SAMJ Vol 105, No 9 (2015)

SEPTEMBER 2015

VOL. 105 NO. 9

Ebola and the haemorrhagic fevers

698, 709, 748

Endoscopic lung volume reduction for severe emphysema

721

Bronchial thermoplasty in the management of severe asthma

726

Anticoagulation of pregnant patients with mechanical heart valves

733

Gender and sexual diversity

746

POC testing of diabetic ketoacidosis

756

Time to implement infant HIV testing at 9 months?

765

CME: update on COPD

785-792

ARVs

Respiratory

Cardio

Pain

CNS

Dermatology

SEPTEMBER 2015

VOL. 105 NO. 9

SAMJ

GUEST EDITORIAL

698

Ebola: Lessons learned R Burton

EDITOR-IN-CHIEF Janet Seggie, BSc (Hons), MD (Birm), FRCP (Lond), FCP (SA)

700

EDITOR’S CHOICE

DEPUTY EDITOR Bridget Farham, BSc (Hons), PhD, MB ChB

CORRESPONDENCE 702

Rural district hospitals – essential cogs in the district health system – and primary healthcare re-engineering M Bac, J Hugo

702

Use of the Mentzer index will assist in early diagnosis of iron deficiency in South African children D Lawrie, D K Glencross

703

HIV/AIDS stigma and discrimination in South Africa – still a problem K G Koodibetse

703 CORRECTION

IZINDABA 704 706 707

Contested PMB amendments – ‘funders the chief beneficiaries’ Inept drug supply management causing stock-outs ‘Populist politicians’ take aim at ‘soft-target’ doctors

SAMJ FORUM

709

CLINICAL ALERT Nososcomial transmission of viral haemorrhagic fever in South Africa G A Richards

713

Subacute sclerosing panencephalitis in South African children following the measles outbreak between 2009 and 2011* E Kija, A Ndondo, G Spittal, D R Hardie, B Eley, J M Wilmshurst

719

REFLECTIONS A human perspective on body donation: A case study from a psychosocial perspective* C Manicom

721

HEALTHCARE DELIVERY Endoscopic lung volume reduction in severe emphysema C F N Koegelenberg, J Theron, J W Bruwer, B W Allwood, M J Vorster, F von Groote- Bidlingmaier, K Dheda

724

Implementation of electronic scripts in South Africa K du Toit, S Naicker, J Bodenstein

726

RECOMMENDATIONS Recommendations for the use of bronchial thermoplasty in the management of severe asthma* K Dheda, C F N Koegelenberg, A Esmail, E Irusen, M E Wechsler, R M Niven, E D Bateman, K F Chung, on behalf of the Assembly on Interventional Pulmonology of the South African Thoracic Society

733

Recommendations for the anticoagulation of pregnant patients with mechanical heart valves* E Schapkaitz, B F Jacobson, P Manga, R S Chitsike, E Benade, S Jackson, S Haas, H R Buller, on behalf of the South African Society of Thrombosis and Haemostasis

EDITORIALS 739

National Health Insurance in South Africa: Relevance of a national priority-setting agency K J Hofman, S McGee, K Chalkidou, S Tantivess, A J Culyer

741

Reforming South Africa’s procedures for granting patents to improve medicine access C Tomlinson, J Ashmore, A Yawa, J Hill

743

South African Guidelines Excellence (SAGE): Clinical Practice Guidelines – quality and credibility S Machingaidze, T Kredo, Q Louw, T Young, K Grimmer

746

Gender and sexual diversity – changing paradigms in an ever-changing world M S Pepper

696

September 2015, Vol. 105, No. 9

EDITORS EMERITUS Daniel J Ncayiyana, MD (Groningen), FACOG, MD (Hon), FCM (Hon) JP de V van Niekerk, MD, FRCR ASSOCIATE EDITORS Q Abdool Karim, A Dhai, N Khumalo, R C Pattinson, A Rothberg, A A Stulting, J Surka, B Taylor, M Blockman HMPG CEO AND PUBLISHER Hannah Kikaya Email: hannah.kikaya@hmpg.co.za MANAGING EDITOR Ingrid Nye TECHNICAL EDITORS Emma Buchanan Paula van der Bijl NEWS EDITOR Chris Bateman | Email: chrisb@hmpg.co.za PRODUCTION MANAGER Emma Jane Couzens DTP & DESIGN Carl Sampson HEAD OF SALES AND MARKETING Diane Smith | Tel. 012 481 2069 Email: dianes@hmpg.co.za JOURNAL ADVERTISING Charles Duke Benru de Jager Reneé van der Ryst Ladine van Heerden ONLINE SUPPORT Gertrude Fani | Tel. 072 635 9825 Email: publishing@hmpg.co.za FINANCE Tshepiso Mokoena HMPG BOARD OF DIRECTORS Prof. M Lukhele (Chair), Dr M R Abbas, Dr M J Grootboom, Mrs H Kikaya, Adv. Y Lemmer, Prof. E L Mazwai, Dr M Mbokota, Mr G Steyn, Dr G Wolvaardt Production and distribution services supplied and managed by Media Outsourcing, a wholly owned subsidiary of Cape Media Corporation. Tel. 021 681 7000 ISSN 0256-9574 Publisher website: www.hmpg.co.za SAMA website: www.samedical.org Journal website: www.samj.org.za

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CONTENTS LISTED IN Index Medicus (Medline).

Excerpta Medica (EMBASE).

Biological Abstracts (BIOSIS).

Science Citation Index (SciSearch). Current Contents/Clinical Medicine

REVIEW 748

Viral haemorrhagic fevers in South Africa G A Richards, J Weyer, L H Blumberg

RESEARCH 752

Antimicrobial resistance of bacteria isolated from patients with bloodstream infections at a tertiary care hospital in the Democratic Republic of the Congo* L M Irenge, L Kabego, F B Kinunu, M Itongwa, P N Mitangala, J-L Gala, R B Chirimwami

756 The role of point-of-care blood testing for ketones in the diagnosis of diabetic ketoacidosis* A Coetzee, M Hoffmann, B H Ascott-Evans 760

Reproductive knowledge and use of contraception among women with diabetes* A Osman, A Hoffman, S Moore, Z van der Spuy

765

Time to implement 9-month infant HIV testing in South Africa* L Fairlie, C A Madevu-Matson, V Black, G G Sherman

769

Pharmacological treatment of painful HIV-associated sensory neuropathy* P Pillay, A L Wadley, C L Cherry, A S Karstaedt, P R Kamerman

773

Bone marrow aspirate microscopy v. bone marrow trephine biopsy microscopy for detection of Mycobacterium tuberculosis infection* Q Sedick, J Vaughan, T Pheeha, N A Alli

776

Codeine misuse and dependence in South Africa – learning from substance abuse treatment admissions* S Dada, N Harker Burnhams, M C van Hout, C D H Parry

780

Affordable moisturisers are effective in atopic eczema: A randomised controlled trial* C Hlela, N Lunjani, F Gumedze, B Kakande, N P Khumalo

CONTINUING MEDICAL EDUCATION

785

GUEST EDITORIAL Chronic obstructive pulmonary disease in South Africa: Under-recognised and undertreated B Allwood, R N van Zyl-Smit

786

REVIEW Chronic obstructive pulmonary disease – diagnosis and classification of severity P J Viviers, R N van Zyl-Smit

789

ARTICLES Pathogenesis of chronic obstructive pulmonary disease: An African perspective* B Allwood, G Calligaro

789

Non-pharmacological management of chronic obstructive pulmonary disease* S Abraham, G Symons

790

Pharmacological management of chronic obstructive pulmonary disease* E Shaddock, G Richards

791

Lung volume reduction in chronic obstructive pulmonary disease* M J Vorster, C F N Koegelenberg

791

Five tips for good office spirometry D M Maree

*Full article available online only.

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‘The lion (Panthera leo) is synonymous with wild Africa, however few people realize that illegal killing, relentless habitat loss, and habitat fragmentation has left this species teetering on the brink of extinction.’ (http:// www.panthera.org/node/8)

Photo: Susan Flegg

697

September 2015, Vol. 105, No. 9

GUEST EDITORIAL

Ebola: Lessons learned On Ebola we went from global indifference, to global fear, to global response and now to global fatigue. We must finish the job. (Joanne Liu, President, Médicins sans Frontières, July 2015[1]) The international response to the Ebola outbreak in West Africa was slow and inadequate, destroying families, economies and the already fragile health systems of Guinea, Liberia and Sierra Leone.[2] To date, there have been 27 705 documented cases and 11 269 reported deaths.[3] Previous Ebola outbreaks occurred in isolated areas of Central Africa, affected at most a few hundred people, and were rapidly contained.[4] There were more cases and more deaths with this West African outbreak than with all previous outbreaks added together.

It is important that lessons are learned so that a humanitarian crisis on this scale never occurs again, whether due to Ebola or another infectious disease.

Ebola is real

‘Ebola is real’ appeared on posters everywhere in Monrovia. In Liberia they referred to cultural traditions, and the widespread belief that Ebola is caused by witchcraft.[5] Treatment centres were regarded with suspicion; rumours abounded that patients were given tablets that caused death. Challenging misconceptions of disease causation is not a simple matter of ‘health education’. Infection control measures such as mass quarantine and isolation were imposed to varying extents at different times during the outbreak.

However reasonable these may have seemed in theory, in practice they tended to be seen as coercive social control, engendering further mistrust in healthcare providers and contributing to further transmission.[6] ‘Ebola is real’ is also a message the world should have recognised many months earlier. When Ebola appeared to affect only poor African countries, it was easily ignored. The World Health Organization declared a Global Health Emergency in August 2014.

This was 5 months after Médicins sans Frontières had launched an emergency response, and there were then only 49 infections and 29 deaths.[7] When Ebola appeared in the USA and Europe, it became all too real; fear and irrationality set in. Healthcare workers returning from working with Ebola were vilified, and accused of selfishly putting the lives of the entire population at risk.[8] Finally governments mobilised, sending in healthcare workers, military personnel, with their logistics experience, and funding. However, in resource-rich countries, Ebola at home was more of a concern than the thousands who were dying in West Africa.[9]

Optimising survival

Until this outbreak, death seemed an almost inevitable consequence of infection with Ebola, with mortality around 90%.[3] Overall, 60% of people have died in the current outbreak; surviving Ebola in Africa is no longer a rarity. Survival rates have been higher for the small number of people treated in resource-rich countries. Improving survival is therefore on the agenda. The need to understand Ebola’s pathophysiology better in order to optimise goal-directed care is now clear.[10] Supportive care alone is not enough. Specific treatments are also needed, but can only be properly tested in an outbreak setting. The ethical issues involved in conducting clinical trials in vulnerable

698

patients at high risk of imminent death are challenging.[11] Trial design has been much debated, from both ethical and scientific perspec­tives.[12-14] Non-randomised trials of two antiviral drugs, favi­piravir and brincidofovir, and of passive immunisation with convalescent plasma, began in late 2014/early 2015.[15] However, by the time the trials were implemented, there had been a significant reduction in new cases, and consequent lack of recruitment. A further lesson learned is that clinical trials in an ever-changing outbreak need rapid and flexible implementation.[16]

Ebola is not over yet

Ebola is no longer headline news. At the height of the outbreak, there were hundreds of cases a week. Currently there are around 30, which before this outbreak would have been considered alarming rather than welcome news.[1] This is not a time to forget about Ebola, or to concentrate only on doing everything better next time. Now is not the time for resourcerich nations to withdraw financial and human support. Deaths from non-Ebola causes are likely to significantly outnumber deaths from Ebola.[17] Closure of contaminated health facilities and deaths of already scarce health workers have had a severe impact on access to healthcare. Health workers, being 21 - 32 times more likely to become infected than the general adult population, suffered 879 confirmed infections and 510 deaths.[3,18] Evidence is also increasing that for those who have survived, Ebola is not over yet. Survivors have faced stigma within their communities, and post-traumatic stress disorder is common. Physical sequelae are increasingly recognised. Common complaints of ‘post-Ebola syndrome’ include loss of vision, joint pains and general body pains.[19] Viable virus seems capable of surviving in protected sites including aqueous humor, the testes and the fetoplacental unit.[20-22] The implications for further transmission and the ongoing health needs of survivors are therefore of great concern.

Ebola will not be eradicated by science alone

Finally, this outbreak has clearly shown that infectious diseases cannot be separated from the context in which they occur. As has been all too apparent, historical, social, economic and political factors also determine the course of an epidemic, and the nature of the global response.[23] Rosie Burton Physician and Infectious Diseases Specialist, Khayelitsha District Hospital, Cape Town, South Africa, and Department of Medicine, Groote Schuur Hospital, Cape Town 1. Médicins sans Frontières. Ebola in West Africa: ‘We must finish the job’. MSF July operational update. 17 July 2015. http://www.msf.org/article/ebola-west-africa-%E2%80%9Cwe-must-finishjob%E2%80%9D (accessed 23 July 2015).

2. Piot P, Muyembe JJ, Edmunds WJ. Ebola in West Africa: From disease outbreak to humanitarian crisis.

Lancet Infect Dis 2014;14(11):1034-1035. [http://dx.doi.org/10.1016/S14733099(14)70956-9] 3. WHO Ebola Situation Report. 22 July 2105. http://apps.who.int/ebola/current-situation/ebolasituation-report-22-july-2015 (accessed 23 July 2015).

4. Kortepeter MG, Bausch DG, Bray M. Basic clinical and laboratory features of filoviral hemorrhagic fever. J Infect Dis 2011;204(Suppl 3):S810-S816. [http://dx.doi.org/10.1093/infdis/jir299] 5. Chandler C, Fairhead J, Kelly A, et al. Ebola: Limitations of correcting misinformation. Lancet 2015;385(9975):1275-1277. [http://dx.doi.org/10.1016/S0140-6736(14)62382-5] 6. Eba PM. Ebola and human rights in West Africa. Lancet 2014;384(9960):2091-2093. [http://dx.doi. org/10.1016/S0140-6736(14)61412-4]

September 2015, Vol. 105, No. 9

GUEST EDITORIAL

7. Médicins sans Frontières. Guinea: Ebola epidemic declared, MSF launches emergency response. 22 March 2014. http://www.msf.org/article/guinea-ebola-epidemic-declared-msf-launches-emergencyresponse (accessed 23 July 2015).

8. Miles SH. Kaci Hickox: Public health and the politics of fear. Am J Bioeth 2015;15(4):17-19. [http:// dx.doi.org/10.1080/15265161.2015.1010994] 9. Editorial. The medium and the message of Ebola. Lancet 2014;384(9955):1641. [http://dx.doi. org/10.1016/S0140-6736(14)62016-X] 10. Fletcher TE, Fowler RA, Beeching NJ. Understanding organ dysfunction in Ebola virus disease.

Intensive Care Med 2014;40(12):1936-1939. [http://dx.doi.org/10.1007/s00134-014-3515-1] 11. Caplan AL. Morality in a time of Ebola. Lancet 2015;385(9971):e16-e17. [http://dx.doi.org/10.1016/ S0140-6736(14)61653-6] 12. World Health Organization. Ethical considerations for use of unregistered interventions for Ebola virus disease. Report of an advisory panel to WHO. http://www.who.int/csr/resources/publications/ ebola/ethical-considerations/en/ (accessed 23 July 2015).

13. Cox E, Borio L, Temple R. Evaluating Ebola therapies – the case for RCTs. N Engl J Med 2014;371(25):2350-2351. [http://dx.doi.org/10.1056/NEJMp1414145] 14. Cooper BS, Boni MF, Pan-ngum W, et al. Evaluating clinical trial designs for investigational treatments of Ebola virus disease. PLoS Med 2015;12(4):e1001815. [http://dx.doi.org/10.1371/journal.pmed.1001815] 15. Gulland A. Clinical trials of Ebola therapies to begin in December. BMJ 2014;349:g6827. [http://dx.doi. org/10.1136/bmj.g6827]

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16. Check Hayden E. Ebola R&D woes spur action. Nature 2015;521(7553):405-406. [http://dx.doi. org/10.1038/521405a] 17. Helleringer S, Noymer A. Magnitude of Ebola relative to other causes of death in Liberia, Sierra Leone and Guinea. Lancet Glob Health 2015;3(5):e255-256. [http://dx.doi.org/10.1016/S2214-109X(15)70103-8] 18. World Health Organization. WHO Ebola report on health worker infections. Special Ebola situation report. 20 May 2015. http://www.who.int/csr/resources/publications/ebola/health-worker-infections/ en/ (accessed 25 July 2015).

19. Médicins sans Frontières. Ebola: Surviving survival – life after recovery. 13 April 2015. http://www.msf. org/article/ebola-surviving-survival-life-after-recovery (accessed 25 July 2015).

20. Varkey JB, Shantha JG, Crozier I, et al. Persistence of Ebola virus in ocular fluid during convalescence.

N Engl J Med 2015;372(25):2423-2427. [http://dx.doi.org/ 10.1056/NEJMoa1500306] 21. Fecht S. Why testicles are the perfect hiding spot for Ebola. 5 May 2015. http://newsinformer.info/us-healthnews/why-testicles-are-the-perfect-hiding-spot-for-ebola-popular-science/ (accessed 25 July 2015).

22. Black, BO. Obstetrics in the time of Ebola: Challenges and dilemmas in providing lifesaving care during a deadly epidemic. BJOG 2015;122(3):284-286. [http://dx.doi.org/10.1111/1471-0528.13232] 23. Castillo-Chavez C, Curtiss R, Daszak P, et al. Beyond Ebola: Lessons to mitigate future pandemics.

Lancet Glob Health 2015;3(7):e354-e355. [http://dx.doi.org/10.1016/S2214-109X(15)00068-6]

S Afr Med J 2015;105(9):698-699. DOI:10.7196/SAMJnew.8492

September 2015, Vol. 105, No. 9

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EDITOR’S CHOICE

CME: COPD in South Africa – under-recognised and undertreated

Chronic obstructive pulmonary disease (COPD) is frequently a challenge for both patient and doctor. Even the name causes much head scratching for many sufferers. ‘Asthma I know’, and ‘emphysema I have heard of ’, but COPD – a complex syndrome extending from chronic bronchitis to emphysema – is not well understood or easily explained. This is in part the fault of pulmonologists, but as knowledge grows, there are increasing attempts to split COPD into more clinically relevant phenotypes. This will hopefully allow for clearer understanding and better treatment choices. With COPD, much can still be done despite its being incurable and lung function impairment being irreversible.

COPD is a common, preventable but incurable disease currently ranked third in global mortality. Worldwide 65 million people are estimated to have moderate to severe disease, and COPD accounts for 3 million deaths annually, of which 90% are said to occur in lowand middle-income countries. Yet despite these staggering numbers, COPD remains both under-recognised and undertreated in most populations, including our own. There are many reasons for this, not least clinicians’ often fatalistic attitude with regard to its treatment.

This CME highlights key aspects of the diagnosis and pharmacological and non-pharmacological treatment, as well as new developments in management of severe COPD. We also include articles highlighting non-smoking-related COPD and some tips for accurate spirometry.

Improving pulmonary function in emphysema and asthma

This issue of SAMJ carries a Forum article[1] on endoscopic lung volume reduction to improve pulmonary function in severe emphysema that is a distillation of recommendations for its use, based on published evidence, international expert opinion, local expertise and local commercial access to devices, that will be published in full in the October issue.[2] In addition, we publish recommendations for the use of bronchial thermoplasty in the management of severe asthma.[3] It is recommended that all endoscopic bronchothermoplasty procedures for severe asthma should be performed in the context of a local and/or international registry. The Assembly on Interventional Pulmonology of the South African Thoracic Society is willing to assist potential centres wishing to establish a thermoplasty and endoscopic lung volume reduction service in terms of training and accreditation.

Nine-month infant HIV testing

In South Africa (SA) excellent gains have been made in prevention of mother-to-child transmission (PMTCT) since 2002, with over 90% of HIV-infected women accessing PMTCT. The national early transmission rate of HIV infection as measured at around 6 weeks of age is on track to meet the National Strategic Plan target of <2% in 2015.

To detect postnatal transmission of HIV (via maternal infections not diagnosed during pregnancy, infection acquired late in pregnancy or during breastfeeding, poor adherence to ART during breastfeeding, and mixed infant feeding practices), national guidelines recommend that HIV-exposed uninfected (HEU) infants undergo repeat HIV testing 6 weeks after weaning and at 18 months of age. But HIV testing after weaning and at 18 months is poorly implemented and monitored. Consequently the rate of postnatal transmission and the extent of the paediatric HIV epidemic in SA remain unmeasured, and HIV-infected infants and children remain unidentified.

700

In an article suggesting that it is time to implement 9-month infant HIV testing in SA, Fairlie et al.[4] explore a model that posits the adoption in SA of World Health Organization (WHO) guidelines, available since 2008, that recommend infant HIV diagnosis using an antibody detection assay at 9 months of age for all HEU infants and a confirmatory HIV polymerase chain reaction test if the HRT is positive. If SA were to adopt the WHO recommendation to test all HEU infants at the 9-month measles vaccine visit (Expanded Programme on Immunization), when measles (MCV1) coverage rates in SA are reported at 95%, more HIV-infected infants would be identified earlier and benefit from early initiation of combination antiretroviral therapy, while HIV infection would be excluded in 80 100% of HEU infants.

With dwindling early vertical transmission rates as a result of SA’s successful PMTCT programme, proportionately more infants and children diagnosed after 6 weeks of age will contribute to the paediatric HIV epidemic, and it is clearly important that they be identified.

Codeine misuse and dependence in SA

Misuse of prescription and over-the-counter codeine-containing products is a global public health issue. SA is considering introducing regulations to reduce the amount of codeine in a tablet to 10 mg and to up-schedule norcodeine and acetylcodeine. Dada et al.[5] analysed substance abuse treatment admissions to investigate the extent of treatment demand related to the misuse of codeine or codeine dependence in SA and the profile of patients seeking treatment for their misuse or dependency on codeine (as part of a comprehensive, multicountry Codeine Misuse and Dependence (Codemisused) Study funded by the European Union). Fewer than 1% of persons had codeine as their primary substance of abuse, similar to findings reported from centres in the UK and Ireland. These percentages are low compared with alcohol, cannabis, methamphetamine and other substances of abuse in SA, but translate to over 400 persons per year needing treatment for their codeine misuse in specialist substance abuse treatment centres.

Recommendations for the anticoagulation of pregnant patients with mechanical heart valves

The above recommendations[6] are key reading for anyone in­volved in the management of pregnant women with mechanical heart valves. The Southern African Society of Thrombosis and Haemostasis reviewed available literature and comprehensive evidence-based guidelines for the anticoagulation of these patients.

These SA recommendations discuss the use of enoxaparin (Clexane), unfractionated heparin and warfarin. (The recommendation to only use enoxaparin is based on the fact that adequate laboratory monitoring is available in SA for enoxaparin and not other lowmolecular-weight heparins (LMWHs) – the testing of LMWH is not interchangeable.) The choice of anticoagulant remains challenging because both vitamin K antagonists and heparins may be associated with maternal and fetal adverse events and should be considered in conjunction with risk factors for thromboembolism (valve type, position and history of thromboembolism), economic factors (availability and cost of the anticoagulants, access to laboratory testing and specialist care) and maternal preferences.

For colleagues wishing to understand the mechanisms of action and pharmacology of antithrombotic agents, I recommend ‘Pharmacology of antithrombotic drugs: An assessment of oral antiplatelet and anticoagulant treatments’, published in a recent issue of The Lancet.[7]

September 2015, Vol. 105, No. 9

EDITOR’S CHOICE

Ebola: Lessons learned

The dangerous, debilitating and deadly Western African Ebola outbreak, which caused >10 000 deaths in some 430 days, has been magnificently brought under control thanks to Médicins sans Frontières, followed by many dedicated health personnel (some of them South African) and deployment by several countries of their military personnel possessing key logistics capability. Also, there was superb shared intergovernmental decision-making (on the part of the governments of the countries directly involved and those threatened as neighbours) in spite of an initial crippling of any response by the decisions of the airlines. As expressed by Bruce Aylward, Assistant Director-General of the WHO Polio and Emergencies cluster,[8] success in controlling the epidemic required turning the traditional public health strategies of support and education of affected communities, contact tracing and isolation to stop transmission, treatment of victims and safe burial of those who did die, on its head – rapid establishment of treatment centres, with rapid training of burial teams (led by the Red Cross) first, followed by contact tracing, and creation of a UN air-bridge to ensure humanitarian aid to affected communities.

There can be no complacency, as Ebola does smoulder on in Sierra Leone, while new cases have recently occurred in Liberia and are likely to occur in the future … see ‘Ebola: Lessons learned’.[9]

Viral haemorrhagic fever (VHF) in South Africa

In a ‘Forum’ article on nososcomial transmission of VHF in South Africa,[10] Guy Richards describes several cases of haemorrhagic fever and the measures required to prevent nosocomial transmission. In SA the only endemic haemorrhagic fever is Crimean-Congo haemorrhagic fever, transmitted by the Hyalomma tick, which is ubiquitous in cattle farming areas. Johannesburg’s health centres have had to deal with all imported cases of VHF, whether from rural areas in SA or from countries to the north.

The accompanying review by Richards et al.[11] on VHF in South Africa is mandatory reading.

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reg red! e n i Onl is requi

WORLD FORUM FOR MEDICINE BE PART OF IT!

JS 1. Koegelenberg CFN, Theron J, Bruwer JW, et al. Endoscopic lung volume reduction in severe emphysema. S Afr Med J 2015;105(9):721-723. [http://dx.doi.org/10.7196/SAMJnew.8144] 2. Koegelenberg CFN, Theron J, Dheda K, et al. Recommendations for the use of endoscopic lung volume reduction in South Africa. S Afr Med J 2015;105(10) (in press). [http://dx.doi. org/10.7196/SAMJnew.8147] 3. Dheda K, Koegelenberg CFN, Esmail A, et al. Recommendations for the use of bronchial thermoplasty in the management of severe asthma. S Afr Med J 2015;105(9):726-732. [http://dx.doi.org/10.7196/SAMJnew.8207] 4. Fairlie L, Madevu-Matson CA, Black V, Sherman GG. Time to implement 9-month infant HIV testing in South Africa. S Afr Med J 2015;105(9):765-768. [http://dx.doi.org/10.7196/ SAMJnew.8175] 5. Dada S, Harker Burnhams N, van Hout MC, Parry CDH. Codeine misuse and dependence in South Africa – learning from substance abuse treatment admissions. S Afr Med J 2015;105(9):776-779. [http://dx.doi.org/10.7196/SAMJnew.8172] 6. Schapkaitz E, Jacobson BF, Manga P, et al. Recommendations for the anticoagulation of pregnant patients with mechanical heart valves. S Afr Med J 2015;105(9):733-738. [http:// dx.doi.org/10.7196/SAMJnew.7928] 7. Mega JL, Simon T. Pharmacology of antithrombotic drugs: An assessment of oral antiplatelet and anti­ coagulant treatments. Lancet 2015;386(9990):281-291 [http://dx.doi.org//10.1016/S01406736(15)60243-4] 8. TED. Aylward B. Beating Ebola. https://www.ted.com/talks/bruce_aylward_humanity_vs_ ebola_the_winning_strategies_in_a_terrifying_war?language=en (accessed 20 July 2015).

9. Burton R. Ebola: Lessons learned. S Afr Med J 2015;105(9):698-699. [http://dx.doi. org/10.7196/SAMJnew.8492] 10. Richards GA. Nososcomial transmission of viral haemorrhagic fever in South Africa. S Afr Med J 2015;105(9):709-712. [http://dx.doi.org/10.7196/SAMJnew.8168] 11. Richards GA, Weyer J, Blumberg LH. Viral hemorrhagic fever in South Africa. S Afr Med J 2015;105(9):748-751. [http://dx.doi.org/10.7196/SAMJnew.8330]

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Southern African - German Chamber of Commerce and Industry 47 Oxford Road _ Forest Town 2193 JOHANNESBURG P.O. Box 87078 _ Houghton 2041 Tel. +27 (0)11 486 2775 _ Fax +27 (0)86 675 2175 tradefairs@germanchamber.co.za _ www.germanchamber.co.za

CORRESPONDENCE

Rural district hospitals – essential cogs in the district health system – and primary healthcare re-engineering

To the Editor: The article by Le Roux et al.[1] raises the question why it is so difficult to re-engineer primary healthcare (PHC) and why the results so far have been disappointing. They highlight the critical role of the district hospital as the hub from which all activities in the rural districts should be co-ordinated.

Le Roux et al. write from their own experience at rural hospitals.

We agree that there are many examples of well-run public district hospitals with excellent reputations, which have contributed towards improved patient care together with improved health status of the community. Hospitals that have built up reputations as providers of excellent rural healthcare services in the past decades are Elim, Donald Fraser, Gelukspan, Manguzi, Bethesda, Mosveld, Mseleni, Rietvlei, Zithulele, and many more.

Some of the following aspects will have played an important role: • Integration of hospital and district services. The doctors and allied healthcare workers (HCWs) working in the hospital went out to visit the clinics in the district, saw patients with the clinic nurses, and did on-the-job training of clinic staff.

• Strong leadership in the form of committed champions who had built up good-quality programmes to address the major health problems diagnosed by assessment of the community (‘community diagnoses’).

• A co-ordinated team approach to the major health problems in the district, e.g. a mental health programme run by a community psychiatric nurse who also saw the admitted patients in the ward and followed them up after discharge at their homes and nearby clinics. The same applied to programmes to control malnutrition, tuberculosis, measles, maternal health and diarrhoeal diseases. These and other common public health challenges are addressed by integrated programmes such as GOBI-FFF (growth monitoring, breastfeeding, immunisation, family planning, female education and food supplementation), diarrhoeal disease control including safe water supply and sanitation, tuberculosis control with active case-finding and contact tracing, and school visits by the dentist and school nurse.

• Optimal use of the available resources in the district such as manpower, scarce skills (doctors and allied HCWs) and transport, and efficient supply of drugs, stationery and other necessities to the clinics from the district hospital.

• Optimal communication, because the HCWs in the district and the hospital knew each other well. A continuous rotation of staff through the hospital and clinics ensured good understanding of the community’s health needs.

• Joint planning and evaluation by the district health team, or what Le Roux et al.[1] call ‘primary care management teams’. This structured and intensive co-operation between district health teams of clinics, mobile teams and the hospital made significant progress possible despite limited resources and other adverse conditions such as apartheid and homeland policies.

The presence of primary care management teams in properly supported and well-run district hospitals, as called for by Le Roux et al., is vitally important in the delivery of PHC. District clinical specialist teams can get involved by adding their expertise and monitoring the impact on the health status of the community in the catchment area.

The establishment of the monitoring and response units in the Waterberg, Gert Sibande and OR Tambo districts to accelerate the decline in infant, child and maternal mortality is an example of

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how the divide between the district hospital and the district health services can be healed and a united response to the unacceptable high mortality rates among infants and mothers created. The whole district healthcare team will take responsibility for the health of the population in the district and be accountable for performance.

The development of ward-based outreach teams makes it possible to integrate care from the home to the clinic and the hospital through a community-orientated primary care approach. The district hospital is an integral part of such integrated care.

Common sense and the experience of many HCWs in rural districts support the call for re-establishment of the district hospital as the ‘hub of expertise, training, supervision and support for its feeder clinics and [to] be the guardian of the health of each member of the community it serves’.

Martin Bac, Jannie Hugo

Department of Family Medicine, School of Medicine, Faculty of Health Sciences, University of Pretoria, South Africa martin.bac@up.ac.za 1. Le Roux KWDP, Couper I. Rural district hospitals – essential cogs in the district health system – and primary healthcare re-engineering. S Afr Med J 2015;105(6):440-441. [http://dx.doi.org/10.7196/ SAMJ.9284]

S Afr Med J 2015;105(9):702. DOI:10.7196/SAMJnew.8379

Use of the Mentzer index will assist in early diagnosis of iron deficiency in South African children

To the Editor: A recent review article by Dr R Thejpal[1] in CME provided a comprehensive update on the diagnosis, treatment and challenges of early diagnosis of iron deficiency in South African (SA) children. Although several definitive laboratory tests are readily available in SA National Health Laboratory Service (NHLS) laboratories for diagnosing iron deficiency in both children and adults, laboratory testing is expensive and, as noted previously, regions with a high prevalence of anaemia also have a large burden of infectious diseases[2] that invariably become the laboratory priority in resource-constrained settings.

This scenario is not limited to our local environment. Articles from India and Turkey describe similar diagnostic challenges and possible approaches for more cost-effective screening of iron deficiency anaemia. The first study, by Sazawal et al.,[2] included 2 091 children from an impoverished population in Delhi. This study used two haematological indices, namely haemoglobin concen­ tration ≤10 g/ dL and red cell distribution width (RDW) >15%, to identify iron-deficient children between 1 and 3 years of age (confirmed by zinc protoporphyrin and serum ferritin assays). Statistical analysis confirmed a sensitivity of 99% and specificity of 90% if haemo­globin and RDW alone were used for screening.[2] The second study,[3] from Turkey, assessed 290 children aged 1 - 16 years and used the red blood cell count, RDW and Mentzer index (mean corpuscular volume/red blood cell count ratio) to differentiate beta-thalassaemia trait from iron deficiency anaemia. These results indicated that the Mentzer index was the most reliable indicator, with a sensitivity of 98.7% and specificity of 82.3%.[3] In our recently reported limited assessment of 381 ‘clinically’ healthy children between infancy and 12 years of age from a semi-informal settlement in Cape Town, SA, we used a similar screening approach of haemoglobin concentration, RDW and calculated Mentzer index. In this study we were able to show that 14.2% (54/381) of the children who had a full blood count performed during routine testing could have possible iron deficiency anaemia.[4]

September 2015, Vol. 105, No. 9

CORRESPONDENCE

Although these screening approaches have only been assessed on participants or patients with physiological anaemia (decreased haemoglobin concentration), the excellent sensitivities and specificities reported suggest that these screening methods could also be applied to identify subclinical iron deficiency anaemia. Although further studies are indicated to test this hypothesis, we propose that in the interim all full blood count results reported should include the Mentzer index. With no attached additional cost, the RDW result and the Mentzer index could provide an immediate screening tool that can be accompanied with an interpretive comment to assist local clinicians in identifying children with possible subclinical or latent iron deficiency.

D Lawrie, D K Glencross

Department of Molecular Medicine and Haematology, University of the Witwatersrand and National Health Laboratory Service, Johannesburg, South Africa debbie.glencross@nhls.ac.za 1. Thejpal R. Iron deficiency in children. S Afr Med J 2015;105(7):607. http://dx.doi.org/10.7196/ SAMJnew.7781] 2. Sazawal S, Dhingra U, Dhingra P, et al. Efficiency of red cell distribution width in identification of children aged 1 - 3 years with iron deficiency anemia against traditional hematological markers. BMC Pediatr 2014;14:8. [http://dx.doi.org/10.1186/1471-2431-14-8] 3. Mentzer WC, Jr. Differentiation of iron deficiency from thalassaemia trait. Lancet 1973;1(7808):882. [http://dx.doi.org/10.1016/S0140-6736(73)91446-3] 4. Vehapoglu A, Ozgurhan G, Demir AD, et al. Hematological indices for differential diagnosis of beta thalassemia trait and iron deficiency anemia. Anemia 2014 (2014), Article ID 576738. [http://dx.doi. org/10.1155/2014/576738]

S Afr Med J 2015;105(9):702-703. DOI:10.7196/SAMJnew.8589

HIV/AIDS stigma and discrimination in South Africa – still a problem

To the Editor: Awareness of global health issues is most effectively raised through global campaigns.[1] In 2002 - 2003, the World AIDS Campaign adopted the theme ‘Live and Let Live: Stigma and Discrimination’ to address various hostile determinants powering HIV/AIDS stigma and discrimination (S&D).[1-3] Among the effects of HIV/AIDS-related S&D are blame, denial, and difficulties in adhering to treatment.[3,4] While campaigns raise awareness of global health issues,[5] it was HIV/AIDS that propelled global crusades for advocacy and mobilisation. HIV/AIDS S&D demanded a robust response at all levels of society, as efforts against HIV/AIDS were becoming futile.[3] The various determinants of S&D should be placed in context to address the root causes that are specific to a particular nation or community. Otherwise, campaigns will come and go without a positive impact.

HIV/AIDS-related S&D are ingrained in societal structures,[3] which calls for internal solutions. As the ‘blame’ persists and increasing numbers of people living with HIV/AIDS (PLWHA) shoulder the burden of lack of support and need for secrecy, they are deprived of their rights as human beings. To counter this, South Africa (SA) adapted the Vision for Zero Discrimination, with the overarching goal of halving S&D by 50%.[6]

To be effective and successful, interventions need to take underlying influencing factors into consideration.[7] The pervasiveness and persistence of stigma in areas with high HIV prevalence remains an important yet difficult area of research, and calls for the international public health community to be creative in designing and then implementing HIV/AIDS anti-stigma interventions.[8] The expectation that areas with high prevalence rates of HIV, such as SA and sub-Saharan Africa, would easily succeed in implementing Vision for Zero Discrimination is optimistic, as people’s perceptions are greatly impacted on by influential social institutions – what has been embedded cannot easily be ejected.

Interventions to address S&D in SA[9] include a policy to audit interventions to assist PLWHA in accessing social services from their workplaces.[6] After the murder of Gugu Dlamini in her own community after disclosure of her positive status,[10] the Gugu Dlamini Foundation was established to raise awareness of HIV/AIDS issues, including S&D. This community-based intervention seeks to challenge S&D while offering advocacy for PLWHA.[10] Edu-entertainment[11] is another SA intervention. The Soul City Programme, for example, is aired in SA and neighbouring countries. The episodes are contextualised by SA actors familiar with the issues of S&D in the country, and portrayal of familiar issues in a local language promotes better understanding.

With its huge population, SA still has to scale up S&D interventions to reach the majority of those who need them. Difficult-to-reach rural areas with access to the ‘Phelophepa train’[12] can potentially receive an additional package of S&D interventions through it. Furthermore, individual citizens should jointly make HIV/AIDS S&D interventions their priority to carry SA forward.

Keikotlhae Gomolemo Koodibetse Fulbright Scholar, Ohio University, USA koodibetsekk@gmail.com

1. World Health Organization. WHO campaigns. http://www.who.int/campaigns/en/ (accessed 13 February 2015).

2. World Health Organization. Message on World AIDS Day 2002 by Kofi Annan. http://www.who.int/ hiv/events/wad2002/speech/en/ (accessed 13 February 2015).

3. UNAIDS. Stigma & Discrimination: Live and Let Live! Global campaign 2002 - 2003. World AIDS Day 2002 Advocacy Kit. http://data.unaids.org/pub/manual/2002/20021021_wad_kit_en.pdf (accessed 13 February 2015).

4. Karim SSA, Karim QA. HIV/AIDS in South Africa. 2nd ed. Cape Town: Cambridge University Press, 2010.

5. Speicher S. World AIDS Day marks 20th anniversary of solidarity. http://www.medicalnewstoday.com/ releases/130044.php (accessed 13 February 2015).

6. UNAIDS. South Africa launches its new National Strategic Plan on HIV, STIs and TB, 2012-2016. http://www.unaids.org/en/resources/presscentre/featurestories/2011/december/20111220sansp/ (accessed 13 February 2015).

7. Airhihenbuwa CO, Ford CL, Iwelunmor JL. Why culture matters in health interventions: Lessons from HIV/AIDS stigma and NCDs. Health Education and Behavior 2014;41(1):78-84. [http://dx.doi. org/10.1177/1090198113487199] 8. Brown L, Macintyre K, Trjillo L. Intervetions to reduce HIV/AIDS stigma: What have we learned?

AIDS Educ Prev 2003;15(1):49-69. [http://dx.doi.org/10.1521/aeap.15.1.49.23844] 9. UNAIDS. 2011-2015 Strategy: Getting to Zero http://www.unaids.org/sites/default/files/sub_landing/ files/JC2034_UNAIDS_Strategy_en.pdf (accessed 1 April 2015).

10. AIDS Foundation of South Africa (Internet). I returned to the community where my mother was killed, to educate them about HIV. http://www.aids.org.za/i-returned-to-the-community-where-my-motherwas-killed-to-educate-them-about-hiv/ (accessed 14 February 2015).

11. Singhal A, Cody MJ, Rogers EM, Sabido M, eds. Entertainment – Education and Social Change: History, Research, and Practice. Hillsdale, NJ, USA: Lawrence Erlbaum Associates, 2004.

12. American Friends of Phelophepa Train of Hope. http://www.trainofhope.org/ (accessed 15 February 2015).

S Afr Med J 2015;105(8):703. DOI:10.7196/SAMJnew.7811

Correction In the article ‘The South African Surgical Outcomes Study: A 7-day prospective observational cohort study’ by Biccard et al., which appeared on pp. 465 - 475 of the June 2015 SAMJ, there was an error in the ‘Conflict of interest’ section: R Machekano and not R Moreno received payment for statistical analyses for SASOS from SASOS grant funds for the submitted work. In Appendix 3, T Kisten was omitted as a SASOS investigator for Inkosi Albert Luthuli Central Hospital, KwaZulu-Natal Province. The online version of the article (http://dx.doi. org/10.7196/SAMJ.9435) was corrected on 31 August 2015.

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IZINDABA

Contested PMB amendments – ‘funders the chief bene­ficiaries’ If promulgated as origi­ nally proposed, ‘shortsighted’ changes to the Medical Schemes Act, in par­ ticular sections of Regulation 8, will financially hurt both bene­ficiaries of medical schemes and many private practitioners – via inadequate funder payments for prescribed minimum benefits (PMBs).

In spite of reassurances to the contrary by both the Board of Healthcare Funders (BHF) and Dr Anban Pillay, Deputy Director-General for Health Regulation and Compliance Management at the National Department of Health (NDoH), most doctor groups remain deeply wary of the arbitrary way in which medical aid rates have been linked to ‘deeply flawed’ 2006 National Health Reference Price List (NHRPL) tariffs (adjusted for the consumer price index (CPI)).

The proposed legal amendment, induced by decade-long pricing strife and intransigence on the part of most stakeholders in the private healthcare sector, errs on the side of funders, allowing (but not obliging) them to negotiate tariffs with any healthcare provider for which no co-payment or deductible is payable by the member. PMBs cover both chronic and catastrophic conditions suffered by medical scheme members and are intended to offer them a measure of financial protection. However, since the ‘provider-cost deficient’ 2006 NHRPL list was drawn up, there have been numerous advancements in medical technology and procedures that are not included. This means that unless it is updated, patients stand to no longer be funded for optimal and up-to-date treatment.

Dr Anban Pillay, NDoH Deputy DirectorGeneral for Health Regulation and Compliance Management.

Where’s the science? – SAMA

Dr Mzukisi Grootboom, Chairman of the 17 000-member South African Medical Asso­ciation (SAMA), says the amendment is ‘difficult to explain’, given that the Minister of Health failed to give the profession and patients the scientific basis upon which he is proposing the amendments.

The oft-heard rhetoric, both from funders and politicians, was that ‘paying in full’ (the existing and historically much-contested regulatory wording for PMBs) amounted to a ‘blank cheque’ for doctors. However, the truth was that this would ‘unfortunately affect not only our patients but also a lot of colleagues in private practice by forcing them to charge prices at a level below the cost of running their practices’.

Feedback from the funding industry was that medical aids were only prepared to pay an ‘unsustainable’ 30% of the costs of running a medical practice.

Grootboom contends that the minority of doctors who funders claim charge way more than the average medical scheme rates, or who fraudulently abuse the system, can easily be identified and held to account. Using this minority to justify legislation based on an outdated, flawed and unscientific price list would simply chase doctors out of the profession. Any further erosion of the widening historical gap between what medical aids pay doctors and what it costs doctors to deliver services would damage overall healthcare delivery, threatening the very existence of private practice. Doctors in private practice, who a reading of the latest Council for Medical Schemes (CMS) annual report showed charged on average between 80% and 150% of medical aid rates, would ‘simply leave the profession, change professions or go overseas’, he claimed.

Grootboom said that feedback from the funding industry was that medical aids were only prepared to pay an ‘unsustainable’ 30% of the costs of running a medical practice.

He described those few GPs and (mainly) consultants who charged three or four times the medical aid rates as ‘outliers’, stressing that there were mechanisms in the current

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system to deal with them, ‘particularly those medical aids that have well-resourced IT platforms and can document practices that grossly abuse. There is also the HPCSA [Health Professions Council of South Africa] that can deal with unethical conduct,’ he added.

Definition of ‘pay in full’ remains unresolved

Health minister Dr Aaron Motsoaledi, chief architect of the proposed amendment to Regulation 8 of the Medical Schemes Act, and the BHF (which warmly welcomes the change) claim that doctors do have a ‘blank cheque’ under the current Act. For a variety of complex legal reasons, no court has yet ruled on or engaged with all the facts behind whether the legislator meant that medical aids must ‘pay in full’ what the doctor charges – or what medical schemes set as payment rates. In practice it is the patient who most often suffers, paying for the shortfall regardless of whose interpretation pertains on the day. Motsoaledi’s draft tries to introduce greater certainty by linking medical aid rates to the 2006 NHRPL tariffs (adjusted for the CPI). Healthcare economist Alex van den Heever warns that if passed, the amendment will not only reduce financial risks for medical schemes but shift the cost burden further onto consumers – who have virtually no power to negotiate with healthcare providers.

Van den Heever, Chair of Social Security Administration and Management Studies at the University of the Witwatersrand School of Governance, said that ‘no country in the world expects consumers to fight at the point of service about a

BHF chair Dr Clarence Mini.

IZINDABA

price for healthcare’, and described the regulations as ‘a gift to vested interests’.

Pillay said that the aim of the draft regulation is to protect medical schemes from open-ended liability for PMB claims.

At the BHF annual conference held in Cape Town in July, he told delegates that a recent overview of private health insurance in South Africa (SA) by the Organisation for Economic Co-operation and Development (OECD – 34 countries with market economies) showed that SA was second only to the USA in respect of high prices.

Archer described the proposed amendment as ‘retrogressive, undermining the whole ethos of the current system which is to protect families from massive medical expenses and prevent dumping on the state’.

Pillay rolls out evidence of ‘abuse’

Displaying a graph of local healthcare provider billing for PMBs v. non-PMBs, Pillay said that the variance dramatically illustrated how providers hiked their bills for PMBs: ‘Ít’s like walking into a restaurant and there are no prices on the menu. The waiter says, “Choose what you like, but when you leave I’ll decide what you have to pay.”’ He said the current system meant that funders had to pay whatever was billed, with no opportunity to negotiate. While he agreed that a small subset of healthcare providers was abusing the payment system, he said this had ‘a massive impact’ on the medical schemes involved. ‘It’s about dealing with this behaviour and its impact.

More and more providers will start doing it – until it becomes the norm. We want a reimbursement system that is fair to both patients and providers, and one that results in no co-payments,’ he asserted.

He claims that the CMS will protect consumers by not approving medical schemes’ benefit packages if they fail to make adequate provision for members.

Grootboom and his colleagues believe that one of the chief motivations behind the current Competitions Commission Healthcare Inquiry is to find reasons to justify price control. They cite the current amendment as strong circumstantial proof of this, and have launched a patient advocacy campaign outlining the ‘iniquitous history’ behind the NRHPL from the time medical aids began in SA

(in 1947) to the ‘discredited’ changes in 2006 to the proposed set-up. SAMA says that the 2006 schedule was ‘anything but’ the cost-based tariff it was disingenuously disguised as, and was implemented despite loud protestations by healthcare professionals. Not only did it fail to reflect realistic prevailing costs at the time, but the technological and scientific advances in healthcare had resulted in more than 1 000 new services becoming available since 2006.

The net result was that ‘the public needs to understand that doctors cannot be expected to charge for their services at below the cost of running their practices’.

Amendment threatens private practice – as we know it

‘We have to make a living, and the unin­ tended consequence of this is that those who remain in the profession have to work longer hours while still being unable to fund their retirement. A few [doctors] have even resorted to unacceptable and/or fraudulent behaviour, driven by trying to make ends meet. The most shocking thing about this is that we’ve yet to see any evidence of alleged widespread abuse or trends. It would be far more helpful if the NDoH, rather than play politics while dancing to the tune of different funders, showed us the evidence’.

Dr Tony Behrman, CEO of the Inde­ pendent Practitioners Association Found­ a­ tion, predicts that if passed ‘as is’, the amendment will result in healthcare providers quickly agreeing to charge what medical schemes are willing to pay – because patients will simply refuse to pay out of their own pockets. ‘The market will rule, and specialists and hospitals will find their bills remain unpaid because the average South African can’t afford the excess,’ he said.

Pillay conceded that neither doctors nor hospitals were consulted, explaining ‘this is our attempt to solve the problem – we’re wide open to alternatives over the next 3 months while the draft is open for comment and input’.

Grootboom said that one of the key failures of the legislative funding framework was the lack of a risk equalisation fund and enforced enrolment (where all employees have to contribute towards a fund to widen the risk pool). ‘Somebody needs to monitor how much burden of disease a scheme is dealing with and then set aside a relevant risk fund. These are all key deficiencies – the minister, for political reasons, is actually missing the point.’

Patient advocacy group Section 27 said that the proposed amendment was a ‘step backwards’ and diminished patient access

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to healthcare services, pushing more South Africans towards dysfunctional public healthcare. Several patient advocacy groups, SAMA and the South African Private Practitioners Forum (SAPPF) believe that the amendment is unconstitutional.

SAPPF CEO Dr Clive Archer said that the NDoH’s submission to the Competition Commission inquiry spoke about an independently produced, cost-based tariff.

This was at wide variance with the proposed legal amendment. ‘The Department’s health inquiry submission recommends that the state establish a negotiation framework to support collective bargaining using a costbased structure as a point of departure,’ he said. Archer described the proposed amendment as ‘retrogressive, undermining the whole ethos of the current system, which is to protect families from massive medical expenses and prevent dumping on the state’.

The proposed legal amendment, induced by decade-long pricing strife and intransigence by most stakeholders in the private healthcare sector, errs on the side of funders, allowing (but not obliging) them to negotiate tariffs with any healthcare provider for which no co-payment or deductible is payable by the member.

Anaesthetists awaken colleagues to another problem

Meanwhile, the South African Society of Anaes­thesiologists said that another amend­ ment to Regulation 5 of the Medical Schemes Act, while less publicly reported, required attending doctors to provide a ‘discharge summary’ to medical schemes for all ailments, including PMB conditions, for hospital and doctor (potentially all medical) bills. While medical bills could be submitted at present using multiple digital platforms, these summaries were not catered for in current medical scheme systems. There was therefore ‘every possibility and likelihood’ that schemes would simply not reimburse medical practitioners ‘for months or years’, pending finalisation of such reports. These reports may also contain patient confidential information the sharing of which requires specific consent. Grootboom said that this lent statutory authority to an already worrying trend among medical schemes to get doctors to perform administrative functions on

IZINDABA

Healthcare prices architect in last-gasp appeal A former legal adviser to the CMS, who drew up the much-contested 2006 NHRPL, has told healthcare providers and funders to ‘man-up’ and bury the hatchet – or face ceding pricing control to government.

Stephen Harrison, a 9-year veteran of the CMS (2000 - 2009), has watched with growing exasperation for more than a decade as the players now suddenly and potentially most affected by his price referencing (in terms of the new Regulation 8 amendment) continue to grandstand while failing to move towards any solution or mutual accommodation.

Now a lecturer in emergency medicine at the Cape Peninsula University of Technology, Harrison bluntly told the July BHF conference that the ‘degree of hopelessness and despair’ displayed in the private healthcare industry’s submissions to the Competitions Commission healthcare inquiry invited ‘a radical interventionist approach’ from government.

With the Regulation 8 amendment – probably due for enactment early next year – now ‘Get it together’ – ex-CMS lawyer Stephen Harrison. basing PMB pricing on the 2006 NHRPL and, in his opinion, likely to benefit funders at the cost of patients and providers, his message to delegates was clear.

‘For goodness’ sake, let’s actually resolve this impasse and come up with a practical solution. This is an opportunity for a small group of leaders in the health sector to come together. The publication of the amendment provides an opportunity to do that. I’m not optimistic that this [regulation] is a sustainable way forward – historically we’ve never addressed the heart of the problem, we’ve just introduced more subterfuge in the industry. We need a reality check – and to admit that we’re now at a crossroads.’ Earlier he had said that private healthcare sector leaders needed to ‘stand up … remember we’re all in this boat together’.

While he accepted the bona fides of the NDoH in introducing the legislative amendment to attain a greater degree of certainty in the market – and that it did not intend to increase co-payments by patients – the net effect of Regulation 8 would be to create greater disparity between what providers charged and what medical schemes paid. The gap cover market would burgeon, and patients would either be denied care or revert to the public sector.

‘You can argue the long-term reductionist effect on premiums (as schemes save on PMB payout amounts), but the crunch will come when the consumer gets ill and needs cover for PMBs. The original intention for PMBs has been lost. If you go back to the Memorandum on the Objects of the Medical Schemes Bill of 1998, this was to protect necessary and cost-effective care and not to shift patients arbitrarily to a public hospital when their benefits are depleted.’ The amendment would create a significant barrier to necessary care and flouted Section 2 in the Constitutional protection of Section 27 – that government would take reasonable, progressive legislative and other measures within its resources to achieve the progressive realisation of access to healthcare. ‘To me this is a retrogressive step in the protection of rights of consumers. The main roleplayers are intractable and in significantly dug-in positions,’ he stressed. The protagonists needed to move from unilateral action, confrontation and ‘adversarialism’ to joint problem-solving, from competition for slices of the pie to a focus on enlarging the pie, and from entrenched respective positions to respective interests as departure points. Harrison advocated ‘Codesa-type’ talks between the adversaries, saying that SA had a rich history of resolving seemingly impossible disputes. their behalf. SAMA was examining the legal validity of all the intended amendments, as well as the practical implications for both its members and their patients, and would soon be submitting this to the minister.

BHF chair Dr Clarence Mini, speaking at the end of the July conference, said that BHFinitiated task teams would focus on ‘inclusive solutions and consensus’ during the draft

amendment input period. He appealed to all service providers to take part in creating a ‘road map’ that would provide fair remuneration to all parties and avoid patients sitting with co-payments. The BHF has been in tariff negotiations with the South African Dental Association (SADA) for the past 18 months, and recently met with SADA to evaluate coding changes and set up a risk advisory panel. Pushed

on when the ‘road map’ would be finalised, Mini said that a draft would ‘probably be ready between mid-September and mid-October’, describing it as ‘open-ended’.

Chris Bateman chrisb@hmpg.co.za S Afr Med J 2015;105(7):704-706.

DOI:10.7196/SAMJnew.8560

Inept drug supply management causing stock-outs Poor drug supply chain management by inappro­ priately skilled provincial officials – not the ‘red herring’ of manufacturer supply issues cited by national health minister Dr Aaron Motsoaledi – is primarily responsible for massive medi­

cine stock-out problems in the public health system.

This is the conclusion reached by Ground Up, a community news organisation focus­ ing on social justice stories in vulnerable communities, and the Treatment Action Cam­paign (TAC) and its Stop Stock Outs advocacy campaign. Verifying claims made in

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three identically labelled anony­mous letters detailing stock-outs in healthcare facilities in KwaZulu-Natal (KZN) (reflecting widespread pockets of dysfunction nationally), Ground Up said that items included basic over-thecounter medicines such as paracetamol. As of 10 June this year, King Edward VIII Hospital had 389 line items out of stock,

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Northdale Hospital 200, Grey’s Hospital 132, Ladysmith Provincial Hospital 191, East Street Clinic 96, and Imbalenhle Clinic 159, the last faci­lity stock-out count having been taken on 5 June. Sterile water for inhalation, alcohol and eyedrops were absent, as were various antibiotics, some antiretrovirals and some doses of fluconazole, an essential drug used to treat two potentially lethal opportunistic infections associated with HIV. Several products used for the management and treatment of tuberculosis were also out of stock across most facilities.

The whistle blowers, who insisted on anonymity, said that veiled threats had been made against them for speaking out, citing a ‘henchman in a big, pricey suit and pointy shoes, talking the whole time on his cell phone’ who came to their facility from the National Department of Health (NDoH).

The man reportedly told them that the national health minister ‘knows the names’ of the doctors who were reporting stockouts. They qualified their complaints by saying that the NDoH was ‘trying to get it right’ but was hamstrung by provincial

dysfunction, while health workers were innovatively sourcing alternative drugs using the private sector. Yet provincial medicine depots continued to fail hospitals and clinics because of poor stock level maintenance, poor processing of orders and dismal distribution.

A national audit by Stop Stock Outs last year found that only 20% of reported cases were caused by manufacturing issues. The remaining 80% were attributed to manage­ ment and logistical challenges between the medicine depot and clinics at both provincial and district levels. These included incorrect quantities of drugs being ordered by clinics, inaccurate forecasting of drugs per population, and poor stock management at facility level. Marcus Low, head of policy at the TAC, said that the NDoH ‘keeps shifting the focus to international supply shortages, but this is a red herring’. He said drugs such as penicillin and abacavir were the exception, as they were facing actual supply problems. ‘To deal with this crisis we must address the underlying problems of poor management, cadre deployment and

under-investment in medicines distribution,’ he stressed.

Motsoaledi has repeatedly cited problems with suppliers and even referred to an international report showing ‘that we are not the only country that has shortages’.

Responding to the latest specific KZN revelations, Motsoaledi said: ‘It is quite unfortunate that this whole saga emerged from KZN, because this is one of two provinces where we are piloting. KZN in particular is fully covered by the new cell phone technology that traces drug stock-outs right up to facility level.’ In his closing speech at the South African AIDS Conference on 12 June, Motsoaledi admitted that when drugs are not out of stock internationally and are still being manufactured, the problem lay with logistics. ‘I never denied, I never ran away,’ he added.

Chris Bateman chrisb@hmpg.co.za S Afr Med J 2015;105(7):706-707.

DOI:10.7196/SAMJnew.8543

‘Populist politicians’ take aim at ‘soft-target’ doctors Politicians responsible for healthcare delivery, espe­ ­ cially those who are medi­ cally qualified, should stop ‘playing to the crowd’ by making irresponsible and premature state­ ments about doctors who sometimes fail to save lives in an underequipped and dys­ functional public health system.

Both national health minister Dr Aaron Motsoaledi and his KwaZulu-Natal (KZN) counterpart Dr Sibongiseni Dlomo publicly slammed three doctors who they summarily suspended in June and July in Mpumalanga and KZN when they failed to save the lives of a critically ill pregnant mother, her unborn child and a car crash victim.

The entire leadership of the South African Medical Association, (SAMA) bristled at the way in which the politicians, as SAMA deputy chairperson Dr Mark Sonderup put it, ‘played judge, jury and executioner, with flagrant disregard to due process’.

‘We’re alarmed and concerned that in both instances the politicians climbed into the fray very quickly with comments about criminal activity and suspensions. You

need to be very cautious – professional conduct is not within their ambit – it’s not their role. Their role is to follow proper process, establish the facts and allow the proper authorities to deal with it. We expect them, both qualified doctors, to know better.’ His chairperson, Dr Mzukisi Grootboom, promptly e-mailed Motsoaledi asking for an explanation and set up urgent meetings with the minister, KZN Health MEC Dhlomo and the chief executives of the two hospitals. Said Grootboom: ‘We’re appealing for a measured response. The best thing they could have said is “We’re extremely concerned and will deploy all our resources to get to the bottom of it.”’

He said that continuation of such political behaviour would result in a slow erosion of respect for healthcare professionals and a loss of faith in the public health system.

‘Once that attitude sets in, it’s very difficult to reverse,’ he warned.

Motsoaledi brings criminal charges

Motsoaledi set in motion criminal pro­ ceedings against the two Evander Hospital

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Dr Aaron Motsoaledi, Minister of Health.

doctors in Mpumalanga, saying they had ‘a tendency to disregard instructions with impunity’, after they performed an emergency caesarean section on 15 June on a 37 weeks pregnant girl whose heart stopped during an eclampsia episode in a labour ward. He said that in his 32 years in the medical profession he had ‘never seen such an operation done on a young girl outside theatre’. In stark contrast, Prof. Guy Richards, Academic Head of Critical Care at the University of the Witwatersrand and

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Director of the Department of Critical Care at Charlotte Maxeke Academic Hospital, said that the doctors, one with 15 years of experience and teacher of a course on obstetric emergencies, should be ‘praised for their heroic actions in trying to save the baby’s life’. Richards said they had very little time before the baby suffered brain damage. The interventions failed to save the baby, and the teenage mother died 10 days after being transferred to a private hospital.

SAMA’s own unofficial preliminary probe concluded that an emergency C-section was necessary to save the baby’s life, presenting the only chance of stopping the mother’s seizures. There had been no time to transfer the mother to the theatre on the far side of the hospital, and a helicopter initially called to transfer her to a bigger hospital arrived only 3 hours later. Dr Cedric Sihlangu, Deputy Chairperson of the Junior Doctors Association of South Africa, said an urgent call was made to the theatre for equipment to be taken to the labour ward where the operation was conducted. The mother’s heart stopped at one stage while oxygen was being administered, but she had stabilised after the delivery. ‘In their hearts and minds the doctors were doing all they could to save the mother and child – for people to turn around and call them names is pretty disheartening,’ Sihlangu said.

Mahlane Phalane, Mpumalanga public sector doctor and Secretary-General of SAMA’s public sector trade union, said that the initial SAMA probe showed that the

doctors had acted correctly. He labelled Motsoaledi’s comments ‘reckless, premature, misguided and irresponsible’.

The second death, in mid-July, occurred at Osindisweni Hospital near Verulam on the KZN north coast after pedestrian Revishan Pandather, aged 19, was hit by a car in nearby Canelands. A private security guard, Prem Balram, alleged that he bled to death on a stretcher without being given medical attention. Shortly afterwards, KZN Health MEC Dhlomo went on television (prior to any probe being conducted), saying he was ‘appalled’ by the incident. The distraught doctor who had attended to Pandather appealed to SAMA for help when she was summarily suspended before being called to a formal inquiry by the region’s district health manager. Izindaba has established that paramedics delivered the patient (who had been fitted with a manual breathing assistance device) to the doctor, who tried to suction and clear his airway before realising that there was no laryngoscope in the hospital. She reportedly remonstrated with the paramedics for bringing the patient to an inappropriate and under-equipped facility, and he was then rerouted to the Mahatma Ghandi regional hospital. Grootboom said it was established from the hospital manager that Osindisweni had ‘not had a laryngoscope for a while’.

How it should be done …

Grootboom said that proper inquiry procedure would have involved the doctor’s

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senior consultant or line manager asking for and recording a full report, which they would then hand over to the hospital CEO or general manager, before any official internal local probe was launched. Instead the district manager suspended the doctor and the MEC made public pronouncements a full day before the probe. Sonderup concluded: ‘This is not the way the game is played. We ask the politicians to please stay out of it – let the proper people deal with issues of professional conduct. We’d perhaps understand if the MEC was a teacher or something, but he’s a doctor and should know better. They should try not to be populist about these issues.’

Dr Norman Mabasa, Chairman of the National Convention on Dispensing and an executive council member of the Society for General/Family Practitioners, said that such ‘demoralisation of doctors’ was now happening with ‘monotonous regularity’.

‘Doctors seem to be under siege, and this must be condemned. The ministry is supposed to regulate, not disorganise and demoralise. The message must be to follow due process without fail.’ Mabasa is a former SAMA general manager, chairperson and president and a former Limpopo Health MEC. Chris Bateman chrisb@hmpg.co.za S Afr Med J 2015;105(7):707-708.

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CLINICAL ALERT

Nososcomial transmission of viral haemorrhagic fever in South Africa G A Richards Prof. Guy Richards is currently Academic Head and Professor of the Division of Critical Care in the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa. He is Director of the Department of Critical Care at Charlotte Maxeke Johannesburg Academic Hospital, Johannesburg, and a chief physician in the Department of Medicine and Pulmonology there. Prof. Richards specialised in internal medicine in 1985 and subsequently qualified as a pulmonologist and intensivist, and was awarded his PhD in medicine in 1992 from the University of the Witwatersrand.

Corresponding author: G A Richards (guy.richards@wits.ac.za)

Recent events in West Africa have highlighted the potential for the viral haemorrhagic fevers (VHFs) to cause considerable mortality and morbidity among heathcare workers. However, this is not a new threat as, although the risk is currently increased, it has always been present.

In South Africa (SA) the only endemic haemorrhagic fever is Crimean-Congo haemorrhagic fever, transmitted by the Hyalomma tick, which is ubiquitous in cattle farming areas. Johannesburg, the commercial and transport hub of SA, is unusual in that all cases of VHF seen there are imported, either from rural areas in SA or from countries to the north. Johannesburg functions as the gateway to and from the rest of Africa, and as a destination for more affluent residents of neighbouring countries seeking medical attention. Numerous outbreaks of nosocomial infection have occurred in SA, and these are described in the form of brief case reports.

S Afr Med J 2015;105(9):709-712. DOI:10.7196/SAMJnew.8168

Emergency department personnel must be constantly aware of the risk of exposure to a patient with a communicable viral haemorrhagic fever (VHF). This requires that they are familiar with the symptoms and signs of this group of formidable diseases and that they should also be aware of geographical regions where VHFs are endemic or, as has lately been the case, epidemic. The subsequent care of a patient with a suspected or proven VHF requires strict attention to infection control and access to appropriate personal protective equipment (PPE). The following case reports illustrate the possibility of exposure in South Africa (SA) and highlight the potential for loss of life if these diseases are not recognised or infection control is inadequate.

Case reports

Marburg virus, 1975

The first documented case of Marburg virus in Africa, and the first since the original epidemic in West Germany and Yugoslavia in 1967, occurred in Johannesburg in February 1975.[1,2] The primary case, a young Australian, was admitted to Johannesburg Hospital (JH) after having toured what was then Rhodesia (now Zimbabwe).

He had a high fever, myalgia, vomiting, diarrhoea, a maculopapular rash, hepatitis, leucopenia and thrombocytopenia, and died on the 7th day after presentation without a diagnosis, from disseminated intravascular coagulation (DIC)-related haemorrhage and hepatic failure. Because a VHF was suspected and appropriate infection control practices had not initially been observed, all 35 direct contacts were isolated in the Johannesburg Fever Hospital (JFH), and all less close contacts kept under daily surveillance.

The travelling companion of the first patient subsequently became ill with similar symptoms, and was also admitted to JFH. She recovered after 10 days following a stormy course, having been cared for by volunteers from among the staff who had been placed in isolation. Eight days later, a 20-year-old nurse who had cared for the first patient before initiation of appropriate barrier nursing, and had

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in addition handled wet facial tissues while consoling patient 2 on the death of her travelling companion, also became ill. She continued to work at JFH, only stopping 24 hours later when symptoms became intolerable. Over the next 2 days she developed diarrhoea, fever, backache, myalgia, a rash and hepatitis. By day 7 she fortunately began to improve and was later discharged. The travelling companion could have contracted the disease prior to admission to hospital, and the nurse, although having had unprotected contact, had no more contact than many others.

Crimean-Congo haemorrhagic fever

On 28 August 1984, a 26-year-old man presented to a hospital near Cape Town, with haemorrhagic manifestations.[3] He was subsequently transferred to an intensive care unit (ICU) in an academic hospital, where he died from multiple organ dysfunction on 4 September.

The diagnosis was confirmed by isolation of the Crimean-Congo haemorrhagic fever (CCHF) virus from admission bloods, and from liver tissue removed post mortem. This was prior to the availability of identification techniques utilising the polymerase chain reaction (PCR), and initially no antibodies were detected. Seven healthcare workers (HCWs) subsequently became ill with CCHF, primarily because stringent isolation procedures were instituted only 36 hours after admission of the index patient, and initially numerous blood specimens were handled in the laboratory without precautions. The first three were nurses who had cared for the index patient during his first few hours in the ICU; two other nurses came into contact with contaminated material during the setting up of isolation procedures; a 37-year-old surgeon without known direct contact with the index patient but who had visited the ICU before isolation fell ill following an incubation period of 5 days and died 8 days later (the virus was subsequently isolated from his blood); and a nurse had a needlestick injury after initiation of contact precautions.[4] Once appropriate infection control with isolation had been introduced, the latter was the only infection that occurred.

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In December 1985, a 47-year-old nurse at Kimberley Hospital died of CCHF. She had been caring for a 52-year-old man from the Kimberley area who had contracted CCHF by tick bite. This patient survived. There are few further details available about this incident (personal communication, Jacqueline Weyers, National Institute of Communicable Diseases, SA).

On 4 April 2006, a 24-year-old employed in a private pathology laboratory was admitted to the JH ICU with a 2-day history of an influenza-like illness (unpublished data, GAR). The only clinical abnormality was a platelet count of 7 × 109/L. He had no travel history, no tick bites and no contact with animals. However, the laboratory in which he worked had processed specimens from an importer of birds and monkeys from the Democratic Republic of the Congo who had died on 1 April from an unidentified haemorrhagic illness. This patient had also been fishing in KwaZulu-Natal Province on 15 March, where he had been bitten by ticks; however, the PCR had been negative for VHFs. The laboratory worker had been on duty from 28 to 31 April. It was subsequently established that he had sorted through and repacked other specimens into the same refrigerator in which those from the first patient were stored (as had others in the laboratory), but there was no record of any specific exposure. He was tested for VHFs, all of which were negative, as were tests for other infectious diseases. However, barrier nursing procedures were maintained throughout. He was unresponsive to any form of therapy, and 3 days after admission he was intubated and mechanically ventilated after developing a large spontaneous hemopneumothorax. Twelve days after admission, repeat PCR for CCHF tested positive. Treatment with ribavirin was commenced when he developed a refractory hyperpyrexia of 41oC, but he died shortly thereafter.

PCR tests are not always reliable initially, and VHFs should be considered in any HCW, including laboratory workers presenting with haemorrhagic manifestations. If an alternative diagnosis is not established, barrier precautions should be continued until a VHF is excluded. In this instance, no further transmission to staff members at JH occurred.

Ebola Gabon virus

In 1996 - 1997 an outbreak of Ebola virus disease (EVD) occurred in the Booué area of Gabon, with many patients subsequently transported to the capital, Libreville.[5] This distant incident later impacted on SA.[6] On 2 November 1996, a 46-year-old nursing sister/anaesthetic assistant became ill with fever and headache, requiring admission to a Johannesburg clinic on the 6th. She had no history of travel or insect bites, and as far as she was aware had not treated anyone with a communicable disease. The diagnosis was unclear, but because there was leucopenia (2.4 × 109/L on admission, decreasing to 0.8 × 109/L by 9 November) she was treated as having bacteraemia. She subsequently developed hepatitis and severe diarrhoea, and both the platelet count and renal function declined precipitously. Prior to definitive diagnosis, she developed haematemesis and melaena requiring active resuscitation, gastroscopy, intubation and mechanical ventilation. These were performed without precautions other than surgical masks, gloves, plastic aprons and in some cases permeable surgical gowns. When the bleeding continued, laparotomy was performed using standard surgical apparel, which confirmed an oedematous, haemorrhagic gastritis for which surgical intervention was not possible. The clinical features led to the suspicion of a VHF, and diagnostic investigations later confirmed the diagnosis of EVD by culture and immunofluorescence (again prior to the availability of PCR testing).

The patient was transferred to JH and the Department of Health was involved in logistical aspects. At JH she was found to have

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haematological evidence of DIC, and had visible petechiae and haematomas. She was continued on mechanical ventilation because of a low Glasgow Coma Score and because she became progressively more hypotensive. A Swan-Ganz catheter (SGC) was inserted; the initial pulmonary artery occlusion pressure was 22 mmHg, and both the left ventricular stroke work index and calculated systemic vascular resistance were low and remained so throughout the illness.

The SGC did not measure continuous cardiac output, and these parameters were measured only occasionally to minimise exposure to bodily fluids. The platelet count remained low despite transfusions, methlyprednisone, broad-spectrum antibiotics, gammaglobulin and a relook laparotomy, and the temperature failed to settle. On day 23, she died from an intracranial haemorrhage. No antivirals or immune serum were utilised. Despite a strong antibody response and sustained improvement in liver enzymes, Ebola antigen was still detected in the blood up to day 20 and in the urine up to day 23.

Once a definitive diagnosis had been made, a search was undertaken for the source of the infection. The only possible candidate was a doctor who had been brought to SA on a commercial flight from Libreville, with a history of 8 days of fever and diarrhoea.

The nursing sister, although wearing gloves, surgical gown and mask, had been exposed to a great deal of blood from this patient during and after placement of a central venous catheter. However, there were no reports of needlestick injury and she had no more exposure than those who placed the catheter or performed the gastroscopy or laparotomy on the Gabonese doctor at a later stage.

The Gabonese doctor, who had been discharged, was found to have highly positive serology for Ebola, and antigen was also recovered from a semen sample. Although he denied knowledge of an Ebola outbreak in Gabon, it was determined that he had treated a patient from Booué, the epicentre of the epidemic.[5] Little was known about Ebola at the time, and even experts in the field were uncertain as to the mode of transmission. It was presumed usually to be via contact with body fluids, but airborne transmission was considered possible, as breathable 0.8 - 1.0 - 2.0 µm droplets had been documented to be highly infectious to rhesus monkeys exposed to the Reston and Zaire strains of Ebola virus in laboratory conditions.[7] This was the first time JH staff had managed a patient with EVD, and initially there was considerable consternation. Highlevel barrier nursing was considered preferable and the patient was isolated, PPE was worn, and high-efficiency particulate air (HEPA)filtered respirators were used for invasive procedures. Case definitions were developed and distributed widely, as were definitions outlining what constituted significant exposure, and protocols were devised to optimise management.

Novel arenavirus, 2008

In 2008 an outbreak of an arenavirus infection similar to Lassa fever occurred.[8] The primary case was a travel consultant in Zambia who became ill with fever and sore throat. Rapid deterioration required her transfer from Zambia to a Johannesburg clinic on 12 September, where she died 2 days later with cerebral oedema and multiple organ dysfunction. On 22 September, patient 2, an emergency medical therapist who had accompanied the primary case between Zambia and SA, became ill and on 27 September was transferred to the same clinic, where he died on 2 October. Given the similarity of clinical presentation,[9] tests for VHF and other communicable diseases were performed, but were negative. Contact tracing was nevertheless initiated, which identified two further cases, a nursing sister and a cleaner, both of whom had been in contact with the primary patient.

Both also tested negative for Lassa, CCHF, Marburg and Ebola viruses and had a rapid and fatal course. However, all four of these patients

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were subsequently found to be PCR-positive for a new arenavirus that was named the Lujo virus. On 5 October, another nursing sister who had been involved in the care of patient 2 became ill with fever, leucopenia, thrombocytopenia and a rash and tested positive for the arenavirus.[9] This engendered considerable fear among all the staff, and in particular the nursing sister herself, who was a young mother.

She was treated at the clinic at which she worked with assistance from the JH departments of Critical Care, Infectious Diseases and Infection Control. Oral ribavirin was initiated along with supportive therapy, but the hepatitis and thrombocytopenia worsened and she became confused. Consultations with international colleagues indicated that oral therapy was unlikely to achieve the minimum inhibitory concentrations necessary to eradicate the virus rapidly (personal communication, D G Bausch), so intravenous ribavirin was sourced from Valeant Pharmaceuticals (USA) in The Netherlands for the (iniquitous) price of USD45 000 for a 10-day course.[10] On initiation of this therapy there was prompt improvement, and the patient was subsequently discharged well.

It is not known how the two nursing sisters contracted the illness.

All had used standard infection control procedures in the emergency department, including gown, gloves and surgical mask. It is possible that breaches occurred, because use of PPE is seldom sufficiently strictly supervised in the emergency room (ER), particularly prior to a definitive diagnosis being made. Neither reported needlestick injuries or contamination of open wounds with secretions. It is also not certain how the cleaner became ill; however, standard infection control procedures may not have been strictly followed, particularly if the cubicle was scrubbed down without use of gloves. This event emphasised the need for universal precautions for all patients admitted to the ER and ICU, regardless of the diagnosis.

Discussion

Many hospitals internationally are preparing for the management of patients with VHF, specifically because of the impact of the current Ebola outbreak. Many of these institutions have biosafety level 3 and 4 laboratories and designated isolation areas that enable them to deal with these formidable viruses safely.[11,12] However, there is no telling where a VHF might appear, as most patients unfortunately do not know which are the specific referral hospitals, and do not know or suspect their own diagnoses. We therefore recommend that all hospitals have some awareness of the VHFs and have PPE available in the emergency department in order to obviate the dreadful consequences of what is, in many cases, the unnecessary loss of a colleague. We acknowledge that epidemics such as those in West Africa transiently increase adherence to infection control procedures. Nevertheless, even once the panic has died down, regular reinforcement of standard precautions should be practised in all hospitals to avoid a tendency to complacency.[13]

Reduction of risk

A detailed travel history is mandatory for all patients presenting at any hospital, and if positive should include details of possible incubation periods and specific exposures.[14] Hospitals in areas of greatest risk should have a case definition that alerts frontline doctors to the possibility of a VHF, and this should be modified according to each outbreak. While these diseases are rare, they must be recognised as possible in any HCW or laboratory worker presenting with acute onset of documented fever (oral ≥38ºC or axillary ≥37.5ºC) and thrombocytopenia without any obvious alternative diagnosis, or in any patient with a history of travel to an area where these diseases are prevalent. Over 3 billion people travel by air annually, and as has recently been shown, any transmissible disease is but a few hours away. Whereas malaria is the most common diagnosis among travellers requiring hospitalisation for fever and thrombocytopenia,

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accounting for 27 - 42% of cases, this should not lead to a decrease in vigilance.[15,16] Personal protection has become increasingly important because of the risk of exposure to transmissible diseases such as HIV, tuberculosis, influenza, anthrax and measles.[17-19]

Preparation of hospitals

Following the 1996 Ebola scare, JH was designated as a referral centre, and recently a number of other hospitals around the country have been similarly designated despite minimal instruction and training in infection control techniques. HCWs most likely to be exposed should receive regular training in the use of high-level PPE and in the reduction of environmental contamination.[20-22] At JH, now Charlotte Maxeke Johannesburg Academic Hospital (CMJAH), ICU and ER staff had been familiarised with disease recognition and PPE on a regular basis, even before the current Ebola outbreak. Infection control staff at CMJAH are also always available to instruct staff in the event of an outbreak, and in an ongoing fashion, between outbreaks.

An isolation area has been created capable of managing three critically ill patients in separate cubicles with a negative-pressure environment, with monitors no longer in use in the main ICU. This facility is maintained by infection control personnel and is permanently stocked with PPE. Specific items have been added to reduce overall exposure in the ICU cubicles, such as plastic specimen and 24-hour urine containers, buckets with biocide in which instruments are soaked, rubbish-disposal boxes containing two red plastic bags, and X-ray, dialysis and ECG machines and a cardiac output monitor. Linen that has been condemned owing to wear is used and incinerated after use.

Specific infection control procedures have been established, and intensive education, particularly with regard to the donning and doffing of PPE, has been instituted; in the event of an outbreak, 24-hour supervision by infection control staff has been mandated. We believe this to be critical to management of these cases, and it was often not the case in Europe and the USA where transmission occurred. The education and supervision includes the safe performance of invasive procedures and protocols that must be followed when drawing and transporting laboratory specimens.

The stress of managing such cases requires reorganisation of staff schedules; in the CMJAH unit, four nursing staff at a time would work 12-hour shifts, 3 hours on and 3 hours off. A record is kept of all contacts, and all staff are monitored with daily temperature and symptom charts.

Baseline platelet count and transaminase values are obtained. Protocols have also been developed for collection and transport of specimens (only the most experienced laboratory staff process samples) and the efficient and safe management of waste. Similarly, procedures have been developed for the management of patients who die.

The World Health Organization and Centers for Disease Control guidelines with regard to PPE have until recently been somewhat contradictory, in that an N95 respirator has been advised for laboratory workers, whereas clinicians have been advised to use surgical masks.

We believe this to be illogical, considering that the circumstances in which patients are managed are always more chaotic than those in the controlled laboratory environment, and as such (especially since the viruses are potentially lethal) an N95 mask as a minimum should be mandatory. It should be noted that there remains some uncertainty as to the modes of transmission of viruses such as Ebola, and that many of the procedures involved in management are aerosol generating.[23]

Ethics and personal liberties

An often neglected component of training relates to professional and ethical responsibilities, including responses to unjustified absenteeism and individual liberty and autonomy. While it may be compulsory to provide care for infected patients, HCWs still have to weigh this against competing obligations.[24] In our experience

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there is a remarkable commitment and sense of duty among staff who are involved. We find that regular training in infection control procedures creates a sense of reality that makes staff more likely to consider management of these patients as a routine event. This does not imply negligence, but rather a reduction in the ‘fear’ element often associated with lapses in infection control. It is critical also that staff designated to care for these possible VHF patients feel supported by the hospital administration and senior staff members, and that they are recognised for the sacrifices that they are called on to make.

In the management of multiple patients with a variety of VHFs in various Johannesburg hospitals, no doctor or nurse, or any member of the ancillary staff, has refused to care for the patients. This has been a reflection of the availability of appropriate PPE and the reassurance, leadership and support from clinical heads and infection control staff.

We hope that our experiences in somewhat resource-constrained environments may be of assistance to others faced with similar situations.

1. Gear JS, Cassel GA, Gear AJ, et al. Outbreak of Marburg virus disease in Johannesburg. BMJ 1975;4(5995):489-493.

2. Martini GA. Marburg agent disease in man. Trans R Soc Trop Med Hyg 1969;63(3):295-302.

3. Van Eeden PJ, Joubert JR, van de Wal BW. A nosocomial outbreak of Crimean-Congo haemorrhagic fever at Tygerberg Hospital: Part I. Clinical features. S Afr Med J 1985;68(10):711-717.

4. Centers for Disease Control Crimean-Congo hemorrhagic fever – Republic of South Africa. MMWR Morb Mortal Wkly Rep 1985;34(7):94, 99-101.

5. Georges AJ, Leroy EM, Renaud AA, et al. Ebola hemorrhagic fever outbreaks in Gabon, 1994-1997: Epidemiologic and health control issues. J Infect Dis 1999;179(Suppl 1):S65-S75.

6. Richards GA, Murphy S, Jobson R, et al. Unexpected Ebola virus in a tertiary setting: Clinical and epidemiologic aspects. Crit Care Med 2000;28(1):240-224.

7. Peters CJ, LeDuc LW. An Introduction to Ebola: The virus and the disease. J Infect Dis 1999;179(Suppl 1):ix-xvi. [http://dx.doi.org/10.1086/514322] 8. Paweska JT, Sewlall NH, Ksiazek TG, et al. Nosocomial outbreak of novel arenavirus infection, southern Africa. Emerg Infect Dis 2009;15(10):1598-1602. [http://dx.doi.org/10.3201/eid1510.090211] 9. Sewlall NH, Richards GA, Duse A, et al. PLoS Negl Trop Dis 2014;8:e3233. [http://dx.doi.org/10.1371/ journal.pntd.0003233]

10. Richards GA, Sewlall N, Duse A. Availability of drugs for formidable communicable diseases. Lancet Infect Dis 2009;373(9663):545-546. [http://dx.doi.org/10.1016/S0140-6736(09)60202-6] 11. Risi GF, Bloom ME, Hoe NP, et al. Preparing a community hospital to manage work-related exposures to infectious agents in biosafety level 3 and 4 laboratories. Emerg Infect Dis 2010;16(3):373-378. [http://dx.doi.org/10.3201/eid1603.091485] 12. Kortepeter MG, Martin JW, Rusnak JM, et al. Managing potential laboratory exposure to Ebola virus by using a patient biocontainment care unit. Emerg Infect Dis 2008;14(6):881-887. [http://dx.doi. org/10.3201/eid1406.071489] 13. Randle J, Arthur A, Vaughan N. Twenty-four-hour observational study of hospital hand hygiene compliance. J Hosp Infect 2010;76(3):252-255. [http://dx.doi.org/10.1016/j.jhin.2010.06.027] 14. Ryan ET, Wilson ME, Kain KC. Illness after international travel. N Engl J Med 2002;347(7):505-516. [http://dx.doi.org/10.1056/NEJMra020118] 15. O’Brien D, Tobin S, Brown GB, Torresi J. Fever in returned travelers: Review of hospital admissions for a 2-year period. Clin Infect Dis 2001;33(5):603-609. [http://dx.doi.org/10.1086/322602] 16. Doherty JF, Grant AD, Bryceson AD. Fever as the presenting complaint of travellers returning from the tropics. QJM 1995;88(4):277-281.

17. Sprung CL, Zimmerman JL, Christian MD, et al. Recommendations for intensive care unit and hospital preparations for an influenza epidemic or mass disaster: Summary report of the European Society of Intensive Care Medicine’s Task Force for intensive care unit triage during an influenza epidemic or mass disaster. Intensive Care Med 2010;36(3):428-443. [http://dx.doi.org/10.1007/s00134-010-1759-y] 18. Brouqui P, Puro V, Fusco FM, et al., for the EUNID Working Group. Infection control in the management of highly pathogenic infectious diseases: Consensus of the European Network of Infectious Disease.

Lancet Infect Dis 2009;9(5):301-311. [http://dx.doi.org/10.1016/S1473-3099(09)70070-2] 19. Wang C, Weia S, Xianga H, et al. Evaluating the effectiveness of an emergency preparedness training programme for public health staff in China. Public Health 2008;122(5):471-477. [http://dx.doi. org/10.1016/j.puhe.2007.08.006] 20. Richards GA, Sprung CL. Educational process: Recommendations and standard operating procedures for intensive care unit and hospital preparations for an influenza epidemic or mass disaster. Intensive Care Med 2010;36(Suppl 1):S70-S79. [http://dx.doi.org/10.1007/s00134-010-1768-x] 21. Lau J, Fung K, Wong T, et al. SARS transmission among hospital workers in Hong Kong. Emerg Infect Dis 2004;10(2):280-286. [http://dx.doi.org/10.3201/eid1002.030534] 22. Rebmann T, English JF, Carrico R. Disaster preparedness lessons learned and future directions for education: Results from focus groups conducted at the 2006 APIC conference. Am J Infect Control 2007;35(6):374-381. [http://dx.doi.org/10.1016/j.ajic.2006.09.002] 23. MacIntyre CR, Chughtai AA, Seale H, Richards GA, Davidson PM. Respiratory protection for healthcare workers treating Ebola virus disease (EVD): Are facemasks sufficient to meet occupational health and safety obligations? Int J Nurs Stud 2014;51(11):1421-1426. [http://dx.doi.org/10.1016/j. ijnurstu.2014.09.002] 24. Thompson AK, Faith K, Gibson JL, Upshur REG. Pandemic influenza preparedness: An ethical framework to guide decision-making. BMC Med Ethics 2006;7:12 PMID:17144926. [http://dx.doi.org/10.1186/1472-6939-7-12]

Accepted 30 June 2015.

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12/2014/LAM/157

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CLINICAL ALERT

Subacute sclerosing panencephalitis in South African children following the measles outbreak between 2009 and 2011 E Kija, A Ndondo, G Spittal, D R Hardie, B Eley, J M Wilmshurst Edward Kija completed his training in the Paediatric Neurology Unit, Department of Paediatrics and Child Health, Red Cross War Memorial Children’s Hospital (RCWMCH) and the Faculty of Health Sciences, University of Cape Town, South Africa, where he collated the patient data included in this study. He has since returned to work as the first accredited paediatric neurologist in Dar es Salaam, Tanzania. Alvin Ndondo, a consultant in the Paediatric Neurology Unit, was integral in the clinical recognition and diagnosis of these children. Graeme Spittal, a paediatrician in the Paediatric Neurology Unit, assisted in their management. Diana Hardie works in the Division of Medical Virology in the Department of Clinical Laboratory Sciences, Faculty of Health Sciences, University of Cape Town and National Health Laboratory Service. She completed and analysed the screens undertaken to confirm the diagnosis of SSPE in these children. Brian Eley is head of the Paediatric Infectious Diseases Department in the Department of Paediatrics and Child Health, RCWMCH and Faculty of Health Sciences, University of Cape Town. He assisted in the collation of the data on the patients and relevant aspects in the literature. Jo Wilmshurst is head of paediatric neurology at RCWMCH and the Faculty of Health Sciences, University of Cape Town. She co-managed the patients, oversaw the data collation and co-ordinated the writing of the manuscript.

Corresponding author: J Wilmshurst (jo.wilmshurst@uct.ac.za)

Between 2009 and 2011, there was an outbreak of measles throughout South Africa (SA). The largest age category infected was children <5 years of age. In 2014, four patients, with a median age of 4 years and 5 months (range 4 years 3 months - 4.5 years), three males and one female, presented with subacute sclerosing panencephalitis (SSPE). All were infected with measles during the period of the 2009 - 2011 outbreak in early infancy, at a time when their immune systems were immature and before they were vaccinated against the measles virus.

One patient was immunocompromised, with vertically acquired HIV infection. All the children presented with cognitive and behavioural decline, abnormal movements and medically intractable myoclonic and atonic seizures. Outcome was poor in all and no reversibility was evident with standard therapeutic interventions. Optimal seizure control with carbamazepine is reported in patients with SSPE. Three of our patients who received carbamazepine experienced improved seizure control, but their neuroregression continued. Since submission of this case series, patient 1 (see Table 1) has died, and a further child has presented with the same clinical phenotype as described. On the basis of this clustering of patients in the Western Cape Province, SA, it is important to screen children admitted with acute cognitive decline and intractable seizures for SSPE, especially those who were infants during the measles outbreak.

S Afr Med J 2015;105(9):713-718. DOI:10.7196/SAMJnew.7788

Between 2009 and 2011, 18 431 laboratory-confirmed cases of measles were reported from the nine provinces of South Africa (SA) (cumulative incidence 3/100 000 population).[1] The highest incidence was in children <1 year of age (603/100 000). The incidence in infants <6 months of age was 302/100 000, in those aged 6 - 8 months 1 083/100,000, and in those aged 9 - 11 months 724/100 000. Forty-eight per cent of the patients were <5 years of age, with the result that significant additional demand was placed on child health services.[1] A single strain of measles virus (genotype B3) circulated throughout this outbreak.

Across SA in 2002, following the ‘catch-up’ campaign in 1996 - 1997, there was a 96% decrease in patients admitted with measles, and a 100% decline in reported deaths.[2] When the outbreak in 2009 occurred, a nationwide mass vaccination campaign was therefore undertaken over a 2-week period in mid-April 2010. Concern was raised that, compared with the effectiveness of the previous vaccination campaign, the one in 2010 lacked the same uptake levels, with anecdotal reports of poor uptake on the part of some parents and schools.[3] As an immediate consequence of the measles outbreak, a cohort of eight HIV-infected patients with probable (n=3) or definite (n=5) measles inclusion body encephalitis (MIBE) were managed in the

713

neurology department at Groote Schuur Hospital, Cape Town, SA, between July and October 2010.[4,5] MIBE manifests between 1 and 7 months after acute measles infection. Patients present with seizures, often epilepsy partialis continua, and altered cognitive awareness. [6] The mortality rate is 85%, and survivors are left with significant neurosequelae. In the case series reported from the Western Cape Province, six of the eight patients died and all followed the clinical course reported above.[4,5] The youngest confirmed patient was 14 years of age. Anecdotally, two additional children, aged 10 (male) and 11 (female) years and suspected to have MIBE, were managed at Red Cross War Memorial Children’s Hospital, Cape Town, with a parallel clinical course and findings on neuroimaging; both these patients also had HIV infection. However, serum and cerebrospinal fluid (CSF) screening in these patients, and even brain biopsy in one patient, failed to identify the measles virus. Albertyn et al.[4] suggested that additional cases of MIBE were probably occurring across the country, but were potentially not detected without screening for the virus or completing the required notifications; in addition, some patients may have died before reaching medical services.

Five years after the most recent (2010) measles outbreak in SA, a new cohort of children have presented with subacute sclerosing panencephalitis (SSPE).

September 2015, Vol. 105, No. 9

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Case summaries

Between April and June 2014, four children were admitted to Red Cross War Memorial Children’s Hospital with intractable seizures and neuroregression (Table 1). All had previously been well, and they were aged between 4 years and 3 months and 4.5 years (median 4 years and 5 months) at presentation. Typical seizures consisted of recurrent myoclonic and atonic seizures. The atonic seizures manifested as ‘head nods’.

Cognitive function was progressively affected in all. Patient 3 had optic disc swelling at presentation, which remained static and was not associated with evidence of raised intracranial pressure. One of the children (patient 1) was immunocompromised as a result of HIV-1 infection, but had an undetectable viral load on antiretroviral therapy (ART).

CSF and serum analysis showed raised measles antibody titres, confirming the diagnosis of SSPE. Prior analysis with the polymerase chain reaction (PCR) for measles was negative on CSF in all, and initially led to the misleading assumption that the children did not have SSPE. Additional results included normal findings on CSF analysis and microscopy in all patients.

CSF oligoclonal bands were positive in all the patients except patient 1. Findings on magnetic resonance imaging (MRI) (Figs 1A, 1B, 2A and 2B) varied from unremarkable at presentation to the typical nonspecific white matter hyperintensities described in SSPE.[6] Electroencephalograms (EEGs) (Figs 3 - 6B) typically demonstrated generalised periodic spike, or polyspike, wave discharges with suppression of background activity, which were intermittent and correlated with seizure events. Serial studies confirmed progressive deterioration with increasingly suppressed background activity.

Prior measles infection was rarely reported on routine history taking and had to be actively sought. Further questioning of the accompanying adults revealed that all the children had been infected with measles, either definitely or based on a history of a typical rash, between 3 months and 1 year of age. All would have received their first measles vaccination at 9 months of age, but were younger than this when they contracted measles.

Treatment in all children involved multi­ ple combinations of antiepileptic drugs (AEDs), but with minimal response. How­ ever, improved control of myoclonic and atonic seizures was evident following the introduction of carbamazepine in three of the four children. Patient 3 remained on lamotrigine, as his seizures appeared to

A

A a

a

a

Fig. 1A. Patient 2. MRI of the brain (T2-weighted fluid attenuation inversion recovery (FLAIR)) 4 months after presentation. Imaging demonstrates nonspecific, bifrontal white matter foci of signal abnormality (a).

a

Fig. 2A. Patient 3. MRI of the brain (T2-weighted FLAIR) 1 month after presentation, showing diffuse nonspecific small areas of hyperintensity scattered in the superficial and deep white matter in the frontal temporal lobes bilaterally, with no mass effect (a).

B

B a

a b d

e

c

b a

Fig. 1B. Patient 2. MRI of the brain (T2weighted FLAIR) 8 months after presentation, demonstrating an interval progression of signal abnormality in the frontal lobes (a). The imaging shows high signal, and there is corresponding restricted diffusion in the deep white matter of both frontal lobes (a), the genu of the corpus callosum (b) and the right centrum semi ovale (c). The entire right temporal lobe is now swollen with high-signal white matter and blurring of the grey/white junction (d). This area is also restricted. The medial thalami and left parietal white matter are also involved (e).

Fig. 2B. Patient 3. MRI of the brain (T2-weighted FLAIR) 6 months after presentation, showing marked interval deterioration with high signal in the white matter throughout the left cerebral hemisphere, most prominent in the parietal lobe (a). This also involves the posterior corpus callosum and posterior limb of the left internal capsule (b). Similar changes, but to a lesser extent were evident in the right parietal white matter. There was global volume loss within the left cerebral hemisphere, also involving the left cerebral peduncle and midbrain. In view of the previous measles infection, these findings were considered to be in keeping with SSPE with interval worsening.

respond to this agent. In the management of patient 1, since carbamazepine is usually avoided in combination with ART, infectious diseases specialists were consulted; given the strong data supporting the use of carbamazepine in patients with SSPE, the drug was initiated and levels of both

carbamazepine and ART closely monitored.

To date no further complications have occurred and the patient has experienced improved seizure control.

All the patients had progressive neuro­ cognitive regression, loss of ambulation and speech, feeding dependency and frequent

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4 yr 3 mo.

(April 2014)

2 (M)

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September 2015, Vol. 105, No. 9

4.5 yr (June 2014)

3 mo.

3 mo.

8 mo.

<1 yr

Age when infected with measles

GTCS with fever, 1 mo., later ‘tics’, abnormal movement then myoclonus, cognitive regression and behavioural difficulties

Prior viral illness, then acute 3-d history of falling, followed by a GTCS and unsteadiness. Then rapidly evolving seizures. Emotional lability with motor and cognitive regression. Swollen optic discs, which remained unchanged.

Developed obtunded state with right hemiplegia

Seizures for 5 mo., but 1 mo. of evolving seizures and cognitive regression, then coma

1 wk Hx, seizures, low tone unsteadiness, cognitive regression

Presentation and evolution Seizure types

Myoclonic and atonic seizures

Myoclonic and atonic seizures, focal motor seizures

Focal seizures then myoclonic and atonic seizures, GTCS

‘Head nodding’ – atonic seizures then myoclonic seizures

EEG

Slow background and period high-amplitude slow waves (Fig. 6a) At 1/12 slow background, frequent generalised polyspike and wave discharges (Fig. 6b)

At presentation very slow background awake. Asleep recorded generalised and independent polyspike and spike and wave discharges At 2/12 markedly abnormal with persistent spike and wave discharges associated with myoclonic jerks, compatible with electrical status (Fig. 5)

At 5/12 generalised spike and wave activity more marked over the left (Fig. 4) At 6/12 frequent spikes and generalised polyspike and spike and wave activity on a severely encephalopathic background

At 4/12 s burst-suppression in sleep. Myoclonic jerks on an encephalopathic background on awakening (Fig. 3)

F = female; M = male; Hx = history; GTCS = generalised tonic-clonic seizures; Neg. = negative; Ab = antibody; Y = yes; N = no. *Assay: Enzygnost anti-measles virus IgG (Siemens) (mIU) quantified according to the α-method described in the kit insert. † HIV exposed.

4 (F)

4 yr 5 mo.

(May 2014)

4 yr 5 mo.

(April 2014)

1 (M)

3 (M)

Age at presentation

Patient No. (gender)

Table 1. Demographics of the children with SSPE, and clinical findings

Neuroimaging (MRI)

Normal at presentation

At presentation nonspecific diffuse, small white matter T2 and FLAIR hyperintensities in the superficial and deep areas bifrontally (Fig. 2a) At 5/12 progression with T2/FLAIR white matter hyperintensities throughout left hemisphere more than right.

Involvement of posterior corpus callosum and posterior internal capsule on the left. Global volume loss with left cerebral hemispheric and cerebral peduncle predominance (Fig. 2b)

At 8/12 nonspecific bifrontal foci of signal abnormality (Fig. 1a) At 9/12 progression of the frontal lobes, swollen right temporal lobe, involvement of medial thalami and left parietal lobe (Fig. 1b)

Arachnoid cyst. Mild cerebellar atrophy.

Thinning of splenium of corpus callosum

Neg.

Neg.

Neg.

Neg.

Measles virus PCR

28 745

19 845

46 933

73 453

CSF Ab* (mIU/ml)

Valproate, levetiracetam, clobazam, carbamazepine, isoprinosine

Phenobarbitone, sodium valproate, clobazam, lamotrigine, pyridoxine, folinic acid

Sodium valproate, clobazam, lamotrigine, carbamazepine, phenobarbitone

Valproate, levetiracetam, clobazam, carbamazepine

Interventions (therapeutic and AEDs) HIV

N

N

N†

Y

Outcome

Poor Stage 3

Poor Stage 3

Poor Stage 4

Poor Stage 3

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Table 2. Clinical stages of progression of SSPE[6]

a

b

a

b

a

Fig. 3. EEG from patient 1 in sleep state 4 months after presentation, demonstrating profoundly attenuated background (b) with recurrent periodic generalised paroxysms (a) consistent with a burst suppression pattern.

a

b

b

b

b

Fig. 4. EEG from patient 2 in sleep state 4 months after presentation, demonstrating slow attenuated background and recurrent periodic generalised spike and wave (a) and polyspike discharges (b) with suppression in between discharges.

seizure activity. Based on the four stages of the disease progression, as summarised in Table 2, three patients had reached stage 3 of the disease at the time of writing, and patient 2 was at the most severe stage 4.

Patient 4 was commenced on isoprinosine after the product was imported from abroad with approval from the Medicines Control Council and the local pharmacy therapeutics committee. Motivations are in place for the remaining patients.

Discussion

In children aged <5 years, measles is the second most common cause of death due to a vaccine-preventable disease, and it is in the top ten causes of death due to infectious diseases.[6] The World Health Organization predicts an increase in the

numbers of measles cases and deaths as a result of logistical and financial challenges affecting vaccination coverage.[7] In 2009, the US Centers for Disease Control published a report supporting this statement, and in the same year this is exactly what transpired in SA.[1,7] Between 2009 and 2010, 28 African countries reported measles outbreaks.[8] In Europe measles outbreaks were reported in 36 of the 53 European member states between 2009 and 2011, with the primary reason for the outbreaks reported to be failure to vaccinate susceptible popula­tions. [9] Vaccine safety concerns and perceived fewer benefits from vaccinations were found to be leading reasons for parents delaying vaccination of their children or refusing to vaccinate.[10] The USA, which had declared itself ‘measles eliminated’ in 2000, issued a warning

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Stage

Clinical features

1

Mental deterioration accompanied by alterations in personality

2

Myoclonus and often seizures

3

Progressive neurological deterioration marked by rigidity

4

Optic atrophy, akinetic mutism and coma

in 2014 of disease recrudescence due to im­ported cases.[11] It can be concluded that this vaccine-preventable disease is far from contained.

There are three neurological compli­ cations following measles virus infection: acute disseminated encephalomyelitis, MIBE and SSPE.[6] SSPE affects immune-competent and immune-compromised hosts. The virus is present in the brain, and the incidence is reported to be 1/10 000, increasing to 1/2 500 in children who contracted measles under 5 years of age.[6] As in our patients, the condition occurs more commonly in boys than in girls.[6] The risk of central nervous system (CNS) infection is increased when infection with the measles virus occurs at a young age, especially <2 years, when the immune system is immature and residual maternal antibodies may still be present.[6] This was the case for the patients reported in this case series, all of whom were known or believed to have been infected with measles before 9 months of age. The pathogenesis of SSPE is poorly understood. Although viral antigen and RNA are abundant in the brain in both MIBE and SSPE, fever is unusual and the virus is difficult, if not impossible, to culture from CNS tissue. Resource-poor settings tend to have a higher incidence of measles infection than high-income countries and carry a higher burden of SSPE, although the condition may not be readily diagnosed.[6] It is not unusual for the diagnosis of SSPE to be challenging and delayed owing to preferential consideration of other diverse differential diagnoses. Over 78% of patients were misdiagnosed in one large study of 307 patients, with the median time to diagnosis of SSPE being 6 months (range 0.2 - 96).[6] Similar challenges were evident with our patients. Even when the diagnosis was suspected, there were a number of barriers to diagnostic closure.

Furthermore, in settings such as SA where there is a high burden of HIV infection, the

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a

b

Fig. 5. EEG of patient 3 in sleep state 2 months after presentation, showing a markedly abnormal recording with persistent spike and wave discharges (a) associated with myoclonic jerks and suppression (b) and compatible with electrical status.

a Fig. 6A. Patient 4. EEG at presentation in sleep state, demonstrating a slow attenuated background with a generalised high-amplitude slow wave (a) which occurred periodically throughout the recording.

incidence may be expected to be further increased. Children of HIV-infected mothers are at particular risk of acquiring measles early, even before 9 months of age, which is the recommended age for vaccination in resource-limited settings.[6] The average time to onset of SSPE after measles is 6 - 10 years (range 1 - 24). [6] The onset is insidious and the diagnosis is often not suspected early in the disease. [6] All the children in our series presented before 6 years of age and the SSPE followed an aggressive course, rapidly reaching either stage 3 or 4 disease. Patient 3 presented with swelling of the optic discs, which was identified during his acute management when he presented with seizures and regression. This finding, in combination with positive oligoclonal

bands, led to extended screening for antibodies related to anti-NMDA (N-methyl D-aspartate) receptor antibody encephalitis, which was negative. The association of ocular and visual manifestations is reported in SSPE and was found in 42.5% of patients with SSPE in one study; the optic disc swelling in our patient 3 was in keeping with a diagnosis of SSPE.[12,13] There are four stages to the disease, which are summarised in Table 2. Death occurs within months to years after onset.[6] The diagnosis of SSPE is usually con­ firmed by a combination of elevated levels of anti­­body to measles virus in the serum and CSF and detection of characteristic periodic slow-wave complexes on an EEG.[6] The EEGs (Figs 3 - 6) in our patients were

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helpful and supportive of the diagnosis of SSPE. Neuroimaging is generally unhelpful, findings often being normal in the early stages of the disease, and the focal or diffuse T2-weighted hyperintense lesions that appear later are not pathognomonic. [6] This was the case in our patients; even patient 3, who developed extensive white matter hyperintensities, would have had a wide range of differential diagnoses with­ out the finding of raised CSF measles anti­ bodies that supported a diagnosis of SSPE. While in our patients the seizure presen­ tation was a major indicator of a more complex condition, all had been well before their abrupt onset of cognitive dysfunction and seizures. Their seizures were very stereotyped, persistent and resistant to typical medical interventions. Despite relatively early suspicion of SSPE, the initial lack of history of infection and negative CSF PCR results were misleading. It was only with persistence (largely on the part of author AN) that the history of prior measles infection was confirmed in all, after which pursuit of the correct screening in the CSF, namely the measles antibody titres, enabled the diagnosis to be confirmed. Viral nucleic acid is rarely found in the CSF of patients with SSPE.[14] This is due to absence of a typical productive infection of the brain with extracellular release of virus. In the case of patients with SSPE, only the genome and nucleocapsid replicates and these spread from cell to adjacent cell through membrane fusion across synapses. Viral nucleic acid will therefore only be present in infected cells. Findings were similar in the patients reported with MIBE, of whom only two were PCR-positive in the CSF.[5] Numerous therapeutic agents, including amantadine, interferon, isoprinosine and ribavirin, have been used for treatment of SSPE. Evaluation of efficacy is difficult, as most cases are isolated and occur in small clusters.[6] The most commonly used regimen is a combination of isoprinosine and interferon-alpha, with some suggestion that this combination slows disease progression.[6] The latter intervention is not available in SA. Turkey is in the unfortunate position of having significant experience in the condition. Guler et al.[15] reported 64 patients with SSPE, diagnosed at an average age of 12.3 years (range 5 - 17). None of the interventions attempted, including iso­ prinosine and interferon, altered the longterm outcome. Furthermore, there was no difference between those who received isoprinosine in isolation and those receiving isoprinosine and interferon in combination.

Guler et al. commented on high levels of

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a

b

Fig. 6B. Patient 4. Follow-up EEG at 1 month in awake state, demonstrating normal posterior alpha rhythms with overriding 2 Hz generalised slow waves and periodic spike and slow wave (a) followed by 2 seconds of attenuation (b). This discharge correlated with a myoclonic seizure and was recurrent throughout the recording.

consanguinity, and questioned whether an additional genetic modifying factor in their patients made them more susceptible to developing SSPE. A study from Karachi in Pakistan reported on 43 patients with similar clinical findings and outcomes.[16] There are several implications for management, which is significantly deter­ mined by confirmation of the diagnosis, beyond the importance to the family of having diagnostic closure. Presentation with myoclonic or atonic seizures would normally preclude the use of carbamazepine, but for patients with SSPE this agent has the best seizure efficacy.[17-20] For our patient with HIV this led to further complications relating to the need for more aggressive monitoring of his HIV viral titres and the carbamazepine levels, owing to the risk of cross-reactivity with ART. An alternative agent could have been levetiracetam, but in fact careful monitoring of drug levels enabled carbamazepine to be used successfully.

There are no data in the literature to guide a treatment care plan in the setting of SSPE and the immunocompromised patient, and colleagues in Turkey had not managed such a case (personal communication, B Anlar).

This scenario is likely to be a uniquely African challenge.

Routine measles vaccination is the best approach for preventing SSPE.[6] Measles vaccine is a live attenuated vaccine, and vaccine strains have not caused SSPE. Furthermore, it is widely accepted that SSPE cannot occur in the absence of direct infection with wild-type measles virus.[6] The incidence of SSPE is directly related to the incidence of measles in a population, and has decreased dramatically since the introduction of measles vaccination.[6] The four cases described here may repre­ sent only a proportion of the cases across SA. In addition, it is likely that the reported numbers of children infected during the measles outbreak are an underestimation, and further patients are therefore likely to present with SSPE. Children presenting with acute-onset intractable seizures, especially myoclonus and atonic siezures, and showing neuroregression should have a careful history of prior measles infection in infancy documented, and there should be a low threshold for screening for measles CSF antibodies.

1. Ntshoe GM, McAnerney JM, Archer BN, et al. Measles outbreak in South Africa: Epidemiology of laboratory-confirmed measles cases and assessment of intervention, 2009-2011. PLoS One 2013;8(2):e55682. [http://dx.doi.org/10.1371/journal. pone.0055682]

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2. Uzicanin A, Eggers R, Webb E, et al. Impact of the 1996-1997 supplementary measles vaccination campaigns in South Africa.

Int J Epidemiol 2002;31(5):968-976. [http://dx.doi.org/10.1093/ ije/31.5.968] 3. Siegfried N, Wiysonge CS, Pienaar D. Too little, too late: Measles epidemic in South Africa. Lancet 2010;376(9736):160. [http:// dx.doi.org/10.1016/S0140-6736(10)61100-2] 4. Albertyn C, van der Plas H, Hardie D, et al. Silent casualties from the measles outbreak in South Africa. S Afr Med J 2011;101(5):313-314, 316-317.

5. Hardie DR, Albertyn C, Heckmann JM, Smuts HE. Molecular characterisation of virus in the brains of patients with measles inclusion body encephalitis (MIBE). Virol J 2013;10:283. [http:// dx.doi.org/10.1186/1743-422X-10-283] 6. Griffin DE. Measles virus and the nervous system. Handb Clin Neurol 2014;123:577-590. [http://dx.doi.org/10.1016/B978-0444-53488-0.00027-4] 7. Centers for Disease Control and Prevention (CDC). Global measles mortality, 2000-2008. MMWR Morb Mortal Wkly Rep 2009;58(47):1321-1326. http://www.cdc.gov/mmwr/preview/ mmwrhtml/mm5847a2.htm (accessed 6 August 2015).

8. Centers for Disease Control and Prevention (CDC). Measles outbreaks and progress toward measles preelimination – African region, 2009-2010. MMWR Morb Mortal Wkly Rep 2011;60(12):374-378. http://www.cdc.gov/mmwr/preview/ mmwrhtml/​mm6012a3.htm (accessed 6 August 2015).

9. Centers for Disease Control and Prevention (CDC). Increased transmission and outbreaks of measles – European Region, 2011. MMWR Morb Mortal Wkly Rep 2011;60(47):1605-1610. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6047a1. htm (accessed 10 August 2015).

10. Smith PJ, Humiston SG, Marcuse EK, et al. Parental delay or refusal of vaccine doses, childhood vaccination coverage at 24 months of age, and the Health Belief Model. Public Health Rep 2011;126(Suppl 2):135-146. http://www.ncbi.nlm.nih.gov/ pmc/articles/PMC3113438/pdf/phr126s20135.pdf (accessed 6 August 2015).

11. Thaku K. World Neurology: Re-emergence of measles in the United States: A warning to neurologists. 2014. http://www. worldneurologyonline.com/article/re-emergence-measles-unitedstates-warning-neurologists/ (accessed 20 November 2014).

12. Yuksel D, Sonmez PA, Yilmaz D, Senbil N, Gurer Y. Ocular findings in subacute sclerosing panencephalitis. Ocul Immunol Inflamm 2011;19(2):135-138. [http://dx.doi.org/10.3109/092739 48.2010.535636] 13. Oray M, Tuncer S, Kir N, Karacorlu M, Tugal-Tutkun I. Optic neuritis and rapidly progressive necrotizing retinitis as the initial signs of subacute sclerosing panencephalitis: A case report with clinical and histopathologic findings. Int Ophthalmol 2014;34(4):983-987. [http://dx.doi.org/10.1007/s10792-014-9914-z] 14. Yanagi Y, Takeda M, Ohno S, Hashiguchi T. Measles virus receptors. Curr Top Microbiol Immunol 2009;329:13-30. [http:// dx.doi.org/10.1007/978-3-540-70523-9_2] 15. Guler S, Kucukkoc M, Iscan A. Prognosis and demographic characteristics of SSPE patients in Istanbul, Turkey. Brain Dev 201537(6):612-617. [http://dx.doi.org/10.1016/j.braindev.​2014.09.​ 006] Sep 27.

16. Rafique A, Amjad N, Chand P, et al. Subacute sclerosing panencephalitis: Clinical and demographic characteristics.

J Coll Physicians Surg Pak 2014;24(8):557-560. [08.2014/ JCPSP.557560] 17. Hayashi T, Ichiyama T, Nishikawa M, Furukawa S. Carbamazepine and myoclonus in SSPE subacute sclerosing panencephalitis. Pediatr Neurol 1996;14(4):346. [http://dx.doi. org/10.1016/0887-8994(96)00086-0] 18. Yigit A, Sarikaya S. Myoclonus relieved by carbamazepine in subacute sclerosing panencephalitis. Epileptic Disord 2006;8(1):77-80. http:// www.jle.com/en/revues/epd/e-docs/myoclonus_relieved_by_ carbamazepine_in_subacute_sclerosing_panencephalitis_268140/ article.phtml (accessed 6 August 2015).

19. Aydin OF, Senbil N, Gurer YK. Nonconvulsive status epilepticus on electroencephalography in a case with subacute sclerosing panencephalitis. J Child Neurol 2006;21(3):256-260. [http:// dx.doi.org/10.2310/7010.2006.00056] 20. Ravikumar S, Crawford JR. Role of carbamazepine in the symptomatic treatment of subacute sclerosing panencephalitis: A case report and review of the literature. Case Rep Neurol Med 2013;2013:327647. [http://dx.doi.org/10.1155/2013/327647]

Accepted 18 December 2014.

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REFLECTIONS

A human perspective on body donation: A case study from a psychosocial perspective C Manicom Clare Manicom, Oncology Social Worker in the GVI (Gouws en Vernote Ingelyf/Gouws and Partners Incorporated) oncology practice, Cape Town, South Africa, holds a master’s degree in social work and has over 15 years’ experience in oncology care. She is involved in the emotional support of people with cancer and their families throughout their treatment and recovery or during palliative care. Clare works with people attending outpatient treatments and in hospital, and has a particular interest in end-of-life care.

Corresponding author: C Manicom (clare.manicom@cancercare.co.za)

Using a case study of how a son consented to his mother becoming a body donor, the factors that may have contributed to that decision are outlined. Social and psychological considerations about body donation in general are presented. These are followed by suggestions for organisational improvements for healthcare facilities and medical schools, including ease of access to accurate information for both medical professionals and members of the public. Finally, it is recommended that medical school staff dealing with potential donors and their families should be trained to communicate empathically and with compassion.

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While helping family members prepare for the imminent death of a loved one, there may be discussion around procedures to be followed after death in a hospital ward or at home, such as appointment of an undertaker. The family situation described below (names changed) highlights the importance of a compassionate response to discussion around the topic of body donation, and the relief that adequate information can provide to the family.

Case study

In 2012, Mrs X signed a Living Will, including a gentle preamble and some instructions to her family that requested that her body be donated to medical science. She was 78 years old at the time, and apart from some arthritic pains, was living an independent life.

In early 2015, Mrs X died of metastatic lung cancer, having outlived her husband and one of her sons. She had been in pain, and had experienced a partial spinal cord compression which required hospitalisation. Her remaining son, John, had numerous conversations with the oncology social worker about his mother’s quality of life and symptom management. While in hospital Mrs X become aggressive and confused; brain metastases were diagnosed, and John and the oncologist made the joint decision not to treat these, as the patient’s overall condition was deteriorating.

John had already discussed his mother’s wish to die peacefully with his mother’s oncologist, the medical officer caring for her in the ward, and the social worker. She was nursed in a private ward until her death.

During the preterminal phase of his mother’s illness, John found the Living Will document and discussed the contents with the social worker five days before his mother’s death. He was conflicted regarding its content – he wanted to honour his mother’s wishes, but had reservations about whether he wanted her body to be used by medical science. He had discussed the situation with a trusted friend, who had advised him to pursue the directive and did not have any religious or cultural objections. John felt that he would be reassured if he knew what process to follow, and how the logistics would be

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organised. This would reduce his stress, and allow him to focus on his own grief and that of his family.

On exploration of John’s quandary, the social worker learned that he felt alone in his decision, without any siblings to share the responsibility, and was uncertain about how to make the necessary arrangements if he proceeded with his mother’s directive. Following enquiry at the local university’s medical school, the necessary paperwork was obtained. Both John and the social worker were provided with clear instructions that were shared in turn with the medical attendants and ward staff. He was required to forward the Living Will document to the medical school contact, along with his signed consent on his mother’s behalf and a copy of her identity document. Information was obtained about which undertakers would be used to remove Mrs X’s body, and John was able to decide whether or not he wanted the body to be available for a funeral, or whether he would like the ashes returned to him after cremation.

During conversations in the remaining few days, and after the death of his mother, John expressed gratitude and reassurance that he had clarity about the arrangements, and that he had had personal contact with a very pleasant and professional person at the medical school. This contact gave John the confidence that he had made the correct decision, after discussion with his family, who had supported him in this.

Discussion

On reflecting on this case, the social worker wondered what factors may encourage family members to support a decision on body donation. There are many academic articles about organ donation that explore cultural and religious factors, and the influences on family members to proceed with such donations. However, there appears to be little formal information to assist the family members of body donors, or the potential donors themselves.

What follows is a brief observation of some possible factors that may encourage body donation.

Honouring the wishes of the deceased

This is likely to be a primary driver for families to support a loved one’s decision to donate their body to medical research. It has been

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suggested in the academic literature that an individual’s desire to become a body donor suggests an autonomous character in life, and a relatively unconventional approach towards disposal of his/her own remains after death.[1] If a person has displayed such strength of character and opinion, family members are likely to feel duty bound to honour their wishes after the person is dead.

that her body donation could make a contribution to medical knowledge.

In South Africa the family members of body donors are not financially rewarded, but the costs of removal of the body to the medical school (within a certain radius) and cremation are covered by the university.

Ease of access to information regarding logistics after death

Support and guidance

The period leading up to the death of someone who is terminally ill is frequently a time of some disorganisation within the family system, and confusion about roles, responsibilities and rights of family members. If they are aware of the dying person’s intention to donate their body, the family may have little or no knowledge of how to act on this intention. Medical school websites are designed for students and academics to navigate, and simply accessing information about who to contact and what paperwork is required calls on investigative skills and time that family members may not have. In the case of Mrs X, this process was facilitated by the social worker, thereby reducing additional stress on the decision-maker.

Trust in the logistical arrangements

There is a very real human need to trust that the deceased’s body will be respectfully removed and handled by professionals.[2] Details of reputable undertakers who work with the relevant medical school are therefore helpful. Likewise, having 24-hour contact numbers for the undertakers alleviates concern about arrangements after death. For John, this certainty permitted him to move in and out of his mother’s room, without a desperate need to be there ‘at the end’ or to oversee arrangements after she had died.

Sense of purpose/need in the donation

This factor may seem self-explanatory, but in a culture where urban mythology suggests that medical schools have ‘too many bodies’ (whereas in fact there is a paucity of cadavers in certain medical schools in South Africa, and elsewhere in the world[1-3]), it was helpful and encouraging for John to know that his mother’s body would be welcomed and would be of use to the university. There are exclusion criteria for body donations, which may vary between medical schools; these criteria are understandable in the context of academic study of the body, and obtaining clarity about them ahead of time can once again reduce stress for the family.

Altruism

For many people, motivation for requesting donation of their body is based on a sense of altruism – of making a contribution to the learning of students, or to the body of medical knowledge in general.[2-4] John may have found some comfort in this aspect, as he recalled that his mother had been treated with a new medication several years previously, and had been diligently followed up by her doctor over the subsequent years to monitor its effect. John informed the liaison person at the university of these details, with the thought that there might be evidence of the response/treatment when her body was examined. There is no way of knowing whether the medical school used that specific information, but for John there was a possibility that his mother’s experience in life could aid the development of medical treatments after her death, and confirm

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What information and structures could support and guide people facing decisions about body donation?

Ideally, the prospective donor should discuss their intention with the family before illness or frailty sets in – debate and discussion at this stage should facilitate easier and smoother decision-making in future.

Hospitals and other places of care where death commonly occurs should have current information readily available for family members who may make enquiries. Staff such as social workers, psychologists and nurses should be able to access this information with ease. Even if it is not a common situation, the request for body donation could be included in the institution’s standard operating procedures. This access to information is described by Valderrama-Canales et al.[5] as ‘transparency of data’ (p. 165), with the implication that easier access to information regarding body donation would lead to an increased number of donations.

Medical students should be made aware of the process of body donation, so that they are able to pass this information on to patients once they are practising as doctors.[2] University medical schools and their websites could have details or links that are easy to find and navigate, bearing in mind that many would-be donors will not know which department works with cadavers, and may therefore battle to find the correct person to assist them.

Personnel at medical schools who are likely to encounter such enquiries should be equipped with current information, should have easy access to the necessary paperwork, and should possibly receive training in working with members of the public in an empathic and compassionate manner, rather than in a clinical fashion that could be perceived by family members as emotionally cold or unfeeling.

Conclusion

It is suggested that clear communication between family members and ease of access to information about body donation would considerably assist people in the decision to commit to being body donors. Staff involved in receiving such donations should be professional in their approach, with excellent insight into the dilemmas faced by families as they move towards consenting to the donation.

1. Bolt S, Venbrux E, Eisinga R, Kuks JBM, Veening JG, Gerrits PO. Personality and motivation for body donation. Ann Anatomy 2011;193(2):112-117. [http://dx.doi.org/10.1016/j.aanat.2011.01.005] 2. Ranjan R, Jain A, Jha K. Evaluation of awareness of voluntary body donation among hospital visiting population in Ujjain, MP. International Journal of Medical and Applied Sciences 2014;3(1):116-119.

3. Biasutto SN, Sharma N, Weiglein AH, et al. Debate. Cuerpos humanos para la enseñanza de la Anatomía: Importancia y procuración – experiencia con la donación de cadavers. Argentina Journal of Clinical Anatomy 2014;6(2):72-86.

4. Bolt S, Venbrux E, Eisinga R, Kuks JBM, Veening JG, Gerrits PO. Motivation for body donation to science: More than an altruistic act. Ann Anatomy 2010;192(2):70-74. [http://dx.doi.org/10.1016/j. aanat.2010.02.002] 5. Valderrama-Canales FJ, Alcaide EM, Tirado FV, Melián AP, Osorio TV. Debunking myths and building realities: Human body donation in times of crisis. European Journal of Anatomy 2012;16(2):163-166.

Accepted 12 June 2015.

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Endoscopic lung volume reduction in severe emphysema C F N Koegelenberg, J Theron, J W Bruwer, B W Allwood, M J Vorster, F von Groote-Bidlingmaier, K Dheda Prof. Coenie Koegelenberg is a consultant in Pulmonology and Critical Care at Stellenbosch University and Tygerberg Academic Hospital, Tygerberg, Cape Town, South Africa, and the current chairman of Assembly on Interventional Pulmonology of the South African Thoracic Society. Dr Johan Theron is an interventional pulmonologist in private practice at Panorama Mediclinic, Cape Town, and an honorary lecturer at Stellenbosch University. Dr Willie Bruwer is an interventional pulmonologist in private practice at Windhoek Mediclinic, Namibia. Dr Brian Allwood is a consultant in pulmonology and critical care, Dr Morné Vorster a senior registrar and Dr Florian von Groote-Bidlingmaier an honorary lecturer at Stellenbosch University and Tygerberg Academic Hospital. Prof. Keertan Dheda is a consultant and head of the Division of Pulmonology at the University of Cape Town and Groote Schuur Hospital, Cape Town.

Corresponding author: C F N Koegelenberg (coeniefn@sun.ac.za)

Therapeutic options in severe emphysema are limited. Endoscopic lung volume reduction (ELVR) refers to bronchoscopically inducing volume loss to improve pulmonary mechanics and compliance, thereby reducing the work of breathing. Globally, this technique is increasingly used as treatment for advanced emphysema with the aim of obtaining similar functional advantages to surgical lung volume reduction, while reducing risks and costs. There is a growing body of evidence that certain well-defined subgroups of patients with advanced emphysema benefit from ELVR, provided that a systematic approach is followed and selection criteria are met. In addition to endobronchial valves, ELVR using endobronchial coils is now available in South Africa. The high cost of these interventions underscores the need for careful patient selection to best identify those likely to benefit from such procedures.

S Afr Med J 2015;105(9):721-723. DOI:10.7196/SAMJnew.8144

Emphysema is a very com­ mon cause of morbidity and mortality in South Africa (SA). Smoking remains the most common risk factor for the development of emphysema, but longterm biomass fuel exposure, tuberculosis and HIV co-infection contribute to the disease burden in southern Africa.[1] However, therapeutic options for severe emphysema are currently limited.

In the subgroup of patients with pre­ dominantly upper-lobe emphysema and low exercise capacity, surgical lung volume reduction improves functional status, but not without a significant risk of mortality and morbidity as well as high financial costs.[2] Endoscopic lung volume reduction (ELVR), which is increasingly being used internationally, aims to reduce the risks and costs of surgery, while obtaining the same functional advantages. It refers to the placement of a device (e.g. a valve or coil) through a bronchoscope into a bronchus with the aim of decreasing the volume of the lung segments distal to the device, thereby improving pulmonary mechanics and compliance.[3] The work of breathing is reduced, resulting in significant improvements in symptoms, particularly breathlessness.

There is a growing body of evidence that certain well-defined subgroups of patients with advanced emphysema benefit from ELVR, with the caveat that a systematic

approach is followed and selection criteria are met. Recently, endobronchial coils, in addition to endobronchial valves, have become available in SA for ELVR; however, the cost of both remains high, emphasising the need for careful patient identification and selection to best identify those who are most likely to benefit from these procedures.

Modalities and devices available in SA

Unidirectional endobronchial and intrabronchial valves

Unidirectional valves induce either lobar or segmental lung collapse by preventing the entrance of air during inspiration, while allowing exhalation of air and secretions.

There are currently two such devices commercially available in SA: Zephyr endo­ bronchial valves (Pulmonx Inc.) (Fig. 1) and IBV intrabronchial valves (Olympus Respiratory America) (Fig. 2). Both devices are self-expanding and delivered using a catheter introduced through the working channel of a flexible bronchoscope.[3] These devices have been shown to be less effective when emphysema is found uniformly throughout the lungs (i.e. homo­ geneous emphysema). The distri­ bution of emphysema is assessed on high-resolution computed tomography (HRCT) scanning of the chest, either by visual inspection of the parenchyma or by using specifically designed automated quantification soft­

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Fig. 1. An endobronchial (Zephyr) valve.

Fig. 2. An intrabronchial (IBV) valve.

ware.[3] Additionally, valves fail to induce collapse when the affected portion of the lung has collateral ventilation. This is a normal physiological phenomenon in many individuals, but significant interlobar collateral ventilation subverts the deflating effect of endobronchial blocking devices.

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Prior to placement of a valve, both hom­ ogeneous emphysema and collateral venti­ lation therefore need to be excluded. The evidence for this requirement is derived from numerous studies in which the minimal clinically important differences were significantly more likely to be observed in patients with advanced heterogeneous emphysema and no collateral ventilation.

Moreover, unilateral (as opposed to bilateral ELVR) valve placement was found to have better outcomes.[4-7] The recently completed STELVIO trial provided the strongest evidence for use of valves in patients without collateral ventilation.[8] Dutch investigators random­ ised 68 patients with severe emphysema on HRCT with visual estimation of complete or near-complete fissures to endobronchial Zephyr valve treatment (n=34) or standard medical care (n=34). The primary outcome measures were change in spirometric measures and the 6-minute walking distance (6MWD) at 6 months. Clinical relevance was assessed relative to minimal clinically important differences. At 6 months, the minimal clinically important differences were attained in all parameters in the treated group compared with controls (p<0.001 for all endpoints).

The most common reported adverse events experienced with endobronchial valve placement have been pneumothoraces (5 - 10%), mild haemoptysis (2 - 6%) and exacerbations of underlying chronic obstructive pulmonary disease (COPD) (8 40%).[4-7]

Coils

Coils (RePneu; BTG Inc.) (Fig. 3) are nitinol devices designed to be deployed into a straight airway, and thereafter to resume their preformed shape. This conformational shape change after deployment results in parenchymal retraction with volume loss, while maintaining airway patency.[9] The device is currently available in three lengths to accommodate different-sized airways.

The coils are implanted via a flexible bronchoscope under general anaesthesia

Fig. 3. An endobronchial (RePneu) coil.

or conscious sedation and fluoroscopic guidance using a proprietary delivery system.

In theory, coils not only cause lung volume reduction but additionally re-tension the remaining airway network and mechanically increase elastic recoil. This re-tensioning of the lung tethers open the small airways, thus preventing their collapse on expiration, known to be the pathogenetic mechanism of emphysema.

Current evidence suggests that candi­ dates with both heterogeneous and homo­ geneous emphysema can experience clinically signi­ ficant benefit from ELVR using coils. This benefit is obtained regardless of the presence of collateral ventilation or complete lobar collapse post procedure, but requires that least >25% of the total lung paren­ chyma is unaffected by radiological emphysema prior to insertion.[10,11] Approxi­mately 75 - 80% of patients will experience minimal clinically important differences in lung function and quality of life, while mild haemoptysis of <5 mL (50 - 75%), exacerbations of COPD (5 - 12%), mild chest discomfort (15 - 50%) and infrequent pneumothoraces (3%) are the described adverse events.[10,11] A recent report on the 3-year follow up data on 38 patients who underwent ELVR using coils suggested that the coil treatment was safe; no late pneumothoraces, coil migrations or unexpected adverse events occurred.[12] Although clinical benefit grad­ ually declined over time, at 3 years post treatment approximately 50% of the patients maintained improvement in 6MWD and dyspnoea and quality of life scores.

Other devices

Synthetic polymeric foam (Aeris Thera­ peutics Biological) has been used to obtain atelectasis. This technology is currently not available in SA. A recent study on synthetic polymeric foam, which was terminated prematurely, raised some safety concerns.[13]

The future of endoscopic lung volume reduction in SA

Current evidence suggests that not all classes and phenotypes of emphysema will benefit from ELVR, and that individual techniques offer benefit to different subgroups of patients.[5,9,10] Only a few centres in SA currently have the capacity to evaluate prospective candidates properly and potentially offer ELVR to appropriate cases. The high cost of these interventions makes careful patient selection imperative to prevent wasteful treatment of patients who are unlikely to gain clinical benefit.

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The initial screening for suitable candidates should be performed at subspecialist (pul­ monologist) level, and on patients with stable disease and no recent exacerbations.

Routine special investigations should include HRCT (to estimate heterogeneity, integrity of fissures and degree of tissue destruction, and evaluate for possible underlying lung cancer), full pulmonary function testing, arterial blood gas measurement and echo­ cardiography (to exclude pulmonary hypertension).[10] The general indications and contraindications for valves and coils are summarised in Table 1. ELVR should not be offered to active smokers, patients with pulmonary hypertension, unstable cardiac pathology, active respiratory infections or very poor exercise tolerance, patients without clear evidence of hyperinflation, or patients who use antiplatelet or anticoagulant therapy that cannot be stopped for 7 days prior to the procedure.[10,11,14] Appropriate or borderline candidates (Table 1) should be referred to a centre with the capacity to evaluate, treat and follow up these patients, and manage compli­ cations and undertake removal of devices if required.

Conclusions and recommendations

There is currently no head-to-head evidence comparing the various techniques and devices, and no official guideline from any of the major thoracic societies is currently available. The Assembly on Interventional Pulmonology of the South African Thoracic Society has extensively reviewed all relevant publications, and consulted international experts on the use of ELVR in SA in the form of recommendations based not only on published evidence, international expert opinion and local expertise, but also on local commercial access to devices.[14] It is also recommended that all endoscopic lung volume reduction procedures should be performed in the context of a local and/ or international registry. The Assembly on Interventional Pulmonology of the SA Thoracic Society is willing to assist potential centres wishing to establish an ELVR service in terms of training and accreditation.

In summary, appropriate candidates with marked hyperinflation and relatively preserved lung parenchyma are more likely to benefit from ELVR with bilateral coils, irrespective of the collateral ventilation and heterogeneity of the disease. In contrast, patients with heterogeneous disease and no collateral ventilation are more likely to benefit from unilateral ELVR with valves aiming to achieve complete lobar collapse.

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Table 1. General indications and contraindications for endobronchial lung volume reduction with endobronchial and intrabronchial valves and coils in patients with stable emphysema Indications 40 - 75 years Heterogeneous emphysema and no collateral ventilation* Dyspnoea despite maximal medical therapy and pulmonary rehabilitation FEV1 15 - 45% Hyperinflation with TLC >100% and RV >150 - 175% PaCO2 <6.7 kPa (50 mmHg) PaO2 >6 kPa (45 mmHg) while breathing ambient air 6MWD ≥140 m (post rehabilitation) Contraindications Homogeneous emphysema* Collateral ventilation/non-intact fissures* >75% parenchymal destruction on HRCT† Current smoking (last 6 months) DLCO <20% (relative contraindication) Giant bullae (>1/3 of hemithorax) Alpha-1-antitrypsin deficiency Previous thoracotomy, pleurodesis or chest wall deformity Excessive sputum Severe pulmonary hypertension (>50 mmHg) Active infection Unstable cardiac conditions Significant pleural or interstitial changes on HRCT Any type of antiplatelet or anticoagulant therapy that cannot be stopped for 7 days prior to procedure FEV1 = forced expiratory volume in 1 second; TLC = total lung capacity; RV = residual volume; PaCO2 = partial pressure of carbon dioxide; PaO2 = partial pressure of carbon dioxide; 6MWD = 6-minute walking distance; DLCO = carbon monoxide diffusing capacity. *Specific for endobronchial and intrabronchial valves. † Specific for endobronchial coils.

A well-structured evidence-based approach to ELVR, including initial screening and subsequent referral to a specialised centre,

is important to avoid inappropriate use of devices, which may be both wasteful and harmful.

References 1. Allwood B, Myer L, Bateman E. A systematic review of the association between pulmonary tuberculosis and the development of chronic airflow obstruction in adults. Respiration 2013;86(1):76-85. [http://dx.doi.org/10.1159/000350917] 2. National Emphysema Treatment Trial Group. A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema. N Engl J Med 2003;348(21):20592073. [http://dx.doi.org/10.1056/NEJMoa030287] 3. Gasparini S, Zuccatosta L, Bonifazi M, Bolliger CT. Bronchoscopic treatment of emphysema: State of the art.

Respiration 2012;84(3):250-263. [http://dx.doi. org/10.1159/000341171] 4. Shah P, Slebos D, Cardoso P, et al. Bronchoscopic lung-volume reduction with Exhale airway stents for emphysema (EASE trial): Randomised, sham-controlled, multicentre trial. Lancet 2011;378(9795):997-1005. [http://dx.doi.org/10.1016/S0140-6736(11)61050-7] 5. Sciurba FC, Ernst A, Herth FJF, et al. A randomized study of endobronchial valves for advanced emphysema. N Engl J Med 2010;363(13):1233-1244. [http://dx.doi.org/10.1056/ NEJMoa0900928] 6. Mor Z, Leventhal A, Diacon AH, Finger R, Schoch OD. Tuberculosis screening in immigrants from high-prevalence countries: Interview first or chest radiograph first? A pro/ con debate. Respirology 2013;18(3):432-438. [http://dx.doi. org/10.1111/resp.12054] 7. Herth FJF, Noppen M, Valipour A, et al. Efficacy predictors of lung volume reduction with Zephyr valves in a European cohort. Eur Respir J 2012;39(6):1334-1342. [http://dx.doi. org/10.1183/09031936.00161611] 8. Klooster K, ten Hacken N, Hartman J, Kerstjens H, van Rikxoort E, Slebos D. Endobronchial valve treatment versus standard medical care in patients with emphysema without interlobar collateral ventilation (the STELVIO-Trial). Am J Respir Crit Care Med 2015;191(9):A6312.

9. Herth FJF, Eberhard R, Gompelmann D, Slebos DJ, Ernst A. Bronchoscopic lung volume reduction with a dedicated coil: A clinical pilot study. Ther Adv Respir Dis 2010;4(4):225-231. [http://dx.doi.org/10.1177/1753465810368553] 10. Deslee G, Klooster K, Hetzel M, et al. Lung volume reduction coil treatment for patients with severe emphysema: A European multicentre trial. Thorax 2014;69(11):980-986. [http://dx.doi. org/10.1136/thoraxjnl-2014-205221] 11. Klooster K, ten Hacken NHT, Franz I, Kerstjens HM, van Rikxoort EM, Slebos D-J. Lung volume reduction coil treatment in chronic obstructive pulmonary disease patients with homogeneous emphysema: A prospective feasibility trial. Respiration 2014;88(2):116-125. [http://dx.doi.org/10.1159/000362522] 12. Hartman J, Klooster K, Gortzak K, ten Hacken N, Slebos D. Long-term follow-up after bronchoscopic lung volume reduction treatment with coils in patients with severe emphysema. Respirology 2015;20(2):319-326. [http://dx.doi. org/10.1111/resp.12435] 13. Come C, Kramer M, Dransfield M, et al. A randomised trial of lung sealant versus medical therapy for advanced emphysema.

Eur Respir J 2015:1-12. [Epub ahead of print] [http://dx.doi. org/10.1183/09031936.00205614] 14. Koegelenberg CFN, Theron J, Dheda K, et al. Recommendations for endoscopic lung volume reduction in South Africa: Role in emphysema. S Afr Med J 2015;105(10)(in press). [http://dx.doi. org/10.7196/SAMJnew.8147]

Accepted 29 June 2015.

This month in the SAMJ ...

Leonid M Irenge* is co-ordinator of a co-operation project between the Université catholique de Bukavu (South Kivu Province, Democratic Republic of the Congo (DRC)) and the Université catholique de Louvain (Belgium), which aims to improve identification of micro-organisms involved in infectious diseases in South Kivu. This entails overseeing development of microbiology capabilities at the provincial hospital in Bukavu, the capital of South Kivu, as well as at the level of the Healthcare Inspection in that province. A senior scientist at UCL/CTMA (Faculty of Medicine of the Université catholique de Louvain and Defence Laboratories Department, Belgium), he holds a doctorate in molecular biology and has been working in the field of microbiology for a decade. His research efforts focus on development of assays for rapid and unambiguous detection and identification of pathogenic micro-organisms, both in the field and in reach-back facilities, and on characterisation of antimicrobial resistance on isolates from DRC. * Irenge LM, Kabego L, Kinunu FB, et al. Antimicrobial resistance of bacteria isolated from patients with bloodstream infections at a tertiary care hospital in the Democratic Republic of the Congo. S Afr Med J 2015;105(9):752-755. [http://dx.doi.org/10.7196/SAMJnew.7937]

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Implementation of electronic scripts in South Africa K du Toit, S Naicker, J Bodenstein Karen du Toit is a pharmacist with a PhD in applied chemistry. She is also an Honorary Associate Professor in the Discipline of Pharmaceutical Sciences, University of KwaZulu-Natal, Durban, South Africa (SA), and an admitted attorney. Sarisha Naicker is a pharmacist based in Pretoria with many years’ experience in the retail sector. She has been involved in the implementation of electronic scripts in SA. Johannes Bodenstein is a pharmacist with a PhD in pharmacology. He is a senior lecturer in the Discipline of Pharmaceutical Sciences, University of KwaZulu-Natal.

Corresponding author: J Bodenstein (bodensteinj@ukzn.ac.za)

The legal framework in South Africa (SA) provides for strict requirements regarding prescriptions. However, pharmacists are still confronted daily with illegible handwritten scripts, increasing the risk of medication errors. E-prescribing is being implemented in SA to overcome these disadvantages. The general regulations made in terms of the Medicines and Related Substances Act as well as the Electronic Communications and Transactions Act must be read conjointly for the purposes of understanding the legal framework of electronic prescriptions in SA. S Afr Med J 2015;105(9):724-725. DOI:10.7196/SAMJnew.7920

The Oxford Dictionary[1] defines a prescription as a doctor’s written instruction authorising a patient to be issued with a medicine or treatment. In South Africa (SA), according to the general regulations made in terms of the Medicines and Related Substances Act,[2] prescriptions must be written in legible print, typewritten or computer generated and signed in person by an authorised prescriber. Despite these requirements, pharmacists are confronted daily with illegible hand-written prescriptions that pose the risk of medication errors. It has been reported in the USA that medication errors resulting from many factors, including illegible handwriting, patient allergies, wrong dosages and drug interactions, account for the deaths of 7 000 patients annually, and for nearly 1 in 20 hospital admissions.[3] While no reliable SA data are available, similar safety concerns apply.

In an effort to overcome the disadvantages of written prescriptions, e-prescribing has been implemented in countries such as the USA, with use increasing by 72% between 2009 and 2010. Other countries that have adopted e-prescribing are Denmark, Estonia, Iceland, Sweden, Norway, The Netherlands, Greece, England, Scotland, Wales and Northern Ireland. Pilot e-prescribing is currently being undertaken in the Czech Republic, Finland, Italy and Poland.[3] SA has begun the process of implementing e-prescribing. E-prescribing allows a prescriber to electronically send an accurate and understandable prescription directly to a pharmacy from the point of care.

However, the term e-prescribing encompasses more than merely the creation of an electronic script. A complete e-prescribing system requires support software, electronic medication administration records, robots, automated pharmacy systems, bar coding, electronic discharge prescriptions and targeted patient information.[3] An e-prescribing system serves as an electronic reference handbook.

More sophisticated e-prescribing systems act as stand-alone prescription writers. They can create and refill prescriptions for individual patients, manage medications and view patient history, connect to a pharmacy or other drug dispensing site, and integrate with an electronic version of the South African Medicines Formulary (SAMF).

During e-prescribing, a computer-generated prescription is created, validated with an electronic signature, recorded or stored by

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electronic means, issued and transmitted by electronic means directly from the prescriber to a pharmacist.

The legal framework with regard to electronic scripts

The Electronic Communications and Transactions Act (ECT Act)[4] came into effect on 30 August 2002. The objectives of this Act are to enable and facilitate electronic communications and transactions in the public interest. The Medicines and Related Substances Act[5] must be read conjointly with the ECT Act for the purposes of understanding the legal framework of electronic prescriptions in SA. The ECT Act[4] provides that information is not without legal force and effect merely on the grounds that it is wholly or partly in the form of a data message (data message is further defined as data generated, sent, received or stored by electronic means). A computergenerated prescription could therefore have the same legal force as any valid prescription. The requirement that a prescription must be in writing is met if it is in the form of a data message and accessible in a manner usable for subsequent reference. An electronic signature accompanying the script is also not without legal force and effect merely on the grounds that it is in electronic form. An advanced electronic signature is regarded as being a valid electronic signature when applied properly, unless the contrary is proved.

In SA, a faxed, e-mailed, telephonic or electronic prescription must be followed by the original prescription or order within 7 working days.[2] It is questionable whether this requirement will be applicable to e-prescribing, since such scripts will have the same legal force as a written script. In respect of a data message, the addressee is the person who is intended by the originator to receive the data message, but not a person acting as an intermediary in respect of that data message. It is therefore important that an authorised prescriber, with the consent of the patient, sends a data message in the form of a prescription to a chosen pharmacy. Patients have the right to choose their own pharmacy, and any action to the contrary would constitute unprofessional conduct.

Adequate procedures necessary for receipt of an electronic pre­ scrip­tion and confirmation of the integrity of communication must be in place. Pharmacists are responsible for verifying the authenticity

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of an electronic prescription, and must be aware of the probable methods of prescription forgery and exercise reasonable care to ensure that prescriptions are genuine.[6] This can be done in a number of ways, such as software programs that require a password, personal identification numbers (PINs), or other methods of authentication.

Some programs are able to notify the pharmacist if the message has been tampered with or altered. The pharmacist must assess the integrity of an electronic prescription by judging whether the information remains complete and unaltered, except for the addition of any endorsement and any change arising in the normal course of communication and storage.[5] In the event of the patient keeping the ‘original’ prescription, or requesting to use a different pharmacy, the e-script can be validated by a barcode on the e-script that is detected by all the different dispensing software programs to enable tracking of the history of the prescription.

In SA, a permanent copy of the faxed, e-mailed, telephonic or other electronic transmitted prescription or order must be made for record purposes and filed.[5] The prescription must be endorsed with necessary changes, such as repeats, confirmation of the prescriber, reasons for not dispensing certain medications, and the request to dispense a generic equivalent. Prescriptions should be retained for 5 years.[2] An electronic script will have to be dealt with in the same manner.

Patient health information must always be collected, recorded and used in a manner that protects confidentiality and privacy.[6] Prescribers and pharmacists must therefore have a secure system for electronic transmission, and equipment used must be placed in secure locations to ensure security and confidentiality of the transmission.

Transmissions must also not be delegated to third parties. It must be noted that e-mailed prescriptions from a prescriber to a pharmacy do not ensure the confidentiality of patient records and are not advisable without patient consent.

The advantages and disadvantages of electronic scripts

Electronic scripts improve patient safety and the quality of care by reducing scripting errors and time spent on phone calls and call-backs to pharmacies.[7] The e-prescribing system ensures the provision of enough specific and required information to fill a prescription. Warning and alert systems at the point of care may assist in averting adverse drug events. The system also improves formulary adherence to the patient’s health plan or insurance, permitting substitution of less expensive drug alternatives.[7] Furthermore, automated prescription renewals may be submitted, increasing

patient convenience. Clinicians using e-prescribing systems can manage their patients’ medications safely and efficiently and also have the convenience of greater prescribing mobility.[7] Furthermore, downloading scripts electronically will not only reduce the patient’s waiting time at the pharmacy but allow pharmacists to dispense more scripts per day and to provide an increased professional service and counselling of patients.

Disadvantages of electronic scripts include high costs associated with purchasing, implementing, supporting and maintaining the e-prescribing system, as well as training of staff. System downtime may cause frustration.[7] Security and privacy of patient information may be infringed through errors that lead to accidental disclosure of health information on the internet. Furthermore, new technology makes it easier to alter and forge prescriptions. In SA, challenges such as ensuring that electronic scripts are available in our 11 languages are experienced. Maintenance of correct pack sizes and doses and the elimination of typing errors may also be challenging. ICD-10 codes form part of electronic scripts, and patients may not be comfortable with disclosing their illnesses. The storage of automated repeats often needs to be completed manually. Training of all staff, including locum personnel, may be costly but needs to be achieved.[7]

Conclusion

Electronic scripts significantly enhance safety, are convenient for the prescriber, and save time at the pharmacy. Although the implementation process is potentially troublesome, the advantages of electronic scripts outweigh the disadvantages. E-prescribing would most certainly be more convenient for a patient. Automated prescription renewals can never replace the need for direct 6-monthly evaluation and reassessment of chronic medical conditions by a medical practitioner.

1. Waite M, ed. Oxford Dictionary & Thesaurus. 2nd ed. Oxford: Oxford University Press, 2007.

2. General Regulations made in terms of the Medicines and Related Substances Act No. 101 of 1965. http://www.saflii.org/za/legis/consol_reg/marsa101o1965rangnr510723.pdf (accessed 6 November 2014).

3. Digitome e-Prescribing. 2011. http://digito.me/eprescribing (accessed 6 November 2014).

4. Electronic Communications and Transactions Act, Act No. 25 of 2002. http://www.internet.org.za/ ect_act.html (accessed 6 November 2014).

5. The Medicines and Related Substances Act 101 of 1965. http://www.hpcsa.co.za/Uploads/editor/ UserFiles/downloads/legislations/acts/medicines_and_related_sub_act_101_of_1965.pdf (accessed 19 June 2015).

6. South African Pharmacy Council. Good Pharmacy Practice in South Africa. 4th ed. Pretoria: SAPC, 2010.

7. Cohen J, Banchilhon J-M, Jones M. South African physicians’ acceptance of e-prescribing technology: An empirical test of a modified UTAUT model. South African Computer Journal 2013;50:43-54.

Accepted 20 July 2015.

This month in the SAMJ ...

Guy Richards*† is a chief physician in the Department of Medicine and Pulmonology at the University of the Witwatersrand, Johannesburg. He is Academic Head and Professor of the Division of Critical Care and Director of the Department of Critical Care at Charlotte Maxeke Johannesburg Academic Hospital, and currently Chairman of the South African National Critical Care and Thoracic Society Congress. Prof. Richards has been received awards for best research paper, best presentation and best publication on a number of occasions, and has authored 11 book chapters and 126 peer-reviewed scientific papers. *Richards GA. Nososcomial transmission of viral haemorrhagic fever in South Africa. S Afr Med J 2015;105(9):709-712. [http://dx.doi.org/10.7196/SAMJnew.8168] †

Richards GA, Weyer J, Blumberg LH. Viral haemorrhagic fevers in South Africa. S Afr Med J 2015;105(9):748-751. [http://dx.doi.org/10.7196/SAMJnew.8330]

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RECOMMENDATIONS

Recommendations for the use of bronchial thermoplasty in the management of severe asthma K Dheda, C F N Koegelenberg, A Esmail, E Irusen, M E Wechsler, R M Niven, E D Bateman, K F Chung, on behalf of the Assembly on Interventional Pulmonology of the South African Thoracic Society Prof. Keertan Dheda is Head of the Lung Infection and Immunity Unit and the Division of Pulmonology, Department of Medicine and UCT Lung Institute, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa. Prof. Coenie Koegelenberg is a consultant in Pulmonology and Critical Care at Stellenbosch University and Tygerberg Academic Hospital, Tygerberg, Cape Town. Dr Aliasgar Esmail is a consultant pulmonologist in the Lung Infection and Immunity Unit and the Division of Pulmonology, Department of Medicine and UCT Lung Institute, UCT and Groote Schuur Hospital. Prof. Elvis Irusen is Head of the Division of Pulmonology at Stellenbosch University and Tygerberg Academic Hospital. Prof. Michael Wechsler is Co-Director of the Asthma Institute, Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, National Jewish Health, Denver, CO, USA. Dr Rob M Niven is a consultant chest physician and Senior Lecturer in Respiratory Medicine at the University Hospital of South Manchester NHS Foundation Trust, University of Manchester, UK. Emeritus Prof. Eric Bateman is Director of the UCT Lung Institute and Honorary Consultant in the Division of Pulmonology, UCT and Groote Schuur Hospital. Prof. Kian Fan Chung is the Head of Experimental Studies at the National Heart and Lung Institute, Imperial College London and National Institute for Health Research, and Consultant Chest Physician at the Royal Brompton & Harefield NHS Trust.

Corresponding author: Prof. K Dheda (keertan.dheda@uct.ac.za)

There are approximately 3 million asthma sufferers in South Africa, and the national death rate is ranked as one of the highest in the world. Approximately 5% have severe asthma (uncontrolled despite being adherent on maximal and optimised therapy). Such uncontrolled asthma is associated with high healthcare expenditure and may require treatment with anti-IgE and/or systemic corticosteroids, in addition to inhaler therapy and oral agents. These treatments may be costly, and those such as oral corticosteroids may have potential serious adverse events. There is therefore a need for more effective, affordable and safe therapies for asthma. A new modality of treatment, bronchial thermoplasty (BT), has recently been developed and approved for the treatment of severe asthma. BT involves delivering radio frequency-generated thermal energy to the airways, with the goal of reducing airway-specific smooth-muscle mass. Several clinical studies have confirmed that BT is effective and safe, that it improves control and quality of life in patients whose asthma remains severe despite optimal medical therapy, and that the beneficial effects are sustained for at least 5 years. We provide recommendations for the management of severe asthma, with an emphasis on the role of BT, and endorse the use of BT in patients with severe persistent asthma who remain uncontrolled despite optimal medical therapy as outlined in steps 4 and 5 of the British Thoracic Society (BTS)/Scottish Intercollegiate Guidelines Network (SIGN), UK National Institute of Clinical Excellence (NICE) and Global Initiative for Asthma (GINA) guidelines. We outline the context in which BT should be used, how it works, its associated potential adverse events and contraindications, and unanswered questions and controversies.

S Afr Med J 2015;105(9):726-732. DOI:10.7196/SAMJnew.8207

1. The unmet need for interventions at treatment steps 4 and 5 of asthma guidelines

Over 300 million people suffer from asthma worldwide, and the prevalence of asthma is predicted to increase to over 400 million people globally by 2025.[1] In South Africa (SA), approximately 8Â - 10% of the population is asthmatic, and by country SA is ranked fourth highest in terms of asthma mortality.[2] Of some 3 million SA asthma sufferers, approximately 5% have confirmed uncontrolled severe asthma despite being adherent to maximal and optimised therapy. Individuals with asthma that is difficult to control consume a disproportionate percentage (up to 80%) of asthma-specific healthcare expenditure owing to the high cost of hospitalisation, physician visits, and increased healthcare utilisation.[3] Moreover, there is considerable morbidity, and an economic burden to patients and the state from days lost from school or work.

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Currently proposed individual therapies at step 5 of the Global Initiative for Asthma (GINA) and British Thoracic Society (BTS)/ Scottish Intercollegiate Guidelines Network (SIGN) guidelines favour the use of oral corticosteroids (OCSs) and/or omalizumab.

Maintenance treatment with oral or systemic corticosteroids is associated with serious adverse events such as osteoporosis, fractures and disability, an increased risk of serious or fatal infections including tuberculosis (TB), peptic ulceration, skin thinning, cataracts and diabetes, and their use should be avoided wherever possible. In SA, where the incidence of TB in many areas is >1 000/100 000 persons per year, the risk of TB is a particular concern.[4] Omalizumab is an injectable monoclonal anti-IgE antibody recently approved for use in SA for patients with severe allergic asthma (confirmed by the presence of increased serum total IgE) uncontrolled on step 4 treatments. In those who respond (40 - 60% in the first few months), monthly injections may need to be continued indefinitely. The cost of omalizumab in SA is approximately ZAR175Â 428 per year (calculated in April 2015 for a person weighing 60 - 70 kg with an IgE level of

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500 - 600 IU/L). Effective, affordable, and less toxic therapies are therefore urgently needed.[5]

2. B ronchial thermo­ plasty: What is it and how does it work?

Bronchial thermoplasty (BT) is a devicebased intervention that delivers thermal energy to the airways via a bronchoscopically guided catheter, with the goal of reducing airway smooth-muscle mass (Fig. 1). BT has been shown to increase the level of symptom control and improve quality of life in adults (>18 years) with severe asthma, with reductions in the frequency of exacerbations and asthma-related emergency room (ER) visits. BT was approved by the US Food and Drug Administration in 2010, and is included in several asthma treatment guidelines.[6-8] It is viewed as complementary therapy rather than a replacement for pharmacotherapy, although drug replacement is achieved in some cases.

BT is not curative, but aims to improve the quality of life of asthma sufferers and minimise the need for systemic corticosteroid therapy.

It is performed as an outpatient hospital procedure over three treatment sessions by a trained pulmonologist under conscious sedation, after which the patient returns to the primary referring physician for long-term asthma management. The BT procedure itself has been outlined and reviewed in detail elsewhere[9-11] and is summarised in Fig. 1.

The mechanism whereby BT achieves these clinical results is unclear. It may atten­ uate bronchoconstriction through altering the dynamics of airway smooth-muscleinduced bronchoconstriction. Indeed, air­ way narrowing in asthma in the context of smooth-muscle hypertrophy increases the airway resistance 20-fold when compared with resistance in normal airways.[12] How­ ever, it seems unlikely that attenuation of bronchoconstriction alone is responsible for improvements, since improved lung function is not consistently seen. Animal studies have shown that airways treated at 65oC and 75oC, but not 55oC, show a reduction in airway responsiveness and smooth-muscle mass that persists for 3 years,[13] and in human lungs this effect is seen as soon as 1 - 3 weeks after BT.[14] BT therefore appears to influence lung remodelling and to have a disease-modifying effect. A recent study in ten patients with severe asthma has shown that 3 months after BT, a significant reduction in smooth muscle was observed not only in all the treated lung lobes but even in the untreated right middle lobe, which is not normally subjected to BT.[15] Regression in smooth-muscle mass has therefore been demonstrated in the larger

Fig. 1. Outline of the equipment, the BT procedure, and effects on airway smooth muscle. A: Alair radiofrequency controller; B: Alair BT catheter tip (basket electrode) with the 5 mm spacer markings guiding sequential activations; C: Handle grip controlling expansion of the catheter tip; D: Gel-type return electrode to complete the circuit; E: Foot pedal triggering delivery of the radiofrequency-mediated thermal energy; F: BT procedure performed using a flexible fibreoptic bronchoscope; G: Catheter in the bronchus delivering controlled radiofrequency thermal energy; H: Histological sections of dog bronchial wall before (top) and 12 weeks after BT (bottom), showing reduction in airway smooth muscle and preserved integrity of the epithelium, mucous glands and subepithelial tissue;[13] I: Biopsies before and after BT in the lower lobes of two patients, showing reduction in airway smooth-muscle mass (the percentage of airway smoothmuscle surface area/total biopsy area) is shown numerically in the sub-figure. From www.btforasthma. com, reproduced with permission.

airways (>3 mm in diameter)[13] and in the segmental and sub-segmental airways.[15] The impact of BT on the more distal airways down to the level of the respiratory bronchioles, which also contain smooth muscle and are an important site of airway obstruction in asthma, remains unclear.[16,17] The beneficial smooth-muscle-related effects may be due to several factors, including direct reduction in muscle mass, interference with contractile function, reduction in the secretion of inflammatory mediators from smooth muscle, reduction in muscle inflammation, a potential neural mechanism, disruption of a potential pacemaker effect, and possibly an indirect effect mediated by changes in the epithelium or other structures. How­ever, there are hardly any data on the impact of BT on the immuno­pathology in human airways, or on the impact of other potential smoothmuscle-specific functions including immune modulation and angiogenesis. Interestingly, airway smooth-muscle regression associated with a reduction in exacerbations has also recently been demonstrated with the calcium channel blocker gallopamil.[18] BT is currently offered at 448 sites in 32 countries, and as of March 2015, more than

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4 100 patients have been treated with BT (source: Boston Scientific). The use of BT for severe persistent asthma has now been endorsed by several guidelines, including the British Guideline on the Management of Asthma[6] (BTS/SIGN), the UK National Institute of Clinical Excellence (NICE)[7] and GINA[8] guidelines, the European Respiratory Society/American Thoracic Society Guide­ lines on the Evaluation and Treatment of Severe Asthma,[19] and the American College of Chest Physicians guideline.[20] This article seeks to clarify the recommen­ dations of the South African Thoracic Society and its interventional pulmonology subgroup on how BT should be offered and used in the SA context. It is anticipated that this document will evolve and be updated as more evidence becomes available.

3. What do global and national guidelines say about BT?

Based on the available evidence (out­ lined in sections 5 and 6 below), BT has been en­ dorsed by several international guidelines and professional societies.

In the international 2014 joint European

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Respiratory Society/American Thoracic Society (ERS/ATS) guideline on the definition, evaluation and treatment of severe asthma, and based on evidence that was evaluated to be strong but of low quality, the recommendation was for BT be performed in adults with severe asthma in the context of an independent institutional review board (research ethics committee)-approved systematic registry or clinical study.[19] Contextually, this recommendation placed a higher value on avoiding adverse events, on increased use of resources and on a lack of understanding about which specific patients may benefit, and a lower value on improvement in symptoms and quality of life. The statement, prepared before the 5-year AIR2 (Asthma Intervention Study-2) data became available, reiterated the need for better understanding of the phenotypes of patients responding to BT and the effect that BT was having in patients with more severe obstructive asthma (forced expiratory volume in 1 second (FEV1) <60% of predicted), or those in whom systemic maintenance OCSs are used.

The 2014 BTS/SIGN asthma guideline (British Guideline on the Management of Asthma) recommends that BT be considered for the treatment of adult patients who have poorly controlled asthma despite optimal therapy (grade A recommendation).[6] It suggests that BT should be undertaken only in centres that have expertise in the assessment of ‘difficult-to-control’ asthma and in regularly performing fibreoptic bronchoscopic procedures, and reiterates the need for research that could better identify patients who could benefit from BT. The 2014 UK NICE guideline endorses the use of BT, provided that patients understand the limitations in efficacy and longer-term safety (beyond 5 years) and the potential for adverse events.[7] It further recommends that the details of all patients undergoing BT should be submitted to a ‘difficult asthma registry’, and emphasises that BT should be carried out by a respiratory team with special expertise in managing difficult and severe asthma.

The GINA revised 2014 report states that BT may be considered for some adult patients with severe asthma (evidence grade B).[8] GINA states that BT is a potential step 5 treatment option in adult patients with uncontrolled asthma despite use of recommended therapeutic regimens and referral to a specialist asthma centre.

BT is endorsed by the Asthma and Allergy Foundation of America, which urges ‘that health plans and insurance carriers fully cover the cost of BT for those whose severe asthma is not well managed by less invasive therapies, and whose physicians deem it appropriate’. BT has also been endorsed by INTERASMA, a global asthma association,[21] which suggests that ‘BT should not be considered as experimental but ... important option for patients ... and should be covered and paid by the social security system and/or private insurance to facilitate the accessibility for this special group of patients’. BT is now available in ~32 countries and is currently being funded or reimbursed by the national health system or medical insurance companies in the USA, Australia, the UK, Japan, Switzerland and Germany, among others. The American College of Chest Physicians has endorsed such reimbursement.[20]

4. Recommendations and approach

4.1 Evaluate difficult-to-control asthmatics. Difficult-to-control asthmatics should be investigated to confirm the diagnosis of severe asthma (as per the ERS/ATS definition).[19] We recommend that a high-resolution computed tomography (HRCT) scan of the lungs be performed to exclude alternative diagnoses or those precluding BT, including significant bronchiectasis, sarcoidosis, chronic obstructive pulmonary disease (COPD), endobronchial TB, bronchial stenosis, other endobronchial disease, tracheobronchomalacia, etc., which

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may all masquerade as asthma. Other potential diagnoses such as vocal cord dysfunction, and comorbid conditions or other modifiable contributory or risk factors, such as gastro-oesophageal reflux disease, rhinosinusitis or use of concomitant medication or exposures that may subvert asthma control, should be considered. Further work-up may include other investigations to rule in alternative diagnoses or determine the underlying endotype, including total and specific IgE levels, exhaled nitric oxide (FeNO), blood and sputum eosinophilia, etc. At each visit, the patient’s inhaler technique should be carefully checked, adherence to medication confirmed, and environmental modification implemented. These approaches cannot be overemphasised, as these factors frequently explain poor asthma control.

4.2. Optimise treatment. Patients should have a trial of at least 3 months’ treatment with optimal and/or maximal doses of inhaled corticosteroids (ICSs) (ICS thresholds that define severe asthma are outlined in the ERS/ATS severe asthma guidelines[19]), long-acting b2-agonists (LABAs) and/or long-acting muscarinic antagonists (LAMAs), and possibly other step 4 and 5 treatments (leukotriene receptor antagonists, and/or low-dose theophylline, and/ or omalizumab (if appropriate)) in an attempt to optimise asthma control.[6,7] In suitable patients with an appropriately raised serum IgE level and sensitivity to aeroallergens, a 4-month trial of omalizumab is advised.[6,8] Immunosuppressive treatments such as methotrexate, cyclosporine, etc. are toxic but are included as treatments for severe asthma in some, but not all, guidelines;[6,18] having limited efficacy, they are rarely used and should not be considered as routine treatment before considering BT. If used, they should be given for a minimum 3-month period, and stopped if there is no response to treatment.[6] While it is unnecessary to try all the abovementioned options, these steps are intended to ensure that any potential benefit from medical therapy is realised before recommending BT. 4.3 Confirm the diagnosis of severe asthma. If the patient remains uncontrolled despite appropriate work-up and optimisation of treatment as outlined in 4.1 and 4.2 above, a diagnosis of severe asthma can be established as per the ERS/ATS guideline,[19] i.e. asthma that remains uncontrolled despite use of GINA step 4 or 5 therapeutic options (high-dose ICSs, LABAs, leukotriene modifiers, theophylline, omalizumab and/or OCSs).

4.4 Use of BT. We recommend that BT be considered and offered to patients who remain uncontrolled despite optimal therapy that includes maximal doses of ICSs and optimised GINA step 4 and 5 therapy (see 4.2 above).

4.5 Where should the procedure be performed, and by whom?

BT should be offered to patients at a facility accredited by the Assembly on Interventional Pulmonology of the South African Thoracic Society and that has experience in dealing with difficultto-control or severe asthma. The procedure should be performed by a pulmonologist experienced in performing bronchoscopy and BT. Patients should ideally form part of a national and/or international registry, or prospective study, so that long-term outcomes can be monitored and audited, and optimal patient selection is facilitated.

Such a registry has been started in SA. 4.6 Recommendations for the procedure. Three sessions of BT approximately 3 - 4 weeks apart should be offered, preferably using local anaesthesia and conscious sedation where appropriate and if tolerated. General anaesthesia may be employed in appropriate patients. Periprocedural corticosteroids should be adminstered for a total of 5 days, beginning 3 days prior to the procedure.

Prior to the procedure, spirometry should be performed to ensure that the post-bronchodilator predicted FEV1 is within 90% of

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the prior baseline. The procedure is relatively contraindicated in the presence of bronchiectasis because of the risk of infection.

Other contraindications include the presence of an implantable pacemaker, defibrillator or other electronic device, sensitivity to any of the medications used during bronchoscopy, and any general contraindication to bronchoscopy, including those relevant to fitness, sedation and anaesthesia.

4.7 Post-procedural aspects. Patients should be closely monitored for exacerbations after the procedure, and those with a postprocedure FEV1 <80% of their pre-procedure baseline should be considered and carefully evaluated for possible hospitalisation should they continue to deteriorate (defined as persistently reduced lung function, suboptimal oxygen saturation, persistent tachycardia, etc.).

A chest radiograph should be performed after the procedure if clinically indicated, e.g. in the case of suspected pneumothorax, segmental or lobar collapse, or suspected aspiration. Routine postprocedure chest radiography is unnecessary. Patients should be reassessed 6 - 12 weeks after their last BT procedure and regularly thereafter, and medication dosages, particularly of OCSs (if being used), should be reduced over time as appropriate, to the lowest dose that maintains asthma control. Patients may report an improvement in their symptoms as early as immediately after the first procedure.

Increasing benefit after the second and third procedure is often reported.

4.8 Post-procedure follow-up. We suggest that all BT patients be enrolled in a national and international registry so that adverse events can be reported and audited. In the immediate post-procedure period (within 2 weeks), clinicians should be vigilant concerning complications such as asthma exacerbation, lung collapse and lung abscess. Data on long-term safety are accumulating.

5. W hat is the impact of BT on patient-related outcomes?

The clinical effectiveness of BT has been confirmed in two prospective cohort feasibility studies,[14,22] three randomised controlled trials (RCTs),[23-25] one of which was published in the New England Journal of Medicine, and three prospective cohort followup studies interrogating long-term outcomes and safety[26-28] (the relevant studies are summarised in Table 1). The AIR trial enrolled 112 patients with moderate to severe asthma (FEV1 60 - 85% of predicted).[23] Patients with three or more lower respiratory tract infections (LRTIs) requiring antibiotics in the preceding year, or those with recent respiratory tract infections (RTIs), were excluded.

The BT group showed a significant decrease in mild exacerbations (the primary outcome), significant improvement in asthma control (ACQ), significant improvement in quality of life (asthma qualityof-life questionnaire; AQLQ), and significantly increased symptomfree days.[23] There was no impact on airway responsiveness or lung function.

The RISA (Research In Severe Asthma) open-label trial enrolled 34 patients with severe asthma (FEV1 >50% of predicted) and evaluated safety as the primary outcome.[24] Patients with post-bronchodilator FEV1 <50% of predicted, >3 LRTIs requiring antibiotics prior to BT, or a recent LRTI were excluded from this study. The study found that BT was well tolerated in severe asthma. The BT group showed an increase in pre-bronchodilator FEV1, improved asthma control (ACQ) and improved AQLQ scores, and significantly more subjects were weaned from OCSs (a 64% reduction in OCS use).[24] The BT participants also had significant reduction in rescue medication use at 22 weeks.

The AIR2 study, designed specifically to minimise confounding and a placebo effect, enrolled 297 patients in a double-blinded sham-

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controlled fashion, where all the enrolled patients had a bronchoscopy and catheter insertion, but radiofrequency-generated thermal energy was not delivered to the airways in the control group (sham).[25] This study enrolled patients with severe asthma (FEV1 >60% of predicted and using >1 000 µg beclomethasone per day with or without OCSs and omalizumab). Patients with ≥3 prior hospitalisations, ≥3 LRTIs in the previous year, ≥4 pulses of OCSs in the previous year, previous life-threatening asthma, or a need for ≥10 mg of OCSs per day were excluded from the study. The primary outcome was the change in the AQLQ. The study found significantly greater patient-level improvement in AQLQ in the BT group, and secondary outcomes (severe exacerbations and ER visits) were significantly reduced in the BT group. Pre-bronchodilator FEV1 did not improve significantly, however, and rescue medication use did not decrease significantly in the BT group. In addition to the reduction in severe exacerbations during the 12-month follow-up period, asthma-related days lost from work, school or other activities were also significantly reduced in the BT group. Notably, there was a strong placebo effect in the shamtreated subjects.

A Cochrane-based systematic review and meta-analysis incorpor­ ating all three RCTs concluded that BT in patients with moderate to severe asthma provided modest clinical benefit, improved quality of life, and lowered rates of asthma exacerbation.[29] However, the procedure increased the risk of adverse events during treatment but had a reasonable safety profile after treatment. The authors rated the overall quality of evidence regarding BT as ‘moderate’. They suggested that ‘future research would provide better understanding of the mechanisms of action of BT, as well as its effect in different asthma phenotypes, or in patients with worsening lung function’. There are currently no data on the impact of BT on mortality in severe asthma, but it is noteworthy that the percentage of the bronchial wall occupied by smooth muscle is increased in fatal asthma (12% in segmental bronchi v. 5% in normal subjects).[30]

6. What is the response rate and who is most likely to respond?

In the AIR2 study, 78.9% of BT patients recorded at least a 0.5 change in AQLQ score, and there was a ~53% reduction in ED visits for BT patients, a ~35% reduction in severe exacerbations experi­enced, and a ~50% reduction in respiratory-related hospitalisations.[27] In several respects, the magnitude of changes are not dissimilar to that seen with omalizumab (e.g. a ~25% reduction in exacerbations, and a 70% reduction in ED visits).[31-33] 6.1 Who is most likely to respond? In a recent study, Sheshardi et al.[9] showed that a good response to BT was associated with more gas trapping on HRCT, reduction in specific quantities of ICSs or OCSs, and an incremental improvement in the AQLQ score of >0.5.

The pathogenesis of bronchial asthma is complex and is broadly characterised by an interrelating combination of smooth-muscle dysfunction, airway remodelling, and T-helper (Th)2- and nonTh2-related inflammation.[34] Several subgroups of bronchial asthma have now been described, including those with high symptom counts but minimal eosinophilic inflammation, and those that are inflammation dominant but have fewer daily symptoms.[35] Phenotypes may also be categorised based on biomarker profiles, and some biomarkers (e.g. blood eosinophils, serum periostin, IgE levels, FeNO, etc.) predict response to therapy with biological agents that target specific inflammatory pathways.[34,36-38] It remains unclear what clinical phenotype (e.g. obese v. non obese; those with airway hyperresponsiveness (AHR) v. those without), endotype or molecular phenotype (e.g. atopic v. non-atopic or Th2 v. non-Th2), or genotype is most likely to respond to BT.[38] The value of specific biomarkers

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Table 1. Summary of key clinical studies evaluating the safety, efficacy and long-term outcomes of BT Key inclusion criteria

Key exclusion criteria

Efficacy measures

Adverse events

Comments

Miller et al.,[14] 2005 Number enrolled: 16 Design: Feasibility study

Patients with suspected or proven lung cancer scheduled for lung resection

N/A

Safety, airway smooth-muscle mass reduction in the resected lung segments

No serious adverse events

Decrease in airway smooth muscle documented

Cox et al.,[22] 2006 Number enrolled: 16 Design: Feasibility study

Adults with mild to moderate asthma

Recent RTI, frequent use of recue medication

Safety, methacholine PC20 at 2 years post BT

No serious adverse events, no hospitalisations

Mean PC20 increased post-BT, increase in symptom-free days, morning and evening peak flows remained stable

AIR trial[23] (Cox et al.), 2007 Number enrolled: 112 Design: RCT

Adults ≤65 years with moderate to severe asthma (FEV1 60 - 85% predicted)

Recent RTI and ≥3 or more LRTIs requiring antibiotics in the preceding year

Primary: rate of mild asthma exacerbation Secondary: ACQ/ AQLQ

Asthma worsening post BT requiring hospitalisation (7.6% BT v. 4.08% control group), but rates of adverse events between 6 weeks and 12 months were equal in the two groups

Decrease in mild exacerbations, improvements in ACQ/ AQLQ scores, and increase in symptom-free days

RISA trial[24] (Pavord et al.), 2007 Number enrolled: 34 Design: RCT

Adults ≤65 years on highdose ICS/LABA with AHR and uncontrolled symptoms (FEV1 <50% of predicted)

Post-BD FEV1 <50% of predicted, >3 LRTIs requiring antibiotics prior to BT, and those who had a recent LRTI

Primary: safety Secondary: ACQ/ AQLQ, OCS and ICS dose reduction, and FEV1

Hospitalisation in 4/17 patients (23%) in the BT group v. none in the control group, mostly within 3 days of BT procedure, but similar rates of hospitalisation in post-treatment phase compared with control group

Overall BT well tolerated in severe asthma, increase in pre-BD FEV1, increase in ACQ/AQLQ scores, and increased proportion of OCS weaning post BT

AIR2 trial[25] (Castro et al.), 2008 Number enrolled: 297 Design: RCT – double blind sham controlled

Adults ≤65 years on high-dose ICS/LABAs (FEV1 >60% of predicted)

Previous lifethreatening asthma, ≥3 prior hospitalisations or LRTIs in the previous year, ≥4 or more pulses of OCSs in the previous year, need for ≥10 mg of OCSs per day

Primary: change in AQLQ Secondary: severe exacerbations, healthcare utilisation

Increased rate of hospital admissions (8.4% in the BT group v. 2% in the control group)

Greater increase in AQLQ in BT group, decrease in severe exacerbation and asthma-related ER visits in BT group

AIR 5-year follow-up[26] (Thompson et al.), 2011 Number enrolled: 45 Design: Prospective cohort

As above

As above at baseline

Adverse events, hospitalisation, FEV1 and FVC

No long-term adverse events

Absence of reported clinical complications, no increase in asthma-related healthcare utilisation, stable FEV1 and FVC over 5 years

RISA 5-year follow-up[27] (Pavord et al.), 2013 Number enrolled: 14 Design: Prospective cohort

As above

As above at baseline

Safety, severe exacerbations, lung function

No long-term adverse events

Decrease in asthmarelated ER visits, hospitalisations and FEV1 maintained post BT

AIR2 5-year followup[28] (Wechsler et al.), 2013 Number enrolled: 162 Design: Prospective cohort

As above

As above at baseline

Safety, asthma control, severe exacerbation, asthma-related ER visits

No long-term adverse events

Decrease in severe exacerbation, asthma-related ER visits and hospitalisations post-BT maintained over the follow-up period

Study details

N/A = not applicable; PC20 = provocative concentration (concentration of methacholine at which the FEV1 falls by ≥20%); FVC = forced vital capacity.

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to predict response to BT therefore requires clarification. As already outlined, severe asthmatics with previous life-threatening asthma, OCS requirements of >10 mg/d and >3 - 4 exacerbations or hospitalisations in the preceding year were excluded from the clinical trials. Such patients are frequently seen in severe asthma clinics in day-to-day clinical practice, and studies on the effect of BT in this specific subgroup of patients are urgently required. Prospective studies will be required to delineate exactly which phenotype of patient is most suitable for and responsive to BT.

7. W hat adverse events are associated with BT?

In the AIR study, four of 66 subjects in the BT group (6%) were hospitalised (six hospitalisations).[23] In the RISA trial, four of the 17 BT-treated patients had seven hospitalisations, of which two were secondary to the development of segmental lobar collapse, and one patient required bronchoscopic aspiration of mucus.[24] In the AIR2 study, in which 850 bronchoscopies were performed (558 BT and 292 sham procedures), there were no device-related deaths or major adverse events such as pneumothorax, exacerbations requiring mechanical ventilation, airway stenosis or focal airway narrowing. However, during the within-BT treatment period, hospitali­ sation occurred more frequently in the BT group (8.4%) than in the sham broncho­ scopy group (2%).[25] It is clear from these studies that BT can be associated with complications requiring immediate postprocedure hospitalisation due to an asthma exacerbation. Periprocedural corticosteroids (administered 3 days before, on the day, and 1 day after) are given to minimise this risk. The risk of hospitalisation must be balanced against the long-term clinical improvements achieved, including reduc­ tions in exacerbations, absenteeism and corticosteroid use.

The long-term safety of BT (up to 5 years) has been demonstrated in three studies.[26-28] There is no consistent evidence that BT is causally associated with bronchial stenosis or bronchiectasis. In the AIR2 follow-up study, only three of 93 patients developed new (n=1) or worsening bronchiectasis (n=2) as shown on HRCT; it remains unclear whether this was a complication of asthma or related to BT. Minor bleeding in the airways may sometimes be seen during the procedure, but haemoptysis is rare (one patient in the AIR2 study developed major haemoptysis requiring embolisation

Table 2. Unanswered questions and outstanding controversies regarding BT 1

What is the mechanism whereby BT reduces smooth-muscle mass in humans and animals, and what is its effect on different cellular and structural components of the human airway?

2

What specific phenotypes of severe asthma that remain symptomatic despite optimal treatment will best respond to BT?

3

Do patients with more severe persistent asthma, who were excluded from the clinical trials, benefit to the same extent, or more, from BT?

4

Does BT have increasing benefit in those who have partially responded or in whom the benefit later lapses?

5

How far beyond 5 years does the BT effect last?

6

Can the same effect be obtained in fewer BT sessions?

7

Is there any incremental benefit from more than three BT sessions, and what parameters portend room for further response?

8

In patients with atopic severe persistent asthma and who are suitable for omalizumab (or in future other biologicals), should BT be offered in the first instance taking into account their comparative efficacy, safety and cost?

9

Are there longer-term (beyond 5 years) safety issues in patients who undergo BT?

10

Should BT should be recommended in an earlier treatment step to attempt to reduce costs of multiple drug treatments and the potential morbidity of prolonged uncontrolled asthma, or must it be undertaken as a last resort at step 5 when all else has failed?

11

What is the relationship between asthma severity, and other biological factors, and the probability of post-procedure complications?

12

Will patients with emphysema or the asthma-COPD overlap syndrome benefit from BT, and what parameters should be used to guide the decision to employ it?

about 1 month after bronchoscopy).[25] A recent case report describes a lung abscess that occurred during the first week after a single BT treatment session,[39] and another reports recurrent atelectasis caused by fibrin plugs.[40] These published cases indicate the need to remain vigilant during the postprocedure period.

8. Is the effect of BT sustained, and is it cost-effective?

Two prospective cohort studies have shown that the beneficial effects of BT are sus­ tained.[27,28] A follow-up of the RISA cohort demonstrated that the reductions in hospitalisations (70% reduction) and ER visits (~66% reduction) were sustained for 5 years.[27] There was no long-term change in the predicted FEV1. A follow-up of the AIR2 cohort showed that the reduction in severe exacerbations (38% reduction, i.e. 52% in the 12 months preceding BT and ~30% for each year of the follow-up period) and ER visits (88% reduction) post BT were also sustained for 5 years.[28] Although no comparison with the control groups was made during this follow-up study, the results at least confirm sustained benefit across several endpoints.[41] The estimated comparative 2015 cost of BT, including bronchoscopy and physician visits at the time of writing, was estimated to

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be ~ZAR120 000, being a one-time cost. A cost-effectiveness study in the USA showed that in poorly controlled severe persistent asthma, with a 5-year view in the basecase scenario, the cost-effectiveness of BT was USD5 495 per quality-adjusted life-year, which was below the ‘willingness to pay’ [42] threshold of USD50 000 in the USA. Further cost-effectiveness studies are re­quired in different contexts.

9. Unanswered questions and controversies

The AIR2 study[41] has been criticised for several reasons. Firstly, as already mentioned, it excluded patients with more severe asthma who would possibly have benefited the most from BT; only 3.7% of patients undergoing BT in AIR2 were on OCSs, a group that may be considered to have more severe asthma, although otherwise the patients enrolled met the minimal criteria for the definition of severe asthma.[25] Secondly, although there was potentially significant improvement in the predetermined AQLQ-specific primary outcome (mean difference of 0.19 between the groups), this fell below the threshold for a clinically meaningful difference (change in AQLQ score >0.5); however, when analysed differently, i.e. at an individual level (percentage of subjects with an AQLQ

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change of >0.5), AQLQ was statistically significantly better in the BT-treated than in the sham bronchoscopy group (78.9% v. 64.3%).

The latter approach is justified when interpreting AQLQ scores, which reflect within-group differences better than between-group differences.[11] Thirdly, the placebo effect is well recognised in asthma trials, and the AQLQ improvement in the sham group was probably due to more meticulous and protocol-driven asthma care during the trial, as well as standardisation of care before recruitment. Given this consideration, the AIR2 study should ideally have incorporated a longer run-in period, and in retrospect, chosen asthma exacerbation or ER visits as an a priori primary outcome. Indeed, there was a significant reduction in exacerbations and ER visits, but this was a secondary outcome rather than a prespecified primary outcome.[25] Nevertheless, the reduction in severe exacerbations was significant, and this is an important determinant of patient-related quality of life and utilisation of healthcare costs. Fourthly, it has been suggested that there were outliers in the control group that could have driven a meaningful part of the statistical difference between the groups. However, it was clarified that removal of the outlier would still substantially reduce ER visits from 84% to 70%. These points have been openly debated and are outlined in detail in several editorials and letters to the editor.[41,43] Other unanswered questions are outlined in Table 2.

These include questions related to the mechanism of action of BT and the identification of patients most likely to benefit from it.

Conclusions

BT is indicated as a treatment for severe asthma that remains uncontrolled despite an optimal trial of step 4 and 5 GINA therapeutic options.[8] BT has been shown to significantly lower the rates of asthma exacerbation and ER visits, and has shown modest benefits in improvement of quality of life scores. The procedure has been confirmed to be safe with no significant long-term adverse effects up to 5 years after the initial intervention. Complications of BT include exacerbations and hospitalisation due to transient worsening of asthma symptoms in a small proportion of patients. As this treatment is directed towards treating severe asthma, further studies are needed to establish both its short-term and longer-term safety (beyond 5 years) in patients with more severe disease, and those features that identify patients most likely to benefit from BT. Disclosures. CFNK, AE, EI, EDB and KFC have no disclosures relating to the topic of this paper. RMN has received speaker fees and advisory board payments from Boston Scientific over the past 5 years. MEW and KD have received honoraria from Boston Scientific for industry-funded symposia given at local or international conferences. None of the authors report patents, grant funding, shares/stock options or consultancy agreements that are in any way relevant to this publication.

References 1. Masoli M, Fabian D, Holt S, Beasley R. Global Burden of Asthma – Developed for the Global Initiative for Asthma. Global Initiative for Asthma, 2004.

2. Global Asthma Report 2014. Auckland, New Zealand: Global Asthma Network, 2014.

3. Smith DH, Malone DC, Lawson KA, Okamoto LJ, Battista C, Saunders WB. A national estimate of the economic costs of asthma. Am J Resp Crit Care Med 1997;156(3):787-793. [http://dx.doi.org/10.1164/ ajrccm.156.3.9611072] 4. World Health Organization. Global Tuberculosis Report. Geneva: WHO, 2014.

5. Sweeney J, Brightling CE, Menzies-Gow A, et al. Clinical management and outcome of refractory asthma in the UK from the British Thoracic Society Difficult Asthma Registry. Thorax 2012;67(8):754756. [http://dx.doi.org/10.1136/thoraxjnl-2012-201869] 6. British Thoracic Society, Scottish Intercollegiate Guidelines Network. British Guideline on the Management of Asthma, 2014. Thorax 2014;69( Suppl 1):1-192.

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9. Sheshadri A, McKenzie M, Castro M. Critical review of bronchial thermoplasty: Where should it fit into asthma therapy? Curr Allergy Asthma Rep 2014;14(11):470-474. [http://dx.doi.org/10.1007/ s11882-014-0470-4] 10. Dombret MC, Alagha K, Philippe Boulet L, et al. Bronchial thermoplasty: A new therapeutic option for the treatment of severe, uncontrolled asthma in adults. Eur Respir Rev 2014;23(134):510-518. [http:// dx.doi.org/10.1183/09059180.00005114] 11. Miller RJ, Murgu SD. Interventional pulmonology for asthma and emphysema: Bronchial thermoplasty and bronchoscopic lung volume reduction. Semin Respir Crit Care Med 2014;35(6):655-670. [http:// dx.doi.org/10.1055/s-0034-1395939] 12. James AL, Pare PD, Hogg JC. The mechanics of airway narrowing in asthma. Am Rev Respir Dis 1989;139(1):242-246. [http://dx.doi.org/10.1164/ajrccm/139.1.242] 13. Danek CJ, Lombard CM, Dungworth DL, et al. Reduction in airway hyperresponsiveness to methacholine by the application of RF energy in dogs. J Appl Physiol 2004;97(5):1946-1953. [http:// dx.doi.org/10.1152/japplphysiol.01282.2003] 14. Miller JD, Cox G, Vincic L, Lombard CM, Loomas BE, Danek CJ. A prospective feasibility study of bronchial thermoplasty in the human airway. Chest 2005;127(6):1999-2006. [http://dx.doi. org/10.1378/chest.127.6.1999] 15. Pretolani M, Dombret MC, Thabut G, et al. Reduction of airway smooth muscle mass by bronchial thermoplasty in patients with severe asthma. Am J Resp Crit Care Med 2014;190(12):1452-1454. [http://dx.doi.org/10.1164/rccm.201407-1374LE] 16. Hamid Q, Song Y, Kotsimbos TC, et al. Inflammation of small airways in asthma. J Allergy Clin Immunol 1997;100(1):44-51. [http://dx.doi.org/10.1016/S0091-6749(97)70193-3] 17. Tashkin DP. The role of small airway inflammation in asthma. Allergy Asthma Proc 2002;23(4):233-242.

18. Girodet PO, Dournes G, Thumerel M, et al. Calcium channel blocker reduces airway remodeling in severe asthma: A proof-of-concept study. Am J Resp Crit Care Med 2015;191(8):876-883. [http:// dx.doi.org/10.1164/rccm.201410-1874OC] 19. Chung KF, Wenzel SE, Brozek JL, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J 2014;43(2):343-373. [http://dx.doi. org/10.1183/09031936.00202013] 20. CHEST. Coverage and Payment for Bronchial Thermoplasty for Severe Persistent Asthma. Glenview, IL: American College of Chest Physicians, 2014.

21. INTERASMA. Bronchial Thermoplasty: An Additional Option for Managing Patients with Severe Asthma. INTERASMA Global Asthma Association, 2014.

22. Cox G, Miller JD, McWilliams A, Fitzgerald JM, Lam S. Bronchial thermoplasty for asthma. Am J Resp Crit Care Med 2006;173(9):965-969. [http://dx.doi.org/10.1164/rccm.200507-1162OC] 23. Cox G, Thomson NC, Rubin AS, et al. Asthma control during the year after bronchial thermoplasty. N Engl J Med 2007;356(13):1327-1337. [http://dx.doi.org/10.1056/NEJMoa064707] 24. Pavord ID, Cox G, Thomson NC, et al. Safety and efficacy of bronchial thermoplasty in symptomatic, severe asthma. Am J Resp Crit Care Med 2007;176(12):1185-1191. [http://dx.doi.org/10.1164/rccm.200704-571OC] 25. Castro M, Rubin AS, Laviolette M, et al. Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: A multicenter, randomized, double-blind, sham-controlled clinical trial.

Am J Resp Crit Care Med 2010;181(2):116-124. [http://dx.doi.org/10.1164/rccm.200903-0354OC] 26. Thomson NC, Rubin AS, Niven RM, et al. Long-term (5 year) safety of bronchial thermoplasty: Asthma Intervention Research (AIR) trial. BMC Pulm Med 2011;11:8. [http://dx.doi.org/10.1186/1471-2466-11-8] 27. Pavord ID, Thomson NC, Niven RM, et al. Safety of bronchial thermoplasty in patients with severe refractory asthma. Ann Allergy Asthma Immunol 2013;111(5):402-407. [http://dx.doi.org/10.1016/j.anai.2013.05.002] 28. Wechsler ME, Laviolette M, Rubin AS, et al. Bronchial thermoplasty: Long-term safety and effectiveness in patients with severe persistent asthma. J Allergy Clin Immunol 2013;132(6):1295-1302. [http://dx.doi.org/10.1016/j.jaci.2013.08.009] 29. Torrego A, Sola I, Munoz AM, et al. Bronchial thermoplasty for moderate or severe persistent asthma in adults. Cochrane Database of Systematic Reviews 2014, Issue 3. Art. No.: CD009910. [http://dx.doi. org/10.1002/14651858.cd009910.pub2] 30. Jeffery PK. Remodeling and inflammation of bronchi in asthma and chronic obstructive pulmonary disease. Proc Am Thorac Soc 2004;1(3):176-183. [http://dx.doi.org/10.1513/pats.200402-009MS] 31. Humbert M, Beasley R, Ayres J, et al. Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE. Allergy 2005;60(3):309-316. [http://dx.doi.org/10.1111/j.1398-9995.2004.00772.x] 32. Barnes N, Menzies-Gow A, Mansur AH, et al. Effectiveness of omalizumab in severe allergic asthma: A retrospective UK real-world study. J Asthma 2013;50(5):529-536. [http://dx.doi.org/10.3109/0277 0903.2013.790419] 33. Hanania NA, Alpan O, Hamilos DL, et al. Omalizumab in severe allergic asthma inadequately controlled with standard therapy: A randomized trial. Ann Intern Med 2011;154(9):573-582. [http:// dx.doi.org/10.7326/0003-4819-154-9-201105030-00002] 34. Olin JT, Wechsler ME. Asthma: Pathogenesis and novel drugs for treatment. BMJ 2014;349:g5517. [http://dx.doi.org/10.1136/bmj.g5517] 35. Haldar P, Pavord ID, Shaw DE, et al. Cluster analysis and clinical asthma phenotypes. Am J Resp Crit Care Med 2008;178(3):218-224. [http://dx.doi.org/10.1164/rccm.200711-1754OC] 36. Ray A, Oriss TB, Wenzel SE. Emerging molecular phenotypes of asthma. Am J Physiol Lung Cell Mol Physiol 2015;308(2):L130-L140. [http://dx.doi.org/10.1152/ajplung.00070.2014] 37. Fajt ML, Wenzel SE. Biologic therapy in asthma: Entering the new age of personalized medicine. J Asthma 2014;51(7):669-676. [http://dx.doi.org/10.3109/02770903.2014.910221] 38. Chung KF. Managing severe asthma in adults: Lessons from the ERS/ATS guidelines. Curr Opin Pulm Med 2015;21(1):8-15. [http://dx.doi.org/10.1097/MCP.0000000000000116] 39. Balu A, Ryan D, Niven R. Lung abscess as a complication of bronchial thermoplasty. J Asthma 2015;Mar 13:1-3. [Epub ahead of print] 40. Facciolongo N, Menzella F, Lusuardi M, et al. Recurrent lung atelectasis from fibrin plugs as a very early complication of bronchial thermoplasty: A case report. Multidiscip Respir Med 2015;10(1):9. [http://dx.doi.org/10.1186/s40248-015-0002-7] 41. Iyer VN, Lim KG. Bronchial thermoplasty: Reappraising the evidence (or lack thereof). Chest 2014;146(1):17-21. [http://dx.doi.org/10.1378/chest.14-0536] 42. Cangelosi MJ, Ortendahl JD, Meckley LM, et al. Cost-effectiveness of bronchial thermoplasty in commercially-insured patients with poorly controlled, severe, persistent asthma. Exp Rev Pharmacoecon Outcomes Res 2015;15(2):357-364. [http://dx.doi.org/10.1586/14737167.2015.978292] 43. Castro M, Cox G, Wechsler ME, Niven RM. Bronchial thermoplasty: Ready for prime time – the evidence is there! Chest 2015;147(2):e73-e74. [http://dx.doi.org/10.1378/chest.14-2296]

Accepted 7 July 2015.

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RECOMMENDATIONS

Recommendations for the anticoagulation of pregnant patients with mechanical heart valves E Schapkaitz, B F Jacobson, P Manga, R S Chitsike, E Benade, S Jackson, S Haas, H R Buller, on behalf of the South African Society of Thrombosis and Haemostasis Dr Elise Schapkaitz is a haematologist at Charlotte Maxeke Johannesburg Academic Hospital and the Department of Molecular Medicine and Haematology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; Prof. Barry Jacobson is Head of the Division of Clinical Haematology at Charlotte Maxeke Johannesburg Academic Hospital and the Faculty of Health Sciences, University of the Witwatersrand, and chairman of the South African Society of Thrombosis and Haemostasis; Prof. Pravin Manga is Head of the Division of Cardiology at Charlotte Maxeke Johannesburg Academic Hospital and the Faculty of Health Sciences, University of the Witwatersrand; Dr Rufaro Chitsike is a clinical haematologist at Medicine Memorial University of Newfoundland Health Sciences Center, Newfoundland, Canada; Dr Estee Benade is a senior haematology registrar at Charlotte Maxeke Johannesburg Academic Hospital and the Faculty of Health Sciences, University of the Witwatersrand; Dr Sarah Jackson is an obstetrician and gynaecologist at Charlotte Maxeke Johannesburg Academic Hospital and the Faculty of Health Sciences, University of the Witwatersrand; Prof. Sylvia Haas is a clinical haematologist at the Technical University of Munich, Germany, and an international expert in the field of thrombosis and haemostasis; and Prof. H R Buller, an international expert in the same field, is a clinical haematologist at the Academic Medical Centre, University of Amsterdam, The Netherlands.

Corresponding author: E Schapkaitz (elise.schapkaitz@nhls.ac.za)

Background. The management of pregnant patients with mechanical heart valves remains challenging. Both vitamin K antagonists and heparins may be associated with maternal and fetal adverse events.

Method. The Southern African Society of Thrombosis and Haemostasis reviewed available literature and comprehensive evidence-based guidelines for the anticoagulation of pregnant patients with mechanical heart valves. A draft document was produced and revised by consensus agreement. The recommendations were adjudicated by independent international experts to avoid local bias.

Results and conclusion. We present concise, practical guidelines for the clinical management of pregnant patients with mechanical heart valves.

Recommendations reflect current best practice, which it is hoped will lead to improved anticoagulation practice in this select group of high-risk patients.

S Afr Med J 2015;105(9):733-738. DOI:10.7196/SAMJnew.7928

1. Introduction

Pregnancy in patients with mechanical heart valves is associated with considerable morbidity, mortality and health cost utilisation. Management should be individualised in consultation with a multidisciplinary team including an obstetrician, a cardiologist and a haematologist to undertake laboratory monitoring, with appropriate consideration for the risk/benefit ratio of each patient.

We have designed practice guidelines to assist doctors and nurses caring for pregnant women with mechanical heart valves, with a view to achieving improved anticoagulation practice in this select group of high-risk patients.

2. Methodology

On behalf of the Southern African Society of Thrombosis and Haemostasis, a repre足 sentative guideline panel of professionals from the fields of haematology, cardiology and obstetrics reviewed the available English language literature on the anticoagulation of pregnant patients with mechanical heart valves on Pubmed. This included systematic reviews and randomised controlled trials as

well as case series, observational studies and cohort studies. In addition, comprehensive evidence-based guidelines, namely the 9th edition of the American College of Chest Physicians (ACCP) and American Heart Association (AHA) guidelines,[1,2] were consulted and referenced where applicable.

A draft document was produced and revised

by consensus agreement. These resulting recommendations were adjudicated and co-authored by independent international experts to avoid local bias.

The recommendations have been graded as strong (grade 1) or weak (grade 2) according to the risks, adverse effects, health benefits and cost (Table 1).

Table 1. Grading recommendation of the ACCP for antithrombotic therapy[1] Grade

Methodological quality of supporting evidence

1A

Consistent evidence from RCTs without important limitations, or exceptionally strong evidence from observational studies

1B

Evidence from RCTs with important limitations (inconsistent results, methodological flaws), or very strong evidence from observational studies

1C

Evidence for at least one critical outcome from observational studies or case series, or from RCTs with serious flaws

2A

Consistent evidence from RCTs without important limitations, or exceptionally strong evidence from observational studies

2B

Evidence from RCTs with important limitations (inconsistent results, methodological flaws), or very strong evidence from observational studies

2C

Evidence for at least one critical outcome from observational studies or case series, or from RCTs with serious flaws or indirect evidence

RCT = randomised controlled trial.

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3. Anticoagulation of pregnant patients with mechanical valves

Anticoagulant therapy is essential because of the risk of valve thrombosis and systemic embolism (grade 1A).[3] The ideal anticoagulant in pregnancy should be one that does not cross the placenta, to avoid teratogenicity and fetal haemorrhage, and one that can easily be reversed. Anticoagulants available for the management of pregnant patients with mechanical heart valves include: • Vitamin K antagonists • Unfractionated heparin (UFH) • Low-molecular-weight heparin (LMWH).

These South African (SA) guidelines discuss the use of enoxaparin (Clexane; Sanofi Aventis), UFH and warfarin. (The recommendation to use enoxaparin only is based on the fact that adequate laboratory monitoring is available in SA for enoxaparin and not other LMWHs. The testing of LMWH is not interchangeable.)

The choice of anticoagulant remains challenging, because both vitamin K anta­ gonists and heparins may be associated with maternal and fetal adverse events.[3-5] The choice of anticoagulation should be considered in conjunction with risk factors for thromboembolism (valve type, position and history of thromboembolism) and economic factors (availability and cost of the anticoagulants, access to laboratory testing and specialist care), as well as maternal preferences (Table 2).[1] Pregnant patients with mechanical heart valves should be referred to a specialist antenatal clinic for management by a multidisciplinary team including an obstetrician and a cardiologist, with laboratory monitoring by a haematologist.

Table 2. Factors affecting choice of anticoagulant Risk factors for thromboembolism Valve type

4. Anticoagulants 4.1 LMWH (enoxaparin)

LMWH does not cross the placenta, and is associated with improved fetal outcomes.

In pregnant patients, LMWH at fixed doses is less effective than warfarin therapy in preventing thromboembolic complications. LMWH therefore requires dose adjustment with laboratory monitoring (grade 1A).[1] LMWH offers definite advantages over UFH because of its longer plasma half-life, dose-dependent clearance (resulting in a more predictable anticoagulant response), improved side-effect profile and less frequent monitoring requirements (grade 1B).[6] Allergic skin reactions can occur with LMWH, but are uncommon.

LMWH (enoxaparin) with monitoring and dose adjustment is strongly recommended throughout pregnancy (grade 1A).

4.1.1 LMWH dosage The recommended dosage for enoxaparin is: • Subcutaneous LMWH 12-hourly with dose adjustment to achieve a peak anti-Xa level ~1 U/mL (1.0 - 1.2 U/mL) 3 - 4 hours post injection.[1,2,7] 4.1.2 Monitoring of therapy • LMWH activity is measured using an anti-Xa activity assay.

Table 3. Laboratories in SA that offer anti-Xa testing Laboratory

Contact number

National Health Laboratory Service central laboratories

Charlotte Maxeke Johannesburg Academic Hospital, Gauteng

(011) 489-8534

Red Cross War Memorial Children’s Hospital, Western Cape

(021) 658-5203/4

Groote Schuur Hospital, Western Cape

(021) 404-4151

I nkosi Albert Luthuli Central Hospital, KwaZulu-Natal (separated and referred on ice to Ampath NRL)

(031) 240-2677

Private laboratories Ampath

Economic factors

Lancet

Availability of the anticoagulants Cost of the anticoagulants Access to laboratory testing Access to specialist care Maternal preferences Fetal and maternal adverse outcomes

(012) 678-0591

Milpark, Gauteng

(011) 482-5406

Pencardia, Gauteng

(012) 483-0100

Vermaak

Unitas, Gauteng Pathcare

(012) 677-8341

Cape Town, Western Cape NRL = national referral laboratory.

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NRL, Gauteng or Separated and referred on ice to Ampath NRL

Valve position History of thromboembolism

• Anti-Xa testing is performed by special­ ised National Health Laboratory Service central laboratories and private lab­ oratories in SA (Table 3).

• A 5 mL citrate tube is required for the assay. Avoid sampling blood from indwelling lines.

• Samples must reach the reference lab­ oratory (or local laboratory for shipping) within 1 hour.

• Samples must be drawn 3 - 4 hours after the last LMWH subcutaneous injection.

• Repeat testing is indicated until a therapeutic anti-Xa level is achieved (1.0 1.2 U/mL).[2] • A higher anti-Xa range than that proposed by international guidelines (0.7 - 1.2 U/ mL) is recommended owing to the high risk of valve thrombosis.[2,8] • There is an increased dose requirement during pregnancy because of increased volume of distribution and renal clearance, and continued regular monitoring and dose adjustments (increase or decrease by 10 mg) according to anti-Xa levels are therefore recommended (Table 4).[7] • Anti-Xa levels should be monitored weekly (as opposed to monthly) to reduce the likelihood of subtherapeutic anti-Xa levels and subsequent valve thrombosis.[8-10] • The role of trough anti-Xa levels in adjusting the dose of LMWH is uncertain and pre-dose monitoring is not currently recommended.

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(021) 596-3400

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Table 4. Interpretation of anti-Xa levels in patients on LMWH Target anti-Xa levels 1.0 - 1.2 anti-Xa U/mL Low anti-Xa level Inadequate dosing Delayed specimen draw Dose of LMWH omitted Weight gain Gestation (volume of distribution of LMWH changes) High anti-Xa level Excessive dosing Weight loss Renal dysfunction Reduced creatinine clearance (end of third trimester)

4.1.3 Management of bleeding • LMWH (plasma half-life 3 - 6 hours) should be discontinued, as well as any other agents that may contribute to bleeding.

• Measurement of anti-Xa levels is suggested.

• One intravenous (IV) dose of protamine sulphate can neutralise about 60 - 75% of the anti-Xa activity.[4] • 1 mg protamine sulphate IV can be administered per 1 mg (equivalent to 100 anti-Xa units) enoxaparin, given in the last dose over 10 minutes.

• If the patient continues to bleed, a repeat dose of 0.5 mg protamine sulphate IV per 1 mg of enoxaparin, up to a maximum of three doses, may be administered in conjunction with replacement therapy.

4.2 UFH

UFH does not cross the placenta and is associated with improved fetal outcome.

UFH at fixed doses is less effective than warfarin in preventing maternal thromboembolic complications.[9,11] UFH therefore requires dose adjustment with frequent laboratory monitoring. Furthermore, the efficacy and dosage of adjusted-dose subcutaneous UFH has not been definitively established. The use of low-dose UFH is inade­ quate.[3] LMWH is recommended instead of UFH (grade 1B).[8] Long-term UFH use is associated with an increased risk of heparin-induced thrombocytopenia (HIT), osteoporosis and allergic skin reactions.

4.2.3 Management of bleeding • UFH (plasma half-life 1 - 2 hours) should be discontinued, as well as any other agents that may contribute to bleeding.

• Measurement of aPTT levels may be indicated.

• If bleeding is life-threatening, immediate reversal of UFH activity can be achieved by administration of protamine sulphate.

• 1 mg of protamine sulphate IV should be administered per 1 mg (equivalent to 100 units of heparin) given in the last subcutaneous dose over 10 minutes.

• Rapid infusion can cause hypotension and convulsions.

• Following IV administration, neutralisation occurs within 5 minutes. The maximum dose of protamine sulphate that can be administered is 50 mg.

4.3 Warfarin

Warfarin is the most effective anticoagulant for the prevention of valve thrombosis.[10] Warfarin is easy to administer and monitor.

Warfarin is safe during the first 6 weeks of gestation, but is associated with a teratogenic effect between 6 and 12 weeks. This results in a 4 - 10% risk of warfarin embryopathy (Table 5).[2-3,13,14] A dose-dependent (<5 mg/d) relationship for warfarin embryopathy has not been found in all cohorts.[15] Warfarin is therefore not recommended in the first trimester (grade 1A).[16-17] In addition, there is an increased risk of fetal ocular and neurological abnormalities, a 30% risk of fetal loss, and an increased risk of fetal intracranial haemorrhage at any time during pregnancy, but particularly at the time of delivery.[3,18-21] In pregnant women at higher risk of thromboembolism, such as those with older-generation valve types in the mitral position, e.g.

Starr-Edwards and Bjork-Shiley, or a history of thromboembolism on heparin, warfarin can be considered throughout pregnancy with replacement by UFH or LMWH at 36 weeks (grade 2C).[7] Warfarin in the first trimester is not recommended (grade 1A).

UFH is not recommended in pregnant patients with mechanical heart valves (grade 1B).

4.2.1 UFH dosage There is no consensus on the recommended dosage for UFH: • Subcutaneous UFH in high doses 12-hourly with dose adjustment 6 hours post injection to achieve an activated partial thromboplastin time (aPTT) ratio of 2 - 2.5 times the baseline value.[1,3,12] 4.2.2 Monitoring of therapy • Anticoagulant activity is measured using an aPTT test.

• A 5 mL citrate tube is required for the assay. Avoid sampling blood from indwelling lines.

• Samples must reach the reference laboratory within 2 hours.

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• Samples must be drawn 6 hours after the last UFH subcutaneous injection and repeated until a therapeutic aPTT is achieved (at least twice the baseline value).

• Once therapeutic levels are achieved, continued regular weekly monitoring with dose adjustments for changes with weight gain is recommended. UFH is more difficult to monitor owing to its unpredictable pharmacokinetics, and more frequent monitoring may be indicated.

• The patient’s platelet count should be monitored on initiation of UFH and 7 days later while on therapy to assess for HIT. If the patient has been exposed to UFH in the past 100 days, a repeat platelet count is indicated within 24 hours of starting UFH.

4.3.1 Warfarin dosage The recommended dosage for warfarin is: • 5 mg daily and the dose adjusted to achieve a target international normalised ratio (INR) of 3.0 (range 2.5 - 3.5).[1] 4.3.2 Monitoring of therapy • Anticoagulant activity is monitored using an INR test.

• A 5 mL citrate tube is required for the assay. Avoid sampling blood from indwelling lines.

• INR monitoring is indicated every 1 - 4 weeks. The dose should be adjusted to achieve a target INR of 3.0 (range 2.5 - 3.5).

• Fluctuations of the INR outside the desired target range should be investigated.

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4.3.3 Management of bleeding • Women may go into preterm labour or develop complications requiring urgent delivery.

• Bleeding associated with warfarin therapy can be severe because of the drug’s long plasma half-life of 40 hours.

• If bleeding is significant, warfarin activity can be reversed immediately by administration of fresh-frozen plasma (15 - 20 mL/kg IV), prothrombin complex concentrates (50 U/kg) and/or vitamin K (1 - 2 mg) orally or intravenously.[22] • Neonates born to mothers on warfarin will be over-anticoagulated, and caesarean section is the recommended mode of delivery.

• Assisted delivery with forceps and ventouse is contraindicated.[4] • Maternal and neonatal INR monitoring is indicated daily.

4.4 Aspirin

The addition of low-dose aspirin in pregnant patients with mechanical heart valves is not routinely recommended (grade 2C).[1]

5. Management of pregnant patients with mechanical heart valves

The suggested regimen for anticoagulation in pregnant patients with mechanical heart valves is set out in Fig. 1.

5.1 Pre-pregnancy

• A multidisciplinary team needs to be involved in the management of pregnancy, Table 5. Adverse effects of warfarin in the fetus Warfarin embryopathy (6 - 12 weeks) Nasal hypoplasia Stippled epiphyses Saddle-nose deformity Mental retardation Optic atrophy Frontal bossing

including an obstetrician, a cardiologist and a haematologist, with easy access to an anaesthetist, a paediatrician and a geneticist as the time of delivery approaches.

• Discuss the choice of anticoagulant with the patient, detailing the risks and benefits for all anticoagulant options and other cardiac medications (Table 2).

• Continue warfarin until pregnancy is achieved (grade 2C).[1] • Advise patients to present early to a specialist antenatal clinic when men­ struation is delayed.

5.2 Antenatal

The first visit to the antenatal clinic should include: • A full history and examination, including cardiac, obstetric, haematological and anaesthetic assessment • Baseline transthoracic echocardiography and 12-lead electrocardiography • Antenatal bloods and INR (to exclude over-anticoagulation) • A switch to subcutaneous LMWH, e.g. enoxaparin 1 mg/kg 12-hourly, is recom­ mended in the first trimester once the

INR is ≤2.5 and if there are no signs or symptoms of bleeding (grade 1A).[1] • Adjust the dose of LMWH (by 10 mg upwards or downwards) to achieve a peak anti-Xa level ~1 U/mL 3 - 4 hours post injection. Thereafter anti-Xa levels should be monitored, ideally on a weekly basis.[8] Follow-up antenatal visits (in addition to routine obstetric management) include: • A history of bleeding, valve thrombosis (chest pain, shortness of breath), peri­ pheral thromboembolic disease (focal neurological signs and symptoms) • An examination of haematological (signs of bleeding, injection sites), cardiac (cardiac dysrythmias, congestive cardiac failure and auscultation to assess valve function), and neurological (signs of a cerebrovascular insult) systems • Transthoracic echocardiography at the first antenatal visit and in the third tri­ mester, or if clinically indicated to exclude valve thrombosis • Continued adjusted-dose subcutaneous LMWH until 38 weeks is strongly rec­ ommended (grade 1A) (Table 6).

Antenatal

• Present early to a specialist antenatal clinic when menstruation is delayed • Switch to subcutaneous LMWH, e.g. enoxaparin (Clexane) 1 mg/kg 12-hourly with dose adjustment to achieve a peak anti-Xa level ~1 U/mL (1.0 - 1.2) 3 - 4 hours post injection • Alternative anticoagulant options from the 13th week include substitution with warfarin from 13 weeks until 36 weeks

Delivery

• Delivery at 38 weeks’ gestation • Warfarin: Discontinue 2 weeks prior to delivery and switch to LMWH or IV UFH • LMWH: Admit and stop LMWH 24 hours prior to a planned delivery. Deliver by caesarean section or normal vaginal delivery when the anti-Xa is 0.2 - 0.5 U/mL • UFH: Admit and stop UFH 36 hours prior to a planned delivery. Start IV UFH with aPTT monitoring 12-hourly to achieve an aPTT of 2 - 2.5 times the baseline aPTT. Discontinue when labour is established if a normal vaginal delivery is planned, or 4 - 6 hours prior to a caesarean section

Hypertelorism High-arched palate Short neck Short stature Fetal effects (all trimesters and delivery) Ocular abnormalities – blindness eurological abnormalities – N microcephaly, mental retardation, low intelligent quotients Fetal loss Bleeding

Postpartum

• Neonate: Examination for warfarin embryopathy • Maternal management: Restart heparin therapy 6 - 12 hours post delivery, or later if there is any evidence of bleeding from the surgical site • UFH: Restart at the expected maintenance infusion with aPTT monitoring 12-hourly • LMWH: Restart at half the pre-delivery antepartum dose for the first 24 hours. Adjust dose to achieve an anti-Xa level of 0.8 - 1.0 U/mL • Start warfarin at prior dose simultaneously with heparin • Stop heparin once INR is therapeutic (2.5 - 3.5) • Discharge to follow-up at an anticoagulation clinic (as per INR), obstetrics and cardiology at 6 weeks post partum Fig. 1. Suggested regimen for anticoagulation in pregnant patients with mechanical heart valves.

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Table 6. Recommended anticoagulant regimens[1] Adjusted-dose LMWH 12-hourly throughout pregnancy with dose adjustment to achieve a peak anti-Xa level ~1 U/mL 3 - 4 hours post injection (grade 1A) LMWH (as above) until the 13th week with substitution by warfarin until close to delivery, when UFH or LMWH is resumed (grade 1A) In pregnant women at higher risk of thromboembolism, such as those with older-generation valve types in the mitral position or a history of thromboembolism on heparin, warfarin can be considered throughout pregnancy with replacement by UFH or LMWH close to delivery (grade 2C)

• Alternative anticoagulant options from the 13th week include substitution with warfarin from 13 weeks until 36 weeks (grade 1A) (Table 6).

• Close monitoring with dose adjustment is indicated. If the range is subtherapeutic and non-compliance is suspected, admission may be indicated.

5.3 Delivery

Delivery is planned at 38 weeks’ gestation. The mode of delivery is determined by the obstetrician.[23] In pregnant patients with HIV infection, specific guidelines should be consulted.

If warfarin is used, it should be discontinued 2 weeks prior to delivery and patients switched to LMWH or IV UFH. The fetal INR takes longer to normalise than the maternal INR, and delivery with the mother on warfarin poses a severe risk of haemorrhage to the fetus.

Suggested intrapartum anticoagulant protocols for delivery include: 5.3.1 LMWH Suggested LMWH bridging regimen for peripartum anticoagulation: • Admit and stop LMWH at least 24 hours prior to a planned delivery.

• Neuraxial anaesthesia should be avoided and epidural catheters should not be used (grade 1B).

• In order to reduce the risk of bleeding, anti-Xa levels should be used to guide the timing of delivery.[8] • Perform serial anti-Xa testing 12 hours after the last dose of LMWH. • Deliver by caesarean section or normal vaginal delivery when the anti-Xa level is 0.2 - 0.5 U/mL. • Post induction of labour, if the anti-Xa level is <0.5 U/mL and the patient is not in the active phase of labour, delivery by caesarean section is recommended.

• Assess for major bleeding postpartum (resulting in a drop in the haemoglobin concentration by ≥2 g/dL, or bleeding requiring transfusion of at least two units of packed red blood cells).

5.3.2 UFH Suggested UFH bridging regimen for peripartum anticoagulation:[4,24] • Admit and stop anticoagulation at least 36 hours prior to a planned delivery.

• Start IV UFH 24 hours prior to delivery.

• Start IV UFH (5 000 - 10 000 U as an intravenous infusion in 200 mL normal saline at 33 mL/h).

• aPTT monitoring is indicated 12-hourly to monitor UFH. Aim to achieve an aPTT of 2 - 2.5 times the baseline aPTT. • Induction of labour: IV UFH therapy should be discontinued when labour is established. This should be individualised and determined by the risk of bleeding.

• Delivery by caesarean section: IV UFH therapy should be discontinued 4 - 6 hours prior to surgery.

• Assess for major bleeding postpartum (resulting in a drop in the haemoglobin concentration by ≥2 g/dL or as bleeding requiring transfusion of at least two units of packed red blood cells).

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5.4 Post partum

5.4.1 Management of the neonate The neonate requires examination by a paediatrician and/or geneticist for warfarin embryopathy.

5.4.2 Maternal management Early reinstitution of anticoagulant therapy in these patients, in order to reduce the time off anticoagulation, results in a high risk of primary and secondary postpartum haemorrhage.[19] Heparin therapy with LMWH or UFH should be restarted 6 - 12 hours post delivery (see dosage below), or should be delayed if there is any evidence of bleeding from the surgical site.

Suggested postpartum regimens include: 5.4.2.1 UFH • UFH should be restarted without a bolus, at no more than the expected maintenance infusion.[4] The PTT should be checked 12 hours after restarting therapy to allow time for a stable anticoagulant response.

• IV UFH, with its short half-life, allows for more flexible anti­ coagulant control.

5.4.2.2 LMWH • The anti-Xa level at delivery should guide the timing and dosing of LMWH.[8] • After delivery, LMWH should be restarted at half the pre-delivery antepartum dose for the next 24 hours.

• The anti-Xa should be monitored 3 - 4 hours post therapeutic dose.

• Adjust the dose to achieve an anti-Xa level of 0.8 - 1.0 U/mL. Start warfarin at previous dose simultaneously with LMWH. Warfarin therapy should be delayed post delivery in order to reduce the risk of major bleeding. Stop LMWH once the INR is therapeutic (2.5 - 3.5).

Discharge, for follow-up at an anticoagulation clinic (as per INR), and for cardiology and obstetrics and gynaecology follow-up at 6 weeks post partum.

Declaration of conflicting interests. HRB reported having served as a scientific advisory board member for Sanofi-Aventis, Bayer HealthCare, Bristol-Myers Squibb, Daichi-Sankyo, GlaxoSmithKline, Pfizer, Roche, Isis and Thrombogenics, and received honoraria from Sanofi-Aventis, Bayer HealthCare, Bristol-Myers Squibb, DaichiSankyo, GlaxoSmithKline, Pfizer, Roche, Isis and Thrombogenics. SH reported having served as a scientific advisory board member for Bayer HealthCare, Bristol-Myers Squibb, Daiichi-Sankyo and Sanofi-Aventis, and received honoraria from Aspen, Bayer Healthcare, Bristol-Myers Squibb, Daiichi-Sankyo and Pfizer. BFJ has received honoraria from Bayer HealthCare, Boehringer and Sanofi-Aventis. RSC reported having served as a scientific advisory board member for Sanofi-Aventis, and has received honoraria from Pfizer, Sanofi-Aventis, Bayer HealthCare and LEO Pharma.

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1. Bates SM, Greer IA, Middeldorp S, et al. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141(2 Suppl):e691S-e736S. [http://dx.doi. org/10.1378/chest.11-2300] 2. Bonow RO, Carabello BA, Chatterjee K, et al. ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing Committee to Revise the 1998 guidelines for the management of patients with valvular heart disease) developed in collaboration with the Society of Cardiovascular Anesthesiologists endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. J Am Coll Cardiol 2006;48(3):e1-e148. [http:// dx.doi.org/10.1016/j.jacc.2006.05.021] 3. Chan WS, Anand S, Ginsberg JS. Anticoagulation of pregnant women with mechanical heart valves: A systematic review of the literature. Arch Intern Med 2000;160(2):191-196. [http://dx.doi.org/10.1001/ archinte.160.2.191] 4. McLintock C. Anticoagulant therapy in pregnant women with mechanical prosthetic heart valves: No easy option. Thromb Res 2011;127(Suppl 3):S56-S60. [http://dx.doi.org/10.1016/S00493848(11)70016-0] 5. Ginsberg JS, Chan WS, Bates SM, Kaatz S. Anticoagulation of pregnant women with mechanical heart valves. Arch Intern Med 2003;163(6):694-698. [http://dx.doi.org/10.1001/archinte.163.6.694] 6. Greer IA, Nelson-Piercy C. Low-molecular-weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: A systematic review of safety and efficacy. Blood 2005;106(2):401-407. [http://dx.doi.org/10.1182/blood-2005-02-0626] 7. Saeed CR, Jacobson BF, Pravin M, Aziz RH, Serasheini M, Dominique TG. A prospective trial showing the safety of adjusted-dose enoxaparin for thromboprophylaxis of pregnant women with mechanical prosthetic heart valves. Clin Appl Thromb Hemost 2011;17(4):313-319. [http://dx.doi. org/10.1177/1076029610371470] 8. Salazar E, Izaguirre R, Verdejo J, Mutchinick O. Failure of adjusted doses of subcutaneous heparin to prevent thromboembolic phenomena in pregnant patients with mechanical cardiac valve prostheses. J Am Coll Cardiol 1996;27(7):1698-1703. [http://dx.doi.org/10.1016/0735-1097(96)00072-1] 9. Al-Lawati AA, Venkitraman M, Al-Delaime T, Valliathu J. Pregnancy and mechanical heart valves replacement: Dilemma of anticoagulation. Eur J Cardiothorac Surg 2002;22(2):223-227. [http://dx.doi. org/10.1016/S1010-7940(02)00302-0] 10. Regitz-Zagrosek V, Blomstrom Lundqvist C, et al. ESC Guidelines on the management of cardiovascular diseases during pregnancy: The Task Force on the Management of Cardiovascular Diseases during Pregnancy of the European Society of Cardiology (ESC). Eur Heart J 2011;32(24):3147-3197. [http:// dx.doi.org/10.1093/eurheartj/ehr218] 11. Geelani MA, Singh S, Verma A, Nagesh A, Betigeri V, Nigam M. Anticoagulation in patients with mechanical valves during pregnancy. Asian Cardiovasc Thorac Ann 2005;13(1):30-33. [http://dx.doi. org/10.1177/021849230501300107]

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12. Guidozzi F. Pregnancy in patients with prosthetic cardiac valves. S Afr Med J 1984;65(24):961963.

13. Hall JG, Pauli RM, Wilson KM. Maternal and fetal sequelae of anticoagulation during pregnancy. Am J Med 1980;68(1):122-140. [http://dx.doi.org/10.1016/0002-9343(80)90181-3] 14. Sareli P, England MJ, Berk MR, et al. Maternal and fetal sequelae of anticoagulation during pregnancy in patients with mechanical heart valve prostheses. Am J Cardiol 1989;63(20):1462-1465. [http:// dx.doi.org/10.1016/0002-9149(89)90008-8] 15. Vitale N, de Feo M, de Santo LS, Pollice A, Tedesco N, Cotrufo M. Dose-dependent fetal complications of warfarin in pregnant women with mechanical heart valves. J Am Coll Cardiol 1999;33(6):1637-1641. [http://dx.doi.org/10.1016/S0735-1097(99)00044-3] 16. Mazibuko B, Ramnarain H, Moodley J. An audit of pregnant women with prosthetic heart valves at a tertiary hospital in South Africa: A five-year experience. Cardiovasc J Afr 2012;23(4):216-221. [http:// dx.doi.org/10.5830/CVJA-2012-022] 17. Soma-Pillay P, Mathivha T, Macdonald P. Correlation between warfarin dose and maternal and fetal outcomes in pregnant women with prosthetic heart valves. Presented at the 1st International Conference on Cardiac Problems in Pregnancy, Valencia, Spain, 20-25 February 2010.

18. Elkayam U, Singh H, Irani A, Akhter MW. Anticoagulation in pregnant women with prosth­ etic heart valves. J Cardiovasc Pharmacol Ther 2004;9(2):107-115. [http://dx.doi.org/10.​ 1177/107424840400900206] 19. McLintock C, McCowan LM, North RA. Maternal complications and pregnancy outcome in women with mechanical prosthetic heart valves treated with enoxaparin. BJOG 2009;116(12):1585-1592. [http://dx.doi.org/10.1111/j.1471-0528.2009.02299.x] 20. Shannon MS, Edwards MB, Long F, Taylor KM, Bagger JP, de Swiet M. Anticoagulant management of pregnancy following heart valve replacement in the United Kingdom, 1986-2002. J Heart Valve Dis 2008;17(5):526-532.

21. Topol EJ. Anticoagulation with prosthetic cardiac valves. Arch Intern Med 2003;163(18):2251-2252. [http://dx.doi.org/10.1001/archinte.163.18.2251] 22. Schulman S, Beyth RJ, Kearon C, Levine MN. Hemorrhagic complications of anticoagulant and thrombolytic treatment: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008;133(6 Suppl):257S-298S. [http://dx.doi.org/10.1378/ chest.08-0674] 23. Pieper PG. The pregnant woman with heart disease: Management of pregnancy and delivery. Neth Heart J 2012;20(1):33-37. [http://dx.doi.org/10.1007/s12471-011-0209-y] 24. Bates SM. Management of pregnant women with thrombophilia or a history of venous thromboembolism. ASH Education Book 2007;1:143-150. [http://dx.doi.org/10.1182/asheducation-​ 2007.1.143]

Accepted 20 July 2015.

September 2015, Vol. 105, No. 9

EDITORIAL

National Health Insurance in South Africa: Relevance of a national priority-setting agency Universal health coverage (UHC) has become a comprehensive global aspiration, and many countries have now committed to processes to deliver it.[1] In pursuit of realising this objective, it will be crucial to find ways to contend with the tensions between supply of and demand for quality services, as well as effective interventions in health systems with finite budgets. In doing so, trade-offs are inevitable and the need to set priorities becomes crucial.

The World Health Assembly Resolution (67.23) of 2014, to which South Africa (SA) is a signatory, is entitled ‘Health Intervention and Technology Assessment in Support of Universal Health Coverage’.[2] It identifies the ‘critical role of independent health intervention and technology assessment’ in generating evidence to inform prioritisation, selection, introduction, distribution and management of interventions for health promotion, disease prevention, diagnosis and treatment, rehabilitation and palliation.[2] SA has pledged to deliver UHC over two decades through the mechanism of National Health Insurance (NHI).[3] Its governance and the mechanism of its financing are still under consideration, but NHI pilot districts have been identified and work in these has begun. One aspect of the NHI policy that has received little attention is ensuring that everyone has access to a ‘defined comprehensive package of healthcare services’.[3] There are few, if any, countries that can provide complete coverage of quality services, whether preventive or curative, to every citizen, so addressing the comprehensiveness of a package in SA is a pressing issue.

The Lancet Commission on Investing in Health has recommended ‘progressive universalism’ as a means to achieving UHC.[4] Some countries have begun the process with a minimum package that is increasing incrementally over time,[5] while others have defined a comprehensive healthcare service package that is available for a subset of the public at first and subsequently expanded to other subpopulations.[6] While currently implicit in SA, a more explicit transparent and evidence-informed approach is needed with regard to which services and technologies might realistically be covered or not. Without this understanding we will not achieve the best value for healthcare spending, nor is NHI likely to successfully address our severely unequal society, with life expectancies and health-related qualities of life much below what they could be.

Policy-makers faced with similar challenges around the world are increasingly adopting instruments and mechanisms that overtly define the technologies and health services covered and reimbursed by public or private entities.[7] These include medicines lists, health benefit plans and health technology assessment (HTA).[7,8] HTA has been implemented formally by several high-income countries where UHC exists, and is increasingly being adopted in low- and middle-income settings.[7] There are several criteria to use in making decisions about what elements that link to equity to include in the package, and how to include them – cost-effectiveness thresholds, feasibility of implementation and burden of disease, among others. Techniques for combining these disparate elements can be challenging, some of them related to uncertainties regarding data and evidence. In this respect, learning from other settings is important, while ensuring that due consideration is given to the country-specific historical, political and social context.[9,10] In addition, it is widely recognised that wide and transparent stakeholder engagement on issues of decision-making and prioritisation is key to the success of these processes, with authorities setting out

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guidelines aimed at encouraging participation from the public, patient groups, healthcare providers and the medicines and devices industry.[11,12]

Institutionalising decision-making and priority-setting

The SA National Health Act of 2003 places the responsibility for equitable prioritisation of health services provided by the state with the Minister of Health and the Director-General, who are tasked to ‘identify national health goals and priorities and monitor the progress of their implementation’.[13] The Minister’s prioritisation process is to be informed by the National Health Council, which is also supposed to advise the Minister on ‘development procurement and use of health technology’.[13] At the subnational level, provincial health councils are to advise provincial executive committees on the same issues.[13] The trend internationally seems to be one of increased institution­ alisation of HTA and decision-making bodies.[14] HTA agencies have developed in several middle-income countries in South-East Asia, Latin America and Central Europe. They take various forms, but have generally been empowered to generate and apply evidence in a consultative process and either to advise on or make resource allocation decisions for the health systems in which they operate. The successes of institutions such as the Health Intervention and Technology Assessment Program (HITAP) in Thailand[15] and development of their counterparts in other South-East Asian countries in support of UHC have highlighted several models to consider for others embarking on this journey.[16-18] In many cases these agencies are directly affiliated to, but at arms’ length from, their ministries of health. This has the benefit of distancing ministers from potentially unpopular decisions while also reinforcing the professional independence of the agency.

Taking up the cause

In March 2015, the first meeting of the International Decision Support Initiative (iDSI) in Africa was held at the School of Public Health at the University of the Witwatersrand, Johannesburg, SA. The iDSI (http://www.idsihealth.org/), established in 2013, is a global partnership of leading government institutes, universities and think tanks, including NICE International (the National Institute for Health and Care Excellence) in England and Wales, HITAP, PRICELESS SA (Priority Cost-Effective Lessons for System Strengthening) (www. pricelesssa.ac.za), the Center for Global Development in Washington, DC, and the universities of York in England and Glasgow in Scotland, to support policy makers in priority-setting for UHC. The mission of the collaboration is to guide decision makers to effective and efficient healthcare resource allocation strategies for improving people’s health.

The iDSI supports low- and middle-income governments in considering how to formulate resource allocation decisions for healthcare. Specifically, the initiative aims to share experiences, showcase lessons learned and identify practical ways to scale up technical support for systematic, fair and evidence-informed prioritysetting processes. Strengthening priority-setting institutions will enhance access to effective health interventions, and the quality and efficiency of healthcare delivery. Most importantly, it helps elevate the value of priority-setting as essential for attaining and sustaining UHC. The first meeting brought together some 70 stakeholders to begin to identify ways of scaling up practical support for more systematic, fair and evidence-informed healthcare priority-setting

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for all South Africans. Delegates included senior government officials and policy makers from the Department of Health and the Treasury, development partners, statutory bodies, the private sector (medical schemes, pharmaceuticals and devices), researchers and leaders in priority-setting from the UK, Thailand and Zambia.

The focus of discussions was to learn from the experience of prioritysetting in SA and abroad and to identify the current range and depth of available technical capacity to support priority-setting and to strengthen such capacity. A health technology was defined in the broadest sense as ‘an intervention that may be used to promote health, to prevent, diagnose or treat acute or chronic disease, or for rehabilitation’. The term HTA is often confined to pharmaceuticals and devices, but can also include clinical guidelines and organisational systems used in healthcare.[19]

Karen J Hofman, Shelley McGee PRICELESS SA and Medical Research Council/University of the Witwatersrand Rural Public Health and Health Transitions Research Unit (Agincourt), School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa

Current priority-setting in SA

Anthony J Culyer Centre for Health Economics, University of York, UK, and Institute for Health Policy Management and Evaluation, University of Toronto, Canada

While not always transparent, some public and private sector groups are already using HTA and economic evaluation in SA for prioritysetting and decision-making processes.

Several research units based at academic and self-funded institutions are already conducting research and providing training in economic evaluation and pharmacoeconomic assessment. The Directorate of Affordable Medicines in the National Department of Health recognises the importance of economic evaluation and has included it as one of the criteria for their processes for essential medicines selection. The recently published tertiary and quaternary essential medicines list suggests that these specialised medicines have been scrutinised, but the rationale for positive or negative recommendations is not explicit.[20] The Council for Medical Schemes, which regulates the private medi­cal schemes, is endeavouring to incorporate aspects of HTA in its decision-making for benefit design and protocols for reim­bursement.[21] Much of the economic evaluation research work in SA has focused on the curative aspects of the HIV/AIDS and tuberculosis epidemics, but it is increasingly expanding to four other priority areas: maternal and child health,[22] reproductive health,[23] injury, and non-communicable disease.[24] It is not clear to what extent any of these analyses are utilised in resource allocation decisions. Without institutionalising and formalising processes to inform such decisions, the current approach can perversely impact on capacity, resources and government ability to spend its healthcare and prevention budget. Strong stewardship could assist in co-ordinating and guiding activities to address the policy demand for good-quality evidence for decision-making.

Supported by the iDSI, the PRICELESS SA programme at the Wits School of Public Health is investigating existing functions, processes and capacity available for priority-setting mechanisms and health technology assessment in SA to determine ways to improve the adoption and use of critical appraisal and analytics, and the evidence they generate, for policy-making.

Conclusion

SA could achieve better value for money in its healthcare services.

Plans to reform the system have implications for affordability, as salaries increase and new technologies and medications come on line. Consideration of health system constraints, cost-effectiveness of programmes and preventive interventions and the full assessment of new and existing technologies through a democratic process should form the basis of a priority-setting function to advise the Department of Health on the incorporation of these into its future UHC plans.

With evidence mounting that implementation of UHC can be a costly exercise, informed priority-setting will be key to ensuring that public financing for health is used effectively, efficiently and equitably.

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Kalipso Chalkidou National Institute for Health and Care Excellence, NICE International, Brighton and Hove, UK Sripen Tantivess Health Intervention and Technology Assessment Programme, Ministry of Public Health, Thailand

Corresponding author: K J Hofman (karen.hofman@wits.ac.za) 1. World Bank Group. Universal Health Coverage Overview. 2015. http://www.worldbank.org/en/topic/ universalhealthcoverage/overview (updated March 2015, accessed 2 June 2015).

2. World Health Assembly Resolution 67.23: Health Intervention and Technology Assessment in Support of Universal Health Coverage. Geneva: World Health Organisation, 2014. http://apps.who.int/gb/ ebwha/pdf_files/WHA67/A67_R23-en.pdf (accessed 7 August 2015).

3. National Health Insurance Policy Paper. Pretoria: National Department of Health, 2011.

4. Jamison DT, Summers LH, Alleyne G, et al. Global health 2035: A world converging within a generation. Lancet 2013;382(9908):1898-955. [http://dx.doi.org/10.1016/S0140-6736(13)62105-4] 5. Damrongplasit K, Melnick G. Funding, coverage, and access under Thailand’s universal health insurance program: An update after ten years. Appl Health Econ Health Policy 2015;13(2):157-166. [http://dx.doi.org/10.1007/s40258-014-0148-z] 6. Ha BTT, Frizen S, Thi LM, Duong DTT, Duc DM. Policy processes underpinning universal health insurance in Vietnam. Glob Health Action 2014;7:24928. [http://dx.doi.org/10.3402/gha.v7.24928] 7. Glassman A, Chalkidou K. Priority-setting in Health: Building Institutions for Smarter Public Spending. Washington, DC: Center for Global Development’s Priority-setting Institutions for Global Health Working Group, 2012.

8. Giedion U, Bitran R, Tristao I, eds. Health Benefit Plans in Latin America: A Regional Comparison.

Washington, DC: Inter-American Development Bank Social Protection and Health Division, 2014.

9. Pichon-Riviere A, Augustovski F, Garcia Marti S, Sullivan SD, Drummond M. Transferability of health technology assessment reports in Latin America: An exploratory survey of researchers and decision makers.

Int J Technol Assess Health Care 2012;28(2):180-186. [http://dx.doi.org/10.1017/S0266462312000074] 10. Goeree R, He J, O’Reilly D, et al. Transferability of health technology assessments and economic evaluations: A systematic review of approaches for assessment and application. Clinicoecon Outcomes Res 2011;3:89-104. [http://dx.doi.org/10.2147/CEOR.S14404] 11. Health Information and Quality Authority. Guidelines for Stakeholder Engagement in Health Technology Assessment in Ireland. Dublin: Health Information and Quality Authority, 2014.

12. National Institute for Health and Clinical Excellence. The Guidelines Manual. November 2012. http:// www.nice.org.uk/article/pmg6/chapter/11-the-consultation-process-and-dealing-with-stakeholdercomments (accessed 10 July 2015).

13. South African National Department of Health. National Health Act 61 of 2003. 2003. http://www.gov. za/sites/www.gov.za/files/a61-03.pdf (accessed 7 August 2015).

14. Hailey D. Development of the International Network of Agencies for Health Technology Assessment. Int J Technol Assess Health Care 2009;25(Suppl 1:)24-27. [http://dx.doi.org/10.1017/S0266462309090370] 15. Teerawattananon Y, Tritasavit N, Suchonwanich N, Kingkaew P. The use of economic evaluation for guiding the pharmaceutical reimbursement list in Thailand. Z Evid Fortbild Qual Gesundhwes 2014;108(7):397-404. [http://dx.doi.org/10.1016/j.zefq.2014.06.017] 16. Chiu W-T, Pwu R-F, Gau C-S. Affordable health technology assessment in Taiwan: A model for middle-income countries. J Formos Med Assoc 2015;114(6):481-483. [http://dx.doi.org/10.1016/j. jfma.2015.01.016] 17. Teerawattananon Y, Tantivess S, Yothasamut J, Kingkaew P, Chaisiri K. Historical development of health technology assessment in Thailand. Int J Technol Assess Health Care 2009;25(Suppl. 1):1-12. [http://dx.doi.org/ 10.1017/S0266462309090709] 18. Augustovski F, Alcaraz A, Caporale J, García Martí S, Pichon Riviere A. Institutionalizing health technology assessment for priority setting and health policy in Latin America: From regional endeavors to national experiences. Expert Rev Pharmacoecon Outcomes Res 2014;15(1):9-12. [http:// dx.doi.org/10.1586/14737167.2014.963560] 19. Facey K. International HTA Glossary: English Version: International Network of Agencies for Health Technology Assessment (INAHTA). 2006. http://htaglossary.net/HomePage (accessed 1 June 2015).

20. National Department of Health. Tertiary and Quaternary Level Essential Medicines Recommendations.

Pretoria: NDoH, 2015.

21. Council for Medical Schemes. Methodology to Assess the Cost Impact of PMB Benefit Definitions.

Pretoria: CMS, 2012.

22. Chola L, Pillay Y, Barron P, Tugendhaft A, Kerber K, Hofman K. Cost and impact of scaling up interventions to save lives of mothers and children: Taking South Africa closer to MDGs 4 and 5. Glob Health Action 2015;8:27265. [http://dx.doi.org/10.3402/gha.v8.27265] 23. Chola L, McGee S, Tugendhaft A, Buchmann E, Hofman K. Scaling up family planning to reduce maternal and child mortality: The potential costs and benefits of modern contraceptive use in South Africa. PloS One 2015;10(6):e0130077. [http://dx.doi.org/10.1371/journal.pone.0130077] 24. Volmink HC, Bertram MY, Jina R, Wade AN, Hofman KJ. Applying a private sector capitation model to the management of type 2 diabetes in the South African public sector: A cost-effectiveness analysis.

BMC Health Serv Res 2014;14:444. [http://dx.doi.org/10.1186/1472-6963-14-444]

S Afr Med J 2015;105(9):739-740. DOI:10.7196/SAMJnew.8584

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Reforming South Africa’s procedures for granting patents to improve medicine access Led by the Department of Trade and Industry (DTI), South Africa (SA) is undergoing a process of reviewing and amending national laws governing the protection of intellectual property (IP). This process has the potential to remedy significant shortcomings in the current legislation that allow for the granting of an excessive number of patents, and evergreening of monopoly periods, at the expense of medicine access.

As a member of the World Trade Organization, SA is required to uphold minimum standards of IP protection as defined by the international Agreement on Trade Related Aspects of Intellectual Property Rights (the ‘TRIPS’ agreement). The TRIPS agreement requires SA to grant 20 years of patent protection on products and processes that meet SA’s patentability criteria. These criteria are the standards of novelty, innovativeness and industrial applicability required to receive a patent.[1] A key shortcoming of SA’s current IP system is that the majority of patents granted fail to meet the country’s patentability criteria.[2] Patents that do not meet the country’s patentability criteria are granted as a result of the depository system used for granting patents in the country without examination of their merits.[2-4] In observing their TRIPS obligations, countries may use depository or examination systems for granting patents.[3-5] In countries with depository systems, patent applicants are simply required to file the correct forms and pay the requisite fees in order to receive a patent. In other words, nobody checks patent applications to ensure that patentability criteria are met prior to the granting of patents.

Conversely, under examination systems, the merits of a patent application are reviewed and applicants must demonstrate that patentability criteria have been met in order to receive monopoly protection.[3,4] Given the lack of examination in SA, many patents are granted in this country that are rejected by countries and regions – including Brazil, the USA and the European Union (EU) – that have examination systems in place.[4,6] A comparative analysis showed that SA granted 66% more pharmaceutical patents than the USA and the EU on identical patent applications filed between 2000 and 2002.[6] Another study demonstrated that SA granted 2 442 pharmaceutical patents in 2008 alone, while in comparison, Brazil granted only 278 in the 6 years between 2003 and 2008.[4] The ease with which pharmaceutical patents are granted in SA permits pharmaceutical companies to gain multiple, successive patents on individual medicines, extending their periods of monopoly protection beyond the 20 years required by the TRIPS agreement.

This practice is commonly known as ‘evergreening’.

The challenge of evergreening in SA was highlighted in recent litigation over patents held on the popular birth control pill containing drospirenone and ethinyl oestradiol, sold by pharmaceutical company Bayer as Yasmin.

The initial 20-year period of patent protection on this medicine ended in 2010 in SA. However, secondary, evergreening patents prevented generic versions from being brought to the market at a 30% price reduction when the initial patent expired. The Supreme Court of Appeal in Bloemfontein upheld Bayer’s secondary patent in 2014, which means that generic use may continue to be blocked until 2024. Generic versions are already available in the USA and countries in Europe following rejection of Bayer’s secondary patents in these countries.[7]

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The hepatitis B medicine entecavir, marketed by Bristol-Myers Squibb in SA as Baraclude, further demonstrates the challenge of evergreening. The initial patent on this medicine expired in 2011, but secondary patents could prevent use of generic equivalents until 2026. Given the high local cost of Baraclude – between ZAR4 700 and ZAR5 500 per month for a hepatitis B patient – entecavir is not currently provided in the public sector. Yet generic equivalents are available outside SA at one-tenth of the price charged by the patent holder.[7] Similarly, generic versions of aripiprazole (marketed in SA as Abilify), used to treat depression and bipolar disorder, are now available in the USA, yet secondary patents may block availability of generics in SA until 2033. SA consumers pay up to 35 times more for aripiprazole than those in India, where generic competition exists.[7] Excessive patenting and evergreening of monopoly periods prevents South Africans from accessing more affordable, generic versions of many medicines, despite their widespread use and availability in other parts of the world. To address this challenge, SA must amend its laws and procedures for examining applications and granting patents.

Encouragingly, the DTI is currently undertaking a process of reviewing and amending SA’s IP legislation. During 2013, the DTI released a Draft National Policy on Intellectual Property for public comment that contained commitments to pro-public health reform.

According to the DTI, the finalised policy will be adopted this year, after which bills to amend IP legislation will be brought before Parliament.

The Fix the Patent Laws coalition has called on the DTI to urgently release a finalised policy recommending key reforms to curb evergreening and improve medicine access. The Fix the Patent Laws coalition comprises 15 health organisations in SA that represent patients seeking treatment and care in the realms of HIV, tuberculosis, sexual and reproductive health, cancer, mental health conditions, diabetes and other non-communicable diseases.

The reforms recommended by the Fix the Patent Laws coalition include, among others, setting stricter patent standards and requiring examination of pharmaceutical patent applications.

Under the TRIPS agreement, SA has the flexibility to set stricter patentability criteria that explicitly restrict patent evergreening.

TRIPS-compliant countries – India, Argentina and the Philippines – have adopted legislation or patent examination guidelines that limit or prevent patenting of new formulations (new dosages, combinations or forms (i.e. isomers, salts or polymorphs) of existing medicines) and new uses (new clinical uses of medicines other than those for which they are already registered or sold), except in very limited circumstances. Brazil is currently considering legislation to restrict these types of patents. In amending its patent legislation, SA should adopt similarly strict criteria to ensure that only truly innovative compounds and processes are granted monopoly protection.

In addition to setting stricter patentability criteria, SA must amend its system for granting patents to ensure that only patents meeting patentability criteria are granted. To do this, the country must replace its depository system with an examination system. In order to implement patent examination, SA will have to overcome capacity challenges.

The feasibility of an examination system in SA is currently the subject of rigorous debate.[8] Discussions have centred largely on

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the human resource requirements for implementing examination, and whether SA can attract and hire sufficient numbers of qualified examiners. Patent examiners often have advanced degrees in their fields, and must have sufficient technical knowledge to judge the merits of a patent application. During 2013, the Indian Patents Office reported that 337 patent examiners were employed in the country.[5] Attracting and hiring sufficient patent examiners will be a hurdle to implementing examination in SA. However, there are different approaches and models that could be pursued.[1,3]

A partial or phased approach

A partial or phased approach would initially focus on implementing examination for a few key sectors. This would reduce the number of examiners that the country would initially need to hire and train, allowing for capacity building over time. A partial or phased-in approach should initially focus on implementing examination for sectors that impact on government’s ability to achieve its constitutional obligations – such as realising the right to health.[1,3]

A collaborative approach

A collaborative approach would allow SA to share the workload of examination with the patent offices of other countries or regions.

If SA were to draw on decisions from other patent offices, many applications could be rejected automatically. However, in pursuing such an approach, careful consideration would have to be paid as to which patent offices ought to be selected for collaboration, taking into account that country and regional IP priorities and patentability criteria frequently differ. A rational approach would be for SA to collaborate with patents offices with comparable patentability criteria and adequate capacity for examination, in countries with similar socioeconomic backgrounds.[3]

An opposition approach

Patent opposition procedures are commonly used in many TRIPScompliant developed, and developing, country patent offices with examination systems in place.

An opposition approach would allow the SA Patents Office to draw on expertise from third parties operating in industry and civil society in determining whether patents should be granted. An opposition approach would require patent law reform to allow third parties (such as competing companies or NGOs) to comment on the validity of patents prior to and/or shortly after they are granted. This approach should be adopted together with a phased and/or collaborative approach.

For an opposition approach to work, information regarding pending, or recently granted, patents must be made publicly available.

Additionally, third parties must be allowed to submit evidence to the SA Patents Office when patentability criteria have not been met during a designated time frame.[1,3]

Conclusion

While capacity challenges are a concern in implementing patent examination, given the negative impact of abusive patenting on medicines access, they should be assessed and dealt with accordingly. Implementing an opposition approach together with a partial/phased-in approach and/or a collaborative approach – or a combination of all these approaches – can assist SA in overcoming capacity constraints.

Currently, the only way for third parties to oppose the granting of patents in SA is through undertaking lengthy and expensive judicial challenges – despite the fact that patents are granted without ever assessing whether or not patentability criteria have been met.[1]

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Frankly, SA’s market is too small for most generic companies to bear the risk and cost of such a judicial challenge.

Adopting stricter patentability criteria, and implementing patent examination in SA, would significantly reduce the number of patents granted. Granting fewer patents will, in turn, facilitate generic competition, lower medicine prices, and ensure increased access to medicines for individuals who are currently unable to afford the treatments that they need, and for the government in its procurement of medicines for the public sector.

Endorsed by: Organisations (in alphabetical order): AIDS and Rights Alliance of Southern Africa; Association of Clinical Endocrinologists of South Africa; BreastSens; Cancer Association of South Africa; CanSurvive; Cape Mental Health; Centre for Diabetes & Endocrinology; Diabetes South Africa; Diamond Life Impact Projects; Epilepsy South Africa; Marie Stopes South Africa; Médecins Sans Frontières Khayelitsha HIV/TB Project; Médecins Sans Frontières South Africa; National Association of Pharmaceutical Manufactures; Paediatric Neurology and Neurodevelopment Association of Southern Africa; Patient Health Alliance of Non-Governmental Organisations; People Living With Cancer; Rural Health Advocacy Project; Schizophrenia & Bipolar Disorders Alliance; SECTION27; Society for Endocrinology, Metabolism and Diabetes of South Africa; South African Depression and Anxiety Group; South African Federation for Mental Health; Southern African HIV Clinicians Association; South African Medical Association (SAMA); South African Non-Communicable Diseases Alliance; Stop Stock Outs; TB Proof; Treatment Action Campaign; and the University of Cape Town’s School of Public Health and Family Medicine. Individuals (in alphabetical order): Kwanele Asante-Shwonge, lawyer and African cancer equity activist, SA; Dr Elizabeth Augustine, City of Cape Town, SA; Prof. Brook K Baker, Northeastern University School of Law, Honorary Research Fellow at the University of KwaZulu-Natal, SA, Senior Policy Analyst at Health Gap, NGOs Alternate Board Member UNITAID; Dr Helen Cox, senior researcher, Division of Medical Microbiology, University of Cape Town (UCT); Prof. Larry A Distiller, specialist physician/endocrinologist, Principal Physician and Managing Director, Centre for Diabetes and Endocrinology, and Hon. Visiting Professor, Cardiff University School of Medicine, UK; Dr Kirsty Donald, Secretary, Paediatric Neurology and Neurodevelopment Association of Southern Africa; Laura Foster, Assistant Professor of Gender Studies, Indiana Maurer School of Law, Indiana University, USA, and visiting researcher, UCT; Veloshnee Govender, Lecturer, Health Economics Unit, UCT; Dr Mzukisi Grootboom, Chairman, SAMA; Ellen ’t Hoen, Medicines Law and Policy, France; Prof. Mohamed Jeebhay, Head of Department and Director, School of Public Health and Family Medicine, UCT; Dr Bram de Jonge, Law & Governance Group, Wageningen University, The Netherlands, and UCT IP Unit; Katie Kirk, intellectual property and legal consultant, USA; Jade Kouletakis, Lecturer, University of the Western Cape, Teaching and Research Assistant, UCT, and PhD student, UCT; Prof. Leslie London, Head, Division of Public Health Medicine, UCT; Prof.

Diane McIntyre, Health Economics Unit, UCT; Prof. Graeme Meintjes, Department of Medicine, UCT; Mr Andrew Mews, Head of Mission for South Africa and Lesotho, MSF; Dr Caroline Ncube, Associate Professor/ Head, Department of Commercial Law, UCT; Dr Lonias Ndlovu, Senior Lecturer in Mercantile Law and Head of the Law Department, University of Zululand, SA; Lesley Odendal, TB/HIV activist and independent public health and communications consultant, SA; Marsha Orgill, researcher,

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Health Economics Unit, UCT; Dr Nesri Padayatchi, Deputy Director, Centre for the AIDS Programme of Research in South Africa; Dr Julian te Riele, Clinical Manager, Brooklyn Chest Hospital, Cape Town; Prof. Gail Scher, Chair, Paediatric Neurology and Neurodevelopment Association of Southern Africa; Morgan Scholtz, XDR-TB patient, Cape Town; Dr Tobias Schonwetter, Director, Intellectual Property Unit, UCT, and Regional Coordinator for Africa for the Creative Commons Corporation; Dr Edina Sinanovic, Director, Health Economics Unit, UCT; Dr Ronald van Toorn, Treasurer, Paediatric Neurology and Neurodevelopment Association of Southern Africa; Prof. Yousuf A Vawda, Academic Leader, Public Law, School of Law, University of KwaZulu-Natal; Lynne Wilkinson, project coordinator, MSF Khayelitsha Project, SA; and Prof. Jo Wilmshurst, PANDA SA committee board member, Head of Paediatric Neurology, Red Cross War Memorial Children’s Hospital, Cape Town, and Director, African Paediatric Fellowship Program.

Catherine Tomlinson, John Ashmore Médecins Sans Frontières Cape Town/Johannesburg, South Africa Anele Yawa Treatment Action Campaign, Cape Town, South Africa

Julia Hill Médecins Sans Frontières Cape Town/Johannesburg, South Africa Corresponding author: C Tomlinson (catherine.tomlinson@joburg.msf.org) 1. Park C, Prabhala A, Berger J. Using Law to Accelerate Treatment Access in South Africa: An Analysis or Patent, Competition and Medicines Law. New York: United Nations Development Programme, 2013. http://www.undp.org/content/undp/en/home/librarypage/hiv-aids/using-law-to-accelerate-treatmentaccess-in-south-africa.html (accessed 25 May 2015).

2. Pouris A, Pouris A. Patents and economic development in South Africa: Managing intellectual property rights. S Afr J Sci 2011;107(11/12), Art. #355, 10 pages. [http:// dx.doi.org/10.4102/sajs. v107i11/12.355] 3. Ncube C. The draft national Intellectual Property Policy proposals for improving South Africa’s patent registration system: A review. Journal of Intellectual Property Law & Practice 2014;9(10:822-829. [http://dx.doi:10.1093/jiplp/jpu158] 4. Correa C. Pharmaceutical Innovation, Incremental Patenting and Compulsory Licensing. Research Paper 41. Geneva: South Centre, 2011. http://apps.who.int/medicinedocs/documents/s21395en/s21395en.pdf (accessed 28 May 2015).

5. Treatment Action Campaign, Médecins Sans Frontières, Research and Information System for Developing Countries. Why South Africa Should Examine Pharmaceutical Patents: How Legislative Reform Could Boost the Affordability and Accessibility of Medicines for South Africans.

Johannesburg: Médecins Sans Frontières, 2013. http://www.msfaccess.org/content/why-south-africashould-examine-pharmaceutical-patents (accessed 27 May 2015).

6. Kapczynski A, Park C, Sampat B. South African Pharmaceutical Patenting: An Empirical Analysis. 2012. http://www.tac.org.za/sites/default/files/resources/Create%20Resources/files/Sampat%20presentation. pdf (accessed 25 May 2015).

7. Treatment Action Campaign, Médecins Sans Frontières. Accessing Oral Contraceptives, Hepatitis B Drugs and Medicines for Depression. Cape Town: Treatment Action Campaign, 2014. http://www. fixthepatentlaws.org/?p=911 (accessed 27 May 2015).

8. Daniels L. Comments Received on South Africa’s Process for New IP Policy. Geneva: Intellectual Property Watch, 2013. http://www.ip-watch.org/2013/11/18/comments-received-to-south-africasprocess-for-new-ip-policy/ (accessed 4 June 2015).

S Afr Med J 2015;105(9):741-743. DOI:10.7196/SAMJnew.8270

South African Guidelines Excellence (SAGE): Clinical practice guidelines – quality and credibility Over the past 15 years, the processes for developing clinical practice guidelines (CPGs) have shifted from their being written by experts (or based on expert opinion) to being largely written by methodologists.

CPGs are quality improvement tools, and although they are presented in different ways, their aims are commonly to standardise care, improve its quality and safety, reduce wastage, decrease unnecessary costs, and improve access to care and patient outcomes.[1-3] With the emergence of international collaborations such as the Guidelines International Network (G-I-N),[4] there have been concerted attempts to standardise CPG writing practices across countries, to increase the credibility of the final products.[5-7] Without adherence to rigorous guideline development and reporting standards, the considerable time and effort put into developing guidelines may be wasted, as intended users may not have confidence in the recommendations made.

South Africa (SA) is an emerging African leader in CPGs. However, there is room for improvement if SA CPG activities are to match global standards.[7] In April 2014, the SAMJ signalled on its website the appointment of an editorial subcommittee whose specific mandate would be to review guidelines submitted for publication.

The SAMJ has regularly published guidelines and recommendations for the management of a variety of conditions. These will in future be adjudicated using the AGREE II instrument (www.agreetrust.org).

An editorial in the May issue entitled ‘AGREE to disagree’ recognised the important role that CPGs play in setting standards of clinical practice in SA, and introduced a formalised mechanism to assess CPG quality prior to publication.[8] This editorial outlines and discusses key aspects of CPG quality, and sets the scene for the South African Guidelines Excellence (SAGE)

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project, funded for 3 years by the South African Medical Research Council. This innovative research partnership aims to improve the quality and reach of SA primary care CPGs. Using stakeholderdriven processes, SAGE will provide tools to assist effective SA CPG activities in developing, adapting, adopting, contextualising and implementing primary care CPGs.

International standards for guideline developers

Between 2011 and 2013, three standards were independently proposed, to assist CPG developers in addressing key issues of quality (Institute of Medicine (IOM) 8 standards,[2] G-I-N 11 standards,[4] and McMaster University group 18 standards[9]). Concurrently, two checklists were independently developed to appraise CPG quality. The AGREE II checklist (Appraisal of Guideline ResEarch and Evaluation) uses six domains incorporating 23 items (each scored 1 - 7),[10] while the iCAHE checklist (International Centre for Allied Health Evidence) provides a simpler alternative for policy makers and clinicians, with seven domains incorporating 14 binary items. [11] Table 1 compares the items in each checklist, using the AGREE II domains to standardise comparison. Domains common to all instruments are ‘stakeholder involvement’, ‘underlying evidence’, ‘currency’ and ‘clarity’.

Stakeholder involvement. Stakeholder (end-user) involvement directly links CPGs to ownership, and downstream implementation. It is therefore an essential initial step to identify all relevant stakeholders within a CPG’s scope and purpose, and then determine the role each stakeholder might play in the CPG development process. This assists determination of clear terms of reference. Stakeholder engagement can either occur individually (‘experts’ working with the methodology team) or as a collective (providing feedback on CPG drafts, or at public consultations).

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8. Updating

6. Articulation of recommendations

2. Management of conflict of interest

Currency

Clarity

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7. Conflict of interest considerations

13. Developing recommendations and determining their strength 14. Wording of recommendations and of considerations of implementation, feasibility and equity

Q13. The guideline has been eternally reviewed by experts prior to its publication Q22. The views of the funding body have not influenced the content of the guideline Q23. Competing interests of guideline development group members have been recorded and addressed

Q15. The recommendations are specific and unambiguous Q16. The different options for management of the condition or health issues are clearly presented Q17. Key recommendations are easily identifiable

Q14. A procedure for updating the guideline is provided

Q7. Systematic methods were used to search for the evidence Q8. The criteria for selecting the evidence are clearly described Q9. The strengths and limitations of the body of evidence are clearly described Q10. The methods for formulating the recommendations are clearly described Q11. The health benefits, side-effects and risks have been considered in formulating the recommendations Q12. There is an explicit link between the recommendations and the supporting evidence

Q6. The target users are clearly defined Q4. The guideline development group includes individuals from all relevant professional groups Q5. The views and preferences of the target population have been sought

Q1. The overall objectives of the guideline are specifically described Q2. The health questions covered by the guideline are specifically described Q3. The population to whom the guideline is meant to apply is specifically described

AGREE II questions

PICO: P = patient, population, problem; I = intervention (or exposure); C = comparator (or control); O = outcome. *The table only lists common domains with agreement from at least four/five instruments. â&#x20AC; The relevant item in each instrument, and its item number, are mapped against each AGREE II domain, hence item numbers of instruments other than the AGREE II may be out of numerical order.

11. Financial support and sponsoring organisation

7. Guideline recommendations

18. Updating

8. PICO question generation 9. Considering importance of outcomes and interventions, values, preferences and utilities 10. Deciding what evidence to include and searching for evidence 11. Summarising evidence and considering additional information 12. Judging quality, strength or certainty of a body of evidence

2. Decision-making process 5. Methods 6. Evidence reviews 8. Rating of evidence and recommendations

1. Establishing transparency 4. Clinical practice guideline â&#x20AC;&#x201C; systematic review intersection 5. Establishing evidence foundations for and rating strength of recommendations

Underlying evidence/ rigour

10. Guideline expiration and updating

3. Guideline group membership 6. Consumer and stakeholder involvement 15. Reporting and peer review

1. Composition of guideline development group 3. Conflicts of interest 9. Peer review and stakeholder consultations

3. Guideline development group composition 7. External review

2. Priority setting 5. Identifying target audience and topic selection

McMaster topics

Stakeholder involvement

G-I-N elements

4. Scope of a guideline

IOM standards

Scope and purpose

Domainsâ&#x20AC;

Table 1. Common domains and strategies for clinical guideline quality from various quality assessment tools*

Q14. Is the guideline readable and easy to navigate?

Q1. Is the guideline readily available in full text?

Q2. Does the guideline provide a complete reference list?

Q3. Does the guideline provide a summary of its recommendations?

Q4. Is there a date of completion available?

Q5. Does the guideline provide an anticipated review date?

Q7. Does the guideline provide an outline of the strategy used to find underlying evidence?

Q8. Does the guideline use a hierarchy to rank the quality of the underlying evidence?

Q9. Does the guideline appraise the quality of the evidence which underpins its recommendations?

Q10. Does the guideline link the hierarchy and quality of underlying evidence to each recommendation?

Q6. Does the guideline provide dates for when literature was included?

Q11. Are the developers clearly stated?

Q12. Do the qualifications and expertise of the guideline developers link with the purpose of the guideline and its end users?

Q13. Are the purpose and target users of the guideline stated?

iCAHE questions

EDITORIAL

EDITORIAL

Scope and purpose. The CPG purpose intrinsically links with endusers and the target audience (people to whom the guidance is being directed). The CPG scope also underpins the framing of the research questions. For instance, for a CPG aimed at primary care clinicians, research questions would not be raised about care provided in other sectors. Defining scope and purpose early, and clearly, assists in determining which stakeholders need to be engaged, how, and in what ways.

Independence. It is critical that everyone involved in CPG development is identified, their qualifications listed and their role on the guideline team described, and potential conflicts of interest declared in writing throughout the CPG activity. Funding for the CPG and endorsements should be stated clearly.[12] Independence is essential when sourcing and critiquing the evidence, so that one person’s or group’s view of the literature does not dominate.[13] Underlying evidence. A good-quality CPG should include a comprehensive ‘Methods’ section, which outlines the research questions, how the literature was accessed (databases, search terms/ key words, inclusion/exclusion criteria), how the research was critiqued (hierarchy of evidence, critical appraisal tools), how data were extracted, and how the strength of the body of evidence was determined and reported for each recommendation. A comprehensive reference list of included papers should be provided, so that end-users can identify literature underpinning each recommendation.

Currency. With an estimated 1.8 million peer-reviewed articles published in academic journals by the end of 2012,[14] ensuring that CPGs are based on current evidence is a constant challenge. This requires regular updating, using the protocols established during initial CPG development. Before updating, CPG developers should first identify new issues that have arisen since the previous CPG was published. They should also consider the relevance of the questions ‘carried forward’ from the last CPG. Literature searches should be undertaken from the date of completion of the previous search to the present, to update the evidence base. The relevance of any new findings should be factored into previous recommendations, using a standard approach.[1] Clarity. Clearly written CPGs and comprehensive supporting documentation are essential to ensure that end-users can be confident that they can trust the recommendations. This reduces barriers to uptake and implementation.[2] Moreover, the use of standard clear wording when writing recommendations is encouraged, to clearly link the strength of the evidence body with the wording of the recommendation.[6,15]

Conclusion

In this editorial, the first in a series of six, we present issues critical to CPG development and uptake, relevant to SA and beyond.

While recent local efforts to improve CPG quality and credibility in SA are commendable,[8,7] opportunities to progress SA CPG quality and uptake are limited by the lack of a central, nationally recognised and accepted CPG development unit. Such a unit has the potential to significantly increase SA efforts to improve and standardise high-quality, credible CPG development, reporting and uptake. To this end, the Project SAGE team is engaging in a 3-year stakeholder-driven process that aims to better understand the guideline development arena in SA, and improve the standard of local

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guideline development, adaptation, contextualisation, and ultimately implementation of primary healthcare guidelines.

Shingai Machingaidze, Tamara Kredo Cochrane South Africa, South African Medical Research Council, Cape Town, South Africa Quinette Louw Department of Physiotherapy, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Cape Town, South Africa, and Cochrane South Africa, SA Medical Research Council, Cape Town Taryn Young Centre for Evidence-Based Health Care, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Cape Town, South Africa, and Cochrane South Africa, SA Medical Research Council, Cape Town Karen Grimmer International Centre for Allied Health Evidence, University of South Australia, Adelaide, Australia, and Department of Physiotherapy, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Cape Town, South Africa Corresponding author: S Machingaidze (shingai.machingaidze@mrc.ac.za) 1. Field MJ, Lohr KN. Clinical Practice Guidelines: Directions for a New Program. Washington, DC: National Academy Press, 1990.

2. Graham R, Mancher M, Wolman D, Greenfield S, Steinberg E. Clinical Practice Guidelines We Can Trust. Washington, DC: Institute of Medicine Committee on Standards for Developing Trustworthy Clinical Practice Guidelines/National Academies Press, 2011:15.

3. Clearing House, International Centre for Allied Health Evidence (UniSA). http://www.unisa.edu.au/ Research/Sansom-Institute-for-Health-Research/Research-at-the-Sansom/Research-Concentrations/ Allied-Health-Evidence/Resources/GuidelineCH/Low-Back-Pain-Guidelines/ (accessed 28 April 2015).

4. Guidelines International Network (G-I-N). http://www.g-i-n.net/ (accessed 28 April 2015).

5. Guyatt GH, Oxman AD, Vist GE, Falck-Ytter Y, Alsonso-Coello P, Schünemann HJ, and the GRADE working group. GRADE: An emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008;336:924. [http://dx.doi.org/10.1136/bmj.39489.470347.AD] 6. Treweek S, Oxman A, Alderson P, et al. and the DECIDE Consortium. Developing and evaluating communication strategies to support informed decisions and practice based on evidence (DECIDE): Protocol and preliminary results. Implement Sci 2014;8:6. [http://dx.doi. org/10.1186/1748-5908-8-6] 7. Kredo T, Gerritsen A, van Heerden J, Conway S, Siegfried N. Clinical practice guidelines within the Southern African Development Community: A descriptive study of the quality of guideline development and concordance with best evidence for five priority diseases. Health Res Policy Syst 2012;10:1. [http://dx.doi.org/10.1186/1478-4505-10-1] 8. Wiseman R, Cohen K, Gray A, et al. AGREE to disagree: Critical appraisal and the publication of practice guidelines. S Afr Med J 2014;104(5):345-346. [http://dx.doi.org/10.7196/samj.8215] 9. McMaster Guideline Development Checklist. http://cebgrade.mcmaster.ca/guidelinechecklistonline. html (accessed 28 April 2015).

10. Brouwers M, Kho ME, Browman GP, et al. for the AGREE Next Steps Consortium. AGREE II: Advancing guideline development, reporting and evaluation in healthcare. Can Med Assoc J 2010;82(18):E839-E842. [http://dx.doi.org/10.1503/cmaj.090449] 11. Grimmer K, Dizon J, Milanese S, et al. Efficient clinical evaluation of guideline quality: Development and testing of a new tool. BMC Res Notes 2014;14:63. [http://dx.doi. org/10.1186/1471-2288-14-63] 12. Lurie P, Almeida CM, Stine N, Stine AR, Wolfe SM. Financial conflict of interest disclosure and voting patterns at Food and Drug Administration Drug Advisory Committee meetings. JAMA 2006;295(16):1921-1928. [http://dx.doi.org/10.1001/jama.295.16.1921] 13. Shea BJ, Grimshaw JM, Wells GA, et al. Development of AMSTAR: A measurement tool to assess the methodological quality of systematic reviews. BMC Med Res Methodol 2007;7:10. [http://dx.doi. org/10.1186/1471-2288-7-10] 14. Ware M, Mabe M. The STM Report: An Overview of Scientific and Scholarly Journal Publishing.

The Hague: STM: International Association of Scientific, Technical and Medical Publishers, 2012.

15. Shiffman RN, Dixon J, Brandt C, et al. The GuideLine Implementability Appraisal (GLIA): Development of an instrument to identify obstacles to guideline implementation. BMC Med Inform Decis Mak 2005;5:23. [http://dx.doi.org/10.1186/1472-6947-5-23]

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September 2015, Vol. 105, No. 9

EDITORIAL

Gender and sexual diversity – changing paradigms in an ever-changing world Enshrined in the Bill of Rights of South Africa’s Constitution[1] are a number of rights that affirm the democratic values of human dignity, equality and freedom. Section 9(3) states that ‘The state may not unfairly discriminate directly or indirectly against anyone on one or more grounds, including race, gender, sex, pregnancy, marital status, ethnic or social origin, colour, sexual orientation, age, disability, religion, conscience, belief, culture, language and birth.’

Despite these rights, which are also embodied in policy and law at the highest levels internationally, lesbian, gay, bisexual, transgender and intersex (LGBTI) people are subjected to discrimination, abuse, violence and even death because they do not fit into the expectations of what certain sectors of society consider to be the ‘norm’.

In his book A Social Justice Advocate’s Handbook: A Guide to Gender, Sam Kellerman[2] defines four elements that together contribute to gender and sexual diversity: 1. Biological sex (which I also refer to as physical sex) 2. Gender identity (which I also refer to as psychological sex) 3. Sexual orientation 4. Gender expression (which is a manifestation of 1, 2 and 3).

All possible permutations of the above four elements in combination are found in all societies and to varying degrees. Gender is defined by the World Health Organization (WHO) as ‘socially constructed roles, behaviors, activities, and attributes that a given society considers appropriate for men and women’. It is therefore society that establishes gender norms, which in turn determine the extent to which variations in gender have the freedom to be expressed.

As health professionals confronted with people who seek our help, we might ask at what point variations in biological structure and function per se require intervention. Variations require intervention when they lead to: 1. Distress or suffering that is the consequence of the variant itself and not the consequence of judgmental factors emanating from the external environment 2. Significant impairment of personal, social, occupational or other important areas of life as a consequence of 1 above, and 3. Death.

In the context of the present discussion on gender and sexual diversity, some people who do not fit into the generally accepted ‘norm’ do suffer and do experience significant impairment of personal, social, occupational or other important areas of their lives.

Yet this is due in large part to the inability of society to embrace diversity, and in the process society’s tendency to marginalise people who do not conform. Although the inability to have children may be a cause of distress, several mechanisms are in place that allow the perceived limitation on parenthood to be overcome.

Development of physical and psychological sex

It is well established that fetal androgen signalling strongly influences sexual development. Sexual differentiation of the gonads (ovary, testis), internal reproductive organs and external genitalia occurs in the first half of pregnancy, i.e. between 9 and 15 weeks of gestation, with the Y chromosome (SRY gene) being required for

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male development. Sexual differentiation of the brain starts in the second half of pregnancy. Testosterone masculinises the fetal brain, whereas absence of the dominant effect of this hormone results in a female brain. A recent study found that ‘a primary effect of gonadal steroids in the highly sexually dimorphic preoptic area (POA) is to reduce activity of DNA methyltransferase (Dnmt) enzymes, thereby decreasing DNA methylation and releasing masculinizing genes from epigenetic repression ... [The] data show that brain feminization is maintained by the active suppression of masculinization via DNA methylation.’[3] Gender identity is therefore largely programmed into our brains while we are still in the womb. Important to recognise is the fact that the establishment of physical and psychological sex is separated during fetal development, the former occurring in the first trimester and the latter in the second trimester. This provides a window between the two during which environmental influences (for example endocrine disruptors) may affect the alignment between physical and psychological sex. In the event of ambiguous sex at birth (intersex – see below), the degree of feminisation/masculinisation of the genitals may not reflect the degree of feminisation/masculinisation of the brain. The interplay between nature (genes and genetics) and nurture (the environment) is at the heart of the debate around what is responsible for gender and sexual diversity. The increasing importance of the intrauterine environment on gene expression (DNA) is being recognised,[4] and is embodied in the rapidly emerging field of epigenetics.

Gender dysphoria and transgenderism

Gender dysphoria, previously known as gender identity disorder, occurs in relation to transsexualism and transgenderism and is a potentially life-threatening condition if unresolved. It is characterised by a dissociation between an individual’s biological or physical sex and their gender identity or psychological sex. This leads to social isolation (by choice or through ostracism), low self-esteem and impaired relationships with parents and other family members, and may lead to anxiety, depression, suicidal ideation and suicide attempts. Gender dysphoria requires treatment. This may take several forms including psychological counselling, hormone therapy and gender affirmation/reassignment surgery.

Sexual orientation

Views on sexual orientation are conditioned by the belief that heterosexuality is the normal default occurrence, also referred to as heteronormativity. The long-held views that sexual orientation in most people is a choice, can be directly transmitted from one individual to another and can be cured if it does not conform to the ‘norm’ are not substantiated by reliable evidence.[5]

Mechanisms governing sexual orientation[6]

The following is known about the molecular basis of homosexuality: 1. Homosexuality occurs in ~8% of individuals in most populations.

2. Pedigree and twin studies show that homosexuality is familial.

3. Although there is no consistent evidence for a single major gene contributing to homosexuality, studies performed in the 1990s identified a region in the X chromosome (Xq28) that is associated with development of homosexuality in males.[7,8] A more recent study[9] has confirmed the importance of this locus, and has

September 2015, Vol. 105, No. 9

EDITORIAL

added a second locus on chromosome 8. The identification of these loci does not imply that homosexuality is a disorder, nor does it imply that there may be ‘mutations’ in the ‘causative’ genes in these regions that remain to be identified. It simply points to chromosomal regions (DNA) that are associated with the determination of sexual orientation.

4. The relatively low concordance in monozygotic twins and the importance of the non-shared environment point to homosexuality as being epigenetically determined.[10] 5. In the experimental setting, environmentally induced epigenetic modifications of genes in males that feminise their brains and behaviour can be transgenerationally inherited by their offspring.

6. Homosexual and bisexual behaviour has been observed in many non-human species, and includes sexual activity, courtship, affection, pair bonding, and parenting in same-sex pairs;[11] the motivations for, and implications of, these behaviours have yet to be fully understood.

Conversion or reparative therapy has been advocated for sexual orientation that is not heteronormative. In his book entitled Pilgrim, Pieter Cilliers graphically describes his experiences with conversion therapy and the long-lasting negative consequences thereof.[12] Recently President Obama has called for an end to such therapies for gay, lesbian and transgender youth in the USA. The official White House statement reads as follows: ‘Conversion therapy generally refers to any practices by mental health providers that seek to change an individual’s sexual orientation or gender identity ... Often, this practice is used on minors, who lack the legal authority to make their own medical and mental health decisions ... The overwhelming scientific evidence demonstrates that conversion therapy, especially when it is practiced on young people, is neither medically nor ethically appropriate and can cause substantial harm.’[13] The Obama statement follows the recommendations of the WHO and a number of major medical institutions. Within the USA, the view on this matter is bipartisan, with several states being either for or against the initiative.

Intersex

Intersex is the lack of conformity at birth of the reproductive system to what is traditionally considered to be male or female. Children born with intersex may be subjected to ‘normalisation’ surgery.

There are at least two consequences of a decision of this nature, one implicit and the other explicit. The former assumes that intersex is ‘wrong’, as this is not seen as a variation along a wide spectrum of sexual diversity. The latter denies affected individuals the right to make choices about their own bodies. Since these procedures rarely increase the likelihood that fertility will be improved, and on the contrary may in fact cause infertility, there is little justification for considering the need to ‘fix’ an intersex child as a medical emergency.

There are several potential short- and long-term consequences of ‘normalisation’ surgery,[14] including incontinence, scarring, loss of sexual pleasure, pain, lifelong feelings of being abnormal, and depression. Little regard is given to the fact that the individual’s gender identity or psychological sex might not correlate with the gender they are to be assigned during surgery, and there is often a lack of adequate informed consent.

The ‘Report of the Special Rapporteur on torture and other cruel, inhuman or degrading treatment or punishment’ presented at the

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22nd session of Human Rights Council of the United Nations General Assembly in 2013 notes that ‘Children who are born with atypical sex characteristics are often subject to irreversible sex assignment, involuntary sterilisation, involuntary genital normalising surgery, performed without their informed consent, or that of their parents, “in an attempt to fix their sex” ..., leaving them with permanent, irreversible infertility and causing severe mental suffering.’[15] In line with the changes in the paradigm of managing children with intersex, Malta has recently become the first country to pass a law that will ban normalisation surgery on intersex infants. This is seen as a landmark event in the move away from the use of corrective surgery to ‘normalise’ intersex children, opening the way to selfdetermination of gender identity.

Conclusion

Given the complexity of the development of male and female physical and psychological sex and sexual orientation, it is not surprising that there is a great deal of variation along the spectrum of possible manifestations of these three elements. Global trends are seen with regard to attitudes towards LGBTI people, of increased liberalism in some regions and increased conservatism in others. The latter impacts negatively on the health and socioeconomic status of both these individuals and the community at large. The factors that drive these attitudes are complex. While it is recognised that science alone cannot shift prejudice, the discrimination and suffering experienced

by LGBTI people will be reduced by embracing diversity.

Michael S Pepper Institute for Cellular and Molecular Medicine, Faculty of Health Sciences, University of Pretoria, South Africa Corresponding author: M S Pepper (michael.pepper@up.ac.za) 1. Constitution of the Republic of South Africa, 1996. http://www.gov.za/documents/constitution/ constitution-republic-south-africa-1996-1 (accessed 28 July 2016).

2. Kellerman, S. A Social Justice Advocate’s Handbook: A Guide to Gender. Austin, TX: Impetus Books, 2013:60.

3. Nugent BM, Wright CL, Shetty AC, et al. Brain feminization requires active repression of masculinization via DNA methylation. Nat Neurosci 2015;18:690-697. [http://dx.doi.org/10.1038/ nn.3988] 4. Films for Action. http://www.filmsforaction.org/watch/this-video-dispels-every-nature-vs-nurturemyth-youve-ever-heard/ (accessed 12 April 2015).

5. Academy of Science of South Africa. Diversity in Human Sexuality: Implications for Policy in South Africa. Pretoria: ASSAf, 2015. http://www.assaf.co.za/wp-content/uploads/2015/06/8-June-Diversityin-human-sexuality1.pdf (accessed 15 June 2015).

6. The Conversation. The science behind a more meaningful understanding of sexual orientation. https:// theconversation.com/the-science-behind-a-more-meaningful-understanding-of-sexual-orientation42641#comment_697908 (accessed 15 June 2015).

7. Hamer DH, Hu S, Magnuson VL, Hu N, Pattatucci AM. A linkage between DNA markers on the X chromosome and male sexual orientation. Science 1993;261(5119):321-327.

8. Hu S, Pattatucci AM, Patterson C, et al. Linkage between sexual orientation and chromosome Xq28 in males but not in females. Nat Genet 1995;11(3):248-256.

9. Sanders AR, Martin ER, Beecham GW, et al. Genome-wide scan demonstrates significant linkage for male sexual orientation. Psychol Med 2014;45(7):1379-1388. [http://dx.doi.org/10.1017/ S0033291714002451] 10. Rice WR, Friberg U, Gavrilets S. Homosexuality as a consequence of epigenetically canalized sexual development. Q Rev Biol 2012;87(4):343-368. [http://dx.doi.org/10.1086/668167] 11. Bagemihl B. Biological Exuberance: Animal Homosexuality and Natural Diversity. New York: St Martin’s Press, 1999.

12. Cilliers P. Pilgrim. 1st ed. Pretoria: Protea Book House, 2013.

13. We the People. Response to your petition on conversion therapy. https://petitions.whitehouse.gov/ response/response-your-petition-conversion-therapy (accessed 12 April 2015).

14. Ms. Magazine blog. http://msmagazine.com/blog/2013/02/07/un-condemns-normalization-surgeryfor-intersexuality/ (accessed 12 April 2015).

15. United Nations General Assembly. Report of the Special Rapporteur on torture and other cruel, inhuman or degrading treatment or punishment, Juan E. Méndez. http://www.ohchr.org/ Documents/HRBodies/HRCouncil/RegularSession/Session22/A.HRC.22.53_English.pdf ?utm_ source=AIC+mailing+list&utm_campaign=0940e5a7fc-&utm_medium=email (accessed 12 April 2015).

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Viral haemorrhagic fevers in South Africa G A Richards,1 MB BCh, PhD, FRCP; J Weyer,2 PhD; L H Blumberg,3 MB BCh, MMed (Micro), DTM&H, DOH, DCH ivision of Critical Care, Faculty of Health Sciences, University of the Witwatersrand and Charlotte Maxeke Johannesburg Academic D Hospital, Johannesburg, South Africa 2 Centre for Emerging and Zoonotic Diseases, National Institute for Communicable Diseases, Sandringham, Johannesburg, South Africa 3 Division for Public Health, Surveillance and Response, National Institute for Communicable Diseases, Sandringham, Johannesburg, South Africa

1

Corresponding author: G A Richards (guy.richards@wits.ac.za)

Viral haemorrhagic fevers (VHFs) include a diverse array of diseases caused by a broad range of viruses transmitted from various animal hosts and originating from almost all the continents in the world. These are potentially fatal and highly transmissible diseases without specific treatments or prophylactic vaccines. As has been demonstrated during the Ebola virus disease outbreak in West Africa, the consequences of VHFs are not limited to specific countries â&#x20AC;&#x201C; they may become epidemic, and may have considerable economic impact and disrupt local public health and social service structures. Intensive public health intervention is necessary to contain these diseases. Here we provide a concise overview of the VHFs that are of current public health importance to South Africa.

S Afr Med J 2015;105(9):748-751. DOI:10.7196/SAMJnew.8330

Viral haemorrhagic fevers (VHFs) are caused by infection with one of a number of zoonotic RNA viruses. Although the aetiology of the infections may differ, the clinical presentation can be remarkably similar.[1] Patients typically experience nonspecific symptoms (especially early during the acute phase of illness) including fever of abrupt onset, headache, myalgia, lumbar pain, nausea, vomiting and diarrhoea. Progression to multisystem involvement is typically fairly rapid. Laboratory features of VHF include leucopenia, thrombocytopenia and elevated transaminases, while coagulation profiles become progressively abnormal and overt haemorrhagic features (ecchymoses, epistaxis, gingival bleeding, melaena, haematuria, etc.) may supervene from about day 5 after the onset of symptoms, or even earlier. Contrary to the name given to these conditions, haemorrhage is not a constant feature, as evidenced by the minority of patients who presented with overt haemorrhage during the current Ebola virus disease (EVD) outbreak.[2] A petechial or maculopapular rash may also appear from day 3 to 10, the exact timing of which varies with the virus concerned but is also related to the patientâ&#x20AC;&#x2122;s response to the infection. There are few or no specific treatments available, as antivirals and preventive and therapeutic vaccines remain in the developmental phase. For this reason, given the extremely high mortality rates and the highly infectious nature of VHFs (infectious doses are as low as one viral particle for some), the haemorrhagic fever (HF)-causing viruses have to be handled and stored in the highest biosafety- and security-level laboratory conditions, and patient management must adhere to stringent isolation and barrier nursing protocols. The appropriate use of adequate personal protective equipment (PPE) is critical in all instances. However, there is controversy regarding the type of PPE that should be used, as highlighted by the lack of consensus among role players in West Africa during the EVD outbreak. For example, the use of respirators (specifically N95 respirators) v. surgical masks is disputed, since most VHFs are not considered to be airborne.[3,4] Nevertheless, because aerosolisation is frequent during disinfection procedures, it is recommended that respirators be worn and that healthcare workers be observed by infection control staff to reduce transmission that occurs from contact of the virus with the face or

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neck, most frequently during removal of PPE or on inadvertently touching the face.

In Africa, the HF viruses belong to one of three families, namely the Arenaviridae (Lassa and Lujo viruses), Bunyaviridae (CrimeanCongo haemorrhagic fever (CCHF) and Rift Valley fever (RVF) viruses) and Filoviridae (Ebola and Marburg viruses). In general these diseases are limited to specific areas, and outbreaks most often occur in fairly isolated and rural settings. However, as demonstrated during the current EVD outbreak, increasing interconnectedness and ease of travel render the occurrence of VHFs a possibility anywhere in the world. Although the risk of importation into South Africa (SA) is considered to be low,[5] the fact that considerable travel occurs between the rest of Africa and Johannesburg in particular, and vice versa, cannot be ignored. The indirect effects of VHF outbreaks have been demonstrated clearly during the ongoing West African EVD outbreak. Countries around the globe have been preparing their ports, healthcare systems and laboratories to detect and manage such cases at great financial cost, while travel restrictions and economic activities in numerous African economies (not just those directly affected) have also suffered.[6] Interestingly, this effect is disproportionate to the actual number of cases of EVD, which remains small compared with other formidable public health problems such as malaria, tuberculosis and HIV-AIDS. The differential diagnosis of VHF is broad and may include many treatable infectious diseases, most notably malaria, bacteraemia (including meningococcaemia) and African tick bite fever, as well as non-infectious conditions such as haematological malignancies and heatstroke. The diagnostic approach must consider each possibility carefully, as delay in diagnosis increases the potential for mortality and transmission. As such, it is wise to maintain a high index of suspicion, especially for patients presenting with a compatible clinical syndrome and who have histories that indicate a risk of having contracted an HF-causing virus (such as travel to endemic regions or contact with animals, raw bushmeat, sick patients, etc.).

The HF-causing viruses have a propensity to spread in the hospital setting, and delay in recognition may have dire effects.[1] A small number of nosocomial outbreaks have occurred in SA: Marburg virus disease (MVD) in Johannesburg in 1975, CCHF near Cape Town

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in 1984, EVD in Johannesburg in 1996, and the Lujo virus, a newly identified arenavirus, in Johannesburg in 2008[7-10] (these are dealt with in detail in the ‘Clinical Alert’ article in this issue of SAMJ[11]).

Here we provide a concise account of VHFs, endemic and nonendemic, of perceived importance to SA.

The bunyaviruses

CCHF is one of the most widely distributed VHFs, and has been described from more than 30 countries worldwide.[12] These include central, south-western and south-eastern Europe, the Middle East, Africa including SA, and more recently Malaysia.[12,13] The virus is typically ubiquitous in cattle-farming areas and corresponds to the distribution of the Hyalomma tick, the primary source of transmission. However, transmission also occurs following contact with infected animal blood or tissues, the majority of such cases having involved people in the livestock industry, such as agricultural and slaughterhouse workers and veterinarians.

In SA a total of 199 laboratory-confirmed cases of CCHF have been reported from 1981 to 2014 (data source: National Institute for Communicable Diseases, SA). These have been concentrated in the semi-arid farming areas of the Free State and Northern Cape provinces, although some have been recorded from all nine provinces. Interestingly, human cases remain relatively rare in SA, despite remarkably high seroprevalence rates in cattle and other ruminants.[14,15] Cases of nosocomial and laboratory transmission[8,16,17] have been noted on four occasions (data source: National Institute for Communicable Diseases) (see ‘Clinical Alert’[11]). An outbreak was reported in 1996 in which a total of 17 laboratory-confirmed cases occurred involving slaughterhouse workers following contact with infected ostriches.[18] CCHF has a case fatality rate of 5 - 30%, and the clinical features, which are similar to those described above, are divided into four phases: incubation, pre-haemorrhagic, haemorrhagic and convalescence.[19,20] The incubation period is usually 1 - 5 days following tick bite and slightly longer following exposure to blood products. The pre-haemorrhagic phase is manifested by sudden onset of fever, muscle aches, back pain, headache, sore eyes and photophobia. As with all the VHFs there may be early sore throat, nausea, vomiting, diarrhoea, lymphadenopathy and abdominal pain with hepatomegaly, often followed by confusion and lethargy.

Thereafter the haemorrhagic phase begins on day 3 - 6 with a petechial rash, purpura, ecchymoses and gastrointestinal and urinary tract bleeding. We have found that the majority of these cases initially present with leucopenia, thrombocytopenia occurring later in the disease process. At that time there may be a prolonged prothrombin time and activated partial prothrombin time (aPTT), and fibrin degradation products and D-dimers may be present. Hepatitis occurs with elevated transaminases (alanine (ALT) and aspartate (AST) transaminases). The disease is characterised by a diffuse capillary leak with hypovolaemia and acute kidney injury, and a fatal outcome may often be predicted by a persistently low platelet count, elevation of the AST and ALT to >200 and >150 IU/L, respectively, and of the aPTT to >60 seconds, and a decrease in the fibrinogen level to <110 mg/dL.[19] Bleeding and profound thrombocytopenia was a common finding in the SA cases, whereas in Central Europe clinical disease is highly variable with many mild cases reported.

The diagnosis is made by virus-specific reverse transcriptionpolymerase chain reaction (RT-PCR) and is usually positive at the onset of symptoms, although in circumstances that are highly suggestive of the disease it should be repeated a few days later and barrier nursing continued.[11,21] Seroconversion may be expected from day 5 onwards, although this may be delayed in severe CCHF

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and may be a useful marker of prognosis.[19] Anti-CCHF antibodies may be measured by indirect immunofluorescence assays or enzymelinked immunofluorescence assays for IgG and IgM.[19,21] Therapy for CCHF is primarily supportive, and although the therapeutic benefit of ribavirin has not been adequately supported by studies to date, it is nevertheless recommended that it be used early in the disease at a loading dose of 30 mg/kg, then 15 mg/kg every 6 hours (4 × 1 g) for 4 days, and then 7.5 mg/kg every 8 hours (4 × 0.5 g) for 6 days.[22] The argument against the use of ribavirin is based on its potential renal and hepatic toxicity and the anecdotal nature of data supporting its use.[23] Prevention of infection is based on prevention of tick exposures and use of appropriate PPE prior to contact with blood and tissues of ruminants in endemic areas. No vaccines are available.

RVF is caused by the mosquito-borne phlebovirus, also belonging to the family Bunyaviridae. The virus is widely distributed in Africa, including SA, but has also been reported from Saudi Arabia (after its introduction in 2000) and Madagascar.[24,25] The RVF virus has caused intermittent outbreaks in domestic and wildlife ruminant species and humans in SA.[26-29] The most recent outbreak in this country over the 4-year period 2008 - 2011 concluded with 25 deaths among 302 laboratory-confirmed cases from all nine provinces (although most were from the Free State and Northern Cape).[28] RVF virus infection is typically asymptomatic or mild, manifesting as a febrile, flu-like syndrome with headache, nausea, myalgia and arthralgia. In a small proportion of cases, complications including encephalitis and HF may occur.[29] The latter manifest during the first week of illness and are accompanied by severe hepatic impairment. The fatality rate of the haemorrhagic form may be up to 50%. As with other VHFs, raised liver transaminases and thrombocytopenia generally precede death.[29,30] Clinical diagnosis should be supported by specific laboratory testing, which includes RT-PCR, detection of anti-RVF virus IgG and IgM antibodies and virus isolation. Currently there is no accepted therapy for RVF and management is supportive only. In vivo studies of the antiviral favipiravir in small laboratory animals have shown promise.[31] No vaccines are commercially available to offer protection against RVF virus infection in humans.

The filoviruses

The filoviruses, EVD and MVD viruses, are known to cause highly fatal HF in humans and non-human primates.[32] To date five distinct viral species have been ascribed to the Ebolavirus genus, namely Zaire, Sudan, Taï Forest, Reston and Bundibudyo Ebola viruses.[33] These viruses vary enormously in terms of our current understanding of their geographical spread and also in their virulence in humans.

For example, Reston Ebola viruses are not known to cause overt illness in humans (despite causing fatal HF in Asian non-human primates),[34] while Zaire Ebola viruses cause one of the most lethal infections known to mankind. The current West African outbreak is caused by a Zaire Ebola virus very similar to those that have caused previous outbreaks in the Democratic Republic of the Congo and Gabon.[35] The natural ecology of Ebola viruses remains largely obscure.

Evidence hints at a specific arboreal species of bat as the reservoir for the Zaire species,[36-38] but the specific mechanism of transfer from bat to human or bat to other forest-dwelling animals is not known.

However, various human outbreaks have however been traced to contact with bushmeat, including the slaughtering of chimpanzees and bats.[39,40] The recent West African outbreak has been traced to a 2-year-old child in Guinea who may have had contact with bats while at play.[35,41] Once the virus enters the human population,

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transmission is through direct contact with infected body fluids such as blood, faeces and vomitus. Owing to this mode of transmission, the virus has a propensity to spread in the hospital setting and between close contacts. More than 20 outbreaks of EVD have been reported since 1976.[42] Before 2014, these occurred in isolated settings with the largest involving 425 laboratory-confirmed cases reported from Gulu, Uganda, in 2000 and 2001.[42] By the end of March 2015, one year after the World Health Organization (WHO) declared an outbreak situation, the diseases had accounted for a total of 14 646 laboratory-confirmed cases (and 24 754 in total if suspected and probable cases are included) and more than 10 000 deaths.[43] During this period more than 800 healthcare workers have contracted the disease, with nearly 500 losing their lives.[44] The scale of this outbreak has been exacerbated by poor socioeconomic conditions in the affected countries and an inadequate medical infrastructure that caused delays in the initial recognition of the disease and failure to respond timeously.[2] Consequently intensive international support on all fronts was, and continues to be, required.

Marburg virus is thought to be more widely distributed than Ebola virus, but despite this there have been only 12 outbreaks between 1967 and 2014,[45] four of which consisted of single cases without further spread. There have been a total of 466 laboratory-confirmed cases with 373 deaths (an average fatality rate of 80%, range 23 - 100%). [45] The largest outbreak centered in Uige Province in Angola, with 252 laboratory-confirmed cases from 2004 to 2005 with a 90% case fatality rate.[46] In six of the outbreaks, the epidemiological history implicated bats as the source of the infection and this was further reinforced by the finding of serological and molecular evidence of Marburg virus in the Egyptian fruit bat, Rousettus aegyptiacus.[47] Clinically the signs and symptoms of EVD and MVD are not dissimilar to those of the other VHFs.[32,48-50] There are three phases: initially fever, headache, and myalgia, followed by diarrhoea, vomiting and dehydration; thereafter, in the second week, there may be recovery or deterioration with collapse, neurological manifestations and bleeding that can lead to a fatal outcome.

Fatal nosocomial infection with EVD and MVD has been reported in SA.[7,9] It is noteworthy that appropriate management limited the outbreaks to single secondary cases (see ‘Clinical Alert’[11]). Management of both diseases is supportive, involving active resuscitation and haemodynamic support. The usefulness of hyperimmune serum is uncertain, but it has been approved by the WHO for EVD in the context of the West African outbreak and clinical trials of various antiviral therapies are underway at the time of writing.[51] To date there are no licensed vaccines for the prevention of either EVD or MVD.[32,52,53] However, the extent of the current outbreak has led to the WHO expediting the evaluation and clinical validation of developmental vaccines. Since February 2015, case numbers have decreased leading to concerns that there may be insufficient healthcare workers and other volunteers to support clinical trial efforts in the affected countries.[54]

The arenaviruses

Before 2008, Lassa virus was the only arenavirus known to cause HF in Africa. The affected countries include Sierra Leone, Guinea, Liberia and Nigeria, where up to 500 000 cases are estimated to occur annually.[55,56] In West Africa, seroprevalence in select populations ranges from 8 - 52% in Sierra Leone and 4 - 55% in Guinea to 21% in Nigeria. Like other arenaviruses, Lassa virus is rodent-borne with the multimammate rat (Mastomys natalensis) the primary reservoir and vector of the disease. Transmission to the human population is mainly through aerolised urine and faecal matter that is contaminated with the virus.

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Lassa fever has a variable clinical presentation from asymptomatic or mild infection to severe fatal HF in 20% of cases. Other common features include rigors, muscle pain, sore throat with exudates, nausea, vomiting, and chest and abdominal pain.[56-57] Haemorrhagic features may include bleeding from the gums and internal bleeding, although the latter has been reported in less than one-third of severe Lassa fever cases.[56] As with other VHFs, in severe cases progression is rapid to include multisystem dysfunction following an incubation period of 3 - 21 days.[56] A feature of fatal illness is impaired or delayed cellular immunity leading to fulminant viraemia and shock, associated with platelet and endothelial dysfunction.[56] The virus is excreted in urine for 3 - 9 weeks following infection and in semen for 3 months. Sensorineural hearing deficit may be found in 29% of cases v. zero in febrile controls.[57] Lymphocytopenia and a moderate thrombocytopenia occur and are maximal 10 - 11 days after symptom onset. Diagnosis is as for other VHFs, confirmed by specific laboratory testing involving RT-PCR, serology and virus isolation. Previously convalescent serum was used in the treatment of patients, but currently, if available, intravenous ribavirin may reduce mortality by up to 90%.[58] No vaccines exist for the prevention of infection with Lassa fever virus.

In 2008, a highly fatal outbreak of HF in Johannesburg was attributed to a previously unknown arenavirus, dubbed the Lujo virus (i.e. Lusaka-Johannesburg virus) (see ‘Clinical Alert’[11]).[10,59,60] The Lujo virus appears to have a particularly aggressive course[59] in that among the five reported cases there has been only one survivor. The incubation period is 9 - 13 days and is followed by fever, headache and myalgia, and thereafter by diarrhoea, pharyngitis and a morbiliform rash on the face and trunk, reported in three cases. Facial oedema also occurred in three patients, with marked pharyngeal ulceration in one. There appeared to be initial clinical improvement after hospital admission in three patients, followed by sudden, rapid deterioration in those who died. Bleeding was not a prominent feature in these cases. The sole survivor of the outbreak received treatment including intravenous ribavirin.[60] All the patients had thrombocytopenia on admission (range 42 - 104 × 109/L), and the transaminases were raised in all five at some point during the course of their illness.[60] The diagnosis of Lassa or Lujo virus infections, as for other VHFs, is based on specific laboratory testing involving RT-PCR, serology and virus isolation.

Conclusion

It is predicted that VHFs will continue to emerge and re-emerge in the future. With the ease of global travel and increasing interconnectivity, the isolated African VHF outbreaks of the past have changed dramatically, and the risk of exporting these diseases to new locations is now well appreciated.

Although the risk of introduction of VHF cases is relatively low, Johannesburg remains the gateway to and from Africa. Vigilance and awareness of VHF are therefore necessary to ensure rapid clinical recognition and implementation of systems that allow for the rapid and accurate laboratory investigation and containment of potential outbreaks.

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27. Archer VN, Weyer J, Paweska J, et al. Outbreak of Rift Valley fever affecting veterinarians and farmers in South Africa, 2008. S Afr Med J 2011;101(4):263-266.

28. Archer BN, Thomas J, Weyer J, et al. Epidemiologic investigations into outbreaks of Rift Valley fever in humans, South Africa, 2008-2011. Emerg Infect Dis 2013;19(12):1918-1924. [http://dx.doi. org/10.3201/eid1912.121527] 29. Paweska JT. Rift Valley fever. In: Ergönül Ő, Can F, Akova M, Madoff L, eds. Emerging Infectious Diseases: Clinical Case Studies. London: Academic Press,2014:73-93.

30. Al Hazmi M, Ayooka EA, Abdurahman M, et al. Epidemic Rift Valley fever in Saudi Arabia: A clinical study of severe illness in humans. Clin Infect Dis 2003;36(3):245-252. [http://dx.doi. org/10.1086/345671] 31. Scharton D, Bailey KW, Vest Z, et al. Favipiravir (T-705) protects against peracute Rift Valley fever virus infection and reduces delayed-onset neurological diseases observed with ribavirin treatment.

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Infect Genet Evol 2011;11(7):1514-1519. [http://dx.doi.org/ 10.1016/j.meegid.2011.06.017] 34. Morikawa S, Saijo M, Kurane I. Current knowledge on lower virulence of Reston Ebola virus (a review). Comp Immunol Microbiol Infect Dis 2007;30(5-6):391-398. [http://dx.doi.org/10.1016/j. cimid.2007.05.005] 35. Baize S, Pannetier D, Oestereich L, et al. Emergence of Zaire Ebola virus disease in Guinea – preliminary report. N Engl J Med 2014;371(15):1418-1428. [http://dx.doi.org/ 10.1056/NEJMoa1404505] 36. Pourrut X, Kumulungui B, Wittmann T, et al. The natural history of Ebola virus in Africa. Microbes Infect 2005;7(7-8):1005-1014. http://dx.doi.org/10.1016/j.micinf.2005.04.006] 37. Groseth A, Feldmann H, Strong JE. The ecology of Ebola viruses. Trends Microbiol 2007;15(9):408416. [http://dx.doi.org/10.1016/j.tim.2007.08.001] 38. Olival KJ, Hayman DT. Filoviruses in bats: Current knowledge and future directions. Viruses 2014;6(4):1759-1788. [http://dx.doi.org/10.3390/v6041759] 39. World Health Organization. Outbreak(s) of Ebola haemorrhagic fever, Congo and Gabon, October 2001-July 2002. Wkly Epidemiol Rec 2003;78(26):223-225.

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EMBO Mol Med 2014;7(1):17-23. [http://dx.doi.org/10.15252/emmm.201404792] 42. Centers for Disease Control and Prevention. Outbreaks chronology: Ebola virus disease. http://www. cdc.gov/vhf/ebola/outbreaks/history/chronology.html (accessed 23 March 2015).

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PLoS One 2007;8:e764. [http://dx.doi.org/10.1371/journal.pone.0000764] 48. Hartman AL, Towner JS, Nichol ST. Ebola and Marburg hemorrhagic fever. Clin Lab Med 2010;30(1):161-177. [http://dx.doi.org/10.1016/j.cll.2009.12.001] 49. Beeching NJ, Fenech M, Houlihan C. Ebola virus disease. BMJ 2014;349:g7348. [http://dx.doi. org/10.1136/bmj.g7348] 50. Formenty P. Ebola virus disease. In: Ergönül O, Can F, Akova M, Madoff L, eds. Emerging Infectious Diseases, Clinical Case Studies. London: Academic Press, 2014:121-134.

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Accepted 13 July 2015.

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RESEARCH

Antimicrobial resistance of bacteria isolated from patients with bloodstream infections at a tertiary care hospital in the Democratic Republic of the Congo L M Irenge,1,2,3 MD, PhD; L Kabego,1 MD; F B Kinunu,1 MSc; M Itongwa,1 MSc; P N Mitangala,4 MD, PhD; J-L Gala,2,3 MD, PhD; R B Chirimwami,1 MD, PhD ukavu General Hospital/Université Catholique de Bukavu, Bukavu, Democratic Republic of the Congo B Centre for Applied Molecular Technologies, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium 3 Defence Laboratories Department, Belgian Armed Forces, Peutie, Belgium 4 Laboratoire Provincial de Santé Publique du Nord Kivu, Goma, Democratic Republic of the Congo

1 2

Corresponding author: L M Irenge (leonid.irenge@uclouvain.be)

Background. Bloodstream infection (BSI) is a life-threatening condition that requires rapid antimicrobial treatment.

Methods. We determined the prevalence of bacterial isolates associated with BSI at Bukavu General Hospital (BGH), South Kivu Province, Democratic Republic of the Congo, and their patterns of susceptibility to antimicrobial drugs, from February 2013 to January 2014.

Results. We cultured 112 clinically relevant isolates from 320 blood cultures. Of these isolates, 104 (92.9%) were Gram-negative bacteria (GNB), with 103 bacilli (92.0%) and one coccus (0.9%). Among GNB, Escherichia coli (51.9%), Klebsiella spp. (20.2%), Enterobacter spp.

(6.7%), Shigella spp. (5.8%) and Salmonella spp. (4.8%) were the most frequent agents causing BSIs. Other GNB isolates included Proteus spp., Citrobacter spp. and Pseudomonas aeruginosa (both 2.9%), and Acinetobacter spp. and Neisseria spp. (both 0.9%). High rates of resistance to co-trimoxazole (100%), erythromycin (100%) and ampicillin (66.7 - 100%) and moderate to high resistance to ciprofloxacin, ceftazidime, ceftriaxone, cefuroxime and cefepime were observed among GNB. Furthermore, there were high rates of multidrug resistance and of extended-spectrum β-lactamase (ESBL) production phenotype among Enterobacteriaceae. Gram-positive bacteria included three Staphylococcus aureus isolates (2.7%), four oxacillin-resistant coagulase-negative staphylococci (CoNS) isolates (3.6%) and one Streptococcus pneumoniae (0.9%). No oxacillin-resistant S. aureus was isolated. Among clinically relevant staphylococci, susceptibility to co-trimoxazole and ampicillin was low (0 - 25%). In addition, 58 contaminant CoNS were isolated from blood cultures, and the calculated ratio of contaminants to pathogens in blood cultures was 1:2.

Conclusions. Multidrug-resistant and ESBL-producing GNB are the leading cause of BSI at BGH. S Afr Med J 2015;105(9):752-755. DOI:10.7196/SAMJnew.7937

Bloodstream infection (BSI) refers to the presence of microbial pathogens in the blood. These are present as a result of infection, not specimen contamination.[1-3] BSI is a major cause of community and healthcare-associated infections and is associated with high mortality.[3-7] Infectious diseases are the leading cause of death in the Democratic Republic of the Congo (DRC).[8] In fact, the DRC has a crude mortality rate well above the average for sub-Saharan countries[9] and the highest under-5 mortality rate in Africa,[10] with malaria, pneumonia and diarrhoea the leading causes of death.[11,12] In South Kivu Province, most healthcare facilities lack the capacity to identify causative agents of infectious diseases reliably, including invasive bacterial infections such as BSIs. BSI and malaria are practically indistinguishable on clinical examination,[13] and available World Health Organization (WHO) guidelines for managing childhood illnesses fail to identify up to half of the cases of BSI.[14] In view of the fact that fever – a symptom common to malaria and BSI – is the most frequent reason for presentation to hospital in most developing countries,[5,15] the development of laboratory capacity for identification of pathogens is critical in order to improve the outcome of febrile diseases and enable rapid differential diagnosis between malaria and BSI.[16,17] We report the results of our first year’s experience using blood cultures in the laboratory of Bukavu General

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Hospital (BGH), South Kivu Province, in order to identify pathogens involved in BSIs. This report follows on from a previous study that documented a high rate of antimicrobial drug-resistant isolates in patients with urinary tract infections at the same healthcare facility.[18]

Methods

Study design

This cross-sectional study was conducted in inpatients in various wards of BGH who were suspected of having BSI. This hospital has 385 beds, handles 6 400 admissions and 4 900 outpatients per year, and is one of the main healthcare facilities in Bukavu, a city of more than 500 000 inhabitants in South Kivu Province in eastern DRC.

Laboratory methods

BAC/ALERT FA FAN Aerobic and BAC/ALERT FA FAN Anaerobic blood culture bottles and BAC/ALERT PF Pediatric FAN (Biomérieux, Belgium) were dispatched to various wards of the hospital. The decision to perform blood culture was based on the following criteria: fever (temperature >38.0°C), a negative thick blood smear for detection of Plasmodium spp., and a white blood cell count of >10 × 109/L with >70% neutrophils. Nurses were instructed to sample blood during a febrile episode. For sampling, the patient’s skin was cleaned with 70% ethanol and allowed to dry prior to venous puncture. Blood was collected using strict aseptic technique, and approximately 10 mL

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RESEARCH

for adult patients was immediately inoculated into the BAC/ALERT FA FAN Aerobic and BAC/ALERT FA FAN Anaerobic blood culture bottles. In the case of children, 2 - 5 mL of blood was inoculated in a BAC/ALERT PF Pediatric FAN. The inoculated vials were incubated straight away at 37°C for up to 7 days. The vials were checked visually every day to detect any colour change at the bottom of the bottle, from a blue-green to a yellow colour. For vials displaying a positive signal, cultures were Gram-stained and subcultures performed on 5% sheep blood agar plates for staphylococci. For Streptococcus, a disc of optochin was added to the streaked blood agar plate and incubation was carried out at 37°C in a 5% CO2 atmosphere. Subculture of Gramnegative bacilli was performed on MacConkey agar, whereas Gram-negative cocci were subcultured on chocolate agar. Standard biochemical methods were subsequently used to identify bacteria at the species level.[19] Antimicrobial susceptibility tests were performed using the disc diffusion method on Mueller-Hinton agar II (BioRad, Nazareth Eke, Belgium), and the results were interpreted according to the guidelines of the European Committee on Antimicrobial Susceptibility Testing (EUCAST, 2015).[20] Antibiotic discs were purchased from Bio-Rad (Nazareth Eke). For isolates of staphylococci, testing of antimicrobial drug susceptibility to ampicillin, amikacin, clindamycin, erythromycin, gentamicin, oxacillin and vancomycin was performed.

In order to assess the antimicrobial drug susceptibility pattern of Gram-negative isolates, ampicillin, gentamicin, amoxicillinclavulanic acid, ceftriaxone, cefuroxime, ceftazidime, cefepime, imipenem, amikacin, ciprofloxacin, erythromycin and clindamycin were tested. Isolates showing resistance to at least one cephalosporin were tested for extended-spectrum β-lactamase (ESBL) production by the double-disc synergy test on Mueller-Hinton agar using ceftazidime and ceftriaxone placed at a distance of 20 mm from a disc containing amoxicillin plus clavulanic acid. A clear-cut enhancement of the inhibition in front of either ceftazidime and ceftriaxone discs towards the clavulanic acid-containing disc (also called ‘champagne cork’ or ‘keyhole’) was interpreted as positive for ESBL production.[21] E-test strips (BioMérieux, France) were used for confirmation of ESBL production. Minimum inhibitory concentrations of cefotaxime and ceftazidime, with and without clavulanic acid, were determined after 16 - 18 hours’ incubation on Mueller-Hinton plates inoculated with suspension of isolates at a fixed density (0.5 - 0.6 McFarland standard).

Escherichia coli ATCC 35218 and Klebsiella pneumoniae ATCC 700603 strains were used as ESBL-negative and positive controls, respectively. Multidrug resistance (MDR) was defined as non-susceptibility to at least one agent in three or more antimicrobial categories.[16] All MDR isolates were cryopreserved at –80°C for further studies, with the exception of methicillin-resistant coagulase-negative staphylococci (CoNS), all CoNS being considered contaminants.

Statistical analysis

Statistical analyses were performed using the SPSS statistical package release 12.0 for Windows (SPSS, USA). Comparisons of proportions of bacteria isolated and antimicrobial susceptibility results were analysed using the χ2 test. The level of significance was p<0.05.

Ethics

Ethical approval was granted by the Ethical Committee of the Université catholique de Bukavu, DRC, and the DRC Ministry of Health. The study complies with WHO and international guidelines (European Society of Clinical Microbiology and Infectious Diseases Study Group for Antimicrobial Resistance Surveillance and Clinical Laboratory Standards Institute) on antibiotic surveillance, for which no recommendation for an informed consent has been issued. The diagnostic procedure (blood cultures) is part of the standard diagnostic work-up of patients suspected of having bacteraemia. Clinical information

as presented, and information about use of antibiotics, was the standard information on the laboratory request form. Data were reviewed and analysed anonymously.

Results

A total of 320 blood samples from 320 different patients were cultured. The mean age of the patients was 21.6 years (range 0 - 75), and 162 were males and 158 females. Bacterial pathogens were detected in 170 cultures, 29.4% of which were from children (<17 years). The distribution and percentages of the various bacterial isolates are shown in Table 1.

Isolates of Gram-negative bacteria (GNB) (104, 61.2%) were significantly more prevalent than Gram-positive isolates (66, 38.8%) (p<0.05). Among the Gram-positive isolates, the predominant isolate was CoNS (n=62); of these, 58 were susceptible to oxacillin. Four CoNS isolates displayed low susceptibility to oxacillin and were accordingly considered methicillin-resistant CoNS. Staphylococcus aureus was represented by three isolates, none resistant to oxacillin. Only one S. pneumoniae was isolated, from a blood sample of a 3-year-old girl; this isolate was resistant to erythromycin and amikacin, while retaining susceptibility to gentamicin. The Gram-negative isolates were overwhelmingly represented

by Enterobacteriaceae (100/104 isolates).

Enterobacteriaceae included E. coli (48.6%), Klebsiella spp. (18.9%) and Enterobacter spp.

(6.3%). Rare Enterobacteriaceae included Shigella spp., Salmonella spp, Citrobacter spp. and

Table 1. Distribution of isolates in blood cultures at BGH, February 2013 - January 2014 Bacterial isolate

Isolates, n

% of total isolates (N=170)

% of BSI pathogens (N=112)

Escherichia coli

54

31.8

48.2

Klebsiella spp.

21

12.4

18.3

Enterobacter spp.

7

4.1

6.3

Shigella spp.

6

3.5

5.4

Salmonella spp.

5

2.9

4.5

Citrobacter spp.

3

1.8

2.7

Pseudomonas aeruginosa

3

1.8

2.7

Proteus spp.

3

1.8

2.7

Acinetobacter spp.

1

0.6

0.9

Neisseria spp.

1

0.6

0.9

Staphylococcus aureus

3

1.8

2.7

Methicillin-resistant CoNS

4

2.4

3.6

Streptococcus pneumoniae

1

0.6

0.9

Methicillin-susceptible CoNS (contaminants)

58

34.1

-

Total

170

100

100

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Table 2. Antimicrobial resistance (%) in 104 Gram-negative blood isolates collected at BGH, February 2013 - January 2014 Antimicrobial drug

Escherichia coli (n=54)

Klebsiella spp. (n= 21)

Enterobacter spp. (n=7)

Citrobacter spp. (n=3)

Salmonella spp. (n=5)

Shigella spp. (n=6)

Proteus spp. (n=3)

Acinetobacter spp. (n= 1)

Pseudomonas aeruginosa (n=3)

Neisseria spp. (n=1)

Amikacin

5.6

4.8

0

0

0

0

66.7

0

0

0

Ampicillin

98.1

95.2

100.0

100.0

100.0

83.3

66.7

100

100

NT

Amoxicillin/ clavulanate

7.4

19.0

14.2

33.3

0

50.0

0

100

100

NT

Cefepime

13.0

91

57.1

33.3

0

83.3

66.7

NT

NT

NT

Ceftazidine

46.3

52.4

14.2

66.7

20

83.3

66.7

100

100

NT

Ceftriaxone

24.1

19.0

28.5

33.3

80

83.3

0

100

NT

NT

Cefuroxine

81.5

85.7

85.6

66.7

80

100

100

100

66.7

NT

Ciprofloxacin

31.5

33.3

57.1

0

20

33.3

66.7

0

66.7

100

Erythromycin

100

100

100

100

100

100

100

100

100

NT

Gentamicin

7.4

28.6

14.2

0

100

100

66.7

0

0

NT

Imipenem

0

4.8

0

0

0

0

0

0

0

NT

Co-trimoxazole

100

100

100

100

100

100

100

100

100

100

MDR phenotype

20.4

47.6

57.1

66.7

0

66.7

0

100

100

0

ESBLproducing phenotype

16.7

47.6

28.5

33.3

0

0

0

NT

NT

NT

NT = not tested.

Proteus spp. The four non-Enterobacteriaceae Gram-negative isolates included three Pseudomonas aeruginosa, one Acinetobacter spp. and one Neisseria spp.

Tables 2 and 3 show the antimicrobial susceptibility patterns of Gram-negative and Gram-positive bacterial isolates. With the exception of the two Proteus spp., Gramnegative isolates were often susceptible to amikacin, gentamicin and ciprofloxacin. The MDR phenotype was present in 36 (34.6%) Gram-negative isolates, with >50% also displaying an ESBL-production phenotype.

Indeed, 82% MDR E. coli isolates were also ESBL producers, whereas 100% of Klebsiella spp. isolates displayed the ESBL-production phenotype. Of note, all Gram-negative bacilli displayed low susceptibility to co-trimoxazole, ampicillin and erythromycin. Worryingly, two MDR and ESBL-producing Klebsiella spp. isolates also displayed resistance to imipenem, one of the few carbapenems available in the province.

Nitrofurantoin, an oral drug displaying satisfactory activity against uropathogens in South Kivu,[18] was not included in the antimicrobial panel because only parenteral antimicrobials were administered for the treatment of BSIs.

Discussion

BSI is associated with high mortality and high healthcare costs, especially when the bacteria

Table 3. Antimicrobial resistance (%) in 8 Gram-positive blood isolates collected at BGH, February 2013 to January 2014 Antimicrobial drug tested

Staphylococcus aureus (3 isolates)

CoNS (4 isolates)

Streptococcus pneumoniae (1 isolate)

Amikacin

0

0

100.0

Ampicillin

100

75.0

NT

Sulphamethoxazole + trimethoprim

100

100

NT

Clindamycin

0

0

NT

Gentamicin

0.00

50.0

0

Erythromycin

33.3

0

0

Oxacillin

0

10.0

NT

Vancomycin

0

0

NT

NT = not tested.

have low susceptibility to antimicrobial drugs.[22] Accordingly, the implementation of laboratory capacity for specific diagnosis of causative bacterial agents and determination of their antimicrobial susceptibility profile is pivotal in curbing mortality related to BSI. Although blood cultures have been performed at our hospital for many years, they were characterised by a very low yield of positive isolates, with unreliable identification resulting in largely empirical treatment of presumptive BSI. Changes in the blood culture process in the past year have resulted in a spectacular rise in positive

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blood cultures in patients with suspected BSI. Despite these encouraging improvements, blood culture at our hospital is still plagued by a high rate of contaminant CoNS, when compared with benchmarks in the field.[23,24] Action must therefore be taken to improve skin decontamination prior to blood sampling; the low susceptibility of CoNS to oxacillin needs further confirmation, as it has been shown that disc testing is not an accurate method for the determination of methicillin susceptibility of CoNS.[25] In our study, 32.5% of blood cultures yielded significant positive growth. This rate

RESEARCH

is high when compared with rates in other African countries.[22,26-28] We found a high prevalence of MDR GNB as major causative agents of BSI. Among GNB, Enterobacteriaceae, particularly E. coli, were the most frequently isolated pathogens. Our results diverge from those previously reported in this province more than a decade ago that documented Salmonella spp. as the leading cause of bacteraemia in a rural paediatric hospital.[5] Oddly, Gram-positive bacteria did not play an important role in BSI when compared with other studies in developing countries;[15,27,29,30] in fact, only three S. aureus and one S. pneumoniae were isolated. Given this steadily growing danger of MDR and ESBL-producing isolates in South Kivu, as underlined by our findings, a strict antibiotic policy should be implemented urgently in the province with an emphasis on local susceptibility findings.

Another important issue in the province is the lack of regulation regarding prescription of antibiotics, which are widely used, even for minor illnesses such as rhinitis. Whereas no study has assessed this phenomenon, it is worth noting that a recent study documented a high level of irrational prescription of antibiotics by healthcare professionals in the Orientale Province of DRC,[31] and that this practice is often associated with a steady increase of antimicrobial drug resistance in low-income countries. The identification of two carbapenem-resistant Klebsiella spp. isolates in the province is consistent with a recent observation of a carbapenem-resistant Enterobacter spp. in a urinary tract infection in the same province.[18] The emergence and possible spread of carbapenem-resistant Enterobacteriaceae isolates in the province would represent an additional step in the wrong direction that might be enhanced by misuse of carpabenems, as observed a few years ago in some Asian countries.[32]

Study limitations

Our study has several limitations. We analysed only 320 blood cultures, a low number that might result in selection bias. Rates obtained during this study should therefore be interpreted with caution. Whereas no patient reported having HIV infection, no objective data were available regarding HIV status of BSI patients.

Conclusion

Although performed on a limited set of blood cultures, our study underscores the high prevalence of MDR-resistant bacteria responsible for BSI at BGH. The high rate of MDR ESBL-producing GNB is consistent with a previous study performed on isolates from urinary tract infections at the same hospital. Accordingly, these findings should compel provincial healthcare stakeholders to take immediate action aimed at tackling this dangerous trend, before the situation slips beyond any possible repair. These actions should include the establishment of guidelines for prescription of antimicrobial drugs and the setting up of antimicrobial drug control in the province.

Author contributions. LMI, LK and RBC participated in the design of the study, LMI oversaw the data collection, LMI and LK were responsible for the laboratory assays, and FBK, MI and PNM contributed to implementation of blood culture assays. LMI wrote the first draft of the article, and all the authors participated in the manuscript revision. All the authors read and approved the final manuscript.

Acknowledgments. We thank the staff of the Clinical Biology Department at BGH for their technical assistance. We also gratefully acknowledge the assistance of Olga Mineeva (Université catholique de Louvain) and AnneSophie Piette (Institut Royal Supérieur de la Défense-Koninlijk Hoger Instituut voor Defensie). This project was funded by Belgian Cooperation

755

Agency through the 2012 PIC project (Projet Inter-Universitaire de Coopération) of the ARES (Académie de Recherche et d’Enseignement Supérieur) and by the Department Management of Scientific & Technological Research of Defence (IRSD-RSTD; Royal High Institute for Defence) supporting research and development (grants MED-20).

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The Neurohospitalist 2013;3(3):144-1451. [http://dx.doi.org/10.1177/1941874413476043] 2. Laupland KB. Incidence of bloodstream infection: A review of population-based studies. Clin Microbiol Infect 2013;19(6):492-500. [http://dx.doi.org/10.1111/1469-0691.12144] 3. Coburn B, Morris AM, Tomlinson G, et al. Does this adult patient with suspected bacteremia require blood cultures? JAMA 2012;308(5):502-511. [http://dx.doi.org/10.1001/jama.2012.8262] 4. Bates DW, Pruess KE, Lee TH. How bad are bacteremia and sepsis? Outcomes in a cohort with suspected bacteremia. Arch Intern Med 1995;155(6):593-598. [http://dx.doi.org/10.1001/ archinte.1995.00430060050006, http://dx.doi.org/10.1001/archinte.155.6.593] 5. Bahwere P, Levy J, Hennart P, et al. Community-acquired bacteremia among hospitalized children in rural central Africa. Int J Infect Dis 2001;5(4):180-188. [http://dx.doi.org/10.1016/S12019712(01)90067-0] 6. Hounsom L, Grayson K, Melzer M. Mortality and associated risk factors in consecutive patients admitted to a UK NHS trust with community acquired bacteraemia. Postgrad Med J 2011;87(1033):757762. [http://dx.doi.org/10.1136/pgmj.2010.116616] 7. Lillie PJ, Allen J, Hall C, et al. Long-term mortality following bloodstream infection. Clin Microbiol Infect 2013;19(10):955-960. [http://dx.doi.org/10.1111/1469-0691.12101] 8. Moszynski P. 5.4 million people have died in Democratic Republic of Congo since 1998 because of conflict, report says. BMJ 2008;336(7638):235. [http://dx.doi.org/10.1136/bmj.39475.524282.DB] 9. Coghlan B, Brennan RJ, Ngoy P, et al. Mortality in the Democratic Republic of Congo: A nationwide survey. Lancet 2006;367(9504):44-51. [http://dx.doi.org/10.1016/S0140-6736(06)67923-3] 10. Kandala NB, Mandungu TP, Mbela K, et al. Child mortality in the Democratic Republic of Congo: Cross-sectional evidence of the effect of geographic location and prolonged conflict from a national household survey. BMC Public Health 2014;14:266. [http://dx.doi.org/10.1186/1471-2458-14-266] 11. Kandala NB, Emina JB, Nzita PD, et al. Diarrhoea, acute respiratory infection, and fever among children in the Democratic Republic of Congo. Soc Sci Med 2009;68(8):1728-1736. [http://dx.doi. org/10.1016/j.socscimed.2009.02.004] 12. Black RE, Cousens S, Johnson HL, et al. Global, regional, and national causes of child mortality in 2008: A systematic analysis. Lancet 2010;375(9730):1969-1987. [http://dx.doi.org/10.1016/S01406736(10)60549-1] 13. Evans JA, Adusei A, Timmann C, et al. High mortality of infant bacteraemia clinically indistinguishable from severe malaria. QJM 2004;97(9):591-597. [http://dx.doi.org/10.1093/qjmed/hch093] 14. Factor SH, Schillinger JA, Kalter HD, et al. Diagnosis and management of febrile children using the WHO/UNICEF guidelines for IMCI in Dhaka, Bangladesh. Bull World Health Organ 2001;79(12):1096-1105.

15. Van Herp M, Parqué V, Rackley E, et al. Mortality, violence and lack of access to healthcare in the Democratic Republic of Congo. Disasters 2003(2);27:141-153. [http://dx.doi.org/10.1111/14677717.00225] 16. Magiorakos AP, Srinivasan A, Carey RB, et al. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: An international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect 2012;18(3):268-281. [http://dx.doi.org/10.1111/j.14690691.2011.03570.x] 17. Kang CI, Kim SH, Park WB, et al. Bloodstream infections caused by antibiotic-resistant Gram-negative bacilli: Risk factors for mortality and impact of inappropriate initial antimicrobial therapy on outcome.

Antimicrob Agents Chemother 2005;49(2):760-766. [http://dx.doi.org/10.1128/AAC.49.2.760-766.2005] 18. Irenge LM, Kabego L, Vandenberg O, et al. Antimicrobial resistance in urinary isolates from inpatients and outpatients at a tertiary care hospital in South-Kivu Province (Democratic Republic of Congo).

BMC Res Notes 2014;7:374. [http://dx.doi.org/10.1186/1756-0500-7-374] 19. Baron EJ. Processing and interpretation of blood cultures. In: Isenberg HD, ed. Essential Procedures for Clinical Microbiology. Washington, DC: ASM Press, 1998:58-62.

20. EUCAST Clinical breakpoints. 2015. http://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_ files/Breakpoint_tables/v_5.0_Breakpoint_Table_01.pdf (accessed 21 December 2014).

21. Drieux L, Brossier F, Sougakoff W, et al. Phenotypic detection of extended-spectrum beta-lactamase production in Enterobacteriaceae: Review and bench guide. Clin Microbiol Infect 2008;14(Suppl 1):90-103. [http://dx.doi.org/10.1111/j.1469-0691.2007.01846.x].

22. Blomberg B, Jureen R, Manji KP, et al. High rate of fatal cases of pediatric septicemia caused by Gram-negative bacteria with extended-spectrum beta-lactamases in Dar es Salaam, Tanzania. J Clin Microbiol 2005;43(2):745-749. [http://dx.doi.org/10.1128/JCM.43.2.745-749.2005] 23. Schifman RB, Strand CL, Meier FA, et al. Blood culture contamination: A College of American Pathologists Q-Probes study involving 640 institutions and 497134 specimens from adult patients.

Arch Pathol Lab Med 1998;122(3):216-221.

24. Murillo TA, Beavers-May TK, English D, et al. Reducing contamination of peripheral blood cultures in a pediatric emergency department. Pediatr Emerg Care 2011;27(10):918-921. [http://dx.doi. org/10.1097/PEC.0b013e318230285b] 25. York MK, Gibbs L, Chehab F, et al. Comparison of PCR detection of mecA with standard susceptibility testing methods to determine methicillin resistance in coagulase-negative staphylococci. J Clin Microbiol 1996;34(2):249-253.

26. Berkley JA, Lowe BS, Mwangi I, et al. Bacteremia among children admitted to a rural hospital in Kenya.

N Engl J Med 2005;352(1):39-47. [http://dx.doi.org/10.1056/NEJMoa040275] 27. Reddy EA, Shaw AV, Crump JA. Community-acquired bloodstream infections in Africa: A systematic review and meta-analysis. Lancet Infect Dis 2010;10(6):417-432. [http://dx.doi.org/10.1016/S14733099(10)70072-4] 28. Lochan H, Bamford C, Eley B. Blood cultures in sick children. S Afr Med J 2013;103(12):918-920. [http://dx.doi.org/10.7196/SAMJ.6979] 29. Murdoch DR. Microbiological patterns in sepsis: What happened in the last 20 years? Int J Antimicrob Agents 2009;34(Suppl 4):S5-S8. [http://dx.doi.org/10.1016/S0924-8579(09)70557-6] 30. Moyo S, Aboud S, Kasubi M, et al. Bacteria isolated from bloodstream infections at a tertiary hospital in Dar es Salaam, Tanzania – antimicrobial resistance of isolates. S Afr Med J 2010(12);100:835-838.

31. Thriemer K, Katuala Y, Batoko B, et al. Antibiotic prescribing in DR Congo: A knowledge, attitude and practice survey among medical doctors and students. PloS One 2013;8(2):e55495. [http://dx.doi. org/10.1371/journal.pone.0055495] 32. Poirel L, Revathi G, Bernabeu S, et al. Detection of NDM-1-producing Klebsiella pneumoniae in Kenya.

Antimicrob Agents Chemother 2011;55(2):934-936. [http://dx.doi.org/10.1128/AAC.01247-10].

Accepted 20 July 2015.

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The role of point-of-care blood testing for ketones in the diagnosis of diabetic ketoacidosis A Coetzee,1 MMed (Int), FCP (SA); M Hoffmann,2 MMed (Chem Path); B H Ascott-Evans,1 FCP (SA) ivision of Endocrinology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Cape Town, D South Africa 2 Department of Chemical Pathology, Tygerberg National Health Laboratory Service, Stellenbosch University, Tygerberg, Cape Town, South Africa 1

Corresponding author: A Coetzee (blommeland@gmail.com)

Background. Urine dipstick testing for ketones is widely used when diabetic ketoacidosis (DKA) is suspected in patients with hyperglycaemia.

If urinary ketones are positive, patients are referred for further management – often inappropriately, as the test is a poor surrogate for plasma ketones. Plasma beta-hydroxybutyrate (β-OHB) levels >3 mmol/L are diagnostic of DKA, while levels <1 mmol/L are insignificant.

Objectives. To evaluate a hand-held electrochemical (point-of-care testing; POCT) ketone monitor and compare it with the gold-standard manual enzymatic method (MEM) for detection of plasma ketones.

Methods. In a prospective and comparative study, we evaluated the measurement of β-OHB by means of POCT and the MEM in 61 consecutive samples from patients with suspected DKA at Tygerberg and Karl Bremer hospitals, Cape Town, South Africa. Capillary (for POCT) and plasma samples (for the MEM) were obtained simultaneously and compared for accuracy. Precision was assessed with control samples.

Results. The POCT method was precise (coefficient of variation <4.5%), and there was a good correlation between the two methods (r=0.95). Regression analysis showed a proportional bias, with POCT reading higher than the MEM. However, when assessed at the relevant medical decision limits (β-OHB >3 mmol/L and <1 mmol/L), the total allowable error (bias + imprecision) was not exceeded. Patients will therefore still be classified correctly. The POCT method had a sensitivity of 100% and specificity of 89% for DKA (β-OHB >3 mmol/L), while at levels <1 mmol/L sensitivity was 100% and specificity 87.5%.

Conclusion. The POCT device provides an accurate and precise result and can be used as an alternative to the MEM in the diagnosis of DKA. S Afr Med J 2015;105(9):756-759. DOI:10.7196/SAMJnew.7889

Diabetic ketoacidosis (DKA) is a common and severe acute complication of diabetes mellitus. The annual incidence is 46 - 50 episodes per 10 000 diabetic patients. DKA accounts for 14% of hospital admissions of diabetic patients and 10% of all deaths from diabetes in the Western world.[1] In sub-Saharan Africa the picture is bleaker, with mortality rates up to 30%.[2] It has been estimated that the annual cost of treating DKA in the USA exceeds 1 billion USD[3] and that the average cost per DKA episode is USD6 500 - 7 500. This represented 25% of the total spent on the healthcare of patients with type 1 diabetes in 2010.[4] No published costing data are available from South Africa (SA).

When significant hyperglycaemia occurs, it is important to know whether it is accompanied by ketosis or ketoacidosis. Highrisk patients should be identified early, so that timely measures can be taken to prevent the significant morbidity and mortality associated with DKA. Ketone measurement allows the clinician to distinguish accurately between simple hyperglycaemia and metabolic decompensation with ketoacidosis, thus speeding up referral and management of patients with suspected DKA, when appropriate.

Urine dipstick testing for ketones (Ketostix) is the screening test currently widely used in our drainage area when DKA is suspected in patients with hyperglycaemia. It is used as a ‘surrogate’ because serum ketone and blood gas pH measurements are not readily available in most state health centres. However, the dipstick method has limitations. The test is based on the nitroprusside reaction, which gives a semiquantitative measurement of acetoacetate. It reacts weakly with acetone, but does not measure beta-hydroxybutyrate (β-OHB), and may give false-negative results. β-OHB is in fact the main metabolic product in the setting of DKA. It reflects the degree

756

of ketosis, as levels of β-OHB correlate better than acetoacetate with falls in pH and bicarbonate levels. Early detection has been shown to lead to improved patient outcomes.[5] Tests based on the nitroprusside reaction have also been reported to give false-positive results in various clinical scenarios such as the fasting state, pregnancy and the use of sulphydryl-containing medications, e.g. angiotensinconverting enzyme inhibitors.[6] In a position statement, the American Diabetes Association (ADA) emphasises that urine ketone tests are not reliable for diagnosing DKA and that measurement of β-OHB in blood is preferred for diagnosis.[7] At present, if urinary ketones are positive, these patients are referred to secondary or tertiary facilities for further management. This results in large numbers of patients being referred inappropriately as having DKA. Uncontrolled hyperglycaemia in the presence of a β-OHB level of >3.0 mmol/L indicates unequivocal DKA,[8] whereas a level of <1 mmol/L excludes any significant ketosis.[9] Quantitative β-OHB measurement is unfortunately not offered by the routine laboratory at Tygerberg Hospital (TBH), Cape Town, SA (a tertiary academic training hospital). Samples are referred across town to the Red Cross War Memorial Children’s Hospital (RCWMCH) laboratory, and results are reported within 2 - 3 days.

As a result, values cannot be used for decision-making in a medical emergency setting. Quantitative serum β-OHB measurement on a point-of-care testing (POCT) device has the potential to negate inappropriate referrals, which may translate into large cost savings if incorporated in initial patient assessment. It would also identify the ‘false negatives’ missed on Ketostix testing. POCT provides an attractive alternative to our current practice. Prior to its clinical use, it is essential that the POCT be evaluated to determine whether the device is accurate and precise and therefore fit for purpose. The

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Objectives

(i) To evaluate a hand-held electrochemical (POCT) ketone monitor (Medisense/Abbott Optium Xceed) and compare it with the manual enzymatic method (MEM), the current gold standard, to assess its accuracy and precision; (ii) to assess diagnostic performance of the POCT v. the MEM; and (iii) to calculate possible cost implications of utilising POCT as an alternative to the MEM.

Methods

Study design and setting

The study was prospective and comparative, evaluating the measurement of β-OHB by means of electrochemical POCT and the MEM in consecutive patients referred from primary levels of care with suspected DKA. Referral was based on hyperglycaemia (capillary glucose >13.9 mmol/L) and the presence of urinary ketones on dipstick testing.

The study was conducted over a 4-month period in the acute medical admission ward and the high-care ward at TBH as well as in the acute medical admission ward at Karl Bremer Hospital (KBH), also in Cape Town.

Blood samples were collected at admission and during treatment to ensure that a wide range of ketone values would be obtained. Patients were assessed clinically and attempts were made to identify the precipitant of the DKA episode.

Analytical performance

Method validations are performed to assess the degree of error inherent in a method and to determine whether the inaccuracy/bias and imprecision of the method will affect the interpretation of a test. CLSI documents EP09[10] (‘Method comparison and bias estimation using patient samples’) and EP15[11] (‘User verification of performance for precision and trueness’) (www.clsi.org) were followed. These documents state that precision can be determined using quality control samples, and that accuracy can be assessed by analysing at least 40 samples spanning the measurement range.

POCT was performed using the Medisense/Abbott Optium Xceed β-OHB meter, and results were expressed in mmol/L. Laboratory testing was performed by means of a MEM, results being expressed in µmol/L and then converted to mmol/L. The investigators were blinded to the results.

For precision studies, quality control samples at two levels close to the medical

decision limits were provided by the manufacturer. Samples were analysed in triplicate over a 5-day period on the POCT device. The mean, standard deviation (SD) and coefficient of variation (CV, %) (mean/ SD × 100) were calculated and compared with the manufacturer’s published results as per the package insert. The manufacturer claims a total imprecision of 8.8% at a β-OHB level of 0.7 mmol/L and a total imprecision of 3.1% at a β-OHB level of 4.3 mmol/L.[12] Accuracy studies were performed on 61 samples collected from the 41 patients enrolled in the study. Samples from consecutively presenting patients were used with ketone levels that spanned the measurement range and included clinical decision-making levels. Capillary and serum samples were obtained at the same time. Capillary blood was used for POCT. Venous whole blood was collected in lithium heparin tubes (BD Vacutainer) and immediately transported on ice to the TBH National Health Laboratory Service (NHLS) laboratory. The transit time ranged from 10 to 20 minutes. At the laboratory, samples were immediately deproteinised with per­chloric acid as per the RCWMCH protocol, stored at –70oC and transported to RCWMCH within 48 hours. At the RCWMCH laboratory the samples were stored at –20oC and analysed between 1 and 7 days of arrival. According to the literature, plasma samples are stable for several weeks at –20oC.[13] Linear regression analysis and a BlandAltman plot were used for analytical comparison and for depicting allowable bias and total allowable error. Method comparison statistics was performed with

the Analyse-It version 2.3 data package for Excel.

Diagnostic performance

Sensitivity and specificity were calculated at the clinical decision-making limits (1 mmol/L and 3 mmol/L) to assess diag­ nostic performance.

Cost

The cost of reagent strips for POCT was borne by the manufacturer. The cost of the MEM was borne by the NHLS. The cost for POCT is currently ZAR22 per strip, and the POCT device costs ZAR249.

The cost of MEM for detection of serum ketones (including β-OHB + acetoacetate) is ZAR228.88.

Results

Demographics and descriptive parameters

Most patients seen at TBH and KBH are of mixed ancestry, the gender and ethnic distribution being representative of the general population served by these hospitals.

In total, 61 samples were collected from 41 patients, of whom 24 were females and 17 males. The mean age was 33 years (range 17 52). The majority had type 1 diabetes (n=29, 70.7%), seven being newly diagnosed. All the patients were found to have ketones present on dipstick testing of the urine, ranging from 1+ to 3+. Of the 41 referred patients with suspected DKA, only 15 were true DKA cases when using MEM ketones (>3 mmol/L) and hyperglycaemia (fingerprick blood glucose >13.9 mmol/L). The majority of the patients (n=26, 63.4%) were therefore inappropriately referred on the basis of positive urinary

6 5 4 Patients, n

Clinical and Laboratory Standards Institute (CLSI) has published guidelines to facilitate this evaluation process.

3 2 1 0

New diagnosis

No insulin

Fig. 1. Precipitants of DKA.

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September 2015, Vol. 105, No. 9

Sepsis

Illicit substance

RESEARCH

ketones and hyperglycaemia. When evaluating ketosis (β-OHB >1 mmol/L and <3 mmol/L), an additional five patients had ketosis but not ketoacidosis. Even if these five patients are added to the 15 with DKA, more than half of all the patients (n=21, 51.2%) were inappropriately referred.

The factors that precipitated the DKA episodes are shown in Fig. 1. Although our study was not designed to investigate the causes thereof, it was clear that lack of adherence to insulin therapy and sepsis seemed to be the major contributors.

Analytical performance

Discussion

DKA is a common complication in our diabetic population. It is clear that the majority of patients were inappropriately referred with suspected DKA, and that this might have been avoided had the means to detect serum ketones been available at referral centres.

Only a minority of patients had pH measurements before being referred. Is it then correct to diagnose DKA at a certain level of β-OHB (in an uncontrolled diabetic), without knowing the pH level?

Ketone body anion concentrations directly reflect the rate of ketone body production, which is accompanied by equimolar production of

Precision Precision of POCT was assessed by adhering to guidelines of the CLSI.[14] A summary of the results is presented in Table 1. At both low and high control levels, the total imprecision of the POCT device did not exceed the imprecision claimed by the manufacturer.

Manufacturer claims were therefore verified at both control levels.

Table 1. Manufacturer claims for precision of the POCT device validated using control samples

Accuracy As the data were not normally distributed, non-parametric statistics were used. Spearman rank order correlation, performed with regard to actual values in mmol/L of both results obtained from POCT and the MEM (Fig. 2), demonstrated a very high correlation between the two methods (r=0.95). Since high correlation coefficients do not imply agreement of methods, we examined the agreement using the Bland-Altman difference plot and depicting allowable bias (18.4%) and total allowable error (68.7%).[15] The Bland-Altman plot demonstrated a proportional bias, with the POCT device reading higher than the MEM. The bias exceeded the total allowable bias, but when combined with the precision, did not exceed the total allowable error (Fig. 3).[16] When assessed at medical decision limits, the positive bias was 0.22 mmol/L at 1 mmol/L (p=0.77) and 0.68 mmol/L at 3 mmol/L (p=0.85).

Claimed CV, %

Obtained CV, %

Claim verified

0.7

8.8

4.3

Yes

4.3

3.1

2.3

Yes

Serum ketones, mmol/L – POCT

8

Diagnostic performance

When compared with the MEM, the POCT device demonstrated a sensitivity of 100% and a specificity of 89.5% for diagnosing DKA (β-OHB >3 mmol/L) and a sensitivity of 100% and specificity of 87.5% for excluding DKA (β-OHB <1 mmol/L) (Table 2). Other performance criteria are summarised in Table 2.

β-OHB, mmol/L

7 6 5 4 3 2 1 0

0

2

Difference between POCT and MEM

6

Serum ketones, mmol/L – MEM Fig. 2. Scatter plot showing correlation between the POCT method and the MEM.

5

Identity

4

Allowable bias (18.4%)

3

Total allowable error (68.7%)

2 1 0 -1 -2 -3 -4 -5

4

-1

1

3 5 Mean serum ketones, mmol/L

7

Fig. 3. Bland-Altman plot depicting allowable bias and total allowable error.

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Table 2. Ability of the POCT device to diagnose DKA and ketosis n/N (%) DKA (β-OHB >3 mmol/L) Sensitivity

23/23 (100.0)

Specificity

34/38 (89.5)

Positive predictive value

23/27 (85.2)

Negative predictive value

34/34 (100.0)

Ketosis excluded (β-OHB <1 mmol/L) Sensitivity

33/33 (100.0)

Specificity

28/32 (87.5)

Positive predictive value

33/37 (89.2)

Negative predictive value

28/28 (100.0)

hydrogen ions. Over the years numerous proposed markers and cutoffs have confirmed that any diagnostic criterion for DKA is arbitrary.

This led the ADA to issue a consensus statement in 2006 that included set levels of pH, HCO3, ketones, anion gap and glucose.[17] While all five of these criteria have serious limitations, the most robust criterion is regarded to be a serum bicarbonate level of <18 mEq/L. However, in a 2008 Mayo Clinic study comparing this cut-off level with appropriate levels of β-OHB, there was a statistically strong correlation overall, but 16% false-positive and 17% false-negative rates at this bicarbonate level. Similarly, when a pH of <7.3 was the comparator, 20% of DKA patients had a false-negative pH.[8] Although our study was not designed to investigate the causes of DKA, it was clear that lack of adherence to insulin therapy and sepsis seemed to be the major contributors. All the patients we evaluated were positive for urinary ketones on dipstick testing at the referring centres.

Measurement of urinary ketones has various limitations, especially in the diag­ nosis of DKA. Reliable quantitative serum ketone measurement is preferable. Measurement of serum ketones has many applications in the management of patients with diabetes. The need for a rapid, reliable and accurate method led to the development of POCT for the measurement of β-OHB. In our study we evaluated a handheld electrochemical POCT ketone monitor v. the MEM (current gold standard) and evaluated its use in a resource-limited setting.

The method validation performed in this study proved that POCT was precise and accurate. The POCT device did show a proportional bias (increase in the magnitude of the error as the test result increased), which exceeded the allowable bias as stated in the literature. However, when taking the low imprecision of the method into account, the total error did not exceed the total allowable error (bias + imprecision), making this method acceptable. The performance was also evaluated at the medical decision limits of 1 mmol/L (rule out DKA) and 3 mmol/L (rule in DKA). This confirmed that patients will not be incorrectly classified because of the observed bias. The POCT device was therefore deemed fit for purpose.

How should diabetic patients with β-OHB in the ketosis range be managed? Five of our patients had levels between 1 and 3 mmol/L with the MEM, and all five were also within this range on POCT. In general, it should therefore not be necessary to up-refer these patients. However, if such patients look unexpectedly ill or acidotic, they should be referred, as other factors such as lactic acidosis or renal failure may be present.

759

The current cost to user of performing a serum ketone test is ZAR228.88. This includes a serum qualitative ketone determination as well as acetoacetate and β-OHB quantitative determination. The cost of the POCT is ZAR22 per strip. For this study the point of care machine (Abbott OptiumXceed) was provided free of charge by the manufacturer. It retails for ZAR205 - 249. Even adding capital outlay, cost of disposables and sundries, it is clear that POCT is far more cost-effective than the MEM.

Study limitations

The aim of the study was to evaluate POCT in measuring blood ketones and not to ratify POCT for treatment monitoring. POCT was not incorporated in the decision-making in this study, so we cannot comment on its use to improve outcomes. Although use of POCT appears to be more economical than the MEM, a formal cost analysis was not performed. Consecutive patient samples were used for the method comparison, so the spread of results advised by the CLSI documents/Westgard Basic Method Validation guidelines[14] (which state that one-third of results must be in the low to low-normal range, one-third in the normal range, and one-third in the high-abnormal range) could not be followed.

Conclusions

The Abbot OptiumXceed POCT device prov­ ides an accurate and precise blood β-OHB result. This device offers a cost-effective practical alternative to laboratory measurement of ketones in patients with suspected DKA. Its adoption would bypass the use of urine dipstick testing to diagnose DKA, leading to more appropriate referrals and major cost savings. Our findings may potentially lead to better management of patients with DKA. However, appropriately designed studies will be needed to confirm this.

References 1. Faich GA, Fishbein HA, Ellis SE. The epidemiology of diabetic acidosis: A population-based study. Am J Epidemiol 1983;117(5):551-558.

2. Otieno CF, Kayima JK, Omonge EO, Oyoo GO. Diabetic ketoacidosis: Risk factors, mechanisms and management strategies in sub-Saharan Africa: A review. East Afr Med J 2005;82(12 Suppl):S197-S203.

3. Javor KA, Kotsanos JG, McDonald RC, Baron AD, Kesterson JG, Tierney WM. Diabetic ketoacidosis charges relative to medical charges of adult patients with type 1 diabetes. Diabetes Care 1997;20(3):349354. [http://dx.doi.org/10.2337/diacare.20.3.349] 4. Maldonado MR, Chong ER, Oehl MA, Balasubramanyam A. Economic impact of diabetic ketoacidosis in a multiethnic indigent population. Diabetes Care 2003;26(4):1265-1269. [http://dx.doi.org/10.2337/ diacare.26.4.1265] 5. Vanelli M, Chiari G, Capuano C. Cost effectiveness of the direct measurement of 3-betahydroxybutyrate in the management of diabetic ketoacidosis in children. Diabetes Care 2003;26(3):959. [http://dx.doi.org/10.2337/diacare.26.3.959] 6. Csako G. False-positive results for ketone with the drug mesna and other free-sulfhydryl compounds.

Clin Chem 1987;33(2):289-292.

7. Goldstein DE. Tests of glycemia in diabetes. Diabetes Care 2004;27(Suppl 1):S91-S93. [http://dx.doi. org/10.2337/diacare.​27.7.1761] 8. Sheikh-Ali M, Karon BS, Basu A, et al. Can serum beta-hydroxybutyrate be used to diagnose diabetic ketoacidosis? Diabetes Care 2008;31(4):643-647. [http://dx.doi.org/10.2337/dc07-1683] 9. Wallace TM, Matthews DR. Recent advances in the monitoring and management of diabetic ketoacidosis. QJM 2004;97(12):773-780. [http://dx.doi.org/10.1093/qjmed/hch132] 10. Clinical and Laboratory Standards Institute. Method comparison and bias estimation using patient samples.

EP09-A2, Vol. 13, No. 17:1-80.

11. Clinical and Laboratory Standards Institute. User verification of performance for precision and trueness.

EP15-A2, Vol. 25, No. 17:1-64.

12. Abbott Diabetes Care Inc. Clinical evaluation of a faster, smaller sample volume blood beta ketone test strip. http://www.abbottdiabetescare.co.uk/_resources/media/documents/hcps/clinical_papers/08_ KII_white%20_paper.pdf (accessed 1 October 2014).

13. Sacks DB, Arnold M, Bakris GL, et al. Guidelines and recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus. Diabetes Care 2011;34(6):e61-e99. [http://dx.doi. org/10.2337/dc11-9998, http://dx.doi.org/10.2337/dc11-9997] 14. Chesher D. Evaluating assay precision. Clin Biochem Rev 2008;29(Suppl. 1):S23-S26.

15. Widjaja A, Morris RJ, Levy JC, Frayn KN, Manley SE, Turner RC. Within and between subject variation in commonly measured anthropometric and biochemical variables. Clin Chem 1999;45(4):561-566.

16. Westgard JO. Basic Method Validation. 3rd ed. Madison, WI: Westgard QC, 2008:27-84.

17. Kitabchi AE, Umpierrez GE, Murphy MB, Kreisberg RA. Hyperglycemic crises in adult patients with diabetes: A consensus statement from the American Diabetes Association. Diabetes Care 2006;29(12):2739-2748. [http://dx.doi.org/10.2337/dc06-9916]

Accepted 4 July 2015.

September 2015, Vol. 105, No. 9

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Reproductive knowledge and use of contraception among women with diabetes Ayesha Osman, MB ChB, FCOG (SA), MMed (O&G); Anne Hoffman, RN, RM; Shane Moore, RN, RM; Zephne van der Spuy, MB ChB, PhD, FRCOG, FCOG (SA) Department of Obstetrics and Gynaecology, Faculty of Health Sciences, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa Corresponding author: A Osman (ayesha2309@gmail.com)

Background. Poorly controlled diabetes is associated with poor maternal and fetal outcomes, yet many women become pregnant before establishing control. Reducing unintended pregnancies is a vital step towards improving perinatal and maternal morbidity and mortality.

Objectives. To assess the reproductive knowledge and use of contraception in women of reproductive age attending diabetes outpatient clinics.

Methods. A prospective descriptive study was conducted of women known to have diabetes, aged 18 - 45 years, attending the diabetic clinics at Groote Schuur Hospital or the local community health centres in Cape Town, South Africa. A questionnaire consisting of social, demographic and family details as well as contraceptive use and knowledge was administered.

Results. Some common themes emerged, namely that 44.2% of the women with previous pregnancies had had unintended pregnancies, and that this was more common among single (58.8%) and younger women. Women with type 1 diabetes had better knowledge than those with type 2 diabetes of how pregnancy affects diabetes, but better knowledge did not translate to better contraception use. Despite the fact that 102 participants (88.7%) attended diabetes clinics two or more times a year, knowledge of pregnancy- and reproductive health-related complications was limited, and only 30 participants (26.1%) had received advice on contraception at these clinics.

Conclusion. Knowledge about the impact of diabetes on pregnancy and that of pregnancy on diabetes was suboptimal. We recommend that reproductive health services be included at the routine diabetes clinic visit.

S Afr Med J 2015;105(9):760-764. DOI:10.7196/SAMJnew.8170

The prevalence of diabetes mellitus is increasing rapidly worldwide. Diabetes currently affects 366 million people globally, and the number is expected to rise to 552 million by the year 2030.[1,2] In South Africa (SA) 3 million men and women have diagnosed diabetes, and there are an estimated further 3 million living with the disease who remain undiagnosed.[1] Fetal complications of maternal diabetes can be divided into two major categories: (i) early complications, reflecting the impact of maternal disease on early fetal development due to poor glucose control during the period of organogenesis in the first trimester; and (ii) late complications, including unexplained stillbirths and macrosomia in the second and third trimesters and hypoglycaemia, respiratory distress syndrome and jaundice in the neonatal period. Direct obstetric complications include spontaneous miscarriage, pre-eclampsia, polyhydramnios and obstructed labour because of macrosomia.[3,4] Maternal complications of pre-existing diabetes can be equally severe, and even life-threatening, but are often ignored by women desperate to have a child.

The 2007 Saving Mothers report stated that 76% of women with pre-existing maternal disease attended antenatal clinics.[5] The health system is therefore in a good position to intervene and prevent death, yet pre-existing maternal disease (6%) remains one of the five leading causes of maternal deaths, both in SA and internationally.[5] This suggests that antenatal intervention is too late to initiate optimal care for some patients, and that there is a lack of preconception planning and counselling, which are central to good management.

The 2007 Saving Mothers report stated that â&#x20AC;&#x2DC;the best way to prevent maternal deaths is to prevent pregnancyâ&#x20AC;&#x2122;.[5] One of its

760

recommendations was to promote contraceptive use through education and service provision. This also promotes reproductive health. Women with unplanned pregnancies, especially those with an underlying medical condition such as pregestational diabetes, are at an increased risk of maternal and neonatal complications. Tight glycaemic control for diabetic women in the periconception period is essential to reduce the risks of complications.[6] There are limited SA data on chronic medical diseases and contraceptive use and knowledge, with the exception of HIV. The 2003 South Africa Demographic and Health Survey (SADHS) 2003 data[7] are already more than 10 years old, and we have not been able to find anything more on chronic medical disorders and contraception in recent published research.

Objectives

To assess the reproductive knowledge of diabetic women of reproductive age attending outpatient clinics for the management of diabetes, and their use of contraception. A secondary objective was to elicit what counselling women with diabetes received on the implications of their condition with regard to pregnancy and reproductive health.

Methods

Study design and population

A prospective descriptive study design was used. The study population comprised women aged 18 - 45 years attending diabetes outpatient clinics between 1 March and 31 July 2012.

Recruitment was by convenience sampling, and patients were initially recruited from the three diabetes clinics at Groote Schuur Hospital

September 2015, Vol. 105, No. 9

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The 77 women who had previously been pregnant had a total of 180 pregnancies between them. Of these women, 34 (44.2%) reported

1.7% 0.9%

Consent

Approval for the study was granted by the Human Research Ethics Committee of the Faculty of Health Sciences, University of Cape Town (HREC REF: 500/2011) and the Provincial Health Research Council of the Western Cape (RP 48/2012). All participants provided signed informed consent before the questionnaire was administered.

4.3%

Single, in a stable relationship Single, not in a relationship 40.0%

Single and cohabiting

27.8%

Divorced Separated 18.3%

Widowed

Fig. 1. Marital status of the study subjects.

120

Respondents, n

100 80 60 Yes

40

No I don’t know

20

Results

he r Ot

ia ae m id

io n

Dy sli p

ns rte pe Hy

ph ro p Ne

at hy op tin Re

at hy

0

Patient characteristics

A total of 115 women aged 18 - 45 years were recruited. No patient declined to participate.

Less than half of the participants were employed (41.7%, n=48), but no woman identified herself as being without financial support. Of note, 19 participants were

Married

7.0%

Data management and statistical analysis

Data were processed in the Reproductive Medicine Unit. All data were double-entered into a database created using Microsoft Office Excel 2007 and then cross-checked using the statistical analysis programme Stata. Statistical analysis was performed using Stata software version 11 (StataCorp 2009, USA), with assistance from the Department of Statistical Sciences of the University of Cape Town.

Demographic details were presented in a descriptive manner. In the analysis of continuous data such as age and parity, which are non-normally distributed, we used the Mann-Whitney U-test/Wilcoxon rank sum test for formal comparisons. In the case of categorical variables, cross-tabulations were used together with χ2 tests of association and Fisher’s exact tests where appropriate. The level of significance was set as p<0.05.

some of their pregnancies as unintended. The Mann-Whitney U-test/Wilcoxon rank sum test demonstrated an association between age and intended pregnancy, unintended pregnancy tending to be associated with younger age (z=2.308, p=0.0210).

Single women were also more likely to have had unintended pregnancies, with 20 of the reported 34 unintended pregnancies (58.8%) having been in women who classified themselves as single (Pearson χ2(6)=16.8552, Fisher’s exact p=0.003). The remaining 14 women, who were currently married, did not specify whether the unintended pregnancy had occurred before or after marriage.

Only 10 of the 43 women (23.3%) who reported having had an intended pregnancy identified themselves as single; the remaining 33 (76.7%) were currently married, divorced or separated, but as their marital status at the

Obstetric history

at hy

Data were collected by means of a questionnaire administered by experienced research staff in the Reproductive Medicine Unit, GSH. Additional clinical information was obtained from the medical folder.

The study investigators were not involved in the medical management of the patients.

Interviews were conducted in private rooms to maintain strict confidentiality, and personal identifying information was not entered into the database. The questionnaire consisted of demographic and social details of patients as well as medical and obstetric history, knowledge about reproduction and contraception use.

ro p

Data collection

receiving disability grants and four received child support grants which they cited as financial support. The majority of the participants lived in a dwelling with access to basic amenities (water, electricity, plumbing), and less than 10% (n=11) lived in an informal dwelling without these amenities.

Sixty-two respondents (53.9%) had com­ pleted a minimum of grade 12 level of education, and only four (3.5%) had less than a grade 7 education. Sixty-seven women (58.3%) were either married or in a stable relationship (Fig. 1). Only one participant was unable to identify a source of emotional support.

Ne u

(GSH), Cape Town, SA. The recruitment area was later extended to include community health centres (CHCs) with ‘diabetes clubs’ (Woodstock, Lady Michaelis, Hanover Park and Gugulethu CHCs).

Disease status and comorbidity

Fig. 2. Current status of disease and comorbidity. (Other = amputations, heart attacks, heart failure, comas, strokes, poor healing.)

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September 2015, Vol. 105, No. 9

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Women were asked, without prompting, to name methods of contraception they had

ne No

r he

M

en

st

Fe r

ru

til

al

ity

Ot

s pr ob

le

m

at ed re l

at ed yr el nc

Pr eg na

Ne

ur op

at hy

at hy op tin

Re

ph

ro p

at hy

Respondents, n

Contraceptive history

90 80 70 60 50 40 30 20 10 0

Ne

Type of complication identified

Fig. 3. Knowledge of complications associated with diabetes mellitus.

120

100

80

60 Knowledge of method 40

Previously used method Currently using method

20

No

ne

0

TO P

Sixty-one participants (53.0%) had type 1 diabetes (requiring insulin from the time of diagnosis), and 70 were using additional medication such as antihypertensives and statins.

Eighty-five women (73.9%) had comorbid conditions or compli­ cations secondary to diabetes (most commonly hypertension and dylipidaemia) (Fig. 2). We found no association between complications of diabetes or comorbid disease and current or previous use of contraception (Pearson χ2(1)=0.1780, Fisher’s exact p=0.826).

Patients with type 1 diabetes did not differ from those with type 2 diabetes with regard to number of intended pregnancies and unintended pregnancies (Pearson χ2(1)=1.9057, Fisher’s exact p=0.248). We also found no association between type of diabetes and knowledge of complications (Pearson’s χ2(1)=1.3587, Fisher’s exact p=0.343). However, women with type 1 diabetes demonstrated better knowledge of how pregnancy affects diabetes (26/61, 42.6%) than those with type 2 diabetics (12/54, 22.2%), (Pearson χ2(1)=5.3881, Fisher’s exact p=0.029). Women with type 1 diabetes reported a lower rate of contraception use than those not using insulin (type 2 diabetes) (Pearson χ2(1)=3.3556, Fisher’s exact p=0.082).

Of the respondents, 90.4% (n=104) had some knowledge of the complications of diabetes. It is noteworthy, however, that knowledge of pregnancy- and reproductive health-related complications was limited in our study population (Fig. 3). There was no association between the number of clinic visits and the knowledge participants displayed (Pearson χ2(3)=0.7514, Fisher’s exact p=0.881). Knowledge of complications of diabetes did not impact on whether patients were currently using contraception (Pearson χ2(1)=0.4187, Fisher’s exact p=0.527).

Respondents, n

Medical history

of clinic visits (Pearson χ2(3)=3.66, Fisher’s exact p=0.263).

In respect of knowledge of patients with diabetes about their disease and their demographic profile, the only association we found was between marital status and knowledge of how diabetes affects a pregnancy, single women being less likely to know how diabetes affected a pregnancy (Pearson χ2(2)=7.8510, Fisher’s exact p=0.018). Multiple confounders could be present if looking at marital status alone, and we attempted to adjust for age and parity.

Sixty-three respondents (54.8%) were unable to identify how diabetes affected a pregnancy, and 77 (67.0%) had no knowledge of how pregnancy affected diabetes. This was despite the fact that 102 participants (88.7%) had access to diabetes clinic staff at their regular clinic visits, which occurred at least every 6 months. There was also no association between women’s knowledge of how diabetes affects a pregnancy and current use of contraception (Pearson χ2(1)=0.1488, Fisher’s exact p=0.846), and no association between knowledge of how pregnancy affects diabetes and current use of contraception (Pearson χ2(1)=2.5499, Fisher’s exact p=0.150). We also showed no difference in contraception uptake among participants in relation to the number

Pi ll ( CO C) In In tra je ct ut io er n in e de M v ice al e co Fe nd m om Fe ale co m nd al e om st er M ilis al at e io st n er M i lis or at ni io ng n af te rp ill

time of the pregnancy was not specified, this information should be interpreted with caution.

We found no association between educational level and emotional support and intended v. unintended pregnancies (Pearson χ2(9)=10.6226, Fisher’s exact p=0.250 and Pearson χ2(1)=0.8011, Fisher’s exact p=1.000, respectively.)

A high proportion of the respondents who had been pregnant reported that they had been offered contraception after the birth of the baby (151 of 180 pregnancies, 83.9%).

Despite this high number, in the group of 34 women with unintended pregnancies, 24 were not using any contraception at the time of conception.

Contraception method

Fig. 4. Knowledge, previous use and current use of contraception by different methods. (COC = combined oral contraceptive; TOP = termination of pregnancy.)

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September 2015, Vol. 105, No. 9

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heard of, methods of contraception they had used in the past, and methods of contraception they were currently using (Fig. 4).

Significant findings were that 12 participants (10.4%) had never used contraception and a further 38 (33.0%) were not currently using contraception.

Only 26.1% of the participants (n=30) had previously received contraceptive advice at the diabetes clinic, and an overwhelming majority (88.7%, n=102) felt uncomfortable about asking for advice there. Of particular note, 73.9% (n=85) indicated that they would like their diabetes doctor/sister to initiate a discussion about contraception. The most common place identified to access contraception was a family planning clinic (54.8%, n=63), but other outlets were also mentioned. Significantly, no woman identified the diabetes clinics as a source of contraception.

We found no association between parity, level of education, emotional support or lifestyle and contraceptive use. In the case of marital status, we found an increased association between being single and not using contraception when compared with married women or women in stable relationships (Pearson Ď&#x2021;2(2)=7.9214, Fisherâ&#x20AC;&#x2122;s exact p=0.025).

Discussion

The themes that emerged from this study were that women attending outpatient diabetes clinics in our services have a limited knowledge of the impact of diabetes on pregnancy outcome, as well as on the impact of pregnancy on disease progression. Counselling on reproductive health, contraception and the effect of diabetes in pregnancy appears to be inadequate. This is supported by the fact that a large proportion of participants in our study (34/77, 44.2%) reported unintended pregnancies, indicating that their use of contraception was suboptimal. Although women with type 1 diabetes had a better understanding than those with type 2 diabetes of how pregnancy affects diabetes, there was still low use of contraception among these patients that we cannot explain.

Studies in the USA have reported that in general women at highest risk of unintended pregnancies are unmarried and of low socioeconomic status, have a low literacy level, and belong to minority groups. These women also tend to have poor glycaemic control and are less likely than other women to talk to their doctor before planning a pregnancy. They usually present for antenatal care at a late gestational age, which makes it difficult to provide optimal care.[8-10] Our study showed an association between younger age and unintended pregnancies, as well as between single status and unintended pregnancies. It is a misconception that women who are not currently in a sexual relationship do not need contraceptive advice. Sexual activity is a status that can change suddenly, and all women of reproductive age, particularly those with high-risk medical conditions, should have contraceptive counselling irrespective of their current status as defined by the SADHS. Waiting till they become sexually active can be too late for some.

Women with diabetes need to remain on contraception until optimal glucose control is achieved, chronic medications are adjusted and lifestyle adjustments (e.g. smoking cessation) have been made; this should be reiterated at every visit.

Adequate glycaemic control at the time of conception and during the period of organogenesis in early pregnancy reduces the risks of congenital malformations and spontaneous miscarriages to virtually the same as those in women without diabetes. International recommendations are haemoglobin A1c levels <7% (American Diabetes Association (ADA) guidelines) and <6.1% (UK National Institute of Clinical Excellence (NICE) guidelines).[11,12]

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All but one of the women in our study were using some form of medical treatment (114/115). These included oral agents, insulin, antihypertensives and statins, some of which need to be revised during pregnancy. Despite the risk associated with pregnancy, our data showed that 12 of the participants (10.4%) had never used contraception, and a further 38 (33.0%) were not currently using contraception. The importance of contraception did not appear to feature in the otherwise excellent counselling they received in the diabetes clinics.

We found that only 30 of the study participants (26.1%) had previously received any contraceptive or pregnancy planning advice at the diabetes clinics. Varughese et al.[13] concluded in a 2007 review of women attending adult general diabetes clinics in Telford, UK, that the aim of diabetes services should be to enable the pregnant woman with diabetes to present to her obstetrician with such well-controlled levels that her pregnancy will proceed without any complications.

Studies by Schwarz et al.[9] and Chuang et al.[14] both demonstrated that despite relatively frequent contact with healthcare providers, adolescent women with diabetes rarely identified a doctor or nurse as a major source of information about contraception and furthermore that they did not feel comfortable asking a healthcare professional for advice about contraception. Our findings were similar in that despite the fact that 89% of the participants were attending specialist diabetes clinics two or more times a year for routine visits, none identified the clinic as a point of contact for their contraception needs.

It is of concern that women attending diabetes clinics three or four times a year may neglect their family planning clinic appointments, as they perceive these to be less important. It falls to the doctor or nurse in the general clinics to make access to these services as easy as possible, especially when they can be accessed in the same facility.

Women with chronic medical conditions are at an increased risk of pregnancy-related complications, yet little research (with the exception of research among HIV-positive patients) has addressed how they perceive their pregnancy-associated risks or make reproductive health choices.

Crede et al.[15] showed in a study among postpartum women in Cape Town that the majority of the subjects in both the HIV-positive and HIV-negative sample groups indicated that their last pregnancy had been unintended (61.6% and 63.2%, respectively). Nearly 90% of women in both groups reported they were using a modern method of contraception (89.8% of HIV-positive and 89.0% of HIV-negative women), but typically this was a short-acting method with a higher failure rate than the long-acting reversible contraceptives. This was very similar to the types of contraception identified by the participants in our study.

Women with diabetes are generally aware that they have a risk of complications, but they have very little knowledge about the risk of pregnancy-related complications.[14] This was illustrated in our study, where 104 of the 115 patients interviewed had some knowledge of the complications of diabetes. When pregnancy- and reproductive health-related complications were looked at more specifically, however, knowledge was limited: 63 respondents (54.8%) were unable to identify how diabetes affected a pregnancy, and 77 (67.0%) were unable to suggest any way in which pregnancy could affect diabetes.

Conclusion

Contraceptive advice and pregnancy planning discussions should form part of the clinical review of every woman in the general diabetes clinic, and should be initiated in their early reproductive years.[13] Ideally, women with diabetes should conceive when they are best prepared for a pregnancy, financially, socially and medically.

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Improved patient motivation, intensive input from diabetes services, and interdisciplinary interactions between the obstetric and medical teams managing these high-risk patients should form the essential components of care if we are to successfully address the challenge of reducing the current unacceptably high rates of maternal and perinatal morbidity and mortality in SA. Acknowledgements. We appreciate the support we received from the staff in the diabetes clinics and thank the Department of Internal Medicine, GSH, for allowing us to conduct this research within their clinics. This research was partly sponsored by the JS Scratchley Trust.

References 1. International Diabetes Federation. IDF Diabetes Atlas. 6th ed. Brussels, Belgium: IDF, 2013. http:// www.idf.org/diabetesatlas (accessed 17 February 2015).

2. Federation of European Nurses in Diabetes and International Diabetes Federation – Europe. Diabetes: The Policy Puzzle: Is Europe making progress? 2nd ed. International Diabetes Federation, 2008:3-6. https://www.idf.org/sites/default/files/EU-diabetes-policy-audit-2008%20-2nd%20edition.pdf (accessed 11 August 2015).

3. Kitzmiller JL, Block JM, Brown FM, et al. Managing pre-existing diabetes for pregnancy: Summary of evidence and consensus recommendations for care. Diabetes Care 2008;31(5):1060-1079. [http:// dx.doi.org/10.2337/dc08-9020] 4. Walkinshaw SA. Type 1 and type 2 diabetes and pregnancy. Curr Obstet Gynaecol 2004;14(6):375-386. [http://dx.doi.org/10.1016/j.curobgyn.2004.07.002]

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5. National Committee on Confidential Enquiries into Maternal Deaths. Saving Mothers 2005-2007: Fourth Report on Confidential Enquiries into Maternal Deaths in South Africa: Expanded Executive Summary. Pretoria: Department of Health, 2009.

6. McDonagh M. Is antenatal care effective in reducing maternal morbidity and mortality? Health Policy Plan 1996;11(1):1-15. [http://dx.doi.org/10.1093/heapol/11.1.1] 7. Department of Health, Medical Research Council, OrcMacro. South Africa Demographic and Health Survey 2003. Pretoria: Department of Health, 2007.

8. Dunlop AL, Jack BW, Bottalico JN, et al. The clinical content of preconception care: Women with chronic medical conditions. Am J Obstet Gynecol Supplement to December 2008;199(6,Suppl B):s310-s327. [http://dx.doi.org/10.1016/j.ajog.2008.08.031] 9. Schwarz EB, Sobota M, Charron-Prochownik D. Perceived access to contraception among adolescents with diabetes: Barriers to preventing pregnancy complications. Diabetes Educ 2010;36(3):489. [http:// dx.doi.org/10.1177/0145721710365171] [PMID: 20332282] 10. Henshaw SK. Unintended pregnancy in the United States. Fam Plann Perspect 1998;30(1):24-29,46. [http://dx.doi.org/10.2307/2991522] 11. American Diabetes Association. Standards of medical care in diabetes – 2010. Diabetes Care 2010;33(1):s11-s61. [http://dx.doi.org/10.2337/dc10-S011] 12. Guideline Development Group. Guidelines: Management of diabetes from preconception to the postnatal period: Summary of NICE guidance. BMJ 2008;336(7646):714-717. [http://dx.doi. org/10.1136/bmj.39505.641273.AD] 13. Varughese GI, Chowdhury SR, Warner DP, Barton DM. Preconception care of women attending adult general diabetes clinics – are we doing enough? Diabetes Res Clin Pract 2007;76(1):142-145. [http:// dx.doi.org/10.1016/j.diabres.2006.07.025] 14. Chuang CH, Velott DL, Weisman CS. Exploring knowledge and attitudes related to pregnancy and preconception health in women with chronic medical conditions. Matern Child Health J 2010;14(5):713-719. [http://dx.doi.org/10.1007/s10995-009-0518-6] 15. Crede S, Hoke T, Contant D, et al. Factors impacting knowledge and use of long acting and permanent contraceptive methods by postpartum HIV positive and negative women in Cape Town, South Africa: A cross-sectional study. BMC Public Health 2012;12:197. [http://dx.doi.org/10.1186/1471-2458-12-197]

Accepted 30 June 2015.

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Time to implement 9-month infant HIV testing in South Africa L Fairlie,1 MB ChB, FCPaed (SA), MMed; C A Madevu-Matson,1,2 MSc; V Black,1 MD, MSc; G G Sherman,3 MB BCh, PhD its Reproductive Health and HIV Institute, University of the Witwatersrand, Johannesburg, South Africa W ICAP at Columbia University, Mailman School of Public Health, Columbia University, New York, USA 3 Department of Paediatrics and Child Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa, and Centre for HIV and STI, National Institute for Communicable Diseases, Johannesburg 1 2

Corresponding author: L Fairlie (lfairlie@wrhi.ac.za)

Background. South Africa (SA) is likely to meet the National Strategic Plan target of <2% mother-to-child HIV transmission at 6 weeks of age in 2015. Children infected with HIV after 6 weeks often remain undiagnosed because of poor implementation of post-weaning and final outcome 18-month HIV testing. The World Health Organization recommends a screening HIV rapid test (HRT) in HIV-exposed infants at the 9-month immunisation visit to exclude postnatal infection, with a confirmatory HIV polymerase chain reaction (PCR) test if the HRT is positive.

Objective. To evaluate the impact of substituting this recommendation for the post-weaning HIV testing recommended by SA guidelines.

Methods. Rates of seroreversion and probability of infection at 9 months of age were applied to a theoretical population of 100 HIV-exposed infants, uninfected at birth and breastfed for 1 year with antiretroviral prophylaxis. Nine scenarios were developed and the number of HIV PCRs saved compared with current guidelines was calculated.

Results. Nine-month testing using the HRT reduced the number of follow-up PCR tests done in all scenarios by >50%, with differences ranging from 51% to 59% and 81% to 89% for low and high seroreversion rates, respectively.

Conclusions. Nine-month testing using HRT would increase identification and early treatment of HIV-infected infants, improve monitoring of postnatal transmission rates, and reduce the number of HIV PCR tests done with resultant cost saving. Training of healthcare workers implementing HRT would be required. Ongoing efforts to improve implementation and monitoring of testing at 9 and 18 months will be essential.

S Afr Med J 2015;105(9):765-768. DOI:10.7196/SAMJnew.8175

In South Africa (SA), excellent gains have been made since 2002 in prevention of mother-to-child transmission (PMTCT) of HIV, with >90% of HIVinfected women accessing PMTCT.[1] The national early transmission rate of HIV infection at around 6 weeks of age is measured by the District Health Information System, the National Health Laboratory Service and the 2010 - 2013 South African PMTCT Evaluation (SAPMTCTE) studies and is on track to meet the National Strategic Plan target of <2% in 2015.[2-4] To detect postnatal transmission of HIV, national guidelines recommend that HIV-exposed uninfected (HEU) infants undergo repeat HIV testing 6 weeks after weaning and at 18 months of age. With dwindling early vertical transmission rates as a result of SAâ&#x20AC;&#x2122;s successful PMTCT programme, proportionately more infants and children diagnosed after 6 weeks of age will contribute to the paediatric HIV epidemic, and it is vital that they are identified.

HIV testing after weaning and at 18 months is poorly implemented and monitored, with post-weaning HIV testing being particularly problematic because in practice it lacks a specific time point. Exclusive breastfeeding for the first 6 months of life under antiretroviral therapy (ART) cover for HIV-exposed infants has been recommended in SA since 2010, with continued breastfeeding to 12 months of age.[5] After the 6-week HIV polymerase chain reaction (PCR) test, no HIV test is scheduled for a period of 1 year for the majority of breastfed HEU infants at daily risk of postnatal transmission, unless they are weaned earlier or become symptomatic. Coverage of 18-month testing for HEU infants is also poor and data from programmatic settings are scarce. Grimwood et al.[6] of Khethâ&#x20AC;&#x2122;Impilo report HIV positivity rates

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in children tested at 18 months of 10.7% in 2009, reduced to 3.8% in 2011; however, only 24% of HIV-exposed children were tested.

The rate of postnatal transmission and the extent of the paediatric HIV epidemic in SA therefore remain unmeasured and HIV-infected infants and children remain unidentified.

Factors that increase the risk of postnatal transmission are maternal infections not diagnosed during pregnancy, infection acquired late in pregnancy or during breastfeeding, poor adherence to ART during breastfeeding, and mixed infant feeding practices.[7,8] Exclusive breastfeeding rates are low, with the SAPMTCTE reporting rates of 35.5% at 6 weeks in 2010.[4] Furthermore, there is mounting evidence that the 6-week HIV PCR test yields false-negative results in the presence of maternal and/or infant antiretroviral prophylaxis.[9] These infants are likely to be diagnosed later in life, with their infection attributed to postnatal transmission.

A new routinely offered and provider-initiated testing strategy is required in SA to ensure testing of infants exposed to HIV through breastmilk and those who are missed in the first few months of life. Since 2008, World Health Organization (WHO) guidelines for infant HIV diagnosis have recommended using an antibody detection assay such as an HIV rapid test (HRT) at 9 months of age for all HEU infants, with a confirmatory HIV PCR test if the HRT is positive.[10] HRTs performed on whole blood are able to detect seroreversion (the loss of maternal HIV antibodies) in the majority of HEU infants by 8 - 10 months of age, depending on the HRT used.[11] This means that a carefully selected HRT routinely offered at the 9-month Expanded Programme on Immunization (EPI) visit could exclude HIV infection in 80 - 100% of HEU infants. Measles

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coverage rates at 9 months (MCV1) in SA in 2010 were reported to be 95%, higher than the 83% in the same year of the second measles vaccine (MCV2), suggesting that if 9-month HRT were introduced at the 9-month measles vaccine visit, coverage of HIV-exposed infants might potentially be greater than at the 18-month visit. [12] The vast burden of testing costs in an infant HIV testing programme lies in the number of HIV PCR tests performed, costing between ten and 30 times more than any HRT used in SA (Prof. Gayle Sherman, personal communication). An inexpensive screening test that coincides with a routine (EPI) visit at 9 months will diagnose HIV-infected infants early at a routine visit, provide data to monitor transmission at 9 months and plan for the numbers of children requiring combination antiretroviral therapy (cART), facilitate initiation of cART to prevent morbidity and mortality, and assist with identifying gaps in prevention programmes. Additionally, performing HRT will reduce the costs associated with the more expensive HIV PCR test, which will be unnecessary in infants testing HIV-negative on HRT.

To directly compare the number of HIV PCR tests performed under current guidelines with the proposed 9-month HRT testing, a model was constructed for a population of 100 breastfeeding HEU infants and restricted to include only the HIV PCR tests performed after weaning and after a positive HRT. Breastfeeding exposure was assumed to be 100% and to continue to 12 months of age, as recommended in the WHO and NDoH guidelines. The model did not include recently introduced targeted birth and 16-week testing, the 6-week HIV PCR, clinically indicated testing in symptomatic children, and testing at or after 18 months of age, because the numbers of these tests would not differ between the NDoH guidelines and the proposed testing.

Nine scenarios were developed that factored in a combination of low, middle and high levels of both seroreversion and the probability of becoming HIV-infected over 9 months of breastfeeding.[8,11,13] Ranges

Results

In a hypothetical population of 100 breast­ feeding HIV-exposed infants, replacing post-​

DoH guidelines

Objective

Proposed algorithm

• HIV PCR for all

• HIV PCR for all

• None

• HIV Ab/PCR combo if ever BF exposed

• HIV Ab test for all

• HIV Ab test for all

6 wk

To evaluate the impact of introducing a screening HRT test for HEU infants at the routine 9-month EPI visit for measles immunisation in line with WHO recommendations, with a confirmatory HIV PCR test for infants testing positive on HRT, instead of a post-weaning HIV PCR test.

9 mo.

Methods

Estimating the number of HIV PCR tests avoided with 9-month HRT

Under current National Department of Health (NDoH) guidelines, all infants who ever start breastfeeding require one HIV PCR test after cessation of breastfeeding (assuming they are <18 months of age), occurring around 13.5 months of age in those breastfed until 12 months. In the testing proposed in this article, all infants who ever start breastfeeding will be tested with a screening HRT at 9 months and a confirmatory HIV PCR test if the HRT is positive. Only infants who test positive on the HRT at 9 months, which would include infants who are HIV-infected and those who have not yet seroreverted, therefore require an HIV PCR test. If an infant is HIV-uninfected but still breastfeeding at the 9-month visit, they would receive a followup HRT at 18 months as per the current guidelines unless they became symptomatic (Fig. 1).

described in published literature were used to determine low, middle and high levels of: (i) the rate of seroreversion at 9 months of age (~80%, range 60 - 90%)[8] and (ii) the probability of infant infection per month of HIV-exposed breastfeeding with 0 - 100% coverage of infant prophylaxis or maternal cART (~0.002, range 0.0016 - 0.01).[8,13] Under the nine resulting scenarios, the diff­ erence in the number of PCR tests between post-weaning PCR testing and replacement of post-weaning testing with 9-month HRT screening and PCR confirmatory testing was calculated (Table 1). The probability of becoming HIV-infected as a result of late maternal seroconversion and masked intrapartum infection was not taken into account by the model. All calculations were done using Microsoft Excel.

18 mo.

at any age

6 wk after weaning

• <18 mo.: HIV PCR • ≥18 mo.: HIV Ab test

• None

• <9 mo.: HIV PCR Clinically indicated (symptomatic)

• <18 mo.: HIV PCR • ≥18 mo.: HIV Ab test

• ≥9 mo. to <18 mo.: HIV Ab/PCR combo • ≥18 mo.: HIV Ab test

Fig. 1. Guideline for service delivery models for exposed infant HIV testing. HIV testing by age and timing for all HEU infants included in current DoH guidelines and proposed 9-month HRT algorithm. (BF = breastfed; Ab = antibody; Ab/PCR combo = Ab test screening, confirmatory PCR if Ab test is positive.)

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Table 1. Number of HIV PCRs avoided per 100 HIV-exposed breastfed infants* Seroreversion at 9 months Low (60%)

Mid (80%)

High (90%)

Low (0.0016)

59

79

89

Mid (0.0020)

58

78

88

High (0.0100)

51

71

81

Probability of infection per month of breastfeeding

*Using ranges described in published literature for HIV exposed infant seroreversion rates at 9 months of age (~80%, range 60 - 90%) and the probability of infant HIV infection per month of breastfeeding (~0.002, range 0.0016 - 0.01), the number of follow-up PCRs per 100 HIV-exposed breastfed infants saved by doing a screening HRT at 9 months compared with post-weaning PCR testing, depending on low, medium and high probability of HIV infection and low, medium and high rates of seroreversion, is shown.

weaning PCR testing with 9-month HRT testing reduces the number of follow-up PCR tests done in all scenarios by >50%. The differences ranged from 51% to 59% with a low seroreversion rate, from 71% to 79% if the seroreversion rate was middle range, from 81% to 89% with a high seroreversion rate, from 59% to 89% with a low monthly probability of infection, from 58% to 88% with a middle estimate of infection rates, and from 51% to 81% with a high probability of infection (Table 1). The number of HIV PCRs done under the proposed 9-month HRT testing did not change by a large amount with different values for the probability of infection per month of breastfeeding, with no more than eight HIV PCR tests saved between the low and high estimates, because the main burden of HIV PCR tests carried out was for infants who have not seroreverted and will need an HIV PCR test to confirm or exclude HIV infection.

Consequently, the number of HIV PCR tests done was very sensitive to the seroreversion rates used, with 30 HIV PCR tests saved between the low and high seroreversion estimates (Table 1).

Discussion

In this hypothetical calculation that sought to evaluate the potential impact of integrating HRT into the 9-month routine EPI visit, we show that the number of HIV PCR tests can be reduced by >50% in all scenarios. This would reduce the costs associated with HIV PCR testing and the need for follow-up visits in children testing negative with HRT and no longer breastfeeding. Additionally, infants infected as a result of breastfeeding, masked intrapartum infection or late maternal infection, provided that women are tested 3-monthly post partum as recommended in the guidelines, will be diagnosed earlier than with the current NDoH guidelines. Currently infants infected with HIV postnatally who are breastfeeding at 9 months would only be tested 6 weeks after cessation of breastfeeding, if symptomatic or at 18 months, resulting in late diagnosis and late cART initiation. Considering the low rates of post-cessation and 18-month HIV testing, it is likely that these children would continue for many years without being diagnosed, eventually presenting ill and immunocompromised in late childhood or early adolescence.[14] Routine testing at 9 months, integrated into the EPI, is more likely to be implemented than post-breastfeeding cessation testing that may not coincide with EPI visits. It would also allow for collection of routine data for monitoring the postnatal transmission rate at 9 months of age in a breastfeeding population, data that are not available programmatically at present.

Implementation of a 9-month HIV testing strategy requires consideration of potential barriers. The strategy requires buy-in from

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EPI nurses, who may be unable or reluctant to include HIV testing in the 9-month EPI visit because of the added workload. SAâ&#x20AC;&#x2122;s routine health data sources in 2012/13 demonstrate 94% immunisation coverage in the first year of life and 77% at 18 months of age, whereas the infant HIV testing rate at 6 weeks was 73% with no routine data available for 18-month HIV testing.[2,3] Attendance at routine EPI visits therefore does not automatically translate into HIV testing at these visits. The emphasis placed on 6-week HIV PCR testing dramatically increased coverage from 33% in 2008 to 74% in 2012,[2] during which time 18-month HIV testing stagnated. Prioritising HIV testing in the maternal and child health programme would be required to improve HIV testing rates at 9 and 18 months of age.

The SA HCT policy recommends provider-initiated counselling and testing for children at every contact with a healthcare facility.

Since breastfed HEU children are at daily risk of HIV transmission, there is no harm in using HRT more frequently in infants aged â&#x2030;Ľ9 months. HIV testing in a â&#x2030;Ľ9-month-old child, identified as being 6 weeks post weaning, is indicated to determine final HIV status following maternal HIV exposure. Healthcare workers will also require education regarding the different interpretation of the HRT results in children <18 months of age, indicating HIV exposure if positive and not necessarily HIV infection. The consequences of failing to convey this message will result in HEU infants who serorevert later than 9 months of age being labelled as HIV-infected and initiated on lifelong therapy.

There are barriers to HIV testing in children that are not encountered in adults. A child may be accompanied to EPI visits by a caregiver who is not the parent, legal guardian or primary caregiver and is unable to provide consent for HIV testing on behalf of the child. In a study from Tanzania, children were five times more likely to be tested if they were brought to the clinic by a biological HIVinfected parent.[15] If caregivers want to avoid testing themselves and/or their infants, there may be an adverse effect of decreased attendance at the 9-month immunisation visit. However, these barriers have not been reported in the current PMTCT programme at the 6-week visit. The nationally representative SA PMTCT evaluation study demonstrated that 97% of infants attending the 6-week EPI visit were accompanied by their mothers and caregivers, and there was high (94%) acceptance and willingness to undergo HIV testing for themselves and their infants.[4] Ongoing monitoring for barriers to the 9-month HIV testing strategy will be necessary.

As with any diagnostic test, false-negative results can occur, but the risk of failing to identify an HIV-infected infant can be minimised by an appropriately validated HRT and conducting concurrent clinical examinations.[11] In programme settings, false negatives may occur because of incorrect use of the test, such as not waiting the recommended time for the true result on HRTs with 15 minutes or longer turnaround time. This can be minimised by using an HRT with a short turnaround time, which may also increase acceptability of the test to staff and clients accessing testing. Sherman et al.[11] have shown that Insti HRT is a highly specific test for exclusion of HIV infection in this setting, has a 1-minute turnaround time for ease of use in a busy EPI clinic, and reduces the time barrier to implementing this new intervention in an already overwhelmed system.

Study limitations

This model has limitations. Owing to a lack of local data we assumed that women would breastfeed for 12 months as recommended by guidelines, but this may be an over- or underestimate, as women breastfeed for variable time periods. Maternal refusal of HIV testing for themselves and their infants was not factored into the model.

Infants infected as a result of late maternal seroreversion or masked

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intrapartum infections were not included, but given that these would be the same in either testing strategy, the reported outcomes are unlikely to be affected. We did not model a detailed costing of 9-month HRT implementation, particularly the cost of training healthcare workers, and are only able to make assumptions based on the reduction in the number of HIV PCRs required.

Conclusions

If SA were to adopt the WHO recommendation to test all HEU infants at the 9-month EPI visit with an HRT and a confirmatory HIV PCR for those testing positive, more HIV-infected infants would be identified earlier, with the potential benefit of early cART initiation and monitoring of postnatal transmission rates at 9 months of age. This model suggests that replacing post-weaning testing with 9-month HIV testing would save costs for the country in terms of HIV tests performed. Training healthcare workers to interpret positive HRT results in children <18 months of age is likely to increase costs initially. Ongoing efforts would be required to improve implementation of testing at 9 and 18 months to determine the extent of and properly manage the paediatric HIV epidemic. A multicentre, nationwide pilot study would validate these findings and allow for a formal cost analysis of the introduction of a 9-month immunisation HRT. References 1. UNAIDS. 2013 progress report on the global plan towards the elimination of new HIV infections among children by 2015 and keeping their mothers alive. http://www.unaids.org/sites/default/files/ media_asset/20130625_progress_global_plan_en_0.pdf 2013 (accessed 3 March 2015).

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2. Sherman G, Lilian R, Bhardwaj S, Candy S, Barron P. Laboratory information system data demonstrate successful implementation of the prevention of mother-to-child transmission programme in South Africa. S Afr Med J 2014;104(3):235-238. [http://dx.doi.org/10.7196/SAMJ.7598].

3. Massyn N, Day C, Dombo M, Barron P, English R, Padarath A, and editors. District Health Barometer 2012/13. Durban: Health Systems Trust, 2013.

4. Goga A, Dinh T, Jackson D, for the SAPMTCTE study group. Evaluation of the Effectiveness of the National Prevention of Mother-to-Child Transmission (PMTCT) Programme Measured at Six Weeks Postpartum in South Africa, 2010. South African Medical Research Council, National Department of Health of South Africa and PEPFAR/US Centers for Disease Control and Prevention. 2012. http:// www.mrc.ac.za/healthsystems/SAPMTCTE2010.pdf (accessed 15 January 2015).

5. South African National Department of Health. Clinical Guidelines: PMTCT (Prevention of Motherto-Child Transmission). http://www.sahivsoc.org/upload/documents/NDOH_PMTCT.pdf (accessed 10 November 2014).

6. Grimwood A, Fatti G, Mothibi E, Eley B, Jackson D. Progress of preventing mother-to-child transmission of HIV at primary healthcare facilities and district hospitals in three South African provinces. S Afr Med J 2012;102(2):81-83.

7. Drake AL, Wagner A, Richardson B, John-Stewart G. Incident HIV during pregnancy and postpartum and risk of mother-to-child HIV transmission: A systematic review and meta-analysis. PLoS Med 2014,11(2):e1001608 [http://dx.doi.org/10.1371/journal.pmed.1001608] 8. Rollins N, Mahy M, Becquet R, Kuhn L, Creek T, Mofenson L. Estimates of peripartum and postnatal mother-to-child transmission probabilities of HIV for use in Spectrum and other population based models. Sex Transm Infect 2012;88(suppl 2):i44-i51. [http://dx.doi.org/10.1136/sextrans-2012-050709] 9. Nielsen-Saines K, Watts H, Veloso VG, et al. Three postpartum antiretroviral regimens to prevent intrapartum HIV infection. N Engl J Med 2012;366(25):2368-2379. [http://dx.doi.org/10.1056/NEJMoa1108275] 10. World Health Organization. WHO Recommendations on the Diagnosis of HIV Infection in Infants and Children. 2010. http://whqlibdoc.who.int/publications/2010/9789241599085_eng.pdf (accessed 11 July 2012).

11. Sherman GG, Lilian RR, Coovadia AH. The performance of 5 rapid human immunodeficiency virus tests using whole blood in infants and children: Selecting a test to achieve the clinical objective. Pediatr Infect Dis J 2012;31(3):267-272. [http://dx.doi.org/10.1097/INF.0b013e31823752a0] 12. Vergueta S, Jassat W, Hedberg C, Tollman S, Jamison DT, Hofman KJ. Measles control in sub-Saharan Africa: South Africa as a case study. Vaccine 2012;30(9):1594-1600. [http://dx.doi.org/10.1016/j. vaccine.2011.12.123] 13. Chasela CS, Hudgens MG, Jamieson DJ, et al. Maternal or infant antiretroviral drugs to reduce HIV1 transmission. N Engl J Med 2010,362(24):2271-2281. [http://dx.doi.org/10.1056/NEJMoa0911486] 14. Ferrand RA, Munaiwa L, Matsekete J, et al. Undiagnosed HIV infection among adolescents seeking primary health care in Zimbabwe. Clin Infect Dis 2010;51(7):844-851. [http://dx.doi.org/10.1093/cid/cis271] 15. Oâ&#x20AC;&#x2122;Donnell K, Yao J, Ostermann J, et al. Low rates of child testing for HIV persist in a high-risk area of East Africa. AIDS Care: Psychological and Socio-medical Aspects of AIDS/HIV 2014;26(3):326-331. [http://dx.doi.org/10.1080/09540121.2013.819405]

Accepted 1 July 2015.

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Pharmacological treatment of painful HIVassociated sensory neuropathy P Pillay,1 MSc; A L Wadley,1 PhD; C L Cherry,1,2,3 MBBS, PhD; A S Karstaedt,4 MB BCh; P R Kamerman,1 PhD rain Function Research Group, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa B International Clinical Research Laboratory, Centre for Biomedical Research, Burnet Institute, Melbourne, Victoria, Australia 3 Infectious Diseases Unit, Alfred Hospital and Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Victoria, Australia 4 Department of Medicine, Chris Hani Baragwanath Hospital, Johannesburg, South Africa 1 2

Corresponding author: P Pillay (prinishapillay_13@yahoo.com)

Background. HIV-associated sensory neuropathy (HIV-SN) is a common and frequently painful complication of HIV infection and its treatment. However, few data exist describing the frequency, type and dosage of pain medications patients are receiving in the clinic setting to manage the painful symptoms of HIV-SN. Objective. To report on analgesic prescription for painful HIV-SN and factors influencing that prescription in adults on combination antiretroviral therapy.

Methods. Using validated case ascertainment criteria to identify patients with painful HIV-SN, we recruited 130 HIV-positive patients with painful HIV-SN at Chris Hani Baragwanath Hospital, Johannesburg, South Africa. Demographic and clinical data (including current analgesic use) were collected on direct questioning of the patients and review of the medical files.

Results. We found significant associations, of moderate effect size, between higher pain intensity and lower CD4 T-cell counts with prescription of analgesic therapy. Factors previously identified as predicting analgesic treatment in HIV-positive individuals (age, gender, level of education) were not associated with analgesic use here. Consistent with national guidelines, amitriptyline was the most commonly used agent, either alone or in combination therapy. Importantly, we also found that despite the relatively high analgesic treatment rate in this setting, the majority of patients described their current level of HIV-SN pain as moderate or severe.

Conclusion. Our findings highlight the urgent need for both better analgesic options for HIV-SN pain treatment and ongoing training and support of clinicians managing this common and debilitating condition.

S Afr Med J 2015;105(9):769-772. DOI:10.7196/SAMJnew.7908

HIV-associated sensory neuropathy (HIV-SN) is a common and frequently painful complication of HIV infection and its treatment, and is likely to remain prevalent for the foreseeable future.[1-3] Painful HIV-SN is associated with substantially reduced health-related quality of life,[2] but evidence-based analgesic options are lacking.[4] Several national and international agencies[5-10] have recommended the tricyclic antidepressant amitriptyline for HIV-SN pain, despite evidence that this is no better than placebo.[11,13] Despite the high prevalence[1,2] and considerable impact of HIVSN, and the lack of proven effective analgesics, few data exist describing the frequency, type and dosage of pain medication patients are receiving. We are aware of only one retrospective case review, with low-quality case ascertainment criteria, that attempted to describe the treatment of HIV-SN pain in a clinical setting.[14] This showed that only 7% of a cohort of Malawians who may have had painful HIV-SN were prescribed amitriptyline.

We used validated case ascertainment criteria to identify patients with painful HIV-SN, and provide the first report on analgesic prescription for HIV-SN among South African (SA) adults on combination antiretroviral therapy (cART).

Methods

Consecutive consenting HIV-positive adults on cART were screened for HIV-SN at the Greenhouse Pharmacy, which services patients attending the Ntabiseng Clinic at Chris Hani Baragwanath Hospital, Johannesburg, SA, between June 2012 and January 2014. Researchers

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attended all pharmacy days servicing ambulatory adults infected with HIV. All individuals on stable cART (any regimen) for longer than 6 months and who had HIV-SN (painful or non-painful) were included in the study. The study was approved by the Human Research Ethics Committee (Medical) of the University of the Witwatersrand, Johannesburg. Informed consent was obtained from all participants.

Patients were screened for HIV-SN using the AIDS Clinical Trials Group (ACTG) Brief Neuropathy Screening Tool (BPNS).[15] HIV-SN was diagnosed on the basis of at least one bilateral sign (vibration sense <10 seconds using a 128 Hz tuning fork in the great toe or absent ankle reflexes) and at least one symptom (pain, paraesthesiae or numbness) in both feet. Symptom severity was rated on an 11-point numerical pain rating scale (NRS) ranging from 0 (not present) to 10 (most severe imaginable). Demographic and clinical data (including current prescribed and self-medicated analgesic use) were collected on direct questioning of the patient and review of the medical file.

Descriptive statistics are presented as means (standard deviation (SD)) for parametric data, medians (interquartile range (IQR)) for non-parametric data, and percentages for frequency data. Univariate analyses comparing patients receiving and not receiving analgesic therapy included Fisherâ&#x20AC;&#x2122;s exact test (gender, years of formal education, number of pain sites, ART regimen, current tuberculosis (TB) infection, sensory symptoms other than pain), the Wilcoxon rank sum test (pain intensity, CD4 T-cell count, years of formal education), and Studentâ&#x20AC;&#x2122;s t-test (age). Variables with p<0.1 on univariate analysis were included in multivariate logistic regression analysis. For those patients who were receiving analgesic therapy, the Cochrane-Armitage test for

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trend was used to assess whether there was an association between the dose of analgesic prescribed and pain intensity. Pain was categorised as mild if rated 1 - 3, moderate if rated 4 - 7, and severe if rated 8 - 10, as set out in the ACTG BPNS.[15]

Results

One hundred and thirty black SA patients with painful HIV-SN were recruited. Consistent with the population seen in clinics in Johannesburg,[16] the subjects were predominantly middle-aged women (72% female, mean (SD) age 45.7 (9.4) years) with well-preserved CD4 T-cell counts.

Current HIV-SN pain was rated as severe by two-thirds of the subjects, with an overall median pain intensity of 7.5 (IQR 2 - 10) on the numerical rating scale. Details of the clinical and demographic features of the cohort are shown in Table 1.

Significant associations were observed between the use of analgesic medication and current pain severity (individuals with greater pain were more likely to be using analgesics: median difference in pain intensity rating on the 11-point NRS (95% CI of difference in medians) 4 (0 - 5)), and between the use of analgesic medication and the latest CD4 T-cell count (individuals with lower CD4 T-cell counts were more likely to be using analgesics: median difference in CD4 T-cell count (95% CI of difference in medians) –138 (–315 21) cells/µL). Multivariate logistic regression models incorporating combinations of pain intensity, CD4 T-cell count and number of pain sites (p<0.1 on univariate analysis) were not significantly better than a model only incorporating pain intensity as an independent variable (analysis of deviance p>0.05). CD4 T-cell count was not associated with pain intensity (Spearman’s rho –0.08, p=0.35).

Pharmacological treatments prescribed to the patients are shown in Table 2. Overall, 64% of patients were using at least one analgesic medication, including three-quarters of those with severe pain, half of those with moderate pain and one-quarter of those who described their current pain as mild. Consistent with national guidelines, amitriptyline was the most commonly used agent, either alone or in combination therapy.

In patients receiving analgesic therapy, there was no association between drug dosage prescribed and pain intensity for amitriptyline (χ2=1.88, p=0.18), or for para­ cetamol and codeine (χ2=0.01, p=0.94).

During the patient interview, we also collected information on over-the-counter medications participants were taking. The majority of patients were only taking those medications provided at the pharmacy, as they could not afford to buy their own

Table 1. Demographic and clinical characteristics of the cohort and univariate associations with use of any analgesic medication for HIV-SN

Entire cohort (N=130)

Participants prescribed analgesics (N=83)

Participants not prescribed analgesics (N=47)

p-value

Female gender, n (%)

93 (71.5)

57 (68.7)

36 (76.6)

0.42

Age (years), mean (SD)

45.7 (9.4)

45.4 (9.3)

46.2 (9.8)

0.63

CD4 T-cell count (cells/ µL), median (IQR)

409 (34 - 1 606)

369 (34 - 1 092)

507 (63 - 1 606)

0.04

Formal education (years), median (IQR)

6 (0 - 8)

6 (0 - 8)

6 (0 - 8)

0.94

Current TB infection, n (%)

8 (6.2)

6 (7.2)

2 (4.3)

0.71

Treatment regimen, n (%)

0.26

TDF based

81 (62.3)

52 (62.7)

29 (61.7)

AZT based

25 (19.2)

17 (20.5)

8 (17.0)

D4T based

17 (13.1)

12 (14.5)

5 (10.6)

Other

7 (5.4)

2 (2.4)

5 (10.6)

7.5 (2 - 10)

10 (2 - 10)

6 (2 - 10)

Pain intensity, median (IQR) Pain intensity rating, n (%)

0.01 <0.01*

Mild

12 (9.2)

3 (3.6)

9 (19.1)

Moderate

34 (26.2)

18 (21.7)

16 (34.0)

Severe

84 (64.6)

62 (74.7)

22 (46.8)

3 (1 - 9)

3 (1 - 9)

3 (1 - 7)

0.06

Paraesthesiae

114 (87.7)

79 (95.2)

35 (74.5)

0.001

Numbness

116 (89.2)

77 (92.8)

39 (83.0)

0.13

Number of pain sites, median (IQR) Prevalence of other symptoms, n (%)

TDF = tenofovir; AZT = zidovudine; D4T = stavudine. *Post-hoc analysis identified a greater proportion of patients with severe pain in the group receiving analgesics.

Table 2. Pharmacological medications prescribed for patients with painful HIV-SN Analgesic (mg)

n (%)

Median daily dose (mg) (min - max)*

Ami 25, monotherapy

23 (27.7)

25 (25 - 50)

Ami 25 + para 320 + cod 8

33 (39.8)

Ami 25 (25 - 75)/para 2 560 (1 920 - 2 560)/cod 64 (48 - 64)

Ami 25 + ibu 200

3 (3.6)

Ami 25 (25 - 25)/ibu 200 (200 - 200)

Ami 25 + para 320 + cod 8 + ibu 200

4 (4.8)

Ami 37.5 (25 - 75)/para 2 560 (2 560 - 2 560)/cod 64 (64 - 64)/ibu 200 (200 - 400)

Ami 25 + para 320 + cod 8 + carb 200

6 (7.2)

Ami 25 (25 - 50)/para 2 240 (1 920 - 2 560)/cod 56 (48 - 64)/carb 100 (100 - 200)

Para 320 + cod 8 only

14 (16.9)

Para 1 920 (1 920 - 2 560)/cod 48 (48 - 64)

Ami = amitriptyline; para = paracetamol; cod = codeine; ibu = ibuprofen; carb = carbamazepine. *Dose frequency was prescribed according to recommended dosing strategies for individual drugs in all cases.

medications. Of the few patients who did so, none purchased pain medications.

Discussion

We provide the first report of analgesic use for HIV-SN pain in which HIV-SN was defined using standard, objective criteria. Ninety per cent of patients in our sample had moderate or

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severe pain, despite almost two-thirds being on some form of analgesic therapy. In most cases the tricyclic antidepressant amitriptyline was included in the analgesic regimen, consistent with national guidelines.[6,7] We found significant associations, of moderate size, between pain intensity and analgesic therapy as well as between CD4 T-cell count and analgesic

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therapy; subjects with more severe pain and those with lower CD4 T-cell counts were more likely to be receiving treatment. However, greater pain was not associated with analgesic dose used, and lower CD4 T-cell counts were not associated with pain intensity. Factors previously identified as predicting analgesic treatment in HIV-positive individuals (age, gender, level of education) were not associated with analgesic use in this study.[17] Our finding that 36% of patients with HIV-SN pain were not receiving any analgesic therapy is worrying. Nevertheless, analgesic use in this cohort was high compared with the very low rates we and others have reported in similar ambulatory HIV-positive populations with pain of similar intensity, but of any origin.[18-21] Clinicians may be more aware of HIV-SN as a common cause of pain, and therefore be more likely to recognise and treat HIV-SN pain than other pain conditions. Although more than a third of patients with HIV-SN pain in this cohort were not receiving analgesics, we cannot exclude the possibility that they may previously have used agents such as amitriptyline and ceased these owing to poor tolerability or efficacy. Indeed, the high levels of pain reported by many patients using amitriptyline in this cohort highlight the need for more effective treatments for HIV-SN pain,[12] or greater awareness of optimal dosing of amitriptyline for the management of neuropathic pain.

Our finding that use of some form of analgesic agent increases with pain severity may indicate that physicians believe that regular analgesics are required only for HIV-SN pain of greater severity, despite evidence that health-related quality of life is reduced across all levels of pain in this condition.[2] However, it is also possible that patients do not report mild pain. In addition, our finding that analgesic use increases with lower initial CD4 T-cell count may indicate that patients perceive sensory neuropathy to be a complication of ART, and more of those patients with severe pain and severe paraesthesiae (median 8, IQR 2 - 10) may therefore not take their ART reliably, possibly thinking that they are being harmed by these drugs, and therefore have a poor CD4 T-cell count.

Amitriptyline was prescribed to most patients receiving analgesia in this cohort. While there is no evidence that amitriptyline is more effective than placebo for painful HIV-SN,[11-13] its proven efficacy in other types of neuropathic pain[22] prompted an expert panel to recommend it as a first-line option for HIV-SN pain in SA.[7] These patients were therefore receiving a recommended treatment, albeit at a relatively low dose (25 - 50 mg/d).[7] Amitriptyline was commonly used in combination with codeine and paracetamol. Neither of these drugs have proven efficacy in neuropathic pain,[22] but their use may reflect concurrent sources of pain (common in HIV) that may be responsive to standard opioid and non-opioid analgesics and non-steroidal antiinflammatory agents.[23] Use only of agents with no evidence of efficacy for neuropathic pain by 16% of our cohort may reflect poor knowledge of neuropathic pain management on the part of clinicians, inadequate efficacy and/or tolerability of available neuropathic pain treatments, or treatment of concurrent nociceptive pains while the neuropathic pain went unrecognised. This finding highlights the need for both better analgesic options for HIV-SN pain treatment and ongoing training and support of clinicians managing this difficult condition.

Six patients (7%) were prescribed amitriptyline together with the anticonvulsant carbamazepine, largely owing to the preference of a single clinician. Carbamazepine decreases levels of amitriptyline and paracetamol by affecting hepatic/intestinal enzyme CYP3A4 metabolism.[24] There is also potential for increased sedation in patients taking codeine and amitriptyline concurrently, but at the doses of codeine prescribed, this interaction was probably not significant.[25]

Study limitations

Our study has a number of limitations. The modest sample size limits our ability to understand factors associated with use of less common

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analgesic choices. The cross-sectional nature of this work means that we are unable to comment on patientsâ&#x20AC;&#x2122; previous level of HIV-SN pain or prior use of analgesics for this condition. We therefore cannot comment on the level of pain relief achieved by the treatments used.

Patients also express preferences for analgesic therapy, with some not wanting certain analgesics because they fear side-effects, which may affect treatment choices. Moreover, we do not have data on comorbid diseases for which analgesics may have been prescribed, including depression (amitriptyline) and seizure disorders (carbamazepine), although we would have expected higher doses to have been used in these situations.[26,27]

Conclusion

We found that most patients with HIV-SN pain in a large SA HIV care clinic were receiving analgesics consistent with the recommendation in the national guidelines. However, about one in six patients were only receiving agents with no demonstrated efficacy for neuropathic pain. Furthermore, despite the observed high level of treatment coverage, the majority of patients described their current level of HIV-SN pain as moderate or severe, highlighting the urgent need for better therapies for this common and disabling condition.

Acknowledgements. The authors thank the patients and staff of the Greenhouse Pharmacy at Chris Hani Baragwanath Hospital, and Florence Mtsweni for acting as an interpreter. We thank Mr Rashid Adam of the Greenhouse Pharmacy for his assistance. The authors gratefully acknowledge the contributions of the Victorian Operational Infrastructure Support Program received by the Burnet Institute (CLC) and Hillel Friedland Trust for Fellowship funding (ALW).

Funding. Funding was received from the Medical Faculty Research Endowment Fund of the University of the Witwatersrand (PP), the Medical Research Council of South Africa (PRK), the National Research Foundation Rated Researchers Programme (PRK), the Victorian Operational Infrastructure Support Program received by the Burnet Institute (CLC), and a Developed-Developing Countries Collaborative Research Grant of the International Association for the Study of Pain (CLC, PRK).

References 1. Kamerman PR, Wadley AL, Cherry CL. HIV-associated sensory neuropathy: Risk factors and genetics.

Curr Pain Headache Rep 2012;16(3):226-236. [http://dx.doi.org/10.1007/s11916-012-0257-z] 2. Ellis RJ, Rosario D, Clifford DB, et al. Continued high prevalence and adverse clinical impact of human immunodeficiency virus-associated sensory neuropathy in the era of combination antiretroviral therapy: The CHARTER Study. Arch Neurol 2010;67(5):552-558. [http://dx.doi.org/10.1001/ archneurol.2010.76] 3. Cherry CL, Kamerman P, Bennet DLH, Rice AS. HIV-associated sensory neuropathy: Still a problem in the post-stavudine era? Future Virol 2012;7(9)849-854. [http://dx.doi.org/10.2217/fvl.12.77] 4. Phillips TJ, Cherry CL, Cox S, Marshall SJ, Rice AS. Pharmacological treatment of painful HIVassociated sensory neuropathy: A systematic review and meta-analysis of randomised controlled trials.

PLoS One 2010;5:e14433. [http://dx.doi.org/10.1371/journal.pone.0014433] 5. World Health Organization. Palliative care: Symptom management and end-of-life care. 2004. http:// www.who.int/hiv/pub/imai/genericpalliativecare082004.pdf (accessed 5 August 2014).

6. South African National Department of Health. Standard treatment guidelines and national essential medicines list of South Africa. http://www.kznhealth.gov.za/pharmacy/edladult_2012.pdf (accessed 4 August 2014).

7. Chetty S, Baalbergen E, Bhigjee AI, et al. Clinical practice guidelines for management of neuropathic pain: Expert panel recommendations for South Africa. S Afr Med J 2012;102(5):312-325.

8. World Health Organization. Standard treatment guidelines and national essential medicines list of Iran. 2009. http://www.who.int/selection_medicines/country_lists/irn_EDL_2009.pdf (accessed 4 August 2014).

9. World Health Organization. Standard treatment guidelines and national essential medicines list of Tanzania. 2013. http://www.who.int/medicinedocs/en/d/Js20988en/ (accessed 4 August 2014).

10. World Health Organization. Standard treatment guidelines and national essential medicines list of Zimbabwe. 2006. http://www.who.int/selection_medicines/country_lists/EDLIZ06.pdf?ua=1 (accessed 4 August 2014).

11. Shlay JC, Chaloner K, Max MB, et al. Acupuncture and amitriptyline for pain due to HIV-related peripheral neuropathy: A randomized controlled trial. Terry Beirn Community Programs for Clinical Research on AIDS. JAMA 1998;280(18):1590-1595. [http://dx.doi.org/10.1001/jama.280.18.1590] 12. Dinat N, Marinda E, Moch S, et al. Randomized, double-blind, crossover trial of amitriptyline for analgesia in painful HIV-associated sensory neuropathy. PLoS One 2015;10(5):e0126297. [http:// dx.doi.org/10.1371/journal.pone.0126297] 13. Kieburtz K, Simpson D, Yiannoutsos C, et al. A randomized trial of amitriptyline and mexiletine for painful neuropathy in HIV infection. AIDS Clinical Trial Group 242 Protocol Team. Neurology 1998;51(6):1682-1688. [http://dx.doi.org/10.1212/WNL.51.6.1682]

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14. Beadles WI, Jahn A, Weigel R, Clutterbuck D. Peripheral neuropathy in HIV-positive patients at an antiretroviral clinic in Lilongwe, Malawi. Trop Doct 2009;39(2):78-80. [http://dx.doi.org/10.1258/ td.2008.080213] 15. Cherry CL, Wesselingh SL, Lal L, McArthur JC. Evaluation of a clinical screening tool for HIVassociated sensory neuropathies. Neurology 2005;65(11):1778-1781. [http://dx.doi.org/10.1212/01. wnl.0000187119.33075.41] 16. Wadley AL, Cherry CL, Price P, Kamerman PR. HIV neuropathy risk factors and symptoms characterisation in stavudine-exposed South Africans. J Pain Symptom Manage 2011;41(4):700-706. [http://dx.doi.org/10.1016/j.jpainsymman.2010.07.006] 17. Breitbart W, Rosenfeld BD, Passik SD, et al. The undertreatment of pain in ambulatory AIDS patients.

Pain 1996;65(2-3):243-249. [http://dx.doi.org/10.1016/0304-3959(95)00217-0] 18. Maree JE, Dreyer Wright SC, Makua MR. The management of HIV- and AIDS-related pain in a primary health clinic in Tshwane, South Africa. Pain Manag Nurs 2013;14(2):94-101. [http://dx.doi. org/10.1016/j.pmn.2010.10.037] 19. Narasimooloo C, Naidoo S, Gaede B. Adequacy of pain management in HIV-positive patients. S Afr Fam Pract 2011;53(1):71-76. [http://dx.doi.org/10.1080/20786204.2011.10874063] 20. Mphahlele NR, Mitchell D, Kamerman PR. Pain in ambulatory HIV-positive South Africans. Eur J Pain 2012;16(3):447-458. [http://dx.doi.org/10.1002/j.1532-2149.2011.00031.x] 21. Mphahlele N, Kamerman PR, Mitchell D. Progression of pain in ambulatory HIV-positive South Africans. Pain Manag Nurs 2015;16(1):e1-e8 [http://dx.doi.org/10.1016/j.pmn.2014.05.013]

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22. Finnerup NB, Sindrup SH, Jensen TS. The evidence for pharmacological treatment of neuropathic pain. Pain 2010;150(3):573-581. [http://dx.doi.org/10.1016/j.pain.2010.06.019] 23. Kamerman P, Mitchell D. Current perspectives on HIV-related pain and its management: Insights from Sub-Saharan Africa. Pain Manag 2011;1(6):587-596. [http://dx.doi.org/10.2217/pmt.11.65] 24. Seitz CS, Pfeuffer P, Raith P, et al. Anticonvulsant hypersensitivity syndrome: Cross-reactivity with tricyclic antidepressant agents. Ann Allergy Asthma Immunol 2006;97(5):698-702. [http://dx.doi. org/10.1016/S1081-1206(10)61103-9] 25. American Cancer Society. Guide to cancer drugs (Codeine). 2014. http://www.cancer.org/treatment/ treatmentsandsideeffects/guidetocancerdrugs/codeine (accessed 6 August 2014).

26. Mattson RH, Cramer JA, Collins JF, et al. A comparison of valproate with carbamazepine for the treatment of complex partial seizures and secondarily generalised tonic-clonic seizures in adults. N Engl J Med 1992;327(11):765-771. [http://dx.doi.org/10.1056/NEJM199209103271104] 27. American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 3rd ed. Arlington, VA: American Psychiatric Association, 2010. http:// psychiatryonline.org/data/books/prac/PG_Depression3rdEd.pdf (accessed 5 August 2014).

Accepted 4 July 2015.

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Bone marrow aspirate microscopy v. bone marrow trephine biopsy microscopy for detection of Mycobacterium tuberculosis infection Q Sedick, MB ChB, FCPath (Haem), MMed (Haem); J Vaughan, MB ChB, FCPath (Haem), MMed (Haem); T Pheeha, MB ChB, FCPath (Haem), MMed (Haem); N A Alli, MB ChB, FCPath (Haem) Haematopathology Department, National Health Laboratory Service, Chris Hani Baragwanath Hospital, Johannesburg, South Africa Corresponding author: Q Sedick (docqanita@gmail.com)

Background. Tuberculosis (TB) remains a global health problem. According to the 2013 Global Report on Tuberculosis, 8.6 million people developed TB in 2012 and 1.3 million died from the disease. An estimated 13% of people who developed TB in 2012 were HIV-positive, and 75% of these lived in Africa. While pulmonary TB is the commonest form of Mycobacterium tuberculosis infection, extrapulmonary TB is increasingly being detected in HIV-positive patients. Definitive diagnosis of disseminated TB is a challenge owing to atypical presentations and diagnostic difficulties (negative chest radiograph and sputum microscopy and culture). A rapid diagnosis of disseminated TB is desirable, as early initiation of treatment can reduce mortality. Although TB culture is the gold standard for diagnosis of TB, it has a long turnaround time (up to 6 weeks).

Objectives. To identify a potentially faster and more effective diagnostic strategy for disseminated TB. Methods. A retrospective 18-month review, conducted at a tertiary hospital, comparing histological findings of an auramine O-stained bone marrow aspiration (BMA) smear and a bone marrow trephine (BMT) biopsy specimen with the gold standard of TB culture.

Results. Microscopic examination of BMA smears and BMT biopsy specimens offers a rapid diagnostic strategy, with results available on the same day for the former and within 4 days for the latter. BMT histological examination had a significantly higher detection rate than BMA auramine O staining compared with TB culture.

Conclusion. We recommend that BMT biopsies remain an essential part of the diagnostic work-up for disseminated TB. S Afr Med J 2015;105(9):773-775. DOI:10.7196/SAMJnew.8171

Tuberculosis (TB) remains a significant global health problem. According to the 2013 Global Tuberculosis Report, an estimated 8.6 million people developed TB in 2012 and 1.3 million died from the disease.[1] An estimated 1.1 million (13%) of the 8.6 million people who developed TB in 2012 were HIV-positive, 75% of whom were from Africa. In 2012, approximately 450 000 people developed multidrug-resistant tuberculosis, of whom an estimated 170 000 died. The majority of cases worldwide in 2012 were in South-East Asia (29%), Africa (19%) and the Western Pacific region (19%).[1] The TB incidence rate in South Africa (SA) is among the highest in the world, currently exceeding 1 000 cases per 100 000 people.[1,2] The predominant age group afflicted with TB is the second and third decades, with devastating socioeconomic implications.

The diagnosis of TB currently includes a detailed medical history, clinical examination, and radiological, microbiological, immunological, molecular and histological investigations. Culture-based detection of Mycobacterium tuberculosis (MTB) in sputa has remained the gold standard of diagnosis until recently, and sputum microscopy for acidfast bacilli (AFB) is the most commonly employed method of screening in the SA setting. However, culture of MTB takes an average of 2 or more weeks, and only 44% of all new cases (15 - 20% of children) are actually identified through the presence of AFB on sputum smears.[3] In the setting of TB and HIV co-infection, the sensitivity of sputum smear microscopy is even lower (~35%).[3] The high false-negative rate causes delays in diagnosis and therapeutic intervention, and may lead to further spread of the disease.

Definitive diagnosis of disseminated TB poses a challenge owing to atypical clinical presentations, and often a negative chest radiograph

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and negative findings on sputum microscopy and culture. This necessitates invasive procedures such as bone marrow aspiration (BMA), bone marrow trephine (BMT) biopsy, soft-tissue biopsy, lumbar puncture, etc.

TB culture is considered to be the gold standard for definitive diagnosis, but the turnaround time is undesirably long (up to 6 weeks), which has an adverse impact on infection control.[3] Microscopic examination of the BMA smears and BMT biopsy specimens offers a far more rapid diagnostic strategy, where results can be available on the same day for the former and within 4 days for the latter. The diagnosis of TB in the bone marrow is made microscopically by the identification of granulomas and/or AFB

by Ziehl-Neehlsen (ZN) staining in the BMT biopsy sections. ZN staining is not currently routinely performed on BMA samples owing to its low sensitivity. However, auramine O staining is reportedly more sensitive than ZN in sputum,[4] and may offer a higher yield in BMA samples as well.

Objective

To compare the diagnostic yield for TB between the BMA smear and BMT biopsy specimen against TB culture as the gold standard, and thereby identify a potentially faster and more effective diagnostic strategy for a resource-poor setting.

Methods

A retrospective 18-month review (January 2009 - June 2010) of bone marrow MTB test results was conducted at Chris Hani Baragwanath Hospital, a tertiary level hospital in Johannesburg, SA. The study was approved by the Human Research Ethics Committee

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of the University of the Witwatersrand (ethics number: M090688).

The study population comprised 410 adult and paediatric patients who had a BMA smear and BMT biopsy specimen submitted for analysis to exclude MTB infection. Clinical data were obtained from the bone marrow request forms completed by clinicians, and results were retrieved from the laboratory information system (DisaLab version 04.16.04.373). BMA slides from BMA samples submitted to the National Health Laboratory Service (NHLS) for TB testing were stained with auramine O. The results of the latter were compared with those of BMT biopsy specimen microscopy and BMA TB culture.

BMA smears were stained with Giemsa for conventional microscopy and with auramine O for detection of AFB using fluorescent microscopy. BMT sections were stained with haemotoxylin and eosin for conventional microscopy. The presence of granulomas necessitated further staining for detection of infective organisms at the discretion of the reporting pathologist. TB culture was done on BMA samples inoculated into special Myco-Flytic culture vials during the BMA procedure. These were then incubated in the Bactec 9240 automated system and inspected weekly for 6 weeks.

The diagnosis of bone marrow TB was made on the basis of one or more of the following criteria: (i) positive TB culture of bone marrow; (ii) detection of granulomas and/or AFB on the BMT biopsy specimen; and (iii) detection of AFB on the BMA sample using the auromine-O staining method.

Exclusion criteria were: (i) samples not inclusive of all test methods, viz. BMA auramine O staining, BMT biopsy specimen staining and TB culture; and (ii) suboptimal quality samples.

Statistical analysis

Statistical analysis was performed using STATISTICA software, version 12.0 (Stat Soft (Pty) Ltd). Data are presented as medians (interquartile range (IQR)) and proportions, as appropriate.

Sensitivity and specificity were calculated for each test method using TB culture as the gold standard. The Mann-Whitney U-test was used to compare continuous variables of interest. The level of statistical significance was taken as p≤0.05.

Table 1. Indications for bone marrow examination Indications for bone marrow examination

Requests, n (%)

Peripheral cytopenias

187 (45.6)

Haematological malignancies (lymphoma and leukaemia)

158 (38.5)

Suspected disseminated TB

65 (15.8)

Table 2. Characteristics of the cohort Total sample size, N

410

Adults (>18 years), n

355

Paediatric patients (<18 years), n

55

HIV-positive patients in cohort, n/N (%)*

251/330 (76.1) 123 (30.0)

Patients diagnosed with TB† Patients with peripheral cytopenia/s, n/N (%)

71/123 (57.7)

Patients with clinical suspicion of disseminated TB, n/N (%)‡

40/123 (32.5)

Patients with suspected haematological malignancies, n/N (%)‡

12/123 (9.8)

‡

*Of patients tested for HIV. † According to the inclusion and exclusion criteria listed under ‘Methods’. ‡ Of the total number of TB-positive patients.

Table 3. Sensitivity and specificity of method against TB culture as reference method Test

Sensitivity, %

Specificity, %

TB culture

100

100

BMT granuloma detection

56

82

ZN staining for AFB

46

94

BMA auramine O staining

9.3

99

Results

Table 4. Relationship between TB culture (gold standard) and other methods (BMA auramine O stain, BMT ZN stain and BMT granulomas)

Results from a total of 410 patient samples were analysed (Table 1).

Diagnostic method positive

Characteristics of the cohort

Characteristics of patients diagnosed with tuberculosis

Out of the 410 patient samples, 123 were positive for TB. Of the samples in which a BMA/BMT biopsy was performed specifically to investigate for TB, 32.5% were positive for TB. The remainder of the patients with TB-positive samples had cytopenias (57.7%) and haematological malignancies (0.95%) (Table 2).

Of the 123 samples that were positive for TB, 7 (5.7%) were diagnosed on BMA auramine O staining, 97 (78.9%) had granulomas on the BMT biopsy specimen, and 63 (51.2%) were positive on TB culture. ZN staining was performed in only 90 cases (73.2%), and was found to be positive for AFB in 38 (42.2%). Sensitivity and specificity results for the various methods are set out in Table 3.

The organism identified on TB culture was MTB in 58 (92%) of cases, and M. avium intracellulare complex in the remaining 5. All the BMA auramine O-positive cases with a positive TB culture were positive for MTB. Of the 347 patients with samples negative for TB culture (84.6%), 83 (23.9%) had TB diagnosed by examination of BMA/BMT biopsy

774

TB culture negative, N=347 (84.6%), n (%)

Auramine O stain (BMA) positive

1 (0.3)

Granuloma (BMT) positive

61 (17.6)

ZN stain positive

21 (6.1)

Diagnostic method negative

TB culture positive, N=63 (15.4%), n (%)

Auramine O stain (BMA) negative

56 (88.9)

Granuloma (BMT) negative

28 (44.4)

ZN stain negative

20 (31.7)

specimens. This is an interesting finding with respect to TB culture being the gold standard. In contrast, of the 63 patients with positive TB culture results, 56 (88.9%) had a negative BMA auramine O stain, 28 (44.4%) had no granulomas on the BMT biopsy specimen, and 20 (of an available 37) (54.1%) were negative for AFB on ZN staining (Table 4).

In order to assess the value added by each of the four methods, test positivity rates in isolation were calculated, viz. TB culture n=24

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Table 5. TB detection rates in HIV-positive patients Tested for TB, N

Positive for TB, n (%)

CD4 count (cells/µL) (n=99), median (IQR)

HIV-positive patients tested for TB

251

113 (45.0)

33 (11 - 95)

TB culture method

113

58 (51.3)

27 (9 - 82)

BMT granuloma detection

113

88 (77.9)

33 (14 - 81)

ZN staining for AFB (BMT)

83

36 (43.4)

28 (6 - 76)

BMA auramine O staining

113

7 (6.2)

7 (4 - 16)

(38.1%), BMT granulomas n=38 (39.2%), BMT ZN stain n=0 (0%), BMA auramine O stain n=0 (0%).

Characteristics of TB patients with HIV

Of the 330 patients tested for HIV, 251 (76.1%) were HIV-positive. The number of dual HIV- and TB-positive patients was 113/251 (45.0%). The sensitivity of TB detection in HIV-positive patients was best with BMT granuloma detection (56.9%) when compared with ZN staining (48.5%) and BMA auramine O staining (10.3%) against the gold-standard TB culture. In HIV-positive patients, the median CD4 count was significantly lower in patients with TB than in those without TB: 33 cells/µL (range 11 - 95) and 117 cells/µL (range 41 - 221), respectively (p<0.0001).

Furthermore, the median CD4 count in patients with positive BMA auramine O staining was significantly lower (p<0.0001) than that in patients diagnosed with TB by any other modality, viz. 7 cells/µL (range 4 - 16) and 35 cells/µL (range 15 - 98), respectively (p=0.022) (Table 5).

Discussion

TB remains a significant health problem, the detection of which requires prompt diagnosis. TB culture-based algorithms for diagnosis are relatively expensive[5] and have an unacceptably long turnaround time. Current rapid methods quoted in the literature include rapid liquid culture systems,[3] nucleic acid amplification tests[6] and the microscopic observation suscepti­ bility assay.[7] Studies have also recently shown that in HIV-positive patients with CD4 cell counts <100 cells/µL, the TB lipoarabinomannan urine test can detect over half of culture-positive TB patients in less than 30 minutes.[8] In the SA setting, the GeneXpert MTB/RIF assay has become widely available, and reportedly performs better than smear microscopy where TB and HIV are both highly endemic.[9] However, these tests are generally expensive and

require specialised equipment and expertise, and to date none has been validated on BMA and BMT biopsy samples. In this study, we evaluated the role of BMT biopsy specimen examination and BMA auramine O staining in reducing the time taken to establish a diagnosis of disseminated TB, using TB culture as the gold standard.

Over 95% of the patients with disseminated TB were HIV-positive, with a median CD4 count of 33 cells/µL. Approximately a third of these patients had a BMA/BMT biopsy performed to investigate for possible TB, and over half had unexplained cytopenias.

The sensitivity for detecting TB was highest for histological examination of BMT biopsy specimens (56%), followed by ZN staining (46%), and least sensitive for auramine O staining of BMA samples (9.3%).

Interestingly, the median CD4 counts in HIV-positive patients with TB diagnosed by auramine O staining of BMA samples were significantly lower than those in patients diagnosed with the other test methods, possibly reflecting a higher TB bacillary load as a consequence of immune compromise.

Although the BMA auramine O method is rapid and showed excellent specificity, its sensitivity is too low for it to be advocated for routine practice. The reasons for the poor yield using this method are likely to be multifactorial, including poor quality of BMA samples, reduced macrophage activity on the BMA smear and overall poor sensitivity of the test method.

The utility of BMT biopsy specimen examination in the setting of HIV/ TB co-infected patients was reported on previously by Akpek et al.,[10] who showed that although the diagnostic sensitivity of bone marrow cultures was equal to that of blood cultures, histological examination of bone marrow resulted in rapid identification of nearly one-third of infected patients who underwent bone marrow examination, and that infection was identified in some patients who were culture-negative. In our study, examination of BMT biopsy specimens proved highly valuable; approximately half

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of the cases of TB were diagnosed micro­ scopically without a positive TB culture, and the diagnosis was expedited in over 60% of patients in whom the TB culture was positive. Nevertheless, over one-third of patients with a positive TB culture had no bone marrow morphological abnormalities, highlighting the potential utility of mole­ cular techniques in this setting.

Conclusion

We found that histological examination of BMT biopsy specimens had a significantly higher detection rate than auramine O staining of BMA samples, compared with the gold-standard TB culture in our setting, where there is a high HIV burden. We recommend that BMT biopsies remain an essential part of the diagnostic work-up for disseminated TB. However, as microscopic examination failed (p<0.0001) to detect a substantial proportion of cases in whom TB culture was positive, other rapid molecular techniques such as GeneXpert are required.

Acknowledgement. The authors thank the Chris Hani Baragwanath Hospital NHLS laboratory staff.

References 1. Zumla A, George A, Sharma V, Herbert N, Baroness Masham of Ilton. WHO’s 2013 global report on tuberculosis: Successes, threats, and opportunities. Lancet 2013;382(9907):1765-1767. [http://dx.doi.org/10.1016/S0140-6736(13)62078-4] 2. World Health Organization (WHO). Global Tuberculosis Report 2013. Geneva: WHO, 23 October 2013. http://apps. who.int/iris/bitstream/10665/91355/1/9789241564656_eng.pdf (accessed 10 August 2015).

3. Lange C, Mori T. Advances in the diagnosis of tuberculosis.

Respirology 2010;15(2):220-240. [http://onlinelibrary.wiley.com/ doi/10.1111/j.1440-1843.2009.01692.x/abstract ] 4. Hooja S, Pal N, Malhotra B, Goyal S, Kumar V, Vyas L. Comparison of Ziehl Neelsen & auramine O staining methods on direct and concentrated smears in clinical specimens. Indian J Tuberc 2011;58(2):72-76. [http://tbassnindia.org/forms/ IJT_12.pdf] 5. Yakhelef N, Audibert M, Varaine F, et al. Is introducing rapid culture into the diagnostic algorithm of smearnegative tuberculosis cost-effective? Int J Tuberc Lung Dis 2014;18(5):541-546. [http://dx.doi.org/10.5588/ijtld.13.0630] 6. Adelman MW, Kurbatova E, Wang YF, et al. Cost analysis of a nucleic acid amplification test in the diagnosis of pulmonary tuberculosis at an urban hospital with a high prevalence of TB/ HIV. PloS One 2014;9(7):e100649. [http://dx.doi.org/10.1371/ journal.pone.0100649] 7. Solomon S, Balakrishnan P, Vignesh R, et al. A rapid and lowcost microscopic observation drug susceptibility assay for detecting TB and MDR-TB among individuals infected by HIV in South India. Indian J Med Microbiol 2013;31(2):130-137. [http://dx.doi.org/10.4103/0255-0857.115225] 8. Lawn SD, Kerkhoff AD, Burton R, Meintjes G. Underestimation of the incremental diagnostic yield of HIV-associated tuberculosis in studies of the Determine TB-LAM Ag urine assay. AIDS 2014;28(12):1846-1848. [http://dx.doi.org/10.1097/ QAD.0000000000000305] 9. O’Grady J, Bates M, Chilukutu L, et al. Evaluation of the Xpert MTB/RIF assay at a tertiary care referral hospital in a setting where tuberculosis and HIV infection are highly endemic. Clin Infect Dis 2012;55(9):1171-1178. [http://dx.doi.org/10.1093/ cid/cis631] 10. Akpek G, Lee SM, Gagnon DR, Cooley TP, Wright DG. Bone marrow aspiration, biopsy, and culture in the evaluation of HIVinfected patients for invasive mycobacteria and histoplasma infections. Am J Hematol 2001;67(2):100-106. [http://dx.doi. org/10.1002/ajh.1086]

Accepted 30 June 2015.

RESEARCH

Codeine misuse and dependence in South Africa – learning from substance abuse treatment admissions S Dada,1 MPH; N Harker Burnhams,1,2 PhD; M C van Hout,3 PhD, C D H Parry,1,4 PhD Alcohol, Tobacco and Other Drug Research Unit, South African Medical Research Council, Cape Town, South Africa S chool of Public Health and Family Medicine, Faculty of Health Sciences, University of Cape Town, South Africa 3 School of Health Sciences, Waterford Institute of Technology, Ireland 4 Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Cape Town, South Africa 1 2

Corresponding author: C Parry (cparry@mrc.ac.za)

Background. Misuse of prescription and over-the-counter codeine-containing products is a global public health issue.

Objectives. To investigate the extent of treatment demand related to the misuse of codeine or codeine dependence in South Africa (SA) and the profile of patients seeking treatment, so as to understand the nature and extent of the problem.

Method. Data were collected from centres participating in the South African Community Epidemiology Network on Drug Use in 2014. A total of 17 260 admissions were recorded.

Results. There were 435 recorded treatment admissions for codeine misuse or dependence as a primary or secondary substance of abuse (2.5% of all admissions). Of treatment admissions, 137 (0.8%) involved codeine as the primary substance of abuse; 74.9% of patients were males, with an even spread across population groups. Ages ranged from 11 to 70 years, with the highest proportion aged 20 - 29 years; >40% were referred by self, family and/or friends, and 26.7% by health professionals; and 36.8% had received treatment previously. The majority reported misuse of tablets/capsules, with 17.6% reporting misuse of syrups. Oral use comprised 96.6% and daily use 63.1%.

Conclusions. Data from treatment admissions related to codeine misuse and dependence are informative, but provide an incomplete picture of the nature and extent of codeine-related problems in SA. Other data sources must be considered before further regulatory/policy changes regarding codeine are implemented.

S Afr Med J 2015;105(9):776-779. DOI:10.7196/SAMJnew.8172

The global misuse of prescription or over-the-counter (OTC) pharmaceutical opioid analgesics, including those containing codeine, is an increasing public health issue.[1] Misuse is ‘the use of a medicine, with or without a doctor’s prescription, clearly outside of accepted medical practice or guidelines, for recreational purposes or in the framework of self-medication, in greater dosages or for longer periods than were prescribed, in which the risks and problems associated with use outweigh the benefits’.[2] Dependence refers to a diagnosable psychiatric condition.

In response to concerns about the potential misuse of products containing (pseudo)ephedrine, the South African (SA) government up-scheduled products containing these compounds, which now require a doctor’s prescription,[3] despite little evidence that OTC medicines containing these substances were purchased to manufacture methamphetamine. Similarly, in response to concerns about codeine misuse and dependence, some countries such as Australia allow codeine only by prescription. SA is considering introducing regulations to reduce the amount of codeine in a tablet to 10 mg and to up-schedule norcodeine and acetylcodeine.[4] The availability to the public of OTC codeine products has compromised efforts to quantify and address hidden codeine misuse. Codeine misusers vary: some are dependent on codeine, aware of their dependence but using it in response to cravings and avoiding withdrawals; some unknowingly misuse codeine by using it within the recommended limits, but doing so frequently and regularly to treat withdrawal-associated headaches; and some deliberately disobey codeine product instructions for intoxication purposes. Indicators of the prevalence and incidence of this ‘hidden’ form of non-compliant use of habit-forming medicines remain

776

scant and rely on individuals who recognise their addiction and seek help.[5-8] We investigated: (i) the extent of treatment demand related to the misuse of codeine or codeine dependence in SA; and (ii) the profile of patients coming to treatment who are misusing or dependent on codeine as part of the comprehensive, multicountry Codeine Use, Misuse and Dependence (Codemisused) Study funded by the European Union (EU) to inform the design of pharmacy screening and brief interventions, risk management, monitoring and surveillance, continuing professional development training, and the development of specific clinical/community pharmacy treatment protocols.

Methods

The South African Community Epidemiology Network on Drug Use (SACENDU), established in 1996, is a network of researchers, practitioners and policy makers from all nine provinces in SA who meet every 6 months to provide community-level public health surveillance information about alcohol and other drug (AOD)-related trends.[9] All AOD treatment centres are requested to join the network, although participation is voluntary. SACENDU collects data from 66 treatment centres nationally with an estimated 75% national coverage, particularly focusing on the larger treatment centres, including statefunded, private non-profit and private for-profit facilities. Our data were collected from SACENDU participating centres between January and December 2014, and 17 260 admissions were recorded.

For monitoring, a standardised form is completed for each person treated by a given centre during a 6-month period.

This records the source of referral for treatment, biographical information, the type of treatment received (inpatient and/or outpatient), whether the admission was voluntary or not, the

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primary and secondary substances of abuse (including alcohol, OTC and prescription medicines and illicit drugs), the mode(s) of substance use, frequency of use, age of first use, whether treatment had been received before the current episode, who pays for treatment, and whether they had received an HIV test during the past 12 months. The data collection is completed at admission to the treatment centre or shortly thereafter. As a result of our participation in the Codemisused Study on use, misuse or dependence on codeine, specific questions were added to the form at the start of 2014. These focused on the type of codeine medication misused or on which the person is dependent, the frequency of codeine use, non-communicable illnesses from which the person suffers, and use of tobacco products. The instrument is broadly based on that developed by the Pompidou Group in Europe and on the treatment demand indicators used by the European Monitoring Centre for Drugs and Drug Addiction.[10] Data were analysed using IBM SPSS version 22, and mainly comprised descriptive statistics and cross-tabulations.

Ethical approval was provided by the South African Medical Research Council’s Ethics Committee and Stellenbosch University’s Health Research Ethics Committee. The study was a record review, and consent from patients was not required.

Results

In 2014, 435 treatment admissions (2.5% of all admissions) involved codeine misuse or dependence as a primary or secondary sub­ stance of abuse. Only 137 patients (0.8%) had codeine as their primary substance of abuse.

Patient demographics

Of admissions recorded, 124 (29.0% of admissions for codeine misuse/dependence) were in Gauteng Province, 104 (23.9%) in the Eastern Cape and 92 (21.1%) in the Western Cape. Other regions reported fewer admissions: 56 (12.9%) in the central region

(Free State, Northern Cape and North West provinces), 35 (8.0%) in KwaZulu-Natal, and 22 (5.1%) in the northern region (Mpumalanga and Limpopo provinces). Across the six regions/provinces, 14 centres saw two-thirds of all patients reporting misuse/dependence on codeine as either a primary or secondary substance of abuse (Table 1).

Males comprised 74.9% of the patients, of whom all except six were SA citizens. The youngest in treatment for codeine misuse or dependence were 11 years old and the oldest was 70 years old. The age category with the highest proportion of patients was 20 - 29 years, followed by 30 - 39 years (Table 2). Just over 15% were aged ≤19 years, with two aged 11, one aged 13, and five aged 14.

Only 12 were aged ≥60. Almost 60% had a high-school education or higher, and 45.5% reported being currently employed.

Referral sources, sources of payment, current illnesses and tobacco use

While over 40% of patients with codeine as a primary or secondary substance of abuse were referred by self, family and/or friends, 26.7% were referred by health professionals; 36.8% had previously received treatment for codeine misuse or dependence. The primary source of payment was medical aid (43.8%), family (16.4%) and self (13.9%). When asked about current illnesses, 78.9% of patients indicated ‘none’. The most common illness reported was mental health problems (5.3%), followed by blood pressure problems (4.1%).

With regard to tobacco use (more than once a week), over half of the patients reported not using any tobacco, with 4.3% indicating at least weekly cigarette use.

Type of codeine, frequency of use and whether it was the primary substance of abuse

Of the 435 admissions across the SACENDU treatment centres, 14 (3.0%) did not contain detailed information on the specific product containing codeine that was most frequently

Table 1. Listing by region of centres seeing ten or more patients reporting codeine misuse or dependence as a primary or secondary substance of abuse

used. Table 3 shows the codeine products most frequently reported as being misused.

Together they comprise 80.7% of the medications containing codeine listed. Most of the codeine products reported were in tablet/capsule form, but 17.6% (n=74) were syrups. Most included paracetamol, and many also included caffeine.

The codeine was most frequently taken through swallowing (96.6%), with 2.5% of patients snorting/sniffing, 0.7% smoking and 0.2% swallowing/snorting. Most patients (63.1%) reported daily use of products containing codeine, but 14.3% reported using 2 - 6 days per week and 11.4% once per week or less often; 11.2% reported not having used in the past month. Of the patients, 31.7% had an OTC or prescription medication as their primary drug of abuse (Table 4) and 68.3% reported other substances as their primary drug of abuse, mainly alcohol, cannabis and heroin.

Discussion

In treatment centres participating in SACENDU, fewer than 1% of persons had codeine as their primary substance of abuse, similar to findings in centres participating in the National Drug Treatment Moni­ toring System (NDTMS) in the UK in 2012/13 (1.2%) and in the National Drug Treatment Reporting System (NDTRS) in Ireland between 2008 and 2012 (0.8%).[11] Considering codeine as a primary or secon­ dary substance of abuse, the figure rises to 2.5% in the 2014 SA data, again similar to the NDTMS (2.1%) and NDTRS (1.9%).[11] These percentages are low compared with alcohol, cannabis, methamphetamine and other substances of abuse in SA, but because of the large numbers who receive treatment, many persons in specialist substance abuse treatment centres misuse or are dependent on codeine: 435 in SA, 1 548 in Ireland and 4 065 in the UK.[11] However, many people who misuse or are dependent on codeine do not seek help from specialist substance abuse treatment centres, instead consulting general practitioners or Table 2. Codeine misuse/dependence by age category

Province/region

Treatment centres seeing ≥10 patients, n centres

Range across centres treating ≥10 patients, n patients

Age category (years)

n (%)

Central region

3

12 - 17

≤19

67 (15.5)

Eastern Cape

3

10 - 78

20 - 29

157 (36.3)

Gauteng

3

14 - 29

30 - 39

100 (23.1)

KwaZulu-Natal

1

13

40 - 49

69 (15.9)

Northern region

1

10

50 - 59

28 (6.5)

10 - 29

≥60

12 (2.8)

Western Cape

3

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Table 3. Codeine products most frequently reported as being misused or causing dependence Product

Quantity of codeine per tablet/capsule, mg

Codeine and other components

n (%)

Rank*

Stilpane

8

Paracetamol, caffeine, meprobamate

124 (28.5)

1

Adco-Dol

10

Paracetamol, caffeine, doxylamine

104 (23.9)

2

Benylin syrup with codeine

N/A

Diphenhydramine hydrochloride, levomenthol

33 (7.6)

3

Myprodol

10

Paracetamol, ibuprofen

19 (4.4)

4

Bronchleer cough syrup

N/A

Diphenhydramine hydrochloride, ammonium chloride, sodium citrate

16 (3.7)

5

Lenazine Forte cough syrup

N/A

Ephedrine hydrochloride, promethazine hydrochloride

11 (2.5)

=6

Syndol

10

Paracetamol, caffeine, doxylamine

11 (2.5)

=6

Panado-Co

8

Paracetamol, potassium sorbate

10 (2.3)

8

Adco-Sinal CO

15

Paracetamol, phenylpropanolamine HCl, phenyltoloxamine citrate

9 (2.0)

9

Acurate

10

Paracetamol, caffeine, doxylamine

7 (1.6)

=10

Disprin Plus

8

Aspirin

7 (1.6)

=10

NA = not applicable. *1 = most misused, 10 = least misused.

other healthcare providers. The vast majority are unlikely to seek or be able to access any assistance, as they do not view themselves as needing help or as ‘drug addicts’.[12] To obtain a better picture of the national prevalence rate for codeine misuse/dependence, the extent of patients misusing or dependent on codeine who access a broader range of service providers, or who do not access services of any kind, must therefore be investigated.

We found that less than a third of persons who came to specialist substance abuse treatment centres with codeine-related problems had codeine as their primary substance of abuse. In most cases codeine use was secondary to other substances of abuse, namely alcohol, cannabis, heroin/opiates and methamphetamine. Other studies have found a link between codeine and alcohol use.[13] In Australia, at times when heroin is not easily available, prescription opioids such as morphine are used as an alternative.[13] That codeine may be being used as a substitute for heroin in SA when the latter is not available warrants further investigation. Use of codeine by methamphetamine users has been reported infrequently; a New Zealand study found that 15.3% in 2008 and 12.2% in 2009 had reported simultaneous use of methamphetamine and codeine.[13] Table 4. Primary drug of abuse for persons in treatment misusing/dependent on codeine Primary substance of abuse

%

OTC/prescription drug

31.7

Alcohol

21.4

Dagga (cannabis)

14.7

Heroin/opiates

10.6

Methamphetamine

8.3

Methcathinone

6.9

Dagga/methaqualone combination

3.0

Crack/cocaine

2.5

Other

1.1

778

Our finding that three-quarters of persons in treatment reporting misuse or dependence on codeine were male and under 40 years of age contrasts with international research, where the clinical profiles of codeine-dependent persons are over-represented by females and those in middle to late age.[13] Given that our sample comprises persons seen in specialist drug treatment centres, it is highly likely that females and older persons are under-represented in such samples, reflecting their experience of barriers to accessing specialist substance abuse treatment.[14] The finding that >15% of persons in treatment who reported misusing or being dependent on codeine were aged ≤19 years, and that these included children as young as 11 years of age, also warrants further investigation.

In terms of geographical distribution of persons in SA receiving specialist substance abuse treatment with codeine as a primary or secondary substance of abuse, Gauteng and the Western Cape may have been expected to feature prominently because of the number of treatment centres and persons in treatment in these provinces. That the Eastern Cape had such high numbers of codeine-misusing or dependent persons was unexpected. This finding is due to the inclusion of a private treatment facility that has recently seen an increase in patients admitted for mental health and substance abuse comorbidity. The clinical profile of codeine-dependent persons has been found in New Zealand to include those with underlying psychiatric condi­tions. [13] Some 18% of persons reporting codeine as a primary or secondary substance of abuse indicated use of syrups containing codeine. This contrasts with 1.2% in the 2012/13 UK NDTMS dataset and 2.3% in the Irish NDTRS dataset,[11] reflecting much easier access to syrups containing codeine in SA and suggesting another area for further study and possibly greater regulation. Many of the codeine preparations were combined with paracetamol, a compound the long-​term use of which can cause kidney damage.[12] In the UK, boxes containing codeine tablets or capsules have a warning not to use them for longer than 3 days, something that should perhaps be considered in SA.

Study limitations

Our study has several limitations. Chief among them is that there are barriers to accessing treatment and certain population sectors

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are less likely to be included, especially females[12] and persons from less advantaged communities.[15] It should also be noted that the data collection instrument used by SACENDU does not enable determination of whether the patient’s use of one or more substances has reached the level of dependence as determined by the Diagnostic and Statistical Manual, version IV (DSM-IV) or the International Classification of Diseases, version 10 (ICD-10). Furthermore, our data represent treatment admissions. It is therefore possible that some admissions are of the same person, thus inflating the number of people treated. A further limitation is that the study is crosssectional in nature and cannot offer evidence about how the situation might change over time. This is important in guiding policy, and the increasing demand for treatment related to codeine misuse and dependence found in the UK[11] suggests that it should be studied further in SA.

Conclusions

With regard to the intention of the Medicines Control Council and the SA National Department of Health to further tighten up on the sale of OTC medications containing codeine,[4] our research has shown that while there is a low level of treatment demand from specialist substance abuse treatment centres related to misuse of or dependence on products containing codeine compared with other substances of abuse, such misuse or dependence is likely to translate to over 400 persons per year.[16] However, more information is needed on the prevalence of codeine misuse and dependence in SA from other sources of data, including community samples.

Acknowledgements. The authors thank the National Department of Health (Mental Health and Substance Abuse Directorate) for funding this project over many years, and the participating substance abuse treatment centres staff for regularly submitting data. The first, third and last authors were on secondment as part of the multicountry Codemisused project

779

and working with the Local Choice pharmacy group in SA (SD), Cara Pharmacy in Ireland (MCvH) and Weldricks Pharmacy in the UK (CDHP), with funding from the EU’s Seventh Framework Programme FP7/2007-2013 under grant agreement No. 611736.

References 1. United Nations Office on Drugs and Crime. The Non Medicinal Use of Prescription Drugs, Discussion Paper. Vienna: UNODC, 2011.

2. Casati A, Sedefov R, Pfeiffer-Gerschel T. Misuse of medicines in the European Union: A systematic review of the literature. Eur Addict Res 2012;18(5):228-245. [http://dx.doi.org/10.1159/000337028] 3. Osman L. Rescheduling of ephedrine, pseudoephedrine and d-nor-pseudoephedrine – what does it mean? SA Pharmacist’s Assistant 2008;Winter:4.

4. Registrar of Medicines, South Africa. Rescheduling of Acetyldihydrocodeine, Codeine, Dihydrocodeine and Norcodeine. Pretoria: Department of Health and Medicines Control Council, February 2015.

5. Pates R, McBride AJ, Li S, Ramadan R. Misuse of over-the-counter medicines: A survey of community pharmacies in a South Wales heath authority. Pharm J 2002;268(7184):179-182.

6. Dobbin M, Tobin C. Over-the-counter Ibuprofen/Codeine Analgesics: Misuse and Harm. Melbourne, Australia: Drugs Policy and Services Branch, Department of Human Services, 2008.

7. Skurtviet S, Faru K, Borchgrevink P, Handal M, Fredheim O. To what extent does a cohort of new users of weak opioids develop persistent or probable problematic opioid use? Pain 2011;152:15551561. [http://dx.doi.org/10.1016/j.pain.2011.02.045] 8. Roussin A, Bouyssi A, Pouche L, Pourcel L, Lapeyre-Mestre M. Misuse and dependence on nonprescription codeine analgesics or sedative h1 antihistamines by adults: A cross-sectional investigation in France. PLoS One 2013;8(10):e76499. [http://dx.doi.org/10.1371/journal.pone.0076499] 9. Parry CDH, Plüddemann A, Bhana A. Monitoring alcohol and drug abuse trends in South Africa via SACENDU (1996-2006): Reflections on treatment demand trends over the past 10 years and the project’s impact on policy and other domains. Contemp Drug Probl 2009;36(Fall-Winter):685-703. [http://dx.doi.org/10.1177/009145090903600319] 10. Simon R, Donmall M, Hartnoll R, et al. The EMCDDA/Pompidou Group treatment demand indicator protocol: A European core item set for treatment monitoring and reporting. Eur Addict Res 1999;5(4):197-207. [http://dx.doi.org/10.1159/000018994] 11. Deluca P, Parry C, van Hout MC. Mid Term Review Report: Interviews with Addiction Treatment Providers (WP5). Brussels: CODEMISUSED Project European Commission 7th Framework Programme, 2015.

12. Van Hout MC, Bergin M, Foley M, et al. A Scoping Review of Codeine Use, Misuse and Dependence: Final Report. Brussels: CODEMISUSED Project European Commission 7th Framework Programme, 2014.

13. Wilkins C, Sweetsur P, Griffiths R. Recent trends in pharmaceutical drug use among frequent injecting drug users, frequent methamphetamine users and frequent ecstasy users in New Zealand, 2006-2009.

Drug and Alcohol Review 2011;30(3):255-263. [http://dx.doi.org/10.1111/j.1465-3362.2011.00324.x] 14. Myers B, Louw J, Pasche S. Gender differences in barriers to alcohol and other drug treatment in Cape Town, South Africa. Afr J Psychiatry 2011;May:146-153. [http://dx.doi.org/10.4314/ajpsy.v14i2.7] 15. Myers BJ, Louw J, Pasche SC. Inequitable access to substance abuse treatment services in Cape Town, South Africa. Subst Abuse Treat Prev Policy 2010:5:28. [http://dx.doi.org/10.1186/1747-597X-5-3, http://dx.doi.org/10.1186/1747-597X-5-28] 16. Myers B, Siegfried N, Parry CDH. Over-the-counter and prescription medicine misuse in Cape Town, South Africa. Findings from specialist treatment centres. S Afr Med J 2003;93:367-370.

Accepted 6 June 2015.

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Affordable moisturisers are effective in atopic eczema: A randomised controlled trial C Hlela,1 MB ChB, PhD; N Lunjani,1 MB ChB; F Gumedze,2 PhD; B Kakande,1 MB ChB; N P Khumalo,1 MB ChB, PhD 1 2

ivision of Dermatology, Red Cross War Memorial Children’s Hospital and Groote Schuur Hospital, Cape Town, South Africa D Department of Statistical Sciences, Faculty of Science, University of Cape Town, South Africa

Corresponding author: N P Khumalo (n.khumalo@uct.ac.za)

Background. Many patients depend on moisturisers issued by public health services in the management of atopic dermatitis (AD).

Methods. In a randomised controlled trial of patients with mild to moderate AD, aged 1 - 12 years, study 1 compared aqueous cream v. liquid paraffin (fragrance-free baby oil) as a soap substitute, all patients using emulsifying ointment as moisturiser, and study 2 compared four moisturisers, emulsifying ointment, cetomacrogol, white petroleum jelly and glycerine/petroleum (proportion 1:2; ‘the 1:2 moisturiser’), all using fragrance-free baby oil as soap substitute. Assessments were one quality of life and three AD severity scores, at baseline and weeks 4, 8 and 12. Differences were compared using repeated measures of analysis of variance.

Results. In both studies (120 children randomised, 20 in each group of the two trials) disease severity scores declined with time. The only significant difference was in one AD severity score (SCORing Atopic Dermatitis) in study 1, both at baseline and over time (p=0.042 and p=0.022). The groups did not differ with regard to topical steroid use or side-effects. Itching from baby oil applied as soap was reported by four patients in the two studies, the petroleum jelly group had more dropouts than the 1:2 moisturiser group, although this was not statistically significant, and 110 patients (91.7%) completed the trial.

Conclusions. The small sample limits generalisability, but the duration was longer than in most AD moisturiser studies. Fragrance-free baby oil as a soap substitute may be better tolerated (if irritation occurs) as a bath additive. The 1:2 moisturiser may be preferable to white petroleum jelly, but both are equivalent to cetomacrogol and emulsifying ointment. Use of accessible moisturisers could reduce the cost of managing mild to moderate AD. S Afr Med J 2015;105(9):780-784. DOI:10.7196/SAMJnew.8331

Moisturisers are cornerstones of the management of atopic dermatitis (AD). Recently published guidelines on the management of AD recommend that ‘while the choice of moisturiser depends on individual preference, it should be safe; effective; cost-effective; and be fragrance/perfumes/additives-free’.[1] In spite of these recommendations, there has been an explosion of prescription and expensive moisturisers that contain various ingredients aimed at addressing the impaired skin barrier function in AD. These agents include prescription emollient devices and those containing ceramides and/or filaggrin breakdown products.[2-6] Such products increase the options for treating AD, but are expensive. There is also evidence that prescription moisturisers may not be superior to overthe counter-preparations.[7] The prevalence of AD is increasing worldwide.[8] In Cape Town, South Africa (SA), the 1-year prevalence in 13 - 14-year-old children was 8.3%, increasing to 13.3% in a later study.[9] Intractable pruritus and sleep disturbance can be severe in AD, compromising quality of life. Consistent with international practice, potential topical irritants (e.g. from ingredients responsible for fragrance, colour and foam) should be avoided. In keeping with the SA Essential Drugs List (EDL), the most commonly used products in public health facilities are aqueous cream as a soap substitute, with emulsifying ointment and cetomacrogol as moisturisers. Recently reported impairment of the skin barrier function in healthy subjects resulting from the use of aqueous cream as a daily moisturiser has raised concern.[10] AD is the leading single contributor to the ‘top ten paediatric dermatology diagnoses’, which account for >70% of patients in 12 of 19 international studies. [11] Up to 60% of patients attending the Dermatology Clinic at Red Cross War Memorial Children’s Hospital, Cape Town, SA, have

780

AD, and often return with disease flares.[11] Many of these patients use only clinic-supplied EDL moisturisers, which are not stocked by rural shops, presumably because of cost. We found no data comparing commonly used AD emollients with products that are routinely used and available in most homes (petroleum jelly, glycerine and baby oil). Petroleum jelly and liquid paraffin combined in a 50:50 formulation has been used locally and in the UK for AD.[12-14] We prefer the term ‘fragrance-free baby oil’ to ‘liquid paraffin’ in order to eliminate confusion with paraffin (kerosene) that is used as fuel (for cooking/heating). Baby oil is widely used all over the world on children, including neonates. Fragrance-free baby oil is also used as a bath additive in AD and locally as a soap substitute for patients who are unable to tolerate aqueous cream. Glycerine (glycerol) is a good humectant;[15,16] a deterrent to its use is its sticky consistency, which we have found disappears completely when it is combined with petroleum jelly. Mixing with glycerine also reduces the shine of petroleum jelly. A proportion of glycerine/petroleum in 1:2 formulation for use as a hand cream was preferred to other unlabelled proportions by 45 of 50 hospital staff (‘the 1:2 moisturiser’; unpublished data, N P Khumalo, 2012).

Objective

To compare the efficacy of easily accessible moisturisers with those currently recommended in patients with mild to moderate AD.

Methods

Study design and treatment groups Approval to conduct the study was received from the Ethics Committee, Faculty of Health Sciences, University of Cape Town (ref: 146/2013). The trial was registered (NCT0208447). Two separate

September 2015, Vol. 105, No. 9

RESEARCH

substudies were conducted using a randomised controlled single (assessor)-blind trial design. Patients were randomised using an automatic online enrolment system in a 1:1 ratio for study 1 or a 1:1:1:1 ratio for study 2.

Study 1 compared aqueous cream v. baby oil as a soap substitute.

All the participants used emulsifying ointment as a moisturiser.

Study 2 compared four moisturiser formulations: cetomacrogrol, emulsifying ointment, glycerine/petroleum (1:2) and petroleum jelly. Study 2 participants all washed with baby oil and applied this as soap instead of aqueous cream. All the participants continued to use clinic-prescribed topical steroids during the study period, and brought back all tubes so that the amount used during the previous month could be recorded at every visit.

Patients

Patients aged 1 - 12 years were enrolled at Red Cross Children’s War Memorial Hospital from 1 February 2013 to 31 June 2013.

Written consent was signed by parents/guardians. All had active but stable mild to moderate atopic eczema according to the UK working party formulary criteria at screening and at baseline,[17] and all had dry eczematous skin as the predominant feature.

Patients were not eligible if they had severe atopic eczema or secondary infection, were medically unwell, or were on systemic therapy for their AD.

Assessments

Visits occurred at baseline and monthly for 3 months, and the outcomes of interest were recorded. At each of the four visits, one ‘blinded’ dermatologist, who was the same for all visits, did all assessments. Disease severity was asessed using the validated objective SCORing Atopic Dermatitis (SCORAD), the Nottingham Atopic Eczema Severity Score (NESS) and the Patient Oriented Eczema Measure (POEM) scores. A validated quality-of-life form using the infant’s dermatitis quality of life (IDQOL) scale was completed by caregivers at each visit. The amount of topical steroids used in the preceding month was documented at each visit (i.e. number of tubes and proportion of partially used tubes). All

caregivers were also requested to return all medication (received from any/all health facilities attended during the previous month). Adverse events were asked about and recorded at each visit.

Statistical analysis

Data were analysed using STATA version 13.1.[18] With an estimate of proportions of 33% v. 5% and a non-inferiority margin of 5%, the total sample size was 40 (20 per group for study 1). In the paralleldesign study, with the same parameters as above with adjustment for multiple testing, the total sample size was 44 × 2 = 88 (22 per group for study 2). We compared SCORAD/NESS/POEM and IDQOL mean scores at baseline and weeks 4, 8 and 12 and summarised the findings by treatment group and time with interaction plots produced using R Version 3.0.2.[19] We used repeated-measures analysis of variance which utilised all data and assessed the effect of treatment and time effect (interaction between time and treatment) using generalised estimating equations. The level of significance was set at p<0.05.

Results

A total of 125 children were screened and 120 randomised to provide 20 in each treatment group in the two studies (Fig. 1) (it was only noticed towards the end of the study that 20 instead of 22 participants per group had been recruited for study 2). All baseline characteristics were similar between the groups except for the objective SCORAD in study 1, aqueous cream v. baby oil (mean (standard deviation, SD) 23.02 (11.79) v. 33.11 (16.82); p=0.042) (Table 1). One hundred and ten children completed the trial. Ten children (8.3%) dropped out, four having complained (noted at a visit before dropping out) of itching, presumed to be from baby oil (one in study 1 and three in study 2 – one from each group except the emulsifying ointment group). All participants in the aqueous cream and emulsifying ointment group completed the study. The reason for dropping out of the trial was unknown in six patients (two from study 1 and four from study 2 – two from the cetomacrogol group and two from the petroleum jelly group) (Fig.1). Overall there was no statistical difference in the number of dropouts between groups.

Table 1. Baseline characteristics of study participants* Study 1

Baby oil

Aqueous cream

p-value

Age (years), mean (SD)

5.63 (2.43)

5.66 (2.39)

0.966

Females, n (%)

8/20 (40.0)

9/17 (52.9%)

0.431

SCORAD

23.02 (11.79)

33.11 (16.82)

0.042

POEM

9.00 (5.06)

11.50 (7.97)

0.366

NESS

10.20 (1.96)

9.50 (3.25)

0.429

6.45 (4.78)

7.00 (4.86)

0.736

Baseline scores (mean (SD)

IDQOL Study 2

Emulsifying ointment

Cetomacrogol

Glycerine/petroleum jelly

Petroleum jelly

p-value

Age (years), mean (SD)

5.83 (2.61)

4.71 (2.86)

5.55 (2.58)

4.95 (2.45)

0.549

Females, n (%)

20 (55)

17 (41)

19 (58)

17 (53)

0.767

SCORAD

28.40 (16.16)

24.78 (16.90)

21.52 (15.24)

26.77 (12.09)

0.529

POEM

9.10 (4.56)

9.47 (6.02)

9.75 (7.23)

11.29 (7.06)

0.742

NESS

9.85 (2.83)

9.35 (2.40)

9.25 (3.64)

10.00 (3.35)

0.856

IDQOL

7.25 (5.84)

7.23 ( 4.48)

7.35 (6.75)

6.76 (3.72)

0.989

Baseline scores, mean (SD)

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Enrollment

Assessed for suitability n=125 • Randomised n=120

Study 1 n=40

Allocation Follow-up Analysis

Excluded n=125 Not meeting inclusion criteria n=3 • Withdrawal of consent n=2

Study 2 n=40

Aqueous cream n=20

Unscented baby oil n=20

Cetomacrogol n=20

Completed n=20 Adverse effects n=0 Lost to follow-up n=0

Completed n=17 Adverse reaction n=1 Lost to follow-up n=3

Completed n=19 Adverse reaction n=1 Lost to follow-up n=3

Emulsifying ointment n=20

Glycerine/ petroleum n=20

Completed n=20 Adverse reaction n=0 Lost to follow-up n=0

Completed n=19 Adverse reaction n=1 Lost to follow-up n=1

Petroleum n=20

Completed n=17 Adverse reaction n=1 Lost to follow-up n=3

Analysed n=73 of 80

Analysed n=37 of 40

Fig. 1. Flow diagram depicting the overall study design.

Three separate disease severity scores were used in this trial to determine consistency of the results. It is interesting that overall there were no differences in severity scores between the groups from baseline and over time in any of the scores except SCORAD in study 1 (Fig. 2). However, this difference in the objective SCORAD was present both at baseline and over time and is therefore unlikely to be the result of

40

40

Aqueous cream Baby oil

20 10

Aqueous cream Baby oil

30 POEM

30 SCORAD

(B) POEM by treatment

20

p=0.431

10

p=0.022

0

0 0

1

2

3

0

1

(C) NESS by treatment 40

40

Aqueous cream Baby oil

30 20

2

3

(D) IDQOL Aqueous cream Baby oil

30 IDQOL

Discussion

(A) SCORAD by treatment

NESS

All mean scores decreased over time. In study 1, scores were similar except for the objective SCORAD, both at baseline and at the end of the study (p=0.022) (Fig. 2). In study 2, all mean scores tended to decline over time, but there were no differences in all treatments compared with emulsifying ointment (p=0.529) (Fig. 3). Furthermore, the IDQOL index did not change significantly from baseline in either study (p=0.736 for study 1 and p=0.989 for study 2). There was no statistical difference in the amount of topical steroids (of various strengths) used between groups for either study (Fig. 3). Overall, there was no difference in adverse effects (itching) between groups (Fig. 1).

p=0.477

10

20

p=0.239

10

0

0 0

1

2

3

0

1

2

3

Fig. 2. Interaction plots of treatment by time (aqueous cream v. baby oil) in study 1. The y-axes show means at each time point. All the scores tend to decline over time for all the treatments. There is a significant difference between the treatments for objective SCORAD only (p=0.022), but this difference was also present at baseline (p=0.042) and is unlikely to be the result of treatment.

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(A) Hydrocortisone acetate (1%) by treatment 50

Aqueous cream Baby oil

40

Betamethasone valerate (g)

Hydrocortisone acetate (1%) (g)

50

(B) Betamethasone valerate by treatment

30 20 p=0.466

10 0

40 30 20 p=0.402

10

Aqueous cream Baby oil

0 0

1

2

3

1

2

3

(C) Clobetasol propionate by treatment

Clobetasol propionate (g)

50

Aqueous cream Baby oil

40

clinics (including SA 59%, London 36%, Greece 35% and Hong Kong 33%) in 19 studies from 16 countries.[11] Families of AD sufferers in poor settings become increasingly dependent on public health services, increasing pressure on public healthcare facilities. Although cetomacrogol and emulsifying ointment are considered inexpensive in Western countries, they are not affordable for most of our patients, who have easy access to but do not use petroleum jelly and baby oil, depending instead on government clinic suppliers. Even in wellresourced countries, spiralling medical costs have increased the demand for evidencebased cost-effective treatments. Results from this prospective controlled study revealed that more affordable moisturisers are effective alternatives for AD.

Study limitations

30 p=0.362

20 10 0 0

1

2

3

Fig. 3. Interaction plots of treatment by time (aqueous cream v. baby oil) in study 1 for amount and class strength of topical steroids used during the preceding month.

different treatments. It is noteworthy that the amount (and potency) of steroids used did not differ between groups. Scores tended to decline over time from baseline for all the four treatment groups in study 2, suggesting that the moisturisers may be equivalent.

Consistent with this finding is the IDQOL, which did not differ between groups in the two studies.

Fragrance-free baby oil baths, glycerine/ petroleum (the ‘1:2 moisturiser’) and petro­ leum jelly were generally well tolerated in both studies, with only four of 100 users (one in each of four study groups) complaining of itching, which was presumed to be associated with baby oil (applied directly to the skin as a soap substitute). Fragrance-free baby oil is commonly used and well tolerated as a bath additive by patients in our unit. Although there was no statistical difference in the prevalence of side-effects between groups, the few cases of irritation with baby oil were also unexpected because it is so commonly used worldwide in healthy neonates and children as well as as a moisturiser in the formulation liquid paraffin/petroleum jelly 50:50 in AD. Liquid paraffin-based emollients may contain 1% sodium lauryl sulphate, which may irritate the skin. It was interesting that no participant complained of the shine of petroleum jelly,

and that no case of (expected) occlusive folliculitis was noted. However, the petroleum jelly group did have a larger number of dropouts, although not significantly so, than the glycerine/petroleum group. A recent study has demonstrated impairment of the skin barrier function in healthy subjects using aqueous cream as a daily moisturiser; this is also thought to be the result of sodium lauryl sulphate in aqueous cream.[10] In our unit aqueous cream is not recommended as a moisturiser, a subset of patients finding it irritating even as a soap substitute. For these patients, emulsifying ointment or fragrancefree baby oil have been acceptable soap substitutes.

Moisturisers are important as maintenance treatment and for prevention of flares in AD. Several clinical trials have shown that moisturisers can lessen the symptoms and signs of AD and enhance the effects of, as well as reduce the amount of, topical corticosteroids needed for disease control.[1,20-21] Recently published studies tend to focus on new agents without comparing them with available treatments for AD. Despite a myriad of moisturiser choices in the literature, uncertainty as to which one to choose remains.

Patients with AD constitute the largest single diagnosis in paediatric dermatology

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The small sample size is a limitation to this study, although calculations were adequately powered to detect differences in groups (at 20 and 22 participants per group in studies 1 and 2, respectively). However, it was only noticed towards the end of the study that 20 instead of 22 participants per group had also (erroneously) been recruited for study 2. Loss to follow-up was minimal, with retention of 92% of participants to the end of the study at 12 weeks – a longer duration of follow-up than in most AD moisturiser studies.[20,22-24]

Conclusion

This study suggests that affordable moisturisers are effective in the management of AD. The small sample size and single-centre setting limit generalisability. Fragrance-free baby oil is an alternative soap substitute, but may be better tolerated as a bath additive.

Glycerine/petroleum (the ‘1:2 moisturiser’) may be preferred to petroleum jelly, but both are equivalent to standard moisturisers (cetomacrogol and emulsifying ointment) in mild to moderate AD. Use of accessible and affordable moisturisers could help empower families to better manage and reduce the cost of treating AD. Acknowledgements. We are grateful to the participating families. The study was investigator initiated, and all emollients were requested from and donated by Sekpharma (SA), a generic medicine supply company.

References 1. Eichenfield LF, Tom WL, Berger TG, et al. Guidelines of care for the management of atopic dermatitis: Section 2. Management and treatment of atopic dermatitis with topical therapies.

J Am Acad Dermatol 2014;71(1):116-132. [http://dx.doi. org/10.1016/j.jaad.2014.03.023]

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2. Draelos ZD. An evaluation of prescription device moisturizers. J Cosmet Dermatol 2009;8(1):40-43. [http://dx.doi.org/10.1111/j.1473-2165.2009.00422.x] 3. Chamlin SL, Kao J, Frieden IJ, et al. Ceramide-dominant barrier repair lipids alleviate childhood atopic dermatitis: Changes in barrier function provide a sensitive indicator of disease activity. J Am Acad Dermatol 2002;47(2):198-208. [http://dx.doi.org/10.1067/mjd.2002.124617] 4. Eberlein B, Eicke C, Reinhardt HW, Ring J. Adjuvant treatment of atopic eczema: Assessment of an emollient containing N-palmitoylethanolamine (ATOPA study). J Eur Acad Dermatol Venereol 2008;22(1):73-82. [http://dx.doi.org/10.1111/j.1468-3083.2007.02351.x] 5. Sugarman JL, Parish LC. Efficacy of a lipid-based barrier repair formulation in moderate-to-severe pediatric atopic dermatitis. J Drugs Dermatol 2009;8(12):1106-1111.

6. Morren MA, Przybilla B, Bamelis M, Heykants B, Reynaers A, Degreef H. Atopic dermatitis: Triggering factors. J Am Acad Dermatol 1994;31(3):467-473. [http://dx.doi.org/10.1016/S0190-9622(94)70213-6] 7. Miller DW, Yentzer BA, Clark AR, et al. An over-the-counter moisturizer is as clinically effective as, and more cost-effective than, prescription barrier creams in the treatment of children with mild-tomoderate atopic dermatitis: A randomized, controlled trial. J Drugs Dermatol 2011;10(5):531-537.

8. Asher MI, Montefort S, Bjorksten B, et al. Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC Phases One and Three repeat multicountry cross-sectional surveys. Lancet 2006;368(9537):733-743. [http://dx.doi.org/10.1016/ S0140-6736(06)69283-0] 9. Chalmers DA, Todd G, Saxe N, et al. Validation of the U.K. Working Party diagnostic criteria for atopic eczema in a Xhosa-speaking African population. Br J Dermatol 2007;156(1):111-116. [http://dx.doi. org/10.1111/j.1365-2133.2006.07606.x] 10. Danby SG, Al-Enezi T, Sultan A, Chittock J, Kennedy K, Cork MJ. The effect of aqueous cream BP on the skin barrier in volunteers with a previous history of atopic dermatitis. Br J Dermatol 2011;165(2):329-334. [http://dx.doi.org/10.1111/j.1365-2133.2011.10395.x] 11. Kakande B, Gumedze F, Hlela C, Khumalo NP. The top ten diagnoses could reduce referrals to paediatric dermatology clinics. Paediatric Dermatology 2015 (in press).

12. Moncrieff G, Cork M, Lawton S, Kokiet S, Daly C, Clark C. Use of emollients in dry-skin conditions: Consensus statement. Clin Exp Dermatol 2013;38(3):231-238; quiz 238. [http://dx.doi.org/10.1111/ ced.12104] 13. McHenry PM, Williams HC, Bingham EA. Management of atopic eczema. Joint Workshop of the British Association of Dermatologists and the Research Unit of the Royal College of Physicians of London. BMJ 1995;310(6983):843-847. [http://dx.doi.org/10.1136/bmj.310.6983.843] 14. Proksch E, Lachapelle JM. The management of dry skin with topical emollients â&#x20AC;&#x201C; recent perspectives. J Dtsch Dermatol Ges 2005;3(10):768-774. [http://dx.doi.org/10.1111/j.1610-0387.2005.05068.x]

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15. Bissonnette R, Maari C, Provost N, et al. A double-blind study of tolerance and efficacy of a new ureacontaining moisturizer in patients with atopic dermatitis. J Cosmet Dermatol 2010;9(1):16-21. [http:// dx.doi.org/10.1111/j.1473-2165.2010.00476.x] 16. Wiren K, Nohlgard C, Nyberg F, et al. Treatment with a barrier-strengthening moisturizing cream delays relapse of atopic dermatitis: A prospective and randomized controlled clinical trial. J Eur Acad Dermatol Venereol 2009;23(11):1267-1272. [http://dx.doi.org/10.1111/j.1468-3083.2009.03303.x] 17. Williams HC, Pembroke AC, Hay RJ. The UK working partyâ&#x20AC;&#x2122;s diagnostic criteria for atopic dermatitis lll: Independent hospital validation. Br J Dermatol 1994;131(3):406-416. [http://dx.doi. org/10.1111/j.1365-2133.1994.tb08532.x] 18. Stata Corp. Stata Statistical Software: Release 13. College Station, TX: StataCorp LP, 2013.

19. Foundation for Statistical Computing. A Language and Environment for Statistical Computing.

Vienna, Austria: R Foundation for Statistical Computing, 2013. http://www.R-project.org/ (accessed 2012).

20. Breternitz M, Kowatzki D, Langenauer M, Elsner P, Fluhr JW. Placebo-controlled, double-blind, randomized, prospective study of a glycerol-based emollient on eczematous skin in atopic dermatitis: Biophysical and clinical evaluation. Skin Pharmacol Physiol 2008;21(1):39-45. [http://dx.doi. org/10.1159/000111134] 21. Msika P, de Belilovsky C, Piccardi N, Chebassier N, Baudouin C, Chadoutaud B. New emollient with topical corticosteroid-sparing effect in treatment of childhood atopic dermatitis: SCORAD and quality of life improvement. Pediatr Dermatol 2008;25(6):606-612. [http://dx.doi.org/10.1111/j.15251470.2008.00783.x] 22. Hoare C, Li Wan Po A, Williams H. Systematic review of treatments for atopic eczema. Health Technol Assess 2000;4(37):1-191. [http://dx.doi.org/10.3310/hta4370] 23. Hanifin JM, Hebert AA, Mays SR, et al. Effects of a low-potency corticosteroid lotion plus a moisturizing regimen in the treatment of atopic dermatitis. Current Therapeutic Research 1998;59(4):227-233. [http://dx.doi.org/10.1016/S0011-393X(98)85076-5] 24. Korting HC, Schollmann C, Cholcha W, Wolff L, Collaborative Study Group. Efficacy and tolerability of pale sulfonated shale oil cream 4% in the treatment of mild to moderate atopic eczema in children: A multicentre, randomized vehicle-controlled trial. J Eur Acad Dermatol Venereol 2010;24(10):11761182. [http://dx.doi.org/10.1111/j.1468-3083.2010.03616.x]

Accepted 1 July 2015.

September 2015, Vol. 105, No. 9

Designed to protect

In addition to efficacy, safety and proven outcomes, valsartan1: •

is effective beyond the 24 hour dosing interval

•

delivers smooth BP control

•

mimics the circadian rhythm

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attenuates the negative effects of hydrochlorothiazide

UP TO

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PACKED IN

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For further product information contact PHARMA DYNAMICS P O Box 30958 Tokai Cape Town 7966 Tel 021 707 7000 Fax 021 701 5898 Email info@pharmadynamics.co.za CUSTOMER CARE LINE 0860 PHARMA (742 762) www.pharmadynamics.co.za Dynaval Co 80/12,5 mg. Each fi lm coated tablet contains 80 mg valsartan and 12,5 mg hydrochlorothiazide. Reg. No.: RSA S3 44/7.1.3/0018. NAM NS2 14/7.1.3/0061. Dynaval Co 160/12,5 mg. Each fi lm coated tablet contains 160 mg valsartan and 12,5 mg hydrochlorothiazide. Reg. No.: RSA S3 44/7.1.3/0019. NAM NS2 14/7.1.3/0062. Dynaval Co 160/25 mg. Each fi lm coated tablet contains 160 mg valsartan and 25 mg hydrochlorothiazide. Reg. No.: RSA S3 44/7.1.3/0020. NAM NS2 14/7.1.3/0063. For full prescribing information, refer to the package insert approved by the Medicines Control Council, 19 April 2013. 1) Black HR, et al. Valsartan. More than a decade of experience. Drugs 2009;69(17):2393-2414. 2) Department of Health website http://www.doh.gov.za – Accessed 28/04/2015. 3) IMS data, March 2015. Units sold in the period 1 April 2014 – 31 March 2015. DLCG180/06/2015

GUEST EDITORIAL

Chronic obstructive pulmonary disease in South Africa: Under-recognised and undertreated Chronic obstructive pulmonary disease (COPD) is a common, preventable but incurable condition currently ranked third in global mortality estimates.[1] Worldwide, 65 million people are estimated to have moderate to severe COPD, and the disease accounts for 3 million deaths annually, of which 90% are said to occur in low- and middle-income countries. Yet, despite these staggering numbers, COPD remains both under-recognised and undertreated in most populations, also in South Africa (SA).[2] There are many reasons for this, not least of which is the attitude of clinicians, which can often be fatalistic with regard to COPD. This edition of CME highlights key aspects of the diagnosis[3] and treatment – pharmacological[4] and non-pharmacological[5] – and new developments in the management of severe disease.[6] Furthermore, we have included articles focusing on non-smokingrelated COPD[7] and tips for good spirometry.[8] COPD is often a challenging disease for the patient and the doctor.

Even the name causes much head-scratching for many sufferers.

‘Asthma I know’, and ‘emphysema I have heard of’, but COPD – a complex syndrome extending from chronic bronchitis to emphysema – is not well understood or easily explained. This is in part a problematic historical nomenclature issue, but as knowledge grows, there are increasing attempts to split COPD into more clinically relevant phenotypes. It is hoped that this will allow for a clearer understanding and better treatment choices.

Tobacco smoking is still the predominant cause of COPD worldwide, but there is a growing understanding of the importance of non-tobacco causes. SA is unique in many ways, having significant contributions from tuberculosis, HIV and biomass as well as mining exposure, creating ‘colliding epidemics’, with resultant chronic lung disease.[9] Unfortunately, very little is known about the natural history or the response to therapy of these non-smoking forms of COPD, which are currently receiving due attention. For smoking-related COPD, it is critical that smokers cease smoking; the South African Clinical Practice Guideline is available to assist clinicians in helping their patients quit.[10] So why bother making a diagnosis of COPD and distinguishing it from asthma? This is a critical question, especially in resource-limited settings with limited access to spirometry and few treatment options.

The first good reason we would propose is ‘managing expectations’ for both the physician and patient. Many patients are resigned to their chronic symptoms; however, if truly asthmatic, neither party should accept this lightly. In most asthma patients complete control of symptoms is possible with good therapy.[11] In COPD, by contrast, complete symptom resolution is not necessarily realistic. However, with the arrival of new long-acting muscarinic antagonists and ultralong-acting β2-agonists, improvement in symptom control may be dramatic. Secondly, the long-term prognosis is significantly worse in COPD compared with asthma and patients need to be appropriately counselled regarding their expected disease progression. The final reason is the choice of drugs to manage the disease. Inhaled corticosteroids are undoubtedly the mainstay of asthma therapy[12]

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compared with COPD, where bronchodilators are the anchor and inhaled corticosteroids are reserved for a select group.[2] Hope is not lost with COPD. Despite it being incurable, with irreversible lung function impairment, much can still be done. Early detection and smoking cessation will slow the disease progression.

Appropriate and adequate therapy to improve symptoms and prevent the ominous progression of acute exacerbations, in addition to vaccination, pulmonary rehabilitation and good nutrition, will ensure that COPD patients continue to live active lives. Novel therapies are being developed and evaluated in SA, which could potentially improve symptoms of patients with the most severe disease. Consider the diagnosis early, confirm it with spirometry and treat the patient with renewed enthusiasm!

Brian Allwood Guest editor brianallwood@sun.ac.za

Richard N van Zyl-Smit Guest editor richard.vanzyl-smit@uct.ac.za 1. World Health Organization. The Global Burden of Disease: 2004 Update. Geneva: WHO, 2008.

2. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for Diagnosis, Management and Prevention of COPD. 2015. http://www.goldcopd.org/uploads/users/files/GOLD_ Report_2015.pdf (accessed 23 July 2015).

3. Viviers PJ, van Zyl-Smit RN. Chronic obstructive pulmonary disease – diagnosis and severity classification. S Afr Med J 2015;105(9):786-788. [http://dx.doi.org/10.7196/SAMJnew.8421] 4. Shaddock E, Richards G. Pharmacological management of chronic obstructive pulmonary disease. S Afr Med J 2015;105(9):790. [http://dx.doi.org/10.7196/SAMJnew.8426] 5. Abraham S, Symons G. Non-pharmacological management of chronic obstructive pulmonary disease.

S Afr Med J 2015;105(9):789. [http://dx.doi.org/10.7196/SAMJnew.8489] 6. Vorster MJ, Koegelenberg CFN. Lung volume reduction in chronic obstructive pulmonary disease. S Afr Med J 2015;105(9):791. [http://dx.doi.org/10.7196/SAMJnew.8427] 7. Allwood B, Calligaro G. Pathogenesis of chronic obstructive pulmonary disease: An African perspective.

S Afr Med J 2015;105(9):789. [http://dx.doi.org/10.7196/SAMJnew.8424] 8. Maree DM. Five tips for good office spirometry. S Afr Med J 2015;105(9):791. [http://dx.doi.org/10.7196/ SAMJnew.8428] 9. Van Zyl-Smit RN, Pai M, Yew WW, et al. Global lung health: The colliding epidemics of tuberculosis, tobacco smoking, HIV and COPD. Eur Respir J 2010;35(1):27-33. [http://dx.doi.org/10.1183/09031936.00072909] 10. Van Zyl-Smit RN, Allwood B, Stickells D, et al. South African tobacco smoking cessation Clinical Practice Guideline. S Afr Med J 2013;103(11):869-876. [http://dx.doi.org/10.7196/samj.7484] 11. Bateman ED, Boushey HA, Bousquet J, et al. Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma ControL study. Am J Respir Crit Care Med 2004;15;170(8):836-844. [http:// dx.doi.org/10.1164/rccm.200401-033OC] 12. GINA. Global Strategy for Asthma Management and Prevention. 2014. http://www.ginasthma.org (accessed 23 July 2015).

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REVIEW

Chronic obstructive pulmonary disease – diagnosis and classification of severity P J Viviers,1 MB ChB, MMed (Int), Cert Pulmonology (SA); R N van Zyl-Smit,2 MB ChB, MRCP (UK), FCP (SA), Dip HIV Man (SA), MMed, Cert Pulmonology (SA), PhD 1 2

Private Practice, Life-Wilgers Hospital, Pretoria, South Africa UCT Lung Institute, Division of Pulmonology, Department of Medicine, Faculty of Health Sciences, University of Cape Town, South Africa

Corresponding author: P J Viviers (drpjv@live.com)

Chronic obstructive pulmonary disease (COPD) is a common, progressive and preventable non-communicable respiratory disorder. It is often confused with asthma and poorly understood by many lay people. The primary cause of COPD is tobacco smoking, but in the South African (SA) context, biomass fuel exposure/household pollution, tuberculosis, HIV and mining exposure are additional important causes.

There is a very high prevalence of COPD in SA and it is the third leading cause of mortality globally.

The diagnosis of COPD is based predominantly on symptoms, i.e. progressive shortness of breath and cough in a patient with risk factors – usually smoking. Lung function testing is required to formally make the diagnosis, which places a significant hurdle in correctly identifying COPD in SA, given the limited access to spirometry in many areas. Spirometry is also required to grade the severity of lung function obstruction.

Severity assessment, which is used to plan a management strategy (predominantly bronchodilators with inhaled steroids in severe cases), combines symptoms, lung function and exacerbations. Based on these 3 factors, a patient can be categorised into 1 of 4 groups and appropriate management instituted. Additional comorbidities, particularly cardiovascular and mental illness, should also be evaluated.

Early identification of COPD, with further avoidance of an aetiological cause such as smoking, is key in preventing disease progression.

Appropriate therapy, comprising non-pharmacological and pharmacological interventions and based on a comprehensive severity assessment, should result in symptom improvement and reduced risk for exacerbations.

S Afr Med J 2015;105(9):786-788. DOI:10.7196/SAMJnew.8421

Chronic obstructive pulmonary disease (COPD) is a common, progressive and preventable disorder of the airways. It is often poorly understood by patients, and frequently referred to as ‘asthma’ or emphysema, which adds to the confusion. It is characterised by predominantly fixed airway obstruction as a result of exposure to inhaled noxious environmental particles or gases, e.g. cigarette smoke, biomass fuels, occupational exposure.[1] The predominant symptoms are progressive dyspnoea, cough and wheeze, interlaced with periods of acute worsening or so-called exacerbations.

COPD is a prevalent condition (329 million people are affected worldwide), with an increasing incidence. Currently, the World Health Organization (WHO) ranks COPD as the fourth most important cause of death due to non-communicable disease worldwide, which is predicted to rise to the third place by 2020.[2] In South Africa (SA) there are limited data, but data from Cape Town estimated the prevalence to be high (>20%); compared with other countries in the BOLD study, Cape Town ranked highest.[3] The population studied was not representative of the entire country, and there is no clear estimate of how prevalent COPD is. There are also no substantial data from the rest of Africa.

Compared with COPD, asthma, a chronic inflammatory disease of the airways, features highly variable airflow obstruction (i.e. clinically suggested by a positive bronchodilator response) in most cases, leading to episodes of cough, wheeze and dyspnoea, but usually with a return to normal baseline lung function between these acute ‘attacks’. The focus of this review is the correct diagnosis of COPD. It is important to differentiate the condition from asthma as the progression of disease, expectation of patient and doctor, and management are different.

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It is not always easy to distinguish COPD from asthma because of shared clinical features. The term asthma-COPD overlap syndrome (ACOS) has been coined to identify this group, which includes features of both conditions.[4] It is the subject of much debate and beyond the scope of this review, but if in doubt it is considered safer to treat the patient as if they are asthmatic. This review focuses on the diagnosis and severity evaluation of COPD and relies heavily on the South African Thoracic Society Guidelines[5] and the updated GOLD strategy document and teaching slides.[1]

Diagnosis of COPD

A complete history and thorough clinical examination are vital and cannot be substituted by any other measure when considering a diagnosis of COPD. A progressive decline in respiratory function, characterised by dyspnoea or worsening shortness of breath on effort (e.g. walking on the level or climbing stairs), cough and wheeze, interlaced by periods of intermittent worsening (or exacerbations), in a patient with known risk factors is typical for a diagnosis of COPD. The disease usually presents after the age of 40 years, with a slow progressive onset of symptoms. Importantly, such patients generally do not enjoy a full return to normal functioning over a period of time, despite treatment (as is the case with asthma). A rapid onset of symptoms should raise suspicion of an alternative condition.

The second key element is a significant exposure history, specifically to tobacco smoking – generally >10 pack-years (20 per day for 10 years) – for the diagnosis to be considered. If the person started smoking in their teenage years, used dagga and/or methaqualone (Mandrax), COPD may well occur before the age of 40. One should also enquire about additional exposures such as biomass/indoor air pollution, mining exposure, previous tuberculosis (TB), HIV, and childhood diseases.

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Clinical examination is characterised by hyperinflation, reduced breath sounds and possibly expiratory wheezing. Be certain to look for clubbing and lymphadenopathy, as the risk of cancer is high in heavy smokers. Findings on clinical examination often parallel disease severity in advanced cases; a myriad of clinical signs might be quite obvious (e.g. sarcopenia, pursed-lip breathing, a tripod stance, soft-to-absent breath sounds), but in the earlier stages there might be a paucity of clinical findings. The presence of signs of right heart failure/cor pulmonale (raised jugular venous pressure, hepatomegaly and peripheral oedema) and cardiac arrhythmias (e.g. atrial fibrillation) should be sought, as these require additional management and in most cases prompt referral.

A major stumbling block to the correct diagnosis of COPD is the requirement for spirometry. The use of this technique is recognised by international and local guidelines; without it a diagnosis cannot be confirmed. Airway obstruction is spiro­ metrically defined as the forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) ratio <0.7, with an absolute value of FEV1 <80% of predicted for age, gender and height. Clinicians are urged to refer to the published guidelines on the practical use of office spirometry.[6] The post-bronchodilator FEV1 is also used to grade the severity of obstruction, which is important when deciding on management.

This is percentage-predicted FEV1, not the severity of the ratio that is used to grade lung function impairment. Lung function may help to distinguish a COPD patient from one with asthma, but reversibility or the lack thereof does not rule out either.

Lung function must be viewed against the clinical picture. Reversibility of >12%/200 mL occurred in >50% of patients enrolled in the large UPLIFT COPD study, but reversibility does not always help to differentiate asthma from COPD.[7] A chest radiograph may depict features of hyperinflation, but does not distinguish between asthma and COPD. The value of an initial chest radiograph during work-up is mainly in screening for addition­ al or alternative lung pathology, such as malignancy, parenchymal disease (pulmonary fibrosis), or previous TB with scarring, but is not a prerequisite to start therapy. High-resolution computed tomography (HRCT) scanning of the chest is excellent for anatomical assessment in COPD, as it can precisely locate and categorise emphysema. Its use is limited by the high cost and lack of general

Fig. 1. Global Initiative for Chronic Obstructive Lung Disease classification of COPD severity.

Evaluation of symptoms and breathlessness (x-axis), lung function (y-axis, left) and exacerbation history (y-axis, right) provides a combined severity assessment upon which to base a treatment strategy (CAT = COPD assessment test; mMRC = modified Medical Research Council dyspnoea scale; GOLD classification of airflow limitation 1 and 2 FEV1 ≥50% predicted, 3 and 4 FEV1 <50% predicted). (From the Global Strategy for Diagnosis, Management and Prevention of COPD 2015, © Global Initiative for Chronic Obstructive Lung Disease (GOLD), all rights reserved. Available from http://www.goldcopd.org.) availability, and it is not required for the diagnosis of COPD in the vast majority of cases.

Oxygen saturation or arterial blood gas determination is useful in severe disease, where respiratory failure is suspected and long-term home oxygen is being considered.

In patients who present very early or have a family history of COPD, consider testing for alpha-1 antitrypsin deficiency.

Assessment of severity

COPD and asthma are graded according to severity, and management recommendations are based on severity categories. Tradition­ ally, management was decided on by lung function severity alone, but there has been a growing realisation that FEV1 and clinical symptoms correlate poorly; therefore, other factors are integrated into the severity grading. The second conceptual change is that severity is ‘graded’ rather than ‘staged’, as patients do not necessarily move linearly from one stage to another over time.

The South African Thoracic Society Guidelines[5] and the GOLD strategy docu­ ment[1] both incorporate assessments of FEV1 and dyspnoea; however, the presence of exacerbations is prominent in the newer GOLD guidelines. We focus on these as the most current approach to severity assessment. Based on the severity grading,

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appropriate therapy with bronchodilators and inhaled steroids (in severe cases) may then be instituted. For all grades of severity, smoking cessation, structured exercise plans, good nutrition and vaccination should be considered as part of a holistic treatment plan.

The GOLD ‘square box’ is the focus of the assessment and may be daunting at first, but once used it is relatively easy (Fig. 1). It is easiest to follow a step-wise approach: 1. Assess symptoms and breathlessness Either the COPD assessment test (CAT)[8] or the modified Medical Research Council (mMRC) dyspnoea scale (Fig. 2) may be used.[1] Patients can fill in the CAT or mMRC form in the waiting room prior to seeing the doctor, saving valuable consultation time.

It also allows for objective assessment of symptoms/dyspnoea severity over time. The form is available in several local languages.

For the mMRC the cut-off of ≥2 can be simply defined as not being able to keep up with a healthy peer. This assessment places the patient left or right of the centre line (Fig. 1).

2. Evaluate the severity of lung function In patients with a post-bronchodilator FEV1/ FVC ratio <0.70: • GOLD 1: Mild – FEV1 ≥80% predicted • GOLD 2: Moderate – FEV1 <80% to ≥50% predicted

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risk, especially if they still smoke. COPD contributes to overall fracture risk, and fractures increase long-term morbidity and mortality.[13] It is therefore essential that this frequently overlooked risk factor is evaluated and managed appropriately.

Conclusion

Fig. 2. Modified Medical Research Council dyspnoea scale. Patients may review their own shortness of breath grade based on the description provided for each grade. (From the Global Strategy for Diagnosis, Management and Prevention of COPD 2015, © Global Initiative for Chronic Obstructive Lung Disease (GOLD), all rights reserved. Available from http://www.goldcopd.org.)

• GOLD 3: Severe – FEV1 <50% to ≥30% predicted • GOLD 4: Very severe – FEV1 <30% predicted.

An FEV1 <50% predicted places a patient in a category above the horizontal line.

3. Review the occurrence of exacerbations in the past 12 months An exacerbation is generally considered as a worsening of COPD symptoms, resulting in treatment with corticosteroids and/or antibiotics. More than 2 exacerbations or 1 exacerbation requiring hospitalisation places the patient ‘above the line’. Exacerbations are considered more important than lung function in the assessment of risk; thus, their presence places one above the line even if FEV1 >50% predicted.

4. Evaluate for comorbid diseases such as hypertension, heart failure, diabetes This is not used to place a patient in a box, but is important for risk evaluation and treatment decisions.

With these elements, the patient can then be ‘allocated’ to box A, B, C or D. The combined assessment therefore takes the following into consideration: lung function severity, symptoms and exacerbations. The patient should be allocated to the highest risk category, e.g. a patient with an mMRC >2, plus 2 exacerbations, but FEV1 >50%, should be D – not B. For groups A and B long-acting bronchodilators are the

primary treatment option, and for groups C and D the addition of inhaled steroids in patients with more severe disease.[1]

Assessment of comorbidities

Cardiovascular disease contributes to the majority of deaths in COPD, despite stage or severity, and it is therefore prudent that the medical practitioner evaluate all patients for cardiovascular risk factors. This includes blood pressure measurements, assessment of lipid and glucose metabolism, and electrocardiography, with effort testing where indicated. Treatment of these risk factors contributes to a decreased risk of incident myocardial infarction, stroke and arrhythmias – the major causes of mortality in COPD.[9] Obstructive sleep apnoea is an increasingly common condition, adding to baseline risk, and questionnaires such as the Epworth sleepiness scale[10] may be used to assess risk and determine referral for sleep evaluation.

Psychiatric comorbidity and psychosocial stressors influence patient behaviour, particularly regarding smoking cessation. The presence of a major depressive disorder decreases continued abstinence rates.[11] Furthermore, psychiatric conditions are prevalent in COPD, as in most chronic disorders, and if left untreated might lead to decreased compliance with management and reduced quality of life.[12] Osteoporosis screening should be done in male and female patients with increased

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A diagnosis of COPD should be suspected in patients who present with slowly progressive shortness of breath, even without a history of smoking. Take a detailed history of exposure to tobacco, dagga, methaqualone and other environmental pollutants.

Document the history of exacerbations and identify other comorbid diseases. Clinical examination is helpful to support the diagnosis and rule out other respiratory conditions. Spirometry/lung function tests (pre- and post-FEV1 and FVC) are required to confirm the diagnosis and aid in severity grading. Radiology is often supportive but not a prerequisite, unless one is screening for lung cancer, and other specialised tests are generally not needed. With this holistic evaluation in place, appropriate decisions on management can be taken. Where symptoms and signs do not match, the disease progression is rapid, or in young patients referral to a specialist may be needed to exclude another unrecognised pulmonary condition.

References 1. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for Diagnosis, Management and Prevention of COPD. 2015. http://www.goldcopd.org (accessed 24 July 2015).

2. World Health Organization. The Global Burden of Disease: 2004 update. Geneva: WHO, 2008.

3. Buist AS, McBurnie MA, Vollmer WM, et al. International variation in the prevalence of COPD (the BOLD Study): A population-based prevalence study. Lancet 2007;370(9589):741750.

4. GINA-GOLD. Diagnosis of diseases of chronic airflow limitation: Asthma, COPD and asthma-COPD overlap syndrome (ACOS). 2014. http://www.goldcopd.org/asthmacopd-overlap.html (accessed 24 July 2015).

5. Abdool-Gaffar MS, Ambaram A, Ainslie GM, et al. Guideline for the management of chronic obstructive pulmonary disease – 2011 update. S Afr Med J 2011;101(1):61-73.

6. Koegelenberg CF, Swart F, Irusen EM. Guideline for office spirometry in adults, 2012. S Afr Med J 2013;103(1):52-62. [http://dx.doi.org/10.7196/samj.6197] 7. Tashkin DP, Celli B, Decramer M, et al. Bronchodilator responsiveness in patients with COPD. Eur Respir J 2008;31(4):742750. [http://dx.doi.org/10.1183/09031936.00129607] 8. COPD assessment test. http://www.catestonline.org (accessed 24 July 2015).

9. Boggon R, van Staa TP, Timmis A, et al. Clopidogrel discontinuation after acute coronary syndromes: Frequency, predictors and associations with death and myocardial infarction – a hospital registry-primary care linked cohort (MINAP-GPRD). Eur Heart J 2011;32(19):2376-2386.

10. Epworth sleepiness scale. http://yoursleep.aasmnet.org/pdf/ Epworth.pdf (accessed 24 July 2015).

11. Prochaska JJ. Smoking and mental illness – breaking the link.

N Engl J Med 2011;365(3):196-198. [http://dx.doi.org/10.1056/ NEJMp1105248] 12. Hanania NA, Mullerova H, Locantore NW, et al. Determinants of depression in the ECLIPSE chronic obstructive pulmonary disease cohort. Am J Respir Crit Care Med 2011;183(5):604-611. [http://dx.doi.org/10.1164/rccm.201003-0472OC] 13. Romme EA, Geusens P, Lems WF, et al. Fracture prevention in COPD patients; a clinical 5-step approach.

Respir Res 2015;16:32. [http://dx.doi.org/10.1186/s12931015-0192-8]

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ARTICLE

Pathogenesis of chronic obstructive pulmonary disease: An African perspective B Allwood,1 MB BCh, DCH (SA), DA (SA), FCP (SA), MPH, Cert Pulmonology (SA), PhD; G Calligaro,2 BSc (Hons), MB BCh, Dip PEC, FCP (SA), MMed, Cert Pulmonology (SA) Division of Pulmonology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University and Tygerberg Academic Hospital, Cape Town, South Africa 2 Lung Infection and Immunity Unit, Division of Pulmonology and UCT Lung Institute, Department of Medicine, Faculty of Health Sciences, Groote Schuur Hospital and University of Cape Town, South Africa 1

Corresponding author: B Allwood (brianallwood@sun.ac.za)

The importance of chronic obstructive pulmonary disease (COPD) as a global health problem cannot be overstated. According to the latest World Health Organization statistics (2005), 210 million people suffer from COPD worldwide, and 5% of all deaths globally are estimated to be caused by this disease. This corresponds to >3 million deaths annually, of which 90% are thought to occur in low- and middle-income countries.

While cigarette smoking remains the major risk factor, and much of the increase in COPD is associated with projected increases in tobacco use, epidemiological studies have demonstrated that in the majority of patients in developing countries the aetiology of COPD is multifactorial.

This article summarises the epidemiology of and risk factors for COPD in Africa, including influences other than cigarette smoking that are important contributors to chronic irreversible airflow limitation in our setting.

S Afr Med J 2015;105(9):789. DOI:10.7196/SAMJnew.8424

The importance of chronic obstructive pulmonary disease (COPD) as a global health problem cannot be overstated. According to the latest World Health Organization (WHO) statistics (2005), approximately 210 million people suffer from COPD worldwide, and 5% of all deaths globally are estimated to be caused by this disease. This corresponds to >3 million deaths annually, of which 90% are thought to occur in low- and middle-income countries. A projection published by the WHO Global Burden of Disease Project indicates that COPD will be the third leading cause of death globally by 2030.[1] Much of this burden will be in the developing populations of Africa, Asia and the Indian subcontinent. As developing countries can ill afford the added economic burden of COPD, there is an urgent need to understand and address the risk factors for the development of COPD in these countries.

While cigarette smoking remains the major risk factor, and much of the increase in COPD is associated with projected increases in tobacco use, epidemiological studies have demonstrated that in the majority of patients in developing countries the aetiology of COPD is multifactorial.

Research has suggested that a quarter to almost a half of all patients with COPD are non-smokers.[2] Attributable fractions have been calculated for diverse influences such as environmental tobacco smoke exposure (passive smoking), smoke from biofuel combustion, exposure to dust, fumes and vapours, childhood illness, and previous tuberculosis (TB).

Combinations of these risk factors are likely to be highly prevalent or even the rule in poor communities in developing countries, and may account for the greater frequency and severity of COPD in these settings.

In this article, we summarise the epidemiology of and risk factors for COPD in Africa, including influences other than cigarette smoking that are important contributors to chronic irreversible airflow limitation in our setting.

Tobacco smoking

Cigarette smoking remains the most well-documented and important cause of COPD. However, the old adage that â&#x20AC;&#x2DC;only 15% of smokers

will get COPDâ&#x20AC;&#x2122;, and by implication the remaining 85% are immune to the effects of cigarette smoke, should be viewed with increasing scepticism. Susceptibility to the effects of smoke should rather be viewed as a continuous variable, not as an either/or phenomenon.

Therefore, almost all smokers will develop reduced lung function if they smoke sufficient cigarettes over a sufficient period of time.[3] While some smokers develop very severe COPD, and the rare smoker is unaffected, the majority of smokers lie between these two extremes.

Possibly a more reliable figure, derived from a large Copenhagen cohort, is that after 25 years of smoking, 30 - 40% of smokers with normal baseline lung function will develop COPD, with 25% deemed to have clinically significant disease.[4] Rather unsurprisingly, the chance of developing COPD increases with the number of cigarettes smoked. The adjusted hazard ratio has been reported to be 1.9 for smokers with a <10 pack-year history of smoking, and 8.8 for those with a >50 pack-year history of smoking.[5] Consistent with this dose-response relationship, early cessation of smoking has been shown to dramatically reduce the chance of developing severe disease.[4] However, the absence of clinical disease should not be viewed as reassuring, as emphysema on computed tomography (CT) imaging can be seen in 40% of smokers, with no evidence of abnormalities of lung function testing.[6] Passive smoking, which frequently begins in early childhood, has also been confirmed as a risk factor for COPD. Similar to smoking, an exposure-response gradient exists, with greater exposure being associated with greater risk.[7] Cannabis smoking and its relationship with COPD is more controversial and difficult to prove, as cannabis and tobacco are frequently smoked concurrently. Some studies suggest that heavy use (>20 joint-years) is associated with airflow obstruction, but these findings are inconsistent. In a local study, Jithoo[8] found cannabis use to be a strong predictor of chronic bronchitis, and concluded that the drug is a likely contributor to both chronic respiratory symptoms and possibly COPD, if not a sufficient cause in its own right.

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Airway inflammation with mucus hyper足 secretion (chronic bronchitis) as well as enlargement and destruction of the walls of the distal air spaces (emphysema) are the end results of cigarette smoking, and underlie the mechanisms of airflow obstruction observed in COPD. In a person with COPD, either chronic bronchitis or emphysema may predominate; however, both frequently coexist in varying proportions.

Globally, the attributable fraction of cigarette smoking towards COPD deaths varies by both gender and geographical region, with cigarettes being responsible for more deaths from COPD in developed nations and in males compared with developing nations and females. In developed nations, the attributable fraction is 77 - 84% for men and 61 - 62% for women, while the corresponding rates in developing nations are 45 - 49% and 12 - 20%, respectively.[7] In South Africa (SA), Groenewald et al.[9] estimated the overall population-attributable fraction of COPD to smoking as 62% overall (69% for men and 51% for women). However, the prevalence of smoking is not uniform across the entire population, with coloureds having the highest rates of smoking, followed by whites and blacks.[10] From the abovementioned figures it is clear that cigarette smoking is not the only cause of COPD. Salvi and Barnes[2] estimate that 25 - 45% of patients with COPD have never smoked. Ninety per cent of COPD deaths occur in low- and middle-income countries, and it is likely that non-smoking causes contribute to this excess burden of disease.[1]

Biomass smoke exposure

Foremost among non-smoking causes of COPD is the use of biomass fuels for daily indoor cooking and heating. It is estimated that approximately 3 billion people worldwide are exposed to smoke from the burning of wood, dung, crop residue and other organic fuels. This represents 50% of all households and 90% of rural households, and it has been suggested that biomass exposure may be a more important global cause of COPD than cigarette smoking.[2] The use of stoves and open fires indoors, with poor ventilation, produces high levels of pollutants, similar to tobacco smoke, and places primarily women and young children at risk. The WHO estimates that biomass exposure kills 2 million women and children, and that lung growth in young children may be particularly affected.[1] The odds ratio for the development of COPD in women exposed to biomass has been estimated at 2.40 (95% confidence interval (CI) 1.47 - 3.93).[11] In 2007, 20% of SA households were said to be exposed to indoor smoke, with marked variations between the different population

HIV

groups. Biomass use in SA was estimated to account for 13.1% of COPD in men and 31.1% in women, and to be responsible for 2 957 and 8 920 disability-adjusted life-years (DALYs) in men and women, respectively.[12]

The lung is a major target organ for HIV, render足 ing it susceptible to a wide array of infectious and non-infectious complications.[18,19] With the advent of early antiretroviral therapy (ART) and widespread antimicrobial prophylaxis, HIV-associated mortality[20,21] and incidence of opportunistic and recurrent infections[22] have been greatly reduced. In the developed world, this has resulted in a large-scale shift in the epidemiology of adult HIV-related pulmonary diseases. With a decrease in opportunistic infections and an increase in life expectancy, COPD has emerged as a potentially important non-infectious complication of HIV.[23] Preliminary crosssectional studies have documented a high prevalence of COPD among HIV-infected individuals, and described an association with risk factors such as cigarette smoking, previous opportunistic infections, markers of HIV infection and ART use.[24-30] A few longitudinal studies have suggested that the magnitude of lung function decline in individuals with uncontrolled HIV infection exceeds that which is generally attributed to current smoking alone.[31] Despite the high burden of HIV infection in sub-Saharan Africa, there is a paucity of data on lung function in HIV-infected individuals from this region: a study from Nigeria found significantly lower forced expiratory volume in 1 second (FEV1) values and a higher inci足 dence of COPD among HIV-positive compared with HIV-negative individuals,[30] while an SA report of a relatively young, predominantly female and largely non-smoking cohort of treated HIV-infected individuals on ART found that irreversible airflow obstruction was present in 7%,[24] a higher figure than

Tuberculosis

The association between TB and the later development of COPD was previously contro足 versial; however, several large population cross-sectional studies have confirmed the association, with some studies claiming that it is stronger than that for either smoking or biomass exposure.[13-16] In an SA study, Jithoo[8] found that the odds ratio of TB for mild and moderate COPD was 2.6 (95% CI 1.5 - 4.6), while for severe and very severe disease is was 8.9 (95% CI 4.2 - 18.9). Furthermore, it was found that almost 50% of adults >40 years of age with a history of previous TB had evidence of chronic airflow limitation.[8] The mechanism of airflow obstruction, in what is increasingly being termed TB-associated obstructive pulmonary disease, remains uncertain; also whether this should be considered the same as smoking-related COPD or as a different phenotype with its own treatment, rate of decline and outcomes. We have found subtle but important physiological differences in these two conditions, implying a somewhat different pathogenesis of airflow limitation not accounted for by the presence of bronchiectasis. It is clear that a significant proportion of patients who complete TB treatment have residual chronic airflow limitation, with varying degrees of disability. Considering the estimated 9 million annual cases of TB globally (330 000 in SA), the potential problem of chronic airflow limitation is immense and requires urgent further study.[17] Pre-antiretroviral era

Antiretroviral era

Infections Pneumocystis jirovecii Bacterial pneumonia Tuberculosis Polimicrobial infection CD4 T cells

HIV

CD8 T cells Lymphocytic alveolitis Up-regulation of antioxidant pathways (increased metalloproteinase expression)

Increased autoimmunity

Lung function abnormalities in HIV Airflow obstruction Lung diffusion Airway hyper-reactivity

High viral load

Colonisation of microbial pathogens

Antiretroviral therapy

Decreased antioxidant tolerance Renewed immunological response to persistent microbial pathogens (IRIS) Chronic inflammation

Smoking Infection

Pneumocystis jirovecii Drug use

Fig. 1. Factors underlying the interaction between HIV and chronic lung disease.

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would be expected in an HIV-uninfected population with similar demographics.

The mechanisms behind HIV-associated COPD are unknown, but may result from the HIV infection, the effect of long-term ART and immune reconstitution, the development of autoimmunity, or the effects of repeated pulmonary infections, or may simply be due to living with HIV for an extended period of time (Fig. 1). These interactions have major public health implications – the direct and indirect effects of HIV infection, together with the projected increases in tobacco use, biomass fuel exposure, and high rates of childhood infections, have the potential to create a ‘perfect storm’ of chronic pulmonary disability in Africa.[32]

Occupational exposures

There is accumulating evidence that COPD is caused by occupational exposures to respirable dusts, smoke, vapours and fumes. The American Thoracic Society’s consensus statement suggests that between 10% and 20% of COPD is attributable to workplace exposures.[33] In SA, much epidemiological work has been done on the association between respirable silica dust and airflow obstruction (independent of radiological silicosis) in underground gold miners.[34] In one study, the contribution of FEV1 loss due to silica was estimated at about half that of smoking 30 cigarettes a day for 30 years.[35] Although this effect is observed even in non-smokers, smoking and silica exposure are multiplicative, potentiating the development of and mortality from COPD.[36] Lastly, workers exposed to silica dust are at increased risk of developing TB, even in the absence of silicosis.[33] As described above, residual damage from treated TB is also associated with airflow obstruction and chronic respiratory symptoms.

The association between occupational exposures to dust and chemicals and COPD has been demonstrated in studies of workers employed in other industries in Africa.[37-41] These occupational exposures include (but are not limited to) inorganic dust, cadmium, coal, organic dust, cotton, grain, diesel fumes, and welding. In a hospital-based case control study from KwaZulu-Natal, self-reported occupational exposures to biological dust or gas and fumes were associated with a two-fold increased odds of developing COPD, after adjustment for smoking and previous TB.[42]

Intra-uterine environment, p ­ re­ maturity and childhood respiratory infections

COPD may originate in childhood, or even in utero. Low-birthweight babies or those whose mothers smoked during pregnancy have reduced lung function.[43,44] Other antenatal effects that may negatively affect fetal lung development include maternal hypertension or pre-eclampsia, diabetes, medication use[45] and exposure to air pollution.[46] The effects of perinatal events, such as premature birth on lung function, are well documented.[47] Preterm infants have an increased risk of impaired lung function in infancy, childhood and adulthood, and an increased risk of respiratory illness. Long-term lung injury is caused by arrest of structural lung development at an immature stage (bronchopulmonary dysplasia), and is exacerbated by the use of mechanical ventilation and high-concentration supplemental oxygen in infancy.[48,49] Severe pulmonary viral and bacterial infections in childhood have been shown to be associated with reduced lung function and obstructive spirometry in adult life.[50] Childhood infection damages a vulnerable lung undergoing rapid postnatal growth, and may also make it increasingly susceptible to additional noxious agents such as cigarette smoke or indoor air pollution. Postinfective

bronchiolitis obliterans and bronchiectasis are common sequelae that cause chronic airflow limitation in survivors of severe childhood respiratory infection.

Conclusion

In the developing world, the pathogenesis of COPD is likely to be multifactorial. Colliding epidemics of TB, cigarette smoking, pulmonary infection and HIV threaten to greatly increase the burden of chronic lung disease in these regions.[32] There is therefore an urgent need to study the influences and interaction between these putative causative factors, particularly in Africa.

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4. Løkke A, Lange P, Scharling H, Fabricius P, Vestbo J. Developing COPD: A 25 year follow up study of the general population. Thorax 2006;61(11):935-939.

5. Van Durme YMT, Verhamme KMC, Stijnen T, et al. Prevalence, incidence, and lifetime risk for the development of COPD in the elderly: The Rotterdam study. Chest 2009;135(2):368-377. [http://dx.doi. org/10.1378/chest.08-0684] 6. Mastora I, Remy-Jardin M, Sobaszek A, Boulenguez C, Remy J, Edme JL. Thin-section CT finding in 250 volunteers: Assessment of the relationship of CT findings with smoking history and pulmonary function test results. Radiology 2001;218(3):695-702.

7. Eisner MD, Anthonisen N, Coultas D, et al. An official American Thoracic Society public policy statement: Novel risk factors and the global burden of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2010;182:693-718. [http://dx.doi.org/10.1164/rccm.200811-1757ST] 8. Jithoo A. Respiratory Symptoms and Chronic Obstructive Pulmonary Ddisease. Prevalence and Risk Factor in a Predominantly Low-income Urban Area of Cape Town, South Africa. PhD thesis. Cape Town: University of Cape Town, 2006:1-284.

9. Groenewald P, Vos T, Norman R, et al. Estimating the burden of disease attributable to smoking in South Africa in 2000. S Afr Med J 2007;97(8):674.

10. Sitas F, Egger S, Bradshaw D, et al. Differences among the coloured, white, black, and other South African populations in smoking-attributed mortality at ages 35-74 years: A case-control study of 481,640 deaths. Lancet 2013;382(9893):685-693. [http://dx.doi.org/10.1016/S0140-6736(13)61610-4] 11. Po JYT, FitzGerald JM, Carlsten C. Respiratory disease associated with solid biomass fuel exposure in rural women and children: Systematic review and meta-analysis. Thorax 2011;66(3):232-239. [http:// dx.doi.org/10.1136/thx.2010.147884] 12. Norman R, Barnes B, Mathee A, Bradshaw D. Estimating the burden of disease attributable to indoor air pollution from household use of solid fuels in South Africa in 2000. S Afr Med J 2007;97(8):764-771.

13. Menezes AMB, Perez-Padilla R, Jardim JB, et al. Chronic obstructive pulmonary disease in five Latin American cities (the PLATINO study): A prevalence study. Lancet 2005;366(9500):1875-1881.

14. Caballero A, Torres-Duque CA, Jaramillo C, et al. Prevalence of COPD in five Colombian cities situated at low, medium, and high altitude (PREPOCOL Study). Chest 2008;133(2):343-349.

15. Lam KB, Jiang CQ, Jordan RE, et al. Prior TB, smoking, and airflow obstruction : A cross-sectional analysis of the Guangzhou Biobank Cohort Study. Chest 2010;137(3):593-600. [http://dx.doi. org/10.1378/chest.09-1435] 16. Idolor LF, de Guia TS, Francisco NA, et al. Burden of obstructive lung disease in a rural setting in the Philippines. Respirology 2011;16(7):1111-1118. [http://dx.doi.org/10.1111/j.1440-1843.2011.02027.x] 17. World Health Organization. Tuberculosis country profiles. http://www.who.int/tb/country/data/ profiles/en/ (accessed 31 July 2015).

18. Morris A, Crothers K, Beck JM, Huang L. An official ATS workshop report: Emerging issues and current controversies in HIV-associated pulmonary diseases. Proc Am Thorac Soc 2011;8(1):17-26. [http://dx.doi.org/10.1513/pats.2009-047WS] 19. Kanmogne GD. Noninfectious pulmonary complications of HIV/AIDS. Curr Opin Pulm Med 2005;11(3):208-212.

20. Gortmaker SL, Hughes M, Cervia J, et al. Effect of combination therapy including protease inhibitors on mortality among children and adolescents infected with HIV-1. N Engl J Med 2001;345(21):15221528.

21. Violari A, Cotton MF, Gibb DM, et al. Early antiretroviral therapy and mortality among HIV-infected infants. N Engl J Med 2008;359(21):2233-2244.

22. Nesheim SR, Kapogiannis BG, Soe MM, et al. Trends in opportunistic infections in the pre- and post-highly active antiretroviral therapy eras among HIV-infected children in the Perinatal AIDS Collaborative Transmission Study, 1986-2004. Pediatrics 2007;120(1):100-109.

23. Hull MW, Phillips P, Montaner JSG. Changing global epidemiology of pulmonary manifestations of HIV/AIDS. Chest 2008;134(6):1287-1298. [http://dx.doi.org/10.1378/chest.08-0364] 24. Calligaro G, Bateman ED, Rom WN, Dheda K, van Zyl-Smit RN, Weiden M. Respiratory symptoms and pulmonary function abnormalities in HIV-infected patients on antiretroviral therapy in a high tuberculosis burden country. American Thoracic Society 2011 International Conference, Denver, Colorado, 13 - 18 May 2011. Abstract A6262-A. 25. Cui Q, Carruthers S, McIvor A, Smaill F, Thabane L, Smieja M. Effect of smoking on lung function, respiratory symptoms and respiratory diseases amongst HIV-positive subjects: A cross-sectional study.

AIDS Res Ther 2010;7:6. [http://dx.doi.org/10.1186/1742-6405-7-6] 26. Drummond MB, Kirk GD, Astemborski J, et al. Association between obstructive lung disease and markers of HIV infection in a high-risk cohort. Thorax 2012;67(4):309-314. [http://dx.doi. org/10.1136/thoraxjnl-2011-200702] 27. George MP, Kannass M, Huang L, Sciurba FC, Morris A. Respiratory symptoms and airway obstruction in HIV-infected subjects in the HAART era. PLoS One 2009;4(7):e6328. [http://dx.doi. org/10.1371/journal.pone.0006328] 28. Gingo MR, George MP, Kessinger CJ, et al. Pulmonary function abnormalities in HIV-infected patients during the current antiretroviral therapy era. Am J Respir Crit Care Med 2010;182(6):790-796. [http:// dx.doi.org/10.1164/rccm.200912-1858OC] 29. Hirani A, Cavallazzi R, Vasu T, et al. Prevalence of obstructive lung disease in HIV population: A cross sectional study. Respir Med 2011;105(11):1655-1661. [http://dx.doi.org/10.1016/j.rmed.2011.05.009] 30. Onyedum CC, Chukwuka JC, Onwubere BJC, Ulasi II, Onwuekwe IO. Respiratory symptoms and ventilatory function tests in Nigerians with HIV infection. Afr Health Sci 2010;10(2):130-137.

31. Anthonisen NR, Connett JE, Murray RP. Smoking and lung function of Lung Health Study participants after 11 years. Am J Respir Crit Care Med 2002;166(5):675-679.

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32. Van Zyl-Smit RN, Pai M, Yew WW, et al. Global lung health: The colliding epidemics of tuberculosis, tobacco smoking, HIV and COPD. Eur Respir J 2010;35(1):27-33. [http://dx.doi. org/10.1183/09031936.00072909] 33. American Thoracic Society Committee of the Scientific Assembly on Environmental and Occupational Health. Adverse effects of crystalline silica exposure. Am J Respir Crit Care Med 1997;155(2):761-768.

34. Hnizdo E. Loss of lung function associated with exposure to silica dust and with smoking and its relation to disability and mortality in South African gold miners. Br J Ind Med 1992;49(7):472479.

35. Cowie RL, Mabena SK. Silicosis, chronic airflow limitation, and chronic bronchitis in South African gold miners. Am Rev Respir Dis 1991;143(1):80-84.

36. Hnizdo E. Combined effect of silica dust and tobacco smoking on mortality from chronic obstructive lung disease in gold miners. Br J Ind Med 1990;47(10):656-664.

37. Ballal SG. Respiratory symptoms and occupational bronchitis in chromite ore miners, Sudan. J Trop Med Hyg 1986;89(5):223-228.

38. Laraqui CH, Laraqui O, Rahhali A, et al. Prevalence of respiratory problems in workers at two manufacturing centers of ready-made concrete in Morocco. Int J Tuberc Lung Dis 2001;5(11):1051-1058.

39. Laraqui CH, Yazidi AA, Rahhali TA, et al. The prevalence of respiratory symptoms and immediate hypersensitivity reactions in a population exposed to flour and cereal dust in five flour mills in Morocco. Int J Tuberc Lung Dis 2003;7(4):382-389.

40. Mustafa KY, Lakha AS, Milla MH, Dahoma U. Byssinosis, respiratory symptoms and spirometric lung function tests in Tanzanian sisal workers. Br J Ind Med 1978;35(2):123-128.

41. Yach D, Myers J, Bradshaw D, Benatar SR. A respiratory epidemiologic survey of grain mill workers in Cape Town, South Africa. Am Rev Respir Dis 1985;131(4):505-510.

42. Govender N, Lalloo UG, Naidoo RN. Occupational exposures and chronic obstructive pulmonary disease: A hospital based case-control study. Thorax 2011;66(7):597-601. [http://dx.doi.org/10.1136/ thx.2010.149468] 43. Lødrup Carlsen KC, Jaakkola JJ, Nafstad P, Carlsen KH. In utero exposure to cigarette smoking influences lung function at birth. Eur Respir J 1997;10(8):1774-1779.

44. Stick SM, Burton PR, Gurrin L, Sly PD, LeSouëf PN. Effects of maternal smoking during pregnancy and a family history of asthma on respiratory function in newborn infants. Lancet 1996;348(9034):1060-1064.

45. Rusconi F, Galassi C, Forastiere F, et al. Maternal complications and procedures in pregnancy and at birth and wheezing phenotypes in children. Am J Respir Crit Care Med 2007;175(1):16-21.

46. Latzin P, Röösli M, Huss A, Kuehni CE, Frey U. Air pollution during pregnancy and lung function in newborns: A birth cohort study. Eur Respir J 2009;33(3):594-603. [http://dx.doi. org/10.1183/09031936.00084008] 47. Baraldi E, Filippone M. Chronic lung disease after premature birth. N Engl J Med 2007;357(19):19461955.

48. Gross SJ, Iannuzzi DM, Kveselis DA, Anbar RD. Effect of preterm birth on pulmonary function at school age: A prospective controlled study. J Pediatr 1998;133(2):188-192.

49. Jones M. Effect of preterm birth on airway function and lung growth. Paediatr Respir Rev 2009;10(Suppl 1):9-11. [http://dx.doi.org/10.1016/S1526-0542(09)70005-3] 50. Samet JM, Tager IB, Speizer FE. The relationship between respiratory illness in childhood and chronic air-flow obstruction in adulthood. Am Rev Respir Dis 1983;127(4):508-523.

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ARTICLE

Non-pharmacological management of chronic obstructive pulmonary disease S Abraham,1 MB ChB, FCP (SA); G Symons,2 MB ChB, Dip PEC, FCP (SA), Cert Pulmonology (SA) 1 Division of Pulmonology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University and Tygerberg Academic Hospital, Cape Town, South Africa 2 Division of Pulmonology, Department of Medicine, Faculty of Health Sciences, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa

Corresponding author: S Abraham (shinu_29@yahoo.com)

Chronic obstructive pulmonary disease (COPD) is the third leading cause of morbidity and mortality globally, contributing to a substantial use of resources. According to World Health Organization estimates, 65 million people have moderate to severe COPD. The condition is also recognised as a systemic disease with extrapulmonary manifestations, such as peripheral muscle dysfunction, malnutrition and depression, which further contribute to disability, poor quality of life, exacerbations and mortality. Optimum management requires nonpharmacological interventions combined with pharmacological treatment. However, the former is often neglected and not widely used in daily practice, with the focus mainly on the latter.

S Afr Med J 2015;105(9):789. DOI:10.7196/SAMJnew.8489

Chronic obstructive pulmonary disease (COPD) is the third leading cause of morbidity and mortality glo­bally, contributing to a substantial use of resources.[1] According to World Health Organization estimates, 65 million people have moderate to severe COPD.[2] The condition is also recognised as a systemic disease with extrapulmonary manifestations, such as peripheral muscle dysfunction, malnutrition and depression, which further contribute to disability, poor quality of life, exacerbations and mortality. Optimum management requires non-pharmacological interventions combined with pharmacological treatment. However, the former is often neglected and not widely used in daily practice, with the focus mainly on the latter.

Non-pharmacological management options for COPD include smoking cessation, pulmonary rehabilitation, pneumococcus and influenza vaccinations, non-invasive positive pressure ventilation (NPPV), long-term oxygen therapy (LTOT), surgery and broncho­ scopic lung volume reduction.

Smoking cessation remains the only proven intervention to slow the decline of lung function and should be prioritised in the management of COPD patients. A gradual decline in forced expiratory volume in 1 second (FEV1) is a normal part of ageing; however, decline is accelerated in patients with COPD, with greater decline in the early stages of COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD I and II)),[3] emphasising the importance of early smoking cessation interventions.

Pulmonary rehabilitation has been shown to be the most effective non-pharmacological intervention for improving health status and quality of life in COPD patients and addresses aspects of the disease not sufficiently covered by medical therapy, including peripheral muscle dysfunction, cachexia, social isolation and psychological issues.

Pneumoccocal and influenza vaccines may reduce infectious exacerbations – the most common cause of acute decompensation.

NPPV is beneficial during acute exacerbations, reducing the need for intubation, length of stay in the intensive care unit, and mortality rate during hospitalisation. Long-term supplemental oxygen improves

the mortality rate and quality of life in patients with severe resting hypoxaemia. Surgical options in COPD include lung volume reduction surgery (LVRS), bullectomy and lung transplantation.

Bronchoscopic lung volume reduction is still being studied and is an emerging therapy in the management of COPD, not yet approved for use in the clinical setting. This article elaborates on the nonpharmacological interventions available for the management of COPD, which complement appropriate pharmacological therapy.

Smoking cessation

As smoking is the most important modifiable risk factor for COPD, quitting smoking is critical to reduce the occurrence and progression of the disease. Findings from landmark studies such as the Lung Health Study from the USA[4] show that long-term smoking cessation is associated with a reduction in the rate of FEV1 decline and survival.

Smoking cessation not only benefits the lung (reduction in lung cancer, reduced lung function loss), but also reduces the risk of cardiovascular disease and other smoking-related conditions.

Effective smoking cessation requires a combination of pharmaco­ logical therapy and behavioural support and counselling. The South African Thoracic Society clinical practice guideline is a useful resource to assist clinicians.[5] Pharmacological options include nicotine replacement therapies, such as nicotine gum, patches, oral inhalers and sprays, varenicline (Champix) and bupropion (Zyban). All healthcare professionals should give smoking cessation advice to every smoker at every point of contact. The 5 major steps of a smoking intervention may be summarised as 5 As: • Ask: enquire about tobacco use during every patient contact (both current and past patterns of smoking).

• Alert: urge all smokers to quit and provide information on the benefits of quitting.

• Assess: determine willingness to make an attempt to quit.

• Assist: help the patient to quit by referral for further counselling and pharmacotherapy.

• Arrange: schedule a follow-up visit.

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Pulmonary rehabilitation

Advanced COPD is associated with systemic inflammation, and increased circulating levels of cytokines and oxidative stress promote muscle loss, peripheral muscle dysfunction and cachexia.

Deconditioning is associated with a shift from type I to type II fibres, which are less-endurance fibres. Furthermore, progressive dyspnoea associated with moderate to severe disease leads to limitation of physical activity, resulting in disuse atrophy and a vicious cycle of progressive deconditioning. Other factors that possibly play a role in peripheral muscle dysfunction include corticosteroid use, hypoxia and malnutrition.[6] Pulmonary rehabilitation (PR) is a broad therapeutic concept defined as a multidisciplinary intervention comprising exercise training, education and psychological support aimed at improving quality of life and reducing disability in patients with chronic respiratory disease.[6] PR addresses extrapulmonary problems in COPD not covered by pharmacological therapies, such as exercise deconditioning, social isolation, anxiety, depression, muscle wasting and weight loss.

A comprehensive PR programme has various components and may include patient assessment, exercise training, smoking cessation, nutrition, education and psychosocial support. Multidisciplinary teams are involved, including healthcare professionals such as physicians, nurses, physiotherapists, psychologists, dieticians and social workers. Current guidelines suggest a minimum length of an effective rehabilitation programme (6 weeks), with longer programmes showing better results.[7] The optimal duration has not yet been determined. In the absence of formally structured PR programmes, home-based exercise programmes may be encouraged, e.g. leisure walking is associated with increased endurance.[8] The benefits of PR are summarised in Table 1. Indications include patients with chronic respiratory impairment who, despite optimal medical management, have dyspnoea, reduced exercise tolerance or restriction of activities.[7] PR is also effective in reducing rates of hospitalisation and mortality after an acute exacerbation.[9]

used. Guidelines suggest a training frequency varying from daily to weekly, with duration ranging from 10 to 45 minutes and intensity from 50% of peak oxygen consumption to the maximum tolerated.[7,8] Interval training is another option for patients unable to tolerate continuous endurance training and consists of high-intensity exercise alternating with periods of rest or lower-intensity exercise. Resistance training provides a greater increase in muscle mass and strength than endurance training and causes less dyspnoea, making it an option for patients with severe dyspnoea and those who are hospitalised. Endurance and strength training also complement each other.[7] Transcutaneous neuromuscular electrical stimulation (NMES) of leg muscles is a technique involving involuntary muscle contraction induced by electrical stimulation with training of selected muscle groups.[10] NMES improves leg muscle strength and reduces dyspnoea in stable patients with severe COPD and poor baseline exercise tolerance.[10] It also has added benefits and can be continued during COPD exacerbations.[11] Some programmes include upper-extremity training, as everyday activities require the hands. However, studies have shown no benefit for dyspnoea and quality of life. Another non-conventional form of exercise includes ventilatory muscle training (studies done mostly in inspiratory muscle training), which has shown mixed results in clinical trials.

Nutritional support

Malnutrition and cachexia are common in COPD patients. Low body mass index (BMI) and fat free mass index (FFMI) are predictors of poor prognosis and associated with a higher mortality (BMI forms part of the body mass index, airflow obstruction, dyspnoea and exercise capacity (BODE) index for COPD mortality prediction).

Nutritional supplementation should be considered in individuals with a BMI <21. No beneficial effects have been seen in trials investigating the use of testosterone, appetite stimulants and creatine in COPD patients with a low BMI.

Education Table 1. Benefits of Pulmonary Rehabilitation in COPD • • • • • • • • • • •

Improves exercise capacity (Evidence A).

Reduces the perceived intensity of breathlessness (Evidence A).

Improves health-related quality of life (Evidence A).

Reduces the number of hospitalizations and days in the hospital (Evidence A).

Reduces anxiety and depression associated with COPD (Evidence A).

Strength and endurance training of the upper limbs improves arm function (Evidence B).

Benefits extend well beyond the immediate period of training (Evidence B).

Improves survival (Evidence B).

Respiratory muscle training can be beneficial, especially when combined with general exercise training (Evidence C).

Improves recovery after hospitalization for an exacerbation (Evidence A).

Enhances the effect of long-acting bronchodilators (Evidence B).

From the Global Strategy for Diagnosis, Management and Prevention of COPD 2015, © Global Initiative for Chronic Obstructive Lung Disease (GOLD), all rights reserved.

Available from http://www.goldcopd.org.

Exercise training

Exercise training involves aerobic lower-extremity endurance training. Baseline exercise tolerance can be assessed by formal cardiopulmonary testing using treadmill or ergometry bicycling.

Simpler methods such as the 6-minute walk test may also be

Patient education is an important part of PR and includes information about COPD, smoking cessation, appropriate use and administration of pharmacological therapies, decision-making during exacerbations, and advance directives, recognising and treating complications and end-of-life issues. The benefits include better adherence to treatment and fewer hospital and emergency visits.

Influenza and pneumococcal vaccinations

Acute exacerbations are a major cause of morbidity and mortality worldwide. Most acute exacerbations are triggered by communityacquired respiratory infections (viral or bacterial). Although clinical trial data are limited and not conclusive, vaccinations can prevent some of the infections that cause exacerbations. The current GOLD guidelines[3] recommend that all patients with COPD receive influenza and pnemoccocal (pneumococcal polysaccharide vaccine) vaccines, depending on availability. Small cohort studies have suggested additive benefits of administering both influenza and pneumoccocal vaccines in reducing hospitalisation and mortality.[12,13]

Non-invasive positive pressure ventilation

NPPV improves the outcome in severe exacerbations of COPD complicated by hypercapnia and respiratory acidosis. Evidence regarding long-term NPPV in COPD patients with hypercapnia is contradictory

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and there are no recommendations on its use.[7] An exception is the subsets of patients with COPD and coexisting obstructive sleep apnoea or obesity hypoventilation, where clear benefits are seen.

Long-term oxygen therapy

The Nocturnal Oxygen Therapy Trial (NOTT) and Medical Research Council (MRC) trials demonstrated that LTOT (>15 hours/day) is associated with improved survival in patients with severe resting hypoxaemia, with no benefits seen in moderate hypoxaemia PO2 >8 kPa (60 mmHg). Indications for LTOT include the following:[7] • PaO2 = 7.3 kPa or SaO2 ≤88%, with or without hypercapnia.

• PaO2 between 7.3 kPa (55 mmHg) and 8 kPa (60 mmHg or SaO2 88%), if there is evidence of pulmonary arterial hypertension, peripheral oedema suggestive of congestive heart failure or polycythaemia.

Surgery

Surgical options for COPD include LVRS, bullectomy and lung transplantation.

Conclusion

Non-pharmacological interventions are complementary to pharma­ cological therapies in COPD. Smoking cessation is the only proven method to prevent decline in lung function and therefore must be addressed during all patient visits, with the implementation of an appropriate individually tailored pulmonary rehabilitation programme. Yearly influenza vaccination will reduce the risk of influenza with subsequent COPD exacerbations or pneumonia.

Pneumococcal vaccination shows great promise and should be used where available. Keeping one’s patients healthy and strong by means of nutrition and moderate exercise will contribute to their sense of wellbeing and improve their respiratory health.

References

Lung volume reduction surgery

LVRS involves the surgical reduction of lung volume, with multiple excisions improving elastic recoil and reducing hyperinflation. It is also thought to improve the mechanical function of the diaphragm and intercostal muscles by returning the diaphragm to a more normally curved and lengthened configuration. It is beneficial in selected COPD patients with upper-lobe emphysema. The National Emphysema Treatment Trial (NETT)[14] demonstrated survival benefits in patients with upper-lobe emphysema and low exercise capacity, with no benefits and increased mortality seen in FEV1 <20% predicted, diffusing capacity of the lungs for carbon monoxide <20 and non-upper-lobe emphysema on computed tomography scanning.

It is, however, associated with significant morbidity postoperatively.

Bullectomy

Bullectomy involves removal of one or more large bullae that do not contribute to gas exchange, decompressing the adjacent lung parenchyma and improving ventilation. Indications include dyspnoea from giant bullae occupying >30% of the hemithorax (especially >50%), spontaneous pneumothorax, haemoptysis and repeated infections.

Lung transplantation

for placing a patient with COPD on the transplant list would include a BODE index ≥7, FEV1 <15 - 20% of predicted, ≥3 exacerbations in the last year, 1 severe exacerbation with hypercapnic respiratory failure and moderate to severe pulmonary hypertension.[15]

Lung transplantation is done infrequently in resource-limited countries such as South Africa (7 lung transplantations done in 2013). COPD is the most common indication for a single lung transplant. Indications

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2. World Health Organization. Chronic respiratory diseases. Burden of COPD. http://www.who.int/ respiratory/copd/burden/en/ (accessed 3 August 2015).

3. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for Diagnosis, Management and Prevention of COPD. 2015. http://www.goldcopd.org (accessed 3 August 2015).

4. Anthonisen NR, Connett JE, Kiley JP, et al. Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1. Lung Health Study. JAMA 1994;272:1497-1505.

5. Van Zyl-Smit RN, Allwood B, Stickells D, et al. South African tobacco smoking cessation clinical practice guideline. S Afr Med J 2013;103:869-876.

6. Patel AR, Hurst JR. Extrapulmonary comorbidities in chronic obstructive pulmonary disease: State of the art. Expert Rev Respir Med 2011;5(5):647-662. [http://dx.doi.org/ 10.1586/ers.11.62] 7. Nici L, Donner C, Wouters E, et al.; ATS/ERS Pulmonary Rehabilitation Writing Committee. American Thoracic Society/ European Respiratory Society statement on pulmonary rehabilitation. Am J Respir Crit Care Med 2006;173:1390-1414.

8. Leung RW, Alison JA, McKeough ZJ, Peters MJ. Ground walk training improves functional exercise capacity more than cycle training in people with chronic obstructive pulmonary disease (COPD): A randomised trial. J Physiother 2010;56:105-112.

9. Puhan M, Scharplatz MA, Troosters T, et al. Pulmonary rehabilitation following exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2009(3):CD005305.

10. Sillen MJ, Speksnijder CM, Eterman RM, et al. Effects of neuromuscular electrical stimulation of muscles of ambulation in patients with chronic heart failure or COPD: A systematic review of the English-language literature. Chest 2009;136:44-61. [http://dx.doi.org/10.1378/chest.08-2481] 11. Clini EM, Ambrosino N. Nonpharmacological treatment and relief of symptoms in COPD. Eur Respir J 2008;32:218-228. [http://dx.doi.org/10.1183/09031936.00134007] 12. Nichol KL. The additive benefits of influenza and pneumococcal vaccinations during influenza seasons among elderly persons with chronic lung disease. Vaccine 1999;17:S91-S93.

13. Sumitani M, Tochino Y, Kamimori T, et al. Additive inoculation of influenza vaccine and 23-valent pneumococcal polysaccharide vaccine to prevent lower respiratory tract infections in chronic respiratory disease patients. Intern Med 2008;47:1189-1197.

14. Weinmann GG, Chiang Y-P, Sheingold S. The National Emphysema Treatment Trial (NETT): A study in agency collaboration. Proc Am Thoracic Soc 2008;5(4):381-384. [http://dx.doi.org/10.1513/ pats.200709-154ET] 15. Weill D, Benden C, Corris PA, et al. A consensus document for the selection of lung transplant candidates: 2014 – an update from the Pulmonary Transplantation Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 2015;34(1):1-15. [http://dx.doi. org/10.1016/j.healun.2014.06.014]

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ARTICLE

Pharmacological management of chronic obstructive pulmonary disease E Shaddock,1 MB BCh, FCP (SA), Cert Pulmonology (SA), Cert Critical Care (SA); G Richards,2 MB BCh, PhD, FCP (SA), FCCP, FRCP Division of Pulmonology and Critical Care, Department of Medicine, Faculty of Health Sciences, University of the Witwatersrand and Charlotte Maxeke Johannesburg Academic Hospital, Johannesburg, South Africa 2 Critical Care, Faculty of Health Sciences, University of the Witwatersrand and Charlotte Maxeke Johannesburg Academic Hospital, Johannesburg, South Africa 1

Corresponding author: E Shaddock (eshaddock@metroweb.co.za)

There have been significant changes in the approach to the management of chronic obstructive pulmonary disease (COPD) over the past decade. The World Health Organization suggests four com­ponents to a COPD management plan: (i) assess and monitor disease; (ii) reduce risk factors; (iii) manage stable COPD; and (iv) manage exacerbations. Encouraging patients to limit their risk exposure is essential, whether it be smoking cessation or removing exposure to biomass.

The main objective of treatment is to relieve daily symptoms, improve quality of life and importantly decrease the risk of future exacerbations. Current guidelines are based on grade A and B evidence. Pneumococcal and annual influenza vaccinations are encouraged.

A holistic approach that augments pharmacological treatment includes good nutrition and pulmonary rehabilitation.

Bronchodilators are the cornerstone of management. Depending on the patient’s placement in the GOLD ABCD classification, treatment is individualised. Short-acting bronchodilators are used as rescue medication, while long-acting bronchodilators or/and long-acting muscarinic agents are the treatment of choice for patients in groups B, C and D. Inhaled corticosteroids are only recommended for groups C and D. Most patients respond well to combinations of the abovementioned medications. For patients who still have frequent exacerbations, alternative choices include long-term macrolides and phosphodiesterase 4 inhibitors.

S Afr Med J 2015;105(9):790. DOI:10.7196/SAMJnew.8426

Over the past decade there have been significant changes in the approach to the management of chronic obstructive pulmonary disease (COPD).

Previously, drugs were used that had originally been developed for asthma and were relatively nihilistic with regard to COPD management. Currently, the availability and use of drugs that have been developed primarily for the COPD patient have become mainstream treatment. There is now more optimism and empathy towards this rapidly growing group of patients.

According to 2004 World Health Organization (WHO) estimates, 64 million people have COPD and 3 million have died of the condition. The WHO also predicts that COPD will become the third leading cause of death worldwide by 2030.[1] It suggests that there are four very useful components to a COPD management plan: (i) assess and monitor disease; (ii) reduce risk factors; (iii) manage stable COPD; and (iv) manage exacerbations.

Assess and monitor disease

The correct diagnosis of COPD and its severity is essential if the appropriate treatment is to be prescribed. If COPD is suspected after taking a history and performing a clinical examination, it should be confirmed with spirometry. A forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) of <0.7, with no or minimal reversibility after the administration of an inhaled shortacting bronchodilator, is in keeping with the diagnosis. The new GOLD (Global Initiative for Chronic Obstructive Lung Disease) guidelines[2] have added symptoms and risk for exacerbations into the classification, which allows for a more evidence-based approach when deciding on appropriate medications.

Reduce risk factors

It is essential to discuss modifying or removing risk factors for COPD in all patients who have been diagnosed with the condition, as ongoing exposure to a risk factor results in a more rapid decline of FEV1. This most frequently involves advice on smoking cessation or attempts to reduce biomass exposure. Smoking cessation programmes have significant benefit to patients who have decided to quit the habit.

Manage stable COPD Bronchodilators

Except in patients with very mild disease and minimal symptoms, short-acting bronchodilators (SABAs) alone are no longer routinely recommended for COPD. SABAs and short-acting anticholinergic agents are used ‘as required rescue medications’ and not for maintenance therapy. The backbone of treatment for most COPD patients is long-acting β2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs). These agents have been shown to provide improvements in dyspnoea, healthrelated quality of life (QoL), lung function, rescue medication use, exercise capacity and exacerbation risk.[3-7] The decision as to which agent to start with is often based on patient preference, available finances (LABAs are usually less expensive than LAMAs) and preferred delivery device. There are many drug choices and brands to choose from (Table 1).

Over the past 10 years evidence has been emerging with regard to bronchodilator maintenance therapy in COPD patients. Large randomised studies such as TORCH and UPLIFT, with long-term follow-up of 3 and 4 years, respectively, have become landmark studies and the evidence on which many guidelines are based.[8,9] Bronchodilators are effective in most patients with COPD and not

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Table 1. Inhaler therapy for COPD available in South Africa Drug class

Available drug

Trade name

Short-acting bronchodilators (SABAs)

Fenoterol Salbutamol

Berotec Ventolin/Astavent/Venteze

Long-acting bronchodilators (LABAs)

Formoterol Salmeterol

Foratec Serevent

Ultra-long-acting bronchodilators

Indacaterol

Ombrez

Short-acting anticholinergics

Ipratropium

Atrovent

Long-acting muscarinic agents (LAMAs)

Tiotropium

Spiriva/Forvent

Inhaled corticosteroids (ICS)

Beclometasone Ciclesonide Budesonide Fluticasone

Beclate/Beceze Alvesco Budaflam/Pulmicort/Inflammide Flixotide

Combinations

Fluticasone/salmeterol Budesonide/formoterol Ipratropium/β2-agonists

Seretide/Sereflo/Foxair Symbicord Atrovent Beta/Combivent/Duolin

only in those with reversible disease on spirometry. An important benefit of LABAs and LAMAs is their effect on decreasing dynamic hyperinflation, which directly affects QoL. The TORCH study compared four groups, placebo v. salmeterol and fluticasone alone and the latter v. a salmeterol-fluticasone combi­ nation (SFC) over 3 years (6 112 patients).[8] The primary outcome was death from any cause for the comparison between the combination regimen and placebo. The study also assessed frequency of exacerbations, health status and lung function over the 3 years.

The results showed that the all-cause mortality was 12.6% in the combination therapy group, 15.2% in the placebo group, 13.5% in the salmeterol group, and 16.0% in the fluticasone group. The hazard ratio for death in the combination therapy group compared with the placebo group was 0.825 (95% confidence interval (CI) 0.681 - 1.002; p=0.052), corresponding to a 17.5% reduction in the risk of death.[8] This did, however, not meet the predetermined level of statistical significance (p=0.052). Even though not a primary outcome, it is important to note that SFC, compared with placebo, decreased the annual rate of exacerbations from 1.13 to 0.85 and improved health status and lung function (p<0.001 for all comparisons with placebo).[8] There was, however, an increase in the risk of pneumonia in the groups that received inhaled corticosteroids (ICS); this will be discussed in more detail below.

UPLIFT was a 4-year randomised, doubleblind trial, which compared either tiotropium (a LAMA) or placebo in patients with COPD.[9] Importantly, 75% of patients in

both groups were already on LABAs and ICS; therefore, any benefit was over and above that of standard therapy. The primary endpoints were the rate of decline in the mean FEV1 before and after bronchodilator use, starting on day 30. Secondary endpoints included measures of FVC, changes in St George’s Respiratory Questionnaire (SGRQ) score, number and timing of acute exacerbations of COPD and mortality. The study did not find a significant difference between the groups in the rate of decline of FEV1. However, there was a significant improvement in the SGRQ in the tiotropium group compared with the placebo group at each time point throughout the 4 years (ranging from 2.3 U to 3.3 U; p<0.001).[9] At 4 years, tiotropium was also associated with a reduction in the risk of exacerbations, related hospitalisations, and respiratory failure.[9] There was no benefit in its primary outcome; however, all its secondary outcomes showed improvement. If we consider the main complaints of COPD patients, this drug was shown to have a real-life benefit.

LABAs can be used safely without ICS in COPD compared with asthma. When adding an ICS in COPD, it is necessary to decide if the benefit will be greater than the increased risk of pneumonia. ICS in combination with LABAs has been shown in some studies to improve lung function and QoL and reduce exacerbations.[8,10] The best evidence for these benefits, however, is in patients with ≥2 exacerbations per year, especially in GOLD groups C and D. In patients without frequent exacerbations, these agents should not be initiated or should be gradually discontinued owing to the risk of pneumonia. There have

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been concerns about withdrawal of ICS in patients who have received the medication inappropriately or who are stable on LABALAMA-ICS. However, the WISDOM study found that in patients with severe COPD, who were receiving tiotropium plus sal­ meterol, the risk of moderate or severe exacerbations was similar among those who gradually discontinued ICS and those who continued with the medication. The study did, however, note a slightly greater decrease in lung function during the final step of ICS withdrawal, but it is nevertheless considered safe to discontinue these agents if their use is not indicated.[11] The review article in this edition of CME discusses the diagnosis and classification of the severity of COPD.[12] The majority of COPD patients, especially as the severity of the condition increases, are not usually managed with one agent only. Combination therapy, including 2 or even 3 agents, possibly in the same dispen­ sing device, has become the ultimate management choice. It allows for improved patient compliance and disease control.

There is growing interest in LABA/LAMA combinations, and as these combinations are not yet available in a single dispenser in South Africa (SA), the agents can be used together.

There are numerous studies (although no large randomised controlled studies) demonstrating that combinations improve lung function and decrease exacerbation rates more than either component alone.

There is a trend in lower-income countries for ICS to be used early in the management of COPD. This is certainly true in SA, primarily because of the cost and availability in clinics and hospitals. COPD patients are mostly managed as asthmatics with ICS and SABAs, as required. This is not in the best interests of the patient; LABAs and possibly LAMAs should be available at clinic level.

Oral medications

Theophylline is still widely used as an oral bronchodilator, mainly because of its low cost and easy accessibility. Theophylline has been shown to improve QoL, but its toxicity profile limits its acceptability as a first-line agent. The SA guidelines[13] recommend considering low-dose theophylline (as an anti-inflammatory agent and with measure­ ment of blood levels) as a treatment option, and the GOLD guidelines[2] suggest it as an alternative if no other bronchodilators are available.

Phosphodiesterase inhibitors, such as roflumilast, inhibit the airway inflammatory processes associated with COPD. They have

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been shown to be effective in Phase III clinical trials and have recently been registered for use in SA. In a pooled analysis of 2 large trials, a significant 17% reduction in the frequency of moderate or severe acute exacerbations (AEs) was demonstrated.[14] This drug is expensive, but has been shown to be cost-effective if used in suitable patients, although there are significant gastrointestinal side-effects.[15] Long-term macrolide antibiotics are not currently recommended by the GOLD guidelines. However, they may be considered in patients with >2 exacerbations per year.

The use of macrolides for the prevention of AEs is based on their immunomodulatory and anti-inflammatory effects, which have been long recognised in patients with cystic fibrosis and diffuse panbronchiolitis.

Macrolides decrease sputum production, inhibit biofilm formation and reduce production of different virulence factors; recently, antiviral effects have also been reported.[16] There have been a number of small studies showing the benefits of long-term macrolides. A recent randomised controlled trial of 1 142 patients with a 1-year follow-up period, using azithromycin 250 mg daily, showed that the median time to first AE was 266 days (95% CI 227 - 313) in the azithromycin group and 174 days (95% CI 143 - 215) in the placebo group (p<0.001). The hazard ratio for having an AE per patient-year in the azithromycin group was 0.73 (95% CI 0.63 - 0.84; p<0.001).

They also demonstrated improved QoL, but there was a small increase in the risk for hearing loss in the treatment arm.[17] The side-effects of macrolides need to be considered and monitored when initiating therapy, as the most serious side-effects include ototoxicity (hearing loss, tinnitus and vertigo), cardiac arrhythmias (especially prolonged QTc interval) and hepatotoxicity.

When deciding on which agent to use, the GOLD method of classifying patients into their respective ABCD group allows one to make a better evidence-based choice of agents (Fig. 1).

Inhalation device

An often forgotten component of COPD treatment is the decision about the type of inhaler device. Inhaler technique, regardless of the device, should be checked regularly at every consultation and, if incorrect, re-taught repeatedly. It is important to match the patient’s ability with the correct device. Because of the lower

A

SABA or SAMA Alternatives

B

LABA or LAMA Alternatives

LABA or LAMA or SABA plus SAMA

C

ICS plus LABA or LAMA Alternatives LAMA plus LABA or LABA plus PDE4 inhibitor or LAMA plus PDE4 inhibitor

LABA plus LAMA

D

ICS plus LABA plus/or LAMA Alternatives

ICS plus LABA plus LAMA or ICS plus LABA plus PDE4 inhibitor or LABA plus LAMA or LAMA plus PDE4 inhibitor

Fig. 1. Pharmacological management of COPD, based on the GOLD classification (adapted from the GOLD guideline (http://www.goldcopd.org[2])). (PDE4 = type 4 phosphodiesterase.)

cost, pressurised metered-dose inhalers (pMDIs) are most commonly prescribed, and if used correctly are good options.

They are, however, most often incorrectly used. Dry powder inhalers (DPIs) are the inhalers of choice in patients with poor hand-lung co-ordination. DPIs are usually more expensive than pMDIs, but are very popular as patients find them easier to use. An equally important determinant of choosing a device is the patient’s ability to generate adequate inspiratory flow. In advanced COPD and in those having an exacerbation, the patient may not be able to generate sufficient inspiratory pressure to trigger the release of medication in DPIs. Similarly, pMDIs may not be inhaled sufficiently deeply and nebulisation may be necessary. In advanced COPD, inspiratory muscles can become weaker and be a mechanical disadvantage in the presence of severe hyperinflation. During follow-up, inhaler choice should be regularly evaluated and a change made if necessary.

Manage exacerbations

A vital part of COPD management is to try to decrease the risk of AEs. It has been shown that AEs have a negative impact on patient prognosis. Soler-Cataluna et al.[18] showed that patients with the greatest risk of mortality were those with ≥3 AEs (hazard ratio 4.13; 95% CI 1.80 - 9.41). AEs also result in an accelerated decline in lung function, poor QoL and increased health resource use. As discussed above, many of the current treatments, including ICS, LABAs and LAMAs, have been shown to decrease AEs.

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References 1. Burden of COPD. www.who.int/respiratory/copd/burden/en (accessed 4 July 2015).

2. Global Initiative for Chronic Obstructive Lung Disease (GOLD).

Global Strategy for Diagnosis, Management and Prevention of COPD. 2015. http://www.goldcopd.org (accessed 3 July 2015).

3. Keating GM. Tiotropium bromide inhalation powder: A review of its use in the management of chronic obstructive pulmonary disease. Drugs 2012;72(2):273-300. [http://dx.doi. org/10.2165/11208620-000000000-00000] 4. O’Donnell DE, Flüge T, Gerken F, et al. Effects of tiotropium on lung hyperinflation, dyspnoea and exercise tolerance in COPD. Eur Respir J 2004;23(6):832-840.

5. Steiropoulos P, Tzouvelekis A, Bouros D. Formoterol in the management of chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis 2008;3(2):205-215.

6. Stockley RA, Whitehead PJ, Williams MK. Improved outcomes in patients with chronic obstructive pulmonary disease treated with salmeterol compared with placebo/usual therapy: Results of a meta-analysis. Respir Res 2006;7:147.

7. Bateman ED, Mahler DA, Vogelmeier CF, et al. Recent advances in COPD disease management with fixed-dose long-acting combination therapies. Expert Rev Respir Med 2014;8(3):357379. [http://dx.doi.org/10.1586/17476348.2014.910457] 8. Calverley PMA, Anderson JA, Celli B, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007;356:775-789.

9. Tashkin DP, Celli B, Stephen SS, et al. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med 2008;359:1543-1554.

10. Anzueto A, Ferguson GT, Feldman G, et al. Effect of fluticasone propionate/salmeterol (250/50) on COPD exacerbations and impact on patient outcomes. COPD 2009;6:320-329.

11. Magnussen H, Disse B, Rodriguez-Roisin R, et al. Withdrawal of inhaled glucocorticoids and exacerbations of COPD. N Engl J Med 2014;371:1285-94. [http://dx.doi.org/10.1056/NEJMoa1407154] 12. Viviers PJ, van Zyl-Smit RN. COPD – diagnosis and classification of severity. S Afr Med J 2015;105(9):786-788. [http://dx.doi.org/10.7196/SAMJnew.8421] 13. Abdool-Gaffar MS, Ambaram A, Ainslie GM, et al. Guideline for the management of chronic obstructive pulmonary disease – 2011 update. S Afr Med J 2011;101:61-73.

14. Calverley PM, Rabe KF, Goehring UM, et al. Roflumilast in symptomatic chronic obstructive pulmonary disease: Two randomised clinical trials. Lancet 2009;374(9691):685-694. [http://dx.doi.org/10.1016/S0140-6736(09)61255-1] 15. Samyshkin Y, Kotchie RW, Mörk AC, et al. Cost-effectiveness of roflumilast as an add-on treatment to long-acting bronchodilators in the treatment of COPD associated with chronic bronchitis in the United Kingdom. Eur J Health Econ 2014;15(1):69-82. [http:// dx.doi.org/10.1007/s10198-013-0456-5] 16. Yamaya M, Azuma A, Takizawa H, et al. Macrolide effects on the prevention of COPD exacerbations. Eur Respir J 2012;40(2):485494. [http://dx.doi.org/10.1183/09031936.00208011] 17. Albert RK, Connett J, Bailey WC, et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med 2011;365:689-698. [http://dx.doi.org/10.1056/NEJMoa1104623] 18. Soler-Cataluna JJ, Martinez-Garcia MA, Roman Sanchez P, et al.

Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease. Thorax 2005;60:925-931.

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ARTICLE

Lung volume reduction in chronic obstructive pulmonary disease M J Vorster, MB ChB, MRCP (UK), MMed (Int), FCP (SA); C F N Koegelenberg, MB ChB, MMed (Int), FCP (SA), FRCP (UK), Cert Pulmonology (SA), PhD Division of Pulmonology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University and Tygerberg Academic Hospital, Cape Town, South Africa Corresponding author: C F N Koegelenberg (coeniefn@sun.ac.za)

Pathognomonic features of advanced emphysema include a markedly reduced alveolar surface area due to the formation of blebs and bullae and significantly reduced elastic recoil. The aim of lung volume reduction, which can be achieved by either surgery or endoscopic techniques, is volume loss of the targeted, diseased region(s) and redirecting airflow to less affected regions.

Lung volume reduction surgery (LVRS) entails reducing the lung volume by wedge excision of emphysematous tissue. LVRS carries significant morbidity and mortality, but can offer survival benefit and increased exercise capacity in selected patients with predominantly upper-lobe emphysema and low exercise capacity.

Endoscopic lung volume reduction (ELVR) refers to bronchoscopically inducing volume loss to improve pulmonary mechanics and compliance, thereby reducing the work of breathing. Globally, this technique is increasingly used as treatment for advanced emphysema with the objective of obtaining similar functional advantages to surgical lung volume reduction, while decreasing risks and costs. Current evidence suggests that patients with either homogeneous or heterogeneous disease may benefit from ELVR. It remains paramount that a systematic approach is followed and selection criteria are met, given the high costs and potential complications related to both LVRS and ELVR. S Afr Med J 2015;105(9):791. DOI:10.7196/SAMJnew.8427

Pathognomonic features of advanced emphysema include a markedly reduced alveolar surface area due to the formation of blebs and bullae and significantly reduced elastic recoil of the lung.[1,2] Early airway closure occurs during expiration, with resultant air trapping and hyperinflation. Consequently, the range of expansion of preserved areas of lung tissue decreases. Furthermore, air trapping and hyperinflation place the diaphragm at a mechanical disadvantage owing to its flattened configuration. These processes in combination lead to refractory dyspnoea.[1] The aim of lung volume reduction (whether done surgically or endoscopically) is to achieve volume loss of the targeted, diseased region(s) and to redirect airflow to less affected areas.[2] This decreases dynamic hyperinflation, and improves diaphragmatic and chest wall mechanics.

In theory, the remaining lung tissue has better elastic properties that can restore the outward radial pull on the small airways, thereby reducing airflow limitation. Reducing inhomogeneity of regional ventilation and perfusion may lead to improved ventilation/perfusion matching.

Lung volume reduction can in essence be achieved by either surgical or endoscopic techniques. This article aims to provide the practising general practitioner with an overview of the practical aspects of and current evidence for the use of the various techniques in South Africa (SA). The general indications and contraindications for lung volume reduction are summarised in Table 1.

Lung volume reduction surgery

Lung volume reduction surgery (LVRS) entails reducing the lung volume by wedge excision of emphysematous tissue. It is most often performed as a bilateral procedure, but occasionally as a unilateral one. Examples of the latter would include cases of severely asymmetrical emphysema, contralateral pleurodesis, contralateral

thoracotomy and haemodynamic instability or massive air leak during the first side of a planned bilateral procedure.

The National Emphysema Treatment Trial (NETT) is still the largest randomised trial of LVRS. It compared the benefits of LVRS with maximal medical therapy in >1 000 patients with advanced emphysema.[3] Within the first few months of starting the trial, a high risk of death (16% v. 0% controls) was identified in a subgroup of patients with a forced expiratory volume in 1 second (FEV1) <20% of predicted and either homogeneous emphysema or a diffusing capacity for carbon monoxide (DLCO) <20% of predicted. Patients with these characteristics were subsequently excluded from enrolment in NETT. Among patients without these high-risk characteristics, the 30-day mortality rate was 2.2% in the LVRS group, compared with 0.2% in the control group (p<0.001). At 2 years, total mortality among non-high-risk patients did not differ between the LVRS and medical therapy groups. The effect of LVRS on exercise capacity was modest, and the investigators concluded that LVRS does not confer a survival advantage over medical therapy. Only in a subgroup of patients with predominantly upper-lobe emphysema and low exercise capacity, was LVRS shown to reduce long-term mortality.

There has been a significant decline in the number of LVRSs performed, both locally and internationally, mostly because of the modest benefit, strict selection criteria, morbidity and mortality associated with major thoracic surgery in patients with compromised pulmonary and cardiovascular reserves and the advent of endoscopic lung volume reduction (ELVR).[2]

Endoscopic lung volume reduction

Rationale

The use of ELVR as a minimally invasive procedure with significantly lower morbidity and mortality than surgery is fast becoming a

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Table 1. General indications and contraindications for lung volume reduction in patients with stable emphysema Indications 40 - 75 years Heterogeneous emphysema and no collateral ventilation* Dyspnoea despite maximal medical therapy and pulmonary rehabilitation FEV1 15 - 45% Hyperinflation with TLC >100% and RV >150 - 175% PaCO2 <6.7 kPa (50 mmHg) PaO2 >6 kPa (45 mmHg) while breathing ambient air 6MWD ≥140 m (post-rehabilitation) Contraindications Homogeneous emphysema* Collateral ventilation/non-intact fissures* >75% parenchymal destruction on HRCT† Current smoking (last 6 months) DLCO <20% (absolute for LVRS, relative for ELVR) Giant bullae (>1/3 of hemithorax) α1-antitrypsin deficiency Previous thoracotomy, pleurodesis or chest wall deformity Excessive sputum Severe pulmonary hypertension (>50 mmHg) Active infection Unstable cardiac conditions Significant pleural or interstitial changes on HRCT Any type of antiplatelet or anticoagulant therapy that cannot be discontinued for 7 days before a procedure FEV1 = forced expiratory volume in 1 second; TLC = total lung capacity; RV = residual volume; PaCO2 = partial pressure of carbon dioxide; PaO2, = partial pressure of oxygen; 6MWD = 6-minute walking distance; DLCO = carbon monoxide diffusing capacity; LVRS = lung volume reduction surgery; ELVR = endoscopic lung volume reduction; HRCT = high-resolution computed tomography. * Specific for endobronchial and intrabronchial valves. † Specific for endobronchial coils.

new treatment modality for patients with severe emphysema. The objective is to reduce the risks and costs of surgery and also to achieve comparable physiological benefits. The procedure involves a standard endoscopic technique with endobronchial deployment of the device, which decreases the volume of the distal lung segments, thereby improving pulmonary mechanics and compliance.[2] By reducing airflow limitation and the work of breathing, the result is an almost instantaneous improvement in symptoms – most notably dyspnoea. The two most commonly used devices are endobronchial valves and coils.

Valves

One-way bronchial valve implantations have been available for use for over a decade, with the greatest clinical experience worldwide. Several clinical trials have been performed, leading to expanded knowledge and expertise with this technology, but the recently completed STELVIO-trial provided the strongest evidence for use of valves in patients without collateral ventilation.[4] Unidirectional valves allow one-way passage of air and secretions from the distal bronchus,

thus preventing postobstructive infectious complications. By preventing the entrance of air during inspiration it causes atelectasis of the distal lung segments and a functional lung volume reduction.

The success of the valves depends on whether there is complete collapse of the distal lung segments with the most severe disease, which is determined by two characteristics of emphysema, i.e. the degree of homogeneity and the presence of collateral ventilation. The valves are only effective if there is inhomogeneous emphysema as assessed on chest computed tomography (CT) scanning, either by visual inspection of the parenchyma or using specifically designed automated quantification software.[2] Furthermore, valves fail to induce collapse when the affected portion of the lung has collateral ventilation. This is a normal physiological phenomenon in many individuals, but significant interlobar collateral ventilation subverts the deflating effect of endobronchial blocking devices. Therefore, before placement of a valve, both homogeneous emphysema and collateral ventilation need to be excluded.

Moreover, unilateral (compared with bilateral ELVR) valve placement was found to have a better outcome.[5-8]

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Fig. 1. An endobronchial (Zephyr) valve.

Fig. 2. An intrabronchial (IBV) valve.

There are currently two commercially available devices available in SA: Zephyr endobronchial valves (Pulmonx Inc., USA, Fig. 1) and IBV intrabronchial valves (Olympus Respiratory America, USA, Fig. 2). Both devices are selfexpanding and delivered using a catheter that is introduced through the working channel of a flexible bronchoscope.[2] The most common reported adverse events experienced with endobronchial valve placement have been pneumothoraces (5 - 10%), mild haemoptysis (2 - 6%) and exacerbations of underlying chronic obstructive pulmonary disease (COPD) (8 40%).[4-7]

Coils

While valves have been used for more than a decade, coils have only recently been introduced, with the first coils inserted in SA as recently as 2014. Coils (RePneu, BTG Inc., USA) are nitinol devices (Fig. 3) designed to be deployed into a straight airway, and thereafter to resume their preformed shape. This conformational shape change after deployment results in parenchymal retraction with associated volume loss, while maintaining airway patency.[9] The device is currently available in three lengths to accommodate different-sized airways. The coils are implanted via a flexible bronchoscope under general anaesthesia or conscious sedation and fluoroscopic guidance using a proprietary delivery system. Coils, in theory, not only cause lung volume reduction but also reduce airflow limitation by retensioning

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setting – an effective treatment with associated clinical benefit independent of collateral ventilation.[14]

Future of lung volume reduction in South Africa

Fig. 3. An endobronchial (RePneu) coil.

the remaining airway network and tethering of the small airways, preventing collapse on expiration.

Current evidence suggests that candidates with both heterogeneous and homogeneous emphysema can experience clinically significant benefit from ELVR using coils.

This benefit is obtained regardless of the presence of collateral ventilation or complete lobar collapse after the proce­dure.

However, it requires that <25% of the total lung parenchyma be affected by radiological emphysema before insertion.[10,11] Approx­imately 75 - 80% of patients will experience minimal clinically important differences in lung function and quality of life, while mild haemoptysis of <5 mL (50 - 75%), exacerbations of COPD (5 - 12%), mild chest discomfort (15 - 50%) and infrequent pneumo­thoraces (3%) are described as adverse events.[10,11] A recent report on the 3-year follow-up data of 38 patients who underwent ELVR using coils suggested that the treatment was safe; no late pneumothoraces, coil migrations or unexpected adverse events occurred.[12] Although clinical benefit gradually declined over time, 3 years after treatment approximately 50% of the patients main­ tained improvement in 6-minute walking distance, dyspnoea and quality of life scores.

Other devices/procedures

Synthetic polymeric foam (Aeris Thera­ peutics Biological, USA) has been used to obtain atelectasis, but a recent study, which was prematurely terminated, raised some safety concerns.[13] This technology is currently not available in SA. Broncho­ scopic thermal vapour ablation (BTVA, Uptake Medical Corporation, USA) uses heated water vapour delivered to emphysematous lung parenchyma within a targeted region.

The vapour induces an inflammatory reaction with subsequent fibrosis, result­ing in lung volume reduction within 8 - 12 weeks.

In a multicentre trial in Europe and Australia 44 patients with severe upper-lobe-pre­ dominant emphysema were treated by unilateral BTVA in a single procedural

Current evidence suggests that not all classes and phenotypes of emphysema will benefit from ELVR, and that individual techniques may benefit different subgroups of patients.[6,9,10] Only a few centres in SA currently have the capacity to properly evaluate prospective candidates and potentially offer LVRS and/or ELVR in appropriate cases. The high cost of these interventions makes careful patient selection imperative to prevent wasteful insertion in those unlikely to gain clinical benefit.

The initial screening for suitable candi­ dates should be performed at sub­specialist (pulmo­ nologist) level in SA, and on patients with stable disease and no recent exacerbations. Routine special investigations should include high-resolution CT (to estimate heterogeneity, fissure integrity and degree of tissue destruction, and evaluate for possible underlying lung cancer), full pulmonary function testing, arterial blood gas sampling and echocardiography (to exclude pulmonary hypertension).[10] Lung volume reduction should not be offered to active smokers, patients with pulmonary hypertension, unstable cardiac pathology, active respiratory infections, very poor exercise tolerance, without clear evidence of hyperinflation, and those on antiplatelet or anticoagulant therapy that cannot be discontinued for 7 days prior to the procedure.[10,11,15] Appropriate or borderline candidates should be referred to a centre with the capacity to evaluate, treat and follow up, including the managing of complications related to LVRS or ELVR and removal of devices if required.

Conclusion

A well-structured evidence-based approach to ELVR, including initial screening and subsequent referral to a specialised centre, is important to avoid inappropriate use of devices, which may be both wasteful and harmful. Appropriate candidates with marked hyperinflation and relatively preserved lung parenchyma are more likely to benefit from ELVR with bilateral coils, irrespective of the collateral ventilation and heterogeneity of the disease. By contrast, patients with heterogeneous disease and no collateral ventilation are more likely to benefit from unilateral ELVR with valves,

September 2015, Vol. 105, No. 9

aiming to achieve complete lobar collapse.

LVRS should be reserved for patients with heterogeneous disease who have collateral ventilation and an acceptable operative risk profile.

Both LVRS and ELVR are currently available in SA, but there are no head-tohead studies comparing LVRS with ELVR or the various techniques and devices available to perform ELVR, and there are no official guidelines from any of the major thoracic societies. A task group of the Assembly on Interventional Pulmonology of the South African Thoracic Society has extensively reviewed all relevant publications and consulted international experts on the use of ELVR in SA in the form of local recommendations.[16] References 1. McDonough J, Yuan R, Suzuki M, et al. Small-airway obstruction and emphysema in chronic obstructive pulmonary disease. N Engl J Med 2011;365(17):1567-1575. [http://dx.doi. org/10.1056/NEJMoa1106955] 2. Gasparini S, Zuccatosta L, Bonifazi M, Bolliger CT. Bronchoscopic treatment of emphysema: State of the art. Respiration 2012;84(3):250-263. [http://dx.doi.org/10.1159/000341171] 3. Fishman A, Martinez F, Naunheim K, et al. A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema. N Engl J Med 2003;348(21):2059-2073. [http://dx.doi.org/10.1056/NEJMoa030287] 4. Klooster K, ten Hacken N, Hartman J, Kerstjens H, van Rikxoort E, Slebos D. Endobronchial valve treatment versus standard medical care in patients with emphysema without interlobar collateral ventilation (The STELVIO-Trial). Am J Respir Crit Care Med 2015;191(9):A6312.

5. Shah P, Slebos D, Cardoso P, et al. Bronchoscopic lung-volume reduction with Exhale airway stents for emphysema (EASE trial): Randomised, sham-controlled, multicentre trial. Lancet 2011;378(9795):997-1005. [http://dx.doi.org/10.1016/S01406736(11)61050-7] 6. Sciurba FC, Ernst A, Herth FJF, et al. A randomized study of endobronchial valves for advanced emphysema. N Engl J Med 2010;363(13):1233-1244. [http://dx.doi.org/10.1056/ NEJMoa0900928] 7. Mor Z, Leventhal A, Diacon AH, Finger R, Schoch OD. Tuberculosis screening in immigrants from high-prevalence countries: Interview first or chest radiograph first? A pro/con debate. Respirology 2013;18(3):432-438. [http://dx.doi.org/10.1111/resp.12054] 8. Herth FJF, Noppen M, Valipour A, et al. Efficacy predictors of lung volume reduction with Zephyr valves in a European cohort. Eur Respir J 2012;39(6):1334-1342. [http://dx.doi. org/10.1183/09031936.00161611] 9. Herth FJF, Eberhard R, Gompelmann D, Slebos D-J, Ernst A. Bronchoscopic lung volume reduction with a dedicated coil: A clinical pilot study. Ther Adv Respir Dis 2010;4:225-231. [http:// dx.doi.org/10.1177/1753465810368553] 10. Deslee G, Klooster K, Hetzel M, et al. Lung volume reduction coil treatment for patients with severe emphysema: A European multicentre trial. Thorax 2014;69(11):980-986. [http://dx.doi. org/10.1136/thoraxjnl-2014-205221] 11. Klooster K, ten Hacken NHT, Franz I, Kerstjens HM, van Rikxoort EM, Slebos D-J. Lung volume reduction coil treatment in chronic obstructive pulmonary disease patients with homogeneous emphysema: A prospective feasibility trial. Respiration 2014;88(2):116-125. [http://dx.doi.org/10.1159/000362522] 12. Hartman J, Klooster K, Gortzak K, ten Hacken N, Slebos D. Long-term follow-up after bronchoscopic lung volume reduction treatment with coils in patients with severe emphysema. Respirology 2015;20(2):319-326. [http://dx.doi.org/10.1111/resp.12435] 13. Come C, Kramer M, Dransfield M, et al. A randomised trial of lung sealant versus medical therapy for advanced emphysema. Eur Respir J 2015:1-12. [http://dx.doi.org/10.1183/09031936.00205614] 14. Snell G, Herth F, Hopkins P, et al. Bronchoscopic thermal vapour ablation therapy in the management of heterogeneous emphysema. Eur Respir J 2012;39(6):1326-1333. [http://dx.doi. org/10.1183/09031936.00092411] 15. Eberhardt R, Gompelmann D, Schuhmann M, et al. Complete unilateral vs partial bilateral endoscopic lung volume reduction in patients with bilateral lung emphysema. Chest 2012;142(4):900-908. [http://dx.doi.org/10.1378/chest.11-2886] 16. Koegelenberg CFN, Theron J, Dheda K, et al. Recommendations for endoscopic lung volume reduction in South Africa: Role in emphysema. S Afr Med J (in press).

CONTINUING MEDICAL EDUCATION

ARTICLE

Five tips for good office spirometry D M Maree, National Diploma in Clinical Technology (Pulmonology and Critical Care) Lung Unit, Division of Pulmonology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University and Tygerberg Academic Hospital, Cape Town, South Africa Corresponding author: D M Maree (david.maree@westerncape.gov.za)

1. Spirometry is critical for the correct diagnosis of chronic obstructive pulmonary disease (COPD) and is part of the severity classification. It ultimately guides treatment choices. When per­ forming spirometry on a COPD patient, one expects a flow volume loop to have some degree of obstruction. To obtain and confirm this result, there are a few important steps that have to be followed and rules that have to be adhered to.[1,2] 2. The spirometer has to be adjusted for atmospheric variables, i.e. temperature, humidity and barometric pressure. These variables are necessary to adjust the correction factor of the spirometer for volume measurement at BTPS (body temperature and pressure, saturated), as the inhaled air is at ambient conditions but the exhaled air is at body environment conditions. The spirometer also has to be calibrated daily, or prior to patients being tested, by means of a 3 L calibrating syringe. This calibration and variable adjustment ensure correct/accurate measurement.

3. The patient’s demographics must be entered into the spirometer: age, height (in socks/barefoot), gender, race and weight, as these are used to calculate the predicted values for each individual.

Without the correct predicted values, the resultant spirometric grading and the GOLD COPD classification[3] will be incorrect, which will result in the patient being managed inappropriately.

4. When performing the test on a patient, each attempt (minimum – 3; maximum – 8) has to be acceptable in the following ways: • At the start, the exhalation must be forced out as hard and fast as possible, without any hesitation.

• The minimum exhalation time is 6 seconds, although the more severe the COPD (a disease of airflow limitation) the longer the patient needs to exhale their full vital capacity; this could take up to 15 seconds. One should be extremely cautious at this point, as the patient could have a syncopal attack and collapse. Therefore, it is advisable to always perform the spirometry with the patient seated on a chair with armrests.

• There must be no artefacts such as coughing during the expiratory phase of the test, especially during the first 2 seconds, as this will affect the forced expiratory volume at 1 second (FEV1). As coughing (and excessive phlegm production) is one

of the symptoms of COPD, there is a strong possibility that the patient may have coughing bouts during the exhalation period. Any coughing after the first second has no effect on the grading of the spirometry and only affects the flow parameters.

• If the patient inserts his/her tongue into the mouthpiece, it causes an obstruction, resulting in abnormal flows and an erroneous FEV1, with a resultant incorrect COPD grading.

• If the patient does not maintain an adequate seal around the mouthpiece, flow of air passes around outside of the measuring device, leading to volume loss and hence the incorrect forced vital capacity (FVC). This will result in a flow volume loop that could be interpreted as a restrictive lung disease that is not in keeping with COPD, and the patient being incorrectly graded.

5. With the 3 acceptable attempts having been obtained, reproduci­ bility is controlled by ensuring that the largest FVC and FEV1 are within 150 mL of each other. In severely impaired COPD patients, there is a possibility of reduced vital capacity of <1 L. If this occurs, the two largest FVCs and FEV1s have to be within 100 mL of each other.

It is most important for spirometry and with the classification of the COPD patient that the procedure must also be performed after an adequate dose of a bronchodilator, i.e. post bronchodilator FEV1. This is required to standardise the assessment across patients and visits.

Administering 400 µg of salbutamol by means of a spacer is most effective, with a waiting period of at least 15 minutes before attempting the spirometry.

References 1. Koeglenberg CFN, Swart F, Irusen EM. Guideline for office spirometry in adults, 2012. S Afr Med J 2013;103(1):52-61. [http://dx.doi.org/10.7196/samj.6197] 2. Miller MR, Hankinson J, Brusasco V, et al. Standardisation of spirometry. Eur Respir J 2005;26:319338. [http://dx.doi.org/10.1183/09031936.05.00034805] 3. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for Diagnosis, Management and Prevention of COPD. 2015. http://www.goldcopd.org (accessed 21 July 2015).

S Afr Med J 2015;105(9):791. DOI:10.7196/SAMJnew.8428

September 2015, Vol. 105, No. 9

CAREERS & CLASSIFIEDS Tel: 012 481 2121 | E-mail: ladinev@hmpg.co.za www.hmpg.co.za We accept credit card payments - Visa or MasterCard.

GP Locum / Assistant Randburg

Full time employment opportunity available

General Practitioners required for a busy Family Practice.

Short / Long term Locums available.

For GP’s interested in working in a 24 hour Emergency Unit Situated in a new private hospital in Midrand.

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Please send CV’s to Harriet at: admin@cosmed.co.za Tel no: +27 11 024 0500

Woonhuis met spreekkamer to koop Groot 6 slaapkamer woonhuis met spreekkamer in Potchestroom, 1 Kilometer vanaf dir hoofingang van die NWU kampus.

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Locum Specialist Obstetrician & Gynaecologist with General Medicine Skills St Helena, South Atlantic 6 weeks FTC commencing February 2016

Interested parties can email their CV’s to info@careatmidstream.co.za

MEDICAL PRACTICE FOR SALE Well established multi-disciplinary medical practice and property located in LANSDOWNE for sale due to owner (doctor) retiring.

Easily accessible & long standing clientele.

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Locum Specialist Anaesthetist with General Medicine Knowledge St Helena, South Atlantic 6 weeks FTC commencing February 2016

Competitive package circa £12k for the 6 week period, includes salary, pension, cost of living, relocation, rent and utilities (see Overseas Vacancy Information)

Competitive package circa £12k for the 6 week period, includes salary, pension, cost of living, relocation, rent and utilities (see Overseas Vacancy Information)

An application form can be found at www.sthelenacareers.com

An application form can be found at www.sthelenacareers.com

CAREERS & CLASSIFIEDS

TRUST DOCTOR IN PEADIACTRICS AND NEONATOLOGY ROYAL DEVON & EXETER NHS FOUNDATION TRUST Applications are invited for a Trust Doctor in Paediatrics and Neonatology, to work on the middle grade rota. This post is available from the beginning of August, initially for a six month period with the intention of extending to a year for the right candidate, with opportunities to develop sub-specialty interests.

This post presents a fantastic opportunity to work in a busy and dynamic department in acute and neonatal paediatrics. The Royal Devon and Exeter hospital has a busy level 2 neonatal unit which stabilises and manages all neonatal problems. There is a newly established paediatric assessment unit. In addition to acute general paediatrics, there are many areas of specialisation including sub-regional CF and paediatric oncology services, serving a population of 850,000.

The post is based at the Royal Devon & Exeter Hospital, which is a first wave Foundation Trust teaching hospital within the Peninsular College of Medicine and Dentistry. The hospital has excellent links with both Exeter and Plymouth Universities. Exeter is a beautiful historical cathedral city, offering the variety and facilities of a university centre, while within a few minutes’ drive you can be exploring Dartmoor National Park or enjoying the stunning Devonshire coastline. It is well served by rail, road and air links, with London only two hours away by train.

A job description and person specification can be obtained via NHS Jobs on www.jobs.nhs.uk. Should you wish to make further enquiries please contact Dr. Simon Parke, Consultant Paediatrician on 01392 402684.

Taunton, Somerset, UK

Consultant Gastroenterologist Full time 10 PA’s Somerset is situated in South West England and offers beaches, caves and moors as well as being home to the world famous Glastonbury Festival. Taunton itself is a bustling town with a rich heritage and good transport links to the neighbouring cities of Bristol and Exeter, and London is within less than two hours by rail.

This new post is to help expand and improve gastroenterology, hepatology and endoscopy services within Somerset. Our team of eight consultants provide a full range of services with interests in hepatology, IBD, nutrition, ERCP, GI stenting, bowel cancer screening and have excellent specialist nurse support.

Our 750 bed hospital serves a population of 350,000 with an excellent reputation for providing a comprehensive range of medical, surgical and specialist services and an excellent teaching environment.

Successful candidates will receive support with relocation expenses.

For an informal discussion contact Dr Rudi Matull, Clinical Service Lead for Gastroenterology on 0044 1823 342720.

Find out more about what its like to work here at: www.musgroveparkhospital.nhs.uk and search under ‘Working here’. To apply online please visit: www.jobs.nhs.uk and search under Job Ref: 403-CONTB001 Closing Date: 30 September 2015

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CPD

SEPTEMBER 2015 The CPD programme for SAMJ is administered by Medical Practice Consulting.

CPD questionnaires must be completed online at www.mpconsulting.co.za.

True (A) or false (B): SAMJ Ebola and the haemorrhagic fevers 1. The only endemic haemorrhagic fever in SA is Crimean-Congo haemorrhagic fever, transmitted by the Hyalomma tick, which is ubiquitous in cattle farming areas.

2. Viral haemorrhagic fevers include a diverse array of diseases caused by a broad range of viruses that originate exclusively from Africa.

3. Physical sequelae of the ‘post-Ebola syndrome’ include loss of vision, joint pains and general body pains.

Insights into body donation to medical schools 4. In South Africa (SA) the family members of body donors are not financially rewarded, but the costs of removal of the body to the medical school (within a certain radius) and of cremation are covered by the university.

Anticoagulation of pregnant patients with mechanical heart valves 5. The recommendation to only use enoxaparin is based on the fact that adequate laboratory monitoring is available in SA for enoxaparin and not other low-molecular-weight heparins (LMWHs).

6. LMWH (enoxaparin) does not cross the placenta and is associated with improved fetal outcomes.

7. Warfarin is associated with a teratogenic effect between 6 and 12 weeks of gestation, and therefore is not recommended in the first trimester.

Time to implement 9-month infant HIV testing 8. In SA, over 90% of HIV-infected women access prevention of motherto-child transmission, with the result that the early transmission rate of HIV infection, as measured in their infants at around 6 weeks of age, is likely to meet the National Strategic Plan target of <2% in 2015.

Bone marrow aspirate microscopy v. bone marrow trephine micro­ scopy for detection of Mycobacterium tuberculosis infection 9. Bone marrow trephine histology shows a significantly higher detection rate of tuberculosis (TB) and is recommended as an essential part of the diagnostic work-up in suspected disseminated TB.

Codeine misuse and dependence in SA 10. Codeine misuse and dependence in SA is high compared with alcohol, cannabis and methamphetamine abuse.

CME Chronic obstructive pulmonary disease (COPD) – diagnosis and classification of severity 11. When making a diagnosis of COPD, a rapid onset of symptoms should suggest an alternative condition.

12. Spirometry is not necessary for the correct diagnosis of COPD. 13. Cardiovascular disease is the major contributor to mortality in COPD. Pathogenesis of COPD: An African perspective 14. Almost all smokers will develop reduced lung function if they smoke sufficient cigarettes over a sufficient length of time.

15. Biomass fuels are an important factor in the aetiology of COPD in developing countries such as SA. 16. The development of COPD is not associated with pulmonary TB. Non-pharmacological management of COPD 17. Smoking cessation remains the only proven intervention to slow the decline of lung function in patients with COPD. 18. Long-term supplemental oxygen improves mortality and quality of life in patients with severe resting hypoxaemia.

Pharmacological management of COPD 19. The backbone of treatment for most patients with COPD is shortacting bronchodilators.

Five tips for good office spirometry 20. Spirometry is critical for the correct diagnosis of COPD, is part of the severity classification, and ultimately guides treatment choices.

Readers please note: articles may appear in summary/abstract form in the print edition of the journal, with the full article available online via www.hmpg.co.za

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September 2015, Vol. 105, No. 9

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