SAMJ Vol 108, No 5 (2018) by HMPG

MAY 2018

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CME Perioperative medicine and anaesthetics (part 1) EDITORIALS Potential for autochthonous transmission of Aedes aegypti-transmitted viruses in KZN Recommendation 16 and the Life Esidimeni tragedy IN PRACTICE Life Esidimeni: Moral pathology and an ethical crisis REVIEW Fanconi anaemia in South Africa RESEARCH Differentiating Crohnâ&#x20AC;&#x2122;s disease from intestinal tuberculosis Incidence of myocardial injury after noncardiac surgery Healthcare-associated infections in paediatric and neonatal wards

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MAY 2018 PRINT EDITION

FROM THE EDITOR 4

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

Caring for the mentally ill B Farham

EDITORS EMERITUS Daniel J Ncayiyana, MD (Groningen), FACOG, MD (Hon), FCM (Hon) JP de V van Niekerk, MD, FRCR

EDITOR’S CHOICE CORRESPONDENCE

Rabies – ghastly deaths are vaccine preventable A Khan

Palliative care for drug-resistant tuberculosis: An urgent call to action T Govender, S Naidoo, N Padayatchi, L Gwyther

IZINDABA 11

30 days in medicine B Farham

EDITORIALS Unpacking Recommendation 16 of the Health Ombud’s report on the Life Esidimeni tragedy L J Robertson, B Janse van Rensburg, M Talatala, C Chambers, C Sunkel, B Patel, S Stevenson

Back-to-the-future potential for autochthonous transmission of Aedes aegypti-transmitted viruses in eThekwini and urban coastal KwaZulu-Natal Province, South Africa P D Rotz

GUEST EDITORIAL Perioperative evaluation of patients who are due to undergo surgery N Ntusi

ARTICLES A practical approach to managing diabetes in the perioperative period L du Toit, T Biesman-Simons, N Levy, J A Dave Point-of-care and lung ultrasound incorporated in daily practice E Neethling, F Roodt, C Beck, J L C Swanevelder

IN PRACTICE

MEDICINE AND THE LAW The Life Esidimeni tragedy: Moral pathology and an ethical crisis A Dhai CASE REPORTS Co-infection with Streptococcus pneumoniae and Listeria monocytogenes in an immunocompromised patient C J Opperman, C Bamford Fulminant hepatitis B virus (HBV) infection in an infant following mother-to-child transmission of an e-minus HBV mutant: Time to relook at HBV prophylaxis in South African infants O Babatunde, H Smuts, B Eley, S Korsman, R de Lacy, D R Hardie

REVIEW 43

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

Fanconi anaemia in South Africa: Past, present and future C Feben, T Wainstein, J Kromberg, F Essop, A Krause

RESEARCH 49

Differentiating Crohn’s disease from intestinal tuberculosis at presentation in patients with tissue granulomas G Watermeyer, S Thomson

The ‘ins and outs’ of faecal microbiota transplant for recurrent Clostridium difficile diarrhoea at Wits Donald Gordon Medical Centre, Johannesburg, South Africa S Lee, K Drennan, G Simons, A Hepple, K Karlsson, W Lowman, P C Gaylard, L McNamara, J Fabian

TECHNICAL EDITORS Emma Buchanan Kirsten Morreira Paula van der Bijl PRODUCTION MANAGER Emma Jane Couzens DTP AND DESIGN Clinton Griffin

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MANAGING EDITORS Claudia Naidu Naadia van der Bergh

ASSOCIATE EDITORS Q Abdool Karim, A Dhai, R C Pattinson, A Rothberg, A A Stulting, J Surka, B Taylor, M Blockman, J M Pettifor, W Edridge, R P Abratt, D L Clarke

May 2018, Print edition

CHIEF OPERATING OFFICER Diane Smith | Tel. 012 481 2069 Email: dianes@hmpg.co.za SALES MANAGER (CAPE TOWN) Azad Yusuf JOURNAL ADVERTISING Reneé Hinze Ladine van Heerden Makhadzi Mulaudzi Charmalin Comalie ONLINE SUPPORT Gertrude Fani FINANCE Tshepiso Mokoena HMPG BOARD OF DIRECTORS Prof. M Lukhele (Chair), Dr M R Abbas, Mrs H Kikaya, Dr M Mbokota, Dr G Wolvaardt ISSN 0256-9574 HMPG website: www.hmpg.co.za SAMA website: www.samedical.org Journal website: www.samj.org.za

Incidence of myocardial injury after non-cardiac surgery: Experience at Groote Schuur Hospital, Cape Town, South Africa* E Coetzee, B M Biccard, R A Dyer, N D Meyersfeld, C Chishala, B M Mayosi

A raised serum lactate level is an independent predictor of in-hospital mortality in patients with isolated cerebral gunshot wounds* V Y Kong, R D Weale, G L Laing, J L Bruce, G V Oosthuizen, B Sartorius, P Brysiewicz, D L Clarke

Healthcare-associated infections in paediatric and neonatal wards: A point prevalence survey at four South African hospitals* C Olivier, H Kunneke, N O’Connell, E von Delft, M Wates, A Dramowski

The costs and outcomes of paediatric tuberculosis treatment at primary healthcare clinics in Johannesburg, South Africa* E P Budgell, D Evans, R Leuner, L Long, S Rosen

Assessing the value of Western Cape Provincial Government health administrative data and electronic pharmacy records in ascertaining medicine use during pregnancy* U Mehta, A Heekes, E Kalk, A Boulle *Abstract only, full article available online. CAREERS AND CLASSIFIEDS

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MAY 2018

Background photo: Whipple’s procedure on a 9-year-old girl with a neuroendocrine tumour | Karien Purchase, the anaesthetist. Photo sent to us by Christian Jeske Box photos: Aedes aegypti mosquito | Shutterstock; Hypoplastic thumb in Fanconi anaemia | Candice Feben; From ‘Your 5 Moments for Hand Hygiene’ poster (http://www.who.int/gpsc/5may/ tools/en/) | World Health Organization

May 2018, Print edition

PRINT EDITION

CME Perioperative medicine and anaesthetics (part 1) EDITORIALS Potential for autochthonous transmission of Aedes aegypti-transmitted viruses in KZN Recommendation 16 and the Life Esidimeni tragedy IN PRACTICE Life Esidimeni: Moral pathology and an ethical crisis REVIEW Fanconi anaemia in South Africa RESEARCH Differentiating Crohn’s disease from intestinal tuberculosis Incidence of myocardial injury after noncardiac surgery Healthcare-associated infections in paediatric and neonatal wards

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FROM THE EDITOR

Caring for the mentally ill I did a stint as a locum psychiatry registrar in a large London hospital in 1995, where I first came across some of the consequences of the deinstitutionalisation of the mentally ill. Late on a Sunday afternoon a distraught family contacted me about their mentally ill brother, who had been managed in the community for some time. Although generally well controlled on medication, he was decompensating and at that time on a weekend, their only recourse was to a busy emergency department of a large hospital. And here their point of contact was a locum, from another country, with no specialised training in psychiatry. I probably wasn’t an awful lot of use to them, and, unable to contact their normal GP or community mental health practitioner, I landed up admitting the patient. I am sure that this was an enormous relief to the family, who had been struggling for days, but it suggested to me that dealing with the mentally ill in the community was difficult. And this was in the UK, with all the massive public resources they have available. Driving along the M3 highway in Cape Town, I regularly used to see a young man under the various bridges – sometimes naked, sometimes in a wetsuit, and once with an old telephone handset held to his ear (perhaps rationalising where the voices were coming from). I haven’t seen him for some time, but there are other similar people on the various routes that I travel. I am sure that not all of them represent failures in community care of the mentally ill, but some of them must do. The Life Esidimeni tragedy threw some of these failures into full and appalling view. The Health Ombud’s report was into the ‘… circumstances surrounding the deaths of mentally ill patients transferred … to community-based facilities’ – my emphasis. South Africa (SA) escalated the pace of deinstitutionalisation of the mentally ill following the promulgation of the Mental Health Care Act 17 of 2002, but, as pointed out in the editorial in this issue by Lesley

Robertson and colleagues,[1] this was not accompanied by the necessary development of community-based services. A key recommendation (Recommendation 16) of that report speaks to the future of mental healthcare in SA, again pointing to the need for full communitybased mental health resources. In Gauteng at least, it would appear that the failure is intimately linked to poor budget planning – how money has not ‘followed the patient’. It is also apparent that, again in Gauteng at least, the amount of money allocated for mental health is woefully short of the minimum recommended by the World Health Organization. Furthermore, while the budget for pyschiatric hospitals had increased over the past few years, that for community-based mental health services had fallen. The mentally ill are some of the most vulnerable in our society and deserve the best of care. In this same issue, Ames Dhai[2] quotes Steve Biko: ‘In time, we shall be in a position to bestow on South Africa the greatest possible gift – a more human face.’ We as health professionals need to make that happen. Bridget Farham Editor ugqirha@iafrica.com 1. Robertson LJ, Janse van Rensburg B, Talatala M, et al. Unpacking Recommendation 16 of the Health Ombud’s report on the Life Esidimeni tragedy. S Afr Med J 2018;108(5):362-363. https://doi. org/10.7196/SAMJ.2018.v108i5.13223 2. Dhai A. The Life Esidimeni tragedy: Moral pathology and an ethical crisis. S Afr Med J 2018;108(5):382385. https://doi.org/10.7196/SAMJ.2018.v108i5.13232

S Afr Med J 2018;108(5):358. DOI:10.7196/SAMJ.2018.v108i5.13330

May 2018, Print edition

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EDITOR’S CHOICE

CME: Anaesthetics and perioperative medicine (part 1)

The aim of perioperative evaluation is to determine the risk of a procedure and to minimise that risk by identifying unrecognised comorbid disease and risk factors for medical complications of surgery; optimising the preoperative medical condition; recognising and treating potential complications; and working effectively as a member of the preoperative team (including those from nursing, medical, surgical and anaesthesia backgrounds). Data from published studies reveal that physicians and anaesthetists are more likely to identify conditions that may affect surgical outcomes. They then recommend interventions for these conditions, and occasionally cancel or delay surgery so that medical conditions can be optimally managed, ensuring a high level of satisfaction with co-management arrangements. In this CME issue, Du Toit and colleagues[1] review the perioperative management of diabetes. In this comprehensive summary, they look at the guidelines for optimisation and perioperative management of diabetic patients, and importantly place their discussion within the South African (SA) context. Ultimately, perioperative diabetic care should be driven by a multidisciplinary team considering the evidence base within a resource and patient context. Neethling et al.[2] discuss the role of point-of-care ultrasound (POCUS) as an essential modality in assessment of critically ill patients and those in the perioperative period. POCUS can be performed by trained non-cardiologist physicians at the patient’s bedside as an adjunct to the physical examination. It aids the rapid diagnosis of severe and life-threatening pathological conditions, often changes clinical management, and may affect patient outcomes.

Co-infection with Streptococcus pneumoniae and Listeria monocytogenes in an immunocompromised patient

A 34-year-old HIV-positive man with a history of chronic substance abuse was admitted with dual infection with Streptococcus pneumoniae and Listeria monocytogenes.[3] Combined bacteraemia with S. pneumoniae and L. monocytogenes is very rare. This would seem to be the first such case documented at Groote Schuur Hospital and in SA. Ampicillin should be added to antibiotic regimens to improve patient outcome if L. monocytogenes infection is suspected. Co-infections that occur with L. monocytogenes may have conflicting antibiotic treatment options. This case report emphasises the need for a good relationship between the local microbiology pathologist and the physician to select appropriate antibiotic treatment before definitive results are available.

The costs and outcomes of paediatric tuberculosis treatment at primary healthcare clinics in Johannesburg, SA

Little up-to-date information is available about the costs of providing drug-susceptible tuberculosis (DS-TB) treatment to paediatric patients in SA, nor have actual costs incurred at clinics been compared with costs expected from guidelines. Budgell et al.[4] estimated actual and guideline treatment costs by means of a retrospective cohort analysis, reporting patient characteristics, outcomes and treatment costs from paediatric and adolescent (<18 years) DS-TB patients registered for treatment from 1 April 2011 to 31 March 2013 at three primary healthcare clinics in Johannesburg, SA. Actual treatment costs in 2015 SA rands and US dollars were estimated from the provider perspective using a standard bottom-up microcosting approach and compared with an estimate of guideline costs.

Eighty-eight DS-TB patients were enrolled (median age 4 years (interquartile range 1.0 - 9.5), 44.3% female, 22.7% HIV co-infected, 92.0% pulmonary TB). Treatment success was high (89.8%; 13.6% cured, 76.1% completed treatment), and the mean (standard deviation (SD)) cost per patient with treatment success was ZAR1 820/USD143 (ZAR593/USD46), comprising fixed costs (44.0%), outpatient visits (30.7%), medication (19.3%) and laboratory investigations (6.0%). This was 17% more than the mean (SD) cost estimated by applying treatment guidelines (ZAR1 553/USD122 (ZAR1 620/USD127)), with differences due mainly to higher laboratory costs and more outpatient visits taking place than were recommended in national guidelines. These results are the first reported estimates of paediatric DS-TB treatment costs in SA and show the potential cost savings of closer adherence to national treatment guidelines. The findings were robust in sensitivity analyses and are lower than previous cost estimates in adults.

Healthcare-associated infections in paediatric and neonatal wards: A point prevalence survey at four SA hospitals

Healthcare-associated infections (HAIs) cause substantial morbidity, mortality and healthcare cost. The prevalence of neonatal/paediatric HAI at SA district and regional hospitals is unknown. Olivier et al.[5] documented HAI rates, antimicrobial use for HAI, infection prevention staffing, hand hygiene (HH) provisions and HH compliance rates in neonatal and paediatric wards in two district and two regional hospitals in the Western Cape Province, SA. They conducted an HAI point prevalence survey (PPS) during December 2016, applying National Healthcare Safety Network HAI definitions. HAI events and antimicrobial therapy active at 08h00 on the PPS day and during the preceding 7 days (period prevalence) were recorded. Provisions for HH and HH compliance rates were observed on each ward using the World Health Organization’s HH surveillance tool. Pooled point and period HAI prevalence were 9.9% (15/151; 95% confidence interval (CI) 6 - 15.8) and 12.6% (19/151; 95% CI 8 - 18.9), respectively. Hospital-acquired pneumonia (5/15, 33.3%), bloodstream infection (3/15, 20.0%) and urinary tract infection (3/15, 20.0%) were predominant HAI types. Risk factors for HAI were a history of recent hospitalisation (8/19, 42.1% v. 17/132, 12.9%; p<0.001) and underlying comorbidity (17/19, 89.5% v. 72/132, 54.5%; p<0.004). HH provisions (handwash basins/ alcohol hand rub) were available and functional. HH compliance was higher in neonatal than in paediatric wards (125/243, 51.4% v. 25/250, 10.0%; p<0.001). Overall HH compliance rates were higher among mothers (46/107, 43.0%) than among nurses (73/265, 27.8%) and doctors (29/106, 27.4%). Neonatal and paediatric HAIs are common adverse events at district and regional hospitals. This at-risk population should be prioritised for HAI surveillance and prevention through improved infection prevention practices and HH compliance.

Differentiating Crohn’s disease from intestinal tuberculosis at presentation in patients with tissue granulomas

Overlapping clinical, endoscopic, radiographic and histological features, coupled with poor microbiological yield, make differentiating Crohn’s disease (CD) from intestinal tuberculosis (ITB) challenging. Granulomas are present in both diseases; in CD they predict the need for immunosuppressive therapy that requires ITB to be excluded before initiation.

May 2018, Print edition

EDITOR’S CHOICE

Watermeyer and Thomson[6] compared granulomapositive CD and ITB to identify factors that may aid in diagnosis, using a retrospective cohort study evaluating granuloma-positive CD and ITB identified from a pathology database: 68 ITB and 48 CD cases were identified. Patients with ITB were more likely to be male, and to have HIV infection, isolated colitis, night sweats and tachycardia. ITB was also associated with lower serum albumin and haemoglobin and higher C-reactive protein levels, a chest radiograph showing active tuberculosis, and lymph nodes >1 cm on imaging. Extraintestinal manifestations (EIMs) were predictive of CD. There were no significant differences in smoking status, symptom duration or perianal disease. On multivariate analysis, HIV positivity (odds ratio (OR) 29.72, 95% CI 2.15 410.96; p=0.01), isolated colitis (OR 6.17, 95% CI 1.17 32.52; p=0.03) and the absence of EIMs (OR 0.10, 95% CI 0.01 - 0.65; p=0.02) remained significant risk factors for ITB. This is the first study to identify clinical and biochemical factors to aid in differentiating granuloma-positive ITB from CD. EIMs support a diagnosis of CD, while isolated colitis and HIV are predictors of ITB. BF 1. Du Toit L, Biesman-Simons T, Levy N, Dave JA. A practical approach to managing diabetes in the perioperative period. S Afr Med J 2018;108(5):369-375. https://doi. org/10.7196/SAMJ.2018.v108i5.13311 2. Neethling E, Roodt F, Beck C, Swanevelder JLC. Point-of-care and lung ultrasound incorporated in daily practice. S Afr Med J 2018;108(5):376-381. https://doi. org/10.7196/SAMJ.2018.v108i5.13313 3. Opperman CJ, Bamford C. Co-infection with Streptococcus pneumoniae and Listeria monocytogenes in an immunocompromised patient. S Afr Med J 2018;108(5):386388. https://doi.org/10.7196/SAMJ.2018.v108i5.12957 4. Budgell EP, Evans D, Leuner R, Long L, Rosen S. The costs and outcomes of paediatric tuberculosis treatment at primary healthcare clinics in Johannesburg, South Africa. S Afr Med J 2018;108(5):418-426. https://doi.org/10.7196/SAMJ.2018.v108i5.12802 5. Olivier C, Kunneke H, O’Connell N, von Delft E, Wates M, Dramowski A. Healthcare-associated infections in paediatric and neonatal wards: A point prevalence survey at four South African hospitals. S Afr Med J 2018;108(5):413-417. https://doi.org/10.7196/SAMJ.2018.v108i5.12862 6. Watermeyer G, Thomson S. Differentiating Crohn’s disease from intestinal tuberculosis at presentation in patients with tissue granulomas. S Afr Med J 2018;108(5):404-407. https://doi.org/10.7196/SAMJ.2018.v108i5.13108

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

CORRESPONDENCE

Rabies – ghastly deaths are vaccine preventable

To the Editor: The rabies virus can be likened to a stealthy demon that infects and kills its host in a horrific manner. It is deadlier than Ebola or HIV, yet its prevalence and lethality are often unpublicised. Human rabies accounts for a substantial proportion of deaths worldwide, especially affecting children in settings with limited access to healthcare or lack of awareness.[1,2] The majority of human rabies is transmitted by dog bites, and the One Health approach focusing on prevention of rabies in animals, primarily by vaccination, will therefore have a direct effect on preventing human rabies.[3] Despite this, rabies elimination is not prioritised and knowledge on rabies prevention among the general public and healthcare workers is often inadequate. In 2017 there were six laboratory-confirmed cases of human rabies in South Africa (SA), and in 2018 there have been three confirmed cases, one probable case and two suspected cases to date.[4,5] In KwaZulu-Natal and Eastern Cape provinces, there has been a recent surge in rabies with deaths in children following dog and cat bites. The tragic loss of these young lives could have been entirely preventable, since effective post-exposure prophylaxis for rabies is available in the form of wound care, rabies immunoglobulin and rabies vaccine.[6] Rabies immunoglobulin in addition to rabies vaccine is indicated for category 3 exposures, which include bites or scratches that penetrate the skin, licking of mucous membranes or broken skin, and direct contact with bats (Table 1). Although the supply of human rabies immunoglobulin has been limited owing to cost, equine rabies immunoglobulin is available, which is effective and reported as safe with a low risk of anaphylaxis.[8] Education in rural and urban communities by engaging with community leaders, chiefs, farmers, pet owners and schools on rabies prevention will create awareness among the public.[9] Annual vaccination of dogs and cats provided free of charge proved to be successful campaigns in reducing the burden of rabies.[10] These efforts must be sustained in order to achieve elimination and prevent resurgence.[11] The primary school education curriculum should include basic content to educate young children on the dangers of an animal bite and encourage them to seek help. Healthcare centres should display posters and provide information on rabies, and all healthcare workers must be adequately trained on how to manage a patient with potential rabies exposure from primary healthcare level

where patients often present. Improving access to safe, effective and inexpensive post-exposure prophylaxis must be prioritised. SA commemorated Human Rights Day on 21 March. Children are among the most vulnerable in our population and have a constitutional right to be protected. Against this backdrop exists a rabies outbreak with loss of lives. It is therefore imperative for us as healthcare workers to promote education on rabies prevention and provide effective healthcare. Working with veterinarians to vaccinate animals and with community leaders to educate the public will help in advancing the goal of human rabies elimination by 2030.[12] Aabida Khan Department of Virology, School of Laboratory Medicine and Medical Sciences, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa; and National Health Laboratory Service, Inkosi Albert Luthuli Central Hospital, Durban, South Africa aabida.khan1@gmail.com 1. Fooks AR, Banyard AC, Horton DL, Johnson N, McElhinney LM, Jackson AC. Current status of rabies and prospects for elimination. Lancet 2014;384(9951):1389-1399. https://doi.org/10.1016/S01406736(13)62707-5 2. Hampson K, Coudeville L, Lembo T, et al. Estimating the global burden of endemic canine rabies. PLoS Negl Trop Dis 2015;9(4):e0003709. https://doi.org/10.1371/journal.pntd.0003709 3. Durrheim DN, Blumberg L. Rabies – what is necessary to achieve ‘zero by 30’? Trans R Soc Trop Med Hyg 2017;111(7):285-286. https://doi.org/10.1093/trstmh/trx055 4. National Institute for Communicable Diseases. Rabies in South Africa. NICD Communicable Diseases Communique February 2018;17(2). http://www.nicd.ac.za/index.php/publications/nicd-nhlscommunicable-diseases-communique/ (accessed 10 April 2018). 5. National Institute for Communicable Diseases. An update on rabies in South Africa. NICD Communicable Diseases Communique March 2018;17(3). http://www.nicd.ac.za/index.php/ publications/nicd-nhls-communicable-diseases-communique/ (accessed 10 April 2018). 6. National Department of Health, South Africa. Affordable Medicines: Hospital Level Paediatrics Standard Treatment Guidelines and Essential Medicine List, 2017 edition. http://www.health.gov.za/ index.php/standard-treatment-guidelines-and-essential-medicines-list (accessed 10 April 2018). 7. National Department of Health, South Africa. Affordable Medicines: Primary Health Care Level Standard Treatment Guidelines and Essential Medicine List for South Africa, 2014 edition. http://www. health.gov.za/index.php/standard-treatment-guidelines-and-essential-medicines-list/category/285phc (accessed 10 April 2018). 8. National Department of Health, South Africa. Notice: Recommended therapeutic alternative for human rabies immunoglobulin. 2016. http://www.nicd.ac.za/assets/files/Circular_Therapeutic%20 alternative%20for%20HRIG_07June2016.pdf (accessed 10 April 2018). 9. Hasanov E, Zeynalova S, Geleishvili M, et al. Assessing the impact of public education on a preventable zoonotic disease: Rabies. Epidemiol Infect 2018;146(2):227-235. https://doi.org/10.1017/ S0950268817002850 10. Shwiff SA, Hatch B, Anderson A, et al. Towards canine rabies elimination in KwaZulu-Natal, South Africa: Assessment of health economic data. Transbound Emerg Dis 2016;63(4):408-415. https://doi. org/10.1111/tbed.12283 11. Dürr S, Fahrion AS, Knopf L, Taylor LH. Editorial: Towards elimination of dog mediated human rabies. Front Vet Sci 2017;4(142). https://doi.org/10.3389/fvets.2017.00142 12. World Health Organization. New global framework to eliminate rabies 2015. http://www.who.int/ mediacentre/news/releases/2015/eliminate-rabies/en/ (accessed 10 April 2018).

S Afr Med J 2018;108(5):359. DOI:10.7196/SAMJ.2018.v108i5.13302

Table 1. Categories of exposure and management for suspected rabies exposure[7] Category 1 2

Type of exposure Touching or feeding of animal Licking of intact skin Nibbling of uncovered skin Superficial scratch without bleeding

Bites/scratches that penetrate the skin and with any visible blood Licking of broken skin or mucous membranes, e.g. eyes and mouth Direct contact with a bat

Management No treatment if history is reliable If history not reliable, treat as category 2 Wound management Administer full course vaccine. Only stop if animal tested negative for rabies or is still healthy after 10 days’ observation Do not give immunoglobulin, except in immunocompromised patients Wound management Administer full course vaccine. Only stop if animal tested negative for rabies or is still healthy after 10 days’ observation Administer rabies immunoglobulin Administer tetanus vaccine Prescribe antibiotics

May 2018, Print edition

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CORRESPONDENCE

Palliative care for drug-resistant tuberculosis: An urgent call to action

To the Editor: The recent article entitled ‘Development of a hospitalbased model of palliative care in the Western Cape, South Africa’[1] recognised the important milestone South Africa (SA) has reached in adopting a policy on palliative care and begs the question of models of palliative care for drug-resistant (DR) tuberculosis (TB). The mortality rates for multidrug-resistant (MDR)-TB and extensively drug-resistant (XDR)-TB are 40% and 60%, respectively.[2] Of concern are a growing number of patients with programmatically incurable TB who remain smear- and culture-positive, giving rise to secondary cases. Currently there is no package of care available to these patients when treatment options have been exhausted. Therapeutic failure has become synonymous with additional failures from policy, programmatic, patient and social care perspectives. The World Health Organization (WHO) issued the ‘Declaration on Palliative Care and MDR/XDR TB’,[3] which recognised palliative care as a human right and an essential component of managing patients with DR-TB, in November 2010. The World Health Assembly’s resolution in May 2014[4] mandated member states to strengthen and integrate palliative care into public health systems. In March 2014, the WHO adopted the End TB Strategy with the vision of ‘A world free of tuberculosis – zero deaths, disease and suffering’, emphasising patient-centred care.[5] In 2015, the SA National Department of Health commissioned a WHO-led evaluation of the DR-TB programme on the implementation of decentralisation and deinstitutionalised management of MDR-TB. The report estimates that 90% of patients who experience treatment failure will receive home-based care and only 10 - 15% of patients will require specialised long-term stay facilities.[6] Palliative care is an essential component of universal health coverage, requiring a scalable, integrated response into DR-TB care. It must include infection control measures to mitigate transmission, symptom assessment and management, including access to opioids, to improve the quality of life of patients, while supporting their families. Patients with DR-TB experience a myriad of distressing symptoms including total pain, nausea, cachexia, dyspnoea and haemotypsis, adding to the emotional angst of confronting their mortality. Effective implementation can reduce suffering and potentially decrease community transmission with infection control, screening of contacts and retention in care. While the search for better drugs, vaccines and diagnostic tests must be intensified, palliative care for patients with DR-TB must be provided now! This can be achieved with political leadership

and allocation of resources including palliative care training for health workers. SA, a signatory to the World Health Assembly resolution, must champion the inclusion of palliative care for patients with DR-TB at the first United Nations High Level Meeting on Tuberculosis to be held on 26 September 2018 in New York with the theme ‘United to end tuberculosis: An urgent global response to a global epidemic’. T Govender King Dinuzulu Hospital Complex, KwaZulu-Natal Department of Health, Durban, South Africa; Discipline of Public Health Medicine, School of Nursing and Public Health, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa; and Developing Research Innovation, Localisation and Leadership in South Africa (DRILL) Fellow, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa thilo.govender@gmail.com

S Naidoo Discipline of Public Health Medicine, School of Nursing and Public Health, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa

N Padayatchi Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, South Africa

L Gwyther Palliative Medicine, School of Public Health and Family Medicine, Faculty of Health Sciences, University of Cape Town, South Africa; and Hospice Palliative Care Association of South Africa, Cape Town, South Africa 1. Gwyther L, Krause R, Cupido C, et al. The development of hospital-based palliative care services in public hospitals in the Western Cape, South Africa. S Afr Med J 2018;108(2):86-89. https://doi. org/10;10.7196/SAMJ2018.v12524 2. Dheda K, Gumbo T, Maartens G, et al.; Lancet Respiratory Medicine Commission. The epidemiology, transmission, diagnosis, and management of multi-drug-resistant, extensively drug-resistant, and incurable tuberculosis. Lancet Respir Med 2017;5(4):291-360. https://doi.org/10.1016/S22132600(17)30079-6 3. World Health Organization. Declaration on Palliative Care and MDR/XDR-TB: Geneva, Switzerland, 19 November 2010. Stop TB Palliative Care and MDR/XDR-TB Integration Meeting, 18 - 19 November 2010. 4. World Health Assembly. Strengthening of palliative care as a component of comprehensive care throughout the life course. http://apps.who.int/gb/ebwha/pdf_files/WHA67/A67_R19-en.pdf (accessed 16 April 2018). 5. World Health Organization. The End TB Strategy. Geneva: WHO, 2015. http://www.who.int/tb/End_ TB_brochure.pdf (accessed 9 April 2018). 6. World Health Organization, USAID, National Department of Health, South Africa. Towards Universal Health Coverage: Report of the Evaluation of South Africa Drug-Resistant TB Programme and its Implementation of the Policy Framework on Decentralised and Deinstitutionalised Management of Multidrug Resistant TB. February 2016.

S Afr Med J 2018;108(5):360. DOI:10.7196/SAMJ.2018.v108i5.13240

May 2018, Print edition

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IZINDABA

30 days in medicine Lose weight before puberty to reduce risk of type 2 diabetes

Losing weight before puberty will reduce the risk of type 2 diabetes in adulthood, according to a study published in the New England Journal of Medicine. The study looked at 62 565 Danish men whose weights and heights had been measured at 7 and 13 years of age and in early adulthood (17 to 26 years). Data from a diabetes registry provided follow-up on 6 710 men aged >30 years. Being overweight at 7 and then still overweight at 13 or in early adulthood was positively associated with the risk of type 2 diabetes, with stronger associations at older ages at overweight and younger ages at diagnosis of the disease. However, those who lost weight before they turned 13 had the same risk of type 2 diabetes as those who had never been overweight. Bjerregaard LG, Jensen BW, Ängquist L, et al. Change in overweight from childhood to early adulthood and risk of type 2 diabetes. N Engl J Med 2018;378:1302-1312. https://doi.org/10.1056/NEJMoa1713231

Start antiretrovirals the day of diagnosis to improve later linkage to care

HIV-positive adults in Lesotho offered same-day home-based antiretroviral initiation had signficantly improved linkage to care at 3 months as well as HIV viral suppression at 12 months. These are the findings of an open-label, two-group, randomised clinical trial involving six healthcare facilities in northern Lesotho. During home-based HIV testing, 6 655 households were enrolled and 138 participants randomly assigned to be offered same-day home-based antiretroviral initiation and follow-up at intervals of 1.5, 3, 6, 9 and 12 months or to receive usual care (n=140), with referral to the nearest

health centre for counselling followed by antiretroviral initiation and monthly follow-up. At 3 months, 68.6% of patients in the same-day group had linked to care, as opposed to 43.1% in the usual-care group. Viral suppression at 12 months was achieved by 50.4%, compared with 34.3% in the usual-care group. Labhardt ND, Ringera I, Lejone TI, et al. Effect of offering same-day ART vs usual health facility referral during home-based HIV testing on linkage to care and viral suppression among adults with HIV in Lesotho: The CASCADE Randomized Clinical Trial. JAMA 2018;319(11):1103-1112. https://doi.org/10.1001/ jama.2018.1818

Sexual violence against children leads to serious health problems

Sexual violence is widespread among both girls and boys in South Africa (SA) and is associated with serious health problems. These are the findings of a nationally representative, cross-sectional study in SA, sampling from 5 631 households and schools. Physical abuse, emotional abuse, neglect, family violence and other victimisations were all strongly associated with sexual victimisation. School enrolment, living in a rural area, having a flush toilet, parental substance misuse, being disabled, female caregiver’s poor knowledge of the child’s whereabouts, friends and activities, and poor quality of relationship with the child all predisposed to sexual abuse. Ward CL, Artz L, Leoschut L, Kassanjee R, Burton P. Sexual violence against children in South Africa: A nationally representative cross-sectional study of prevalence and correlates. Lancet Glob Health 2018;6(4):e460-e468. https://doi.org/10.1016/S2214-109X(18)30060-3

B Farham Editor ugqirha@iafrica.com

May 2018, Print edition

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EDITORIAL

Unpacking Recommendation 16 of the Health Ombud’s report on the Life Esidimeni tragedy The Health Ombud released the ‘Report into the circumstances surrounding the deaths of mentally ill patients transferred from Life Esidimeni to community-based facilities, Gauteng province’ on 1 February 2017.[1] The past year has been filled with activity as his recommendations have been implemented: data on mental healthcare users (MHCUs) have been collected, survivors have been re-hospitalised in newly contracted long-stay beds, and efforts have been made to locate those lost to the system. Forensic services have begun examining causes of death, and the South African Police Service, Special Investigations Unit and Human Rights Commission have commenced investigations into the process and its outcomes. Finally, closing arguments have been made at the Life Esidimeni Arbitration, which gave graphic description to the tragedy. Recommendation 16 of the Health Ombud’s report, which speaks to the future of mental healthcare in South Africa (SA), however, remains to be addressed. It recognises that ‘for deinstitutionalisation to be undertaken properly … community based mental health care services must be focused upon, must be resourced and must be developed …’.[1] Given the lack of understanding of the links between deinstitutionalisation, community-based mental health services and the budget made apparent at the arbitration hearings, we believe that Recommendation 16 deserves unpacking for proper implementation to occur. Firstly, deinstitutionalisation is not a new concept in SA. The term ‘deinstitutionalisation’ belongs to a shift in mental health practice that began in Europe and the USA in the 1950s and refers to the change in care setting from specialised institutions to community-based facilities. Having inherited a colonial-era custodial-care mental health system, SA built institutions for the care of the severely mentally ill and disabled. It began deinstitutionalising its severely mentally ill in the mid-1990s, in response to the human right of MHCUs to receive care close to their homes.[2] The pace of deinstitutionalisation escalated following the promulgation of the Mental Health Care Act 17 of 2002,[3] but it was not accompanied by the development of community psychiatry.[4] The National Mental Health Policy Framework and Strategic Plan 2013 - 2020[5] recognises this imbalance when it states on page 16 that ‘Deinstitutionalisation has progressed at a rapid rate in South Africa, without the necessary development of community-based services. This has led to a high number of homeless mentally ill, people living with mental illness in prisons and revolving door patterns of care.’ The transfer of so many MHCUs from Life Esidimeni to ill-prepared nongovernmental organisations (NGOs) represented the closure of the last remaining long-stay beds. It represented the completion of rapid, poorly planned deinstitutionalisation in the province, not the beginning. Secondly, the NGOs to which Life Esidimeni MHCUs were transferred are not themselves ‘community-based mental health services’, but ‘supported housing’ run by NGOs that should operate within the community-based mental health service system. They serve as homes for mentally disabled people who, for whatever reason, cannot live with their families. They should provide structure, routine and security; a place in which the person may live within their community and hopefully have a sense of purpose and quality of life. As such, most NGOs do not themselves provide healthcare; they should access healthcare from the local general and mental health services.

As indicated in Recommendation 16, community-based mental health services comprise both integrated primary mental healthcare and community-based psychiatric care. They need to include specialist psychiatric expertise for people with severe mental illness, primary care of people with uncomplicated mental illness, and general healthcare of the mentally disabled. These services support the NGOs, ideally offering rehabilitation outreach, education and supervision to caregivers in the NGOs. In her testimony at the Arbitration, MEC for Finance Barbara Creecy provided key insights into the budget for mental healthcare in Gauteng. She described how the mental health budget is scattered among different programmes in the budget. This could explain why money has not ‘followed the patient’ in the deinstitutionalisation process – an institution budget may not follow the patient to the community, which falls under district health services. She testified that ZAR1.4 billion (3.5% of the Gauteng Province health budget) was allocated to mental health in Gauteng for the 2017/18 financial year. This is considerably less than the World Health Organization’s recommended 5%.[6] She found that the budget for community-based mental health services has been reduced over the past few years, while that for psychiatric hospitals increased. This is consistent with an analysis of the Gauteng community mental health services, which found that staffing of district psychiatric clinics was reduced between 2005 and 2015 despite an increase in the numbers of MHCUs.[7] The inequity in mental healthcare in Gauteng, both between mental and general health and between community and hospital psychiatric care, is not unique to this province.[4,5] As Recommendation 16 recognises, SA as a whole must now catch up on funding community mental health services after two decades of deinstitutionalisation. The mental healthcare budget is currently insufficient, and is still being financed along historical, institution-based principles. While the role of specialised psychiatric hospitals must not be underestimated, if SA is to provide accessible, human rights-focused, equitable psychiatric care, it cannot do so without community mental health services. Lesley J Robertson, Bernard Janse van Rensburg, Mvuyiso Talatala South African Society of Psychiatrists, Johannesburg, South Africa lesley.robertson@wits.ac.za Cassey Chambers South African Depression and Anxiety Group, Johannesburg, South Africa Charlene Sunkel, Bharti Patel South African Federation for Mental Health, Johannesburg, South Africa Sasha Stevenson SECTION27, Johannesburg, South Africa 1. Makgoba MW. The report into the ‘Circumstances surrounding the deaths of mentally ill patients: Gauteng Province’. South Africa: Office of the Health Ombud, 2017. http://healthombud.org.za/reportinto-the-circumstances-surrounding-the-deaths-of-mentally-ill-patients-gauteng-province/ (accessed 10 April 2018). 2. Lazarus R. Managing de-institutionalisation in a context of change: The case of Gauteng, South Africa. S Afr Psychiatry Rev 2005;8(2):65-69. https://www.ajol.info/index.php/ajpsy/article/view/30186/22805 (accessed 11 April 2018).

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Getting to the Critical

ACCREDITED

24-25 November Venue: Misty Hills Muldersdrift Estate 69 Drift Blvd, Muldersdrift

CRITICAL CARE SOCIETY OF SOUTHERN AFRICA EGOLI BRANCH

For more information Janice Candlish

T: + 27 11 894 1278 E: ccssa@velocityvision.co.za W: www.velocityvision.co.za

EDITORIAL

3. South Africa. Mental Health Care Act No. 17 of 2002. https://www.gov.za/sites/www.gov.za/files/a1702.pdf (accessed 7 April 2018). 4. Lund C, Petersen I, Kleintjes S, Bhana A. Mental health services in South Africa: Taking stock. Afr J Psychiatry 2012;15(6):402-405. https://doi.org/10.4314/ajpsy.v15i6.48 5. National Department of Health, South Africa. National Mental Health Policy Framework and Strategic Plan 2013 - 2020. Pretoria: NDoH, 2012.

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6. World Health Organization. Mental Health Atlas, 2014. Geneva: WHO, 2015. 7. Robertson LJ, Szabo CP. Community mental health services in southern Gauteng: An audit using District Health Information Systems data. S Afr J Psychiatry 2017;23:a1055. https://doi.org/10.4102/ sajpsychiatry.v23i0.1055

S Afr Med J 2018;108(5):362-363. DOI:10.7196/SAMJ.2018.v108i5.13223

Back-to-the-future potential for autochthonous transmission of Aedes aegypti-transmitted viruses in eThekwini and urban coastal KwaZulu-Natal Province, South Africa

The Aedes aegypti (Linnaeus) mosquito transmits several important arboviruses, principally chikungunya (CHIKV), dengue (DENV), yellow fever (YFV) and Zika (ZIKV).[1-4] Ninety years ago this journal featured an account of the DENV-1 epidemic that crippled Durban during the summer of 1926/27.[5,6] Summary estimates described 50 000 sufferers and 60 attributed deaths along the coast between Kelso Junction and Stanger (KwaDukuza) and inland as far as Pinetown.[7] Some residents suffered haemorrhagic manifestations now associated with repeat infections involving another of the four DENV types.[2,8-12] A 1996 SAMJ editorial suggested that the 1926/27 epidemic occurred during a brace of remarkably wet years when the rainfall was five and eight times greater than the historical average.[13] However, the Durban rainfall during 1925/26 was the lowest then on record and drought persisted through the first months of the 1927 epidemic, before plentiful March rains.[14] Empty skies compounded structural water supply challenges later relieved by completion of the Shongweni Water Scheme.[15] The 1926/27 epidemic was not an anomaly. In the early 1870s, a pandemic often identified as ‘dengue’ – but more likely in fact chikungunya – swept through Indian Ocean ports.[16-20] The pandemic reached Mauritius in 1873.[21,22] In late January 1874, an epidemic resembling chikungunya took hold in Durban: ‘a low fever, accompanied by rheumatic pain’, affecting black and white populations alike, ‘almost put a stop to business’.[23] ‘The first symptoms of the attack are stiffness and soreness in the legs and joints, pains in the head, and tightness in the chest,’ The Natal Mercury detailed. ‘Then the fever soon shows itself and prostrates the victim. There is nothing of fatal character about the sickness but it completely knocks up those it attacks, for at least two or three days.’[24] Four summers later, in March 1878, the port town’s district surgeon reported that ‘this is the first time dengue has shown itself epidemically in this Colony’,[25] and The Natal Mercury observed that ‘at least every other person has suffered’.[26] In addition to the epidemics in 1874 and 1878, medical observers reported disease events they described as ‘dengue’ during 10 additional summers over the next 50 years.[27-28] Eight of those 12 years saw rainfall in Durban below the historical average (Table 1), often coincident with El Niño-associated drought.[29-31] While the precise viral aetiologies of outbreaks and epidemics prior to 1926/27 are elusive, the better documented occurrences of probable chikungunya or dengue point to the presence of humanbiting, virus-transmitting Ae. aegypti populations and recurring intersections with water stress.

Table 1. Summers with reports of dengue-like illness in the Durban area and recorded rainfall at Durban Botanical Gardens, 1873/74 - 1926/27 Year (July - June)/ summer 1873/74 1877/78 1891/92 1895/96 1896/97 1897/98 1899/00 1900/01 1901/02 1913/14 1925/26 1926/27

Number of days with recorded rainfall[14] 137 136 126 136 119 138 127 127 127 107 98 106

Recorded rainfall[14] (mm)* 1 283.5 865.3 783.5 917.7 954.0 992.8 686.5 1 119.3 1 242.0 878.0 669.0 842.7

Rainfall as % more or less than annual average 1871 - 1997 (1 002 mm)[31] +28.1 –13.6 –21.8 –8.5 –4.8 –1.0 –31.5 +11.7 +24.0 –12.4 –33.3 –15.9

*Documentary records recorded in inches, converted here into millimetres.

In 2016, during a summer marked by El Niño drought, eThekwini’s dengue history went unmentioned after the World Health Organization declared Zika a public health emergency of international concern. Leading South African health officials made statements to the press[32-36] and Parliament’s Portfolio Committee on Health,[37] dismissing the vector capacity and competence of the country’s Ae. aegypti populations, regardless of region. All six urgent actions prioritised by the Department of Health focused on travellers and the translocation of mosquitoes from abroad.[38] The more nuanced assessment that National Institute for Communicable Diseases officials placed in this journal[39] referenced unspecified ‘prediction models based on the distribution of Ae. aegypti’ as indicating a low risk for autochthonous viral transmission. Ae. aegypti is a polymorphic species whose populations exhibit variable traits influenced by genetics and environment – for example, colour pattern, bloodmeal preference, egg-laying site selection and vector competence.[40] A 1991 morphology-focused study reached a similar conclusion: ‘in South Africa Ae. aegypti is a single polymorphic species displaying plasticity in its manbiting behavior’. [41] Entomologists in the 1950s and 1990s described focally abundant, domestic, human-biting Ae. aegypti populations

May 2018, Print edition

EDITORIAL

in eThekwini and the KwaZulu-Natal (KZN) coast.[42-44] Between 1970 and 2002, vector competence tests yielded the following results: Ae. aegypti populations from both ends of KZN – a forest population from Ndumu and another from Glenmore Beach – were readily infected with CHIKV at viral titres >5.3 logs and capably transmitted the virus;[45,46] Ae. aegypti from eThekwini were competent vectors of DENV-1 and DENV-2, albeit with lower efficiency than seen in South America;[47] and Ae. aegypti from eThekwini were relatively poor vectors of YFV.[48] Less competent vectors still warrant consideration.[49] From November through April, eThekwini summers favour Ae. aegypti abundance, with average high temperatures of 25 - 28°C, relative humidity around 80%, and summer rainfall.[50-54] If the city’s Ae. aegypti mosquitoes obtain bloodmeals containing CHIKV, DENV or ZIKV from infected visitors or returning residents – and subsequently survive beyond the virus’s extrinsic incubation period (EIP) within mosquitoes – local transmission could result. Most of eThekwini’s 3.5 million residents presumably have no acquired immunity to these viruses. Entrenched inequality deprives many eThekwini residents of protection against blood-feeding Ae. aegypti afforded by goodquality dwelling construction, in-house piped water, and airconditioning. [55-57] A third of eThekwini households are located in informal settlements.[58] Barely 60% of city households enjoy in-house piped water.[59] Where piped water is present, residents may still collect and store water to hedge against prohibitive costs or restrictions and interruptions. This is not to suggest that eThekwini’s well-to-do are unlikely to be affected. Their disposable income and international travel make them candidates for virus importation. As in 1927 – when dengue beset Berea households – water-holding receptacles and vegetation prized in the gardens of the wealthier classes can foster and shelter Ae. aegypti, while outdoor living areas can increase vector exposure during peak morning and evening biting times.[60,61] Up to 80% of ZIKV and 75% of DENV infections may be asymptomatic.[62,63] Moreover, a 2015 study revealed that people with asymptomatic DENV infections can still infect biting mosquitoes. [64] Visitors or returning residents may infect blood-feeding Ae. aegypti without displaying signs of illness. This understanding – and the reality that 7 in 10 eThekwini households depend upon public healthcare facilities[65] – blunts the sensitivity of passive disease surveillance focused on recent travellers and dominated by private sector test requests. Looking forward, resident mobility as well as expansionary goals for the city’s aerotropolis[66,67] and international tourism[68] could increase the possibilities for virus importation. In addition, climate change may make summers more conducive to virus transmission. Projections suggest temperature increases in eThekwini of 1.5 2.5°C by 2065 and, by 2100, a rise of 3 - 5°C.[69] Higher temperatures shorten EIPs in Ae. aegypti. One DENV study found EIPs of ≥12 days at 30°C, but 7 days at 32 - 35°C;[70] another reported EIPs of 9 days at 26 - 28°C that fell to 5 days at 30°C.[71] While the net influence rising temperatures will exert on larval development, adult size and abundance, female biting rates, EIPs and adult longevity is complex, warmer summers in eThekwini may increase the likelihood that Ae. aegypti – if infected – will survive long enough to deliver infecting bites. Human adaptation to water insecurity and climate change may influence eThekwini’s disease ecology more than the direct impact of rising temperatures.[72,73] Rainwater tanks were a common feature of Durban’s urban ecology during its dengue past.[74-79] Residents, climate change planners, water officials and NGOs who practise

or promote rainwater harvesting unwittingly restore one of Ae. aegypti’s most prolific larval habitats from yesteryear.[80-85] These considerations warrant further study and engagement beyond the health sector with the potential for Ae. aegypti-transmitted viruses in urban coastal KZN. Philip D Rotz PhD candidate, Environmental History/African History, History Department/African Studies Center, Boston University, USA; and affiliated researcher, 2014 - 2016, School of Social Sciences, University of KwaZulu-Natal, Durban, South Africa protz@bu.edu Acknowledgements. I am grateful for stimulating exchanges with past and present staff of South Africa’s National Institute for Communicable Diseases and the eThekwini Health Unit from 2014 to 2016. Any errors are wholly my own. Author contributions. Sole author. Funding. This text draws on dissertation fieldwork supported by a Graduate Research Abroad Fellowship from Boston University and a Fulbright-Hays Doctoral Dissertation Research Abroad Fellowship from the US Government’s Department of Education. The composition of a more expansive essay on this subject (in press) received support from the Pardee Center for the Study of the Longer-Range Future at Boston University. Conflicts of interest. None. 1. World Health Organization. Chikungunya Factsheet. Geneva: WHO; updated April 2017. http://www. who.int/mediacentre/factsheets/fs327/en/ (accessed 15 July 2017). 2. World Health Organization. Dengue and Severe Dengue Factsheet. Geneva: WHO; updated April 2017. http://www.who.int/mediacentre/factsheets/fs117/en/ (accessed 15 July 2017). 3. World Health Organization. Yellow Fever Factsheet. Geneva: WHO; updated May 2016. http://www. who.int/mediacentre/factsheets/fs100/en/ (accessed 12 October 2016). 4. World Health Organization. Zika Factsheet. Geneva: WHO; updated September 2016. http://www. who.int/mediacentre/factsheets/zika/en/ (accessed 12 October 2016). 5. Edington AD. ‘Dengue’ as seen in the recent epidemic in Durban. J Med Assoc S Afr 1927;1(17):446-448. 6. Kokernot RH, Smithburn KC, Weinbren MP. Neutralising antibodies to arthropod-borne viruses in human and animals in the Union of South Africa. J Immunol 1956;77(5):313-323. 7. Department of Public Health, Union of South Africa. Annual Report of the Department of Public Health, Year Ended 30th June 1927. Pretoria: Government Printing and Stationery Office, 1927. 8. Katzelnick LC, Fonville JM, Gromowski GD, et al. Dengue viruses cluster antigenically but not as discrete serotypes. Science 2015;349(6254):1338-1343. https://doi.org/10.1126/science.aac5017 9. Guzman MG, Alvarex M, Halstead SB. Secondary infection as a risk factor for dengue hemorrhagic fever/dengue shock syndrome: An historical perspective and role of antibody-dependent enhancement. Arch Virol 2013;158(7):1445-1459. https://doi.org/10.1007/s00705-013-1645-3 10. Correspondence from Assistant Health Officer, Durban, to Secretary for Public Health re: ‘Dengue’, 19 March 1927. Folder 61/12, Box 580, Series GES (Records of the Union Department of Public Health), National Archives Repository, Public Records of Central Government since 1910, National Archives and Record Service of South Africa. 11. Correspondence from Assistant Health Officer, Durban, to Secretary for Public Health re: ‘Dengue Fever: Durban’, 22 March 1927. Folder 61/12, Box 580, Series GES (Records of the Union Department of Public Health), National Archives Repository, Public Records of Central Government since 1910, National Archives and Record Service of South Africa. 12. Kuno G. Emergence of the severe syndrome and mortality associated with dengue and dengue-like illness: Historical records (1890 to 1950) and their compatibility with current hypotheses on the shift of disease manifestation. Clin Microbiol Rev 2009;22(2):186-201. https://doi.org/10.1128/cmr.00052-08 13. Jupp PG, Kemp A. What is the potential for future outbreaks of chikungunya, dengue and yellow fever in southern Africa? S Afr Med J 1996;86(1):35-37. 14. Durban Borough Water Engineer. Annual Report for year ending 31st July, 1927. In: Durban Corporation. Mayor’s Minute, with Departmental Reports, Appendices, and Balance Sheets for the Municipal Year ended 31st July 1927. Durban: Hayne & Gibbon, 1928. 15. Durban Borough Water Engineer. Correspondence from Borough Water Engineer to Works Committee re ‘Present Position of Water Supply’, May 18, 1926. Reports of the Durban Borough Water Engineer, 1925 - 26. Durban: Borough Water Engineer Office, 1926. 16. Christie J. Remarks on ‘Kidinga Pepo’: A peculiar form of exanthematous disease epidemic in Zanzibar, East Coast of Africa, from July 1870 till January 1871. BMJ 1872;1(596):577-579. 17. Christie J. On epidemics of dengue fever: their diffusion and etiology. Glasgow Med J 1881;3:161-176. 18. Carey D. Chikungunya and dengue: A case of mistaken identity? Hist Med Allied Sci 1971;26(3):243262. https://doi.org/10.1093/jhmas/XXVI.3.243 19. Kuno G. A re-examination of the history of etiologic confusion between dengue and chikungunya. PLoS Negl Trop Dis 2015:9(11):1-11. https://doi.org/10.1371/journal.pntd.0004101 20. Halstead S. Reappearance of chikungunya, formerly called dengue, in the Americas. Emerg Infect Dis 2015;21(4):557-561. https://doi.org/10.3201/eid2104.141723 21. Labonte J. Epidemic of dengue in the island of Mauritius in 1873. Edinb Med J 1874;20:322-325. 22. Army Medical Department, Great Britain. On the health of troops serving in the island of Mauritius. Army Medical Department Report for the Year 1873. London: Her Majesty’s Stationery Office, 1875:95-100. 23. Durban (From our Correspondent). The Natal Witness 23 January 1874. 24. Local and General: The Sickness. The Natal Mercury 27 January 1874.

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25. Correspondence from District Surgeon, Durban, to Colonial Secretary re: ‘Dengue Prevailing in Durban,’ March 14, 1878. Folder 966/1878, Box 634, Series CSO (Correspondence of the Colonial Secretary, Natal), KwaZulu-Natal Provincial Archives. 26. The Week. The Natal Mercury 19 March 1878. 27. Rotz PD. The fever next time: Aedes aegypti and the back-to-the-future risk of arbovirus outbreaks in Durban, South Africa. The Pardee Papers (in press). 28. Rotz PD. Sweetness and Fever? Sugar production, Aedes aegypti, and dengue fever in Natal, South Africa, 1926-27. S. Afr Hist J 2016;68(3):286-303. https://doi.org/10.1080/02582473.2016.1246590 29. Nicholson SE, Entekhabi D. The quasi-periodic behavior of rainfall variability in Africa and its relationship to the southern oscillation. Arch Meteorol Geophys Bioclimatol A 1986;34(3-4):311-348. https://doi.org/10.1007/BF02257765 30. Lindesay JA, Vogel CH. Historical evidence for southern oscillation-southern African rainfall relationships. Int J Climatol 1990;10:679-689. https://doi.org/10.1002/joc.3370100703 31. Nash DJ, Pribyl K, Klein J, et al. Seasonal rainfall variability in Southeast Africa during the nineteenth century reconstructed from documentary sources. Clim Change 2016;134(4):605-619. https://doi. org/10.1007/s10584-015-1550-8 32. Lindeque M. Zika virus: Is SA at risk? Eyewitness News 29 January 2016. http://ewn.co.za/2016/01/29/ WHO-says-Zika-virus-spreads-explosively-4-million-cases-forecast (accessed 9 June 2016). 33. Farber T. ‘No risk in SA’ as WHO meets on Zika. The Sunday Times 31 January 2016. http://www. pressreader.com/south-africa/sunday-times/20160131/281801397989937 (accessed 9 February 2017). 34. Child K. SA blood not to Zika’s taste. The Sunday Times 1 February 2016. http://www.timeslive.co.za/ thetimes/2016/02/01/SA-blood-not-to-Zikas-taste (accessed 9 June 2016). 35. Skosana I. Key institutes keep watch on Zika for Africa. Bhekikisa Centre for Health Journalism. 19 February 2016. http://bhekisisa.org/article/2016-02-18-key-institutes-keep-keen-watch-on-zika-forafrica (accessed 9 June 2016). 36. South African Broadcasting Corporation, Digital News. Minister Motsoaledi on Zika virus disease (televised interview). 19 February 2016. https://www.youtube.com/watch?v=5-TdFgkNHmQ (accessed 1 June 2016). 37. Parliamentary Monitoring Group. Minister of Health on Zika virus and typhoid preparedness and response. Briefing given to the Portfolio Committee on Health, Parliament of South Africa (audio recording). 9 March 2016. https://soundcloud.com/pmgza/minister-of-health-on-zika (accessed 28 January 2017). 38. National Institute for Communicable Diseases, South Africa. An update on Zika virus. Commun Dis Commun 2016;15(3):1-2. http://www.nicd.ac.za/assets/files/NICD%20Communicable%20 Diseases%20Communique_Mar2016_final.pdf (accessed 14 April 2016). 39. Van Vuren PJ, Weyer J, Kemp A, et al. Is South Africa at risk for Zika virus disease? S Afr Med J 2016;106(3):232-233. https://doi.org/10.7196/SAMJ.2016.v106i3.10615 40. Powell JR, Tabachnik WJ. History of domestication and spread of Aedes aegpyti – a review. Mem Inst Oswaldo Cruz 2013;108(Suppl 1):11-17. https://doi.org/10.1590%2F0074-0276130395 41. Jupp PG, Kemp A, Frangos C. The potential for dengue in South Africa: Morphology and the taxonomic status of Aedes aegypti populations. Mosq Systematics 1991;23(3):182-190. 42. De Meillon B. Proved and potential vectors of yellow fever in South Africa. Bull World Health Organ 1954;11(3):443-451. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2542194/pdf/ bullwho00552-0131.pdf (accessed 15 July 2016). 43. Muspratt J. The Stegomyia mosquitoes of South Africa and some neighbouring territories. Mem Entomological Soc South Afr 1956;4:1-138. 44. Kemp A, Jupp PG. Potential for dengue in South Africa: Mosquito ecology with particular reference to Aedes aegypti. J Am Mosq Control Assoc 1991;7(4):574-583. 45. McIntosh BM, Jupp PG. Attempts to transmit chikungunya virus with six species of mosquito. J Med Entomol 1970;7(5):615-618. https://doi.org/10.1093/jmedent/7.5.615 46. Jupp PG, McIntosh BM, dos Santos I, de Moor, P. Laboratory studies on six mosquito and one tick species with chikungunya virus. Trans R Soc Trop Med Hyg 1981;75(1):15-19. https://doi. org/10.1016/0035-9203(81)90005-5 47. Jupp PG, Kemp A. The potential for dengue in South Africa: Vector competence tests with DENV 1 and 2 viruses in 6 mosquito species. Trans R Soc Trop Med Hyg 1993;87(6):639-643. https://doi. org/10.1016/0035-9203(93)90271-q 48. Jupp PG, Kemp A. Laboratory vector competence with yellow fever viruses and five South African mosquito species, including Aedes aegypti. Trans R Soc Trop Med Hyg 2002;96(5):493-498. https://doi. org/10.1016/s0035-9203(02)90417-7 49. Miller BR, Monath TP, Tabachnick WJ, Ezike VI. Epidemic yellow fever caused by an incompetent mosquito vector. Trop Med Parasitol 1989;40(4):396-399. 50. Statistics South Africa. South African Statistics, 2004/05. Pretoria: Stats SA, 2005. https://www.statssa. gov.za/publications/SAStatistics/SAStatistics2004.pdf (accessed 28 July 2016). 51. Christophers SR. Aedes aegypti (L), the Yellow Fever Mosquito: Its Life History, Bionomics, and Structure. Cambridge: Cambridge University Press, 1960. 52. Rueda LM, Patel KJ, Axtell RC, Stinner RE. Temperature dependent development and survival rates of Culex quinquefasciatus and Aedes aegypti (Diptera, Culicidae). J Med Entomol 1990;27(5):892-898. https://doi.org/10.1093/jmedent/27.5.892 53. Tun-Lin W, Burkot TR, Kay BH. Effects of temperature and larval diet on development rates and survival of the dengue vector Ae. aegypti in north Queensland, Australia. Med Vet Entomol 2000;14(1):31-37. https://doi.org/10.1046/j.1365-2915.2000.00207.x 54. De Almeida Costa EAP, de Mendonca Santos EM, Correia JC, de Albuquerque CMR. Impact of small variations in temperature and humidity on the reproductive activity and survival of Aedes aegypti. Rev Bras Entomol 2010;54(3):488-493. https://doi.org/10.1590/s0085-56262010000300021 55. World Health Organization. Global Strategy for Dengue Prevention and Control, 2012 - 2020. Geneva: WHO, 2012. http://apps.who.int/iris/bitstream/10665/75303/1/9789241504034_eng.pdf (accessed 9 June 2016). 56. Moreno-Madrinan MJ, Turell M. Factors of concern regarding Zika and other Aedes aegyptitransmitted viruses in the United States. J Medical Entomol 2017;54(2):251-257. https://doi. org/10.1093/jme/tjw212

57. Reiter P, Lathrop S, Bunning M, et al. Texas lifestyle limits transmission of dengue virus. Emerg Infect Dis 2003;9(1):86-89. https://doi.org/10.3201/eid0901.020220 58. eThekwini Municipality. Integrated Development Plan: 2016 - 17 Annual Review. eThekwini: eThekwini Municipality, 2016. http://www.durban.gov.za/City_Government/City_Vision/IDP/ Documents/Final%202016_17%20IDP%2029052016.pdf (accessed 24 July 2016). 59. Statistics South Africa. GHS Series Report, volume VIII: Water and Sanitation, In-depth Analysis of General Household Survey 2002 - 2005 and Community Survey 2016 Data. Pretoria: Stats SA, 2016. http://www.statssa.gov.za/publications/03-18-07/03-18-072015.pdf (accessed 24 July 2016). 60. Durban Corporation. Medical Officer of Health’s Report for the year ended 30th June 1927. Durban: Hayne & Gibson Printers, 1928. 61. McClelland GAH. Observations on the mosquito Aedes (Stegomyia) aegypti (L.), in East Africa. II: The biting cycle in a domestic population on the Kenya Coast. Bull Entomol Res 1959;50(4):687-696. https://doi.org/10.1017/S0007485300054729 62. Duffy MR, Chen TH, Hancock WT, et al. Zika virus outbreak on Yap Island, Federated States of Micronesia. N Engl J Med 2009;360(24):2536-2543. https://doi.org/10.1056/nejmoa0805715 63. Bhatt S, Gething PW, Brady OJ, et al. The global distribution and burden of dengue. Nature 2013;496(77446):504-507. https://doi.org/10.1038/nature12060 64. Duong VL, Lambrechts RE, Paul RE, et al. Asymptomatic humans transmit dengue virus to mosquitoes. Proc Natl Acad Sci U S A 2015;112(47):14688-14693. https://doi.org/10.1073/pnas.1508114112 65. Statistics South Africa. General Household Survey: Selected Development Indicators – Metros, 2015. Pretoria: Stats SA, 2015. http://www.statssa.gov.za/publications/Report-03-18-20/ Report-03-18-202015.pdf (accessed 5 July 2016). 66. King Shaka International Airport: Built for the long haul. The SA Mag (undated). http://thesa-mag. com/features/transport/king-shaka-international-airport-built-long-haul/ (accessed 5 August 2016). 67. Dube TradePort Corporation. King Shaka International Airport hits new highs 46 percent increase in international passenger growth (press release). 6 September 2016. ht t p : / / w w w. d u b e t r a d e p o r t . c o. z a / Ne w s / 7 / P r e s s - R e l e a s e s - a n d - S t at e m e nt s / 6 0 2 0 1 / KingShakaInternationalAirporthitsnewhighswitha46percentincreaseininternationalpassengergrowth (accessed 8 October 2016). 68. eThekwini Municipality. Taking Durban to the World: Durban Tourism and Visitor Marketing Strategy, 2013 - 2020. Durban: eThekwini Municipality, 2012. http://www.durbanexperience. co.za/Media/Download/Documents/Strategies/Durban%20Visitor%20Marketing%20Strategy%20 Summary%20booklet.pdf (accessed 24 July 2016). 69. eThekweni Municipality, Environment Planning and Climate Protection Department. Durban Climate Change Strategy. Durban: eThekweni Municipality, 2014. http://www.durban.gov.za/City_Services/ energyoffice/Documents/DCCS_Final.pdf (accessed 6 June 2016). 70. Watts DM, Burke DS, Harrison BA, Whitmire RE, Nisalak A. The effect of temperature on the vector efficiency of Aedes aegypti for dengue 2 virus. Am J Trop Med Hyg 1987;36(1):143-152. https://doi. org/10.4269/ajtmh.1987.36.143 71. Rohani A, Wong YC, Zamre I, Lee HL, Zurainee MN. The effect of extrinsic incubation temperature on development of dengue serotype 2 and 4 viruses in Aedes aegypti (L). Southeast Asian J Trop Med Public Health 2009;40(5):942-950. http://www.tm.mahidol.ac.th/seameo/2009-40-5/12-4570.pdf (accessed 10 August 2018). 72. Reiter P. Climate change and mosquito-borne disease. Environ Health Perspect 2001:109(1):141-161. https://doi.org/10.2307/3434853 73. Beebe NW, Cooper RD, Mottram P, Sweeney AW. Australia’s dengue risk driven by human adaptation to climate change. PLoS Negl Trop Dis 2009;3(5):e429. https://doi.org/10.1371/journal.pntd.0000429 74. Sutherland PCG, Meller HJ, Addison WH. Report on the Government Hospital, Durban. 20 June 1871. Box 103, Series CO 179, Public Records Office, The National Archives of the UK. 75. Durban (from our Correspondent). The Natal Witness 16 February 1877. 76. Durban Township Water Supply Commission Evidence, June - July 1898. Box 2836, Series CSO (Correspondence of the Colonial Secretary, Natal), KwaZulu-Natal Provincial Archives. 77. Correspondence from Harbour Department Engineer to Secretary of Railways and Harbours, re ‘Notices received from Health Department ordering the removal from their premises of all water tanks’, 12 January 1906. Folder 72/1906, Box II/1/95, Series NHD (Records of the Natal Harbour Department), KwaZulu-Natal Provincial Archives. 78. Office of the Chief Sanitary Inspector, Report on Activities in Connection with Anti-Mosquito Campaign, 5 April 1928. Folder 184, volume 3 (Eradication of Flies and Mosquitoes), Box 4/1/2/831, Series 3/DBN (Records of the Durban Town Clerk), Durban Archives Repository. 79. Borough of Durban, Annual Report of Borough Medical Officer of Health, Year Ending 30th June, 1935. Durban: Durban Corporation, 1935. 80. Golder & Associates. Community-based Adaptation to Climate Change in Durban. Durban: eThekweni Municipality, 2011. 81. eThekwini Water and Sanitation. Good Science Makes Good Policy: eThekwini Water and Sanitation Innovations, 2012. Durban: eThekwini Municipality, 2012. http://prg.ukzn.ac.za/docs/default-source/ supporting-documentation/ews-innovations-2012.pdf?sfvrsn=2 (accessed 10 December 2017). 82. eThekwini Municipality. Nexus: Projects Under taken by the eThekwini Municipality, Durban. Durban, eThekweni Municipality, 2013. http://prg.ukzn.ac.za/docs/default-source/ews/nexusbooklet-final.pdf?sfvrsn=2 (accessed 24 July 2016). 83. Galvin M. A hot climate for civil society engagement with climate change and water in Durban. In: Perkins PE, ed. Water and Climate Change in Africa: Challenges and Community Initiatives in Durban, Maputo and Nairobi. New York: Routledge, 2013:63-70. 84. eThekwini’s 10-year water security plan. Daily News 1 August 2017. https://www.iol.co.za/dailynews/ ethekwinis-10-year-water-security-plan-10577656 (accessed 20 September 2017). 85. Trewin B, Darbo J, Jansen C, et al. The elimination of the dengue vector, Aedes aegypti, from Brisbane, Australia: The role of surveillance, larval habitat removal and policy. PLoS Negl Trop Dis 2017;11(8):e0005848. https://doi.org/10.1371/journal.pntd.0005848

S Afr Med J 2018;108(5):364-366. DOI:10.7196/SAMJ.2018.v108i5.12900

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GUEST EDITORIAL

Perioperative evaluation of patients who are due to undergo surgery Physicians are often requested to evaluate patients before surgery, either in response to a request from a surgeon or a primary care clinician assessing the patient prior to surgical referral. The objectives of this preoperative evaluation are to determine the risk to the patient of the proposed procedure and to minimise risk by: (i) identifying unrecognised comorbid disease and risk factors for medical complications of surgery; (ii) optimising the preoperative medical condition; (iii) recognising and treating potential complications; and (iv) working effectively as a member of the preoperative team (including those from nursing, medical, surgical and anaesthetic backgrounds). Does preoperative evaluation of patients improve surgical outcomes? Data from published studies reveal that physicians and anaesthetists are more likely to identify conditions that may affect surgical outcomes. They then recommend interventions for these conditions[1,2] and occasionally cancel or delay surgery so that medical conditions can be optimally managed,[3] ensuring a high level of satisfaction with co-management arrangements.[4] Data on the effect of preoperative medical consultation on cost measures are conflicting. Three large studies reported a decrease in hospital stay after perioperative evaluation and care of patients undergoing thoracic,[5] hip[6] and various other operations.[7] Some studies, however, showed increased costs and a similar length of stay for patients who had been consulted.[4,8] Similarly, studies of the impact of perioperative medical evaluation on perioperative mortality are contradictory. In an investigation of neurosurgical patients, medical consultation had no effect on mortality,[4] while in a different study, it was shown to increase 30-day and 1-year mortality rates and length of hospital stay, respectively.[9] Overall, robust evidence demonstrating clear improvements in resource utilisation or patient outcomes is currently lacking. Nevertheless, the practice of perioperative evaluation is widespread and, assuming doctors make evidence-based recommendations that improve surgical outcomes, it is reasonable to infer that consultation will improve the care of the surgical patient if consultative recommendations are implemented. Closer to home, perioperative research remains unco-ordinated in South Africa (SA). A group of investigators and interested individuals collaborated under the auspices of the SA Perioperative Research Group (SAPORG). Members of SAPORG believe that: (i) collaborative research is necessary to address the clinical challenges encountered in perioperative care and outcomes, both in SA and globally; (ii) there is capacity to conduct national and international collaborative research in SA; (iii) collaborative research conserves limited research resources; (iv) there are urgent public health issues in perioperative medicine that need to be addressed to improve the health of the SA population; and (v) a national research prioritysetting process is necessary to prioritise research in an environment of limited research resources.[10] To this end, SAPORG has defined 10 research priorities for perioperative medicine in SA: (i) the establishment of a national database of critical care outcomes and critical care resources; (ii) a randomised controlled trial of preoperative B-type natriuretic peptide-guided medical therapy to decrease major adverse cardiac events after non-cardiac surgery; (iii) a national prospective obser-

vational study of the outcomes associated with paediatric surgical cases; (iv) a national observational study of maternal and fetal outcomes following operative delivery in SA; (v) a stepped-wedge trial of an enhanced recovery-after-surgery programme; (vi) a stepped-wedge trial of a surgical safety checklist of patient outcomes in SA; (vii) a prospective observational study of perioperative outcomes after surgery in district general hospitals in SA; (viii) shortcourse interventions to improve anaesthetic skills of rural doctors; (ix) studies of the efficacy of simulation training to improve patient outcomes, team dynamics and leadership; and (x) the development and validation of a risk stratification tool for SA surgery based on the SA Surgical Outcomes Study (SASOS) data.[10] A recent publication in the Lancet reported on a 7-day, international, prospective, observational cohort study of patients aged ≥18 years undergoing any inpatient surgery in 25 countries in Africa (African Surgical Outcomes Study).[11] A total of 11 422 patients were included from 247 hospitals serving a median population of 810 000, with a combined number of specialist surgeons, obstetricians and anaesthetists of 0.7/100 000 population. A median of 212 surgical procedures per 100 000 population were performed in hospitals each year. Patients were younger (mean age 38.5 years) and had a lower risk profile than that reported in high-income countries. Patients (11%) were infected with HIV, 57% of procedures were urgent or emergent, and the most common procedure was caesarean delivery (33%). Postoperative complications occurred in 18.2%, and 2.1% of patients died the day after surgery. In this important publication, despite a low-risk profile and few postoperative complications, patients in Africa were twice as likely to die after surgery compared with the global average for postoperative deaths. The authors conclude that initiatives to increase access to surgical treatments in Africa therefore should be coupled with improved surveillance for deteriorating physiology in patients who develop postoperative complications and the resources necessary to achieve this objective.[11] In this CME issue, Du Toit et al.[12] review the perioperative management of diabetes. In their comprehensive summary, the authors review the guidelines for optimisation and perioperative management of diabetic patients, and importantly place their discussion within the SA context. Ultimately, perioperative diabetic care should be driven by a multidisciplinary team considering the evidence base within a resource and patient context. The second article, by Neethling et al.,[13] discusses the role of point-of-care ultrasound (POCUS) as an essential modality in the assessment of critically ill patients and those in the perioperative period. POCUS can be performed by trained non-cardiologist physicians at the patient’s bedside as an adjunct to the physical examination, and aids with the rapid diagnosis of severe and life-threatening pathological conditions, often changes clinical management and may have an impact on patient outcomes. While no large studies have definitively shown a decrease in perioperative morbidity associated with perioperative medical consultation, the practice is nevertheless widespread and, assuming that consultants make evidence-based recommendations that improve surgical outcomes, it is reasonable to infer that consultation will improve the care of the surgical patient. The experienced

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perioperative medicine physician should be able to identify the pertinent medical problems, anticipate potential perioperative problems, avoid addressing issues outside of their area of expertise or issues unrelated to the procedure, assess a patient’s risk and need for further interventions, and communicate effectively with the surgeon and anaesthesiologist. There is now emerging evidence of the status of perioperative medicine and outcomes on the African continent. In the future, it is my hope that further research in this area will improve surgical outcomes of patients in SA and beyond. Conflicts of interest. None. Funding. This manuscript is not funded. Prof. N Ntusi gratefully acknowledges support from the National Research Foundation and the Medical Research Council of South Africa, as well as the Harry Crossley Foundation.

Ntobeko Ntusi Division of Cardiology, Department of Medicine, Faculty of Health Sciences, University of Cape Town and Groote Schuur Hospital; Cape Universities Body Imaging Centre, Faculty of Health Sciences, University of Cape Town; and Hatter Institute of Cardiovascular Research in Africa, Department of Medicine, Faculty of Health Sciences, University of Cape Town, South Africa ntobeko.ntusi@uct.ac.za

1. Devereaux PJ, Ghali WA, Gibson NE, et al. Physicians’ recommendations for patients who undergo noncardiac surgery. Clin Invest Med 2000;23(2):116-123. 2. Clelland C, Worland RL, Jessup DE, East D. Preoperative medical evaluation in patients having joint replacement surgery: Added benefits. South Med J 1996;89(10):958-960. https://doi. org/10.1097/00007611-199610000-00004 3. Mollema R, Berger P, Girbes AR. The value of peri-operative consultation on a general surgical ward by the internist. Neth J Med 2000;56(1):7-11. https://doi.org/10.1016/s0300-2977(99)00081-9 4. Auerbach AD, Wachter RM, Cheng HQ, et al. Comanagement of surgical patients between neurosurgeons and hospitalists. Arch Intern Med 2010;170(22):2004-2010. https://doi.org/10.1001/ archinternmed.2010.432 5. Macpherson DS, Parenti C, Nee J, Petzel RA, Ward H. An internist joins the surgery service: Does comanagement make a difference? J Gen Intern Med 1994;9(8):440-444. https://doi.org/10.1007/ bf02599059 6. Phy MP, Vanness DJ, Melton LJ, et al. Effects of a hospitalist model on elderly patients with hip fracture. Arch Intern Med 2005;165(7):796-801. https://doi.org/10.1001/archinte.165.7.796 7. Vazirani S, Lankarani-Fard A, Liang LJ, Stelzner M, Asch SM. Perioperative processes and outcomes after implementation of a hospitalist-run preoperative clinic. J Hosp Med 2012;7(9):697-701. https:// doi.org/10.1002/jhm.1968 8. Auerbach AD, Rasic MA, Sehgal N, Ide B, Stone B, Maselli J. Opportunity missed: Medical consultation, resource use, and quality of care of patients undergoing major surgery. Arch Intern Med 2007;167(21):2338-2344. https://doi.org/10.1001/archinte.167.21.2338 9. Wijeysundera DN, Austin PC, Beattie WS, Hux JE, Laupacis A. Outcomes and processes of care related to preoperative medical consultation. Arch Intern Med 2010;170(15):1365-1374. https://doi. org/10.1001/archinternmed.2010.204 10. Biccard BM, Alphonsus CS, Bishop DG, et al. National priorities for perioperative research in South Africa. S Afr Med J 2016;106(5):58-59. https://doi.org/10.7196/SAMJ.2016.v106i5.10269 11. Biccard BM, Madiba TE, Kluyts HL, et al; African Surgical Outcomes Study (ASOS) investigators. Perioperative patient outcomes in the African Surgical Outcomes Study: A 7-day prospective observational cohort study. Lancet 2018;(epub ahead of print). https://doi.org/10.1016/S01406736(18)30001-1 12. Du Toit L, Biesman-Simons T, Levy N, Dave JA. A practical approach to managing diabetes in the perioperative period. S Afr Med J 2018;108(5):369-375. https://doi.org/10.7196/SAMJ.2018.v108i5. 13311 13. Neethling E, Roodt F, Beck C, Swanevelder JLC. Point-of-care and lung ultrasound incorporated in daily practice. S Afr Med J 2018;108(5):376-381. https://doi.org/10.7196/SAMJ.2018.v108i5.13313

S Afr Med J 2018;108(5):367-368. DOI:10.7196/SAMJ.2018.v108i5.13329

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A practical approach to managing diabetes in the perioperative period L du Toit,1 MB ChB, FCA (SA), MMed (Anaes); T Biesman-Simons,1 MB ChB, DA (SA); N Levy,2 MBBS, BSc, FRCA, FFICM; J A Dave,3 MB ChB, PhD, FCP (SA), Cert Endocrinology (SA) Department of Anaesthesia and Perioperative Medicine, Groote Schuur Hospital, Cape Town, South Africa Department of Anaesthesia and Perioperative Medicine, West Suffolk Hospital, UK 3 Division of Endocrinology and Diabetic Medicine, Groote Schuur Hospital, Cape Town, South Africa 1 2

Corresponding author: L du Toit (leon.alive@gmail.com)

Diabetes mellitus (DM) is a common multisystem disease with hyperglycaemia as the hallmark. It is a modifiable risk factor of complications after surgery. The incidence of DM and its impact on public health are steadily increasing globally. In South Africa (SA), it is estimated that a large proportion of people living with DM are undiagnosed. A number of international groups have addressed the problem of DM in the perioperative period, proposing guidelines for optimisation and management of these patients. The guidelines fail to address the variety of contexts within which surgery is delivered in SA. In this review, the authors discuss DM within the SA context. The article provides a range of approaches to managing the patient with DM in the perioperative period. Importantly, the perioperative healthcare providerâ&#x20AC;&#x2122;s approach should be steered by a local multidisciplinary team that considers the evidence base in light of their resource and patient context. S A fr Med J 2018;108(5):369-375. DOI:10.7196/SAMJ.2018.v108i5.13311

The burden of non-communicable disease in South Africa (SA) is escalating. Undiagnosed and uncontrolled diabetes mellitus (DM) are common in patients requiring surgery. Access to resources and expertise to safely control blood glucose levels in the perioperative period are variable in the SA public healthcare system. The combination of an increasing burden of disease and inadequate perioperative diabetes management is likely to increase surgical complication rates, mortality and cost of care. This article focuses on perioperative diabetes management of type 1 and type 2 DM patients who are undergoing surgery in a noncritical care setting. Obstetric, paediatric and critical care patients are excluded from this discussion.

Burden of disease

Type 2 DM is the most common type of diabetes, representing >90% of the DM disease burden in SA. The International Diabetes Federation reports that there are currently ~1.8 million adults in SA known to have DM, while a further 1.5 million adults remain undiagnosed.[1] The SA National Health and Nutrition Examination Survey (SANHANES) 2012 showed a national prevalence of abnormal glucose regulation of 18.6%, varying according to ethnicity and degree of urbanisation. According to SANHANES, 45% of people with diabetes were previously undiagnosed.[2] Over the past decade, DM has become one of the major underlying causes of mortality globally; in SA it now ranks second only to tuberculosis.[3] The SA Surgical Outcomes Study (SASOS) reports a 10.2% prevalence of diabetes in our surgical population (5.8% non-insulin dependent, and 4.4% insulin dependent).[4]

Diabetes mellitus in the perioperative context

The perioperative period is associated with worsening glycaemic control, probably due to the stress response of surgery.[5] Starvation,

tissue trauma and pain lead to increased levels of pro-inflammatory mediators and circulating stress hormones. These substances alter insulin secretion and sensitivity, producing a state of relative insulin resistance, protein catabolism and lipolysis with liberation of free fatty acids. This state can extend for multiple days into the postoperative period, driving adverse patient outcomes.[6] These include increased mortality, increased length of hospital stay, as well as increased infective (surgical site infections, urinary tract infections and pneumonia) and non-infective complications (cardiac events, acute kidney injury and stroke).[7] Protocol-driven quality improvement projects result in improved perioperative glycaemic control, but strict control strategies increase hypoglycaemic events.[8,9] As hypoglycaemia has been linked to mortality, it is essential to avoid the condition by targeting a perioperative blood glucose level in the range of 6.0 - 10.0 mmol/L.[10] A capillary blood glucose (CBG) measurement up to 12.0 mmol/L may be tolerated for brief periods if it is regularly monitored and expected to decrease.[11,12] Hyperglycaemia in the perioperative period may be due to physiological stress and should not be diagnosed as DM without input from the local diabetes healthcare provider. Stress hyperglycaemia without DM is a poorly understood entity, the management of which remains unclear.[5]

Perioperative management

Consider perioperative management of DM in three phases: preoperative, intraoperative, and postoperative. Preoperative In the preoperative phase the patient with DM must be identified and assessed to define a perioperative management plan. Screen for undiagnosed DM according to the Society for Endocrinology, Diabetes and Metabolism of SA (SEMDSA) guidelines.[13] Evaluate the diabetic patientâ&#x20AC;&#x2122;s capacity to manage the disease, chronic glycaemic

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control and invasiveness of the planned surgery. Where available, a glycated haemoglobin (HbA1c) should be used to determine adequacy of glycaemic control in those diagnosed with diabetes. An elevated HbA1c correlates with poor patient outcomes after surgery and an HbA1c >8.5% (69 mmol/mol) warrants postponement of elective surgery.[11,12] More stringent cut-off values are recommended by some, but may currently be unattainable in many parts of SA.[14] The patient’s comorbidities and glycaemic control should always be optimised before elective surgery. In an emergency, there is little time for optimisation, as surgery must proceed promptly. Often though, patients present for surgery that is time sensitive. In this ‘grey zone’ between elective and emergency, the timing of surgery should be determined by a multidisciplinary team with a patientcentred discussion about how best to balance risk and benefit.[15] The decision to proceed with surgery in the face of uncontrolled DM must acknowledge the increased risk to the patient and define ways to manage this risk. Resources and access to expertise vary among healthcare centres. It is therefore important to choose an appropriate perioperative glycaemic management plan. Although many options are available, four are commonly used and recommended (Table 1): • modification of usual treatment (Tables 2 and 3) • basal-bolus subcutaneous (SC) insulin (Fig. 1) • Alberti’s glucose-insulin-potassium (GIK) intravenous infusion (Box 1) • variable rate intravenous insulin infusion (VRIII) (Fig. 2). Monotherapy with SC short- or rapid-acting insulin according to a sliding scale is not recommended for in-hospital management of

DM, as it increases the risk of hypoglycaemia and provides inferior glycaemic control.[16,17] In all cases, limiting of the starvation period has to be planned, as well as where the patient will be managed postoperatively (day case, surgical ward or high-care facility). For short starvation periods (one missed meal), modification of the usual medication will often suffice (Tables 2 and 3). Missing more than one perioperative meal is considered a prolonged starvation period. If the CBG is >12 mmol/L, it will necessitate either basal SC insulin or an intravenous insulin infusion. Intraoperative The intraoperative phase starts at the time of arrival in theatre and continues until transfer to the postoperative ward. The patient with DM must have a documented CBG prior to commencement of anaesthesia. While under anaesthesia, the CBG should be monitored at least 2-hourly, more frequently if abnormal and in patients receiving insulin.[18] If the intraoperative CBG levels were abnormal, the CBG measurement should be repeated in the post-anaesthetic recovery area. When possible, administer SC short- or rapid-acting insulin to avoid unnecessary intravenous insulin for short surgical procedures. Limit SC short- or rapid-acting insulin to two intraoperative doses. In type 2 DM, a first dose of 0.1 U/kg (up to a maximum of 6 U) is appropriate; alternatively, use the correction dosing scale in Fig. 1 as a starting point. To prevent insulin stacking intraoperatively, do not administer a top-up dose of SC insulin within 2 hours of the first dose. Intravenous insulin is preferred when SC insulin does not control hyperglycaemia. This is common in surgery of longer duration, prolonged starvation and emergency cases.[11]

Table 1. Indications, advantages and disadvantages of four perioperative diabetes management strategies Management Modification of usual therapy

Indications HbA1c <8.5% Short starvation period (<1 meal missed) Basal-bolus SC insulin Those already on basal-bolus insulin with correction doses Type 1 diabetes Patients with poor baseline control Newly diagnosed DM requiring perioperative insulin therapy Short surgical duration Where IV insulin therapy is not feasible Alberti’s glucosePoor control on SC insulin insulin-potassium (CBG >12.0 mmol/L) infusion Prolonged starvation period (>1 meal missed) Long surgical duration Periods of inadequate tissue perfusion High-care or ICU setting VRIII is not an option VRII Poor control with SC insulin (CBG >12.0 mmol/L) Prolonged starvation period (>1 meal missed) Long surgical duration Periods of inadequate tissue perfusion High-care or ICU setting

Advantages Lowest risk for hypoglycaemia Decreased burden on ward staff Suitable for patient self-management Improved glycaemic control Flexible dosing Decreased risk of hypoglycaemia

Disadvantages Often not possible, as patients have poor baseline control or there is prolonged starvation Intensive Regular monitoring required Not to be used if the patient is not eating meals Unpredictable absorption when there is impaired tissue perfusion

Improved glycaemic control Flexible

Labour intensive Need trained staff Risk of hypo-Na+/K+ Risk of hypoglycaemia

Improved glycaemic control Flexible

Requires specialised equipment Labour intensive Need trained staff Risk of hypo-Na+/K+ Risk of hypoglycaemia

SC = subcutaneous; DM = diabetes mellitus; IV = intravenous; CBG = capillary blood glucose; ICU = intensive care unit; VRIII = variable rate intravenous insulin infusion.

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Table 2. Summary of non-insulin antidiabetic agents with recommendations for perioperative management[21,22] Management Insulin sensitisers

Secretagogues

Incretin family

Increased glucosuria

Impairs absorption

Class of drug (examples) Biguanides Metformin

Considerations Does not cause hypoglycaemia Risk of lactic acidosis

Thiazolidinediones Pioglitazone (roziglitazone)

Does not cause hypoglycaemia Concern of hepatotoxicity Contraindicated in haemodynamic instability Risk of hypoglycaemia

Sulphonylureas Glibenclamide Gliclazide Glimepiride Meglitinides Repaglinide Nateglinide GLP-1 analogues Exenatide Liraglutide DPP-4 inhibitors (gliptins) Saxagliptin Vildagliptin SGLT-2 inhibitors (gliflozins) Empagliflozin Dapagliflozin Alpha-glucosidase inhibitors Acarbose

Recommendations Continue while eating Omit on day of surgery Omit if risk of renal impairment (IV contrast, other nephrotoxic agents, haemodynamic instability) Omit if >1 meal missed Omit on day of surgery Restart when tolerating meals

Omit while fasting Restart when tolerating meals

Risk of hypoglycaemia

Omit while fasting Restart when tolerating meals

Delayed gastric emptying concern for aspiration risk Injectable only

Limited information May improve perioperative glycaemic control Limited information May improve perioperative glycaemic control Avoid in the perioperative period

Association with DKA

Causes severe flatulence and bloating

Avoid in the perioperative period

GLP-1 = glucagon-like peptide 1; DPP-4 = dipeptidyl peptidase-4; SGLT-2 = sodium-glucose co-transporter 2; DKA = diabetic ketoacidosis; IV = intravenous.

Table 3. Perioperative modification of insulin therapy*† Insulin regimen‡ Once daily (evening dosing) intermediate- or long-acting insulin Once daily (morning dosing) intermediate- or long-acting insulin Twice daily dosing Premixed insulin, or intermediate- or long-acting insulin Basal-bolus regimen

Day before surgery Reduce dose by 20% Usual dose Usual dose Usual bolus doses Reduce night-time basal dose by 20%

Day of surgery Restart insulin with evening meal Reduce dose by 20% Reduce morning dose to 50% Normal evening dose with dinner If basal dose in the morning, reduce by 20% Omit bolus doses while fasting

*Adapted from the Joint British Diabetes Society for Inpatient Care guidelines, with permission.[11] Appropriate where no more than one meal missed in the perioperative period. ‡ Check capillary blood glucose regularly while fasting. The majority of international guidelines advise 1- or 2-hourly measurements. Protocols with a 4-hourly measurement interval carry a 10% hypoglycaemia risk.[18] †

Postoperative After surgery, intravenous insulin therapy must not be discontinued without overlapping and restarting the patient’s basal SC insulin. Check the CBG before discharge from the post-anaesthetic recovery area. Ensure that the patient is sent to the appropriate level of care for continuation of their glycaemic control strategy. Early reinstatement of normal enteral feeding and usual antidiabetic medication is the goal. The agents and regimen used for glycaemic control will largely depend on the feeding status of the patient (Table 4).

There is a real risk of diabetic ketoacidosis (DKA) with transition to and from intravenous insulin therapy. Delays in commencing the intravenous insulin infusion, and discontinuation of the infusion prior to administration of basal insulin, cause acute insulin deficiency in insulin-dependent patients.[20] This risk can be mitigated by continuation of basal SC insulin while using intravenous insulin, or by administration of intermediate- or long-acting insulin 30 minutes before discontinuing the intravenous insulin (GIK or VRIII).[12]

Safe insulin therapy

Non-insulin antidiabetic agents should not be started in the immediate perioperative period. These medications have multiple contraindications and are not rapidly titratable. However, diabetic patients who are well controlled could be considered for continuation of their non-insulin agents during the perioperative period. Guidance

Insulin is an extremely potent agent. Drug errors can cause significant harm to the patient. Staff education and involvement of the local pharmacy are needed to ensure constant safe prescribing, dispensing and dosing practices.[19]

Non-insulin antidiabetic agents

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Three components • Basal – once daily intermediate- or long-acting insulin • Bolus – dosing at meal times with short- or rapid-acting insulin • Correction – additional dosing at meal times with short- or rapid-acting insulin to achieve or maintain the desired individualised glycaemic target For patients already on insulin, start with the patient’s usual TDD For insulin-naive patients, start with a TDD of 0.2 - 0.3 U/kg/day â Give 50% of the TDD as basal insulin Give 50% of the TDD as bolus doses (divide into 3 equal doses and give before each meal) â Give correction doses (added to the already prescribed insulin doses) according to the following dosing scale: Insulin correction dose, U

CBG, mmol/L

Level 1 (insulin sensitive, incl. fasting)

Level 2 (usual patient)

Level 3 (insulin resistant, TDD >80 U)

10.1 - 12.0 12.1 - 14.0 14.1 - 16.0 16.1 - 20.0 >20.0

2 3 4 5 6

4 6 8 10 12

6 9 12 15 18

To prevent insulin stacking, allow at least 4 hours between SC doses of insulin Two-hourly dosing is acceptable intraoperatively Reduce the basal doses to 80% of the usual dose on the night before and the morning of surgery Omit prandial dosing while fasting Provide hypoglycaemia management instructions wherever insulin is prescribed Fig. 1. Basal-bolus insulin regimen.[16,25,26] (TDD = total daily dose; CBG = capillary blood glucose; SC = subcutaneous.)

on the management of these agents during the perioperative period is given in Table 2. Modification of oral therapy as the primary perioperative glycaemic control strategy is only appropriate in uncomplicated surgical patients who miss one meal during the perioperative period. Critically ill patients, those with poor glycaemic control and those who miss multiple meals, should be managed with an appropriate insulin regimen.[21,22]

Hypoglycaemia

The perioperative period represents an increased risk for undiagnosed hypoglycaemia while patients are fasting and under the influence of sedative agents. Whenever insulin is prescribed in hospital, hypoglycaemia treatment must be prescribed on the same chart. Perioperatively, a CBG <6.0 mmol/L should be interpreted as imminent hypoglycaemia. A CBG <4.0 mmol/L is associated with harm and must be treated. Interruption of insulin therapy is discouraged, but dose

reduction may be necessary. Assess the patient with a low CBG for signs and symptoms of hypoglycaemia. Consider their feeding status (eating or fasting) and their risk of hypoglycaemia unawareness. Fig. 3 provides a suggested hypoglycaemia management algorithm. While under the influence of anaesthesia, treat all patients with a low CBG with intravenous dextrose. If the CBG is ˂6.0 mmol/L, administer 10 g intravenous dextrose; if the CBG is ˂4.0 mmol/L, give 20 g intravenous dextrose. Thereafter, the CBG should be measured every 15 minutes and treatment repeated until the blood glu cose is corrected.[11]

Special circumstances

SC insulin infusion (SCII) (or insulin pump therapy) is increasingly used in the management of type 1 DM. Patients using an insulin pump should,as far as possible, maintain control of their own perioperative glycaemic management. When assessing

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these patients, consider the invasiveness, duration and site of the surgery, as well as the anticipated postoperative course. Question how many meals the patient will skip. Will the anaesthetist have access to the SCII intraoperatively? Will the device location infringe on the surgical site? Ideally, a preoperative basal test is done to establish glycaemic response to the fasting state. If this was not done, ask the patient to decrease the SCII to 70 - 80% of the basal rate while fasting. Ensure that the anaesthetic provider understands how to adjust, discontinue and remove the SCII if necessary. If continued intraoperatively, one or two small (2 - 4 U) SC correctional doses of insulin may be administered if the CBG rises ≥10.0 12.0 mmol/L. If this fails to correct the CBG, start a VRIII. If the CBG decreases to ˂4.0 - 6.0 mmol/L, treat the hypoglycaemia with intravenous dextrose. If hypoglycaemia persists, disconnect the SCII and switch to a VRIII. SCII is not appropriate for emergency surgery or where more than one meal is missed in the perioperative period.[23,24] For patients with DM, day-case surgery must be considered.[14] It reduces the risk of iatrogenic complications and empowers the patient to manage their own perioperative glycaemic control. When assessing diabetic patients for day-case surgery, three aspects must be considered: • Is the patient physically, mentally and socioeconomically capable to self-manage their DM and do they have easy access to emergency healthcare should they need it? • Is their DM adequately controlled, with a recent HbA1c <8.5%? • Is the nature of the surgery suitable for a day case?

A multidisciplinary contextsensitive approach

No single scenario describes every patient with DM who has to undergo surgery. At each facility (or group of facilities) a representative multidisciplinary team must evaluate the unique patient-resource environment and develop an evidence-based clinical practice guideline that fits their context. Smaller facilities should obtain input from their regional specialist centre. It is essential to empower patients to selfmanage their diabetes, especially in a setting where access to resources or healthcare personnel is limited. When appropriate, patients should be given guidance to manage their own insulin and non-insulin antidiabetic therapy in the ward.[21] The dietician, or equivalent team member, must engage the kitchen service to ensure

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Box 1. Alberti glucose-insulin-potassium infusion[21,27] The GIK infusion is an alternative IV insulin regimen when a VRIII is not feasible. It provides substrate, IV insulin and electrolytes via a single infusion. The original GIK regimen was published by Alberti and Thomas in 1979. It provides a safe and effective method of giving substrate, IV insulin in the same infusion. Alterations of the original regimen remain in use today.[28,29,30] The original GIK regimen uses a bag containing 500 mL 10% dextrose and adds: • 10 U short-acting insulin • 10 mL 10% KCl. The infusion runs at a fixed rate of 100 mL/h, providing 2 U insulin per hour. CBG is measured 1 - 2-hourly. To increase or decrease the insulin infusion rate by 1 U/h the insulin content of the bag is changed up or down by 5 U. A new bag must be mixed each time it is decided to adjust the insulin infusion rate. Problems with the GIK infusion are: • labour intensive and wasteful when multiple bag changes are needed • maintenance at 100 mL/h exceeds current standards for care of surgical patients • 500 mL 10% dextrose bags are not available at all locations • 10% dextrose water is not an acceptable maintenance fluid • risk of DKA in type 1 DM if GIK infusion is stopped. If deemed appropriate for the location, the local multidisciplinary team must adapt the GIK regimen to suite their context and address the concerns mentioned. Involve specialist input. GIK = glucose-insulin-potassium; IV = intravenous; VRIII = variable rate intravenous insulin infusion; CBG = capillary blood glucose; DKA = diabetic ketoacidosis; DM = diabetes mellitus.

Use a dedicated IV access site and infusion set with an antireflux valve for glucose management Add 50 U of regular short-acting insulin to 50 mL 0.9% NaCl (1 mL = 1 U) Administer with a syringe driver connected to a port close to the dedicated IV cannula Run dextrose-containing maintenance solution at 25 mL/kg/day (20 - 30 mL/kg/h range) Monitor serum Na+ and K+ daily Measure CBG hourly while the patient is under the influence of anaesthesia; 2-hourly if normoglycaemic, awake, attended, and not confused Insulin rates, mL/h

CBG, mmol/L

Level 1 (insulin sensitive, incl. fasting)

Level 2 (usual patient)

Level 3 (insulin resistant, TDD >80 U)

<4.0

Reduce VRIII to 0.2 - 0.5 mL/h (stop VRIII if SC basal insulin continued) Administer 20 g dextrose IV Repeat CBG in 15 min

4.1 - 6.0

Reduce VRIII to 0.2 - 0.5 mL/h (stop VRIII if SC basal insulin continued) Consider administration of 10 g dextrose IV to prevent CBG decreasing to ˂4.0 mmol/L Repeat CBG in 15 min

6.1 - 8.0

0.5

8.1 - 12.0

12.1 - 16.0

16.1 - 20.0

20.1 - 24.0

>24.1

Seek specialist advice Target CBG range 6.0 - 12.0 mmol/L. CBG up to 12.0 mmol/L is acceptable for a short period Only increase VRIII if CBG remains high after 3 hours and is decreasing by ˂3 mmol/L/h There is a risk of DKA when discontinuing a VRIII, as it creates a state of acute insulin withdrawal Continue SC basal insulin while using a VRIII or administer SC basal insulin 30 min before discontinuing a VRIII Fig. 2. Variable rate intravenous insulin infusion regimen.[21,22] (CBG = capillary blood glucose; IV = intravenous; TDD = total daily dose; VRIII = variable rate intravenous insulin infusion; SC = subcutaneous; DKA = diabetic ketoacidosis.)

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Key points

Table 4. Blood glucose management according to feeding status Feeding status Eating normally Fasting

Management options Modification of usual therapy or basal-bolus SC insulin with correction doses VRIII, modified Alberti’s GIK, or basal insulin only*

Tube enteral feeding Total parenteral feeding

VRIII, modified Alberti’s GIK, or basal insulin only* VRIII, modified Alberti’s GIK, or basal insulin only*

SC = subcutaneous; VRIII = variable rate intravenous insulin infusion; GIK = glucose-insulin-potassium infusion. *It is best to avoid short- or rapid-acting insulin, as there is an increased risk of hypoglycaemia. However, small correction doses with frequent monitoring may be required if glucose readings are >12 mmol/L.

Provide the diagnostic criteria and management of hypoglycaemia with every in-patient diabetes prescription A low CBG must be interpreted in the context of the patient’s feeding status and symptomatology Decide whether the patient is at risk of hypoglycaemia unawareness. These include the frail, patients on beta-blockers, with long-standing DM, and those on medications with sedative effects. All such patients, including those under the influence of anaesthesia, should automatically be treated as symptomatic

CBG, mmol/L

Without symptoms and signs of hypoglycaemia

With symptoms or signs of hypoglycaemia

Normal diet

Fasting

Normal diet

Fasting

<4.0

Provide a snack and repeat the CBG in 15 30 min

Give 10 g dextrose IV and repeat the CBG in 15 - 30 min

Give 20 g dextrose IV and repeat CBG in 15 min Seek urgent help if no response to treatment

4.0 - 6.0

Increase monitoring frequency

Repeat CBG within 30 min If persistent, give 10 g dextrose IV and increase monitoring frequency

Provide a snack and repeat CBG in 15 - 30 min

Give 10 g dextrose IV and repeat CBG in 15 min Seek urgent help if no response to treatment

Fig. 3. Management of perioperative hypoglycaemia. (CBG = capillary blood glucose; DM = diabetes mellitus; IV = intravenous.)

that the diabetic diet provides a constant caloric intake from meal to meal and day to day. This will reduce prandial fluctuations in blood glucose and reduce the need for correction doses of insulin. The surgical team should understand the meal plan to ensure that minimal time elapses from the start of preoperative fasting until the first postoperative meal. The local protocol should consider how care will be escalated for selected patients. Every DM patient cannot be referred to a diabetologist. Also define how feedback on perioperative DM management will be used to bring the patient back into the primary healthcare system after the perioperative period.

Conclusion

DM is an ever-growing public health problem affecting patient outcomes after surgery. This article addresses the SA scope of the problem and provides a structure for managing the patient with DM presenting for surgery. A local multidisciplinary team should guide practice at each facility. The recommended reading section provides essential information for individual perioperative providers and teams caring for surgical patients with DM. Where a patient scenario falls outside the scope of this discussion, the provider must consult the local multidisciplinary team or referral specialist centre for guidance.

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• DM is a modifiable risk factor of adverse surgical outcomes. Undiagnosed DM or an HbA1c >8.5% (69 mmol/mol) is an indication to postpone elective surgery. • Monotherapy using SC short- or rapidacting insulin according to a sliding scale is not recommended. • In all patients with DM, attempt to mini mise the starvation period to only one missed meal. • A CBG range of 6.0 - 10.0 mmol/L is the recommended target in the perioperative period. A CBG up to 12 mmol/L may be acceptable. • Safe insulin prescribing practice requires prescription of hypoglycaemia treatment on every insulin prescription chart. • In-hospital interruption of insulin therapy is a common cause of DKA in patients with type 1 DM. • A multidisciplinary team should drive context-sensitive perioperative manage ment of DM. Acknowledgements. None. Author contributions. All authors contributed to the design, research and editing of this manuscript. Funding. None. Conflicts of interest. None. 1. International Diabetes Federation. IDF Diabetes Atlas. 8th ed. Brussels: IDF, 2017. http://www.diabetesatlas.org (accessed 8 April 2018). 2. Shisana O, Labadarios D, Rehle T, et al. The South African National Health and Nutrition Examination Survey, 2012: SANHANES-1. Pretoria: Human Sciences Research Council, 2014:477-473. 3. Statistics South Africa. Mortality and causes of death in South Africa, 2016: Findings from death notification. http://www. statssa.gov.za/publications/P03093/P0309320165.pdf (accessed 8 April 2018). 4. Biccard BM, Madiba TE. The South African Surgical Outcomes Study: A 7-day prospective observational cohort study. S Afr Med J 2015;105(6):465-475. https://doi.org/10.7196/SAMJ.9435 5. Davis G, Fayfman M, Reyes-Umpierrez D, et al. Stress hyperglycemia in general surgery: Why should we care? J Diabet Comp 2018;32(3):305-309. https://doi.org/10.1016/j. jdiacomp.2017.11.010 6. Duggan EW, Klopman MA, Berry AJ, Umpierrez G. The Emory University perioperative algorithm for the management of hyperglycemia and diabetes in non-cardiac surgery patients. Curr Diab Rep 2016;16(3):34. https://doi.org/10.1007/s11892016-0720-z 7. Frisch A, Chandra P, Smiley D, et al. Prevalence and clinical outcome of hyperglycemia in the perioperative period in noncardiac surgery. Diabet Care 2010;33(8):1783-1788. https:// doi.org/10.2337/dc10-0304 8. Alexanian SM. Glycemic outcomes three years after implementation of a perioperative glycemic control algorithm in an academic institution. Endocr Pract 2016;23(2):123-231. https://doi.org/10.4158/EP161354 9. Buchleitner AM, Martínez‐Alonso M, Hernández M, Solà I, Mauricio D. Perioperative glycaemic control for diabetic patients undergoing surgery. Cochrane Database Syst Rev 201;(9):CD007315. https://doi.org/10.1002/14651858.CD007315.pub2 10. Turchin A, Matheny ME, Shubina M, Scanlon JV, Greenwood B, Pendergrass ML. Hypoglycemia and clinical outcomes in patients with diabetes hospitalized in the general ward. Diabet Care 2009;32(7):1153-1157. https://doi.org/10.2337/dc08-2127 11. Barker P, Creasey PE, Dhatariya K, et al. Peri-operative management of the surgical patient with diabetes 2015: Association of Anaesthetists of Great Britain and Ireland. Anaesthesia 2015;70(12):1427-1440. https://doi.org/10.1111/ anae.13233

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12. Dhatariya K, Levy N, Hall GM. The impact of glycaemic variability on the surgical patient. Curr Opin Anaesthesiol 2016;29(3):430-437. https://doi.org/10.1097/ACO.0000000000000326 13. The Society for Endocrinology, Metabolism and Diabetes of South Africa Type 2 Diabetes Guidelines Expert Committee. Screening and diagnosis of type 2 diabetes and intermediate hyperglycaemia. SEMDSA guideline for the management of type 2 diabetes. J Endocrinol Metab Diabet S Afr 2017;22(1)(Suppl 1):S15-S19. 14. Joshi GP, Chung F, Vann MA, et al. Society for Ambulatory Anesthesia consensus statement on perioperative blood glucose management in diabetic patients undergoing ambulatory surgery. Anesth Analg 2010;111(6):1378-1387. https://doi.org/10.1213/ANE.0b013e3181f9c288 15. Levy N, Penfold NW, Dhatariya K. Perioperative management of the patient with diabetes requiring emergency surgery. BJA Educ 2016;17(4):129-136. https://doi.org/10.1093/bjaed/mkw056 16. Jaram MK. Hyperglycaemia management of type 2 diabetes mellitus inpatients in surgical wards at Livingstone Hospital. S Afr Pharmaceut J 2016;83(8):52-55. 17. Hirsch IB. Sliding scale insulin – time to stop sliding. JAMA 2009;301(2):213-214. https://doi.org/10.1001/ jama.2008.943 18. Sebranek JJ, Lugli AK, Coursin DB. Glycaemic control in the perioperative period. Br J Anaesth 2013;111(Suppl 1):i18-i34. https://doi.org/10.1093/bja/aet381 19. Hellman R. A systems approach to reducing errors in insulin therapy in the inpatient setting. Endocr Pract 2004;10(Suppl 2):100-108. https://doi.org/10.4158/EP.10.S2.100 20. National Diabetes Inpatient Audit England and Wales. 2016. http://www.digital.nhs.uk/pubs/ nadia2016 (accessed 8 April 2018). 21. Dhatariya KLN, Flanagan D, Hilton L, Kilvert A, Rayman G, Watson B. Management of adults with diabetes undergoing surgery and elective procedures: Improving standards. http://www.diabetologistsabcd.org.uk/JBDS/JBDS_IP_Surgical_Guideline_2015_Full.pdf (accessed 8 April 2018). 22. Stubbs DJ, Levy N, Dhatariya K. Diabetes medication pharmacology. BJA Educ 2017;17(6):198-207. https://doi.org/10.1093/bjaed/mkw075 23. Draznin B. Managing Diabetes and Hyperglycemia in the Hospital Setting: A Clinician’s Guide. Virginia: American Diabetes Association, 2016. https://doi.org/10.2337/9781580406086 24. Partridge H, Perkins B, Mathieu S, Nicholls A, Adeniji K. Clinical recommendations in the management of the patient with type 1 diabetes on insulin pump therapy in the perioperative period: A primer for the anaesthetist. Br J Anaesth 2016;116(1):18-26. https://doi.org/10.1093/bja/aev347 25. Umpierrez GE, Smiley D, Jacobs S, et al. Randomized study of basal-bolus insulin therapy in the inpatient management of patients with type 2 diabetes undergoing general surgery (RABBIT 2 surgery). Diabet Care 2011;34(2):256-261. https://doi.org/10.2337/dc10-1407

26. The Society for Endocrinology, Metabolism and Diabetes of South Africa Type 2 Diabetes Guidelines Expert Committee. In-hospital management of hyperglycaemia. SEMDSA guideline for the management of type 2 diabetes. J Endocrinol Metab Diabet S Afr 2017;22(1)(Suppl 1):S68-S73. 27. Alberti K, Thomas D. The management of diabetes during surgery. Br J Anaesth 1979;51(7):693-710. https://doi.org/10.1093/bja/51.7.693 28. Polderman JA, Steen SC, Thiel B, Godfried MB. Peri-operative management of patients with type2 diabetes mellitus undergoing non-cardiac surgery using liraglutide, glucose-insulin-potassium infusion or intravenous insulin bolus regimens: A randomised controlled trial. Anaesthesia 2018;73(3):332-339. https://doi.org/10.1111/anae.14180 29. Kayes MN, Prodhan NK, Malik RH. Perioperative management of diabetes: A review. Delta Med Coll J 2014;2(2):71-76. https://doi.org/10.3329/dmcj.v2i2.20528 30. Khan NA, Ghali WA, Cagliero E. Perioperative management of blood glucose in adults with diabetes mellitus. UpToDate. http://www.uptodate.com (accessed 8 April 2018).

Recommended reading Barker P, Creasey PE, Dhatariya K. Peri-operative management of the surgical patient with diabetes. Anaesthesia 2015;70(12):1427-1440. https://doi.org/10.1111/anae.13233 Hirsch IB. Sliding scale insulin – time to stop sliding. JAMA 2009;301(2):213-214. https://doi.org/10.1001/ jama.2008.943 Safer insulin prescribing. http://nice.org.uk/guidance/ktt20 (accessed 8 April 2018). Stubbs DJ, Levy N, Dhatariya K. Diabetes medication pharmacology. BJA Educ 2017;17(6):198-207. https:// doi.org/10.1093/bjaed/mkw075 The Society for Endocrinology, Metabolism and Diabetes of South Africa Type 2 Diabetes Guidelines Expert Committee. The 2017 SEMDSA guideline for the management of type 2 diabetes. J Endocrinol Metab Diabet S Afr 2017;22(1)(Suppl 1):S1-S196. Umpierrez GE, Smiley D, Jacobs S. Randomized study of basal-bolus insulin therapy in the inpatient management of patients with type 2 diabetes undergoing general surgery (RABBIT 2 surgery). Diabet Care 2011;34(2):256-261. https://doi.org/10.2337/dc10-1407

Accepted 3 April 2018.

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

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Point-of-care and lung ultrasound incorporated in daily practice E Neethling,1 MB ChB, DA (SA), FCA (SA); F Roodt,1 MB ChB, FCA (SA); C Beck,2 MB ChB, DA (SA); J L C Swanevelder,1 MB ChB, DA (SA), FCA (SA), MMed (Anaes), FRCA Department of Anaesthesia and Perioperative Medicine, Faculty of Health Sciences, Groote Schuur Hospital and University of Cape Town, and Red Cross War Memorial Children’s Hospital, Cape Town, South Africa 2 Department of Anaesthesia and Perioperative Care, Frere Hospital and Cecilia Makiwani Hospital, and Walter Sisulu University, East London, South Africa 1

Corresponding author: J L C Swanevelder (justiaan.swanevelder@uct.ac.za)

Point-of-care ultrasound (POCUS) is a fast-growing clinical utility and is becoming an essential clinical skill for all practitioners attending to critically ill patients. Ultrasound equipment is now smaller, more affordable and readily available in clinical work areas. POCUS is performed by a non-cardiologist physician at the patient’s bedside as an adjunct to the physical examination. It is easily taught, non-invasive and allows for real-time clinical information. Bedside use of ultrasound imaging aids with rapid diagnosis of severe and life-threatening pathological conditions. It can be repeated, may change clinical management, and impact on patient outcome. POCUS has a broad clinical use, including, but not limited to, focused assessed transthoracic echocardiography (FATE), lung ultrasound imaging, extended focused assessment with sonography for trauma (e-FAST), vascular access and regional blocks. It may also be extended to detect endotracheal intubation and the estimation of intracranial pressure. Assessment of cardiac pathology by POCUS, performed by a novice examiner, has been shown to compare with the gold standard of an expert. Training is paramount. The physician should know his limitations and always relate the information back to the clinical scenario and context. By incorporating POCUS as part of our armamentarium and into our daily medical practice, we might see it reach its full clinical potential, optimising patient care and improving patient outcomes. S Afr Med J 2018;108(5):376-381. DOI:10.7196/SAMJ.2018.v108i5.13313

Point-of-care ultrasound (POCUS) is a fast-growing clinical utility, and an essential clinical skill for all practitioners attending to patients in the perioperative period. It has been adopted in multiple areas of medicine and is fast becoming the standard of care, including but not limited to anaesthesia, surgery, intensive care, general medicine, emergency medicine and paediatrics.[1] Bedside use of ultrasound imaging assists with rapid diagnosis of severe and life-threatening pathological conditions, and the effective management thereof. During the past decade, the development of new digital technology, miniaturisation of hand-held devices, affordability and increased availability of equipment have led to the introduction of this skill in everyday practice. Assessment of cardiac pathology by POCUS performed by a novice examiner is comparable to that of the gold standard specialist ultrasonographer.[2] In resourcepoor environments it has been adopted as a screening tool before patient referral to larger centres. In a recently published article in Heart by Ploutz et al.,[3] the authors used hand-held echo equipment to screen school-age children in Uganda for rheumatic heart disease. The study confirmed that non-expert findings correlated with expert review. POCUS not only includes cardiac imaging, but also lung and abdominal ultrasonography, and is used when achieving vascular access. Essential features of POCUS: • simplified, limited scope • goal and problem orientated • time sensitive and repeatable • qualitative • performed by physician at the point of care • adjuncts to physical examination.

When using ultrasound to examine the heart, it is important to distinguish between focused cardiac ultrasound (FOCUS), limited transthoracic echocardiography (TTE) and a comprehensive examination.[4] A comprehensive TTE examination involves the use of specific equipment, assists with diagnosing pathology, and requires a larger knowledge base with specialised training. FOCUS as a screening modality has a more focused scope, and is used to answer a specific clinical question, often looking for a ‘yes’ or ‘no’ answer. This application does not require cardiology knowledge, and less intensive training is needed.[4] However, interpretation of the images requires adequate training and is operator dependent. Clinical common sense is also needed to apply the additional echo findings to the clinical scenario. There is a well-known saying that ‘a fool with a stethoscope is also a fool with an echoprobe’. FOCUS does not negate or replace the need for a formal diagnostic echocardiography investigation. Each has a distinct role and clinical use. There are currently multiple different protocols, and acronyms abound, all available for training in POCUS: focused assessed transthoracic echocardiography (FATE), POCUS, extended focused assessment with sonography for trauma (e-FAST), FOCUS, emergency point-of-care ultrasound (EPCUS), bedside lung ultrasound in emergency (BLUE), internal medicine bedside ultrasound (IMBUS), rapid obstetric sonographic evaluation (ROSE), focused echocardiographic evaluation in life (FEEL) support, focused intensive care echocardiography (FICE), focused perioperative risk evaluation sonography involving gastro-abdominal haemodynamic and transthoracic ultrasound (FORESIGHT), and haemodynamic echocardiography examination in real time (HART). These different protocols all have a similar goal, i.e. to provide a structure to

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non-cardiologist practitioners to diagnose or confirm a specific clinical cardiorespiratory emergency that is responsible for patient haemodynamic instability. POCUS is easily taught,[5] non-invasive and readily available. In trained hands, it is the perfect diagnostic tool at the patient’s bedside, outside the radiology department.[6] POCUS provides real-time information that can guide clinical management, and should be used routinely in practice and training.[7] POCUS should always be considered to complement the clinical evaluation, and the information must be related back to the clinical context.

Positioning of the patient

The ideal position of the patient is supine, with head elevated 30 - 45° (Fig. 4). The anterior chest wall is divided into 8 zones (4 left and 4 right). The rules of gravity apply; air (pneumothorax) accumulates

Probe selection

In the emergency unit, theatre and intensive care unit, linear, curvilinear and phased-array probes are most commonly available. Probe selection is of critical importance in answering the relevant clinical question.

Phased-array probe (1.5 - 2.0 MHz)

This is most suitable for use in transthoracic echocardiography, and it can also be used for lung ultrasound to identify artefacts, but clarity of the lung image is not comparable to that of the curvilinear probe.[8] Phased-array probes (Fig. 1) have a low frequency, with good penetration but poor resolution. Different sizes of probes are available. The normal adult size probe has a footprint area of 20 × 14 mm (depending on the manufacturer). The correct footprint size should fit into the intercostal space, optimising the scanned area. In lung and cardiac ultrasonography a larger imaging depth is necessary.

Fig. 2. Curvilinear probe.

Curvilinear probe (3 - 5 MHz)

First introduced in the 1970s, this remains the probe of choice for abdominal ultrasound imaging (Fig. 2). The probe has a larger footprint than the phased-array probe, with a higher frequency, producing superior imaging in abdominal and lung ultrasound. The large footprint requires careful manipulation in the intercostal spaces, specifically posteriorly and laterally.[8]

Straight linear probe (8 - 12 MHz)

This probe is designed for imaging of superficial structures (Fig. 3). The higher frequencies provide better image resolution, but less penetration. The probe is ideal for intravascular line placement (central and peripheral), peripheral nerve blocks and superficial lung imaging to identify lung sliding.[8]

Fig. 3. Linear probe.

Lung ultrasound

There are different protocols adapted for lung ultrasound scans: BLUE – for the rapid diagnosis of life-threating respiratory failure,[9] and fluid administration limited by lung sonography (FALLS).

Fig. 4. Anterior and lateral lung zones. (Prof. Erik Sloth and USABCD.org, with permission.)

Fig. 1. Phased-array probe.

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in the least dependent part of the chest, and fluid in the most dependent part.

Normal anatomy visualised

During lung ultrasound, it is important to remember that the assessment is based on artefact identification and real-time image assessment. Lung sliding The normal anatomy of the pleural cavity consists of two pleural layers. The parietal pleura is adherent to the inner surface of the thoracic cavity and the visceral pleura is a delicate membrane covering the underlying lung tissue. The space between the pleurae is normally closely opposed with a small film of serous fluid. During normal respiration, the pleurae slide over each other. The arte fact caused by this phenomenon can be appreciated as lung sliding. It may appear as a line of ‘marching ants’, with a line of black and white dots moving to and fro. The absence of lung sliding may occur in: Any condition causing absent ventilation of the lung being investigated • pneumonectomy • inadvertent intubation of the other bron chus • lung isolation during single lung ventilation • bullous lung disease • apnoea.

B-lines The B-lines are formed owing to the presence of fluid in the interstitial space, and are hyperechoic reverberation artefacts (Fig. 5B). They are vertical in nature, start at the pleural line, span the entire depth of the image, move with normal respiration and erase the appearance of A-lines. They remind one of ‘Hollywood lights’ or comet tails. The appearance of B-lines can be normal or abnormal, indicating the presence of pulmonary interstitial syndrome. The presence of occasional B-lines (>2), especially in the dependent bases, can be considered normal. The presence of >3 lines in >2 zones per side defines the diagnosis of pulmonary interstitial syndrome.[10]

Motion-mode assessment

Motion mode (M-mode) examines the change/movement of structures on a chosen ultrasound line over time. If lung sliding is present, the image would symbolise a seashore. The ‘sand’ represents normal lung sliding (Fig. 6), created by a motion artefact, while the ‘sea and rolling waves’ represent

the subcutaneous tissue. If lung sliding is absent (Fig. 7), there is no motion artefact; therefore, only horizontal straight lines can be visualised. It is similar to a barcode or is also referred to as the stratosphere sign.[9] This may indicate the presence of a pneumothorax.

Lung pulse

Movement of the pleural line vertically in synchrony with the cardiac rhythm is called the lung pulse. This is normally transmitted through a consolidated area and is useful in distinguishing pneumothorax from consoli dation.[11] The presence of this sign rules out the diagnosis of a pneumothorax.

Clinical applications

The identification and interpretation of the signs are operator dependent and require adequate training in image acquisition and interpretation.

Pneumothorax

Ultrasonography identification of a pneumo thorax has a higher sensitivity than chest X-ray identification.[12]

Abnormal adherence or absence of the parietal and visceral pleura • pneumothorax • pleural effusion • pleurectomy/pleurodesis • massive atelectasis • acute respiratory disress syndrome • pneumonia. Common reasons for absent lung sliding in trauma: • apnoea • pneumothorax • selective bronchus intubation.

Fig. 5. Examples of lung ultrasound findings. (A) Hyperechoic horizontal artefacts arising from the pleural line (A-lines) (white arrows). The presence of A-lines in lung ultrasound imaging indicates normal lung insterstitium. (B) Hyperechoic reverberation artefacts arising from the pleural line to the bottom of the screen (B-lines) (red arrows). The presence of B-lines in lung ultrasound imaging indicates increased fluid contents in lung interstitium.

The Bat sign This was originally described by Lichtenstein[15] to correctly identify the pleura. The inter costal ribs appear as the wings of a bat and the pleural line represents the bat’s body. A-lines These lines are seen inside the space and represent reverberations of the pleural line (Fig. 5A). They are horizontal with the pleural line and motionless. They may be complete or incomplete and occur owing to the presence of air below the pleural line.

Fig. 6. Motion mode: normal lung sliding visualised as the seashore sign. (Prof. Erik Sloth and USABCD.org, with permission.)

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Assessment should start at the least dependant areas of the lung. The initial plane of assessment is longitudinal with the long axis of the body; placement of the probe should be between the parasternal and mid-clavicular line. The probe is then moved towards the dependent lateral aspect of the chest, assessing all 4 anterior lung zones on the left and right side of the chest. At each point assess for: lung sliding, B-line pattern and lung pulse.[11] The absence of one or more of these may indicate the possibility of a pneumothorax.

point as where normal sliding of the lung is replaced by the pneumothorax.[13]

parts of the lung. The sitting position is used to assess the size of a pleural effusion.

Pleural effusion

Normal anatomy Chest wall, hemidiaphragm, liver (right) and spleen (left) can be identified. If there is no fluid in the pleural space, the hemidiaphragm appears as though the image is ‘wiped off ’ the screen during the normal inspiration.

The sensitivity and specificity of ultrasound as a modality to identify pleural effusion approaches 100%. Ultrasound imaging can detect as little as 5 - 20 mL fluid in the pleural space. Chest radiography requires a minimum amount of 200 - 300 mL fluid in the pleural space to obliterate the costophrenic angle.[14] Ultrasound imaging also assists with the differentiation between pleural thickening and pleural fluid accumulation, and may assist in differentiating a transudate from an exudate.

Lung point Identification of the lung point is 100% specific in diagnosing a pneumothorax (Fig. 8).[13] If there is absence of lung sliding and a B-line pattern in the anterior chest, movement of the probe laterally to the dependent part of the lung may identify this

Positioning The patient is positioned in a sitting or semiFowler position. The rules of gravity apply and therefore fluid accumulates in the dependent

Fig. 7. Motion mode: absent lung sliding visualised as the barcode and stratosphere sign. (Prof. Erik Sloth and USABCD.org, with permission.)

Clinical suspicion of a pneumothorax

Image visible Consolidation/atelectasis/effusion

Lung sliding

Yes

B-lines

Lung pulse

Yes

Lung point

Yes

No pneumothorax

Pneumothorax

Unstable

Stable

Chest drain

Further investigations/ monitoring

Fig. 8. Algorithm for identification of a pneumothorax.

Sinusoid sign By placing M-mode through the effusion, the free movement of lung line towards pleural line can be seen. The movement of visceral pleura during inspiration and expiration creates the sinusoidal waveform, which indicates the presence of a pleural effusion.[14] Determining the size of a pleural effusion Numerous methods and formulas have been described to quantify the size of a pleural effusion. Estimation of an accurate volume remains difficult. As a rule of thumb any effusion >4 cm will measure >1 000 mL.[14] Volume of pleural effusion = (distance between visceral and parietal pleura in mm) × 20. The measurement is end-expiratory and measured as the maximum distance between pleura.[15] Differentiating transudate from exudate Traditionally, the differentiation is done biochemically using Light’s criteria. With the use of ultrasound, the nature of the image may suggest a possible diagnosis. Azam et al.[16] proposed a simple scoring system, awarding each finding with 1 point. Bilateral pleural effusions, absence of loculated fluid, anechoic fluid, non-thickened pleura, congested liver and non-collapsing inferior vena cava each scores 1 point. A score of >4 is highly sensitive and specific for the diagnosis of a transudate.[16]

Motion artefacts identifiable

Signs on ultrasound Quad sign This is a static sonographic image observed in the presence of a pleural effusion. The image demonstrates four distinct lines, which represent the lung, parietal pleura, rib and fluid. This sign is classically seen when a smaller pleural effusion is present, with the fluid appearing anechoic.[9]

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Alveolar syndromes

Alveolar consolidations are easily visualised. Most consolidated areas reach the pleural surface and can therefore be assessed by ultrasound imaging. The consolidation appears hypoechoic or anechoic and is therefore

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easily distinguishable from normally aerated lung that appears hyperechoic.[18] Sonographic signs of consolidation Hepatised lung If the lung is highly fluid filled, it resembles tissue in echogenicity. If the consolidation is right sided, the lung resembles the liver. If the area of consolidation is left sided, it will resemble the spleen. Presence of a bronchogram A bronchogram refers to the phenomenon of visible bronchi. Bronchi become visible owing to surrounding fluid-filled alveoli. Within areas of consolidation, these can be seen as hyperechoic areas. Air bronchograms have a white appearance, while fluid bronchograms have a hypoechoic appearance and are specific for the diagnosis of pneumonia.

Limitations in performing focused lung ultrasound imaging are as follows: • it is an extension of the physical examination • clinician should know his/her limitations • inherent to the techniques • individual level of skill • training and experience • neither comprehensive nor qualitative assessment • pattern recognition of major/life-threatening pathology • training is of the utmost importance.

Point-of-care thoracic echocardiography

The suggested targets for a focused POCUS according to the international consensus statement are the following:[19] • left ventricular dimensions and systolic function • right ventricular dimensions and systolic function • volume status • pericardial effusion and tamponade physiology • gross signs of chronic heart disease • gross valvular abnormalities • large intracardiac masses.

Indications for POCUS

Indications for POCUS are the following: • haemodynamic instability or undifferentiated shock • cardiac arrest • pericardial effusion/tamponade • heart failure • high-risk cardiac patients.

Parasternal short-axis views • ‘birds-eye’ view of biventricular size and function • presence of pericardial effusion • left ventricular filling • regional wall motion abnormalities. Parasternal long-axis view • left ventricular size and function • mitral and aortic valves • right ventricular size • presence of pericardial and left pleural effusions.

The main application of abdominal POCUS is the detection of free abdominal fluid in the patient in the trauma and medical emergency unit. Ultrasound is the ideal tool for the rapid assessment of the haemodynamically unstable patient when the use of other diagnostic modalities, such as abdominal computed tomography (CT), is not practical. A full review of abdominal ultrasound is beyond the scope of this article. The four basic views are: • subcostal window • identification of haemopericardium, which appears as a dark anechoic stripe • right upper quadrant • evaluate for fluid in the pleura, subphrenic and hepatorenal areas (Morison’s pouch) and around the kidney • left upper quadrant • evaluate for fluid in the pleural, subphrenic and splenic areas and around the kidney • pelvic transverse and longitudinal views • assessment for fluid collection behind the bladder. Aetiology of spontaneous haemoperitoneum in the non-trauma setting can vary and causes can be classified as follows:[20] • hepatic • splenic • vascular (aneurysmal) • gynaecological • coagulopathy.

Ultrasound for vascular access

A full review of transthoracic echocardiography is beyond the scope of this article. Numerous protocols have been developed for use in point-of-care thoracic echocardiography. All of the protocols focus on four basic cardiac views: • parasternal short axis • parasternal long axis • subcostal 4-chamber view • apical 4-chamber view.

atrial size obvious valvular pathology pericardial effusion cardiac motion during cardiac arrest/resuscitation (subcostal view).

Abdominal point-of-care ultrasound

Limitations in performing focused lung ultrasound imaging

The following views are used to answer specific questions: Subcostal and apical 4-chamber views • biventricular size and function

• • • •

Central venous catheters are routinely used in anaesthesiology, the intensive care unit, trauma unit and radiology suite. Complications arising from the procedure, such as inadvertent arterial puncture, haemothorax, pneumothorax and haematoma, can be life threatening. A recent Cochrane review,[21] comparing ultrasound guidance with the landmark technique for the placement of internal jugular venous catheterisation, found improved safety and a decreased number of attempts when ultrasound is used.

Systematic approach to ultrasound-guided vascular access

A systematic approach to ultrasound-guided vascular access is as follows:[22] • identify anatomy and site of insertion • confirm arterial (pulsatile, non-compressible) v. venous (compressible/ collapsible) anatomy

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• ensure patency of desired vein/artery • real-time ultrasound imaging, in-plane or out-of-plane technique with visualisation of cannula • confirm guide wire position in desired vein prior to dilation. The use of ultrasound for vascular access is not limited to only central venous access, but is now common in the angiography suite to improve safety and decrease complications during arterial puncture. It is also an indispensible tool in patients with difficult peripheral venous access.

Conclusion

POCUS is a fast-growing clinical modality and becoming an essential skill for all physicians dealing with potentially unstable patients. It allows rapid evaluation in life-threatening clinical scenarios. Imaging is performed by the caring physician at the patient’s bedside to answer a specific clinical question. It improves patient safety, prevents complications, allows rapid treatment and improves diagnostic accuracy. It is easily taught and can be used effectively in a variety of clinical arenas and situations. It is, however, imperative to understand that POCUS is a screening tool and does not replace formal imaging techniques. Adequate training is paramount to ensure patient safety, as this modality is operator dependent. The caring physician should know his/her limitations, always relate the information back to the clinical scenario, and communicate with experts and other specialists in the field. The physician should keep up to date with the development of different techniques and incorporate those in daily practice to improve accuracy of the imaging interpretation. Incorporating POCUS into daily medical practice has a major impact on the outcome of haemodynamically unstable patients. Acknowledgements. None. Author contributions. EN: literature review and manuscript preparation. FR: literature review and manuscript preparation. CB: manuscript preparation. JLCS: literature review, manuscript preparation and senior author. Funding. None. Conflicts of interest. None. 1. Andronikou S, Sergot L. ‘Point-of-care ultrasound’ – legitimate terminology. Pediatr Radiol 2017;47(13):18491850. https://doi.org/10.1007/s00247-017-3978-7

2. Frederiksen CA, Juhl-Olsen P, Andersen NH, et al. Assessment of cardiac pathology by point-of-care ultrasonography performed by a novice examiner is comparable to the gold standard. Scand J Trauma Resusc Emerg Med 2013;21:87. https://doi.org/10.1186/1757-7241-21-87 3. Ploutz M, Lu JC, Scheel J, et al. Handheld echocardiographic screening for rheumatic heart disease by non-experts. Heart 2016;102(1):35-39. https://doi.org/10.1136/heartjnl-2015-308236 4. Coker BJ, Zimmerman JM. Why anesthesiologists must incorporate focused cardiac ultrasound into daily practice. Anesth Analg 2017;124(3):761-765. https://doi.org/10.1213/ANE.0000000000001854 5. Heiberg J, Hansen LS, Wemmelund K, et al. Point-of-care clinical ultrasound for medical students. Ultrasound Int Open 2015;1(2):E58-E66. https://doi.org/10.1055/s-0035-1565173 6. Enghard P, Rademacher S, Nee J, et al. Simplified lung ultrasound protocol shows excellent prediction of extravascular lung water in ventilated intensive care patients. Crit Care 2015;19:36. https://doi. org/10.1186/s13054-015-0756-5 7. Ramsingh D, Gudzenko V, Martin RD. Point-of-care ultrasound: Novel technology to routine perioperative assessment tool. Anesth Analg 2017;124(3):709-711. https://doi.org/10.1213/ANE. 0000000000001529 8. Szabo TL, Lewin PA. Ultrasound transducer selection in clinical imaging practice. J Ultrasound Med 2013;32(4):573-582. https://doi.org/10.7863/jum.2013.32.4.573 9. Lichtenstein DA. BLUE-protocol and FALLS-protocol: Two applications of lung ultrasound in the critically ill. Chest 2015;147(6):1659-1670. https://doi.org/10.1378/chest.14-1313 10. Volpicelli G, Elbarbary M, Blaivas M, et al. International evidence-based recommendations for point-ofcare lung ultrasound. Intens Care Med 2012;38(4):577-591. https://doi.org/10.1007/s00134-012-2513-4 11. Volpicelli G. Sonographic diagnosis of pneumothorax. Intens Care Med 2011;37(2):224-232. https://doi. org/10.1007/s00134-010-2079-y 12. Vafaei A, Hatamabadi HR, Heidary K, et al. Diagnostic accuracy of ultrasonography and radiography in initial evaluation of chest trauma patients. Emerg (Tehran) 2016;4(1):29-33. 13. Lichtenstein D, Meziere G, Biderman P, et al. The ‘lung point’: An ultrasound sign specific to pneumothorax. Intens Care Med 2000;26(10):1434-1440. https://doi.org/10.1007/s001340000627 14. Capper SJ, Ross JJ, Sandstrom E, Braidley PC, Morgan-Hughes NJ. Transoesophageal echocardiography for the detection and quantification of pleural fluid in cardiac surgical patients. Br J Anaesth 2007;98(4):442-446. https://doi.org/10.1093/bja/aem010 15. Lichtenstein D. Lung ultrasound in the critically ill. Curr Opin Crit Care 2014;20(3):315-322. https://doi. org/10.1097/MCC.0000000000000096 16. Azam SM, Owen WT, Kamalanathan M, et al. A simple score based on ultrasound criteria to distinguish between exudative vs. transudative pleural effusion. Eur Resp J 2014;44(Suppl 58):666. 17. Balik M, Plasil P, Waldauf P, et al. Ultrasound estimation of volume of pleural fluid in mechanically ventilated patients. Intens Care Med 2006;32(2):318. https://doi.org/10.1007/s00134-005-0024-2 18. Volpicelli G, Silva F, Radeos M. Real-time lung ultrasound for the diagnosis of alveolar consolidation and interstitial syndrome in the emergency department. Eur J Emerg Med 2010;17(2):63-72. 19. Via G, Hussain A, Wells M, et al. International evidence-based recommendations for focused cardiac ultrasound. J Am Soc Echocardiogr 2014;27(7):e1-e33. https://doi.org/10.1016/j.echo.2014.05.001 20. Lucey BC, Varghese JC, Anderson SW, et al. Spontaneous hemoperitoneum: A bloody mess. Emerg Radiol 2007;14(2):65-75. 21. Brass P, Hellmich M, Kolodziej L, et al. Ultrasound guidance versus anatomical landmarks for internal jugular vein catheterization. Cochrane Database Syst Rev 2015;(1):CD006962. https://doi. org/10.1002/14651858.CD006962.pub2 22. Saugel B, Scheeren TWL, Teboul JL. Ultrasound-guided central venous catheter placement: A structured review and recommendations for clinical practice. Crit Care 2017;21(1):225. https://doi.org/10.1186/ s13054-017-1814-y 23. Zimmerman JM, Coker BJ. The nuts and bolts of performing focused cardiovascular ultrasound (FoCUS). Anesth Analg 2017;124(3):753-760. https://doi.org/10.1213/ANE 0000000000001861

Additional free and downloadable resources FATE card for android or iOS devices Virtual transthoracic echocardiography Toronto – www.pie.med.utoronto.ca www.echopedia.org www.123sonography.com

Accepted 3 April 2018.

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

IN PRACTICE

MEDICINE AND THE LAW

The Life Esidimeni tragedy: Moral pathology and an ethical crisis A Dhai, PhD, MB ChB, FCOG, LLM, PG Dip (Int Res Ethics) Steve Biko Centre for Bioethics, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa Corresponding author: A Dhai (ames.dhai@wits.ac.za)

The Life Esidimeni tragedy highlights several ethical transgressions. Health professionals’ ethics are put to the test when their own interests are balanced against competing claims. Core values of compassion, competence and autonomy, together with respect for fundamental human rights, serve as the foundation of ethical practice in healthcare. These values are increasingly being challenged by governments and other third parties. The duties conferred on healthcare practitioners require them to act responsibly and be accountable for their actions. Codes in healthcare serve as a source of moral authority. The Gauteng health authorities exerted tremendous power and created a culture of fear and disempowerment among healthcare practitioners. When health professionals choose to support state interests instead of those of patients, problematic dual-loyalty conflicts arise. S Afr Med J 2018;108(5):382-385. DOI:10.7196/SAMJ.2018.v108i5.13232

‘In time, we shall be in a position to bestow on South Africa the greatest possible gift – a more human face.’ (Steve Biko[1]) The Gauteng Mental Health Marathon Project highlights shocking ethical transgressions. While the Health Ombud’s report[2] underscored the three most senior officials in the Gauteng Department of Health (GDoH) as the most culpable, several other health professionals were also implicated. However, many others attempted to avert the predicted disaster by drawing on ethical values in medical practice and their technical and clinical skills. It is sad that their efforts were ignored by the two senior members in the Department, the Head of Department (HoD) and the Director Mental Health Services, both health professionals who could have challenged the overall head and member of the Executive Committee, GDoH, rather than succumbing to the pressure she exerted. The tragedy raises several ethical issues, including the ethical dimensions of healthcare practice, the moral authority of codes and oaths, dual-loyalty conflicts and human rights violations. It serves as a harsh warning for the need to return to basics to understand the meaning of being a healthcare professional.

The ethical dimensions of healthcare practice

Health professionals’ ethics are put to the test when their own interests are balanced against competing claims. Practice in healthcare, whether at policy decision-making level or in management, administration or the patient-practitioner relationship, requires the effacement of self-interest even to the point of personal risk. Altruism remains a moral obligation in this context. Certain obligations specific to healthcare distinguish it from other careers:[3] • Ill-health results in patients being vulnerable, dependent, relatively powerless and exploitable. A health need can be likened to a moral claim on those that have been trained to help.[2] • An education in healthcare is a privilege. It involves invasions of privacy such as dissecting the human body, training using sick patients, and clinical research. Because society permits this, healthcare professionals automatically become parties to a collective pledge.[3]

• New graduates publicly acknowledge the pledge when the oath is taken at graduation, a promise that the gravity of their calling is understood. There is also a promise to be competent and to use that competence in the interests of the sick.[3] The World Medical Association (WMA) states that practitioners must know and exemplify the core values of medicine, especially compassion, competence and autonomy. These values, together with respect for fundamental human rights, serve as the foundation of ethical practice in healthcare. While compassion, competence and autonomy are not exclusive to healthcare practice, its practitioners are expected to epitomise them to a higher degree than in many other professions.[4] Compassion, described as understanding and concern for another’s distress, is essential in healthcare.[4] It is a crucial trait required to deliver morally good care and is closely linked to caring. Empathy, where practitioners put themselves in the patient’s situation of pain and suffering and recognise their care needs, is essential for caring. Caring practitioners engage with the needs of patients and undertake to meet these professionally.[5] A high degree of competence is expected and required from healthcare practitioners because incompetence can result in serious morbidity or death. A truly competent healthcare professional requires scientific knowledge, technical skills, and also ethical knowledge, skills and attitudes.[4] Autonomy or self-determination is the core value that has undergone change over time. Globally, practitioners have accepted the notion of patient autonomy, which mandates patients to make decisions in matters that affect themselves. Moreover, practitioners have traditionally enjoyed a high degree of autonomy in managing patients. However, governments and others have increasingly challenged the core foundational values of practitioners.[4]

Professionalism and professional integrity

Practice in healthcare, irrespective of the context, is a moral and social contract between the profession and the public. Its nucleus is

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IN PRACTICE

professionalism and professional integrity, against which patients and the public measure their expectations of healthcare professionals.[6] In healthcare, professionalism has been defined as ‘… an occupation that is characterised by high moral standards, including a strong commitment to the well-being of others, mastery of a body of knowledge and skills, and a high level of professional autonomy’.[7] The goals of healthcare are always caring for the sick, promoting health interests and wellbeing, and striving towards a healing environment.[8] Healthcare practitioners bridge the gap between science and society and are important agents through which scientific knowledge is applied to human health. However, practice in healthcare is also about experiences, feelings and interpretations of human beings in often extraordinary moments of fear, anxiety and doubt. In this vulnerable position, professionalism underpins the trust that the public has in healthcare practitioners.[9] Professional integrity and honesty are pivotal for upholding their reputation and credibility. Professionalism in healthcare is regulated to protect the public from unsafe practices; to set professional and ethical standards to ensure quality service; and to confer responsibility, accountability, identity and professional status upon practitioners.[6] The duties conferred on healthcare practitioners require them to act responsibly and be accountable for their actions, with responsibility denoting a duty to satisfactorily perform some function, and accountability that of giving an account of one’s acts or omissions.[6] In some situations control of healthcare has steadily been moved away from healthcare practitioners to professional managers and bureaucrats, and sadly, some see healthcare practitioners as obstacles rather than partners.

The moral authority of codes and oaths

Codes serve as a source of moral authority and are used among professionals and lay persons to set standards for ethical conduct, to define new ethical issues, and to support positions in ethical discourse.[10] Despite the Hippocratic Oath being over 2 500 years old, the principles have remained relevant and have been included in modern versions of the oath by the WMA[11] and the International Council of Nurses (ICN)[12] and nationally by statutory councils including the Health Professions Council of South Africa[13] and the South African Nursing Council (SANC).[14] South African (SA) health science faculties have also developed their own versions of the oath.

Nursing codes and oaths

The Florence Nightingale Pledge,[15] first taken in 1893, is an adaptation of the Hippocratic Oath emphasising the following principles: Leading by example, Faithfulness, Accountability, Responsibility, Confidentiality, Devotion and Quality. An international code of ethics for nurses was first adopted by the ICN in 1953, its latest revision being in 2012.[16] While the SANC Code of Ethics for Nursing Practitioners[17] was promulgated in May 2013, the Nurses’ Pledge of Service[18] as mandated by the SANC to be taken by all nurses is nearly 50 years old. Service to humanity, practising with conscience and with dignity, pursuing justice and advocating on behalf of vulnerable and disadvantaged patients are the principles that resonate through the codes and oath. Despite the public promise of allegiance to these values, the Director of Mental Health, a nurse by training, ruthlessly executed the Gauteng Mental Health Marathon Project, albeit being advised by concerned clinicians against the move. At the Health Ombudsman’s enquiry, she stated that she understood the risks raised by specialists,

and yet went ahead and licensed non-governmental organisations (NGOs) to take over the ‘care’ of the patients whose discharge and transfer she was directly responsible for. The Ombud concluded that she was responsible for several faulty decisions that at times changed the final course of events in the project and were central to the disaster. She was key to the rushed and chaotic transfers without medical records and discharge summaries to ill-equipped, unprepared and poorly staffed NGOs.[2] She issued licences without service level agreements (SLAs) and did not specify the service level requirements. When the SLAs were later issued, they did not even make it obligatory for meals to be adequate to meet patient needs. While she admitted that community services for intellectual disabilities were not well established or developed, she attributed the deaths to winter due to the vulnerabilities of the patients. Staff at the NGOs were untrained, unqualified, and lacked basic competence or experience (including lack of leadership and managerial staff). Regrettably, NGOs could not distinguish between the professional care requirements of these patients and a business opportunity.[2] Patients were objectified as commodities, for sale in a marketplace, and as business prospects.

Medical codes and oaths

The Hippocratic Oath embodies the highest aspirations of the healthcare professional and stipulates two categories of duties: to the patient and to other members of the profession. It emphasises the duty of the practitioner to help and not harm patients:[19] ‘I will apply dietetic measures for the benefit of the sick according to my ability and judgement; I will keep them from harm and injustice.’ The WMA Declaration of Geneva,[20] adopted by the second General Assembly of the WMA in September 1948 and amended several times including in June 2017, is the modern version of the Hippocratic Oath. Its pledge is to devote life to the service of humanity, to practise with conscience and dignity, to ensure the health of the patient as the doctor’s first consideration, not to allow certain considerations, including political affiliations, to intervene with the doctor’s duty to the patient, and to maintain the utmost respect for human life. Graduates from SA medical schools take modified Hippocratic Oaths before commencing medical practice. While the texts differ, all pledge devotion to the service of humanity and conscientious and dignified practice. The HoD, GDoH, was unaware of the number of deaths when interviewed by the Health Ombud, but reduced the issue to a ‘number game’. He did not correlate the deaths with poor planning, but admitted that it was inhumane to move patients between NGOs. He stated that staff were put under extreme pressure because of the project and that this led them to cut corners and make errors during implementation. He indicated that junior officials were constrained to do as directed.[2] He was aware that communities had not matured to the extent of deinstitutionalisation. He agreed that the project could have been done differently, and that leadership got too involved and made the managers commit serious errors in execution. He admitted that families were forgotten in the process. The Ombud found that his evidence was evasive and contradictory and stated that following the interview, Dr Selebano back-dated all the licences to 1 April 2016 and did not indicate the date on which he signed them.[2] Despite knowing that the approach to the project and the implementation processes were wrong, and despite being ‘sidelined’ when putting a viable alternative on the table, Dr Selebano continued to administer the wrong actions as HoD. He was aware that communities had not matured and were not ready and that

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deinstitutionalisation was premature, yet as HoD he allowed it. Professional integrity and honesty are measures of the extent to which the professional’s reputation and credibility remain untainted, yet he back-dated licences and did not include the date on which this was done on the documents. It is perplexing that despite the immense scale of the tragedy, he did not inform the Ombud where the pressure came from and who stalled the process of the purchase of Life Esidimeni, and therefore by inference was ‘protecting’ someone. As a doctor, he needed to use his professional judgement and not to have allowed extraneous factors to interfere. The fundamental role of healthcare professionals is to alleviate the distress of their fellow human beings, and no motive, whether personal, collective or political, must prevail against this higher purpose.[21]

Medical and death certificates

The Ministerial Advisory Committee’s report on this tragedy states that there was no evidence to show that patients were evaluated to determine functionality or acuity levels before placement with NGOs. Neither were they medically and functionally examined and assessed on admission to the NGOs. In some cases patients arrived at facilities already very ill, frail, weak and with severe bedsores; most were profoundly disabled.[2] The unanswered question is who discharged these patients from Life Esidimeni, especially in light of there being no evidence of evaluation prior to discharge. According to the Ombud, only 13 of the 38 that his report was confined to were regarded as fit enough for transfer.[2] In terms of the Mental Health Care Act,[22] different forms are to be completed when a patient is discharged, transferred or remains an assisted mental healthcare user (MHCU). Should the patient’s condition improve to the extent of being able to make an informed decision and provide valid informed consent, the patient is then discharged to outpatient care as a voluntary MCHU. A Form 03 is required for this together with clinical evidence of recovery in capacity to consent. It was found that Form 03s were completed for 11 patients as discharge forms. However, only one patient had clinical evidence of recovery of capacity to consent. There was no evidence of this recovered capacity in the other 10 because of the irreversible nature of the primary cognitive impairment.[2] The Births and Deaths Registration Act[23] provides for medical practitioners who attended to patients before their death to issue a Notification of Death Certificate stating the cause of death conditional to being satisfied that the death is due to natural causes. Where the practitioner has not attended to the patient prior to death but examines the corpse and is satisfied that the death was due to natural causes, a prescribed death certificate may be issued. If a medical practitioner is of the opinion that the death was not due to natural causes, the Notification of Death Certificate requires that ‘unnatural’ is certified and the police informed. According to the Ombuds Report, several of the deceased had died from illnesses that questioned the conditions/circumstances under which they were being cared for and the quality of care they received at the NGOs, e.g. fits, dehydration, aspiration pneumonia, acquired pneumonia, cardiac arrest, ‘being found dead in the morning without night observations’. These deaths were recorded as natural in the death certificates.[2] This is corroborated by a review done by Health-E News of 34 family affidavits and death certificates which revealed that 85% of deaths were certified as natural and some were in contravention of SA law.[24] Notification of Death Certificates were signed by different medical officers, showing a trend across the health profession in which they ignored or did not

see the signs of neglect and abuse that pointed to poor treatment of these patients. Almost 50% were incorrectly completed, some with cause of death left blank and some with only natural causes filled in.[24] Given the conditions surrounding the deaths of these patients, it is problematic that so many deaths were from ‘natural’ causes and it is of concern that the Births and Deaths Registration Act[23] was probably infringed. Issuing a medical certificate highlights doctors’ unique privilege and power. Accordingly, attention to integrity, truthfulness and responsibility is ethically essential. The actions of these doctors were not consistent with the oaths taken to practise their profession with conscience and dignity and to uphold the honour of their profession. The fraudulent signing of the medical and death certificates is an unhappy reminder of Steve Biko’s death. Despite the fact that he had been walking with an ataxic gait and had evidence of lacerations and bruising, the medical certificate provided by the doctor stated that there was no evidence of abnormality or pathology on the patient.[25] Submissions on false medical reports were made in SA’s Truth and Reconciliation hearings on the health sector. Extensive complicity of health professionals in falsifying death certificates and medical records to move responsibility away from state forces was reported. Records failed to mention bullet wounds, neglect and trauma from prolonged abuse.[26] While employment relationships may increase the difficulty of complying with duties to the human rights of patients, health professionals must comply with the oaths taken at graduation and the several other international and local codes and declarations. There is no place for lip service to oaths in the context of healthcare.

Conclusions

When health professionals choose to support state interests instead of those of patients, problematic dual-loyalty conflicts arise. Repressive governments generate some of the gravest human rights violations because of dual-loyalty conflicts.[27] However, as seen by the Life Esidimeni tragedy, this can also occur in open societies where policies imposed by state actors and pressure to yield to their powerful interests violate healthcare rights. Pressures include the culture of the institution and fears or threats of professional harm. Third-party interests that conflict with patients’ medical interests, are irrelevant to the health professional’s concern for the ‘patient as a patient’.[25] An understanding of the gravity of their calling is necessary so that they can have the courage to withstand institutional pressures. The three key players identified in the Ombud’s report[2] exerted tremendous power and created a culture of fear and disempowerment. The Director and HoD clearly did not take the gravity of their calling as health professionals seriously. This tragedy also highlights that political appointments fail our patients and our country and result in politics determining ethics – a moral pathology that must be eradicated for the ethical crisis to be comprehensively addressed. The treatment of mentally ill patients in the Gauteng Mental Health Marathon Project is a reminder of how most citizens in our country were treated before 1994 – oppressed, subjected to the repressive apartheid regime, and considered to be subhuman, lacking human dignity and of decreased or no moral status. The apartheid government conducted itself with impunity. The leadership of the Gauteng Mental Health Marathon Project conducted itself with impunity, and in so doing betrayed our Constitution and their oaths taken as health professionals. Steve Biko died for an idea that would live, that of bestowing on SA the greatest possible gift – a more human face. We cannot allow that idea to be killed by those who do not care.

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Acknowledgements. None. Author contributions. Sole author. Funding. None. Conflicts of interest. None. 1. IZ Quotes. http://izquotes.com/author/steve-biko (accessed 1 November 2017). 2. Makgoba MW. The report into the ‘Circumstances surrounding the deaths of mentally ill patients: Gauteng Province’. 2017. http://www.politicsweb.co.za/documents/the-life-esidimeni-disaster-themakgoba-report (accessed 1 November 2017). 3. Pellegrino ED. Altruism, self-interest and medical ethics. JAMA 1987;258(14):1939-1940. https://doi. org/10.1001/jama.1987.03400140101036 4. World Medical Association. Medical Ethics Manual. Ferney-Volatire, France: WMA, 2005:15-19. 5. Vanlaere L, Gastmans C. Ethics in nursing education: Learning to reflect on care practices. Nurs Ethics 2007;14(6):758-766. https://doi.org/10.1191/0969733002ne557oa 6. McQuoid-Mason D, Dhai A. Professionalism and the healthcare practitioner-patient relationship. In: Dhai A, Mcquoid-Mason DJ, eds. Bioethics, Human Rights and Health Law: Principles and Practice. Cape Town: Juta, 2011:59-68. 7. Williams JR. The future of medical professionalism. S Afr J Bioeth Law 2009;2(2):48-50. 8. Cruess RL, Cruess SR, Johnston SE. Professionalism: An ideal to be sustained. Lancet 2000;356(9224):156-169. https://doi.org/10.1016/S01040-6736(00)02458-2 9. Royal College of Physicians. Doctors in society: Medical professionalism in a changing world. 2005. https:// cdn.shopify.com/s/files/1/0924/4392/files/doctors_in_society_reportweb.pdf?15745311214883953343 (accessed 1 November 2017). 10. Pellegrino ED. Codes, virtue, and professionalism. In: Sugarman J, Sulmasy D, eds. Methods in Medical Ethics. 2nd ed. Washington, DC: Georgetown University Press, 2010:91-107. 11. World Medical Association. https://www.wma.net/ (accessed 10 November 2017). 12. International Council of Nurses. http://www.icn.ch/ (accessed 10 November 2017). 13. Health Professions Council of South Africa. http://www.hpcsa.co.za/ (accessed 10 November 2017). 14. The South African Nursing Council. http://www.sanc.co.za/ (accessed 10 November 2017). 15. The Florence Nightingale Pledge. http://nursingcrib.com/news-blog/nightingales-pledge/ (accessed 28 November 2017).

16. International Council of Nurses. Code of Ethics for Nurses. http://www.icn.ch/who-we-are/code-ofethics-for-nurses/ (accessed 28 November 2017). 17. South African Nursing Council. Code of Ethics for Nursing Practitioners in South Africa. http:// www.sanc.co.za/pdf/Learner%20docs/SANC%20Code%20of%20Ethics%20for%20Nursing%20in%20 South%20Africa.pdf (accessed 21 November 2017). 18. South African Nursing Council. The Nurses’ Pledge of Service. http://www.sanc.co.za/aboutpledge. htm (accessed 12 November 2017). 19. The Hippocratic Oath. In: Mappes TA, DeGrazia D, eds. Biomedical Ethics. 5th ed. New York: McGraw-Hill, 2001:66. 20. World Medical Association. Declaration of Geneva. 2006. https://www.wma.net/what-we-do/medicalethics/declaration-of-geneva/ (accessed 27 November 2017). 21. World Medical Association. Declaration of Tokyo. https://www.wma.net/policies-post/wma-declarationof-tokyo-guidelines-for-physicians-concerning-torture-and-other-cruel-inhuman-or-degradingtreatment-or-punishment-in-relation-to-detention-and-imprisonment/ (accessed 29 November 2017). 22. South Africa. Mental Health Care Act No. 17 of 2002. https://www.gov.za/sites/www.gov.za/files/a1702.pdf (accessed 12 November 2017). 23. South Africa. Births and Deaths Registration Act No. 51 of 1992. https://www.gov.za/documents/ births-and-deaths-registration-act (accessed 10 November 2017). 24. Wild S. Health-E News – Esidimeni ‘unnatural’ deaths erased. https://www.dailymaverick.co.za/ article/2017-09-04-health-e-news-esidimeni-unnatural-deaths-erased/#.Wh1elbT1Vok (accessed 27 November 2017). 25. Mclean GR, Jenkins T. The Steve Biko affair: A case study in medical ethics. Dev World Bioeth 2003;3(1):77-95. https://doi.org/10.1111/1471-8847.00060 26. International Dual Loyalty Working Group. Dual Loyalty and Human Rights in Health Professional Practice. Cape Town: Physicians for Human Rights and School of Public Health and Primary Health Care, Faculty of Health Sciences, University of Cape Town, 2002:36. 27. International Dual Loyalty Working Group. Dual Loyalty and Human Rights in Health Professional Practice. Cape Town: Physicians for Human Rights and School of Public Health and Primary Health Care, Faculty of Health Sciences, University of Cape Town, 2002:1-3.

Accepted 5 March 2018.

CASE REPORT

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

Co-infection with Streptococcus pneumoniae and Listeria monocytogenes in an immunocompromised patient C J Opperman, MB ChB, BSc Hons (Microbiology); C Bamford, MB ChB, FCPath MMed Pathology (Microbiology)

Division of Medical Microbiology, National Health Laboratory Service, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa Corresponding author: C J Opperman (stefanopperman1@gmail.com)

A 34-year-old HIV-positive man with a history of chronic substance abuse was admitted with dual infection of Streptococcus pneumoniae and Listeria monocytogenes. Combined bacteraemia with S. pneumoniae and L. monocytogenes is very rare. To the best of our knowledge, this is the first such case documented at our institution and in South Africa. Ampicillin should be added to antibiotic regimens to improve patient outcome if L. monocytogenes infection is suspected. Co-infections that occur with L. monocytogenes may have conflicting antibiotic treatment options. This case report emphasises the need for a good relationship between the local microbiology pathologist and physician to select appropriate antibiotic treatment before definitive results are available. S Afr Med J 2018;108(5):386-388. DOI:10.7196/SAMJ.2018.v108i5.12957

In September 2017, the National Institute for Communicable Diseases (NICD) released a statement reporting an unprecedented increase in the number of Listeria cases across South Africa (SA). The increase was noted in the private and public sectors, with 190 confirmed cases of listeriosis across the country between January and August 2017. The NICD also initiated enhanced surveillance at a number of hospitals nationally to gather additional information.[1] An increase in Listeria monocytogenes isolates was detected at our institution. Seven cases were reported at our laboratory in 2016. This figure increased to 14 confirmed listeriosis cases up to October 2017, with 12 of these clustering between June and October (unpublished data –

Division of Medical Microbiology, Department of Pathology, Groote Schuur Hospital, Cape Town, SA, 2017). This case report increases awareness about L. monocytogenes and highlights the potential for co-infections.

Case report

A 34-year-old man presented to a local hospital with a 3-week history of worsening cough and dyspnoea. He had a long-standing history of methamphetamine and cannabis use. The patient was also HIV-positive, with a recent absolute CD4+ count of 32 cells/µL. He was not on antiretroviral therapy and had not been admitted

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to hospital previously. He required intubation and ventilation because of respiratory distress, and the chest radiograph confirmed a multilobar pneumonia. The patient also required inotropes for septic shock and blood transfusion for severe anaemia (haemoglobin 4.8 g/ dL). Laboratory tests showed hypoglycaemia, hypocalcaemia and deranged liver enzymes, with normal kidney function. The patient was treated empirically with ceftriaxone and azithromycin before being transferred to a tertiary hospital intensive care unit.

Management and investigations

A blood sample was taken on admission. After 14 hours, a Gram stain showed a combination of Gram-positive cocci in chains and small Gram-positive bacilli. The following day, based on preliminary laboratory results, the presence of Listeria and Streptococcus pneumoniae was suspected. Ampicillin was added to the patient’s antibiotic treatment, which had in the interim been escalated to imipenem by the attending clinicians owing to the severity of the illness and apparent concern about Gram-negative infection. The identification of both organisms was subsequently confirmed using routine laboratory methods (Fig. 1), including the Vitek 2 system (bioMérieux, SA). Both organisms were susceptible to penicillin, with minimum inhibitory concentrations (MICs) of <0.06 µg/mL and 0.125 µg/mL for S. pneumoniae and L. monocytogenes, respectively. MIC determinations were done using the Vitek 2 streptococcal antibiotic susceptibility test card (AST-ST01, USA), supported by oxacillin disc testing for S. pneumoniae and Epsilometer testing (E-test) (bioMérieux, SA) for L. monocytogenes (Fig. 2). L. monocytogenes was also cultured from a second blood sample taken on admission, which showed growth after 35 hours. Once antibiotic susceptibility results were available, definitive treatment with ampicillin and co-trimoxazole was initiated and administration of other antibiotics was discontinued. Acute renal failure at the time precluded the use of gentamicin. Meningo-encephalitis was not suspected, as no cells or organisms were present in the cerebrospinal fluid and there was no subsequent growth of bacteria. No pathology

Fig. 2. Disc diffusion susceptibility testing of a Streptococcus pneumoniae isolate on Mueller-Hinton, with 5% sheep blood agar (optochin (OP) (green arrow) and oxacillin (OX) (blue arrow)). Based on the zones of inhibition observed, it was possible to make the presumptive identification of penicillinsensitive S. pneumoniae.

was noted on a computed tomography scan of the brain. No additional pathogens were detected and results of laboratory tests for Mycobacterium tuberculosis and Legionella serogroup 1 were negative. An echocardiogram revealed cardiomegaly with signs of biventricular failure, conduction abnormalities and an akinetic septum. An ischaemic hepatic liver injury was suspected. Multiorgan failure followed an acute kidney injury secondary to sepsis, with a metabolic acidosis. A poor response to adequate treatment, decline in clinical presentation, two resuscitating events in the intensive care unit and poor prognosis with multi-organ failure prompted the withdrawal of active treatment. The patient passed away within 7 days of initial admission to hospital.

Discussion

Fig. 1. Mixed culture of Streptococcus pneumoniae and Listeria monocytogenes on a 2% blood agar plate after 24 hours of incubation. There is alpha-haemolytic activity owing to S. pneumoniae (green arrow), and betahaemolytic activity produced by L. monocytogenes (blue arrow).

Dual infection with S. pneumoniae and L. monocytogenes is rare, but not unknown. A retrospective Danish study between 1997 and 2012 reviewed 231 patients with L. monocytogenes bacteraemia and/or meningitis. The investigators documented 4 polymicrobial patients, 2 of whom were co-infected with S. pneumoniae. One patient died after 2 days of definitive treatment with ampicillin in combination with gentamicin. The other patient received benzylpenicillin as monotherapy and survived. The remaining 2 co-infected patients were also infected with Escherichia coli.[2] L. monocytogenes has been documented as a rare concomitant infection in an immunocompetent patient with cryptococcal disease.[3] Interactions between bacteria and viruses are an emerging topic in human infections, with evidence that an indirect interaction between the measles virus and L. monocytogenes promotes their co-infection.[4] The mortality rate associated with L. monocytogenes is high – ranging from 20% to 30%, even with adequate antibiotic treatment. The variability in mortality can be explained by differences in risk factors, delay in diagnosis and inadequate empirical antibiotic treatment.[2,5] Significant risk factors associated with 30-day mortality in the above-mentioned Danish study included septic shock,

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altered mental state and inadequate treatment, especially with the cephalosporins.[2] The Multicentric Observational NAtional Study on LISteriosis and ListeriA (MONALISA)[6] was a national prospective observational cohort study performed in France between 2009 and 2013. It showed that the most important mortality prognostic factors for both Listeria bacteraemia and neurolisteriosis are multi-organ failure, aggravation of any pre-existing organ dysfunction, ongoing cancer, and monocytopenia.[6] It is unfortunate that our patient had multi-organ failure, anaemia, septic shock and an altered mental state, despite being on adequate antibiotic treatment. Therapeutic guidelines for the treatment of Listeria lack a strong evidence base, as no clinical trials have been done regarding this disease, which is considered rare. The incidence of listeriosis is estimated at 3 - 6 cases per million population per year in the western hemisphere.[6,7] Listeria is intrinsically resistant to cephalosporins, while ampicillin and benzylpenicillin remain the preferred antibiotics for treatment.[8,9] The addition of a second agent, usually gentamicin, is recommended in cases of meningitis/encephalitis, endocarditis or bacteraemia in immunocompromised hosts.[10,11] Co-trimoxazole is an acceptable alternative, either as monotherapy in patients with anaphylactic reactions to penicillins, or as combination therapy when gentamicin is not tolerated.[12-14] The diagnosis of Listeria organisms is made by culturing clinical specimens such as blood, cerebrospinal fluid, amniotic fluid, placenta or other sterile body fluids. Ideally, these specimens should be taken before administering antibiotics. In our case, ampicillin was added early, based on the provisional detection of Listeria co-infection. Blood cultures were done before starting antibiotics, and the broadspectrum antibiotics were subsequently de-escalated to narrowspectrum agents once the organisms had been identified.

Conclusion

It can be concluded from this case that ampicillin may be added to the antibiotic cover if listeriosis is suspected in a high-risk group. Vulnerable patients include those who are immunocompromised, pregnant women, neonates and the elderly. However, in the setting of the current national listeriosis outbreak, ampicillin should be added to ceftriaxone/ cefotaxime for the empirical treatment of suspected bacterial meningitis in all patients.[15] Challenging empirical antibiotic choices might have to be made regarding co-infections, which require consultation with an

infectious diseases specialist or microbiology pathologist. The current case report also highlights the importance of a close relationship between the local microbiologist and physician to select appropriate antibiotic therapy and potentially improve patient outcome. Acknowledgement. We thank the family of the deceased patient, who gave permission and their blessing to write this report. Author contributions. Both authors contributed equally. Funding. None. Conflicts of interest. None. 1. National Institute for Communicable Diseases, Division of the National Health Laboratory Service. An unprecedented increase of listeriosis in 2017 in Gauteng Province. Communicable Diseases Communique 2017;16(9):8. http://www.nicd.ac.za/wp-content/uploads/2017/09/NICDCommunicable-Diseases-Communique_September2017_final.pdf (accessed 4 October 2017). 2. Thønnings S, Knudsen JD, Schønheyder HC, et al. Antibiotic treatment and mortality in patients with Listeria monocytogenes meningitis or bacteraemia. Clin Microbiol Infect 2016;22(8):725-730. https:// doi.org/10.1016/j.cmi.2016.06.006 3. Deiss RG, Bolaris M, Wang A, Filler SG. Cryptococcus gattii meningitis complicated by Listeria monocytogenes infection. Emerg Infect Dis 2016;22(9):1669-1671. https://doi.org/10.3201/eid2209. 160142 4. Almand EA, Moore MD, Jaykus LA. Virus-bacteria interactions: An emerging topic in human infection. Viruses 2017;9(3):1-10. https://doi.org/10.3390/v9030058 5. Hernandez-Milian A, Payeras-Cifre A. What is new in listeriosis? BioMed Res Int 2014;2014:1-7. https://doi.org/10.1155/2014/358051 6. Charlier C, Perrodeau É, Leclercq A, et al. Clinical features and prognostic factors of listeriosis: The MONALISA national prospective cohort study. Lancet Infect Dis 2017;17(5):510-519. https://doi.org/ 10.3410/f.727254731.793533940 7. Krawczyk-Balska A, Markiewicz Z. The intrinsic cephalosporin resistome of Listeria monocytogenes in the context of stress response, gene regulation, pathogenesis and therapeutics. J Appl Microbiol 2016;120(2):251-256. https://doi.org/10.1111/jam.12989 8. Mardis BA, Conley CS, Kyle JA. Listeriosis: An overview. US Pharm 2012;37(8):38-41. 9. Valckx WJARM, Lutgens SPM, Haerkens-Arends HE, Barneveld PC, Beutler JJ, Hoogeveen EK. Listeria endocarditis: A diagnostic challenge. J Investig Med 2017;5(2):1-3. https://doi.org/10.1177/ 2324709617698995 10. Rajalakshmi A, Gopalakrishnan R, Nambi PS, Rao PV, Ramasubramanian V. Listeria in adults – truly rare or rarely diagnosed in India. J Assoc Phys India 2017;65:106-108. 11. Boyles TH, Bamford C, Bateman K, et al. Guidelines for the management of acute meningitis in children and adults in South Africa. S Afr J Epidemiol Infect 2013;28(1):5-15. 12. Goldberg E, Bishara J. Contemporary unconventional clinical use of co-trimoxazole. Clin Microbiol Infect 2012;18(1):8-17. https://doi.org/10.1111/j.1469-0691.2011.03613.x 13. Hof H, Nichterlein T, Kretschmar M. Management of listeriosis. Clin Microbiol Rev 1997;10(2):345-357. 14. Mitjà O, Pigrau C, Ruiz I, et al. Predictors of mortality and impact of aminoglycosides on outcome in listeriosis in a retrospective cohort study. J Antimicrob Chemother 2009;64(2):416-423. https://doi. org/10.1016/s0513-5117(10)79313-3 15. National Institute for Communicable Diseases, Division of the National Health Laboratory Service. Centre for Enteric Diseases. Listeriosis: Clinical recommendations for diagnosis and treatment, 2017. http://www.nicd.ac.za/wp-content/uploads/2017/12/Listeriosis_Clinical_Guidelines.pdf (accessed 4 December 2017).

Accepted 18 December 2017.

May 2018, Print edition

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

IN PRACTICE

CASE REPORT

Fulminant hepatitis B virus (HBV) infection in an infant following mother-to-child transmission of an e-minus HBV mutant: Time to relook at HBV prophylaxis in South African infants O Babatunde,1 MBBS, MSCI, FMCPaed; H Smuts,2,3 PhD; B Eley,1 MB ChB, FCP (SA) (Paed), BSc Hons; S Korsman,2,3 MB ChB, FC Path (SA) Viro, MMed; R de Lacy,4 MB ChB, FCP (SA) (Paed); D R Hardie,2,3 MB ChB, MMed Paediatric Infectious Diseases Unit, Red Cross War Memorial Children’s Hospital, Cape Town, South Africa; and Department of Paediatrics and Child Health, Faculty of Health Sciences, University of Cape Town, South Africa 2 National Health Laboratory Service, Groote Schuur Hospital, Cape Town, South Africa 3 Division of Virology, Department of Pathology, Faculty of Health Sciences, University of Cape Town, South Africa 4 Gastroenterology Unit, Red Cross War Memorial Children’s Hospital, Cape Town, South Africa; and Department of Paediatrics and Child Health, University of Cape Town, South Africa 1

Corresponding author: D R Hardie (diana.hardie@uct.ac.za)

The prevalence of hepatitis B virus (HBV) infection in pregnant women is high in South Africa (SA), yet prophylaxis to prevent motherto-child transmission (MTCT) falls short of international recommendations. We describe a 10-week-old infant who developed fulminant hepatic failure following MTCT. The mother was hepatitis e-antibody positive and had a viral load of only 760 IU/mL. Genetic analysis of virus from mother and infant showed that both had the G1896A mutation in the preC/C gene, which truncates hepatitis e antigen (HBeAg) during translation, causing an HBeAg-negative phenotype. HBeAg attenuates antiviral immune responses, and its absence was probably responsible for the infant’s fulminant hepatitis, due to an uncontrolled immune attack on infected liver cells. Pregnant women are not tested for HBV infection in SA and MTCT rates are unknown. Addition of a birth dose of vaccine, HBV screening of pregnant women and antiviral prophylaxis to positive mothers should be prioritised. S Afr Med J 2018;108(5):389-392. DOI:10.7196/SAMJ.2018.v108i5.13017

Sub-Saharan Africa is a region of high hepatitis B virus (HBV) prevalence, where >75% of individuals have evidence of HBV exposure and 10% of people are chronically infected.[1] HBV is transmitted by parenteral exposure to infected blood or body fluids and from mother to child. Exposure to HBV at an early age increases the chance of persistent infection and is responsible for maintaining the cycle of infection in regions of high endemicity. Prevalence studies conducted in South Africa (SA) before the introduction of infant immunisation suggested that peak acquisition of HBV mainly occurred in children between 1 and 5 years of age and that mother-to-child transmission (MTCT) was uncommon.[2-4] Accordingly, when the HBV vaccine was added to the infant immunisation schedule in the 1990s, it was given at 6, 10 and 14 weeks of age. Notably, a birth dose of vaccine was omitted for logistical reasons. Since then there has been a dramatic reduction in acute HBV infections and associated disease in children, and carriage rates have also declined.[5-6] However, HBV infections in children still occur in SA, owing either to gaps in vaccine coverage or MTCT as a result of failed prophylaxis.[7] The high rate of maternal HIV and HBV co-infection in SA may be another factor increasing transmission risk.[8-10] Mechanisms of MTCT of HBV are similar to those for HIV and transmission may occur in utero, intrapartum or via breast-feeding. Women who are hepatitis e-antigen (HBeAg)positive with high HBV viral loads (VLs) are more likely to transmit to their infants. Breakthrough infections occur in ~1 - 9% of this group, despite prophylaxis.[11] Though less common, HBeAg-negative

women can also transmit HBV infection and this can have severe consequences for their infants.[12] The current HBV prophylaxis in SA falls woefully short of current international recommendations, namely that all infants should receive a birth dose of HBV vaccine (as recommended by the World Health Organization[13]), pregnant women should be screened for hepatitis B surface antigen (HBsAg), and HBV VL should be performed on positive patients. Lastly, mothers with HBV VLs >200 000 IU/mL (American Association for the Study of the Liver and European Association for the Study of the Liver) or >6 log IU/mL (Asian Pacific Association for the Study of the Liver) should receive antiviral prophylaxis with lamivudine, telbivudine or tenofovir in the second and third trimesters of pregnancy.[14]

Case report

A 10-week-old male infant was admitted to Red Cross War Memorial Children’s Hospital in Cape Town, SA, on 25 November 2016 with fever and poor feeding of 3 days’ duration. He was receiving breast and formula milk feeds. He had received an intramuscular dose of a combination vaccine (HBV, Haemophilus influenzae type B, diphtheria, tetanus, acellular pertussis and inactivated polio) 4 days prior to admission. There was no history of diarrhoea, vomiting, cough, seizures, jaundice or recent travel. His mother was from the Democratic Republic of Congo (DRC). She had arrived in Cape Town while pregnant and had a normal vaginal delivery in Cape Town at

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39 weeks’ gestation. The baby’s birth weight was 3 660 g, he had good Apgar scores, birth RPR for syphilis was negative, his immunisation status was up to date, and there was no history of contact with individuals with tuberculosis. He had not received any medication prior to presentation. At presentation, his temperature was 38.8oC, he was active and not jaundiced, the findings on abdominal examination were normal, and there was no clinically evident focus of infection. Dipstick examination of the urine was negative, cerebrospinal fluid examination was not suggestive of meningitis, and a chest radiograph showed patchy infiltrates in the left lung field. Because neonatal sepsis was suspected he was commenced on intravenous cefotaxime and ampicillin pending the results of blood culture, which ultimately demonstrated no microbial growth. On the 4th day of admission, marked jaundice was observed and the results of liver function tests and a coagulation profile were markedly deranged: total bilirubin (TB) 170 mmol/L (normal 5 - 21 mmol/L), conjugated bilirubin (CB) 98 mmol/L (normal 0 - 6 mmol/L), alanine aminotransferase (ALT) 1 880 U/L (normal 4 - 35 U/L), aspartate aminotransferase (AST) 3 424 U/L (normal 0 - 65 U/L), alkaline phosphatase (ALP) 1 481 U/L (normal 82 - 383 U/L), gamma-glutamyl transpeptidase (GGT) 145 U/L (normal 12 - 122 U/L), lactate dehydrogenase (LDH) 626 U/L (normal 180 - 430 U/L), ammonia 105 mmol/L (normal 40 - 80 mmol/L), international normalised ratio (INR) 8.7 (normal 2.0 - 3.0), prothrombin time (PT) 115.6 seconds (control 14.7 seconds), activated partial thromboplastin time (PTT) 119.3 seconds (control 30.0 - 40.0 seconds), fibrinogen 0.9 g/L (normal 2.0 - 4.0 g/L) and factor V 7.5% (normal 48 - 132%). He had microcytic anaemia, a sickle test was normal, and his C-reactive protein (CRP) level was 21 mg/dL (normal <10 mg/dL). Further laboratory results were as follows: negative hepatitis A immunoglobulin M (IgM), low-positive HBsAg (signal close to the cut-off for the assay), positive hepatitis B surface antibody (antiHBs) of 80.7 mIU/mL and negative hepatitis B core IgM. Hepatitis C antibody, hepatitis E IgM, herpes simplex virus 1 and 2 polymerase chain reaction (PCR), HIV DNA PCR, parvovirus B19 PCR, rubella IgM and Treponema pallidum antibody tests were negative. The cytomegalovirus VL was 730 IU/mL, the Epstein-Barr virus VL was lower than the detectable level, the thyroid-stimulating hormone level was 0.86 mIU/L (normal 0.72 - 11.0 mIU/L) and the thyroxine level was 21.2 pmol/L (normal 11.5 - 28.3 pmol/L). Galactosaemia and MPV17-related hepatocerebral mitochondrial DNA depletion syndrome were considered, but the common c.404C >T (p.5135L) and c.C106T (P.Q36X) mutations in the galactose-1-phosphate uridyltransferase (GALT) and MPV17 genes, respectively, were not detected. An abdominal ultrasound scan revealed a non-enlarged

liver with coarse echotexture. The mother tested positive for HBsAg and hepatitis B e antibody (anti-HBe), but was HBeAg-negative. Her HBV VL was detectable at 760 IU/mL. The clinical manifestations together with the laboratory findings suggested a diagnosis of fulminant hepatic failure secondary to vertical HBV infection. Treatment included vitamin K, oral lactulose and N-acetylcysteine. The infant received lamivudine and his antibiotics were changed to piperacillin/tazobactam and amikacin. He remained critically ill, requiring several platelet, cryoprecipitate and fresh frozen plasma infusions, and continued to deteriorate, becoming hypoglycaemic on day 10 of admission. Table 1 shows evolution of the HBV markers. Repeat liver function tests and a repeat coagulation profile on day 15 of admission showed persistent derangements, i.e. TB 369 mmol/L, CB 93 mmol/L, ALT 51 U/L, AST 55 U/L, ALP 3 227 U/L, GGT 32 U/L, LD 436 U/L, INR 7.54, PT 86.3 seconds (control 12.6 seconds), PTT 109.8 seconds (control 29.5 seconds) and fibrinogen 0.7 g/L (normal 2.0 - 4.0 g/L). The infant remained critically ill, his liver transaminases continued to decline, the coagulopathy persisted, the jaundice worsened, and he continued to experience hypoglycaemic spells. He subsequently developed melaena and grade II encephalopathy. He continued to deteriorate and died on day 45 of admission.

Genetic analysis of HBV from mother and infant

Total nucleic acid was extracted from serum samples of mother and infant using the MagNA Pure LC automated extraction method as per the manufacturer’s instructions (Roche Diagnostics GmbH, Germany). For HBV genotype assignment, a semi-nested PCR was used to amplify a region of the surface and overlapping polymerase (S/pol) gene: primers P6F and P2R[15] in the first round and P7F[16] and P2R in the second. The PCR protocol from Smuts et al.[17] was followed with minor modifications. The basal core promoter (BCP), pre-core/core region (PC) was amplified using a nested PCR protocol.[18] The entire surface antigen gene (preS1, preS2 and S) was amplified using primers and protocol from Chook et al.[19] Bidirectional Sanger sequencing of the S/pol, BCP/PC and S amplicons was performed using the BigDye terminator cycle sequencing kit (Applied Biosystems, USA). The HBV genotype was determined using the web-based geno2pheno program (http:// www.geno2pheno.org/index.php). To determine the heterogeneity of the BCP/PC and S genes, amplicons from both mother and infant were cloned into a pGEM-T vector according to the manufacturer’s instructions (Promega Corp., USA). Multiple clones were subjected to Sanger sequencing and aligned using BioEdit version 7.2.6.1 (Softpedia, Romania).

Table 1. Plasma markers of HBV infection in mother and infant HBV marker HBsAg Anti-HBs (mIU/mL) HB core IgM HB e antigen Anti-HBe HBV VL (IU/mL) Hepatitis D PCR

Mother Positive Negative Negative Negative Positive 760 ND

Infant, day 4 of admission Low positive 80 Negative ND* ND 465 Negative

Infant, day 17 of admission Negative 126 Low positive (1.21 S/CO) ND* ND 209 ND

HBV = hepatitis B virus; HBsAg = hepatitis B surface antigen; anti-HBs = hepatitis B surface antibody; IgM = immunoglobulin M; anti-HBe = hepatitis B e antibody; S/CO = signal/cut-off; ND = not done; VL = viral load; PCR = polymerase chain reaction. *Insufficient sample available to perform e-antigen testing. Sequence analysis of infant’s virus indicated the e-minus phenotype.

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Discussion

We present this case because it highlights the need to improve HBV prophylaxis to infected mothers and their infants. The case is unusual because the mother was anti-HBe-positive and had a low VL, only 760 IU/mL, but still transmitted infection to her infant. Also, the infant developed a fulminant infection that led to his death. The commonest scenario associated with MTCT of HBV is when the mother is HBeAg-positive and has a high HBV VL (>6 log IU/mL). This was previously reported to be relatively uncommon in Africa and accounted for the decision to omit a birth dose of HBV vaccine from the infant immunisation schedule in SA. However, more recent studies have found that between 18% and 37% of HBV-positive pregnant women in SA are HBeAg-positive. [9,10,20] Many HBV-positive individuals are co-infected with HIV, and this could influence the HBeAg status of infected individuals.

Was this MTCT?

Genetic analysis of the virus in mother and infant samples showed that both were infected with HBV genotype E. The mother was from the DRC, and genotype E is a predominant HBV genotype found in that country.[1] Sequence analysis of the BCP/ PC genomic region and the preS1, preS2 and S open reading frames (ORFs) of HBV revealed that the mother’s and infant’s viruses had multiple signatures in common, providing evidence that their infections were indeed epidemiologically linked. Common motifs included a near-identical deletion in the preS2 region (position 399 - 420 in the mother and position 402 - 420 in the infant), a 3-nucleotide insertion at position 598 - 600 in the small S ORF, and multiple singlenucleotide polymorphisms (Fig. 1, A and B).

The HBeAg-negative phenotype and its significance

HBV infection in infants and young children is usually associated with subclinical infection. Liver damage/hepatitis in HBV infection is immune mediated (due to cellmediated immune attack on HBV-infected liver cells). The milder clinical illness in the very young has been attributed to the tolerising effect of HBeAg. This protein is a potent immune modulator and immune evasion molecule, acting at multiple levels to induce immune tolerance: it blocks cellular responses to type 1 and 3 interferons,[21] interferes with toll-like receptor signalling and induces the expression of PD-1 (an exhaustion marker) on CD8+ cells, com-

A BCP

Pre-C ORF

BCP/PC

A1762T

G1764A

C1766T

T1768A

KOZAC

PC start codon 1814 - 16

T1858C

G1862T

G1896A

G1899A

Mother

GCAC

ATG

Infant

GCAC

ATG

B preS1

preS2 start

preS2 open reading frame

s ag start

s ag open reading frame

'a' determinant

Mother

ATG

21nt del 399 - 420 (in frame 7 aa deletion)

ATG

3nt insertion at position 598 - 600 (aa = L, 200)

Wild type

Infant

ATC

18nt del 402 - 420 (in frame 6 aa deletion)

ATG

3nt insertion at position 598 - 600 (aa = L, 200)

Wild type

Fig. 1. Genetic features of HBV present in mother and infant blood. (A) Sequence analysis of the BCP and PC region revealed that immune escape mutations A1762T and G1764A were present in the mother’s virus, but absent from the infant’s virus. Both contained the G1896A mutation, which truncates the HBeAg protein and confers the e-minus phenotype. (B) In the preS/S genes, the preS2 start codon was mutated in the infant’s virus, but intact in the mother’s. Both had large deletions in the preS2 gene, and there was a 21nt deletion from 399 to 420 in the mother’s virus and an 18nt deletion from 402 to 420 in the infant’s virus. A 3nt insertion was present in the small S ORF in both the mother’s and the infant’s virus. The ‘a’ determinant was unchanged. (BCP = basal core promoter; Pre-C = pre-core; ORF = open reading frame; PC = pre-core/core; s Ag = surface antigen; nt = nucleotide; aa = amino acid. Mutations and deletions in the HBV genome in mother and infant blood are indicated in red.)

promising their antiviral activity.[22] The effect of this is to attenuate the antiviral immune response (and severity of clinical hepatitis) and enable the virus to establish persistent infection in the host. Both the mother’s and the infant’s virus had the common G1896A mutation in the BCP/PC region. This mutation is frequently selected for during the immune-active phase of chronic HBV infection and probably became the predominant species in the mother’s blood years before. This mutation introduces a stop codon that truncates the HBeAg protein at the level of translation. In addition, the mother’s virus had further mutations in the BCP region (1762T, 1764A), known to reduce the synthesis of the pre-C mRNA transcript from which the HBeAg is synthesised. Transmission of HBV lacking functional HBeAg prevents the establishment of chronic infection but predisposes to more severe clinical hepatitis (due to the vigorous immune attack on infected liver cells). The fact that HBsAg was negative in the second blood sample from the infant is evidence that he was indeed clearing the infection. In a study of infants infected with HBV through MTCT, HBeAg-negative status in mothers was more likely to be associated with

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fulminant hepatitis in their infants, while infants of HBeAg-positive mothers were more likely to have mild hepatitis followed by chronic infection.[12]

When did transmission happen?

MTCT of HBV can occur in utero, intrapartum or after birth (in breast-fed infants). As for HIV, the greatest risk of HBV transmission is during birth and this is when transmission probably occurred in this case. [23] The infant received his first dose of HBV vaccine at 6 weeks of age and the second, just days before the clinical presentation, too late to prevent transmission. Viruses from breakthrough infections that occur in infants who have received HBV immunoglobulin or vaccine at birth frequently have mutations that alter the antigenicity of the major neutralising domain of the viral HBsAg, in the so-called ‘a’ determinant. Most common is a glycineto-arginine change at amino acid position 145, first described by Carman et al.[24] This mutation arises because the presence of neutralising antibody early on selects for viral variants with altered HBsAg protein that is not neutralised by the antibody. No changes were present in this region in either

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the mother’s or the infant’s virus, suggesting that the infection was already well established before the first dose of vaccine.

Conclusion

While this is a rare complication of HBV infection, it highlights the fact that vertical infections in infants do occur in SA despite current prophylaxis. Most transmissions from HBeAg-positive mothers are probably missed, as the infants do not present with a typical clinical illness, and it is the rare fulminant presentations that draw attention. Current HBV prophylaxis in SA is out of step with current guidelines.[14] Introduction of a birth dose of vaccine alone would improve efficacy, but given the prevalence of HBV infection among local pregnant women, we consider that prenatal screening is needed. Screening could be done at booking using a rapid test for HBsAg. The most cost-effective approach would be for women who test positive to receive tenofovir prophylaxis in the second to third trimesters. A small field study has already demonstrated the feasibility of this approach in the Western Cape Province.[25] Also, the safety and acceptability of this drug has already been established for HIVinfected pregnant women.

Teaching points

• Mother-to-child HBV transmission may occur even when the maternal VL is low (<3 log IU/mL). • Fulminant hepatitis in this infant was due to transmission of an HBV strain unable to express the e-antigen. • This case provides evidence of failure of the current infant HBV prophylaxis programme in SA. Acknowledgements. None. Author contributions. DRH and SK conceived the study and wrote part of the article. OB, BE and RdL provided clinical management of the case and wrote the clinical part of the case report. HS performed molecular testing and analysis and gave input into writing the article. Funding. None. Conflicts of interest. None. 1. Kramvis A, Kew MC. Epidemiology of hepatitis B virus in Africa, its genotypes and clinical associations of genotypes. Hepatol Res 2007;37(s1):S9-S19. https://doi.org/10.1111/j.1872-034X.2007.00098.x 2. Dibisceglie AM, Kew MC, Dusheiko GM, et al. Prevalence of hepatitis B virus infection among black children in Soweto. BMJ 1986;292(6533):1440-1442. https://doi.org/10.1136/bmj.292.6533.1440 3. Botha JF, Dusheiko GM, Ritchie MJJ, Mouton HWK, Kew MC. Hepatitis B virus carrier state in black children in Ovamboland: Role of perinatal and horizontal infection. Lancet 1984;323(8388):12101212. https://doi.org/10.1016/S0140-6736(84)91694-5

4. Abdool Karim SS, Coovadia HM, Windsor IM, Thejpal R, van den Ende J, Fouche A. The prevalence and transmission of hepatitis B virus infection in urban, rural and institutionalized black children of Natal/KwaZulu, South Africa. Int J Epidemiol 1988;17(1):168-173. https://doi.org/10.1093/ije/17.1.168 5. Bhimma R, Coovadia HM, Adhikari M, Connolly CA. The impact of the hepatitis B virus vaccine on the incidence of hepatitis B virus-associated membranous nephropathy. Arch Pediatr Adolesc Med 2003;157(10):1025-1030. https://doi.org/10.1001/archpedi.157.10.1025 6. Tsebe KV, Burnett RJ, Hlungwani NP, Sibara MM, Venter PA, Mphahlele MJ. The first five years of universal hepatitis B vaccination in South Africa: Evidence for elimination of HBsAg carriage in under 5-year-olds. Vaccine 2001;19(28-29):3919-1326. https://doi.org/10.1016/S0264-410X(01)00120-7 7. Hoffmann CJ, Mashabela F, Cohn S, et al. Maternal hepatitis B and infant infection among pregnant women living with HIV in South Africa. J Int AIDS Soc 2014;17(1):1-5. https://doi.org/10.7448/ IAS.17.1.18871 8. Chotun N, Nel E, Cotton MF, Preiser W, Andersson MI. Hepatitis B virus infection in HIV-exposed infants in the Western Cape, South Africa. Vaccine 2015;33(36):4618-4622. https://doi.org/10.1016/j. vaccine.2015.06.076 9. Diale Q, Pattinson R, Chokoe R, Masenyetse L, Mayaphi S. Antenatal screening for hepatitis B virus in HIV-infected and uninfected pregnant women in the Tshwane district of South Africa. S Afr Med J 2016;106(1):97-100. https://doi.org/10.7196/SAMJ.2016.v106i1.9932 10. Thumbiran NV, Moodley D, Parboosing R, Moodley P. Hepatitis B and HIV co-infection in pregnant women: Indication for routine antenatal hepatitis B virus screening in a high HIV prevalence setting. S Afr Med J 2014;104(4):307-309. https://doi.org/10.7196/SAMJ.7299 11. Chen HL, Lin LH, Hu FC, et al. Effects of maternal screening and universal immunization to prevent mother-to-infant transmission of HBV. Gastroenterology 2012;142(4):773-781. https://doi. org/10.1053/j.gastro.2011.12.035 12. Tseng YR, Wu JF, Kong MS, et al. Infantile hepatitis B in immunized children: Risk for fulminant hepatitis and long-term outcomes. PLoS One 2014;9(11):1-8. https://doi.org/10.1371/journal. pone.0111825 13. World Health Organization. Hepatitis B vaccines: WHO position paper – July 2017. Wkly Epidemiol Rec 2017;92(27):369-392. http://www.who.int/wer/2017/wer9227/en/ (accessed 11 April 2018). 14. Li J, Chang MS, Tran TT, Nguyen MH. Management of chronic hepatitis B in pregnancy. J Clin Gastroenterol 2017;51(9):1. https://doi.org/10.1097/MCG.0000000000000908 15. Liu BM, Li T, Xu J, et al. Characterization of potential antiviral resistance mutations in hepatitis B virus reverse transcriptase sequences in treatment-naiive Chinese patients. Antiviral Res 2010;85(3):512519. https://doi.org/10.1016/j.antiviral.2009.12.006 16. Kew MC, Kramvis A, Yu MC, Arakawa K, Hodkinson J. Increased hepatocarcinogenic potential of hepatitis B virus genotype A in Bantu-speaking sub-saharan Africans. J Med Virol 2005;75(4):513-521. https://doi.org/10.1002/jmv.20311 17. Smuts H, Sonderup M, Gogela N, Spearman CW. Hepatitis B virus genotype G: First report of complete genomic analysis from the African continent. J Emerg Dis Virol 2017;3(2). https://doi. org/10.16966/2473-1846.130 18. Makondo E, Bell TG, Kramvis A. Genotyping and molecular characterization of hepatitis B virus from human immunodeficiency virus-infected individuals in southern Africa. PLoS One 2012;7(9). https:// doi.org/10.1371/journal.pone.0046345 19. Chook JB, Teo WL, Ngeow YF, Tee KK, Ng KP, Mohamed R. Universal primers for detection and sequencing of hepatitis B virus genomes across genotypes A to G. J Clin Microbiol 2015;53(6):18311835. https://doi.org/10.1128/JCM.03449-14 20. Andersson MI, Maponga TG, Ijaz S, et al. The epidemiology of hepatitis B virus infection in HIV-infected and HIV-uninfected pregnant women in the Western Cape, South Africa. Vaccine 2013;31(47):5579-5584. https://doi.org/10.1016/j.vaccine.2013.08.028 21. Yu Y, Wan P, Cao Y, et al. Hepatitis B virus e antigen activates the suppressor of cytokine signaling 2 to repress interferon action. Sci Rep 2017;7(1):1729. https://doi.org/10.1038/s41598-017-01773-6 22. Chen LM, Fan XG, Ma J, He B, Jiang YF. Molecular mechanisms of HBeAg in persistent HBV infection. Hepatol Int 2017;11(1):79-86. https://doi.org/10.1007/s12072-016-9734-5 23. Wen Y-M, Wang Y-X. Biological features of hepatitis B virus isolates from patients based on full-length genomic analysis. Rev Med Virol 2009;19(1):57-64. https://doi.org/10.1002/rmv.600 24. Carman WF, Karayiannis P, Waters J, et al. Vaccine-induced escape mutant of hepatitis B virus. Lancet 1990;336(8711):325-329. https://doi.org/10.1016/0140-6736(90)91874-A 25. Chotun N, Preiser W, van Rensburg CJ, et al. Point-of-care screening for hepatitis B virus infection in pregnant women at an antenatal clinic: A South African experience. PLoS One 2017;12(7):1-11. https://doi.org/10.1371/journal.pone.0181267

Accepted 19 December 2017.

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

REVIEW

Fanconi anaemia in South Africa: Past, present and future C Feben,1 FCMG (SA); T Wainstein,2 MSc Med (Genetic Counselling); J Kromberg,2 PhD; F Essop,1 MSc; A Krause,1 PhD Division of Human Genetics, National Health Laboratory Service and School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa 2 Division of Human Genetics, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa 1

Corresponding author: C Feben (candice.feben@nhls.ac.za)

Fanconi anaemia (FA) is an inherited genetic disorder characterised by somatic anomalies, bone marrow failure and an increased predisposition to solid tumours and haematological malignancies. South African (SA) black and Afrikaner individuals are at higher than average risk for this condition owing to genetic founder mutations in certain Fanconi-associated genes. This review explores the epidemiology, clinical presentation, diagnostic modalities and recommended care of affected patients, focusing on the founder population groups in SA. The early diagnosis of FA is important and provides improved opportunities for early intervention, but remains challenging. S Afr Med J 2018;108(5):393-398. DOI:10.7196/SAMJ.2018.v108i5.13004

Fanconi anaemia (FA) is an inherited disorder of impaired DNA repair, first described by Swiss paediatrician Guido Fanconi in 1927 and since then extensively documented in individuals of diverse ethnic origin.[1-3] Characterised clinically by somatic, haematological and oncological anomalies, most often manifesting in childhood, the condition is cytogenetically typified by spontaneous and induced chromosome breakage and is usually inherited in an autosomal recessive manner.[1] In South Africa (SA), in contrast to other populations worldwide where genotypic heterogeneity typically underpins this complicated disorder,[1] two population subgroups with well-characterised founder mutations have allowed for focused and genotype-specific research into FA.[4-6] However, despite our research and enhanced understanding of this disorder, the diagnosis of FA remains a clinical and laboratory challenge in the SA healthcare system. This article reviews the epidemiology, molecular pathogenesis, clinical phenotype, available local and international genetic testing and recommended surveillance and treatment for FA, with a focus on the local black and Afrikaner population groups. Additionally, we discuss some rare cases of FA caused by mutations in non-founder FA genes that have highlighted a need for broadened genetic testing capacity for this condition in SA. The term ‘black’ is used to describe individuals of indigenous ancestry originally descended from sub-Saharan Bantu-speaking groups and in whom genetic founder mutations have been noted. The term ‘Afrikaner’ is used to describe Caucasian individuals of selfreported Dutch-European descent.

Epidemiology

FA has been reported in numerous racial and ethnic groups and is considered worldwide to be an important heritable cause of aplastic anaemia in children.[7] The condition is usually inherited in an autosomal recessive manner, although autosomal dominant and X-linked forms are described, with a slight male preponderance (skewing of the male-to-female ratio 1.2:1 v. expected 1:1). North American carrier frequencies are estimated at 1/181. The carrier rate and the expected prevalence of the condition in two subgroups of the SA population (as well as other population subgroups elsewhere, including the Ashkenazi Jewish population, the Spanish gypsies and the Japanese) is estimated to be much higher than the quoted North

American figure as a result of founder effects.[1] The National Cancer Institute Dictionary of Genetic Terms defines a founder mutation as ‘a genetic alteration observed with high frequency in a group that is or was geographically or culturally isolated, in which one or more of the ancestors was a carrier of the altered gene’.[8] Based on haplotype analysis and evaluation of population genetic data, a founder mutation in the black population (FANCG: NM_0046 29.1g.35077270_35077264del) appears to predate the arrival of Bantu speakers in southern Africa in AD 400, and is therefore an ancient mutation, possibly with its origins in West Africa.[2,5] The estimated carrier frequency of the mutation is 1/100, with the predicted birth incidence of FA in black South Africans approximating 1/40 000.[2] Molecular and genealogical evidence indicates that the three Afrikaner founder mutations (FANCA: NM_000135.2 g.89858955_89818546del; NM_000135.2 g.89847979_89861587del; NM_000135.2 g.89813249_89813249del) were probably introduced into SA following the 17th-century migration of the French Huguenots to the Cape.[3,6] The prevalence of FA in individuals of Afrikaner ancestry, based on birth incidence and point prevalence data, respectively, has been estimated as between 1/22 000 and 1/26 000.[3,6] These figures are at least double those seen elsewhere, despite significant under-ascertainment of FA locally. Based on these predicted frequencies and the well-documented and reported clinical phenotype, we would anticipate that FA is readily diagnosed in secondary and tertiary healthcare facilities. However, a large discrepancy exists between the number of observed and expected cases of FA and indicates that many cases are unrecognised or undiagnosed. Unpublished data suggest that only one of every 15 cases of FA will have molecular confirmation of the diagnosis in SA (A Krause, personal communication, May 2017). This does not appear to be a situation unique to SA, as it has been widely reported that the diagnosis is most often made at the time of bone marrow failure[9] despite the frequency of associated physical congenital anomalies.

Molecular pathogenesis

The complex FA pathway has been extensively investigated over many years to elucidate the mechanisms by which multiple protein products interact synergistically to provide genome stability and ensure cellular survival through DNA repair mechanisms.[10-12] As

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of 2017, the FA multistep, S-phase specific cellular response to damaged DNA involved 22 genes, designated FANC A, B, C, D1, D2, E, F, G, I, J, L, M, N, O, P, Q, R, S, T, U, V and W.[1,10,13-16] Collectively, mutations in FANCA, FANCC and FANCG account for >90% of cases.[1] The pathway is activated when DNA replication is stalled[12] and its critical functions include homologous recombination for inter-strand cross-link repair, nucleolytic incision and translesion DNA synthesis.[11,17] The more recent discovery that BRCA1 (FANCU) and BRCA2 (FANCD1), implicated in the causation of hereditary breast and ovarian cancer syndrome (HBOC), are also part of the FA pathway highlights the interplay between abnormal DNA repair mechanisms and the evolution of cancer.[11,18] Most of the FA genes exhibit mutational or allelic heterogeneity, which is evidenced by the large number of sequence variants and mutations that have been described, particularly in the FANCA and FANCG genes.[19-21] In >80% of black patients with FA, a homozygous seven basepair deletion mutation in the FANCG gene (NM_004629.1 g.35077270_35077264del p.Tyr213Lysfs)[2] has been confirmed as the cause of the disease. In a further 5% of cases, black patients with FA are heterozygous for the founder mutation, and preliminary molecular analysis of these FANCG heterozygotes revealed a second FANCG mutation on the other allele in 57% of a small cohort. [22] The molecular aetiology for the so-called ‘G-negative’ black patients with a clinical and/or cytogenetic diagnosis of FA is poorly understood, although most recently mutations in rarer FA genes, including BRCA2, have been identified.[18] In SA individuals with Afrikaner ancestry, three mutations in FANCA have been shown to account for ~80% of FA cases.[3] A founder mutation described in individuals of Ashkenazi Jewish ancestry is also found in SA individuals of this origin. This splicesite mutation in the FANCC gene (IVS4+4A>T) accounts for most cases of FA in Ashkenazi Jewish cohorts worldwide.[23] There is no published literature on the molecular pathogenesis of FA in SA population groups other than those in which founder mutations exist.

Clinical phenotype

Clinically, FA is characterised by a triad of somatic, haematological and oncological abnormalities. Congenital abnormalities, including skeletal, cardiovascular, genitourinary, gastrointestinal and central nervous system malformations, are well documented,[1,24] as are poor postnatal growth, short stature, pigmentary anomalies and endocrine dysregulation.[25] Internationally, data from large patient cohorts have been collated under the auspices of the International Fanconi Anaemia Registry (IFAR) and composite frequency figures for the physical anomalies observed in genetically heterogeneous cohorts have been documented (Table 1).[1,26] Genotype-phenotype correlation studies performed in the black and Afrikaner populations in SA show that the frequencies of physical anomalies mirror the IFAR data in some respects, but also highlight population- and possibly mutation-specific features in our patient cohorts (Table 2).[4-6] A trend towards significant physical differences between the two founder populations in SA has also been noted and suggests that future research is needed to provide greater definition, particularly for the Afrikaner phenotype.[6] It has been observed that in both population groups, identification and recognition of the FA phenotype may be improved by referral of children with growth restriction, pigmentary anomalies and unusual hands to a paediatrician or medical geneticist for an assessment.[4,6] Certainly in a small Afrikaner patient cohort, the frequency of major congenital anomalies appears high, and patients

may meet criteria for the diagnosis of VACTERL-H association (vertebral, ano-rectal, cardiac, tracheo-esophageal, renal and limb anomalies and hydrocephalus). Additional screening of patients with these abnormalities would be warranted.[6] From a haematological perspective, bone marrow failure remains the significant identified cause of morbidity and mortality in FA patients, with initial pancytopenia and progression to acute myeloid leukaemia (AML), myelodysplastic syndrome (MDS) or aplastic anaemia.[1,27] Thrombocytopenia, macrocytosis (raised mean corpuscular volume) and a raised fetal haemoglobin (Hb) usually precede the onset of more severe haematological anomalies.[1,28] Based on data collected by the IFAR, haematological abnormalities appear to present in childhood at a median age of 7 years, with progression to bone marrow failure by the age of 40 years in >90% of patients. [28] Research in a black SA FA cohort determined that the median age of presentation with symptoms of FA, usually concurrent with the diagnosis of bone marrow aplasia, was 7 years and 1 month of age. In the same cohort it was shown that the most common presenting symptom was recurrent epistaxis and that apart from macrocytosis, a severely low Hb (<8 g/dL) was a common initial haematological finding.[5] Based on the ascertainment of patients from haematology/oncology clinics, it is possible that referral bias in this study led to exclusion of more or less severely affected individuals.[5] FA is also recognised as a cancer susceptibility syndrome.[1,28,29] A predisposition to solid tumours of the head and neck, liver, oesophagus and female genital tract is well described and has become more evident in developed-world countries as the treatment for the haematological complications of the disease has improved. [30] In developed nations, the availability of haematopoietic stem cell transplantation (HSCT) as treatment for bone marrow failure has prolonged life and is therefore predicted to result in a higher prevalence of solid tumours as a common clinical manifestation in later life.[28,29] In SA, solid tumours are rarely seen in patients with FA as most still die in childhood and adolescence from bone marrow disease. HSCT is only available to a minority of patients in the private healthcare sector.[5] The clinical phenotype of individuals with biallelic BRCA2 mutations as the cause of their FA is characteristically different to that described in more typical cases of FA, with more severe somatic anomalies, earlier-onset haematological compromise and childhood susceptibility to solid tumours, including Wilms tumours and medulloblastomas.[31-34] A case report on two black SA children with FA in whom biallelic BRCA2 mutations were identified (Table 3) highlights the difficulties in care and management of these families, in that the children had severe anomalies associated with their FA phenotype, while the parents are obligate heterozygote carriers of a BRCA2 fault and receive an obligatory diagnosis of HBOC.[18] HBOC is associated with variable risks for breast, ovarian, prostate and pancreatic cancers as well as melanomas.[34] Solid-tumour risk for carriers of other rare FA genes, including FANCN (PALB2) and FANCO (RAD51C), is established in cohorts of patients with breast and/or ovarian cancer, with increased risks for breast cancer (33 - 58% in PALB2)[35] and ovarian cancer (≤9% in RAD51C). [36] Whether the mutation spectrum related to tumour risk in heterozygous carriers of mutations in these genes is the same as that seen in carriers of FA is uncertain, although consideration of these potential risks is important. There does not appear to be a significantly increased risk of cancer in carriers of mutations in the more common FA genes, including FANCA, FANCC and FANCG,[37] but larger studies are required to clarify this.

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Table 1. Composite frequencies of physical anomalies in patients with Fanconi anaemia (adapted from Mehta and Tolar, 2017[1]) Physical anomalies Skin Pigmentation CafĂŠÂ auÂ lait macules Hypopigmentation/ hyperpigmentation Upper limbs Thumbs Absent/hypoplastic Bifid/duplicated Triphalangeal/long Proximally inserted Radii Absent/hypoplastic Absent/weak pulse Hands Flat thenar eminence Absent 1st metacarpal Clinodactyly/polydactyly Ulnae Short/dysplastic Lower limbs Congenital hip dysplasia, talipes equinovarus, syndactyly CNS Microcephaly Structural Small pituitary gland abnormality Pituitary stalk interruption syndrome Absent corpus callosum Hydrocephalus Cerebellar hypoplasia Eyes Microphthalmia Cataracts Strabismus Ptosis Hypertelorism Epicanthic folds Astigmatism Genitourinary Renal Horseshoe Ectopic/pelvic Absent/hypoplastic Hydronephrosis/hydroureter Male genitalia Hypospadias Micropenis Cryptorchidism Hypo/azospermia Female Bicornuate uterus/ genitalia malpositioned, small ovaries Heart Congenital ASD/VSD/PDA malformations Coartation of the aorta Truncus arteriosus GIT Tracheo-oesophageal fistula, imperforate anus, oesophageal, duodenal or jejenal atresias, annular pancreas, malrotation Total

Frequency of anomalies, % 40

7 5

1 5

20 3

CNS = central nervous system; GIT = gastrointestinal tract; ASD = atrial septal defect; VSD = ventricular septal defect; PDA = patent ductus arteriosus.

Diagnosis

Traditionally, and possibly still regarded as the gold standard, the diagnosis of FA is confirmed by evaluation of the response of metaphase and interphase cells exposed to diepoxybutane or mitomycin C, two commonly used clastogenic DNA cross-linking agents. FA cells show hypersensitivity to these agents, with increased chromosome breakage and the formation of multiple abnormal structures including multi-radials, tri-radials and breaks.[1,12,38] The results should be compared with normal and positive control cells for standardisation.[1] Chromosome breakage abnormalities are not unique to FA and do not elucidate the underlying molecular abnormality, but rather provide cytogenetic evidence of the disease process.[1] Diagnostic molecular testing for FA has evolved from predominantly single-gene analysis based on the results of complementation analysis (a cell-based technique used to identify the most likely affected gene) to the use of multi-gene next-generation sequencing (NGS) panels that simultaneously evaluate all known FA genes on a single testing platform. This testing strategy has the advantage of allowing many genes to be tested at the same time, which limits waiting periods involved with sequential testing and, as the costs are falling, may possibly replace the use of chromosome breakage and single-gene analysis for FA diagnostics.[39] A number of commercially available NGS panel tests are available through international laboratories. In SA, as founder mutations exist in certain population groups, diagnostic mutation-specific testing is currently offered by the Molecular Genetics Laboratory of the Division of Human Genetics, National Health Laboratory Services and School of Pathology (University of the Witwatersrand) in Johannesburg. Testing is offered for the common founder Ashkenazi Jewish mutation in the FANCC gene, for three founder mutations in the FANCA gene in the Afrikaner population, and for the seven base-pair deletion mutation in the FANCG gene in black SA patients (F Essop, personal communication, May 2017). BRCA2 mutation analysis is available through the Department of Human Genetics at the University of the Free State in Bloemfontein for those patients in whom a more severe phenotype is noted that may suggest the FANCD1 (BRCA2) subgroup. Patients with a clinical or haematological phenotype suggestive of FA in whom founder mutation testing is inappropriate or negative are currently unable to access NGS testing in the SA state healthcare system. In this regard, a number of research partnerships have been established to attempt to determine the molecular basis of FA in these individuals. Although the results have not been verified in a diagnostic setting, a number of plausible results, indicating possible deleterious mutations in rare FA genes, may suggest that NGS panel testing should augment the current testing strategy for those who have negative founder mutation analysis, or be used as first-line testing in those who do not have Afrikaner or black ancestry. Such testing is being developed and optimised for SA.

Management strategies

Most patients with FA will be cared for by a multidisciplinary team of specialists with the paediatric haematologist/oncologist and ideally the medical geneticist or genetic counsellor at the forefront, and including other specialist paediatricians depending on the congenital anomalies identified.[1] The aims of care are to ensure correct medical and surgical management of the patient and to provide the patient and the family with genetic counselling and psychosocial support. [40] Treatment protocols will differ according to local expertise and resources. Currently HSCT remains the only available cure for the haematological complications of FA, including

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Table 2. Frequency of somatic abnormalities in Fanconi’s anaemia patients with founder FANCA and FANCG mutations (adapted from Feben et al., 2015[5] and Feben et al., 2017[6]) Mutation, n/N (%) FANCG 637_643delTACCGCC 34/35 (97.1) 35/35 (100) 26/35 (74.3) 33/35 (94.3) 12/31 (38.7) 3/35 (8.5) 1/16 (12.5) 0/35 (0)

FANCA mutations* 7/8 (87.5) 5/8 (62.5) 7/8 (87.5) 4/8 (50.0) 4/8 (50.0) 1/8 (12.5) 2/8 (25.0) 0/8 (0)

Abnormality Pigmentary anomalies Head anomalies‡ Radial ray anomalies Ulnar ray anomalies Kidney malformations§ GIT malformations Cardiac malformations¶ CNS anomalies

p-value† 0.3411 0.0045 0.6563 0.0072 0.6937 1 0.2490 -

GIT = gastrointestinal tract; CNS = central nervous system. *Founder mutations: g.89858955_89818546del; g.89847979_89861587del; g.89813249_89813249del. † Frequency of anomalies in two cohorts compared using Fisher’s exact test. ‡ Head anomalies include microcephaly, micrognathia, a triangular face, and eye and ear anomalies (as described by Faivre et al., 2000[48]). § Detected on ultrasound. ¶ Confirmed on echocardiography.

Table 3. Phenotype of two South African patients with Fanconi’s anaemia caused by biallelic FANCD1/BRCA2 mutations (adapted from Feben et al., 2017[18]) Patient 1 BRCA2 mutation Allele 1 Allele 2 Cytogenetic phenotype Haematological phenotype Oncological phenotype Physical phenotype

Age at death

Patient 2

c.5771_5774delTTCA p.Ile924Argfs*38 c.5771_5774delTTCA p.Ile924Argfs*38 c.582G>A p.Trp194* c.67+3A>G Spontaneous and induced (DEB + MMC) chromosome breakage; multiple fragments, tri-radials and translocations Acute leukaemia at 1 year and 10 months of age Aplastic anaemia at 1 year of age; acute leukaemia at 1 year and 7 months of age Unilateral Wilms tumour at 7 months of age Postnatal onset symmetrical growth restriction, multiple Postnatal onset symmetrical growth restriction, café au lait macules, hypo- and hyperpigmented skin multiple café au lait macules, hypo- and lesions, bilateral ptosis, minor radial anomalies hyperpigmented skin lesions, bilateral choanal atresia, a patent ductus arteriosus, single pelvic kidney 1 year and 10 months 1 year and 7 months

DEB = diepoxybutane stimulation; MMC = mitomycin C stimulation.

MDS and AML. The timing of transplantation is critical and it has been suggested that transplantation be performed before the onset of significant haematological complications, and specifically before the patient requires a number of blood product transfusions.[41] After successful transplantation, affected individuals remain at risk for the development of solid tumours, specifically squamous cell malignancies of the head and neck and female genital tract.[1,28] These systems require regular surveillance to ensure early detection. Treatment is challenging owing to the increased toxicity of chemotherapy and radiation in individuals with FA.[1] Unfortunately HSCT is not routinely available in the state healthcare system in SA, so noncurative palliative measures are often utilised. In the local setting these non-curative measures include androgen administration, which is the mainstay of initial treatment for FA once marrow aplasia is evident. This therapy has been shown to be effective in up to 50% of individuals within 1 month of commencement. It acts to increase the red cell count and Hb level, with a variable platelet and white cell response.[1] A number of complications have been noted, including liver toxicity and risk of the development of hepatic tumours,[1] hirsutism, acne, hyperactivity, and restricted growth leading to short stature.[1,42] Overall, however, survival is thought to be better in androgen-treated v. non-treated patients.[43] Androgen therapy is not advocated in the preanaemic phase of the condition (Hb >8 g/dL) owing to the side-effect profile of the medication.[1] Transfusion of platelets and packed cells is

used as supportive therapy during crisis periods and at later stages of the disease for palliation.[1] A comprehensive list of investigations and care recommendations has been made available by the Fanconi Anaemia Research Fund (FARF).[44] These extensive guidelines indicate the optimal care recommended for patients and families with FA. The guidelines detail both childhood and adult surveillance for the anticipated complications of the condition. Some of these recommendations may be challenging to implement in resource-restricted settings. To streamline the necessary and prudent investigations required in a local context, recommendations for management have been made for both black and Afrikaner patients with FA based on the frequency of certain anomalies in genotype-phenotype correlation studies. These recommendations include a baseline renal ultrasound scan and a hearing test in all diagnosed patients. Additionally, recommendations were made to primary and secondary healthcare practitioners to improve the recognition of FA and refer patients for appropriate paediatric or medical genetic assessment (Fig. 1).[4-6] Studies evaluating the endocrine profile of a cohort of black individuals with FA to assess their need for endocrine screening are currently underway. SA data on cohorts of affected adult patients with FA are currently lacking. With improvements in therapy and treatment modalities and the concomitant increase in longevity of patients, we may need to determine suitable local recommendations for adolescent and

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adult cancer screening. Of note, the FARF recommends screening for oral cancers (which affect 14% of FA patients) from the age of 10 years, with 6-monthly clinical assessment by a dentist with knowledge of and experience in detecting pre-malignant lesions of the oral mucosa.[44] Lifestyle advice on the avoidance of alcohol and smoking should also be provided.[44] These recommendations should be considered for our patients, even in resource-restricted settings.

MULTIPLE SKIN PIGMENTARY LESIONS

UNUSUAL HANDS

POSTNATAL GROWTH FAILURE >2

HISTORY OF EPISTAXIS

MICROCEPHALY

Genetic counselling

Individuals diagnosed with FA and their parents, siblings and other at-risk relatives can all benefit from genetic counselling. The aim of genetic counselling is to provide information and support in the understanding of the condition from medical, genetic and psychosocial viewpoints. In most cases, as FA is inherited in an autosomal recessive manner, the parents of an affected child have a 25% chance of having another affected child. Prenatal and preimplantation genetic diagnosis (PGD) can be offered to the parents of an affected child,[45] although in many cases the diagnosis of FA is made in the first child only after the birth of a second or third child. Prior knowledge of an affected fetus may allow for the option of termination of pregnancy in cases where this is acceptable to the parents, or allow parents to prepare for the birth of an affected child. Ideally, knowledge of the impending birth of an affected child may allow for pre-emptive preparation for HSCT. Prenatal testing can be performed by chorionic villus sampling (at 11 - 14 weeks’ gestation) or by amniocentesis (at 16 - 20 weeks’ gestation) to obtain fetal cells for assessment. Chromosome breakage analysis is theoretically possible on fetal cells and can be used in the event that the causative mutation in the affected child is unknown.[1] However, molecular targeted mutational analysis is the best option for cases in which mutations have been detected. PGD, which utilises an in vitro fertilisation technique and allows for single-cell testing of an eight- to 16-cell embryo, can also be used to ‘select’ unaffected embryos for implantation. Additionally, embryos have been successfully tested for ‘negative’ FA status and ‘positive’ HLA matching to facilitate HSCT in the affected child.[1] This procedure is very costly and not currently available in the state healthcare system in SA. In instances where the carrier parents of an affected child are identified as having an increased susceptibility to developing cancers,[37] screening and prophylactic management options can be implemented to

REFER TO PAEDIATRICIAN TREAT COMMON CONDITIONS CONSIDER FANCONI ANAEMIA

Renal anomaly supportive

Raised MCV supportive

REFER TO MEDICAL GENETICIST Fig. 1. Recommended referral pathway to enhance recognition of Fanconi anaemia in South Africa. (MCV = mean corpuscular volume.)

mitigate these risks. Risk evaluation as well as screening and management guidelines for HBOC should be guided by clinical judgement, family history and genetic testing results.[45,46] Referral of such FA carriers to a specialist genetic clinic for discussion should be encouraged. Given the variability and complexity of the FA clinical presentation, siblings of individuals with FA would also benefit from evaluation, including genetic testing, to exclude a possible FA diagnosis, which would allow for earlier implementation of the appropriate care. Carrier testing for at-risk relatives (such as the parents’ siblings) should also be encouraged; this is especially true in the context of founder populations, in which the carrier frequency of founder mutations is increased.[45] The psychosocial consequences of a diagnosis of FA in a child have been described as similar to those in childhood cancer diagnoses [47] A constant sense of uncertainty and the stress of lifelong medical care necessities, as well as lack of awareness of FA both in the public domain and among healthcare

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professionals, constitute some of the ongoing stressors and emotional challenges that parents of children with FA must face.[47] Genetics professionals are in a good position to assist such families, as they are equipped to deal with the complicated technological, medical and genetic information as well as these psychosocial aspects for all family members and throughout the lifespan of the affected child and adult.

Conclusions

This review emphasises important aspects related to the recognition, diagnosis, management, care and prevention of FA, a rare but important inherited disorder in the SA context. Research in our local SA populations over the past several decades has brought to light two ethnic groups (black and Afrikaner populations) that have higher than average carrier rates owing to the presence of founder mutations. This information has been essential as the background to the offering of a diagnostic genetic testing service for FA and provision of genetic

REVIEW

counselling services for families of affected individuals. More recent research endeavours have shown that NGS technologies may hold the answers for an improved and fully comprehensive service for all SA patients suspected of having FA. It is hoped that ongoing research initiatives on the clinical phenotype of black and Afrikaner FA patients will allow for enhanced recognition of the diagnosis among healthcare professionals. In the local context, the diagnosis of FA should be considered more readily when characteristic features are present. Like many other inherited disorders, FA is complicated in every aspect and requires management and co-ordination by a multidisciplinary team of healthcare professionals and support structures. Acknowledgements. We thank the clinical, laboratory, counselling and support staff at the Division of Human Genetics, National Health Laboratory Services and the University of the Witwatersrand, as well as our clinical and laboratory collaborators at paediatric haematology/ oncology clinics at Chris Hani Baragwanath Hospital and Charlotte Maxeke Johannesburg Academic Hospital, Universitas Hospital (and the University of the Free State), the Polokwane/Mankweng Hospital Complex (and the University of Limpopo), and Unitas Hospital (and the University of Pretoria). We also thank our patients and their families for helping us to share their stories. Author contributions. Study design and conception: CF, AK, JK; data collection and analysis: CF, AK, TW, FE; writing of article: CF, TW; editing: AK, JK. Funding. Medical Research Council of South Africa, Phyllis Knocker Bradlow Award (Colleges of Medicine of South Africa). Conflicts of interest. None. 1. Mehta PA, Tolar J. Fanconi anaemia. Gene Reviews. Last updated February 2017. http://www.ncbi.nlm. nib.gov/books/NBK1401 (accessed 15 July 2017, 16 October 2017). 2. Morgan NV, Essop F, Demuth I, et al. A common Fanconi anaemia mutation in black populations of sub-Saharan Africa. Blood 2005;10(9):3542-3544. https://doi.org/10.1182/blood-2004-10-3968 3. Tipping AJ, Pearson T, Morgan NV, et al. Molecular and genealogical evidence for a founder effect in Fanconi anaemia families of the Afrikaner population of South Africa. Proc Natl Acad Sci USA 2001;98(20):5734-5739. https://doi.org/10.1073/pnas.091402398 4. Feben C, Kromberg J, Wainwright R, et al. Phenotypic consequences in black South African Fanconi anaemia patients homozygous for a founder mutation. Genet Med 2014;16(5):400-406. https://doi. org/10.1038/gim.2013.159 5. Feben C, Kromberg J, Wainwright R, et al. Haematological consequences of a FANCG founder mutation in black South African patients with Fanconi anaemia. Blood Cells Mol Dis 2015;54(3):270274. https://doi.org/10.1016/j.bcmd.2014.11.011 6. Feben C, Haw T, Stones D, et al. Fanconi anaemia in South African patients with Afrikaner ancestry. S Afr J Child Health 2017;11(3):141-145. https://doi.org/10.7196/SAJCH.2017.v11i2.1312 7. Shimamura A, Alter B. Pathophysiology and management of inherited bone marrow failure syndromes. Blood Rev 2010;24(10):101-133. https://doi.org/10.1016/j.blre.2010.03.002 8. National Cancer Institute. Dictionary of genetic terms. https://www.cancer.gov/publications/ dictionaries/genetics-dictionary (accessed 6 June 2017). 9. Giampietro PF, Adler-Brecher B, Verlander PC, et al. The need for more accurate and timely diagnosis in Fanconi anaemia: A report from the International Fanconi Anaemia Registry. Pediatrics 1993;91(6):1116-1120. 10. Sawyer SL, Tian L, Kahkonen M, et al. Biallelic mutations in BRCA1 cause a new Fanconi anaemia subtype. Cancer Discov 2015;5(2):135-142. https://doi.org/10.1158/2159-8290.cd-14-1156 11. Kim H, d’Andrea AD. Regulation of DNA cross-link repair by the Fanconi anaemia/BRCA pathway. Genes Dev 2012;26(13):1393-1408. https://doi.org/10.1101/gad.195248.112 12. De Winter JP, Joenje H. The genetic and molecular basis of Fanconi anaemia. Mutat Res 2009;668(12):11-19. https://doi.org/10.1016/j.mrfmmm.2008.11.004 13. Ameziane N, May P, Haitjema A, et al. A novel Fanconi anaemia subtype associated with a dominantnegative mutation in RAD51. Nat Commun 2015;6:8829. https://doi.org/10.1038/ncomms9829 14. Bluteau D, Masliah-Planchon J, Clairmont C, et al. Biallelic inactivation of REV7 is associated with Fanconi anaemia. J Clin Invest 2016;126(9):2580-3584. https://doi.org/10.1172/JCI88010

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Blood 2003;101(3):822-826. https://doi.org/10.1182/blood-2002-05-1498 31. Hirsch B, Shimamura A, Moreau L, et al. Association of biallelic BRCA2/FANCD1 mutations with spontaneous chromosomal instability and solid tumors of childhood. Blood 2004;103(7):2554-2559. https://doi.org/10.1182/blood-2003-06-1970 32. Wagner JE, Tolar J, Levran O, et al. Germline mutations in BRCA2: Shared genetic susceptibility to breast cancer, early onset leukemia, and Fanconi anaemia. Blood 2004;103(8):3226-3229. https://doi. org/10.1182/blood-2003-09-3138 33. Reid S, Renwick A, Seal S, et al., for the Familial Wilms Tumour Collaboration. Biallelic BRCA2 mutations are associated with multiple malignancies in childhood including familial Wilms tumour. J Med Genet 2005;42(2):147-151. https://doi.org/10.1136/jmg.2004.022673 34. Meyer S, Tischkowitz M, Chandler K, et al. Fanconi anaemia, BRCA2 mutations and childhood cancer: A developmental perspective from clinical and epidemiological observations with implications for genetic counselling. J Med Genet 2014;51(2):71-75. https://doi.org/10.1136/jmedgenet-2013-101642 35. Antoniou AC, Casadei S, Heikkinen T, et al. Breast cancer risk in families with mutations in PALB2. N Engl J Med 2014;371(17):497-506. https://doi.org/10.1056/NEJMc1410673 36. Sopik V, Akbari MR, Narod SA. Genetic testing for RAD51C mutations: In the clinic and community. Clin Genet 2015;88(4):303-312. https://doi.org/10.1111/cge.12548 37. Mathew CG. Fanconi anaemia genes and susceptibility to cancer. Oncogene 2006;25(43):5875-5884. https://doi.org/10.1038/sj.onc.1209878 38. Neveling K, Endt D, Hoehn H, et al. Genotype-phenotype correlations in Fanconi anaemia. Mutat Res 2009;668(1-2):73-91. https://doi.org/10.1016/j.mrfmmm.2009.05.006 39. Nicchia E, Greco C, de Rocco D, et al. Identification of point mutations and large intragenic deletions in Fanconi anaemia using next generation sequencing technology. Mol Genet Genomic Med 2015;3(6):500-512. https://doi.org/10.1002/mgg3.160 40. Christianson A, Howson C, Modell B. March of Dimes Global Report on Birth Defects: The hidden toll of dying and disabled children. 2006. https://www.marchofdimes.org/materials/global-report-on-birthdefects-the-hidden-toll-of-dying-and-disabled-children-full-report.pdf (accessed 16 October 2017). 41. MacMillan ML, Wagner JE. Haematopoietic stem cell transplantation for Fanconi anaemia – when and how? Br J Haematol 2010;149(1):4-21. https://doi.org/10.1111/j.1365-2141.2010.08078.x 42. Tischkowitz M, Dokal I. Fanconi anaemia and leukaemia – clinical and molecular aspects. Br J Haematol 2004;126(2):176-191. https://doi.org/10.1111/j.1365-2141.2004.05023.x 43. Dufour C, Svahn J. Fanconi anaemia: New strategies. Bone marrow transplant 2008;41:S90-S95. https:// doi.org/10.1038/bmt.2008.63 44. Frohnmayer D, Frohnmayer L, Guinan E, Kennedy T, Larsen K, eds. Fanconi Anaemia: Guidelines for Diagnosis and Management. 4th ed. Fanconi Anemia Research Fund, 2014. https://fanconi.org/images/ uploads/other/Guidelines_4th_Edition.pdf (accessed 15 April 2018). 45. Zierhut HA, Tryon R, Sanborn EM. Genetic counseling for Fanconi anemia: Crosslinking disciplines. J Genet Couns 2014;23(6):910-921. https://doi.org/10.1007/s10897-014-9754-z 46. Berliner JL, Fay AM, Cummings SA, et al. NSGC Practice Guideline: Risk assessment and genetic counseling for hereditary breast and ovarian cancer. J Genet Couns 2013;22(2):155-163. https://doi. org/10.1007/s10897-012-9547-1 47. Zierhut HA, Bartels DM. Waiting for the next shoe to drop: The experience of parents of children with Fanconi anemia. J Genet Couns 2012;21(1):45-58. https://doi.org/10.1007/s10897-011-9394-5 48. Faivre L, Guardiola P, Lewis C, et al. Association of complementation group and mutation type with clinical outcome in Fanconi anaemia. Blood 2000;96(13):4064-4070.

Accepted 8 January 2018.

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RESEARCH

Differentiating Crohn’s disease from intestinal tuberculosis at presentation in patients with tissue granulomas G Watermeyer, MB ChB, FCP, Cert Gastroenterology (SA), MPH; S Thomson, ChM, FRCS (Ed & Eng), FRCP (Ed) Division of Gastroenterology, Department of Medicine, Groote Schuur Hospital and Faculty of Health Sciences, University of Cape Town, South Africa Corresponding author: G Watermeyer (gillian.watermeyer@uct.ac.za) Background. Overlapping clinical, endoscopic, radiographic and histological features, coupled with poor microbiological yield, make differentiating Crohn’s disease (CD) from intestinal tuberculosis (ITB) challenging. Granulomas are present in both diseases; in CD they predict the need for immunosuppressive therapy that requires ITB to be excluded before initiation. Objectives. To compare granuloma-positive CD and ITB, to identify factors that may aid in diagnosis. Methods. This was a retrospective cohort study evaluating granuloma-positive CD and ITB identified from a pathology database. Results. Sixty-eight ITB and 48 CD cases were identified. Patients with ITB were more likely to be male, and to have HIV infection, isolated colitis, night sweats and tachycardia. ITB was also associated with lower serum albumin and haemoglobin and higher C-reactive protein levels, a chest radiograph showing active tuberculosis, and lymph nodes >1 cm on imaging. Extraintestinal manifestations (EIMs) were predictive of CD. There were no significant differences in smoking status, symptom duration or perianal disease. On multivariate analysis, HIV positivity (odds ratio (OR) 29.72, 95% confidence interval (CI) 2.15 - 410.96; p=0.01), isolated colitis (OR 6.17, 95% CI 1.17 - 32.52; p=0.03) and the absence of EIMs (OR 0.10, 95% CI 0.01 - 0.65; p=0.02) remained significant risk factors for ITB. Conclusion. This is the first study to identify clinical and biochemical factors to aid in differentiating granuloma-positive ITB from CD. EIMs support a diagnosis of CD, while isolated colitis and HIV are predictors of ITB. S Afr Med J 2018;108(5):399-402. DOI:10.7196/SAMJ.2018.v108i5.13108

Crohn’s disease (CD) is a chronic inflammatory disorder that can affect any part of the gastrointestinal tract (GIT), notably the terminal ileum and caecum. The major differential diagnosis of CD in our setting in Cape Town, South Africa (SA), is intestinal tuberculosis (ITB). Both disorders share overlapping clinical, endoscopic, radiographic and histological features, notably the presence of tissue granulomas. Coupled with a poor microbiological yield in ITB, this makes differentiating these diseases challenging. Traditional diagnostic modalities such as acid-fast bacilli (AFB), Mycobacterium tuberculosis (MTB) culture, tuberculin skin testing, interferongamma release assays and chest radiographs are often negative in ITB.[1] In addition, polymerase chain reaction (PCR) testing of the GIT for MTB is not validated in our setting and is not currently recommended or approved. Given the very high incidence and prevalence of MTB infection in SA, a diagnosis of CD is only made once ITB has been excluded. This often requires an empirical trial of anti-tuberculosis (anti-TB) therapy.[1,2] Misdiagnosis leads to delays in initiating effective therapy for CD, while the use of potent immunomodulators (IMMs) and biologicals in the setting of ITB can have fatal consequences. It is therefore important to make an accurate diagnosis at the earliest possible stage. The differentiation of ITB from CD is particularly problematic in patients with non-caseating granulomas, as these suggest a very real possibility of ITB.[3] To date, no study has been done in this particular subgroup to analyse factors that could aid in this diagnostic dilemma.

Objective

To compare patients with granuloma-positive CD and ITB, to identify variables that could aid in differentiating between the two conditions.

Methods

The research protocol was approved by the Ethics Committee of the University of Cape Town (ref. no.833/2014). A retrospective cohort study (2005 - 2015) was conducted evaluating adult patients with granuloma-positive CD or ITB. Subjects were identified from a pathology database and information was extracted from patient folders and laboratory and radiology records. The following data were collected at presentation: demographics, clinical, biochemical, histological and radiographic variables, and HIV status (Tables 1 - 4). The diagnosis of CD was made on the basis of a combination of clinical, radiological, endoscopic and histological features as per the European Crohn’s and Colitis Organisation consensus statement.[4] ITB was diagnosed if any of the following were present: AFB positivity on tissue biopsy, positive culture for MTB, and full response after completion of anti-TB treatment.

Statistical analysis

The association between all baseline risk factors and the diagnosis of CD and ITB was assessed by univariate analysis. Normally distributed continuous variables are expressed as means (standard deviations (SDs)). Continuous variables that were not normally distributed are expressed as medians and interquartile ranges (IQRs). Categorical variables were compared using the χ2 test, or Fisher’s exact test when appropriate. Variables with p-values <0.05 were further tested in a series of logistic multivariate regression models. The most parsimonious model was selected. The analysis was performed using Stata version 11 (StataCorp, USA).

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Results

Sixty-eight patients with ITB and 48 with CD with granulomas were identified. Of those with ITB, 42 (61.8%) had AFB present on Ziehl-Neelsen staining and 36 (52.9%) were culture-positive for MTB. At presentation (Table 1), patients with ITB were younger than those with CD (p=0.03), and more likely to be male (p=0.03) and of black ethnicity (p<0.0001). Isolated colonic involvement was significantly more common in ITB than in CD (p=0.04). There were no significant differences in smoking status, symptom duration or perianal disease. Clinical variables associated with a diagnosis of ITB (Table 2) were a history of night sweats (p=0.01) and tachycardia (p<0.0001) at presentation. Patients with CD were significantly more likely to have extraintestinal manifestations (EIMs) than those with ITB (p<0.0001). The commonest EIM in CD was iron deficiency anaemia (IDA). The only other two EIMs of note were erythema nodosum (n=4 cases) and uveitis (n=2), all in patients with CD. Other symptoms such as diarrhoea, abdominal pain and weight loss were

not significant. Similarly, fever, the presence of an abdominal mass on palpation and ascites on clinical examination were not predictive. Thirty-three percent of patients with ITB had a chest radiograph with features of active tuberculosis (TB); this was predictive of concurrent ITB (p<0.0001). In contrast, radiographic features suggesting past TB were not. Overall, only 62.1% of the cohort had undergone cross-sectional imaging at presentation (Table 4). Of the radiographic abnormalities reported, only lymph nodes >1 cm in size and ascites were predictive of ITB. There were no significant differences with regard to the presence of central node attenuation, splenic abscesses, inflammatory masses or intraabdominal collections. Thirty-five patients with ITB (51.5%) were HIV-positive, as opposed to a single patient in the CD group. HIV positivity was significantly associated with a diagnosis of ITB (p<0.0001). The mean (SD) CD4+ count in the HIV-positive patients was 269 (250) cells/µL. ITB was also associated with lower serum albumin (p<0.0001) and haemoglobin (p<0.0001) values at presentation than CD, as well

Table 1. Patient demographics at presentation Duration of symptoms before diagnosis (months), median (IQR) Age (years), median (IQR) Gender (female), n (%) Self-declared ethnicity, n (%) White Coloured Black Asian Current smoker, n (%) Site of involvement, n (%) Ileum Colon Ileum and colon Upper GIT Isolated perianal disease Any perianal disease Previous TB, n (%)

CD (N=48) 9.5 (4 - 12) 28 (19 - 24) 32 (66.7)

ITB (N=68) 3 (1 - 8) 35 (26 - 44) 31 (45.6)

7 (14.5) 36 (75.0) 5 (10.4) 0 (0.0) 23 (47.9)

3 (4.4) 29 (42.7) 35 (51.5) 1 (1.5) 24 (35.3)

27/45 (60.0) 5/45 (11.1) 10/45(22.2) 3/45 (6.7) 0/45 (0.0) 11/45 (24.4) 2/45 (4.4)

28/67 (41.8) 17/67 (25.4) 10/67 (14.9) 5/67 (7.5) 7/67 (10.5) 12/67 (17.9) 11/68 (16.2)

p-value 0.06 0.03 0.03 <0.0001

0.11 0.04

0.40 0.11

CD = Crohn’s disease; ITB = intestinal tuberculosis; IQR = interquartile range; GIT = gastrointestinal tract; TB = tuberculosis.

Table 2. Clinical features at presentation Night sweats, n (%) Abdominal cramps, n (%) Nausea and vomiting, n (%) Bowel action, n (%) Normal Diarrhoea Constipation EIMs, n (%) Loss of weight, n (%) Weight loss (kg), median (IQR) Temperature (ºC), median (IQR) Pulse rate (bpm), median (IQR) Pulse rate >100 bpm, n (%) Palpable abdominal mass, n (%) Ascites on examination, n (%)

CD (N=48) 4/45 (8.9) 39/45 (86.7) 26/45 (57.8)

ITB (N=68) 21/67 (31.3) 49/67 (73.1) 34/60 (56.7)

18/45 (40.0) 20/45 (44.4) 7/45 (15.6) 17/45 (37.8) 31/45 (68.9 7.5 (5 - 10) 36 (36 - 37) 80 (76 - 90) 5/44 (11.4) 6/45 (13.3) 0/45 (0.0))

26/67 (38.8) 32/67 (47.8) 9/67 (13.4) 3/67 (4.5) 51/67 (76.1) 10 (5 - 15) 36.8 (35.6 - 37.9) 100 (80 - 115) 35/66 (53.0) 9/67 (13.4) 2/64 (3.1)

CD = Crohn’s disease; ITB = intestinal tuberculosis; EIMs = extraintestinal manifestations; IQR = interquartile range; bpm = beats per minute.

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p-value 0.01 0.09 0.58 0.92

<0.0001 0.4 0.54 0.70 0.001 <0.0001 0.10 0.23

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Table 3. Laboratory parameters at presentation CD (N=48) 11.5 (10.4 - 12.5) 37/43 (86.1) 39 (35 - 42) 37/42 (88.1) 412 (322 - 533) 26 (10 - 65)

Haemoglobin (g/dL), median (IQR) Haemoglobin >10 g/dL, n (%) Serum albumin (g/L), median (IQR) Serum albumin >30 g/L, n (%) Platelet count (× 109/L), median (IQR) CRP (mg/L), median (IQR)

ITB (N=68) 9.7 (8.3 - 11.8) 29/64 (45.3) 30.5 (23 - 36) 22/42 (52.4) 411 (289 - 507) 75 (30 - 109)

p-value 0.01 <0.0001 0.91 <0.0001 0.43 0.04

CD = Crohn’s disease; ITB = intestinal tuberculosis; IQR = interquartile range; CRP = C-reactive protein.

Table 4. Radiographic imaging at presentation Features of previous TB on CXR, n (%) Features of active TB on CXR, n (%) Patients who had cross-sectional imaging, n (%) Type of imaging, n (%) Ultrasound MRE CT Central areas of low attenuation, n (%) An inflammatory mass, n (%) Ascites, n (%) Splenic abscesses, n (%) Lymph nodes >1 cm, n (%) Intra-abdominal collections, n (%)

CD (N=48) 2/45 (4.4) 0/45 (0) 26/45 (57.8)

ITB (N=68) 12/68 (17.7) 22/68 (32.4) 46/66 (69.7)

6/26 (23.1) 4/26 (15.4) 16/26 (61.5) 0/23 (0) 16/26 (61.5) 0/26 (0) 0/26 (0) 1/26 (3.9) 5/26 (19.2)

17/46 (36.9) 1/46 (2.2) 28/46 (60.9) 5/34 (14.7) 26/46 (56.5) 9/46 (29.6) 2/34 (5.9) 16/46 (34.8) 8/46 (17.4)

p-value 0.11 <0.0001 0.24 0.08

0.16 0.54 0.02 0.23 0.004 0.79

CD = Crohn’s disease; ITB = intestinal tuberculosis; TB = tuberculosis; CXR = chest X-ray; MRE = magnetic resonance enterography; CT = computed tomography.

Discussion

1.00

0.75 Sensitivity

as higher C-reactive protein (CRP) levels (p=0.04) (Table 3). Ninety percent of cases of anaemia in ITB were secondary to anaemia of chronic disease. On multivariate analysis, HIV positivity (odds ratio (OR) 29.72, 95% confidence interval (CI) 2.15 - 410.96; p=0.01), isolated colonic disease (OR 6.17, 95% CI 1.17 - 32.52; p=0.03) and the absence of EIMs (OR 0.10, 95% CI 0.01 - 0.65; p=0.02) remained significant risk factors for ITB. The presence of these three risk factors yielded 93% specificity for the diagnosis of ITB. On receiver operating characteristic curve analysis, the area under the curve for a model of these three risk factors was 0.88 (Fig. 1).

0.50

0.25

0.00

Differentiating ITB from CD is notoriously challenging, as they share numerous clinical, endoscopic and radiographic features. Both diseases can affect the GIT at any point from the mouth to the anus, with a predilection for the ileocaecal region. Both may present with perianal disease, intestinal strictures or fistulas, and in addition they share many EIMs. Distinguishing ITB from CD in SA is further complicated by very high rates of MTB infection. Although most cases are pulmonary, extrapulmonary TB can occur, and the GIT is commonly affected.[5,6] Treating undiagnosed ITB with potent immunosuppressive CD medications can have potentially fatal consequences, particularly the risk of dissemination. If the diagnosis is unclear, common practice is therefore to give a trial of anti-TB therapy and assess the clinical response.[2] This approach is far from ideal, as it delays implementation of appropriate CD medication, which may affect long-term outcomes. CD is a progressive and destructive illness that evolves over time to be complicated by the development of strictures, fistulas or abscesses. Ultimately the majority of patients require surgery.[7] Aggressive medical therapy with IMMs such as

0.00

0.25

0.50

0.72

1.00

1 – specificity Area under the ROC curve = 0.8796

Fig. 1. ROC curve analysis for the model including EIMs, HIV and isolated colonic disease. The presence of these three risk factors yielded 93% specificity for the diagnosis of ITB. On ROC analysis, the AUC for a model of these three risk factors was 0.88. (ROC = receiver operating curve; EIMs = extraintestinal manifestations; ITB = intestinal tuberculosis; AUC = area under the curve.)

azathioprine or methotrexate and biologicals may alter this natural history and improve long-term outcomes.[6] However, to be effective these should be introduced early in the disease course, ideally at diagnosis, before the development of irreversible complications.[6] Several studies have analysed factors early in the course of CD that may predict future outcomes and identify patients at risk of developing complicated CD who would receive greatest benefit

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from early, aggressive therapy.[6] One such predictor is the presence of tissue granulomas on histological examination. A recent cohort study in the Western Cape Province, SA, showed a two-fold increase in the risk of developing complicated CD in those with this finding at diagnosis.[8] The differentiation of ITB from CD is even more challenging in patients with histological evidence of non-caseating granulomas, as this further heightens the suspicion of ITB.[3] Patients with ITB are significantly more likely to have non-caseating granulomas than those with CD.[1,3] This was highlighted in a recent meta-analysis of 38 studies differentiating CD from ITB. There were 2 117 cases of CD and 1 589 cases of ITB. The authors used the data to construct a Bayesian model to predict the probability of ITB v. CD. In this analysis, the presence of granulomas was significantly associated with a diagnosis of ITB.[3] Ours is the first study with the objective of identifying factors differentiating ITB from CD in exclusively granuloma-positive patients. Several factors were identified as being valuable in this regard. On multivariate analysis, the presence of EIMs at diagnosis strongly suggested a diagnosis of CD. This is in concordance with reports from several cohort studies, as well as the formerly mentioned Bayesian model.[3,9] The commonest EIM in CD was IDA. This finding is not unexpected, as it is the most common systemic complication of CD.[10] The other reported EIMs in the CD patients were erythema nodosum and uveitis. Several studies have shown that the presence of perianal disease strongly supports a diagnosis of CD. Interestingly, this was not seen in our study. In fact, in our cohort all seven cases of isolated perianal disease were proven to be TB. It is possible that the prevalence of perianal TB is underestimated. A 2009 prospective study from our institution evaluated 96 patients with perianal fistulas. TB was present in 7.3% of cases, suggesting that this is not an uncommon manifestation of TB in our setting.[11] In our study, significantly more patients with ITB than CD had isolated colonic involvement (25.4% v. 11.1%). This is higher than in other series, where only 10% of patients demonstrated this finding. [12] However, the incidence of colonic involvement was increased in immunocompromised patients and in those with HIV.[12] In our cohort, 50.1% of patients with isolated colonic involvement were HIV-infected. This could explain the high incidence of this location. Other variables supporting a diagnosis of ITB, such as anaemia, hypoalbuminaemia, tachycardia and higher median CRP levels, were no longer significant on multivariate analysis. This probably reflects their association with systemic toxicity and the inflammatory burden seen in HIV-TB co-infection, as they were no longer significant after adjusting for HIV status. Not unexpectedly HIV, infection was shown to be the strongest risk factor for ITB. It is well recognised that the burden of TB in SA is fuelled by the HIV epidemic, with 7 million South Africans infected with the virus.[13] SA is currently home to 22.5% of all individuals with TB and HIV co-infection across the globe.[13] Interestingly, in our study patients with granulomatous ITB-HIV co-infection had a mean CD4+ count of 269 cells/µL, suggesting that granuloma-positive ITB, which is difficult to differentiate from CD, requires a degree of immune competence. This is supported by data showing that reductions in CD4+ counts in co-infected persons were associated with both poorer granuloma formation and higher bacterial load.[14]

Study limitations

Given the retrospective nature of this study, there were some missing data points. In addition, there were some disease characteristics that were poorly documented, on which availability of more detail would have enhanced the analysis. These were the number and morphology of granulomas, tuberculin skin testing, the endoscopic mucosal appearance, the number of diseased colonic segments, and features on routine cross-sectional imaging. These would have been useful additional tools, as they have been shown to have good diagnostic accuracy in differentiating CD from ITB.[15]

Conclusion

Excluding ITB is essential when considering potent immunosuppressive therapies for CD. This study focused on subjects with tissue granulomas at diagnosis, as these predict a severe course of CD. Several clinical and biochemical factors were identified that will aid in making the correct diagnosis, notably HIV infection, which was the strongest risk factor for ITB in this study. Isolated colonic involvement was also associated with ITB, while EIMs predicted a diagnosis of CD. To our knowledge, this is the first study to restrict analysis to granuloma-positive patients, the subgroup in which differentiating CD from ITB is most challenging. These data will aid in ensuring a timely diagnosis and reduce the risk of delayed CD treatment, as well as misdiagnosing ITB. Acknowledgements. None. Author contributions. GW was responsible for study design, data collection, statistical analysis, and preparation of the manuscript. ST critiqued and modified the final document. Funding. None. Conflicts of interest. None. 1. Epstein D, Watermeyer G, Kirsch R. Review article: The diagnosis and management of Crohn’s disease in populations with high-risk rates for tuberculosis. Aliment Pharmacol Ther 2007;25(12):1373-1388. https://doi.org/10.1111/j.1365-2036.2007.03332.x 2. Ooi CJ, Hilmi I, Makharia GK, et al. The Asia Pacific Consensus Statements on Crohn’s Disease. Part 1: definition, diagnosis and epidemiology. J Gastroenterol Hepatol 2015;31(1):45-55. https://doi. org/10.1111/jgh.12956 3. Limsrivilai J, Shreiner AB, Pongpaibul A, et al. Meta-analytic Bayesian model for differentiating intestinal tuberculosis from Crohn’s disease. Am J Gastroenterol 2017;112(3):415-427. https://doi. org/10.1038/ajg.2016.529 4 4. Gomollón F, Dignass A, Annes V, et al. 3rd European Evidence-based Consensus on the Diagnosis and Management of Crohn’s Disease 2016: Part 1: Diagnosis and medical management. J Crohns Colitis 2017;11(1):3-25. https://doi.org/10.1093/ecco-jcc/jjw168 5. Donoghue HD, Holton J. Intestinal tuberculosis. Curr Opin Infect Dis 2009;22(5):490-496. https://doi. org/10.1097/QCO.0b013e3283306712 6. Torres J, Mehandru S, Colombel JF, et al. Crohn’s disease. Lancet 2017;389(10080):1741-1755. https:// doi.org/10.1016/S0140-6736(16)31711-1 7. Beaugerie L, Seksik P, Nion-Larmurier I, et al. Predictors of Crohn’s disease. Gastroenterology 2006;130(3):650-656. https://doi.org/10.1053/j.gastro.2005.12.019 8. Watermeyer G, Thomson SR. Granulomas at initial diagnosis of Crohn’s disease signals a poor outcome. S Afr Med J 2015;105(6):480-483. https://doi.org/10.7196/SAMJ.9093 9. Singh B, Kedia S, Konijeti G, et al. Extraintestinal manifestations of inflammatory bowel disease and intestinal tuberculosis: Frequency and relation with disease phenotype. Indian J Gastroenterol 2015;34(1):43-50. https://doi.org/10.1007/s12664-015-0538-7 10. Filmann N, Rey J, Schneeweiss S, et al. Prevalence of anemia in inflammatory bowel diseases in European countries: A systematic review and individual patient data meta-analysis. Inflamm Bowel Dis 2014;20(5):936-945. https://doi.org/10.1097/01.MIB.0000442728.74340 11. Stupart D, Goldberg P, Levy A, et al. Tuberculous anal fistulas-prevalence and clinical features in an endemic area. S Afr J Surg 2009;47(4):116-118. 12. Debi U, Ravisankar V, Prasad KK, et al. Abdominal tuberculosis of the gastrointestinal tract: Revisited. World J Gastroenterol 2014;20(40):14831-14840. https://doi.org/10.3748/wjg.v20.i40.14831 13. World Health Organization. Global Tuberculosis Report 2016. Geneva: WHO, 2016. www.who.int/tb/ publications/global_report/gtbr2016_annex2.pdf (accessed 6 January 2018). 14. Diedrich CR, O’Hern J, Wilkinson RJ. HIV-1 and the Mycobacterium tuberculosis granuloma: A systematic review and meta-analysis. Tuberculosis 2016;98:62-76. https://doi.org/10.1016/j. tube.2016.02.010 15. Kedia S, Sharma R, Nagi B, et al. Computerized tomography-based predictive model for differentiation of Crohn’s disease from intestinal tuberculosis. Indian J Gastroenterol 2015;34(2):135-143. https://doi. org/10.1007/s12664-015-0550-y

Accepted 12 February 2018.

May 2018, Print edition

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

RESEARCH

The ‘ins and outs’ of faecal microbiota transplant for recurrent Clostridium difficile diarrhoea at Wits Donald Gordon Medical Centre, Johannesburg, South Africa S Lee,1 MB BCh; K Drennan,1 MB BCh; G Simons,1 MB BCh; A Hepple,1 MB BCh; K Karlsson,1 MB BCh, MRCP, FCP (SA); W Lowman,1,2 MB BCh, MMed; FC Path (SA); P C Gaylard,3 PhD; L McNamara,4 MSc (Med); J Fabian,1,4 MB BCh, FCP (SA), Cert Neph (SA) Wits Donald Gordon Medical Centre, Johannesburg, South Africa Department of Clinical Microbiology and Infectious Diseases, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa 3 Data Management and Statistical Analysis, Johannesburg, South Africa 4 Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa 1 2

Corresponding author: J Fabian (june.fabian@mweb.ac.za) Background. Clostridium difficile-associated diarrhoea (CDAD) is a potentially life-threatening condition that is becoming increasingly common. A persistent burden of this infectious illness has been demonstrated over the past 4 years at Wits Donald Gordon Medical Centre (WDGMC), Johannesburg, South Africa, through implementation of active surveillance of hospital-acquired infections as part of the infection prevention and control programme. Oral treatment with metronidazole or vancomycin is recommended, but there is a major problem with symptomatic recurrence after treatment. Replacement of normal flora by the administration of donor stool through colonoscopy or nasogastric/duodenal routes is becoming increasingly popular. Objectives. To identify risk factors for the development of CDAD in patients referred for faecal microbiota transplant (FMT) and evaluate the safety of administration of donor stool as an outpatient procedure, including via the nasogastric route. Methods. A retrospective record review of patients with recurrent CDAD referred for FMT at WDGMC between 1 January 2012 and 31 December 2016 was conducted. Results. Twenty-seven patients were identified, all of whom fulfilled the criteria for recurrent CDAD. One-third were aged >65 years, and the majority were female. The most common risk factors were prior exposure to antibiotics or proton-pump inhibitors and underlying inflammatory bowel disease. Three procedures were carried out as inpatients and 24 in the outpatient gastroenterology unit. At 4-week follow-up, all patients reported clinical resolution of their diarrhoea after a single treatment and there were no recurrences. The FMT procedure was associated with no morbidity (with particular reference to the risk of aspiration when administered via the nasogastric route) or mortality. Conclusions. This case series confirms that FMT is a safe and effective therapy for recurrent CDAD. In most cases it can be administered via the nasogastric route in the outpatient department. We propose that the recently published South African Gastroenterology Society guidelines be reviewed with regard to recommendations for the route of administration of FMT and hospital admission. Meticulous prescription practice by clinicians practising in hospitals and outpatient settings, with particular attention to antimicrobials and chronic medication, is urgently required to prevent this debilitating and potentially life-threatening condition. S Afr Med J 2018;108(5):403-407. DOI:10.7196/SAMJ.2018.v108i5.12367

Clostridium difficile-associated diarrhoea (CDAD) is becoming increasingly common. It is a potentially life-threatening condition with mortality as high as 33% and a 28% possibility of relapse. [1] Risk factors for acquiring CDAD include increasing age (>65 years), multiple antibiotic treatments, lengthy stays in hospital and concurrent proton-pump inhibitor (PPI) therapy.[2] Most infections are healthcare associated, occurring in hospitals and long-term care facilities, but outpatient acquisition has also been described.[3] The disease is spread via the faecal-oral route by ingestion of acid-resistant spores. Meticulous hand hygiene on the part of of healthcare workers, by washing with soap and water or disinfectants to help remove spores, is extremely important, and isolation of patients with acute diarrhoea can limit the spread of the disease in healthcare facilities. The burden of this condition has been demonstrated clearly at Wits Donald Gordon Medical Centre (WDGMC), Johannesburg, South Africa (SA), through established active surveillance of hospital-

acquired infections as part of the infection prevention and control programme (Fig. 1).[4] Much effort has been focused on patient therapies to prevent symptomatic disease. Probiotics have been used in the treatment of CDAD, but their role remains uncertain. A meta-analysis conducted in 2010 suggested that there may be a benefit to using probiotics in addition to standard therapy for the management of patients with severe or relapsing C. difficile infection (CDI) or to prevent infection. However, the studies included in the review were small and there are currently insufficient data to support the use of probiotics in patients with CDAD.[5] Recommended treatment for the disease is via the oral route using metronidazole or vancomycin, to which 90% of patients respond and experience no further symptoms.[6] The major problem with CDAD is symptomatic recurrence after antimicrobial therapy is complete. The frequency of recurrence has been reported to be as high as 50%, and if a patient has experienced

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60 8

40 30

20 2

10 0

HAI rate per 10 000 inpatient days

70 Patients with CDI, n

whereas larger volumes are used for colonoscopic insertion (400 mL). All modes of administration require that concurrent antimicrobial treatment be discontinued 24 - 48 hours before the procedure. When the nasogastric route is used, a PPI should be administered for 24 - 48 hours prior to transplantation to render the stomach achlorhydric and increase survival of the new organisms.[15] The definitive role of FMT as a therapeutic intervention is evolving, such as whether it should be considered at the time of initial diagnosis of CDAD or only after recurrence occurs. The preferred route of administration of FMT is also under investigation and may depend on the severity of the associated symptoms, as well as patient preference.

0 2013

2014

2015

2016

Year HAI

Non-HAI

HAI rate

Objectives

WDGMC, an academic specialist referral hospital, is one of few centres in SA that offers FMT for recurrent CDAD. In this article, we report on the clinical profile and outcomes of a case series of FMT recipients. We hope to create awareness in the healthcare profession of who may be at risk and the importance of judicious antibiotic prescription to prevent this condition. We highlight clinical methods utilised at our hospital that appear to make FMT safe, successful and cost-effective. Finally, we discuss funding issues in the private health environment and relate these to the recently published South African Gastroenterology Society (SAGES) guideline.[16]

Fig. 1. Clostridium difficile infection rates at Wits Donald Gordon Medical Centre, 2013 - 2016. (CDI = C. difficile infection; HAI = hospital-acquired infection.)

Risk factors for recurrent CDAD

Prior userisk of antibiotics one recurrence, the of subsequent recurrence is even higher. [7] Disruption of the Chronic normal gut microbiota is the main cause of PPI use susceptibility to and recurrence of infection. Replacement of Pre-existing IBD normal flora is becoming an increasingly popular therapeutic Immunocompromised intervention, and treatment by the administration of donor stool Chronic corticosteroid use through colonoscopy or the nasogastric/duodenal route is well [7-9] Prior hospitalisation described. Faecal microbiota transplant (FMT) is considered Resident in nursing home/institution a safe and effective treatment for recurrent CDAD and has a reported success rate of Other 80 - 90% from one infusion of donor stool.[7] While there are many published case series and reports 0 10 20 30 40 50 confirming the efficacy of the treatment, to date there have only Patients, % (N=25) been two randomised controlled trials comparing FMT with current treatment, which includes extended vancomycin therapy. In both studies, early termination was recommended because the superiority of FMT made continuation unethical.[10,11] It is also noteworthy that patients who receive FMT experience minimal or no short-term complications, although the long-term consequences are unknown.[12] There are no absolute contraindications to faecal transplantation. The choice to undergo faecal transplant has been positively influenced by its cost-effectiveness compared with continuing antibiotic treatment, as well as its success rate. Patients typically respond well to the idea of faecal transplantation, once the benefits of the procedure are explained to them, but the idea of the procedure is an obstacle to some.[13] The most acceptable and safe methods of administering FMT are nasogastric via insertion of a nasogastric tube (NGT), and into the large bowel via colonoscopy. Nasogastric administration is cost-effective, readily accessible as an outpatient and easy to perform, and does not require bowel preparation (lavage). An added advantage of nasogastric over colonic administration is potentially greater exposure of gut surface area to the new flora.[13] Reported complications have been related to the insertion of the NGT itself rather than the transplantation. Exceptions to eligibility for nasogastric administration are delayed bowel transit, ileus and small-bowel Crohnâ&#x20AC;&#x2122;s disease. Colonoscopic insertion delivers faecal matter directly into the large bowel after standard lavage and is the preferred route for severe CDAD complicated by ileus.[13,14] Preparation of the faeces for both methods is to liquidise the stool and blend it with saline or water, making a faecal suspension which is then filtered to remove any fibrous particles that may cause blockage of the NGT or colonoscopic channel.[13,14] A smaller volume of this suspension is used for NGT administration (30 - 50 mL),

Methods

Permission for this study was obtained from the Human Research 70 Ethics Committee (Medical), University of the Witwatersrand (ref. no. M150319). A retrospective record review of patients with recurrent CDAD referred for FMT between 1 January 2012 and 31 December 2016 was conducted. Patients were referred by local clinicians to a medical gastroenterology practice at WDGMC. The following data were collected: age at time of referral, gender, associated risk factors, prior antibiotic treatment received for CDAD, relationship of recipient to donor, method of administration of FMT, and results of 4-week follow-up for remission. Laboratory reports confirming CDI were obtained, where possible. The definitions used and treatment regimens prescribed are according to published guidelines.[17,18] Clinical remission was assessed 4 weeks after FMT and defined as complete resolution of clinical symptoms (mostly diarrhoea). Patients were also requested to submit a stool specimen for laboratory confirmation of clearance of C. difficile. Private laboratory testing for C. difficile was mainly performed through molecular tests (polymerase chain reaction (PCR)) that detect the toxin genes (tcdA/tcdB) responsible for producing toxins A and B. Testing for the actual toxin was sometimes also performed. Each patient was asked if they could source a potential donor from family members (related), spouses/partners or friends (unrelated but known). If a patient was unable to source a donor, the attending clinician sourced an anonymous donation (unrelated and unknown) from previous donors. The donor was approached if they were still within 6 months of their last screening. If agreeable, they were questioned to ensure that they had remained well during this period, and that they had not received antibiotics or had any new piercings, tattoos or sexual partners. For the evaluation of each potential donor, a confidential screening interview was conducted to identify any risk factors that may preclude donation as per the SAGES guideline.[16] If eligible, the donor then gave a full medical history and underwent examination.

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The majority of the patients in this study group were female (20/27, 74%), the median age at first visit was 57 years (IQR 37 - 72, range 19 - 88), and 9/27 (33%) were aged >65 years. In this sample, the main risk factors for the development of CDAD, in decreasing frequency, were prior antibiotic use (15/25, 60%), chronic use of PPIs (11/25, 44%) and comorbid inflammatory bowel disease, which included ulcerative colitis and Crohnâ&#x20AC;&#x2122;s disease (11/25, 44%) (Fig. 2). Forty percent of the patients had three or more risk factors. In those with prior antibiotic use, antibiotics had been prescribed for the Results following conditions: gastrointestinal (5/15, All 27 patients in this study group fulfilled 33.3%), respiratory (4/15, 27%), and skin/ the criteria for recurrent CDAD and, at soft tissue (each 3/15, 20%). the time of presentation, 72% had had Of the faecal donor pool, approximately between one and three previous infections. two-thirds were either related (9/27, 33%) or Three procedures (11%) were performed known to the recipients as a spouse/partner as inpatients, two from the intensive care or friend (10/27, 37%). The remainder were unit (ICU) and one from the general ward. unknown to the recipients The remainder (24/27) were done in the 12 and were sourced 80 from previous donors (7/27, 26%). The outpatient70 gastroenterology unit. Laboratory10 donor-recipient relationship could not be confirmed reports of CDI were available 60 determined in one case. in 21/27 cases. Most of these (86%) were 8 The most common route of administration was via NGT (21/27, diagnosed50 by PCR, 29% with demonstration 40 toxin and three patients by 78%), with 4/27 (15%)6procedures done by of C. difficile colonoscopy and 2/27 (7%) nasoduodenal. both methods. All patients with known 30 4 Both the nasoduodenal insertions were previous treatments (26/27) had been treated 20 for ICU patients and were administered in with vancomycin, while 65% had also been 2 10 the radiology unit under X-ray guidance, treated with metronidazole. One patient 0 a previous faecal transplant. In 0 not via endoscopy. There were no serious had received 2013 2014 2015 2016 procedure-related complications, notably 24/27 of the patients, data were available for aspiration. One patient vomited 3 hours after the median time between diagnosis ofYear the administration, but the transplant was still first episode of laboratory-confirmed CDAD HAI Non-HAI HAI rate effective. Another reported feeling nauseous, and FMT, which was 4 months (interquartile but this settled on symptomatic treatment. range (IQR) 3 - 7, range 0.2 - 25). Patients with CDI, n

HAI rate per 10 000 inpatient days

was based on the key research question to be answered, in this case the estimation of proportions (e.g. the proportion of females in the study group). Based on worst-case (for sample size) estimates of 50%, 5% precision and the 95% confidence level, an ideal sample size of 385 would be required.[20] The actual sample size of 27 corresponds to a precision of 19% (rather than 5%), which is a limitation of the study. Descriptive data analysis was carried out using SAS version 9.4 for Windows.

Prior use of antibiotics Risk factors for recurrent CDAD

Donors were excluded if they had any of the following: history of antibiotic use in the past 3 months; history of irritable bowel syndrome or irregular bowel habits; history of any major gastrointestinal disease (such as inflammatory bowel disease or malignancy); diabetes mellitus; morbid obesity; use of any immunosuppressive or chemotherapeutic agents; recent piercings or tattoos; or a history of high-risk sexual behaviour. All donors were then screened for HIV, hepatitis A, B and C and syphilis. Donor stool was tested to exclude infection with ova, cysts, parasites and C. difficile. Additional screening tests were performed at the discretion of the attending physician. Donors were prescribed a single dose of an osmotic laxative containing macrogol (polyethylene glycol) to be taken with water the night before the planned stool donation. On the day of the procedure, the fresh stool specimen was liquidised with 200 400 mL normal saline (depending on the volume of the sample) and passed through a gauze filter to remove particulate matter. For the nasogastric method, a PPI was administered to each recipient 48 hours prior to the procedure. After insertion of the NGT, placement was checked via auscultation and aspiration. A 60 mL volume of the sample was administered slowly and flushed with a further 60 mL normal saline. The NGT remained in situ for a further 20 minutes and was then removed. Each patient was observed for a further 30 minutes before discharge. The total time taken for the procedure was 60 - 120 minutes. To minimise the risk of aspiration, no sedation or local anaesthetic throat spray was used and the procedure was performed with the patient in a seated position. For the colonoscopic method, standard bowel preparation was performed prior to the FMT procedure. During the FMT procedure, 300 mL of the total 400 mL faecal sample was placed in the terminal ileum, provided the terminal ileum was intubated, with the remaining 100 mL dispersed on withdrawal of the colonoscope. If terminal ileal intubation was not achieved, 300 mL of the faecal sample was instilled into the caecum and the remaining 100 mL sprayed on withdrawal. Study data were collected and managed using Research Electronic Data Capture (REDCap) which is a secure, web-based application designed to support data capture for research studies hosted at the Faculty of Health Sciences, University of the Witwatersrand.[19] Sample size estimation

Chronic PPI use Pre-existing IBD Immunocompromised Chronic corticosteroid use Prior hospitalisation Resident in nursing home/institution Other 0

Patients, % (N=25)

Fig. 2. Risk factors for the development of recurrent Clostridium difficile-associated diarrhoea in patients referred to Wits Donald Gordon Medical Centre for faecal microbiota transplant. (CDAD = C. difficile-associated diarrhoea; PPI = proton-pump inhibitor; IBD = inflammatory bowel disease; immunocompromised = individuals with comorbidity that required immunosuppressive therapy other than corticosteroids; other = 1 patient with diabetic gastroparesis, 2 with surgical procedures relating to colon cancer and 1 with surgical site sepsis after caesarean section.)

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The majority of FMT recipients (23/27, 85%) returned for a followup visit after 4 weeks. The others were contacted telephonically. All the recipients experienced clinical resolution of their diarrhoea by 4 weeks, and there were no recurrences or deaths. Of those who submitted a stool sample for C. difficile PCR at 4 weeks (23/27), 20 tested negative (87%) and 1 tested positive (4%); 2 results could not be found.

Discussion

To date, this is the largest case series published from SA that has described the role of FMT in the management of recurrent CDAD. The success of the procedure in our context is significant, given the persistent burden of disease observed at WDGMC (Fig. 1). It is important to note that the increase in the number of infections in 2016 may be attributable to the status of the hospital as a referral facility, previous diagnostic barriers in diagnosis of CDAD and mechanisms for laboratory reporting (which may have led to underreporting), or a combination thereof.[21] While there are no national surveillance data to confirm the trend at our hospital, it reflects similar findings internationally and adds urgency to the implementation of the South African Antimicrobial Resistance Strategy Framework.[22] This comprises a regulatory framework within which surveillance and antimicrobial stewardship in combination with infection prevention and control are prioritised to reduce morbidity and mortality associated with antibiotic-resistant infections. While a regulatory framework is essential, clinicians need to be far more aware of the impact of CDAD on the individual and the healthcare system in which they seek care. The findings in this study are sobering. At the time of referral, the majority of our patients had suffered from between one and three infections requiring at least two courses of antibiotics over a median period of 4 months. Of the identified risk factors, prior antibiotic exposure and chronic PPI and corticosteroid use predominated. All these are potentially modifiable and even preventable with judicious prescription practice. With regard to the non-modifiable risk factors, namely female gender, older age (one-third of the patients were aged >65 years) and underlying inflammatory bowel disease, our findings are consistent with the published literature, but we had far fewer patients from long-term care facilities. At WDGMC the preferred mode of administration for FMT is via the nasogastric route in the outpatient unit. This means that no gastroscopy or bowel preparation is required (as in the case of colonoscopy) and the need for hospital admission is eliminated. The results from this series confirm unequivocally that this is safe and effective. Nasoduodenal or colonoscopic routes are only considered if nasogastric administration is not feasible. This method has evolved over the past 5 years from clinical experience based on good patient tolerance, the success rate and ease of administration. However, it counters the recently published SAGES guideline[16] that recommends duodenal or colonoscopic administration and inpatient observation overnight. The administration of FMT via the nasogastric route at WDGMC also evolved from difficulties regarding funding in the private healthcare sector. There is currently no procedural code for FMT, as it is not a registered form of treatment. This forces clinicians to code for alternative ‘proxy’ procedures which, besides being ethically problematic, results in wide variations in cost to the funder and the patient. There is also no funding mechanism for evaluation of the donor, which results in most recipients carrying the costs themselves.

Study limitations

The limitations of the study are its retrospective design, small sample size and restriction to the private sector.

Conclusion

This case series confirms that FMT is a safe and effective therapy for recurrent CDAD. In most cases it can be administered via the nasogastric route as an outpatient. We propose that the recently published SAGES guideline be reviewed regarding recommendations for the route of administration of FMT and hospital admission. We hope that by making our experience available, we can assist healthcare funders to formalise billing procedures for FMT that include the costs of the donor evaluation. More broadly, this study highlights an urgent need for the medical community to address antimicrobial prescription at all levels – governmental health policy and regulation, implementation in healthcare institutions, and bedside practice. It is incumbent upon each clinician to critically review prescription practice and implement appropriate changes that minimise the risk of patients developing these debilitating and potentially life-threatening conditions. Acknowledgements. We thank Heather Maher for setting up the REDCap database, supporting the students, data collection and data integrity, and the hospital management and staff of the outpatient unit who have given their full support to the establishment of faecal transplantation at WDGMC Author contributions. SL and KD: data collection, literature review and writing the first draft of the article; GS and AH: data collection and literature review; KK: study design, conceptualisation and implementation of the research project, provision of clinical information and access to records, and editing the final draft of the article; WL: senior consultant and advisor regarding the infectious diseases component of the article, specifically provision of surveillance data for C. difficile infection at WDGMC and advice on interpretation of the laboratory tests for C. difficile, and editing the final draft of the article; PCG: statistical analysis; LMcN: final editing of the article for submission; JF: supervision of the project and the medical students and writing and editing the final draft of the article. Funding. Wits Donald Gordon Medical Centre. Conflicts of interest. None. 1. Musher DM, Aslam S, Logan N, et al. Relatively poor outcome after treatment of Clostridium difficile colitis with metronidazole. Clin Infect Dis 2005;40(11):1586-1590. https://doi.org/10.1086/430311 2. Bignardi GE. Risk factors for Clostridium difficile infection. J Hosp Infect 1998;40(1):1-15. https://doi. org/10.1016/S0195-6701(98)90019-6 3. Burke KE, Lamon JT. Clostridium difficile infection: A worldwide disease. Gut Liver 2014;8(1):1-6. https://doi.org/10.5009/gnl.2014.8.1.1 4. Lowman W. Active surveillance of hospital-acquired infections in South Africa: Implementation, impact and challenges. S Afr Med J 2016;106(5):489-493. https://doi.org/10.7196/SAMJ.2016.v106i5.10783 5. Simor AE. Diagnosis, management, and prevention of Clostridium difficile infection in long-term facilities: A review. J Am Geriatr Soc 2010;58(8):1556-1564. https://doi.org/10.1111/j.1532-5415.2010.02958.x 6. Bartlett JG. Management of Clostridium difficile infection and other antibiotic-associated diarrhoeas. Eur J Gastroenterol Hepatol 1996;8(11):1054-1061. 7. Persky SE, Brandt LJ. Treatment of recurrent Clostridium dfficile-associated diarrhea by administration of donated stool directly through a colonoscope. Am J Gastroenterol 2000;95(11):3283-3285. https://doi. org/10.1111/j.1572-0241.2000.03302.x 8. Owens C, Broussard E, Surawicz C. Fecal microbiota transplantation and donor standardization. Trends Microbiol 2013;21(9):443-445. https://doi.org/10.1016/j.tim.2013.07.003 9. Kronman MP, Nielson HJ, Adler AL, Gief MJ. Fecal microbiota transplantation via nasogastric tube for recurrent Clostridium difficile infection in pediatric patients. J Pediatr Gastroenterol Nutr 2015;60(1):2326. https://doi.org/10.1097/MPG.0000000000000545 10. Cammarota G, Masucci L, Ianiro G, et al. Randomised clinical trial: Faecal microbiota transplantation by colonoscopy vs. vancomycin for the treatment of recurrent Clostridium difficile infection. Aliment Pharmacol Ther 2015;41(9):835-843. https://doi.org/10.1111/apt.13144 11. Van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med 2013;368(5):407-415. https://doi.org/10.1056/NEJMc1303919 12. Allegretti JR, Korzenik JR, Hamilton MJ. Fecal microbiota transplantation via colonoscopy for recurrent C. difficile infection. J Vis Exp 2014;94:e52154. https://doi.org/10.3791/52154 13. Postigo R, Kim J. Colonoscopic versus nasogastric fecal transplantation for the treatment of Clostridium difficile infection: A review and pooled analysis. Infection 2012;40(6):643-648. https://doi. org/10.3791/5215410.1007/s15010-012-0307-9 14. Rohlke F, Surawicz CM, Stollman N. Fecal flora reconstitution for recurrent Clostridium difficile infection: Results and methodology. J Clin Gastroenterol 2010;44(8):567-570. https://doi. org/10.3791/5215410.1097/MCG.0b013e3181dadb10 15. McDonald EG, Milligan J, Frenette C, Lee TC. Continuous proton pump inhibitor therapy and the associated risk of recurrent Clostridium difficile infection. JAMA Intern Med 2015;175(5):784-791. https://doi.org/10.3791/5215410.1001/jamainternmed.2015.42 16. SAGES clinical guidelines for faecal microbiota transplantation (FMT). S Afr Gastroenterol Rev 2015;13(3):27-28. https://www.sages.co.za/content/images/FMT_guidelines_(003).pdf (accessed 10 April 2018).

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17. Debast S, Bauer M, Kuijper E. European Society of Clinical Microbiology and Infectious Diseases: Update of the treatment guidance document for Clostridium difficile infection. Clin Microbiol Infect 2014;20(s2):1-26. https://doi.org/10.3791/5215410.1111/1469-0691.12418 18. Surawicz CM, Brandt LJ, Binion DG, et al. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J Gastroenterol 2013;108(4):478-498. https://doi. org/10.3791/5215410.1038/ajg.2013.4 19. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap) – a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009;42(2):377-381. https://doi.org/10.3791/5215410.1016/j. jbi.2008.08.010 20. Daniel WW. Biostatistics: A Foundation for Analysis in the Health Sciences. 10th ed. New York: John Wiley & Sons, 2015:191.

21. Wilcox MH. Overcoming barriers to effective recognition and diagnosis of Clostridium difficile infection. Clin Microbiol Infect 2012;18(Suppl 6):13-20. https://doi.org/10.3791/5215410.1111/14690691.12057 22. Mendelson M, Matsoso MP. The South African Antimicrobial Resistance Strategy Framework. In: Carlet J, ed. AMR Control 2015: Overcoming Global Antimicrobial Resistance. Ipswich, Suffolk, UK: Global Health Dynamics Limited in official association with the World Alliance Against Antibiotic Resistance, 2015:54-61. https://www.fidssa.co.za/Content/Documents/2015_01.pdf (accessed 10 April 2018).

Accepted 31 January 2018.

Incidence of myocardial injury after non-cardiac surgery: Experience at Groote Schuur Hospital, Cape Town, South Africa This open-access article is distributed under CC-BY-NC 4.0.

E Coetzee,1 MB ChB, DA (SA), FCA (SA); B M Biccard,1 MB ChB, FFARCSI, FCA (SA), MMed (Anaesth), PhD; R A Dyer,1 BSc Hons, MB ChB, FCA (SA), PhD; N D Meyersfeld,2 MB ChB, FCA (SA); C Chishala,3 MB ChB, FCP (SA); B M Mayosi,4,5 BMedSci, MB ChB, FCP (SA), DPhil, AMP

Department of Anaesthesia and Perioperative Medicine, Groote Schuur Hospital and Faculty of Health Sciences, University of Cape Town, South Africa 2 Private practice, Southern Anaesthetic Associates, Cape Town, South Africa 3 Department of Cardiology, Groote Schuur Hospital and Faculty of Health Sciences, University of Cape Town, South Africa 4 Dean’s Office, Faculty of Health Sciences, University of Cape Town, South Africa 5 Department of Medicine, Groote Schuur Hospital and Faculty of Health Sciences, University of Cape Town, South Africa 1

Corresponding author: E Coetzee (ettiennec@gmail.com) Background. Myocardial injury after non-cardiac surgery (MINS) is a newly recognised entity identified as an independent risk factor associated with increased 30-day all-cause mortality. MINS increases the risk of death in the perioperative period by ~10-fold. More than 80% of patients with MINS are asymptomatic, so the majority of diagnoses are missed. Awareness of MINS is therefore important for perioperative physicians. Objectives. To investigate the incidence of MINS after elective elevated-risk non-cardiac surgery at Groote Schuur Hospital, Cape Town, South Africa (SA). Methods. Patients aged ≥45 years undergoing elective elevated-risk non-cardiac surgery were enrolled via convenience sampling. The new fifth-generation high-sensitivity cardiac troponin T blood test was used postoperatively to identify MINS. Preoperative troponin levels were not measured. Results. Among 244 patients included in the study, the incidence of MINS was 4.9% (95% confidence interval (CI) 2.8 - 8.5), which was not significantly different from that in a major international prospective observational study (VISION) (8.0% (95% CI 7.5 - 8.4)); p=0.080. Conclusions. Our SA cohort had a lower cardiovascular risk profile but a similar incidence of MINS to that described in international literature. The impact of MINS on morbidity and mortality is therefore likely to be proportionally higher in SA than in published international studies. The limited sample size and lower event rate weaken our conclusions. Larger studies are required to establish patient and surgical risk factors for MINS, allowing for revision of cardiovascular risk prediction models in SA. S Afr Med J 2018;108(5):408-412. DOI:10.7196/SAMJ.2018.v108i5.12784

Full article available online at https://doi.org/10.7196/SAMJ.2018.v108i5.12784

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

RESEARCH

A raised serum lactate level is an independent predictor of in-hospital mortality in patients with isolated cerebral gunshot wounds V Y Kong,1 MB ChB, MSc, PhD, MRCS (Ed); R D Weale,2 MBBS; G L Laing,1 MB ChB, PhD, FCS (SA); J L Bruce,1 MB ChB, FCS (SA); G V Oosthuizen,1 MB ChB, FCS (SA); B Sartorius,3 PhD; P Brysiewicz,3 PhD; D L Clarke,1,4 MB BCh, MPhil, MBA, PhD, FCS (SA) Pietermaritzburg Metropolitan Trauma Service, Department of Surgery, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa 2 Department of Surgery, Wessex Deanery, UK 3 Department of Public Health Medicine, School of Nursing and Public Health, University of KwaZulu-Natal, Durban, South Africa 4 Department of Surgery, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa 1

Corresponding author: V Y Kong (victorywkong@yahoo.com) Background. Cerebral gunshot wounds (CGSWs) represent a highly lethal form of traumatic brain injury, and triaging these patients is difficult. The prognostic significance of the serum lactate level in the setting of CGSWs is largely unknown. Objectives. To examine the relationship between elevated serum lactate levels and mortality in patients with isolated CGSWs. Methods. A retrospective review of the regional trauma registry was undertaken at the Pietermaritzburg Metropolitan Trauma Service, South Africa, over a 5-year period from 1 January 2010 to 31 December 2014. All patients with an isolated CGSW were included. Results. A total of 102 patients with isolated CGSWs were identified. Of these, 92.2% (94/102) were male. The mean age (standard deviation) was 29 (8) years, and the in-hospital mortality rate was 21.6% (22/102). The mean serum lactate level was significantly higher among non-survivors than among survivors (6.1 mmol/L v. 1.3 mmol/L; p<0.001). Lactate levels among non-survivors were <2 mmol/L in 4.5%, 2 - 3.99 mmol/L in 9.1%, 4 - 5.99 mmol/L in 36.4% and ≥6 mmol/L in 50.0%. The odds ratio for mortality with a lactate level of 4 5.99 mmol/L was 67 (95% confidence interval (CI) 1.7 - 2 674.2), while for a lactate level of ≥6 mmol/L it was 1 787 (95% CI 9.0 - 354 116.1). The serum lactate level accurately predicted mortality even after adjustment for other variables. Based on a receiver operating curve analysis, an optimal cut-off of 3.3 mmol/L for serum lactate as a predictor for mortality was identified (area under the curve = 0.957). Conclusions. CGSWs are associated with significant mortality, and a raised serum lactate level appears to be an independent predictor of in-hospital mortality. It is a potentially useful adjunct in the resuscitation room for identifying patients with a very poor prognosis. S Afr Med J 2018;108(5):413-417. DOI:10.7196/SAMJ.2018.v108i5.12837

Full article available online at https://doi.org/10.7196/SAMJ.2018.v108i5.12837

Healthcare-associated infections in paediatric and neonatal wards: A point prevalence survey at four South African hospitals C Olivier,1 6th-year medical student; H Kunneke,2 MB ChB, FC Paed (SA), MMed (Paed); N O’Connell,3 MB ChB, MMed (Paed); E von Delft,4 MB ChB, FCPaed, MMed (Paed); M Wates,5 MB ChB, BSc, MMed (Paed); A Dramowski,6 MB ChB, FC Paed (SA), MMed (Paed), Cert Paed ID, DCH, PhD Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa Department of Paediatrics, Worcester Provincial Hospital, South Africa 3 Department of Paediatrics, Khayelitsha District Hospital, Cape Town, South Africa 4 Department of Paediatrics, Paarl Hospital, South Africa 5 Department of Paediatrics, Karl Bremer Hospital, Cape Town, South Africa 6 Division of Paediatric Infectious Diseases, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa 1 2

Corresponding author: C Olivier (courtney_olivier@hotmail.com)

May 2018, Print edition

RESEARCH

Background. Healthcare-associated infections (HAIs) cause substantial morbidity, mortality and healthcare costs. The prevalence of neonatal/paediatric HAI at South African (SA) district and regional hospitals is unknown. Objectives. To document HAI rates, antimicrobial use for HAI, infection prevention staffing, hand hygiene (HH) provisions and HH compliance rates in neonatal and paediatric wards in two district and two regional hospitals in the Western Cape Province, SA. Methods. An HAI point prevalence survey (PPS) was conducted in neonatal and paediatric wards at two district and two regional hospitals in the Western Cape during December 2016, applying National Healthcare Safety Network HAI definitions. HAI events and antimicrobial therapy active at 08h00 on the PPS day and during the preceding 7 days (period prevalence) were documented. Provisions for HH and HH compliance rates were observed on each ward using the World Health Organization’s HH surveillance tool. Results. Pooled point and period HAI prevalence were 9.9% (15/151; 95% confidence interval (CI) 6 - 15.8) and 12.6% (19/151; 95% CI 8 18.9), respectively. Hospital-acquired pneumonia (5/15, 33.3%), bloodstream infection (3/15, 20.0%) and urinary tract infection (3/15, 20.0%) were predominant HAI types. Risk factors for HAI were a history of recent hospitalisation (8/19, 42.1% v. 17/132, 12.9%; p<0.001) and underlying comorbidity (17/19, 89.5% v. 72/132, 54.5%; p<0.004). HH provisions (handwash basins/alcohol hand rub) were available and functional. HH compliance was higher in neonatal than in paediatric wards (125/243, 51.4% v. 25/250, 10.0%; p<0.001). Overall HH compliance rates were higher among mothers (46/107, 43.0%) than nurses (73/265, 27.8%) and doctors (29/106, 27.4%). Conclusions. Neonatal and paediatric HAIs are common adverse events at district and regional hospitals. This at-risk population should be prioritised for HAI surveillance and prevention through improved infection prevention practices and HH compliance. S Afr Med J 2018;108(5):418-422. DOI:10.7196/SAMJ.2018.v108i5.12862

Full article available online at https://doi.org/10.7196/SAMJ.2018.v108i5.12862

The costs and outcomes of paediatric tuberculosis treatment at primary healthcare clinics in Johannesburg, South Africa E P Budgell,1 MSc; D Evans,1 PhD; R Leuner,1 MCom; L Long,1,2 PhD; S Rosen,1,2 MPA Health Economics and Epidemiology Research Office, Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa 2 Department of Global Health, School of Public Health, Boston University, USA 1

Corresponding author: D Evans (devans@heroza.org) Background. Little up-to-date information is available about the costs of providing drug-susceptible tuberculosis (DS-TB) treatment to paediatric patients in South Africa (SA), nor have actual costs incurred at clinics been compared with costs expected from guidelines. Objectives. To estimate actual and guideline treatment costs by means of a retrospective cohort analysis. Methods. We report patient characteristics, outcomes and treatment costs from a retrospective cohort of paediatric and adolescent (<18 years) DS-TB patients registered for treatment from 1 April 2011 to 31 March 2013 at three primary healthcare clinics in Johannesburg, SA. Actual treatment costs in 2015 SA rands and US dollars were estimated from the provider perspective using a standard bottom-up microcosting approach and compared with an estimate of guideline costs. Results. We enrolled 88 DS-TB patients (median age 4 years (interquartile range 1.0 - 9.5), 44.3% female, 22.7% HIV co-infected, 92.0% pulmonary TB). Treatment success was high (89.8%; 13.6% cured, 76.1% completed treatment), and the mean (standard deviation (SD)) cost per patient with treatment success was ZAR1 820/USD143 (ZAR593/USD46), comprising fixed costs (44.0%), outpatient visits (30.7%), medication (19.3%) and laboratory investigations (6.0%). This was 17% more than the mean (SD) cost estimated by applying treatment guidelines (ZAR1 553/USD122 (ZAR1 620/USD127)), with differences due mainly to higher laboratory costs and more outpatient visits taking place than were recommended in national guidelines. Conclusions. These results are the first reported estimates of paediatric DS-TB treatment costs in SA and show the potential cost savings of closer adherence to national treatment guidelines. The findings were robust in sensitivity analyses and are lower than previous cost estimates in adults. S Afr Med J 2018;108(5):423-431. DOI:10.7196/SAMJ.2018.v108i5.12802

Full article available online at https://doi.org/10.7196/SAMJ.2018.v108i5.12802

May 2018, Print edition

RESEARCH

Short-term outcomes of down-referral in provision of paediatric antiretroviral therapy at Red Cross War Memorial Children’s Hospital, Cape Town, South Africa: A retrospective cohort study J Copelyn,1 MBBS, FC Paed (SA), MMed; P Apolles,2 RN; M-A Davies,3 MB ChB, MMed, FCPHM, PhD; B Eley,2 MB ChB, FC Paed (SA), BSc Hons Department of Paediatrics and Child Health, Faculty of Health Sciences, University of Cape Town, South Africa Paediatric Infectious Diseases Unit, Red Cross War Memorial Children’s Hospital and Department of Paediatrics and Child Health, Faculty of Health Sciences, University of Cape Town, South Africa 3 Centre for Infectious Disease Epidemiology and Research, School of Public Health and Family Medicine, Faculty of Health Sciences, University of Cape Town, South Africa 1 2

Corresponding author: J Copelyn (julie_copelyn@yahoo.com) Background. The large scale-up of paediatric HIV care necessitated down-referral of many children receiving antiretroviral therapy (ART) from Red Cross War Memorial Children’s Hospital (RCWMCH), Cape Town, South Africa. Few published data exist on the outcomes of these children. Objectives. To assess outcomes of children receiving ART in the first 12 months after down-referral to primary healthcare (PHC) clinics and identify determinants of successful down-referral. Methods. A retrospective cohort study of children <15 years of age who initiated ART at RCWMCH and were subsequently down-referred to one of two PHC clinics between January 2006 and December 2012 was completed. Baseline characteristics of patients and caregivers as well as CD4+ counts, viral loads (VLs) and weights were collected 6 and 12 months after down-referral. Outcomes included retention in care and viral suppression. Results. Of 116 children down-referred to the two study PHC clinics, 81.9% arrived at the designated PHC clinic and a further 8.6% continued care at other clinics, the remaining 9.5% being lost to follow-up. Of those successfully down-referred, 11.4% took >8 weeks to present, possibly experiencing treatment interruption. At 12 months after down-referral, only 81.0% remained in care. No factors were associated with retention in care in multivariable analysis. For children who remained in care at the designated PHC clinics, the clinical and immunological gains achieved prior to down-referral were sustained through 12 months of follow-up, and 54.7% of this cohort had documented viral suppression at 12 months. However, if only children with VL results are considered, 75.9% (41/54) were virally suppressed 12 months after down-referral. Conclusions. Down-referral of children on ART is complex, with risk of loss to follow-up and treatment interruption. S Afr Med J 2018;108(5):432-438. DOI:10.7196/SAMJ.2018.v108i5.12855

Full article available online at https://doi.org/10.7196/SAMJ.2018.v108i5.12855

May 2018, Print edition

RESEARCH

Assessing the value of Western Cape Provincial Government health administrative data and electronic pharmacy records in ascertaining medicine use during pregnancy U Mehta,1 PharmD, DrPH; A Heekes,1 BSc, BMedSci Hons; E Kalk,1 MB ChB, PhD; A Boulle,1,2 MB ChB, PhD Centre for Infectious Disease Epidemiology and Research, School of Public Health and Family Medicine, Faculty of Health Sciences, University of Cape Town, South Africa 2 Health Impact Assessment, Department of Health, Western Cape Provincial Government, Cape Town, South Africa 1

Corresponding author: U Mehta (ushma.mehta@uct.ac.za) Background. In African settings, where there is a high disease burden, there is a need to improve the science of documenting and analysing accurate information regarding medicine exposures in women immediately before and during pregnancy to assess the extent of use and safety in pregnant women and their unborn children. Objectives. To compare evidence of medicine use during pregnancy, as documented in paper-based clinical records (maternity case records (MCRs)) against electronic health information resources (Provincial Health Data Centre (PHDC)) and assess the level of concordance between the two as part of baseline investigations before piloting a provincial pregnancy exposure registry and birth defect surveillance system. The PHDC consolidates electronic clinical and pharmacy data. Methods. A folder review of completed pregnancies between November 2013 and January 2016 was conducted on randomly selected MCRs from midwife-run obstetric units and a secondary maternity hospital in Cape Town, South Africa. Medication exposures in the MCR were captured and compared with a customised PHDC data extract. The type and timing of drug exposures were compared. Total exposures were compiled from all data sources. Results. Two hundred and six MCRs from three facilities were sampled: 83 women had documented antiretroviral therapy (ART) exposure; all but 1 (1%) had been recorded in the PHDC extract. There was no evidence of ART use in the MCRs of 4 (5%) cases, despite evidence in the PHDC. There were imprecise drug names in the MCRs of 14 (17%) ART patients, discordant dates of onset between the MCRs and PHDC extracts in 10/83 (12%) and inaccurate medicine names and incorrect dates in 1 (1%) case each. Nine of 10 (90%) women who were administered antituberculosis medication were recorded in the PHDC extract. Ten of 21 (48%) isoniazid preventive therapy treatments appeared in the MCRs and PHDC; 9 (42%) in the PHDC only and 2 (10%) in the MCRs only. Half (n=18/36) of all antibiotic use was reflected only in the MCRs, while 13/36 (36%) appeared only in the PHDC extract. In the former cases, antibiotics used for treatment of sexually transmitted infections and urinary tract infections were dispensed from ward stock and not captured electronically. Antibiotics reflected only in the PHDC were either dispensed at a referral facility or before the first recorded antenatal clinic visit. Folic acid and iron were mostly documented in the MCR only (n=79/99 (80%) and n=107/128 (84%), respectively). However, analgesics and antihistamines more often appeared in the PHDC extract only (n=11/16 (73%) and n=5/5 (100%), respectively). Conclusions. The PHDC extract provided a better and more complete reflection of chronic drug exposures compared with the MCRs, especially when women sought care at facilities other than the antenatal care unit where they first attended, or when exposures occurred before the initial antenatal visit. The exception was antibiotics dispensed from ward stock to treat sexually transmitted and urinary tract infections. S Afr Med J 2018;108(5):439-443. DOI:10.7196/SAMJ.2018.v108i5.12879

Full article available online at https://doi.org/10.7196/SAMJ.2018.v108i5.12879

May 2018, Print edition

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The convenient pocket-sized design enables you to fit it comfortably into your hospital bag or coat pocket, so it The convenient pocket-sized design enables you to fit it comfortably into your hospital bag or coat pocket, so it can always be at hand for ready reference. South African Medicines Formulary (SAMF), a joint initiative of the can always be at hand for ready reference. South African Medicines Formulary (SAMF), a joint initiative of the University of Cape Town’s Division of Clinical Pharmacologyyand the Health and Medical Publishing Group, University of Cape Town’s Division of Clinical Pharmacolog and the Health and Medical Publishing Group, publishers for the South African Medical Association, provides easy access to the latest, scientifically accurate publishers for the South African Medical Association, provides easy access to the latest, scientifically accurate information, including full drug profiles, clinical notes and special prescriber’s points. The thoroughly updated information, including full drug profiles, clinical notes and special prescriber’s points. The thoroughly updated 12th edition of SAMF is your essential reference to the rational, cost-effective and safe use of medicines. 12th edition of SAMF is your essential reference to the rational, cost-effective and safe use of medicines.

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True (A) or false (B): SAMJ Co-infection with Streptococcus pneumoniae and Listeria monocytogenes in an immunocompromised patient 1. Combined bacteraemia with S. pneumoniae and L. monocytogenes is very common. 2. Ampicillin should be added to antibiotic regimens to improve patient outcome if L. monocytogenes infection is suspected. Fanconi anaemia (FA) in South Africa (SA): Past, present and future 3. FA is an inherited disorder of impaired DNA repair, first described by Swiss paediatrician Guido Fanconi in 1927. 4. There are two sub-groups in SA who have well-characterised founder mutations responsible for FA. Differentiating Crohn’s disease from intestinal tuberculosis (TB) at presentation in patients with tissue granulomas 5. Differentiating Crohn’s disease from intestinal TB is challenging because of overlapping clinical, endoscopic, radiographic and histological features and poor microbiological yield. 6. Crohn’s disease can affect any part of the gastrointestinal tract. The ‘ins and outs’ of faecal microbiota transplant for recurrent Clostridium difficile diarrhoea at Wits Donald Gordon Medical Centre, Johannesburg, SA 7. C. difficile-associated diarrhoea is a potentially life-threatening condition with mortality as high as 33% and a 28% possibility of relapse. 8. The disease is spread via the faecal-oral route by ingestion of acidresistant spores.

CME A practical approach to managing diabetes in the perioperative period 11. Diabetes mellitus is now the second most important cause of morbidity and mortality in SA. 12. Circulating stress hormones alter insulin secretion and sensitivity, producing a state of relative insulin resistance. 13. There is no need to assess a diabetic patient’s chronic glycaemic control before surgery. 14. Monotherapy with subcutaneous short- or rapid-acting insulin according to a sliding scale is not recommended for in-hospital management of diabetes mellitus preoperatively. 15. Non-insulin antidiabetic agents should not be started in the immediate perioperative period. Point-of-care and lung ultrasound incorporated in daily practice 16. Point-of-care ultrasound is performed by a non-cardiologist at the patient’s bedside along with the physical examination. 17. Point-of-care ultrasound is never used to detect endotracheal intubation and the examination of intracranial pressure. 18. Focused cardiac ultrasound as a screening modality has a more focused scope, and is used to answer a specific clinical question, often looking for a ‘yes’ or a ‘no’ answer. 19. The absence of lung sliding may occur as a result of absent ventilation caused by, for example, inadvertent intubation of the other bronchus. 20. Ultrasound for vascular access is limited to central venous access.

Healthcare-associated infections in paediatric and neonatal wards: A point prevalence survey at four SA hospitals 9. HIV infection and HIV exposure have recently been identified as novel risk factors for healthcare-associated infections in SA children. The costs and outcomes of paediatric TB treatment at primary healthcare clinics in Johannesburg, SA 10. TB is the fourth leading cause of child mortality in SA.

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