SAMJ Vol 107, No 1 (2017) by HMPG

JANUARY 2017

PRINT EDITION

GUEST EDITORIAL A novel TB blood test CME Anaemia (part 1) CASE REPORT Behçet disease uveitis: CD4/CD8 RESEARCH COP 21 and public hospitals – an opportunity for change Healthcare-associated infection in hospitalised children – what works best?

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FROM THE EDITOR 4

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

Climate change – no denial B Farham

GUEST EDITORIAL 5

A novel blood test for tuberculosis prevention and treatment A Penn-Nicholson, T J Scriba, M Hatherill, R G White, T Sumner

EDITOR’S CHOICE

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, J M Pettifor HMPG

CORRESPONDENCE 10

Transoral robotic surgery (TORS) in South Africa J J Fagan, J Wetter, C Joseph, B Donde; C A Joseph

CEO AND PUBLISHER Hannah Kikaya | Email: hannahk@hmpg.co.za

Cost considerations in determining the affordability of adjuvant trastuzumab in breast cancer M Sereda, response from R P Abratt; W Szpak, response from R P Abratt

MANAGING EDITORS Ingrid Nye Claudia Naidu

Yes, we can eradicate tuberculosis in South Africa W Shasha

From an exasperated pathologist R D Mohanlal

HIV/AIDS: Emerging threat to cardiovascular health in sub-Saharan Africa H Strijdom, P De Boever, T S Nawrot, N Goswami

TECHNICAL EDITORS Emma Buchanan Paula van der Bijl

IZINDABA 20

22 23 23

PRODUCTION MANAGER Emma Jane Couzens DTP AND DESIGN Clinton Griffin Travis Arendse

30 days in medicine B Farham

CHIEF OPERATING OFFICER Diane Smith | Tel. 012 481 2069 Email: dianes@hmpg.co.za

OBITUARIES Steve Lawn Pieter Stephanus Bothma Theo Berkowitz

SALES MANAGER (CAPE TOWN) Azad Yusuf JOURNAL ADVERTISING Charles William Duke Reneé Hinze Ladine van Heerden Kenni Gambo Charmalin Simpson Ismail Davids

EDITORIALS 24

Missed opportunities for circumcising boys P S Millard, N Goldstuck

South Africa’s salt reduction strategy: Are we on track, and what lies ahead? J Webster, C Crickmore, K Charlton, K Steyn, E Wentzel-Viljoen, P Naidoo

ONLINE SUPPORT Gertrude Fani

CME

FINANCE Tshepiso Mokoena Makhadzi Mulaudzi

GUEST EDITORIAL Anaemia (part 1) N Alli

ARTICLE Anaemia: Approach to diagnosis N Alli, J Vaughan, M Patel

HMPG BOARD OF DIRECTORS Prof. M Lukhele (Chair), Dr M R Abbas, Dr M J Grootboom, Mrs H Kikaya, Prof. E L Mazwai, Dr M Mbokota, Dr G Wolvaardt ISSN 0256-9574

IN PRACTICE 33

CLINICAL UPDATE Cutting the cost of South African antiretroviral therapy using newer, safer drugs W D F Venter, B Kaiser, Y Pillay, F Conradie, G B Gomez, P Clayden, M Matsolo, C Amole, L Rutter, F Abdullah, E J Abrams, C P Casas, M Barnhart, A Pillay, A Pozniak, A Hill, L Fairlie, M Boffito, M Moorhouse, M Chersich, C Serenata, J Quevedo, G Loots Outbreak of carbapenem-resistant Providencia rettgeri in a tertiary hospital V S Tshisevhe, M R Lekalakala, N Tshuma, S Janse van Rensburg, N Mbelle ISSUES IN PUBLIC HEALTH Tackling the climate targets set by the Paris Agreement (COP 21): Green leadership empowers public hospitals to overcome obstacles and challenges in a resource-constrained environment E Weimann, B Patel

January 2017, Print edition

SAMA website: www.samedical.org Journal website: www.samj.org.za

HEALTHCARE DELIVERY The National Health Insurance, the decentralised clinical training platform, and specialist outreach R I Caldwell, C Aldous

CASE REPORTS The intraocular CD4/CD8 ratio in a black South African patient with Behçet’s disease uveitis A Makgotloe

Pulmonary nocardiosis caused by Nocardia otitidiscaviarum in an adult asthmatic female patient: The presence of acid-fast branching filaments is always significant A Mahgoub, S A Gumaa, M R P Joseph, M S Saleh, A H A Elsheikh, A I Elkhalifa, E Elhaj, R R M Salih, M E Hamid

RESEARCH 49 49

Classifying snakebite in South Africa: Validating a scoring system* D Wood, B Sartorius, R Hift Immunisation coverage in the rural Eastern Cape – are we getting the basics of primary care right? Results from a longitudinal prospective cohort study* K le Roux, O Akin-Olugbade, L S Katzen, C Laurenzi, N Mercer, M Tomlinson, M J Rotheram-Borus

Surveillance of healthcare-associated infection in hospitalised South African children: Which method performs best?* A Dramowski, M F Cotton, A Whitelaw

Retinopathy of prematurity in a cohort of neonates at Groote Schuur Hospital, Cape Town, South Africa* Q Keraan, C Tinley, A Horn, T Pollock, J Steffen, Y Joolay

Characteristics and outcome of long-stay patients in a paediatric intensive care unit in Cape Town, South Africa* T L Nupen, A C Argent, B M Morrow

Supernumerary registrar experience at the University of Cape Town, South Africa* S Peer, S A Burrows, N Mankahla, J J Fagan

A novel FKRP-related muscular dystrophy founder mutation in South African Afrikaner patients with a phenotype suggestive of a dystrophinopathy* M M Mudau, F Essop, A Krause Primary cutaneous malignancies in the Northern Cape Province of South Africa: A retrospective histopathological review* K York, N C Dlova, C Y Wright, N P Khumalo, P E Kellett, R Kassanjee, A Mosam

ONLINE CONTENTS LISTED IN Index Medicus (Medline) Excerpta Medica (EMBASE) Biological Abstracts (BIOSIS) Science Citation Index (SciSearch) Directory of Open Access Journals (DOAJ) Current Contents/Clinical Medicine SAMJ SUBSCRIPTION RATES Local subscriptions ZAR1 488.00 p.a. Foreign subscriptions ZAR3 408.00 p.a. Single copies ZAR124.00 local, ZAR284.00 foreign Members of the South African Medical Association receive the SAMJ only on request, as part of their membership benefit. Subscriptions: Tel. 012 481 2071 Email: members@samedical.org The SAMJ is published monthly by the Health and Medical Publishing Group (Pty) Ltd, Co. registration 2004/0220 32/07, a subsidiary of SAMA. HEAD OFFICE Health and Medical Publishing Group (Pty) Ltd Block F, Castle Walk Corporate Park, Nossob Street, Erasmuskloof Ext. 3, Pretoria, 0181 Tel. 012 481 2069 Email: dianes@hmpg.co.za EDITORIAL OFFICE Suite 11, Lonsdale Building, Lonsdale Way, Pinelands, 7405 Tel. 021 532 1281 | Cell. 072 635 9825 Email: publishing@hmpg.co.za Please submit all letters and articles for publication online at http://www.editorialmanager.com/samj © Copyright: Health and Medical Publishing Group (Pty) Ltd, a subsidiary of the South African Medical Association

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CAREERS & CLASSIFIEDS

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CPD QUESTIONS

JANUARY 2017

Background photo: Waiting to receive healthcare at the Manenberg Clinic, Cape Town | City Press, Jaco Marais Box photos: TB graphic | Nauma; Uveitis | ARZTSAMUI; Preventing hospital-associated infection | ThamKC

January 2017, Print edition

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FROM THE EDITOR

Climate change – no denial As this issue of SAMJ goes to press, we may well be about to see the USA reject the Paris Agreement (COP 21) if president-elect Donald Trump makes good his election campaign promise to leave COP 21, fuelled by listening to climate-change denialists and reinforced by his own apparent rejection of science. This will be a massive blow to all involved in trying to mitigate the effects of humankind’s industrial revolution and decades of pumping carbon dioxide and other damaging gases into the atmosphere. Although there is precious little about climate change and health in the medical journals, we know that there will be effects on health. In this issue of the SAMJ, the article by Weimann and Patel[1] shows that at least some areas of healthcare are starting to address the issues. They also point out that as far back as 2009, the Lancet Commission stated that climate change is ‘the biggest public health threat of the 21st century’. Since then, the climate crisis has deepened severely, with a higher frequency of extreme weather events and recurrences of El Niño. Climate change is already aggravating a wide range of health problems. As our planet warms, infectious diseases are spreading, threatening to reverse health improvements gained by great effort in many parts of the world. Heatwaves are growing in intensity and number, killing thousands of people and children, and aggravating chronic lung disease, heart disease and heatstroke. Increasingly severe storms, tornadoes, droughts and floods, as recently experienced in China, but also in South Africa (SA), harm human health and put often overstretched and ill-prepared health systems at risk. If greenhouse gas emissions remain at the current level or even increase, climate change will have severe persistent and irreversible effects, undermining the food and water supply in many parts of the world, setting off mass migrations, and thereby triggering potentially unmanageable public health crises. We have already reached atmospheric carbon dioxide concentrations of 440 ppm in both hemispheres – the level at which global average temperature increases of 2 - 3°C are inevitable, with all the ecological effects that this will have. We will all be affected by climate change, but it is the

poor who are most vulnerable. Already cities in Asia have life- and health-threatening levels of air pollution, and some of our own cities may not be far behind. Africa is one of the continents singled out as most vulnerable to the effects of climate change, and SA has the largest carbon footprint on the continent because of our high level of industrialisation, relative to the rest of the continent. Although we have almost certainly passed some major tipping points, we can still do what we can to mitigate the inevitable public health effects. As I write this, the Western Cape Province is currently feeling the effects of a severe drought and it is likely that without very good winter rains, we will start to see water shedding across the community. I understand that the poorest communities are already experiencing water shedding, while in my leafy suburb neighbours are still topping up their swimming pools with precious drinking water. The health effects of a poor water supply are, I am sure, already evident among those living in poor communities. Our summer temperatures are noticeably higher, affecting elderly people, those with chronic diseases and those living in shacks that concentrate the heat. These are the relatively small, day-to-day effects of this global phenomenon that will slowly start to enter our conciousness. As health professionals, we need to be activists, lobbying for mitigation. As individuals, we need to be responsible and compassionate – and help affected people wherever we can. Bridget Farham Editor ugqirha@iafrica.com S Afr Med J 2017;107(1):3. DOI:10.7196/SAMJ.2017.v107i1.12259 1. Weimann E, Patel B. Tackling the climate targets set by the Paris agreement (COP 21): Green leadership empowers public hospitals to overcome obstacles and challenges in a resource-constrained environment. S Afr Med J 2017;107(1):34-38. http://dx.doi.org/10.7196/SAMJ.2017.v107i1.12023

January 2017, Print edition

This open-access article is distributed under Creative Commons licence CC-BY-NC 4.0.

GUEST EDITORIAL

A novel blood test for tuberculosis prevention and treatment Almost 1 in every 100 South Africans is diagnosed with active tuberculosis (TB) disease every year, an incidence that ranks among the highest of the world’s 22 high-TB-burden countries; TB accounted for an astounding 14.6% of deaths among 15 - 44-year-olds in South Africa (SA) in 2014.[1] Globally, TB is recognised as the leading cause of mortality by an infectious agent, with 1.4 million deaths and 10.4 million new TB cases in 2015.[2] Although most forms of TB are treatable, prompt diagnosis is challenging and passive case-finding approaches have failed to control the epidemic. The estimated 80% of SA adults who are latently infected with Mycobacterium tuberculosis form a massive reservoir for future reactivation cases.[3,4] Indeed, even if all new M. tuberculosis infections were prevented, the incidence of TB stemming from the global reservoir of 1.7 billion latently infected people (23% of the world population) would be 16.5 per 100 000 person-years in 2035, falling short of the 2050 target for eradicating TB.[4] As preventive therapy at this scale is not feasible, no single current intervention is likely to achieve the goals of The End TB Strategy.[5] There is an urgent need for earlier TB case identification, using novel non-sputum-based diagnostics, linked to more effective preventive and curative strategies. A blood-based triage test that allows targeted investigation of individuals with active and sub-clinical TB disease, including asymptomatic individuals at highest risk of progression from latency to disease, could help to shorten the time to treatment start, or even prevent incipient disease before symptoms emerge.[6,7] The vision of a TB blood test to identify high-risk individuals for targeted preventive or curative therapy is within reach. We recently identified a blood ribonucleic acid (RNA) signature capable of predicting TB disease before the onset of symptoms.[8] This RNA signature, which measures expression of interferon response genes, has been translated into a polymerase chain reaction (PCR) test and was independently validated in cohorts from The Gambia and SA. The 16-gene PCR test predicted incident TB in adolescents, with a specificity of 82% and sensitivity of 70% within a year of testing – in the combined training and test sets.[8] To improve throughput of the test, we have refined the RNA signature to 11 genes, resulting in prognostic specificity of 84% and sensitivity of 71% (area under the curve = 0.76) 1 year before the onset of TB disease (A PennNicholson – unpublished data). The PCR assay has been qualified, and engagement is underway with commercial partners to translate this test technology to a smaller, simpler, faster and cheaper pointof-care test. Prevention of TB disease arising from latent infection is a key requirement to achieving global elimination targets, but the inability to detect M. tuberculosis in vivo during latent infection constitutes a major hurdle to effective prognostics.[4] The Foundation for Innovative New Diagnostics (FIND) has proposed that the target product profile of a prognostic test for incident TB should have at least 75% sensitivity and 75% specificity (and optimally >90% for both).[9] Neither the tuberculin skin test nor the interferon-gamma release assay (IGRA) meets this minimum standard. For example, if IGRA were used as a prognostic test in SA, the number needed to treat (NNT) to prevent one case of TB would be 85, based on an assumed 2% cumulative incidence of TB over 2 years and 50% effectiveness of isoniazid preventive therapy (IPT). However, if the RNA signature performs as predicted, the NNT would be more than halved, which might make large-scale, targeted TB preventive therapy feasible, even in high-TB-incidence countries.[10,11] The RNA signature is being assessed in a clinical trial to identify healthy adults at high risk of TB disease, and to test whether targeted short-course preventive therapy (3 months of once weekly, high-dose

isoniazid plus rifapentine (3HP)) can prevent TB disease in individuals who test positive for the RNA signature. The Correlate of Risk (COR) Targeted Intervention Study (CORTIS),[12] currently underway at 5 sites across SA, intends to screen >10 000 healthy adults for the RNA signature and follow 3 200 participants over 15 months for incident TB disease. CORTIS tests the hypotheses that high-risk signaturepositive individuals (COR+) will have a higher incidence of active TB disease than low-risk signature-negative individuals (COR−); and that 3HP will reduce the incidence of TB disease in COR+ participants compared with COR+ participants under active surveillance. The RNA signature might also have diagnostic utility for undiagnosed, sub-clinical TB disease when deployed as a triage tool to trigger investigation in otherwise healthy, RNA signature-positive individuals. We have provisionally demonstrated 93% specificity and 92% sensitivity to discriminate healthy South Africans with latent M. tuberculosis infection from those with active TB disease (F Darboe et al. – unpublished data). Within CORTIS, we will further assess the use of the RNA signature to diagnose prevalent TB in HIV-negative adults. If successful, this would enable targeted investigation of RNA signature-positive individuals for sub-clinical TB disease, allowing early curative treatment; RNA signature-positive individuals found not to have active disease would be offered preventive therapy; and those found to be RNA signature negative would be spared unnecessary intervention (Fig. 1). It is estimated that 11% of South Africans live with HIV; yet, 57% of the burden of all TB in SA is borne by those living with HIV.[2] HIV infection significantly elevates the risk of TB disease.[13] Performance of the RNA signature will also be tested in an observational study of SA adults living with HIV, in parallel with CORTIS. If the prognostic RNA signature performs as expected, it might also be used to identify HIV-positive individuals at highest risk of TB disease within a year of testing, and thus trigger initiation of targeted, short-course preventive therapy regimens that may in future replace chronic IPT.[14] Should the CORTIS screen-and-treat strategy prove efficacious in predicting and reducing the incidence of TB disease by targeted preventive therapy, the critical question is whether implementation would be feasible for the SA healthcare system. Key considerations are: (i) test performance; (ii) population level impact; (iii) cost/benefit ratio; (iv) operational feasibility; and (v) political commitment. RNA signature performance is being tested prospectively in CORTIS, but preliminary models predict that a TB screen-and-treat strategy that reached 30% of HIV-negative SA adults annually could reduce the Local community-based COR screening: annual campaigns

COR+

COR−

Investigate for TB, sputum/Xpert

Treat for TB (standard of care)

Preventive therapy (3HP)

Repeat in next screening cycle

Fig. 1. Proposed RNA signature screen-and-treat algorithm.

January 2017, Print edition

GUEST EDITORIAL

national TB incidence by 14% (95% confidence interval (CI) 11 - 18%) over 5 years. If extended to both HIV-negative and HIV-positive people, estimations suggest a reduction in TB incidence of 29% (95% CI 24 - 32%), and in TB mortality of 35% (95% CI 29 - 37%), within 5 years (R G Sumner and T White â&#x20AC;&#x201C; unpublished data). In the face of the potential impact, the cost/benefit assessment of such a strategy needs to be compared with that of untargeted IPT for all latently infected South Africans, which is clearly not feasible. SA already has an established health infrastructure for large-scale HIV test-and-treat programmes, which could be augmented to enable annual community-based screening for TB, using an affordable nearpoint-of-care device. Finally, with nearly 100 000 South Africans dying from TB in 2015,[2] scientific, pharmaceutical and governmental stakeholders have a collective responsibility to act promptly on new TB research findings and implement novel strategies to save lives. The current inadequate tools for screening, diagnosing, treating and preventing TB must be urgently and significantly improved if we are to end TB in our lifetime.

Adam Penn-Nicholson, Thomas J Scriba, Mark Hatherill South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine, and Division of Immunology, Department of Pathology, Faculty of Health Sciences, University of Cape Town, South Africa adam.penn-nicholson@uct.ac.za

Richard G White, Tom Sumner TB Modelling Group, TB Centre, Faculty of Epidemiology and Public Health, London School of Hygiene and Tropical Medicine, London, UK 1. Statistics South Africa. Mortality and Causes of Death in South Africa, 2014: Findings from Death Notification. Pretoria: Statistics SA, 2015. 2. World Health Organization. Global Tuberculosis Report 2016:1-211. Geneva: WHO, 2016. 3. Mahomed H, Hughes EJ, Hawkridge T, et al. Comparison of mantoux skin test with three generations of a whole blood IFN-gamma assay for tuberculosis infection. Int J Tuberc Lung Dis 2006;10(3):310316. http://dx.doi.org/10.1164/rccm.200608-1088OC 4. Houben RMGJ, Dodd PJ. The global burden of latent tuberculosis infection: A re-estimation using mathematical modelling. PLoS Med 2016;13(10):e1002152. http://dx.doi.org/10.1371/journal. pmed.1002152 5. Houben RMGJ, Menzies NA, Sumner T, et al. Feasibility of achieving the 2025 WHO global tuberculosis targets in South Africa, China, and India: A combined analysis of 11 mathematical models. Lancet Glob Health 2016;4(11):e806-815. http://dx.doi.org/10.1016/S2214-109X(16)30199-1 6. Malherbe ST, Shenai S, Ronacher K, et al. Persisting positron emission tomography lesion activity and Mycobacterium tuberculosis mRNA after tuberculosis cure. Nat Med 2016;22(10):1094-1100. http:// dx.doi.org/10.1038/nm.4177 7. Esmail H, Lai RP, Lesosky M, et al. Characterization of progressive HIV-associated tuberculosis using 2-deoxy-2-[(18)F]fluoro-D-glucose positron emission and computed tomography. Nat Med 2016;22(10):1090-1093. http://dx.doi.org/10.1038/nm.4161 8. Zak DE, Penn-Nicholson A, Scriba TJ, et al. A blood RNA signature for tuberculosis disease risk: A prospective cohort study. Lancet 2016;387(10035):2312-2322. http://dx.doi.org/10.1016/S01406736(15)01316-1 9. Foundation for Innovative New Diagnostics. Draft target product profile: Test for incipient tuberculosis. 2016. http://www.finddx.org/wp-content/uploads/2016/10/TPP-LTBIprogression-v82_20OCT2016.pdf (accessed 30 November 2016). 10. Petruccioli E, Scriba TJ, Petrone L, et al. Correlates of tuberculosis risk: Predictive biomarkers for progression to active tuberculosis. Eur Respir J 2016;pii:ERJ-01012-2016. http://dx.doi.org/ 10.1183/13993003.01012-2016 11. Zak D, Scriba TJ, Hatherill M, Penn-Nicholson A, Hanekom W. Predicting tuberculosis risk. Lancet 2016;388(10057):2233-2234. http://dx.doi.org/10.1016/S0140-6736(16)31653-1 12. The Correlate of Risk (COR) Targeted Intervention Study. http://www.clinicaltrials.gov.NCT02735590 (accessed 30 November 2016). 13. Lawn SD, Churchyard G. Epidemiology of HIV-associated tuberculosis. Curr Opin HIV AIDS 2009;4(4):325-333. http://dx.doi.org/10.1097/COH.0b013e32832c7d61 14. World Health Organization. Guidelines on the Management of Latent Tuberculosis Infection. Geneva: WHO, 2015.

S Afr Med J 2017;107(1):4-5. DOI:10.7196/SAMJ.2017.v107i1.12230

January 2017, Print edition

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EDITOR’S CHOICE

CME: Anaemia (part 1)

Anaemia is the most common haematological abnormality. The causes are numerous and varied, necessitating a structured diagnostic approach at presentation. While basic investigations suffice for most patients presenting with this condition, the less common types of anaemia often require expertise and more specialised diagnostic tests and equipment. However, in resource-challenged countries, budgetary constraints limit the scope of investigations and management options. This applies particularly to the inherited and chronic anaemias that are likely to have a significant (and in some instances total) degree of transfusion dependency. In this edition of CME, various classification systems have been employed to construct a practical approach for the investigation of anaemia. Emphasis is placed on the diagnostic approach, broadly touching on pathophysiology and management issues. This vast subject will be split into two parts: part 1, which focuses on central causes, i.e. decreased bone marrow output of erythrocytes; and part 2, which covers peripheral causes, i.e. peripheral loss, destruction or sequestration of erythrocytes.

COP 21 and public hospitals

Climate change is likely to be one of the most important factors affecting life in southern Africa in the next few decades, so it is good to see that research into these issues is being carried out in our major academic centres. Weimann and Patel[1] show that so-called ‘green leadership’ can empower our local hospitals, even with our resource contraints. In South Africa (SA), the National Department of Health (NDoH) approved a national climate change adaptation plan in 2014. This covers a general approach to climate change responses for the health sector. The government has also undertaken a set of in-depth analyses in a number of sectors, one of which was an analysis of the health sector. The effect of climate change on human health will be investigated through the analysis of a variety of complex interactions between changes in climate variables (temperature, heatwaves, rainfall) and health aspects. However, the main focus is on building resilience, defined in this context as preparing for the effects of extreme weather and the shifting burden of disease. The healthcare sector itself contributes to climate change, the creation of hazardous waste, and water and air pollution. To mitigate the effect of healthcare provision on the deteriorating environment and avoid creating further challenges for already burdened health systems, Global Green Hospitals was formed as a global network. Groote Schuur Hospital (GSH), as the leading academic hospital in Africa, joined the network in 2014. Since then, several projects have been initiated to reduce the amount of general waste, energy consumption and food waste, and create an environmentally friendlier and more sustainable hospital in a resource-constrained public healthcare setting. Weimann and Patel[1] outline the various efforts made to reduce GSH’s carbon footprint and reduce waste and hazardous substances such as mercury and polystyrene, and elaborate how obstacles and resistance to change were overcome.

Healthcare-associated infection (HAI) in hospitalised SA children

HAIs are the most common complication of hospitalisation, resulting in adverse patient outcomes and increased healthcare costs. Their burden in most high-income settings is well established by national internet-based reporting systems or repeated national/facility-level HAI point prevalence surveys (PPSs). In sub-Saharan Africa, most healthcare facilities are unable to perform HAI surveillance because they lack trained infection prevention staff, data analysts and information technology infrastructure. The situation in SA is similar. A single study in 2005 estimated a prevalence of 9.7% for four major

HAI types, with higher prevalence among children (16.5%) and patients in intensive care units (ICUs) (28.5%). In 2012, the SA NDoH mandated surveillance of HAI, but made no recommendations of appropriate surveillance methods. Dramowski et al.[2] carried out prospective clinical HAI surveillance (the reference method) at Tygerberg Children’s Hospital, Cape Town, from 1 May to 31 October 2015. Performance of three surveillance methods PPSs, laboratory surveillance and tracking of antimicrobial prescriptions) was compared with the reference method using surveillance evaluation guidelines. Factors associated with failure to detect HAI were identified by logistic regression analysis. During the 6-month surveillance period, 1 347 children were transferred in and/or admitted for ≥48 hours to the three wards and the paediatric intensive care unit (PICU), generating 13 401 patient days. The reference method detected 417 HAI events during 324 patient admission episodes for 296 discrete patients (1.4 HAI events per affected patient). The overall HAI incidence rate was high at 31/1 000 patient days, with a period prevalence of 22/100 admissions. HAI rates were highest among children admitted to the PICU. The reference method measured HAI prevalence at 22%, far exceeding rates of 4 - 5% reported in hospitalised children in high-income settings. SA paediatric wards should select an HAI surveillance method based on available resources, expertise and technology infrastructure. Where clinical HAI surveillance is not possible, monitoring of antimicrobial prescriptions in combination with laboratory data analysis appears a reasonable alternative.

A validated scoring system for snakebite in SA

Snakebite is relatively rare in SA, so for that reason alone it is valuable to have systems in place that may help practitioners when patients present with snakebite. This study from KwaZulu-Natal[3] examined 879 patients with snakebite who presented to the Ngwelezane Hospital emergency department from December 2008 to December 2013. Darryl Wood and his co-authors developed an active treatment outcome (ATI), defined as antivenom treatment or any surgical procedure using this cohort of patients. Factors predictive of ATI and the optimal cut-off score for predicting an ATI were identified. These factors were then used to develop a standard scoring system. The score was then tested prospectively for accuracy in a new validation cohort consisting of 100 patients admitted for snakebite to their unit from 1 December 2014 to 31 March 2015. Accuracy of the score was determined. Six risk factors were identified from the development cohort: age <14 years, delay to admission of >7 hours, white cell count >10 × 109/L, platelets <92 × 109/L, haemoglobin <7.1 g/dL and international normalised ratio >1.2. Each risk predictor was assigned a score of 1; receiver operating characteristic curve analysis returned a value of >4 out of 6 as the optimal cut-off for prediction of an ATI. Testing of the score on the validation cohort produced a specificity of 96.6% and a sensitivity of 22.5%. The positive predictive value and negative predictive value were 81.8% and 65.2%, respectively. The results suggest that the score is useful, particularly for those patients who fall into the mild to moderate clinical category. Until further work is done, this score will be named the Zululand Severity Score. BF 1. Weimann E, Patel B. Tackling the climate targets set by the Paris agreement (COP 21): Green leadership empowers public hospitals to overcome obstacles and challenges in a resource-constrained environment. S Afr Med J 2017;107(1):34-38. http://dx.doi.org/10.7196/SAMJ.2017.v107i1.12023 2. Dramowski A, Cotton MF, Whitelaw A. Surveillance of healthcare-associated infection in hospitalised South African children: Which method performs best? S Afr Med J 2017;107(1):56-63. http://dx.doi. org/10.7196/SAMJ.2017.v107i1.11431 3. Wood D, Sartorius B, Hift R. Classifying snakebite in South Africa: Validating a scoring system. S Afr Med J 2017;107(1):46-51. http://dx.doi.org/10.7196/SAMJ.2017.v107i1.11361

January 2017, Print edition

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Transoral robotic surgery (TORS) in South Africa

To the Editor: A series of two-page advertisements have appeared in the September and November 2016 issues of the SAMJ, entitled ‘da Vinci Transoral Robotic Surgery (TORS) is a minimally invasive alternative to open surgery and full-dose chemoradiation therapy for diseases of the head and neck’. As these advertisements go beyond simply marketing surgical equipment, but seek to influence patients, referring doctors, oncologists and head and neck surgeons on how to treat cancers of the head and neck and sleep apnoea, we have taken the unusual step of writing to the editor of the SAMJ to correct some misconceptions in the advertisement. The objectives of surgical resection of any cancer are to obtain clear surgical margins with acceptable morbidity. In the oropharynx, hypopharynx and larynx this can be achieved by transoral approaches, using either a headlight with electrocautery (as with a conventional tonsillectomy) or CO2 laser microsurgery, open surgical approaches, or TORS. TORS is simply a surgical tool that provides an excellent endoscopic view of the base of tongue, and has angled instruments to grab tissues and cut them with electrocautery. It is currently licensed by the US Food and Drug Administration (FDA) only to be used for T1 and T2 base-of-tongue cancers and may be particularly beneficial for selected, difficult-to-get-to cancers of the base of tongue. It has been widely adopted in the USA, but not in many other regions of the world owing to its very high cost. Purchasing a new TORS system is in the order of USD2 million, the annual maintenance costs are ~USD165 000, and the cost per case is ~USD15 000. Because of the high costs, hospitals have been known to encourage surgeons to use TORS to resect cancers, which can be more cheaply resected with CO2 laser or even with a headlight and cautery, to recover their investment. However, most T1 and T2 base-of-tongue and oropharyngeal cancers can be resected with transoral CO2 laser, which is extremely cheap compared with TORS and is a well-established validated technique, also in South Africa (SA). Therefore, while TORS has benefits to resect base-of-tongue cancers in cases where CO2 laser does not provide adequate access, such cases are uncommon and the costs involved simply cannot be justified in the SA healthcare setting. Base-of-tongue cancers that cannot be resected by transoral CO2 laser can still be resected by suprahyoid or lateral pharyngotomy approaches, with minimal morbidity. Transoral CO2 laser resection has all the benefits of TORS listed in the advertisement, such as avoiding mandibulotomy, return to speech and swallowing, less blood loss, minimal scarring, and avoidance of tracheotomy. The comment that TORS can reduce the requirement for chemoradiotherapy is to date not supported by results from randomised clinical trials. The majority of patients who undergo surgery for oropharyngeal cancers – especially that involving the base of tongue – will require adjuvant treatment to the postoperative tumour bed and/or the neck. If the tumour is excised with positive margins or the lymph nodes have extracapsular spread, many oncologists would still advocate chemoradiation. In theory, if a tumour of the base of tongue is excised, the postoperative radiotherapy target area may be smaller than if the tumour had not been excised. This in turn could result in at least some sparing of the pharyngeal constrictor muscles. However, this theoretical advantage would not be limited to TORS, but would apply to all the surgical techniques mentioned above. Several randomised controlled trials are currently underway to better define the impact of TORS on the treatment of oropharyngeal cancers. In one such study the option of de-escalated treatment after

TORS is being examined in patients with human papillomavirus (HPV)-positive tumours, while another study is comparing TORS with/without adjuvant treatment to chemoradiation in patients with HPV-negative tumours. Until the results of these and other studies are available, the role that TORS (or any surgery that achieves clear surgical margins) may or may not play in reducing the need for chemoradiotherapy is not known. Therefore, even though TORS is an established surgical technique, it is extremely expensive in the SA context when there are cheaper alternatives available. Johannes J Fagan

Professor and Chairman, Multidisciplinary Head and Neck Cancer Clinic, Groote Schuur Hospital and Division of Otolaryngology, Faculty of Health Sciences, University of Cape Town, South Africa johannes.fagan@uct.ac.za

Julie Wetter

Radiation Oncologist, Multidisciplinary Head and Neck Cancer Clinic, Department of Radiation Oncology, Groote Schuur Hospital and Faculty of Health Sciences, University of Cape Town, South Africa

Chris Joseph

Honorary Associate Professor, Department of Otolaryngology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg; Senior Lecturer, Department of Otolaryngology, Faculty of Health Sciences, University of Pretoria; and Consultant Surgeon, Sandton Head and Neck Forum, Morningside Mediclinic, Johannesburg, South Africa

Bernard Donde

Radiotherapist, Sandton Head and Neck Forum, Morningside Mediclinic, Johannesburg, South Africa S Afr Med J 2017;107(1):6. DOI:10.7196/SAMJ.2017.v107i1.12241

To the Editor: As members of a multidisciplinary team, we are extremely concerned about the da Vinci Transoral Robotic Surgery (TORS) advertisement that appeared in the SAMJ of September and November 2016. It is misleading, makes false and unsubstantiated claims, and contravenes Health Professions Council of South Africa guidelines. ‘Minimisation or elimination of the need for chemoradiation therapy’ is a false statement. Combined therapy is determined by the disease process and staging, not by the surgery. TORS has no advantage over current transoral techniques in head and neck cancer management. ‘Avoidance of disfiguring mandibulotomy’: TORS has no advantage over current techniques that avoid mandibulotomy/ mandibulectomy. ‘Quicker return to normal speech, swallowing and a full recovery’: there is no evidence that this is better than with proven transoral laser techniques. ‘Less blood loss and fewer transfusions’: there is no evidence that this is true compared with transoral laser and similar techniques. ‘Minimal scarring’: no evidence exists that scarring is less than with transoral laser techniques. ‘Avoidance of tracheostomy’: this has been demonstrated with transoral laser techniques, which have been in use for >20 years. ‘Less risk of infection’: there is no evidence that the risk of infection is less than when current techniques are used. Our team’s surgical complication rate is 3%, with only one wound infection in 497 head and neck cases. ‘Shortened hospital stay’: this has already occurred with the use of current transoral techniques. There is no evidence that TORS would shorten the hospital stay further.

January 2017, Print edition

Bio-Oil_medical_print_ad_297x210.indd 1

2016/06/07 9:19 AM

CORRESPONDENCE

There is no evidence that TORS has any advantage over current surgical management of head and neck tumours. Our team cannot currently support the use of TORS in head and neck cancer surgery. C A Joseph

on behalf of the multidisciplinary team, Sandton Head and Neck Forum, Morningside Mediclinic, Johannesburg, South Africa josephca@surgeon.co.za S Afr Med J 2017;107(1):7. DOI:10.7196/SAMJ.2017.v107i1.12244

Cost considerations in determining the affordability of adjuvant trastuzumab in breast cancer

To the Editor: Roche (Pty) Ltd would like to comment on the article ‘Cost considerations in determining the affordability of adjuvant trastuzumab in breast cancer’ by Prof. Abratt.[1] Trastuzumab is indicated in South Africa (SA) for the treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast and gastric cancer, as well as HER2-positive early breast cancer.[2] Large multinational studies evaluating the product in over 18 000 patients with early HER2-positive breast cancer have shown marked long-term clinical benefit in this population. This treatment represents the largest degree of therapeutic benefit in early breast cancer reported since the introduction of tamoxifen for hormone-receptor-positive disease approximately 25 years ago.[3] One year of treatment with trastuzumab is associated with a significant and sustained reduction in the risk of disease recurrence or death, irrespective of a patient’s nodal status, hormone-receptor positivity, previous (neoadjuvant) chemotherapy regimen and age.[3-5] A recent update covering over 10 years’ (median 11 years) follow-up of the pivotal HERA trial of patients treated with trastuzumab for 1 year showed an approximately 25% reduction in the incidence of disease-free and overall survival (OS) events when compared with the chemotherapy-only arm. Trials with a shorter duration of trastuzumab treatment of <1 year have to date failed to show noninferiority to 1 year of trastuzumab. Updated results from these and other ongoing trials are not promising but have yet to conclusively determine whether shorterduration trastuzumab is an efficacious option.[6,7] International guidelines confirm that 1 year of trastuzumab remains the standard of care as part of an adjuvant therapy regimen for patients with HER2positive early breast cancer.[8-10] W e n o te th e fo llo w in g s p e c ific is s u e s in re la tio n to th e c o m m e n ta ry : 1. Parameters used in the number needed to treat (NNT) calculation: The author notes that more sophisticated or accurate methods are available. Survival at 10 years of patients who are treated with adjuvant trastuzumab is approximately 81%.[5] A more accurate estimate of baseline survival at 10 years is derived if the actual 10-year survival of those who are eligible for adjuvant trastuzumab (the control arm from HERA) are used. Using this value of 75% the NNT is calculated as 17, about half the value presented in the commentary. The author states ‘The HR [hazard ratio] is the ratio of the relative survival of two patient groups, with and without the test therapy. This ratio will not vary much over time.’[1] This result has been shown to be broadly truthful for adjuvant trastuzumab treatment for HER2-positive breast cancer. It is, however, more frequently the case that the HR increases over time, showing reduced benefits from specific treatments.

2. Cost as a single basis for decision-making By using the NNT for OS and simply multiplying this by the drug cost, there is an implication that OS at 10 years is the only benefit from this treatment. There are other very important financial and clinical benefits for patients treated with trastuzumab, most notably prevention of local, regional and distant recurrences, as well as additional years of disease-free life gained. Those treated are significantly more likely to be disease free for longer and, given that the baseline disease-free survival (DFS) rates are of course less than the baseline survival rate (BLSR), this leads to a profound reduction in the NNT. The high costs, quality-of-life impacts, and debilitating consequences of recurrent disease suggest that prevention of recurrence is of considerable importance, in addition to the benefits of increased survival.[11] Using DFS as the endpoint of focus is most appropriate in settings where it is expected that recurrence of disease presents the major component of mortality in the treated population. This would be the case for most solid tumours, for which secondary therapies at the time of recurrence may prolong survival but ultimately are unlikely to result in a full remission. DFS is most relevant when there is an extended interval between recurrence and death, thus requiring a longer follow-up for a primary trial endpoint of OS.[12] This contrasts with complete response, partial response, or stable disease, which are considered meaningful in the neoadjuvant setting.[13,14] In light of these comments, it is Roche’s position that in order to informatively and appropriately make scientifically based local or policy-level best-treatment recommendations, the following as a minimum are required: • a careful and thorough systematic literature search • accumulation of true local cost information • a robust review of the evidence with regard to clinical benefits and potential harms of the treatment options • a robust cost-effectiveness analysis incorporating quality-of-life measures and all pertinent costs over a relevant post-treatment interval • an evaluation of the personal and financial impacts at a patient level (ability to work, maintain family roles and responsibilities, self-care, and productivity) and country level (economic impact, burden of disease on healthcare system). The far-reaching social and financial consequences of recommendations relating to novel treatments mean that these decisions need to be made in a robust, transparent and objective manner. The approximation of costs as published in this article[1] is inaccurate and potentially misleading for an intervention that provides DFS benefit for HER2-positive women, particularly if all the benefits and harms of the treatment are to be accounted for. Maksym Sereda

Head: Medical Affairs Management Centre South Africa Roche Products (Pty) Ltd Medical Department, Sandton, South Africa maksym.sereda@roche.com 1. Abratt RP. Cost considerations in determining the affordability of adjuvant trastuzumab in breast cancer. S Afr Med J 2016;106(10):981-982. http://dx.doi.org/10.7196/SAMJ.2016.v106i10.11141 2. Roche Products (Pty) Ltd. Herceptin Package Insert, South Africa. June 2016. 3. Untch M, Gelber RD, Jackisch C, et al. Estimating the magnitude of trastuzumab effects within patient subgroups in the HERA trial. Ann Oncol 2008;19:1090-1096. http://dx.doi.org/10.1093/annonc/mdn005 4. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al., Herceptin Adjuvant (HERA) Trial Study Team. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005;353(16):1659-1672. http://dx.doi.org/10.1056/nejmoa052306 5. Jackisch C, Piccart MJ, Gelber RD, et al. HERA trial: 10 years follow up of trastuzumab after adjuvant chemotherapy in HER2 positive early breast cancer – Final analysis. Oral presentation at: San Antonio Breast Cancer Symposium 2015; 10 December 2015; San Antonio, Texas.

January 2017, Print edition

CORRESPONDENCE

6. Pivot X, Romieu G, Debled M, et al. 6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE): A randomised phase 3 trial. Lancet Oncol 2013; 14:741-748. http://dx.doi.org/10.1016/s1470-2045(13)70225-0 7. Joensuu H, Kellokumpu-Lehtinen PL, Bono P, et al. FinHer Study Investigators. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med 2006;354:809-820. http:// dx.doi.org/10.1056/nejmoa053028 8. Goldhirsch A, Winer EP, Coates AS, et al. Personalizing the treatment of women with early breast cancer: Highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013. Ann Oncol 2013;24:2206-2223. http://dx.doi.org/10.1093/annonc/mdr304 9. Curigliano G, Cardinale D, Suter T, et al. Cardiovascular toxicity induced by chemotherapy, targeted agents and radiotherapy: ESMO Clinical Practice Guidelines. Ann Oncol 2012;23(Suppl 7):vii155-66. http://dx.doi.org/10.1093/annonc/mds293 10. Gradishar WJ, Anderson BO, Balassanian R, et al. Invasive Breast Cancer Version 1.2016, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2016;14(3):324-354. 11. Sargent DJ, Wieand HS, Haller DG, et al. Disease-free survival versus overall survival as a primary end point for adjuvant colon cancer studies: Individual patient data from 20 898 patients on 18 randomized trials. J Clin Oncol 2005;23:8664-8670. http://dx.doi.org/10.1200/jco.2005.01.6071 12. Gill S, Sarge D. End points for adjuvant therapy trials: Has the time come to accept disease-free survival as a surrogate end point for overall survival? Oncologist 2006;11:624-629. http://dx.doi.org/10.1634/ theoncologist.11-6-624 13. Wardley AM, Cameron DA, Bell R, et al. Modelling predicts a long-term benefit from trastuzumab (HerceptinÂŽ) use in HER2-positive breast cancer. Poster Presentation at 31st ESMO Congress, 29 September - 3 October 2006; Istanbul, Turkey. 14. Murthy RK, Varma A, Mishra P, et al. Effect of adjuvant/neoadjuvant trastuzumab on clinical outcomes in patients with HER2-positive metastatic breast cancer. Cancer 2014;120(13):1932-1938. http://dx.doi. org/10.1002/cncr.28689

Prof. Raymond Abratt responds: The vast majority of patients with human epidermal growth factor receptor (HER)-positive breast cancer in South Africa (SA) do not have access to and do not receive adjuvant trastuzumab, be they cared for in the public sector or the less well-resourced medical scheme options in the private sector. The letter commenting on the article on cost considerations in determining the affordability of adjuvant trastuzumab in SA[1] is founded on guidelines for patient care in affluent healthcare systems only. In such systems, trastuzumab is affordable upfront for patients. The letter ignores patients in less well-off healthcare systems. To rationally plan for quality healthcare for all patients in SA, we need to address drug access and its related budget impact, affordability and value. The original article fully recognises the clinical activity of trastuzumab. It notes that baseline survival rate (BLSR) of patients (the survival rate without adjuvant trastuzumab) depends on their prognostic group. The expected survival rate for the different prognostic groups with adjuvant trastuzumab can be calculated with the hazard ratio (HR). The number needed to treat (NNT) to benefit one patient can then be determined. The drug costs, which are the major factor determining affordability, to benefit one patient are described for different prognostic groups. This provides data to initiate a rational discussion of patient benefit from adjuvant trastuzumab, in healthcare systems with finite resources. The ethical principle of doing the best for all patients with the available resources is described. There are scientific inaccuracies in the letter which need to be answered, even though it would be preferable to focus on improving patient care. 1. The letter comments on the parameters used in NNT calculation in the original article: a. The author of the letter does not appreciate that calculations in the original article were done using the more sophisticated method and is referenced. The method of approximation was described in addition as it is helpful to clinicians. b. The author of the letter quotes a single 10-year survival rate of adjuvant trastuzumab and ignores prognostic groupings which result in different survival rates and have different cost implications in the NNT to benefit one patient. c. The author of the letter uses the 10-year survival rate from a single study rather than using all the scientific information from studies, which informs the HR. Moreover, the author states that with a BLSR of 75%, the NNT to benefit one patient is 17 and that the value in the original article is double that. This is incorrect.

In the original article the table indicates that for a BLSR of 80%, the NNT = 17.5 and for a BLSR of 70%, the NNT = 12.2, which is similar to or lower than that in the letter. d. The comment in the letter about HR is tangential and does not impact on the calculations in the original article. The assumption in the Cox model is that the HR is constant over time. It is indeed possible for it not to be so. If after a while, there is a substantial difference in the proportion of patients who are completely cured in one arm of a trial, they will no longer be experiencing the hazard (death) at the same rate as they were before. The control group may be dying (experiencing the hazard) at the same rate as before and so the HR will be different from what it has been earlier. However, the differences in cure rates between the two arms is relatively small, particularly in the clinical range described. 2. The letter notes that trials with a duration of trastuzumab treatment of <1 year have, to date, failed to show non-inferiority to 1 year of trastuzumab. However, the appropriate comparator for the vast majority of patients in SA and used in the original article is not 1 year of adjuvant trastuzumab but no treatment with trastuzumab at all. 3. The author makes a series of statements that cost cannot be used as the single basis for decision-making. This is discussed in the original article but is ignored in the letter. Nevertheless, drug costs merit specific consideration because they have a dominant role in determining access for patients. The author makes a series of aspirational statements about determining cost-effectiveness. These are theoretically correct but do not take account of locally available resources to do these determinations. Moreover, the letter provides no data. Simpler and pragmatic methods, which at least provide data, are helpful in discussions of resource allocation in this difficult area. The original article sought to be constructive and urges ongoing engagement of the state, healthcare institutions and the pharmaceutical industry to address high drug costs and to progressively bring the benefits from advances in cancer treatment to all patients. Raymond P Abratt

Head of Clinical Governance, Independent Clinical Oncology Network Emeritus Professor of Radiation Oncology, University of Cape Town, South Africa raymond.abratt@cancernet.co.za 1. Abratt RP. Cost considerations in determining the affordability of adjuvant trastuzumab in breast cancer. S Afr Med J 2016;106(10):981-982. http://dx.doi.org/10.7196/SAMJ.2016.v106i10.11141

S Afr Med J 2017;107(1):8-9. DOI:10.7196/SAMJ.2017.v107i1.12152

To the Editor: Cost considerations in determining affordability are extremely important for the sustainable health policy of all countries. It is of utmost importance that applied cancer treatment would result in a significantly improved cure rate being the primary objective, or at least a meaningfully reduced recurrence rate.Â The proposition presented by Abratt,[1] that state institution and lower-level medical schemes should consider <6 months of trastuzumab adjuvant therapy, is not supported by any solid clinical evidence and, if implemented, would result in fruitless depletion of resources. Two small trials included in the Cochrane analysis, to which his article refers, merely suggested possible efficacy of shortened time of treatment.[2] Both studies were conducted with different primary objectives, other than duration of treatment and its effectiveness. In addition: (i) the first one included only 42 patients and the effect on overall survival (OS) was not reported;[3] and (ii) the 5-year update

January 2017, Print edition

The South African Responsible Gambling Foundation (SARGF) who's primary objective is to grow awareness of responsible gambling and to manage and minimise the potential harmful effects of problem gambling, through its initiative National Responsible Gambling Programme (NRGP) has identied several warning signs that may indicate a person is developing a gambling problem. These are: 1. 2. 3. 4. 5.

Having constant thoughts about and a preoccupation with gambling Lying or concealing gambling activities from family and friends Attempting to recoup one's losses Taking extreme measures access money to gamble Preferring to gamble rather than attend other important events like a family get together 6. Feeling anxious or moody when not gambling 7. Racking up large debts due to gambling activities 8. Experiencing a deterioration in close relationships as a result of gambling 9. Neglecting personal needs like sleeping, hygiene and eating in favour of gambling 10. Manipulating people into lending or giving money to be used in gambling Like any addiction the rst step to receiving help and support is by admitting to the problem. A gambling addiction is difcult to ght alone and support is readily available via the NRGP 24 hour, free and condential helpline 0800 006 008 or via SMS HELP To 076 675 0710 or email helpline@sargf.org.za

AM OGR ME PR

NATIONAL RE

IBLE GAMBL NS IN O P

South African Responsible Gambling Foundation @SARGFoundation www.responsiblegambling.org.za

CORRESPONDENCE

of the second trial (FinHer) demonstrated no statistical difference in metastatic recurrence and mortality between control and trastuzumab arms.[4] The lack of effectiveness of 6 months’ therapy has been confirmed by the robust PHARE trial.[5] The National Institute for Health and Care Excellence (NICE) UK, known for its rigorous approach to cost-effectiveness, approved 1 year of trastuzumab treatment as being appropriate for the cash-strapped National Health Service (NHS).[6] Emerging 10-year follow-up BCIRG-006 data show that the addition of 12 months of trastuzumab therapy resulted in a 24 - 36% improvement in OS and a 24 - 36% reduction in recurrence rates, depending on the chemotherapy regimen used. Cardiac toxicity risk could be halved by the choice of a non-anthracycline chemotherapy regimen.[7] When calculating any cost-effectiveness, the state should also look at the cost of education of persons affected by the disease, as well as their role in the much-required stabilisation of the South African community. Cost-effectiveness calculations should include savings resulting from cure and avoidance of further lines of treatment. It should also include costs incurred by state, funders, community and family for continuous care of affected patients, should their breast cancer relapse. Any other calculations are usually biased to the financial needs of relevant interest groups. Should we rather advocate the use of scarce resources to effectively treat patients with defined intermediate and high risk for mortality and recurrence, instead of wasting them on futile, 6-month and less trastuzumab treatment regimens, as suggested by the author of this clinical alert? Waldemar Szpak

Rainbow Oncology, Amanzimtoti, South Africa drszpak@rainbowoncology.co.za 1. Abratt RP. Cost considerations in determining the affordability of adjuvant trastuzumab in breast cancer. S Afr Med J 2016;106(10):981-982 http://dx.doi.org/10.7196/SAMJ.2016.v106i10.11141 2. Moja I, Tagliabue I, Balduzi S, et al. Trastuzumab containing regimens for early breast cancer. Cochrane Database Syst Rev 2012, Issue 4. Art. No.: CD006243. http://dx.doi.org/10.1002/14651858.CD006243 3. Buzdar A, Ibrahim N, Francis D, et al. Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: Results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol 2005;23(16):3676-3685. http://dx.doi.org/10.1200/JCO.2005.07.032 4. Joensuu H, Bono P, Kataja V, et al. Fluorouracil, epirubicin, and cyclophosphamide with either docetaxel or vinorelbine, with or without trastuzumab, as adjuvant treatments of breast cancer: Final results of the FinHer trial. J Clin Oncol 2009;27(34):5685-5692. http://dx.doi.org/10.1200/JCO.2008.21.4577 5. Pivot X, Romieu G, Debled M, and the PHARE Trial investigators. 6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE): A randomised phase 3 trial. Lancet Oncol 2013;14(8):741-748. http://dx.doi.org/10.1016/S1470-2045(13)70225-0 6. National Institute for Health and Care Excellence UK. Trastuzumab for the adjuvant treatment of earlystage HER2-positive breast cancer. Technology appraisal guidance. http://www.nice.org.uk/guidance/ ta107 (accessed 7 November 2016). 7. Slamon DJ, Eiermann W, Robert NJ, on behalf of the BCIRG-006 investigators. Ten year follow-up of BCIRG-006 comparing doxorubicin plus cyclophosphamide followed by docetaxel (AC→T) with doxorubicin plus cyclophosphamide followed by docetaxel and trastuzumab (AC→TH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2+ early breast cancer [Abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 8 - 12 December 2015, San Antonio, Texas. Cancer Res 2016;76(4 Suppl):Abstract S5-04. http://dx.doi.org/10.1158/1538-7445. SABCS15-S5-04

Prof. Raymond Abratt responds: T h e o r i g i n a l a r t i c l e [ 1] f o c u s e d o n c o s t c o n s id e ra tio n s in d e te rm in in g th e a ffo rd a b ility o f a d ju v a n t tra s tu z u m a b . In th e fin a l s e c tio n o f th e a rtic le , th e c lin ic a l e th ic a l p rin c ip le w a s n o te d th a t ‘c lin ic ia n s s h o u ld p ro v id e th e b e s t tre a tm e n t p o s s ib le w ith a v a ila b le re s o u rc e s , p ro v id e d th e re is e v id e n c e o f b e n e fit a n d th e c lin ic ia n is p re p a re d to u n d e rta k e th e tr e a tm e n t.’ I n a w e l l - r e s our c e d e nvi r onm e nt , 12 m ont hs of t r a s t uz um a b s houl d be of f e r e d t o pa t i e nt s . H ow e ve r , f or t he va s t m a j or i t y of pa t i e nt s i n S out h A f r i c a ( S A ) t hi s i s not a va i l a bl e a nd t he y r e c e i ve no

a dj vau nt t r a s t uz um a b t r e a t m e nt a t a l l . A n opt i on w hi c h on c ol ogi s t s i n S A m a y c ons i de r , i s < 12 m ont hs of a dj uva nt t r a s t uz um a b. I n t h e P H A R E t r i a l , [ 2] 6 m o n t h s o f a d j u v a n t t r a s t u z u m a b w a s s h o w n t o b e m a r g i n a l l y l e s s e f f e c t i v e t h a n t h e 12- m o n t h s r e g i m e n i n t e r m s o f d i s e a s e - f r e e s u r v i v a l ( D F S ) . T h e 2- y e a r D F S w a s 9 3. 8 % ( 9 5 % c o n f i d e n c e i n t e r v a l ( C I ) 9 2. 6 - 9 4. 9 ) i n t h e 12- m o n t h g r o u p a n d 9 1. 1% ( 8 9 . 7 - 9 2. 4) i n t h e 6 - m o n t h g r o u p . H o w e v e r , s i g n i f i c a n t l y m o r e p a t i e n t s i n t h e 12- m o n t h g r o u p e x p e r i e n c e d a c a r d i a c e v e n t t h a n d i d t h o s e i n t h e 6 - m o n t h g r o u p , 5 . 7 % v . 1. 9 % , p< 0 . 0 0 0 1. S o, t he num be r ne e de d t o t r e a t ( N N T ) t o pr e ve nt 1 r e c ur r e nc e a t 2 ye a r s , by gi vi ng a n e xt r a 6 m ont hs of t r a s t uz um a b, i s 100/ ( 93.8 – 91.1) = 37. T he N N T t o pr e ve nt 1 r e c ur r e nc e a t 23 m ont hs i s 16 w he n 12 m ont hs of t r a s t uz um a b i s c om pa r e d w i t h no t r e a t m e nt . [ 3] T hi s s uge s t s a di m i ni s hi ng r e t ur n i n be ne f i t a nd de c r e a s i ng va l ue , t ha t i s out c om e / c os t , [ 4] w i t h t he a di t i ona l 6 m ont hs of t he r a py . B u t to x ic ity in c re a s e s w ith th e a d d itio n a l 6 m o n th s o f tre a tm e n t. T h e n u m b e r n e e d e d t o h a r m ( N N H ) f o r a n e x t r a c a r d i a c e v e n t i s 10 0 / ( 5 . 7 – 1. 9 ) = 26 . I t i s t h e r e f o r e m o r e l i k e l y t h a t a p a t i e n t w i l l s u f f e r a c a rd ia c e v e n t th a n h a v e a b re a s t c a n c e r e v e n t p re v e n te d w ith a n e x tra 6 m o n th s o f tra s tu z u m a b . The drug cost for an additional 6 months of trastuzumab is ZAR205 000 per patient. The drug cost to prevent one recurrence in the treated population, as described in the PHARE study, for an NNT of 37 = ZAR7 585 000. This is not affordable for SA’s healthcare systems. Downstream differences in costs between 6 and 12 months of adjuvant trastuzumab are irrelevant to patients who do not receive the drug at all. T he s t udy f i ndi ng s a nd dr ug c os t s i ndi c a t e t ha t t he 6- m ont h r e gi m e n i s a s ound opt i on a nd w i l l i nc r e a s e t he num be r of pa t i e nt s w ho w i l l ha ve a c c e s s t o a dj uva nt t r a s t uz um a b w i t hi n t he budge ta ry c ons t r a i nt s of S A ’ s he a l t hc a r e s ys t e m s . T he 12- m ont h r e gi m e n s houl d not be r e ga r de d a s t he onl y a c c e pt a bl e opt i on i n S A . T he vi e w t ha t i t i s pr e f e r a bl e t ha t pa t i e nt s r e c e i v e no a dj uva nt t r a s t uz um a b t r e a t m e nt r a t he r t ha n 6 m ont hs of a dj uva nt t r a s t uz um a b doe s not s e r ve t he pur pos e of be ne f i t t i ng pa t i e nt s . S c i e n t i f i c q u e s t i o n s a n d c o s t s i n f l u e n c e p a t i e n t c a r e g l o b a l l y . [5 ] W e n e e d to w o rk w ith P h a rm a a n d o th e rs to re d u c e th e p ric e o f tre a tm e n t a n d a ls o to c la rify a ll th e a s s o c ia te d c o s t-to -b e n e fit p a t i e n t s i n d i f f e r e n t p r o g n o s t i c g r o u p s . [ 1] O u r a i m i s t o p r o v i d e h ig h -q u a lity c a re to a ll p a tie n ts w ith in th e n e c e s s a ry c o n s tra in ts o f c o s t. Acknowledgements. The author thanks Dr Fergus Macbeth for his very helpful comments.

Raymond P Abratt

Head of Clinical Governance, Independent Clinical Oncology Network Emeritus Professor of Radiation Oncology, University of Cape Town, South Africa Raymond.Abratt@cancernet.co.za 1. Abratt RP. Cost considerations in determining the affordability of adjuvant trastuzumab in breast cancer. S Afr Med J 2016;106(10):981-982. http://dx.doi.org/10.7196/SAMJ.2016.v106i10.11141 2. Pivot X, Romieu G, and the PHARE Trial investigators. 6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE): A randomised phase 3 trial. Lancet Oncol 2013;14(8):741-748. http://dx.doi.org/10.1016/S1470-2045(13)70225-0 3. Smith I, Procter M, Gelber RD, et al. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: A randomised controlled trial. Lancet 2007;369(9555):29-36. http:// dx.doi.org/10.1016/S0140-6736(07)60028-2 4. Abratt RP. Modelling cost-effective therapies. S Afr Med J 2015;105(11):884. http://dx.doi.org/10.7196/ SAMJ.2015.v105i11.9880 5. Elzawawy AM. Could African and low- and middle-income countries contribute scientifically to global cancer care? J Glob Oncol 2015;1(2):49-53.

S Afr Med J 2017;107(1):10-11. DOI:10.7196/SAMJ.2017.v107i1.12172

January 2017, Print edition

DIE SUID AFRIKAANSE VERENIGIGING VAN ANESTSIOLOË THE SOUTH AFRICAN SOCIETY OF ANAESTHESIOLOGISTS

ANAESTHESIOLOGY UPDATE MEETING Hosted by SASA, Western Cape Branch

INVITATION

Lagoon Beach Hotel, Cape Town Saturday, 6 May 2017 OVERVIEW Doctors: For speaker topics please see the programme on www.sasawesterncape.co.za Nurses: For speaker topics please see the programme on www.sasawesterncape.co.za COST SASA Members: Early Registration: R250.00 • Late Registration: R350.00 Non-SASA Members: Early Registration: R1 000.00 • Late Registration: R1 200.00 Nurses: Early Registration: R450.00 • Late Registration: R500.00 CPD The Update Meeting will be accredited REGISTRATION Early registration closes 22 April 2017 To register please visit our website: www.sasawesterncape.co.za Date: Venue:

Saturday, 6 May 2017 Lagoon Beach Hotel Milnerton Cape Town

Contact: Tel: Fax: Email:

Eastern Sun Events +27 41 374 5654 +27 41 373 2042 sasa@easternsun.co.za

Don’t miss the 2017 SASA Congress in Johannesburg! www.sasa2017.co.za

CORRESPONDENCE

Yes, we can eradicate tuberculosis in South Africa

To the Editor: Tuberculosis (TB) is a major killer in South Africa (SA), responsible for 40 542 deaths in 2013[1] and with an estimated incidence of 450 000 per year. [2] The World Health Organization (WHO) aims to eradicate the disease by 2035,[3] and the first milestones in the process of eradication are to reduce the 2015 deaths and incidence by 35% and 20%, respectively, by 2020. The last indicator is to reduce the deaths by 95% by 2030. Are the WHO indicators achievable for SA? The answer is unequivocally in the affirmative, and for the following reasons. Firstly, the reduction in TB deaths in SA was 45% between 2008 and 2013,[1] much higher than 35%. Secondly, a definitive diagnosis of suspected TB can be made within a week if all patient specimens can have access to the GeneXpert, and all can be achieved. Thirdly, effective treatment of all drug-sensitive TB infections can be achieved within 6 months. Moreover, all drugresistant infections can be identified with the aid of GeneExpert and then treated with bedaquiline and other new drugs when these become available for all patients.[4] Fourthly, the biggest challenge in SA has been that of a weak healthcare system. Some good news is that I have piloted an innovative mHealth approach in one municipal ward of the Eastern Cape Province, and the results of proof of concept are now available.[5] The new approach entails a 100% household survey in one municipal ward. It is eminently scalable to national level, and can address most of the weaknesses of the health system very effectively through the following mechanisms: • Determining the prevalence and distribution of TB infections at household level in

•

each municipal ward and district (Table 1). The activity would identify all TB infections, as recommended by the Stop TB Partnership’s theme for 2015. [6] This would help with more accurate monitoring of the epidemics of TB and HIV, where patients can be followed up electronically. Enhanced effectiveness and efficiency of ward-based primary healthcare outreach teams, as they help to facilitate diagnosis, treatment and prevention of TB and HIV infections. Strengthening of community participation, community health action and health promotion, both within the structures of local government and in partnership with local non-governmental organisations and the private sector. Facilitating strong and effective partnerships with research and tertiary institutions in documenting the epidemiology of TB infections and related risk factors, as well as development and testing of TB drugs, and monitoring and evaluation of control of the epidemic. Facilitating the process of addressing social determinants of disease by all departments of government at provincial and national level, with a special focus on unemployment, access to social grants and household food security. Providing a quick and cost-effective mechanism that can be used by National Health Insurance pilot districts to leapfrog strengthening of the health system in all the provinces of SA.

Welile Shasha

Public health specialist and CEO of the Household Surveys Foundation, Pretoria, South Africa welile.shasha@gmail.com 1. National Department of Health, South Africa. TB in South Africa. www.tbfacts.org/tb-south-africa (accessed 21 July 2016).

Table 1. Number of persons reported with cough/TB in each village of municipal ward[5] Village Bongolethu

Cough, n (%) 6 (0.7)

TB, n (%) 5 (0.6)

Total, n (%) 11 (1.2)

Population size 897

Maya

2 (0.1)

6 (0.4)

8 (0.5)

1 469

Ntlakwefolo

5 (0.3)

19 (1.0)

24 (1.6)

1 457

Mkhukhwini

1 (0.3)

2 (0.7)

282

Mngqanga

2 (0.5)

13 (3.6)

15 (4.1)

363

Zwelitsha

0 (0.0)

8 (1.0)

766

Ntlonze

0 (0.0)

12 (0.8)

1 479

Mtyhintyini

5 (0.5)

10 (1.0)

15 (1.5)

1 019

Mbinzana

1 (0.1)

6 (0.5)

7 (0.8)

929

Holi

0 (0.0)

7 (0.9)

771

Total

22 (0.2)

87 (0.9)

109 (1.1)

9 432

January 2017, Print edition

2. World Health Organization. Tuberculosis statistics. www.tbfacts. org/tb-statistics-south-africa (accessed 1 December 2016). 3. World Health Organization. Global strategy and targets for tuberculosis prevention, care and control after 2015. www.who. int/tb/post2015-tbstrategy.pdf (accessed 1 December 2016) 4. Engineering News. South Africa to introduce new TB treatment. http://www.engineeringnews.co.za/article/south-africa-tointroduce-new-tb-treatment-2016-03-29 (accessed 17 July 2016). 5. Shasha W. Mobile health and leapfrogging of health system strengthening in South Africa. J mHealth 2016;3(4):32-36. http:// media.wix.com/ugd/85fd63_fc5c5209195b4bf59e974abe36f9264a. pdf (accessed 24 September 2016). 6. Pai M, Dewan P. Testing and treating the missing millions with tuberculosis. PLoS Med 2015;12(3):e1001805. http://dx.doi. org/10.1371/journal.pmed.1001805

S Afr Med J 2017;107(1):12. DOI:10.7196/SAMJ.2017.v107i1.12081

From an exasperated pathologist

To the Editor: I have been a histopathologist for 5 years, and am now practising in a regional teaching hospital. I see incredible pathology, but to the detriment of the population who are biopsied. I see gross pathology – the ugly blue tumour literally stares back at me on naked-eye examination of my slide. My office is a mess. The boards are piled up on every conceivable work surface, and I can’t remember the last time I saw my desk calendar – it is well and truly buried. I am so busy that I cannot write an article in under a year. On that note, I fear the day open access becomes the norm, because we cannot afford to pay in dollars and pounds to have our work published. I fear the day when all histological diagnoses must be supported by molecular investigations, because these guidelines are developed in First-World institutions without a thought to the resources available to pathologists in the underdeveloped parts of the world. I studied medicine for the noble reason of wanting to help others, and every day I feel that I make a difference. I send out histological diagnoses that will expedite treatment, as quickly and as accurately as I can. There is no reason why the underprivileged should not get a first-class pathological report. Almost everything I diagnose is malignant and marked ‘urgent’, and I feel post-traumatic stress disorder symptoms coming on. I must ask my psychiatrist husband if there is such a thing as work-related PTSD. I need him to keep me in check; his raised eyebrow lets me know I’m sounding hysterical. I should keep going, he always says. And keep going I will, because I am afraid – afraid that if I leave they will get left, the biopsies and the patients of Soweto. We live in a world of contrasts. I am reminded of this every day as I turn my Mercedes (albeit bottom of the range) into the hospital grounds and stop to let small

CORRESPONDENCE

children cross the entrance on their way to school. They walk with schoolbags bigger than themselves, and I am happy that they are going to school. I silently pray, ‘I hope I never have to diagnose your biopsy with tumour.’ All is not morbid. I have a corner office with a view of the entire hospital, and the warm sun shines on me as I sign out my cases. The birds perch on the window ledge and peck at the window to greet me. And when I close my door to leave work every day, I go home to four beautiful children who greet me with such vigour that I am rejuvenated for the next day and all the atrocities it may hold. There are people all over the world who service war-stricken and diseaseburdened communities. This very hospital is serviced by dedicated practitioners who worked tirelessly in the pre-HIV years and may still be hobbling around the corridors in the post- (dare I dream?) HIV era. We are so inundated with service delivery that there is no opportunity for research and publications – those elusive academic components that ensure a brisk climb up the career ladder. The point is, not to lose faith. Every little bit counts, and when I meet my maker at the pearly gates I can honestly say I tried. No tombstone, I think, has ever read ‘Here lies the greatest pathologist that ever lived’! Reena Dhansukh Mohanlal

Department of Anatomical Pathology, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand and National Health Laboratory Service, Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa reena.mohanlal@nhls.ac.za;reenadm@mweb.co.za

factors in HIV-infected participants, including hypertension, obesity, dyslipidaemia and endothelial activation.[5,8,9] Unfortunately the vast majority of these studies are observational, cross-sectional or hospital based, with no longitudinal follow-up. This hampers thorough assessment of the incidence and nature of cardiovascular risk and disease trajectories in people living with HIV/AIDS. Furthermore, HIV infection is inextricably linked with antiretroviral therapy (ART), another putative cardiovascular risk factor. It is well established that several ARV drugs can result in increased cardiovascular risk;[10] however, for as long as this possible link is not investigated in our context, serious future cardiovascular health challenges may arise, particularly in view of the massive ART roll-out programmes initiated in recent years.[6] In conclusion, we believe there is a real possibility that HIV infection and ART are emerging driving forces behind the rapidly increasing cardiovascular risk factor and CVD rates in SSA. If the lack of population studies investigating this question persists, public health services may be even less prepared for the multiple burden of disease facing the continent. Hans Strijdom, Patrick De Boever, Tim Nawrot and Nandu Goswami are members of the EndoAfrica research consortium. The EndoAfrica study is investigating the effects of HIV-infection and ARV treatment on cardiovascular health and endothelial function in SA populations.

Hans Strijdom

PS. This letter took me 7 days to write. I found it quite therapeutic.

Cardiovascular Research Group, Division of Medical Physiology, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Cape Town, South Africa jgstr@sun.ac.za

S Afr Med J 2017;107(1):13. DOI:10.7196/SAMJ.2017.v107i1.12079

Patrick De Boever

HIV/AIDS: Emerging threat to cardiovascular health in sub-Saharan Africa

To the Editor: Public health in sub-Saharan Africa (SSA) is at a crossroads owing to an increasing non-communicable disease burden, with a sizeable contribution from cardiovascular disease (CVD). CVD is the top cause of death globally,[1] and an estimated 80% of CVD-related deaths occur in low- to middle-income countries, including South Africa (SA).[2] Although epidemiological transition is an important factor contributing to the rise in cardiovascular risk factors and CVD,[3] the emerging interaction between communicable diseases such as HIV/AIDS and CVD should not be neglected. HIV infection is now recognised as an independent cardiovascular risk factor; however, the data are mainly from developed countries.[4,5] The paucity of studies investigating this question in SSA, where demographic and socioeconomic realities, HIV strains and antiretroviral (ARV) guidelines are different, is of great concern. In high-income countries, HIV-related CVD manifests as coronary heart disease;[4] conversely, the incidence of coronary heart disease is believed to be relatively low in HIV-infected SSA populations.[6] Most reports cite pulmonary hypertension, cardiomyopathy and tuberculous pericarditis as the predominant HIV-related cardiovascular conditions.[6] A recent cross-sectional study in Soweto, SA, showed that only 2.4% of patients presenting with coronary heart disease for the first time were HIV-positive.[7] We believe that these and other findings may not represent the full picture or future trends of HIVrelated CVD in SSA. In recent years, data have started to emerge pointing to a high incidence of proatherogenic cardiovascular risk

Environmental Risk and Health Unit, Flemish Institute for Technological Research (VITO), Belgium; Centre for Environmental Studies, Hasselt University, Belgium

Tim S Nawrot

Centre for Environmental Studies, Hasselt University, Belgium; Department of Public Health and Primary Care, Leuven University, Belgium

Nandu Goswami

Gravitational Physiology and Medicine Research Unit, Institute of Physiology, Medical University of Graz, Austria 1. Institute for Health Metrics and Evaluation (IHME). GBD Compare. Seattle, WA: IHME, University of Washington, 2013. http://vizhub.healthdata.org/gbd-compare (accessed 8 February 2015). 2. Yusuf S, Rangarajan S, Teo K, et al. Cardiovascular risk and events in 17 low-, middle-, and highincome countries. N Engl J Med 2014;371(9):818-827. http://dx.doi.org/10.1056/NEJMoa1311890 3. Muna WF. Comprehensive strategies for the prevention and control of diabetes and cardiovascular disease in Africa: Future directions. Prog Cardiovasc Dis 2013;56(3):363-366. http://dx.doi.org/10.1016/j.pcad.2013.10.012 4. Zanni MV, Schouten J, Grinspoon SK, Reiss P. Risk of coronary heart disease in patients with HIV infection. Nat Rev Cardiol 2014;11(12):728-741. http://dx.doi.org/10.1038/nrcardio.2014.167 5. Bloomfield GS, Hogan JW, Keter A, et al. Hypertension and obesity as cardiovascular risk factors among HIV seropositive patients in Western Kenya. PLoS One 2011;6(7):e22288. http://dx.doi. org/10.1371/journal.pone.0022288 6. Mayosi BM, Flisher AJ, Lalloo UG, Sitas F, Tollman SM, Bradshaw D. The burden of noncommunicable diseases in South Africa. Lancet 2009;374(9693):934-947. http://dx.doi.org/10.1016/ S0140-6736(09)61087-4 7. Sliwa K, Carrington MJ, Becker A, Thienemann F, Ntsekhe M, Stewart S. Contribution of the human immunodeficiency virus/acquired immunodeficiency syndrome epidemic to de novo presentations of heart disease in the Heart of Soweto Study cohort. Eur Heart J 2012;33(7):866-874. http://dx.doi. org/10.1093/eurheartj/ehr398 8. Julius H, Basu D, Ricci E, et al. The burden of metabolic diseases amongst HIV positive patients on HAART attending the Johannesburg Hospital. Curr HIV Res 2011;9(4):247-252. http://dx.doi. org/10.2174/157016211796320360 9. Fourie CM, Schutte AE, Smith W, Kruger A, van Rooyen JM. Endothelial activation and cardiometabolic profiles of treated and never-treated HIV infected Africans. Atherosclerosis 2015;240(1):154-160. http://dx.doi.org/10.1016/j.atherosclerosis.2015.03.015 10. Currier JS, Lundgren JD, Carr A, et al. Epidemiological evidence for cardiovascular disease in HIV-infected patients and relationship to highly active antiretroviral therapy. Circulation 2008;118(2):e29-e35. http://dx.doi.org/10.1161/CIRCULATIONAHA.107.189624

S Afr Med J 2016;106(6):537. DOI:10.7196/SAMJ.2016.v106i6.10721

January 2017, Print edition

These-open access articles are distributed under Creative Commons licence CC-BY-NC 4.0.

IZINDABA

30 days in medicine Nurse-led management of chronic diseases

This study of 38 public sector primary care clinics in the Western Cape Province, South Africa (SA), suggests that training nurses in the use of a management tool involving an expanded role in managing non-communicable diseases (NCDs) is safe and feasible, but did not result in treatment intensification or improved case detection for index diseases. However, the intervention, with some adjustment, has been adopted for implementation in primary care clinics throughout SA. Primary Care 101 (PC101) is a programme designed to support and expand nurses’ role in NCD care, and is made up of educational outreach and a clinical management tool with enhanced prescribing provisions. Nurses in the intervention clinics were trained to use the PC101 management tool during educational outreach sessions delivered by health department trainers and were authorised to prescribe an expanded range of drugs for several NCDs. Control clinics continued use of the Practical Approach to Lung Health and HIV/AIDS in South Africa (PALSA PLUS) management tool and usual training. Patients attending these clinics with one or more of hypertension (n=3 227), diabetes (n=1 842) or chronic respiratory disease (n=1 157) or who screened positive for depression (n=2 466), totalling 4 393 patients, were enrolled between 28 March 2011 and 10 November 2011. Primary outcomes were treatment intensification in the hypertension, diabetes, and chronic respiratory disease cohorts, defined as the proportion of patients in whom treatment was escalated during follow-up over 14 months, and case detection in the depression cohort. However, treatment intensification rates in the intervention clinics were no better than those in the control clinics. Fairall LR, Folb N, Timmerman V, et al. Educational outreach with an integrated clinical tool for nurseled non-communicable chronic disease management in primary care in South Africa: A pragmatic cluster randomised controlled trial. PLoS Med 2016. http://dx.doi.org/10.1371/journal.pmed.1002178 (published 22 November 2016).

Minimally invasive autopsy: Identifying the cause of death in Mozambique

An observational study that coupled minimally invasive autopsy (MIA) and complete diagnostic autopsy (CDA) performed in 112 dead patients in Mozambique suggests that the simple MIA can identify the cause of many adult deaths. In many low-income regions, current methods used to identify cause of death (verbal autopsy, clinical records and complete autopsies) are either inaccurate, not feasible or poorly accepted. In this study, the MIA analyses were done blindly, with no knowledge of the clinical data or the results of the CDA, and the MIA diagnosis was compared with the CDA diagnosis of cause of death. CDA diagnoses comprised infectious diseases (n=80, 71.4%), malignant tumours (n=16, 14.3%), and other diseases, including non-infectious cardiovascular, gastrointestinal, kidney, and lung diseases (n=16, 14.3%). An MIA diagnosis was obtained in 100/112 cases (89.2%). The overall concordance between the MIA diagnosis and CDA diagnosis was 75.9% (85/112). The concordance was higher for infectious diseases and malignant tumours (63/80 (78.8%) and 13/16 (81.3%), respectively) than for other diseases (9/16, 56.2%). The specific micro-organisms causing death were identified in the MIA in 62/74 (83.8%) of the infectious disease deaths with a recognised cause. This tool could have a major role in improving the understanding and surveillance of causes

of death in areas where infectious diseases are a common cause of mortality. Castillo P, Martinez MJ, Ussene E, et al. Validity of a minimally invasive autopsy for cause of death determination in adults in Mozambique: An observational study. PLoS Med 2016. http://dx.doi.org/10.1371/ journal.pmed.1002171 (published 22 November 2016).

Diet, lifestyle, body mass index and mortality

In this longitudinal study, with up to 32 years of follow-up of 74 582 women from the Nurses’ Health Study and 39 284 men from the Health Professionals Follow-up Study, the conclusions were that although people with a high BMI can have lower risk of premature mortality if they also have at least one low risk lifestyle factor, the lowest risk of premature mortality is those with a BMI in the range 18.5 - 22.4, with high scores on healthy eating and physical activity, moderate alcohol intake and who do not smoke. During the 32 years of follow-up there were more deaths from cancer (n=10 808) than from cardiovascular disease (n=189) – interesting in itself. A combination of at least three low-risk lifestyle factors, along with the range of BMI mentioned, was associated with the lowest risk of all cause and cardiovascular mortality. The greatest risk was found in those with a BMI in the range 22.5 - 24.9 with none of the four low risk lifestyle factors. Veronese N, Li Y, Monson JE, et al. Combined associations of body weight and lifestyle factors with all cause and cause specific mortality in men and women: Prospective cohort study. BMJ 2016;355:i5855. http:// dx.doi.org/10.1136/bmj.i5855 (published 24 November 2016).

Methylprednisone injected through the eardrum effective in combating Ménière’s symptoms

A recent study published in The Lancet shows that injections of the steroid methylprednisone through the eardrum are as effective as current standard treatment of gentamicin in reducing the dizziness associated with Ménière’s disease, but without the associated risk of hearing loss. This current treatment relies on the ototoxic effect of the antibiotic, and around 20% of patients are left with permanent hearing loss. In this double-blind trial, 60 patients with unilateral Ménière’s disease were randomly assigned to two intratympanic injections of methylprednisone or gentamicin, given 2 weeks apart. Patients treated with methylprednisolone showed a 90% reduction in the mean number of attacks they experienced, from 16.4 in the 6 months before treatment to 1.6 at 18 - 24 months after treatment. This compared with an 87% reduction in attacks with gentamicin, from a mean of 19.9 to 2.5. Patel M, Agarwal K, Arshad Q, et al. Intratympanic methylprednisolone versus gentamicin in patients with unilateral Ménière’s disease: A randomised, double-blind, comparative effectiveness trial. Lancet 2016;388(10061):2753-2762. http://dx.doi.org/10.1016/S0140-6736(16)31461-1

Prediabetes associated with increased risk of cardiovascular and all-cause mortality

A meta-analysis of 53 prospective cohort studies with 1 611 339 individuals suggests that prediabetes is associated with an increased risk of cardiovascular disease. The analysis looked at different definitions of prediabetes and for associations between the risk of composite cardiovascular disease, coronary heart disease, stroke, all-cause mortality and prediabetes. Prediabetes was defined as

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impaired fasting glucose level according to the criteria of the American Diabetes Association (IFG-ADA; fasting glucose 5.6 6.9 mmol/L), the WHO expert group (IFG-WHO; fasting glucose 6.1 - 6.9 mmol/L), impaired glucose tolerance (2-hour plasma glucose concentration 7.8 - 11.0 mmol/L during an oral glucose tolerance test), or raised glycated haemoglobin (HbA1c) of 39 - 47 mmol/mol (5.7 - 6.4%) according to American Diabetes Association criteria or 42 - 47 mmol/mol (6.0 - 6.4%) according to the National Institute for Health and Care Excellence (NICE) guideline. Increases in HBA1c to 39 - 47 mmol/mol or 42 - 47 mmol/mol were both associated with an increased risk of composite cardiovascular disease (1.21 and 1.25, respectively) and coronary heart disease (1.15 and 1.28, respectively), but not with an increased risk of stroke and all-cause mortality. Huang Y, Cai X, Mai W, Li M, Hu Y. Association between prediabetes and risk of cardiovascular disease and all cause mortality: Systematic review and meta-analysis. BMJ 2016;355:i5953. http://dx.doi.org/10.1136/ bmj.i5953 (published 23 November 2016).

E-cigarettes raise risk of persistent cough and wheeze in teenagers

A questionnaire administered to more than 2 000 teenagers aged between 16 and 18 years as part of the Southern California Children’s Health Study showed that those who used e-cigarettes had twice the risk of respiratory symptoms such as persistent cough, bronchitis and wheeze as those who did not. The risk of bronchitis rose with frequency of use, from a two-thirds higher risk in teenagers who used e-cigarettes for 1 - 2 days in the previous months to two and a half times the risk in those using them on ≥3 days, when compared with never users. Just under a tenth (9.6%, n=201) of the adolescents who responded to the survey were current users of e-cigarettes, having used them at least once in the previous 30 days, 14.4% were past users, reporting that they had used e-cigarettes previously but not in the past month, and 76% said that they had never used e-cigarettes. E-cigarettes contain chemicals toxic to the lungs, including oxidant metals, glycerol vapour, diketone flavouring compounds and nicotine. McConnell R, Barrington-Trimis JL, Wang K, et al. Electronic-cigarette use and respiratory symptoms in adolescents. Am J Respir Crit Care Med 2016. http://www.atsjournals.org/doi/abs/10.1164/rccm.2016040804OC (published online 2 November 2016).

Alcohol consumption and different stroke types

Light and moderate alcohol consumption appears to be inversely associated with ischaemic stroke, while heavy drinking is associated with increased risk of all types of stroke, particularly haemorrhagic stroke, according to a meta-analysis conducted by Swedish researchers. Additional data from 73 587 Swedish adults in two prospective studies were included. Study-specific

results were combined in a random-effects model. The metaanalysis included 27 prospective studies with data on ischaemic stroke (25 studies), intracerebral haemorrhage (11 studies), and/ or subarachnoid haemorrhage (11 studies). Light and moderate alcohol consumption was associated with a lower risk of ischaemic stroke, whereas high and heavy drinking was associated with an increased risk. Light and moderate alcohol drinking was not associated with any haemorrhagic stroke subtype. High alcohol consumption (>2 - 4 drinks/day) was associated with a non-significant increased risk of both haemorrhagic stroke subtypes, and the relative risk for heavy drinking (>4 drinks/day) was 1.67 for intracerebral haemorrhage and 1.82 for subarachnoid haemorrhage. Larsson S, Wallin A, Wolk A, Markus HS. Differing association of alcohol consumption with different stroke types: A systematic review and meta-analysis. BMC Med 2016;14:178. http://dx.doi.org/10.1186/s12916016-0721-4

Stage at breast cancer diagnosis and survival in sub-Saharan Africa

A recent meta-analysis of breast cancer stage at diagnosis in subSaharan Africa suggests that strategies for early diagnosis of breast cancer should be regarded as a major priority by cancer control programmes in the region. The authors included 83 studies, which consisted of 26 788 women from 17 sub-Saharan African countries. They found wide between-study heterogeneity in the percentage of later-stage disease at diagnosis. The percentage of patients with latestage disease at diagnosis did not vary by region in black women, but was lower in non-black women from southern Africa than in black women in any region (absolute difference from black women in western Africa −18.1%,), and higher for populations from mixed (urban and rural) settings rather than urban settings (13.2%, 5.7 - 20.7, in analyses restricted to black women). The percentage of patients with late-stage disease at diagnosis in black Africans decreased over time (–10.5%, −19.3 - −1.6; for 2000 or later v. 1980 or before), but it was still higher around 2010 than it was in white and black women in the USA 40 years previously. The incidence of breast cancer in sub-Saharan Africa is relatively low, but as survival from the disease in the region is poor, mortality rates are as high as in high-income countries. Stage at diagnosis is a major contributing factor to poor survival from breast cancer. Jedy-Agba E, McCormack V, Adebamowo C, dos-Santos-Silva I. Stage at diagnosis of breast cancer in subSaharan Africa: A systematic review and meta-analysis. Lancet Global Health 2016;4(12):e923-e935. http:// dx.doi.org/10.1016/S2214-109X(16)30259-5

Bridget Farham Editor ugqirha@iafrica.com

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OBITUARIES Steve Lawn (13 March 1966 - 23 September 2016)

Prof. Steve Lawn was a ‘mensch’ – a compassionate doctor, a loving husband and father, a prolific researcher, a gifted teacher and an extraordinary human being. He died at the age of 50 years on 23 September 2016, from aggressive cerebral glioblastoma multiforme that he bravely battled for two years. He was Professor of Infectious Diseases and Tropical Medicine at the London School of Hygiene and Tropical Medicine, UK, and honorary associate Professor of Infectious Diseases and HIV Medicine at the University of Cape Town, South Africa. Steve Lawn was born in 1966, the youngest of three boys. He grew up in Yorkshire and won a place at the University of Nottingham to read medicine. There he met Joy, the love of his life, whom he married in December 1989. He won eight awards as an undergraduate, including the John Moir Gold Medal for the best student in general medicine. After completing his clinical training in infectious diseases in London, he engaged in tuberculosis work in 1993 in Ghana, where he researched and

taught at the Kwame Nkrumah University of Science and Technology in Kumasi until 1997. From there, he moved to Atlanta, USA, as a Wellcome Trust Fellow to conduct laboratory-based research on the pathogenesis of HIV and tuberculosis. He returned to London in 2001, working at St George’s Hospital and the Hospital for Tropical Diseases before his long-time mentor, Prof. George Griffin of St George’s Hospital, introduced him to the Desmond Tutu HIV Centre in Cape Town. This resulted in Steve’s heading to Cape Town with Joy and their two children Tim and Jo-Ann in 2005, as a Wellcome Trust Researcher. Steve rapidly became an integral part of the DTHC team. To go with his lifelong passion for Africa, another passion that blossomed during the years in Cape Town was his love for running and participation in marathons. Both on the road and in front of his laptop he paced himself like a true athlete, publishing over 180 scientific articles, starting at a brisk pace of four papers in 2005 and with a particularly strong finish at almost two papers a month in the last three years. Quantity was not substituted for quality, as he won the prize at the IAS conferences of 2010 and 2012 for the highest-cited article in AIDS in those years. Besides his original studies his publishing output included several highly cited scientific reviews, demonstrating his deep grasp of his subject. This publishing output was awe-inspiring and was evidence of his legendary drive and capacity for hard work, together with his impressive intellect and a remarkable ability to focus. Academic output was not limited to papers, for Steve was also mentor to many students and post docs. He was regularly asked to give ‘state of the ART’ lectures at both national and international conferences. His popularity as a speaker was in large part a result of his Yorkshire proclivity for plain

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speaking, together with a mischievous sense of humour. Early in 2016 he recognised that he would have to pass on the opportunity to give an invited talk on the role of GeneXpert at the TB conference in Durban later that year, because his illness had made it impossible for him to travel. He expressed his deep sense of regret, but mischievously told us that his planned talk was going to draw parallels between the response of the San to a Coca-Cola bottle that had fallen to earth in the well-known Jamie Uys film ‘The Gods must be Crazy’ and the TB world’s response to the GeneXpert test. We will never know the wisdom that lay in this metaphor. Steve was much more than just an academic with a razor-sharp mind. He was very proud of his family – Joy, Jo, Tim, and an over-exuberant spaniel, Toffee. Another major part of his life was his very strong religious faith. It was this faith, combined with his family’s support and a lot of Yorkshire perseverance, that helped him cope so remarkably with his devastating illness and the gruelling treatment he endured during the last two years. Many of you will know that we, together with the London School of Hygiene and Tropical Medicine and the International Union against Tuberculosis and Lung Disease have initiated a trust in memory of Steve’s important contributions to TB. The trust will enable memorial lectures in Cape Town and London, together with bursary support of researchers early in their careers. We hope that this will be a fitting tribute to someone who dedicated so much of his fartoo-short life to the study of TB. Linda-Gail Bekker, Robin Wood Desmond Tutu HIV Centre, Faculty of Health Sciences, University of Cape Town, South Africa linda-gail.bekker@hiv-research.org.za

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Pieter Stephanus Bothma (29 August 1957 - 21 July 2016) Pieter Stephanus Bothma was born in Bothaville, Free State, on 29 August 1957. He matriculated from the Hoër Volkskool Potchefstroom in 1975 and obtained his MB ChB degree from the University of the Free State in 1983. After completing his compulsory military service, and after a short stint in general practice in Virginia, Free State, Pieter commenced practice in East London in the Eastern Cape in 1988, where he remained until his death in 2016. Pieter had a deep passion for the arts. He served on the board of the Arts Theatre Club in East London between 2006 and 2016 and as its chairman in 2010 and 2011, making a single appearance on stage in the 1990 production of Bobaas van die

Boendoe (in which he played ‘Jimmy’, a barfly). A kind-hearted man, Pieter devoted his energy to the wellbeing of his patients, family and friends. His gentle manner and sharp sense of humour left an indelible mark on all who met him. Those who knew him will remember him as one of nature’s true gentlemen. He was compassionate, kind and well loved, and will be sorely missed. Pieter is survived by his wife Amanda, son Pieter-Schalk, daughter-in-law Ilené and granddaughter Mia, whom he adored. Pieter-Schalk Bothma East London, South Africa abothma@webmail.co.za

Theo Berkowitz, MB BCh, FRCS (Edin), FRCS (Glasg) (3 February 1929 - 3 July 2016)

Born in Heidelberg, Transvaal, in 1929, Theo was the son of immigrants from Russia and Latvia. He graduated from the University of the Witwatersrand in 1952, having completed a year of a BA as well as his medical degree. After his marriage to Rae Hochman in 1960, they sailed to England where he worked

in London, Cambridge and Liverpool, following his interest in orthopaedics. Theo and Rae returned to Johannesburg after the birth of their second child in 1963. They moved to East London in 1965 when Theo took up a post at Frere Hospital. He maintained a part-time position as consultant at the Frere as well as a private practice for over 52 years. He was still attending weekly orthopaedic outpatient clinics at the Frere and taking on medicolegal work at the age of 87, only weeks before his death. Theo enjoyed sport. He played first-team baseball at Wits, and in later years represented Border in interprovincial veterans’ squash. He was an adventurer, a hiker and a cyclist, and participated in the Argus Cycle Tour in 1992. He loved tennis (and his tennis friends) and played regularly until very shortly before his death, when his health deteriorated significantly. Theo was known for his love of classical music and art, and his passion for Persian rugs – he was an avid collector. He was active in the Jewish community and a Rotarian.

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Those close to him will remember him for his generosity and humility. He believed deeply in giving, generously and often anonymously. We have been both overwhelmed and comforted by the warm wishes and stories of his generosity from friends, patients and strangers since his death. His children and grandchildren remember him for his unconditional love. He taught us the wisdom of listening, of brevity of speech, and to speak of others ‘only when you have something good to say about them’. He was the true centre and rock of the family after Rae died in 2007. They had been married for 47 years. Theo showed incredible strength and stoicism in health and in sickness. He remains an inspiration to his three children, Mark, Linda and Gail, and his grandchildren, Jessye, Asher, Jason and Jenna. We thought he would live to at least 120, and miss him terribly. Linda Berkowitz Brighton, UK linda.berkowitz@bracketglobal.com

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EDITORIAL

Missed opportunities for circumcising boys The UNAIDS Fast Track: Ending the Global AIDS epidemic by 2030[1] circumcision programme is in trouble. After several years of rapid increases, the annual number of circumcisions performed in 8 of the 14 priority countries stayed level or decreased in 2015, dropping to 2.6 million in 2015 (compared with 3.2 million in 2014).[2] In South Africa (SA), medical circumcisions reached a peak of 500 000 in 2013 and declined slightly in each subsequent year.[2] This decrease comes in spite of improved surgical infrastructure and high-level marketing. The Fast Track plan calls for an additional 25 million medical circumcisions in these high-priority countries by 2020. This is an optimistic, probably unrealistic goal that would require increasing circumcisions to 5 million a year, nearly double the current rate. To reach its goals, UNAIDS is counting on programme changes and technical advances in circumcision devices, but the latest setback with Prepex is likely to further disrupt those plans. After six cases of tetanus following Prepex circumcision, the World Health Organization (WHO) recently recommended a full series of five tetanus immunisations, or two immunisations at least 4 weeks apart, with the second dose at least 2 weeks before Prepex placement.[3] This will further impede acceptance and utilisation of an innovation that has shown neither safety, efficiencies, or costeffectiveness.[4] The great hope is ‘demand creation.’ Funding agencies (primarily the Bill and Melinda Gates Foundation) are squarely behind marketing circumcision to men, and demand creation now plays a central role in the Clearinghouse on Male Circumcision (http://www. malecircumcision.org). Marketing materials are exclusively focused toward men. However, many African men see circumcision as a rite of passage into adulthood (and not therefore appropriate for them), and a recent survey in Orange Farm suggests that demand creation is not working.[5] Data showing who was actually circumcised in 2015 tell the story. In Swaziland, for example, 73% of all circumcisions performed were among boys <15 years of age; in Lesotho, it was 52%, and Botswana, Ethiopia, Kenya, Zimbabwe and Mozambique all reported rates of more than 40%.[6] In the most recent data from South Africa, 45% of all 2014 circumcisions were among boys <15 years of age. As these data clearly demonstrate, adult circumcision has consistently lagged behind. Four of the high-priority countries – Malawi, Swaziland, Uganda and Zambia – have revised their operational plans to reflect this reality.[8] Demand creation is trying to sell something that many men don’t want. As those who are motivated get circumcised, it becomes

increasingly expensive and ineffective to attempt to ‘sell’ circumcision to the rest.[5] The resources expended for marketing to adult men could be better spent. It is time for SA to change gears and orient marketing and programmes to males of all ages, but particularly to boys <15 years of age. Circumcising boys who have not been sexually active does not immediately affect the HIV epidemic, but will have the greatest impact on HIV incidence in the long term.[1] Let’s take a lesson from immunisation programmes and not allow for a lost opportunity at any age. Mothers are an influential but neglected target of circumcision promotion. Our experience is clear: mothers motivate their boys to get circumcised, come to the clinic with them, and spread the word to their friends about the availability of circumcision. The time to change course is now. Peter S Millard University of New England, Portland, Maine, USA pmillard@mac.com Norman Goldstuck Department of Obstetrics and Gynaecology, Faculty of Medicine and Health Sciences, Stellenbosch University and Tygerberg Hospital, Cape Town, South Africa 1. Joint United Nations Programme on HIV/AIDS (UNAIDS). Fast Track: Ending the Global AIDS Epidemic by 2030. Geneva: World Health Organization, 2014. http://www.unaids.org/sites/default/ files/media_asset/JC2686_WAD2014report_en.pdf (accessed 10 October 2016). 2. Joint United Nations Programme on HIV/AIDS (UNAIDS). Prevention Gap Report, 2016. Geneva: UNAIDS, 2016. http://www.unaids.org/sites/default/files/media_asset/2016-prevention-gap-report_ en.pdf (accessed 10 October 2016). 3. World Health Organization (WHO). WHO informal consultation on tetanus and voluntary medical male circumcision. Geneva: WHO, 2016. http://www.who.int/hiv/pub/malecircumcision/malecircumcision-2016-update/en/ (accessed 10 October 2016). 4. Ridzon R, Reed JB, Sgaier SK, Hankins C. VMMC devices – introducing a new innovation to a public health intervention. J Acquir Immune Defic Syndr 2016;72(Suppl 1):S1-4. http://dx.doi.org/10.1097/ qai.0000000000000967 5. Marshall E, Rain-Taljaard R, Tsepe M, et al. Sequential cross-sectional surveys in Orange Farm, a township of South Africa, revealed a constant low voluntary medical male circumcision uptake among adults despite demand creation campaigns and high acceptability. PLoS One 2016;11(7):e0158675. http://dx.doi.org/10.1371/journal.pone.0158675 6. AIDSInfoOnline. UNAIDS. 2016. http://www.aidsinfoonline.org/devinfo/libraries/aspx/home.aspx (accessed 10 October 2016). 7. Kripke K, Chen PA, Vazzano A, et al. Cost and impact of voluntary medical male circumcision in South Africa: Focusing the program on specific age groups and provinces. PLoS One 2016;11(7):e0157071. http://dx.doi.org/10.1371/journal.pone.0157071 8. Hankins C, Warren M, Njeuhmeli E. Voluntary medical male circumcision for HIV prevention: New mathematical models for strategic demand creation prioritizing subpopulations by age and geography. PLoS One 2016;11(10):e0160699. http://dx.doi.org/10.1371/journal.pone.0160699

S Afr Med J 2017;107(1):19. DOI:10.7196/SAMJ.2017.v107i1.12177

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EDITORIAL

South Africa’s salt reduction strategy: Are we on track, and what lies ahead? Excessive levels of salt consumption contribute to high blood pressure and are a major contributor to cardiovascular diseases and stroke.[1] Population salt reduction is a cost-effective intervention to reduce chronic disease.[2] Member states of the World Health Organization (WHO) have agreed to a salt reduction target of 30% towards the WHO’s recommended amount of 5 g per day.[3] In its strategic plan for non-communicable diseases (NCDs) (2013 - 2017), the South African (SA) National Department of Health (NDoH) includes the target to reduce the mean population salt intake to <5 g per day. SA has legislated salt reduction for the main contributors to salt in the diet.[4] The first set of targets came into effect on 30 June 2016, with the second level of implementation scheduled for June 2019. It is against this backdrop that 25 key participants from government, non-governmental organisations, universities, research organisations and professional societies met in Cape Town on 2 September 2016 for a meeting hosted by the Heart and Stroke Foundation South Africa (HSFSA). The objective of the meeting was to discuss progress, challenges and the way forward for SA’s salt reduction strategy. It was acknowledged that SA is playing a leading role in salt reduction globally. It was the first country to include mandated maximum salt targets across a wide range of processed foods. Legislation aims to address the 60% of salt in the diet contributed by processed foods.[5] Effective monitoring mechanisms are needed to assess the impact of the salt legislation on population-level salt intake and health-related outcomes. Beulah Pretorius from the University of Pretoria emphasised that analysis of salt levels in foods presents a number of challenges, which could partly explain noted inconsistencies between industry’s self-reported sodium levels and initial independent chemical analysis. These were reported by Melvyn Freeman, NCD chief director at the NDoH, who noted that close consultation with and involvement of the food industry during the development of the legislation has helped to foster a working relationship with laboratory managers and food companies to better understand methodological issues. Jacqui Webster, director of the WHO Collaborating Centre on Population Salt Reduction at the George Institute for Global Health, Australia, confirmed that the totality of evidence supports the need to reduce salt and that salt reduction programmes are indeed working. [6] It has been estimated that SA’s salt reduction policy will reduce 11% of deaths from heart disease per year and save the government approximately ZAR713 million per year in healthcare costs. At the individual level, healthcare cost savings could prevent 2 000 households being pushed into poverty.[7] New data on salt intake in SA presented by Karen Charlton from the University of Wollongong, Australia, and Bianca Swanepoel from North-West University (NWU), SA, provide further support for the government’s salt reduction strategy. Preliminary results from the WHO Study on global AGEing and adult health (SAGE) showed that 53% of adults aged ≥50 years (N=574) and one-third of 18 - 49-yearolds (N=312) had hypertension.[8] Sixty-five percent of individuals were consuming levels of salt above the WHO target of 5 g per day. Of particular concern was the finding that 40% of younger adults had very high salt intakes, >9 g per day. Similarly, in the NWU study, 65.6% of the sample population (N=692) consumed >6 g of salt per day and the majority (92.8%) of the sample did not meet the recommended daily potassium intake.[9]

High discretionary salt intake (41%)[5] in South Africans means that a population education and awareness campaign in parallel with legislation is also required. The Salt Watch multisectoral coalition, led by the HSFSA and supported by the NDoH, implemented a 4-month awareness campaign to address people’s salt-related behaviours. The campaign included television and radio advertising supplemented by health professional and media engagement, development of educational materials and social media campaigns. Edelweiss Wentzel-Viljoen from NWU said that the outcome of the evaluation was promising, showing a significant positive change in reported knowledge, attitudes and behaviours of the study participants (N=477) in respect of excessive salt intake and health (Wentzel-Viljoen et al., ‘Evaluation of a mass-media campaign to increase the awareness of the need to reduce discretionary salt use in the South African population’, unpublished data, 2016). Five priority areas were identified as a roadmap for continued action on salt reduction. First of these was the need to support industry compliance with the existing legislation and increase efforts to prepare for the 2019 legislative thresholds, which would include strengthening the monitoring processes and expanding engagement with the food industry to reach out to broader groups, including the informal food production sectors. Second was the importance of better understanding the contribution of foods eaten out of the home (including fast foods) to total salt intake and developing an ongoing strategy to address this factor. The third priority was implementing the next stage of the Salt Watch campaign to change consumer behaviours. This could be achieved by identifying key behavioural change goals and messages that could then be integrated into broader health communication strategies, for example using the Food-based Dietary Guidelines as a framework to address salt reduction based on a whole-of-diet approach. Ensuring that effective measures are in place to prevent efforts inadvertently exacerbating health inequalities between rich and poor was identified as the fourth priority. Upstream interventions that influence the food environment, including food regulations, are less likely than individual-focused policies (e.g. nutrition education) to result in such disparity. Lastly, efforts need to focus on obtaining additional funds for research and monitoring in order to build capacity to continue to monitor changes in salt intake and salt-related behaviours. This may include integration of salt monitoring into national surveys and identifying opportunities to measure children’s salt intake. Given that salt is fortified with iodine in SA, it is also essential to continue to monitor iodine intakes and adjust iodine levels in salt accordingly. Global action could support ongoing activities, for example engaging multinational companies to encourage salt reduction across products and fast foods on a global scale. SA’s salt reduction efforts will potentially have a knock-on effect in neighbouring countries that rely on SA for imports of processed foods. The efforts of SA food companies should also provide the impetus for multinational food companies looking at their own corporate social responsibilities to contribute to reformulate their products to improve the healthfulness of the food supply, particularly in lowand middle-income countries. The SA legislation to limit salt levels in manufactured foods is an example of what a progressive government can do to improve health at

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EDITORIAL

a population level, with an increasing number of countries following suit.[10] This multicountry and multiagency consultation reflects not only the importance of this issue in SA, but the importance of our taking the global lead in pressing for change. Acknowledgements. Financial support for the salt consultation meeting and the SAGE Waves 2 and 3 salt sub-study in SA was provided by the Centers for Disease Control and Prevention Foundation with a grant from Bloomberg Philanthropies. Contributors at the consultation meeting further included Prof. Melvyn Freeman, Dr Beulah Pretorius, Ms Bianca Swanepoel, Dr Lisa Ware and Dr Paul Kowal. All opinions reflect views of the contributors, not necessarily the organisations that they represented at this consultation. Conflicts of interest. JW is supported through a National Health and Medical Research Council Career Development Fellowship and a Heart Foundation Future Leaders Award and receives additional funding from the WHO for her work on salt reduction. The Salt Watch advertising campaign was supported by grants from the NDoH and the SA National Lotteries Board. Additional Salt Watch activities were supported by Unilever, Kellogg’s, Lucky Star, the South African Sugar Association and Sea Harvest.

Jacqui Webster Food Policy Division, George Institute for Global Health, University of Sydney, NSW, Australia Christelle Crickmore Science and Programme Development Department, Heart and Stroke Foundation South Africa, Durban, South Africa Karen Charlton School of Medicine, Faculty of Science, Medicine and Health, University of Wollongong, NSW, Australia

Krisela Steyn Chronic Disease Initiative in Africa, Department of Medicine, Faculty of Health Sciences, University of Cape Town, South Africa Edelweiss Wentzel-Viljoen Centre of Excellence for Nutrition and Medical Research Council Research Unit for Hypertension and Cardiovascular Disease, Faculty of Health Sciences, North-West University, Potchefstroom, South Africa Pamela Naidoo Heart and Stroke Foundation South Africa, Cape Town; and Professor Extraordinaire, Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa Corresponding author: C Crickmore (christelle@heartfoundation.co.za) 1. Mozaffarian D, Fahimi S, Singh GM, et al. Global sodium consumption and death from cardiovascular causes. N Engl J Med 2014;371(7):624-634. http://dx.doi.org/10.1056/nejmoa1304127 2. World Health Organization and World Economic Forum. From Burden to ‘Best Buys’: Reducing the Economic Impact of Non-Communicable Diseases in Low- and Middle-Income Countries. Geneva: WHO, 2011. 3. World Health Organization. A Comprehensive Global Monitoring Framework Including Indicators and a Set of Voluntary Global Targets for the Prevention and Control of Noncommunicable Diseases. Second WHO discussion paper. Geneva: WHO, 2012. 4. Hofman KJ, Tollman SM. Population health in South Africa: A view from the salt mines. Lancet Glob Health 2013;1(2):e66-e67. http://dx.doi.org/10.1016/s2214-109x(13)70019-6 5. Charlton KE, Steyn K, Levitt NS, et al. Diet and blood pressure in South Africa: Intake of foods containing sodium, potassium, calcium, and magnesium in three ethnic groups. Nutrition 2005;21(1):39-50. http://dx.doi.org/10.1016/j.nut.2004.09.007 6. Cogswell ME, Mugavero K, Bowman BA, Frieden TR. Dietary sodium and cardiovascular disease risk – measurement matters. N Engl J Med 2016;375(6):580-586. http://dx.doi.org/10.1056/ nejmsb1607161 7. Watkins DA, Olson ZD, Verguet S, Nugent RA, Jamison DT. Cardiovascular disease and impoverishment averted due to a salt reduction policy in South Africa: An extended cost-effectiveness analysis. Health Policy Plan 2016;31(1):75-82. http://dx.doi.org/10.1093/heapol/czv023 8. Schutte A, Ware L, Charlton K, Kowal P. PS 18-15 Salt and potassium intake, and blood pressure in South African adults: Preliminary results from the WHO SAGE Study. J Hypertens 2016;34(Suppl 1):e502. http://dx.doi.org/10.1097/01.hjh.0000501362.87753.bc 9. Swanepoel B, Schutte AE, Cockeran M, Steyn K, Wentzel-Viljoen E. Sodium and potassium intake in South Africa: An evaluation of 24-hour urine collections in a white, black and Indian population. J Am Soc Hypertens 2016;10(11):829-837. http://dx.doi.org/10.1016/j.jash.2016.08.007 10. Webster J, Trieu K, Dunford E, Hawkes C. Target salt 2025: A global overview of national programs to encourage the food industry to reduce salt in foods. Nutrients 2014;6(8):3274-3287. http://dx.doi. org/10.3390/nu6083274

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CME

GUEST EDITORIAL

Anaemia (part 1) Anaemia is the most common haematological abnormality, affecting an estimated 1.6 billion people globally. Healthcare workers, particularly general practitioners, regularly encounter patients who present with anaemia. The causes of anaemia are numerous and varied, necessitating a structured diagnostic approach at presentation. While basic investigations suffice for most patients presenting with this condition, the less common types of anaemia often require expertise and more specialised diagnostic tests and equipment. Costs involved in infrastructure development and the acquisition of equipment pay dividends in the long term in the form of prompt and accurate diagnosis and appropriate interventions. However, in resource-challenged countries, budgetary constraints limit the scope of investigations and management options. This applies particularly to the inherited and chronic anaemias that are likely to have a significant (and in some instances total) degree of transfusion dependency. From the 1990s onwards, South Africa (SA) has faced the following unique challenges that have placed added strain on the health budget: â&#x20AC;˘ A steady influx of visitors for business, employment or health reasons. â&#x20AC;˘ A rising incidence of HIV and tuberculosis, coupled with limited intervention by the health ministry, saw a significant increase in the complication rate, especially as patients often seek medical attention at an advanced stage of their disease. Anaemia is commonly detected at presentation. However, with progression of the disease, complications develop and anaemia of increasing severity often supervenes, which may require urgent intervention. These challenges demand innovative approaches, such as sharing of resources and expertise between centres and a streamlined referral system. Construction of guidelines specific for the SA setting would be a step towards standardising treatment protocols and also highlight resource constraints with feasible solutions. A working example is the SA recommendations for the management of sickle cell disease.[1]

Numerous approaches to the investigation of anaemia are described in the literature; these are generally based on different classifications of the subject. In this edition of CME various classification systems have been employed to construct a practical approach for the investigation of anaemia. Emphasis is placed on the diagnostic approach, broadly touching on pathophysiology and management issues. Given the vastness of the subject, it will be split into two parts: part 1, which focuses on central causes, i.e. decreased bone marrow output of erythrocytes; and part 2, which covers peripheral causes, i.e. peripheral loss, destruction or sequestration of erythrocytes. An in-depth review of disorders causing anaemia is beyond the scope of this two-part CME series. For ease of reference, selected tables have been duplicated in both parts. The authors are indeed privileged to have the opportunity to present an overview of this very common, yet vast, topic. N Alli Department of Molecular Medicine and Haematology, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, and National Health Laboratory Service, Johannesburg, South Africa nazeer.alli@nhls.ac.za

1. Alli NA, Patel M, Dawood H, et al. Recommendations for the management of sickle cell disease in South Africa. S Afr Med J 2014;104(11):743-751. http://dx.doi.org/10.7196/SAMJ.8470

S Afr Med J 2017;107(1):22. DOI:10.7196/SAMJ.2017.v107i1.12147

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This open-access article is distributed under Creative Commons licence CC-BY-NC 4.0.

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Anaemia: Approach to diagnosis N Alli,1 MB BCh, FCPathHaem (SA); J Vaughan,1 MB BCh, FCPathHaem (SA), MMed (Haem); M Patel,2 MB ChB, FCP (SA), MMed, FRCP (Lond), PhD Department of Molecular Medicine and Haematology, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, and National Health Laboratory Service, Johannesburg, South Africa 2 Department of Clinical Haematology, Division of Internal Medicine, Chris Hani Baragwanath Academic Hospital, Johannesburg, and School of Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa 1

Corresponding author: N Alli (nazeer.alli@nhls.ac.za)

Anaemia is defined as a condition in which the number of red cells or their oxygen-carrying capacity is insufficient to meet physiological needs. It is the most common disorder globally and one of the conditions that general practitioners most frequently encounter. In the World Health Organization global database, anaemia is estimated to affect 1.6 billion people. As anaemia manifests in a wide range of conditions, it is important to embrace a structured diagnostic approach. The recommended approach set out in this article incorporates clinical and pathophysiological considerations, red cell characteristics, and bone marrow activity. In this issue of CME, the first of two parts on anaemia, the causes of anaemia related specifically to decreased red cell production are discussed. S Afr Med J 2017;107(1):23-27. DOI:10.7196/SAMJ.2017.v107i1.12148

Red cells are produced in the bone marrow (BM) from myeloid progenitor cells, where their production requires a permissive BM micro-environment and adequate substrate (including iron, vitamin B12 and folate) for Hb, protein and DNA synthesis. Erythropoiesis is controlled by erythropoietin (EPO), which is synthesised by peritubular fibroblasts in the renal cortex in response to reduced oxygen tension. According to the World Health Organization (WHO), anaemia is defined as ‘a condition in which the number of red blood cells or their oxygen-carrying capacity is insufficient to meet physiologic needs’. It is the most common disorder globally and one of the conditions that general practitioners most frequently encounter. Anaemia is rarely an isolated disease and is most often a sign of an acquired or inherited disorder.[1] According to the WHO global database,[2] anaemia is estimated to affect 1.6 billion people. The highest prevalence is found in preschool-age children (47.4%), followed by pregnant females (41.8%), non-pregnant females (30.2%), school-age children (25.4%), and males (12.7%).[2] When investigating patients with anaemia, two fundamental questions have to be considered: (i) What is the cause of the anaemia?; and (ii) What is the urgency for correcting the anaemia, i.e. is a blood transfusion or other urgent intervention indicated?

Classification

Anaemia may be classified as follows: Based on red cell characteristics (red cell size, chromia and morphology): • hypochromic microcytic • macrocytic normochromic • normochromic normocytic • morphology: • leuco-erythroblastic • micro-/macroangiopathic. Based on underlying mechanism: • decreased BM production/output: • BM aplasia/infiltrate

• ineffective haematopoiesis, e.g. megaloblastic anaemia (MA), myelodysplastic syndromes (MDSs), HIV • substrate deficiency • EPO insufficiency • peripheral loss/destruction: • bleeding • sequestration • haemolysis. In this issue of CME, the focus is on anaemia resulting from decreased BM output. Anaemia caused by peripheral loss will be discussed in the next issue.

Diagnostic approach to a patient with suspected anaemia

As anaemia may manifest in a wide range of disorders, a streamlined diagnostic approach is vital (Fig. 1). The approach outlined here is based on the abovementioned classification, clinical scenario and full blood count (FBC) findings.[3] Patients generally present with symptoms of anaemia, i.e. increased tiredness/fatigue, dyspnoea and decreased effort tolerance. The severity of symptoms depends on the degree of anaemia and rate of Hb decrease. Therefore, at a given Hb level, anaemia from acute blood loss is likely to manifest more severely than anaemia of insidious onset (weeks to months). Symptoms during early childhood should remind one of possible inherited forms of anaemia, e.g. thalassaemia.

History

A detailed history is of paramount importance and often eliminates much of the speculation during investigation. This should include: • interrogation of the presenting complaint and duration of the problem • transfusion history • dietary history, including pica (craving for unusual food items, generally associated with iron deficiency) • travel history (to endemic malarial or other infectious areas) • change in bowel habits • bleeding (e.g. gastrointestinal and genito-urinary)

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Anaemia

FBC and differential count Reticulocyte count

Blood smear microscopy

Decreased count

BM failure/infiltration

Increased count

Nutritional deficiency

Bleeding

Locate source of blood loss

BM aspirate and trephine biopsy MCV • Serum Fe studies and ferritin

Normal Fe studies • Hb electrophoresis

Hypersplenism

Investigate cause of splenomegaly

Normal/ MCV Blood smear morphology • Oval macrocytes serum vitamin B12 and folate • Target cells LFT, TFT, cholesterol

Fe deficiency • Fe treatment • Exclude bleeding

Normal vitamin B12 and folate • BM examination

vitamin B12/folate • Supplementation • Investigate cause

See Table 1 for guidance

Haemolysis

Serum haptoglobin level suggests haemolysis

Haemosiderinuria/ haemoglobinuria IVH

Indirect serum bilirubin EVH

Family history If chronic haemolysis, check • Serum folate • Serum ferritin

Fig. 1. Algorithm depicting diagnostic approach to anaemia. (TFT = thyroid function test; LFT = liver function test; MCV = mean cell volume; IVH = intravascular haemolysis; EVH = extravascular haemolysis; FBC = full blood count; Fe = iron.)

• drug history (e.g. anticoagulants, antiplatelet agents, renotoxic agents, anticonvulsants) • chronic disease (e.g. HIV, tuberculosis (TB)) • surgery (e.g. gastrectomy, small-bowel surgery) • current or recent pregnancy • family history (particularly in children).

Clinical examination

A wide range of signs and symptoms may be apparent. Systematic examination directs further investigation and may reveal the possible cause. • Skin and mucous membrane: • pallor is the cardinal clinical sign for anaemia, which should be confirmed by measuring the Hb level • angular stomatitis • glossitis in nutritional deficiencies • koilonychia (spoon-shaped nails) in iron deficiency • premature greying, which often accompanies MA

• scleral ictus, which indicates possible haemolysis or ineffective erythropoiesis. • Neuromuscular: • muscle weakness • headache, lack of concentration, drowsiness, tinnitus • paraesthesias, peripheral neuropathy, ataxia and loss of vibration sense, and proprioception in pernicious anaemia. • Cardiovascular: • hyperdynamic circulation with haemic ‘flow’ murmurs • cardiac failure. • Clues for infection, malignancy (e.g. lymphoma, leukaemia, metastatic carcinoma): • hepatosplenomegaly • lymphadenopathy • bleeding manifestations (petechiae, purpura, ecchymosis), BM failure.

Laboratory testing

An FBC, differential and reticulocyte counts together with microscopic blood smear

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examination should be the starting point of investigations. These confirm the clinical suspicion of anaemia and direct further investigation. Local laboratory/population reference ranges that are age and gender specific should be used. The normal reference ranges for Hb in adults in the Witwatersrand area, Johannesburg, South Africa (SA) are as follows:[4] • male: 13.8 - 17.9 g/dL (anaemia <13 g/dL) • female: 12.4 - 15.5 g/dL (anaemia <12 g/dL; pregnancy <11 g/dL). A reticulocyte count gives an indication of the BM status, i.e. decreased activity v. appropriate response to the anaemia. A reticulocyte production index (RPI) provides a more accurate representation of marrow activity than an isolated reticulocyte count, as it corrects for the degree of anaemia and presence of immature reticulocytes in the peripheral blood. The RPI is calculated as follows:

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Table 1. Red cell morphological characteristics Morphological observation

Significance

Further tests indicated and expected result

Oval macrocytes, teardrops, basophilic stippling, right shift

Serum vitamin B12 and folate levels

Hypochromia Microcytosis

Iron deficiency anaemia (also see pencil cells) Chronic disorder; thalassaemia trait

Serum ferririn, transferrin and iron levels Hb electrophoresis/HPLC

Sickle cells

Seen in sickle cell disease

Hb electrophoresis to confirm presence of Hb S, and quantitate Hb F level

Spherocytes

Noted in hereditary spherocytosis, warm AIHA

Coombs test: positive for IgG in warm AIHA Red cell membrane analysis: selected membrane protein abnormalities

Elliptocytes/ovalocytes

Hereditary elliptocytosis/ovalocytosis

Red cell membrane analysis: selected membrane protein abnormalities

Autoagglutination

Cold AIHA

Coombs test: positive for C3d in cold AIHA

Red cell fragmentation

If platelets decreased → microangiopathic haemolysis If platelets normal → macroangiopathic haemolysis

Microangiopathic haemolysis: DIC screen → consumptive coagulopathy U&E: marked renal dysfunction in HUS Altered neurological status: suspect TTP

Malaria

Life-threatening infection

Identify species Monitor FBC and parasite count while on treatment

AIHA = auto-immune haemolytic anaemia; U&E = urea and electrolytes; DIC = disseminated intravascular coagulation; HUS = haemolytic uraemic syndrome; HPLC = high-performance liquid chromatography; TTP = thrombotic thrombocytopenic purpura.

• % reticulocytes × patient haematocrit/45 ÷ reticulocyte maturation time (days) in peripheral blood The reticulocyte maturation time is calculated as follows: • haematocrit >40% = 1 day, 30 - 40% = 1.5 days, 20 - 30% = 2 days, <20% = 2.5 days A decreased RPI signifies a suboptimal BM response for correction of the anaemia. Clues for further investigation are derived from red cell indices (Fig. 1) and peripheral blood smear microscopy (Table 1). BM examination is appropriate if pathology is suspected, e.g. BM infiltration, BM failure, and myelodysplasia. BM aspirate smears permit morphological assessment in cellular detail, but the architecture is disrupted, whereas in trephine biopsy sections the architecture is preserved, which makes it possible to detect pathology, such as granulomata and fibrosis. More specialised tests are performed in individuals suspected of having rarer conditions that cause anaemia.

Important causes of anaemia due to inadequate BM output

Causes of red cell production failure include EPO deficiency (usually secondary to chronic kidney disease), substrate deficiency, ineffective erythropoiesis, BM aplasia/hypoplasia and BM displacement (malignancy/fibrosis), all of which are characterised by a low RPI.

BM aplasia/hypoplasia (primary BM failure)

BM failure may be inherited or acquired. In SA, the majority of patients have acquired idiopathic aplastic anaemia (AA). Inherited BM failure syndromes generally manifest in childhood and represent <10% of patients with AA.

Patients may present with one or more of the following: (i) symptoms of anaemia; (ii) infection (due to leucopenia/neutropenia); and (iii) mucocutaneous bleeding (due to thrombocytopenia). The FBC shows a pancytopenia of varying degrees (depending on the severity), reticulocytopenia with a low RPI, and reversal of the normal neutrophil:lymphocyte ratio. The diagnosis is confirmed on microscopic BM examination. Numerous secondary causes and associations have been identified in AA, but in 60 - 70% of cases the cause remains unknown. It has been proposed that a triggering event, such as a virus or drug, leads to an immune response and to inappropriate expansion of cytotoxic T cells that destroy haematopoietic cells. Causes include viruses (e.g. hepatitis virus, HIV, Epstein-Barr virus, cytomegalovirus); autoimmune disorders (e.g. systemic lupus erythematosis, eosinophilic fasciitis, Sjögren’s syndrome); drugs (a wide range, including sulfonamides, anticonvulsants, antimalarials; chemicals (e.g. benzene); and environmental factors (e.g. agricultural pesticides and radiation). The idiopathic variety is the largest group. Paroxysmal nocturnal haemoglobinuria (PNH), caused by expansion of a clone with mutation of the glycosylphosphatidyl-inositol gene, manifests with the clinical triad of haemolysis, thrombosis and BM failure. PNH clones can be detected on flow cytometry. Some inherited disorders are characterised by BM hypoplasia/ aplasia (affecting one or more haematopoietic cell lines), and are usually accompanied by one or more somatic abnormalities, i.e. part of a clinical syndrome. Inherited BM failure syndromes may be present at birth or develop later in childhood. Of these, the syndromes that affect all three cell lines include Fanconi anaemia, SchwachmanDiamond syndrome and dyskeratosis congenita. Further discussion of these syndromes is beyond the scope of this edition of CME. Pure red cell aplasia is characterised by an isolated, often severe anaemia with a marked reticulocytopenia. It may be congenital

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(Diamond Blackfan syndrome) or acquired (including viral infections, lymphoproliferative disorders, autoimmune disorders or drugs). In SA, parvovirus B19 infection in HIV-positive individuals is the most common cause of pure red cell aplasia. BM examination reveals the absence or maturation block of erythroid progenitors. Patients with BM failure should be referred to a specialist haematology/oncology unit for further work-up and management.

BM displacement by malignancy or fibrosis

The presence of a leuco-erythroblastic reaction and teardrop poikilocytosis on peripheral blood smear microscopy should lead one to suspect possible BM infiltration. Leukaemia and lymphoma can be further characterised on flow cytometry, cytogenetic analysis and polymerase chain reaction testing on a bone marrow aspirate sample. Immunohistochemical stains are also available to identify subtypes and cell types on BM trephine biopsy sections.

Ineffective haematopoiesis

In ineffective haematopoiesis, the BM activity ranges from normal to increased, but cells die before or shortly after release into the circulation. Common causes for ineffective haematopoiesis include MA (discussed below), drugs that interrupt DNA synthesis or folate metabolism (e.g. methotrexate, trimethoprim, phenytoin), HIV infection, and the MDSs. The MDSs are clonal haematopoietic disorders characterised by peripheral blood cytopenias and dysplastic haematopoiesis, with a predisposition towards developing acute leukaemia. When suspected, MA should be excluded by means of serum vitamin B12 and folate levels (performed prior to blood transfusion), as should HIV and other chronic infections.Where no other cause for ineffective haematopoiesis is found, further work-up for MDSs may be necessary (including BM examination with cytogenetic analysis), particularly in older patients.

Substrate deficiency

Iron deficiency is the most common cause of anaemia, occurring in an estimated 15% of the world’s population.[5] The causes of iron deficiency can be broadly classified as inadequate iron intake (e.g. nutritional deficiency, iron malabsorption) or excessive iron loss (mostly due to bleeding). It is most common in young children and women of childbearing age because of the increased iron demands related to rapid growth and menstrual blood losses/pregnancy, respectively. Iron deficiency causes a microcytic and/or hypochromic anaemia. Serum iron studies show low serum ferritin and raised transferrin (TF) levels, and low TF percentage saturation. The differential diagnosis for microcytic anaemia includes anaemia of chronic disorder (ACD), thalassaemia trait and sideroblastic anaemia. The frequency of these differential diagnoses depends on the demographics of the population served, with thalassaemia trait being common in patients of Indian or Mediterranean ancestry, and ACD occurring frequently in patients with chronic infection (e.g. HIV or TB), malignancy or autoimmune disorders. ACD is caused by a combination of functional iron deficiency (due to reticuloendothelial iron blockade), and EPO deficiency or resistance, and is characterised on iron studies by raised ferritin and low TF levels with low or normal TF percentage saturation. The anaemia is usually normocytic and normochromic, but can be microcytic in approximately one-third of cases due to long-standing iron restriction at the macrophage level.

Occasionally, the distinction between iron deficiency anaemia (IDA) and ACD can be blurred, as ferritin is an acute-phase protein and may be falsely normal or raised in patients with iron deficiency in the presence of acute inflammation. In this setting, the gold standard for discriminating IDA from ACD is evaluating BM iron stores microscopically. Measuring the soluble TF receptor (STFR) levels and calculating the STFR index (STFR:log ferritin ratio) is also of use in this regard, where a ratio >2 suggests iron deficiency with coexisting ACD.[6] Unfortunately, STFR testing is not universally available in SA laboratories. Of note is that serum iron levels are of minimal use in assessing iron stores, reflecting recent iron intake as opposed to overall iron status. IDA should therefore not be diagnosed solely on the basis of a low serum iron level. To establish if someone has iron deficiency, one has to include a thorough dietary history, with emphasis on the frequency of red meat consumption, excessive dietary phytates (present in grains and legumes) or tannins (present in tea), which inhibit iron absorption, and pica. In the absence of an obvious nutritional cause, a source of bleeding should be sought (e.g. urogenital, gastrointestinal), particularly in men and postmenopausal women. Oral iron supplementation is the mainstay of therapy for IDA, but intravenous iron is occasionally necessary when more rapid correction of the Hb level is desired, if iron malabsoprtion is the main cause for the IDA, or if oral iron is not tolerated. A blood transfusion is indicated for severe, symptomatic anaemia, especially in patients who are bleeding. Treatment of IDA should aim at restoring the Hb to normal, followed by a further 4 - 6 months of therapy to replenish iron stores (Table 2). Iron should ideally be given between meals together with vitamin C to maximise absorption, but it can be administered with food or at reduced doses in patients who experience excessive abdominal side-effects (e.g. abdominal discomfort, nausea or constipation). For patients who are refractory to oral iron therapy, iron malabsorption, ongoing blood loss and non-compliance should be considered. The treatment of ACD is centred on management of the underlying cause. There may be a role for EPO supplementation, particularly in patients with underlying malignancy[7] and HIV.[8] Intravenous iron may additionally benefit patients with functional iron deficiency.[9] MA is the other major nutritional anaemia caused by vitamin B12 or folate deficiency. As both are required for purine biosynthesis, a deficiency of either nutrient hampers normal DNA synthesis, which results in ineffective haematopoiesis. Vitamin B12 deficiency is the most frequent cause of MA seen in general practice, the most common cause being pernicious Table 2. Suggested therapeutic protocols for nutritional anaemia Micronutrient deficiency Iron

Suggested therapeutic protocol Ferrous sulphate 200 mg orally 3 times daily between meals together with vitamin C for 4 - 6 months

Folate

5 mg orally daily for 2 4 months (or while the underlying risk factor persists)

Vitamin B12

1 000 µg daily intramuscularly for 5 - 7 days, followed by 1 000 µg intramuscularly weekly for a month, and then 1 000 µg intramuscularly every 2 months for life

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Table 3. Causes of vitamin B12 and folate deficiencies Vitamin B12 deficiency Dietary deficiency Ovolactovegetarians Malabsorption Pernicious anaemia Ileal pathology Crohn’s disease/ulcerative colitis Infection, e.g. HIV, TB Infiltration, e.g. lymphoma surgery Gastrectomy, ileal resection Diphyllobothrium latum (fish tapeworm) Blind loop syndrome Drugs (e.g. proton pump inhibitors, metformin)

Folate deficiency Dietary deficiency Poor diet (e.g. alcoholics, elderly) Malabsorption Inflammatory bowel disease Coeliac disease Short-bowel syndrome Impaired folate metabolism* Drugs (e.g. methotrexate, anticonvulsants, antimalarials) Alcoholism Hypothyroidism Excessive folate demand Chronic haemolytic anaemia Pregnancy and lactation (particularly if the diet is poor)

*Serum folate levels may be normal.

anaemia. The latter leads to impaired vitamin B12 absorption owing to immune-mediated destruction of the gastric parietal cells and consequent intrinsic factor deficiency. In contrast, dietary deficiency and the postpartum phase most commonly cause folate depletion. Dietary deficiency is currently relatively uncommon in SA owing to mandatory fortification of maize meal and wheat flour. Other causes of vitamin B12 and folate deficiency are summarised in Table 3. MA is diagnosed by demonstrating low serum levels of vitamin B12 or folate, along with characteristic peripheral blood smear morphology (including macro-ovalocytosis, teardrops, varying numbers of red cell fragments and basophilic stippling, and hypersegmentation (right shift) of neutrophils). Importantly, MA is not universally macrocytic, and cannot be excluded solely owing to the presence of a normal or even a low mean cell volume. When MA is strongly suspected, a trial of vitamin B12 and folate supplementation is advisable, particularly if levels are borderline low. When vitamin B12 deficiency is diagnosed, further investigation for pernicious anaemia is warranted. Intrinsic-factor antibodies are positive in 50 - 70% of cases.[10] In patients with pernicious anaemia, other organ-specific auto-immune disorders should be excluded (e.g. Addison’s disease and auto-immune thyroiditis). Vitamin B12 deficiency is treated with lifelong parenteral vitamin B12 replacement therapy, while folate depletion is treated with oral folate supplementation (Table 3). Importantly, folate administration in patients with MA secondary to vitamin B12 deficiency may partially correct the anaemia, but does not address the effects of vitamin B12 deficiency on the central nervous system. Owing to the risk of neurological complications (such as subacute combined degeneration of the spinal cord) in patients with vitamin B12 deficiency, MA should not be presumptively treated with folate alone, as this may

accelerate irreversible neurological damage. Although the mainstay of treatment in vitamin B12 deficiency is supplementation with vitamin B12, patients with very severe/life-threatening anaemia may benefit from a blood transfusion. Crucially, these patients should be transfused conservatively and cautiously (no more than 1 or 2 units of blood should be transfused, each unit running over ~2 - 4 hours, followed by 20 mg of intravenous furosemide (Lasix) after each unit), as aggressive transfusion practices are associated with a risk of sudden death in this setting.

Conclusion

There are numerous and varied causes of anaemia. Given the vastness of the topic, a thorough history, physical examination and systematic laboratory investigation are key elements towards determining the cause of the condition. 1. World Health Organization. The Global Prevalence of Anaemia in 2011. Geneva: WHO, 2015. 2. De Benoist B, McLean E, Ines E, et al. Worldwide prevalence of anaemia 1993 - 2005. Geneva: WHO, 2008. 3. Means RT Jr, Glader B. Anaemia: General considerations. In: Greer JP, Arbor DE, Glader B, et al., eds. Wintrobe’s Clinical Hematology. 13th ed. Philadelphia: Wolters Kluwer, 2013. 4. Lawrie D, Coetzee LM, Becker P, Mahlangu J, Stevens W, Glencross DK. Local reference ranges for full blood count and CD4 lymphocyte count testing. S Afr Med J 2009;99(4):243-248. 5. Lopez A, Cacoub P, Macdougall IC, Peyrin-Biroulet L. Iron deficiency anaemia. Lancet 2016;387(10021):907916. http://dx.doi.org/10.1016/S0140-6736(15)60865-0 6. Punnonen K, Irjala K, Rajamaki A. Serum transferrin receptor and its ratio to serum ferritin in the diagnosis of iron deficiency. Blood 1997;89(3):1052-1057. 7. Erslev AJ. Erythropoietin and anemia of cancer. Eur J Haematol 2000;64(6):353-358. http://dx.doi. org/10.1034/j.1600-0609.2000.9r116.x 8. Henry DH, Beall GN, Benson CA, et al. Recombinant human erythropoietin in the treatment of anemia associated with human immunodeficiency virus (HIV) infection and zidovudine therapy. Overview of four clinical trials. Ann Intern Med 1992;117(9):739-748. 9. Auerbach M, Ballard H, Trout JR, et al. Intravenous iron optimizes the response to recombinant human erythropoietin in cancer patients with chemotherapy-related anemia: A multicenter, open-label, randomized trial. J Clin Oncol 2004;22(7):1301-1307. http://dx.doi.org/10.1200/JCO.2004.08.119 10. Walters HM, Smith C, Howarth JE, et al. New enzyme immunoassay for detecting total, type I, and type II intrinsic factor antibodies. J Clin Pathol 1989;42(3):307-312. http://dx.doi.org/10.1136/jcp.42.3.307

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IN PRACTICE

CLINICAL UPDATE

Cutting the cost of South African antiretroviral therapy using newer, safer drugs W D F Venter,1 FCP (SA), MMed; B Kaiser,2 MPH, PharmD, BCPS; Y Pillay,3 PhD; F Conradie,4 MB BCh; G B Gomez,5 PhD; P Clayden;6 M Matsolo;7 C Amole,8 BA; L Rutter,7 BA; F Abdullah,9 MB ChB, FCPHM, BSc Hons (Epi); E J Abrams,10 MD; C P Casas,11 MSc; M Barnhart,12 MD, MPH; A Pillay,13 PhD; A Pozniak,14 MD, FRCP; A Hill,14 PhD; L Fairlie,1 FCPaed (SA); M Boffito,14 MD, PhD; M Moorhouse,1 MB BCh; M Chersich,1 MB BCh, PhD; C Serenata,1 MBA; J Quevedo,8 BS; G Loots15 Wits Reproductive Health and HIV Institute, University of the Witwatersrand, Johannesburg, South Africa Formerly UNITAID, Geneva, Switzerland 3 HIV/AIDS, TB and Maternal, Child and Women’s Health in the South African National Department of Health, Pretoria, South Africa 4 Clinical HIV Research Unit, University of the Witwatersrand and Southern African HIV Clinicians Society, Johannesburg, South Africa 5 Amsterdam Institute for Global Health and Development, Department of Global Health, Academic Medical Center, Amsterdam, The Netherlands 6 HIV i-Base, London, UK 7 Treatment Action Campaign, Cape Town, South Africa 8 Clinton Health Access Initiative, New York, USA 9 South African National AIDS Council, Pretoria, South Africa 10 International Center for AIDS Care and Treatment Programs (ICAP), Mailman School of Public Health and College of Physicians and Surgeons, Columbia University, New York, USA 11 UNITAID, Geneva, Switzerland 12 USAID Bureau for Global Health, Washington, DC, USA 13 Health Regulation and Compliance, South African National Department of Health, Pretoria, South Africa 14 Chelsea and Westminster Hospital and St Stephens AIDS Trust, London, UK 15 South African Department of Science and Technology, Pretoria, South Africa

Corresponding author: W D F Venter (fventer@wrhi.ac.za)

Antiretrovirals are a significant cost driver for HIV programmes. Current first-line regimens have performed well in real-life programmes, but have a low barrier to virological resistance and still carry toxicity that limits adherence. New drug developments may mean that we have access to safer, more robust and cheaper regimens, but only if the appropriate clinical trials are conducted. We briefly discuss these trials, and demonstrate the large cost savings to the South African HIV programme if these are successful. S Afr Med J 2017;107(1):28-30. DOI:10.7196/SAMJ.2017.v107i1.12058

South Africa (SA) may be able to provide antiretroviral therapy (ART) to several million more people with HIV by 2019, using the current drug budget. While planned simplification of HIV service delivery promises to reduce expenditure, the drug cost of ART provision consumes the bulk of most HIV programme budgets, and is unlikely to decrease significantly, as multiple generic competitors have realised manufacturing efficiencies for current formulations. SA has the largest ART programme in the world, with domestic funding accounting for >75% of all HIV spending.[1] For the year 2014 - 2105, USD350 million was spent on ART for just <3 million people living with HIV, most of it on first-line treatment.[2-4] From mid-2016, the number of people on ART has increased to 3.4 million, ~145 000 of them on secondline treatment and >700 on third-line treatment. An increase in public spending is expected to continue, owing in part to recent changes in ART initiation guidelines. The national Department of Health (DoH) announced its endorsement to ‘treat all’ approaches from September 2016, dropping CD4 thresholds for ART initiation completely, theoretically doubling the number eligible for ART to >6 million people.[4] This change and the steady improvement in life expectancy of patients on ART mean that the ART budget must accommodate millions of people for several decades of life.[5,6]

With >300 000 people initiating therapy annually (a number that will almost double, according to the DoH) on the efavirenz/tenofovir disoproxil fumarate/emtricitabine/ (EFV/TDF/FTC) fixed-dose generic (FTC and lamivudine (3TC) are interchangeable in terms of efficacy and cost, with 3TC used more in the private sector and outside SA[5]), SA is the largest consumer of generic ART in the world, using a quarter of global production. Two drugs, dolutegravir (DTG) and a new prodrug variant of tenofovir, tenofovir alafenamide (TAF), have been or are currently in the process of being licensed to multiple generic manufacturers by originator manufacturers directly or through voluntary licensing via Medicine Patent Pool (United Nations, Switzerland) processes. In short, replacing EFV, which is very vulnerable to resistance and drives most first-line side-effects, with DTG provides a better tolerated and cheaper drug with a high resistance barrier, limiting transition to expensive and less welltolerated, toxic next-line treatments. TAF is substantially cheaper than TDF, a major cost driver of first-line therapy, and provides some bone and renal toxicity benefits.[5,7] Co-formulating the two drugs with FTC or 3TC would also substantially reduce the size of the current tablet, making it easier to manufacture, while saving on packaging and storage space. However, the two drugs – TAF and DTG – are manufactured by competing companies, where commercial

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IN PRACTICE

Table 1. Summary of the ADVANCE study Investigator driven, study drug donated by company Funded by USAID and UNITAID Conducted in Johannesburg, start date: beginning 2017 Non-inferiority design, ~1 100 participants, over 96 weeks Eligibility criteria Needing first-line ART No TB treatment, not pregnant (addressed in other studies; those contracting TB or falling pregnant may continue in the study) No CD4 threshold >12 years of age, >40 kg Compares three combinations: DTG/TAF v. DTG/TDF v. EFV/ TDF (current first line in SA), all with FTC Primary endpoint is viral suppression at 48 weeks Pharmacokinetic sampling of both DTG/TAF in those who contract TB or become pregnant USAID = United States Agency for International Development.

interests in high-income countries compel them to develop other co-formulations, which are of substantially higher cost or have significant questions regarding their use in patients with tuberculosis (TB) or in pregnancy. Botswana is planning a move to a DTG-based regimen for first line, based on the impressive performance of this regimen in high-income countries, but in the absence of data on TB and pregnancy. A large, independent, randomised controlled study (ADVANCE) (Table 1), will address the substantial burden of evidence needed to change guidelines, with the hope that this study will provide evidence for initiating and switching millions of people on ART to the new regimen (to date, the combination DTG/TAF/FTC has not been specifically tested in clinical trials). Results from ADVANCE may be available by the end of 2018 for Medicines Control Council (MCC) registration and DoH guidelines and tender processes, so that the new regimen can be rolled out from 2019. The ADVANCE study has been designed by a unique multidisciplinary group of researchers, clinicians, activists, donors, and public health specialists, with substantial input and support from agencies, such as the World Health Organization (WHO) and the national DoH, as well as both originator and generic manufacturers. Aligned studies will address certain issues, such as the use of the new drugs in patients receiving rifampicin-containing TB regimens, and among pregnant women and adolescents, while partners are further working on new technologies, including nanotechnologies, to reduce the price of second-line drugs. The introduction in SA of this new regimen has the potential to substantially reduce the cost of first-line ART, while also being safer and better tolerated, therefore limiting the need for second-line ART. We estimate potential cost savings for SA if the studies demonstrate efficacy and safety, and justify the urgency in completing the study swiftly and transitioning to the new combination without delay.

Cost and other assumptions in the model

Cost savings of introducing the new regimen can be expected from: • Lower drug costs of DTG/TAF-containing regimens compared with current first-line drugs. The cost of current first-line

therapy is ~USD110/patient/year.[3,6] We have estimated an initial 20% saving (a conservative estimate provided to the authors by manufacturers for DTG/TAF cost saving over the current regimen of EFV/TDF/FTC) and a 50% saving once volumes are met (as estimated by the Clinton Health Access Initiative (CHAI), USA). • Limiting transition of patients from first- to second-line therapy owing to better tolerability and robustness of DTG/TAF-containing regimens. These savings are expected to accumulate through lower second-line drug costs (second-line therapy costs ~USD350[5,8]), but also lower service delivery costs and decreased viral load monitoring. The rate of transition from first-line to second-line regimens is not available. Since 2004, the number of SA patients on second-line treatment have increased to 145 000. These figures may have been initially inflated owing to the use of more toxic stavudine-containing regimens in use until 2010. In the calculations, we assume a 2% annual transition from first- to second-line treatment for anyone on the EFV-containing regimen (DoH assumed 4% for the previous tender, but the limited data suggest that this is an underestimation). In comparison, as no DTG-related virological failure due to resistance has occurred in the initial 600 000 patients on first-line treatment in Europe or the USA, we assumed that there would be no significant switching to second-line therapy in the years modelled.[9] For simplicity, and because the numbers are small, we have not factored in the effect on third-line initiations. A move to DTG-TAF-based regimens will have to be phased as manufacturers scale-up and patients (both new initiations and established patients) transition to the new regimen. In this analysis, we compare three transition scenarios of different scale-up assumptions with the current status quo: • Status quo: EFV/TDF/FTC remains the first-line regimen, with 300 000 people initiating first-line treatment annually and 2% migrating to second-line treatment. • Conservative scenario: continued initiation at 300 000 annually – at first only new initiations qualifying for DTG/TAF/FTC, others remaining on EFV/TDF/FTC and slowly transitioning to the new regimen over 3 years. • Moderate scenario: initiations at 400 000 annually, with at first only new initiations qualifying for DTG/TAF/FTC, and transitioning over 2 years. • Aggressive scenario: initiations at 500 000 annually, with everyone moving to DTG/TAF/FTC within a year. Calculations are for expected savings in drug costs for 4 years from 2019; USD values are used, as manufacturing is largely dependent on USD-based acquisitions of materials. The USD450 million baseline is the estimated cost of ART in 2019, based on the current costs for 2014 - 2015 and the estimated programme growth. We note that there are currently wide currency fluctuations, introducing manufacturing and other uncertainties. Future costs have not been discounted, nor lost-to-follow-up costs or decreased costs associated with less second-line monitoring; we have also not factored in costs of the introduction of new regimens, such as training.

Results

As shown in Figs 1 and 2, all scenarios for the introduction of DTG/TAF-based regimens translate into substantial reductions in ART drug costs for SA. The aggressive model with new drugs treats 800 000 people more than the status quo over 4 years, and with >USD200 million saving. Moreover, using the current budget for ART drugs, we could cover the ART drug costs of treating an additional 2 million people.

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People on ART (million)

7 6 5 4

Status quo

Conservative Moderate Aggressive

2 1

Years (assuming implementation in 2019 - 2020)

Fig. 1. Estimated increase in patients needing ART in SA. Number of people on antiretrovirals in SA (status quo = 300 000 initiating therapy annually, 2% migration to second line; conservative = 300 000 annually, transition from old regimen (EFV/TDF/FTC) to new (DTG/TAF/FTC) over 3 years; moderate = new regimen, 400 000 annually, transition over 2 years; aggressive = new regimen, 500 000 annually, transition over 1 year).

900

USD (million)

800 700 600 500

Aggressive Moderate Conservative

400

300 200 100 0

Years (assuming implementation in 2019 - 2020)

Fig. 2. Estimated crude savings on antiretroviral drugs (assuming implementation of new regimen in 2019 - 2020). Cumulative savings compared with status quo (conservative = 300 000 annually, transition from old regimen to new over 3 years; moderate = new regimen, 400 000 annually, transition over 2 years; aggressive = new regimen, 500 000 annually, transition over 1 year).

Conclusion

The introduction of DTG/TAF-based regimens could potentially translate into substantial savings to the SA health budget, if ADVANCE is completed rapidly and is successful, and if manufacturing is quickly scaled up to meet demand. Essentially, with the current ART budget, we could purchase DTG/TAF/FTC for everyone taking ART at the end of 4 years, even assuming the high end of 500 000 new patients needing treatment annually. Clinical evidence of the efficacy of both drugs is compelling, although questions remain around drug interactions with rifampicin and use in pregnancy, all being evaluated in clinical trials. In tandem, addressing the complex registration of new drugs (TAF has yet to be registered by the MCC) and combinations, including those of generic manufacturers, will need synchronisation, currently being

co-ordinated locally by CHAI, in partnership with the DoH. If TAF is not registered in time, or if problems arise in the TB or pregnancy studies, the DTG/TAF/FTC regimen also being tested in ADVANCE confers significant clinical and cost benefits. Finally, ART drug costs account for about a quarter of cost of HIV care in SA (it is a greater proportion in countries where salaries are lower and laboratory monitoring is more limited); therefore, attention to systemic cost drivers are still needed.[7,10] If successful, patients will benefit with a much safer and more forgiving regimen in a smaller tablet, government and other funders will save money, while pharmaceutical producers will have simplified manufacturing, using lower volumes of active pharmaceutical ingredients. In an age of escalating medical costs, we are seldom presented with a win-win scenario with regard to clinical care. The clinical studies and registration processes to secure inclusion of these two new drugs, if successful, would be a huge SA victory to complement the current successful ART roll-out, with knock-on effects for the entire region and other low- and middle-income countries. Disclosure. Several authors are involved in the ADVANCE studies and sub-studies, with the support of the United States President’s Emergency Plan for AIDS Relief (PEPFAR)/United States Agency for International Development (USAID) and UNITAID, in a broader collaboration addressing drug formulation and introduction, called OPTIMIZE. The study drug is donated by the originator companies, ViiV Healthcare (UK) and Gilead Sciences (USA). The views of this study are those of the authors and do not necessarily reflect the views of USAID, UNITAID or the SA or US governments. Raw data may be requested from the corresponding author, W D F Venter (fventer@wrhi.ac.za). 1. National Department of Health and South African National AIDS Council. South African HIV and TB investment case – summary report phase 1. 2016. http://sanac.org.za/wp-content/uploads/2016/03/1603Investment-Case-Report-LowRes-18-Mar.pdf (accessed 13 August 2016). 2. Surgey G, Cohen S, Guthrie T. Public health spending on antiretroviral medication in South Africa: An analysis of the annual ARV budget and expenditure for the financial year 2013/14, prepared for the South African National AIDS Council (in press). 3. South African Government News Agency. Tender to supply ARVs awarded to companies. 2015. http:// www.sanews.gov.za/south-africa/tender-supply-arvs-awarded-companies (accessed 17 September 2016). 4. Centre for Health Journalism. Health Minister Aaron Motsoaledi admits that ‘key leaders were in denial’. 2016. http://bhekisisa.org/article/2016-07-15-aids2016-health-minister-aaron-motsoalediadmits-that-key-leaders-were-in-denial/ (accessed 27 July 2016). 5. Clinton Health Access Initiative. ARV market report: The state of the antiretroviral drug market in low- and middle-income countries, 2014 - 2019. 2015. http://www.clintonhealthaccess.org/content/ uploads/2015/11/CHAI-ARV-Market-Report-2015_FINAL.pdf (accessed 27 July 2016). 6. Sabin CA. Do people with HIV infection have a normal life expectancy in the era of combination antiretroviral therapy? BMC Med 2013;27(11):251. http://dx.doi.org/10.1186/1741-7015-11-251 7. Barnhart M, Shelton JD. ARVs: The next generation. Going boldly together to new frontiers of HIV treatment. Glob Health Sci Pract 2015;3(1):1-11. http://dx.doi.org/10.9745/GHSP-D-14-00243 8. Médecins Sans Frontières. Untangling the web of antiretroviral price reductions. http://issuu.com/ msf_access/docs/hiv_report_untangling-the-web-18the/25?e=3239302/37230248 (accessed 27 July 2016). 9. Brenner BG, Wainberg MA. Clinical benefit of dolutegravir in HIV-1 management related to the high genetic barrier to drug resistance. Virus Res 2016;pii:S0168-1702(16)30283-0. http://dx.doi.org/10.1016/j. virusres.2016.07.006 10. Vu L, Waliggo S, Zieman B, et al. Annual cost of antiretroviral therapy among three service delivery models in Uganda. J Int AIDS Soc 2016;20(19)(5 Suppl 4):20840. http://dx.doi.org/10.7448/IAS.19.5.20840

Accepted 3 October 2016.

January 2017, Print edition

This open-access article is distributed under Creative Commons licence CC-BY-NC 4.0.

IN PRACTICE

CLINICAL UPDATE

Outbreak of carbapenem-resistant Providencia rettgeri in a tertiary hospital V S Tshisevhe,1,2 MB ChB, MBA, Dip HIV Man (SA), DTM&H; M R Lekalakala,3 BSc; MB ChB, DTM&H, MMed, PDIC; N Tshuma,4 BSc, MBA; S Janse van Rensburg,1 B Med Tech; N Mbelle,1,2 BSc, MSc, MB BCh, MMed, DTM&H, MAP, FCPath (SA) Department of Medical Microbiology, Tshwane Academic Division, National Health Laboratory Service, Pretoria, South Africa Department of Medical Microbiology, Faculty of Health Sciences, University of Pretoria, South Africa 3 Department of Medical Microbiology, Polokwane National Health Laboratory Service, and Department of Medical Microbiology, Faculty of Health Sciences, University of Limpopo, Polokwane, South Africa 4 Community AIDS Response, Johannesburg, South Africa 1 2

Corresponding author: V S Tshisevhe (vhudzani@gmail.com)

The emergence of resistance to multiple antimicrobial agents in pathogenic bacteria is a significant public health threat, as there are limited effective antimicrobial agents for infections caused by multidrug-resistant (MDR) bacteria. Several MDR bacteria are now frequently detected. Carbapenem resistance in Enterobacteriaceae is often plasmid mediated, necessitating stringent infection control practices. We describe an outbreak of carbapenem-resistant Providencia rettgeri involving 4 patients admitted to intensive care and high-care units at a tertiary hospital. Clinical and demographic characteristics of 4 patients with carbapenem-resistant P. rettgeri were documented. All P. rettgeri isolated in these cases had a carbapenem-resistant antibiogram, with resistance to imipenem, ertapenem and meropenem. These cases could be epidemiologically linked. A multiprong approach, simultaneously targeting antibiotic stewardship, universal precautions and appropriate transmission-based precaution practices, is integral to prevention and control of nosocomial infections. S Afr Med J 2017;107(1):31-33. DOI:10.7196/SAMJ.2017.v107i1.12002

Providencia rettgeri is a member of the Enterobacteriaceae, known to cause urinary tract infections (UTIs), bacteraemia, skin infections, gastroenteritis and wound infections, especially in immunocompromised patients and those with indwelling urinary catheters.[1-3] P. rettgeri is an aerobic Gram-negative bacillus that displays marked resistance to most of the currently available antibiotics.[2] The organism is part of the normal gastrointestinal flora.[3] Immunocompromised or debilitated patients are highly susceptible to hospital-acquired infections – either after colonisation with environmental strains or following invasive procedures, such as catheterisation, bronchoscopy, colposcopy or surgical biopsies.[4] P. rettgeri is commonly found to cause traveller’s diarrhoea and has also been isolated from more severe human infections such as meningitis.[3,5,6] Among the Providencia species, P. stuartii and P. rettgeri are the most common causes of infections, especially UTIs in hospitalised patients, although other infections can occur. Virtually all Providencia species can produce inducible AmpC beta-lactamases, and many isolates may also produce extended-spectrum beta-lactamases (ESBLs) in nosocomial settings.[3] P. rettgeri has been associated with hospital-acquired infections, including catheter-related UTIs. Multiple factors contribute to the high frequency of UTIs in hospitalised patients. Comorbid illnesses and interventions to manage bladder voiding are the most important contributing variables. Prostatic hypertrophy in men promotes infection through urethral obstruction and turbulent urine flow and the additional risks associated with the use of instruments. Bacterial prostatitis, once established, is difficult to eradicate and may be a source of recurrent UTI over many years.[7] The emergence of resistance to multiple antimicrobial agents in pathogenic bacteria has become a significant public health threat,

as there are fewer and sometimes no effective antimicrobial agents available for infections caused by multidrug-resistant bacteria.[8] The mechanism of resistance of Enterobacteriaceae to carbapenems is most commonly by the production of an enzyme that breaks down the antibiotic before it can affect the bacterium.[9] Resistance to antimicrobial agents in several bacteria is increasing, often because of poor application of antibiotic stewardship. Antimicrobial resistance is destroying the premise of modern medicine, i.e. whenever required, adequate antibiotic cover is available to save the patient’s life.[10] The emergence of carbapenem resistance in Providencia species is of particular concern because these bacteria are intrinsically resistant to polymyxins and tigecycline.[11] These antibiotics are often used as part of regimens in the treatment of carbapenem-resistant isolates. New Delhi metallo-beta-lactamase-1 (NDM-1)-mediated carbapenemase is the most common class B carbapenemase in Enterobacteriaceae and has been detected increasingly in several countries.[12] The broad distribution of NDM-producing isolates and the apparent ease of transfer of the blaNDM gene are a major threat to public health globally.[13] P. rettgeri has recently been recognised as a key organism for the dissemination of NDM-1, requiring measures for timely control of the spread of this organism.[14] Our objective was to characterise a cluster of identified carbapenem-resistant P. rettgeri and determine the epidemiological link of the isolates.

Methods

A P. rettgeri outbreak was identified at Steve Biko Academic Hospital (SBAH), Pretoria, South Africa between November 2014 and January 2015. SBAH is a tertiary hospital with referrals from lower-level hospitals in the Tshwane municipal area. The urine samples were obtained from patients admitted to SBAH and the analysis was

January 2017, Print edition

IN PRACTICE

conducted at the medical microbiology laboratory of the Tshwane Academic Division of the National Health Laboratory Service (NHLS). Ethical clearance was given by the Faculty of Health Sciences Research Ethics Committee, University of Pretoria (ref. no. 247/2015).

After 2 months she presented with pyrexia, haematuria and positive urine nitrites. A urine sample was submitted to the laboratory for culture, where P. rettgeri was isolated.

Bacteria isolation and identification

An HIV-positive 32-year-old woman was admitted to the ICU a month after Case 1; they shared the ICU. She had renal failure with pulmonary oedema and received dialysis while there. A urine sample was submitted to the laboratory a month later for a suspected UTI; P. rettgeri was isolated. After 2 months in the ICU the patient was transferred to the high-care unit, where she continued receiving treatment for renal failure.

A loopfull of urine was streaked on blood agar and MacConkey agar media. The culture plates were incubated at 35±2°C for 18 - 24 hours. Plates that showed growth were observed and the colonies were further identified using the Vitek 2 system (bioMérieux, USA).

Antibiotic susceptibility test

The following antibiotics were tested by the disc diffusion method: ampicillin (10 µg), amoxicillin-clavulanic acid (30 µg), cefotaxime (30 µg), ceftazidime (30 µg), cefoxitin (30 µg), imipenem (10 µg), meropenem (10 µg), ertapenem (10 µg), cefuroxime (30 µg), ciprofloxacin (5 µg), and trimethoprim/sulfamethoxazole (25 µg). The isolates were inoculated on Mueller-Hinton agar and the antibiotic discs were placed on the agar surfaces. The plates were incubated at 35±2°C for 18 - 24 hours. The susceptibility was read after 24 hours’ incubation as per 2015 Clinical and Laboratory Standards Institute guidelines. Detection of ESBL production was determined among the Gramnegative bacteria resistant to third-generation cephalosporins by the double-disc synergy test, with ceftazidime (30 µg) and cefotaxime (30 µg) discs placed 20 mm centre-to-centre around an amoxicillin-clavulanic acid (30 µg) disc. This was done on the surface of a Mueller-Hinton agar plate inoculated with the isolates’ suspension equivalent to 0.5 McFarland standards by surface spreading using sterile swab sticks. After incubation at 35±2°C for 24 hours, ESBL production was inferred when the zone of inhibition around the cephalosporin discs was expanded by ≥5 mm by the presence of clavulanic acid. Carbapenem resistance was defined by reduced susceptibility to imipenem, ertapenem and meropenem. Carbapenem resistance was characterised for carbapenemase production by the modified Hodge test.

Results

A total of 4 isolates were collected from patients who were admitted to the intensive care unit (ICU) and high-care unit. Clinical and demographic characteristics of the 4 patients with carbapenemresistant P. rettgeri are outlined in Table 1.

Case 1

An HIV-positive 26-year-old woman who was not yet receiving treatment was admitted to the ICU with a respiratory tract infection. While in the ICU, she developed renal failure and received dialysis.

Case 2

Case 3

A 40-year-old man with known hypertension was admitted to the same high-care unit as Case 2. He presented with renal failure, for which he received dialysis. Four days after admission he complained of symptoms suggestive of a possible UTI. A midstream urine sample was collected and sent to the laboratory, where P. rettgeri was isolated. The patient was deemed stable and transferred to a regular ward to continue with renal failure treatment.

Case 4

An HIV-positive 33-year-old woman was admitted to the surgical ICU with multiple gunshot wounds of the head and abdomen. The patient had a laparotomy, and a hysterectomy and nephrectomy were performed. Amoxicillin-clavulanic acid and metronidazole were administered after the operation to cover for possible contamination during surgery. While in the ICU, the patient developed bedsores on the sacral and occipital regions. Three weeks after admission, she was transferred to the high-care unit, where cases 2 and 3 were previously admitted. While in the high-care unit, a biopsy of the bedsore was sent to the laboratory, where P. rettgeri was isolated. All P. rettgeri isolated in these cases had a carbapenem-resistant antibiogram with resistance to imipenem, ertapenem and meropenem.

Discussion

The cases presented in this study demonstrated carbapenem-resistant P. rettgeri, which showed that they were epidemiologically linked. This may partly be explained by some of the carbapenem-resistant genes being known to be transmitted horizontally. This organism inhabits moist areas or moisture-containing instruments, such as dialysis machines, which may have been the main source in this outbreak. As some patients acquired the infection after they were discharged, transmission from inanimate objects and healthcare workers is a possibility.

Table 1. Clinical and demographic characteristics of 4 cases of carbapenem-resistant P. rettgeri Case

Sex

Age (years)

Site of isolation

Antimicrobial therapy

Treatment

Outcome

HIV status

Urine

Carbapenem

Dialysis

Transferred to high-care unit

Positive

Respiratory infection

Urine

Carbapenem

Dialysis

Discharged home

Positive

Renal failure

Urine

Carbapenem

Dialysis

Transferred to renal unit

Negative

Renal failure

Tissue

Carbapenem

Dialysis

Died

Positive

Polytrauma

F = female; M = male.

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Reason for ward admission

IN PRACTICE

Several studies have indicated that immune-compromised patients are more prone to UTIs â&#x20AC;&#x201C; all of the cases reported here were immunecompromised.[1-3] Catheterisation is a predisposing factor for the development of a UTI and all patients investigated in this study had urinary catheterisation. All patients were also dialysed, which may have exposed them to fluids containing P. rettgeri. This association will require a larger study to provide conclusive evidence. Caution needs to be exercised when using common equipment, such as dialysis machines, to prevent the transfer of bacteria. Thorough sterilisation and cleaning of equipment is of paramount importance in the prevention of microbial contamination and infection. A point prevalence surveillance of colonisation must be conducted on a regular basis for early detection of environmental and equipment contamination. Cohorting of patients infected and colonised by resistant organisms may limit the spread of infection to other patients in the unit. Studies have demonstrated that isolating and cohorting infected or colonised patients with contact precautions, healthcare personnel hand hygiene and environmental cleaning are integral to the disruption of the spread of infection within the hospital setting.[15]

Conclusion

The prevention and control of nosocomial infections depend on a multipronged approach, simultaneously targeting antibiotic stewardship, universal precautions and appropriate transmission-based precaution practices. Education of healthcare personnel plays a pivotal role in preventing and controlling the outbreak. Hand hygiene and equipment sterilisation must be reiterated to healthcare personnel, as proper hygienic practices are important in the prevention of bacterial infections in a healthcare facility.

1. Cho H-J, Lim S-J, Chun S-Y, et al. A case of Providencia rettgeri sepsis in a patient with cervical cord injury. Infect Chemother 2010;42(6):428. http://dx.doi.org/10.3947/ic.2010.42.6.428 2. Olaitan AO, Diene SM, Assous MV, Rolain JM. Genomic plasticity of multidrug-resistant NDM1 positive clinical isolate of Providencia rettgeri. Genome Biol Evol 2016;8(3):723-728. http://dx.doi. org/10.1093/gbe/evv195 3. Zavascki AP, Carvalhaes CG, da Silva GL, et al. Outbreak of carbapenem-resistant Providencia stuartii in an intensive care unit. Infect Control Hosp Epidemiol 2012;33(6):627-630. http://dx.doi. org/10.1086/665730 4. Pollett S, Miller S, Hindler J, Uslan D, Carvalho M, Humphries RM. Phenotypic and molecular characteristics of carbapenem-resistant Enterobacteriaceae in a health care system in Los Angeles, California, from 2011 to 2013. J Clin Microbiol 2014;52(11):4003-4009. http://dx.doi.org/10.1128/ JCM.01397-14 5. Galac MR, Lazzaro BP. Comparative genomics of bacteria in the genus Providencia isolated from wild Drosophila melanogaster. BMC Genomics 2012;13(1):612. http://dx.doi.org/10.1186/1471-2164-13-612 6. Barrios H, Garza-Ramos U, Reyna-Flores F, Sanchez-Perez A, Rojas-Moreno T, Garza-Gonzalez E. Isolation of carbapenem-resistant NDM-1-positive Providencia rettgeri in Mexico. J Antimicrob Chemother 2013;68(8):1934-1936. http://dx.doi.org/10.1093/jac/dkt124 7. Nicolle LE. Urinary tract infections in long-term-care facilities. Infect Control Hosp Epidemiol 2001;22(3):167-175. http://dx.doi.org/10.1086/501886 8. Magiorakos A, 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 2011;18(3):268-281. http://dx.doi.org/10.1111/j.14690691.2011.03570.x 9. Australian Commission on Safety and Quality in Health Care. Recommendations for the control of multi-drug resistant Gram-negatives: Carbapenem resistant Enterobacteriaceae. 2013. http://www. safetyandquality.gov.au/wp-content/uploads/2013/12/MRGN-Guide-Enterobacteriaceae-PDF1.89MB.pdf (accessed 4 November 2016). 10. Rodrigues C. Carbapenem-resistant Enterobacteriaceae: A reality check. Regional Health Forum 2011;15(1):83-86. 11. Sidjabat H, Nimmo GR, Walsh TR, et al. Carbapenem resistance in Klebsiella pneumoniae due to the New Delhi metallo-Î˛-lactamase. Clin Infect Dis 2011;52(4):481-484. http://dx.doi.org/10.1093/cid/ ciq178 12. Rozales FP, Ribeiro VB, Magagnin CM, et al. Emergence of NDM-1-producing Enterobacteriaceae in Porto Alegre, Brazil. Int J Infect Dis 2014;25:79-81. http://dx.doi.org/10.1016/j.ijid.2014.01.005 13. Pasteran F, Meo A, Gomez S, et al. Emergence of genetically related NDM-1-producing Providencia rettgeri strains in Argentina. J Glob Antimicrob Resist 2014;2(4):344-345. http://dx.doi.org/10.1016/j. jgar.2014.07.003 14. Gefen-Halevi S, Hindiyeh MY, Ben-David D, et al. Isolation of genetically unrelated bla(NDM-1)positive Providencia rettgeri strains in Israel. J Clin Microbiol 2013;51(5):1642-1643. http://dx.doi. org/10.1128/JCM.00381-13 15. Maltezou HC. Metallo-beta-lactamases in Gram-negative bacteria: Introducing the era of panresistance? Int J Antimicrob Agents 2009;33(5):405. http://dx.doi.org/10.1016/j.ijantimicag.2008.09.003

Accepted 19 September 2016.

ISSUES IN PUBLIC HEALTH

This open-access article is distributed under CC-BY-NC 4.0.

Tackling the climate targets set by the Paris Agreement (COP 21): Green leadership empowers public hospitals to overcome obstacles and challenges in a resourceconstrained environment

E Weimann,1,2 MD, MMed (Paed), Endocrinology & Metabolism, Habil, MPH; B Patel,1 BSc, MB ChB, MFamMed, FCFP, FCPHM, MSc (Med Bioethics and Health Law) 1 2

Groote Schuur Academic Hospital, Cape Town, South Africa Department of Information Systems, Faculty of Commerce, University of Cape Town, South Africa

Corresponding author: E Weimann (edda.weimann@westerncape.gov.za)

The healthcare sector itself contributes to climate change, the creation of hazardous waste, use of toxic metals such as mercury, and water and air pollution. To mitigate the effect of healthcare provision on the deteriorating environment and avoid creating further challenges for already burdened health systems, Global Green Hospitals was formed as a global network. Groote Schuur Hospital (GSH), as the leading academic hospital in Africa, joined the network in 2014. Since then, several projects have been initiated to reduce the amount of general waste, energy consumption and food waste, and create an environmentally friendlier and more sustainable hospital in a resourceconstrained public healthcare setting. We outline the various efforts made to reduce the carbon footprint of GSH and reduce waste and

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hazardous substances such as mercury and polystyrene, and elaborate how obstacles and resistance to change were overcome. The hospital was able to halve the amount of coal and water used, increase recycling by 50% over 6 months, replace polystyrene cups and packaging with Forest Stewardship Council recyclable paper-based products, reduce the effect of food wastage by making use of local farmers, and implement measures to reduce the amount of expired pharmaceutical drugs. To improve commitment from all involved roleplayers, political leadership, supportive government policies and financial funding is mandatory, or public hospitals will be unable to tackle the exponentially increasing costs related to climate change and its effects on healthcare. S Afr Med J 2017;107(1):34-38. DOI:10.7196/SAMJ.2017.v107i1.12023

On 22 April 2016, Earth Day, 177 nations gathered to sign the Paris Agreement (COP 21), and at the time of writing 187 countries have made their official commitment to take action on climate change. Minister Molewa signed the agreement on behalf of South Africa (SA). To reach the goals set out in this agreement will require a profound global effort. Each and every sector must step up to develop a low-carbon path for the future. The health sector plays a significant role, not only in taking action to reduce its own climate impacts, but also to act as a leader to inspire others to serve as role models. As the Lancet Commission stated in 2009, climate change is ‘the biggest public health threat of the 21st century’.[1] Since then, the climate crisis has deepened severely, with higher frequency of extreme weather events and recurrences of El Niño. Scientific findings have become increasingly indisputable, intensifying the urgency for action. Climate change is already aggravating a wide range of health problems. As our planet warms, infectious diseases are spreading, threatening to reverse health improvements gained by great effort in many parts of the world. Heatwaves are growing in intensity and number, killing thousands of people and children, and aggravating chronic lung disease, heart disease and heatstroke. Increasingly severe storms, tornados, droughts and floods, as recently experienced in China, but also in SA, harm human health and put often overstretched and ill-prepared health systems at risk. If greenhouse gas emissions remain at the current level or even increase, climate change will have severe persistent and irreversible effects, undermining the food and water supply in many parts of the world, setting off mass migrations, and thereby triggering potentially unmanageable public health crises. Based on scientific evidence, we need to prevent atmospheric carbon dioxide concentrations exceeding 450 - 500 parts per million (ppm) to avoid the serious, often irreversible, damage to many natural systems and ecological processes that a global average temperature increase of 2 - 3°C would cause.[2] Alarmingly, compared with 280 ppm before industrialisation, a 400 ppm target was already reached in both hemispheres earlier than expected, in June 2016. Radical action is therefore needed. While everyone will experience the hazards of climate change, the most vulnerable populations, especially in developing countries – the urban and rural poor – will endure the biggest impact. Fossil fuel and coal are the greatest contributors to greenhouse gas emissions. The deterioration of air quality of large metropolitan areas in SA such as Johannesburg and Cape Town has become evident over the past decade. There has been very little research on climate change and its effect on health in SA, nor have policies been implemented to mitigate climate change and protect the population. The burning of wood and coal as well as uncontrolled air pollution from cars and trucks are major sources of significant local health problems such as airway diseases, chronic obstructive pulmonary disease and asthma. The use of fossil fuels makes a major contribution to air pollution, which, according to the World Health Organization (WHO), killed

7 million people globally in 2012, causing twice as many deaths as AIDS, malaria and tuberculosis combined.[3] To protect local and global health from climate change and its sources, the developed, together with developing, countries need to move towards an economy based on clean, renewable, healthy energy and significantly reduce the pollution of our environment. A transition to a clean-energy economy will benefit both the climate and public health. Healthcare providers such as hospitals, health systems and government health institutions can play a leadership role in this transition. In SA, the National Department of Health approved a national climate change adaptation plan in 2014.[5] This plan covers a general approach to climate change responses for the health sector. It does not offer a plan for implementation, but highlights the key areas of concern for the sector. In the SA Risk and Vulnerability Atlas,[6] the identification of risks associated with climate change and the effects on health are addressed, inter alia. The government has also undertaken a set of in-depth analyses in a number of sectors, under the Long Term Adaptation Scenarios process, one of which was an analysis of the health sector.[7] The effect of climate change on human health will be investigated through the analysis of a variety of complex interactions between changes in climate variables (temperature, heatwaves, rainfall) and health aspects. This will be examined by investigating influences on existing diseases via temperature spikes, vulnerable groups and psychological effects. However, the main focus is on building resilience, rather than mitigating the effect of climate change, through implementing and executing appropriate policies. Resilience in this context is defined as preparing for the effects of extreme weather and the shifting burden of disease. Human health is likely to be affected, directly and indirectly, by increasing temperatures, more frequent heatwaves and changing rainfall patterns. A reduction in the availability of water, as well as in the supply of clean, potable water, may lead to reduced levels of personal hygiene and an increase in related diseases. Population growth, especially in metropolitan areas, coupled with a situation of less water, may lead to an increase in the incidence of water-borne diseases, further affected by deterioration in the quality of water sanitation. Higher temperatures will increase the quantity and spread of animal species such as rodents, some of which directly affect human health. The population’s immune systems may be further compromised by extreme temperatures caused by climate change. Temperatures are expected to rise and rainfall to decrease in all regions in Western Cape Province. Over the past 50 years, the Western Cape Province has seen the average temperature increase by more than 1°C, resulting in more days over 32°C and even days over 36°C.[4] Heat and heatwaves have an impact on human health, and in particular on people living in informal settlements. People exposed to heat and sunlight will be more prone to develop renal failure as a result of the high incident rate of hypertension in the SA population,[8] an event that is also reported in other developing countries such as India. Vector- and food-borne diseases and temperature-related ill-

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nesses are likely to increase in the Western Cape in particular. Billions of litres of waste water, tons of plastic and other hazardous chemicals are dumped into the oceans, rivers and waterways every day, leading to disturbed ecosystems, affecting the food chain and augmenting the infection rate of bathers.[9,10] The increased acidity of the oceans further aggravates climate change. Climate change will have a severe socioeconomic impact and will probably decrease the already low life expectancy of South Africans further (currently 57 years).[11] Some population groups are more vulnerable, especially the elderly, who are more prone to heat stress, as well as low-income communities and agricultural workers, who are more exposed to the sun and heat. The SA health system is characterised by stark inequality between public and private healthcare providers, austerity measures, and shortages of hospital beds, transport facilities and skills.[12] Every effort should therefore be made to minimise the effect of climate change[5] and avoid further burdening the overstretched health system. Consequently, it is mandatory to implement and execute policies to boost renewable energies, to insulate buildings and healthcare facilities, and to reduce greenhouse gas emission, air, water and soil pollution, coal consumption and hazardous waste,[3] as resilience can only be partly achieved and at very high costs.

Goals and objectives of our Green Leadership projects 1. Reducing our own climate footprint

Hospitals and healthcare providers are major energy consumers and can make a large contribution to the reduction in greenhouse gas emissions. Since 2014, Groote Schuur Hospital (GSH) in Cape Town, SA, has been a member of the Global Green and Healthy Hospitals Initiative (www.greenhospitals.net) that aims to lead the way towards low-carbon healthcare by reducing greenhouse gas and setting renewable energy targets. GSH’s vision is to reduce its emissions, moving towards low-carbon and preferably carbonneutral healthcare. Considering the SA energy crisis, and the load shedding experienced over the last decade, we aim to deploy renewable energy, as this may be financially supported by the government[5] and hospitals could receive additional funding for green energy solutions. We will further increase our energy efficiency measures, eliminate waste and leakages and when feasible deploy clean renewable energy to power our buildings. Currently, we are exploring the potential of solar thermal energy to address the heat requirements of the hospital, in collaboration with non-government organisations. Our progress is measured and reported on a monthly basis within the hospital and the Western Cape Province, and includes the financial savings related to these actions. We identify our practices that affect the climate, including purchasing and waste generation, and are currently also implementing plans to reduce the effects of these methods.

GSH itself is at present not adapted for the already-experienced rise in temperature and increased number of heatwaves.

3. Leading the way to a low-carbon future in healthcare

GSH, as a tertiary care facility and academic hospital, is committed to providing leadership for a healthy climate, backed up by our Healthcare Innovation Hub. To do so we educate healthcare professionals, students and hospital staff on the challenges and solutions relating to climate and health. In collaboration with the Provincial Climate and Health Committee we encourage public policy to move away from fossil fuel dependency and instead foster a healthy energy future, thereby protecting local health from climate change. As proposed by the Global Green Hospital Initiative, by moving towards low-carbon health systems, healthcare can mitigate its own climate impact, save money and lead by example. Consequently, we engage in green procurement methods,[13] avoiding mercury content, and preferably acquire products produced locally or from neighbouring countries in southern Africa. Through providing societal leadership,[14] we encourage a vision of a future with sustainable and green hospitals living with environmentally responsible communities on a healthy planet.

The GSH Green Leadership projects

To achieve the goals and objectives, we have embarked on various projects (Fig. 1) and have created a GSH green hospital leadership framework:

1. Reducing the energy, coal and water consumption of the hospital

This project is mainly driven by the engineering department. To keep up with the hospital ‘steam demand’ the boiler house was running two 8-ton boilers at 6 tons of coal per hour in winter and 4.5 tons per hour in summer. Based on these extreme inefficiencies, a complete overhaul of the boiler house and steam reticulation was done. The hospital boiler house was built with 4 tons of coal-fired boilers in 1965, which replaced the original steam generation system installed in the old hospital basement in the late 1930s. In the mid 1990s, three of the 4-ton boilers were replaced with two 8-ton coal-fired boilers and one of the 4-ton boilers remained. Over the years, the boilers became fouled with soot and fly ash, and the steam reticulation

First polystyrene-free hospital in SA

Improving energy efficiency

Green GSH

2. Preparing for climate impact and creating resilience

We need to be equipped to manage the health needs of our community, as well as be prepared for shifting disease patterns and an increasing incidence of extreme weather, creating resilience overall. To serve our communities, our hospital must remain operational during and after an extreme weather event. Hence, measures are required to ensure that our infrastructure, staff and communities are prepared for the immediate impact of extreme weather events and the longer-term impact of changing patterns of disease, as well as other climate impacts, combining these efforts with low-carbon solutions whenever possible. With regard to its lack of insulation,

Cultural and awareness programme (cultural change and climate change agents)

Reduction in food and pharmaceutical waste

Recycling initiative (fully managed and generating revenue)

Fig. 1. GSH achievements to reduce the carbon footprint and environmental impact (GSH Green Leadership Framework).

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Table 1. Reduction in water and coal consumption at GSH 2011

2012

2013

2014

2015

Coal (tons)

3 433

3 469

3 163

2 214

1 885

â&#x20AC;&#x201C;45.1

Water (kL)

652 424

Electricity (kW)

532 088

503 860

420 782

371 705

â&#x20AC;&#x201C;43.0

4 256 750

4 256 255

4 269 498

4 016 333

â&#x20AC;&#x201C;5.7

110.7

144.0

+23.0

Recycling (tons)

had a defective steam trapping system as well as many leaks. By understanding the design, repairing leaks and improving efficiencies, we reduced the coal consumption of the hospital by 48% between 2009 and 2015. There is an environmental benefit to using far less coal for the amount of steam required to ensure that the hospital operates efficiently and effectively. Not only do we now produce less carbon emissions, but as a result of the increased reticulation efficiency, we are also using less energy and water to produce steam and, as a result, using fewer water treatment chemicals. This also positively affects human health, as the physical load of the staff is reduced as well as the respiratory implications for people working in the surrounding neighbourhood. To minimise the effect of the remaining coal emission, we are currently applying for funding from the provincial government to install filters, to reduce the fine-particle pollution that is visible at GSH. While the engineering department focused on reducing energy consumption and waste, management engaged in an awareness programme to promote the switching off of lights and appliances when not needed. Different presentations were given to encourage various departments and teams (e.g. students, doctors, nurses) to become agents tackling climate change.[11] Appropriate signage to encourage energy-sensitive behaviour is displayed. The Western Cape provincial government has implemented a portal to monitor and visualise energy consumption (http://www.energyshop.co.za/WCDOH.html). The baseline consumption of GSH during the night remains elevated, despite awareness campaigns. We are now monitoring the energy consumption of the hospital on a daily basis via the governmental Smartmeter application. In addition, as outlined above, we aim to install filters to reduce the small-particle emission of the hospital. GSH was able to save coal, water and electricity over the past 5 years and therefore we have significantly reduced our carbon footprint (Table 1).

2. Introducing recycle bins and improvement in waste management

Staff members from different areas of the hospital are continually trained in proper triaging and waste separation. In addition, presentations are given at staff meetings and the correct procedures are explained. Several departments have introduced recycling bins in their areas, including the management suites, GSH Healthcare Innovation Hub, the hospital facility board, and the Departments of Radiation Medicine and Medicine (Fig. 2). The University of Cape Town (UCT) Private Academic Hospital, which is located in the Groote Schuur building, has joined our effort by introducing recycling bins and adhering to improved waste management. Another effort is that departments install printers that print double-sided, to save paper. The total tonnage of recycled waste increased by 23% in 2015 and by 50% in the first 6 months of 2016; the total amount of recycling removed in 2015 was 144 tons, in contrast to 110.7 tons in 2014. In 2015, we generated ZAR106 174 from recycling alone. Additionally, food waste from the GSH kitchen is collected on a regular basis by a local farmer, for use as pig feed.

3. Creating a polystyrene-free hospital

Polystyrene is known as a major health and environmental hazard. It creates a major litter problem and is the fifth-largest creator of harmful waste worldwide. It is non-degradable and stays in the environment for hundreds of years, and toxic chemicals released by polystyrene are ingested, becoming part of marine life and the food chain.[15] Polystyrene is suspected of causing cancer and leading to hormonal disturbances.[16] In addition, polystyrene production contributes considerably to the depletion of the ozone layer. In spite of these well-established facts, polystyrene is still widely used in the environment by retailers and in the food processing industry, although alternative Forest Stewardship Council (FSC) paperbased products exist. At GSH, polystyrene cups and packaging were used for water dispensing and in the canteens. We engaged in finding suppliers who provide FSC-based paper cups and packaging. The UCT Private Academic Hospital also changed their procurement policy and introduced an FSC paper-based system. As the amount of paper that is recycled in SA is low, recycled paper needs to be imported from other countries. To achieve buy-in from the various roleplayers, meetings, discussions and presentations took place to provide the reasoning for replacing waste-intensive polystyrene packaging with biodegradable paper and gelatinebased bioplastic. This new strategy was rolled out in the hospital to reduce greenhouse gas emissions, and to limit the amount of waste and well-established health hazards created by the use of polystyrene cups. The hospital supply chain policy was therefore amended accordingly. As there was resistance to changing current habits, active change management processes were used. Finally, the canteens (outsourced to Feedem), GSH Private Academic Hospital (which belongs to the Netcare hospital group) and GSH hospital management agreed to dispense with polystyrene and use biodegradable paper packaging instead, enabling us to create the first polystyrene-free hospital in SA.

4. Reducing the amount of pharmaceutical waste

Pharmaceutical waste is a major problem, as it is toxic to the environment. Medicines prescribed unnecessarily in a resourceconstrained environment add to the quantity of waste.[17] We are therefore working towards reducing polypharmacy and the amount of expired drugs.[17] Currently, waste by medicine expiry is <1% of total pharmaceutical procurement, although in a tertiary care facility this can amount to ZAR500 000 per year (Fig. 3). The GSH pharmacy

Fig. 2. Establishing recycling bins in the hospital.

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accomplishments and in the difference made towards achieving an environmentally friendly and greener hospital. Additionally, the projects were designed in such a way that the innovations can be rolled out in other health facilities. The Green Hospital projects could prosper from the support of governmental funding. Some countries (e.g. the USA, the UK, European countries) provide governmental support and therefore enhance green leadership initiatives. Healthcare facilities could become more energy independent by installing green energy solutions such as solar, thermal and wind energy. In addition, the carbon and waste footprint of each healthcare facility could be calculated and advertised on a regular basis to encourage competition between facilities. By creating a governmental green healthcare platform, different green teams would be able to crosspollinate and inspire each other.

Fig. 3. Medicines returned after expiry date (wasteful expenditure).

has implemented measures to use or redistribute medicines before they expire, to reduce the amount of expired drugs and hence the waste. In addition, patients are asked, when they collect their prescribed medicines, what they do not need or still have in stock. Targets are set for the forthcoming year to use prescribed medicine more efficiently and economically.

Discussion

The GSH Green Hospital Leadership projects have demonstrated green leadership and environmental responsibility. We were able to engage staff from various levels of the hospital hierarchy to take ownership and drive the project in their areas. The effect and results are regularly disseminated throughout the hospital. In addition, the UCT Private Academic Hospital has joined our going-green projects, in particular by improving recycling and replacing polystyrene with FSC paper-based products. As we aim to engage staff members to work as a team to find solutions to existing problems, we implement sustainability with this approach as changes and new measures are taken up by the staff and are used in the everyday life of the hospital. In this way, a shift of mindset and thinking towards a culture of continuous improvement will occur. With the success of this project, we hope that the green leadership concept can be rolled out to other public healthcare facilities and schools in the country, and that combined green solutions can be initiated and implemented through the GSH Healthcare Innovation Hub, which the hospital created as a space where such creative thinking could be encouraged. This hub is the first of its kind in the public sector and several of the initiatives involving the changing of mindset and creation of awareness are happening there. This project’s innovation is addressing the daily challenges of reducing the carbon footprint, saving energy and minimising the amount of hazardous waste in a public hospital by generating profits through our actions. Our data clearly show that the Green Hospital projects are sustainable and revenues are growing. The successful project rollout has created enthusiasm among the staff to act as climate change agents and environmental activists and has generated innovative solutions from within. The teams working on the projects had a sense of ownership over and pride in the

Acknowledgements. R de Jager is in charge of waste management at GSH and we acknowledge his engagement in the Green Leadership projects. D Smith, head of the engineering department at GSH, kindly provided input on water, energy and coal consumption. V Naicker, head of the pharmacy, drives the project to reduce pharmaceutical waste. We commend the support for polystyrene-free canteens received by S Esterhuizen and her team from Feedem at GSH. L Shield, executive hospital manager at Netcare UCT Private Academic Hospital, joined our green projects and implemented a polystyrene-free policy, recycling bins and improved waste management at the hospital facility. We appreciate her commitment. We recognise the input of the Western Cape Provincial Climate and Health Committee and the Global Green and Healthy Hospitals Initiative. 1. Haines A. Climate Change and Health. Am J Prev Med 2008;35(Sept):1-5. http://dx.doi.org/10.1016/j. amepre.2008.08.003 2. McMichael AJ, Friel S, Nyong A, Corvalan C. Global environmental change and health: Impacts, inequalities, and the health sector. BMJ 2008;336(7637):191-194. http://dx.doi.org/10.1136/bmj.39392.473727.AD 3. Watts N, Adger WN, Agnolucci P, et al. Health and climate change: Policy responses to protect public health. Lancet 2015;386(10006):1861-1914. http://dx.doi.org/10.1016/S0140-6736(15)60854-6. 4. Costello A, Mustafa Abbas M, Allen A, et al. Managing the health effects of climate change. Lancet 2009;373(9672):1659-1733. http://dx.doi.org/10.1016/S0140-6736(09)60935-1 5. Government of the Republic of South Africa.The South African Climate Change Response Strategy. 2001. http://www.climateresponse.co.za/home/gp/1 (accessed 19 November 2016). 6. Department of Science and Technology, South Africa. South African Risk and Vulnerabilty Atlas. http://sarva.dirisa.org/ (accessed 19 November 2016). 7. Department of Environmental Affairs, South Africa. Long Term Adapation Scenarios (LTAS). https:// www.environment.gov.za/longterm_adaptationscenarios (accessed 19 November 2016). 8. Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J. Global burden of hypertension: Analysis of worldwide data. Lancet 2005;365(9455):217-223. http://dx.doi.org/10.1016/S01406736(05)17741-1 9. Weimann E. Blue Flag beaches – bathers at risk for thalassogenic diseases. J Environ Ecol 2014;5(1):3845. http://dx.doi.org/10.5296/jee.v5i1.5773 10. Weimann E. Improved waste water treatment could create jobs and reduce health care costs. Cape Times, 9 January 2015. https://www.pressreader.com/south-africa/cape-times/20150109/281809987272483 (accessed 27 August 2016). 11. World Bank. Data. South Africa. 2016. http://data.wordbank.org/country/south-africa (accessed 17 June 2016). 12. Weimann E, Stuttaford MC. Consumers’ perspectives on National Health Insurance in South Africa: Using a mobile health approach. JMIR mHealth uHealth. 2014;2(4):1-14. http://dx.doi.org/10.2196/ mhealth.3533 13. Western Cape Provincial Government. Guideline on greening procurement of goods or services in the Western Cape Government. 2013. http://www.sa-tenders.co.za/content/green-procurement-policyguidelines-part-sustainable-public-procurement-delivery-state (accessed 24 June 2016). 14. Duvivier RJ, Watts NR, Rukavina, S, Kaduru C. Doctors talk climate change – students take action. Lancet 2011;377(9770):995. http://dx.doi.org/10.1016/S0140-6736(11)60384-X 15. Koelmans AA, Besseling E, Shim WJ. Marine anthropogenic litter. 2015. http://dx.doi.org/10.1007/9783-319-16510-3 16. Yang CZ, Yaniger SI, Jordan VC, Klein DJ, Bittner GD. Most plastic products release estrogenic chemicals: A potential health problem that can be solved. Environ Health Perspect 2011;119(7):989996. http://dx.doi.org/10.1289/ehp.1003220. 17. Kreisberg J, Zheng C. Managing unused pharmaceuticals in a hospice setting: A pilot study. Am J Hosp Palliat Care 2011;28(8):536-538. http://dx.doi.org/10.1177/1049909111405788

Accepted 3 October 2016.

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This open-access article is distributed under Creative Commons licence CC-BY-NC 4.0.

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HEALTHCARE DELIVERY

The National Health Insurance, the decentralised clinical training platform, and specialist outreach R I Caldwell,1 BSc (Med), MB ChB, FCP (SA), FRCP (Lond); C Aldous,1 PhD School of Clinical Medicine, Department of Internal Medicine, College of Health Sciences, University of KwaZulu-Natal, Pietermaritzburg, South Africa Corresponding author: R I Caldwell (ric@caldwells.co.za)

According to the Constitution of South Africa (SA), citizens living in remote areas are entitled to the same level of healthcare as those with access to tertiary hospitals. Specialist outreach has been shown to achieve this. When SA’s National Health Services Commission convened (1942 - 1944), Gluckman summarised: ‘Where the need is greatest the supply of hospitals is least.’ Primary healthcare (PHC) characterised the Kark’s Pholela Health Centre and was highly regarded. Although PHC underpins National Health Insurance (NHI) planning, both preventive and curative healthcare are needed. The KwaZulu-Natal (KZN) provincial Department of Health and the University of KZN College of Health Sciences’ 5-year plan for a decentralised clinical teaching platform (DCTP) is ambitious, requiring optimum co-operation between health department and university. Reservations can be addressed through sustained specialist outreach. Above all, the patient must be the chief beneficiary. The NHI and DCTP overlap with specialist outreach, but cannot do without it. S Afr Med J 2017;107(1):39-40. DOI:10.7196/SAMJ.2017.v107i1.12008

According to the Constitution of South Africa (SA), an impoverished citizen living in a rural area is entitled to the same level of specialist healthcare as an employed person living in a city with ready access to a tertiary hospital. A proven way to accomplish this is through multifaceted specialist outreach, as shown in numerous international studies, particularly those from Australia, Canada, and SA.[1-6] The 1971 inverse care law stated: ‘Availability of medical care is inversely related to the needs of the population.’[7] When the 1942 - 1944 SA National Health Services Commission convened, Gluckman summarised: ‘Where the need is greatest the supply of hospitals is least,’ referring to impoverished remote rural areas.[8] The Commission had the task of reporting on ‘the provision of an organised National Health Service, in conformity with the modern conception of “Health” for all sections of the people of the Union of South Africa’.[8,9] In 1940, the concept of primary healthcare (PHC) and community health centres (CHCs) was pioneered by Drs Sidney and Emily Kark at Pholela in rural Natal, and was highly regarded as ‘a continuous process by which primary care is provided to a defined community on the basis of its assessed health needs’.[10,11] Because of the emphasis on PHC, this philosophy is included in strategies for the SA National Health Insurance (NHI) and in the decentralised clinical teaching platform (DCTP)/community-based training in a PHC model (CBTPHCM). Such principles are well founded, but to achieve a comprehensive system they must go hand-in-hand with curative healthcare, with a specialist component.[12-14] Neglecting the financing of tertiary services soon after democracy led to near closure of Cape Town’s Red Cross War Memorial Children’s Hospital, for example.[15] Even at the time of the Commission, reservations were expressed about the adequacy of the Pholela/Kark health strategy, and major advances in medicine during the past 80 years are a sine qua non of modern healthcare.[16-18] The national health plan was never launched and consequently CHCs did not survive in SA.[16] Nonetheless, the minister of health, Dr Aaron Motsoaledi, is a proponent of Gluckman’s principles; therefore it is imperative to keep these in the forefront of any discussion on public health matters.

Discussion

In line with NHI philosophy, the KZN provincial Department of Health (DoH) and the University of KwaZulu-Natal (UKZN) College of Health Sciences have an ambitious CBTPHCM/DCTP 5-year plan: piecemeal social engineering in its most well-intentioned manner, perhaps?[19,20] The programme could achieve the following: embodying PHC principles; doubling the 1st-year MB ChB intake at UKZN in 2017 to 512 students; mechanisms for the retention of doctors in rural areas; training of under- and postgraduates away from the major centres; and registrars available to staff these sites. Reservations include provision of three specialists in each discipline for every site when it is problematic to fill posts at regional hospitals, as an unfulfilled consultant-registrar-undergraduate ratio (1:3:12) would be contrary to Health Professions Council of SA (HPCSA) regulations.[19] Although studies have suggested that doctors originating from rural areas are more likely to practise in such areas, this is not guaranteed.[21-23] Specialist outreach experience in KZN suggests a different situation, i.e. foreign doctors comprise a large proportion of district hospital staff.[3,4] Given current militant attitudes, would an undergraduate body not feel that they are being engineered into a situation contrary to the tendency towards globalisation? Apart from optimum co-operation between the DoH and UKZN, DCTP requires the contribution of specialist outreach alongside focused PHC development. Specialist outreach serves disadvantaged patients in remote areas.[1-6] Infrastructure in KZN includes a competent transport provider, i.e. the Red Cross Air Mercy Service – if their contract is renewed.[3-5] This programme already provides specialists from the major disciplines to district hospitals on a regular monthly basis, encompassing both a teaching and a clinical service. These consultants continue in their accustomed role as specialists in urban communities, and yet provide specialist outreach. The DCTP envisages a service to its patients, and under- and postgraduate training, dovetailing best with specialist outreach; indeed, it cannot do without it. Outreach consultants increase the

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specialist presence on site, improve service delivery to patients, establish liaison between peripheral and central hospitals, and provide under- and postgraduate teaching. This may obviate or postpone physical referral and transport, as appropriate treatment can be recommended and initiated at the base hospital, or it may facilitate rapid acceptance and transfer of patients when it is apparent that urgent specialist intervention is needed. For ‘in-between’ degrees of urgency, there may be an opportunity for patients to be assessed by a specialist during the regular monthly outreach visit. However, the only reference to peripheral specialist contribution in the NHI White Paper of early 2016 is in the form of ‘district specialists’.[24] These are limited to four disciplines: paediatrics, obstetrics, anaesthetics and family medicine, whose consultants travel to hospitals within a particular health district. Therefore, if excluded from formal policy in the NHI, long-established multifaceted specialist outreach programmes of proven ability to ‘deliver the goods’ might come to an end, denying the sustainability that is a prerequisite for the full benefit of such outreach. Above all, there has to be assurance that the patient is the chief beneficiary in the three-way process involving patient, health department and university. The sheer necessity is that the NHI must include specialist outreach. Consequently, both will be compatible with the DCTP, as the NHI is based on the principles of PHC and CHCs.

Conclusion

Specialist outreach is a proven strategy worldwide and has an indispensable role to play in both the DCTP and the NHI. These have much to be commended, but there are serious reservations that need to be researched and answered.[25] Preventive health is vital – but so is curative medicine. Certainly, as Prof. Dan Ncayiyana stated in 1994 in support of Karkian philosophy, ‘there is no need to rediscover the wheel’.[26] Equally, one must be sure not to throw the baby out with the bathwater.[3,4,27] 1. Gruen RL, Bailie RS. Specialist clinics in remote Australian aboriginal communities: Where rock art meets rocket science. J Health Serv Res Policy 2004;9(Suppl 2):61. http://dx.doi.org/10.1258/1355819042349844 2. Gruen RL, Weeramanthri TS, Knight SE, Bailie RS. Specialist outreach clinics in primary care and rural hospital settings. Cochrane Database Syst Rev 2004;(1):CD003798. http://dx.doi. org/10.1002/14651858.CD003798.pub2 3. Caldwell RI, Gaede BM, Aldous C. Description of an internal medicine outreach consultant appointment in western KwaZulu-Natal, South Africa, 2007 to mid-2014. S Afr Med J 2015;105(5):353356. http://dx.doi.org/10.7196/SAMJ.9173

4. Caldwell RI, Gaede BM, Aldous C. The value of internal medicine outreach in rural KwaZulu-Natal. S Afr Med J 2016:106(3):259-262. http://dx.doi.org/10.7196/SAMJ.2016.v106i3.10278 5. Gaede BM, McKerrow NH. Outreach programme: Consultant visits to rural hospitals. CME 2011;29(2):57-58. 6. Schoevers J, Jenkins L. Factors influencing specialist outreach and support services to rural populations in the Eden and Central Karoo districts of the Western Cape. Afr J Primary Health Care Fam Med 2015;7(1). http://dx.doi.org/10.4102/phcfm.v7i1.750 7. Tudor Hart J. The inverse care law. Lancet 1971;1(7696):405-412. 8. Marks S. Reflections on the 1944 National Health Services Commission: A response to Bill Freund and Anne Digby on the Gluckman Commission. S Afr Historical J 2014;66(1):169-187. http://dx.doi.org/ 10.1080/02582473.2014.890331 9. Gluckman H. The provision of an organized national health service for all sections of the people of the Union of South Africa, 1942 - 1944. Report of the National Health Services Commission. Pretoria: Government Printer, 1944. 10. Tollman S. The Pholela Health Centre – the origins of community-oriented primary health care (COPC). An appreciation of the work of Sidney and Emily Kark. S Afr Med J 1994;84(10):653-658. 11. Mullan F, Epstein L. Community-oriented primary care: New relevance in a changing world. Am J Public Health 2002;92(11):1748-1755. http://dx.doi.org/10.2105/AJPH.92.11.1748 12. Kautzkyi K, Tollman SM. A Perspective on Primary Health Care in South Africa. South African Health Review. Durban: Health Systems Trust, 2008. 13. Schaayi N, Sanders D. International Perspective on Primary Health Care Over the Past 30 Years. Perspective on Primary Health Care in South Africa. Durban: Health Systems Trust, 2008. 14. Coovadia H, Jewkes R, Barron P, Sanders D, McIntyre D. Health in South Africa 1. The health and health system of South Africa: Historical roots of current public health challenges. Lancet 2009;374(9692):817-834. http://dx.doi.org/10.1016/S0140-6736(09)60951-X 15. Baleta A. Children’s hospital has to shut doors. http://www.iol.co.za/news/south-africa/childrenshospital-has-to-shut-doors-18619 (accessed 14 July 2016). 16. Digby A. Evidence, encounters and effects of South Africa’s reforming Gluckman National Health Services Commission, 1942 - 1944. S Afr Historical J 2012;64(2):187-205. http://dx.doi.org/10.1080/ 02582473.2011.651623 17. Freund B. The South African developmental state and the first attempt to create a national health system: Another look at the Gluckman Commission of 1942 - 1944. S Afr Historical J 2012;64(2):170186. http://dx.doi.org/10.1080/02582473.2011.640708 18. Digby A. Debating the Gluckman Commission: A rejoinder. S Afr Historical J 2014;66(3):588-592. http://dx.doi.org/10.1080/02582473.2014.932951 19. KwaZulu-Natal Department of Health and University of KwaZulu-Natal. Community based training in a primary health care model. Durban: KZN DoH, 2013. 20. Popper K. The Open Society and its Enemies. Princeton, NJ: Princeton University Press, 1971. 21. Wilson NW, Couper ID, de Vries E, Reid S, Fish T, Marais BJ. A critical review of interventions to redress the inequitable distribution of healthcare professionals to rural and remote areas. Rural Remote Health 2009;9(2):1060-1081. 22. Muzigaba M, Naidoo K, Ross A, Nadesan-Reddy N, Pillay S. Predictors of site choice and eventual learning experiences in a decentralised training programme designed to prepare medical students for careers in underserved areas in South Africa. Afr J Health Professions Educ 2016;8(1 Suppl 1):92-98. http://dx.doi.org/10.7196/AJHPE.2016.v8i1.741 23. Grobler L, Marais BJ, Mabunda SA, Marindi PN, Reuter H, Volmink J. Interventions for increasing the proportion of health professionals practising in rural and other underserved areas. Cochrane Database Syst Rev 2009;(1):CD005314. http://dx.doi.org/10.1002/14651858.CD005314.pub2 24. National Department of Health. National Health Insurance for South Africa. Towards Universal Health Coverage. Version 40. Pretoria: NDoH, 2015. 25. Tollman SM, Pick WM. Roots, shoots, but too little fruit: Assessing the contribution of COPC in South Africa. Am J Public Health 2002;92(11):1726. 26. Ncayiyana D. The Pholela PHC model – no need to rediscover the wheel. S Afr Med J 1994:84(10):91. 27. Phillips H. The return of the Pholela experiment. Medical history and primary health care in post-apartheid South Africa. Am J Publ Health 2014;104(10):1873. http://dx.doi.org/10.2105/ AJPH.2014.302136

Accepted 19 September 2016.

January 2017, Print edition

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IN PRACTICE

CASE REPORT

The intraocular CD4/CD8 ratio in a black South African patient with Behçet’s disease uveitis A Makgotloe, MB BCh, FC Ophth, MMed Division of Ophthalmology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa Corresponding author: A Makgotloe (makgotloe@gmail.com)

A 33-year-old black South African male patient was referred to our uveitis service with a 5-year history of panuveitis refractory to treatment. He had an associated history of recurrent mouth and genital ulcers, predating the uveitis history by about 2 years. The measurement of his intraocular CD4/CD8 ratio helped make a diagnosis of Behçet’s disease uveitis. S Afr J Med 2017;107(1):41-42. DOI:10.7196/SAMJ.2017.v107i1.12039

Behçet’s disease (BD) is a systemic inflammatory disease of unknown origin.[1] Its diagnosis is based on the recognition of its clinical features as defined by the international criteria for Behçet’s disease.[2] These include recurrent oral ulcers with one of the following: penile ulcers, uveitis, skin lesions or positive pathergy test. BD is uncommon in sub-Saharan Africa (SSA), making its diagnosis delayed in most cases.[3] I present a case of bilateral panuveitis caused by BD with a delayed diagnosis of about 5 years. Intraocular CD4/CD8 ratio was used to help make the diagnosis of Behçet’s uveitis. Measurement of the intraocular CD4/CD8 ratio could aid in the diagnosis of BD in countries where BD is less endemic, such as SSA countries.

Case report

A 33-year-old black South African (SA) male patient was referred to our uveitis service with a 5-year history of panuveitis refractory to corticosteroids (oral/regional) and methotrexate 20 mg/week. He had an associated history of recurrent mouth and genital ulcers, predating the uveitis history by about 2 years. His visual acuity was light perception without projection on the right eye and no light perception (NLP) on the left eye. He had pigmented keratic precipitates and hypopyon in both eyes. He had bilateral posterior synechiae and no associated iris atrophy. He was bilaterally pseudophakic and intraocular pressure was 10 mmHg and 8 mmHg on the right and left eye, respectively. He had severe vitritis and extensive retinal vasculitis bilaterally, with associated chronic retinal detachment on the left side. Systemic examination revealed oral and penile ulcers. He had multiple papulomacular skin lesions over his entire body. The white cell count (WCC) was normal and erythrocyte sedimentation rate (ESR) elevated at 60 mm/hour. Serum Treponema pallidum particle agglutination assay (TPHA) and rapid plasma reagin (RPR) were non-reactive and toxoplasma serology was negative. Serum angiotensin converting enzyme (ACE) was 30 μL (normal) and the chest X-ray was normal. Serum HIV and human leukocyte antigen (HLA) B51 were negative. The aqueous tap result for herpes simplex polymerase chain reaction (PCR) was negative. T-lymphocyte profiling revealed a CD8 percentage of 20.6% in peripheral blood and 45.1% in the aqueous humor. The CD4/CD8 ratio was 2.13 in the peripheral blood and 1.19 in the aqueous humor. Based on the Behçet diagnostic criteria of the international study group, a diagnosis of Behçet’s uveitis was made.

The patient was started on oral prednisone 1 mg/kg per day, oral cyclosporine 100 mg twice a day and oral azathioprine 75 mg at night. At 6 months follow-up his right eye had counting fingers vision (navigational) while the right eye remained NLP. Uveitis was not active in either eye, and renal and liver functions and blood pressure were all normal.

Discussion

The diagnosis of BD depends on the recognition of multiple organ involvement, which often appears at different times in the course of the disease. There was initial hesitation in making the diagnosis of BD in our patient, even though he had typical mouth and penile ulcers together with skin lesions. This is largely because it is very uncommon in SSA countries. In SA, for example, only one case series has been reported on BD in black SA patients and none of the patients reported in this series had uveitis in their clinical course.[4] The rarity of BD in SA black patients made it an unlikely diagnosis in our case, with conditions such as syphilis and herpes simplex infection more likely possibilities. Syphilis serology, aqueous PCR testing for herpes simplex and HIV testing were negative. The low aqueous CD4/CD8 ratio relative to peripheral blood in our patient increased our index of suspicion and helped us make the diagnosis of BD. A low CD4/CD8 ratio has been reported in patients with BD uveitis before.[5] This low aqueous CD4/CD8 ratio relative to peripheral blood is due to elevated intraocular CD8 cells. The pathogenesis of the elevated intraocular CD8 cells in Behçet’s uveitis is unclear. Intraocular CD4/CD8 ratio has been reported to be useful in the diagnosis of other uveitis entities such as sarcoidosis,[6] in which the uveitis is mediated by CD4 cells, resulting in significantly elevated intraocular CD4 cells compared with peripheral blood. This gives rise to an aqueous CD4/CD8 that is much higher than in peripheral blood. The incidence of HLA B51 is reportedly high in patients with BD and yet in SSA patients, this is often negative on testing.[7] This, together with the rarity of BD in SSA, often results in a decreased index of suspicion of BD, resulting in its delayed diagnosis. This may, in all likelihood, result in irreversible loss of vision by the time the diagnosis is made. Measurement of the intraocular CD4/CD8 ratio may aid in making an early diagnosis of Behçet’s uveitis, particularly in countries where BD is uncommon.

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IN PRACTICE

Acknowledgements. Dr Denise Lawrie from the Flow Cytometry Unit is acknowledged for assisting with flow cytometry. 1. Nussenblatt RB. Uveitis in Behcet’s disease. Int Rev Immunol 1997;14(1):67-79. http://dx.doi. org/10.3109/08830189709116845 2. International Team for the Revision of the International Criteria for Behçet’s Disease. Revision of the International Criteria for Behçet’s disease (ICBD). Clin Exp Rheumatol 2006;24(Suppl 42):S14-S15. 3. Yurdakul S, Yazici Y. Epidemiology of Behçet’s syndrome and regional differences in disease expression. In: Yazici Y, Yazici H, eds. Behçet’s Syndrome. New York: Springer, 2010:35-53. 4. Jacyk WK. Behçet’s disease in South African blacks: Report of five cases. J Am Acad Dermatol 1994;30(5):869-873.

5. Yu HG, Lee DS, Seo JM, et al. The number of CD8+ T cells and NKT cells increases in the aqueous humor of patients with Behçet’s uveitis. Clin Exp Immunol 2004;137(2):437-443. http://dx.doi. org/10.1111/j.1365-2249.2004.02536.x 6. Kojima K, Maruyama K, Inaba T, et al. The CD4/CD8 ratio in vitreous fluid is of high diagnostic value in sarcoidosis. Ophthalmol 2012;119(11):2386-2392. http://dx.doi.org/10.1016/j. ophtha.2012.05.033 7. Liozon E, Roussin C, Puechal X, et al. Behçet’s disease in East African patients may not be unusual and is an HLA-B51 negative condition: A case series from Mayotte (Comoros). Joint Bone Spine 2011;78(2):166-170. http://dx.doi.org/10.1016/j.jbspin.2010.05.007

Accepted 29 September 2016.

CASE REPORT

This open-access article is distributed under CC-BY-NC 4.0.

Pulmonary nocardiosis caused by Nocardia otitidiscaviarum in an adult asthmatic female patient: The presence of acid-fast branching filaments is always significant

A Mahgoub,1 DMLT, BSc; S A Gumaa,2 MD, PhD; M R P Joseph,3 BSc, MSc, PhD; M S Saleh,4 BSc, MSc; A H A Elsheikh,2 BSc, MSc; A I Elkhalifa,2 BSc, MSc; E Elhaj,5 MD, MRCP; R R M Salih,6 BSc, PhD; M E Hamid,3 BVSc, MSc, PhD Department of Preventive Medicine, Faculty of Veterinary Medicine, University of Khartoum, Sudan Department of Microbiology, Royale Care International Hospital, Khartoum, Sudan 3 Department of Microbiology, College of Medicine, King Khalid University, Abha, Kingdom of Saudi Arabia 4 Department of Microbiology, Faculty of Medical Laboratory Science, Omdurman Islamic University, Omdurman, Sudan 5 Department of Medicine, Royale Care International Hospital, Khartoum, Sudan 6 Department of Clinical Medicine, Faculty of Veterinary Medicine, University of Khartoum, Sudan 1 2

Corresponding author: M E Hamid (mehamid2@yahoo.com)

We report a case of pulmonary nocardiosis in a 41-year-old asthma patient. Chest radiographs showed bilateral air space and consolidations. Acid-fast branching filaments were demonstrated in sputum, and the grown organism was identified phenotypically and confirmed using 16S rDNA sequencing (accession no. KX500116). The patient received a combination of medical treatments, but developed complications, which were managed over the next 3 months, after which she was discharged. Pulmonary nocardiosis should be considered in patients undergoing steroid therapy or when a chronic infection does not respond to first-line treatment. S Afr Med J 2017;107(1):43-45. DOI:10.7196/SAMJ.2017.v107i1.12006

Nocardiae (genus Nocardia) are aerobic, Gram-positive, mycolic acidcontaining actinomycetes and characteristically form acid-alcohol-fast branching filaments. They are saprophytes, but have been known to cause invasive and disseminated infections in humans and animals for >100 years.[1,2] Infections caused by N. otitidiscaviarum are rare (3%) compared with those caused by other Nocardia spp. Infection in humans was first reported in the mid-1960s and the first systemic infection in humans was reported in 1974,[3,4] when Nocardia sp. was diagnosed in the lungs of a 76-year-old man who had asthma since the age of 6 years. His asthma problem worsened owing to pulmonary nocardiosis or prolonged steroid therapy.[5] The diagnosis of pulmonary nocardiosis based on clinical and radiological features is problematic, as these resemble other lung pathogens, including Mycobacterium tuberculosis. There is a dearth of knowledge in the epidemiological, clinical presentations, outcomes and laboratory information of nocardiosis, which challenge its importance as a threatening health risk.[2,6] This report aimed to identify a unique isolate that caused a severe illness in a female asthmatic patient.

Case report

We report the case of a 41-year-old woman with severe pneumonia. She had an 18-month history of bronchial asthma and underwent a cholecystectomy 5 years previously. On admission, the patient was suffering from bronchial asthma and severe pneumonia, with a productive cough (yellow sputum) of >3 months’ duration. She complained of high-grade fever and appeared ill, with dyspnoea and wheezing. Crepitations could be heard over the right lower zone of the chest. An electrocardiogram (ECG) indicated sinus tachycardia, abnormal rhythm and possible atrial enlargement. A computed tomography (CT) scan of the chest showed bilateral asymmetrical patchy air space disease, more evident on the right side. There was consolidation on the middle lobe and bilateral pleural effusion, but no cavities. These signs are suggestive of atypical pneumonia. Chest radiographs of the patient indicated consolidation on the right lower lobe, left lobular infiltration and right pleural effusion (Fig. 1).

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IN PRACTICE

Fig. 1. Chest radiograph of the 41-year-old patient, showing right lower-lobe consolidation and left lobular infiltration. There is also right pleural effusion. (A) Anteroposterior view. (B) Posteroanterior view.

Fig. 2. A Ziehl-Neelsen-stained smear, which was obtained from sputum of the 41-year-old female patient with pulmonary infection. The smear shows partially acid-fast branching filaments, which fragmented into short chains; notice the many inflammatory and granulomatous cells.

Fig. 3. Growth of isolate SD16 on blood agar after 7 days under aerobic conditions. (A) The growth indicates actinomycete-type organisms with chalky grey-white, rough, wrinkled colonies, which are embedded into agar. (B) The antimicrobial assay shows clear sensitivity of the isolate to amikacin. The dark zone of inhibition is discernable around the amikacin-impregnated disk.

Pleural aspirates were collected using ultra sound guidance. The pleural fluid appeared bloody, with a white blood cell count of 10 000/µL, comprising 80% neutrophils and 20% lymphocytes. The protein content was 3.09 g/dL and the

glucose content 168 mg/dL. A ZiehlNeelsen-stained smear was made from the aspirate and from a sputum sample. The smear showed acid-fast branching filaments (Fig. 2) suggestive of Nocardia infection.

January 2017, Print edition

On admission the patient was administered cefuroxime and clarithromycin. The following day, after we received the laboratory report, the patient was administered sulfamethoxazole 3 tablets (160 mg) 3 times daily, and amikacin 500 mg and imipenem 500 mg intravenously. Ten days later the patient developed pancytopenia. The sulfamethoxazole and amikacin regimen was discontinued. The patient was administered ceftriaxone 2 g intravenously twice daily plus imipenem 500 mg intravenously and was given a blood transfusion. On receiving the results of the laboratory antimicrobial assay, we started the patient on ceftriaxone 2 g intravenously twice daily, amikacin 500 mg intravenously twice daily plus ciprofloxacin 500 mg orally twice daily. Three days later she was progressing well, and no crepitations were detected. The patient recovered, but had a dry cough and crepitations for a while. Growth of the causative agent was obtained from both sputum and pleural aspirate specimens on blood agar (BBL Microbiology Inc., USA) after 3 days under aerobic conditions at 30°C. Subsequently, the organism was sub-cultured for identification on other bacteriological media, including glucose malt extract, yeast extract agar, tryptic soya agar and Löwenstein-Jensen media. The morphological properties of the grown culture indicated an actinomycete-type organism with a chalky grey-white, rough, wrinkled appearance deeply embedded into agar (Fig. 3). Smears made from the culture revealed Gram-positive and partially acidfast branching filamentous organisms when stained with the modified Ziehl-Neelsen method. The filaments appeared as short chains of rods and coccobacillary elements, which are characteristic for organisms of the genus Nocardia.[1] The organism displayed in vitro sensitivity to amikacin, cefditoren, ciprofloxacin, meropenem and streptomycin, but resistance to azithromycin, erythromycin, ceftazidime, penicillin, rifampin, and sulfamethoxazole/trimethoprim (Fig. 3). Six days later Acinetobacter spp. were isolated from the sputum, which were found to be sensitive to only colistin, a clear multidrug-resistant nosocomial complication. The patient was then administered colistin intravenously and nebulised. She improved, sputum culture was negative, colistin was discontinued and she was discharged. 16S rDNA nucleotide sequences data (1473 bp; Genbank (National Institutes of Health, USA) accession no. KX500116) were first analysed using the basic local alignment search tool (BLAST, USA) system[7] to determine a swift phylogenetic position. After designation of the isolate with Nocar-

IN PRACTICE

dia spp. in the BLAST system, the sequences were analysed using Molecular Evolutionary Genetics Analysis version 6.0 (MEGA6) software (Center for Evolutionary Medicine and Informatics, USA)[8] and compared with all known sequences of Nocardia spp. found in the GenBank database.[9] The isolate SD16 was identical to that of N. otitidiscaviarum in the 16S rDNA gene phylogenetic tree (Fig. 4). Our patient had signed an informed consent form, indicating her agreement to participate in the study.

fer from chronic lung diseases in African countries.[10] Previously, we noticed that Nocardia spp. cause pulmonary infections in both immunocompetent and immunocompromised patients.[11] Pulmonary nocardiosis is a rare opportunistic infection that predominantly affects immunocompromised patients. A high clinical suspicion is vital for an early diagnosis and appropriate treatment in such patients, who present with chest involvement or signs of chronic pneumonia.[12] N. otitidiscaviarum is commonly resistant to beta-lactams, including most broadspectrum cephalosporins, amoxicillin-clavulanic acid, and imipenem, but are usually susceptible to amikacin, fluoroquinolones,

Discussion

Pulmonary nocardiosis is diagnosed in a considerable number of patients who suf-

Nocardia pseudovaccinii DSM 43406 AF430046 Nocardia anaemiae IFM 0323 AB162801 Nocardia caishijiensis F829 AF459443 Nocardia asteroides DSM 43757 AF430019 Nocardia brasiliensis DSM 43758 AF430038

and sulfonamides.[6,9] The isolate showed in vitro antibiotic susceptibilities similar to those reported previously.[6] Our patient was treated empirically with trimethoprimsulfamethoxazole, but it was discontinued on receiving the laboratory report. Complications and difficulties with regard to treatment seem similar to those in a previously reported pulmonary nocardiosis patient with asthma,[5] who was treated with a series of antimicrobials, including sulfamethoxazole and trimethoprim, followed by imipenem/cilastatin, amikacin and minocycline.[5] Acknowledgements. We are grateful to all staff of the microbiology department at Royal Care International Hospital, Khartoum, Sudan, notably to Ms M K Sivaprakasam, Mr A A Hassan and Mr M Azhari.

Nocardia farcinica ATCC 3318 Nocardia vinacea MK703-102F1 AB024312 Nocardia jiangxiensis 43401 AY639902 Nocardia miyunensis 117 AY639901 Nocardia vermiculata IFM 0391 AB126873 Nocardia africana DSM 44491 AF430054 Nocardia vaccinii DSM 43285 AF430045 Nocardia thraciensis A2019 HQ157184 Nocardia terpenica IFM 0706 AB201298 Nocardia endophytica KLBMP 1256 HM153801 Nocardia callitridis CAP 290 FJ805428 Nocardia nova JCM 6044 AF430028 Nocardia crassostrease JCM 10500 AF430049 Nocardia sp. SD16 (forward) Nocardia otitidiscaviarum DSM 43242 AF430067 Nocardia sp. SD16 (reverse) Nocardia uniformis DSM 43136 AF430044 Nocardia concava IFM 0354 AB126880 Nocardia seriolae DSM 44129 AF430039 Nocardia yamanashiensis IFM 0265 AB092561 Nocardia inohanensis IFM 0092 AB092560 Nocardia niigatensis DSM 44670 DQ659910 Nocardia acidivorans GW4-1778 AM402972 Nocardia jejuensis N3-2 AY964666 Nocardia coubleae OFN N11 DQ235688 Nocardia ignorata IMMIB R-1434 DSM 44496 NRRL B-24141 AJ303008 Nocardia fluminea S1 AF277204 Nocardia salmonicida DSM 40472 AF430050 Nocardia cummidelens DSM 44490 AF430050 Nocardia soli DSM 44488 AF430051 0.005

Fig. 4. A phylogenetic tree showing the relationship of Nocardia sp. strain SD16 (reverse and forward sequences) with the majority of related Nocardia spp. (bold bar). The tree was determined using the NeighborJoining method. All positions containing gaps and missing data were eliminated. Evolutionary analysis was performed using MEGA6 software.[8] The scale bar indicates 0.005 substitution per nucleotide position.

January 2017, Print edition

1. Goodfellow M, Maldonado LA. Genus Nocardia trevisan 1889AL. In: Goodfellow M, Kampfer P, Busse HJ, et al., eds. Bergeyâ&#x20AC;&#x2122;s Manual of Systematic Bacteriology, vol. 5. 2nd ed. New York: Springer, 2012:376-419. http://dx.doi.org/10.1007/978-0-38768233-4 2. Kandi V. Human Nocardia infections: A review of pulmonary nocardiosis. Cureus 2015;7(8):e304. http://dx.doi.org/10.7759/ cureus.304 3. Arroyo JC, Nichols S, Carroll GF. Disseminated Nocardia caviae infection. Am J Med 1977;62(3):409-412. 4. Causey WA, Arnell P, Brinker J. Systemic Nocardia caviae infection. Chest 1974;65(3):360-362. 5. Bandoh C, Amano M, Suzuki M, Aoki S, Matsuoka R. A case of pulmonary nocardiosis during steroid therapy for asthma. Nihon Kokyuki Gakkai Zasshi 2008;46(12):1024-1028. 6. Amin A, Mahmood SF, Anis M, et al. Pulmonary nocardiosis: A comparative analysis of Nocardia asteroides and non-asteroides species. Trop Doct 2012;42(2):94-96. http://dx.doi.org/10.1258/ td.2011.110311 7. National Center for Biotechnology Information. Basic local alignment search tool. 2016. http://blast.ncbi.nlm.nih.gov/Blast.cgi (accessed November 2016). 8. Tamura K, Stecher G, Peterson D, Filipski A, Kumar S. MEGA6: Molecular Evolutionary Genetics Analysis version 6.0. Mol Biol Evol 2013;30(12):2725-2729. http://dx.doi.org/10.1093/molbev/ mst197 9. National Center for Biotechnology Information. Nucleotide. 2016. https://www.ncbi.nlm.nih.gov/nucleotide/ (accessed November 2016). 10. Hamid ME, Maldonado L, Sharaf Eldin GS, Mohamed MF, Saeed NS, Goodfellow M. Nocardia africana sp. nov., a new pathogen isolated from patients with pulmonary infections. J Clin Microbiol 2001;39(2):625-630. http://dx.doi.org/10.1128/JCM.39.2.625630.2001 11. Alnaum HM, Elhassan MM, Mustafa FY, Hamid ME. Prevalence of Nocardia species among HIV-positive patients with suspected tuberculosis. Trop Doct 2011;41(4):224-226. http://dx.doi. org/10.1258/td.2011.110107 12. Chen J, Zhou H, Xu P, Zhang P, Ma S, Zhou J. Clinical and radiographic characteristics of pulmonary nocardiosis: Clues to earlier diagnosis. PLoS ONE 2014;9(3):e90724. http://dx.doi. org/10.1097/MD.0000000000001561

Accepted 19 September 2016.

These open-access articles are distributed under Creative Commons licence CC-BY-NC 4.0.

RESEARCH

Classifying snakebite in South Africa: Validating a scoring system D Wood,1 MB BCh, FCEM, MPhil; B Sartorius,2 PhD; R Hift,1 MB BCh, FRCP, PhD 1 2

School of Clinical Medicine, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa School of Public Health, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa

Corresponding author: D Wood (darrylrwood@yahoo.co.uk) Objective. To develop and validate a scoring system for managing snakebites in South Africa (SA). Methods. We studied all snakebite admissions to a regional hospital in KwaZulu-Natal, SA. The primary outcome was an active treatment intervention (ATI) defined as antivenom treatment or any surgical procedure. The development cohort consisted of 879 patients with snakebite who presented to the Ngwelezane Hospital Emergency Department from December 2008 to December 2013. Factors predictive of ATI and the optimal cut-off score for predicting an ATI were identified. These factors were then used to develop a standard scoring system. The score was then tested prospectively for accuracy in a new validation cohort consisting of 100 patients admitted for snakebite to our unit from 1 December 2014 to 31 March 2015. Accuracy of the score was determined. Results. Of 879 snakebite admissions, 146 in the development cohort and 40 of 100 in the development validation cohort reached the primary endpoint of an ATI. Six risk predictors for ATI were identified from the development cohort: age <14 years (odds ratio (OR) 2.13), delay to admission >7 hours (OR 4.63), white cell count >10 × 109/L (OR 3.15), platelets <92 × 109/L (OR 2.35), haemoglobin <7.1 g/dL (OR 5.68), international normalised ratio >1.2 (OR 2.25). Each risk predictor was assigned a score of 1; receiver operating characteristic curve analysis returned a value of >4 out of 6 as the optimal cut-off for prediction of an ATI (area under the curve 0.804; 95% confidence interval 0.758 - 0.84). Testing of the score on the validation cohort produced a specificity of 96.6% and a sensitivity of 22.5%. The positive predictive value and negative predictive value were 81.8% and 65.2%, respectively. Conclusion. Our results show that the identified score is a useful adjunct to clinical assessment in managing snakebite. Its value is greatest when used in those patients who fall in the mild to moderate clinical category. Until our severity score has been validated (or modified) for use across SA, we propose to name it the Zululand Severity Score; a true SA Severity Score may follow. S Afr Med J 2017;107(1):46-51. DOI:10.7196/SAMJ.2017.v107i1.11361

Full article available online at http://dx.doi.org/10.7196/SAMJ.2017.v107i1.11361

Immunisation coverage in the rural Eastern Cape – are we getting the basics of primary care right? Results from a longitudinal prospective cohort study K le Roux,1 MB ChB, MMed Sci; O Akin-Olugbade,2 BA; L S Katzen,3 BSc, MSc; C Laurenzi,4 BA, MSc; N Mercer,5 MS; M Tomlinson,6 PhD; M J Rotheram-Borus,7 PhD Visiting research scholar, Center for Health and Wellbeing, Woodrow Wilson School, Princeton University, New Jersey, USA (at time of study); Primary Healthcare Directorate, University of Cape Town, South Africa; Zithulele Hospital, Eastern Cape, South Africa 2 Undergraduate student at Princeton University, New Jersey, USA (at time of study) 3 Philani Centres Nutrition Trust, Khayelitsha, Cape Town, South Africa 4 Prevention Research for Community, Family and Child Health, Stellenbosch University, Cape Town, South Africa 5 Center for HIV Identification, Prevention, and Treatment Services (CHIPTS), University of California, Los Angeles, USA (at time of study) 6 Department of Psychology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa 7 Department of Psychiatry, Semel Institute, University of California, Los Angeles, USA 1

Corresponding author: K le Roux (karlleroux@gmail.com) Background. Immunisations are one of the most cost-effective public health interventions available and South Africa (SA) has implemented a comprehensive immunisation schedule. However, there is disagreement about the level of immunisation coverage in the country and few studies document the immunisation coverage in rural areas.

January 2017, Print edition

RESEARCH

Objective. To examine the successful and timely delivery of immunisations to children during the first 2 years of life in a deeply rural part of the Eastern Cape Province of SA. Methods. From January to April 2013, a cohort of sequential births (N=470) in the area surrounding Zithulele Hospital in the OR Tambo District of the Eastern Cape was recruited and followed up at home at 3, 6, 9, 12 and 24 months post birth, up to May 2015. Immunisation coverage was determined using Road-to-Health cards. Results. The percentages of children with all immunisations up to date at the time of interview were: 48.6% at 3 months, 73.3% at 6 months, 83.9% at 9 months, 73.3% at 12 months and 73.2% at 24 months. Incomplete immunisations were attributed to stock-outs (56%), lack of awareness of the immunisation schedule or of missed immunisations by the mother (16%) and lack of clinic attendance by the mother (19%). Of the mothers who had visited the clinic for baby immunisations, 49.8% had to make multiple visits because of stock-outs. Measles coverage (of at least one dose) was 85.2% at 1 year and 96.3% by 2 years, but 20.6% of babies had not received a second measles dose (due at 18 months) by 2 years. Immunisations were often given late, particularly the 14-week immunisations. Conclusions. Immunisation rates in the rural Eastern Cape are well below government targets and indicate inadequate provision of basic primary care. Stock-outs of basic childhood immunisations are common and are, according to mothers, the main reason for their children’s immunisations not being up to date. There is still much work to be done to ensure that the basics of disease prevention are being delivered at rural clinics in the Eastern Cape, despite attempts to re-engineer primary healthcare in SA. S Afr Med J 2017;107(1):52-55. DOI:10.7196/SAMJ.2017.v107i1.11242

Full article available online at http://dx.doi.org/10.7196/SAMJ.2017.v107i1.11242

Surveillance of healthcare-associated infection in hospitalised South African children: Which method performs best? A Dramowski,1 MB ChB, DCH, FCPaed (SA), Cert Paed ID; M F Cotton,1 MB ChB, DCH, FCPaed (SA), PhD; A Whitelaw,2 MB ChB, MSc, FCPath (SA) (Micro) Department of Paediatrics and Child Health, Division of Paediatric Infectious Diseases, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa 2 Division of Medical Microbiology, Department of Pathology, Faculty of Medicine and Health Sciences, Stellenbosch University and National Health Laboratory Service, Tygerberg Hospital, Cape Town, South Africa 1

Corresponding author: A Dramowski (dramowski@sun.ac.za) Background. In 2012, the South African (SA) National Department of Health mandated surveillance of healthcare-associated infection (HAI), but made no recommendations of appropriate surveillance methods. Methods. Prospective clinical HAI surveillance (the reference method) was conducted at Tygerberg Children’s Hospital, Cape Town, from 1 May to 31 October 2015. Performance of three surveillance methods (point prevalence surveys (PPSs), laboratory surveillance and tracking of antimicrobial prescriptions) was compared with the reference method using surveillance evaluation guidelines. Factors associated with failure to detect HAI were identified by logistic regression analysis. Results. The reference method detected 417 HAIs among 1 347 paediatric hospitalisations (HAI incidence of 31/1000 patient days; 95% confidence interval (CI) 28.2 - 34.2). Surveillance methods had variable sensitivity (S) and positive predictive value (PPV): PPS S = 24.9% (95% CI 21 - 29.3), PPV = 100%; laboratory surveillance S = 48.4% (95% CI 43.7 - 53.2), PPV = 55.2% (95% CI 50.1 - 60.2); and antimicrobial prescriptions S = 66.4% (95% CI 61.8 - 70.8%), PPV = 88.5% (95% CI 84.5 - 91.6). Combined laboratory-antimicrobial surveillance achieved superior HAI detection (S = 84.7% (95% CI 80.9 - 87.8%), PPV = 97% (95% CI 94.6 - 98.4%)). Factors associated with failure to detect HAI included patient transfer (odds ratio (OR) 2.0), single HAI event (OR 2.8), age category 1 - 5 years (OR 2.1) and hospitalisation in a general ward (OR 2.3). Conclusions. Repeated PPSs, laboratory surveillance and/or antimicrobial prescription tracking are feasible HAI surveillance methods for low-resource settings. Combined laboratory-antimicrobial surveillance achieved the best sensitivity and PPV. SA paediatric healthcare facilities should individualise HAI surveillance, selecting a method suited to available resources and practice context. S Afr Med J 2017;107(1):56-63. DOI:10.7196/SAMJ.2017.v107i1.11431

Full article available online at http://dx.doi.org/10.7196/SAMJ.2017.v107i1.11431

January 2017, Print edition

RESEARCH

Retinopathy of prematurity in a cohort of neonates at Groote Schuur Hospital, Cape Town, South Africa Q Keraan,1 MB ChB, FC Paed (SA), Cert Neonatology (SA), MPhil (Neonatol); C Tinley,2 MB ChB, FRC Ophth; A Horn,3 MB ChB, DCH (SA), FC Paed (SA), Cert Neonatology (SA), PhD; T Pollock,2 MB ChB, FCS Ophth (SA); J Steffen,4 MB ChB, FC Ophth (SA), MMed Ophth; Y Joolay,3 MB ChB, FC Paed (SA), Cert Neonatology (SA), MPhil Neonatology Private practice, Cape Town, South Africa (previously affiliated to Neonatal Medicine, Groote Schuur Hospital, Cape Town; and Department of Paediatrics, Faculty of Health Sciences, University of Cape Town, South Africa) 2 Department of Ophthalmology, Red Cross War Memorial Children’s Hospital, Cape Town, and Faculty of Health Sciences, University of Cape Town, South Africa 3 Neonatal Medicine, Groote Schuur Hospital, Cape Town; and Department of Paediatrics, Faculty of Health Sciences, University of Cape Town, South Africa 4 Department of Ophthalmology, Groote Schuur Hospital, Cape Town, and Faculty of Health Sciences, University of Cape Town, South Africa 1

Corresponding author: Y Joolay (yaseen.joolay@uct.ac.za) Background. Severe retinopathy of prematurity (ROP) can cause blindness. Before 2016, resource limitations precluded routine screening for ROP at Groote Schuur Hospital (GSH), Cape Town, South Africa. Previous pilot studies at GSH found no patients with ROP requiring treatment; however, improved preterm infant survival may affect the prevalence. Objectives. To determine the prevalence and severity of ROP, describe potential risk factors, and assess the feasibility of ROP screening. Methods. Infants with a birth weight (BW) of <1 251 g or a gestational age (GA) of ≤31 weeks were screened from November 2012 to May 2013. Results. Three hundred and thirteen ROP examinations were performed in 135 of 191 eligible infants. The mean GA and BW were 30.1 weeks (standard deviation (SD) 1.9) and 1 056 g (SD 172), respectively. ROP was diagnosed in 40 infants (29.6%); 8 (5.9%) had severe ROP and 2 (1.5%) received laser treatment. Infants with ROP had a lower mean GA (29.2 weeks (SD 1.6) v. 30.5 weeks (SD 1.9)) (p<0.002) and a lower mean BW (988 g (SD 181) v. 1 085 g (SD 160)) (p=0.001) than those without ROP. Infants weighing <1 000 g had a 2.5 times higher risk than those with a BW of ≥1 000 g of having ROP (95% confidence interval 1.05 - 5.90; p=0.03). Blood transfusions (p<0.002) and late-onset sepsis (p=0.024) were strongly associated with ROP. Screening was completed in 91.1% (123/135) of the infants. Conclusions. The prevalence and severity of ROP have increased at GSH. The strong association between ROP, BW and GA suggests that infants with lower BWs and GAs should be prioritised for screening in our resource-limited setting. S Afr Med J 2017;107(1):64-69. DOI:10.7196/SAMJ.2017.v107i1.11226

Full article available online at http://dx.doi.org/10.7196/SAMJ.2017.v107i1.11226

Characteristics and outcome of long-stay patients in a paediatric intensive care unit in Cape Town, South Africa T L Nupen,1 FCPaed (SA); A C Argent,1,2 MD, FCPaed (SA); B M Morrow,1 PhD 1 2

Department of Paediatrics and Child Health, Faculty of Health Sciences, University of Cape Town, South Africa Paediatric Intensive Care Unit, Red Cross War Memorial Children’s Hospital, Cape Town, South Africa

Corresponding author: B M Morrow (brenda.morrow@uct.ac.za) Background. Paediatric intensive care is a costly, specialised and limited resource in low- and middle-income countries. The implications of extended paediatric intensive care unit (PICU) stay in South Africa (SA) are not known. Objectives. To describe the characteristics, outcomes and resource consumption of long-stay patients (LSPs) and to identify predictive factors for long PICU stay. Methods. A retrospective review of routinely collected data on all children admitted to an SA PICU over one calendar year. Long PICU stay was defined statistically as >19 days. Long- and short-stay patient (SSP) groups were compared, and variables significantly associated with long stay on univariate analysis were entered into a stepwise multiple regression model. Results. Over the study period, 1 126 children (median age 8 months, 60.9% male) were admitted to the PICU, occupying 5 936 bed-days; 54 LSPs (4.8%) utilised 1 807 (30.4%) bed-days. Mortality and the standardised mortality ratio (actual/mean predicted mortality) in LSPs and SSPs were 29.6% v. 12% (p=0.002) and 2.4 v. 0.7 (p=0.002), respectively. Median duration of stay for LSPs and SSPs was 29.5 days and 2

January 2017, Print edition

RESEARCH

days, respectively (p<0.0001). LSPs were younger than SSPs (median 4 months (interquartile range 2 - 17) v. 9 months (2 - 34); p=0.03), and fewer were male (48% v. 61.6%, p=0.049). On multivariate analysis, only female gender was independently associated with long PICU stay. Conclusions. LSPs represent a small proportion of PICU admissions, yet have a higher mortality rate than SSPs and consume disproportionate PICU resources. No predictive model could be established for early recognition of potential LSPs to plan PICU bed allocation effectively. S Afr Med J 2017;107(1):70-75. DOI:10.7196/SAMJ.2017.v107i1.11279

Full article available online at http://dx.doi.org/10.7196/SAMJ.2017.v107i1.11279

Supernumerary registrar experience at the University of Cape Town, South Africa S Peer,1 MB BCh, FC Orl (SA), MMed (Otol); S A Burrows,2 MBBS, FRCS (ORL-HNS); N Mankahla,3 MB ChB, FC Neurosurg (SA); J J Fagan,1 MB ChB, FCS (SA), MMed (Otol) Division of Otolaryngology, Faculty of Health Sciences, University of Cape Town, South Africa Norfolk and Norwich University Hospital, UK 3 Division of Neurosurgery, Faculty of Health Sciences, University of Cape Town, South Africa 1 2

Corresponding author: S Peer (shazia.peer@uct.ac.za) Background. Despite supernumerary registrars (SNRs) being hosted in South African (SA) training programmes, there are no reports of their experience. Objectives. To evaluate the experience of SNRs at the University of Cape Town, SA, and the experience of SNRs from the perspective of SA registrars (SARs). Methods. SNRs and SARs completed an online survey in 2012. Results. Seventy-three registrars responded; 42 were SARs and 31 were SNRs. Of the SNRs 47.8% were self-funded, 17.4% were funded through private organisations, and 34.8% were funded by governments. Average annual income was ZAR102 349 (range ZAR680 460Â 000). Funding was considered insufficient by 61.0%. Eighty-seven percent intended to return to their home countries. Personal sacrifices were deemed worthwhile from academic (81.8%) and social (54.5%) perspectives, but not financially (33.3%). Only a small majority were satisfied with the orientation provided and with assimilation into their departments. Almost half experienced challenges relating to cultural and social integration. Almost all SARs supported having SNRs. SNRs reported xenophobia from patients (23.8%) and colleagues (47.8%), and felt disadvantaged in terms of learning opportunities, academic support and on-call allocations. Conclusions. SNRs are fee-paying students and should enjoy academic and teaching support equal to that received by SARs. Both the university and the teaching hospitals must take steps to improve the integration of SNRs and ensure that they receive equal access to academic support and clinical teaching, and also need to take an interest in their financial wellbeing. Of particular concern are perceptions of xenophobia from SA medical colleagues. S Afr Med J 2017;107(1):76-79. DOI:10.7196/SAMJ.2017.v107i1.11345

Full article available online at http://dx.doi.org/10.7196/SAMJ.2017.v107i1.11345

A novel FKRP-related muscular dystrophy founder mutation in South African Afrikaner patients with a phenotype suggestive of a dystrophinopathy M M Mudau, MSc (Biotech); F Essop, MSc (Med); A Krause, MB BCh, PhD Division of Human Genetics, National Health Laboratory Service and School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa Corresponding author: M M Mudau (maria.mudau@nhls.ac.za)

January 2017, Print edition

RESEARCH

Background. Fukutin-related protein (FKRP) muscular dystrophy is an autosomal recessive disorder caused by mutations in the FKRP gene. The condition is often misdiagnosed as a dystrophinopathy. A previously unreported mutation, c.1100T>C in exon 4 of FKRP, had been identified in homozygous form in two white South African (SA) Afrikaner patients clinically diagnosed with a dystrophinopathy. Objectives. To investigate whether the c.1100T>C mutation and the common European FKRP mutation c.826C>A are present in other patients of Afrikaner origin with suspected dystrophinopathy, and whether a founder haplotype exists. Methods. The c.1100T>C mutation was initially tested for using an amplification refractory mutation system technique in 45 white SA Afrikaner patients who had tested negative using multiplex ligation probe amplification screening for exonic deletions/duplications in the dystrophin gene. Sequencing analysis was used to confirm the c.1100T>C mutation and screen for the c.826C>A mutation. Two cohorts (each numbering 100) of Afrikaans and other white controls were screened for the c.1100T>C and c.826C>A mutations, respectively. Results. Of the 45 patients, 8 patients (17.8%) were homozygous for c.1100T>C, 2 (4.4%) were compound heterozygotes for c.1100T>C and c.826C>A, and 1 (2.2%) was heterozygous for c.1100T>C with a second unidentified mutation. The c.1100T>C mutation was found in 1/100 controls, but no heterozygotes for the c.826C>A mutation were identified. Linked marker analysis for c.1100T>C showed a common haplotype, suggesting a probable founder mutation in the SA Afrikaner population. Conclusion. FKRP mutations may be relatively common in Afrikaners, and screening should be considered in patients who have a suggestive phenotype and test negative for a dystrophinopathy. This test will be useful for offering diagnostic, carrier and prenatal testing for affected individuals and their families. As FKRP muscular dystrophy is autosomal recessive in inheritance, the implications of a positive diagnosis in a family differ significantly from those of an X-linked dystrophinopathy. S Afr Med J 2017;107(1):80-82. DOI:10.7196/SAMJ.2017.v107i1.10907

Full article available online at http://dx.doi.org/10.7196/SAMJ.2017.v107i1.10907

Primary cutaneous malignancies in the Northern Cape Province of South Africa: A retrospective histopathological review K York,1 MB BCh; N C Dlova,2 MB ChB, FC Derm (SA), PhD; C Y Wright,3 PhD; N P Khumalo,1 MB ChB, FC Derm (SA), PhD; P E Kellett,4 N Dip Med Tech; R Kassanjee,5 PhD; A Mosam,2 MB ChB, FC Derm (SA), PhD Department of Dermatology, Groote Schuur Hospital and Faculty of Health Sciences, University of Cape Town, South Africa Department of Dermatology, School of Clinical Medicine, College of Health Sciences, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa 3 Environment and Health Research Unit, South African Medical Research Council and Department of Geography, Geoinformatics and Meteorology, Faculty of Natural and Agricultural Sciences, University of Pretoria, South Africa 4 National Cancer Registry, National Health Laboratory Service, Johannesburg, South Africa 5 Department of Statistical Sciences, Faculty of Science, University of Cape Town, South Africa 1 2

Corresponding author: K York (kathyork20@gmail.com) Background. Excessive sun exposure and a high prevalence of HIV increase skin cancer risk in South Africa (SA). Objective. To describe the nature and extent of skin cancers presenting in the public and private health sectors of the Northern Cape Province of SA. Methods. A retrospective analysis of histologically confirmed new primary cutaneous malignancies from 1 January 2008 to 31 December 2012 was conducted using public and private health sector databases. Types, quantity and distribution of common invasive malignancies by population group, age, gender, anatomical site and health sector were explored. One-year cumulative incidence was calculated and logistic regression models were used to analyse incidence and melanoma thickness trends. Results. A total of 4 270 biopsies (13 cutaneous malignancies) were identified. The commonest was squamous cell carcinoma (SCC), followed by basal cell carcinoma, Kaposi’s sarcoma (KS), cutaneous malignant melanoma (CMM) and basosquamous carcinoma, in descending order. The odds of a white male developing SCC increased by 8% each year (odds ratio (OR) 1.08, 95% confidence interval (CI) 1.01 - 1.15; p=0.022), while the odds of a black male developing SCC and KS decreased by 9% (OR 0.91, 95% CI 0.84 - 0.99; p=0.033) and 18% (OR 0.82, 95% CI 0.70 - 0.97; p=0.022), respectively, each year. SCC and CMM were diagnosed at more advanced stages in the public than in the private healthcare sector. CMM is being detected earlier, as indicated by low-stage depth increasing by 72% annually (OR 1.72, 95% CI 1.04 - 3.01; p=0.042). Conclusions. Results suggest that reported skin cancer patterns are changing. There is a need for further research and equitable appropriation of financial resources and effort towards developing primary skin cancer prevention initiatives in SA. S Afr Med J 2017;107(1):83-88. DOI:10.7196/SAMJ.2017.v107i1.10924

Full article available online at http://dx.doi.org/10.7196/SAMJ.2017.v107i1.10924

January 2017, Print edition

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True (A) or false (B): SAMJ Tackling the climate targets set by the Paris Agreement (COP 21): Green leadership empowers public hospitals to overcome obstacles and challenges in a resource-constrained environment 1. COP 21 is also called the Paris Agreement. 2. A carbon dioxide concentration of 400 ppm was reached in June 2016. 3. According to the World Health Organization (WHO), air pollution killed 7 million people globally in 2012. Classifying snakebite in South Africa (SA): Validating a scoring system 4. Age <14 years and platelet count <92 Ă&#x2014; 109Â were among the six risk predictors for active treatment intervention. 5. Only about half of the venomous snake species in SA are dangerous to humans. 6. Bites from the boomslang are invariably fatal.

CME Anaemia: Approach to diagnosis 11. The World Health Organization definition of anaemia is a condition in which the number of red blood cells or their oxygencarrying capacity is insufficient to meet physiological needs. 12. Anaemia is usually a disease by itself. 13. The highest prevalence of anaemia is found in preschool-age children. 14. Anaemia may be classified by red cell characteristics and underlying mechanism. 15. Severity of symptoms depends on the degree of anaemia and the rate of drop in the Hb level. 16. A dietary history is not necessary in the approach to anaemia. 17. Pallor is the cardinal clinical sign of anaemia, and should be confirmed by measuring the Hb level. 18. Premature greying is often seen in megaloblastic anaemia. 19. Anaemia can be an underlying cause of cardiac failure. 20. The reticulocyte count is the marker of bone marrow status.

Surveillance of healthcare-associated infection in hospitalised SA children: Which method performs best? 7. Factors associated with failure to detect healthcare-associated infection (HAI) included patient transfer, single HAI event, age category 1 - 5 years, and hospitalisation in a general ward. 8. Healthcare-associated infections are an uncommon complication of hospitalisation. Primary cutaneous malignancies in the Northern Cape Province of SA: A retrospective histopathological review 9. Since 2011, cancer has been a reportable disease in SA. 10. Approximately 90% of non-melanoma skin cancer is attributable to personal ultraviolet radiation (UVR) exposure, so South Africans are especially susceptible to skin cancer owing to their year-round exposure to high ambient solar UVR.

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ADCOCK INGRAM GENERICS, IT'S A MATTER OF TRUST. S5 Adco-Alzam 0,25 mg. Each tablet contains alprazolam 0,25 mg. Reg. No. 30/2.6/0212. S5 Adco-Alzam 0,5 mg. Each tablet contains alprazolam 0,5 mg. Reg. No. 30/2.6/0211. S5 Adco-Alzam 1,0 mg. Each tablet contains alprazolam 1,0 mg. Reg. No. 30/2.6/0213. S5 Adco-Mirteron 15. Each film-coated tablet contains mirtazapine 15 mg. Reg. No. 39/1.2/0217. S5 Adco-Mirteron 30. Each film-coated tablet contains mirtazapine 30 mg. Reg. No. 39/1.2/0218. S5 Adco-Paroxetine 20 mg. Each tablet contains paroxetine mesylate equivalent to 20 mg paroxetine. Reg. No. 36/1.2/0096. S5 Adco-Talomil 20 mg. Each tablet contains citalopram hydrobromide 24,99 mg equivalent to citalopram 20 mg. Reg. No. 35/1.2/0272. S5 Adco-Zolpidem Hemitartrate 10 mg. Each tablet contains zolpidem hemitartrate 10 mg. Reg. No. 36/2.2/0132. S5 Adco-Zopimed. Each film-coated tablet contains 7,5 mg zopiclone. Reg. No. 33/2.2/0450. S3 Valeptic CR 300. Each controlled release tablet contains sodium valproate 300 mg. Reg. No. 44/2.5/0067. S3 Valeptic CR 500. Each controlled release tablet contains sodium valproate 500 mg. Reg. No. 44/2.5/0068. S5 Serez 25. Each film-coated tablet contains quetiapine fumarate, equivalent to quetiapine free base 25 mg. Reg. No. 43/2.6.5/0796. S5 Serez 100. Each film-coated tablet contains quetiapine fumarate, equivalent to quetiapine free base 100 mg. Reg. No. 43/2.6.5/0797. S5 Serez 200. Each film-coated tablet contains quetiapine fumarate, equivalent to quetiapine free base 200 mg. Reg. No. 43/2.6.5/0798. S5 Serez 300. Each film-coated tablet contains quetiapine fumarate, equivalent to quetiapine free base 300 mg. Reg. No. 43/2.6.5/0799. S5 Venlafaxine XR 37,5 Adco. Each extended release capsule contains venlafaxine HCl equivalent to venlafaxine 37,5 mg. Reg. No: 43/1.2/0577. S5 Venlafaxine XR 75 Adco. Each extended release capsule contains venlafaxine HCl equivalent to venlafaxine 75 mg. Reg. No: 43/1.2/0578. S5 Venlafaxine XR 150 Adco. Each extended release capsule contains venlafaxine HCl equivalent to venlafaxine 150 mg. Reg. No: 43/1.2/0579.

For full prescribing information, refer to the package insert approved by the medicines regulatory authority. 10271683 07/2016 Adcock Ingram Limited. Reg. No. 1949/034385/06. Private Bag X69, Bryanston, 2021. Tel. +27 11 635 0000 www.adcock.com