SAMJ Vol 107, No 2 (2017) by HMPG

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CME Anaemia (part 2) IN PRACTICE Skin scarring after IM diclofenac injections CASE REPORT Metabolic acidosis in metformin overdose RESEARCH Antibiotic stewardship: 4-year outcomes from GSH HIV infection and age dependence of squamous cell skin carcinoma Gastric cancer in KwaZulu-Natal Adult sickle cell disease in Cape Town

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FROM THE EDITOR 4

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

Infectious diseases – the next big challenge B Farham

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

EDITOR’S CHOICE

ASSOCIATE EDITORS Q Abdool Karim, A Dhai, N Khumalo, R C Pattinson, A Rothberg, A A Stulting, J Surka, B Taylor, M Blockman, J M Pettifor, W Edridge

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30 days in medicine B Farham OBITUARY Jeanne Marie Erica de Villiers (née Du Plessis)

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

CONTINUING MEDICAL EDUCATION 10

GUEST EDITORIAL Anaemia (part 2) N Alli

ARTICLE Anaemia: Approach to diagnosis (part 2) N Alli, J Vaughan, M Patel

TECHNICAL EDITORS Emma Buchanan Kirsten Morreira Naadia van der Bergh Paula van der Bijl

IN PRACTICE

PRODUCTION MANAGER Emma Jane Couzens

MANAGING EDITORS Ingrid Nye Claudia Naidu

CLINICAL UPDATE The prevalence of skin scars in patients previously given intramuscular diclofenac injections attending the Pain Clinic at Universitas Academic Hospital, Bloemfontein, South Africa D Tarloff, G Lamacraft, G Joubert

A biobank to support HIV malignancy research for sub-Saharan Africa J W Schneider, M Sanderson, D Geiger, M Nokta, S Silver

CRISPR-Cas: Revolutionising genome engineering S A Nicholson, M S Pepper

27 29

MEDICINE AND THE LAW Exporting DNA – striking a balance between preventing exploitation and promoting innovation M S Pepper Should doctors provide futile medical treatment if patients or their proxies are prepared to pay for it? D J McQuoid-Mason CASE REPORTS Metabolic acidosis in a patient with metformin overdose I Ebrahim, M Blockman

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Primary ethmoid sinus squamous cell carcinoma in a young adult man N Goncalves, L A Burnell, S Motakef, P C Modi

Intentional intravenous mercury injection G Yudelowitz

Three cases of intentional isoniazid overdose – a life-threatening condition D F Stead, C R Mason

RESEARCH 39

Antibiotic prescription patterns of South African general medical practitioners for treatment of acute bronchitis N B Q Ncube, G C Solanki, T Kredo, R Lalloo

Adenovirus-associated pneumonia in South African children: Presentation, clinical course and outcome M Zampoli, Z Mukuddem-Sablay

DTP AND DESIGN Clinton Griffin Travis Arendse

February 2017, Print edition

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The influence of HIV infection on the age dependence of squamous cell carcinoma of the skin in South Africa* B L Diffey, M Norval, P N Albers, C Y Wright

The spectrum of gastric cancer as seen in a large quaternary hospital in KwaZulu-Natal, South Africa* F Benamro, B Sartorius, D L Clarke, F Anderson, E Loots, L Olinger

The spectrum and outcome of surgical sepsis in Pietermaritzburg, South Africa* S Green, V Y Kong, D L Clarke, B Sartorius, J Odendaal, J L Bruce, G L Laing, P Brysiewicz, W Bekker, E Harknett

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An investigation of diverticular disease among black patients undergoing colonoscopy at Dr George Mukhari Academic Hospital, Pretoria, South Africa* M Vally, M Z Koto, M Govender

Members of the South African Medical Association receive the SAMJ only on request, as part of their membership benefit.

Calcific uraemic arteriolopathy (calciphylaxis) in patients on renal replacement therapy* S Sebastian, H F Jordaan, J W Schneider, M R Moosa, M R Davids

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Analysis of mutations causing familial hypercholesterolaemia in black South African patients of different ancestry* U K Ibe, R Whittall, S E Humphries, G Pilcher, F Raal

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Burden, genotype and phenotype profiles of adult patients with sickle cell disease in Cape Town, South Africa* G D Pule, K Mnika, M Joubert, S Mowla, N Novitzky, A Wonkam

Is it possible to differentiate tuberculous and cryptococcal meningitis in HIV-infected patients using only clinical and basic cerebrospinal fluid characteristics?* J E Vidal, E J F Peixoto de Miranda, J Gerhardt, M Croda, D R Boulware

Readiness to adopt a performance measurement system for substance abuse treatment: Findings from the Service Quality Measures initiative* B Myers, P Petersen Williams, K Johnson, R Govender, R Manderscheid, J R Koch *Full article available online only.

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Background photo: The friendly Sister Beukes on night shift, Clanwilliam Hospital | Ingrid Nye Box photos: Extensive scar from IM diclofenac injection | Tarloff et al.; Squamous cell carcinoma | David Litman; Sickle cell anaemia | Kateryna Kon

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FROM THE EDITOR

Infectious diseases – the next big challenge In September 2016 a woman in her 70s died in Nevada, USA from an infection with carbapenem-resistant Enterobacteriaceae (CRE), which was resistant to all antibiotics available in the States.[1] The woman had apparently returned from an extended trip to India, where she had received treatment for a fractured femur and hip problems, with multiple hospital admissions. The CRE isolated from her wounds in August that year was Klebsiella pneumoniae, which proved resistant to all 26 antibiotics that it was tested against. A specific enzyme, New Delhi metallo-beta-lactamase, making bacteria resistant to a broad range of antibiotics, was detected in one of her wounds, according to the Centers for Disease Control and Prevention, USA. Multidrug-resistant K. pneumoniae has been described by the World Health Organization as an ‘urgent threat to human health’. In May 2016, international newspapers carried stories of a ‘superbug resistant to “antibiotic of last resort”’, which was isolated in the USA. The CRE in this instance was isolated from the urine of a 49-year-old woman in Pennsylvania. In this case, the bacterium was a strain of Escherichia coli resistant to the antibiotic colistin, widely regarded as the ‘antibiotic of last choice’. The authors of this article[2] stated that ‘The recent discovery of a plasmid-borne colistin resistance gene, mrc-1, heralds the emergence of a truly pan-drug resistant bacteria’. This was the first time that this colistin-resistant strain was found in a person in the USA. The woman survived the infection, but someone older or with comorbidities may not have done. CREs are known in India, now in the USA, and they are right here in South Africa.[3] What is particularly worrying is that these resistant strains are being isolated in relatively common infections – an apparent osteomyelitis from a femur fracture in an elderly woman and from a urinary tract infection in a relatively young woman. The story of multidrug- and extreme-drug-resistant tuberculosis is well known and has been a problem for many years, albeit with slow buyin from the larger pharmaceutical companies in terms of developing new treatments. But the emergence of resistant strains of more commonly encountered bacteria in the developed world may change this, as multidrugresistant strains of commonly encountered bacteria cause illness and

death across the world. Metacillin-resistant Staphylococcus aureus has been with us for many years now. My father fell prey to it in a private Cape Town hospital >6 years ago and I first encountered it as a locum in UK hospitals >25 years ago. We did not pay enough attention then, and now developing new – and more expensive – antibiotics is not the answer. Doctors in primary care continue to prescribe, often at the patient’s request, unnecessary antibiotics. In hospitals without good infection control and antibiotic stewardship policies doctors prescribe inappropriate antibiotics – my father was first treated with amoxicillin/ clavulanic acid (Augmentin) when it became obvious that he had a severe wound infection. We urgently need to stop unnecessary and inappropriate prescription of antibiotics across the board. And we also need to put pressure on manufacturers of ‘antiseptic’ household cleaners and hand washes to stop producing and marketing these. Public education campaigns explaining that simple handwashing with ordinary soap and water, and that most infections in primary care are self-limiting and caused by viruses, are urgently needed. Shocking headlines in newspapers about serious hospital infections are not sufficient. People need to realise that this is something that affects their daily lives and could result in the death of a loved one from a common – and previously treatable – infection. Bridget Farham Editor ugqirha@iafrica.com 1. US woman dies of infection resistant to all 26 available antibiotics. https://medicalxpress.com/ news/2017-01-woman-dies-infection-resistant-antibiotics.html (accessed 16 January 2017). 2. Boyles TH, Naicker V, Rawoot N, Raubenheimer PJ, Eick B, Mendelson M. Sustained reduction in antibiotic consumption in a South African public sector hospital: Four-year outcomes from the Groote Schuur Hospital antibiotic stewardship programme. S Afr J Med 2017;107(2):115-118. http://dx.doi. org/10.7196/SAMJ.2017.v107i2.12067 3. McGann P, Snesrud E, Maybank R, et al. Antimicrob Agents Chemother 2016;60(7):4420-4421. http:// dx.doi.org/10.1128/AAC.01103-16

S Afr Med J 2017;107(2):91. DOI:10.7196/SAMJ.2017.v107i2.12324

February 2017, Print edition

EDITOR’S CHOICE

CME: Anaemia (part 2)

The number of anaemic people worldwide is estimated to be a staggering 2 billion, of whom ~50% have iron deficiency anaemia (IDA). IDA can have serious consequences on the cognitive and physical development of children and the work productivity of adults. Furthermore, the increased risk of maternal, child and postoperative morbidity due to severe anaemia has been well documented. In this CME series, anaemia has been divided into two causative categories: decreased bone marrow production or output of red cells, discussed in the previous issue, and peripheral loss (bleeding, sequestration or haemolysis) of red cells, discussed this month. Of the causes due to peripheral loss of red cells, haemolytic anaemia represents the largest group. Understanding the pathophysiology of intra- and extravascular haemolysis is of paramount importance, as the clinical presentation and management of the two varieties differ in many respects.

Reducing antibiotic consumption in a public sector hospital

The global increase in bacterial resistance to antibiotics has resulted in a tipping point towards a post-antibiotic era, where common infections that were previously easily treated now require antibiotics of last resort or are de facto untreatable. South Africa (SA) has seen an alarming increase in rates of extended-spectrum beta-lactamase-producing Gram-negative bacteria and carbapenem-resistant Enterobacteriaceae, which have been reported from every province. The main driver of antibiotic resistance is overuse and misuse of antibiotics. Antibiotic stewardship programmes (ASPs) aim to optimise the use of antibiotics, combining targeted interventions with surveillance, guidelines, education, and monitoring and evaluation through audit. Boyles et al.[1] report on antibiotic consumption and cost from an ASP at Groote Schuur Hospital over a 4-year period beginning in 2012. The initial programme included a dedicated antibiotic prescription chart and dedicated antibiotic stewardship ward rounds, which alternated weekly between two medical wards, with infectious disease subspecialists leading rounds, and a team including medical microbiologists, pharmacists, infection prevention control practitioners, and the junior clinicians directly responsible for the patients’ care. There have been important changes to the ASP since 2012. Ward rounds have been extended to cover all four of the internal medicine wards weekly, and as institutional knowledge has increased, ward rounds have focused on smaller numbers of patients with complex problems rather than including every patient on all four wards. Initially, certain antibiotics were restricted and required release by a microbiologist or infectious diseases physician; these were intravenous ciprofloxacin, carbapenems, piperacillin-tazobactam, colistin, tigecycline, aztreonam, linezolid and vancomycin. In March 2013, the restrictions for intravenous ciprofloxacin, ertapenem, piperacillintazobactam and vancomycin were lifted, although release by the consultant responsible for the patient was still required. The total consumption of antibiotics on the four wards in 2011, the control period, was 1 046 defined daily doses/1 000 patient bed days. There was no change overall in 2012, but in each of the subsequent years there was a decrease of ~18% compared with 2011. This reduction was driven mainly by a decrease in intravenous antibiotic consumption, which fell by 25 - 30% in the years 2013 - 2015, compared with 2011. In contrast, there was very little difference in consumption of oral antibiotics over this period. This study demonstrates that when rolled out on a greater scale this programme can deliver sustained reductions in antibiotic consumption

without compromising patient care, and achieve cost savings within 4 years that could pay for the programme itself.

Antibiotic prescription patterns for treatment of acute bronchitis

Continuing the theme of antibiotic overuse, Ncube et al.[2] analysed the antibiotic prescription patterns of SA general practitioners in the treatment of acute bronchitis, for which antibiotics are often given even though guidelines recommend not prescribing them for uncomplicated acute bronchitis, which is usually self-limiting and viral. Analysis of the 2013 claims for members of 11 health insurance schemes (166 821 events) showed that an antibiotic was prescribed in more than half (52.9%), with significant differences by type of bronchitis and chronic health status. Patients with viral bronchitis were more likely to be prescribed an antibiotic than those with bacterial bronchitis. Patients with a chronic illness were less likely to be prescribed an antibiotic than those without. More than 70% of antibiotics were cephalosporins, penicillins and other beta-lactams. Prescription rates of antibiotics for acute bronchitis by SA general medical practitioners are high. There is an urgent need to follow the guidelines for antibiotic use for acute bronchitis to reduce the likelihood of increasing resistance to available antibiotics.

Adenovirus-associated pneumonia in SA children

Respiratory tract infections remain a common and significant source of morbidity and mortality in children worldwide. With global access to effective immunisation programmes having resulted in a decline in the incidence of bacterial-associated pneumonia, respiratory viruses have emerged as important aetiological agents. Respiratory syncytial virus (RSV) is the leading viral cause of pneumonia in high- and low-income countries. However, the pathogenic role of adenovirus in childhood pneumonia is unclear and the clinical presentation, complications and outcome of AVP in SA children are unknown, as is the role of HIV infection and malnutrition in the outcome of AVP. Zampoli and Mukuddem-Sablay[3] investigated the clinical presentation, severity and outcome of AVP in children using a retrospective analysis of cases over 12 months, including demographic, clinical course and outcome (death, persistent lung disease (PLD)) data. Two hundred and six AVP cases (median age 12 months, interquartile range 6 - 24) were identified; 70 children (34.0%) were malnourished and 14 (6.8%) were HIV-infected. Twenty-nine (14.1%) developed PLD, associated with hypoxia at presentation in 26 cases (89.7%; p=0.01) and necessitating admission to the intensive care unit (ICU) in 18 (62.1%; p<0.01); 18/206 children (8.7%) died. Admission to the ICU and a positive blood culture were independent risk factors for mortality. Adenovirus was isolated in 10.9% of all respiratory tract samples tested, highlighting its potential contribution to pneumonia aetiology. Furthermore, the study confirms previous reports of adenovirus causing severe pneumonia and significant morbidity in children, as supported by data documenting 36.9% of patients needing ICU admission and 14.1% developing PLD. BF 1. Boyles TH, Naicker V, Rawoot N, Raubenheimer PJ, Eick B, Mendelson M. Sustained reduction in antibiotic consumption in a South African public sector hospital: Four-year outcomes from the Groote Schuur Hospital antibiotic stewardship programme. S Afr Med J 2017;107(2):115-118. http://dx.doi. org/10.7196/SAMJ.2017.v107i2.12067 2. Ncube NBQ, Solanki GC, Kredo T, Lalloo R. Antibiotic prescription patterns of South African general medical practitioners for treatment of acute bronchitis. S Afr Med J 2017;107(2):119-122. http://dx.doi. org/10.7196/SAMJ.2017.v107i2.11276 3. Zampoli M, Mukuddem-Sablay Z. Adenovirus-associated pneumonia in South African children: Presentation, clinical course and outcome. S Afr Med J 2017;107(2):123-126. http://dx.doi.org/10.7196/ SAMJ.2017.v107i2.11451

February 2017, Print edition

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30 days in medicine Mouthwash reduces oral gonorrhoea

Gargling daily with the antiseptic mouthwash, Listerine, may control oral gonorrhoea, according to a study in Australia. Researchers in Melbourne looked at 196 gay or bisexual men positive for Neisseria gonorrhoea, who presented at the Melbourne Sexual Health Centre for treatment. Of the 58 men who tested positive for oral gonorrhoea, 33 were randomly assigned to gargle with Listerine Cool Mint and 25 with a saline solution. After rinsing and gargling for 1 minute, the proportion of viable gonorrhoea in the throat was 52% in the men using Listerine, compared with 84% in those using saline (p=0.013). Five minutes after gargling, men in the Listerine group were 80% less likely to test positive for gonorrhoea in their throat than the men using the saline solution. The researchers also tested different dilutions of Listerine in a laboratory setting. Listerine, at dilutions of up to 1 in 4 and applied for 1 minute, considerably reduced the number of N. gonorrhoea on the culture plates, whereas the saline solution had no effect. The effects may be short lived as the follow-up time was short, even though the laboratory evidence of an inhibitory effect of Listerine is encouraging. Chow E, Howden B, Walker S, et al. Antiseptic mouthwash against pharyngeal Neisseria gonorrhoeae: A randomised controlled trial and an in vitro study. Sex Transm Infect 2016;92:A2. http://dx.doi. org/10.1136/sextrans-2016-052718.4

Living near major roads increases risk of dementia

Living next to a major road slightly increases the risk of dementia, but not of Parkinson’s disease or multiple sclerosis. These are the results of a population-based cohort study, recently published in the Lancet. Two cohorts of people were studied to assess the link between living near a busy road and incident neurodegenerative disease. The first cohort, studied for the onset of multiple sclerosis, included all 4.4 million adults aged 20 - 50 in Ontario, Canada, on 1 April 2001. The second, studied for the risk of dementia and Parkinson’s disease, included all the older adults (2.2 million aged 55 - 85 years) living in the same area. Results showed that people living <50 m from a busy road had a 7% higher risk of new-onset dementia than those living 300 m away, after adjusting for age, sex, comorbidities and education. This increased risk was even higher for people living <50 m from a busy road and for those who had always lived next to major traffic. It would seem that this risk may operate through exposure to nitrogen dioxide (NO2) and fine particulate matter (PM2.5). Adjusting for these two pollutants attenuated the association with proximity to a roadway. Chen J, Kwong JC, Copes R, et al. Living near major roads and the incidence of dementia, Parkinson’s disease and multiple sclerosis: A population-based cohort study. Lancet 2017. http://dx.doi.org/10.1016/ S0140-6736(16)32399-6 (published online 4 January 2017).

‘Weekend warriors’ as fit as those who exercise through the week

The World Health Organization and US Department of Health and Human Services recommend at least 150 minutes a week of moderate-intensity aerobic activity or 75 minutes a week of vigorous activity spread through the week. However, many people concentrate their exercise over the weekend because of time constraints during the week. There has been little research on the effects of the ‘weekend warrior’ physical activity pattern, until recently. Now, a study published in JAMA Internal Medicine suggests that compressing this amount of physical activity into a weekend rather than spreading it

through the week may be enough to reduce all-cause, cardiovascular and cancer mortality. The research, from Loughborough University, UK, was carried out on a pooled analysis of 63 591 adults from 11 cohorts of respondents to English and Scottish health surveys. Data from 1994 to 2008 were collected, and the mean age of participants was 58.6 years. Participants reported the amount of exercise carried out in the previous 4 weeks and were divided into inactive; insufficiently active, if they did less than the recommended amount of exercise; weekend warrior, if they did the recommended amount of exercise in 1 or 2 sessions; or regularly active, if the exercise was spread across 3 or more sessions. The researchers found 8 802 deaths from all causes, 2 780 from cardiovascular disease, and 2 526 from cancer during 561 159 personyears of follow-up. The risk of death from all causes was about 30% lower in weekend warriors than in inactive adults. When compared with inactive adults, the risk of cardiovascular death in weekend warriors was 40% lower and the risk of death from cancer was 18% lower. However, the risk of all-cause mortality was still lowest among the regularly active adults, although the authors concluded that ‘The weekend warrior and other physical activity patterns characterised by one or two sessions per week of moderate or vigorous intensity physical activity may be sufficient to reduce risks for all cause, cardiovascular and cancer mortality regardless of adherence to prevailing physical activity guidelines’. O’Donovan G, Lee I, Hamer M, et al. Association of ‘weekend warrior’ and other leisure time physical activity patterns with risks for all-cause, cardiovascular disease and cancer mortality. JAMA Intern Med 2017. http://dx.doi.org/10.1001/jamainternmed.2016.8014 (published online 9 January 2017).

Elderly patients do better with female doctor

Elderly hospital patients have a lower 30-day mortality and readmission rate if treated by female doctors, according to a study published in JAMA Internal Medicine. Previous studies have found that men and women practise medicine differently; for example, women are more likely to adhere to clinical practice guidelines and offer preventive care more often. However, it is not known whether these differences affect clinical outcomes. In this new study by Tsugawa et al. from Harvard T H Chan School of Public Health, Cambridge, Massachusetts, 1.6 million admissions of patients aged >65 years for medical conditions, treated by general physicians, were analysed. After adjusting for many factors, such as type and severity of the patients’ medical conditions, patient and physician characteristics, and hospital size and type, researchers found that those treated by a female physician had a lower 30-day mortality and readmission rate. Tsugawa Y, Jena AB, Figueroa JF, Orav EJ, Blumenthal DM, Jha AK. Comparison of hospital mortality and readmission rates for Medicare patients treated by male vs female physicians. JAMA Intern Med 2016. http://dx.doi.org/10.1001/jamainternmed.2016.7875 (published online 19 December 2016).

Use inhaled corticosteroids regardless of asthma symptom frequency

Low-dose inhaled corticosteroids (ICS) are highly effective for reducing asthma exacerbations and mortality, but conventionally ICS treatment is recommended for patients who have symptoms on >2 days a week, although there is little evidence to support this recommendation. This study, published in the Lancet, assessed the validity of the

February 2017, Print edition

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previous symptom-based cut-off by establishing whether there was a differential response to budesonide v. placebo for severe asthma exacerbations, lung function, and asthma symptom control across subgroups identified by baseline asthma symptom frequency. They used a post-hoc analysis of the 3-year inhaled Steroid Treatment As Regular Therapy (START) study, done in 32 countries, with clinic visits every 3 months. Patients (aged 4 - 66 years) with mild asthma diagnosed within the previous 2 years and no previous regular use of corticosteroids were randomised to receive once daily, inhaled budesonide 400 μg (those aged <11 years 200 μg) or placebo. They found that in mild recent-onset asthma, once daily, lowdose budesonide decreases severe asthma-related risk, reduces lung

function decline, and improves symptom control similarly across all symptom subgroups. The results do not support restriction of inhaled corticosteroids to patients with symptoms on >2 days per week and suggest that treatment recommendations for mild asthma should consider both risk reduction and symptoms. Reddel HK, Busse WW, Pedersen S, et al. Should recommendations about starting inhaled corticosteroid treatment for mild asthma be based on symptom frequency: A post-hoc efficacy analysis of the START study. Lancet 2017;389(10065):157-166. http://dx.doi.org/10.1016/S0140-6736(16)31399-X

Bridget Farham Editor ugqirha@iafrica.com

OBITUARY Jeanne Marie Erica de Villiers (née Du Plessis)

Jeanne de Villiers (née du Plessis) was born in Middelburg, Eastern Cape on 14 September 1933. After matriculating at the Hoërskool Sentraal, Bloemfontein, she studied at the University of Cape Town (UCT) and graduated with an MB ChB degree in 1956 as one of only 11 women in a class of 98 students. She was an exceptional student and was awarded the university’s gold medal for medicine in her final year. The following year she was appointed as the first female intern in Prof. Jannie Louw’s

surgical firm in the Department of Surgery at Groote Schuur Hospital (GSH). After her internship, Jeanne worked in the UK, where she developed an interest in anaesthesia. In 1958 she returned to GSH to specialise. She showed an aptitude for research and began investigating problems relating to the rapid transfusion of cold bank blood that was becoming necessary for major surgery. In 1963 she was awarded the MMed (Anaes) degree by UCT for research on the safety of a novel radiofrequency blood warmer that was being developed as a collaborative project between UCT’s Departments of Electrical Engineering and Anaesthesia. Dr Du Plessis was only the third female to specialise in anaesthesia at UCT. She became a lecturer in the department and published several articles in academic journals between 1966 and 1970. In her later years she was the medical officer at the Poisons Information Centre located at the Red Cross War Memorial Children’s Hospital in Rondebosch. She married Prof. J C (Kay) de Villiers, head of UCT’s Department of Neurosurgery, in 1968. Unwilling to do things halfheartedly, she resigned from her professional duties and committed herself completely

February 2017, Print edition

to her new role as the supportive wife, mother and later grandmother. Jeanne’s sterling academic achievements and medical career are complemented by her genial manner, modest disposition, warm personality and abiding love of nature. She and Kay would oft be seen walking in the National Botanical Garden, Kirstenbosch, enjoying the splendour of the indigenous flora. She always subscribed to a rather simplistic philosophy of keeping complex matters uncomplicated. Besides being the very epitome of a lady, her loyal, loving support of her spouse and her kind, caring dedication to her children and grandchildren were exemplary and laudable. She passed away after a valiant and patient fight against cancer on 20 November 2016. She had indeed lived life optimally. Peter Gordon Emeritus Associate Professor, Department of Anaesthesia, Faculty of Health Sciences, University of Cape Town, South Africa peter.gordon@uct.ac.za Nathan Finkelstein Visiting Professor, Faculty of Pharmacy, Rhodes University, Grahamstown, South Africa

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CME

GUEST EDITORIAL

Anaemia (part 2) According to the World Health Organization, anaemia is defined as ‘a condition in which the number of red blood cells or their oxygencarrying capacity is insufficient to meet physiologic needs’.[1] The number of anaemic people worldwide is estimated to be a staggering 2 billion, of whom ~50% have iron-deficiency anaemia (IDA).[1] Of major concern are the more serious consequences of IDA on the cognitive and physical development of children and the work productivity of adults. Furthermore, the increased risk of maternal, child and postoperative morbidity due to severe anaemia has been well documented. Given the vastness of the subject, a systematic approach to diagnosis is crucial. In this series, anaemia has been divided into two causative categories, i.e.: • Decreased bone marrow production or output of red cells, discussed in the previous issue of this CME series.[2] • Peripheral loss (bleeding, sequestration or haemolysis) of red cells, which is the subject of discussion in the current issue. Of the causes of anaemia due to peripheral loss of red cells, haemolytic anaemia represents the largest group. Understanding the pathophysiology of intra- and extravascular haemolysis is of paramount importance, as the clinical presentation and management of the two varieties differ in many respects. Globally, the prevalence of inherited haemolytic anaemias (including thalassaemia, glucose-6-phosphate dehydrogenase deficiency, globin chain variants, e.g. sickle cell disease (SCD)), is highest in areas endemic to malaria. A striking overlap between the geographical distribution of inherited haemolytic anaemias and malaria endemicity led researchers to explore the effect of this co-existence. In vitro studies have demonstrated decreased parasite survival in the red cells of affected individuals (mostly heterozygous). These experiments led investigators to conclude that selective survival from partial protection against malaria has ensured persistence of these conditions. SCD serves as a classic example to illustrate the point. In some parts of Africa, the childhood mortality for the homozygous state (SS) exceeds 60%. As a consequence of such a severe clinical entity, the sickle gene is expected to dwindle to extinction as a result of its progressive dilution over subsequent generations. However, the

sickle gene is anything but extinct, and is prevalent in polymorphic frequencies in some geographical regions. The primary reason for this observation is attributed to partial protection enjoyed by the heterozygous state against malaria, and it is this selective survival advantage that has led to persistence of the sickle gene. Various mechanisms for protection against malaria have been proposed, of which two are widely accepted: (i) K+ is an absolute requirement for parasite surival. Sickle cells have decreased intracellular K+ (from K+ loss due to red cell membrane damage), thus compromising parasite survival; (ii) the intracellular pH in parasite-infected red cells drops, which triggers the sickling process. The parasitised sickle cells are then selectively removed by splenic macrophages. Transformation of the South African (SA) political landscape after the first democratic election in 1994 occasioned relaxation of SA immigration laws. This led to an influx of visitors for business, leisure and employment purposes from various parts of the world. Consequently, healthcare workers are now exposed to inherited haemolytic conditions previously not highly prevalent in SA. Physiological states of anaemia, e.g. pregnancy, are not included for discussion in this CME series. N Alli Department of Molecular Medicine and Haematology, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, and National Health Laboratory Service, Johannesburg, South Africa nazeer.alli@nhls.ac.za 1. World Health Organization. The Global Prevalence of Anaemia in 2011. Geneva: WHO, 2015. 2. Alli N, Vaughan J, Patel M. Anaemia: Approach to dagnosis. S Afr Med J 2017;107(1):23-27. http://dx.doi.org/10.7196/SAMJ.2017.v107i1.12147

S Afr Med J 2017;107(2):95. DOI:10.7196/SAMJ.2017.v107i2.12224

February 2017, Print edition

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CME

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

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

Anaemia is defined as a condition in which the number of red cells or their oxygen-carrying capacity is insufficient to meet physiological needs. It is the most common disorder globally and one of the conditions that general practitioners most frequently encounter. In the World Health Organization global database, anaemia is estimated to affect 1.6 billion people. Anaemia may result from (i) decreased bone marrow output; or (ii) peripheral loss, destruction or sequestration of red cells. As anaemia manifests in a whole range of conditions, it is important to embrace a structured diagnostic approach. The recommended approach incorporates clinical and pathophysiological considerations, red cell characteristics, and bone marrow activity. Causes of anaemia related to decreased bone marrow output have been discussed in the previous issue of SAMJ, in the first part of this two-part series. The focus of the current article is on peripheral causes of anaemia. S Afr Med J 2017;107(2):96-100. DOI:10.7196/SAMJ.2017.v107i2.12223

This article is the second of a two-part CME series on anaemia. According to the World Health Organization (WHO), anaemia is defined as a condition in which the number of red blood cells or their oxygen-carrying capacity is insufficient to meet physiological needs, which vary by age, sex, altitude, smoking, and pregnancy status.[1] The causes of anaemia are divided into two broad categories (Fig. 1): • Central: decreased bone marrow production/output of red blood cells, discussed in part 1 of the CME series on anaemia.[2] • Peripheral: loss or destruction of red cells through haemolysis, bleeding or splenic sequestration, which is the subject of discussion in this issue. While the two categories form a sound basis for diagnostic work-up, they are not mutually exclusive. As a rule, a good reticulocyte response essentially excludes bone marrow failure. However, a combination of the two categories may give mixed signals that could present a confusing picture. By way of example, uncomplicated haemolysis with normal bone marrow function invokes a brisk reticulocyte response in the initial stages (Fig. 1), but with time, as folate is lost and stores are depleted, the response is blunted owing to ineffective haematopoiesis.

Haemolysis

Haemolysis is defined as the premature destruction of red cells. The lifespan of normal red cells is 100 - 120 days.

Haemolysis is classified as: • intravascular, where red cells are destroyed within the vascular compartment • extravascular, where red cells are destroyed outside the vascular system by macrophages. It is important to understand the pathophysiology of the two categories of haemolysis, as clinical manifestations and treatment principles differ in the two types (Table 1).

Intravascular haemolysis

Red cells break up within the vascular compartment and its contents are released into the circulating plasma. Free Hb tetramers dissociate into α/non-α dimers, which are small enough to filter through the glomerulus and pass out into the urine (haemo-

globinuria). Hb loss is accompanied by iron loss and may cause iron deficiency. Some of the filtered Hb is reabsorbed by the proximal tubular cell, where it is degraded, and the iron is packaged as haemosiderin. Tubular cells have a rapid turnover and these slough off into the urine. Haemosiderinuria is detected by microscopic viewing of a slide prepared from urine sediment. Iron present in tubular cells stains deep blue with the prussian blue iron stain. Folic acid and carbonic anhydrase molecules are small enough to filter through the glomerulus and pass out into urine. A third of total body folic acid is stored in red cells; therefore, ongoing haemolysis is likely to cause megaloblastic anaemia secondary to folate loss and deficiency. Similarly, loss of

Table 1. Intra- v. extravascular haemolysis: medium- to long-term clinical effects Clinical effects

Intravascular haemolysis

Extravascular haemolysis

Haemoglobinuria/ haemosiderinuria

Yes

Jaundice

Yes

Substrate deficiency

Iron, folic acid, zinc

Folic acid

Bony abnormalities

Yes, e.g. frontal bossing, maxillary hyperplasia

Splenomegaly

Yes (medium/long-term)

Gallstones

Less frequent

Yes

Iron overload

Yes

Leg ulcers

Yes

Pulmonary hypertension

Common, earlier onset (from second decade onwards)

Less common, late onset

February 2017, Print edition

CME

Anaemia

FBC and differential count

Reticulocyte count

Blood smear microscopy See Table 3 for guidance Increased count

Decreased count

BM failure/ infiltration

Nutritional deficiency

BM aspirate and trephine biopsy

Bleeding

Hypersplenism

Haemolysis

Locate source of blood loss

Investigate cause of splenomegaly

Serum haptoglobin level suggests haemolysis

MCV • Serum Fe studies and ferritin

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

Normal Fe studies • Hb electrophoresis

Normal vitamin B12 and folate • BM examination

Fe deficiency • Fe administration • Exclude bleeding

Vitamin B12/folate • Supplementation • Investigate cause

Haemosiderinuria/ haemoglobinuria IVH

Indirect serum bilirubin EVH

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

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

carbonic anhydrase, a metallo-enzyme that contains zinc, could lead to zinc deficiency. The red cell membrane comprises a large meshwork of interconnected lipoproteins, and is therefore unable to be filtered through the kidneys. Massive intravascular haemolysis (IVH) (e.g. immediate blood transfusion reaction) frequently results in obstruction of glomerular capillaries and may cause pre-renal renal failure.

HS PNH β-thal major MAHA Hb H disease

Extravascular haemolysis

Red cells are haemolysed within the macrophage and its contents released into the cytosol. The haem component of Hb is enzymatically transformed to bilirubin, which is then released into the circulation. As unconjugated bilirubin is water insoluble, it is bound to albumin and the complex is finally absorbed by hepatocytes, where it is conjugated and excreted through the biliary system. As there is no mechanism to release excess iron, it continues to accumulate over the duration of haemolysis. Folic acid is also released into the circulation, but much of it is lost through the kidneys.

IVH

EVH

SCD

Warm AIHA

Cold AIHA Delayed BTR G6PD def

Immediate BTR Malaria

Fig. 2. Examples of haemolytic conditions with varying degrees of IVH and EVH. (HS = hereditary spherocytosis; SCD = sickle cell disease; AIHA = autoimmune haemolytic anaemia; BTR = blood transfusion reaction; MAHA = micro/macro-angiopathic haemolytic anaemia; PNH = paroxysmal nocturnal haemoglobinuria; G6PD def = glucose-6-phosphate dehydrogenase deficiency; thal = thalassaemia.)

February 2017, Print edition

CME

Clinical manifestations and complications of chronic IVH and extravascular haemolysis (EVH) are summarised in Table 1. It should be noted that haemolysis is seldom purely intravascular or extravascular. In instances where both IVH and EVH exist, the clinical picture is determined by the predominant type of haemolysis. Examples of conditions that cause haemolysis are summarised in Fig. 2.

Laboratory tests for haemolysis

The most sensitive laboratory indicator of haemolysis is a decreased haptoglobin level. Available tests for haemolysis are summarised in Table 2.

Diagnostic approach to haemolysis Clinical approach

A detailed history is essential, including duration and frequency of symptoms, age of onset, blood transfusions and family history. Inherited varieties generally present during early childhood. Patients with homozygous beta thalassaemia become progressively anaemic during the first few months of infancy and present at the age of ~3 - 6 months with severe anaemia. During the third trimester of pregnancy (~27 - 30 weeks), a switch from Hb F to Hb A production begins. Owing to non-functioning beta globin genes, there is no beta globin chain expression and therefore no Hb A production to substitute the gradual decline of Hb F. This results in a gradual but progressive drop in Hb during the first few months of infancy. Patients with sickle cell disease (SCD) have a unique mode of presentation. The hallmark of SCD is an acute pain crisis, most commonly affecting long bones, although any site/organ may be affected. Severe pain is experienced at the site of vaso-occlusion. Dactylitis (pain crisis in the bones of the hands and feet) is often the presenting symptom of SCD in early childhood.[3] Glucose-6-phosphate dehydrogenase (G6PD) deficiency is inherited in an X-linked fashion and therefore typically manifests in males, although homozygous females are

occasionally encountered. The haemolysis is most commonly episodic, following exposure to oxidant compounds, e.g. antimalarial drugs or sulphonamides. At birth, neonatal jaundice is common and may require intervention with ultraviolet light or exchange transfusion in more severe cases. Of the red cell membrane disorders, hereditary spherocytosis is the most common variety. It presents with the classic triad of anaemia, jaundice and splenomegaly. The red cells are destroyed in the macrophages of the spleen, i.e. they undergo EVH. In chronic haemolytic states, e.g. thalassaemia major or intermedia, splenomegaly and bony abnormalities, such as frontal bossing, develop at an early age and are usually a sequel to inadequate management or poor patient compliance.[4]

Laboratory approach

A full blood count, differential count, reticulocyte count and microscopic blood smear examination serve as baseline tests from whence further investigations are performed (Fig. 1). If haemolysis is suspected, it should be confirmed with a low haptoglobin level, which typically decreases during an haemolytic episode. Haptoglobin is a sensitive indicator of IVH and EVH. It should, however, be noted that haptoglobin levels may also decrease in liver disease (due to decreased synthesis) and rise in inflammatory states or malignancy (as it is an acute-phase reactant).[5] Peripheral blood smear microscopy (May-Grünwald-Giemsa and reticulocyte preparations) often provides the diagnosis or additional clues for further investigation (Table 3). Reticulocytes, Heinz bodies and Hb H inclusions in red cells can be detected through microscopic examination of smears prepared from reticulocyte preparations (peripheral blood incubated with brilliant cresyl blue for 20 minutes). Newergeneration blood cell counting analysers have the ability to enumerate reticulocytes.

Fragmentation haemolysis

Fragmentation haemolytic anaemias occur as a result of disturbances in blood flow, either in large (macroangiopathic haemoly-

Table 2. Tests for intra- and extravascular haemolysis Test Serum haptoglobin Plasma Hb Haemoglobinuria Haemosiderinuria Serum lactate dehydrogenase Serum unconjugated bilirubin

Intravascular haemolysis Present Present Present Normal

Extravascular haemolysis Absent Absent Absent

February 2017, Print edition

sis) or small (microangiopathic haemolysis) blood vessels. They are characterised by the presence of varying numbers of red cell fragments in the peripheral blood and accompanying thrombocytopenia in microangiopathic haemolysis. Causes of macroangiopathic haemolysis include prosthetic heart valves, arteriovenous malformations and aortic stenosis. The anaemia is typically not severe, and active management is usually not required. Microangiopathic haemolysis is caused by small-vessel obstruction by microthrombi, the distribution of which determines the organ system predominantly involved. Causes of microangiopathic haemolytic anaemia (MAHA), their associations and the specific clinical and laboratory derangements seen with each entity are summarised in Table 4. Several are pregnancy associated, and can be difficult to differentiate in the peripartum setting. Thrombotic thrombocytopenic purpura (TTP) is an important cause of MAHA in South Africa (SA), as it is relatively common in HIV-positive patients. It carries a high mortality in the event of a missed diagnosis (~90%),[6] but with appropriate management survival is excellent (~80%).[7] Other causes include autoimmune disease, a variety of drugs (including clopidogrel, ticlodipine and quinine) and congenital deficiency of ADAMTS13 (a metalloproteinase that cleaves high molecular weight Von Willebrand factor). HIV remains the most common cause in SA. TTP is characterised by a pentad of features: fragmentation haemolysis, thrombocytopenia, fever, renal failure (usually not severe), and fluctuating neurological derangement (including confusion or psychiatric manifestations, seizures and focal signs). However, all five features are not invariably present, and a presumptive diagnosis of TTP is made when there is MAHA and thrombocytopenia, with exclusion of all other causes of a thrombotic microangiopathy (e.g. disseminated intravascular coagulation). In the developed world, much emphasis is placed on the importance of documenting ADAMTS13 levels in the diagnosis of TTP, where its activity is reportedly consistently low (<10%) in congenital and autoimmune-mediated TTP, but normal or more modestly reduced in other microangiopathies.[7] However, ADAMTS13 levels are not universally low in HIV-associated TTP, which places the use of this test in question in the SA context.[8] Furthermore, ADAMTS13 testing is not universally available in SA, and it is therefore not routinely recommended. Although the gold standard of treatment for TTP is plasma exchange, large-volume fresh frozen plasma may suffice in some

CME

Table 3. Red cell morphological characteristics and interpretation Morphological observation Target cells with microcytosis and/or hypochromia

Differential diagnosis Iron deficiency Thalassaemia trait Anaemia of chronic disorder

Further test/s indicated Iron studies, Hb electrophoresis

Oval macrocytes, right shift

Megaloblastic anaemia

Vtimain B12 and folic acid levels

Round macrocytes with target cells

Possible liver disease Hypothyroidism Hyperlipidaemia

Liver function and thyroid function tests, lipid profile

Sickle cells

Sickle cell disease

Hb electrophoresis: to confirm presence of Hb S and check Hb F level

Spherocytes

Hereditary spherocytosis Warm AIHA

Gamma Coombs test: positive in warm AIHA Red cell membrane analysis Autoimmune screening

Elliptocytes

Hereditary elliptocytosis

Red cell membrane analysis

Severe anisopoikilocytosis, diffuse/punctate basophilia, red cell fragmentation

Hereditary pyropoikilocytosis Thalassaemia major

Red cell membrane analysis, Hb electrophoresis

Coarse basophilic stippling

5'PNT deficiency Glycolytic pathway enzyme deficiency Lead poisoning

Plasma lead levels, red cell 5'PNT assay, analysis of glycolytic pathway enzymes

Autoagglutination

Noted in cold AIHA

Non-gamma Coombs test: positive in cold AIHA

Red cell fragmentation

Decreased platelet count → microangiopathic haemolysis Normal platelet count → macroangiopathic haemolysis

See Table 4

Malaria

Plasmodium falciparum life-threatening infection

Identify species Monitor FBC and parasite count during treatment

Heinz bodies (reticulocyte preparation) Bite cells (May-Grünwald-Giemsa preparation)

G6PD deficiency Exposure to oxidant compounds Unstable Hb

Oxidant drug or toxin history, check red cell G6PD level

Hb H inclusions

Present in alpha thalassaemia

Hb electrophoresis, PCR for alpha thalassaemia

5'-PNT = 5'-pyrimidine nucleotidase; AIHA = autoimmune haemolytic anaemia; PCR = polymerase chain reaction.

patients. Corticosteroids should also be initiated at diagnosis, and HIV-seropositive patients should receive concomitant combination antiretroviral therapy, irrespective of their CD4 count. The lactate dehydrogenase level and platelet count are used to monitor response to treatment. Importantly, TTP is a relative contraindication for platelet transfusion, as this may fuel the microthrombotic process. However, platelets should not be withheld in the event of significant bleeding. Patients with TTP should be referred to and managed by specialist haematologists.

response that develops over 2 - 3 days. Chronic low-volume blood loss causes a microcytic anaemia without an elevation of the reticulocyte production index (RPI) (due to iron deficiency). Where the source of the blood loss is not obvious, the following investigations may be helpful: (i) stool analysis for faecal occult blood; (ii) urine dipstix and microscopy for haemoglobinuria and detection of red cells, respectively; (iii) gynaecological review; and (iv) examination of sputum for iron-laden macrophages (detected in pulmonary haemosiderosis due to intra-alveolar bleeding).

Bleeding

Hypersplenism

Anaemia due to acute bleeding usually occurs after substantial blood loss and is most often encountered in patients with a bleeding diathesis, or in trauma, postoperative or obstetric settings. In the hyperacute phase of bleeding, the anaemia is usually normocytic and normochromic. This is followed by macrocytosis due to a reticulocyte

Hypersplenism refers to an enlarged spleen with sequestration or destruction of blood cells, which leads to the development of anaemia and/or neutropenia and/or thrombocytopenia. It is characterised by a hypercellular bone marrow response and improvement after splenectomy. There may be some degree of associated haemolysis.

February 2017, Print edition

CME

Table 4. Summary of common microangiopathic haemolytic anaemias Microangiopathic entity

Common features

Associations/risk factors

Management

TTP

Anaemia and thrombocytopenia ++ red cell fragmentation + renal impairment Fever Fluctuating neurological manifestations ADAMSTS13 levels may be low

HIV infection Autoimmune disease Drugs (clopidogrel, ticlodipine, quinine) Metastatic adenocarcinoma Allogeneic stem cell/solid organ transplantation Congenital deficiency of ADAMTS13 (rare)

Plasma exchange Steroids

DIC

Anaemia and thrombocytopenia + red cell fragments Deranged coagulogram ( INR and/or PTT, D-dimers, fibrinogen and AT levels)

Major trauma Sepsis Obstetric accidents

Treat underlying cause FFP/cryoprecipitate infusion LMWH* Platelet infusion if bleeding

HUS

+/++ red cell fragments Marked renal impairment Moderate anaemia and thrombocytopenia Complement 3 and 4 levels may be low in aHUS

Shiga toxin-associated diarrhoeal illness Shigella dysenteriae Escherichia coli (O157:H7 and O104:H4) aHUS dysregulation of alternate C' pathway Congenital factor H or I deficiency Antibodies to factor H

Supportive measures A trial of plasma exchange for aHUS Eculizumab (limited availability) Dialysis, usually for aHUS

HELLP syndrome/preecclampsia

Anaemia and thrombocytopenia + red cell fragments Raised AST/ALT Hypertension Headache and visual disturbance, RUQ pain, pulmonary oedema

Risk of recurrence in subsequent pregnancies

Emergency delivery by caesarean section

DIC = disseminated intravascular coagulation; TTP = thrombotic thrombocytopenic purpura; aHUS = atypical haemolytic uraemic syndrome; RUQ = right upper quadrant; INR = international normalised ratio; PTT = partial thromboplastin time; LMWH = low-molecular-weight heparin; AT = antithrombin; HELLP = haemolysis/elevated liver enzymes/ low platelet count; ++ = moderate to severe; + = mild to moderate; FFP = fresh frozen plasma; AST = aspartate transaminase; ALT = alanine transaminase; C' = complement. *LMWH is particularly useful if thrombotic manifestations predominate.

The spleen functions as a reservoir for blood cells and a filter that removes senescent, abnormal or antibody-coated red cells from the circulation. When it is enlarged, these functions are amplified; therefore, red cell survival is somewhat attenuated and the number of cells sequestered is increased. This may result in mild to moderate reductions in red cell, white cell and/or platelet counts, as well as biochemical evidence of haemolysis. Hypersplenism may occur in any patient with splenomegaly, regardless of the cause, including portal hypertension, infectious causes (such as chronic malaria), chronic haemolytic states, or haematological malignancies. A peripheral blood smear review is routinely indicated in patients with splenomegaly, and bone marrow examination in instances where the cause for the splenomegaly is not readily apparent. Where anaemia is caused by hypersplenism alone, i.e. without an underlying cause, the red cells are usually normocytic and normochromic. The reticulocyte count and RPI are usually raised, but may be lower than anticipated owing to sequestration of reticulocytes in the spleen. In patients with portal hypertension, anaemia is often microcytic and hypochromic because of iron deficiency from chronic

blood loss, e.g. bleeding oesophageal varices, haematuria or gastrointestinal bleeding in chronic schistosomiasis. The latter is not an uncommon cause of portal hypertension in SA.

Conclusion

Causes of anaemia are numerous and varied. Owing to its manifestation in a wide variety of conditions, investigating the cause requires a thorough history, physical examination and systematic laboratory and ancillary investigations. 1. World Health Organization. The Global Prevalence of Anaemia in 2011. Geneva: WHO, 2015. 2. Alli N, Vaughan J, Patel M. Anaemia: Approach to diagnosis. S Afr Med J 2017;107(1):23-27. http:// dx.doi.org/10.7196/SAMJ.2017.v107i1.12147 3. Alli NA, Patel M, Alli HA, et al. Recommendations for the management of sickle cell disease in South Africa. S Afr Med J 2014;104(11):743-751. http://dx.doi.org/10.7196/SAMJ.8470 4. Olivieri NF, Weatherall DJ. Clinical aspects of β thalassaemia. In: Steinberg MH, Forget BG, Higgs DR, Nagel RL, eds. Disorders of Hemoglobin, Genetics, Pathophysiology and Clinical Management. Cambridge: Cambridge University Press, 2001. 5. Means RT Jr, Glader B. Anaemia: General considerations. In: Greer JP, Arbor DE, Glader B, et al., eds. Wintrobe’s Clinical Hematology. 13th ed. Philadelphia: Wolters Kluwer, 2013. 6. Amorosi EL, Ultmann JE. Thrombotic thrombocytopenic purpura: Report of 16 cases and review of the literature. Medicine 1966;45(2):139-159. http://dx.doi.org/10.1097/00005792-196603000-00003 7. Scully M, Goodship T. How I treat thrombotic thrombocytopenic purpura and atypical haemolytic uraemic syndrome. Br J Haematol 2014;164(6):759-766. http://dx.doi.org/10.1111/bjh.12718 8. Gunther K, Garizio D, Nesara P. ADAMTS13 activity and the presence of acquired inhibitors in human immunodeficiency virus-related thrombotic thrombocytopenic purpura. Transfusion 2007;47(9):1710-1716. http://dx.doi.org/10.1111/j.1537-2995.2007.01346.x

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IN PRACTICE

CLINICAL UPDATE

The prevalence of skin scars in patients previously given intramuscular diclofenac injections attending the Pain Clinic at Universitas Academic Hospital, Bloemfontein, South Africa D Tarloff,1 MB ChB, DA (SA), FCA (SA); G Lamacraft,1 MBBS, MRCP, FRCA, PhD; G Joubert,2 BA, MSc 1 2

Department of Anaesthesiology, Faculty of Health Sciences, University of the Free State, Bloemfontein, South Africa Department of Biostatistics, Faculty of Health Sciences, University of the Free State, Bloemfontein, South Africa

Corresponding author: D Tarloff (debstarloff@yahoo.com)

Intramuscular (IM) diclofenac rarely causes scarring (reported incidence <0.05%). Some patients attending the Pain Clinic at Universitas Academic Hospital, Bloemfontein, South Africa, presented with scars that had developed after IM diclofenac injections. We investigated the prevalence of scars in patients at the clinic and how the injections had been obtained. Patients attending the clinic over a period of 9 months who said they had received diclofenac (N=131) were included. Information was collected using a questionnaire and physical examination. Data obtained from 118 patients who were certain that they had received diclofenac were analysed. Ninety-three patients (78.8%) indicated they had not been warned about the possibility that a diclofenac injection could result in scarring. Scarring had occurred in 10 patients (8.5%). Two-thirds of the patients who had obtained diclofenac from a pharmacy had never had a prescription for it. Four patients had required medical treatment for an ulcer or abscess, of whom two had undergone surgery. The risk of skin lesions associated with IM diclofenac is higher than reported previously. Contrary to regulations, diclofenac injections were often dispensed to patients without a prescription. S Afr Med J 2017;107(2):101-105. DOI:10.7196/SAMJ.2017.v107i2.12012

The Pain Clinic at Universitas Academic Hospital in Bloemfontein, South Africa (SA), sees patients with various forms of chronic pain, most commonly back pain. Treating patients with low back pain often includes exposure of the patient’s buttocks. Doctors in the clinic have occasionally noted disfiguring skin scars on the buttocks of patients that had developed after they had received intramuscular (IM) injections for their pain. These injections had been given elsewhere and were often reported by the patients to be IM diclofenac (Voltaren). It is not practice in this clinic to use or prescribe IM diclofenac. Some patients also reported that they had received IM diclofenac without a prescription, and that the injections had been administered by persons other than healthcare professionals. IM diclofenac is on the South African Standard Treatment Guidelines and Essential Medicines List for treatment of adults with acute pain.[1] The current national contract for IM diclofenac in SA is for the period 1 June 2014 to 28 February 2017 and comprises ~ 6.77 million ampoules of IM diclofenac. The Free State Province had an annual usage rate of 115 700 ampoules for the period 1 December 2014 - 30 November 2015, while usage at Universitas Academic Hospital was 1 910 ampoules between 1 July 2014 and 30 June 2015. [2] This information was confirmed by personal communication with the assistant manager, Pharmaceutical Services, Medpharm, Free State Department of Health (9 November 2015) and a pharmacist at Universitas Academic Hospital (9 July 2015). The extensive use of IM diclofenac in SA, where it is the only parenteral non-steroidal anti-inflammatory drug (NSAID) widely used in public hospitals, contrasts with the situation in other countries, where its use has been limited because of the ulceration, scarring and tissue loss that can result following its administration.[3,4]

Objective

The objective of this questionnaire-based study was to determine: (i) the prevalence of skin scars due to IM diclofenac in our patient community; (ii) how patients had obtained IM diclofenac; and (iii) who had administered it to them.

Methods

A prospective descriptive study was performed using a questionnaire and clinical examination. The study protocol was approved by the Ethics Committee of the Faculty of Health Sciences, University of the Free State (ref. no. 173/2013). All patients who attended the Pain Clinic at Universitas Academic Hospital over a 9-month period (1 December 2013 - 31 August 2014) were included in the study. Patients who attended the clinic more than once during this period were included for their first visit only. Informed consent was obtained from each patient. Consent documents and information forms were available in the three main languages of the region, namely English, Afrikaans and Sesotho. Each patient who attended clinic during the study period was asked by the admitting nurse if they had ever received an IM diclofenac or Voltaren injection. If they answered ‘yes’, they were asked to participate in the study. The nurse kept a record of how many patients seen at the clinic answered ‘yes’ or ‘no’. Participants included in the study completed a questionnaire and underwent a non-invasive physical examination of the injection site by the doctor working in the clinic, who was either an anaesthetic consultant or a registrar. Information was collected confidentially. The folders were marked to ensure that each patient participated only once during the period of the study.

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Data analysis was performed by the Department of Biostatistics, University of the Free State. Results were summarised by frequencies and percentages (categorical variables) and means and standard deviations (SDs) of percentiles (numerical variables).

Results

Two hundred and nineteen patients attended the Pain Clinic during the study period. When asked whether they had ever received a diclofenac or Voltaren injection, 131 patients (59.8%) answered ‘yes’ and were asked to participate in the study. The mean age of the participants was 54.2 years (SD 12.1, range 23 - 80). The BMI was recorded in 127 participants, who had a median BMI of 29.2 kg/m2 (range 16.2 56.6). Approximately two-thirds (66.4%) of the participants were female. Seventeen participants (13.0%) had diabetes mellitus. The median number of injections received by each participant was 8 (range 1 - 95). One hundred and twenty-five participants (95.4%) stated in the questionnaire that the pain-relieving injection they had previously received had been diclofenac (Voltaren). The remaining 6 participants were unsure of the name of the drug injected (although they had initially said they thought they had received a diclofenac injection). Of the 125 participants who stated that the injection had been diclofenac, 94.4% (n=118) were 100% sure of the name of the injection, 4.0% (n=5) were 60 - 90% sure, and 1.6% (n=2) were less than 60% sure. The data analysis was continued only for the 118 participants who indicated that they were 100% sure that the pain-relieving injection they had received had been diclo-

of the participants indicated it had been obtained from a general practitioner and 37.3% (n=44) had obtained it from a private pharmacist. Other sources are also shown in Fig. 2. In response to the question ‘If you received the injection from a pharmacist, did you have a prescription?’, 38 (66.7%) of the 57 participants who had obtained the diclofenac from either a private or a hospital pharmacy said that they had never had a prescription for it (Table 1); these 38 participants lived a median of 3 km from a medical doctor (range 1 - 32 km). In response to the question ‘Have you ever been warned that you may get a skin scar from IM diclofenac injection?’, 93 participants (78.8%) indicated that they had not been warned.

100

Participants (N=118), % Participants (N=118), %

Statistical analysis

fenac. Ten (8.5%) of these participants were identified as having a scar, of whom 5 had a BMI >30 kg/m2. Of the patients with diabetes, 18.8% had a scar, compared with 6.9% of patients without diabetes (p=0.14). Of the 118 participants who were 100% sure that the pain-relieving injection had been diclofenac, 66 (55.9%) indicated that it had been administered by a general practitioner. Diclofenac injections had also been administered by a trained nurse (n=37, 31.4%) and a pharmacist (n=29, 24.6%), and in 6 cases (5.1%) by a family member with medical training (Fig. 1). In 3 cases (2.5%) the diclofenac injection had been administered by a family member without medical training, and in 3 cases (2.5%) it was self-administered. When asked where the IM diclofenac had been obtained from (Fig. 2), 51.7% (n=61) 100 80 80 60 60 40

55.9

31.4

24.6

31.4

40 20 0 20 r l e ra tion e i 0 en ct G ra p er al n ertitio n Ge rac p

ed ain e Tr urs n

ed ainrse r T u n

5.1

24.6

2.5

5.1 t2.5 ith ed2.5 ou w er rg th t i e s m i b in ar in rw emrain Ph being t adm t h d t m s u t m i i o fe in re ac ily al r wgy m l tra th Sel te i e s mam dic i r b inil ca a F e in rw emrFaainmedi Ph m being dm m a t m n m e i lf ily al m tra m ic Se ilyical Fa ed m m Fa ed m ist

Fig. 1. Participants’ responses to the questionnaire item ‘Who administered the pain-relieving injection?’ (More than one option could be chosen.)

Participants % Participants (N=118), (N=118), %

On physical examination of the participant, the following information was recorded: body mass index (BMI) of the patient; site of the intramuscular injection(s); and skin changes at the injection sites, such as scarring, ulcer formation or changes suggestive of a healed ulcer. When a scar was observed, its size was measured and any changes in colour and/or sensation (increased or decreased sensation) associated with the scar were noted. A photograph of the scar was taken as documentation, with the patient’s consent. A pilot study conducted on five patients during the month before the study period resulted in some items on the questionnaire being rephrased. The amendments to the questionnaire were approved by the Ethics Committee before commencement of the study. The results from the pilot study were not included in subsequent data analysis.

100 80

100 60

51.7 37.3

80 40 60 20 40 0

18.6

51.7 37.3

5.9

0.9

1.7

4.2

0.9

18.6 l c l e5.9 y y rk er c c l ni ta ed ta a n a a om pi 0.9 Cli 1.7 f wo 1.7 spi 4.2 cifi 0.9 m m s ertitio H r r e o o n a a h H sp eo 0Ge rac ph ph y/ p ot lac al te ac t P N a i l l me k y p y ic iv r ed ar m or in ita ac ita Pral ne Hos ac w Cl phHo sp cifi sp ertitio rm f rm t e o o n a a a h H sp eo Ge rac ph ph y/ se p ot lac al te ur ac t P N a i N m iv sp ar Pr Ho ph t Fig. 2. Participants’ responses to the questionnaire item ‘Where did you obtain the pain-relieving injecea rs u tion?’ (More than one option could be chosen.) N

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Fig. 3. Examples of skin scars associated with previous IM diclofenac injections in three patients. The black circles on the skin are the sites marked for trigger point injections. The more extensive scar seen in panel B resulted from abscess formation requiring surgical drainage.

Most injections had been given recently, with 80 participants (67.8%) indicating that they had received their last IM diclofenac injection during the preceding year, 22 (18.6%) in the past 5 years and 16 (13.6%) >5 years previously. Of the 10 participants who had developed a scar from the diclofenac injection, 7 had received the injection within the preceding year, 1 within the preceding 5 years, and 2 >5 years previously. As shown in Table 2, the most common complication noted after the diclofenac injection reported by participants who were 100% sure that they had received IM diclofenac was pain (n=27, 22.9%), followed by pruritus (n=23, 19.5%) and erythema (n=19, 16.1%) at the site of injection. Scarring at the injection site was initially reported by only 2 patients, although 10 patients were subsequently identified on the medical examination as having a scar. Of the participants who could provide information regarding the site of injection, the majority indicated that the IM diclofenac had been administered into the buttocks (n=110, 93.2%). Other sites included the arm, thigh and shoulder, directly into the painful muscle, and the abdomen, knee and back, as shown in Table 3. The patients with scars had received a median of 15 injections (range 2 - 95), compared with a median of 6 injections (range 1 - 50) for the patients without scars (p=0.08). Of the 10 participants who had scars associated with IM diclofenac injections (Table 4), all had scars on the buttocks and 2 also had scars on the upper arm (deltoid region). No scars were observed elsewhere. Three participants experienced ongoing hyperalgesia or allodynia over the site of the scars, and 2 had decreased sensation at the site of the scar. The size of the scars ranged from 5 × 5 mm2 to 30 × 40 mm2. Skin colour changes, observed in 4 participants, were described as either a blue discolouration or hyperpigmentation. Panels A, B and C in Fig. 3 show examples of the skin lesions associated with IM diclofenac injections observed in the participants in the study. Two of the 10 participants with confirmed scarring (Table 4) and needing medical attention had also required surgical treatment in the form of incision and drainage of an abscess.

Discussion

Diclofenac is an NSAID with analgesic, anti-inflammatory and antipyretic properties. NSAIDs are used to treat a wide spectrum of ailments including musculoskeletal or joint pain, soft-tissue injury, acute gout, renal colic and postoperative pain. Parenteral administration is favoured for acutely painful conditions, with the IM route often used as a stat injection. When given intravenously, diclofenac has to be given as a slow infusion, and thrombophlebitis may result.[5] Skin complications from IM diclofenac have been reported previously. The findings of a 25-year analysis of complications due

Table 1. Responses to the questionnaire item on whether the participant had a prescription for IM diclofenac obtained from a pharmacist (N=57) Prescription used Never Sometimes Always

n (%) 38 (66.7) 9 (15.8) 10 (17.5)

Table 2. Complications noted after administration of the IM diclofenac injection (N=118) n (%) 27 (22.9) 23 (19.5) 19 (16.1) 3 (2.5) 2 (1.7) 1 (0.9) 65 (55.1)

Complications* Pain at injection site Pruritus at injection site Erythema at injection site Ulceration/skin damage at injection site Scarring at injection site Nausea No skin changes *Participants could report more than one complication.

Table 3. Sites of diclofenac injections (N=118) Site* Buttock Arm Thigh Shoulder Painful muscle Abdomen Knee Back

n (%) 110 (93.2) 6 (5.1) 6 (5.1) 2 (1.7) 1 (0.8) 1 (0.8) 1 (0.8) 1 (0.8)

*Participants could indicate more than one site.

to IM diclofenac injections published in the BMJ in 2003[6] (response to Wright et al.[4]), reviewing the Novartis Global Safety Database of spontaneous and clinical trial reports for diclofenac ampoules from 1978 to 2003, revealed 115 reports of injection site necrosis, 37 reports of site abscess, 11 reports of injection site reaction, 6 reports of necrotising fasciitis and 2 cases of necrotising myositis. Pain on injection was only reported in 9 of these recorded cases.[6] The review[6] compared these complications with the frequency that IM diclofenac was used. Over the 25-year period it was estimated that >100 million units of IM diclofenac were used (4 million per annum) in the UK. The incidence of lesions associated with IM

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Table 4. Summary of the 10 participants who developed scars associated with IM diclofenac injections Patient no. 1

BMI (kg/m2) 26.9

Diabetes mellitus No

25.7

3 4 5 6 7 8

29.8 25.0 33.8 29.4 37.2 34.3

No No Yes No Yes No

37.6

Buttock, deltoid Buttock Buttock Buttock Buttock Buttock Buttock, deltoid Buttock

32.3

Yes

Buttock

Injection site Buttock

diclofenac could therefore be regarded as diminutive. The review[6] also reported that for 10 167 IM injections of diclofenac the incidence of abscess was 0.05%, necrosis at the injection site 0.02% and pain at the injection site 5.6%. The results of the present study show a much higher risk of scars from IM diclofenac injection, with an 8.5% prevalence of scarring. The markedly different results from the Novartis Database could indicate a considerable under-reporting of skin lesions resulting from diclofenac injections. While skin scars can be unsightly or painful (30% of the scars in this study were associated with hyperalgesia or allodynia), the skin complications of IM diclofenac can have more serious results. A particularly severe skin complication of IM diclofenac is Nicolau syndrome (embolia cutis medicamentosa). This is a rare occurrence that has followed IM injections of diclofenac and other common drugs, including other NSAIDs, corticosteroids and penicillin. The clinical presentation is typically pain around the injection site, followed by erythema, liveoid patch, haemorrhagic patch and finally necrosis of the skin, subcutaneous fat and muscle tissue. Several case reports of Nicolau syndrome following intramuscular diclofenac have been published, with severe scarring and even death as an outcome.[6-8] Nicolau syndrome was first described in 1925 following the use of bismuth salts for the treatment of syphilis. This phenomenon has now been related to the administration of a variety of drugs such as corticosteroids, local anaesthetics and antihistamines.[7] The pathogenesis of Nicolau syndrome is not

Injection site complications Erythema, abscess Pain, scarring, pruritus, ulcer Pain, pruritus Pain, pruritus Pruritus Pruritus, ulcer Pain, abscess Pain, erythema, pruritus None

Treatment required Medical; incision and drainage Medical Incision and drainage Medical

well understood, but probably involves acute vasospasm, arteritis and thromboembolic occlusion of small arteries resulting in end-organ damage. Diclofenac is associated with the vasoconstrictive phenomenon as it inhibits prostaglandin synthesis due to cyclooxygenase inhibition, and can therefore cause Nicolau syndrome or milder forms of skin necrosis.[9] The manufacturer’s instructions for IM diclofenac are very detailed and explicit, clearly stating that the injection should be administered by deep intragluteal injection (not in other sites such as the leg or arm), using strict aseptic techniques and not exceeding the recommended dose. It also states that subcutaneous and intravascular injection must be avoided to prevent skin scarring.[6,8] Furthermore, the Z-track method of IM injection, as described and illustrated by Lie et al.,[8] can minimise subcutaneous irritation by blocking the needle track after injection and should be adopted as a standard procedure. According to this method, with the skin, subcutaneous fat and muscle in a normal position, the skin and subcutaneous layer should be pulled down 1 cm to de-align with the underlying muscle. The needle should be inserted at 90o to administer the injection into the muscle and then withdrawn. When the finger is released to break the needle track, the drug is trapped inside the muscle.[8] In SA, IM diclofenac is a schedule 3 drug and should only be dispensed to patients with chronic pain with a prescription by a medical doctor. However, diclofenac may be dispensed by a pharmacist without a prescription as a schedule 2 drug (Medicines

February 2017, Print edition

and Related Substances Act 101 of 1965, Section 22A(5)(a)) for the emergency treatment of acute gout and post-traumatic injuries for 5 days only.[10,11] IM diclofenac should only be administered by a trained healthcare professional. A pharmacist may administer IM diclofenac if he or she has received the necessary training and is competent in the technique. Our findings show that IM diclofenac was inappropriately dispensed by some pharmacists, as twothirds of the patients who were dispensed IM diclofenac from a pharmacy received it without a prescription – a matter of concern, because it implies that some pharmacists dispense this drug illegally. This cannot be excused by claiming that these individuals were not able to visit a doctor to obtain a prescription for the injection because they lived in remote, rural areas, as they lived on average only a few kilometres away from a medical doctor. This study did not investigate whether the participants who received the injection from a pharmacist received it from one trained in the correct technique. This may be investigated in a further study. A concerning finding was that several participants received IM diclofenac injections from an unauthorised person or even administered the injection themselves. This suggests that when IM diclofenac is dispensed, there should be tighter regulations to ensure that the patient only receives the injection from an appropriately trained healthcare professional. Incorrect administration was confirmed by the observation that two of the scars from IM diclofenac were on the upper arms of the participants. Before receiving IM diclofenac, patients should be warned of the potential for skin scarring, which is clearly stated in the package insert. The scars are probably more common than previously thought, as 8.5% of the participants in this study who had received IM diclofenac had scars from this injection. Despite this cautionary note, 78.8% of the study population indicated that they had never been warned about skin scarring as a potential side-effect. Medical professionals should warn patients against this side-effect when prescribing IM diclofenac, as there may be legal implications if scars develop. The skin scars from IM diclofenac given at the correct intragluteal site may not be visible to the affected individual and therefore not necessarily of concern to them. Some people, however, do not wish to have scars on their buttocks for their own personal reasons, and patients should therefore be informed of the possible risk before IM diclofenac

IN PRACTICE

is prescribed. In this study, some scars were large and some were chronically painful, demonstrating that there is notable morbidity associated with these scars. Patients with diabetes are at risk of developing infections after any invasive procedure, and an infected IM diclofenac injection site increases the risk of scar formation. We suggest that diabetes mellitus should be considered a risk factor for developing scars from IM diclofenac. The prevalence of skin scars in diabetic participants was more than double that in non-diabetics, although the difference was not statistically significant. A larger study is necessary to determine the role of diabetes as a risk factor.

Study limitations

A major limitation of this study is that it relied on the memory of the participants completing the questionnaire. Recall bias may have exaggerated symptoms. They may not accurately have recalled all the IM diclofenac injections they had received in the past, or other related facts, or may have had an injection with another medication and erroneously said that it was diclofenac. Some participants did not answer all the questions, and data were lost in this small number of cases.

Conclusions

A larger prospective study to investigate the risk of skin scars from IM diclofenac injections is required. Until this has been done, patients should be warned that they may develop a skin scar after IM diclofenac, as stated in the package insert. This warning should

be documented as having been given, and oral diclofenac should be prescribed where possible. Acknowledgements. We thank Dr Daleen Struwig, medical writer/editor, Faculty of Health Sciences, University of the Free State, for technical and editorial preparation of the manuscript. 1. National Department of Health, South Africa. Standard Treatment Guidelines and Essential Medicines List for South Africa. Hospital level adults. 2012 edition. http://www.kznhealth.gov.za/pharmacy/ edladult_2012.pdf (accessed 30 June 2016). 2. South African Government. Supply and delivery of small volume parenteral and insulin devices to the Department of Health for the period 1 June 2014 to 28 February 2017. HP06-2014 SVP. Government Tender Bulletin 2012;564(2732). http://www.gov.za/sites/www.gov.za/files/ten_2732.pdf (accessed 30 June 2016). 3. World Health Organization. 19th WHO Model List of Essential Medicines (April 2015). www.who.int/ medicines/publications/essentialmedicines/EML2015_8-May-15.pdf (accessed 30 June 2016). 4. Wright PJ, English PJ, Hungin APS, Marsden SNE. Managing acute renal colic across the primary-secondary care interface: A pathway of care based on evidence and consensus. BMJ 2002;325(7377):1408-1412. http://dx.doi.org/10.1136/bmj.325.7377.1408 5. Chung CH. The use of injectable non-steroidal anti-inflammatory drugs in local accident and emergency practice. Hong Kong J Emerg Med 2002;9(2):65-71. http://hkcem.com/html/publications/ Journal/2002-2/065-071.pdf (accessed 30 June 2016). 6. O’Sullivan DP, Collins J. Intramuscular diclofenac: 25 year worldwide safety perspective is vital to consider. BMJ 2002;325:1408. http://dx.doi.org/10.1136/bmj.325.7377.1408 7. Panariello L, Ayala F. Nicolau syndrome following intramuscular diclofenac injection: A case report. Dermatol Ther 2008;21(Suppl 1):S10-S12. http://dx.doi.org/10.1111/j.1529-8019.2008.00195.x 8. Lie C, Leung F, Chow SP. Nicolau syndrome following intramuscular diclofenac administration: A case report. J Orthop Surg (Hong Kong) 2006;4(1):104-107. http://dx.doi.org/10.1177/230949900601400123 9. Park HJ, Kim MS, Park NH, Jung SW, Park SI, Park CS. Sonographic findings in Nicolau syndrome following intramuscular diclofenac injection: A case report. J Clin Ultrasound 2011;39(2):111-113. http://dx.doi.org/10.1002/jcu.20743 10. South African Legal Information Institute (SAFLII). Medicines and Related Substances Act 101 of 1965 – Regulations and Notices – Government Notice R510. http://www.saflii.org/za/legis/consol_reg/ marsa101o1965rangnr510723/ (accessed 10 January 2017). 11. Medicines Control Council of South Africa. Scheduling of substances for prescribing by authorised prescribers. http://www.mccza.com/Publications/DownloadDoc/83 (accessed 28 August 2016).

Accepted 24 October 2016.

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

A biobank to support HIV malignancy research for sub-Saharan Africa

J W Schneider,1 MB ChB, MMed, FCPath; M Sanderson,1 PhD; D Geiger,1 MSc; M Nokta,2 MD, PhD; S Silver,3 DA Division of Anatomical Pathology, National Health Laboratory Service, Tygerberg Academic Hospital and Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa 2 Office of HIV and AIDS Malignancy, AIDS Cancer Clinical Program, National Cancer Institute, National Institutes of Health, Bethesda, Md, USA 3 Department of Microbiology, Immunology, and Tropical Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC, USA 1

Corresponding author: J W Schneider (jws2@sun.ac.za)

Sub-Saharan Africa has one of the highest incidences of infection with HIV globally, but more people in this region are living longer owing to increased access to antiretroviral therapy. However, along with increased care and treatment, this population is expected to have an increase in HIV-associated cancers, as is being seen in the USA and other developed countries. To support translational research in HIV-associated cancers, Stellenbosch University in Cape Town, South Africa, was funded to house the state-of-the-art AIDS and Cancer Specimen Resource Sub-Saharan Africa Regional Biorepository (SSA RBR) to proactively obtain, manage and process biospecimens and associated clinical data representing both AIDS-defining and non-AIDS-defining cancers for research. The SSA RBR furthermore functions as the biorepository for AIDS Malignancy Consortium sub-Saharan clinical trial activities in this region. Although the site had much experience with cryopreservation and storage of specimens, capacity building revolving around operations under International Society for Environmental and Biological Resources/National Cancer Institute best practices took place in such areas as custodianship v. ownership, data sharing and facilities management. The process from selection until launch took 14 months. S Afr Med J 2016;106(9):867-869. DOI:10.7196/SAMJ.2016.v106i9.10891

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The generation of quality data in biomedical research is dependent on utilisation of high-quality specimens. Although scientific publications overflow with research results and mounds of data, not necessarily all bring useful results. As stated by the US National Cancer Institute (NCI), the lack of standardised high-quality biospecimens is the cause of the lack in progress in cancer research.[1] High-quality research material and matching clinical data are also essential to comply with growing international requirements from regulatory authorities and funding agencies that biospecimens should be handled according to best practices. The latter include appropriately qualified staff who operate in a facility that can demonstrate high-quality management of research specimens pertaining to conditions of sample collection, preparation, storage and transportation, secure record-keeping, processes that regulate access to and utilisation of biospecimens, long-term sustainability strategies, and compliance with ethical and legal requirements.[2] After collection, specimens for research are usually stored until they are needed. Ubiquitous in most research laboratories is the –80˚C freezer, loaded with saved specimens from one or more investigators. However, in view of the globally expanding drive for population-based and evidence-based research, access to and utilisation of biospecimens in this familiar environment are growing to the scale of requiring a biobank/biorepository. A biobank is defined as an entity that acquires, preserves, develops and distributes biological specimens along with information, technology, intellectual property, and standards for the advancement and application of scientific knowledge.[3] Biobanks operated under best practices are important partners to translational health researchers, as they ensure high-quality specimens for their studies and employ functions and policies to ensure not only sound ethics but also quality through technical standards and operational practices. Additionally, some countries have legislation[4] covering the collection and use of human specimens in research. Governmental agencies and professional organisations such as the International Society for Environmental and Biological Resources (ISBER) produce standards to set a benchmark for quality.[5,6] Variations in biobanks exist. Biobanks can be devoted to the collection of human specimens (e.g. tissues, DNA/RNA, blood, sperm) or animal, plant (e.g. seeds), microbial and environmental specimens. The biobank’s mission determines its scope and size. For example, biobanks related to human research can support basic science, translational science or clinical research. Biobanks vary in their size and in the type of specimens they store, and in the case of human biobanks, according to whether the specimens are from healthy individuals or from individuals with disease. Specimens can be banked from a single research project or represent diverse research areas. The structure of a biobank can take numerous forms. If a bank is traditional, it holds specimens and data that are stored centrally. A procurement biobank collects specimens to meet a specific need, and may only have a limited data set. Virtual biobanks have multiple collection locations but a central location for the storage of data. A fully virtual/distribution bank has data and multiple collections and storage sites.[7] The AIDS and Cancer Specimen Resource (ACSR), in existence since 1994, operates under a cooperative agreement between the NCI and various institutions. Its mandate is to collect and preserve tissues and biological fluids along with clinical data from patients with HIV-related malignant tumours and normal controls, which will be dispersed to qualified investigators.[8,9] The ACSR recently expanded its scope to include a regional biorepository to serve sub-Saharan Africa (SSA RBR), located in the Division of Anatomical Pathology, National Health Laboratory Service (NHLS), Tygerberg Academic

Hospital and Faculty of Medicine and Health Sciences, Stellenbosch University (Cape Town, South Africa (SA)). Under the auspices of the ACSR, the SSA RBR aims to proactively obtain, manage and process biospecimens (tissues, body fluids and derivatives, such as DNA and RNA) representing both AIDS-defining cancers (i.e. Kaposi’s sarcoma, non-Hodgkin’s lymphoma, cervical cancer) and non-AIDS-defining cancers (e.g. lung cancer, breast cancer, colon cancer) and associated clinical data (e.g. date of diagnosis, site of biopsy, antiretroviral and cancer therapies, CD4 counts). Ethics approval was secured and regulatory aspects ensured for specimen movement within the continent. Additional aims include the provision of information and training related to biobanking for African researchers and scientists, and the establishment of a community advisory board and community outreach portal to educate and to inform the public about the benefits and implications of biobanking for the health of African populations. The SSA RBR also hosts the AIDS Malignancy Consortium (AMC) biorepository for support of its clinical trial activities in SSA. The AMC[10] supports innovative clinical trials for optimising treatment and prevention of AIDS-related cancers. The AMC was established in 1995 to perform domestic studies in the USA. In the past 5 years the AMC widened its scope to conduct trials in international settings, particularly in SSA. The SSA RBR supports the biorepository requirements for AMC clinical trials performed on the African continent. This function involves receiving and storage of specimens under controlled conditions before sending them to specified core laboratories in Africa and globally. The process of establishing a biobank to fulfil both the ACSR and AMC mandates is described.

Developing the biobanking concept

Acceptance of biobanks to support research in SA and other African countries cannot be automatically assumed. One must be sensitive to past infringements of ethicoregulatory standards by international researchers, where many Africans repeatedly witnessed biological specimens leaving the continent to other countries[11] for research with no clear benefit to the African communities. Scientifically and technologically, establishing the biobank was not a concern, but various concepts covered by the NCI and ISBER best practices were new and required adequate time to be adopted. Concomitantly, it was essential that this new site would relate to the ACSR mission ‘to acquire, store, and equitably distribute tumor tissues, biological fluids, and other biospecimens and associated clinical information from patients with HIV-associated malignancies to the scientific research community-at-large’. The concept and scope of the biobank were easily accepted, particularly since the prevalence of HIV/AIDS in SA is one of the highest in the world. The biobank’s location in the immediate proximity of the laboratories of the Division of Anatomical Pathology at Tygerberg Academic Hospital facilitated the identification of qualified individuals who supported the establishment of the RBR infrastructure, and adoption of the manual of operations, standard operating procedures and bioinformatics platform of the ACSR. Besides discussions related to laboratory procedures for biobanks, and of the importance of preanalytical variables and controlling for them on research specimens,[12,13] selected best practices identified for more in-depth exploration are presented below.

Organisation, management and governance

Stellenbosch University, the site chosen for the new AMC/ACSR SSA biorepository, already had in-house repositories holding research study specimens for storage and distribution. In the existing scenarios, all specimens in the respective repositories

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were obtained as part of approved research projects and controlled and managed by the respective study investigators. Stellenbosch University already had regulatory offices in place to handle entry and exit permits and material transfer agreements; consequently, the mission of the AMC biorepository fitted aptly with other established projects. In addition, most of the African countries involved with AMC trials were already research partners with Stellenbosch University. What was new, however, was the ACSR mission of procuring specimens to be used by investigators at that institution as well as by individuals from outside the institution, outside SA, and even outside Africa. At this point, in-depth discussions occurred regarding: (i) the ACSR mission; (ii) the functions of the ACSR regional biorepositories; (iii) the governance of the ACSR; (iv) how the new SAA RBR would fit into the present ACSR; (v) the mechanism for investigators to request specimens; (vi) how the requests were reviewed; and (vii) distribution of biospecimens and information sets. A specific challenge emerged in view of the mandate by the NCI to ensure that findings derived from its inventory would benefit Africa and assist in building capacity for research. The SSA RBR would be unique within the ACSR in that investigators desiring specimens from its collection would need to be African or collaborating with an African researcher. This mission required various discussions between individuals ranging from other ACSR directors and members of the Health Research Ethics Committee (HREC) to people working with regulatory issues, e.g. entry/exit permits and material transfer agreements. The SSA RBR complies with the South African National Health Act 61 of 2003 and adheres to the Ethics in Health Research Principles, Processes and Structures, as published in 2015 by the SA National Department of Health. Following extensive discussions with relevant authorities, the SSA RBR obtained permission from the Department of Health in the Western Cape Province and support from the NHLS. The SSA RBR operates according to inspection criteria as determined and monitored by the inspector of anatomy from the Western Cape Department of Health. It conforms and contributes to evolving ethicoregulatory detail and policies on biobanking and biospecimen utilisation in SA, and will pursue similar involvement in other SSA countries.

Custodianship v. ownership

The ACSR’s mandate to collect specimens and make them available to any African or collaborating researcher approved through peer review was a new concept, and one requiring some discussion. A major discussion with the HREC revolved around Stellenbosch University’s role as the custodian of the specimen (i.e. the caretaker of the specimen that ensures the privacy of the donor, the integrity of the specimen and its associated data, and that use of both conforms to informed consent) rather than its role as owner of the specimen (that ‘donates’ its specimen to research and can retract that permission at any time). Also needing clarification was concern regarding the return of data from successful investigators who performed research on the SSA RBR specimens. The ACSR encourages successful recipients of ACSR samples to share their findings with the ACSR to enrich the remaining specimens’ value. However, as the specimens are only used for research and not clinical decisions, the donor of a specimen is never notified about investigative findings; rather, investigators share and disseminate findings through published articles and presentations of research findings at scientific meetings, acknowledging the ACSR.

Community awareness and involvement

The SSA RBR promotes ethical and equitable biobanking policies for community and public education regarding biobanking and its role and value in improving the health of people on the African continent. For this purpose, the SSA RBR has developed a marketing and promotion strategy that is based on established ACSR principles but specifically directed at various SA target groups. Briefly, the strategy includes regular sharing of information pertaining to the SSA RBR with clinicians, health authorities, the general public and selected SA and African researchers; close collaboration with established researchers with African involvement to explore recruitment of specimens from clinical trial patients, involvement of selected societies that are active in the field of HIV and cancer, co-operation with community advisory boards, and regular presentations at regional congresses are further components of the marketing and promotion strategy. A further responsibility taken on by the ACSR and its role of custodianship is the reporting of data found by investigators utilising ACSR specimens. The ACSR lists publications by inventory users on its website (http://acsr.ucsf.edu). Specific to the SSA RBR is sharing of information and results through the SSA RBR Community Advisory Board. This group of individuals comprises lay people working within the fields of or living with either HIV or cancer. The SSA RBR will periodically present, in lay language, summaries of the proposed research and the findings from research performed on the specimens to the group. This is a work in progress, with emphasis on the appropriate level of presentation of information to facilitate comprehension.

Discussion

The interval from award to launch of the SSA RBR was 14 months. The approach involved taking small steps at a time, with different levels of involvement from the administration, the faculty and the principal staff as necessary. Long-range plans include bringing in specimens from other sites in the Western and Eastern Cape provinces, as well as the rest of SA and eventually SSA. Targeted discussions were held between the biorepository leadership and the stakeholders, ethics officers and regulatory officials at various steps of biobank development. The biobank currently has full HREC approval from the Faculty of Medicine and Health Sciences at Stellenbosch University and Tygerberg Academic Hospital, the tertiary academic hospital of Stellenbosch University. Meetings with most of the clinical departments pertinent to HIV malignancies have been held. The SSA RBR nurses have been trained as research nurses, and they request informed consent from patients identified by clinicians. The inventory is growing, and the first request for biospecimens (by an African investigator) has occurred. All requests for biospecimens will be vetted by an independent research evaluation and decision panel composed of experts identified by the NCI, including one or two representatives from Africa. Final approval for dispersal of ACSR biospecimens lies with the ACSR executive committee, in which the director of the SSA RBR is a member. The SSA RBR director has begun outreach to other hospitals in Cape Town and the surrounding areas to raise the awareness of clinicians, scientists and junior investigators of the existence of the biobank. This effort involves meeting with clinical heads and pathologists from each hospital, and presenting the ACSR mission and the operation logistics envisioned for collaborating sites. In

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this scenario, the SSA RBR will work with the site to produce a standard operating procedure for informed consent and collection and transport of the specimen and data to the SSA RBR. Appropriate support will be supplied in the form of personnel needed for consent and collection, a pathologist for verification of diagnosis, and transport. These actions go towards the long-range plan for the SSA RBR to eventually house inventory from all of SSA.

Conclusion

The SSA RBR is a resource to benefit researchers, patients and communities in Africa. It offers numerous advantages, including operation under accepted best practices in biorepository management, with quality management in governance, personnel, operations and safety. It furthermore offers an opportunity to monitor trends in biospecimen research from an African perspective. Through collaboration with other institutions in SSA, the SSA RBR creates an opportunity to develop unique specimen collections and clinical data sets to promote multi-institutional collaborative research in the field of HIV-related cancers. The SSA RBR serves as a site for future National Institutes of Health/NCI cancer activities in Africa. 1. National Cancer Institute. Biospecimen and biorepository research branch website. http://biospecimens.cancer.gov/about/overview.asp (accessed 8 July 2015).

2. Somiari SB, Somiari RI. The future of biobanking: A conceptual look at how biobanks can respond to the growing human biospecimen needs of researchers. Adv Exp Med Biol 2015;864:11-27. http:// dx.doi.org/10.1007/978-3-319-20579-3_2 3. Cunningham A, Martinez RM, Hernandez DR, et al. The microbe farms: Microbial biorepositories in clinical microbiology. Clin Microbiol Newsl 2014;36(6):41-48. http://dx.doi.org/10.1016/j. clinmicnews.2014.02.003 4. García-Merino IM, Consuegra I, Jiménez JL, et al. Specific legislation on biobanks in Spain. Biopreserv Biobank 2015;13(3):207-211. http://dx.doi.org/10.1089/bio.2014.0070 5. NCI Best Practices for Biospecimen Resources. Table of contents. 2011. http://biospecimens.cancer. gov/bestpractices/toc/ (accessed 24 June 2015). 6. Campbell LD, Betsou F, Garcia DL, et al. Development of the ISBER Best Practices for Repositories: Collection, storage, retrieval and distribution of biological materials for research. Biopreserv Biobank 2012;10(2):232-233. http://dx.doi.org/10.1089/bio.2012.1025 7. Reijs BLR, Teunissen CE, Goncharenko N, et al. The central biobank and virtual biobank of BIOMARKAPD: A resource for studies on neurodegenerative diseases. Front Neurol 2015;15(6):216. http://dx.doi.org/10.3389/fneur.2015.00216 8. Ayers LW, Silver S, Orenstein JM, et al. The AIDS and cancer specimen resource. Methods Mol Biol 2011;675:193-203. http://dx.doi.org/10.1007/978-1-59745-423-0_8 9. Ayers LW, Silver S, McGrath MS, et al. The AIDS and cancer specimen resource: Role in HIV/AIDS scientific discovery. Infect Agent Cancer 2007;2:7. http://dx.doi.org/10.1186/1750-9378-2-7 10. AIDS Malignancy Consortium. http://pub.emmes.com/study/amc/public/index.htm (accessed 5 March 2016). 11. Staunton C, Moodley K. Challenges in biobank governance in Sub-Saharan Africa. BMC Med Ethics 2013;14:35. http://dx.doi.org/10.1186/1472-6939-14-35 12. Lehmann S, Guadagni F, Moore H, et al. International Society for Biological and Environmental Repositories ISBER Working Group on Biospecimen Science F. Standard preanalytical coding for biospecimens: Review and implementation of the Sample PREanalytical Code (SPREC). Biopreserv Biobank 2012;10(4):366-374. http://dx.doi.org/10.1089/bio.2012.0012 13. Ellervik C, Vaught J. Preanalytical variables affecting the integrity of human biospecimens in biobanking. Clin Chem 2015;61(7):914-934. http://dx.doi.org/10.1373/clinchem.2014.228783

Accepted 3 May 2016.

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

CRISPR-Cas: Revolutionising genome engineering

S A Nicholson, PhD; M S Pepper, MB ChB, PhD, MD Institute for Cellular and Molecular Medicine; South African Medical Research Council Extramural Unit for Stem Cell Research and Therapy; and Department of Immunology, Faculty of Health Sciences, University of Pretoria, South Africa Corresponding author: M S Pepper (michael.pepper@up.ac.za)

The ability to permanently alter or repair the human genome has been the subject of a number of science fiction films, but with the recent advent of several customisable sequence-specific endonuclease technologies, genome engineering looks set to become a clinical reality in the near future. This article discusses recent advancements in the technology called ‘clustered regularly interspaced palindromic repeat (CRISPR)-associated genes’ (CRISPR-Cas), the potential of CRISPR-Cas to revolutionise molecular medicine, and the ethical and regulatory hurdles facing its application. S Afr Med J 2016;106(9):870-871. DOI:10.7196/SAMJ.2016.v106i9.11061

Within the repeating As, Cs, Gs and Ts of the human genome is the blueprint for all the organs and tissues of our bodies, from skin and hair to the complex neuronal pathways that make up the brain. This information is contained in six billion base pairs of DNA that reside in the nucleus of every nucleated cell, half the information from our mothers and half from our fathers. Since the launch of the human genome project more than 20 years ago, understanding of DNA and its various interactions that make us who we are has increased exponentially. It has also been discovered that even small, seemingly insignificant changes in the sequence of our DNA can have drastic consequences. The search is on for tools that will allow these mutations to be changed to correct the DNA sequence, in much the same way as one

might correct a spelling error in a manuscript before publication – editing the genome, if you will.

Unpacking the basics

The term ‘editing’ implies a precise and predictable process by which the genome might be changed, and for the past 10 years – at least – the search for the best tool to do this has been on. Identification of a tool to change the genome started as whisper, but during the past 5 years it has grown to a deafening roar and at last there seems to be a technology with genuine potential to revolutionise the field of genome engineering. Clustered regularly interspaced palindromic repeat (CRISPR)-associated genes (CRISPR-Cas) have

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emerged as a novel class of sequence-specific endonucleases with unparalleled flexibility, cost-effectiveness and ease of application. This technology is derived from a bacterial pathway that allows the organism to detect and degrade invading genetic material. Although there are three naturally occurring types of CRISPR-Cas technologies, only the type II system has been proven to be relevant to the genome engineering field so far. Initial work by Jinek et al.[1] has seen the progression of CRISPR-Cas from an interesting bacterial phenomenon to a potentially useful molecular tool.Later work by Cong et al.[2] ushered CRISPR-Cas to the forefront of the gene-editing technology race.In 3 years, CRISPR-Cas has outshone, outpaced and outperformed the majority of the other gene editing technologies, including the broadly applied zinc finger nucleases and transcription activator-like effector nucleases.

Acknowledging flaws

This is not to say that CRISPR-Cas has been without its problems. One of the major considerations is the predictability and accuracy of targeted outcomes of the DNA cleavage events, and in the earliest iterations of this technology CRISPR-Cas was a dismal failure. Early estimates of unintentional and potentially catastrophic cleavage events suggested that the sequence specificity for targeting might be off by as much as much as 25%, with DNA double-strand breaks occurring at sites with as little as 75% sequence homology to the targeted locus.[3] In a field reliant on absolute precision with zero tolerance for error, this was an early setback for the technology. However, diligent investigation has yielded important results, and in early 2016 two research groups from the Broad Institute identified four novel mutations in the Cas9 protein that rendered Cas9 totally reliant on 100% sequence homology to facilitate cleavage.[4] These groups used next-generation sequencing of the whole genome to establish that no unintended breaks had been introduced at other sites – so-called ‘off-target’ effects. This has potentially delivered the Holy Grail for gene editing, a technology that is now precise and accurate with no potentially mutagenic side-effects, and with this quantum leap in technology we can finally start looking to clinical applications.

Therapeutic applications of CRISPR-Cas

Genome editing has already broadened our ability to investigate the contribution of specific genes and mutations to disease by facilitating the creation of accurate cellular and animal models. This is certainly where CRISPR-Cas9 has cut its teeth, while several groups have also worked to improve the targeted activity of CRISPR-Cas9 and its overall safety. This is by no means where the application of gene editing ends. A particularly attractive application is correction of underlying mutations to treat diseases, particularly in conditions that have proved to be refractory to traditional therapies. Genome editing-based therapy can be accomplished in a number of ways, including correction or inactivation of deleterious mutations, introduction of protective mutations, addition of therapeutic transgenes and disruption of viral DNA. Work is already underway across the globe to translate the potential of targeted gene therapy into viable clinical applications. This includes the recapitulation of the Δ32 mutation in the CCR5 gene, rendering cells immune to HIV;[5] the correction of deleterious mutations in the DNA that result in a number of inherited diseases, including cystic fibrosis, Fanconi’s anaemia, β-thalassaemia[6] and Duchenne’s muscular dystrophy;[7] the integration of exogenous DNA that returns function to mutated proteins, where the mutations are too

large to allow simple correction; the integration of protective genes that confer therapeutic potential to specific cell types; and therapeutics that would allow us to target and eliminate viral DNA such as HIV, reducing the burden of latent viral infections.[8] These studies have produced promising results, and the number of indications under investigation for gene editing is growing exponentially. Gene editing, and in particularly CRISPR-Cas technologies, look set to revolutionise the treatment of a wide variety of diseases in the near future.

Ethical questions

As with any progressive idea, the implementation of genome engineering is not without ethical and regulatory concerns. Many of the breakthroughs in the genome engineering sphere have been viewed as huge scientific triumphs, but the translation of these technologies from the bench to the bedside is not without ethical, legal and social issues requiring vigorous debate. First, can we predict the ultimate consequences of gene editing on the evolution of the human race? Mutation is the backbone of the evolutionary process, and developing a technology that introduces novel mutations while repairing others could have a profound effect on the direction of human natural history. The only answer to this question seems to be that time will tell. We should, however, make informed decisions around the types of genome editing we wish to undertake. Second, should we allow embryonic/germline engineering, or only permit somatic cell engineering? The genome engineering community has spent much time debating this point, and at the end of 2015 reached a consensus at a meeting in Washington that involved the global community. Genome engineering for research purposes should be allowed in both somatic and embryonic cells, but with important ethical concerns and the concerns around safety, genome engineering for therapeutic applications should be restricted to somatic cells. Moreover, human beings have the right to health, and as such it is imperative that we find ways to ensure that genome engineering as a therapeutic modality is accessible to all people and not only to those who can afford it. Along with the ethical concerns around genome engineering, this rapidly evolving field also presents novel regulatory questions. As more and more clinical applications are developed, so the burden on developing processes for their evaluation by various regulatory boards will increase. How will trials select control groups? Will it be ethical to engineer healthy individuals? How will we compensate for unknown side-effects? What will the threshold be for acceptable off-target mutations? These and other questions will need to be answered before gene editing can be applied in a therapeutic setting.

The future

In conclusion, despite a number of important ethical and practical concerns, genetic engineering remains set to shape the future of molecular medicine. This technology has the potential to fundamentally alter the way we treat diseases that have a genetic/genomic component, and with careful consideration, continued discussion and improved sharing of information on a global scale, CRISPR-Cas looks as if it may become one of the most valuable medicinal tools of the 21st century. CRISPR-Cas was only discovered 3 years ago, and while navigating the road to its clinical application is likely to require a great deal of effort, one can only imagine what the landscape of genome engineering will look like in another 5 or even 10 years.

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Sources of funding. South African Medical Research Council University Flagship and Extramural Unit awards. 1. Jinek M, Chylinski K, Fonfara I, et al. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science 2012;337(6096):816-821. http://dx.doi.org/10.1126/ science.1225829 2. Cong L, Ran FA, Cox D, et al. Multiplex genome engineering using CRISPR/Cas systems. Science 2013;339(6121):819-823. http://dx.doi.org/10.1126/science.1231143 3. Lin Y. CRISPR/Cas9 systems have off-target activity with insertions or deletions between target DNA and guide RNA sequences. Nucleic Acids Res 2014;42(11):7473-7485. http://dx.doi.org/10.1093/nar/gku402 4. Kleinstiver BP, Pattanayak V, Prew MS, et al. High-fidelity CRISPR-Cas9 nucleases with no detectable genome-wide off-target effects. Nature 2016;529(7587):490-495. http://dx.doi.org/10.1038/ nature16526

5. Kang H, Minder P, Park MA, Mesquitta W-T, Torbett BE, Slukvin II. CCR5 disruption in induced pluripotent stem cells using CRISPR/Cas9 provides selective resistance of immune cells to CCR5tropic HIV-1 virus. Mol Ther Acids 2015;4(12):e268. http://dx.doi.org/10.1038/mtna.2015.42 6. Xie F, Ye L, Chang JC, et al. Seamless gene correction of β-thalassemia mutations in patient-specific iPSCs using CRISPR/Cas9 and piggyBac. Genome Res 2014;24(9):1526-1533. http://dx.doi.org/10.1101/ gr.173427.114 7. Mendell JR, Rodino-Klapac LR. CRISPR/Cas9 treatment for Duchenne muscular dystrophy. Cell Res 2016;26(5):513-514. http://dx.doi.org/10.1038/cr.2016.28 8. Kennedy EM, Kornepati AVR, Cullen BR. Targeting hepatitis B virus cccDNA using CRISPR/Cas9. Antiviral Res 2015;123:188-192. http://dx.doi.org/10.1016/j.antiviral.2015.10.004

Accepted 30 May 2016.

MEDICINE AND THE LAW This open-access article is distributed under CC-BY-NC 4.0.

Exporting DNA – striking a balance between preventing exploitation and promoting innovation

M S Pepper, MB ChB, PhD, MD Institute for Cellular and Molecular Medicine; South African Medical Research Council Extramural Unit for Stem Cell Research and Therapy; and Department of Immunology, Faculty of Health Sciences, University of Pretoria, South Africa Corresponding author: M S Pepper (michael.pepper@up.ac.za)

DNA contains the blueprint of life. Variations in the script determine the great diversity that characterises our planet. As the analysis of large datasets derived from DNA reveals the hidden secrets of normal and abnormal structure and function as well as our ancestry, the movement of DNA between research laboratories is becoming commonplace. DNA is a resource that can be used for the benefit or to the detriment of the individuals and communities from which it is derived. But can DNA be treated as a simple commodity? How do we deal with questions such as sovereignty, discrimination and commercialisation? What underlies the current trends in attempting to regulate the movement of DNA? And how can we achieve a balance between preventing exploitation and promoting innovation? This brief overview attempts to contextualise the current landscape in South Africa with regard to the DNA that is destined to leave our shores. S Afr Med J 2017;107(2):106-107. DOI:10.7196/SAMJ.2017.v107i2.12122

Given the great genetic diversity of South Africa (SA)’s population and our high burden of disease, researchers and industry are keen to access the information contained in the DNA of our people. DNA from southern Africans is highly coveted, especially that derived from indigenous populations such as the San. Considered to be one of the oldest living populations on the planet, the San originate from the original hunter-gatherer populations that roamed the subcontinent before the arrival of populations from the north, either by land or by sea.

Preventing exploitation

With its history of colonisation and exploitation, Africa is now pushing back.[1] Many countries are tightening up the processes required for the export of DNA, and SA is no exception.[2] Our legislation clearly states that all DNA that leaves our shores requires an export permit in order to do so.[3] In the past, this was all that was required. This has allowed for the mass export of DNA, particularly by pharmaceutical companies conducting clinical trials, often for purposes of undertaking pharmacogenetic analyses.[4] However, as the problem of exploitation is still fresh in the minds of many South Africans, and with the realisation that this information could be used in the design of pharmaceuticals that might ultimately find their way back to the country and be used to treat its diverse peoples,

the question arises whether this cycle could become a form of exploitation itself, if not correctly managed. In response to these issues, which are now uppermost in the minds of many of the country’s regulators, the requirements for export of DNA are increasing. It is no longer sufficient just to complete an export permit request form supplied by the National Department of Health (NDoH); additional documentation that would apparently limit this exploitation is now required. This includes: (i) a material transfer agreement (MTA) that details what will be done with the DNA and how the information derived therefrom will be used; and (ii) where appropriate, approval from a research ethics committee when the DNA is being used for research purposes (Department of Health, personal communication 14 October 2016). Three important points that complement the above need to be considered: (i) the details in the MTA must reflect what is stipulated in the informed consent document, and the latter should ideally form part of the submission to the NDoH, although this is not a formal requirement at present; (ii) additional information regarding commercial exploitation of the data and possible benefit-sharing arrangements must be dealt with in the MTA; and (iii) information on the ownership/custodianship of the DNA (and its eventual destruction) and the data derived therefrom should be clearly set out.

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There is a lack of agreement between the DoH, the research community, genetics service providers and industry regarding the need for an MTA. As a result, a discretionary approach has been requested based on whether or not the activity for which the DNA will be utilised is fee-for-service, research or has commercial intent. Ownership of DNA and data is a thorny issue for which there is at present no consensual view.[2] It is not only important in the context of intellectual property ownership and commercialisation, but also with regard to judgemental and discriminatory attitudes that impact negatively on the individuals or populations concerned. The notion of genomic sovereignty, which refers to the need to regulate ownership of human genetic resources, is an area of intense debate.[5-7] So is the notion that commercialisation of DNA, which is derived from cells that constitute organs and tissues, could be viewed as ‘trading’, which in the context of organs is clearly not well viewed. And what about the data that are derived from DNA? How should these be viewed, since they not only contain information that may be of importance from the point of drug metabolism (in the case of pharmacogenetics), but can literally be used to ‘reconstruct’ an entire person and are likely to reveal that individual’s strengths and vulnerabilities? In the absence of oversight, nothing prevents the custodians of the DNA from utilising it for purposes other than those for which it was initially intended. Part of an oversight mechanism should be to ensure that the emerging and increasingly accepted norms governing informed consent should be adhered to.[8]

Promoting innovation

Should we hinder the progress of science by restricting access to information that might, in the right hands, lead to the discovery of the next blockbuster drug? Should we not adopt a more liberal and open policy that would speed up the already rapid rate of discovery, ultimately to the benefit of all humankind?

Striking a balance

The answer probably lies somewhere in between. Individuals and populations that have been subjected to decades of repression and exploitation will tend to be protective of their assets (including DNA and the data derived therefrom), and this is understandable. Time, improvements in quality of life and the transfer of appropriate information will be required to alleviate some of the suffering generated by the ills of the past. Those who utilise DNA for research purposes and ultimately for commercial gain should be sensitive to the needs of the individuals and populations from whom the DNA

originated. This means, for example, that the wholesale export of DNA by the pharmaceutical industry must be tempered by a set of checks and balances that include recognition of the source of the DNA and acknowledgement of the benefits that may be derived therefrom. If this argument is followed through to completion, mechanisms should be put into place to ensure that this recognition translates into tangible benefits to the affected communities. These benefits may take many forms that do not necessarily need to be monetary, but at the very least should influence pricing of the medications that emerge, which will be used on the very same populations that contributed to their design. In summary, with the advent of next-generation sequencing, the power of computational biology (including bioinformatics) and the ability to manage large sets of data from which very precise information can be derived,[9] care should be taken to strike a balance between preventing exploitation and promoting innovation. Only by considering all the facts at hand and by anticipating possible future scenarios will we be able to ensure that human suffering is limited, whether it be though illness or through less tangible factors such as exploitation and discrimination. A brave and exciting new era is unfolding as technology opens up multiple new avenues that existed previously only in the realms of science fiction, and we should ensure that we are alert to the opportunities and do not miss or sink the boat. 1. De Vries J, Tindana P, Littler K, et al. The H3Africa policy framework: Negotiating fairness in genomics. Trends Genet 2015;31(3):117-119. http://dx.doi.org/10.1016/j.tig.2014.11.004 2. Mahomed S, Behrens K, Slabbert M, Sanne I. Managing human tissue transfer across national boundaries – an approach from an institution in South Africa. Dev World Bioeth 2016;16(1):29-35. http://dx.doi.org/10.1111/dewb.12080 3. South Africa. National Health Act of 2003. Regulations relating to the import and export of human tissue, blood, blood products, cultured cells, stem cells, embryos, foetal tissue, zygotes and gametes. Government Gazette 2012, No. 35099 (published under Government Notice R181). 4. Alessandrini M, Pepper MS. Priority pharmacogenetics for the African continent: Focus on CYP450. Pharmacogenomics 2014;15(3):385-400. http://dx.doi.org/10.2217/pgs.13.252 5. Benjamin R. A Lab of Their Own: Genomic sovereignty as postcolonial science policy. Policy and Society 2009;28(4):341-355. http://dx.doi.org/10.1016/j.polsoc.2009.09.007 6. Slabbert MN, Pepper MS. ‘A room of our own?’ Legal lacunae regarding genomic sovereignty in South Africa. Tydskrif vir Hedendaagse Romeins-Hollandse Reg (Journal of Contemporary South African Roman-Dutch Law) 2010;73:432-450. 7. De Vries J, Pepper M. Genomic sovereignty and the African promise: Mining the African genome for the benefit of Africa. J Med Ethics 2012;38(8):474-478. http://dx.doi.org/10.1136/medethics-2011-100448 8. Mulder NJ, Adebiyi E, Alami R, et al.; H3ABioNet Consortium. H3ABioNet, a sustainable pan-African bioinformatics network for human heredity and health in Africa. Genome Res 2016;26(2):271-277. http://dx.doi.org/10.1101/gr.196295.115 9. Wright GE, Adeyemo AA, Tiffin N. Informed consent and ethical re-use of African genomic data. Hum Genomics 2014;8:18. http://dx.doi.org/10.1186/s40246-014-0018-7

Accepted 24 October 2016.

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

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MEDICINE AND THE LAW

Should doctors provide futile medical treatment if patients or their proxies are prepared to pay for it? D J McQuoid-Mason, BComm, LLB, LLM, PhD Centre for Socio-Legal Studies, University of KwaZulu-Natal, Durban, South Africa Corresponding author: D J McQuoid-Mason (mcquoidm@ukzn.ac.za)

Ethically and legally doctors are not obliged to provide futile treatment to patients, even if the patient or their proxies are prepared to pay for it. However, it may be justified where such treatment is harmless and has a placebo effect. In deciding about a request for futile treatment, doctors should be guided by the ethical principles of patient autonomy, beneficence, non-maleficence and justice. Guidelines are provided to assist doctors in making such decisions. Where futile treatment is withdrawn or refused, palliative care must always be offered. If it is decided to withdraw or refuse treatment, the patient or their proxy should be given the opportunity to contact another practitioner or institution that may be prepared to offer such treatment. S Afr Med J 2017;107(2):108-109. DOI:10.7196/SAMJ.2017.v107i2.12191

Is it ethical and legal for doctors to provide futile medical treatment if patients or their proxies are prepared to pay for it and what should doctors do in this situation? In answering this question the following must be considered: (i) the meaning of futile medical treatment; (ii) the ethical principles with regard to futile treatment; (iii) its legal position; and (iv) the action doctors should take when faced with such requests.

Futile medical treatment

The concept of ‘futile medical treatment’ is controversial because of the current emphasis on patient autonomy and rights. According to the American Medical Association ‘it cannot be meaningfully defined’.[1] Hippocrates stated that doctors should refuse to treat patients in cases where ‘medicine is powerless’.[2] The World Medical Association Medical Ethics Manual[3] states that a doctor has ‘no obligation to offer a patient futile or non-beneficial treatment’ and describes treatment as ‘medically futile’ when it ‘offers no reasonable hope of recovery or improvement or because the patient is permanently unable to experience any benefit’. In other cases the Manual[3] states that ‘the utility and benefit of a treatment can only be determined with reference to the patient’s subjective judgment about his or her overall well-being’, and a patient should generally ‘be involved in determining futility in his or her case’, except where it ‘may not be in the patient’s best interests’. Doctors also ‘should feel free to refuse if the treatment is unlikely to be beneficial, even if it is not harmful, although a potential placebo effect should not be discounted’, implying that it is justified to prescribe a placebo if it improves a patient’s quality of life. Such treatment plays a palliative care role, which differs from futile treatment.[4] Palliative care aims at alleviating the patient’s pain or suffering – not curing their condition – and becomes futile if it can no longer reduce the patient’s pain or suffering.[5] Futile treatment usually means treatment that is ineffectual and inadequate to cure the patient or alleviate their suffering – it is a ‘clinical action serving no useful purpose in attaining a specified goal for a given patient’.[4]

Ethical theories and principles relating to futile treatment Once it is decided that further treatment is futile, can it be terminated or refused against the wishes of the patients or their legal proxies?

Many ethical theories regarding futile treatment could be invoked, such as virtue ethics, Kantian deontology, utilitarianism, communitarianism, liberal individualism, social contract theory, ethics of care, and casuistry.[6] However, most of these are not useful for practitioners. The same applies to classifications of futility into:[7] (i) ‘physiological futility’ – where the treatment cannot achieve its physiological effect; (ii) ‘imminent-demise futility’ – where the patient will die soon despite the proposed medical treatment; (iii) ‘lethal condition’ – where the patient has a terminal illness that treatment will not affect and the patient will die soon; and (iv) ‘quality futility’ – where the treatment fails to allow the patient to lead an acceptable quality of life.[1] Another suggestion is to distinguish between ‘the effect of a treatment’, i.e. how it may alter ‘some bodily function’, and ‘the benefit of a treatment’, i.e. ‘something that can be appreciated by the patient’.[8] This has also been referred to as ‘physiological futility’ and ‘normative futility’,[9] and is consistent with the recommendations of the Manual[3] that patients or their proxies should be involved in discussions about withdrawal of treatment on grounds of futility. It has also been suggested that ‘medical futility’ exists when: ‘there is a goal’; ‘there is an action and activity aimed at achieving this goal’; and ‘there is virtual certainty that the action will fail in achieving this goal’.[10] However, the bounds of ‘virtual certainty’ have not been drawn, and it has been suggested that it applies where the chances of the treatment succeeding are <1 - 5%.[4] However, I prefer to use ‘principlism’, because it is the most popular and widely used approach.[11] It refers to the commonly accepted principles of patient autonomy, non-maleficence, beneficence and justice,[12] and has an easier practical clinical application than most other theories. Deciding to terminate or refuse a patient’s request for futile treatment causes a conflict between the principles of their right to autonomy and beneficence, non-maleficence and justice. Patients exercise patient autonomy when they demand to be treated if their prognosis is hopeless and further medical treatment is futile. However, such autonomy has limits, for instance where a patient asks a doctor to do something illegal or unethical, as in the Michael Jackson case, when the patient’s right to autonomy may be overridden, and the other principles of beneficence, non-maleficence and justice should be applied.[13] This requires ‘a balance between benefits and burdens,

February 2017, Print edition

IN PRACTICE

including immediate detriment, inconvenience, risk of harm, and other costs’.[14] It may, for example, be ‘inhumane or cruel’ to prolong life where ‘the pain may be so severe and the physical restraints so burdensome as to outweigh the limited anticipated benefits’.[14] Conversely, it may be justified to prescribe a futile medication with a placebo effect.[3] When deciding to terminate or refuse treatment against a patient’s or their proxy’s wishes because of futility, doctors must discuss this with them and decide whether it will benefit patients, if it is in their best interests, and whether it will save them from further harm.[14] This is an application of the principles of beneficence and non-maleficence. Families and relatives usually do not want to see their loved ones suffer, and are grateful when doctors guide them about withdrawing futile treatments.[4] Where such treatment is withdrawn, patients should be given palliative care, unless that has also become ineffectual and futile in end-of-life situations.[5] Apart from the principles of beneficence and non-maleficence, doctors must also consider whether the termination or refusal of treatment will lead to a just and equitable distribution of medical resources for others dependent on the healthcare system. This includes the private sector, where futile care may prevent non-terminally ill patients from accessing life-support equipment and intensive care units.[15] This is in line with the principle of justice. This approach has been criticised as the beginning of the ‘slippery slope’ that uses medical futility as a cover for ‘rationing of resources’ and reducing the ‘costs of end-of-life care’.[4] However, the principlism approach, based on beneficence, nonmaleficence and justice, balances the subjective concerns of patients or their surrogates and the medical profession with the objective concerns of society regarding the just allocation of medical resources. The ethical principles provide useful guidelines to practitioners and the courts when determining how a reasonably competent doctor would be expected to behave in particular circumstances, although the courts are not bound by these principles.[16]

The law in relation to futile treatment

Doctors have no legal duty to provide useless or futile treatment to patients whose prognosis is hopeless.[17] These situations often arise when end-of-life decisions must be made. The South African Constitutional Court has ruled that a state hospital is not obliged to provide renal dialysis to a chronically ill person requesting such treatment, who does not qualify for it in terms of the hospital’s criteria.[18] The court stated that it would ‘be slow to interfere with rational decisions taken in good faith by the political organs and medical authorities whose responsibility it is to deal with such matters’.[18] The court refused treatment by renal dialysis based on the justice principle that sometimes the courts must ‘adopt a holistic approach to the larger needs of society rather than to focus on the specific needs of particular individuals within society’.[18] Courts in the UK, in several cases dealing with the termination or withholding of futile treatment, have also deferred to the decisions of the doctors – even when it was against the wishes of patients or their surrogates.[19] They have stated that ‘in a perfect world any treatment which a patient … sought would be provided if doctors were willing to give it, no matter the cost … . It would, however, be shutting one’s eyes to the real world if the court were to proceed on the basis that we do live in such a world.’[19] This statement was approved by the South African Constitutional Court in the abovementioned renal dialysis case.[18] The UK Court of Appeal has also stated that ‘no patient can require a doctor to treat him against his best clinical judgment’.[20]

What should doctors do when futile medical treatment is requested for patients who can pay for it themselves or through their proxies?

Ethically[3] and legally[17] doctors are not obliged to offer patients futile or non-beneficial treatment. The ethical principles provide useful guidelines to practitioners and the courts, but the courts may decide not to follow them.[16] When doctors receive requests for futile aggressive medical treatment, by patients who can afford to pay for it or through their proxies, they should consider the following: • Decide whether or not the requested treatment is futile and confirm this by obtaining another opinion from a specialist in the field.[21] • Use the ethical principle of patient autonomy to consider the request for such treatment by the patient or their proxy; then use the other principles to make a decision.[4,13] • Use the ethical principles of beneficence and non-maleficence to decide whether it would be ethical to provide such treatment by determining whether it will benefit or cause them harm. Balance the benefits against the burdens of continuing the treatment,[4,14] including whether it could have a placebo effect.[3] • Use the justice principle to decide whether such treatment will divert resources away from non-terminal or curable patients with positive prognoses – in the public and private sectors.[14,15] • Having decided that the treatment is futile, and that it is ethically justified to discontinue it, explain the reasons for this decision to the patient or their proxy.[4,22] • Ensure that if treatment is discontinued, the patient is provided with palliative care.[4] • Provide the patient or their proxy with an opportunity to transfer the former to the care of another practitioner or facility that may assist,[4] e.g. terminal patients to a hospice. 1. Clark PA. Medical futility: Legal and ethical analysis. Virtual Mentor 2007;9(5):375-383. http://dx.doi. org/10.1001/virtualmentor.2007.9.5.msoc1-0705 2. Jones WHS, trans-ed. Hippocrates, vol. 2: Prognostic. Cambridge, MA: Harvard University Press, 1981:193. 3. Willams JR. Word Medical Association Medical Ethics Manual. 3rd ed. Ferney-Voltaire Cedex, France: WMA, 2015:46. 4. Kasman DL. When is medical treatment futile? A guide for students, residents and physicians. J Gen Intern Med 2004;19(10):1053-1056. http://dx.doi.org/10.1111/j.1525-1497.2004.40134.x 5. Stransham-Ford v the Minister of Justice and Correctional Services 2015 (4) SA 50 (GP). 6. Dhai A, McQuoid-Mason D. Bioethics, Human Rights and Health Law. Cape Town: Juta, 2011:9-15. 7. Brody BA, Halevy A. Is futility a futile concept? J Med Philos 1995;20(2):123-144. http://dx.doi. org/10.1093/jmp/20.2.123 8. Mason JK, Laurie GT. Mason and McCall Smith’s Law and Medical Ethics. 8th ed. Oxford: Oxford University Press, 2011:476-500. 9. Schneiderman LJ, Jecker NS. Futility in practice. Arch Intern Med 1993;153(19):2195-2198. http:// dx.doi.org/10.1001/archinte.1993.00410190031004 10. Trotter G. Mediating disputes about medical futility. Camb Q Healthc Ethics 1999;8(4):527-537. 11. Moodley K, ed. Medical Ethics, Law and Human Rights. Pretoria: Van Schaik, 2011:19-30. 12. Beauchamp TL, Childress JF. Principles of Biomedical Ethics. 3rd ed. Oxford: Oxford University Press, 1994:67-113;120-184;194-249;256-302. 13. McQuoid-Mason D. Michael Jackson and the limits of patient autonomy. S Afr J Bioethics Law 2012;5(1):11-14. 14. Beauchamp TL, Childress JF. Principles of Biomedical Ethics. 3rd ed. Oxford: Oxford University Press, 1994:153-155. 15. Knox R. When medical care is futile, other patients pay the hidden price. CommonHealth 26 August 2014. http://www.wbur.org/commonhealth/2014/08/26/cost-futile-care (accessed 15 December 2016). 16. Cf. Castell v De Greef 1993 (3) SA 501 (C). 17. Cf. Airedale NHS Trust v Bland [1993] 1 All ER 821 (HL). 18. Soobramoney v Minister of Health, KwaZulu-Natal 1998 (1) SA 765 (CC). 19. R v Cambridge Health Authority, ex p B [1995] 2 All ER 129 (CA). 20. R (on the application of Burke) v General Medical Council 2004 (3) FCR 579 (CA). 21. Cf. Health Professions Council of South Africa. Guidelines for the Withdrawing or Withholding of Treatment. Pretoria: HPCSA, 2008:para 4. 22. Cf. Health Professions Council of South Africa. Guidelines for the withdrawing or withholding of treatment. Pretoria: HPCSA, 2008:para 7.

Accepted 23 November 2016.

February 2017, Print edition

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

IN PRACTICE

CASE REPORT

Metabolic acidosis in a patient with metformin overdose I Ebrahim, MB ChB; M Blockman, BPharm, MB ChB, PGDip Int Res Ethics, MMed Division of Clinical Pharmacology, Department of Medicine, Faculty of Health Sciences, University of Cape Town, South Africa Corresponding author: I Ebrahim (ebrism003@myuct.ac.za)

We report a rare fatal case of acute metformin overdose in a 19-year-old woman. S Afr Med J 2017;107(2):110-111. DOI:10.7196/SAMJ.2017.v107i2.10971

A 19-year-old woman presented to a district-level emergency centre (EC) 1 hour after an intentional ‘unquantifiable’ metformin overdose. Clinical examination at that time was unremarkable except for a respiratory rate (RR) of 28 breaths per minute (bpm). No specific toxidrome was identified. In the EC, 6 hours post metformin ingestion, she appeared restless and complained of severe abdominal pain for which ranitidine, hyoscine butylbromide and lorazepam were administered orally. The patient was observed overnight in the EC. Eighteen hours post ingestion her tachypnoea worsened to 40 bpm and she developed hypoglycaemia, with a finger prick blood glucose reading of 1.8 mmol/L. Venous blood gas findings taken at room temperature at this time are shown in Table 1. Calculation of the anion gap was not possible because lactate and chloride values were not readily available. Based on the patient history and biochemical findings, a diagnosis of metabolic acidosis secondary to acute metformin overdose was made. Infusions of 5% dextrose w/v and 0.5% sodium bicarbonate were initiated separately, and the patient was immediately transferred to a secondary level hospital. Ongoing hypoglycaemia and worsening tachypnoea, accompanied by a drop in Glascow Coma Scale (GCS) to 12/15, occurred en route and 50 ml of a 50% dextrose bolus was administered. The patient developed a prolonged QT interval which precipitated cardiac arrest, with a GCS of 4T/15 requiring full resuscitation including inotropes. Arterial blood gas findings on 30% oxygen at this time revealed a metabolic acidosis as shown in Table 2. At that time her creatinine was 235 mmol/L and the calculated increased anion gap was 27.3. The patient was then transferred to a tertiary hospital for dialysis and intensive care unit (ICU) care. In the ICU, she had persistent refractory hypotension and worsening metabolic acidosis. Despite repeated doses of intravenous sodium bicarbonate and high-dose inotropic support, the GCS and metabolic acidosis remained unchanged. The patient died 42 hours post overdose despite aggressive ICU support.

Discussion

Metformin is a dimethylbiguanide. When prescribed in therapeutic doses for the management of type 2 diabetes mellitus, it is not known to cause hypoglycaemia. It is currently the only biguanide derivative available for this purpose. Two biguanides, phenformin and buformin, were removed from the market in the 1970s owing to their unpredictable association with lactic acidosis.[1,2] Sixty percent of ingested metformin is absorbed from the gastrointestinal tract (GIT), not metabolised, and is dependent

Table 1. Venous blood gas on room air pH

pCO2

pO2

HCO3

Base excess

6.9

11.7 kPa

8.9 kPa

23 mmol/L

3 mmol/L

Table 2. Arterial blood gas on 30% oxygen on arrival at the secondary hospital pH

pCO2

pO2

HCO3

Base excess

<6.8

1.5 kPa

22 kPa

Not reported

Table 3. Prescribed drugs associated with type B hyperlactataemia[5] Drug class

Drug

Lipid lowering

Statins Fibrates

Analgesics

Aspirin Paracetamol

Anticonvulsants

Sodium valproate

Biguanides

Metformin

Anti-arrhythmic

Amiodarone

Psychotropic

Fluoxetine Amitriptyline Chlorpromazine Haloperidol

Antiretroviral

Stavudine Didanosine Zidovudine

on glomerular filtration for elimination. It is excreted in urine, therefore reduced estimated glomerular filtration rate will affect its excretion. Its mechanism of action is complex, including reduction of intestinal glucose absorption, inhibition of hepatic gluconeogenesis and enhanced peripheral insulin sensitivity.[1,3] Lactate is a byproduct of glucose and amino acid metabolism. Hyperlactataemia arises due to increased production or reduced metabolism of lactate. The condition is broadly classified into two types:[4] • Type A: increased lactic acid in ischaemic tissue • Type B: normal tissue perfusion in the presence of a mitochondrial

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IN PRACTICE

Metformin

Metformin overdose should be treated immediately. The drug is extensively excreted renally and therefore haemodialysis is ideal in acute overdose for effective removal of both metformin and circulating lactate. [1,2,12]

Inhibition of pyruvate carboxylase

Inhibition of electron transport chain

Increased NADH levels

Decreased flow through Krebs cycle

Increased pyruvate

Conclusion Lactate

Increased lactate dehydrogenase

Fig. 1. Proposed mechanism for metformin-induced hyperlactataemia. (NADH = nicotinamide adenine dinucleotide, reduced form.)

defect (inherent or acquired secondary to pharmacotherapy). (Table 3) Metformin-associated lactic acidosis (MALA) is a form of type B hyperlactataemia with a high anion gap. The estimated rate of MALA ranges between 3 and 9 cases per 100 000 patient-years with a mortality >50%.[6,7] Metformin inhibits gluconeogenesis by direct inhibition of pyruvate carboxylase, which causes pyruvate to accumulate and an increase in lactate production. It also inhibits oxidative phosphorylation, impairing generation of NAD+ from NADH by the mitochondria. This increase in NADH further favours conversion of pyruvate into lactate through inhibition of pyruvate dehydrogenase (Fig. 1).[8] The resultant acidosis predisposes to dysrhythmias and diminished response to catecholamines.[9,10] This may explain why

our patient had refractory hypotension despite high-dose inotropic support. The management goals of MALA include restoration of acid-base status, removal of absorbed metformin and support of cardiovascular functions.[1] Knowledge of the pharmacokinetic properties of metformin is essential in formulating the management plan. Metformin is partially absorbed through the gastrointestinal tract, with the unabsorbed portion binding to the intestinal wall.[3] Activated charcoal is theoretically capable of binding the unabsorbed metformin[11] and should be administered early if the patient is awake and has a protected airway. Management of lactic acidosis with the use of sodium bicarbonate (NaHCO3) is controversial despite its regular use.[1,2,9] Theoretical disadvantages are a leftward shift of the oxygen dissociation curve, worsening intracellular acidosis, rebound metabolic alkalosis and fluid overload.[1,2,9]

February 2017, Print edition

Acute metformin overdose is rare and potentially life threatening. Severe metabolic acidosis hypoglycaemia and cardiovascular collapse are the main clinical features. Patients should be treated promptly in a critical care unit, with early consideration for haemodialysis and cautious use of intravenous sodium bicarbonate. 1. Spiller HA. Management of antidiabetic medications in overdose. Drug Saf 1998;19(5):411-424. 2. Heaney D, Majid A, Junor B. Bicarbonate haemodialysis as a treatment of metformin overdose. Nephrol Dial Transplant 1997;12(5):1046-1047. 3. Scheen AJ. Clinical pharmacokinetics of metformin. Clin Pharmacokinet 1996;30(5):359-371. 4. Cohen RD, Woods H. Clinical and Biochemical Aspects of Lactic Acidosis. Oxford: Blackwell Scientific Publication, 1976. 5. Neustadt J, Pieczenik SR. Review of medication-induced mitochondrial damage and disease. Mol Nutr Food Res 2008;52(7):780-788. https://dx.doi.org/10.1002/mnfr.200700075 6. Stang M, Wysowski DK, Butler-Jones D. Incidence of lactic acidosis in metformin users. Diabetes Care 1999;22(6):925-927. 7. Lalau JD, Race JM. Lactic acidosis in metformin-treated patients. Prognostic value of arterial lactate levels and plasma metformin concentrations. Drug Saf 1999;20(4):377-384. 8. Dembo AJ, Marliss EB, Halperin ML. Insulin therapy in phenformin-associated lactic acidosis. Diabetes 1975;24(9):2835. https://dx.doi.org/10.2337/diab.24.9.791 9. Velissaris D, Karamouzos V, Ktenopoulos N, et al. The use of sodium bicarbonate in the treatment of acidosis in sepsis: A literature update on a long term debate. Crit Care Res Pract 2015;2015:605830. http://dx.doi.org/10.1155/2015/605830 10. Orchard CH, Cingolani HE. Acidosis and arrhythmias in cardiac muscle. Cardiovasc Res 1994;28(9):1312-1319. 11. Spiller HA, Sawyer TS. Toxicology of oral antidiabetic medications. Am J Health Syst Pharm 2006;63(10):929-938. https://dx.doi.org/10.2146/ajhp050500 12. Nguyen HL, Concepcion L. Metformin intoxication requiring dialysis. Hemodial Int 2011;15(1):S68-71. https://dx.doi. org/10.1111/j.1542-4758.2011.00605.x

Accepted 19 October 2016.

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

IN PRACTICE

CASE REPORT

Primary ethmoid sinus squamous cell carcinoma in a young adult man N Goncalves, MB BCh; L A Burnell, MB ChB, FCORL (SA); S Motakef, MB BCh, FCORL (SA); P C Modi, MB BCh, FCS (ORL) (SA) Department of Otorhinolaryngology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa Corresponding author: N Goncalves (drnicgoncalves@gmail.com)

In this case report we describe an aggressive primary ethmoid squamous cell carcinoma in an unusually young patient. S Afr Med J 2016;106(9):893-894. DOI:10.7196/SAMJ.2016.v106i9.10575

Malignancies of the sinonasal cavity are uncommon, accounting for 3 - 5% of all malignancies of the head and neck.[1,2] The predominant histological subtype of sinonasal tumours is sinonasal squamous cell carcinoma (SNSCC), accounting for up to 50 - 80% of all sinonasal malignancies. These most commonly occur in the maxillary sinus.[2] The remaining 10 - 20% are intestinal-type adenocarcinoma, which mostly occur in the ethmoid sinus.[2] There have been fewer than 500 reported cases of primary squamous cell carcinoma of the ethmoid sinus in the English literature.[3-15] Sinonasal tumours typically present between the 5th and 6th decades of life.[2] Environmental exposures to wood and leather dust, as well as glues, formaldehyde, nickel and chrome, are strongly associated with the development of some sinonasal tumours.[2]

Case report

A 31-year-old black African man presented to our department with a 5-month history of swelling of the left side of the forehead, associated with a dull frontal headache and with progressive painless blindness of the left eye. The patient also reported a decrease in his sense of smell, along with loss of taste. There had also been an intermittent report of a bloodstained nasal discharge. The patient was an occasional smoker, with no occupational exposure to wood dust or industrial and textile compounds. He was HIV-negative. The physical examination revealed a 6 Ă&#x2014; 5 cm diffuse, ill-defined, firm, mildly tender mass over the lower part of the left forehead. It appeared to be the head of a mushroom-type growth, with the stem arising through the nasion. The mass dominated over the left forehead with encroachment to the left medial epicanthal area, without causing epiphorea. There was intraorbital mass effect with proptosis and leftward and downward displacement of

the globe, without ophthalmoplegia. His decreased visual acuity implied optic canal/ optic nerve involvement. There was no ptosis or chemosis. Anterior rhinoscopy revealed no intranasal sinus disease. Endoscopic middle meatus examination showed an illdefined ethmoid tumour mass not extending inferiorly. The drainage ostia of the maxillary sinus and anterior ethmoids were clear of disease. Endoscopic examination of the cribriform plate area was difficult owing to the distortion of the middle turbinate superiorly. Apart from cranial nerve I (loss of smell) and cranial nerve II (decreased visual acuity), all other cranial nerves were functionally intact. A computed tomography (CT) scan showed a soft-tissue mass with contrast enhancement originating in the ethmoid sinus and extending superolaterally to the left side and infiltrating through the floor and posterior table of frontal sinus. There was also erosion through the cribriform plate. Destruction of the frontal sinus and frontal bone with intracranial extension into the frontal lobe was evident. Proptosis of the left orbit with destruction of the left bony orbital roof and lamina papyracea medially was noted. Magnetic resonance imaging (MRI) confirmed the mass as seen on the CT scan, with the tumour abutting and encasing the left extraconal optic nerve and with direct extension to the left frontal lobe (Fig.Â 1). A formal external open tissue biopsy via a Lynch incision was undertaken, under general anaesthesia. The histopathological report was that of an invasive, moderately to poorly differentiated squamous cell carcinoma. Immunohistochemical staining, carried out to detect human papillomavirus and/or Epstein-Barr virus infection, was negative. Surgical resection was deemed contraindicated owing to the erosion of the tumour directly through

February 2017, Print edition

Fig. 1. T1 coronal MRI scan showing the epicentre of the tumour mass (arrow) in the ethmoid sinus with intracranial extension and erosion of frontal bone.

the cribriform plate to the frontal lobe, transgressing the cerebrospinal fluid space. Further treatment therefore involved radiation and cycles of chemotherapy.

Discussion

Primary ethmoid SNSCCs make up 5 - 25% of all sinus malignancies.[10] The literature is deficient on the precise incidence, as ethmoid tumours are often grouped with more common maxillary and nasal tumours. Squamous cell carcinomas are often grouped with other tumours, which may occur primarily within the ethmoid sinuses.[10] While the average age of primary ethmoid SNSCC onset is known, only a few reports detailing a young age of onset are currently available in the published literature. The tumorigenesis of paranasal sinus tumours is unknown. Theories abound regarding certain chemical or viral agents that cause persistent or chronic inflammatory changes.[2] Chronic inflammation in turn results in aberrant

IN PRACTICE

activation of tumour suppressor genes that support tumorigenesis.[2] The above fails to explain the development of SNSCC in young patients or patients who have not been exposed to any known carcinogens. Early-onset tumorigenesis in young patients could be attributed to existing genetic precursor lesions and the accumulation of genetic alterations.[2] The optimal care for patients with localised sinonasal carcinoma is complete surgical resection and postoperative radiotherapy.[2] Ansa et al.[1] showed the combination of surgery and radiation to be superior to radiation alone.

Conclusion

A complex interplay between genetic factors and yet-to-be-identified environmental triggers is likely to have contributed to the development of primary ethmoid SNSCC in an unusually young patient with a limited risk profile. Unveiling the molecular pathophysiology of SNSCC is likely to uncover potential molecular diagnostic markers and aid the identification of specific treatment modalities. 1. Ansa B, Goodman M, Ward K, et al. Paranasal sinus squamous cell carcinoma incidence and survival based on surveillance, epidemiology, and end results data, 1973 to 2009. Cancer 2013;119(14):26022610. http://dx.doi.org/10.1002/cncr.28108 2. Llorente JL, López F, Suárez C, Hermsen MA. Sinonasal carcinoma: Clinical, pathological, genetic and therapeutic advances. Nat Rev Clin Oncol 2014;11(8):460-472. http://dx.doi.org/10.1038/ nrclinonc.2014.97

3. Nicolai P, Castelnuovo P, Lombardi D, et al. Role of endoscopic surgery in the management of selected malignant epithelial neoplasms of the naso-ethmoidal complex. Head Neck 2007;29(12):1075-1082. http://dx.doi.org/10.1002/hed.20636 4. Gras-Cabrerizo JR, Montserrat-Gili JR, León-Vintró X, et al. Treatment results for ethmoid sinus carcinoma. J Laryngol Otol 2009;123(10):1120-1124. http://dx.doi.org/10.1017/S0022215109990752 5. Islam S, Cole CV, Hoffman GR, Brennan PA. Bilateral axillary metastasis from a primary ethmoidal squamous cell carcinoma. J Laryngol Otol 2006;120(4):353-355. http://dx.doi.org/10.1017/S0022215106000375 6. Uchida D, Shirato H, Onimaru R, et al. Long-term results of ethmoid squamous cell or undifferentiated carcinoma treated with radiotherapy with or without surgery. Cancer J 2005;11(2):152-156. 7. Bhattacharyya N. Factors predicting survival for cancer of the ethmoid sinus. Am J Rhinol 2002;16(5):281-286. 8. Tiwari R, Hardillo JA, Tobi H, Mehta D, Karim AB, Snow G. Carcinoma of the ethmoid: Results of treatment with conventional surgery and post-operative radiotherapy. Eur J Surg Oncol 1999;25(4):401-405. http://dx.doi.org/10.1053/ejso.1999.0665 9. Waldron JN, O’Sullivan B, Warde P, et al. Ethmoid sinus cancer: Twenty-nine cases managed with primary radiation therapy. Int J Radiat Oncol Biol Phys 1998;41(2):361-369. http://dx.doi.org/10.1016/ S0360-3016(98)00018-2 10. Kraus DH, Sterman BM, Levine HL, et al. Factors influencing survival in ethmoid sinus cancer. Arch Otolaryngol Head Neck Surg 1992;118(4):367-372. http://dx.doi.org/10.1001/ archotol.1992.01880040025005 11. Morokhoev VI. [Errors in the early diagnosis of malignant tumors of the ethmoid sinus]. Vestn Otorinolaringol 1990;(5):60-64. 12. Lavertu P, Roberts JK, Kraus DH, et al. Squamous cell carcinoma of the paranasal sinuses: The Cleveland Clinic experience 1977 - 1986. Laryngoscope 1989;99(11):1130-1136. http://dx.doi.org/10. 1288/00005537-198911000-00005 13. Spiro JD, Soo KC, Spiro RH. Squamous carcinoma of the nasal cavity and paranasal sinuses. Am J Surg 1989;158(4):328-332. 14. Lampe HB, St Pierre S, Baker SR. Carcinoma of the ethmoid sinus. Am J Otolaryngol 1986;7(3):209212. 15. Badib AO, Kurohara SS, Webster JH, Shedd DP. Treatment of cancer of the paranasal sinuses. Cancer 1969;23(3):533-537.

Accepted 24 January 2016.

CASE REPORT

Intentional intravenous mercury injection This open-access article is distributed under CC-BY-NC 4.0.

G Yudelowitz, MB BCh Tambo Memorial Hospital, Boksburg, South Africa

Corresponding author: G Yudelowitz (gregyudels@gmail.com)

Mercury toxicity is commonly associated with vapour inhalation or oral ingestion, for which there exist definite treatment options. Intravenous mercury injection is rarely seen, with few documented cases. Treatment strategies are not clearly defined for such cases, although a few options do show benefit. This case report describes a 29-year-old man suffering from bipolar disorder, who presented following self-inflicted intravenous injection of mercury. Clinical and radiographic features, possible adverse clinical sequelae in preexisting mental illness and further complications are discussed, as well as possible treatment strategies in light of relevant literature. S Afr Med J 2017;107(2):112-114. DOI:10.7196/SAMJ.2017.v107i2.12046

Three forms of mercury exist: elemental, inorganic and organic, all of which may be toxic with clinical consequences, depending on the type of exposure. Elemental mercury poisoning usually occurs via vapour inhalation, as mercury is well absorbed through the lungs. The central nervous system is then the major site of deposition. Elemental mercury is the well-known silver liquid and usually causes pulmonary, neurological and nephrological toxicity.[1] Sources of exposure are mainly occupation related and include thermometer and barometer manufacturing, and gold mining, where liquefied elemental mercury may be used to concentrate gold. Other sources are dentistry, as amalgam dental fillings consist of mercury, and metal refineries.[1] Inorganic mercury is present in an oxidised state, allowing the formation of mercury salts and, if ingested, may cause gastroenteritis and renal failure. The kidneys are the final site for deposition.

Sources of inorganic mercury exposure may include occupational exposure in the electroplating industry and exposure to laboratory reagents.[1] In this case report, intravenous complications, treatment strategies and possible neuropsychiatric manifestations, where there is preexisting mental disease, are explored in a South African (SA) setting. As far as the author is aware this is the first reported case in SA.

Case report

A 29-year-old man presented to Tambo Memorial Hospital, Boksburg, SA in June 2016 after having injected mercury intravenously his right and left arms 10 weeks earlier in an attempted suicide. The patient had presented owing to nonspecific symptoms of loss of appetite, occasional diarrhoea and fatigue. On further questioning a history of intravenous mercury injection was uncovered.

February 2017, Print edition

IN PRACTICE

The patient was known to suffer from bipolar mood disorder type 1, diagnosed in 2010, with subsequent default of treatment in the same year, soon after initiating treatment. Three previous suicide attempts were reported. At this presentation, the patient was not expressing suicidal ideation or features of major depression. Clinically the patient was stable, apyrexial and not distressed. Systemic examination was largely unremarkable, except for multiple areas of induration and granuloma formation on the right and left forearms. Radiographs of the forearms, chest and abdomen were obtained (Figs 1 - 4). Images showed numerous metallic hyperdensities in the soft tissues surrounding the sites of intravenous injection (Figs 1 and 2) as well as numerous small hyperdensities throughout the lung fields (Fig. 3), abdomen and pelvis (Fig. 4). Blood mercury level is indicative of short-term exposure and its measurement is not of great benefit in chronic exposure;[1] therefore, this was not tested. Hair mercury levels are a good indication of chronic exposure leading to toxicity;[1] however, following discussion with the National Institute for Occupational Health (NIOH), Johannesburg, SA, considering the cost and already significantly raised urinary levels, it was decided not to test hair levels. The patient was admitted with an acute kidney injury for treatment with intravenous fluids and further investigation of the mercury injection and bipolar mood disorder. On subsequent psychiatric evaluation of the patient, further information was obtained. The patient’s suicide attempt 3 months previously was precipitated by severe stressors at the time, including

Fig. 3. Radiograph of the chest.

Fig. 4. Radiograph of the abdomen and pelvis.

loss of employment, involvement in a motor vehicle accident with resultant loss of his car, and his father having suffered from a cerebral vascular accident. These events were subsequently followed by mood symptoms, resulting in the mercury injection. The patient was reportedly not experiencing mood or manic symptoms prior to these stressors, according to his mother, despite having defaulted treatment for bipolar mood disorder. He was not experiencing any psychotic or ictal symptoms at the time of admission. He did describe a history of panic attacks since the age of 20, during which he experiences sudden fear, palpitations, shortness of breath, shaking and lightheadedness, often associated with agoraphobia. Further stressors included an experience of date rape at the age of 22, shortly before the index episode with the first suicide attempt. Treatment with sodium valproate and lamotrigine was started at that stage. On mental state examination, he was noted to have a low mood with no features of major depression, mania or hypomania, and was not suicidal. The patient was restarted on lamotrigine. Because of the appearance of multiple hyperdensities within the lung field on chest X-ray, the patient was discussed with staff at the respiratory unit at the referral hospital. No further treatment was advised at this point, but discussion with the nephrology department was suggested to assess further treatment options and the possibility of dialysis. Results of blood tests done on admission are shown in Table 1. During admission, the patient’s creatinine level increased to 169 µmol/L, urea level was 13 mmol/L and electrolytes were normal. Urine

Fig. 1. Radiograph of the right forearm.

Fig. 2. Radiograph of the right elbow.

February 2017, Print edition

IN PRACTICE

Table 1. Initial blood analysis results of patient Component

Reference range*

Value

Urea (mmol/L)

11.5

2.1 - 7.1

Creatinine (µmol/L)

129

64 - 104

Total protein (g/L)

60 - 78

Albumin (g/L)

35 - 52

Alanine transaminase (µ/L)

10 - 40

Aspartate transaminase (µ/L)

15 - 40

C-reactive protein (mg/L)

<10

Thyroid-stimulating hormone (mU/L)

1.29

0.27 - 4.2

Haemoglobin (g/dL)

14.8

13.4 - 17.5

Urinary mercury (µ g/mL)

>150 000

2.5†

*References obtained from the National Health Laboratory Service (NHLS), Tambo Memorial Hospital. † Reference obtained from NIOH.

testing gave a urine protein:creatinine ratio of 0.33 g/mmol (normal <0.015 g/mmol, nephrotic range >0.350 g/mmol; references from the NHLS, Johannesburg). After discussion with the nephrology departments of both Charlotte Maxeke Academic Hospital, Johannesburg, and Groote Schuur Hospital, Cape Town, it was decided that no benefit would be derived from dialysis, but long-term chelation would most likely be necessary. The case was further referred to the Department of Clinical Pharmacology at the University of Cape Town, which, in discussion with the Medicines Control Council (MCC), advised lifelong treatment with penicillamine. Documented consent was obtained from the patient for the writing of this case report and the publication of radiographs and blood analysis results.

Discussion

Organic mercury toxicity often leads to gastrointestinal, neurological and pulmonary symptoms, as organic mercury deposits in the kidneys and liver and in the central nervous system.[2] Most documented clinical sequelae of mercury toxicity are from exposure to vaporised elemental mercury or ingestion of other forms of mercury.[1] Initial signs and symptoms may include cough, pleuritic chest pain, stomatitis, gingivitis, nausea, vomiting and diarrhoea, conjunctivitis and dermatitis. Prolonged exposure can lead to neurological and psychiatric symptoms, such as insomnia and tremors. A traditional pathognomonic feature of mercury toxicity is known as erethism mercurialis, consisting mainly of neurological manifestations. Features include change in personality, anxiousness, irritability, insomnia, depression and drowsiness.[1] However, the effect on the central nervous system in pre-existing mental illness remains to be seen. Rare cases of nephrotic syndrome have been described. Renal tubular dysfunction has also been noted.[1] A diagnosis of mercury toxicity is confirmed in blood and 24-hour urine collection levels, but is dependent on whether the patient has had acute or prolonged exposure.

Treatment strategies include removing the source of exposure if possible, bronchodilators for respiratory complications, and careful fluid and electrolyte management for patients with gastrointestinal features. Chelation therapy increases urinary excretion of mercury and has been shown to improve clinical manifestations.[3] Chelation is recommended by the World Health Organization for severe mercury toxicity. Toxicity from intravenous injection of mercury usually occurs in relation to attempted suicide, accidental exposure, or possibly through experimentation by drug addicts.[4] Intravenous injection of mercury has been shown to be less detrimental than ingestion or inhalation. The heavy metal moves to dependent areas and extravasates into tissues. It is then transported via the circulation, where it tends to lodge in the lungs and mediastinum and is also known to reach other organs over a period of time.[5] Treatment strategies for intravenous injection are still being explored, but some show areas of promise. Chelation is of benefit; however, the effect of long-term chelation for chronic parenteral exposure is still uncertain.[6] The excision of deposits is also a suggested strategy.[7] Currently, penicillamine is a section 21 substance according to the Medicines and Related Substances Act 101 of 1965, regulated by the MCC. The hospital pharmacy involved in this case is trying to procure the drug. Other treatment options include dialysis and surgical removal of granulomas and subcutaneous deposits, which have shown benefit.[7] In discussion with the patient it was ultimately decided to treat him medically at this stage and consider surgical intervention later. Further psychiatric evaluation and monitoring was suggested based on the patient’s pre-existing mental state, and the possibility of neuropsychiatric manifestations of mercury toxicity as described above. Suggested further monitoring includes regular renal function testing, and dialysis could be considered depending on the burden of disease. A multidisciplinary approach involving dental and ophthalmology assessments to screen for the possible complications described above, as well as a surgical review to assess the possibility of deposit excision, may be recommended in similar cases. The patient is waiting for penicillamine delivery via a section 21 application and is attending the outpatient department at Tambo Memorial Hospital, where renal function monitoring continues and psychiatric progression of the disease is being monitored. 1. Beauchamp G, Kusin S, Elinder C. Mercury Toxicity. UpToDate. 2016. https://www.uptodate.com/ contents/mercury-toxicity (accessed 23 August 2016). 2. Kumar P, Clark M. Clinical Medicine. Edinburgh: Saunders, 2002:984. 3. Zhang J. Clinical observations in ethyl mercury chloride poisoning. Am J Ind Med 1984;5(3):251-258. http://dx.doi.org/10.1002/ajim.4700050308 4. Garg S, Wale J, Yadav P. Elemental mercury poisoning caused by subcutaneous and intravenous injection: An unusual self-injury. Indian J Radiol Imaging 2010;20(2):147. http://dx.doi.org/10.4103/0971-3026.63056 5. Gopalakrishna A, Pavan Kumar T. Intravenous injection of elemental mercury: A report of two cases. Indian J Plast Surg 2008;41(2):214. http://dx.doi.org/10.4103/0970-0358.44942 6. McFee R, Caraccio T. Intravenous mercury injection and ingestion: Clinical manifestations and management. J Toxicol Clin Toxicol 2001;39(7):733-738. http://dx.doi.org/10.1081/clt-100108515 7. Netscher D, Friedland J, Guzewicz R. Mercury poisoning from intravenous injection: Treatment by granuloma resection. Ann Plast Surg 1991;26(6):592-596. http://dx.doi.org/10.1097/00000637-199106000-00018

Accepted 6 October 2016.

February 2017, Print edition

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

IN PRACTICE

CASE REPORT

Three cases of intentional isoniazid overdose – a life-threatening condition D F Stead,1,2 MB ChB, FCP (SA), Cert ID (SA); C R Mason,2 MB ChB, FCP (SA) 1 2

Division of Infectious Diseases, Department of Medicine, Frere Hospital, East London, South Africa Department of Medicine, Frere and Cecilia Makiwane hospitals, East London; and Department of Medicine, Faculty of Health Sciences, Walter Sisulu University, Mthatha, South Africa

Corresponding author: D F Stead (dfstead@gmail.com)

Currently, isoniazid (INH) overdose seems to be a growing and life-threatening problem, partly due to the recent national roll-out of INH preventive therapy (IPT) for HIV-positive adults. We present three cases, two of which were fatal, seen at Frere and Cecilia Makiwane hospitals, East London, South Africa, over the past 16 months. S Afr Med J 2016;106(9):891-892. DOI:10.7196/SAMJ.2016.v106i9.10582

Case 1

A 21-year-old HIV-infected woman with a CD4 count of 215 cells/µL, who was on unidentified antiretroviral (ARV) treatment, presented to her local district hospital, having ingested 70 rifampicin (150 mg)/ isoniazid (INH) (75 mg) combination tablets for continuation-phase treatment of tuberculosis (TB). No specific therapy was given. She was fully conscious on days 1 and 2, but had a Glascow coma scale (GCS) score of 7/15 on day 3. No seizures were observed. On the day of her arrival at our institution, her GCS score was 6/15 and she was intubated and ventilated in the intensive care unit (ICU). The patient had a compensated metabolic acidosis on analysis of arterial blood (standard bicarbonate 18 mmol/L), but the lactate level was not measured. On admission, her serum creatinine was 254 μmol/L, but it normalised within 3 days. Pyridoxine 5 g was administered via a nasogastric tube (NGT), but with no response in her level of consciousness. She spent almost 4 months in the ICU, without any neurological recovery, and died shortly after transfer to a general ward.

Case 2

A 32-year-old HIV-infected woman, who was receiving tenofovir/emtricitabine/efavirenz fixed-dose combination ARVs, and 300 mg INH daily as INH preventive therapy (IPT), was found unconscious with two empty bottles of each of the abovementioned agents. She suffered multiple seizures while being transferred to our hospital, was assessed as being in status epilepticus on arrival, and required 60 mg diazepam and a phenytoin loading dose to terminate her seizures. She suffered a cardiorespiratory arrest, and was resuscitated, intubated and ventilated in the ICU. Once the INH ingestion was recognised, 5 g pyridoxine was administered via an NGT. Her arterial blood lactate level was 15.3 mmol/L, and her serum creatinine 220 μmol/L, both of which normalised with supportive care. A computed tomography (CT) scan of her brain was normal. Her GCS improved from 3/15 to 7/15 by day 10, but failed to recover further. On day 31 she was transferred to a general ward and died.

Case 3

A 52-year-old HIV-infected woman, with a CD4 count of 274 cells/µL, was found unconscious with empty tenofovir/emtricitabine/efavirenz fixed-dose combination ARVs and IPT containers. She was also heavily intoxicated with ethanol. She arrived at the hospital in

status epilepticus, her seizures were refractory to clonazepam and a phenytoin loading dose infusion, but her convulsions decreased during a propofol infusion in the ICU. There was a 48-hour delay before INH toxicity was recognised as the possible cause of her seizures; 5 g pyridoxine was then administered via an NGT, after which she experienced no further seizures. Her arterial lactate was 16.6 mmol/L and serum creatine kinase 41 015 U/L. She developed acute renal failure, requiring 7 days of haemodialysis, after which her renal function recovered fully. A CT scan of her brain was normal. She was extubated after 11 days, and continued to full recovery after almost 4 weeks.

Discussion

INH, the hydrazide of isonicotinic acid, has been the mainstay of TB treatment and prevention since the 1950s. Most clinicians are familiar with the common side-effects of peripheral neuropathy and hepatotoxicity, but lesser known, severe INH toxicity is characterised by recurrent seizures, lactic acidosis, coma and death. As little as 1.5 g INH has been reported to cause mild toxicity, doses of 6 - 10 g may result in severe toxicity, while doses >15 g may be fatal.[1] INH is rapidly absorbed, reaching peak levels in 1 - 2 hours, with minimal protein binding. It is metabolised in the liver by polymorphic acetylation, with a half-life of between 1 and 4 hours, varying between fast and slow acetylators. INH exerts toxicity by inhibiting pyridoxine kinase, the enzyme responsible for the production of pyridoxal phosphate, the active form of pyridoxine. Pyridoxal phosphate is a co-factor in the synthesis of gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter.[1] Consequently, INH toxicity leads to reduced GABA, which can induce seizures. Lactic acidosis is thought to occur by INH inhibition of lactate dehydrogenase via its effect on the co-enzyme nicotinamide adenine dinucleotide. This is exacerbated by increased lactate production during seizures. For the management of an INH overdose, after initial stabilisation, gastric lavage is indicated within 1 hour of INH ingestion. This can be followed by charcoal administration, which can be given with sorbitol,[2] concurrently with the prompt administration of high doses of pyridoxine, preferably as an intravenous preparation, but as crushed tablets via an NGT if the former is unavailable. Most authors recommend a mass equivalent dose according to the amount of INH ingested, if known. This was shown to have superior seizure control in a case series of five patients compared with 41 cases reported in

February 2017, Print edition

IN PRACTICE

the literature, where other approaches were used.[3] If the ingested dose is unknown, 70 mg/kg pyridoxine is recommended, up to a total of 5 g.[1] This alone may be enough to terminate seizures, but if not, benzodiazepines are the preferred anticonvulsant. Animal studies have demonstrated synergy between pyridoxine and diazepam (a GABAA, benzodiazepine-site agonist) in reducing INH-induced seizures, but not with phenytoin (a sodium channel antagonist).[1] Haemodialysis will eliminate INH, but it is generally not required, except in the most severe cases that do not respond to pyridoxine. Based on the half-life of INH, it should be used early to obtain an optimal effect.[1] Notably, all three of our patients developed acute renal failure, one requiring dialysis, but renal function recovered in all. This has only been described in one other INH toxicity case report, where INH was combined with rifampicin.[4] Two, and possibly all three patients, co-ingested unknown amounts of tenofovir-containing fixeddose combination tablets. Even though tenofovir is known to cause nephrotoxicity over time in therapeutic doses, no cases of acute renal failure have been reported with an overdose.[5] Case 3 had a high creatine kinase level, presumably caused by seizure-induced rhabdomyolysis, which may have contributed to acute tubular necrosis. From a public health perspective, our concern is that severe INH overdose cases are likely to become more frequent following the recent roll-out of IPT for HIV-positive adults in South Africa (SA). INH is now available as a 300 mg tablet (previously 100 mg or a maximum of 150 mg in combination with rifampicin), giving a total dose of 8.4 g in a monthâ&#x20AC;&#x2122;s supply (well into the range of severe toxicity). IPT is administered for long periods (6 - 36 months), and potentially most of SAâ&#x20AC;&#x2122;s estimated 6.5 million HIV-infected adults qualify to

receive it.[6] While the benefits of IPT in preventing TB are clear, we believe clinicians need to be aware of the risk of INH overdose, and be cautious when considering IPT for patients with suicidal risks. HIV-positive patients have a high level of suicidal ideation (up to 83% in a recent post-voluntary testing and counselling study in KwaZuluNatal[7]), and there is evidence that efavirenz may further increase the risk of suicidality.[8] Emergency clinicians need to have a high index of suspicion for INH overdose in patients presenting with resistant status epilepticus or unexplained lactic acidosis, and be familiar with the emergency management, as discussed above. The registration and supply of intravenous pyridoxine, and the availability of laboratories determining INH levels, would also assist in better managing suspected cases. 1. Bateman DN, Page C. Antidotes to coumarins, isoniazid, methotrexate and thyroxine; toxins that work via metabolic processes. Br J Clin Pharmacol 2016;81(3):437-445. http://dx.doi.org/10.1111/bcp.12736 2. Romero JA, Kuczler FJ. Isoniazid overdose: Recognition and management. Am Fam Physician 1998;57(4):749-752. 3. Wason S, Lacouture PG, Lovejoy FH, Jr. Single high-dose pyridoxine treatment for isoniazid overdose. JAMA 1981;246(10):1102-1104. http://dx.doi.org/10.1001/jama.246.10.1102 4. Sridhar A, Sandeep Y, Krishnakishore C, Sriramnaveen P, Manjusha Y, Sivakumar V. Fatal poisoning by isoniazid and rifampicin. Ind J Nephrol 2012;22(5):385-387. http://dx.doi.org/10.4103/09714065.103930 5. Margolis AM, Heverling H, Pham PA, Stolbach A. A review of the toxicity of HIV medications. J Med Toxicol 2014;10(1):26-39. http://dx.doi.org/10.1007/s13181-013-0325-8 6. Joint United Nations Programme (UNAIDS) on HIV/AIDS. HIV and AIDS estimates, 2014. http:// www.unaids.org/en/regionscountries/countries/southafrica (accessed 25 January 2016). 7. Schlebusch L, Govender RD. Elevated risk of suicidal ideation in HIV-positive persons. Depress Res Treat 2015;2015:1-6. http://dx.doi.org/10.1155/2015/609172 8. Mollan KR, Smurzynski M, Eron JJ, et al. Association between efavirenz as initial therapy for HIV-1 infection and increased risk of suicidal ideation, attempted, or completed suicide. Ann Intern Med 2014;1:161(1):1-10. http://dx.doi.org/10.7326/M14-0293

Accepted 7 February 2016.

February 2017, Print edition

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

RESEARCH

Sustained reduction in antibiotic consumption in a South African public sector hospital: Four-year outcomes from the Groote Schuur Hospital antibiotic stewardship programme T H Boyles,1 MA, BM BCh (Oxon), MRCP, MD, Cert ID (SA), DTM&H; V Naicker,2 BSc (Pharm); N Rawoot,2 BPharm; P J Raubenheimer,3 MB ChB, FCP; B Eick,4 MB ChB; M Mendelson,1 BSc, MBBS, PhD, FRCP, DTM&H Division of Infectious Diseases and HIV Medicine, Department of Medicine, Groote Schuur Hospital and Faculty of Health Sciences, University of Cape Town, South Africa 2 Pharmacy Department, Groote Schuur Hospital, Cape Town, South Africa 3 Division of General Internal Medicine, Department of Medicine, Groote Schuur Hospital and Faculty of Health Sciences, University of Cape Town, South Africa 4 Groote Schuur Hospital, Cape Town, South Africa 1

Corresponding author: T H Boyles (tomboyles@yahoo.com) Background. Overuse of antibiotics has driven global bacterial resistance to the extent that we have entered a post-antibiotic era, where infections that were once easily treatable are now becoming untreatable. Efforts to control consumption have focused on antibiotic stewardship programmes (ASPs), aimed at optimising use. Objective. To report antibiotic consumption and cost over 4 years from a public hospital ASP in South Africa (SA). Methods. A comprehensive ASP comprising online education, a dedicated antibiotic prescription chart and weekly dedicated ward rounds was introduced at Groote Schuur Hospital, Cape Town, in 2012. Electronic records were used to collect data on volume and cost of antibiotics and related laboratory tests, and to determine inpatient mortality and 30-day readmission rates. These data were compared with a control period before the intervention. Results. Total antibiotic consumption fell from 1 046 defined daily doses/1 000 patient days in 2011 (control period) to 868 by 2013 and remained at similar levels for the next 2 years. This was driven by reductions in intravenous antibiotic use, particularly ceftriaxone. Inflation-adjusted cost savings on antibiotics were ZAR3.2 million over 4 years. Laboratory tests increased over the same period with a total increased cost of ZAR0.4 million. There was no significant change in mortality or 30-day readmission rates. Conclusions. The effects of a comprehensive ASP on medical inpatients at a public sector hospital in SA were durable over 4 years, leading to a reduction in total antibiotic consumption without adverse effect. When increased laboratory costs were offset there was a net cost saving of ZAR2.8 million. S Afr Med J 2017;107(2):115-118. DOI:10.7196/SAMJ.2017.v107i2.12067

Methods Setting

Groote Schuur Hospital, the 945-bed tertiary academic teaching hospital of the University of Cape Town, offers medical, surgical, obstetric, psychiatric and emergency care to Cape Townâ&#x20AC;&#x2122;s Metro West population. Four wards are dedicated to long-stay (>48 hours) acute general internal medicine admissions, and consultant-led antibiotic prescribing is the norm.

AS intervention

The activities of the ASP have been presented previously in 2012.[14] Briefly, we instituted a dedicated antibiotic prescription chart and dedicated antibiotic stewardship ward rounds, which alternated weekly between two medical wards. Rounds were led by an infectious diseases subspecialist, and the team included medical microbiologists, pharmacists, infection prevention control practitioners and the junior clinicians directly responsible for the patientsâ&#x20AC;&#x2122; care. Each patient on a ward was reviewed individually and a pertinent history was given regarding antibiotic prescribing and the use of intravenous cannulas and urinary catheters. Each case was then discussed, an action plan agreed upon and education around AS imparted.

February 2017, Print edition

RESEARCH

Patient data

Data on inpatient mortality and hospitalwide, all-cause readmission to Groote Schuur Hospital within 30 days of discharge were obtained from the hospital electronic admissions database (Clinicom).

Ethics

The study was approved by the Human Research Ethics Committee of the Faculty of Health Sciences, University of Cape Town (ref. no. 004/2012). DDDs/1 000 patient bed days

Change in antibiotic consumption

The total consumption of antibiotics on the four wards in 2011 was 1 046 DDD/1 000 patient bed days. There was no change overall in 2012, but in each of the subsequent years there was a decrease of approximately 18% compared with 2011. This reduction was driven mainly by decrease in intravenous antibiotic consumption, which fell by 25 30% in the years 2013 - 2015, compared with 2011. By contrast, there was very little

250

2011

200 150

2012 2013

100

2014

2015

he rs Ot

cil

lin

lyc os

id es pe ni cil lin Ce f tr ia xo Ca ne rb ap en em s Cl ox ac illi Co n -a m ox icl av M ac ro lid Va es nc om yc in

Antibiotic consumption

Fig. 1. Changes in use of intravenous antibiotics on four medical wards over 5 years (2012 - 2015 and the control period 2011). 2 500 000

Expenditure Savings

2 000 000

Cost (ZAR)

Electronic pharmacy dispensing records were used to calculate consumption and cost of antibiotics, with oral and parenteral formulations of the same antibiotic treated separately. Antibiotics used to treat mycobacterial, parasitic and fungal infections, including co-trimoxazole, were excluded. Antibiotic use during the intervention period (1 January 2012 31 December 2015) was compared with that during the control period (1 January 2011 - 31 December 2011). Consumption of antibiotics was converted into defined daily doses (DDDs) according to the World Health Organization standard. All costs were adjusted for inflation using the SA Consumer Price Index (CPI) (December 2012 = 100).

Results

There have been important changes to the ASP since 2012. Ward rounds have been extended to cover all four of the internal medicine wards on a weekly basis, and as institutional knowledge has increased, ward rounds have been able to focus on smaller numbers of patients with complex problems rather than including every patient on all four wards. Initially, certain antibiotics were restricted and required release by a microbiologist or infectious diseases physician; these were intravenous ciprofloxacin, carbapenems, piperacillintazobactam, colistin, tigecycline, aztreonam, linezolid and vancomycin. In March 2013 the restrictions for intravenous ciprofloxacin, ertapenem, piperacillin-tazobactam and vancomycin were lifted, although release by the consultant responsible for the patient was still required.

1 500 000 1 000 000 500 000

Laboratory tests

The number and costs of blood culture (BC), full blood count (FBC), white blood cell count differential (WBC), C-reactive protein (CRP) and procalcitonin (PCT) requests were calculated from the National Health Laboratory Service database.

0 2011

2012

2013

2014

2015

Year Fig. 2. Direct cost of antibiotics used on four medical wards over 5 years (2012 - 2015 and the control period 2011). Costs adjusted for inflation using SA CPI: December 2012 = 100.

Table 1. Antibiotic use on four medical wards over 5 years (2012 - 2015 and the control period 2011)

Year

All antibiotics, DDDs/1 000 patient bed days

2011

1 046

2012

1 061

Change in all antibiotics since 2011, %

Intravenous antibiotics, DDDs/ 1 000 patient bed days

Change in intravenous antibiotics since 2011, %

Oral antibiotics, DDDs/1 000 patient bed days

–0.1

470

592 +1.5

591

Change in oral antibiotics since 2011, %

454 +3.5

2013

868

–17.1

411

–31

457

+0.7

2014

843

–19.4

409

–31

434

–4.4

2015

864

–17.4

443

–25

421

–7.3

February 2017, Print edition

RESEARCH

Table 2. Direct cost of antibiotics used on four medical wards over 5 years (2012 - 2015 and the control period 2011) Decrease from 2011* (ZAR)

Decrease from 2011, %

1 800 808

390 786

2013

1 277 481

914 113

2014

1 236 797

954 796

2015

1 187 942

1 003 652

Year

Cost* (ZAR)

2011

2 191 594

2012

*Costs adjusted for inflation using the SA CPI: December 2012 = 100.

Table 3. Cost of infection-related blood tests (BC, FBC, WBC, CRP and PCT) requested from four medical wards over 5 years (2012 - 2015 and the control period 2011) Increase from 2011* (ZAR)

Increase from 2011, %

721 280

216 947

2013

575 875

71 542

2014

546 936

42 603

2015

575 144

70 811

Year

Costs* (ZAR)

2011

504 333

2012

Tests/1 000 patient bed days, n

*Costs adjusted for inflation using the SA CPI: December 2012 = 100. 1 000

FBC BC CRP

100

Table 4. Patient outcomes on four medical wards over 5 years

Year

Inpatient days

Average length of stay (days)

Mortality rate, deaths/ admission

Readmissions, %

2011

39 578

7.4

0.12

9.6

2012

37 033

7.3

0.12

10.4

2013

41 428

6.5

0.12

11.1

2014

42 621

6.8

0.12

10.3

2015

42 995

7.6

0.12

11.0

WBC PCT

1 2011

2012

2013

2014

2015

Year

Fig. 3. Numbers of requests for infection-related investigations from four medical wards over 5 years (2012 - 2015 and the control period 2011).

difference in consumption of oral antibiotics over this period (Table 1). The change in consumption of individual intravenous antibiotics is shown in Fig. 1. There were consistent reductions in most antibiotics, notably a 54% reduction in use of ceftriaxone between 2011 and 2015. An exception was cloxacillin, which increased by 56% over the same period, coinciding with increased education around the correct recommended dose.

Change in antibiotic cost

The inflation-adjusted cost of antibiotics was ZAR2 191 594 in 2011 and lower for each of the subsequent years. By 2015, inflationadjusted cost was 46% lower than in 2011 (Table 2, Fig. 2). The total saved over the 4 years was ZAR3 263 340.

Laboratory tests

Fig. 3 shows the trend in use of infection-related laboratory tests over the study period. The number of requests for FBCs and BCs rose from 162 to 204, and 24.7 to 30.9 per 1 000 patient bed days, respectively. PCT requests peaked in 2012 shortly after their introduction and subsequently declined year on year. The inflation-adjusted cost of these tests was ZAR504 333 in 2011, peaking at ZAR721 280 in 2012 (43% above baseline), before falling to <15% above baseline for the subsequent 3 years (Table 3). The total extra spending on tests over 4 years was ZAR401 903.

Inpatient mortality and readmission rates

The total number of patient days increased over the duration of the study from <39 000 in 2011 to almost 43 000 in 2015. During this time the mortality rate remained constant at 0.12 deaths/admission and only non-significant changes in the readmission rate were observed (Table 4).

Discussion

This study confirms that the introduction of an ASP into a public sector hospital in SA is feasible, and can produce a sustained reduction

in antibiotic consumption without compromising patient care. As there was no significant change in oral antibiotic consumption over the intervention period, our results suggest that the main driver of inappropriate antibiotic use in our hospital was unnecessary intravenous antibiotics. Our results showing ~18% reduction in antibiotic use are consistent with a systematic review of change in antibiotic prescribing for controlled before-after studies where the median reduction in antibiotic usage was 17.7%.[13] Our ASP realised a >40% reduction in direct antibiotic costs from the second year onwards, and a much smaller rise in the cost of laboratory tests despite an 8.6% increase in patient bed days from 2011 to 2015. It is noteworthy that the 19.6% reduction in antibiotic use reported in our pilot study intervention was maintained as the ASP was rolled out to all four wards. Total cost savings are likely to be much higher than the direct costs of the antibiotics themselves when the reduction in use of consumable items such as intravenous giving sets and cannulas, as well as savings in nurses’ time, are taken into account. Although we have not been able to demonstrate reductions in complications such as peripheral line infections and Clostridium difficile-associated diarrhoea (CDAD), these are strongly associated with reductions in use of intravenous therapy and broad-spectrum antibiotics. The ASP is a multifaceted programme and it is therefore not possible to determine which of the individual features has been most successful. Our impression however has been that dedicated weekly ward rounds with AS ‘champions’, where fundamental principles of stewardship are reinforced, have led to an improved knowledge base, particularly in the registrar grade of doctors. Registrars rotate through the general internal medicine wards on a 3-monthly basis and many have returned for more than one rotation, which reinforces their learning. Interestingly, the medical consultants have not attended rounds despite invitation to do so, which has created an unexpected tension in that junior doctors are often better educated than their seniors when it comes to optimal antibiotic prescribing. With the continued hierarchical approach to medicine in SA, this is creating a barrier to patients receiving optimal antibiotic management.

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Our study has a number of limitations. Owing to its observational design we were unable to control for any confounding variables that may affect antibiotic prescribing. We are also unable to determine the effects of our intervention on important patient-orientated outcomes such as rates of CDAD or multidrug-resistant Gram-negative bloodstream infections. However, it has previously been shown that reduction in antibiotic use leads to reductions in resistance rates[15] and it is reasonable to assume that our intervention has had an effect in this area. A further limitation is the lack of potential reproducibility of the intervention in hospitals across SA and in other resource-limited settings. As the O’Neill report[12] has highlighted, investment in persons practising infection-related specialties in the workplace has been poor and SA is no exception, with a severe shortage in infectious diseases specialists and microbiologists in particular. However, we would contend that AS champions who can create change and optimise antibiotic use in hospitals do not have to be limited to these role-players. To this end, two national training centres for AS have been funded, and the first 5-day trainthe-trainer course was held at Groote Schuur Hospital in July 2016. The express objective of this initiative is to address inequity of access to healthcare practitioners with expertise in AS in provinces that have limited or no infection specialists and no ASPs currently in place. The first course hosted trainees from six hospitals in the Eastern Cape, and provided practical teaching on how to set up an ASP and perform AS rounds. Follow-up visits to each hospital will help mentor teams in the development of their ASPs. The recent demonstration that a non-specialist pharmacist intervention in Netcare hospitals across SA was able to achieve similar reductions in consumption highlights the opportunity to develop a number of different ASP models within SA that could be tailored to different settings.[16] ASPs centred around nurses have yet to be trialled, but the success of task-shifting antiretroviral treatment management from doctors to nurses in the STRETCH model,[17] suggests that this cadre of healthcare professional could be an important addition to stewardship programmes within and outside SA.

Conclusions

The cost savings realised as a result of our ASP should be of interest to hospital, provincial and national health managers, as well as key operators in the private sector, including medical aids. ASPs can not only fund themselves, but potentially be a source of revenue to put back into infection prevention and quality improvement programmes

improving patient safety related to infection. Internationally, ASPs are recognised as reducing length of hospital stay, affecting already overburdened health institutions.[18] Future work in this area will focus on the reproducibility of our intervention in other healthcare settings, as a result of the national training programme. Additionally, further research is needed on combining different models of ASP in low-resource settings. 1. Ardal C, Outterson K, Hoffman SJ, et al. International cooperation to improve access to and sustain effectiveness of antimicrobials. Lancet 2016;387(10015):296-307. http://dx.doi.org/10.1016/S01406736(15)00470-5 2. Coetzee J, Corcoran C, Prentice E, et al. Emergence of plasmid-mediated colistin resistance (MCR-1) among Escherichia coli isolated from South African patients. S Afr Med J 2016;106(5):449-450. http://dx.doi. org/10.7196/SAMJ.2016.v106i5.10710 3. Mendelson M, Matsoso MP. The World Health Organization Global Action Plan for antimicrobial resistance. S Afr Med J 2015;105(5):325. http://dx.doi.org/10.7196/SAMJ.9644 4. Perovic O, Singh-Moodley A, Duse A, et al. National sentinel site surveillance for antimicrobial resistance in Klebsiella pneumoniae isolates in South Africa, 2010 - 2012. S Afr Med J 2014;104(8):563-568. http:// dx.doi.org/10.7196/SAMJ.7617 5. Center for Disease Dynamics, Economics and Policy. Resistance Map. http://resistancemap.cddep.org/ (accessed 12 August 2016). 6. Brink A, Coetzee J, Clay C, et al. The spread of carbapenem-resistant Enterobacteriaceae in South Africa: Risk factors for acquisition and prevention. S Afr Med J 2012;102(7):599-601. http://dx.doi.org/10.7196/ SAMJ.5789 7. Dellit TH, Owens RC, McGowan JE Jr, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis 2007;44(2):159-177. http://dx.doi.org/10.1086/510393 8. Lepper PM, Grusa E, Reichl H, Hogel J, Trautmann M. Consumption of imipenem correlates with betalactam resistance in Pseudomonas aeruginosa. Antimicrob Agents Chemother 2002;46(9):2920-2925. http:// dx.doi.org/10.1128/aac.46.9.2920-2925.2002 9. Mendelson M, Rottingen JA, Gopinathan U, et al. Maximising access to achieve appropriate human antimicrobial use in low-income and middle-income countries. Lancet 2016;387(10014):188-198. http:// dx.doi.org/10.1016/S0140-6736(15)00547-4 10. Visser A, Moore DP, Whitelaw A, et al. Global antibiotic resistance partnership situation analysis: Antibiotic use and resistance in South Africa: Part VII. Interventions. S Afr Med J 2011;101(8):587-595. 11. Levy SB, Marshall B. Antibacterial resistance worldwide: Causes, challenges and responses. Nat Med 2004;10(12 Suppl):S122-S129. http://dx.doi.org/10.1038/nm1145 12. O’Neill J. Review on antimicrobial resistance. Tackling drug-resistant infections globally. 2016. https:// amr-review.org/sites/default/files/160518_Final%20paper_with%20cover.pdf (accessed 7 December 2016). 13. Davey P, Brown E, Charani E, et al. Interventions to improve antibiotic prescribing practices for hospital inpatients. Cochrane Database Syst Rev 2013, Issue 4. Art. No.: CD003543. http://dx.doi. org/10.1002/14651858.CD003543.pub3 14. Boyles TH, Whitelaw A, Bamford C, et al. Antibiotic stewardship ward rounds and a dedicated prescription chart reduce antibiotic consumption and pharmacy costs without affecting inpatient mortality or readmission rates. PLoS One 2013;8(12):e79747. http://dx.doi.org/10.1371/journal.pone.0079747 15. Friedman CR, Whitney CG. It’s time for a change in practice: Reducing antibiotic use can alter antibiotic resistance. J Infect Dis 2008;197(8):1082-1083. http://dx.doi.org/10.1086/533450 16. Brink AJ, Messina AP, Feldman C, et al. Antimicrobial stewardship across 47 South African hospitals: An implementation study. Lancet Infect Dis 2016;16(9):1017-1025. http://dx.doi.org/S1473-3099(16)30012-3 17. Fairall L, Bachmann MO, Lombard C, et al. Task shifting of antiretroviral treatment from doctors to primary-care nurses in South Africa (STRETCH): A pragmatic, parallel, cluster-randomised trial. Lancet 2012;380(9845):889-898. http://dx.doi.org/10.1016/S0140-6736(12)60730-2 18. Bauer KA, West JE, Balada-Llasat JM, Pancholi P, Stevenson KB, Goff DA. An antimicrobial stewardship program’s impact. Clin Infect Dis 2010;51(9):1074-1080. http://dx.doi.org/10.1086/656623

Accepted 4 October 2016.

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

RESEARCH

Antibiotic prescription patterns of South African general medical practitioners for treatment of acute bronchitis N B Q Ncube,1 MSc (Med Sc); G C Solanki,2 DrPH; T Kredo,3 MSc; R Lalloo,4 PhD School of Public Health, Faculty of Community and Health Sciences, University of the Western Cape, Cape Town, South Africa Towers Watson, Cape Town, South Africa; and Health Economics Unit, Department of Public Health, Faculty of Health Sciences, University of Cape Town, South Africa 3 Cochrane South Africa, South African Medical Research Council, Cape Town, South Africa 4 School of Dentistry, Faculty of Health Sciences, University of Queensland, Brisbane, Australia 1 2

Corresponding author: N B Q Ncube (nncube@uwc.ac.za) Background. Antibiotic resistance is a significant public health problem. Prudent use of antibiotics is crucial in reducing this resistance. Acute bronchitis is a common reason for consultations with general medical practitioners, and antibiotics are often prescribed even though guidelines recommend not prescribing them for uncomplicated acute bronchitis. Objective. To analyse the antibiotic prescription patterns of South African (SA) general medical practitioners in the treatment of acute bronchitis. Methods. The 2013 claims for members of 11 health insurance schemes were analysed to assess antibiotic prescription patterns for patients diagnosed with acute bronchitis. The patterns were assessed by type of bronchitis, chronic health status of the patients, sex and age group. The types of antibiotic prescribed were also analysed. Results. Of 166 821 events analysed, an antibiotic was prescribed in more than half (52.9%). There were significant differences by type of bronchitis and chronic health status. Patients with viral bronchitis were more likely to be prescribed an antibiotic than those with bacterial bronchitis (odds ratio (OR) 1.17, 95% confidence interval (CI) 1.08 - 1.26). Patients with a chronic illness were less likely to be prescribed an antibiotic than those without (OR 0.58, 95% CI 0.57 - 0.60). More than 70% of the antibiotics prescribed were cephalosporins, penicillins and other beta-lactams. Conclusions. Prescription rates of antibiotics for acute bronchitis by SA general medical practitioners are high. There is an urgent need to follow the guidelines for antibiotic use for acute bronchitis to reduce the likelihood of increasing resistance to available antibiotics. S Afr Med J 2017;107(2):119-122. DOI:10.7196/SAMJ.2017.v107i2.11276

While antibiotics save millions of lives globally each year, their indiscriminate use poses an increasingly serious threat to public health.[1] The emergence of antibiotic resistance is of significant concern, with the Centers for Disease Control and Prevention having estimated that in the USA alone, at least two million illnesses and 23 000 deaths are caused by antibiotic-resistant bacteria.[2] The emergence of antibiotic-resistant bacteria adversely affects mortality, treatment costs, disease spread and duration of illness, and increases pressure on the choice of appropriate antibiotics as more first-line antibiotics are used for self-limiting conditions and bacteria become resistant to these.[3] Acute bronchitis is a common reason for consultations with a general medical practitioner, and antibiotics are often prescribed to treat this self-limiting and usually viral condition.[4,5] A Cochrane review highlights the fact that considerable research has been done on the effectiveness of using antibiotics in the treatment of acute bronchitis.[4] For patients presenting with acute bronchitis, the National Institute for Health and Care Excellence (NICE) guidelines[6] recommend that unless a patient is at high risk, a no-antibiotic prescribing strategy or a delayed antibiotic prescribing strategy should be agreed on with the patient. Based on the NICE guidelines, a patient is considered to be at high risk if he or she is systemically very unwell, has symptoms suggestive of serious illness/or complications, is at risk of complications because of pre-existing comorbidity, is a young child

born prematurely, or is >65 years old with acute cough and two or more of the following criteria (or >80 years old with acute cough and one or more of the following criteria): (i) hospitalisation during the previous year; (ii) type 1 or type 2 diabetes; (iii) a history of congestive heart failure; and (iv) current use of oral glucocorticoids. For these patients, the no-antibiotic prescribing strategy and the delayed antibiotic prescribing strategy should not be considered.[6] The South African (SA) Standard Treatment Guidelines and Essential Medicines List (SA STG/EML)[7] for the primary healthcare level recommends that antibiotics should not be given for uncomplicated acute bronchitis, but should be considered in patients infected with HIV as they are at a high risk of developing bacterial lower respiratory tract infections.[7] For HIV-infected patients, the guidelines recommend prescribing penicillin for 5 days, or a macrolide-like azithromycin for 3 days in penicillin-allergic patients. [7] For all other patients, if an antibiotic is prescribed, amoxicillin or tetracycline should be the first choice, while in the case of penicillin allergy, a tetracycline or macrolide is a good alternative.[8] Studies from the USA show that broad-spectrum macrolides are increasingly being prescribed for acute bronchitis, and this is not an appropriate choice considering both international and local recommendations.[9,10] While national and international guidelines for treating acute bronchitis do not recommend the use of antibiotics,[4,6,7,11,12] more than 50% of patients are prescribed one.[3] A study summarising multistage

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probability surveys of ambulatory care in the USA reported a prescription rate of 71% between 1996 and 2010, from 60 - 80% between 1980 and 1999. [9] A study in The Netherlands focusing on children reported a prescription rate of 46% for a diagnosis of acute bronchitis.[13] In SA there is limited information on the antibiotic prescribing patterns of general medical practitioners for acute bronchitis.

Objective

The objective of this exploratory study was to analyse the antibiotic prescription patterns of SA health insurance-linked general medical practitioners treating patients with acute bronchitis, and to assess the extent to which the prescribing patterns are in alignment with evidence-informed clinical guidelines.

Methods

Approximately 8.78 million lives were covered by private health insurance (medical aid) schemes in SA in 2013. For this study, the 2013 claims for members of 11 health insurance schemes comprising 1.04 million lives (11.8% of the insured population) were analysed. Data for the study were obtained from the data warehouse of Towers Watson, an independent consulting firm providing consulting and actuarial services to SA health insurance schemes and pension funds. The company does not advise its clients on the use of the antibiotics and therefore had no vested interest in the outcome of the study. Data for the study were made available as part of Towers Watson’s commitment to support research initiatives with broader public health significance. The data were accessed in terms of and under the conditions set out in the consulting agreement between Towers Watson and their client schemes. The data were analysed by Towers Watson internally and were not made available to any other third party. All findings were presented at an aggregate level, and at no point was confidential scheme or member information disclosed. For this study, the claims submitted to medical schemes for reimbursement of services rendered or items dispensed to members in the treatment of acute bronchitis were analysed. For each of these claims, the health provider submits a claim to the medical scheme that has at least the following information: (i) a unique identifier for the patient being treated; (ii) the date on which the service was rendered; (iii) a unique identifier for the provider providing the services; (iv) a code and description for each service rendered/item dispensed; (v) the

ICD-10 (10th revision of the International Statistical Classification of Diseases and Related Health Problems) code for the diagnosis of the condition being treated; (vi) a Current Procedural Terminology (CPT) code for the procedure carried out; (vii) a National Pharmaceutical Product Index (NAPPI) code for any surgical, medical or consumable item dispensed; and (viii) the amount being claimed. An underlying assumption of the analysis was that all the claims for a patient on the same date were related to the same ‘event’. An ‘event’ was defined as consisting of all claims with the same service date from general practitioners and pharmacists related to the treatment of acute bronchitis for a particular patient. If the claims related to an event included any of the ICD-10 codes listed in Table 1, the event was defined as an ‘acute bronchitis’ event. Each acute bronchitis event was further categorised into one of three types (bacterial, viral, or unknown/ unspecified), based on the ICD-10 code categorisation as set out in Table 1. An event was considered to be positive for antibiotic prescription if there was a claim related to the event for any of the following categories of antibiotics: penicillins, fluoroquinolones, erythromycin and other macrolides, tetracyclines, and chloramphenicol. Again, the underlying assumption was that if there was an antibiotic claim and a claim for the treatment of acute bronchitis on the same day, the antibiotic claim was related to the treatment of acute bronchitis. The study was limited to analyses and claims related to the first visit for an episode of acute bronchitis. Claims related to repeat visits for the same episode (acute bronchitis events for the same patient within a 7-day period) were excluded.

The SA STG/EML guidelines[7] recommend that antibiotics should not be given for uncomplicated acute bronchitis, except for patients co-infected with HIV. The NICE guidelines recommend a no-antibiotic or delayed prescribing strategy unless the patient is at high risk of developing complications when he or she has acute bronchitis (e.g. chronically ill patients), is >65 years of age and has other co-morbidities, or has been confirmed to have a bacterial infection.[6] Given the limitations of the data available for this study, the extent to which prescribing patterns were in alignment with these clinical guidelines was assessed by analysing antibiotic prescription patterns by acute bronchitis type (bacterial, viral, unknown/unspecified), age (≤5 years, 6 65 years, >65 years), gender (male, female) and medical status (chronic if the member had asthma, a cardiovascular disease, diabetes mellitus or HIV infection; non-chronic if the member did not have any of the stated conditions). Within these analytical categories, older patients (>65 years) and/or patients with chronic conditions (regardless of age) were generally considered to fall into the ‘high-risk’ category and were expected to have higher prescription rates. Chronic status of a member was determined on the basis of ongoing medicine use by the member. A logistic regression model was used to test the adjusted statistical significance of the association between the exploratory variables (bronchitis type, gender, age group and chronic status) and the dependent variable (antibiotic prescription). Sample sizes, percentages and odds ratios (ORs) with 95% confidence intervals (CIs) are reported, a 95% CI excluding 1 being considered statistically significant. The type of antibiotic prescribed was also assessed by type of acute bronchitis.

Table 1. Classification of acute bronchitis types by ICD-10 code Acute bronchitis type

ICD code

World Health Organization full description

Bacterial (antibiotics may be indicated)

J20.0

Acute bronchitis due to Mycoplasma pneumoniae

0.6

J20.1

Acute bronchitis due to Haemophilus influenzae

2.3

J20.2

Acute bronchitis due to Streptococcus

2.9

Viral (antibiotics not indicated)

J20.3

Acute bronchitis due to Coxsackie virus

0.1

J20.4

Acute bronchitis due to parainfluenza virus

1.5

J20.5

Acute bronchitis due to respiratory syncytial virus

0.3

J20.6

Acute bronchitis due to rhinovirus

0.4

J20.7

Acute bronchitis due to echovirus

0.0

J20

Acute bronchitis

0.0

J20.8

Acute bronchitis due to other specified organisms

5.3

J20.9

Acute bronchitis; unspecified

86.6

Type unknown/ unspecified

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Ethics approval

Ethics approval for the study was granted by the University of the Western Cape’s Senate Research Committee, project registration number 15/3/24.

Results

Of the 1 043 653 lives analysed, 48.5% were female. By age group, 8.5% were ≤5 years, 82.8% 6 - 65 years and 8.7% >65 years old. The average age was 32 years. A quarter (24.8%) of members had a chronic condition. Thirtyfour percent of the claims for acute bronchitis were from Gauteng Province, 17.2% from the Western Cape, 15.6% from KwaZulu-Natal, 10.4% from the Eastern Cape, 6.4% from the Free State, 6.2% from Mpumalanga, 5.0% from the Northern Cape, 3.0% from North West and 2.1% from Limpopo. There were 166 821 acute bronchitis events in the study population during the study

period. Causative agents for acute bronchitis were determined according to the ICD-10 codes listed in Table 1. Table 2 sets out the proportions of prescription rates for acute bronchitis by type of infection, gender, age, and whether a patient had a coexisting chronic condition or not. Antibiotics were prescribed in 52.9% of the acute bronchitis events (Table 2). However, there was some variation in prescription patterns across the various analytical categories. Compared with an antibiotic prescription rate of 53.6% for bacterial events, the prescription rate for viral events was significantly higher (59.2%; OR 1.17, 95% CI 1.08 - 1.26) and that for unknown/unspecified events significantly lower (52.7%; OR 0.95, 95% CI 0.91 0.99). Prescription rates for patients with a chronic condition (38.2%) were significantly lower than those for patients without any of the specified chronic conditions (56.3%;

Table 2. Acute bronchitis events and prescription rates

Events, n (%)

Antibiotic prescribed, n (%)

Adjusted OR (95% CI)

Overall

166 821 (100)

88 193 (52.9)

Bronchitis type

Bacterial

9 551 (5.7)

5 119 (53.6)

Viral

3 987 (2.4)

2 360 (59.2)

1.17 (1.08 - 1.26)*

Unknown/unspecified

153 283 (91.9)

80 714 (52.7)

0.95 (0.91 - 0.99)*

Female

80 933 (48.5)

41 132 (50.8)

Male

85 888 (51.5)

47 061 (54.8)

1.15 (1.13 - 1.17)*

Gender

Age group (years)

≤5

28 180 (16.9)

16 691 (59.2)

1.19 (1.16 - 1.22)*

6 - 65

129 268 (77.5)

69 107 (53.5)

>65

9 373 (5.6)

2 395 (25.6)

0.41 (0.39 - 0.43)*

Chronic

135 515 (81.2)

76 240 (56.3)

Yes

31 306 (18.8)

11 953 (38.2)

0.58 (0.57 - 0.60)*

*p<0.01.

OR 0.58; 95% CI 0.57 - 0.60). There were also significant differences in rates of antibiotic prescriptions by sex and age group. More males than females were prescribed antibiotics, and patients aged >65 years were less likely to be prescribed antibiotics than younger patients (OR 0.41, 95% CI 0.39 - 0.43). Penicillins (27.0%), cephalosporins (5.7%) and other beta-lactams were the most commonly prescribed antibiotics (Table 3). Overall, almost 72% of prescriptions were for these antibiotics.

Discussion

Based on the study findings, health insurance-linked general practitioners prescribed antibiotics in just over half of the acute bronchitis events that presented to them. While prescribing antibiotics for acute bronchitis events of a bacterial nature may be justified if a patient is at high risk of developing complications, the NICE[6] and SA STG/EML[7] guidelines suggest that antibiotics should not be prescribed for uncomplicated bacterial bronchitis or viral bronchitis, or where the causative agent is unknown. In this study, almost 92% of acute bronchitis was unknown or unspecified. Use of antibiotics in the viral and unknown/ unspecified events is therefore considered inappropriate. With regard to age, based on the NICE guidelines, antibiotic use may be justified if the patient is >65 years of age and has a chronic illness.[6] Results from this study indicate that after adjusting for all other exploratory factors, patients aged >65 years were least likely to receive antibiotics when presenting for treatment of acute bronchitis. Similarly, with regard to medical status, both the NICE[6] and SA[7] guidelines broadly recommend that use of antibiotics in the treatment of acute bronchitis be limited to patients with chronic illnesses. The limitations of the data used for this study did not allow for the identification of chronically ill individuals as defined by

Table 3. Type of antibiotics prescribed by type of acute bronchitis Acute bronchitis type Unknown/ unspecified, n (%)

Bacterial, n (%)

Viral, n (%)

Total, N (%)

Cephalosporins, penicillins, other beta-lactams

57 342 (71.0)

3 892 (76.0)

1 852 (78.5)

63 086 (71.5)

Protein synthesis inhibitors

Macrolides, tetracyclines

8 858 (11.0)

579 (11.3)

179 (7.6)

9 616 (10.9)

DNA synthesis inhibitors

Quinolones

3 869 (4.8)

224 (4.4)

140 (5.9)

4 233 (4.8)

Folic acid inhibitors

Sulphonamides and combinations

1 220 (1.5)

28 (0.5)

70 (3.0)

1 318 (1.5)

Other combinations

9 425 (11.7)

396 (7.7)

119 (5.0)

9 940 (11.3)

Mechanism of action

Type of antibiotic

Cell wall synthesis inhibitors

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both the guidelines. Instead, individuals with asthma, cardiovascular diseases, diabetes mellitus or HIV were used as a crude proxy. The sample for HIV-positive patients was too small for a separate analysis. After adjusting for all other exploratory factors, chronically ill individuals, as defined above, were significantly less likely to be prescribed antibiotics than non-chronically ill individuals. Data collected for this study did not allow us to explain the lower rates of antibiotic prescription for the elderly and medically compromised patients. It is possible that older patients and those with chronic illnesses were already on numerous medications, and practitioners were more cautious in adding to this medication intake; however, this theory needs to be explored further using qualitative methods. Cephalosporins were the second most common beta-lactam prescribed. Neither the NICE[6] or SA[7] guidelines recommend cephalosporins in the treatment of acute bronchitis. Further studies need to be conducted to ascertain the use of cephalosporins to treat the condition. Findings of this study suggest that compliance with evidenceinformed clinical guidelines for the use of antibiotics to treat acute bronchitis is generally poor among general medical practitioners in SA. Reasons for the poor compliance may be related to concerns about maintaining the doctor-patient relationship, patient expectations, and the fact that general practitioners are ‘just used to prescribing antibiotics’,[3] as found in other settings. There is therefore a need for practitioners to discuss the nature of the condition, i.e. that it is self-limiting but symptoms may persist for about 3 weeks, and that antibiotics are unlikely to be effective or substantially reduce the time to recovery.[14] As recommended by the NICE guidelines,[6] the practitioner should also consider a delayed antibiotic prescription. Practitioners may also consider rapid tests such as C-reactive protein (CRP) rapid testing, as CRP testing has been shown to potentially reduce prescribing of antibiotics for patients with acute respiratory tract infections.[15] Research shows that antibiotic prescription is lower when these tests are used to make a decision for prescribing antibiotics.[3] Poor compliance of general practitioners with guidelines in the use of antibiotics for the treatment of acute bronchitis as found in this study raises concerns at two levels. Firstly, it raises questions regarding the appropriateness of antibiotic use in the treatment of other acute respiratory tract infections (ARTIs). Many studies have shown that there is little or no benefit in treating predominantly viral ARTIs with antibiotics.[3] Despite the evidence, the use of antibiotics to treat acute upper respiratory tract conditions remains common. Secondly, studies elsewhere have attributed increasing antimicrobial resistance to inappropriate use of antibiotics for selflimiting conditions,[16] and the findings of this study raise concerns regarding the contribution inappropriate antibiotic use is making towards the growing public health concern of antibiotic resistance.

Study limitations

This study has a number of limitations. The ICD-10 codes as submitted by general practitioners were key to the analyses carried out for this study, yet there are questions around the accuracy and consistency of this coding. There is also some ambiguity regarding

which ICD-10 code should be used, e.g. the Department of Health lists J20 as acute bronchitis and J20.0 as acute bronchitis caused by Mycoplasma pneumoniae.[7] Another limitation is that we assumed that if the acute bronchitis consultation and antibiotic provision were on the same day, they were directly related. Also, members of the scheme who opted to pay cash for treatment were not captured in the analyses. Furthermore, the SA STG/EML guidelines[7] give HIV as a chronic condition for which patients with acute bronchitis should be prescribed antibiotics. However, we were not able to determine from our sample how many patients were co-infected with HIV (and hence used ‘presence of a chronic condition’ as an exploratory factor). Despite these limitations, we believe that the study findings are valuable in terms of prescribing of antibiotics for acute bronchitis.

Conclusions

Findings of this exploratory study point to the need for further research and work in the use of antibiotics for acute bronchitis. Further research, including qualitative methods to probe reasons for the use of antibiotics in treating acute bronchitis, will guide local understanding of the extent of practitioners’ non-compliance across all sectors in SA. Qualitative study approaches would be valuable in exploring the reasons for poor compliance and identifying contextspecific approaches to improve the implementation and uptake of antibiotic prescribing guidelines. Without action, we may well be faced with a reality in the near future where we are longer able to use antibiotics to treat common infections. 1. Editorial. Antibiotic resistance: Long-term solutions require action now. Lancet Infect Dis 2013;13(12):995. http://dx.doi.org/10.1016/S1473-3099(13)70290-1 2. Center for Disease Dynamics, Economics & Policy. State of the World’s Antibiotics, 2015. Washington, DC: CDDEP, 2015. 3. Llor C, Bjerrum L. Antibiotic prescribing for acute bronchitis. Expert Rev Anti Infect Ther 2016;14(7):633-642. http://dx.doi.org/10.1080/14787210.2016.1193435 4. Smith SM, Fahey T, Smucny J, et al. Antibiotics for acute bronchitis. Cochrane Database Syst Rev 2014, Issue 3. Art. No.: CD000245. http://dx.doi.org/10.1002/14651858.CD000245.pub3 5. Albert RH. Diagnosis and treatment of acute bronchitis. Am Fam Physician 2010;82(11):1345-1350. 6. National Institute for Health and Care Excellence. Respiratory Tract Infections (Self-limiting): Prescribing Antibiotics. London: NICE, 2008. 7. National Department of Health, South Africa. Standard Treatment Guidelines and Essential Medicines List for South Africa – Primary Health Care Level. Pretoria: NDoH, 2014. 8. Woodhead M, Blasi F, Ewig S, et al. Guidelines for the management of adult lower respiratory tract infections – full version. Clin Microbiol Infect 2011;17(Suppl 6):E1-E59. http://dx.doi.org/10.1111/ j.1469-0691.2011.03672.x 9. Barnett ML, Linder JA. Antibiotic prescribing for adults with acute bronchitis in the United States, 1996-2010. JAMA 2014;311(19):2020-2022. http://dx.doi.org/10.1001/jama.2013.286141 10. Grijalva CG, Nuorti JP, Griffin MR. Antibiotic prescription rates for acute respiratory tract infections in US ambulatory settings. JAMA 2009;302(7):758-766. http://dx.doi.org/10.1001/jama.2009.1163 11. Harris AM, Hicks LA, Qaseem A, et al. Appropriate antibiotic use for acute respiratory tract infection in adults: Advice for high-value care from the American College of Physicians and the Centers for Disease Control and Prevention. Ann Intern Med 2016;164(6):425-434. http://dx.doi.org/10.7326/ M15-1840 12. Woodhead M, Blasi F, Ewig S, et al. Guidelines for the management of adult lower respiratory tract infections – summary. Clin Microbiol Infect 2011;17(Suppl 6):1-24. http://dx.doi.org/10.1111/j.14690691.2011.03602.x 13. Ivanovska V, Hek K, Mantel Teeuwisse AK, et al. Antibiotic prescribing for children in primary care and adherence to treatment guidelines. J Antimicrob Chemother 2016;71(6):1707-1714. http://dx.doi. org/10.1093/jac/dkw030 14. Brink AJ, Cotton MF, Feldman C, Geffen L, Hendson W. Guideline for the management of upper respiratory tract infections. 2004. https://scholar.sun.ac.za/handle/10019.1/7133 (accessed 29 April 2016). 15. Andreeva E, Melbye H. Usefulness of C-reactive protein testing in acute cough/respiratory tract infection: An open cluster-randomized clinical trial with C-reactive protein testing in the intervention group. BMC Fam Pract 2014;15:80. http://dx.doi.org/10.1186/1471-2296-15-80

Accepted 14 October 2016.

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Adenovirus-associated pneumonia in South African children: Presentation, clinical course and outcome M Zampoli, MB BCh, FCPaed, Cert Paed Pulm; Z Mukuddem-Sablay, MB ChB, FCPaed, MMed Department of Paediatrics and Child Health, Red Cross War Memorial Children’s Hospital and Faculty of Health Sciences, University of Cape Town, South Africa Corresponding author: M Zampoli (m.zampoli@uct.ac.za) Background. Viruses have emerged as important aetiological agents of childhood pneumonia. Objective. To investigate the clinical presentation, severity and outcome of adenovirus-associated pneumonia (AVP) in children. Methods. A retrospective analysis of AVP cases over 12 months was performed, including demographic, clinical course and outcome (death, persistent lung disease (PLD)) data. Results. Two hundred and six AVP cases (median age 12 months, interquartile range 6 - 24) were identified; 70 children (34.0%) were malnourished and 14 (6.8%) were HIV-infected. Twenty-nine children (14.1%) developed PLD, which was associated with hypoxia at presentation in 26 cases (89.7%; p=0.01) and necessitated admission to the intensive care unit (ICU) in 18 (62.1%; p<0.01); 18/206 children (8.7%) died. Admission to the ICU (odds ratio (OR) 8.3, 95% confidence interval (CI) 2.3 - 29.0) and a positive blood culture (OR 11.2, 95% CI 2.3 - 54.1) were independent risk factors for mortality. Conclusions. Adenovirus is a potential cause of pneumonia and PLD in young children in South Africa. ICU admission and a positive blood culture were associated with poor outcome. S Afr Med J 2017;107(2):123-126. DOI:10.7196/SAMJ.2017.v107i2.11451

Respiratory tract infections remain a common and significant source of morbidity and mortality in children worldwide. This is of relevance in low- to middle-income countries where pneumonia is an important cause of death in children under 5 years of age.[1] With global access to effective immunisation programmes having resulted in a decline in the incidence of bacterial-associated pneumonia, respiratory viruses have emerged as important aetiological agents in childhood pneumonia. This holds true in high-income countries, where respiratory viruses are the commonest cause of childhood pneumonia.[1,2] Respiratory syncytial virus (RSV) is the leading viral cause of pneumonia in high- and low-income countries.[2-4] The prevalence of adenovirus by polymerase chain reaction (PCR) testing of nasopharyngeal aspirates in childhood pneumonia cases in South Africa (SA) has been reported to be 19 - 26%.[5,6] However, the pathogenic role of adenovirus in childhood pneumonia is unclear. Some studies report an increased prevalence of adenovirus in pneumonia cases, while others found a similar prevalence in population-matched controls.[6,7] The ability of some adenovirus strains to cause severe and fatal necrotising pneumonia has been described.[8.9] Furthermore, long-term sequelae following adenovirus-associated pneumonia (AVP), including bronchiectasis, bronchiolitis obliterans, unilateral hyperlucent lung and persistent abnormal pulmonary function, have been reported.[8,10-13] The clinical presentation, complications and outcome of AVP in SA children are unknown. Furthermore, the role of HIV infection and malnutrition in the outcome of AVP is unknown.

Objective

To document the presentation, clinical course and outcome of AVP at a tertiary paediatric referral hospital in SA.

Methods

Study design and patient selection

A retrospective descriptive study was conducted in children 0 13 years of age admitted with laboratory-confirmed AVP to Red Cross War Memorial Children’s Hospital (RCWMCH), a tertiary paediatric hospital in Cape Town, SA. Children admitted from 1 January to 31 December 2011 were included. For the purposes of the study, AVP was defined as clinician-diagnosed pneumonia or lower respiratory tract infection (LRTI; cough, tachypnoea with or without chest indrawing) and positive adenovirus PCR from any respiratory tract samples, which included tracheal aspirates, bronchoalveolar lavage, induced sputum and nose swabs or nasopharyngeal aspirates. Adenovirus subtypes were not identified in routine clinical samples. Children without pneumonia or LRTI documented in the records or laboratory request form details were excluded. The National Health Laboratory Service (NHLS) database was searched to extract all PCR adenovirus-positive respiratory samples with the diagnosis of pneumonia, bronchiolitis or LRTI collected in children admitted to RCWMCH during the study period. Respiratory viruses were identified using SeeplexRV7 Detection assay (Seegene, Korea), which includes influenza A and B, human metapneumovirus, RSV, rhinovirus A, parainfluenza virus and adenovirus.

Clinical and laboratory data

The medical records of identified patients were retrieved and relevant data were recorded on a data capture form. Clinical and demographic information at the time of hospital admission for community-acquired AVP cases, or acquisition of adenovirus infection in hospital-acquired AVP cases, was collected. The presence of fever (temperature >38oC for >48 hours), diarrhoea, conjunctivitis and skin rash was recorded. AVP cases were classified into community acquired or hospital

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acquired. Community-acquired AVP was defined as AVP confirmed within 48 hours of hospital admission. Hospital-acquired AVP was defined as AVP acquired >48 hours after hospital admission when the presenting illness on admission was not pneumonia. The HIV status of patients was classified as HIV-exposed but uninfected, HIV-infected or HIV-unexposed. In the HIV-infected group, CD4 count and percentage, HIV viral load and antiretroviral treatment details were recorded. The nutritional status of each child was determined by calculating the World Health Organization (WHO) weight-for-age z-score (WAZ score) using igrowup macro for Stata (WHO Anthro version 3.2.2; StataCorp, USA). Malnutrition was defined as a WAZ score of <–2. The presence of an underlying medical condition was recorded and categorised as cardiac, respiratory, renal, neurological, immune suppression, prematurity or other. Routine laboratory investigations recorded were total white cell count (WCC), haemoglobin, C-reactive protein (CRP) and procalcitonin (PCT) at the time of hospital admission. The presence of significant laboratory-confirmed co-infections was documented and recorded as other respiratory viruses, positive blood culture, and tuberculosis (TB) (positive culture of Mycobacterium tuberculosis from any site). Pneumonia severity was established according to the presence or absence of hypoxia at presentation (oxygen saturation <90% in room air), need for intensive care unit (ICU) admission and need for ventilator support. The ventilation modality and total duration of ventilation and ICU stay were recorded.

infections. Of the clinical features recorded, fever was the most common (76.4%). There was a high prevalence of underlying medical conditions, with 47.0% of participants having at least one underlying medical condition. All HIV-infected children (n=14) were previously undiagnosed; antiretroviral therapy was initiated in 12/14 (85.7%) during the same admission. The mean WCC on admission was 15 × 109/L (SD 8.0) and the mean haemoglobin concentration 11 g/dL (SD 2.0). The mean CRP and PCT were 20 mg/L (IQR 5 - 53, n=145) and 2.5 µg/L (IQR 1 - 12, n=10), respectively.

Pneumonia severity

Hypoxia was common, and present in 146/206 patients (70.9%); 76/ 206 (36.9%) needed ICU admission for respiratory support, of whom Table 1. Demographic, clinical and co-infection data in children with AVP, 1 January - 31 December 2011 (n=206) Demographic data Age at onset (mo.), median (IQR)

12.0 (6 - 24)

Male, n (%)

116 (56.3)

WAZ, mean (SD)

1.38 (1.91)

WAZ <–2, n (%)

70 (34.0)

Community acquired, n (%)

148 (71.8)

Hospital acquired, n (%)

58 (28.1)

Clinical features, n (%)

Outcome measures

Two outcome measures were examined: development of persistent lung disease (PLD) and in-hospital mortality. PLD was defined as the persistence of clinical signs of respiratory disease as documented in the medical records and/or need for supplemental oxygen beyond 30 days of hospital admission.

Data analysis

Data were collected and entered into EpiData Entry version 2.0 (Denmark). Thereafter statistical analysis was done using SPSS version 22.0 (IBM, USA). Data were tested for normality using the Shapiro-Wilks W-test. Continuous variables were expressed as means with standard deviations (SDs) for normally distributed variables or medians and interquartile ranges (IQRs) for nonnormally distributed variables. The Mann-Whitney U-test was used for comparing non-normally distributed measures and the t-test for normally distributed measures. Univariate analysis was conducted using Yates-corrected χ2 tests where cell values were <10. Multivariate logistic regression analysis was conducted for risk factors for death outcome using variables with a p-value of <0.05. Approval to conduct the study was obtained from the Human Research Ethics Committee of the University of Cape Town (ref. no. 120/2013).

Results

Between 1 January and 31 December 2011, a total of 1 910 respiratory samples were submitted to the NHLS from RCWMCH for viral PCR testing. After excluding children without a diagnosis of pneumonia, 206 AVP cases were identified for analysis, of which 65 (31.6%) were co-infected with other respiratory viruses.

Demographic and clinical characteristics (Table 1)

The median age was 12 months (IQR 6 - 24), with a slight male predominance. Of the study population, 34.0% (70/206) were malnourished and 71.8% (148/206) had community-acquired

Rash

5 (2.4)

Conjunctivitis

34 (16.5)

Fever (>38°C)

159 (76.4)

Diarrhoea

31 (15.0)

Underlying conditions, n (%) Cardiac

48 (23.3)

Respiratory

26 (12.6)

Neurological

15 (7.2)

Renal

4 (1.9)

Immune suppression

19 (9.2)

Prematurity

36 (17.4)

Other (including tracheostomy)

27 (13.1)

HIV status HIV-exposed, uninfected, n (%)

42 (20.3)

HIV-infected, n (%)

14 (6.7)

CD4%, median (IQR) (n=14)

18.1 (8 - 20.3)

HIV viral load (log × 10 ), median (IQR) (n=14)

6.4 (5.1 - 6.6)

Co-infections, n (%) Any viral co-infection

65 (31.5)

Rhinovirus

29 (14.0)

RSV

29 (14.0)

Influenza virus

8 (3.8)

Parainfluenza virus

6 (2.9)

Human metapneumovirus

5 (2.4)

11 (5.3)

Positive blood culture

11 (5.3)

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54/76 (71.1%) were mechanically ventilated, 31/76 (40.8%) received continuous positive airway pressure ventilation, and 13/76 (17.1%) needed high-frequency oscillatory ventilation. The median stay in the ICU was 9 days (IQR 4 - 17). The median length of hospital stay was 10 days (IQR 3 - 21).

Outcomes

Persistent lung disease Most children recovered completely (168/ 206, 81.6%) and were discharged with no sequelae. Twenty-nine children (14.1%) developed PLD. Hypoxia (p=0.016) and ICU admission (p=0.002) were significantly associated with the development of PLD. Viral co-infection (8/29 (27.6%) with PLD v. 57/177 (32.2%) without PLD; p=0.6) and TB (3/29 (10.3%) with PLD v. 8/177 (4.5%) without PLD; p=0.18) were not associated with PLD. Compared with children without PLD, children with PLD had a longer but non-significant median ICU stay (9 days v. 5 days; p=0.06) and a longer median hospital stay (41 days v. 9 days; p<0.001). In-hospital mortality (Table 2) Eighteen of the 206 children (8.7%) died. Hypoxia (p=0.02), ICU admission (p=0.01), underlying cardiac disease (p=0.02) and a positive blood culture (p=0.001) were associated with in-hospital mortality on univariate analysis (Table 2). Logistic regression analysis revealed that ICU admission (odds ratio (OR) 8.3, 95% confidence interval (CI) 2.3 - 29.0) and positive blood culture (OR 11.2, 95% CI 2.3 - 54.1) were independently associated with mortality. Underlying cardiac disease trended towards significant association with mortality (OR 2.88, 95% CI 0.98 - 8.5).

Discussion

This study investigated adenoviral respiratory infections in SA children, for which there were previously no data. In this study, adenovirus was isolated in 10.9% of all respiratory tract samples tested, highlighting the potential contribution of adenovirus to pneumonia aetiology in our setting. Furthermore, the study confirms previous reports of adenovirus causing severe pneumonia and significant morbidity in children, as supported by our data documenting 36.9% of patients needing ICU admission and 14.1% developing PLD.[14,15] An underlying medical condition and malnutrition was found in almost half and one-third of patients, respectively, which is consistent with previous studies. [9] Prematurity and congenital cardiac diseases were the most common underlying conditions, highlighting the vulnerability of children with these conditions to AVP. Underlying cardiac disease was not an independent risk factor for death in our analysis. However, this finding must be interpreted with caution owing to small numbers. Adenovirus is directly cardiotoxic, and is a common cause of myocarditis and dilated cardiomyopathy in children.[16] Children with heart disease are therefore likely to be at increased risk of acquiring severe pneumonia with further myocardial impairment secondary to the direct effects of adenovirus infection on the myocardium. In contrast to other studies, HIV exposure, HIV infection and malnutrition were not associated with mortality. The prevalence of HIV infection in this study was low (6.8%) and reflects effective strategies to prevent perinatally acquired HIV infection in SA.

Table 2. Clinical factors associated with in-hospital mortality in children with AVP Died, n (%)

Alive, n (%)

p-value

Age (mo.), median (IQR)

19 (10 - 36)

12 (6 - 24)

0.06

WAZ <–2

7/15 (46.6)

63/177 (35.5)

0.70

Underlying cardiac disease

8/18 (44.4)

40/188 (21.2)

0.02

Any viral co-infection

8/18 (44.4)

57/188 (30.3)

0.21

RSV co-infection

4/18 (22.2)

25/188 (13.2)

0.29

TB co-infection

0 (0)

11/177 (6.2)

0.60

Underlying respiratory disease

1/18 (5.5)

25/188 (13.2)

0.35

Immune suppression

2/18 (11.1)

17/188 (9.0)

0.70

Prematurity

3/18 (16.6)

33/188 (17.5)

0.92

HIV-exposed, uninfected

2/18 (11.1)

40/188 (21.2)

0.53

HIV-infected

0 (0)

14/188 (7.4)

0.61

Hypoxia

17/18 (94.4)

129/188 (68.6)

0.02

ICU admission

14/18 (77.7)

62/188 (32.9)

0.01

Positive blood culture

4/18 (22.2)

7/188 (3.7)

0.01

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A positive blood culture was also associated with increased mortality in this study. The synergistic effect produced by bacterial and viral co-infection resulting in more severe pneumonia has been described.[17] The severity of AVP as measured by hypoxia and need for ICU admission was associated with both development of PLD and death. This finding is consistent with previous studies looking at outcomes following adenoviral infections. A meta-analysis of longterm sequelae of childhood pneumonia from mostly developed countries found that adenovirus was associated with the highest prevalence of sequelae; more than half of AVP cases resulted in long-term sequelae of chronic obstructive pulmonary disease.[13] Three studies from South America identified mechanical ventilation, prolonged oxygen requirement and prolonged hospitalisation as risk factors for the development of bronchiectasis obliterans.[10-12] In a study by Murtagh et al.,[10] 36% had chronic sequelae and 15% died. In our study, 14.1% developed PLD and 8.7% died. The lower incidence of PLD and death in our cohort compared with the Argentinian study could be explained by different study design, different definition of PLD or different epidemiology of adenovirus serotypes and disease spectrum in our setting.

Study limitations

This study has several limitations. Firstly, the retrospective search for eligible patients may not have represented all AVP cases, as testing for respiratory viruses was not routinely performed on all children admitted with pneumonia. There may have been a bias towards more severe pneumonia cases in this study, as clinicians were likely to request viral testing when pneumonia was more severe. Secondly, the attributable role of adenovirus infection in pneumonia was not established owing to the lack of controls. However, co-infection with other viruses or TB was not associated with a worse outcome. Furthermore, evidence of community-acquired pneumonia causality and increased adenovirus-associated morbidity in a paediatric intensive care setting in our population has been described.[6,15] Lastly, we were unable to identify adenovirus serotypes in this study, as testing for serotype is not routinely offered in our setting. Knowledge of serotype patterns may explain some observed differences in the spectrum of AVP disease severity, as described elsewhere.[9]

Conclusions

Adenovirus is potentially an important and under-recognised cause of severe pneumonia and PLD in young children in SA. Severe AVP

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necessitating ICU admission and a positive blood culture are associated with poor outcome. Early recognition of severe AVP is important to identify children at risk of developing chronic sequelae of AVP. Acknowledgements. We thank Dr Marvin Hsiao of the NHLS, who helped with the database identification of eligible cases, and Ushma Galal for her invaluable assistance with the statistical analysis. Funding. Non-funded research. 1. Walker CL, Rudan I, Liu L, et al. Global burden of childhood pneumonia and diarrhoea. Lancet 2013;381(9875):1405-1416. http://dx.doi.org/10.1016/S0140-6736(13) 60222-6 2. Jain S, Williams DJ, Arnold SR, et al. Community-acquired pneumonia requiring hospitalization among U.S. children. N Engl J Med 2015;372(9):835-845. http://dx.doi.org/10.1056/NEJMoa1405870 3. Berkley JA, Munywoki P, Ngama M, et al. Viral etiology of severe pneumonia among Kenyan infants and children. JAMA 2010;303(20):2051-2057. http://dx.doi.org/10.1001/jama.2010.675 4. Rhedin S, Lindstrand A, Hjelmgren A, et al. Respiratory viruses associated with community-acquired pneumonia in children: Matched case-control study. Thorax 2015;70(9):847-853. http://dx.doi. org/10.1136/thoraxjnl-2015-206933 5. Cohen C, Walaza S, Moyes J, et al. Epidemiology of viral-associated acute lower respiratory tract infection among children <5 years of age in a high HIV prevalence setting, South Africa, 2009 - 2012. Pediatr Infect Dis J 2015;34(1):66-72. https://dx.doi.org/10.1371/journal.pone.0117716 6. Zar HJ, Barnett W, Stadler A, Gardner-Lubbe S, Myer L, Nicol MP. Aetiology of childhood pneumonia in a well vaccinated South African birth cohort: A nested case-control study of the Drakenstein Child Health Study. Lancet Respir Med 2016;4(6):463-472. http://dx.doi.org/10.1016/S2213-2600(16)00096-5 7. Shi T, McLean K, Campbell H, Nair H. Aetiological role of common respiratory viruses in acute lower respiratory infections in children under five years: A systematic review and meta-analysis. J Glob Health 2015;5(1):010408. http://dx.doi.org/10.7189/jogh.05.010408

8. Carballal G, Videla C, Misirlian A, Requeijo PV, Aguilar MdelC. Adenovirus type 7 associated with severe and fatal acute lower respiratory infections in Argentine children. BMC Pediatr 2002;2:6. https://dx.doi.org/10.1186%2F1471-2431-2-6 9. Lee J, Choi EH, Lee HJ. Clinical severity of respiratory adenoviral infection by serotypes in Korean children over 17 consecutive years (1991-2007). J Clin Virol 2010;49(2):115-120. http://dx.doi. org/10.1016/j.jcv.2010.07.007 10. Murtagh P, Giubergia V, Viale D, Bauer G, Pena HG. Lower respiratory infections by adenovirus in children: Clinical features and risk factors for bronchiolitis obliterans and mortality. Pediatr Pulmonol 2009;44(5):450-456. http://dx.doi.org/10.1002/ppul.20984 11. Castro-Rodriguez JA, Daszenies C, Garcia M, Meyer R, Gonzales R. Adenovirus pneumonia in infants and factors for developing bronchiolitis obliterans: A 5-year follow-up. Pediatr Pulmonol 2006;41(10):947-953. https://dx.doi.org/10.1002/ppul.20472 12. Colom AJ, Teper AM, Vollmer WM, Diette GB. Risk factors for the development of bronchiolitis obliterans in children with bronchiolitis. Thorax 2006;61(6):503-506. http://dx.doi.org/10.1136/ thx.2005.044909 13. Edmond K, Scott S, Korczak V, et al. Long term sequelae from childhood pneumonia: Systematic review and meta-analysis. PLoS One 2012;7(2):e31239. http://dx.doi.org/10.1371/journal.pone.0031239 14. Castro-Rodriguez JA, Giubergia V, Fischer GB, et al. Postinfectious bronchiolitis obliterans in children: The South American contribution. Acta Paediatr 2014;103(9):913-921. http://dx.doi.org/10.1111/ apa.12689 15. Lonngren C, Morrow BM, Haynes S, Yusri T, Vyas H, Argent AC. North-South divide: Distribution and outcome of respiratory viral infections in paediatric intensive care units in Cape Town (South Africa) and Nottingham (United Kingdom). J Paediatr Child Health 2014;50(3):208-215. http://dx.doi. org/10.1111/jpc.12458 16. Bowles NE, Ni J, Kearney DL, et al. Detection of viruses in myocardial tissues by polymerase chain reaction: Evidence of adenovirus as a common cause of myocarditis in children and adults. J Am Coll Cardiol 2003;42(3):466-472. http://dx.doi.org/10.1016/S0735-1097(03)00648-X 17. Wolter N, Tempia S, Cohen C, et al. High nasopharyngeal pneumococcal density, increased by viral coinfection, is associated with invasive pneumococcal pneumonia. J Infect Dis 2014;210(10):16491657. http://dx.doi.org/10.1093/infdis/jiu326

Accepted 24 October 2016.

February 2017, Print edition

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

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The influence of HIV infection on the age dependence of squamous cell carcinoma of the skin in South Africa B L Diffey,1 BSc, AKC, PhD, DSc; M Norval,2 BSc, PhD, DSc; P N Albers,3 BSocSci, MSc; C Y Wright,3,4 BSocSci, MSocSci, PhD Dermatological Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK Biomedical Sciences, University of Edinburgh Medical School, UK 3 Environment and Health Research Unit, South African Medical Research Council, Pretoria, South Africa 4 Department of Geography, Geoinformatics and Meteorology, Faculty of Natural and Agricultural Sciences, University of Pretoria, South Africa 1 2

Corresponding author: B L Diffey (brian.diffey@ncl.ac.uk) Background. Cancer incidence typically increases with age, but it is not known whether ethnic characteristics influence the age dependence of squamous cell carcinoma of the skin (SCC). Objectives. (i) To determine the age dependence of SCC in the black African, coloured and white population groups of South Africa (SA); and (ii) to show whether any differences in the rate of change of age dependence could be influenced by diversity in behaviour and lifestyle, especially with regard to the prevalence of HIV infection, rather than by a fundamental variation in cancer biology between the populations. Methods. Linear regression analysis was applied to the logarithm of the age-specific incidence rates for SCC v. the logarithm of age between 35 and 74 years. The slopes of the regression (age exponent) were compared for each subset of gender, population group and year of diagnosis (between 2000 and 2010). Results. The most notable feature was the low value of the age exponent in both male and female black African compared with the white and coloured populations. This finding could be explained in part by the difference in the prevalence of HIV infection in the black African population group compared with the white and coloured population groups. Conclusions. The prevalence of HIV infection in black Africans in SA tends to decrease the apparent age component in SCC compared with the white and coloured population groups. Other factors relating to lifestyle and behaviour that differ between the population groups are also likely to influence the age component in SCC. S Afr Med J 2017;107(2):127-129. DOI:10.7196/SAMJ.2017.v107i2.10837

Full article available online at http://dx.doi.org/10.7196/SAMJ.2017.v107i2.10837

The spectrum of gastric cancer as seen in a large quaternary hospital in KwaZulu-Natal, South Africa F Benamro,1,2 MB ChB, MMed, FCS (SA); B Sartorius,3,4 BSc, BSc Hons, MSc, PhD; D L Clarke,2,3,5 M M e d S c i , M B A , M P h i l , P h D , F C S ( S A ) ; F Anderson,1,2,3 MB ChB, MMed, FCS (SA); E Loots,1,2,4 MB ChB, FCS (SA), Cert Gastroenterology (SA) Surg; L Olinger,7 MSc (Biostatistics) Department of Surgery, Inkosi Albert Luthuli Central Hospital, Durban, South Africa Department of Surgery, School of Clinical Medicine, College of Health Sciences, Nelson R Mandela School of Medicine, University of KwaZuluNatal, Durban, South Africa 3 Discipline of Public Health Medicine, School of Clinical Medicine, College of Health Sciences, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa 4 South African Medical Research Council/University of KwaZulu-Natal Gastrointestinal Cancer Research Centre, Durban, South Africa 5 Department of General Surgery, Grey’s Hospital, Pietermaritzburg, South Africa 6 Department of General Surgery, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa 7 School of Health Systems and Public Health, Faculty of Health Sciences, University of Pretoria, South Africa 1 2

Corresponding author: F Benamro (farajak2000@yahoo.com) Background. Gastric cancer (GC) is the fifth most commonly diagnosed cancer in the world, with the third-highest associated mortality. It has a varying geographical, ethnic and socioeconomic distribution. Objective. To assess the presentation and management of GC in the Durban metropolitan area, South Africa. Methods. A retrospective review of 131 patients treated at the quaternary Inkosi Albert Luthuli Central Hospital in Durban from 2009 to 2014 was performed.

February 2017, Print edition

RESEARCH

Results. The 131 patients were predominantly black African (n=59, 45.0%) and Indian (n=63, 48.1%). Gender was evenly distributed, with 72 males (55.0%) and 59 females (45.0%). The average age of the patients was 60 years (standard deviation 13.3). More than 70% were in advanced stages of cancer and were treated conservatively. There was no significant relationship between body mass index (BMI) and the position of the tumour (p=0.175). Creatinine and albumin levels differed significantly between the genders (p<0.001 and p=0.01, respectively). Conclusions. GC appears to have a disproportionately high prevalence among Indians in Durban, and the prevalence of GC appears to be slightly higher among males. Both these observations may simply reflect referral patterns and warrant further investigation. More than 70% of patients presented with advanced-stage disease, and anaemia was common. No relationship was found between BMI and the location of the tumour, although most of the cancers were in the body and distal part of the stomach. S Afr Med J 2017;107(2):130-133. DOI:10.7196/SAMJ.2017.v107i2.11383

Full article available online at http://dx.doi.org/10.7196/SAMJ.2017.v107i2.11383

The spectrum and outcome of surgical sepsis in Pietermaritzburg, South Africa S Green,1 BSc Hons, MSc, MB BCh, DA (SA); V Y Kong,1 MB ChB, MSc, PhD, MRCS; D L Clarke,1,2 MMedSci, MBA, MPhil, PhD, FCS (SA); B Sartorius,3 BSc, BSc Hons, MSc, PhD; J Odendaal,1 BSc (Med Sci) Hons; J L Bruce,1 FCS (SA); G L Laing,1 FCS (SA), PhD; P Brysiewicz,3 BSocSc, BA, MCur, PhD; W Bekker,1 FCS (SA); E Harknett,1 BMedSci, BMBS, DA (SA) Department of Surgery, Pietermaritzburg Hospital Complex and School of Clinical Medicine, College of Health Sciences, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa 2 Department of Surgery, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa 3 School of Nursing and Public Health, College of Health Sciences, Howard College Campus, University of KwaZulu-Natal, Durban, South Africa 1

Corresponding author: D L Clarke (damianclar@gmail.com) Background. Sepsis is a leading cause of morbidity and mortality worldwide, and the incidence appears to be increasing. In the resourcelimited environment in low- and middle-income countries, the management of surgical sepsis (SS) continues to represent a significant portion of the workload for most general surgeons. Objective. To describe the spectrum of SS seen at a busy emergency department, and categorise the outcomes. Methods. The Pietermaritzburg Metropolitan Trauma Service (PMTS) and Pietermaritzburg Metropolitan Surgical Service (PMSS) in KwaZulu-Natal Province, South Africa (SA), maintain a prospective electronic registry. All patients with features of sepsis among emergency general surgical patients >15 years of age admitted to the PMSS over the period January 2012 - January 2015 were identified. From this cohort, all patients with sepsis that required surgical source control or who had a documented surgical source of sepsis (i.e. had SS) were selected for analysis. Results. Of a total of 6 020 adult surgical patients on the database, a cohort of 1 240 acute surgical patients with features of sepsis were identified, and 675 with SS were then analysed further. Of the 675 patients, 49.2% were male, and the mean age was 46 years (standard deviation (SD) 19); 47.0% presented to the PMSS directly from within the metropolitan area, while the remaining 53.0% were referred from hospitals outside the area. Physiological parameters (mean values on presentation were as follows: systolic blood pressure 123 mmHg (standard deviation (SD) 23), respiratory rate 22 breaths/min (SD 5.2), heart rate 107 bpm (SD 19), temperature 37°C (SD 2) and white cell count 20 × 109/L (SD 8). Of the patients, 21.6% were known to be HIV-positive, 13.5% (91/675) were negative and 64.9% were of unknown status; 57.6% had intra-abdominal sepsis, 26.1% diabetes-related limb sepsis and the remaining 16.3% soft-tissue infections; 17.5% required intensive care unit admission, with a mean length of stay of 4 days (SD 4), and 30.7% developed complications. In this last group (n=207), a total of 313 morbidities were identified. The overall mortality rate was 12.7% (86/675). The mortality rate for intra-abdominal sepsis was 13.1%, for diabetic foot sepsis 14.2% and for necrotising fasciitis 27.3%. Conclusions. The spectrum of SS in SA is different to that seen in the developed world. Intra-abdominal sepsis is the most common SS and is overwhelmingly caused by acute appendicitis. Diabetic foot infection is a major cause of SS, reflecting the increasing burden of noncommunicable chronic diseases in SA. S Afr Med J 2017;107(2):134-136. DOI:10.7196/SAMJ.2017.v107i2.11339

Full article available online at http://dx.doi.org/10.7196/SAMJ.2017.v107i2.11339

February 2017, Print edition

RESEARCH

An investigation of diverticular disease among black patients undergoing colonoscopy at Dr George Mukhari Academic Hospital, Pretoria, South Africa M Vally, MB ChB; M Z Koto, MB ChB, FCS (SA), FACS; M Govender, MB ChB, FCS (SA) Department of General Surgery, Sefako Makgatho Health Sciences University, Ga-Rankuwa, Pretoria, South Africa Corresponding author: M Vally (moinuddeen.vally@gmail.com) Background. Diverticular disease was previously thought to be non-existent in the black African population. Studies over the past four decades, however, have shown a steady increase in the prevalence of the disease. Objective. To report on the profile and current prevalence of diverticular disease in the black South African (SA) population at Dr George Mukhari Academic Hospital, Pretoria, SA. Methods. A retrospective descriptive study was performed in black SA patients who were diagnosed with diverticular disease by colonoscopy between 1 January and 31 December 2015. Results. Of 348 patients who had undergone colonoscopies and who were eligible for inclusion in this study, 47 were diagnosed with diverticular disease â&#x20AC;&#x201C; a prevalence of 13.50% (95% confidence interval 10.30 - 17.50%). The greatest number of patients diagnosed were in their 7th and 8th decades, with an age range of 46 - 86 (mean 67) years. There was a female predominance of 57.45%. Lower gastrointestinal bleeding was the most common (65.96%) indication for colonoscopy. The left colon was most commonly involved (72.34%), followed by the right colon (55.31%). A substantial number of patients had pancolonic involvement (27.65%). Conclusion. This retrospective study suggests that there has been a considerable increase in the prevalence of diverticular disease among black South Africans, possibly owing to changes in dietary habits and socioeconomic status. S Afr Med J 2017;107(2):137-139. DOI:10.7196/SAMJ.2017.v107i2.12007

Full article available online at http://dx.doi.org/10.7196/SAMJ.2017.v107i2.12007

Calcific uraemic arteriolopathy (calciphylaxis) in patients on renal replacement therapy S Sebastian,1 MB ChB, FCP (SA), MMed (Internal Medicine), Cert Nephrology (SA) Phys, MPhil (Nephrology); H F Jordaan,2 MB ChB, MMed (Dermatology); J W Schneider,3 MB ChB, MMed (Anatomical Pathology), FCPath; M R Moosa,1 MB ChB, FCP (SA), MD, FRCP (Lond); M R Davids,1 MB ChB, FCP (SA), MMed (Internal Medicine), PhD Division of Nephrology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University and Tygerberg Hospital, Cape Town, South Africa 2 Division of Dermatology, Faculty of Medicine and Health Sciences, Stellenbosch University and Tygerberg Hospital, Cape Town, South Africa 3 Division of Anatomical Pathology, National Health Laboratory Service, Faculty of Medicine and Health Sciences, Stellenbosch University and Tygerberg Hospital, Cape Town, South Africa 1

Corresponding author: M R Davids (mrd@sun.ac.za) Background. Calcific uraemic arteriolopathy (calciphylaxis) is an unusual and potentially fatal condition characterised by small-vessel calcification and ischaemic skin necrosis. It mainly affects patients with end-stage renal disease (ESRD) on haemodialysis, but may rarely occur in the absence of ESRD in conditions such as primary hyperparathyroidism, malignancy, alcoholic liver disease and connective tissue disease. Methods. We reviewed the records of all patients diagnosed with calciphylaxis while on renal replacement therapy at Tygerberg Hospital, Cape Town, South Africa, between 1990 and 2014, to describe its presentation, course and final outcome. Results. Nineteen patients developed calciphylaxis over this period. Their median age was 34 years and 13 (68.4%) were female. Fifteen (78.9%) had received a kidney transplant. All patients had painful skin lesions that rapidly progressed to infarction. Small-vessel calcification

February 2017, Print edition

RESEARCH

was seen on skin biopsy in 13 patients. Twelve patients had hyperparathyroidism. Several of the transplanted patients had been treated for graft rejection in the year preceding the diagnosis. Treatment consisted of good wound care and efforts to normalise serum calcium and phosphate levels. Five patients received an urgent parathyroidectomy. The outcome was fatal in 17 patients, with sepsis being the main cause of death. Conclusions. In our patients, calciphylaxis carried a worse prognosis than previously reported internationally. It should always be considered in the differential diagnosis of painful skin lesions in the dialysis or transplant patient. S Afr Med J 2017;107(2):140-144. DOI:10.7196/SAMJ.2017.v107i2.11058

Full article available online at http://dx.doi.org/10.7196/SAMJ.2017.v107i2.11058

Analysis of mutations causing familial hypercholesterolaemia in black South African patients of different ancestry U K Ibe,1 BSc, MSc; R Whittall,1 BSc, MSc; S E Humphries,1 BSc, PhD; G Pilcher,2 BSc, MSc; F Raal,2 MMed, PhD 1 2

Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Institute of Cardiovascular Sciences, University College London, UK Carbohydrate and Lipid Metabolism Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa

Corresponding author: S E Humphries (steve.humphries@ucl.ac.uk) Background. Familial hypercholesterolaemia (FH) is usually caused by mutations in three genes (LDLR, APOB and PCSK9). Objective. To identify the spectrum of FH-causing mutations in black South African (SA) patients. Methods. DNA samples of 16 unrelated South African FH patients with elevated low-density lipoprotein cholesterol levels, tendon xanthomas and corneal arcus (3 clinically homozygous FH and 13 heterozygous FH) of ethnic African origin were screened for mutations in the LDLR (coding region, promoter and intron/exon boundaries), APOB (part exon 26) and PCSK9 genes (exon 7), using high-resolution melting. Results. Eight LDLR mutations were identified, for an overall detection rate of 8/19 predicted FH-causing alleles (42.1%). The previously reported six base pair deletion p.(D47_G48del) was found in two patients, and two novel variants (c.1187-25T>C and c.1664T>G p.(L555R)) were found, both predicted to be pathogenic using in silico web-based predictive algorithms. No pathogenic variants in APOB or PCSK9 were found. Conclusions. These findings contribute to the knowledge of allelic heterogeneity in the spectrum of FH-causing mutations in black SA patients, signifying their ancestral diversity. The relatively low overall detection rate may reflect locus heterogeneity of the FH phenotype in black SA FH patients. S Afr Med J 2017;107(2):145-148. DOI:10.7196/SAMJ.2017.v107i2.12022

Full article available online at http://dx.doi.org/10.7196/SAMJ.2017.v107i2.12022

February 2017, Print edition

RESEARCH

Burden, genotype and phenotype profiles of adult patients with sickle cell disease in Cape Town, South Africa G D Pule,1 PhD; K Mnika,1 BSc Hons; M Joubert,2,4 MB ChB; S Mowla,3 PhD; N Novitzky,2,3,4 MD, PhD; A Wonkam,1 MD, DMedSc, PhD Division of Human Genetics, Department of Pathology, Faculty of Health Sciences, University of Cape Town, South Africa Haematology Clinic, Groote Schuur Hospital, Cape Town, South Africa 3 Division of Haematology, Departments of Internal Medicine and Pathology, Faculty of Health Sciences, University of Cape Town, South Africa 4 National Health Laboratory Service, Groote Schuur Hospital, Cape Town, South Africa 1 2

Corresponding author: A Wonkam (ambroise.wonkam@uct.ac.za) Background. An exponential increase in the number of sickle cell disease (SCD) patients in paediatric services in Cape Town, South Africa, has been reported. The trend in adult/adolescent services has not been investigated. Objectives. To evaluate epidemiological trends of SCD and the profile of patients affected by SCD attending the Haematology Clinic at Groote Schuur Hospital (GSH), Cape Town. Methods. (i) A retrospective review of the number of SCD patients over the past 20 years; (ii) a cross-sectional analysis of clinical and haematological characteristics of SCD patients; and (iii) molecular analysis of the haemoglobin S mutation, the haplotype in the β-globinlike genes cluster, the 3.7 kb α-thalassaemia gene deletion and 19 selected single-nucleotide polymorphisms (SNPs) associated with fetal haemoglobin (HbF) levels. Results. From 1995 to 2016, 81 adolescent/adult patients with SCD were registered, mostly originating from other African countries (n=61, 75.3%). There was an increase of over 200% in new cases (n=47) during the last quarter of the two decades investigated. Data from 34 of 58 regular attendees (58.6%) were analysed. The mean age of the patients was 26.1 years (standard deviation (SD) 9.8), and 70.6% were male. With the exception of four patients with sickle/β-thalassaemia, all the patients had SCD (haemoglobin SS). The co-inheritance of a single 3.7 kb α-globin deletion was found in 42.3% of cases (n=11). The Bantu haplotype was the most observed (65.4% of chromosomes). Most HbF-promoting SNPs were not associated with variable levels of haematological indices. Conclusions. There is an increasing burden of adult SCD patients at GSH. National health and academic institutions need to adapt policies and healthcare professional training accordingly. S Afr Med J 2017;107(2):149-155. DOI:10.7196/SAMJ.2017.v107i2.10849

Full article available online at http://dx.doi.org/10.7196/SAMJ.2017.v107i2.10849

Is it possible to differentiate tuberculous and cryptococcal meningitis in HIV-infected patients using only clinical and basic cerebrospinal fluid characteristics? J E Vidal,1,2,3 MD, PhD; E J F Peixoto de Miranda,4 MD; J Gerhardt,5 MD; M Croda,5 MD; D R Boulware,6 MD, MPH, C Trop Med Department of Neurology, Emílio Ribas Institute of Infectious Diseases, São Paulo, Brazil Division of Infectious Diseases, University Hospital, School of Medicine, University of São Paulo, Brazil 3 Institute of Tropical Medicine, University Hospital, School of Medicine, University of São Paulo, Brazil 4 Division of Internal Medicine, University Hospital, School of Medicine, University of São Paulo, Brazil 5 Department of Infectious Diseases, Emílio Ribas Institute of Infectious Diseases, São Paulo, Brazil 6 Division of Infectious Diseases and International Medicine, University of Minnesota, USA 1 2

Corresponding author: J E Vidal (josevibe@gmail.com) Background. Tuberculous and cryptococcal meningitis (TBM and CM) are the most common causes of opportunistic meningitis in HIVinfected patients from resource-limited settings, and the differential diagnosis is challenging. Objective. To compare clinical and basic cerebrospinal fluid (CSF) characteristics between TBM and CM in HIV-infected patients.

February 2017, Print edition

RESEARCH

Methods. A retrospective analysis was conducted of clinical, radiological and laboratory records of 108 and 98 HIV-infected patients with cultureproven diagnosis of TBM and CM, respectively. The patients were admitted at a tertiary centre in São Paulo, Brazil. A logistic regression model was used to distinguish TBM from CM and derive a diagnostic index based on the adjusted odds ratio (OR) to differentiate these two diseases. Results. In multivariate analysis TBM was independently associated with: CSF with neutrophil predominance (odds ratio (OR) 35.81, 95% confidence interval (CI) 3.80 - 341.30, p=0.002), CSF pleocytosis (OR 9.43, 95% CI 1.30 - 68.70, p=0.027), CSF protein >1.0 g/L (OR 5.13, 95% CI 1.38 - 19.04, p=0.032) and Glasgow Coma Scale <15 (OR 3.10, 95% CI 1.03 - 9.34, p=0.044). Nausea and vomiting (OR 0.27, 95% CI 0.08 - 0.90, p=0.033) were associated with CM. Algorithm-related area under the receiver operating characteristics curve was 0.815 (95% CI 0.758 - 0.873, p<0.0001), but an accurate cut-off was not derived. Conclusion. Although some clinical and basic CSF characteristics appear useful in the differential diagnosis of TBM and CM in HIV-infected patients, an accurate algorithm was not identified. Optimised access to rapid, sensitive and specific laboratory tests is essential. S Afr Med J 2017;107(2):156-159. DOI:10.7196/SAMJ.2017.v107i2.11162

Full article available online at http://dx.doi.org/10.7196/SAMJ.2017.v107i2.11162

Readiness to adopt a performance measurement system for substance abuse treatment: Findings from the Service Quality Measures initiative B Myers,1,2 PhD; P Petersen Williams,1,2 PhD; K Johnson,1 MA; R Govender,3 PhD; R Manderscheid,4 PhD; J R Koch,5 PhD Alcohol, Tobacco and Other Drug Research Unit, South African Medical Research Council, Cape Town, South Africa Department of Psychiatry and Mental Health, Faculty of Health Sciences, University of Cape Town, South Africa 3 Department of Sociology, Faculty of Humanities, University of Cape Town; and Violence, Injury and Peace Research Unit, South African Medical Research Council, Cape Town, South Africa 4 National Association of County Behavioral Health and Developmental Disability Directors, Washington DC, USA 5 Department of Psychology, Virginia Commonwealth University, Richmond, VA, USA 1 2

Corresponding author: B Myers (bmyers@mrc.ac.za) Background. A performance measurement system – the Service Quality Measures (SQM) initiative – has been developed to monitor the quality of South Africa (SA)’s substance abuse treatment services. Identifying factors associated with readiness to adopt this system may inform strategies to facilitate its robust implementation. Objective. To examine factors associated with readiness to adopt a performance measurement system among SA substance abuse treatment providers. Methods. We surveyed 81 treatment providers from 13 treatment sites in the Western Cape, SA. The survey examined awareness, resources, organisational climate, leadership support and readiness to adopt the SQM system. Regression analysis was used to identify factors associated with readiness to adopt this system. Results. Readiness to adopt the SQM initiative was high (M=5.64, standard deviation 1.63). In bivariate analyses, caseload size (F=3.73 (degrees of freedom (df)=3.70), p=0.015), awareness (r=0.78, p<0.0001), leadership support (r=0.70, p<0.0001), resources (r=0.65, p<0.0001), openness to change (r=0.372, p=0.001), and external pressure to change were associated with readiness to adopt the SQM. In multivariate analyses, only awareness of the SQM initiative (B=0.34, standard error (SE) 0.08, t=4.4, p<0.0001) and leadership support (B=0.45, SE 0.11, t=4.0, p<0.0001) were significantly associated with readiness to adopt this system. Conclusion. While treatment providers report high levels of readiness to adopt the SQM system, findings show that the likelihood of adoption can be further increased through improved provider awareness and enhanced leadership support for this health innovation. S Afr Med J 2017;107(2):160-164. DOI:10.7196/SAMJ.2017.v107i2.11331

Full article available online at http://dx.doi.org/10.7196/SAMJ.2017.v107i2.11331

February 2017, Print edition

CPD

FEBRUARY 2017 The CPD programme for SAMJ is administered by Medical Practice Consulting. CPD questionnaires must be completed online at www.mpconsulting.co.za.

True (A) or false (B): SAMJ Sustained reduction in antibiotic consumption in a South African (SA) public sector hospital: Four-year outcomes from the Groote Schuur Hospital antibiotic stewardship programme 1. The main driver of antibiotic resistance is overuse and misuse of antibiotics. 2. An alarming increase in rates of extended-spectrum betalactamase-producing Gram-negative bacteria and carbapenemresistant Enterobacteriaceae has been reported from every province. Antibiotic prescription patterns of SA general medical practitioners for treatment of acute bronchitis 3. The SA standard treatment guidelines and essential medicines list for the primary healthcare level recommend that antibiotics should not be considered in patients with HIV. 4. Broad-spectrum macrolides are increasingly being prescribed for acute bronchitis, and this is not an appropriate choice considering both international and local recommendations. Adenovirus-associated pneumonia in SA children: Presentation, clinical course and outcome 5. Respiratory syncytial virus is the leading viral cause of pneumonia in high- and low-income countries. 6. Effective immunisation programmes have resulted in a decline in the incidence of viral-associated pneumonia.

CME Anaemia: Approach to diagnosis (part 2) 11. Causes of anaemia are divided into central (decreased bone marrow production or output of red cells) and peripheral (loss or destruction of red cells by various means). 12. Central and peripheral causes of anaemia never overlap. 13. The lifespan of a normal red cell is 100 - 120 days. 14. The red cell membrane cannot be filtered through the kidney. 15. Intravascular and extravascular haemolysis can coexist. 16. The most sensitive laboratory indicator of haemolysis is a decreased haptoglobin level. 17. Inherited varieties of haemolysis generally present during early childhood. 18. Hereditary spherocytosis, which presents with the classic triad of anaemia, jaundice and splenomegaly, is the least common of the red cell membrane disorders. 19. Fragmentation haemolytic anaemias occur as a result of disturbances of blood flow, either in large (macroangiopathic haemolysis) or small (microangiopathic haemolysis) blood vessels. 20. Microangiopathic haemolysis is caused by small-vessel obstruction by microthrombi, the distribution of which determines the organ system predominantly involved by each entity.

The influence of HIV infection on the age dependence of squamous cell carcinoma (SCC) of the skin in SA 7. The decrease in efficacy of the immune system with ageing and multiple genetic changes acquired during ageing may contribute to the age-related increase in cancer incidence. 8. The difference in prevalence of HIV infection between population groups could explain the difference in the age at which each population group presented with SCC of the skin. The spectrum of gastric cancer (GC) as seen in a large quaternary hospital in KwaZulu-Natal, SA 9. The mixed-race population of the Western Cape Province is known to have a high incidence of GC. 10. GC is the fifth most common visceral malignancy in the world, and the third-highest cause of cancer-related death.

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February 2017, Print edition

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Invitation to be placed on the Panel for the Independent Tribunal for Social Assistance Appeals The Minister of Social Development, Ms BO Dlamini, MP, seeks to appoint tribunal members constituted of suitably qualified South African citizens, to form part of the Independent Tribunal for Social Assistance Appeals (hereinafter referred to as the Tribunal). Section 18 of the Social Assistance Act, 13 of 2004, makes provision for the Minister of Social Development to appoint an independent tribunal to consider appeals lodged by social grant applicants who are dissatisfied with the decision of the South African Social Security Agency (SASSA). Applicants from Eastern Cape, Free State, KwaZuluNatal, Limpopo, Mpumalanga, Northern Cape, North West and Western Cape are hereby invited to submit their applications for consideration and appointment to serve in the Tribunal. Applicants should have a broad understanding of social assistance legislation and the social security system in South Africa. The term and deployment of the tribunal members will be determined from time to time by the Minister or her duly authorized delegate. Remuneration is as determined by the Minister of Finance in line with the Service Benefit Packages for Office-Bearers of Certain Statutory and Other Institutions (Category Level A1).

5 years post-registration experience in the practise of medicine and must not be in the full-time employ of the public health service or in the full-time or part-time employ of SASSA. Experience in the evaluation of medical impairment will be an added advantage. Enquiries: Dr Jan Olivier (012) 741 6877 Applications: All applications should be submitted with a covering letter, clearly indicating the professional category and must be accompanied by a detailed Curriculum Vitae together with the certified copies of the relevant qualification(s). Applications should be forwarded to: The DirectorGeneral, Department of Social Development, Private Bag X901, Pretoria 0001 and be clearly marked for the attention of the Director-General: The closing date for applications is 28 February 2017. The Tribunal reserves the right not to appoint any applicant and should you not hear from us within 6 months of your application, kindly consider your application unsuccessful.

Please take note that appointment is on assignment basis and does not guarantee automatic assignment of work. Medical Practitioners: Requirements: Duly qualified medical practitioner and registered with the Health Professions Council of South Africa. The candidate must be in possession of at least

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