01 Inection

SECTION 1

Infection 1.

Dengue - Management and Prevention Sangeeta Madhok

3

2.

Cardiac Manifestations in Dengue Fever Mohit Arora, Rekha S Patil

8

3.

Management of Dengue Sujata Rege, Subramanian Swaminathan

12

4.

Antimicrobial Resistance (AMR) - A Scientific Challenge with Political Repercussions Abdul Ghafur

20

5.

Approach to Fever in a Returning Traveler Bibhuti Saha, Manab Kumar Ghosh

22

6.

Adult Immunization in India V Ramasubramanian

30

7.

Approach to patients with Pyrexia of Unknown Origin Suspected to have Tuberculosis MA Jalil Chowdhury

35

8.

Adult Influenza Vaccination Ashray Naik

40

9.

Tackling the Challenge of Antibiotic Resistance Rajesh Chawla, Aakanksha Chawla

45

10.

Bad Bugs, No Drugs: The Saga of Antibiotic Resistance Sandeep Puri, Arshdeep Singh

48

11.

Gene Therapy for Cure of HIV Infection S Bhagyabati Devi, T Jeetenkumar Singh, Ksh. Birendra Singh

53

C H A P T E R

1

Dengue - Management and Prevention

Sangeeta Madhok

INTRODUCTION

Dengue, a mosquito-borne disease, is a critical global threat and a major public health concern throughout the tropical and subtropical regions of the world.1,2 Dengue is the most rapidly spreading mosquito-borne viral disease of mankind, with a 30-fold increase in global incidence over the last five decades.1 While dengue is a global threat, the Asia-Pacific region bears the major brunt with almost 75% of the disease burden present here.1 Infection with the dengue virus can result in a variety of clinical states ranging from ‘asymptomatic’ to mildly symptomatic dengue fever (DF) to more dangerous clinical conditions with capillary leakage syndrome such as dengue shock syndrome (DSS) and dengue hemorrhagic fever (DHF).3 In India, dengue has been not only expanding with enormous rapidity over the last few decades, but also changing in its epidemiology. Although the first mention of occurrence of dengue in India was in 1780, and the first confirmed outbreak in Kolkata in 1963–1964, it took almost further 30 years for dengue to eventually spread throughout the entire country, resulting in the first major nationwide outbreak of DHF in the year 1996.3 At present, in most states in India, dengue has firmly established its roots and is almost endemic.

EPIDEMIOLOGY

Global scenario

Due to substantial under-reporting of dengue within health systems and to World Health Organization (WHO), the global disease burden still remains uncertain.

However, the patterns are definitely a cause for concern for human health and economy.1,2 Based on mathematical modelling, the global annual incidence has been estimated at about 50 million – 100 million symptomatic cases in recent years, predominantly in Asia, followed by Latin America and Africa, with clinical cases likely to represent about 25% of all dengue virus infections.2 Hundreds of thousands of severe cases arise, of which 20 000 lead to death every year. Loss to the economy is 264 disabilityadjusted life years (DALYs) per million population per year.1 1.8 billion of the population at risk for dengue worldwide live in Member States of the WHO South-East Asia Region (SEAR) and Western Pacific Region. Of the 11 countries in SEAR, 10 are endemic for dengue and this includes India

too.1 Data from 2012 shows that Thailand contributes ~30%, Indonesia 29% and India 20% to this burden. Of the 0.33 million cases from Western Pacific countries, more than half is contributed to by Philippines (52%), followed

by Vietnam (24%) and Cambodia (14%).

Indian scenario

According to the World Health Organization, the incidence of dengue globally has shot up 30-fold in the past 50 years. More than 1.25 billion people reside in India; hence, a huge population is at risk and there is a high cumulative dengue disease burden.3 Of the 36 states/union territories (UTs), 35 (all except Lakshadweep) have reported dengue cases during the last two decades. Recurring outbreaks of DF/DHF have been reported from various states/UTs—Andhra Pradesh, Chandigarh, Delhi, Goa, Haryana, Gujarat, Karnataka, Kerala, Maharashtra, Rajasthan, Uttar Pradesh, Puducherry, Punjab, Tamil Nadu and West Bengal.1 There is an upsurge in the cases of dengue/DHF every year, during the period July–November. The disease has a seasonal pattern; the cases peak after the monsoons and are not uniformly distributed throughout the year.

However, the states in the southern and western parts of the country report perennial transmission. Dengue, earlier a disease more prevalent in urban areas, is demonstrating changing trends with socio-economic and man-made ecological changes. This has significantly increased the chances of spread of the disease in rural areas.1 The most severe outbreaks in India have been reported in 1996, 2006 and then 2010. During 2010, a total of 28 292 cases were reported, which increased to 50 222 in 2012 and 75 808 in 2013 – the highest since 1991. The case fatality ratio (CFR – deaths per 100 cases) has declined from 3.3% in 1996 to 0.4% in 2010 after the national guidelines on clinical management of DF/DHF/DSS were developed and circulated in 2007. A further decrease in the CFR to 0.3% was seen in 2013.1

THE PATHOGEN AND ITS SEROTYPES

Dengue virus belongs to the genus Flavivirus in the family Flaviviridae. These viruses contain single stranded RNA and are small in size (50 nm). It is transmitted mainly by the Aedes aegypti mosquito and also by the Aedes albopictus mosquito. There are four dengue virus serotypes which are designated as DENV-1, DENV-2, DENV-3 and DENV-4.1 There are several subtypes or

INFECTION

4

Table 1: Dengue serotypes in India

Table 2: Clinical Criteria for Dengue1

Year

State

1964

Tamil Nadu

Prevalent Serotype 2

1968

Tamil Nadu

1,2,3 & 4

1970

Uttar Pradesh

1,2,3 & 4

1996

Uttar Pradesh

2

1996

Delhi

2

1996

Haryana

3

1997

Delhi

1

2001

Madhya Pradesh

2

2003-2005

Delhi

1,2,3 & 4

2007-2009

Delhi

1,2,3 & 4

2009-2010

Maharashtra

4

2010-2011

Delhi

1

2009-2012

Uttar Pradesh

1,2 & 3

genotypes of each serotype. It is believed that infection with one serotype gives lifelong immunity against reinfection, but only partial immunity against other serotypes. Each serotype has unique characteristics and can present with severe manifestations in a particular population depending upon its interaction with the host response.3 All 4 serotypes are capable of causing severe dengue disease and dengue epidemics.4

Changing serotypes in India

Serotypes of dengue virus have kept on changing over the years. Each time the serotype or genotype shows a change, there is an increase in cases in that particular area. Between 1996-2003, all the four serotypes have been reported and there has been also a parallel increase in outbreaks.

Clinical Features of DF: An acute febrile illness of 2-7 days duration with two or more of the following manifestations: • Headache, retro-orbital pain, myalgia, arthralgia, rash, haemorrhagic manifestations Dengue Haemorrhagic Fever (DHF): a. A case with clinical criteria of dengue Fever Plus b. Haemorrhagic tendencies evidenced by one or more of the following • Positive tourniquet test • Petechiae, ecchymoses or purpura • Bleeding from mucosa, gastrointestinal tract, injection sites or other sites Plus c. Thrombocytopenia (<100 000 cells per cu mm)

Plus

d. Evidence of plasma leakage due to increased vascular permeability, manifested by one or more of the following: • A rise in average haematocrit for age and sex > 20% • A more than 20% drop in haematocrit following volume replacement treatment compared to baseline • Signs of plasma leakage (pleural effusion, ascites, hypoproteinemia) Dengue Shock Syndrome (DSS): All the above criteria for DHF with evidence of circulatory failure manifested by rapid and weak pulse and narrow pulse pressure (mmHg) or hypotension for age, cold and clammy skin and restlessness.

Table 1 shows the changing serotypes from 1964 to 2012.

Infection with individual serotypes and concurrent infection with multiple serotypes have been seen over this period. Along with changing serotypes, a shift has also been seen in the age group involvement from children to young adults.3

•

From all this data, one can infer that there is a definite increase in the number of outbreaks and change in serotypes, indicating hyperendemicity of dengue in India.3

DHFI: Above criteria plus positive tourniquet test and evidence of plasma leakage. Thrombocytopenia with platelet count less than 100000/ mm3 and hematocrit (Hct) rise more than 20% over baseline.

•

DHFII: Above plus some evidence of spontaneous bleeding in skin or other organs (black tarry stool, epistaxis, gum bleeds) and abdominal pain.

Thrombocytopenia with platelet count less than 100000/ mm3 and Hct rise more than 20% over baseline.

•

DHFIII (DSS): Above plus circulatory failure (weak rapid pulse, narrow pulse pressure < 20 mm Hg, Hypotension, cold clammy skin, restlessness).

Thrombocytopenia with platelet count less than 100000/ mm3 and Hct rise more than 20% over baseline.

•

DHFIV (DSS): Profound shock with undetectable

with or without leukopenia, thrombocytopenia and no evidence of plasma leakage.

THE DISEASE SPECTRUM

There are different forms of the disease seen: DF, DHF or DSS. Accordingly, the clinical manifestations of a dengue viral infection range from undifferentiated fever to the very severe signs of widespread hemorrhage and shock.1 The majority of dengue virus infections are asymptomatic.

For clinical cases the incubation period is usually 4–7 days but can be in the range of 3–14 days.2 The clinical features for each of the disease types is shown in Table 2.

Grading of DF/DHF1 •

DF: Fever of 2-7 days with two or more of followingheadache, retro orbital pain, myalgia, arthralgia

MAC-ELISA has become an invaluable tool for surveillance of DF/DHF. The anti-dengue IgM antibody develops a little faster than IgG and is usually detectable by day 5 of the illness. However, the rapidity with which IgM develops varies considerably among patients. This test is especially useful in hospitalized patients to confirm diagnosis.1

5

IgG-ELISA can be used to differentiate primary and secondary dengue infections. The test is simple and easy to perform, however, since this test indicates only past infections it cannot be used as a diagnostic test.1

The Government of India recommends the following tests for diagnosis of dengue infections: •

ELISA-based NS1 antigen test – for diagnosing cases from 1st day onwards

•

MAC-ELISA – for diagnosing cases from 5th day of onset of disease

TREATMENT

Fig. 1: Classification of dengue cases1 blood pressure or pulse. Thrombocytopenia with platelet count less than 100000/ mm3 and Hct rise more than 20% over baseline.

A simple way to classify dengue cases is presented in the algorithm below (Figure 1).1

LABORATORY DIAGNOSIS

In endemic areas, it is important to be differentiate early symptoms of dengue fever from other prevalent diseases such as chikungunya, malaria, viral infection, urinary tract infection, typhoid, leptospirosis, etc. Excluding these diseases is critical for proper management of dengue and hence the importance of a confirmed laboratory diagnosis.1 Laboratory confirmation of dengue virus infection is usually done by enzyme-linked immunosorbent assay (ELISA)-based NS1 antigen tests, serology [IgM antibodycapture ELISA (MAC-ELISA), IgG ELISA, or by molecular methods [reverse transcriptase-polymerase chain reaction (RT-PCR); virus isolation is used less commonly.1 RT-PCR and NS1 tests offer earlier and more specific diagnosis (80%–90% sensitivity if assessed 1–3 days after the onset of illness) and are considered virological proof of infection.2 Early, viremic stage detection is possible with these two tests and hence, these tests have epidemiological significance for containing the transmission.1 RT-PCR has become the new standard for early detection in acutephase and has gradually replaced the virus isolation method. Differentiating between different flaviviruses can be done with the NS1 assay due to its specificity.1

Currently no effective or specific anti-viral treatments are available for treatment of dengue infection.2 Thus, dengue is clinically managed with supportive and symptomatic therapy depending on the severity of illness.1 Patients with simple fever without any danger signs or complications may be managed with symptomatic approach. Progression of disease should be closely watched for in patients with warning signs and symptoms.

Aggressive management is needed in patients with grade III and IV DHF, significant bleeding or involvement of various organs, to reduce morbidity and mortality. Patient can also develop complications during later stage of fever (defervescence) or in their afebrile phase. A clinician should be careful to look for danger signs and signs of fluid overload.1 Improvements in case management have reduced the case fatality rate of hospitalized dengue illness to less than 1%, whereas historically it was as high as 20%.2

PREVENTION

In order to mitigate the ever-increasing social and economic burden of dengue, WHO targets to reduce the overall dengue mortality and morbidity by 50% and 25%, respectively, by 2020.5 In the current scenario of no specific therapeutic interventions, the only approach in India to control or prevent the dengue virus is through interventions targeting the vector.2 A. aegypti followed by A. albopictus are the two most common vectors in India.3 However, increasing migration between rural and urban areas, rapid growth in population, unplanned urbanization and the evolution and spreading of insecticide resistance in mosquitoes affects the control of dengue vectors.6 Further, there is a paucity of data to show an impact of vector control interventions on the incidence of dengue illness.2

CHAPTER 1

National vector borne disease control programme (NVBDCP)recommended tests for laboratory diagnosis

6

100 93.2

92.9

Efficacy against severe dengue

Efficacy against DHF

Efficacy (%)

80.8

50

INFECTION

0

Efficacy against hospitalisation

Fig. 2: Pooled efficacy results of the CYD-TDV dengue vaccine In addition to vector control measures, there is also a need to focus on diagnosis, surveillance and outbreak preparedness. Surveillance is an essential component and provides information for risk assessment and guidance for an effective program. Passive and active data collection with a good laboratory support are critical components of a good surveillance plan. Towards improving dengue surveillance, the government of India has set up laboratories to diagnose dengue in different states across the country couples with a national program plan.3 Despite all these extensive efforts in developing effective prevention strategies for dengue control, several factors pose difficulties such as our large population, lack of awareness, illiteracy, and poverty.3 Given this scenario, there is an urgent need for a safe and effective dengue vaccine for preventing and controlling dengue in endemic areas.6 An ideal dengue vaccine should be able to produce a protective immune response which is lifelong in the form of neutralizing antibodies. Very importantly these should be equally effective against all the four serotypes of dengue virus (DENV 1 to 4).6 A lot of progress has been made over the last decade in the development of various approaches towards dengue vaccine candidates and clinical trials of these are being conducted in both endemic and non-endemic areas.

The various vaccine/vaccine candidates being developed are.7 •

Live-attenuated vaccines, including live chimeras based on attenuated DENV or yellow fever virus backbones

•

Recombinant vector vaccines, such as those using adenoviruses

•

DNA vaccines

•

Inactivated vaccines or subunit proteins, used in combination with adjuvants

•

Combinations of several of these technologies

The live-attenuated chimeric yellow fever – dengue virus tetravalent dengue vaccine (CYD- TDV) has been licensed for use in several countries. This dengue vaccine (manufactured by Sanofi Pasteur) is a scientific and technological breakthrough developed for use in dengue-

endemic countries. It is composed of four CYD vaccine viruses each of which express the structural genes — encoding the membrane protein (prM) and envelope protein (E) — of one of the four DENV serotypes. These structural genes are expressed using a yellow fever virus strain 17D (YFV17D) genetic backbone, which is a wellcharacterized live-attenuated flavivirus vaccine for which immunogenicity and safety have been documented for several decades. This strategy results in the generation of vaccine viruses that collectively express the structural antigens of the four DENV serotypes, and these antigens act as the targets of the host immune response involving innate immune cells, neutralizing antibodies and T cell responses.7

CYD-TDV DENGUE VACCINE

The CYD-TDV dengue vaccine has undergone an extensive clinical development program including 25 clinical trials. It has successfully completed all 3 phases of global clinical development plan enrolling over 40,000 people of different ages, geographic and epidemiological settings, ethnic and socio-economic backgrounds from 15 countries around the world.7 A global view of the clinical profile of the CYD-TDV dengue vaccine was provided by an integrated efficacy and safety analysis which has been published in the New England Journal of Medicine.8 The trials included for assessing efficacy and safety in this analysis were two phase III trials (Asian trial/CYD 14 and Latin American trial/CYD 15), a phase II b (CYD 23) trial in Thai children.

All these 3 trials included a 4 -year long term follow up period beyond the 25-month active surveillance period as recommended by WHO. The data set involves more than 34,000 children from Asia and Latin America in the age group of 2 to 16 years.8 In these efficacy studies the vaccine was administered as a 0.5 ml dose given subcutaneously at 0, 6 and 12 months

Pooled efficacy over 25-month active surveillance period and safety analysis8

The objective of the pooled CYD14 and CYD15 analyses was to assess the efficacy of CYD-TDV against virologically confirmed dengue, hospitalization for dengue and severe illness (defined according to the criteria of the independent data monitoring committee and the WHO criteria for dengue hemorrhagic fever) associated with any serotype. The objective of the follow-up analyses was to describe the long-term safety of the dengue candidate vaccine, in terms of predisposition to severe disease or increase in risk of severe disease with time.

The pooled efficacy analysis demonstrated high levels of protection against severe disease and DHF. It also showed lower hospitalization rates for dengue among participants who were 9 years of age or older in the vaccine group (Figure 2).

The vaccine protects two-thirds (65.6%) of the vaccinated individuals above 9 years of age against dengue of any severity and due to any serotype. Serotype-wise pooled efficacy is shown in Figure 3.

100

83.2

Efficacy (%)

73.6

50

58.4 47.1

has been submitted in more than 20 countries including the European Medicines Agency and the Therapeutic Goods Administration in Australia. The dossier will be submitted to US FDA shortly. More countries are expected to approve the use of the vaccine in the coming months. In keeping with the WHO recommendations, 2 countries (the Philippines and Brazil) have introduced a public dengue vaccination program in the dengueendemic parts of their countries.

7

CONCLUSION

0

Serotype 2

Serotype 3

Serotype 4

The long-term follow-up analyses confirmed the persistency of the longer-term safety profile of this dengue vaccine for individuals 9 years of age and older, for three years after the first dose in the two phase III studies (Asian study/CYD14 and Latin American study/CYD15) and for four years after the first dose in phase IIb study (Thailand/ CYD23, extension study: CYD57).8

Indian phase 2 trial analysis9

In India, an observer-blind, randomized, placebocontrolled, phase II safety and immunogenicity trial (CYD 47) was conducted in subjects from 18 – 45 years in five centers (Delhi, Ludhiana, Pune, Bangalore and Kolkata). The clinical doses used in this trial were from same batches used in the Phase III global program. The Indian results show that the dengue vaccine after 3 doses of 0.5 ml each administered subcutaneously at 0, 6 and 12 months was well tolerated and produced antibodies against all 4 dengue serotypes in both dengue seropositive and seronegative Indian adults in the study. There were no cases of severe dengue reported, no deaths and no related serious adverse events reported during the trial.

The Indian phase 2 clinical trial results are consistent with the results of the global dengue vaccine clinical trials.

WHO position on CYD-TDV dengue vaccine

The WHO has published its position on the CYD-TDV dengue vaccine in July 2016 and has recommended the introduction of this vaccine in dengue-endemic areas.

They recommend that dengue vaccine introduction should be a part of a comprehensive dengue control strategy together with a communication strategy, wellexecuted and sustained vector control, the best evidencebased clinical care for all patients with dengue, and robust dengue surveillance.2

Current status of the CYD-TDV vaccine

The vaccine is currently licensed in Mexico, the Philippines, Brazil, El Salvador, Costa Rica, Guatemala, Peru, Paraguay, Indonesia, Thailand, Singapore, Bolivia and Cambodia for the prevention of dengue disease caused by all 4 virus serotypes (1, 2, 3, 4) in dengueendemic areas. The regulatory dossier of this vaccine

ACKNOWLEDGEMENTS

The author acknowledges Dr. Preeti Modi, Head- Medical Communications, Mool Tatvam Consulting LLP, Mumbai, India for literature research and writing support.

REFERENCES

1. National guidelines for clinical management of dengue fever 2014. Available [online] at URL: http://pbhealth.gov. in/Dengue-National-Guidelines-2014%20Compressed.pdf.

Accessed on September 7th, 2016.

2. Dengue Vaccine. WHO position paper 2016. Available [online] at URL: http://www.who.int/wer/2016/wer9134. pdf?ua=1. Accessed on September 7th, 2016.

3. Gupta E, Ballani N. Current perspectives on the spread of dengue in India. Infection and Drug Resistance 2014; 7:337– 342.

4. Natasha Evelyn Anne Murray, Mikkel B Quam, Annelies Wilder-Smith. Epidemiology of dengue: past, present and future prospects. Clin Epidemiol 2013; 5:299–309.

5. World Health Organization, Geneva, 2012. Global Strategy for dengue prevention and control, 2012-2020: WHO report. Available from: http://www.who.int/ denguecontrol/9789241504034/en/. Accessed on September 7th, 2016.

6. Ghosh A, Dar L. Dengue vaccines: Challenges, development, current status and prospects. Indian J Med Microbiol 2015; 33:3-15.

7. Guy B, Jackson N. Dengue vaccine: hypotheses to understand CYD-TDV-induced protection. Nature Reviews Microbiology 2016; 14:45–54.

8. Hadinegoro SR, Arredondo-García JL, Capeding MR, Deseda C, Chotpitayasunondh T, Dietze R, et al. Efficacy and Long-Term Safety of a Dengue Vaccine in Regions of Endemic Disease. N Engl J Med 2015; 373:1195-206.

9. Dubey AP, Agarkhedkar S, Chhatwal J, Narayan A, Ganguly S, Wartel TA, et al. Immunogenicity and safety of a tetravalent dengue vaccine in healthy adults in India: A randomized, observer-blind, placebo-controlled phase II trial. Human Vaccines & Immunotherapeutics 2016; 12:512518.

CHAPTER 1

Serotype 1

Fig. 3: Pooled efficacy results of the CYD-TDV dengue vaccine against different serotypes in children 9 years and older

Dengue poses a major healthcare concern in the tropical and sub-tropical regions of the world. Due to the lack of specific treatment and failure of current control measures to reduce dengue epidemic occurrence, vaccination can be a potentially effective strategy for dengue control when used as a part of a comprehensive dengue control strategy.

Cardiac Manifestations in Dengue Fever

C H A P T E R

2

Mohit Arora, Rekha S Patil

ABSTRACT

Dengue fever, also known as “break bone” fever is a mosquito borne infection caused by Dengue virus. The disease can have a self-limiting febrile course or can range to severe forms like dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). Cardiac involvement in dengue fever in not uncommon. The involvement is more in severe forms of the disease. Although most of them are transient and self-limiting but a proper diagnosis is a must and aggressive management should be given to avoid hemodynamic collapse. Treatment involves supportive care with antipyretics and IV fluids to replenish intravascular fluid compartment.

INTRODUCTION

Dengue fever has emerged as one of the most important viral disease in the world. It is transmitted by the bite of female Aedes aegypti mosquito infected with the dengue virus. There are 4 known strains of the dengue virus (DEN1, DEN2, DEN3 and DEN4) and all the 4 strains are known to cause disease. The disease can range from mild dengue fever to the severe forms like dengue hemorrhagic fever and dengue shock syndrome1. Although the disease is not new and humans have been trying to curb it since many decades but there has been an endemic in the tropical areas of the world where the environmental factors favors breeding of the Aedes aegypti mosquito.

Dengue fever emerged from Africa almost 500 to 600 years ago, and the first outbreaks reached different parts of world such as Asia and South America concurrently in the 1780 2. India faced first outbreak in 1780 in madras and the condition is worsening every year. In 2012, WHO classified Dengue Fever “the most important mosquito borne viral disease in the world”3. DF has been the 99913 100000 90000 80000 70000 60000 50000 40000 30000 20000 10000 0

75808 50222 40571 28292 18860 110 2010

169 2011

242 2012 CASES

193 2013

220

137 2014

2015

DEATHS

Fig. 1: Number of Dengue Cases and Deaths in India (since 20104)

major cause of hospitalization and mortality after acute respiratory and diarrhea infections among children. Cases of dengue related deaths have increased significantly. In 2015, 99913 cases were reported from all over the county (Figure 1).4 The numbers quote only the reported number of cases and many more cases that are not diagnosed or not reported.

The mosquito, Aedes aegypti breeds in clean water bodies and bite during the daytime. The peak biting hours range from early morning to evening before dawn.

After incubation period of 4 – 10 days the viremia ensues producing clinical signs and symptoms of the disease.

People infected with the dengue virus serve as source of infection by transmitting it to the non-infected Aedes aegypti mosquito during their bite.

PATHOPHYSIOLOGY

The exact mechanism of the cardiac injury in dengue fever remains unknown, however it is proposed that the direct invasion of the cardiac myocyte by the virus and damage to the cardiac cells by the ongoing inflammatory damage are the major mechanism of the cardiac manifestations.

Dengue virus upon its entry in the body is taken up by the macrophages which causes activation of the T cells. These activated T cells cause release of various inflammatory cytokines, interleukins (IL1, IL2, IL6 etc), tumor necrosis factors (and activation of the complement pathway(C3a, C5a) and histamine.5 This leads to the inflammation and necrosis of the endothelial cells leading to their dysfunction and plasma leakage. Leakage of the plasma in the interstitial space cause myocardial interstitial edema leading to impairment of myocardial function.

Decreased fluid in the intravascular compartment secondary to plasma leakage leads to alteration in the coronary circulation(Figure 2). Various inflammatory markers released cause direct suppression of the cardiac contractility and alteration in the electrical conduction of heart leading to various conduction blocks and ventricular arrhythmia. The release of these inflammatory markers is more in severe form of the disease that correlates with the higher incidence of cardiac manifestations in patients with severe form of the disease.

CLINICAL FEATURES

The disease has an incubation period of 4 – 10 days before the symptoms starts appearing. The characteristic symptoms include fever, headache, body ache, multiple joint pain including both small and large joints of body, retro orbital pain, myalgia, itching and rash.

9

Dengue Virus Enters body

Infect Macrophages

Myocyte Infec8on and Inflamma8on

Endothelial dysfunc8on causing capillary leakage

Release of vasoac8ve mediators

Decreased intravascular volume

Altered coronary microcircula8on

Ac8vated T cells

Release of Inflammatory cytokines

Altered intracellular calcium homeostasis

Myocardial Impairment

Electrical abnormali8es • Bradyarrythmias • ST segment changes • T- wave abnormali8es

Fig. 2: Proposed Viral and Immune Mechanisms for Cardiac & Vascular Manifestations in dengue5 Table 1: Grading the severity of Dengue infection DF/DHF

Grade

DF

Symptoms/signs

Laboratory findings

Fever with two or more of following

Leucopenia, thrombocytopenia

- Headache - Retro-orbital pain - Myalgia - Arthralgia DHF

I

Above criteria for DF plus positive tourniquet test, evidence of plasma leakage

Thrombocytopenia: Platelet count less than 100,000/cu.mm Haematocrit rise 20% or more

DHF

II

Above signs and symptoms plus some evidence of spontaneous bleeding in skin or other organs (black tarry stools, epistaxis, bleeding from gums, etc) and abdominal pain

Thrombocytopenia platelet count less than 100,000/cumm Haematocrit rise 20% or more

DHF

III

Above signs and symptoms plus circulating failure (weak rapid pulse, pulse pressure ≤20 mm Hg or high diastolic pressure, hypotension with the presence of cold clammy skin and restlessness)

Thrombocytopenia: Platelet count less than 100,000/cumm Haematocrit rise more than 20%

DHF

IV

Profound shock with undetectable blood pressure or pulse Haematocrit rise more than20%

Thrombocytopenia: Platelet count less than 100,000/cumm Haemotocrit rise more than 20%

Depending upon the severity, it can be classified into – Dengue Fever, Dengue Hemorrhagic Fever and Dengue

Shock Syndrome (Table 1).

Cardiac symptoms in dengue fever can range from

CHAPTER 2

Myocardial inters88al Edema

10

Investigations for cardiac monitoring:

Table 2: Holliday and Segar Formula6

INFECTION

Maintenance Fluid Requirement Holliday and Segar formula6 Body weight (kg)

Maintenance fluid requirement for 24 hours

Less than 10 kg

100 ml / kg

10 – 20 kg

1000 ml + 50 ml per kg

More than 20 kg

1500 ml + 20 ml per kg

asymptomatic bradycardia to life threatening myocarditis and pericardial effusion. Most of the manifestations are self limiting and tend to settle with other symptoms of the disease.

These include •

Sinus tachycardia

•

Sinus bradycardia

•

Non specific ST T changes

•

SA node dysfunction

•

AV dissociation with variable degree of heart block

•

Tachyarrhythmia – Atrial fibrillation, ventricular tachycardia

•

Pericardial effusion

•

Wall hypokinesia

•

Elevation of cardiac enzymes

•

BP charting

•

ECG monitoring – if the admission ECG shows any abnormality a repeat ECG should be conducted daily to monitor the ongoing cardiac insult and pulse chart to be maintained to know the rate and rhythm abnormality.

•

Cardiac enzymes

-

CK MB

-

Troponin I

-

Troponin T

•

Echocardiography – to rule out wall hypokinesia or pericardial effusion

MANAGEMENT6

The incidence of these cardiac manifestations has been co related with the severity of the disease. Patients with more severe forms of disease like DHF or DSS are more at risk of developing cardiac manifestations. Among severe dengue, fluid accumulation causing respiratory distress was found to have a significant correlation with the cardiac manifestations.

DIAGNOSIS6

A high suspicion of dengue fever should be kept in mind in endemic areas with patients complaining of symptoms of the dengue fever. All the patients with suspected dengue fever must go under routine hematological examination including – Hb, TLC, Platelet count, hematocrit and peripheral smear. A tourniquet test should be performed to exclude DHF. Blood tests for diagnosis of Dengue infection include: •

NS1 ANTIGEN detection – detectable before 5 days of fever

usually

comes

•

IgM capture Enzyme linked immunosorbent assay (MAC- ELISA)-becomes positive after 5 days and persist detectable levels upto 90 days.

•

IgG ELISA – it is used to differentiate primary and secondary dengue infection.

A detailed blood workup including LFT, KFT and cardiac enzymes level should be done to rule out any hepatic, renal or cardiac damage.

Till date no anti viral drug has been licensed for treatment. Dengue vaccine has been developed and is in Phase 3 trial7. No vaccine has been liscenced till date. The mainstay for prevention of the disease personal protection and environmental management of mosquitos. Some of the personal preventive methods include •

Maintaining cleanliness and avoid stagnation of the water in and around homes and office to reduce mosquito habitat. The mosquito typically breed in stagnant water bodies. Reduce the habitat to lower the mosquito population.

•

Avoiding mosquito bite by wearing protective clothes like long sleeve shirts, socks and shoes.

•

Using mosquito repellent sprays, creams

Once the symptoms appear no casual attitude should be adopted and urgent medical help must be sought.

Symptomatic care •

Bed rest

•

Antipyretics – Use Paracetamol. NO ASPIRIN/ NSAIDS

IV Paracetamol can be used in case of high-grade fever •

Tepid sponging

•

I.V. Fluids

•

Watch for bleeding manifestations

•

Look for signs of DHF/DSS

Criteria for admission6 •

DF with warning signs or symptoms

•

Significant bleeding from any site

• Hypotension •

Persistent high grade fever

•

Rapid fall of platelet count

•

Sudden drop in temperature

•

Evidence of organ dysfunction

Prophylactic platelet transfusion may be given at level of <10,000/mm3 in absence of bleeding manifestations.

•

Prolonged shock; with coagulopathy and abnormal coagulogram

Management of DHF III and IV 6 •

Rapid assessment of vital signs, hematocrit and platelet count

•

In case of Systemic massive bleeding, platelet transfusion may be needed in addition to red cell transfusion.

•

Initiation of IV fluids

•

•

Blood transfusion if hematocrit falls suddenly indicating suspected concealed bleeding

Compatibility testing is not required for platelet transfusion.

•

Platelet transfusion if indicated

Management of cardiac manifestation per se

•

Testing for PT, aPTT and LFT

•

General symptomatic care

•

Volume replacement therapy

•

Careful monitoring for development of shock

Requirement of IV fluids6

The amount of fluid replaced should be sufficient to maintain effective circulation during the period of plasma leakage. To ensure adequate fluid replacement and avoid over-fluid infusion, the rate of intravenous fluid should be adjusted throughout the 24 to 48 hour period of plasma leakage by periodic hematocrit determination.

The amount of fluid correction in 24 hours should be calculated as double the amount of maintance fluid. The maintanance fluid should be calculated with Holliday and Segar formula (Table 2): Therefore for a 60 kg individual, 24 hour fluid requirement would be = 1500 +(20 x 40) = 4600 ml.

Choice of IV fluid • •

•

•

There is no clear advantage of colloid over crystalloids in terms of the overall outcome.

Sam S-S, Omar SFS, Teoh B-T, Abd-Jamil J, AbuBakar S. Review of Dengue Hemorrhagic Fever Fatal Cases Seen Among Adults: A Retrospective Study. PLoS Negl Trop Dis 2013; 7:e2194.

2.

Side effects of colloid include allergic reaction, impact on coagulation and osmotic renal injury in hypovolemic patients.

Mairuhu ATA, Wagenaar J, Brandjes DPM, van Gorp ECM. Dengue: an arthropod-borne disease of global importance.

Eur J Clin Microbiol Infect Dis 2004; 23:425-33.

3.

Crystalloids – start with 0.9 % NS. However plenty of the same can cause hyperchloremic acidosis. So follow with Ringer Lactate.

World Health Organization (WHO) Global Stratergy for Dengue Prevention and Control, 2012 – 2020, Geneva: WHO Press; 2012.

4.

Dengue Cases and Deaths in the Country since 2010, NVBDCP

5.

Sophie Yacoub, Heiman Wertheim, Cameron P. Simmons, Gavin Screaton & Bridget Wills et al. Cardiovascular manifestations of the emerging dengue pandemic. Nature Reviews Cardiology 2014; 11:335–345.

6.

National Guidelines for Clinical Management of Dengue Fever 2014, NVBDCP

Colloids restore BP quickly and reduce the hematocrit faster than crystalloid in patients with intractable shock and pulse pressure les than 10 mm Hg.

Loss of blood (overt blood loss) -10% or more of total blood volume -Preferably whole blood/ component to be used.

•

Refractory shock despite adequate administration and declining hematocrit.

•

Replacement volume should be 10 ml/kg body wt. at a time and coagulogram should be done.

•

If fluid overload is present PCV is to be given.

Indications of Platelet transfusion6 •

REFERENCES

1.

Indications of red cell transfusion6 •

The cardiac insult in dengue fever is acute and transient and no specific guidelines are available for its management. The treatment is to provide symptomatic support and maintain hemodynamic stability. The role of anti arrythmics is not clearly defined. Atrial fibrillation, the most commonly clinically encountered arrhythmia.

However viral dengue causing AF is extremely rare and thus the treatment of AF caused by dengue fever is not well established. Role of drugs like calcium channel blockers and beta-blocker in management of AF secondary to DF is controversial in view of impending hypotension. However some of the studies have shown use of anti arrythmics for non self limiting AF8.AV dissociation, premature ventricular complexes, wall hypokinesia, nonspecific ST – T changes are transient and subside within 4 – 8 weeks of follow up. However such patients should be kept under strict monitoring and any event of hemodynamic instability should be managed aggressively.

fluid

In general there is no need to give prophylactic platelets even at < 20,000/mm3

7. Dengue Vaccine Research, Immunization Vaccine and Biologics, WHO. 8. Mahmod, M., Darul, N. D. M., Mokhtar, I., Nor, N. M., Anshar, F. M., & Maskon, O. Atrial fibrillation as a complication of dengue hemorrhagic fever: non-selflimiting manifestation. International Journal of Infectious Diseases, 2009; 13(5). DOI: 10.1016/j.ijid.2009.01.017

11

CHAPTER 2

•

Management of DHF I and II 6

C H A P T E R

3

INTRODUCTION

Dengue is the world’s most common mosquito-borne viral infection and a leading cause of morbidity throughout the tropics and subtropics.1 Each year, there are about 50-100 million dengue infections and about 5,00,000 individuals hospitalized with DHF, mainly in Southeast Asia.2 Globally, dengue virus transmission has expanded in recent years, and all four dengue virus serotypes are now circulating in Asia, Africa, and the Americas, representing a global pandemic.3 Approximately 70% of the population at risk for dengue worldwide lives in the WHO south east Asian region and western Pacific region, which bear nearly 75% of the current global disease burden due to dengue.4 Dengue epidemiology in India has dramatically changed over the last few decades. After the first major nationwide outbreak of DHF in the year 1996, gradual dengue virus expansion started in the entire nation. A steady increase in the number and frequency of outbreaks has followed, and, at present, in most of the states of India, all four serotypes are prevalent.5

EPIDEMIOLOGY6

The epidemiology of dengue depends upon a complex relationship between epidemiological factors, viz. host (man and mosquito), agent (virus) and the environment.

Dengue Virus

Dengue virus belongs to the genus Flavivirus in the family Flaviviridae. It is a positive-stranded encapsulated ribonucleic acid (RNA) virus composed of three structural protein genes that encode the nucleocapsid or core protein, a membrane-associated protein, an enveloped glycoprotein, and seven nonstructural proteins.

There are four antigenetically related but distinct serotypes of the dengue virus: DENV-1, DENV-2, DENV3, and DENV-4. Each serotype has several genotypes.

DENV-1 has three, DENV-2 has two, and DENV-3 and DENV-4 each have four. In humans, one serotype produces lifelong immunity against reinfection but only temporary and partial immunity against the other serotypes. Each serotype has unique characteristics and can present with severe manifestations in a particular population depending upon its interaction with the host response.

Host

People of all ages and both genders are at risk of being infected. Travel to dengue endemic areas is a very

Management of Dengue Sujata Rege, Subramanian Swaminathan

important risk factor in transmission of disease- it is the commonest cause of fever in the travelers returning from these areas, overtaking malaria and typhoid.

Dengue is transmitted from an infected person to others by the bite of the female Aedes aegypti mosquito (main urban vector) and the Aedes albopictus mosquito.

Though transmission primarily occurs through the bite of a vector, there are reports of transmission through blood transfusion,7 organ transplantation8 and vertical transmission.9

Environment

Ae.aegypti breeds in domestic man-made water receptacles whereas Ae.albopictus prefers natural larval habitats. Seasonal variation in dengue transmission is due to the survival characteristics of vectors, best between 1630°C at relative humidity of 60-80%.

CLINICAL FEATURES

Dengue viruses cause symptomatic infections or asymptomatic seroconversion. Symptomatic dengue infection is a systemic and dynamic disease. It has a wide clinical spectrum that includes both severe and non-severe clinical manifestations. After the incubation period of 4 to 7 days, it is followed by three phases − febrile, critical and recovery.6,10 Febrile phase: Onset of DF with sudden rise in temperature, lasts for around 4-5 days and is usually associated with severe frontal headache, myalgia, retro-orbital pain, flushing and rash. Rash may be maculopapular or scarlatiniform, usually appears after 3rd/ 4th day of fever.

A second episode of fever and symptoms can arise, called “saddleback” pattern. Atypical features are enumerated in Table 1.

Potential complications can include •

Dehydration due to decreased fluid intake, emesis, and increased metabolic state.

•

Febrile convulsions

Critical phase (Leakage phase): Occurs after 3-4 days after onset of fever. It is characterized by hypovolemia and hemorrhagic manifestations due to increased vascular permeability and plasma leakage, which persists for 3648 hours.

Potential complications can include11 •

Unrecognized plasma leakage/ hemorrhage leading to shock.

Table 1: Atypical clinical presentations of Dengue

Table 2: Differential Diagnosis of Other Febrile Illness

System

Clinical presentation

OFI

Respiratory system

ARDS, pulmonary oedema, pulmonary hemorrhage12,13

Malaria

Myocarditis,14 arrhythmias, pericardial effusion15

Neurological system

Encephalitis,16 encephalopathy, intracranial hemorrhage,17 Guillan-Barre syndrome,18 febrile seizures19

Gastrointestinal system

Renal system

â&#x20AC;˘

Acalculous cholecystitis,20 Febrile diarrhea,21 Hepatitis/Fulminant hepatic failure,22 acute pancreatitis,23 bleed from pre-existing peptic ulcers,24 spontaneous splenic rupture25 Acute renal failure, acute tubular necrosis,26 hemolytic uremic syndrome, metabolic abnormalities27

Enteric fever33

Potential complications can include Intravascular fluid overload due to continual aggressive volume resuscitation during convalescence.

Presence of Upper respiratory tract symptoms

Leptospirosis35

Progressive jaundice more often in leptospirosis.

Sepsis and Meningococcal infection36

Shock will coincide with high temperatures in sepsis. Dengue-shock usually occurs after defervescence, and will have clinical-radiological signs of plasma leakage.

Chikungunya Fever37

Symmetric arthritis of small joints pathognomic of chikungunya.

Scrub Typhus38

Presence of eschar in typhus. Bleeding uncommon in patients of typhus.

Viral Exanthems39

Rash distribution: Measles,Rubella-from head to trunk and extremities.

Dengue-Trunk to face and extremities

Gall bladder edema Acute acalculous cholecystitis/appendicitis40 on USG due to plasma leakage in dengue, as compared to inflammation in cholecystitis/ appendicitis.

Primary HIV infection41

Differentiating Dengue from other febrile illnesses (OFIs) (Table 2): India, like most developing countries have epidemics of febrile illnesses that can be confused with DF. At presentation, DF and other febrile illnesses may share similar clinical features, including headache, myalgia, and rash.28 Early distinction between dengue and OFI would help clinicians to identify patients who should be closely monitored for signs of DHF and stratify them accordingly.

Differences in clinical and laboratory features between dengue and other febrile illnesses have been reported; however, published studies vary considerably in terms of the parameters used, which impacts the clinical applicability of these differences.

A diagnostic accuracy study done in Brazil showed that conjunctival redness and decreased leukocyte count were independent predictors of DF.29

Fever with rigors and presence of Splenomegaly

Influenza34

Pleural effusion

Convalescent phase (Recovery phase): Usually occurs after 6-7 days of fever and lasts for 2-3 days. ECF lost during capillary leakage returns to circulatory system.

Clinical improvement is seen. â&#x20AC;˘

Feature 32

Generalised adenopathy and lack of signs of plasma leakage

A systematic review of literature published by NIH showed that patients with dengue had significantly lower platelet, white blood cell and neutrophil counts, and a higher frequency of petechiae than OFI patients.

Higher frequencies of myalgia, rash, hemorrhagic signs, lethargy/prostration, and arthralgia/joint pain and higher hematocrits were reported in adult patients with dengue but not in children.28 More prospective studies are needed to construct a valid and generalizable algorithm to guide the differential diagnosis of dengue in endemic countries.

APPROACH TO DENGUE

1.

Assessment:

a. History b. Examination

CHAPTER 3

Cardiac system

13

14

Table 3: Classification of Dengue Fever DF

Symptoms

Laboratory

Fever of 2-7 days with 2 or more of the following:

Leucopenia, Thrombocytopenia No evidence of plasma leakage

• Headache • Retro-orbital pain • Myalgia

INFECTION

• Arthralgia DHF I

DF features + Positive Tourniquet testand evidence of plasma leakage

Platelet count < 1,00,000 /cu.mm

DHF II

DF + evidence of spontaneous bleeding and abdominal pain

Platelet count < 1,00,000 /cu.mm

DF + circulatory failure: weak rapid pulse, narrow pulse pressure <20 mm Hg, Hypotension, cold clammy skin, restlessness

Platelet count < 1,00,000 /cu.mm

Profound shock with undetectable blood pressure/ pulse

Platelet count < 1,00,000 /cu.mm

DHF III (DSS) DHF IV (DSS) c.

Investigations and Diagnosis

2.

Grading of severity, case classification

3.

Management and Disease Notification

4.

Prevention of Dengue

1.

Assessment:42

a.

Obtain complete history:

-

Onset of fever/ illness,

-

Associated symptoms: diarrhea, respiratory

-

Fluid intake and Urine output

-

Warning signs

-

Prior episodes of dengue

-

Travel history, Family history

-

Presence of co-existing conditions: infancy, pregnancy, obesity, diabetes mellitus, hypertension

b.

Evaluation:

-

Hemodynamic status: heart rate, capillary refill, skin color and temperature, peripheral pulse volume, pulse pressure, blood pressure, mentation.

-

Hydration status

-

Bleeding manifestations, Rash, positive tourniquet test

-

Evidence of plasma leakage: pleural effusions, ascites, hemoconcentration, abdominal tenderness, hepatomegaly, acidotic breathing

c.

Investigations: All patients:

i.

Complete Blood count including Hematocrit

ii.

Dengue serology for diagnosis:43

-

NS1 Ag is a marker of acute dengue infection :first

+ Haematocrit rise > 20% over baseline + Haematocrit rise > 20% over baseline + Haematocrit rise > 20% over baseline + Haematocrit rise > 20% over baseline 3 days of illness.

-

Single sample after day 5 : Specific IgM detection, upto 3 months after onset of fever.

-

Primary infection : High IgM,Low IgG.

-

Secondary infection : Low IgM, High IgG

iii.

Specific tests:

-

Blood Sugar Level

-

Organ Function tests

-

Coagulation profile

-

Blood culture

2.

Grades:44

2009 WHO case classification for Dengue45 Dengue

Without leakage/ warning signs Probable Dengue Live in/travel to Dengue endemic area Fever + 2 of following: -Nausea, Vomiting -Rash -Aches and Pains -Tourniquet test +ve -Leucopenia

Severe Dengue

With warning signs -Abdominal pain,tenderness -Persistent vomiting -Clinical fluid accumulation -Mucosal bleed -Lethargy/restlessness -Hepatomegaly >2cm Laboratory: Haematocrit rise and rapid drop in platelet count

1)Severe plasma leakage -Fluid accumulation -Shock 2) Severe bleeding 3) Severe organ involvement

Laboratory confirmed Dengue

Management algorithms: (Adapted from 46) Dengue Viral Infection

Symptomatic

Mild

Asymptomatic

Moderate Management algorithms:

Severe

(Adapted/from 46) MILD DENGUE DENGUE WITHOUT WARNING SIGNS

Undifferentiated Fever without complications/warning signs Fever without evidence of capillary leakage

COMPENSATED SHOCK

Infants/ Old Age Diabetes Mellitus Hypertension Pregnancy Coronary Artery Disease Hemoglobinopathies Immunocompromised status

GROUP B: REFERRAL FOR IN-HOSPITAL CARE GROUP B: REFERRAL FOR IN-HOSPITAL CARE

WARNING SIGNS PRESENT

HOSPITALIZATION •Check Haematocrit, Plt, BSL, UOP, perfusion, organ function •Intravenous Fluids: Isotonic solution @ 5-7 ml/ kg/hr over 1-2 hours

Encourage oral fluids Close Monitoring: HCT, Plt,Hb,Intake-Output, HR,RR,BP,Consciousness, Warning Signs Improvement?

Clinical Response

NO/WORSENING

YES

Temperature pattern� Fluid intake-output� Warning signs� Lab: HCT, WBC, Platelets�

Fluids: 3-5 ml/kg/hr

2-3 ml/kg/hr Reassess Hematocrit

HOME BASED MANAGEMENT WITH MONITORING

Same/ Minimal Increase: Continue @ 2-3 ml/kg/hr for 2-4 hrs

Monitor: •Vitals, peripheral perfusion 1-4hrly •UOP 4-6 hrly •HCT 6 hrly •BSL •LFT, RFT, Coagulation profile

Criteria for discharge45 1.

Afebrile > 48 hours

2.

Clinical improvement

3.

Platelet count increasing

NO

YES Decrease IVF as per clinical status: 5-7ml/kg/hr *1-2h 3-5ml/kg/hr *2-4h 2-3ml/kg/hr *2-4h Boluses as required Continue IVF for 24-48 hours.

Check Hematocrit Low

Increasing/High 2nd bolus of crystalloid/colloid 10-20ml/kg/hr * 1 hr Improvement?�� Y

N

Overt Bleed?

No

Yes: Urgent Blood Transfusion

Colloids @ 10-20ml/kg/hr Check for improvement

N

4.

No Respiratory distress

5.

Stable haematocrit without intravenous fluids

Criteria for principal discharge:underlying (45) The the treatment of dengue is 1. Afebrile > 48 hoursof the volume contraction in the vascular the correction DENGUE FEVER2. Clinical improvement system due to the capillary leak syndrome. This has been + shown to correspond 3. Platelet count increasing to the risk of complications. Early WARNING SIGNS and continual assessments of the fluid volume status as 4. No Respiratory distress Recurrent Vomiting reflected in changes to haematocrit reasonably accurate 5. Stable haematocrit without intravenous is fluids Abdominal pain to follow.

Lethargy/ Restlessness Clinical Fluid accumulation Hepatomegaly> 2cm Hematocrit rise >20% Bleeding manifestations

CO-EXISTING CONDITIONS, COMORBIDITIES OR SOCIAL CIRCUMSTANCES + WITHOUT WARNING SIGNS

Improvement?

IVF@10ml/kg/h * 1h Decrease IVF as per clinical status: 5-7ml/kg/hr *1-2h 3-5ml/kg/hr *2-4h 2-3ml/kg/hr *2-4h Stop at 48 hours

IVF @ 7-10ml/kg/hr *1-2h

MODERATE DENGUE

�

Improvement?

upto 4gm/day

DENGUE FEVER + HIGH RISK COMORBIDITIES

IV Isotonic Crystalloid/Colloid @ 20ml/kg/hr *15 mins YES

Worsening:Increase to 5-10ml/kg/hr for 1-2 hrs Reassess and revise fluid infusion rates

Adequate Fluid intake, Urine Output HCT below baseline in stable patient Decrease IVF Gradually

It is important to ensure that patients do not have a sudden rise in values during the critical phase of capillary leak.

The approach to dehydration depends on clinical scenario and the severity of volume loss during evaluation. This determines the speed of replacement of volume and additional measures for support.

Most patients can be managed at home with daily outpatient reviews with a checklist to assess severity and alarm symptoms. This can prevent overcrowding of hospitals without endangering patient care. However, it is important to remember that the risk of complications is most just after the patient becomes afebrile, and appropriate counseling is imperative to ensure that monitoring is continued into this critical phase.

Patients who may be at risk, including those with other medical conditions may be best cared for in the wards of hospitals, where regular monitoring and hydration should suffice. Patients with severe symptoms are best managed in areas with access to good monitoring and intervention services.

For most patients, only crystalloids are required for volume expansion, and colloids including blood may be considered in those in the most severe category. The role of platelets is minimal, if any, and is best restricted to those with active bleeding.

Discharge may be considered once the patient has crossed the critical phase. Again, those with difficulty handling the volume that is reabsorbed, like those with renal or

CHAPTER 3

Group A: Home Management GROUP A: HOME MANAGEMENT Criteria ManagementManagement Criteria No warning signs Bed rest Daily Review for No warning Bed rest Daily Review disease signs for disease progression progression Adequate oral fluid Adequate fluid Warning signs Adequate oral Adequate fluid Warning signs intake intake fluid intake intake Good urine output Paracetamol upto Home care card Good urine Paracetamol Home care card (every 6 hours) 4gm/day

DECOMPENSATED SHOCK

Isotonic Crystalloids @ 5-10 ml/kg/hr * 1 hr

No comorbid conditions

output (every 6 hours)

15

SEVERE DENGUE GROUP C: EMERGENCY HOSPITALISATION

Mild Dengue / Dengue Without Warning Signs

16

High risk

Low risk

•

Patients on cancer chemotherapy

Recent CAG with stenting <3mn

Stable CAD or stenting > 6mn previously

•

Patients with haematological disorders

Mechanical valve

Biological valve

•

Post transplant patients on immunosuppression

Chronic AF with past history of thromboembolism

Chronic AF without risk factors

•

Primary/congenital immunodeficiency disorders

•

Chronic steroid therapy

•

Autoimmune therapy

•

HIV/AIDS with CD4 count <500

Clinical presentation is similar in immunocompromised patients, although the course is usually prolonged.48 Principles of treatment remain the same, although close monitoring is preferred.

Transplant and Dengue: In post-solid organ transplant patients, dengue usually follows a benign course with no evidence of longterm damage / rejection episodes.49,50 Thrombocytopenia is more severe in patients receiving steroids, azathioprine and cyclosporine concomitantly. Tacrolimus is found to prolong duration of thrombocytopenia.50 Graft survival and outcome following dengue fever was not affected in the studies.

In studies involving renal transplant recipients, likelihood of developing severe forms of dengue was found to be low, probably due to diminished T-cell responses.51

There are reports of dengue in stem cell recipients, sometimes donor-derived.52,53 Dengue fever complicating patients with aplastic anemia have been salvaged with stem cell therapy.54 However, this disease appears to be more severe in this population and poor outcome is reported.

A case series of patients on biotherapy for rheumatological diseases, infected with dengue, found that none of them developed severe dengue.55 However there are no guidelines regarding continuing biological therapy during the course of treatment.

2.

Dengue in Pregnancy:

•

High index of suspicion for diagnosis is necessary as the consequences due to dengue infection are multifold.56 Multiple studies have shown complications ranging from miscarriages, preterm births, haemorrhages in labour, perinatal deaths, adverse maternal outcomes and vertical transmission of infection to the fetus.57,58

•

Serial Haematocrit measurement is crucial for disease monitoring.59

•

Unless imperative, to avoid induction of labour / Caesarian section during critical phase, as risk of bleeding is at its peak during that period.

•

Baby should be evaluated and monitored post-

INFECTION

Multiple risk factors for thromboembolism • Already on antiplatelets: • Should be continued • In case of significant bleed, Platelet count <50,000 or patient in shock: stop medications

• Withhold aspirin and consider withholding clopidogrel and warfarin for one week, with close monitoring.

• Patient on Warfarin: withhold and do serial coagulation parameters. When INR below therapeutic range, heparin bridging and monitor cardiac disease, may need additional observation during this phase as well.

Patients may experience additional manifestations during the recovery phase in addition to post viral asthenia like pruritus, joint pain and bradycardia. These tend to resolve spontaneously over time, and may only require rare. Other unusual manifestations include Gullian-Barre reassurance. syndrome, myocarditis, renal failure, and lung injury. In most cases, these unusual resolve with appropriateof symptomatic There are many manifestations dengue, and management. should be considered in all patients with a short febrile illness. Raised liver enzymes are very common, and usually the AST is higher than ALT. However, severe liver injury is rare. Other unusual manifestations include Gullian-Barre syndrome, myocarditis, renal failure, and lung injury. In most cases, these resolve with appropriate symptomatic management.

PREVENTION OF DENGUE: (47)

ENVIRONMENTAL MEASURES

PERSONAL PROTECTION

- Improving water supply - Environmental sanitation improvement - Mosquito-proofing overhead tanks, screens on doors/windows.

- Education to public

- Protective clothing - Mosquito repellants - Insecticidetreated mosquito nets - Dengue vaccine

MOSQUITO CONTROL (Aedes) - Larvivorous fish in large water bodies - Bacillus thuringiensis serotype H-14, endotoxin producing bacteria.

- Chemical Larvicide: Temephos(50 EC) - Adulticide: Pyrethrum spray (indoor) Malathion/ Ultra Low volume spray (fogging)

Special circumstances 1.

Dengue in immunocompromised patients:

diseases

on

immunomodulator

delivery as vertical transmission of disease has been observed.9,60 •

Breastfeeding has been shown to transmit dengue in a case study, however there are no clear guidelines on the same.61 Dengue in patients on Antithrombotic treatment:62

4.

Surgery and Dengue:

Acalculous cholecystitis due to plasma leakage leading to gall bladder wall edema is a clinical manifestation of Dengue Fever. The patient presents with right hypochondrial pain. The course is usually self-limiting and surgery is not warranted unless there is diffuse peritonitis.63

5.

6.

There are no guidelines on management of surgical patients with Dengue. Post-operative bleeding from surgical sites should be closely monitored.

As removal of in-dwelling vascular catheters may cause hemorrhage, it could be deferred till critical phase is over. Platelet transfusion is not necessary in all surgical patients.64 Dengue and Diabetes Mellitus: Diabetes Mellitus is an independent risk factor for developing profound thrombocytopenia and severe forms of dengue infection.65,66 Studies have shown DM to be a predictor of mortality in dengue.66,67 A study has shown that stress-induced hyperglycemia found at the time of acute infection disappeared after recovery, warranting use of HbA1c for checking glycemic status. (68) Early diagnosis of dengue in diabetics is hence of importance. It will ensure closer glycemic control and adjusted fluid management in this population.

Dengue and Zika: Zika virus (ZIKV), an emerging arboviral infection also transmitted by Aedes spp belonging to genus Flavivirus is an important public health issue.69 A recent report on coinfection between dengue and Zika raised the concern of missed / underdiagnosis of Zika. The effect of coinfection needs to be studied further.70 Data suggests that there is an interplay between host antibody response to ZIKV and DENV, with concern of DENV being a cofactor for increasing severity of Zika infection.71

There is speculation that this could affect how Zika behaves in pregnant women, and more research on this is ongoing.

That dengue has become a major public health issue is beyond doubt; following well established protocols and pathways for assessment and management is the only way to reduce the morbidity, mortality and the financial impact of this disease, not to mention the overcrowding of already over burdened medical facilities.

1.

Gubler DJ. The global pandemic of dengue/dengue haemorrhagic fever: current status and prospects for the future. Ann Acad Med Singapore 1998; 27:227–234.

2.

Stanaway JD, Shepard DS, Undurraga EA, Halasa YA, et al.

The global burden of dengue: an analysis from the Global Burden of Disease Study 2013. Lancet Infect Dis 2016; 16:71223.

3.

Messina JP, Brady OJ, Scott TW, Zou C, Pigott DM, Duda KA, et al. Global spread of dengue virus types: mapping the 70 year history. Trends Microbiol 2014; 22:138-46.

4.

Shepard DS, Undurraga EA, Halasa YA, 2013. Economic and disease burden of dengue in Southeast Asia. PLoS Negl Trop Dis 2013; 7:e2055.

5.

National Vector Borne Disease Control Programme, 2013.

Dengue Cases and Deaths in the Country since 2007.

Ministry of Health and Family Welfare, Directorate General of Health Services. Available at: http://www.nvbdcp.gov.in/ den-cd.html.

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Thomas SJ, Endy T, Rothman A, Barrett A. Flaviviruses (Dengue, Yellow Fever, Japanese Encephalitis, WestNile Encephalitis, St Louis Encephalitis, Tick-Borne Encephalitis, Kyanasur Forest Disease, Alkhurma Hemorrhagic Fever, Zika) In: Bennett JE, Dolin R, Blaser M, editors. Mandell, Douglas, and Bennett’s principles and practice of infectious diseases. 8th ed. Philadelphia: Elsevier Churchill Livingstone; c2015. p. 1881-1903.

7.

Stramer SL, Linnen JM, Carrick JM, Foster GA, Krysztof DE, Zou S, et al. Dengue viremia in blood donors identified

by RNA and detection of dengue transfusion transmission during the 2007 dengue outbreak in Puerto Rico. Transfusion 2012; 5298:1657-66.

8.

Gupta RK, Gupta G, Chorasiya VK, Bag P, Shandil R, Bhatia V, et al. Dengue Virus Transmission from Living Donor to Recipient in Liver Transplantation: A Case Report. J Clin Exp Hepatol 2016; 6:59-61.

9.

Chye JK, Lim CT, Ng KB, Lim JM, George R, Lam SK. Vertical transmission of dengue. Clin Infect Dis 1997; 25:1374-7.

10. Kalayanarooj S, Vaughn DW, Nimmannitya S, Green S, Suntayakorn S, Kunentrasai N, et al., Early clinical and laboratory indicators of acute dengue illness. J Infect Dis 1997; 176:313–321.

11. Srikiatkhachorn A, Krautrachue A, Ratanaprakarn W, Wongtapradit L, Nithipanya N, Kalayanarooj S, et al., Natural history of plasma leakage in dengue hemorrhagic fever: a serial ultrasonic study. Pediatr Infect Dis J 2007; 26:283−290.

12. Sen MK, Ojha UC, Chakrabarti S, Suri JC. Dengue Hemorrhagic fever (DHF) presenting with ARDS. Indian J Chest Dis Allied Sci 1999; 41:115-119.

13. Setlik RF, Ouellette D, Morgan J, McAllister KC, Dorsey D, Agan BK, et al. Pulmonary hemorrhage syndrome associated with an autochthonous case of dengue hemorrhagic fever.

South Med J 2004; 97:688-92.

14. Promphan W, Sopontammarak S, Pruekprasert P et al.

Dengue myocarditis. Southeast Asian J Trop Med Public Health 2004; 35:611-3.

15. Veloso HH, Ferriera JA, Paiva JM, Honorio JF, Bellei NC, Paola AA. Acute atrial fibrillation during dengue hemorrhagic fever. Braz J Infect Dis 2003; 7:418–422.

16. Lum LC, Lam SK, Choy YS, George R, Harun F. Dengue

17

CHAPTER 3

3.

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encephalitis: a true entity? Am J Trop Med Hyg 1996; 54:256– 9.

17. Solomon T, Dung NM, Vaughn DW, Kneen R, Raengsakulrach B, Loan HT, et al. Neurological manifestations of dengue infection. The Lancet 2000; 355:1053-9.

18. Soares CN, Faria LC, Peralta JM, De Freitas MR, PuccioniSohler M. Dengue infection: neurological manifestations and cerebrospinal fluid (CSF) analysis. J Neurol Sci 2006; 249:19–24.

INFECTION

19. Martinez-Torres E, Polanco-Anaya AC, Pleites-Sandoval EB. Why and how children with dengue die? Rev Cubana Med Trop 2008; 60:40−47.

20. Wu KL, Changchien CS, Kuo CM, Chuah SK, Lu SN, Eng HL et al. Dengue fever with acute acalculous cholecystitis.

Am J Trop Med Hyg 2003; 68:657–660.

21. Ooi ET, Ganesananthan S, Anil R, Kwok FY, Sinniah M. Gastrointestinal manifestations of dengue infection in adults. Med J Malaysia 2008; 63:401–405.

22. Lum LC, Lam SK, George R, Devi S., Fulminant hepatitis in dengue infection. Southeast Asian J Trop Med Public Health 1993; 24:467-71.

23. Chen TC, Chen TC, Perng DS, Tsai JJ, Lu PL, Chen TP. Dengue Hemorrhagic Fever complicated with pancreatitis and seizure. J Formos Med Assoc 2004; 103:865–868.

24. Tsai CJ, Kuo CH, Chen PC, Changcheng CS. Upper gastrointestinal bleeding in dengue fever. Am J Gastroenterol 1991; 86:33–35.

25. Miranda LE, Miranda SJ & Rolland M. Case Report: Spontaneous Rupture of the Spleen Due to Dengue Fever.

Braz J Infect Dis 2003; 7:423–425.

26. Wiwanitkit V. Acute Renal Failure in the Fatal Cases of Dengue Hemorrhagic Fever, a Summary in Thai Death Cases. Renal Failure 2004; 27:647-.

27. Wiersinga WJ, Scheepstra CG, Kasanardjo JS et al. Dengue fever induced hemolytic uremic syndrome. Clin Infect Dis 2006; 43:800–801.

28. Potts JA, Rothman AL. Clinical and laboratory features that distinguish dengue from other febrile illnesses in endemic populations. Trop Med Int Health 2008; 13:1328-40.

29. Daumas RP, Passos SR, Oliveira RV, Nogueira RM, Georg I, Marzochi KB, Brasil P. Clinical and laboratory features that discriminate dengue from other febrile illnesses: a diagnostic accuracy study in Rio de Janeiro, Brazil. BMC Infect Dis 2013; 13:1 30. Kuo CH, Tai DI, Chang-Chien CS, Lan CK, Chiou SS, Liaw YF. Liver biochemical tests and dengue fever. Am J Trop Med Hyg 1992; 47:265-70.

31. Jaenisch T, Tam DT, Kieu NT, Ngoc T, Nam NT, Van Kinh N, et al. Clinical evaluation of dengue and identification of risk factors for severe disease: protocol for a multicentre study in 8 countries. BMC Infect Dis 2016; 16:1.

32. Epelboin L, Boullé C, Ouar-Epelboin S, Hanf M, Dussart P, Djossou F, et al. Discriminating malaria from dengue fever in endemic areas: clinical and biological criteria, prognostic score and utility of the C-reactive protein: a retrospective matched-pair study in French Guiana. PLoS Negl Trop Dis 2013; 7:e2420.

33. Parry CM, Wijedoru L, Arjyal A, Baker S. The utility of diagnostic tests for enteric fever in endemic locations.

Expert Rev Anti Infect Ther 2011; 9:711-25.

34. Fisher RG, Boyce TG. Nonstreptococcal pharyngitis. In: Moffet ́s Pediatric Infectious Diseases. A problem- oriented approach, 4th ed. Philadelphia, PA, Lippincott Williams and Wilkins, 2005: 34–35.

35. Flannery B, Pereira MM, De Codes LG, Dourado CM, Riley LW, Reis MG, et al., Referral pattern of leptospirosis cases during a large urban epidemic of dengue. Am J Trop Med Hyg 2001; 65:657–663.

36. Van de Beek D, de Gans J, Spanjaard L, Weisfelt M, Reitsma JB, Vermeulen M. Clinical features and prognostic factors in adults with bacterial meningitis. N Engl J Med 2004; 351:1849-59.

37. Kularatne SA, Gihan MC, Weerasinghe SC, Gunasena S. et al., Concurrent outbreaks of Chikungunya and Dengue fever in Kandy, Sri Lanka, 2006-07: a comparative analysis of clinical and laboratory features. Postgrad Med J 2009; 85:342–346.

38.

Watt G, Jongsakul K, Chouriyagune C, Paris R. Differentiating dengue virus infection from scrub typhus in Thai adults with fever. Am J Trop Med Hyg 2003; 68:536-8.

39. Keighley CL, Saunderson RB, Kok J, Dwyer DE. Viral exanthems. Curr Opin Infect Dis. 2015 Apr 1;28(2):139-50.

40. Premaratna R, Bailey MS, Ratnasena BG, De Silva HJ. Dengue fever mimicking acute appendicitis. Trans R Soc Trop Med Hyg 2007; 101:683-5.

41. Cabié A, Abel S, Lafaye JM, Béra O, Césaire R, Sobesky G. Dengue or acute retroviral syndrome?. Presse Med 2000; 29:1173-4.

42. Martinez TE. Preventing deaths from dengue: a space and challenge for primary health care. Rev Panam Salud Publica 2006; 20:60−74.

43. Buchy F, Yoksan S, Peeling RW, Hunsperger E. Laboratory tests for the diagnosis of dengue virus infection.TDR/ Scientific Working Group.TDR/SWG/08 Geneva, Switzerland. 2006 Oct (1): 74–85.

44. Deen JL, Harris E, Wills B, Balmaseda A, Hammond SN, Rocha C, et al. The WHO dengue classification and case definitions: time for a reassessment. Lancet 2006; 368:170–3.

45. World Health Organization, Special Programme for Research, Training in Tropical Diseases, World Health Organization. Department of Control of Neglected Tropical Diseases, World Health Organization. Epidemic, Pandemic Alert. Dengue: guidelines for diagnosis, treatment, prevention and control. World Health Organization; 2009.

46. WHO, 2013.

Handbook on Dengue Clinical Management. Available at: http://apps.who.int/iris/ bitstream/10665/76887/1/9789241504713_eng.pdf 47. Gupta N, Srivastava S, Jain A, Chaturvedi UC. Dengue in India. Indian J Med Res 2012; 136:373.

48. Sharma SK, Seth T, Mishra P, Gupta N, Agrawal N, Broor S, et al. Clinical profile of dengue infection in patients with hematological diseases. Mediterr J Hematol Infect Dis 2011; 3.

49. Azevedo LS, Carvalho DB, Matuck T, Alvarenga MF, Morgado L, Magalhaes I, et al. Dengue in renal transplant patients: a retrospective analysis. Transplantation 2007; 84:792-4.

50. Weerakkody RM, Palangasinghe DR, Dalpatadu KP, Rankothkumbura JP, Cassim MR, Karunanayake P. Dengue fever in a liver-transplanted patient: a case report. J Med Case Rep 2014; 8:1.

51. Franco-Paredes C, Jacob JT, Hidron A, Rodriguez-Morales

AJ, Kuhar D, Caliendo AM. Transplantation and tropical infectious diseases. Int J Infect Dis 2010; 14:e189-96.

vertical transmission of dengue virus? Clin Infect Dis 2013; 57:415-7.

52. Visuthranukul J, Bunworasate U, Lawasut P, Suankratay C. Dengue hemorrhagic fever in a peripheral blood stem cell transplant recipient: the first case report. Infect Dis Rep 2009; 1:3.

62. Verdeal JC, Costa Filho R, Vanzillotta C, Macedo GL, Bozza FA, Toscano L, et al. Guidelines for the management of patients with severe forms of dengue. Rev Bras Ter Intensiva 2011; 23:125-33.

53. Punzel M, Korukluoğlu G, Caglayik DY, Menemenlioglu D, Bozdag SC, Tekgündüz E et al. Dengue virus transmission by blood stem cell donor after travel to Sri Lanka; Germany, 2013. Emerg Infect Dis 2014; 20:1366.

63. Beniwal P, Kumar S, Gulati S. Acalculous cholecystitis in dengue fever. Indian Journal for the Practising Doctor 2000; 3:2006-08.

55. Deligny C, de Bandt M, Dehlinger V, Numéric P, Cabié A, Lombard F et al. Dengue fever in patients under biologics. J Clin Virol 2014; 61:442-3.

56. Pouliot SH, Xiong X, Harville E, Paz-Soldan V, Tomashek KM, Breart G, Buekens P. Maternal dengue and pregnancy outcomes: a systematic review. Obstet Gynecol Surv 2010; 65:107-18.

57. Restrepo BN, Isaza DM, Salazar CL, Ramirez JL, Upegui GE, Ospina M et al. [Prenatal and postnatal effects of dengue infection during pregnancy]. Biomedica 2003; 23:416-23.

58. Waduge R, Malavige GN, Pradeepan M, Wijeyaratne CN, Fernando S, Seneviratne SL. Dengue infections during pregnancy: a case series from Sri Lanka and review of the literature. J Clin Virol 2006; 37:27-33.

59. Bunyavejchevin S, Tanawattanacharoen S, Taechakraichana N, Thisyakorn U, Tannirandorn Y, Limpaphayom K. Dengue hemorrhagic fever during pregnancy: antepartum, intrapartum and postpartum management. J Obstet Gynaecol Res 1997; 23:445-8.

60. Thaithumyanon P, Deerojnawong J, Innis BL. Dengue infection complicated by severe hemorrhage and vertical transmission in a parturient woman. Clin Infect Dis 1994; 18:248-9.

61. Barthel A, Gourinat AC, Cazorla C, Joubert C, DupontRouzeyrol M, Descloux E. Breast milk as a possible route of

64. Arya SC, Agarwal N. Dengue fever in a patient recovering from coronary artery bypass grafting. Ann Card Anaesth 2011; 14:245 65. Chen CY, Lee MY, Lin KD, Hsu WH, Lee YJ, Hsiao PJ, Shin SJ. Diabetes Mellitus Increases Severity of Thrombocytopenia in Dengue-Infected Patients. Int J Mol Sci 2015; 16:3820-30.

66. Pang J, Salim A, Lee VJ, Hibberd ML, Chia KS, Leo YS, et al.

Diabetes with hypertension as risk factors for adult dengue hemorrhagic fever in a predominantly dengue serotype 2 epidemic: a case control study. PLoS Negl Trop Dis 2012; 6:e1641.

67. Karunakaran A, Ilyas WM, Sheen SF, Jose NK, Nujum ZT. Risk factors of mortality among dengue patients admitted to a tertiary care setting in Kerala, India. J Infect Public Health 2014; 7:114–20.

68. Hasanat MA, Ananna MA, Ahmed MU, Alam MN. Testing blood glucose may be useful in the management of dengue.

Mymensingh Med J 2010; 19:382–5.

69. Joob B, Wiwanitkit V. Zika virus infection and dengue: A new problem in diagnosis in a dengue-endemic area.

Annals of Tropical Medicine and Public Health 2015; 8:145-6.

70. Dupont-Rouzeyrol M, O’Connor O, Calvez E, Daurès M, John M, Grangeon JP, et al. Co-infection with Zika and dengue viruses in 2 patients, New Caledonia, 2014. Emerg Infect Dis 2015; 21:381-2.

71. Dejnirattisai W, Supasa P, Wongwiwat W, Rouvinski A, Barba-Spaeth G, Duangchinda T, et al. Dengue virus serocross-reactivity drives antibody-dependent enhancement of infection with zika virus. Nat Immunol 2016.

CHAPTER 3

54. Khoj L, Baksh R, Aslam M, Kelta M, Albeirouti B, Rehman JU. A Case of Dengue Fever-Induced Severe Aplastic Anemia Salvaged by Allogeneic Bone Marrow Transplant. J Leuk 2013; 2013.

19

C H A P T E R

4

Antimicrobial Resistance (AMR) A Scientific Challenge with Political Repercussions Abdul Ghafur

Antibiotic resistance coupled with a lack of new antibiotics, is a major threat to health care system, global economy and the civilisation. Although some countries (for e.g.

Scandinavian countries) are successful in maintaining very low rates of antibiotic resistant bacteria; globally the numbers of resistant bacteria continue to increase in both humans and animals.1

obstacle in banning the use of antibiotics as a growth promoter, even in US. Many European countries have banned this usage in 2006. In India, extent of the usage is unknown. OIE (World Organisation for Animal Health) and The Food and Agriculture Organization of the United Nations (FAO) have worked actively to promote the appropriate use of antibiotics in animals.

The sharp increase in resistance and lack of new treatment options are especially serious in the case of infections caused by Gram-negative bacteria. Gram-positive superbug issue (such as MRSA) is serious problem in North America and some European countries. South Asian countries and Mediterranean countries are seriously hit by the Gram-negative superbug crisis. Now, even the North American and European countries are catching up fast with the Gram-negative bacterial resistance problem.2

Till recently, WHO actions on AMR were partial and without coordination. This inertia resulted in many nonGovernmental organisations taking the much-needed lead in the field of AMR.1 Well known initiatives in the international arena are ReAct (Action on Antibiotic Resistance, Sweden), Antibiotic Action Led by BSAC (British Society for Antimicrobial Chemotherapy), GARP aimed at LAMIC (Low and Middle income countries), The World Alliance Against Antibiotic Resistance (WAAAR, France) and Alliance for the Prudent Use of Antibiotics (APUA, USA).

Antimicrobial resistance issue has been considered a scientific and technical issue. This is one of the main reasons for the global failure in tackling resistance.1 Antibiotic resistance is a scientific topic with very serious political implications. Antibiotic resistance issue can only be tackled if politicians and policy makers get directly involved and take ownership.

Antibiotic resistance was raised at the World Economic Forum meeting in 2013 and 2014 as well as at the 2013 G8 meeting of Finance Ministers in London and at G20 meetings.1 As per the statement by World Health Organisation in May 2014, antibiotic resistance is one of the most serious public health issues of our time.3 AMR is considered by the WHO to be one of the three greatest threats to human health and was the focus of World Health Day in 2011. The Transatlantic Taskforce on Antimicrobial Resistance (TATFAR) was created in 2009 by U.S. President Obama, Swedish Prime Minister and the then-European Council President Reinfeldt, and European Commission President Barroso at the 2009 U.S. – EU summit.

Indiscriminate usage of antibiotics in veterinary practice is one of the most important derivers of antibiotics resistance. For instance, 80% of the total antibiotics produced in USA are used in veterinary practice. These antibiotics are not used to treat or prevent infections in animals, instead used as growth promoters to make animals grow fat and fast. Excessive pressure by the pharmaceutical industry and veterinary lobby is a serious

Indian Health Ministry published National policy for containment of AMR, in 2011. Unfortunately for various reasons the implementation was delayed. This was the main inspiration for the development of Chennai declaration.

Chennai declaration: An initiative by medical societies and other stakeholders in India, since its publication in 2012, has received widespread national and international acclaim. The “Chennai declaration”4 was published in Indian Journal of Cancer in 2012 and the “Chennai declaration- Five year plan”5 the follow up document was published in Indian Journal of Medical Microbiology in 2014.

India needs “An implementable antibiotic policy” and not “A perfect policy” was the basic principle of Chennai declaration.4-6 Step- by- step regulation of antibiotic usage, concentrating on higher end antibiotics first and then slowly extending the list to second and first line antibiotics seemed to be a more viable option.4,5 Chennai declaration document and initiative created serious attitude change among Indian medical community, politicians and bureaucrats.6 Chennai declaration played a significant role in speeding up various initiatives by Indian Health Ministry towards tackling AMR. It is not surprising that Chennai declaration received entry to the “brief history of antibiotics”, a compilation of the most important events in the history of antibiotics. Chennai

declaration has been discussed in dozens of reputed medical journals, prestigious policy meetings including World Health Assembly and Parliaments including British Parliament. Chennai declaration can be a role model for initiatives in other developing countries as well.

Drugs Controller General of India, in 2013, published a modified rule (H1 rule) to rationalize over the counter (OTC) sales of antibiotics in the country and the rule came into effect in 2014.7 In 2016 Indian Health Ministry released a National Antibiotic guideline.8

We will not be able to tackle AMR without coordinated action by doctors, scientists, politicians, bureaucrats and various organisations like WHO. Doctors, the most knowledgeable community on the impact of AMR must take the leadership role in convincing politicians on the need for efforts to tackle this serious menace. If we don’t demonstrate this leadership, our future generations will not have the blessing of antibiotics-the miracle moleculesthat revolutionized the modern medicine and civilization.

21

REFERENCES

1.

Carlet J, Pulcini C, Piddock LJ. Antibiotic resistance: a geopolitical issue. Clin Microbiol Infect 2014; 20:949-53. doi: 10.1111/1469-0691.12767.

2.

Abdul Ghafur. Can India be the wing commander in the global fight against antimicrobial resistance? JAPI 2012; 60:42-43.

3.

Concerned about the rising levels of drug resistance whereby microbes evolve to become immune to all known drugs, the UK Prime Minister (former) David Cameron commissioned economist and the British Treasury minister Lord Jim O’Neill to analyse this global problem of antimicrobial resistance (AMR) and propose concrete actions to tackle it internationally.9 According to Jim O’Neil report, the AMR crisis will cost the global economy 100 trillion US dollars by 2050 and ten million additional deaths will happen across the world every year.

h t t p : / / a p p s . w h o . i n t / i r i s / bitstream/10665/112642/1/9789241564748_eng.pdf?ua=1

4.

Ghafur A, Mathai D, Muruganathan A et al. “The Chennai Declaration” Recommendations of “A roadmap- to tackle the challenge of antimicrobial resistance” – A joint meeting of medical societies of India. IndianJCancer2012;49(4) http://www.indianjcancer.com/article.asp?issn=0019-509X; year=2013;volume=50;issue=1;spage=71;epage=73;aulast=G hafur

5.

Longitude prize is a £10 million prize announced by the British Prime minister, to create an affordable, accurate, rapid, and easy-to-use point of care test for bacterial infections that will allow health professionals worldwide to administer the right antibiotics at the right time.

Longitude prize has created wide spread enthusiasm among scientists across the globe.10

Team C. “Chennai Declaration”: 5-year plan to tackle the challenge of anti-microbial resistance. Indian J Med Microbiol 2014; 32:221–28. http://www.ijmm.org/article. asp?issn=0255-0857;year=2014;volume=32;issue=3;spage=2 21;epage=228;aulast=Team

6.

Abdul Ghafur. Perseverance, persistence, and the Chennai declaration. The Lancet Infectious Diseases :1007-1008.

7.

Department of Health and Family Welfare. The Gazette of India. 441, part 2. August 30, 2013. http://www.cdsco.nic. in/588E30thAug2013.pdf

8.

http://www.ncdc.gov.in/writereaddata/linkimages/AMR_ guideline7001495889.pdf

UN assembly meeting in September 2016 will organize detailed discussion on AMR and hopefully will lead to legally binding agreements between countries.

9.

http://amr-review.org/

10. https://longitudeprize.org/

CHAPTER 4

After the early inertia, WHO has definitely found a new and forceful momentum over the last three years. In 2013, WHO established the Strategic and Technical Advisory Group (STAG) on antimicrobial resistance chaired by the UK Chief Medical Officer Dame Sally Davies. In 2014, WHA (World Health Assembly) resolution on AMR decided to prepare a global action plan for AMR.

C H A P T E R

5

Approach to Fever in a Returning Traveler

INTRODUCTION

“Sudha Singh, who participated in the 3000m steeplechase at the Rio 2016 Olympics, has given blood samples for tests to check for the Zika virus.” “A blood sample tested at the virology lab at the National Institute of Mental Health and Neuro Sciences in Bengaluru has tested positive for the H1N1 virus while a blood sample sent to the National Institute for Virology in Pune has tested negative for the Zika virus,”.- These were important recent news headlines. Travelling is increasing day by day in almost all parts of the world. The number of international tourist is going to rise from one billion recorded in 2012, to 1.8 billion by 2030 according to UNTWO.1 There are usually 5 reasons for travel — tourism, business, research/ education, missionary/volunteer and visiting friends and relatives (VFR). It is a charming experience for the traveller to visit different parts of the world or country, their natural beauties, the animal resources, different population groups with diverse social cultures. But, during their visit and stay, the traveller is always at risk of acquiring some illness which are prevalent in the areas and against which they may not be protected. Hence, travelling is an important factor in globalizing infections and introducing pathogens into new regions.2 Many of such diseases present with fever after their return.

Post-travel evaluation

Health related problems are experienced by about 22%–64% of travelers to developing countries and about 15 to 37 percent of short-term travelers during an international trip. Up to 11% of returned travelers have a febrile illness.3 Although most of these illnesses are mild, up to 8% of travelers are ill enough to seek care from a health care provider. Most post-travel infections become apparent soon after travel, but because incubation periods vary, some syndromes can present months to years after initial infection.

DEMOGRAPHIC FACTORS

Male (32%) travelers are more likely to present with fever than females (24%). There was no age difference between travelers presenting with fever and those without that symptom.4 In children after international travels, malaria is the most common cause of systemic febrile diseases, followed by viral syndromes (28%), unspecified febrile illnesses (11%), dengue and enteric fever (6% each).5

Some important points in history for fever in a returned traveller •

Travel itinerary and duration of travel

Bibhuti Saha, Manab Kumar Ghosh

•

Timing of onset international travel

of

illness

in

relation

to

•

Severity of illness

•

Past medical history and medications

•

History of a pre-travel consultation

•

Travel immunizations

•

Adherence to malaria chemoprophylaxis

•

Individual exposures

•

Type of accommodations

•

Insect precautions taken (such as repellent, bed nets)

•

Source of drinking water

•

Ingestion of raw meat / seafood / unpasteurized dairy products

•

Insect or arthropod bites

•

Freshwater exposure (e.g. swimming, rafting)

•

Animal bites and scratches

•

Body fluid exposure (such as tattoos, sexual activity)

•

Medical care while overseas (such as injections, transfusions)

TRAVEL ITINERARY

Travelers VFRs who visited Sub-Saharan Africa, SouthCentral Asia, Indian Ocean Islands, Oceania and Latin America are more likely to report fever (malaria and enteric fever) after returning home than other groups of travelers.6 P. falciparum malaria was also more frequent in VFRs, while P. vivax malaria was more likely to be reported in missionary or expatriate travelers. Acute diarrhoea was more common among classic tourist travelers. Tuberculosis and human immunodeficiency virus (HIV) infection as a reason of fever were much more often diagnosed in VFR travelers and foreign visitors or migrants.7 Potential exposures differ depending on the region of travel and unnecessary testing can be avoided. Malaria is the most common cause of fever in travelers to subSaharan Africa, and dengue in febrile patients who travelled to Latin America or Southeast Asia. The duration of travel is also important, since the risk of a travel-related illness increases with the length of the trip.

Timing of Illness in Relation to Travel

Diseases with short incubation periods usually presents within 1 month of return from their destination. However, schistosomiasis, leishmaniasis, or tuberculosis can manifest months or even years later.

SEVERITY OF ILLNESS

23

Some potentially life-threatening infections, such as malaria, severe respiratory syndrome or hemorrhagic fever, may necessitate prompt involvement of public health authorities.

UNDERLYING MEDICAL ILLNESS

Table 1: Specific exposures for various infectious diseases Diseases

Undercooked food

Cholera, Nontyphoidal salmonellosis, Trichinosis, Typhoid fever

Untreated water

Cholera, Hepatitis A, Nontyphoidal salmonellosis, Typhoid fever

Unpasteurized dairy products

Brucellosis, Tuberculosis

Fresh water contact

Leptospirosis, Schistosomiasis

Sexual contact

Chancroid, Gonorrhoea, Hepatitis B, HIV, Syphilis

Animals

Brucellosis, Plague, Q fever, Rabies, Tularaemia

Insects Mosquitoes

Dengue, Malaria, Filaria, JE, YF and Chikungunya, Zika

Ticks

Rickettsial diseases, Tularaemia

Reduvid bug

American Trypanosomiasis

Tsetse flies

African Trypanosomiasis

Sick contacts

Meningococcal disease, Tuberculosis, Viral hemorrhagic fevers

Adapted from Suh KN, Kozarsky PE, Keystone JE. Evaluation of fever in the returned traveller. Med Clin North Am 1999; 83:1000.

VACCINES RECEIVED AND PROPHYLAXIS USED

The history of vaccinations and adherence to malaria chemoprophylaxis are important. The most common vaccine-preventable diseases found in returned travelers included enteric fever (typhoid and paratyphoid), viral hepatitis, measles and influenza. More than half of these patients need hospitalization.

INDIVIDUAL EXPOSURE HISTORY

Type of the patient’s exposures during travel, purpose of the patient’s trip and the type of accommodations can also influence the risk for acquiring certain diseases. Infections can be acquired en route, so layovers and intermediate stops should be identified. The type of transportation also is relevant, because outbreaks of many types of infections have been linked specifically to airplanes, trains, and cruise ships. Travelers who stay in modern hotels in major urban centres generally have fewer exposures than backpackers or volunteer workers who spend significant time in rural settings with the local population.8 Persons who visit family and friends while abroad also are at increased risk of becoming ill because they often stay in homes away from usual tourist routes.9 The sexual history should include the number of partners, types of sexual activities, and protection used. A patient’s awareness of illnesses among fellow travelers or exposures to sick contacts also may provide a diagnostic clue.8

DIFFERENTIAL DIAGNOSIS OF ACUTE FEVER WITH RASH OR ULCER:

Maculopapular

Arboviral infections (Dengue, Chikungunya), Measles,

Table 2: Common causes of fever, by geographic area Geographic Area

Common Tropical Disease Causing Fever

Other Infections Causing Outbreaks in Travelers

Caribbean

Dengue, Malaria (Haiti)

Acute Histoplasmosis, Leptospirosis, Chikungunya

Central America

Dengue, Malaria (primarily P.vivax)

Leptospirosis, Histoplasmosis, Coccidioidomycosis

South America

Dengue, Malaria (primarily P. vivax)

Bartonellosis, Leptospirosis, Enteric fever, Histoplasmosis

South-central Asia

Dengue, Enteric fever, Malaria (primarily non-falciparum)

Chikungunya

Southeast Asia

Dengue, Malaria (primarily non-falciparum)

Chikungunya, Leptospirosis

Sub-Saharan Africa

Malaria (primarily P. falciparum), tick-borne Rickettsia (main cause of fever in southern Africa), acute Schistosomiasis, Filariasis

African trypanosomiasis, Chikungunya, Enteric fever, Filariasis

CHAPTER 5

Exposure

Comorbidities and Immunocompromised state can affect the susceptibility to infection, as well as the clinical manifestations and severity of illness.

24

Table 3: Common infections, by incubation period Disease

Usual Incubation Period (Range)

Distribution

Chikungunya

2–4 days (1–14 days)

Tropics, subtropics

Dengue

4–8 days (3–14 days)

Topics, subtropics

Encephalitis, arboviral (Japanese encephalitis, tick-borne encephalitis, West Nile virus, other)

3–14 days (1–20 days)

Specific agents vary by region

Enteric fever

7–18 days (3–60 days)

Especially in Indian subcontinent

Acute HIV

10–28 days (10 days to 6 weeks)

Worldwide

Influenza

1–3 days

Worldwide, can also be acquired while traveling

Legionellosis

5–6 days (2–10 days)

Widespread

Leptospirosis

7–12 days (2–26 days)

Widespread, most common in tropical areas

Malaria, P. falciparum

6–30 days (98% onset within 3 months of travel)

Tropics, subtropics

Malaria, P. vivax

8 days to 12 months (almost half have onset >30 days after completion of travel)

Widespread in tropics and subtropics

Spotted-fever Rickettsia

Few days to 2–3 weeks

Causative species vary by region

Amoebic liver abscess

Weeks to months

Most common in developing countries

Hepatitis A

28–30 days (15–50 days)

Most common in developing countries

Hepatitis E

26–42 days (2–9 weeks)

Widespread

Acute Schistosomiasis (Katayama syndrome)

4–8 weeks

Most common in sub-Saharan Africa

Hepatitis B

90 days (60–150 days)

Widespread

Visceral Leishmaniasis

2–10 months (10 days to years)

Asia, Africa, Latin America, southern Europe and the Middle East

Tuberculosis

Primary: weeks; Reactivation: years

Global distribution, rates and levels of resistance vary widely

INFECTION

Incubation <14 days

Incubation 2 to 6 Wks

Incubation >6 wks

Rubella, Parvovirus, drug rash, fungal infections (Histoplasmosis, Penicilliosis), Rickettsial infections (Tick Typhus), viral haemorrhagic fever, syphilis, infectious mononucleosis Group (EBV, CMV), HIV seroconversion, lepra reaction.

Vesicular

Herpes simplex, Herpes zoster, Chicken pox, Monkey pox, Rickettsial pox

Purpuric

Dengue haemorrhagic fever, Viral haemorrhagic fevers (Lassa, Ebola,Crimean Congo haemorrhagic fever, rift valley fever), Meningococcal/Gonococcal infection, severe Rickettsial infection, Severe sepsis with DIC, Plague, Haemorrhagic herpes zoster.

Erythroderma

Early dengue, Kawasaki disease, toxic shock syndrome, Scarlet fever, sunburn.

Ulcer

Chancre: Trypanosoma rhodesiense, Yersinia pestis (bubonic plague) Eschar: Tick typhus, Anthrax Genital ulcer: Syphilis, Herpes simplex virus Skin ulcer: Anthrax, Diphtheria, Fungal infection, Superinfected bacterial ulcer, Buruli’s ulcer.

PRIMARY LABORATORY INVESTIGATIONS FOR RETURNED TRAVELLERS WITH FEVER

The febrile traveller to a malaria endemic area10 should be considered to have malaria until proven otherwise. Travel history should be cited on all laboratory requisitions.

Table 4: Physical Findings

Table 5: Fever with Lymphadenopathy

Area of physical Examination

Diagnostic interpretation

Vital signs

A pulse rate that is slow for the degree of fever (pulse-temperature dissociation) may suggest typhoid fever or a Rickettsial disease.

Skin

Eyes

The eyes should be examined for evidence of conjunctivitis (leptospirosis).

Lymph nodes

The presence of localized or generalized lymphadenopathy may be diagnostically helpful.

Sinuses, ears, teeth

Sinuses, ears, and teeth are common sites of occult infection (sinusitis, otitis media, tooth abscess); attention to these areas can help avoid unnecessary testing for travel-related causes of infections.

Heart, lungs

Abdomen

Neurologic system

1.

Localized Bacterial: Bartonellosis (cat scratch disease), Plague, Staphylococcus, Streptococcus, Tuberculosis, Typhus, Tularaemia Parasitic: African Trypanosomiasis, American Trypanosomiasis, Filariasis and Toxoplasmosis Generalized

Bacterial: Brucellosis, Leptospirosis, Melioidosis, Secondary Syphilis, Tuberculosis, Enteric fever ProtozoalToxoplasmosis Viral: Epstein–Barr virus, Cytomegalovirus, Acute HIV, Rubella, Hepatitis B, Measles, Lassa fever, Dengue fever Fungal: Histoplasmosis, Blastomycosis, Coccidioidomycosis Parasitic: Visceral Leishmaniasis Non-infectious: Malignancy, SLE, Rheumatoid arthritis, Sarcoidosis, Drugs.

thrombocytopenia in dengue, malaria, typhoid, acute HIV and severe sepsis.

2.

Liver enzymes; electrolytes; creatinine.

3.

Malaria smears ± antigen detection dipstick at least 3 times over 24-48 hours.

4.

Auscultation of the lungs should focus on the detection of inspiratory crackles and wheezes, whereas auscultation of the heart should focus on detection of a murmur (Subacute bacterial endocarditis).

Blood cultures x 2 (S.typhi or paratyphi; Meningococcus; common agents of bacteremia).

5.

Urinalysis (± urine culture): proteinuria and haematuria in leptospirosis, haemoglobinuria in malaria.

6.

Stool culture for enteropathogens x 1 (Salmonella, Shigella, Campylobacter, E. coli O157: H7, Yersinia).

Splenomegaly is associated with mononucleosis, malaria, visceral leishmaniasis, typhoid fever, and brucellosis.

7.

Stool for ova and parasites (Cyclospora, Cryptosporidium, Entamoeba histolytica, Giardia).

8.

Chest x-ray.

9.

Dengue serology if probable incubation period <2 weeks and traveller to South Asia, Southeast Asia, or Latin America.

10.

EDTA sample for PCR if VHF/Arboviral disease is suspected.

11.

Acute serology tube to be saved in lab and paired with convalescent sera if no diagnosis in 10-14 days. HIV, arboviral or Brucella serology may be done.

Fever and altered mental status in the returned traveller represent a medical emergency.

Complete blood count with differential: lymphopenia in viral infections and typhoid, eosinophilia indicates parasitic or fungal infections,

SUPPLEMENTARY TESTS BASED ON HISTORY AND EPIDEMIOLOGY

CHAPTER 5

Rash may be present in many travel-related infections. The type of rash, its distribution and time of appearance and disappearance are important in differentiating the cause of fever.

25

INFECTION

26

13.

Table 6: Fever with jaundice Hepatic

Leptospirosis, hepatitis A – E, Severe falciparum malaria, EBV, CMV, Relapsing fever, viral hemorrhagic fever, typhus, enteric fever, nontyphoid salmonellosis, septicaemia (pneumococcal)

Post-hepatic

Ascending cholangitis (including helminths)

Haemolytic

Bartonellosis, malaria, mycoplasma pneumoniae, sickle cell crisis with infective trigger, haemolytic-uremic syndrome (Shigella, E.coli).

Fever with hepato splenomegaly

Bacterial: brucellosis, enteric fever, leptospirosis, Q fever, relapsing fever, rickettsial fever (tick typhus) Flukes: Fascioliasis, Schistosomiasis (Katayama syndrome) Protozoal: Amoebic liver abscess, malaria, trypanosomiasis, visceral leishmaniasis.

Viral: Dengue, acute hepatitis (A, B, E), HIV/CMV/EBV seroconversion.

Non-infectious: CML, lymphoma, myelofibrosis, haemoglobinopathy.

Chronic fever >2wks

Bacterial: Brucellosis, infective endocarditis, enteric fever, Q fever, tuberculosis, pyogenic deep seated abscess.

Fungal: Histoplasmosis, cryptococcosis, penicilliosis, coccidioidomycosis, para coccidioidomycosis

MANAGEMENT

Treatment of many of these infections will require specialist input from infectious diseases physicians and microbiologists. Drug-resistant malaria is widespread and up-to-date treatment guidelines or advice should be followed.

Where there is a strong suspicion of enteric fever, antibiotic treatment should be started without delay with either oral Azithromycin or intravenous Ceftriaxone until antibiotic sensitivities are known. However the clinical response to Ceftriaxone is slow and the symptoms may not resolve for 7–14 days. Most cases of enteric fever from Africa (not in Asia) are ciprofloxacin sensitive.

Rickettsial infections usually respond promptly to Doxycycline. For dengue the treatment is judicious fluid replacement and supportive care. Empirical treatment will often be indicated after all appropriate specimens have been collected, and sent.

Travel-related infections must be notified to public health services so that epidemiological data can be collected and where necessary infection prevention and control measures initiated.

Finally, we have a duty to our patients to educate them so that they take all available measures to prevent ill health on future travel. This should include advice on vaccine preventable infections, safe sex, food and drink hygiene, malaria prophylaxis and the importance of compliance and insect bite avoidance.

KEY POINTS

•

Initial symptoms of life-threatening and selflimited infections can be identical.

Protozoal: Amoebic liver abscess, toxoplasmosis, malaria, visceral leishmaniasis.

•

Viral: HIV plus opportunistic infections, EBV, CMV

Fever in returned travelers is often caused by common, cosmopolitan infections, such as pneumonia and pyelonephritis

•

Respiratory complaints are typically associated with common respiratory viruses. Influenza is among the most common vaccine-preventable diseases associated with international travel.

Severe respiratory symptoms may be due to seasonal influenza, bacterial pneumonia, malaria but could also suggest more unusual entities, such as Legionnaires’ disease, emerging respiratory infections such as Middle East respiratory syndrome (MERS) and H7N9 avian influenza if the travel history is appropriate and respiratory symptoms do not have a clear alternative diagnosis.

Delayed onset and chronic cough after travel could be tuberculosis, especially in a long-term traveller or health care worker.

•

Patients with malaria may be afebrile at the time of evaluation but typically give a history of fever or chills. Malaria is the most common cause of acute undifferentiated fever after travel to sub-Saharan Africa and to some other tropical areas. Patients with

Helminth: strongyloidiasis hyperinfestation syndrome, schistosomiasis (acute Katayama syndrome) Others: Malignancy, autoimmune disease, drugs, vasculitis Fever with any of the symptoms, which deserves Public health Importance

Skin rash Shortness of breath/persistent cough Decreased consciousness Bruising or unusual bleeding Persistent diarrhoea/ vomiting/ Jaundice Paralysis of recent onset

12.

Others as per clinical situation

Ultrasonography (hepatosplenomegaly)

of

abdomen

27

Table 7: Specific Laboratory tests Travel-acquired infection

Diagnostic test(s)

Malaria

1. Thick and thin blood smears ± antigen-based dipstick assay; minimum 2-3 times over 24-48 hours 2. Blood for malaria polymerase chain reaction (PCR): if smears and/or dipstick negative but index of suspicion high

Acute travellers’ diarrhoea / gastroenteritis (60-80% bacterial)

1. Stool culture for enteropathogens x 1 (will detect Salmonella, Shigella, Campylobacter, E. coli O157:H7, and often Yersinia) 2. Stool for Clostridium difficile toxin

4. Amoebic serology ± stool Entamoeba histolytica ELISA if bloody stool Respiratory tract infection

1. Chest x-ray 2. Nasopharyngeal swab (NP) swab for viral antigen testing or PCR (influenza A/B, respiratory syncytial virus [RSV], adenovirus, parainfluenza virus 1-3, human metapneumovirus, corona virus) 3. Sputum for culture and susceptibility (C&S) and acid-fast bacilli (AFB) (as directed by index of suspicion) 4. Legionella urine antigen 5. Epstein-Barr virus (EBV) – EBV monospot unreliable in children ≤ 4 years of age; EBV viral capsule antigen (VCA) IgM/IgG, EBV nuclear antigen (EBNA) IgM/IgG 6. (Serology for Q-fever, Histoplasma, Blastomyces, Coccidioides as directed by index of suspicion and travel exposures; urinary antigen for Histoplasma)

Dengue

1. Dengue NS1 antigen before 5 days and IgM/IgG antibody after 5 days (both by ELISA)

Enteric fever due to Salmonella typhi or paratyphi

1. Blood culture x 2 (caution if the patient has received antibiotics as they may have negative blood cultures) 2. Stool culture 3. Bone marrow aspirate and culture

Skin and soft tissue infection

1. Clinical diagnosis 2. Skin swab for methicillin-susceptible and methicillin-resistant Staphylococcus aureus (MSSA and MRSA) if exudative 3. If ulcerative: smears for Giemsa stain, biopsy or aspirate for Leishmania culture or PCR; consider skin swab to rule out ecthyma ulcer due to Staphylococcus or Pseudomonas

Rickettsioses

1. Clinical diagnosis – presence of an eschar is diagnostic (but may not be present) 2. Acute and convalescent sera for Rickettsial serology

Acute UTI / STI

1. Urinalysis and urine microscopy 2. Urine culture 3. Urine and/or endocervical swabs for CT/GC (Chlamydia trachomatis /Neisseria gonorrhoea) 4. Swab for viral PCR of genital vesicles 5. Blood for HIV, HBV, HCV and syphilis serology Contd...

CHAPTER 5

3. Stool for ova and parasites (O&P) x 3 (be aware that not all laboratories screen for all protozoa, including coccidia, routinely; check with local laboratory for special staining request requirements)

28

Table 7: Specific Laboratory tests Travel-acquired infection

Diagnostic test(s)

Viral hepatitis

1. HAV – HAV IgM, HAV IgG (unless history of previous vaccination) 2. HBV – HBsAg (surface antigen), HBsAb (surface antibody), HBcAb (core antibody), HBeAg (e antigen), HBeAb (e antibody); HBV DNA 3. HCV – HCV total antibody, PCR 4. Hepatitis D virus (HDV) – Anti-HDV antigen; serum HDV RNA reverse transcription PCR (RT-PCR)

INFECTION

5. Hepatitis E virus (HEV) – Anti-HEV IgM antibody; blood or stool for HEV PCR 6. EBV – EBV monospot unreliable in children ≤ 4 years of age; EBV VCA IgM/IgG, EBNA IgM/IgG 7. Cytomegalovirus (CMV) – IgM/IgG; CMV antigenemia; serum for CMV PCR Other potentially travelacquired infections diagnosed by serology

1. Viral – Chikungunya, arboviruses 2. Bacterial – Q-fever, Brucella (can also be cultured from blood or bone marrow), Leptospira 3. Fungal – Histoplasma, Blastomyces, Coccidioides, Cryptococcus (can detect by serum or CSF or urinary antigen also) 4. Parasitic – Strongyloides, Schistosoma, Amoebiasis (can also detect in stool O&P and by stool ELISA)

Adapted from “Fever in the returning international traveler” by Dr. Anton Helman, Emergency Physician and Assistant Professor at the University of Toronto, Division of Emergency Medicine, March, 1ST, 2016 with some modifications

malaria can have prominent respiratory (including ARDS), gastrointestinal, or central nervous system findings. H/o malaria chemoprophylaxis does not exclude the possibility of malaria. Malaria, especially P. falciparum, can progress rapidly and needs early diagnosis and prompt treatment.

3. Bruni M, Steffen R. Impact of travel-related health impairments. J Travel Med 1997; 4:61–4.

4. Wilson ME, Weld LH, Boggild A et al. GeoSentinel Surveillance Network. Fever in returned travelers: results from GeoSentinel surveillance network. Clin Infect Dis 2007; 44:1560–1568.

•

Dengue is the most common cause of febrile illness among people who seek medical care after travel to Latin America or Asia.

5. Hagmann S, Neugebauer R, Schwartz E et al. Illness in children after international travel: Analysis from the GeoSentinel Surveillance Network 2009. Pediatrics 2010; 125:e1072–e1080.

•

Viral hemorrhagic fevers are important but are rare in travelers; bacterial infections, such as Leptospirosis, Meningococcemia, and Rickettsial infections, can also cause fever and haemorrhage and needs early diagnosis and prompt specific treatment.

6. Boggild AK, Geduld J, Libman M et al. Travel-acquired infections and illnesses in Canadians: surveillance report from CanTravNet surveillance data, 2009–2011. Open Med 2014; 8: e20–e32. www.intmarhealth.pl 83 Krzysztof Korzeniewski et al., Fever of unknown origin in returning travelers.

•

Sexually transmitted diseases, including acute HIV, can cause acute febrile infections.

•

Infection control, public health implications, and early reporting is important.

REFERENCES

1. World Tourism Organization. UNWTO Tourism Towards 2030- Global Overview, Republic of Korea.

2. Schlagenhauf P, Weld L, Goorhuis A et al. Travelassociated infection presenting in Europe (2008–2012): an analysis of EuroTravNet longitudinal, surveillance data, and evaluation of the effect of the pre-travel consultation.

Lancet Inf Dis 2014; 15:55–64.

7. Bottieu E, Clerinx J, Schrooten W et al. Etiology and outcome of fever after a stay in the tropics. Arch Intern Med 2006; 166:1642–1648.

8. Saxe SE, Gardner P. The returning traveller with fever. Infect Dis Clin North Am 1992; 6:427–39.

9. Ryan ET, Wilson ME, Kain KC. Illness after international travel. N Engl J Med. 2002;347:505–16.

10. Committee to Advice on Tropical Medicine and Travel. Canadian Recommendations for the Prevention and Treatment of Malaria among International Travellers. CCDR 2009; 34:1-45.

TRAVEL ITINERARY: Reason for travel, Area of travel, Type of transportation, Area & type of stay, length of trip Timing of onset of fever, Severity of illness, Underlying illness, Prophylactic measures & valid Vaccine taken travel, Type of exposure: water, food, dairy product, animal, sick person, unprotected sex, insect bite

29

before

Incubation period: short (<14 days)- Malaria, Dengue, Chikungunya, AES, Influenza, Enteric fever, Typhus, Leptospirosis, Legionellosis, acute HIV seroconversion. 2- 6wks- Amoebic liver abscess, Hepatitis A/E, Acute Schistosomiasis. >6wks- Hepatitis B, Visceral Leishmaniasis, Tuberculosis Common clinical findings with fever and associated infections

Bleeding: Dengue, other VHF, severe Malaria, Leptospirosis, Rickettsial infection,Meningo coccal infection Septicaemia

CNS involve: AES, Malaria, Typhus, Meningitis, Rabies, Angiostrongyliasis Trypanosomiasis,

Low WBC count: Dengue, Malaria, Rickettsial infection, Enteric fever, VL Chikungunya, Fever after 6wks Pv malaria, TB, Amoebic liver abscess, Acute hepatitis B,C,E

Resp. symptoms: Influenza, Viral & bact. Pneumonia, severe Malaria, severe Dengue, Q fever, Plague etc.

Jaundice: YF, Viral hepatitis AE, CMV, EBV, Leptospirosis, severe Malaria, VHF, Rickettsial

Pain abdomen: Enteric fever, Amoebic liver abscess, Dengue , Viral hepatitis

Eosinophilia: Schistosomiasis Fascioliasis, TB drugs, Round worm, Hook worm Strongyloidiasis Hydatid, Filaria, Trichinosis, HIV HTLV-I, Toxoplasmosis, Fungal infection

Mononucleosis: EBV, CMV, HIV , Toxoplasmosis

Hepatosplenomegaly: Malaria, VL, Enteric fever, Brucellosis, Leptospirosis, Liver abscess, Flukes, Rickettsial Lymphadenopathy: Staph, Strepto, TB, Typhus, Brucellosis, Plague, Bartonellosis, Leptospirosis, EBV, CMV, Toxoplasmosis, Filariasis, Trypanosomiasis, Rubella, SS, Histoplasmosis, Acute HIV, Melioidosis,

Laboratory investigations for Returned travellers with fever 1.

2.

3.

4.

5.

6.

7.

8.

9.

CBC Liver enzymes; electrolytes; creatinine Malaria smears Âą antigen detection dipstick at least 3 times over 24-48 hours Blood cultures x 2 (S.typhi or paratyphi; Meningococcus;) Urinalysis (Âą urine culture): Stool for ova and parasites & culture for Enteropathogens Chest x-ray, USG Serology for Dengue, HIV, Arboviral or Brucella PCR for VHF/Arboviral disease

Management: 1. Drug-resistant malaria is widespread and up-to-date treatment guidelines to be followed 2. Enteric fever: Start with oral Azithromycin or IV Ceftriaxone until antibiotic sensitivities are known 3. Rickettsial infections: Doxycycline 4. Dengue: treatment is judicious fluid replacement and supportive care.

5. Other infections are treated according to standard treatment guidelines 6. Travel-related infections must be notified to Public Health services 7. Finally educate to take all available measures to prevent ill health on future travel including vaccine, safe sex, food and drink hygiene, malaria prophylaxis and the importance of compliance and insect bite avoidance.

Algorithm for Approach to Fever in a Returned Traveler

CHAPTER 5

Rash: Dengue, Chikungunya, Typhus, Enteric fever, Measles, acute HIV, Drug rash

Adult Immunization in India

C H A P T E R

6

V Ramasubramanian

Immunization is one of the most beneficial and costeffective disease prevention measures. Successes of immunization include worldwide eradication of smallpox, control of poliomyelitis with hopes of eradication, and elimination of measles and rubella. Although childhood immunization programs have been very successful, adult immunization is a neglected and underpublicized issue in India. Adults too need vaccinations to boost efficacy of childhood vaccines, aid immunity for newer comorbidities and afford protection when immunity is suppressed due to acquired illnesses. The CDC has come out with recommendations for adult vaccines1.

•

pregnant women at any stage of pregnancy

•

children aged 6 months to 5 years

•

elderly individuals (≥65 years of age)

•

individuals with chronic medical conditions (disorders of the cardiovascular or pulmonary systems, including asthma; chronic metabolic diseases, including diabetes mellitus; renal or hepatic dysfunction, hemoglobinopathies, or the immunocompromised

•

health-care workers

INFLUENZA VACCINATION

The TIV is administered by an annual, single intramuscular dose of 0.5 ml. The LAIV is administered by the intranasal route. The vaccine is contraindicated for persons who had severe reaction to the initial dose and for persons having egg allergy. From this year, a quadrivalent vaccine having two strains of influenza A and two of influenza B is available.

Trivalent inactivated influenza vaccine (TIV) and live attenuated influenza vaccine (LAIV) are available for use in adults. Vaccination is indicated for all persons over the age of six months. WHO recommends annual vaccination for (Figure 1):

Recommended Adult Immunization Schedule—United States - 2016 Note: These recommendations must be read with the footnotes that follow containing number of doses, intervals between doses, and other important information.

VACCINE 

AGE GROUP 

19-21 years

22-26 years

Influenza

27-49 years

50-59 years

60-64 years

≥ 65 years

1 dose annually

*,2

Tetanus, diphtheria, pertussis (Td/Tdap)*,3

Substitute Tdap for Td once, then Td booster every 10 yrs

Varicella*,4

2 doses

Human papillomavirus (HPV) Female*,5

3 doses

Human papillomavirus (HPV) Male*,5

3 doses

1 dose

Zoster

6

Measles, mumps, rubella (MMR)*,7

1 or 2 doses depending on indication

Pneumococcal 13-valent conjugate (PCV13)*,8 Pneumococcal 23-valent polysaccharide (PPSV23)8 Hepatitis A

1 dose

1 or 2 doses depending on indication

1 dose

2 or 3 doses depending on vaccine

*,9

3 doses

Hepatitis B*,10 Meningococcal 4-valent conjugate (MenACWY) or polysaccharide (MPSV4)*,11

2 or 3 doses depending on vaccine

Meningococcal B (MenB)11 Haemophilus influenzae type b (Hib)

*,12

*Covered by the Vaccine Injury Compensation Program Recommended for all persons who meet the age requirement, lack documentation of vaccination, or lack evidence of past infection; zoster vaccine is recommended regardless of past episode of zoster Recommended for persons with a risk factor (medical, occupational, lifestyle, or other indication) No recommendation

1 or more doses depending on indication

1 or 3 doses depending on indication Report all clinically significant postvaccination reactions to the Vaccine Adverse Event Reporting System (VAERS). Reporting forms and instructions on filing a VAERS report are available at www.vaers.hhs.gov or by telephone, 800-822-7967.

Information on how to file a Vaccine Injury Compensation Program claim is available at www.hrsa.gov/vaccinecompensation or by telephone, 800-338-2382. To file a claim for vaccine injury, contact the U.S. Court of Federal Claims, 717 Madison Place, N.W., Washington, D.C. 20005; telephone, 202-357-6400.

Additional information about the vaccines in this schedule, extent of available data, and contraindications for vaccination is also available at www.cdc.gov/vaccines or from the CDC-INFO Contact Center at 800-CDC-INFO (800-232-4636) in English and Spanish, 8:00 a.m. - 8:00 p.m. Eastern Time, Monday Friday, excluding holidays.

Use of trade names and commercial sources is for identification only and does not imply endorsement by the U.S. Department of Health and Human Services.

The recommendations in this schedule were approved by the Centers for Disease Control and Prevention’s (CDC) Advisory Committee on Immunization Practices (ACIP), the American Academy of Family Physicians (AAFP), the America College of Physicians (ACP), the American College of Obstetricians and Gynecologists (ACOG) and the American College of Nurse-Midwives (ACNM).

Fig. 1: Recommended Immunization schedule for adults aged 19 years or older by vaccine and age group1

DIPHTHERIA, TETANUS, (TD) AND ACELLULAR PERTUSSIS (TDAP) VACCINE Adults who have completed their primary vaccination series should receive a Td vaccine every 10 years till the age of 65 years; one dose of Tdap vaccine may be administered in place of Td vaccine at any time2.

MEASLES MUMPS AND RUBELLA

VARICELLA VACCINE

All adults without evidence of immunity to varicella or previous infection should receive 2 doses of singleantigen varicella vaccine or the second dose if they have received only one dose. Minimum interval between first and the second doses should be 4 weeks. Varicella vaccine is contraindicated in pregnant women and those with a compromised immune system.

HERPES ZOSTER VACCINE

Herpes zoster vaccine (Zostavax) is a lyophilized preparation of the Oka strain of live, attenuated varicella zoster virus (VZV). Each 0.65 ml dose contains a minimum of 19,400 plaque-forming units [PFU]. A single dose of zoster vaccine is recommended for adults aged 60 years and older regardless of whether they report a prior episode of herpes zoster.

HUMAN PAPILLOMAVIRUS (HPV) VACCINE:

Two HPV vaccines are commercially available. These include a quadrivalent (HPV4) vaccine containing the HPV virus L1 protein like particles of HPV 6, 11, 16, and 18 and a bivalent (HPV2) vaccine containing L1 VLPs of HPV 16, 18. HPV vaccination is recommended at age 11 or 12 years with catch up vaccination at ages 13 through 26 years. Ideally, vaccine should be administered before potential exposure to HPV through sexual activity. A complete series for HPV4 3 doses are administered as 0.5 ml intramuscular injection at 0, 2, and 6 months.

PNEUMOCOCCAL VACCINATION

There are two types of pneumococcal vaccine, a conjugate vaccine containing 13 serotypes and a polysaccharide vaccine containing 23 serotypes. A combination of these two serially is recommended in adults with certain comorbidities3-5. The recommendations are given in Tables 1 & Figure 3.

HEPATITIS A (HEPA) VACCINE

Vaccines available for immunization against hepatitis A virus (HAV) include inactivated vaccines such as single antigen (HAV antigen) vaccines, or combination vaccines containing both HAV and HBV antigens. Vaccination is advised for persons with any of the following indications and any person seeking protection from hepatitisA virus (HAV) infection.

Persons with chronic liver disease

2.

Men who have sex with men and persons who use illegal drugs

4.

Persons infected with other hepatitis virus

5.

Persons who receive clotting factor concentrates.

6.

Persons who have received, or are awaiting a liver transplant

7.

Food handlers

Single-antigen vaccine formulations should be administered in a 2-dose schedule at either 0 and 6–12 months (Havrix®). If the combined hepatitis A and hepatitis B vaccine(Twinrix®) is used, administer 3 doses at 0, 1, and 6 months; alternatively, a 4-dose schedule, administered ondays 0, 7, and 21 to 30 followed by a booster dose at month 12 may be used.

HEPATITIS B (HEPB) VACCINE

The hepatitis B virus (HBV) vaccine is available as a single antigen recombinant vaccine or combination with hepatitis A vaccine. Currently it is advised for all adults in India6. Administer a 3-dose series of HepB to those persons not previously vaccinated. The second dose should be administered one month after the first dose; the third dose should be administered at least two months after the second dose (and at least four months after the first dose). If the combined hepatitis A and hepatitis B vaccine is used, administer 3 doses at 0, 1, and 6 months; alternatively, a 4-dose schedule, administered on days 0, 7, and 21 to 30 followed by a booster dose at month 12 may be used. Adult patients receiving hemodialysis or with other immunocompromised conditions should receive 1 dose of 40 μg/mL administered on a 3-dose schedule or 2 doses of 20 μg/mL administered simultaneously on a 4-dose schedule at 0, 1, 2 and 6 months.

MENINGOCOCCAL VACCINE

Two types of vaccines are in use for meningococcal meningitis (i) the polysaccharide vaccines and (ii) conjugate vaccines. Bivalent (A+C) and quadrivalent (A,C,Y,W135) vaccines are available. Meningococcal vaccine should be administered to persons with the following indications.

•

Adults with anatomic or functional asplenia, or complement component deficiencies

•

First-year college students living in dormitories

•

Microbiologists routinely exposed to isolates of Neisseria meningitides

•

Military recruits

•

Persons who travel to or live in countries where the disease is hyperendemic or epidemic (sub Saharan Africa)

•

All travelers to Mecca during the annual Hajj.

•

During an outbreak given to health care workers, laboratory workers and close contacts of cases

31

CHAPTER 6

All adults should receive two doses of MMR vaccine or one dose of measles followed by a dose of MMR, administered atleast 4 weeks after the first dose. Since it is a live vaccine, it is contraindicated in pregnant women and the immunosuppressed.

1.

32

Table 1: Recommendations for Pneumococcal Vaccine Risk group

Underlying medical condition

PCV 13

PPSV23

Reconmmended Recommended

INFECTION

Immunocompetent persons

Chronic heart disease†

ü

Chronic lung disease§

ü

Diabetes mellitus

ü

Cerebrospinal fluid leak

ü

ü

Cochlear implant

ü

ü

Alcoholism

ü

Chronic liver disease, cirrhosis

ü

Cigarette smoking

ü

Persons with functional Sickle cell disease/other or anatomic asplenia hemaglobinopathy Immunocompromised persons

VACCINE 

ü

ü

ü

Congenital or acquired asplenia

ü

ü

ü

Congenital or acquired immunodeficiency¶

ü

ü

ü

Human immunodeficiency virus infection

ü

ü

ü

Chronic renal failure

ü

ü

ü

Nephrotic syndrome

ü

ü

ü

Leukemia

ü

ü

ü

Lymphoma

ü

ü

ü

Hodgkin disease

ü

ü

ü

Generalized malignancy

ü

ü

ü

Latrogenic immunosuppression**

ü

ü

ü

Solid organ transplant

ü

ü

ü

Multiple myeloma

ü

ü

ü

INDICATION  Pregnancy

Immunocompromising conditions (excluding HIV infection) 4,6,7,8,13

HIV infection CD4+ count (cells/μL) 4,6,7,8,13 < 200 ≥ 200

Men who have sex with men (MSM)

Kidney failure, end-stage renal disease, on hemodialysis

Heart disease, chronic lung Asplenia and persistent disease, chronic complement component alcoholism deficiencies 8,11,12

Chronic liver disease

Diabetes

Healthcare personnel

1 dose annually

Influenza*,2 Tetanus, diphtheria, pertussis (Td/Tdap)*,3

1 dose Tdap each pregnancy

Substitute Tdap for Td once, then Td booster every 10 yrs Contraindicated

Varicella*,4 Human papillomavirus (HPV) Female*,5 Human papillomavirus (HPV) Male*,5

2 doses

3 doses through age 26 yrs

3 doses through age 26 yrs

3 doses through age 26 yrs

3 doses through age 21 yrs

Zoster6

Contraindicated

1 dose

Measles, mumps, rubella (MMR)*,7

Contraindicated

1 or 2 doses depending on indication

Pneumococcal 13-valent conjugate (PCV13)*,8

1 dose

Pneumococcal polysaccharide (PPSV23)8

1, 2, or 3 doses depending on indication

Hepatitis A

2 or 3 doses depending on vaccine

Hepatitis B

3 doses

*,9

*,10

Meningococcal 4-valent conjugate (MenACWY) or polysaccharide (MPSV4)*,11

1 or more doses depending on indication 2 or 3 doses depending on vaccine

Meningococcal B (MenB)

11

Haemophilus influenzae type b (Hib)

*,12

*Covered by the Vaccine Injury Compensation Program

After first dose

3 doses post-HSCT recipients only

Recommended for all persons who meet the age requirement, lack documentation of vaccination, or lack evidence of past infection; zoster vaccine is recommended regardless of past episode of zoster

1 dose Recommended for persons with a risk factor (medical, occupational, lifestyle, or other indication)

No recommendation

Contraindicated

Fig. 2: Vaccine that might be indicated for adults aged 19 years or older based on medical and other indications1

33

CHAPTER 6

Fig. 3: Recommended pneumococcal vaccination schedule and intervals, by age, health condition, and other risks.

Table 2: Categories of travel vaccines

Table 3: Vaccine recommendations for Hajj pilgrims

Category

Vaccine Diphtheria/tetanus/pertussis (DTaP)

Vaccine recommendations

Comments

Routine

Meningococcal

Mandatory

Influenza

Recommended

Polio

< 15 years, endemic countries

Yellow fever

Endemic countries

Pneumococcal

Recommended for > 65 years

Hepatitis A

Recommended

Hepatitis B

Recommended

Hapatitis B virus (HBV) Measles, mumps, rubelia (MMR) Inactivated poliomyelitis (IPV) Recommended

Influenza Hepatitis A virus (HAV) Japanese encephalitis Meningococcal meningitis Pneumococcal disease Rabies Tick-borne encephalitis

Required (mandatory)

Table 4: Vaccine recommendations for Kumbh Mela

Typhoid fever

Vaccine recommendations

Comments

Yellow fever (for individual protection)

Typhoid

Strong recommendation

Hepatitis A

Strong recommendation

Cholera

Hepatitis B

For prolonged stay

Yellow fever (for protection of vulnerable countries)

Japanese encephalitis

If stay is over 1 month

Meningococcal meningitis (for Hajj, Umrah)

Influenza

Strong recommendation

Yellow fever

From endemic countries

Diphtheria, pertussis, tetanus update Measles, mumps, rubella

Update

A single dose of 0.5 ml of the reconstituted vaccine is administered subcutaneously in the deltoid region.

Rabies

Pre-exposure

Polio

1 booster

TYPHOID VACCINE

Cholera

Oral vaccine adviced

(family members and immediate neighbors).

Vaccines available for typhoid fever include the live oral Ty21a vaccine and an injectable Vi polysaccharide vaccine.

Typhoid vaccine is recommended as part of routine

immunization in adolescents. It is also recommended to the entire community at risk during an outbreak situation and to immunocompromised individuals. Three

INFECTION

34

doses of Ty21a capsules/sachets (liquid formulation) are administered on alternate days. It is also recommended that this series should be repeated once in every 3 years as a booster dose. The Vi vaccine is given as a single subcutaneous or intramuscular dose of 0.5 ml. A booster is recommended once in every 3 years. The live vaccine should not be given to immunocompromised individuals including those affected with HIV. Apart from routinely recommended adult vaccines, certain vaccines are indicated in persons with underlying co-morbidities. The following table highlights vaccines in persons with certain underlying risk factors1,7.

VACCINES FOR TRAVELLERS (TABLES 2, 3 AND 4)

Indications for vaccinating travellers depend on the place of travel, staying conditions, activities at place of visit and other risk behaviours. Current recommendations for yellow fever vaccine mandate only one dose for lifetime unless persistent exposure to high risk conditions prevails, when a booster is indicated after 10 years. Travel vaccine recommendations for Indians are given in the following tables6.

VACCINES FOR PREGNANT WOMEN

Pregnant women are recommended to have one dose of Tdap and influenza vaccine after the 26 week unless the risk of flu is high, as in epidemics, when the flu vaccine can be given earlier during pregnancy.

VACCINES FOR HEALTH CARE WORKERS

The following vaccines are advised for all susceptible health care workers •

Hepatitis B

•

Influenza

• MMR • Varicella • Tdap Adult vaccines are an integral part of the approach to comprehensive well-being. It is high time that practicing physicians in India resort to this safe and effective intervention for all their patients to ensure that their patients stay healthier and happier.

REFERENCES

1.

www.cdc.gov/vaccines/schedules/hcp/adult.html

2. MMWR / January 14, 2011 / Vol. 60 / No. 1.

3.

MMWR / September 19, 2014 / Vol. 63 / No. 37.

4.

MMWR / October 12, 2012 / Vol. 61 / No. 40.

5. JAMA. 2015;313:719-720.

6.

Murugananthan, Mathai, Sharma; Adult Immunization 2014; 2nd Edition - Association of Physicians of India

7.

Cl Infect Dis 2014; 58:309-318.

C H A P T E R

7

Approach to patients with Pyrexia of Unknown Origin Suspected to have Tuberculosis MA Jalil Chowdhury

ABSTRACT

One of the most challenging problems a physician faces in his daily practice is the evaluation of a patient with prolonged pyrexia—a truly significant test of his clinical skills.

Causes of PUO vary according to geographical area, health care setup, investigations facilities, and physicians’ attitude. Because of socioeconomic and other factors, infectious diseases are still very common in developing countries. Amongst the infectious causes tuberculosis usually extra pulmonary or miliary is the single most common infection in most PUO series.

In 1961, Petersdorf and Beeson first defined PUO as “fever lasting for more than 3 weeks, more than 38.3°C on several occasions and no diagnosis after 1 week of indoor investigations”.1 Three weeks duration eliminated short lived infections; mainly viral fevers and 1 week of indoor investigations allow sufficient time for appropriate initial investigations to be completed.

Mycobacterium tuberculosis is a genius organism which can affect any and every organ system of the body. It can virtually produce any known clinical syndrome except true pregnancy. So it is reasonable to think of tuberculosis as a cause of fever in a PUO setting when no cause is obvious.

Cost of hospitalization is increasing day by day. Now a days most of the patients of PUO can be managed as outdoor patients and incidence of HIV (human immunodeficiency virus), nosocomial infections and neutropenic patients are increasing day by day. Considering this, Durack and Street (1991) proposed a new classification of PUO (Table 1).2 Major changes in new classification were that it didn’t require 3 weeks duration to satisfy diagnosis of PUO and blood culture negative at 48 hours was a must.

One of the most challenging problem a physician used to face in day to day practice is the evaluation of patients with prolonged pyrexia—a truly significant test of his clinical skills.

The most important investigation in a case of PUO is to evaluate the patient by a physician who has not seen the patient previously. The tests already done should be reviewed attentively. There might have some clue to diagnosis in those. Some investigations may have to be repeated; new investigations may have to be ordered.

Definitive diagnosis of tuberculosis requires isolation of the tubercle bacillus from the body fluid or any tissue obtained by FNA or biopsy, which is often difficult.

Institution of empirical anti tuberculous therapy may be justified in any patient of PUO where no specific diagnosis is evident after a reasonable diagnostic workup and tuberculosis is a strong possibility and the patient is rapidly deteriorating.

“Humanity has three great enemies: fever, famine and wars. Of these by far the greatest, by far the most terrible is fever” – Sir William Osler (1849-1919). Terrible for the patient because of not curing within expected period and terrible for the physician for not reaching a diagnosis even after exhaustive investigation.

There are 3 types of fever usually the physicians encounter: acute onset fever usually producing no diagnostic or therapeutic problem; Recurrent fever; and third group having prolonged fever amongst which a group remains undiagnosed even after logical extensive investigations termed as pyrexia or fever of unknown or undetermined origin (PUO or FUO).

PYREXIA OF UNKNOWN ORIGIN

WHEN A FEVER CASE DOES BECOMES PUO?

Unawareness of atypical presentations of common diseases (most important), lack of detailed initial clinical work up, delay in advising appropriate investigation, misinterpretation of either clinical feature or investigation result, false negative or positive test results and multiple pathologies in the same patient - are the few factors responsible for a fever case to be labeled as PUO. Repeated basic clinical evaluation is probably most important factor in reaching a diagnosis. But in some cases of PUO, the cause remains undiagnosed even after exhaustive investigations. Explanation for such fevers could be pathologies which are yet unidentified or diagnostic tests for them are not available widely or not advised.

Often a patient who complains of fever does not have fever when checked by thermometer. So ‘I feel feverish, ‘fever is inside the body...does not come in thermometer’ should not be considered as PUO. According to one study (PUO of >1 year duration on average) 28% patients did not have fever when oral temperatures were taken for several weeks. 3 They are the most anxious people and do doctor shopping. By this time they have done so many investigations failing to find any clue or solving their problem. They may be asked to record the temperature

36

Table 1: Classification of Fever of Unknown Origin (FUO)5 Category of FUO

Definition

Common etiologies

Classic

Classic Temperature >38.3°C (100.9°F)

Infection, malignancy, collagen vascular disease

Duration of >3 weeks Evaluation of at least 3 outpatient visits or 3 days in hospital Nosocomial

Temperature >38.3°C

INFECTION

Patient hospitalized >24 hours but no fever on admission Evaluation of at least 3 days Immune deficient (neutropenic) Temperature >38.3°C Neutrophil count < 500 per mm Evaluation of at least 3 days HIV-associated

3

Temperature >38.3°C Duration of > 4 weeks for outpatients, >3 days for inpatients

HIV infection confirmed HIV = human immunodeficiency virus.

Table 2: Common Etiologies of Fever of Unknown Origin5 Infections

Autoimmune conditions

Tuberculosis (especially extrapulmonary)

Systemic lupus erythematosus (SLE)

Endocarditis

Adult Still’s disease

Abdominal abscesses

Polymyalgia rheumatica

Pelvic abscesses

Temporal arteritis

Dental abscesses

Rheumatoid arthritis

Osteomyelitis

Rheumatoid fever

Sinusitis

Inflammatory bowel disease

Cytomegalovirus Epstein-Barr virus Human immunodeficiency virus

Reiter’s syndrome Vasculitides

Prostatitis Sinusitis Malignancies

Miscellaneous

Lymphoma

Drug-induced fever

Metastatic cancers

Complications from cirrhosis

Colon carcinoma Hepatoma Myelodysplastic syndromes

Opportunistic bacterial infections, aspergillosis, candidiasis, herpes virus Cytomegalovirus, Mycobacterium avium-intracellulare complex, Pneumocystis carinii pneumonia, druginduced, Kaposi’s sarcoma, lymphoma

daily consecutively for about two weeks before going for further evaluation.

CAUSES OF PUO

Causes vary according to geographical area, health care setup, investigations facilities, demographic pattern of population, and physicians’ attitude for getting specific diagnosis. Infections (40%), neoplasms (20%), and collagen-vascular diseases (15%) are ultimately found responsible for the majority of the cases of PUO worldwide (The “Big Three”). Because of socioeconomic and other multiple factors, infectious diseases are still very common in developing countries. Amongst the infectious cause tuberculosis usually extra pulmonary or miliary is the single most common infection in most PUO series. 4 Incidence of tuberculosis is many times higher in Indian subcontinent as compared to western countries (Table 2).

APPROACH TO PATIENTS WITH PUO

Lyme disease

Renal cell carcinoma

Clostridium difficile enterocolitis, druginduced, pulmonary embolism, septic thrombophlebitis, sinusitis

Hepatitis (alcoholic,granulomatous, or lupoid)

Pancreatic carcinoma

Hepatic cirrhosis with active hepatocellular necrosis

Chronic leukemia

Deep venous thrombosis

Sarcomas

Sarcoidosis Factitious fever Undiagnosed

The first and foremost step is to establish that fever really exists. Patients should be instructed to measure oral temperature and record daily for at least two weeks.

Detailed history and physical examination has probably not more significance in any other category of patients than PUO. Clinical evaluation should be repeated frequently. History should be re taken and patient should be re-examined by a physician who has not seen the patient previously. The investigations already done by the patient should be reviewed attentively. 3, 5 There might have some clue to diagnosis. Some investigations may have to be repeated; new investigations may have to be ordered. All medications should, if possible, be discontinued early in the evaluation to rule out a druginduced fever. Persistence of fever beyond 72 hours after the suspected drug has been removed allows one to conclude that the drug is not the offending agent in producing the fever. 6

• Not suspecting tuberculosis

re-evaluation of the film only after the diagnosis is made by other means. Anemia and leukopenia may be present.

A leukemoid response may indicate bone-marrow involvement and suggest diagnosis. Monocytosis may occur, but it is also found with other infections and neoplasia. Bone marrow biopsy may be diagnostic. 7, 8

• Delay in ordering appropriate tests

Pleural Tuberculosis

APPROACH TO A PATIENT WITH PROLONGED PYREXIA WHEN TUBERCULOSIS IS SUSPECTED AS THE CAUSE

TB might have been missed at initial work up because of • Failure to identify the findings correctly

• Insufficient sample collection • Difficulty in getting appropriate sample

• Pulmonary TB in AIDS is often subtle (normal chest x-rays in 15–30%) • Misinterpretation of test result • PPD is positive in < 50% of TB with PUO • Less sensitivity of sputum smear microscopy

Why and when to suspect TB as PUO? 1.

When no other cause found for fever

2.

Organ based symptoms: there may not be any symptom other than fever

3.

Organ based signs e.g., hepatomegaly

4.

Past history of Tuberculosis

5.

History of contact with smear positive TB patient

6.

Lung infiltrates on previous chest x-ray; the subtle changes might have been missed in the past. Serial x-rays are essential tool

7.

Clue in the investigations already done e.g., sterile pyuria.

High ADA on the background of lymphocyte predominant exudative effusion is the diagnostic of tuberculosis.

Pleural biopsy is sometimes helpful.

Cryptic Tuberculosis

Cryptic disseminated tuberculosis is an insidious form of presentation which mainly affects middle aged and elderly. Often the diagnosis is missed because possibility of tuberculosis is not considered. Lassitude, loss of weight, chronic ill health in the aged are erroneously attributed to some co-existent chronic disease or presumed occult tumors. Diagnosis is particularly difficult because choroidal tubercles are often absent, miliary pulmonary mottling may not be seen on chest radiography and the tuberculin test may be negative. The clinical features are often so non-specific that the diagnosis is frequently made only at autopsy. 9

Splenic Tuberculosis

Isolated splenic tuberculosis is rare but can be a part of miliary tuberculosis. Abdominal ultrasonography revealing splenomegaly with multiple small hypo echoic lesions within the spleen can be anything from tuberculosis to abscess, lymphoma or carcinoma of spleen. Splenic puncture and biopsy can reveal the actual diagnosis. 10-11

Hepatic tuberculosis

Mycobacterium tuberculosis is a genius organism which can affect any and every organ system of the body. It can virtually produce any known clinical syndrome except true pregnancy.

Localized hepatic tuberculosis is rare; can be a part of disseminated miliary tuberculosis. There may be hepatomegaly. Sign symptoms are nonspecific. A moderate or marked increase in the serum levels of alkaline phosphatase, along with normal or mildly increased serum bilirubin, is considered suggestive of hepatic tuberculosis; however, these findings are not specific and may occur in other conditions, such as metastatic carcinoma, liver abscess, echinococcosis, amyloidosis, granulomatous diseases of varying etiologies, and active cirrhosis. Some authors suggest that, whenever there is a lack of etiological diagnosis of a granulomatous hepatitis, patients should be considered for an empirical trial with antituberculous drugs, especially if there is clinical deterioration, particularly in areas where tuberculosis is endemic. 12-14 Liver biopsy points to the diagnosis. The specimen should be cultured for tubercle bacilli as well as examined histologically.

Miliary or chronic disseminated Tuberculosis

Gastrointestinal tuberculosis

8. Malnutrition 9.

Immunosuppression

10.

Diabetes, renal insufficiency or uremia/ dialysis, transplant

11.

HIV

12.

Drug abuser

13. Homelessness

Search for TB as a cause of PUO by organ based symptoms and signs and investigations

Splenomegaly may be found in miliary chronic disseminated tuberculosis. Choroid tubercle may be rarely found. MT is often negative. Miliary pulmonary lesions may not be obvious. It is to be noted that miliary pattern of chest x ray sometimes detected after meticulous

Peritoneal biopsy: laparoscopic biopsy preferred to percutaneous biopsy. The role of ascitic fluid adenosine deaminase (ADA) in the diagnosis of TB peritonitis is unclear. 15 The presence of an abnormal chest x-ray in a patient with ascites should alert one to the possibility of TB peritonitis. 16 Colonoscopy with ileoscopy may be

CHAPTER 7

• Not motivated for sending sample for mycobacterial staining, culture or PCR in addition to cytology and histopathology

37

38

useful for the diagnosis of ileocaecal tuberculosis.

INFECTION

Lymph node tuberculosis

Lymph node biopsy is the most frequent invasive test.

If possible, anterior cervical, axillary, or inguinal node biopsy should be avoided because biopsies of these nodes are usually unhelpful/nondiagnostic and are often reported as “non specific inflammatory changes, cannot rule out infection/malignancy.” More likely to be diagnostic are posterior cervical, supra/infraclavicular, or epitrochlear node biopsies.17-19 Hilar, mediastinal, or retroperitoneal node biopsies have a high diagnostic yield.20 Certain characteristics like matted lymph node, calcification and preferential involvement of right para tracheal lymph node favors diagnosis of tuberculosis.

Psoas abscess

Patient may present with pain in the groin. MRI may or may not detect spinal tuberculosis; may be consequence of tuberculosis of the paravertebral glands. 21

Pericardial tuberculosis

Pericarditis usually presents in three clinical forms, consisting of pericardial effusion, constrictive pericarditis and a combination of effusion and constriction.22 The definite diagnosis of TB pericarditis is made by identification of mycobacterium TB in the pericardial fluid or tissue or the presence of caseous granulomas in the pericardium. Polymerase chain reaction (PCR) can identify DNA of mycobacterium TB from pericardial fluid. Pericardial biopsy provides a rapid and definite diagnosis but requires high technical skill and the yield from culture is low even with optimum specimen.2,6,12 The Tygerberg 23 scoring system helps the clinician to decide whether pericarditis is due to TB or whether it is due to another cause : night sweats (1 point), weight loss (1 point), fever (2 points), blood leucocytes < 10 x 109/L (3points) serum globulin >40g/L (3points). A total score of 6 or more is highly suggestive of TB pericarditis.13 In a developing nation such as ours, a high index of suspicion is required in all cases of prolonged fever and evidence of hemodynamic instability with high Tygerberg score.

Echocardiography is indicated and finding of pericardial effusion with irregular border projecting into the effusion should suggest tuberculosis as the cause of the effusion.

Anti tuberculous chemotherapy should be exhibited in such a patient and response to this treatment should therefore confirm the diagnosis. This is important because TB pericarditis is difficult to diagnose since definitive diagnosis requires culturing the TB bacilli from aspirated pericardial fluid or pericardial biopsy which requires technical skill and is often non diagnostic.

Renal tuberculosis

Microscopic hematuria may give clue to diagnosis. AFB can be found in urine sample collected over a period of 24 hours. 24

Adrenal tuberculosis

Rarely cause PUO, may be a part of chronic disseminated form of tuberculosis

Pott’s disease

There may or may not be pain in the affected vertebra, commonly lower dorsal region. Care full examination may reveal gibbus. . Pott’s disease can be missed in conventional X-ray. MRI and histopathological diagnosis are usually needed.

Mycobacterial culture and acid fast stain of specimens including sputum, urine, gastric juice, bone marrow aspirate, cerebrospinal fluid, pleural fluid, and pericardial fluid, paravertebral abscess, and lymph node aspirate are the main stay of diagnosis of tuberculosis in a patient with prolonged pyrexia.

NONSPECIFIC INVESTIGATIONAL HELP

Analysis of the previous films meticulously can reveal any subtle finding missed earlier.

ESR, CRP, IGRA are not of so much diagnostic. MT may be false positive in BCG vaccinated, asymptomatic infection with Mycobacterium tuberculosis or atypical mycobacteria. Serological tests (TB IgG, IgM, PCR blood) are not useful and are not recommended in many countries where false positive rates are expected to be high.

BAL can yield AFB when conventional examination fails to diagnose tuberculosis. 1

sputum

Often in an appropriate clinical setting ADA in body fluids sometimes help to reach a diagnosis of tubercular origin.

Exploratory Laparotomy/laparoscopic examination: Before the era of laparoscopy and CT scan laparotomy used to consider for diagnosis of pyrexia of unknown origin when abdominal pathology was considered to be the cause. 25 Various nuclear scans e.g., PET (positron emission tomography) scan, indium 111 scan, radiolabelled leucocyte scan are done some times in work-up of PUO but they are not cost effective especially in developing countries. 3 Positron emission tomography (PET) scan combined with computed tomography (CT) scan has been found to be helpful in diagnosis of extra pulmonary tuberculosis in patients with PUO. 26 PET/CT is helpful in identifying a site for biopsy. FDG PET scan can identify the hyper metabolic state in case of inflammation or tumor. 27

EMPIRICAL THERAPY IN PUO

Tuberculosis, particularly extra pulmonary tuberculosis, has emerged as the most common final diagnosis in patients presenting with FUO in most Indian studies. Sharma et al, in a combined prospective and retrospective study of 150 cases of FUO, found that infections, particularly tuberculosis, were the most common cause of FUO (50%).

28 Another group of investigators found tuberculosis as the cause of FUO in 26 of 121 patients (21.5%) in a prospective study. A recent study involving 60 patients with FUO who met the strict revised criteria established

by Petersdorf found extra pulmonary tuberculosis to be the most common cause of FUO. All the patients tested

negative for human immunodeficiency virus (HIV).

Extra pulmonary tuberculosis, particularly tuberculous mediastinal adenopathy, was the final diagnosis in 27 (45%) patients. Tuberculosis was the single most common in most PUO series. 4 This strongly supports the view that the institution of empirical antituberculous therapy is justified in any patient of PUO where no specific diagnosis is evident after a reasonable diagnostic work-up.

REFERENCES

1.

Petersdorf RG, Beeson PB. Fever of unexplained origin: report on 100 cases. Medicine (Baltimore) 1961; 40:1-30.

2.

Durack DT, Street AC. Fever of unknown origin— reexamined and redefined. Curr Clin Top Infect Dis 1991; 11:37.

3.

K Ramamoorthy and Mangesh Bang. Pyrexia of unknown origin. API India. Medicine CME 2004; 385-390.

4.

Haq SA, Alam MN, Hossain SM, Dhar UK, Rahim S, Rahman M, et al. A study of prolonged pyrexia in Dhaka.

Bangladesh Med Res Counc Bull 1996; 22:33-42.

5.

Roth AR and Basello GM. Approach to the adult patient with Fever of Unknown Origin. Am Fam Phys 2003; 68:222428.

6.

Johnson DH and Cunha BA. Drug fever. Infect Dis Clin North Am 1996; 1085-91.

7.

Glasser RM, Walker RI, Herion JC. The significance of hematologic abnormalities in patients with tuberculosis.

Arch Intern Med 1970; 125:691-95.

8.

Jacoby GA and Swartz MN. Current concepts: Fever of undetermined origin. N Eng J Med 1973; 289:1407-10.

9.

Bobrowitz ID. Active tuberculosis undiagnosed until autopsy. Am J Med 1982; 72:650.

10. Kabir A, Das A, Banna MH, Minnat B, Ahasan HAMN. Splenic tuberculosis: a cause of pyrexia of unknown origin: report of two case. J Medicine 2013; 14:88-90.

11. Singh B, Ramdial PK, Royeppen E, Moodley J and Chetty

39

12. Mert A, Ozaras R, Tabak F, et al. Localised hepatic tuberculosis. Eur J Intern Med 2003; 14:511-12.

13. Ferrari TCA, Couto CM, Vilaca TS and Xavier MAP. Localized Hepatic tuberculosis presenting as fever of unknown origin. The Brazilian Journal of Infectious Disease 2006; 10:364-67.

14. Hersch C. Tuberculois of the liver. : a study of 200 cases. S Afr Med J 1964; 38:857-63.

15. Hillebrand Dj, Runyon BA, Yasmineh WG, et al. Ascitic fluid adenosine deaminase insensitivity in detecting tuberculous peritonitis. Hepatology 1996; 24:1408-12.

16. Gonnella JS, Hudson EK. Clinical pattern of tuberculous peritonitis. Arch Intern Med 1966; 117:164-9.

17. Mohseni S, Shojaiefard A , Khorgami Z, Alinejad S, Ghorbani A, Ghafouri A. Peripheral lymphadenopathy: Approach and Diagnostic Tools. Iran J Med Sci 2014; 39(2 Suppl):158–170.

18. Gupta PR. Difficulties in managing tuberculosis. Lung India 2004; 21:5053.

lymph

node

19. Fontanilla JM, Barnes A and von Reyn CF. Current diagnosis and management of peripheral tubercular lymphadenitis. Clin Infect Disease 2011; 53:555-562.

20. Dandapat MC, Mishra BM, Dash SP, Kar PK. Peripheral lymph node tuberculosis: a review of 80 cases. Br J Surg 1990; 77:911.

21. Kapoor OP. Psoas Abscess (Tuberculosis) as the cause of PUO. Bombay Hopspital Journal 2009; special issue: p122.

22. Mbata GC, Omejua EG, Okereke J, Ogah SO. Tuberculous pericarditis: a cause of pyrexia of unknown Origin: case report. Pioneer Medical Journal 2013; 3:1-8.

23. Reuter H, Burgess, Van Vuuren W, Doubell A. Diagnosis of tuberculous pericarditis. Q J Med 2006; 99:827-839.

24. Cunha BA. Nonspecific tests in the diagnosis of fever of unknown origin. In: Cunha BA, editor. Fever of unknown origin. New York: Informal Health care; 2007: 9-16 25. Geraci JE, Weed LA, Nichols DR. Fever of obscure originthe value of abdominal exploration in diagnosis: report of seventy cases. JAMA 1959; 169:1306-15.

26. Yu HYand Sheng JF. Liver tuberculosis presenting as an uncommon cause of PUO: PET/CT identifies the correct site for biopsy. Med Prince Pract 2014; 23:577-79.

27. Castaldi P, Leccisotti L, Bussu F, et al: Role of 18F-FDG PET-CT in head and neck squamous cell carcinoma. Acta Otorhinolaryngol Ital 2013; 33:1–8.

28. Sepkowitz. Tuberculosis as the Cause of Fever of Unknown Origin: A Review. International Journal of Infectious Diseases 1997; 2:47-5 1.

CHAPTER 7

But therapeutic trial with ethambutol and INH is not usually not practiced now a days because of fear of rapid development of resistance. If the patient is hemodynamically unstable and rapidly deteriorating e.g., in cryptic tuberculosis empirical antituberculous therapy may be rewarding. In the others temptation to start antituberculous therapy may be stopped till a reasonable diagnosis is reached. It is to be remembered that rifampicin has significant antimicrobial properties and many bacterial infections may respond partially to rifampicin.3

R. Isolated splenic tuberculosis. Tropical Doctor 2005; 35:4849.

C H A P T E R

8

Adult Influenza Vaccination

ABSTRACT

Acute respiratory infection is a common medical problem across the world including in India. Influenza is one of the important causes of acute respiratory infection. Influenza is associated with several complications mainly secondary bacterial pneumonia. In some patients such as elderly and those with chronic medical conditions, the risk of complications is higher. Prevention of influenza plays an important role in avoiding complications. Vaccination has been proved to be a effective measure for prevention of influenza. This article discusses the basics of influenza, clinical features, and diagnosis and preventive aspects of disease focusing on vaccination.

INTRODUCTION

Acute respiratory infection (ARI) is an important health problem worldwide. Influenza is one of the most important causes of ARI. Influenza is seen across the world. The annual global attack rate of disease is estimated to be 5-10% in adults and 20-30% in children.1 Influenza is also associated with significant economic burden because of the direct cost involved in health-care (medicines, hospital visits, hospitalization etc) as well as indirect cost in the form of loss of workday or general social disturbance among people of all age groups. Influenza can result in several complications including hospitalization and sometimes it may even lead to death.1,2 Because of these concerns, prevention of influenza in both healthy people as well as those at risk is of paramount importance.

INFLUENZA BASICS

Influenza is caused by viruses belonging to the family “orthomyxoviridae”. Influenza virus is a single stranded RNA virus with helical shape. These are RNA viruses.

Based on the presence of nuclear material i.e. core proteins, influenza viruses are divided into three different types; A, B, and C. The viruses have two types of envelop glycoproteins; haemagglutinin (HA) or neuraminidase (NA) activity. “A” type of influenza viruses are further subdivided into several types based on the type of these envelope glycoproteins (e.g. A/H1N1, A/H3N2).1,3 Influenza “B” and “C” viruses mainly cause disease in human being. Influenza A viruses can infect different mammalian and avian species. Type “A” virus causes moderate to severe illness. The virus can affect people of all age groups. Influenza “B” type virus generally causes milder form of illness as compared to influenza type “A” and mainly affects children.4 The concern of influenza in humans is mainly because of the viruses belonging to type “A” and “B” type.1

Ashray Naik An Indian epidemiology study, evaluating data from September 2004 to December 2008, reported that seasonal influenza A(H1N1), H3N2, and type B co-circulated in all regions without any particular pattern of movement of any subtype. Year-round limited influenza activity with peaks during rains was observed in this study.5

GENETIC CHANGES- A CHARACTERISTIC OF INFLUENZA VIRUSES

Influenza virus has a peculiarity of undergoing frequent mutations and genetic reassortment, resulting in generation of a new viral strain due to combination and rearrangement of genetic material. There are two processes by which the protein structure of influenza virus can change; “antigenic drift” and “antigenic shift”.

“Antigenic drift” i.e. minor changes in the protein structure of influenza “A” strains occurs commonly. Antigenic drift is responsible for repeated influenza outbreaks. The major changes in the influenza type A occur because of the “antigenic shift”. This is the result of genetic reassortment from different influenza “A” subtypes. Antigenic shift can result in large pandemic outbreaks.1

SPREAD OF INFLUENZA

Influenza is a contagious disease. Healthy people can also get infected with the influenza virus and transmit it to others. Transmission of infection from one person to the other occurs mainly through droplets or respiratory secretions of infected people. Transmission of influenza can also occur through direct contact with infected person or fomites.1,3

PATHOGENESIS, SYMPTOMS AND COMPLICATIONS OF INFLUENZA

After the entry of influenza virus into respiratory system, the virus attaches to the respiratory epithelial cells penetrates into it. Viral replication causes destruction of the host cell, but viremia is rare. Influenza virus is shed in the respiratory secretions for about five to ten days.

The incubation period of influenza is generally two days, but may range from one to four days. The presentation of infection differs from asymptomatic nature to severe illness.4 Influenza is different from the usual common cold. The disease illness is characterized by symptoms such as acute onset of fever, chills, rhinorrhea (running nose), cough, sore throat, headache and myalgia. In most cases, the febrile illness lasts for 3-4 days the disease resolves in 7-10 days.3

Diseases such as diabetes, chronic renal failure, chronic respiratory disease, heart disease and cirrhosis of liver are associated with higher risk of influenza related complications. Generally, infections in people with diabetes are more common and severe due to immunological deficiency6,7 and other comorbidities.

Diabetics are at higher risk of developing infections and dying due to them.8 Given the complications related to infections in these patients, anti-pneumococcal and influenza vaccines can be useful to reduce hospitalization , morbidity and mortality7,9-11Patients with chronic kidney disease and those with end-stage renal disease are also susceptible to infection because of the immune impairment,12 hence need special care in terms of prevention of infections.13 Vaccination against influenza has been shown to be associated with better survival in dialysis patients in a retrospective study.14 Influenza in patients with chronic respiratory illness is associated with adverse outcomes.15 Patients with moderate to severe chronic obstructive pulmonary disease having respiratory viral infections require more hospital visits or hospitalization16,17 resulting in higher utilization of health care resources.17 Mortality due to influenza in patients with acute exacerbation of COPD is more compared those who do not have influenza.15 Influenza infection in smokers can increase the risk of hospitalization.18 Influenza infection has also been linked to significant morbidity and mortality in patients with congestive heart failure.19 Influenza activity can result in higher admission rates for pneumonia, COPD, and heart failure in elderly people.20 Influenza infection through activation of systemic inflammatory responses increase the risk of atrial fibrillation.21 Influenza increases the risk of hepatic decompensation and hospitalization in patients with cirrhosis.22 Another at risk population is pregnancy. Influenza in pregnancy is associated with adverse outcomes. Pregnant women can develop severe and sometimes even can result in mortality.23

DIAGNOSIS

Influenza is suspected based on the clinical history and patient presentation. Confirmation of disease can be done by viral culture, reverse transcription polymerase chain reaction (RT-PCR) or demonstrating presence of specific

neutralizing antibodies in the blood.3

41

MANAGEMENT OF INFLUENZA

The management of influenza includes preventive aspects and the treatment component. The treatment components of influenza include timely measures for controlling the infection spread, early identification of high risk people, supportive care of patient and administration of antiviral drugs. For the prevention of disease, vaccine and chemoprophylaxis are two commonly methods.

People should follow cough etiquette, use of face masks and maintain hand hygiene in order to reduce the risk of disease transmission to others.3 Antiviral agents i.e. neuraminidase inhibitors are used for the treatment of infection in affected people or prevention of influenza in high risk people. A recently published review examined the risk and benefits of these agents for influenza in people of all age and also evaluated the effect of oseltamivir on mortality in patients with 2009A/ H1N1 influenza. Oseltamivir and zanamivir reduced the time to first improvement of symptoms in adults by 16.8 hours and 0.60 days respectively, demonstrating small reductions in the time to first alleviation of influenza.

The review findings suggested that oseltamivir use is associated with increased risk of gastrointestinal side effects such as nausea, vomiting and psychiatric events in adults. In children, oseltamivir use was associated with increased risk of vomiting. Oseltamivir did not show protective effect on mortality among patients with 2009A/ H1N1 influenza.24 The findings of this recent publication suggest, that risk-benefit ratio should be considered while using neuraminidase inhibitors for the management of influenza.

PREVENTION OF INFLUENZA WITH VACCINATION

Two types of influenza vaccines are currently available; inactivated influenza vaccine and live attenuated influenza vaccine. The live attenuated vaccine is administered as nasal spray whereas inactivated influenza vaccine is administered as an injection. The trivalent vaccine provides protection against two strains of influenza “A” virus and one strain of influenza “B” strain whereas quadrivalent provides protection against one additional Influenza “B” strain. The quadrivalent vaccine is currently not available for commercial use in India.25 The inactivated vaccines can be of either split virion or subunit type.26 The split virus vaccines is produced by using virus which is disrupted by a detergent. In subunit vaccines, the envelop proteins are further purified by removing other viral components.1 A study compared effectiveness of split-virion influenza vaccines versus subunit influenza vaccines in adults with >50 years who presented with acute respiratory illness during three influenza seasons.

Effectiveness of split-virion vaccine in this study was 77.8% as opposed to 44.2% effectiveness with subunit vaccine.26

WHO SHOULD GET VACCINATED?

Ideally every individual who is six months of age and above should get influenza vaccination every year.2,25

CHAPTER 8

Primary influenza viral pneumonia is not a common complication, but has a high mortality rate.4 People can develop secondary complications because of influenza infection. Secondary bacterial pneumonia is a common complication of influenza. Bacteria such as Streptococcus pneumoniae, Haemophilus influenzae, or Staphylococcus aureus are responsible for secondary infection. Other complications associated with influenza include myocarditis or worsening of chronic bronchitis and other chronic lung diseases.4 The risk of complications differs among individuals. The risk is particularly higher in elderly people and those with concurrent chronic illnesses. The disease and its complications can result in significant morbidity or event mortality.1Mortality rate is higher in people 65 years of age and older.4

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42

Table 1: Recommended composition of influenza virus vaccines for use in the 201628,29 Southern hemisphere winter

Northern hemisphere winter

1. an A/California/7/2009 (H1N1)pdm09-like virus;

1. an A/California/7/2009 (H1N1)pdm09-like virus;

2. an A/Hong Kong/4801/2014 (H3N2)-like virus;

2. an A/Hong Kong/4801/2014 (H3N2)-like virus;

3. a B/Brisbane/60

3. a B/Brisbane/60/2008like virus.

It is recommended that quadrivalent vaccines containing two influenza B viruses contain the above three viruses and a B/Phuket/3073/2013-like virus/2008-like virus.

It is recommended that quadrivalent vaccines containing two influenza B viruses contain the above three viruses and a B/Phuket/3073/2013-like virus.

Vaccination is particularly important in people with higher risk for influenza-related complications. Such population include children less than five years of (especially less than two years of age), elderly people, pregnant mothers, health care workers, residents of nursing homes and other long-term care facilities, patients with certain medical conditions (e.g. asthma, chronic lung disease, cystic fibrosis, neurological and neurodevelopmental conditions, congenital heart disease, congestive heart failure sickle cell disease, diabetes mellitus, kidney disorders, liver disorders, those with weak immunity etc).

Similarly, Haj pilgrims, people attending Kumbh mela, military personnel, students living boarding schools, prisoners and students going abroad for further studies should also receive vaccination against influenza.25

CHOICE OF INFLUENZA VACCINE

Both inactivated influenza vaccine and nasal spray vaccine i.e. live attenuated vaccine can be used for the prevention of influenza. Live attenuated influenza vaccine is recommended for 2-49 years of age.25 Live attenuated influenza vaccine should not be used in immunocompromized patients. Similarly, in pregnancy live attenuated influenza vaccine is contraindicated.7 In such cases, inactivated influenza vaccine is recommended.

The Center for Disease Control and Preventionâ&#x20AC;&#x2122;s (CDC) Advisory Committee on Immunization Practices (ACIP) has voted against use of live attenuated influenza vaccine for use during 2016-2017 season due to its poor/relatively lower effectiveness.27

NEED FOR ANNUAL VACCINATION

Serum antibodies play an important role in the protection against influenza while mucosal IgA antibodies help in providing resistance against infection. Because of the antigenic drift and antigenic shift, the protective effect of antibody induced by one strain might be decreased or lost over time. This loss of protective function

makes person susceptible for infection either because of the relative or complete unprotected against the new circulating strains.1 Because of these characteristics of the virus, annual vaccination against influenza virus is recommended. Every adult person should be offered influenza vaccination.

WHICH STRAINS?

Continuous surveillance is very important to find out currently circulating, emerging or reemerging strains of influenza virus. The World Health Organization (WHO) through its surveillance centers across collects the data of currently circulating strains of influenza virus and predicts the likely circulating viral strains in the coming season. The WHO reviews the world epidemiological situation twice in year and if necessary recommends new vaccine strain(s) based on the available evidence.

The composition of these likely viral strains is provided to the pharmaceutical companies for manufacturing vaccines. Table 1 gives WHO recommended composition of influenza virus vaccine for use in 2016.

ADVERSE EVENTS WITH INFLUENZA VACCINE

Influenza vaccine is generally very well tolerated. Even if some side effects occur, they are mostly mild and shortlasting in nature. The adverse events associated with the use of nasal vaccine include runny nose, fever, malaise, wheezing, headache, vomiting, sore throat and cough.

Inactivated influenza vaccine may cause local adverse events at the site of injections such as soreness, redness and swelling.25

TIMING OF VACCINATION

The peak of influenza activity differs between different countries. Saha and colleagues conducted to a study to find out influenza seasonality and the best time for influenza vaccination. They examined the weekly influenza surveillance data (2006 to 2011) from different countries including India. Based on the findings, the investigators suggested that most southern and south-eastern Asian countries north of the equator should consider vaccination between April to June. Countries near the equator without a significant peak in influenza activity can base vaccination timing on local factors.30 Another epidemiological study from India also suggests staged timing for vaccination against influenza.31 The peak season for influenza in India is typically the monsoon period. Influenza vaccine should be ideally be given before the initiation of monsoon i.e. in the months of April-May. Second peak of influenza activity is seen during winter season in northern states i.e.

Jammu Kashmir, Himachal and Delhi during NovemberFebruary. Tamil Nadu receives north -east monsoon, so the peak season for influenza activity for this reason is November-February. Generally, for the areas where there is peak of influenza activity in winter season, the vaccine should be administered during September-October and for remaining areas of the country where monsoon is the peak season for influenza activity, vaccine should be administered pre-monsoon i.e. during April-May.25

CONTRAINDICATIONS FOR THE USE OF INFLUENZA VACCINE

Influenza vaccination should not be given to children younger than six months of age, people having known hypersensitivity to the active substance or any other ingredient in the vaccine prepatation, history of chicken egg allergy or history of Gullain Barre Syndrome within six weeks of previous influenza vaccination. People with known egg allergy, need to discuss it with their physician.25 Vaccination should be postponed if the person has acute febrile illness. The vaccine needs to be stored s per the recommended storage conditions.

Influenza vaccination has shown beneficial effects in diabetic patients.11,33 It can reduce complications, hospitalizations and mortality among patients with diabetes.33 Influenza vaccination is also effective in prevention of acute respiratory infections. Vaccination is associated with reduced consultations and hospitalizations in patients with chronic obstructive pulmonary disease.34 In patients with chronic obstructive pulmonary disease, influenza vaccination has been shown to prevent influenza-related acute respiratory infections regardless of the severity of disease.35

NEED FOR IMPROVED AWARENESS ON VACCINE

Though vaccination is an important for prevention of influenza, vaccine uptake is very poor worldwide including in India.36 The rates of vaccine uptake are not only poor in community residents18 but even among the high risk population.37-39 There are several reasons for low uptake of vaccine by the community. Some of the important reasons for the less vaccination rate are low perceived risk among people, availability and access to vaccination, cost of the vaccine and insufficient information about the disease and the vaccine.36 Given the risk of complications and availability of vaccine, coordinated efforts should be done to improve the uptake of vaccine in healthy people as well as those at high risk of infection.

SUMMARY

Influenza is a global health problem. The disease related concerns are more in people with other risk factors such as age or associated chronic diseases. Influenza is associated with significant economic burden, morbidity and even mortality in some cases. Prevention of influenza is important in order to avoid complications. Currently, two types of viruses are available for use; inactivated influenza vaccine and live attenuated vaccine. Spilt viron vaccine provides better effectiveness compared to subunit vaccine. The vaccines are generally very well tolerated.

Live attenuated vaccine should be avoided in pregnancy

43

REFERENCES

1. Influenza. Available at http://www.who.int/biologicals/ vaccines/influenza/en/ accessed on 24th September 2016 2.

Key facts about seasonal flu vaccine. Available at http:// www.cdc.gov/flu/protect/keyfacts.htm. Accessed on 24th September 2016

3.

Kumar V. Influenza in Children. Indian J Pediatr Sep 19.

[Epub ahead of print]

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Influenza. Available at http://www.cdc.gov/vaccines/pubs/ pinkbook/flu.html accessed on 24th September 2016.

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Chadha MS, Broor S, Gunasekaran P, Potdar VA, Krishnan A, Chawla-Sarkar M, et al.

Multisite virological influenza surveillance in India: 20042008. Influenza Other Respir Viruses 2012; 6:196-203.

6.

Calvet HM, Yoshikawa TT. Infections in diabetes. Infect Dis Clin North Am 2001; 15:407-21.

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Casqueiro J, Casqueoro J, Alves C. Infections in patients with diabetes mellitus: A review of pathogenesis. Indian J Endocrinol Metab 2012; Suppl 1: S27-36.

8.

Shah BR, Hux JE. Quantifying the risk of infectious diseases for people with diabetes. Diabetes Care 2003; 26:510-3.

9.

Lau D, Eurich DT, Majumdar SR, Katz A, Johnson JA. Effectiveness of influenza vaccination in workingage adults with diabetes: a population-based cohort study.

Thorax 2013; 68:658-63.

10. Looijmans-Van den Akker I, Verheij TJ, Buskens E, Nichol KL, Rutten GE, Hak E. Clinical effectiveness of first and repeat influenza vaccination in adult and elderly diabetic patients. Diabetes Care 2006; 29:1771-6.

11. Colquhoun AJ, Nicholson KG, Botha JL, Raymond NT. Effectiveness of influenza vaccine in reducing hospital admissions in people with diabetes. Epidemiol Infect 1997; 119:335-41.

12. Bitsori M, Galanakis E. Vaccine-preventable infection morbidity of patients with chronic kidney disease and cocoon vaccinationstrategies. Expert Rev Vaccines 2015; 14:1385-95.

13. Choudhury D, Luna-Salazar C. Preventive health care in chronic kidney disease and end-stage renal disease. Nat Clin Pract Nephrol 2008; 4:194-206.

14. Bond TC, Spaulding AC, Krisher J, McClellan W. Mortality of dialysis patients according to influenza and pneumococcal vaccination status. Am J Kidney Dis 2012; 60:959-65.

15. Koul PA, Khan UH, Asad R, Yousuf R, Broor S, Lal RB, et al.

Contribution of influenza to acute exacerbations of chronic obstructive pulmonary disease in Kashmir, India, 20102012. Influenza Oher Respir Viruses 2015; 9:40-2.

16. Wedzicha JA. Role of viruses in exacerbations of chronic obstructive pulmonary disease. Proc Am Thorac Soc 2004; 1:115-20.

17. Greenberg SB, Allen M, Wilson J, Atmar RL. Respiratory viral infections in adults with and without chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000; 162:167-73.

18. Godoy P, Castilla J, Mayoral JM, Delgado-Rodriguez M, Martin V, Astray J, et al. Smoking may increase the risk of hospitalization due to influenza. Eur J Public Health 2016; Apr 16. pii: ckw036.

CHAPTER 8

BENEFITS OF INFLUENZA VACCINATION

Influenza vaccines are effective in reducing medical complications associated with influenza like illness. The vaccination can also mitigate economic losses by reducing work related loss or reducing absenteeism and avoid losses because of reduced productivity.32

and patients with immunocompromized functions.

44

19. LaSyone L, Hand J, Ratard RC. Intensity of influenzalike illness (ILI) and congestive heart failure (CHF) deaths: A correlation study in Louisiana, 2000-2012. J La State Med Soc 2015; 167:177-82.

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20. Yap FH, Ho PL, Lam KF, Chan PK, Cheng YH, Peiris JS. Excess hospital admissions for pneumonia, chronic obstructive pulmonary disease, and heart failure during influenza seasons in Hong Kong. J Med Virol 2004; 73:61723.

21. Chang TY, Chao TF, Liu CJ, Chen SJ, Chung FP, Liao JN, et al. The association between influenza infection, vaccination, and atrial fibrillation: A nationwide case-control study.

Heart Rhythm 2016;13:1189-94.

22. Duchini A, Viernes ME, Nyberg LM, Hendry RM, Pockros PJ. Hepatic decompensation in patients with cirrhosis during infection with influenza A. Arch Intern Med 2000; 160:113-5.

23. van Riel D, Mittrucker HW, Engels G, Klingel K, Markert UR, Gabriel G. Influenza pathogenicity during pregnancy in women and animal models. Semin Immunopathol 2016; Jul 7. [Epub ahead of print].

24. Heneghan CJ, Onakpoya I, Jones MA, Doshi P, Del Mar CB, Hama R, et al. Neuraminidase inhibitors for influenza: a systematic review and meta-analysis of regulatory and mortality data. Health Technol Assess 2016; 20:1-242.

25. Muruganathan A, Guha S, Munjal YP, Agarwal SS, Parikh KK, Jha V, et al. Recommendations for vaccination against seasonal influenza in adult high risk groups: South Asian recommendations. Supplement to Journal of The Association of Physicians of India Published on 1st of Every Month 1st July, 2016 available at http://www.japi.org/july_2016_ special_issue_recommendations_for_various/01_ recommendations_for_vaccination.pdf accessed on 24th September 2016.

26. Talbot HK, Nian H, Zhu Y, Chen Q, Williams JV, et al. Clinical effectiveness of split-virion versus subunit trivalent influenza vaccines in older adults. Clin Infect Dis 2015; 60:1170–1175.

27. ACIP votes down use of LAIV for 2016-2017 flu season http://www.cdc.gov/media/releases/2016/s0622-laiv-flu. html accessed on 7th October 2016.

28. Recommended composition of influenza virus vaccines for use in the 2016 southern hemisphere influenza season.

Available at http://www.who.int/influenza/vaccines/ virus/recommendations/2016_south/en/ accessed on 24th September 2016.

29. Recommended composition of influenza virus vaccines for use in the 2016-2017 northern hemisphere influenza season.

Available at http://www.who.int/influenza/vaccines/virus/ recommendations/2016_17_north/en/ accessed on 14th June 2016.

30. Saha S, Chadha M, Al Mamun A, Rahman M, SturmRamirez K, Chittaganpitch M, et al. Influenza seasonality and vaccination timing in tropical and subtropical areas of southern and south-eastern Asia. Bull World Health Organ 2014; 92;5:318-30.

31. Chadha MS, Hirve S, Dawood FS, Lele P, Deoshatwar A, Sambhudas S, et al. Burden of seasonal and pandemic influenza-associated hospitalization during and after 2009 A(H1N1) pdm09 pandemic in a rural community in India.

PLoS One 2013; 8:e55918.

32. Poland GA. Valuing influenza vaccine: Medical, economic, and social benefits. Clinical Infectious Diseases 2009; 48:299– 301.

33. Akker ILVD, Verheij TJM, Buskens E, Nichol KL, Rutten GEHM, Hak E. Clinical effectiveness of first and repeat influenza vaccination in adult and elderly diabetic patients.

Diabetes Care 2003; 29:1771–1776.

34. Menon B, Gurnani M, Aggarwal B. Comparison of outpatient visits and hospitalisations, in patients with chronic obstructive pulmonary disease, before and after influenza vaccination. Int J Clin Pract 2008, 62:593–598.

35. Wongsurakiat P, Maranetra KN, Wasi C, Kositanont U, Dejsomritrutai W, Charoenratanakul S. Acute respiratory illness in patients with COPD and the effectiveness of influenza vaccination. A randomized controlled study.

Chest 2004; 125:2011–2020.

36. Sundaram N, Purohit V, Schaetti C, Kudale A, Joseph S, Weiss MG, et al. Community awareness, use and preference for pandemic influenza vaccines in Pune, India. Hum Vaccin Immunother 2015; 11:2376–2388.

37. Bali NK, Ashraf M, Ahmad F, Khan UH, Widdowson MA, Lal RB. Knowledge, attitude, and practices about the seasonal influenza vaccination among healthcare workers in Srinagar, India. Influenza and Other Respiratory Viruses 2013; 7:540–545.

38. Koul PA, Bali NK, Ali S, Ahmad SJ, Bhat MA, Mir H, et al. Poor uptake of influenza vaccination in pregnancy in northern India. Int J Gynaecol Obstet 2014; 127:234-7.

39. Koul PA, Bhat MA, Ali S, Rahim S, Ahmad SJ, Ahmad S, et al. Influenza and pneumococcal vaccination in patients with diabetes. Journal of Diabetology 2014; 2:5.

C H A P T E R

9

Tackling the Challenge of Antibiotic Resistance

INTRODUCTION

The devastating effects of rising antimicrobial resistance (AMR) are emerging all across the world1-6. There may be variation in the pattern of resistance among different countries often experiencing different problems.

Antibiotic resistance is also threatening the advances made in the management of infectious diseases and if actions are not taken, the future generation will have to pay very heavy economic and personal cost.

With progress in the level of living, many people have access to second and third line treatment. The mortatility rate for infections caused by multi drug resistant organism is higher as also the cost of treatment. The problem of rising drug resistance is not limited to developed world. It is as bad or worse in developing countries. This variation is partially related to how liberally they use antimicrobials.

Even a small use of appropriate and limited use of antibiotics can lead to the emergence of drug resistance but if it is overused and misused like in India, the overall situation is much worse. The major problem in India is the availability of drug over the counter without physician prescription and over prescription of antibiotics2. Another problem is that antibiotics are used for longer than prescribed. This situation becomes worse further by the availability of substandard drug entering the market. This happens because of poor control by the governmental authorities. The movement of individuals from one place to another creates new possibilities for antimicrobial pathogens to spread easily. These resistant strains share their genetic material with each other and create new resistance strain at a very fast speed.

Antimicrobial resistance not only increases the mortality, length of hospitalization, but it also increases health cost7.

Methicillin resistance Staphylococcus aureus, extended spectrum beta lactamase producing bacteria have become a major problem all over the world. Multidrug resistant (MDR) and extended drug resistance (XDR) have become a major threat in the developing countries like india.

The need to use antibiotics against these will ensure the spread and prevalence of these and future emerging multidrug resistant microorganism. Once developed the antimicrobial resistance can’t be reversed. This has compelled the investigators and physicians to develop new drugs for difficult to treat MDR and XDR pathogens7.

It is estimated that by 2050, 10 million people will die of AMR every year. This will decrease 2-3.5% GDP. Antimicrobial resistance is also becoming a problem because very few novel antibiotics are being discovered

Rajesh Chawla, Aakanksha Chawla and pace has tremendously slowed down. On the other hand, the antibiotic use is rising8.

HOW DO THE MICROORGANISMS DEVELOP RESISTANCE?

Over the time the bacteria learn to survive antibiotics treatment. Usually the resistance is initiated with a mutation in genetic code or transfer of DNA between bacteria. They survive treatment if the mutations are favourable to them. Then they pass resistance to future generations.

THE PROBLEM

The problem is that the pace of development of antibiotic resistance is faster than the development of new agents to treat these resistant bugs. There is a great need to understand the evolutionary, molecular and ecological mechanism which controls the spread of AMR. So there is need to develop new strategies to tackle this menace of rising AMR. India has a great problem as infectious diseases are major cause of increase mortality. The situation is much worse for nosocomial infections where all antibiotics are becoming ineffective6.

The non human use of antibiotic is also contributing to the emergence of drug resistance9. There is enough evidences that resistant bacteria or their determinants might be passed from animals to humans directly or indirectly through food, environment and during animal husbandry. In some countries antimicrobials are used as growth promoters. Many predict that these could be return of preantibiotic era in some years10.

SUGGESTED MEASURES TO TACKLE RESISTANCE

“Chennai declaration” made after a joint meeting of medical societies of India1 in 2012 recommended a roadmap to tackle antibiotic resistance. There are also major efforts by international countries in this regard.

The fight has to be on multiple fronts which should include government, medical and social organizations and medical community. The health ministry need to formulate required policy to control AMR involving all stake holders, medical council of India and related associations. India needs practical policy and it should be done as early as possible but in a phased manner. The most important factor which will determine the success of this campaign is to create political support. The corrective steps can be taken to reduce AMR as also suggested by Chennai declaration.

•

Adopt a strict policy of antibiotic use particularly of high end antibiotics to begin with.

INFECTION

46

•

There is urgent need to stop over the counter sales.

The government may do this but implementation of this would be greatly difficult so it is essential to equip the department with more manpower to ensure this.

•

The easiest step which can be implemented is to control the use of antibiotics in the hospital. First of all it should be mandatory to have infection control team in every hospital. Infection control team should ensure the following;

-

Monitor all antibiotic use especially high end antibiotic use in the hospital.

-

Have a clear policy and monitor use of high end antibiotic based on current literature.

-

Monitor use of colistin and other newer antibiotic.

After the first dose its use must be endorsed by monitoring team. It is even suggested to get second opinion to endorse usage of high end antibiotic which may not be practical always.

-

•

•

Hospital/pharmacist need to keep a record of higher end antibiotic usage like colistin, Tigecycline , fosfomycin for gram negative and targocid,linzolid,vancomycin for gram positive.

Out of these it is most important to monitor colistin and its use very closely. Any new antibiotic introduced should be included in this list. Infection control committee should not only monitor the data every 3 months but also inform the surveillance data to the treating physicians.

Microbiological laboratories must be stepped up and the number accredited laboratories should be expanded. We will have to find out the low cost diagnostic methods.

National accreditation board of hospitals (NABH) may have a very significant role not only in implementing infection control directives but also antibiotic stewardship policy.The level of compliance NABH accredited hospitals to the antibiotic policy and infection control guidelines should be ensured.. NABH should insist on strict implementation of hospital antibiotic and infection control policy, during re-accreditation processes

•

There is also need of national antibiotic resistance surveillance by india council of medical research and ministry of health as suggested Chennai declaration.

•

Antibiotic stewardship policy should be followed in all hospitals.

•

There is a need for launch a massive, global problem awareness campaign of antibiotic resistance as the problem of resistance is not understood in developing countries.

•

World Health Organization should not only play

an active role in tackling antibiotic resistance. but also co-ordinate initiatives in various countries, provide them technical and financial support.

Since AMR is a global phenomenon so the efforts has to be without worrying about borders.

•

There is a need to improve hygienic and spread of infection. Everyone access to clean water sanitation and encourage people to wash their hands.

•

One of the important steps to be taken is to reduce the use of antibiotic in nonhuman use. 70% of medically useful antibiotics are actually sold for animal use. So it is important to restrict antibiotic sales for animals because lot of resistance comes from the overuse of antibiotic for animals.

•

There is great need of rapid diagnostic test to reduce unnecessary use of antibiotics.

•

There has to be long term attempt to improve the strength and emolument of people working in infectious diseases.

•

The directorate of public health (DPH) / directorate of medical services (DMS)may have important role in implementing infection control and antibiotic stewardship policies in government hospitals and help in establishing district infection control committee.

•

Since infectious diseases courses are available at very few places , Medical council should introduce infectious disease postgraduate degree course at large number of places to have large force to fight infections in the long term.

•

Teaching faculty should be role models for appropriate antibiotic usage. Every efforts should be made to educate youngsters to follow infection cont rol practices.

•

There has to be global collation. A collaboration for joint guidelines and research as infection spread from one country to another.

•

The pharmaceutical industries are not interested in doing research on antibiotics because the lack of great profit so the meaningful incentive are needed to promote antibiotic research by pharma.

•

The threat of AMR is grave if is allowed like this we will have post antibiotic era similar to pre antibiotic era in which the treatment of minor infections,surgery, to major transplant will become extremely difficult. The cost of treatment will rise as we try to use expansive new antibiotic and increase in long time in hospitalization which will lead to extremely high costs.

•

If we want people to survive more ,than a joint effort is needed on a continuation basis. Time to begin it is now.

REFERENCES

1.

Ghafur A, Mathai D, Muruganathan A et al. “The Chennai

6.

Roberts R, Hota B, Ahmad I, Scott RD II, Foster SD. Hospital and societal costs of antimicrobial-resistant infections in a Chicago teaching hospital: implications for antibiotic stewardship. Clin Inf Dis 2009; 49:1175–1184.

2.

UP, Sharma NK, Garg R, Unnikrishnan B, Gopalakrishna HN. A study on the sale of antimicrobial agents without prescriptions in pharmacies in an urban area in South India. J Clin Diagn Res 2012; 6:951-4.

7. Medina E, Pieper DH.Tackling. Threats and Future Problems of Multidrug-Resistant Bacteria. Curr Top Microbiol Immunol 2016 DOI: 10.1007/82_2016_492

3.

Mohamudha PR, Harish BN, Parija SC. Emerging carbapenem resistance among nosocomial isolates of klebsiella pneumoniae in South India. Int J Pharm Biol Sci 2010; 51:1-11.

4.

Laura J. S, Simon J. H, Fowler T,et al.Tackling the threat of antimicrobial resistance: from policy to sustainable action.

Philos Trans R Soc Lond B Biol Sci 2015; 370:1670.

5.

Ling LL, et al. A new antibiotic kills pathogens without detectable resistance. Nature 2015; 517:455–45.

8.

Daulaire N, Bang A. Tomson G, Kalyango JN, Cars O.Universal Access to Effective Antibiotics is Essential for Tackling Antibiotic Resistance. J Law Med Ethics 2015; 43 Suppl 3:17-21.

9.

Watkins RR1, Bonomo RA.Overview: Global and Local Impact of Antibiotic Resistance. Infect Dis Clin North Am 2016; 30:313-22.

10. Appelbaum PC. 2012 and beyond: Potential for the start of a second pre-antibiotic era? J Antimicrob Chemother 2012; 67:2062-8.

47

CHAPTER 9

Declaration” Recommendations of “A roadmap- to tackle the challenge of antimicrobial resistance” - A joint meeting of medical societies of India. Indian Journal of Cancer 2012 ; 49:84-94.

C H A P T E R

10

Bad Bugs, No Drugs: The Saga of Antibiotic Resistance Sandeep Puri, Arshdeep Singh

as a remedy for many illnesses) and presence of active INTRODUCTION The word “antibiotic” was coined by soil microbiologist antimicrobial components in many of the ancient herbal Selman Waksman, the nobel prize-winning discoverer of remedies corroborate that antibiotics were in use much Streptomycin. Antibiotics are among the most important before the advent of ‘antibiotic era’. discoveries of medical science. It is not necessary to reTHE ANTIBIOTIC ERA emphasize the important role antibiotics have played in The foundation of modern antibiotic era is attributed BAD BUGS, NO DRUGS: SAGA OF ANTIBIOTIC RESISTANCE saving millions of lives THE till date.

Anne Sheafe Miller was the to three exemplary discoveries by Paul Ehrlich, Josef first patient to be saved by antibiotics. Medicine had failed Sandeep Puri, Arshdeep Singh Klarer and Alexander Fleming. Ehrlich is credited with Miller. During four weeks of treatment her temperature the discovery of Arsphenamine (Salvarsan; first organic soared above 106 degrees, and no medications, not antisyphilitic); Klarer synthesized Prontosil (Sulfa drug) even sulfa drugs, had broken the fever. She was dying ODUCTION and Fleming discovered Penicillin.5-7 These impeccable of streptococcal septicemia. A sample of Penicillin was milestones in the antibiotic history led to the development The wordarranged “antibiotic” from was coined by soil microbiologist Selmanexpanded Waksman, the Dr. Howard Florey (who onNobel Prize-winning of a number erer of Streptomycin. Antibiotics are among the most important discoveries of medical science.

It is not of new classes of antibiotics, many of which Alexander Fleming’s 1928 discovery of penicillin by sary to re-emphasize the important role antibiotics have played in saving millions of lives till date.

Annetheir Sheafe made way to the patient’s bedside (Figure 1). active ingredient andfailed demonstrating was the firstisolating patient to beits saved by antibiotics.

Medicine had Miller. During four its weeks of treatment her therapeutic properties).

Miller began first theAs is evident erature soared above 106 degrees, and no medications, not evenreceiving sulfa drugs, her had broken fever.

She was in Figure 1, the period from 1950s to 1970s of streptococcal A sample of Penicillin arranged Florey (who expanded on dosesepticemia. via intravenous drip atwas3:30 p.m.from onDr.a Howard Saturday. was the golden age for discovery of new classes of nder Fleming’s 1928 discovery of penicillin by isolating its active ingredient and demonstrating its therapeutic The next morning her temperature, which had hovered antibiotics, with no new structural classes of antibiotics rties). Miller began receiving her first dose via intravenous drip at 3:30 p.m. on a Saturday. The next morning 103 and 106.5 dropped to normal forthe introduced mperature, between which had hovered between 103degrees, and 106.5 degrees, dropped to normal for first time in four between 1970s and 2000, representing a time four weeks.

By eaten Monday her appetite had count serious innovation gap during the genomic era. Therefore, . By Mondaythe herfirst appetite hadinreturned and she had four full meals.

Her bacteria dropped.

(1) owed her last 57 years ofand life toshe antibiotics. returned had eaten four full meals. Her bacteria with the decline in the rate of discovery of new drugs, the 1 count dropped.

Miller owed her lastis 57 years ofoflife main approach of combating resistance in the pathogens Contrary to the popular belief that exposure to antibiotics a benefaction the to modern era, traces of antibiotics. modification of the existing classes of antibiotics. As otics have been found in the skeletal remains of the ancient humans from Africa. (2,3,4) was The presence of otics in the bones can be accounted for only by acknowledging the consumption of these compounds in their a consequence of this ‘discovery void’ and ‘adaptation’ Contrary theantibiotic-like popular belief that to antibiotics Similarly, anecdotes abouttothe properties of exposure red soils in Jordan that were used for ofhistorically pathogenic microbes to the available antimicrobials, is a benefaction of the modern antibiotics ng skin infections, discovery of anti-malarial artemisinin era, from traces Artemisiaof plants (which were used by Chinese antibiotic resistance has emerged as the deepest and the ages as a remedy many illnesses) and the presence of active antimicrobial in many of the ancient haveforbeen found in skeletal remains of components the ancient gravest crisis staring at the medical fraternity worldwide. l remedies corroborate antibiotics were 2-4 in use much before the advent of ‘antibiotic era’.

The presence of antibiotics in the humans that from Africa.

A 2011 national survey of infectious disease specialists, bones can be accounted for only by acknowledging the conducted by the IDSA Emerging Infections Network, ANTIBIOTIC consumption ERA of these compounds in their diet. Similarly, found that more than 60% of participants had seen a pananecdotes about the era antibiotic-like properties ofdiscoveries red soilsby Paul Ehrlich, Josef The foundation of modern antibiotic is attributed to three exemplary resistant, untreatable bacterial infection within the prior in Jordan that were used treating skin and Alexander Fleming. Ehrlich is credited withhistorically the discovery for of Arsphenamine (Salvarsan; first organic year.8 In 2013, the CDC declared that the human race is philitic); Klarer synthesized Prontosil (Sulfaof drug) and Fleming discovered Penicillin.from (5,6,7). These impeccable infections, discovery anti-malarial artemisinin now the “post-antibiotic era,” and the World Health ones in the antibiotic history led to (which the development of a number of new classes of ages antibiotics, manyin of which Artemisia plants were used

by Chinese since their way to the patient’s bedside. (Fig.1) Organization, one year later, warned that the antibiotic resistance crisis is becoming dire.

SUPERBUGS WITH SUPER-RESISTANCE

2000s Oxazolidinones Lipopeptides, Mutilins Fidaxomicin 1940-1970

Diarylquinolones

Sulfonamides, Beta Lactams Tetracyclines, Aminoglycosides Macrolides, Quinolones

Fig. 1:Fig.1 Timeline showing discovery of new antibiotics Timeline showing discovery of new antibiotics

‘Superbugs’ are the microbes associated with significant morbidity and mortality subsequent to multiple mutations conferring high levels of resistance to the antibiotic classes specifically recommended for their treatment. The microbes which acquire this ‘superresistance’ have increased virulence and transmissibility and limited therapeutic options. A superbug infection leads to prolonged duration of hospitalisation as well as increased cost of treatment. These include infections with Acinetobacter baumannii, Burkholderia cepacia, Campylobacter jejuni, Citrobacter freundii, Clostridium difficile, Enterobacter spp., Enterococcus faecium,

expectations and a high background of infections that should ideally be contained by better sanitation and vaccination have contributed to the overuse.

difficile, Carbapenem resistant Enterobacteriaceae, Drug resistant Neisseria gonnorrhoeae. Multidrug resistant Acinetobacter, Pseudomonas, Salmonella, Shigella; drug resistant Streptococcus, tuberculosis, Campylobacter, Candida; extended spectrum beta lactamase producing Enterobacteriaceae (ESBLs) complete the list of ‘serious’ threats. Vancomycin resistant Staphylococcus aureus, erythromycin resistant Group A Streptococcus and clindamycin resistant Group B Streptococcus are the ‘concerning’ threats.9

Sale of Antibiotics in India (2005-2009) 200000 Units of Antibiotics sold x 1000

180000 160000 140000 120000 100000 80000 60000 40000 20000 0

2006

2007

2008

2009

CAUSES OF ANTIBIOTIC RESISTANCE

Antibiotic resistance is a complex problem requiring a Fig.Antibiotic 3. Antibiotic sales in India by type by (12)type12 Fig. 2: sales in India collaborative effort of microbiologist, ecologist, health care specialist, educationist, policy makers, legislative Enterococcus faecalis, Escherichia coli, Haemophilus Epidemiological studies have demonstrated a direct relationship between antibiotic consumption and the bodies, agricultural and pharmaceutical industry emergenceinfluenzae, and dissemination Klebsiella of resistant bacteria strains.

While antibiotic resistance has predominantly been a pneumoniae, Proteus mirabilis, clinical problem in hospital settings, recent data show resistant organisms have also been detected in patients in and the public to deal with. There are no examples of Pseudomonas aeruginosa, Salmonella spp.,a prescription. primary care.

Most of the antibiotics are unregulated and available spp., over theSerratia counter without antibacterial agents against which bacteria have not been Antibiotics Staphylococcus remove drug-sensitive competitors, leavingStaphylococcus resistant bacteria behind toepidermidis, reproduce as a result of natural aureus, selection. This lack of regulation results in prescription of antibiotics that are easily accessible, plentiful, and cheap, able to develop resistance.l9 In the last 15 years, significant Stenotrophomonas maltophilia, and Streptococcus deficiencies have occurred in the development and pneumoniae. availability of new antibiotic (discovery void). Therefore, Among gram-positive pathogens, resistant S. aureus and the implementation of strategies to preserve the activity Enterococcus species currently are the biggest threats. of existing antimicrobial agents has become an urgent Methicillin Resistant Staphylococcus aureus (MRSA) is public health priority. By knowing how resistance evolves amongst the most frequently occurring of all antibiotic and spreads in a population, steps can be introduced to resistant threats. (10) Resistant S. pneumoniae infections prevent or at least delay the spread. are another leading cause of death among adults 50 years The various mechanisms of development of antibiotic of age or older. Nearly one-third of severe S. pneumoniae resistance can be ‘bullet’ or‘target’ related.The ‘bullet’ cases are fully resistant to one or more clinically relevant (drug) related mechanisms are: modification (so antibiotics.(9) M. tuberculosis can also be resistant to one the efficiency is lost, as in the case of acetylation of or more of the first-line drugs. Treatment of drug-resistant aminoglycosides), destruction (as the beta-lactam TB is complex. Extensively drug-resistant TB (XDR-TB) antibiotics by the action of beta-lactamases), and has fewer treatment options available for patients and that expulsion (pumped out from the cell as in efflux pump too at the expense of efficacy.(9) An enzyme called New mechanisms of resistance). Target (microbe) related Delhi metallo-beta-lactamase (NDM-1) is present in some means can be: protection by modification (mutations in gram negative Enterobacteriaceae including E.coli and RNA polymerase conferring resistance to rifampicin; Klebsiella that makes them resistant to virtually all betamodification by an enzyme (methylation of an adenine lactams, including carbapenems. Many of the bacterial residue in 23S rRNA making it insensitive to macrolides); pathogens associated with epidemics of human disease replacement (ribosomal protection proteins conferring have evolved into multidrug-resistant (MDR) forms resistance to tetracyclines); and protection at cellular or subsequent to antibiotic use. Acinetobacter baumannii is a population levels (formation of a protective barrier by more recent nosocomial Gram-negative pathogen, which secretion). derives its infectious properties from its robust survival and biodegradation capabilities in the environment and Overuse of Antibiotics high rates of natural transformation. Recent genome In 2011, the World Health Organisation (WHO) warned: sequence studies have identified at least 28 genomic “Combat Drug Resistance – No Action Today, No Cure islands encoding antibiotic resistance determinants. Tomorrow.” The slogan was coined, urging governments (11) Some strains of MDR P. aeruginosa have been to ensure responsible use of antibiotics in order to prevent found to be resistant to nearly all antibiotics, including drug-resistant viruses and bacteria, or ‘super bugs’. aminoglycosides, cephalosporins, fluoroquinolones, Brazil, Russia, India, China, and South Africa account and carbapenems. However, in terms of the number of for 76 percent of the increase in antibiotic use around infections and consequences, Vibrio cholerae should be at the world. A combination of increasing income and the head of the superbug list. affordability, over the counter availability of antibiotics, The CDC assessed antibiotic-resistant bacterial infections willingness of physicians to prescribe antibiotics freely, according to seven factors: clinical impact, economic patient expectations and a high background of infections impact, incidence, 10-year projection of incidence, that should ideally be contained by better sanitation and transmissibility, availability of effective antibiotics, and vaccination have contributed to the overuse. (Figure 2) barriers to prevention. Based on these, the threat level of each bacterium has been classified as “urgent,” “serious,” or “concerning”. The ‘urgent threats’ include Clostridium

Epidemiological studies have demonstrated a direct relationship between antibiotic consumption and the

CHAPTER 10

2005

49

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50

emergence and dissemination of resistant bacteria strains.

While antibiotic resistance has predominantly been a clinical problem in hospital settings, recent data show resistant organisms have also been detected in patients in primary care. Most of the antibiotics are unregulated and available over the counter without a prescription.

Antibiotics remove drug-sensitive competitors, leaving resistant bacteria behind to reproduce as a result of natural selection. This lack of regulation results in prescription of antibiotics that are easily accessible, plentiful, and cheap, which promotes overuse. Apart from increasing the resistance, antibiotic overuse is associated with increased incidence of more severe diseases, increased duration of the disease, increased risk of complications, increased mortality rate, increased healthcare costs, increased risk of adverse effects and increased medicalization of self-limiting infectious conditions. A reduction in antibiotic consumption leads to a reduction of resistance.

Bergman et al. in their study focusing on macrolide resistant Streptococcus pyogenes showed that a reduction in macrolide use is associated with reduction in antibiotic resistance (9.2% in 1997 to 7.4% in 2000).13

Inappropriate Prescribing

bacteria, allowing antibiotic-resistant bacteria to thrive which are then transmitted to humans and may lead to adverse health consequences. Both resistant bacteria, as well as significant volumes of antibiotics consumed, are then excreted by animals releasing resistant bacteria into the environment as well as causing the environment to be contaminated with antibiotics, providing further opportunities for exposure to bacteria and creating additional selective pressure that leads to the development of drug resistance.

Colistin is the last resort antibiotic against multi-resistant bacteria, especially those resistant to carbapenems. Liu and colleagues examined areas in China where colistin is routinely given to pigs and they found colistin-resistant E. coli in more than 20 percent of animals and in 15 percent of raw meat samples. Among these bacteria, all had colistin resistance that could easily be transferred between different bacteria. They also found that about one percent of hospital patients sampled were infected

by E. coli or Klebsiella bacteria that had the same piece of DNA, making them resistant to colistin too, thereby highlighting the need for a more cautious, preventive approach.16

Antibiotic prescribing is influenced by several factors, including cultural aspects, socio-economic factors, cultural beliefs of the patient and the prescriber and patient demand. According to the CDC vital signs report, about one-third prescriptions to treat urinary tract infections and prescriptions for the critical and common drug vancomycin included a potential error i.e. many patients are given drugs without proper testing or evaluation, or were given drugs for too long. Clinicians in some hospitals prescribed three times as many antibiotics than actually needed. Inappropriately prescribed antibiotics contribute to the promotion of antibiotic resistant bacteria by supporting genetic alterations, such as changes in gene expression, horizontal gene transfer and mutagenesis; which can increase the virulence as well as transmission of the infectious agent. Literature review reveals that indications of antibiotic use, choice of the agent, dose and the duration of antibiotic therapy is incorrect in 30% to 50% of cases. 30% to 60% of the antibiotics prescribed in intensive care units (ICUs) have been found to be unnecessary, inappropriate, or suboptimal.14 These incorrectly prescribed antibiotics have a questionable therapeutic benefit and expose the patients to potential complications of antibiotic therapy including strain diversification in organisms and induction of broad proteomic alterations.15

The vast majority of antimicrobial classes in use today have been isolated in the golden era of antibiotic discovery from a small number of ecological niches and taxonomic groups. So the treatment options for already existing multidrug-resistant bacterial infections are limited, resulting in high morbidity and mortality.

The development of newer antibiotics is driven by two factors: economy and regulations. Investing into the development of newer antibiotics is considered a poor economic decision for a pharmaceutical as antibiotics are not as profitable as drugs that treat chronic conditions.

The net present value (NPV) of a new antibiotic is only about $50 million, compared to approximately $1 billion for a drug used to treat a neuromuscular disease.17 In addition, difficulties in pursuing regulatory approval has essentially stalled the development of new antibiotics, leaving fewer options to treat resistant bacteria.

Extensive Use in Farm Animals

Genetics of resistance

Approximately 80 percent of the antibiotics sold in the United States are used in meat and poultry production.

These are said to improve the overall health of the animals and hence are widely used as growth supplements in livestock to produce larger yield and a higher-quality product. The antibiotics used in livestock are ingested by humans when they consume food. Antibiotic use in food-producing animals kills or suppresses susceptible

Antibiotics (tetracyclines and streptomycin) are also sprayed on fruit trees as pesticides in the west, resulting in a considerable geographical spread and exposure of microorganisms in the environment to growth-inhibiting agents. The precise impact of agricultural antibiotic use on resistance levels in the general population is not known anywhere, but the evidence points to a link.

Lack of New Classes of Antibiotics

The genetics of resistance is a poorly understood subject despite having been studied extensively.

Putative antibiotic r genes are omnipresent in natural environments. Also there are a large number of lowmolecular-weight natural products identified to have antibiotic activity in the laboratory. The science is still ignorant of the roles of millions of low-molecular-weight organic compounds that are produced by bacteria, other

of the adults who seek medical care for viral infections are prescribed antibiotics due to various reasons discussed previously. A 2005 Cochrane review concluded that the only intervention sufficient to impact bacterial resistance was “delayed prescription,” meaning that antibiotic prescriptions are to be filled a few days later if symptoms do not improve.20 The important part is also to comply with the drug use regimen. The contributing factor to the dissemination of antibiotic resistance, even in the case of absolute compliance, may be the practice of empirical prescription of antibiotics.

HOW TO CONTROL OR REDUCE ANTIBIOTIC RESISTANCE DEVELOPMENT

•

Know what types of drug-resistant infections are present in their facility and patients

•

Request immediate alerts when the lab identifies drug-resistant infections

•

Prescribe antibiotics wisely, de-escalate the antibiotics based on culture sensitivity analysis

•

Remove temporary medical devices such as catheters and ventilators as soon as they are no longer needed

•

Develop an antibiotic stewardship programme and institutional antibiotic policy to preserve and properly use existing antibiotics.

Antibiotic resistance is a universal and inevitable phenomenon. Over the years a large number of solutions have been proposed by knowledgeable experts and all the major international health groups. The various proposals for action are discussed.

Development of national action plan and guidelines on antibiotic use: Such action plans serve as a road map to achieve the goal of slowing the emergence of resistant bacteria and prevent the spread of resistant infections.

In June 2016, National Centre for Disease Control in collaboration with Ministry of Health and Family Welfare, Govt. Of India has issued National Treatment Guidelines for Antimicrobial Use in Infectious Diseases.19 International collaboration: At UN, in September 2016, world leaders, for the first time committed to taking a broad, coordinated approach to address the root causes of antibiotic resistance across multiple sectors, especially human health, animal health and agriculture.

This international co-ordination for antibiotic-resistance prevention, surveillance, control, and antibiotic research and development is expected to impact positively on the currently grim scenario.

Establishing a database for antibiotic use and resistance: There is an urgent need to establish methods for surveillance on antibiotic consumption and resistance profiles by microbial species, drug, and date; which can serve as a guide on the future use of antimicrobials.

Avoid inappropriate antibiotic use: Approximately 60%

Addressing antibiotic abuse in farm animals: There is good evidence that use of antimicrobials in farm animals has serious consequences to human health and no clear benefit to farmers, although quantification of this effect is a tough task. Bans on antibiotic abuse in farm animals in the European Union have been accompanied by significant declines in antibiotic resistance in humans and animals.21 Prevention of nosocomial infections: Implementation of the scientific advances to practice to reduce rates of multiple common nosocomial infections including Clostridium difficile–associated diarrhea, ventilator-associated pneumonia, catheter-associated urinary tract infects, selected surgical site infections, and MRSA bacteremia is the need of hour. Inpatient Healthcare Providers need to

Promote development of newer antibiotics: Strict regulatory barriers in the past two decades hampered the research into development of newer antibiotics. However more recently, the regulatory authorities have relaxed the norms which are expected to encourage substantially smaller, less-expensive, and faster clinical trials. Newer approaches for antimicrobial development include: • Manipulating bacterial communication: eg. probiotics

signaling

and

•

Use of antibiotics in combination: eg. efflux pump inhibitors (EPIs) combined with antibiotics

•

Increased sampling in diverse environments and increased application of the techniques of metagenomics

-

To identify bioactive compounds produced by currently unknown and uncultured microorganisms

51

CHAPTER 10

microbes, and plants. However the existing knowledge on the molecular mechanisms of resistance to antibiotics in the animal kingdom suggests that these can be disseminated by one or more gene transfer mechanisms.

Multidrug resistance in bacteria is a result of accumulation of multiple genes, each coding for resistance to a single drug, on R plasmids. The different phenomena associated with resistance development, which have been the focus of interest include: gene pickup, heterologous expression, horizontal gene transfer and mutations. (eg. a random mutation of genes encoding β-lactamase enzymes has lead to the emergence of an increasingly extended spectrum of resistance, a specific rRNA modification that engenders resistance to all antibiotics acting at 50sRNA has been described).18 Integrons are especially powerful in producing multidrug resistance because they assemble several resistance genes in a correct orientation on the R plasmid and provide a strong promoter for their expression. Another mechanism of multidrug resistance is the active pumping out of drugs by multidrug efflux pumps (for example, the RND superfamily pumps in gram-negative bacteria, the MFS, ABC, SMR and MATE superfamilies in both gram negative and gram positive bacteria). These are especially important because they are usually coded by chromosomal genes and can be overexpressed easily. In addition these can pump out most of the antibiotics currently in use.

52

• Development of small-molecule customized for bacterial targets.

libraries

Antibiotic recycling: The use of previously approved drugs and outmoded antibiotics show promise as an alternative combinatorial drug strategy for treating infections caused by drug-resistant bacteria.

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CONCLUSION

Rapidly emerging resistant bacteria threaten the remarkable health benefits that have been achieved with antibiotics. Resistance mechanisms are pandemic and create an enormous clinical and financial burden on health care systems. We need to learn to be more precise in targeting the pathogens and limit the indiscriminate use of antimicrobials. There is no perfect antibiotic, and once the most appropriate use of any new compound is identified, it is essential that prescription of the antibiotic be restricted to that use only. Synchronized efforts to implement new policies, renew research efforts for development of new agents to treat bacterial infections and pursue the preventive strategies to manage the crisis, as discussed, are greatly needed.

8.

Spellberg B, Gilbert DN. The fuure of antibioyics and resistance: a tribute to a career of leadership by John Bartlett. Clin Infect Dis 2014; 59 suppl 2: S71-S75.

9.

Centers for Disease Control and Prevention, Office of Infectious Disease. Antibiotic resistance threats in the United States, 2013. April 2013. Available at: http://www. cdc.gov/drugresistance/ threat-report-2013.

10. Rossolini GM, Arena F, Pecile P, Pollini S. Update on the antibiotic resistance crisis. Clin Opin Pharmacol 2014; 18:5660.

11. Gomez MJ and Neyfakh AA. Genes involved in intrinsic antibiotic resistance of Acinetobacter baylyi. Antimicrob.

Agents Chemother 2006; 50:3562–3567.

12. Ganguly NK, Arora N K, Chandy SJ, Fairoze MN, Gill JS, Gupta U, et al. Rationalizing antibiotic use to limit antibiotic resistance in India +. Indian J Med Res 2011; 134:281-94.

13. Bergman M., Huikko S., Pihlajamäki M., Laippala P., Palva E., Huovinen P., et al. Effect of macrolide consumption on erythromycin resistance in Streptococcus pyogenes in Finland in 1997–2001. Clin Infect Dis 2004; 38:1251–1256.

14. Luyt CE, Brechot N, Trouillet JL, Chastre J. Antibiotic stewardship in the intensive care unit. Crit Care 2014; 18:480.

REFERENCES

1.

http://yalemedicine.yale.edu/autumn1999/features/ capsule/55396/ (Accessed on 9th September, 2016)

15. Viswanathan VK. Off-label abuse of antibiotics by bacteria.

Gut Microbes 2014; 5:3–4.

2.

Bassett EJ, Keith MS, Armelagos GJ, Martin DL and Villanueva AR. Tetracycline-labeled human bone from ancient Sudanese Nubia (A.D. 350). Science 1980; 209:1532– 1534.

16. Liu YY, Wang Y, Walsh TR, et al. Emergence of plasmidmediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study. Lancet Infect Dis 2016; 16:161-8.

3.

Cook M, Molto E and Anderson C. Fluorochrome labelling in Roman period skeletons from Dakhleh Oasis, Egypt. Am J Phys Anthropol 1989; 80:137–143.

4.

Nelson ML, Dinardo A, Hochberg J and Armelagos GJ. Brief communication: mass spectroscopic characterization of tetracycline in the skeletal remains of an ancient population from Sudanese Nubia 350–550 CE. Am J Phys Anthropol 2010; 143:151–154.

5.

Ehrlich P, and Hata S. Die Experimentelle Chemotherapie der Spirilosen. 1910. Berlin: Julius Springer.

6.

Domagk G. Ein Beitrag zur Chemotherapie der bakteriellen Infektionen. Dtsch Med Wochensch 1935; 61:250.

7. Fleming, A. On antibacterial action of culture of Penicillium, with special reference to their use in isolation of B. influenzae. Br J Exp Pathol 1929; 10:226–236.

17. Bartlett JG, Gilbert DN, Spellberg B. Seven ways to preserve the miracle of antibiotics. Clin Infect Dis 2013; 56:1445–1450.

18. Long, K. S., J. Poehlsgaard, C. Kehrenberg, S. Schwartz, and B. Vester. The Cfr rRNA methyltransferase confers resistance to phenicols, lincosamides, oxazolidinones, pleuromutilins, and streptogramin A antibiotics.

Antimicrob. Agents Chemother 2006; 50:2500–2505.

19. www.ncdc.gov.in/writereaddata/linkimages/AMR_ guideline7001495889.pdf. (Accessed on 4th September 2016) 20. Arnold SR, Strauss SE. Interventions to improve antibiotic prescribing practices in ambulatory care. Cochrane Database Syst Rev 2005;19:CD003539.

21. Aarestrup FM, Jensen VF, Emborg HD, Jacobsen E, Wegener HC. Changes in the use of antimicrobials and the effects on productivity of swine farms in Denmark. Am J Vet Res 2010; 71:726-33.

C H A P T E R

11

Gene Therapy for Cure of HIV Infection S Bhagyabati Devi, T Jeetenkumar Singh, Ksh. Birendra Singh

ABSTRACT

The effectiveness of highly active antiretroviral therapy (HAART) has brought about a paradigm shift in transforming HIV infection into a chronic manageable disease. HAART is required to be given life long which needs good adherence as HIV provirus integrated within the infected cells cannot be eliminated and virus replication resumes following its discontinuation. It is well established that HAART is associated with drug toxicities, drug-drug interactions and multiple co-morbid complications like early ageing due to immune activation and inflammatory phenomena. Long term medication with antiretroviral drugs also leads potentially to diseases of cardiovascular, neurocognitive, kidney, liver, and selection of drug resistance viruses which leads to limitation of prolong therapy. To avoid and overcome the inherent limitations of HAART a series of trials and treatment modalities have been tried with a hope to attempt cure of HIV infection. Genetic association studies have served as a powerful means to identify host factors that influence HIV-AIDS pathogenesis in vivo. The most dramatic example of a genetic factor influencing HIV infection and/or pathogenesis relates to the gene that codes for CC chemokine receptor 5 (CCR5), the major HIV co-receptor for cell entry. Gene manipulations could eliminate latent viral reservoirs in HIV infection and further, prevent infection in newly exposed individuals.

Gene therapy strategies are being studied with the endeavour to find cure for HIV.

INTRODUCTION

HIV infection continues to be a major global public health issue with more than 35 million people living with HIV (PLHIV) worldwide.1 In spite of its effectiveness, HAART for HIV disease does have a number of limitations. Antiretroviral drugs do not fully restore health. Chronic inflammation and immune dysfunction often persist indefinitely during ARV treatment leading to increased number of AIDS morbidity and mortality. It does not fully suppress the viral replication as cryptic viral replication persists within dispersed haemato lymphoid organs with potentially significant effects on T cells, myeloid cell homeostasis and function (2). It needs strict adherence to regimes. Even with the massive global investment in HIV cure, access to these drugs will remain incomplete and thus epidemic will continue to spread. Destruction of the immune system by HIV is driven by the loss of CD4 T cells in the peripheral blood and lymphoid tissues. HAART controls the HIV replication and allows the immune system to partially restore and delays disease progression but cure

of HIV infection still remains unachievable with use of the currently available ARV drugs. As ARV cannot eradicate provirus present as reservoirs in latent infected cells as HIV virus will reseed the body once ART is discontinued.

Viral entry into CD4T cells is mediated by the interaction with a cellular chemokine receptor, the most common of which are CCR5 and CXCR4. Subsequent viral replication requires cellular gene expression followed by depletion of activated memory CD4 T cells most of which reside in GI mucosa (3).Most viruses isolated from individuals shortly after sero-conversion and during asymptomatic phase of infection are using CR5 co-receptor while CXCR4 coreceptor using viruses are seen in late stage of infection and are associated with a rapid disease progression and development of AIDS. As HAART cannot completely eradicate HIV, multiple strategies for HAART free treatment are approached by many researches with the aim of achieving (i) sterilizing cure of HIV -eradication and elimination of all replicative competent viruses, (ii) functional cure -undetectable plasma viraemia and (iii) building a host cell which is able to resist initial HIV infection. Since 2009 there is growing interest in development of potentiality curative approaches for HIV infection. An ideal therapeutic cure would be one that is safe, scalable, administered for a limited period of time and prevents infection of all susceptible cells including cells in tissues.

CCR5 is the major co-receptor found in T-cell subsets and is utilized by HIV to gain entry into targeted cells.

It is well established that Individuals lacking functional CCR5 due to the naturally occurring CCR5 Î&#x201D;32 mutation homozygotes are highly resistant to HIV infection and AIDS. Genetic manipulative strategies to make CCR5 receptor in T cells non-functional with an endeavour to prevent attestation of HIV to targeted cells is the basis for the realistic search for cure of HIV.

Inspiration from the Berlin patient

Mr. Timothy Ray Brown - a case of HIV seropositive from Berlin who suffered from acute myeloid leukaemia in whom HIV virus remains undetectable after allogenic stem cell transplantation from a donor having homozygous for the CCR5 Î&#x201D; 32 mutation following aggressive cytoablative chemotherapy (cyclosporine). HAART was stopped before the transplantation. His serum did not show the presence of HIV up to 7 years after transplantation.4-7 This well documented first case of HIV cure gives rise to a hope for new strategies for eradication of HIV infection.

Gene therapy for HIV infection was first proposed by

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54

David Baltimore in 1988 with the term “intracellular immunisation” with an intention to make HIV target cells resistant to virus infection by using anti HIV genes.

In 2007 Gero Hutter an oncologist and haematologist performed the procedure of transplantation for the Berlin patient providing for the first time the real “proof of the concept” of genetic manipulation for the cure of HIV. HIV resistant phenotype is obtained in individuals with the Δ 32 mutation following hematopoietic stem cell transplantation. This gene modified cells are introduced into the patient safely and efficiently. These findings have opened up treatment to many more HIV-infected patients and Sangamo Bio Sciences. Inc has recently taken this approach and applied it to HIV-infected patients. In the most recently published Phase 2 clinical trials, infusion of zinc finger nuclease CCR5 modified autologous CD4 T cells (SB-728-T) has been shown to increase CD4 counts and decreased HIV pro-viral load in HIV infected patients when ARVs are withdrawn during treatment interruption. This findings and the experience with the Berlin patient validates use of genetically modified early cytokines as an effective strategy in finding a “functional cure” for HIV.

inspired attempt to obtain HIV resistant cells through gene therapy. One of the most promising strategies has aimed to disrupt the CCR5 gene by expressing an engineered zinc-finger nucleus (ZFN). ZFNs are an artificial implanted DNA at specific sites in humanised models. It can deliver adenoviral or retroviral vectors or nucleofection.

These genetically modified cells are transferred back into the autologous donor. It can inactivate CCR5 in CD4-T cells and CD34+ hematopoietic stem cells limiting HIV replication.10 Following this study site specific modification of CCR5 gene was made ex vivo, autologous modified CD4+ T cells & subsequently infused back to corresponding patients. These cells harboured a CCR5 gene modified using a ZFN (SB-728-T) to make dysfunctional CCR5 co-receptor. These genetically primed cells can persist in-vivo with a half-life of nearly year and this procedure was safe and the cells could protect from HIV infection.11 To emulate the Berlin patient, the use of cyclophosphamide as a immunomodulatory agent prior to infusion of SB-728-T-1002) is currently being evaluated in ART naive HIV infected individual. There is inherent risk of increase in the percentage of X4 tropic virus which occurs after transplantation most likely driven by pre-existing X4 tropic minority variants. This case highlights the fact that viral escape mechanisms might jeopardize CCR5 knock out strategies to control HIV infection. Thus ZFNs have been designed to simultaneously target CCR5 & CXCR4 as a pilot study showed primary CD4 T cells were resistance to both R5 and X4 viruses.13

Strategies of gene therapy

Gene therapy is focussed on three major steps: 1.

Blocking HIV entry using transduced cells with modified HIV receptors.

a.

Blocking CD4 binding

b.

Blocking co-receptor binding and expression

c.

Blocking membrane fusion

2.

Producing disruption or inactivation of Pro-virus using specific endo nucleases

3.

Inhibiting the expression of integrated genome with RNA decoys.

1.

Blocking HIV entry into Host cells

1a.

Blocking CD4 binding: CD4 plays a crucial function in cellular immunity; Abrogation of CD4 expression is not possible to prevent HIV infection since the final result may lead to lethal immune deficiency in a given patient. Early gene therapy for this technique was done by introducing chimeric T cell receptors (TCR) in cytotoxic CD8T cells allowing them to recognize and kill HIV infected cells. Following promising pre clinical studies two clinical trials was done to investigate the effects of adoptive transfer chimeric TCR-modified CD4+ and CD8+ T cells on HIV infection. In both trials the genetically modified cells successfully engrafted and trafficked to the rectal mucosa, a major site of HIV replication. Both studies however did not show significance reduction in viral load in treated individuals.9

1b.

Blocking co-receptor binding and expression: The apparent cure of the Berlin patient after receiving HSCT from a CCR 5Δ32 homozygous donor have

1c.

Blocking membrane fusion: The final step for HIV entry into target cell is membrane fusion. HIV gp4 is largely responsible for membrane fusion. It contains two heptad repeat domains (HRI & HR2) downstream of the N-terminal fusion peptide.

Enfuvirtide (T20) was the first entry inhibitor approved for HIV treatment.C46 member anchored form is another gp41 mimetic peptide also inhibit HIV entry. Safety and a modest antiviral effect were recognized in a phase 1 clinical trial. A study on animal model using pigtailed macaque model mC46 for modelling functional cure strategies was presented at CROI 2014.Following these encouraging preclinical data, a phase I/II clinical trial named safety study of a dual anti HIV gene transfer construct to Treat HIV1 infection (clinical trials gov NCT 01734850) looked at the experimental gene transfer Cal-1 (LVsh 5/C46).

This agent is designed to inhibit HIV infection by removing CCR5 from bone marrow & peripheral blood mononuclear cells and also by producing C46 that mimics of gP41. Amino acid peptide from the C terminal heptad repeat -2 domain of gp41, named C34 has been designed for inhibition of CCR5 & CXCR(4) HIV+ tropic strain.14 Engineering primary CD4 + T cells provides trans-dominant

and heterologous resistance to diverse HIV1isolates. Cross-clade protection leads to survival and selective expansion of C34COR HIV resistant, functional CD4+T cells that can be expanded ex-vivo and adoptively re-infused represents a promising and innovative approach with the potential to control HIV infection in humans.15 2.

Inhibiting the expression of integrated genome with RNA decoys: RNA base factor approaches like antisense RNAs, RNA decoys, ribozymes, aptamers and sh/siRNAs have investigated as anti HIV gene therapy. It finds the target protein due to their three dimensional structure.17 Two RNA decoys have been tested to inhibit HIV replication.

Those are 1. Rev response element (RRE) and 2.

Trans-activating region hairpin at the 5-end of viral mRNA transcripts that binds viral Tat protein. HIV provirus has several essential genes and a long single-reading frame gag-pol transcript encoding multiple proteins thereby giving many excellent targets for gene disruption. Further the infected CD4 cells in majority have only one provirus copy suggesting that gene disruption might only need to target one provirus per infected cell. Therefore, a provirus directed anti-HIV agent could be the clue toward HIV cure.

CONCLUSION

Antiviral drugs have been successful in containing HIV infection and making it a chronically manageable disease, yet it cannot achieve complete eradication of the virus from the reservoir. The pursuit for a cure for HIV is making significant stride. Gene therapy proves to be a unique and realistic option as clinically proven by Berlin patient. There are many strategies of manipulating gene by targeting multiple stages of viral cycle with an attempt to disrupt and/or inactivate the genetically reserve viral material in HIV patients to ultimately achieve functional or possibly sterilizing cure. HSCT from donor with 32bp mutated CCR5 receptor or gene editing using nucleases are approaches being studied with encouraging results.

Gene therapy may hold the key for a cure for HIV.

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CHAPTER 11

3.

Producing disruption or inactivation of Pro-virus using specific endo nucleases: Endonucleases could disrupt and inactivate gene expression from an integrated lentiviral reporter provirus. Trerecombinase can excise integrated HIV from host cell chromosome and has shown potent antiviral effect. There is a need for focus on development of rare cutting endonucleases that can target essential HIV genes.16 Endonucleases like TALENs & CRISPR-Cas could disturb & inactivate gene expression from an integrated lentiviral receptor protein.20

therapy for HIV disease. Cell Stem Cell 2012; 10:137-47.