SAMJ Vol 105, No 3 (2015)

MARCH 2015

VOL. 105 NO. 3

‘Over-servicing’, ‘underservicing’ and ‘abandonment’: What is the law?

181

Care and prevention of congenital disorders

186

Dementia in rural South Africa

189

Two-dose HPV vaccination is sufficient

191

Traumatic brain injury, the hidden pandemic

195

Kidney disease in methamphetamine users

199

Emergency care research priorities CME: Diagnosis and management of chronic kidney disease

202 232-238

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MARCH 2015

VOL. 105 NO. 3

FROM THE EDITOR

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

160 The ch in children stands for cherish

J Seggie 162

EDITOR EMERITUS Daniel J Ncayiyana, MD (Groningen), FACOG, MD (Hon), FCM (Hon)

EDITOR’S CHOICE

CONSULTING EDITOR JP de V van Niekerk, MD, FRCR

CORRESPONDENCE 164

Conflict of interest and regulatory authorities R Jobson, A Gray

164

Inaugural International Association of Student Surgical Societies Symposium N Rich

IZINDABA 165 168 169 170

Eastern Cape treatment dysfunction boosts virulent new XDR-TB strain Will Basson come out on top?

Zuma’s legal advisors ‘led him astray’, turned healthcare professionals into criminals The risky lives of South Africa’s children: Why so many die or are traumatised

OBITUARIES/HULDEBLYKE 172 Ajay Makanjee 172 Alewyn Petrus Rossouw

DEPUTY EDITOR Bridget Farham, BSc (Hons), PhD, MB ChB SCIENTIFIC EDITOR Ingrid Nye, BSc TECHNICAL EDITORS Emma Buchanan, BA Paula van der Bijl, BA, HDipLib NEWS EDITOR Chris Bateman | Email: chrisb@hmpg.co.za CEO AND PUBLISHER Hannah Kikaya HEAD OF PUBLISHING Robert Arendse

SAMJ FORUM

PRODUCTION MANAGER Emma Jane Couzens

173

CLINICAL PRACTICE Carbohydrate loading in the preoperative setting L T Hill, M G A Miller

ART DIRECTOR Brent Meder

175

CLINICAL ALERT Recommendations for the treatment and prevention of malaria: Update for the 2015 season in South Africa L H Blumberg

ONLINE MANAGER Gertrude Fani

179

Chronic pancreatitis, depression and substance use disorders: A not uncommon combination C Y Jeppe, C P Szabo, M D Smith

181

MEDICINE AND THE LAW ‘Over-servicing’, ‘underservicing’ and ‘abandonment’: What is the law?

D J McQuoid-Mason

EDITORIALS 183 The Global Status Report on Violence Prevention 2014: Where to for the South African

health sector?

C L Ward, G Lamb 185

Prevention of Liver Fibrosis and Cancer in Africa: The PROLIFICA project – a collaborative study of hepatitis B-related liver disease in West Africa J Howell, N G Ladep, M Lemoine, S Nayagam, P S Toure, M M Diop, J A Daveiga, A S Sall, G Lo, M M E Crossey, M R Thursz, S D Taylor-Robinson, M M Ka

186

Need for services for the care and prevention of congenital disorders in South Africa as the country’s epidemiological transition evolves H L Malherbe, A L Christianson, C Aldous

189

Dementia in rural South Africa: A pressing need for epidemiological studies C A de Jager, J A Joska, M Hoffman, K E Borochowitz, M I Combrinck

RESEARCH 191

The Vaccine and Cervical Cancer Screen project 2 (VACCS 2): Linking cervical cancer screening to a two-dose HPV vaccination schedule in the South-West District of Tshwane, Gauteng, South Africa L C Snyman, G Dreyer, C Visser, M H Botha, F H van der Merwe

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March 2015, Vol. 105, No. 3

DTP & DESIGN Carl Sampson

DISTRIBUTION MANAGER Edward Macdonald | Tel. 021-681-7085 HEAD OF SALES AND MARKETING Diane Smith | Tel. 012-481-2069 Email: dianes@samedical.org PROFESSIONAL ADVERTISING Bronlyne Granger | Tel. 021-681-7000 E-mail: bronlyne.granger@hmpg.co.za HMPG BOARD OF DIRECTORS Prof. M Lukhele (Chair), Dr M R Abbas, Dr M J Grootboom, Mrs H Kikaya, Adv. Y Lemmer, Prof. E L Mazwai, Dr M Mbokota, Mr G Steyn, Dr G Wolvaardt ASSOCIATE EDITORS Q Abdool Karim, A Dhai, N Khumalo, R C Pattinson, A Rothberg, A A Stulting, J Surka, B Taylor, M Blockman ISSN 0256-9574 Publisher website: www.hmpg.co.za SAMA website: www.samedical.org Journal website: www.samj.org.za

195

Traumatic brain injury, the hidden pandemic: A focused response to family and patient experiences and needs J Webster, A Taylor, R Balchin

199

Hypertension, end-stage renal disease and mesangiocapillary glomerulonephritis in methamphetamine users E S W Jones, B L Rayner

202

Emergency care research priorities in South Africa* D J van Hoving, B K Barnetson, L A Wallis

209

Oral v. pulse intravenous cyclophosphamide: A retrospective analysis of adverse events in a setting with a high burden of infectious disease* E Pretorius, M R Davids, R du Toit

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

215

Prevalence and causes of thrombocytopenia in an academic state sector laboratory in Soweto, Johannesburg, South Africa* J L Vaughan, J Fourie, S Naidoo, N Subramony, T Wiggill, N Alli

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Short-term treatment outcomes of children starting antiretroviral therapy in the intensive care unit, general medical wards and outpatient HIV clinics at Red Cross War Memorial Children’s Hospital, Cape Town, South Africa: A retrospective cohort study* V Pillay, M-A Davies, S King, B Eley

228

An investigation of fingerstick blood collection for point-of-care HIV-1 viral load monitoring in South Africa* T J Maiers, N Gous, M Nduna, S M McFall, D M Kelso, M J Fisher, K M Palamountain, L E Scott, W S Stevens

CONTINUING MEDICAL EDUCATION

232

GUEST EDITORIAL Chronic kidney disease A M Meyers

233

REVIEW Significance, definition, classification and risk factors of chronic kidney disease in South Africa A M Meyers

236

ARTICLES Diagnostic approach to chronic kidney disease* I P Naiker, A G Assounga, A M Meyers

237

Management of patients with chronic kidney disease* T Gerntholtz, G Paget, P Hsu, A M Meyers

237

Clinical aspects of chronic kidney disease* B van Rensburg, A M Meyers

List of contributors to the articles and information compiled by the National Kidney Foundation of South Africa† F du Toit

*Abstract only, full article available online.

Available online only.

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E-mail: publishing@hmpg.co.za Website: www.samedical.org 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 Use of editorial material is subject to the Creative Commons Attribution – Noncommercial Works License. http://creativecommons.org/licenses/bync/3.0 Plagiarism is defined as the use of another’s work, words or ideas without attribution or permission, and representation of them as one’s own original work. Manuscripts containing plagiarism will not be considered for publication in the SAMJ. For more information on our plagiarism policy, please visit http://www.samj.org.za/ index.php/samj/about/editorialPolicies Printed by Creda Communications

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March 2015, Vol. 105, No. 3

FIRST PUBLISHED IN 1884

The ch in children stands for cherish But South Africa (SA) does not cherish her child­ren, in spite of their right to care and protection, enshrined in our Constitution’s Bill of Rights. Of course this failure occurs in a milieu of social tolerance of use of force and violence in the country as a whole, with high levels of family violence in the home, violence in the community, and violence at the hands of police and in schools (with frequent resort to corporal punishment[1]). Children from poorer households and from rural areas are particularly affected.[2] An editorial in this issue of SAMJ[3] informs us of the SA position in relation to other countries around the world in the Global Status Report on Violence Prevention 2014,[4] jointly released by the World Health Organization (WHO), the United Nations Development Programme and the United Nations Office on Drugs and Crime.

Izindaba[5] features the harsh lives of SA’s children in this issue.

‘The risky lives of South Africa’s children: Why so many die or are traumatised’ reveals that 80% of children live in informal settlements (‘danger-filled environments’), and because of the widespread, tragic absence of the most effective risk-mitigating factor possible – their biological parents – they are highly vulnerable.

Children need adults who will cherish them and on whom they can depend for love, care and, most of all, protection. But many of SA’s children are not raised within the conventional nuclear family … 14.6 million of our 18.5 million children have both parents known to be alive, according to Statistics South Africa’s General Household Survey of 2010,[1] only 6.0 million (one in three) aged under 18 years live with both their mother and father, 2.3 million have a mother alive but father deceased or unknown, 0.7 million have father alive but mother deceased or unknown, and 0.9 million have both parents either deceased or unknown. Of 12.4 million children in single-parent homes, the majority live with their mother, a fraction with their father, and the remainder with neither parent.

Daily, thousands of children experience physical, sexual and/or psychological abuse. It is no comfort to learn that the scourge is a global one and rife in so-called sophisticated, developed countries such as the USA and the UK. In the USA, with a population of 360 million, 1 500 children (2012 statistics) die as a result of abuse.[6] SA, with a population of 55 million, a sixth of that of the USA, achieves the same: three children a day (1 200 a year) are murdered.[7] In the UK, sexual abuse (defined by the WHO as ‘the involvement of a child in a sexual activity that he or she does not fully comprehend, is unable to give consent to, or for which the child is not developmentally prepared and cannot give consent’) is rife, as recent news bulletins and the Home Office Secretary confirm, with one in 20 children subject to sexual abuse despite rigorous legal sanctions against perpetrators.[8] Everywhere, the youngest are most vulnerable.[2] The Teddy Bear Clinic in Johannesburg has dealt with cases of sexual abuse in very young children,[2] and there are statistics of rapes of children aged between 1 and 3 years.[9] Of female victims of rape, 85% had been raped when aged between 10 and 14 years.[10] Boys are not exempt – 3.5% of young men report having been raped by a man.[11] The perpetrator is typically known to the victim – a friend, a teacher,[12] or worse, a relative or household member, with sexual assault typically occurring in the child’s home.[7] Jewkes et al.[11] point out that ‘The numerous experiences of sexual harassment by male teachers (and male learners) confirm that it is a major problem in schools. The greatest concern is the teachers’ abuse of their power over the schoolgirls to gain sexual access to them. The teachers’ conspiracy to support each other is an indication of its pervasiveness.

These experiences diminish the educational chances of girls.’

160

On rare, widely publicised occasions children are the perpetrators, but the Teddy Bear Clinic Constitutional Court case[13] decriminalised sexual conduct between adolescent consenting children aged under 16 years and placed a moratorium on the reporting duties of doctors and others.

SA appears, in large measure, to have become inured to the horrors perpetrated against her children, and even seeks to rationalise that poverty is the cause. Why, invoking the lyric ‘I’m depraved on account of I’m deprived!’ (an exclamation by one of the youths serenading Officer Krupke in Leonard Bernstein and Stephen Sondheim’s ‘West Side Story’[14]), should deprivation be an excuse for depravity? Around the world poverty – in our own country resulting from high levels of parental unemployment – is one possible explanation, but child abuse occurs across all socioeconomic levels. Beyond poverty and unemployment, a look at the ‘ecology’ of SA’s communities reveals a multiplicity of adverse factors that render the neighbourhoods in which children live dangerous, and make crime and sexual violence easy for the perpetrator: failure of electricity and hence poor lighting; poor access to water, with children spending long hours collecting water and exposed along the route; the proliferation of shebeens in townships, and high levels of alcohol and substance abuse.

The long-term mental, physical and social consequences of child abuse can be intuited:[6] damage to the eyes, brain and spinal cord resulting from shaken-baby syndrome; rib and long bone fractures; impaired mental development, depression and withdrawal; psychiatric illness (including depression, anxiety, anger, post-traumatic stress disorder and eating disorders); and academic underachievement, perhaps because of a greater tendency to attention deficit and/or hyperactivity disorder. A third of abused and neglected children develop chronic health disorders as adults, being more prone to suffer from allergies, arthritis, asthma, bronchitis, high blood pressure and ulcers, in addition to physical disabilities caused by the abuse. Add to these antisocial behaviours and a tendency to perpetrate (often violent) crime, which leads to arrest in youth and adulthood, and abuse of alcohol and drugs, with a majority of adults in drug treatment programmes having been abused as children. Abused children are more likely to experience teen pregnancy. A vicious cycle is established … abused and neglec­ted children tend to go on to abuse their own children.

The cost (estimated at USD124 billion annually in the USA[6]) to the SA fiscus is huge, as the editorial by Ward and Lamb[3] affirms.

According to a KPMG report, violence against women alone costs the SA economy between R28.4 and R42.2 billion per year (0.9 1.3% of the GDP), before adding the costs of child welfare and protection, special-needs education, and demands on the health system and on law enforcement, the courts and prisons.

There is hope … that ‘at the southern tip of the continent of Africa, a rich reward in the making … will and must be measured by the happiness and welfare of the children, at once the most vulnerable citizens in any society and the greatest of our treasures.’[15] A survey in progress has ‘massive potential to inform the design and delivery of inter­ ventions to reduce child maltreatment’.[3] Janet Seggie Editor

janet.seggie@hmpg.co.za

March 2015, Vol. 105, No. 3

FROM THE EDITOR

1. Statistics South Africa. General household survey 2010. Statistical release P0318. http://www.statssa. gov.za/publications/p0318/p0318june2010.pdf (accessed 5 January 2015).

2. Department of Social Development/Department of Women, Children and People with Disabilities/ UNICEF. Violence against children in South Africa. http://www.cjcp.org.za/uploads/2/7/8/4/27845461/ vac_final_summary_low_res.pdf (accessed 5 January 2015).

3. Ward CL, Lamb G. The Global Status Report on Violence Prevention 2014: Where to for the South African health sector? S Afr Med J 2015;105(3):183-184. [http://dx.doi.org/10.7196/SAMJ.9305] 4. World Health Organization. Global Status Report on Violence Prevention 2014. Geneva: WHO, 2014.

(SA profile p. 195.) http://www.undp.org/content/dam/undp/library/corporate/Reports/UNDP-GVAviolence-2014.pdf (accessed 5 January 2015).

5. Bateman C. The risky lives of SA’s children: Why so many die or are traumatised. S Afr Med J 2015;105(3):170-171. [http://dx.doi.org/10.7196/SAMJ.9462] 6. Childhelp. https://www.childhelp.org/child-abuse-statistics/Childhelp (accessed 5 January 2015).

7. Mathews S, Abrahams N, Jewkes R, Martin LJ, Lombard C. Child homicide patterns in South Africa: Is there a link to child abuse? http://www.mrc.ac.za/policybriefs/childhomicide.pdf (accessed 5 January 2015).

8. National Society for the Prevention of Cruelty to Children. http://www.nspcc.org.uk/preventingabuse/child-abuse-and-neglect/child-sexual-abuse/sexual-abuse-facts-statistics/ (accessed 5 January 2015).

9. Vetten L, Jewkes R, Fuller R, Christofides N, Loots L, Dunseith O. Tracking Justice: The Attrition of Rape Cases through the Criminal Justice System in Gauteng. Johannesburg: Tshwaranang Legal

Advocacy Centre, Medical Research Council, Centre for the Study of Violence and Reconciliation. http://www.csvr.org.za/docs/tracking_justice.pdf (accessed 5 January 2015).

10. Jewkes R, Levin J, Mbananga N, Bradshaw D. Rape of girls in South Africa. Lancet 2002;359(9303):319321. [http://dx.doi.org/10.1016/S0140-6736(02)07530-X] 11. Jewkes R, Abrahams N, Mathews S, et al. Preventing rape and violence in South Africa: Call for leadership in a new agenda for action. MRC Policy Brief, November 2009. www.mrc.ac.za/gender/ prev_rapedd041209.pdf (accessed 5 January 2015).

12. Abrahams N, Mathews S, Ramela P. Intersections of ‘sanitation, sexual coercion and girls’ safety in schools’. Trop Med Int Health 2006;11(5):751-756. [http://dx.doi.org/10.1111/j.13653156.2006.01600.x] 13. 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] 14. Officer Krupke in Leonard Bernstein and Stephen Sondheim’s ‘West Side Story’. https://www.youtube. com/watch?v=pq28qCklEHc (accessed 5 January 2015).

15. Nobel Lecture Acceptance and Nobel Lecture. Nelson Mandela’s Nobel Peace Prize acceptance speech, 10 December 1993. http://www.nobelprize.org/nobel_prizes/peace/laureates/1993/mandela-lecture_ en.html (accessed 5 January 2015).

S Afr Med J 2015;105(3):160-161. DOI:10.7196/SAMJ.9452

EDITOR’S CHOICE

Recognising and diagnosing chronic kidney disease: Part 1

For many reasons, general physicians find renal disease difficult to diagnose, understand and treat. The terms ‘chronic kidney disease’ (CKD) and ‘glomerular filtration rate’ – representing the renal function equation – have been introduced to clarify some of these difficulties.

Unfortunately, these pivotal concepts are often poorly understood.

CKD risks being unrecognised because there are no specific symptoms, and it is often not diagnosed or only diagnosed at an advanced stage.

Tests for CKD are, however, simple and freely available.

CKD and advancing chronic renal failure (CRF) are underdiagnosed generally, particularly in rural areas. At the same time, there is an alarming rise in the incidence of serious CRF. From global estimates, we can suppose that 5 million South Africans over the age of 20 have CKD, and the figure is almost certainly higher among black South Africans.

In South Africa (SA), hypertension and diabetes, both diseases that are markedly influenced by lifestyle choices, are by far the main causes of CKD and CRF. This being so, the potential for prevention by early diagnosis and proper treatment to slow or minimise the progression of functional deterioration is huge.

The annual cost of renal replacement therapy is approximately ZAR200 000 per patient for dialysis and about ZAR300 000 in the first year, and ZAR160 000 - 180 000 in subsequent years, for transplantation.

The March CME is the first of a two-part series of articles derived from the National Kidney Foundation of South Africa guidelines for the diagnosis and management of CKD. April will carry the second part of these guidelines. The intention is to help generalists be aware of this heterogeneous condition, diagnose and manage it to the best of their ability, and mitigate the burden of disease that CKD represents.

Effects of methamphetamine abuse on the kidneys and blood pressure

Methamphetamine abuse has risen dramatically in SA, particularly in the Western Cape Province and by young people of lower socioeconomic status and educational level. Methamphetamine is relatively easy and inexpensive to produce, making it readily accessible.

A closely related amphetamine, known as Ecstasy, initially used as an appetite suppressant, rapidly became a recreational drug used in dancing clubs and was found to cause hyperthermia, dehydration and rhabdomyolysis, and an increased risk of acute renal failure. The toxic effects of amphetamines include cardiomyopathy, ischaemic heart disease, aneurysm formation, seizures, psychosis, hallucinations, stroke, hyperthermia, rhabdomyolysis, pulmonary hypertension, systemic hypertension, acute renal failure and hepatocellular damage.

There have been isolated reports of adverse renal effects, including necrotising renal vasculopathy, an exaggerated decline in renal function over a 15-year follow-up of patients who used methamphetamines, a higher serum creatinine level 1 year after transplant in recipients from donors who had used methamphetamines, and early graft loss of two kidneys from donors who had used methamphetamines.

The chronic effects of methamphetamine abuse on the kidneys and blood pressure have not been documented. Jones and Rayner[1] reviewed patients referred for evaluation of kidney disease and/or hypertension who had been abusing methamphetamines and whose mean age was just 29 years, and concluded that methamphetamine use is associated with severe hypertension, half of the subjects fulfilling criteria for malignant hypertension and mesangiocapillary glomerulonephritis that rapidly evolves to end-stage renal disease.

Preventing liver fibrosis and cancer in Africa

As is well recognised, hepatitis B virus (HBV) infection is endemic in sub-Saharan Africa (SSA), and the HBV-related disease burden is high.

162

The lifetime risk of HBV infection is >60%, and >8% of those infected remain chronic HBV carriers who are at risk of progressive liver disease and HBV-related hepatocellular carcinoma (HCC). SSA has one of the highest HBV-related liver cancer rates in the world, as it is the most common cancer among males and third most common among females.

Unfortunately, HCC is usually a highly aggressive tumour with limited treatment options, particularly in resource-poor settings, such as SSA. Furthermore, HBV-related HCC affects patients in their working and reproductive years.

The achievements of a collaborative research project, the PROLIFICA project, are outlined in an editorial entitled ‘Preven­tion of Liver Fibrosis and Cancer in Africa: The PROLIFICA project – a collaborative study of hepatitis B-related liver disease in West Africa’.[2] So far the project has succeeded in achieving capacity building in each of the three countries (The Gambia, Sénégal and Nigeria) involved in the study. Local health infrastructure has benefited from new technologies, such as the Fibroscan to assess liver fibrosis using ultrasound-based transient elastography, a mass spectroscopy system in The Gambia for local biomarker research, and the development of in-house laboratory assays, as well as skills transference for improved liver cancer healthcare, in West Africa.

Local nursing, medical and laboratory staff have benefited from training, education and employment opportunities. Procedures and training in effective and secure data management and ethical research practices have been a central part of the PROLIFICA platform. Local researchers have availed themselves of specialised academic mentorship at each of the three sites involved in the study to obtain higher research degrees and academic publications. Finally, community education on HBV infection, mode of transmission and prevention is also likely to have had a positive impact on HBV awareness, at both community and political levels. Above all, the PROLIFICA platform has facilitated the development of strong relationships for future research collaborations and a deeper under­ standing of the barriers to improved healthcare delivery in Africa.

The Vaccine and Cervical Cancer Screen project 2

This issue of SAMJ carries the third in the series of articles dealing with HPV and cervical cancer, ‘The Vaccine and Cervical Cancer Screen project 2 (VACCS 2): Linking cervical cancer screening to a two-dose HPV vaccination schedule in the South-West District of Tshwane, Gauteng, South Africa’.[3] This study again provided the opportunity to investigate the outcome of cervical cancer screening in mothers and guardians by linking this to the vaccination of the girls in their care.

Female parents and guardians of primary school girls were invited to take part in self-administered HPV screening, the screen kit consisting of a sample collector with user instructions available as an Evalyn brush.

Linking self-testing HPV screening to HPV vaccination proved a promising alternative to the current screening policy, although greater uptake rates are required. Given the effective communication of results via the school system and using mobile phone technology, large numbers of women can potentially be screened without impacting on the over-burdened primary care services.

Dementia in rural SA: A pressing need for epidemiological studies

With older age being a major risk factor for dementia, the increasing numbers of older adults worldwide will increase demand for services to diagnose, treat and care for people with dementia. Little is known about the prevalence of dementia or its impact on older adults living in low- and middle-income countries (LMICs) in Africa, including SA. Furthermore, research into the aetiology and risk factors in LMICs is scant. The need for studies to investigate these factors in SA is therefore critical, say De Jager et al. [4]

March 2015, Vol. 105, No. 3

EDITOR’S CHOICE

Alzheimer’s disease is the most common form of dementia in older adults and possibly contributes to 60 - 70% of cases. Other major varieties include vascular dementia, dementia with Lewy bodies and frontotemporal dementia. In SA, disorders associated with neurodegeneration such as traumatic brain injury (TBI), alcohol dependence and HIV infection are affecting increasing numbers of older adults. There is also a growing burden of disease from non-communicable diseases such as diabetes, heart disease and obesity resulting from increasingly unhealthy lifestyles and diet, which contribute to dementia risk.

TBI: The hidden pandemic

Few resources are available for the rehabilitation of TBI patients in SA, and access to rehabilitation facilities in the public sector is limited. TBI can require a long and arduous recovery process, and many survivors are left with permanent physical, emotional and cognitive disabilities.

Perhaps unsurprisingly, TBIs from interpersonal violence are largely inflicted by right-handed perpetrators, which results in frontal lobe and/or left temporal lobe injuries. The neurocognitive and behavioural sequelae of frontal lobe injuries include poor judgement, impaired problem-solving ability and loss of the ability to think abstractly, poor organisational skills, loss of inhibition and impulsive behaviour, aggression, personality changes, depression, anxiety and reduced social skills. Left temporal lobe injuries can result in communication difficulties due to disorders of language (receptive aphasia), including loss of the ability to comprehend speech. These deficits have a disabling effect on survivors’ ability to cope with activities of daily living and with constructive engagement within their families and communities. Poor impulse control and weak social skills result in dangerous situations for survivors and for those around them.

The experiences of TBI survivors and their family members as outlined

by Webster et al.[5] served to inform the development of simple, integrated coping strategies, namely two ‘S-Plan’ tools, one for survivors and their

families/caregivers, and the other for care workers, in conjunction with counselling and support-group processes. The S-Plan constitutes a discharge resource to inform patients and their carers.

Successful TBI support will not only benefit survivors and their family units, but can also contribute towards a reduction in future violent acts perpetrated by TBI survivors. The ComaCARE Trust is a non-profit organisation based at Groote Schuur Hospital in Cape Town. ComaCARE has been addressing the needs of survivors and families since 2005 by providing a psychosocial service that employs community caregivers in the acute-care setting. In 2012, recognising that TBI survivors are usually discharged into the care of an unprepared family unit, ComaCARE developed a brain injury prevention and family support service in Khayelitsha. This HeadsUP! Hub provides supportive intervention for families that involves counselling by social workers and training for families (to know what to do if their relative displays disruptive behaviour at school or the workplace, aggression, memory problems, anxiety, depression or sleep disturbances). For the next phase of this research, these integrated tools will be piloted from 2015 as part of a longitudinal research project to be conducted in under-resourced communities in Cape Town.

JS 1. Jones ESW, Rayner BL. Hypertension, end-stage renal disease and mesangiocapillary glomerulo­nephritis in methamphetamine users. S Afr Med J 2015;105(3):199-201. [http://dx.doi.org/10.7196/SAMJ.8731] 2. Howell J, Ladep NG, Lemoine M, et al. Prevention of Liver Fibrosis and Cancer in Africa: The PROLIFICA project – a collaborative study of hepatitis B-related liver disease in West Africa. S Afr Med J 2015;105(3):185-186. [http://dx.doi.org/10.7196/SAMJ.8880] 3. Snyman LC, Dreyer G, Visser C, Botha MH, van der Merwe FH. The Vaccine and Cervical Cancer Screen project 2 (VACCS 2): Linking cervical cancer screening to a two-dose HPV vaccination schedule in the South-West District of Tshwane, Gauteng, South Africa. S Afr Med J 2015;105(3):191194. [http://dx.doi.org/10.7196/SAMJ.8888] 4. De Jager CA, Joska JA, Hoffman M, Borochowitz KE, Combrink MI. Dementia in rural South Africa: A pressing need for epidemiological studies. S Afr Med J 2015;105(3):189-190. [http://dx.doi. org/10.7196/SAMJ.8904] 5. Webster J, Taylor A, Balchin R. Traumatic brain injury, the hidden pandemic: A focused response to family and patient experiences and needs. S Afr Med J 2015;105(3):195-198. [http://dx.doi. org/10.7196/SAMJ.9014]

UNIVERSITY OF OXFORD, ENGLAND

OXFORD NUFFIELD MEDICAL FELLOWSHIP 2015/16 Applications are invited for an award under the Scheme for Oxford Nuffield Medical Fellowships normally to be held in a department within the Medical Science Division of the University. This prestigious fellowship carries an allowance of £41 564 (plus any cost of living increases). This allowance is subject to UK tax. The Trustees will also pay direct, economy class return air fares for the appointee, his/her spouse and children up to the age of 18 years. A generous baggage allowance is also provided.

Applicants should have graduated from one of the universities listed below and should either hold a medical qualification or have appropriate research experience. There is no limit as to age or status.

The fellowship is tenable for two years in the first instance, with the possibility of an extension for a third year. Fellows are expected to return to South Africa at the end of the fellowship to continue to do work of a similar nature.

The award is available from 1 October 2015 or, subject to consultation with the University’s Medical Sciences Office and the department concerned, from such other later date as may be agreed. The next round of Nuffield Medical Fellowship for South Africa will be in 2016/17.

If the fellow requires a visa to come to the UK, a Tier 5 Temporary Worker Visa (http://www.admin.ox.ac.uk/personnel/permits/tier5/ temporaryworkers/) will be sponsored by the University to allow the fellow to undertake Collaborative Research (only). Supplementary employment (such as clinical work) might be permitted only if the specialty is listed by the UKBA as a shortage occupation (Medical practitioners – 2211) (see http://www.ukba.homeoffice.gov.uk/sitecontent/documents/workingintheuk/shortageoccupationlistnov11. pdf ). Please note that the visa regulations are constantly updated by the UK Border Agency.

Participating universities University of Cape Town, University of Limpopo, University of KwaZulu-Natal, University of the Free State, University of Pretoria, Stellenbosch University h, University of the Witwatersrand.

Further information may be obtained from Ms Nandie Makatesi (nandie.makatesi@uct.ac.za). Details of the research interests of those departments in which the fellowship may be held may be obtained at the website http://www.ox.ac.uk/divisions/medical_sciences.html

Candidates must provide a letter describing their plans and proposed work at the University of Oxford (prior contact with suitable academic hosts at the University is highly recommended), as well as a full curriculum vitae and the names of at least three contactable referees. These should be sent, only via e-mail, to Ms Nandie Makatesi at nandie.makatesi@uct.ac.za by

no later than 31 May 2015.

CORRESPONDENCE

Conflict of interest and regulatory authorities

To the Editor: Parrish and Blockman[1] make excellent points about conflict of interest (COI), particularly in the context of ‘medical leadership’. As key opinion leaders themselves (both are members of the National Essential Medicines List Committee (2013 - 2015), as is the second signatory to this letter – the term does not imply membership of an advisory panel to any for-profit vendor of healthrelated goods or services), the authors are well placed to make comments. An aspect of COI not considered in their article relates to regulatory authorities.

Managing COI effectively is a regulatory concern internationally.[2,3] The most explicit legislation about COI, of all the Acts controlling statutory health councils, is the Medicines and Related Substances Act.[4] Section 6 of this Act has the heading ‘Disqualifications, vacation of office, filling of vacancies and declaration of interest’. Subsection 1(d) unequivocally states that ‘No person shall be appointed as a member of the council – who is employed in the pharmaceutical industry.’ Parrish and Blockman point out the shortcomings of ‘disclosure’ as an intervention for dealing with COI. The Medicines Act goes further than disclosure, and demands, in sub-section 6(4), that a Council or Committee member ‘shall recuse’ themselves ‘from any discussion or decision-making to which the said interests relate or may relate’[4] (our emphasis).

Unfortunately these clear directives do not appear in the Medicines and Related Substances Amendment Act, 2008 (Act 72 of 2008), or in the Medicines and Related Substances Amendment Bill (Bill 6 of 2014). Once brought into effect, these legislative instruments will replace the Medicines Control Council with a South African Health Products Regulatory Authority (SAHPRA). Section 34, the ‘preservation of secrecy’ clause, remains, as do deficiencies in the description of the roles of advisory committees; and whether their advice to the authority will routinely be made public (with the necessary redaction of commercially sensitive information).

It is vital that the employees of this new authority should not have any commercial interests related to the pharmaceutical, foods, cosmetics, medical devices or in vitro diagnostics industries. The members of ‘expert committees’ envisaged for the new authority should not be employed by these industries. Apart from declaring their interests, members of such committees should recuse themselves from ‘any discussion or decision-making to which the said interests relate or may relate’. Whether or not such members actually leave the room for the duration of such discussion should be a policy decision of SAHPRA. How transparently declarations of COI are shared publicly also requires careful consideration.

Inaugural International Association of Student Surgical Societies Symposium

To the Editor: A noteworthy event for global undergraduate surgical education took place when the University of Cape Town Student Surgical Society successfully hosted the inaugural International Association of Student Surgical Societies (IASSS) Symposium.

The IASSS is a recently established global surgical society with the objectives of creating an international movement to represent the needs of surgical societies, developing partnerships between these societies across the globe, and facilitating surgical open education, surgical electives and undergraduate research. While students run the society, the IASSS is fortunate to be able to call on the mentorship of patrons Profs Del Kahn (UCT) and Georges Azzie (University of Toronto).

The symposium was held at UCT on 7 - 10 July 2014, and had an exceptional turnout of 115 undergraduate delegates from five continents and 15 countries. The theme of the symposium was ‘Pioneering in surgery’, and delegates were treated to a programme filled with engaging talks by world-renowned speakers, practical workshops, a high-quality research competition and an intriguing debate on surgical training in developing v. developed countries. Some highlights of the programme included talks on ‘The scope of ENT surgery’ (which included a live endoscopic cadaver dissection) by Dr Darlene Lubbe and ‘The brains for neurosurgery’ by Prof. Anathony Figaji, and a workshop on FATE (focused assessment with trans-thoracic echocardiography) and eFAST (extended focused assessment with sonography for trauma). The symposium afforded the perfect forum for networking with tomorrow’s leaders in surgery, fostering collaboration between societies and sharing of ideas. This was illustrated by a student-led transcontinental multicentre research study that is currently in process.

Among many guests, the symposium hosted Prof. Sats Pillay, Treasurer of the International Surgical Society (ISS/SIC), which has endorsed the IASSS as being ‘in line with the ISS/SIC endeavours’.

With an official IASSS surgical journal, the Journal of Surgical Sciences, established and the next symposium already being planned, the future looks bright for the IASSS and student surgical education.

Medical Student, University of Cape Town, and Treasurer, IASSS and UCT Surgical Society, 2014 10nicholas.rich@gmail.com

Discipline of Pharmaceutical Sciences, University of KwaZulu-Natal, Durban, South Africa

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S Afr Med J 2015;105(2):164. DOI:10.7196/SAMJ.9302

Nicholas Rich

Roy Jobson

Dr George Mukhari Academic Hospital and Sefako Makgatho Health Sciences University, Medunsa campus, Ga-Rankuwa, Gauteng, South Africa royjobson@gmail.com

Andy Gray

1. Parrish A, Blockman M. Who will guard the guards? Medical leadership and conflict of interest in South African healthcare. S Afr Med J 2014;104(11):757-758. [http://dx.doi.org/10.7196/SAMJ.8546] 2. Watson R. European Medicines Agency is accused of weakening its conflict of interest policy. BMJ 2014;349:g7431. [http://dx.doi.org/10.1136/bmj.g7431] 3. EMA. European Medicines Agency policy on the handling of declarations of interests of scientific committees’ members and experts. EMA/626261/2014. http://www.ema.europa.eu/docs/en_GB/ document_library/Other/2014/11/WC500177253.pdf (accessed 17 December 2014).

4. Medicines and Related Substances Act, 1965 (Act No. 101 of 1965). http://www.mccza.com/ genericDocuments/Act_101_of_1965_published_2003.pdf (accessed 17 December 2014).

S Afr Med J 2015;105(3):164. DOI:10.7196/SAMJ.8892

March 2015, Vol. 105, No. 3

IZINDABA

Eastern Cape treatment dysfunction boosts virulent new XDR-TB strain At least half of all known drug-resistant tuberculosis (DR-TB) patients in the Port Elizabeth area (and possibly the entire Eastern Cape) are being treated with too few drugs, fuelling the spread of extensively drug-resistant (XDR)-TB and condemning them to death.

Similar dynamics, though not quite as alarming, pertain in KwaZulu-Natal and to a lesser extent in the Western Cape. An atypi­ cal (Beijing) strain of multiple-drug-resis­ tant (MDR)-TB, first detected by researchers at Stellenbosch University 2 years ago, is being created via a ‘one-size-fits-all’ system of de­ centralised, nurse-led TB clinics with an insufficient array of drugs and wholly in­adequate expertise. In the Eastern Cape, the situation is being worsened by a woeful lack of local political will and/or understanding – resul­ting in a virulent, ‘export-ready’ budget-​ crippling potential domestic time bomb.

Researchers spoken to by Izindaba say that patients carrying this ‘aberrant’ pre-XDR MDR strain and/or the ensuing full-blown XDR are being detected in significant numbers in the Western Cape metropole, the primary destination for the Eastern Cape’s huge migrant worker popu­lation. The Beijing strain is one mutation away from XDR and is being driven by treatment with an insufficient array of drugs. Izindaba has reliably learnt that the National Health Laboratory Service (NHLS) in Port Elizabeth conducted a Line Probe Assay (using the latest Hain LifeSciences technology) on two locally predominant MDR-TB strains, one in particular (Beijing) described as ‘pre-programmed to become XDR’. The conclusion of their lab technicians?

The Port Elizabeth (PE) metropole, in parti­ cular, has a ‘real problem’.

In the Eastern Cape, the situation is being worsened by a woeful lack of local political will and/ or understanding – resulting in a virulent, ‘export-ready’ budgetcrippling potential domestic time bomb.

When slower is better

‘It appears to be fuelled by our patients being put onto a standard regimen of treatment in which very few drugs are effective,’ one

source said. An infectious diseases doctor working in the Eastern Cape explained that nurses could wait for up to 6 weeks for culture results to confirm the DR strain. This ‘archaic’ confirmation followed the 2-hours-or-less GeneXpert result confirming rifampicin resistance. While the samples were at the laboratory to confirm or identify additional resistance markers by culture, nurses and doctors were ‘blindly’ putting patients onto standard MDR-TB treatment – inadequate to treat many of the circulating strains and thus amplifying resistance. Médecins Sans Frontières (MSF) is strengthening its MDR drug regimen in the Western Cape, leading the way in combating this new pre-XDR strain. (National policy on TB treatment is to get as many patients onto treatment as soon as possible and to refer patients, but some experts believe there is insufficient emphasis on, and education about, the multiple complexities of drug resistance.) The national guidelines encourage NGOs and provincial clinics to promote nurse-initiated DR-TB treatment based on single GeneXpert results. However, most healthcare workers, including many doctors, do not understand how to tailor MDR treatment based on mutational analysis, resulting (in the case of the Beijing strain) in the rough equivalent of pouring petrol onto a veld fire, the Izindaba sources claim.

First doing more harm …

One as yet unpublished research paper on the aberrant MDR-TB strain shows that 25% of the PE laboratory samples examined are pre-XDR and 25% are full-blown XDR – clearly demonstrating that half of all the cases scrutinised are being inadequately/ incorrectly treated.

A doctor source at the coalface explained that ‘essentially treatment has selected this strain out – the issue here is the current system not dealing with the current problem’.

He said that infrastructure issues, misguided provincial budget allocation, insufficient training and staff, and a general lack of MDR treatment knowledge on the part of both nurses and doctors aggravated matters. The latest available data from the Jose Pearson TB Hospital in PE show that in 2011, just 35% of MDR TB patients who completed 24 months of treatment remained cured after a year, while only 12% of XDR-TB patients who

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completed 24 months of treatment remained cured a year later. In 2012, this treatment ‘success’ for MDR patients dropped to 29% and for XDR patients to 9%. This is roughly in line with much of the published data.

(The implication is that the remainder have died, will die or have been lost to follow-up, unless the debilitated survivors can quickly access the latest drugs now coming on line – bedaquiline and linezolid.)

According to the treatment register at the Jose Pearson TB Hospital, there were 24 confirmed cases of XDR-TB (of which 17 were HIV-positive) in the last quarter of last year. The number of patients started on treatment in the first quarter of 2014 was 48.

The hospital sees up to 15 new cases of XDRTB per month, draining a huge area in the western part of the province – from Graaff Reinet to Port Alfred and from Humansdorp to Kareedouw. The clinicians emphasised that this probably represents the ‘tip of the iceberg’ in terms of actual MDR/XDR-TB prevalence. Many TB sufferers never make it to a clinic or present too late, having ignored the initial night sweats or the persistent cough. ‘TB is a classic for presenting too late.

Active case finding needs to be drastically addressed,’ says Prof. Rob Warren, associate professor in the Department of Medical Biochemistry at Stellenbosch University, whose team first identified the aberrant preXDR-TB Beijing strain at the heart of the latest development.

Prof. Rob Warren, associate professor in the Department of Medical Biochemistry at Stellen­ bosch University.

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IZINDABA

‘A tide … when taken at the flood …’

The Eastern Cape coalface doctor warned: ‘We’re at a crossroads. If we don’t have a complete revamp of how we approach this problem, we’ll lose a golden opportunity to really make a difference. We have a threshold; something needs to be done now. If we continue blindly on, we’ll expand resistance to the new drugs we have ...’ Chief among the solutions, he believes, is a centralised system to allow the appropriate use of new drugs in a regulated manner based on better diagnostics with good monitoring and follow-up (at least until better training and systems are in place to allow more widespread use of the new drug resources). He said patients needed to be put on the correct therapy as soon as possible, with much-improved case-finding and follow-up.

Eastern Cape a TB treatment ‘black hole’

One doctor typified the Eastern Cape (when compared with the other high-TB-burden provinces of the Western Cape and KwaZuluNatal) as ‘a black hole – it’s left up to poorly trained people to implement a very difficult programme’. The historical/political context is showing. The other two provinces have ‘a lot of academic research going on and use their resources more efficiently. In the Eastern Cape programmes are poorly applied and badly implemented – to the point where they don’t work. My sense is that things are getting worse.’ Eastern Cape doctors said that staff shortages and a lack of ongoing monitoring have rendered contact tracing and follow-up wholly ineffective. Warren’s team found that the Beijing MDR/XDR-TB strain was causing a huge amount of primary transmission, not only within a specific HIV-positive cohort of patients, but across the board. His team’s research centres on novel strategies to reduce the time-to-detection period of both drugsensitive and DR-TB – and to understand the causative agents of the disease better. Their goal is to ‘develop a foolproof diagnostic method that can be used by anyone, anywhere’.

TB diagnosis ‘behind the research curve’

The current TB diagnostic method remains an arduous process that requires the patient to present to the health facility for screening, diagnosis and treatment. Sputum samples are sent to a peripheral laboratory for GeneXpert testing and to a central laboratory for drug susceptibility testing. The patient is therefore not present when the results arrive. Up to 20% of patients do not return at all for their results, and even top government TB Directorate

XDR-TB on the increase nationally

Prof. Keertan Dheda, Head of Pulmonology, Uni­ versity of Cape Town and Groote Schuur Hospital.

officials admit that the systems for tracing them are weak. On testing, Warren observed: ‘The tools are out there. There’s the first-line probe and then the probe for second-line drugs – if we implemented the second-line test, we could probably reduce the [laboratory test] turn-around time from around 50 days to 3 days.’ The test is not perfect yet (a reason given for its low use in spite of its being approved by the World Health Organization (WHO)), but it picks up over 80% of secondline resistance (both are Hain LifeSciences assays). Warren emphasised that in the South African (SA) TB ‘outbreak’ context, the success rate would probably be much higher because outbreaks generally contain the same mutations, making identification much easier.

Assuming proper adherence to national DR-TB management guidelines, the current per patient cost of XDR-TB is ZAR303 508 (USD26 392), four times greater than MDR-TB at ZAR77 878 (USD6 772), and 103 times greater than drug-sensitive TB at ZAR2 955 (USD257).

An Izindaba canvassing of some top TB res­ earchers revealed that they do not necessarily have ‘the ear’ of the National Department of Health (NDoH). Said Warren: ‘Unfortunately there isn’t good liaison between research, and policy and practice. Things filter slowly through the academic journals into their expert group discussions where they may or may not take on an idea and put it forward.’

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Between 2007 and 2012, SA’s recorded cases of MDR-TB (i.e. resistant to at least two of the primary drugs used to combat standard TB) almost doubled. SA has the highest incidence of TB among the 22 high-burden countries (860/100 000), and when adjusted for population, it outdoes India and China.

According to 2012 government figures, just 42% of patients diagnosed with MDR-TB began treatment. Observes Dr Gilles van Cutsem, MSF’s medical co-ordinator for SA and Lesotho: ‘We have in SA one of the only rising epidemics of drug-sensitive TB and DR-TB. And we’re not doing very well at detecting it and treating it.’

In a highly cited paper[1] co-authored

by Prof. Keertan Dheda, Head of the Lung Infection and Immunity Unit in the Uni­versity of Cape Town’s Lung Institute, the budgetary implications of not responding appropriately to the DR-TB challenge are daunting.

Assuming proper adherence to national DR-TB management guidelines, the current per patient cost of XDR-TB is ZAR303 508 (USD26 392), four times greater than that of MDR-TB at ZAR77 878 (USD6 772), and 103 times greater than drug-sensitive TB at ZAR2 955 (USD257). Despite DR-TB’s comprising only 2.2% of the case burden, it consumed 32% of the total estimated 2011 national TB budget of ZAR2.5 billion (USD218 million).

A frightening 45% and 25% of the DR-TB costs were attributed to anti-TB drugs and hospitalisation, respectively. XDR-TB consumed 28% of the total DR-TB diagnosis and treatment costs. Laboratory testing and anti-TB drugs comprised the majority (71%) of MDR-TB costs, while hospitalisation and anti-TB drug costs comprised the majority (92%) of XDR-TB costs. A decentralised XDRTB treatment programme could potentially reduce costs by ZAR79 695 (USD6 930) (26%) per case and reduce the total amount spent on DR-TB by 7%, the authors conclude.[1]

Dr Norbert Ndjeka, head of the National MDRTB Directorate.

IZINDABA

Dr Lindiwe Mvusi, National TB Directorate chief.

SA’s TB control ‘a comedy of errors’

Both Warren and Dheda have emphasised that unless the drug-susceptible ‘TB tap’ is turned off, DR-TB will continue to grow.

Dheda’s work currently centres on creating an effective new combination regimen for DR-TB. In a paper published in the South African Respiratory Journal,[2] Warren and his co-​ authors bluntly say that their review of TB statistics ‘suggests that the current National Tuberculosis Control Programme is unable to curb the emergence and spread of this difficult-to-treat epidemic’. The country’s TB control history was ‘a comedy of errors’, which more modern technology could have helped avoid. ‘It is therefore essential that we learn from these mistakes and use current knowledge to design diagnostic algorithms and treatment guidelines that prevent acquisition of resistance and ensure improved treatment outcomes,’ they conclude.[2] Warren emphasised that he was not blaming anyone in the current national TB Directorate, but merely pointing to the treatment mistakes of the past that they were now saddled with.

Neither Dr Norbert Ndjeka, head of the MDR-TB Directorate, nor Dr Lindiwe Mvusi, National TB Directorate chief, had seen the PE NHLS research paper – but they were eager to study it. Ndjeka said the national guidelines ‘clearly stated’ that the standard­ ised regimen was for newly diagnosed MDRTB patients only. MDR-TB patients exposed to second-line drugs, pre-XDR-TB and XDR-TB were treated with an ‘individualised regimen’ (however, Izindaba established that this was only after drug susceptibility results were made available after a wait that could take 6 weeks – again, it is in this time that patients are being ‘undertreated’).

Ndjeka denied that many clinicians lacked sufficient knowledge, describing them as ‘well trained, and educated’. He said he was

due to hold a workshop with his provincial staff and clinicians in Johannesburg in midto late February – and invited Izindaba to bring Warren and its other sources to address them. He described the Jose Pear­ son Hospital MDR/XDR figures cited as ‘another gross inaccuracy’, saying last year’s WHO Global Tuberculosis Report had SA’s 2011 cohort analysis and that the 2012 report was still incomplete, but due for finalisation this April.

Ndjeka said that SA was a ‘very high’ MDR-TB country, and his directorate had consulted the ‘best brains in the country’ on this issue. ‘We cannot work with each and everybody, though the top ones are in constant communication with us – I can provide proof of this,’ he asserted.

He said that describing the country’s TB control history as a ‘comedy of errors’ was ‘malicious’. ‘We need experts who provide solutions, given the little existing evidence,’ he added. Mvusi conceded that the Hain Line Probe Assay, version 2, would ‘help greatly in reducing the waiting time for con­firmatory first- and second-line drug suscep­ tibility testing because the patient could then be switched to the appropriate regimen earlier’.

Ndjeka said that linezolid and bedaquiline were being introduced ‘in a very responsible manner’ in the public sector, SA being the first TB programme in the world to introduce new agents in about 40 years.

In the Eastern Cape, the situation is being worsened by a woeful lack of local political will and/ or understanding - resulting in a virulent, ‘export-ready’ budgetcrippling potential domestic time bomb.

Eastern Cape admits there’s a problem – but it’s ‘being addressed’

An Eastern Cape health department spokes­ man revealed that bedaquiline had already been ‘responsibly’ introduced at the Jose Pearson Hospital (and a few other selected hospitals nationwide), and ‘so far no adverse events have been reported’. TB clinicians across the country had just met to discuss the scale-up of linezolid and bedaquiline. The Jose Pearson Hospital ‘performance figures’ quoted by Izindaba were ‘acknowledged’, but the data were ‘currently being cleaned up to April this year before being submitted as final to the WHO’. He said that the province had a very high MDR-TB burden and admitted

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that treatment outcomes were poor – but a ‘lot of progress’ in managing the disease had been made in recent years. The NHLS had produced evidence that positive GeneXpert rifampicin-resistant cases were more likely to be MDR-TB, ‘hence our guidelines recommend starting MDR-TB treatment, taking a sample for confirmatory test through the Line Probe Assay or conventional drug susceptibility testing’. He repeated the NDoH assertion that MDR-TB patients exposed to second-line TB drugs, pre-XDR TB patients and XDR-TB patients were treated with an individualised drug regimen. An expert provincial MDR-TB committee met every quarter to review and discuss complicated cases and facilitate/regulate access to the new drugs. The reported increase in DR-TB in the province between 2007 and 2012 was actually an indication of intensified case finding and better diagnostic technology.

Active steps to address the challenges inclu­ ded partnering with the NHLS to improve the response to positive DR-TB results with rapid follow-up diagnostics. The DR-TB decentralisation programme involved ten hospitals, with intensive training of health­ care workers on MDR-TB management being accelerated, while outreach vehicles had been hired to address late presentation of patients and improve case finding and contact tracing. Four hospitals were either under construction or renovation to comply with national infection prevention and control guidelines.

Although Izindaba did not source its most alarming data directly from the PE laboratory, technicians there received a stern warning: ‘Permission is required to conduct research or make use of departmental data/ information – this being granted only on condition that these findings are shared with provincial health management before being presented on any platform.’

Izindaba has chosen to withhold the names of some of its Eastern Cape sources, who said they fear becoming targets of angered local officialdom – historically a common anxiety among that province’s many deeply committed healthcare workers.

Chris Bateman chrisb@hmpg.co.za S Afr Med J 2015;105(3):165-167.

DOI:10.7196/SAMJ.9475 1. Pooran A, Pieterson E, Davids M, Theron G, Dheda K. What is the cost of diagnosis and management of drug resistant tuberculosis in South Africa? PLoS One 2013;8(1):e54587. [http://dx.doi.org/10.1371/journal.pone.0054587] 2. Warren RM, Hoek K, Sirgel F, et al. Emergence and treatment of drug resistant tuberculosis: A comedy of errors. South African Respiratory Journal 2011;16(4):112-116.

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IZINDABA

Will Basson come out on top?

The seasoned legal team of apartheid-era chemical warfare expert and top cardiologist Dr Wouter Basson will within a fort­ night ask the Medical and Dental Prof­ essions Board (MDPB) committee that found him guilty of violating basic medical ethics to recuse itself entirely.

Prof. Jannie Hugo.

This follows their having secured a High Court injunction on 19 January to halt Basson’s professional conduct sentencing hearing so they could prepare an application to the committee to recuse itself, claiming that its two members signed or approved of at least one of about 30 petitions calling for Basson to be struck from the medical register of the Health Professions Council of South Africa (HPCSA). The MDPB (one of the many HPCSA boards) committee last year found Basson guilty of unprofessional conduct, saying that he ‘defiled the unique and sacred position of doctors’ by actively furthering warfare via the production, distribution and use of teargas and drugs against the apartheid regime’s enemies some 30 years ago. The HPCSA, charged with ‘guiding the professions and protecting the public’, has taken 7 years to get to this point, in a roller-coaster ride of legal technicalities and procedural delays. Now there is the possibility that should Jaap Cilliers, SC, the veteran legal counsel of several high-profile right-wing court victories, succeed in getting the committee to reluctantly recuse itself, the entire hearing will have to start from scratch – either that, or new committee appointees will have to pick up the hearing where it left off in January (i.e. witnesses testifying in aggravation of sentence, the central theme of which was Basson’s demonstrable lack of any remorse for

his actions). On 12 and 13 March, Basson’s legal team will try to provide compelling evidence to committee chairperson Prof. Jannie Hugo and committee member Prof. Eddie Mhlanga (both advised by retired former Judge President Fritz Eloff) that they signed or approved of any one of the many petitions calling for Basson to be struck from the medical register. The defence team have also argued that Hugo’s and Mhlanga’s ‘conduct’ after it asked them whether they were members of any organisation that signed an anti-Basson petition is a telling factor in support of their recusal application. The unspoken threat of yet another Cilliers High Court application will perforce focus the minds of the committee.

In his response to the successful High Court defence application, Hugo admitted that he was a member of the Rural Doctors Association of South Africa and the South African Medical Association, both of which circulated strongly worded petitions calling for Basson to be struck from the medical roll. However, he denied ever signing any petition or taking part in formulating any of them. He said that the reason was simple: ‘I could not allow myself to be influenced by and/or participate in processes relevant to the issues to be determined in the proceedings, which were occurring outside the hearings.’ Mhlanga did not submit anything to the High Court about membership of any of the organisations that circulated ‘anti-Basson’ petitions, but Hugo testified that Mhlanga had informed him that his response was identical to his own. Judge A J Bam said that both Hugo and Mhlanga were constitutionally obliged to furnish a proper explanation of their possible involvement and/or knowledge of the petition to Cilliers. Their refusal to do so was not justified, and was irregular. Judge Bam ordered the HPCSA to pay the costs of the application.

Walk-out drama precedes High Court intervention

The impending recusal move is without precedent in the HPCSA’s history of professional conduct hearings, and may well lay bare its often controversial and sometimes dysfunctional processes – at least as much as whether its professional conduct committee conducted itself towards Basson with any historical bias.

There was drama during the January hearing when the pro forma complainant (the HPCSA) called a fresh witness in aggravation of sentence.

Cilliers stood up and asked that proceedings be adjourned to enable him to prepare a recusal application, explaining why. Hugo refused, saying that proceedings should continue. Cilliers walked out of the hearing in protest, filing his

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High Court application. Basson, in testimony prior to his earlier acquittal on multiple charges of murder, fraud and drug dealing in his 2002 criminal trial (which earned the professionally highly regarded Durbanville cardiologist the moniker ‘Dr Death’), and the State’s subsequent failed appeal bids to the Supreme Court and the Constitutional Court (ending in 2005), has insisted that his conduct came within the context of war and conflict and that no proof was ever obtained that he caused harm or death.

However, the professional conduct committee found that the ethical values of ‘beneficence, non-malificence, justice and autonomy’ had not changed since the time of his ethical offences, and that medical ethics were especially important in times of war and conflict. Hugo found that Basson had contravened both the Geneva Declaration of 1948 and the UN convention on the prohibition of and stockpiling of dangerous weapons. No doctor could claim ignorance of their expected professional behaviour, he added.

Basson, while project officer of the 1980s and early 1990s secret ‘Project Coast’ and its military front teargas and drugs manufacturing company Delta G, co-ordinated the largescale production and stockpiling of Mandrax, ecstasy and teargas and provided ‘disorientating substances for cross-border kidnapping’. He also supplied cyanide suicide capsules to apartheid under­cover operatives for use when captured – something the committee heard caused an agonising death, not the quick and painless demise of spy novels.

Cilliers’ colourful court career

Cilliers, regarded as one of the more able senior counsels by his peers, took on the so-called ‘generals case’ in the mid-1990s when former defence minister Magnus Malan and 20 senior military officers stood trial for murdering 13 people, some of them children, in the Kwa­ Makhutha township massacre of 1987. All were acquitted in a 1996 ruling that polarised black and white South Africa. Besides getting Basson acquitted of the criminal charges, Cilliers less successfully took on the case of Jewell Crossberg, the Limpopo farmer given a 20-year sentence for shooting dead a Zimbabwean farmworker, and that of the ‘Waterkloof Four’, young Pretoria men sentenced to 12 years for ‘cruelly’ murdering and assaulting a homeless black man.

Chris Bateman chrisb@hmpg.co.za S Afr Med J 2015;105(3):168.

DOI:10.7196/SAMJ.9463

IZINDABA

Zuma’s legal advisors ‘led him astray’, turned healthcare profess­ionals into criminals President Jacob Zuma’s legal advisors ‘led him astray’, resulting in him ‘irrationally’ signing into existence a law that crimin­ alised the provision of healthcare services in South Africa and flouted several provisions of the Constitution. That is the nub of the Constitutional Court’s 27 January finding after Zuma, his Minister in the Presidency Jeff Radebe, Minister of Health Dr Aaron Motsoaledi and National Health Director-General (DG) Precious Malebona Matsoso applied to have the controversial Certificate of Need (CoN) provisions deproclaimed.

‘Irrational’ – President Jacob Zuma on the CoN.

The earlier and premature proclamation brought into effect sections 36 - 40 of the National Health Act from April 2014, forcing tens of thousands of healthcare providers to apply to Matsoso for a CoN within a very narrow time frame (2 years), and making it impossible for her department to properly process and decide on the ‘appropriate’ geographical placement of each practitioner, or for her to consult widely before drafting appropriate regulations. It was always a nonstarter – in spite of the health department’s brave assertions to the contrary as multiple and furious healthcare organisations protested. Penalties for non-compliance included a jail term of up to 5 years.

CoN: not dead, just sleeping …

The law is not dead. It will be re-proclaimed, probably in toto, once a more pragmatic time frame has been written up, almost certainly leading to another High Court or

Constitutional Court application, this time by its adversaries. One or several of the more bold, cash-fluid healthcare bodies will probably argue that the CoN is a blunt instrument, giving almost unfettered power to the Health DG to restrict and control the placement of healthcare practices – or even effectively close them down, with unintended consequences including accelerating the overseas migration of newly qualified healthcare professionals, thus undermining the very National Health Insurance scheme the CoN intends to support.

Government’s embarrassing legal somer­ sault brings into serious question the quality and competence of Zuma’s top legal advisors and the health department’s own legal architects, and/or the quality of communication between them and the country’s health policy implementers. It was left up to the South African Dental Association (SADA) to properly examine the ‘teeth’ of the legal provisions and warn the presidency that they were effectively criminalising all healthcare provision in the country (SADA and the Hospital Association of South Africa were cited as co-respondents in the Constitutional Court application, having brainstormed with several other healthcare bodies, including the South African Medical Association and the SA Private Practitioners Forum). All agree with government that better access to healthcare is vital and are willing to help address the geographical mismatch of services and patients – but differ strongly on the use of the CoN to do this.

Trust us, this is no ‘Con’

The protestors see the certificate as arbitrary and dictatorial, in spite of Motsoaledi’s and the DG’s repeated reassurances that they won’t use it to crowbar healthcare prof­ essionals in an over-served area out of their current practices. Motsoaledi is even on record as saying that the law will merely be used ‘incrementally’ to prevent new practitioners buying into already well-staffed practices in adequately served geographical areas. However, unlike several similar pieces of overseas legislation, it goes well beyond that, enabling any less enlightened future DG to strong-arm healthcare prof­

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Director-General of Health, Precious Malebona Matsoso.

essionals, arguably in defiance of several Constitutional provisions. In agreeing with the government’s admission that its CoN proclamation was premature and irrational, the Constitutional Court judges said that the poor timing resulted in a failure to respect, promote and fulfil fundamental tenets of the Bill of Rights, including the right to life, the right of access to healthcare and the right to transparency and accountability. Zuma’s actions were described as ‘untenable and unintended’, and ‘ill-advised, irrational and thus invalid’. He was led astray by his legal advisors, who gave him mistaken counsel.

Zuma didn’t know at the time that signing the proclamation into law was fruitless because nobody could apply for a certificate without the vital regulations being in place, nor could the regulations be drafted without widespread consultation. He was unable to withdraw the proclamation because the date for its commencement had long since passed and there was no mechanism contained in the Act itself to remedy the situation. The judges said that the other remedy – taking the parliamentary legislative amendment route – would be ‘lengthy and burdensome’ and would fail to address the ‘precarious position the health service industry finds itself in’.

Chris Bateman chrisb@hmpg.co.za S Afr Med J 2015;105(3):169.

DOI:10.7196/SAMJ.9468

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The risky lives of South Africa’s children: Why so many die or are traumatised Of the 18.5 million children under the age of 18 in South Africa (SA), 8% have no fathers, 23% do not live with their biological parents, and 60% live in poverty – frightening figures that top local epidemiologists and clinicians agree help explain why the risk of a child dying here is ten times higher than in Europe.

Prof. Sebastian van As.

These figures emerged with the release of the annual South African Child Gauge report by the Children’s Institute at the Uni­ versity of Cape Town (UCT) in November 2014, and from an Izindaba interview with Prof. Sebastian van As, chief paediatric surgeon at Red Cross War Memorial Children’s Hospital in Cape Town, the only dedicated children’s hospital in the country. Since 1991, Red Cross Hospital has built up the world’s single largest data base on child trauma. The experts at both institutions agree that poverty and the widespread, tragic absence of the most effective risk-mitigating factors possible – one or both of a child’s biological parents – render the 8% of SA’s children living in urban informal areas the most vulnerable as they roam danger-filled environments, many bordered by highways, train routes or bodies of water. HIV/AIDS in the

pre-antiretroviral (ARV) era has left SA with one of the world’s largest orphan populations (3% being double orphans and 8% having no father). According to Katharine Hall, project leader of the Child Poverty Programme at UCT’s Children’s Institute, a major contributor to the Child Gauge, the overall orphan count rose dramatically from the early 1990s, with the graph currently levelling off (an indicator of how dramatically the introduction of ARVs has impacted on mortality). Hall emphasised that household survey data continued to show that children who were not living with their biological parents were ‘overwhelmingly in the care of other kin’ – a legacy of migrant labour and urban housing shortages. This was ‘not something that poor households can easily resolve’. An aggravating risk factor is that even those children lucky enough to have working parents or guardians are often left unsupervised as their primary minders leave in the early hours to eke out a living, and return home in darkness.

Van As told Izindaba that a child younger than 6 years of age was insufficiently deve­ loped neurologically to properly assess the dangers around him or her, with the lack of sufficient child-minding facilities and crèches in the townships a major problem. He feels so strongly about this that he believes it should a criminal offence to allow a child to wander alone unsupervised: ‘If you let a dog roam free without a licence, you can be fined – but there’s no legal protection for kids.’ Asked about the ten times greater risk of an SA child dying v. a European one, Van As said this came from a World Health Organization country-by-country child mortality comparison. Three years ago his own unit had compared the relative risk of a child ending up in a Cape Town hospital v. a child being admitted to Birmingham Hospital in the UK. The data showed that there was a 25 times greater chance locally.

Ten times as many children die in accidents as are abused

SA was ‘anything but a child-centred society’, and the media attention on violence against children disguised the ‘true numbers’, which showed that ten times as many children died from accidental injuries as were violated.

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Just 5% (or 500) of the 10 000 children seen at Red Cross Hospital annually were physically or sexually abused. (According to Western Cape Health Department policy, Red Cross Hospital admits only children 13 years old and younger). Van As and his Red Cross team of two trauma and three orthopaedic consultants (backed by an average of 10 paediatric registrars) admit 3 000 children annually, 1 000 suffering from burns and 2 000 from a mixture of other injuries, the biggest overall killer being motor vehicle accidents. He said that poverty also drove malnutrition, which impeded neurological development, further hampering less-privileged children from reaching their full potential. The country’s violent past and the generational passing on of violent behaviour, aggravated by widespread poverty, meant that ‘we are world champions at killing children’, he observed. In the hour Izindaba spent interviewing him, Van As treated a child with 32 fractures (as a result of domestic violence between adults with the child being used as a ‘shield’, a common cause of severe trauma) and watched another die after the upper part of her torso had been kept alive for two days. Hit by a heavy-duty truck while walking on a township road, she had literally been torn in two.

The experts at both institutions agree that poverty and the widespread, tragic absence of the most effective riskmitigating factors possible – one or both of a child’s biological parents – render the 8% of SA’s children living in informal urban areas highly vulnerable as they roam danger-filled environments, many bordered by highways, train routes or bodies of water.

Violence learnt and passed on

The 2014 Child Gauge report, entitled Preven­­ ting Violence against Children: Break­ing the Inter-generational Cycle, found that over half of SA’s children frequently experience some

IZINDABA

form of violence from a very early age. This had long-term consequences that could be avoided by investing in prevention initiatives.

While there was a paucity of systematic research on the extent and range of violent experiences, population-based prevalence studies showed that over half of children experience physical violence at the hands of a caregiver, teacher or relative. Incidents of sexual violence were under-reported – a ‘disturbing reality’ when considering that half of the 45 230 ‘contact crimes’ against children reported in the 2013/2014 crime statistics were sexual offences (an average of 62 cases per day). A two-province study found that one-third of participating children experienced emotional abuse. Emotional violence and neglect, and corporal and humiliating punishment of children, were ‘common in the home’, where abuse and neglect especially of young children could result in death. Physical punishment at schools was still ‘pervasive’ in spite of being banned for almost 20 years.

Shanaaz Mathews, director of the Child­ ren’s Institute and lead editor of the 2014 Child Gauge report, said that these experiences hampered a child’s development, learning ability, self-esteem and emotional security and had long-term consequences for employment prospects and life expectancy. Hervé Ludovic de Lys, UNICEF’s SA representative, said that the current epidemic of violence undermines the fabric of society, affecting productivity, well-being and prosperity. ‘The good news is that it is possible to see a dramatic reduction in violence against children in a relatively short time by implementing the right strategies, allocating enough resources and mobilising the highest political will,’ he added brightly. Mathews said that the impact of violence went beyond physical scars. Research showed that an intergenerational cycle of violence was created when children were exposed to violence in their early years, with these children more likely to become perpetrators or victims of violence when they were older because of neurological and psychological damage.

resolution skills to deal with peer pressure, substance abuse and social norms that promoted violence between young men and between them and their partners.

Within the social development services there was currently too much focus on response services instead of prevention and early intervention measures. Lucy Jamieson of the Children’s Institute said that nonprofit organisations, which delivered the bulk of services on behalf of government, were ‘not fairly compensated’, resulting in a funding crisis that was hampering services to children and families in need.

Dena Lomofsky of the research consultancy South­ern Hemisphere said that while multi­ ple intersectoral committees had been set up to strengthen collaboration between government departments and civil society, each structure tended to focus on ‘a speci­fic issue with little collaboration between them to address children’s needs holistically’.

This led to a fragmented response to a com­ plex problem that required strong leader­ ship from within government. Joan van Niekerk of Childline South Africa said that the National Department of Health could play a key role by identifying caregivers and children at risk and referring them to social services – but this was ‘neglected in both policy and practice’.

Parenting and lifeskills programmes essential

Violence ‘normalised’ in SA

Parenting programmes could play a major role in providing essential support to families ravaged by poverty, intimate partner violence and substance abuse, while lifeskills programmes for young people could help develop communication and conflict

In the hour Izindaba spent interviewing him, Van As treated a child with 32 fractures (as a result of domestic violence between adults with the child being used as a ‘shield’, a common cause of severe trauma) and watched another die after the upper part of her torso had been kept alive for two days. Hit by a heavyduty truck while walking on a township road, she had literally been torn in two.

The Child Gauge report states that due to the ‘normalisation of violence’ in SA’s past, there was now a widespread tolerance of it that would require ‘a great deal of work’, including engendering an attitude that ‘preventing violence is everybody’s business’.

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Red Cross Hospital is home to one of the world’s oldest child-safety NGOs. Started in 1978 by its renowned former head of peadiatric surgery, Prof. Sid Cywes, when he noticed that he was doing more operations on children hurt in accidental injuries than on those suffering from all other diseases combined, Child Safe SA is aimed at promoting awareness through research, interventions (e.g. educating caretakers, crèche managers and teachers), and advocacy – based on hard data. A pre­ fabricated ‘home’ on the hospital grounds highlights all the potential dangers in every room of the house, including things like dangling electric kettle cords (responsible for a disproportionate number of nearfatal burns in toddlers), containers with water, and age-specific posters on ‘Living safely’ and ‘Travelling safely’. The NGO won a global award at the 2008 World Safety conference in Mexico.

Gun law improvements – 70% fewer child gunshot admissions

A manifestation of the violence referred to in the Child Gauge report, and a shining example of basic interventions, can be seen in how Child Safe SA tackled a virtual epidemic of child gunshot wounds in 2000. That year the hospital’s trauma unit treated 50 children with firearmrelated injuries, mainly ‘collateral injuries’ resulting from adults intending to harm other adults (most children were hit by stray bullets) – a ‘morbid’ measurement of how many bullets were fired in Cape Flats communities, sparking an evidence-based campaign supporting the NGO ‘GunFree South Africa’. A petition demanding stricter gun laws was delivered after a march on Parliament, resulting in a new firearm bill being adopted in 2002 that requires a gun-handling safety competency certificate, raises the minimum age requirement for possessing a firearm from 16 to 21, and declares ‘gun-free zones’ (e.g. places of worship, schools, hospitals).

After these changes in the law, there was an ‘astonishing’ 70% decrease in admissions of children with gunshot wounds to Red Cross Hospital. ‘We cannot make it better, we have to go out there and prevent,’ Van As stressed.

Chris Bateman chrisb@hmpg.co.za S Afr Med J 2015;105(3):170-171.

DOI:10.7196/SAMJ.9462

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OBITUARIES/HULDEBLYKE Ajay Makanjee

This tribute to Dr Ajay Makanjee, general surgeon and founding member of the KwaZulu-Natal Specialist Network, was extracted from a eulogy at his memorial service.

Ajay was born in Durban to Jaymati and Amaratlal Makanjee on 13 November 1959.

He matriculated at the Gandhi Desai School in Durban and then attended medical school at the University of Natal, graduating in 1982.

At medical school, his habit of questioning his teachers whenever he saw a reason to challenge their views raised the ire of many.

He also refused to attend lectures that he considered mundane, preferring to study those subjects on his own. He was a master

Alewyn Petrus Rossouw

Dit is met innige leedwese dat ek verneem het van Alewyn se dood. Op 27 Januarie 2015 sou hy 79 jaar oud geword. Alewyn kom vanaf Lydenburg, waar sy vader ’n gesinsdokter was. Sy moeder was ’n sjarmante dame vanaf Nederland, maar het goed hier ingeburger.

Alewyn se ouer broer, Braam, was ook ’n algemene praktisyn en sy suster, Corrie, was getroud met ds. Punt Janson, wat later ’n parlementslid geword het.

Alewyn se ouers het op Graskop afgetree en ons het as koshuis-studente gereeld piesangs, lietsjies en pynappels vanaf hul plaas ontvang. Hierdie ‘eksotiese’ vrugte was ’n eienaardigheid vir ons Vrystaters met ons waatlemoene, pruime, kersies en perskes!

Alewyn was ’n briljante student. In sy eerste jaar het dr. B Cholnoky (plantkunde) rondgeloop met Alewyn se antwoordstel en verklaar: ‘Hier is nou ’n papier’, tewyl hy ander gewaarsku het: ‘Menere, julle sal sak soos bakstene!’.

brag and table-tennis player, and spent many hours in the medical school sports hall honing his skills.

Ajay had a strong intuitive sense of ethics, and when the United Nations promulgated International Woman’s Day to highlight the plight of women, Ajay wrote a letter to request that they also found an Inter­national Youth Day. In 1990 he qualified as a general surgeon.

With a special interest in diseases of the breast, he was a founding member and remained actively involved in the metropolitan breast oncology team in Durban. Such was his dedication to this team that he attended his last clinic the day before his sudden illness.

Known for his formidable intellect and irreverent sense of humour, Ajay was happiest in the company of his family and friends or immersed in a book, Sudoku or a crossword puzzle while listening to jazz. His love of golf was matched only by his passion for soccer, and he shared both with his son Amar and daughter Deeya. He and his wife Vasie also had a younger son named Arjun and an older daughter, Veena.

Described as a loving son, father and brother, with a heart of gold, Ajay was quite an adventurer. He hiked the peaks of the Drakensberg to train for his successful ascents of Mount Kilimanjaro and Machu Picchu.

He had to abandon his Otter Trail trek on the penultimate day, when he dislocated his

kneecap while climbing a rocky precipice along the Southern Cape coast. Despite this, he stayed on to greet his fellow hikers at the Storms River mouth with a six-pack of Black Label beer to celebrate their accomplishment.

Ajay also enjoyed regular fishing with the Medics Angling Club, resulting in many a tall fishing tale that will be told for years to come!

Fiercely loyal, infuriatingly resolute and abundantly generous, Ajay stepped to the beat of his own drum. He sought the truth at all costs and claimed no easy victories.

The measure of his life lies in the simplicity, humility and nobility of spirit for which he will always be remembered. He was a vocal member of the KZN Specialist Network, where his incisive questions and challenges at our academic meetings and annual general meetings will be very much missed. He was ever prepared to criticise the board of directors, and never spared any advice or recommendations to make the KZNSN a better organisation.

Ajay will be sorely missed by all our members, by his colleagues, and by the staff he worked with at Ethekwini Hospital in Durban. His indomitable spirit will forever live on in our midst. Rest in peace, Ajay.

Die eerste ses jaar van ons studie het maar redelik roetinegewys verloop. Ek en Alewyn was kamermaats vir ’n hele aantal jare. Hy was besonder belese en kon interessant gesels oor etiek en filosofie. Hy was versot op O Henry en Damon Runyon se kortverhale en het later John Steinbeck bewonder en gelees.

Sy ware potensiaal het gou na sy huis­ dokterjare te voorskyn gekom en hy het kliniese assistent in neurologie geword. Hy het baie hoofstukke in akademiese boeke geskryf, bv. saam met prof. Ben Meyer (fisiologie). Hy was ’n gesogte mentor vir kliniese assistente in neurologie. Sover ek weet, was hy die eerste magisterstudent wat hierdie graad met lof geslaag het by Pretoria se Fakulteit Geneeskunde. Ironies genoeg is hy gediagnoseer met motorneuronsiekte, wat hom gou afgetakel het.

Hy was vir baie jare in vennootskap met dr.

C Guldenpfennig (‘Pennie’) en het betreklik onlangs sy kliniese deel van die praktyk vaarwel geroep. Daarna het hy waardevolle werk

gedoen as kundige met betrekking tot mediesgeregtelike neurologies-verwante gevalle.

Alewyn was ’n betroubare mens vir wie ek grenslose agting gehad het. Hy het onbaatsugtige diens aan sy medemens verskaf. Hy was ook minsaam, met ’n wonderlike humorsin.

Ons klasmaats, met wie ons op dieselfde verdieping in die mediese koshuis gebly het, sluit in Frik Booysen en Johan van Wyk, internasionaal bekende lewerchirurg. Johan was ook later hoof van die Departement Chirurgie by Tygerberg Akademiese Hospitaal.

Alewyn was getroud met Elna de Villiers en hulle het drie kinders gehad. Sy was oorspronklik ’n plaasnooi – ook uiters intelligent – en ’n steunpilaar in sy lewe.

Ons harte gaan uit na Elna, sy gesin en sy familie. Ons sal Alewyn nie vergeet nie.

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Executive Committee, KZN Specialist Network KwaZulu-Natal, South Africa info@kznspecialist.co.za

Prof. Ben Smit 2de Laan 22, Melkbosstrand, Wes-Kaap, Suid-Afrika bensmit@sonicwireless.co.za

FORUM

CLINICAL PRACTICE

Carbohydrate loading in the preoperative setting L T Hill, M G A Miller Lauren Hill is a critical care dietitian with a PhD in physiology and 20 years’ experience as a clinical dietitian, academic and researcher. Her special interest, knowledge and expertise is in nutritional support of critically ill adults, trauma patients and difficult-to-treat patients who have undergone surgery to the gastrointestinal tract. Malcolm Miller is a specialist anaesthetist and intensivist in clinical and academic practice at the University of Cape Town/Groote Schuur Hospital, South Africa. Nutritional support of the critically ill is among his interests. Both authors are affiliated to the Division of Critical Care and Department of Anaesthesia, Faculty of Health Sciences, University of Cape Town.

Nutrition support is an evolving field, and modern clinical nutrition practice should actively incorporate strategies to enhance various clinical outcomes. In surgical patients, clinical benefits can be maximised by nutritional support protocols that minimise and manage the perioperative fasting period. This approach, which includes the perioperative provision of clear carbohydrate-containing fluids, has been shown to be safe, is evidence based, and is supported by many professional societies. Such a strategy has been shown to aid the anaesthetic process and maintain an optimal metabolic state, including improved insulin sensitivity and blunted muscle catabolic activity.

Some important consequences of this improved metabolic control include shorter hospital stay and fewer postoperative complications. A proactive multidisciplinary team approach is essential to use this nutrition support strategy with success across a hospital’s surgical service.

S Afr Med J 2015;105(3):173-174. DOI:10.7196/SAMJ.8746

The past decade has seen an evolution in clinical practi­ces and protocols governing perioperative fast­ ing for elective surgical procedures. Various pro­ fessional associ­ ations for both surgery (Enhanced Recovery After Surgery (ERAS)) and anaesthesiology (Canadian, American, European, and South African (SA) society guide­ lines) (Table 1) support more modern nil per mouth guidelines of 6 hours for solids and only 2 hours for clear fluids, even in some instances for some patient subgroups known to have delayed gastric emptying. It has been suggested that minimising the preoperative fasting period, by allowing the consumption of oral carbohydrate-containing clear fluids with or without protein, has a number of clinical advantages, including more stable hae­ modynamics during induction of anaesthesia, greater glycaemic stability, reduced lean tissue catabolism, and a more positive patient experience.

Nevertheless, consistent compliance of anaesthetists with the updated recommendations to allow carbohydrate-containing clear fluids in the immediate preoperative period is low.[1] This short review addresses the issues of permitting preoperative free fluids in view of lack of associated risk, and actively encouraging preoperative consumption of carbohy­ drate-containing free fluids due to the associated clinical benefits.

Aspiration risk

The main rationale for maintaining patients in a preoperative fasted state is the purported risk of pulmonary aspiration upon induction of anaesthesia. In fact, the incidence of aspiration is very low – perhaps 1/45 000 elective anaesthetics in stable, otherwise healthy patients – and clinically important consequences of such an event are even rarer. It has been shown that gastric residual volume is a very poor marker of

Table 1. Summary of professional association guidelines for preoperative fasting Professional body

Current guideline

European Society of Anaesthesiologists

Adults and children should be encouraged to drink clear fluids (including water, pulp-free juice and tea or coffee without milk) up to 2 hours before elective surgery (including caesarean section).

ERAS

Preoperative clear fluid intake (exclusions from free intake according to national guidelines): 800 ml carbohydrate-rich drink the evening before surgery, and 400 ml 2 hours before anaesthesia.

Association of Anaesthetists of Great Britain and Ireland

Intake of water up to 2 hours before induction of anaesthesia. A minimum preoperative fasting time of 6 hours for food (solids, milk and milk-containing drinks).

European Society for Parenteral and Enteral Nutrition

Patients undergoing surgery who are considered to have no specific risk for aspiration may drink clear fluids until 2 hours before anaesthesia. Solids are allowed until 6 hours before anaesthesia.

Use preoperative carbohydrate loading (the night before and 2 hours before surgery) in most patients undergoing major surgery.

American Society of Anesthesiologists

Fast from intake of clear fluids (water, fruit juices without pulp, carbonated beverages, clear tea, coffee) at least 2 hours before anaesthesia. Fast from intake of light solids and non-human milk 6 hours before anaesthesia. Fast for 8 hours following fatty meals.

Canadian Anesthesiologists’ Society

Before elective anaesthesia, duration of fasting should be 8 hours after a meal including meat or fatty foods, 6 hours after light solid meals, and 2 hours after clear fluids.

South African Society of Anaesthesiologists

Fasting guidelines of 6 hours for solids and 2 hours for clear fluids should be applied.

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FORUM

aspiration risk, and that, with the exception of meals with a high fat content, intake of non-particulate meals such as carbohydrate-based drinks has no relevant bearing on increasing gastric residual volume. In fact, the opposite may be true: judicious use of appropriate oral fluids during the preoperative hours may actually reduce volume residue in the stomach.[2] The emphatic, traditional practice of prolonged preoperative fasting as a risk-reduction approach is therefore unnecessary and is a dogma not founded upon good evidence.

The metabolic response to surgery

The typical physiological response to surgery includes a well-described stress hormone- and cytokine-induced hyperglycaemic and catabolic metabolic profile. This occurs in part as a result of poor movement of GLUT4 glucose transporters to the cell membrane, leading to insulin resistance, along with low muscle glycogen synthetase activity, leading to poor glycogen storage, in a counter-regulatory hormonal environment that enhances muscle protein degradation due to glucoeneogenesis. The response can persist for days to weeks after surgery, and its amplitude is influenced by the magnitude and duration of the surgery and the extent of intraoperative blood loss.[3] Both nutritional compromise going into surgery and the fasting state worsen the response, owing to underlying glycogen and lean tissue depletion.

In the SA clinical setting, poor nutritional status of surgical patients is common. It is generally advocated that purposive nutritional support of such patients in the pre- and perioperative period is of clinical benefit. However, the intentional use of nutrition-providing clear fluids in the acute preoperative phase, regardless of nutritional status, may not be practised as uniformly. This is despite the support for such practice by both the American and European societies for parenteral and enteral nutrition, as outlined in their guidelines.[4,5]

The carbohydrate loading concept

Control of the metabolic response is understood to improve clinical outcomes. One of the recommended methods of control is the provision of isotonic, carbohydrate-containing clear fluids until 2 hours preoperatively, so that patients enter surgery in a fed rather than fasted state. This has been called ‘carbohydrate loading’. The principle of the approach is the provision of an energy-containing liquid meal, which will result in insulin secretion necessary to alter the fasted metabolic state.[6] Since fat and hypertonic fluids inhibit gastric emptying, for safety reasons the preferred energy source is carbohydrate in an isotonic solution.

An amount of 50 g is sufficient to produce an insulin response similar to that of a mixed solid meal. Recommendations for preoperative carbohydrate loading have therefore been based around this amount and include 100 g carbohydrate on the evening prior to surgery and a further 50 g 2 hours prior to induction of anaesthesia.[7] There is now more than one commercially available sip drink oral supplement that can provide this amount in the form of complex carbohydrate polymers without providing excessive fluid or producing a hyperosmolar product.

The isotonic nature of the sip drink is important, as hyperosmolar solutions may delay gastric emptying or provoke other gastrointestinal symptoms such as diarrhoea. Several thousand patients in clinical trials and several million patients in routine clinical practice worldwide have used these commercial carbohydrate-rich drinks without adverse events. The use of such products is therefore safe.

Both carbohydrate and protein produce the desired insulin response. It has therefore been postulated that the addition of protein to carbohydrate-rich sip drinks would enhance the clinical benefits of carbohydrate loading. Importantly, by using non-particulate, fatfree, lactose-free protein sources, carbohydrate drinks containing medical nutrition therapy-grade protein still meet the characteristics of a ‘clear’ fluid.

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Clinical benefits

Benefits of the above approach to preoperative fasting are both physiological and patient orientated. The physiological consequences of intake of carbohydrate-rich sip drinks up to 2 hours before surgery are an up to 50% reduction in insulin resistance, which in turn shortens hospital stay and reduces postoperative complications;[6,8] lower muscle catabolism;[9-11] improved intraoperative haemodynamic stability, particularly in children, as a result of more favourable fluid balance status; reduced days to discharge fitness; and superior handgrip strength, a sensitive marker of early muscle protein loss. Perrone et al.,[12] in a small study in 2011, showed that the addition of whey protein to a carbohydrate drink further improved insulin sensitivity and reduced acute-phase markers compared with carbohydrate alone. In addition, benefits on various aspects of patient comfort (such as thirst and anxiety), co-operation, compliance and overall subjective satisfaction have been reported.

Conclusion

There has been a distinct shift in the clinical approach to optimally preparing patients for surgery. There is mixed but good evidence that preoperative oral carbohydrate delivery up to 2 hours before induction should be part of this optimising, and improves outcomes. This practice is widely supported by professional societies for nutrition, surgery and anaesthesiology, and therefore requires co-operative participation from the relevant members of the clinical team. However, it appears that compliance may not be ideal. A change in culture is still necessary so that practice is based on evidence rather than the beliefs or fears of individual practitioners working defensively. Better implementation may depend not only on increasing awareness of modern fasting guidelines but also on packaging nutrition interventions like this one into audit bundles in order to incentivise compliance through a systems-based approach. The time has come for consistent metabolic preparation of patients in the preoperative period through delivery of carbohydrate loading in order to improve surgical outcomes.

Disclosures. LH received an unrestricted writing grant from Nestlé Healthcare, SA. 1. Bosse G, Breuer JP, Spies C The resistance to changing guidelines – what are the challenges and how to meet them. Best Pract Res Clin Anaesthesiol 2006;20(3):379-395. [http://dx.doi.org/10.1016/j. bpa.2006.02.005] 2. Maltby JR. Fasting from midnight – the history behind the dogma. Best Pract Res Clin Anaesthesiol 2006;20(3):363-378. [http://dx.doi.org/10.1016/j.bpa.2006.02.001] 3. Nygren J. The metabolic effects of fasting and surgery. Best Pract Res Clin Anaesthesiol 2006;20(3):429438. [http://dx.doi.org/10.1016/j.bpa.2006.02.004] 4. McClave SA, Martindale RG, Vanek VW, et al.; A.S.P.E.N. Board of Directors; American College of Critical Care Medicine; Society of Critical Care Medicine. Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). JPEN J Parenter Enteral Nutr 2009;33(3):277-316. [http://dx.doi.org/10.1177/0148607109335234] 5. Weimann A, Braga M, Harsanyic L, et al. ESPEN guidelines on enteral nutrition: Surgery including organ transplantation. Clin Nutr 2006;25(2):224-244. [http://dx.doi.org/10.1016/j.clnu.2006.01.015] 6. Ljungqvist O. Modulating postoperative insulin resistance by preoperative carbohydrate loading. Best Pract Res Clin Anaesthesiol 2009;23(4):401-409. [http://dx.doi.org/10.1016/j.bpa.2009.08.004] 7. Kratzing C. Pre-operative nutrition and carbohydrate loading. Proc Nutr Soc 2011;70(3):311-315. [http://dx.doi.org/10.1017/S0029665111000450] 8. Sato H, Carvalho G, Sato T, Lattermann R, Matsukawa T, Schricker T. The association of preoperative glycemic control, intraoperative insulin sensitivity, and outcomes after cardiac surgery. J Clin Endocrinol Metab 2010;95(9):4338-4344. [http://dx.doi.org/10.1210/jc.2010-0135] 9. Donatelli F, Corbella D, Di Nicola M, et al. Preoperative insulin resistance and the impact of feeding on postoperative protein balance: A stable isotope study. J Clin Endocrinol Metab 2011;96(11):E1789-E1797. [http://dx.doi.org/10.1210/jc.2011-0549] 10. Henriksen MG, Hessov I, Dela F, et al. Effects of preoperative oral carbohydrates and peptides on postoperative endocrine response, mobilization, nutrition and muscle function in abdominal surgery.

Acta Anaesthesiol Scand 2003;47(2):191-199. [http://dx.doi.org/10.1034/j.1399-6576.2003.00047.x] 11. Yuill KA, Richardson RA, Davidson HI, et al. The administration of an oral carbohydratecontaining fluid prior to major elective upper-gastrointestinal surgery preserves skeletal muscle mass postoperatively – a randomised clinical trial. Clin Nutr 2005;24(1):32-37. [http://dx.doi.org/10.1016/j. clnu.2004.06.009] 12. Perrone F, da-Silva-Filho AC, Adôrno IF, et al. Effects of preoperative feeding with a whey protein plus carbohydrate drink on the acute phase response and insulin resistance: A randomized trial. Nutr J 2011;10:66. [http://dx.doi.org/10.1186/1475-2891-10-66]

Accepted 11 August 2014.

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Recommendations for the treatment and prevention of malaria: Update for the 2015 season in South Africa L H Blumberg Lucille Blumberg is an infectious diseases specialist and microbiologist, and Head of the Division of Public Health Surveillance and Response at the National Institute for Communicable Disease, Johannesburg, South Africa. She has compiled this article for the South African Malaria Elimination Committee (SAMEC), the national malaria advisory group to the National Department of Health, Pretoria, South Africa, in her capacity as chairperson.

Corresponding author: Lucille Blumberg (lucilleb@nicd.ac.za)

Notified malaria cases in South Africa (SA) decreased significantly over the past 14 years, from over 60 000 in the 1999/2000 malaria season to less than 13 000 in 2013/2014. However, the past two seasons have seen increases in both local and imported cases. Mozambique contributes the highest number of imported cases in SA. This update provides recommendations for malaria treatment and prevention (in travellers and residents) for 2015.

S Afr Med J 2015;105(3):175-178. DOI:10.7196/SAMJ.9407

Management of malaria

Key components of successful management are early and accurate diagnosis (Table 1) and prompt treatment with effective drugs.

Treatment should ideally be based on confirmed parasitological diagnosis.[1,2] Microscopy of Giemsa-stained thick and thin blood smears remains the diagnostic mainstay.[3] Rapid antigen detection diagnostic tests (RDTs) are more widely accessible than expert microscopy, provide prompt results and are adequately sensitive for Plasmodium falciparum infections.

However, RDTs cannot quantify parasite density (so do not detect hyperparasitaemia that indicates severe malaria) and are less sensitive for non-falciparum species than for falciparum infections.

RDTs are unsuitable for monitoring treatment response because of antigen persistence.[4] A negative (rapid or microscopy) test does not exclude malaria; repeat testing within 8 - 24 hours, without attempting to coincide with fever peak timing, is mandatory until a positive result or an alternative definitive diagnosis is achieved. Blood smears should be checked for malaria whenever thrombocytopenia is unexpectedly identified. Test any patient with unexplained fever for malaria, even in the absence of a travel history. Occasionally, infected mosquitoes are transported from endemic areas in suitcases and vehicles (Odyssean malaria).[5] All malaria cases must be notified to local health authorities.

Treatment of malaria

The choice and route of treatment depends primarily on disease severity, which is often underestimated. Uncomplicated malaria is symptomatic infection without signs of severity or evidence of vital organ dysfunction. Persistent vomiting, clinical jaundice, change in mental state or increase in respiratory rate constitutes severe malaria (Table 2).[6,7] Treat uncomplicated malaria with artemether-lumefantrine (Coartem) (Table 3).[2] For optimal absorption it must be taken with milk or fat-containing food. Adequate fluids, temperature control with paracetamol, and careful follow-up are important. Avoid non-steroidal anti-inflammatory agents. Patients should respond clinically and parasitologically within 24 - 48 hours. Consider poor compliance, misdiagnosis and possible drug resistance if no significant improvement occurs within 72 hours. Artemetherlumefantrine remains efficacious in South Africa (SA),[8,9] with no reports of artemisinin resistance in Africa as yet. In the rare event of artemether-lumefantrine treatment failure despite full compliance, give a full directly observed 7-day course of oral quinine (plus doxycycline or clindamycin) in hospital.

Oral quinine, combined with 7 days of doxycycline, remains an alternative to artemether-lumefantrine (Table 4), but compliance is poor. In pregnancy or children aged <8 years, substitute clindamycin for doxycycline (Table 4). Doxycycline or clindamycin add no early

Table 1. Diagnosis of malaria Keep a high index of suspicion for malaria in travellers to, or residents of, malaria transmission areas presenting with fever or other ’flu-like illness, irrespective of the time of year, intensity of transmission or use of chemoprophylaxis. Always take an adequate travel history.

Typical presentation: paroxysms of fever and rigors in adults, also headache, myalgia, loss of appetite, nausea and vomiting. In young children, fever, lethargy, poor feeding, vomiting and diarrhoea are most common.

Important differential diagnoses: meningitis, African tick-bite fever, typhoid, viral haemorrhagic fever, trypanosomiasis.

Progression to severe disease may be rapid, particularly in non-immune and immune-compromised persons, young children and pregnant women.

Often missed in patients with comorbid disease.

Frequently misdiagnosed in pregnancy, requiring differentiation from pregnancy complications including intrauterine and urinary tract infections.

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treatment benefit, so are started only once symptoms improve, as gastrointestinal side-effects may exacerbate those of quinine.

Second and third trimesters. Artemether-lumefantrine is con­ sidered safe and efficacious.

Drug interactions

Large adults

Concomitant use of certain other drugs (e.g. efavirenz, rifampicin) may alter blood concentrations of artemether-lumefantrine and quinine. There is no evidence of the clinical significance of these interactions, but full adherence and fat co-administration is advised, and response to treatment should be monitored particularly carefully.

Pregnancy

First trimester. Supervised 7-day course of oral quinine plus clindamycin.

Table 2. Clinical and laboratory criteria for severe malaria (any one or combination of these criteria applies) Clinical Impaired consciousness, multiple convulsions Respiratory distress, acidotic breathing, pulmonary oedema

Artemether-lumefantrine is registered in SA only for use in patients weighing ≤65 kg. Minimal pharmacokinetic data exist for larger patients; one study suggests a trend towards increased risk of treatment failure in patients >80 kg.[10] Again, adequate adherence and fat co-administration is important, with careful monitoring of response. If adherence is assured, consider administering the same total dose over 5 days (dosing at 0, 8, 24, 48, 72 and 96 hours).

Recommendations for non-falciparum malaria

Malaria species should be confirmed by a reliable laboratory. Nonfalciparum infections are usually uncomplicated, but occasionally produce severe illness. Use artemether-lumefantrine for initial therapy of uncomplicated P. vivax and P. ovale infections. To prevent relapses, this should be followed by a course of primaquine after excluding glucose-6-phosphate dehydrogenase (G6PD) deficiency.

Table 3. Dosing schedule for artemether-lumefantrine (Coartem) Time of dosing (hours) and number of tablets

Circulatory collapse Jaundice Bleeding Prostration Laboratory Hypoglycaemia (blood glucose <2.2 mmol/L) cidosis (plasma bicarbonate <15 mmol/L or serum lactate A >5 mmol/L) Hepatic transaminases >3 times normal enal impairment (serum creatinine >265 µmol/L or rapidly R rising creatinine or urine output <400 mL/day in an adult) Haemoglobin <5 g/L Parasitaemia ≥5% ≥5% neutrophils contain malaria pigment Presence of schizonts of P. falciparum in peripheral blood smear

Body weight (kg)

0

8 - 12

24

36

48

60

5 - 14

1

1

1

1

1

1

15 - 24

2

2

2

2

2

2

25 - 34

3

3

3

3

3

3

≥35

4

4

4

4

4

4

Table 4. Dosing schedule for oral quinine with doxycycline or clindamycin Drug

Schedule

Oral quinine

10 mg/kg 8-hourly for 7 days

Doxycycline

200 mg stat, thereafter 100 - 200 mg once daily, or 3.5 mg/kg once daily for 7 days

Clindamycin

10 mg/kg bd for 7 days

Table 5. Dosing schedule and adverse effects for mefloquine, doxycycline and atovaquone-proguanil Chemoprophylactic

Schedule

Adverse effects

Mefloquine (Lariam, Mefliam)

Weekly, starting 1 - 2 weeks before travel, weekly while there and continue for 4 weeks after Adults: 250 mg weekly Children: 5 mg/kg weekly Not recommended for children <3 months or <5 kg

Gastrointestinal, headache, dizziness, imbalance, mood changes, insomnia, nightmares, and rarely, psychosis. Increased risk of eye disorders Contraindications: epilepsy, neuropsychiatric disorders, those who require fine motor co-ordination, divers and pilots

Doxycycline (daily)

Daily, starting 1 day before travel, daily while there and continue for 4 weeks after Adults: 100 mg daily Not recommended for children <8 years

Skin photosensitivity, oesophagitis, upper gastrointestinal symptoms, vaginal candidiasis or diarrhoea (normal flora disruption)

Atovaquone-proguanil (Malanil, Numal)

Daily, starting 1 day before travel, daily while there and continue for 1 week after Adults: 1 tablet daily Children >11 kg: Malanil Paediatric at prescribed dose per body weight

Adverse reactions uncommon; include headache, nausea, vomiting, abdominal pain, diarrhoea

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Table 6. Drug choice according to patient factors Patient factor

Mefloquine

Doxycycline

Atovaquone-proguanil

Pregnancy â&#x20AC;&#x201C; avoid travel to malaria areas.

Now recommended for all trimesters[12,13] if travel is necessary.

Contraindicated

Contraindicated owing to lack of data.

Young children â&#x20AC;&#x201C; avoid taking children <5 years to high-risk areas.

Can be used in children >3 months or >5 kg. Generally well tolerated by children.

Use only in children >8 years.

Paediatric tablets can be given to children >11 kg. Breaking of tablets is not recommended.

Persons requiring long-term prophylaxis

Can be used for up to 3 years.

Longer-term use may be justified by risk of malaria.

Can be safely used for up to 2 years. Longer term use may be justified by risk of malaria.

Can be used confidently for up to 1 year. Longer-term use may be justified by risk of malaria.

HIV-positive (on ARVs)

Best option

ARVs = antiretrovirals.

Fig. 1. Malaria risk map for SA (adopted 2014).

The recommended dose in children is 0.25 - 0.3 mg/kg daily for 14 days, and that for adults is 15 mg daily for 14 days. Currently primaquine is only available on a named-patient basis with Section 21 MCC approval.

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Severe malaria (Table 5)

Severe malaria is a medical emergency requiring prompt parenteral treatment, intensive nursing care, and careful monitoring and management of complications.[6.7] Intravenous artesunate (2.4 mg/kg

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at 0, 12 and 24 hours, then daily until the patient is able to tolerate oral treatment) is preferred treatment, but is currently unregistered and only available on a named-patient basis with Section 21 MCC approval.[2,11] When intravenous artesunate is not promptly available, intravenous quinine (with an initial loading dose of 20 mg/kg and then maintenance doses of 10 mg/kg, each dose slowly infused over at least 4 hours) is initiated urgently and given 8-hourly until oral treatment is tolerated. Follow with a complete course of artemetherlumefantrine.[2] Reassess frequently to ensure that all complications are promptly detected and optimally managed.

Critical issues in management of severe malaria

Hypoglycaemia. Urgently exclude (or administer empiric glucose) if there is a depressed level of consciousness or convulsions. Repeat glucose monitoring 4-hourly.

Renal failure. This is a frequent, early complication in adults. Severe malaria requires careful fluid management, with frequent measurement of renal function (urea, electrolytes and creatinine), ongoing monitoring of urine output and judicious fluid administration. Strictly avoid overhydration, as the acute respiratory distress syndrome is a common and difficult-to-treat complication, particularly in pregnancy.

Prevention of malaria

Prevention of mosquito bites is the mainstay of malaria prevention.

Malaria-transmitting mosquitoes generally bite at night, so people in malaria-endemic areas should ideally remain indoors from dusk to dawn, and sleep under insecticide-treated bednets in rooms with screened windows and doors. Fig. 1 shows endemic areas in SA; residents and travellers in these areas should take necessary precautions to avoid mosquito bites.

Effective repellents contain DEET (diethyl toluamide). Use products containing 20 - 50% DEET for long-lasting protection for adults and children aged >2 months. Products containing >50% DEET have no additional benefit. Avoid applying to eyes or mouth.

Additionally, travellers to malaria-endemic areas should use chemoprophylaxis depending on the malaria risk assessment. Three similarly effective chemoprophylactic agents are currently registered in SA (Table 5), all requiring a doctor’s prescription. Selection should be based on patient factors (Table 6) and which option is likely to be best tolerated for optimal adherence.

Scope of protection

Chemoprophylactics are most effective against parasite asexual blood stages. While they will prevent initial illness caused by all species, they will not prevent relapses due to P. vivax and P. ovale.

1. World Health Organization. Guidelines for the Treatment of Malaria. 2nd ed. Geneva: WHO, 2010. http://www.who.int/malaria/publications/atoz/9789241547925/en/ (accessed 14 January 2015).

2. South African National Department of Health. Guidelines for the Treatment of Malaria in South Africa. Pretoria: NDoH, 2010.

3. Payne D. Use and limitations of light microscopy for diagnosing malaria at primary health care level.

Bull World Health Organ 1988;66(5):621-626.

4. Bell DR, Wilson DW, Martin LB. False-positive results of a Plasmodium falciparum histidinerich protein 2-detecting malaria rapid diagnostic test due to high sensitivity in a community with fluctuating low parasite density. Am J Trop Med Hyg 2005;73(1):199-203.

5. Frean J, Brooke B, Thomas J, Blumberg L. Odyssean malaria outbreaks in Gauteng Province, 20072013. S Afr Med J 2014;104(5):335-338. [http://dx.doi.org/10.7196/SAMJ.7684] 6. World Health Organization. Management of Severe Malaria – a Practical Handbook. 3rd ed. Geneva: WHO, 2013. http://www.who.int/malaria/publications/atoz/9789241548526/en/ (accessed 14 January 2015).

7. World Health Organization. Severe malaria. Trop Med Int Health 2014;19(Suppl 1):1-131. [http:// dx.doi.org/ 10.1111/tmi.12313_2] 8. Barnes KI, Durrheim DN, Little F, et al. Effect of artemether-lumefantrine policy and improved vector control on malaria burden in KwaZulu-Natal, South Africa. PloS Med 2005;2:e330. [http://dx.doi. org/10.1371%2Fjournal.pmed.0020330] 9. Vaughan-Williams CH, Raman J, Raswiswi E, et al. Assessment of the therapeutic efficacy of artemether-lumefantrine in the treatment of uncomplicated Plasmodium falciparum malaria in northern KwaZulu-Natal: an observational cohort study. Malar J 2012;11:434. [http://dx.doi. org/10.1186/1475-2875-11-434] 10. Leykin Y, Miotto L, Pellis T. Pharmacokinetic considerations in the obese. Best Pract Res Clinical Anesthesiol 2011;25(1):27-36. [http://dx.doi.org/10.1016/j.bpa.2010.12.002] 11. Kift EV, Kredo T, Barnes KI. Parenteral artesunate access programme aims at reducing malaria fatality rates in South Africa. S Afr Med J 2011;101(4):240-241.

12. Schlegenhauf P, Blumentals WA, Suter P, et al. Pregnancy and fetal outcomes after exposure to mefloquine in the pre- and periconception period and during pregnancy. Clin Infect Dis 2012;54(11):e124-131. [http://dx.doi.org/10.1093/cid/cis215] 13. Centers for Disease Control and Prevention. CDC Update: New recommendations for mefloquine use in pregnancy. http://www.cdc.gov/malaria.new_info/2011.mefloquine_pregnancy.html (accessed 14 January 2015).

Accepted 26 January 2015.

This month in the SAMJ ...

Maud Lemoine* is a clinical senior lecturer and honorary consultant in hepatology at St Mary’s Hospital, Imperial College London. She completed her medical degree and a PhD in physiology and physiopathology in Paris, France, where she also graduated in political sciences from the Institute of Political Studies. She worked at the Medical Research Council laboratories in The Gambia, West Africa, running the PROLIFICA (Prevention of Liver Fibrosis and Cancer in Africa) project (EU-FP7) on hepatitis B virus and liver cancer. She is also leading a study on HIV/hepatitis C virus co-infection in Vietnam, funded by the ANRS (the French research agency on HIV/AIDS and viral hepatitis), and is co-investigator in a forthcoming pilot study on sofobuvir/ribavirinbased, interferon-free therapy in Cameroon, Côte d’Ivoire and Sénégal. She is a member of the World Health Organization scientific advisory board for the development of hepatitis C guidelines and of the ANRS. * Howell J, Ladep NG, Lemoine M, et al. Prevention of Liver Fibrosis and Cancer in Africa: The PROLIFICA project – a collaborative study of hepatitis B-related liver disease in West Africa. S Afr Med J 2015;105(3):185-186. [http://dx.doi.org/10.7196/SAMJ.8880]

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Chronic pancreatitis, depression and substance use disorders: A not uncommon combination C Y Jeppe, C P Szabo, M D Smith Cara Yvonne Jeppe is a research facilitator in the Hepatopancreatobiliary Unit in the Department of Surgery at Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa. She has a professional background as a medical technologist and her interests include social determinants of disease and the outcomes of their surgical management. Prof. Christopher Paul Szabo is Head of the Department of Psychiatry, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, and Head of the Department of Psychiatry at Charlotte Maxeke Johannesburg Academic Hospital, Johannesburg. His areas of special interest include eating disorders and ethics. Adjunct Prof. Martin Derrick Smith is Head of the Department of Surgery, Faculty of Health Sciences, University of the Witwatersrand, and Head of the Department of Surgery at Chris Hani Baragwanath Academic Hospital. He has a special interest in hepatopancreatobiliary surgery.

Corresponding author: C P Szabo (christopher.szabo@wits.ac.za)

Chronic pancreatitis (CP) is a progressive and debilitating disease. A potentially important consideration is the relationship between CP, depression and substance use disorders, which seems to be circular and multiplicative. Pain management is a critical component of intervention, and it would seem that in the context of chronic illness this requires a biopsychosocial approach aiming for a tailored intervention that strikes an appropriate therapeutic balance.

S Afr Med J 2015;105(3):179-180. DOI:10.7196/SAMJ.8885

Chronic pancreatitis (CP), a progressive and debili­ tating disease that usually presents with pain, is frequently attributed to alcohol misuse. Patients generally present for treatment in their fourth decade after recurring absenteeism and job loss; some have become (or have always been) indigent. There is a need for prevention. A potentially important consideration is the relationship between CP, depression and substance use disorders (SUDs), which seems to be circular and multiplicative.

Pain, depression and substance abuse

Compared with people in good health, ‘depression is approximately two to three times more common in people with a chronic physical health problem’.[1] In their article discussing the neurobiology and clinical presentation of pain and its synergies with SUD, Savage et al.[2] stated: ‘Pain and substance abuse co-occur frequently, and each can make the other more difficult to treat’; ‘each may reinforce components of the other’; and ‘depression is the most common psychiatric symptom seen among pain patients’. They found that clinicians’ fear that patients might develop SUD with opioid treatment for pain compromised effective treatment.[2] Mavandadi et al.[3] found that pain ‘may hinder or minimize treatment-related improvements in depressive symptoms’.

Concerns about substance dependence resulting from opioid use may therefore contribute to inadequate pain relief and also lead to suboptimal response to treatment of depression, while potentially contributing towards depressive symptoms. The interplay of these factors has clear implications for the management of CP and calls for a multidisciplinary approach to optimise outcome.

Diagnosis of depression

Depression is frequently undetected and untreated. While poor socioeconomic status can predispose people to depression, which can begin in childhood or adolescence, it can also make diagnosis and treatment less likely. Other risk factors for a depressive disorder include alcohol abuse, stressful life events, adverse childhood experiences, job

179

loss, close personal relationship problems, poverty, and a family history of depression. Severe pain is a major contributor to depression, and pain amelioration can improve collaborative care interventions for depression.

In 1985 David Goldberg[4] identified five main reasons why patients failed to have their psychiatric conditions diagnosed by physicians: they would not be asked directly about their psychological conditions; only somatic symptoms would be discussed; privacy during consultations would be lacking; there would be an exclusive focus on organic causes of symptoms; and physicians lacked confidence in their ability to make psychiatric assessments. Ideally, consultants should have knowledge of the culture of origin of patients with depression, within a holistic biopsychosocial approach to disease management. Knowledge of the social environment of such patients is critical for determining what measures can be taken to improve their circumstances and thus contribute to amelioration of depression. Social workers from the community are well placed to facilitate such measures.

Depression and physical illness

Objective evidence on the incidence and severity of depression in com­ bination with chronic physical health problems is not available.[1] Somatic symptoms of the latter can occur with, and mask, the symptoms of the former, making distinction between the two problematic.[1] The simultaneous presence of both increases the likelihood and extent of functional, social and occupational disabilities, and may lead to shorter life expectancies. Depression worsens medical prognosis and may play an aetiological role in SUD and CP. In 2000, DiMatteo et al.[5] found that depressed patients with physical illness were ‘three times more likely to be non-compliant with treatment recommendations’. Although active treatment for depression may have a lesser beneficial effect for severe pain, and may not improve length of survival, it improves quality of survival.

Chronic pancreatitis, substance abuse and depression

Depression and low self-esteem arising from poor education and unemployment are associated with high-risk behaviours such as

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substance abuse, while SUD can be both the cause and effect of depression. Wehler et al.[6] lamented the lack of knowledge about poor mental health in patients with CP and noted that a substantially increased risk for onset of major depressive disorders arises from alcohol abuse. Such a causal link has also been suggested by Fergusson et al.[7] Drug addiction has been cited as a complication of depressive disorders, and dependence on opioids can result from their use as prescribed treatment for CP pain. Unemployment may be a predictor of abuse of prescription opioids and vice versa, while both increase dependence on disability grants.

Chronic pancreatitis, surgery and pain management

The Frey procedure (local resection of the pancreatic head with late­ral pancreaticojejunostomy) undertaken at the Hepatopancreato­ biliary (HPB) Unit in the Department of Surgery at Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa, between 2002 and 2009 improved quality of life and functioning and reduced symptoms in 32 patients with painful CP.[8] The median duration of pain before surgery was 72 months (range 10 - 264).

There was no significant correlation between preoperative pain duration and the pain score or pain intensity of the 32 patients. The traditional view that with time there is ‘burn-out’ of pain has been invalidated,[8-10] and deferment of surgery in anticipation of future ‘burn-out’ is therefore not appropriate. Rather, deferment of surgery increases the risk of dependence on opioids.

In a later unpublished study from the same authors, 35 patients treated between 2009 and 2012 answered a structured interview before and after the Frey procedure in the HPB Unit. All patients answered questions relating to hopelessness and pain, as measured on a visual analogue scale from 0 to 10. The use of prescribed opioids was recorded at both interviews. The duration of postoperative follow-up was a mean of 27.5 months (standard deviation 24.9).

Before surgery, 68.6% of the patients felt hopeless, 100% had a pain score of ≥5, and 38.2% were using prescribed opioids. After surgery, at the last recorded visit, 34.3% felt hopeless, 54.5% had pain ≥5, and there was an increase in the use of prescribed opioids to 64.7% of the sample. The increasingly liberal prescribing of opioids has raised concern about dependence and deleterious side-effects.[11] Misuse of opioids for the relief of depression can lead to behaviours that exaggerate pain in order to increase the amount of opioids prescribed.

In a rare study on interventions for alcohol abuse in patients with

alcohol use disorders and painful pancreatitis, a reduction in alcohol consumption and a decreased need for analgesics was achieved by a multidisciplinary group of pancreatic surgeons and addiction and pain specialists.[12]

Conclusion

The use of adequate analgesia is a key component in preventing depressive symptoms, but may promote substance dependence and abuse. The clinician is therefore caught in a double bind.

Pain management in the context of chronic illness requires a bio­ psychosocial approach aiming for a tailored intervention that strikes an appropriate therapeutic balance.

Surgeons, pain and addiction clinicians working in collaboration with nurses, social workers, psychologists and psychiatrists can contribute to improved quality of life for patients with CP, and raise professional and public awareness at all levels of healthcare.

1. National Collaborating Centre for Mental Health. Depression in adults with a chronic physical health problem. In: Depression in Adults with a Chronic Physical Health Problem: The NICE Guideline on Treatment and Management. Chap. 2. British Psychological Society and Royal College of Psychiatrists, 2010:15-27. http://www.nice.org.uk/guidance/cg91/evidence/cg91-depression-with-a-chronic-physicalhealth-problem-full-guideline2 (accessed 30 January 2015).

2. Savage SR, Kirsh KL, Passik SD. Challenges in using opioids to treat pain in persons with substance use disorders. Addict Sci Clin Pract 2008;4(2):4-25. [http://dx.doi.org/10.1151/ascp08424] 3. Mavandadi S, Ten Have TR, Katz IR, et al. Effect of depression treatment on depressive symptoms in older adulthood: The moderating role of pain. J Am Geriatr Soc 2007;55(2):202-211. [http://dx.doi. org/10.1111/j.1532-5415.2007.01042.x] 4. Goldberg D. Identifying psychiatric illness among general medical patients. BMJ 1985;291(6489):161162. [http://dx.doi.org/10.1136/bmj.291.6489.161] 5. DiMatteo MR, Lepper HS, Croghan TW. Depression is a risk factor for noncompliance with medical treatment: Meta-analysis of the effects of anxiety and depression on patient adherence. Arch Intern Med 2000;160(14):2101-2107. [http://dx.doi.org/10.1001/archinte.160.14.2101] 6. Wehler M, Nichterlein R, Fischer B, et al. Factors associated with health-related quality of life in chronic pancreatitis. Am J Gastroenterol 2004;99(1):138-146. [http://dx.doi.org/10.1111/j.15720241.2004.04005.x] 7. Fergusson DM, Boden JM, Horwood J. Tests of causal links between alcohol abuse or depen­ dence and major depression. Arch Gen Psychiatry 2009;66(3):260-266. [http://dx.doi.org/10.1001/ archgenpsychiatry.2008.543] 8. Jeppe CY, Becker P, Smith MD. Post-Frey procedure quality of life in South African patients with painful chronic pancreatitis. J Pancreas (Online) 2013;14(1):21-30. [http://dx.doi.org/10.6092/15908577/933] 9. Mullady DK, Yadav D, Amann ST, et al. Type of pain, pain-associated complications, quality of life, disability and resource utilization in chronic pancreatitis: A prospective cohort study. Gut 2011;60(1):77-84. [http://dx.doi.org/10.1136/gut.2010.213835] 10. Liu LS, Shenoy M, Pasricha PJ. Substance P and calcitonin gene related peptide mediate pain in chronic pancreatitis and their expression is driven by nerve growth factor. J Pancreas (Online) 2011;12(4):389-394.

11. Sehgal N, Colson J, Smith HS. Chronic pain management with opioid analgesics: Benefits versus harms of long-term therapy. Expert Review of Neurotherapeutics 2013;13(11):1201-1220. [http://dx.doi.org /10.1586/14737175.2013.846517] 12. Lang MB, Segersvard R, Grundsten M, et al. Management of alcohol use disorders in patients with chronic pancreatitis. J Pancreas (Online) 2012;13(6):654-659. [http://dx.doi.org/10.6092/15908577/1037]

Accepted 8 September 2014.

This month in the SAMJ ...

Greta Dreyer* is a gynaecological oncologist at Steve Biko Academic Hospital, Pretoria, where she heads the clinical and research units in the Department of Obstetrics and Gynaecology at the University of Pretoria. She is a founder member of the South African HPV Advisory Board and its research fund and of the University of Pretoria and Netcare Familial Cancer Centre, and established the Southern African Journal of Gynaecological Oncology, of which she is still Editor-in-Chief. She holds a doctorate in basic research and clinical cancer genetics for work done on the PTEN gene in gynaecological cancer. Her research efforts in oncology are currently mostly aimed at the control of lower genital tract cancer via immunisation and screening, the recognition, diagnosis and prevention of familial cancer, and surgical treatment of women’s cancer. She established the Vaccine and Cervical Cancer Screen (VACCS) study group in 2009, consisting of clinicians and academics from various South African universities. The group has completed two multicentre projects aiming to improve vaccination against and screening for cervical cancer in South Africa and the developing world. * Snyman LC, Dreyer G, Visser C, Botha MH, van der Merwe FH. The Vaccine and Cervical Cancer Screen project 2 (VACCS 2): Linking cervical cancer screening to a twodose HPV vaccination schedule in the South-West District of Tshwane, Gauteng, South Africa. S Afr Med J 2015;105(3):191-194. [http://dx.doi.org/10.7196/SAMJ.8888]

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MEDICINE AND THE LAW

‘Over-servicing’, ‘underservicing’ and ‘abandonment’: What is the law?

D J McQuoid-Mason David McQuoid-Mason is Professor of Law at the Centre for Socio-Legal Studies, University of KwaZulu-Natal, Durban, South Africa, and publishes and teaches in medical law.

Corresponding author: D J McQuoid-Mason (mcquoidm@ukzn.ac.za)

The Ethical Rules and Policy Document of the Health Professions Council of South Africa (HPCSA) do not define ‘over-servicing’, ‘underservicing’ and ‘abandonment’. The HPCSA Guidelines on Over-servicing, Perverse Incentives and Related Matters define ‘over-service’ only. The converse of this definition can be used to define ‘underservicing’. The courts do not refer to these concepts, but apply general rules regarding professional negligence and malpractice based on what a reasonably competent doctor in the same position would do. In deciding the standard to be adopted, the courts may consult the ethical rules of the medical profession, but are not bound to take them into account.

S Afr Med J 2015;105(3):181-182. DOI:10.7196/SAMJ.9141

The Health Professions Council of South Africa (HPCSA) rules[1] mention ‘over-servicing’ and ‘underservicing’ of patients in terms of fees and over-charging (rule 7(3)). However, ‘over-servicing’ and ‘underservicing’ are not defined, and they are silent on ‘abandonment’ of patients. The Guidelines on Over-servicing, Perverse Incentives and Related Matters[2] define ‘over-servicing’ but not ‘underservicing’ or ‘abandonment’ of patients. The definition of ‘over-servicing’ in the Guidelines can assist in defining a meaning for ‘underservicing’. ‘Abandonment’ of patients may sometimes be linked to ‘underservicing’.

The legal standard of care required of doctors is often influenced by the ethical rules of the profession, but the courts are not bound by them. As South Africa (SA) has no ethical guidelines for practitioners defining ‘underservicing’ and ‘abandonment’ of patients, the courts will apply the general principles of legal liability for professional negligence and malpractice.

treating patients.[4] In a sense, ‘underservicing’ is the opposite of ‘overservicing’. The converse of the Guidelines definition of ‘over-servicing’ could therefore be used to define ‘underservicing’.

What is the meaning of ‘underservicing’?

What does ‘over-servicing’ mean?

‘Underservicing’ generally means failing to provide a patient with the standard of care that a reasonably competent doctor in a similar situation and in the same field of medical practice would be expected to provide.[5] This definition can be refined by formulating one that is the converse of the ‘over-servicing’ definition in the Guidelines[2] (para 2.14), which could read as follows: The failure to supply, provide, administer, use or prescribe any treatment or care (including diagnostic and other testing, medicines and medical devices) which are medically and clinically indicated, necessary or appropriate under the circumstances or which is in accordance with the recognised treatment protocols and procedures, without due regard to the patient’s financial and health interests.

They also state that healthcare practitioners shall not ‘[p]rovide a service or perform or direct certain procedures to be performed on a patient that are neither indicated nor scientific or have been shown to be ineffective, harmful or inappropriate through evidence-based review’. The same principle applies to referrals to another healthcare practitioner for a service or a procedure that is not indicated or unscientific, or that evidence-based review has shown to be ineffective, harmful or inappropriate.

The HPCSA Policy Document on Undesirable Business Practices[3] provides that ‘[i]ncentives may not be used to encourage either “over” or “under” servicing of patients’ and that ‘[a]ppropriate care should be provided at all times’ (para 4.8), but does not define the terms.

The Guidelines and Policy Document are consistent with the law, which requires doctors to act with reasonable skill and care when

This definition could also be incorporated into the Guidelines, as could the converse of the two examples of ‘over-servicing’ in the Guidelines (para 2.1.4). The latter could be used to indicate that healthcare practitioners should not ‘underservice’ patients by ‘failing to provide a service or perform or direct certain procedures to be performed on a patient that are indicated or have been shown to be effective and appropriate’, or by ‘failing to refer a patient to another healthcare practitioner for a service or a procedure that is indicated or has been shown to be effective and appropriate’.

These definitions and examples of ‘underservicing’ are consistent with the law[5] and could be used to guide the courts.

The treatment of cancer patients in the USA is a good example of ‘underservicing’. Research concluded that the ‘slow pace of adoption of early palliative care for patients with serious cancer is a tragic under­ service of health care, leading to much unnecessary suffering’.[6] This is because many hospitalised patients receive ‘aggressive care’ instead of hospice services,[6] which indicates that ‘underservicing’ may sometimes be linked to ‘over-servicing’. Unnecessary interventions in terminally ill cancer patients, causing patients to suffer needless expense and pain, are examples of ‘over-servicing’. The use of unnecessary treatment in futile situations is also unethical and unlawful.[7]

The HPCSA Guidelines[2] define ‘over-servicing’ as: ‘[T]he supply, provision, administration, use or prescription of any treatment or care (including diagnostic and other testing, medicines and medical devices) which is medically and clinically not indicated, unnecessary or inappropriate under the circumstances or which is not in accordance with the recognised treatment protocols and procedures, without due regard to both the financial and health interests of the patient.’

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Continual ‘underservicing’ of patients by medical practitioners may also constitute ‘abandonment’ if this forces patients to terminate their doctor’s services.

What constitutes ‘abandonment’?

‘Abandonment’ of a patient occurs when a doctor unilaterally ceases treatment before the patient has recovered or terminates the patient’s contract,[8] without giving adequate notice or referring the patient to another practitioner.[9] ‘Abandonment’ may include doctors: (i) closing their practices without proper notice; (ii) denying the doctor-patient relationship; (iii) refusing to see a patient previously seen; (iv) failing to visit a hospitalised patient; (v) failing to provide follow-up care; and (vi) failing to provide a competent substitute when away from practice[10] or closing their practice.

Where doctors continually ‘underservice’ their patients, so that they must seek healthcare from somebody else, this may amount to ‘constructive abandonment’ because it forces the patients to terminate the doctor-patient relationship.

These definitions and examples are consistent with the law regarding professional negligence and malpractice in situations where the doctor’s conduct amounts to an actionable omission.

The law regarding ‘over-servicing’, ‘underservicing’ and ‘abandonment’ of patients

Doctors are expected to exercise the same degree of skill and care as reasonably competent practitioners in their branch of the pro­fession.[4] Although the courts usually follow what the medical profession regards as reasonable professional conduct, they are not bound to follow this.[5] When deciding the level of skill and care required, the courts may take into account the ethical rules of the profession where they are consistent with statute or common law.[5] Failure by practitioners to measure up to the expected standard of skill and care may result in legal action by patients for professional negligence or malpractice.[4] In deciding whether the harm suffered by a patient was caused by ‘over-servicing’, ‘underservicing or ‘abandonment’, the courts must decide whether the doctor failed to measure up to the standard of a reasonably competent doctor in the same field of practice.[4] The courts may refer to the HPCSA’s Ethical Rules,[1] the Policy Document[3] and the ethical Guidelines[2] regarding ‘over-servicing’ and ‘underservicing’ of patients. However, they will rely on what they consider to be professional negligence or malpractice according to the law[4] – which may or may not be based on what the medical profession considers to be ‘underservice’, ‘over-service’ or ‘abandonment’.

Overservicing

There are few reported court cases on ‘over-servicing’. The former SA Medical Council disciplined doctors who engaged in such practices, especially when they charged excessive fees, e.g. removing teeth surgically instead of by ordinary extraction, unnecessary house calls by a general practitioner, and having unnecessary tests done.[11] The Council also disciplined practitioners in cases where the procedures were unnecessary, e.g. unnecessary X-rays and the needless amputation of toes.[11] In these circumstances, according to the common law, the patients could refuse to pay the healthcare practitioner’s fees for the services not required. They could also claim damages in a civil action provided they could prove to have suffered harm as a result of such over-service. These definitions and examples in the Guidelines[2] could assist the courts in deciding whether there was ‘over-servicing’.

Underservicing

The law does not mention ‘underservicing’, but it usually takes the form of an actionable omission based on a failure to treat a according to good

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medical practice.[12] Many cases of ‘underservicing’ have come before the courts, usually involving the failure to provide follow-up treatment and postoperative care,[13] e.g. the patient is not informed by the doctor when test results after discharge from a hospital indicate that further diagnosis or treatment is necessary, or the doctor does not advise the patient to return if abnormal symptoms are experienced after treatment.[12] In these situations the test is whether a reasonably competent practitioner in the same position would have exercised the same degree of skill and care as the practitioner concerned.[5] This is inherent in the suggested definition and examples of ‘underservicing’, which could assist the courts but would not be binding on them.

‘Abandonment’

A patient is abandoned ‘when a doctor interrupts a course of necessary treatment without proper notice and referral to another practitioner’.[14] A doctor who causes harm by such action will be liable for damages.[8] Once a doctor engages in treating a patient, treatment may not be abandoned if this would harm the patient – unless the patient makes treatment by the doctor impossible.[15] In SA law, ‘abandonment’ is generally not mentioned by the courts, as it is treated as an actionable omission (as in the case of ‘underservicing’) under the general principles of liability for professional negligence or malpractice. Professional negligence or malpractice resulting from failure to provide follow-up treatment and postoperative care usually involves: ‘(a) A complete and unreasonable refusal to look after a patient after the completion of the immediate treatment; (b) withdrawal from the doctor/ patient relationship at a critical stage and without the consent of the patient and without reasonable notice … to the patient; [and] (c) the premature discharge of a patient’.[16] In the USA the courts have found doctors liable for ‘abandonment’ of their patients where they terminated their professional relationship at an unreasonable time or without affording the patient an opportunity to find an equally qualified replacement.[17] The former SA Medical Council also disciplined practitioners for refu­sing to treat patients after being requested to do so, not visiting a patient in hospital who subsequently died, and failing to treat a patient in labour after he had treated her from the beginning of her preg­ nancy.[11] The courts are likely to take a similar approach – provided the patient can prove harm as a result of such ‘abandonment’. The decisions of the courts will be based on the principles of professional negligence and malpractice.[18] The above definitions and examples could provide useful guidelines for the courts when deciding whether the doctors concerned had abandoned their patients.[11] 1. Ethical and Professional Rules of the Health Professions Council of South Africa. GN R717 in Government Gazette 29079 of 4 August 2006, as amended by GN R68 in Government Gazette 31825 of 2 February 2009.

2. Health Professions Council of South Africa. Guidelines on Over-servicing, Perverse Incentives and Related Matters. Pretoria: HPCSA, 2008.

3. Health Professions Council of South Africa. Policy Document on Undesirable Business Practices.

Pretoria: HPCSA, 2005.

4. Castell v De Greeff 1993 (3) SA 501 (C).

5. Van Wyk v Lewis 1924 AD 438.

6. Wiencke MC. Cancer care: ‘Tragic underservice’. Dartmouth Medicine, Spring 2011. http://www. dartmed.dartmouth.edu/spring11/html/disc_cancer.php (accessed 3 November 2014).

7. Cf. Airedale NHS Trust v Bland [1993] 1 All ER 821 (HL).

8. McQuoid-Mason D, Dada M. A-Z of Medical Law. Cape Town: Juta, 2011:1.

9. USLegal. Patient Abandonment Law & Legal Definition. http://definitions.uslegal.com/p/patientabandonment/ (accessed 16 October 2014).

10. Segen’s Medical Dictionary. http:// medical-dictionary.thefreedictionary.com/abandonment (accessed 3 November 2014).

11. Verschoor T. Verdicts of the Medical Council. Pretoria: Digma, 1990:95-96.

12. Carstens P, Pearman D. Foundational Principles of South African Medical Law. Durban: LexisNexis, 2007:815-816.

13. Cf. Webb v Isaac 1915 EDL 273.

14. Dube v Administrator, Transvaal 1963 (4) SA 260 (W).

15. Boumil MM, Elias C. The Law of Medical Liability. St Paul, Minn.: West Publishing Co., 1995:17.

16. Strauss SA. Doctor, Patient and the Law. 3rd ed. Pretoria: JL van Schaik, 1993:3.

17. Hill v Midlantic Health Care Group 33 A.2d 314 (D.C. 2007). http://definitions.uslegal.com/p/patientabandonment/ (accessed 16 October 2014).

18. Classen NJB, Verschoor T. Medical Negligence in South Africa. Pretoria: Digma, 1992:38-39.

Accepted 12 November 2014.

March 2015, Vol. 105, No. 3

EDITORIAL

The Global Status Report on Violence Prevention 2014: Where to for the South African health sector?

The World Health Organization (WHO), the United Nations Development Programme and the United Nations Office on Drugs and Crime jointly released the first Global Status Report on Violence Prevention[1] on 10 December 2014. The report reviews how governments around the world, including in South Africa (SA), are attempting to curb interpersonal violence.

There is some good news in the report. In common with many other countries, SA’s homicide rate has declined over the past decade: it was 40.3/100 000 in 2004/5, and 32.2/100 000 in 2012/2013.[2] Across the five types of interpersonal violence assessed in the report – child maltreatment, youth violence, intimate partner violence, sexual violence and elder abuse – SA has national action plans for all but two, namely youth violence and elder abuse (and in these two cases, some provinces have action plans).

But manifestly it is not all good news. Homicide levels in SA are fluctuating around 32/100 000, and over the past 4 years, the lowest level achieved was 30.9/100 000 (in 2011/2012).[2] Homicide is a robust indicator of the prevalence of other forms of violence,[3,4] so this demonstrates that SA is struggling to reduce violence below the horizon achieved in 2011/2012. That rate is in itself exceedingly high: in 2012, the African Region as a whole had a rate of 10.9/100 000, making SA one of the most lethally violent African countries for which data are available.[1] This is a health sector issue for several reasons. First, the injuries and deaths caused by interpersonal violence place a considerable burden on the health sector. Second, evidence-based public health approaches to preventing violence are increasingly demonstrating their effectiveness.[1,3,5] The Global Status Report on Violence Prevention addresses several key areas for violence prevention: action plans, laws and policies, prevention programmes and services for victims of violence, and data on violence, and the SA health sector has a role to play in each.

There are two key policy-level public health interventions that are likely to reduce all forms of violence: limiting access to firearms and to alcohol.[1,3] In terms of firearms control, SA has a comprehensive legal system in place to restrict firearm proliferation and misuse. However, recent experiences of trauma surgeons (A Nicol, A B van As, oral communication, 22 October 2014) and high-profile firearm murders suggest that firearm homicides are increasing after an initial drop.[6] In March 2015, the SA parliament will initiate a national Firearm Summit to review the state of the country’s firearm controls with a view to improving them.[7] This review will need evidence – evidence best obtained through injury surveillance in trauma centres and mortuaries. With the National Non-Natural Mortality Surveillance System[8] we are well placed to record deaths due to firearms: we now urgently need surveillance of injuries across trauma centres to complete the picture, as injuries tend to be more frequent than deaths and so provide a more complete picture of the role of firearms in violence.[9] Alcohol control geared towards reduction presents a more complicated picture, especially with SA’s history of alcohol abuse dating back to colonial times.[10] The government taxes most forms of alcohol in order to discourage excessive consumption. Nonethe­ less, a large proportion of South Africans binge drink, which carries a number of possible serious health consequences, including an

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in­creased risk of being both a perpetrator and a victim of violence.[1] There is a plethora of policy-level interventions that can reduce this, such as increasing taxes on alcohol and restricting hours of sale, and collaboration between health professionals, law enforcement and communities to develop and implement appropriate policies, as well as treatment and prevention programmes.[11] Most recently, Minister of Health Aaron Motsoaledi is to be commended for his call for a ban on alcohol advertising:[12] the rest of the health sector should support him in this.

SA laws to prevent interpersonal violence are progressive and comprehensive in most areas. The only gaps are laws providing for victim compensation and legal representation, and in the area of child maltreatment, prevention (such as banning female genital mutilation, and a comprehensive ban on corporal punishment).[1] But the real problem is lack of enforcement. At best our laws are only partially enforced, and most are applied in a very limited way.[1] A case in point is the banning of corporal punishment in schools: data from national surveys conducted by the Centre for Justice and Crime Prevention (CJCP) reveals that 49.8% of SA children still suffer corporal punishment at the hands of teachers.[13] Violence in schools has serious consequences for children, including increasing the likelihood that they will go on to commit violent acts.[14] Health professionals, such as educational psychologists, urgently need to roll out evidence-based programmes to provide teachers with skills for non-violent discipline.

Of course, it takes considerable resources to implement large-scale interventions, but countries with similar circumstances to SA, such as Brazil, Colombia, El Salvador, Mexico and India, are faring much better in this regard.[1] Similarly, there are a number of violence prevention programmes across the country that address each form of violence and services for victims, but these are typically provided in a very limited way and not on the large scale that can meaningfully address the problem. Notable exceptions include programmes that train children to recognise and avoid sexually abusive situations, preschool enrichment programmes, life-skills training for young people, and anti-bullying policies.[1] However, an investigation 10 years ago found that youth violence prevention programmes in SA were typically not evidence based and had not been rigorously evaluated,[15] and a more recent survey of parenting programmes had similar findings,[16] suggesting that there is not yet a culture of evidence-based intervention and evaluation in prevention programming in SA. There is therefore very little to give us confidence that programmes implemented here are effective – yet globally there is mounting evidence about effective programmes that could be applied in SA.[5] In addition, SA’s victim services are less developed in comparison with countries with similar challenges of violence in the Americas and South-East Asia.[1] This too needs attention, within the health sector and elsewhere. Supporting victims can prevent them both from becoming victims again and from becoming perpetrators.[17,18] If policies and programmes are to be effective, they need to be driven by relevant and accurate data. Compared with most other low- to middle-income countries, SA is data rich, and has national statistics on youth violence, intimate partner violence and sexual violence.[1] A survey that will give us the first-ever nationally representative data on child maltreatment is in progress, and is being led by researchers at CJCP and the University of Cape Town and funded by the UBS Optimus Foundation. These data will be released

March 2015, Vol. 105, No. 3

EDITORIAL

in mid-2015, and have massive potential to inform the design and delivery of interventions to reduce child maltreatment where they are needed the most. Elder abuse, however, remains under-researched in SA (as in many other countries). We need to continue to uphold these high standards, and expand on and use the data we have to design evidence-based interventions.

Reducing violence is of course important from a human rights and safety perspective, but it will also contribute to national development.

First, violence costs the economy a great deal. Patching up injuries, physical rehabilitation, conducting autopsies, treating mental health problems, prosecuting and incarcerating perpetrators, and putting children in foster care are all enormously costly things to do. According to a recent report from KPMG Human and Social Services, violence against women in SA alone costs the economy between R28.4 and R42.2 billion per year – 0.9 - 1.3% of the gross domestic product.[19] That would build many, many houses, and one of the recommendations of the Global Status Report on Violence Prevention is good housing design to reduce concentrated poverty, an area in which SA is failing.[1] Second, violence prevention programmes typically do not only prevent violence but also promote other good outcomes. Parenting programmes that aim to reduce child maltreatment, for instance, not only reduce child abuse and neglect but also teach parents the skills that promote child wellbeing more broadly. From the prevention perspective, their children are less likely to use drugs, to become HIVpositive, or to begin lives of crime. From the promotion perspective, their children are more likely to stay in school, and to have the skills to hold down a job and hence to contribute to the economy.[20] Reducing violence should therefore be a national priority, both to promote the rights of citizens to lives free from fear, and to release more funding for national development. Violence prevention initiatives that follow the public health approach can be effective.

Since early calls to take this approach,[21] SA has established a solid foundation of relevant data and policy. Now is the time to build on this base by acting on the World Health Assembly Resolution[22] passed earlier this year, and implement the recommendations of the World Report on Violence and Health,[3] namely: • Create, implement and monitor a national action plan for violence prevention.

• Enhance capacity for collecting data on violence.

• Define priorities for, and support research on, the causes, consequences, costs and prevention of violence.

• Promote primary prevention responses.

• Strengthen responses for victims of violence.

• Integrate violence prevention into social and educational policies, and thereby promote gender and social equality.

• Increase collaboration and exchange of information on violence prevention.

• Promote and monitor adherence to international treaties, laws and other mechanisms to protect human rights.

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• Seek practical, internationally agreed responses to the global drugs trade and the global arms trade.

Catherine L Ward Department of Psychology, Faculty of Humanities, University of Cape Town, South Africa, and Safety and Violence Initiative, University of Cape Town Guy Lamb Safety and Violence Initiative, University of Cape Town, South Africa Corresponding author: C L Ward (catherine.ward@uct.ac.za, cathy.ward.sa@gmail.com) 1. World Health Organization. Global Status Report on Violence Prevention 2014. Geneva: WHO, 2014.

(SA profile p. 195.) http://www.undp.org/content/dam/undp/library/corporate/Reports/UNDP-GVAviolence-2014.pdf (accessed 17 December 2014).

2. South African Police Service. Crime Categories: Figures and Ratios. Pretoria: South African Police Service, 2014. http://www.saps.gov.za/resource_centre/publications/statistics/crimestats/2014/crime_ stats.php (accessed 17 December 2014).

3. Krug E, Dahlberg L, Mercy J, Zwi A, Lozano R. World Report on Violence and Health. Geneva: World Health Organization, 2002.

4. Matzopoulos R, Bhalla K, Harrison J. Homicide. In: Donnelly PD, Ward CL, eds. The Oxford Textbook of Violence Prevention: Epidemiology, Evidence and Policy. Oxford: Oxford University Press, 2015:11-18.

5. Donnelly PD, Ward CL, eds. The Oxford Textbook of Violence Prevention: Epidemiology, Evidence and Policy. Oxford: Oxford University Press, 2015.

6. Matzopoulos RG, Thompson ML, Myers JE. Firearm and nonfirearm homicide in 5 South African cities: A retrospective population-based study. Am J Public Health 2014;104(3):455-460. [http://dx.doi. org/10.2105/AJPH.2013.310650] 7. Merrington Z. Parliament to host gun control summit next year [television broadcast]. South African Broadcasting Corporation, 6 November 2014.

8. Butchart A, Peden M, Matzopoulos R, et al. The South African National Non-Natural Mortality Surveillance System – rationale, pilot results and evaluation. S Afr Med J 2001;91(5):408-417.

9. Schuurman N, Cinnamon J, Matzopoulos R, Fawcett V, Nicol A, Hameed SM. Collecting injury surveillance data in low- and middle-income countries: The Cape Town Trauma Registry pilot. Glob Public Health 2011;6(8):874-889. [http://dx.doi.org/ 10.1080/17441692.2010.516268] 10. Mager A. ‘White liquor hits black livers’: Meanings of excessive liquor consumption in South Africa in the second half of the twentieth century. Soc Sci Med 2004;59(4):735-751. [http://dx.doi.org/ doi:10.1016/j.socscimed.2003.12.005] 11. Parry CDH, Dewing S. A public health approach to addressing alcohol-related crime in South Africa.

Afr J Drug Alcohol Stud 2006;5(1):41-56.

12. Makuyana I. Motsoaledi says no alcohol adverts. The New Age [newspaper on the Internet], 12 September 2013. http://www.thenewage.co.za/106998-1056-53-Motsoaledi_says_no_alcohol_ adverts/?switcher=1 (accessed 17 December 2014).

13. Burton P, Leoschut L. School Violence in South Africa: Results of the 2012 National School Violence Study. Cape Town: Centre for Justice and Crime Prevention, 2013.

14. Souverein F, Ward CL, Visser I, Burton P. Serious, violent young offenders in South Africa: Are they life-course persistent offenders? J Interpers Violence (in press).

15. Farr V, Dawes A, Parker Z. Youth violence prevention and peace education programmes in South Africa: A preliminary investigation of programme design and evaluation practices. Cape Town: Children’s Institute, University of Cape Town, 2003.

16. Wessels IM. Child maltreatment prevention programmes in South Africa: Investigating design and evaluation practices. MA thesis. Cape Town: University of Cape Town, 2012.

17. Hawkridge S, Berg A, Seedat S. The consequences of violence: Mental health issues. In: Donnelly PD, Ward CL, eds. The Oxford Textbook of Violence Prevention: Epidemiology, Evidence and Policy.

Oxford: Oxford University Press, 2015:97-104.

18. Feder G, Sardinha L. Preventing intimate partner violence thorugh advocacy and support programmes.

In: Donnelly PD, Ward CL, eds. The Oxford Textbook of Violence Prevention: Epidemiology, Evidence and Policy. Oxford: Oxford University Press, 2015:193-200.

19. KPMG Human and Social Services. Too costly to ignore – the economic impact of gender-based violence in South Africa. Johannesburg: KPMG, 2014.

20. Hawkins JD, Catalano RF, Arthur MW. Promoting science-based prevention in communities. Addict Behav 2002;27(6):951-976. [http://dx.doi.org/10.1016/S0306-4603(02)00298-8] 21. Kruger J, Butchart A, Seedat M, Gilchrist A. A public health approach to violence prevention in South Africa. In: Van Eeden R, Wentzel M, eds. The Dynamics of Aggression and Violence in South Africa.

Pretoria: Human Sciences Research Council, 1998:399-424.

22. World Health Organization. Resolution WHA67.15. Strengthening the role of the health system in addressing violence, in particular against women and girls, and against children. 67th World Health Assembly, Geneva, 19-24 May 2014. Documentation WHA67: main documents, information documents, diverse documents, resolution. Geneva: WHO, 2014.

S Afr Med J 2015;105(3):183-184. DOI:10.7196/SAMJ.9305

March 2015, Vol. 105, No. 3

EDITORIAL

Prevention of Liver Fibrosis and Cancer in Africa: The PROLIFICA project – a collaborative study of hepatitis B-related liver disease in West Africa Hepatitis B and hepato­ cellular carcinoma in subSaharan Africa (SSA)

Achievements of the PROLIFICA project so far

Hepatitis B virus (HBV) infection causes a spectrum of acute and chronic liver disease ranging from inactive chronic carrier status to progressive chronic hepatitis, culminating in end-stage cirrhosis and liver cancer.[1] In SSA, HBV infection is endemic and the HBV-related disease burden is high.

The lifetime risk of HBV infection is over 60%, and more than 8% of the population remain chronic HBV carriers who are at risk of progressive liver disease and HBV-related hepatocellular carcinoma (HCC). SSA has one of the highest HBV-related liver cancer rates in the world,[2] and it is the most common cancer among males and third most common among females.[3,4] Unfortunately, HCC is usually a highly aggressive tumour with limited treatment options, particularly in resource-poor settings such as SSA.[5] Furthermore, HBV-related HCC affects patients in their working and reproductive years.[5] HBV therefore represents a threat to health on the African continent.

Early detection and treatment of HBV infection reduces HCC incidence and mortality (primary prevention).[6,7] Furthermore, HCC survival is improved by early detection of potentially treatable HCC by screening of patients at risk.[8] However, limited access to affordable medical care is a major limiting factor in hepatitis and liver cancer management in SSA. Routine HBV and HCC screening and surveillance programmes for the general population are virtually nonexistent, and there is a lack of infrastructure to support channelling of screened patients into long-term treatment programmes.[9] Safe and effective treatments for HBV exist, but in SSA treatment access is severely limited. Despite highly effective nucleoside analogues such as tenofovir being available in most countries in SSA at a generic price for the treatment of HIV infection, very few African countries offer publicly funded HBV treatment.[9]

Prevention of hepatitis B-related liver fibrosis and cancer in Africa: The PROLIFICA study

Against this sombre backdrop of HBV-related liver disease in SSA, the Prevention of Liver Fibrosis and Cancer in Africa (PROLIFICA) project was established in 2011 to address some of the urgent HBV research needs in West Africa. This is an ongoing 5-year translational research project funded by the European Union Framework 7[10] and represents a collaboration between Imperial College, London; the Medical Research Council (The Gambia Unit) in Fajara, The Gambia; the International Agency for Research on Cancer, Lyon, France; Le Dantec University Hospital, Dakar, and University of Thiès, Sénégal; and Jos University Teaching Hospital, Jos, Nigeria.

The overall aim of the project is to reduce the incidence of HBVrelated HCC in West Africa. The three specific aims of the project are demonstrating the feasibility of widespread screening for HBVrelated liver disease; establishing whether treatment of HBV with nucleoside analogues is a cost-effective method to reduce the burden of HBV-related liver disease and liver cancer in West Africa; and developing novel biomarkers to predict and diagnose HBV-related liver fibrosis and HCC.

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To date, the PROLIFICA study has provided important insights into HBV-related HCC in West Africa, including identification of novel metabonomic biomarkers that may prove useful for HCC diagnosis in resource-poor settings;[11,12] identification of genomic determinants of HCC and epidemiological insights into risks for more severe HBVrelated liver disease;[13] validation of point-of-care tests for HBV (manuscript in submission) and the optimal use of the Fibroscan to measure liver stiffness[14] as a surrogate imaging marker for liver fibrosis; and the non-invasive aspartate aminotransferase-to-platelet ratio (APRI score) to determine the severity of liver cirrhosis from simple blood tests (manuscript in submission).

Importantly, the PROLIFICA platform has resulted in crucial capacity building in each of the three countries involved in the study.

Local health infrastructure has benefited from new technologies, such as the Fibroscan to assess liver fibrosis using ultrasound-based transient elastography, a mass spectroscopy system in The Gambia for local biomarker research and the development of in-house laboratory assays, as well as skills transference to build capacity for improved liver cancer healthcare in West Africa.

Local nursing, medical and laboratory staff have benefited from training, education and employment opportunities. Procedures and training in effective and secure data management and ethical research practices have also been a central part of the PROLIFICA platform.

Local researchers have availed themselves of specialised academic mentorship at each of the three sites involved in the study to obtain higher research degrees and produce highly regarded academic publications. Finally, community education on HBV infection, mode of transmission and prevention is likely to have had a positive impact on HBV awareness, both at the community and political level.

Above all, the PROLIFICA platform has facilitated the development of strong relationships for future research collaborations and a deeper understanding of the barriers to improved healthcare delivery in Africa. All centres have benefited equally from the experience and knowledge shared between the investigating teams. Arguably these are the greatest achievements of the project. International collaborative projects between academic institutions in Africa and the rest of the world are a fantastic opportunity to share ideas, specialised expertise and new technologies and foster a united approach to solving some of the greatest public health challenges in Africa today. Collaborations also provide a stronger international voice to raise global awareness of the importance of liver disease in Africa among governments, the pharmaceutical industry and the international community.

Acknowledgements. All the authors are grateful to the UK National Institute for Health Research Biomedical Facility at Imperial College London for infrastructure support. MMEC is supported by a Fellowship grant from the Sir Halley Stewart Foundation (Cambridge, UK). All the authors are participant workers in the European Union Framework 7-funded PROLIFICA project in West Africa, which aims to diagnose, treat and follow up a cohort of hepatitis B-positive patients in The Gambia, Sénégal and Nigeria (EC FP7, P34114; www.prolifica.eu). JH is supported by an NHMRC Early Career Post Doctoral fellowship.

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Jessica Howell Department of Medicine, Imperial College London, UK, Centre for Population Health, Macfarlane-Burnet Institute, Victoria, Australia, and Department of Medicine, University of Melbourne, Victoria Nimzing G Ladep Department of Medicine, Imperial College London, UK, and Department of Medicine, Jos University Teaching Hospital, Plateau State, Nigeria Maud Lemoine Department of Medicine, Imperial College London, UK, and Medical Research Council (The Gambia Unit), Fajara, The Gambia Shevanthi Nayagam Department of Medicine, Imperial College London, UK Papa Souleymane Toure Magatte Madoky Diop Joao Armindo Daveiga UFR Santé, Thiès University, Thiès, Sénégal Amina Sow Sall Gora Lo Laboratoire de Bacteriologie Virologie, Le Dantec Hospital, Dakar, Sénégal Mary M E Crossey Mark R Thursz Simon D Taylor-Robinson Department of Medicine, Imperial College London, UK

Mamadou Mourtalla Ka UFR Santé, Thiès University, Thiès, Sénégal Corresponding author: J Howell (j.howell@imperial.ac.uk) 1. European Association for the Study of the Liver. EASL clinical practice guidelines: Management of chronic hepatitis B virus infection. J Hepatol 2012;57(1):167-185. [http://dx.doi.org/10.1016/j. jhep.2012.02.010] 2. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005;55(2):74108. [http://dx.doi.org/10.3322/canjclin.55.2.74] 3. Parkin DM, Sitas F, Chirenje M, Stein L, Abratt R, Wabinga H. Part I: Cancer in indigenous Africans – burden, distribution, and trends. Lancet Oncol 2008;9(7):683-692. [http://dx.doi.org/10.1016/S14702045(08)70175-X] 4. Kirk GD, Lesi OA, Mendy M, et al. The Gambia Liver Cancer Study: Infection with hepatitis B and C and the risk of hepatocellular carcinoma in West Africa. Hepatology 2004;39(1):211-219. [http:// dx.doi.org/10.1002/hep.20027] 5. European Association for the Study of the Liver, European Organisation for Research and Treatment of Cancer. EASL-EORTC clinical practice guidelines: Management of hepatocellular carcinoma. J Hepatol 2012;56(4):908-943. [http://dx.doi.org/10.1016/j.jhep.2011.12.001] 6. Robotin MC, Kansil MQ, George J, et al. Using a population-based approach to prevent hepatocellular cancer in New South Wales, Australia: Effects on health services utilisation. BMC Health Serv Res 2010;10:215. [http://dx.doi.org/10.1186/1472-6963-10-215] 7. Liaw YF, Sung JJ, Chow WC, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med 2004;351(15):1521-1531. [http://dx.doi.org/10.1056/NEJMoa033364] 8. Lopez PM, Villanueva A, Llovet JM. Systematic review: Evidence-based management of hepatocellular carcinoma – an updated analysis of randomized controlled trials. Aliment Pharmacol Ther 2006;23(11):1535-1547. [http://dx.doi.org/10.1111/j.1365-2036.2006.02932.x] 9. World Health Organization.Global policy report on the prevention and control of viral hepatitis in WHO Member States. http://www.who.int/csr/disease/hepatitis/global_report/en/ (accessed 21 April 2014).

10. European Union Framework 7. www.prolifica.eu (accessed August 2014).

11. Shariff MI, Ladep NG, Cox IJ, et al. Characterization of urinary biomarkers of hepatocellular carcinoma using magnetic resonance spectroscopy in a Nigerian population. J Proteome Res 2010;9(2):10961103. [http://dx.doi.org/10.1021/pr901058t] 12. Ladep NG, Dona AC, Lewis MR, et al. Discovery and validation of urinary metabotypes for the diagnosis of hepatocellular carcinoma (HCC) in West Africans. Hepatology 2014;60(4):1291-301. [http://dx.doi.org/10.1002/hep.27264] 13. Shimakawa Y, Yan HJ, Tsuchiya N, Bottomley C, Hall AJ. Association of early age at establishment of chronic hepatitis B infection with persistent viral replication, liver cirrhosis and hepatocellular carcinoma: A systematic review. PLoS One 2013;8(7):e69430. [http://dx.doi.org/10.1371/journal. pone.0069430] 14. Lemoine M, Shimakawa Y, Njie R, et al. Food intake increases liver stiffness measurements and hampers reliable values in patients with chronic hepatitis B and healthy controls: The PROLIFICA experience in The Gambia. Aliment Pharmacol Ther 2014;39(2):188-96. [http://dx.doi.org/10.1111/apt.12561]

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Need for services for the care and prevention of congenital disorders in South Africa as the country’s epidemiological transition evolves The lack of prioritisation of congenital disorders (CDs) in health­ care, and the limited resources allocated to prevention and to the care of those affected, is an issue of global concern. This is especially true in low- and middle-income countries (LMICs), where over 90% of CDs currently occur, resulting in 95% of CD deaths worldwide.[1,2] In 2010 the World Health Organization’s World Health Assembly (WHA) prioritised services for the care and prevention of CDs, particularly in LMICs, by passing Resolution WHA63.17.[2] This recognised the importance of CDs as a cause of stillbirths and neonatal deaths, their contribution to under-5 mortality, and their contribution to failure to attain Millennium Development Goal 4 (MDG4). WHA63.17 urged member states to recognise and address CDs as a public health issue. It also highlighted the lack of accurate epidemiological data available for many LMICs.[2] CDs are often undiagnosed or misdiagnosed and the cause of death wrongly attributed. Collectively, this prevents policy decision-makers from correctly assessing the burden of CDs in these LMICs.[3]

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In South Africa (SA), the constitutional, legal and regulatory framework exists to promote the development of services for the care and prevention of CDs. It is the government’s responsibility to provide such services. To understand the renewed need for these services, it is important to consider, contemplate and review the epidemiological transition that has occurred in SA over the last 25 years.

Epidemiology of CDs in SA

Modelled data of genetic causes of CDs[1] and an estimate of teratogenic causes (A L Christianson, personal communication, 2014) indicate that a minimum of 6.8% of births, representing one in every 15 live births in SA, is affected by a CD. Of these, 80.5% are genetic or partially genetic in cause, while 19.5% are caused by teratogens. The latter is higher than the 10 - 15% expected, owing to the high prevalence of fetal alcohol syndrome.[1] With 26.2% of CDs diagnosable in the first day of life, over 18 000 cases annually should be identified and reported in SA.[4] However, in 2012 only 2 174 CDs were reported via the Birth Defects Collection Tool administered by the National Department of Health (NDoH) (V Mtyongwe,

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personal communication, 2013). This indicates under-reporting of 88%!

Although serious CDs can be life threatening or result in longterm disability, up to 70% can be prevented, cured or ameliorated by appropriate care.[1,5] Many interventions are relatively inexpensive and low-tech, including surgery for congenital malformations and community-based preventive measures (e.g. iodine and folic acid fortification of staple foods).[1]

Epidemiological transition

Epidemiological transition is the term for the change in population health statistics and pattern of diseases of a country or region, consequent on change in socioeconomic, education, infrastructure and healthcare development.[1] Omran’s three-stage model of epi­ demiological transition[6] has been used extensively to describe this process, particularly in industrialised nations. During this transition, infant and child mortality rates decrease and longevity rises, communicable diseases are controlled and eradicated, and noncommunicable and degenerative diseases emerge.

Most high-income or industrialised countries completed the first two stages of epidemiological transition decades ago. Stage one, the ‘age of pestilence and famine’, is characterised by high fluctuating mortality rates, a low life expectancy at birth, and epidemics, famine and war as the main causes of death. This is followed by stage two, the ‘age of receding pandemics’, when mortal­ity starts to decrease and is accompanied by a marked increase in life expec­ tancy, although high levels of communicable disease re­ main.[6] By controlling infectious diseases, reducing malnutrition and improving healthcare (including maternal) services, industrialised countries moved into stage three, the ‘age of degenerative and man-made diseases’.[1,6] Deaths from CDs remain invisible during this process of transition – ‘buried’ among deaths caused by communicable diseases – to emerge only as the latter are adequately controlled. CDs then become proportionately more significant in overall neonatal, infant and child mortality.

CDs attained public health significance in industrialised nations as they moved into the third stage of epidemiological transition in the early 1960s.[1] Since 85 - 90% of CDs have a genetic cause, their birth prevalence and resulting mortality remained high,[1] causing them to emerge and persist as a leading cause of child death in industria­lised nations. A comparative study of death rates in England and Wales for 1901 and 1971 demonstrates this: a 68% reduction in non-communicable diseases occurred between 1901 and 1971, but the number of deaths caused by CDs remained un­changed.[1]

Epidemiological transition and CDs in SA

SA, like many LMICs, has not followed the classic model of epidemiological transition experienced by industrialised nations, as a result of the HIV/AIDS and TB epidemics.[7] Fig. 1 plots the under-5 mortality rate (U5MR), infant mortality rate (IMR) and life expectancy at birth (longevity) data for SA over the past 25 years.

From 1960, a clear trend of decreasing infant and under-5 mortality and increasing longevity continued until 1992, when life expectancy at birth peaked at 62.33 years. In 1993, both the U5MR and the IMR were at an all-time low of 58.2/1 000 live births and 45.1/1 000 live births, respectively. At this point it appeared as if SA would follow the three classic stages of epidemiological transition, approaching the early phases of transition from stage two of the ‘age of receding pandemics’ to stage three, the ‘age of degenerative and man-made diseases’.[6] As a result of this falling childhood mortality in the early 1990s, CDs began to emerge as a public health issue. The Policy Guidelines for the Management and Prevention of Genetic Disorders, Birth Defects and Disabilities were published by the NDoH in 2001.[8] These outlined goals, objectives, strategies and delivery of clinical and laboratory services appropriate for the care and prevention of CDs. In 2004, the National Guidelines for the Care and Prevention of the Most Common Genetic Disorders, Birth Defects and Disabilities[9]

35.0

Deaths, n /1 000 live births

80

30.0

70 25.0

60 50

20.0

40

15.0

30

10.0

20 5.0

10 0

HIV-infected pregnant women, %

90

1988 1989 1990 199119921993 1994 1995 1996 1997 1998 1999 2000 20012002 2003 2004 2005 2006 20072008 2009 2010 2011 2012 2013

MDG set

U5MR

IMR

Longevity

HIV prevalence (% of pregnant women infected)

0.0

ARV roll-out

Fig. 1. Epidemiological transition in SA over the past 25 years, as demonstrated by data for childhood mortality,[18] longevity[19] and the HIV epidemic.[20]

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were published, targeting primary healthcare providers, describing common CDs and strategies for their care and prevention. However, progress in epidemiological transition was dramatically interrupted and reversed in the mid-1990s with the advent of the concomitant HIV/AIDS and TB epidemics (Fig. 1). Over a 10-year period, HIV prevalence in pregnant women soared from 7.6% in 1994 to 29.5% in 2004. Child mortality rose dramatically, with the U5MR peaking at 80.8/1 000 live births in 2003 and the IMR at 53.2/1 000 in 2002.

Life expectancy dropped to 51.56 years in 2005, an all-time low since the 1960s. SA was no longer following the sequential stages of transi­tion as HIV/AIDS caused the resurgence of TB, adding a stage to Omran’s concept known as the ‘age of emergent and re-emergent infections’.[7,10,11] Combined with the simultaneously increasing burden of non-communicable diseases in the population, this has led to a ‘double burden of disease’.[11] In 2004, the prevalence of HIV infection among pregnant women plateaued at 30% and the U5MR started to reduce as a result of scaledup prevention of mother-to-child transmission and expanded rollout of antiretroviral (ARV) therapy.[12] The 2002 IMR of 53.2/1 000 live births dropped to 33.5 in 2012 (Fig. 1). This is lower than the all-time best IMR of 45/1 000 live births in 1993 prior to the HIV/ AIDS epidemic. However, since 2011 both the IMR and U5MR have stagnated without significant further reductions.[13] A major effect of the HIV/AIDS and TB epidemics was to ‘bury’ the issue of CDs. As services for HIV/AIDS developed, funding and attention were diverted away from tertiary medical genetic services.

If child mortality, including neonatal deaths, is to decrease further, control of these ongoing epidemics cannot be at the expense of other child healthcare needs.[12] Services for the care and prevention of CDs in SA are now at a lower base than in 2001. The 2003 recommendations for human capacity requirements to be trained and in-post by 2010 to meet the expected, and now increased, health needs remain unful­ filled.[14] Personnel levels are similar to, or lower than, those in 2001, with 11 medical geneticists today compared with four in 2001 and the 20 recommended by 2010.[14] Of the nine genetic counsellors in posts today, only four are in the state system (T Wessels, personal communication, 2014), compared with approximately 20 in 2001, and the 80 recommended.[14] Budget cuts have compromised medical genetic diagnostic laboratory services countrywide.

In 2013, SA was reported as the only country of eight emerg­ing economies evaluated where positive development in improv­ing med­ ical genetic service structures had ceased and indeed regressed.[3] This decline will take time to reverse, and the dire state of these services, including the lack of policy addressing childhood disability, must be recognised by those in authority and urgently rectified.

Conclusion

While SA has missed attaining MDG4, it has significantly reduced the U5MR and IMR under difficult circumstances. The previous negative epidemiological transition, premised on the HIV/AIDS epidemic, has reversed and is once again positive with an IMR of 33/1 000 live births.[7] SA must now confront the issue of developing services for the care and prevention of CDs to reduce the stagnating child mortality rates.[13] The current IMR is now below 40/1 000 live births, at which point countries recognise the coming health needs of CDs and strive to implement appropriate services.[15] The proportion of deaths from CDs in SA under-5s was 4% in 2008,[3] and may be expected to rise as childhood deaths from CDs increasingly emerge

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as a leading cause of death in children while deaths from infections, particularly HIV/AIDS, decrease.

Legislation entitles those affected and living with CDs, including those disabled as a result, to the ‘best possible patient care’ in the prevailing circumstances, and provides for access to prevention by appropriate interventions.[16] With the global focus, including that of SA, shifting to non-communicable diseases, CDs must be con­textualised as the first non-communicable disease experienced by people. CDs deserve to be prioritised, in accordance with WHA Resolution WHA63.17, to ensure the human dignity and con­stitutionally and legally enshrined human rights of those affected and their families.[2,17] H L Malherbe School of Clinical Medicine, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa, and National Chair, Southern African Inherited Disorders Association A L Christianson Division of Human Genetics, National Health Laboratory Service and Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa C Aldous School of Clinical Medicine, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa Corresponding author: H L Malherbe (helen@hmconsult.co.za) 1. Christianson A, Howson CP, Modell B. March of Dimes: Global Report on Birth Defects, the Hidden Toll of Dying and Disabled Children. White Plains, NY: March of Dimes Birth Defects Foundation, 2006:85.

2. World Health Organization. Sixty-Third World Health Assembly – Birth Defects. Geneva: WHO, 2010. http://apps.who.int/gb/ebwha/pdf_files/WHA63/A63_R17-en.pdf (accessed 11 September 2013).

3. Nippert I, Christianson A, Gribaldo L, et al. Genetic Testing in Emerging Economies (GenTEE) Summary Report. Ispra, Italy: Joint Research Centre, European Commission, 2013:176.

4. Venter P, Christianson A, Hutamo C, Makhura M, Gericke G. Congenital anomalies in rural black South African neonates – a silent epidemic? S Afr Med J 1995;85(1):15-20.

5. Czeizel AE, Intôdy Z, Modell B. What proportion of congenital abnormalities can be prevented? BMJ 1993;306(6876):499-503. [http://dx.doi.org/10.1136/bmj.306.6876.499] 6. Omran AR. The epidemiologic transition: A theory of the epidemiology of population change. Milbank Mem Fund Q 1971;49(4):509-538. [http://dx.doi.org/10.2307/3349375] 7. Kahn K, Garenne ML, Collinson MA, Tollman SM. Mortality trends in a new South Africa: Hard to make a fresh start. Scand J Public Health Suppl 2007;35(69):26-34. [http://dx.doi. org/10.1080/14034950701355668] 8. Department of Health. Policy Guidelines for the Management and Prevention of Genetic Disorders, Birth Defects and Disabilities. Pretoria: Department of Health, 2001.

9. Department of Health. National Guidelines for the Care and Prevention of the Most Common Genetic Disorders, Birth Defects and Disabilities. Pretoria: Department of Health, 2004.

10. Smallman-Raynor M, Phillips D. Late stages of epidemiological transition: Health status in the developed world. Health Place 1999;5(3):209-222. [http://dx.doi.org/10.1016/S1353-8292(99)00010-6] 11. Agyei-Mensah S, de-Graft Aikins A. Epidemiological transition and the double burden of disease in Accra, Ghana. J Urban Health 2010;87(5):879-897. [http://dx.doi.org/10.1007/s11524-010-9492-y] 12. Kerber KJ, Lawn JE, Johnson LF, et al. South African child deaths 1990-2011: Have HIV services reversed the trend enough to meet Millennium Development Goal 4? AIDS 2013;27(16):2637-2648. [http://dx.doi.org/10.1097/01.aids.0000432987.53271.40] 13. Dorrington R, Bradshaw D, Laubscher, R. Rapid Mortality Surveillance Report 2012.

Cape Town: South African Medical Research Council, 2012. http://www.mrc.ac.za/bod/ RapidMortalitySurveillanceReport2012.pdf (accessed 29 October 2014) 14. Department of Health. Strategic Framework for the Modernisation of Tertiary Hospital Services.

Discussion Document. Pretoria: Department of Health, 2003.

15. Modell M, Kuliev A. The history of community genetics: The contribution of the haemoglobin disorders. Community Genet 1998;1(1):3-11. [http://dx.doi.org/10.1159/000016129] 16. World Health Organization, World Alliance of Organizations for the Prevention of Birth Defects. Services for the Prevention and Management of Genetic Disorders and Birth Defects in Developing Countries (Report of a Joint WHO/WAOPBD Meeting, The Hague, 5-7 January 1999). Geneva: WHO, 1999.

17. Christianson AL. Attaining human dignity for people with birth defects: A historical perspective. S Afr Med J 2013;103(12):1014-1019. [http://dx.doi.org/10.7196/samj.7277] 18. UN Inter-agency Group for Child Mortality Estimation (IGME). Child mortality estimates. www. childmortality.org (accessed 3 November 2014).

19. World Bank. Life expectancy at birth total (years). http://data.worldbank.org/indicator/SP.DYN.LE00.

IN (accessed 2 November 2014).

20. Health Systems Trust. 2012 National Antenatal Sentinel HIV & Herpes Simplex Type-2 Prevalence Survey. www.hst.org.za/publications/2012-national-antenatal-sentinel-hiv-herpes-simplex-type-2prevalence-survey (accessed 4 November 2014).

S Afr Med J 2015;105(3):186-188. DOI:10.7196/SAMJ.9136

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Dementia in rural South Africa: A pressing need for epidemiological studies Dementia is a growing public health concern globally, with total estimated worldwide costs per year at USD604 billion in 2010.[1] With older age being a major risk factor for dementia, the increasing numbers of older adults worldwide will increase demand for services to diagnose, treat and care for people with dementia (PWD).

Little is known about the prevalence of dementia or its impact on older adults living in low- and middle-income countries (LMICs) in Africa, including South Africa (SA). Furthermore, there has been little research into the aetiology and risk factors in LMICs. The need for studies to investigate these factors in SA is therefore critical.

Primary dementia is a non-communicable disease (NCD) or syndrome, usually of a chronic or progressive nature, caused by neurodegeneration in the brain that affects a range of cognitive domains including memory, language, orientation and executive functions. As a result, behaviour, mood and the ability to perform everyday activities are affected. Although dementia mainly affects older people, it is not a normal part of ageing. Alzheimer’s disease (AD) is the most common form of dementia in older adults and possibly contributes to 60 - 70% of cases.[2] Other major varieties include vascular dementia, dementia with Lewy bodies and frontotemporal dementia. In SA, disorders associated with neurodegeneration such as traumatic brain injury, alcohol dependence and HIV infection are affecting increasing numbers of older adults. There is also a growing burden of disease from NCDs such as diabetes, heart disease and obesity resulting from increasingly unhealthy lifestyles and diet, which contribute to dementia risk.[3] Dementia causes a loss of independence and is overwhelming for individuals living with the condition, their carers and their families. Comorbidities and frailty become increasingly common as dementia progresses, requiring more health, social and home/community care services.

Worldwide prevalence

Recent estimates are that there are approximately 44 million PWD worldwide, with 60% of these living in LMICs. This percentage is predicted to rise to 71% by 2050,[4] with expected increases between 134% and 146% in Latin America, North Africa and the Middle East. Projected increases for sub-Saharan Africa are between 70% and 90%. This relatively modest increase is consistent with limited demographic ageing owing to high child and adult mortality and the HIV epidemic.[2] Estimated age-standardised dementia prevalences for individuals aged >60 years have been reported for 21 Global Burden of Disease regions,[1] with a four-fold variation in prevalence from 2.1% to 8.5%. The 10/66 Dementia Research Group conducted a multicentre study in ten LMICs that included Nigeria but not SA. The dementia prevalence using Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) criteria was 3.9% for persons aged over 60 years.[5] With the 10/66 screening algorithm, prevalences were higher, ranging from 5.6% to 11.7%, being lowest in rural China and India and highest in Cuba. The difference in prevalence with different diagnostic criteria was reportedly due to lack of sensitivity of the DSM-IV for less severe cases. Cases of dementia generally progress in severity over time, which calls for earlier detection.

Research on dementia conducted in sub-Saharan Africa indicates a higher prevalence in urban v. rural areas. The prevalence ranges from 2 - 3.7% in rural Nigeria and Benin to 6 - 7.6% in cities in

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Central Africa.[6] The differing prevalence ranges may reflect the methods employed in the studies, or differences in genetic, familial, environmental, cultural or educational factors in the regions studied.

AD risk due to the ApoE4 allele is weaker for Yoruba Nigerians than for African Americans,[7] and it is not known how genetic risk varies among other African populations. Moreover, milder dementia may be underdetected in LMICs because of low awareness, the high levels of support routinely provided to older people, and reluctance to report social and occupational failings to outsiders. These factors all contribute to difficulties in establishing a diagnosis.

Dementia prevalence in SA

There is a paucity of published research on the prevalence of dementia in SA.[8] A survey of individuals aged >60 years in residential homes found 7.9% with dementia; this was not, however, a population prevalence study. The University of the Free State, with the 10/66 Group, investigated dementia in an urban black community and reported a higher than expected preliminary prevalence of approximately 6% in a small sample of 200 older persons.[9]

Prevalence of HIV-associated dementia

There is potentially a growing epidemic of dementia in older South Africans, especially among those with HIV infection. The prevalence of HIV-associated dementia (HAD) is 15 - 30% in untreated populations with late-stage disease, presenting with neurocognitive impairments, emotional disturbances, and motor dysfunction.[10] The prevalence in individuals receiving highly active antiretroviral therapy (HAART) is 10%, with an annual incidence of 1%. The prevalence of less severe forms of HIV-associated neurocognitive disorder (HAND) is 20 - 30%.[11] Prevalences are higher among people accessing HIV care in sub-Saharan African countries with a high HIV seroprevalence. Prevalences of 42% for HAND and 25% for HAD were reported among individuals starting HAART in primary care centres in Cape Town,[12] with all study participants being in later stages of HIV infection. Cognitive disorder in HIV is particularly important in view of associations with poor adherence to HAART, faster disease progression and mortality.[12] It is difficult to quantify the impact of numbers of people with dementia and of the age distribution of dementia cases in the region. Given an adult HIV seroprevalence of 15 - 25% in southern African countries, it is conceivable that most patients with dementia in the region are likely to have HAD.[10]

Services for PWD in SA

It is anticipated that by 2030 the proportion of the SA population aged >60 years will have increased to 11%,[13] with a concomitant rise in cases of dementia. However, the level of awareness and preparedness for the detection and costs of dementia care in the country is low, particularly in rural areas.

In 2011, SA had fewer than ten geriatricians and fewer than five specialists in old-age psychiatry for a population of 3.8 million persons aged >60 years.[14] Basic curricula for training of health professionals in screening and diagnosis of dementia, and of social workers and other practitioners in management and care options for PWD, are limited. Dementia is often unrecognised by primary care practitioners, with signs and symptoms often ascribed simply

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EDITORIAL

to old age. As in many LMICs, primary level healthcare concentrates on treatable diseases. Health and social services often fail to meet the needs of older persons, especially those with mental health problems and dementia.[15] In rural areas, the burden of HIV cases on the health system results in limited access to good treatment for PWD.[1] Dementia drugs to improve cognitive function and treat underlying depression and/or behavioural disorders are expensive and unavailable on the Essential Drug List, and are therefore beyond the reach of the majority of older persons.

A great need for family support and care services for problems encountered with daily living and behaviour has been identified. A study in Cape Town found that 79% of a memory clinic’s clients were being cared for by family members, some of whom had given up their jobs to do so.[16] Caregiver stress is highlighted as an important factor in dementia care in LMICs, even in traditional cultures where family care is regarded as the norm.[15] There are problems with access to care for older persons in urban areas, but the situation is worse in rural areas, where more than 40% of the SA population live and where service provision is fragmented and often severely underresourced. If dementia and its associated behavioural symptoms are poorly understood in rural communities, there is the risk that individuals with dementia may be stigmatised, with their symptoms ascribed to witchcraft, ostracised and subject to abuse. The policy on ageing in SA promotes deinstitutionalisation and limits statesubsidised residential care, so that no more than 2% of frail older persons who are in need of 24-hour nursing care are catered for.[17] The national dementia associations, Alzheimer’s SA and Dementia SA, both non-governmental organisations (NGOs), do provide informal education and support for carers and pursue activist roles to improve both policy and services. Similarly, a few other NGOs, including religious groups, provide services for older people.

The paucity of epidemiological data in SA makes it difficult to advocate for improved services or prioritisation of funding for dementia studies. Research on prevalence and risk factors pertinent to the local population is needed to estimate the public health burden of dementia. Increased knowledge about dementia will enable earlier detection and diagnosis of this NCD. Thereafter, healthcare, interventions and support can be implemented and improved. This is particularly relevant at the present time in SA, as the government plans to introduce a National Health Service with National Health Insurance, and it would be timely to ensure that services for older persons are incorporated.

The following are needed now to address dementia in SA: • Robust prevalence data using culture-fair screening tests • Earlier diagnosis and intervention options • Destigmatisation and increased awareness • Increased preparedness and service provision • Integration of older persons’ needs and rights into national health policies across all sectors, e.g. health and justice, adequate protection of vulnerable PWD from abuse and neglect • Prioritised research funding • Education at all levels, including communities, to better manage PWD and enable them to live meaningful and purposeful lives • Training and skills development for healthcare providers

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• Career advancement for professionals in geriatric medicine and related disciplines.

Celeste A de Jager Divisions of Geriatric Medicine and Neurology, Department of Medicine, Faculty of Health Sciences, University of Cape Town, South Africa John A Joska Division of Neuropsychiatry, Department of Psychiatry and Mental Health, Faculty of Health Sciences, University of Cape Town, South Africa Margaret Hoffman School of Public Health and Family Medicine, Faculty of Health Sciences, University of Cape Town, South Africa Karen E Borochowitz Dementia SA, Cape Town, South Africa Marc I Combrinck Divisions of Geriatric Medicine and Neurology, Department of Medicine, Faculty of Health Sciences, University of Cape Town, South Africa Corresponding author: C A de Jager (celeste.dejager@uct.ac.za) 1. World Health Organization. Dementia: A Public Health Priority. Geneva: WHO, 2012. http:// www.who.int/mental_health/publications/dementia_report_2012/en/ (accessed 31 January 2015).

2. Alzheimer’s Association. Alzheimer’s disease facts and figures. Alzheimers Dement 2012;8(2):131-168. [http://dx.doi.org/10.1016/j.jalz.2012.02.001] 3. Mayosi BM, Flisher AJ, Lalloo UG, Sitas F, Tollman SM, Bradshaw D. The burden of noncommunicable diseases in South Africa. Lancet 2009;374(9693):934-947. [http://dx.doi.org/10.1016/ S0140-6736(09)61087-4] 4. Ferri CP, Prince M, Brayne C, et al; Alzheimer’s Disease International. Global prevalence of dementia: A Delphi consensus study. Lancet 2005;366(9503):2112-2117. [http://dx.doi.org/10.1016/S01406736(05)67889-0] 5. Prince M, Acosta D, Chui H, et al. Dementia diagnosis in developing countries: A cross-cultural validation study. Lancet 2003;361(9361):909-917. [http://dx.doi.org/10.1016/S0140-6736(03)12772-9] 6. Guerchet M, Mouanga AM, M’belesso P, et al. Factors associated with dementia among elderly people living in two cities in Central Africa: The EDAC multicentre study. J Alzheimers Dis 2012;29(1):15-24. [http://dx.doi.org/10.3233/JAD-2011-111364] 7. Hendrie HC, Murrell J, Baiyewu O, et al. APOE ε4 and the risk for Alzheimer disease and cognitive decline in African Americans and Yoruba. Int Psychogeriatr 2014;26(6):977-985. [http://dx.doi. org/10.1017/S1041610214000167] 8. Olayinka OO, Mbuyi NN. Epidemiology of dementia among the elderly in sub-Saharan Africa. Int J Alzheimers Dis 2014;2014:195750. [http://dx.doi.org/10.1155/2014/195750] 9. Radebe M. Media release, Media Liaison. http://www.ufs.ac.za/templates/archive. aspx?news=1871&cat=1 (accessed 31 January 2015).

10. Grant I. Neurocognitive disturbances in HIV. Int Rev Psychiatry 2008;20(1):33-47. [http://dx.doi. org/10.1080/09540260701877894] 11. Valcour VG, Shikuma CM, Walters MR, et al. Cognitive impairment in older HIV-1-seropositive individuals: Prevalence and potential mechanisms. AIDS 2004;18(Suppl 1):S79-S86.

12. Joska JA, Westgarth-Taylor J, Myer L, et al. Characterization of HIV-associated neurocognitive disorders among individuals starting antiretroviral therapy in South Africa. AIDS Behav 2011;15(6):1197-1203. [http://dx.doi.org/10.1007/s10461-010-9744-6] 13. United Nations, Department of Economic and Social Affairs, Population Division. World Mortality Report. New York: UN, 2013.

14. Kalula S, Petros G. Responses to dementia in less developed countries with a focus on South Africa.

Global Aging 2011;7(1):31-40.

15. Patel V, Prince M. Ageing and mental health in a developing country: Who cares? Qualitative studies from Goa, India. Psychol Med 2001;31(1):29-38.

16. Kalula SZ, Ferreira M, Thomas KGF, de Villiers L, Joska JA, Geffen LN. Profile and management of patients at a memory clinic. S Afr Med J 2010;100(7):449-451.

17. Follentine S. Ageing in South Africa: An overview. Bold 2006;16(4):7-16.

S Afr Med J 2015;105(3):189-190. DOI:10.7196/SAMJ.8904

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RESEARCH

The Vaccine and Cervical Cancer Screen project 2 (VACCS 2): Linking cervical cancer screening to a two-dose HPV vaccination schedule in the SouthWest District of Tshwane, Gauteng, South Africa L C Snyman,1 MB ChB, MPraxMed, MMed (O&G), FCOG (SA); G Dreyer,1 MB ChB, MMed (O&G), MCOG (SA), PhD; C Visser,1 BSc (Hons), MSc; M H Botha,2 MB ChB, MMed (O&G), FCOG (SA), PhD; F H van der Merwe,2 MB ChB, MMed (O&G), FCOG 1 2

ynaecological Oncology Unit, Faculty of Health Sciences, Department of Obstetrics and Gynaecology, University of Pretoria, South Africa G Unit for Gynaecological Oncology, Department of Obstetrics and Gynaecology, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Cape Town, South Africa

Corresponding author: L C Snyman (leon.snyman@up.ac.za)

Background. Cervical cancer is a preventable disease with a high prevalence in South Africa (SA), where screening is opportunistic.

Primary prevention is now possible through HPV vaccination. In VACCS 1 the feasibility of linking cervical cancer with HPV vaccination was demonstrated.

Objectives. To investigate the feasibility of linking HPV self-testing with a two-dose HPV vaccination schedule and to compare results with VACCS 1.

Methods. The project was conducted in five schools in the South-West District of Tshwane, Gauteng, SA. Leaflet information on cervical cancer and screening was provided, with requests for consent and assent for a two-dose HPV vaccination of schoolgirls. Female caregivers were invited to take part in HPV self-screening.

Results. Of 965 girls invited for vaccination, 519 (53.7%) had full consent and 518 (99.8%) received at least one vaccine dose. The invited uptake rate was 53.7% and 495 girls received both doses, giving a completion rate of 95.4% v. 82.6% in VACCS 1. Of 1 135 self-screen kits handed out, 560 (49.3%) were not returned. The mean age (standard deviation) of the 160 women who participated in self-screening was 38.7 (7.7) years. HPV testing was negative in 116 women (72.5%), 15 women (9.4%) tested positive for HPV 16 and/or 18, and 27 (16.9%) were positive for non-16/18 oncogenic HPV. Conclusion. Data from the VACCS projects suggest that school-based vaccine programmes can be successfully implemented. A two-dose schedule allowed for higher completion rates. Linking self-collected HPV screening to HPV vaccination is feasible, is a promising and viable screening strategy, and reached the appropriate age group for screening.

S Afr Med J 2015;105(3):191-194. DOI:10.7196/SAMJ.8888

Cervical cancer incidence rates in South Africa (SA) have reached epidemic proportions, where cervical cancer accounts for 18.0/100 000 of deaths (age-standardised rate). Cancer of the cervix is the leading cause of cancer-related death in Africa.[1] HIV infection increases the risk of developing cervical cancer and lowers the age at diagnosis.[2] Although the disease is largely preventable through screening programmes aimed at treatment of detected cancer precursor lesions, successful screening programmes have not been implemented anywhere in the developing world.[3] Fortunately effective vaccines are registered and available against the viral cause of the disease, namely human papillomavirus (HPV).[4] Before 2014, these vaccines were not yet introduced into the national vaccine programme in SA – the Expanded Program on Immunization (EPI). During 2014, a two-dose vaccination programme was introduced in some schools for girls in grade 4 in SA. The vaccines are available for private healthcare users, but are underutilised in this sector as well. It is predicted that in the future cervical cancer vaccination will be a more cost-effective and much more effective strategy than screening for this disease.[5] HPV vaccines were originally tested in a three-dose regimen in adult women and found to be highly immunogenic and effective in preventing cervical cancer precursor lesions. Recently new data

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have demonstrated that vaccination with two doses of the same vaccine in younger girls (aged 9 - 14 years) also provides high levels of antibodies. Indeed, the antibody response was demonstrated to be non-inferior to the immunogenicity obtained with a two-dose schedule in females aged 15 - 25 years. A similar safety profile was also demonstrated when compared with the three-dose group.[6,7] Countries in the developed and developing world are increasingly opting to provide two doses of HPV vaccine as part of their national policy in response to these preliminary data. This method of bridging to efficacy data is a well-established approach in vaccinology. It is proposed that introduction of the HPV vaccine into the EPI programme in SA will be greatly facilitated by providing only two doses (at months 0 and 6) to primary school girls, while immunogenicity will be uncompromised because of the young age of the recipients.[7] Herd immunity will depend upon high uptake and completion rates, while affordability and success of the programme will also depend upon resources needed as well as direct and indirect programme costs.

The first arm of the Vaccine and Cervical Cancer Screen (VACCS) project (VACCS 1) showed that cervical cancer screening of women with self-testing can be successfully linked to implementation of an HPV vaccination programme at the schools attended by their daughters. In this trial, the conventional three-dose regimen was used and more than 1 000 girls were vaccinated.[8]

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RESEARCH

The current study, done in the same district as VACCS 1, aimed to investigate the feasibility of linking two-dose vaccination of eligible primary school girls with HPV self-testing of their female caregivers.

In addition, this study compared some differences in methodology and outcomes with the first VACCS project. Screening uptake and outcomes were also investigated and compared with the outcomes achieved in VACCS 1. The major differences in study methods between VACCS 1 and 2 included the invitation to female parents and guardians to take part in self-screening, the two-dose vaccination schedule, and the collection and testing of HPV DNA. HPV tests were sent with the girls attending school and, unlike with VACCS 1, there were no additional information events in the form of an oral presentation presented by a doctor.

Methods

As with the first VACCS project, this national study was conducted in Gauteng and Western Cape provinces with the approval of the national and provincial departments of Basic Education and Health. The method and results of the Gauteng part of the study are described here.

Five primary schools neighbouring those in which girls had been vaccinated in VACCS 1 were identified in the South-West District of Tshwane. After obtaining consent from the governing body and princi­ pal of each school, study packs containing printed leaflet information, informed consent and assent forms and self-screen kits were handed out to all the girls in grades 4 - 7 (aged â&#x2030;Ľ9 years) to take home.

The printed leaflet contained information about cervical cancer and its symptoms, accurate and complete information about the safety and efficacy of the HPV vaccine for primary prevention of cervical cancer, and information on screening for the disease.

Parents and guardians of eligible girls were requested to provide informed consent for a two-dose HPV vaccine schedule, while all eligible girls were requested to provide assent for vaccination. Two bivalent vaccine doses donated by the manufacturing company were administered to the consented girls, 6 months apart, by a team of registered nurses during school hours.

Female parents and guardians of eligible girls were invited to take part in self-administered HPV screening. The screen kit consisted of a sample collector with user instructions available as an Evalyn brush.

Specimens together with personal information were returned to the school in sealed containers. DNA was extracted from the Evalyn brush and tested using Roche Cobas 4800.[9] HPV DNA results were reported as positive for HPV 16, HPV 18 and other high-risk HPV (hrHPV) types (31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68) or negative for oncogenic HPV. HPV test results were interpreted as positive if DNA of any of the 15 high-risk viral types was found, and were interpreted as invalid if no DNA amplification occurred as tested by the internal control.

Women who screened positive were informed of the results via the school system and by making use of mobile phone technology, and invited

to the gynaecology department at Kalafong Hospital for treatment or requested to visit their own healthcare provider with the screen results.

Definitions

The invited cohort (IC) was defined as all female learners enrolled in the selected schools in grades 4 - 7 and the consented cohort (CC) as participants with written consent from the parent or guardian as well as assent from the learner. Girls whose parents or guardians had given consent but who did not attend vaccine events were included in the CC. The vaccinated cohort (VC) comprised all girls who received at least one vaccine dose. Vaccine uptake rates were calculated in a number of ways in order to allow comparison with other published HPV vaccine reports and with VACCS 1. The consented uptake rate (CUR) was calculated as VC/CC and the invited uptake rate (IUR) as VC/IC. Vaccine completion rates (VCRs) were determined using the vaccine cohort as a denominator. The VCR was calculated using all girls who received both vaccine doses, while the insufficiently vaccinated rate (IVR) used the number of girls who received only one vaccine dose.

The study was approved by the Research Ethics Review Committee of the Faculty of Health Sciences, University of Pretoria (90/2013).

Results

Vaccination data

In the five schools selected for the project, the IC consisted of 965 girls. The CC consisted of 519 girls (53.7%) of whom 518 received the first vaccine dose (VC), giving a consented uptake rate of 99.8%.

The IUR was 53.7%. Four hundred and ninety-five girls received both doses and 23 received only one dose, resulting in an IVR of 4.4%. The VCR was 95.4% for two doses.

The vaccination uptake and completion rates for the five different schools are shown in Table 1. One adverse event was reported as a rash developing a few hours after vaccination in a girl known to be allergic to various substances, but could not be confirmed to be related to the vaccine.

Screening

A total of 1 135 self-screen kits were handed out to eligible girls attending the five schools, to be passed on to their female parents and guardians. Female staff members at the schools also requested selfscreen kits, which accounts for the difference between the numbers of tests handed out and the IC. Of the 1 135 self-screen kits handed out, 378 (33.3%) were returned unused and undamaged, 37 (3.3%) were unused but damaged, and 560 (49.3%) were not returned. Unused but damaged kits were not tested for the presence of HPV DNA. One hundred and sixty women participated in self-screening. The return rate as a proportion of tests distributed was 14.1%. Screening uptake was 16.6% when calculated as a proportion of the IC (160 from 965) and 30.8% when calculated as a proportion of the CC (160 from 519). The proportion of the CC was calculated to compare with similar

Table 1. Vaccination uptake and completion rates for the different schools School

IC, n

CC, n

VC, n

IUR, %

CUR, %

Received 2 doses, n

VCR, %

Received 1 dose, n

IVR, %

1

351

156

156

44.4

100.0

149

95.5

7

4.5

2

203

136

135

66.5

99.3

128

94.1

7

5.2

3

226

120

120

53.1

100.0

113

94.2

7

5.8

4

25

16

16

64.0

100.0

16

100.0

0

0.0

5

160

91

91

56.8

100.0

89

97.8

2

2.2

Total

965

519

518

53.7

99.8

495

95.4

23

4.4

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Discussion

Reported vaccine uptake differs widely and is influenced by many factors such as social, religious, cultural and awareness aspects.[10] School-based vaccination programmes also tend to be more effective than other pro­ grammes.[11] In this study, informed consent from parents as well as assent from the girls were prerequisites for inclusion in the vaccine cohort. A vaccine uptake rate of 53.7%, calculated as a proportion of all girls eligible for vaccination, compares well with reports from other parts of the world. It is lower than the 64.0% overall uptake reported for VACCS 1[12] and can be attributed to the modification in information transfer. In VACCS 1 the vaccine uptake was 51.7% for girls whose parents or guardians did not attend the information sessions and 87.5% for those whose parents or guardians attended. Although such information events result in higher uptake rates, they are not sustainable during a mass vaccine roll-out programme. Higher vaccine uptake rates can be accomplished by introducing an opt-out programme combined with assent from girls.

Several studies have confirmed the noninferiority of two vaccine doses compared with three doses.[6,7] The VCR of 95.4% achieved during this study compares favourably with other published data from SA[13] and with the sufficiently vaccinated

year during VACCS 1.[8] A vaccine programme in which two doses are administered should

rate (two doses 6 months apart) of 94.5% in Gauteng schools vaccinated in one calendar

Table 2. Comparison of different screen uptake rates for VACCS 1 and VACCS 2 Participation rates

VACCS 1, %

VACCS 2, %

Return rate: Self-test kits returned used/self-test kits distributed

31.8

14.1

Participation rate: IC

15.3

16.6

Participation rate: CC

23.9

30.8

Table 3. Comparison of HPV screen outcomes for VACCS 1 and 2 HPV self-screen

VACCS 1 (Roche Linear Array and tampons), %

VACCS 2 (Cobas and Evalyn samplers), %

Invalid tests

3.6

1.3

hrHPV-negative

66.7

72.5

Any hrHPV

29.6

26.3

HPV 16- and/or 18-positive

9.1

9.4

Non-16/18 hrHPV-positive

20.6

16.9

80

73

70 60 Participants, n

uptake rates calculated in VACCS 1.[8] A comparison of the different screen uptake rates is presented in Table 2.

When calculating screening uptake, the size of the true target population needs to be clarified. Although not investigated in the current study, data from the questionnaires administered to a similar population during the VACCS 1 study suggested that at least 52.6% of women were in need of a screening test (‘had last test >10 years ago’). Using these data, the true target population in VACCS 2 is 538 women, corresponding to an uptake of 29.7%.

The mean (standard deviation) age of women participating in self-screening was 38.7 (7.7) years (range 20 - 67). The age distri­ bution for this population is shown in Fig. 1.

Of the 160 women tested, 2 (1.3%) had invalid tests and 116 (72.5%) tested negative for hrHPV. Fifteen women (9.4%) tested positive for HPV 16 and/or 18 and 27 (16.9%) tested positive for non-16/18 hrHPV (Fig. 2). Of the 15 women who tested positive for HPV 16/18, 3 had only HPV 16 and 1 had only HPV 18. Eleven women tested positive for both HPV 16 and 18.

These screening results per age group are shown in Fig. 2. The comparative data from VACCS 1 are shown in Table 3.

50

45

40 30 21

20 10

13 8

0 Unknown

≤29

30 - 39

40 - 49

≥50

Age, years

Fig. 1. Age distribution of women participating in self-screening.

1.3%

9.4% HPV 16- and/or 18-positive 16.9% Non-16/18 hrHPV-positive 72.5%

hrHPV-negative

Invalid

Fig. 2. HPV self-testing screen results.

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Participants, n

RESEARCH

90.0

HPV 16- and/or 18-positive

80.0

Non-16/18 hrHPV-positive

70.0

hrHPV-negative

60.0 50.0 40.0 30.0 20.0 10.0 0.0 ≤29

30 - 39

40 - 49

References

≥50

Age, years

Fig. 3. Age distribution of participants.

be less complicated to implement and more cost-effective, and results in the vaccination of more individuals.[7] Screening for cervical cancer using conven­ tional cytology has had limited success in SA[1] despite being effective and having been available for more than 50 years. It is therefore vital to investigate alternative screening options and screening opportunities. Selftesting for HPV as a screening tool for cervical cancer has been well documented and can be implemented even in resource-poor settings.

[14-16] Both VACCS 1 and 2 investigated the feasibility of implementing HPV self-screening in an urban population without making use of the health system. The method followed in the current study of inviting female parents and guardians to participate in screening and to distribute information about the vaccination of their children in an information package delivered at home via the children is a realistic, feasible and cost-effective alternative compared with a strategy that has not been widely implemented. The screened population falls largely into the ideal age group of women requiring screening (Fig. 1).

In this study, screening uptakes compared favourably with similar calculations from VACCS 1 despite the different methods of providing information. In VACCS 1, self-test kits were distributed to women after they had attended lectures at information events, while in VACCS 2 self-test kits were distributed to all female parents and guardians together with written information about cervical cancer, screening and vaccination. In comparable studies conducted on European non-respon­ ders via a mailed invitation, compliance rates varied between 6.4% (UK) and 31.3% (Netherlands), with most groups reporting uptake rates around 30%.[17] Screening uptakes achieved during this study of 30.8% (CC) and 29.7% (unscreened cohort) compare favourably with these data.

When comparing the results, it is important to note that the screening methodology used in VACCS 1 and VACCS 2 differed in two important aspects: (i) VACCS 1 employed tampon-based self-screening transported in a buffer solution, while Evalyn brushes were used for self-collection and transported dry in VACCS 2; and (ii) different HPV testing technology was used: Roche linear array in VACCS 1, and Roche Cobas 4800 in VACCS 2.

Conclusion

Data from the VACCS project suggest that school-based vaccine programmes can be implemented successfully in suburban areas.

A two-dose vaccine schedule yields higher VCRs and will also allow for more girls to be vaccinated. Results from the current study support the SA Department of Health HPV vaccination programme.

Screening uptake and results in this study confirm the feasibility of HPV screening in this population. Linking self-testing HPV screening to HPV vaccination is a promising alternative to the current screening policy. The screening method used in this study was successful in reaching the appropriate target population, uptake rates were acceptable, and results were effectively communicated via the school system and mobile phone technology. Screening options other than conventional population-based cervical cytology are promising and should be further investigated and implemented.

Acknowledgements. The assistance of the follow­ ing groups and persons that enabled the successful completion of this project is gratefully acknowledged.

Financial support was received from the Cancer Research Initiative of South Africa, a national collaborative research programme supported by the South African Medical Research Council and the Cancer Association of South Africa, and from First for Women Insurance for screening and

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treatment of screen-positive women and investigator support. Funding for this study was provided

by GlaxoSmithKline Biologicals SA (117280).

GlaxoSmithKline Biologicals SA was provided the opportunity to review a preliminary version of this manuscript for factual accuracy, but the authors are solely responsible for final content and interpretation.

The authors received no financial support or other form of compensation related to the development of the manuscript. Teams of registered nurses handled vaccine processes, and Dr Karin Richter managed the laboratory screening data.

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1. ICO (Institut Català d’Oncologia) Information Centre on HPV and Cancer. South Africa. Human papillomavirus and related cancers, fact sheet 2013. http://www.hpvcentre.net/statistics/reports/ZAF_ FS.pdf (accessed 17 April 2014).

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PLoS Med 2008;5(6):e132. [http://dx.doi.org/10.1371/journal. pmed.0050132] 4. Harper DM, Franco EL, Wheeler CM, et al. Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: Follow-up from a randomised control trial. Lancet 2006;367(9518):1247-1255. [http://dx.doi. org/10.1016/S0140-6736(06)68439-0] 5. Villa LL, Costa RL, Petta CA, et al. High sustained efficacy of a prophylactic quadrivalent human papillomavirus types 6/11/16/18 L1 virus-like particle vaccine through 5 years of follow-up. Br J Cancer 2006;95(11):1459-1466. [http://dx.doi.org/10.1038/ sj.bjc.6603469] 6. Dobson SR, McNeil S, Dionne M, et al. Immunogenicity of 2 doses of HPV vaccine in younger adolescents vs 3 doses in young women: A randomized clinical trial. JAMA 2013;309(17):1793-802. [http:// dx.doi.org/10.1001/jama.2013.1625] 7. Romanowski B, Schwarz TF, Ferguson LM, et al. Immune response to the HPV-16/18 AS04-adjuvanted vaccine administered as a 2-dose or 3-dose schedule up to 4 years after vaccination: Results from a randomized study. Hum Vaccine Immunother 2014;10(5):1155-1165. [http://dx.doi.org/10.4161/hv.28022] 8. Snyman LC, Dreyer G, Botha MH, van der Merwe, FH, Becker PJ. The Vaccine and Cervical Cancer Screen (VACCS) project: Linking cervical cancer screening to HPV vaccination in the SouthWest District of Tshwane, Gauteng, South Africa. S Afr Med J 2015;105(2):115-120. [http://dx.doi.org/10.7196/SAMJ.8418] 9. Heideman DA, Hesselink AT, Berkhof J, et al. Clinical validation of the cobas 4800 HPV test for cervical screening purposes. J Clin Microbiol 2011;49(11):3983-3985. [http://dx.doi.org/10.1128/ JCM.05552-11] 10. Brewer NT, Fazekas KI. Predictors of HPV vaccine acceptability: A theory-informed, systematic review. Prev Med 2007;45(2-3):107114. [http://dx.doi.org/10.1016/j.ypmed.2007.05.013] 11. Brotherton JM, Murray SL, Hall MA, et al. Human papillomavirus vaccine coverage among female Australian adolescents: Success of the school-based approach. Med J Aust 2013;199(9):614-617. [http:// dx.doi.org/10.5694/mja13.10272] 12. Botha MH, van der Merwe FH, Snyman LS, Dreyer G. The Vaccine and Cervical Cancer Screen (VACCS) project: Acceptance of human papillomavirus vaccination in a school-based programme in two provinces of South Africa. S Afr Med J 2015;105(1):40-43. [http:// dx.doi.org/10.7196/SAMJ.8419] 13. Moodley I, Mubaiwa V, Tathiah N, Denny L. High uptake of Gardasil vaccine among 9 - 12-year-old schoolgirls participating in an HPV vaccination demonstration project in KwaZuluNatal Province. S Afr Med J 2013;103(5):318-321. [http://dx.doi. org/10.7196/SAMJ.6414] 14. Mnisi EF, Dreyer G, Richter KL, Horton A, Snyman LC. Human papillomavirus DNA testing on self-collected vaginal tampon samples as a cervical cancer screening test in a Gauteng population.

S Afr J Gynaecol Oncol 2013;5(2):S15-S20.

15. Richter KL. Understanding and incorporating human papillomavirus testing in cervical cancer screening: A South African perspective. S Afr J Gynaecol Oncol 2011;3(1):9-14.

16. Cuzick J, Arbyn M, Sankaranarayanan R, et al. Overview of human papillomavirus-based and other novel options for cervical cancer screening in developed and developing countries.

Vaccine 2008;26(Suppl 10):K29-K41. [http://dx.doi.org/10.1016/j. vaccine.2008.06.019] 17. Racey CS, Withrow DR, Gesink D. Self-collected HPV testing improves participation in cervical cancer screening: A systematic review and meta-analysis. Can J Pub Health 2013;104(2):e159-e166. [http://www.ncbi.nlm.nih.gov/pubmed/23618210]

Accepted 12 January 2015.

RESEARCH

Traumatic brain injury, the hidden pandemic: A focused response to family and patient experiences and needs J Webster,1 MA (Sociology, Philosophy); A Taylor,2 MB BCh, FCS (Neurosurgery), MMed; R Balchin,3 BSocSci, MA (Neuropsychology), PhD (Neuropsychology) ComaCARE Trust, Groote Schuur Hospital, Cape Town, South Africa Division of Neurosurgery, Faculty of Health Sciences, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa 3 Department of Psychology, Faculty of Humanities, University of Cape Town, South Africa 1 2

Corresponding author: A Taylor (allan.taylor@uct.ac.za)

Introduction. Traumatic brain injury (TBI) has many potential cognitive, behavioural and psychological consequences, and contributes significantly to the national burden of disease and to ongoing violent behaviour. Few resources are available for the rehabilitation of patients with TBI in South Africa, and access to rehabilitation facilities in the public sector is limited. Consequently, it is the families impacted on by TBI that ultimately carry the care and rehabilitation burden once survivors are discharged from hospital. Families are generally ill equipped to cope with the complex and potentially long-term disabilities that accompany brain injury.

Methods. Reviewing interviews with 175 family members and 354 patients recovering from TBI helped identify the key challenges that the survivors of TBI and their families face.

Results. Nine problem areas were identified that formed the basis for development of a discharge resource, the S-Plan, which serves to inform patients and carers and provide practical solutions for the problems they face.

Conclusion. The experiences of TBI survivors and their family members served to inform the development of simple, integrated coping strategies, namely two S-Plan tools, one for survivors and their families/caregivers and the other for care workers, in conjunction with counselling and support group processes. The S-Plan constitutes a discharge resource to inform patients and carers and provide practical solutions for the problems they face in caring for family members who have suffered TBI. S Afr Med J 2015;105(3):195-198. DOI:10.7196/SAMJ.9014

The context of trauma

In South Africa (SA), the high prevalence of violence con­tributes to the national burden of disease.[1] In the Western Cape Province in 2009, 7% of deaths (n=3 217) were caused by intentional injuries, which also accounted for 9.7% of years of life lost (YLL) – a total of 79 653 YLL.[2]

Traumatic brain injury (TBI) upstream factors and injury profile

In 2009, an internal audit conducted at Groote Schuur Hospital (GSH), Cape Town, Western Cape, revealed that of the total of 10 046 trauma patients admitted that year, approximately 24% were classified as head-injury patients, with 654 having a moderate to severe TBI. The direct cost of these patients to the tertiary service in 2009 was R17 448 756 (T King, Coma Care Trust audit, 2010 – unpublished).

This audit also identified that 82% of assault-related head trauma was experienced by young black and coloured men, and that the average length of stay in hospital for a patient receiving neurosurgical intervention was 10.2 days. This brief slice of the patient’s life in the acute-care setting is usually preceded by an upstream reality involving poverty, unemployment, poor community infrastructure, high rates of alcohol consumption and a weakened family unit.

Downstream impact of TBI

TBI can require a long and arduous recovery process. Many survi­ vors are left with permanent physical, emotional and cognitive disabilities. TBIs that are caused by interpersonal violence are inflicted largely by right-handed perpetrators, and typically result in frontal lobe and/or left temporal lobe injuries. The neurocognitive and behavioural sequelae of frontal lobe injuries are severe and

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include poor judgement, impaired problem-solving ability and loss of the ability to think abstractly, poor organisational skills, loss of inhibition and impulsive behaviour, aggression, personality changes, depression, anxiety and reduced social skills.[3-5] Left temporal lobe injuries can result in communication difficulties due to disorders of language (receptive aphasia), including loss of the ability to comprehend speech.[3-6] These deficits have a disabling effect on survivors’ ability to cope with activities of daily living and with constructive engagement within their families and communities.

Poor impulse control and weak social skills result in dangerous situations for survivors and for those around them.

The link between TBI and criminal behaviour is internationally well evidenced. In a Finnish study, adolescent TBI survivors were found to have committed crimes significantly more often than adolescents without a TBI (53.8% v. 14.7%, respectively).[7] In addition, the prevalence of both violent crimes (42.9% v. 9.1%), and non-violent crimes (29.4% v. 6.8%) was also higher in the TBI group.

Similarly, in a study of 186 young offenders in the UK, the frequency of self-reported TBI was associated with more convictions; three or more self-reported TBIs were associated with greater violence in the offences that were committed.[8] The rehabilitation of TBI survivors is therefore not only a health issue for survivors and their families, but also a critical violence prevention strategy for SA.

The current rehabilitation response

In SA, there is limited access to rehabilitation facilities in the public sector. The consequence for TBI survivors is that very few receive adequate rehabilitation services; only 16 of the 654 survivors in the 2009 GSH audit were admitted to a public rehabilitation facility.

Over a 5-year period (2008 - 2012), TBI survivors made up less

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than 9% of the Western Cape Rehabilitation Centre (WCRC)’s intake (Dr Jenny Hendry, personal communication, 2014). The WCRC is a 240-bed rehabilitation centre and the only dedicated rehabilitation service available to public patients. In addition, a TBI may include an initial period of post-traumatic amnesia and usually involves a slow recovery period, yet candidates for rehabilitation centres are expected to behave appropriately and recover in a 6 12-week period. This means that few survivors receive the necessary re­ habilitation support, and the majority are instead discharged to unprepared families who typically become their main support structure. This ultimately negatively affects caregiver wellness and family resilience.[9,10] Outpatient rehabilitation is also very limited, and most patients receive no more than 30 minutes of physio­ therapy or occupational therapy per week at their community healthcare centre.

Addressing the need

The ComaCARE Trust is a non-profit organisation based at GSH. ComaCARE has been addressing the needs of survivors and families since 2005 by providing a psychosocial service that employs community caregivers in the acute-care setting. In 2012, recognising that TBI survivors are usually discharged into the care of an unprepared family unit, ComaCARE developed a brain injury prevention and family support service in Khayelitsha, one of the Western Cape’s hot spots for interpersonal violence as identified through injury mortality surveillance data.[2] This HeadsUP! Hub provides supportive intervention for families that involves counselling by social workers and training to know what to do if their relative displays any of the sequelae of TBI (e.g. disruptive behaviour at school or in the workplace, aggression, memory problems, anxiety, depression and sleep disturbances).

Objectives

To faciliate the provision of relevant and sustainable TBI services, this study had two primary objectives: (i) to examine in a systematic way the key challenges that survivors of brain injury and their family members face; and (ii) to create tools as guides in helping families and care workers to manage and cope with the consequences of brain injury in under-resourced settings.

Methods

This was an applied, exploratory study. The approach to data collection was qualitative, as the interview data collected were analysed thematically to extract and highlight the topics that emerged. Participants (families of TBI survivors and the survivors themselves) were identified using purposive sampling. The overall study design had two distinct phases: (i) the process of identifying the key problems faced by survivors of TBI and their families through interviews gathered from various sources (see below); and (ii) the process of creating the content for tools to serve as guides in assisting families and care workers to manage and cope with the consequences of brain injury. This second phase was dependent on the data collected during phase one, which served to inform the content and structure of the tools created.

The experiences of 175 family members and 354 survivors were recorded. These interview data were collected between 2008 and 2013 from: (i) the acute-care hospital support service offered by ComaCARE at GSH; (ii) intake interviews for the HeadsUP! survivor care programme; (iii) bimonthly outpatient support service clinics linked to the Division of Neurosurgery at GSH; and (iv) HeadsUP! support groups. In both the individual and the group sessions, survivors and family members were interviewed separately, thereby

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enabling each group to express themselves freely. Feedback from all sources was recorded in written notes, which were subsequently analysed thematically to extract and highlight the common topics that emerged.

Results

Phase 1: Family and survivor feedback

Several critical factors emerged from the data collection process to aid the provision of better services for TBI survivors and their families.

Lack of accessible information In general, it was evident that there was initially a communication problem between family members and medical professionals in the acute-care setting. Family members felt that they had not been adequately informed by medical professionals about TBI and its potential consequences. When they did receive feedback, it was often too complex to be understood, families lacking a frame of reference to be able to contextualise any knowledge received. Families related that in their traumatised state, they were unable to absorb spoken information and then convey it to other family members. Family feedback also identified the clear lack of information regarding the longer-term requirements of recovery and possible strategies to cope with cognitive impairments, personality changes and behavioural issues.

Content of required information The key themes that emerged from families, and the areas where information is desperately needed, included coping with personality changes, how to manage aggressive behaviour, issues regarding memory, issues regarding motivation, sleep disturbances, language and communication problems, sexual disinhibition and/or disinterest, depression and safety concerns. Family members reported that their own mental health was adversely affected as a result of the stress of having to look after survivors; depression, fatigue, utter frustration and burnout were commonly reported.

The issues most commonly reported by the TBI survivors (who often revealed a lack of insight into their neurocognitive and behavioural problems) were the need for a social life and meaningful activity, sensitivity to noise, difficulty sleeping, depression, anxiety and headaches. Some survivors also reported that family members no longer had the time or patience to engage and listen to them, and consequently failed to understand their problems, their needs and their frustrations. The issues of depression, aggressive behaviour, headaches and anxiety were probed through further questioning in order to establish whether there were any triggers that preceded these experiences.

Type of information and support Families stated that at the acute stage of injury, verbal information alone was not adequate, given that they needed time to review information and to share it with family members. On the survivor’s return home, families reported that their information needs changed, as survivors’ behavioural issues only became apparent as new challenges presented over time. Families therefore needed written information that could be consulted at different stages of the recovery process, and that could be used to help the survivor to take part in his/her own rehabilitation process wherever possible. In addition, both families and survivors expressed the need for access to advisors and counsellors, and wanted to counter their feelings of isolation in fora where people could understand and relate to their problems.

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Finding practical solutions Some of the more experienced family members interviewed descri­bed their coping strategies to avoid and manage the most distressing survivor behaviours, noting that, as with parenting a child, survivors needed to have a balanced and structured day to ensure a sense of wellbeing and safety, and that they needed regular sleep, a healthy diet, stimulation and friendship. The problems experienced, and the strategies that families employed, were then analysed and compiled under nine central topics/themes based on words starting with ‘S’ (Fig. 1). This decision to incorporate the key topics identified under headings that all began with the same letter (in English) was made in order to make them easier to remember and to provide a framework for the varied information from the often very different sources available. English was chosen as the language of written communication, as many of the participants refused to accept written information in isiXhosa, despite its being their home language.

Phase 2: The development of the S-Plan process

Survivors and families identifying challenges Two sets of posters were designed (one with images of adults and the other of children) in order to allow for both survivors and family members to have each of the elements of the poster explained to them by a care worker who speaks English and also their home language. In their use, the care worker explains the behaviours and challenges that families may experience on the road to recovery, or that trigger, or are triggered by, difficult emotions or symptoms. Family members and survivors are then asked whether they are currently facing difficulties in any of these areas. If one of the ‘S issues’ is identified through this process, the care worker will interview the family member and survivor separately using the questionnaires pertaining to the relevant component of the S-Plan. Next, in discussion with both parties, the care worker will support them in choosing one or two areas to focus on in the coming weeks.

Support with written material, counselling and engagement in support groups After an agreed issue to work on has been identified, an S-Plan guide booklet is given to the family member and survivor. This guide contains an introduction and also covers all nine topics, with each of the sections including information under the following headings: ‘What is the problem?’,

Fig. 1. The S-Plan.

‘When it is likely to happen’, ‘What it looks like’, ‘What can make things worse?’, ‘How does this make life difficult for survivors?’, ‘How it might make you feel as a caregiver’, ‘What you can do to help’, and ‘Who can help further?’. These guides are currently used with family units, and at the three HeadsUP! support groups that were established in 2012.

Posters for teaching and training purposes have also been designed to accompany these S-Plan guides. The posters include spaces for the nine words starting with ‘S’ to be translated when necessary. In the future, the guides will be translated into isiXhosa/ English and Afrikaans/English versions.

Discussion

SA faces many healthcare challenges, including a high burden of physical trauma with few rehabilitation services. Funding limitations and the demand for additional acute-care services mean that it is unlikely that new rehabilitation services will be added in the near future, and patients will continue to be discharged home from acutecare settings. While this study focused on TBI patients treated in Cape Town, it is likely that TBI patients and their families throughout SA face the same, or worse, difficulties. Inpatient admission times are typically short (10 days on average) and

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acute rehabilitation during this time is limited, with many families having to take on the burden of looking after a person with impairments such as hemiparesis, dysphasia, confusion and aggression. No local studies have surveyed outcomes for TBI survivors who are discharged early into a setting with limited outpatient rehabilitation, although the outcomes of stroke patients discharged in similar circumstances in Cape Town have been examined. One of the findings from a study examining survival, disability and functional outcomes of stroke patients following discharge was that patients requiring nasogastric feeding did particularly poorly at home, indicating that their caregivers were not equipped to deal with the complexity of the care required.[11] It is evident that TBI is a huge problem globally, and that families ultimately bear the burden of care provision, yet there is little available literature from underresourced communities regarding the needs of families of survivors and the problems they face.[12] Studies (mainly in developed countries) that have looked at families’ needs (both met and unmet) and the problems they face in relation to TBI have identified high levels of stress, lack of education regarding TBI, lack of information on how to prepare for the

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future, behavioural problems and prob­lems at school on the part of the TBI survivor, and survivors’ loss of inter­est in activities, anxiety, memory problems and aggressive tempera­ment.[12-16] Commonly reported needs, which like the reported problems can change over time, include the need for social/instrumental care, emotional care and healthcare; the need for professional and financial support and information; the need for access to relevant information regarding TBI and its consequences; and the need to be actively involved with the care of the TBI survivor.[12-15] Successful TBI support will not only benefit survivors and their family units, but can also contribute towards a reduction in future violent acts perpetrated by TBI survivors. In SA, as in many other parts of the world, inadequate information and support, along with the lack of appropriate rehabilitation facilities, places a massive care burden on unprepared family members and community care workers. The participants in this study identified a multitude of complex daily challenges when survivors returned to their homes and communities. These challenges cover a wide spectrum, ranging from survivors’ behavioural and memory problems to depression and sleep disturbances. Caregivers’ own mental health is negatively affected, with depression, fatigue, stress and frustration all reported.

Consequently, the ability of families to cope is often compromised, adversely affecting TBI recovery.

The S-Plan tools (the family guide, posters and questionnaires) have been created to compensate for the lack of resources that are necessary to respond to the hidden pandemic that is TBI. The provision of these tools aims to empower families, survivors and healthcare professionals by offering a structured and interactive approach to identifying and then addressing the specific challenges that each TBI survivor and their family members face. The S-Plan has been developed to educate families and survivors about the need for a balanced, structured day, and will help families to reflect on the triggers of disruptive behaviour and to plan the survivor’s rehabilitation process. It also raises taboo subjects such as sexuality, substance abuse and security, and enables conversation about concerns and fears around such subjects. The questionnaires have been designed with specific emphasis on: (i) helping to identify the perceptions of survivors and families about their behaviours; (ii) revealing where there is a disabling lack of insight, sometimes from both parties; and (iii) helping survivors and families to decide together on priority areas for goal setting.

The ComaCARE Trust acknowledges families as the experts in this process, and hopes to strengthen their advocacy role in exposing the hidden epidemic of TBI and the dangers inherent in failing to provide adequate rehabilitation services that can impact favourably on family wellness and violence prevention.

Further research will be conducted in communities in the Western Cape in order to systematically investigate the efficacy of the new S-Plan tools. This will involve an iterative research process, testing

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separate elements of the S-Plan tools based on families’ and care workers’ firsthand experience of their effectiveness, with the aim of improving them.

Conclusion

The experiences of TBI survivors and their family members have served to inform the development of simple, integrated coping strategies (S-Plan tools in conjunction with counselling and support group processes). One S-Plan tool is for survivors and their families/ caregivers, and the other is for care workers. For the next phase of this research, these integrated tools will be piloted from 2015 onwards as part of a longitudinal research project to be conducted in underresourced communities in Cape Town.

Acknowledgements. JW thanks the Nussbaum Foundation, the Norwegian Centre for Human Rights and the Western Cape Department of Social Development for their support of this research. RB sincerely thanks the Claude Leon Foundation for their funding and support of this research.

References 1. Matzopoulos R, Bowman B, Mathews S, Myers J. Applying upstream interventions for interpersonal violence prevention: An uphill struggle in low- to middle- income contexts. Health Policy 2010;97(1):62-70. [http://dx.doi.org/10.1016/j.healthpol.2010.03.003] 2. Groenewald P, Bradshaw D, Msemburi W, et al. Western Cape Mortality Profile 2009.

Cape Town: South African Medical Research Council, 2012. http://www.mrc.ac.za/bod/ WesternCapeMortalityProfile2009.pdf (accessed 9 October 2014).

3. Walsh K, Darby EJ. Neuropsychology: A Clinical Approach. 4th ed. Edinburgh: Churchill Livingstone, 1999.

4. McDonald BC, Flashman LA, Saykin AJ. Executive dysfunction following traumatic brain injury: Neural substrates and treatment strategies. NeuroRehabilitation 2002;17(4):333-344.

5. Kolb B, Whishaw IQ. Fundamentals of Human Neuropsychology. 5th ed. Alberta: Worth Publishers, 2003.

6. Stuss DT. Traumatic brain injury: Relation to executive dysfunction and the frontal lobes. Curr Opin Neurol 2011;24(6):584-589. [http://dx.doi.org/10.1097/WCO.0b013e32834c7eb9] 7. Luukkainen S, Riala K, Laukkanen M, Hakko H, Räsänen P. Research Reports – Association of traumatic brain injury with criminality in adolescent psychiatric inpatients from Northern Finland.

Psychiatry Res 2012;200(2-3):767-772. [http://dx.doi.org/10.1016/j.psychres.2012.04.018] 8. Williams WH, Cordan G, Mewse AJ, Tonks J, Burgess CN. Self-reported traumatic brain injury in male young offenders: A risk factor for re-offending, poor mental health and violence? Neuropsychol Rehabil 2010;20(6):801-812. [http://dx.doi.org/10.1080/09602011.2010.519613] 9. Chesnut RM, Carney N, Maynard H, et al. Evidence Report on Rehabilitation of Persons with Traumatic Brain Injury. Rockville, Md: Agency for Health Care Policy and Research, 1998. http://www. ncbi.nlm.nih.gov/books/NBK32897/ (accessed 9 October 2014) 10. Carney N, du Coudray H, Davis-O’Reilly C, et al. Rehabilitation for Traumatic Brain Injury in Children and Adolescents. Evidence Report No. 2, Supplement. Rockville, Md: Agency for Health Care Policy and Research, 1999. http://www.ncbi.nlm.nih.gov/books/NBK32918/ (accessed 9 October 2014).

11. De Villiers L, Badri M, Ferreira M, Bryer A. Stroke outcomes in a socio-economically disadvantaged urban community. S Afr Med J 2011;101(5):345-348.

12. Hassan STS, Khaw WF, Rosna AR, Husna J. Traumatic brain injury: Caregivers’ problems and needs. J Nepal Med Assoc 2011;51(181):53-55.

13. Rotondi AJ, Sinkule J, Balzer K, Harris J, Moldovan R. A qualitative needs assessment of persons who have experienced traumatic brain injury and their primary family caregivers. J Head Trauma Rehabil 2007;22(1):14-25. [http://dx.doi.org/10.1097/00001199-200701000-00002] 14. Arango-Lasprilla JC, Quijano MC, Aponte M, et al. Family needs in caregivers of individuals with traumatic brain injury from Colombia, South America. Brain Inj 2010;24(7-8):1017-1026. [http:// dx.doi.org/10.3109/02699052.2010.490516] 15. Hawley CA. Reported problems and their resolution following mild, moderate and severe traumatic brain injury amongst children and adolescents in the UK. Brain Inj 2003;17(2):105-129. [http://dx.doi. org/10.1080/0269905021000010131] 16. Hall KM, Karzmark P, Stevens M, Englander J, O’Hare P, Wright J. Family stressors in traumatic brain injury: A two-year follow-up. Arch Phys Med Rehabil 1994;75(8):876-884. [http://dx.doi. org/10.1016/0003-9993(94)90112-0]

Accepted 20 October 2014.

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Hypertension, end-stage renal disease and mesangiocapillary glomerulonephritis in methamphetamine users E S W Jones, MB BCh, PhD, FCP (SA), Cert Nephrol (SA); B L Rayner, MB ChB, FCP (SA), MMed, PhD Department of Medicine, Faculty of Health Sciences, University of Cape Town, and Renal Unit, Groote Schuur Hospital, Cape Town, South Africa Corresponding author: E S W Jones (eswjones@gmail.com)

Background. Methamphetamine abuse has risen dramatically in South Africa. The chronic effects of abuse on the kidneys and blood pressure have not been documented. This study reviewed patients referred for evaluation of kidney disease and/or hypertension, who had been abusing methamphetamines.

Methods. The records of patients referred to the renal unit between 2005 and 2013 who had been using methamphetamines were retrospectively reviewed. Patient demographics, biophysical parameters, blood pressure, renal function, renal ultrasound and biopsy findings, complications of chronic kidney disease and comorbidities were recorded.

Results. Forty-seven patients were included in the study. Their mean age was 29 years. Hypertension was present in 42 (89.4%) of patients, with malignant hypertension in 21 (44.7%). Forty-five (95.7%) had chronic kidney disease (CKD), and 26 (55.3%) had end-stage renal disease. Renal biopsies were performed in 24 patients. Twelve (50.0%) of the biopsies showed hypertensive changes and 14 (58.3%) mesangiocapillary glomerulonephritis type 1, with deposition of IgM and C3 complement.

Conclusion. Methamphetamine use is associated with severe hypertension, mesangiocapillary glomerulonephritis and CKD. S Afr Med J 2015;105(3):199-201. DOI:10.7196/SAMJ.8731

South Africa (SA) is experiencing a dramatic rise in the use of methamphetamines, particularly in the Western Cape Province.[1] The drug is commonly used by young people of mixed ancestry,[2] and particularly those of lower socioeconomic status and educational level.[3] A closely related amphetamine, known as Ecstasy, was initially used as an appetite suppressant but rapidly became a recreational drug used in dancing clubs, where it was found to cause hyperthermia, dehydration and rhabdomyolysis, and an increased risk of acute renal failure.[4] Methamphetamine is relatively easy and inexpensive to produce, making it readily accessible.[5] The use of amphetamines is associated with significant adverse physical effects. The toxic effects include cardiomyopathy,[6] ischaemic heart disease, aneurysm formation, seizures, psychosis, hallucinations, stroke,[7] hyperthermia, rhabdomyolysis, pulmonary hypertension, systemic hypertension, acute renal failure[8] and hepatocellular damage.[9] A review of the histopathological findings in drug users does not mention any renal effects in amphetamine users.[10] There have been isolated reports of adverse renal effects including necrotising renal vasculopathy,[8] an exaggerated decline in renal function over 15-year follow-up of patients who used methamphetamines,[11] an increased serum creatinine level 1 year after transplant in recipients of kidneys from donors who had used methamphetamines,[12] and early graft loss of two kidneys from donors who had used methamphetamines.[13] In Africa there is even less information on the health outcomes of methamphetamine use. What literature there is addresses the dental, psychiatric and social impact of drug use in SA, particularly in the Western Cape.[14-16] This study reviewed patients attending a single tertiary hospital with hypertension and/or chronic kidney disease (CKD) and who reported the use of methamphetamines.

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Methods

Patients with a history of methamphetamine use who were referred to the Division of Nephrology and Hypertension at Groote Schuur Hospital, Cape Town, for evaluation were retrospectively studied from their medical records from 2005 to 2013. Patient demographics, biophysical parameters, blood pressure, renal function, renal ultrasound and biopsy findings, complications of CKD defined in terms of the Kidney Disease: Improving Global Outcomes guidelines,[17] and comorbidities were recorded.

The estimated glomerular filtration rate was calculated using the Modification of Diet in Renal Disease formula (Table 1). Hypertensive retinopathy was graded 1 - 4 according to the presence of silver wiring, arteriovenous nipping, haemorrhages/exudates or papill足 oedema, respectively.[18] Malignant hypertension on fundoscopy was defined as grade 3 - 4 hypertensive retinopathy. Left ventricular hyper足 trophy (LVH) was defined by Sokolow-Lyon criteria of >35 mm.[19] Renal biopsy was performed in patients with impaired renal function of unknown cause and/or proteinuria >3 g/d in the presence of normal-sized kidneys. Malignant hypertension on histology was defined as the presence of fibrinoid necrosis and onion-skinning of the arterioles associated with crenation of the glomerular basement membrane.

The study was approved by the University of Cape Town Research Ethics Committee (HREC REF: 573/2011).

Results

Forty-seven patients were identified, of whom 40 (85.1%) were male. Their mean (standard deviation (SD)) age was 29 (8) years.

Table 1 shows the baseline demographics. Five patients (10.6%) were black Africans and the remainder (89.4%) of mixed ancestry. At the time of data collection, 11 patients had died, all of whom had endstage renal disease (ESRD) at presentation and were not eligible for chronic dialysis in terms of the criteria for long-term dialysis and

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Table 1. Patient demographics

Patients, N

Mean (SD)

Age (years)

47

29.4 (8.0)

Systolic BP (mmHg)

47

183 (37)

Diastolic BP (mmHg)

47

114 (24)

BMI (kg/m )

29

24.6 (4.4)

Creatinine (µmol/l)

47

716 (623)

Urea (mmol/l)

44

31.4 (20.1)

Potassium (mmol/l)

45

4.6 (0.88)

UPCR (g/mmol)

41

0.52 (0.44)

Haemoglobin (g/dl)

45

9.9 (2.7)

MCV (fl)

43

85 (6)

Albumin (g/l)

42

32 (9)

Cholesterol (mmol/l)

25

5.9 (2.8)

2

SD = standard deviation; BP = blood pressure; BMI = body mass index; UPCR = urinary protein-creatinine ratio; MCV = mean cell volume.

transplantation in the Western Cape; all died as a consequence of chronic renal failure.

At presentation, 42 (89.4%) of the patients were hypertensive, with evidence of malignant hypertension (defined by grade 3 or 4 hypertensive retinopathy and/or evidence on renal biopsy) in 21 (44.7%). The mean (SD) blood pressure was 183 (37)/114 (24) mmHg. Significant target organ damage (TOD) as a result of hypertension was evident in 34 patients (72.3%). Of the 37 patients (78.7%) who had documentation of electrocardiographic findings, LVH was found in 26 (70.3%). Findings on fundoscopy were recorded in 26 patients (55.3%): stage 1 hypertensive retinopathy was seen in 2 (7.7%) patients, stage 2 in 5 (19.2%), stage 3 in 11 (42.3%) and stage 4 in 7 (26.9%). CKD was found in 45 patients (95.7%). On ultrasound, 24 patients (51.1%) had evidence of CKD (i.e. small kidneys in 10, loss of corticomedullary differentiation in 4, increased echogenicity in 19). The mean (SD) urine protein-creatinine ratio was 0.52 (0.44) g/mmol. Twenty-six patients (55.3%) had stage 5 CKD, 4 (8.5%) stage 4, 4 (8.5%) stage 3, 5 (10.6%) stage 2, and 6 (12.8%) stage 1; only 2 (4.3%) had no evidence of CKD. Renal biopsy was performed in 24 patients (51.1%). Hypertensive changes were found in 12 biopsies (50.0%) with 6 (25.0%) showing malignant changes (Fig. 1, E and F). Six (25.0%) showed ESRD. Mesangiocapillary glomerulonephritis (MCGN) type 1 was found in 14 biopsy cases (58.3%) (Fig. 1, A and B), all of which were positive for IgM and C3 complement (Fig. 1, C and D). In addition, 9 (37.5%) showed staining for IgG and 7 (29%) for IgA. One individual (2.1%) tested positive for HIV, and 2 (4.3%) for syphilis. The HIV-positive patient underwent renal biopsy, the histological findings showing hypertensive changes only. No patients were positive for hepatitis B or C, or had infective endocarditis or systemic lupus erythematosus.

All the patients in this study had been using methamphetamines, but in only a few cases was the length of drug use documented. Some patients used other recreational drugs, methaqualone in 10 cases (21.3%) and cocaine in 3 (6.4%); no patient used intravenous drugs.

All three patients using cocaine had malignant hypertension and ESRD. Two of these patients underwent renal biopsy, which showed hypertensive changes and ESKD in both cases, but no evidence of MCGN. Of the patients who had used methaqualone, 7 underwent renal biopsies; 6 had hypertensive changes and 5 had MCGN.

A

B

C

D

E

F

[20]

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Fig. 1. Light microscopic features of kidney changes seen in methamphet­ amine users. A: Lobular glomerulus with thickened GBM (H&E); B: Glomerulus showing split GBM (JMS); C: Immunohistochemistry for C3 and D, IgM subendothelial deposits; E: Concentric myointimal thickening (‘onion skinning’) (H&E); F: Ischaemic retraction of glomeruli with corrugation of the GBM (JMS). (GBM = glomerular basement membrane; H&E = haematoxylin and eosin; JMS = Jones methenamine silver.)

Discussion

This study investigated the association between hypertension and/ or CKD and methamphetamine use in patients referred to a single large tertiary hospital in Cape Town for evaluation of CKD and/or hypertension between 2005 and 2013. The major findings were the presence of severe hypertension, with 44.7% of cases complicated by malignant hypertension; CKD (stage 4 or 5 in 64%) was present in in 95.7%. The unexpected and novel finding was the presence of MCGN in 58.3% of the 24 biopsies performed.

The association of methamphetamine use with hypertension is not unexpected, as the drug has vasoconstrictive properties causing increased systemic vascular resistance and raised blood pressure.

However, the severity of the hypertension is remarkable. The mean (SD) blood pressure was 183 (37)/114 (24) mmHg, and 44.7% had malignant hypertension. TOD was commonly seen: 70.3% had LVH and 96.2% hypertensive retinopathy. On renal biopsy of hypertensive methamphetamine users, there were vascular changes of hypertension in 12 with evidence of malignant hypertension in 6.

The prevalence of CKD in this group of patients was 95.7%, with 63.8% of patients having very severe disease (CKD stages 4 and 5). In the cohort, 41 cases of CKD were related to hypertension on clinical grounds, and this was confirmed by renal biopsy in 12 cases. The unexpected finding in this study was that not all cases of CKD were

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a consequence of hypertension. MCGN was found to be the cause in 14 cases (58.3% of biopsies and 29.7% of the entire group). Idiopathic MCGN is the most common biopsy finding in Cape Town[21] and in other areas of SA the second most common,[22] although it is declining in incidence in developed countries.[23] Known associations with MCGN did not explain the link between methamphetamine use and MCGN. All the biopsies that showed MCGN had IgM and C3 deposits, supporting chronic antigenaemia as a possible cause. Hepatitis C virus, hepatitis B virus, HIV, malaria and infective endocarditis are common infectious agents associated with MCGN, but these were excluded on clinical and serological grounds in all except one patient, who was HIV-positive. This patient had hypertensive changes on renal biopsy without evidence of MCGN. The two patients who tested positive for syphilis did not undergo renal biopsy.

MCGN is thought to result from chronic antigenaemia with defects in elimination or clearing of foreign antigen.[24] It is possible that people who use methamphetamines are exposed to multiple infectious antigens through the sharing of drugs and devices to inhale the drug. Another possible means of exposure to infectious antigens is through close physical contact between people during the process of taking the drug. It is also possible that methamphetamines alter self-proteins, making them immunogenic or creating haptens.

However, these explanations are highly speculative.

On renal biopsy, MCGN and hypertension were fairly equally repres­ ented (14 and 12 cases, respectively). MCGN has a poor prog­nosis, with 50% of patients progressing to ESRD within 5 years.[24] Severe hyper­ tension (affecting 37 patients (78.7%)) also results in ESRD. Seven patients (14.9%) had isolated hypertension without ESRD. This suggests that there are at least two pathways to ESRD for patients using methamphetamines.

MCGN has been associated with intravenous drug use, especially of heroin.[25] However, it is unlikely that intravenous drug use was relevant in this group of patients; no such drug use was reported, and no patient was hepatitis B- or C-positive. Only one patient was found to be HIVpositive. The prevalence of HIV in the mixed-ancestry community it is ~5.5 - 6.6%[26] and in SA overall ~8.5%,[27] considerably higher figures than in this study. Similarly, hepatitis B prevalence is high in SA (~8%).[28]

Study limitations

The limitations of this study are that it is purely observational of the presence of hypertension, MCGN and ESRD in patients using methamphetamines. In addition, there is no clear pathophysiological pathway linking methamphetamine abuse to MCGN. Further studies, while difficult in the setting of illicit substances, are clearly required.

Conclusion

The abuse of methamphetamines appears to be associated with severe hypertension and MCGN, both of which can lead to ESRD and death.

In a resource-limited setting, this has important implications for the management of these young patients. Strategies to prevent exposure to this easily accessible drug need to be implemented.

Acknowledgements. This research was initiated by Dr Nazier Khan, who tragically died before he could complete the project.

201

References 1. Peltzer K, Ramlagan S, Johnson BD, Phaswana-Mafuya N. Illicit drug use and treatment in South Africa: A review. Subst Use Misuse 2011;45(13):2221-2243. [http://dx.doi.org/10.3109/10826084.201 0.481594] 2. Matsha TE, Yako YY, Rensburg MA, Hassan MS, Kengne AP, Erasmus RT. Chronic kidney diseases in mixed ancestry South African populations: Prevalence, determinants and concordance between kidney function estimators. BMC Nephrol 2013;14(1):75-84. [http://dx.doi.org/10.1186/1471-236914-75] 3. Plüddemann A, Flisher AJ, McKetin R, Parry C, Lombard CJ. Methamphetamine use, aggressive behavior and other mental health issues among high school students in Cape Town, South Africa.

Drug Alcohol Depend 2010;109(1-3):14-19. [http://dx.doi.org/10.1016/j.drugalcdep.2009.11.021] 4. Fahal IH, Sallomi DF, Yaqoob M, Bell GM. Acute renal failure after ecstasy. BMJ 1992;305(6844):29. [http://dx.doi.org/10.1136/bmj.305.6844.29] 5. Plüddemann A, Myers B, Parry C. Fact sheet – Methamphetamine. Cape Town: Medical Research Council, 2007:1-3.

6. Ito H, Yeo K-K, Wijetunga M, Seto TB, Tay K, Schatz IJ. A comparison of echocardiographic findings in young adults with cardiomyopathy: With and without a history of methamphetamine abuse. Clin Cardiol 2009;32(6):E18-E22. [http://dx.doi.org/10.1002/clc.20367] 7. Ances BM, Vaida F, Cherner M, et al. HIV and chronic methamphetamine dependence affect cerebral blood flow. J Neuroimmune Pharmacol 2011;6(3):409-419. [http://dx.doi.org/10.1007/s11481-0119270-y] 8. Bingham C, Beaman M, Nicholls AJ, Anthony PP. Necrotizing renal vasculopathy resulting in chronic renal failure after ingestion of methamphetamine and 3,4-methylenedioxymethamphetamine (‘ecstasy’). Nephrol Dial Transplant 1998;13(10):2654-2655. [http://dx.doi.org/10.1093/ndt/13.10.2654] 9. Albertson TE, Derlet RW, van Hoozen BE. Methamphetamine and the expanding complications of amphetamines. West J Med 1999;170(4):214-219.

10. Milroy CM, Parai JL. The histopathology of drugs of abuse. Histopathology 2011;59(4):579-593. [http://dx.doi.org/10.1111/j.1365-2559.2010.03728.x] 11. Vupputuri S, Batuman V, Muntner P, et al. The risk for mild kidney function decline associated with illicit drug use among hypertensive men. Am J Kidney Dis 2004;43(4):629-635. [http://dx.doi. org/10.1053/j.ajkd.2003.12.027] 12. Inouye DS, Kickertz K, Wong LL. Methamphetamine use in deceased kidney donors impairs one-yr graft function. Clin Transplant 2007;21(5):643-650. [http://dx.doi.org/10.1111/j.13990012.2007.00703.x] 13. De Ligny BH, El Haggan W, Comoz F, et al. Early loss of two renal grafts obtained from the same donor: Role of ecstasy? Transplantation 2005;80(1):153-156. [http://dx.doi.org/10.1097/01.

TP.0000158713.70266.06] 14. Meade CS, Watt MH, Sikkema KJ, et al. Methamphetamine use is associated with childhood sexual abuse and HIV sexual risk behaviors among patrons of alcohol-serving venues in Cape Town, South Africa. Drug Alcohol Depend 2012;126(1-2):232-239. [http://dx.doi.org/10.1016/j. drugalcdep.2012.05.024] 15. Wechsberg WM, Luseno WK, Karg RS, et al. Alcohol, cannabis, and methamphetamine use and other risk behaviours among black and coloured South African women: A small randomized trial in the Western Cape. Int J Drug Policy 2008;19(2):130-139. [http://dx.doi.org/10.1016/j.drugpo.2007.11.018] 16. Jones HE, Browne FA, Myers BJ, et al. Pregnant and nonpregnant women in Cape Town, South Africa: Drug use, sexual behavior, and the need for comprehensive services. Int J Pediatr 2011;2011:353410. [http://dx.doi.org/10.1155/2011/353410] 17. Stevens PE, Levin A. Clinical guidelines. Evaluation and management of chronic kidney disease: Synopsis of the Kidney Disease: Improving Global Outcomes 2012 Clinical Practice Guideline. Ann Intern Med 2013;158(11):825-831. [http://dx.doi.org/10.7326/0003-4819-158-11-201306040-00007] 18. Talley NJ, O’Connor S. Clinical Examination. 3rd ed. Talley NJ, O’Connor S, eds. Eastgardens, NSW, Australia: Blackwell Science, 1996.

19. Romhilt DW, Bove KE, Norris RJ, et al. A critical appraisal of the electrocardiographic criteria for the diagnosis of left ventricular hypertrophy. Circulation 1969;40(2):185-195. [http://dx.doi. org/10.1161/01.CIR.40.2.185] 20. Swanepoel CR, Wearne N, Duffield MS, Okpechi IG. The evolution of our knowledge of HIVassociated kidney disease in Africa. Am J Kidney Dis 2012;60(4):668-678. [http://dx.doi.org/10.1053/j. ajkd.2012.04.034] 21. Okpechi I, Swanepoel C, Duffield M, et al. Patterns of renal disease in Cape Town South Africa: A 10year review of a single-centre renal biopsy database. Nephrol Dial Transplant 2011;26(6):1853-1861. [http://dx.doi.org/10.1093/ndt/gfq655] 22. Van Rensburg BWJ, van Staden AM, Rossouw GJ, Joubert G. The profile of adult nephrology patients admitted to the renal unit of the Universitas Tertiary Hospital in Bloemfontein, South Africa from 1997 to 2006. Nephrol Dial Transplant 2010;25(3):820-824. [http://dx.doi.org/10.1093/ndt/gfp535] 23. Simon P, Ramée MP, Autuly V, et al. Epidemiology of primary glomerular diseases in a French region.

Variations according to period and age. Kidney Int 1994;46(4):1192-1198. [http://dx.doi.org/10.1038/ ki.1994.384] 24. Floege J, Johnson RJ, Feehally J. Section IV: Glomerular disease. In: Floege J, Johnson RJ, Feehally J, eds. Comprehensive Clinical Nephrology. 4th ed. St Louis: Elsevier Saunders, 2010:193-358. [http://dx.doi.org/10.1016/B978-0-323-05876-6.00015-0] 25. Jaffe JA, Kimmel PL. Chronic nephropathies of cocaine and heroin abuse: A critical review. Clin J Am Soc Nephrol 2006;1(4):655-667. [http://dx.doi.org/10.2215/CJN.00300106] 26. Connolly C, Shisana O, Colvin M, Stoker D. Epidemiology of HIV in South Africa – results of a national, community-based survey. S Afr Med J 2004;94(9):776-781.

27. Lehohla P. Mid-Year Population Estimates 2013. Pretoria: Statistics South Africa, 2013:1-17.

28. Kew MC. Epidemiology of chronic hepatitis B virus infection, hepatocellular carcinoma, and hepatitis B virus-induced hepatocellular carcinoma. Pathol Biol 2010;58(4):273-237. [http://dx.doi. org/10.1016/j.patbio.2010.01.005]

Accepted 13 October 2014.

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Emergency care research priorities in South Africa D J van Hoving, MB ChB, Dip PEC (SA), MMed (Em Med), MScMedSci (Clin Epi); B K Barnetson, MB ChB; L A Wallis, MB ChB, FCEM, MD Division of Emergency Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Cape Town, South Africa Corresponding author: D J van Hoving (nvhoving@sun.ac.za)

Background. Emergency care research is rarely undertaken in low- and middle-income countries. A manageable ‘road map’ for research in South African (SA) emergency care is needed to address research gaps.

Objective. To identify, collate and prioritise research topics from identified knowledge gaps in emergency care in SA. Methods. Seventy-six individuals were invited to participate in a modified Delphi study. Participants were requested to suggest important research topics before rating them. Consensus was achieved when >75% of participants strongly agreed or disagreed. Participants then ranked the agreed statements before selecting the most appropriate methodology relating to study design, funding and collaboration.

Results. Three hundred and fifty topics were suggested by 31 participants. Topics were collated into 123 statements before participants rated them.

Consensus was achieved for 39 statements. The highest-ranked priority in the prehospital group was to determine which prehospital interventions improve outcomes in critically ill patients. The competence of emergency care providers in performing common lifesaving skills was deemed the most important in clinical emergency care. Implementing and reviewing quality improvement systems scored the highest under general systems and safety management. Only 22 statements achieved consensus regarding study design. The National Department of Health was the preferred funding source, while private organisations and emergency care societies were identified as possible collaborative partners.

Conclusion. This study provides expert consensus on priority research areas in emergency care in SA as a guide for emergency care providers to ensure evidence-based care that is relevant to the SA population.

S Afr Med J 2015;105(3):202-208. DOI:10.7196/SAMJ.8967

Health research has a high value to society and has resulted in a noteworthy improvement in healthcare. South Africa (SA) has a quadruple burden of disease that is being addressed by the strate­ g ic priorities of the National Department of Health (NDoH).[1] A continuous reduction in morbidity and mortality can only be guaranteed if research is ongoing, if the efficacy and adverse effects of medical interventions are continuously monitored, and by ensuring that research is relevant to a specific patient population.[2] High-quality healthcare implies practice that is consistent with the current best evidence.[3] It is essential to know which interventions work and which do not, and which are likely to be harmful. This becomes vitally important in settings with a mismatch between the burden of disease and available resources.

While healthcare professionals in low- and middle-income countries (LMICs) should use evidence-based decisions in day-today patient care, implementing evidence-based medicine remains difficult.[4] Since the majority of studies are done in high-income countries for high-income countries relating to health conditions important to high-income countries,[5] their limited applicability and transferability to LMICs creates a knowledge vacuum in LMICs, including SA.[4] Research in the field of emergency care specifically related to LMICs is sparse. A single consensus study related to clinical research priorities, emergency centre management and administration exists,[6] but there are no lists or identified gaps for any aspects of emergency or acute care specific to SA. Research related to emergency care in SA demands a manageable ‘road map’ to address the research gaps. This study aimed to identify, collate and prioritise research topics from identified knowledge gaps in emergency care in SA.

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Methods

Study design

A three-phase modified Delphi study was undertaken from 1 March 2012 to 5 April 2013. The Delphi study design was modified in that each phase was limited to only two or three rounds (Fig. 1).

Ethics approval was obtained from the Human Research Ethics Committee, Stellenbosch University, Tygerberg, Cape Town (Reference S12/02/034).

Study population

Seventy-six participants were invited to represent the expert panel (Appendix 1). They included doctors, nurses, prehospital care providers, and policy makers from all the provinces in SA. Invited panel members were given the option of appointing a representative in their place.

Data collection and management

All potential panel members were invited by e-mail, and partici­ pation implied consent. An online survey tool (SurveyMonkey) was used to facilitate the process. The views of all participating panellists were given equal weight. Participants were given 4 weeks to complete each round; weekly reminders were sent by e-mail until a response was received or the 4 weeks had expired.

All panel members were invited to participate in rounds 1 and 2 of phase 1 and re-invited for the first round of phases 2 and 3.

In phase 1 (identifying research topics), participants were requested to suggest important research topics in five categories of emergency care (adult emergency care, paediatric emergency care, pre­hospital emergency care, emergency nursing care, and a ‘general’ section for any other area related to emergency care). An example was provided for each category, and categories were randomised to avoid question order bias. The suggested research topics were then collated

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Phase 1. Identifying research topics

•

Round 1: Submission of free-text suggestions regarding important research needed in emergency care

• •

Round 2: Rate agreement of proposed research statements Round 3: Determine consensus on research statements

Phase 2. Prioritising research topics

• •

Round 1: Ranking of agreed research statements Round 2: Determine consensus on ranking of statements

Phase 3. Best approach to prioritised research topics

• •

Round 1: Select the most appropriate method to address the research statements related to study design, funding and collaboration Round 2: Determine consensus regarding most appropriate study design

Fig. 1. The Delphi process used to attain a coherent list of research topics for emergency care in SA.

Table 1. Examples to determine rank order of research statements Ranked value Participant A

Participant B

Participant C

Average per statement

Ranking

Statement A

1

2

N/A

1.5

1

Statement B

2

3

N/A

2.5

3

Statement C

3

4

3

3.3

4

Statement D

4

1

1

2

2

Statement E

N/A

5

2

3.5

5

N/A = not applicable.

into 123 research statements. Participants were then asked to rate their agreement that each statement was a priority for research in emergency care in SA. A 10-point Likert scale was used, and consensus was achieved when >75% of participants strongly agreed (scores 8 - 10) or strongly disagreed (scores 1 - 3). The mean score for each statement was calculated, while statements completed as ‘not applicable’ were excluded. Surveys were then individualised, and participants were presented with all non-consensus statements. Both the participant’s rating score and the mean rating score for each nonconsensus statement were provided to allow participants to consider an alternative rating score.

In phase 2 (prioritising research topics), consensus statements from phase 1 were regrouped into three new categories: (i) prehospital; (ii) clinical; and (iii) general systems and safety. Panellists were asked to rank the statements in each category in order of importance. Categories per se and statements within each category were randomised to prevent question order bias. Participants could exclude statements by indicating them as ‘not applicable’ to their area of expertise. Submission was blocked until all statements were either ranked or excluded. The overall rank order per category was subsequently determined. For each participant, the first ranked statement (i.e. most important) was given a value of 1. The lowestranked or least important statement received the value of the number of statements in that category less the number of statements selected as ‘not applicable’. An average ranking score was calculated for every

203

statement by adding the values given by all participants, and dividing that by the number of participants that ranked that specific statement; the top ranking statement would therefore have the lowest average score (Table 1).

The ranked statements were presented to the participants. The categories were randomised, but the statements in each category were presented in the order of the average ranking scores achieved.

Both the participant’s ranking score and the mean ranking score were provided to allow participants to consider an alternative ranking score.

For the final phase (best approach to prioritised research topics), participants were requested to choose one or more study design options. Participants were also given the option of using free text to suggest funding and collaboration options for each statement.

Participants were again allowed to select ‘not applicable’ to exclude themselves from that statement if they considered the topic out of their area of expertise. Only the study design options for each research statement were redistributed to determine consensus.

Collected data were transferred to and analysed on a passwordprotected electronic spreadsheet (Microsoft Office Excel 2010, Microsoft Corporation, USA).

Results

Seventy-six panel members were invited to participate in the study. Two medical and three nursing panel members appointed

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Delphi process used to determine consensus regarding the ranking of the research state­ ments was completed by 19 participants (65%). Tables 2, 3 and 4 provide the final consensus ranking order of consensus priority statements in each category.

The response rate for suggesting study design options was 28% (n=21); only three statements initially achieved consensus. The last round of the study (reconsidering study design options) was completed by 15 partici­ pants (71%). An additional 22 statements achieved consensus regarding the most appropriate study design to use (Tables 2 - 4).

One to three suggestions per statement for funding options were received for 32 (84%) of the 38 statements. The NDoH (n=26) and private organisations (n=12) were most often indicated as potential funding sources.

One to two collaboration suggestions per statement were provided for 29 statements (76%). Private organisations (n=7) and emergency care-related societies (n=7) were considered as options with which to do collaborative work.

representatives in their place. The response statistics for all study phases are summarised in Fig. 2.

Three hundred and fifty research topics were suggested by 31 participants (41%).

The suggested topics were collated into 123 research statements. Seventy-five of the original 76 panel members were invited to rate their agreement of the proposed collated research statements as a priority for research in emergency care in SA (one panel member was unintentionally not invited). Thirty-one (41%) responded, and consensus was achieved for 11 statements. The remaining statements were resent for re-rating. Consensus was achieved for 39 statements after 25 participants (81%) changed their initial scores.

These statements were then grouped into the three categories as described under ‘Methods’. One of the statements was only identified late in the study and was subsequently not included. The consensus statements were ranked by 29 panel members (39%). Statements were re-ordered according to their average ranking scores achieved. The

Response rates, % of total invitees

100

Unresponded

90

Unknown

80

Prehospital

70

Policy makers

60

Nursing

50

Medical

40 30 20 10

(1

(2

5/

1/

21

75

)

)

)

sig n

ig n

de

es -su gg es

ts

tu

dy

yd ud st

Thirty-nine statements related to emergency care were identified as high priorities for the SA setting.

Prehospital emergency care

Prehospital interventions on patient outcomes were ranked first among prehospital research priorities. The need to substantiate clinical care by evidence and to use clinically relevant performance measures was echoed by studies from Europe and the USA, including both adult and child populations.[7-9] There have been substantial international debates regarding the scope of prehospital care, and it is clear that the issue has not been resolved. The SA emerg­ ency medical services system has adopted the Anglo-American system, which minimises on-scene time (as opposed to the FrancoGerman model, which includes prehospital physicians with an extensive scope of practice and very advanced technology).[10] A prolonged on-scene time, usually as a result of additional prehospital interventions, has been shown to be detrimental to patient outcomes (especially in trauma); it is therefore important to ensure that only the necessary interventions, backed by substantial evidence, are performed.[11] Appropriate management strategies ranked second in the prehospital group. Any pre­ hospital system faces challenges with the acquisition and appropriate allocation of assets and resources, including human resources.[12] SA has been losing significant numbers of prehospital practitioners with advanced training over the past decade.[13] Poor working conditions, physical security and economic considerations were identified as some of the main ‘push’ factors.[13] Govender et al.[14] also hinted that current measures are inadequate to actively manage the shortages of prehospital practitioners with advanced training and their migration out of SA.

Re 2

1

Clinical emergency care

3.

3.

-ra Re

2.

2

Su

nk i

gg es

t

ng

im po

r ta

nc e

nc e

(2

(1

9/

9/

75

29

)

1) /3 25 rta im po

nk i Ra

2.

1

Re 3 1.

ng

-ra te

ag re e

m

en t(

31 en t( m

Ra te 2 1.

1.

1T op

ic

su

ag re e

gg es

tio

n

(3

1/

/7

76

5)

)

0

Discussion

All phases rounds (respondents, n/invitees, n)

Fig. 2. Summary of response statistics for all study phases.

Emergency care (prehospital, medical and nursing) is a procedure-orientated field that

Table 2. Ranked research priority topics related to prehospital emergency care Rank

Research statement

Study design

1

Determine which prehospital interventions improve outcomes in trauma or critically ill patients

Randomised controlled trial

2

Determine the most appropriate prehospital management strategies in southern Africa

Systematic review ± meta-analysis

Tie 3rd

Optimise the use of resources in terms of transfers and transport in emergency medical services

Non-consensus

Tie 3rd

Compile evidence-based guidelines for the critical care transfer of patients

Systematic review ± meta-analysis

5

Determine the outcomes of prehospital drug-facilitated intubations

Non-consensus

6

Determine an appropriate mass casualty system for southern Africa

Systematic review ± meta-analysis

7

Implications of the abuse of ambulance services to transport non-emergency cases

Descriptive study

8

Define the role of aeromedical transport in rural areas

Descriptive study

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Table 3. Ranked research priority topics related to clinical emergency care Rank

Research statement

Study design

1

Determine how competent emergency care providers are in performing common lifesaving skills within their scope of practice

Non-consensus

2

Determine whether emergency care providers are competent in recognising and handling a failed airway

Descriptive study

3

Determine the burden of disease and patient conditions that present to the emergency centre

Descriptive study

4

Determine how competent emergency nurses are in recognising critically ill patients

Descriptive study Systematic review ± meta-analysis

5

Determine markers of severity in the trauma or critically ill patient

6

Determine how competent emergency care providers are in providing paediatric critical care

Descriptive study

7

Develop effective pain management strategies for all acute-care patients

Systematic review ± meta-analysis

8

Determine the knowledge and utilisation of non-invasive ventilation by emergency care providers

Descriptive study

9

Determine the efficacy of nurse-led triage

Non-consensus

10

Determine the need for a national poison information centre

Descriptive study

11

Determine appropriate spinal immobilisation techniques in the SA context

Non-consensus

12

Determine whether paediatric seizures are managed appropriately by all emergency care providers

Descriptive study

13

Determine whether toxicological cases are appropriately managed by all emergency care providers

Non-consensus

14

Determine whether paediatric febrile illnesses are managed appropriately

Descriptive study

15

Determine the impact of low-dose digital X-ray (LODOX) machines on emergency trauma patient management

Non-consensus

Table 4. Ranked research priority topics related to general systems and safety management Rank

Research statement

Study design

1

Implement and review quality improvement systems

Non-consensus

2

Determine whether evidence-based healthcare is adhered to in providing emergency care

Descriptive study

3

Develop strategies to reduce child and infant morbidity and mortality

Systematic review ± meta-analysis

4

Comparison of the different acute-care systems in order to improve understanding and implement integrated care pathways

Systematic review ± meta-analysis

Tie 5th

Determine whether lifesaving equipment is checked before commencing duty

Systematic review ± meta-analysis or descriptive study

Tie 5th

Determine the cost-effectiveness of providing emergency care

Systematic review ± meta-analysis

7

Determine the true implication of prolonged length of stay in emergency centres

Non-consensus

8

Determine the impact of National Health Insurance on emergency care

Non-consensus

9

Determine efficacy of infection control measures in various acute-care settings

Non-consensus

10

Determine valid and reliable assessment methods for emergency care educational examinations

Non-consensus

11

Determine the efficacy of hospital case load policies

Non-consensus

12

Determine whether informed consent is appropriately undertaken in the emergency care setting

Descriptive study

13

Determine whether adequate emergency centre discharge instructions are given to patients

Descriptive study

14

Determine how emergency care trainees perceive their future in emergency care in southern Africa

Descriptive study

15

Determine the impact of occupation-specific dispensation on recruitment and retention of emergency centre staff

Descriptive study

requires adequate knowledge and skills to diagnose and manage acute aspects of illnesses and injuries.[15] Overcrowding and prolonged length of patient stay mean that the management of critically ill and trauma patients frequently extends beyond initial stabilisation in the emergency centre when intensive care unit capacity is limited (and exhausted). The consequences were reflected in the research priorities related to clinical emergency care, where statements relating to competence in managing critically ill patients featured repeatedly.

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However, SA-trained healthcare providers have always been sought after internationally owing to the high quality and standard of their medical education and their hands-on experience.[16] The focus on competence is also in stark contrast to other international studies, which highlighted clinical outcomes as their top research priorities.[17,18] Emergency medicine is still a relatively young specialty in SA, with the focus on competence revealing that it is still establishing its place in the broader medical field.

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The burden of disease and patient conditions presenting to emergency centres ranked third in the clinical emergency care section. Knowing the acuity mix of patients presenting to emergency centres is essential to plan service delivery accurately.

The efficient deployment of staff relative to temporal patterns of patient presentations and developing strategies for dealing with non-referred minor cases has been highlighted previously.[19] This information can also help in identifying key areas to optimise patient flow from as early as the initial presentation to the emergency medical service, so that emergencies can be dealt with promptly and appropriately.[19] The emergency medicine setting is a unique environment of high patient volumes, brief clinical encounters, and patients from all age groups representing a spectrum of acuity. Risk stratification is the initial step towards a personalised patient care plan to ensure that patients are safely managed and appropriately investigated. Although the identification of appropriate markers of severity (5th-ranked statement) was identified as an international priority,[17] it would be just as useful, or even more useful, in resource-limited settings.

The early identification of disease severity and subsequent focused management of high-risk patients is therefore as important from a healthcare economics point of view as from a morbidity and mortality perspective.

General systems and safety management

The expectation and requirement to deliver safe and highquality emergency care have never been greater. Healthcare systems are not as reliable as has been thought, and highquality care is often lacking.[20,21] Cost-effectiveness of emergency medical interventions and quality assurance are considered global priorities.[6,21] According to the Institute of Medicine in the USA, a healthcare system should aim to be safe, effective, efficient, patient-centred, timely and equi­table.[20] Components of emergency care that can improve quality and patient safety include well-trained and motivated staff, appropriate physical structures, effective processes to enable high-quality care, co-ordinated clinical pathways supported by best evidence-based practice, and monitoring objective outcome measures to reflect continuous quality improvement (e.g. diagnostic errors, mortality and morbidity rates, etc.).[22]

Study limitations

Purposeful sampling was used for the panel selection, the criteria being that experts were identified by their specialist qualification and roles as leaders in their fields or heads of academic institutions or societies. Policymakers remained largely non-contactable, limiting the knowledge gained pertaining to policies and resource allocation at provincial or national levels.

Participants in a Delphi study have an interest and involvement in the question being examined. Researcher and subject bias is a known limitation, but the wide range of panellists should offset this. The opinion of a subset of experts with special interests in certain aspects of emergency care (e.g. paediatric emergency care) may have been under-represented.

The lack of participant discussion may have prevented participants from changing their views and responding according to the majority opinion.

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Collating free text statements was undertaken in an effort to reduce the number of statements to avoid panel fatigue and attrition.

Abstraction may have led to omission of details and potential oversimplification of suggested priority topics.

The response rate and consensus thresholds (75%) mean that final agreement is not implied; guidelines for further research were essentially identified.

Conclusion

This study provides expert consensus on the current priority research areas in emergency care in SA. It can ultimately guide emergency care providers to serve the SA population with evidence-based emergency medical care that is relevant.

Acknowledgement. We thank Ms Rachel Allgaier for her input on the initial proposal.

References 1. Department of Health (South Africa). NSDA: A Long and Healthy Life for All South Africans. Pretoria: Department of Health, 2013. http://www.hst.org.za/sites/default/files/NSDA_booklet.pdf (accessed 24 July 2014).

2. Wallis LA. Knowing and doing: Negotiating resource constraints through research. African Journal of Emergency Medicine 2013;3(4):151. [http://dx.doi.org/10.1016/j.afjem.2013.08.002] 3. Guyatt GH, Meade MO, Jaeschke RZ, Cook DJ, Haynes RB. Practitioners of evidence based care. BMJ 2000;320(7240):954-955. [http://dx.doi.org/10.1136/bmj.320.7240.954] 4. Lowe M. Evidence-based medicine – the view from Fiji. Lancet 2000;356(9235):1105-1107. [http:// dx.doi.org/10.1016/S0140-6736(00)02743-4] 5. Chinnock P, Siegfried N, Clarke M. Is evidence-based medicine relevant to the developing world? PLoS Med 2005;2(5):e107. [http://dx.doi.org/10.1371/journal.pmed.0020107] 6. Hodkinson PW, Wallis LA. Emergency medicine in the developing world: A Delphi study. Acad Emerg Med 2010;17(7):765-774. [http://dx.doi.org/10.1111/j.1553-2712.2010.00791.x] 7. Fevang E, Lockey D, Thompson J, Lossius HM. The top five research priorities in physician-provided pre-hospital critical care: A consensus report from a European research collaboration. Scand J Trauma Resusc Emerg Med 2011;19(1):57. [http://dx.doi.org/10.1186/1757-7241-19-57] 8. Snooks H, Evans A, Wells B, et al. What are the highest priorities for research in emergency prehospital care? Emerg Med J 2009;26(8):549-550. [http://dx.doi.org/10.1136/emj.2008.065862] 9. Foltin GL, Dayan P, Tunik M. Priorities for pediatric prehospital research. Pediatr Emerg Care 2010;26(10):773-777. [http://dx.doi.org/10.1097/PEC.0b013e3181fc4088] 10. Al-Shaqsi S. Models of international emergency medical service (EMS) systems. Oman Med J 2010;25(4):320-323. [http://dx.doi.org/10.5001/omj.2010.92] 11. Seamon MJ, Doane SM, Gaughan JP, et al. Prehospital interventions for penetrating trauma victims: A prospective comparison between advanced life support and basic life support. Injury 2013;44(5):634638. [http://dx.doi.org/10.1016/j.injury.2012.12.020] 12. Institute of Medicine. Challenges facing the prehospital system. In: Preparedness and Response to a Rural Mass Casualty Incident: Workshop Summary. Washington, DC: National Academies Press, 2011. http://www.ncbi.nlm.nih.gov/books/NBK62391/ (accessed 31 July 2014).

13. Govender K, Grainger L, Naidoo R, MacDonald R. The pending loss of advanced life support paramedics in South Africa. African Journal of Emergency Medicine 2012;2(2):59-66. [http://dx.doi. org/10.1016/j.afjem.2011.11.001] 14. Govender K, Grainger L, Naidoo R. Developing retention and return strategies for South African advanced life support paramedics: A qualitative study. African Journal of Emergency Medicine 2013;3(2):59-66. [http://dx.doi.org/10.1016/j.afjem.2012.11.005] 15. Emergency Medicine Society of South Africa. Practice guideline EM001 – Definition of emergency medicine. 2008. http://emssa.org.za/documents/em001.pdf (accessed 31 July 2014).

16. Bezuidenhout M, Joubert G. Reasons for doctor migration from South Africa. S Afr Fam Pract 2009;51(3):211-215.

17. Eagles D, Stiell IG, Clement CM, et al. International survey of emergency physicians’ priorities for clinical decision rules. Acad Emerg Med 2008;15(2):177-182. [http://dx.doi.org/10.1111/j.15532712.2008.00035.x] 18. Keijzers G, Thom O, Taylor D, Knott J, Taylor DM. Clinical research priorities in emergency medicine.

Emerg Med Australas 2014;26(1):19-27. [http://dx.doi.org/10.1111/1742-6723.12141] 19. Hodkinson PW, Wallis LA. Cross-sectional survey of patients presenting to a South African urban emergency centre. Emerg Med J 2009;26(9):635-640. [http://dx.doi.org/10.1136/emj.2008.063362] 20. Institute of Medicine. Crossing the Quality Chasm: A New Health System for the 21st Century.

Washington, DC: National Academy Press, 2001. http://www.nap.edu/books/0309072808/html/ (accessed 14 August 2014).

21. Lutge E, Friedman I, Mbatha T. A review of health research in South Africa from 1994 to 2007. In: Barron P, Roma-Reardon J, eds. South African Health Review 2008. Durban: Health Systems Trust, 2008.

22. Lecky F, Mason S, Benger J, Cameron P, Walsh C. Framework for quality and safety in the emergency department. International Federation for Emergency Medicine, 2012. http://www.ifem.cc/site/ DefaultSite/filesystem/documents/Policies%20and%20Guidelines/Framework%20for%20Quality%20 and%20Safety%20in%20the%20Emergency%20Department%202012.doc.pdf (accessed 18 August 2014).

Accepted 20 October 2014.

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Appendix 1 Invited panel list Group

Panel member

Position

Emergency medicine academic programme head

Prof. Efraim Kramer

University of the Witwatersrand

Emergency medicine academic programme head

Prof. Dries Engelbrecht

University of Pretoria

Emergency medicine academic programme head

Prof. Lee Wallis

Stellenbosch University/University of Cape Town

Emergency medicine academic programme head

Dr William Lubinga

University of Limpopo

Emergency medicine academic programme head

Dr Darryl Wood

University of KwaZulu-Natal

Selected other medical doctors

Dr Hein Lamprecht

Head: Continuous Quality Improvement, Western Cape EMS

Selected other medical doctors

Dr Roger Dickerson

SA College of Emergency Medicine

Selected other medical doctors

Dr Basil Bonner

Emergency physician (private sector)

Selected other medical doctors

Dr Tim Hardcastle

Trauma surgeon

Selected other medical doctors

Dr Steve Holt

Emergency physician (private sector)

Selected other medical doctors

Dr NiĂŤl van Hoving

Emergency physician

Selected other medical doctors

Dr P H Hargovan

University of KwaZulu-Natal

Selected other medical doctors

Dr Baljit Cheema

Paediatric emergency physician

Selected other medical doctors

Dr Charl van Loggerenberg

Medical Director: International SOS

Selected other medical doctors

Dr Mike Wells

Emergency physician

Selected other medical doctors

Dr Wayne Smith

Head: Disaster Medicine (Western Cape)

Selected other medical doctors

Dr Heike Geduld

Head: Education (Western Cape)

Emergency medicine-related society

Dr Jonathan Witt for Prof. Walter Kloeck

Head: Research task force team at Resuscitation Council of South Africa

Emergency medicine-related society

Dr Melanie Stander

Emergency Medicine Society of South Africa

Emergency medicine-related society

Dr Elmin Steyn

Trauma Society of South Africa

Academic nursing institutions

Ms Jean Augustyn

Medi-Clinic

Academic nursing institutions

Ms Tanya Heyns on behalf of Prof.

Mulder

Senior lecturer: Emergency Nursing at University of Pretoria

Academic nursing institutions

Ms S Schmollgruber for Prof. L Maree

Head: Nursing Education, University of the Witwatersrand

Academic nursing institutions

Prof. S Duma

University of Cape Town

Academic nursing institutions

Mande Toubkin

Netcare

Academic nursing institutions

Prof. B Ncama

University of KwaZulu-Natal

Academic nursing institutions

Janet Bell on behalf of Prof. Marina Clarke

Stellenbosch University

Academic nursing institutions

Dr Doriccah Peu

University of Pretoria

Academic nursing institutions

Dr Carin Maree

University of Pretoria

Academic nursing institutions

Theo Lighthelm

School for Military Health Training

Other nursing professionals

Prof. Petra Bryciewicz

Professional emergency care nurse

Emergency medicine-related society

Lynette Thomas

Emergency care education

Emergency medicine-related society

Kathy Bodmer

Emergency Nurses Society of South Africa

Emergency medicine-related society

Yolande Magerman

Emergency Nurses Society of South Africa

Dr Cleeve Robertson

Western Cape, EMS Director

Medical

Nursing

Policy makers Prehospital directors

Continued ...

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March 2015, Vol. 105, No. 3

RESEARCH

Prehospital directors

Mr N Sithole

KwaZulu-Natal, EMS Director

Prehospital directors

Mr AK Munilal

Free State, EMS Director

Prehospital directors

Mr A Dhai

Northern Cape, EMS Director

Prehospital directors

Mr T Dludlu

Gauteng, EMS Director

National government

Mr Peter Fuhri

National EMS, EMS Director

National government

Dr Charles Theu

DoH National EMS Director

Provincial government

Dr Beth Engelbrecht

Western Cape: Deputy-Director General Health

Provincial government

Dr Samuel Beja

Chief Directorate: Clinical Support, Eastern Cape

Provincial government

Dr Theys

Head: Health, Northern Cape

Provincial government

Dr Moji

Deputy Director-General, Free State

Provincial government

Dr Nomonde Xundu

Head: Health, Gauteng

Provincial government

Dr Sibongiseni Dlomo

MEC Health, KZN

Provincial government

Dr Sibongile Zungu

Head: Health, KZN

Provincial government

Dr Clifford Mkasi

MEC Health, Mpumalanga

Provincial government

Dr Lydia Sebego

Head: Health, North West

Provincial government

Dr Aggrey Morake

Head: Health and Social Development, Limpopo

Prehospital training programmes

Ian Howard (on behalf of Cheryl Pedersen)

South African Air Mercy Service

Prehospital training programmes

Mr Raveen Naidoo

Durban University of Technology

Prehospital training programmes

Mr W van der Net

COJEMS Training Academy

Prehospital training programmes

Ms A Millum

Academy of Emergency Medical Training

Prehospital training programmes

Mr D J Taylor

Human Emergency Life Programme (H.E.L.P) Emergency Medical Training

Prehospital training programmes

Mr A Malgas

Lebone College of Emergency Care

Prehospital training programmes

Ms Rosslyn Prinsloo

Mankwe Ambulance Training Centre

Prehospital training programmes

Mr Craig Lambert

University of Johannesburg

Prehospital training programmes

Mr N C Gargan

Ambutek

Prehospital training programmes

Mr Ajesh Nundlall

Central University of Technology, Free State

Prehospital training programmes

Dr R Holgate

ER24

Prehospital training programmes

Mr K D Rowe-Rowe

Free State College of Emergency Care

Prehospital training programmes

Mr K Moodley

Western Cape College of Emergency Care

Prehospital training programmes

Mr L D Christopher

Cape Peninsula University of Technology

Prehospital training programmes

Mr S J Mfeka

College of Emergency Care, KwaZulu-Natal

Prehospital training programmes

Mr S Naguran

Durban University of Technology

Prehospital training programmes

Mr A W Muller

Eastern Cape Ambulance Training College

Prehospital training programmes

Mr S M Makwala

Limpopo College of Emergency Care

Prehospital training programmes

Mr N M Zungu

Mpumalanga Ambulance Training College

Prehospital training programmes

Mr R Menkveld

North West Province EMS Rescue Services College

Prehospital training programmes

Mr S Ramduth

Netcare 911 School of Emergency and Critical Care

Prehospital training programmes

Col I Bux

School for Military Health Training

Prehospital training programmes

Mr A Keruparshad

Sharaj Training Service

Prehospital training programmes

Mr Adrian Trollip

Academy of Dynamic Emergency Training

Emergency medicine-related society

Mr Cristopher Stein

Emergency Care Society of South Africa

Prehospital

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Oral v. pulse intravenous cyclophosphamide: A retrospective analysis of adverse events in a setting with a high burden of infectious disease E Pretorius,1 MB ChB, MMed (Int) FCP (SA); M R Davids,2 MB ChB, FCP (SA), MMed (Int); R du Toit,3 MB ChB, MMed (Int), Cert Rheum Phys (SA) epartment of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University and Tygerberg Academic Hospital, D Tygerberg, Cape Town, South Africa 2 Division of Nephrology, Faculty of Medicine and Health Sciences, Department of Medicine, Stellenbosch University and Tygerberg Academic Hospital, Tygerberg, Cape Town, South Africa 3 Division of Rheumatology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University and Tygerberg Academic Hospital, Tygerberg, Cape Town, South Africa 1

Corresponding author: R du Toit (rdutoit@sun.ac.za)

Background. Cyclophosphamide (CPM) is still considered to be the first-line treatment for many life-threatening autoimmune conditions. It does, however, carry a significant risk of serious adverse events, especially infections. At present CPM is administered as either a daily oral dose (DOC) or an intravenous pulse (PIVC). There is uncertainty regarding the safety profiles of both regimens in settings with a high burden of infectious diseases.

Objective. To compare the frequency and nature of adverse events related to the use of DOC and PIVC in such a setting.

Methods. A cohort of patients treated with CPM for autoimmune diseases at Tygerberg Academic Hospital, Cape Town, South Africa, from 1 January 2008 to 31 May 2013 was studied. We compared participants receiving DOC and PIVC with regard to disease characteristics and the occurrence of major adverse events.

Results. A total of 134 participants (92 DOC and 42 PIVC) were included. Participants in the DOC group were treated for longer (174 v.

101 days; p<0.01) and with higher cumulative doses (17 276 v. 3 327 mg; p<0.01). Risk of infection was similar in the two groups, although there were 6 deaths from leucopenic sepsis in the DOC group (v. 0; p=0.18). Nadir leucocyte counts were also lower in the DOC group (median 3.8 v. 5.3 Ă&#x2014; 109/L; p=0.02).

Conclusion. Infection rates in the two groups were similar, but DOC was associated with longer treatment duration, greater cumulative CPM doses and more severe leucopenia. If resources allow and available literature provides support for efficacy, consideration should be given to greater use of PIVC. S Afr Med J 2015;105(3):209-214. DOI:10.7196/SAMJ.8785

Autoimmune diseases affecting major organs carry significant morbidity and mortality. Immunosuppressive therapy with agents such as cyclophosphamide (CPM) significantly improves quality of life and survival in many patients suffering from such diseases.[1,2] CPM is still considered to be the first-line treatment for many life-threatening autoimmune conditions owing to its well-established therapeutic benefits. It does, however, carry a significant risk of severe adverse events including cytopenias, infections, infertility and bladder toxicity. At present CPM is administered either as a daily oral dose (DOC) or as an intravenous pulse at various intervals (PIVC). The optimal dosing route and regimen remain controversial, especially in the treatment of lupus nephritis.

Large head-to-head trials comparing DOC with PIVC are lacking.

Many opinions exist on the optimal dosing regimen, based on small studies or indirect conclusions from larger studies. Overall it seems that DOC has the advantages of lower cost, simpler administration and avoidance of high-dose exposure should the drug be inappropriately administered.[3,4] PIVC has the advantage of a reduced incidence of short- and long-term adverse events and avoids the need for daily compliance with treatment. Data regarding the comparative efficacy of the two regimens are conflicting and briefly discussed below.

209

Total drug costs for treatment regimens are lower for DOC than for PIVC. PIVC also requires allocated space, consumables and personnel to administer the infusion. Patients need to take time off work and have additional travel expenses, which all contribute to the overall cost of this regimen.[3,4] Although DOC is associated with an increase in long-term sideeffects, adverse events due to inappropriate dosing are more easily managed. Examples include administration when a contraindication exists, mistaking sepsis for a flare of disease or not adjusting doses for renal function. Reducing or omitting further oral doses under these circumstances, which cannot be done with PIVC, reduces the toxicity.[4] Austin et al.[5] initially published data in 1986 supporting superior treatment outcomes and reduced side-effect profiles with the use of PIVC as opposed to DOC in patients with lupus nephritis. This led to PIVC becoming the standard treatment in lupus nephritis, with fewer subsequent trials and recommendations that include DOC.[3,6] This practice is now contested, as subsequent trials[4,7,8] and a recent Cochrane review[9] showed no difference in outcomes or adverse events. An increased tendency to relapse has also been shown in patients with lupus nephritis treated with PIVC.[10] DOC was associated with a higher frequency of adverse events in the same study. Another small trial showed a slightly larger increase in serum

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albumin in patients with membranous nephropathy treated with PIVC in comparison with DOC.[11] Trials in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides have also suggested equal to increased ability of PIVC to induce remission compared with DOC, but a greater tendency towards relapse.[12-14] Episodes of leucopenia and infection were less frequent in ANCA-associated vasculitides treated with PIVC.[14-17] Increased gonadal toxicity with oral CPM has also been shown in patients treated for ANCA-associated vasculitides.[18] Decreased toxicity with PIVC is thought to be due to the lower cumulative CPM doses used.

No difference in outcomes has been shown between the two regimens in treating pulmonary involvement in scleroderma.[19] The use of CPM in a resource-constrained and infectious diseasesburdened environment, as in our setting at Tygerberg Academic Hospital (TBAH), Cape Town, South Africa, has unique challenges and considerations in respect of cost, efficacy and safety. Cost of treatment to hospitals, lack of allocated space and trained personnel to administer intravenous medication, patients’ ability to travel to a tertiary setting to receive treatment, compliance with treatment and follow-up, access to healthcare in the event of drug toxicity, and the overall increased burden of infectious diseases associated with a low socioeconomic environment are all factors to consider in choosing an appropriate treatment plan.

Of special concern in our setting is safety. The high prevalence of tuberculosis (TB) in communities serviced by TBAH[20] and exposure to overpopulated and unhygienic environments can significantly endanger patients should they become severely immunosuppressed. To our knowledge, no studies comparing DOC and PIVC are available that address these safety issues when CPM is used in such settings.

Clinicians at TBAH make use of both intravenous pulse and oral regimens of CPM for the treatment of autoimmune diseases.

Treatment choice is largely based on the condition treated and the preference of the discipline involved in initiating treatment (e.g. lupus nephritis is generally treated with DOC by nephrologists, while vasculitis and other severe systemic complications of connective tissue diseases are treated with PIVC by rheumatologists). As a general guideline, DOC is initiated at a dose of 1.5 mg/kg and PIVC at 750 mg/m2, and then titrated according to disease severity and leucocyte count. Serious adverse events related to therapy have been encountered with both regimens, but the overall prevalence, differences in frequency and spectrum of adverse events between the two treatment regimens are not known.

Objective

Our primary objective was to compare the frequency and nature of adverse events related to the use of oral and intravenous CPM in patients with autoimmune diseases.

Methods

A retrospective cohort study was conducted at TBAH to compare patients treated with DOC with those who were treated with PIVC. Data were extracted from hospital records of adult patients (>18 years) suffering from autoimmune diseases treated with CPM. Pharmacy records were used to identify all patients who started treatment between 1 January 2008 and 31 May 2013. Participants were only included if they had been on treatment with CPM for at least 1 month, unless adverse events due to CPM occurred earlier, in which case the participant was also included. Patients who had received CPM for indications other than autoimmune disease (e.g. chemotherapy, transplant recipients) were excluded. Patients on

210

treatment for purely neurological diseases were also excluded owing to the different dosing regimens and treatment duration used.

Data collected included demographics, comorbid disease, mass, diagnosis and disease involvement, duration of disease prior to CPM initiation, treatment prior to CPM initiation, baseline leucocyte and neutrophil counts, indication for CPM therapy, initial dosage, subsequent adjustment to dosing and indication for changes, cumulative total drug dose, concurrent immunosuppressive drug use, use of preventive therapy (isoniazid, co-trimoxazole, contraception and gonadal protection), documentation of counselling regarding contraception, occurrence of major side-effects and discontinuation due to drug toxicity. Data collected on side-effects included cytopenias, infections, bladder toxicity and infertility. Adverse events were reported and graded according to the Common Terminology Criteria for Adverse Events guidelines.[21] Data were captured on a Microsoft Excel spreadsheet and analysed using Statistica version 11. The two groups were compared with regard to patient characteristics, disease profiles and risk factors for developing major side-effects. Continuous variables were analysed using the Mann-Whitney U-test, while categorical data were analysed using the χ2 and Fisher’s exact tests. A significance level of 5% was used throughout.

The study was approved by the Health Research Ethics Committee of Stellenbosch University (protocol No. S13/07/121). Owing to the retrospective nature of the study, the difficulty in tracing individual participants and the low risk to the participants, a waiver of informed consent was granted. Data were collected on standardised capture sheets using study codes assigned to each participant. Codes linking confidential data to the identity of the participants were kept separately and securely.

Results

After exclusion of oncology patients, 221 subjects were identified. A total of 134 participants were included in the study, 92 in the DOC group and 42 in the PIVC group. Eighty-seven subjects were excluded for reasons that included treatment for non-rheumatological disease, pharmacy errors and missing records, early withdrawal of treatment not related to drug side-effects, failure to follow up after initiation of treatment, concomitant participation in other drug trials, or receiving both PIVC and DOC. The characteristics of the participants are summarised in Table 1.

There were no significant differences between the groups in terms of age, mass, comorbid disease (HIV and diabetes mellitus) and leucocyte count at baseline. Overall, participants were young (mean age 34 years) with a female predominance (74.6%), especially in the PIVC group (85.7 v. 69.6%; p=0.03).

As expected, there was a marked difference in disease spectrum between the two groups, both in terms of primary diagnosis and organ involvement.

The indications for starting CPM varied significantly. The most frequent indication in the DOC group was class IV lupus nephritis (32.6%), followed by non-lupus-related renal disease including nephrotic syndrome (27.1%) and rapidly progressive (RPGN) or crescentic glomerulonephritis (GN) (21.7%). The most frequent indication in the PIVC group was neuropsychiatric lupus (45.2%), followed by interstitial lung disease due to various autoimmune diseases (28.6%), and lupus myocarditis (28.6%).

A total of 676 patient-months of treatment were observed.

Treatment details are summarised in Table 2. Participants in the PIVC group were treated for significantly shorter periods (mean 101 v. 174 days; p<0.01) and had much lower mean cumulative doses (3 327 v.

17 276 mg; p<0.01).

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Table 1. Participant baseline characteristics

All (N=134)

DOC (N=92)

PIVC (N=42)

p-value

M

34 (25.4)

28 (30.4)

6 (14.3)

0.03

F

Gender, n (%)

100 (74.6)

64 (69.6)

36 (85.7)

Age (years), mean (SD)

34.0 (12.7)

34.2 (13.3)

33.4 (11.4)

0.95

Mass (kg), mean (SD)

69.5 (18.4)

70.5 (18.0)

67.0 (19.5)

0.37

Diabetes mellitus

15 (11.2)

9 (9.8)

6 (14.3)

0.44

HIV

5 (3.7)

5 (5.4)

0 (0.0)

0.12

Comorbid disease, n (%)

Primary diagnosis, n (%)

SLE

63 (47.0)

41 (44.6)

22 (52.4)

0.55

Membranous GN

16 (11.9)

16 (17.4)

0 (0.0)

*

Mesangiocapillary GN

7 (5.2)

7 (7.6)

0 (0.0)

*

SLE/systemic sclerosis overlap

5 (3.7)

3 (3.3)

2 (4.8)

*

Crescentic GN

5 (3.7)

5 (5.4)

0 (0.0)

*

IgA nephropathy

5 (3.7)

5 (5.4)

0 (0.0)

*

Systemic sclerosis

8 (6.0)

2 (2.2)

6 (14.3)

*

Granulomatosis with polyangiitis

11 (8.2)

5 (5.4)

6 (14.3)

*

FSGS

2 (1.5)

2 (2.2)

0 (0.0)

*

Goodpasture’s syndrome

1 (0.8)

1 (1.1)

0 (0.0)

*

Mesangioproliferative GN

3 (2.2)

3 (3.3)

0 (0.0)

*

Minimal-change nephropathy

2 (1.5)

2 (2.2)

0 (0.0)

*

Eosinophilic granulomatosis with polyangiitis

1 (0.8)

0 (0.0)

1 (2.4)

*

SLE/rheumatoid arthritis overlap

1 (0.8)

0 (0.0)

1 (2.4)

*

SLE/dermatomyositis overlap

1 (0.8)

0 (0.0)

1 (2.4)

*

SLE/polymyositis overlap

1 (0.8)

0 (0.0)

1 (2.4)

*

Rheumatoid arthritis

1 (0.8)

0 (0.0)

2 (4.8)

*

Vasculitis of unknown cause

1 (0.8)

0 (0.0)

1 (2.4)

*

RPGN/crescentic GN other than lupus

25 (18.7)

20 (21.7)

5 (11.9)

0.18

Nephrotic syndrome other than lupus

25 (18.7)

25 (27.2)

0 (0.0)

<0.01

Vasculitis

4 (3.0)

0 (0.0)

4 (9.5)

0.01

Class III lupus nephritis

5 (3.7)

5 (5.4)

0 (0.0)

0.12

Class IV lupus nephritis

31 (23.1)

29 (31.5)

2 (4.8)

<0.01

Class V lupus nephritis

7 (5.2)

5 (5.4)

2 (4.8)

0.87

Interstitial lung disease

20 (14.9)

8 (8.7)

12 (28.6)

<0.01

Lupus myocarditis

16 (11.9)

4 (4.4)

12 (28.6)

<0.01

Eye disease (granulomatosis)

1 (0.8)

1 (1.1)

0 (0.0)

0.50

Neuropsychiatric lupus

21 (15.7)

2 (2.2)

19 (45.2)

<0.01

23.3 (44.8)

17.4 (42.2)

36.2 (48.1)

0.04

Indication for CPM, n (%)

Diagnosis to initiation of CPM (days), mean (SD) Duration of disease prior to CPM initiation (months), n (%)

0-3

70 (52.2)

51 (55.4)

19 (45.2)

0.04

3 - 12

19 (14.2)

16 (17.4)

3 (7.1)

0.04

45 (33.6)

25 (27.2)

20 (47.6)

0.04

Leucocyte count at baseline (× 109/L), mean (SD)

>12

9.9 (7.7)

9.2 (4.3)

11.4 (11.9)

0.72

Initiation dose (mg/kg), mean (SD)†

1.6 (0.4)

10.3 (4.4)

SD = standard deviation; M = male; F = female; SLE = systemic lupus erythematosus; FSGS = focal segmental glomerulosclerosis. *Owing to low frequency of observations, p-values not determined. † No comparison made between DOC and PIVC owing to different dosing regimens.

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Table 2. Treatment characteristics

All (N=134)

DOC (N=92)

PIVC (N=42)

p-value

Treatment duration (days), mean (SD)

151.4 (116.3)

174.0 (127.9)

100.9 (61.1)

<0.01

Cumulative dose (mg), mean (SD)

12 903.7 (12 087.5)

17 275.5 (12 210.7)

3 327.4 (2 489.3)

<0.01

Cumulative dose (mg/kg), mean (SD)

193.9 (198.0)

262.6 (205.5)

46.7 (32.5)

<0.01

Indication to stop treatment, n (%)

Lost to follow-up

14 (10.5)

9 (9.8)

5 (11.9)

0.71

Infection

15 (11.1)

10 (10.9)

5 (11.9)

0.86

Treatment failure

16 (11.9)

15 (16.3)

1 (2.4)

0.02

Completion of induction

61 (45.5)

36 (39.1)

25 (59.5)

0.02

Leucopenia

16 (11.9)

13 (14.1)

3 (7.1)

0.25

Transferred

1 (0.9)

0 (0.0)

1 (2.4)

0.14

Not stopped

9 (6.7)

8 (9.0)

1 (2.4)

0.18

Episodes of infection, n

25 20 15

9

6

10 10

5

11 5

1

1

2 1

1

3

1

1

3 1

PIVC

1

2

1

1

1

DOC

ep

ve re s

Se

Pn e

um

on

ia UT tic I ae m ia UR T Ce I llu lit i s Se pt ic SBE w o CM Ent und Ca V p eroc s He nd ne oli rp ida um tis es o zo eso onit ste p is r p hag ne iti Cr yp He um s to r co pe onia sz cc al os He men ter rp in es gi sim tis Pe pl ex rio rb M ita OT l Gi cel T l ar di ulit i al am s bl ia

0

1 1

Fig. 1. Infections during CPM treatment. (UTI = urinary tract infection; URTI = upper respiratory tract infection; SBE = subacute bacterial endocarditis; CMV = cytomegalovirus; MOTT = mycobacterium other than TB.)

The most frequent indication for stopping therapy was the successful completion of induction therapy. This was significantly more frequent in the PIVC group, while cessation of treatment due to treatment failure was more frequent in the DOC group (Table 2). Loss to follow-up, infection and leucopenia were also frequent reasons for discontinuation of treatment in both groups.

There were nine patients remaining on CPM at the time the study concluded, while one patient had requested to be transferred to a private physician for further management.

Prescription of prophylactic antimicrobials was consistently achieved, with 91.8% and 94.8% of all participants receiving isoniazid and co-trimoxazole, respectively. There was no difference between the groups. All patients received concomitant prednisone.

Only 43.3% of the participants who required contraception were documented to have been prescribed contraceptive therapy.

A total of 64 episodes of infection were documented, of which 37 were considered

serious and required hospitalisation. The profile of infections is illustrated in Fig. 1. There were no statistically significant differences in the number of infections (42 v. 22; p=0.53) or hospitalisations (25 v. 12; p=0.12) between the DOC and PIVC groups.

The most frequent infection was urinary tract infection, followed by pneumonia. The most common opportunistic infection was herpes zoster in the PIVC group and CMV pneumonitis in the DOC group. There were no new cases of TB diagnosed in either group.

Infections occurred early during therapy (median 57.5 days) in both groups, with no significant difference between the groups (63.0 v. 55.0 days; p=0.72), but occurred at a higher cumulative dose at the time of infection in the DOC group (7 964 mg v.

2 126 mg; p<0.01).

Overall, 61.2% of all participants (59.8% of the DOC group and 64.3% of the PIVC group; p=0.70) had one or more treatment-related adverse events (infection or leucopenia). The relative risk for developing an adverse event

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in the DOC group v. the PIVC group was 0.93 (95% confidence interval 0.70 - 1.23).

Over a third (38.1%) of participants developed one or more infections during CPM therapy. In the DOC group, 35.9% of participants developed infections compared with 42.9% in the PIVC group (p=0.45). The overall risk of a participant having one or more hospitalisations as a result of serious infection was 24.6%; this was slightly higher in the DOC group (26.1 v. 21.4%; p=0.67).

In the DOC group, six participants (6.5%) died due to leucopenia-related sepsis. There were no treatment-related deaths recorded in the PIVC group. This difference was not statistically significant (p=0.18). Treatmentrelated deaths are summarised in Table 3.

Because the frequency of monitoring of leucocyte counts was highly variable, we determined the proportion of participants who became leucopenic at any time during therapy, rather than the leucopenia event rate.

The lowest recorded leucocyte counts were significantly lower in the DOC group, with a median of 3.8 v. 5.3 × 109/L (p=0.02) (Table 4).

Leucopenia also occurred later in the DOC group than in the PIVC group (99 v. 76 days; p=0.04) and at higher cumulative doses (mean 3 542 v. 1 929 mg; p<0.01). Notably, neutrophil counts were infrequently done.

Comparing the DOC and PIVC groups, 51.1% v. 33.3% (p=0.06) of participants developed leucopenia during treatment. The mean duration of leucopenia before the CPM dose was adjusted or the drug stopped was 5 days, with a maximum delay of up to 28 days. However, delays in stopping CPM appeared not to have contributed to any of the leucopenia-related deaths.

Discussion

Adverse events due to the use of CPM were frequent in both groups, emphasising

RESEARCH

Table 3. Leucopenia-related deaths Age (years), gender

Diagnosis

Duration of treatment (days)

Lowest leucocyte count (× 109/L)

Cause of death

41, F

Mesangiocapillary GN with crescents

59

0.79

Varicella zoster pneumonia

21, F

SLE with class IV nephritis and myocarditis

21

3.31

Severe pneumonia and renal failure*

23, F

SLE with class IV nephritis

69

0.54

CMV pneumonitis

51, F

Crescentic GN

25

0.65

Neutropenic sepsis (unknown source)

37, F

SLE with class IV nephritis and myocarditis

31

1.58

CMV pneumonitis

30, F

SLE with class IV nephritis

49

0.34

Overwhelming Acinetobacter baumannii sepsis†

SLE = systemic lupus erythematosus; CMV = cytomegalovirus. *Subject had renal failure, which significantly contributed to death. † Leucocyte count at baseline 2.66 × 109/L.

the reality that CPM is a potent cytotoxic drug that should be prescribed with caution and with careful follow-up and monitoring.

To our knowledge this is the first study from a developing country comparing DOC and PIVC. Other studies have reported leucopenic episodes in 17 - 26% of PIVC and 19 - 45% of DOC participants[7,14,16] and infection in 10 - 39% of PIVC and 14 - 57% of DOC participants.

Similar infection rates were observed in our study (DOC 36% v. PIVC 43%), while leucopenia was more frequent (DOC 51% v. PIVC 33%).

In our setting, it appears that PIVC may be safer than DOC. Six treatment-related deaths occurred in the DOC group and none in the PIVC group, although this difference was not statistically significant.

DOC was also associated with more frequent and more severe leucopenia, and with a non-significant increase in hospitalisations suggesting more serious infections, while PIVC was associated with a non-significant increased frequency of all infections.

The participants in the DOC group were treated for a significantly longer time and may therefore have been more likely to experience adverse events. Most adverse events in our study, as in other studies,[16] occurred early in the course of treatment.

It is important to appreciate that in our study the condition being treated determined the route of CPM administration and, by default, also selected for differences in management. Different teams of clinicians and differences in follow-up and monitoring may therefore have affected the results.

The high cumulative doses used in the DOC group could have increased efficacy, but are the likely explanation for the increased risk of leucopenia associated with DOC. Another factor was that PIVC was only administered if there was an acceptable leucocyte count on the day of each pulse infusion. With DOC, a leucocyte count before every dose is not feasible. There was some variability in the frequency of leucocyte counts done in the DOC group. Counts were not always available at the time of follow-up, and were occasionally only reacted to at the next visit. PIVC is perceived as high-dose intravenous chemotherapy and instinctively enforces caution and meticulous follow-up. DOC may be perceived as less potent and not elicit the same careful follow-up by those not familiar with its serious side-effect profile.

This study has identified the need to critically evaluate the current practice of CPM administration at our institution. Most drugattributable deaths and infections occurred early in the course of treatment; it is therefore strongly suggested that leucocyte counts be monitored more frequently soon after initiation of CPM, and that same-day leucocyte counts be available at all follow-up visits. The paucity of neutrophil counts was disappointing. Differential leucocyte counts should be requested routinely, as severe neutropenia may be

213

Table 4. Lowest recorded leucocyte count in participants who developed leucopenia

Severity class*

All n (%)

DOC n (%)

PIVC n (%)

1 (3.01 - 4.00)

20 (32.8)

14 (29.8)

6 (42.9)

2 (2.01 - 3.00)

13 (21.3)

8 (17.0)

5 (35.7)

3 (1.01 - 2.00)

13 (21.3)

11 (23.4)

2 (14.3)

4 (<1.00)

9 (14.8)

8 (17.0)

1 (7.1)

5 (death)

6 (9.8)

6 (12.8)

0 (0.0)

*Leucocyte count (× 109/L) according to Common Terminology Criteria for Adverse Events.[21]

masked by other cell lines in mild leucopenia if only total leucocyte counts are requested.

An unexpected finding was that no new episodes of TB were documented in any participant. This is especially noteworthy considering the high prevalence of TB of up to 32/1 000 population in communities serviced by this hospital.[20] This suggests that current screening protocols for active TB prior to initiation of CPM and the regular use of isoniazid prophylaxis are effective. Cyclomegalovirus (CMV) pneumonitis was a significant opportunistic infection in the DOC group and a cause of leucopenia-associated death. Patients on CPM who present with leucopenic sepsis should be screened and treated early (and probably empirically) for CMV infection.

Current evidence to support prophylactic antiviral treatment for CMV is lacking, and it is unlikely to be cost-effective in a resourceconstrained setting. Consideration could be given to determining patients’ CMV status prior to CPM initiation. Knowing the baseline CMV serology and viral load may aid in the decision whether or not to treat for suspected CMV disease when patients on CPM present with leucopenia and signs of infection. However, the costeffectiveness of such an approach would need to be determined.

Alarmingly, almost 10% of participants initiated on CPM were lost to follow-up immediately after discharge from hospital. Another 10% were lost to follow-up later in the study. Considering the poor prognosis of the underlying conditions if left untreated, it is possible that many of these patients died as a result of their autoimmune disease.

However, adverse events due to CPM are probably a contributing factor.

The need for excellent record keeping and tracking of patients on CPM must be emphasised, and clinic staff should be prompted to contact patients should a follow-up visit be missed.

If resources allow, consideration should be given to the greater use of PIVC where its use in the treatment of the specific condition in

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question is supported by current literature. This would be especially useful in cases where compliance with daily medication is in doubt.

Owing to the differences in conditions treated, we did not evaluate the efficacy of treatment, which might be the decisive factor in choosing between DOC and PIVC. As pointed out, in many conditions there is a lack of compelling evidence regarding efficacy to preferentially advocate the use of DOC or PIVC.

Study limitations

This study relied on the completeness and accuracy of TBAHâ&#x20AC;&#x2122;s pharmacy database to identify all patients receiving CPM during the study period. The study was retrospective with data extracted from patient records. A heterogeneous group of conditions were included and allocation to PIVC and DOC was not random but determined by the disease process and the preference of the clinicians involved (rheumatology v. nephrology). The primary disease process as well as differences in practices by clinicians are likely to influence treatment outcomes and risk of adverse events. The long-term complications of CPM (e.g. bladder toxicity, infertility) were not studied.

Conclusion

This study has provided new data on adverse events due to CPM in a developing world setting with a very high burden of infectious diseases. We found that a greater proportion of participants receiving DOC developed severe leucopenia, which may be explained by the higher cumulative doses taken over longer periods. There was, however, no significant difference in the proportions of participants who developed infections or required hospitalisation as a consequence.

Six participants in the DOC group and none in the PIVC group died as a result of complications of CPM treatment; this difference was not statistically significant.

Local randomised trials are needed to compare PIVC and DOC where follow-up is standardised and where homogeneous groups of conditions are compared. This will provide not only more data with regard to safety, but also much-needed data on differences in treatment outcomes.

Acknowledgements. We thank Ms Rhadika Muruvan for help in providing pharmacy data and Dr Justin Harvey from the Stellenbosch University Centre for Statistical Consultation for assistance with data analysis.

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References 1. Flossmann O, Berden A, de Groot K, et al. Long-term patient survival in ANCA-associated vasculitis.

Ann Rheum Dis 2011;70(3):488-494. [http://dx.doi.org/10.1136/ard.2010.137778] 2. Urowitz MB, Gladman DD, Tom BD, Ibanez D, Farewell VT. Changing patterns in mortality and disease outcomes for patients with systemic lupus erythematosus. J Rheumatol 2008;35(11):2152-2158. [http://dx.doi.org/10.3899/jrheum.080214] 3. Hebert LA, Rovin BH. Oral cyclophosphamide is on the verge of extinction as therapy for severe autoimmune diseases (especially lupus): Should nephrologists care? Nephron Clin Pract 2011;117(1):c8-c14. [http://dx.doi.org/10.1159/000319641] 4. McKinley A, Park E, Spetie D, et al. Oral cyclophosphamide for lupus glomerulonephritis: An underused therapeutic option. Clin J Am Soc Nephrol 2009;4(11):1754-1760. [http://dx.doi. org/10.2215/CJN.02670409] 5. Austin HA 3rd, Klippel JH, Balow JE, et al. Therapy of lupus nephritis: Controlled trial of prednisone and cytotoxic drugs. N Engl J Med 19866;314(10):614-619. [http://dx.doi.org/10.1056/ NEJM198603063141004] 6. Bargman JM. How did cyclophosphamide become the drug of choice for lupus nephritis? Nephrol Dial Transplant 2009;24(2):381-384. [http://dx.doi.org/10.1093/ndt/gfn640] 7. Yee CS, Gordon C, Dostal C, et al. EULAR randomised controlled trial of pulse cyclophosphamide and methylprednisolone versus continuous cyclophosphamide and prednisolone followed by azathioprine and prednisolone in lupus nephritis. Ann Rheum Dis 2004;63(5):525-529. [http://dx.doi.org/10.1136/ ard.2002.003574] 8. Bansal VK, Beto JA. Treatment of lupus nephritis: A meta-analysis of clinical trials. Am J Kidney Dis 1997;29(2):193-199. [http://dx.doi.org/10.1016/S0272-6386(97)90029-9] 9. Henderson L, Masson P, Craig JC, et al. Treatment for lupus nephritis. Cochrane Database Syst Rev 2012;12:CD002922. [http://dx.doi.org/10.1002/14651858.CD002922.pub3] 10. Mok CC, Ho CT, Siu YP, et al. Treatment of diffuse proliferative lupus glomerulonephritis: A comparison of two cyclophosphamide-containing regimens. Am J Kidney Dis 2001;38(2):256-264. [http://dx.doi.org/10.1053/ajkd.2001.26084] 11. Dede F, Ayili D, Sahiner S. Effective treatment administration of cyclophosphamide in membranous nephropathy. J Nephrol 2008;21(4):560-565.

12. Guillevin L, Cordier JF, Lhote F, et al. A prospective, multicenter, randomized trial comparing steroids and pulse cyclophosphamide versus steroids and oral cyclophosphamide in the treatment of generalized Wegenerâ&#x20AC;&#x2122;s granulomatosis. Arthritis Rheum 1997;40(12):2187-2198 [http://dx.doi. org/10.1002/art.1780401213] 13. Harper L, Morgan MD, Walsh M, et al. Pulse versus daily oral cyclophosphamide for induction of remission in ANCA-associated vasculitis: Long-term follow-up. Ann Rheum Dis 2012;71(6):955-960. [http://dx.doi.org/10.1136/annrheumdis-2011-200477] 14. De Groot K, Adu D, Savage CO, EUVAS (European Vasculitis Study Group). The value of pulse cyclophosphamide in ANCA-associated vasculitis: Meta-analysis and critical review. Nephrol Dial Transplant 2001;16(10):2018-2027. [http://dx.doi.org/10.1093/ndt/16.10.2018] 15. Haubitz M, Schellong S, Gobel U, et al. Intravenous pulse administration of cyclophosphamide versus daily oral treatment in patients with antineutrophil cytoplasmic antibody-associated vasculitis and renal involvement: A prospective, randomized study. Arthritis Rheum 1998;41(10):1835-1844 [http:// dx.doi.org/10.1002/1529-0131(199810)41:10<1835::AID-ART16>3.0.CO;2-Q] 16. De Groot K, Harper L, Jayne DR, et al. Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: A randomized trial. Ann Intern Med 2009;150(10):670-680. [http://dx.doi.org/10.7326/0003-4819-150-10-200905190-00004] 17. Gayraud M, Guillevin L, Cohen P, et al. Treatment of good-prognosis polyarteritis nodosa and ChurgStrauss syndrome: Comparison of steroids and oral or pulse cyclophosphamide in 25 patients. French Cooperative Study Group for Vasculitides. Br J Rheumatol 1997;36(12):1290-1297. [http://dx.doi. org/10.1093/rheumatology/36.12.1290] 18. Haubitz M, Ehlerding C, Kamino K, Koch KM, Brunkhorst R. Reduced gonadal toxicity after i.v. cyclophosphamide administration in patients with nonmalignant diseases. Clin Nephrol 1998;49(1):19-23.

19. Davas EM, Peppas C, Maragou M, Alvanou E, Hondros D, Dantis PC. Intravenous cyclophosphamide pulse therapy for the treatment of lung disease associated with scleroderma. Clin Rheumatol 1999;18(6):455-461. [http://dx.doi.org/10.1007/s100670050138] 20. Claassens M, van Schalkwyk C, den Haan L, et al. High prevalence of tuberculosis and insufficient case detection in two communities in the Western Cape, South Africa. PLoS One 2013;8(4):e58689. [http:// dx.doi.org/10.1371/journal.pone.0058689] 21. CTCAE Files. http://evs.nci.nih.gov/ftp1/CTCAE/About.html (accessed 30 July 2014).

Accepted 12 January 2015.

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Prevalence and causes of thrombocytopenia in an academic state sector laboratory in Soweto, Johannesburg, South Africa J L Vaughan, MB BCh, FCPath (Haem) (SA), MMed (Haem); J Fourie, MB ChB; S Naidoo, MB BCh; N Subramony, MB ChB; T Wiggill, MB BCh, MMed (Haem); N Alli, MB BCh, FCPath (Haem) (SA) Department of Molecular Medicine and Haematology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa, and National Health Laboratory Service, Johannesburg Corresponding author: J Vaughan (jenifer.vaughan@nhls.ac.za)

Background. Causes of thrombocytopenia range from laboratory errors to life-threatening pathological conditions. To establish the cause, appropriate laboratory investigation is required.

Objectives. To determine the prevalence and causes of platelet counts <100 × 109/L in state health facilities in Johannesburg, South Africa, as well as the quality of the subsequent laboratory work-up in this setting.

Methods. Full blood counts (FBCs) performed on 7 randomly selected days at the National Health Laboratory Service laboratory at Chris Hani Baragwanath Academic Hospital were retrospectively reviewed. Samples with platelet counts <100 × 109/L were identified, and pertinent information was extracted from the laboratory database.

Results. Of 4 456 FBCs included, 381 (8.6%) had a platelet count of <100 × 109/L. Thrombocytopenia prevalence rates were high in haematology/oncology wards (34.4%), intensive care units (20.5%) and medical wards (18.7%) and among neonatal inpatients (16.5%), and were lowest in outpatient clinics (1 - 2%). A cause was apparent in ~60% of patients, the commonest causes being chemotherapy and sepsis (each comprising >20% of the recognised causes). Spurious thrombocytopenia, disseminated tuberculosis, aplastic anaemia, immune thrombocytopenia and malignant marrow infiltration each accounted for 5 - 10% of the causes, while malaria, thrombotic thrombocytopenic purpura, HIV effect and liver disease were each identified in <5% of cases. HIV status was documented in ~70% of the patients, of whom ~50% tested positive. The quality of the laboratory work-up showed differences between specialties within the hospital setting, and was poorest in the primary healthcare clinic sector.

Conclusion. Thrombocytopenia is common in hospitalised patients in the Johannesburg academic state sector. Differences in the quality of the laboratory work-up emphasise the need for a standardised approach to thrombocytopenia investigation and increased awareness among clinicians.

S Afr Med J 2015;105(3):215-219. DOI:10.7196/SAMJ.8791

The full blood count (FBC) is among the most frequently requested laboratory tests, and a low platelet count is a common finding. Thrombocytopenia is defined as a platelet count below the normal reference range (~150 × 109/L in adults), but is most clinically significant when the platelet count is <100 × 109/L.[1] The causes of thrombocytopenia range from laboratory errors to life-threatening medical emergencies, and appropriate laboratory investigation is indicated in its work-up. First-line testing includes a differential white cell count and peripheral blood smear microscopy, which serve as a guide for further investigation. This could include bone marrow aspirate and trephine biopsy examination, exclusion of an underlying coagulopathy, and testing for a variety of infections.[1,2] In the South African (SA) context, exclusion of HIV infection is particularly important, as this may cause thrombocytopenia through several mechanisms. These include involvement of the bone marrow by opportunistic infections and malignancies and increased incidences of immune thrombocytopenia (ITP) and thrombotic thrombocytopenic purpura (TTP), as well as impaired platelet production as a result of both HIV-associated stromal cell dysfunction[3] and direct HIV infection of megakaryocytes.[4] The aims of this study were to determine: (i) the prevalence and causes of platelet counts <100 × 109/L in the state sector in Johannesburg, SA, with emphasis on the effect of HIV infection; and

215

(ii) the adequacy of the subsequent laboratory investigation. For this purpose, FBCs performed at the National Health Laboratory Service laboratory at Chris Hani Baragwanath Academic Hospital (CHBAH) were retrospectively reviewed. This laboratory serves several strata of public health services in Soweto, Johannesburg, ranging from over 50 primary healthcare (PHC) clinics to CHBAH.

Methods

Sample selection and data collection

FBCs performed on 7 non-consecutive days in 2012 were extracted from the laboratory information system (DisaLab Version 04.16.04.373). Sample selection was random, but in order to avoid temporal bias with respect to the prevalence or causes identified, each day of the week as well as each season of the year were equally represented. Samples with platelet counts <100 × 109/L were identified, and details available in patients’ laboratory histories recorded. These included the clinical history, demographic details, evidence of infection (including HIV), presence of a coagulopathy, peripheral blood and bone marrow microscopy findings, and the results of any other investigations judged to be pertinent. The cause for the thrombocytopenia (if apparent) was documented, and the adequacy of the laboratory work-up judged in accordance with previously published recommendations.[1,2] Peripheral blood

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Table 1. Patient epidemiological data, location and TP Platelet count >100 × 109/L (N1 = 4 075) n (%)

Platelet count <100 × 109/L (N2 = 381) n (%)

TP N2/(N1 + N2) (%)

p-value¶

Age (years), mean (SD)

37.6 (0.6)*

30.6 ( 2.1)

N/A

<0.0001

WCC (× 109/L), mean (SD)

8.32 (0.18)

9.77 (3.5)

N/A

0.019

Hb (g/dL), mean (SD)

11.8 (0.1)

9.8 (0.3)

N/A

<0.0001

All patients

-

-

381/4 456 (8.6)

N/A

Medical

479 (11.8)

110 (28.9)

110/589 (18.7)

<0.0001

Surgical

493 (12.1)

26 (6.8)

26/519 (5.0)

0.002

Obstetrics/gynaecology

252 (6.2)

19 (5.0)

19/ 271 (7.0)

0.35

Haematology/oncology

168 (4.1)

88 (23.1)

88/256 (34.4)

<0.0001 0.28

†

Paediatrics

186 (4.6)

15 (3.9)

15/201 (7.5)

Neonatal wards

129(3.2)

23 (6.3)

23/152 (16.5)

0.0005

ICU§

159 (3.9)

41 (10.8)

41/200 (20.5)

<0.0001

Casualty

234 (5.7)

10 (2.6)

10/244 (4.1)

0.013

Miscellaneous outpatient clinics

956 (23.5)

17 (4.4)

17/973 (1.7)

<0.0001

PHC clinics

824 (20.2)

12 (3.1)

12/836 (1.4)

<0.0001

‡

WCC = white cell count; Hb = haemoglobin value; N/A= not applicable. *N=4 006. † N=378. ‡ Excluding neonates, paediatric oncology and ICU. § Includes maternity high-care and coronary care units. ¶ Statistically significant results are shown in bold.

smear review was regarded as a minimum essential additional test.

Investigations for infection-related causes of thrombocytopenia (such as bacterial sepsis, viral hepatitis, etc.) were similarly regarded as mandatory in cases where a cause was not apparent from either the peripheral smear or the clinical history. In the presence of red cell fragments on the peripheral smear or any clinical risk factors for disseminated intravascular coagulation (DIC) (such as sepsis, trauma, etc.), a coagulopathy screen was considered to be indicated (except in neonates), and if ITP was the favoured cause for the low platelet count, testing for secondary causes (such as an underlying autoimmune pathology or viral infection, particularly viral hepatitis) was judged necessary. The need for further investigation (such as a bone marrow aspirate and trephine biopsy) was judged on a case-by-case basis.

Analysis was conducted by medical staff (consultants and registrars) in the Department of Molecular Medicine and Haematology at the University of the Witwatersrand, Johannesburg, and the study was approved by the university’s human research ethics committee.

Assessment of work-up adequacy

The thrombocytopenia work-up was considered adequate if the cause for the thrombocytopenia was discovered and/or all the indicated laboratory investigations were performed. If only some of the investigations were performed, the work-up was judged to be partially adequate, and if no additional laboratory investigation was performed, it was considered inadequate. Although HIV testing is a crucial component of thrombocytopenia investigation in SA, this was excluded from our analysis of work-up adequacy because it was not possible to determine which patients were known to be HIV-positive from previous testing at an alternative site.

Statistical analysis

Statistical analysis was performed using Statistica software, version 12.0 (StatSoft (Pty) Ltd). Continuous data are presented as means (standard deviation (SD)) and categorical data as frequencies and

216

percentages. Means were compared using Student’s t-test, and cate­ gorical variables using the χ2 statistic or Fisher’s exact test when necessary. Multivariate logistic regression was performed to deter­ mine predictors of the presence of a coagulopathy. Data were presented as odds ratios (ORs) with 95% confidence intervals (CIs).

Statistical significance was accepted at a two-sided p-value of ≤0.05.

Results

Thrombocytopenia prevalence (TP)

A total of 4 456 FBCs were extracted from the laboratory data­ base, of which 381 (8.6%) had platelet counts <100 × 109/L. The registered patient locations included inpatient, outpatient and casualty facilities of CHBAH, as well as PHC clinics in Soweto (Table 1). Thrombocytopenia was most commonly encountered in the haematology/oncology wards/clinic, in the intensive care units (ICUs) and among medical and neonatal inpatients, where the TP rates were 34.4%, 20.5%, 18.7% and 16.5%, respectively. Conversely, thrombocytopenia was least frequent in patients seen in nonhaematology/oncology outpatient (TP 1.7%) and PHC clinic facilities (TP 1.4%) (Table 1).

Causes of thrombocytopenia identified

Fifteen of the original samples with thrombocytopenia were found to be repeat specimens collected from the same patient on the same day, and these were excluded from further analysis. For the remaining 366 patients, a cause for the thrombocytopenia was apparent from the laboratory records in 229 (62.6%), unclear in 95 (26.0%) and completely unknown in 42 (11.5%). Chemotherapy and sepsis together comprised >40% of the causes identified. Spurious thrombocytopenia, disseminated tuberculosis involving the bone marrow (BMTB), aplastic anaemia, ITP and a malignant marrow infiltration each accounted for 5 - 10% of the causes, while malaria, TTP, HIV effect and liver disease were each present in <5% of cases (Table 2).

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Table 2. Causes of thrombocytopenia identified Total cohort with a cause identified (N=229) n (%)

Causes identified in patients with known HIV status HIV-positive (N=83) v. HIV negative (N=99), n (%); p-value‡

Chemotherapy*

47 (20.5)

15 (18.1) v. 26 (26.3); 0.13

Sepsis

56 (24.5)

21 (25.3) v. 16 (16.2); 0.09

Spurious thrombocytopenia

13 (5.7)

4 (4.8) v. 1 (1.0); 0.13

TTP

4 (1.7)

3 (3.6) v. 1 (1.0); 0.25

Malaria

7 (3.1)

0 (0.0) v. 3 (3.0); 0.16

Malignant marrow infiltrate

17 (7.4)

3 (4.8) v. 14 (14.1); 0.013

ITP

19 (8.3)

8 (9.6) v. 11 (11.1); 0.5

Aplastic anaemia

22 (9.6)

3 (3.6) v. 19 (19.2); 0.0009

BMTB

16 (7.0)

16 (19.3) v. 0 (0.0); <0.0001

HIV effect†

6 (2.6)

6 (7.2) v. 0 (0.0); 0.008

Liver disease

8 (3.5)

2 (2.4) v. 2 (2.0); 0.6

*Chemotherapy was used in HIV-positive patients, predominantly in the treatment of high-grade lymphoma. † These patients had HIV-related bone marrow changes without any other cause for the low platelet count identified. ‡ Statistically significant results are shown in bold.

HIV test results were available in 261 (71.3%) of the patients with a low platelet count, of whom just under half tested positive. BMTB was significantly more prevalent among the HIVpositive patients than among those who were negative (Table 2), while thrombocytopenia due to aplastic anaemia and a malignant marrow infiltrate were seen more often in HIV-negative patients. All patients who had BMTB were HIVpositive, with evidence of AIDS in all those in whom a CD4 count was available.

Hepatitis B and C serology was performed in 84 (23.0%) and 73 (20.0%) of the 366 patients, respectively. Of these, 11/84 (13.1%) tested positive for hepatitis B surface antigen and 4/73 (5.5%) for hepatitis C. The cause of the thrombocytopenia was evident in 12/15 (80.0%) of the patients with either hepatitis B or C; of these, 5/12 (41.7%) had evidence of liver disease, 2/12 (16.7%) and 2/12 (16.7%) had BMTB or a malignancy, respectively, and only 1/12 (8.3%) had ITP. Of interest was that none of the patients with aplastic anaemia was proven to be either hepatitis B- or C-positive.

Laboratory work-up

Peripheral blood smear review was per­ formed in 292 patients (79.8%), and 102

(27.9%) had had a recent bone marrow aspirate and trephine biopsy. Cultures of a variety of specimen types were performed in 232 patients (63.4%), of whom 33 (14.2%) had documented evidence of bac­ terial infection. Coagulation testing was requested in 150 patients (41.0%) and revealed some evidence of a coagulopathy in 35 (23.3%) of the tested patients. Of note was that coagulation testing was performed in only 48.6% of patients with documented sepsis (excluding neonatal patients).

Multivariate logistic regression revealed significant independent associations between the presence of a coagulopathy and sepsis (OR 4.5 (95% CI 3.9 - 5.0); p=0.006), liver disease (OR 34.3 (95% CI 33.0 - 35.5); p=0.005) and BMTB (OR 5.3 (CI 4.7 - 6.0); p=0.017).

Adequacy of laboratory work-up

Laboratory work-up was judged to be adequate in 181 patients (49.5%), partially adequate in 143 (39.1%) and completely inadequate in 42 (11.5%). Investigation was most complete in neonatal and haematology/ oncology patients, where the work-up was adequate in >80% of cases. Completely

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inadequate work-up very seldom occurred in paediatric and ICU patients (<1% and 2.7%, respectively). Work-up was generally suboptimal in surgical inpatients and those seen in non-haematology outpatient clinics, both of which had an inadequate work-up in >25% of cases. Work-up was very poor in patients seen in PHC clinics, with >90% having a completely inadequate work-up (Table 3). Reasons for work-up inadequacy varied, but important contributors included omission of peripheral blood smear review in 70 patients (37.8% of those with an incomplete work-up). This was most striking in patients seen in PHC clinics, where peripheral smear review was performed in only one patient. There was failure to screen for a coagulopathy in 118 (63.7%) of the 185 patients with an incomplete work-up, with a full DIC screen performed in only eight (4.3%) of these patients (Table 3). Among the patients with an incomplete work-up, the omission of a coagulopathy screen was relatively more common in medical patients, while testing in ICU, surgical or haematology/oncology patients was generally carried out more frequently.

Discussion

This study reveals that thrombocytopenia is common among hospitalised patients in the Johannesburg academic state sector, particularly among haematology/oncology patients, neonatal inpatients and patients admitted to medical wards or ICUs. In contrast, a low platelet count is unusual in patients seen in PHC clinics or nonhaematology/oncology outpatient clinics, being present in only 1 - 2% of the FBCs received from these locations. However, since >40% of the FBCs processed at the CHBAH laboratory were received from outpatient or PHC clinics, patients attending these facilities comprised a relatively substantial proportion of all cases of thrombocytopenia.

Although the study is somewhat compromised by a paucity of clinical information, the critical role of laboratory testing allowed for determination of the cause of the low platelet count in 62% of the patients based on a review of laboratory records, as well as for evaluation of the adequacy of the laboratory work-up.

Since CHBAH is a haematology referral centre, chemotherapy effect and primary haematological causes of thrombocytopenia (such as aplastic anaemia and malignant marrow infiltration) were prominent in this cohort, collectively comprising some 40% of the low platelet counts seen. Although malaria and TTP are often emphasised as

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Table 3. Analysis of adequacy of laboratory work-up

Adequate work-up frequency n/N (%); p-value

Frequency of coagulation testing omission among patients with an incomplete work-up n/N (%); p-value

Frequency of peripheral smear review omission among patients with an incomplete work-up n/N (%); p-value

42/366 (11.5); N/A

181/366 (49.5); N/A

118/185 (63.8); N/A

70/185 (37.8); N/A

Medical

9/107 (8.4); 0.16

41/107 (38.3); 0.004

40/65 (61.5); 0.38

14/65 (21.5); 0.0005

Surgical

6/23 (26.1); 0.036

8/23 (34.8); 0.11

2/15 (13.3); <0.0001

7/15 (46.7); 0.32

Obstetrics/gynaecology

2/19 (10.5); 0.62

4/19 (21.0); 0.009

7/15 (46.7); 0.12

4/15 (26.7); 0 .26

Haematology/oncology (adult and paediatric)

1/86 (1.2) 0.0001

74/86 (86.0); <0.0001

8/12 (33.3); 0.027

0/12 (0.0); 0.026

Paediatrics†

0/13 (0.0); 0.2

8/13 (61.5); 0.27

4/5 (80.0); 0.4

1/5 (20.0); 0.37

Neonatal wards

0/23 (0.0); 0.055

23/23 (100.0); <0.0001

N/A

N/A

ICU‡

1/37 (2.7); 0.055

12/37 (32.4); 0.02

10/25 (40.0); 0.008

14/25 (56.0); 0.26

Miscellaneous outpatient clinics

5/16 (31.3); 0.026

6/16 (37.5); 0.24

8/10 (80.0); 0.23

5/10 (50.0); 0.31

PHC clinics

11/12 (91.7); <0.0001

1/12 (8.3); 0.003

5/11 ( 45.6) 0.16

11/11 (100.0) <0.0001

Completely inadequate work-up frequency n/N (%); p-value* All patients

N/A= not applicable. *p-values are derived from Fisher’s exact analysis of each group v. the rest of the cohort. Statistically significant results are shown in bold. † Excluding neonates, paediatric oncology and ICU. ‡ Includes maternity high-care and coronary care units.

causes of thrombocytopenia, they proved comparatively rare, each accounting for <5% of the thrombocytopenic samples. Among the HIV-positive patients, common causes of thrombocytopenia included chemotherapy for high-grade lymphomas, BMTB and sepsis. Interestingly, although both ITP and TTP are well-described causes of HIV-associated thrombocytopenia, the prevalence rates of these diseases did not differ between HIV-positive and negative patients in this cohort, possibly in part because of small sample sizes.

HIV status was documented in approximately 70% of the patients, of whom just under half were HIV-positive. This is not surprising given the high background prevalence of HIV in the SA population, as well as the strong association between HIV infection and thrombocytopenia. In contrast, hepatitis B and C positivity were uncommon, and presented most frequently in patients with thrombocytopenia attributable to chronic liver disease. However, as most patients were not tested for hepatitis B and C, their roles in the pathogenesis of thrombocytopenia in this setting remain unclear.

Nonetheless, we noted with interest that none of the patients with aplastic anaemia had viral hepatitis, and only one patient with ITP tested seropositive for hepatitis C. Among the hospitalised patients, laboratory work-up was judged to be good in the majority of paediatric and ICU patients as well as in neonates and haematology/oncology patients. In contrast, workup was generally suboptimal in patients seen in outpatient clinics or admitted to surgical wards, and was very poor in patients seen at PHC clinics. While it is possible that some of the latter patients

218

might have been transferred to an alternative hospital for work-up, this finding could reflect a deficiency in the clinical approach to thrombocytopenia among healthcare workers at primary facilities.

Further studies in this regard would be of interest. Of concern is that among the common reasons for the work-up being judged incomplete was the absence of peripheral blood smear review, which was omitted in ~20% of patients. As it is a laboratory policy to review a blood film in samples with a platelet count <100 × 109/L, this finding highlights deficiencies in both the clinical and laboratory services, possibly as a result of the pressures of high case volumes and a skills shortage in both these settings. Also of note was that investigation for coagulopathy was poor, being requested in just over 40% of all patients. This is of particular concern in view of the fact that DIC is an important cause for thrombocytopenia in patients with sepsis, the prevalence of which was high in our cohort. DIC is associated with a high mortality rate and may necessitate fresh-frozen plasma and/or cryoprecipitate infusion. It is therefore important that a coagulopathy screen (including an INR, PTT, fibrinogen level and D-dimer assay) be performed in all patients with thrombocytopenia in the presence of any of its possible precipitants, including sepsis.[5,6] Not unexpectedly, we found an independent association between the presence of laboratory evidence of a coagulopathy and the presence of both chronic liver disease and sepsis. Of interest was that an association was also evident in patients with BMTB, suggesting that a consumptive coagulopathy (such as DIC) is a likely contributor to the low platelet count frequently seen in these patients. This is supported by the normal megakaryocyte numbers

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as well as the raised immature platelet fraction (a parameter that reflects increased platelet production) seen in many patients with BMTB.[7]

Conclusion

Thrombocytopenia was found to be common in hospitalised patients in the academic state sector in Johannesburg, but relatively rare in the outpatient setting. Chemotherapy and sepsis were identified as the commonest causes, irrespective of HIV status. The quality of laboratory work-up was found to be poorest in the PHC clinic sector, and varied between disciplines within the hospital setting. The findings emphasise the need for a standardised approach to thrombocytopenia investigation and increased awareness on the part of clinicians, most particularly among PHC providers and those working in surgical disciplines.

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References 1. Stasi R. How to approach thrombocytopenia. Hematology Am Soc Hematol Educ Program 2012;2012:191-197. [http://dx.doi.org/10.1182/asheducation-2012.1.191] 2. Sekhon SS, Roy V. Thrombocytopenia in adults: A practical approach to evaluation and management.

South Med J 2006;99(5):491-498; quiz 499-500, 533. [[http://dx.doi.org/10.4021/jh28w] 3. Schwartz G, Kessler SW, Rothwell SW, et al. Inhibitory effects of HIV-1-infected stromal cell layers on the production of myeloid progenitor cells in human long-term bone marrow cultures. Exp Hematol 1994;22(13):1288-1296.

4. Sakaguchi M, Sato T, Groopman JE. Human immunodeficiency virus infection of megakaryocytic cells.

Blood 1991;77(3):481-485.

5. Hunt BJ. Bleeding and coagulopathies in critical care. N Engl J Med 2014;370(9):847-859. [http:// dx.doi.org/10.1056/NEJMra1208626] 6. Levi M. Current understanding of disseminated intravascular coagulation. Br J Haematol 2004;124(5):567-576. [[http://dx.doi.org/10.1046/j.1365-2141.2003.04790.x].

7. Vaughan J, Wiggill T, Munster M. Immature platelet fraction levels in a variety of bone marrow pathologies in South African HIV-positive patients with thrombocytopenia. Hematology 2014;19(7):417-423. [http://dx.doi.org/10.1179/1607845413Y.0000000143]

Accepted 13 October 2014.

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Short-term treatment outcomes of children starting antiretroviral therapy in the intensive care unit, general medical wards and outpatient HIV clinics at Red Cross War Memorial Children’s Hospital, Cape Town, South Africa: A retrospective cohort study V Pillay,1 MB ChB, MPH, DCH, Dip HIV Man; M-A Davies,2 MB ChB, MMed, FCPHM (SA), PhD; S King,1 APCN; B Eley,1 MB ChB, FCPaed, BSc (Hons) aediatric Infectious Diseases Unit, Red Cross War Memorial Children’s Hospital and Department of Paediatrics and Child Health, P Faculty of Health Sciences, University of Cape Town, South Africa 2 School of Public Health and Family Medicine, Faculty of Health Sciences, University of Cape Town, South Africa 1

Corresponding author: V Pillay (vash.pillay@uct.ac.za) Background. Many HIV-infected children are initiated on antiretroviral therapy (ART) during hospitalisation in South Africa (SA). No published data on these outcomes exist.

Objectives. To assess the short-term outcomes of children initiated on ART in the intensive care unit (ICU), general medical wards (GMWs) and outpatient HIV clinics (OHCs) at Red Cross War Memorial Children’s Hospital (RCWMCH), Cape Town, SA. Methods. We conducted a retrospective cohort study of HIV-infected children aged <13 years commenced on first-line ART between January 2008 and December 2011. Outcomes included death, virological suppression and changes in CD4 count. Kaplan-Meier estimates, multivariate Cox proportional hazard ratios and logistic regression were used to estimate outcomes at 6 months.

Results. One hundred and six children were commenced on ART in the ICU, 509 in the GMWs and 127 in the OHCs; 65.7% of all children were <12 months old. Of children qualifying for rapid ART initiation according to the 2013 national treatment guidelines, 182 (24.9%) started therapy within 7 days of diagnosis. Overall mortality was 6.4% (95% confidence interval (CI) 4.9 - 8.4). Of children remaining in care at RCWMCH, 51.0% achieved a CD4 percentage ≥25% and 62.3% a viral load ≤50 copies/mL 6 months after ART initiation. Mortality was higher in the ICU cohort (13.2%) than in the GMW and OHC cohorts (5.5% and 3.9%, respectively, log-rank p=0.004). Predictors of mortality included moderate underweight (adjusted hazard ratio (aHR) 2.4; 95% CI 1.1 - 5.2), severe underweight (aHR 3.2; 95% CI 1.6 - 6.5), absence of caregiver counselling sessions (aHR 2.9; 95% CI 1.4 - 6.0) and ART initiation in the ICU (aHR 2.6; 95% CI 1.4 - 4.9).

Conclusion. These results highlight the importance of understanding the context in which children are initiated on ART, when comparing outcomes in different settings.

S Afr Med J 2015;105(3):220-227. DOI:10.7196/SAMJ.8950

The majority of HIV-infected children manifest clinical features of disease by 12 months of age.[1,2] A pooled analysis of HIV-infected children living in Africa showed that without optimal therapy 35.2% and 52.5% died by 12 and 24 months of age, respec­tively.[3] Conversely, the Children with HIV Early Antiretroviral Therapy (CHER) Study showed that if antiretroviral therapy (ART) was commenced during the first 3 months of life in asymptomatic HIV-infected infants with limited immunological suppression, mortality risk was reduced by 76% and disease progression by 75%.[4] Consequently, treatment programmes have progressively increased access to universal ART for infected children. In South Africa (SA), ART for all HIV-infected children aged <12 months was implemented in December 2009.[5] In March 2013, this policy was extended to all HIV-infected children aged <5 years, and expedited initiation of ART within 7 days of HIV diagnosis was recommended for all infants and older children with advanced clinical disease and/or severe immunosuppression.[6] Although these policy changes encouraged increased access to ART, treatment coverage has remained relatively low in SA, resulting in high hospitalisation rates among HIV-infected children due to severe comorbidity.

At the end of 2012, an estimated 63% of 220 000 children <15 years

220

of age who required therapy were actually receiving ART in SA.[7] The majority of HIV-infected children requiring hospitalisation at Red Cross War Memorial Children’s Hospital (RCWMCH), Cape Town, are ART-naïve infants, including many young infants. The median age of 1 360 children initiated on ART at RCWMCH during a 6-year period was 8 months, and 25% were ≤3 months of age.[8] Because the majority are infants with severe comorbidity, initiating ART during hospitalisation is a common clinical practice at RCWMCH.[9] With the advent of the 2013 national guidelines, it is likely that increas­ing numbers of young HIV-infected infants and children at other healthcare facilities across SA are being initiated on ART during hospitalisation. No published local studies have reported the outcomes of children initiated on ART during hospitalisation. To address this question, we examined the short-term outcomes of children initiated on ART in the intensive care unit (ICU), general medical wards (GMWs) and outpatient HIV clinics (OHCs) at RCWMCH.

Methods

Study location

This study was undertaken at RCWMCH, a tertiary referral hospital dedicated to the care of children up to 13 years of age. This includes

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Table 1. Characteristics of HIV-infected children prior to ART initiation* Patient characteristics stratified according to ART initiation location

Overall patient baseline characteristics

OHCs

GMWs

ICU

p-value

Age (months), median (IQR)

N=749 5 (3 - 23)

N=127 22 (5 - 71)

N=509 5 (3 - 21)

N=106 3 (3 - 4)

0.0001

Age categories (months), n (%)

0.0001

N=749

N=127

N=509

N=106

<3

130 (17.4)

14 (11.0)

90 (17.7)

25 (23.6)

3 - 12

362 (48.3)

37 (29.1)

247 (48.5)

72 (67.9)

13 - 60

147 (19.6)

39 (30.7)

102 (20.047)

6 (5.7)

>60

110 (14.7)

37 (29.1)

70 (13.8)

3 (2.8)

N=749

N=127

N=510

N=106

Female

379 (50.6)

60 (47.2)

258 (50.6)

57 (53.8)

Male

370 (49.4)

67 (52.8)

252 (49.4)

49 (46.2)

WAZ, median (IQR)

N=700 –2.14 (–3.42 - –0.95)

N=115 –1.14 (–2.47 - –0.23)

N=477 –2.33 (–3.56 - –1.17)

N=102 –2.48 (–3.91 - –1.37)

0.0001

WAZ categories, n (%)

0.0001

Gender, n (%)

0.61

N=700

N=115

N=477

N=102

Mild-normal

331 (47.3)

82 (71.3)

210 (44.0)

47 (46.1)

Moderate underweight

141 (20.1)

14 (12.2)

109 (22.9)

17 (16.7)

Severe underweight

228 (32.6)

19 (16.5)

167 (35.0)

38 (37.3)

HAZ, median (IQR)

N=525 –2.14 (–3.55 - –0.95)

N=121 –1.92 (–2.84 - –0.91)

N=338 –2.16 (–3.7 - –1.1)

N=61 –2.00 (–3.72 - –0.2)

0.20

HAZ categories, n (%)

0.02

N=525

N=121

N=338

N=61

Mild-normal

248 (47.2)

63 (52.1)

153 (45.8)

30 (49.2)

Moderate stunting

110 (201.0)

34 (28.1)

64 (18.9)

10 (16.4)

Severe stunting

167 (31.8)

24 (19.8)

120 (35.5)

21 (34.4)

WHZ, median (IQR)

N=446 –1.2 (–2.61 - –0.04)

N=83 –0.04 (–1.29 - –0.8)

N=297 –1.53 (–2.8 - –0.3)

N=61 –1.37 (–2.82 - –0.31)

0.0001

WHZ categories, n (%)

0.0001

N=446

N=81

N=297

N=61

Mild-normal

293 (65.7)

72 (88.9)

180 (60.6)

37 (60.7)

Moderate wasting

70 (15.7)

7 (8.6)

50 (16.8)

12 (19.7)

Severe wasting

83 (18.6)

2 (2.5)

67 (22.6)

12 (19.7)

CD4 percentage, median (IQR)

N=742 17.00 (10.0 - 24.6)

N=127 17.6 (10.4 - 24.4)

N=509 17.12 (10 - 25.3)

N=106 14.35 (8.9 - 22.5)

0.12

CD4 percentage, n (%)

0.27

N=742

N=127

N=509

N=106

≤25%

180 (24.3)

29 (22.8)

132 (25.9)

19 (17.9)

>25%

562 (75.7)

98 (77.2)

377 (74.1)

87 (82.1)

N=691

N=123

N=465

N=96

≤100 000

183 (26.5)

58 (47.2)

109 (23.4)

15 (15.6)

>100 000

508 (73.5)

65 (52.9)

356 (76.6)

81 (84.4)

N=741

N=127

N=502

N=106

Stage 1

39 (5.3)

9 (7.1)

29 (5.8)

1 (1.0)

Stage 2

62 (8.4)

19 (15.0)

40 (8.0)

3 (2.8)

Stage 3

258 (34.8)

68 (53.5)

182 (36.3)

6 (5.7)

Stage 4

382 (51.6)

31 (24.4)

251 (50.0)

96 (90.6)

N=743

N=127

N=504

N=105

None

558 (75.1)

82 (64.6)

380 (75.4)

89 (84.8)

PTB

133 (17.9)

33 (26.0)

87 (17.3)

6 (5.7)

EPTB

15 (2.0)

8 (6.3)

10 (1.98)

4 (3.8)

PTB + EPTB

37 (5.0)

4 (3.1)

27 (5.4)

6 (5.7)

VL, n (%)

WHO stage, n (%)

TB disease, n (%)

0.0001

0.0001

0.0001

Continued ...

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Table 1. (continued) Characteristics of HIV-infected children prior to ART initiation* Overall patient baseline characteristics

Patient characteristics stratified according to ART initiation location OHCs

GMWs

ICU

p-value

Time to ART initiation relative to TB rx initiation (days), median (IQR)

N=173 12 (24 - 1)

N=43 29 (92 - 16)

N=114 9 (16 - 2)

N=16 –6.5 (3 - –16)

0.0001

Time to ART initiation relative to HIV dx (days), median (IQR)

N=648 13 (7 - 38.5)

N=100 48 (26 - 250.5)

N=445 12 (7 - 28)

N=97 5 (3 - 9)

0.0001

Time to ART initiation relative to hospital admission (days), median (IQR)

N=749 7 (3 - 11)

N=127 NA

N=510 8 (6 - 13)

N=106 5 (3 - 7)

0.0001

IQR = interquartile range; PTB = pulmonary TB; rx = treatment; dx = diagnosis; NA = not applicable. *In Table 1, non-normally distributed continuous variables were analysed using the Kruskal-Wallis non-parametric test. The χ2 test of association and Fisher’s exact test were used to test associations between categorical variables.

inpatient care, intensive care and outpatient follow-up for HIV-infected children.

Table 2. Characteristics of caregivers of HIV-infected children prior to ART initiation*

Study design, inclusion criteria and baseline data collection

A retrospective cohort study was conducted.

Children <13 years of age commenced on firstline ART between January 2008 and December 2011 at RCWMCH were included. Data were extracted from the ART Microsoft Access database. Additional baseline patient clinical information and maternal information were extracted retrospectively from hospital records.

Data collected prior to starting ART included age, gender, CD4 percentage and absolute count, plasma HIV RNA concentration (viral load (VL)), growth status, World Health Organization (WHO) clinical stage, the presence of active tuberculosis (TB), and the time interval between HIV diagnosis and ART initiation. Ages were grouped into one of four categories: <3 months, 3 - 12 months, 13 - 60 months and >60 months. Mass and length/height measurements were transformed into weight-for-age z-scores (WAZ), heightfor-age z-scores (HAZ) and weight-for-height z-scores (WHZ) using the WHO 2006 Child Growth Standards.[10] Moderate underweight, stunting and wasting were defined as WAZ, HAZ and WHZ between –2 and –3, and severe underweight, stunting and wasting as WAZ, HAZ and WHZ below –3. Primary baseline clinical conditions were defined as the disease process that probably contributed to hospital admission, as determined by the attending clinician. Extrapulmonary TB (EPTB) for the purpose of this analysis was defined as a patient with TB involving organs other than the lungs such as pleura, pericardium, lymph nodes, abdomen, joints and bones and meninges.

Patients were stratified into one of three groups based on the site of ART initiation, i.e. ICU, GMWs or OHCs. Counselling of caregivers by trained paediatric ART counsellors prior to ART initiation is usually practised at RCWMCH. The aim is to impart the knowledge and

Reported maternal HIV status at ART initiation, n (%) Positive

Overall baseline caregiver characteristics

Caregiver characteristics stratified according to ARV initiation location OHCs

GMWs

ICU

p-value

N=749

N=127

N=509

N=106

0.1

540 (72.1)

103 (81.1) 358 (70.3)

72 (67.9)

Negative

46 (6.1)

4 (3.2)

32 (6.3)

10 (9.4)

Unknown

163 (21.8)

20 (15.8)

119 (23.4)

24 (22.6)

N=749

N=127

N=509

N=106

Maternal MTCT prophylaxis, n (%) Yes

258 (34.5)

43 (33.9)

164 (32.2)

46 (43.4)

No

353 (47.1)

68 (53.5)

243 (47.7)

40 (37.7)

Unknown

138 (18.4)

16 (12.6)

102 (20.0)

20 (18.9)

N=749

N=127

N=509

N=106

Yes

98 (13.1)

21 (16.5)

67 (13.2)

9 (8.5)

No

487 (65.0)

85 (66.9)

325 (63.9)

70 (66.0)

Unknown

118 (15.7)

10 (7.9)

94 (18.5)

15 (14.2)

46 (6.1)

11 (8.7)

23 (4.5)

12 (11.1)

N=749

N=127

N=509

N=106

Maternal ART at ART initiation, n (%)

NA Primary caregiver status, n (%) Mother

647 (86.4)

104 (81.9) 435 (85.8)

101 (95.3)

Other

69 (9.2)

18 (14.2)

50 (9.9)

1 (0.9)

None

33 (4.4)

5 (3.9)

24 (3.9)

4 (3.8)

0.05

0.33

0.004

MTCT = mother-to-child transmission; NA = not applicable. *In Table 2 the χ2 test of association and Fisher’s exact test were used to test associations between categorical variables.

skills needed to provide treatment to their children. Three counselling sessions, each covering different aspects of the disease process, practical issues around treatment, and a formal demonstration in administering ART to affected children on an individualised basis, are provided before and during the course of ART initiation. These sessions are documented on a prescribed checklist.

Study outcomes

Outcome measures included death, loss to follow-up (LTFU), attrition, virological suppres-

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sion and changes in CD4 count and percentage.

Outcomes were evaluated at 6 months using the measure taken closest to 6 months after initiation, within a window of 3 - 9 months after ART initiation. LTFU was defined as failure to attend a follow-up visit within 3 months after the last scheduled appointment was missed.

Attrition was defined as a combination of patients who had died and those who were LTFU during the study period.

Outcomes of those transferred out were determined using linkage with the Western Cape provincial laboratory database and

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folder reviews. Mortality ascertainment was based on death docu­ mented in the RCWMCH folder, usually after re-presenting and being admitted to RCWMCH. Children who had specimen results of any nature recorded on the National Health Laboratory Service database at 6 months after ART initiation were considered alive.

Children with no record of specimen results after transfer out and who were not documented to have died by 31 March 2013 were assumed to be LTFU. Two cut-off values were used to define virological suppression, i.e. a VL of <400 copies/mL or <50 copies/mL. HIV RNA measurements were performed using Abbott Realtime HIV-1 assay and CD4 measurements by the PanLeucogated method.[11,12]

Statistical analysis

Pre-ART continuous variables were non-normally distributed and therefore compared using the Kruskal-Wallis test. Frequencies and proportions were used to describe pretreatment categorical variables. The χ2 test of association or Fisher’s exact test was used to assess associations between these variables. CD4 percentage and VL results at 6 months were compared with the respective baseline results using the Wilcoxon signed-rank test for paired samples.

Kaplan-Meier curves were fitted to estimate mortality, LTFU and attrition probabilities during the first 6 months of ART. Multivariable Cox proportional hazards regression was used to assess factors associated with mortality, LTFU and attrition during the first 6 months of ART, adjusting for pretreatment clinical and demographic variables. Logistic regression was used to assess factors associated with an unsuppressed VL during the first 6 months of ART, i.e. plasma HIV RNA concentration >400 copies/mL or >50 copies/ mL, adjusting for pretreatment clinical and demographic variables.

Variables with p-values of <0.1 on univariate analysis were included in the regression models.

The data were analysed using the STATA Release 12.0 statistical software package (STATACorp, College Station, USA).

were ART experienced, and 28 had been initiated on ART at other healthcare facilities. Data from the remaining 749 children who fulfilled the inclusion criteria were analysed.

Baseline characteristics

Tables 1 and 2 describe patient and caregiver characteristics prior to ART initiation. One hundred and six children (14.5%) were commenced on ART in the ICU, 509 (68.0%) in the GMWs and 127 (17.0%) in the OHCs. Seven hundred and thirty-two children (97.7%) would have qualified for expedited initiation of ART according to the 2013 South African national treatment guidelines (492 were aged <12 months, 129 were aged >12 months with CD4 percentages <15%, and 111 were aged >12 months with WHO stage 4 disease). Of these children, 182 (24.9%) were initiated on treatment expeditiously, within 7 days of diagnosis. However, 367 (50.1%) were initiated within 7 days of hospital admission and a further 198 (27.0%) within 14 days. Children commenced on ART in the OHCs were significantly older than those in the ICU and GMWs. Overall, 65.7% of all children initiated on ART were <12 months old. Children in the ICU and GMW cohorts had significantly lower median WAZ scores and more wasting. More than 75% of children had subnormal CD4 percentages of <25%, and 385 (51.4%) had CD4 percentages <15% and/or CD4 counts <200 cells/µL. More children in the ICU and GMW cohorts than in the OHC cohort

Ethical considerations

The study was conducted in accordance with the Declaration of Helsinki, and was approved by the Human Research Ethics Committee, Faculty of Health Sciences, University of Cape Town (reference number: HREC REF: 261/2002).

Results

In total, 878 children were treated with ART at RCWMCH during the study period. Of these, 129 were excluded from the analysis: 101

Table 3. Primary diagnoses of children on presentation to hospital ICU (N=106)

GMWs (N=509)

Pneumonia

96

229

Gastroenteritis

5

137

Malnutrition

1

33

Septicaemia

1

14

PTB

-

13

EPTB

1

19

Upper airway obstruction

-

17

Meningitis

1

11

Non-accidental injury

-

4

Surgical conditions

1

9

Other medical conditions

-

23

PTB = pulmonary tuberculosis.

Table 4. CD4 percentage and VL responses after 6 months of ART CD4 percentage at 6 months, n (%)

GMWs

OHCs

ICU

p-value 0.1

N=330

N=99

N=59

≥25

158 (47.9)

55 (55.6)

36 (61.0)

<25

172 (52.1)

44 (44.4)

23 (39.0)

CD4% change at 6 months, median % difference (IQR)

N=320 4.7 (0.7 - 11.3)

N=91 3.2 (0.1 - 9.2)

N=54 9.1 (4.9 - 14.7)

VL (copies/mL) at 6 months, n (%)

N=280

N=93

N=51

≤50

171 (61.1)

69 (74.2)

24 (47.1)

0.004

≤400

198 (70.7)

75 (80.7)

32 (62.8)

0.05

N=216 –4.7 (–2.9 - –5.9)

N=90 –4.7 (–3.8 - –5.4)

N=39 –4.1 (–1.5 - –5.3)

0.35

Log10 VL change at 6 months,* median % difference (IQR)

IQR = interquartile range. * Analyses of the differences between 6-month and baseline CD4% or log10 VL values in children with paired specimen results.

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had a baseline VL >100 000 copies/mL. Younger children, particularly infants, presented with higher VLs. The median VL log10 value of children aged <12 months was 6.0, while the median value for those aged >60 months was 4.8 (p=0.001). Overall a quarter of the children (24.7%) had current TB; of these, 6.5% had culture-confirmed disease and 19.2% probable TB. The times from HIV diagnosis and hospital admission to ART initiation were significantly shorter in the ICU cohort. No obvious differences were noted in caregiver characteristics prior to ART initiation. Most of the caregivers (92.9%) had at least one counselling session at RCWMCH, 53 (7.1%) receiving none.

Not receiving counselling sessions was due to lack of caregiver availability during ART initiation (61.4%), patients being transferred out to other healthcare facilities before counselling sessions could be initiated (10.3%), or counselling taking place during follow-up visits after discharge from hospital (17.2%); in 11.1% of cases there was no documentation of reasons why counselling sessions were not performed. Pneumonia was the predominant primary diagnosis, present in 90.6% and 45.0% of children initiated on ART in the ICU and GMWs, respectively (Table 3).

Outcomes at 6 months

The Kaplan-Meier probability of overall mortality after 6 months of ART was 6.4% (95% confidence interval (CI) 4.9 - 8.4).

Mortality at 6 months was significantly higher in the ICU cohort than in the GMW and OHC cohorts (Fig. 1, A). Among those who died, the median time to death after ART

initiation was 25 days. Of the deaths in the GMW and ICU cohorts, 38 (90.5%) occurred during the primary hospital admission. Six children (3.1%) from the GMW cohort, 4 (3.2%) from the OHC cohort and 4 (2.4%) from the ICU cohort were LTFU by 6 months after starting ART. No statistical differences were found in the probabilities of LTFU (logrank p=0.78) or attrition (log-rank p=0.12) between the three groups (Fig. 1, B).

After 6 months of ART, 51.0% of children remaining in care at RCWMCH had achieved a CD4 percentage of ≥25% and 62.3% a VL of ≤50 copies/mL. Paired analyses documented a significantly greater increase in median CD4 percentage over the first 6 months of ART among children initiated on ART in the ICU, with substantial declines in the median log10 VL values across all three treatment cohorts. The proportion of children achieving virological suppression was significantly lower in the ICU cohort (Table 4).

Of the 749 patients analysed, 257 were transferred out to primary healthcare facilities for continuation of care within 6 months of ART initiation. Where possible, CD4 and VL results after transfer out were obtained from the Western Cape provincial laboratory database. Of those transferred out, 142 (55.3%) had CD4 count results and 109 (42.4%) had VL results available 6 months after ART initiation. Paired analyses showed no significant differences in CD4 or VL log values at 6 months in children who were transferred out compared with those who remained in care at RCWMCH. Median increases in CD4 percentage at

A 1.00

B 1.00

OHCs cohort (5)

OHCs cohort (9)

0.95

0.95 GMWs cohort (28)

0.90

GMWs cohort (45)

0.90 ICU cohort (14)

0.85

Log-rank p=0.004

0.80

ICU cohort (18)

0.85

0.75

Log-rank p=0.12

0.80

0.75 0

30

60

90

120

150

180

0

Analysis time, days ICU cohort GMWs cohort

30

60

90

120

150

180

Analysis time, days

OHCs cohort

ICU cohort GMWs cohort

OHCs cohort

Fig. 1. Kaplan-Meier estimates for outcomes of (A) mortality (n=742) and (B) attrition (n=742) at 6 months, according to ART initiation location.

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6 months in those transferred out and those remaining in care were 4.0 and 5.8, respectively (p=0.165). Similarly, median decreases in VL log values at 6 months were 4.4 and 4.6, respectively (p=0.33), and there were no significant differences in the proportions of children achieving virological suppression. Of patients who were transferred out, 10 (3.9%) were LTFU and 9 (3.5%) died.

Predictors of mortality, attrition and an unsuppressed VL

On multivariable analysis, factors influencing mortality (Table 5) included age <3 months (adjusted hazard ratio (aHR) 1.8; 95% CI 0.9 - 3.4), moderate and severe malnutrition (aHR 2.4; 95% CI 1.1 - 5.2 and aHR 3.2; 95% CI 1.6 - 6.5, respectively), no caregiver counselling sessions before and during ART initiation (aHR 2.9; 95% CI 1.4 - 6.0), and starting ART in the ICU (aHR 2.6; 95% CI 1.4 - 4.9). Children with caregivers who were not on ART at baseline had a decreased hazard of death (aHR 0.5; 95% CI 0.3 - 0.9).

Regression modelling of those children who were LTFU within 6 months of ART initiation revealed that age was the only variable associated with LTFU; children between the ages of 3 and 12 months had a 3.16 increased risk of LTFU (p=0.02) com­ pared with older children.

Factors influencing attrition included patient age, WAZ scores, number of caregiver counselling sessions, and caregivers who were on ART at baseline. Older children aged between 13 and 60 months had a decreased hazard of attrition (aHR 0.5; 95% CI 0.2 - 1.1).

Children who were severely malnourished and children who had caregivers who did not receive any counselling sessions were at increased risk of attrition (aHR 1.8; 95% CI 1.1 - 2.8 and aHR 2.6; 95% CI 1.4 - 5.0, respectively).

Age was a major predictor of an un­suppressed VL (Table 6). Younger children were significantly less likely to achieve an undetectable VL. After 6 months on ART, 35.8% of children <12 months of age and 15.9% of those aged >12 months at the time of starting ART did not achieve a VL of <400 copies/mL. Furthermore, children <3 months of age had a 3.1-fold increased risk of a VL of >50 copies/ml (95% CI 1.8 - 5.3), while children between 3 and 12 months of age had a 2.6-fold increased risk of a VL of >50 copies/ml (95% CI 1.3 - 4.9) after adjusting for other predictors of virological response. Similarly, children <3 months of age had a 3.0-fold increased risk of a VL of >400 copies/ml (95% CI 1.5 - 5.9), while children 3 - 12 months of age had a 2.6-fold

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Table 5. Predictors of mortality during the first 6 months of ART Univariate HR (95% CI) of mortality

1.8 (0.95 - 3.4)

p-value

Adjusted HR (95% CI) of mortality (N=700)

p-value

0.07

1.8 (0.9 - 3.4)

0.07

Age at ART initiation (months) (N=749) <3 3 - 12

1.2 (0.7 - 2.1)

0.59

1

13 - 60

0.5 (0.2 - 1.2)

0.12

1

>60

1

1

WAZ categories (N=700) Mild-normal

1

Moderate malnutrition

2.3 (1.1 - 4.8)

0.02

2.4 (1.1 - 5.2)

1 0.02

Severe malnutrition

2.5 (1.3 - 4.9)

0.008

3.2 (1.6 - 6.5)

0.001

3.8 (1.9 - 7.6)

0.0001

2.9 (1.4 - 6.0)

0.005

Caregiver counselling sessions, n* (N=749) 0 1

2.7 (0.7 - 11.1)

0.17

1

2

0.6 (0.1 - 4.1)

0.58

1

3

1

1

ART initiation location (N=742) GMW

0.7 (0.4 - 1.2)

OHC

1

ICU

0.144

1 1

2.6 (1.4 - 4.9)

0.002

2.6 (1.4 - 4.9)

0.003

Caregiver support (N=749) †

Yes

1

1

No

1.0 (0.6 - 1.8)

0.95

1

Not available

2.5 (1.2 - 5.2)

0.013

2.4 (1.1 - 5.0)

0.02

Maternal ART at ART initiation (N=749) Yes

1.1 (0.5 - 2.5)

0.762

1

No

0.5 (0.3 - – 0.8)

0.011

0.5 (0.3 - 0.9)

Not available

2.3 (1.3 - 4.3)

0.005

NA

1

0.02

1 1

HR = hazard ratio; NA = not applicable. *Number of counselling sessions received by caregiver prior to or during ART initiation. † Is there a second caregiver who is able to administer ART to the child in the event of the primary caregiver not being present?

increased risk of a VL of >400 copies/ml (95% CI 1.4 - 4.6).

Discussion

Our study shows that ART-naïve HIVinfected children are still very much at risk of HIV-related morbidity and mortality, particularly those who are <3 months old.

The majority of children initiating ART at RCWMCH were <12 months old; 85.4% had WHO stage 3 or 4 disease and 75.7% were immunocompromised (CD4 percentage <25%) at presentation to hospital. These findings are consistent with a previous analysis of infants <3 months old being initiated

on ART across 20 clinics in Cape Town and Soweto, Johannesburg, SA. Advanced HIV disease was present in 62% of infants, suggesting that even earlier initiation of ART is required to prevent mor­bidity and mortality in young children.[13] Nevertheless, our study demonstrates that it was feasible to initiate ART rapidly after admission even in sick children, with mortality of 6.4% overall and <15% even in the sickest children who started ART in the ICU. In addition, LTFU was <5% among all groups of children. While most children experienced immune recovery, the low proportion with virological suppression by 6 months after

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starting ART, especially among infants, is a concern.

Only 24.9% of all children who fulfilled the 2013 SA national treatment criteria for expedited initiation commenced ART within 7 days of diagnosis. This figure is low because ART initiation in our cohort preceded the 2013 recommendations.

Diagnosis of 152 study children prior to hospitalisation at RCWMCH also contributed to delayed initiation. The proportions of children initiated on ART within 7 and 14 days of hospitalisation were 49.0% and 75.4%, respectively, suggesting that not all hospitalised children who meet the criteria for expedited ART initiation will be commenced on ART within 7 days of HIV diagnosis.

A VL of <400 copies/mL was not achieved within 6 months of ART initiation in 35.8% of children aged <12 months and 15.9% of children aged >12 months, which is consistent with previous studies. Poor response in young children was described in a Soweto clinic, where the cumulative probability of achieving virological suppression (<400 copies/mL) 6 months after ART initiation was 59.4%. Children aged >36 months were more likely to achieve suppression at an earlier stage.[14] Failure to achieve virological suppression in young children may be attributed to several factors, including unpalatability of paediatric drug formulations, high baseline VLs in HIVinfected infants requiring a longer period to suppress, and choice of first-line ART regimens.

Before the roll-out of ART in the public sector, a sizeable proportion of HIV-infected children required admission to ICU facilities.

Mortality in these children was high, with rates of 27% and 44% recorded at RCWMCH and Tygerberg Hospital, respectively.[15] Since the introduction of ART, mortality in children has decreased substantially.

Our study reports a 13.2% probability of mortality in children admitted to the ICU and subsequently commenced on ART, which although significantly higher than those in the GMW and OHC cohorts, is approximately half the pre-ART ICU mor­ tality. This reduction could be due to a combination of factors, including increased early HIV diagnosis and ART initiation in the ICU. Children requiring ICU care are more ill on presentation to hospital, which probably influences clinical, immunological and virological outcomes and possibly explains the increased mortality rate compared with the GMWs and OHCs. However, our results suggest that ART may have played a role in lowering ICU mortality. Other factors

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Table 6. Predictors of an unsuppressed VL after 6 months of ART Univariate OR (95% CI)

p-value

Adjusted OR (95% CI) (N=338)

p-value

1.6 (0.95 - 2.7)

0.078

3.1 (1.8 - 5.3)

0.001 0.005

Predictors of VL >50 copies/mL Age at ART initiation (months) (N=429) <3 3 - 12

2.4 (1.6 - 3.5)

0.001

2.6 (1.3 - 4.9)

13 - 60

0.6 (0.4 - 0.9)

0.029

1

>60

1

1

1

1

Caregiver support* (N=429) Yes No

0.6 (0.4 - 0.97)

0.039

0.5 (0.3 - 0.9)

Not available

0.7 (0.3 - 1.4)

0.298

1

Yes

0.8 (0.5 - 1.4)

0.433

1

No

1.7 (1.1 - 2.7)

0.012

1

Not available

0.4 (0.2 - 0.8)

0.009

0.4 (0.2 - 0.8)

NA

1

0.013

Maternal ART at ART initiation (N=429)

0.011

1

Predictors of VL >400 copies/mL Age at ART initiation (months) (N=429) <3

1.9 (1.1 - 3.3)

0.018

2.95 (1.5 - 5.9)

0.002

3 - 12

1.7 (1.1 - 2.7)

0.01

2.6 (1.4 - 4.6)

0.002

13 - 60

0.6 (0.4 - 1.1)

0.12

1

>60

1

1

1

1

Caregiver support* (N=429) Yes No

0.6 (0.4 - 0.97)

0.039

0.5 (0.3 - 0.9)

Not available

1.0 (0.5 - 2.3)

0.871

1

0.017

eported maternal HIV status at ART initiation R (N=429) Negative

1

Positive

1.8 (1.1 - 3.1)

0.024

1 1

Not available

0.4 (0.2 - 0.7)

0.005

0.3 (0.1 - 0.6)

0.002

OR = odds ratio; NA = not applicable. *Is there a second caregiver who is able to administer ART to the child in the event of the primary caregiver not being present?

possibly leading to improved outcomes, but not assessed in our study, include increased awareness and experience in managing ill HIV-infected children, as well as improved treatment practices. A quarter of children presenting to RCWMCH were diagnosed with TB either before or during presentation to hospital. The majority were commenced on anti-TB treatment before ART initiation, consistent with WHO and national guidelines Psychosocial factors contribute substantially to successful outcomes of ART, in particular counselling of caregivers before and during ART initiation. Our study demonstrates a greater than twofold increased risk of both mortality and attrition in the absence of caregiver counselling sessions. As most deaths occurred early during hospitalisation, absence of counselling is unlikely to have a causal effect on mortality. Indeed, caregiver unavailability was the major reason for caregivers not receiving counselling during ART initiation, reflecting the probable rapidity of ART initiation in these patients and the challenge of providing counselling when expediting ART.

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Study strengths and limitations

A strength of this study lies in its novel contribution to the existing literature by examining the impact of ART initiation at different levels of healthcare in a tertiary hospital setting. It also provides an accurate reflection of healthcare function at an operational level in an overburdened healthcare system with a high turnover of patients.

Because this was a retrospective analysis, limitations in availability of routine data existed. Owing to a high transfer-out rate of children to other healthcare facilities after ART initiation, access to followup clinical and laboratory data proved challenging. In particular, missing outcomes data impeded our ability to reflect accurately on growth patterns, immunological reconstitution and virological suppression in the original cohort of children initiated on therapy.

In general, children who are transferred out are less ill than those remaining in care. Virological and immunological outcomes of the entire cohort initially started on ART could in fact have been better than reported, had complete follow-up data on those transferred out been available. The results of this study are not generalisable to the

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entire HIV-infected paediatric population, as our cohort was a select group, admitted to a tertiary healthcare centre and having severe disease. Also, the study was restricted to children starting ART as this was its primary focus; this limits our ability to assess the feasibility of commencing ART in all severely ill children, some of whom may have died before treatment could be initiated.

Conclusion

These results highlight the importance of understanding the context in which children start ART when comparing outcomes in different settings, and demonstrate feasibility and good mortality outcomes in very ill young HIV-infected children. Similar studies at other tertiary hospitals should be performed in order to corroborate our findings and provide a basis for developing and optimising consensus guidelines for managing severely ill HIV-infected children.

Funding. MAD receives funding from the National Institutes of Allergy and Infectious Diseases (Grant 2U01AI069924) for the International Epidemiologic Databases to Evaluate AIDS Southern Africa Collaboration.

References 1. Bourne DE, Thompson M, Brody LL, et al. Emergence of a peak in early infant mortality due to HIV/ AIDS in South Africa. AIDS 2009;23(1):101-106. [http://dx.doi.org/10.1097/QAD.0b013e32831c54bd] 2. Mphatswe W, Blanckenberg N, Tudor-Williams G, et al. High frequency of rapid immunological progression in African infants in the era of perinatal HIV prophylaxis. AIDS 2007;19(10):1253-1261. [http://dx.doi.org/10.1097/QAD.0b013e3281a3bec2]

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3. Newell ML, Coovadia H, Cortina-Borja M, et al. Mortality of infected and uninfected infants born to HIV-infected mothers in Africa: A pooled analysis. Lancet 2004;364(9441):1236-1242. [http://dx.doi. org/10.1016/S0140-6736(04)17140-7] 4. Violari A, Cotton MF, Gibb DM, et al. Early antiretroviral therapy and mortality among HIV-infected infants. N Engl J Med 2008;359(21):2233-2244. [http://dx.doi.org/10.1056/NEJMoa0800971] 5. President Zuma and UNAIDS Executive Director, call for mass prevention movement at World AIDS Day commemoration in Pretoria. http//www.unaids.org/en/resources/presscentre/featurestories/2009/ December/20091201wadms/ (accessed 4 March 2014).

6. Department of Health, South Africa. South African Antiretroviral Treatment Guidelines 2013. http// www.kznhealth.gov.za/medicine/2013_art_guidelines.pdf (accessed 4 March 2014).

7. Towards an AIDS-free generation. Children and AIDS. 6th Stocktaking Report, 2013. http// www.unaids.org/en/media/unaids/contentassets/documents/unaidspublication/2013/20131129_ stocktaking_report_children_aids_en.pdf (accessed 4 March 2014).

8. Davies M-A, Phiri S, Wood R, et al. Temporal trends in the characteristics of children at antiretroviral therapy initiation in southern Africa: The IeDEA-SA Collaboration. PLoS One 2013;8(12):e81037. [http://dx.doi.org/10.1371/journal.pone.0081037] 9. Finlayson H, Eley B. Treatment and outcome of hospitalised, very young HIV-infected children. South African Journal of Child Health 2007;1(4):140-144 10. World Health Organization. The WHO Child Growth Standards. Geneva: World Health Organization, 2006. http://www.who.int/childgrowth/en/ (accessed 31 July 2014).

11. Swanson P, Holzmayer V, Huang S, et al. Performance of the automated Abbott RealTimeTM HIV-1 assay on a genetically diverse panel of specimens from London: Comparison to VERSANT HIV-1 RNA 3.0, AMPLICOR HIV-1 MONITOR v1.5, and LCxR HIV RNA quantitative assays. J Virol Methods 2006;137(2):184-192. [http://dx.doi.org/10.1016/j.jviromet.2006.06.010] 12. Glencross DK, Janossy G, Coetzee LM, et al. CD8/CD38 activation yields important clinical information of effective antiretroviral therapy: Findings from the first year of the CIPRASA cohort. Cytometry B Clin Cytom 2008;74B(S1):S131-A140. [http://dx.doi.org/10.1002/ cyto.b.20391] 13. Innes S, Lazarus E, Otwombe K et al. Early severe HIV disease precedes early antiretroviral therapy in infants: Are we too late? J Int AIDS Soc 2014;17(1):18914. [http://dx.doi.org/10.7448%2FIAS.17.1.18914] 14. Meyers TM, Yotebieng M, Kuhn L, Moultrie H. Antiretroviral therapy responses among children attending a large public clinic in Soweto, South Africa. Pediatr Infect Dis J 2011;30(11):974-979. [http:// dx.doi.org/10.1097/INF.0b013e31822539f6] 15. Argent AC. Managing HIV in the PICU â&#x20AC;&#x201C; the experience at the Red Cross War Memorial Childrenâ&#x20AC;&#x2122;s Hospital in Cape Town. Indian Journal of Paediatrics 2008;75(6):615-620. [http://dx.doi.org/10.1007/ s12098-008-0118-2]

Accepted 20 October 2014.

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An investigation of fingerstick blood collection for pointof-care HIV-1 viral load monitoring in South Africa T J Maiers,1 BS; N Gous,2 MSc; M Nduna,3 DipN; S M McFall,4 PhD; D M Kelso,4 PhD; M J Fisher,4 MS, PE; K M Palamountain,4,5 MBA; L E Scott,2 MD; W S Stevens,2,3 MB BCh, MMed (Haem), FCPath (Haem) einberg School of Medicine, Northwestern University, Chicago, IL, USA F Department of Molecular Medicine and Haematology, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa 3 National Health Laboratory Service, Johannesburg, South Africa 4 Center for Innovation in Global Health Technologies, Northwestern University, Evanston, IL, USA 5 Kellogg School of Management, Northwestern University, Evanston, IL, USA 1 2

Corresponding author: T J Maiers (tyler.maiers@northwestern.edu)

Background. Viral load (VL) quantification is an important tool in determining newly developed drug resistance or problems with adherence to antiretroviral therapy (ART) in HIV-positive patients. VL monitoring is becoming the standard of care in many resource-limited settings.

Testing in resource-limited settings may require sampling by fingerstick because of general shortages of skilled phlebotomists and the expense of venepuncture supplies and problems with their distribution.

Objective. To assess the feasibility and ease of collecting 150 µL capillary blood needed for the use of a novel collection device following a classic fingerstick puncture.

Methods. Patients were recruited by the study nurse upon arrival for routine ART monitoring at the Themba Lethu Clinic in Johannesburg, South Africa. Each step of the fingerstick and blood collection protocol was observed, and their completion or omission was recorded.

Results. One hundred and three patients consented to the study, of whom three were excluded owing to the presence of callouses. From a total of 100 patients who consented and were enrolled, 98% of collection attempts were successful and 86% of participants required only one fingerstick to successfully collect 150 µL capillary blood. Study nurse adherence to the fingerstick protocol revealed omissions in several steps that may lower the success rate of capillary blood collection and reduce the performance of a subsequent VL assay.

Conclusion. The findings of this study support the feasibility of collecting 150 µL of capillary blood via fingerstick for point-of-care HIV-1 VL testing in a resource-limited setting.

S Afr Med J 2015;105(3):228-231. DOI:10.7196/SAMJ.7799

The World Health Organization (WHO) has esti­ mated that about 34 million individuals are infected by the current HIV/AIDS pan­ demic.[1] Although much progress has been made in controlling this disease, in sub-Saharan Africa approximately 23 million people remain infected,[1] with South Africa (SA) alone contributing about 11 087 cases/100 000 population.[1] The monitoring of the HIV viral load (VL) in patients receiving antiretroviral therapy (ART) is critical to ensure treatment success, identify problems with treatment adherence, and identify HIV drug resistance to inform the decision to switch to second-line or future third-line therapies.[2] Currently there is much discussion regarding the role of VL monitoring in the care of HIV/AIDS patients. The WHO recommends VL monitoring as the preferred approach because of its ability to identify treatment failure earlier than immunological and clinical modalities.[2] Treatment failure is defined by the WHO as a plasma VL >1 000 copies/mL after two consecutive measurements during a 3-month interval accompanied by adherence support.[2] However, despite the updated WHO recommendations, poor access to VL testing often persists in resource-limited settings owing to simple logistical issues such as the collection and transportation of specimens.

Recently, alternatives such as dried blood spots (DBSs) and pointof-care (POC) devices are being investigated as potential ways to

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increase access to VL testing in low- and middle-income countries (LMICs). While standard laboratory platforms typically retain high accuracy when utilising the recommended threshold of 1 000 copies/ mL, both DBS and POC devices may need to utilise a higher limit (3 000 - 5 000 copies/mL has been suggested) until better sensitivity is established at the lower limit of detection.[2] A study by Viljoen et al.[3] in Durban using DBS HIV-1 RNA testing appeared accurate and feasible down to approximately 3 000 copies/mL. In a study conducted in southern India by Neogi et al.,[4] DBS HIV-1 RNA testing revealed 100% sensitivity and specificity at 5 000 copies/mL, but only 50% sensitivity with 100% specificity at 1 000 copies/mL. Most recently, when Kleshik et al.[5] quantified HIV-1 RNA in single 50 µL DBSs and limited incubation time prior to sample preparation to 30 minutes, a limit of detection of 866 copies/mL was reported.

An important concern regarding the use of DBSs for HIV-1 RNA quantification is the amplification of cell-associated HIV nucleic acid in whole blood, leading to a falsely high VL measurement when compared with the amplification of viral nucleic acid in plasma specimens. Several recent studies using DBSs have shown reasonable correlation for VLs >3 000 copies/mL, but significant overquantification has been observed in specimens with <3 000 copies/ mL.[6-9] Unless this over-quantification is addressed, the usefulness of DBSs for VL monitoring may be limited in samples containing <3 000 copies/mL.

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DBSs may serve to improve access to VL monitoring by linking any existing central laboratory infrastructure to regions with poor access to VL testing, where transport delays and centrifugation to plasma are not feasible. However, blood collection and the shipment of DBSs, with subsequent VL quantification and reporting of results, is not easily achieved during the same day in order to impact on patient care on the same visit.

Rapid POC testing may address this logistical shortcoming by quantifying VL on site during the same visit. Subsequent ART intervention may then take place during the same day, as patients with poor adherence to treatment or those with newly developed drug resistance are screened earlier in the process.

Shortages of skilled phlebotomists and the expense of venepuncture supplies have contributed to the development of a POC VL quantification device for use in resource-limited settings that may utilise sampling by fingerstick instead of venepuncture. Fingerstick specimens are currently used for a wide range of tests for haematology, chemistry and serology.[10-13] Recently the University of the Witwatersrand, Johannesburg, SA, investigated the feasibility and accuracy of performing multiple pointof-care tests (POCTs) on fingersticks. This study found that capillary blood for up to four POCTs (95 µL) could be obtained from a single fingerstick in 92% of the subjects.[14] A collaboration between the Quidel Corpor­ ation and the Northwestern Global Health Foundation (NWGHF), USA, is deve­loping a POC RT-PCR testing platform and VL assay that will require a volume of 150 µL capillary blood to reach a sensitivity with a lower limit of detection of 1 000 copies/mL.[12] The 150 µL whole blood will be converted to plasma using sample preparation materials provided by the NWGHF.[12] A significant barrier to implementing this platform in the future will be overcome if 150 µL capillary blood can be reliably collected following a fingerstick. In order to facilitate the collection of capillary blood for this study, a novel EDTA-treated capillary blood collection device with a capacity of 150 µL was developed.

The aim of this study was to assess: (i) the proportion of collection attempts that obtain 150 µL capillary blood using a newly developed fingerstick-based collection device; (ii) the number of puncture sites required to obtain 150 µL blood; and (iii) study nurse adherence to the fingerstick and blood collection protocol.

Methods

Setting and participants

The study was conducted at the Themba Lethu Clinic at Helen Joseph Hospital,

Johannesburg, where a medical student from the Feinberg School of Medicine in Chicago, USA, observed a study nurse perform fingerstick punctures and collect capillary blood specimens from 100 patients having routine blood tests for ART monitoring. Each patient routinely received one venepuncture for blood collection during their visit.

Fingerstick punctures were not performed at this clinic for the routine blood tests involved in ART monitoring. For the purposes of this study, a phlebotomist first performed a venepuncture on each patient for their routine blood tests and then one or more fingersticks were performed by the study nurse. The study nurse was highly experienced, with over 1 000 venepunctures and 1 000 fingersticks performed during her career.

Eligible patients were HIV-positive indi­ viduals currently receiving ART who had previously been tested for CD4 and/or HIV VL. Primary exclusion criteria included the presence of heavy callouses, severe dehydration, clinically identifiable illness and/ or opportunistic infection, and persistently cold fingers after a warming attempt. Suitable participants were recruited from the blood collection room after a phlebotomist had administered venepuncture and collected the requested routine standard-of-care blood specimens. Each patient was asked to sign an informed consent waiver before enrolling in the study and receiving a fingerstick. Ethics approval for this study was granted by the Institutional Review Board at Northwestern University (ID: STU00076689) and the Human Research Ethics Committee at the University of the Witwatersrand (Protocol M120143).

Data collection and measurements

Fingerstick punctures were delivered using a device with a blade depth and width of 2.0 mm and 1.5 mm, respectively. The BD Microtainer Contact-Activated Lancet (BD Diagnostics, USA) was initially used to deliver fingerstick punctures until a stock shortage necessitated the use of the BD Genie Lancet (BD Diagnostics), with identical blade depth and width specifications. The study nurse was not given explicit instructions on how to perform the fingersticks; instead, she was simply asked to perform them according to her usual methods until blood collection was complete. A fingerstick and blood collection protocol checklist was created for the purpose of this study to assess baseline study nurse adherence to the protocol without training or specific instructions provided. The study nurse was blinded with respect to the fingerstick and blood

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collection protocol checklist used to assess adherence (Appendix 1) for the fingerstick and blood collection protocol in its entirety.

A novel blood collection device capable of holding 150 µL was used to discriminate between successful and unsuccessful collection attempts. The device contained several layers of EDTA-treated membrane strips designed to wick exactly 150 µL capillary blood. A complete collection was described to the nurse as the moment when both the front and rear of the membrane strips in the collection device appeared solid red in colour. Each step of the protocol checklist was observed, and completion or omission of any step was recorded on a template for every patient. A stopwatch was started immediately after the fingerstick to time the duration of the fingerstick procedure followed by blood collection. When more than one fingerstick was necessary, the study nurse obtained verbal consent before proceeding with each additional fingerstick. The result of each collection attempt was recorded. The study nurse performed translations as needed. Any unique insights offered by her were documented.

Results

A total of 132 patients were approached for participation in this study. Twenty-nine patients refused to give consent: 18 offered no reason for their refusal to do so, 7 stated that they were in a hurry, 2 did not want additional tests performed, and 2 stated that they were scared of receiving a fingerstick. Of the remaining 103 patients, 3 were excluded from the study because of the presence of callouses and/or extremely thick skin, selfdescribed as relating to their respective occupations. One hundred remaining patients participated in the study.

Ninety-eight out of 100 collection attempts were successful, and 86% required only one fingerstick to successfully collect 150 µL of capillary blood (Table 1). The two failed collection attempts were in adult men without callouses, exceptionally thick skin

Table 1. Number of fingersticks required to obtain 150 µL blood Fingersticks received, n

Patients (N=100), n

1

87*

2

10

3

2

4

1†

*One collection attempt failed to obtain 150 µl blood. † The combined collection from four fingersticks failed to produce 150 µL blood.

RESEARCH

Table 2. Nurse adherence to protocol Protocol steps

Adherence, % (N)

Pair of gloves worn by nurse

0 (0)

Patient sitting

100 (100)

Patient’s fingers warmed in advance

7 (7)

Puncture site disinfected with alcohol pad

86 (101)

First drop of blood wiped away

5 (109)

Hand positioned palm down

100 (100)

Hand positioned below elbow

56 (65)

Collection device held above skin; scraping avoided

96 (104)

Gentle pressure applied; strong milking avoided

95 (103)

Pressure applied after collection

100 (100)

or persistently cold fingers after a warming attempt. After four consecutive fingersticks were conducted on the first patient, he refused additional attempts. In the second patient, slow blood flow was observed after the first fingerstick. He declined to give consent to perform any additional fingersticks. Neither patient exhibited a negative response to receiving their fingerstick(s), as neither was observed to wince in pain, pull away or cry out. Neither patient exhibited physical signs of dehydration, but further questioning revealed a history of possible low fluid intake.

The mean time to perform one fingerstick followed by a successful collection was 76 seconds (range 27 - 225). Study nurse adherence to the fingerstick and blood collection protocol is summarised in Table 2.

Discussion

The successful monitoring of VL in patients receiving ART is critical in identifying treatment failure resulting from adherence issues or the development of HIV drug resistance. The world’s largest population of HIV-positive individuals resides in sub-Saharan Africa, yet this region has variable and often limited access to VL testing.

Development of a simple, cost-effective and readily accessible VL assay with high sensitivity is therefore needed. Currently, DBSs and novel POC platforms are being investigated as opportunities to expand access to VL monitoring in LMICs. Failure to access VL testing is frequently due to simple issues such as sample collection and transport. This study aimed to assess the feasibility of collecting 150 µL of capillary blood following a fingerstick puncture for use in a POC rapid RT-PCR testing platform and VL assay.

Although 86% of collection attempts successfully achieved a complete collection from a single fingerstick, the study nurse adherence to the protocol (Table 2) revealed omissions in several key steps that may adversely affect the success of capillary blood collection and/or the sensitivity of a subsequent VL assay. However, it should be noted that fingerstick device training may occur in an informal manner that fails to emphasise strict adherence to every step of the detailed manufacturer’s protocol for fingerstick blood collection. Notably, with 0% adherence, the study nurse was never observed wearing a pair of gloves during this study. While wearing gloves ultimately has no effect on the success of blood collection, repeated omission of this step may inform the subsequent design of a blood collection device that minimises the risk of healthcare worker contact with the collected blood specimen.

The two most commonly omitted steps that may adversely affect the success of blood collection were: (i) patient’s fingers warmed

230

in advance by any method; and (ii) positioning of the patient’s hand below elbow level, with 7% and 56% adherence, respectively (Table 2). Occasionally a patient with cold fingers was asked to rub their hands together quickly to generate heat. A warm cloth, which would have been ideal, was not readily available for the purpose of warming fingers. Placement of the patient’s hand below the level of their elbow also presented a significant challenge in many cases. Patients were seated in a chair rather than on an elevated examination table because they were subjected to phlebotomy immediately before fingerstick testing, and the routine practice in this setting was for phlebotomy to be done with the patient in a chair. Placing the patient’s hand below the level of their elbow while seated in a chair meant that the study nurse would have to bend over and painstakingly reach down in order to perform the fingerstick and observe progress in filling the collection device. Lastly, the first drop of blood was wiped away from the puncture site in only 5% of all fingersticks performed in this study (Table 2). It is hypothesised that the first drop of blood may contain interstitial fluid that could adversely affect the results of a subsequent VL assay, but this has yet to be confirmed.

Omissions in potentially important steps of the protocol suggest that when a POC VL platform and novel VL assay are first introduced to clinics, supplemental quick reference materials and/or brief maintenance training may improve the quantitative performance of a POC VL assay. When training healthcare personnel or preparing a protocol checklist for them in the future, special attention should be given to those frequently omitted steps that may adversely affect the outcome of a subsequent assay. The need for ongoing quality monitoring and training has been reported for performing rapid HIV testing and is a critical component of successful diagnostics.[15] Additionally, all necessary fingerstick materials should be conveniently located to facilitate optimal adherence to the manufacturer’s fingerstick protocol.

The unique perspective of the study nurse highlighted several important benefits of performing a fingerstick over venepuncture.

First, nurses or community healthcare workers with minimal training can perform fingersticks, potentially resulting in increased access to VL monitoring for patients. Nursing assistants in SA, for instance, receive 1 year of formal training and are not qualified to perform venepuncture on patients. A POC VL quantification assay relying on fingersticks rather than venepuncture could be widely utilised by this workforce. Second, fingersticks result in fewer blood spills and so decrease biohazard risk to healthcare workers, and require far less blood than venepuncture. In some cases a dehydrated and/or sick patient will provide an insufficient quantity of blood by venepuncture, requiring the test(s) to be completed again at a later time. Fingerstick blood collection may be more successful than venepuncture in certain patients. Finally, fingersticks require less counter space, fewer waste bins and less disposal of packaging materials.

The transition to fingerstick blood collection for VL testing may initially complicate the workflow in clinics that require other routine tests for ART monitoring. Venepuncture blood collection is often used for a variety of laboratory tests, including but not limited to CD4, a full blood count, liver function tests, and haemoglobin, creatinine, cholesterol and triglyceride measurements. A transition to fingerstick blood collection for VL testing would initially require phlebotomists to perform one or more fingersticks in addition to venepuncture for most patients.

The overall utility of fingerstick blood collection would therefore increase if multiple POC tests could be performed simultaneously for ART monitoring.

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RESEARCH

Conclusions

Capillary blood collection was highly successful in this study, with the vast majority of patient encounters yielding 150 µL blood after only one or two fingersticks. The widespread implementation of a POC VL assay in a resource-limited setting would not be hindered by the ability to collect the targeted volume of 150 µL capillary blood when using the appropriate lancet, but would require training and ongoing quality monitoring.

Acknowledgements. This work was supported by a Global Health Initiative grant from the Center for Global Health at Northwestern University. Grand Challenges Canada provided funding for the Themba Lethu Clinic staff, laboratory equipment, and supervision (grant number 0007-02-01-01). Finally, the friendly Blood Room staff at the Themba Lethu Clinic deserve recognition for their willingness to accommodate us for the duration of this study.

References

1. World Health Organization. World Health Statistics. 2013. http://www.who.int/gho/publications/ world_health_statistics/EN_WHS2013_Full.pdf (accessed 6 November 2013).

2. World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: Recommendations from a public health approach. June 2013. http://apps. who.int/iris/bitstream/10665/85321/1/9789241505727_eng.pdf (accessed 6 November 2013).

3. Viljoen J, Gampini S, Danaviah S, et al. Dried blood spot HIV-1 RNA quantification using open realtime systems in South Africa and Burkina Faso. J Acquir Immune Defic Syndr 2010;55(3):290-298. [http://dx.doi.org/10.1097/QAI.0b013e3181edaaf5]

4. Neogi U, Gupta S, Rodridges R, et al. Dried blood spot HIV-1 RNA quantification: A useful tool for viral load monitoring among HIV-infected individuals in India. Indian J Med Res 2012;136(6):956-962. [http://dx.doi.org/10.1097/QAI.0b013e3181edaaf5] 5. Kleshik F, Brooks J, Cosenza C, et al. Analytical performance of an automated assay quantifying HIV-1 from dried blood spots. J Clin Virol 2013;57(3):271-273. [http://dx.doi.org/10.1016.j.jcv.2013.03.001] 6. Marconi A, Balestrieri M, Comastri G, et al. Evaluation of the Abbott Real-Time HIV-1 quantitative assay with dried blood spot specimens. Clin Microbial Infect 2009;15(1):93-97. [http://dx.doi. org/10.1111/j.1469-0691.2008.02116.x] 7. Kane CT, Ndiaye HD, Diallo S, et al. Quantitation of HIV-1 RNA in dried blood spots by the realtime NucliSENS EasyQ HIV-1 assay in Senegal. J Virol Methods 2008;148(1-2):291-295. [http://dx.doi. org/10.1016/j.jviromet.2007.11.011] 8. Brambilla D, Jennings C, Aldrovandi G, et al. Multicenter evaluation of use of dried blood and plasma spot specimens in quantitative assays for human immunodeficiency virus RNA: Measurement, precision, and RNA stability. J Clin Microbiol 2003;41(5):1888-1893. [http://dx.doi.org/10.1128/JCM.41.5.1888-1893.2003] 9. Vidya M, Saravanan S, Rifkin S, et al. Dried blood spots versus plasma for the quantitation of HIV1 RNA using a real-time PCR, m2000rt assay. J Virol Methods 2012;181(2):177-181. [http://dx.doi. org/10.1016/j.jviromet.2012.02.006] 10. Glencross DK, Coetzee LM, Faal M, et al. Performance evaluation of the PimaTM point-of-care CD4 analyser using capillary blood sampling in field tests in South Africa. J Int AIDS Soc 2012;15:3. [http:// dx.doi.org/10.1186/1758-2652-15-3] 11. Nkrumah B, Nguah SB, Sarpong N, et al. Hemoglobin estimation by the HemoCue® portable hemoglobin photometer in a resource poor setting. BMC Clin Pathol 2011;11(1):5. [http://dx.doi. org/10.1186/1472-6890-11-5] 12. UNITAID. HIV/AIDS Diagnostic Technology Landscape. 3rd ed. June 2013. http://www.unitaid.eu/ images/marketdynamics/publications/UNITAID-HIV_Diagnostic_Landscape-3rd_Edition.pdf.pdf (accessed 6 November 2013).

13. Sherman GG, Stevens G, Jones SA, et al. Dried blood spots improve access to HIV diagnosis and care for infants in low-resource settings. J Acquir Immune Defic Syndr 2005;38(5):615-617. [http://dx.doi. org/10.1097/01.qai.0000143604.71857.5d] 14. Gous N, Scott L, Potgieter J, et al. Feasibility of performing multiple point of care testing for HIV anti-retroviral treatment initiation and monitoring from multiple or single fingersticks. PLoS One 2013;8(12):e85265. [http://dx.doi.org/10.1371/journal.pone.0085265] 15. Strategic Evaluation, Advisory & Development Consulting. Analysis of POCT/VCT performed at South African primary health care clinics. 2010. http://www.sead.co.za/downloads/POCT-clinics-2011. pdf (accessed 29 April 2014).

Accepted 20 October 2014.

Appendix 1 Fingerstick and blood collection protocol 1. Assemble materials • Disposable gloves • 70% isopropyl alcohol pads • Lancets • Blood collection device • Sterile gauze pad • Warming device (moist towel or sodium acetate hand warmer) 2. Wash hands and put on pair of disposable gloves 3. Position patient and select the fingerstick puncture site • Patient should be sitting or lying down • Patient should have their hand in a downward position, allowing gravity to increase blood supply to the hand • Middle or ring finger is preferable; fifth finger should not be punctured, because tissue depth is insufficient to prevent bone injury 4. Warm the site • Use a warm, moist towel or other appropriate warming device (not exceeding 40oC/105oF) for 3 minutes; alternatively, have the patient vigorously rub their hands together to generate heat 5. Disinfect the site • Cleanse the site using a 70% isopropyl alcohol pad • Allow the site to air dry in order to provide effective disinfection and to prevent possible haemolysis or erroneous results from residual alcohol

231

6. Perform the puncture • Have the patient hold their hand below elbow level • Turn the patient’s hand palm down • Hold the lancet with two fingers • Position the lancet firmly against the puncture site • Press lancet against puncture site until release mechanism is activated 7. Discard used lancet into a sharps container 8. Collect the blood specimen • Wipe away the first drop of blood, as this drop may contain an excess of tissue fluids that may cause erroneous results • Position the collection device directly beneath the puncture site and avoid scraping across skin • Gently apply intermittent pressure along finger capillaries and open the puncture slightly to maximise blood flow • Avoid strong repetitive pressure or ‘milking’, as this may cause haemolysis or tissue fluid contamination of the specimen • Blood collection is complete when both sides of the collection device appear solid red in colour 9. Cover the puncture site and dispose of all materials • Wipe the site dry and apply direct pressure with a sterile gauze pad until bleeding has stopped • Place all used materials in appropriate biohazard containers

March 2015, Vol. 105, No. 3

GUEST EDITORIAL

Chronic kidney disease It is known that, for many reasons, general practitioners (GPs) find renal disease difficult to diagnose, understand and treat. The terms chronic kidney disease (CKD) and glomerular filtration rate (GFR), representing the renal function equation, have been introduced to clarify some of these difficulties. Unfortunately, even these pivotal concepts remain either unknown or poorly understood by the majority of GPs in South Africa (SA). CKD is often not recognised because there are no specific symptoms, and not diagnosed or only diagnosed at an advanced stage.

Tests for CKD are, however, simple and freely available.

Diagnostic difficulties are especially relevant in rural areas where CKD and advancing chronic renal failure (CRF) are seldom diagnosed.

At the same time, there is an alarming rise in the incidence of serious CRF. It has been estimated that 10% of the world’s population has some degree of CKD. From this statistic, it can be estimated that 5 million South Africans >20 years of age have CKD, and in black South Africans the figure is almost certainly higher.

Global statistics clearly and definitely show the importance of CKD in terms of the ever-increasing number of dialysis patients, often because of diabetes and, in our black population, even more so because of hypertension. Furthermore, patients with CKD have a high risk of cardiovascular disease (CVD), including heart failure, myocardial infarction and stroke.

Statistics in SA show that hypertension (especially in blacks) and diabetes (especially in whites and Asians) are by far the main causes of CKD and CRF. Apart from known genetic factors, both diseases are markedly influenced by lifestyle aberrations – particularly gross excesses of dietary salt and calories (obesity). Therefore, there is a huge potential to prevent these disorders by modification of lifestyle, early diagnosis and/or correct treatment or to minimise or slow the progression of kidney functional deterioration.

By December 2012, there were 8 559 patients receiving chronic renal replacement therapy (RRT) in SA – 6 952 on dialysis and 1 607 with a functioning kidney transplant. More than half of these were from the private sector, which serves <20% of the population. Facilities in the public sector, which not only serves >80% of the population, but where the ‘burden of CRF’ is about three times that in the private sector, are strictly limited. This means that only 15 - 20% of those who require RRT obtain such treatment, clearly because of limited resources (mostly funding). The approximate annual cost of dialysis is R200 000 per patient and that of transplantation R300 000 in the first year – R160 000 - R180 000 in subsequent years (based on 2014 figures).

With these alarming statistics in mind, the National Kidney Foundation of South Africa (NKFSA) set up a task team at the time of World Kidney Day 2008. Keeping in mind that there is a need for the entire nation to cope with CKD and its threat to the national health system, the objectives were to set up projects to prevent CKD, educate medical professionals and nursing practitioners to identify risk factors of CKD, making early diagnoses and equipping them with the necessary expertise to correctly treat CKD and prevent progression to CRF. This was the beginning of a long process that culminated in the publication of guidelines on CKD in the format of CME articles.

This CME publication focuses on all aspects related to CKD and is therefore intended principally for GPs, both in urban and especially in rural areas, and covers all the most important problems. These are clearly and succinctly presented with a view to relevance and practicality for our environment.

It must be stressed that this is far from a comprehensive review of the subject. We have attempted rather to be brief, clear and to the

232

point, emphasising the most important aspects. It is hoped that these guidelines will assist in achieving the abovementioned goals and that we will eventually be able to prevent or significantly slow progression to renal failure in many of our citizens with CKD. To achieve these goals, intense and ongoing education for the public as well as doctor and nurse practitioners is required nationally.

The rewards for both SA kidney disease sufferers and our economy if these ambitious projects succeed are palpably obvious.

Moreover, the NKF has tasked itself to lobby governmental departments to adequately fund these primary healthcare projects and improve facilities for kidney disease sufferers. Also, when considering that CKD is currently among the 90% most common diseases affecting the public, conservative treatment and all treatments for end-stage kidney disease should be included in the government’s treatment guidelines at all levels of healthcare, i.e. primary, secondary and tertiary.

To make a diagnosis using the recently developed concept of CKD, the GFR can now be estimated by the so-called Modification of Diet in Renal Disease (MDRD) formula which, in a given patient, will yield a reasonably accurate GFR. This has enabled the classification and categorisation of all degrees of kidney diseases and kidney failure. Furthermore, the classification aids in both diagnostic skills and rational approaches to therapy. Considering that CKD is usually asymptomatic, this concept becomes very important in alerting the doctor that his/her patient has a serious kidney disorder that needs correct diagnosis and management.

Another very important fact about CKD is that timeous referral to a nephrologist or nephrology centre is essential for adequate management of kidney sufferers. Because there are so few nephrologists in SA, the NKFSA proposes a clinical collaboration between GPs and nephrology specialists.

We need to initiate and participate in GP educational lectures throughout SA. Our GPs should become involved in our primary prevention programmes. These endeavours must not be a ‘once-off splurge’, but must be constantly maintained in both the public and private sectors.

Education should not only be aimed at the medical fraternity, but there should also be a massive national drive towards public education and early diagnosis, resulting in adequate treatment programmes for everyone (peri-urban and rural). We must advertise the importance of CKD to our citizens, patients, medical and nursing professionals and government to ensure that this is reflected in our health policy.

Lastly, the importance of research, particularly epidemiological research, and exchanging of important and relevant knowledge with the national and international CKD community, should never be underestimated, but encouraged and funded.

The NKFSA is most grateful to all the nephrologists, both from the public and private sector, who have given so much of their time to contribute to this publication. We are also grateful for the assistance from the South African Renal Society and we especially acknowledge the Japanese Guidelines.[1] From this and other publications came the concept and framework upon which the NKFSA’s educational guidelines are based.

A M Meyers Guest editor nkfsa@mweb.co.za 1. Japanese Society of Nephrology. Japanese Guidelines. Clin Exp Nephrol 2009;13(3):192-248. [http:// dx.doi.org/10.1007/s10157-009-0188-0]

S Afr Med J 2015;105(3):232. DOI:10.7196/SAMJ.9444

March 2015, Vol. 105, No. 3

CONTINUING MEDICAL EDUCATION

REVIEW

Significance, definition, classification and risk factors of chronic kidney disease in South Africa A M Meyers, MB BCh, FCP (SA), Cert Nephrology (SA), FRCP (Lond) Donald Gordon Medical Centre, Klerksdorp Hospital, and National Kidney Foundation of South Africa, Johannesburg, South Africa Corresponding author: A M Meyers (nkfsa@mweb.co.za)

Renal dysfunction or chronic kidney disease (CKD) is found in 10% of the global population and is classified into five stages according to the estimated glomerular filtration rate (eGFR). No matter where a patient lives, estimation of the GFR is mandatory for decision-making and obtained by the simple measurement of a serum creatinine level. The objective of diagnosing CKD lies in its future prevention, early detection and proper treatment, which will prevent or delay functional deterioration.

Primary hypertension (PH) occurs in 25% of South Africa (SA)’s black population and is the putative cause of stage 5 CKD in 40 - 60% of these patients. Moreover, in this group, stage 5 CKD occurs at a relatively young age (35 - 45 years) compared with other population groups in whom stage 5 CKD resulting from PH usually occurs between 60 and 70 years of age. In the cohort study, PH has been found in 12 - 16% of black school learners (mean age 17 years) compared with 1.8 - 2% of other ethnic groups (mixed race, Asian, white). End-stage renal failure (ESRF) is the fifth most common cause of death in SA, excluding post-traumatic cases. In addition, undiagnosed or poorly controlled PH is a potent risk factor for other cardiovascular disease (CVD), e.g. congestive cardiac failure, myocardial infarction, stroke.

Significant protein is also associated with CVD and protein >1 g/d is a significant risk factor for ESRF. S Afr Med J 2015;105(3):233-236. DOI:10.7196/SAMJ.9412

•

•

•

•

•

• C KD is an important disease group that threatens health.

End-stage kidney disease (ESKD) has led to an increasing number of dialysis and transplanted patients worldwide, posing a massive burden on health economics, especially in developing countries.

ESKD resulting from hypertensive and/ or diabetic nephropathy is increasing glo­ bally, especially in the elderly. However, hypertension with renal dysfunction is an even greater problem in South Africa (SA), occurring in relatively young black patients who often also have severe target organ damage (heart and kidney).

The development of CKD is associated with atherosclerosis caused by lifestylerelated diseases such as obesity, hyper­ tension and diabetes. Even in the absence of lifestyle diseases, CKD is a risk factor for cardiovascular disease (CVD).

CKD is an important disease group that is most likely to cause CVD, hospitalisation or death, thus threatening the health of South Africans.

In an article by Mayosi et al.,[1] end-stage renal failure (ESRF) has been shown to be the fifth highest cause of non-traumatic death in SA.

Only estimated or deduced statistics exist for SA. However, with our burden

of CKD is far higher than that in developed countries. In Japan, with a population of >104 000 000, the prevalence of CKD was

of hypertensive ESKD, HIV nephropathy and other poverty-related disorders, it is highly likely that the sub-Saharan burden

Table 1. Prevalence of adult CKD in a developed country (Japan). The number of patients with stage 1 or 2 CKD was estimated according to the presence of pathological proteinuria. Patients on dialysis (N=275 000) were excluded CKD stage

Patients, n*

eGFR

CKD, % (approximately)

1

≥90

605 313

5

2

60 - 89

1 708 876

13

3

30 - 59

10 743 236

80

4

15 - 29

191 045

1.9

5

<15

45 524

0.1

eGFR = estimated glomerular filtration rate. *Total = 13 293 985 patients.

7 Risk per 100 person-years, age adjusted

Chronic kidney disease (CKD) matters

6 5 4 All-cause death 3

Cardiovascular disease Hospitalisation

2 1 0 ≥60

45 - 59

30 - 44

15 - 29

<15

GFR (mL/min/1.73 m2)

Fig. 1. The poorer the kidney function, the higher the risk of all-cause death, cardiovascular disease and hospitalisation. (GFR = glomerular filtration rate.)

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March 2015, Vol. 105, No. 3

CONTINUING MEDICAL EDUCATION

13.3 million (i.e. 12.9% of the population) (Table 1).[2] A decline in kidney function is an important risk factor for CVD. The poorer the kidney function, the higher the risk of CVD. Besides CVD, a large-scale epidemiological investigation revealed that relative risks for total mortality or hospitalisation rise irrespective of

cause in proportion to the degree of reduction in kidney function (Fig. 1).[3] Fig. 2 shows the relative risk of death from cardiovascular events according to the presence or absence of proteinuria and kidney function level. The relative risk was regarded as 1.0 for the cohort in the general health examination. This group comprised 30 704

3 Age adjusted Multivariate Relative risk

2

1

0 UP (-) GFR ≥60

A

UP (-) GFR <60

UP (+) GFR ≥60

UP (+) GFR <60

Age adjusted

Relative risk

Multivariate

3

2

1

0 B

UP (-) GFR ≥60

UP (-) GFR <60

Definition and classification of CKD

• CKD is diagnosed by proteinuria, album­ inuria, haematuria (not all cases are renal) or decreased glomerular filtration rate (GFR).

• CKD stages are classified according to the GFR. Most laboratories give a calculated GFR, which is derived from the serum creatinine value. The most commonly given value is the estimated GFR (eGFR).

• CKD should be appropriately treated, depending on its stage (Fig. 3).

Kidney Disease Improving Global Outcomes divides stage 3 into 3(a) and 3(b) to facilitate therapeutic intervention in 3(b) patients in whom kidney dysfunction is easily aggravated.

Furthermore, albuminuria is categorised as normal (<30 µmol/d), or positive (30 - 299 µmol/d), and proteinuria as normal (<150 µmol/d), mild (150 - 490 µmol/d) and severe (≥300 µmol/d), i.e. categories A1, A2 and A3.

Diagnostic criteria of CKD

CKD is defined and described in Table 2 and Fig. 3. It includes all morbid conditions associated with reduced kidney function indicated by the GFR or persistent findings that suggest kidney damage.

Instances of kidney damage: • urinary abnormalities such as proteinuria, including micro­albuminuria • abnormalities of imaging tests, such as single kidney or polycystic kidney • abnormalities of blood biochemistry, such as those indicating kidney dysfunction, including abnormal glomerular and tubular dysfunction • abnormalities of histological findings.

5

4

men and 60 668 women aged 40 - 79 years with an eGFR ≥60 mL/min/1.73 m² and no proteinuria. The age-adjusted relative risk of CVD mortality is shown for men and women.

UP (+) GFR ≥60

UP (+) GFR <60

Fig. 2. (A): Men. (B): Women. The relative risk of cardiovascular death associated with proteinuria and CKD. (General population: men 30 764, women 60 668, age 40 - 79 years; reference: GFR ≥60, proteinuria ( - ).) Data, with modification, from Irie et al.[4] (UP = proteinuria; GFR = glomerular filtration rate.)

The eGFR as the measurement of creatinine levels in blood provides vital information on the management of CKD. eGFR should, however, not be accepted as the single only measurement of kidney function (Table 3).

CKD: High-risk groups

• The most important risk factor in SA’s black population for CKD is the

Table 2. CKD definition A. Obvious kidney damage shown by urinalysis, blood chemistry, images or pathology of the kidney. The presence of albuminuria or proteinuria is especially important. Note: Kidney cysts in the elderly do not represent CKD unless they are the result of autosomal-dominant polycystic kidney disease B. GFR as a risk factor for ESRF: ≤60 mL/min/1.73 m² for ages 40 - 49 years and ≤40 for ages ≥70 years Persistent evidence of A and/or B for ≥3 months

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development of essential hypertension. In SA, hypertension develops much earlier than in developed areas of the world, is more severe, usually not diagnosed early, and often poorly treated. All of this is compounded by poor patient compliance.

• There are also the usual risk factors for the development of CKD: ageing, family history of CKD (including essential hypertension and type 2 diabetes mellitus (DM)), habitual use of non-steroidal antiinflammatory drugs (NSAIDs), history of abnormal urinary findings and/or abnormal kidney function, abnormal morphology of the kidney, dyslipidaemia, hyperuricaemia, obesity, metabolic syn­ drome, auto-immune disorders, kidney infections, nephrotic syndrome and kidney stones.

120

>90

GFR (mL/min/1.73 m2)

1

90

GFR normal or possibly with some kidney damage

90 - 60 2

60

• In the SA context, the HIV epidemic is another relevant factor in the development of CKD (10% of these patients may develop advanced CKD).

• Pregnancy-related factors are also important.

Fetuses whose mothers abuse alcohol and/ or cigarettes during pregnancy or who are malnourished or immunocompromised are at risk. Infants born to these mothers have a high incidence of low birthweight (≤2 kg) and a high occurrence of subsequent severe CKD. • As a safeguard against the development of CKD, the following basic strategies must be implemented: • All individuals with a positive family history (i.e. parental or sibling) of hypertension or any other familial renal disease should have their blood

• Mild GFR, kidney damage and age

60 - 30 3

Moderate GFR, kidney damage and age

•

30 - 15

30

4

Severe GFR <15 5

• ESKD

Stages (shown in boxes) Fig. 3. Classification of the stages of CKD (generally referred to as CKD # where # is classified according to the eGFR). (GFR = glomerular filtration rate; ESKD = end-stage kidney disease.)

•

pressure (BP) checked annually from an early age (e.g. 20 years onwards) and managed appropriately. Checking of BP should always be accompanied by urine dipstick testing, and abnormalities must be assessed by a doctor.

• The same applies to DM patients, but checking should start at an older age (e.g. 35 years).

• Major risk factors for the above­mentioned two disorders are lifestyle eating aber­ rations and, in particular, the excessive intake of dietary sodium. Obesity, which is often seen in SA as a societal attraction, must be condemned and prevented.

• The HIV epidemic must be controlled by all means possible.

• One of the most important causal factors of kidney function deterioration in healthy people is ageing. From about the age of 50 - 55 years, the GFR reduces by approximately 1.2 - 1.5 mL/min/year.

This calls for careful drug administration with advancing age, especially drugs that are largely excreted by the kidneys.

If patients with proteinuria smoke, are obese, or develop hypertension or an impaired glucose tolerance, CKD advances at a more rapid rate. Men are at particular risk; they should be put on stricter treatment regimens and be required to modify their lifestyle.

Obesity (especially morbid obesity) is a risk factor for proteinuria, which can result in ESKD – even in the absence of diabetes or hypertension (especially in men).

Dyslipidaemia is a risk factor for CVD. Although based on scant evidence, it has been suggested that dyslipidaemia may promote ESKD. Conversely, an increase in proteinuria is associated with an increased incidence and severity of dyslipidaemia, probably resulting in further proteinuria and progressive CKD. Hyperuricaemic patients frequently suffer from kidney disorders and vice versa, and

Table 3. Interpretation of serum creatinine • Creatinine – not urea – is of pivotal importance in assessing GFR • If eGFR testing reveals stage 2 CKD, repeat test twice per year. If stage 3 or 4, repeat test three or four times per year • Factors other than GFR can influence levels of serum creatinine: • age (progressive decrease in GFR is physiological) • muscle bulk (lower in females, increased in males) • diet, e.g. vegetarian • some drugs, e.g. cimetidine, result in a falsely high creatinine • Examples of major pitfalls: • a muscular man with a serum creatinine of 120 µmol/L may have a normal GFR • conversely, a thin elderly woman with a serum creatinine of 90 µmol/L may have reduced eGFR, e.g. <40 mL/min/1.73 m² • Important practice point: • A serum creatinine of ≥150 µmol/L in females or 160 µmol/L in males indicates serious underlying renal dysfunction. These patients must be referred to a nephrologist

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stages 4 - 5 CKD patients tend to have hyperuricaemia. There is accumulating evidence, however, that hyperuricaemia is an independent risk factor for atherosclerosis and progressive CKD. • To summarise, all individuals with a positive family history of renal disorders are potentially at high risk and should be regarded as such.

Sixteen dos and don’ts in the basic management of CKD patients

1. CKD is defined as either: • a kidney disorder (e.g. proteinuria) with or without impairment of GFR, and/or • decreased GFR, i.e. ≤60 mL/min/1.73 m² lasting for >3 months.

2. eGFR is calculated using the so-called modification of diet in renal disease (MDRD) formula: eGFR mL/min/1.73 m² = 32 788 ↓× serum creatinine-1.154 × age-0.203 (× 1.210 if black and × 0.742 if female) 3. CKD is a critical risk factor for the development of CVD and ESKD. 4. A CKD patient should be managed by a multidisciplinary team of primary care physicians and nephrologists.

5.

It is desirable that patients with the following are referred to nephrologists: • proteinuria 0.5 g/g creatinine or higher; or on dipstick ≥2+ • eGFR of <50 mL/min/1.73 m² • proteinuria plus haematuria of ≥1+.

6. The treatment goal in cases of proteinuria is to achieve levels of <0.5 g/g creatinine, i.e. <500 µg/24 h.

7. CKD management should be started with modification of lifestyle, i.e. smoking cessation, salt restriction and improvement of obesity.

8. The goal of BP control is <130/80 mmHg and should be achieved gradually. Automatic home BP devices should be used whenever possible, and BP charts maintained and checked by doctors.

9. Antihypertensive agents of first choice are angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs).

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Combination with other antihypertensives should be as required but ACE I or A II RB should always be combined with a thiazide diuretic in black patients. Thiazide diuretics (other than furosemide) are inactive if the GFR is <30 mL/min/1.73 m².

10. When ACE I or ARBs are used, a physician must be aware of the possible risk of a slight rise in the creatinine level and the possible occurrence of hyperkalaemia with stage 3(b), 4 or 5 CKD patients.

11.

In diabetic nephrology, the target level of HbA1C should be approximately 6.5% to control the blood glucose level.

12. The low-density lipoprotein cholesterol should be controlled at ≤2.5 mmol/L. 13. The primary physician should consult a nephrologist when renal anaemia is suspected.

14. Physicians should consult a nephrologist whenever erythropoiesisstimulating agents are considered.

15. Physicians should reduce the dose or extend the administration interval, depending on kidney function, when administering drugs that are renally excreted.

16. NSAIDs, contrast media and diuretics are high-grade risk factors for a decline (often permanent) in kidney function in patients with advanced CKD. The same occasionally applies with the use of ACE I and A II RB in stages 4 and 5 CKD, especially in elderly, hypertensive or diabetic populations.

References 1. Mayosi BM, Flisher AJ, Lalloo UG, Sitas F, Tollman SM, Bradshaw D. The burden of noncommunicable diseases in South Africa. Lancet 2009;374(9693):934-947. [http://dx.doi.org/10.1016/ S0140-6736(09)61087-4] 2. Japanese Society of Nephrology. Japanese Guidelines. Clin Exp Nephrol 2009;13(3):192-248. [http:// dx.doi.org/10.1007/s10157-009-0188-0] http://link.springer.com/article/10.1007/s10157-009-0131-4/ fulltext.html (accessed 30 January 2015).

3. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004;351:1296-1305.

4. Irie F, Iso H, Sairenchi T, et al. The relationships of proteinuria, serum creatinine, glomerular filtration rate with cardiovascular disease mortality in Japanese general population. Kidney Int 2006;69(7):12641271.

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ARTICLE

Diagnostic approach to chronic kidney disease I P Naiker,1 MB ChB, MRCP (UK), FRCP (Lond), FCP (SA); A G Assounga,2 MD, CES, PhD; A M Meyers,3 MB BCh, FCP (SA), Cert Nephrology (SA), FRCP (Lond) Private practice, St Augustine’s Hospital, Durban, South Africa Department of Nephrology, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa 3 Donald Gordon Medical Centre, Klerksdorp Hospital, and National Kidney Foundation of South Africa, Johannesburg, South Africa 1 2

Corresponding author: A M Meyers (nkfsa@mweb.co.za)

Chronic kidney disease (CKD) can be considered to be present if a patient has a glomerular filtration rate <60 mL/min or markers of kidney disease that have been present for >3 months. These include proteinuria, haematuria and radiological abnormalities. Regardless of the stage of CKD, the approach is mainly similar. As stated in the South African Renal Society Guidelines for the early detection and management of CKD, early and appropriate investigation and timeous referral of these patients enable one to establish a specific diagnosis; treat reversible diseases; optimise management to slow the progression of CKD; identify and optimally manage comorbid conditions; and plan renal replacement therapy well before the patient develops end-stage kidney disease.

S Afr Med J 2015;105(3):236. DOI:10.7196/SAMJ.9414

Clinical aspects

Chronic kidney disease (CKD) can be considered to be present if a patient has a glomerular filtration rate (GFR) <60 mL/min or markers of kidney disease that have been present for >3 months. These include proteinuria, haematuria and radiological abnormalities. Regardless of the stage of CKD, the approach is mainly similar. As stated in the South African Renal Society Guidelines for the early detection and management of CKD, early and appropriate investigation and timeous referral of these patients enable one to: • Establish a specific diagnosis and treat reversible diseases.

• Optimise management to slow the progression of CKD. • Identify and optimally manage comorbid conditions.

• Plan renal replacement therapy well before the patient develops end-stage kidney disease.

History

As with any facet of clinical medicine, the clinician starts by taking a sound medical history. This is especially important with CKD, as the clinical manifestations are often subtle and insidious.

Past history

Patients may volunteer a history of definite kidney disease; if not, one should enquire about the following: • a history of periorbital or peripheral oedema • bouts of macroscopic haematuria in relation to viral infections (suggestive of immunoglobulin dimer isotype A (IgA) nephropathy) • recurrent urinary tract infections (vesico-ureteric reflux or anatomical abnormalities) • a past history of acute renal failure • symptoms of prostatism.

One should enquire routinely about a past history of hypertension, diabetes, gout, renal calculi, collagen vascular disease and chronic inflammatory diseases, such as rheumatoid arthritis.

Any chronic painful condition, such as chronic headache, back­ ache, osteoarthritis and dysmenorrhoea, may be significant, as they may result in excessive chronic analgesic intake.

• Drug history. The drugs most commonly responsible for CKD are non-steroidal anti-inflammatory drugs and compound analgesics.

Remember lithium in patients with bipolar disorders. Angiotensinconverting enzyme inhibitors and angiotensin II receptor blockers tend to cause acute or subacute deterioration of renal function in patients with CKD. • Past laboratory data. Having access to previous laboratory and radiological investigations is particularly important in CKD, as it enables the doctor to confirm chronicity and assess the rate of progression of the disease.

• Pregnancy. A history of pregnancy-induced hypertension (in the second or third pregnancies) or early-onset pre-eclampsia suggests pre-existing hypertension or CKD. • Family history. A family history of kidney failure or nephrotic syndrome may suggest disorders such as polycystic kidney disease, Alport syndrome, focal segmental glomerulosclerosis and IgA nephropathy. A family history of hypertension, diabetes and the metabolic syndrome assists with the evaluation of the patient’s cardiovascular risk profile.

• Current symptoms. A history of anorexia, nausea, weight loss, weakness, impaired effort tolerance, nocturia and muscle cramps suggests chronicity.

Physical examination

Although the clinical features of CKD are nonspecific, the examination may reveal the following: • General. Periorbital and/or peripheral oedema, pallor, gouty tophi, arthritis, signs of collagen vascular disease and macroglossia (amyloidosis).

• Cardiovascular. Hypertension, particularly with clinical evidence of established hypertension. Ejection systolic murmurs (anaemia) and a pericardial friction rub (uraemia).

• Chest. Pulmonary oedema suggests advanced CKD and pleural effusions occur in patients with nephrotic syndrome.

• Abdomen. Palpable kidneys (polycystic kidney disease), hepato­ megaly (amyloidosis), bruits (renal artery stenosis).

• Fundoscopy. Hypertensive and diabetic retinopathy.

• Prostate gland. Hypertrophy.

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• Central nervous system. Overt confusion or more subtle impair­ment of intellectual functions. Generalised muscle weakness, asterixis and sensory-motor peripheral neuropathy.

(CAT) scan) without contrast in patients with suspected renal calculi.

• Magnetic resonance angiography, CT angiography or a radio-isotope study for suspected renal artery stenosis.

Special investigations

In general, the clinician should – if possible – avoid exposing the patient to intravenous radio-contrast agents because of their nephrotoxicity.

Investigations are conducted to (i) ascertain the cause of the CKD; and (ii) assess the severity and chronicity of the disease.

Kidney biopsy

The following are indications for a kidney biopsy: • Patients with CKD whose kidneys are normal or near normal in size, where the diagnosis cannot be made by other means.

• Patients with a definite diagnosis, where the histology is essential for appropriate management and prognosis, e.g. lupus nephritis, vasculitis.

Laboratory investigations

• A urine examination is mandatory in all cases, i.e. dipstick, microscopy and quantitation of protein excretion. The last can be measured on a random specimen by calculating the protein/creatinine ratio. An ‘active’ urine sediment with microscopic haematuria and red cell casts suggests an underlying glomerulonephritis.

• Further tests to assist with the diagnosis include antinuclear antibody profile, antineutrophil cytoplasmic antibody, C-reactive protein, cryoglobulins, serum complement, hepatitis B and C profile, HIV, venereal disease research laboratory test and uric acid levels. Serum/urine protein electrophoresis and serum Freelite assay should be done in patients >40 years of age with unexplained CKD and anaemia in order to exclude paraproteinaemia.

• Tests to determine the severity of the CKD and associated metabolic/haematological abnormalities include: urea and electro­lytes, serum creatinine and estimated GFR. The last may be cal­culated by the CockcroftGault or modification of diet in renal disease (MDRD) formula or by measuring the 24-hour urinary creatinine clearance.

• Other tests include: full blood count, serum calcium, phosphate and iron studies.

Alkaline phosphatase and parathyroid hormone levels are measured to assess the presence of renal osteodystrophy.

Radiological investigations

The most cost-effective examination is renal ultrasonography. This should be performed in all patients and the documentation of small echogenic kidneys supports the diagnosis of CKD. However, the presence of normal-sized kidneys, while suggesting acute renal disease, does not exclude CKD. Ultrasound is also useful for diagnosing obstructive uropathy and may detect asymmetrical kidney size, suggesting possible renovascular disease.

Other important investigations include: • Voiding cysto-urethrography to rule out vesico-ureteric reflux.

• A computed tomography (CT) scan (also known as the computed axial tomography

Screening

Proteinuria/haematuria

No

Yes Next year: screening Clinic/ General practitioner

History, physical examination, spot urine, urinalysis

Specialist physician

U/E creatinine/eGFR decline 24-h proteinuria

Nephrologist

Medical check and renal biopsy

Fig. 1. Urine dipstick screening for renal disease. (U/E = urea and electrolytes; eGFR = estimated glomerular filtration rate.)

Screening

Haematuria

No

Yes Next year: screening Clinic/ General practitioner

History, physical examination early-morning urine, spot urine

Specialist physician

Medical check and imaging

Cytology Ultrasound imaging

Nephrologist

Possible blood chemistry ?

Urologist

Fig. 2. Management of positive haematuria screening.

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• Patients with an established diagnosis, such as diabetic nephropathy, who have unexplained deterioration of kidney function.

Contraindications to kidney biopsy include bilateral small kidneys, uncontrolled hypertension, urinary tract or perinephric infection, polycystic kidneys and a bleeding diathesis.

Significance and evaluation of urine tests

A urine test at the bedside or in a clinic (urine dipstick) is a valuable screening and management tool.

Key findings are: • proteinuria • haematuria • leucocyturia and nitrites • other.

Proteinuria. The role of proteinuria testing using urine dipsticks, is key in the screening for renal diseases.

• A proteinuria >3+ is most likely of glomerular origin. Proteinuria is toxic to the tubules; hence it may lead to renal failure.

• Proteinuria of 2+ or 1+ is significant and needs to be further quantified to estimate the 24-hour protein loss. This can be further quantified by measuring the protein/creatinine ratio. Timed urine collections, traditionally for 24 hours, are cumbersome and often inaccurate. These can now be replaced by the more convenient spot urine protein/creatinine ratio. A positive proteinuria test needs to be repeated to minimise the non-significant proteinuria found during heavy exercise, fever and stress.

• Common significant proteinuria is found in pyelonephritis, glomerulonephritis, nephrotic syndrome, diabetes, pre-eclampsia, HIV associated nephropathy, congestive heart failure and malignant hypertension.

Haematuria. If a urine dipstick is positive for blood, this needs to be confirmed by urine microscopy, as a urine dipstick test cannot distinguish blood from haemoglobinuria or myoglobinuria.

• Haematuria, and proteinuria, can be of renal or post-renal origin.

• Haematuria is associated with urethral causes (stricture, trauma), bladder causes (infections, tumour, trauma, stones) or ureteric (stones) renal causes, including glomerulonephritis, interstitial nephritis, tumours and trauma.

• A combination of proteinuria and haematuria may help to define the diagnosis of a condition, e.g. a diabetic patient is expected to

have pure proteinura owing to diabetic nephropathy. Additional haematuria may prompt investigation for other causes, including pyelonephritis.

Leucocyturia and nitrites • Leucocyturia often indicates infection anywhere in the urinary tract; when combined with a positive nitrite test, it is associated with infection in three-quarters of cases.

• Persistent leucocyturia could be associated with the tubercle bacillus, renal stones or interstitial nephritis.

• A urine culture needs to be performed to diagnose the causal organism, followed by an antimicrobial sensitivity test.

Other useful tests. More tests are available on some urine dipsticks; these may include pH and specific gravity, which are useful for the assessment of patients with acidosis and dehydration.

Figs 1 and 2 show algorithms that may assist in the management of a patient with proteinuria and/or haematuria.

Essential renal function tests

The serum creatinine – not the serum urea – is the most essential measurement. Taken alone, a mere creatinine level is not sufficient to estimate kidney function. A normal creatinine in a thin and especially elderly female, i.e. those with reduced muscle mass, could represent significant renal failure. Therefore, all patients who are at risk of CKD should have an eGFR.[1] The previously discussed MDRD formula is more routinely available from all pathology laboratories in South Africa and laboratories express the eGFR as correlated to the definitions of CKD. If 24-hour urine collection is to be used to estimate the GFR, there are two prerequisites: (i) if the doctor explains to the patient what is required, an accurate 24-hour collection can usually be obtained, but only as an outpatient; (ii) creatinine clearance overestimates stages 1 - 4 CKD. Accurate clearance can be obtained by measuring the 24-hour urine collection (creatinine and urea clearances, adding them together and dividing by 2) (B Goldburg – personal communication).

Whichever method is used, the eGFR not only stages the CKD but is essential in monitoring progress over time. eGFR tests should be performed more frequently in potentially high-risk and elderly persons.

References 1. Meyers AM. Significance, definition, classification and risk factors of chronic kidney disease in South Africa. S Afr Med J 2015;105(3):233-236. [http://dx.doi.org/10.7196/SAMJ.9412]

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ARTICLE

Management of patients with chronic kidney disease T Gerntholtz,1 FCP (SA); G Paget,2 MB BCh, FCP (SA), Cert Nephrology (SA), MMed; P Hsu,3 MB BCh, FCP (SA); A M Meyers,4 MB BCh, FCP (SA), Cert Nephrology (SA), FRCP (Lond) Life Fourways Hospital, Johannesburg, South Africa Division of Medicine (Nephrology), Faculty of Health Sciences, University of the Witwatersrand, and Charlotte Maxeke Johannesburg Academic Hospital, Johannesburg, South Africa 3 Netcare Milpark Hospital, Johannesburg, South Africa 4 Donald Gordon Medical Centre, Klerksdorp Hospital, and National Kidney Foundation of South Africa, Johannesburg, South Africa 1 2

Corresponding author: A M Meyers (nkfsa@mweb.co.za)

Co-operation between primary healthcare workers (clinic staff and general practitioners) and nephrologists is essential and the ability to refer patients timeously should be on a pre-negotiated and organised basis. This article deals with these aspects, including follow-up guidelines and management and treatment strategies, including lifestyle changes where indicated and referral for end-stage renal failure, i.e. for dialysis and transplantation.

S Afr Med J 2015;105(3):237. DOI:10.7196/SAMJ.9417

Referral of patients to a nephrologist

It is crucial to establish a trusting and co-operative relationship between the primary care practice/ unit and nephrologist, with easy access between both. Many patients with chronic kidney disease (CKD) can be sufficiently managed in-between infrequent nephrological consultations.

It is important to first screen those at risk for kidney disease, including those with: • hypertension • diabetes • HIV infection • a family history of kidney disease • a clinical picture compatible with kidney disease.

In the abovementioned cases, those with the following clinical characteristics would require timeous referral: • urinary abnormalities on dipstick testing • haematuria • proteinuria (>1+); this should be measured using a spot urine albumin or protein to creatinine ratio (first morning void preferred but not essential) • reduced glomerular filtration rate (GFR), i.e. stage 3 - 5 CKD (GFR <30 - 60 mL/min) or with rapidly rising serum creatinine • resistant hypertension, typically requiring ≥3 antihypertensive agents • any noticeable or significant changes in their clinical or histological status.

It is essential that all intervening blood and urine results are communicated to both a nephrologist and primary care practice.

Timeous referral to a nephrologist will allow: • management of the complications of CKD, e.g. renal anaemia, bone mineral disease, hypertension • preparation for the appropriate renal replacement therapy, i.e. transplantation v. dialysis, either peritoneal or haemodialysis • insertion of catheters and fistulas • exploration of funder options, e.g. state or private.

Follow-up of CKD patients in South Africa Importance of CKD follow-up

Worldwide, CKD is believed to affect 10% of the population; so one could expect around 500 000 people to be affected in South Africa (SA).

SA has very high prevalence rates of three important diseases that put people at risk of CKD, i.e. hypertension, type 2 diabetes mellitus and HIV. Prevention of progression of CKD is best achieved earlier than later.

Delay of progression to end-stage kidney disease (ESKD) is particularly important in a resource-limited setting such as SA, where access to dialysis is limited by suitability for renal transplantation, particularly in the state sector.

Identifying patients who need follow-up and follow-up strategies

Those most at risk should be screened annually by assessing GFR and urinary protein (this can be easily performed on spot urine protein or albumin/creatinine ratios). Patients with the following are included: • hypertension • diabetes • HIV infection • vascular disease (coronary and peripheral) • advanced age, especially bone pain and proteinuria in the elderly (myeloma is quite common) • a family history of kidney disease • a recurring urinary tract infection (especially in children) • nephrotoxic drug use – non-steroidal anti-inflammatory drugs (NSAIDs), lithium and tenofovir.

One should consider referral to a nephrologist for an opinion in the following situations: • Proteinuria, especially >1 g/day or worsening proteinuria and/or persistent haematuria, as these may indicate glomerulonephritis.

• GFR <60 mL/min or GFR worsening rapidly (acutely or >5 mL/year).

• All children should be referred.

• Familial kidney diseases, e.g. polycystic kidney disease.

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Most patients can be reviewed annually, but consider more frequent visits/investigations in the following situations: • When patients are ill or have to undergo surgery.

• Poor blood pressure (BP) control, provided the patient is compliant.

Aim to maintain BP <130/80 mmHg. • Poor control of diabetes (glycated haemoglobin (HbA1C) >8%).

Beware of increased potency of hypoglycaemic drugs at lower GFR. • GFR <30 mL/min.

• Significant comorbidities (especially cardiac disease).

Types and frequency of investigations in CKD

• BP should be checked at each visit.

• Proteinuria and creatinine should be checked at least annually, but more frequently in those with glomerular disorders and progressive CKD. • Renal imaging should be performed as a screening test on every person with CKD. It may need to be repeated to screen for malignancies and when a sudden decline in renal function occurs – to rule out obstruction.

• Haemoglobin (Hb) should be checked at least annually, but needs to be reviewed at least every 3 months when GFR <30 mL/min.

In anaemic patients, it is important to check iron status before starting erythropoietin therapy – try to maintain Hb 11 - 12 g/dL. • In all patients with GFR <30 mL/min it is important to monitor secondary hyperparathyroidism – check corrected serum calcium and phosphate. Check parathyroid hormone at least 6-monthly.

• Monitoring of serum potassium is also important in CKD patients, especially those on angiotensin-converting enzyme (ACE) inhibitors and with a lower GFR (<30 mL/min).

• Remember comorbid conditions – patients with diabetes need cardiovascular review, including stress and pulse rate testing, review of foot health and retinopathy/cataracts at least once a year; those with ischaemic heart disease also require cardiac review at least once a year.

Remember that cardiovascular mortality is high in cases of CKD.

Conservative management of CKD patients in SA Importance of management of CKD

• CKD management is particularly important to prevent or delay progression to ESKD in a resource-limited setting such as SA, where the state will only chronically dialyse patients suitable for transplantation.

• Seeing patients earlier in the course of ESKD, allows better planning for renal replacement therapy (RRT) should the need arise. Patients not eligible for state dialysis programmes will have waiting periods for cover for RRT imposed by medical aids for up to 12 months. Patients may also be able to undergo transplantation before needing dialysis.

Aspects of management of CKD

• Lifestyle and diet. These will be covered in the next section.

• Hypertension. Aim to achieve consistent BP <130/80 mmHg. Multiple drugs may be required. ACE inhibitors and angiotensin II receptor blockers (ARBs) are useful agents, particularly in proteinuric patients, but need to be used with care in the elderly and in those with vasculopathy and advanced CKD. Refer to the hypertension guideline for use of antihypertensive agents for multiple therapeutic purposes.[1]

• Proteinuria. There is currently little and controversial evidence for the use of ACE inhibitors and ARBs as agents to prevent the onset of albuminuria and progression of renal disease in patients with microalbuminuria other than in hypertensive nephrosclerosis.

However, in diabetes or chronic non-diabetic glomerulonephritis with overt proteinuria evidence supports the use of ACE inhibitors or ARBs to prevent or delay progression of CKD. Currently, evidence for the combined use of these agents to delay progression is controversial (see results of the ONTARGET study[2]). Overall control of BP to at least 130/80 mmHg is perhaps the most important aspect of control of proteinuria, regardless of the agents used.

Note that non-dihydropyridine calcium channel blockers such as verapamil also have antiproteinuric properties and act synergistically with ACE inhibitors or ARBs. Of considerable importance is review of the use of ACE inhibitors and ARBs in patients with stages 4 and 5 CKD due to the possible production of potentially dangerous electrolyte charges or sudden and permanent end-stage renal failure (ESRF). This is of particular importance in the elderly and diabetics.

• Diabetes. In both type 1 and 2 diabetes evidence exists that good control (HBA1c <7%) of glucose has a beneficial effect on progression and prevention of CKD, particularly of other microvascular complications.

• Anaemia. This will be covered in more detail in the April 2015 edition of CME. Maintenance of Hb 10 - 12.5 g/dL is optimal and improves quality of life. However, published evidence does not support the notion that control of anaemia delays progression or improves cardiovascular mortality. Care should be exercised with therapy so as not to exceed Hb 13 g/dL. • Planning RRT. This is an often neglected area of CKD management. It is acceptable and ideal below a GFR 20 mL/min to consider and arrange access for dialysis, or ideally pre-emptive kidney transplantation.

• Avoidance of nephrotoxic procedures and medications. This is a particularly important area of CKD management. Thought should be given to the real risk/benefits ratio of contrast procedures.

Patients should be educated to discuss the advisability of continuing medications such as diuretics, certain antihypertensives and metformin with their doctors when they are ill or have to undergo surgery. CKD patients need to be warned to avoid NSAIDs, certain combination analgesics and some herbal medications that may lead to acute renal failure.

Modification of lifestyle and diet for CKD patients in SA Importance of lifestyle/behaviour

• Prevention of progression of CKD. There is good evidence that practices such as smoking can accelerate progression to ESKD. Obesity may induce renal disease and/or diabetes.

• Prevention of cardiovascular morbidity/mortality. It is well known that CKD patients are at high risk of cardiovascular disease, which is exacerbated by being centrally obese, smoking or having poor control of diabetes and hypertension.

• Eligibility for RRT. This is a somewhat uniquely SA issue. Severe obesity (body mass index (BMI) >35 kg/m2), smoking and abuse of substances such as alcohol, may preclude patients from state dialysis and transplantation programmes.

Aspects of lifestyle and diet

• Smoking cessation is important to avoid the progression of CKD and the development of cardiovascular disease.

• Ideally, keep caloric intake to 30 - 35 kcal/kg/day, although if overweight, reduce it to 25 kcal/kg/day.

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• In earlier stages of CKD (3 - 5) protein restriction of 0.8 g/kg/day may be beneficial to avoid progression of CKD. Protein restriction is not advisable for dialysis patients, who should eat protein 1 - 2 g/kg/day.

• Fluid intake should exceed urine output by around 500 mL/day, or patients can be advised to weigh themselves daily to titrate intake/diuretic doses/fluid restriction against their established dry weight. Patients with cardiac failure may need more aggressive fluid restriction. Patients should be cautioned to reduce diuretic doses when fluid losses are high, e.g. sweating in hot environments, gastroenteritis.

• It is unhealthy to consume more than 14 units of alcohol per week for males, or 7 units per week for females.

• Salt restriction helps to control thirst and maintain dry weight (and BP). Ideally, patients should add no salt when cooking food or to any food. Salt intake should be restricted to 1 - 2 g/day.

• It is advisable to keep potassium intake at 2 - 3 g/day. Foods to be avoided are potatoes (soaking overnight in water will remove potassium), dried fruits, tomatoes, bananas, nuts and sweets. It is best to refer patients to a dietitian to discuss their diets.

• In terms of calcium and phosphate, patients should be advised to limit the intake of high calcium foods (dairy products), and avoid vascular and other ectopic calcification, especially when using calcium-containing phosphate binders. Once the GFR falls below ~30 mL/min, it is important that patients are advised to limit phosphate in the diet (e.g. bran, brown rice, dried beans, lentils, offal, salmon, chocolate, cola drinks and milk products).

RRTs – dialysis, transplantation and organ donation

RRTs place a great financial burden on our healthcare system. The demand for dialysis and transplantation greatly outweighs the supply of available facilities. This is essentially why early preventive therapy is vitally important to delay and minimise progression of renal disease.

For those with ESKD, timeous referral for assessment for transplantation is vital. Increased non-related living donation, related living donation and pre-emptive transplantation will improve quality of life and increase available dialysis slots to accommodate new ESKD patients.

In SA there is a significant number of patients suffering from ESKD, especially among the African population (as a result of malignant hypertension). HIV infection has also increased the number of patients requiring RRT, as it is a cause of CKD. All patients suffering from ESKD should be considered for RRT, which includes: • peritoneal dialysis • automated peritoneal dialysis • haemodialysis • renal transplantation.

Dialysis

There are few contraindications to dialysis, the main concern usually being quality of life and survival. Patients with the following chronic illnesses will probably not benefit from dialysis, as mortality will be high: • severe cardiomyopathy with refractory cardiac failure • advanced liver cirrhosis • disseminated, terminal malignancy • end-stage chronic obstructive pulmonary disease • severe dementia • debilitating cerebrovascular accident.

Regrettably, in SA, financial constraints often play an important role in determining the availability of dialysis. We should endeavour to offer all our patients appropriate RRT, as the alternative is unthinkable. Nevertheless, currently probably only about 10% of those who would benefit from dialysis are receiving this therapy. In the past 10 years, the economy of SA has grown and the availability of dialysis centres should likewise have improved. This is, however, questionable but nonetheless all patients with ESKD should at least be referred to a renal facility for assessment.

Transplantation and renal donation

The number of patients awaiting renal transplantation has increased over time. The waiting time has increased owing to widening of the gap between allograft supply and demand.

There is an urgent need to increase the donor pool, potentially from: • deceased donors • living related donors • living non-related donors.

All provinces have organ transplant co-ordinators who should be contacted for all potential deceased donors. A complete list of co-ordinators is available from the Organ Donor Foundation (ODF), telephone number 0800226611, or after hours emergency number 0847419484. The ODF website can also be visited at www.odf.org.za. We should all try to encourage an increase in living kidney donation despite cultural misconceptions. This will entail educating and increasing awareness of organ donation in our communities. Potential living donors can contact the National Kidney Foundation of SA (NKFSA) for more information by sending an e-mail to nkfsa@mweb.co.za.

SA has led the world in transplanting deceased HIV-positive donors to HIV-positive recipients, with good preliminary results. This programme has already transplanted a growing number of patients under the leadership of Dr Elmi Muller at Groote Schuur Hospital, Cape Town, SA. Living-related allograft recipients enjoy a significant graft survival advantage over those who receive deceased donor graft. Living donor transplant has the advantage of being performed with minimum delay.

Pre-emptive transplant (transplantation prior to dialysis) is possible.

Evaluation of a living donor would entail: • compatible donor and recipient blood group • cross-match between the individuals • human leukocyte antigen • typing.

If compatible, the donor is to be scheduled for further evaluation.

Contraindications to donation: • proteinuria/haematuria • moderately abnormal urological anatomy • active infection • chronic active viral infection (hepatitis B or C and/or HIV) • active malignancy • history of malignancy – lung, breast, renal, gastrointestinal, haematological, melanoma • chronic illness, or cardiac, pulmonary, liver, autoimmune, neurological ilnesses • family history of renal cell cancer • diabetes mellitus • significant hypertension • nephrocalcinosis and bilateral or recurrent kidney stones • poorly controlled psychosis • substance abuse • pregnancy.

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Donor nephrectomy

Although 50% of functioning renal mass is removed, post-nephrectomycompensating hypertrophy in the remaining normal kidney returns the GFR to approximately 70% of baseline at 10 - 14 days.

Long-term follow-up studies have not shown progressive loss of GFR over time.

Donor survival was similar to that of the general population matched for age, sex and race. The rate of ESKD in the donor group was lower than that among the general population.

Laparoscopic donor nephrectomy is performed in some transplant centres in SA, which may shorten hospital stay for the donor.

Female donor

A female donor of child-bearing age should have completed any plans for a family prior to considering kidney donation. There is an increased risk for fetal loss, gestational diabetes, gestational hypertension and pre-eclampsia during pregnancy after kidney donation than in pregnancy in non-donors.

N.B.: Organ trading and organ donation involving any financial transaction between donor and recipient are illegal in SA.

Evaluation of potential renal transplant recipient

Kidney transplantation is the treatment of choice for ESKD, although there is growing evidence that the dialysis survival rate in SA is higher than in most other countries. Successful kidney transplantation improves the quality of life of most patients compared with dialysis.

Contraindications: • untreated infection • malignancy with short life expectancy • chronic illness with life expectancy <1 year • poorly controlled psychosis • active substance abuse.

All other patients should be assessed and evaluated by the transplant team to ascertain age suitability for transplantation. Age is no longer considered a contraindication to transplantation. Many patients >60 years of age have been transplanted safely. Assessment will focus on fitness of the patient to undergo surgery.

Renal diagnosis

The type of original kidney disease is not a contraindication to transplantation. Although many diseases recur in the allograft and occasionally lead to graft failure, e.g. focal segmental hyalinosis and IgA nephropathy, no disease recurrence is so common as to preclude a patient from transplant.

Renal function

There are recommendations for adult candidates for placement on the transplant list when the GFR is <18 mL/min with progressive renal disease.

Nephrectomy

Pre-transplant nephrectomy of a potential recipient is not recommended. The only exception is autosomal polycystic kidney disease, which may require nephrectomy owing to recurrent symptomatic cyst-related complications or a very large size cystic kidney that makes transplant surgery difficult.

Coronary artery disease (CAD)

All patients with a high risk for CAD (especially diabetics) usually have a full cardiac assessment by a cardiologist prior to consideration for listing. Cardiovascular disease is the leading cause of death after kidney transplantation.

Cerebrovascular disease

Older patients and patients with risk factors will be evaluated with carotid Doppler to exclude carotid stenosis. All patients who have had a transient ischaemic attack need to be evaluated fully by a neurologist.

Obesity

Extremely obese patients (BMI >35 - 40 kg/m2) are excluded from transplantation, unless significant weight loss is achieved.

References 1. James PA, Oparil S, Carter BL et al. 2014 evidence-based guideline for the management of high blood pressure in adults: Report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014;311(5):507-520. [http://dx.doi.org/10.1001/jama.2013.284427] 2. The ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008;358:1547-1559. [http://dx.doi.org/10.1056/NEJMoa0801317]

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ARTICLE

Clinical aspects of chronic kidney disease B van Rensburg,1 MB ChB, MMed (Int); A M Meyers,2 MB BCh, FCP (SA), Cert Nephrology (SA), FRCP (Lond) Emeritus Professor, Division of Nephrology, Department of Internal Medicine, Faculty of Health Sciences, University of the Free State, Bloemfontein, South Africa 2 Donald Gordon Medical Centre, Klerksdorp Hospital, and National Kidney Foundation of South Africa, Johannesburg, South Africa 1

Corresponding author: A M Meyers (nkfsa@mweb.co.za)

Any patient seeking any form of medical advice at any clinic or hospital, or from a doctor or other healthcare worker, should have their blood pressure recorded and a urine dipstick test done. The most useful indication of a diagnosis of any stage of chronic kidney disease, is the presence of either hypertension, urinary dipstick abnormality or both. Many practitioners frequently refer such patients to urologists, which must be discouraged. Referral should be to a nephrologist or specialist physician.

S Afr Med J 2015;105(3):237. DOI:10.7196/SAMJ.9413

Clinical course of chronic kidney disease

Although patients with kidney disease may present with symptoms such as oedema (nephritic or nephrotic syndrome) and changes in urine composition, histological and functional renal decompensation can often not be diagnosed owing to a lack of symptoms. Undetected loss of kidney function over an extended period of time can eventually lead to the symptomatic stage of kidney failure or even end-stage renal disease. The only indication of the presence of renal disease in an asymptomatic patient may be a raised blood pressure with or without urine abnormalities detectable on urine examination, such as microalbuminuria and proteinuria cells, and casts on urine microscopy.

General practitioners – not the nursing staff – should therefore perform urine dipstick tests for all their patients. Current trends where tests are not conducted by the examining medical professional but rather at a ‘test station’ should be dis­ couraged as consistency and expertise in the interpretation of the results are very important in the examination process. If blood or protein is detected, a fresh specimen should be centrifuged and examined under the microscope.

General practitioners commonly mistake urine abnormalities for urinary tract infections and invariably refer patients to urologists. Factors that would necessitate referral to a nephrologist rather than a urologist are: • degree of proteinuria – more protein, more likely glomerular disease • presence of casts

The aetiology of CKD cannot always be easily determined and it is important to take a detailed history combined with a thorough clinical examination. It is often necessary to include examination of both structure (renal ultrasound) and function (estimated GFR (eGFR)) of the kidneys in the evaluation.

CKD often presents as a urinary abnormality in the face of normal renal function. Detecting such patients early may protect renal function and delay the need for dialysis by treating the underlying disease, reducing hyperfiltration and treating comorbidities. A complication of CKD is that patients have a higher risk

• in addition, any of the following: • kidney failure • complicated hypertension • serological activity on blood tests (e.g. erythrocyte sedimentation rate and antinuclear factor).

When a reduced glomerular filtration rate (GFR) is present, comorbidities should always be managed in their own right, e.g. anaemia, hyperkalaemia, metabolic disorders (i.e. calcium and phosphorus disorders) and – very important in the South African (SA) context – primary hypertension, which is the main cause of chronic kidney disease (CKD).

Normal High risk Hypertension DM Smoking

Death Complication Stroke Acute MI CHF

End-stage kidney disease

Kidney damage Proteinuria Haematuria

(Dialysis) Kidney failure GFR

CKD

Fig. 1. Clinical course of chronic kidney disease (CKD). CKD progresses from stage 1 to stage 5. More patients may die of cardiovascular diseases than progress to a higher stage of CKD. (MI = myocardial infarction; CHF = congestive heart failure; GFR = glomerular filtration rate; DM = diabetes mellitus.)

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CKD and CVD: Cardiorenal association

The classic target organs in CVD (heart, brain and kidneys) may be associated with CKD. Specifically, patients with CKD (especially those on dialysis) often have a combination of chronic inflammation and chronic malnourishment that may contribute to the pathogenesis of accelerated atherosclerosis.

CKD and CVD share many common risk factors, which is evident in the increased morbidity and mortality rates for stroke, MI

50 CVD risk or renal death, %

Death 40

Renal death

30 20 10 0

GFR (mL/min) Proteinuria

60 - 89 (+)

60 - 89 (-)

30 - 59

15 - 29

US general population (15≤GFR<90 mL/min/1.73 m2), N=27 998, follow-up 66 months

Fig. 2. Comparison of the rate of death prior to transplant/dialysis and renal replacement therapy. Data, with modification, from Keith et al.[2] 1 200 <60 mL/min/1.73 m2 1 000

Patients, n

of developing cardiovasvular disorders (CVDs), e.g. stroke, acute myocardial infarction (MI) and congestive heart failure (CHF). This risk increases exponentially as CKD progresses towards end-stage kidney disease and patients sometimes die of this complication before they reach the final stage of CKD, when renal replacement therapy is required. This is indicated by wider arrows in Fig. 1.[1] The diagnosis of CKD is often accompanied by (i) microalbuminuria (earliest abnormality) or (ii) proteinuria on the urine dipstick test, even before any significant reduction in kidney function can be detected.

It may happen that CKD is only diagnosed when a complication such as anaemia or a bone mineral disorder occurs. These complications are more frequently found in stages 4 and 5 CKD, when kidney function is significantly reduced. This again shows the importance of early diagnosis in order to limit or prevent such complications.

Unfortunately, a large group of public sector patients in SA are referred to renal units for the first time when they present with end-stage renal failure (ESRF). This may be the result of insufficient access to adequate healthcare facilities and no regular follow-up visits, especially when abnormalities are detected in the earlier stages of CKD. Patients are often admitted for acute kidney failure, which could have been prevented with regular checkups.

Kidney disease as a result of drug toxicity is not always associated with urine dipstick test abnormalities. Furthermore, there may not be any evidence of previous risk factors for CKD. When prescribing drugs that are excreted via the kidney or that are nephrotoxic, one should evaluate and regularly monitor the eGFR. Importantly, patients >45 years of age lose GFR by 1 mL/min/year, even though they may present with a ‘normal’ serum creatinine level.

Consequently, many elderly people fall into stage 3 CKD (<60 mL/min/1.73 m2), despite an apparent normal creatinine level.

800 600 400 200 0

6

14

22 30

38

46 54

62

70 78

86

94

102 110 118 126 134

Estimated GFR (mL/min/1.73 m2) VALIANT study: N=14 527. GFR<60 mL/min/1.73 m2 was 4 862 (33.5%)

Fig. 3. Distribution of estimated glomerular filtration rate at baseline among 14 527 patients. Data, with modification, from Anavekar et al.[3]

and CHF. It is therefore very important to establish the possible relationship between CKD and CVD for any patient with early signs of CVD. Statistics show that CKD patients are more at risk of dying from CVD than ESRF. This is highlighted in Fig. 2,[2] where CVDrelated deaths and renal-related deaths in the US population are compared according to CKD function levels. In the earlier stages of CKD and even in the progressive stage 4 of CKD, patients are more likely to die from CVD than renal failure. Deaths from CVD in patients with proteinuria are more common than in those without proteinuria.

It has been reported in Europe, the USA and Japan that even a mild reduction in kidney function (stages 1 and 2) and/or the presence of proteinuria increases the risk of MI and stroke.

March 2015, Vol. 105, No. 3

It has, however, also been shown that kidney function is affected by CVD. In this regard the data from Anavekar et al.[3] show that one-third of patients who suffered from MI had kidney function related to stage 3 CKD (eGFR <60 mL/min/1.73 m2) (Fig. 3).

From the same study[3] the follow-up of MI sufferers within 3 years after the first attack showed that there is a correlation between increased risk of reinfarction and advanced stages of CKD. This can be seen in Fig. 4.

Common risk factors preceding either CKD, CVD or both include endothelial damage caused by fluid retention and hypervolaemia. Anaemia is a risk factor for the development of CVD. In patients with stages 3b - 5 CKD, anaemia is a risk factor in hastening progression to ESRF. Therefore, anaemia should be treated accordingly. In

CONTINUING MEDICAL EDUCATION

60 GFR: ≥75.0 mL/min/1.73 m2 GFR: 60.0 - 74.9 mL/min/1.73 m2 GFR: 45.0 - 59.9 mL/min/1.73 m2 GFR: <45.0 mL/min/1.73 m2

p<0.001

Estimated event rate, %

50

CKD and lifestylerelated diseases

40 30 20 10 0

Consequently, it might in future become advisable to place our earlier CKD patients (e.g. those with stages 3a or 3b CKD) on a fish/poultry/egg diet and omit red meat completely.[4]

Death from reinfarction Cardiovascular causes

CHF

Stroke

Resuscitation Composite endpoint

VALIANT study: Acute myocardial infarction (N=14 527) Fig. 4. Kaplan-Meier estimates of the rates of death at 3 years from cardiovascular disease causes reinfarction, congestive heart failure, stroke, resuscitation after cardiac arrest, and the composite endpoint, according to the estimated glomerular filtration rate at baseline. Data, with modification, from Anavekar et al.[3]

Table 1. WHO clinical criteria for metabolic syndrome* Insulin resistance, identified by one of the following: • Type 2 diabetes • Impaired fasting glucose • Impaired glucose tolerance • Or, for those with normal fasting glucose levels (<110 mg/dL), glucose uptake below the lowest quartile for background population under investigation under hyperinsulinaemic, euglycaemic conditions Plus any two of the following: • Antihypertensive medication and/or high blood pressure (≥140 mmHg systolic or ≥90 mmHg diastolic) • Plasma triglycerides ≥150 mg/dL (≥1.7 mmol/L) • High-density lipoprotein cholesterol <35 mg/dL (<0.9 mmol/L) in men, or <39 mg/dL (1.0 mmol/L) in women • BMI >30 kg/m2 and/or waist:hip ratio >0.9 in men, or >0.85 in women • Urinary albumin BMI = body mass index. *Derived from Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: Diagnosis and classification of diabetes mellitus: Provisional report of a WHO consultation. Diabet Med 1998;15:539-553.

addition, the following factors affect the function and structure of the kidneys and heart vasculabia: hypertension, calcium, phosphate and parathyroid hormone abnormalities, inflammation, increased sympathetic tone, disturbances in the renin-angiotensin-aldosterone axis, oxidative stress, dyslipidaemia, smoking and an increase in the levels of asymmetric dimethylarginine.

NB: A recent and very important study was done on the role of increased plasma levels of trimethylamine N-oxide (TMAO)

in CKD, which is also associated with coronary artery disease pathogenesis. This study found that a gut microbial-dependent metabolite of dietary choline, lecithin (phosphatidylcholine) and L-carnitine occur early in patients with CKD. These serum levels increase with the severity of CKD. TMAO was found to cause more rapid renal functional deterioration, vascular endothelial damage, renal fibrosis, atheroma and CVD. These dietary amino acids are especially high in all red meats (including pork), but not in poultry or most fish.

March 2015, Vol. 105, No. 3

Generally, lifestyle-related disease (LRD) is defined as a disorder affected by and normally related to aspects of diet and lifestyle. As communities progress from hunter gatherers/subsistence farmers, where food was less readily available and required physical effort to obtain, to a more affluent lifestyle with less exercise and ‘fast food’, this problem has increased worldwide. SA is no exception, and in future the impact on healthcare is expected to increase.

It needs to be acknowledged that there is also a genetic factor to LRDs, but the most common complications of metabolic syndrome (excessive or non-balanced eating and lack of exercise or movement, which causes fat accumulation even to the extent of morbid obesity) are hypertension, diabetes and dyslipidaemia. The similarities between insulin resistance (pre-diabetes) and metabolic syndrome often result in the interchangeability of the two terms, with the only distinction related to the symptomatic presentation for diagnosis. Table 1 provides a guideline for the diagnosis of metabolic syndrome.

The direct relationship between contri­ buting factors of LRDs (e.g. smoking, lack of exercise and stress) and CKD has been well researched and can be caused by abdominal obesity accumulating in visceral fat, which may cause proteinuria or reduced kidney function. It is therefore of vital importance that early diagnosis of CKD should trigger changes in lifestyle and diet for the management and prevention of progression of CKD. This is even more important in the SA context, where healthcare is greatly affected by limited resources and funding.

References 1. Japanese Society of Nephrology. Japanese Guidelines. Clin Exp Nephrol 2009;13:201-202. [http://dx.doi.org/10.1007/s10157009-0135-0] 2. Keith DS, Nichols GA, Gullion CM, Brown JB, Smith DH. Longitudinal follow-up and outcomes among a population with chronic kidney disease in a large managed care organization.

Arch Intern Med 2004;164(6):659-663.

3. Anavekar NS, McMurray JJ, Velazquez EJ, et al. Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. N Engl J Med 2004;351(13):1285-1295.

4. Tang WHW, Wang Z, Kennedy DJ, et al. Gut microbiotadependent trimethylamine N-oxide (TMAO) pathway contributes to both development of renal insufficiency and mortality risk in chronic kidney disease. Circulation Res 2014;116(3):448-455. [http://dx.doi.org/ 10.1161/CIRCRESAHA.116.305360]

CONTINUING MEDICAL EDUCATION

ABSTRACT

Follow up raised blood pressure early for optimal results A recent study published in the BMJ investigated the optimal systolic blood pressure goal above which new antihypertensive medications should be added or doses of existing medications increased (‘systolic intensification threshold’). It also aimed to determine the relation between delays in medication intensification and followup and the risk of cardiovascular events or death. The authors used a retrospective cohort study of 88 756 adults with hypertension from The Health Improvement Network nationwide primary care research database.

Rates of acute cardiovascular events or death from any cause for patients with different hypertension treatment strategies (defined by systolic intensification threshold, time to intensification, and time to follow-up over the course of a 10-year treatment strategy assessment period) after adjustment for age, sex, smoking status, socioeconomic deprivation, history of diabetes, cardiovascular disease or chronic kidney

disease, Charlson comorbidity index, body mass index, medication possession ratio, and baseline blood pressure were followed.

During a median follow-up of 37.4 months after the treatment strategy assessment period, 9 985 (11.3%) participants had an acute cardiovascular event or died. No difference in risk of the outcome was seen between systolic intensification thresholds of 130 - 150 mmHg, whereas systolic intensification thresholds >150 mmHg were associated with progressively greater risk.

Systolic intensification thresholds >150 mmHg, delays >1.4 months before medication intensification after systolic blood pressure elevation, and delays of >2.7 months before blood pressure follow-up after anti­ hypertensive medication intensification were associated with increased risk of an acute cardiovascular event or death.

Xu W, Goldberg SI, Shubina M, Turchin A. Optimal systolic blood pressure target, time to intensification, and time to follow-up in treatment of hypertension: Population based retrospective cohort study. BMJ 2015;350:h158. [http://dx.doi.org/10.1136/bmj.h158] (Published 05 February 2015.)

Use the QR code above to access the full version of the article.

March 2015, Vol. 105, No. 3

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Chronic kidney disease List of contributors to the articles and information compiled by the National Kidney Foundation of South Africa Enquiries: Fanie du Toit (email: nkfsa@mweb.co.za; tel. number: 011-4472531)

List of contributors

Prof. A M Meyers Prof. A G Assounga Dr T Gerntholtz Dr P Hsu Dr B Mahala Prof. R Moosa Dr I P Naiker Prof. S Naicker Dr S Naidoo Dr G Paget Prof. C R Swanepoel Prof. I van Biljon Dr I van der Walt Prof. B van Rensburg

The National Kidney Foundation of South Africa (NKFSA) is most grateful to all the contributors, both from the public and private sectors, who have given so much of their time to make this publication possible.

References

The CME articles on chronic kidney disease (CKD) were inspired by and based on the format used in the Japanese Guidelines for the treatment of CKD. (Japanese Society of Nephrology. Japanese Guidelines. Clin Exp Nephrol 2009;13(3):192-248. [http://dx.doi.org/10.1007/s10157-009-0188-0]) Other references are included in some instances, but any reference not included may be requested by sending an email to nkfsa@mweb.co.za

Other resources and references

South African Renal Society (SARS): www.sa-renalsociety.org/ South African Transplantation Society (SATS): www.sats.org.za/ International Society of Nephrology (ISN): www.theisn.org S Afr Med J 2015;105(3). DOI:10.7196/SAMJ.9439

March 2015, Vol. 105, No. 3

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Nelson Mandela Children’s Hospital Trust is offering Bursaries for Paediatric Surgical Training and Subspecialty Paediatric Fellowships in 2015.

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University Hospital Limerick (UHL) seeks NCHDs for July 2015 intake “Supporting excellence in clinical care and medical education” What has UHL to offer?

1. The Hospital University Hospital Limerick (UHL) is one of the fastest growing academic hospitals in Ireland and our stated aim is to be in the top three University hospitals in Ireland by 2018 www.ulh.ie UHL is the principal teaching hospital of the Graduate Entry Medical School (GEMS), University of Limerick and has excellent research and educational links with the University of Limerick (UL). The hospital is the regional trauma centre serving a population of 378,410 in the mid-west region.

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2. Educational Activities In a recent Medical Council survey of trainees’ experience, trainees in the UL network of hospitals rated their clinical training higher than trainees at any of the other hospital networks in Ireland. This finding continues to bear testimony to the strong academic programmes that are in place within the UL Hospital network of hospitals.

With the advent of the Graduate Entry Medical School (GEMS) and its academic programmes, the delivery of strong post-graduate education and research programmes are now major goals. Within each specialty, there has been an expansion of consultant staff and development of a range of educational programmes and research opportunities. Career development programmes are available for all SHOs & Registrars.

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Lahinch, a premier surfing resort, is 50 minutes drive from the hospital. Today, the city has a growing multicultural population which is reflected in the diversity of cultural and entertainment needs of its population. The city is home to the Irish Chamber Orchestra, the World Music Centre, Daghda Dance Company and the internationally renowned Hunt Museum. It is growing in academic stature with several learning institutes available for students.

July 2015 Intake Applications are invited for the July 2015 intake in the following specialties:

Senior House Officers & Registrars in University Hospital Limerick n Emergency Medicine n Anaesthesia n Paediatrics & Neonatology n Medicine – Respiratory, Gastroenterology, Endocrinology, Rheumatology, Cardiology, Nephrology, Haematology, Oncology, Neurology, Acute Medical Assessment Unit, Elderly Medicine, Palliative Medicine n Obstetrics & Gynaecology n Surgery – Breast, Urology, Vascular, Colorectal n Ophthalmology n ENT n Oral Maxillofacial n Orthopaedics

For any of the above posts, please apply by forwarding your CV to mwhrecruitment@hse.ie Enquiries about any of these positions are welcomed on Tel: +353 61 482694/482786 and contact with the relevant Consultants can be arranged if required.

Caring, Courteous & Professional

www.ulh.ie

CPD

MARCH 2015

The CPD programme for SAMJ is administered by Medical Practice Consulting.

CPD questionnaires must be completed online at www.mpconsulting.co.za.

True (A) or false (B): SAMJ Prevention of Liver Fibrosis and Cancer in Africa: The PROLIFICA project 1. In sub-Saharan Africa (SSA), hepatitis B virus (HBV) infection is endemic and the HBV-related disease burden is high.

2. SSA has one of the highest HBV-related liver cancer rates in the world, and it is the most common cancer among both males and females.

Dementia in rural South Africa (SA) 3.

Primary dementia can be classified as a non-communicable disease caused by neurodegeneration in the brain.

4. In SA, disorders associated with neurodegeneration include traumatic brain injury (TBI), alcohol dependence and HIV infection.

The Vaccine and Cervical Cancer Screen project 2 (VACCS 2): Linking cervical cancer screening to a two-dose human papilloma­ virus (HPV) vaccination schedule 5. It is proposed that introduction of HPV vaccine into the Expanded Program on Immunization in SA will be greatly facilitated by providing two doses (at months 0 and 6) to primary school girls, while immunogenicity will be uncompromised because of the young age of the recipients.

TBI, the hidden pandemic 6. TBIs that are caused by interpersonal violence are inflicted largely by right-handed perpetrators, and typically result in frontal lobe and/or left temporal lobe injuries.

7. Poor impulse control and weak social skills result in dangerous situations for survivors and for those around them.

8. Adolescent TBI survivors were found to have committed crimes significantly more often than adolescents who had not had a TBI. Hypertension, end-stage renal disease and mesangiocapillary glomerulo­nephritis in methamphetamine users 9. Methamphetamine use is associated with malignant hypertension, mesangiocapillary glomerulonephritis and chronic kidney disease (CKD).

10. In addition to acute renal failure, the toxic effects of amphetamines include cardiomyopathy and ischaemic heart disease.

CME Significance, definition, classification and risk factors of CKD in SA 11. Primary hypertension occurs in 25% of SA’s black population and is the putative cause of stage 5 CKD in 40 - 60% of these patients.

12. Excluding post-traumatic causes, end-stage renal failure is the 5th most common cause of death in SA. Diagnostic approach to CKD 13.

Establishing the baseline estimated glomerular filtration rate (eGFR) is essential in deciding management of patients with CKD. 14. CKD can be considered to be present if a patient has a GFR <90 mL/min.

Management of patients with CKD 15. Dialysis is only available in state institutions to those patients who are considered candidates for renal transplantation.

16. In diabetes or chronic non-diabetic glomerulonephritis with overt proteinuria, evidence supports the use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers to prevent or delay progression of CKD. 17. Overall control of blood pressure to at least 130/80 mmHg is perhaps the most important aspect of the control of proteinuria, whatever the agents used.

Clinical aspects of CKD 18. The only clue to the presence of renal disease in an asymptomatic patient may be a raised blood pressure with or without urine abnormalities (such as microalbuminuria, proteinuria, and cells and casts on urine microscopy) detectable on urine examination.

19. Provided renal function remains normal in the face of persistent urinary abnormality, CKD can be ruled out.

20. Even a mild reduction in kidney function (stages 1 and 2) and/ or the presence of proteinuria increases the risk of myocardial infarction and stroke.

Readers please note: articles may appear in summary/abstract form in the print edition of the journal, with the full article available online via http://www.samj.org.za

A maximum of 3 CEUs will be awarded per correctly completed test.

INSTRUCTIONS 1. Read the journal. All the answers will be found there, in print or online.

2. Go to www.mpconsulting.co.za to answer the questions.

Accreditation number: MDB015/167/02/2015

March 2015, Vol. 105, No. 3

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