immune response of the patient and the duration of the disease. Then, leprosy can be diagnosed by 3 cardinal signs specified by the World Health Organization (WHO): hypopigmented or erythematous macules with sensory loss, thickened peripheral nerves, and a positive acid-alcoholfast smear or skin biopsy 2

.

According to submitted data for 2018, South-East Asian Regions accounted for 71% of the new leprosy cases globally; 2 countries, India and Indonesia, contributed 92% of the Region’s case load. Brazil contributed 93% of new leprosy cases in Regions of America (AMR). These 3 countries together accounted for 79.6% of the new case load globally. Therefore, Indonesia has the highest leprosy case in the South-East Asian Regions 3. According to Ridley and Jopling, the classification of leprosy is tuberculous form (TT), lepromatous form (LL) overloading of microorganisms at the other end and three types of borderline leprosy; borderline tuberculoid leprosy (BT), mid-borderline (BB), borderline lepromatous leprosy (BL) between these two end. Moreover, WHO created a classification that is divided to 3 subgroup: single lesion leprosy, PB (2–5 lesions) and MB (more than 5 lesions) 1

.

Leprosy can be effectively treated with multidrug therapy (MDT) before the disability develops. For the first-line treatment, WHO introduced multidrug therapy with rifampicin, clofazimine, and dapsone. Then, minocycline, ofloxacin, and clarithromycin are among the drugs used as second-line treatments 2. Nonetheless, this treatment period is long and presents logistical problems; adherence is difficult to achieve. Beside that, these 2 reactions are often incorrectly viewed as complications of multidrug therapy (MDT). The first reaction is Reversal Reaction, occurs even years after MDT. Clinically, patients display abrupt inflammatory changes of the skin, nerves, or both. The second reaction is Erythema Nodusum Leprosum (ENL), happens any time during the course of leprosy but is most common within 1 year of starting MDT. Eventually, fibrosis, scarring, and postinflammatory hyperpigmentation develop. Patients may have anemia, neutrophilic leukocytosis, albuminuria,lymphadenopathy, hepatosplenomegaly, and neuritis. In addition, according to the histopathological features, ENL lesions are characterized by neutrophil infiltration, endhotelial vasculitis, and oedema. 5.

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Nowadays, management of ENL requires high doses of oral corticosteroids, which may not be universally effective and pose serious adverse effects. Thalidomide has proven to be a steroidsparing agent and is useful in controlling the reactions. However, many centres do not employ it in outpatient settings due to adverse effects and teratogenicity risk 6.Therefore, it is also needed an antioxidant and anti-inflammatory ingredient which can induce cytokine or neutrophils activity in intracellular. Nigella sativa commonly known as black cumin, fennel flower, or nutmeg flower is an annual herb having a wide range of medicinal uses 8. Nigella sativa is found in several areas such as the Middle East to India and the Mediterranean region. Since ancient times, black cumin has been widely used as spices and medicinal plants. The position of this plant in the taxonomic system is as follows Kingdom : Plantae Divisio : Magnoliophyta Class : Magnoliopsida Order : Ranunculales Famili : Ranunculaceae Genus : Nigella Species : Nigella sativa 10 Black cumin is a shrub type of plant with a height of approximately 30 cm. Black cumin has small flower petals, usually five petals in total, and shaped oval. The tip is slightly tapered to a bit blunt. Black cumin fruit like pods, elliptical, and blackish brown. Inside the fruit are seeds. The seeds are small, round, black, three-crookedly irregular and slightly conical, 3 mm long, and glandular 10. Black Cumin seeds contain several components such as carbohydrates, fats, proteins, minerals and vitamins. Black cumin seeds also contain 35-41% fixed oil and 0.5-1.6% volatile oil. Fixed oil contains 8 fatty acids and 32 compounds. Some of the main fatty acid content in Black Cumin seeds are 55.6% linoleic acid, 23.4% oleic acid and 12.5% palmitic acid. The major terpenes found in volatile oil are monoterpenes in the form of (27.8-57%) thymoquinone, (7.115.5%) p-cymene and (5.8-11.6%) 11.

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Thymoquinone is the major bioactive ingredient found in Nigella sativa seed. Thymoquinone has been proven to work as antioxidant, anti-inflammatory, anti-microbial, anti-bacterial, anticancer, anti-fungal, and so on 12. With the many benefits of thymoquinone in Black Cumin, we want to dig deeper into the benefits of Thymoquinone in suppressing TNF-α production in Leprosy patients to prevent Erythema Nodosum Leprae.

MATERIALS AND METHODS Literature searching was conducted using online databases obtained through search engines such as Google Scholar, PubMed, ResearchGate, ScienceDirect and NCBI. The article Two groups of keywords are used in the search field : (1) TNF-a in leprosy with erythema nodosum leprae reaction, (2) anti-inflammatory effects of thymoquinone in Nigella sativa. The inclusion criterias that we use are (1) the study was no later than 2005, (2) was trustworthy and (3) correlated with the aim of this study. The studies which did not meet the criteria were excluded. Literature searching process is shown in Figure 1.

Figure 1. Flow Diagram of Study Selection

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RESULT From the search, 116 studies were identified and finally obtained 12 studies that fulfill the criterion of this literature review. According to the studies, Thymoquinone (2- isopropyl-5methyl-1,4-benzoquinone) is one of the major chemical compounds in Nigella Sativa that are known to have anti-inflammatory that has been shown to decrease the the production of cytokines that are pro-inflammatory agents.

DISCUSSION Thymoquinone in Nigella Sativa Thymoquinone (2-Isopropyl-5-methyl-1,4-benxoquinone), a major bioactive compound of the volatile oil of Black Cumin seed, has been widely used due to its various health promoting capacities. Thymoquinone has a chemical structure as shown in Fig. x and bears the chemical formula C10H12O2 and molecular weight of 164.204 g/mol. TQ is a 10 carbon compound having a basic quinone ring moiety of 6 carbons while the 7th methyl group carbon at position C2 and 8th, 9th and 10th propyl group at position C5 9. Chemical structure of thymoquinone shown in Figure 2.

Figure 2. Chemical Structure of Thymoquinone Thymoquinone can be found in the volatile oil extract of Black Cumin seed. Volatile oil, including thymoquinone, accumulates on the inside of the seed coat, so that it cannot be extracted directly from whole seeds, but it is necessary to destroy the seed coat first 10.

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Inflammatory Effect of Thymoquinone Thymoquinone has been shown to provide anti-inflammatory effects. Thymoquinone has been shown to decrease the production of cytokines that are pro-inflammatory agents. There are numerous cytokines such as TNF-α, IL-1, IL-2, IL-6, and IL-10 which have a considerable role in inflammation. Among these TNF-α and IL-1 is important for the overexpression of other pro-inflammatory cytokines (IL-6 and IL-8), reactive oxygen/nitrogen species (ROS/RNS) and lipid mediators 9. Several studies has been proven that thymoquinone could inhibit TNF-α production resulting in an anti-inflammatory effect. TNF-α is a potent cytokine that exerts diverse effects by stimulating a variety of cells. It is mainly produced by monocytes and macrophages, but also by B-cells, T-cells, and FLS. TNF-α acts as a potent inducer of inflammatory responses through up-regulation of many genes, including cytokines, chemokines, and adhesion molecules. TNF- α in Erythemal Nodosum Leprae The occurrence of ENL reactions in leprosy involves Tumor Necrosis Factor (TNF-α) which is a primary mediator in the inflammatory process, which can also cause systemic complications. Although TNF-α plays an important role in granuloma formation to resist invasion of germs, its excessive amount can cause tissue damage. The results of previous studies indicated that TNF-α levels were significantly higher in heavy ENL tissue (p <0.05) and a strong association was obtained. This fact strengthens the hypothesis that these cytokines play an important role in the occurrence of ENL. The high level of TNF-α is probably the result of the production of macrophages or various other cells in the tissue, which is triggered by lipopolysaccharide (LPS) material from the leprosy bacillus fragments deposited in the tissue. This high local production pathologically causes damage that leads to ENL. The second possibility is that the TNF-α in the tissue comes from TNF- α in the serum which is already high in levels, then sticks to the tissue because of the large number of TNF- α receptors. This high level of TNF- α indicates an important role for TNF- α in the incidence of ENL in leprosy 7

.

Based on the previous statement which states that thymoquinone can suppress TNF- α production, it can be said that thymoquinone can prevent ENL. Given that ENL is a reaction that can worsen leprosy, preventing ENL can improve the patient's quality of life.

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CONCLUSION Nigella sativa can be alternative antioxidant with MultiDrug Therapy in leprosy patient. Thymoquinone (2-isopropyl-5-methyl-1,4-benzoquinone) in Nigella Sativa is one of the major chemical compounds that are known to have anti-inflammatory, anti-oxidant, and anti-cancer effects, that has been shown to decrease the production of cytokines that are pro-inflammatory agents. Thymoquinone also can suppress TNF- α production. While TNF-α is the major cytokine produced during ENL reaction, it can be said that thymoquinone can prevent ENL. Furthermore, giving volatile oil of Nigella sativa extract containing thymoquinone to leprosy patients with MultiDrug Therapy can prevent the patient's condition from worsening.

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OMS. Weekly epidemiological record. Global leprosy update, 2018: moving towards a leprosy. Wkly Epidemiol Rec [Internet]. 2019;94(August 2019):389–412. Available from: https://apps.who.int/iris/bitstream/handle/10665/326775/WER9435-36-en-fr.pdf

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Kamath S, Vaccaro SA, Rea TH, Ochoa MT. Recognizing and managing the immunologic reactions in leprosy. J Am Acad Dermatol [Internet]. 2014;71(4):795–803. Available from: http://dx.doi.org/10.1016/j.jaad.2014.03.034

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Upputuri B, Pallapati MS, Tarwater P, Srikantam A. Thalidomide in the treatment of erythema nodosum leprosum (ENL) in an outpatient setting: A five-year retrospective analysis from a leprosy referral centre in India. PLoS Negl Trop Dis [Internet]. 2020;14(10):1–13. Available from: http://dx.doi.org/10.1371/journal.pntd.0008678

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Ahmad, A., Mishra, R. K., Vyawahare, A., Kumar, A., Rehman, M. U., Qamar, W., Khan, A. Q., & Khan, R. Thymoquinone (2-Isopropyl-5-methyl-1, 4-benzoquinone) as a chemopreventive /anticancer agent: Chemistry and biological effects. Pharmaceutical

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The Use of Digital Health in Enhancing Medical Adherence and Reducing Stigma of Leprosy Patients Ausi Syazana Manurung, Bella Renata, Hanun Nabila Putri ABSTRACT Background: MDT has been used in leprosy treatments in order to reduce the prevalence of the disease <1 cases/10,000 populations. Adherence to MDT has always been challenging due to long duration of treatment and stigma among leprosy patients. On the other hand, tuberculosis is a disease with a high burden case in Indonesia which has similar MDT regimen with long duration of treatment. Technology interventions in adherence to tuberculosis and leprosy treatment have been studied, some of them are video-directly observed therapy (VDOT) and e-leprosy. Moreover, it also has been studied that videos can help to combat stigma. Therefore, we conducted this research to analyze articles which are related to the use of digital health in enhancing MDT adherence and reducing stigma among leprosy patients. Materials and methods: We used literature review as our research design, the articles were searched in Google Scholar. We included articles which were published in 2015-2020 and used RCT, cohort, and mixed method as their study design. Results and discussion: Based on the articles, there are three major results on this discussion. Firstly, medical adherence in tuberculosis patients could be increased by the use of VDOT. Due to the similarity of tuberculosis and leprosy in terms of long-term medication, it can be concluded that the use of VDOT is also applicable in leprosy patients. Secondly, e-leprosy is effective to be used as a tool on reminding leprosy patients using SMS. Thirdly, video interventions are proven effective enough to reduce mental health stigma, which is also applicable to reduce leprosy stigma. Conclusion: Digital health technologies such as VDOT, e-leprosy, and videos to combat stigma could be used to solve leprosy’s problems. By these solutions, we hope that Indonesia’s leprosy patients could have better medical adherence and our health department resources could be maintained effectively.

Keywords: leprosy, digital health, e-leprosy, video-directly observed therapy, video stigma

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The Use of Digital Health in Enhancing Medical Adherence and Reducing Stigma of Leprosy Patients Indonesian Medical Students’ Training and Competition

Arranged by: Ausi Syazana Manurung Bella Renata Hanun Nabila Putri

Asian Medical Students’ Association-Indonesia

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1. Introduction The World Health Organization has indexed neglected tropical diseases as a major health issue in certain countries, with leprosy as one of the most common NTDs in Indonesia. The World Health Organization reported that there were approximately 208,613 new leprosy cases globally in 2018, with 94% of leprosy patients located in 13 countries, one of them was Indonesia. In Indonesia, new leprosy cases reached 17,439 by 20191. Leprosy is a chronic infectious disease caused by Mycobacterium leprae, an acid-fast, rodshaped, and slow-growing bacillus. The disease predominantly affects the skin and peripheral nerves, resulting in neuropathy and associated long-term consequences, including deformities and disabilities2. Leprosy patients require regular multi-drug therapy (MDT) treatment for up to a six or twelve-month period, depending on their leprosy type3. Over 16 million leprosy patients from 138 countries globally have been treated with MDT which helped rapidly reduce the prevalence of the disease to <1 case/10,000 population globally in 2000 and at a national level in most countries by 20052. Despite the elimination of leprosy as a public health problem, leprosy cases continue to occur. Accordingly, there are 10 provinces in Indonesia that have not reached leprosy elimination status, as the prevalence still exceeds >1 case/10,000 population4. Although a powerful tool in controlling leprosy, adherence to MDT has always been challenging due to a number of personal, psychosocial, economic, and medical factors. One of the most contributing factor, which is long duration of treatment, may lead to incomplete cure, residual sources of infection, persisting infections, transmission to new susceptible individuals, irreversible complications, multi-drug resistance, disability or deformity development, thus causing failure of leprosy control program5–7. Furthermore, health-related stigma is a significant problem because it has various adverse and interconnected effects on the person affected – physical, social, and psychological. In case of leprosy, disability among patients causes the emergence of stigma in the society, reducing their self-esteem, which results in negative feelings and emotions8–10. Accordingly, social stigma influences a patient’s adherence to MDT and motivation for healing, which results in an elevated prevalence of leprosy in the community11. Digital health could be used to overcome these problems. Digital health is the distribution of healthcare services including telemedicine and telehealth features through the internet. This helps both health workers and patients to resolve distance, cost and time problems. It is also

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efficient in spreading health information to the public. There are a lot of digital health features that have been used around the world. Patients monitoring, medication adherence and health education are some common examples12. Tuberculosis as a high burden case in Indonesia has a similar condition to leprosy in terms of its long-term medication. Therefore, they both need medication adherence observation. One of the most commonly used adherence interventions in tuberculosis treatment is directly observed therapy (DOT), in which a health worker, family member, or community member observes the patient taking medications13. In recent years, video-directly observed therapy (VDOT) has gained attention as an alternative way of delivering DOT for tuberculosis medication14,15. Moreover, there have been studies on efforts to combat leprosy-related stigma16–18. It also has been reported that videos have the potential to address stigma19. Until then, no evidence-based recommendations on leprosy treatment adherence by using a telemedicine-based application with VDOT and videos which help to combat stigma among leprosy patients, thus increasing their adherence towards MDT. To our knowledge, so far there has only been a research on the use of e-Leprosy to increase its medical adherence. In order to inform this process, we conducted a literature review about the use of telemedicine interventions on leprosy therapy adherence and stigma. Our goal was to identify any adherence and stigma interventions associated with improvement in treatment outcomes. 2. Materials and Methods 2.1 Search Strategy In December 2020, using search terms to denote VDOT on tuberculosis, e-leprosy, and video to reduce mental health stigma, and video to reduce leprosy stigma, we searched for relevant studies from Google Scholar. Databases were taken from articles which were published in Pubmed, ScienceDirect, NCBI, and ResearchGate. The total studies found was 155 which was counted thoroughly, and 9 references were used as our databases. 2.2 Study Selection After the preliminary search, we independently screened all titles and abstracts for eligibility. Upon initial review, any studies not related to digital health interventions were

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excluded. We included articles which were published in 2015-2020 and used randomized controlled trial (RCT), cohort, and mixed method as their study design. We excluded studies which were published in the year before 2015. 3. Results and Discussion Our search initially identified 155 studies that were published in 2015 - 2020 from various sources. Then, those articles were selected based on title, abstract, and keywords. 146 irrelevant articles were excluded. Finally, we chose 9 studies that mostly related to our discussion. Table 1 presents an overview of all the studies included in the final sample and all data collected and used during sample analysis. 3.1 e-Leprosy e-Leprosy is a web-based application featuring automated SMS reminders for leprosy patients in which the sending and receiving of notification messages among leprosy surveillance officers (LSOs) and the developed system. Reminders were sent the Paucibacillary (PB) type for six months and the Multibacillary (MB) type for 12 months. The e-Leprosy program was designed to stop sending messages when the program recognized that patients had already completed their treatments. The main outcomes of this implementation is to measure the proportion of on-time attendances (OTAs) of leprosy patients as well as the perceptions of LSOs regarding the e-Leprosy program, which ranked the usefulness, easiness, and suitability need. From this study, we can conclude that e-Leprosy increased On-Time Attendance (OTA) for both PB and MB patients. However, LSOs and patients still encountered difficulties related to not all LSOs and patients had smartphones and internet connections due to lack of mobile service in rural areas. To overcome these problems, E. Rachmani et al20 were using SMS reminders as part of the surveillance process for MDT treatments. SMS reminders have been proven to increase adherence among leprosy patients. Further study is needed considering the limitations of studies on e-leprosy. 3.2 Video-Directly Observed Therapy (VDOT) Due to its long-term medication and the need of observation, leprosy patients’ medication adherence could be elevated by the use of VDOT. By reviewing these articles, we can conclude that VDOT is found mostly feasible and acceptable by TB patients in countries with various

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economic conditions. A study by C. Chuck21 compared the use of DOT and VDOT in the USA, which is categorized as a high income country with great human resources. The result of VDOT usage shows similar treatment outcomes with DOT, but with better health department resources. Similar result is found in a study by Peng Guo et al22 in China with an application by Youping Technology, Co. Ltd. With its high resource, VDOT proves that it can be used as a cost-effective application. Studies by Thu Anh Nguyen et al23 and Juliet S. Sekandi et al24 shows that VDOT are also feasible in countries such as Vietnam with its high rate of phone ownership and Uganda which has a very high rate in tuberculosis. Both are categorized as middle to low income countries. This proves that VDOT is acceptable even in low resources situations. A study by Samuel B Holzman et al25 shows a magnificent result of VDOT in India, a country with middle to low income with a high burden of tuberculosis. A magnificent result is proven due to its use of mobile app emocha VDOT, an application which is already accepted by US Health Insurance Portability and Accountability Act (HIPAA) regulations. However, in most of the cases, it is reported that poor internet connection and loss of battery become the main problem on VDOT. Even though there are still some obstacles that need to be diminished, VDOT’s benefits outweigh its drawbacks. Therefore, Indonesia as a country with similar economic conditions with a high rate of tuberculosis could use VDOT as a tool to elevate medication adherence in leprosy patients. 3.3 Video Stigma Stigma on leprosy is still at a high level. To provide a better social environment for leprosy patients, interventions need to be made to reduce stigma. Video intervention may be an answer to it since it has been used in many occasions to reduce mental health stigma. There are three literatures that are reviewed regarding this matter. Two of them explained the use of video intervention to reduce stigma on mental health while one of them explained the use of it in leprosy. The first study was conducted by Marta Gonçalves et al26 in 2015. It shows that the use of video could reduce mental health stigma on adolescents. Another study, conducted by Petr Winkler et al27 in 2017 shows that even though seminars still have the highest impact on reducing mental health, videos are proven that it is more cost-friendly and sustainable. Therefore, it is feasible to be used in leprosy. The last study was conducted by Ruth M Peters et al28 in 2016. It explained the effect on making participatory videos to reduce leprosy stigma in Cirebon, Indonesia. The result shows a change in stigmas on intrapersonal, interpersonal and community level. Participants make

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changes in their perspectives and some of their self-esteem grew positively. In conclusion, the use of video is highly feasible to reduce leprosy stigma. 4. Conclusion From the thorough explanation above, it can be concluded that Indonesia as a country with high-burden of leprosy needs an advancement to improve its medical adherence. Telemedicine may be a feasible solution to it. Thus, we propose a system where leprosy patients’ medical adherence are being observed using electronic technology. The first technology which can be used is VDOT, a system which has been proven could be effectively implemented in tuberculosis patients. Time and cost could be reduced by using this technology with the hope that they could be used more in other areas. However, there are still some disadvantages such as poor connection, low battery or even the lack of smartphone ownership. Rural areas in Indonesia are mostly hampered by this condition. E-leprosy, as the second solution proposed could be an option to be used here. E-leprosy as a system where it requires only an SMS feature to remind patients to take their medications could be used effectively. Another important problem of leprosy in Indonesia is its high rate of stigma. Numerous data of video usage in reducing mental health stigma have shown great results on changing people’s perspective. Therefore, this system could be applicable to reduce people's stigma on leprosy. By these solutions, we hope that Indonesia’s leprosy patients could have better medical adherence and our health department resources could be maintained effectively. 5. References 1. WHO | World Health Organization [Internet]. [cited 2020 Dec 10]. Available from: https://apps.who.int/neglected_diseases/ntddata/leprosy/leprosy.html 2. Guidelines for the diagnosis, treatment and prevention of leprosy. New Dehli: World Health Organization, Regional Office for South East Asia; 2017. 3. Blok DJ, De Vlas SJ, Richardus JH. Global elimination of leprosy by 2020: are we on track? Parasit Vectors. 2015 Oct 22;8:548. 4. InfoDATIN: Hapuskan Stigma dan Diskiriminasi terhadap Kusta. Pusat Data dan Informasi Kementerian Kesehatan RI; 2018.

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5. Costa LG, Cortela D, Soares RCFR, Ignotti E. Factors associated with the worsening of the disability grade during leprosy treatment in Brazil. Leprosy Review. 2015 Sep 1;86(3):265– 72. 6. Honrado ER, Tallo V, Balis AC, Chan GP, Cho SN. Noncompliance with the World Health Organization-Multidrug Therapy Among Leprosy Patients in Cebu, Philippines: Its Causes and Implications on the Leprosy Control Program. Dermatologic Clinics. 2008 Apr 1;26(2):221–9. 7. Rao PSS. A study on non-adherence to MDT among leprosy patients. Indian J Lepr. 2008 Jun;80(2):149–54. 8. van Brakel WH, Sihombing B, Djarir H, Beise K, Kusumawardhani L, Yulihane R, et al. Disability in people affected by leprosy: the role of impairment, activity, social participation, stigma and discrimination. Glob Health Action. 2012;5. 9. Tsutsumi A, Izutsu T, Islam AM, Maksuda AN, Kato H, Wakai S. The quality of life, mental health, and perceived stigma of leprosy patients in Bangladesh. Soc Sci Med. 2007 Jun;64(12):2443–53. 10. Heijnders ML. Experiencing leprosy: perceiving and coping with leprosy and its treatment. A qualitative study conducted in Nepal. Lepr Rev. 2004 Dec;75(4):327–37. 11. Susanti IA, Mahardita NGP, Alfianto R, Sujana IMIWC, Siswoyo, Susanto T. Social stigma, adherence to medication and motivation for healing: A cross-sectional study of leprosy patients at Jember Public Health Center, Indonesia. Journal of Taibah University Medical Sciences. 2018 Feb 1;13(1):97–102. 12. Health C for D and R. What is Digital Health? FDA [Internet]. 2020 Sep 22 [cited 2020 Dec 10];

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excellence/what-digital-health 13. Karumbi J, Garner P. Directly observed therapy for treating tuberculosis. Cochrane Database Syst Rev [Internet]. 2015 May 29 [cited 2020 Dec 10];2015(5). Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4460720/ 14. Mirsaeidi M, Farshidpour M, Banks-Tripp D, Hashmi S, Kujoth C, Schraufnagel D. Video directly observed therapy for treatment of tuberculosis is patient-oriented and cost-effective. Eur Respir J. 2015 Sep;46(3):871–4.

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15. Sinkou H, Hurevich H, Rusovich V, Zhylevich L, Falzon D, de Colombani P, et al. Videoobserved treatment for tuberculosis patients in Belarus: findings from the first programmatic experience. Eur Respir J. 2017;49(3). 16. Lusli M, Peters R, Brakel W van, Zweekhorst M, Iancu S, Bunders J, et al. The Impact of a Rights-Based Counselling Intervention to Reduce Stigma in People Affected by Leprosy in Indonesia. PLOS Neglected Tropical Diseases. 13 Des 16;10(12):e0005088. 17. Dadun D, Van Brakel W, Peters R, Lusli M, Zweekhorst M, Irwanto I, et al. Impact of socioeconomic development, contact and peer counselling on stigma against persons affected by leprosy in Cirebon, Indonesia - a randomised controlled trial. Leprosy review. 2017 Mar 5;88. 18. Dadun D, Peters RMH, van Brakel WH, Bunders JGF, Irwanto I, Regeer BJ. Assessing the Impact of the Twin Track Socio-Economic Intervention on Reducing Leprosy-Related Stigma in Cirebon District, Indonesia. International Journal of Environmental Research and Public Health. 2019 Jan;16(3):349. 19. Peters RMH, Zweekhorst MBM, van Brakel WH, Bunders JFG, Irwanto. ‘People like me don’t make things like that’: Participatory video as a method for reducing leprosy-related stigma. null. 2016 Jul 2;11(5–6):666–82. 20. Rachmani E, Lin M-C, Hsu CY, Jumanto J, Iqbal U, Shidik GF, et al. The implementation of an integrated e-leprosy framework in a leprosy control program at primary health care centers in Indonesia. International Journal of Medical Informatics. 2020 Aug 1;140:104155. 21. Chuck C, Robinson E, Macaraig M, Alexander M, Burzynski J. Enhancing management of tuberculosis treatment with video directly observed therapy in New York City. Int J Tuberc Lung Dis. 2016 May;20(5):588–93. 22. Guo P, Qiao W, Sun Y, Liu F, Wang C. Telemedicine Technologies and Tuberculosis Management: A Randomized Controlled Trial. Telemedicine and e-Health. 2019 Dec 2;26(9):1150–6. 23. Nguyen TA, Pham MT, Nguyen TL, Nguyen VN, Pham DC, Nguyen BH, et al. Video Directly Observed Therapy to support adherence with treatment for tuberculosis in Vietnam: A prospective cohort study. Int J Infect Dis. 2017 Dec;65:85–9. 24. Sekandi JN, Buregyeya E, Zalwango S, Dobbin KK, Atuyambe L, Nakkonde D, et al. Video directly observed therapy for supporting and monitoring adherence to tuberculosis treatment

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in Uganda: a pilot cohort study. ERJ Open Res [Internet]. 2020 Apr 6 [cited 2020 Dec 10];6(1). Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7132038/ 25. Holzman SB, Atre S, Sahasrabudhe T, Ambike S, Jagtap D, Sayyad Y, et al. Use of Smartphone-Based Video Directly Observed Therapy (vDOT) in Tuberculosis Care: SingleArm, Prospective Feasibility Study. JMIR Form Res. 2019 Aug 27;3(3):e13411. 26. Goncalves M, Moleiro C, Cook B. The Use of a Video to Reduce Mental Health Stigma Among Adolescents. Adolescent Psychiatry. 2015 May 21;05:1–1. 27. Winkler P, Janoušková M, Kožený J, Pasz J, Mladá K, Weissová A, et al. Short video interventions to reduce mental health stigma: a multi-centre randomised controlled trial in nursing high schools. Soc Psychiatry Psychiatr Epidemiol. 2017;52(12):1549–57. 28. Peters RMH, Dadun, Zweekhorst MBM, Bunders JFG, Irwanto, Brakel WH van. A ClusterRandomized Controlled Intervention Study to Assess the Effect of a Contact Intervention in Reducing Leprosy-Related Stigma in Indonesia. PLOS Neglected Tropical Diseases. 20 Okt 15;9(10):e0004003.

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6. Table Table 1. Overview of selected studies. Author

Year

Objective

Result

Conclusion

E. Rachmani, et al.

2020

To measure the proportion of on-time attendances (OTAs) of leprosy patients as well as the perceptions of LSOs regarding the e-Leprosy program.

The PB type had less late patients (19.3 %) when compared to the MB type (22 %). Reminders increased On Time Attendances (OTA) by 10.3 % and 14.9 % for both PB and MB patients, respectively. For total patients comparison between before and after the intervention, the increase of OTA was 13.9 % (p<0.01, OR = 2.41). All of the LSOs had a mobile phone, though only 39.3 % had a smartphone. Furthermore, 71 % of LSOs did not have internet connections on their mobile phones, and 75 % never accessed the internet from their workplace.

SMS reminder for e-Leprosy increased On-Time Attendance (OTA) for both PB and MB patients. However, LSOs and patient still encountered difficulties due to poor connection, and lack of smartphone ownership.

C. Chuck et al

2016

To determine whether VDOT is as effective as in-person DOT.

Among 390 patients on DOT for the treatment of TB, 61 (16%) were on VDOT and 329 (84%) on in-person DOT. Adherence to scheduled VDOT sessions was 95% compared to 91% with DOT (P , 0.01). VDOT enabled a DOT worker to observe a maximum of 25 patients per day, similar to DOT workers who observed patients in clinic (n ¼ 25), but twice that of DOT workers who observed patients in the community (n¼12). Treatment completion with VDOT was similar to that with DOT (96% vs. 97%, P ¼ 0.63). The primary problems encountered during VDOT

Implementation of VDOT resulted in successful antituberculosis treatment outcomes while maximizing health department resources.

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sessions were interruption of video and audio connectivity. Peng Guo et al

2019

To asses clinical and cost benefit of VDOT compared with DOT service.

Very high rates of treatment completion were found from 405 patricipants (96.1% with VDOT vs. 94.6% with DOT). Average time per dose observed was 16.5 min for VDOT, while 44.1 min for DOT (including traveltime), p < 0.01. And the cost incurred on VDOT was Y-- 34.3 manmo, which was statistically lower compared with Y-- 71.6 manmo in the DOT group, p < 0.01. Patients in the VDOT group had a better experience compared with those in DOT group.

VDOT enabled meaningful direct observation for TB patients through mobile devices, which was highly acceptable to patients and health care providers. It also saved time and is a cost-effective method, enabling the use of the saved money to other much-needed areas for TB.

Thu Anh Nguyen et al

2017

To evaluate the feasibility of using asynchronous VDOT to support treatment adherence among patients with confirmed tuberculosis.

Among 40 participating patients, 27 (71.1%) of patients took all required doses. A median of 88.4% (interquartile range 75.8%-93.7%) of doses were correctly recorded and uploaded. Participants rated the VDOT interface highly, despite facing some initial technical difficulties.

VDOT was feasible and resulted in high rates of treatment adherence in a resource-limited setting.

Samuel B Holzman et al

2019

To assess the feasibility and acceptability of vDOT for adherence monitoring within a resource-limit d, high TB burden setting of India.

A total of 25 patients enrolled. The median number of weeks on vDOT was 13 (interquartile range [IQR] 11-16). Median adherence was 74% (IQR 62%84%), and median verifiable fraction was 86% (IQR 74%98%). More than 90% of patients reported recording and uploading videos without difficulty.

VDOT may be a feasible and acceptable approach to TB treatment monitoring in India.

Juliet N. Sekandi et al

2019

To evaluate the feasibility of using VDOT for supporting TB

Of 52 patients enrolled, 50 were analysed. Of the 5150 videos expected, 4231 (82.2%) were received. The median FEDO was

VDOT was feasible and acceptable for monitoring and supporting TB

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Ruth M. H. Peters et al

2016

treatment adherence in Uganda.

85% (interquartile range 66%– 94%) and this significantly differed by follow-up duration. Phone malfunction, uncharged battery and VDOT app malfunctions were the commonest reasons for missed videos. 92% of patients reported being very satisfied with using VDOT.

treatment. It resulted in high levels of adherence, suggesting that digital technology holds promise in improving patient monitoring in Uganda.

The impact on the video makers of making a participatory video and to Increase understanding of how to deal with foreseeable difficulties.

During the making of the participatory video in three different stages, there are some positive changes made in the social dynamic of the video makers.

Participatory video has the potential to address stigma at least at three levels – intrapersonal, interpersonal and community – and possibly more.

 

Marta Gonçalves et al

2015

To present results from a pilot test of a video-based mental health destigmatization intervention administered in a school setting.

An inclusive and collaborative group dynamics is established. Some group members felt a desire to change community perspectives, increase knowledge and call for inclusion. There has been an impressive impact on their self-esteem and the internalised stigma disappeared, some others said it had lessened The intervention significantly reduced scores on all three stigma scales for the treatment group at the post- time period. This decline in scores among the treatment group was significantly greater than the decline in scores observed in the control group. The decrease in perceived stigma remained greater for the treatment than the control group in the follow-up time period, though these results did not reach statistical significance. After adjustment

378

Quick and low cost stigma reducing interventions can be successful in increasing access to mental health treatment for those in need.


for SES measures, grade, and sex, we identified significant intervention effects at the post time period on the Self-Stigma and Seeking Help Scale. Petr Winkler et al

2017

To assess whether short video interventions could reduce stigma among nursing students

Compared to the baseline, effect sizes immediately after the intervention were small in the flyer arm (CAMI: d = 0.25; RIBS: d = 0.07), medium in the seminar arm (CAMI: d = 0.61; RIBS: d = 0.58), and medium in the video arm (CAMI: d = 0.49 RIBS: d = 0.26; n = 237). Effect sizes at the follow-up were vanishing in the flyer arm (CAMI: d = 0.05; RIBS: d = 0.04), medium in the seminar arm (CAMI: d = 0.43; RIBS: d = 0.26; n = 254), and small in the video arm (CAMI: d = 0.22 RIBS: d = 0.21; n = 237).

379

Seminar had the strongest and relatively stable effect on students’ attitudes and intended behaviour, but the effect of short video interventions was also considerable and stable over time. We recommend videos for further research and development.


Development of Indonesia Public Health System to Overcome Filariasis Holistically by Preventive, Curative, and Rehabilitative Ways in The Medical Field Asti Ayundasari, Ferliana Nurmalita, and Luthfiyyah Nuur Haniifah Abstract Filariasis is a disease caused by filarial worms which can be transmitted by mosquitoes as vectors. This disease spreads almost in all regions. From year to year, the number of provinces reporting filariasis cases continues to increase and in some areas have quite high levels of endemicity.This scientific paper was created using the literature study method. The publishers are NCBI and several main data on filariasis elimination programs in Indonesia, and Information Center of the Indonesian Ministry of Health.The government agrees to eradicate filariasis as part of the global elimination of filariasis through two pillars, namely breaking the chain of filariasis transmission with the POPM through the BELKAGA program which has been held every October since 2015 which takes place in the regions throughout Indonesia which is an elephant legged area and the prevention of disability through the handling of filariasis cases independently. The development of a health system in the response to filariasis can be carried out by developing the existing stages of the filariasis elimination program, including mapping endemic areas preceded by research on the prevalence of lymphatic filariasis. The existence of a filariasis POPM implementation program and monitoring the area and residents' homes. As for the treatment of preventive and curative aspects of filariasis, intensive monitoring for three days, taking health promotion and rehabilitative measures for filariasis sufferers. The surveillance program for the stop POPM filariasis period was carried out by xeno-monitoring to prove the transmission of filariasis, especially post POPM and the filariasis elimination certification program for districts implementing POPM for 5 consecutive years. Finally there is the WHO verification program. Keywords: filariasis, POPM, health system development

380


Literatur Review

Development of Indonesia Public Health System to Overcome Filariasis Holistically by Preventive, Curative, and Rehabilitative Ways in The Medical Field

Arranged by : Asti Ayundasari Ferliana Nurmalita Luthfiyyah Nuur Haniifah

UNIVERSITY OF JEMBER 2020

381


Province

INTRODUCTION

(microfilia)

which

can

Wuchereriabancrofti,

worms,

districts each. A total of 6 provinces do not have endemic filariasis districts . The six

namely

Brugimalayi,

endemic

West Papua with 12 filariasis endemic

vectors. Filariasis is caused by three species filarial

filariasis

districts, and Aceh, Southeast Sulawesi and

be

transmitted by means of mosquitoes as

of

23

districts, NTT with 18 filariasis endemic

Filariasis is a disease caused by filarial worms

with

provinces are North Sulawesi, NTB, Bali,

and

East Java, DIY and DKI Jakarta2.

Brugiatimori. This disease is chronic and if it does not receive treatment it can cause

MATERIALS AND METHODS

permanent disabilities for life in the form of

This scientific paper was made using the

enlargement of the legs, arms and genitals

literature

of both women and men which can cause

review

method.

Several

publishers are used to search for several

psychological impact on sufferers and their

scientific articles related to filariasis,

families. As a result, the sufferer cannot

filariasis

work optimally and even his life depends

elimination

programs,

and

developments in elimination programs that

on other people so that it becomes a burden

have been carried out in Indonesia. The

to the family, community and state1.

publishers are NCBI, Google scholar, and

Lymphatic filariasis (LF) affects 120

several main data on filariasis elimination

million people worldwide and 1.1 billion

programs in Indonesia which were obtained

people are at risk of contracting this

from the Data and Information Center of

infection in 83 countries. In 2017, out of

the Indonesian Ministry of Health. The

514 districts in the territory of Indonesia,

articles that are obtained are sorted which

236 districts were classified as endemic for

are relevant to the topic of the article being

filariasis. Of that number, 152 districts of

written. The keywords used are filariasis,

which are still implementing POPM. The

POPM, filariasis elimination program,

provinces with the highest number of

BELKAGA and others.

filariasis endemic districts are Papua

1

Pusdatin. Menuju Eliminasi Filariasis 2020 Pusdatin. Menuju Indonesia Bebas FILARIASIS. Jakarta Selatan; 2018 2

382


RESULT AND DISCUSSION The development of a health system to

very important to determine priorities and

tackle filariasis can be done by looking at

management in the eradication of filariasis,

the stages of the existing

so it must be done intensively.

filariasis

elimination program, namely:

2. Implementation of filariasis POPM and

1. Mapping of filariasis endemic areas

monitoring evaluation

The number of filariasis cases in Indonesia

The implementation of POPM is through

is estimated to be under-reporting. This can

the BELKAGA program which has been

be caused, both from the community

held every October since 2015 which takes

themselves who do not know what filariasis

place in areas all over Indonesia which are

is, its dangers and symptoms or from health

endemic areas for elephant feet. This stage

workers who are simply not observant or

really must be strengthened and developed.

lack

So, in practice, it can be described:

of

knowledge

and

training.

Meanwhile, there is no national data on

a. Inspection of areas and houses of

lymphatic filariasis endemicity. Thus, it is

residents

necessary to conduct research on the The first thing that should be done is to

prevalence of lymphatic filariasis.

check and collect data on the house and A district / city is declared endemic for

environment, whether it is clean or dirty.

filariasis if the microfilaria rate in that area

Several health teams were divided to visit

is 1% or more. If the area is declared

residents' homes one by one. This is done in

filariasis endemic, the POPM program will

order to provide solutions and suggestions

be implemented for at least five consecutive

that can prevent the spread of filariasis.

years. The implementation of filariasis

This activity is carried out in one week. In

POPM must be continued if an endemic

this socialization, it should start with an

area of treatment coverage does not meet

explanation

the requirements of at least 65% of the total

transmission,

population for five consecutive years. The

of

filariasis,

prevention

modes with

of

drugs,

categories that can take drugs, the benefits

implementation of filariasis POPM is added

of taking the drugs given, how to use them,

for two years if based on the results of an

side effects of drugs, symptoms, dangers,

evaluation survey of filariasis transmission,

and post infection treatment. In addition,

there is still transmission in the area.

health workers can provide suggestions,

Therefore, mapping of endemic areas is

solutions, and schedules for cleaning the

383


environment. And the last session of the

3B) or 1 ml venous blood filtration

socialization was drug administration.

examination (Figure 3C) stained with

Socialization can be done in every

giemsa stain. Blood filtration tests can be

kelurahan in the district / city. This

used to monitor the treatment program

socialization can be done just once right

because they are more sensitive than thick

before POPM with the intention that people

blood tests (due to a higher amount of

understand and do not hesitate to take

blood). However, taking 1 ml of venous

medicine.

blood causes people to feel afraid to be examined. Therefore, for monitoring and

The socialization can be scheduled for one

evaluation of the filariasis elimination

week. This is a stage that should be done

program, the 60 ul finger blood test should

intensively because it can have an impact

be used. To overcome obstacles in areas

on society. People become aware of what

that are very difficult to reach at night, a

filariasis is, its dangers, and its symptoms. In addition, the public is more concerned about this disease so that they no longer

symptoms

of

filariasis,

if

there the

bancrofti

can

also

for be

available. Currently only antibody serology

effects that may occur after taking the addition,

Wuchereria

examination

examination for Brugia sp. not yet

already know the positive effects and side

In

antigen

performed (Figure 4A). However, antigen

hesitate to take medicine because they

medicine.

serological

is available (Figure 4B)3.

are

public

Filariasis treatment must be done en masse

understands so they can report. This will

using Diethyl Carbamazine Citrate (DEC).

have an impact on the mapping of endemic

DEC can kill microfilariae and adult worms

areas and the measures taken to prevent

on long-term treatment. DEC is given each

disability.

person as much as 6 mg / kg body weight and combined with Albendazol 400 mg

b. treatment

once a year for a period of five years during Treatment will first begin with diagnostic

the implementation of BELKAGA4. The

action. Diagnosis of filariasis can be done

details of the dosage for

through finger blood examination (20 ul-60

consumption of DEC-Albendazol by age.

ul) on thick blood slides (Figures 3A and

Another drug that is also used is Ivermectin.

3

Kementerian Kesehatan RI. Infodatin Filariasis Per Halaman. Pdf. 2018 4 Pusdatin. Menuju Eliminasi Filariasis 2020

384

use and


Ivermectin is a semisynthetic antibiotic

who are seriously ill, people with chronic

from the macrolide class that has broad

clinical filariasis who are experiencing

activity

acute attacks, and children with marasmus

against

ectoparasites.

This

nematodes drug

only

and

or kwashiorkor.7

kills

microfilariae. Ivermectin is also used once

c. Intensive monitoring for three days

a year or when BELKAGA is held 5. Intensive monitoring here is intended to The effects of filariasis treatment, the side

check and make sure if the drugs that have

effects of this drug are due to the effects of

been given have been taken. Because in

drugs on the human body (pharmacological effects),

due

to

drug

some cases, people are afraid of the side

interactions,

effects of drugs so they don't take them.

intolerance (not suitable for drugs), and

This can be done by home visits and by

idiosyncrasies (odd / unusual individual

telephone. In addition, to check and resolve

responses to drugs). An allergic drug

side effects and complaints from the public

reaction will cause several symptoms, such

after taking the medicine. In order to know

as fever, headache, myalgia (muscle pain),

the progress of each resident in taking steps

vomiting, weakness, and asthma. Post

to prevent filariasis, residents are required

Infection or referred to as a post-treatment

to fill in the monitoring paper that has been

after-event, namely the body's reaction to

distributed when the health team checks

the results of treatment. Where this reaction

each resident's house. This aims to

can occur due to the presence of foreign

determine whether residents have made

objects in the body, namely the dead bodies

recommendations or suggestions from the

of macrophilaria and microfilariae, not reactions

caused

by

drugs6.

health team.

The

administration of POPM filariasis is

d. Health Promotion

postponed to pregnant women, people with

Health promotion is the process of enabling

kidney function disorders, people with liver

people to increase control and improve their

dysfunction, people with epilepsy, people

health (WHO, 1984). Health promotion

with heart and blood vessel disease, people

aims to provide education and convey

5

Deasy, F. Penurunan Prevalensi Penyakit Filariasis. 4-15. 2019. 6 Purwantyastuti. Pemberian obat massal pencegahan (pomp) filariasis. Buletin Jendela Epidemiologi. 1(1):15-19.2010 7 Dinas Kesehatan Kabupaten Alor. Buku pedoman pengobatan masal filariasis bagi bidan desa dan tenaga pembantu eliminasi. 1-33. 2002

385


health information to the public regarding

These plants can be used to prevent the

diseases, health, and living habits that

spread of filariasis-causing mosquitoes by

reflect healthy living. Not only that, health

cutting the plants and boiling them. This

promotion also has another goal, namely a

boiled water will be used with a diffuser 8.

program aimed at changing people's

The promotional methods used can be in

behavior that is not / less good (negative)

the form of: question and answer lectures,

into better (positive) behavior. Of course, it

demonstrations, using props such as:

is not only about diseases, medicines

posters. Health promotion can be carried

consumed, but health promotion also has a

out at schools, posyandu counseling and at

preventive level health service aspect to the

religious activities. Through these efforts, it

community,

providing

is hoped that it can break the chain of

education, direction, understanding, and

lymphatic filariasis transmission so that

advice to the public so that they are willing

lymphatic filariasis does not become a

and

public health problem.

able

namely

to

by

protect

their

health

independently, such as always care for, maintain

and

clean

the

e. Rehabilitative for filariasis sufferers

surrounding

environment to keep it clean and tidy,

Usually, people with filariasis experience

diligently drain the tub, close waterlogged

psychological disorders9. This happens

places, and use mosquito repellent lotion

because of the pressure of not being able to

for independent preventive measures. In

do things freely and also being embarrassed

addition, there is an innovative mosquito

to meet people. Therefore, socialization is

repellent drug that causes filariasis using

needed for people with filariasis which can

shrubs.

namely

be in the form of an explanation of good

lemongrass, which is a plant capable of

care so that infection does not occur, how

repelling mosquitoes because it contains

to clean and handle it in any situation, such

citronnellol and geraniol which can emit an

as sleeping time, eating, wearing sandals,

odor that mosquitoes do not like and even

and how to socialize with people around.

citronnellol can make mosquitoes die.

Then, there can be a two-way conversation,

One of the shrubs,

8

Dinas kesehatan DIY. Tanaman Pengusir Nyamuk. 2017 9 Lismayanti, L. dkk. Pengalaman Hidup Orang Terinfeksi Filariasis. Stikes Tasikmalaya, Fakultas Keperawatan Universitas Padjadjaran, Politeknik Kemenkes Bandung, Poltekkes Kemenkes Bandung. 1(1). 2013.

386


asking each other and health workers

years. Proof of transmission can be done by

answering.

xeno-monitoring.

Not

only

socialization

measures, but people with filariasis can

4.

follow surgical or surgical procedures to

National

/

filariasis

elimination

certification

restore the size of the swollen legs and feet. However, not all people with filariasis can

5. WHO verification

be

CONCLUSION

treated

directly

through

surgical

procedures. Because each condition, the The development of a health system in the

severity of people with filariasis is certainly

response to filariasis can be carried out by

different from one another. The more

developing the existing stages of the

filariasis is found, the earlier it is treated so

filariasis elimination program, including

that the possibility of filariasis sufferers

mapping endemic areas preceded by

being saved is greater so that they avoid

research on the prevalence of lymphatic

permanent disability. The rehabilitative

filariasis. The existence of a filariasis

level service aspect is very important to

POPM

reduce disability and help sufferers adapt to

implementation

program

and

monitoring the area and residents' homes.

their lives biologically, psychologically,

As for the treatment of preventive and

socially, and spiritually.

curative aspects of filariasis, intensive 3. Surveillance for filariasis POPM stop

monitoring for three days, taking health

period

promotion and rehabilitative measures for

The implementation of filariasis POPM is

filariasis

stopped if based on the results of an

program for the stop POPM filariasis period

evaluation survey of filariasis transmission,

was carried out by xeno-monitoring to

there is no transmission. After the cessation

prove

of filariasis POPM has been going on for

especially post POPM and the filariasis

two years, in these areas a re-evaluation

elimination / national certification program

survey of filariasis transmission was carried

for districts / cities implementing POPM for

out. If the results of the re-evaluation of

5 consecutive years. And finally there is the

filariasis

WHO

transmission

showed

no

sufferers.

the

The

transmission

verification

surveillance

of

program.

filariasis,

In

this

transmission, filariasis POPM was still

program, the thing that must be considered

stopped and a re-survey of filariasis

is that all stages of cooperation are needed

transmission was again carried out after two

between the community, health workers and local government.

387


REFERENCES Litbangkes. 2019. Strategi Nasional Riset Implementasi atau Operasional untuk Mendukung Pencegahan dan Pengendalian Tuberkulosis, Malaria, dan Neglected Tropical Diseases. Jakarta Dinkes. Buku Pedoman Pengobatan Masal Filariasis bagi Bidan Desa dan Tenaga Pembantu Eliminasi Pusdatin. Menuju Eliminasi Filariasis 2020 Pusdatin. 2018. Menuju Indonesia Bebas FILARIASIS. Jakarta Selatan Newman, Thomas E., Andrew L Juergens. 2020. Filariasis. Diakses dari https://www.ncbi.nlm.nih.gov/books/NBK556012/ Lismayanti, L dkk. 2013. Pengalaman Hidup Orang Terinfeksi Filariasis. Stikes Tasikmalaya, Fakultas Keperawatan Universitas Padjadjaran, Politeknik Kemenkes Bandung, Poltekkes Kemenkes Bandung. 1(1). Kementerian Kesehatan. 2014. Peraturan menteri kesehatan republik indonesia no. 94 tahun 2014 tentang penanggulangan filariasis. Penanggulangan Filariasis. 1–118. Kementerian Kesehatan RI. 2018. Infodatin Filariasis Per Halaman.Pdf. 2018. Purwantyastuti. 2010. Pemberian obat massal pencegahan (pomp) filariasis. Buletin Jendela Epidemiologi. 1(1):15–19. Dinas Kesehatan Kabupaten Alor. 2002. Buku pedoman pengobatan masal filariasis bagi bidan desa dan tenaga pembantu eliminasi. 1–33. Veri, N. 2010. Pencapaian kompetensi sesi di dalam kelas sesi dengan fasilitasi pembimbing sesi praktik dan pencapaian kompetensi. 1229–1241. Deasy, F. 2019. Penurunan Prevalensi penyakit Filariasis. 4-15. Dinas kesehatan DIY. 2017. Tanaman Pengusir Nyamuk.

388


TABLE AND FIGURES

Gambar 1. Grafik Peningkatan Kasus Filariasis di Indonesia Tahun 2002-2014 (Pusdatin).

Gambar 2. Grafik Penurunan Kasus Filariasis di Indonesia 2014-2017 (Pusdatin, 2018).

389


Gambar 5. Grafik dari Efek yang Ditimbulkan Selama Pengobatan Filariasis

Gambar 6. Tabel Gejala Post Infection

390


mRNA VACCINE FOR COVID-19 WITH TERPENES PEPTIDE AS AN INHIBITOR AND NANOPARTIKEL AS A PROTEIN DELIVERY Mellybeth Indriani Louis[1], Merlionarsy Tammuan[2], Nadya Mangasi Sitau Tombi[3] [1]

Program Studi Pendidikan Dokter Fakultas Kedokteran Universitas Tadulako, Palu

Abstract Introduction: Corona virus desease 19 (COVID-19) is an emergency disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 cases are still increasing. Therefore, the authors are interested in describing the potential of the mRNA vaccine using terpenes peptide binds to the ACE-2 receptor protein via surface residues with nanoparticles as protein delivery. Objective of the work: The objective of this literature review is to describe the potential of the mRNA vaccine using nanoparticle as a protein delivery with terpenes peptide as a SARS-CoV-2-ACE2 binding inhibitor. Methods: Author collected various analyzed journals to compile this literature review. Result: SARS-CoV-2 recognizes ACE2 through the amino acids present on the surface of RBD of SARS-Cov-2. These amino acids will bind to the amino acids on the surface of the ACE2 receptors. Terpene peptide is a phytochemical. This active molecule is able to reduce infection by preventing virus entry and replication of viral DNA / RNA. Based on Molecular docking, three compounds that can interact directly with the SARS-CoV-2 S-RBD through hydrogen bonding and hydrophobic interactions, those are NPACT01552,

NPACT01557 and

NPACT00631. Nanoparticles can be populated with multiple antigenic groups, their correct antigenic appearance makes them a very relevant alternative in vaccinology when compared to conventional approaches. For the COVID-19 vaccine strategy, modulating the APCs using nanoparticles could be very important. Conclusion: Terpene peptide compound can prevent SARS-CoV-2 S-RBD from bonding with ACE2 protein through hydrogen bonding and hydrophobic interactions between NPACT01552, NPACT01557, NPACT00631 compounds with surface residues on S-RBD. The mRNA vaccine can induce activation of B cells and cytotoxic T cells. The mRNA vaccine will produce target proteins through translation, then immune cells will recognize this viral protein and produce antibodies.

Keywords: COVID-19, SARS-CoV-2,Terpenes Peptide, , mRNA vaccine, nanoparticle

1 391


SCIENTIFIC PAPER mRNA VACCINE FOR COVID-19 WITH TERPENES PEPTIDE AS AN INHIBITOR AND NANOPARTIKEL AS A PROTEIN DELIVERY

Disusun oleh : Mellybeth Indriani Louis Merlionarsy Tammuan Nadya Mangasi Sitau Tombi

392


Latar belakang Coronavirus disease 19 (COVID- 19) adalah penyakit emergensi yang ditemukan di china pada akhir tahun 2019 dan disebabkan oleh Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Penyakit ini menyebabkan pandemi. SARS-CoV merupakan kasus emergensi di tahun 2002 dengan jumlah 8000 kasus dan tingkat kematian 10%. SARSCoV dan sars-cov-2 merupakan bagian dari subgenus sarbecovirus (genus betacoronavirus, family coronaviridae). Kedua virus ini telah berkembang, di mana pada awalnya virus ini hanya bisa menginfeksi hewan, namun saat ini kedua virus tersebut bahkan dapat mengancam nyawa manusia karena penyakit pernapasan[1]. Semua Coronavirus merupakan virus yang berkapsul dan berbentuk bola/ pleumorfik dengan ukuran 80-120 nm. Coronavirus tersebut memiliki genom rna sense positif beruntai lima yang dibatasi dengan panjang antara 26,2 dan 31,7 kb, yang terpanjang diantara semua virus rna. Genom terdiri dari 6-10 Open Reading Frames (ORFs). ORF pertama terdiri dari dua pertiga genom dan mengkode protein replikase, sedangkan sepertiga terakhir mengandung gen protein struktural dalam urutan tetap: (HE)-S-E-M-N. Kapsul pada Coronavirus mengandung tiga protein virus, yaitu spike protein (s), membrane protein (m), dan envelope protein (e). Protein M dan E terlibat dalam pembentukan virus, sedangkan mediator untuk masuknya virus adalah protein S[1]. Cara penyebaran SARS-CoV-2 belum diketahui. Sebagian besar penelitian terbaru tentang tranmisi SARS-CoV-2 didasarkan pada Coronavirus yang memiliki struktur yang sama, yaitu SARS-CoV dan MERS-CoV. Dimana transmisi dari Human To Human terjadi melalui droplet, kontak, dan benda mati. Membran mukus di mata, hidung, dan mulut sebagian besar menjadi media penyebaran SARS-CoV melalui kontak secara langsung maupun tidak langsung. Masyarakat yang tidak memakai masker dan tidak memakai pelindung mata rentan terhadap penyebaran SARS-CoV[2] Orang yang tidak terinfeksi dapat terinfeksi COVID-19 ketika mereka mengalami kontak dekat (< 1 meter) dengan orang yang terinfeksi SARS-CoV-2[3]. Manifestasi klinis pada COVID-19 dari gejala yang ringan, seperti batuk dan demam hingga sulit bernapas. Gejala yang paling sering ditemukan yaitu demam (88,8%), diikuti batuk kering (68%), kelelahan (33%). Batuk berdahak (28,5%), napas pendek (17%), nyeri otot (14,4%), sakit tenggorokan (11,4%), dan sakit kepala (10,2%) merupakan gejala lain yang tercatat. Diare (4,4%), mual muntah (4,1%), hidung meler (3,2%), nyeri perut (0,1%),

1 393


dan nyeri dada (0,1%) merupakan gejala yang juga dapat ditemukan pada pasien COVID-19. Resiko terinfeksi COVID-19 akan meningkat pada pasien dengan hipertensi (15%), diabetes (9,4%), penyakit hati (hepatitis b 1,5%), paru-paru, ginjal (0,8 %), pasien kanker yang sedang melakukan kemoterapi, perokok, penerima transplantasi organ, konsumsi steroid jangka panjang[4]. Prevalensi kasus COVID-19 di indonesia hingga saat ini, tanggal 1 september 2020, terdapat 177.571 pasien terkonfirmasi positif, pasien sembuh 128.057 orang, dan pasien meninggal dunia 7.505 orang. Di indonesia, kasus terkonfirmasi positif COVID-19 tertinggi terdapat pada rentang usia 25-34 tahun[5] . Kasus terkonfirmasi positif COVID-19 juga diprediksikan akan terus meningkat. Berdasarkan permasalahan di atas, maka penulis tertarik untuk mendeskripsikan tentang potensial vaksin mRNA dengan Nanopartikel sebagai Protein Delivery yang diformulasikan dengan senyawa terpene sebagai adjuvant.

Metode Studi literatur ini disusun dengan metode kajian pustaka. Penulis mengumpulkan berbagai jurnal yang dianalisis untuk menyusun karya ini melalui mesin pencari: ncbi, google, springer, dan pubmed dengan kata kunci SARS-CoV-2, inhibitor, vaccine, COVID19, ACE2, didapatkan 42 jurnal dengan 10 jurnal yang sesuai dengan kriteria inklusi dan eksklusi yang termasuk dalam 10 tahun terakhir.

Hasil dan pembahasan Patogenesis SARS-CoV-2 Siklus hidup virus dengan sel host terdiri dari beberapa langkah, yaitu perlekatan, penetrasi, biosintesis, pematangan dan pelepasan. Perlekatan terjadi ketika virus berikatan dengan reseptor pada sel host. Tahap selanjutnya, penetrasi, virus memasuki sel host dengan cara endositosis atau membrane fusion. Di dalam sel host, nucleocapsid dan RNA akan dilepaskan dan kemudian RNA akan melakukan replikasi di dalam nukleus. Selanjutnya virus akan melakukan biosintesis, di mana mrna virus digunakan sebagai bahan untuk membuat protein virus. Setelah ketiga hal tersebut, partikel virus mengalami pematangan dan dilepaskan (gambar 1). Protein struktural yang dimiliki semua coronavirus terdiri dari spike(S) ,membran(M) yang menjaga bentuk membran dari partikel virus, envelope (E) yaitu protein kecil yang berperan dalam pembentukan dan pertumbuhan struktur virus, dan nukleokapsid (N) yang akan berikatan dengan RNA dan pembentukan nukleokapsid. Bagian 2 394


menonjol dari virus merupakan spike yang terdiri dari transmembrane trimetric glycoprotein yang menjadi penentu keragaman dari coronavirus. S1 dan S2 merupakan subunit fungsional dari proteinS. S1 berfungsi untuk mengikat reseptorsel host dan S2 berfungsi untuk membrane fusion dari virus dan sel host. Reseptor untuk SARS-CoV yang teridentifikasi adalah Angiotensin Converting Enzyme 2 (ACE2). Berdasarkan analisis struktural dan fungsional, SARS-CoV-2 berikatan dengan ACE2 yang terdapat di sel epitel paru-paru, tetapi terdapat juga di ginjal, hati, kandung kemih, dan ileum. Dilaporkan bahwa, asam amino Gln498 pada S-RBD SARS-CoV 2 berikatan dengan ACE2 melalui asam amino Asp38, Tyr41, Gln42, Leu45, dan Lys353 membentuk ikatan hidrogen. Sementara Leu455 dari SARS-CoV2 berikatan dengan Asp30, Lys31, And His34. Ikatan SARS-CoV 2 dengan ACE2 lebih kuat jika dibandingkan dengan SARS-CoV karena salah satu asam amino SARCoV-2 yaitu Lys417berikatandenganAsp30dariACE2 membentuk jembatan garam, juga terdapat bidang bermuatan positif pada permukaan RBD yang berperan dalam potensial elektrostatik dan penambahan asam amino Lys417 yang tidak ada pada SARS-CoV. Setelah SARS-CoV-2 berikatan dengan protein sel host, akan terjadi pembelahan pada protein S[6,7].. Pembelahan protein S ini terdiri dari2 langkah yang bertujuan untuk mengaktifkan protein S MERS-CoV dan SARS-CoV yang digunakan sebagai model, pembelahan yang terjadi di S1/S2 akan menjadi dasar dan pembelahan untuk pengaktifan terjadi di S’2, yang posisinya berdekatan dengan fusion peptide dalam subunitS2[6,7].. Subunit S1 dan S2 tetap terikat secara non-kovalen setelah pembelahan yang terjadi di S1/S2 dan subunit S1 distal berperan dalam stabilisasi membrane- anchored dari S2 pada keadaan prefusi. Pembelahan yang terjadi diS2 ini mungkin mengaktifkan protein S untuk Membrane Fusion yang Irreversible (perubahan konformasi)[6,7].. Protein S pada Coronavirusberbeda dibandingkan dengan virus lainnya karena memiliki

protease

[Human

Airway

Trypsin-LikeProteaseAndCathepsinsAnd

Transmembrane Protease Serine 2 (TMPRSS2)] berbeda yang dapat membelah dan mengantifkan protein S itu sendiri[6,7].. Karakeristik yang hanya dimiliki SARS-CoV-2 adalah adanya tempat pembelahan furin (urutan RRPA). Seluruh S1/S2 dari SARS-CoV-2 menjadi sasaran pembelahan saat biosintesis, hal ini sangat berbeda dengan protein S yang terdapat pada SARS-CoV, di mana protein S tersebut bersatu tanpa harus membelah. Sifat virus yang sangat patogen ini disebabkan oleh ekspresi furin yang ada dimana-mana[6,7].

3 395


Gambar 1.Patogenesis SARS-CoV 2[7]. Gejala pasien yang terinfeksi SARS-CoV- 2 berkisar dari gejala ringan hingga gagal pernapasan berat dengan gagal organ multipel. Pada CT scan, karakteristik paru Ground Glass Opacification juga dapat terlihat bahkan pada pasien yang tidak bergejala. Hal tersebut dikarenakan ACE2 sangat terekspresi di sisi apikal sel epitel paru di ruang alveolar, virus ini dapat masuk dan menghancurkan sel epitel paru. Hal ini sesuai dengan fakta bahwa cedera paru-paru dini sering terlihat di saluran napas bagian distal. Tiga komponen utama untuk innate immune di saluran pernapasan yaitu sel epitel, sel dendritik, dan makrofag alveolus. Sel dendritik terletak di bawah epitel, sementara makrofag terletak di bagian apikal epitelium. Makrofag dan sel dendritik berperan sebagai innate immune untuk melawan virus hingga adaptive immune aktif. Penyajian antigen menginisiasi respon sel T 4 396


melalui sel dendritik dan makrofag. Sel yang terinfeksi virus akan mengalami apoptosis, sel yang terapoptosis akan difagosit oleh makrofag dan sel dendritik. Sel epitel terinfeksi yang mengalami apotosis dapat difagositosis oleh sel dendritik dan magrofag dan kemudian diarahkan untuk penyajian antigen pada sel T. Antigen presenting cell (APC) akan membawa antigen virus ke nodus limfe terdekat mengaktivasi sel T. Sel T CD4+ mengaktivasi sel B untuk merangsang produksi antibodi spesifik virus, sementara CD8+ dapat membunuh sel yang terinfeksi virus[6]. Sel epitel paru yang terinfeksi virus memproduksi IL-8 dan IL-6 pada sebuah penelitian tetang SARS-CoV-2 . IL-8 dikenal sebagai chemoattractant untuk neutrofil dan sel T. Di dalam paru-paru pasien COVID-19 berat dapat ditemukan infiltrasi yang banyak dari sel inflamasi, dan sel ini mungkin berisi kumpulan sel innateimmune dan sel adaptive immune. Neutrofil dapat bertindak sebagai “pedang bermata dua” karena neutrofil dapat menyebabkan cedera paru.Mayoritas inflitrasi dari sel adaptive immune yang diobservasi adalah sel T dengan mempertimbangkan penurunan yang signifikan dari sel T dalam sirkulasi.Sel T CD8+ adalah sel T sitotoksik primer. Pasien dengan gejala yang berat juga menunjukkan adanya sifat patologis sel T sitotoksik yang berasal dari sel TCD4+. Sel T sitotoksik ini dapat membunuh virus, tetapi juga berkontribusi dalam cedera paru[6]. Peptide terpene sebagai inhibitor Peptida terpene merupakan salah satu fitokimia yang berperan sebagai metabolit sekunder dan aktif dalam tanaman obat. Molekul biologi aktif ini adalah bagian dari sistem pertahanan yang dapat mengurangi infeksi pada tanaman dengan mencegah masuknya virus dan replikasi DNA/RNA virus. Sebagian besar terpene aktif secara biologis dan banyak digunakan untuk mengobati banyak penyakit seperti kanker serta memiliki efek anti malaria. Banyak penelitian in-silico yang dilakukan untuk mengetahui efek senyawa fitokimia dalam melawan SARS-CoV-2 / COVID-19[8]. Molecular docking (AutoDOCK Vina) adalah metode yang digunakan untuk menyeleksi senyawa terpene dalam melawan SARS-CoV-2 S-RBD. Dalam seleksi ini didapatkan tiga senyawa yang berinteraksi langsung dengan permukaan SARS-CoV-2 SRBD, yaitu 3-beta-O-[alpha-L-rhamnopyranosyl-(1- > 2)-alpha-L-arabinopyranosyl] olean12-ene-28-O-[alpha-L-rhamnopyranosyl-(1- > 4)-beta-D-glucopyranosyl-(1- > 6)- beta-Dglucopyranosyl] ester (NPACT01552), 3-O-[beta-D-gluco pyranosyl (1- > 3)-beta-Dgalactopyranosyl(1-

>

2)]-beta-D-glucu

ronopyranosyl-oleanolic

acid-28-O-beta-D-

5 397


glucopyranoside (NPAC T01557) dan Glycyrrhizin (NPACT00631). Seperti disebutkan sebelumnya, domain RBD berikatan dengan protein reseptor ACE2 melalui residu permukaan, yaitu Gly502, Gly496, Thr500, Gln498, Tyr449, Ala475, Asn487, lys417, Tyr489, Phe486, Glu484, Gln493, Ser494, Leu455 and Phe486. NPACT01552 menunjukkan interaksi ikatan hidrogen dengan Gly496, Tyr453, GLn493, Ser494 dan Glu484 di mana Gly496, GLn493, Ser494. NPACT01552 menunjukkan jumlah interaksi hidrofobik tertinggi dengan residu permukaan Lys417, Leu452, Tyr489, Phe456 dan Leu455. NPACT01557 berinteraksi dengan Thr500, Asn501, Gln498, TYr449 dan Glu484 melalui ikatan Hidrogen dan

dengan

Leu455

melalui

interaksi

hidrofobik.

NPACT00631 berinteraksi dengan Asn501, Gln498, Gly496, Tyr449, Tyr453 dan Glu484 melalui interaksi ikatan hidrogen dan berinteraksi dengan Tyr489, Phe456 dan Leu455 melalui interaksi hidrofobik[8].

Gambar 2.Gambaran terpene yang berikatan dengan residu permukaan aktif dari SARSCoV-2 S-RBD. NPACT01552 (ungu), NPACT01557 (merah muda), NPACT00631 (kuning), S-RBD (hijau). (a-b) interaksi NPACT01552, (c-d) NPACT01557, (e-f) NPACT00631 dengan S-RBD SARS-CoV-2[8]. Dilakukan tes farmakokinetik pada ketiga senyawa tersebut yaitu absorbsi, distribusi, metabolisme, ekskresi dan toksisitas. Hasil yang didapatkan pada tes ini terdapat dalam table berikut[8].

6 398


Media

NPACT01552

NPACT01557

NPACT00631

Blood brain-berrier

No

No

No

Permeabilitas caco-2

High

High

High

Yes

Yes

Yes

Renal organic cation

Inhibitor

Inhibitor

Non Inhibitor

transporter

Non inhibitor

Non inhibitor

Non inhibitor

CYP4502C9

Non inhibitor

Non inhibitor

Non inhibitor

CYP4502D6

Non inhibitor

Non inhibitor

Non inhibitor

CYP4503A4

Non inhibitor

Non inhibitor

Non inhibitor

CYP4501A2

Non inhibitor

Non inhibitor

Non inhibitor

CYP4502C19

Non inhibitor

Non inhibitor

Non inhibitor

AMES (mutagen)

Non ames toxic

Non ames toxic

Non ames toxic

karsinogen

Non carcinogens

Non carcinogens

Non carcinogens

a. Absorbsi dan distribusi

P-glycoprotein inhibitor

b. Metabolism

c. toksisitas

Tabel 1. Hasil uji farmakokinetik senyawa terpene[8]. Sumber ini mengatakan, energy bebas yang digunakan senyawa-senyawa tersebut untuk mengikat S-RBD yaitu NPACT01552 −23.234 ± 41.377 kcal/mol, NPACT01557 −62.565 ± 39.091 kcal/mol, dan NPACT00631 is −38.100 ± 35.383 kcal/mol. Energy bebas ini dihitung dengan kalkulasi MM/PBSA[8]. Vaksin mRNA Berdasarkan ekspresi sitoplasma, vaksin mRNA chimeric mengandung urutan virus ORF yang dikurasi, memiliki potensi besar untuk diterjemahkan secara langsung ke dalam sitoplasma dan memblokir integrasi kromosom. Setelah diinjeksikan, mrna diproses oleh sel imun dan mulai memproduksi protein yang ditargetkan secara langsung melalui translasi,

7 399


diikuti dengan pengaktifan sel imun lain untuk mengenali protein virus yang baru diproduksi untuk membuat antibodi. Ada dua jenis vaksin mRNA untuk melawan patogen infeksius, yaitu vaksin mRNA yang tidak bereplikasi dan vaksin mRNA yang direplikasi. Vaksin mRNA non-replikasi selanjutnya dibagi menjadi ex

vivo

loading

dendritic cells dan

injeksi secara in vivo langsung ke berbagai letak anatomis. Penetrasi barrier pada membran lipid adalah langkah pertama mrna eksogen untuk mencapai sitoplasma sebelum terjadi translasi protein fungsional. Mekanisme pengambilan vaksin mRNA menunjukkan spesifisitas sel, sifat fisikokimia mrna secara signifikan dapat mempengaruhi pengiriman seluler dan distribusi ke organ. Semua faktor ini harus dipertimbangkan saat merancang vaksin berbasis mRNA yang efektif.Vaksin mRNA dianggap kandidat vaksin yang menjanjikan karena dapat diperbanyak dengan cepat, sehingga dapat menghemat waktu.Sebagai virus (+) SS-RNA, SARS-CoV-2 memiliki RNA yang dapat memperkuat dirinya sendiri yang dapat mewujudkan replikasi RNA di dalam sitosol. Temuan ini mendukung peran pengembangan vaksin berbasis mRNA.Vaksin berbasis mRNA secara aktif menginduksi aktivasi respon sel B dan sel T sitotoksik. Pertama, vaksin mRNA menggunakan urutan mRNA dari protein target yang direkombinasi

secara in

vitro.

Selanjutnya, urutan mRNA ini dibawa oleh lnp dan masuk ke sitoplasma somatik untuk melakukan translasi langsung dan mengkodeprotein target. Ketika protein target dilepaskandari sel inang, sel penyaji antigen akan dengan cepat menangkap dan memproses protein target ini. Kemudian, MHC I dan MHC II akan menyajikan informasi pada permukaan sel penyaji antigen yang akan mengaktivasi sel B dan sel T, proses inimerupakan kunci untuk respon humoral dan sitotoksik[9]. Berdasarkan penelitian Jackson dkk, mereka melakukan percobaan vaksin mRNA kepada 45 partisipan dengan dosis pemberian 25 µm (n=15), 100 µm (n=15) dan 250 µm(n=15) sebanyak 2 kali vaksinasi. Dari percobaan ini, dilaporkan bahwa tidak ada efek samping yang serius. Setelah vaksinasi pertama, efek sistemik yang diinginkan terjadi pada 5 partisipan di kelompok 25 µm, 10 di kelompok 100 µm, dan 8 di kelompo 250 µm. Efek sistemik ini umumnya terjadi pada vaksinasi kedua, dan tidak ada partisipan yang mengalami demam pada kedua vaksinasi. Efek samping yang terjadi dari penggunaan vaksin Mrna berkisar dari efek ringan atau sedang, dan nyeri di lokasi injeksi yang biasanya umum terjadi pada vaksinasi.Dari vaksinasi mRNA efek samping yang terjadi pada sebagian subjek yang diteliti adalah kelelahan, menggigil, sakit kepala, mialgia, dan nyeri di sekitar lokasi injeksi[10].

8 400


Gambar 3. mekanisme kerja vaksin mRNA[9]. Nanopartikel sebagai protein delivery Persamaan dari SARS-CoV-2 dengan virus lain (terutamaSARS-CoVdan MERSCoV) yang dikaitkan dengan pengetahuan sebelumnya tentang reaksi sistem imun mereka, sangat membantu untuk mengembangkan vaksin COVID-19. Nanopartikel dapat diisi dengan berbagai gugus antigenik (dengan penjeratan fisik atau konjugasi kimiawi), dan tampilan antigenik yang benar menjadikannya alternatif yang sangat relevan dalam vaksinologi bila dibandingkan dengan pendekatan konvensional. Nanopartikel akan meningkatkan

pengiriman

dan

presentasi

antigen

ke

sel

penyaji

antigen

(APCs),nanopartikel juga menjaga struktur asli dari antigen. Banyak sistem biologis seperti virus (termasuk SARS-CoV-2) dan protein juga berukuran nano, sehingga menjadi sebuah keuntungan ketika menggunakan vaksin nanocarriers. Nanopartikel dapat diberikan melalui jalur oral, intranasal, injeksi subkutan, dan intramuskular. Nanopartikel memberikan beberapa keuntungan utama dengan melewati tissue barriers dan menargetkan lokasi utama seperti kelenjar getah bening, menembus mukosa, dan epitel barriers (saluran napas, hidung, gastrointestinal, dll). Laporan sebelumnya menunjukkan bahwa imunitas humoral dan seluler berperan sebagai pelindung dalam infeksi SARS-CoV. Nanopartikel telah menunjukkan kemampuannya dalam menargetkan sistem adaptive immune sel T, sel B) dan sistem innate immune (makrofag,monosit, neutrofil) pada tingkat sel. Untuk strategi vaksin 9 401


COVID-19, memodulasi APC menggunakan nanopartikel bisa menjadi sangat penting. Imunitas sel T dapat meningkat sesuai kemampuan nanopartikel untuk mengantarkan antigen ke sel dendritik (DC) dengan meningkatkan presentasi antigen dan beberapa mekanisme lain. Untuk meningkatkan kemanjuran dan keamanan dari vaksin terdapat beberapa keuntungan besar yang disajikan oleh nanopartikel yaitu kemampuanan adjuvant molekuler, dan dalam beberapa kasus, bahan nano itu sendiri memiliki properti adjuvant intrinsik untuk memuat antigen[8]. Kesimpulan Senyawa peptide terpene dapat mencegah ikatan SARS-CoV-2 S-RBD dengan protein ACE2. Melalui ikatan hydrogen dan interaksi hidrofobik antar senyawa-senyawa NPACT01552, NPACT01557, NPACT00631dengan residu permukaan pada S-RBD yaitu Gly502, Gly496, Thr500, Gln498, Tyr449, Ala475, Asn487, lys417, Tyr489, Phe486, Glu484, Gln493, Ser494, Leu455 and Phe486, akan mencegah ikatannya dengan reseptor ACE2. Vaksin mRNA dapat menginduksi aktivasi sel B dan sel T sitotoksik. Vaksin mRNA akan memproduksi protein target melalui translasi, kemudian sel imun akan mengenali protein virus ini dan memproduksi antibodi. Nanopartikel akan meningkatkan pengiriman dan presentasi antigen ke sel penyaji antigen (APCs), nanopartikel juga menjaga struktur asli dari antigen. Untuk strategi vaksin COVID-19, memodulasi apc menggunakan nanopartikel bisa menjadi sangat penting. Imunitas sel T dapat meningkat sesuai kemampuan nanopartikel untuk mengantarkan antigen ke sel dendritik (DC) dengan meningkatkan presentasi antigen dan beberapa mekanisme lain. Nanopartikel memberikan beberapa keuntungan utama dengan melewati tissue barriers dan menargetkan lokasi utama seperti kelenjar getah bening, menembus mukosa, dan epitel barriers (saluran napas, hidung, gastrointestinal, dll.). Saran Dibutuhkan penelitian lebih lanjut untuk mengetahui efektivitasnya.

10 402


Daftar pustaka 1. Wang C, Li W, Drabek D, Okba NMA, Haperen RV, Osterhaus ADME, et al. A human

monoclonal

communications.

antibody

2020;

2.

blocking

Cited

SARS-CoV-2

2020

agustus

infection.

22.

Nature

Available

from:

https://www.nature.com/articles/s41467-020-16256-y 2. World Health Organization. How is covid-19 transmitted. Who, 2020. 3. Zheng J. SARS-CoV-2: an Emerging Coronavirus that Causes a Global Threat. International Journal of Biological Sciences. 2020; 16:1680-81. Cited 2020 Agustus 24.

Available

from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098030/#:~:text=Ivyspring% 20International%20Publisher,SARS%2DCoV%2D2%3A%20an%20Emerging%20Co ronavirus,that%20Causes%20a%20Global%20Threat 4. Sanyaolu A, Okorie C, Marinkovic A, Patidar R, Younis K, Desai P, et al. Comorbidity and its impact on patients with COVID-19. Sn comprehensive clinical medicine.

2020;

2:

1070.

Cited

2020

November

26.

Available

from:

https://link.springer.com/article/10.1007/s42399-020-00363-4 5. Kemenkes RI. Infodatin covid-19. Kemenkes RI, 2020. 6. Yuki K, Fujiogi M, Koutsogiannaki S. COVID-19 pathophysiology: a review. Clinical immunology. 2020; 215: 2-3. Cited 2020 November 28. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7169933/ 7. Cauhan G, Madou MJ, Kalra S, Chopra V, Ghosh D, Chapa SOM. Nanotechnology for COVID-19: therapeutics and vaccine research. American chemical society. 2020; 14(7):

7760-70.

Cited

2020

November

28.

Available

from:

https://pubs.acs.org/doi/10.1021/acsnano.0c04006 8. Muhseen ZT, Hameed AR, Al-hasani HMH, Qamar MTU, Li G. Promising terpenes as SARS-CoV-2 spike receptor-binding domain (RBD) attachment inhibitors to the human ACE2 receptor: Integrated computational approach. Journal of Molecular Liquids.

2020;

320:

2-7.

Cited

2020

Desember

4.

Available

from:

https://www.sciencedirect.com/science/article/pii/S0167732220359389 9. Wang F, Kream RM, Stefano GB. An evidence based perspective on mRNA-SARSCoV-2 vaccine development. Medical science monitor. 2020; 26: 2-5. Cited 2020 Desember

6.

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from:

https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7218962/

11 403


10. Jackson LA, Anderson EJ, Rouphael NG, Roberts PC, Makhene M, Coler RN, et al. An mRNA vaccine against SARS-CoV-2 — preliminary report. The new england journal

of

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2020

Desember

9.

Availablefrom:https://www.nejm.org/doi/pdf/10.1056/nejmoa2022483?Articletools=t rue

12 404


Ways to Ameliorate Unending Leprosy Cases in Indonesia: A Literature Review

Donnatella Valentina December 14, 2020

405


Introduction​: Ranking third worldwide, Indonesia leprosy cases reached an outstanding 17,017 new cases in 2018. Despite ongoing preventive, curative and rehabilitative efforts by the Indonesian government, leprosy cases continue to rise at an alarming rate in the nation. Methods​: This literature review analyzes these efforts in relation to the immense number of cases through published journals from three databases: PubMed, ScienceDirect, and GoogleScholar with “Leprosy”, “Hansen’s Disease”, and “Kusta'' as the main keywords between 30th of November 2020 to 9th of December 2020. No language or time restriction was applied. Result​: The main findings of the data are as follows, preventative measures like health advocacy (a)are engineered mostly through public advertisements (b) done to raise awareness and break down stigmas surrounding leprosy (c) has been found to be ineffective in increasing leprosy literature among Indonesians. More clinical solutions like Multidrug therapy (MDT) (a) is a long-term drug therapy treatment of leprosy (b) many lepers fail to commit to therapy and Medical rehabilitation (a) offers great services in handling later symptoms like physical disabilities. Other social issues such as poverty (a) is a detrimental risk factor that increases susceptibility towards leprosy (b) that can be improved by advocating proper nutrition. Indonesia has also chosen to place its priority on other diseases, leaving less room for leprosy programs to grow. Conclusion​: It’s important to address the problem of leprosy due to the extensive number of cases in many parts of Indonesia. Untangling issues such as stigmatisation, low-adherence to MDT, and poverty that continually spark high cases of leprosy is best done through educational campaigns within social media, the implementation of short message service (SMS) programs to improve patients’ attendance and adherence to MDT, and the advocacy of a proper, nutritious diet to lessen the risk of being infected with leprosy.

406


Ways to Ameliorate Unending Leprosy Cases in Indonesia: A Literature Review

Donnatella Valentina December 14, 2020

407


Abstract Introduction​: Ranking third worldwide, Indonesia leprosy cases reached an outstanding 17,017 new cases in 2018. Despite ongoing preventive, curative and rehabilitative efforts by the Indonesian government, leprosy cases continue to rise at an alarming rate in the nation. Methods​: This literature review analyzes these efforts in relation to the immense number of cases through published journals from three databases: PubMed, ScienceDirect, and GoogleScholar with “Leprosy”, “Hansen’s Disease”, and “Kusta'' as the main keywords between 30th of November 2020 to 9th of December 2020. No language or time restriction was applied. Result​: The main findings of the data are as follows, preventative measures like health advocacy (a)are engineered mostly through public advertisements (b) done to raise awareness and break down stigmas surrounding leprosy (c) has been found to be ineffective in increasing leprosy literature among Indonesians. More clinical solutions like Multidrug therapy (MDT) (a) is a long-term drug therapy treatment of leprosy (b) many lepers fail to commit to therapy and Medical rehabilitation (a) offers great services in handling later symptoms like physical disabilities. Other social issues such as poverty (a) is a detrimental risk factor that increases susceptibility towards leprosy (b) that can be improved by advocating proper nutrition. Indonesia has also chosen to place its priority on other diseases, leaving less room for leprosy programs to grow. Conclusion​: It’s important to address the problem of leprosy due to the extensive number of cases in many parts of Indonesia. Untangling issues such as stigmatisation, low-adherence to MDT, and poverty that continually spark high cases of leprosy is best done through educational campaigns within social media, the implementation of short message service (SMS) programs to improve patients’ attendance and adherence to MDT, and the advocacy of a proper, nutritious diet to lessen the risk of being infected with leprosy.

408


Introduction Leprosy or Hansen's disease is caused by an infection of ​Mycobacterium leprae or

Mycobacterium lepromatosis​, commonly transmitted via droplets of an untreated Leprosy

patient, causing disturbance primarily to the skin and peripheral nerves.​1 Ranked third highest

nation with new emerging cases of Leprosy annually, Indonesia is in no doubt still struggling for solutions to eradicate the disease. The World Health Organization (WHO) declared leprosy as a continuing major health issue in Indonesia, with 17,017 new cases in 2018 alone.​2 Given the data, current efforts may not be sufficient enough in treating leprosy, this may be caused by several prominent issues found between leprosy patients (lepers) in Indonesia. Stigmatisation, low adherence in undergoing therapy and poverty are key determinants to the unending leprosy predicament in Indonesia. Leprosy-related stigma is still very apparent among Indonesian society, affecting not only lepers and former lepers’ lives costing their relationships, jobs, and participation in social and religious gatherings among other things, but also contributing to interference in leprosy treatment process.​3 Low adherence in therapy is another major problem faced in eliminating leprosy. Multidrug therapy (MDT) is a prominent cure in treating leprosy all over the world, Indonesia included. As patients’ attendance in Multidrug Therapy (MDT) regimen are intermittent, leprosy microbes inside a patient’s body become immune to MDT, causing the patient to retain leprosy symptoms and be vulnerable to the development of deformities. Poverty is the last major leprosy hindrance identified in Indonesia that will be discussed in this paper. People with poor education, insecure income, no land ownership and nutrient deficiencies are proven more susceptible to leprosy​4​. With 26.42 million Indonesians still living in poverty​5 and the people’s major lack of knowledge on nutritional value of food in general, a large percentage of Indonesians have poor diet choices and are at an increased risk of leprosy infection. The aim of this review is to present the current state of leprosy in Indonesia including ongoing preventive, curative and rehabilitative methods against leprosy, identify prevailing problems, and propose feasible solutions and improvements for the amelioration of leprosy in Indonesia. Materials and Methods This literature review was conducted based on publicly available information on the Internet. The literature search was accomplished from three databases: PubMed,

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ScienceDirect and GoogleScholar with “Leprosy”, “Hansen’s Disease”, and “Kusta'' as the main keywords followed by “Indonesia'' as the primary supporting keyword. The last search date was on 9th of December 2020 with initial search date on 30th of November 2020. No language or time restriction was applied, however, data’s credibility is ensured with prioritization of recent publications within the last ten years. Author’s participation throughout the review includes screening of titles and abstracts of journals, assessing the full text to ensure journal’s eligibility and correlation to the topic of discussion, as well as individual evaluation of courses of action needed to achieve amelioration of leprosy in Indonesia. Results and Discussion Based on the journals analysed, it was found that leprosy control in Indonesia is maintained by implementing preventive and control measures through health advocacy, surveillance programs, chemoprophylaxis, and leprosy management. Health advocacy includes educating the public on early signs and symptoms of leprosy​6​, which, among others, includes the appearance of discolored patches of the skin that may include numbness, growths on the skin, thick and dry skin, painless swelling or lumps on the face/earlobes, and enlarged peripheral nerves.​7 Besides increasing awareness on initial signs of leprosy, health advocacy programs are also aimed to influence society’s perception on leprosy to eliminate prevailing stigma and discrimination against leprosy-affected persons. These objectives are actualized through leaflets, posters, banners, community outreach programs, public advertisements, and short films.​6 Besides health advocacy, surveillance programs are enforced as one of the preventive methods, directed to detect early onset leprosy patients to receive initial treatment and to discover the magnitude of leprosy in an area, it is enforced in areas of high leprosy prevalence as well as areas that have successfully eradicated leprosy to maintain the leprosy-free status. Surveillance programs are implemented in the form of data collection, data processing, data analysis, and information dissemination. While the data is gathered through active and passive investigations, of which active includes rapid village surveys, examination of school children and contact investigation of individuals with their surroundings. Meanwhile passive investigation includes data retrieval mostly from health service facilities and the community.​6 Surveillance programs in Indonesia are carried out by approximately 9000 primary health care (PHC) facilities led by 530 district health officers to discover new cases, oversee patients’ treatment, and assess the outcome.​8

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Chemoprophylaxis is another preventive method encompassing the administration of drugs for individuals mainly in areas of high leprosy prevalence. Chemoprophylaxis of leprosy is implemented on residents that meets a certain criteria that ensures the person as a resident in an area of high leprosy prevalence for at least three months, is older than two years of age and not an elderly with cognitive impairment, is not suspected of leprosy or diagnosed with leprosy or tuberculosis, have not consumed rifampin within the last two years, and do not have kidney and liver dysfunction. Chemoprophylaxis for leprosy is only consumed once and may be repeated after two years from the previous administration. Implementation methods of chemoprophylaxis enforcement are adapted to the circumstances of the target area. These implementation methods include the blanket approach, community participation approach (based on a self-screening format (SSF) for leprosy), and the contact approach.​6 Besides preventive measures, a leprosy-infected person must be treated accordingly. A widely-known, effective cure for leprosy is recognized as multidrug therapy. Multidrug therapy (MDT) is an internationally-adopted combination drug therapy consisting of rifampicin, clofazimine, and dapsone recommended by the WHO to treat leprosy patients for a timespan of 6 months for paucibacillary leprosy patients and 12 months for multibacillary leprosy patients, with differing blister packs corresponding to leprosy type and varying age groups. As implemented in the rest of the world, MDT also serves as a prominent cure for leprosy in Indonesia. This combination drug therapy treatment is aimed to break the chain of transmission, prevent drug resistance, increase constancy of medication, and prevent the development of deformities.​8 If lepers fail to acquire treatment regularly, leprosy bacteria inside the body may be immune to MDT, hence symptoms of the disease will persist or even pose more threats, potentially causing relapse or disabilities to occur. This calls for the urgency of lepers’ consistent attendance in undergoing therapy. The MDT regimen in Indonesia is in accordance with that recommended by the WHO displayed in Table 2.1 and Table 2.2. Since it was initially recommended in 1981,​9 MDT has proven to effectively heal leprosy patients and reduce infectivity in the community. Unfortunately, MDT management in Indonesia is still poor and has a lot of room for improvements. Leprosy patients who have completed their course of treatment but still require further medical attention will undergo rehabilitation specialized for each leprosy survivor. Medical rehabilitation designated for leprosy-affected persons in Indonesia encompass specialized treatments for each patient and may involve the participation of specialists in various fields. For example, leprosy sufferers with severe lagophthalmos will endure corrective surgery, same goes to deficiencies in fingers of the hand such as the claw

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hand condition, provided the joints are still mobile. Severe infections of the hand and feet of former lepers will be provided with antibiotics or a surgical procedure. Chronic ulcers of the feet or other extensive wounds will undergo septic surgery/sequestrectomy/amputation. Leprosy patients who have completed their course of medication will undergo treatment monitoring and evaluation by community health center officers to avoid development of disabilities.​6 Despite ongoing preventive, curative, and rehabilitative measures, Indonesia is still ranked third highest nation with leprosy cases after India and Brazil, with 20,160 total cases and 17,202 new cases in 2015, contributing to 8% of the global case load.​7 In 2018, the number of new cases reported remained relatively equivalent to its amount in 2015, standing at 17,017.​2 As of 2018, complete leprosy elimination has been achieved in 24 provinces and 142 districts/cities. Unfortunately, leprosy-infected individuals are still found widespread in approximately 7,548 villages, 1,975 community health centers (Puskesmas), in 341 districts/cities in Indonesia.​6 The endless number of new cases each year may be caused by the major problems found among leprosy patients in Indonesia including stigmatisation, low adherence in undergoing therapy, limited access to healthcare, and poverty. Leprosy-related stigma is still profoundly apparent in Indonesia, especially among the society of Southeast Sulawesi. Leprosy is believed to be inherited and correlated with ideas of unsanitized blood that is shameful and disgraced by the people.​3 The stigma, also generally linked with the perception of deformity, is often associated with a religious perspective and fear of an incurable disease.​9 The main cause of the fear and animosity towards leprosy is lack of accurate information of the disease, mostly apparent in rural, secluded areas in many parts of Indonesia. This widely believed apocryphal claim has caused drawbacks in leprosy treatment process and adversely impacted the lives of leprosy-infected persons, including their mobility, interpersonal relationships, marriage, employment, leisure activities, and attendance at social and religious gatherings.​3 It is only when stigmatisation is eliminated and the society’s perception of leprosy is altered, that discrimination and marginalization be reduced, leaning towards the amelioration of leprosy in the country and eventually the utter elimination of the disease as a public health problem. Besides prevailing stigma, low adherence in MDT is another major hindrance towards the amelioration of leprosy. As recommended by the WHO in 1981,​9 leprosy patients should undergo MDT for 6 or 12 months, according to the leprosy type. Due to the long course of medication, low adherence to leprosy treatment is perceived as one of the main challenges in reducing the disease’s prevalence in Indonesia. Failure to uphold treatment may result in residual sources

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of infection, incomplete cure, persisting infections, irreversible complications, and transmission to new, susceptible, multidrug resistance, as well as exposure to advanced leprosy including the development of disabilities.​8 In addition to leprosy-related stigma and low adherence in MDT, people living in poverty are proven to be more susceptible to leprosy. Leprosy has long been established as a disease of poverty. Most of the affected areas worldwide are underdeveloped nations with high endemic areas being those that are rural and out of reach. Most people affected by leprosy are born and raised in poor surroundings and continually pressured into poverty due to the stigma and deformities. A 2016 study focused on rural areas of Bangkalan, Madura, Indonesia found that compared to the control population, people with leprosy have less favorable socioeconomic and demographic conditions including low educational levels, unstable income and no land ownership, along with inadequate dietetic consumption.​4 The lack of knowledge on nutritional values of food causes a poor diet choice to be fairly common among Indonesians. Nutrient deficiencies are important risk factors for leprosy susceptibility, this ​is due to the fact that a low consumption

of antioxidants impairs the immune system against leprosy microbes​. ​A study found that nutrient deficiencies in lepers lead to decreased serum levels of vitamin A, C, D, and E, as well as magnesium, selenium, and zinc. Those antioxidants serve an essential role in counterbalancing reactive oxygen species (ROS), nitric oxide (NO), and reactive nitrogen species (RNS) activities that are generated during leprosy infection to exterminate microbes, that could potentially damage body tissues due to high inflammation from high oxidant activities.​10 Therefore, insufficient dietary antioxidant levels generated by a poor diet could complicate leprosy treatment and advance leprosy progression. Besides some of the problems mentioned, other obstacles identified by the Indonesian Ministry of Health that hinders the elimination of leprosy in the country include a poor MDT management, the lack of proficient ability by community health center (puskesmas) officers in early case detection and management, and the nation’s diverted attention to other diseases such as Tuberculosis and Human Immunodeficiency Virus (HIV), hence the lack of concern on leprosy in Indonesia.​6 As current efforts by the Indonesian government are proven to be insufficient provided the number of cases still plaguing the nation, several adjustments have to be made. Ongoing health advocacy programs through leaflets, banners and other current methods are proven to be less effective as stigma is still highly apparent among Indonesians. Therefore, social media, which could be an unforeseen solution to strengthening health advocacy, must be utilized to conduct campaigns and intensify the public’s knowledge of the disease. Social

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media is one of the most powerful platforms to change people’s perception these days with approximately 150 million social media users or equivalent to about 56% of the entire population in 2019.​11 By utilizing widely used applications like Facebook, Youtube, Instagram, Twitter, and the currently-trending application Tiktok, leprosy awareness can be raised, and by educating those who have access to the Internet, those who don’t can also be educated through community outreach programs from healthcare workers. Through social media, a specific hashtag can be used to fight leprosy-related stigma and more people, especially local health workers, medical students, leprosy patients, and leprosy survivors, can be part of the movement, help raise leprosy awareness and provide factual information to the public. As stigma negatively impacts leprosy survivors in various aspects of their life, leprosy-affected persons

must be empowered through self-esteem restoration in

rehabilitation, and especially for those struggling for employment after being diagnosed with leprosy, must be guided by PHC facilities to be employed once again. This can be done by having PHCs collaborate with various companies from different fields that welcome leprosy survivors and pay a fair income. Other than widespread stigma, low adherence to therapy is another major hindrance in eliminating leprosy in Indonesia, considering irregular treatment is commonly associated with relapse and disabilities. Until recently, mHealth innovations haven’t been cultivated in leprosy combat. Late studies have proven the effectiveness of short message service (SMS) features in improving attendance and adherence for diseases that require long-term medication such as HIV, tuberculosis and diabetes, presenting a potential solution in increasing patient’s attendance in leprosy MDT regimen. A 4 year study from 2012 to 2016 conducted in Pekalongan, Central Java, has proven the effectiveness of a web-based application featuring automated SMS notified monthly to patients aimed to control patients’ adherence in therapy. Of 188 leprosy patients evaluated, 124 patients never received SMS reminders (control group) and 64 patients received SMS reminders throughout the course of treatment (experimental group). A remarkable 21% increase in on-time completion and an approximate 15% increase in on-time attendance was found in the experimental group whose members are notified with SMS reminders (Figure 1). SMS reminders must be sent to the patient, a relative and leprosy surveillance officers (LSO). This is done so that in special circumstances when patients can’t handle a mobile phone or do not have access to it, patients’ relatives and confidantes can remind patients of their schedules for therapy. Meanwhile, it is LSOS’ responsibility to update the status of MDT patients and ensure regular treatment of patients. This solution can be actualized through the enforcement of low-cost text message

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systems in PHC services which enables automated text message reminders to be notified to patients and ameliorate disease control.​8 Besides prevailing stigma and low adherence in therapy, as poverty and nutrient deficiencies are proven to increase susceptibility for leprosy, nutritional security among leprosy-affected persons must be ensured. Poor diet in leprosy patients can weaken their cellular immunity to poorly defend against leprosy infections. Therefore, to ameliorate leprosy cases in the country, a low-cost, high protein balanced diet​10 must be advocated among leprosy patients undergoing MDT as well as inhabitants in areas of high leprosy prevalence. This is done to achieve potential cure and prevent development of deformities for lepers, as well as avoid surrounding inhabitants from being infected with leprosy. The program can be implemented by conducting proper dietary campaigns and the establishment of an affordable diet catering that contains nutritious food specialized to cater leprosy patients or residents in high endemic areas for leprosy. This can be done by regional medical workers that are well-educated on appropriate diet needs of leprosy patients, and if this were to be actualized, it can be provided in PHC facilities widely dispersed all over Indonesia. As future doctors, our job as medical students is to take part in raising leprosy awareness, help remove stigma in the society by acknowledging and publicizing the fact that leprosy is a curable disease by initiating or taking part in social media campaigns surrounding leprosy. We should educate the public on the early signs and symptoms of leprosy so anyone who experiences or identifies someone with those symptoms could be reported and examined with leprosy, which we must do too whenever we encounter a possible leprosy patient. Conclusion The alarming prevalence of leprosy in Indonesia should be taken in all seriousness. Despite ongoing preventive, curative, and rehabilitative methods, leprosy cases are still highly evident in multiple parts of Indonesia. Therefore, apparent issues that propose major hindrance such as widespread leprosy-related stigma, low adherence in therapy, and poverty must be resolved. This can be achieved by disseminating accurate information on leprosy through intensified educational campaigns by utilizing various social media platforms, implementing SMS programs in all PHC facilities to improve patients’ attendance and adherence to MDT procedures, and advocating a proper, nutritious diet in high endemic areas for leprosy. Self-esteem restoration and job opportunities should also be implemented as part of the rehabilitation program. If these proposals were to be actualized, amelioration of leprosy in Indonesia is guaranteed.

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References 1. Leprosy (Hansen’s disease) [Internet]. [cited 2020 Nov 30]. Available from: https://www.who.int/westernpacific/health-topics/leprosy 2. indonesia-health-profile-2018.pdf [Internet]. [cited 2020 Dec 3]. Available from: https://www.kemkes.go.id/resources/download/pusdatin/profil-kesehatan-indonesia/in donesia-health-profile-2018.pdf 3. Tosepu R, Gunawan J, Effendy DS, Fadmi FR. Stigma and increase of leprosy cases in SouthEast Sulawesi Province, Indonesia. Afr Health Sci. 2018 Mar;18(1):29–31. 4. Oktaria S, Hurif NS, Naim W, Thio HB, Nijsten TEC, Richardus JH. Dietary diversity and poverty as risk factors for leprosy in Indonesia: A case-control study. PLoS Negl Trop Dis [Internet]. 2018 Mar 13 [cited 2020 Dec 6];12(3). Available from:​ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865754/ 5. The World Bank in Indonesia [Internet]. World Bank. [cited 2020 Dec 9]. Available from:​ https://www.worldbank.org/en/country/indonesia/overview 6. PMK_No__11_Th_2019_ttg_Penanggulangan_Kusta.pdf [Internet]. [cited 2020 Dec 3].

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http://hukor.kemkes.go.id/uploads/produk_hukum/PMK_No__11_Th_2019_ttg_Pena nggulangan_Kusta.pdf 7. Hansen’s Disease (Leprosy) | CDC [Internet]. 2018 [cited 2020 Nov 30]. Available from:​ https://www.cdc.gov/leprosy/index.html​World Health Organization - 2017 8. Rachmani E, Hsu C-Y, Chang PWS, Jumanto J, Fuad A, Ningrum DNA, et al. Encouraging On-Time Completion of Leprosy Patients Treatment: Implementing E-Leprosy Framework to Primary Health Care in Indonesia. Asia Pac J Public Health. 2019;31(4):296–305. 9. Naaz. Challenges beyond elimination in leprosy [Internet]. [cited 2020 Dec 3]. Available

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https://www.ijmyco.org/article.asp?issn=2212-5531;year=2017;volume=6;issue=3;sp age=222;epage=228;aulast=Naaz 10. Dwivedi VD, Banerjee A, Das I, Saha A, Dutta M, Bhardwaj B, Biswas S, Chattopadhyay D. Diet and nutrition: An important risk factor in leprosy ScienceDirect

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https://www.unescap.org/sites/default/files/03_Building_A_Statistics_Society_throug h_Youtube_Indonesia.pdf [cited 2020 Dec 9]. 12. World Health Organization. State of health inequality: Indonesia. 2017 [Internet]. [cited

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9];2016.

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from:


Tables and Figures Table 2.1: MDT treatment type PB based on age group recommended by the WHO

Drug type

<5 y.o.

5-9 y.o.

10-15 y.o.

>15 y.o.

Description

Rifampicin

Treatment based on body weight

300 mg/month

450 mg/month

600 mg/month

Consume in front of an officer

100 mg/month

Consume in front of an officer

100 mg/day

Consume at home

Dapsone

25 mg/month 50 mg/month

25 mg/day

50 mg/day

Duration: six months (six blister packs), * y.o. = years old Table 2.2: MDT treatment type MB based on age group recommended by the WHO

Drug type

<5 y.o.

5-9 y.o.

10-15 y.o.

>15 y.o.

Description

Rifampicin

Treatment based on body weight

300 mg/month

450 mg/month

600 mg/month

Consume in front of an officer

100 mg/month

150 mg/month

300 mg/month

Consume in front of an officer

50 mg, 2x a week

50 mg/2 days

50 mg/day

Consume at home

25 mg/month 50 mg/month

100 mg/month

Consume in front of an officer

25 mg/month 50 mg/month

100 mg/month

Consume at home

Clofazimine

Dapsone

Duration: 12 months (12 blister packs), * y.o. = years old

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Figure 1: The Trend of On Time Attendance (OTA) between MDT. Source: ​Encouraging

On-Time Completion of Leprosy Patients Treatment: Implementing E-Leprosy Framework to Primary Health Care in Indonesia, ​2019

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What is Wrong Filariasis Control and Prevention In Indonesia? A Literature Review Rayya Az-Zahra, 1​​ Shofiya Assyifa, ​1​Thyfa Annisa

1​

1​

Asian Medical Student’s Association, Batch 2019

ABSTRACT Introduction : ​Filariasis is one of the endemic diseases in Indonesia that tends to be neglected. This transmissible disease is still classified as one of Indonesia’s unifinished agenda which causes lifelong disability leading decline in human capacity and ability. Despite the rigorous prevention and treatment of filariasis has been proclaimed by the government for over 10 years, it is inconceivable that even now in 2020 Indonesia is still a filariasis endemic country. This review is conducted to explore filariasis control and prevention programs that have been carried out in Indonesia, and what could be done to improve them. Material and Methods : ​This literature review is conducted by collecting the database from PubMed, Science Direct, Google Scholar, and Indonesian Ministry of Health official data. The keywords used are: “filariasis”, “prevention”, “control”. “policy”, elimination”, “Indonesia”, “compliance”, “consumption”, “traditional mindset” and “mass drug administration”. Results and Discussion : ​Filariasis prevention program in Indonesia has been unsuccessful due to lack of education and socialization to the community and health workers, abundant

mosquitoes’ breeding and resting places near houses and low compliance in taking medication. Therefore, we should increase the socialization to health workers and community, reduce the contact between human and the vector of filariasis, and ​lower drug hesitation​. Conclusion : ​It is not only the responsibility of the government and medical officers to deal with filariasis in Indonesia, but also the community and multisectoral collaboration. Healthcare workers as the front line workers should increase people’s awareness on the disease and engage the community in preventing and controlling Filariasis.

420


What is Wrong with Filariasis Control and Prevention in Indonesia? A Literature Review Indonesian Medical Students’ Training and Competition​ 2021 Scientific Paper

Rayya Az-Zahra (1907101010010) Shofiya Assyifa (1907101010043) Thyfa Annisa (1907101010089)

FACULTY OF MEDICINE UNIVERSITAS SYIAH KUALA BANDA ACEH 2020

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INTRODUCTION Filariasis is one of the endemic diseases in Indonesia that tends to be neglected. This transmissible disease is still classified as one of Indonesia’s unifinished agenda which causes lifelong disability leading decline in human capacity and ability. According to Indonesian Health Profile (Profil Kesehatan Indonesia) 2019, 10,758 cases of filariasis were recorded in 34 provinces in Indonesia of which the eastern part of Indonesia recorded the highest numbers: Papua with 3,615 cases, East Nusa Tenggara with 1,540 cases, and West Papua with 1,089 cases. On the other hand, Bali with (2 cases), DI Yogyakarta (3 cases), and Gorontalo (5 cases) had the lowest prevalence.​1

Figure 1.1 The number Of Chronic Filariasis Cases in Indonesia 2010-2019​1 Indonesian government has agreed to contribute in eradicating filariasis as a part of global elimination through two pillars of action. The first pillar is to break the chain of filariasis transmission by administration of DEC (​Diethylcarbamazine Citrate) 6 mg/Kg BW combined with Albendazole 400 mg, in endemic areas once a year for five consecutive years. While the second pillar is to prevent and limit disability with self-management of filariasis cases.​2 Despite the rigourous prevention and treatment of filariasis has been proclaimed by the government for over 10 years, it is inconceivable that even now in 2020 Indonesia is still a filariasis endemic country. Meanwile, countries like Korea, Malaysia, Vietnam, Cambodia, and China have succeeded in eradicating filariasis. Interestingly, these countries in general took the same steps taken by Indonesian government.​3,4,5 But why does the program seemed

422


to be unsuccessful in Indonesia? This review is conducted to explore filariasis control and prevention programs that have been carried out in Indonesia, and what could be done to improve them. MATERIALS AND METHODS This literature review is conducted by collecting the database from PubMed, Science Direct, Google Scholar, and Indonesian Ministry of Health official data. The keywords used are: “filariasis”, “prevention”, “control”. “policy”, elimination”, “Indonesia”, “compliance”, “consumption”, “traditional mindset” and “mass drug administration” in both English and Indonesian were used here. Literatures included in this study have to be published between 2010-2020 and contain : 1) weakness and/or solution regarding filariasis control in Indonesia, 2) Indonesian government programs to deal with filariasis, 3) Programs of other countries to deal with filariasis.

Figure 2.1 Selection process of articles RESULTS AND DICUSSION After obtaining several journal and related liteatures, ten articles were included in this study, all of which discussed the filariasis control and prevention in Indonesia. Several topics emerged as potential problems and solution for filariasis control and prevention program in Indonesia. Community Education and Awareness Mara Ipa et al (2020) reported several causes of unsuccessful filariasis eradication in Indonesia, consisted of low education coverage and traditional mindset of the community regarding the etiology, prevention and control of filariasis. The study found that respondents from three endemic regions ​(Tanggerang, Pasaman Barat ​and Donggala) did not have sufficient education about filarisasis. For example, some respondents were able to mention mosquito as the reservoir but unable to explain further. However, respondents assumed that filariasis is a cursed disease. In the city of West Waringin, people with filariasis use grated

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galangal to treat their disease due to a lack of knowledge. The study also added that Aceh Jaya residents used tobacco leaves tied tightly with rubber until mucus came out. Another significant finding is that respondents did not immediately consult a professional healer and preferred to go to a traditional healer or treat the disease independently.​6 This finding is coherent with previous study by Tumanggor (2010), in which most of Indonesians still tends to stick with supernatural beliefs causing more obstacles in the development of health and healhcare.​7 Filariasis eradication requires multi sector cooperation. Based on the research of Udin Rosidin et al. (2020), a public figure such as religious leaders, community or organization leaders, professionals, and also stakeholders who had adequate knowledge about Covid19 were contributing highly in preventing and overcoming Covid19.​8 As they have the power to influence the society, this opportunity has to be utilized in tackling filariasis by collaborating with known public figures in order to gain public belief and awareness. Medical professionals should approach public figures to help them educating the community about prevention and management of filariasis. Mosquitos’ Breeding and Resting Place According to Robo Rahamyantel et al (2019), from a sample of 45 people selected by purposive sampling method and scattered in the work area of ​6 health centres in Semarang Regency, 64.4% of respondents' houses were found breeding places, and 35% were not found breeding places. 60% of respondents found resting areas around their homes, and 40% did not find resting places. ​Besides, it also known that ​26.7% of respondents leaving the house at night and 73.3% did not leave the house.​9​ Mansonia Uniformis​, which is one of the vectors for filariasis, usually lays its eggs underwater plants and wood chips.​10 Mosquito breed and rest their egg in the tubs, dispensers, bird drinking places, drainage, open sewers, bushes, puddle and calm water flow in rivers. The existence of mosquito breeding places around the respondents’ house provide places to lay eggs, to find food, or as shelters for adult mosquitoes. Therefore, the community should not let stagnant water exposed, remove breeding places of the mosquitoes, bury worn stuffs potential for becoming water receptacles, drain water containers, use insecticide to minimize the availability of breeding and resting places for filariasis’ vector mosquitoes. Moreover, contact between humans and mosquitoes should also be reduced by using mosquito nets while sleeping, wearing self-protective materials when working at a farm, and using mosquito-repelling chemicals. 9,11 ​ 424


Socialization to Health Workers The filariasis elimination program policy has not been implemented optimally. ​As observed in Kotawaringin Barat Regency, there are several factors related to this issue, such as lack of socialization to health workers and the community, undeveloped cross-sector cooperation, very limited operational costs for implementing mass treatment, and inadequate quality of human resources, incomplete supporting facilities for the implementation of mass medication, the organizational structure has not been formed and the instructions for carrying out tasks are unclear.​12 Similarly, A study conducted in Sorong also found that there were uncertainty due to lack of communications. Besides, the health office also does not have adequate resources in implementing its programs due to unclear SOPs, inadequate health facilities, insufficient budget, and incompetent human resources.​13 Due to lack of socialization to health workers, It is recommended that knowledge about filariasis is transferred fully to the health workers by Public Health Service and all staff at the ​puskesmas. A clear SOP is also needed in order to increase clear socialization to health workers and the community by involving community leaders. Hence, several solutions are important to be implemented such as fostering multisector collaboration, advocating additional financial spending, increase human resource competence, complete supporting facilities for the implementation of mass medicine, form an organizational structure, and make clear instructions for carrying out tasks. Finally, carry out regular monitoring and evaluation.​13 Compliance in taking medication Yuziani and Mulyati found that 2.7% of 256 respondents aged 17-25 years old were known to ​be compliant in consuming filariasis drugs, while 97.3% were known to be non-compliant. 14 ​ ​Marya Yenita Sitohang, et al stated in their publication that from 10 urban villages in the city of Pekalongan, they took 250 samples with an age range of 15-75 years, the compliance of respondents to take medication to prevent filariasis was 76%. More than some

respondents

said

that

there

is

support

from

TPE

(​Tenaga

Pelaksana

Eliminasi/​Eliminating Agents) in MDA program even though support in the form of explaining about side effects and making sure respondents taking medicines has not been obtained by most of the respondents. Therefore, it is better for TPE to provide more support by notifying the side effects of the medicine ​to lower drug hesitation ​and drug consumption follow up is also needed to ensure that patients follow the medication regimen.​15

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CONCLUSION Filariasis prevention program in Indonesia has been unsuccessful due to lack of education to the community and health workers, abundant mosquitoes’ breeding and resting place near houses and low compliance in taking medication. Hence, it is not only the responsibility of the government and medical officers to deal with filariasis in Indonesia, but also the community. Healthcare workers as the front line workers should increase people’s awareness on the disease and engage the community in preventing and controlling Filariasis. Multi-sectoral collaboration is adamant to increase coverage of the program and ensure success. Only by doing so, Indonesia could be freed from filariasis. REFERENCES 1.

Kemenkes RI. Profil Kesehatan Indonesia Tahun 2019. Vol. 42, Kementrian Kesehatan Repoblik Indonesia. 2019. 97–119 p.

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Pan J. Filariasis. Vol. 2, Radiology of Infectious Diseases. 2015. p. 307–14.

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Cho SH, Ma DW, Koo BR, Shin HE, Lee WK, Jeong BS, et al. Surveillance and Vector Control of Lymphatic Filariasis in the Republic of Korea. Osong Public Heal Res Perspect. 2012;

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Hotez PJ. Whatever happened to China’s neglected tropical diseases? Infectious Diseases of Poverty. 2019.

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Hotez PJ, Bottazzi ME, Strych U, Chang LY, Lim YAL, Goodenow MM, et al. Neglected Tropical Diseases among the Association of Southeast Asian Nations (ASEAN): Overview and Update. PLoS Negl Trop Dis. 2015;9(4):1–16.

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Ipa M, Puji Astuti E, Ikawati B, Wijayanti T, Yulidar Y, Ramadhan N, et al. Indigenous Perspective of Lymphatic Filariasis in Endemic Region Indonesia. Balaba J Litbang Pengendali Penyakit Bersumber Binatang Banjarnegara. 2020;29–38.

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Tumanggor R. Masalah - Masalah Sosial Budaya Dalam Pembangunan Kesehatan di Indonesia. J Masy dan Budaya. 2010;

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Rosidin U, Rahayuwati L, Herawati E. Perilaku dan Peran Tokoh Masyarakat dalam Pencegahan dan Penanggulangan Pandemi Covid -19 di Desa Jayaraga, Kabupaten Garut. Umbara. 2020;5(1):42.

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Boesri H. Bioekologi Mansonia dan Peranannya Sebagai vektor Filariasis. Fokus Utama. 2012;25–31.

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Ikhwan Z, Herawati L, Suharti. Environmental, behavioral factors and filariasis incidence in Bintan district, Riau Islands Province. Kesmas. 2016;

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Penelitian A, Setyaningtyas DE, Ridha MR, Indriyati L, Litbangkes B. Implementasi kebijakan eliminasi filariasis di kabupaten kotawaringin barat. 2020;09(02):68–76.

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Sampel P. DOI: http://dx.doi.org/10.33846/2trik10102 Pelaksanaan Program Eliminasi Filariasis di Kota Sorong Muhamad Faizal Arianto. 2020;10(2):6–12.

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Yuziani Y, Rahayu MS. Hubungan Sikap Masyarakat Dengan Kepatuhan Pengobatan Massal Filariasis Di Kecamatan Baktiya Aceh Utara. AVERROUS J Kedokt dan Kesehat Malikussaleh. 2020;6(1):29.

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ABSTRACT Analysis Of Indonesia Prevention And Control Program Towards Rabies, What’s Wrong In The Implementation? A Literatur Review Cut Salsabila Mahfiza, Zarfan Fawwaz Muhammad, Tasnim Faculty of Medicine, Syiah Kuala University Asian Medical Students Assosiation Indonesia 2020 cutbella2018@gmail.com

ABSTRACT: Introduction: Rabiesvirus is a virus that attacks the central nervous system in both humans and animals. Transmission of the virus can be via bites or wounds through reservoir’s saliva such as dog, cats, apes, and bats. This literature review aims to explain the challenges faced by goverments and regulation programs for the treatment of rabies in Indonesia. Matherials and Methods: The data was collected from google, google scholar, Kemenkes (https://www.kemkes.go.id/), NCBI (National Centre for Biotechnology Information), and PubMed database with the range of year of 2010-2020 fulfilling inclusion and exclusion criteria. Results: There were more than 100 sources identified. However, there were only 12 literatures met the criteria to be analyzed. This can be observed from the spread of rabies that has been stopped until now. Conclusion: The goverment’s preventive and control program had not been working optimally due to ineffective disparity into the Indonesia region. It is necessary to do crucial steps as recommended in this literature review in order to achive “Indonesia Rabies Free” by 2030.

Keywords: Rabies prevention; rabies di Indonesia; treatment protocols; neglected tropical diseases.

428


Scientific Paper Analysis Of Indonesia Prevention And Control Program Towards Rhabies, What’s Wrong In The Implementation? A Literatur Review

By: Cut Salsabila Mahfiza Zarfan Fawwaz Muhammad Tasnim

Faculty of Medicine Syiah Kuala University Aceh Asian Medical Students Assosiation Indonesia 2020

429


Introduction

infection is already in highlight for every

Rabiesvirus

Lyssavirus,

fluctuating year since 2013. According to

family Rhabdoviridae) is the aetiology of

UNAIDS 2020, an increased in rhabies

rhabies disease that can be transmitted by

disease was seen in two years since 2013

reservoir animals such as dog, bat, monkey,

and then declined to 64,774 cases in 2016.

and cat. This virus can be transmitted via

In 2019, the incidence rate was increased in

reservoir’s saliva which enters human body

significant number which is 100.826 cases. 2.

by a bite wound or mucous membranes.

The prevalence and mortality rate

This virus will replicate and enter the

of rabies remains high with significant

circulation of the human body until it

annual increase. Although the government

reaches target organs such as the central

has launched adequate regulations and

nervous system. 1

guidelines, the effect was too minor

WHO

had

(genus

global

compared to other countries with similar

planning guideline to manage Neglected

approach. It can be inferred that the program

Tropical Diseases from 2008 to 2019. The

has not been succeeded. Hence, this

guidelines focused on developments in

literature review aims to find out the

combating

challenges faced by government in the

the

created

a

transmission

of

the

rabiesvirus by conducting vaccination and

implementation

approaches

Program in 2020.

to prevent

the spread

of

rabiesvirus as also to increase the chances of

The

The government of Indonesia has

google

24 out of 34 provinces in Indonesia has been rabies

endemic

review

scholar,

(National

was

Kemenkes

Centre

for

NCBI Biotechnology

Information) and PubMed database with the

ASEAN Rabies Elimination Strategy in

range of year of 2010-2020. The topic is in

2020 which runs general health programs

the

designed by each country to handle NTD

scope

of

Indonesia's

discussion

regarding incomplete eliminate virus. The

such as preventive chemotherapy; intensive

keywords used were: Rabies; prevention;

problem governance; vector handling; clean

rabies

water provision and sanitation; and animal 3

literature

(https://www.kemkes.go.id/),

areas.

Indonesia has also set the target according to

health experts among of people.

Elimination

conducted by collecting data from google,

paid attention for this zoonosis disease since as

Rabies

Materials and Methods

cure once infected.2

acclaimed

of

di

Indonesia;

rabies

global;

epidemiology; Rabies vaccine; VAR (Vaksin

The

Anti Rabies); dogs; treatment protocols;

government prevention plans over this

430


neglected tropical diseases; by observing

increase the health standard to fight the

title then the main point of the literature and

virus, including Indonesian. The focuses of

adjusting to the topics that fits the criteria.

the program established to reduce the rabies

The inclusion criteria used in this

disease occurrence are:

study were: (1) National journals about

1. Wounds

rabies virus spread and the completion

handling

of

rabies

transmitting animal bites.

program in Indonesia; (2) International

2. Anti-rabies vaccine distribution.

journals that contain neglected tropical

3. Anti-rabies serum distribution.

disease; (3) Literatures published within

4. Health socialization among of the

2010 to 2020. While exclusion criteria of this

study

were:

(1)

National

people.

and

Indonesia is committed to decrease

international journals which are not related

the incidence rate of rabies. However, the

to the topic of rabies virus spread and

vaccination program was not implemented

finishing program in Indonesia; (2) Journals

as planned as it supposed to be depends on

and articles that can’t be implemented in

the provinces and districts authority in

Indonesia; (3) Journals cannot be accesessed.

Indonesia. However, adequate vaccination coverage is still difficult to achieve so

Result and Discussion

further testing, for examples VAR, FAT, etc,

We have identified more than 100

should be carried out.

literatures based on determined keywords

b. Rabies Diagnostic

from various sources. Based on inclusion and exclusion criteria, there were only 12

Cases calibration of rabies suspects

literatures fulfilling the requirements to be

had been done at 8 national and 23

analyzed.

provincial veterinary laboratory service

Indonesia’s

program

about

using FAT (Flourescent Antibody Test) as

prevention and elimination of rabiesvirus

the main rhabies diagnostic tests. More

has not been succeeded. So, our study

precise rhabies diagnostic tests are available

identified 3 causal factors, they are:

such

as

dRIT

(direct

Rapid

Immunohistochemistry Test) which uses the

a. Government Policy

mix of monoclonal Antibodies (mAbs) to

Rhabies has been known to be

detect rabies antigen on brain, so the therapy

endemic in more than 150 countries all over

could be decided effectively and efficiently.

the world 4. Each country creates policy to

5

treat the disease and puts high efforts to

431


Along

with

global

rabies

reinforcement of prevention planning in

elimination strategy, Indonesia continues to

order to face a pandemic, and grow up the

create new innovation to achieve the target

capacity of laboratory diagnosis.

of zero human deaths due to rabies by 2030

4. Awareness Enhancement

inn accordance with “One Health Roadmap

By realizing the TAKGIT (Integrated Bite

Eliminasi Rabies Nasional 2030”. To make

Case

“Indonesia Free Rabies 2030,” happens,

strengthen

strategies are needed as follow:

outbreak response and increase the capacity

1. Rabies Elimination over Dogs The

rabies

elimination

program

dog

preparedness

it

will

plan

for

5. Legislation Reinforcement 6. Operational

dog populations in three consecutive years; sterilization;

the

system,

of laboratory diagnosis.

consists of mass vaccination among 70% legislation;

Management)

Research

Implementation

shelter

7. The Enhancement of Multi-sectoral

facilities; dogs control against trash and

and Sponsorship Coordination

waste contamination; education for dog

A coordination team to control the

owners which includes care for animal

policy

health

Guidelines for Cross-Sector Coordination in

and

welfare,

registration,

and

has

to

be

decided

based

on

vaccination obligations; as also surveillance

Facing Extraordinary Events

of dog traffic. This study suggests that

and Emerging Infectious Diseases, by

government needs to collect data of animal

cooperating with international institutions.

/ Zoonoses

ownerships that have the potential to

8. Resource Mobilization

transmit rabies.

This step is crucial to organize a well

2. Rabies Prevention for Humans

annual financial planning in order to get the

For all suspect cases of rabies,

best result. The fund that allocated from

provision of timely access to post-exposure

government and sponsorship could be

prophylaxis (PEP) is highly required, along

managed as well as possible.

with wound treatment, vaccination, and rabies

immunoglobulin

With few strategies above, hopefully

(RIG)

could help Indonesia Free Rabies 2030

administration.

realization happens in a good way. 6

3. Reinforcement Surveliant for Human

c. Vaccination

and Animal The (Integrated TAKGIT

implementation Bite

Case

system

can

of

Vaccination must be significantly

the

adjusted to the geographical accessibility by

Management) provide

the government. This requires related parties

the

432


to disseminate information to various areas,

as an area with low rabies cases, Flores

especially villages with poor accessibility.

(East Nusa Tenggara) and Bali as an area

This is certainly useful for understanding

with high rabies cases.

society in the future which information

1. The good level knowledge of Aceh

about vaccination schedule and methods for

society that higher reservoir bite cases

restraining the dog. 7

on percentage 6,6%, while lower on the

Vaccine awareness in community

16,7%. 10

and government is very low. Rahmah et al

Comparison of community attitudes

found that the knowledge and attitude level

about rabies control with high and low

towards rabies disease and vaccination in

recervoir bite cases, level good attitude

society was only 50%.

The rate of rabies

on percentage 90% dan 27 frekuency

cases fluctuating, followed by negative

with a high recervoir bite, while a low

public

vaccination

on 96,7%. For poor attitude level, there

despite government’s socialization efforts.

is no frequency and percentage. So it is

This is due to the weakness control of

known that Aceh society have a good

animal health authorities. Of course in the

attitude in controlling rabies and it is

government policy, such a target is not fully

true that Aceh is not a province with

executed.9

high rabiesvirus cases.10

assumption

8

towards

Indonesia's economy and culture

2. The

data

shown

in

the

journal

are the major obstacles in controlling rabies.

Estimation of Dog Population and

The

virus

Owner Knowladge Toward Rabies Risk

achieve

of Dog in Padang Ganting Sub-district,

especially in areas that are dominant with

that the percentage of understanding

the distribution of reservoir animals, such as

about rabies in the Padang Ganting

Bali, East Nusa Tenggara (NTT), and Flores.

Sub-district has an average above 70%

In addition, for (Vaksin Anti Rabies) VAR,

which can be said to be sufficient but

(Gigitan Hewan Penular Rabies) GHPR,

needs to be improved again.

(Serum Anti Rabies) SAR assistance, and

Research

going into the field such as socialization,

rabies

Funds is crucially needed as it supports the

with/without rabies experience, those

problem solving.

who

government

eradication

are

regulations difficult

to

on

We compared 3 regions for rabies

results

in heard

partisipants,

knowledge

Bali,

150

of

rabies

both

97%.

participants from

146

the

same

control cases in Indonesia to see how the

precentage

actual conditions, which consisted of Aceh

information are obtained by citizens,

433

of

have

about

Sources

of


more

from

broadcast

with elimination of reservoir are on

(television and radio) 65%, followed by

percentage 43, 26% or 93 frekuency.

neighbours, media prints, etc, while 0%

Treatment of rabiesvirus with medical

from internet. Seeking medication if

health center got on percentage 22, 73%

bitten

or

by

the

media

suspected

dogs

for

112

frekuency.

And

type

of

society have experience 87% and

rabiesvirus cure with (vaksin anti

have not 85%, it shows not fully

rabies ) got the major percentage, above

society think to look for treatment

65% or 85 frekuency.12

With a

Efforts to eradicate of rabiesvirus

high dog population, it is even

are limited to reservoirs vaccine. Another

harder for goverments to resolve

attempt at recervoirs restriction has meant

rabiesvirus without the awareness

reduce the number of stray dogs that roamed

of

of

in the environment. The fact that in

understanding in the Bali regional

Government Regulation No 40 of 1991

data is calculated based on several

regarding Disease Outbreak Management

backgrounds from the respondents.

Contagious on chapter 10, it also states that

There are several categories taken,

against the plague includes investigation,

such

examination, treatment, and isolation of

when bitten by a dog.

society.

as

The

gender,

11

level

age,

religion,

sufferer.13

educational background, role in the local community.

Conclusion

3. Percentage of respondent's knowledge

Rabiesvirus

about rabiesvirus in Flores Island, NTT;

“zero” human death target of dog-borne

percentage 100% or 120 frekuency.

rabies in 2030. Based on the demographics

33,07% or 85 frekuency had known

of Indonesia’s population, Java is the most

about rabiesvirus in society (front,

desenly populated island, so the distribution

friend, and neighbour). Rabiesvirus

of vaccines to isolated areas is becoming

transmition through a bite is percentage 66,

24%

or

104

requires

government attention in order to achieve the

level ever heard about rabiesvirus on

on

still

uneven. Uncontrolled human and pets

frekuency.

mobility to other areas affects the problem.

Prevention of rabiesvirus with vaccine

Furthermore, goverments only rely on

ejection and serrum anti rabies are on

vaccines only as also lack of socialization

percentage 39,61% or frekuency. it's

about the costs and procedures of the

same with not having contact with

vaccine. It is hoped that more advanced

reservoir. eradication of rabiesvirus

434


treatment methods could be found to

4.

facilitate the socialization about HPR, and

Kementerian Kesehatan. InfodatinRabies.Pdf. Published online 2014.

can make it easier for the government to

5.

Rahmadane I, Certoma AF, Peck GR,

accurately record the existence of HPR in

et al. Development and validation of

achieving virus elimination. And with

an immunoperoxidase antigen

several rain-elimination programs it is

detection test for improved diagnosis

expected to suppress the death toll of this

of rabies in Indonesia. PLoS Negl

virus. For this regulation properly not only

Trop Dis. 2017;11(11):1-14.

governments must contribute but people

doi:10.1371/journal.pntd.0006079

must also contribute to the fight against the

6.

virus rabies. Hence, it is expected that

2030-kemenko-pmk-2324-mei-2019.

Indonesia can be free from rabies diseases in

7.

2030.

by Dog Owners in Flores Island, Indonesia. PLoS Negl Trop Dis.

Dibia IN, Sumiarto B, Susetya H,

2015;9(3):1-23.

Putra AAG, Scott-Orr H, Mahardika

doi:10.1371/journal.pntd.0003589

GN. Phylogeography of the current

8.

rabies viruses in Indonesia. J Vet Sci.

Owner Knowledge Toward Rabies

doi:10.4142/jvs.2015.16.4.459

Risk of Dog in Padang Ganting Sub-

UNAIDS. Data 2020. Published

district. 1 Estim Dog Popul Own

online 2020:Accessed 16 September

Knowl Towar Rabies Risk Dog

2020.

Padang Ganting Sub-district.

https://www.unaids.org/sites/default/f

2017;11(1):1-9.

iles/media_asset/2020_aids-data-

doi:10.21157/j.med.vet..v11i1.4065

book_en.pdf 3.

Rahmah T, Ferasyi TR, Hambal M. 1. Estimation of Dog Population and

2015;16(4):459-466. 2.

Wera E, Mourits MCM, Hogeveen H. Uptake of Rabies Control Measures

References 1.

one-health-roadmap-eliminasi-rabies-

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World Health Organization. Regional

balita-4-tahun-digigit-anjingtetangga-orangtua-takut-biaya-vaksin.

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Widyastuti MDW, Bardosh KL,

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Health. Balaba J Litbang Pengendali

Indriaty I, Bule P, Mau F. dengan

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kejadian rabies di Kabupaten Flores

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436


OCIMUM SANCTUM LINN. (HOLY BASIL OR TULSI) AS A POTENTIAL NATURAL ANTHELMINTICS REMEDY FOR STRONGYLOIDIASIS: A LITERATURE REVIEW Author: Rifkanisa Nur Faiza

(20/455193/KU/22107)

Rafif Faza Pradana

(20/455188/KU/22102)

Septeswa Mulatarum Jati

(20/455198/KU/22112)

ABSTRACT Introduction Strongyloidiasis is a chronic parasitic infection caused by Strongyloides stercoralis and currently believed as the most neglected among all Neglected Tropical Diseases (NTD). It is hyperendemic with a high prevalence in some tropics and subtropics countries. Currently, ivermectin is the most effective medicine for treating the infection. However, it is still not available in all endemic countries and causes various side effects. Based on that problem, this literature review aims to explore potential tropical herbal plants for treating strongyloidiasis that are effective, cheap, and have fewer side-effects by utilizing Ocimum sanctum Linn.

Materials and Method The literature review was conducted using PubMed, ScienceDirect, ResearchGate, SpringerLink, and ProQuest databases by using specific keywords. Keywords used: “Pathogenesis” OR “Infection” AND “Strongyloides stercoralis”; “Phytochemical” OR “Secondary Metabolites” AND “Ocimum sanctum”; “Ocimum Sanctum” AND “Anthelmintic” AND “Strongyloides sp.” OR “Nematodes; “Safety” OR “Side effect” OR “Toxicological” AND “Ocimum sanctum.” Articles were included if they provide correlated and detailed information, but excluded if it was inaccessible and later than ten years.

437


Result and Discussion Our literature searching found 16 journals that are relevant to the purpose of our study. Two studies stated that strongyloidiasis might cause hyperinfection, systemic sepsis, multiorgan failure, complications, and death. Four studies revealed that various active anthelmintic substances (phenolics, flavonoids, tannins, eugenol, saponins) are present in O. sanctum Linn extract. Four studies reported that O. sanctum Linn has potent anthelmintic activities, and work in various ways leads to helminth paralysis and death. Four studies showed that O. sanctum Linn is safe, has no adverse events except mild nausea on obese participants, and even showed positive effects.

Conclusion The present study leads to a strong conclusion that O. sanctum Linn is a potential, cheap, effective, and safe natural anthelmintics remedy for strongyloidiasis. In the future, it is necessary to explore the efficacy and effectiveness of O. sanctum Linn for S. stercoralis anthelmintic treatment.

438


OCIMUM SANCTUM LINN. (HOLY BASIL OR TULSI) AS A POTENTIAL NATURAL ANTHELMINTICS REMEDY FOR STRONGYLOIDIASIS : A LITERATURE REVIEW

Author : Rifkanisa Nur Faiza

(20/455193/KU/22107)

Rafif Faza Pradana

(20/455188/KU/22102)

Septeswa Mulatarum Jati

(20/455198/KU/22112)

AMSA-UNIVERSITAS GADJAH MADA 2020/2021

439


ABSTRACT Introduction Strongyloidiasis is a chronic parasitic infection caused by Strongyloides stercoralis and currently believed as the most neglected among all Neglected Tropical Diseases (NTD). It is hyperendemic with a high prevalence in some tropics and subtropics countries. Currently, ivermectin is the most effective medicine for treating the infection. However, it is still not available in all endemic countries and causes various side effects. Based on that problem, this literature review aims to explore potential tropical herbal plants for treating strongyloidiasis that are effective, cheap, and have fewer side-effects by utilizing Ocimum sanctum Linn. Materials and Method The literature review was conducted using PubMed, ScienceDirect, ResearchGate, SpringerLink, and ProQuest databases by using specific keywords. Keywords used: “Pathogenesis” OR “Infection” AND “Strongyloides stercoralis”; “Phytochemical” OR “Secondary Metabolites” AND “Ocimum sanctum”; “Ocimum Sanctum” AND “Anthelmintic” AND “Strongyloides sp.” OR “Nematodes; “Safety” OR “Side effect” OR “Toxicological” AND “Ocimum sanctum.” Articles were included if they provide correlated and detailed information, but excluded if it was inaccessible and later than ten years. Result and Discussion Our literature searching found 16 journals that are relevant to the purpose of our study. Two studies stated that strongyloidiasis might cause hyperinfection, systemic sepsis, multiorgan failure, complications, and death. Four studies revealed that various active anthelmintic substances (phenolics, flavonoids, tannins, eugenol, saponins) are present in O. sanctum Linn extract. Four studies reported that O. sanctum Linn has potent anthelmintic activities, and work in various ways leads to helminth paralysis and death. Four studies showed that O. sanctum Linn is safe, has no adverse events except mild nausea on obese participants, and even showed positive effects. Conclusion The present study leads to a strong conclusion that O. sanctum Linn is a potential, cheap, effective, and safe natural anthelmintics remedy for strongyloidiasis. In the future, it is necessary to explore the efficacy and effectiveness of O. sanctum Linn for S. stercoralis anthelmintic treatment.

440


INTRODUCTION Strongyloidiasis is a chronic parasitic infection caused by Strongyloides stercoralis and currently believed as the most neglected among all Neglected Tropical Diseases (NTD).1,2 It is hyperendemic, mostly in the tropics and subtropics, with a high prevalence of over 70% in selected countries and widely distributed, affecting up to 370 million humans worldwide, particularly in remote rural areas.3,4 Chronic strongyloidiasis can develop mild symptoms involving the gastrointestinal tract (abdominal pain, diarrhea, bloating, constipation), the skin (pruritus, rashes, urticaria), the respiratory system (dry cough, asthma, chronic bronchitis, chronic obstructive pulmonary disease), and others (arthritis, kidney problems, heart conditions). However, the infection may be severe and life-threatening in the case of immunodeficiency (immunosuppressed, transplant recipients, haematological diseases). It leads to hyperinfection and develops complications, including intestinal obstruction, paralytic ileus, respiratory failure, and in the worst case, death.1,3,4,5 For these reasons, it is vital to suspect, diagnose, and treat the infection. Ivermectin, thiabendazole, and albendazole are the most effective medicines for treating the infection. A recent report stated that Ivermectin, the drug of choice, is as effective as thiabendazole, with the cure rate varying between 55-100% (ivermectin) and 52-100% (thiabendazole).6,7 Ivermectin works by binding to glutamate-gated chloride ion channels, resulting in hyperpolarization of the parasite's neuronal cells and death due to paralysis.8 However, it is still not available in all endemic countries and causes various side effects such as nausea, vomit, sleepiness, and disorientation.1,6 It is also reported that ivermectin's neurotoxic side-effects contributed to neurologic effects, including encephalopathy, stupor, tremors, lethargy, and coma.9 Moreover, repeated ivermectin treatment is needed to eliminate larvae generated by autoinfection, leading to anthelmintic resistance.7 For this reason, researchers want to find alternative materials for treating strongyloidiasis that are effective and have fewer side-effects by utilizing tropical herbal plants. Ocimum sanctum Linn. or Holy Basil, or Tulsi belongs to the family Lamiaceae.10 This plant is cheap, easily found, available in large quantities around us, and widely used for therapeutic purposes in Asia, Africa, and Central and Southern America, especially India.11,12,13 Some of Ocimum sanctum Linn's bio-potential activities include analgesic, antiasthmatic, antibacterial, and anthelmintic activity.10 Some studies show that various and abundant anthelmintic substances could be found in this plant. Besides, a study focused on haematological, biochemical, and histopathological aspects of holy basil consumption shows no severe toxicological side effects.14 However, it is still difficult to find research articles

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related to Ocimum sanctum Linn's more in-depth therapeutic implementation. Thus, the aim of this study is to explore the potential of Ocimum sanctum Linn. as tropical herbal plants for treating strongyloidiasis.

MATERIALS AND METHOD Literature searching was conducted in December 2020 on five databases, e.g., PubMed, ScienceDirect, ResearchGate, SpringerLink, and ProQuest. In this literature review, researchers discuss four topics and use a set of different keywords refers to The Boolean Logic for each topic: (1) The pathogenesis of Strongyloides stercoralis using keywords (“Pathogenesis” OR “Infection”) AND (''Strongyloides stercoralis”). (2) Phytochemical properties of Ocimum sanctum Linn. using keywords (“Phytochemical” OR “Secondary Metabolites”) AND (“Ocimum sanctum Linn” OR “Holy Basil” OR “Tulsi”). (3) Ocimum Sanctum Linn anthelmintic activity against Strongyloides stercoralis using keywords (“Ocimum Sanctum”) AND (“Anthelmintic”) AND (“Strongyloides sp.” OR “Nematodes”). (4) Clinical safety, side effect, & toxicological study of Ocimum sanctum Linn using keywords (“Safety” OR “Side effect” OR “Toxicological”) AND (“Ocimum sanctum”). The included studies fulfilled several inclusion criteria. The aims of the research must be about the pathogenesis of S. stercoralis, the potential phytochemical substance with anthelmintic activity, especially against nematodes in O. sanctum Linn, and clinical safety, including side effects and toxicological study of the substance in humans. This study uses various research types, including cross-sectional descriptive study, clinical case study, in vitro, randomized controlled trial (RCT), double-blinded controlled trial, clinical trial, qualitative, and quantitative analysis study. The study would be excluded if the study was inaccessible and published later than ten years ago.

RESULT AND DISCUSSION Topic 1. The pathogenesis of Strongyloides stercoralis From the literature searching, we found two studies about the pathogenesis of S. stercoralis. Based on the first study, S. stercoralis infection starts when an infectious filariform larva penetrates the host's skin who walks barefoot on contaminated skin. The larva enters the venous circulation and migrates to the lungs. In the small intestine, the larva develops into adult females, which reproduce asexually and release eggs into the gastrointestinal tract. The eggs then hatch into non-infectious rhabditiform larvae and are excreted in the stool. The free-living rhabditiform larva either mature into male and female adult worms outside of the human host,

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which reproduce sexually or transform directly into filariform larvae. This larva can penetrate the gut wall and re-enter the circulation back to the lungs to begin the cycle again. This phenomenon is called autoinfection.8 Furthermore, S. stercoralis could cause hyperinfection syndrome in immunosuppressed patients and develops acute strongyloidiasis. Based on research conducted in Myanmar, the elderly are more vulnerable and have a higher risk factor in getting acute strongyloidiasis leads to hyperinfection.15 Hyperinfection results in uncontrolled over-proliferation of larvae that leads to systemic sepsis and multiorgan failure.8 Based on the second study, S. stercoralis is known to cause persistent autoinfection in the host that can influence the development of a life-threatening disease. When it is associated with immunosuppression, S. stercoralis can act as an opportunistic agent. Severe strongyloidiasis occurs when immunity is impaired with a consequent increase of larvae burden. As a result, parasites cross the intestinal wall, causing a hyperinfection syndrome (HIS) or disseminated strongyloidiasis with a high mortality rate. Other complications such as septic shock and meningitis can also occur when gram-negative bacteria is carried through the intestine or bowel ulcers along with the larvae.16

Topic 2. Phytochemical properties of Ocimum sanctum Linn. There are four studies about the phytochemical properties of O. sanctum Linn. The first study reported that various secondary metabolites such as carbohydrate, tannin, flavonoids, saponins, glycoside, terpenoid, fatty acids, and phenols are present in O. sanctum Linn. High amounts of phenols (1,6-7,6%), alkaloid (0,91-1,28%), and flavonoids (1,56-2,24 %) are found more in organic solvent extract. From the GC-MS analysis of methanolic extract, three compounds were identified as major constituents, eugenol, α-Farnesene, benzene, 1,2dimethoxy-4-(1-propenyl), and cyclohexane,1,2,4, triethyl.12 Another study reveals that O. sanctum Linn is rich in both total polyphenolic content (TPC) (212.26 ± 6.3 mg GAE/ g extract) and total flavonoid contents (TFC) (54.51 ± 3,5 mg QE/g extract). Methanol is reported to extract polar polyphenols and flavonoids to a better extent as compared to water and other solvents. n-Butanol fraction contained maximum flavonoids while only a small fraction was left in the residue. Alcoholic extract of holy basil is reported to contain alkaloids, triterpenes, steroids, quinines, lactonic groups, amines, aminoacids, flavonoids, and anthocyanins as ethyl/methyl esters, glucosides, and glucuronides.17 A different study has also reported that methanol extract of holy basil leaves contains various bioactive compounds, including alkaloids, terpenoids, phenol, tannins, steroids, polyphenols, flavonoids, saponins, anthocyanin, and coumarin. Total phenolic content (TPC)

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and total flavonoid content (TFC) of methanol extract were 102.12 mg/g and 146.634 mg/g, respectively.18 A qualitative analysis study of the O. sanctum Linn extract showed the presence of phytochemical constituents such as tannins, saponin, flavonoids, steroids, terpenoids, and cardiac glycerides. The major components present in leaves of O. sanctum Linn were eugenol (43.88%), caryophyllene (26.53%), cyclopentane, cyclopropylidene-(1.02%), cyclohexane, 1,2,4-trimethyl (15.31%), octadecane, 1,1-dimethoxy-(2.04%) and benzene methenamine, N,N,a,4-tetramethyl-(2.04%).19

Topic 3. Ocimum Sanctum Linn anthelmintic activity against Strongyloides stercoralis The phytochemical properties studies of O. sanctum Linn stated that this plant contains some active anthelmintic substances such as phenolics, flavonoids, tannins, eugenol, and saponins.20,

21, 22, 23

There are four studies on anthelmintic substance activity against S.

stercoralis. The first study reports the anthelmintic activity of O. sanctum Linn that tannin and phenolic blocks the glucose uptake by the nematode parasite, therefore altering their mobility and survivability. The compound tannins, present in O. sanctum Linn, interact with proteins in the nematode cuticle, thus considerably changing their chemical and physical properties.20 An in vitro comparative study about the anthelmintic activity of O. sanctum Linn shows the active compound Eugenol, present in O. sanctum Linn, has been found to be the therapeutic potential of Tulsi. This study has proved that O. sanctum Linn leaves have vigorous anthelmintic activity against Syphacia muris in mice and can be considered for anthelmintic agents during the first trimester of pregnancy. Aqueous extract of O. sanctum Linn took 145 ± 14 minutes to paralyze and 223+11 minutes to death of the worm.21 Another study reported that tannins and phenolic are known to interfere with the energy generation in helminth by uncoupling oxidative phosphorylation and bind to free proteins in the host animal’s gastrointestinal tract glycoprotein on the cuticle of the parasite. This action is leading to helminth death. With 15% concentration of O. sanctum Linn infusion, a study found that it is the effective concentration that can kill 100% of the A.suum during 36 hours of immersion.22 Another research on ethanol extract of O. sanctum Linn leaves reveals that flavonoid, present in O. sanctum Linn, affects the helminth’s nerve system, which leads to neuron degeneration. The disturbance in nerve impulse could affect the helminth’s homeostasis, paralyzing the worm, and finally dying. Alkaloids in O. sanctum Linn can also cause helminth’s cells excitation and neurological dysfunction. The compound saponin in O. sanctum Linn also

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affects both the flukes and the extract. It damages the extract by decreasing the extract’s tension so that there will be faster and more effective contact between the helminth’s integument and the extract. The saponin mechanism affecting the fluke is by destabilizing the cell membrane, increasing the permeability.23 As a review, anthelmintic substances present in Ocimum sanctum Linn work in various ways, such as blocking glucose uptake, altering mobility, survivability, chemical, and physical properties, affecting nerve system, and disturbing homeostasis of the parasites. These activities are leading to the paralysis and death of the parasites. Thus, researchers believe that this plant can be a potential natural anthelmintics remedy for strongyloidiasis.

Topic 4. Clinical safety, side effect, & toxicological study of Ocimum sanctum Linn After understanding O. sanctum Linn anthelmintic activity, researchers conduct studies about its safety for clinical use. There are several studies with different points of view in reviewing safety evaluation of O. sanctum Linn. There are four studies about Tulsi’s effect on metabolic disorders, immune system, and cognitive function. Most studies reported no adverse events and did not describe or refer to any adverse events. Only one randomized controlled clinical trial reported mild nausea due to O. sanctum Linn intervention to 30 adult obesity 250 mg/day for eight weeks. However, it shows improvement in lipid profiles, as well as BMI of obese participants.24 A double-blinded randomized controlled trial for immunomodulatory effects of Tulsi leaves’ ethanolic extracts on 22 healthy adults 300 mg/day for four weeks shows an increased cytokine level, interferon-ϒ, and interleukin-4 with no adverse events.25 A clinical trial that studied the neurocognitive effect of O. sanctum Linn on 150 adults with stress showed positive effects on stress reduction, and no adverse event was observed.26 Another clinical trial of O. sanctum Linn to 24 adults with psychosomatic reported a significant anxiety reduction and has no side effects.27 These studies prove that O. sanctum Linn is a safe herbal and has no adverse events except mild nausea in obese participants.

CONCLUSION From the studies, it is known that S. stercoralis can cause persistent autoinfection in the host and can act as an opportunistic agent when associated with immunosuppression, which leads to the development of several life-threatening diseases. Those such as hyperinfection syndrome (HIS) or disseminated strongyloidiasis with high mortality rate and other

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complications including septic shock, meningitis, multiorgan failure, and in the worst case, death. Based on the phytochemical properties studies of O. sanctum Linn, it contains some active anthelmintic substances such as phenols (1,6-7,6%), alkaloid (0,91-1,28%), and flavonoids (1,56-2,24 %), eugenol (43.88%), tannins (ND), and saponins (ND). Those substances work in various ways leading the parasites to paralysis and death. O. sanctum Linn also has been proven to be a safe herbal and has no adverse events except mild nausea on obese participants. The present study leads to a strong conclusion that O. sanctum Linn can be a potential, effective, and safe, natural anthelmintics remedy for strongyloidiasis. In the future, researchers will research further to prove the clinical efficacy, effectiveness, and safety of O. sanctum Linn on strongyloidiasis patients using ethanol extract of Tulsi leaves. A randomized, double-blind, placebo-control (RDBPC) trial will be used to avoid bias in both patients and examiners. The subjects must be chronic strongyloidiasis patients suffering from medium to severe symptoms. Strongyloidiasis patients will be divided into two groups: A and B. Group A will get a standard treatment of ± 300 mg ethanol extracts of Tulsi leaves three times a day, while group B will get a standard treatment of placebo three times a day. The exact dose will be determined after the researchers conduct in vitro trial.

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Peptide-Based Non Structural Protein 1 Inhibitor Potential in Inhibiting Dengue Virus Production: A Literature Review Ahmad Fauzi1,*, Muhammad Mikail Athif Zhafir Asyura1,*, Fakhru Adlan Ayub1,* 1Faculty

of Medicine, Universitas Indonesia *a.fauzi216@gmail.com

Introduction: Dengue Virus (DENV) is a main pathogen in human dengue fever, west nile, and yellow fever. DENV are responsible for 390 million infections per year. DENV has 4 different serotypes: DENV-1, DENV-2, DENV-3, and DENV-4 which produce about 10 viral protein products. Three of them are structural proteins and the others are non-structural proteins, one of them being NS1. The NS1 protein plays a key role in viral replication and stimulates immune cells to release vasoactive cytokines which lead to vascular leakage. This protein can be a perfect candidate to create an effective and safe DENV vaccine or antiviral drug. Materials and Methods: This review was carried out from various databases namely Pubmed/Medline, Science Direct, Proquest, Wiley Online Library, DOAJ, and Cochrane library using specific keywords. 11 studies were included in this review, with 9 discussing about NS1 and 2 about peptides based interventions Results and Discussions: Dengue is a global health issue, particularly in endemic countries. In Indonesia, it shows a positive trend of Incidence Rate (IR) per 100. populations. Vaccine development against dengue has been proven to be futile due to the different serotypes of the virus. Recently discovered, the NS1 protein is an integral protein that’s pivotal in the replication of the virus. Being a non-structural protein that exists in all serotypes, comes the possibility to target the protein using peptide based interventions. Efficacy analysis via in vitro on dengue infected Huh7 cells yielded a significant decrease in viral production that is dose dependent. Furthermore, in vivo studies on mice resulted in an overall increase in survivability, indicating the effectiveness of the treatment. Conclusion: The review established promising results of using peptide based intervention on NS1. Further randomized controlled trials on endemic populations are suggested with the aid of locals and governmental organizations Keywords: dengue virus, non-structural protein, NS1, peptide based intervention

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Peptide-Based Non Structural Protein 1 Inhibitor Potential in Inhibiting Dengue Virus Production: A Literature Review Ahmad Fauzi1,*, Muhammad Mikail Athif Zhafir Asyura1,*, Fakhru Adlan Ayub1,* 1Faculty

of Medicine, Universitas Indonesia *a.fauzi216@gmail.com

Introduction: Dengue Virus (DENV) is a main pathogen in human dengue fever, west nile, and yellow fever. DENV are responsible for 390 million infections per year. DENV has 4 different serotypes: DENV-1, DENV-2, DENV-3, and DENV-4 which produce about 10 viral protein products. Three of them are structural proteins and the others are non-structural proteins, one of them being NS1. The NS1 protein plays a key role in viral replication and stimulates immune cells to release vasoactive cytokines which lead to vascular leakage. This protein can be a perfect candidate to create an effective and safe DENV vaccine or antiviral drug. Materials and Methods: This review was carried out from various databases namely Pubmed/Medline, Science Direct, Proquest, Wiley Online Library, DOAJ, and Cochrane library using specific keywords. 11 studies were included in this review, with 9 discussing about NS1 and 2 about peptides based interventions Results and Discussions: Dengue is a global health issue, particularly in endemic countries. In Indonesia, it shows a positive trend of Incidence Rate (IR) per 100. populations. Vaccine development against dengue has been proven to be futile due to the different serotypes of the virus. Recently discovered, the NS1 protein is an integral protein that’s pivotal in the replication of the virus. Being a non-structural protein that exists in all serotypes, comes the possibility to target the protein using peptide based interventions. Efficacy analysis via in vitro on dengue infected Huh7 cells yielded a significant decrease in viral production that is dose dependent. Furthermore, in vivo studies on mice resulted in an overall increase in survivability, indicating the effectiveness of the treatment. Conclusion: The review established promising results of using peptide based intervention on NS1. Further randomized controlled trials on endemic populations are suggested with the aid of locals and governmental organizations Keywords: dengue virus, non-structural protein, NS1, peptide based intervention

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1. Introduction Dengue Virus (DENV) is a single stranded RNA flavivirus and a major causative agent in dengue fever, West Nile, and yellow fever.[1] DENV are transmitted via mosquito (aedes aegypti and aedes albopictus) saliva to humans. DENV are responsible for 390 million infections per year and 96 million among them have manifested clinically and 2.5% mortality rate each year.[2,3] DENV infections are more common in tropical countries as in Indonesia, the prevalence of DENV infections are 77.96 cases per 100,000 person-years in 2016.[4] DENV has 4 different serotypes: DENV-1, DENV-2, DENV-3, and DENV-4.[5] DENV RNA strain contains 10 viral protein products. These proteins can be classified into 3 structural proteins and 7 non-structural proteins. The 3 structural protein classes are Envelope (E), Capsid (C), and pre-Membrane (prM). The other 7 non-structural (NS) proteins are NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5.[1,5-7] NS1 is a major protein in DENV viral replication.[5,6] NS1 sequenced by 352 amino acid residue and has 70% similarity to other DENV serotype. [5] Other NS1 role is NS1 extracellular form can stimulate immune cell to release vasoactive cytokines which lead to vascular leakage.[8] NS1 protein has 3 important domains: the hydrophobic β-roll as a domain for dimerization process (located on 1-29 residue), the wing as a connector subdomains (located on residue number 30–37 and 152–180, the α/β subdomain and residues number 38–151), and β-ladder (residue number 181–352) as we can see in figure 1. These structures play a vital role in NS1 physiology.[1,9] Many researches have been conducted to search for DENV vaccines or drugs.[10-14] Nevertheless, there is still no effective and specific vaccine or drug to treat DENV infection. [2,10,12-14].

On the other side, data shows that dengue fever prevalence is very high and keeps

rising especially in Asia. [2,4] Treatment for dengue fever and severe dengue fever are focused on maintaining and controlling patient body fluid. [2,15] Therefore, to control and prevent DENV infection more effectively, research for DENV vaccines or drugs is still one of major focus. Understanding which type of vaccines and the mechanism of action are big challenges for scientists. In this paper, we focused on reviewing the NS1 mechanism of action and effectiveness if the NS1 protein is inhibited. Despite many researches that had been conducted, there is still no certain mechanism of NS1 exact role in viral replication. Although a study suggests that NS1 plays a role in formation and stabilization of viral membrane organelles.

[6]

By understanding these NS1 mechanisms, scientists have found some effective vaccines. Therefore, these vaccines still need to be investigated to improve it’s efficacy and safety. [10]

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2. Materials and Methods This literature review was assembled by searching, compiling, and analysing various studies that investigated the role of non structural protein 1 (NS1) in viral replication and the potential use of peptide-based treatment that inhibit the protein. Search terms used included ("Peptide" OR "Peptide drug") AND ("Nonstructural protein 1" OR "NS1") AND ("Dengue") AND ("Inhibit" OR "Reduce"). The sources were cited from Pubmed/Medline, Science Direct, Proquest, Wiley Online Library, Directory of Open Access Journal (DOAJ), and Cochrane library. From the databases, 11 studies were included in this review in which 9 assessed the potential of NS1 as a target and 2 studies assessing the potential usage of peptide-based interventions to inhibit viral replication. Figure 2. provides a visual representation of the literature search method for this review.

Figure 2. Flowchart of the literature search method 3. Results and Discussions Result and Discussion: 1. Current state of dengue Dengue was a global health issue that endemic in around 100 countries, mostly tropical and subtropical. Over the last decade, Dengue issues have increased quickly. WHO states that dengue infects about 390 million and causes up to 100 million cases every year. WHO proposed a new dengue classification based on the severy because of changes in epidemiology and incidence rates.[16] Indonesia is one of endemic countries and the epidemiology of dengue fever often shows as a case series. Indonesia has the second largest dengue fever cases among 30

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other endemic countries and the most prevalent in Java, particularly West, Central, and East Java.[17] The first case of dengue fever was in Jakarta, 1968, since then the Incidence Rate (IR) of dengue fever shows an increasing trend. It increased from 0.05 - 35-40 per 100.000 population in 2013. Incidence rate for every 100.000 population in Indonesia’s province shows that Bali has the highest IR and the lowest is Papua. The Incidence rate of each Indonesia’s province in 2016 has shown in figure 3 and figure 4.[17] Dengue fever has infected all of 34 provinces and 80% of 497 cities in 2017. The spreading in the cities of Indonesia can be looked at from the incidence rate per 100.000 population in cities from each year and it shows positive trends. IR per 100.000 populations from 1968-2016 has show in the figure above.[17] Vaccine for dengue is still an issue to this day because there is no effective or commercial vaccine.[16] The first dengue vaccine introduced is Dengvaxia developed by Sanofi Pasteur. The vaccine licensed in Desember 2015 in Mexico for individuals between 9-45 years of age.[17] Many approaches have been used, such as live attenuated, DNA Vaccine, subunit antigen, and other approaches, and several groups show good progress and efforts in vaccine development. Currently, the strategy has each status and phase, as shown in the table below. [16]

2. NS1 protein, and why is it important As mentioned before, no such anti-dengue drug or vaccine has been successfully synthesized and was proven effective against the viral strain despite its increasing need and urgency. Connected to that concern, increasing focus is needed to be put on modalities other than supportive care. Antiviral approaches have been shown to target structural and nonstructural proteins of DENV due to their pivotal role in viral replication and transmission. Multiple candidate proteins have been identified with NS proteins being the majority, especially the NS1 protein.[18,19] The DENV NS1 protein is a glycoprotein translated by the viral genome in different structural forms (Figure X.) depending on its location. The NS1 protein is expressed in the form of a monomer but transforms into a membrane-bound dimer on the cell surface of the host cell. Moreover, the protein is secreted in the form of a hexamer (open barrel structure with three dimers forming a hydrophobic region) that cycles in the patient’s circulatory system.[18,20] Functionality wise, the protein plays an essential role in viral replication but the exact mechanism is still unknown. Study conducted by Plaszczyca et al managed to clarify this question by demonstrating different domains of the protein being required for the synthesis of membrane organelles of DENV.[5,20] This output provides useful

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information in designing and determining peptide interventions with the property to bind on these domains to inhibit viral replication as a whole. Akey et al. further expanded on this idea by identifying different potential binding domains in the various structural forms of the protein, especially in its dimer form. [6] In Figure 1, the NS1 protein is presented in its dimer form with its three binding domains: the hydrophobic β-roll (blue), the wing that consists of α/β subdomain (yellow), and the β-ladder domain (red). Despite the β-ladder having minimal structural functionality, the hydrophobic βroll plays an important role in the dimerization process of the protein while the wing domain is responsible to connect all the domains together into an integral structure.[18,6] Hence, in theory, there is a possibility to design certain peptides that are complementary to these domains with the purpose in intercepting their physiology.[1] Similar methods have been implemented by Huang et al. in which peptide-based antimicrobial agents are used on non structural proteins. In this study, three major pathways were tested: the inhibition of viral entry, immunomodulation of the viral strain, and the interception of detailed steps on the viral replication cycle, with the latter being the most effective in reducing viral titre in the infected cell.[10] The strategies were implemented on nonstructural proteins that plays a role in viral replication such as NS2B/NS3 (protease), NS5 (RNA-dependent RNA polymerase, RdRp), and NS3 (helicase) being the prime targets.[10,21] Although, NS1 proteins have yet to be targeted due to its enigmatic role in viral replication, there are a few properties of the protein that alleviate its status as a therapeutic agent compared to current interventions. Firstly, one of the biggest hurdles of vaccine development against dengue is due to the many serotypes of DENV. This translates to multiple vaccines needing to be tailored for each serotype and thus slowing the overall development. This is tackled by the housekeeping nature of NS1 protein, meaning that it exists in every serotype of DENV. Thus, treatment made against NS1 in theory would be effective regarding the DENV serotype. Secondly, previous peptide based treatment targets structural proteins of DENV such as the envelope protein. These interventions named “neutralizing antibodies' 'block the attachment and entry of the virus into host cells. Albeit it being successful in doing so, they impose the risk of antibody dependent enhancement (ADE) in which viral infection is induced by antibody production of the host cell. This concern is tackled by the non-structural nature of NS1. Instead, antibodies made against NS1 or anti-NS1 showed a therapeutic effect in some studies, reducing viral replication by complementary binding to complement-dependent cytotoxicity (CDC) of infected cells.[22-25]

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3. Peptide based intervention on viral proteins of dengue Antiviral peptides of DENV infection development focus on blocking virus entry of viral structural proteins function and enzymes. Furthermore, it blocks viral RNA processing host cells.[5] Peptides drugs roles as inhibitors of viral replication which the main targets are host cell receptors or attachment factors, viral structural proteins, and viral non-structural proteins. The drugs will prevent the attachment and binding of the viral proteins and subsequent entry of DENV. Furthermore, it will inhibit viral fusion and viral entry by targeting viral structural proteins. Modified peptide drugs that directing non-structural proteins will restrain the viral replication cycle.[11] Antiviral peptides have several limitations. The major problems are the peptide’s instability and bioavailability. In vivo activities shown as unmodified peptides in human serum degrade in a short time. There are numerous chemical modifications for increasing the peptides’ stability and bioavailability by controlling the physicochemical parts of peptides. There are various ways to enhance the peptides’ antiviral, such as identifying vital amino acids for inhibition by mutagenesis assays and cell-penetrating peptides and increasing cell permeability. To settle the oral bioavailability, it uses peptide sequence associated with cell-penetrating peptides (CPP) to deliver antiviral peptides for inhibitory activity by crossing the permeability barrier enter the cell. Galactoside conjugated by tar protein can deliver the fusion protein to all the tissues in mice without restrained.[11]

4. Efficacy analysis of the NS1 protein targeted by the peptides There are limited studies that directly analysed the effectiveness of peptide based drugs on NS1 protein due to the only recent clarification of its function within the viral replication cycle. Despite that, there are two studies conducted by Songprakhon et al and Chen et al that analysed the protein via in vivo and in vitro respectively. In Songprakhon et al, 11 potential peptides are identified using biopanning assays and were then further screened in silico using molecular docking to yield 4 sequences. These 4 sequences were then transferred into Huh7 cells that were infected by DENV-2 and viral production were then compared between the treated culture and control. Results are shown in Figure X. and all the peptides identified showed significant reduction in viral production compared to the untreated control. Furthermore, increasing the administration dose from 10 µM or 20 µM improves the reduction of viral production, concluding a dose-dependent relation between inhibition of viral production and peptide concentration.[20] From Chen et al., different in vivo studies were evaluated that target the NS1 protein as shown by figure 5. Most studies yielded positive results

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with the outcome being improved survivability of the infected mice with DENV. Moreover, the peptide based intervention also prevented hemorrhage due to severe DENV and reduced viremia within the mice.

Figure 6. Viral production values after peptide intervention [19]

Figure 7. Review of different in vivo studies on the peptide intervention [20] 4. Conclusion and Recommendation In conclusion, DENV has been a lingering problem globally especially in developing and tropical countries. Despite having much focus being put on the disease beforehand, the possibility of developing a vaccine has been futile due to the many serotypes of the virus. With the functional discovery of the NS1 protein, arose the possibility to implement peptide based intervention that targets the protein. The protein plays a major role in the viral replication cycle, hence by inhibiting its role, transmission of the virus could be prohibited. In vitro and in vivo studies of the interventions yielded positive results in decreasing the viral concentration and improving the survivability rate of the subjects. Although, further in vivo trials are

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recommended to ensure the optimal dose, administration method, and efficacy of the peptide intervention. Moreover, collaboration with the government and locals should be instigated to achieve randomized controlled trials in endemic populations to further test the efficacy of the treatment in preventing dengue transmission

5. References: 1. Akey DL, Brown WC, Jose J, Kuhn RJ, Smith JL. Structure-guided insights on the role of

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doi:10.1002/bies.201400182 2. World Health Organization. Dengue and severe dengue [internet]. 2020 June 23. Accessed 9 Dec 2020. Available from: https://www.who.int/en/news-room/factsheets/detail/dengue-and-severe-dengue. 3. Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow AW, Moyes CL, et al. The global distribution and burden of dengue. Nature. 2013 Apr 25; 496(7446): 504–7 4. Harapan H, Michie A, Mudatsir M, Sasmono RJ, Imrie A. Epidemiology of dengue hemorrhagic fever in Indonesia: analysis of five decades data from the National Disease Surveillance. BMC Res Notes. 2019; 12: 350 5. Songprakhon P, Thaingtamtanha T, Limjindaporn T, Puttikhunt C, Srisawat C, Luangaram P, et al. Peptides targeting dengue viral nonstructural protein 1 inhibit dengue virus production. Sci Rep. 2020; 10: 12933 6. Płaszczyca A, Scaturro P, Neufeldt CJ, Cortese M, Cerikan B, Ferla S, et al. A novel interaction between dengue virus nonstructural protein 1 and the NS4A-2K-4B precursor is required for viral RNA replication but not for formation of the membranous replication

organelle.

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doi:10.1371/journal.ppat.1007736 7. Jacobs MG. Dengue virus nonstructural protein 1 is expressed in a glycosylphosphatidylinositol-linked form that is capable of signal transduction. The FASEB Journal. 2000; 14(11): 1603–10. 8. Glasner DR, Puerta-Guardo H, Beatty PR, Harris E. The Good, the Bad, and the Shocking: The Multiple Roles of Dengue Virus Nonstructural Protein 1 in Protection and Pathogenesis. Annu Rev Virol. 2018; 10–101416. 9. Scaturro P, Cortese M, Chatel-chaix L, Fischl W, Bartenschlarger R. Dengue Virus Non-structural Protein 1 Modulates Infectious Particle Production via Interaction with the Structural Proteins. PLoS Pathog. 2015 Nov 12; 11(11):e1005277.

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10. Huang Y, Lee C, Wang T, Kao Y, Yang C, Lin Y, et al. The Development of Peptidebased Antimicrobial Agents against Dengue Virus. Curr Protein Pept Sci. 2018 Oct; 19(10): 998–1010. 11. Chew MF, Poh KS, Poh CL.Peptides as Therapeutic Agents for Dengue Virus. Int J Med Sci. 2017; 14(13):1342-1359. 12. De La Guardia C, Lleonart R. Progress in the identification of dengue virus entry/fusion inhibitors. Biomed Res Int. 2014; 2014:825039. 13. Alen MM, Schols D. Dengue virus entry as target for antiviral therapy. J. Trop. Med. 2012; 2012:628475 14. Bhakat S, Karubiu W, Jayaprakash V, Soliman ME. A perspective on targeting nonstructural proteins to combat neglected tropical diseases: Dengue, West Nile and Chikungunya viruses. Eur. J. Med. Chem. 2014;87:677–702 15. World Health Organization. Dengue guidelines, for diagnosis, treatment, prevention and control. World Health Organization; 2009 16. Nedjadi T, El-Kafrawy S, Sohrab S, Desprès P, Damanhouri G, Azhar E. Tackling dengue fever: Current status and challenges. Virology Journal. 2015;12(1). 17. Haryanto B. Indonesia Dengue Fever: Status, Vulnerability, and Challenges. Current Topics in Tropical Emerging Diseases and Travel Medicine. 2018;. 18. Norazharuddin H, Lai NS. Roles and Prospects of Dengue Virus Non-structural Proteins as Antiviral Targets: An Easy Digest. Malays J Med Sci. 2018 Sep; 25(5): 6– 15. 19. Cervantes-salazar M, Angel-ambrocio AH, Soto-acosta R, Bautista-carbajal P, Hurtado-monzon AM, Alcaraz-estrada S, et al. Dengue virus NS1 protein interacts with the ribosomal protein RPL18: This interaction is required for viral translation and replication in Huh-7 cells. Virology. 2015; 484: 113-26 20. Songprakhon P, Thaingtamtanha T, Limjindaporn T, Puttikhunt C, Srisawat C, Luangaram P et al. Peptides targeting dengue viral nonstructural protein 1 inhibit dengue virus production. Scientific Reports. 2020;10(1). 21. Stevens A, Gahan M, Mahalingam S, Keller P. The Medicinal Chemistry of Dengue Fever. Journal of Medicinal Chemistry. 2009;52(24):7911-7926. 22. Akey D, Brown W, Dutta S, Konwerski J, Jose J, Jurkiw T et al. Flavivirus NS1 Structures Reveal Surfaces for Associations with Membranes and the Immune System. Science. 2014;343(6173):881-885.

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23. Chen H, Lai Y, Yeh T. Dengue virus non-structural protein 1: a pathogenic factor, therapeutic target, and vaccine candidate. Journal of Biomedical Science. 2018;25(1). 24. Wan S, Lu Y, Huang C, Lin C, Anderson R, Liu H et al. Protection against Dengue Virus Infection in Mice by Administration of Antibodies against Modified Nonstructural Protein 1. PLoS ONE. 2014;9(3):e92495. 25. Lai Y, Chuang Y, Liu C, Ho T, Lin Y, Anderson R et al. Antibodies Against Modified NS1 Wing Domain Peptide Protect Against Dengue Virus Infection. Scientific Reports. 2017;7(1).

6. Table and figures Figure 1. NS-1 protein structure [9]

Figure 3. Incidence rate of dengue in Indonesia by province [17]

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Figure 4. Incidence rate of dengue in Indonesia and number of cities infected [17]

Figure 5. Current vaccines for dengue status [23]

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PREVENTIVE, CURATIVE, REHABILITATIVE MEASURES, AND ACTIVITIES TO RAISE AWARENESS OF THE INDONESIAN PEOPLE TOWARDS NEGLECTED TROPICAL DISEASES, ESPECIALLY FILARIASIS Azizah Nadzir1), Bella La Rosa Husna2), and Endis Lailatul Qodri Munawwaro3)

ABSTRACT Introduction: One of the problems is the increasing number of Filariasis cases from year to year and the increasing number of provinces affected by Filariasis. So one of many solutions we could increase public awareness about filariasis, improving the quality of public health and reducing the number of people exposed to the disease by providing clear information. There are three species of worms that cause filariasis: Wuchereria bancrofti; Brugia malayi; Brugia timori. Objective: As a referall to indonesian people to raise awareness of the society in dealing with Neglected Tropical Disease to improve community health, especially in Filariasis Method: This Scientific paper is based on literature review through analytic study to search journal sources. Results and Discussions: Microfilariae migrate between the lymph system and blood channels to reach the peripheral blood vessels, often at times of the day that coincide with the peak biting activity of local vectors. When female mosquitoes ingest a blood meal, they consume microfilariae with the blood. Survey on 2000 reported 1.553 village there are 6.233 chronic cases and it is such a serious health problem in Indonesia. Therefore, Indonesian people need to raise awareness of Filariasis, there are some prevention to avoid Filariasis. Also, there are ways to cure people with Filariasis and ways to bring them back to their normal life if they succed to recover from Filariasis so they won’t lose hope to recover. Conclusion : The most effective method for reducing filariasis is prevention of transmission of the parasite, several drugs are effective at reducing the levels of microfilariae in the blood. While Filariasis sufferers who have undergone treatment can be completely cured. However, their condition could not recover as before. Rehabilitation of enlarged body can be done by surgery. Keywords: Negelected Tropical Disease, Filariasis, Epidemiology, Service Health, Public Health

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PREVENTIVE, CURATIVE, REHABILITATIVE MEASURES, AND ACTIVITIES TO RAISE AWARENESS OF THE INDONESIAN PEOPLE TOWARDS NEGLECTED TROPICAL DISEASES, ESPECIALLY FILARIASIS

By : Azizah Nadzir Bella La Rosa Husna Endis Lilatul Qodri Munawwaro AMSA - UNIVERSITAS MUHAMMADIYAH MALANG

Faculty of Medicine, Universitas Muhammadiyah Malang Malang Azizah Nadzir1), Bella La Rosa Husna2), and Endis Lilatul Qodri Munawwaro3) - PREVENTIVE, CURATIVE, REHABILITATIVE MEASURES, AND ACTIVITIES TO RAISE AWARENESS OF THE INDONESIAN PEOPLE TOWARDS NEGLECTED TROPICAL DISEASES, ESPECIALLY FILARIASIS

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2020 INTRODUCTION Filariasis is a contagious disease caused by filarial worms which are transmitted by various types of mosquitoes.There are three species of worms that cause filariasis, namely: Wuchereria bancrofti; Brugia malayi; Brugia timori. All of these species found in Indonesia, but more than 70% of cases of filariasis inIndonesia is caused by Brugia malayi. The worm is alivein the glands and lymph channels causing damage to the lymphatic system that can cause symptoms acute and chronic. Acute symptoms are inflammation of the glands and lymph channels (adenolymphangitis) especially in the base areathighs and armpits but can also be in other areas. Chronic symptoms occur due to obstruction of lymph flow especially in the same area with inflammation and causing leg-like symptomselephant (elephantiasis), and hydrocele. Based on reports from district/city, the number of chronic filariasis cases reported until 2009 there were 11,914 cases.Filariasis can be transmitted by all types of mosquito species. InIndonesia is estimated to have more than 23 vector species mosquitoes that transmit filariasis consisting of the genus Anopheles, Aedes,Culex, Manisonia and Armigeres. Filariasis is becoming a world public health problem accordingly by the resolution of the World Health Assembly (WHA) in 1997.The filariasis elimination program in the world was started based on the declaration WHO 2000. In Indonesia, a filariasis elimination program was started in 2002. Indonesia applied 2 points to elimination of filariasis: 1) chain of transmission with the provision of preventive mass drugs filariasis (POMP filariasis) in endemic areas; and 2). Preventand limiting disability due to filariasis. Filariasis is mainly found in regions equator and in landlow. In Indonesia, filariasis widespread in many islands throughout Indonesia, such as in Sumatra and surrounding areas, Java, Kalimantan, Sulawesi, NTT, Maluku, and Irian Jaya. From year to year, the number of provinces reporting filariasis cases continues increase. In fact, some areas have quite high levels of endemicity. MATERIAL AND METHODS This Scientific paper is based on literature review through analytic study on effort of the progress to enchance in Indonesia and report on filariasis case data in Indonesia. some methods and program were carefully evaluated in order to find the right method to create innovative pathway for health warranty of people in the area of Indonesia. Data collection in this study are conducted by the method of literature (literature review) based on issue, both trough digital and non digital information from literature such as 2

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journals

and reports.The moethod of data analysis literature conducted through two

approaches, namely : 1.) Method of Exposition, that the presented data and facts that may untimately osught correlation between these data 2.) Analytic methods, namely trough the analysis of data or information by giving the argument trough logical thinking and were than takes to a conclusion. RESULTS AND DISCUSSION 1. The Epidemiology of Filariasis in Indonesia There are two types of Filariasis, Filariasis W. bancrofti and Filariasis Brugia. Filariasis W. bancrofti is caused by nematode Wuchereria bancrofti, that usually stay in lymphatic system. Microfilariae migrate between the lymph system and blood channels to reach the peripheral blood vessels, often at times of the day that coincide with the peak biting activity of local vectors. When female mosquitoes ingest a blood meal, they consume microfilariae with the blood. In the mosquitoes’ stomachs, they lose their sheath, and some of the parasites migrate through the stomach wall to reach the thoracic flight muscles, where they develop into firststage larvae (L1). The larvae grow and moult into second-stage larvae (L2) and moult again to produce highly active infective third-stage larvae (L3), a process that takes 10–12 days from the L1 stage to the L3 stage. The infective larvae migrate to the mosquito’s proboscis, where they can infect another human host when the mosquito takes a blood meal. The L3 are deposited on the skin and find their way through a bite wound. The L3 develop to fourth-stage larvae (L4) as they migrate through the human body to the lymphatic vessels and lymph nodes, where they develop into adult worms (Figure 1). The reservoir is human’s blood which already contain microfilaries W. brancofti, B. malayi and B. timori. There are some factors that affect transmissions of filariasis; mosquito’s bite that contain infective larvae (L3), transmissions of W. bancrofti through any type of mosquito yet the Culex quinquefasciatus, Anopheles gambiae, An. Funestus, Aedes polynesiensis, An. Scapularis, dan Ae. Pseudoscutellaris are the dominants. B. malayi transmitted through Mansonia, Anopheles, and Aedes. B. timori transmitted by An. barbirostis. There are no direct transmissions from person to person. Wuchereria bancrofti endemic in most parts of the world, areas with high humidity include Latin America, Africa, Asia, and Pasific. B. malayi endemic at the village in India, Azizah Nadzir1), Bella La Rosa Husna2), and Endis Lilatul Qodri Munawwaro3) - PREVENTIVE, CURATIVE, REHABILITATIVE MEASURES, AND ACTIVITIES TO RAISE AWARENESS OF THE INDONESIAN PEOPLE TOWARDS NEGLECTED TROPICAL DISEASES, ESPECIALLY FILARIASIS

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Southeast Asia, north China and South Korea. B. timori endemic at the village in Timor, Flores, Alor, and Rote, Southeast Indonesia. Survey on 2000 reported 1.553 village there are 6.233 chronic cases and it is such a serious health problem in Indonesia. In 2009, more than 125 million population are at risk of the filariasis (Graph 1). Indonesia become the second highest country with filariasis in the whole world after India. The filariasis cases highly increase since 2000 (Graph 2).

2. Signs and Symptoms of People Who Suffer Filariasis The disease generally presents with the symptoms like swelling of legs, and hydrocele and can cause a raft of societal stigma. The clinical symptoms of filariasis consist of symptoms acute and chronic clinical course. Acute symptoms include lymphadenitis, lymphangitis, adenolymphangitis can be like fever, headache, feeling weak and can also become an abscess. Abscess can broke and gave rise scarring, especially in the armpit and fold area thigh. Chronic symptoms include lymphedema, lymph scrotum, kiluri and hydrocele. Lymphedema is the swelling caused by impaired drainage of lymph back to in the blood. The scrotum lymph is widening of the superficial lymph channels of the skin scrotum. Also found vesicles with vary in size on the skin, which can break and soaks clothes. Kiluria is leaks that occur as a result of the rupturelymph channels and blood vessels in the kidneys (renal pelvis) .A hydrocele is swelling that occurs in the scrotum due to the accumulation of lymph fluid inside tunica vaginalis testis. 3. The Prevention for Indonesian People to Avoid Filariasis Factor-based prevention of filariasis risk can be done in ways such as: (a) provide counseling in endemic area about the mode of transmission and the means mosquito vector control (b) Identifies vectors by detecting presence of infective larvae in mosquitoes with using human bait, identify the place and time of the bite mosquitoes, as well as their breeding grounds appropriately. Possible precautions done when transmission occurs by mosquitoes that bite at night on in the house is by spraying use residual pesticides, put up gauze, sleep with using mosquito net (better if already dyed with pyrethroid insecticide), using anti liniment mosquitoes (repellents) and clean the place reproduction of mosquitoes such as latrines open. If found Mansonia sp. as a vector on an area, the action taken is by cleaning the pools from

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water plants which are the source of oxygen for the larvae. And doing treatment by using diethylcarbamazine citrate. (c) Prevention bulk through vector control (mosquitoes) can done, but this proved ineffective given the long life span of parasites about 4-8 years. Recently awarded single dose of treatment, once per year, with two drug regimens namely Albendazol 400 mg and Ivermectin 200mg / kgBW. 4. Activities to Raise Awareness Towards Negelcted Tropical Disease Especially Filariasis Neglected diseases can be successfully integrated into larger health sector reform projects with lasting positive results to both agendas. This has been proved with the elimination of lymphatic filariasis (LF) in GTZ project in Alor district, Indonesia. The programme helped strengthened district health services and created a positive spill over on health service delivery at the district, province and central levels. Building trust, confidence and delivering results The situation at the outset was typical for many remote areas and was characterized by extremely poor morbidity and mortality indicators, low utilisation of health services, and a breakdown of social systems. LF was an important public health problem with prevalence rates ranging from 1-27%. The strategy was to manage LF as an integral part of a decentralised district health scheme thereby contributing to improving trust and utilisation of local health services. Empowerment of local health services District health team, and provided the opportunity for hands on technical assistance to improve the quality of the LF programme. Included motivation of the health services staff , drug distribution including simplified protocols (age based dosing table), monitoring tools and a combination of health services and community driven approach for distribution. And declaration of “Bulan Eliminasi Kaki Gajah (BELKAGA)” which is celebrated every year in October Impressive results

Azizah Nadzir1), Bella La Rosa Husna2), and Endis Lilatul Qodri Munawwaro3) - PREVENTIVE, CURATIVE, REHABILITATIVE MEASURES, AND ACTIVITIES TO RAISE AWARENESS OF THE INDONESIAN PEOPLE TOWARDS NEGLECTED TROPICAL DISEASES, ESPECIALLY FILARIASIS

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There was a dramatic increase in awareness of filaria from 20% prior to the intervention to 89% after. 75% coverage rate for 6 villages and good community acceptance. This was scaled up to two districts with 80% coverage rate. 5. The Curative Way to Cure People with Filariasis Treating filariasis is not an easy task. The damage strats in early stages of infection, and for individuals who live in endemic areas, reinfection becomes a big concern. The most effective method for reducing filariasis is prevention of transmission of the parasite by controlling the vector and reducing the microfilarial levels in the human population. There are several drugs that are effective at reducing the levels of microfilariae in the blood : 1. DEC DEC is a synthetic organic compound that inhibits are arachidonic acid metabolism in microfilariae, making them more susceptible to attack by the immune system. This anthelmintic drug is typically used to treat filarial diseases including lymphatic filariasis caused by infection with W.bancrofti, B.malayi, and B.timori, as well as tropiccal pulmonary eosinophilia and loiasis. DEC is generally effective againstadult worms as a single annual dose of 6mg/kg body weight. 2.

Ivermectin Ivermectin is a synthetic macrocylic lactone molecule that is used as broad spectrum antiparasitic drug. this drug kills microfilaria directly by binding to and opneing glutamate-gated chloride ion channels in the nerve and muscle. Ivermectin rapidly lowers the level of microfifilaria in the blood when given as a single dose of 150–400 mg/kg body weight.

3. Albendazole Albendazole is a broad-spectrum anthelmintic drug that kills adult fifilarial worms by binding to tubulin molecules and inhibiting the polymerization of microtubules. The drug also inhibits the enzyme fumarate reductase, which is helminth specifific. 4. Anti-wolbachial therapy A new treatment for lymphatic fifilariasis takes advantage of the mutualistic relationship between Wolbachia bacteria and the parasite. The WHO-sponsored Global Programme to Eliminate Lymphatic Filariasis (GPELF) recommends two strategies to

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reduce the levels of microfifilariae in the population in hopes of reducing the transmission of fifilariasis. The fifirst strategy is the mass administration of an annual single dose two-drug regimen of 400 mg albendazole plus either 6 mg/kg DEC or 150 mg/kg ivermectin (in the case of co-endemicity with onchocerciasis) for 5 years. By focusing on providing annual treatment, the GPELF hopes to eventually eradicate fifilariasis. 6. The Rehabilitative for People that Survive from Filariasis to Get Into the Normal Life Treatment of filariasis is indeed challenges for all health workers in Indonesia. Filariasis prevention is very important to prevent the resulting disability filariasis. On the other hand, rehabilitative treatment also no less important, especially for minimize the disabilities that have been suffered due to filariasis and assisted adaptation sufferers of filariasis in everyday life. Filariasis sufferers who have undergone treatment can be completely cured. However, their condition could not recover as before it meant, some parts an enlarged body cannot return to normal as before. Rehabilitation This enlarged body can be done by surgery. CONCLUSION In this review Falariasis can prevent by Identifies vectors by detecting presence of infective larvae in mosquitoes with using human bait, identify the place and time of the bite mosquitoes, as well as their breeding grounds appropriately and Individual prevention by reducing contact with mosquitoes through use mosquito nets, anti-mosquito topical medication, as well insecticide.

The most effective method for reducing filariasis is prevention of

transmission of the parasite by controlling the vector and reducing the microfilarial levels in the human population,several drugs that are effective at reducing the levels of microfilariae in the blood is DEC, Ivermectin, Albendazole, etc.

While Filariasis sufferers who have

undergone treatment can be completely cured. However, their condition could not recover as before it meant, some parts an enlarged body cannot return to normal as before. Rehabilitation This enlarged body can be done by surgery. REFERENCES 1. Arsin, Arsunan A. Epidemiology Filariasis di Indonesia. Makassar: Masagena Press; 2019. 2. Ameneshewa, Birkinesh, et al. Lymphatic Filariasis. Italy: WHO; 2013. Azizah Nadzir1), Bella La Rosa Husna2), and Endis Lilatul Qodri Munawwaro3) - PREVENTIVE, CURATIVE, REHABILITATIVE MEASURES, AND ACTIVITIES TO RAISE AWARENESS OF THE INDONESIAN PEOPLE TOWARDS NEGLECTED TROPICAL DISEASES, ESPECIALLY FILARIASIS

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3. Nasronudin, Eddy Soewandojo, Suharto, Usman Hadi. Filariasis dalam buku ajar ilmu penyakit dalam. Fakultas Kedokteran Universitas Airlangga – RSU Dr. Soetomo: Airlangga University Press; 2007. 4. H. I. Malewa, Prihatini. Diagnosis of Filariasis Based on Thick Smear. Indonesian Journal Of Clinical Pathology and Medical Laboratory. Vol 15. Airlangga University Press. 2008 5. Brian F. Linch, MD, DTM&H. Filariasis Treatment and Management. Department of Medicine, University of Oklahoma College of Medicine. 2018 6. Wibawa Tri, Tunggul Satoto. Magnitude of Negelected Tropical Disease in Indonesia at Postmillenium Development Goals Era. Faculty of Medicine, Universitas Gajah Mada. 2016. Publish at Hudawi 7. dr. Tri Yunis Miko, dkk.Buletin Jendela Epidemiologi Filariasis di Indonesia. Pusat Data dan Surveilans Epidemiologi Kementrian Kesehatan RI.2010 8. Samykutty A, Dakshinamoorthy G, Klayanasundaram R. Multivalent Vaccine For Lymphatic Filariasis. Department of Biomedical Sciences, College of Medicine, University of Illinois Rockford. PMCID: PMC3121258. 2011 9. Palumbo E. Filariasis : diagnosis, treatment and prevention. ffiliations expand PMID: 18788504. 2008 10. Mutiara H, Anindita. Filariasis : Pencegahan terkait faktor resiko. Faculty of Medicine, Universitas Lampung. 2016

GRAPH AND ILUSTRATION

Figure 1. Filariasis Life cycle W. bancrofti

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Graph 1. Filariasis cases in Indonesia.

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Graph 2. Outgrowth Filariasis in Indonesia

Figure 2. sugessted treatment of filariasis

Azizah Nadzir1), Bella La Rosa Husna2), and Endis Lilatul Qodri Munawwaro3) - PREVENTIVE, CURATIVE, REHABILITATIVE MEASURES, AND ACTIVITIES TO RAISE AWARENESS OF THE INDONESIAN PEOPLE TOWARDS NEGLECTED TROPICAL DISEASES, ESPECIALLY FILARIASIS

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The number of cases of dengue infection reported by WHO has increased 8-fold over the past 20 years and reports of dengue virus deaths have also increased between 2000 and 2015, namely, from 960 to 4032. In Indonesia alone, the incidence rate of dengue fever in 2019 is 51.48 per 100,000 population. This figure shows an increase compared to the previous two years, namely 2016 and 2017 when the DHF Incidence Rate was 26.1 and 24.75 per 100,000 population. In the picture of IR DHF trends in 2010-2019, there are no known IR DHF peaks, namely in 2010, 2016, and 2019. We collected data from PubMed and Google Schoolar for literature that published for range 2015-2020. In 2015, the number of dengue cases reported was 1,510 with 6 deaths. In 2016, the number of dengue cases reported was 2,631 with 21 deaths. In 2017, there were 2,950 cases of dengue fever. In 2018 there were 1,533 cases of dengue fever in Aceh, with 4 deaths. The incidence rate of dengue fever in 2019 is 51.53 per 100,000 population. From the data, the DHF in aceh still become a problematic with high incidence rate and high case fatality rate in some city/district in Aceh Province.

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Epidemiology of Dengue Hemorrhagic Fever In Aceh in the Last 5 years : A Literature Review

Author(s) : M. Aziz Arridho M. Raihan Ramadhan T M. Arif Ritonga

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Introduction NTD is 17 diseases whose biggest health and economic burden lies in poor communities1. One example of NTD disease is dengue. The dengue virus is transmitted through the bite of Aedes mosquito species. Often causes problems in areas. This dengue virus has several serotypes, namely DENV-1, DENV-2, DENV-3, and DENV-4 and can cause several spectrums of disease, from asymptomatic to dengue fever (DD) to dengue hemorrhagic fever (DHF) to Dengue shock syndrome (DSS)2. Infection of one of these serotypes will only have a detrimental impact on that serotype as well, but not on other serotypes (Dengue Hemorrhagic Fever)3. The number of cases of dengue infection reported by WHO has increased 8-fold over the past 20 years and reports of dengue virus deaths have also increased between 2000 and 2015, namely, from 960 to 40324. In Indonesia alone, the incidence rate of dengue fever in 2019 is 51.48 per 100,000 population. This figure shows an increase compared to the previous two years, namely 2016 and 2017 when the DHF Incidence Rate was 26.1 and 24.75 per 100,000 population. In the picture of IR DHF trends in 2010-2019, there are no known IR DHF peaks, namely in 2010, 2016, and 20195. In 2014, one of the provinces that became an endemic area for dengue hemorrhagic fever was Aceh. The incidence of dengue fever in Aceh Province has increased sharply from 2.75 per 100,000 population in 2003 to 57 per 100,000 in 20116. The purpose of this paper is to describe how the magnitude of DHF in Aceh after 2014 to the present, namely 2015-2020. Materials and methods Literature search was carried out through the database pubmed and google scholar using the keyword aceh and dengue. Then we conducted a screening by applying our inclusion criteria, namely studies published between 2015-2020 and related to the topic. Results and discussion 20157 In 2015, the number of dengue cases reported was 1,510 with 6 deaths (Incidence Rate = 30 per 100,000 population and CFR / mortality rate = 0.4%). Compared to 2014 with cases of 2,211 and IR of 45 per 100,000 population, there was a decrease in cases in 2015. Deaths due to dengue are categorized as high if the CFR is> 2%. Thus in 2015 there were two districts

475


/ cities that had high CFR, namely Subulussalam City and North Aceh District. In the two districts / cities, efforts still need to improve the quality of health services and increase the quality and quantity of health human resources in hospitals and health centers (doctors, nurses, etc.), including improving diagnostic support and management facilities for sufferers in health service facilities. 20168 In 2016, the number of dengue cases reported was 2,631 with 21 deaths (Incidence Rate = 52 per 100,000 population and CFR / mortality rate = 0.8%). Compared to 2015 with 1,510 cases and 30 per 100,000 population of IRs, there was a decrease in cases in 2015. Death due to dengue is categorized as high if the CFR is> 2%. Thus in 2016 there were 4 districts / cities that had high CFR, namely Southeast Aceh District, East Aceh District, North Aceh District, and Aceh Jaya District. The four districts / cities still need efforts to improve the quality of health services and increase the quality and quantity of health human resources in hospitals and health centers (doctors, nurses, etc.), including improving diagnostic support and management facilities for sufferers in health service facilities. 20179 In 2017, there were 2,950 cases of dengue fever, an increase compared to the number of cases in 2016 (2,631 cases). IR (Incidence Rate) or dengue fever morbidity rate in 2017 also increased from 2016, from 52 to 57 per 100,000 population. However, the Case Fatality Rate (CFR) decreased from 0.8% in 2016 to 0.4% in 2017. Deaths due to dengue are categorized as high if the CFR is> 2%. Thus in 2017 there were 2 districts / cities that had high CFR, namely East Aceh District and Subulussalam Municipality. In the two districts / cities, efforts still need to improve the quality of health services and increase the quality and quantity of health human resources in hospitals and health centers (doctors, nurses, etc.), including improving diagnostic support and management facilities for sufferers in health service facilities. 201810 In 2018 there were 1,533 cases of dengue fever in Aceh, with 4 deaths. This number decreased quite drastically from the previous year, namely 2,950 cases and the number of deaths as many as 11 people. The incidence rate (IR) or dengue fever rate in 2018 decreased compared to 2017, from 57 to 29 per 100,000 population. However, the decline in the case fatality rate (CFR) from the previous year was not too high, namely 0.4% in 2017 to 0.3% in 2018.

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201911 The incidence rate of dengue fever in 2019 is 51.53 per 100,000 population. This figure shows an increase compared to the previous two years, namely 2017 and 2018 when the DHF Incidence Rate was 26.1 and 24.75 per 100,000 population. The provinces of North Kalimantan, East Kalimantan and Bali have the highest IR among 34 other provinces, namely 239, 180.66 and 114.8 per 100,000 population, respectively. Meanwhile, the provinces with the lowest IR DHF were Maluku at 13.09, Papua at 17.67, and Banten at 22.55 per 100,000 population. The comparison of IR DHF in 2018-2019 shows that most provinces have experienced an increase. The Provinces of North Kalimantan and North Maluku experienced a significant increase of 10 times, from 24.01 and 8.92 in 2018 to 239 and 95.16 per 100,000 population in 2019, respectively. In 2019, only three provinces experienced reduction in IR DHF, namely Central Kalimantan, West Kalimantan, and Maluku. Apart from morbidity, the magnitude of DDB problems can also be known from the mortality rate or CFR obtained from the proportion of deaths to all reported cases. Nationally, the CFR shows a slight decrease from 0.71% in 2018 to 0.67% in 2019. Provinces are said to have high CFR if they exceed 1%. In 2019 there were 10 provinces with CFR above 1%, namely Maluku, Gorontalo, Central Kalimantan, NTT, Central Java, North Maluku, North Sulawesi, East Java, Papua and West Sulawesi. The high CFR requires steps to improve the quality of health services. Efforts to educate the public are also needed to increase public knowledge and awareness so that they immediately go to health facilities if there are family members who have symptoms of dengue. This becomes important as immediate help to prevent severity and complications that lead to fatality.

Results and discussion Number

City/ District

Incidence Rate 20157

20168

20179

201810

201911

1

Simelulue

4

74

82

92

18

2

Aceh Singkil

20

12

11

57

184

3

Aceh Selatan

113

197

85

28

60

477


4

Aceh Tenggara

3

47

8

26

20

5

Aceh Timur

51

156

88

84

142

6

Aceh Tengah

211

293

119

73

85

7

Aceh Barat

59

67

133

100

113

8

Aceh Besar

78

149

389

119

153

9

Pidie

211

189

357

111

238

10

Bireuen

189

278

410

81

134

11

Aceh Utara

36

108

60

43

61

12

Aceh Barat Daya

9

67

63

75

266

13

Gayo Lues

9

2

34

2

5

14

Aceh Tamiang

85

252

47

187

94

15

Nagan Raya

10

19

27

31

68

16

Aceh Jaya

2

5

44

18

39

17

Bener Meriah

2

20

22

6

19

18

Pidie Jaya

50

77

100

10

74

19

Banda Aceh

127

152

236

108

344

20

Sabang

51

51

51

48

88

21

Langsa

67

129

453

119

91

22

Lhokseumawe

115

280

95

111

84

23

Subulussalam

8

7

36

4

6

The city/ district of Banda Aceh, Aceh Barat Daya, and Pidie have the highest IR among 23 other provinces in 2019, namely 238, 266 and 344 per 100,000 population, respectively. Meanwhile, the city/ district with the lowest IR DHF were Gayo Lues at 5, Subulussalam at 6, and Simelulue at 18 per 100,000 population. The comparison of IR DHF in 2018-2019 shows that most provinces have experienced an increase.

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Incidence Rate DHF per 100.000 in Aceh 2015-2019 57

60

52 50

44

40 30

29

30 20 10 0 2015

2016

2017

2018

2019

Incidence Rate

The incidence rate of dengue fever in 2019 is 44 per 100,000 population. This figure shows an increase compared to the previous year, namely 2018 when the DHF Incidence Rate was 29 per 100,000 population. In the 2015-2019 IR DHF trend image, it is also known that there are two IR DHF peaks, namely in 2017 and 2019. Number

City/ District

Case Fatality Rate (%) 20157

20168

20179

201810

201911

1

Simeulue

0

0

0

0

0

2

Aceh Singkil

0

0

0

0

0

3

Aceh Selatan

0.9

0

0

0

0

4

Aceh Tenggara

0

9

0

0

0

5

Aceh Timur

0

3

6

4

0

6

Aceh Tengah

0

0

0

0

0

7

Aceh Barat

0

0

0

0

0

8

Aceh Besar

0

0

0

0

0

9

Pidie

0

1

0

0

0

10

Bireuen

0.5

0

0

0

0.75

11

Aceh Utara

5.6

3

0

0

0

12

Aceh Barat Daya

0

0

0

0

0.38

13

Gayo Lues

0

0

0

0

0

14

Aceh Tamiang

0

1

0

0

0

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15

Nagan Raya

0

0

0

0

1.47

16

Aceh Jaya

0

20

0

0

2.56

17

Bener Meriah

0

0

0

0

0

18

Pidie Jaya

0

0

0

0

0

19

Banda Aceh

0.8

0

0

0

0.29

20

Sabang

0

0

0

0

0

21

Langsa

0

0

0

0

1.1

22

Lhokseumawe

0

0

1

1

0

23

Subulussalam

12.5

0

3

0

0

Note: Death due to DHF is categorized as high if the CFR is> 2%. The city/ district of Aceh Jaya, Nagan Raya, and Langsa have the highest CFR among 23 other provinces in 2019, namely 2.56%, 1.47%, and 1.1%, respectively. Meanwhile, there are 17 city/ district with 0% CFR DHF in 2019 . City/ district are said to have high CFR if they exceed 2%. In 2015, 2016, 2017, 2018, and 2019 there were 2, 4, 2, 1, and 1 city/district with CFR above 2%. The comparison of CFR DHF in 2015-2019 shows that most city/ district have experienced an increase.

Case Fatality Rate DHF in Aceh 2015-2019 (%) 0,9 0,8

0,7 0,6 0,5 0,4 0,3 0,2 0,1

0 2015

2016

2017

2018

2019

Case Fatality Rate

The case fatality rate of dengue hemorrhagic fever in 2019 is 44 per 100,000 population. This figure shows an increase compared to the previous year, namely 2018 when the DHF Incidence Rate was 29 per 100,000 population. In the 2015-2019 IR DHF trend image, it is also known that there are two IR DHF peaks, namely in 2017 and 2019. Conclusion

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DHF in Aceh Province still high in this recent year, but not the highest in Indonesia. In 2017, the case fatality rate was the lowest in the past 5 years, but in 2018 it was get higher. Some city/district like Aceh Timur have a high case fatality rate, although it was not city/district with the highest incidence rate at that time. In 2019, dengue still become a problem for Aceh citizen. Because of that people should be more aware of factor associated with dengue hemorrhagic fever, like the vector or the environment that support the factor to breed. Government program for termination of dengue have not changed for recent year, but the DHF case is still high. So, actually what we need to terminate DHF was not only come from government, but also came from ourself Reference 1. Bangert M, Molyneux D, Lindsay S, Fitzpatrick C, Engels D. The cross-cutting contribution of the end of neglected tropical diseases to the sustainable development goals. Infectious Diseases of Poverty. 2017;6(1). 2. Murugesan A, Manoharan M. Dengue Virus. Emerging and Reemerging Viral Pathogens. 2020;:281-359. 3. Gubler D, Clark G. Dengue/Dengue Hemorrhagic Fever: The Emergence of a Global Health Problem. Emerging Infectious Diseases. 1995;1(2):55-57. 4. Dengue and severe dengue [Internet]. Who.int. 2020 [cited 15 December 2020]. Available from: https://www.who.int/news-room/fact-sheets/detail/dengue-and-severe-dengue 5. PROFIL KESEHATAN INDONESIA TAHUN 2019. Jakarta: Kementrian Kesehatan Republik Indonesia; 2020. 6. Yulidar Y. STATUS ANGKA BEBAS JENTIK KOTA BANDA ACEH SEBAGAI DAERAH ENDEMIS DEMAM BERDARAH DENGUE TAHUN 2014. BIOTIK: Jurnal Ilmiah Biologi Teknologi dan Kependidikan. 2017;5(1):78. 7. Profil Kesehatan Aceh 2015. Banda Aceh: Dinas Kesehatan Provinsi Aceh; 2016. 8. Profil Kesehatan Aceh 2016. Banda Aceh: Dinas Kesehatan Provinsi Aceh; 2017. 9. Profil Kesehatan Aceh 2017. Banda Aceh: Dinas Kesehatan Provinsi Aceh; 2018. 10. Profil Kesehatan Aceh 2018. Banda Aceh: Dinas Kesehatan Provinsi Aceh; 2019. 11. Profil Kesehatan Aceh 2019. Banda Aceh: Dinas Kesehatan Provinsi Aceh; 2020.

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