SARJ Vol 22, No 2 (2016) by HMPG

ISSN 2304-0017

SouthAfrican African South

Respiratory Respiratory Journal Journal VOLUME 22

NUMBER 2

South African

Respiratory

Journal

OFFICIAL JOURNAL OF THE S.A. THORACIC SOCIETY

JUNE 2016

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S4 FOXAIR® 50/250 and 50/500 ACCUHALER® - 42/21.5.4/0582; 0583. Each blister contains a mixture of salmeterol xinafoate equivalent to 50 µg of salmeterol and microfine fluticasone propionate (250 µg or 500 µg). Applicant: GlaxoSmithKline South Africa (Pty) Ltd. (Co. Reg. No. 1948/030135/07). 39 Hawkins Avenue, Epping Industria 1, Cape Town, 7460. For full prescribing information plese refer to the package insert approved by the Medicines Regulatory Authority. All adverse events should be reported by calling the Aspen Medical Hotline number or directly to GlaxoSmithKline on +27117456000. FO/0713/933 A16772 08/13

THE SOUTH AFRICAN

RESPIRATORY JOURNAL VOLUME 22 | NUMBER 2 | JUNE 2016

CONTENTS EDITORIAL 34

Cystic fibrosis: The urgent need to report on mutations among patients of African descent A Wonkam

ORIGINAL ARTICLE

An analysis of outcomes in children with cystic fibrosis in a tertiary African centre: A retrospective study R E M Mphahlele, V Naidoo, S Thula, R Masekela

REVIEW 38

Diphtheria and the respiratory system: Lessons from the 2015 outbreak M Annamalai

CASE REPORT

The different faces of pulmonary hydatid disease S A Thula, M Ndlovu, R Masekela

BREATH-TAKING NEWS

WHO’S WHO

50 52

PRODUCT NEWS SATS CONGRESS 2016

SARJ EDITOR-IN-CHIEF Prof. K Dheda DEPUTY EDITOR Prof. C Koegelenberg SECTION EDITOR Breath-taking News: Prof. E Irusen EDITORIAL BOARD Prof. G Ainslie, Prof. E Bateman, Prof. R Green, Prof. E Irusen, Prof. M Jeebhay, Prof. P Jeena, Prof. U Lalloo, Prof. A Linegar, Prof. R Masekela, Dr K Nyamande, Dr J O’Brien, Dr R Raine, Prof. G Richards, Dr R van Zyl Smit, Prof. M Wong, Prof. H Zar INTERNATIONAL EDITORIAL BOARD Prof. Adithya Cattamanchi - USA Prof. Fan Chung - UK Prof. GB Migliori - Italy Prof. Surendra Sharma - India Prof. Wing Wai Yew - China PRESIDENT SA THORACIC SOCIETY Prof. U Lalloo

HMPG

CEO AND PUBLISHER Hannah Kikaya Email: hannahk@hmpg.co.za EXECUTIVE EDITOR Bridget Farham MANAGING EDITORS Ingrid Nye, Claudia Naidu PRODUCTION MANAGER Emma Jane Couzens DTP AND DESIGN Carl Sampson CHIEF OPERATING OFFICER Diane Smith | Tel. 012 481 2069 Email: dianes@hmpg.co.za JOURNAL ADVERTISING Charles Duke, Reneé van der Ryst, Ladine van Heerden ONLINE SUPPORT Gertrude Fani | Tel. 021 532 1281 Email: publishing@hmpg.co.za FINANCE Tshepiso Mokoena

The Editor The South African Respiratory Journal PO Box 13725, Mowbray, 7705 Telephone: 021 650 3050, Fax: 021 650 2610, Email: sarj@iafrica.com The views expressed in individual articles and advertising material are the personal views of the authors and are not necessarily shared by the editors, the advertisers or the publishers. No articles may be reproduced without the written consent of the publishers. The SARJ is published by the Health and Medical Publishing Group (Pty) Ltd, Co. registration 2004/0220 32/07, a subsidiary of SAMA. HEAD OFFICE: Block F, Castle Walk Corporate Park, Nossob Street, Erasmuskloof Ext. 3, Pretoria, 0181 EDITORIAL OFFICE: Suites 9 & 10, Lonsdale Building, Gardener Way, Pinelands, 7405 | 021 532 1281 All letters and articles for publication must be submitted online at www.sarj.org.za E-mail: publishing@hmpg.co.za

HMPG BOARD OF DIRECTORS Prof. M Lukhele (Chair), Dr M R Abbas, Dr M J Grootboom, Mrs H Kikaya, Prof. E L Mazwai, Dr M Mbokota, Dr G Wolvaardt PRINTED BY TANDYM PRINT

EDITORIAL

Cystic fibrosis: The urgent need to report on mutations among patients of African descent In this SARJ issue, Mphahlele et al.[1] have reported on a condition that is being increasingly diagnosed in people of African descent: cystic fibrosis (CF). The article will contribute to rectifying the misconception that this condition is restricted to people of European descent and underscore the need to further investigate the mutations specific to people of African descent. The delayed age of diagnosis, specifically among patients of African descent, further illustrates the need to educate health professionals, to improve their awareness and raise their index of suspicion of CF in patients of African ancestry. The research also emphasises the need to initiate newborn screening for CF, which has been shown to be critical in identifying the condition in non-white patients in the USA.[2] In the Mphahlele et al.[1] study, the absence of any detected mutation in almost all the non-white patients is consistent with the literature, as this is expected with the currently used 30-mutation CFTR panel for which the diagnosis rate of CF in non-European populations is very low.[2] However, mutations in CFTR in South Africans of black African ancestry were first reported 2 decades ago;[3] a specific mutation found in black South Africans, 3120+1G>A, which was initially reported in three African-American CF patients, has been shown to account for 9 - 14% of African-American CF chromosomes.[4] This mutation (3120+1G>A) is now routinely tested for in selected medical genetic settings in South Africa (SA).[5] The investigation of specific CFTR mutations in various populations of non-European ancestry is gaining increasing attention globally, especially in countries that, like SA, have a population of diverse ethnic background, such as Reunion Island,[6] Brazil[7] and the USA.[2] This research is shedding light on ethnic-specific variants that cannot be detected by the routinely used 30-mutation CFTR panel. It is, therefore, reasonable to call for urgent further studies using the full sequencing of the CFTR gene in patients

34 SARJ VOL. 22 NO. 2 2016

of non-European ancestry in SA, in Africa and globally, to reveal more specific mutations that will increase the diagnostic validity and yield of the molecular testing of the CFTR gene. A well-designed CFTR expanded panel using ethnic-specific variants is desirable to improve CF carrier detection rates within specific populations in SA, specifically in populations of African ancestry. Ambroise Wonkam Division of Human Genetics, Department of Medicine, Faculty of Health Sciences, University of Cape Town, South Africa ambroise.wonkam@uct.ac.za 1. Mphahlele REM, Naidoo V, Thula S, Masekela R. An analysis of outcomes in children with cystic fibrosis in a tertiary African centre: A retrospective study. S Afr Respir J 2016;22(2):35-37. DOI:10.7196/SARJ.2016.v22i2.76 2. Pique L, Graham S, Pearl M, Kharrazi M, Schrijver I. Cystic fibrosis newborn screening programs: Implications of the CFTR variant spectrum in non-white patients. Genet Med 2016;May. DOI:10.1038/gim.2016.48 3. Carles S, Desgeorges M, Goldman A, et al. First report of CFTR mutations in black cystic fibrosis patients of southern African origin. J Med Genet 1996;33(9):802-804. DOI:10.1136/jmg.33.9.802 4. Padoa C, Goldman A, Jenkins T, Ramsay M. Cystic fibrosis carrier frequencies in populations of African origin. J Med Genet 1999;36(1):41-44. DOI:10.1111/j.1399-0004.1994.tb04405.x 5. Goldman A, Graf C, Ramsay M, Leisegang F, Westwood AT. Molecular diagnosis of cystic fibrosis in South African populations. S Afr Med J 2003;93(7):518-519. 6. Marion H, Natacha G, Brigitte M, et al. The p.Gly622Asp (G622D) mutation, frequently found in Reunion Island and in black populations, is associated with a wide spectrum of CF and CFTR-RD phenotypes. J Cyst Fibros 2015;14(3):305-309. 7. Faucz FR, Souza DA, Olandoski M, Raskin S. CFTR allelic heterogeneity in Brazil: Historical and geographical perspectives and implications for screening and counselling for cystic fibrosis in this country. J Human Genet 2010;55(2):71-76

S Afr Respir J 2016;22(2):34. DOI:10.7196/SARJ.2016.v22i2.78

ORIGINAL RESEARCH

An analysis of outcomes in children with cystic fibrosis in a tertiary African centre: A retrospective study R E M Mphahlele, MB ChB; V Naidoo, Cert Pulm (SA)(Paeds); S Thula, FCPaeds; R Masekela, PhD Department of Maternal and Child Health, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa Corresponding author: R E M Mphahlele (mphahleler@ukzn.ac.za)

Background. Cystic fibrosis (CF) is a common genetic disorder in the white population that has become increasingly prevalent in populations of black African descent. Black African children with CF commonly present with nutritional and growth abnormalities. Objectives. To describe the characteristics of children followed up at the CF clinic at Inkosi Albert Luthuli Central Hospital, South Africa (SA). Methods. A retrospective chart review of clinical, laboratory and spirometric data of patients registered from January 2013 to January 2016. Results. Fifteen patients’ data were reviewed. Their mean age was 132 months (range 26 - 219) and 53% were male. Sixty percent of these children were white and 26.6% were black African. Collectively, the mean age at diagnosis was 45 months (range 0 - 156), although this was higher in non-whites: 104 months (range 48 - 156) v. whites 1.3 months (range 0 - 3). The white group had better nutritional status with body mass index (BMI) of 17.2 kg/m2 compared with 14.5 kg/m2 for non-whites. Age at diagnosis had a negative correlation with weight-for-age z-score (–0.61, p<0.05) and body mass index (BMI) (–0.54, p<0.05). The mean predicted forced expiratory volume in 1 second (FEV1%p) was 70.0 (range 16.1 - 120.2). FEV1%p had a positive correlation with weight z-score (0.83, p<0.001) and BMI (0.59, p<0.05). Five of the non-white patients had no mutations identified on the 30-mutation panel test. Conclusion. CF is diagnosed late in non-white children in SA, affecting their growth and lung function. A genetic panel that includes mutations specific to children of African descent is required. S Afr Respir J 2016;22(2):35-37. DOI:10.7196/SARJ.2016.v22i2.76

Cystic fibrosis (CF) is an autosomal recessive disorder common in white people, which has an increasing prevalence among people of African descent. In South Africa (SA), CF affects 1:2 000 white, 1:4 624 mixed-race and 1:12 000 black people.[1] It is caused by mutations in the CF transmembrane conductance regulator gene located on chromosome 7q31.[2] This results in impaired chloride transport across cell membranes causing characteristic respiratory and gastrointestinal symptoms. The typical clinical presentation is that of recurrent chest infection due to poor airway clearance of mucus, and failure to thrive because of pancreatic insufficiency. This phenotypic presentation has been shown to be different in the context of the SA population, of whom the majority are black African or of mixed-race descent. These populations commonly present with failure to thrive and protein energy malnutrition.[3] Early diagnosis of CF prevents severe malnutrition and improves long-term growth.[4] In CF, nutrition and growth are determinants of lung health and, ultimately, survival.[5] As a result of improved treatment in recent years, pulmonary function is reported to be better in children who are diagnosed with CF earlier in life.[6] Data from various SA CF centres have shown improvements in lung function[7] and nutritional status[8,9] when compared with previous years, thought to be largely owing to earlier diagnosis, and improved treatment and diagnostic strategies. Concerning the genetic diagnosis of CF, the most common mutation is phelF508.del, which accounts for 81% of mutations in whites.[10] It is less common in mixed-race populations, where it accounts for 53% of mutations, and is rarely found in black South Africans. The most common mutation in black South Africans is 3120+1G>A, with a carrier rate of 1:90.[1] At least 1 000 babies are

expected to be born with CF in SA each year, but with a detection rate of only 46%, most are missed by conventional genetic mutation testing panels.[3] This not only reduces confirmation of CF in black patients but the use of genetic-based prognostic measures and treatment opportunities. In the clinical course of CF, Pseudomonas aeruginosa colonisation has been reported to affect growth and lung function, with those colonised at a higher risk of deteriorating lung health.[11] P. aeruginosa status, mean predicted forced expiratory volume in 1 second (FEV1%p), age and sex have all been shown to predict mortality in children with CF.[11,12] CF is not a condition confined to a single population. Understanding the differences and similarities in diagnosis, presentation and clinical course is a necessity in the southern African context. We therefore undertook a study to describe the clinical, laboratory and spirometric characteristics of a representative clinic population in KwaZulu-Natal (KZN) Province, SA.

Methods

Study population A retrospective chart review of all patients attending the CF clinic at Inkosi Albert Luthuli Central Hospital, Durban between the period January 2013 and January 2016 was conducted. All patients attending the clinic during this period were included in the study. Clinical investigations Clinical data collected included age at diagnosis, current age, gender, weight, height, body mass index (BMI), race and z-scores for weight, height and BMI (calculations according to World

SARJ VOL. 22 NO. 2 2016

ORIGINAL RESEARCH

Laboratory investigations Data collected included sweat test (Gibson and Cooke, with measurement of sweat chloride), genotype test (30-mutation panel test; Elucigene, UK) and sputum microbiology including colonisation status of the respiratory tract. Chronic colonisation was defined as the persistence of a pathogen on two or more sputum samples over a period of 6 months, as per Leeds criteria.[14] Spirometry Pulmonary function tests were conducted for all patients over the age of 6 years; this study reported on FEV 1%p. The highest FEV 1%p value for the most recent year that the patient was seen during the study period was reported for each patient. Date of birth, gender and height, at the time of lung function test, were recorded for calculation of prediction values. Recorded spirometry test results were prebronchodilator values. Data analysis Data were recorded and stored using Excel, Microsoft Office Professional Plus 2013 (USA). Data were analysed using Stata 13.0 (StataCorp, USA). Means were calculated for age, weight, height, BMI and FEV1%p. Pearson correlation was used for comparing non-categorical variables, with p<0.05 considered significant. Ethical clearance Ethical approval to access patient records was obtained from the Biomedical Research Ethics Committee of the University of KZN (Ref. BCA469/15).

Results

Data were reviewed for a total of 15 patients, with mean age 132 months (range 26 - 219), 53% of whom were male. Forty percent of the children were non-white: 26.6% of black African descent, 6.7% Indian and 6.7% mixed race. Collectively, the mean age of diagnosis was 45 months (range 0 - 156) (Table 1). On mutational analysis, five of the nonwhite patients had no mutations identified on the 30-mutation panel used for testing.

36 SARJ VOL. 22 NO. 2 2016

phelF508.del was the most commonly identified mutation in the clinic. Of the white population, four were heterozygote, four homozygote and one unknown. One non-white patient was heterozygote and of mixed-race descent (Table 1). Age at diagnosis (Fig. 1) was higher in non-whites, at a mean age of 104 months (8.6 years) (range 48 - 156 months) compared with whites at a mean age of 1.3 (range 0 3) months. Age at diagnosis had a negative correlation with weight-for-age z-score (–0.61, p<0.05) and BMI (–0.54, p<0.05). The non-white group had poorer nutritional status than the white group, with mean BMI 14.5 kg/m2 v. 17.2 kg/m2, respectively. The mean FEV1%p for the study population was 70.0 (range 16.1 - 120.2) (Table 2). FEV1%p was positively correlated with weight z-score (0.83, p<0.001) and BMI (0.59, p<0.05). Table 1. Demographics of children with CF Variable

n (%)

Gender (male/female)

8/7 (53/47)

Mean age at diagnosis (months) 45

Only three patients from the study population were chronically colonised with bacterial pathogens. One of these, with chronic Haemophilus influenzae colonisation, had a low FEV1%p of 49.9, BMI 16.6 kg/m2 and intermittent Staphylococcus aureus growth on sputum. Chronic P. aeruginosa infection occurred only in two patients, both of whom were >16 years old. One of these patients was an 18-year-old male with a last recorded FEV1%p of 31.0 and BMI 15.6 kg/m2. His FEV1%p fell by 18% during the 7-month lung function recording period before his death. The other patient was 16 years old, malnourished (BMI 14.7 kg/m2) with FEV1%p of 27.9%, and previously colonised with S. aureus and Candida albicans.

Discussion

CF is a life-limiting condition that has encouraged a considerable amount of research, the bulk of which is undertaken in Western and developed countries, with developing countries such as SA following suit. The diverse populations within SA have presented a broader spectrum for the manifestation of CF.

Ethnic group White

9 (60.0)

Black African

4 (26.6)

Indian

1 (6.7)

Mixed race

Table 2. Comparison of age at diagnosis, lung function and growth between white and non-white children Variable

White Non-white

1 (6.7)

Age at diagnosis (months), mean

1.3

104.0

Heterozygous phelF508.del

5 (33.3)

Weight-for-age z-score

–1.8

–3.5

Homozygous phelF508.del

4 (26.7)

FEV1%p, mean

77.9

56.1

Negative

5 (33.3)

BMI (kg/m ), mean

17.2

14.5

Unknown

1 (6.7)

Weight z-score

1.7

–3.6

Mutations

Percentage, %

Health Organization guidelines).[13] Weight and height data were collected on the same day as lung function tests were performed. Age was calculated to the time at which data were collected in January 2016.

100 90 80 70 60 50 40 30 20 10 0

67 56 44 33

0 <1 month

1 mo - 1 yr

1 - 5 yr Age

Non-white (n=6)

White (n=9)

Fig. 1. Comparison of age at diagnosis in non-white v. white children.

>5 years

ORIGINAL RESEARCH Validating other studies, we show that there is a correlation between lung function, growth and age at CF diagnosis.[4-6] We have also shown that for almost half of the population of our clinic, all of whom are black, recognition of CF is difficult, leading to late diagnosis and detrimental effects on disease progression.[15] There may be many reasons for this, including a high prevalence of poverty-associated conditions with similar presentation, i.e. protein energy malnutrition, HIV infection and tuberculosis, which affect the black population in SA to a considerable extent.[3] Another reason may be a high threshold for suspicion, as CF is not common in this population. One study in a Western country showed that features associated with late diagnosis were pancreatic insufficiency and certain genotypes.[16] In addition, the definitive diagnosis of CF is difficult in this same population, with the current commercial 30-mutation panel proving too narrow for diagnosis.[17] There is a great need for research in this field, as research into the treatment and prognosis of CF currently focuses on individual mutations in patients.[18,19] Despite our small patient cohort, we were able to observe a trend in morbidity and mortality associated with increasing age and P. aeruginosa colonisation.[11] The only patient who died in this study was severely undernourished, had P. aeruginosa colonisation and a yearly FEV1%p decline of 18% – all clinical predictors of mortality.[11,20,21] Some aspects of CF are similar across populations.[22] However, knowledge about CF in the black population is limited. Despite the small numbers, this study highlights how this field requires dedicated research, with SA in an optimal position for this.

Conclusion

CF is diagnosed late in children of non-white origin in SA, and this negatively affects both their nutritional and pulmonary function outcomes. The current genetic panel misses a large number of mutations in the non-white population and, thus, research in this area is required. Acknowledgements. We would like to acknowledge Mrs Ashleigh Robertson from the KZN CF association for her assistance with tracing a number of the patients. References

1. Padoa C, Goldman A, Jenkins T, Ramsay M. Cystic fibrosis carrier frequencies in populations of African origin. J Med Genet 1999;36(1):41-44. 2. Riordan JR, Rommens JM, Kerem B, et al. Identification of the cystic fibrosis gene: Cloning and characterization of complementary DNA. Science 1989;245(4922):10661073. DOI:10.1126/science.2475911

3. Masekela R, Zampoli M, Westwood A, et al. Phenotypic expression of the 3120+1G>A mutation in non-Caucasian children with cystic fibrosis in South Africa. J Cyst Fibros 2013;12(4):363-366. DOI:10.1016/j.jcf.2012.11.003 4. Farrell PM, Kosorok MR, Rock MJ, et al. Early diagnosis of cystic fibrosis through neonatal screening prevents severe malnutrition and improves long-term growth. Pediatrics 2001;107(1):1-13. DOI:10.1542/peds.107.1.1 5. Peterson ML, Jacobs DR, Milla CE. Longitudinal changes in growth parameters are correlated with changes in pulmonary function in children with cystic fibrosis. Pediatrics 2003;112(3):588-592. DOI:10.1542/peds.112.3.588 6. Wang SS, O’Leary LA, FitzSimmons SC, Khoury MJ. The impact of early cystic fibrosis diagnosis on pulmonary function in children. J Pediatr 2002;141(6):804-810. DOI:10.1067/mpd.2002.129845 7. Morrow BM, Argent AC, Zar HJ, Westwood AT. Improvements in lung function of a pediatric cystic fibrosis population in a developing country. J Pediatr (Rio J) 2008;84(5):403-409. DOI:10.2223/jped.1829 8. Westwood AT, Ireland JD. Children with cystic fibrosis in South Africa: An improving nutritional picture. J Trop Pediatr 2000;46(2):119-121. DOI:10.1093/tropej/46.2.119 9. Van der Spuy DA, Cader S, van der Spuy GD, Westwood AT. Improving nutritional status of children with cystic fibrosis at Red Cross War Memorial Children’s Hospital. J Paediatr Child Health 2011;47(5):282-286. DOI:10.1111/j.1440-1754.2010.01954.x 10. Goldman A, Labrum R, Claustres M, et al. The molecular basis of cystic fibrosis in South Africa. Clin Genet 2001;59(1):37-41. DOI:10.1034/j.1399-0004.2001.590106.x 11. Emerson J, Rosenfeld M, McNamara S, Ramsey B, Gibson RL. Pseudomonas aeruginosa and other predictors of mortality and morbidity in young children with cystic fibrosis. Pediatr Pulmonol 2002;34(2):91-100. DOI:10.1002/ppul.10127 12. Kerem E, Reisman J, Corey M, Canny GJ, Levison H. Prediction of mortality in patients with cystic fibrosis. N Engl J Med 1992;326(18):1187-1191. DOI:10.1056/ nejm199204303261804 13. World Health Organization. WHO Child Growth Standards: Length/height-for-age, Weight-for-age, Weight-for-length, Weight-for-height and Body Mass Index-for-age: Methods and Development. Geneva: WHO, 2006. 14. Proesmans M, Balinska-Miskiewicz W, Dupont L, et al. Evaluating the ‘Leeds criteria’ for Pseudomonas aeruginosa infection in a cystic fibrosis centre. Eur Respir J 2006;27(5):937-943. 15. Sims EJ, Clark A, McCormick J, Mehta G, Connett G, Mehta A. Cystic fibrosis diagnosed after 2 months of age leads to worse outcomes and requires more therapy. Pediatrics 2007;119(1):19-28. DOI:10.1542/peds.2006-1498 16. McCloskey M, Redmond A, Hill A, Elborn J. Clinical features associated with a delayed diagnosis of cystic fibrosis. Respiration 2000;67(4):402-407. DOI:10.1159/000029538 17. Goldman A, Graf C, Ramsay M, Leisegang F, Westwood A. Molecular diagnosis of cystic fibrosis in the South African population. S Afr Med J 2003;93(7):518. 18. Ramsey BW, Davies J, McElvaney NG, et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med 2011;365(18):1663-1672. DOI:10.1056/nejmoa1105185 19. Ratjen FA. Cystic fibrosis: Pathogenesis and future treatment strategies. Respir Care 2009;54(5):595-605. DOI:10.4187/aarc0427 20. Sharma R, Florea V, Bolger A, et al. Wasting as an independent predictor of mortality in patients with cystic fibrosis. Thorax 2001;56(10):746-750. DOI:10.1136/ thorax.56.10.746 21. Milla CE, Warwick WJ. Risk of death in cystic fibrosis patients with severely compromised lung function. Chest 1998;113(5):1230-1234. DOI:10.1378/chest.113.5.1230 22. Hamosh A, FitzSimmons SC, Macek Jr M, Knowles MR, Rosenstein BJ, Cutting GR. Comparison of the clinical manifestations of cystic fibrosis in black and white patients. J Pediatr1998;132(2):255-259. DOI:10.1016/s0022-3476(98)70441-x

SARJ VOL. 22 NO. 2 2016

REVIEW

Diphtheria and the respiratory system: Lessons from the 2015 outbreak M Annamalai, MB BCh, DCH (SA), Dip HIV Man (SA), Dip Allerg (SA), FCPaed (SA), Cert Pulm (SA) Paeds Department of Paediatrics, Stanger Regional Hospital, Stanger, South Africa Corresponding author: M Annamalai (medeshni@yahoo.com)

South Africa experienced a diphtheria outbreak in KwaZulu-Natal Province between March and August 2015. Diphtheria is a contagious and potentially life-threatening bacterial disease caused by the toxigenic strains of Corynebacterium diphtheriae. S Afr Respir J 2016;22(2):38-42. DOI:10.7196/SARJ.2016.v22i2.75

Outline of the 2015 Kwa-Zulu Natal Province diphtheria outbreak

In March 2015, the National Institute of Communicable Diseases (NICD) in South Africa (SA) received a case report of an 8-year-old boy confirmed to have Corynebacterium diphtheriae pharyngitis at Inkosi Albert Luthuli Central Hospital (IALCH), Durban, SA.[1] The patient presented with an acute severe illness, with a massively swollen neck, marked drooling and in respiratory distress. A whitish membrane was noted covering the uvula. The patient required an emergency tracheostomy and was transferred to the paediatric intensive care unit. The patient was treated with penicillin, gentamycin and metronidazole. Diphtheria antitoxin (DAT) was not indicated at the time of presentation. The parent confirmed that the child had received all the diphtheria-containing vaccines until 18 months of age but had missed the 6-year booster vaccine. The National Health Laboratory Services laboratory at IALCH isolated C. diphtheriae from his clinical samples and the isolate was

positive for the toxin production.[1] The patient unfortunately died on 22 March 2015.[1] According to the NICD, by July 2015 there were four reported deaths from diphtheria. In May 2015, the Japanese Ministry of Health, Labour and Welfare organised the nationwide collection and donation of 416 vials of the freeze-dried diphtheria equine antitoxin ‘Kaketsuken’ (with an approximate value of ZAR2 million). Japan is one of only three countries globally that currently manufactures the DAT. By June 2015, there were 15 reported cases. Of these, 10 were confirmed cases, 2 were probable and 3 were possible, with no further cases under investigation[2] (refer to case definition below). The cases were reported from two of the 11 districts in KwaZulu-Natal (KZN) – Ugu and Ethekwini (Fig. 1). The age of the cases ranged from 4 to 41 years old (median 10 years). Children under 15 years of age accounted for the majority (73% (11/15)). Of these, 40% were aged between 5 and 9 years (6/15) and males accounted for 60% (9/15).

District: Ugu Ethekwini

Cases, n

March

April

May

Fig. 1. Epidemic curve illustrating the number of diphtheria cases by date of illness onset and district, KZN, March - 19 June 2015.[2]

June

Date of onset

38 SARJ VOL. 22 NO. 2 2016

REVIEW In the under-22 years age group (n=13), the vaccination history was known for 35% (5/13) of cases. Of these, only one with probable diphtheria had received all age-appropriate diphtheria-containing vaccine doses.[2] There were three asymptomatic carriers of laboratory-confirmed toxigenic C. diphtheriae. Two of these were epidemiologically linked to two confined areas in Margate (siblings from the same family). The other carrier was epidemiologically linked to a possible case from Umlazi.[2] In August 2015, the NICD released the molecular epidemiology results of the C. diphtheriae outbreak isolates and performed molecular sequencing on isolates from the outbreak. Two novel sequence types were identified, neither of which were related to any other sequence type listed in the global database.[3] Seventeen toxin-producing isolates from the cases and contacts had the same sequence type (ST-378). A second cluster comprised the four non-toxigenic KZN isolates and one of a group of historical non-toxigenic clinical isolates from 1980. These five isolates were of the same sequence type (ST-395).[3] The NICD concluded that it was not yet possible to determine the origin of these outbreak strains, as there were no data describing circulating genotypes in SA.[3]

Pathophysiology of diphtheria

C. diphtheriae is a non-sporulating, Gram-positive bacillus. The name is derived from korynee, meaning ‘club’ – referring to its clubbed ends. Diphtheria describes the ‘leather-hide’ characteristic leaky pharyngeal membrane that is formed.[4] The species is subdivided into four biovars – gravis, intermedius, mitis and belfanti. Currently there are 86 ribotypes of toxigenic and non-toxigenic C. diphtheriae. C. diphtheriae exotoxin production depends on the presence of a lysogenic Β-phage, which carries the gene encoding for the toxin.[4] Humans are the only known reservoir for C. diphtheriae. It is spread by airborne respiratory droplets and direct contact with either respiratory secretions or infected skin lesion exudate.[4]

Clinical manifestations of respiratory tract diphtheria

C. diphtheriae infection occurs locally in the respiratory tract or skin due to non-invasive infection. Absorption and dissemination of diphtheria toxin result in bacteraemia, endocarditis and arthritis. The incubation period ranges from 2 to 4 days with local symptoms and signs of inflammation, described as follows:[4] • Anterior nasal infection. Infection of the interior nares presents with a serosanguinous or seropurulent nasal discharge. There may be a whitish mucosal membrane present particularly on the septum. The discharge can incite an erosive reaction on the external nares and upper lip. Symptoms are usually mild.[4] • Faucial infection. Pharyngeal fauces, the posterior mouth and proximal pharynx are the common sites for clinical diphtheria. Onset is over several days, with a low-grade fever, malaise and sore throat. Toxin elaboration locally induces a dense necrotic coagulum. Removal of this adherent grey-brown ‘pseudomembane’ reveals a bleeding, oedematous submucous. The underlying softtissue oedema and cervical adenitis can result in a characteristic bull-neck appearance, stridor and respiratory embarrassment.[4]

• Laryngeal and tracheobronchial infection. Laryngeal infection may begin de novo or spread from the pharynx. Presentation includes hoarseness, a brassy cough, stridor and dyspnoea. Oedema and membrane formation result in respiratory embarrassment, severe respiratory distress and cyanosis. Immediate membrane removal and intubation are required to prevent death.[4]

Epidemiology of diphtheria

Diphtheria is endemic in certain countries in Asia, Africa and South America. The World Health Organization (WHO) reported 7 321 cases of diphtheria worldwide in 2014 (Table 1). Table 1. WHO-reported cases of diphtheria in different regions of the world from 2010 to 2014.[5] Reported diphtheria cases per annum, n Region

2014

2013

2012

2011

2010

Africa

128

Americas

South-east Asia

7 217

4 080

3 953

5 179

4 120

Europe

Eastern Mediterranean

392

334

352

154

Western Pacific

142

153

Global

7 321

4 680

4 490

5 626

4 573

In 1990, a major epidemic occurred in some of the countries of the former Soviet Union. Over 157 000 cases and 5 000 deaths were reported.[6] In SA between January 2008 and March 2015, three laboratoryconfirmed cases of respiratory diphtheria were reported. Two of these were from Western Cape Province and one from Eastern Cape Province. These were followed by the KZN case in March 2015.[1]

Case definition and classification: NICD May 2015[7]

Clinical case definitions The clinical case definition for respiratory diphtheria is a person who presents with an upper-respiratory tract illness characterised by sore throat, low-grade fever and an adherent membrane of the nose, pharynx, tonsils or larynx. Other presentations of diphtheria include patients presenting with: • mild respiratory symptoms but no membrane, • skin lesion, with C. diphtheria, C. ulcerans or C. pseudotuberculosis isolated from a nasopharyngeal swab or skin lesion swab, or • rare presentations such as endocardial, laryngeal, conjunctival, otic or genital diphtheria. Laboratory diagnostic criteria confirmation is by isolation of toxinproducing C. diphtheriae/C. ulcerans/C. pseudotuberculosis from a clinical specimen. Case classification • Suspected case: a person who meets the clinical case definition for respiratory diphtheria and has no laboratory confirmation and

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no epidemiological link to a laboratoryconfirmed case. Probable case: a person who meets the clinical case definition for respiratory diphtheria plus one of the following: • Isolation of C. diphtheriae/C. ulcerans/ C. pseudotuberculosis but with toxigenicity status not yet confirmed • An epidemiological link with a laboratory-confirmed case or a person who presents with mild respiratory symptoms with no membrane or other presentations of diphtheria, but has an epidemiological link to a laboratory. Confirmed case: a person who meets the clinical case definition for respiratory diphtheria and is laboratory confirmed or a person presenting with mild respiratory symptoms with no membrane or other presentations of diphtheria and is laboratory confirmed. Symptomatic carrier: a person with no symptoms but for whom there is laboratory confirmation of a toxigenic strain. Discarded: a suspected or probable case in whom other compatible organisms are isolated or C. diphtheriae/ C. ulcerans/C. pseudotuberculosis is isolated but is confirmed to be a nontoxigenic strain.

In June 2015, a new category was added:[2] • Possible case:[2] a person who meets the clinical case definition for respiratory diphtheria and has no epidemiological link to a laboratory-confirmed case. This definition accommodates a typical clinical presentation with a negative swab.

Diphtheria treatment

Diphtheria antitoxin DAT is a hyperimmune antiserum produced in horses. DAT reduces mortality from 7% to 2.5%. It is critical for the antibody to be administered as soon as a clinical diagnosis is made and before laboratory confirmation, as the antibodies will only neutralise the toxin before it enters the cell. The American Academy of Pediatrics recommends 20 000 to 40 000 units for pharyngeal or laryngeal disease of 48 hours’ duration or less; 40 000 to 60 000 units for nasopharyngeal lesions; and 60 000 to 120 000 units for extensive disease of 3 or more days’ duration or patients with

40 SARJ VOL. 22 NO. 2 2016

brawny swelling of the neck. Hypersensitivity to horse serum must be assessed first.[4] Antibiotic therapy Penicillin and erythromycin are generally recommended. By killing the organism, the antibiotic terminates toxin production, ameliorates local infection and prevents spread to uninfected contacts.[4]

Diphtheria vaccination in SA

Diphtheria toxoid was developed in 1921 and has been used routinely since 1940. Diphtheria toxoid is combined with tetanus toxoid (DT) as a paediatric or adult formulation (Td) and with acellular pertussis vaccine as DTaP and TDap. The paediatric formulation contains three to four times as much diphtheria toxoid as the adult dose.[8] Diphtheria serum concentrations of 0.01 - 0.1 IU/mL are thought to confer protection.[4] Data from one outbreak showed that 90% of clinical cases had antitoxin levels below 0.01 IU/mL.[4] In the same outbreak, 92% of asymptomatic carriers had concentrations above 0.1 IU/mL.[4] After immunisation, antitoxin levels decline slowly, so that up to 50% of adults over 60 years of age have serum titres below 0.01 IU/mL. Therefore, booster doses are recommended every 10 years.[4]

Postulates for the decreasing incidence of diphtheria in the West

A number of postulates have been put for ward to explain the decreasing incidence of diphtheria in the West: • Historical evidence suggests diphtheria occurs in cycles of 100 years or more. • Organisms isolated from immunised individuals are less likely to be toxigenic than from those who are unimmunised. • Local elaboration of toxin, in the absence of antibody, enhances an organism’s ability to colonise, and immunisation with toxoid could counteract this selective advantage of toxigenic strains. • Virulence factors other than toxin production may exist. • Protection may correlate with lower serum concentrations of antitoxin levels or immune mechanisms that are untested.[4] In the diphtheria epidemic in the former Soviet Union, 50% of cases occurred in

individuals aged 15 years or older. This suggested that the young were protected by infant immunisation and older people were vulnerable because of lack of childhood immunisation or fading antibody levels.[2] Good paediatric immunisation schedules appear to be sufficient for keeping toxigenic strains from circulation and causing adult disease. Efficient immunisation programmes require 90% coverage to remain effective.[4] The SA paediatric immunisation pro gramme provides DTaP in a hexavalent combination vaccine at 6, 10 and 14 weeks of age and at 18 months of age. Two booster doses of TD are given at 6 and 12 years of age. In addition, Td vaccine is administered to individuals who have had tetanus-prone injuries. WHO and the United Nations Children’s Fund (UNICEF) estimated national im munisation coverage in SA in 2014 to be approximately 80% for DTP1 and 70% for DTP3[9] (Figs 2 and 3). SA has ensured universal access to vaccines, and rapid introduction of new vaccines into the national Expanded Programme of Immunisation; however, without highquality surveys, the uncertainty of vaccine coverage in SA remains a challenge.[10]

Effect of immigrants and refugees on an immunisation programme

South Africa (SA) offers free routine childhood immunisations to all children irrespective of nationality. SA border controls check for all routine vaccinations in individuals entering the country but not routine childhood vaccination. Immigrants may be uneducated about immunisation, have preconceived ideas about it or be unaware of local protocols. An Australian study conducted in 2011 reported that immigrant children from east Africa are likely to be inadequately immunised. Patient recall was also unreliable, as it did not correlate with serum antibody levels. [11] Another immigrant study in Minnesota, USA found that 81.1% of refugees lacked the necessary documentation for having received the three doses of diphtheria and tetanus vaccines. Documentation rates were lowest for refugees from sub-Saharan Africa.[12] A study carried out in Israel analysed immigrants from the former Soviet Union. Of males between 17 and 19 years of age,

REVIEW 100

120 000

90 100 000

80 000 Cases, n

60 50

60 000

40 40 000

Immunisation coverage (%)

20 000

10 0 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

Year Number of cases

Official coverage

WHO/UNICEF estimates

Fig. 2. Global annual reported cases of DTP3 coverage between 1980 and 2014.[5]

Fig. 3. World map of immunisation coverage with DTP3 vaccine in infants in 2014.[5] 4.8% had antitoxin antibody levels below the protective level of 0.01 IU/mL. The research also found that the immigrants appeared more susceptible to diphtheria, and recommended they receive booster doses of diphtheria toxoid.[13] However, an analysis in Greece of eastern European immigrants’ diphtheria status actually found lower immunity rates among Greek adults. It was suggested that Greek adults had no natural contact with toxigenic strains of Corynebacteria and recommended they receive booster doses, to reduce their risk of acquiring toxigenic strains from individuals who may carry the

bacteria without exhibiting clinical disease.[14] SA should consider developing its policies and programmes to offer immunisation to all immigrants. Healthcare providers should be vigilant in providing immunisations when these children do present to healthcare facilities. The introduction of an adult booster vaccine every 10 years is also suggested.

International postepidemic surveys

Post-European epidemic Resurgence of diphtheria in Europe in 1990 was thought to be caused by a number

of factors: there were many unnecessary contraindications to vaccination; the breakup of the Soviet Union led to large-scale population movements; and there was lack of adequate supplies and disruption to health services.[9] Following that outbreak, a number of identified strategies were implemented to decrease the incidence of diphtheria. These included the following: • The introduction by some European countries of adult booster vaccination every 10 years, or as part of a programme to administer Td vaccine for tetanusprone injuries[9] • The introduction of adult vaccination surveys by the Latvian government[9] • Greater attention given to checking the vaccination records of high-risk groups. In Latvia, new recruits into the military were given the diphtheria vaccine where appropriate.[9] Post-Dominican Republic epidemic In 2004 - 2005, the largest diphtheria outbreak this century in the western hemisphere occurred in the Dominican Republic and Haiti.[15] In contrast to the outbreak in the former Soviet Union, children aged 1 - 4 years were the most at risk. Children living in low-income urban areas with difficult access to vaccination were affected. The main factor in the outbreak was a low vaccine coverage rate (<90%). The outbreak resulted in revision of the diphtheria case definition and epidemiology case investigation procedure. Protocols for clinical management protocols and laboratory specimen collection were updated and widely distributed, with laboratory diagnostic capabilities improved. Management of diphtheria and access to the DAT was improved.[15]

Insights from the KZN diphtheria outbreak

Following the KZN diphtheria outbreak, a number of areas of vulnerability to future outbreaks were identified: • Power outages due to ‘load-shedding’ of electricity have resulted in an unreliable vaccine cold chain. • SA has limited financial capacity for vaccine surveillance. • SA continues to have <90% vaccine coverage. • The presence of illegal and legal immigrant and refugee population

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groups poses a risk of introducing pockets of unvaccinated individuals. Children who do not attend school or clinics may miss out on routine and catch-up immunisation programmes. Poor maternal education and lack of access to healthcare because of financial difficulty or residence in remote areas promotes noncompliance with the local vaccine schedule. Diphtheria is not endemic in SA, so a stock of the DAT is not maintained. Diphtheria booster vaccines are not offered to adults routinely every 10 years.

The SA response to the epidemic was as follows: • The NICD case definition was updated. • The SA diphtheria guidelines and laboratory guidelines were updated and widely distributed. • Vaccine campaigns were implemented in KZN to administer booster vaccine and catch-up immunisations. • Antimicrobials were provided to contacts. • The epidemic was widely publicised in the media to increase public awareness. • The KZN Department of Health, University of KZN, NICD and a consultant from the WHO are reviewing the epidemic to determine appropriate future interventions. • Emergency access to DAT was obtained by humanitarian assistance from Japan. • The KZN Department of Health led widespread education programmes. • The NICD has requested that all laboratories submit stored or prospectively identified Corynebacterium isolates to them for molecular characterisation.[3] In summary, the KZN diphtheria outbreak has highlighted factors that make SA vulnerable to disease outbreaks, but has also shown that collaborative effort and far-sightedness may be able to prevent or

42 SARJ VOL. 22 NO. 2 2016

limit future outbreaks. SA needs to maintain a robust immunisation programme with high-level surveillance programmes. References

1. National Institute of Communicable Diseases. Communicable Diseases Communiqué 2015;14(3). http://www.nicd.ac.za/assets/files/NICD-NHLS (accessed 22 February 2016). 2. National Institute of Communicable Diseases. Communicable Diseases Communiqué 2015;14(6). http://www.nicd.ac.za/assets/files/NICD-NHLS (accessed 22 February 2016). 3. National Institute of Communicable Diseases. Communicable Diseases Communiqué 2015;14(8). http://www.nicd.ac.za/assets/files/NICD-NHLS (accessed 22 February 2016). 4. MacGregor R, Bennett JE. Corynebacterium diphtheria. In: Dolin R, Blaser MJ (eds). Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases, 8th ed. Philadelphia: Elsevier; 2015:2366-2372. 5. World Health Organization. Global Health Observatory Data Repository. Geneva: WHO, 2015. http://apps.who.int/gho/data/view.main (accessed 2 April 2016). 6. Wagner KS, White JM, Lucenko I, Mercer D, Crowcraft NS, et al. Diphtheria in the post-epidemic period, Europe 2000 - 2009. Emerg Infect Dis J 2012;18(2):217-225. DOI:10.3201/eid1802.110987 7. National Institute of Communicable Diseases. Recommendations for the Management and Public Health Response to Diphtheria, Version 1. Johannesburg: Division of Public Health Surveillance and Response, NICD, National Health Laboratory Service, 2015. 8. Centers for Disease Control and Prevention. Epidemiology and Prevention of VaccinePreventable Diseases – The Pink Book. 13th ed. Atlanta, Georgia: CDC, 2015:107-118. 9. World Health Organization and United Nations Children’s Emergency Fund. Estimates of National Immunisation Coverage. Geneva: WHO, 2015. http://apps. who.int/gho/data/view.main (accessed 2 April 2016). 10. Madhi SA, Bamford L, Ngcobo N. Effectiveness of pneumococcal conjugate vaccine and rotavirus introduction into the SA public immunisation programme. S Afr Med J 2014;104(3Suppl1):228-234. DOI:10.7196/samj.7597 11. Paxton GA, Rice J, Davie G, Carapetis JR, Skull SA. East African immigrant children in Australia have poor immunisation coverage. J Paediatr Child Health 2011;47(12):888892. DOI:10.1111/j.1440-1754.2011.02099.x 12. Lifson AR, Thai D, Hang K. Lack of immunization documentation in Minnesota refugees: Challenges for refugee preventative health care. J Immigr Health 2001;3(1):47-52. 13. Low M, Almog R, Green MS, et al. Immune status against diphtheria among immigrants from the former USSR who arrived in Israel during 1990 - 1991. Infection 1998;26(2);104-108. DOI:10.1007/bf02767769 14. Pournaras S, Tsakris A, Hadjichristodoulou C, et al. Diphtheria immunity of Albanian and other eastern European immigrants in Greece compared with the local population – the risk of re-emergence in Greece. Infection 1999;27(6):361-364. DOI:10.1007/s150100050044 15. Garib Z, Danovaro-Holliday CM, Tavarez Y, Leal I, Pedreira C. Diphtheria in the Dominican Republic: Reduction of cases following a large outbreak. Pan Am J Pub Health 2015;38(4):292-299.

CASE REPORT

The different faces of pulmonary hydatid disease S A Thula, FCPaeds; M Ndlovu, MB BCh; R Masekela, PhD Division of Paediatric Pulmonology, Department of Maternal and Child Health, Nelson R Mandela School of Clinical Medicine, University of KwaZulu-Natal, Durban, South Africa Corresponding author: R Masekela (masekelar@ukzn.ac.za)

Hydatid disease is responsible for causing cystic disease. In children, it classically involves the liver, lung and brain but can involve almost any organ or numerous organs simultaneously. The lung is the most common target organ in children, while in adults hepatic involvement is more common. We present three case reports of children who presented with hydatid disease with varying clinical manifestations of pulmonary hydatidosis and complications, and their related management. S Afr Respir J 2016;22(2):43-45. DOI:10.7196/SARJ.2016.v22i2.74

Case presentations

Case 1 The first case is an 11-year-old boy referred to our hospital for the assessment of ring lesions seen on X-ray. He was from a rural area of KwaZulu-Natal Province. He had a 3-month history of cough, fever and loss of appetite. He had no history of tuberculosis (TB) contact. On examination he was wasted, had tachypnoea and had bilateral crackles in both lung fields. The rest of the system examination was normal. His chest X-rays showed bilateral well-circumscribed round lesions (Fig. 1). The enzyme-linked immunosorbent assay (ELISA) HIV test was negative and sputum microscopy sensitivity and culture revealed no pathogens. The hydatid indirect haemagglutinin assay was positive and the full blood count smear showed eosinophilia. A diagnosis of bilateral diffuse echinococcosis was made. The thoracic surgeons were consulted; however, because of the extent of the disease, with multiple lesions bilaterally, the agreed therapeutic option was a trial of medical treatment, as the lesions were inoperable. Medical management was then instituted with albendazole 400 mg/day for 6 months. The follow-up X-rays showed dramatic improvement of the lesions and good resolution. Case 2 A 5-year-old boy was referred from rural Eastern Cape Province for assessment of a suspected non-resolving pleural effusion. The parents gave a history of progressively worsening symptoms of a tight chest and breathlessness on exertion over the past 3

Fig. 1. Chest X-rays of Case 1: (A) pre-treatment; and (B) post-treatment. years. He had been diagnosed with asthma by numerous general practitioners but the symptoms had not improved on treatment. On clinical examination, he had respiratory distress with tachypnoea, bilateral wheezes over both lung fields and decreased air entry. The remaining systems were normal. The chest X-ray revealed an almost complete white-out of the right hemithorax with an air-fluid level (Fig. 2). He had been suspected of having a pleural effusion/empyema at the referral hospital and this had been drained, with clear blood-tinged fluid aspirated. The full blood count smear showed eosinophilia. The hydatid indirect haemagglutination assay was highly positive. Computed tomography (CT) scan confirmed the presence of a large cystic lesion with a thick wall and air-fluid levels (Fig. 3). Ultrasound did not show any

Fig. 2. Chest X-ray of Case 2 showing almost complete white-out of the right hemithorax and an air-fluid level, as well as obliteration of the right main bronchus. The blue arrow indicates a large cyst involving the entire right hemithorax with no midline shift. lesions in the liver. The child was referred to cardiothoracic surgeons, the lesion operated and a cyst removed (Fig. 4).

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CASE REPORT

Fig. 4. Cyst removed surgically in Case 2, measuring 13 cm.

Fig. 3. Axial (A) and coronal (B) views showing large, well-circumscribed cystic lesion in the right hemithorax with air-fluid levels. (A) CT axial view with arrow demonstrating thick-walled rightsided cyst. (B) Coronal view with arrow demonstrating large right-lung cyst. Case 3 The final case was a 12-year-old male from rural Eastern Cape, referred for the assessment of a mediastinal mass and a query of hydatid cyst. The history was that of weight loss and chest pain present for 3 months. There was no history of TB contact and the child was confirmed as HIV-negative. On clinical examination he had a respiratory rate of 25 breaths per minute with a symmetric chest shape, poor air entry bilaterally and dullness to percussion. Chest X-ray showed bilateral masses, with a large circular lesion occupying almost the entire right hemithorax and a smaller round lesion in the left upper lobe with air-fluid levels (Fig. 5). CT scan confirmed multiple cystic masses in the left and right hemithoraces. Full blood count revealed eosinophilia and the Echinococcus indirect haemagglutination assay was positive. Thoracic surgeons were consulted and during surgery it was evident that the left-side cyst was infected and collapsed (Fig.â&#x20AC;&#x201A; 6). The patient received albendazole for 1 month post surgery. The left-side cyst was removed a month later.

Discussion Pulmonary hydatid disease is caused by the tapeworm Echinococcus. The two common

44 SARJ VOL. 22 NO. 2 2016

types of Echinococcus prevalent in South Africa (SA) are E. granulosus and E. multilocularis. The life cycle of these worms includes a definitive and intermediate host (Table 1) and Echinococcus infection is found worldwide. In some parts of Canada (Ontario) about 50% of moose are infected with the parasite, while dog infestation is estimated to be 28 - 50% in the same area.[1] In SA, the disease is prevalent in Limpopo, Eastern Cape, North West and Northern Cape provinces.[2] Retrospective National Health Laboratory Service inforÂ mation system results for serology, microscopy and histopathology from eight provinces (excluding KwaZulu-Natal) gave an overall positivity rate in submitted diagnostic samples of 17.0% (1 056/6 211), with Eastern Cape leading at 30.4%, North West 19.0% and Northern Cape 18.0%.[3,4] The life cycle of the Echinococcus worm begins with the host animal shedding, via its faeces, a mature segment full of eggs. The eggs are picked up by herbivores (intermediate host), where the eggs hatch in the small intestine and grow to a larval stage, known as an oncosphere. Oncospheres penetrate the small intestine and are then transported to the liver and other organs via the portal and lymphatic systems. The oncospheres grow into cysts in the organs of the intermediate host. The cysts enlarge

Fig. 5. Chest X-ray of Case 3: (A) arrow shows a large, intact, right-sided, well-circumscribed cyst; and (B) arrow shows a ruptured left-sided cyst with air-fluid levels.

Fig. 6. Collapsed right-sided cyst on removal. slowly and create protoscolices and daughter cysts. The definitive hosts are infected by eating the infected organs of the intermediate host. The protoscolices grow into adult worms on reaching the small intestine of the host animal. Handling soil or consuming drinking water infested by the eggs may incidentally infect humans. The larvae penetrate the intestines, and enter the portal and lymphatic systems into the liver and other organs. Pulmonary echinococcosis is the most common manifestation and presentation site for children with hydatid disease and may present as either alveolar or mediastinal

CASE REPORT

Table 1. The life cycle of two different types of Echinococcus worm and hosts involved Organism

Definitive host

Intermediate host

E. granulosus

Dogs and other canines

Sheep and goats, other herbivores

E. multilocularis

Dogs and foxes

Rodents

disease, or both. These cases illustrate the difficulty that may confront a doctor in approaching the patient with hydatid disease. The presentation may mimic other common diseases such as TB and asthma, and the doctor should be aware of these, with a high index of suspicion in patients who present with cystic lesions. The vast majority of pulmonary cysts in children are congenital. In endemic areas, Echinococcus must always be in the differential diagnosis as a secondary cause of lung or mediastinal cysts.[4] The diagnosis of Echinococcus infection is usually made by serological tests. Indirect haemagglutination test and indirect fluor escent antibody tests have sensitivity ranging from 60% to 90%; therefore, patients may be missed using these tests.[6] ELISA assays were found to have a high sensitivity at 97% but are poor in differentiating the serological infection type.[5] Radiological investigations should include a chest X-ray, and chest CT scan where complications are suspected, in unusual presentations or for presurgical planning. Liver cysts can be diagnosed on ultrasonography. Chest X-ray features include solitary or multiple cysts in the lung or in the middle mediastinum. CT scan features include multiple or solitary cysts with well-defined

borders, in uncomplicated cases. The contents are hypodense when compared with the capsule. In complicated cases, CT scan may present with the following features:[6] • Meniscus or air crescent sign: describes the crescent of air that can be seen in the hydatid cyst. This usually results during enlargement of the cyst, when the cyst ruptures into an adjacent bronchus and air enters between the pericyst and endocyst. • Cumbo or onion-peel sign: air between the endocyst and pericyst in addition to rupture of the cyst with air tracking into the endocyst. This creates a double air layer appearance. • Water-lily sign: detachment of the endocyst membrane resulting in floating membranes within the pericyst that mimic the appearance of a water lily. The treatment of choice is surgical enucleation of the cyst. Where this is not possible, as in our first case report, medical therapy with albendazole should be considered as first-line treatment. Chemoprophylaxis with albendazole is also indicated pre- and postsurgical intervention. Another important learning point is that in patients treated for

suspected pleural effusions, as in the second case report, it is critical that an alternative diagnosis is entertained on non-resolution of symptoms, and further investigations should be performed. The prognosis of hydatid disease depends on a number of factors, and is better with low internal complexity of the cyst and small cyst size. With proper diagnosis and treatment, outcomes are good.

Conclusion

Healthcare providers working in areas with high prevalence of hydatidosis should be aware of the possibility of this condition being present in patients presenting with respiratory complaints. Other target organ involvement should be excluded, particularly in adults. References

1. Grosso G, Gruttadaria S, Biondi A, Marventano S, Mistretta A. Worldwide epidemiology of liver hydatidosis including the Mediterranean area. World J Gastroenterol 2012;18(13):1425-1437. DOI:10.3748/wjg.v18.i13.1425 2. Wahlers K, Menezes CN, Wong ML, Zeyhle E, Ahmed ME, et al. Cystic echinococcus in sub-Saharan Africa. Lancet Infect Dis 2012;12(11);871-880. DOI:10.1016/ s1473-3099(12)70155-x 3. Mogoye KB. Human Echinococcus in South Africa. MMed dissertation, Johannesburg: University of the Witwatersrand, 2013. 4. Mogoye B, Menezes CN, Grobusch MP, Wahlers K, Frean J. Human cystic echinococcosis in South Africa. Onderstepoort J Vet Res 2012;79(2):e1. DOI:10.4102/ ojvr.v79i2.469 5. Centers for Disease Control. Echinococcus. http:// www.cdc.gov/parasites/echinococcus/ (accessed 30 March 2016). 6. Morar R, Feldman C. Pulmonary echinococcus. Eur Resp J 2003;21:1069-1077. DOI:10.1183/09031936.03 .00108403

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BREATH-TAKING NEWS

Do we need more tools in the management of bronchiolitis or are only oxygen, salt water and a cool head required? Acute bronchiolitis is a common cause of lower respiratory tract infection and is associated with considerable morbidity. There is an increase in the number of hospitalisations and, because of the improved quality of neonatal care, a number of neonatal intensive care unit (ICU) graduates present with this illness. Prophylactic therapy with palivizumab is not curative and its use is extremely limited in low- to middle-income countries, resulting in a number of children presenting with bronchiolitis, particularly in the respiratory syncytial virus season. A subset of these children may develop severe disease without identified risk factors. As the majority are seen at a primary healthcare level, there is a need to find tools that can assist in the prediction of disease severity. Capnography is used in the assessment of percutaneous end-tidal CO2 (ETCO2) measurements and is useful for the measurement of ventilation, perfusion and acid base status. Jacob et al.[1] conducted a prospective, single-blind cohort study in children younger than 2 years presenting to the emergency department (ED) with bronchiolitis. Their primary outcome was the correlation between the ETCO2 and the clinical decision of hospital admission and discharge. Their secondary outcome measure was the correlation of ETCO2 upon arrival at the ED and clinical measures of bronchiolitis severity. They enrolled 114 children over a 1-year period. Physicians who made decisions on admission or discharge were blinded to the ETCO2 results. ETCO2 measurements were also repeated prior to discharge. The mean age of the study population was 6.9 months; 16% were ex-premature, with 21% having had a previous episode of

wheezing. The median ETCO2 upon arrival at the ED was 34Â (range 24 - 65) mmHg. ETCO2 values upon admission or discharge were not statistically different among patients hospitalised and those discharged from the ED. There was also no correlation between capnometry readings on admission and the number of oxygen desaturation days, nor with the length of hospitalisation. The Wang clinical respiratory severity score was found to predict the need for nasogastric tubes, oxygen desaturation days and length of hospitalisation. The authors concluded that ETCO2 was not useful for predicting the need for hospital admission or discharge. The clinical severity score was the most consistent predictor of significant outcome. Again, the message for the management of acute bronchiolitis is probably that the best tool is what lies between the physicianâ&#x20AC;&#x2122;s ears, and not technology.

R Masekela Paediatric Pulmonologist and Head of Department of Maternal and Child Health, Nelson R Mandela School of Clinical Medicine, University of KwaZuluNatal, Durban, South Africa 1. Jacob R, Bentur L, Brik R, Shavit I, Hakim F. Is capnometry helpful in children with bronchiolitis? Respir Med 2016;113:37-41. DOI:10.1016/j.rmed.2016.02.007

S Afr Respir J 2016;22(2):47. DOI:10.7196/SARJ.2016.v22i2.84

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BREATH-TAKING NEWS

Should sedation holidays be given in the paediatric intensive care unit? Although sedation interruption in the intensive care unit (ICU) is recommended in the literature for adults, its place in paediatrics has been much debated. The arguments for not using sedation interruption protocols include the danger of extubation, ventilatorassociated pneumonia, safety, comfort and, most importantly, synchronisation with the ventilator. There are also conflicting reports and a poor evidence base for the use of this strategy, with only two published randomised controlled trials comparing daily sedation interruption and protocolised sedation. An article by Vet et al.[1] presented the results of a multicentre, randomised controlled trial in the Netherlands on this much-debated issue. The aim of their study was to compare daily sedation interruption plus protocolised sedation (DSI + PS) with protocolised sedation (PS) only in critically ill children. They excluded premature neonates born at <37 weeks gestational age and children with cardiac, neurological or respiratory conditions who would not tolerate inadequate sedation. How this was determined is unclear and is an important confounder in this study, as only 132 (12%) of 1 059 patients screened over a 5-year period could be assigned to the intervention arm of either DSI + PS (n=66) or PS (n=63). Unfortunately, the study was terminated prior to the expected recruitment total of 200 patients because of low recruitment rates, making the interpretation of the results – using a primary endpoint of number of ventilator-free days at day 28 – difficult. Their results showed no difference in ventilator-free days; 24.0 days in both groups. The median ICU and hospital length of stay were

similar in both groups: DSI + PS 6.9 days (interquartile range (IQR) 5.2 - 11.0) v. PS 7.4 days (IQR 5.3 - 12.8) (p=0.47), and DSI + PS 13.3 days (IQR 8.6 - 26.7) v. PS 15.7 days (IQR 9.3 - 33.2) (p=0.19). Mortality at 30 days was higher in the DSI + PS group than in the PS group (6/66 v. 0/63, respectively, p=0.03), though no causal relationship with the intervention could be established. The median cumulative midazolam dose did not differ: DSI + PS 14.1 mg/kg (IQR 7.6 - 22.6) v. PS 17.0 mg/kg (IQR 8.2 - 39.8) (p=0.11). This surprising finding of increased mortality could not be explained by the authors but is a signal of possible harm as a result of drug interruption in children, in contrast to the experience among adults. Thus, DSI in the paediatric ICU is currently not recommended, as the adverse effects are well known and should be minimised and avoided.

R Masekela Paediatric Pulmonologist and Head of Department of Maternal and Child Health, Nelson R Mandela School of Clinical Medicine, University of KwaZuluNatal, Durban, South Africa 1. Vet NJ, de Wildt SN, Verlaat CW, et al. A randomized controlled trial of daily sedation interruption in critically ill children. Intensive Care Med 2016;42(2):233244. DOI:10.1007/s00134-015-4136-z

S Afr Respir J 2016;22(2):48. DOI:10.7196/SARJ.2016.v22i2.90

The South African Respiratory Journal PO Box 13725 Mowbray 7705 Any correspondence to the Editor should be sent to the same address or via email to: sarj@iafrica.com The website of The South African Thoracic Society can be found at www.pulmonology.co.za

WHO’S WHO

Who’s who in pulmonology Prof. Heather Zar heads the Division of Paediatric Pulmonology at Red Cross War Memorial Children’s Hospital (RCWMCH), University of Cape Town (UCT), with Drs Marco Zampoli, Aneesa Vanker and Diane Gray, sharing consultant responsibilities. It is a diverse unit, managing a wide range of paediatric respiratory conditions, and has an active training and research programme with trainees from both South Africa (SA) and the African continent. Heather is also Professor and Head of the Paediatrics and Child

Health Department, and Director of the School of Child and Adolescent Health at RCWMCH. She is Director of the Medical Research Council Unit on Child and Adolescent Health. Her work on childhood respiratory diseases, including pneumonia, tuberculosis, asthma and HIV-associated lung diseases has been internationally recognised; she has published more than 250 peer-reviewed publications and has substantial international grant support. She currently serves as President of the Pan African Thoracic Society and on the Forum of International Respiratory Societies. She received the World Lung Health Award in 2014.

Dr Marco Zampoli completed his paediatric and sub-specialist training at RCWMCH and UCT in 2007. His clinical and research interests in the field of paediatric pulmonology are wide and include HIVrelated lung disorders, cystic fibrosis, neuromuscular diseases and sleep medicine. Dr Zampoli is head of

the cystic fibrosis clinic and provides clinical oversight and leadership for the Breatheasy programme at RCWMCH, which supports children on the tracheostomy and ventilation home-care programme. Dr Zampoli is the current chair of the SA Cystic Fibrosis Medical and Scientific Advisory Committee and treasurer of the South African Paediatric Association.

Dr Aneesa Vanker completed her paediatric pulmonology training at Tygerberg Children’s Hospital and Stellenbosch University in 2010. Following that, she has been working as a paediatric pulmonologist at RCWMCH, UCT, where she is involved in the care of children with a wide range

of both congenital and acquired respiratory conditions. She is also a clinical researcher with a particular interest in the environmental determinants of childhood lung diseases. This is the subject of the PhD degree for which she is currently registered. Dr Vanker is the current paediatric pulmonology representative for the South African Thoracic Society.

Dr Diane Gray is a paediatric pulmonologist based at RCWMCH. Her interests include HIVassociated lung disease and respiratory function testing in children. She has spent much of the past 3 years developing infant and preschool lung

function tests for SA children while completing her PhD in the early-life determinants of lung function in African infants. She is also interested in adolescent health, and hopes to support the development of appropriate transitioning care for adolescents with chronic respiratory disease.

SARJ VOL. 22 NO. 2 2016

PRODUCT NEWS Rivaroxaban reduces length of hospital stay in patients with symptomatic venous thromboembolism The phase III EINSTEIN deep vein thrombosis (DVT) and EINSTEIN pulmonary embolism (PE) trials demonstrated the potential of oral rivaroxaban (Xarelto, Bayer) – 15 mg twice daily for 21 days, followed by 20 mg once daily – for the treatment of venous thromboembolism (VTE), a term that embraces DVT and PE. A subsequent study by van Bellen et al.,[1] published in Current Medical Research and Opinion in 2014, was undertaken to assess the length of initial hospitalisation in patients presenting with either symptomatic DVT or PE using hospitalisation records from these trials. The authors found that overall 52% of EINSTEIN DVT patients and 90% of EINSTEIN PE patients were admitted to hospital. The proportion of hospitalised DVT patients with a length of stay 5 days or fewer, receiving rivaroxaban, was 54% compared with 31% for those receiving enoxaparin/vitamin K antagonist (VKA), the current standard of care for the treatment of patients with symptomatic DVT and PE. For patients with PE, the corresponding values were 45% and 33%. Stays of 6 - 10 days were observed in 29% of rivaroxaban-treated patients compared with 45% for enoxaparin/VKA-treated patients for DVT. For patients with PE, these values were 39% and 46% in the rivaroxaban and enoxaparin/ VKA groups, respectively. Overall, length of stay was significantly shorter in the rivaroxaban group, compared with the enoxaparin/VKA group across all analyses performed (p<0.0001). VTE is associated with significant morbidity and mortality and therefore carries a considerable healthcare burden. Rivaroxaban is as effective as enoxaparin/VKA for the treatment of acute symptomatic DVT or PE, with the additional benefit of significantly reducing the period of hospitalisation in patients being treated for an initial DVT or PE. ‘Coupled with improved patient treatment satisfaction and no requirement for routine monitoring or dose adjustment, this presents strong advantages for treating patients with VTE with rivaroxaban,’ the authors wrote. They concluded that a single-drug regimen with rivaroxaban may reduce the burden on healthcare systems and patients by providing effective and well-tolerated treatment. ‘The convenience of a single-drug approach with oral rivaroxaban has the potential to allow discharge based on a patient’s clinical condition and to facilitate the transition from in-hospital to outpatient care. […] However, assessment of patient risk is still warranted to identify candidates who can safely receive outpatient treatment, and patient monitoring is essential to ensure adherence to the specified dosing regimen.’

Reference

1. van Bellen B, Bamber L, Correa de Carvalho F, et al. Reduction in the length of stay with rivaroxaban as a single-drug regimen for the treatment of deep vein thrombosis and pulmonary embolism. Curr Med Res Opin 2014; 30(5):829-837. [http://dx.doi.org/10.1185/03007995.2013.879439]

For full prescribing information, refer to the package insert approved by the Medicines Regulatory Authority (MCC). PHARMACOLOGICAL CLASSIFICATION: A.8.2 Anticoagulants. S4 XARELTO® 10. Reg. No.: 42/8.2/1046. Each film-coated tablet contains rivaroxaban 10 mg. INDICATION: Prevention of VTE in patients undergoing major orthopaedic surgery of the lower limbs. S4 XARELTO® 15 and XARELTO® 20. Reg. No.: 46/8.2/0111 and 46/8.2/0112. Each film-coated tablet contains rivaroxaban 15 mg or 20 mg, respectively. INDICATIONS: Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation; Treatment of DVT and for the prevention of recurrent DVT and PE; Treatment of PE and for the prevention of recurrent PE and DVT. Bayer (Pty) Ltd, Co. Reg. No.: 1968/011192/07, 27 Wrench Road, Isando, 1609. Tel: 011 921 5044 Fax: 011 921 5041. L.ZA.GM.06.2014.1007

50 SARJ VOL. 22 NO. 2 2016

PRODUCT NEWS NEW Antistatic Chamber: small, solid and effective ®

Aspen is proud to announce the launch of VORTEX , an innovative aluminium antistatic holding chamber with ‘cyclone twist’ principle, as an addition to our respiratory portfolio.

NEW Antistatic Chamber: small, solid andsolid effective NEW Antistatic Chamber: small, and effective ® [1]

VORTEX inhalation aid is suitable in providing: ® ® • High lung deposition, lowis throat deposition Aspen proud to launch announce launch of VORTEX , an innovative aluminium antistaticholding holding AspenAntistatic is proud toChamber: announce the ofthe VORTEX , an innovative aluminium antistatic NEW small, solid and effective • High dosage consistency chambertwist’ with ‘cyclone twist’as principle, as an to addition to our respiratory portfolio. chamber with ‘cyclone principle, an addition our respiratory portfolio. • Disinfectable, ergonomic SmartTouch masks ®

Aspen is proud to announce® the launch of VORTEX , an innovative aluminium antistatic holding [1] VORTEX inhalation aid is suitable in[1]providing: ® chamber ‘cyclone twist’ principle, as an addition to our respiratory portfolio. inhalation aid is suitable in providing: VORTEXwith • High lung deposition, low throat deposition

• High lung deposition, throat deposition • High low dosage consistency ®

[1]

• Disinfectable, ergonomic SmartTouch masks inhalation aid is suitable in providing: VORTEX • High dosage consistency ••High lung deposition, low throat deposition Disinfectable, ergonomic SmartTouch masks • High dosage consistency • Disinfectable, ergonomic SmartTouch masks

Reference: 1. Laube BL, Janssens HM, de Jongh FHC, et al. What the pulmonary specialist should know about the new inhalation therapies. Eur Respir J 2011;37:1308-1331.

Reference: 1. Laube BL, Janssens HM, de Jongh FHC, et al. What the pulmonary specialist should know about the new inhalation therapies. Eur Respir J 2011;37:1308-1331. Reference: 1. Laube BL, Janssens HM, de Jongh FHC, et al. What the pulmonary specialist should know about the new inhalation therapies. Eur Respir J 2011;37:1308-1331.

1 1

SARJ VOL. 22 NO. 2 2016

NEW

Antistatic Chamber

small, solid and effective

NEW aluminium Aspen is proud to announce the launch of an innovative new antistatic holding chamber, as an addition to our respiratory portfolio. VORTEX® inhalation aid is suitable in providing: (1) • High lung deposition, low throat deposition • High dosage consistency • Disinfectable, ergonomic SmartTouch masks Description (2)

Indication (2)

VORTEX® with a mouthpiece

VORTEX® with mouthpiece and baby mask ‘Ladybug’

To be used in conjunction with medication sprays or "metered dose inhalers" in the treatment of respiratory tract diseases.

VORTEX® with mouthpiece and child mask ‘Frog’

Nappi Code

SEP (Excl VAT)

SEP (Incl VAT)

216379001

R 267,27

R 304,69

216375001

R 291,66

R 332,50

216376001

R 291,66

R 332,50

The NEW VORTEX® aluminium chamber inhalation aid!

Attach. Breathe. Relax. S3 FLIXOTIDE® 50/125/250 INHALER CFC-FREE. Reg No.: 35/21.5.1/0377-0082/3. Delivers 50/125/250 µg of fluticasone propionate per actuation. INDICATIONS: Prophylactic management of atopic asthma in adults and children of 6 years and older. CONTRA-INDICATIONS: History of allergy to any of its components. PREGNANCY AND LACTATION: Safety not established. DOSAGE AND DIRECTIONS FOR USE: For inhalation use only. Should be taken regularly even when asymptomatic. The onset of therapeutic effect is 4 to 7 days. Should not be used for relief in acute attacks but for routine long term management. Patients will require a fast- and short-acting inhaled bronchodilator to relieve acute symptoms. If patients find that relief with short-acting bronchodilator treatment becomes less effective or they need more inhalations than usual, medical attention must be sought. Adults and children over 16 years of age: 100-1000 µg twice daily. Starting dose should be appropriate for severity of the disease. Dose may be adjusted until control is achieved or reduced to the minimum effective dose, according to the individual response. Children over 6 years of age: 50-100 µg twice daily. The dose may be adjusted until control is achieved and should be reduced to the minimum effective dose according to the individual response. Special patient groups: No dose adjustment in elderly patients. For the transfer of patients being treated with oral corticosteroids: Patients treated with systemic steroids for long periods of time or at a high dose may have adrenocortical suppression and adrenocortical function should be monitored regularly and their dose of systemic steroid reduced cautiously. After approximately a week, gradual withdrawal of the systemic steroid may be commenced. Decrements in dosages should be appropriate to the level of maintenance systemic steroid, and introduced at not less than weekly intervals. In some patients on oral corticosteroids the dose reduction or replacement with inhaled corticosteroids may not be possible. Some patients feel unwell in a non-specific way during the withdrawal phase despite maintenance or even improvement of the respiratory function. They should be encouraged to persevere with inhaled fluticasone propionate and to continue withdrawal of systemic steroid, unless there are objective signs of adrenal insufficiency. SIDE EFFECTS AND SPECIAL PRECAUTIONS: Treatment should not be stopped abruptly as adrenal insufficiency may be precipitated. Candidiasis of the mouth and throat (thrush) may occur. May be helpful to rinse out mouth with water after use. Symptomatic candidiasis can be treated with topical anti-fungal therapy whilst continuing treatment. Hoarsenes. Paradoxical bronchospasm with an immediate increase in wheezing. Treat immediately with a fast-acting inhaled bronchodilator. Treatment should be discontinued immediately, the patient assessed, and if necessary alternative therapy instituted. Cutaneous hypersensitivity. Systemic corticosteroid effects may occur. Patients transferred from other inhaled steroids or oral steroids remain at risk of impaired adrenal reserve for a considerable time after transferring to inhaled fluticasone propionate. Increasing use to control symptoms indicates deterioration of asthma control and patient should be reassessed. Sudden and progressive deterioration in asthma control is potentially life-threatening and may have several causes. Consideration should be given to increasing corticosteroid dosage if not caused by otherwise treatable causes of deterioration. Severe asthma requires regular medical assessment as death may occur. Sudden worsening of symptoms may require increased corticosteroid dosage which should be administered under urgent medical supervision. Patients weaned off oral steroids whose adrenocortical function is still impaired should carry a steroid warning card indicating that they may need supplementary systemic steroid during periods of stress, e.g. worsening asthma attacks, chest infections, major intercurrent illness, surgery, trauma, etc. Inhaled therapy may unmask underlying eosinophilic conditions (e.g. Churg Strauss syndrome). These cases have usually been associated with reduction or withdrawal of oral corticosteroid therapy. Similarly replacement of systemic steroid treatment with inhaled therapy may unmask allergies such as allergic rhinitis or eczema previously controlled by the systemic drug. These allergies should be symptomatically treated with antihistamine and/or topical preparations, including topical steroids. Patients in a medical or surgical emergency, who require high doses of inhaled steroids and/or intermittent treatment with oral steroids, are at risk of impaired adrenal reserve. The extent of the adrenal impairment may require specialist advice before elective procedures. The possibility of residual impaired adrenal response and elective situations likely to produce stress and appropriate corticosteroid treatment must be considered. Lack of response or severe exacerbations of asthma should be treated by increasing the dose of inhaled fluticasone propionate or by giving a systemic steroid and/or an antibiotic if there is an infection. Special care is necessary in patients with active or quiescent pulmonary tuberculosis. Patients on corticosteroid therapy may have adrenocortical suppression. MANAGEMENT OF OVERDOSAGE: Monitoring of adrenal reserve may be indicated. Treatment with inhaled fluticasone propionate should be continued at a dose sufficient to control asthma. APPLICANT: GlaxoSmithKline South Africa (Pty) Ltd; (Co. reg. no.1948/030135/07). 39 Hawkins Avenue, Epping Industria 1, Cape Town, 7460.

Reference: 1. Laube BL, Janssens HM, de Jongh FHC, et al. What the pulmonary specialist should know about the new inhalation therapies. Eur Respir J 2011;37:1308-1331. 2. VORTEX® package insert. For full prescribing information, please refer to the package inserts approved by the Medicines Regulatory Authority. All adverse events should be reported by calling the Aspen Medical Hotline number or directly to GlaxoSmithKline on +27 11 745 6000. ZAF/FP/0004/15a A19615 04/16

The South African Respiratory Journal acknowledges with thanks the invaluable sponsorship of the following companies: Aspen GSK Division Bayer Healthcare