SAMJ Vol 106, No 3 (2016) by HMPG

MARCH 2016

VOL. 106 NO. 3

EDITORIALS Is South Africa at risk for Zika virus disease? Mitochondrial donation to patients with mitochondrial DNA disease CME Cardiology (part 3) IN PRACTICE Amendments to the Sexual Offences Act: Implications for doctors and researchers Case Report: A subepidermal blistering disorder RESEARCH BRCA founder mutation in high-risk Afrikaner families Hereditary cancers â&#x20AC;&#x201C; do GPs have a knowledge gap? Point-of-care INR monitoring The Phoenix Lifestyle Project Health risks to the elderly living near mine dumps

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VOL. 106 NO. 3

FROM THE EDITOR

SAMJ

223

The Age of the Acquisitors – girls and women beware J Seggie

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

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EDITOR’S CHOICE

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

CORRESPONDENCE

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SANS 444:2014. A new standard for small-ampoule labelling and a chance to reduce drug administration errors in South Africa A R Reed, P C Gordon

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

227

Barber as infectious agent D Modi, Z Modi, S Naidoo

227

The burden of drug overdose on critical care units in East London, South Africa K Rowe

Chasteberry) nopause and 229 osis the same pH 231

IZINDABA SA professor and US engineer transform disabled babies’ lives OBITUARY Arnold Waldemar Wiid

ASSOCIATE EDITORS Q Abdool Karim, A Dhai, N Khumalo, R C Pattinson, A Rothberg, A A Stulting, J Surka, B Taylor, M Blockman HMPG CEO AND PUBLISHER Hannah Kikaya | Email: hannahk@hmpg.co.za MANAGING EDITOR Ingrid Nye TECHNICAL EDITORS Emma Buchanan Paula van der Bijl

EDITORIALS 232

Is South Africa at risk for Zika virus disease? P Jansen van Vuren, J Weyer, A Kemp, V Dermaux-Msimang, K McCarthy, L Blumberg, J Paweska

NEWS EDITOR Chris Bateman | Email: chrisb@hmpg.co.za

234

Could we offer mitochondrial donation or similar assisted reproductive technology to South African patients with mitochondrial DNA disease? S Meldau, G Riordan, F van der Westhuizen, J L Elson, I Smuts, M S Pepper, H Soodyall

PRODUCTION MANAGER Emma Jane Couzens

CME

HEAD OF SALES AND MARKETING Diane Smith | Tel. 012 481 2069 Email: dianes@hmpg.co.za

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GUEST EDITORIAL Cardiovascular medicine in primary healthcare in sub-Saharan Africa: Minimum standards for practice (part 3) G Ogunbanjo, N A B Ntusi

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ARTICLES Approach to chest pain and acute myocardial infarction S Pandie, D Hellenberg, F Hellig, M Ntsekhe

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An approach to the patient with a suspected tachycardia in the emergency department A Chin, B Vezi, M Namane, H Weich, R Scott-Millar

IN PRACTICE

251

DRUG ALERT Recommendations pertaining to the use of influenza vaccines and influenza antiviral drugs, 2016 S Walaza, C Cohen

DIAGNOSIS 253 Digitotalar dysmorphism: Molecular elucidation A A Vorster, P Beighton, R S Ramesar 256

ailable from

MEDICINE AND THE LAW Amendments to the Sexual Offences Act dealing with consensual underage sex: Implications for doctors and researchers S Bhamjee, Z Essack, A E Strode

263

CASE REPORT A subepidermal blistering disorder Y Moolla

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JOURNAL ADVERTISING Charles William Duke Benru de Jager Reneé van der Ryst Ladine van Heerden Azad Yusuf ONLINE SUPPORT Gertrude Fani FINANCE Tshepiso Mokoena HMPG BOARD OF DIRECTORS Prof. M Lukhele (Chair), Dr M R Abbas, Dr M J Grootboom, Mrs H Kikaya, Prof. E L Mazwai, Dr M Mbokota, Dr G Wolvaardt ISSN 0256-9574

HEALTHCARE DELIVERY The value of internal medicine outreach in rural KwaZulu-Natal, South Africa R I Caldwell, B Gaede, C Aldous

armacies 259

DTP AND DESIGN Carl Sampson

March 2016, Vol. 106, No. 3

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

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the affordable5 endurance ACE-inhibitor For further product information contact PHARMA DYNAMICS P O Box 30958 Tokai Cape Town 7966 Tel 021 707 7000 Fax 021 701 5898 Email info@pharmadynamics.co.za CUSTOMER CARE LINE 0860 PHARMA (742 762) www.pharmadynamics.co.za Pearinda 4. Each tablet contains 4 mg perindopril tert-butylamine. Reg. No.: RSA S3 41/7.1.3/0649. NAM NS2 10/7.1.3/0476. Pearinda 8. Each tablet contains 8 mg perindopril tert-butylamine. Reg. No.: RSA S3 41/7.1.3/0650. NAM NS2 10/7.1.3/0477. For full prescribing information, refer to the package insert approved by the Medicines Control Council, April 2009. Pearinda Plus 4. Each tablet contains 4 mg perindopril tert-butylamine and 1,25 mg indapamide. Reg. No.: RSA S3 41/7.1.3/0633. NAM NS2 10/7.1.3/0611. For full prescribing information, refer to the package insert approved by the Medicines Control Council, April 2010. 1) The EUROPA study Investigators. “Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomized, double-blind, placebo-controlled, multicentre trial (the EUROPA study)”. The Lancet 2003;362:782788. 2) The PREAMI study Investigators. “Effects of angiotensin-converting enzyme inhibition with perindopril on left ventricular remodelling and clinical outcome. Results of the randomized perindopril and remodelling in elderly with acute myocardial infarction (PREAMI) study”. Arch Intern Med 2006;166:659-666. 3) PROGRESS Collaborative Group. “Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack”. The Lancet 2001;358:1033-41. 4) Guerin AP, et al. “Impact of Aortic Stiffness Attenuation on Survival of Patients in End-Stage Renal Failure”. Circulation 2001;103;987-992. 5) Department of Health website http//www.doh.gov.za – Accessed on 26/03/2015. PAE178/06/2015.

RESEARCH 264

Breast cancer in high-risk Afrikaner families: Is BRCA founder mutation testing sufficient?* H J Seymour, T Wainstein, S Macaulay, T Haw, A Krause

268

272

A clinical and molecular investigation of two South African families with Simpson-Golabi- Behmel syndrome* C Spencer, K Fieggen, A Vorster, P Beighton

276 Alpha-thalassaemia trait as a cause of unexplained microcytosis in a South African population* S B Loonat, N H Naran, S L Thein, N A Alli 280

Validation of the CoaguChek XS international normalised ratio point-of-care analyser in patients at Charlotte Maxeke Johannesburg Academic Hospital, South Africa* E L Benade, B F Jacobson, S Louw, E Schapkaitz

284

High prevalence of cardiovascular risk factors in Durban South African Indians: The Phoenix Lifestyle Project* D R Prakaschandra, T M Esterhuizen, A A Motala, P Gathiram, D P Naidoo

290

Comorbidity of respiratory and cardiovascular diseases among the elderly residing close to mine dumps in South Africa: A cross-sectional study* V Nkosi, J Wichmann, K Voyi

298

A cohort study of elderly people in Bloemfontein, South Africa, to determine health-related quality of life and functional abilities* A M Gerber, R Botes, A Mostert, A Vorster, E Buskens

302

Children with disabling chronic conditions in the Western health subdistrict of Cape Town, South Africa: Estimating numbers and service gaps* A Redfern, A Westwood, K A Donald

308 Providers’ perceptions of the implementation of a performance measurement system for substance abuse treatment: A process evaluation of the Service Quality Measures initiative* B Myers, P P Williams, K Johnson, R Govender, R Manderscheid, J R Koch

CONTENTS LISTED IN Index Medicus (Medline) Excerpta Medica (EMBASE) Biological Abstracts (BIOSIS) Science Citation Index (SciSearch) Current Contents/Clinical Medicine SAMJ SUBSCRIPTION RATES Local subscriptions ZAR 1 368.00 p.a. Foreign subscriptions ZAR 3 108.00 p.a. Single copies ZAR114.00 local, ZAR 259.00 foreign Members of the South African Medical Association receive the SAMJ only on request, as part of their membership benefit. Subscriptions: Tel. 012 481 2071 Email: members@samedical.org The SAMJ is published monthly by the Health and Medical Publishing Group (Pty) Ltd, Co. registration 2004/0220 32/07, a subsidiary of SAMA. HEAD OFFICE Health and Medical Publishing Group (Pty) Ltd Block F, Castle Walk Corporate Park, Nossob Street, Erasmuskloof Ext. 3, Pretoria, 0181 Tel. 012 481 2069 Email: dianes@hmpg.co.za EDITORIAL OFFICE Suites 9 & 10, Lonsdale Building, Gardener Way, Pinelands, 7405 Tel. 021 532 1281 | Cell. 072 635 9825 Email: publishing@hmpg.co.za Please submit all letters and articles for publication online at www.samj.org.za © Copyright: Health and Medical Publishing Group (Pty) Ltd, a subsidiary of the South African Medical Association

*Full article available online only.

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Use of editorial material is subject to the Creative Commons Attribution – Non-commercial Works Licence. http://creativecommons.org/licenses/by-nc/3.0

CPD QUESTIONS

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MARCH 2016

Background photo: Laboratory testing, Comstock images | Thinkstock Hexagon photos: DNA fingerprinting, Alila Medical Media | Shutterstock; In vitro fertilisation, vchal | Thinkstock; Stop silence, Jakkrit Orrasri | Shutterstock; Mammogram, Will Rodrigues | Shutterstock; Johannesburg mine dump, Caradee Wright

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March 2016, Vol. 106, No. 3

VOL. 106 NO. 3

EDITORIALS Is South Africa at risk for Zika virus disease? Mitochondrial donation to patients with mitochondrial DNA disease CME Cardiology (part 3) IN PRACTICE Amendments to the Sexual Offences Act: Implications for doctors and researchers Case Report: A subepidermal blistering disorder RESEARCH BRCA founder mutation in high-risk Afrikaner families Hereditary cancers – do GPs have a knowledge gap? Point-of-care INR monitoring The Phoenix Lifestyle Project Health risks to the elderly living near mine dumps

HEALTHBRIDGE 360. GOOD BUSINESS. BEST PRACTICE.

Despite persistent economic volatility, business needs to run as consistently and efficiently as possible. A medical practice is no different. In fact, as the pressure and stress of our daily grind takes its toll, it is specifically the medical professions that are expected to provide a bedrock of stability, keeping the nation physically and mentally healthy. But who looks out for the medical

available medical aid funds. Prior to

Emphatically, Dr Pillay notes that

essentially ‘self-medicate’ to ensure

isolate and manage the transactional part

by approximately two-thirds of what it used

professionals? How do the trusted doctors that they remain solid, viable pillars of healthcare in their communities?

Being really good at what you do does help.

appointments, your front desk is able to of the consultation, ensuring that your

professional time is properly covered and paid for.

But to run a successful medical practice

Dr Das Pillay has over 20 years of private

a degree of administrative know-how. Some

cosmopolitan practice grew, so he realised

requires not just a medical degree, but also

of us may have a natural inclination towards the paperwork. Most medical professionals, however, want to be focusing on what they know and do best: treating patients.

That means freeing up as much as your

schedule as possible to focus on quality time with your patients. And that is

precisely what Healthbridge does best. Healthbridge 360 is a dedicated programme that has been refined through years of

engaging and adapting to the modern demands of professional medical practice. Patterns of

patient volumes are monitored and analysed. With this comes cash flow projection,

carefully plotting the ebbs and flows of your financial health throughout the year.

Most importantly, Healthbridge 360 affords you real-time confirmation of a patient’s

practice as a specialist paediatrician. As his the need for more rigorous administration.

His practice has been a happy Healthbridge client since 2007.

“Healthbridge 360 has reduced my book debt to be.” He is particularly enthusiastic when sharing the positive side-effects. “With my

staff, the benefit of 360 has psychologically lifted their spirit. They’re very much more

upbeat about their work. Everyone’s working very much more smoothly on a financial level and on a billing level.”

“We make no bones about the difference we want to make in our doctor-clients’

“We’ve been exceptionally happy with their services,” says Dr Pillay of Healthbridge, “not only in terms of the programme … but more importantly is the actual back-up and call-outs when we have problems, and for me I value that tremendously.” Healthbridge MD, Luis da Silva, is determined that this reputation for

committed business partnership continues to grow meaningful, long-term relationships.

“We understand intimately the dynamics of running general and specialist practices,” notes Da Silva. “No practice is the same.

No doctor is just another doctor. That’s why our service levels are tailored to a practice’s specific needs and expectations.”

lives,” says Da Silva.

“It is our single-minded business interest and focus to ensure that doctors enjoy way

more than just a proven admin system. We

participate, we listen, we learn and we

reconfigure to keep enhancing the value we add to every practice.”

It lives up to Healthbridge’s core belief that, when a practitioner runs consulting rooms like a “good business”, the ultimate reward to patients is to enjoy the very “best practice” the doctor has to offer.

Find out how Healthbridge can best enhance the management of your practice. Go to www.healthbridge.co.za, or call 0860 200 222 and a dedicated client specialist will be happy to share all the benefits with you and your administrative team. From start-up practices to larger established practices that are ready to take the next, profitable step, Healthbridge partners from entry-level requirements to hands-on Premium Service.

FROM THE EDITOR

The Age of the Acquisitors – girls and women beware ‘… violence against women and girls continues unabated in every continent, country and culture. It takes a devastating toll on women’s lives, on their families, and on society as a whole. Most societies prohibit such violence – yet the reality is that too often, it is covered up or tacitly condoned … Changing this requires all of us – women and men – to work for enduring change in values and attitudes.’ (Ban Ki-moon, Secretary-General of the United Nations, New York, 6 March 2007[1]) In the 1980s I read a book by Prabhat Rainjan Sarkar,[2] a social philosopher and political revolutionary. Sarkar proposed a socio economic Law of Social Cycles, according to which classes within societies naturally change in a sequential manner. Sarkar’s view was that when one class gained dominance, there was a need to avoid the exploitation of the others. The socioeconomic cycle begins with the hard work of labourers (the cashiers, clerks, waiters, electricians, plumbers, taxi drivers, garbage collectors, truck drivers, security guards and factory workers) who keep society running smoothly. Gradually a warrior society is cycled into existence because labourers need protection. Warrior societies, being inherently stable, promote intellectualism, and an age of intellectuals evolves. Intellectuals’ ideas spread through trade, which in turn leads to acquisitor societies. Acquisitors are the businessmen, managers, entrepreneurs, bankers, brokers and landlords in society. Not as intelligent as the intellectuals, or as strong as the warriors, they aspire to become (super-) rich. Acquisitors recognise neither religious nor ethical restraint to satisfy their greed, and need more labourers to ensure continued production. According to Ravi Batra, an Indian-American Nobel prize-winning economist and mentee of Sarkar, who bases many of his economic predictions on Sarkar’s Law of Social Cycles, right now the world is stuck in the age of the acquisitors,[3] when the rich get richer and the poor get poorer. Because salaries decline, most are forced to adopt the labourers’ way of living; warriors and intellectuals find themselves having to labour harder to support themselves and their families, and often undertake overtime work to make ends meet. Ultimately, there exist only the acquisitors and labourers, or the haves and have-nots. The have-nots increasingly get into debt to maintain their lifestyle, whereupon the acquisitors really rule, further enriching themselves through lending money to the other classes and through their control over businesses, farms and factories. The result is widening income inequality, which, according to a June 2015 report by the International Monetary Fund, is ‘the defining challenge of our time’.[4] In advanced economies, the gap between rich and poor is at its highest level in decades and is at increased levels in many emerging economies such as our own,[5] with inequities in access to education, healthcare and finance. In October 2015, a study by Credit Suisse confirmed that half of the world’s wealth is now in the hands of those in the top percentile.[6] In the developed countries, these inequities are driven by increasing inequality in wages and salaries. Such economic inequality is due inter alia to globalisation with suppression of wages in low-skill jobs. This tends to be especially pervasive in developing countries where there is a surplus of low-skilled labour. The situation is further exacerbated by computerisation and automation of jobs (which means that higherlevel skills are required to obtain moderate or high wages), and by ethnic and gender discrimination (see below). At a global level, 20% of people acquire 76% of annual global income while 80% survive on 24%.[7] In South Africa (SA), ‘inequality is greater today than at the end of apartheid’, according to the Oxfam report Even

223

It Up: Time to End Extreme Inequality;[8] ‘the two richest South Africans hold the same wealth as the bottom half of the population’, with the following consequences: ‘extreme inequality [that] corrupts politics, hinders economic growth and stifles social mobility. It fuels crime and even violent conflict. It squanders talent, thwarts potential and undermines the foundations of society.’ The grim reality is that ‘20% of people earn 75% of the total annual national income, with heads of parastatals and government officials (in particular the President) receiving bloated salaries, while the bottom 80% earn the remaining 25%’.[9] Social grants provided to some 17 million citizens, which have risen exponentially from 4 million in 1994,[10] and free basic services are the only reason things are not worse. Against this background it was probably no accident that economist Thomas Piketty, who specialises in the study of economic inequality and believes that SA is ‘top of its class’ in terms of inequality,[11] was invited to deliver the 13th Nelson Mandela Annual Lecture on 3 October 2015.[7] Piketty cited four rights that the SA citizenry should expect: the right to work for a decent wage (SA is working towards the introduction of a national minimum wage to avoid a situation of extreme exploitation of low-skilled workers, particularly in areas of limited opportunity to move), the right to high-quality education, together with the right to adequate public infrastructure, including transportation infrastructure (‘I think it is fair to say that the quality of public, primary education and junior and secondary education that is available to the most disadvantaged groups in this country is not satisfactory, and that this should be a national priority and a lot of progress could be made in this direction. What has worked in history, in order to have sustainable and equitable growth is to have a well-functioning public education and health system, and SA should go in this direction’), the right to access to property (‘I think we need to think again about more ambitious land reform’), and the fourth and last effective right, which has to do with economic and political democracy: ‘I think it’s important in SA, like in other countries in the world, to have new discussions about worker participation in companies and participatory governance’, as happens in Sweden and Germany. Joseph Stiglitz, another Nobel economics laureate, blames the markets that ‘must be tamed and tempered to make sure they work to the benefit of most citizens’ and the polarisation of wages for the accumulation of wealth and very high incomes among the legendary 1%.[12] Polarisation[13] refers to middle-class jobs disappearing relative to those at the bottom (requiring few skills) of the labour force, and those at the top (requiring greater skill levels). In the developing world, the Credit Suisse research confirms that since 2008 wealth growth has not allowed middle-class numbers to keep pace with population growth, along with a shift in wealth gains in favour of those at higher wealth levels.[6] Furthermore, as intimated above, there is discrimination and polarisation on a gender basis with regard to wages. A recent UK report suggests that women graduating in law and joining a legal practice in 2016 can expect to earn between GBP8 000 and 24 000 less per annum than their male counterparts, despite the passing of the Equal Pay Act nearly half a century ago.[14] An American comedienne, with her tongue not-so-firmly in her cheek, refers to this phenomenon as a ‘vagina tax’.[15] Women in SA earn nearly a third less than men on average, according to the latest tax statistics published by the South African Revenue Service. Research by the International Trade Union Confederation and Incomes Data Services puts the average global gender wage gap at 22.4% … and SA’s, at 33.5%, is at the top end of the gap.[16] This gap can be explained by

March 2016, Vol. 106, No. 3

FROM THE EDITOR

‘gender sorting’, according to the World Bank’s gender and development unit, in a report titled Gender at Work – ‘women are concentrated in less-productive jobs and run enterprises in less-productive sectors with fewer opportunities for business scale-up or career advancement’.[17] According to the Institute of Race Relations’ South Africa Survey 2014/ 2015,[18] 30% of managers and slightly more than 40% of professionals are women, but the largest numbers of women are employed as clerks, in sales and service, and in low-skilled jobs such as domestic workers. Which brings me to ‘girls and women beware’. When the acquisitors are dominant the status of women is low, not least as a result of the prevalence of divorce, prostitution and pornography. There are other societal ills: ‘a breakdown of the family unit due to divorce; rampant (including white collar) crime and disrespect for the rule of law; loose morals and high rates of prostitution; neglect of the children and the elderly; a general aversion to mental and physical discipline; a culture of “supermaterialism” and consumerism and a thriving drug culture. Everything, including art, religion, music and sports, is commercialized. There is educational decline, intellectual dishonesty and the spread of dogma. Acquisitive politicians dominate politics, but may be willing to share power with labourers.’[3] SA has the highest rate of women killed by their intimate partners (intimate partner violence (IPV)) in the world.[19] This is confirmed by research on IPV for the Alan J Flisher Centre for Public Mental Health, compiled by gender-based violence nursing expert Dr Kate Joyner of the Faculty of Medicine and Health Sciences at Stellenbosch University and Simone Honikman from the University of Cape Town, in an effort to raise awareness about femicide.[20] This journal has regularly published research on such ‘rule of the fist’ violence against women and children[21-23] (search ‘gender violence’, ‘violence, children’ and ‘intimate partner violence’), is doing so in the current issue[24] and will do so again.[25] Notably, a letter to the Editor by Mankazana[26] in 2012 pleaded for ‘more focus on children as victims of domestic violence, on the risk factors for such abuse, and the knowledge and skills to recognise signs and symptoms of child abuse …’. The good news perhaps, according to Batra,[3] is that there is increasing awareness of the social ills that dominance by the acquisitors creates: ‘disgruntled intellectuals and warriors, displaced into the labourer class, reach a point where they are moved to take action and join forces with the masses to bring about change. The acquisitors, having lost their credibility, must contemplate a lower status.’ We might question whether we are arguably witnessing just such a transformation.[27,28] Janet Seggie

Editor

janet.seggie@hmpg.co.za

1. Secretary-General’s remarks at informal General Assembly debate on gender equality and the empowerment of women. New York, 6 March 2007. http://www.un.org/sg/STATEMENTS/index. asp?nid=2469 (accessed 4 January 2016). 2. Prabahat Ranjan Sarkar. https://en.wikipedia.org/wiki/Prabhat_Ranjan_Sarkar (accessed 4 January 2016). 3. Ravi Batra. https://en.wikipedia.org/wiki/Ravi_Batra (accessed 4 January 2016). 4. International Monetary Fund Strategy, Policy, and Review Department. Causes and Consequences of Income Inequality: A Global Perspective Prepared by Era Dabla-Norris, Kalpana Kochhar, Frantisek Ricka, Nujin Suphaphiphat, and Evridiki Tsounta (with contributions from Preya Sharma and Veronique Salins). Authorized for distribution by Siddharh Tiwari June 2015. https://www.imf.org/external/pubs/ft/sdn/2015/sdn1513.pdf (accessed 4 January 2016). 5. Treanor J. Half of world’s wealth now in hands of 1% of population – report. The Guardian 13 October 2015. http://www.theguardian.com/money/2015/oct/13/half-world-wealth-in-hands-population-inequalityreport (accessed 4 January 2016). 6. Kings S. Inequality mocks SA’s freedom. 31 October 2014. http://mg.co.za/article/2014-10-30inequality-mocks-sas-freedom (accessed 4 January 2016). 7. Piketty T. Transcript of Nelson Mandela Annual Lecture 2015. https://www.nelsonmandela.org/news/ entry/transcript-of-nelson-mandela-annual-lecture-2015 (accessed 4 January 2016). 8. Even It Up: Time to End Extreme Inequality https://www.oxfam.org/sites/www.oxfam.org/files/file_ attachments/cr-even-it-up-extreme-inequality-291014-en.pdf (accessed 15 February 2016). 9. Benatar S. The poverty of the concept of ‘poverty eradication’. S Afr Med J 2016;106(1):16-17. [http:// dx.doi.org/10.7196/SAMJ.2016.v106i1.10417] 10. Ferreira L. Social grants in South Africa – separating myth from reality. https://africacheck.org/ factsheets/separating-myth-from-reality-a-guide-to-social-grants-in-south-africa/ (accessed 15 February 2016). 11. ‘Black economic empowerment has failed’: Piketty on South African inequality. http://www. theguardian.com/world/2015/oct/06/piketty-south-africa-inequality-nelson-mandela-lecture (accessed 4 January 2016). 12. Wikipedia, the free encyclopedia. Economic inequality. https://en.wikipedia.org/wiki/Economic_ inequality (accessed 4 January 2016). 13. Wikipedia, the free encyclopedia. Polarization (economics). https://en.wikipedia.org/wiki/ Polarization_(economics) (accessed 4 January 2016). 14. Mortimer C. Gender inequality: Female graduates earn up to £8,000 less than men who studied the same subject. Wednesday 30 December 2015. http://www.independent.co.uk/news/uk/home-news/ gender-inequality-female-graduates-earn-up-to-8000-than-men-even-when-they-study-the-samesubject-a6790221.html (accessed 4 January 2016). 15. Sarah Silverman creates provocative new video on women’s salaries and ‘the $500,000 vagina tax’. http://www.theguardian.com/money/us-money-blog/2014/oct/08/sarah-silverman-wage-gap-vaginatax (accessed 4 January 2016). 16. Grant L. Men get lion’s share of income. 24 April 2015. http://mg.co.za/article/2015-04-23-men-stillget-lions-share-of-income (accessed 4 January 2016). 17. Gender at Work. A Companion to the World Development Report on Jobs. http://www.worldbank. org/content/dam/Worldbank/document/Gender/GenderAtWork_web.pdf (accessed 4 January 2016). 18. South Africa Survey Online 2014/2015. http://irr.org.za/reports-and-publications/south-africasurvey/south-africa-survey-online-2014 (accessed 4 January 2016). 19. SA has world’s highest rate of women killed by partner. 12 December 2015. http://www.timeslive. co.za/sundaytimes/stnews/2015/12/12/SA-has-world%E2%80%99s-highest-rate-of-women-killedby-partner (accessed 4 January 2016). 20. Joyner K, Rees K, Honikman S. Intimate partner violence (IPV) in South Africa: How to break the vicious cycle. http://pmhp.za.org/wp-content/uploads/2016/01/IPV_policybrief_2015.pdf (accessed 6 January 2016). 21. Gass JD, Stein DJ, Williams DR, Seedat S. Intimate partner violence, health behaviours, and chronic physical illness among South African women. S Afr Med J 2010;100(9):582-585. 22. Baldwin-Ragaven L. Intimate partner violence: Are we ready for action? S Afr Med J 2010;100(9):577578. 23. Rees K, Zweigenthal V, Joyner K. Intimate partner violence: How should health systems respond? S Afr Med J 2014;104(8):556-557. [http://dx.doi.org/10.7196/SAMJ.8511] 24. Bhamjee S, Essack Z, Strode AE. Amendments to the Sexual Offences Act dealing with underage sex: Implications for doctors and researchers. S Afr Med J 2016;106(3):256-259. [http://dx.doi.org/10.7196/ SAMJ.2016.v106i3.9877 25. De Koker P, Eggers SM, Mathews C, et al. Prevalence of physical and sexual intimate partner violence and its demographic correlates among adolescents in South Africa. S Afr Med J 2016 (in press). 26. Mankazana EM. Intimate partner violence. S Afr Med J 2012;102(10):775. [http://dx.doi.org/10.7196/ SAMJ.6207] 27. Fees Must Fall campaign not over for some. Tuesday 3 November 2015-6:57am. https://www.enca. com/south-africa/persistent-protestors-refuse-give-student-uprising (accessed 4 January 2016). 28. Wesi T. Fees Must Fall analysis reveals promising politicians. national 29.10.2015 02:31 pm. http:// citizen.co.za/842589/fees-must-fall-analysis-reveals-promising-politicians/ (accessed 4 January 2016).

S Afr Med J 2016;106(3):223-224. DOI:10.7196/SAMJ.2016.v106i3.10579

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March 2016, Vol. 106, No. 3

Xpedient Medical is the medical business specialists of choice with a pre-emptive business management approach that is delivering an unmatched and proven 98% collection rate to medical practices nationally within South Africa. Our goal is to enable Medical Specialists to focus on their core competencies and allow us to assist them in making their business a success. We do this by being a billing company, an advisory service, a bureau/administration house, and much much more. Importantly we are the best in our field and we are so confident in this that our business model is based on received money in your bank and not on your turnover. This means you can rest assured that we are working 24/7 to achieve the 98% + results we advertise and deliver time and time again. We are the only company in the country that has “Xpedite” our in-house Data modelling suite that powers us to identify your internal needs to achieve these results, irrespective of your location, specialty or rates you charge. We are proud to announce that Xpedient Medical is now an Official member benefit partner to the South African Medical Association ( SAMA). SAMA and Xpedient Medical have entered into this relationship as our core values, morals and ethics are aligned and together will continue to work to empower doctors to bring health to the nation. Xpedient Medical has tripled in size year on year since its launch and currently administrates over 30,000 patients per month on behalf of its clients. By the end of 2016 we will be administering over 90,000. We are established in Gauteng, Western Cape, Eastern Cape with expansion to Kwazulu Natal and the Free state coming end of 2016. “Our total-service approach includes patient management on all financial matters with the same ethical standards you would apply to clinical matters” Our Vision: GROW BY BEING THE BEST IN SERVICE, QUALITY AND EFFICIENCY Our mission: TO BE THE MEDICAL BUSINESS SPECIALIST OF CHOICE, DEVELOPING INTELLIGENT SOLUTIONS, AND DELIVERING THEM WITH THE HIGHEST LEVEL OF SERVICE, QUALITY, AND EFFICIENCY Objectives: • • • •

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A 98% proven collection rate, irrespective of the specialist type or rates charged. Results based fee structure. Real-time receipting. Monies paid directly into the doctor’s own bank account. Our clients on average benefit from an increased turnover up to 37%. Considerable reduction in financial risk, by streamlining and optimizing your current practice or association.

Prevention is the cure The key to our proven success is through our pre-emptive approach to all aspects of practice management. This eliminates problems at the outset and includes the following efficiencies: correct allocation of medical aid codes from day one, handling medical aid claims, assisting with your PMB claims, providing you with practical management advice, helping to train your staff, minimizing your financial risk and providing you with reports so that you remain in control of your business. To assist your front-of-house, we provide management of patient queries through our dedicated and trained support staff. Critically, this improves both the patient experience and clears up financial queries quicker, resulting in faster payment. This allows you and your team to focus on the wellbeing of patients, while we take care of the financial management challenges to improve your cash flow. Perhaps the greatest benefit is that you will have more time to practice your skills as a medical professional. You will have more quality time to pursue your other interests be they cycling, hiking, golf and other hobbies or simply spending more time with your family For a free consultation with one of our consultants please go to www. Xpedient.co.za and click on free consultation and fill out your details or alternatively call us on 0861 973 343 and one of our friendly consultants will be in touch. As part of our objectives we have a number of exciting new developments being released which we will notify you on including the following:

EDITOR’S CHOICE

CME: Cardiology

ventricular systolic dysfunction and mural thrombus, and in the first 3 months following anterior myocardial infarction. Many POC devices are commercially available. The CoaguChek XS device (Roche Diagnostics, Switzerland) is a small bench-top instrument for INR analysis, suitable for use in anticoagulation clinics. This analyser measures the prothrombin time in seconds using an electrochemical method and shows good correlation with laboratory automated coagulation analysers up to INR values of 3.0. In a study validating the CoaguChek XS INR POC analyser in patients at Charlotte Maxeke Johannesburg Academic Hospital,[2] the authors demonstrated excellent agreement between the CoaguChek XS and laboratory measurement with the STAGO analyser. In SA, the CoaguChek XS POC device could be implemented in peripheral clinics as a screening tool for patients on long-term warfarin therapy in an attempt to lessen the workload of central anticoagulation clinics. However, the capacity and infrastructure of such clinics would need to be assessed prior to installation of CoaguChek XS POC devices.

Comorbidity of respiratory and cardiovascular diseases among the elderly living close to mine dumps in SA

High prevalence of cardiovascular risk factors in Durban SA Indians

Cardiovascular disease (CVD) accounts for approximately 30% of deaths worldwide, with 80% of this burden in developing countries. The epidemiological transition occurring in sub-Saharan Africa has had the consequence of economic and social transformation, resulting in dramatic shifts in disease spectrum from communicable diseases and malnutrition to CVD and cancer. South Africa (SA) is faced with the challenge of four colliding epidemics: (i) poor child and maternal health; (ii) high rates of interpersonal violence; (iii) infectious diseases, including HIV/AIDS and tuberculosis; and (iv) non-communicable diseases, including CVD. This outstanding series of articles spread across three issues of SAMJ/CME represents the collaborative effort of primary health/family physicians and cardiologists from around the country. The authors have synthesised and presented the most current, evidence-based and practical approaches to management of common CVDs. This final issue provides an evidence-based and pragmatic approach to acute coronary syndromes and chest pain, and suspected tachyarrhythmias in the emergency room.

As SA is a mining country, many of our people live close to mine dumps. In this study,[1] part of a larger project initiated by the Mine Health Safety Council of South Africa, elderly persons living in communities 1 - 2 km (exposed) and ≥5 km (unexposed) from five preselected mine dumps in Gauteng and North West provinces were surveyed for deleterious health effects. The crushed sand-like refuse material in these dumps is generated during extraction and milling of ground ore during the mining process. The material contains a complex mixture of heavy metals and trace elements such as gold, copper, lead, zinc, arsenic, cadmium and selenium. The major routes of entry upon exposure include contact with skin or eyes, inhalation and ingestion. Exposed communities are often elderly people and children of lower socioeconomic status living in government-funded houses, informal settlements and retirement homes. Elderly people are potentially highly susceptible to the effects of ambient air pollution as a result of normal and pathological ageing. The results of this study, the first to have investigated the risk factors associated with comorbidity of respiratory and cardiovascular diseases among elderly people in exposed communities, suggest that living in exposed communities, age, smoking habits, occupational exposure to dust/chemical fumes and use of gas for cooking/ heating in the home were significant risk factors for comorbidity of respiratory and cardiovascular diseases.

Validation of the CoaguChek XS international normalised ratio pointof-care analyser

Point-of-care (POC) testing is the fastest growing segment of the diagnostic test repertoire of laboratories in the developed world. Laboratories have become increasingly involved in supporting testing at the bedside in order to improve the turnaround time and cost of healthcare delivery. Measurement of the international normalised ratio (INR) is essential in the management of patients on long-term warfarin therapy. Warfarin has a narrow therapeutic range, and because it is subject to numerous drug and food interactions, frequent monitoring to maintain the target INR is vital. The target INR is 2.5 (range 2.0 3.0) for most indications, including venous thromboembolic disease, non-valvular cardiac conditions including atrial fibrillation, left

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Previous studies have confirmed a high prevalence of cardiovascular risk factors in SA Asian Indians, with the emergence of premature coronary artery disease in young Indian subjects. Earlier epi demiological studies showed that SA Indians have a high prevalence and incidence of diabetes mellitus. In a study[3] involving 1 378 subjects (1 001 women) whose mean age was 45.5 (standard deviation 13) years, there was a high prevalence of hypertension (47.5%), diabetes (20.1%), total body obesity (raised body mass index) (32.4%) and increased waist circumference (73.1%). In the youngest age group, there was a high prevalence of total body obesity (32.1%), increased waist circumference (31.3%) and insulin resistance (28.2%). Over half of males and 14.6 % of females were current smokers. The authors conclude that, compared with Asian Indian subjects with similar risk factor exposure in previous studies, the magnitude of change in risk factor prevalence over the past two decades has been of epidemic proportions. The extremely high prevalence of risk factors explains the emergence of premature coronary heart disease in this community and calls for urgent and aggressive intervention measures aimed at diet, physical activity and cessation of smoking at schoolgoing level.

Amendments to the Sexual Offences Act: Implications for doctors and researchers

Bhamjee et al.[4] deal with the provisions in the new Criminal Law (Sexual Offences and Related Matters) Amendment Act concerning consensual underage sex and sexual activity, indicating how the law has changed from the previous position and exploring the impact that this will have for doctors, researchers and other service providers working with adolescents. These issues came before the Constitutional Court in the Teddy Bear Clinic case when it considered whether consensual, under age sex and sexual activity violated the constitutional rights of children, as reported in the SAMJ in 2014.[5] The Constitutional Court has now concluded that adolescents have a right to engage in healthy sexual behaviour and that such acts are part and parcel of normative development from adolescence to adulthood. The court held further that criminalising consensual sex or sexual activity between adolescents aged 12 - 15 years violated their rights to privacy, bodily integrity and dignity and was also not in the best interests of the affected children.

March 2016, Vol. 106, No. 3

EDITOR’S CHOICE

Focus on genetics

Several genetics articles feature in this issue of SAMJ. In ‘Could we offer mitochondrial donation or similar assis ted reproductive technology to South African patients with mitochondrial DNA disease?’,[6] SA experts ponder the decision taken by the UK House of Commons last year, which sparked world wide controversy and debate, to endorse the use of pioneering in vitro fertilisation (IVF) techniques to protect future generations from the risk of mitochondrial DNA (mtDNA) disease, which is known to occur in SA in all population groups. Although individually rare, as a group mitochondrial genetic disorders are thought to be responsible for a substantial proportion of inherited metabolic disease. While the prevalence of mitochondrial genetic disorders is still largely unknown in SA, an estimated prevalence of 1:5 000 - 1:10 000 has been reported in several developed nation populations. However, considering that there are <70 genetically confirmed cases in a country with a population of ~56 million (i.e. 1:900 000 compared with an estimated 1:5 000 worldwide), the authors assert that the number of undiagnosed cases in SA may be staggeringly high. Adults with mtDNA disease may present with one of the characteristic mtDNA phenotypes such as mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes, whereas children tend to present early with severe, complex neurological manifestations, hepatopathy, renal tubulopathy, endocrinopathy or cardiomyopathy with rapid progression for which symptoms such as growth failure, deafness, epilepsy and muscle weakness are easily recognisable. The declining cost of conducting whole-mtDNA sequencing will allow identification of mtDNA mutations and improve SA’s capacity for accurate diagnosis and appropriate patient counselling and management, and now that strategies are being put in place to offer a basic but robust service for diagnosis of mtDNA diseases, it is time for this country to initiate a debate on the IVF technique that has been topical in the UK and elsewhere (Fig. 1).

cancer syndrome (HBOCS). Up to 10% of breast cancer cases are attributable to germline mutations in cancer susceptibility genes, leading to hereditary syndromes. HBOCS is the best described, and is an autosomal dominant inherited syndrome caused by the presence of heterozygous, pathogenic, germline mutations in either the BRCA1 or BRCA2 genes. Patients with a family history of breast and/or ovarian cancer, women <50 years of age with breast cancer, males with breast cancer and families with cancer from high-risk ethnic groups such as Afrikaners and Ashkenazi Jews should be referred for genetic counselling. Regrettably, in ‘Knowledge regarding basic concepts of heredi tary cancers, and the available genetic counselling and testing services: A survey of general practitioners in Johannesburg, South Africa’,[8] Van Wyk and colleagues show that while GPs tend to obtain some information on cancer family history from their patients, this is seldom sufficient to assess the risks. Only one-third of GPs surveyed referred patients to appropriate facilities for assessment and testing; half were aware of genetic testing services, but most were not familiar with the available genetic counselling facilities. Less than half knew about possible paternal inheritance, the low rate of hereditary mutations and their penetrance. Fortunately, the majority of GPs (87%) were interested in learning more about cancer genetics and available services, and they expected to play an increasing role in the field in the future. Appropriate education needs to be increased so that they are better equipped to identify and refer at-risk families.

Zika virus disease

Is SA at risk? The editorial by Jansen van Vuren et al.[9] is compulsory reading. This will be the last edition of SAMJ that I shall have edited. I wish to thank most sincerely the colleagues who have contributed as authors, reviewers, guest editors and guest editors of CME during my tenure. JS

Damaged mitochondria Mother

Donor

Father

Donor nucleus removed

1 Egg nucleus from mother’s egg is removed and inserted into donor egg

2 Healthy mitochondria

Donor egg with mother’s nucleus is fertilised with sperm from the father

3 Fertilised egg carrying genetic material of two women is inserted into mother’s womb as in normal IVF

Fig. 1. How mitochondrial donation works (from http://www.irishexaminer. com/examviral/science-world/mps-could-make-history-with-ivf-debate- 310486.html).

In ‘Breast cancer in high-risk Afrikaner families: Is BRCA founder mutation testing sufficient?’,[7] Seymour et al. inform us of the presence of three founder mutations in the BRCA genes that occur in the Afrikaner population and lead to hereditary breast and ovarian

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1. Nkosi V, Wichmann J, Voyi K. Comorbidity of respiratory and cardiovascular diseases among the elderly residing close to mine dumps in South Africa: A cross-sectional study. S Afr Med J 2016;106(3):290-297. [http://dx.doi.org/10.7196/SAMJ.2016.v106i3.10243] 2. Benade EL, Jacobson BF, Louw S, Schapkaitz E. Validation of the CoaguChek XS international normalised ratio point-of-care analyser in patients at Charlotte Maxeke Johannesburg Academic Hospital, South Africa. S Afr Med J 2016;106(3):280-283. [http://dx.doi.org/10.7196/SAMJ.2016. v106i3.9422] 3. Prakaschandra DR, Esterhuizen TM, Motala AA, Gathiram P, Naidoo DP. High prevalence of cardiovascular risk factors in Durban South African Indians: The Phoenix Lifestyle Project. S Afr Med J 2016;106(3):284-289. [http://dx.doi.org/10.7196/SAMJ.2016.v106i3.9837] 4. Bhamjee S, Essack Z, Strode AE. Amendments to the Sexual Offences Act dealing with consensual underage sex: Implications for doctors and researchers. S Afr Med J 2016;106(3):256-259. [http:// dx.doi.org/10.7196/SAMJ.2016.v106i3.9877] 5. McQuoid-Mason DJ. The Teddy Bear Clinic Constitutional Court case: Sexual conduct between adolescent consenting children aged under 16 years decriminalised and a moratorium on the reporting duties of doctors and others. S Afr Med J 2014;104(4):275-276. [http://dx.doi.org/10.7196/SAMJ.7653] 6. Meldau S, Riordan G, van der Westhuizen F, et al. Could we offer mitochondrial donation or similar assisted reproductive technology to South African patients with mitochondrial DNA disease? S Afr Med J 2016;106(3):234-236. [http://dx.doi.org/10.7196/SAMJ.2016.v106i3.10170] 7. Seymour HJ, Wainstein T, Macaulay S, Haw T, Krause A. Breast cancer in high-risk Afrikaner families: Is BRCA founder mutation testing sufficient? S Afr Med J 2016;106(3):264-267. [http://dx.doi. org/10.7196/SAMJ.2016.v106i3.10285] 8. Van Wyk C, Wessels T-M, Kromberg JGR, Krause A. Knowledge regarding basic concepts of hereditary cancers, and the available genetic counselling and testing services: A survey of general practitioners in Johannesburg, South Africa. S Afr Med J 2016;106(3):268-271. [http://dx.doi.org/10.7196/SAMJ.2016. v106i3.10162] 9. Jansen van Vuren P, Weyer J, Kemp A, et al. Is South Africa at risk for Zika virus disease? S Afr Med J 2016;106(3):232-233. [http://dx.doi.org/10.7196/SAMJ.2016.v106i3.10615]

March 2016, Vol. 106, No. 3

CORRESPONDENCE

SANS 444:2014: A new standard for small-ampoule labelling and a chance to reduce drug administration errors in South Africa

To the Editor: Drug administration errors remain a hazard in operating theatres and other clinical areas in healthcare facilities worldwide.[1] A prospective study published in 2009 involving over 30 000 anaesthetics at three South African (SA) academic institutions confirmed that drug administration errors by anaesthetists are common.[2] In the study, the incidence of either a drug administration error or a near miss was 1:274 anaesthetics. The most common cause of error (36.9%) was drug ampoule misidentification, and of these errors the majority were due to similar-looking ampoules. Although there were no deaths due to drug errors in the study, a previous survey into drug administration errors by SA anaesthetists revealed that more than 94% of respondents had made a drug error and that in a minority of cases the error caused death or non-fatal cardiac arrest. [3] These figures are similar to those published in the international literature.[1,4] A significant step towards improving drug administration safety is the 2014 publication of a new South African Bureau of Standards (SABS) standard for ampoule labelling.[5] The key feature of the new standard is that labels will be much more legible in the clinical arena. The standard focuses on font size, text legibility and orientation, text contrasts, ordering of label content, and language. It mandates the use of the generic name of the drug on the label and states that, if used, the trade name may not exceed the size of the generic name. To create space for clearer labelling on small ampoules, English is now the only mandatory language. The standard also recommends that where applicable, manufacturers should on part of the label utilise the colours specified for identifying specific drug classes on syringe labels, as per the SABS standard (South African National Standards) SANS 26825.[6] This new SANS standard should decrease the risk of drug substitution errors if adopted by the pharmaceutical industry, and by national professional bodies, hospital groups and the national and provincial departments of health as a key standard to their drug ordering strategies. Anthony R Reed

Head of Clinical Department, New Somerset Hospital, Cape Town, South Africa, and Senior Lecturer, Department of Anaesthesia, Faculty of Health Sciences, University of Cape Town anthony.reed@uct.ac.za

Emeritus Associate Professor and Part-time Senior Lecturer, Department of Anaesthesia, Faculty of Health Sciences, University of Cape Town, South Africa 1. Merry AF, Shipp DH, Lowinger JS. The contribution of labelling to safe medication administration in anaesthetic practice. Best Pract Res Clin Anaesthesiol 2011;25(2):145-159. [http://dx.doi. org/10.1016/j.bpa.2011.02.009] 2. Llewellyn RL, Gordon PC, Wheatcroft D, et al. Drug administration errors: A prospective survey from three South African teaching hospitals. Anaesth Intensive Care 2009;37(1):93-98. 3. Gordon PC, Llewellyn RL, James MFM. Drug administration errors by South African anaesthetists – a survey. S Afr Med J 2006;96(7):630-632. 4. Webster CS, Merry AF, Larsson I, et al. The frequency and nature of drug administration errors during anaesthesia. Anaesth Intensive Care 2001;29(5):494-500. 5. South African Bureau of Standards. South African National Standards SANS 444:2014. Labelling of Small-volume (50 mL or less) Parenteral Drug Containers. Pretoria: SABS Standards Division, 2014. 6. South African Bureau of Standards. South African National Standards SANS 26825 Ed1: 2009/ R2014. Anaesthetic and Respiratory Equipment – User-Applied Labels for Syringes Containing Drugs Used During Anaesthesia – Colours, Design and Performance. Pretoria: SABS Standards Division, 2014.

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To the Editor: There are at least half a dozen barbers on the main streets or ‘high roads’ of suburbs such as Lenasia Ext. 1, Fordsburg and Mayfair in Johannesburg, South Africa. These are run by people of Pakistani, Indian and Bangladeshi origin. We have seen a proliferation of these businesses over the last few years; they provide men’s haircuts for a cheap price of between ZAR25 and ZAR30. As dermatologists and general practitioners, we have been seeing a higher than usual number of new patients with scalp and facial warts, fungal infections and eczematous rashes recently. The common history is frequent visits to the above type of barber, leading to our clinical and expertise-based diagnosis and conclusion. A personal visit to a few of these little ‘barber shops’ led us to the opinion that the dermatological infections listed above are a direct result of transfer of infectious agents between clients. These hardworking barbers do use new ‘sterile Minora’ blades for shaving, which provide a false sense of security. They usually use methylated spirits to sterilise some of their tools of trade. This is not a hygienic method to sterilise equipment, as it is not sufficient to kill fungi, bacteria or viruses. On average, 20 - 40 people are seen in a day, and perhaps more over the weekend. This includes routine haircuts to fancy hairdos, shaving, and head and neck massages using shared oils (i.e. shared by many people). The barber also does not wash his hands regularly. Skin infections with human papillomavirus and dermatophytes, and allergic contact, are probable clinical sequelae to exposure to these unclean practices. The increasing incidence and difficulty in treating these dermatological conditions warrants further investigations into this possible public health problem so that appropriate action and changes in the above practices, such as better education of the barbers, can be taken and implemented. D Modi , Z Modi

Division of Dermatology, Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa howzat@iafrica.com

S Naidoo

School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa S Afr J Med 2016:106(3):227. DOI:10.7196/SAMJ.2016.v106i3.9857

The burden of drug overdose on critical care units in East London, South Africa

Peter C Gordon

S Afr Med J 2016;106(3):227. DOI:10.7196/SAMJ.2016.v106i3.9661

Barber as infectious agent

To the Editor: Intentional self-harm accounted for 1.3% of nonnatural deaths and 0.1% of all-cause mortality in South Africa (SA) in 2013.[1] Fatal suicidal behaviour only represents a portion of the problem. The burden of non-fatal suicidal behaviour on our public health system is significant. Of particular concern is the downward trend in age of those affected, with an exponential increase in suicidal behaviour being seen among the younger generation. Overdoses account for 90% of non-fatal suicidal behavioural events among young people in SA.[2] A small retrospective descriptive study was conducted at Frere Hospital in East London, Eastern Cape Province, to determine the recent burden of drug overdose on the high care unit (HCU) and intensive care unit (ICU) – jointly described as the critical care unit (CCU) – for the 1-year period from March 2014 to February 2015.

March 2016, Vol. 106, No. 3

Fixime 400 mg Ceﬁxime

Fixime

5 PA C K NOW A VAIL ABLE

• Treatment of lower urinary tract infections (5 days)1* Cost of treatment: R146.87** • Single dose treatment of uncomplicated Gonorrhoea1 Cost of treatment: R29.37**

* The usual course of treatment is 5-14 days. For uncomplicated infections of the lower urinary tract, in general treatment over 1-3 days is sufficient. The recommended adult dosage is 200 mg - 400 mg daily as a single dose. ** SEP (Incl. VAT) Pack of 5: R146.87 ; ** SEP (Incl. VAT) Pack of 10: R290.37 Reference: 1. Fixime® Package Insert, South Africa. June 2011. S4 Fixime® 400 mg (film-coated tablets). Each tablet contains 400 mg cefixime. Reg. no.: W/20.1.1/256. For full prescribing information, refer to the package insert approved by the Medicines Regulatory Authority. MERCK (PTY) LTD, Reg. no.: 1970/004059/07. 1 Friesland Drive, Longmeadow Business Estate South, Modderfontein. 1645. Tel: 011 372 5000, Fax: 011 372 5252. Report adverse events to drug.safety.southeastafrica@merckgroup.com or +27 11 608 2588 (Fax line). ZA.FIX.16.02.001

CORRESPONDENCE

The study only included adults and adolescents aged ≥13 years. The patient data were collected from the admission registers in the CCU, as well as from individual patient folders. Casualty statistics were obtained from the casualty clerk’s monthly data sheets. The total number of overdose patients seen in casualty was 352 over the course of the year, with a mean of 29 patients per month. There were peaks noted in December (40 patients) and October (36 patients) – the same two months when male suicides peaked in SA in 2009.[3] Overdose patients accounted for 6.8% of all patients seen by the physician on call in casualty throughout the year. Just over a fifth of overdose patients (71 patients) were admitted to the CCU, with 7.7% spending time admitted to the ICU. There were 57 overdose patients admitted to the HCU during the year, with a mean of five patients per month. These patients accounted for 7.2% of the total number of HCU admissions, and 21.7% of all medical admissions to the HCU. There was a female predominance (61.4%). Females were found to peak in the 13 - 19-year-old and 20 - 29-year-old age groups. Males peaked in the 20 - 29-year-old age group. Both sexes saw an early peak followed by a slow decline until the 60 - 69-year-old age group. The two most common categories of substances ingested were the tricyclic antidepressants (29.8%) and the cholinesterase inhibitors or organophosphates (22.8%). The median duration of stay in the HCU was 3 days, with the usual outcome (82.5%) being transfer to a general medical ward. In total, the overdose admissions accounted for 190 days of admission in the HCU. In the ICU, there were 28 overdose admissions in the year, with a mean of two patients per month. These patients accounted for 5.6% of all ICU admissions, and a quarter of all medical ICU admissions. There was no difference between the two genders in terms of number of admissions. Similar to the pattern noticed in the HCU, females peaked early in the 13 - 19-year-old age group, with males peaking slightly later in the 20 - 29-year-old age group. The two most common categories of substances ingested were the same as in the HCU (28.6% tricyclic antidepressants, 25% organophosphates). The two main outcomes were transfer to the HCU or transfer to the general medical ward. The median duration of stay in the ICU was 3 days, with the overdose admissions accounting for 128 days of ICU admission in total. The cost implications are significant.

Comparison of these findings with those of a similar, larger study – a 5-year (2006 - 2010) retrospective review conducted at Cecilia Makiwane Hospital (CMH), a nearby large referral hospital – reveals certain trends.[4] Cholinesterase inhibitors were also one of the main substance categories resulting in CCU admission; however, they played a more predominant role at CMH, accounting for 55% of all admissions. At both hospitals, females predominated; however, at Frere the difference was more pronounced (60% female, 40% male) than at CMH (53% female, 47% male). The mean age (years) was similar at both hospitals: 30.86 at Frere (females 29.00, males 33.62) and 29.50 at CMH (females 27.91, males 31.31). The mean duration of stay in Frere’s HCU was 3.33 days (79.92 hours), which was similar to CMH’s CCU, where it was 3.31 days (79.32 hours). Overdose admissions peaked in the summer months at both hospitals (January at CMH, December at Frere). These findings demonstrate the recent trends and burden of overdoses on public hospitals in the Buffalo City Municipality, but they probably reflect a much larger, nationwide problem. These patients are managed by the Department of Internal Medicine at Frere Hospital in liaison with the Department of Psychiatry at CMH. There is no dedicated psychiatric unit at Frere Hospital, even though it is a tertiary referral centre. Improved availability and accessibility of psychiatric services as well as better co-ordination of medical and mental healthcare must become a public health priority. Kirsten Rowe

Intern medical doctor, East London Hospital Complex, Eastern Cape, South Africa (currently Community Service Medical Officer, Galeshewe Day Hospital, Kimberley, Northern Cape, South Africa) kirstenrowe@gmail.com

1. Statistics South Africa. Mortality and causes of death in South Africa. Pretoria: Statistics South Africa, 2013:39. 2. Schlebush L. Suicidal behaviour. In: Van Niekerk A, Suffla S, Seedat M, eds. Crime, Violence and Injury in South Africa: 21st Century Solutions for Child Safety. Cape Town: Psychological Society of South Africa, 2012:179-183. 3. Matzopoulos R, Prinsloo M, Bradshaw D, et al. The Injury Mortality Survey: A National Study of Injury Mortality Levels and Causes in South Africa in 2009. Cape Town: South African Medical Research Council, 2013:29. 4. Favara DM. The burden of deliberate self-harm on the critical care unit of a peri-urban referral hospital in the Eastern Cape: A 5-year review of 419 patients. S Afr Med J 2013;103(1):40-43. [http://dx.doi. org/10.7196/SAMJ.6231]

S Afr J Med 2016:106(3):227-228. DOI:10.7196/SAMJ.2016.v106i3.9933

Thank you, Janet Seggie

Prof. Janet Seggie joined the Health and Medical Publishing Group (HMPG) in November 2012 as Editor-in-Chief of the South African Medical Journal (SAMJ), bringing with her the experience gained in an outstanding academic and clinical career that spanned the universities of the Witwatersrand and Cape Town. Her impact on the journal has been significant, ensuring that it is a source of medicopolitical news, up-to-date comment and opinion, and excellent research that is highly relevant to our challenging medical environment in South Africa. She has also offered a publication platform for colleagues from other countries on the continent, who rarely have the chance to publish their research in difficult medical and academic environments. Under Janet’s tenure, the SAMJ once again took on an educational role by incorporating CME within its pages – a highly successful move that has attracted the contributions of some of our top medical academics. We wish Janet well in her well-deserved retirement, and thank her sincerely for her contribution. Bridget Farham

Deputy Editor, SAMJ Executive Editor, HMPG

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March 2016, Vol. 106, No. 3

5th Annual

OUTBREAK CONTROL AND PREVENTION AFRICA CONFERENCE

CPD ACCREDITED

Dates: 20 & 21 April 2016

Venue: Indaba Hotel, Fourways, Johannesburg

CONFIRMED SPEAKER FACULTY Dr Chika Asomugha Senior Medical Advisor for Public Health and the Communicable Diseases Programmes GAutenG DepArtment oF HeAltH professor Stella Anyangwe Honorary Professor of Epidemiology unIVerSItY oF pretorIA Dr Salim parker President SoutH AFrICAn SoCIetY oF trAVel meDICIne mandla Zwane Deputy Director - Health mpumAlAnGA DepArtment oF HeAltH Dr lourens robberts ‎Clinical & Public Health Microbiologist unIVerSItY oF CApe toWn

Dr Jacob Sheehama Deputy Associate Dean SCHool oF meDICIne - unIVerSItY oF nAmIBIA Dr lesego Bogatsu Senior Manager-Aviation Medicine SoutH AFrICAn CIVIl AVIAtIon AutHorItY Thulisa Mkhencele Epidemiologist nAtIonAl InStItute For CommunICABle DISeASeS thomas Dlamini Epidemiologist & Researcher eAStern CApe DepArtment oF HeAltH professor Bethabile lovely Dolamo Professor: Health Services Management and Leadership DepArtment oF HeAltH StuDIeS - unIVerSItY oF SoutH AFrICA

Diana Chebet Microbiologist & Infection Control Unit Team Leader pHArmAKen ltD - KenYA

PRACTICAL CASE STUDY WORKSHOP

Godwill mlambo Assistant Malaria Control Manager tFm proJeCt DemoCrAtIC repuBlIC oF ConGo CPD Accredited: Level 1 – 10 Clinical Points (1pt per hr) 10 Speaker points (per instance)

• • • •

DISCuSSInG tHe InternAtIonAl reSponSe pArADIGm to pAnDemIC DISeASe Control In AFrICA AnD tHe nexuS WItH peACeKeepInG reSponSe meCHAnISmS In tHe lIGHt oF tHe WeSt AFrICAn eBolA outBreAK Andre Juan roux Conflict Management, Peacekeeping and Peacebuilding Expert

Sp e o CIA reg FFer l del i s rec egateter 5 eiv s del e the and e th Fr gate 6 ee

KEY STRATEGIES TO BE DISCUSSED

Analysing the effects of outbreak pandemics on developing countries within Africa Collaborating with national multi-sectoral outbreak response teams managing outbreaks at a national and global level Examining the role of medical and health innovation to prevent and treat deadly infectious diseases

• • • •

Formulating solutions to enhance airport preparedness guidelines for outbreaks of communicable disease Improving the management and control of outbreaks in hospitals and public health centres Discussing the management and control of Tuberculosis within confined spaces Investigating cases of Malaria and providing prevention and control strategies ItC is a proud member of:

De ve

lop

For easy registration contact Therisha +27 (0) 11 326 2501 or email bookings@intelligencetransferc.co.za

ItC IS etDp SetA ACCreDIteD & AorleVel 1 B-BBee CompAnY or fax: +27 (0) 11 326 2960 visit: www.intelligencetransferc.co.za

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SA professor and US engineer transform disabled babies’ lives A former Limpopo physio therapist-turned Professor in Rehabilitation Sciences at the University of Okla homa has coinvented a mobile device that ‘teaches’ disabled infants how to crawl, miraculously trans forming their cognition, early mobility and life prospects. Prof. Thubi A Kolobe conceived the idea behind the self-initiated prone-powered crawler (SIPPC), a skate-like device that miraculously enhances the physical abili ties of infants, particularly those with cerebral palsy (CP). Many of these children would otherwise never acquire the basic motor skills so fundamental to all future potential learning. The ground-breaking device was displayed at the Smithsonian Innovation Festival at the National Museum of American History in Washington, DC, in September last year, where Kolobe was honoured for her creative thinking. The device teaches infants born with disabilities not just to crawl, but to experience and enjoy independent movement.

Kolobe explains that there is a window of very high synaptic connections in the brain at between 2 and 9 months of age, a critical period for neural development, during which neurologists and paediatricians had previously adopted a ‘wait and see’ strategy. Kolobe became frustrated with the limi tations of existing passive therapy, such as gently pulling CP infants around on or suspending them in a towel (which doesn’t reinforce neural pathways). Her research had shown that when babies try to move but do not get the desired effect, their brains prune off that particular motor pathway, leaving them forever disabled. By stratifying five groups of infants and testing them weekly to 6, 9 and 12 months, 3 years and 5 years, she was able to track the trajectories of those who ended up with cerebral palsy and those who did not. She discovered that a developmental gap opened up even before term age (birth),

becoming dramatic by 3 months of age. Kolobe explains that there is a window of very high synaptic connections in the brain at between 2 and 9 months of age, a critical period for neural development during which neurologists and paediatricians had previously adopted a ‘wait and see’ strategy. ‘My frustration was that the gap was opening up.’

Nudging the infant brain into action

Although babies generally don’t crawl before 9 months, introducing the idea of crawling early enough facilitates brain connections and enhances the child’s innate compulsion to move. ‘We were waiting until they failed at 9 months,’ Kolobe observes. The solution was to intervene early to enable the formation of lasting skills – so she turned to technology. ‘I thought there must be a way to support these babies, to bypass those constraints on them and still enable them to drive themselves to move and explore. I wanted something that could harness a baby’s early independent movements, to keep them going and convert them into functional use.’ So in 2003 she sought out Peter Pidcoe, a former Chicago colleague who runs a ‘peculiar’ laboratory at Richmond’s Virginia Commonwealth University (VCU). People come to him – a physical therapist and engineer – when they need help creating a therapy tool that doesn’t yet exist. A ‘tinker’ of note, Pidcoe fiddles away in a garage in the basement of VCU’s West Hospital, constructing devices – from electronic fatigue monitors to predict potential ankle sprains, to prosthetic limbs. Kolobe and her colleagues wrote algorithms incorporated into the electronically powered motorised SIPPC, with sensors that respond to babies’ little kicks and weight shifts, rewarding them with an extra boost. The baby lies directly on a cushioned board, secured in place with soft Neoprene straps, and his/her arms and legs connect to sensors attached to computers. Later versions of the SIPPC now have a ‘onesie mode’, a shirt with embedded sensors to fine-tune directional detection, so that even babies who couldn’t generate much force would be reinforced by forward, lateral or backward motion. ‘There is sophisticated measurement of the movement of a child’s arms and legs, and the SIPPC uses that to identify patterns we

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Prof. Thubi Kolobi.

want to reward,’ Pidcoe explains. ‘You direct the reward to the activities you’re trying to achieve.’

An illustrative case

One of Kolobe’s earliest patient successes was Kara Ellis, a twin born at 25 weeks who failed to thrive, living on and off ventilators and eating badly, and whose determined mother, a nurse, came to her for help when her child started making odd movements and scissoring her fingers. Kolobe had by then developed, with colleagues in Chicago, an assessment called the Test of Infant Motor Performance to identify infants most at risk of CP. She had drawn on her research on how brain growth affects motor development in very young children. At just a few months old Kara was diagnosed with cerebral palsy and other motor development delays. Her mother’s determination and Internet searching paid off – because with CP nearly always affecting muscle control and often undiagnosed until the child is a year or more old, it’s often too late, the baby already having passed through the stages of learning how to move: rolling, sitting, crawling, cruising and toddling. The random kicks and wriggles of a normal 3-month-old baby do important work by

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forming crucial neural connections that lead to advanced motor skills, such as walking or writing with a pencil. Putting a colourful toy just out of Kara’s reach was enough to stimulate her to reach for it – to attempt to lurch in its direction. Kara was rewarded when her effort resulted in movement towards the toy. Eventually, with more and more practice, Kara learnt to quickly move and grab the toy, because her developing brain reinforced the neural connections that control that skill. Tragi cally, the reverse is also true, with infants’ brains having a ruthless ‘use it or lose it’ policy: if a baby tries to move and doesn’t get the desired effect, the brain eventually prunes off that motor pathway. Monica Ellis said of her daughter: ‘Initially she would just lie there on her belly, unmotivated to participate. She sucked her fingers and watched as we tried to entice her to play. To get her moving, we’d pop her fingers out of her mouth, and she’d get mad.’ They then got Kara’s attention with a toy. The first time she reached for an object on her own, Ellis and Kolobe cheered. ‘It flipped a switch,’ Ellis says. ‘She’d turn her head and look at us like “Oh, you like this?” That positive response really helped her to learn to start doing things on her own.’

Kolobe is using a neural feedback net to investigate the real-time activity in babies’ brains as they navigate with the SIPPC, while Pidcoe is working to refine the design in the hope that it will be commercially available to parents and therapists at a relatively affordable price. With help and reinforcement from the SIPPC, Kara learnt how to crawl. Today, an active 4-year-old in preschool with her sister, Kara walks, talks and runs. She has officially been discharged from physical therapy. Ellis says if it weren’t for the SIPPC, the small obstacles of Kara’s infancy would have been infinitely more challenging to overcome. ‘Even as a little preemie, she let everyone do everything for her because she couldn’t do it by herself,’ Ellis says. Kolobe, too, is driven to show that even very young infants are highly capable of making huge gains in the face of a potential disability: ‘This is what can happen when we harness and multiply the little capabilities that they have so that they can be successful – and

Prof. Thubi Kolobi encourages a baby to crawl using the SIPPC.

The motorised SIPPC has sensors that respond to a baby’s kicks and weight shifts. The device rewards the baby with an extra boost. Photo: University of Oklahoma Health Sciences Center.

only technology can allow us to do that. As a scientist, there are so many questions to be answered, and I feel we haven’t even scratched the surface with what we can learn from this.’

‘Five years’ to public launch

Kolobe and Pidcoe continue to work on the SIPPC in their respective labs, but in slightly different capacities. Kolobe is using a neural feedback net to investigate the real-time activity in babies’ brains as they navigate with the SIPPC, while Pidcoe is working to refine the design in the hope that it will be commercially available to parents and therapists at a relatively affordable price. The versions on display at the Smithsonian Institute currently cost between ZAR3 320

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and ZAR5 000 to produce. Ultimately, Kolobe sees versions that can be driven with a cell phone, laptop or iPad-based application. Pidcoe describes the outcome as a classic example of how clinical and engineering tools can blend. Pidcoe and Kolobe patented the SIPPC in January 2015. Although still a prototype, the goal is to miniaturise it, putting all the electronics into a small app, enabling it to be easily stored and transported. Kolobe hopes that within 5 years they will be ready for Federal Drug Administration approval and licensing, with a device that can be used twice a day at home, 5 days a week (currently in use twice a week due to its relatively cumbersome nature). All the infants’ movements and distance and direction travelled are coded – and the less they access the ‘assist’ function, the greater

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the success. A former University of KwaZuluNatal graduate and campus colleague of the late Steve Biko and Mamphele Ramphele in the early 1970s, Kolobe is determined that cost does not become a barrier to access: ‘It’s important to me that the device cost not more than USD500’ (approximately ZAR7 500), she says.

Inventor’s empathic journey

Ironically, a temporary disability of her own set Kolobe off on her unique aca demic journey. ‘In matric I ended up in Baragwanath Hospital after a car crash in which a piece of the steering wheel cost me

my voice. The physios would accompany my speech therapist during rounds and I was fascinated ... My brother, a medical technologist at a research institute, took me to see two of them and that was that.’ After graduating she was the first and only black physiotherapist at the 1 200-bed Kalafong Hospital – and the only physiotherapist when Attridgeville and Mamelodi erupted in violence in 1976, making travel to the hospital too dangerous for her 11 white colleagues. ‘For nearly a month, I did every thing, including ICU, out of which came intense reading of foreign journals which ultimately led to my applying for an unprecedented health bursary from the

American Consulate.’ Today she basks in the recent observation of a 70-year-old selfmade Oklahoman millionaire, with cerebral palsy himself, while watching an infant use her device. He quipped: ‘If I had this when I was small I’d be doing a whole lot better than I am now.’ It seems that countless children’s futures stand to be transformed – simply because a passionate therapist refused to give up.

in the Cape Town day hospitals – where his surgical skills were highly appreciated – and did locums. His work was interspersed with a long, courageous but ultimately futile battle against depression, alcoholism and other gremlins. After many absences, he had to stand down. During this time, he was supported by his children Dane and Lara, his sister Ingrid and her family, his wife Margie and her son David. He was very close to his mother, who died not long before him. The last five years, when his mental and physical faculties waned, were more taxing than anyone would care to imagine. Arnold died peacefully in December 2013. As a doctor, Arnold hid his sensitivity beneath a brusque exterior. This did not deter patients, who admired his compassion and skill. As a father, husband, brother, friend and companion, he was one of the best. Problems notwithstanding, his caring, loyalty and gentle humour were evident to everybody; most of all, there was a sense of dignity that never left him.

Arnold’s failure to achieve his potential in his chosen career is a tocsin call. A sensitive person, he never liked adornment and would probably have disapproved of anything as public as this obituary. But no one can argue with its message. We need to recognise the costs that many pay for doing medicine – far more than we care to admit. Starting at medical school and running through careers until retirement, it is too easy to forget those among us who falter and fall aside. There is much rhetoric, but little more than token attempts to deal with the problem. A very decent and fine human being has paid the penalty. Let us ensure that everything possible is done to prevent more casualties. If we don’t, no one else will. This is the best memorial we can give Arnold Wiid.

Chris Bateman chrisb@hmpg.co.za S Afr Med J 2016;106(3):229-231. DOI:10.7196/SAMJ.2016.v106i3.10681

OBITUARY Arnold Waldemar Wiid, MB ChB (1950 - 2013)

Arnold Wiid, who had the talent and ability to become a fine surgeon, has died. He came from a rich background. His father’s family was Afrikaans (the Danish name went back generations). Daniel Wiid was a geologist of considerable ability who played a role in the developing the copper mines of Springbok and Nababeep. Working in the Gulf, he met Flora Kalisz – a Polish refugee via Russia – and married her. The union also resulted in two daughters before Daniel died when Arnold was 12, a loss that never left him. The family moved to Somerset West, where he attended Hottentots Holland High School before graduating in medicine at the University of Cape Town after 1974. Arnold decided to specialise in surgery at Tygerberg Hospital, as did two friends, Brian Warren and Richard Muller. At this stage the demons that were to haunt him for the rest of his life intervened. He lost his sister, his marriage ended and he left the training scheme. For the rest of his career, he worked

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Robert M Kaplan Graduate School of Medicine, University of Wollongong, Australia rob@rmkaplan.com.au Robert Kaplan (MB ChB UCT 1973) was at school and university with Arnold Wiid.

EDITORIAL

Is South Africa at risk for Zika virus disease? Zika virus (ZIKV) was originally isolated from a sentinel rhesus monkey in the Zika forest in Uganda in 1947.[1] Twenty-one years later the virus was isolated for the first time from naturally infected humans in Nigeria.[2] ZIKV belongs to the genus Flavivirus, family Flaviviridae, comprising enveloped viruses with RNA genomes, mostly arthropod borne.[3] For decades ZIKV remained relatively unknown, affecting mainly monkeys and occasionally causing a mild disease in humans residing across a narrow equatorial belt in Africa and Asia.[4] The virus is transmitted to humans by daytime active Aedes aegypti mosquitoes and usually causes a self-limiting, non-fatal febrile infection characterised by a maculopapular rash, arthralgia, conjunctivitis, myalgia and headache.[5] From 2007 the geographical distribution of ZIKV expanded drastically, with first outbreaks documented in some of the Pacific islands, including the Federated States of Micronesia. Additional Pacific islands were affected in 2013 - 2014, followed by unprecedented spread of the virus in the Americas from 2014.[4,6] As of February 2016, 23 countries in Latin America and the Caribbean had reported active transmission of ZIKV. In Brazil alone, estimation of ZIKV infections in 2015 ranged from 500 000 to 1.5 million.â&#x20AC;&#x201A;[7] This situation is concerning in view of the explosive spread of ZIKV outside its traditional geographical boundaries, and is further complicated by supposed association of ZIKV infections with birth malformations and neurological syndromes. Drastic increases in the birth of babies with abnormally small heads (microcephaly) and unilateral ophthalmological abnormalities, and cases of GuillainBarrĂŠ syndrome, are reported in some areas recently affected by the virus.[8] The newly postulated risks of ZIKV infection, with a potential high burden on families and communities, are of great international concern. On 1 February 2016 the WHO proclaimed the rise in cases of microcephaly and neurological disorders reported in Brazil as a public health emergency of international concern. This declaration calls for a more co-ordinated effort to improve surveillance, improve mosquito control programmes and fast-track the development of diagnostic assays, vaccines and antivirals for ZIKV and to scientifically investigate the causality of the observed disorders.[9] The clinical presentation of ZIKV disease is not characteristic enough to enable even a tentative diagnosis. A known history of recent travel to an area with active ZIKV transmission is informative, and helps to guide specific referral laboratory testing. There is no specific prophylaxis other than prevention of mosquito bites, no specific antivirals are available, and treatment is supportive. Infection rarely leads to hospitalisation, and it is believed that up to 80% of infected individuals remain asymptomatic. While investigations to determine the underlying pathology of ZIKV infection are ongoing, pregnant women are discouraged from travelling to affected areas at any stage of pregnancy. Two cases of possible sexual transmission of ZIKV have been reported. The most recent is associated with the first case of ZIKV disease diagnosed in a traveller (returning from Venezuela) and diagnosis of ZIKV disease in his sexual partner who did not travel outside the USA (unofficial report at time of publication). It would be reasonable to consider precautions (i.e. abstinence, condom use) for pregnant women with sexual partners who have travelled to affected areas and could be affected or are confirmed with ZIKV infection.[10] Two cases of probable

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perinatal transmission are also on record from French Polynesia (2013).[11] The potential for ZIKV transmission through blood transfusion has been demonstrated from the outbreak in French Polynesia (2013).[12] The risk of ZIKV transmission in any given area partly depends on the availability of competent mosquito vectors. A. aegypti mosquitoes are the major transmitters of ZIKV, as for dengue viruses. While causing an increased number of outbreaks in Africa and Asia in recent years, none of the known dengue virus types is endemic in South Africa (SA). Considering that the risk of transmission of the two related viruses is likely to be the same, the prediction models based on the distribution of A. aegypti therefore do not place SA at high risk for transmission of ZIKV. It should be emphasised here that different populations of A. aegypti mosquitoes may have dissimilar competence in vectoring these viruses to humans. No human cases of infection with ZIKV related to local transmission have been diagnosed in SA to date. The first imported case of ZIKV disease in SA was confirmed in the week of 15 February 2016, in a traveller from Colombia with mild illness. Further imported cases in travellers visiting affected areas can be expected. Dengue cases have only been diagnosed in travellers returning home from countries with active circulation of the virus.[13] A. aegypti mosquitoes are found in SA, particularly in the eastern coastal plain but also in the cities of the inland plateau. In urban areas these mosquitoes breed in small collections of water such as in discarded tyres and buckets, or the leaf axils of banana trees. There is a possibility that a traveller infected with ZIKV may return to SA. The transient presence of virus in the blood (viraemia), however, decreases the likelihood of human-to-mosquito transmission and the establishment of an autochthonous transmission cycle. Patients presenting with the symptoms described above and with a history of recent (<2 weeks) travel to an affected area should consider ZIKV disease, but also related infections such as chikungunya or dengue, as a possible diagnosis. Infection with these viruses can be confirmed by specialised referral laboratory testing at the National Institute for Communicable Diseases (NICD). Malaria should also be considered. Laboratory testing for confirmation of ZIKV infection at the NICD requires the submission of serum or clotted blood along with a comprehensive clinical and travel history. Blood/serum collected up to day 5 after the onset of disease is most suitable for confirmation of acute infection by virus culture and detection of ZIKV virus nucleic acid by reverse transcription-polymerase chain reaction (RT-PCR) assay. Although RT-PCR is highly sensitive and specific, its application in laboratory confirmation of ZIKV infection is limited by the short duration of viraemia (2 - 4 days). Serological diagnosis of ZIKV infection is complicated by the high level of cross-reaction with other flaviviruses. For this reason laboratory confirmation of infection based on serological results is only feasible through the testing of paired serum samples taken at least 14 days apart, to demonstrate a four-fold rise in antibody titre. Parallel serological testing for dengue virus antibodies is also important and diagnostic interpretation hinges on the quantitative comparison of these results. Rapid diagnostic tests (point-of-care assays) are not currently available. In response to the increasing spread of ZIKV and the potential high health threats it poses, the following measures need to be considered: (i) detection and monitoring of virus dissemination

March 2016, Vol. 106, No. 3

EDITORIAL

based on event-based surveillance; (ii) vector management; (iii) preparedness of healthcare settings and services for the management of complicated ZIKV cases; (iv) risk communication and public awareness; (v) training and capacity building for clinical and laboratory diagnosis, vector control and communication; and (vi) research and development to address increasing needs for diagnostic reagents and rapid diagnostic kits. Petrus Jansen van Vuren, Jacqueline Weyer, Alan Kemp, Veerle Dermaux-Msimang Centre for Emerging and Zoonotic Diseases, National Institute for Communicable Diseases, National Health Laboratory Service, Sandringham, Johannesburg, South Africa Kerrigan McCarthy, Lucille Blumberg Division of Public Health Surveillance and Response, National Institute for Communicable Diseases, National Health Laboratory Service, Sandringham, Johannesburg, South Africa Janusz Paweska Centre for Emerging and Zoonotic Diseases, National Institute for Communicable Diseases, National Health Laboratory Service, Sandringham, Johannesburg, South Africa Corresponding author: J Paweska (januszp@nicd.ac.za)

Acknowledgement. Allison Glass, Lancet Laboratories, Johannesburg. 1. Dick GW, Kitchen SF, Haddow AJ. Zikavirus. I. Isolations and serological specificity. Trans R Soc Trop Med Hyg 1952;46(5):509-520. 2. Moore DL, Causey OR, Carey DE, Reddy S, Cooke AR, Akinkugbe FM. Arthropod-borne viral infections of man in Nigeria, 1964-1970. Ann Trop Med Parasitol 1975;69(1):49-64. 3. Kuno G, Chang GJ, Tsuchiya KR, Karabatsos N, Cropp CB. Phylogeny of the genus Flavivirus. J Virol 1998;72(1):73-83. 4. Fauci AS, Morens DM. Zika virus in the Americas – yet another arbovirus threat. N Engl J Med 13 January 2016. [http://dx.doi.org/10.1056/NEJMp1600297] 5. Simpson DI. Zika virus infection in man. Trans R Soc Trop Med Hyg 1964;58 (4):335-338. [http:// dx.doi.org/10.1016/0035-9203(64)90201-9] 6. Musso D, Nilles EJ, Cao-Lormeau VM. Rapid spread of emerging Zika virus in the Pacific area. Clin Microbiol Infect 2014;20(10):O595-O596. [http://dx.doi.org/10.1111/1469-0691.12707] 7. Gatherer D, Kohl A. Zika virus: A previously slow pandemic spreads rapidly through the Americas. J Gen Virol 2015. [http://dx.doi.org/10.1099/jgv.0.000381] 8. Ventura CV, Maia M, Bravo-Filho V, Góis AL, Belfort R. Zika virus in Brazil and macular atrophy in a child with microcephaly. Lancet 2016;387(10015):228. [http://dx.doi.org/10.1016/S01406736(16)00006-4] 9. World Health Organization. WHO statement on the first meeting of the International Health Regulations (2005) (IHR 2005) Emergency Committee on Zika virus and observed increase in neurological disorders and neonatal malformations. 1 February 2016. http:// www.who.int/mediacentre/news/statements/2016/1st-emergency-committee-zika/en/ (accessed 2 February 2016) 10. Musso D, Roche C, Robin E, Nhan T, Teissier A, Cao-Lormeau VM. Potential sexual transmission of Zika virus. Emerg Infect Dis 2015;21(2):359-361. [http://dx.doi.org/10.3201/eid2102.141363] 11. Besnard M, Lastère S, Teissier A, Cao-Lormeau VM, Musso D. Evidence of perinatal transmission of Zika virus, French Polynesia, December 2013 and February 2014. Euro Surveill 2014;19(13):20751 [http://dx.doi.org/10.2807/1560-7917.es2014.19.13.20751] 12. Musso D, Nhan T, Robin E, et al. Potential for Zika virus transmission through blood transfusion demonstrated during an outbreak in French Polynesia, November 2013 to February 2014. Euro Surveill 2014;19(14):20761. [http://dx.doi.org/10.2807/1560-7917.es2014.19.14.20761] 13. Msimang V, Weyer J, le Roux C, et al. Dengue fever in South Africa: An imported disease. National Institute for Communicable Diseases Surveillance Bulletin 2013;11(3):58-62.

S Afr Med J 2016;106(3):232-233. DOI:10.7196/SAMJ.2016.v106i3.10615

This month in the SAMJ ... Datshana Prakash Naidoo* is Chief Specialist in and Head of the Department of Cardiology at the Nelson R Mandela School of Medicine, University of KwaZulu-Natal, and Inkosi Albert Luthuli Hospital, Durban. He is Past President of the Southern African Hypertension Society, holds a doctorate in cardiology, and is a Fellow of the Royal College of Physicians. A National Research Foundation-rated researcher, his research interests are directed towards establishing the role of genetic and environmental factors in the pathogenesis of coronary artery disease. He has pioneered the training of cardiac technologists in echocardiography and is responsible for establishing a non-invasive cardiology service across KZN. * Prakaschandra DR, Esterhuizen TM, Motala AA, Gathiram P, Naidoo DP. High prevalence of cardiovascular risk factors in Durban South African Indians: The Phoenix Lifestyle Project. S Afr Med J 2016;106(3):284-289. [http://dx.doi.org/10.7196/SAMJ.2016.v106i3.9837]

Andrew Redfern* is a developmental paediatrician currently working in the Paediatric Emergency and Ambulatory Department at Tygerberg Children’s Hospital, Cape Town. He received his MPhil in developmental paediatrics from the University of Cape Town in 2014. His areas of interest at the time were improving the provision of services for children with disability. Currently he finds himself on a new path, with growing interests in the fields of paediatric emergency medicine and medical education. He is passionate about free open-access medical education, simulation and improving paediatric emergency care and training for all children in South Africa and beyond. * Redfern A, Westwood A, Donald KA. Children with disabling chronic conditions in the Western health subdistrict of Cape Town, South Africa: Estimating numbers and service gaps. S Afr Med J 2016;106(3):302-307. [http://dx.doi.org/10.7196/SAMJ.2016.v106i3.9825]

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EDITORIAL

Could we offer mitochondrial donation or similar assisted reproductive technology to South African patients with mitochondrial DNA disease? Mitochondrial disease comprises a highly hetero geneous group of disorders in which mitochondrial function is impaired as a result of mutations located either in mitochondrial DNA (mtDNA) itself or in a large number of nuclear genes involved in mitochondrial function.[1] In 2015 the House of Commons in the UK voted to endorse the use of pioneering in vitro fertilisation (IVF) techniques to protect future generations from the risk of mtDNA disease by the use of mitochondrial donation. More than one method to implement mitochondrial donation has been suggested in the literature. Options include the transfer of pronuclei from the parents into a mitochondrial donor zygote,[2] or alternatively metaphase II spindle transfer into a mitochondrial donor oocyte.[3] In both these scenarios, the offspring inherit their nuclear DNA (nDNA) from the gametes contributed by both parents but their mtDNA from another female (donor), introducing the three-parent scenario that has sparked controversy and debate.[4,5] Mitochondrial DNA has several properties that distinguish it from nDNA: it is strictly maternally inherited and does not undergo recombination; it is not wrapped around histone proteins for protection, and is consequently exposed to high levels of mutation-generating free radicals; and there are many copies per cell, ranging from two up to several thousand. In addition, the mutation rate in mtDNA is about 10 times greater than in nDNA, and replication errors are less likely to be repaired. The high mutation rate coupled with the polyploid nature of the mitochondrial genome gives rise to an important feature of mitochondrial genetics, namely homoplasmy and heteroplasmy. In simple terms, homoplasmy is when all copies of the mitochondrial genome in a given cell/tissue/organ are identical, and heteroplasmy is when there is a mixture of two or more mitochondrial genotypes.[1] Mutations in mtDNA often lead to deleterious consequences. Some mutations affect all copies of the mitochondrial genome (homoplasmic mutation), whereas others are only present in some copies of the mitochondrial genome (heteroplasmic mutation). In the presence of heteroplasmy, there is a mutation threshold level that is important both for the clinical expression of the disease and for biochemical defects. The precise threshold depends on the pathogenicity and the tissue involved, resulting in a complex and heterogeneous pattern of disease presentation.[1] Another level of complexity is introduced when a population-specific mutation is associated with the aetiology and presentation of a disease.[6,7] Differences in disease presentation are also found between adult and paediatric patients: adults may present with one of the characteristic mtDNA phenotypes such as mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), whereas paediatric patients tend to present early with severe, complex neurological manifestations, hepatopathy, renal tubulopathy, endocrinopathy or cardiomyopathy with rapid progression. The current regulations in the UK state that mitochondrial IVF techniques should be limited to selected cases where ‘there is a particular risk that the patient’s egg or an embryo created using the patient’s egg will carry a mtDNA abnormality and that there is a significant risk that a child born from the use of that egg will have or develop a serious mitochondrial disease’.[8] Suitable infrastructure and capacity to perform the necessary molecular diagnosis together with interpretation of clinical data linking a particular mtDNA mutation to

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the disease is required. While many laboratories in the UK are capable of providing such services, it is timely for us to examine the level of service capability in South Africa (SA). Although individually rare, as a group mitochondrial genetic disorders are thought to be responsible for a substantial proportion of inherited metabolic disease. An estimated prevalence of 1:5 000 1:10 000 has been reported in several (mostly developed-nation) populations.[9-13] However, the prevalence of mitochondrial genetic disorders is still largely unknown in SA. To stimulate dialogue on the status of mitochondrial disease diagnosis and research in SA, a workshop was convened in Potchefstroom, North West Province, in November 2014 that enabled a small group of local scientists and clinicians to engage with colleagues from the UK on this subject.[7] Two centres are involved in mtDNA diagnostics in SA: the Inherited Metabolic Diseases (IMD) Laboratory of the National Health Laboratory Service (NHLS) in Cape Town and the Mitochondria Research Laboratory in the Centre for Human Metabolomics (CHM) at NorthWest University (NWU) in Potchefstroom. The IMD laboratory serves as the referral centre for mtDNA disease genetic studies. Molecular testing for deletions and common point mutations associated with classic phenotypes such as MELAS is offered, as well as limited targeted nuclear gene sequencing (Table 1). Referrals for common mutations were only positive in about 6% of >1 000 cases examined between 1990 and 2012.[7] This low percentage can be attributed in part to incom plete clinical information received with specimens sent for molecular testing, lack of capacity to track and test maternal relatives, and inappro priate requests. Often it is difficult to establish whether: (i) the correct tissue was supplied; (ii) the test requested matched the phenotype; or (iii) other possible diseases were excluded. From August 2015, this laboratory has shifted its diagnostic strategy to that of sequencing of the entire mtDNA genome using a next-generation sequencing approach, as well as widening its nuclear gene sequencing repertoire for non-mtDNA inherited mitochondrial disorders (Table 1). Clinical screening is being strengthened to try to improve diagnostic efficiency. The Mitochondria Research Laboratory in the CHM at NWU, which is not affiliated to the NHLS IMD Laboratory, has since 1998 approached mtDNA disease investigations mainly in cohort investi gations with the Department of Paediatrics, University of Pretoria, as well as ad hoc cases from elsewhere in SA. The laboratory approaches molecular investigations using full-length mtDNA next-generation sequencing, which follows respiratory-chain single-enzyme kinetics in muscle biopsies and urine metabolomics investigations from clini cally selected patients.[14,15] A collaborative research project undertak en by this laboratory with the University of Pretoria involved a cohort study of >200 well-characterised paediatric patients with clinically diagnosed mitochondrial disease drawn from Limpopo, Gauteng and Mpumulanga provinces. Respirometry and single-enzyme analyses were conducted in muscle biopsies to confirm mitochondrial disease in these patients. Even at this high level of resolution, <1% of mtDNA mutations detected were linked with known pathogenic mtDNA mutations, indicating that many novel mtDNA mutations with as yet unresolved impact were present in this cohort.[6] In order to enter the debate on whether or not SA should offer prenatal testing or interventions such as the IVF technique described above to patients with mtDNA disease, we should at least be able to

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Table 1. Molecular tests offered for mtDNA diseases at the NHLS IMD laboratory Test offered

Indication

Methodology used

Scope

NGS

Full mtDNA sequencing (including mtDNA large deletions)

mtDNA testing ull mtDNA sequencing (from F September 2015) mtDNA large-deletion screening

Pearson syndrome; CPEO; KSS

Long-range PCR analysis

Large mtDNA deletions

MELAS m.A3243G

MELAS

RFLP analysis

m.A3243G

MELAS other

MELAS

Sanger sequencing

MT-TL1 mutations

NARP common mutation

NARP

RFLP analysis

m.T8993C/G

LHON common mutations

LHON

RFLP analysis and Sanger sequencing

m.G3460A; m.G11778A; m.C14482A/G; m.T14484C; m.T14487C; m.C14568T

MERRF

Sanger sequencing

MT-TK mutations

Targeted single-mutation screening

Family history/clear clinical phenotype

RFLP analysis and/or Sanger sequencing

Most published mutations

POLG

Alpers syndrome; PEO; SANDO; SCAE

Sanger sequencing

Full gene

C10ORF2*

AD-PEO; SANDO

Sanger sequencing

Full gene

TK2

Myopathic mtDNA depletion

Sanger sequencing

Full gene

SURF1

Leigh syndrome

Sanger sequencing

Full gene

PDHA1

Pyruvate dehydrogenase deficiency

Sanger sequencing

Full gene

ETHE1

Ethylmalonic aciduria

Sanger sequencing

Full gene

MARS2*/DARS2*/AARS2*

Leukoencephalopathy and lactic acidosis

NGS

Full genes

TYMP1*

MNGIE

NGS (as part of a panel)/Sanger sequencing

Full gene

NDUFS1*/NDUFV1*

Leigh syndrome

NGS

Full genes

Nuclear DNA testing

NGS = next-generation sequencing; CPEO = chronic progressive external ophthalmoplegia; KSS = Kearn-Sayre syndrome; PCR = polymerase chain reaction; RFLP = restriction fragment length polymorphism; NARP = neuropathy, ataxia and retinitis pigmentosa; LHON = Leber’s hereditary optic neuropathy; MERRF = myoclonic epilepsy with ragged red fibres; PEO = progressive external ophthalmoplegia; SANDO = sensory ataxic neuropathy with dysarthria and ophthalmoparesis; SCAE = spinocerebellar ataxia with epilepsy; AD-PEO = autosomal dominant progressive external ophthalmoplegia; MNGIE = mitochondrial neurogastrointestinal encephalopathy. *Tests that are new and/or currently being implemented.

predict the number of women who would benefit in this country, as was done for the UK and the USA.[4] Using the data presented above and considering that there are <70 genetically confirmed cases in a country with a population of ~56 million (i.e. 1:900 000 compared with an estimated 1:5 000 worldwide), it would appear that the number of undiagnosed cases in SA is staggeringly high. Furthermore, from observations made on other inherited meta bolic disorders, such as type 1 glutaric aciduria, galactosaemia and cystinosis,[16-18] it is becoming increasingly evident that the mutations commonly reported do not appear to reflect the disease-causing mutations among black African populations.[7] More research is required locally to understand patterns of mtDNA variation in black African groups so that a judicious assessment can be made when attempting to distinguish those mutations that are associated with mtDNA disease from those that have evolved stochastically over time. Given the gaps that exist in identifying mtDNA and nDNA mutations linked with mtDNA disease, coupled with the lack of adequate patient biochemical and clinical information, the situation in SA is far from optimal for diagnosing mtDNA disease. What should be done to improve the situation? A more integrated approach involving the availability of clinical, biochemical, molecular and imaging data, as illustrated in Fig. 1, is required to refine the

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diagnosis of mtDNA disease. Clinicians play a vital role, as robust clinical assessment and diagnosis is required prior to submitting samples for molecular screening. Often the pattern of mtDNA disease symptoms only becomes apparent over time with consistent followup, usually by the same clinician. SA’s overloaded primary healthcare system is not designed to focus on rare disorders, and the time required to conduct proper examinations for more complicated cases is often not available. However, symptoms such as growth failure, deafness, epilepsy and muscle weakness are easily recognisable and are referable. Moreover, good support in terms of access to neuroimaging (magnetic resonance imaging) and experienced histopathology services are also necessary. For the diagnosis of mitochondrial disease, enzyme analyses in tissue biopsies along with the more extensive biochemical analyses (e.g. respirometry and other functional and structural investigations) are needed to support molecular genetic investigations. The availability of next-generation sequencing platforms makes sequencing of the entire mitochondrial genome feasible and cost-effective for consideration as a routine diagnostic test. This will assist in determining at least the involvement of the mitochondrial genome when suggested from clinical observations, particularly in adult patients. However, strong collaborations between diagnostic and research teams are key in linking pathogenicity to novel or known mtDNA mutations detected with this technology.[19,20]

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Corresponding author: S Meldau (surita. meldau@nhls.ac.za)

Mitochondrial disease clinical presentation

Characteristic syndromic clinical presentations

MELAS and LHON

Other

Test for common mutations in urine or muscle, followed by full mtDNA sequencing if negative

Full mtDNA sequencing (preferrably in muscle DNA)

If negative, further investigations are needed as with complex presentations

Complex presentations

KSS /CPEO/Pearson syndrome

Exclude other, more likely diagnoses first: neuroimaging, biochemistry and histology are key

Test for large mtDNA deletions in muscle DNA for KSS/CPEO and blood DNA for Pearson syndrome

If avaliable, do enzyme tests and/or respirometry on muscle or fibroblasts. Test for mtDNA depletion/ over-replication

If negative, continue to full DNA sequencing (possibly including nDNA genes such as POLG and C100RF2)

Decide on the most likely molecular defect in consultation with clinical and molecular experts (Table 1) and devise a case-appropriate genetic testing strategy

Fig. 1. Proposed diagnostic strategy for mitochondrial disease in SA. (LHON = Leber’s hereditary optic neuropathy, KSS = Kearn-Sayre syndrome, CPEO = chronic progressive external ophthalmoplegia.)

Mitochondrial disease is present in all SA populations, but the majority of patients have not been able to obtain a molecular diagnosis. The declining cost of conducting whole-mtDNA sequencing will allow identification of mtDNA mutations and improve our capacity for accurate diagnosis and appropriate patient counselling and management. Extension of molecular testing to look at nuclear genes should enhance this capacity further. Both should be guided by supportive biochemical testing. Now that these strategies are being put in place to offer a basic but robust service for diagnosis of mtDNA diseases, it is time for SA to initiate a debate on the IVF technique that has been topical elsewhere.

Francois van der Westhuizen Human Metabolomics, North-West University, Potchefstroom, South Africa

Surita Meldau Division of Chemical Pathology, Faculty of Health Sciences, University of Cape Town, South Africa, and National Health Laboratory Service, Cape Town

Michael S Pepper Department of Immunology and Institute for Cellular and Molecular Medicine, Faculty of Health Sciences, University of Pretoria, South Africa

Gillian Riordan Department of Paediatrics and Child Health, Faculty of Health Sciences, University of Cape Town, South Africa, and Red Cross War Memorial Children’s Hospital, Cape Town

Himla Soodyall Division of Human Genetics, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa, and National Health Laboratory Service, Johannesburg

Joanna L Elson Mitochondrial Research Group, Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, UK, and Human Metabolomics, North-West University, Potchefstroom, South Africa Izelle Smuts Department of Paediatrics and Child Health, Faculty of Health Sciences, University of Pretoria, South Africa, and Steve Biko Academic Hospital, Pretoria

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1. Tuppen HA, Blakely EL, Turnbull DM, Taylor RW. Mito chondrial DNA mutations and human disease. Biochim Biophys Acta 2010;1797(2):113-128. [http://dx.doi.org/10.1016/j. bbabio.2009.09.005] 2. Craven L, Tuppen HA, Greggains GD, et al. Pronuclear transfer in human embryos to prevent transmission of mitochondrial DNA disease. Nature 2010;465(7294):82-85. [http://dx.doi. org/10.1038/nature08958] 3. Tachibana M, Sparman M, Sritanaudomchai H, et al. Mito chondrial gene replacement in primate offspring and embryonic stem cells. Nature 2009;461(7262):367-372. [http://dx.doi. org/10.1038/nature08368] 4. Gorman GS, Grady JP, Ng Y, et al. Mitochondrial donation – how many women could benefit? N Engl J Med 2015;372(9):885887. [http://dx.doi.org/10.1056/NEJMc1500960] 5. Reznichenko AS, Huyser C, Pepper MS. Mitochondrial transfer: Ethical, legal and social implications in assisted reproduction. S Afr J Bioethics Law 2015;8(2 Suppl 1):32-35. 6. Van der Walt EM, Smuts I, Taylor RW, et al. Characterization of mtDNA variation in a cohort of South African paediatric patients with mitochondrial disease. Eur J Hum Genet 2012;20(6):650656. [http://dx.doi.org/10.1038/ejhg.2011.262] 7. Van der Westhuizen FH, Sinxadi PZ, Dandara C, et al. Understanding the implications of mitochondrial DNA variation in the health of black southern African populations: The 2014 Workshop. Hum Mutat 2015;36(5):569-571. [http:// dx.doi.org/10.1002/humu.22789] 8. Barber DS, Border DP. Mitochondrial Donation. UK House of Commons Library. http://researchbriefings.files.parliament.uk/ documents/SN06833/SN06833.pdf2015 (accessed 29 July 2015). 9. Schaefer AM, McFarland R, Blakely EL, et al. Prevalence of mitochondrial DNA disease in adults. Ann Neurol 2008;63(1):35-39. [http://dx.doi.org/10.1002/ana.21217] 10. Gorman GS, Schaefer AM, Ng Y, et al. Prevalence of nuclear and mitochondrial DNA mutations related to adult mitochondrial disease. Ann Neurol 2015;77(5):753-759. [http://dx.doi.org/10.1002/ ana.24362] 11. Skladal D, Halliday J, Thorburn DR. Minimum birth prevalence of mitochondrial respiratory chain disorders in children. Brain 2003;126(8):1905-1912. [http://dx.doi.org/10.1093/brain/awg170] 12. Darin N, Oldfors A, Moslemi AR, Holme E, Tulinius M. The incidence of mitochondrial encephalomyopathies in childhood: Clinical features and morphological, biochemical, and DNA anbormalities. Ann Neurol 2001;49(3):377-383. [http://dx.doi. org/10.1002/ana.75] 13. Applegarth DA, Toone JR, Lowry RB. Incidence of inborn errors of metabolism in British Columbia, 1969-1996. Pediatrics 2000;105(1):e10. [http://dx.doi.org/10.1542/ peds.105.1.e10] 14. Smuts I, Louw R, du Toit H, Klopper B, Mienie LJ, van der Westhuizen FH. An overview of a cohort of South African patients with mitochondrial disorders. J Inherit Metab Dis 2010;33(Suppl 3):S95-S104. [http://dx.doi.org/10.1007/s10545009-9031-8] 15. Venter L, Lindeque Z, Jansen van Rensburg P, van der Westhuizen F, Smuts I, Louw R. Untargeted urine metabolomics reveals a biosignature for muscle respiratory chain deficiencies. Metabolomics 2015;11(1):111-121. [http://dx.doi.org/10.1007/ s11306-014-0675-5] 16. Owen EP, Nandhlal J, Leisegang F, van der Watt G, Nourse P, Gajjar P. Common mutation causes cystinosis in the majority of black South African patients. Pediatr Nephrol 2015;30(4):595-601. [http://dx.doi.org/10.1007/s00467-0142980-7] 17. Van der Watt G, Owen EP, Berman P, et al. Glutaric aciduria type 1 in South Africa – high incidence of glutaryl-CoA dehydrogenase deficiency in black South Africans. Mol Genet Metab 2010;101(2-3):178-182. [http://dx.doi.org/10.1016/j. ymgme.2010.07.018] 18. Henderson H, Leisegang F, Brown R, Eley B. The clinical and molecular spectrum of galactosemia in patients from the Cape Town region of South Africa. BMC Pediatr 2002;2:7. [http:// dx.doi.org/10.1186/1471-2431-2-7] 19. Yarham JW, Al-Dosary M, Blakely, EL, et al. A comparative analysis approach to determining the pathogenicity of mitochondrial tRNA mutations. Hum Mutat 2011;32(11):13191325. [http://dx.doi.org/10.1002/humu.21575] 20. Montoya J, Lopez-Gallardo E, Herrero-Martin MD, et al. Diseases of the human mitochondrial oxidative phosphorylation system. In: Espinós C, Felipo V, Palau F, eds. Inherited Neuromuscular Diseases: Translation from Pathomechanisms to Therapies. Dordrecht, Netherlands: Springer, 2009:47-67.

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GUEST EDITORIAL

Cardiovascular medicine in primary healthcare in sub-Saharan Africa: Minimum standards for practice (part 3) Cardiovascular disease (CVD) is the leading cause of death worldwide. Approximately 80% of all cardiovascular-related deaths occur in low- to middleincome countries and at a younger age compared with high-income countries.[1] The economic burden imposed by CVD on developing countries in terms of loss of productive years of life and amount of fiscal resources spent on secondary and tertiary care is considerably high. A sizeable proportion of the population-attributable risk for myocardial infarction is accounted for by nine modifiable risk factors, regardless of the geographical region.[2] Heart failure is an important cause of morbidity and mortality in sub-Saharan Africa (SSA) and the spectrum of aetiology in this region is different from that in many high-income countries.[3,4] In Africa, there are major concerns with regard to the success of strategies for primary and secondary prevention of CVD.[1] Challenges include lack of epidemiological and outcome data, limited national resources, poor political will and motivation, suboptimal healthcare infrastructure, low numbers of appropriately skilled healthcare personnel and lack of prediction models in many populations. Sadly, available data suggest that CVD is poorly managed in SSA.[5,6] This issue of CME focuses on the clinical approaches to common cardiovascular challenges. It forms the third part of a series of articles jointly produced by South African (SA) cardiologists and family physicians with the dual objectives of empowering doctors who manage these conditions in primary care settings in SA and improving the care of CVD patients in such settings and emergency departments. In the first issue, heart failure,[7] dyspnoea,[8] hypertension in the young[9] and valvular heart disease[10] were reviewed. In the second issue, the important clinical problems of infective endocarditis[11] and pericardial disease[12] were discussed. The current edition provides an evidence-based and pragmatic approach to acute coronary syndromes and chest pain,[13] and suspected tachyarrhythmias in the emergency room.[14] Pandie et al.[13] discuss the approach to chest pain and acute myocardial infarction. The history and physical examination are the mainstay of clinical assessment, and are complemented by a 12-lead electrocardiogram (ECG) and cardiac biomarkers for correct diagnosis. Chest pain is a common presentation at emergency rooms. The first priority should always be to ensure rapid and accurate diagnosis of serious acute chest pain syndromes, including acute coronary syndromes (ACSs), aortic dissection, pulmonary embolism, cardiac tamponade, tension pneumothorax, and acute abdominal syndromes. Elevated serum cardiac biomarkers provide evidence of myocardial cell injury. While the ECG is a crucial investigative tool, unfortunately many primary and secondary hospitals in SA and throughout SSA lack this equipment (or, if present, have no ECG strips, and the machines are not calibrated regularly). Despite these shortcomings, the authors present what should be the standard approach to chest pain and acute myocardial infarction. For example, the Marburg Heart Score, which has an excellent negative predictive value, can be used at a primary care level in the absence of a functional ECG machine. A systematic approach to the evidence-based management of ACSs is discussed. The management of ST elevation myocardial infarction (STEMI) patients includes providing the fastest and safest method

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of reperfusion therapy available – primary percutaneous coronary intervention or fibrinolysis, while initiating essential adjunctive therapies (antiplatelet therapy – aspirin with P2Y12 inhibitors, anticoagulation heparin or low-molecular-weight heparin), and cardiac monitoring. In the emergency or primary healthcare setting, patients often present with tachycardia or a history of palpitations, which may lead the doctor to suspect an underlying tachycardia. Chin et al.[14] review the mechanisms, diagnostic evaluation and management of tachycardia. A narrow complex tachycardia or supraventricular tachycardia usually has a QRS duration of <120 ms, unless there is bundle branch block or an intraventricular conduction abnormality. Supraventri cular tachycardia comprises a wide range of arrhythmias that have their origin above the bifurcation of the bundle of His, encompassing sinus tachycardia, atrial flutter, atrial fibrillation, atrial tachycardia, atrioventricular junctional re-entrant tachycardia, including atrio ventricular nodal re-entrant tachycardia, atrioventricular re-entrant tachycardia and junctional ectopic tachycardia. A wide complex tachycardia has a QRS duration ≥120 ms and may be caused by one of the following mechanisms: (i) ventricular tachycardia, which must be the default diagnosis in any patient with a wide complex tachycardia; (ii) supraventricular tachycardia with a right or left bundle branch block or an intraventricular conduction abnormality; (iii) pre-excited tachycardia (Wolff-Parkin son-White syndrome) over an accessory pathway; and (iv) pacemaker tachy cardia. A complete history should cover the heart rate and regularity, mode of onset and termination, precipitating factors, associated symptoms, and any associated heart disease. The ECG is the hallmark of diagnosis. One may classify tachycardia into narrow (supraventricular) tachycardia and wide complex tachycardia, which may be regular or irregular, and the differential diagnosis of each of these categories should be considered. It is our sincere hope that this series of articles on common cardiovascular conditions often encountered in primary care settings in SA and SSA will improve the care of patients with CVD. Furthermore, it is our wish that the articles clearly emphasise the minimum standards for management of these common cardiovascular disorders. Gboyega Ogunbanjo Guest editor Department of Family Medicine and Primary Health Care, Sefako Makgatho Health Sciences University, Pretoria, South Africa profbanjo@gmail.com Ntobeko A B Ntusi Guest editor Division of Cardiology, Department of Medicine, Faculty of Health Sciences, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa ntobeko.ntusi@gmail.com

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1. Gersh BJ, Sliwa K, Mayosi BM, Yusuf S. The epidemic of cardiovascular disease in the developing world: Global implications. Eur Heart J 2010;31:642-648. [http://dx.doi.org/10.1093/eurheartjehq030] 2. Yusuf S, Hawken S, Ounpuu S, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): Case-control study. Lancet 2004;364(9438):937-952. 3. Ntusi NAB, Mayosi BM. Epidemiology of heart failure in sub-Saharan Africa. Expert Rev Cardiovasc Ther 2009;7:169-180. [http://dx.doi.org/10.1586/14779072.7.2.169] 4. Damasceno A, Mayosi BM, Sani M, et al. The causes, treatment, and outcome of acute heart failure in 1006 Africans from 9 countries. Arch Intern Med 2012;172(18):1386-1394. 5. Steyn K. Heart Disease in South Africa. Cape Town: Medical Research Council: The Heart and Stroke Foundation of South Africa, 2007. http://www.mrc.ac.za/chronic/heartandstroke.pdf (accessed 6 December 2015). 6. Ntusi NAB. Dismal management of hypertension at primary level: Does it reflect a failure of patients, a failure of the system or a failure of doctors? Cardiovasc J Afr 2011;22(4):172-174. 7. Kraus S, Ogunbanjo G, Sliwa K, Ntusi NAB. Heart failure in sub-Saharan Africa: A clinical approach. S Afr Med J 2016;106(1):23-31. [http://dx.doi.org/10.7196/SAMJ.2016.v106i1.10325] 8. Coccia CBI, Palkowski GH, Schweitzer B, Motsohi T, Ntusi NAB. Dyspnoea: Pathophysiology and a clinical approach. S Afr Med J 2016;106(1):32-36. [http://dx.doi.org/10.7196/SAMJ.2016.v106i1.10324]

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9. Mangena P, Saban S, Hlabyago KE, Rayner B. An approach to the young hypertensive patient. S Afr Med J 2016;106(1):36-38. [http://dx.doi.org/10.7196/SAMJ.2016.v106i1.10329] 10. Cupido BJ, Peters F, Ntusi NAB. An approach to the diagnosis and management of valvular heart disease. S Afr Med J 2016;106(1):39-42. [http://dx.doi.org/10.7196/SAMJ.2016.v106i1.10326] 11. Hitzeroth J, Beckett N, Ntuli P. An approach to the patient with infective endocarditis. S Afr Med J 2016;106(2):145-150. [http://dx.doi.org/10.7196/SAMJ.2016.v106i2.10327] 12. Kyriakakis CG, Mayosi BM, de Vries E, Isaacs A, Doubell AF. An approach to the patient with suspected pericardial disease. S Afr Med J 2016;106(2):151-155. [http://dx.doi.org/10.7196/SAMJ.2016. v106i2.10328] 13. Pandie S, Hellenberg D, Hellig F, Ntsekhe M. An approach to chest pain and acute myocardial infarction. S Afr Med J 2016;106(3):239-245. [http://dx.doi.org/10.7196/SAMJ.2016.v106i3.10323] 14. Chin A, Vezi B, Namane M, Weich H, Scott-Millar R. An approach to the patient with suspected tachycardia in the emergency department. S Afr Med J 2016;106(3):246-250. [http://dx.doi. org/10.7196/SAMJ.2016.v106i3.10322]

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Approach to chest pain and acute myocardial infarction S Pandie,1 FCP (SA), Cert Cardiology (SA); D Hellenberg,2 MFamMed, FCFP (SA); F Hellig,3 BSc, MB BCh, FCP (SA), FSCAI; M Ntsekhe,1 MD, PhD Division of Cardiology, Department of Medicine, Faculty of Health Sciences, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa 2 Division of Family Medicine, School of Public Health and Family Medicine, Faculty of Health Sciences, University of Cape Town, South Africa 3 Sunninghill and Sunward Park Hospitals, Johannesburg, South Africa 1

Corresponding author: S Pandie (s.pandie@uct.ac.za)

Patient history, physical examination, 12-lead electrocardiogram (ECG) and cardiac biomarkers are key components of an effective chest pain assessment. The first priority is excluding serious chest pain syndromes, namely acute coronary syndromes (ACSs), aortic dissection, pulmonary embolism, cardiac tamponade and tension pneumothorax. On history, the mnemonic SOCRATES (Site Onset Character Radiation Association Time Exacerbating/relieving factor and Severity) helps differentiate cardiac from non-cardiac pain. On examination, evaluation of vital signs, evidence of murmurs, rubs, heart failure, tension pneumothoraces and chest infections are important. A 12-lead ECG should be interpreted within 10 minutes of first medical contact, specifically to identify ST elevation myocardial infarction (STEMI). High-sensitivity troponins improve the rapid rule-out of myocardial infarction (MI) and confirmation of non-ST elevation MI (NSTEMI). ACS (STEMI and NSTEMI/unstable angina pectoris (UAP)) result from acute destabilisation of coronary atheroma with resultant complete (STEMI) or subtotal (NSTEMI/UAP) thrombotic coronary occlusion. The management of STEMI patients includes providing urgent reperfusion: primary percutaneous coronary intervention (PPCI) if available, deliverable within 60 - 120 minutes, and fibrinolysis if PPCI is not available. Essential adjunctive therapies include antiplatelet therapy (aspirin, P2Y12 inhibitors), anticoagulation (heparin or low-molecular-weight heparin) and cardiac monitoring. S Afr Med J 2016;106(3):239-245. DOI:10.7196/SAMJ.2016.v106i3.10323

Chest pain is a common cause for attendance at emer gency and primary care consultation rooms. The lifetime prevalence accounts for 20 - 40% of the general population, with an incidence of 0.7% in primary care.[1] The majority of these presentations do not constitute a life-threatening illness, and the most common causes are musculoskeletal, respiratory, gastrointestinal and psychogenic. The challenge to the primary attending clinician is to rapidly and accurately diagnose potentially serious acute chest pain syndromes (Table 1), before turning attention to acute and chronic conditions that may also carry risk for mortality and morbidity, e.g. pneumonia, stable coronary artery disease (CAD), pericarditis, valvular heart disease, lung malignancies and abdominal pathologies. Finally, less serious conditions need consideration. At primary care level, clinicians need to identify serious conditions reliably while not exposing patients to unnecessary investigations and hospital admissions.[2] This review focuses on acute coronary syndromes (ACSs), which are the most common of the life-threatening chest pain presentations. A clear stepwise approach to acute chest pain is critical to avoid mis diagnoses (Fig. 1). In the absence of chest trauma, the initial assessment should focus on ACS (acute myocardial infarction (MI) or unstable angina), aortic dissection, pulmonary embolism, cardiac tamponade, tension pneumothorax and, less commonly, acute abdominal syndromes presenting as chest pain. The patient’s history and risk factor profile, along with the clinical assessment, should direct the clinician to the next most appropriate diagnostic and therapeutic intervention.

Emergency chest pain assessment General considerations

Most chest pain algorithms aim to exclude ACSs. Initial and contin uous assessment of vital signs (blood pressure (BP), pulse, cardiac monitoring and oxygen saturations) should be standard care. If the patient is tachypnoeic or has oxygen saturations <94%, supplemental oxygen should be administered. Pain should be managed with appropriate analgesia, preferably intravenous opioids such as morphine. A focused history, thorough physical examination, meti

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culous review of a 12-lead electrocardiogram (ECG) and appro priately timed measurement of cardiac biomarkers are the key com ponents of an effective chest pain assessment.

History

The history is the most useful component when evaluating chest pain, as both normal and abnormal investigations (such as the ECG, cardiac biomarkers and chest radiograph (CXR)) must be interpreted in the context of the patient’s history. The mnemonic SOCRATES (Site Onset Character Radiation Asso ciation Time Exacerbating/relieving factor and Severity) helps differen tiate cardiac v. non-cardiac (respiratory, gastric or musculoskeletal) pain. Features that make a diagnosis of ACS likely include: central (retro sternal) location; sudden or acute onset; heavy or burning sensation with radiation to the arm or jaw; associated dyspnoea, nausea or sweating; duration >15 minutes; relief of symptoms by nitrates; worsening of symptoms by activity; chest or left-arm discomfort that is the same in nature as previously documented angina; and a known history of CAD (including prior MI).[3] Atypical presentations need to be considered in the elderly, diabetics and women. At the primary care level, the Marburg Heart Score has been shown to have excellent negative predictive value (Table 2). Based only on variables acquired on history and examination, it is an easy-to-apply clinical prediction rule.[4]

Physical examination

All patients presenting with acute chest pain should undergo a thorough physical examination. In ACS, the cardiac examination is often unremarkable, but specific attention should be paid to the vital signs (pulse and BP), features of heart failure, and auscultation precordial murmurs and rubs. The presence of transient mitral regurgitation, hypotension, diaphoresis, pulmonary oedema, crackles or signs of extracardiac vascular disease is highly suggestive of ACS. ACS is less likely if the presenting chest pain is reproducible by chest palpation.[3] Examination of the respiratory system should exclude

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ACUTE CHEST PAIN Assess vital signs (BP, pulse, saturation, GCS, respiratory rate) Do 12-lead ECG (on presentation, and repeat if ongoing chest pain or recurrent chest pain, or at 3 hours)

Resuscitate Likely aetiologies: ACS (STEMI/NSTEMI) pulmonary embolism; aortic dissection; pericardial tamponade; tension pneumothorax

Exclude life-threatening diagnoses: ACS –12-lead ECG for ST-segment changes; cardiac biomarkers (hs-Tc); echocardiogram for wall motion abnormalities PE-CT pulmonary angiogram Aortic dissection – CT angiogram, echocardiogram Pericardial effusion – echocardiogram or ultrasound

12-lead ECG diagnostic for ACS

Working diagnosis of ACS

Yes

Suspected ACS – cardiac biomarkers (hs-Tc) for ACS with no ECG changes

Persistent ST elevation

12-lead ECG suggesting pericarditis – diffuse ST elevation, PR depression V2, PR elevation aVR Additional investigations guided by clinical assessment and suspicion of non-cardiac diagnosis: CXR for infections (pneumonia), pneumothorax, wide mediastinum for dissection CT for pulmonary embolism or aortic dissection Outpatient/non-emergent workup for non-life-threatening diagnosis: GI pathology – gastroscopy Musculoskeletal pain

STEMI

ST/T abnormalities

Normal or undetermined ECG

Troponin rise/fall

Troponin normal

NSTEMI

Unstable angina

Urgent REPERFUSION Anticoagulation, dual antiplatelet therapy, Primary PCI or thrombolytic risk stratification for invasive v. therapy or pharmaco-invasive conservative management therapy

Fig. 1. Chest pain algorithm (BP = blood pressure; GCS = Glasgow coma scale; ACS = acute coronary syndrome; hs-Tc = high-sensitivity troponin; GI = gastrointestinal; PCI = percutaneous coronary intervention; PE-CT = pulmonary embolism-computed tomography; STEMI = ST elevation myocardial infarction; NSTEMI = non-ST elevation myocardial infarction).

tension pneumothoraces and chest infections, while abdominal examination may reveal abdominal aetiologies.

12-lead ECG

Patients presenting with acute chest pain should have a 12-lead ECG performed and interpreted within 10 minutes of first medical contact. If the initial ECG is non-diagnostic but the diagnosis of ACS is highly suspected, serial ECGs should be performed (at 3 hours, 6 hours, 9 hours and 24 hours, or on recurrence of symptoms), including ECGs with additional leads for evaluation of the posterior-lateral myocardial wall V7 V8 V9 or V3R V4R V5R. ACS diagnostic features on the ECG include ST elevation, ST depression, T-wave inversion, and new or presumed new left bundle branch block. ECG features suggesting pericarditis include saddle-shaped ST elevation not confined to an anatomical location, with PR depression in V2 and PR elevation in aVR. ECG features suggestive of pulmonary embolism include tachycardia, features of right ventricular strain (T-wave inversion V1 - V3 with either right axis deviation or tall R in V1) and the typical SIQIIITIII pattern.

Cardiac biomarkers

Cardiac biomarkers reflect myocardial cell injury, the hallmark of MI. Pathophysiologically, MI results from ischaemia sufficient to cause cell death, with the release of cellular proteins and enzymes. Cardiac troponins I and T have been shown to be the most sensitive indicators of cardiac injury, as well as being predictors for short- and long-term outcomes as regards death and MI.[5] The introduction of high-sensitivity troponin (hs-Tc) assays have improved rapid ruleout MI, and the confirmation of non-ST elevation MI (NSTEMI).[6] It is important to understand that the increased sensitivity of the test results in lower specificity. To this end, the universal classification of MI was revised in 2012, acknowledging that for practical purposes, the diagnosis of ST elevation MI (STEMI) is made in the correct clinical setting with the appropriate ECG changes, and that MI without ST elevation (NSTEMI) requires positive biomarkers (Table 3). If serial biomarkers are negative, this implies no MI has occurred, but the

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Table 1. Differential for acute chest pain Cardiovascular Coronary artery disease Acute coronary syndromes Angina due to demand/supply mismatch Chronic stable angina Acutely increased myocardial oxygen demand Coronary vasospasm, ‘variant angina’ Cardiac syndrome X Coronary artery dissection Coronary anatomic anomalies Valvular heart disease Aortic dissection Pericarditis Myocarditis Stress-induced cardiomyopathy Acute aortic syndromes Chest pain related to hyperadrenergic states Cocaine intoxication Amphetamine intoxication Phaeochromocytoma Continued …

patient may still require treatment for unstable angina. In addition, positive biomarkers may reflect myocardial injury secondary to noncoronary causes – usually as a result of imbalance between myocardial oxygen supply and demand – and should therefore be interpreted in the clinical context of the presentation.[7]

CXR

The CXR is helpful when pneumothorax or pneumonia, aortic dissection (wide mediastinum) or pulmonary embolism (oligaemia of lung fields or wedge-shaped infarcts) is suspected. If, on the

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Table 1. (continued) Differential for acute chest pain

Table 2. The Marburg Heart Score

Chest wall Isolated musculoskeletal chest pain syndromes Costochondritis Tietze syndrome Costovertebral joint dysfunction Sternalis syndrome Xiphoidalgia Spontaneous sternoclavicular subluxation Rheumatic diseases Non-rheumatic systemic diseases Stress fractures Metastatic malignancy ACS (sickle cell crisis) Skin and sensory syndromes Herpes zoster (shingles)

Criteria

Score

Female >64 years; male >54 years

Known CAD, cerebrovascular disease or peripheral vascular disease

Pain worse with exercise

Pain not reproducible with palpation

Patient assumes pain is cardiac

Interpretation ~97% of patients with a score of ≤2 will not have CAD ~23% of patients with a score of >3 will have CAD

STEMI

Pathophysiology and initial diagnosis Plaque disruption exposes thrombogenic substances, resulting in intracoronary thrombus formation. Local anticoagulant production is increased and, if successful, will result in thrombus resolution and arrest of the infarction. However, if complete arterial occlusion occurs, myocardial ischaemia followed by infarction results, producing the typical ST elevation seen on the 12-lead ECG. Diagnostic patterns of ST elevation vary depending on which epicardial vessel is involved (Fig. 2).

Gastrointestinal Oesophageal Reflux Rupture Spasm Oesophagitis Pancreatobiliary Pancreatitis Cholecystitis Cholangitis Biliary colic Peptic ulcer disease

Immediate management The optimal management of STEMI patients includes providing the fastest, safest, most effective method of reperfusion therapy available, i.e. primary percutaneous coronary intervention (PPCI) or fibrinolysis, while simultaneously initiating essential adjunct ther pies and monitoring (Fig. 3). Unless contraindicated, all patients should receive antiplatelet therapy (aspirin with P2Y12 inhibitors such as ticagrelor, prasugrel or clopidogrel) and anticoagulation (unfractionated or low-molecular-weight heparins (LMWHs) dosed to body weight). Patients should be connected to a cardiac monitor capable of cardioversion and transcutaneous pacing. Oxygen should be administered if the patient is hypoxic, and opioids for pain relief, breathlessness and anxiety are essential.[9]

Pulmonary Acute pulmonary embolism Pulmonary hypertension Pneumonia Cancer Sarcoidosis Asthma Chronic obstructive pulmonary disease Pleura Pleuritis Pneumothorax (including tension)

Prehospital logistics of care The lack of a formal STEMI referral network for both public and private sectors makes decisions regarding reperfusion therapy challenging, and often impedes the rapid administration of reperfusion therapy.[10] Important timeframes that govern timely STEMI care are outlined in Fig. 4. Prehospital logistics and patientpractitioner education should aim to reduce delays from time of symptom onset to definitive reperfusion.[9,11]

Mediastinal disease Mediastinitis Mediastinal tumours Pneumomediastinum Psychiatric Anxiety Depression Panic attacks Munchausen syndrome

basis of the ECG, ACS is suspected, the urgency of obtaining a CXR should be relegated and implementation of management plans prioritised.

The management of ACSs

The clinical presentations of CAD include stable angina pectoris, silent ischaemia, unstable angina, MI, heart failure and sudden death.[8] ACSs result from acute destabilisation of coronary athe roma with resultant complete or subtotal thrombotic coronary occlusion. Ischaemic discomfort or chest pain is experienced because of reduction in blood flow to the myocardium.

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Reperfusion therapy This includes PPCI, fibrinolysis and pharmaco-invasive strategies. Selecting the most appropriate reperfusion strategy depends on three key factors: the time delay from symptom onset to first medical contact; availability; and clinical factors that may favour one strategy over the other. Patients presenting within 12 hours of onset of symptoms (or since worse exacerbation) As a general guide, STEMI patients presenting to PCI-capable facilities should be offered PPCI (preferably within 60 minutes). If there is an anticipated delay of >120 minutes from the time of first medical contact, fibrinolysis should be administered. Patients presenting to

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Table 3. Universal classification of MI (adapted from Thygesen et al.[7]) Type

Description

Type 1: Spontaneous MI

Related to atherosclerotic plaque rupture, ulceration, erosion or dissection with resultant coronary luminal thrombus in one or more coronaries, leading to decreased myocardial blood flow with ensuing myocyte necrosis. Patients may have underlying CAD (severe obstructive or mild non-obstructive) or no CAD.

Type 2: MI secondary to an ischaemic imbalance

Myocardial injury with necrosis secondary to an imbalance between myocardial oxygen supply and demand. Patients may or may not have underlying CAD. Common examples include coronary endothelial dysfunction, coronary artery spasm, tachycardias, bradycardias, anaemia, respiratory failure, hypotension and hypertension (with or without left ventricular hypertrophy).

Type 3: MI resulting in death when biomarker values are unavailable, or at autopsy

Cardiac death with symptoms and ECG changes of myocardial ischaemia or infarction, but death occurred before confirmatory biomarkers were obtained.

Types 4a and 4b: MI related to PCI

PCI-related infarction with elevation in cardiac troponins, symptoms of myocardial ischaemia, new ECG changes, angiographic changes (loss of vessel patency or new wall motion abnormality), or stent thrombosis.

Type 5: MI related to CABG

CABG-related infarction with elevation in cardiac troponins, symptoms of myocardial ischaemia, new ECG changes, angiographic changes (new graft or native coronary occlusion or new wall motion abnormality).

PCI = percutaneous coronary interventions; CABG = coronary artery bypass grafting.

non-PCI-capable facilities should be considered for fibrinolysis, or transfer for PPCI if PCI can be ensured within 120 minutes. It is important to remember that PPCI and fibrinolysis are of equivalent efficacy for patients presenting within 3 hours of symptoms, and every effort should be made not to delay reperfusion.[12] Fibrinolysis and pharmaco-invasive strategies In most sub-Saharan countries, access to PPCI-capable facilities is limited. Fibrinolysis is therefore the first choice reperfusion therapy. Clear contraindications to fibrinolysis need to be identified during the initial assessment (Table 4). Alteplase (tPA) with concomitant heparin was shown to be more effective than streptokinase (one fewer death per 100 patients treated, at the expense of three additional strokes). Tenectaplase is equivalent to accelerated tPA for 30-day mortality (with lower rate of bleeding).[13,14] Non-patient-related factors when considering choice of fibrinolysis include cost, ease of administration and administration in hospital or before being admitted. Pharmaco-invasive management refers to the combination of fibrinolysis and angiography, with a view to PCI of the culprit lesion. Patients who have had successful fibrinolysis can be referred to a PCIcapable centre for routine angiography and PCI within 24 hours of completing fibrinolysis. This strategy has been shown to reduce recurrent MI and urgent revascularisation for recurrent ACSs, and is currently a very attractive option in South African (SA) clinical settings.[15] Patients presenting after 12 hours of symptom onset (or since worse exacerbation) Beyond 12 hours, fibrinolysis is far less effective than PPCI, while still carrying the risk of bleeding. Decisions regarding reperfusion should therefore be on an individual basis. Patients with persistent myocardial ischaemia, hypotension, haemodynamic instability or ventricular arrhyth mias should be considered for referral for angiography and PCI. Stable patients should receive antiplatelet therapy and anticoagulation with unfractionated heparins or LMWHs.[12] Failed fibrinolysis The 12-lead ECG should be repeated 60 (tPA) - 90 (streptokinase) minutes after fibrinolysis to assess therapeutic success. Failed fibrinolysis is indicated by failure of the ST elevation to reduce by >50% with or without persistent myocardial ischaemia. These patients do not benefit from repeat fibrinolysis, and should be considered for urgent rescue PCI, ideally within 12 hours.[12]

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NSTEMI and unstable angina

Pathophysiology and initial diagnosis The pathophysiology of most NSTEMIs involves the rupture of a vulnerable atheromatous plaque with subsequent thrombus forma tion, leading to reduced blood flow and ischaemia, with or without MI (NSTEMI or unstable angina (UA), respectively). The diagnosis is confirmed by the presence of prolonged (>20 minutes) ischaemic chest pain, new-onset Canadian Class II or III angina, acute deterioration of stable chronic angina or angina following a recent MI, and the absence of ST elevation on the 12-lead ECG. Atypical complaints (including silent ischaemia, epigastric pain, indigestion and dyspnoea) can occur in older patients (>75 years), women and patients with diabetes, chronic kidney disease or dementia. In these settings, ST-T wave abnormalities on ECG should prompt rapid rule-out or rule-in of ACS using hs-Tc assays (Fig. 5). Immediate management and risk stratification The immediate care of UA and NSTEMI patients involves two key steps: (i) risk stratification using validated ischaemia and bleeding prediction tools before deciding on pharmacological and invasive management strategies; and (ii) the administration of evidence-based therapies. If there are no contraindications, a patient with a suspected diagnosis of ACS should receive antiplatelet therapy (aspirin and clopidogrel), anti coagu lation therapy (unfractionated heparins or LMWHs, or indirect factor Xa inhibitors (fondaparinux)), and anti-ischaemic agents (β-blockers, or calcium channel blockers and nitrates). Validated ischaemic risk prediction scores (Thrombolysis in MI (TIMI) Risk Score and the Global Registry of Acute Coronary Events (GRACE) Risk Score) use demographic, clinical, ECG and biochemical variables to estimate the short-, intermediate- and longterm prognosis related to the current presentation (Table 5). The validated CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of ACC/AHA guidelines)bleeding score combines eight predictors of major bleeding, allowing a physician to estimate the baseline risk of in-hospital major bleeding, therefore complementing ischaemic risk prediction tools. These scores are readily available as applications on smartphones and tablets, making them easy to use in daily practice. Patients with intermediate- to high-risk scores should be considered for invasive management, and advanced for coronary angiography with a view to revascularisation. Independent of risk

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ST elevation: New ST elevation at the J-point in two contiguous leads with the cut-points: ≥0.1 mV in all leads other than leads V2 - V3 where the following cut-points apply: ≥0.2 mV in men ≥40 years; ≥0.25 mV in men <40 years; ≥0.15 mV in women Anterior STEMI: Typical ST elevation V2 - V5.

Inferior STEMI: ST elevation in II, III, aVF. Also note the heart block.

scores, patients with significant rise or fall of troponin levels, dynamic ECG changes and ongoing ischaemia should be considered for invasive management. Timing of angiography and intervention High-risk patients benefit from revasculari sation therapy. Patients with ongoing ischae mia, acute heart failure, life-threatening ventricular arrhythmias or haemodynamic instability should be considered for immediate intervention regardless of biomarkers and ECG changes. Patients with high-risk scores who have clinically stabilised should be considered for angiography within 48 hours of admission. Low-risk patients may be managed medically, or have coronary angiography deferred. These timelines are a guide and may differ based on the availability of PCIcapable centres.

Hospitalisation and discharge Lateral STEMI: ST elevation I and aVL, also V5 and V6. ST depression noted II, III, aVF, V1, V2, V3.

Posterior STEMI: Deep ST depression V1 - V3 with prominent R waves V2, V3. When the ECG is viewed ‘from behind’, ST elevation in V1, V2, V3 is clearly seen.

2D and E

Left bundle branch block (new or presumed new) in the setting of ACS. Eponymous signs like Cabrera’s (notching in S-wave of V3 or V4) and Chapman’s (notching in R-wave of I, aVL, or V6) have poor sensitivity, but reasonable specificity. Using the Sgarbossa criteria may be helpful.

De Winter’s sign (proximal LAD occlusion): 1 - 3 mm upsloping ST segment depression at the J-point in leads V1 - V6 that continue into tall, positive symmetrical T-waves. QRS complexes are not wide (<120 ms), and there may be loss of precordial R-wave progression. May have ST elevation (1 - 2 mm) in aVR.[19]

Atypical ECG presentations that deserve prompt management in patients with signs and symptoms of ongoing myocardial ischaemia include left bundle branch block, ventricular paced rhythms, isolated posterior MI, and ST elevation in lead aVR. Fig. 2. ST elevation MI variations.

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All ACS patients should be managed in a high-care setting, specifically for the rapid identification and management of haemo dynamic (cardiogenic shock) and arrhyth mic (ventricular tachycardia and fibrillation) complications, as well as bleeding (access site or secondary to fibrinolysis) and recurrent infarction. ECG monitoring and bed rest should continue for at least 24 hours after successful reperfusion and symptom resolution. Chronic medications that offer mortality benefit should be introduced while in hospi tal (unless contraindicated). Dual antiplatelet therapy should be continued for 1 year, unless there are specific reasons to stop sooner. The introduction of β-blockers, renin-angiotensin system inhibitors, angio tensin-converting enzyme inhibitors (ACE-Is), angiotensin receptor blockers (ARBs) or aldosterone antagonists) and statins should be specific to the individual, rather than introduced as a routine ‘cocktail’. The early introduction of high-dose HMG-CoA reductase inhibitors (statins) is also associated with improved survival and reduced morbidity. Betablockers should be provided to all patients within 24 hours unless there is evidence of haemodynamic compromise, congestive heart failure or brady-arrhythmias (such as heart block). Patients with anterior MI, evidence of heart failure or depressed left ventricular systolic function should receive ACE-Is or ARBs, plus an aldosterone antagonist. Lifestyle and risk factor modification including smoking cessation, diet, physical activity and BP control is essential.[9] Patients who require surgical revascularisation should be discussed with a combined heart team (interventional cardiologist, clinical cardio logist and cardiothoracic surgeon) regarding the optimal timing of surgery (in-patient v. elective re-admission).

CME

First medical contact

Symptom onset

Diagnostic ECG

Table 4. Contraindication to fibrinolysis

Reperfusion therapy

<10 minutes Patient delay System delay

Time to reperfusion therapy

Wire passage in culprit artery if primary PCI Bolus or infusion start if thrombolysis

Fig. 3. Components in the delays from first medical contact to reperfusion therapy for STEMI patients. STEMI diagnosis EMS of non-primary PCI-capable centre

Primary PCI-capable centre

Yes

Primary PCI

PCI possible <120 minutes

Immediate transfer to PCI centre

Rescue PCI Immediate transfer to No PCI centre

Immediate fibrinolysis

Successful fibrinolysis?

Yes

Routine pharmaco-invasive coronary angiography and PCI v. medical therapy

Acute chest pain

High-sensitivity troponin <ULN

High-sensitivity troponin >ULN

Pain < 6 h

Pain free, GRACE <140, differential diagnosis excluded

Discharge or exercise stress test

Significant change (delta troponin)

Very high troponin with clinical pictures of ACS

Repeat high-sensitivity troponin: 3 h

No change

Relative

Previous intracranial haemorrhage or stroke of unknown origin at any time

Transient ischaemic attack in the preceding 6 months

Ischaemic stroke in the preceding 6 months

Oral anticoagulation therapy

Central nervous system damage or neoplasm or atrioventricular malformations

Pregnancy or within 1 week post partum

Recent major trauma/surgery/ head injury (within preceding 3 weeks)

Refractory hypertension (systolic BP >180 mmHg and/or diastolic BP >110 mmHg)

Gastrointestinal bleeding within the past month

Advanced liver disease

Known bleeding disorder (excluding menses)

Infective endocarditis

Aortic dissection

Acute peptic ulcer

Non-compressible puncture in the past 24 hours (e.g. liver biopsy, lumbar puncture)

Prolonged or traumatic resuscitation

drug use, de novo) and stress-induced cardiomyopathy (Takotsubo non-ischaemic cardiomyopathy). Careful history and clinical exam ination can often identify these patients prior to definitive ACS care. Even so, the general principles of management are as outlined above.

ACSs in sub-Saharan Africa

Fig. 4. Prehospital and inpatient management of STEMI (EMS = emergency medical services).

Pain > 6 h

Absolute

Treat as NSTEMI; risk stratify for invasive management

No change

Work-up for differential diagnosis (consider chronic causes of elevated troponin)

Fig. 5. Rapid rule-out of ACS using high-sensitivity troponin (ULN = upper limit of normal).

Less common ACS aetiologies

Infrequently, aetiologies other than ruptured atheroma result in ACS. Examples include coronary artery embolisation (in patients with atrial fibrillation, cardiomyopathy with ventricular clot or septic emboli from infective endocarditis), spontaneous coronary dissection (in patients with fibro muscular dysplasia, coronary vasculitis or thyrotoxicosis), coronary artery spasm (recreational

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ACSs are becoming increasingly prevalent in sub-Saharan Africa, with patients displaying similar myocardial risk factors to those of the developed world.[16,17] There are limited data regarding ACSs in the SA context, with observational data suggesting that there are high intervention rates and frequent use of evidence-based pharmacological therapies with comparative outcomes when compared with international standards.[18] These data reflect mainly the care delivered in the private sector, and do not fully represent care from the public sector where resources are limited and timely presentation to healthcare facilities capable of managing ACSs is often delayed.[10,16] Our current challenge is the provision of equal access and quality ACS care to all sectors of the SA population. This would entail reliance on the pharmaco-invasive strategy (routine and rescue) until there is adequate infrastructure expansion to accommodate the roll-out of a comprehensive, organised, hub-and-spoke PPCI service. Initiatives such as the European Society of Cardiology ‘Stent-for-Life’ project and planned national ACS registries could be the stepping stones to formalising management of ACSs on a national level. References 1. Bösner S, Becker A, Haasenritter J, et al. Chest pain in primary care: Epidemiology and pre-work-up probabilities. Eur J Gen Pract 2009;15(3):141-146. [http://dx.doi.org/10.3109/13814780903329528] 2. Kramer L, Rabanizada N, Haasenritter J, Bösner S, Baum E, Donner-Banzhoff N. Do guidelines on first impression make sense? Implementation of a chest pain guideline in primary care: A systematic evaluation of acceptance and feasibility. BMC Family Practice 2011;12:128. [http://dx.doi.org/10.1186/1471-2296-12-128] 3. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: Executive summary. Circulation 2007;116(7):803-877. [http://dx.doi.org/10.1161/CIRCULATIONAHA.107.185752] 4. Haasenritter J, Bösner S, Vaucher P, et al. Ruling out coronary heart disease in primary care: External validation of a clinical prediction rule. Br J Gen Pract 2012;62(599):415-421. [http://dx.doi. org/10.3399/bjgp12X649106] 5. Antman EM, Tanasijevic MJ, Thompson B, et al. Cardiac-specific troponin I levels to predict the risk of mortality in patients with acute coronary syndromes. N Engl J Med 1996;335(18):1342-1349. [http:// dx.doi.org/10.1056/NEJM199610313351802]

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Table 5. TIMI, GRACE and CRUSADE risk scores TIMI risk score for UA/NSTEMI Risk of cardiac events (%) by 14 days Variable

Points

Risk score

Death or MI

Death, MI or urgent revascularisation

Age ≥65 years

0-1

≥3 CAD risk factors (family history, raised cholesterol, diabetes, hypertension)

Known CAD (stenosis ≥50%)

Aspirin use in past 7 days

Recent severe angina (last 24 hours)

Elevated cardiac biomarkers

6-7

ST deviation ≥0.5 mm

GRACE score for UA/NSTEMI In-hospital mortality Variables*

Risk categories

GRACE score

Death, %

Heart failure

Low

1 - 108

Peripheral vascular disease

Intermediate

109 - 140

1-3

Admission systolic BP

High

141 - 372

Age

6 months post-discharge mortality

Killip class Elevated cardiac biomarkers

Risk categories

GRACE score

Death, %

Initial serum creatinine

Low

1 - 88

Cardiac arrest on admission

Intermediate

89 - 118

3-8

ST segment deviation

High

119 - 263

Variables†

Risk categories

CRUSADE score

Bleeding risk, %

Baseline haematocrit

Very low

1 - 20

Estimated glomerular filtration rate

Low

21 - 30

5.5

Heart rate on admission

Moderate

31 - 40

8.6

Systolic BP on admission

High

41 - 50

Prior vascular disease

Very high

51 - 90

* Variables are inserted into an online calculator to generate the GRACE score (www.gracescore.org).

CRUSADE bleeding risk score

Diabetes mellitus Signs of congestive heart failure on admission Gender †

Variables are inserted into an online calculator to generate the CRUSADE score (www.crusadebleedingscore.org/).

6. Reichlin T, Hochholzer W, Bassetti S, et al. Early diagnosis of myocardial infarction with sensitive cardiac troponin assays. N Engl J Med 2009;361(9):858-867. [http://dx.doi.org/10.1056/NEJMoa0900428] 7. Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. J Am Coll Cardiol 2012;60(16):1581-1598. [http://dx.doi.org/10.1016/j.jacc.2012.08.001] 8. Hamm CW, Bassand J-P, Agewall S, et al. ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation. Eur Heart J 2011;32(23):2999-3054. [http://dx.doi.org/10.1093/eurheartj/ehr236] 9. Steg PG, James SK, Atar D, et al. ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 2012;33(20):2569-2619. [http://dx.doi.org/10.1093/eurheartj/ehs215] 10. Maharaj RC, Geduld H, Wallis LA. Door-to-needle time for administration of fibrinolytics in acute myocardial infarction in Cape Town. S Afr Med J 2012;102(4):241-244. 11. Delport R. Towards developing guidelines and systems of care to facilitate early reperfusion for STelevation myocardial infarction in Africa. Cardiovasc J Afr 2014;25(6):256-258. 12. Harker M, Carville S, Henderson R, Gray H. Key recommendations and evidence from the NICE guideline for the acute management of ST-segment-elevation myocardial infarction. Heart 2014;100(7):536-543. [http://dx.doi.org/10.1136/heartjnl-2013-304717] 13. Lubitz J, Riley G. Trends in medicare payments in the last year of life. N Engl J Med 1993;328(15):10921096. [http://dx.doi.org/10.1056/NEJM199304153281506]

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14. Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT-2) Investigators, van de Werf F, Adgey J, et al. Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: The ASSENT-2 double-blind randomised trial. Lancet 1999;354(9180):716-722. 15. Welsh RC, van de Werf F, Westerhout CM, et al. Outcomes of a pharmacoinvasive strategy for successful versus failed fibrinolysis and primary percutaneous intervention in acute myocardial infarction (from the Strategic Reperfusion Early After Myocardial Infarction [STREAM] Study). Am J Cardiol 2014;114(6):811-819. [http://dx.doi.org/10.1016/j.amjcard.2014.06.011] 16. Shavadia J, Yonga G, Otieno H. A prospective review of acute coronary syndromes in an urban hospital in sub-Saharan Africa. Cardiovasc J Afr 2012;23(6):318-321. [http://dx.doi.org/10.5830/CVJA-2012-002] 17. Ntsekhe M, Damasceno A. Recent advances in the epidemiology, outcome, and prevention of myocardial infarction and stroke in sub-Saharan Africa. Heart 2013;99(17):1230-1235. [http://dx.doi.org/10.1136/ heartjnl-2012-303585] 18. Schamroth C. Management of acute coronary syndrome in South Africa : Insights from the ACCESS (Acute Coronary Events – a Multinational Survey of Current Management Strategies) registry: Cardiovascular topics. Cardiovasc J Afr 2012;23(7):365-370. [http://dx.doi.org/10.5830/ CVJA-2012-017] 19. De Winter RJ, Verouden NJW, Wellens HJJ, Wilde AM. A new ECG sign of proximal LAD occlusion. N Engl J Med 2008;359(19):2071-2073. [http://dx.doi.org/10.1056/NEJMc0804737]

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An approach to the patient with a suspected tachycardia in the emergency department A Chin,1 MB ChB, MPhil, FHRS; B Vezi,2 MB ChB, FCP (SA), Cert Cardiology (SA); M Namane,3 MB ChB, MPhil; H Weich,4 MB ChB, MRCP (UK), MMed (Int), Cert Cardiology (SA); R Scott-Millar,1 MB BCh, FCP (SA) Division of Cardiology, Department of Medicine, Faculty of Health Sciences, Groote Schuur Hospital, University of Cape Town, South Africa Ethekwini Hospital, Durban, South Africa 3 Vanguard Community Health Centre, Cape Town, South Africa 4 Division of Cardiology, Department of Medicine, Faculty of Medicine and Health Sciences, Tygerberg Hospital, Stellenbosch University, Cape Town, South Africa 1 2

Corresponding author: A Chin (ashley.chin@uct.ac.za)

Patients present to the emergency department with either an ongoing tachycardia or a history suspicious of a tachycardia. Either way, the tachycardia needs to be documented, preferably on a 12-lead electrocardiogram (ECG) for diagnosis and management. If a tachycardia is not documented, a careful history of the palpitations should be taken to see if further monitoring and investigations are required. If a tachycardia is confirmed on an ECG, the clinician needs to classify it according to two variables: (i) regularity of the rhythm; and (ii) QRS width. This will allow a differential diagnosis to be made. S Afr Med J 2016;106(3):246-250. DOI:10.7196/SAMJ.2016.v106i3.10322

Patients may present to the emergency department with either an ongoing tachycardia or a history suspicious of a tachycardia. In either case, the tachycardia needs to be documented, preferably on a 12-lead electrocardiogram (ECG) for diagnosis and management. If a tachycardia is not documented, a careful history of the palpitations should be taken to establish if further monitoring and investigations are required. If a tachycardia is confirmed on an ECG, the clinician needs to classify it according to two variables: (i) regularity of the rhythm; and (ii) QRS width. This will enable a differential diagnosis to be made (Fig. 1). A narrow QRS or supraventricular tachycardia (SVT) can be caused by any arrhythmia that arises above the level of the bifurcation of the bundle of His. A wide QRS tachycardia has a differential diagnosis, but by far the most common cause of a wide complex tachycardia (WCT) is ventricular tachy cardia (VT). The ability of the clinician to distinguish between an SVT and a VT is crucial, as the management of these conditions differ and inappropriate management of the tachycardia may have lethal consequences. In a busy emergency department, such patients need to be appropriately triaged. In this review we focus on an approach to a patient with a tachycardia, who presents to the emergency department.

Mechanisms of tachycardia

An SVT usually has a QRS duration of <120 ms, unless there is bundle branch block (BBB) or an intraventricular conduction abnormality. The

QRS is narrow because ventricular activation occurs via the normal His-Purkinje system. SVT includes a wide range of arrhythmias that originate above the bifurcation of the bundle of His, such as sinus tachycardia, atrial flutter (AFL), atrial fibrillation (AF), atrial tachycardia (AT), atrioventricular junctional re-entrant tachycardia (AVJRT) and junctional ectopic tachycardia (JET). AVJRT can be due to atrioventricular nodal re-entrant tachycardia (AVNRT), where the antegrade limb is the slow pathway of the atrioventricular (AV) node and the retrograde limb the fast pathway, or atrioventricular re-entrant tachycardia (AVRT), where the antegrade limb is the AV node and the retrograde limb is the accessory pathway (‘orthodromic’ AVRT).

A WCT has a QRS duration ≥120 ms and may be caused by one of the following four mechanisms: • VT. VT must be the default diagnosis in any patient with a WCT and accounts for 80% of all cases of WCT.[1] The presence of structural heart disease and a previous myocardial infarction (MI) increases the likelihood that the WCT is VT to >90%.[2] VT usually occurs on the basis of a scar re-entrant mechanism (commonly due to a prior MI, cardiac surgery or cardiomyo pathy). Some idiopathic VTs may occur in a structurally normal heart and be due to triggered activity (e.g. right ventricular outflow tract VT). • SVT with a right or left BBB or an intra ventricular conduction abnormality. This

Regular

Irregular Narrow QRS

Narrow QRS

Sinus tachycardia Atrial flutter AVJRT (AVNRT, AVRT) Atrial tachycardia Junctional ectopic tachycardia

Atrial fibrillation Atrial flutter/tachy with variable AVB Multifocal atrial tachycardia

Ventricular tachycardia SVT with BBB Paced rhythm Antidromic AVRT Pre-excited SVT

Atrial fibrillation with BBB Atrial flutter, variable AVB + BBB Pre-excited atrial fibrillation Polymorphic ventricular tachycardia

Wide QRS

Irregular

Fig. 1. Classification of tachycardia (AVJRT = atrioventricular junctional re-entrant tachycardia; AVNRT = atrioventricular nodal re-entrant tachycardia; AVRT = atrioventricular re-entrant tachycardia; BBB = bundle branch block; AVB = atrioventricular block).

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accounts for 15 - 20% of WCTs. The BBB may be pre-existing or only apparent during the SVT, maintained by con cealed retro grade trans-septal conduction (functional). Functional BBB occurs when an impulse conducts across the septum and blocks the contralateral bundle branch retrogradely, which results in BBB with the next con ducted impulse. • Pre-excited tachycardia. This accounts for 1 - 6% of all causes of WCT. Any SVT that conducts antegradely over an accessory pathway (Wolff-Parkinson-White syndrome) will produce a WCT. In ‘antidromic’ AVRT, the antegrade limb is the accessory pathway and the retrograde limb the AV node. • Pacemaker tachycardia. Usually with RV apical pacing the morphology of the paced QRS complexes will have an atypical left bundle branch block (LBBB) pattern in V1 - V3, with left axis deviation. This may be seen in dual-chamber pacemakers (DDD) when there is tracking of the atrial rhythm (e.g. sinus tachycardia, atrial tachycardia). Pacemaker tachycardia may also occur in single-chamber pacemakers (VVIR) when the lower rate is increased by the sensor in the pacemaker.

Diagnostic evaluation

The evaluation of a patient with a tachy cardia should begin with a detailed medical history (including medication history) and physical examination. The clinical context often helps in the interpretation of the 12-lead ECG.

History

In a patient in whom a tachycardia is sus pected but not confirmed, one should focus on the history of palpitations. In the emergency department, palpitations are most commonly due to sinus tachycardia. The following characteristics are important when taking a history, which may raise the suspicion of an underlying arrhythmia: • Rate and regularity. The clinician should ask the patient to tap out the rhythm with his/ her fingers. In this way, the clinician can determine the nature of the palpitations, e.g. rapid regular, rapid irregular, slow regular, slow irregular, ectopic beats, missed beats or strong beats. Rapid regular beats are sugges tive of an SVT or a VT. Rapid irregular beats are suggestive of AF or AFL with variable AV block. Ectopic beats or missed beats suggest premature ventricular complexes (PVCs) or premature atrial complexes (PACs). • Mode of onset. Palpitations with an abrupt onset are suggestive of an SVT or a VT. A gradual onset or ‘warm-up’ is suggestive of sinus tachycardia.

• Mode of termination. Palpitations that end abruptly are suggestive of an SVT or a VT. A gradual termination or ‘warmdown’ is suggestive of sinus tachycardia. A tachycardia that terminates abruptly with a vagal manoeuvre, such as carotid sinus massage, confirms an AV nodal-dependent arrhythmia, i.e. AVNRT or AVRT, using an accessory pathway (Fig. 2). • Circumstance or precipitating factors. Palpi tations that occur at rest usually suggest SVT or VT. Palpitations that occur during exercise may be sinus tachycardia, but SVT or VT may be precipitated by exercise. Sinus tachycardia is a physiological response to sympathetic activation due to a pathological process (such as heart failure, thyrotoxicosis or sepsis). When sinus tachycardia occurs out of proportion to the physiological state, it is termed ‘inappropriate’ sinus tachycardia. This, however, is rare. Apparent inappro priate sinus tachycardia on ECG is more likely to be AFL with 2:1 block, the second flutter wave being hidden by the QRS. • Associated symptoms. Palpitations may be associated with presyncope, syncope, chest pain or abnormal pulsations in the neck. Syncope may occur with a rapid SVT or VT, usually as a result of a fall in cardiac output, or after termination of the tachycardia because of overdrive suppression of the SA node. • Associated heart disease. Underlying struct ural heart disease is an important substrate for the development of arrhythmias, e.g. a history of ischaemic heart disease or prior MI strongly suggests VT. Heart disease raises the suspicion of AF, AFL or VT. Lung disease may lead to atrial dilatation and AF, AFL or multifocal atrial tachycardia (MAT). A family history of sudden cardiac death or syncope should be sought when a familial cause is suspected (torsade de pointes with

the congenital long QT syndrome and VT or PVCs with arrhythmogenic right ventricular cardiomyopathy (ARVC)). SVT usually occurs in a normal heart but can occur in patients with heart disease. If a tachycardia is suspected, but has not been previously documented, the clinician has the option to arrange 24-hour Holter monitoring or inpatient telemetry, depend ing on the frequency of palpitations. In clinical practice, performing an ECG during an episode of future palpitations is likely to have the best yield. An implantable loop recorder can be considered if VT is strongly suspected.

Physical examination

The physical examination is useful to identify underlying cardiac disease that may serve as a substrate for arrhythmias. Signs of an underlying cardiomyopathy and heart failure raise the possibility that the palpitations are due to VT or AF/AFL. SVT can occur in patients with normal hearts and in those with underlying heart disease. Sometimes the SVT can cause left ventricular dysfunction, i.e. tachycardiainduced cardiomyopathy. The physical exam ination during a tachycardia is most helpful if signs of AV dissociation are present, which strongly suggests VT. Intermittent prominent cannon ‘A’ waves in the JVP waveform reflecting simultaneous atrial and ventricular contraction confirm AV dissociation.

Twelve-lead electrocardiography in sinus rhythm

The physician should look for clues to the cause of tachycardia by examining the 12-lead ECG in sinus rhythm. Prior ECGs should be sought and QRS morphology should be examined looking for BBB patterns and intraventricular conduction abnormalities

AF L

AV NR T AV R T

Fig. 2. Carotid sinus massage. (A) Atrial flutter or atrial tachycardia are AV nodal-independent tachycardias. Carotid massage causes transient AV block, which reveals underlying P waves (AFL = atrial flutter; AT = atrial tachycardia). (B) AVJRT (AVNRT/AVRT) are AV nodal-dependent tachycardias. Carotid massage may terminate the tachycardia.

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(Fig. 3). The tachycardia and sinus rhythm QRS complexes may then be compared. Some ECG abnormalities point towards structural heart disease, which may provide clues as to the most likely cause for an arrhythmia: • Left atrial enlargement and/or PACs suggest the diagnosis may be AF or AFL. • The presence of Q waves suggests prior MI and possible VT or AF/AFL. • Marked left ventricular hypertrophy with deep septal Q waves in I, aVL and V4 - V6 suggests hypertrophic cardiomyopathy. Other ECG abnormalities point towards a primary electrical cause for the arrhythmia: • A short PR interval, delta wave and wide QRS complex are evidence of pre-excitation (WolffParkinson-White syn drome) and suggest a diagnosis of AVRT or pre-excited AF. • Frequent PVCs with LBBB morphology and an inferior axis suggest right ventri cular outflow tract VT as a cause, which may be idiopathic or due to ARVC. T-wave inversion in leads V1 - V3 and the presence of an Epsilon wave are further diagnostic signs of ARVC.[3] • A long QT interval, Brugada pattern or early repolarisation pattern suggests polymorphic VT (PMVT) or torsade de pointes.

• Regular, wide complex tachycardias include monomorphic VT (in 80% of cases), SVT with right BBB (RBBB) or LBBB, preexcited tachycardia over an accessory path way, and pacemaker tachycardias. • Irregular, wide complex tachycardias include PMVT, AF or AFL with RBBB or LBBB and pre-excited AF. In patients with SVT, the next step would be to look for underlying P waves, flutter or fibrillary waves. There may be a P wave hidden in the T wave or QRS complex: • P-wave morphology. P waves are usually best seen in the inferior leads (II, III and

The clinician is now able to classify the tachycardia into four groups, based on these three simple observations (Fig. 1): • Regular, narrow complex tachycardias include sinus tachycardia, AT, AFL, AVJRT (AVNRT/AVRT) and JET. • Irregular, narrow complex tachycardias include AF (most likely), AFL with varia ble block or MAT.

LB B B

RBBB

V1 • rSR’ in V1 • B road terminal R in V1

V 6 • Normal left

• V1 and V2 negative • V5 and V6 positive • Initial sharp deflection V1 and V2 (<30 ms)

• Slurred R wave ventricular activation • Absent septal (septal q, rapid q wave R upstroke in V6 • Inverted T wave • V1 and V2 terminals in V6

Twelve-lead electrocardiography of the tachycardia

The initial analysis of the tachycardia is best followed by a methodical approach to ECG interpretation. A high-quality 12-lead ECG is more useful in the clinical setting than individual rhythm strips. The three main observations to consider in the ECG interpretation of a tachycardia are the following: • Confirm the tachycardia (i.e. ventricular rate ≥100 bpm). The easiest way to calcu late the ventricular rate is to count the number of QRS complexes and multiply by 6 (most ECGs are recorded at 25 mm/s = 10-second recording). • Are the QRS complexes wide (≥120 ms) or narrow (<120 ms)? Care must be taken to examine all leads, looking for the widest QRS complex. Some WCTs may have narrow QRS complexes in some leads. • Are the QRS complexes regular or irregular?

aVF) and V1. The P-wave axis should be calculated (normal: 30 - 70°). P waves should be positive in the inferior leads because right atrial activation starts at the sinus node and propagates to the AV node in an inferior direction. By contrast, AVJRT (AVNRT or AVRT) or AT activates the atria in a superior direction, with negative P waves in the inferior leads (Fig. 4). These P waves tend to be narrow (80 ms) because both atria are depolarised simultaneously from the lower septum. • Relative position of the P wave in the R-R interval. A common nomenclature used is to classify SVT as long RP (latter half)

Fig. 3. Typical patterns of right and left BBB.

Antegrade S low R etrograde F as t

Antegrade P s eudo R R etrograde wave in V 1

P s eudo S wave in AV F

S low F as t

P s eudo R wave in V 1

P s eudo S wave in AV F

Fig. 4. An example of a narrow complex (supraventricular) tachycardia. P waves are visible at the end of the QRS complexes. In V1, the P wave is seen as a pseudo R wave in V1 (arrow). In II, III and AVF the P waves are negative and are seen as pseudo S waves in AVF (arrow). In AVNRT the antegrade limb is the slow pathway and the retrograde limb the fast pathway of the AV node.

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or short RP tachycardias (first half), based on the position of the P wave in the R-R interval. This is purely descriptive and does not help the clinician to narrow the differential diagnosis. Examples of a short RP tachycardia include: typical AVNRT, AVRT or AT. Examples of a long RP tachycardia include: atypical AVNRT, AVRT over a slowly conducting accessory pathway (also called permanent junctional reciprocating tachycardia) and AT. JET and AT can present as both types of examples. AVNRT (90%) and AVRT (87%) are usually short RP tachycardias, but ATs are usually long (11%).[4] • Onset and termination. If the SVT starts with a very long PR interval at the onset of the tachycardia, the clinician should diagnose AVNRT with antegrade slow pathway con duction accounting for the prolonged PR interval. An SVT that starts with a PVC is usually an AVJRT, and AT is improbable. SVT that terminates with a P wave is unlikely to be an AT, as the last atrial beat will probably not cause AV block with the same beat. It is more likely an AVJRT, where block in the AV node caused the tachycardia to terminate. A vagal manoeuvre increases vagal tone and may terminate an AV nodal-dependent tachycardia, but never an AT. For AFL and AT, transient AV block may reveal underlying P waves or flutter waves (Fig. 2). A vagal manoeuvre commonly does not terminate an SVT and is thus unhelpful. • Change in cycle length and morphology. The clinician should focus on any change in cycle length of the tachycardia. If a change in QRS rate changes the subsequent P wave (V drives A), AT is unlikely. QRS alternans (phasic alteration in the amplitude of the QRS complex) is a nonspecific finding in faster tachycardias, irrespective of the mechanism. In patients with a WCT, looking for P waves is less important and the following needs to be examined: • QRS morphology. As the main differential diagnosis of VT is an SVT with LBBB or RBBB, the clinician should examine whether the WCT has features of typical LBBB or RBBB. It is imperative that the clinician knows what typical RBBB and LBBB looks like (Fig. 3). In both RBBB and LBBB the initial activation of the QRS complex is rapid. If the width of the R wave in V1 and V2 is >30 ms and/or the initial R wave in V1 and V2 to the nadir of the S wave is >70 ms, the patient is more likely to have VT (Fig. 5).[5] Numerous algorithms have been published, distinguishing VT from SVT (the Brugada algorithm being the most widely cited).[6]

The algorithm is not useful to distinguish VT from pre-excited tachycardias and some have found it to be less accurate than that in the original publication.[7] • Features specific for VT. AV dissociation, fusion beats and capture beats are specific for VT but are not sensitive. Negative concordance (i.e. all the QRS complexes in V1 - V6 are negative), in the absence of pacing, is specific for VT. • Features of pre-excitation during sinus rhythm with QRS complexes similar to the WCT suggest a pre-excited tachycardia. • Pacemaker spikes are not always visible, but the morphology will usually show atypical LBBB with left axis deviation and RV apical pacing.

Management of tachycardia

Acute management of SVT

The golden rule of ABC (airway, breathing, circulation) should be followed in the emer gency management of SVT. If the patient is haemodynamically compromised, urgent direct current (DC) cardioversion should be performed. Most patients who present with an SVT are haemodynamically stable, allowing the physician to obtain a thorough history and do a physical examination. The initial strategy should be to terminate an SVT with a vagal manoeuvre, such as carotid sinus massage, after excluding any carotid artery bruit. This should be performed with the patient in the supine position with a continuous 12-lead ECG. A vagal manoeuvre increases vagal tone and may terminate an

AVJRT (AVNRT/AVRT), but never an AT. For AFL and AT, transient AV block may reveal underlying P waves or flutter waves. If these manoeuvres do not terminate the SVT, the next step is intravenous adenosine. Starting doses of 6 mg with doses of 12 mg and 18 mg are normally used. Adenosine has a short halflife (<10 seconds) and produces transient heart block. Adenosine should be avoided in patients with an obvious AFL, as the reflex sympathetic activation may precipitate 1:1 AFL with haemodynamic decompensation. Adenosine will usually terminate AVJRT as well as some types of AT (making it less specific than carotid sinus massage).[8] Intravenous verapamil should be avoided in the emergency setting. The long-term management of SVT is medical or catheter ablation. Patients with recurrent symptomatic AVJRT can be treated with AV nodal blockers (such as beta-blockers or verapamil). Catheter ablation should be offered to patients with AVJRT as the success rate is high (95%), with 5% requiring a second procedure.[9] The decision to pursue a rate versus rhythm control strategy for AF/AFL should be indi vidualised depending on symptoms, rate of tachycardia and whether there is underlying LV dysfunction.

Acute management of WCT

The golden rule of ABC should be followed in the emergency management of a WCT. If the patient is haemodynamically compromised, urgent DC cardioversion should be performed. It is not uncommon for a WCT to present in an unstable way,

Fig. 5. An example of a ventricular tachycardia (WCT with a ventricular rate of 126 bpm (regular)). Note: the morphology in V1 is not compatible with typical RBBB. There is AV dissociation (arrows show dissociated P waves).

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irrespective of the cause. VT may degenerate into pulseless electrical activity and ventricular fibrillation (VF). As described above, a wide complex tachycardia should always be consider ed VT until proven otherwise. Haemodynamic stability does not exclude VT. The treatment of choice for stable and unstable monomorphic VT is cardioversion after sedation has been administered. Amio darone IVI is recommended in some guidelines as an initial strategy.[10] Amiodarone was only 25% effective in terminating VT, with a sideeffect profile of hypotension that may worsen the haemodynamic status.[11] Therefore, cardioversion should be readily available if amiodarone is chosen as an initial treatment strategy. Beta-blockers and verapamil are contraindicated in the acute setting and can cause severe haemodynamic deterioration and even VF or cardiac arrest. Patients with VT or WCT of uncertain origin should be referred to a cardiologist for further investigation and consideration of an implantable cardioverter defibrillator (ICD). The treatment of PMVT or torsade de pointes due to a long QT interval (either congenital or more often acquired) is different from that of monomorphic VT. Electrical cardioversion is the treatment of choice. As the underlying cause of torsade de pointes is a long QT interval, most anti-

arrhythmic drugs (including amiodarone) will exacerbate this and are contraindicated. Once the patient has been stabilised, the underlying cause should be sought and treated (correct the hypokalaemia and hypomagnesaemia and discontinue all long QT-prolonging drugs). Acute ischaemia is a common cause of PMVT and urgent coronary angiography is indicated. Other causes of PMVT include channelopathies such as Brugada syndrome and catecholaminergic PMVT. Some idiopathic outflow tract VTs may be adenosine sensitive. Adenosine should generally be avoided unless an SVT with BBB is suspected, as the reflex sympathetic activation may worsen VT. Verapamil must be avoided in all WCTs, with the rare exception of a patient with a known history of left fascicular VT proven to be verapamil sensitive in the past. Patients with idiopathic VT should be referred for ablation. A WCT may suggest the diagnosis of pre-excited AF (Fig. 6). There is no role for medical therapy in the treatment of pre-excited AF, as beta-blockers, calcium channel blockers, adenosine and digoxin do not block and may enhance conduction over an accessory pathway, resulting in very rapid ventricular response with cardiac arrest. These patients should receive immediate electrical cardioversion and be

Fig. 6. An example of a wide complex irregular tachycardia. This is pre-excited AFL over a left lateral accessory pathway. Note that the QRS complexes are wide and vary in morphology because of variable degrees of fusion over the accessory pathway and the AV node.

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referred for urgent ablation of the accessory pathway. Carotid sinus massage or adenosine may terminate an antidromic AVRT. Pre-excita tion should be looked for on the sinus rhythm ECG to confirm the diagnosis.

Conclusion

ECG documentation of a suspected tachy cardia is crucial in the management of a patient with a suspected tachycardia. The clinician needs to decide whether the tachycardia is narrow or wide and whether the rhythm is regular or irregular. When an SVT is suspected, the clinician should look for P waves and use vagal manoeuvres (such as carotid sinus massage) before administering adenosine, to differentiate AVJRT from AT and AFL. A WCT should always be considered to be VT until proven otherwise. QRS morphology is the most useful feature to distinguish between VT and SVT with BBB. Electrical cardioversion is the treatment of choice for stable and unstable VT. References 1. Issa ZF, Miller JM, Zipes DP. Clinical Arrhythmology and Electrophysiology. 2nd ed. Philadelphia, USA: Elsevier, 2012. 2. Tchou P, Young P, Mahmud R, Denker S, Jazayeri M, Akhtar M. Useful clinical criteria for the diagnosis of ventricular tachycardia. Am J Med 1988;84(1):53-56. [http:// dx.doi.org/10.1016/0002-9343(88)90008-3] 3. Marcus FI, McKenna WJ, Sherrill D, et al. Diagnosis of arrhythmogenic right ventricular cardio myopathy/ dysplasia: Proposed modification of the task force criteria. Circulation 2010;121(13):1533-1541. [http://dx.doi.org/10.1161/ CIRCULATIONAHA.108.840827] 4. Kalbfleisch SJ, el-Atassi R, Calkins H, Langberg JJ, Morady F. Differentiation of paroxysmal narrow QRS complex tachycardias using the 12-lead electrocardiogram. J Am Coll Cardiol 1993;21(1):85-89. [http://dx.doi.org/10.1016/07351097(93)90720-L] 5. Kindwall KE, Brown J, Josephson ME. Electrocardiographic criteria for ventricular tachycardia in wide complex left bundle branch block morphology tachycardias. Am J Cardiol 1988;61(15):1279-1283. [http://dx.doi.org/10.1016/00029149(88)91169-1] 6. Brugada P, Brugada J, Mont L, Smeets J, Andries EW. A new approach to the differential diagnosis of a regular tachycardia with a wide QRS complex. Circulation 1991;83(5):1649-1659. [http:// dx.doi.org/10.1161/01.CIR.83.5.1649] 7. Vereckei A, Duray G, Szénási G, Altemose GT, Miller JM. Application of a new algorithm in the differential diagnosis of wide QRS complex tachycardia. Eur Heart J 2007;28(5):589-600. [http://dx.doi.org/10.1093/eurheartj/ehl473] 8. Markowitz SM, Nemirovksy D, Stein KM, et al. Adenosineinsensitive focal atrial tachycardia: Evidence for de novo micro-reentry in the human atrium. J Am Coll Cardiol 2007;49(12):13241333. [http://dx.doi.org/10.1016/j.jacc.2006.11.037] 9. Fox DJ, Tischenko A, Krahn AD, et al. Supraventricular tachycardia: Diagnosis and management. Mayo Clin Proc 2008;83(12):14001411. [http://dx.doi.org/10.4065/83.12.1400] 10. Pedersen CT, Kay GN, Kalman J, et al. EHRA/HRS/APHRS expert consensus on ventricular arrhythmias. Europace 2014;16(9):12571283. [http://dx.doi.org/10.1093/europace/euu194] 11. Marill KA, deSouza IS, Nishijima DK, et al. Amiodarone or procainamide for the termination of sustained stable ventricular tachycardia: An historical multicenter comparison. Acad Emerg Med 2010;17(3):297-230. [http://dx.doi. org/10.1111/j.1553-2712.2010.00680.x]

IN PRACTICE

DRUG ALERT

Recommendations pertaining to the use of influenza vaccines and influenza antiviral drugs, 2016 S Walaza, C Cohen Sibongile Walaza and Cheryl Cohen are medical epidemiologists at the Centre for Respiratory Diseases and Meningitis, National Institute for Communicable Diseases (NICD), Johannesburg, South Africa, and have compiled this article on behalf of the Centre for Respiratory Diseases and Meningitis, NICD, South Africa. Corresponding author: S Walaza (sibongilew@nicd.ac.za)

Vaccination is the most effective strategy to prevent influenza. It is recommended that influenza vaccine be administered each year before the influenza season, i.e. from March to June, although for individuals at increased risk of severe influenza in whom vaccination was missed, vaccine may be administered later. For a review of the 2015 influenza season and ongoing real-time updates of the 2016 influenza season when it starts, refer to the website of the National Institute for Communicable Diseases of the National Health Laboratory Service (www. nicd.ac.za). In this article we provide recommendations for the use of influenza vaccines in anticipation of the 2016 southern hemisphere influenza season. Guidance is based on available evidence to assist clinicians in making decisions regarding influenza vaccination. It should be noted that this article includes general recommendations for vaccination with influenza vaccines available in South Africa and may differ from groups targeted in specific vaccination programmes, e.g. the National Department of Health Programme. S Afr Med J 2016;106(3):251-253. DOI:10.7196/SAMJ.2016.v106i3.10586

The burden of influenza in sub-Saharan Africa (and specifically in South Africa (SA)) is substantial, with some studies suggesting elevated influenza-associated mortality rates compared with other regions.[1-3] It is estimated that between 6 734 and 11 619 individuals die of seasonal influenza-associated illness in SA each year.[4,5] Approximately 5% of these deaths are in children aged <5 years. Among individuals aged ≥5 years, an estimated 50% of influenza-associated deaths are in the elderly and ~30% are in HIV-infected individuals.[4] The highest rates of influenza-associated hospitalisation are in the elderly aged ≥65 years, HIV-infected individuals and children aged <5 years.[4-9] Influenza infection may trigger exacerbations of diabetes and pulmonary (e.g. asthma) and cardiovascular disease. For this reason, people with underlying chronic medical conditions are at high risk of serious influenza complications, often resulting in hospitalisation and even death. Surveillance data from SA showed that having underlying illnesses (other than HIV) was a risk for influenza-associated mortality (odds ratio 2.9, 95% confidence interval (CI) 1.2 - 7.3).[7] Pregnant women also represent an important risk group for influenza-associated mortality.[8] Among an estimated 646 - 1 428 seasonal influenzaassociated deaths in women of childbearing age in SA in recent years, the majority (~90%) occurred in HIV-infected individuals and the influenza-associated mortality was three-fold higher (relative risk 2.8, 95% CI 7 - 3.9) in pregnant compared with non-pregnant women.[8] Studies suggest that individuals with underlying tuberculosis may also be at increased risk of influenza-associated death.[10,11] Influenza circulation in SA is highly seasonal, and the influenza season falls in the winter months. The average onset of the influenza season is the first week of June.[12] However, the season has started as early as the last week of April and as late as the first week of July. The average duration of the influenza season is 12 (range 7 - 25) weeks. During the influenza season in SA government facilities, approximately 14% of patients hospitalised with lower respiratory tract infection and 25% of patients with influenza-like illness will test positive for influenza on polymerase chain reaction analysis.

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Vaccinating individuals at risk of severe influenza may provide direct protection for these individuals. In addition, vaccinating individuals in close contact with people at risk for severe influenza may provide indirect protection through preventing transmission to high-risk individuals. This strategy is especially important for individuals in whom influenza vaccine is not indicated, such as children aged <6 months (who may be protected through maternal immunisation). [13] It may also be useful for individuals in whom the immune response may be poor, e.g. children aged <2 years and the elderly. The trivalent inactivated influenza vaccine (IIV) has reduced effectiveness in certain groups, e.g. the elderly and children aged <2 years; however, even for these individuals IIV still provides some protection. Other products, e.g. high-dose influenza vaccine and adjuvanted vaccines, have been shown to be more effective in certain groups,[14] but these vaccines are not available in SA. The trivalent IIV has been shown to provide protection in pregnant women and their infants[13,15,16] and in HIV-infected adults without severe immunosuppression.[17] Data are unclear as to the effectiveness in HIV-infected children aged <5 years.[18]

Recommended influenza vaccine formulation for 2016

Influenza vaccine is updated frequently because circulating influenza viruses continuously evolve. The following strains have been recommended by the World Health Organization (WHO) for the trivalent IIV 2016 southern hemisphere influenza season: • an A/California/7/2009 (H1N1)pdm09-like virus • an A/Hong Kong/4801/2014 (H3N2)-like virus • a B Brisbane/60/2008-like virus. These recommendations include a change in the A (H3N2) and B strains when compared with the composition of the trivalent IIV used for the southern hemisphere during the 2015 season. Standard-dose IIV should contain 15 μg of each haemagglutinin antigen in each 0.5 mL dose.

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IN PRACTICE

Groups recommended for influenza vaccination

• Pregnant women irrespective of stage of pregnancy, or postpartum • Individuals (adults or children) who are at high risk for influenza and its complications because of underlying medical conditions and who are receiving regular medical care for conditions such as chronic pulmonary (including tuberculosis) and cardiac diseases, chronic renal diseases, diabetes mellitus and similar metabolic disorders, individuals who are immunosuppressed and individuals who are morbidly obese (body mass index ≥40 kg/m2) • HIV-infected individuals • Healthcare workers • Residents of old-age homes and chronic care and rehabilitation institutions • Persons aged >65 years • Children aged 6 months - 59 months • Persons aged 6 months - ≤18 years on long-term aspirin therapy • Adults and children who are family contacts of individuals at high risk of severe influenza • Any persons wishing to minimise the risk of influenza acquisition, especially in workplace settings where large-scale absenteeism could cause significant economic losses.

Dosage

Recommended dosages for individuals of different age groups are set out in Table 1.

Contraindications

Persons with a history of severe (anaphylac tic) hypersensitivity to any components of the vaccine, including egg protein, or after a previous dose of any influenza vaccine.

Precautions

• Persons with moderate illness with or with out fever should preferably be immunised after symptoms have disappeared. Having a mild upper respiratory illness is not a reason to defer vaccination. • A history of Guillain-Barré syndrome within 6 weeks of receipt of influenza vaccine.

Timing

Vaccines should be given sufficiently early to provide protection for the winter. A protective antibody response takes about 2 weeks to develop.

Antiviral chemotherapy

Antiviral therapy is recommended as early as possible, ideally within 48 hours, for any

Table 1. Recommended dosages of influenza vaccine for individuals of different age groups Age group*

Dose

Number of doses

Adults and children from 9 years of age

Adult dose (0.5 mL) IMI

Single dose

Children aged 3 - 8 years

Adult dose (0.5 mL) IMI

1 or 2 doses†

Children aged 6 - 35 months

0.25 mL (half an adult dose) IMI

1 or 2 doses†

*Note: influenza vaccine is not recommended for infants <6 months of age. † For individuals who have not previously received a total of ≥2 doses before March 2016, or when vaccine status is unknown, 2 doses should be administered ≥1 month apart.

Table 2. Recommended dosages of influenza antiviral agents for treatment Age group

Oseltamivir dosage*

Zanamivir dosage*

Adults

75 mg twice per day

Two 5 mg inhalations (10 mg total) twice per day

Neonates <38 weeks postmenstrual age

1 mg/kg twice per day

38 - 40 weeks postmenstrual age

1.5 mg/kg twice per day

Neonates and infants (1 day† - 12 months)

3 mg/kg twice a day

Children ≤15 kg

30 mg twice per day

>15 - 23 kg

45 mg twice per day

>23 - 40 kg

60 mg twice per day

>40 kg

75 mg twice per day

Two 5 mg inhalations (10 mg total) twice per day (only in children aged ≥7 years)

*Recommended duration of treatment is 5 days. Zanamivir is recommended for treatment in children ≥7 years of age. † US Food and Drug Administration approves >14 days old; however, experts agree should be used from 1 day.[19]

patient with confirmed or suspected influen za who has complicated or severe illness or is at high risk of influenza complications. At present influenza A(H1N1)pdm09, A(H3N2) and B viruses remain sensitive to oseltamivir and zanamivir. High levels of resistance to adamantanes among influenza A viruses has been detected in a number of countries. The use of amantadine and rimantadine in the treatment of influenza is therefore not recommended. The dosages for treatment with oseltamivir and zanamivir are set out in Table 2.

Antiviral chemoprophylaxis

Antiviral chemoprophylaxis for contacts of persons with influenza is currently not recommended. An annual influenza vaccination is the best way to prevent influenza because it can be given before the possible exposures to influenza occur, and it can provide safe and effective immunity throughout the influenza season. However, WHO recommendations also advise presumptive treatment for highrisk individuals (patients with severe immunosuppression or transplant patients) if any early signs of possible influenza infection are detected during the influenza

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season. Such individuals should be treated presumptively using the treatment regimen described above for a duration of 7 days, instead of the previously recommended long-term lower-dose chemoprophylaxis regimen. For a more detailed description of antiviral management and chemoprophylaxis of influenza, please refer to the Healthcare Workers Handbook on influenza on the NICD website (http://www.nicd.ac.za/assets/files/ Healthcare%20Workers%20Handbook%20 on%20influenza%20in%20SA_%205%20 May%202015.pdf). For the full report on recommended com position of influenza vaccines, refer to the WHO website (http://www.who.int/influenza/ vaccines/virus/recommendations/201509_ recommendation.pdf?ua=1). 1. Dawood FS, Iuliano AD, Reed C, et al. Estimated global mortality associated with the first 12 months of 2009 pandemic influenza A H1N1 virus circulation: a modelling study. Lancet Infect Dis 2012;12(9):687-695. [http://dx.doi.org/10.1016/ S1473-3099(12)70121-4] 2. Cohen C, Simonsen L, Sample J, et al. Influenza-related mortality among adults aged 25-54 years with AIDS in South Africa and the United States of America. Clin Infect Dis 2012;55(7):9961003. [http://dx.doi.org/10.1093/cid/cis549] 3. Cohen C, Simonsen L, Kang JW, et al. Elevated influenza-related excess mortality in South African elderly individuals, 19982005. Clin Infect Dis 2010;51(12):1362-1369. [http://dx.doi. org/10.1086/657314] 4. Tempia S, Walaza S, Viboud C, et al. Deaths associated with respiratory syncytial and influenza viruses among persons >/=5

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years of age in HIV-prevalent area, South Africa, 1998-2009. Emerg Infect Dis 2015;21(4):600-608. [http://dx.doi.org/10.3201/eid2104.141033] 5. Tempia S, Walaza S, Viboud C, et al. Mortality associated with seasonal and pandemic influenza and respiratory syncytial virus among children <5 years of age in a high HIV prevalence setting – South Africa, 1998-2009. Clin Infect Dis 2014;58(9):1241-1249. [http://dx.doi.org/10.1093/cid/ciu095] 6. Murray J, Cohen A, Walaza S, et al. Determining the provincial and national burden of influenzaassociated severe acute respiratory illness in South Africa using a rapid assessment methodology. PloS One 2015;10(7):e0132078 [http://dx.doi.org/10.1371/journal.pone.0132078] 7. Cohen C, Moyes J, Tempia S, et al. Mortality amongst patients with influenza-associated severe acute respiratory illness, South Africa, 2009-2013. PloS One 2015;10(3):e0118884. [http://dx.doi. org/10.1371/journal.pone.0118884] 8. Tempia S, Walaza S, Cohen AL, et al. Mortality associated with seasonal and pandemic influenza among pregnant and non-pregnant women of childbearing age in a high HIV prevalence setting – South Africa, 1999-2009. Clin Infect Dis 2015; 61(7):1063-1070. [http://dx.doi.org/10.1093/cid/civ448] 9. Cohen C, Moyes J, Tempia S, et al. Severe influenza-associated lower respiratory tract infection in a high HIV-prevalence setting – South Africa, 2009-2011. Lancet Infect Dis 2013;19(11):1766-1774. [http://dx.doi.org/3201/eid1911.130546] 10. Walaza S, Cohen C, Nanoo A, et al. Excess mortality associated with influenza among tuberculosis deaths in South Africa, 1999-2009. PloS One 2015;10(6):e0129173. [http://dx.doi.org/10.1371/journal. pone.0129173] 11. Walaza S, Tempia S, Dawood H, et al. Influenza virus infection is associated with increased risk of death amongst patients hospitalized with confirmed pulmonary tuberculosis in South Africa, 20102011. BMC Infect Dis 2015;15(1):26-38. [http://dx.doi.org/10.1186/s12879-015-0746-x] 12. McAnerney JM, Cohen C, Moyes J, et al. Twenty-five years of outpatient influenza surveillance in South Africa, 1984-2008. J Infect Dis 2012;206(Suppl 1):S153-S158. [http://dx.doi.org/10.1093/infdis/ jis575]

13. Madhi SA, Cutland CL, Kuwanda L, et al. Influenza vaccination of pregnant women and protection of their infants. N Engl J Med 2014;371(10):918-931. [http://dx.doi.org/10.1056/NEJMoa1401480] 14. DiazGranados CA, Dunning AJ, Kimmel M, et al. Efficacy of high-dose versus standard-dose influenza vaccine in older adults. N Engl J Med 2014;371(7):635-645. [http://dx.doi.org/10.1056/ NEJMoa1315727] 15. Zaman K, Roy E, Arifeen SE, et al. Effectiveness of maternal influenza immunization in mothers and infants. N Engl J Med 2008;359(15):1555-1564. [http://dx.doi.org/10.1056/NEJMoa0708630] 16. Eick AA, Uyeki TM, Klimov A, et al. Maternal influenza vaccination and effect on influenza virus infection in young infants. Arch Pediatr Adolesc Med 2011;165(2):104-111. [http://dx.doi. org/10.1016/j.amepre.2011.08.006] 17. Madhi SA, Maskew M, Koen A, et al. Trivalent inactivated influenza vaccine in African adults infected with human immunodeficient virus: Double blind, randomized clinical trial of efficacy, immunogenicity, and safety. Clin Infect Dis 2011;52(1):128-137. [http://dx.doi.org/10.1093/cid/ ciq004] 18. Madhi SA, Dittmer S, Kuwanda L, et al. Efficacy and immunogenicity of influenza vaccine in HIVinfected children: A randomized, double-blind, placebo controlled trial. AIDS 2013;27(3):369-379. [http://dx.doi.org/10.1097/QAD.0b013e32835ab5b2] 19. Centers for Disease Control. Prevention and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices — United States, 2013– 2014. 9/20/2013. Report No.: 62(RR07). http://www.cdc.gov/mmwr/preview/mmwrhtml/rr6207a1. htm (accessed 22 January 2016).

Accepted 26 January 2016.

DIAGNOSIS

Digitotalar dysmorphism: Molecular elucidation A A Vorster, P Beighton, R S Ramesar Alvera Vorster is a Senior Technical Officer in the MRC Human Genetics Research Unit in the Division of Human Genetics, Institute for Infectious Diseases and Molecular Medicine, Department of Pathology, Faculty of Health Sciences, University of Cape Town, South Africa, with an interest in molecular genetics of connective tissue disorders. Peter Beighton is an ageing medical geneticist in the Division of Human Genetics with a long-term interest in heritable disorders of the skeleton and connective tissue, and Raj Ramesar is Professor and Head of the Division of Human Genetics and Director of the MRC Human Genetics Research Unit. Corresponding author: A A Vorster (anna.vorster@uct.ac.za)

Dominantly inherited digitotalar dysmorphism (DTD), which is characterised by flexion contractures of digits and ‘rocker-bottom’ feet due to a vertical talus, was first described in a South African family of European stock in 1972. We review the clinical manifestations and document the molecular basis for DTD in this prototype family. This family was restudied in 1995 and 2006 and biological specimens were obtained for molecular studies. Since the distal arthrogryposes (DAs) are genetically heterogeneous, an unbiased approach to mutation identification was undertaken through whole-exome next-generation sequencing of DNA from a single DTD-affected female. Venous blood specimens were obtained for DNA banking and subsequent molecular studies. Analysis of the nine genes that had previously been shown to cause DAs revealed a pathogenic mutation in exon nine of TNNT3. The presence of the p.(Arg63His) missense mutation at position 63 of TNNT3 was confirmed through direct cycle sequencing of genomic DNA in six affected family members for whom DNA had been archived. S Afr Med J 2016;106(3):253-255. DOI:10.7196/SAMJ.2016.v106i3.10134

Background

Digitotalar dysmorphism (DTD; OMIM #126050) is an autosomal dominant disorder characterised by congenital fixed flexion deformities of the digits and ‘rocker-bottom’ feet due to a vertical position of the talus. The condition was originally delineated more than 40 years ago in five generations of a large South African (SA) kindred of European stock.[1] The distal arthrogryposes (DAs) are a group of genetic disorders in which congenital contractures in the hands and feet are the main manifestations.[2] The individual members of the DA category have numerical designations 1 - 10, with subtypes indicated by letters in some instances. A few well-known eponymous genetic disorders with contractures plus craniofacial involvement have also been listed as DAs.

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With ongoing elucidation of the molecular basis of the DAs, several genes that encode the contractile apparatus of the fast-twitch myofibrils have been implicated.[3] It has also emerged that there is considerable molecular heterogeneity in the DAs and that some conditions regarded as having autonomous syndromic status have identical mutational determinants.[4,5] The prototype DTD family was restudied in 1995 and 2006, and biological specimens were obtained for molecular studies. A causative mutation in the TNNT3 (OMIM #600692) gene has now been identified.

The affected family

The proposita of the DTD family was born in SA in 1916 and initially examined in 1971 at the age of 55 years. At that time, nine affected persons in three generations were available for documentation.

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Family photographs revealed that deceased individuals in two preceding generations had the disorder. The pedigree data were in keeping with autosomal dominant inheritance, with some variability in phenotypic expression and complete penetrance. The progenitor of the kindred had emigrated from Holland to SA during the 18th century, and there could be additional affected persons in the extended family in Europe. The kindred was restudied in 1995 and in 2006, by which time three affected children in a new generation had been born and 11 affected persons in four generations were alive. Biological specimens for molecular investigations were obtained.

Feet In the feet, vertical angulation of the talus bone is an important diagnostic manifestation which was present in 10 of the 12 family members for whom clinical information was available. This malpositioning produces the well-known â&#x20AC;&#x2DC;rocker-bottomâ&#x20AC;&#x2122; convex configuration of the soles. The forefeet may be wide and flat with medial bulging of the insteps and flexion of the toes. As with the hands, the severity of involvement of the feet is variable. At the severe end of the spectrum, the fitting of shoes may be difficult and operative intervention may be required to facilitate ambulation.

Clinical manifestations

General health and intellectual function are normal, as are the facies, teeth, hair, nails, viscera and other bodily systems. Stature is normal for the generation and population group of the affected persons. The range of movements in the wrist, ankles and knees is limited to some extent in a minority of affected family members. In recent years two affected women have had caesarean sections for childbirth; the obstetric indications for these procedures are not known. Two family members have had bilateral carpal tunnel release operations in the wrists.

The clinical manifestations in nine affected family members have been documented and depicted in the orthopaedic literature.[1] The main syndromic components are rigidities of the digits in the hands and feet together with vertical alignment of the talus bones in the ankles. Involvement of the extremities is usually bilateral and not necessarily symmetrical or of equal severity. Hands Flexion contracture of the digits, with some ulnar deviation, are consistent features. Severity and distribution are variable, but the deformities are fixed and neither progress nor ameliorate. The thumbs may lie in opposition, internal rotation movements being limited by a fleshy web. The soft tissues of the middle phalanges are attenuated, producing an appearance of digital narrowing and tightness of the overlying skin. The ventral surfaces of the fingers and palms are smooth with few markings, and a single palmar crease may be present. There is no evidence of vascular or neurological deficit, and the degree of physical handicap is usually mild. Radiological examination shows that the bones of the hands are entirely normal.

Other manifestations

Methods

The family was reviewed in 1995 and again in 2006 when members of the new generation were examined and venous blood specimens were obtained for DNA banking and subsequent molecular studies. The specimens were collected with full signed consent, in accordance with established procedure. Genomic DNA (gDNA) was extracted from peripheral blood lymphocytes using the salting-out method[6] and archived for 11 family members, of whom six had the classic DTD phenotype. For the identification of the disease-causing variant, whole-exome sequencing was performed for one patient (DTD1.3ISA) on the Illumina HiSeq 2000 (Illumina Inc., USA) using the NimbleGen V2 exome kit (Roche

Fig. 1. Pedigree structure of relevant family members and direct cycle sequencing results for exon nine of TNNT3. Square symbols represent males, and circles females. Blackened symbols represent family members who are affected with DTD. The arrows in the electropherograms denote the c.188G>A; p.(Arg63His) mutation in exon 9 of TNNT3, which was present in all six affected family members who were sequenced. The mutation was not identified in two spouses (DTD1.4GER and DTD1.11PEM) or in three unaffected siblings (DTD1.2EVE, DTD1.7GLO and DTD1.9LIZ).

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NimbleGen Inc., USA) for capture. A mean coverage of 34.5 times was achieved across all targeted bases to enable whole-exome variant calling. The variants identified in DTD1.3ISA were filtered for known pathogenic mutations from the ClinVar database[7,8] in nine genes (TPM2, MYBPC1, MYH3, TNNT3, TNNI2, PIEZO2, ECEL1, MYH8 and FBN2) that had previously been shown to be mutated in persons with DA (OMIM #108120). To validate the pathogenic variant identified through whole-exome sequencing analysis of DTD1.3ISA, 100 ng of gDNA was amplified for exon nine of TNNT3 (RefSeq NM_006757.3) using 0.4 µM each of the sense (5´-CATGGCAATGTGGAGAAG-3´) and antisense (5´-CTCTGATGAGGCAGCAGT-3´) primers in a final polymerase chain reaction (PCR) volume of 25 µl containing 0.5 U GoTaq DNA polymerase, 1 × colourless reaction buffer (Promega, USA) and 0.2 mM of each deoxynucleoside triphosphate (Bioline, UK). Following 5 minutes of denaturation at 95°C on the BioRad T100 thermal cycler (Bio-Rad, USA), DNA was amplified in 35 cycles of denaturation at 94°C for 30 seconds, with primer annealing at 60°C for 30 seconds and product extension at 72°C for 40 seconds. The reaction was concluded at 72°C for 7 minutes to allow for complete product extension. Direct cycle sequencing of the resulting fragments was completed using 0.08 µM of primers described for PCR with the BigDye direct cycle sequencing chemistry (Life Technologies, USA) on the 3130xl Genetic Analyser (Applied Biosystems, USA). DNA sequences of research participants were aligned to the reference TNNT3 (NG_013085.1) sequence using Unipro UGENE v1.14.2.[9] This investigation received ethical approval from the UCT Faculty of Health Sciences Human Research Ethics Committee (REC REF 917/2014).

Results

Following whole-exome sequencing analysis of a person with DTD, 102 nucleotide variants were identified within the nine known genes that cause DAs. Twenty-one of these variants were described in the ClinVar database, and only one had a pathogenic designation (RCV000009468). The pathogenic variant, identified in TNNT3 (NM_006757.3), is a transition mutation at position 188 of the consensus coding sequence and is predicted to substitute an arginine for a histidine residue at amino acid position 63. The presence of the c.188G>A mutation in the gDNA of DTD1.3ISA was confirmed through direct cycle sequencing of exon 9 of TNNT3 (Fig. 1, DTD1.3ISA). Following direct cycle sequencing of exon nine of TNNT3 in 10 extended-family members for whom DNA was archived, all affected individuals (n=6) were shown to carry the variant allele, while neither of the spouses (n=2) and none of the unaffected members (n=3) inherited the c.188G>A mutation.

Discussion

The prototype SA family with DTD is regarded as having a form of DA, and the vertical talus bones that produce the ‘rocker-bottom’ feet are a prime syndromic component.[1] In addition to DTD, a congenital vertical talus can occur sporadically and as a nonsyndromic autosomal dominant trait.[10,11] The issue of syndromic identity arose when a form of DTD associated with craniofacial abnormalities was documented.[12] In a series of 47 families with either DA2A or DA2B, Sung et al.[13] identified the TNNT3 c.188G>A; p.(Arg63His) mutation in a

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mother and her two DA2B-affected children. Specific phenotypic description was not provided for the family. The Sheldon-Hall type of DA also manifests significant facial features and a vertical talus; considerable non-allelic heterogeneity was demonstrated in this condition, including mutations in the gene TNNT3.[3] Thereafter, in 2011, Zhao et al.[14] documented five members of three generations of a Chinese family with the Sheldon-Hall phenotype and demonstrated that they had a specific mutation in TNNT3 (c.187C>T; p.R63C). These authors suggested that bilateral vertical talus or clubfoot might be a special characteristic of this hot-spot mutation. The TNNT3 mutation, reported by Sung et al.[13] in 2003, has now been identified in the prototype DTD family in SA. It is relevant that the craniofacial structures are entirely normal in this SA kindred, and the reason for the disparity in the genotype-phenotype correlation is unknown. Nevertheless, the recognition of a vertical talus as an indicator of a specific mutation is a useful concept.[13] From the clinical standpoint, the detection of the specific TNNT3 mutation in the SA DTD family will facilitate genetic management. These measures could include diagnostic confirmation, antenatal diagnosis and genetic counselling, among others. In the future, the elucidation of the role of the causative TNNT3 mutation in the pathogenesis of DTD could have implications for targeted forms of therapy. Acknowledgements. Support for the project from the South African Medical Research Council and the National Research Foundation is acknowledged with gratitude by PB. We thank Dr M Solomons from the Life Vincent Pallotti Hospital for assistance in obtaining DNA from DTD patients for molecular investigations. 1. Sallis JG, Beighton P. Dominantly inherited digito-talar dysmorphism. J Bone Joint Surg Br 1972;54(3):509-515. 2. Hall JG, Reed SD, Greene G. The distal arthrogryposes: Delineation of new entities – review and nosologic discussion. Am J Med Genet 1982;11(2):185-239. [http://dx.doi.org/10.1002/ ajmg.1320110208] 3. Toydemir RM, Bamshad MJ. Sheldon-Hall syndrome. Orphanet J Rare Dis 2009;4:11. [http://dx.doi. org/10.1186/1750-1172-4-11] 4. Beck AE, McMillin MJ, Gildersleeve HI, et al. Spectrum of mutations that cause distal arthrogryposis types 1 and 2B. Am J Med Genet A 2013;161A(3):550-555. [http://dx.doi.org/10.1002/ajmg.a.35809] 5. McMillin MJ, Beck AE, Chong JX, et al. Mutations in PIEZO2 cause Gordon syndrome, MardenWalker syndrome, and distal arthrogryposis type 5. Am J Hum Genet 2014;1(5):734-744. [http:// dx.doi.org/10.1016/j.ajhg.2014.03.015] 6. Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988;16(3):1215. [http://dx.doi.org/10.1093/nar/16.3.1215] 7. Landrum MJ, Lee JM, Riley GR, et al. ClinVar: Public archive of relationships among sequence variation and human phenotype. Nucleic Acids Res 2014;42(1):D980-D985. [http://dx.doi.org/10.1093/nar/ gkt1113] 8. ClinVar. http://www.ncbi.nlm.nih.gov/clinvar/ (accessed 7 September 2014). 9. Okonechnikov K, Golosova O, Fursov M. Unipro UGENE: A unified bioinformatics toolkit. Bioinformatics 2012;28(8):1166-1167. [http://dx.doi.org/10.1093/bioinformatics/bts091] 10. Hamanishi C. Congenital vertical talus: Classification with 69 cases and new measurement system. J Pediatr Orthop 1984;4(3):318-326. [http://dx.doi.org/10.1097/01241398-198405000-00007] 11. Stern HJ, Clark RD, Stroberg AJ, Shohat M. Autosomal dominant transmission of isolated congenital vertical talus. Clin Genet 1989;36(6):427-430. 12. Kantaputra PN, Chalidapong P, Visrutaratna P. Digitotalar dysmorphism with craniofacial and other new associated abnormalities. Clin Dysmorphol 2001;10(3):171-175. [http://dx.doi. org/10.1097/00019605-200107000-00003] 13. Sung SS, Brassington AM, Krakowiak PA, Carey JC, Jorde LB, Bamshad M. Mutations in TNNT3 cause multiple congenital contractures: A second locus for distal arthrogryposis type 2B. Am J Hum Genet 2003;73(1):212-214. [http://dx.doi.org/10.1086/376418] 14. Zhao N, Jiang M, Han W, et al. A novel mutation in TNNT3 associated with Sheldon-Hall syndrome in a Chinese family with vertical talus. Eur J Med Genet 2011;54(3):351-353 [http://dx.doi.org/10.1016/j. ejmg.2011.03.002]

Accepted 14 October 2015.

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MEDICINE AND THE LAW

Amendments to the Sexual Offences Act dealing with consensual underage sex: Implications for doctors and researchers S Bhamjee, Z Essack, A E Strode Suhayfa Bhamjee is a senior lecturer in the School of Law, University of KwaZulu-Natal (Pietermaritzburg), South Africa. She is also a consultant to the HIV/AIDS Vaccines Ethics Group, University of KwaZulu-Natal (Pietermaritzburg). Zaynab Essack is a senior research specialist at the Human Sciences Research Council, an Honorary Research Fellow at the School of Law, University of KwaZulu-Natal (Pietermaritzburg), and a consultant to the HIV/AIDS Vaccines Ethics Group. Ann Strode is a senior lecturer in the School of Law, University of KwaZulu-Natal (Pietermaritzburg), and a consultant to the HIV/AIDS Vaccines Ethics Group. Corresponding author: A E Strode (strodea@ukzn.ac.za)

In terms of the Sexual Offences and Related Matters Amendment Act, consensual sex or sexual activity with children aged 12 - 15 was a crime, and as such had to be reported to the police. This was challenged in court in the Teddy Bear case, which held that it was unconstitutional and caused more harm than good. In June 2015, the Amendment Act was accepted by both the National Assembly and the National Council of Provinces, and came into operation on 3 July 2015. This article looks at the amendments to sections 15 and 16 of the Act and what the reporting obligations for medical professionals and researchers are in light of the amendments, as well as the duty to provide medical services and advice to adolescents. S Afr Med J 2016;106(3):256-259. DOI:10.7196/SAMJ.2016.v106i3.9877

South Africa (SA) has a very progressive legal framework which provides that adolescents have a right (largely) from the age of 12 to access a range of sexual and reproductive health services including contraceptives, treatment for sexually transmitted infections and termination of pregnancy (Table 1).[1-2] However, consensual but underage sex was a criminal offence that had to be reported to the police.[3] These conflicting approaches between the various branches of law placed doctors, researchers and other practitioners working with adolescents in an invidious position where they had a duty to provide adolescents with sexual and reproductive services but were required to report all sexual acts (including consensual ‘offences’) against children.[4]

Table 1. Ages of independent consent to sexual and reproductive health services[5] Health intervention/ service

Age at which a child may consent independently to health intervention/service

Contraceptives and contraceptive advice

12 years

HIV testing

12 years, or <12 if the child has ‘sufficient maturity’

Termination of pregnancy

No set age of consent

Medical treatment

12 years, and the child must demonstrate ‘sufficient maturity’

Male circumcision

16 years

Operations

12 years, and the child must demonstrate ‘sufficient maturity’

Research

18 years

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In the Teddy Bear Clinic case[6] these issues came before the Constitutional Court when it considered whether criminalising consensual, underage sex and sexual activity violated the constitutional rights of children.[5] The Constitutional Court held that adolescents have a right to engage in healthy sexual behaviour and that such acts were part and parcel of normative development from adolescence to adulthood.[6] The Court held further that criminalising consensual sex or sexual activity between adolescents aged 12 - 15 violated their rights to privacy, bodily integrity and dignity.[6] Criminalising such behaviour was also not in the best interests of the affected children.[1,2,6] The Court ordered Parliament to amend the Act and bring it in line with the Constitution.[6] Parliament recently did this by passing the Criminal Law (Sexual Offences and Related Matters) Amendment Act in 2015 (hereafter ‘the Act’).[7] The Act amends sections 15 and 16 (among others) of the Sexual Offences Act, which are the sections that deal with consensual underage sex or sexual activity.[7] This article sets out the provisions in the new Act dealing with consensual underage sex and sexual activity, indicates how the law has changed from the previous position, and explores the impact that this will have for doctors, researchers and other service providers working with adolescents.

The Criminal Law (Sexual Offences and Related Matters) Amendment Act 5 of 2015

The Act[7] provides firstly, in section 15 with regard to consensual sexual penetration with certain children (statutory rape), that: ‘S15 (1) A person (“A”) who commits an act of sexual penetration with a child (“B”) who is 12 years of age or older but under the age of 16 years is, despite the consent of B to the commission of such an act, guilty of the offence of having committed an act of consensual sexual penetration with a child, unless A, at the time of the alleged commission of such an act, was –

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(a) 12 years of age or older but under the age of 16 years; or (b) either 16 or 17 years of age and the age difference between A and B was not more than two years.’ This means that it is no longer a criminal offence for adolescents to engage in consensual sex with other adolescents aged 12 - 15 years.[5] It will also not be a criminal offence if the one adolescent is between the ages of 12 and 15 and the other is 16 or 17, provided that there is not more than a 2-year age gap between the parties. Secondly, with regard to sexual violation (statutory sexual assault), the Act provides in section 16 that: ‘S16. (1) A person (“A”) who commits an act of sexual violation with a child (“B”) who is 12 years of age or older but under the age of 16 years is, despite the consent of B to the commission of such an act, guilty of the offence of having committed an act of consensual sexual violation with a child, unless A, at the time of the alleged commission of such an act, was – (a) 12 years of age or older but under the age of 16 years; or (b) either 16 or 17 years of age and the age difference between A and B was not more than two years.’ In section 1 of the Sexual Offences Act many forms of sexual express ion and experi mentation, including kissing, mutual masturbation, or touching of genital organs, breasts, or any part of the body resulting in sexual stimulation, are considered to be a form of sexual violation.[3] These acts will no longer be a criminal offence, provided that both adolescents are between the ages of 12 and 15 years or one adolescent is aged between 12 and 15 and the other is 16 or 17, and there is not more than a 2-year age gap between them.

a child remain in place. Section 54 of the Sexual Offences Act has not been amended. There is therefore an ‘obligation to report (the) commission of sexual offences against children …’.[7] • Adults or older persons who have sex or engage in sexual activity with adolescents will still be committing a crime. There are two main differences in approaches between the old and the new laws. Firstly, peer-group sex and sexual activity between adolescents has been decriminalised. This introduces a new era into our law in terms of which peer-group sex or sexual activity between adolescents is no longer a criminal offence. Fig. 1 illustrates the age spans for decriminalised consensual sex and sexual activity (where the circles overlap, e.g. 12, 13, 14 or 15, sex or sexual activity between those ages is permissible) and where sex and sexual activity remains a criminal offence (where there is no overlap, e.g. 13 and 16, sex or sexual activity between those ages is not permissible). Secondly, the 2-year ‘close-in-age’ defence has been expanded to include sexual violation. This means that it is no longer an offence if a 16- or 17-year-old engages in a sexual act (violation or penetration as defined in the Act) with an adolescent aged between 12 and 15 years, provided they are not more than 2 years older than the younger partner. This inclusion is in line with the proposal made by the applicants in the Teddy Bear case, who argued that adolescents aged 15 - 17 are part of the same peer group given that they complete grades 10 - 12 together. Such peer group relationships would be normative, and therefore should not be criminalised.[8] The inclusion of the close-in-age defence brings our law in line with the approaches adopted in the UK,[9] Canada[10] and various jurisdictions in the

Similarities and differences between the approach to consensual, underage sex in the Sexual Offences Act 2007 and the Amendment Act

There are a number of similarities in the approach taken in the old Sexual Offences Act and the new Amendment Act, namely: • The age of consent to sex or sexual activity remains 16 years.[7] • The age below which a child does not have the capacity to consent to sex or sexual activity remains 12 years.[7] • The mandatory obligations regarding the reporting of any sexual offence against

USA.[11] While in some countries close-inage defences are used to impose lighter penalties on adolescents, in others, such as SA, such defences decriminalise the activity altogether.[12] In recognition that the age of majority is 18, this defence helps protect 16- and 17-year-olds (who are still legally children) from prosecution, as long as they are not more than 2 years older than their younger sexual partner.

Implications of the new Act for doctors and researchers

The main implication for doctors and researchers is that the ethical dilemma they faced regarding reporting consensual sex or sexual activity when providing sexual and reproductive services or undertaking research with adolescents has largely fallen away. Although the Act does not amend the provisions on mandatory reporting, they have been limited by the narrowing down of the activities that are criminalised. This means that doctors and researchers do not need to report such activity unless (Table 2): • One of the parties was under the age of 12 • The activity was non-consensual • The younger participant was 12 - 15 years old and the older participant 16 - 17, and the age difference between them was more than 2 years at the time of the act • The younger participant was 12 - 15 years old and their partner was an adult. However, the changes to the law do not completely resolve the ethical conflicts for doctors and other service providers, as indicated in the following instances. Firstly, with regard to termination of pregnancy, a girl under the age of 12 has a right to choose to terminate a pregnancy provided that she has sufficient capacity to make this deci sion.[6,13] However, given that her consent

Consensual sexual acts allowed 15

Fig. 1. Ages of permissible underage consensual sex (years).

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Table 2. The reporting and service delivery obligations of healthcare providers Age

Consensual/non-consensual sex or sexual activity

Reporting requirement

Sexual and reproductive healthcare services

Under 12

All acts of a sexual nature with this group are rape. Consent even if voluntarily given is not recognised as being legally valid.

Report

Children under 12 years of age should be provided with access to terminations of pregnancy, and HIV testing if they have sufficient maturity.

12 - 15

Consensual

Do not report

Non-consensual

Report

Consensual

Do not report

Non-consensual

Report

Consensual

Do not report

Children in these age categories should be provided with a range of sexual and reproductive healthcare services, including: Contraceptives HIV testing Terminations of pregnancy Treatment of STIs

(14 or 15) and 16 15 and 17

Non-consensual

Report

(12 or 13) and 16

All acts of a sexual nature with this age group are a crime: statutory rape or sexual violation. Consent not even considered because age gap is >2 years.

Report

(12 or 13 or 14) and 17

All acts of a sexual nature with this age group are a crime: statutory rape or sexual violation. Consent not even considered because age gap is >2 years.

Report

to sex is not legally valid, the offence of rape has occurred against her and it must be reported. This leaves service providers in a difficult position, as reporting in this instance may lead to girls choosing to have ‘back-street’ abortions as a way of avoiding their partner being charged with a criminal offence. Secondly, in terms of the Children’s Act, a child under the age of 12 may consent to HIV testing independently if they have ‘sufficient maturity’.[14] Consequently, a service provider may become aware that a child is sexually active below the age of 12 when the child requests HIV testing. Again, as with terminations of pregnancy in this age group, this information places the service provider under an obligation to breach the confidential patient-provider relationship and disclose this information to the police, thus discouraging young persons from coming forward and accessing HIV testing. Thirdly, in line with the Children’s Act[14] and the Termination of Pregnancy Act,[15] healthcare providers are still required to ensure access to sexual and reproductive healthcare services for adolescents, regardless of whether the sex was consensual/ non-consensual or whether it triggered mandatory reporting responsibilities. Again this poses an ethical dilemma, as some adolescents who have been the victims of crimes such as child abuse may want

sexual and reproductive health services but do not wish the service provider to report information relating to such services to the police. Fourthly, reporting consensual sexual relationships between adolescents and their older partners will remain a key ethical complexity.[2] Recent research indicated that among adolescents, significantly more females than males had partners who were at least 1 year older than them.[16] Furthermore, one-third (33.6%) of females and 4.1% of males aged 15 - 19 years reported having sex with partners who were 4 years or more older.[17] Girls (and to a lesser extent boys) in these discordant relationships will still be affected by the criminal law as their partners are committing an offence to which they are a witness, and they may be required, among other things, to give evidence to incriminate their partner. Again, reporting such intergenerational sex may create mistrust and unease in the therapeutic and research relationship and result in a refusal to disclose partners’ ages, which may impact on prevention services and counselling.[2,4] In terms of research, the Act allows for an increase in the scope of potential socially valuable research with young adolescents. It has been noted that there is a paucity of empirical research with pubescent girls and boys, which creates missed opportunities for public health interventions for this age

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group. [18-19] It is contended that one reason for the limited research on sex and sexuality among early adolescents is the previously restrictive legal framework, which created conundrums for researchers who would be legally obliged to report the activity, but ethically required to maintain confidentiality. [2,4,19] Recent amendments may therefore expand the scope of research, minimise ethical conflicts for researchers, and also minimise the potential risks of participating in research for this already vulnerable age group.[19]

Conclusions

The Amendment Act is a significant step forward for children’s rights. It has eased tensions that existed between the Children’s Act[14] and the Sexual Offences Act.[3] This will facilitate both research with, and service provision for, adolescents. Nevertheless, both healthcare providers and researchers must be aware of the particular circumstances that would activate their mandatory reporting responsibilities in the course of providing healthcare services or conducting research. Researchers should develop an informed, nuanced approach to intergenerational sex that is approved by research ethics committees, as argued in earlier articles.[4]

Recommendations

• All service providers who are involved in the care of children should be informed

IN PRACTICE

of amendments to the Sexual Offences Act that clearly articulate that the age of consent to sex remains at 16 and that sex and sexual activity in certain age categories have been decriminalised, and the implications for service delivery and mandatory reporting. • The recently updated Department of Health guidelines on ethics in health research[20] should amend the section on the mandatory reporting of abuse to reflect recent changes in the criminal law. • Researchers working with adolescents should ensure that any standard operating procedures relating to mandatory reporting reflect the narrower circumstances in which reporting will have to take place. Funding acknowledgment and disclaimer. The work described was supported by award number 1RO1 A1094586 from the National Institutes of Health entitled CHAMPS (Choices for Adolescent Methods of Prevention in South Africa). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. It does not necessarily represent the views of any Council or Committee with which the authors are affiliated. 1. McQuoid Mason D. Mandatory reporting of sexual abuse under the Sexual Offences Act and the ‘best interests of the child’. S Afr J Bioethics Law 2011;3(2):75-78. 2. Strode A, Toohey J, Slack C, Bhamjee S. Reporting underage consensual sex after the Teddy Bear case: A different perspective. S Afr J Bioethics Law 2013;6(2):45-47. [http://dx.doi.org/10.7196/SAJBL.289] 3. Criminal Law (Sexual Offences and Related Matters) Amendment Act 32 of 2007. http://www.hsph. harvard.edu/population/aids/southafrica.sexoffenses.07.pdf (accessed 26 January 2016). 4. Strode A, Slack C. Sex, lies and disclosures: Researchers and the reporting of under-age sex. South Afr J HIV Med 2009;10(2):8-10.

5. Strode A, Slack C, Essack Z. Child consent in South African law: Implications for researchers, service providers and policy-makers. S Afr Med J 2010;100(4):247-249. 6. Teddy Bear Clinic for Abused Children and Another v Minister of Justice and Constitutional Development and Another 2013 (12) BCLR 1429 (CC). 7. Criminal Law (Sexual Offences and Related Matters) Amendment Act 5 of 2015. http://www.gov.za/ sites/www.gov.za/files/38977_7-7_Act5of2015CriminalLaw_a.pdf (accessed 26 January 2016). 8. Teddy Bear Clinic for Abused Children and RAPCAN v Minister of Justice and Constitutional Development and National Director of Public Prosecutions 2013 (CCT12/2013). Applicants’ heads of argument. 9. Sexual Offences Act 2003 (UK) c 42. http://www.legislation.gov.uk/ukpga/2003/42/contents (accessed 30 June 2015). 10. Tackling Violent Crime Act, 2908. http://laws-lois.justice.gc.ca/eng/annualstatutes/2008_6/page-1. html (accessed 22 June 2015). 11. Davis NS, Twombly J. Handbook for Statutory Rape Issues. 2000. http://www.mincava.umn.edu/ documents/stateleg/stateleg.pdf (accessed 15 June 2015). 12. Kern JL. Trends in teen sex are changing, but are Minnesota’s Romeo and Juliet laws? William Mitchell Law Rev 2013;39(5). http://open.wmitchell.edu/wmlr/vol39/iss5/72013 (accessed 22 June 2015). 13. Christian Lawyers Association v Minister of Health and Others (Reproductive Health Alliance as Amicus Curiae) 2005 (1) SA 509 (TDP). 14. Children’s Act, No. 38 of 2005 available from http://www.gov.za/sites/www.gov.za/files/a38-05_3.pdf (accessed 26 January 2016). 15. Choice of Termination of Pregnancy Act No. 92 of 1996. http://www.saflii.org/za/legis/consol_act/ cotopa1996325/ (accessed 26 January 2016). 16. Richter L, Mabaso M, Ramjith J, et al. Early sexual debut: Voluntary or coerced? Evidence from longitudinal data in South Africa – the Birth to Twenty Plus study. S Afr Med J 2015;105(4):304-307. http://dx.doi.org/10.7196/SAMJ.8925] 17. Simbayi LC, Shisana O, Rehle T, et al. South African national HIV prevalence, incidence and behaviour survey, 2012. Human Sciences Research Council. 2014. http://www.hsrc.ac.za/en/research-outputs/ view/6871 (accessed 4 May 2014). 18. Sommers M. An overlooked priority: Puberty in sub-Saharan Africa. Am J Public Health 2011;101(6):979-981. [http://dx.doi.org/10.2105/AJPH.2010.300092] 19. Jewnarain D. The ethical dilemmas of doing research with 12-14 year-old school girls in KwaZuluNatal. Agenda 2013;27(3):118-126. 20. Department of Health. Ethics in Health Research: Principles, Processes and Structures. 2nd ed. Department of Health, 2015. http://www.nhrec.org.za/docs/Documents/EthicsHealthResearchFinalAused.pdf (accessed 27 June 2015).

Accepted 15 November 2015.

HEALTHCARE DELIVERY

The value of internal medicine outreach in rural KwaZulu-Natal, South Africa R I Caldwell, B Gaede, C Aldous Doc Caldwell, BSc(Med), MB ChB, FCP (SA), FRCP (Lond), spent more than 25 years in private practice as a specialist physician in Pietermaritzburg, South Africa, and then took up a post at Grey’s Hospital as outreach physician for internal medicine. The outreach contract has come to an end, but he has a part-time position with the School of Clinical Medicine, University of KwaZulu-Natal (UKZN), as undergraduate liaison between Pietermaritzburg and Durban. Bernhard Gaede, MB BCh, MMed (Fam Med), PhD, was recently appointed Head of the Department of Family Medicine at UKZN. Prior to this he was Director of the Centre for Rural Health at UKZN for 4 years after working for more than a decade at Emmaus Hospital in the Drakensberg. His areas of interest and research have included the healthcare system, community-level care (including home-based care and traditional medicine), human rights and medical anthropology. Recent interests include education of health professionals and establishment of a decentralised teaching platform. Colleen Aldous, PhD, is Academic Leader for Research at the School of Clinical Medicine at UKZN. She is a medical scientist with a PhD in science education and is involved in postgraduate research mentorship across several medical disciplines including surgery, orthopaedics, dermatology, paediatrics, ophthalmology, general medicine and psychology. Her own research interest is human genetics. Corresponding author: R I Caldwell (ric@caldwells.co.za)

Background. Sustainable multifaceted outreach is crucial when equity between specialist services available to different sections of South Africa (SA)’s population is addressed. The healthcare disadvantage for rural compared with urban populations is exemplified in KwaZulu-Natal (KZN). Outreach to rural hospitals has reduced the need for patients to undergo journeys to regional or tertiary hospitals for specialist care. Objectives. Multifaceted outreach visits to seven district hospitals in western KZN by a specialist in the Pietermaritzburg Department of Internal Medicine were analysed for the period 2013 - 2014. Methods. Church of Scotland, Vryheid, Dundee, Charles Johnson Memorial, Rietvlei, Estcourt and Greytown hospitals were visited. During each visit, data were collected on data collection forms, including patient numbers, gender and age, whether out- or inpatient, whether referred, and diagnostic categories.

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Results. During 113 visits, of 1 377 contacts made, 631 were outpatients and 746 were inpatients. Females formed the majority overall, but for inpatients males outnumbered females. The majority of patients were aged >40 years, but over half of inpatients seen were aged ≤40 years. A modest 15% of patients seen were referred to hospitals with specialist services. Overall, cardiovascular disease, predominantly among outpatients, was the biggest diagnostic category. Infectious diseases followed, primarily among inpatients, and then general medicine. No other category reached 10%. Conclusions. The analysis showed differences between diagnostic categories, especially when outpatients and inpatients were separated out. Referral patterns, age-distribution and gender distinctions were made. The value of a good database was confirmed. The multifaceted outreach may have suggested useful outcomes as well as output. The vulnerability v. sustainability of outreach programmes was emphasised. S Afr J Med 2016:106(3):259-262. DOI:10.7196/SAMJ.2016.v106i3.10278

Sustainable multifaceted outreach is a necessity if access to specialist services for different sections of the population in South Africa is to be addressed. The disadvantage in terms of healthcare for rural compared with urban populations is starkly exem plified in KwaZulu-Natal (KZN). Outreach programmes are a means of increasing access to specialist care by rural populations, who are in many cases impoverished and therefore unable to reach centralised services provided in cities.[1-3] The World Health Organization defines outreach as ‘… any type of health service that mobilises health workers to provide services to the population or to other health workers, away from the location where they usually work and live’.[4] In southern African terms, specialist outreach to rural hospitals has reduced the need for patients in distant and disadvantaged areas and communities to undergo demanding journeys to regional or tertiary hospitals in order to obtain standard specialist care.[5-7] It is suggested that although simple outreach (specialist outpatient (OP) clinics that are merely displaced from the central to a peripheral hospital) can increase output in terms of patient care, multifaceted outreach is required in order to improve overall outcomes by including inservice training for doctors permanently stationed in rural areas.[1,6,7] Multifaceted outreach may be defined as including two or more discrete interventions, such as liaison with medical staff, ‘problem’ ward rounds, formal teaching and seminars and patient contact sessions.[8] An important aspect of outreach is the perceived skills mix of the visiting consultant and the relationship built up with the relevant doctors at the receiving hospital. There needs to be a match, where the visiting hospitals feel they get the most support and value and where the visiting consultant gives the most input. The tension between being locally responsive and standardising the input is evident in the differences in the patterns of patients seen, as presented in this review. The success of this aspect may be difficult to quantify. The Pietermaritzburg (PMB) Department of Internal Medicine outreach programme has documented outreach over the past 7.5 years (2007 - mid-2014), recording 680 hospital visits, 7 259 patient contacts and 4 497 personnel contacts.[7] The outreach was multifaceted in that it included problem ward rounds, OP clinics requiring the presence of the resident doctors, and formal teaching sessions. The current study made use of a standard data collection form, recording gender and age details of patients, whether they were out- or inpatients (IPs) and whether or not they were referred. The patients were also categorised into broad diagnostic or subspecialty groups based on the 11 existing subspecialties in the PMB Department of Internal Medicine. This analysis considered differences between OP and IP hospital populations when gender, age group, diagnostic category and referral pattern were compared. The chance similarity in the large numbers between the two groups, OP and IP, may have given additional validity to the study. The most important questions to be asked were whether this analysis added useful evidence to research on specialist outreach programmes, and ultimately whether it fulfilled its objective, namely to show the importance of multifaceted outreach and how vital it is to sustain such programmes.

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Methods

As part of the ongoing review of the PMB Department of Internal Medicine outreach service, the database of visits to seven hospitals from January 2013 to December 2014 was analysed with regard to frequency of visits to each hospital, patient numbers, gender and age distribution of patients, whether patients were IPs or OPs, referral pattern and the diagnostic categories into which patients fell. These years rendered comprehensive and representative data, and the analysis was carried out by a single specialist, ensuring consistency of data capture. The data were kept in duplicate at Red Cross Air Mercy Service (AMS)’s Durban base and in the Department of Internal Medicine at Grey’s Hospital, PMB. Permission for access to the database had been granted by the AMS. The identity of patients was not disclosed, and ethics approval previously obtained from the University of KwaZulu-Natal was revised and extended. The seven hospitals visited included Church of Scotland Hospital (COSH) in Tugela Ferry, Vryheid Hospital, Dundee Hospital, Charles Johnson Memorial Hospital (CJM) in Nqutu, Rietvlei Hospital near Umzimkulu, Estcourt Hospital and Greytown Hospital. The diagnostic categories were cardiovascular diseases, general medicine, infectious diseases, endocrinology, pulmonology, neurology, nephrology, haema tology, dermatology, rheumatology and gastroenterology.

Results

In summary, seven hospitals were visited and 113 visits analysed, with an average of 16 visits per hospital (range 13 - 20). A total of 1 377 patients were seen in consultation, of whom 631 were OPs and 746 IPs. In comparing the pattern of the visits it was found that at Vryheid and Dundee hospitals, visits were predominantly for OPs; of the 609 patients seen, all but 45 were OPs. In contrast, at COSH, CJM, Rietvlei and Estcourt hospitals, visits were predominantly for IPs; of 604 patients seen, only one was an OP. Greytown (164 patient contacts) was the only hospital where both IPs (n=98) and OPs (n=66) were regularly seen (Table 1).

Gender and age range of patients seen

Overall, 638 (46%) patients seen were male, and 739 (54%) were female. Females formed the majority in OP-dominated visits: 369/609 (61%) v. males 240/609 (39%), whereas in IP-dominance, males outnumbered females: 330/604 (55%) v. 274/604 (45%). Overall, 57% of patients seen were >40 years old; this proportion rose to 70% for OP-dominated visits and fell to 44% for IP-dominated visits, where 41% of patients fell into the 25 - 40-year-old group. Over half (57%) of patients seen in IP-dominated hospitals were aged ≤40 years.

Referrals to regional or tertiary hospitals

A modest proportion of patients seen (204/1 377) were referred to hospitals with specialist services (15%). For OP-dominated hospital visits, 103/609 patients (17%) seen were referred. For IP-dominated visits, 73/604 (12%) were referred. For mixed IP and OP hospital visits (Greytown), 28/164 (17%) were referred (Table 1).

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Table 1. Hospitals visited, January 2013 - December 2014 Visits to hospital, n

COSH

Vryheid

Dundee

CJM

Rietvlei

Estcourt

Greytown

Total

113

All patients seen, n

184

430

179

115

199

106

164

1 377

Outpatients seen, n

398

166

631

Inpatients seen, n

184

115

198

106

746

Patients referred, n

204

Table 2. Hospitals visited and numbers of patients seen in consultation, January 2013 - December 2014 COSH

Vryheid

Dundee

CJM

Rietvlei

Estcourt

Greytown

Total

184

430

179

115

199

106

164

1 377

Cardiovascular, n

266

404

General medicine, n

256

Infectious diseases, n

305

Endocrinology, n

Pulmonology, n

Neurology, n

108

Nephrology, n

Haematology, n

Dermatology, n

Rheumatology, n

Gastroenterology, n

All patients seen, n

Within categories, 68/404 cardiovascular disease patients seen (17%) were referred, whereas only 4% of both infectious diseases patients (11/305) and general medicine patients (9/256) were referred. With OP domin ance, cardiovascular disease referrals were 15%, and higher at 23% for IP-dominated referrals.

Inpatients

All patients

n=56 n=198

n=119

n=160

n=410

n=403

n=314 n=29

Diagnostic categories

Cardiovascular diseases was the biggest diagnostic category, with 404/1 377 (29%) patients. Infectious diseases patients followed with 305/1 377 (22%), then general medicine with 256/1 377 (19%). No other category reached 10% (Table 2). There was a striking difference between diagnostic categories for OP v. IP dominance. Cardiovascular diseases represented 52% (315/609 patients seen) for the former, with only 9% (56/604) for the latter. In contrast, infectious diseases represented 38% for IP dominance (231/604), and only 5% (30/609) for OP dominance. General medicine provi ded 17% for OP-dominated and 20% for IP-dominated visits, and again the other diagnostic categories remained below 10% irrespective of OP or IP dominance. Fig. 1 shows the comparison between the three major diagnostic categories for IPs, OPs and all patients.

Outpatients

n=231

n=101

n=304

Cardiovascular

General medicine

Infectious diseases

Other categories

n=255

Fig. 1. Main diagnostic categories for all seven hospitals visited, for inpatients, outpatients and all patients, January 2013 - December 2014.

Discussion

The outreach service to the hospitals under consideration was multifaceted in that it included interventions such as liaison with medical staff and teaching meetings as well as patient contact. Even on OP-dominated visits, the booked OP session required the presence and participation of medical officers employed at that hospital, and was therefore not simply a specialist OP clinic held in a peripheral hospital. The question is whether such specialist outreach was sustainable and of value to the recipient hospital.

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Although female medical wards in KZN district hospitals regularly appear more fully occupied than male wards, gender pre dominance elsewhere in Africa is variable. [9-11] In this study, where the overall predominance in the wards and OP clinic was female, the opposite was noted for the IP-dominated group. However, this may be an artificial representation depending on the preparedness of a particular ward for the outreach visit. For example, at one of the hospitals (111:73 male/ female), the male medical ward was usually better prepared for the visit, and the male

IN PRACTICE

tuberculosis (TB) ward invariably added five or six patients per visit. At another, there were invariably additional patients in the male surgical ward with medical problems that were discussed. The gender pattern was therefore more likely to reflect the referral choice of the on-site doctors rather than the burden of disease or the population distribution in rural areas, for IPs at least. With regard to age range, the data confirmed that IPs included a large proportion of young patients, <40 years old, with many under 25, because of communicable diseases. In constrast, a booked OP clinic which largely excluded communicable disease reflected the prominence of degenerative diseases and a preponderance of a population aged >40 years. Again, however, the bookings were determined by the local doctors and did not necessarily reflect the population distribution of diseases. The pattern of referrals illustrated primarily that outreach facilitated the referral of patients to further specialist-level care. Overall, 15% of all patients seen were recommended for such referral. The variation in referral pattern between OP- and IP-dominant or diagnostic groups was small, ranging from 12% to 17%. There was also indication that it was only this minority of patients that was referred, so that the majority continued to be managed at the base hospital, with advice given as to further appropriate treatment. This was of relevance to cardiology, since there was a preponderance of patients with cardiovascular disease seen, particularly in the OP setting. Only 17% of such patients required subspecialist referral, whereas without the outreach service many more of these patients might have been referred, resulting in overcrowding of the cardiology clinic at the receiving hospital. Therefore, even if only half of the patients seen by the outreach physician had otherwise been referred directly to cardiology, the outreach visit would have saved more than 40% of such referrals. Future studies to assess the outcomes of patients referred for further regional or tertiary care will be important in measuring the contribution of a competent specialist opinion towards overall patient care and health system functioning. With regard to diagnostic categories, the data collection sheets used on each hospital visit were detailed enough to afford easy categorisation of patients according to subspecialty. The criterion used was to which subspecialty a patient would belong if referral were required. An option might arise where more than one such subspecialty was involved; here, the dominant symptoms might prevail, or such a patient could be categorised into the general medicine group. A subspecialty that may have received slight over-representation was cardiology, where less specific symptoms and signs, such as palpitations and hypertension, could result in allocation to the cardiovascular diseases category. The results confirmed that there was a different patient population in a booked OP setting compared with those IPs seen as part of a ‘problem’ ward round. As expected, more than a third of the latter fell into the infectious diseases category, where HIV disease and TB predominated. Many other patients in the ward would also belong to the same category; the outreach physician was only seeing those perceived to be presenting management problems. The booked OP clinics, however, were probably little different from unselected medical OP clinics around the world: the cardiovascular category was highly represented,[12,13] and the infectious diseases category was barely represented – HIV-positive patients belonged to antiretroviral clinics, and HIV-TB management was not regarded as an outreach problem unless the patient was sick enough to be admitted. The analysis showed the value of comprehensive documentation of each hospital visit, so that in addition to numbers of patient and personnel contacts made, the gender, age and diagnostic category of patients was recorded, as well as whether they were OPs or IPs and whether they were referred. The virtue of retaining such data consistently is appreciated; this enabled the detailed analysis in this study, and has provided a database of activities since 2007, with useful implications for further comparisons and research, including

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prospective studies. The design of the data collection forms may require modification in the light of this analysis. The data collected did not quantify the outcomes of changes in behaviour by the recipient doctors or by the visiting consultant in response to the input. While this is an important component of a multifaceted outreach service (beyond offering a specialist service at a different location), it is much harder to measure and requires further investigation. This study, like other SA studies, has attempted to show that multifaceted outreach may be beneficial for recipient hospitals, their patients and their personnel.[7,14] In KZN, a province that has a transport agreement between its Department of Health and the AMS, such specialist outreach would be at its most productive when conducted by as many disciplines as possible, in all its health areas, as part of routine health systems functioning. However, outreach programmes are fragile. For example, if the transport contract in KZN were not to be renewed, the service would collapse. Studies have emphasised the need for sustainability of multifaceted outreach programmes in order for them to remain effective in the long term.[15] Regular visits with meticulous data recording and subsequent analysis may be an important contribution to such sustainability.

Conclusion

The study provided interesting comparisons between diagnostic categories, both overall and when OPs and IPs were separated out. Insight was obtained into referral patterns, and age-distribution and gender distinctions were also made. The value of a comprehensive and carefully maintained database was confirmed. As a result of internal medicine outreach, many rural patients received a specialist opinion and referrals were either facilitated or obviated, suggesting useful outcomes for these patients. Further investigations with follow-up on individual patient progress and referrals are required to understand the patient flows and outcomes more comprehensively.[14] The role of multifaceted outreach in increasing the access to specialist healthcare by impoverished rural populations and the ability to sustain such programmes is emphasised. 1. Gaede BM, McKerrow NH. Outreach programme: Consultant visits to rural hospitals. CME 2011;29(2):57-58. 2. De Roodenbeke E, Lucas S, Rouzaut A, Bana F. Outreach Services as a Strategy to Increase Access to Health Workers in Remote and Rural Areas (Technical Report No. 2). Geneva: World Health Organization and International Hospital Federation, 2011. http://whqlibdoc.who.int/ publications/2011/9789241501514_eng.pdf (accessed 3 June 2015). 3. Gruen RL, Bailie RS. Specialist clinics in remote Australian Aboriginal communities: Where rock art meets rocket science. J Health Serv Res Policy 2004;9(Suppl 2):61. [http://dx.doi.org/10.1258/1355819042349844] 4. O’Sullivan BG, Joyce CM, McGrail MR. Adoption, implementation and prioritization of specialist outreach policy in Australia: A national perspective. Bull World Health Organ 2014;92(7):512-519. [http://dx.doi.org/10.2471/BLT.13.130385] 5. Schoevers J, Jenkins L. Factors influencing specialist outreach and support services to rural populations in the Eden and Central Karoo districts of the Western Cape. Afr J Prm Health Care Fam Med 2015;7(1):Art. No. 750. [http://dx.doi. org/10.4102/phcfm.v7i1.750] 6. Reid MJA, Kirk BL. Assessing the impact of airborne outreach to build clinical capacity in rural Botswana. J Public Health Africa 2013;(1):55-59. [http://dx.doi.org/10.4081/jphia.2013.e11] 7. Caldwell RI, Gaede BM, Aldous C. Description of an internal medicine outreach consultant appointment in western KwaZulu-Natal, South Africa, 2007 to mid-2014. S Afr Med J 2015;105(5):353356. [http://dx.doi.org/10.7196/SAMJ.9173] 8. Gruen RL, Weeramanthri TS, Knight SE, Bailie RS. Specialist outreach clinics in primary care and rural hospital settings. Cochrane Database Syst Rev 2004;(1):CD003798. [http://dx.doi. org/10.1002/14651858.CD003798.pub2] 9. Okunola O, Akintunde A, Akinwusi PO. Some emerging issues in medical admission pattern in the tropics. Niger J Clin Pract 2012;15(1):51-54. [http://dx.doi.org/10.4103/1119-3077.94098] 10. Ogun SA, Adelowo OO, Familoni OB, Jaiyesimi AE, Fakoya EA. Pattern and outcome of medical admissions at the Ogun State University Teaching Hospital, Sagamu – a three year review. West Afr J Med 2000;19(4):304-308. 11. Ike SO. The pattern of admissions into the medical wards of the University of Nigeria Teaching Hospital, Enugu (2). Niger J Clin Pract 2008;11(3):185-192. 12. Kadiri S. Tackling cardiovascular disease in Africa. BMJ 2005;331(7519):711-712. [http://dx.doi. org/10.1136/bmj.331.7519.711] 13. Mayosi BM, Flisher AJ, Lalloo UG, Sitas F, Tollman SM, Bradshaw D. The burden of non-communicable diseases in South Africa. Lancet 2009;374(9693):934-947. [http://dx.doi.org/10.1016/S0140-6736(09)61087-4] 14. Clarke DL, Aldous C. Surgical outreach in rural South Africa: Are we managing to impart surgical skills? S Afr Med J 2014;104(1):57-60. [http://dx.doi.org/10.7196/SAMJ.7252] 15. Gruen RL, Weeramanthri TS, Bailie RS. Outreach and improved access to specialist services for indigenous people in remote Australia: The requirements for sustainability. J Epidemiol Community Health 2002;56(7):517-521. [http://dx.doi.org/10.1136/jech.56.7.517]

Accepted 9 November 2015.

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IN PRACTICE

CASE REPORT

A subepidermal blistering disorder Y Moolla Dr Yusuf Moolla is a specialist physician in the Department of Internal Medicine at Addington Hospital, Durban, South Africa. He recently obtained an MMed from the University of KwaZulu-Natal for his work on HIV infection. Corresponding author: Y Moolla (moollayusuf@hotmail.com)

A young woman presented with generalised tense blisters. A tentative diagnosis of linear IgA bullous dermatosis (LABD) was supported by biopsy findings. Dramatic improvement was noted after 5 days of treatment with dapsone. S Afr Med J 2016;106(3):263. DOI:10.7196/SAMJ.2016.v106i3.10129

Case report

A young woman presented with generalised tense blis足 ters, which had developed 2 days earlier (Fig. 1). There appeared to be no mucosal involve足 ment, and the distribution mainly involved the face, trunk and extremities. There had been no previous drug exposure. She had neither clinical signs of autoimmune disease nor evidence of sepsis. Given the abrupt onset and clinical scenario, a skin punch biopsy was performed and a tentative diagnosis of linear IgA bullous dermatosis (LABD) was made. Dapsone, an immunomodulatory sulfone that has been supported for use in LABD by case reports and clinical observation, was administered to the patient. An adjunctive oral corticosteroid was added to accelerate resolution. The biopsy fin足 dings were supportive of a subepidermal blistering disorder, such as LABD. Subepidermal sect足 ions demonstrated fibrin, neutrophils and focal eosinophils. Perivascular infiltrate of lymphocytes was identified in the dermis.

Fig. 1. Multiple blistering lesions evident on admission.

Fig. 2. Clinical response noted at day 5 of therapy. The blistering lesions had resolved, leaving hypopigmented macular areas.

Immunofluorescence was unfortunately unavailable. After just 5 days of therapy, dramatic improvement was noted (Fig. 2), and she continued to improve.

LABD remains an uncommon condition, with incidence rates reported to be ranging from <0.5 to 2.3 cases per million individuals per year.

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Breast cancer in high-risk Afrikaner families: Is BRCA founder mutation testing sufficient? H J Seymour,1 BHSc Hons; T Wainstein,2 MSc (Med); S Macaulay,1,2 MSc (Med); T Haw,1,2 MSc (Med); A Krause,1,2 MB BCh, PhD 1 2

ivision of Human Genetics, National Health Laboratory Service, Johannesburg, South Africa D Division of Human Genetics, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa

Corresponding author: T Wainstein (tasha.wainstein@nhls.ac.za)

Background. Germline pathogenic mutations in cancer susceptibility genes result in inherited cancer syndromes. In the Afrikaner population of South Africa (SA), three founder mutations in the BRCA genes that lead to hereditary breast and ovarian cancer syndrome (HBOCS) have been identified. Objectives. To investigate the uptake and type of molecular testing performed on patients for HBOCS, to determine the prevalence of the three Afrikaner founder BRCA mutations as well as non-founder BRCA mutations in the study population, and to analyse the utility of two mutation prediction models (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) and Manchester scoring method) in assisting with the decision for the most cost-effective testing option. Methods. A retrospective file review was performed on counsellees of self-reported Afrikaner ancestry from Johannesburg, SA (2001 2014), with a personal or family history of breast and/or ovarian cancer. Demographic and family history information was recorded and Manchester and BOADICEA scores were calculated for each patient. Results. Of 86 unrelated counsellees whose files were reviewed, 54 (62.8%) underwent BRCA genetic testing; 18 (33.3%) tested positive for a mutation, and 14 of these (77.8%) for an Afrikaner founder mutation. Twelve counsellees had the BRCA2 c.7934delG mutation. Four non-founder mutations were identified. BOADICEA scores were significantly higher in counsellees who tested positive for a mutation than in those who tested negative. Conclusions. Founder mutation testing should be performed as a first-line option. BOADICEA is very useful in identifying counsellees at high risk for a BRCA mutation and also assists with the decision to pursue further testing following a negative founder mutation result. These findings assist in guiding an informed genetic counselling service for at-risk individuals with an Afrikaner background. S Afr Med J 2016;106(3):264-267. DOI:10.7196/SAMJ.2016.v106i3.10285

Breast cancer is the most common form of cancer in women worldwide. Altogether 6 224 cases were reported in South Africa (SA) in 2009.[1] Up to 10% of breast cancer cases are attributable to germline mutations in cancer susceptibility genes, leading to hereditary syndromes.[2] The most well described of these cancer syndromes is hereditary breast and ovarian cancer syndrome (HBOCS), which is an autosomal dominant inherited syndrome predisposing to several cancers, particularly those of the breast and ovaries. This syndrome is caused by the presence of heterozygous, pathogenic germline mutations in either the BRCA1 or BRCA2 genes. Founder mutations (those that occur more frequently or almost exclusively in a specific founder population group) account for a significant proportion of BRCA mutations. One such example of a founder population is the SA Afrikaner population group, which dates back approximately 330 years, when European settlers arrived in what is now the Western Cape Province of SA. This population (of individuals primarily of Dutch, German and French ancestry) grew rapidly in the first century after arriving in SA, and as a result the mutations in the initial population increased in frequency. The outcome of these events can be seen in the large number of genetic conditions in which Afrikaner founder mutations are documented. [3] The Afrikaner population group, comprising 12.2% of individuals living in the Gauteng Province of SA,[4] has had three founder BRCA mutations identified to date that result in HBOCS: BRCA1 c.1374delC, BRCA1 c.2641G>T and BRCA2 c.7934delG.[5-6] The Division of Human Genetics at the National Health Laboratory Services (NHLS) and the University of the Witwatersrand (Wits) in

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Johannesburg, SA, has offered genetic counselling at clinics in various hospitals in the Johannesburg area since the 1970s. Afrikaner individuals with a personal or family history of breast and/or ovarian cancer are seen at these clinics. The role of the genetic counsellor in this setting is to provide information regarding the genetics of HBOCS and the risks of carrying and passing on a mutation, and to assist the counsellee in making informed decisions about genetic testing. Genetic counsellors consider a variety of factors when analysing each individual case. The family history of cancers, tumour histological features and age of onset of the cancers can influence risk assessment and decisions regarding genetic testing. There are also a number of risk assessment tools available to aid in the analysis of cases. The two tools widely used at the NHLS/Wits are the online Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) risk calculation program[7] and the revised Manchester scoring method.[8] Both prediction models calculate the likelihood of carrying a deleterious mutation in one of the BRCA genes. Although these tools were initially designed for use in European populations, studies have been performed to validate their uses in ethnically diverse populations.[9-10] This type of analysis has not been undertaken in the Afrikaner population of SA. Once the appropriate analyses and risk assessments have been undertaken, the counsellee may be offered a molecular genetic test, including testing for the Afrikaner founder mutations as a firstline testing option (prices range from approximately ZAR1 600 to ZAR3 500). Following a negative founder mutation result, further molecular testing may be offered should the clinical and family history warrant it. These further tests include sequencing

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RESEARCH

of the BRCA1 and BRCA2 genes and large rearrangement analysis to detect large deletions/duplications (prices range from approximately ZAR9 000 to ZAR25 000). The range in prices for BRCA testing is laboratory dependent. No formal guidelines currently exist to assist genetic counsellors or their counsellees in determining whether founder mutation analysis is sufficient or whether additional testing should be pursued following a negative result for the founder mutations identified in this population group.

Objectives

To conduct a retrospective file review of a cohort of Afrikaner individuals presenting for genetic counselling for HBOCS. The objectives were to: (i) investigate the uptake and type of molecular testing carried out; (ii) determine the prevalence of the founder and non-founder mutations identified in this cohort; and (iii) analyse the utility of two prediction models used in genetic counselling for inherited cancers.

Methods

A retrospective file review of all counsellees of self-reported Afrikaner ancestry who received genetic counselling for HBOCS in the genetic counselling clinics offered by the NHLS/Wits Division of Human Genetics in Johannesburg from August 2001 to December 2014 was conducted. The files are maintained and archived at the Division of Human Genetics at the NHLS/Wits. The specific counselling clinics were held at Charlotte Maxeke Johannesburg Academic Hospital, Chris Hani Baragwanath Academic Hospital, the Donald Gordon Medical Centre and Helen Joseph Hospital.

Genetic counsellors at the NHLS/Wits calculate counsellees’ risks of carrying a deleterious BRCA1 or BRCA2 mutation using the online BOADICEA risk calculation program[7] and/or the Manchester scoring method.[8] The outputs of these tools were incorporated into the overall analysis of risk for each counsellee. A data collection sheet was constructed to record the counsellees’ demographic infor mation, the specific tests undertaken, the cancers reported in the family and HBOCS risks given by the genetic counsellors, as well as risks calculated using BOADICEA and the revised Manchester scoring method for each individual. In cases where the BOADICEA or Manchester scores had not been calculated, these were computed from the pedigree data as part of the study for each counsellee (to obtain a pretesting risk output). These data allowed for standardised comparison among the different groups of counsellees. Mann-Whitney tests were carried out to compare the BOADICEA and Manchester risk scores. The first was a comparison between counsellees who tested positive and negative for an Afrikaner founder mutation; this was done to evaluate whether the prediction models could be accurately applied to this population. The second comparison was carried out between those who tested positive and negative for a nonfounder mutation after further sequencing was done. A median BOADICEA risk score, given as a percentage chance of having a mutation, was then calculated for each group. The Manchester scores, given as whole numbers, correspond to the following risks: a score of >16 corresponds to a ≥10%

Results

A total of 122 self-reported Afrikaner coun sellees were seen at the genetic counselling clinics for discussion around testing for HBOCS during the period 1 August 2001 31 December 2014, and their files were available for review. Twenty were found to be related to others already included in the study, 4 were reported to have a family history of cancer on the non-Afrikaner side of their family, and a further 12 were excluded because insufficient information was provided. A total of 86 counsellees (70.5%) therefore matched the inclusion criteria specified for the study. Of the 86 counsellees whose files were reviewed, 54 (62.8%) underwent BRCA Afrikaner founder mutation testing, and 14/54 (25.9%) tested positive for one of the three founder mutations. Of the 40/54 (74.1%) who tested negative for a founder mutation, only 10/40 (25.0%) opted for further analysis. Four of these 10 (40.0%) were found to carry a non-founder mutation (Fig. 1).

Total counsellees eligible for inclusion in file review: N=86

Subjects

Participants for the study were selected on the basis of the following criteria: at least one side of the family had to be of self-identified Afrikaner descent, and the family history of cancer had to be from the Afrikaner side of the family. All counsellees enrolled into the study were unrelated to one another. The counsellee’s family history and demo graphic information was recorded and ana lysed. During a genetic counselling session the genetic counsellor discussed HBOCS and testing options with the counsellees. Clinical judgement alone has been used historically to categorise counsellees as having an average, moderate or high risk of having HBOCS. In more recent years, various tools and prediction models have been used to assist genetic counsellors in determining HBOCS risks.

chance of carrying a deleterious mutation and a score of ≥20 indicates a 20% chance of carrying a deleterious mutation.[11] As with the BOADICEA risk scores, the median Manchester scores for each group were calculated for comparison. Once the counsellees were checked and found to be unrelated to one another, the data were anonymised in accordance with appropriate ethical protocols. Ethics clearance (reference: M101141) was obtained from the University of the Witwatersrand’s Human Research Ethics Committee (Medical).

Afrikaner counsellees tested for founder mutations: 54/86 (62.8%) Tested negative for founder mutations: 40/54 (74.1%)

No further analysis: 30/40 (75.0%)

Tested positive for founder mutations: 14/54 (25.9%)

Continued to sequencing and large rearrangement analysis: 10/40 (25.0%)

Tested positive for non-founder mutations: 4/10 (40.0%)

Afrikaner counsellees not tested: 32/86 (37.2%)

Counsellees offered testing: 15/32 (46.8%)

Counsellees not offered testing: 17/32 (53.1%)

Counsellees who did not follow up: 14/15 (93.3%)

Affected relative offered testing first: 11/17 (64.7%)

Counsellees opting not to test: 1/15 (6.7%)

HBOCS risk too low: 6/17 (35.3%)

Tested negative for non-founder mutations: 6/10 (60.0%)

Fig. 1. Outline of testing options recommended and the outcomes for counsellees in this study (N=86).

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Of the 86 counsellees, 32 (37.2%) did not undergo any testing, although 15/32 (46.9%) were offered founder mutation testing. One counsellee opted not to undergo molecular testing for personal reasons, and 14 did not follow through with providing a blood sample for testing. The remaining 17/32 (53.1%) were not offered testing, either because the risk for HBOCS was considered too low or because an affected relative who presented as a better candidate was offered testing. Eighteen counsellees tested positive for a deleterious mutation in one of the BRCA genes, and 14 of these mutations (77.8%) were founder mutations in the Afrikaner population. The other four non-founder mutations identified were BRCA1 c.45dupT, BRCA1 c.181T>G, BRCA2 c.6621delA and BRCA2 c.6761_6762delTT. The Afrikaner BRCA2 c.7943delG founder mutation was the most common mutation in this cohort, with 12 of the 18 counsellees (66.7%) testing positive for it. The mutations found are summarised in Table 1. A BOADICEA risk score and a Manchester score were calculated for each counsellee, based on personal and family history alone; molecular results were excluded from these calculations so that a pretest prediction of identifying a pathogenic BRCA mutation could be performed. Median scores and ranges for counsellees tested for the Afrikaner founder mutations were calculated, since the data did not follow a normal distribution (Table 2). A Mann-Whitney test was then carried out to examine whether or not the BOADICEA and Manchester prediction models were useful in this founder population. In order to compare the scores effectively, counsellees who tested positive for a founder mutation (n=14) were compared with counsellees who tested negative for a founder mutation (n=40). Significance was assumed at a onetailed p-value of <0.05. There was a highly significant difference in the BOADICEA risk scores for counsellees who tested positive and negative for an Afrikaner founder mutation (p<10-3); however, there was no significant difference in Manchester scores between the two groups (p=0.06). An outlier with a Manchester score of 106 who tested negative for an Afrikaner founder mutation and did not undergo further testing was removed from the group of counsellees. As a result, a significant difference was observed between the two groups (p=0.04). Another Mann-Whitney test was con ducted on the 10 counsellees who opted for further testing after receiving a negative BRCA Afrikaner founder mutation result.

Table 1. Frequencies of BRCA1 and BRCA2 mutations identified in the Afrikaner cohort (N=18) Gene

Mutation

Counsellees who tested positive, n (%)

BRCA1

c.45dupT

1 (5.5)

c.181T>G

1 (5.5)

c.1374delC*

1 (5.5)

c.2641G>T*

1 (5.5)

c.6621delA

1 (5.5)

c.6761_6762delTT

1 (5.5)

c.7934delG*

12 (67.0)

BRCA2

*The three founder mutations previously identified in the Afrikaner population of SA.

Table 2. Median pretesting BOADICEA and Manchester risk scores for counsellees tested for Afrikaner founder mutations in the BRCA genes (N=54) Risk score, median (range) Risk assessment tool

Counsellees who tested positive for a founder mutation (n=14)

Counsellees who tested negative for a founder mutation (n=40)

BOADICEA, %

35.6 (8.2 - 91.6)

5.6 (0.5 - 93.2)

Manchester score

21 (16 - 40)

16.5 (6 - 42)*

*An outlier with a Manchester score of 106 was excluded.

Table 3. Median pretesting BOADICEA and Manchester risk scores for counsellees who underwent further BRCA analysis (N=10) Risk score, median (range)

Risk assessment tool

Counsellees who tested positive for a non-founder mutation (n=4)

Counsellees who tested negative for a non-founder mutation (n=6)

BOADICEA, %

44.6 (2.7 - 74.3)

3.15 (0.9 - 19.0)

Manchester score

24.5 (16 - 32)

15.5 (8 - 28)

They were divided into those who tested positive (n=4) and negative (n=6) for a BRCA mutation (Table 3). A significant difference in BOADICEA scores was observed between the two groups (p=0.04), but there was no significant difference in the Manchester score (p=0.07).

Discussion

According to the study data, the majority of the counsellees in this Afrikaner cohort (54/86, 62.8%) decided to undergo molecular genetic testing to detect a deleterious founder mutation in either of the BRCA genes. Among the counsellees who opted to undergo testing, the total mutation detection rate was 33.3% (18/54); 14 of these mutations (77.8%) were founder mutations prevalent in the Afrikaner population. Considering that a few of the counsellees who did not have molecular testing were also considered to be at a high risk for HBOCS, this detection rate has the potential to be even higher. The most common mutation detected in this cohort was the BRCA2 c.7934delG Afrikaner founder mutation, which was

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identified in 12 counsellees (22.2% of those tested). The other two Afrikaner founder mutations (BRCA1 c.1374delC and BRCA1 c.2641G>T) occurred only once each, which is less than expected. The reason for this distribution is unclear, but may represent a geographical variation. In the original article describing these two mutations, five families with the c.2641G>T mutation and two families with the c.1374delC mutation were reported in a cohort made up of 90 individuals from various population groups. [5] The authors stated that after their article was completed, an additional eight families were identified as having the c.2641G>T mutation and a further two families were reported to have the c.1374delC mutation. The four non-founder mutations were identified only once each. The BRCA1 c.181T>G mutation is a European founder mutation. [11] The other three non-founder mutations (BRCA1 c.45dupT, BRCA2 c.6621delA and BRCA2 c.6761_6762delTT) have not been reported in the literature before. BRCA1 c.45dupT has been identified during BRCA1/2 molecular testing in labora

RESEARCH

tories around SA (Dr Nico de Villiers, personal communication) and the BRCA2 c.6761_6762delTT mutation has been reported in the National Centre for Biotechnology Information, ClinVar database. [12] Further studies, including haplotype analysis around the mutation region, are needed to characterise BRCA1 c.45dupT in SA. Fifteen of the counsellees who were offered testing did not pursue it (17.4%). This raises concern. Counsellees who could potentially be carrying deleterious mutations are not being tested and would therefore not benefit from prevention strategies. A study by Petrucelli et al.[13] on the Ashkenazi Jewish population of Michigan found that only 1 out of 166 (0.6%) had a non-founder BRCA1/2 mutation.[13] The authors observed that the National Comprehensive Cancer Network recommends further molecular analysis following a negative founder mutation result only when there is evidence of non-Ashkenazi Jewish ancestry. Even though only a small number of counsellees from the current study opted for further analysis when initial founder mutation testing was negative, 40% (4/10) had a non-founder mutation, which is a higher proportion than reflected in Petrucelli et al.’s research. This suggests that, in the Afrikaner population of SA, further analysis is required more frequently than suggested by Petrucelli et al. Mutation prediction models have been useful in recent years to assist genetic counsellors in deciding whether or not to offer their clients further analysis. Prediction models of this kind have been validated in various ethnic groups,[9-10] but have not yet been modified to account for founder mutations in populations such as the SA Afrikaner population. Comparison of the two prediction models in the present study has revealed that the BOADICEA prediction model seems to discriminate high-risk individuals better than the Manchester model. Even though the numbers were small, there was a significant difference in the BOADICEA scores between counsellees who tested positive and negative upon further BRCA analysis. This indicates that, following a negative founder result, BRCA sequencing and deletion/duplication analysis should be pursued if the BOADICEA score is >10%. The application of this threshold could reduce unnecessary costs if further testing is not pursued. Further studies are necessary in larger samples to examine the role of these prediction models comprehensively in the Afrikaner founder population. However, in this study, the BOADICEA prediction model provided a good additional indication as to whether or not further testing was warranted.

Conclusions

The findings of this study have shown that 54/86 Afrikaner counsellees underwent BRCA testing in the Johannesburg area over the period 2001 - 2014. Insight is provided into the prevalence of BRCA founder mutations in the local Afrikaner population. The sample in the present study may not be representative of the wider Afrikaner population in the country, and further analysis of samples from at-risk families living elsewhere may indicate a need for regional-specific practice. The presence of four non-founder mutations in the study cohort suggests that screening for founder mutations alone in high-risk counsellees may be insufficient. Clinical judgement and appropriately assessed prediction tools should be used to determine the most cost-effective course of testing and which counsellees would benefit from full sequencing and deletion/duplication analysis after a negative founder screen. A similar analysis to that described here, but performed on a larger sample, would provide more comprehensive results. Efforts in this regard are ongoing locally. While the BOADICEA and Manchester risk prediction models were not designed to take into account founder mutations for the

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Afrikaner population, it is evident that these prediction models are very useful in this population. Genetic counsellors should be encouraged to utilise these models to aid in decision-making regarding testing for BRCA mutations. A high BOADICEA score would support further BRCA testing if the founder mutation screen is negative. Genetic counsellors in SA need to be cognisant of the Afrikaner founder mutations and their possible presence in ethnic groups that may have Afrikaner admixture, and testing options should be considered accordingly. The use of a retrospective, file-based approach limited this study to an analysis of the information contained in the counsellees’ files. Further studies of a prospective and qualitative nature, could obtain insight into the attitudes and perceptions of Afrikaner counsellees regarding the process of genetic counselling and decision-making with regard to BRCA testing. The findings from this study will be useful in the provision of an informed genetic counselling service to at-risk individuals with an Afrikaner background in an SA setting. This research illustrates the necessity of genetic counselling and testing of appropriate patients. Patients with a family history of breast and/or ovarian cancer, women <50 years of age with breast cancer, males with breast cancer and families with cancer from high-risk ethnic groups such as Afrikaners and Ashkenazi Jews should be referred for genetic counselling. Acknowledgements. The authors thank Prof. J G R Kromberg for reading initial drafts of this manuscript and providing insightful feedback. We also thank Mr A May for his assistance and guidance with statistical analysis of the data. We are grateful to the doctors who refer these individuals to our clinics, in particular Drs S Rayne and H Cubasch. We wish to thank the medical scientists at various laboratories who carried out the molecular diagnostic work on the study patients. Finally, HJS thanks the DST-NRF 2015/2016 Internship Programme for funding her internship placement in Human Genetics. References 1. Cancer Association of South Africa. The NIOH SA National Cancer Registry – Files. CANSA, 2015. http://www.cansa.org.za/south-african-cancer-statistics/ (accessed 8 October 2015). 2. Diamond TM, Sutphen R, Tabano M, Fiorica J. Inherited susceptibility to breast and ovarian cancer. Curr Opin Obstet Gynecol 1998;10(1):3-8 3. Botha MC, Beighton P. Inherited disorders in the Afrikaner population of southern Africa. S Afr Med J 1983;64(16):609-612. 4. Statistics South Africa. Metropolitan Municipality – City of Johannesburg. STATSSA, 2015. http:// www.statssa.gov.za/?page_id=1021&id=city-of-johannesburg-municipality (accessed 8 October 2015). 5. Reeves MD, Yawitch TM, van der Merwe NC, van den Berg HJ, Dreyer G, Jansen van Rensburg E. BRCA1 mutations in South African breast and/or ovarian cancer families: Evidence of a novel founder mutation in Afrikaner families. Int J Cancer 2004;110(5):677-682. [http://dx.doi.org/10.1002/ ijc.20186] 6. Van der Merwe NC, Jansen van Rensburg E. P017 hereditary breast/ovarian cancer and BRCA mutations: A South African perspective. Curr Oncol 2009;16(5):91-110. 7. Antoniou AC, Pharoah PP, Smith P, Easton DF. The BOADICEA model of genetic susceptibility to breast and ovarian cancer. Br J Cancer 2004;91(8):1580-1590. [http://dx.doi.org/10.1038/ sj.bjc.6602175] 8. Evans DG, Lalloo F, Cramer A, et al. Addition of pathology and biomarker information significantly improves the performance of the Manchester scoring system for BRCA1 and BRCA2 testing. J Med Genet 2009;46(12):811-817. [http://dx.doi.org/10.1136/jmg.2009.067850] 9. Laitman Y, Simeonov M, Keinan-Boker L, Liphshitz I, Friedman E. Breast cancer risk prediction accuracy in Jewish Israeli high-risk women using the BOADICEA and IBIS risk models. Genet Res (Camb) 2013;95(6):174-177. [http://dx.doi.org/10.1017/s0016672313000232] 10. Anothaisintawee T, Teerawarrananon Y, Wiratkapun C, Kasamesup V, Thakkinstian A. Risk prediction models of breast cancer: A systematic review of model performances. Breast Cancer Res Treat 2012;133(1):1-10. [http://dx.doi.org/10.1007/s10549-011-1853-z] 11. Wagner TM, Moslinger RA, Muhr D, et al. BRCA1-related breast cancer in Austrian breast and ovarian cancer families: Specific BRCA1 mutations and pathological characteristics. Int J Cancer 1998;77(3):354-360. [http://dx.doi.org/10.1002/(sici)1097-0215(19980729)77:3<354::aidijc8>3.3.co;2-a] 12. National Centre for Biotechnology Information. NM_000059.3 (BRCA2): c.6761_6762delTT (p.Phe2254Tyrfs) AND Familial cancer of breast. ClinVar, 2015. http://www.ncbi.nlm.nih.gov/clinvar/ RCV000045042/ (accessed 2 November 2015). 13. Petrucelli N, Mange S, Fulbright JL, Dohany L, Zakalik D, Duquette D. To reflex or not: Additional testing in Ashkenazi Jewish individuals without founder mutations. J Genet Couns 2015;24(2):285293. [http://dx.doi.org/10.1007/s10897-014-9762-z]

Accepted 14 January 2016.

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Knowledge regarding basic concepts of hereditary cancers, and the available genetic counselling and testing services: A survey of general practitioners in Johannesburg, South Africa C van Wyk,1,2 MSc (Med) Genetic Counselling; T-M Wessels,1,3 MSc (Med) Genetic Counselling, PhD; J G R Kromberg,1 BA (Social Work), MA, PhD; A Krause,1 MB BCh, PhD ivision of Human Genetics, National Health Laboratory Service and School of Pathology, Faculty of Health Sciences, University of the D Witwatersrand, Johannesburg, South Africa 2 Current affiliation: Division of Health Sciences Education, Office of the Dean, Faculty of Health Sciences, University of the Free State, Bloemfontein, South Africa 3 Division of Human Genetics, Department of Pathology, Faculty of Health Sciences, University of Cape Town, South Africa 1

Corresponding author: C van Wyk (vanwykc2@ufs.ac.za) Background. In families with hereditary cancer, at-risk individuals can benefit from genetic counselling and testing. General practitioners (GPs) are ideally placed to identify such families and refer them appropriately. Objective. To assess the practices, knowledge and attitudes of GPs regarding common hereditary cancers. Methods. An exploratory research design was used. An existing questionnaire was adapted, piloted and mailed to 196 GPs in Johannesburg, South Africa. The 61 GPs (31.1%) who completed and returned the questionnaire constituted the final sample. Data were analysed using descriptive statistics. Results. The GPs obtained some information on cancer family history from their patients, but not enough to assess the risks. Altogether 22 (36.1%) of the GPs referred patients to appropriate facilities for assessment and testing, while 32 (52.5%) were aware of genetic testing services. Most (38/61, 62.3%) were not familiar with the genetic counselling facilities available, but they felt patients should have counselling before testing. Less than half knew about possible paternal inheritance, or the low rate of hereditary mutations and their penetrance. Overall, the majority of GPs (53/61, 86.9%) were interested in learning more about cancer genetics and available services, and they expected to play an increasing role in the field in the future. Conclusions. Many of the GPs in this study had limited knowledge about inherited cancers, cancer risk management and genetic services. Appropriate education needs to be increased so that they are better equipped to identify and refer families at risk. S Afr Med J 2016;106(3):268-271. DOI:10.7196/SAMJ.2016.v106i3.10162

In the past decade the genetic contributions to cancer syndromes have become clearer[1] and about 500 familial cancer syndromes have been described (a comprehensive list can be found at http://www. familialcancerdatabase.nl/).[2] Recognition of cancer susceptibility in a family can enable individuals at risk to seek cancer genetic counselling. The aims of such counselling are to: (i) assess family histories in detail; (ii) estimate the risk of developing the familial cancer; (iii) provide information so that informed decisions about testing, surveillance and prophylactic surgery can be made; and (iv) offer support in partnership with attending healthcare professionals.â&#x20AC;&#x201A;[1] This service is available in South Africa (SA) to persons who have a family history of cancer and their at-risk family members. The Division of Human Genetics, National Health Laboratory Service (NHLS), School of Pathology, Faculty of Health Sciences, University of the Witwatersrand (Wits), Johannesburg, and several other departments of human genetics throughout SA offer cancer genetics services. The first steps in determining whether a hereditary cancer syndrome is present in a family are to gather detailed family, medical, and lifestyle histories and to obtain details of cancer sites and histological features of the tumours.[1] Primary healthcare providers, in particular general practitioners (GPs), often have first-level contact with patients and are therefore ideally placed to identify individuals

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Table 1. Medical and family history clues that can indicate whether an individual or family is at increased risk for a hereditary cancer (after Lalloo et al.[1]) Two or more first- and/or second-degree relatives with the same cancer Several first- and/or second-degree relatives who have related types of cancer Two members in the family with the same rare cancer Two members in the family with related rare cancers Early age of onset for the specific cancer type (e.g. <50 years for breast cancer) Bilateral cancer Multifocal tumours More than one type of associated cancer in one individual Specific cancers in high-risk population groups (e.g. Afrikaner or Ashkenazi Jewish)

and families who may be at risk for an inherited cancer syndrome, and refer them appropriately to cancer genetic services.[3] Guidelines for identifying individuals and/or families at risk for an inherited cancer are available, and they are summarised in Table 1. Studies in the USA[4] and Europe[5] have explored the knowledge of primary healthcare physicians, including GPs, regarding cancer genetics. The findings showed that they had limited knowledge of

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cancer genetic conditions and services, but other studies showed that physicians accepted that they had an increasing role to play in referring to such services.[6,7] Since more genetic tests for hereditary cancers are becoming available, and public awareness is increasing, the demand for cancer genetic services could also increase substantially. [6] GPs as well as other healthcare professionals therefore need to understand the general principles of cancer genetics[4] so that they are able to identify individuals and families at risk and refer them for cancer genetic counselling.

Table 2. Demographic characteristics of the respondents (N= 61) n (%) Age (years) 30 - 39

14 (23.0)

40 - 49

22 (36.1)

50 - 59

11 (18.0)

60 - 69

14 (23.0)

Primary qualification Bachelor of Medicine and Surgery

To investigate, among GPs in Johannesburg, their current knowledge regarding three common hereditary cancers (hereditary breast and ovarian cancer (HBOC), Lynch syndrome/hereditary non-polyposis colorectal cancer (HNPCC) and familial adenomatous polyposis (FAP)), their management of patients who could be at risk, and their attitudes towards learning more about inherited cancers and the relevant services.

Methods

A quantitative, exploratory research design was selected, as it was most suitable for the study. The research sample was obtained from a list of GPs held by the Department of Family Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand. These GPs were all in private practice and were involved in part-time teaching of postgraduate medical students pursuing higher degrees or diplomas. Altogether 196 GPs were approached (all those listed). The research tool was a modified structured self-administered questionnaire. The original questionnaire was designed by Wideroff et al.[4] in the USA and used in this study with Dr Wideroff ’s permission. SA has a unique combination of ethnic groups, and a few changes were made to the questionnaire to make it suitable for the local situation. The questionnaire was tested in a pilot study on five subjects (private GPs in a multipractice setting in Johannesburg) and minor amendments were made. A research recruitment package was then compiled and posted to the 196 listed GPs. The package contained an information sheet describing the study, the questionnaire, a consent sheet, and separate self-addressed envelopes (one for the completed questionnaire and the other for the response sheet, in order to ensure the anonymity of the GPs) and a covering letter. The GPs were given 4 weeks to complete and return both the questionnaire and the consent sheet, after which a followup recruitment package was sent to non-responders. Seventy questionnaires were returned, including 61 completed questionnaires (round 1 = 26, round 2 = 35), one blank, and eight returned by the post office owing to incorrect addresses or for other unknown reasons. Data were collected between March and August 2005. The responses from the completed questionnaires were entered into an Excel database and analysed using descriptive statistics and t-tests. Ethical approval for the study was provided by the Human Research Ethics Committee (Medical), Faculty of Health Sciences, University of the Witwatersrand (reference number M070219, 7 March 2005).

Degrees: BSc, BSc Hons, BPharm

8 (13.1)

Diplomas: DA, DCH

21 (34.4)

Average number of patients seen per week

110

Average hours per week spent in practice

to Neuman,[9] a response rate of 31% is considered reasonable for a postal survey. The sample of GPs was affiliated with the University of the Witwatersrand and may have been relatively more inclined/ willing to participate in the research project. The demographic details of the respondents are given in Table 2. The GPs estimated that they saw an average of 110 patients (more females (60/110, 54.5%) than males (50/110, 45.5%)) a week, and they worked on average 45 hours per week (range 7 - 72 hours). Forty-five (45/67, 67.2%) of the GPs had a limited family history of cancer themselves. About half of them (32/61, 52.5%) reported that they worked in a multiple practice setting with between 2 and 10 partners.

Family history information, risk assessment management and referral

The GPs stated that they gathered some medical and cancer history on new patients (Fig. 1). Significantly more GPs collected informa tion on their patients (100.0%) and on the patients’ first-degree relatives (93.4%) than on their second-degree relatives (73.8%; p<0.001) or ages at cancer diagnosis (72.1%; p<0.001). However, the GPs were found to make use of several cancer screening procedures including mammography (98.4%), clinical breast examination (95.1%), prostate-specific antigen measurement (91.8%), Pap smears (86.9%), faecal occult blood tests (67%), abdominal ultrasound (60.7%) and CA-125 marker tests (57.4%). About half (34/61, 55.7%) of the respondents stated that some of their patients enquired about the possibility of an increased cancer risk. Overall, 24.6% (15/61) reported that they assessed their patients’ risk of having a hereditary cancer; however, they were not asked to describe how they assessed these risks. The 120.0 100.0

Yes

100.0

73.8

80.0

A total of 61/196 GPs completed and returned the questionnaire, giving a final response rate of 31.1%. A review of published research with a focus on mail survey research concluded that response rates can vary from 2.5% to 97.7%, depending on the study.[8] According

269

72.1

60.0 40.0

0.0

The sample

93.4

26.2

20.0

Results

61 (100.0)

In addition to Bachelor of Medicine and Surgery

Responses, %

Objective

0.0 Patient

27.9

6.6 FDR

SDR

Age of CA diagnosis

Medical and cancer history taken

Fig. 1. Information collected from patients regarding cancer in the family. (FDR = first-degree relatives; SDR = second-degree relatives; CA = cancer.)

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remainder (75.4%, 46/61) were unsure how to perform such risk assessments. Twenty-two GPs (36.1%) referred patients for cancer genetic counselling. Of this group, 54.5% (12/22) referred patients to the Clinical and Counselling Section in the Division of Human Genetics, NHLS/Wits, while 45.5% (10/22) referred patients to other facilities that do not have trained genetic counsellors and medical geneticists.

Knowledge about genes and genetic testing for cancer

When asked about available testing, more participants knew about the tests for breast cancer than about those available for colon cancer (Table 3). About a third (18/61) of GPs correctly responded that <10% of females with breast and ovarian cancer are at risk of carrying a known BRCA1/2 gene mutation. Only 27/61 (44.3%) knew that a breast cancer mutation can be inherited from the paternal side. Further, only 4.9% (3/61) correctly responded to a question about the penetrance of HNPCC mutations (i.e. that penetrance is about ≥50%). Most of the GPs (57/61, 83.4%) thought that patients should have genetic counselling before having genetic testing, while many (39/61, 63.9%) expected that the numbers of patients undergoing cancer genetic testing would increase in the future and that they would be involved in the testing process. All the GPs (61/61, 100%) agreed that a genetic counsellor is the most qualified professional to provide genetic counselling to patients, followed by a medical geneticist (52/61, 85.2%) and an oncologist (42/61, 68.9%). Most (40/61, 65.6%) believed that they themselves were not sufficiently qualified and equipped to provide genetic counselling for hereditary cancers.

Attitudes regarding continuing medical education in cancer genetics

Most GPs (57/61, 93.4%) who participated in this study believed that genetic counselling should be offered prior to testing. Furthermore they reported being interested in learning more about hereditary cancers and becoming more involved in referring at-risk patients appropriately (53/61, 86.9%). The majority (60/61, 98.4%) of GPs believed that there was a need for guidelines on cancer genetics. They felt that continuing medical education sessions (53/61, 86.9%), discussions with their colleagues (50/61, 82.0%), guidelines from government, societies and agencies (50/61, 82.0%) and data published in scientific journals (54/61, 88.5%) were important resources from which they could learn more about cancer genetics.

Discussion

This is the first published study exploring the practice, knowledge and attitudes of GPs in SA regarding their knowledge of hereditary cancer and genetic counselling and testing. Although this was a small study, the knowledge and attitudes of the cohort were similar to those reported from similar surveys of GPs and specialists in other parts of the world.[4-7] A study by Nippert et al.[10] showed that Table 3. GPs’ (N=61) knowledge about genetic testing services for specific cancer genes associated with three of the most common inherited cancer syndromes Inherited cancer syndrome

Associated genes

Testing available, n (%)

HBOC

BRCA1 and BRCA2

28 (45.9)

Lynch syndrome/HNPCC

hMSH2 and hMLH1

8 (13.1)

FAP

APC

9 (14.8)

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confidence on the part of participating physicians in their ability to carry out basic medical genetics tasks was low. The key to identifying individuals at risk for an inherited cancer is to assess their family history carefully,[1] so that responses can be provided to the items presented in Table 1. The results of the present study showed that 26.2% (16/61) of the GPs did not collect a sufficiently comprehensive family history, which should include second-degree family members and the age of cancer onset in affected individuals. Partial family history information would limit a GP’s ability to assess the risks for an inherited cancer susceptibility. These findings support those reported in two studies in the USA on taking, interpreting and assessing cancer family history by family physicians.[11,12] These studies further found that family physicians lack confidence and available time to assess and communicate hereditary cancer risks. In the current study, 75.4% of GPs were not certain of how to assess their patients’ risks for a hereditary cancer and few (36.1%) referred patients to appropriate cancer genetic services. This finding suggests that GPs are not equipped with the correct knowledge and tools to assess their patients’ risks for hereditary cancers, and many are unaware of the available cancer genetic services. A suggested solution could be to create appropriate risk assessment and referral guidelines similar to those of the National Institute for Health and Care Excellence (NICE) in the UK[13] for use in the SA situation. These guidelines should enable healthcare professionals to identify patients at risk and refer them appropriately for more advanced risk assessment, cancer genetic counselling and possibly genetic testing. An assessment of the GPs’ knowledge about key cancer genetic concepts and genetic testing for HBOC, HNPCC and FAP showed an overall better understanding of HBOC. A possible explanation is that HBOC is more common and has probably had more media coverage than other cancer syndromes.[14] About a third of the GPs understood that 5 - 10% of breast and/or ovarian cancers are inherited, and 44.3% knew that the BRCA genes causing HBOC can be inherited from the paternal line. These findings were very similar to those reported by Wideroff et al.,[4] who investigated HBOC, HNPCC and FAP genetic knowledge in a national sample of US physicians. The penetrance of HNPCC genes is ≥50% (i.e. only about half the individuals who carry the gene will show signs and symptoms). In the present study only 5% of GPs understood this fact correctly, compared with 13% reported by Wideroff et al.[4] Also, at the time we did our study, diagnostic testing for HBOC was available, whereas genetic testing for HNPCC and FAP is mostly only available on a research basis. Diagnostic testing, when necessary, was at the time of the study referred to reputable laboratories overseas. However, even in the absence of genetic testing individuals can benefit from genetic counselling, so that they understand their risks and make informed choices about management and future options. It is strongly recommended that patients have genetic counselling prior to any genetic testing. A genetic counsellor can assess risks, empower the counselee with information regarding the testing procedures, discuss the advantages and limitations of the tests, and promote informed choices, as well as provide empathic emotional support throughout the whole process.[15] A very positive finding was that the GPs understood this recommendation, and 93.4% (57/61) agreed that patients should have genetic counselling prior to genetic testing. Fry et al.[6] found that many GPs in Edinburgh, UK, did not feel equipped to counsel patients about cancer risks. These findings support those reported in the current study, where 65.6% of GPs reported that they did not feel qualified or equipped to provide cancer genetic counselling for hereditary cancers. Another study

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in the USA investigated possible reasons why GPs did not want to counsel patients about inherited cancers, and attributed their reluctance to time constraints.[4] However, a study by Watson et al.[7] has shown that GPs are prepared to be gatekeepers and participate in family history taking, deciding which patients to refer for genetic counselling and testing, and managing at-risk patients with a predisposition to cancer. In the current study, GPs showed interest in being more involved in providing cancer genetic services and 86.9% (53/61) wanted to learn more about specific areas of inherited cancer and the available genetic services. There is therefore a need for continuing medical education, the development of specific guidelines in the field, and articles in scientific journals. Such an awareness programme, which includes the distribution of information booklets, cancer genetics pamphlets, educational lectures and workshops, has already been initiated.

some of GPs’ educational needs. Pamphlets have been distributed, advertising services provided and workshops and talks on cancer genetics held. At the same time, medical students are receiving training, in this field, which should be of benefit in future to families with a hereditary cancer syndrome. Acknowledgements. We thank the GPs who participated in this study, the staff of the Department of Family Medicine of the University of the Witwatersrand, Prof. Bruce Sparks for assisting with the sample selection, Dr L Wideroff from the National Cancer Institute, Bethesda, USA, for permission to adapt and use her questionnaire, the Division of Human Genetics, NHLS/Wits for funding for the project, and Prof. Marion McAllister, University of Cardiff, Wales, for final editorial advice. References

Conclusions

The findings from this study showed GPs have limited knowledge about basic concepts of hereditary cancers and available local genetic counselling and testing services. As a result, at-risk patients and their families may not be identified or referred for specialist care and management. Fortunately, however, GPs are interested in learning more about hereditary cancers and in becoming more involved in referring at-risk patients appropriately. It has been suggested that public awareness about the rapid advances in cancer genetics and inherited cancer syndromes would increase the demand for cancer genetic services and testing.[16] Within the past 10 years the numbers of breast, ovarian and colorectal cancer cases seen in the Division of Human Genetics in Johannesburg has increased rapidly. This demand is expected to increase even more in the future, as has occurred in other human genetics departments such as the Queensland Clinical Genetics Service in Australia. [17] It is therefore necessary to meet the educational needs of GPs by putting together and circulating informational documents and pamphlets about the common hereditary cancers, as well as referral guidelines. The NICE guidelines[13] were developed to address primary, secondary and tertiary healthcare professionals and to guide them in classifying and caring for women at risk of breast cancer. Further research involving SA’s unique population and the local healthcare system could enable the development of a similar document, which should be a quick and easy guide for all healthcare professionals. HBOC in black African patients is currently poorly understood, but local patient samples have been studied in an MSc dissertation and guidelines for identifying at-risk patients have been recommended.[18] As an outcome of the present study, the professional staff of the Division of Human Genetics, NHLS/Wits are attempting to meet

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1. Lalloo F, Kerr B, Friedman JM, Evans DGR. Risk Assessment and Management in Cancer Genetics. New York: Oxford University Press, 2006:3-12. 2. Familial Cancer Database Online. Familial cancer syndromes. 2011. http://www.familialcancerdatabase. nl/ (accessed 26 July 2015). 3. McKelvey KD Jr, Evans JP. Cancer genetics in primary care. J Nutr 2003;133(11 Suppl 1):3767S-3772S. 4. Wideroff L, Vadaparampil ST, Greene MH, Taplin S, Olson L, Freedman AN. Hereditary breast/ ovarian and colorectal cancer genetics knowledge in a national sample of US physicians. J Med Genet 2005;42(10):749-755. [http://dx.doi.org/10.1136/jmg.2004.030296] 5. Escher M, Sappino AP. Primary physicians’ knowledge and attitudes towards genetic testing for breastovarian cancer predisposition. Ann Oncol 2000;11(9):1131-1135. 6. Fry A, Campbell H, Gudmunsdottir H, et al. GPs’ views on their role in cancer genetics services and current practice. Fam Pract 1999;16(5):468-474. [http://dx.doi.org/10.1093/fampra/16.5.468] 7. Watson EK, Shickle D, Qureshi N, Emery J, Austoker J. The ‘new genetics’ and primary care: GPs’ views on their role and their educational needs. Fam Pract 1999;16(4):420-425. [http://dx.doi.org/10.1093/ fampra/16.4.420] 8. Larson PD. A note on mail surveys and response rates in logistics research. Journal of Business Logistics 2005;26(2):211-222. [http://dx.doi.org/10.1002/j.2158-1592.2005.tb00212.x] 9. Neuman WL. Social Research Methods: Qualitative and Quantitative Approaches. 7th ed. Boston: Allyn & Bacon, 2009:640. 10. Nippert I, Harris HJ, Julian-Reynier C, et al. Confidence of primary care physicians in their ability to carry out basic medical genetic tasks – a European survey in five countries – Part 1. J Community Genet 2011;2(1):1-11. [http://dx.doi.org/10.1007/s 12687-010-0030-0] 11. Tyler CV, Snyder CW. Cancer risk assessment: Examining the family physician’s role. J Am Board Fam Med 2006;19(5):468-477. [http://dx.doi.org/10.3122/jabfm.19.5.468] 12. Wood ME, Stockdale A, Flynn BS. Interviews with primary care physicians regarding taking and interpreting the cancer family history. Fam Pract 2008;25(5):334-340. [http://dx.doi.org/10.1093/ fampra/cmn053] 13. National Institute for Health and Care Excellence (NICE). 2013. http://www.nice.org.uk/ (accessed 27 September 2013). 14. Gerlach KK, Marino C, Hoffman-Goetz L. Cancer coverage in women’s magazines: What information are women receiving? J Cancer Educ 1997;12(4):240-244. PMID: 9440017. [http://dx.doi. org/10.1080/08858199709528496] 15. Resta R, Biesecker BB, Bennett RL, et al. New Definition of Genetic Counseling: National Society of Genetic Counsellors’ Task Force Report. J Genet Couns 2006;15(2):77-83. [http://dx.doi.org/10.1007/ s10897-005-9014-3] 16. Bathurst L, Huang QR. A qualitative study of GPs’ views on modern genetics. Aust Fam Physician 2006;35(6):462-464. 17. Kromberg JGR, Parkes J, Taylor S. Genetic counselling as a developing healthcare profession: A case study in the Queensland context. Aust J Prim Health 2005;12(1):33-39. [http://dx.doi.org/10.1071/ PY06006] 18. Wainstein T. Family history and risk assessment in black South African women with breast cancer. MSc (Med) dissertation. Johannesburg: University of the Witwatersrand, 2011:70. http://wiredspace. wits.ac.za/bitstream/handle/10539/11052/0611283G_TASHA%20WAINSTEIN_RESEARCH%20 REPORT_CORRECTED_FINAL_11%20.pdf?sequence=1 (accessed 1 October 2015).

Accepted 5 October 2015.

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A clinical and molecular investigation of two South African families with Simpson-Golabi-Behmel syndrome C Spencer,1,2 MB ChB, DCH, FCMG, MMed (Genet); K Fieggen,1 MB ChB, FCPaed (SA), Cert Med Genet; A Vorster,1 MSc; P Beighton,1 OMB, MD, PhD, FRCP, FRSSA 1 2

ivision of Human Genetics, Faculty of Health Sciences, University of Cape Town, South Africa D Division of Human Genetics, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa, and National Health Laboratory Service, Johannesburg

Corresponding author: C Spencer (careni.spencer@nhls.ac.za)

Background. Simpson-Golabi-Behmel syndrome (SGBS) is an X-linked recessive overgrowth syndrome manifesting primarily in boys and characterised by macrosomia, distinctive facial features and multiple congenital abnormalities. Although this rare condition is thought to be underdiagnosed, making a diagnosis is important as affected boys have a 7.5% risk of developing visceral tumours and surveillance is warranted. Mutations in GPC3 are found in up to 70% of boys affected with SGBS. Objectives. A clinical and molecular investigation of two boys with SGBS, probands B and S, and their mothers. Documentation of the clinical phenotype could assist with diagnosis in affected boys and will lead to early initiation of tumour surveillance. Methods. Hospital folders were reviewed and clinical consultations arranged for both probands and their mothers. Molecular investigations initially searched for whole-exon deletions in GPC3 followed by gene sequencing. Results. The clinical phenotype of both probands was consistent with that previously reported in the literature. The main features pointing towards the diagnosis were macrosomia, coarse facial features and macroglossia with a midline groove in the tongue. Proband B developed a Wilms tumour. He was found to have a novel mutation causing a premature stop codon. Conclusions. This research represents the first published report of SGBS in South Africa. Early recognition and confirmation of this condition is important in order to institute tumour surveillance and assist families with accurate recurrence risks. S Afr Med J 2016;106(3):272-275. DOI:10.7196/SAMJ.2016.v106i3.9476

Simpson-Golabi-Behmel syndrome (SGBS) (OMIM #312870) is an X-linked overgrowth syndrome characterised by distinctive facial features, macro somia and multiple congenital abnormalities. [1] This is a rare condition, with only about 100 molecularly confirmed cases reported in the literature.[2] The clinical picture can be difficult to distinguish from other overgrowth conditions, with which it shares many overlapping features.[3] This could lead to misdiagnosis and therefore under-reporting of SGBS. There have been no previous published reports of this condition in South Africa (SA). SGBS was originally delineated by Simpson et al.[4] in 1975, who described boys with ‘bulldog-like’ facies. However, it was only in 1988 that Neri et al.[5] coined the eponymous term ‘SimpsonGolabi-Behmel syndrome’, after the original author and those of two subsequent articles describing the same phenotype. Boys with SGBS have pre- or postnatal macrosomia. Their facial features are coarse, with hypertelorism, downslanted palpebral fissures and a broad nasal bridge.[1] They also have a prominent jaw, with macrostomia and macroglossia. A groove in the lower lip or tongue is frequently present. The nose is often short and upturned and about 25% have a cleft lip or palate.[6] Polydactyly with short, broad hands has been described.[7] Other congenital abnormalities include cardiac defects in 36% of affected boys[8] and skeletal problems such as pectus excavatum, scoliosis and vertebral abnormalities. Gastrointestinal and renal abnormalities can also occur.[1] Common urogenital malformations are undescended testes and inguinal hernias, but hypospadias and ambiguous genitalia have been reported.[9] The intellectual outcome is variable, with some individuals having normal development and

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others exhibiting developmental delay. Speech delay is diagnosed in about 50% of affected boys and motor delay in 36%.[6] Hypotonia is consistently present and structural brain abnormalities can occur.[6] Importantly, boys with SGBS have an approximately 7.5% risk of developing tumours. The spectrum of tumours observed includes Wilms tumour, hepatoblastoma, neuroblastoma, gonadoblastoma, hepatocellular carcinoma and medulloblastoma.[10] It is widely accepted that this risk is sufficient to warrant regular tumour surveillance. SGBS is inherited in an X-linked recessive manner. Males manifest the condition, whereas females are usually asymptomatic carriers. However, females can exhibit some features such as tall stature, coarse facies and occasionally intellectual disability.[1] Two adjacent genes on the X chromosome, GPC3 and GPC4, have been implicated in SGBS. GPC3 was the first gene described in patients with SGBS. Mutations in this gene have been found in up to 70% of people with the syndrome.[7,11] There are no known hotspots, and a variety of mutations ranging from deletions to point mutations can occur in any of the eight exons.[11] Recently, exon duplications have also been reported.[2] Intragenic GPC4 mutations have not been described in isolation and are usually an extension of a deletion that includes GPC3. While there has been a report of a GPC4 duplication causing SGBS in a family,[12] this duplication cannot explain the mechanism of disease. In subsequent studies no other mutations in GPC4 have been identified.[2]

Objectives

A clinical and molecular evaluation of two probands with SGBS. A description of the phenotype could assist medical professionals in SA to make the diagnosis, which in turn would lead to early initiation of tumour surveillance. Molecular testing can not only confirm a

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clinical diagnosis but also offer the option of carrier and prenatal testing to family members at risk.

Methods

Ethics approval was received from the Human Research Ethics Committee of the Faculty of Health Sciences, University of Cape Town, SA (HREC REF 072/2012). Two boys with a clinical diagnosis of SGBS attending the genetics clinic at Red Cross War Memorial Children’s Hospital in Cape Town were identified. These probands were designated B and S. Their hospital folders were reviewed for history, clinical findings and special investigations. Clinical consultations were arranged for both boys along with their mothers, and pertinent clinical features were documented. The molecular analysis was undertaken in the Division of Human Genetics, University of Cape Town. DNA was extracted from venous blood specimens for both probands and their mothers using standard methods. This DNA was analysed for whole-exon deletions and thereafter for sequence abnormalities in GPC3. The primers selected for the amplification of GPC3 coding regions were those reported in 2007 by Sakazume et al.[13] Exon 3 was analysed with two overlapping sets of primers owing to the large size of the coding region. The exons were amplified in singleplex using the polymerase chain reaction (PCR) in a 25 µL final reaction volume consisting of 100 ng template DNA, 10 pmol of each primer, 200 µM of each of the deoxynucleotide triphosphates (Bioline, UK) and 0.5 units of GoTaq DNA polymerase (Promega, USA). Following amplification of this reaction on the BioRad T100 thermal cycler (BioRad Laboratories, USA), the yield and specificity of the resulting fragments were confirmed by electrophoresis on a 1.5% (w/v) agarose gel prior to direct cycle sequencing. Sequencing for both probands and their respective mothers was performed using primers employed for the PCR, with

Fig. 1. The facial features of proband B, showing a broad nasal bridge, an upturned nose and a large, grooved tongue.

subsequent capillary electrophoresis on the 3130xl Genetic Analyser (Life Technologies, USA). The results of the sequencing reaction were analysed using SeqMan (DNASTAR, USA) software systems. The mutation found was investigated using two databases, the Leiden Open Variation Database[14] and the National Center for Biotechnology Information website.[15]

Results

Clinical features

Proband B Proband B was evaluated at the age of 5 years and 9 months. There was no family history of intellectual concerns, although a maternal cousin had a cardiac lesion and bowel problem. No further details were known. The boy is his mother’s only child. Proband B was born prematurely by vaginal delivery in the breech position. His birth weight was 2 100 g (>90th centile) and his head circumference 31 cm (>90th centile). Postnatally he required ventilation for aspiration pneumonia and had pro longed jaundice and a single episode of hypoglycaemia. Proband B demonstrated persistent over growth, all his growth parameters consis tently measuring above the 90th centile with some acceleration of his height and head circumference noted. On examination proband B had a long face with hypertelorism, epicanthic folds and an upturned nose (Fig. 1). His nasal bridge was broad. His mouth tended to be open and he had macrostomia and macroglossia with a grooved tongue and prognathism. He also had pectus excavatum and a marked lordosis. He had an atrioseptal defect with pulmo nary valve stenosis. Genitourinary malform ations including bilateral inguinal hernias,

Fig. 2. Pedigree of proband S’s family.

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undescended testes and hypospadias were noted at birth. He was subsequently found to have right-sided hydronephrosis secondary to pelvoureteric obstruction. At ~6 years of age he was diagnosed with a Wilms tumour of the left kidney. His developmental milestones had all been within the normal range, but he had been noted to be hypotonic. At the initial review his speech was still slightly difficult to comprehend, but the rest of his development was appropriate for his age. Additional investigations revealed a normal male karyotype (46,XY) and 13 pairs of ribs on the chest radiograph. Proband B’s mother was a healthy woman of normal intellect. She had been diagnosed with scoliosis during adolescence, which resolved spontaneously. She was tall, and at 1.81 cm her height plotted above the 97th centile. She had a long face with no other obvious dysmorphic features. Proband S Proband S was evaluated at 4 years and 2 months of age. As shown in the pedigree (Fig. 2), mild intellectual disability was present in the family. His mother has asthma, but was otherwise in good health during the pregnancy. Proband S had been born via normal vertex delivery at term. He had Apgar scores of 8 and 9. His birth weight was 3 200 g (10th centile) and his head circumference 33 cm (5th centile). Postnatally he was ventilated for apnoea and had phototherapy for jaundice. At the time of examination, proband S’s weight was above the 50th centile, his height above the 75th centile and his head circumference above the 95th centile, reflecting growth acceleration. He had a coarse face with hypertelorism, downslanted

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palpebral fissures, epicanthic folds and an upturned nose (Fig. 3). His tongue was protruding, macroglossic and had a central groove. He also had macrostomia. He was mildly hirsute with a low posterior hairline. Proband S had broad, short fingers with bilateral fifth-finger clinodactyly. His toes were broad and he had pes planus. He had mild lumbar lordosis. He had a patent ductus arteriosus with a patent foramen ovale that closed spontaneously. There were no genitourinary abnormalities. Abdominal examination showed hepatomegaly of 2 cm below the costal margin, which had been stable for several years. He was hypotonic and had a developmental quotient of 60, in keeping with mild intellectual disability.

Magnetic resonance imaging of his brain at 2 years of age showed atrophy and a peritrigonal white-matter high signal suggestive of a hypoxic insult at birth. A chest radiograph revealed 11 ribs on the right and 12 on the left. He had a normal male karyotype (46,XY). At the time of examination, proband S had not developed any tumours and was attending a special educational needs school. Proband S’s mother had mild intellectual disability. She was functionally independent and in employment. Her height was 176 cm (above the 97th centile). She had a long face, with a high-arched palate. The other family members with intellectual disability were not available for examination. Table 1 summarises the clinical features observed in the two probands and compares them with those frequently described in the literature.

Molecular investigations

Fig. 3. Proband S. A coarse facies, grooved tongue and macroglossia were present.

No exonic deletions were found in GPC3 of proband B or proband S. Sequencing revealed a mutation in exon 4 of GPC3 in proband B. This mutation consists of a deletion of four nucleotides, TAGA, at nucleotide position 1071, and an insertion of three nucleotides, CTT. This mutation, designated as c.1071_1074delinsCTT (Genbank accession No. NM_004484.3), causes a frameshift that results in a premature stop codon. At a protein level, this tetranucleotide deletion

Table 1. A comparison of the clinical features of the two probands with those reported in the literature[1] Clinical features

Proband B

Proband S

Macrosomia

Yes

Macrocephaly

Yes

Hypertelorism, epicanthic folds, downslanted palpebral fissures

Yes

Redundant skin over glabella

Macrostomia

Yes

Macroglossia

Yes

Midline groove lower lip or tongue

Yes

Cleft lip or palate or high, narrow palate

Macrognathia

Yes

Congenital heart disease

Yes

Conduction defects

Diastasis recti/umbilical hernia

Diaphragmatic hernia

Renal dysplasia/nephromegaly

Yes

Cryptorchidism/hypospadias

Yes

Hand anomalies

Yes

Rib anomalies

Yes

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results in a disruption of the amino acid reading frame that causes arginine to be replaced by phenylalanine at position 358, with a resulting premature stop codon at position 373, p.(Arg358Phefs*16). As this premature stop codon occurs in exon 4, the majority of the coding sequence of GPC3 is not translated. This mutation was confirmed to be present in proband B’s mother in the heterozygous state. No sequence abnormalities were found in proband S or his mother.

Discussion

There are no published data describing SGBS in SA. The two boys in this study exhibited many of the more common features described in SGBS. A limitation of this study is that both of the probands investigated were of Caucasian ancestry. The diagnosis of SGBS is not easy to make, and there is considerable overlap with the other overgrowth syndromes. Equally, the facial features may not be apparent in infants. In SA, where limited genetic testing for these syndromes is available, the clinician relies heavily on clinical presentation. Other genetic overgrowth conditions that need to be considered in the differential diagnosis of SGBS include Sotos syndrome and Weaver and Perlman syndromes. Although these syndromes share some clinical features, it is usually possible to distinguish between them. The condition that is most often confused with SGBS is Beckwith-Wiedemann syndrome (BWS). BWS is one of the more common overgrowth syndromes and is characterised by macrosomia, macroglossia and anterior abdominal wall defects. It is important to distinguish between these conditions, as they have different genetic aetiologies and prognoses. An X-linked inheritance pattern, rib malformations, nail hypoplasia, syndactyly of the second and third fingers and supernumerary nipples are indicative of a diagnosis of SGBS rather than BWS.[3] Omphaloceles are infrequently encountered in SGBS and are more suggestive of BWS. An additional distinguishing feature is that the clinical phenotype and facial features associated with SGBS tend to become more pronounced with age, whereas they tend to normalise in those affected with BWS.[3] Despite this, one should remain aware of the considerable overlap between these two conditions. Both probands in this study were diagnosed with SGBS in early childhood. Macrosomia, coarse facial features, macro glossia and a grooved tongue were the main clinical features leading to the diagnosis, supported by the cardiac and skeletal

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malformations in both boys and the genito urinary anomalies in proband B. The variability in intellectual outcome is also evident in these boys. Proband S has a family history of mild intellectual disability. His mother and his maternal aunt are similarly affected and his maternal grandfather and great-aunt were reported to have intellectual difficulties too. This inheritance pattern could be consistent with X-linked inheritance, with females showing variable clinical expression. It is, however, not the only form of inheritance possible, and multifactorial causes for intellectual disability also warrant consideration. Proband B developed a Wilms tumour. This tumour is known to be associated with SGBS. In a recent review of 63 boys with SGBS and a confirmed GPC3 mutation, only three had developed a Wilms tumour;[2] in this context, proband B represents the fourth published case. Table 2 lists examinations and investi gations recommended to monitor for tumour development. Many different mutations in GPC3 have been described as causative in SGBS. No hotspots for these mutations have been identified, but frameshift mutations and deletions have been reported on numerous occasions. All mutations associated with SGBS either remove a start codon or introduce a premature stop codon. These premature stop codons invariably lead to a truncated protein with insufficient cysteine residues in the conserved cysteine motif.[11] Although the specific mutation found in proband B has not previously been reported, its effect appears to be similar to other mutations associated with SGBS. The sequence anomaly disrupts the reading frame and introduces a premature stop codon, resulting in the majority of the protein not being translated. The databases investigated for this mutation confirmed that it is novel. Proband B’s mother was found to be heterozygous for this mutation. Accurate counselling regarding the recurrence risk for future pregnancies is now possible. In any future pregnancy, a male fetus will have a 50% chance of being affected with SGBS and a female fetus will have a 50% chance of being a carrier of this mutation. Antenatal diagnosis will be available to the mother should she want to pursue this option, following confirmation of the results in a diagnostic laboratory.

Table 2. Recommended tumour surveillance protocol[1]

0 - 4 years

Physical examination

Abdominal ultrasound

Alphafetoprotein and βHCG

Urinary catecholamines VMA and HVA

Chest radiograph

3-monthly

3 - 4-monthly

4-monthly

Annually

4 - 7 years

4-monthly

3 - 4-monthly

6-monthly

Annually

>7 years

Biannually

Annually

βHCG = beta-human chorionic gonadotrophin; VMA = vanillylmandelic acid; HVA = homovanillic acid.

Testing of male offspring in infancy is another option. Testing of a minor would be ethically justified, as the result would have a direct impact on management with tumour surveillance. Cascade screening and genetic counselling have also been offered to proband B’s family. No mutation was identified in proband S, even though mutations in GPC3 are present in up to 70% of individuals with SGBS.[7,11] This could be because a gene other than GPC3 is responsible for his condition. GPC4 is such a candidate owing to the discovery of a duplication; however, since subsequent studies have failed to identify point mutations, other as yet unidentified genes should be considered. Equally, disruption of GPC3 could have been caused by a mechanism not examined in this study, such as splicing variations or intronic alterations. There have also recently been reports in the literature of exon duplications in GPC3 causing SGBS. [2] This abnormality would not have been identified by the methods used in this study and represents a limitation of this research. It is also possible that proband S does not have SGBS, but in fact another genetic condition. Nevertheless, based on his history and clinical features we believe that SGBS remains the most likely diagnosis.

Conclusions

This article represents the first published description of SA patients with SGBS, an underdiagnosed syndrome. The implications of a diagnosis of SGBS relate not only to the clinical diagnosis and recurrence risk in the family, but also to the predisposition for developing tumours. Acknowledgements. This research was funded by the National Research Foundation of South Africa (PB). The authors thank Prof. R Ramesar, the genetic nurses and all the staff in the Division of Human Genetics, University of

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Cape Town, and in particular the patients and parents involved in the research. References 1. Golabi M. Simpson-Golabi-Behmel syndrome type 1 – GeneReviews – NCBI Bookshelf 2011 (updated 23 June 2011). http://www.ncbi.nlm.nih.gov/books/NBK1219/ (accessed 24 August 2015). 2. Cottereau E, Mortemousque I, Moizard M, et al. Phenotypic spectrum of Simpson-Golabi-Behmel syndrome in a series of 42 cases with a mutation in GPC3 and review of the literature. Am J Med Genet C Semin Med Genet 2013;163C(2):92-105. [http:// dx.doi.org/10.1002/ajmg.c.31360] 3. Knopp C, Rudnik-Schoneborn K, Zerres K, Gewncik M, Spengler S, Eggerman T. Twenty-one years to the right diagnosis – clinical overlap of Simpson-Golabi-Behmel and Beckwith-Wiedemann syndrome. Am J Med Genet 2015;167A(1):151-155. [http:// dx.doi.org/10.1002/ajmg.a.36825] 4. Simpson JL, Landey S, New M, German J. A previously unrecognised X-linked syndrome of dysmorphia. Birth Defects Orig Art Ser 1975;11(2):18-24 5. Neri G, Marini R, Cappa M, Borrelli P, Opitz JM. SimpsonGolabi-Behmel syndrome: An X-linked encephalo-trophoschisis syndrome. Am J Med Genet 1988;30(1-2):287-299. [http://dx,doi.org/10.1002/ajmg/a.36317] 6. Mariani S, Iugheti L, Bertorelli R, Coviello D, Pelligrini M, Forabosco A. Genotype/phenotype correlations of males affected by Simpson-Golabi-Behmel syndrome with GPC3 gene mutations: Patient report and review of literature. J Pediatr Endocrinol Metab 2003;16(2):225-232. [http://dx.doi. org10.1515/JPEM.2003.16.2.225] 7. Neri G, Gurreiri F, Zanni G, Lin A. Clinical and molecular aspects of the Simpson-Golabi-Behmel syndrome. Am J Med Genet 1998;79(4):279-283. [http://dx.doi.org/10.1002/ ajmg.a.36317] 8. Lin A, Neri G, Hughes-Benzie R, Weksberg R. Cardiac anomalies in the Simpson-Golabi-Behmel syndrome. Am J Med Genet 1999;83(5):378-381. [http://dx.doi.org10.1002/ (SICI)1096-8628(19990423)83:53.3.CO;2-1] 9. Griffith C, Probert R, Vance G. Genital anomalies in three male siblings with Simpson-Golabi-Behmel syndrome. Am J Med Genet 2009;149A(11):2484-2488. [http://dx.doi.org/10.1002. ajmg.a.33047] 10. Yalchelevich N. Generalised overgrowth syndromes with prenatal onset. Curr Probl Pediatr Adolesc Health Care 2015;45(4):97-111. [http://dx.doi.org/10/1016/j.cppeds.2015.02.005] 11. Veugelers M, de Cat B, Muyldermans S, Reekmans G, Delande N, Frints S. Mutational analysis of the GPC3/GPC4 glypican gene cluster on Xq26 in patients with Simpson-Golabi-Behmel syndrome: Identification of loss-of-function mutations in the GPC3 gene. Hum Mol Genet 2000;9(9):1321-1328. [http:// dx.doi.org/10.1093/hmg/9.9.1321] 12. Waterson J, Stockley T, Segal S, Golabi M. Novel duplication in glypican-4 as an apparent cause of Simpson-Golabi-Behmel syndrome. Am J Med Genet 2010;152A(12):3179-3181. [http:// dx.doi.org/10.1002/ajmg.a.33450] 13. Sakazume S, Okamoto N, Yamamoto T, Kurosawa K, Numabe H, Ohashi Y. GPC3 mutations in seven patients with SimpsonGolabi-Behmel syndrome. Am J Med Genet 2007;143A(15):17031707. [http://dx.doi.org/10.1002/ajmg.a.31822] 14. Fokkema IF, Taschner PE, Schaafsma GC, Celli J, Laros JF, den Dunnen JT. LOVD v.2.0: The next generation in gene variant databases. Hum Mutat 2011;32(5):557-563. [http://dx.doi. org/10.1002/humu.21438] 15. National Center for Biotechnology Information. http://www. ncbi.nlm.nih.gov/gene/2719 (accessed 10 September 2015).

Accepted 13 October 2015.

RESEARCH

Alpha-thalassaemia trait as a cause of unexplained microcytosis in a South African population S B Loonat,1 MT (Haem), MSc; N H Naran,2 PhD; S L Thein,3 MBBS, FRCP, FRCPath, DSc; N A Alli,1 MB BCh, FCPath (Haem) epartment of Molecular Medicine and Haematology, School of Pathology, University of the Witwatersrand and National Health D Laboratory Service, Johannesburg, South Africa 2 Department of Chemical Pathology, School of Pathology, University of the Witwatersrand and National Health Laboratory Service, Johannesburg, South Africa 3 Department of Molecular Haematology, King’s College London, UK 1

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

Background. Red cell microcytosis is a common abnormality detected in a full blood count, which often prompts clinicians to investigate further for a cause. In the absence of iron deficiency and anaemia of chronic disease, the differential diagnosis includes β-thalassaemia trait and α-thalassaemia trait. Methods. We investigated the contribution of α-thalassaemia trait in South African subjects with unexplained microcytosis. Iron studies, haemoglobin subfractionation and multiplex polymerase chain reaction (PCR) analysis for α-globin gene deletions were performed on 97 controls and 86 patients. Results. After excluding iron deficiency, anaemia of chronic disease and β-thalassaemia trait, 78.0% of subjects with unexplained micro cytosis were confirmed on PCR analysis to have α-thalassaemia trait. Conclusion. Alpha-thalassaemia trait accounts for the majority of unexplained microcytosis. S Afr Med J 2016;106(3):276-279. DOI:10.7196/SAMJ.2016.v106i3.10005

Microcytosis, with or without red cell hypochromia, is a common abnormality detected in a full blood count (FBC) and often prompts clinicians to investigate further for a cause. The differential diagnosis of microcytic and hypochromic red cell indices includes iron deficiency anaemia, anaemia of chronic disease, α- or β-thalassaemia trait, and sideroblastic anaemia. In the absence of iron deficiency and chronic disease, clinicians often request a haemoglobinopathy screen to exclude thalassaemia. Whereas heterozygous β-thalassaemia is readily identified through an increased haemoglobin (Hb)A2 level using Hb separation techniques, without DNA analysis α-thalassaemia trait remains a diagnosis of exclusion. Although HbH inclusions are occasionally observed on incubated reticulocyte preparations in two-gene deletion α-thalassaemia, the majority of α-thalassaemia traits remain undetected through routine laboratory methods. In a quest to distinguish iron deficiency from thalassaemia trait, several formulae utilising red cell indices from a routine FBC have been proposed.[1] These serve as good screening tools, but are unable to distinguish between α- and β-thalassaemia. Since definitive exclusion of α-thalassaemia can only be obtained through molecular characterisation of the α-globin gene, the most logical diagnostic approach for unexplained microcytosis would be to use polymerase chain reaction (PCR) analysis to detect the common α-globin gene deletions. In this study we employed a multiplex PCR assay designed to detect the seven most common α-thalassaemia deletions.[2,3]

Methods

Patients and controls

Patient samples were selected from routine specimens received for FBC analysis at the Chris Hani Baragwanath Academic, Charlotte Maxeke Johannesburg Academic and Helen Joseph Hospital

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laboratories in Johannesburg, South Africa. A total of 100 patient samples were collected over a period of 36 months, of which 86 fulfilled the criteria for unexplained microcytosis, as defined below.

Inclusion criteria

Inclusion criteria were: (i) microcytosis with a mean cell volume (MCV) <81 fl; (ii) mean cell haemoglobin (MCH) <27 pg; (iii) normal/borderline serum iron studies (ferritin 30 - 400 µg/L (male), 15 - 150 µg/L (female), and serum iron 9 - 30 µmol/L); and (iv) normal/decreased HbA2 level (normal 2.4 - 3.7%). Control samples (N=146) were obtained from volunteer staff members (aged >18 years). Those with normal FBCs and iron profiles were enlisted as controls. Among the 146 control subjects, 49 had microcytosis and were therefore excluded from the control group.

Analysis

The following tests were performed on the control and patient groups: 1. FBC and reticulocyte count (automated Sysmex XE 5000, analyser; Sysmex Incorporated, Japan), blood smears for microscopy (automated Sysmex 1000i slide maker and stainer; Sysmex Incorporated, Japan), and reticulocyte preparation for microscopy (2-hour incubation with 1% Brilliant Cresyl Blue supravital stain; National Health Laboratory Service, South Africa). 2. Serum iron studies including serum iron, serum ferritin, serum transferrin and percentage saturation (Cobas analyser; Sysmex Incorporated, Japan) using the ferrozine method without deproteinisation for serum iron, and immunological agglutination principle for transferrin and ferritin). The percentage saturation was calculated using the serum iron and transferrin levels. 3. Relative quantification of the Hb subtypes. This was obtained using cation exchange high-pressure liquid chromatography (HPLC) (Bio-Rad D10 analyser; Bio-Rad Laboratories, USA).

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All abnormal results on HPLC were con firmed with alkaline and acid pH Hb electrophoresis (HYDRASYS system, Sebia-Norcross; SEBIA-INC, USA) 4. Multiplex PCR was performed as des cribed by Chong et al.[3] DNA was extrac ted using a High Pure PCR preparation kit (Roche Diagnostics, Germany).

Alpha-thalassaemia PCR methodology

On initial set-up the PCR reaction for each genotype was optimised individually (Table 1), and then adapted for all seven genotypes in a multiplex system with the respective sets of primers. The volumes referred to in Table 1 are for a single PCR reaction. The conditions of the cycler were programmed as follows: PCR reaction initiated at 95°C for 10 minutes followed by 35 cycles, each comprising: (i) denaturation step → 45 seconds at 97°C; (ii) annealing step → 90 seconds at 61°C; and (iii) initial elongation step → 72°C for 90 seconds. A final elongation step then followed the 35 cycles at 72°C for 5 minutes. The deletions were detected through separation of the PCR products by electro phoresis on a 1.5% agarose gel (stained with ethidium bromide). The bands were visualised and photographed under ultraviolet transillumination, and identified using known controls (complements of AS Tan, Department of Paediatrics, National University of Singapore, and SL Thein, King’s College London Hospital, UK). A 1 kb DNA marker was included in each run (Figs 1 and 2).

Table 1. PCR master mix for single-tube multiplex PCR of common α-thalassaemia deletions Reagent

1 tube volume

Final concentration

2 × Qiagen Master mix*

25 mL

1 × 1.5 mM MgCl2

Multiplex Primer mix

3.5 mL

10 mM

Bovine serum albumin

2.0 mL

20 mM

Q-Solution

7.5 mL

Sterile water

7.0 mL

For blank add purified water/patient or control DNA (100 ng/mL)

5.0 mL

Total

50.0 mL

Not added to master mix

*Contains HotStarTaq DNA polymerase, multiplex PCR buffer, deoxynucleotides (dNTPs) mix and 1 mM MgCl2.

Table 2. Haematological results in patients and controls, mean (SD) Parameter

Patients (N=86)

Controls (N=97)

p-value

Hb (g/L)

12.9 (2.35)

14.3 (1.28)

<0.0001

MCV (fl)

73.6 (7.06)

87.8 (4.53)

<0.0001

MCH (pg)

23.8 (3.08)

30.3 (1.88)

<0.0001

RDW

16.1 (4.13)

13.3 (0.89)

<0.0001

HbA2

2.47 (0.63)

2.80 (0.67)

0.0027

Lis 1 control 2503 bp

Statistical analysis

Statistical analysis was carried out using the Statistical Analysis System (SAS) program, version 9.1 (North Carolina State University, USA). The Wilcoxon two-sample test was used to analyse the haematological and biochemical parameters between the patient and control groups. Fisher’s exact test was used to calculate the frequency of the genotypes and the percentage differences in the population groups.

Results

All patients and control subjects were adults, with mean ages for the two groups of 34.5 (standard deviation (SD) 14.5) and 36.4 (SD 12.7) years, respectively. The gender split showed male/female ratios of 0.45 and 0.46 in the patient and control groups, respectively. Ethnic groups were determined as per hospital classification. In the patient group, blacks, Indians and whites comprised

Lane 2. Lane 3. Lane 4. Lane 5.

GeneRuler 100 bp Plus DNA Ladder Blank. αα/– –FIL deletion(1166 bp) αα/– –SEA deletion(1349 bp) αα/– –MED deletion(807 bp)

Lane 6.

αα/– –20.5 deletion(1007 bp)

Lane 1.

Lane 7.

αα/–α4.2 deletion(1628 bp)

Lane 8. Lane 9. Lane 10. Lane 11.

αα/–α3.7 deletion(2022 bp) αα/αα normal(control) αα/αα normal(control) GeneRuler 100 bp Plus DNA Ladder

Fig. 1. PCR gel with known positive controls showing six common α-thalassaemia deletions including αα/––FIL deletion (lane 3).

51.1%, 40.7% and 8.1%, respectively. There were two subjects of mixed ancestry, who were incorporated into the black group for analysis. A similar distribution was noted in the control group, where blacks, Indians and whites comprised 54.6%, 28.8% and 16.4%, respectively.

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Haematological parameters including Hb, MCV, MCH, RDW (red cell distribution width) and HbA2 were significantly lower in the patient group than in the control group (p<0.05) (Table 2). Transferrin and ferritin levels showed no significant difference between the patient

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Lis 1 control 2503 bp

Lane 1. Lane 2. Lane 3. Lane 4.

Blank. –α3.7/– –SEA deletion αα/– –SEA (control) GeneRuler 100 bp Plus DNA Ladder

αα/–α4.2 deletion αα/–α3.7 deletion –α3.7/–α4.2 deletion (control) αα/αα negative (control)

Lane 5. Lane 6. Lane 7. Lane 8.

Fig. 2. PCR gel showing –α3.7, –α4.2 and –αSEA genotypes from the patient group.

Table 3. Breakdown of positive, negative and indeterminate results in each population group Population group

Total patient group, N

Positive PCR, n

Negative PCR, n

Indeterminate PCR, n

Black

Indian

White

Total

Table 4. Breakdown of positive, negative and indeterminate results in each population group Population group

Total positives, N

αα/–α3.7, n

αα/–α4.2, n

–α3.7/–α4.2, n

–α3.7/–αSEA, n

Black

Indian

White

Total

and control groups. Serum iron levels, however, displayed a statistically significant difference (p=0.0441) between patients and controls, but these values were within normal limits (>10 µmol/L). Multiplex PCR for detecting the seven common deletional α-thalassaemia variants was performed in all patient and control subjects (Figs 1 and 2). Of a total of 86 in the patient group, 64 (78.0%) tested positive for α-thalassaemia. The prevalences in the black, Indian and white population groups were 80.0%, 85.3% and 37.5%, respectively. There were four indeterminate results,

which were excluded from analysis. This left 18 subjects (22.0%) for whom the cause of the microcytosis remains unexplained (Table 3). Multiplex PCR analysis on control subjects yielded negative results. The breakdown of the various α-thalass aemia genotypes encountered in the study group is detailed in Table 4. The most common α-thalassaemia genotype was –α3.7, which accounted for 92.1%, whereas the –α4.2 genotype accounted for 4.7% of the total number of positive results. In addition, two subjects had a double heterozygous genotype, viz.–α3.7/–α4.2 and –α3.7/––SEA.

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The subject with the –α3.7/––SEA mutation was of Malaysian descent with HbH disease and was incorporated into the Indian group for analysis. Hb separation revealed seven subjects with sickle cell disease, of whom five had α-thalassaemia on PCR.

Discussion

Red cell microcytosis and hypochromia are commonly encountered in the clinical setting. Differentiating between the causes of microcytosis (with or without hypochromia) poses a challenge to clinicians. Not only does an accurate diagnosis allow for appropriate management and counselling, it also has therapeutic implications, particularly with regard to unnecessary iron therapy. Iron deficiency and chronic disorder remain the leading causes of microcytosis, followed by α-thalassaemia variants caused by deletion of α-globin gene/s, which is the most frequent haemoglobinopathy globally. [4] More than 40 different deletional variants of α-thalassaemia have been described.[5] Globally, the majority of α-thalassaemia is caused by the seven deletions tested for in this study.[2] Of 86 subjects in the patient group, 78.0% tested positive for α-thalassaemia PCR, which leaves 22.0% for whom the cause of the microcytosis remains unexplained. Possible reasons for a negative PCR result include: (i) the presence of α-thalassaemia deletions not tested for, such as the αα/––SA mutation,[6] and (ii) α-thalassaemia caused by non-deletional α-gene mutations, which are uncommon. Sequencing of α-globin genes would be necessary to detect non-deletional α-thalassaemia mutations, as these are not detected by Gap PCR. The most common deletional variant in this study was the αα/–α3.7 genotype (92.1%). The prevalence of the αα/–α3.7 genotype was similar in the black and Indian groups, viz. 80.0% and 85.3%, respectively. Other α-thalasaemia genotypes were uncommon, with αα/–α4.2 and αα/––SEA constituting 4.7% and 1.6% (single case), respectively. The subject with the αα/––SEA deletion had HbH disease and HbH inclusions were detected on microscopy (incubated reticulocyte preparation) in >50% of the red cell popu lation. This finding is not surprising as the patient was of Malaysian descent, a population group in which the deletion is found in high frequencies.[7] Double α-globin deletions in cis (α0) were not encountered in black subjects in our study group. This finding is not unexpected since α0 deletions are rare in the black population, which also explains the rarity of HbH disease in this ethnic group.[8-9]

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This pattern of alpha genotype distribution has been mirrored in other studies. Sankar et al.[10] reported the incidence of ––/α3.7 as the most common genotype (35.7%) in microcytic hypochromic subjects of Indian descent. In their study, other causes of microcytosis such as iron deficiency and β-thalassaemia trait were not excluded from the cohort. A Canadian group[11] yielded a PCR-positive rate of only 24.5% in their unexplained microcytosis cohort. In their study, only 29% of the population were of Asian descent (immigrants), with the remainder being of Canadian descent. Of the positive PCR results, αα/–α3.7, αα/–α4.2, αα/–αSEA and αα/–αMED comprised 81.25%, 6.25%, 10.4% and 2.0% of the total, respectively. In both the studies above, –α3.7 was the most common mutation as a cause for α-thalassaemia. In our study, of the 49 subjects excluded from the control group, 26 were confirmed to have iron deficiency and the remaining 23 tested positive for α-globin gene deletion/s. In the unadjusted control population of 120 subjects (97 normal controls + 23 controls with α-thalassaemia on PCR analysis and excluded from the control group), the extrapolated incidence of α-thalassaemia in the normal population is calculated as 19.1%. Two additional haemoglobin abnormalities were detected in the control group viz., heterozygous β-thalassaemia (in two subjects), and hereditary persistence of fetal haemoglin (HPFH) with an HbF level of 30% and pancellular distribution of HbF (in one subject). In resource-poor settings, PCR analysis may prove prohibitive for routine testing. However, if the MCV were utilised as a screening tool, a significant percentage of cases would remain unsuspected and/or undetected, a scenario that is far from ideal, particularly for prenatal and premarital screening. Multiplex PCR would offer a cost-effective solution for the detection of α-globin gene deletions.

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Conclusion

Unexplained microcytosis is a frequently encountered problem in clinical practice. In this study, α-globin gene deletions accounted for 78% of unexplained microcytosis. Twenty-two percent of cases remain unexplained, and further studies are warranted to explore the possibility of other genetic defects in the α-globin cluster. References 1. Narchi H, Basak RB. Comparison of erythrocyte indices to differentiate between iron deficiency and alpha-thalassaemias in children with microcytosis and/or hypochromia. East Mediterr Health J 2010;16(9):966-971. 2. Tan AS, Quah TC, Low PS, Chong SS. A rapid and reliable 7-deletion multiplex polymerase chain reaction assay for alpha-thalassemia. Blood 2001;98(1):250-251. [http://dx.doi.org/10.1182/blood. V98.1.250] 3. Chong SS, Boehm CD, Higgs DR, Cutting GR. Single-tube multiplex-PCR screen for common deletional determinants of alpha-thalassemia. Blood 2000;95(1):360-362. 4. Mach-Pascual S, Darbellay R, Pilotto PA, Beris P. Investigation of microcytosis: A comprehensive approach. Eur J Haematol 1996;57(1):54-61. [http://dx.doi.org/10.1111/j.1600-0609.1996. tb00490.x] 5. Cao A, Rosatelli MC, Monni G, Galanello R. Screening for thalassemia: A model of success. Obstet Gynecol Clin North Am 2002;29(2):305-328,vi-vii. [http://dx.doi.org/10.1016/S0889-8545(01)00006-7] 6. Vandenplas S, Higgs DR, Nicholls RD, Bester AJ, Mathew CG. Characterization of a new alpha zero thalassaemia defect in the South African population. Br J Haematol 1987;66(4):539-542. [http://dx.doi. org/10.1111/j.1365-2141.1987.tb01341.x] 7. Kattamis AC, Camaschella C, Sivera P, Surrey S, Fortina P. Human alpha-thalassemia syndromes: Detection of molecular defects. Am J Hematol 1996;53(2):81-91. [http://dx.doi.org/10.1002/ (SICI)1096-8652(199610)53:2<81::AID-AJH5>3.0.CO;2-#] 8. Higgs DR, Pressley L, Old JM, et al. Negro alpha-thalassaemia is caused by deletion of a single alphaglobin gene. Lancet 1979;2(8137):272-276. [http://dx.doi.org/10.1016/S0140-6736(79)90290-3] 9. Felice AE, Cleek MP, McKie K, McKie V, Huisman TH. The rare alpha-thalassemia-1 of blacks is a zeta alpha-thalassemia-1 associated with deletion of all alpha- and zeta-globin genes. Blood 1984;63(5):1253-1257. 10. Sankar VH, Arya V, Tewari D, Gupta UR, Pradhan M, Agarwal S. Genotyping of alpha-thalassemia in microcytic hypochromic anemia patients from North India. J Appl Genet 2006;47(4):391-395.[http:// dx.doi.org/10.1007/BF03194650] 11. Bergeron J, Weng X, Robin L, Olney HJ, Soulieres D. Prevalence of alpha-globin gene deletions among patients with unexplained microcytosis in a North-American population. Hemoglobin 2005;29(1):5160.[http://dx.doi.org/10.1081/HEM-47024]

Accepted 27 October 2015.

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Validation of the CoaguChek XS international normalised ratio point-of-care analyser in patients at Charlotte Maxeke Johannesburg Academic Hospital, South Africa E L Benade, MB BCh; B F Jacobson, MB ChB, MMed (Haem), FRCS (Glasg), FCPath (SA), PhD (Med); S Louw, MB BCh, FCPath (SA), MMed (Haem); E Schapkaitz, MB BCh, FCPath (SA), MMed (Haem) National Health Laboratory Service, Johannesburg, South Africa, and Department of Haematology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg Corresponding author: E Benade (estee.benade@nhls.ac.za)

Background. Measurement of the international normalised ratio (INR) is essential in the management of patients on long-term warfarin therapy. The CoaguChek XS portable coagulometer is a point-of-care test for INR measurement. It offers the advantage of improved patient accessibility, particularly in peripheral clinics. Objectives. To evaluate the clinical utility of the CoaguChek XS for monitoring of patients on standard warfarin therapy (INR 2 - 3) as well as those with mechanical heart valve replacements (INR 2.5 - 3.5). Methods. We compared the performance of the CoaguChek XS device with that of the STAGO laboratory analyser with regard to accuracy and precision in 304 patients referred for routine testing. Results. The mean INR value of the CoaguChek XS of 2.75 (standard deviation (SD) 1.18) was comparable to that of the STAGO (2.65 (SD 1.04)). The Bland-Altman difference plot revealed good agreement. Bias between the two methods was small, and the imprecision was within acceptable limits. Within the target range (2.0 - 3.5), 93.9% of the CoaguChek XS INR readings were within 0.5 units of the standard laboratory method result. There was, however, an increase in the variability of the differences between the two test methods when the INR was >3.6. Conclusion. The CoaguChek XS point-of-care device can be used to provide accurate and precise INR measurements over a wide range for monitoring of valvular and non-valvular patients on long-term warfarin therapy. S Afr Med J 2016;106(3):280-283. DOI:10.7196/SAMJ.2016.v106i3.9422

Point-of-care testing (POCT) is the fastest-growing segment of the diagnostic tests used by laboratories in the developed world. Laboratories have become increasingly involved in supporting testing at the bedside in order to improve turnaround time and reduce the cost of healthcare delivery. Measurement of the international normalised ratio (INR) is essential in the management of patients on long-term warfarin therapy, and POCT has an important role to play in this setting. Warfarin has a narrow therapeutic range, and because it is subject to numerous drug and food interactions, frequent monitoring to maintain the target INR is vital. The target INR is 2.5 (range 2.0 3.0) for most indications, including venous thromboembolic disease, non-valvular cardiac conditions including atrial fibrillation, left ventricular systolic dysfunction and mural thrombus, and in the first 3 months following anterior myocardial infarction. The target INR is 3.0 (range 2.5 - 3.5) for most patients with mechanical prosthetic valves. However, a range of 2.0 - 3.0 is recommended for low-risk patients with bileaflet mechanical valves in the aortic position. Predisposing factors for rheumatic fever persist in developing areas of southern Africa, leading to a high incidence of rheumatic valvular heart disease. An average of 1 500 patients attend the anticoagulation clinic at Charlotte Maxeke Johannesburg Academic Hospital (CMJAH), South Africa (SA), every month. Twenty-five percent of these are patients with mechanical valve replacements on lifelong anticoagulation therapy. In the developing world the question still remains whether it is safe to perform mechanical valve replacements in patients who will require lifelong anticoagulation therapy and have

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limited or no access to its monitoring. The introduction of POCT in peripheral clinics has the potential to solve this problem. There is also an opportunity for self-monitoring for patients who are able to test themselves at home and avoid taking time off from work to attend a clinic for INR testing. POCT offers other distinct advantages, including improved turnaround time for dose adjustments in the clinic setting, a small sample volume required for testing and potential long-term cost savings. The volume required for analysis is very small (8 ÎźL), making this technology particularly suitable for paediatric measurements, as blood sampling in this age group is often technically difficult. Many POC devices are commercially available. The CoaguChek XS device (Roche Diagnostics, Switzerland) is a small bench-top instrument for INR analysis, suitable for use in anticoagulation clinics. This analyser measures the prothrombin time (PT) in seconds using an electrochemical method and shows good correlation with laboratory automated coagulation analysers up to INR values of 3.0.[1,2] However, correlation studies at INR values >3.0 are limited.[3-6]

Methods

Study design and population

The study was performed in the main haematology laboratory at the CMJAH National Health Laboratory Service (NHLS) over a 3-week period. Blood samples were obtained from 304 patients attending the anticoagulation clinic at CMJAH. Blood samples for INR analysis were obtained by fingerstick testing for measurement on the CoaguChek XS and by venepuncture using citrate tubes (Becton-Dickinson, UK) for measurement on the STAGO coagulation analysers in

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the laboratory (Fig. 1). Citrate samples of adequate volume (>4 mL) received within 2 hours of collection were included. Samples (n=4) processed on the CoaguChek that yielded error results were excluded from the final analysis. The study was approved by the University of the Witwatersrand Human Research Ethics Committee (M130468), and informed consent was obtained from the patients.

Study protocol

This validation was performed in acc ordance with the International Council for Standardisation in Hematology 1993, and using the method comparison from the Clinical and Laboratory Standards Institute (CLSI EP9-A2, USA). For the method comparison study, a prospective, side-byside comparative study of the CoaguChek XS against the STAGO (Roche Diagnostics, Switzerland) automated coagulation analyser was performed. INR measurement was done on 304 adult patient samples. The samples were analysed sequentially by a dedicated phlebotomist on the CoaguChek XS and by a technologist on the STAGO coagulation analyser using the respective instruments’ standard operating procedures including adequate performance of internal quality control material (Fig. 1). For the analysis, whole blood collected by capillary sampling was placed on a Coagu Chek XS specific test strip. The strips contain recombinant human thromboplastin with an international sensitivity index (ISI) of 1.0. The PT was converted to an INR using the ISI value. A result is obtained within a minute and requires a sample volume of only 8 μL. Within-run precision evaluation was per formed with the normal reference control material analysed 20 times. Acceptable imprecision limits were determined from the manufacturer’s within-run precision data.

Warfarin dosage and INR measurements

Clinical utility was assessed by two methods. Firstly, clinical agreement was measured by discrepant INR measurements resulting in different warfarin dosage adjustments in accordance with the SA guidelines. [7] Warfarin dosage adjustments were made by dedicated nursing sisters at the anti coagulation clinic based on the venous plasma laboratory INR method. Secondly, published criteria for ‘expanded’ and ‘narrow’ clinical agreement were also assessed.[2] ‘Expanded’ agreement was achieved if the CoaguChek XS and lab oratory INR results both fell within one of the three different INR ranges, namely

• Venepuncture for formal INR testing using standard laboratory method • Patients aged >18 years, given information sheet in waiting area Patients presenting to the CMJAH PI clinic for INR monitoring and warfarin dose adjustment

Fingerstick INR testing on two CoaguChek XS devices by trained nursing sister • Patients with antiphospholipid syndrome excluded from study • Informed consent obtained

• If no reading, patient excluded from study (n=4) • Patient’s warfarin dose adjusted according to laboratory INR study Results tabulated and compared with laboratory INR results

Fig. 1. Flow diagram of patient sample collection. (PI clinic = anticoagulation clinic.)

within, above or below the target range, or the difference between the CoaguChek XS and laboratory INR when one of the pair was within the target range and the other outside it was no more than 0.5 INR units. ‘Narrow’ agreement was considered as both readings being between 2 and 3, or below the target range and within 0.4 INR units of each other, or above the target range and within 0.8 INR units of each other. If one reading was within the target range and the other within 0.5 INR units, this was also considered to be in ‘narrow’ agreement.[1,5]

Statistical analysis

The results were collated on an Excel spreadsheet, tabulated and graphically summarised using standard statistical methods. Agreement between results obtained on the different analysers was evaluated using standard difference plots.

Results

Study population

Three hundred and four patients partici pated in the study. In four cases the Coagu Chek XS device failed to produce an INR reading, and these samples were excluded from the analysis (Fig. 1). Patient indications for anticoagulation are listed in Table 1.

Method comparison analysis

The limit of agreement between the two methods is demonstrated in the BlandAltman difference plot (Fig. 2), which revealed good agreement. On the logarith mic scale, the mean of the differences was 0.09 (–0.61, 0.79). Sixteen data points were outside the 95% limits of agreement. The mean INR values of the CoaguChek XS and STAGO were 2.75 (standard deviation (SD) 1.18) and 2.65 (SD 1.04), respectively, representing an overestimation of INR values by the CoaguChek XS (Table 2). Below the target range (<1.9), 100% of the CoaguChek XS INR readings were within 0.5 units of the

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Table 1. Indications for anticoagulation of study patients Indication for anticoagulation

n (%)

Thromboembolic events

110 (36.2)

Deep-vein thrombosis

54 (17.8)

Pulmonary embolism

32 (10.5)

eep-vein thrombosis and D pulmonary embolism

13 (4.3)

Upper limb thrombosis

5 (1.6)

Left ventricular thrombus

5 (1.6)

ural venous sinus D thrombosis

1 (0.3)

Valvular heart disease

59 (19.4)

Non-valvular heart disease

87 (28.6)

Dilated cardiomyopathy

5 (1.6)

Congestive cardiac failure

4 (1.3)

Ischaemic heart disease

4 (1.3)

Stroke

3 (0.9)

Congenital cardiac disease

2 (0.7)

Atrial fibrillation

69 (22.7)

Other/not stated

48 (15.8)

standard laboratory method result. Within the target range (2.0 - 3.5), 93.9% of the CoaguChek XS INR readings were within 0.5 units of the standard laboratory method result. There was, however, an increase in the variability of the differences between the two test methods at INR readings above the target range (>3.6).

Precision analysis

The intra-assay coefficients of variation were within allowable limits of performance in the within-target range (0%).

Clinical utility

Clinical agreement was demonstrated by 93.0% of the values when assessed using

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CoaguCheck - STAGO INR

3 2 1

0 -1

-2

Mean INR

Fig. 2. Bland-Altman analysis. (95% confidence intervals in blue, bias indicated in black. The dots indicate the difference between the CoaguChek and STAGO INR over the mean.)

Table 2. Comparison of CoaguChek XS and laboratory INR results Parameter

CoaguChek XS

All INR results, N (%)

300 (100.0)

Mean INR (SD)

2.75 (1.18)

Mean difference (SD)

–0.09 (0.36)

% within 0.5 units

93.0

INR ≤1.9, n (%)

2.65 (1.04)

71 (23.7)

Mean INR (SD)

1.61 (0.32)

Mean difference (SD)

–0.03 (0.11)

% within 0.5 units

100.0

INR 2.0 - 3.5, n (%)

184 (61.3)

Mean INR (SD)

2.66 (0.50)

Mean difference (SD)

–0.05 (0.28)

% within 0.5 INR units

93.9

INR ≥3.6, n (%)

1.59 (0.30)

2.61(0.39)

45 (15.0)

Mean INR (SD)

4.9 (1.3)

Mean difference (SD)

–0.3 (0.7)

% within 0.5 INR units

64.4

expanded criteria. When using narrow agreement criteria, in the range of 2 - 3.5, the laboratory method recorded 181 readings, whereas the CoaguChek XS device recorded 162 (89.5%). At INR values <2, the difference between the two readings was <0.4 units in 70 of the 71 readings (98.6%). The required difference of <0.8 units in the INR >3.5 category was met in 36 of the 45 readings (80.0%) (Table 2). During the study period, 21 of the 300 CoaguChek XS INR values (7.0%) would have been discrepant with standard lab oratory INR measurements, resulting in different warfarin dosage adjustments according to the SA guidelines.[7,8]

Laboratory

4.5 (1.0)

Discussion

In this prospective study, we demonstrated the analytical and clinical performance of the CoaguChek XS point-of-care device for the monitoring of warfarin therapy across a wide range of INR values. The CoaguChek XS is a portable coagulometer that was introduced into the clinical setting in October 2005. Previous studies on point-ofcare devices have shown increased variability at supratherapeutic INR levels.[2,9,10] A recent study performed on the CoaguChek XS, however, demonstrated improved accuracy even at higher INR values.[11] We demonstrated excellent agreement between the CoaguChek XS and laboratory

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measurement with the STAGO analyser. INR values were overestimated on the coagulometer. Ninety-four percent of the values had a clinically significant difference of <0.5 units in the target range, making this an acceptable alternative method for monitoring stable patients on long-term warfarin therapy with INRs within the therapeutic range of 2 - 3. Using narrow agreement criteria, the point-of-care device also performed well in the INR ranges of <2 and 2 - 3.5. However, in the above-target range of >3.6, 64.4% were in agreement. These findings are consistent with the study by Ryan et al.,[12] in which 162 patients had dual measurements performed using the CoaguChek XS and standard laboratory methods. For laboratory INR values of <1.9, 2 - 3.5 and >3.6, 97.8%, 89.3% and 67% of readings, respectively, were within 0.5 INR units. In the SA setting, where there is a high prevalence of rheumatic heart disease and patients with mechanical heart valves, the CoaguChek XS point-of-care device could be implemented as a method for monitoring these patients, but clinical correlation would be advised at levels >3.6 units with more frequent monitoring and formal laboratory testing. Several research groups have demon strated the advantages of having a simple and reliable POCT for INR monitoring, e.g. small sample volumes and improved turnaround time. However, POCT has limitations including preanalytical (e.g. staff competency) and biological (e.g. temperature variations, heparin contamination, extremes of haematocrit, fibrinogen levels and presence of antiphospholipid antibodies) variables. [13- 15] In SA, the CoaguChek XS point-ofcare device could be implemented in the peri pheral clinics as a screening tool for patients on long-term warfarin therapy in an attempt to reduce the workload of central anticoagulation clinics. The capacity and infrastructure of peripheral clinics would have to be assessed before installation of the devices. It is imperative that implemen tation of POCT be accompanied by a robust quality control system with satisfactory performance in internal and external quality assessment programmes. In specific settings, formal laboratory INR analysis will still be required when INR values >3.6 are obtained using this device and there is a history of bleeding events.

Conclusion

In this cohort, the CoaguChek XS provided accurate and precise INR measurements for a wide range (2 - 3.5 units) of INR

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measurements and would be an accurate and reliable method for warfarin therapy monitoring. Acknowledgment. We thank Dr Michelle Bronze, Dr Yuen On Wan, Dr Jenifer Vaughan and Shamima Vally for assistance with validation and statistical analysis. References 1. Bereznicki LR, Jackson SL, Peterson GM, Jeffrey EC, Marsden KA, Jupe DM. Accuracy and clinical utility of the CoaguChek XS portable international normalised ratio monitor in a pilot study of warfarin home-monitoring. J Clin Pathol 2007;60(3):311-314. [http://dx.doi.org/10.1136/jcp.2006.037820] 2. Douketis JD, Lane A, Milne J, Ginsberg JS. Accuracy of a portable International Normalization Ratio monitor in outpatients receiving long-term oral anticoagulant therapy: Comparison with a laboratory reference standard using clinically relevant criteria for agreement. Thromb Res 1998;92(1):11-17. 3. Plesch W, Wolf T, Breitenbeck N, et al. Results of the performance verification of the CoaguChek XS system. Thromb Res 2008;123(2):381-389. [http://dx.doi.org/10.1016/j.thromres.2008.04.021] 4. Plesch W, van den Besselaar AM. Validation of the international normalized ratio (INR) in a new point-of-care system designed for home monitoring of oral anticoagulation therapy. Int J Lab Hematol 2009;31(1):20-25. [http://dx.doi.org/10.1111/j.1751-553X.2007.00998.x] 5. Sobieraj-Teague M, Daniel D, Farrelly B, Coghlan D, Gallus A. Accuracy and clinical usefulness of the CoaguChek S and XS point of care devices when starting warfarin in a hospital outreach setting. Thromb Res 2009;123(6):909-913. [http://dx.doi.org/10.1016/j.thromres.2008.10.006] 6. Christensen TD, Larsen TB, Jensen C, Maegaard M, Sorensen B. International normalised ratio (INR) measured on the CoaguChek S and XS compared with the laboratory for determination of precision and accuracy. Thromb Haemost 2009;101(3):563-569. [http://dx.doi.org/10.1160/TH08-09-0601]

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7. Jacobson BF, Louw S, Buller H, et al. Venous thromboembolism: Prophylactic and therapeutic practice guideline. S Afr Med J 2013;103(4):261-267. [http://dx.doi.org/10.7196/SAMJ.6706] 8. Dalby AJ, Wessels P, Opie LH. Warfarin in non-valvular atrial fibrillation. S Afr Med J. 2013;103(12):901904. [http://dx.doi.org/10.7196/samj.7172] 9. Rigelsky JM, Choe HM, Curtis DM, Brosnan MJ, Mitrovich S, Streetman DS. Accuracy of the avosure PT pro system compared with a hospital laboratory standard. Ann Pharmacother 2002;36(3):380-385. [http://dx.doi.org/10.1345/aph.1A253] 10. Hentrich DP, Fritschi J, Muller PR, Wuillemin WA. INR comparison between the CoaguChek S and a standard laboratory method among patients with self-management of oral anticoagulation. Thromb Res 2007;119(4):489-495. [http://dx.doi.org/10.1016/j.thromres.2006.04.003] 11. Karon BS, McBane RD, Chaudhry R, Beyer LK, Santrach PJ. Accuracy of capillary whole blood international normalized ratio on the CoaguChek S, CoaguChek XS, and i-STAT 1 point-of-care analyzers. Am J Clin Pathol 2008;130(1):88-92. [http://dx.doi.org/10.1309/DEK41W141Y0KRN8A] 12. Ryan F, Oâ&#x20AC;&#x2122;Shea S, Byrne S. The reliability of point-of-care prothrombin time testing: A comparison of CoaguChek S and XS INR measurements with hospital laboratory monitoring. Int J Lab Hematol 2010;32(1):e26-e33. [http://dx.doi.org/10.1111/j.1751-553X.2008.01120.x] 13. Van den Besselaar AM, Witteveen E, van der Meer FJ. Influence of haematocrit on international normalised ratio (INR) differences between a whole blood point-of-care coagulation monitor and reference prothrombin time in plasma. Thromb Haemost 2008;100(6):1181-1184. 14. Phillips EM, Buchan DA, Newman N, Rajan A, Zia S. Low-molecular-weight heparin may alter pointof-care assay for international normalized ratio. Pharmacotherapy 2005;25(10):1341-1347. [http:// dx.doi.org/10.1592/phco.2005.25.10.1341] 15. Perry SL, Samsa GP, Ortel TL. Point-of-care testing of the international normalized ratio in patients with antiphospholipid antibodies. Thromb Haemost 2005;94(6):1196-1202. [http://dx.doi. org/10.1160/TH05-06-0400]

Accepted 16 November 2016.

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High prevalence of cardiovascular risk factors in Durban South African Indians: The Phoenix Lifestyle Project D R Prakaschandra,1 PhD, MMedSci; T M Esterhuizen,2 MSc; A A Motala,3 MB ChB, MD, FRCP; P Gathiram,4 PhD, MSc; D P Naidoo,5 MB ChB, MD, FRCP epartment of Biomedical and Clinical Technology, Faculty of Health Sciences, Durban University of Technology, South Africa D Centre for Evidence-Based Health Care, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Cape Town, South Africa 3 Department of Diabetes and Endocrinology, School of Clinical Medicine, College of Health Sciences, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa 4 Department of Physiology, School of Clinical Medicine, College of Health Sciences, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa 5 Department of Cardiology, School of Clinical Medicine, College of Health Sciences, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa 1 2

Corresponding author: D P Naidoo (naidood@ukzn.ac.za)

Background. Previous studies show a high prevalence of cardiovascular (CV) risk factors in South African (SA) Asian Indians, with the emergence of premature coronary artery disease in young Indian subjects. Objective. To determine the prevalence of CV risk factors in this population. Methods. This was a cross-sectional study of randomly selected adults aged 15 - 64 years from the suburb of Phoenix in Durban, KwaZulu-Natal Province, SA. All participants had demographic, anthropometric and biochemical measurements using the modified World Health Organization (WHO) STEPwise survey methods. Hypertension, obesity, lipid abnormalities and diabetes mellitus (DM) were diagnosed using WHO criteria. Age-standardised frequencies for glycaemic indices were calculated according to the WHO standard world population distribution. Results. Of the 1 428 subjects who responded (response rate 72.1%), complete data for analysis were available on 1 378 (1 001 women). The mean age was 45.5 (standard deviation 13) years. There were high prevalences of hypertension (47.5%), DM (20.1%), total body obesity (raised body mass index) (32.4%) and increased waist circumference (73.1%). The â&#x20AC;&#x2DC;thin-fatâ&#x20AC;&#x2122; Asian phenotype (isolated abdominal obesity) was found in only 4.8% of participants. High prevalences of total body obesity (32.1%), increased waist circumference (31.3%) and insulin resistance (28.2%) were documented in the youngest age group. Over half of the males and 14.6% of females were current smokers. Diabetic dyslipidaemia was found in 61 subjects (4.4%). In multivariate analysis, age, triglycerides and waist circumference measurement were significant independent risk factors associated with DM and, together with fasting glucose, also predicted hypertension. Conclusion. Compared with Asian Indian subjects with similar environmental exposure in previous studies, the magnitude of change in risk factor prevalence over the past two decades has been of epidemic proportions. S Afr Med J 2016;106(3):284-289. DOI:10.7196/SAMJ.2016.v106i3.9837

The latest data from the International Diabetes Federation[1] show that the prevalence of adults with type 2 diabetes mellitus (DM) is highest in low- and middle-income countries, with sub-Saharan Africa and the Indian subcontinent being highlighted as two of the regions where this rise will be the greatest. Earlier epidemiological studies[2,3] show that South African (SA) Indians have a high prevalence[2] and incidence[3] of DM. In the past two decades there have been major sociopolitical changes in these communities, and the lack of current data on the changes in cardiovascular (CV) risk profile and the emergence of premature coronary artery disease[4] was the rationale for a survey of the CV risk factor profile of SA Indians.

Objective

To determine the CV risk factor prevalence in a community-based sample of SA Indians.

Methods Sampling

The Phoenix Lifestyle Project was a cross-sectional study conducted over a 2-year period (January 2007 - December 2008) on SA Indians aged 15 - 64 years residing in the Phoenix area (eThekwini Municipality,

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Durban, SA). This community forms a heterogeneous population of Dravidian and Aryan ancestry, and are mainly descendants of Indians who arrived in SA from 1860 as indentured labourers on the sugar plantations in Natal.[5] Two-stage cluster sampling was used to select the households. First, a proportional representation of the number of households was selected from each area. Thereafter, the households to be studied in each area were randomly selected. One individual from each household was selected using the Kish method.[6] Fieldworkers were trained to follow a prescribed guideline using the Kish method of selection so that participants were stratified for age (15 - 24, 25 - 34, 35 - 44, 45 - 54 and 55 - 64 years) and gender (male and female), with 198 males and 198 females in each stratum.

Ethical considerations

The study was approved by the University of KwaZulu-Natal Bioethics Committee (ethics reference: E336/05) and conformed to the principles in the Declaration of Helsinki. All subjects gave written informed consent for the collection of the data and were informed of the results of the examinations undertaken. Subjects in whom risk factors were identified were referred to a health facility for further evaluation and management.

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Data collection

The World Health Organization (WHO) modified STEPS question naire for non-communicable disease risk factors (version 1.4 questionnaire)[7] was used to record the demographic (including age, sex, education and income level) information and behavioural measurements at the participants’ homes. Other information included type of diet, physical activity, smoking habits, alcohol consumption and a personal and family (first-degree relatives) history of DM, hypertension and CV risk factors. The clinical examination and investigations were performed at the Lifestyle Centre, Inkosi Albert Luthuli Central Hospital, Durban. Anthropometric measurements performed included height, weight and waist circumference according to WHO criteria.[7] Venous blood samples were taken after an overnight fast for measurement of plasma glucose, serum insulin and serum lipid (total cholesterol, highdensity lipoprotein (HDL) cholesterol and total triglyceride) levels. Fasting plasma glucose was measured using the glucose oxidase method and plasma insulin was measured by immunoassay. A 75 g oral glucose tolerance test (OGTT) was performed on participants who did not self-report a positive history of DM, for fasting and 2-hour plasma glucose levels. Blood pressure (BP) was recorded on three occasions at 2-minute intervals and the average of the three readings was documented.

Definition and classification of CV risk factors

Anthropometry Based on the body mass index (BMI), participants were classified as of normal weight (18.50 - 24.99 kg/m2), overweight (≥25 - 29.99 kg/m2) or obese (≥30 kg/m2). The revised cut-off point for Asian Indians[8] was also applied, i.e. subjects with a BMI <23 kg/m2 were classified as normal, those with a BMI of 23.0 - 24.9 kg/m2 as overweight and those with a BMI of ≥25.0 kg/m2 as obese. The prevalence of the ‘thin-fat Asian phenotype’ was also determined in subjects with isolated abdominal obesity, i.e. Asian criteria for waist circumference (men >90 cm, women >80 cm) and a normal BMI (<23 kg/m2). Hypertension Individuals who self-reported previously diagnosed hypertension, and/or those with blood pressure readings ≥140 and ≥90 mmHg (average of three readings) (Joint National Committee VII (JNC VII) criteria) and/or those on current antihypertensive therapy[9] were defined as having systemic hypertension. Using JNC VII guidelines, individuals with a systolic blood pressure of 120 - 139 mmHg or a diastolic blood pressure of 80 - 89 mmHg[9] were classed as having prehypertension. Biochemistry Lipid parameters were classified using criteria of the National Cholesterol Adult Panel III guidelines:[10] serum total cholesterol >5.17 mmol/L, serum total triglyceride >1.69 mmol/L, HDL cholesterol <1.04 mmol/L (men) and <1.29 mmol/L (women), and low-density lipoprotein (LDL) cholesterol >2.59 mmol/L. LDL cholesterol was calculated using the Friedewald equation. Diabetic dyslipidaemia was diagnosed if raised levels of LDL cholesterol and triglycerides, as well as low levels of HDL cholesterol, were present. The WHO criteria[11] were used to classify glycaemic categories based on fasting plasma glucose (FPG): DM if the FPG was ≥7.0 mmol/L, and impaired fasting glucose (IFG) if the FPG was ≥6.1 and ≤6.9 mmol/L. Impaired glucose tolerance was defined if the FPG was <7.0 mmol/L and the 2-hour plasma glucose level during the OGTT was ≥7.8 and <11.1 mmol/L. Subjects with IFG or IGT were classified as having prediabetes. Homeostatic model assessment

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for insulin resistance (HOMA-IR) values were calculated using the formula: fasting insulin (µU/m) × fasting glucose (mmol/L)/22.5. Insulin resistance was defined as a HOMA-IR value of >2.6.[12] The age-standardised frequencies for glycaemic indices were calculated according to the WHO standard world population distribution.

Statistical analysis

Statistical analysis was performed using the SPSS programme (version 22, SPSS, USA). The distributional properties for all variables were investigated, and variables with a skewed distribution were logtransformed or analysed using non-parametric testing. Means and standard deviations (SDs) and median values with interquartile ranges for non-Gaussian distributed variables were calculated for continuous variables. Categorical data were presented as percentages with corresponding 95% confidence intervals (CIs); the χ2 test was used for intergroup comparisons. For continuous variables, analysis of variance was used. Post-hoc analysis of variance comparisons for continuous variables was based on the Bonferroni correction. Logistic regression (stepwise, backward) was used to identify risk factors associated with DM and hypertension. A p-value of <0.05 was regarded as being statistically significant.

Results

Of 1 980 participants selected, 1 428 individuals (402 males, 1 026 females) participated in the study, giving a response rate of 72.1%. Non-responders were mainly males (40.6%, 402/990 male participants selected), with participation being higher in the older age groups. Complete data on all variables were available on 1 378 participants, who formed the study group for further analysis shown in Table 1. The majority of respondents were women (n=1 001, 72.6%), underrepresented in the 15 - 34-year age groups and over-represented in the 35 - 64-year age groups (Table 1). The mean age of the total sample was 45.5 (SD 13) years, with the highest proportion of subjects in the 45 - 54-year age group (30.7%) (Table 2). The general pattern for blood pressure and biochemical variables among both males and females was an increase with advancing age. Participants in all age groups reported a positive family history for one or more of the following conditions: obesity, DM, hypertension, myocardial infarction (MI), stroke and heart failure (congestive heart failure (CHF), with hypertension being the most frequently reported (71.2%).

CV and metabolic risk factors in the sample

The most frequent abnormality was adiposity, both total (BMI) and central obesity (waist circumference) (Table 3). Almost onethird were classified as obese (32.4%) or overweight (32.0%), with the prevalence increasing with age (p-trend <0.001). Using Asian cut-points, the prevalence of obesity doubled to 64.5%, and was significantly higher in women (71.0%) than in men (44.5%) Table 1. Age and gender distribution of study subjects Age group (years)

Total, n (%)

Males, n (%)

Females, n (%)

15 - 24

131 (9.5)

54 (41.2)

77 (58.8)

25 - 34

161 (11.6)

60 (37.3)

101 (62.7)

35 - 44

295 (21.4)

68 (23.1)

227 (76.9)

45 - 54

423 (30.7)

81 (20.1)

342 (80.9)

55 - 64

368 (26.7)

114 (30.9)

254 (69.0)

Total

1 378

377 (27.3)

1 001 (72.6)

March 2016, Vol. 106, No. 3

88.8 (13.8)

132.6 (19.3)

80.5 (12.9)

BMI (kg/m2), mean (SD)

Waist (cm), mean (SD)

Systolic BP (mmHg), mean (SD)

Diastolic BP (mmHg), mean (SD)

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1.8 (1.1)

3.35 (1.1)

Total triglycerides

LDL cholesterol

28 (7.4)

269 (71.2)

246 (65.3)

150 (39.8)

164 (43.5)

69 (18.3)

180 (47.7)

Obesity

Raised BP

MI/stroke

Coronary artery disease

Peripheral vascular disease

CHF

Family history of, n (%)

1.21 (0.33)

HDL cholesterol

Total cholesterol), mean (SD)

5.4 (1.2)

7.4 (4.1)

Serum lipids (mmol/L), mean (SD)

6.0 (2.4)

0 min

Plasma glucose (mmol/L), mean (SD)

43 (14)

24.6 (5.0)

Age (years), mean (SD)

All

20 (35.1)

8 (14.8)

22 (38.6)

18 (31.6)

36 (64.3)

39 (68.4)

6 (10.5)

2.71 (0.9)

1.1 (0.6)

1.25 (0.35)

4.4 (1.2)

5.2 (1.4)

4.9 (0.4)

69.01 (8.4)

121.7 (11.1)

78 (12.7)

21.6 (4.8)

15 - 24 y

33 (54.1)

16 (26.2)

28 (45.9)

23 (38.2)

36 (59.0)

47 (77.0)

4 (6.7)

3.35 (0.9)

1.8 (1.0)

1.22 (0.37)

5.3 (0.9)

6.3 (2.4)

5.0 (1.1)

79.1 (10.9)

128.3 (15.4)

87.5 (13.6)

24.84 (5.0)

25 - 34 y

33 (45.8)

9 (12.7)

34 (48.6)

31 (44.3)

48 (65.8)

48 (66.7)

5 (6.9)

3.67 (1.2)

1.8 (1.0)

1.24 (0.88)

5.6 (1.0)

7.2 (3.5)

5.9 (2.3)

82.6 (13.5)

129.6 (19.1)

90.5 (13.7)

25.4 (5.4)

35 - 44 y

Men (N=377), n (%)

Table 2. Demographic and clinical characteristics of participants

38(45.2)

12 (14.1)

41 (48.8)

35 (42.2)

55 (64.7)

60 (70.6)

5 (5.9)

3.55 (1.0)

2.1 (1.1)

1.17 (0.25)

5.7 (1.2)

9.4 (5.6)

6.5 (2.7)

85.7 (12.6)

137.9 (18.3)

93.1 (10.8)

25.9 (4.1)

45 - 54 y

56 (48.7)

24 (20.9)

39 (33.9)

43 (37.1)

71 (61.2)

75 (64.7)

8 (7.0)

3.31 (1.1)

2.0 (1.3)

1.25 (0.33)

5.5 (1.2)

8.2 (4.3)

6.8 (2.7)

81.9 (12.0)

138.5 (22.0)

90.6 (13.7)

24.3 (4.9)

55 - 64 y

512 (51.1)

240 (23.9)

519 (51.8)

387 (38.7)

703 (70.2)

804 (80.3)

115 (11.5)

3.35 (1.0)

1.8 (2.6)

1.33 (0.33)

5.5 (1.2)

8.3 (3.8)

6.4 (2.9)

81.7 (11.9)

133.7 (23.4)

95.4 (15.3)

29.1 (6.4)

45 (12)

All

33(42.3)

14 (18.2)

29 (37.7)

32 (59.2)

56 (43.4)

60 (77.9)

4 (5.1)

2.72 (0.8)

1.1 (1.0)

1.51 (0.8)

4.5 (0.9)

6.3 (2.7)

5.3 (3.0)

72.9 (11.6)

114.5 (12.8)

82.3 (15.2)

24.5 (7.6)

15 - 24 y

46 (46.9)

25 (23.2)

58 (57.1)

43 (42.2)

57 (56.1)

75 (73.2)

7 (6.8)

3.04 (0.9)

1.4 (0.6)

1.26 (0.32)

5.0 (1.0)

7.1 (2.9)

5.3 (1.9)

78.8 (11.2)

121.9 (15.9)

94.8 (17.3)

29.4 (7.6)

106 (46.7)

53 (23.5)

111 (48.9)

72 (31.7)

159 (70.0)

176 (77.5)

25 (11.0)

3.27 (1.0)

1.6 (0.7)

1.32 (0.53)

5.3Â (1.2)

7.9 (3.3)

6.0 (2.7)

81.9 (11.9)

129.5 (29.8)

95.9 (15.2)

29.5 (6.7)

35 - 44 y

Women (N=1 001), n (%) 25 - 34 y

194 (55.4)

85 (24.4)

194 (55.6)

148 (42.4)

242 (69.1)

271 (77.4)

44 (12.6)

3.55 (1.0)

1.8 (1.1)

1.36 (0.47)

5.6 (1.1)

9.0 (4.2)

6.7 (3.1)

83.4 (12.1)

137.1 (21.0)

97.2 (14.9)

29.6 (5.4)

45 - 54 y

133 (51.4)

63 (24.3)

127 (48.8)

108 (42)

89 (72.7)

222 (85.7)

35 (13.5)

3.47 (0.9)

2.0 (1.2)

1.34 (0.31)

5.8 (1.2)

9.3 (4.0)

7.1 (2.8)

83.2 (10.7)

143.1 (18.9)

96.9 (13.1)

29.5 (5.9)

55 - 64 y

RESEARCH

BMI (kg/m )

287

655 (47.5)

236 (17.1)

BP ≥140 and ≥90 mmHg

Prehypertension

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401 (29.1)

198 (14.4)

765 (55.5)

Prediabetes

IFG

HOMA-IR >2.6

327 (23.7)

61 (4.4)

Tg >1.69 mmol/L

LDL cholesterol >2.59 mmol/L

Diabetes + dyslipidaemia

[8]

49.6

8.0

17.6

60 (15.9)

25 (6.6)

62 (16.4)

170 (45.1)

116 (30.1)

218 (57.8)

155 (41.1)

46 (12.2)

83 (22.0)

81 (21.5)

96 (25.5)

88 (23.3)

154 (40.8)

12 (3.1)

178 (47.2)

197 (52.3)

168 (44.5)

36 (3.6)

265 (26.5)

412 (41.2)

481 (48.1)

568 (56.7)

610 (60.9)

152 (15.1)

318 (31.8)

294 (29.4)

345 (34.9)

148 (14.8)

501 (50.0)

54 (5.4)

829 (82.8)

147 (14.6)

721 (71.0)

118 (11.8)

162 (16.2)

399 (39.9)

322 (32.1)

280 (27.9)

Females (N=1 001), n (%)

<0.001

0.047

<0.001

0.020

0.003

<0.001

p-value*

1 (0.8)

6 (4.5)

17 (12.9)

46 (35.1)

23 (17.6)

48 (36.6)

3 (2.3)

10 (7.6)

8 (6.1)

38 (29.0)

8 (6.1)

41 (31.3)

35 (26.7)

42 (32.1)

10 (7.6)

79 (60.3)

20 (15.3)

22 (16.8)

89 (67.9)

15 - 24 y (N=131), n (%)

4 (2.5)

13 (8.1)

44 (27.3)

74 (45.9)

71 (44.1)

83 (51.5)

8 (4.9)

32 (19.9)

18 (11.2)

19 (11.8)

39 (24.2)

10 (6.2)

100 (62.1)

49 (30.4)

94 (57.8)

20 (12.4)

47 (29.1)

55 (34.2)

39 (24.2)

67 (41.2)

25 - 34 y (N=161), n (%)

12 (4.1)

61 (20.7)

115 (38.9)

151 (51.1)

165 (55.9)

166 (56.2)

29 (9.8)

80 (27.1)

66 (22.4)

78 (26.4)

21 (7.1)

112 (37.9)

13 (4.4)

227 (76.9)

67 (22.7)

201 (68.1)

33 (11.1)

61 (20.6)

107 (36.3)

94 (31.9)

35 - 44 y (N=295), n (%)

22 (5.2)

115 (27.2)

208 (49.1)

182 (43.0)

275 (65.0)

249 (58.8)

83 (19.6)

164 (38.7)

135 (31.9)

157 (37.1)

42 (9.9)

237 (56.0)

13 (3.1)

351 (82.9)

89 (21.0)

316 (74.7)

56 (13.2)

51 (12.1)

151 (35.7)

165 (39.0)

107 (25.3)

45 - 54 y (N=423), n (%)

22 (5.9)

132 (35.9)

198 (53.8)

144 (39.1)

252 (68.5)

219 (59.5)

75 (20.4)

115 (31.3)

220 (59.8)

179 (48.6)

96 (26.6)

259 (70.4)

22 (5.9)

288 (78.3)

104 (28.2)

236 (64.1)

59 (16.0)

73 (19.8)

114 (30.9)

122 (33.2)

132 (35.8)

55 - 64 y (N=368), n (%)

<0.001

p-trend†

p: comparison between age groups.

†

Asian cut-points = modified criteria for Asian Indians; Waist circumference = International Diabetes Federation criteria (men >90 cm, women >80 cm); Asian phenotype = BMI <23 kg/m and increased waist circumference (men >90 cm, women >80 cm; Prediabetes = IFG or IGT (IFG ≥5.6 - <7.0 mmol/L); TC = serum total cholesterol; Tg = serum total triglyceride; Prehypertension = systolic blood pressure 120 - 139 mmHg or diastolic blood pressure 80 - 89 mmHg; Diabetes + dyslipidaemia = combination of DM + low HDL cholesterol (men <1.03 mmol/L, women <1.29 mmol/L) + TC >5.17 mmol/L + LDL cholesterol >2.59 mmol/L; NS = p-value not statistically significant. *p: males v. females.

597 (43.3)

582 (42.2)

HDL cholesterol <1.03 mmol/L men, <1.29 mmol/L women

786 (57.0)

377 (27.4)

Diabetes (WHO)

TC >5.17 mmol/L

441 (32.0)

Glycaemic category

1 007 (73.1)

66 (4.8)

Asian phenotype

344 (24.9)

Smoking

High waist circumference (cm)

178 (12.9)

889 (64.5)

≥23.0 - <25

≥25

311 (22.5)

<23

149 (39.5)

48 (13.5)

447 (32.4)

Asian cut-points

≥30

120 (31.8)

489 (35.5)

442 (32.0)

209 (55.4)

Males (N=377), n (%)

<25

20.1

Prevalence standardised for age, %

≥25 - <30

All (N=1 378), n (%)

Table 3. Prevalence of CV and metabolic risk factors in the study group

RESEARCH

(p<0.001); of interest, almost a third of the participants (32.1%) in the 25 - 34-year age groups were also obese. Isolated abdominal obesity using the Asian cut-points for waist circumference and a normal BMI (the ‘Asian phenotype’) was recorded in only 4.8% of the sample. Almost half (47.5%) of the total group had hypertension, with the prevalence higher in women than in men (p<0.001) and increasing with age (p<0.001); the peak prevalence was in the oldest age groups. Prehypertension was found in 17.1% (n=236) of participants, and was more common in men than in women. The crude prevalence of DM, including subjects who selfreported, was 32.0%; the prevalence using WHO criteria was 27.4% (age-adjusted 20.1%), being higher in women (p<0.001) and with advancing age (p-trend <0.001). Prediabetes (IFG or IGT) was found in 29.1% of individuals (age-adjusted 17.6%) and IFG in 14.4% (age-adjusted 8.0%); the prevalence of impaired fasting glucose was also higher with advancing age (p-trend <0.001), with a peak in the 55 - 64-year age group. Insulin resistance (HOMA-IR) was found in 55.5% of participants (age-adjusted 49.6%); surprisingly, 36.6% (ageadjusted 28.2%) of the participants in the youngest age group (15 - 24 years) were also so classified (Table 3). Hypercholesterolaemia was found in 57.0% of subjects, hyper triglyceridaemia in 42.2% and raised LDL cholesterol in 23.7%. A low concentration of HDL cholesterol was found in 43.3% of subjects, especially in women (48.1%) as opposed to men (30.1%). Of note is that even in the 15 - 24-year age group, 12.9% had elevated triglyceride levels and 35.1% had low HDL cholesterol levels. Diabetic dyslipidaemia (a combination of elevated triglycerides and LDL cholesterol, as well as low HDL cholesterol) was found in 4.4% of the sample, the prevalence being higher in men (6.6%) than in women (3.6%). Of the subjects 52.3% of males and 14.6% of females were current smokers, the figure for subjects in the 15 - 24-year age group being 26.7%.

Risk factor analysis

Age, total serum cholesterol, serum triglyceride, HDL cholesterol, waist circumference, BMI, blood pressure, smoking and HOMA values were used in a bivariate analysis for DM and hypertension. The BMI, blood pressure, smoking and HOMA values were not significant on bivariate analysis, and were subsequently excluded from the logistic regression model. In multiple logistic regression analysis, age, total serum cholesterol, serum triglyceride, HDL cholesterol and waist circumference were entered into the predictive Table 4. Logistic regression model for risk factors associated with diabetes mellitus and hypertension Variable

Wald

p-value

95% CI

Diabetes Waist (cm)

0.016

12.8

<0.001

1.02

1.007 - 1.026

Tg (mmol/L)

0.576

61.1

<0.001

1.80

1.11 - 1.59

Age

0.02

5.125

<0.005

1.06

1.044 - 1.070

Hypertension Waist (cm)

0.037

<0.001

1.04

1.03 - 1.047

FBG (mmol/L)

0.017

20.8

<0.001

1.02

1.069 - 1.081

Tg (mmol/L)

0.162

8.028

0.05

1.18

1.01 - 1.4

Age

0.070

133

<0.001

1.07

1.06 - 1.086

B = used to predict the dependent variable from the independent variable and presented in log-odds units; Wald statistic = used to assess the significance of the coefficients and contribution of individual predictors in a given model; Waist = waist circumference; Tg = triglyceride; FBG = fasting blood glucose.

288

model. The significant independent risk factors associated with DM included age, waist circumference and serum triglyceride. For hypertension, the same risk factors were independent predictors with the addition of fasting plasma glucose (Table 4).

Discussion

This is the first study of SA Indians to document an extremely high CV risk factor prevalence, and it highlights the evolving epidemic of CV risk in teenagers and young adults in this population. Asian Indians across the diaspora are known to have high CV risk.[13] A previous diabetes epidemiology study reported over 20 years ago in the greater Durban area showed lower prevalences of hypertension (14%) and DM (13%).[2] Our study shows that the magnitude of change over two decades has been of epidemic proportions in subjects with similar environmental exposure. The prevalences of hypertension (47.5%) and DM (agestandardised 20.1%), in particular, are also strikingly high when compared with other population groups in SA. Stewart et al.[14] reported a 33% prevalence of hypertension and a 5% prevalence of DM in their Soweto cohort (black African), with a 28% prevalence of DM in the coloured community.[15] Furthermore, the high number of participants who were currently smoking, particularly in the youngest age group, is concerning since these individuals already had multiple risk factors in the presence of smoking, which is known to exert a detrimental multiplicative effect on CV risk.[16] Our study shows a high prevalence of hypercholesterolaemia (57%), raised triglyceride levels (42.2%), raised LDL cholesterol levels (23.7%) and low HDL cholesterol levels (43.3%). The low HDL cholesterol and raised triglyceride levels are in keeping with the characteristic dyslipidaemia pattern seen in Asian Indians, which together with the ‘thin-fat Asian phenotype’ (low BMI and raised waist circumference) is thought to contribute to the development of excess CVD in this population group.[17] Our findings are in direct contrast to this concept, since most of our subjects had generalised (both abdominal and total body) obesity. This, together with the emergence of multiple CV risk factors, including atherogenic dyslipidaemia, in the younger age group, predicts early onset of coronary heart disease[4] and is likely to impose a greater burden of CV disease in the near future, as these individuals reach adulthood.

Study strengths and limitations

The study is limited by its cross-sectional design, which rendered us unable to observe or to report on trends associated with CV events that could have developed over time. Another limitation was the low response rates of male participants, which means that the data on men should be interpreted with caution; however, this has been reported in other SA population studies.[14,15] In addition, limited participation was noted in the younger age groups, introducing a potential selection bias for non-working participants. The strength of this study is that it was a population-based study that also included a small sample of younger individuals and was able to show that CV risk was significantly high in this age group.

Conclusion

The extremely high prevalence of risk factors in our study explains the emergence of premature coronary heart disease in the community studied and calls for urgent and aggressive intervention measures aimed at diet, physical activity and cessation of smoking at schoolgoing level. A longitudinal follow-up study of these participants to ascertain the degree of CV risk associated with the marked changes in phenotype is urgently required.

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Acknowledgements. We thank our participants from the Phoenix community. Sources of support. This research was made possible in part by a grant from the WHO (Africa Division) and financial support from Servier and Pfizer laboratories. We also wish to acknowledge General Motors (SA) for use of their bus to transport our participants. Disclaimer. The views expressed in this article are the authorsâ&#x20AC;&#x2122; own and not the official position of the Durban University of Technology or the University of KwaZulu-Natal or the funders. References 1. International Diabetes Federation Atlas (2013). http://www.idf.org/sites/default/files/EN_6E_Ch2_ the_Global_Burden.pdf./26/1/14 (accessed 26 January 2014). 2. Omar MAK, Seedat MA, Dyer RB, Motala AA, Knight LT, Becker PJ. South African Indians show a high prevalence of NIDDM and bimodality in plasma glucose distribution patterns. Diabetes Care 1994;17(1):70-73. [http://dx.doi.org/10.2337/diacare.17.1.70] 3. Motala AA, Omar MAK, Gouws E. High risk of progression to NIDDM in South-African Indians with impaired glucose tolerance. Diabetes 1993;42(4):556-563. [http://dx.doi.org/10.2337/ diab.42.4.556] 4. Ranjith N, Pegoraro RJ, Naidoo DP, Shanmugam R, Rom L. Genetic variants associated with insulin resistance and metabolic syndrome in young Asian Indians with myocardial infarction. Metab Syndr Relat Disord 2008;6(3):209-214. [http://dx.doi.org/10.1089/met.2008.0023] 5. Seedat YK, Mayet FG, Khan S, Somers SR, Joubert G. Risk factors for coronary heart disease in the Indians of Durban. S Afr Med J 1990;78(8):447-454. 6. Kish L. Survey Sampling. New York: Wiley-Interscience, 1995. 7. World Health Organization. WHO STEPwise approach to surveillance- Instrument v.1.4. 2003. http://apps.who.int/iris/bitstream/10665/68346/1/ WHO_NMH_CCS_03.03.pdf?ua=1/ (accessed 22 February 2008).

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8. Barba C, Cutter J, Deurenberg P, et al. Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies. Lancet 2004;363(9403):157-163. [http://dx.doi. org/10.1016/s0140-6736(03)15268-3] 9. Chobanian AV, Bakris GL, Black HR, et al. Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42(6):1206-1252. [http://dx.doi.org/10.1161/01.hyp.0000107251.49515.c2] 10. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285(19):2486-2497. [http://dx.doi.org/10.1001/jama.285.19.2486] 11. World Health Organization and International Diabetes Federation. Definition and diagnosis of diabetes mellitus and intermediate hyperglycemia: Report of a WHO/IDF consultation. 2005. http:// apps.who.int/iris/bitstream/10665/43588/1/9241594934_eng.pdf (accessed 16 July 2012). 12. Ascaso JF, Pardo S, Real JT, Lorente RI, Priego A, Carmena R. Diagnosing insulin resistance by simple quantitative methods in subjects with normal glucose metabolism. Diabetes Care 2003;26(12):3320-3325. [http://dx.doi.org/10.2337/diacare.26.12.3320] 13. Yusuf S, Reddy S, Ounpuu S, Anand S. Global burden of cardiovascular diseases: Part II: Variations in cardiovascular disease by specific ethnic groups and geographic regions and prevention strategies. Circulation 2001;104(23):2855-2864. [http://dx.doi.org/10.1161/hc4701.099488] 14. Stewart S, Carrington M, Pretorius S, Methusi P, Sliwa K. Standing at the crossroads between new and historically prevalent heart disease: Effects of migration and socio-economic factors in the Heart of Soweto cohort study. Eur Heart J 2010;32(4):492-499. [http://dx.doi.org/10.1093/eurheartj/ ehq439] 15. Erasmus RT, Soita DJ, Hassan MS, et al. High prevalence of diabetes mellitus and metabolic syndrome in a South African coloured population: Baseline data of a study in Bellville, Cape Town. S Afr Med J 2012;102(11):841-844. [http://dx.doi.org/10.7196/SAMJ.5670] 16. Mikhailidis DP, Papadakis JA, Ganotakis ES. Smoking, diabetes and hyperlipidaemia. J R Soc Promot Health 1998;118(2):91-93. [http://dx.doi.org/10.1177/146642409811800209] 17. Enas EA, Chacko V, Pazhoor SG, Chennikkara H, Devarapalli HP. Dyslipidemia in South Asian patients. Curr Atheroscler Rep 2007;9(5):367-374. [http://dx.doi.org/10.1007/s11883-007-0047-y]

Accepted 16 November 2015.

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Comorbidity of respiratory and cardiovascular diseases among the elderly residing close to mine dumps in South Africa: A cross-sectional study V Nkosi, MPH; J Wichmann, PhD; K Voyi, PhD School of Health Systems and Public Health, Faculty of Health Sciences, University of Pretoria, South Africa Corresponding author: V Nkosi (vnkosi334@gmail.com)

Background. Pollution arising from mine dumps in South Africa (SA) has been a source of concern to nearby communities. Objective. To investigate whether comorbidity of respiratory and cardiovascular diseases among elderly persons (≥55 years) was associated with proximity to mine dumps. Methods. Elderly persons in communities 1 - 2 km (exposed) and ≥5 km (unexposed) from five preselected mine dumps in Gauteng and North West provinces in SA were included in a cross-sectional study. Results. Exposed elderly persons had a significantly higher prevalence of cardiovascular and respiratory diseases than those who were unexposed. Multiple logistic regression analysis indicated that living close to mine dumps was significantly associated with asthma + hyper tension (odds ratio (OR) 1.67; 95% confidence interval (CI) 1.22 - 2.28), asthma + pneumonia (OR 1.86; 95% CI 1.14 - 3.04), emphysema + arrhythmia (OR 1.38; 95% CI 1.07 - 1.77), emphysema + myocardial infarction (OR 2.01; 95% CI 1.73 - 2.54), emphysema + pneumonia (OR 3.36; 95% CI 1.41 - 7.98), hypertension + myocardial infarction (OR 1.60; 95% CI 1.04 - 2.44) and hypertension + pneumonia (OR 1.34; 95% CI 1.05 - 1.93). Conclusion. Detrimental associations between comorbidity of the health outcomes and proximity to mine dumps were observed among the elderly in SA. S Afr Med J 2016;106(3):290-297. DOI:10.7196/SAMJ.2016.v106i3.10243

Pollution arising from mine dumps that serve as depositories for waste materials produced during goldmining processes, has been a source of concern to communities located in close proximity in South Africa (SA).[1,2] The crushed sand-like refuse material is generated during extraction and milling of ground ore during the mining process.[3,4] The material contains a complex mixture of heavy metals and trace elements such as gold, copper, lead, zinc, arsenic, cadmium and selenium.[2,3,5] Mine dumps are generally located in low-lying areas near mining sites, and dust particles or particulate matter are transported to nearby communities by air or by soil and water contamination.[3] The major routes of entry to the body upon exposure include contact with skin or eyes, inhalation and ingestion. Exposed communities tend to be historically marginalised ethnic groups of low socioeconomic status and living in government-funded houses, informal settlements and retirement homes,[8] and are often elderly persons and children.[2,6,7] Moreover, some of the exposed communities also live near highways where there is heavy traffic flow and industries, so are exposed to the effects of ambient particulate matter air pollution, resulting in an increased risk of developing respiratory and cardiovascular diseases.[9–14] Elderly people are potentially highly susceptible to the effects of ambient air pollution as a result of normal and pathological ageing.[15] An increased prevalence of respiratory disease was observed in people living near mining sites in both SA and Portugal, compared with a control group living further away.[6,7,16] No studies have investigated whether exposure to mine dust or living in close proximity to mine dumps poses an increased risk for comorbidity of respiratory and cardiovascular diseases among elderly people, and none have investigated the effects between combinations of various air pollution sources, including mine dust. Comorbidity was defined in the present study as having more than one respiratory or cardiovascular disease. One possible reason for the

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overlap between these two diseases is that they share the same risk factors, which may cause or exacerbate respiratory or cardiovascular diseases in vulnerable individuals.[17] This study is part of a larger project initiated by the Mine Health Safety Council of South Africa (MHSC) around communities located near mine dumps in Gauteng and North West provinces. No studies have investigated the association between potential risk factors and the comorbidity of respiratory and cardiovascular diseases among elderly people living near mine dumps in SA.

Objective

To investigate whether comorbidity of respiratory and cardiovascular diseases among the elderly was associated with proximity to mine dumps. Effect modification between proximity to mine dumps and other air pollution sources was also investigated, e.g. the type of fuel used for cooking/heating in the home, tobacco smoking, and a history of occupational exposure to dust or chemical fumes.

Methods

The study methods have been described in detail elsewhere and a summary of the methods has been provided.[6] Ethical approval (ref. no. 235/2011) was obtained from the Research Ethics Committee, Faculty of Health Sciences, University of Pretoria. Verbal and written consent was obtained from the participants before commencement of interviews.

Population and study design

A cross-sectional study of 2 397 elderly (≥55 years) people from communities living 1 - 2 km (exposed) and ≥5 km (unexposed) from five preselected mine dumps in Gauteng and North West provinces was conducted during November and December 2012. Table 1 lists the selected communities, and Table 2 the population

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size of the elderly people and the targeted sample size in each community under study. The mine dumps were selected before the study by the MHSC because of large population densities around these dumps. Eleven communities were included in the study. A previously validated ATS-DLD-78 questionnaire from the British Medical Research Council was used for face-to-face interviews.[18] The study focused on elderly people who had been living in the study communities for ≥5 years. A ‘knock on the door’ approach was used to recruit study participants. In each community, streets were randomly selected and then four to five houses were randomly selected in each street. The sample size of each community was calculated using Epi Info version 7, with a total sample size of 3 069. Population sizes were based on the 2001 census from Statistics South Africa, because the results of census 2011 were not released when the study commenced.

Questionnaire administration

Twenty-two locally trained fieldworkers were employed, with two assigned to each community. Each fieldworker received thorough training in conducting the interviews using the respiratory health questionnaire before the start of the survey. The interviews were mainly in English and were translated into the local language if the respondent did not understand the questions. The questionnaire included sections on demography, medical history, type of fuel use for residential cooking/heating, tobacco smoking habits, and history of occupational exposure to dust or chemical fumes. The outcomes of interest, e.g. arrhythmia, asthma, emphysema, hypertension, myocardial infarction and pneumonia, were based on positive answers indicating diagnosis of the conditions by a doctor. The main exposure factor of interest in this study was the distance between the study population and the mine dump. For quality control of the interviews, fieldworkers randomly selected 10% of the homes and readministered the same questionnaire to the same previously interviewed respondents to verify their responses. This verification was done 15 - 20 days after the first interview. Within the interviews, a >10% deviation was deemed unacceptable.

Statistical analysis

Two technicians entered the collected questionnaire data into a database set up in Epi Info version 3.5.3. Data were analysed using Stata version 12. Prevalence of the health outcome, the proportion of air pollution sources under investigation, and confounding variables were calculated by dividing the number of participants who responded affirmatively by the number of questionnaires completed. Each question therefore had a different sample size. Observations marked as ‘do not know’, ‘not stated’ or ‘other responses’ were set as missing, but were included in the descriptive analyses. Only two explanatory variables, age and main type of fuel used for heating and cooking in the home, had missing observations. Responses to the number of cigarettes smoked per day were very low and were not included in the analysis. Pearson’s χ2 test was applied to determine the relationship between community (exposed/ unexposed) and confounding variables. Using univariate and multiple logistic regression analysis (LRA) to estimate the likelihood of having asthma, chronic bronchitis, chronic cough, emphysema, pneumonia and wheeze, crude and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Missing values were automatically excluded in each LRA model, so each multiple LRA model had a different sample size. To obtain adjusted ORs for the effect of ‘community (exposed/unexposed)’, outcomes were placed in an initial LRA model. This was followed by the addition of a potential confounder in a stepwise manner, starting with the most statistically

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Table 1. Eleven communities selected in the study located in Gauteng and North West provinces, SA, during November December 2012 Mine dump facility

Province

Exposed

Unexposed

Durban Roodepoort Deep

Gauteng

Braamfischerville

Dobsonville

Crown Gold Recoveries

Gauteng

Diepkloof, Riverlea and Noordgesig

Orlando East

East Rand Proprietary Mines

Gauteng

Reiger Park

Windmill Park

Ergo

Gauteng

Geluksdal

Windmill Park

Anglo Gold Ashanti

North West

Stilfontein

Jouberton

Exposed = communities located 1 - 2 km from mine dumps; Unexposed = communities located ≥5 km from mine dumps.

Table 2. Population sizes of elderly (≥55 years) people in the 11 communities under study Location

Population size, N

Sample size, n

Geluksdal

430

197

Windmill Park

371

184

Reiger Park

155

109

Diepkloof

10 789

351

Dobsonville

4 629

337

Noordgesig

668

235

Orlando East

5 702

334

Jouberton

8 202

348

Stilfontein

2 974

324

Riverlea

1 709

299

Braamfischerville

10 789

351

significant from the univariate analysis. Each time a new potential confounder was added to the model, if the effect estimate between the exposure of interest and comorbidity outcome already in the models changed by more than 5.0%, the additional variable was retained in the final multiple LRA; otherwise, the variable was removed and a different one was added.[19] The most parsimonious multiple LRA models were reported, i.e. those with variables having a p-value of <0.05.[20] Community (exposed/unexposed) was considered as the main exposure factor and was therefore included in all models for each outcome of interest, regardless of whether it was statistically significant in the univariate analyses. Effect modification between community (exposed/unexposed) and other air pollution source variables (smoking habits, occupational exposure history to dust/chemical fumes, and residential cooking/ heating fuel type) was investigated by including a multiplicative term in the model.

Results

Demographic characteristics and air pollution variables by type of community

Detailed demographic characteristics of the respondents and air pollution variables by community type have been published previously (Table 3).[6] There were 1 499 study participants from exposed and 898 from unexposed communities.

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Prevalence of comorbidity stratified by type of community

The prevalences of asthma + emphysema (1.7%), asthma + hyper tension (12.6%), asthma + pneumonia (5.0%), emphysema + myo cardial infarction (0.8%), emphysema + pneumonia (2.5%), hypertension + myocardial infarction (6.5%), hypertension + pneumonia (11.9%) and pneumonia + arrthymia (1.9%) in the exposed communities were higher than those in the unexposed Table 3. Demographic characteristics and air pollution variables by type of community in Gauteng and North West provinces, SA, during November - December 2012 Community Exposed (N=1 499), n (%)

communities, where the percentages were 1.1%, 8.0%, 4.3%, 0.7%, 0.8%, 4.1%, 8.9% and 1.8%, respectively (Table 4).

Table 4. Prevalences of comorbidity by type of community in Gauteng and North West provinces, SA, during November December 2012 Community Exposed, n (%)

Unexposed, n (%)

Total, n (%)

66 (4.4)

44 (4.9)

110 (4.6)

1 432 (95.5)

836 (93.1)

2 268 (94.6)

Missing information

1 (0.1)

18 (2.0)

19 (0.8)

Total

1 499 (62.5)

898 (37.5)

2 397 (100.0)

Yes

26 (1.7)

10 (1.1)

36 (1.5)

1 473 (98.3)

888 (98.9)

2 361 (98.5)

Missing information

Total

1 499 (62.5)

898 (37.5)

2 397 (100.0)

Asthma + arrhythmia Yes

Unexposed (N=898), n (%)

Gender

p-value* 0.66

Female

774 (51.6)

472 (52.3)

Male

725 (48.4)

426 (47.4)

Age (years)

<0.001

55 - 59

500 (33.4)

225 (25.1)

60 - 64

405 (27.0)

221 (24.6)

65 - 69

228 (15.2)

125 (13.9)

70 - 84

309 (20.6)

278 (31.0)

≥85

48 (3.2)

29 (3.2)

Information missing

9 (0.6)

20 (2.2)

Population group

Asthma + hypertension

<0.001

Black

1006 (41.9)

695 (29.0)

Coloured

493 (20.6)

203 (8.5)

Level of education

Asthma + emphysema

Yes

189 (12.6)

72 (8.0)

261 (10.9)

1 292 (86.19)

797 (88.6)

2 089 (87.1)

Missing information

18 (1.2)

29 (3.2)

47 (2.0)

Total

1 499 (64.1)

898 (37.5)

2 397 (100.0)

Yes

75 (5.0)

28 (3.1)

103 (4.3)

1 421 (94.8)

853 (95.0)

2 274 (94.9)

Missing information

3 (0.2)

17 (1.9)

20 (0.8)

Total

1 499 (64.1)

898 (37.5)

2 397 (100.0)

Asthma + pneumonia <0.001

No schooling

262 (17.5)

271 (30.2)

Primary

479 (32.0)

287 (32.0)

Secondary

691 (46.1)

332 (37.0)

Tertiary

67 (4.5)

8 (0.8)

Yes

31 (2.1)

20 (2.2)

51 (2.1)

Non-smoker

888 (59.2)

598 (66.6)

1 468 (97.9)

878 (97.8)

2 346 (97.9)

Ex-smoker

234 (15.6)

187 (20.8)

Missing information

Current smoker

377 (25.2)

113 (12.6)

Total

1 499 (64.1)

898 (37.5)

2 397 (100.0)

Yes

12 (0.8)

7 (0.7)

19 (0.8)

1 487 (99.2)

891 (99.3)

2 378 (99.2)

Missing information

Total

1 499 (64.1)

898 (37.5)

2 397 (100.0)

Yes

38 (2.5)

7 (0.8)

1 461 (97.46) 891 (99.2)

2 352 (98.1)

Missing information

Total

1 499 (64.1)

898 (37.5)

2 397 (100.0)

Smoking habits

<0.001

History of occupational exposure to dust/chemical fumes

<0.001

Yes

637 (42.5)

149 (16.6)

862 (57.5)

749 (83.4)

Main heating/cooking fuel in the home

<0.001

Electricity

1 422 (94.9)

783 (87.2)

Gas

31 (2.1)

67 (7.5)

Paraffin

25 (1.7)

6 (0.7)

Open fires

1 (0.07)

13 (1.5)

20 (1.3)

29 (3.2)

Information missing

Emphysema + arrhythmia

Exposed = communities located 1 - 2 km from mine dumps; Unexposed = communities located ≥5 km from mine dumps.

Emphysema + myocardial infarction

Emphysema + pneumonia

Continued ...

*χ test.

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45 (1.9)

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and were not associated with asthma + hypertension and asthma + pneumonia. A history of occupational exposure to dust/chemical fumes was significantly associated with asthma + hypertension (OR 1.31; 95% CI 1.01 - 1.76). Using polluting fuels such as paraffin or gas for cooking/heating in the home had a significant detrimental association with asthma + pneumonia (OR 2.38; 95% CI 1.08 - 5.23) (Table 6). No significant effect modification between community type (exposed/unexposed) and other air pollution source variables investigated was observed.

Table 4. (continued) Prevalences of comorbidity by type of community in Gauteng and North West provinces, SA, during November - December 2012 Community Exposed, n (%)

Unexposed, n (%)

Total, n (%)

98 (6.5)

37 (4.1)

135 (5.6)

Hypertension + myocardial infarction Yes No

1 394 (93.0)

839 (93.4)

2 233 (93.2)

Missing information

7 (0.5)

22 (2.5)

29 (1.2)

Total

1 499 (64.1)

898 (37.5)

2 397 (100.0)

178 (11.9)

80 (8.9)

258 (10.8)

Hypertension + pneumonia Yes No

792 (88.2)

1 311 (87.5)

2 103 (87.7)

Missing information

10 (2.9)

26 (2.9)

36 (1.5)

Total

1 499 (64.1)

898 (37.5)

2 397 (100.0)

74 (4.9)

52 (5.8)

126 (5.2)

Pneumonia + arrhythmia Yes No

1 422 (94.9)

831 (92.5)

2 253 (94.0)

Missing information

3 (0.2)

15 (1.7)

18 (0.8)

Total

1 499 (64.1)

898 (37.5)

2 397 (100.0)

29 (1.9)

1.7 (1.8)

46 (1.9)

Pneumonia + myocardial infarction Yes No

1 470 (98.1)

867 (96.7)

2 337 (97.5)

Missing information

14 (1.5)

14 (0.6)

Total

1 499 (64.1)

898 (37.5)

2 397 (100.0)

Exposed = communities located 1 - 2 km from mine dumps; Unexposed = communities located ≥5 km from mine dumps.

Multivariate analyses of comorbidity in all 11 study communities

Crude and adjusted ORs for all risk factors except for the main exposure factor are shown in Tables 5 and 6. Results from the multiple LRA (Table 7) indicated that living in the exposed communities was significantly associated with asthma + hypertension (OR 1.67; 95% CI 1.22 - 2.28), asthma + pneumonia (OR 1.86, 95% CI 1.14 - 3.04), emphysema + arrhythmia (OR 1.38, 95% CI 1.07 - 1.77), emphysema + myocardial infarction (OR 2.01; 95% CI 1.73 - 2.54), emphysema + pneumonia (OR 3.36; 95% CI 1.41 - 7.98), hypertension + myocardial infarction (OR 1.60; 95% CI 1.04 - 2.44) and hypertension + pneumonia (OR 1.34; 95% CI 1.05 - 1.93). Population group was not associated with any of the health outcomes considered in this study. The study participants in the age groups 65 - 69 and 70 - 84 years were at an increased likelihood (61.0%) of having asthma + hypertension. Female participants were at an increased risk of having emphysema + arrhythmia (OR 2.02; 95% CI 1.10 - 3.72). Participants with primary school as their highest level of education were 49.0% more likely to have asthma + hypertension. Current smoking and being an ex-smoker significantly increased the likelihood of having asthma + arrhythmia, asthma + emphysema, emphysema + arrhythmia and emphysema + myocardial infarction,

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Discussion

This is the first study to investigate the risk factors associated with comorbidity of respiratory and cardiovascular diseases among elderly people in exposed communities in SA. The results suggest that there was a high prevalence of comorbidity in exposed communities. Living in exposed communities, age, smoking habits, a history of occupational exposure to dust/chemical fumes, and use of gas for cooking/heating in the home were found to be significant risk factors for comorbidity of respiratory and cardiovascular diseases. Mine dumps are considered to be major sources of wind-blown dust that not only constitutes a nuisance but represents a risk to human health.[2,16,21–25] Size distribution analysis of dust particles from mine dumps has revealed high levels of respirable components. According to previous research done on one of the mine dumps in this study, the ambient concentration of particulate matter with an aerodynamic diameter of <10 μm (PM10) greatly exceeded the 24-hour limit set by the SA Department of Environmental Affairs (180 μg/m3).[2,26] Residential developments are encroaching on the bases of mine dumps,[1] and ongoing reclamation of gold from mine dumps observed during the survey increased exposure to particulate matter. Respiratory and cardiovascular diseases were therefore caused or aggravated by exposure to dust from mine dumps. Ageing is an intricate process associated with an increased risk of cardiovascular and respiratory diseases[27–29] as a result of changes in cellular and organ function.[30,31] In this study, an increase in age was not associated with comorbidity of cardiovascular and respiratory diseases. A possible explanation for this finding could be a survivor effect. Contrary to findings reported elsewhere,[32] population group was not associated with the comorbidity outcomes considered in this study. Lower levels of education were also not significantly associated with outcomes of interest in this study, although they are generally known to be linked with lower socioeconomic status and have previously been identified as a risk factor for cardiovascular and respiratory diseases.[33, 34] Current and ex-smoking was significantly associated with respiratory and cardiovascular diseases. Ex-smokers were at higher risk than current smokers of having cardiovascular and respiratory disease comorbidity. Having being diagnosed with cardiovascular and or respiratory disease may have been the reason why study participants stopped smoking. Another possibility could have been advice from doctors, which has been shown to contribute to smoking cessation.[35] The cardiovascular and respiratory systems are vulnerable to occupational exposures owing to direct contact with the ambient environment and inhalation of toxic substances.[36,37] Occupational exposure to dust or chemicals was significantly associated with cardiovascular and respiratory diseases. The findings of this study are in agreement with other research in this respect.[38,39] Domestic use of gas and paraffin (kerosene) was significantly associated with cardiovascular and respiratory diseases, possibly caused by the oxides of nitrogen or carbon monoxide generated when gas or paraffin is burned.[40,41]

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1.06 (0.63 - 1.76)

0.86 (0.52 - 1.43)

0.82 (0.24 - 2.78)

Primary

Secondary

Tertiary

0.71 (0.09 - 5.24)

Paraffin

Open fires

†

1.81 (0.23 - 13.96)

1.68 (0.39 - 7.15)

2.09 (0.98 - 4.43)

0.94 (0.61 - 1.44)

0.97 (0.56 - 1.60)

0.91 (0.53 - 1.57)

1.03 (0.29 - 3.56)

0.83 (0.47 - 1.44)

1.62 (0.94 - 2.77)

1.12 (0.74 - 1.72)

0.66 (0.16 - 2.84)

1.49 (0.89 - 2.49)

1.42 (0.78 - 2.58)

0.82 (0.45 - 1.48)

1.40 (0.94 - 2.09)

Asthma + pneumonia

0.94 (0.22 - 3.91)

1.57 (0.89 - 2.75)

2.27 (1.13 - 4.56)

3.45 (1.79 - 6.63)

0.86 (0.42 - 1.78)

1.10 (0.53 - 2.29)

1.22 (0.68 - 2.18)

2.09 (1.02 - 4.32)

1.55 (0.65 - 3.72)

0.96 (0.41 - 2.25)

1.57 (0.89 - 2.79)

Emphysema + arrhythmia

1.50 (0.60 - 3.73)

3.05 (0.98 - 9.52)

4.17 (1.39 - 12.45)

2.36 (0.51 - 10.94)

2.80 (0.59 - 13.24)

1.12 (0.42 - 2.94)

3.12 (0.97 - 10.01)

2.07 (0.51 - 8.31)

0.29 (0.03 - 2.59)

1.59 (0.62 - 4.05)

Emphysema + myocardial infarction

1.72 (0.23 - 12.88)

0.53 (0.07 - 3.90)

1.25 (0.68 - 2.30)

2.54 (1.24 - 5.19)

2.97 (1.45 - 6.08)

0.58 (0.08 - 4.56)

0.69 (0.32 - 1.47)

0.93 (0.43 - 1.97)

1.47 (0.81 - 2.70)

2.17 (1.02 - 4.59)

1.70 (0.69 - 4.14)

0.52 (0.18 - 1.51)

1.06 (0.59 - 1.91)

Emphysema + pneumonia

Models adjusted for gender, age, population group, smoking habits, level of education, occupational exposure history to dust/chemical fumes and main type of fuel used for heating/cooking in the home.

*Communities located ≥5 km (unexposed) from mine dumps used as reference category.

2.35 (1.00 - 5.51)

2.13 (0.28 - 16.06)

1.63 (0.74 - 3.61)

1.04 (0.55 - 1.98)

1.44 (1.11 - 1.88)

Gas

1.02 (0.51 - 2.06)

1.31 (0.88 - 1.94)

0.96 (0.69 - 1.34)

1.32 (0.96 - 1.83)

0.86 (0.38 - 1.96)

0.76 (0.53 - 1.09)

1.44 (1.02 - 2.03)

0.76 (0.57 - 1.03)

1.26 (0.58 - 2.74)

1.57 (1.10 - 2.24)

1.69 (1.13 - 2.52)

1.26 (0.87 - 1.81)

1.19 (0.92 - 1.55)

Asthma + hypertension

Electricity

Main type of fuel used for heating/ cooking in the home

Yes

1.91 (0.86 - 4.25)

2.23 (1.01 - 4.96)

1.39 (0.86 - 2.24)

Current smoker

1.01 (0.12 - 8.37)

0.97 (0.38 - 2.44)

1.50 (0.60 - 3.71)

1.70 (1.05 - 2.72)

Ex-smoker

History of occupational exposure to dust/ chemical fumes

Non-smoker

Smoking habits

No schooling

Level of education

Coloured

Black

1.66 (0.69 - 3.97)

1.21 (0.61 - 2.43)

1.83 (0.73 - 4.52)

≥85

0.72 (0.46 - 1.13)

1.29 (0.78 - 2.13)

70 - 84

2.08 (0.82 - 5.29)

1.10 (0.60 - 2.00)

65 - 69

0.77 (0.27 - 2.18)

0.75 (0.43 - 1.32)

Population group

1.16 (0.60 - 2.24)

0.98 (0.67 - 1.44)

60 - 64

Asthma + emphysema

55 - 59

Age (years)

Female

Male

Gender

Risk factors†

Asthma + arrhythmia

1.13 (0.27 - 4.79)

1.06 (0.46 - 2.49)

1.67 (1.17 - 2.37)

1.64 (1.09 - 2.46)

1.23 (0.77 - 1.96)

1.17 (0.47 - 2.87)

0.80 (0.52 - 1.23)

0.67 (0.41 - 1.07)

0.86 (0.58 - 1.27)

1.73 (0.70 - 4.27)

2.02 (1.29 - 3.14)

1.03 (0.57 - 1.87)

0.81 (0.48 - 1.39)

1.05 (0.74 - 1.49)

Hypertension + myocardial infarction

2.35 (1.00 - 5.51)

1.04 (0.55 - 1.98)

1.44 (1.11 - 1.88)

0.96 (0.69 - 1.34)

1.32 (0.96 - 1.83)

0.86 (0.38 - 1.96)

0.76 (0.53 - 1.09)

1.44 (1.02 - 2.03)

0.76 (0.57 - 1.03)

1.26 (0.58 - 2.74)

1.57 (1.10 - 2.24)

1.69 (1.13 - 2.52)

1.26 (0.87 - 1.81)

1.19 (0.92 - 1.55)

Hypertension + pneumonia

1.23 (0.29 - 5.21)

0.97 (0.39 - 2.43)

1.13 (0.77 - 1.64)

1.42 (0.92 - 2.20)

1.50 (0.96 - 2.36)

1.61 (0.59 - 4.38)

1.35 (0.81 - 2.24)

1.27 (0.74 - 2.17)

0.96 (0.64 - 1.42)

1.50 (0.57 - 3.98)

1.68 (1.04 - 2.69)

1.10 (0.60 - 2.00)

1.09 (0.66 - 1.81)

0.97 (0.67 - 1.39)

Pneumonia + arrhythmia

3.64 (0.84 - 15.76)

1.10 (0.26 - 4.61)

2.12 (1.18 - 3.80)

3.43 (1.80 - 6.55)

1.56 (0.68 - 3.62)

0.52 (0.06 - 4.08)

0.66 (0.31 - 1.36)

0.78 (0.37 - 1.65)

1.46 (0.80 - 2.65)

2.12 (0.45 - 10.00)

3.10 (1.41 - 6.78)

1.61 (0.59 - 4.36)

0.77 (0.27 - 2.18)

0.63 (0.35 - 1.15)

Pneumonia + myocardial infarction

Table 5. Crude ORs with 95% CIs of risk factors of chronic respiratory and cardiovascular diseases in all 11 study communities located 1 - 2 km and ≥5 km* from mine dumps in Gauteng and North West provinces, SA, during November - December 2012

1.13 (0.75 - 1.70)

Female

0.96 (0.11 - 8.43)

1.18 (0.33 - 4.13)

1.54 (0.67 - 3.50)

0.74 (0.09 - 5.55)

Paraffin

Open fires

1.92 (0.25 - 14.77)

2.18 (0.91 - 5.22)

1.16 (0.55 - 2.25)

1.31 (1.01 - 1.76)

0.87 (0.61 - 1.26)

1.32 (0.94 - 1.87)

0.92 (0.39 - 2.16)

0.80 (0.54 - 1.19)

1.49 (1.04 - 2.12)

0.82 (0.59 - 1.13)

1.01 (0.43 - 2.32)

1.61 (1.11 - 2.32)

1.61 (1.07 - 2.41)

1.22 (0.84 - 1.77)

1.29 (0.98 - 1.70)

Asthma + hypertension

2.37 (0.30 - 19.25)

1.57 (0.36 - 5.23)

2.38 (1.08 - 5.23)

0.80 (0.50 - 1.29)

0.83 (0.59 - 1.78)

0.83 (0.46 - 1.50)

0.83 (0.23 - 3.00)

0.65 (0.35 - 1.23)

1.57 (0.90 - 2.73)

1.29 (0.80 - 2.09)

0.27 (0.03 - 2.01)

1.41 (0.82 - 2.40)

1.34 (0.73 - 2.45)

0.81 (0.45 - 1.47)

1.34 (0.87 - 2.06)

Asthma + pneumonia

0.96 (0.22 - 4.20)

1.71 (0.91 - 3.23)

2.37 (1.11 - 5.07)

3.50 (1.77 - 6.89)

0.87 (0.38 - 1.95)

1.23 (0.58 - 2.62)

1.21 (0.90 - 4.05)

1.91 (0.90 - 4.05)

1.47 (0.61 - 3.57)

0.90 (0.38 - 2.12)

2.02 (0.97 - 3.72)

Emphysema + arrhythmia

1.66 (0.60 - 4.60)

4.03 (1.16 - 14.06)

4.24 (1.32 - 13.63)

2.93 (0.57 - 15.21)

3.41 (0.70 - 16.56)

0.69 (0.21 - 2.18)

3.29 (0.97 - 11.12)

2.13 (0.52 - 8.70)

0.28 (0.03 - 2.53)

2.27 (0.83 - 6.27)

Emphysema + myocardial infarction

1.53 (0.20 - 11.89)

0.70 (0.09 - 5.33)

0.91 (0.46 - 1.79)

1.92 (0.87 - 4.24)

2.77 (1.30 - 5.88)

0.45 (0.05 - 3.85)

0.46 (0.19 - 1.10)

0.80 (0.36 - 1.75)

1.48 (0.74 - 2.93)

2.20 (1.01 - 4.81)

1.61 (0.65 - 3.95)

0.51 (0.18 - 1.49)

1.13 (0.59 - 2.13)

Emphysema + pneumonia

*Communities located ≥5 km (unexposed) from mine dumps used as reference category. † Models adjusted for gender, age, population group, smoking habits, level of education, occupational exposure history to dust/chemical fumes and main type of fuel used for heating/cooking in the home.

0.89 (0.42 - 1.92)

1.31 (0.84 - 2.04)

Gas

Electricity

Main type of fuel used for heating/cooking in the home

Yes

1.83 (0.77 - 4.37)

1.51 (0.89 - 2.55)

History of occupational exposure to dust/ chemical fumes

Current smoker

2.02 (1.01 - 4.71)

1.74 (1.06 - 2.88)

Ex-smoker

Non-smoker

Smoking habits

Tertiary

0.75 (0.27 - 2.09)

1.07 (0.61 - 1.87)

Secondary

1.33 (0.53 - 2.57)

1.18 (0.69 - 1.99)

Primary

No schooling

Level of education

Coloured

Black

1.62 (0.65 - 4.01)

1.17 (0.53 - 2.57)

1.72 (0.63 - 4.67)

≥85

0.60 (0.36 - 1.10)

1.29 (0.77 - 2.17)

70 - 84

2.00 (0.77 - 5.10)

0.76 (0.21 - 2.60)

1.10 (0.60 - 2.03)

65 - 69

1.30 (0.63 - 2.63)

Asthma + emphysema

0.75 (0.43 - 1.32)

60 - 64

Population group

55 - 59

Age (years)

Male

Gender

Risk factors†

Asthma + arrhythmia

1.16 (0.27 - 5.07)

1.02 (0.50 - 2.86)

1.43 (0.97 - 2.86)

1.57 (0.97 - 2.11)

1.25 (1.01 - 2.46)

1.58 (0.61 - 4.05)

1.04 (0.64 - 1.70)

0.75 (0.45 - 1.23)

0.7 (0.46 - 1.09)

2.09 (0.83 - 5.29)

2.31 (1.45 - 3.69)

1.08 (0.59 - 1.98)

0.83 (0.71 - 1.51)

1.18 (0.81 - 1.71)

Hypertension + myocardial infarction

2.82 (1.23 - 6.43)

1.11 (0.57 - 2.14)

0.94 (0.69 - 1.27)

0.91 (0.64 - 1.32)

1.21 (0.85 - 1.71)

1.26 (0.57 - 2.75)

0.98 (0.66 - 1.45)

1.31 (0.90 - 1.89)

0.98 (0.72 - 1.34)

1.23 (0.56 - 2.71)

1.82 (1.28 - 2.60)

1.33 (0.88 - 2.02)

1.03 (0.71 - 1.51)

1.06 (0.81 - 1.40)

Hypertension + pneumonia

1.32 (0.31 - 5.63)

0.99 (0.39 - 2.54)

1.16 (0.76 - 1.77)

1.52 (0.94 - 2.46)

1.43 (0.88 - 2.31)

2.22 (0.79 - 6.27)

1.61 (0.93 - 2.77)

1.37 (0.80 - 2.35)

0.79 (0.50 - 4.39)

1.48 (0.50 - 4.39)

1.73 (1.06 - 2.04)

1.11 (0.61 - 2.04)

1.11 (0.66 - 1.85)

3.81 (0.84 - 17.51)

1.14 (0.26 - 4.97)

1.81 (0.92 - 3.58)

2.89 (1.40 - 5.98)

1.27 (0.52 - 3.11)

0.79 (0.09 - 6.64)

0.71 (0.31 - 1.62)

0.88 (0.40 - 1.91)

1.57 (0.78 - 3.13)

2.55 (0.52 - 12.54)

2.99 (1.32 - 6.74)

1.54 (0.56 - 4.23)

0.75 (0.26 - 2.14)

0.77 (0.41 - 1.48)

1.04 (0.71 - 1.54)

Pneumonia + myocardial infarction

Pneumonia + arrhythmia

Table 6. Adjusted ORs with 95% CIs risk factors of chronic respiratory and cardiovascular diseases in all 11 study communities located 1 - 2 km and ≥ 5km* from mine dumps in Gauteng and North West provinces, SA, during November - December 2012

RESEARCH

Table 7. Univariate and multivariate analyses of respiratory and cardiovascular diseases comorbidity in all 11 study communities located 1 - 2 km and ≥5 km* from mine dumps in Gauteng and North West provinces, SA, during November - December 2012 Respiratory and cardiovascular diseases†

Crude OR (95% CI)

p-value

Adjusted OR (95% CI)

p-value

Asthma + arrhythmia

0.88 (0.59 - 1.29)

0.506

0.82 (0.53 - 1.27)

0.373

Asthma + emphysema

1.57 (0.75 - 3.27)

0.230

1.41 (0.64 - 3.10)

0.390

Asthma + hypertension

1.77 (1.43 - 2.20)

<0.001

1.67 (1.22 - 2.28)

0.001

Asthma + pneumonia

1.72 (1.12 - 2.63)

0.013

1.86 (1.14 - 3.04)

0.016

Emphysema + arrhythmia

1.25 (1.01 - 1.58)

0.018

1.38 (1.07 - 1.77)

0.014

Emphysema + myocardial infarction

1.96 (1.65 - 2.32)

<0.001

2.01 (1.73 - 2.54)

<0.001

Emphysema + pneumonia

3.31 (1.47 - 7.45)

0.004

3.36 (1.41 - 7.98)

0.006

Hypertension + myocardial infarction

1.59 (1.08 - 2.34)

0.018

1.60 (1.04 - 2.44)

0.033

Hypertension + pneumonia

1.34 (1.01 - 1.78)

0.037

1.43 (1.05 - 1.93)

0.022

Pneumonia + arrhythmia

0.83 (0.58 - 1.19)

0.322

0.73 (0.48 - 1.09)

0.130

Pneumonia + myocardial infarction

1.01 (0.55 - 1.84)

0.984

0.77 (0.39 - 1.50)

0.441

Study limitations

Some limitations and advantages of this study have been published previously.[6] The study has additional limitations inherent to crosssectional epidemiological study designs: (i) it cannot provide any evidence of causality; (ii) no quantitative air pollution exposure assessment was conducted; and (iii) it relied on doctor-diagnosed respiratory and cardiovascular diseases, which, although specific, can underestimate disease prevalence. It is therefore assumed that several individuals with respiratory and cardiovascular diseases were missed as a result of restrictive definitions employed in this study or poor access to healthcare facilities.[42] The possibility of estimating falsely low prevalence figures cannot be ignored. However, the observed high prevalence of respiratory and cardiovascular diseases in exposed communities cannot be attributed only to the strict definition used, but is also likely to be due to a complex interaction of social, economic, and behavioural factors such as air pollution, undernutrition, poor access to healthcare or lifestyle behaviours.[43,44] Further limitations are that: (iv) interviewer error may have occurred during translation of the questions into the local language during interviews with study participants who did not understand English; (v) unwillingness of the respondents to provide honest answers, or their giving socially desirable responses, should be taken into account in the interpretation of results; and (vi) no data were collected on possible reasons for declining to take part – the differential participation rate between exposed and unexposed communities is of concern and may well have introduced response bias, which is likely to overestimate the prevalence estimates derived and bias the association in either direction; and (vii) data on how access to healthcare varied between exposed and unexposed communities were not collected. Interviewing 10% of the study respondents twice resulted in 96% repeatability.

Conclusion

The findings of this study suggest a high prevalence of respiratory and cardiovascular diseases, with detrimental associations observed between comorbidity of the health outcomes and proximity to mine dumps, among the elderly in SA. The significant risk factors were proximity to mine dumps, age group, occupational exposure history to dust/chemical fumes, and main type of fuel used for heating/ cooking in the home. Acknowledgments. We thank everybody who participated in the questionnaire interviews, Mr Moses Kebalepile and all the fieldworkers

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who assisted in data collection, the data technicians for the data capturing, and Statistics South Africa for providing the population sizes of elderly people in each study community. The study was funded by the Mine Health Safety Council, the National Research Fund – Deutscher Akademischer Austausch Dienst and the University of Pretoria. References 1. Oguntoke O, Ojelede ME, Annegarn HJ. Frequency of mine dust episodes and the influence of meteorological parameters on the Witwatersrand area, South Africa. Int J Atmos Sci 2013;2013(1):110. [http://dx.doi.org/10.1155/2013/128463] 2. Ojelede ME, Annegarn HJ, Kneen MA. Evaluation of aeolian emissions from gold mine tailings on the Witwatersrand. Aeolian Res 2012;3(4):477-486. [http://dx.doi.org/10.1016/j.aeolia.2011.03.010] 3. Moreno ME, Acosta-Saavedra LC, Meza-Figueroa D, et al. Biomonitoring of metal in children living in a mine tailings zone in Southern Mexico: A pilot study. Int J Hyg Environ Health 2010; 213(4):252-258. 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23. Jonnalagadda SB, Nenzou G. Studies on arsenic rich mine dumps: III. Effect on the river water. J Environ Sci Health 1996;31(10):2547-2555. [http://dx.doi.org/10.1080/10934529609376509] 24. Chang P, Kim JY, Kim KW. Concentrations of arsenic and heavy metals in vegetation at two abandoned mine tailings in South Korea. Environ Geochem Health 2005;27(2):109-119. [http://dx.doi.org/10.1007/s10653-005-0130-7] 25. Kon LC, Durucan S, Korre A. The development and application of a wind erosion model for the assessment of fugitive dust emissions from mine tailings dumps. International Journal of Mining, Reclamation and Environment 2007;21(3):198-218. [http://dx.doi.org/10.1080/17480930701365547] 26. National Environmental Management. Air Quality Act 39 of 2004. Government Notice Gazette 2005, No. 28016. http://www.saflii.org/za/legis/consol_act/nemaqa2004454 (accessed 21 October 2015). 27. Lakatta EG. Age-associated cardiovascular changes in health: Impact on cardiovascular disease in older persons. Heart Fail Rev 2002;7(1):29-49. [http://dx.doi.org/10.1023/A:1013797722156, http:// dx.doi.org/10.1023/A:1013708104410] 28. Deveci F, Deveci SE, TĂźrkoÄ&#x;lu S, et al. The prevalence of chronic obstructive pulmonary disease in Elazig, Eastern Turkey. Eur J Intern Med 2011;22(2):172-176. [http://dx.doi.org/10.1016/j. ejim.2010.12.014] 29. Brashier B, Londhe J, Madas S, Vincent V, Salvi S. Prevalence of self-reported respiratory symptoms, asthma and chronic bronchitis in slum area of a rapidly developing Indian city. Open J Respir Dis 2012; 2(3):73-81. [http://dx.doi.org/10.4236/ojrd.2012.23011] 30. Dimmeler S, Nicotera P. MicroRNAs in age-related diseases. EMBO Mol Med 2013;5(2)180-190. [http://dx.doi.org/10.1002/emmm.201201986] 31. Sharma G, Goodwin J. Effect of aging on respiratory system physiology and immunology. Clin Interv Aging 2006;1(3):253-260. [http://dx.doi.org/10.2147/ciia.2006.1.3.253] 32. Phaswana-Mafuya N, Peltzer K, Chirinda W, et al. Self-reported prevalence of chronic noncommunicable diseases and associated factors among older adults in South Africa. Glob Health Action 2013;6(20936):1-7. [http://dx.doi.org/10.3402/gha.v6i0.20936] 33. Damiani G, Federico B, Bianchi CBNA. Socio-economic status and prevention of cardiovascular disease in Italy: Evidence from a national health survey. Eur J Publ Health 2011;21(5)591-596. [http:// dx.doi.org/10.1093/eurpub/ckq075]

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34. Kanervisto M, Vasankari T, Laitinen T, et al. Low socioeconomic status is associated with chronic obstructive airway diseases. Respir Med 2011;105(8):1140-1146. [http://dx.doi.org/10.1016/j.rmed.2011.03.008] 35. Research Committee of the British Thoracic Society. Smoking cessation in patients: Two further studies by the British Thoracic Society. Thorax 1990;45(11):835-840. [http://dx.doi.org/10.1136/thx.45.11.835] 36. Upadhyay S, Ganguly K, Stoeger T, et al. Cardiovascular and inflammatory effects of intratracheally instilled ambient dust from Augsburg, Germany, in spontaneously hypertensive rats (SHRs). Part Fibre Toxicol 2010;7(27):1-20. [http://dx.doi.org/10.1186/1743-8977-7-27] 37. Balmes JR. Occupational respiratory diseases. Prim Care 2000;27(4):1009-1038. [http://dx.doi. org/10.1016/S0095-4543(05)70187-1] 38. Ibfelt E, Bonde JP, Hansen J. Exposure to metal welding fume particles and risk for cardiovascular disease in Denmark: A prospective cohort study. Occup Environ Med 2010;67(11):772-777. [http:// dx.doi.org/10.1136/oem.2009.051086] 39. Blanc PD, Iribarren C, Trupin L, et al. Occupational exposures and the risk of COPD: Dusty trades revisited. Thorax 2009;64(1):6-12. [http://dx.doi.org/10.1136/thx.2008.099390] 40. Jarvis D, Chinn S, Luczynska C, Burney P. Association of respiratory symptoms and lung function in young adults with use of domestic gas appliances. Lancet 1996;347(8999):426-431. [http://dx.doi. org/10.1016/S0140-6736(96)90009-4] 41. Dennekamp M, Howarth S, Dick CA, et al. Ultrafine particles and nitrogen oxides generated by gas and electric cooking. Occup Environ Med 2001;58(8):511-516. [http://dx.doi.org/10.1136/oem.58.8.511] 42. Harris B, Goudge J, Ataguba JE. Inequities in access to health care in South Africa. J Public Health Policy 2011;32(Suppl 1):S102-S123. [http://dx.doi.org/10.1057/jphp.2011.35] 43. Aggarwal AN, Chaudhry K, Chhabra SK. Prevalence and risk factors for bronchial asthma in Indian adults: A multicentre study. Indian J Chest Dis Allied Sci 2006;48(1):13-22. 44. Agarwal S, Srivastava A, Kumar S. Urban health in developing countries. In: Gibbons MC, Bali R, Wickramasinghe N, eds. Perspectives of Knowledge Management in Urban Health. Springer, 2010:6194. [http://dx.doi.org/10.1007/978-1-4419-5644-6_5]

Accepted 21 October 2015.

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A cohort study of elderly people in Bloemfontein, South Africa, to determine health-related quality of life and functional abilities A M Gerber,1 PhD; R Botes,2 MSc; A Mostert,1 MB ChB; A Vorster,1 MB ChB; E Buskens,2 PhD 1 2

epartment of Basic Medical Sciences, Faculty of Health Sciences, University of the Free State, Bloemfontein, South Africa D Department of Health Technology Assessment, University Medical Centre Groningen, University of Groningen, Netherlands

Corresponding author: A M Gerber (gerberam@ufs.ac.za)

Background. An ageing population has become an issue of global importance. According to statistics, the number of people aged ≥60 years will outnumber children <5 years by 2020. Objective. To identify chronic and comorbid diseases that contribute to reduced quality of life (QoL) and functional ability in elderly people living in nursing homes in Bloemfontein, Free State, South Africa (SA). Methods. This study used utility- and capability-based questionnaires EQ-6D and a modified ICECAP-O to identify chronic and comorbid diseases that contribute to reduced QoL and functioning in the elderly. An information leaflet was supplied to respondents, along with an informed consent form that each signed and dated. The respondents participated voluntarily and anonymously. Structured interviews were conducted. No algorithm for the EQ-6D or ICECAP-O is available for the SA population. Statistical Package for the Social Sciences version 16 was used to perform the sum score calculations. Data were presented using standard descriptive statistics (frequencies, medians, means, standard deviations and standard errors). Results. The total sample comprised 104 elderly respondents, 72.1% females and 27.9% males (mean age 77 years). Most suffered from at least two of the following diseases: hypertension (68.8%), joint disease (46.2%), heart disease (22.1%), cancer (19.2%) and psychological disorders (18.3%). The EQ-6D indicated that ‘pain’ (48.3%) and ‘mobility’ (36.2%) were the domains chiefly affected. Elderly subjects with extreme problems reported all domains to be equally affected, with the exception of ‘cognition’ (29.1%). Conclusions. Our results confirm that diseases result in pain and affect mobility and cognition in old age. Access to healthcare and services for older people involves recognition of the importance of health promotion and activities that will help prevent disease, and there should be a focus on maintaining independence, prevention and delay of disease, and disability treatment. This includes improving QoL in elderly people with existing disabilities. Reform of medical care services is essential to improve healthcare for the elderly and thus improve their QoL. S Afr Med J 2016;106(3):298-301. DOI:10.7196/SAMJ.2016.v106i3.10171

In April 2002, the United Nations Political Declaration and Madrid International Plan of Action on Ageing[1] adopted ‘a turning point in how the world addresses the key challenges of building a society for all ages’. The World Health Organization[2] warns that effective strategies should be found to address the problems faced by an ageing world population, as chronic diseases will greatly affect the quality of life (QoL) of older people. People all over the world are living longer, levels of chronic illness are increasing, and a decrease in general wellbeing is poised to become a major global public health challenge.[2] ‘An ageing world population refers to the process by which the older population becomes a proportionally larger component of the total population. This is an outcome of a population’s demographic transition from higher to lower levels of fertility and mortality.’[3] The increase in longevity has largely been due to the decline in deaths from cardiovascular disease, i.e. stroke and ischaemic heart disease, mainly because of improved health management and effective health interventions. Effective health interventions at the right time can increase life expectancy. Worldwide, life expectancy of older people continues to rise. According to statistics, by 2020 the number of people aged ≥60 years will outnumber children <5 years of age, and by 2050, the world’s population aged ≥60 years is expected to total 2 billion, from 841 million today. Eighty percent of these older people will be living in low-income and middle-income countries. ‘It is therefore ironic that a relative lack of concern is observed in many of the less developed countries in the world.’[3]

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Although people are living longer, they are not necessarily healthier. Nearly a quarter (23%) of the overall global burden of death and illness is in people aged >60 years. This burden is attributable to diseases such as cancer, chronic respiratory diseases, heart disease, musculoskeletal diseases such as arthritis and osteoporosis, and mental and neurological disorders. Sub-Saharan Africa carries a high disease burden, and the elderly population in this region is set to increase from 36.6 million to 141 million by 2050.[4] Multimorbidity causes a cumulative decline in self-rated health in the elderly. Social networks are complex interactions between family, the wider community and spouses to determine mental and physical health.[5] Different subgroups in the elderly population experience health and health-related QoL very differently.[6] Healthcare and treatment choices for the elderly are challenges made unique by various social, psychological and physical problems occurring in advanced age.[7] Factors such as resilience, self-efficacy and the perception of life as meaningful and manageable are important factors to consider when determining QoL and function in this age group.[8] Older people should continue to participate in the economic, social, cultural and political lives of their societies and enjoy health, security and fulfilment.[1] In terms of the capability approach, functional ability is important, focusing on what people actually achieve with the resources at their disposal.[9] Different diseases affect an individual’s ability to function to different degrees, and can induce a state referred to as potential

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disability. In order to make appropriate healthcare and treatment choices, it is therefore essential to understand how health profiles affect QoL and function in the elderly. However, premorbid QoL, age and comorbidity all also have significant effects.[10] Statistics in Europe indicate that two-thirds of European elderly people report disability.[6] According to Unger,[11] it is more than likely that the approach to healthcare for the elderly will change significantly in the future, with more focus on self-care initiatives, e-health systems and patient-centred approaches, whereas Arai et al.[7] suggest that reform of medical care services is essential for better healthcare delivery to the elderly to improve their QoL. To enable us to adapt healthcare services, it is important to prioritise the personal needs of the elderly regarding resource allocation and healthcare services.[12] Medical decision-making should always be a shared interaction between patient and medical staff. Elderly patients with multiple chronic conditions report a desire for individualised patient-centred care. The elderly patient will have to make medical treatment choices based on personal values, beliefs, goals, treatment options, treatment benefits/risks and costs.[13] This study investigated the effects of prevalent chronic diseases and multimorbidity on functional ability and QoL in elderly people in Bloemfontein, South Africa (SA). We expected that elderly individuals suffering from multimorbidity would experience a larger decline in QoL and functional achievement than those suffering from a single chronic disease. We hope that this information can provide an insight into the experiences of the diseased elderly, and thus contribute to a much-needed change in the approach to healthcare and management of this age group.

Objective

Using utility- and capability-based questionnaires, to identify chronic and comorbid diseases that significantly contribute to the reduction of QoL and function in the elderly.

Methods

We recruited 104 elderly individuals living in Bloemfontein. The respondents were all aged ≥65 years, were living in nursing homes, and were dependent and receiving moderate care. Individuals who were unwilling or unable to complete the questionnaires were excluded.

Data collection

The following procedure was followed: the investigators identified themselves and described the purpose and relevance of the study to potential subjects, who were then given an information leaflet and an informed consent form to sign and date. The subjects were asked if they were willing to participate voluntarily and anonymously in the completion of the questionnaires and the evaluations, which would take about 15 minutes. Finally, the investigators assured respondents that their identity and privacy would be maintained if the findings of this study were published. Respondents were asked to describe their own health using the descriptive system of the Six‑Dimensional EuroQol questionnaire (EQ-6D) and a version of the ICEpop capability measure for older people (ICECAP-O). The EQ-6D The EQ-6D is a utility-based questionnaire developed by the Euroqol group. It mainly focuses on health-related QoL. Domains included in the EQ-6D are mobility, self-care, usual activities, pain/discomfort, anxiety/depression and cognition. The EQ-6D is an updated version of the EQ-5D, including a sixth domain, namely cognition. Each

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domain has three possible answer categories: 1 = ‘no problem’, 2 = ‘moderate problems’ and 3 = ‘extreme problems’. This part of the EQ-6D was used to describe the actual self-reported health state of the elderly respondents. ICECAP-O The ICECAP-O is a capability-based questionnaire, designed specifically for the elderly. The ICECAP-O version we used is different from the original questionnaire in that it contains five possible answer categories instead of four. These are attachment (feelings of love and affection), enjoyment (activities providing joy or pleasure), security (feeling secure when considering health and finances), role (having a purpose) and control (making one’s own decisions).[14,15] In the context of this study the five outcomes were viewed as being functions and not capabilities. The five answer categories are as follows: 1 = all functions are achieved, 2 = a lot are achieved, 3 = some are achieved, 4 = few are achieved, and 5 = none are achieved. The respondents were instructed to complete the questionnaire by reflecting on their own health. Evaluation In addition, respondents were asked to evaluate 10 hypothetical health states for each questionnaire. This involved imagining the value they would apply to hypothetical states in the different domains. A visual analogue scale (VAS) was used for this valuation exercise, zero (0) representing the worst imaginable health state and 100 the best imaginable health state. Since there are six domains in the EQ-6D questionnaire, each health state consisted of six consecutive numbers, as follows: 111111, 112112, 212111, 111221, 212121, 133113, 212321, 333211, 323331 and 333333. An identical version of the VAS scale was used in the evaluation of the ICECAP-O questionnaire. The health states evaluated from the ICECAP-O were 11111, 11122, 11245, 11312, 12335, 21114, 33333, 33544, 44433 and 55555. Demographic information and information on disease prevalence was collected, and structured interviews were conducted.

Ethical approval

The University Medical Centre Groningen (UMCG) gave ethical approval for the study, as it was initially part of a bigger study that involved the Dutch population. During the ethical approval of the pilot study, conducted in SA and the Netherlands, the UMCG ethical committee found that the interviews were not classified as invasive interventions, and no additional ethical application was warranted. No additional ethical approval was sought in SA. Each respondent received an information leaflet as well as a document regarding informed consent. They all signed and dated these documents.

Statistical analysis

The proportion of respondents reporting problems was calculated according to each of the EQ-6D and ICECAP-O domains. The EQ-6D sum scores, as well as the sum scores of the two questionnaires, were also calculated. The overall scores were calculated using the Dolan (UK) EQ-5D algorithm. No algorithm for the EQ-6D or ICECAP-O is available for the SA population. Statistical Package for the Social Sciences version 16 was used to perform the sum score calculations. The data were analysed and interpreted by the investigators with the assistance of a statistician. Data were presented using standard descriptive statistics, e.g. frequencies, medians, means, standard deviations and standard errors. Trends, correlations and meaningful differences were noted and interpreted to draw consequential conclusions.

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Results

The total sample comprised 104 respondents, of whom 75 (72.1%) were females. The mean age was 77 years (range 74 - 92) (Table 1). Responses indicated that 16.3% had a primary school education, 50.0% a secondary school education and 18.3% a tertiary education, and that 74.0% were religious. The disease profiles showed that most subjects suffered from two or more comorbid illnesses, the five most prevalent being hypertension, joint disease, heart disease, cancer and psychological disorders. Table 2 shows the EQ-6D domains most affected in the elderly subjects. The respondents experiencing ‘some problems’ rated the domains from the most to the least affected as follows: pain, mobility, cognition, anxiety, activity and self-care. Elderly subjects with ‘extreme problems’ reported all the domains to be equally affected, with the exception of ‘cognition’. Average values for the EQ-6D health states as evaluated by the respondents are shown in Fig. 1. There is very little variation between the health states, with values of between 72 and 75. Table 3 shows that the modified ICECAP-O descriptions indi cating ‘some’ satisfaction showed that the ‘role’, ‘security/pleasure’ and ‘attachment’ functions were most affected. The descriptions indicating ‘a little’ satisfaction showed that ‘pleasure’, ‘role’ and ‘security’ were the functions most affected, while the descriptions indicating ‘none’ showed ‘control’ and ‘role’ to be most affected. The average ICECAP-O health state evaluations of the elderly respondents showed values of between 73 and 76 (Fig. 2). Very little variance is seen between the health states.

Discussion

Respondents reporting some problems in the EQ-6D questionnaire indicated ‘pain’ and ‘mobility’ to be the domains most affected. However, the ‘extreme’ group reported the same amount of problems across all the domains with the exception of ‘cognition’. The general response indicated that ‘pain’, ‘mobility’ and ‘cognition’ were the domains most affected. This is not surprising, since the two most prevalent diseases in this sample were hypertension and joint disorders. We therefore speculate that suffering from hypertension and joint disorders could possibly account for the majority of the group reporting ‘some problems’ regarding pain and mobility. We furthermore suggest that the elderly experiencing ‘extreme problems’ are experiencing such a decline in health that QoL in general is affected. The respondents’ evaluations of the different health states indicate that the better and worse health states are valued similarly. It is difficult to determine which health states are implicitly more acceptable to the elderly and which are more unacceptable. An explanation could be that only 18.3% of the elderly respondents suffered from no or just one disease, while the rest were all suffering from more than one. Multimorbidity and the negative effects on selfrated health could account for this phenomenon, but further research is needed to confirm this finding. The ICECAP-O results indicate that the same three functions were affected in the ‘some’ and ‘a little’ groups, security, pleasure and role being identified as the functions most affected. The ‘none’ group also reported role and control as functions affected. Intriguingly, the role ‘function’ is relevant in all three groups. We therefore speculate that although the majority of the respondents achieved high levels of wellbeing, some experienced difficulty in identifying with their new environment and position in society. These results further support the fact that although the elderly are all part of the same age group, levels of functional achievement subjectively separate them into distinct groups, with lack of achievement causing specific and unique problems. Because the respondents’ evaluations of the

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Table 1. Demographic data of the elderly subjects (N=104) according to the EQ-6D n (%) Gender Male

29 (27.9)

Female

75 (72.1)

Level of education Primary education

17 (16.3)

Secondary education

52 (50.0)

Diploma

19 (18.3)

University degree

16 (15.4)

Other

Religious Yes

77 (74.0)

27 (26.0)

Number of diseases None

5 (4.8)

14 (13.5)

44 (42.3)

17 (16.3)

11 (10.6)

8 (7.7)

5 (4.8)

Disease type* Hypertension

71 (68.3)

Joint disorders

48 (46.2)

Heart disease

23 (22.1)

Cancer

20 (19.2)

Psychological disorder

19 (18.3)

COPD

16 (15.4)

Kidney/gallstones

15 (14.4)

Stroke

7 (6.7)

Diabetes

4 (3.8)

Kidney disorder

2 (1.9)

Epilepsy

2 (1.9)

COPD = chronic obstructive pulmonary disease. *Respondents could list more than one disease.

Table 2. EQ-6D results per domain (%) (N=104) Domain

No problems

Some problems

Extreme problems

Mobility

61.4

36.3

7.2

Self-care

90.1

7.3

7.2

Activity

80.4

17.1

7.1

Pain

48.4

48.2

8.4

Anxiety

69.2

28.1

7.1

Cognition

74.3

29.1

1.3

different health states indicated little variance between the better and worse states, we argue that multimorbidity plays an important role in determining health state evaluations.

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100

Minimum Average

VAS results

Maximum

50 25

333333

323331

333211

212321

133113

212121

111221

212111

111111

112112

Health states

Fig. 1. The EQ-6D VAS evaluation results (N=104).

Table 3. ICECAP results (%) (N=104) Domain

All

A lot

Some

A little

None

Attachment

82.2

11.1

9.3

2.3

0.3

Pleasure

42.4

38.1

15.4

9.2

0.2

Security

61.4

23.2

15.4

5.3

0.3

Role

46.1

31.2

18.4

7.1

2.4

Control

74.4

17.4

6.1

4.4

3.3

100

Minimum Average

VAS results

Maximum

diseases to one of chronic and degenerative diseases.[1] Having more older people than ever before may imply increases in the prevalences of chronic disease and disability. From this study we conclude that policy makers and health services should look at designing interventions to address the onset and management of multimorbidity. Furthermore, integrated cost-effective interventions aimed at improving specific healthrelated domains as well as non-health-related functions according to health profiles should have a positive impact on QoL and functional achievement in the elderly. Our findings show that pain and mobility were the domains most affected. The functions of security, pleasure and especially role were not achieved to satisfaction, which has a profound effect on an individual’s QoL and wellbeing. Addressing these problems through cost-effective health and psychological support will ensure optimal functioning and QoL achievements. Planning, policy development and allocation of resources to the ageing population are particularly difficult in developing countries, since populations often age before significant socioeconomic development has taken place. Advancing age will increasingly demand long-term, chronic, frail and end-of-life care, and at the same time increase the need for appropriately trained healthcare staff and facilities. According to Dr John Beard, Director of Ageing and Life Course at the World Health Organization, ‘Deep and fundamental reforms of health and social care systems will be required.’[2] Acknowledgement. We thank all who were willing to participate in the study and Ms T Mulder, medical editor in the Faculty of Health Sciences, University of the Free State, for technical and editorial assistance with preparation of the manuscript.

References 25

55555

44433

33544

33333

21114

12335

11312

21245

112112

111111

Health states

Fig. 2. The ICECAP VAS evaluation results (N=104).

The demographic ageing of a population is directly related to fundamental changes in its health and disease patterns. We aimed to provide policy makers with information that will help them make decisions regarding prioritisation and resource allocation for the elderly in the future. In addition, general practitioners, gerontologists and geriatric specialists can use this information to identify and assist elderly individuals at risk of declining health-related QoL and impaired functional achievement. Information also needs to be conveyed to the elderly individuals themselves to help them formulate personal, informed and effective healthcare choices.[3]

Study limitations

This study did not differentiate between specific disease types and their individual effects on health-related QoL. Scope exists for a more disease-orientated approach in future studies. The study population was limited to old-age homes in Bloemfontein.

Conclusions

An epidemiological transition under way all over the world indicates a shift from a predominance of infectious and parasitic

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1. United Nations. Political declaration and Madrid International Plan of Action on Ageing. Second World Assembly. Madrid, Spain: United Nations, 2002. http://www.un.org/en/events/pastevents/pdfs/ Madrid_plan.pdf (accessed 2 February 2015). 2. World Health Organization. ‘Ageing well’ Must Be a Global Priority. News release. Geneva: WHO, 6 November 2014. http://www.who.int/mediacentre/news/releases/2014/lancet-ageing-series/en/ (accessed 4 February 2015) 3. Joubert J, Bradshaw D. Population ageing and health challenges in South Africa. In: Steyn K, Fourie J, Temple N, eds. Chronic Diseases of Lifestyle in South Africa: 1995-2005. Cape Town: South African Medical Research Council, 2006:204-219. 4. Kimokoti RW, Hamer DH. Nutrition, health, and aging in sub-Saharan Africa. Nutr Rev 2008;66(11):611-623. [http://dx.doi.org/10.1111/j.1753-4887.2008.00113.x] 5. Alonso-Morán E, Nuño-Solinís R, Orueta JF, Fernandez-Ruanova B, Alday-Jurado A, GutiérrezFraile E. Health-related quality of life and multimorbidity in community-dwelling telecare-assisted elders in the Basque Country. Eur J Intern Med 2015;26(3):169-175. [http://dx.doi.org/10.1016/j. ejim.2015.02.013] 6. König HH, Heider D, Lehnert T, et al. Health status of the advanced elderly in six European countries: Results from a representative survey using EQ-5D and SF-12. Health Qual Life Outcomes 2010;8:143. http://hqlo.biomedcentral.com/articles/10.1186/1477-7525-8-143 (accessed 4 February 2016). 7. Arai H, Ouchi Y, Yokode M, et al. Toward the realization of a better aged society: Messages from gerontology and geriatrics. Geriatr Gerontol Int 2012;12(1):16-22. [http://dx.doi.org/10.1111/j.14470594.2011.00776.x] 8. Bowling A, Iliffe S. Psychological approach to successful ageing predicts future quality of life in older adults. Health Qual Life Outcomes 2011;9:13. [http://dx.doi.org/10.1186/1477-7525-9-13] 9. Anand P. Capabilities and health. J Med Ethics 2005;31(5):299-303. [http://dx.doi.org/10.1136/ jme.2004.008706] 10. Van Jaarsveld CH, Sanderman R, Ranchor AV, Ormel J, van Veldhuisen DJ, Kempen GI. Genderspecific changes in quality of life following cardiovascular disease: A prospective study. J Clin Epidemiol 2002;55(11):1105-1112. [http://dx.doi.org/10.1016/S0895-4356(02)00506-1] 11. Unger F. Health is wealth: Considerations to European healthcare. Prilozi 2012;33(1):9-14. 12. Diederich A, Swait J, Wirsik N. Citizen participation in patient prioritization policy decisions: An empirical and experimental study on patients’ characteristics. PLoS One 2012;7(5):e36824. [http:// dx.doi.org/10.1371/journal.pone.0036824] 13. Holzmueller CG, Wu AW, Pronovost PJ. A framework for encouraging patient engagement in medical decision making. J Patient Saf 2012;8(4):161-164. [http://dx.doi.org/10.1097/ PTS.0b013e318267c56e] 14. Coast J, Flynn TN, Natarajan L, et al. Valuing the ICECAP capability index for older people. Soc Sci Med 2008;67(5):874-882. [http://dx.doi.org/10.1016/j.socscimed.2008.05.015] 15. Coast J, Peters TJ, Natarajan L, Sproston K, Flynn T. An assessment of the construct validity of the descriptive system for the ICECAP capability measure for older people. Qual Life Res 2008;17(7):967976. [http://dx.doi.org/10.1007/s11136-008-9372-z]

Accepted 6 October 2015.

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Children with disabling chronic conditions in the Western health subdistrict of Cape Town, South Africa: Estimating numbers and service gaps A Redfern,1 MB ChB, MPhil; A Westwood,2 MB ChB, MMed, MD; K A Donald,3 MB ChB, MPhil, PhD epartment of Paediatrics and Child Health, Tygerberg Childrenâ&#x20AC;&#x2122;s Hospital, Faculty of Medicine and Health Sciences, D Stellenbosch University, Cape Town, South Africa 2 School of Child and Adolescent Health, Faculty of Health Sciences, University of Cape Town, and General Paediatrics, Metro West, Department of Health, Provincial Government of the Western Cape, Cape Town, South Africa 3 Division of Developmental Paediatrics, Department of Paediatrics and Child Health, Red Cross War Memorial Childrenâ&#x20AC;&#x2122;s Hospital, University of Cape Town, South Africa 1

Corresponding author: A Redfern (redfern@sun.ac.za)

Background. Children with disabling chronic conditions often have extensive, complex and unmet healthcare and educational needs. They can be defined as a subset of the group of children with chronic health conditions whose condition results in some degree of functional or activity limitation. There is limited information in South Africa and other low- and middle-income countries with regard to the percentage of such children that access specialist health and special educational services, particularly in an urban setting, and what services exist for them. Objectives. To count the number of children with disabling chronic conditions who were accessing specialist health and special educational services in the Western health subdistrict of Cape Town, and to briefly describe the access to services outside of hospital-based specialist services. Methods. A cross-sectional observational study was conducted between January 2010 and December 2011. The target population included all children <19 years of age with disabling chronic conditions, living in the Western subdistrict of Cape Town, who were accessing specialist health and special educational services. Such children were identified from the relevant referral hospitals, educational institutions, and private and non-profit organisations in the area. Results. A total of 1 138 children with disabling chronic conditions were identified. In the context of an under-19 population of 112 249, this corresponds to a rate of 10 per 1 000, whereas the expected rate of children with disabling chronic conditions would be about 50 per 1 000. Only 14% of children in special educational institutions attended specialist paediatric services during a 2-year period. Allied health and medical services for children outside of hospitals were very limited. Conclusions. There are a significant number of children with disabling chronic conditions who do not access health and special educational services in the Western health subdistrict of Cape Town. Medical and allied health support for children in institutions is very limited. Current information systems are inadequate to describe the need. S Afr Med J 2016;106(3):302-307. DOI:10.7196/SAMJ.2016.v106i3.9825

Children with disabling chronic conditions represent a vulnerable subset of the childhood population whose medical, social and educational needs are diverse and complex.[1] These children can be defined as a subset of the group of children with chronic health conditions whose condition results in some degree of functional or activity limitation. It is well known that children with chronic conditions frequently have unmet needs and do not access the health and educational services essential to their wellbeing.[2] In the USA, 16.2% of children with chronic health conditions had unmet therapeutic service needs (such as allied health professional therapies) and 9.8% had unmet supportive service needs (such as equipment, transport, respite care).[3] In this group, children with a disabling chronic condition were especially vulnerable. The situation in low- and middle-income countries (LMICs) is almost certainly worse. However, research on children with disabling chronic conditions in such countries is largely lacking, focuses predominantly on epidemiological studies, and is generally of poor scientific quality.[4] In South Africa (SA), scarce information exists with regard to the prevalence of childhood disability or chronic conditions, access to services, or effectiveness of interventions.[5-7] Most studies describe rural or peri-urban populations.[8,9] Rapid

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urbanisation and improving under-5 mortality rates are likely to result in an increased prevalence of these children in urban areas, placing a significant burden on already stretched health and educational services. For the majority of children with disabling chronic conditions, their package of care would include specialist paediatric services or access to a special educational institution. It is not known what percentage of these children access specialist services. Services for these children outside of the hospital setting are not well described. Lack of information with regard to the number of children with disabling chronic conditions and the health and educational services they access, negatively affects service planning.

Objectives

The purpose of this study was to count the number of children with disabling chronic conditions who access specialist healthcare facilities or special needs educational services in an urban metro subdistrict. It was assumed, for the purposes of this study, that the majority of such children would access specialist paediatric health or special educational services at least once during a 2-year period. A second objective was to describe the access to services outside of the hospital setting.

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Methods

A cross-sectional survey was conducted over a 2-year period between January 2010 and December 2011. The target population comprised children <19 years with disabling chronic conditions, residing in the Western subdistrict, who accessed specialist services (Fig. 1). Multiple sources of information were consulted to identify as many access points as possible for children with such conditions. These included hospitals, educational insti tutions for children with special needs, and relevant for-profit organisations (FPOs) and non-profit organisations (NPOs) that provide services to children with chronic disabling conditions and their families. Data were collected from the hospitals that provide specialist outpatient or inpatient services for the subdistrict. It was not possible to obtain information from districtand community-based services, as their information systems did not capture these data. Data from all sources were entered into an electronic database, and duplicates were identified and removed. The tertiary referral hospital (Red Cross War Memorial Children’s Hospital (RCWMCH)) had an electronic patient administration system containing Inter national Classification of Disease (ICD)-10 codes. Two years of admissions/outpatient attendances were captured (January 2010 December 2011). Predominantly neurological, neurodevelopmental and genetic conditions were considered. Chronic conditions likely to have a fairly inevitable progression towards some limitation of activity or functional ability were included. Children with a chronic health condition that would not definitely result in some form of disability were excluded. A list of the clinics and ICD10 codes are given in Appendix 1. The regional referral hospital for the subdistrict, New Somerset Hospital (NSH), did not have an adequate ICD-10 record in its electronic patient administration system. Consequently, children with disabling chronic conditions were identified by a single paediatrician in the second year through ward admissions or the general paediatric outpatient clinic. RCWMCH and NSH paediatric services only attended to children ≤13 years, although children known to have chronic conditions stayed in the paediatric services longer before being transferred owing to the lack of adequate adolescent services. Educational institutions were identified through the 2011 Directory of Services for Children with Special Needs in the Cape Town Area booklet[10] and through communication with the heads of Special

Fig. 1. Map of health subdistricts in the Cape Town metropole. (*Hospital and level of care. †Includes Khayelitsha District Hospital, level 1.)

Education for the relevant Western Cape Education Department district offices. The educational institutions generally catered for children with moderate to severe intellectual disability, cerebral palsy or autism spectrum disorders. They were characterised as either special schools or special care centres (SCCs), depending on the type of institution and educational curriculum. It was assumed, for the purposes of this study, that children in these institutions were appropriately placed. Institutions were requested to provide details of children in their facility and identify the number of children attending hospital appointments at one of the referral hospitals. Furthermore, respondents completed a questionnaire outlining their staff details and the number of sessions/posts each institution had with regard to allied health

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professionals and medical support. Facility managers provided a subjective assessment of the care needs of the children in their institutions with regard to mobility, toileting and feeding. Permission was obtained from the hospitals to access their electronic patient information systems, and ethical approval was obtained from the University of Cape Town Health Research Ethics Committee prior to commencement (HREC 425/2011). Statistical analysis of the combined final dataset was done using Microsoft Excel 2011.

Results

A total of 1 138 children with chronic disabling conditions accessed specialist paediatric services or special educational institutions. Table 1 details the sources through which

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these children were identified – the majority from the tertiary referral hospital or educational institutions. Only one NPO returned information (Autism Western Cape), despite several NPOs from the developmental/disability sector being contacted. The only FPO that was asked for information was Vitalaire, which provides home oxygen to all children in the metro who require it. Only one child on their database was from the Western subdistrict. For 858 children name, age and sex were available. The mean age of this group was 8.1 years (3 months - 18.6 years). There was a male predominance (male:female ratio of 1.4:1). Only 14% of children in educational facilities attended specialist services at one of the referral hospitals. This information was acquired by analysing the hospital and non-hospital data sets for duplicates, or by contacting the facility managers/principals when demographic information was unavailable. Children with physical disability and no significant intellectual disability were more likely to attend specialist services (22%) than those with moderate (2.5%) or severe (11%) intellectual disability. Table 2 outlines the proportion of children from the Western subdistrict in the respective educational institutions. The SCCs were on average at 82.6% of capacity, and special schools at 95.7% of capacity. Three SCCs and one special school provided information on the care needs of 159 children (Figs 2 and 3). As expected, children in

the SCCs were less independent than those in special schools. The majority of children in SCCs were either partially or fully dependent for feeding and mobility. In special schools, only 22% and 11% were dependent for feeding or mobility, respectively. In the SCCs 75% of children were either partially or fully dependent for toileting, compared with 28% of children in the special schools.

Table 1. Children identified through various sources of information, n Source

Table 2. Children from the Western subdistrict in special educational institutions Institution

Western subdistrict, n

Total currently in school, n

School capacity, n (%)

Special care centres Wilge

30 (100.0)

Friends

112

120 (93.3)

Emmanuel

75 (62.7)

Elundini

40 (75.0)

Joe Slovo/ Ukwanda

Total

162

219

265 (82.6)

Molenbeek

123

164

165 (99.4)

Peter Pan

70 (85.7)

Dawn

214

233

233 (100.0)

SEAL College

14 (100.0)

420

450 (93.3)

Special schools

Tertiary referral hospital (RCWMCH)

545

Secondary referral hospital (NSH)

Athlone School for the Blind

Special care centres (n=4)

162

Vista Nova

440

480 (91.7)

Special schools (n=8)

395

Autism Western Cape (NPO)

Mountain View

Vitalaire (FPO)

Filia

182

182 (100.0)

Total

1 138

Total

395

1 513

1 594 (95.7)

Table 3. Health professionals (full time or days per month, n) in educational institutions Institution

Physiotherapist

Occupational therapist

Speech language therapist

Doctor

Psychologist

Nurse/sister

Special care centres Wilge

2 days/year

4 days/year

FT (1)

Friends

Emmanuel

Elundini

Special schools Molenbeek Peter Pan

FT (1)

Yes

FT (1)

Dawn

FT (1)

SEAL College

Athlone School for the Blind

FT (1)

FT (5)

FT (3)

FT (1)

Vista Nova

FT (4)

FT (3)

Yes

FT (1)

Filia

FT (1)

FT (2)

2 days/quarter

FT (1)

FT = full time. Numbers in brackets are the number of people who work full time.

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100 90 80 70 60 50 40 30 20 10 0

Feeding Toileting

n Un kn ow

In de pe nd en t

Pa r

tia

lly d

ep en de nt

Mobility

De pe nd en t

Children, n

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100 90 80 70 60 50 40 30 20 10 0

Feeding Toileting

nd pe de In

pe de Pa r

tia

lly

en t

en t nd

nd pe De

Mobility

en t

Children, n

Fig. 2. Care needs of children in special care centres.

Fig. 3. Care needs of children in special schools.

The availability of health professional services for children in educational institutions is detailed in Table 3. SCCs generally had very limited support from allied health professionals (physiotherapists, occupational therapists and especially speech therapists). There was a great deal of variation in terms of the amount of allied health professional support between the various special schools. Some schools had very little allied health professional input. Five of the seven special schools had at least one full-time therapist. The allied health professional subgroup most poorly represented overall was speech and language therapists. Medical support (doctors, nurses and psychologists) was extremely limited at the SCCs and special schools. Only one SCC received any direct medical support in the form of a full-time nursing sister and a paediatrician who visited quarterly. The medical support at special schools varied considerably. Schools for children with intellectual disability had no medical support, while those that catered for children with other or multiple disabilities had nursing and psychological support, and varying degrees of support from a doctor.

Discussion

This study describes the number of children with disabling chronic conditions in the Western subdistrict who access specialist health and educational services. Robust epidemiological data are not available for such children in SA, and especially in urban settings, where access to care is likely to be greater. The rationale behind our methodology was the assumption that the majority of children with disabling chronic conditions in an urban setting would access specialist paediatric or special educational services at least once in a 2-year period. A total of 1 138 children were identified. At the time of the study, the total population of children <19 years living in the Western subdistrict of Cape Town was 112 249, based on 2011 census data (Hendricks M, et al. A situation analysis of neonatal and child

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health status in the metro West geographic service area of the Western Cape â&#x20AC;&#x201C; unpublished report, 2012). This corresponds to a rate of 10 per 1 000 population. The first notable finding therefore is how few children were identified, despite extensive efforts to gain information from as many sources as possible. To put this in perspective, the World Health Organization (WHO) suggests a global prevalence figure of 51 per 1 000 for moderate to severe disability.[1] This is probably a realistic figure as comparison, because the current study was biased towards identifying children with moderate to severe disability. In SA, previous prevalence estimates ranged from 43 to 60 per 1 000 for overall disability.[8,11] This suggests that a significant number of children were either not identified, or do not access healthcare. Despite the relatively small number of children identified, it is noteworthy that further capacity in special educational institutions in the subdistrict is very limited, with most institutions having >90% of places filled. It has been reported previously that a significant number of children who require special schooling are not in special schools owing to lack of capacity.[12] Our study supports this finding. SA mainstream schools should be creating a more inclusive environment for children with special needs, but the necessary support and remedial structures are not in place in the majority of schools. Inadequate screening, paucity of educational psychologists and lack of viable alternatives mean that many children with milder disabilities are likely to be struggling along in mainstream schools.[9] The majority of children placed in special educational institutions do not attend specialist healthcare services. This is understandable considering the relatively low rate of medical comorbidities in intellectual disability. However, even among children with physical disability, or children with multiple disabilities, 80 - 90% were not attending specialist healthcare services. This is concerning when one notes the very limited amount of therapeutic and medical support provided in specialist educational institutions, despite these children having substantial care needs. A number of factors need to be considered when questioning why so few children were identified. The study design aimed to identify children accessing health facilities or special educational institutions. It is likely that a significant number of children with disability do not access the health or education systems in SA.[13] Two possible reasons are given, i.e. a perception that it is useless to offer care or education to a disabled child; or a desire to avoid the stigma of taking a disabled child into public areas such as a school or hospital.[14] Other practical reasons, such as lack of adequate transport or finances to reach a hospital, may prevent disabled children from accessing care or schools. The number of children who are cared for in their homes or use community-based services is unknown â&#x20AC;&#x201C; they were not counted in this study. Sociocultural factors may also play a role.[13,15] Extended families are important in the raising of children, particularly in African cultures. One of the driving forces of urbanisation is employment seeking by young adults, and often extended families remain in rural areas while the younger generation work in the city. Consequently, many children with disabling chronic conditions may be sent to live with extended family in rural areas to allow the parents to continue working, thereby reducing the prevalence in urban areas. This phenomenon has been described among families affected by HIV.[15] The Western subdistrict has some of the best economic and health indicators in SA.[16] Low unemployment rates, high immunisation rates, and a very successful prevention of mother-to-child transÂmission of HIV programme are some of the factors that may reduce the burden of childhood disability in the region. (Hendricks M, et al. A situation analysis of neonatal and child health status in the metro West geographic

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service area of the Western Cape – unpublished report, 2012). Access to specialist care is relatively good in the subdistrict, which made this an appropriate methodology for our study. The findings highlight the lack of capacity in special educational services, both in terms of number of places and allied health and medical support. Our study also highlights the inadequacy of current information systems to clearly estimate the size of the problem. These findings are generalisable to other parts of SA and other LMICs, where the situation may even be worse. There are several limitations to this study. Firstly, owing to its crosssectional nature, it relied on ICD-10 codes, which will miss a number of children as a result of incorrect coding of patients, poor use of secondary codes and failure of staff to complete coding. Secondly, this study focused mainly on specialist healthcare services and special educational institutions. The lack of information from primary healthcare and community sources may have resulted in a number of children being missed from this count. Thirdly, information from a number of educational institutions was not available owing to the lack of availability of the required information or a lack of response.

Conclusions

Despite the limitations of this study, the fact that a significant number of children with chronic disabling conditions are ‘missing’, i.e. not accessing health and special educational services, is demonstrated. A lack of chronic care services for children in the healthcare system and an insufficient number of services and facilities for children with special educational needs are likely to be contributing factors. This study also shows that the current information systems are inadequate and unreliable for identifying the burden of children with disabling chronic conditions. Information systems need to be significantly improved to plan for services. Intersectoral collaboration between educational and health sectors is crucial to promote inclusivity and integration and avoid that these children fall through the cracks. Larger-scale prevalence studies are needed to facilitate health and educational service planning. There is a need to develop and

capacitate the healthcare system for the care of children with chronic conditions, and an urgent need to capacitate the special educational services available to children. Further studies need to be conducted in SA and other LMICs to establish whether these findings are replicable in other contexts. References 1. World Heath Organization. World report on disability, 2011. http://whqlibdoc.who.int/ publications/2011/9789240685215_eng.pdf (accessed 5 December 2013). 2. Carnevale F, Rehm RS, Kirk S, et al. What we know (and do not know) about raising children with complex continuing care needs. J Child Health Care 2008;12(1):4-6. [http://dx.doi. org/10.1177/1367493508088552] 3. Benedict RE. Quality medical homes: Meeting children’s needs for therapeutic and supportive services. Pediatrics 2008;121(1):e127-e34. [http://dx.doi.org/10.1542/peds.2007-0066] 4. Maulik PK, Darmstadt GL. Childhood disability in low- and middle-income countries: Overview of screening, prevention, services, legislation, and epidemiology. Pediatrics 2007;120:S1-S55. [http:// dx.doi.org/10.1542/peds.2007-0043B] 5. Saloojee G, Phohole M, Saloojee H, et al. Unmet health, welfare and educational needs of disabled children in an impoverished South African peri-urban township. Child Care Health Dev 2007;33(3):230-235. [http://dx.doi.org/10.1111/j.1365-2214.2006.00645.x] 6. Department of Social Development. Strategy for the Integration of Services for children with disabilities. 2009. http://www.ruralrehab.co.za/uploads/3/0/9/0/3090989/strategy_integr_services_ cwd_dsd_2009.pdf (accessed 5 December 2013). 7. Guthrie T. Disability and Chronic Illness Prevalence in Children in South Africa. Committee of Inquiry into a Comprehensive Social Security System in South Africa. Rondebosch: Child Health Policy Institute, 2001. 8. Couper J. Prevalence of childhood disability in rural KwaZulu-Natal. S Afr Med J 2002;92(7):549-552. 9. Giarelli E, Clarke D, Catching C, Ratcliffe S. Developmental disabilities and behavioral problems among school children in the Western Cape of South Africa. Res Dev Disabil 2009;30(6):1297-1305. [http://dx.doi.org/10.1016/j.ridd.2009.05.006] 10. Child Care Information Centre. Directory of Services for Children with Special Needs in the Cape Town Area. Rondebosch: University of Cape Town, 2011. 11. Kromberg J, Zwane E, Manga P, et al. Intellectual disability in the context of a South African population. Journal of Policy and Practice in Intellectual Disabilities 2008;5(2):89-95. [http://dx.doi. org/10.1111/j.1741-1130.2008.00153.x] 12. Ministry of Education. Education White Paper 6 Special Needs Education: Building an Inclusive Education and Training System. Pretoria: Department of Education, 2001. http://www.education.gov. za/LinkClick.aspx?fileticket=gVFccZLi/tI= (accessed 26 September 2013). 13. Donald K, Samia P, Kakooza-Mwesige A, et al. Pediatric cerebral palsy in Africa: A systematic review. Semin Pediatr Neurol 2014;21:30-35. 14. Tallawy E, Farghaly W, Metwaly N, et al. Door to door survey of major neurological disorders in Al Kharga District, New Valley, Egypt: Methodological aspects. Neuroepidemiol 2010;35(3):185-190. 15. Hosegood V, Ford, K. The impact of HIV/AIDS on children’s living arrangements and migration in rural South Africa. 2003. http://www.childmigration.net/files/3-Hosegood.pdf (accessed 2 February 2014). 16. City of Cape Town. 2011 Census. Western Health District. http://www.capetown.gov.za/en/stats/2011 Census Health District Profiles/Western Health District.pdf (accessed 2 February 2014).

Accepted 22 January 2016.

Appendix 1. List of clinics and ICD-10 codes Clinics Neuromuscular Neurodevelopmental Spinal defects Cerebral palsy Relevant ICD-10 codes Condition

ICD-10

Condition

ICD-10

Cerebral palsy: ataxic

G80.4

Neuronal migration disorder

Q04.3

Cerebral palsy: athetoid

G80.3

Schizencephaly

Q04.6

Cerebral palsy: choreoathetoid

G80.3

Cervical spina bifida with hydrocephalus

Q05.1

Cerebral palsy: diplegic

G80.1

Thoracic spina bifida with hydrocephalus

Q05.2

Cerebral palsy: dystonic

G80.3

Lumbar spina bifida with hydrocephalus

Q05.3

Cerebral palsy: hemiplegic

G80.2

Spina bifida with hydrocephalus

Q05.4

Cerebral palsy: hypotonic

G80.8

Cervical spina bifida without hydrocephalus

Q05.5

Cerebral palsy: quadriplegic

G80.0

Thoracic spina bifida without hydrocephalus

Q05.6

Cerebral palsy: triplegic

G80.8

Lumbar spina bifida without hydrocephalus

Q05.7

Cerebral palsy: unspecified

G80.9

Sacral spina bifida without hydrocephalus

Q05.8

Deafness

H91.9

Hypoplasia and dysplasia of spinal cord

Q06.1 Continued …

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Appendix 1. (continued) List of clinics and ICD-10 codes Relevant ICD-10 codes Condition

ICD-10

Condition

ICD-10

Blindness

H54.7

Diastematomyelia

Q06.2

Mental retardation, moderate (IQ 35 - 49)

F71.9

Anophthalmos

Q11.1

Mental retardation, severe (IQ 20 - 34)

F72.9

Tracheostomy care

Z43.0

Mental retardation, profound (IQ <20)

F73.9

Tracheostomy malfunction

J95.0

Autism

F84.0

Tracheostomy present

Z93.0

Development, pervasive developmental disorder

F84.9

Myasthenia, congenital

G70.2

Pervasive developmental disorders

F84.9

Duchenne muscular dystrophy

G71.0

Huntington’s disease

G10.X

Dystrophia myotonica

G71.1

Friedreich’s ataxia

G11.1

Congenital muscular dystrophy

G71.2

Ataxia telangiectasia

G11.3

Mitochondrial myopathy

G71.3

Spinal muscular atrophy, type 1

G12.0

Myopathy, congenital

G71.9

Spinal muscular atrophy, type 2 or 3

G12.1

Myopathy, other, specified

G72.8

Mitochondrial disorder

G31.8

Myelomeningocoele

Q05.9

Brain, degenerative disease

G31.9

Holoprosencephaly

Q04.2

Epilepsy, Lennox-Gastaut syndrome

G40.4

Brain damage, post meningitis

G09.X

Spinocerebellar degeneration

G11.8

Huntington’s disease

G10.X

Basal ganglia, degenerative disease

G23.8

Hereditary spastic paraplegia

G11.4

Multiple sclerosis

G35.X

Opsoclonus myoclonus

G24.8

Acute transverse myelitis

G37.3

Dystonia

G24.9

Hereditary motor and sensory neuropathy

G60.0

HIV infection, encephalopathy

B22.0

Intellectual disability

F79.9

Friedreich’s ataxia

G11.1

Ataxia, hereditary

G11.9

Trisomy 21

Q90.9

Hereditary spastic paraplegia

G11.4

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Providers’ perceptions of the implementation of a performance measurement system for substance abuse treatment: A process evaluation of the Service Quality Measures initiative B Myers,1,2 PhD; P P Williams,1 PhD; K Johnson,1 MA; R Govender,3,4 PhD; R Manderscheid,5 PhD; J R Koch,6 PhD lcohol, Tobacco and Other Drug Research Unit, South African Medical Research Council, Cape Town, South Africa A 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, South Africa 4 Violence, Injury and Peace Research Unit, South African Medical Research Council, Cape Town, South Africa 5 National Association of County Behavioral Health and Developmental Disability Directors, Washington DC, USA 6 Department of Psychology, Virginia Commonwealth University, Richmond, Virginia, USA 1 2

Corresponding author: B Myers (bmyers@mrc.ac.za)

Background. In South Africa, concerns exist about the quality of substance abuse treatment. We developed a performance measurement system, known as the Service Quality Measures (SQM) initiative, to monitor the quality of treatment and assess efforts to improve quality of care. In 2014, the SQM system was implemented at six treatment sites to evaluate how implementation protocols could be improved in preparation for wider roll-out. Objective. To describe providers’ perceptions of the feasibility and acceptability of implementing the SQM system, including barriers to and facilitators of implementation. Methods. We conducted 15 in-depth interviews (IDIs) with treatment providers from six treatment sites (two sites in KwaZulu-Natal and four in the Western Cape). Providers were asked about their experiences in implementing the system, the perceived feasibility of the system, and barriers to implementation. All IDIs were audio-recorded and transcribed verbatim. A framework approach was used to analyse the data. Results. Providers reported that the SQM system was feasible to implement and acceptable to patients and providers. Issues identified through the IDIs included a perceived lack of clarity about sequencing of key elements in the implementation of the SQM system, questions on integration of the system into clinical care pathways, difficulties in tracking patients through the system, and concerns about maximising patient participation in the process. Conclusion. Findings suggest that the SQM system is feasible to implement and acceptable to providers, but that some refinements to the implementation protocols are needed to maximise patient participation and the likelihood of sustained implementation. S Afr Med J 2016;106(3):308-311. DOI:10.7196/SAMJ.2016.v106i3.9969

In South Africa (SA), a large unmet need exists for substance abuse treatment.[1] Negative beliefs about the quality of services are a major deterrent to substance abuse treatment initiation,[2] with studies demonstrating that people with untreated substance use disorders generally perceive available treatment services to be of limited effectiveness.[3-5] Evidence of the quality and effectiveness of substance abuse treatment can help to counter these negative perceptions; however, these data are lacking for SA services.[6] To address this gap, a consortium of stakeholders developed a performance measurement system for SA’s substance abuse treatment services. When implemented routinely, such systems are able to produce data that can be used to monitor the quality of services, identify targets for quality improvement, and assess the impact of interventions designed to improve service quality.[7-9] This performance measurement system, known as the Service Quality Measures (SQM) initiative, emerged from a lengthy develop ment process. This process involved the identification of key domains on which service quality should be assessed, selection of indicators for each domain, and methods for measuring each indicator; the development of a patient survey for measuring some of these

308

indicators; and two pilot tests of this survey to ensure a parsimonious, psychometrically valid measure. This developmental process has been described in detail elsewhere.[10-12] The finalised system comprises three tools: the SA Community Epidemiology Network on Drug Use (SACENDU)’s admission form that collects sociodemographic and substance use history information and is completed on enrolment into treatment, the SA Addiction Treatment Services Assessment (SAATSA) that accumulates patientreported data on perceived outcomes and quality of services, and a discharge form that gathers data on the type of services received and the patient’s response to treatment. To support implementation we developed a toolkit for providers, specifying in detail the protocols to be followed when implementing this system. In developing these protocols, we were guided by providers’ requests for simplicity and congruence with existing administrative practices as much as possible.[10] In 2014, we conducted a pilot implementation of the system at six treatment facilities to identify ways in which the protocols could be improved prior to implementing the system on a larger scale. This article describes providers’ perceptions of the feasibility and acceptability of implementing the SQM system, including barriers and facilitators to implementation.

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Methods

Study design and sites

We conducted qualitative in-depth interviews (IDIs) with providers from six treatment facilities to understand their experiences of implementing the SQM system. Two of these sites (one inpatient and one outpatient) were located in KwaZulu-Natal and the other four (two inpatient and two outpatient) were in the Western Cape Province. These facilities were puposefully selected as sites for this pilot implementation, as they serve diverse population groups with dissimilar patterns of drug use and have different types of treatment infrastructure.

Sample

Managers of the selected sites were asked to identify at least two staff members to participate in the IDIs. To be eligible, they had to have direct experience of implementing the SQM system. The final sample comprised 15 IDI participants, who represented a diverse range of roles and included administrators, clinical psychologists, social workers, counsellors and managers (Table 1). Table 1. Demographic characteristics of substance abuse treatment providers who participated in the in-depth interviews Characteristics

Sample, n (%) (N=15)

Site KwaZulu-Natal Western Cape

5 (33.3) 10 (66.7)

Job description Branch manager Programme manager Administrator Social worker/counsellor Clinical psychologist Marketing co-ordinator Gender Female Male Race* Black Coloured Indian White

1 (6.7) 2 (13.3) 4 (26.7) 5 (33.3) 2 (13.3) 1 (6.7) 12 (80.0) 3 (20.0) 2 (13.3) 8 (53.3) 3 (20.0) 2 (13.3)

*The terms white, black, and coloured refer to demographic markers and do not signify inherent characteristics. The continued use of these terms in SA is important for monitoring improvements in health and socioeconomic disparities, identifying vulnerable sections of the population, and planning effective prevention and intervention programmes.

Data collection

All IDIs were conducted during September and October 2014. Before the interview, each participant was asked to provide written

informed consent. IDIs were guided by a set of open-ended questions that were developed by the SQM national steering committee. These questions explored the participants’ experiences of implementing the SQM system, their perceptions of the feasibility of implementing this system, acceptability of the system, and obstacles to and facilitators of implementation. IDIs were conducted by two experienced qualitative interviewers who were not associated with the implementation process, one of whom assisted with note-taking. All IDIs were conducted in English, and were audio-recorded and transcribed verbatim. The average duration of an IDI was 30 min utes. The study was approved by the Centers for Disease Control and Prevention (CDC) and the South African Medical Research Council’s ethics committee.

seemed like a hell of a thing at the beginning, but it’s just routine. We have so many things to be filled out, forms, and if you just train people properly that’s fine.’ Participants viewed the SQM initiative as acceptable because they thought imple menting this system would help them to improve their services. As one person stated, ‘I think it’s a good thing because it gives us that feedback, you give us the analysis of data and it can help, and we always want to improve our services as much as we can’. Similarly, another stated, ‘I think it is actually nice to have something like this because it tells you about the service that you are rendering and can help improve services’. The acceptability of the system is also reflected in the finding that several of the facilities wanted to continue to implement the system beyond the pilot period.

Analysis

Obstacles to implementation

Qualitative data analysis was conducted using the framework approach,[13] which comprises five stages (familiarisation, identifying a thematic framework, indexing or coding, charting or mapping, and inter pretation of the data). Coding occurred iteratively; as new themes emerged in the analysis all relevant information was retrieved and examined for further coding designations. All transcripts were coded independently by two project staff who met after every two transcripts to compare notes. Coding discrepancies were resolved by discussion. Intercoder reliability checks were conducted, with a kappa score of 0.77 being obtained. We used NVivo 10.0, a qualitative software program, to aid data analysis.

Results

Experiences of implementation

Participants generally reported positive experiences of the implementation process. They described the system as ‘easy to implement’ and the implementation process as ‘understandable’. As one participant stated: ‘Implementing the SQM toolkit was a valuable experience and quite user-friendly.’

Feasibility of implementation and acceptability of the system for providers

With the exception of one participant, who felt that there was a mismatch between the particular structure of their treatment services and the SQM implementation process, almost all participants reported that the SQM system was feasible to implement in their programme as part of routine services. As one participant reflected, ‘It’s feasible, it

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March 2016, Vol. 106, No. 3

Although most participants reported that their patients were positive about participating in this system and appreciated being asked ‘to express their views on treatment’, they also mentioned some barriers to patient participation. In this pilot project, patients were introduced to the SQM system on their initial contact with the treatment facility. Participants reflected that this was not the optimal time to introduce the initiative as some patients felt ‘bombarded’ and ‘overwhelmed’ by the screening and administrative procedures and therefore ‘just refused outright’ to participate in the SQM process. As one participant explained, ‘We do that [introduction] on intake usually and we sometimes sit with psychotic or paranoid patients, or extremely anxious patients and we can’t really do that in the beginning with them’. Another obstacle to patient participation was the requisite level of literacy necessary to complete the SAATSA. Participants noted that although most patients found it ‘easy’ to complete the form, some required assistance, which might place considerable time demands on treatment staff. As one participant reflected, ‘There were other patients who needed help and assistance and I had to explain every single thing’. Participants also mentioned that although the implementation protocols were a ‘well thought out process’, there was a lack of clarity about when each element of the SQM system should be completed. Participants described their initial uncertainty about integrating the system into their usual clinical care processes: ‘We had a big question mark as to where exactly and in which week

RESEARCH

to begin implementation. And we actually had to modify the treatment programme. So that was one of the barriers we had to overcome.’ Similarly, a participant from another facility spoke of the challenges of knowing when to complete forms: ‘The challenge initially was I think making sure that staff understood exactly what they had to [do] and when they had to do it. The challenges of when exactly you apply the initial steps and the timing in all of that.’ Several participants mentioned difficulties in keeping track of when patients needed to complete their SAATSA forms. This was partly due to the lack of a system for reminding providers that patients were due to complete the form, which resulted in counsellors forgetting to ask patients to complete the SAATSA. Irrespective of facility size, difficulties in managing the system intensified when facilities were busy: ‘Remember we have got a lot of clients that come in and a lot of clients are completing phases, so it is hard to keep track of clients especially after they have completed the whole programme. So, they have gone and you’ve forgotten to get them to fill it in, there’s no way we’re going to get them back.’ Participants also reported difficulties in remembering to complete the discharge form. Some treatment sites kept patient folders open for many months after they last had contact with a patient, which delayed the completion of the discharge form. In response to this difficulty, some of the implementing sites developed a tracking system that flagged when patients were due to complete the SAATSA: ‘We have a specific monitoring tool in place … it flags any clients that are due for their SAATSA. And then when it comes time for them to be discharged then the counsellor knows automatically when to do the discharge for the SQM project.’ In a few instances, participants thought that the length of time it took to receive SQM forms from the SQM project team hindered the implementation process. One participant reported that their administrative staff were frustrated when it took longer than expected to receive the forms. Other participants mentioned not receiving enough SAATSA questionnaires in languages other than English. These implementation support issues potentially reduced the number of patients who completed the SAATSA questionnaires. Participants suggested that better communication with administrative staff with regard to their need for additional forms could resolve this issue.

Facilitators of implementation

All participants reported that the training was ‘very good’ and mentioned how it helped to facilitate implementation of the system. Some participants were pleased that all staff in the facility received training in the system. According to these participants, this reduced ambiguities and enhanced staff support for the implementation process: ‘I think originally it was going to be some of us would go and teach the others and then extra space was created for other people. I think that was a very wise decision because for us to secondhand train other people when we have just learnt it is not good and different things, different questions come up you know. People hear different things. The fact that everybody attended the training, you know, they are very much on board.’ Similarly, participants reported that the technical support provided by the SQM project team aided implementation. They approved of the SQM toolkit and reported using it as an important reference guide during the implementation process. They described the technical support as accessible and readily available. As one participant explained, ‘What I think was very helpful, whenever I had a question if I didn’t know something, there was that open communication. So I could pick up the phone and say we don’t know, we’re confused, or please clarify and there were no issues with that.’ A few participants

310

suggested that additional site visits for fidelity and quality assurance purposes may further enhance the implementation process.

Discussion

This article examined the feasibility and acceptability of implementing the SQM system in SA substance abuse treatment facilities. Providers from the full spectrum of available treatment services generally viewed this performance measurement system positively, suggesting that it was acceptable to providers. More specifically, they seemed to appreciate how implementing the SQM system would help them to attain their service delivery goals and could benefit their patients. This finding is encouraging, as the acceptability of a healthcare system innovation is highly predictive of its adoption.[14] While the vast majority of participants reported that the SQM system was feasible to implement as part of standard practice in their resource-constrained settings, they did identify barriers to implementation and areas where the implementation protocols could be refined to facilitate ease of use. They highlighted how the current practice of introducing patients to the SQM system on their first contact with the treatment facility deterred patient participation. They explained how patients were often overwhelmed by administrative processes on entry into treatment and/or the effects of withdrawing from substances and therefore were unwilling to participate in additional, voluntary activities. Based on this feedback and to maximise patient participation, the SQM project team has moved the time at which patients are introduced to the initiative to a later point in the clinical care pathway. Related to this, providers described how they were initially uncertain how to integrate this system into their usual clinical and administrative processes. Although each provider received a toolkit outlining implementation guidelines and had an opportunity to participate in training, the guidelines did not address the many practical implementation questions that arose once the facilities started implementing the system. As the SQM team was available to answer these questions and provide facilities with support for implementation, this probably did not jeopardise the feasibility of implementation. However, in facilities where there were many unresolved queries about the implementation process, it took longer for the SQM system to become fully implemented, which affected the number of patients who participated in the initiative. To address this gap and ensure ease of use, we plan to expand our training materials and implementation guidelines to include more practical information about when and how to implement the SQM system. Providers also reported difficulties in keeping track of when each element of the SQM system was due for completion. Currently, the SQM is a pen-and-paper system that relies on treatment providers to recall when patients are due to complete the SAATSA. Remembering when to complete forms was more difficult when treatment facilities were very busy; during these periods some patients were not given an opportunity to complete the form. This raises concerns about the extent to which the eligible patient population is covered by the SQM system. Some treatment sites had developed their own electronic patient management system with built-in reminders for when each SQM form is due for completion; these appear to resolve difficulties with remembering when to complete forms. We have considered transitioning to an electronic platform to address this challenge, as such a platform will provide for electronic reminders and have the added benefit of reducing the workload of treatment providers. Although the SAATSA is completed by the patients, in cases where they have low literacy levels treatment centre staff help them by reading the questions and recording their answers, which is very time consuming. This is a concern, as findings from earlier work suggest

March 2016, Vol. 106, No. 3

RESEARCH

that excessive burden to providers will threaten the sustainability of any performance measurement system.[10] An electronic system that allows for audio-computer-assisted personal interviewing could help with this difficulty by enabling even functionally illiterate patients to complete the SAATSA. Apart from reducing the workload of treatment providers, such a system would have the added benefit of reducing social desirability bias.[15] It would also obviate providers’ reliance on the SQM team for paper forms and frustration when receipt of forms is delayed. Despite the benefits of an electronic system, we are challenged by the fact that many treatment sites do not have a sufficient number of computers to implement an electronic version of the SQM system.[10] While finding the resources to move the SQM system onto an electronic platform is an important goal for this initiative; in the short term we are trying to identify ways of assisting treatment providers to remember to implement the system. These include helping treatment sites to develop their own systems for tracking patients through the care pathway and also providing treatment sites with more regular on-site support. Findings from this process evaluation should be considered in the light of a limitation synonymous with qualitative research. As this study was limited to treatment providers from two of the nine provinces in SA, findings may not be generalisable to other provinces. However, as our sample included treatment providers across the entire spectrum of facilities available in the country, we are confident that the concerns raised by our participants will be broadly applicable to all substance abuse treatment providers.

Conclusion

Limitations notwithstanding, this process evaluation yielded valuable information that will be used to strengthen the SQM initiative. Firstly, it highlighted that substance abuse treatment providers perceived the SQM system as acceptable and feasible to implement. Secondly, several areas were found where the implementation protocols should be refined prior to widespread implementation of this performance measurement system. These refinements include changing the timing of the implementation to enhance the likelihood of patient participation, introducing processes to remind providers to implement each element of the SQM system, and extending the provider toolkit and implementation guidelines to address practical questions about how to integrate the system into the clinical care pathway. Finally, as there was consensus that the training and ongoing support provided for implementation helped mitigate some of the barriers to implementation experienced by providers,

311

training and support should form a critical part of the roll-out of this performance measurement system. Acknowledgement. This article received support from the President’s Emergency Plan for AIDS Relief (PEPFAR) through the Centers for Disease Control and Prevention, under the terms of Cooperative Agree ment Number 5U2GPS001137-4, and by the Western Cape Department of Social Development. Disclaimer. The findings and conclusions in this article are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention or the Western Cape Department of Social Development. References

1. Herman AA, Stein DJ, Seedat S, Heeringa SG, Moomal H, Williams DR. The South African Stress and Health (SASH) study: 12-month and lifetime prevalence of common mental disorders. S Afr Med J 2009;99:339-344. 2. Myers B, Louw J, Pasche S. Inequitable access to substance abuse treatment services in Cape Town, South Africa. Substance Abuse Treatment, Prevention, and Policy 2010;5:28. [http://dx.doi. org/10.1186/1747-597X-5-28] 3. Myers B, Fakier N, Louw J. Stigma, treatment beliefs, and substance abuse treatment use in historically disadvantaged communities. Afr J Psychiatry 2009;12:218-222. 4. Myers B, Kline LT, Doherty AI, Carney T, Wechsberg WM. Perceived need for substance use treatment among young women from disadvantaged communities in Cape Town, South Africa. BMC Psychiatry 2014;14:100. [http://dx.doi.org/10.1186/1471-244X-14-100] 5. Parry CDH, Petersen P, Carney T, Needle R. Opportunities for enhancing and integrating HIV and drug services for drug using vulnerable populations in South Africa. Int J Drug Policy 2010;21:289-295. 6. Myers B, Burnhams NH, Fakier N. Monitoring and evaluation of substance abuse services in South Africa: Implications for policy and practice. International Journal of Mental Health and Addiction 2010;8:557-565. 7. Garnick DW, Lee MT, Chalk M, et al. Establishing the feasibility of performance measures for alcohol and other drugs. J Subst Abuse Treat 2000;23:375-385. 8. Harris AHS, Kivlahan D, Bowe T, Finney JW, Humphreys KH. Developing and validating process measures of health care quality: An application to alcohol use disorder treatment. Med Care 2009;47:1244-1250. [http://dx.doi.org/10.1097/MLR.0b013e3181b58882] 9. Institute of Medicine. Improving the Quality of Health Care for Mental and Substance-Use Conditions: Quality Chasm Series. Washington: National Academies Press, 2005. 10. Myers B, Petersen Z, Kader R, et al. Identifying perceived barriers to monitoring service quality among substance abuse treatment providers in South Africa. BMC Psychiatry 2014;14:31. [http://dx.doi. org/10.1186/1471-244X-14-31] 11. Myers B, Petersen Z, Kader R, Parry CDH. Moving beyond access. Towards a quality-oriented substance abuse treatment system in South Africa. S Afr Med J 2012;102:667-668. 12. Myers B, Govender R, Koch JR, Manderscheid R, Johnson K, Parry CDH. Development and psychometric validation of a novel patient survey to assess perceived quality of substance abuse treatment in South Africa. Substance Abuse Treatment, Prevention and Policy 2015;10:44. [http:// dx.doi.org/10.1186/s13011-015-0040-3]. 13. Ritchie J, Spencer L. Qualitative data analysis for applied policy research. In: Bryman A, Burgess R, eds. Analyzing Qualitative Data. London: Routledge, 1994. 14. Zhang X, Yu P, Yan J, Spil ITA. Using diffusion of innovation theory to understand the factors impacting patient acceptance and the use of consumer e-health innovations: A case study in a primary care clinic. BMC Health Services 2015;15:71. [http://dx.doi.org/10.1186/s12913-015-0726-2] 15. Azevedo Simões A, Bastos FA, Moreira RA, Lynch KG, Metzger DS. Acceptability of audio computerassisted self-interview (ACASI) among substance abusers seeking treatment in Rio de Janeiro, Brazil. Drug and Alcohol Dependence 2006;82:S103-S107.

Accepted 22 January 2016.

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