SAMJ Vol 105, No 7 (2015) by HMPG

JULY 2015

VOL. 105 NO. 7

Doctor-assisted suicide

513, 522, 526

Cause-of-death information – key to public health action

528

Social franchising primary healthcare clinics – a model for NHI?

531

Introducing the ‘Cochrane Corner’

548

Fibrinolytics for empyema

549

Reducing neonatal bloodstream infections

564

What do maternal ‘near misses’ tell us?

578

CME: Nutrition of infants and toddlers

603-608

JULY 2015

VOL. 105 NO. 7

GUEST EDITORIAL

SAMJ

510

Anger and Afrophobia in South Africa: What is a health practitioner to do? W Long, B Chiliza, D J Stein

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

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EDITOR’S CHOICE

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

CORRESPONDENCE

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

513

Encephalopathy caused by thiamine deficiency K Bateman

513

Legal assisted suicide in South Africa J V Larsen

514

New horizons for the repair of skin defects H Rode

515

Trends in lead exposure in a rural mining town in South Africa, 1991 - 2008 N Naicker, A Mathee

516

William Guybon Atherstone: His 8-day and 1 600 km house call to Oudtshoorn in 1890 S A Craven

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

IZINDABA 517 520 522

Tugela Ferry’s extensively drug-resistant tuberculosis – 10 years on Noakes’s adversaries get him in the ‘dock’ South Africans inured to death

524

OBITUARY Harry Stein

SAMJ FORUM

CEO AND PUBLISHER Hannah Kikaya | Email: hannah.kikaya@ hmpg.co.za MANAGING EDITOR Ingrid Nye TECHNICAL EDITORS Emma Buchanan Paula van der Bijl NEWS EDITOR Chris Bateman | Email: chrisb@hmpg.co.za PRODUCTION MANAGER (CMC) Emma Jane Couzens

CLINICAL ALERT 525 The bronchiolitis season is upon us – recommendations for the management and prevention of acute viral bronchiolitis H J Zar, D A White, B Morrow, C Feldman, S Risenga, R Masekela, H Lewis, P Jeena, S A Madhi 526

MEDICINE AND THE LAW Doctor-assisted suicide: What is the present legal position in South Africa? D J McQuoid-Mason

528

HEALTHCARE DELIVERY The importance of identified cause-of-death information being available for public health surveillance, actions and research P Groenewald, V Azevedo, J Daniels, J Evans, A Boulle, T Naledi, D Bradshaw

531 Social franchising primary healthcare clinics – a model for South African National Health Insurance?* A K L Robinson 535

MEDICAL EDUCATION The state of South African internships: A national survey against HPCSA guidelines* S Bola, E Trollip, F Parkinson

540

GENETICS A South African family with oculopharyngeal muscular dystrophy: Clinical and molecular genetic characteristics* C M Schutte, C M Dorfling, R van Coller, E M Honey, E J van Rensburg

EDITORIALS 544

Understanding the genetic diversity of South Africa’s peoples A Krause

545

Genomics in medicine: From promise to practice M F Urban

548

The Cochrane Corner in the SAMJ: Summaries of Cochrane systematic reviews for evidence-informed practice T Kredo, T Young, C S Wiysonge, M McCaul, J Volmink

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July 2015, Vol. 105, No. 7

DTP & DESIGN (CMC) Carl Sampson HEAD OF SALES AND MARKETING Diane Smith | Tel. 012 481 2069 Email: dianes@samedical.org JOURNAL ADVERTISING Charles William Duke Benru de Jager Reneé van der Ryst Ladine van Heerden ONLINE SUPPORT Gertrude Fani | Tel. 072 463 2159 Email: publishing@hmpg.co.za FINANCE Tshepiso Mokoena 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 Production and distribution services supplied and managed by Media Outsourcing, a wholly owned subsidiary of Cape Media Corporation. Tel. 021 681 7000 ISSN 0256-9574 Publisher website: www.hmpg.co.za SAMA website: www.samedical.org Journal website: www.hmpg.co.za

For further product information contact PHARMA DYNAMICS P O Box 30958 Tokai Cape Town 7966 Tel 021 707 7000 Fax 021 701 5898 Email info@pharmadynamics.co.za CUSTOMER CARE LINE 0860 PHARMA (742 762) www.pharmadynamics.co.za Fedaloc SR 30 mg. Each slow release tablet contains 30 mg Nifedipine. Reg. No.: RSA S3 37/7.1/0302. NAM NS2 10/7.1/0033. Fedaloc SR 60 mg. Each slow release tablet contains 60 mg Nifedipine. Reg. No.: RSA S3 37/7.1/0303. NAM NS2 10/7.1/0034. For full prescribing information, refer to the package insert approved by the Medicines Control Council, 25 November 2011. 1) IMS Data, March 2015; Units sold in the period 1 April 2014 – 31 March 2015. 2) Department of Health website http://www.health.gov.za – Accessed 09/04/2015. * Calculated cost for 30 tablets. FCE177/06/2015

RESEARCH 549

Impact of fibrinolytics on the outcome of empyema in South African children M Zampoli, A Kappos, C Verwey, R Mamathuba, H J Zar

554

The impact of highly active antiretroviral therapy on the burden of bacterial lower respiratory tract infections in children* K R de Campos, D D Granga, S Olorunju, R Masekela

558

Identification of a mutation in the ubiquitin-fold modifier 1-specific peptidase 2 gene, UFSP2, in an extended South African family with Beukes hip dysplasia* C M Watson, L A Crinnion, L Gleghorn, W G Newman, R Ramesar, P Beighton, G A Wallis

564

Impact of an educational intervention and clinical performance dashboard on neonatal bloodstream infections* M S Raban, C Bamford, Y Joolay, M C Harrison

567

Prevalence of Blomia tropicalis allergy in two regions of South Africa* A C Jeevarathnum, A van Niekerk, R Green, P Becker, R Masekela

570

Nodular thyroid disease and thyroid malignancy: Experience at Polokwane Mankweng Hospital Complex, Limpopo Province, South Africa* M M Z U Bhuiyan, A Machowski

573

Household fuel use and child respiratory ill health in two towns in Mpumalanga, South Africa* P N Albers, C Y Wright, K V V Voyi, A Mathee

578

Maternal near miss and maternal death in the Pretoria Academic Complex, South Africa: A population-based study* P Soma-Pillay, R C Pattinson, L Langa-Mlambo, B S S Nkosi, A P Macdonald

584

Intracranial suppuration: Review of an 8-year experience at Umtata General Hospital and Nelson Mandela Academic Hospital, Eastern Cape, South Africa* M A Anwary

589

Observed full blood count and lymphocyte subset values in a cohort of clinically healthy South African children from a semi-informal settlement in Cape Town* D Lawrie, H Payne, M Nieuwoudt, D K Glencross

596

Evaluation of the diagnostic accuracy of the HemoCue device for detecting anaemia in healthy school-aged children in KwaZulu-Natal, South Africa* T P Gwetu, M K Chhagan

600

Use of EMLA cream as a topical anaesthetic before venepuncture procedures in field surveys: A practice that helps children, parents and health professionals* T P Gwetu, M K Chhagan

CONTINUING MEDICAL EDUCATION

603

GUEST EDITORIAL Nutrition in toddlers R J Green

603

REVIEW Vitamin D deficiency and insufficiency in Africa and the Middle East, despite year-round sunny days R J Green, G Samy, M S Miqdady, M El-Hodhod, O O Akinyinka, G Saleh, J Haddad, S A Alsaedi, A Y Mersal, A Edris, M Salah

605

ARTICLES Management of severe acute malnutrition* J Cloete

606

Nutrition in children with long-term health conditions* A Westwood

607

Nutritional support of children with chronic liver disease* E D Nel, A J Terblanche

607

Iron deficiency in children* R Thejpal

*Full article available online only.

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Thomson’s gazelle, common in East Africa. Photo: Susan Flegg

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July 2015, Vol. 105, No. 7

GUEST EDITORIAL

Anger and Afrophobia in South Africa: What is a health practitioner to do? The facts seem to indicate that South Africa (SA) is one of the more violent places on earth. We have been, and continue to be, a country with significant levels of political violence, criminal violence and domestic violence.[1,2] And now, we are witnessing violence against fellow Africans. While many have termed this ‘xenophobia’, a more accurate term may well be ‘Afrophobia’. For clinician-scientists, many questions arise. In this editorial, we briefly consider a few of the most pertinent. An immediate question pertains to the causes of such Afrophobia. Many factors have been put forward, ranging from the macrostructural and socioeconomic (e.g. the colonial-apartheid legacy, persistent socioeconomic inequalities) through to the micropolitical and psychological (e.g. the effects of ‘foreign’ entrepreneurship on township economies, the possibility that some of those involved in the killings have a history of antisocial behaviour). Sadly, both parties in the conflict are among the most marginalised in the country today. A related question involves the relationship between the inter personal, institutional and structural violence that persists in SA. It is tempting to suggest that we are experiencing an epidemic of displaced anger that is sustained by a macropolitics of exclusion and a micropolitics of daily insults. Instead of confronting the source of our anger, we are scapegoating those with little or no connection to that source; certainly, such anger seems to be a dominant public emotion among South Africans today. Displaced anger can be theorised from different perspectives. A structural perspective may emphasise that income inequality has worsened since the advent of democracy, along with a growing recognition of the relationship between such inequality and psychological distress. A biological perspective may emphasise the universality of distress resulting from social hierarchies, while noting that different kinds of distress are seen in patriarchal v. nonpatriarchal societies. Either way, displacement may be helpful in making sense of why violence affects the most vulnerable members of SA society. In The Wretched of the Earth, Frantz Fanon[3] observes presciently that ‘[t]he colonized man will first manifest this aggressiveness which has been deposited in his bones against his own people. This is the period when [they] beat each other up, and the police and magistrates do not know which way to turn when faced with the astonishing waves of crime …’. A final question is how best to respond to this anger. We cannot but note that Nelson Mandela was a man who, by reaching out to all segments of the population and offering a vision of reconciliation,

510

helped to hold and to contain the country. Now is a time when strong and inclusive leadership is needed, in health, educational and research institutions, as well as more broadly. But at the same time, there is also a need for the ongoing factors driving the various manifestations of anger to be robustly addressed. As clinicians and scientists, we understand the significance of the past and how it moulds the present; we also know that the past can, with effort, be overcome. We must, however, be wary of what Leela Gandhi[4] terms ‘the mystifying amnesia of the colonial aftermath’, the antidote to which is, we submit, an ethic of social justice that must direct our professional and academic lives. We adhere to Aristotle’s dictum that, in expressing anger, we need to work hard – with colleagues, patients, citizens and ourselves – to focus this anger as appropriately and effectively as possible. We can certainly attempt to hold and to contain clients, patients and colleagues in our day-to-day interactions. But we cannot afford to ignore the politics of the day. We have feigned ignorance before, and history condemned us for it. Let us not make the same mistake twice. Wahbie Long Department of Psychology, Faculty of Humanities, University of Cape Town, South Africa wahbie.long@uct.ac.za Bonga Chiliza Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Cape Town, South Africa Dan J Stein Department of Psychiatry and MRC Unit on Anxiety and Stress Disorders, Faculty of Health Sciences, University of Cape Town, South Africa

1. Norman R, Schneider M, Bradshaw D, et al. Interpersonal violence: An important risk factor for disease and injury in South Africa. Population Health Metrics 2010;8:32. [http://dx.doi.org/10.1186/1478-7954-8-32] 2. Atwoli L, Stein DJ, Williams DR, et al. Trauma and posttraumatic stress disorder in South Africa: Analysis from the South African Stress and Health Study. BMC Psychiatry 2013;13:182. [http://dx.doi. org/10.1186/1471-244X-13-182] 3. Fanon F. The Wretched of the Earth (C Farrington translation). New York: Grove, 1963:52. 4. Gandhi L. Postcolonial Theory: A Critical Introduction. Melbourne: Allen & Unwin, 1998:4.

S Afr Med J 2015;105(7):510. DOI:10.7196/SAMJnew.7968

July 2015, Vol. 105, No. 7

EDITOR’S CHOICE

CME: Nutrition and malnutrition of young children

This issue of CME is dedicated to the nutrition, and malnutrition, of young children. This is an important topic in paediatric medicine and child health, because toddlers are at an age when they begin to feed independently and patterns of feeding for health in later life are set in motion. By the same token, malnutrition as a result of protein or energy deficiency or chronic illness is relatively common in this age group, even in our modern world. The establishment of normal nutritional patterns in toddlers is precariously balanced between the legacy of infancy, genetic determinants, environmental inputs and social and cultural norms. Healthy nutrition is both physically and emotionally manipulated, and while disease is reflected in growth, it is equally revealed in micronutrient deficiency, intellectual dysfunction, immune disorders and behavioural pathology. A number of overt as well as subtle physical conditions are consequences of malnutrition. This issue focuses on obvious gross malnutrition as well as malnutrition from more subtle deficiencies and deficiencies associated with chronic illness. Ultimately our goal is the improved health of the children of South Africa (SA) and potentially achievement of the Millennium Development Goals (MDGs) of improved child health in our country and on our continent.

Lung health in children

A number of articles in this issue of SAMJ deal with lung health in children, lower respiratory infections (LRTIs) ranking among the top five causes of mortality in children under the age of 4 years. An article on the impact of highly active antiretroviral therapy (HAART) on the burden of bacterial LRTIs in children[1] deals with children presenting to primary care with symptoms of LRTIs. Echoing the May issue,[2] all were treated with amoxicillin with no complications. More significantly, HAART is proving effective in reducing the burden of LRTIs in children, even when the diagnosis of positive HIV status is delayed. Furthermore, immunisations against Streptococcus pneumoniae, Haemophilus influenzae and Varicella have proved safe and effective even in HIV-infected children, despite the fact that their primary immunological response is inferior and there is faster decay in immunological memory. Children are particularly vulnerable when exposed to indoor and outdoor air pollution. A study undertaken in 2002 conservatively indicated that just over 1% of the burden of mortality in young children was a result of exposure to indoor air pollution. According to the 2011 census, around a quarter of SA households still use fuels other than electricity for daily cooking. Against this background, Albers et al.[3] of the Medical Research Council Environment and Health Research Unit in Johannesburg show in an article on household fuel use and child respiratory ill health in two Mpumalanga towns that the prevalence of respiratory illness is significantly greater among children whose homes use non-electrical fuels rather than electricity for cooking or heating. Empyema is one of the commonest complications of pneumonia, the usual treatment of which requires antibiotics, adjusted according to clinical response and microbiological results, insertion of a chest tube to achieve drainage of the pus, and referral for surgery. Zampoli et al.,[4] in the first study describing the use of fibrinolytics in African children, describe the experience at Red Cross War Memorial Children’s Hospital with intrapleural fibrinolytic therapy as first-line

South Africa

treatment in empyema. Tissue plasminogen activator (TPA) (Alteplase; Boehringer Ingelheim) was instilled into the pleura via the chest tube within 24 hours after its insertion. There was a four-fold reduction in requirement for surgical intervention and a trend towards shorter hospital stay and fewer chest drains in children receiving fibrinolytics: 18/47 (38%) children not treated with fibrinolytics required surgery compared with 5/52 (10%) of those treated with TPA.

Intracranial suppuration (ICS)

In an article reviewing an 8-year experience of ICS at Umtata General Hospital and Nelson Mandela Academic Hospital in the Eastern Cape Province, Anwary[5] describes the experience at the two hospitals and the changing epidemiology of ICS over the study period. While, as expected, sinusitis, ear infection and meningitis remain the major source of ICS, head trauma now accounts for 25 - 40% of cases, with a steady decline in cases related to ear infection and meningitis.

Maternal health

The April SAMJ dealt extensively with SA’s failure to meet the MDG 5 maternal health goal – to reduce the maternal mortality rate by three-quarters and achieve universal access to reproductive health. In commemoration of Mother’s Day (10 May 2015), Save the Children published its 16th annual State of the World’s Mothers Report, ‘with a special focus on our rapidly urbanising world and the poorest mothers and children who must struggle to survive despite overall urban progress’.[6] South Africa is ranked 72 of 179 countries (see table). Dr Margaret Chan, Director-General, World Health Organization, observed in her foreword to the report that ‘one of the worst places in the world to be a mother is in an urban slum. Poverty, and the social exclusion that goes with it, leave the urban poor trapped in overcrowded, makeshift or decrepit housing, with few opportunities to stay clean or safe on a daily basis. Diets are poor. Diseases are rife. Pregnancies occur too early in life and too often. Good health care, especially preventive care, is rare. In most cases, the publicly funded health services that reach the urban poor are under-staffed and ill-equipped. These are the women and children left behind by this century’s spectacular socioeconomic advances. Far too often, even the simplest and most affordable health-promoting and lifesaving interventions – such as immunisations, vitamin supplements, safe drinking water, and prenatal check-ups – fail to reach them.’ Extending the MDG 5 maternal health theme, a population-based study of maternal near misses and maternal death in the Pretoria Academic Complex (PAC)[7] reveals that about one in 20 pregnant women admitted to the PAC, 40% of whom had presented with an acute emergency to a primary level facility and had to be transferred for tertiary care, had potentially life-threatening conditions. The emphasis must be on ensuring that all healthcare professionals involved in maternity care have the knowledge and skills to manage obstetric emergencies.

Healthcare delivery

Two Forum articles are key reading. Colleagues from the Medical Research Council Burden of Disease Research Unit, City Health (City of Cape Town), the City of Cape Town Cape Metropole Health Information Group and the Department of Health, Provincial Government of the Western Cape, point to the importance of identified cause-of-death information being available for public health surveillance, actions and research.[8] A recent amendment

Lifetime risk of maternal death

Under-5 mortality rate (/1 000 live births)

Expected number of years of formal schooling

Gross national income per capita (current USD)

Participation of women in national government (% of seats held by women)

Mothers’ index rank (out of 179 countries)

1/300

43.9

13.6

7 190

40.7

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July 2015, Vol. 105, No. 7

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EDITOR’S CHOICE

2008/09

Deaths, n

to the SA Births and Deaths Registration Act has compromised efforts to strengthen local mortality surveillance to provide small-area statistics and information for public health actions. Diarrhoea deaths in children aged under 5 years during the diarrhoea season (November - May) were plotted to identify diarrhoea ‘hot spots’ and provide appropriate public health intervention at subdistrict level in the Cape Metropole. The results are evident in Fig. 1 in the article (see alongside). The authors suggest that a practical solution to overcome the adverse impact of the recent change to the death notification form (DNF) would be for the National Department of Home Affairs to print all pages of the DNF in triplicate, with one copy to be sent to Statistics SA for statistical purposes, one copy to be sent to the health department in each province for public health action, such as that described above, and one copy to remain in the DNF as a paper trail for audit purposes. In ‘Social franchising primary healthcare clinics – a model for South African National Health Insurance?’[9] Robinson introduces the concept of social franchising, which emerged in the 1990s, and describes the North West provincial health department’s social franchising initiative for PHC that is currently being piloted in Dr Kenneth Kaunda District. The project draws on SA’s franchising industry, which has grown since 1945, operates through nearly 30 000 outlets, contributes 12% to the SA gross domestic product and provides stable employment to more than 500 000 people.

2009/10

2010/11

2011/12

2012/13

20 15

16 11

10 5 0

4 Eastern Khayelitsha Klipfontein

Mitchell’s Plain

Northern

Southern

Tygerberg

Western

Subdistrict

Fig. 1. Diarrhoea deaths of children aged <5 years in Cape Town during the diarrhoea seasons 2008 - 2013.

Genomics in medicine

Finally, the editorial by Urban[10] offers a lucid and comprehensive description of the rapidly advancing field of genomics, which is assuming an increasing role in patient care. Genomic medicine is expected to transition into the broader paradigm of precision medicine, with profound long-term implications for the practice of medicine and the training of future practitioners. JS 1. De Campos KR, Granga DD, Olorunju S. The impact of highly active antiretroviral therapy on the burden of bacterial lower respiratory tract infections in children. S Afr Med J 2015;105(7):554-557. [http://dx.doi.org/10.7196/SAMJnew.7820] 2. Lowman W. Key to antimicrobial stewardship success: Surveillance by diagnostic microbiology laboratories. S Afr Med J 2015;105(5):359-360. [http://dx.doi.org/10.7196/SAMJ.9615] 3. Albers P, Wright CY, Voyi KVV, Mathee A. Household fuel use and child respiratory ill health in two towns in Mpumalanga,

South Africa. S Afr Med J 2015;105(7):573-577. [http://dx.doi. org/10.7196/SAMJnew.7934] 4. Zampoli M, Kappos A, Verwey C, Mamathuba R, Zar HJ. Impact of fibrinolytics on the outcome of empyema in South African children. S Afr Med J 2015;105(7):549-553. [http:// dx.doi.org/10.7196/SAMJnew.7796] 5. Anwary MA. Intracranial suppuration: Review of an 8-year experience at Umtata General Hospital and Nelson Mandela Academic Hospital, Eastern Cape, South Africa. S Afr Med J 2015;105(7):584-588. [http://dx.doi.org/10.7196/SAMJnew.7881] 6. The Urban Disadvantage. State of The World’s Mothers 2015. http://www.savethechildren.org/atf/cf/{9def2ebe-10ae-432c9bd0-df91d2eba74a}/SOWM_2015.PDF (accessed 13 May 2015). 7. Soma-Pillay P, Pattinson RC, Langa-Mlambo L, Nkosi BSS, Macdonald AP. Maternal near miss and maternal death in the Pretoria Academic Complex, South Africa – a population-based study. S Afr Med J 2015;105(7):578-583. [http://dx.doi.org/10.7196/SAMJnew.8038] 8. Groenewald P, Azevedo V, Daniels J, et al. The importance of identified cause-of-death information being available for public health surveillance, actions and research. S Afr Med J 2015;105(7):528-530. [http://dx.doi.org/10.7196/ SAMJnew.8019] 9. Robinson AKL. Social franchising primary healthcare clinics – a model for South African National Health Insurance? S Afr Med J 2015;105(7):531-534. [http://dx.doi.org/10.7196/SAMJnew.7814] 10. Urban MF. Genomics in medicine: From promise to practice. S Afr Med J 2015;105(7):545-547. [http://dx.doi.org/10.7196/ SAMJnew.7894]

This month in the SAMJ ... Tamara Kredo* is a senior specialist scientist at the South African Medical Research Council and Deputy Director of Cochrane South Africa. She is a specialist in clinical pharmacology with an interest in evidenceinformed healthcare, including clinical practice guideline development and implementation in resource-limited settings. Her research is focused on developing innovative partnerships to explore primary care guideline activities in South Africa. Her current work aims to expand capacity development initiatives for evidence synthesis in the African region, and dissemination of evidence to inform healthcare decision making. The upcoming Cochrane Corner marks the start of a new collaboration with the SAMJ to regularly bring relevant Cochrane reviews to the readership through brief bite-size summaries. * Kredo T, Young T, Wiysonge CS, McCaul M, Volmink J. The Cochrane Corner in the SAMJ: Summaries of Cochrane systematic reviews for evidence-informed practice. S Afr Med J 2015;105(7):548. [http://dx.doi.org/10.7196/SAMJnew.8035]

Mushtaq Ahmad Anwary* qualified MBBS from the University of Mysore, India, and MMed (Radiology) from the University of Nairobi, Kenya. His main field of interest is ultrasonography and multi-detector computed tomography, and he currently heads the Clinical Unit in the Department of Radiology, Nelson Mandela Academic Hospital, Mthatha, Eastern Cape, and is a senior lecturer at Walter Sisulu University. He provides radiological services to the Transkei region as one of a team of two radiologists who have access to multi-detector CT, magnetic resonance imaging, digital fluoroscopy, digital mammography, colour Doppler ultrasonography and a picture archiving and communication system in a modern radiology department. A radiology registrar training programme has been set up in co-operation with University of Cape Town. * Anwary MA. Intracranial suppuration: Review of an 8-year experience at Umtata General Hospital and Nelson Mandela Academic Hospital, Eastern Cape, South Africa. S Afr Med J 2015;105(7):584-588. [http://dx.doi.org/10.7196/SAMJnew.7881]

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CORRESPONDENCE

Encephalopathy caused by thiamine deficiency

To the Editor: Antel et al.[1] have drawn attention to the acute encephalopathy caused by thiamine deficiency in non-alcohol-related settings. I would like to highlight a different clinical presentation that ought to be readily recognised as a possible manifestation of this deficiency, namely rapidly progressive leg weakness, by briefly describing a woman currently under our care at the Neurology Division, Groote Schuur Hospital, Cape Town, South Africa. A 24-year-old woman pregnant with twins presented at 20 weeks’ gestation with a history of 3 weeks of numbness and weakness of the legs and 1 week of tingling and numbness of the fingers. She described daily vomiting from early in her pregnancy (7 weeks), persisting for 4 months; she had been admitted briefly to the district hospital with hyperemesis gravidarum for intravenous hydration. She did not receive any vitamin supplementation. She had been too weak to walk for 3 weeks on admission, and described symptoms of paroxysmal nocturnal dyspnoea and orthopnoea. On examination, she had a sinus tachycardia with normal blood pressure and chest and cardiac auscultations. She was fully conscious, with reduced tone in the legs, absent leg reflexes, marked proximal and distal leg weakness with mild weakness of hand grip, and glove-and-stocking sensory loss involving all sensory modalities. Laboratory investigations showed mild normochromic anaemia. Vitamin B12 and creatine kinase levels and the results of renal and hepatic function tests were normal. Cerebrospinal fluid parameters and a chest radiograph were normal. The findings on nerve conduction studies were in keeping with a sensorimotor axonopathy. The patient was diagnosed with thiamine deficiency neuropathy (dry beriberi) and intravenous thiamine replacement was commenced (500 mg 8-hourly for 5 days), continuing with 100 mg twice daily orally thereafter. She improved rapidly, developing neuropathic pain requiring symptomatic treatment, and was able to walk again after 6 days. A thiamine assay taken before treatment confirmed low levels. This case highlights the importance of recognising individuals at high risk of developing complications of thiamine deficiency, such as pregnant women with hyperemesis gravidarum. It also draws attention to that fact that the neuropathy of thiamine deficiency may occur without encephalopathy, and can mimic Guillain-Barré syndrome.[2] Given that this is not an infrequent scenario in our hospital, we would like to raise awareness of this easily preventable, life-threatening illness, particularly among healthcare workers in antenatal clinics, and remind them of the importance of adequate thiamine replacement in patient groups at risk. Kathleen Bateman

Neurology Division, Department of Medicine, Groote Schuur Hospital and Faculty of Health Sciences, University of Cape Town, South Africa kathleen.bateman@uct.ac.za 1. Antel K, Singh N, Chisholm B, Heckmann JM. Encephalopathy after persistent vomiting: Three cases of non-alcohol related Wernicke’s encephalopathy. S Afr Med J 2015;105(6):442-443. [http://dx.doi. org/10.7196/SAMJ.9299] 2. Koike H, Iijima M, Sugiura M, et al. Alcoholic neuropathy is clinicopathologically distinct from thiamine-deficiency neuropathy. Ann Neurol 2003;54(1):19-29. [http://dx.doi.org/ 10.1002/ana.10550 ]

S Afr Med J 2015;105(7):513. DOI:10.7196/SAMJnew.8022

Legal assisted suicide in South Africa

To the Editor: Following the Stransham-Ford case in the Pretoria High Court, the South African Medical Association (SAMA) has stated clearly that it does not support the right to die in law, and opposes euthanasia and doctor-assisted suicide in line with the Health Professions Council of South Africa’s policies and the World Medical Association’s guidelines

513

and codes on the subject. Yet this is an emotive issue, and this letter is written in the hope of clarifying the issues that are at stake in South Africa (SA) for the sake of those who do not agree with SAMA. Dan Nciyayana, Editor of the SAMJ at the time, wrote an editorial about this in 2012.[1] He concluded that SA is not a safe place for liberalised voluntary euthanasia legislation. His reasons were as follows: ‘Euthanasia – a recourse of last resort – can only really be justified in a country with the very best medical care for all, a well-organised and universally accessible palliative care and support system, stable and well-functioning (particularly judicial) institutions, and a strong culture of respect for human life. In SA, with its “severe constraints on health care facilities and the totally inadequate allocation of resources for highly effective medical treatments”[2] [reference 4 in the editorial], there is a real risk of euthanasia becoming a substitute for proper care for the terminally ill and other patients in dire medical straits. Even more damning for SA is the pervasive lack of an ethos of respect for human life. We are an extraordinarily violent society, with over 45 murders committed daily and interpersonal violence the second highest cause of death. Mob justice, police brutality and xenophobia abound. Needless deaths occur regularly in our hospitals through staff neglect and indifference. Health care providers think nothing of downing tools and walking off, abandoning critically ill patients, or of blocking ambulances with critical emergencies from entering health facilities during labour disputes.’ Nciyiyana’s words take on fresh meaning when read with those of Prof. Theo Boer, the medical ethicist who was part of the committee that motivated for, and regulated, euthanasia in The Netherlands. In 2007 he wrote: ‘There doesn’t need to be a “slippery slope” when it comes to euthanasia. A good euthanasia law, in combination with the euthanasia review procedure, provides the warrants for a stable and relatively low number of cases.’ Most of his colleagues drew the same conclusion. ‘But’, he wrote in 2014 in a public appeal to the British House of Lords, ‘we were wrong, terribly wrong’.[3] He then describes the rapid escalation in the numbers of assisted suicides, to the point that ‘Euthanasia is on the way to become a “default” mode of dying for cancer patients.’ He laments that the Dutch Right to Die Society (NVVE) has founded a network of travelling euthanising doctors who have no established relationship with the patients, very limited background information on them, and offer only two options: administer life-ending drugs or send the patient away. ‘The NVVE shows no signs of being satisfied even with these developments. They will not rest until a lethal pill is made available to anyone over 70 years who wishes to die. Some slippery slopes are truly slippery.’ There has been a rapid shift in the type of patients being killed in Holland since 2008. In the beginning, euthanasia was offered only to terminally ill patients with severe pain or suffering. Now a rising number of psychiatric patients, especially those who are depressed and those with dementia, and many people who are simply lonely, aged or bereaved, are offered assisted suicide. ‘Whereas the law sees assisted suicide and euthanasia as an exception, public opinion is shifting towards considering them rights, with corresponding duties on doctors to act. A law that is now in the making obliges doctors who refuse to administer euthanasia to refer their patients to a “willing” colleague. Not even the Review Committees, despite hard and conscientious work, have been able to halt these developments.’ He ends his article: ‘I used to be a supporter of the legislation. But now, with 12 years of experience, I take a different view. At the very least, wait for an honest and intellectually satisfying analysis of the reasons behind the explosive increase in the numbers. Is it because the law should have had better safeguards? Or is it because the mere existence of such a law is an invitation to see assisted suicide

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and euthanasia as a normality instead of a last resort? Before those questions are answered, don’t go there. Once the genie is out of the bottle, it is not likely to ever go back in again.’ The case against legalising assisted dying in SA gets stronger when one reads the responses to the BMJ editorial[4] advocating for it to be made available in the British Isles. For instance, Rob George, Professor of Palliative Care, Cecily Saunders Institute, King’s College Hospital, argues that ‘the safety of vulnerable people must take priority over the determined wishes of individuals’.[5] ‘For me the real question is this: “Which is worse: not to kill people who want to die or to kill people who might want still to live?” In my experience it is impossible to separate those who might want to die from those who believe they ought to die and whose view is pretty well never “settled.” No one can be sure that some people, not now at risk, will find themselves [to be] so were the law to change. A full blooded expression of autonomy includes the responsibility at times to restrain oneself on behalf of another. When it comes to having our lives ended, let’s keep it that way. Once this line is crossed there is no going back.’ Wager et al.[6] report that although assisted suicide (not by physicians) for altruistic reasons has been legal in Switzerland since 1918, it is only now that the consequences for other family members are being recognised. They report: ‘Witnessing the unnatural death of a significant person has a strong impact on the bereaved, which may lead to severe mental health problems at 14 to 24 months post loss.’ They observed a 20% incidence of developed or partial post-traumatic stress disorder. Other studies show that such illness is associated with ‘suicide contagion’,[7] which mostly affects teenagers and young adults. There is evidence that interventions such as legislating liberal access to abortion in developing countries result in an increase rather than a decrease in maternal deaths, because of the factors detailed by Ncayiyana. [1] It is also relevant to point out that >80% of the SA population do not have a culture based on the idea of autonomous individuality. Our nation has large cultural groups which have a strong sense that the value of the individual is found in community (cf. the Zulu idiom ‘A person is a person because of people’). They do not hold to a Western view of the importance of individual autonomy, and therefore they value security and family/clan decision-making above autonomy. It is very likely that the introduction of medical assisted suicide in these communities in particular will affect their security. Violence is probable should any healthcare provider be considered to have disdained family and ancestor claims and taken the life of a clan member. Deaths from ‘suicide contagion’ are also likely to be very frequent in such extended families. When put together, this evidence should warn us to be very careful how we interpret section 12 of the Bill of Rights in the SA Constitution.[8] It is commonly interpreted as favouring the dignity of the individual, but a careful reading shows that it balances two values, that of individual security and that of autonomy and dignity. In our circumstances, it is clear that the value of security trumps that of dignity. SAMA is therefore to be applauded for its stand as it associates itself with the April 2013 Resolution of the 194th WMA Council of the World Medical Association, which states: • The World Medical Association reaffirms its strong belief that euthanasia is in conflict with basic ethical principles of medical practice. • The World Medical Association strongly encourages all national medical associations and physicians to refrain from participating in euthanasia, even if national law allows it or decriminalises it under certain conditions.

2. Benatar SR. Dying and euthanasia. S Afr Med J 1992;82(1):35-38. 3. Boer T. Assisted dying: Don’t go there. Daily Mail (UK), 9 July 2014. 4. Delmothe T, Snow R, Godlee F. Why assisted dying should become law in England and Wales. BMJ 2014;349:g4349. [http://dx.doi.org/10.1136/bmj.g4349] 5. George R. We must not deprive dying people of the most important protection. BMJ 2014;349:g4311 [http://dx.doi.org/10.1136/bmj.g4311] 6. Wager B, Muller J, Maecker A. Death by request in Switzerland: Posttraumatic stress disorder and complicated grief after witnessing assisted suicide. Eur Psychiatry 2012;27(7):542-546. [http://dx.doi. org/10.1016/j.eurpsy.2010.12.003] 7. Velting DM, Gould S. Suicide contagion. In: Maris RW, Silverman MM, Canetto S, eds. Review of Suicidology. New York: Guilford Press, 1977:96-137. 8. The Constitution of the Republic of South Africa, Act 108 of 1996: Chapter 2: 12.

S Afr Med J 2015;105(7):513-514. DOI:10.7196/SAMJnew.7706

New horizons for the repair of skin defects

To the Editor: Visible skin defects in adults, and especially those in the developing child, are frequently very unsightly, stigmatising the person and often leading to severe psychological sequelae. This situation can result from surgical treatment of vitiligo, congenital pigmented naevi, vascular hamartomas and skin cancer, and from burn scars and contractures. Many affected people are ostracised from society because of our inability to restore the defect to normality after excision, or at least to an acceptable functional and cosmetic end result. The obvious solution is to replace the excised tissue with a functional and cosmetic substitute similar to the surrounding area. An assortment of dermal substitutes is currently commercially available to replace these surgical defects. They usually require a period of 2 - 3 weeks to vascularise before an epithelial autologous skin graft can be done to complete the process. The Tissue Biology Research Unit at Zurich University has, through the EuroSkinGraft Consortium Project, developed a bioengineered full-thickness skin graft containing dermal and epidermal equivalent components including preformed blood capillaries and melanocytes.[1-6] While these grafts lack innervation, hair follicles and sweat glands, they are the most complete bio engineered skin grafts currently available to treat full-thickness skin defects resulting from acute and elective procedures. In preclinical trials, rapid take, almost no shrinkage of the graft and excellent non-scar remodelling of the skin transplant were achieved.[3,4] Disfigured people have a burning desire to be normal again. A prevascularised pigmented graft would be of immense value in surgery performed on darker-skinned people suffering from a broad spectrum of disfiguring skin defects. It would be indispensable in surgical correction of the depigmented areas of crippling vitiligo or healed burn wounds (subject to squamous carcinoma), or to reconstruct skin defects following scar and keloid excisions or contracture release and repair as a single-stage procedure, without delaying autologous skin grafting. The repaired area would have the same physical appearance as the surrounding unaffected skin. In the future, repair of such defects with equivalent pigmented skin will be considered essential to optimise functional and cosmetic outcomes, and it will be of indispensable value to those affected. Pigmented skin-equivalent grafts for patients with darker skins have been achieved successfully in experimental circumstances, but have not been subject to clinical trials. This is an essential regenerative concept with wide therapeutic and practical advantages for the future. H Rode

Department of Paediatric Surgery, Red Cross War Memorial Children’s Hospital and Faculty of Health Sciences, University of Cape Town, South Africa heinz.rode@uct.ac.za

J V Larsen

Howick, KwaZulu-Natal, South Africa jon.larsen@iuncapped.co.za 1. Ncayiyana D. Euthanasia: No dignity in death in the absence of an ethos of respect for human life. S Afr Med J 2012;102(6):334.

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1. Biedermann T, Bottcher-Haberzeth S, Klar AS, et al. Rebuild, restore, reinnervate: Do human tissue engineered dermo-epidermal skin analogs attract host nerve fibers for innervations? Pediatr Surg Int 2013;29(1):71-78. [http://dx.doi.org/10.1007/s00383-012-3208-1]

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2. Bottcher-Haberzeth S, Klar AS, Biedermann T, et al. ‘Trooping the colour’: Restoring the original donor skin colour by addition of melanocytes to bioengeneered skin analogs. Pediatr Surg Int 2013;29(3):239427. [http://dx.doi.org/1007/s00383-012-3217-0] 3. Hartmann-Fritsch F, Biedermann T, Braziulis E, Meuli M, Reichmann E. A new model for preclinical testing of dermal substitutes for human skin reconstruction. Pediatr Surg Int 2013;29(5):479-488. [http://dx.doi.org/10.1007/s00383-013-3267-y] 4. Marino D, Reichmann E, Meuli M. Skingineering. Eur J Pediatr Surg 2014;24(3):205-213. [http:// dx.doi.org/10.1055/s-0034-1376315] 5. Marino D, Luginbühl J, Scola S, Meuli M, Reichmann E. Bioengineering dermo-epidermal skin grafts with blood and lymphatic capillaries. Sci Transl Med 2014;6(221):221ra14. [http://dx.doi.org/10.1126/ scitranslmed.3006894] 6. Klar AS, Böttcher-Haberzeth S, Schiestl C, Reichmann E, Meuli M. Tissue-engineered dermoepidermal skin analogs exhibit de novo formation of a near natural neurovascular link 10 weeks after transplantation. Pediatr Surg Int 2014;30(2):165-172. [http://dx.doi.org/10.1007/s00383-013-3446-x]

S Afr Med J 2015;105(7):514-515. DOI:10.7196/SAMJnew.7807

Trends in lead exposure in a rural mining town in South Africa, 1991 - 2008

To the Editor: Lead exposure through mining processes contributes significantly to environmental and human contamination world wide.[1-3] Studies have shown that there is no safe level of exposure, and very low levels (blood lead levels <5 µg/dL) have resulted in neurocognitive and behavioural abnormalities in children.[4] This has detrimental economic and social consequences, especially in low- and middle-income countries where resources to mitigate the effects of lead exposure are limited.[5] In 1991, 2002 and 2008, crosssectional surveys assessing lead exposure were conducted in grade 1 children in a remote lead-mining town (Aggeneys) and a control town (Pella) about 40 km away in the Northern Cape Province, South Africa (SA). Blood lead levels (BLLs) were assessed in wholeblood samples using atomic absorption spectrophotometry in 1991 and 2002 and in capillary blood using the LeadCare 1 analyser system in 2008.[6,7] The sociodemographic profiles of the study children remained similar from 1991 to 2008 (Table 1). Socioeconomic status was higher in Aggeneys than in Pella. However, despite the higher socioeconomic status in Aggeneys, the grade 1 children’s mean BLLs were significantly elevated in all three surveys. Between 1991 and 2002 the mean BLL dropped by approximately 50%, but did not fall significantly thereafter. The initial decline between 1991 and 2002 may have been due to the phasing out of leaded petrol from 1996, since declines in BLLs were observed in both Pella and Aggeneys. However, in Pella the proportion of children with BLLs ≥5 µg/dL dropped from 52% in 2002 to 16% in 2008. In Aggeneys, the proportion with BLLs ≥5 µg/dL decreased by only 8%

and the proportion of children with BLLs ≥10 µg/dL increased by 9%, indicating ongoing lead exposure in the mining town community. In higher-income countries, significant decreases in the risk of lead exposure in mining communities have occurred. In the USA, interventions in the Bunker Hill mining community resulted in a drop in children with BLLs ≥10 µg/dL from 48% in 1988 to 3% in 2001.[8] Programmes such as environmental decontamination, including soil treatment, appropriate worker and domestic hygiene measures, and community education and support, as well as continued screening of children’s BLLs, have resulted in a significant reduction in exposure in this site. However, similar measures have seldom been implemented to the same extent in poorer countries. This series of surveys, conducted over a period of 17 years in an SA leadmining town, indicates an elevated and enduring (73% of children had BLLs ≥5 µg/dL), yet avoidable, risk of exposure to lead. Nisha Naicker

Medical Research Council of South Africa Environment and Health Research Unit, Johannesburg, South Africa, and School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg nisha.naicker@gmail.com

Angela Mathee

Medical Research Council of South Africa Environment and Health Research Unit, Johannesburg, South Africa, School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, and Faculty of Health Sciences, University of Johannesburg (Doornfontein Campus) 1. Van Green A, Bravo C, Gil V, Sherpa S, Jack D. Lead exposure from soil in Peruvian mining towns: A national assessment supported by two contrasting examples. Bull World Health Organ 2012; 90(12):878-886. [http://dx.doi.org/10.2471/BLT.12.106419] 2. Moreno ME, Acosta-Saavedra LC, Meza-Figuera D, et al. Biomonitoring of metal in children living in a mine tailings zone in Southern Mexico: A pilot study. Int J Hyg Environ Health 2010;213(4):252-258. [http://dx.doi.org/10.1016/j.ijheh.2010.03.005] 3. Paoliello MMB, de Capitani EM, Goncalves da Cunha F, et al. Exposure of children to lead and cadmium from a mining area of Brazil. Environ Res 2002;88(2):120-128. [http://dx.doi.org/10.1006/enrs.2001.4311] 4. Canfield RC, Henderson CR, Cory-Slechta DA, Cox C, Jusko TA, Lanphear BP. Intellectual impairment in children with blood lead concentrations below 10 µg/dl. N Engl J Med 2003;348 (16):1517-1526. [http://dx.doi.org/10.1056/NEJMoa022848] 5. Attina TM, Trasande L. Economic costs of childhood lead exposure in low- and middle-income countries. Environ Health Perspect 2013;121(9):1097-1102. [http://dx.doi.org/10.1289/ehp.1206424] 6. Von Schirnding Y, Mathee A, Kibel M, Robertson P, Strass N, Blignaut R. A study of pediatric blood lead levels in a lead mining area in South Africa. Environ Res 2003;93(3):259-263. [http://dx.doi. org/10.1016/S0013-9351(03)00117-8] 7. Rollin HB, Mathee A, Levin J, Theodorou P, Tassel H, Naik I. Examining the association between blood manganese and lead levels in schoolchildren in four selected regions in South Africa. Environ Res 2007;103(2):160-167. [http://dx.doi.org/10.1016/j.envres.2006.08.011] 8. Von Lindern I, Spalinger S, Petroysan V, von Braun M. Assessing remedial effectiveness through the blood lead:soil/dust lead relationship at the Bunker Hill Superfund Site in the Silver Valley of Idaho. Sci Total Environ 2003;303(1-2):139-170. [http://dx.doi.org/10.1016/S0048-9697(02)00352-2]

S Afr Med J 2015;105(7):515. DOI:10.7196/SAMJnew.7809

Table 1. Blood lead distribution by town Aggeneys Participants, n

Pella

2002

2008

1991

2002[7]

2008

1991

[6]

[7]

[6]

Sociodemographic profile Age (years), mean Income <ZAR1 000 per household, % Lead exposure (BLL) (µg/dL) Mean (SD)

15.9 (3.68)

7.76 (2.88)

7.37 (3.3)

13.2 (3.52)

5.73 (2.57)

4.57 (2.10)

Median

7.9

6.6

5.1

4.1

Range

9 - 27.5

2.8 - 13.4

2.4 - 15

6 - 22.0

2.5 - 17.1

2.2 - 15.1

<5, n (%)

4 (19.0)

8 (26.7)

26 (47.3)

37 (69.8)

≥5 - 9.9, n (%)

14 (66.7)

15 (50.0)

24 (43.6)

14 (26.4)

≥10, n (%)

3 (14.3)

7 (23.3)

5 (9.1)

2 (3.8)

SD = standard deviation; - = data not available.

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William Guybon Atherstone: His 8-day and 1 600 km house call to Oudtshoorn in 1890

To the Editor: William Guybon Atherstone (1814 - 1898) became well known because for six decades he and his father, John Atherstone, practised medicine in Grahamstown in the Eastern Cape during the turbulent Frontier Wars. When not attending patients, he pursued his interests in geology and botany. He is best known for having performed the first successful surgical procedure under general ether anaesthetic,[1] and for having identified the first diamond found in the Cape Colony.[2] I describe the professional visit of Atherstone to attend a patient with a tumour of the lip and mass in the neck. On 25 August 1890 Atherstone received a telegram from Johannes Hendrik Schoeman asking him to visit because his own doctor was ‘dangerously ill’; Atherstone took the 20h05 train to Prince Albert Road Station, arriving at 23h30 the next day, and then travelled by horse and cart to Prince Albert and over the Swartberg Pass, arriving at Schoemanshoek, Schoeman’s residence near Oudtshoorn, at 17h30 on 27 August – a trip of 800 km and 45½ hours. He took a history, and examined Schoeman and recorded: ‘… I diagnosed the case as one of colloid glandular cancer from a pipe. I measured round Schoeman’s neck over the lobular tumour – one foot five and a half inches [44.5 cm] from the inside of the tumour, over the large colloid projection six and three quarter inches [17.2 cm] across and three and three quarter inches [9.5 cm] across and three and three quarter inches [9.5 cm] vertically! ‘History – two years previously a dry scaly pimple appeared on the lower lip near the angle of the mouth; in six or eight days the crust came off, and then formed again and became like a moist wart for eight to ten months. It would not heal. Dr. Russell burnt it with “No. 5” – it stank because of the discharge. Twice more he burnt it, and it became a sore which he excised together with a wart on the chin. It then healed, but the left gland was slightly swollen; a lump appeared on the left side of the neck, about the size of a walnut and grew steadily. ‘Mr. Schoeman had always been strong, active and healthy until the sore appeared on his lip where he had been accustomed to hold his pipe. He had not however smoked a pipe for a very long time, only the occasional cigar, but confessed that the cigar was also put on the left side, where the pipe had been and where the sore was.’ In keeping with professional ethics, Atherstone then travelled a further 15 km into Oudtshoorn to discuss the patient with Drs George Russell and Herbert Urmson Smith. On 2 October 1890, Atherstone admitted Schoeman to Albany Hospital in the care of the Visiting Surgeon John Baldwin Smithson Greathead. Two weeks later, against medical advice, Schoeman discharged himself, returned home, and died on 28 October 1890 aged 53 years.[3] Atherstone kept records of his activities in about 200 notebooks (Fig. 1), which are kept in the Albany Museum in Grahamstown. They have been published in a somewhat disorganised ‘pseudoautobiography’ in which it is impossible to distinguish between Atherstone’s words and those of his autobiographer.[4] Schoeman almost certainly suffered from an infected squamous cell carcinoma of the lip that had metastasised to the left cervical lymph nodes.[5] Atherstone knew of its association with pipe smoking, as described in the 18th century,[6] and would have been aware of its detailed description more widely published in the mid-19th century.[7] There is no explanation for Schoeman’s summoning Atherstone, rather than a doctor from Cape Town. Perhaps he had impressed the Schoeman family when shown the Cango Caves by Carel Schoeman, the patient’s uncle, in December 1852;[8] also, by 1890 Atherstone had become well known in the Cape Colony, having been elected Member of the Legislative Assembly for Grahamstown in 1881, when he may have retired from medical practice.[9-11]

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Fig. 1. Schoeman’s ‘colloid granular cancer’, taken from Atherstone’s Notebook No. 197. Reproduced with permission from the Albany Museum.

Schoeman was a wealthy man, owning the farm Roodewal which surrounded Schoemanshoek, valued at £2 275, and 10 smaller properties valued at £1 373. His executor paid the accounts of the local doctors, but failed to pay Atherstone’s bill of £75 for 8 days absence from his practice and 1 600 km subsistence and travelling expenses![12] Acknowledgements. Dr Elizabeth van Heyningen brought my attention to Atherstone’s notebooks and pseudoautobiography. Ms Amy van Wezel of the Albany Museum scanned and supplied Fig. 1.

S A Craven

Department of Family Medicine, Faculty of Health Sciences, University of Cape Town, South Africa sacraven@mweb.co.za 1. Sulphuric ether. Graham’s Town Journal 26 June 1847, p. 3. 2. Metrowich FC. William Guybon Atherstone. In: De Kock WJ, ed. Dictionary of South African Biography, Vol. I. National Council for Social Research, 1968:25-27. 3. Mathie N. Man of many facets Atherstone Dr WG 1814-1898. Vol. 2. 1997:466-468. 4. Mathie N. Man of many facets Atherstone Dr WG 1814-1898. 1997:1-1106. 5. Maruccia M, Onesti MG, Parisi P, Cigna E, Troccola A, Scuderi N. Lip cancer: A 10-year retrospective epidemiological study. Anticancer Research 2012;32(4):1543-1548. 6. Friderico DN. Carcinoma labii inferioris absque sectione persanatum. Dissertation 16 pp., Rintelii. 1737. http://digital.slub-dresden.de/werkansicht/dlf/5964/9/ (accessed 31 January 2015). 7. Bouisson DÉF. Du cancer buccal chez les fumeurs. Montpellier Medical 1839;1(2):539-559;1(3):19-41. 8. Mathie N. Man of many facets Atherstone Dr WG 1814-1898. Vol. 1. 1997:70-74. 9. Burrows EH. A History of Medicine in South Africa. Cape Town: Balkema, 1958:168-177. 10. Laidler PW, Gelfand M. South Africa: Its Medical History 1652-1898. Cape Town: Struik, 1971:168, 250, 281–283, 294, 332-334, 346-347, 353, 433, 498. 11. Deacon H, Phillips H, van Heyningen E. The Cape Doctor in the Nineteenth Century: A Social History. Amsterdam: Rodopi, 2004:34-35, 175, 176, 180-181, 256 . 12. Cape Archives MOOC 13/1/609 49.

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IZINDABA

Tugela Ferry’s extensively drug-resistant tuberculosis – 10 years on ‘Smooth seas do not make skilful sailors.’ (African proverb) For 3 stormy years from the time Tugela Ferry’s doctors first uncovered what turned out to be an alarming countrywide extensively drug-resistant tuberculosis (XDR-TB) prevalence (2005 - 2007), they diagnosed 110 new XDR-TB cases per year. Yet by implementing a combination of interventions with a remarkable team, the tap was turned down to less than 10 cases in 2012, making the Church of Scotland Hospital (CoSH) an international beacon of best practice. Izindaba returned there after 6 years to find out how they are helping to quell the general TB epidemic itself. Just a few months short of 60 years old, Thengokwakhe Nkala, a former migrant worker from rural KwaZulu-Natal (KZN), has been to hell and back. His sunken eyes and a humble demeanour are as much clues to his massively againstthe-odds survival of XDR-TB as they are a reflection of the harshly hot, rocky thornveld in which he, his wife and eight children eke out a living near Tugela Ferry. All he knows of the 85% XDR-TB death rate among hundreds of fellow patients at Tugela Ferry’s CoSH between 2005 and now is that ‘a lot’ of people like him who were transferred to King George V Hospital (Durban) suffering from multidrug-resistant (MDR)- or XDRTB died. ‘Aba-sekho’ (they are no longer with us), he shrugs with a millennia-old acceptance of Africa’s cruel mysteries. His coughing began while he was working at a cement factory in Johannesburg and rapidly became so bad that he returned home ‘when I felt my strength had gone’ in 2008. He reported to CoSH within months, a fortuitous 3 years after tenacious medical detective work by its doctors had helped identify ‘XDR’-TB as responsible for the deaths of 52 of the 53 local inpatients whose sputum culture tests resisted every drug thrown at them (by Durban’s Nkosi Albert Luthuli Hospital laboratory technicians) in 2005. Nkala’s quick transfer to the TB-specialising King George V Hospital was a last-gasp hope, driven by the slim chance that a correct diagnosis and appropriate combination of drugs, plus sheer good luck, might work. He spent 18 months in an isolation ward, enduring 160 injections of kanamycin over 6 months, along with an oral

‘Miracle’ XDR-TB survivor Thengokwakhe Nkala, 59, Sr Hlezi Bengu and Dr Tony Moll. All photos by Chris Bateman.

TB and HIV drug regimen, often writhing in pain and discomfort from the debilitating side-effects as he dimly watched members of his clan and tribe daily breathe their last alongside him.

By October 2006, CoSH had diagnosed over 200 XDR-TB cases, the highest number at any single hospital on the planet, and with emerging figures from across the globe, the WHO called a summit in Geneva where Moll presented the team’s findings, and the current definition of XDR-TB was coined.

Unbroken tradition

The remote 83-year-old, 350-bed KZN district hospital, founded by Scottish doctormissionary, George William Gale on what was the Zululand side of the Tugela River (then linked to Natal by a rope-spanned ferry), has a history of selfless, dedicated service by Christian doctors to the estimated 200 000 traditional Zulus of Msinga, the poorest subdistrict in the country. The latest embodiments of this altruistic culture are Drs Tony Moll and Francois Eksteen, veterans of 28 years and 18 years respectively at CoSH. Moll currently heads the local antiretroviral (ARV) programme and with his wife Debbie, a local school principal, has raised four children here. Eksteen manages clinical care for the hospital’s nearly 80 TB inpatients and consults weekly at the specialised MDR-TB clinic in Greytown. Both went for ARV drug training

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under Prof. Gerald Friedland (Epidemiology and Public Health) at Yale University as early as 2003. That decision enabled CoSH to quietly provide ARVs to 100 patients, the drugs coming from Yale. The first sign that the AIDS-denying late Health Minister Dr Manto Tshabalala-Msimang would yield to international pressure came a year later – via an official international-media-attended ARV ‘launch’ at CoSH, the first public hospital to provide ARVs on the national rollout (just one month before the April 2004 national elections). Patients flooded in, mostly with CD4 counts dangerously below 100 cells/µL (today the ARV inception threshold is 500/ µL) and among them a small but significant percentage carrying undiagnosed MDRand XDR-TB, creating the ‘perfect storm’ for nosocomial spread. As the TB-drugresistant contagion multiplied, the doctors were carefully monitoring all ARV treatment side-effects, CD4 cell counts and viral loads, witnessing mostly astounding improvements (after 13 years of AIDS palliative care). Many AIDS patients were too far advanced, but if they managed 3 months on ARVs before succumbing to opportunistic infections, the disease usually turned around and they survived. Moll and Eksteen noticed two patients (initially) whose CD4 cell counts stubbornly (and unusually) refused to budge, their viral loads remaining suppressed. Their opportunistic infections were being treated – but signs and symptoms of TB continued, ‘so we immediately thought of MDR-TB’, says Moll. Two university student interns needed a project, ‘so I said set up a table and do a specimen snapshot of every single coughing in- and outpatient’. Some 45 samples were

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Married Zulu women break into dance at an outreach clinic near Tugela Ferry.

sent off to the Durban lab, and in May 2005 Moll received an alarmed call from chief pathologist Dr Lynne Roux, saying that six of the samples resisted every drug thrown at them – and that four other samples from Greytown and Durban had behaved identically. Their two MDR suspects were in the group. Provincial and national case finding began in earnest. By 2007 some 60 KZN health facilities were identified as having patients with XDR- and MDR-TB, a survey of 19 of them a year later showing an average of 15% MDR-TB and 3% XDR-TB among confirmed TB patients. National data from across all nine provinces in 2007 revealed 1 000 XDR-TB cases and 7 350 MDR-TB cases, almost certainly the tip of an iceberg.

MDR-TB researcher Dr Vijay Guddera and Church of Scotland Hospital Clinical Manager, Dr Tony Moll.

Unmatched initial XDR infections

By October 2006, CoSH had diagnosed over 200 XDR-TB cases, the highest number at any single hospital on the planet, and with emerging figures from across the globe, the World Health Organization (WHO) called a summit in Geneva where Moll presented the team’s findings, and the current definition of XDR-TB was coined. With international interest focused on Tugela Ferry, attracting operational research funding, a strong collaboration was being formed at CoSH including partners from Yale (Profs Friedland, Gandhi, Shah and Shenoi), the University of KZN (Prof. Sturm), an Italian corporation (Dr Marra), the provincial TB office (Dr Margot), the local district manager (Mr Mndebele), and many others who joined later. ‘Without technical assistance from this amazing team and support from the DOH, we would not have been able to crunch this rock or roll it away as we have done,’ says Moll. ‘With a virtually untreatable airborne infection in our midst, this put us healthcare

Sr A R Zungu, District Programme Manager for Umzinyathi in KwaZulu-Natal.

Nurse Thandeka Shabalala with her thriving MDRTB patient, Silindile Mbatha, after administering her daily kanamycin injection at home.

workers into another league of danger and vulnerability.’ The team immediately upped surveillance, resulting in the now famously documented 53 positive cultures, half of whose owners had died by the time the results came back 6 weeks after sputum collection. Even scarier, 26 of them had never had TB before, indicating first-time presentation with XDR-TB. By 2009, when CoSH’s XDR numbers had grown to 500 (98% of them HIV-positive), ‘we (seemingly paradoxically) relaxed a bit; it showed us that it wasn’t so transmissible after all’. The transmission was in fact mostly nosocomial, requiring drastic infection control measures, including isolation and fast-tracking of coughing patients. Every worker in the hospital highrisk areas wears an N95 mask and outpatients

sit in decongested, airy, sheltered outdoor waiting areas. Infection control officers and nurses monitor constantly, ensuring that all windows remain open.

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XDR/MDR-TB down by 90%

XDR/MDR-TB prevalence in the surr ounding Msinga area has dropped by 90%. Going back to basics, the team intervened immediately at community level by screening over 3 200 household contacts of 614 drug-resistant (DR) index patients and launching a community intensified casefinding project. Dr Vijay Guddera, research manager at Philanjalo, CoSH’s research and step-down NGO-funded facility (a hospice in the pre-ARV era), told me that intensive

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case finding has resulted in 15 000 people being screened since 2010 at community congregate settings, with the advantage of bringing patients into care earlier. In the local prison it took 38 people to find one TB case, in the taxi ranks one in 140 and at the local schools one in 240. In some months up to 30 new DR cases were identified at CoSH, which placed an unmanageable load on the provincial King George V MDR-TB hospital in Durban. Moll says, ‘Often patients had to wait up to 6 weeks to get a bed in Durban where they could start treatment, some dying while waiting.’ This gave birth to the province’s first MDR-TB ‘decentralised’ hospital, also the first in the country, which is now in full swing in nearby Greytown, a 45-minute mountainous drive away. It is here that I once again meet Moll, 6 years after spending two nights at his CoSH home while confronting the full reality of what was portrayed in the lay media as an XDR-TB ‘outbreak’ (what the CoSH team found merely epitomised the unseen national contagion that is today an even greater threat than HIV, the precursor MDR-TB pandemic having doubled in size and XDR-TB prevalence slowly burgeoning). Greytown is a small farming village nestled among dairy, beef and crop farms and sprawling timber plantations in misty, green, rolling countryside, dramatically different to the harsh Tugela valley below. It now hosts the hospital lifeline for MDR-TB and pre-XDR-TB patients. Simply called M3, it was rededicated as an exclusive 37-bed MDR-TB hospital in 2007, rolling out treatment in February the following year. Subsequently several similar MDRTB hospitals have opened in South Africa, reducing the major current bed shortages but ‘de-institutionalising’ MDR/XDR-TB management. (According to national MDRTB chief Dr Norbert Ndjeka, nearly half of all diagnosed cases are not started on treatment and patients wait up to 2 months for admission.) As much as political AIDS denialism delayed ARVs, unnecessarily costing countless lives, the triumph of quick intervention when a deadly disease is detected is epitomised by Greytown’s M3 MDR-TB hospital. Fast diagnosis and swift initiation of effective treatment is essential, as patients respond better with early treatment and soon stop transmitting disease. A full 85% of patients are smear-negative after 2 months of treatment. GeneXpert testing for rifampicin resistance has doubled MDR-TB diagnostic accuracy and hugely reduced the time to treatment initiation (from 2 months to just 48 hours). Ninety per cent of all sputum specimens sent from all facilities in the Umzinyathi District (which Greytown M3

MDR-TB patient Silindile Mbatha, 30, could hardly walk when CoSH outreach team nurse Thandeka Shabalala began visiting her for her daily kanamycin injection in her wattle-and-daub Upper Msinga home in November last year. Weak and jaundiced, her initial X-rays at the local clinic were inconclusive so she was sent to CoSH where the GeneXpert test confirmed MDR-TB. ‘I think I got it when I was working in Jeppe in Gauteng in 2013 (a known MDR-TB ‘hot-spot’) – it was very overcrowded and unhygienic there,’ she says. Mbatha’s weight has increased from 67.8 kg to 69.8 kg since her injection and pill home treatment started – ironically in a far-flung rural district that normally spells death for patients. CoSH’s exemplary home-based care made the difference. 120% 100% 80% 60% 40% 20% 0% 2014 Q1/2014 Q2/2014 Q3/2014 Q4/2014

ENDUMENI 99% 97% 100% 100% 97%

NQUTU 94% 97% 93% 97% 87%

MVOTI 98% 97% 99% 99% 98%

MSINGA 80% 84% 79% 79% 79%

DISTRICT 91% 93% 91% 90% 90%

Umzinyathi District turnaround times (percentage returned within 48 hours) for sputum specimen results.

covers as an MDR-TB referral facility) were returned within 48 hours last year, allowing treatment of smear-positive patients to begin immediately. After a short admission to M3, patients are discharged to the novel Community Management of MDR-TB Programme and cared for in their own homes by outreach teams arriving in rugged-terrain vehicles and doing daily home-based administration of the injections, screening and educating family members, and monitoring for any side-effects. Initially there were 13 outreach teams – now only four are needed. The huge success of this programme has its essence in the caring community support wrapped around each patient going through those tough, long 18 - 24 months of treatment, resulting in improved patient satisfaction and excellent outcomes. The programme

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has become a national DR/XDR-TB bench mark model. The University Research Council came on board and bankrolled a 2-year mentoring programme for satellite and decentralised sites in eight other provinces, with most provinces (and several international institutions) sending their top TB and HIV managers and clinicians to learn the ropes at CoSH and Greytown. I ask Eksteen, who comes up from the valley once a week to conduct a clinic at M3, what he’d do if he had a ‘magic wand’. The answer is unsurprising to any TB healthcare worker who’s seen patients die while awaiting lab results (or started them too soon on inappropriate treatment). ‘Well, we don’t have a second-line PCR test yet – I’m not sure whether it’s a validation problem or the cost factor or a combination of the two. If we did, it would make a huge difference to

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140 120 100 Patients, n

XDR patients. I know they were thinking of a GeneXpert type office test on site for fluoroquinolones, I don’t know how far that is. The ideal would be to have the GeneXpert PCR test for fluoroquinolones in a kind of “black box” where you put the specimen in one side and get the result out the other side in a matter of hours.’ Eksteen says if a patient with MDR-TB walks into hospital today, it can take up to 3 months to diagnose XDR-TB. If he starts an XDR patient on MDR treatment there may be some effect if ‘one or two drugs are working, but in principle you need three or more drugs to have a quick outcome. A deficient regimen, and the patient can deteriorate badly and your options become severely limited’ (death being the most likely outcome). Most of Greytown’s M3 referrals come from the Charles Johnson Memorial Hospital in Nqutu; CoSH sends slightly fewer, Dundee and Umvoti hospitals the least. A fleet of emergency medical rescue service (EMRS) buses transports both ‘cold’ and emergency cases from these sub-districts – and more recently from Ladysmith, Estcourt and Emmaus in the Tugela district, plus Illembe near Stanger, closer to the coast. I put the ‘magic wand’ question to veteran Sister LeeMegan Larkan, who runs the MDR-TB clinic at M3 which sees 70 referred patients every Wednesday. ‘To be able to decant patients from here to the satellite units once they’re stable (especially if the satellite hospital team has outreach injection capacity). Also to fasttrack nurse-initiated management TB-drugresistance training so we can have nurses at satellite units who can look after the patients. We have challenges with transport, so if the care can be decentralised, it can be within walking distance.’ Another high priority/ unmet need is overnight accommodation for patients, who currently sleep in a chair or on the floor at the outpatients area of their subdistrict hospital before catching the EMRS bus to Greytown the next day. If they’re late getting their MDR-TB treatment at M3, they

80 60 40 20 0

2012

2013

2014

Q1/2014

Q2/2014

MDR

118

116

Q3/2014 30

Q4/2014 29

Died

XDR

Died

Umzinyathi District cure rates for MDR- and XDR-TB.

again sleep in whatever sheltered area they can find around or near the hospital before catching the bus. However, the most effective solution, says Larkan, would be to get the satellite sites up and running properly to decrease the M3 workload. ‘In that way we could start managing XDRs here. Waiting for a bed at King George can nowadays take up to 3 weeks and it’s detrimental to the patients.’ Eksteen affirms this, ‘Ideally one would like to initiate XDR treatment at the decentralised hospitals.’ Yet they’re obviously doing something right; initially nearly half of all Greytown’s MDR-TB patients were pre-XDR, now it’s down to about 15%. The average inpatient stay is 4 - 6 weeks, compared with 4 months when the facility opened 7 years ago. This is almost entirely due to CoSH’s outreach injection/home-based care programme being closely emulated in the other three satellite feeder health districts, plus improved drug adherence counselling. TB prevalence in CoSH’s Msinga district stands at 1 000/100 000 population (about the national average, the WHO attributing ‘emergency status’ to any country at 250/100 000 or above).

The team has contributed heavily to the national guidelines for community management of MDR-TB and the decentralisation of MDR-TB services. Umzinyathi healthcare workers are saving lives hand over fist (the target being 85%); the overall Umzinyathi district treatment success rate for all regular TB cases was 86.2% in 2011. Last year it was 88.4%. For CoSH in 2011 it was 86.4%. Last year it was 91%. The district’s ‘suspicion index’ (percentage of patients suspected of having TB, irrespective of what services they come for) stands at 4%, the target being 5 - 10%. Living proof of what self-help author and counsellor Douglas Bloch was once quoted as saying: ‘If you think you’re going through hell, don’t stop!’[1] Chris Bateman chrisb@hmpg.co.za 1. Mitchell J. If you’re going through hell, don’t stop! (newspaper interview with Douglas Bloch). The Oregonian, 18 November 1990. (Full quote: ‘When someone says, “I’m going through hell,” the best response is to say, “Don’t stop!” If we see that pain, grief and tough times are a process and that it will get better, we’re less likely to get stuck in the hell.’)

S Afr Med J 2015;105(7):517-520. DOI:10.7196/SAMJnew.7838

Noakes’s adversaries get him in the ‘dock’ The protagonists in the latest clash of the dieting titans (conventional v. Banting diets) agree on one thing – that asking an esteemed panel of Prof. Tim Noakes’s medical peers to rule on whether his cyber-advice on breastfeeding babies was ‘unprofessional conduct’ may prove a turning point for nutritional guidance.

The hearing, postponed in Cape Town early in June after Noakes’s lawyers questioned the proper constitution of the Medical and Dental Professional Board (MDPB)’s Professional Conduct Committee, will focus on three issues raised by Noakes’s cybertwitter. In it, he advises a mother that when she weans her baby, it should be via a lowcarbohydrate, high-fat (LCHF) diet. The issues are basic, one of them with the potential to set a precedent on how

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social media should be used by health professionals. Did Noakes act unethically by: (i) providing information outside the scope of the practice for which he is registered (general practice, but with a special interest in nutrition); and (ii) giving one-on-one nutritional advice on social media to a patient whom he had not assessed? Thirdly, what constitutes best-practice complementary feeding recommendations for infants and children?

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While the last question is not related directly to the ‘charge sheet’, medical professionals in related disciplines will be scouring upcoming hearings’ evidence for answers – and hope that the committee makes substantive findings on it. The charge sheet claims that Noakes is ‘guilty of unprofessional conduct or conduct which, when regard is had to your profession, in that during the period between January 2014 and February 2014 you acted in a manner that is not in accordance with the norms and standards of your profession in that you provided unconventional advice on breastfeeding babies on social networks (tweet/s)’.

Did he diagnose and treat, or merely ‘advise’?

In terms of the Health Professions Council of South Africa (HPCSA) rules, doctors are not allowed to make a diagnosis or offer treatment online – even though they may give advice or share opinions online. Herein lies the rub: was Noakes ‘diagnosing and treating’ or simply advising or opining – in line with cybertechnology’s all-pervasive ‘democratisation’ of fields previously considered the sole domain of science and ‘off limits’ to all but the relevant specialists? Perhaps most importantly – and this is where his critics bang their drums the hardest – was he causing harm (in this specific instance, but they claim far more generally)? Interestingly, there is no reference in the charge sheet to Noakes’s Twitter advice being harmful or dangerous, something Association for Dietetics in South Africa (ADSA) President Claire Julsing-Strydom (who brought the original complaint in her personal capacity) has been publicly claiming. This could open the way for Noakes to bring a counter-claim. Julsing-Strydom says the committee’s findings will provide clarity on issues that will ‘advance healthcare in the best interests of the public and clear any public and professional confusion’. A guilty finding could cost the unperturbed Noakes his licence to practise as a doctor, and get him to pull in his horns, reducing the growing public health threat that, according to his critics – many of them internationally respected academics in endocrinology, diabetic medicine and cardiology – he allegedly represents. Noakes, on the other hand, welcomes the hearing and cannot wait for the cross-examination of his latest detractors to begin. The mother to whom he gave the cyber-advice did not follow it, raising vexed questions about actual harm caused. She was not present at the initial Cape Town hearing.

Noakes ‘out of line’ with paediatric guidelines

Julsing-Strydom, speaking to journalists beforehand, said infants are not supposed

Prof. Tim Noakes with fellow A-rated scientist Prof. Jacques Rossouw, a former director of the Medical Research Council’s Institute for Nutritional Diseases, after their contentious UCT Centenary debate in February 2013. Photo: Chris Bateman.

to have such a high intake of protein (Noakes has consistently said the LCHF diet is not a high-protein diet). She cites several studies showing that even in infant formulas the amount of protein has had to be reduced because it impacted on obesity later in life. ‘A baby’s little kidneys just wouldn’t manage,’ she adds. ADSA argues that the advice, via Twitter, is out of kilter with both international (World Health Organization Guiding Principles for Complementary Feeding of the Breastfed Child) and national (South African Paediatric Food Based Dietary Guidelines) feeding guidelines for infant and young child nutrition. Noakes, who has been researching infant nutrition for the past 4 years, is about to release the follow-up book to The Real Meal Revolution (his guide to the Banting diet), entitled Raising Superheroes, which deals solely with infant and child nutrition. The book is co-written with Bridget Surtees, a registered dietitian and member of ADSA who has been practising child and infant nutrition in London and Sydney for the past 10 years, before recently returning to South Africa. He is unapologetic about advising the mother to wean her child onto LCHF foods. ‘By implication I was saying that the child should not be weaned onto traditional highsugar, high-carbohydrate processed cereals,’ he says. He added that high-carbohydrate, processed-food diets became the norm in the USA after 1936, via the Gerber baby foods company, which is now a subsidiary of the Nestlé Group. ‘Ironically, these were the first “industrial” (i.e. highly processed) foods and they led in time to the highly processed foods that we now eat and think healthy,

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in part because as infants our taste was conditioned by our early exposure to these non-foods.’ He wants to encourage people to understand they will be healthier eating ‘real’ foods, not fake industrially processed staples. This change needs to happen from birth, he emphasises. Noakes told Izindaba that he personally wrote the 20 000-word scientific chapter in Raising Superheroes, but that ‘every word and every sentence’ was checked by his co-author to ensure that it was supported by the scientific evidence. He claims that his chapter argues ‘in great detail and with the support of more than 130 scientific references’ why infants should be weaned onto real foods, giving eight reasons. Noakes agrees with Julsing-Strydom that the professional conduct committee finding could be a ‘turning point in the debate about what our infants, and in turn adults, should be eating’. The hearing was postponed to 23 November at the Newlands Hotel in Cape Town after the committee chairperson, Advocate Joan Adams, conceded to Noakes’s lawyers that her committee had no powers to deviate from the HPCSA Act and its regulations. These required a third person on her committee to be registered with the MDPB and to be in the same discipline as Noakes. ‘We are lacking one member,’ she admitted, adding that only the chairperson of the MDPB could appoint this person. Chris Bateman chrisb@hmpg.co.za S Afr Med J 2015;105(7):520-521. DOI:10.7196/SAMJnew.7955

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South Africans inured to death Death cafés – the concept sounds ghoulish, but they could soon become as much a reality in South Africa (SA) as they are in North America, Europe and Australia. This follows a groundbreaking local judgment that has the best legal and medical minds debating whether euthanasia can ever be justified in this country. Tea, cake and a cosy chat about our demise is not somebody’s idea of dark humour. It’s a sincere and very smart attempt to destigmatise the thing many of us fear the most. By getting together to chat about our mortality and hopefully normalise death as a part of life, we’ll hopefully be able to shuffle off this mortal coil with more peace of mind than if we ignored the issue completely. The café concept, while sounding more like dark comedic science fiction (e.g. ‘The Restaurant at the End of the Universe’ by Douglas Adams), could perhaps more accurately be dubbed ‘The Café about the End of my Life’. The approach, initiated by the worldwide palliative care community, is that, like it or not, we’ll have to make pragmatic decisions about our demise sometime, so why not sooner than later – and in a congenial environment? The recent groundbreaking judgment that legalised (albeit just hours after his natural death) assisted suicide for Cape Town advocate Robin StranshamFord, and described the relevant outdated law as unconstitutional, has evoked huge public interest about a host of end-of-life issues. Discussion, in death cafés or not, has turned to whether and/or under what circumstances we should be able to end our lives (or have somebody help us die).

‘We’re in denial’ – hospice chief

Most of us are in denial about death, says Dr Liz Gwyther, President of the International Hospice and Palliative Care Association (and CEO of the SA equivalent). She believes that both the Stransham-Ford court application and much of the current discussion and debate are driven by our own personal fears and imaginings of how we might die. ‘We don’t ever know how the situation is going to be until we are actually living it. Often our fears and imaginings are a lot worse than reality.’ Perhaps the most powerful underpinning of her contention (and support for death cafés) is that pain – with all its concomitant maladies of depression, indignity, hopelessness and lack of control – is today eminently manageable using opioids (mainly morphine). So much so that death can be peaceful and lucid, with any pain well controlled. Once the body has adjusted to the morphine (3 - 7 days), full

Madiba’s end ‘cynically manipulated’

Dr Liz Gwyther, President of the International Hospice and Palliative Care Association.

lucidity returns. Gwyther has seen hundreds of people die in her 23 years of palliative care and believes that death is an opportunity and process in which there can be ‘a lot of living, richness, incredible growth and family interaction’. She also emphasises that euthanasia is a one-way street with no possibility of return. Research has shown overwhelming relief and gratitude by those people who’ve contemplated it in a moment of despair, but chose holistic palliation. Talk to any severely disabled person who has had to come to terms with their condition, she adds, and they’ll tell you how close they were to ‘ending it all’ – and how far the emotional pendulum can swing. Euthanasia is an anathema to palliative care practice internationally, ‘an unnecessarily extreme measure’, because physical, emotional, psychological and spiritual pain can be addressed, using extrinsic and intrinsic resources, the latter drawing on skills and successful coping mechanisms acquired during previous life crises. Palliative care could control confusion, and people who were well supported with palliative care and experienced alleviation of symptoms could become less afraid. Stransham-Ford had expressed the fear that ‘his last breath might be with the aid of a machine.’ Gwyther said it was recognised that a person could refuse treatment and, in this case, refuse respiratory support, which was ‘inappropriate treatment’ for a person with a short prognosis. The essence of palliative care was the relief of suffering, she stressed. Stransham-Ford had also feared dying while suffering, yet an experience of palliative care would have allayed that fear. Gwyther said palliative care neither hastened nor postponed death, most powerfully citing former President Nelson Mandela’s ‘politically managed’ 6-month, drawn-out death in which he finally succumbed after being put on life support in hospital.

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Both Gwyther and her euthanasia opponent, Prof. Willem Landman of Dignity South Africa (a pro-euthanasia human rights group), believe that Mandela’s drawn-out passing was politically motivated. Gwyther says Mandela was ‘denied the comfort of the old man’s friend’ – a natural and peaceful death from pneumonia. Landman is more forthright. He says that, had Mandela been capable, ‘he would have thought the last 6 months of his life an assault on his dignity, orchestrated by a manipulative and self-interested government’. Landman, Executive Director of the Ethics Institute of South Africa, spoke alongside Gwyther and several other top academics at a Wits University ‘Reflections on End-of-Life Decisions’ public debate at the Steve Biko Centre for Bioethics on 14 May (soon after the Stransham-Ford judgment). Landman was scathing about comments attributed to health minister Dr Aaron Motsoaledi, saying he had ‘no business giving his ‘purely personal interpretations of constitutional rights without engaging with authoritative sources.’ The judgment by Judge H J Fabri cius of the North Gauteng High Court included a recommendation that the law should be ‘developed’ to bring it more in line with 1998 recommendations by the SA Law Commission (SALC) favouring the sanctity of a dignified death and assisted dying – and avoiding the current clash with the Bill of Rights. Landman said the government response to the ruling ‘demeans public debate’, and accused it of being ‘on a crusade’.

Government should ‘accept the Constitution’

Government should instead ‘unam biguously accept the Constitution as the highest authority and uplift public debate’. Both Landman and Prof. David McQuoidMason, Director of the Centre for SocioLegal Studies at the University of KwaZuluNatal, agree that the judgment opens the way for the Constitutional Court to endorse the SALC’s recommended changes on existing euthanasia law – and that it enables anyone to bring a similar application to the High Court, which would then treat each case on its merits. Landman said Judge Fabricius clearly thought that doctor-assisted suicide was ‘a matter of great public importance’ and declined the government’s request to throw out the case because the patient had died shortly before he delivered it. Landman argues that public policy should be developed

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health minister’s argument that any legalising of assisted dying would create a potential rise in fraud and unethical behaviour among doctors as ‘dim, alarmist and insulting to doctors and families as closet killers, and dying patients as fraudulent schemers’.

SA ‘not a safe and appropriate place’ for euthanasia

A capacity audience reflected on end-of-life decisions at the Wits Steve Biko Centre for Bioethics on 14 May.

on the basis of the spirit, values and rights of the Constitution, not personal, religious or cultural beliefs. Dignity SA, which supported Stransham-Ford’s court application, believes in the fundamental ethical values of respect for life and freedom of choice, as well as the virtues of compassion and solidarity with those who suffer. Landman said that as the law stood, the Constitutional rights to dignity and freedom to bodily and psychological integrity were being denied. The draft legislation in the SALC report had been ‘callously ignored’ by Parliament for 17 years, with one of the Stransham-Ford court respondents, the Department of Justice and Correctional Services, saying it had ‘not the remotest intention’ of tabling new legislation. Among the serious disagreements in the public debate were balancing the right to dignity and the right to life, the legitimate limits of a medical practitioner’s professional duties, whether suicide should be a purely personal matter, possible abuse of vulnerable persons, access by the poor, the effectiveness of safeguards, the limits of palliative care and the relevance of ‘God’s will’ and cultural beliefs in constitutional interpretation.

‘It is harder morally to justify letting somebody die a slow and ugly death dehumanised, than it is to justify helping to avoid it.’ (J M T Labuschagne[1])

Whose God decides?

Observed Landman: ‘Assuming God exists and communicates with us, how does one resolve conflicting understandings of his will? Which religion, which interpretation of a specific religion?’ he prodded. Good medicine already ‘played God’ in many

other ways, thereby manipulating the time and manner of death (e.g. surgery, antibiotics, intervening in the dying process). Landman rebutted Motsoaledi’s arguments that doctors were ‘not to be looked upon as people who kill’, that they ‘can kill anytime but don’t, because not killing is imbedded in their minds’ and that doctors should provide palliative care to enable death with dignity. He said Motsoaledi’s concern was ‘misplaced’ given the country’s dysfunctional public hospitals where unnecessary deaths were commonplace and palliative care grossly inadequate. Gwyther says that 4% of South Africans who would clinically qualify for palliative care are getting it and that only 10 hospitals in SA have a palliative care service. Lack of funding has meant that the number of hospices dropped from 202 in 2011 to 153 currently. However, partnerships had been developed between these hospices and 400 state facilities while training and expansion was ongoing, she added.

Doctors have ‘special moral duties’

Landman told the Wits symposium that doctors had ‘special moral duties’ when death was ‘inevitable, and suffering intractable and unbearable’. He said there was also no intrinsic moral difference between assisted dying and standard-of-care practices such as withholding or withdrawing treatment or pain management that shortened life. While palliative care was ‘non-negotiable’, it was limited by freedom of choice. It was not for the state to say ‘we should choose other options (such as palliative care), since we have a constitutional right to dignity, and dignity encompasses one’s own conception of how to cease to live’. A patient might also not want terminal sedation, which may be the only relief from pain. He described the

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Prof. Dan Ncayiyana, Editor Emeritus of the SAMJ, said the justification for active euthanasia or physician-assisted suicide was ‘compelling – all things considered equal and in the right context’. However, SA was ‘not a safe and appropriate place’ for legalised euthanasia ‘at this time’. Current inequalities would benefit the well-off, while opening up the potential for perverse application among the burgeoning poor population and other vulnerable groups. The public health system was ‘broken and decrepit’ with little respect for human life, making a default to euthanasia likely. ‘In SA there is no respect for human life, with 45 murders per day, mob-justice and police killings. There are needless hospital deaths and neglect and indifference in them. Healthcare workers easily down tools, regardless of the cost in human life and suffering,’ he added. Legalised euthanasia needed ‘a functional and reliable framework of supervision to monitor implementation’. SA had a ‘dismal record and reputation, certainly in the health and medical landscape,’ he said, citing the recently probed dysfunctional Health Professions Council of South Africa.

‘My problem with euthanasia is not that it is an immoral way to die, but that it has its roots in a fearful way to live.’ (Gwyther, quoting Fraser[2])

‘From a public policy point of view, for the state to sanction the deliberate taking away of a life would send the wrong message,’ Ncayiyana said, concluding that the time was ‘not yet ripe’ for legally sanctioned active euthanasia. He quoted a scholar on the decriminalisation of euthanasia, Prof. J M T Labuschagne, as saying: ‘It is harder morally to justify letting somebody die a slow and ugly death dehumanised, than it is to justify helping to avoid it.’ Gwyther welcomed the current debate, saying that her Hospice and Palliative Care Association was ‘already challenging

IZINDABA

our hospital managers, asking if they’re ready to cope with even more requests [for palliative care] if they come’. Research by the South African Medical Research Council (Burden of Disease Unit statistics) had shown that 258 268 people who could have benefited from palliative care died in 2010. Her association managed to care for just

94 585 of them. She believes that because of the global move towards safeguarded euthanasia, SA society will choose to allow the right to die, ‘but a lot of people have responded by saying that if you have the right to die, there has to be a law around palliative care. We need equity of access to palliative care.’

Chris Bateman chrisb@hmpg.co.za

disadvantaged situations, while at the same time producing pioneering studies and methodical research on neonatology, child malnutrition and their consequences. He trained a generation of medical students and young doctors, several of whom went on to major positions in paediatrics and child health in South Africa and overseas, for whom he remained a significant role model and who retain vivid memories of him to this day. Harry was born in 1925 in Morgenzon, a remote South African town. His parents were Jewish Lithuanian refugees and he was the youngest of six children. He had a tough start to life, losing his father while his mother was pregnant with him. He spent his early years on a farm, but his mother moved the family to Johannesburg before he started school. When he left school he studied medicine at the University of the Witwatersrand. Following house officer jobs at Baragwanath in 1950, Harry decided on a career in paediatrics. He began higher training in Johannesburg and then spent a year in the UK gaining his paediatric specialist qualifications in London and Edinburgh. He returned to South Africa to complete his training as paediatric registrar at Baragwanath in 1954 and met his wife-to-be Yvonne, who was a social worker. They were married for over 61 years. Following appointment in 1971 as Head of Newborn Services at Baragwanath, with over 3 000 low-birth-weight, often premature babies born each year and most needing specialised care, the idea of turning an entire ward into an incubator, with an adjoining ward for the mothers, took root. This proved a successful intervention, providing good care for babies at high risk. Harry was appointed to the Chair of Paediatrics at Wits in 1977. Most of Harry’s research concerned mal nutrition and its consequences, and premature birth and/or low birth weight. In a randomised trial he conducted with John

Pettifor (later his successor at Chris Hani Baragwanath), it was found that feeding very low-birth-weight babies their own mothers’ untreated milk was demonstrably better than feeding them with pooled pasteurised breastmilk, which was the standard at the time. Harry was an astute observer. He was the first to identify finger clubbing as a sign of cirrhosis of the liver (published in The Lancet) and also the first to recognise that veno-occlusive disease of the liver could occur outside Jamaica (published in papers in the BMJ). He also wrote a number of papers on idiopathic cardiomyopathy in children. During the Soweto uprising of 1976 Harry never missed a day, driving to work whatever the risks. He fought repeated battles with apartheid authorities about the lack of equity for black people, especially around health and training opportunities, and was invariably at odds with them about resources for Soweto. Harry enjoyed active outdoor family holidays, often at a rural farm. Here he provided care to local people, many of whom would arrive seeking medical help for their children and themselves. He loved outdoor activities, hiking in the Drakensberg mountains and following beautiful hiking trails along the South African coast, as well as playing tennis. At 62 he took retirement and moved with Yvonne to London to be near his children. He worked as a consultant community paediatrician in Barnet, finally retiring five years later. He developed a series of health problems, but never lost his spirit and enjoyment of his family. He is survived by his wife Yvonne, his children Alan, Mark and Lynne, and seven grandchildren.

1. Labuschagne JMT. Decriminalisasie van eutanasie. Tydskrif vir Hedendaagse Romeins-Hollandse Reg (THRHR) 1998:176 (as cited in the SA Law Commission). 2. Fraser G. ‘Loose Cannon’ column, The Guardian, 13 May 2013.

S Afr Med J 2015;105(7):522-524. DOI:10.7196/SAMJnew.7835

Obituary

Harry Stein, 1925 - 2014

The career of Harry Stein, who died at 89 on 31 December 2014, touched the lives of countless babies at Baragwanath Hospital in some of South Africa’s darkest years during apartheid. In a career spanning 37 years, Harry became Head of Neonatology and later Head of Paediatrics at Baragwanath Hospital and Professor of Paediatrics at the University of the Witwatersrand until he retired in 1987. Baragwanath (now Chris Hani Baragwanath) was a national referral centre and the only hospital serving Soweto at the time, then with a population estimated to be in excess of 1.5 million people. Running paediatrics was a formidable task. Baragwanath had 400 children’s beds and treated 100 000 child outpatients a year; 17 000 babies were delivered each year. There were very high rates of low birth weight and premature delivery, with over 3 000 babies a year weighing less than 2 500 g at birth and often premature. Many infants and children suffered from malnutrition. Harry made a major contribution to the care of premature babies born into highly

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Hoosen Coovadia Stephen Tollman University of the Witwatersrand, Johannesburg, South Africa hcoovadia@match.org.za

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CLINICAL ALERT

The bronchiolitis season is upon us – recommendations for the management and prevention of acute viral bronchiolitis H J Zar, D A White, B Morrow, C Feldman, S Risenga, R Masekela, H Lewis, P Jeena, S A Madhi Prof. Heather Zar is Head of the Department of Paediatrics and Child Health, Faculty of Health Sciences, University of Cape Town, South Africa, and Director of the Medical Research Council Unit on Child and Adolescent Health, University of Cape Town; Dr Debbie White is a consultant paediatrician in the Department of Paediatrics and Child Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; Prof. Brenda Morrow is a physiotherapist and Associate Professor in the Department of Paediatrics and Child Health, Faculty of Health Sciences, University of Cape Town; Prof. Charles Feldman is head of the Division of Pulmonology, Department of Internal Medicine, Charlotte Maxeke Johannesburg Academic Hospital and Faculty of Health Sciences, University of the Witwatersrand; Prof. Sam Risenga is Head of the Department of Pulmonology, University of Limpopo and Pietersberg Hospital, Limpopo, South Africa; Prof. Refiloe Masekela is Head of the Department of Paediatrics and Child Health, School of Clinical Medicine, College of Health Sciences, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa; Prof. Humphrey Lewis is Honorary Professor in the Department of Paediatrics and Child Health, School of Medicine, Faculty of Health Sciences, University of Pretoria; Prof. Prakash Jeena is Associate Professor in the Department of Paediatrics and Child Health, School of Clinical Medicine, College of Health Sciences, Nelson R Mandela School of Medicine, University of KwaZuluNatal; and Prof. Shabir Madhi is Executive Director of the National Institute for Communicable Diseases and MRC Respiratory and Meningeal Pathogens Research Unit, Faculty of Health Sciences, University of the Witwatersrand. The authors constitute the Management of Acute Viral Bronchiolitis Working Group of the South African Thoracic Society. Corresponding author: H J Zar (heather.zar@uct.ac.za)

Despite being so common, bronchiolitis remains poorly diagnosed and managed. This article is intended as an update on issues pertaining to this condition. S Afr Med J 2015;105(7):525-526. DOI:10.7196/SAMJnew.8040

Definition

Bronchiolitis is a viral-induced lower respiratory tract infection that mainly occurs in children <1 year of age.

Causative organisms

The most frequent cause of severe bronchiolitis is respiratory syncytial virus (RSV). Other respiratory viruses are less common (parainfluenza virus, human metapneumovirus, influenza virus, measles virus), or definitive attribution has yet to be established (e.g. rhinovirus, bocavirus and coronavirus).

Seasonality

In South Africa bronchiolitis peaks in the RSV season, which varies slightly by province. RSV circulation is evident from February through to June, before the influenza season (May September).

Diagnosis

Clinical manifestations

Bronchiolitis is diagnosed on the basis of clinical signs and symptoms. In a young child, the clinical pattern of wheezing and hyperinflation is diagnostic and typically starts with an upper respiratory prodrome including rhinorrhoea, low-grade fever, cough and poor feeding, followed 1 - 2 days later by tachypnoea, hyperinflation and wheeze as a consequence of airway inflammation and air trapping. The most reliable clinical feature of bronchiolitis is hyperinflation of the chest.

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The illness is generally self-limiting but may progress to more severe disease. Measurement of the peripheral arterial oxygen saturation is useful to indicate the need for supplemental oxygen. A saturation of <92% at sea level and <90% inland indicates that the child requires admission to hospital for supplemental oxygen.

Investigations

Chest X-rays are generally unhelpful and are not required in children with a clear clinical diagnosis of bronchiolitis. Haematological testing is not routinely required. Nasopharyngeal aspirates should not be routine, as viral testing adds little to routine management.

Management of bronchiolitis

Management is largely supportive. There is currently no proven effective therapy other than oxygen for hypoxic children (evidence A – well-designed randomised controlled clinical trial or diagnostic studies on relevant well-chosen populations), who can be given humidified low-flow oxygen (0.5 - 3 L/min) by nasal prongs. There is no evidence for routine use of antibiotics, nebulised agents (including bronchodilators, adrenaline, steroids or hypertonic saline), oral steroids, chest physiotherapy or montelukast (evidence A).

Prevention of RSV infection in high-risk children

Specific RSV monoclonal antibody, palivizumab, is available for children at particular risk of severe bronchiolitis (evidence A), as detailed below.

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Indications for palivizumab for children at high risk of severe bronchiolitis

• Premature infants of gestational age <36 weeks at birth and younger than 6 months of age at the start of the RSV season. Prophylaxis should be continued until the end of the RSV season (last dose in May). • Children of any gestation who are <24 months of age at the start of the RSV season with any of the following: chronic lung disease of prematurity, chronic lung disease, primary immunodeficiency, haemodynamically significant congenital heart disease. Note: Based on seasonality, prophylaxis should be started in January. If available, palivizumab prophylaxis for high-risk premature infants should commence prior to discharge from hospital.

Education

Management of children with bronchiolitis requires that parents/ caregivers be educated about the condition. This is particularly important in the case of children who are not admitted to hospital,

but is also beneficial before a child is discharged from hospital. The key elements of an education message are listed below.

Key elements of an education message for parents of children with bronchiolitis

• The condition has a prodrome of an upper respiratory tract infection with low-grade fever. • Symptoms are cough and wheeze, and often fast breathing. • Bronchiolitis is caused by a virus; antibiotics are not needed. • Bronchiolitis is usually self-limiting, although symptoms may occur for up to 4 weeks in some children. Disclosures. HJZ serves on the steering committee and was a speaker at the Global Experts meeting funded by Abbvie. SAM received honoraria from Medimmune and Abbott for an Advisory Board and Speakers’ Bureau, respectively. DAW, BM, SR, HL and PJ served on an Advisory Board to Abbvie. Accepted 3 June 2015.

MEDICINE AND THE LAW

Doctor-assisted suicide: What is the present legal position in South Africa? 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)

In the recent case of Stransham-Ford v. the Minister of Justice and Correctional Services, the North Gauteng High Court held that a terminally ill patient who was experiencing intractable suffering was entitled to commit suicide with the assistance of his doctor and that the doctor’s conduct would not be unlawful. The court was careful to state that it was not making a general rule about doctor-assisted suicide. The latter should be left to the Parliament, the Constitutional Court and ‘future courts’. The judge dealt specifically with the facts of the case at hand. In order to understand the basis of the decision it is necessary to consider: (i) the facts of the case; (ii) the question of causation; (iii) the paradox of ‘passive’ and ‘active’ euthanasia; (iv) the test for unlawfulness in euthanasia cases; and (v) the meaning of doctor-assisted suicide. It is also necessary to clarify the present legal position regarding doctor-assisted suicide. S Afr Med J 2015;105(7):526-527. DOI:10.7196/SAMJnew.7895

The facts of the case

In the case of Stransham-Ford v. the Minister of Justice and Correctional Services,[1] the applicant was a highly qualified lawyer who had terminal cancer that had spread to his lower spine, kidneys and lymph nodes. He had tried a number of traditional and other forms of medication as well as palliative care, but none of these had alleviated his suffering. He had only a few weeks left to live, and died of natural causes just before the judge made his order. After a hasty but well-reasoned judgment, the judge issued an order stating that if Mr Stransham-Ford was assisted to die by a doctor who provided or administered a lethal medication to him, the doctor would ‘not be acting unlawfully, and hence, shall not be subject to prosecution by the [National Prosecuting Authority]

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or subject to disciplinary proceedings by the [Health Professions Council of South Africa]’. Such an order is not unusual, as a similar order in respect of immunity from prosecution was made more than a decade ago, in a ‘passive’ euthanasia case where a wife was allowed to order the withdrawal of treatment from her husband who was in a persistent vegetative state.[2] In terms of the South African (SA) Constitution, where the common law is in conflict with the Constitution the common law must be developed by the courts to bring it into line with the Constitution.[3] Thus the court stated that ‘the common law crimes of murder or culpable homicide as they affected liability for assisted suicide by medical practitioners, unjustifiably limited the patient’s constitutional rights to human dignity (s. 10) and bodily and psychological integrity (s. 12 (2) (b) read with s. 1 and 7)’ were

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‘overbroad’ and unconstitutional.[1] However, apart from the situation in the Stransham-Ford case which dealt with ‘active voluntary euthanasia’, the common law crimes of murder and culpable homicide were not affected by the judgment.[1]

Causation

In law ‘causation’ refers to an act or omission that causes or accelerates death.[4] In cases of murder or culpable homicide, the accused person need not be the sole cause of the death of the deceased – others may also be held liable for contributing to it.[5] ‘Causation’ is clear where a doctor’s act is the sole cause of death by administering a fatal dose of medication that does not enable the underlying illness or injury to kill the patient.[6] However, in situations where one or more events contribute towards the death of a person, the event that finally hastens the death is regarded as its cause.[6] Therefore, in situations of ‘double effect’, where the administration of increasing doses of medication with the motive of lessening pain and suffering hastens the patient’s death, the increased dose will have ‘caused’ the death of the patient. This is so, even though without the increased dosage the patient would have died from the underlying illness or condition – because by increasing the dosages the patient’s death is hastened.[6]

The paradox of ‘passive’ and ‘active’ euthanasia

Previously the courts have observed that the distinction between an act and omission causing death was artificial and the withdrawal of treatment from a persistent vegetative state patient whose prognosis was hopeless would be lawful.[2] In the Stransham-Ford case, the court indicated that there was no logical distinction between ‘passive voluntary’ and ‘active voluntary’ euthanasia and that ‘active voluntary euthanasia’ should be regarded as lawful under the conditions that prevailed in the case.[1] This is because in both situations the act or omission by the doctors in withdrawing or denying medical treatment, or prescribing medical treatment that may hasten the patient’s death, causes the patient to die sooner rather than later. In any event, switching off a ventilator, or prescribing increasing doses of medication until they hasten death, is of itself a positive act that triggers the death of the patient. In ‘passive’ euthanasia cases, doctors have the ‘eventual’ intention to hasten the death of the patient – i.e. they subjectively foresee that their withholding or withdrawing treatment or increased use of certain medication(s) will hasten the patient’s death.[7] In ‘active’ euthanasia cases, doctors who administer or prescribe lethal medication have the ‘actual’ intention to hasten the death of the patient (i.e. they direct their minds to hasten the death of the patient).[7] In terms of the Constitution, terminally ill patients who suffer unbearably are entitled to have their physical and psychological integrity, privacy and right to die in dignity respected.[1] They are also entitled not to be ‘treated or punished in a cruel, inhuman or degrading way’.[8] Whether these rights are protected through ‘passive’ voluntary euthanasia or ‘active’ voluntary euthanasia makes no difference. In both instances the death of the patient is hastened. The court in the Stransham-Ford case followed a recent Canadian Supreme Court decsion[9] that granted a similar application for doctor-assisted suicide.

Test for unlawfulness in euthanasia cases

In cases decided before the Constitution came into effect, the courts held that the test for unlawfulness was the ‘legal convictions of the community’.[2] However, since then the Constitutional Court has held that the courts should not be influenced by public opinion but by the values of the Constitution – the most important of which is the right to dignity.[10] It also held that the right to life is inextricably linked to the right to dignity and means something more than ‘existence’. [10]

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Thus, in determining the patient’s quality of life, the court in the Stransham-Ford case applied the values of the Constitution and concluded that the right to life ‘cannot mean that an individual is obliged to live, no matter what the quality of his life is’.[1] This approach is similar to that of the court in Clarke v. Hurst NO,[2] which found that continued artificial feeding would ‘not serve the purpose of supporting human life as it is commonly known’, and allowed the patient’s wife to order its withdrawal without being exposed to legal sanctions.

Doctor-assisted suicide

Although it has been suggested that the phrase ‘doctor-assisted suicide’ should be replaced with ‘death with dignity’, ‘aid-in-dying’[11] or ‘doctor-assisted death’, the term is still used widely and is applied where doctors administer or supply lethal drugs or mechanisms to patients who are terminally ill to assist them to hasten their death so that they might die with dignity. Whether the doctors actually administer the drugs or mechanisms or provide them, knowing that their patients will use them to take their own lives, makes no difference.[12] In both instances doctors are regarded in law as having ‘caused’ or contributed to the death of their patients. The question of whether or not a doctor is guilty of murder or culpable homicide will depend on whether the courts regard such conduct as unlawful.[7] The Stransham-Ford case now suggests that, in certain cases, the courts may hold that ‘active’ voluntary euthanasia by a doctor is not unlawful because its prohibition is a violation of the Constitution. The court, however, was careful not to elevate this to a general rule because it recognised that the terms and conditions for a general rule need to be considered and determined by Parliament, the Constitutional Court or an appeal court.[1]

The present legal position

In the Stransham-Ford case, the court clearly stated that each application for doctor-assisted suicide by terminally ill patients who wish to die in dignity must be considered on its merits.[1] The judgment implies that, unlike in cases of ‘passive’ euthanasia, where no court order is required unless the decision is challenged in court,[2] in cases of ‘active’ euthanasia it will be necessary to obtain a court order. The requirement of a court order provides a safeguard against abuse,[1] and will be mandatory unless Parliament, the Constitutional Court or an appeal court outlaws the practice or provides other guidelines for how it should be conducted. Until then, the decision in the Stransham-Ford case (which is a judgment by a single judge) is not binding on any of the high courts in Gauteng or the other provinces of SA, but may be of persuasive value to them. The case recognises that people in the position of Mr Stransham-Ford may approach the courts for an order allowing their doctors to assist them in terminating their lives. Such an application may or may not be granted in future, depending on how Parliament, the Constitutional Court or other appeal courts develop the law. 1. Stransham-Ford v the Minister of Justice and Correctional Services and Others 30 April 2015, Case no. 27401/15 (NGHC) (unreported). 2. Clarke v. Hurst NO and Others 1992 (4) SA 630 (D). 3. Section 8 of the Constitution of the Republic of South Africa, 1996. 4. Burchell J. Principles of Criminal Law. 3rd ed. Lansdowne: Juta & Co. Ltd, 2006:209. 5. S v. Daniels and Others 1983 (3) SA 275 (A). 6. S v. Hartmann 1975 (3) SA 532 (C). 7. McQuoid-Mason DJ. Withholding or withdrawal of treatment and palliative treatment hastening death: The real reason why doctors are not held legally liable for murder. S Afr Med J 2014;104(2):102103. [http://dx.doi.org/10.7196/SAMJ.7405] 8. Section 12(1)(e) of the Constitution of the Republic of South Africa. 9. Carter v Canada (Attorney-General) 2015 SCC 5. 10. S v Makwanyane 1995(3) SA 391 (CC). 11. Zaremski MJ. Legal Rx: Suicide and hastening death are different – death with dignity should be seen as just that. http//www.medpagetoday.com/PublicHealthPolicy/Ethics/49429 (accessed 5 June 2015). 12. Cf S v Grotjohn 1970 (2) SA 355 (A).

Accepted 4 June 2015.

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HEALTHCARE DELIVERY

The importance of identified cause-of-death information being available for public health surveillance, actions and research P Groenewald, V Azevedo, J Daniels, J Evans, A Boulle, T Naledi, D Bradshaw Dr Pam Groenewald is a scientist in the Burden of Disease Research Unit, South African Medical Research Council, Cape Town, South Africa. Dr Virginia Azevedo is a health district manager at City Health, City of Cape Town. Johann Daniels is head of the Cape Metropole Information Group, City of Cape Town. Juliet Evans is deputy director of Epidemiology and Surveillance, Department of Health, Provincial Government of the Western Cape. Professor Andrew Boulle is Associate Professor in the School of Public Health and Family Medicine, Faculty of Health Sciences, University of Cape Town, and a public health specialist in the Department of Health, Provincial Government of the Western Cape. Dr Tracey Naledi is Chief Director, Health Programmes, Department of Health, Provincial Government of the Western Cape. Dr Debbie Bradshaw is Director of the Burden of Disease Research Unit, South African Medical Research Council. Corresponding author: P Groenewald (pamela.groenewald@mrc.ac.za)

An amendment to the South African Births and Deaths Registration Act has compromised efforts to strengthen local mortality surveillance to provide statistics for small areas and enable data linkage to provide information for public health actions. Internationally it has been recognised that a careful balance needs to be kept between protecting individual patient confidentiality and enabling effective public health intelligence to guide patient care and service delivery and prevent harmful exposures. This article describes the public health benefits of a local mortality surveillance system in the Western Cape Province, South Africa (SA), as well as its potential for improving the quality of vital statistics data with integration into the national civil registration and vital statistics system. It also identifies other important uses for identifiable cause-of-death data in SA that have been compromised by this legislation. S Afr Med J 2015;105(7):528-530. DOI:10.7196/SAMJnew.8019

In February 2014, an amendment to the South African Births and Deaths Registration Act[1] was regulated. The new format of the death notification form (DNF), making the fourth page (medical certificate of cause of death) self-sealing, was introduced. While this measure is important for confidentiality, it includes the instruction that the page may only be opened by a Statistics South Africa (SSA) official. This has torpedoed an initiative to strengthen local-level mortality surveillance[2] that not only provided statistical information for health subdistricts but also enabled data linkage between different health information systems to provide information for public health actions. Strengthening data linkage within the National Department of Health (NDoH) follows international calls[3] and actions[4,5] aimed at mitigating the impact of restrictive confidentiality laws on public intelligence in the USA, the UK and Australia. Since the early 2000s, the Health Department of the City of Cape Town (CoCT), the University of Cape Town and the South African Medical Research Council have collaborated to set up a local mortality surveillance system that could provide public health information[6] that was not available from national vital statistics. This included inter alia reporting subdistrict cause-of-death data to enable decision-making at the smallest unit of health management, and obtaining the underlying cause of death from forensic mortuaries in order to improve injury mortality data (a high proportion of which are currently ‘unspecifed’). The Western Cape Department of Health (WCDoH) joined this collaboration and expanded the local-level surveillance to the rest of the Western Cape in 2009,[7] and started to explore the scope of data linkage using identified cause-of-death information. The CoCT has been responsible for significant information technology development, moving from a stand-alone computer-

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based system to a web-based system including managed access control. Cause-of-death coding was upgraded from manual coding using a shortlist to automated ICD-10 (10th revision of the International Statistical Classification of Diseases and Related Health Problems) coding using IRIS software.[8] By January 2014, the system was capturing deaths within weeks of the date of death, and automatically coding the underlying cause of death in around 70% of cases. The system was built on co-operation between the WCDoH, the National Department of Home Affairs (NDHA) and the CoCT, with WCDoH and CoCT health officials being given copies of the DNFs at local Home Affairs offices. Despite the challenge of securing an arrangement across different spheres of government, discussions held between the WCDoH, NDHA and CoCT, facilitated by the NDoH, resulted in permission being granted by the NDHA in 2008 for access to the DNFs for mortality surveillance purposes. Under current legislation, the Director-General of the NDHA has the prerogative to provide such information to other organs of state or statutory bodies for their statutory purpose, and even to an individual person, provided it is in the public interest. The Western Cape initiative, making use of identified information, has demonstrated how a local mortality surveillance system can improve the quality of cause-of-death statistics, while providing essential information for public health action, programme monitoring and evaluation, and health policy and planning. Linking data from the forensic mortuaries with cause-of-death data from death certificates has enabled a far more accurate picture of injury mortality than is available nationally,[7] and reduced the proportion of ill-defined natural deaths among infants in 2011 from 33.3% reported in the SSA data to 15.7% in the surveillance data.

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2008/09

Deaths, n

2009/10

2010/11

2011/12

2012/13

20 15 10 5 0

Eastern Khayelitsha Klipfontein

Mitchell’s Plain

Northern

Southern

Tygerberg

Western

Subdistrict

Fig. 1. Diarrhoea deaths of children aged <5 years in Cape Town during the diarrhoea seasons 2008 - 2013.

Public health actions

In terms of public health actions, the CoCT and WCDoH report diarrhoea deaths in children aged under 5 years on a weekly basis during the diarrhoea season campaign (November - May).[9] In addition, geographical information system co-ordinates of the deaths are plotted to identify diarrhoea ‘hot spots’ and provide a stimulus for public health action at subdistrict level in the Cape metropole. As a result, expanded public works project workers have been engaged to do doorto-door health and hygiene education in these areas. Diarrhoea deaths are reported to subdistrict health managers, who request environmental health practitioners (trained in bereavement counselling) to do a home visit, make contact with the family, offer condolences and assess the immediate living environment. At the family’s convenience, they may return to complete a case investigation form. Health education is provided immediately if appropriate, problems with access to water, sanitation and refuse collection services are escalated to the respective departments, and health service and social problems that need attention are discussed at weekly meetings with the clinic diarrhoea champions and sub-district management, to ensure adequate access to quality services and prompt referrals. Mapping of diarrhoea deaths has placed the focus on living conditions in informal settlements and led to the establishment of subdistrict intersectoral fora, with core departments (Human Settlements, Water and Sanitation, Solid Waste, Roads and Stormwater, Electricity, etc.) meeting monthly to discuss ways to mitigate health risks. Although other factors such as the reduction of HIV transmission to babies and the introduction of the rotavirus vaccination have probably made a contribution, the

number of diarrhoea deaths in children aged under 5 years was halved in 4 years (Fig. 1). This campaign has evolved into the ‘Paediatric Surge’ project, which plans to include pneumonia and malnutrition prevention activities. Pneumonia has recently been identified as a major cause of death among children, through linking cause-of-death information on child deaths occurring at home (in which pneumonia is frequently implicated) and investigated at forensic mortuaries, with death certificate information. In mortuary-certified cases the cause of death is frequently not reported on the official death certificate.[7]

Evaluation of health programmes

The WCDoH has used cause-of-death data to evaluate health programmes, identify missed opportunities in care and improve service efficiency. Linking HIV deaths with the antiretroviral therapy (ART) register and laboratory data to ascertain missed opportunities at various stages of patient management identified the need for wider HIV testing, better referral strategies and improved routine care, especially the recognition and management of advanced disease and co-morbidities, as well as improved retention in care, where deaths in patients who had started ART but had defaulted had been under-appreciated.[10] Cervical cancer deaths were linked with laboratory data to identify the proportion screened for cervical cancer prior to diagnosis; only 36% of these cases had been screened, suggesting major challenges facing the screening programme. In some districts, the local mortality surveillance system is checked before tracing TB treatment defaulters, to avoid a wasted home visit in case death is the reason for the ‘treatment default’.

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Improving quality of cause-of-death information

In terms of improving the quality of causeof-death information, local health structures, being close to the medical certifiers, are uniquely positioned to improve the quality of death certification through monitoring and querying ill-defined causes or invalid certificates, and through training in medical certification of death. The WCDoH conducted training in all health districts, and in regional and tertiary hospitals. Formal certification training has also been implemented at both medical schools in Cape Town. Vital registration data show that the Western Cape Province has the lowest proportion of ill-defined causes of death (8.1%), and that the proportion of ill-defined and ‘garbage’ codes have declined by 14.1% and 19.6%, respectively, since 2008, in contrast to the situation in the majority of other provinces.[11] Furthermore, geographical coding is most accurate when done at local level. This is of particular importance in metropolitan subdistricts, where large differentials in mortality can exist and inequities need to be addressed. In Cape Town the mortality differential is 1.6 between the subdistricts with the highest and lowest mortality rates.[7]

Call for Health to use cause-of-death information beyond statistics

As important as cause-of-death statistics are for planning and evaluation, the use of cause-of-death data goes beyond statistics, and they should be used for public health action and surveillance. Other important uses of identified cause-of-death information, not discussed above, include providing data for cancer registries and for epidemiological and public health research that would not be feasible otherwise.[3] It is important for the South African National Cancer Registry[12] to obtain cases from all data sources, including official mortality data. It is also important for researchers to have the ability to set up cohort studies that can study exposure-disease associations with a long lag between exposure and outcome. This is particularly important with regard to identifying hazardous environmental and occupational exposures, quantifying the risk for health outcomes and proposals for compensation mechanisms. Currently, prevention of access to identified cause-of-death data is compromising important public health research being conducted to quantify the risks of exposure to asbestos[13] and other hazards related to mining.

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Given the importance of cause-of-death data for public health, closer engagement with the vital statistics system by the NDoH is essential, both for improving the quality of mortality data and for utilising the data to improve public health. National government should find a way to facilitate local-level health sector input into, and use of, the vital statistics system and enable appropriate public health responses by local and provincial government, as has been done in other countries. In the UK, the National Health Service Act of 2006 makes provision for the supply of information on individual births and deaths to the National Health Service within weeks of the death.[4] In Italy, legislation requires a copy of the death certificate to be sent to both the statistical office and the health department (personal communication – Franscesco Grippo, researcher, Italian National Institute of Statistics), and in France provision is made for checking the validity of the causes of death by the health department prior to processing by the statistical office.[14] South Africa would benefit from any of these approaches: the quality of the national mortality data could be improved by monitoring and validation of the cause-ofdeath certification by the health department, and access to individual birth and death records would facilitate appropriate public health action, as has been demonstrated in the Western Cape. Formalising the role of the health department in validating and processing vital records would probably require an amendment to the National Health Act[15] to require individual birth and death records, as has been done in the UK.[4] In the meantime, a practical solution to overcome the impact of the recent change to the DNF would be for the NDHA to print all pages of the DNF in triplicate, with one copy to be sent to SSA for statistical purposes, one copy to be sent to the health department in each province for public health action, and one copy to remain in the DNF as a paper trail for audit purposes. SSA is currently leading a self-assessment of the civil registration and vital

statistics system, providing an opportune moment for the NDoH to give effect to the practical solution outlined above. 1. Republic of South Africa. Births and Deaths Registration Act No. 51 of 1992. Regulations on the Registration of Births and Deaths, 2014. Government Gazette 26 February 2014;584(37373):5-74. http://www.gov.za/sites/www.gov.za/files/a51_1992.pdf (accessed 22 May 2015). 2. Bateman C. Another law change prevents proper healthcare delivery. S Afr Med J 2015;105(4):244-5. [http://dx.doi.org/10.7196/SAMJ.9553] 3. Wartenberg D, Thompson WD. Privacy versus public health: The impact of current confidentiality rules. Am J Public Health 2010;100(3):407-412. [http://dx.doi.org/10.2105/AJPH.2009.166249] 4. Parliament of the United Kingdom. National Health Service Act of 2006 (amended 2013). http://www. legislation.gov.uk/ukpga/2006/41 (accessed 22 May 2015). 5. Holman C, Bass AJ, Rosman DL, et al. A decade of data linkage in Western Australia: Strategic design, application and benefits of the WA data linkage system. Aust Health Rev 2008; 32(4):766-777. [http:// dx.doi.org/10.1071/AH080766] 6. Groenewald P, Bradshaw D, Daniels J, et al. Local-level mortality surveillance in resource-limited settings: A case study of Cape Town highlights disparities in health. Bull World Health Organ 2010;88(6):444-451. [http://dx.doi.org/10.2471/BLT.09.069435] 7. Groenewald P, Msemburi W, Morden E, et al. Western Cape Mortality Profile 2011. Cape Town: South African Medical Research Council, 2014. http://www.mrc.ac.za/bod/WC2011Report.pdf (accessed 22 May 2015). 8. Johansson L, Pavillon G, Pelikan L, Weber S. Iris Automated Coding System for Causes of Death: User’s Reference Manual (Iris version V4.1.3). Cologne: IRIS Institute, German Institute of Medical Documentation and Information, 2012. https://www.dimdi.de/dynamic/en/klassi/irisinstitute/ downloadcenter/manuals/user-guide/iris-user-reference-manual-v4-4-1s1.pdf (accessed 22 May 2015). 9. Azevedo V, Hawkridge A, Westwood A. Diarrhoeal Disease Season 2012/2013. Cape Town District Report. Cape Town: Western Cape Government Health and City Health, Cape Town: City of Cape Town, November 2013. 10. Boulle A, Zinyakatira N, Evans J, et al. Understanding high ongoing HIV-associated mortality in the era of antiretroviral therapy in the Western Cape Province of South Africa. Presented at the International Epidemiological Association World Epidemiology Congress, Anchorage, Alaska, USA, 17 - 21 August 2014. 11. Massyn N, Day C, Peer N, Padarath A, Barron P, English R, eds. District Health Barometer 2013/14. Durban: Health Systems Trust, October 2014. 12. Singh E, Underwood JM, Nattey C, Babb C, Sengayi M, Kellett P. South African National Cancer Registry: Effect of withheld data from private health systems on cancer incidence estimates. S Afr Med J 2015;105 (2):107-109. [http://dx.doi.org/10.7196/SAMJ.8858] 13. Kielkowski D, Nelson G, Rees D. Risk of mesothelioma from exposure to crocidolite asbestos: A 1995 update of a South African mortality study. Occup Environ Med 2000;57:563-567. [http://dx.doi. org/10.1136/oem.57.8.563] 14. Inserm. CépiDc. http://www.cepidc.inserm.fr/site4/ (accessed 6 June 2015). 15. National Health Act No. 61 of 2003. Government Gazette, 23 July 2004. http://www.gov.za/sites/www. gov.za/files/a61-03.pdf (accessed 22 May 2015).

Accepted 19 April 2015.

South African Thoracic Society

ANNUAL CONFERENCE

7-10 August 2015 CAPE TOWN | South Africa

Further information available online: www.satsconference2015.co.za For more details, please contact Deidre Raubenheimer: deidre.raubenheimer@uct.ac.za

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HEALTHCARE DELIVERY

Social franchising primary healthcare clinics – a model for South African National Health Insurance? A K L Robinson Andrew Robinson, MB ChB, DHSM, FCPHM, a public health medical specialist and health services executive, is currently Head: Clinical Services in North West Province, South Africa, responsible for clinical leadership, governance and delivery of quality health services at hospital and primary healthcare levels. Until recently he was Deputy Director-General of Health Services in North West, and he previously held positions with the Medical Research Council, the pharmaceutical industry and metropolitan government. He has also worked as a rural medical officer in South Africa and in general practice in the UK. Corresponding author: A K L Robinson (arobinson@nwpg.gov.za)

This article describes the first government social franchise initiative in the world to deliver a ‘brand’ of quality primary healthcare (PHC) clinic services. Quality and standards of care are not uniformly and reliably delivered across government PHC clinics in North West Province, South Africa, despite government support, numerous policies, guidelines and in-service training sessions provided to staff. Currently the strongest predictor of good-quality service is the skill and dedication of the facility manager. A project utilising the social franchising business model, harvesting best practices, has been implemented with the aim of developing a system to ensure reliably excellent healthcare service provision in every facility in North West. The services of social franchising consultants have been procured to develop the business model to drive this initiative. Best practices have been benchmarked, and policies, guidelines and clinic support systems have been reviewed, evaluated and assessed, and incorporated into the business plan. A pilot clinic has been selected to refine and develop a working social franchise model. This will then be replicated in one clinic to confirm proof of concept before further scale-up. The social franchise business model can provide solutions to a reliable and recognisable ‘brand’ of quality universal coverage of healthcare services. S Afr Med J 2015;105(7):531-534. DOI:10.7196/SAMJnew.7814

The idea of using franchise business principles to deliver health services in South Africa (SA) came to me while using the toilets at the Spur restaurant in Mahikeng, North West Province, in 2011 – why could such a busy restaurant maintain such clean ablutions, while the health services could not? The Mahikeng Spur bathroom sounds like an unlikely place for a ‘light-bulb moment’ regarding healthcare services delivery! However, it was this evidence of Spur’s service reliability and functional quality systems that provoked my engagement with the Franchise Association of South Africa (FASA) in March 2012.

The current situation

In state health services, many primary healthcare (PHC) clinics run excellent services. However, there is no uniformity of standards across all clinics, nor are there effective mechanisms to implement and maintain standards. Well-run clinics are usually a result of the initiatives, inspiration, motivation and dedication of the facility manager rather than national, provincial or district office efforts or systems. The state can effectively establish excellent clinic facilities, but too often these subsequently perform poorly in respect of reliable, quality service provision. An innovative and dynamic approach is necessary to shift the current situation to the standards that will be required from our clinics within the impending National Health Insurance (NHI). Rather than ‘inventing’ new models, the solution may lie in copying and adapting the various business principles utilised in the franchising concept and business model. Simply put, let us innovate within the health sector with old, but tried-and-tested, ideas.

National Health Insurance

The NHI Green Paper[1] in August 2012 broadly outlined the planning, implementation and reform that aims to improve service

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provision and promote equity and efficiency to ensure that all South Africans have access to affordable, quality healthcare services, regardless of their socioeconomic status. This model of delivering health and healthcare services to the population is globally well accepted, and has been described and widely promoted by the World Health Organization (WHO) as ‘universal health coverage’.[2] Ten districts were selected nationally for the NHI pilot. Dr Kenneth Kaunda District was selected as North West’s pilot site. Subsequent to this, the National Department of Health (NDoH) held an NHI conditional grant workshop in Potchefstroom, North West, for the development and implementation of the NHI business plan (workshop presentation, April 2012 – unpublished). This presentation highlighted the opportunities for the study and testing of best practices, and pointed out that innovative approaches will be necessary to develop and enhance managerial, administrative and financial capacity in the facilities, and skills and competencies at district level. Once tested and approved, these would be scaled up across the health sector.

A history and background of franchising

There are many types of franchising, or replication businesses. The word ‘franchise’ has its origins in the French word ‘franc’, meaning ‘freedom’ or ‘citizenship’, and in essence means the granting of a privilege to a company to sell its goods or services in a prescribed manner. Historically the franchising concept is not new, with rudimentary Chinese examples recorded as far back as 200 BC. The modern franchising concept developed in the 1860s as a distribution system for the Singer sewing machine, followed soon after by the automotive industry. Franchising impetus increased after the end of World

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War II, notably in the fast-food sector. Businesses soon recognised that they could develop, control and dominate a market through the replication of successful business models via a network that could simultaneously gain market share. The franchising industry in SA has grown at an incredible pace since 1945. It operates through nearly 30 000 outlets, contributes 12% to the SA gross domestic product and, despite the economic downturn,[3] provides stable employment to more than 500 000 people. The ‘domino’ effect of franchising, combined with strict operating procedures, enables a product, service or brand to spread rapidly through the marketplace, gaining public support. This public support is based on the confident expectation of uniformly high standards and quality of the product and/or service provision, no matter where the outlet is situated. Whether an individual enters a Kentucky Fried Chicken outlet in Soweto or downtown Seattle, he/she is assured of exactly the same customer experience. Key players are the franchisor and the franchisee. The franchisor is the originator who develops and tests the concept and business systems, while the franchisee is granted the rights, through agreement, to operate under the well-developed brand name, adhering to set standards, methods, procedures, techniques and marketing plans. Typically the franchisor retains control, and by working with dedicated owner-operators is able to increase the value of the brand while growing the business. The franchisee invests with minimal risk and enjoys access to a ready-made business having a recognised brand with the benefits of start-up support and training. Established franchises typically consist of operational, finance, information technology (IT), human resources (HR) and marketing units, with the operational units comprising field staff, training and procurement sections. The field units play a pivotal role in ensuring the success of franchising outlets by supporting operational compliance and efficiencies. Training hubs have a key role in maintaining standards and in introducing new procedures and policies. The field unit operates through face-to-face meetings and remote analysis using IT systems. The IT systems are enabled to monitor key operational functions and identify problems within the system. A typical operational cycle entails stock procurement, production, sales and cash banked, with IT systems able to monitor invoices and stock, time on production and cost of sales. High-value items are monitored daily. For example, a burger outlet using 100 buns and ten meat patties in a cycle would be contacted by the field service manager as soon as the next day. Compare this with current PHC clinic function where, for example, 100 asthma inhalers might be dispensed per month for 10 asthma patients, with data at best recorded at some point, but gross supply chain inefficiencies still persisting. In a franchise, the management information system is able to check operational compliance, efficiencies and variances from the operational manual. These integrated management systems are powerful tools ensuring the success of franchise brands. In summary, the benefits of franchising are: • Replication of a proven system and brand: consumer awareness • Standardisation of products/services • Economies of scale • Rapid expansion to scale • Centralised systems and controls – all facilities are measured, monitored and controlled in the same way, easing comparative performance based on established standards and operating procedures.

Social franchising and healthcare

The commercial franchising model has given rise to the relatively new concept of the social franchise. Its aim is to pursue social rather

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than commercial benefits, using franchising as the model for replication and distribution of the products and services of the organisation. Social franchises are businesses with a social mission, with sharing the defining feature distinguishing them from a classic business. The first examples of social franchising emerged in the 1990s.[4] There are now more than 83 social franchising programmes in 40 countries, which include over 75 000 franchisees and over 60 000 points of service delivery.[5,6] This rapid rise is proving sustainable, and should be seen in the context of the emergence of a socioeconomic shift from ‘self-interest’ towards greater social responsibility.[7,8] Social franchising and social enterprise should not be confused with philanthropy. They are not practical benevolence or charity, but the management of businesses with social goals in a manner that is businesslike and efficient. Most social franchise operations rely on grants and donor funds, and, with decreasing global funding streams, need to operate on commercial principles without the attainment of commercial goals. Other forms of social franchising include fractional franchising, where only a part of the services, commonly in health sectors such as sexual reproductive health (SRH), is offered. Conversion franchising, which will be used in the scale-up phase of the project I am about to describe, is where existing operations are to be converted to replicate the pilot model.

Developing the social franchise model for North West Province’s PHC First steps

Initially, with the FASA’s assistance, a paradigm shift desk-top exercise was done to illustrate how the current status of PHC clinic services and a future envisioned social franchise clinic model could meet NHI needs. This is illustrated in Table 1. The FASA executive was encouraged that government realised the potential of the franchise model to deliver health services and enthusiastically facilitated appropriate contacts with FASA-accredited consultants to develop the idea further. Various business models and practices in place in the franchising industry were examined, along with the concept of social franchising and whether these could be applicable or adaptable to the health services. This formed the basis of the business plan, which was finalised after inputs described in the project planning below. It became increasingly clear through the process that social franchising methodology could fulfil a number of basic NHI requirements in order to realise reliable access to quality health services for disadvantaged communities. This thought leadership did, however, provoke serious head-winds from the National Ministry of Health, who initially perceived it as an attempt to privatise and profit from PHC. At that stage social franchising was considered to be a ‘capitalist evil’, thus advising the use of a different term. Despite this initial opposition, the quick adopters in the NDoH fortunately recognised the merits of the concept, and the social franchising term is now better understood and accepted, with many of its principles giving rise to its very promising Ideal Clinic programme.[9] The next step was to introduce the social franchise model in the pilot district.

Approval processes

The business plan approval filtered through the provincial Department of Health’s executive structures, with full support apart from an initial hesitancy over the term ‘franchise’. It was incorporated into the first NHI conditional grant business plan. The procurement of a service provider with competency and a track record in social franchise development took some perseverance and stamina, withstanding legal challenges from less competent bidders, and enforced cancellation and readvertisement of the bid.

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Table 1. Social franchise – NHI clinic model Current status

‘Brand PHC clinic’

Poor image of PHC clinics held by service users, resulting in bypassing of PHC services and unnecessary congestion of hospital services, with patients treated at inappropriate levels of care

High acceptability by service users, with patients accessing services at an appropriate level of care

Variable number of patients from a geographical area

Fixed number of registered patients mapped from a specific area

Headed by a facility manager, usually an experienced professional nurse, with no training on facility management

Headed by a health professional, who is performance driven and specifically trained and rewarded for this

Run according to: • Core standards • Clinic supervision manual • Various operational SOPs • Various stock management systems • Limited HR plans

Clearly defined operations manual with training manual with specific emphasis on: • Business management administration, processes and procedures • Support and training • Efficient clinical stock management and procurement • HR management systems • Time management and allocations • Asset management • Facility/infrastructure maintenance

All vary between facility and district. Other problems include stock outs, poor patient knowledge of available services, badly maintained facilities, poorly managed appointment and waiting times 5

The full package of PHC services (including, for example, antenatal services, HIV management, chronic care) is only provided if resources exist and provision is of variable quality

Standardised, quality full package of care provided at each facility

Poor data collection, management and usage

Data-driven management with clear outcomes

Limited opportunities for job creation

Numerous opportunities for job creation at a local or rural level

SOPs = standard operating procedures.

Final approval came in November 2013, at least 15 months after the first submission to the Departmental Bid Adjudication Committee. Further delays in the appointment of a service provider to effect necessary refurbishments, alterations and improvements to the pilot clinic to meet the social franchise structural requirements are currently hampering implementation.

Project plan development and implementation

Further research showed that the literature reflected rapid global adoption of the social franchising concept, largely for fractional or NGO-linked operations, primarily in the SRH sector. The only government-initiated social franchise was the Tinh Chi Em (‘Sisterhood’) network in Vietnam, with impressive scale outputs,[10] and the Gold Star programme in Egypt,[11] both serving SRH services. Contact was made with Richard Feachem, Director of the University of California San Francisco’s Global Health Group (CA, USA). This group directs the Private Sector Health Care Initiative, which in turn oversees the Social Franchise for Health (SF4H) organisation. He indicated that to his knowledge this would be the first government PHC social franchise project globally (R Feachem – personal communication). Field trips were made to the best-performing and one of the worst-performing clinics in North West to determine best practices, particularly factors that impacted positively on the patient and staff experience of the clinic. From in-depth analysis of all existing clinic-related operational documents, development of the operations manual is nearing completion. It will be digitised and updated annually. When the model is brought to scale it will be important to allow the manual to reflect necessary regional or area differences. The training manual development mirrored this process. Patient and stock management systems were developed to reduce the overwhelming paperwork and improve efficiencies.

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All aspects of the clinic operations, which include clinical care, support services, health information, monitoring and evaluation and community engagement, were analysed in detail for their inclusion into the operations manual. This even included establishment and maintenance of the clinic garden towards a community nutritional role. The communications strategy included stakeholder workshops with senior departmental executives, local area managers, organised labour and communications staff. It was important to select a well-performing clinic with a receptive facility manager and staff for the pilot clinic, and this selection was based on the findings of the field visits and the NHI pilot district selection. A time-and-motion study done at the clinic highlighted the inordinate time the facility manager (a professional nurse) spent in meetings (>80%) and on other management activities – this prompted the creation of an administrative position in the clinic to free the facility manager of this burden, to improve productivity and to optimise efficiency of the wage spend. Delegation, particularly of financial responsibilities and task shifting, would be important elements – the fractional franchising concept could even consider the consulting room, for example, as a cost centre. The local area manager’s job description was adapted to match that of the franchise field service consultant, which is a pivotal position linking the franchisor and franchisee to support the successful operations of the facility. A competition to select a clinic brand and logo was launched through the provincial consultative forums. The brand ‘Atlarela’ (to embrace/cup hands), with the logo ‘Kalafo ka bokgabane’ (‘Healing through excellence’), was selected. These will be awarded to clinics that meet more than 80% of the set standards. Innovative performance rewards and incentives have been developed to reward the entire clinic workforce, linked to the maintenance and improvement of the branding status.

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The way forward

The operational launch is dependent on the refurbishment of the pilot facility. Refurbishment is an important aspect of the ‘look and feel’ of a franchised facility, addressing patient and staff experiences and needs. Unfortunately, delay in the bid process for this work has directly delayed the launch. The launch process will follow on from staff training on the operations manual as well as training on basic franchising customer care, facility and staff management, stock and asset control, etc. This non-clinical training of the technical staff has resulted in a fundamental change in staff attitude, thereby enhancing the staff members’ status as worthy service providers in their community.[10] The launch will be carefully monitored and all operations reviewed in order to finalise the operations manual and reporting template before replication to another clinic in the NHI pilot district occurs. Once the replication has been completed, the model can be rapidly scaled to include all 360 clinics in the province and support the Ideal Clinic programme. It will be important to keep the brand current and fresh, with a process of unrelenting renewal to avoid the trap of ‘if you always do what you always do, then you’ll always get what you’ve always got’ – there is still a lot to learn from successful franchise operations. To bring PHC social franchising to scale in the province still requires an empowering change management process involving every employee at each clinic. This is not new in SA franchising, with a similar process of rapid scaling having been successfully undertaken in the private sector when Sasol managed to take over 100 outlets in 3 months. This rebranding and empowerment process ensures that each employee understands how the business functions, with cost-centre control reduced to the smallest units. This process needs to be initiated for PHC employees, and methods of doing so are currently being investigated.

Related initiatives

Within this model there could be an opportunity for a number of microenterprises and business opportunities to be created. This would have the potential to create jobs, particularly in rural areas, and enhance the sense of ownership of facilities. These enterprises could comprise: • Cleaning services • Garden services, vegetable and traditional medicine production • Maintenance • Security • Water management • Waste management and recycling • Laundry • Transport. The departments of Trade and Industry and Economic Development, as well as the Youth Development agency and the South African State Information Technology Agency, could all provide resources to enable these initiatives. The NHI social franchise model could therefore have the ability to be a massive job creator on its own, particularly in impoverished rural areas. This model will also standardise the contribution to be made by general practitioners contracted to the NHI, as well as community health work and homebased care. Non-profit organisations could be contracted to deliver fractional franchise services such as SRH or HIV care (FASA – personal communication).

Conclusion

Franchising is a long-established business model that provides a sound basis for investigating and initiating changes to the way services are structured and managed, and fits the new NHI structural

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changes to the SA health system. Implementing a social franchise model for PHC facilities has the following potential advantages: • A standardised look and feel would contribute to positive brand perceptions. It would contribute to a positive image and experience in the clinics. Patients would know what quality care to expect at every branded clinic. • Greater focus on operational and administrative efficiency would increase quality of care and service delivery. • Standardisation of operational and administrative systems would free up valuable time for staff to focus on patient care and outcomes. • Formalisation and standardisation of operational policies would enhance ease of reference and compliance. • Increased efficiency would lead to cost containment and extend the impact of funding streams. • Standardisation of budget management and possible automation of the ordering process would contribute to cost containment. The North West Provincial Health Department’s social franchising project for PHC is the first government-led social franchise initiative globally, and is currently being piloted in Dr Kenneth Kaunda District. This social franchise business model, if successfully implemented, also has potential for other aspects of health service delivery such as hospital care, and for use within the private sector, particularly when considering the contracting of private sector services into the NHI. If the model can be implemented successfully, there is vast potential to use it more widely to improve services in other government sectors such as education, transport, housing and agriculture. The easy part of this project is to develop the pilot social franchise clinic and to replicate it. The more challenging part will be to shift the mindset of the central sectors of healthcare to act like a franchisor, and actively support these PHC clinics in their effort to succeed. All those consulted in the health sector think this is a ‘great idea’ that makes sense. However, a paradigm shift must happen with their verbal support translating into action. After all: Inputs × provider practice = impact and outcomes. Delivery of universal health coverage, particularly to the rural poor, is a matter of urgency. Can we create a health service delivery ecosystem that will combine currently available resources here and now? As a model, social franchising for health shows the way. Acknowledgements. The author would like to thank all who have participated in the development of this social franchise PHC clinic model, as well as those who assisted with the editing of this publication. 1. Ministry of Health. National Health Insurance in South Africa. Policy Paper. Government Notice 657. Government Gazette No. 34523, 12 August 2011. 2. World Health Organization. Universal health coverage. http://www.who.int/universal_health_ coverage/en/ (accessed 8 January 2015). 3. Illetschko K. FASA Directory: How To Franchise Your Business. 6th ed. Bruma, Gauteng: Franchise Association of South Africa, 2012. 4. Montagu D. Franchising of health services in developing countries. Health Policy Plan 2002;17(2):121130. [http://dx.doi.org/10.1093/heapol/17.2.121] 5. Montagu D. Overview of clinical social franchising. July 2013 (ppt). http://www.sf4health.org/ research-evidence/presentations (accessed 21 June 2015). 6. Viswanathan R, Schatzkin E, Sprockett A, Montagu D. Overview of clinical social franchising and findings from the 2014 clinical social franchising compendium. September 2014 (ppt). http://www.sf4health.org/ sites/sf4health.org/files/wysiwyg/2014CompendiumResults_V2.pptx (accessed 8 January 2015) 7. Du Toit A. Social franchising as organisational format – an overview. In: Alon I, ed. Social Franchising. Basingstoke, UK: Palgrave Macmillan, 2014:8-32. 8. Sauer JB. Unnatural virtues for well living: Social economy, civitas, and public philosophy. Int J Soc Econ 1997;24(11):1172-1190. [http://dx.doi.org/10.1108/03068299710193552] 9. Fryatt R, Hunter J, Matsoso P. Innovations in primary health care: Considerations for National Health Insurance. In: South African Health Review. Durban: Health Systems Trust, 2014:33-44. 10. Government social franchising: Using private sector approaches to improve the public sector provision of reproductive healthcare in Vietnam. http://mariestopes.org/sites/default/files/MSI%20 Innovations%20-%20Viet%20Nam_4.pdf (accessed 8 January 2015). 11. Egypt’s Gold Star Quality Program Wins Clients and Communities. http://ccp.jhu.edu/documents/4. pdf (accessed 8 January 2015).

Accepted 9 March 2015.

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The state of South African internships: A national survey against HPCSA guidelines S Bola, E Trollip, F Parkinson Eudiet Trollip is a medical officer at Victoria Hospital, Cape Town, South Africa. Summy Bola and Fran Parkinson are surgical registrars in the UK. Corresponding author: S Bola (sbola@nhs.net) Background. Medical internship is designed to bridge the gap between the theoretical knowledge learned as a student and the skills required as a competent medical practitioner. In South Africa (SA) it is a 2-year structured programme incorporating experience in key domains of medicine selected by the Health Professions Council of South Africa (HPCSA). HPCSA guidelines state that the clinical experience should include teaching, supervision and competency in selected logbook procedures. After concerns were raised over some accredited intern facilities, we investigated whether these guidelines were being met for interns across SA. Methods. An electronic survey was sent to 150 SA doctors who had completed their internship between 2010 and 2013. The questions covered supervision, workload and rest, teaching and perception of patient safety. All responses were anonymous and there was opportunity to comment at the end of each question. Results. The respondents (n=90) included graduates from all eight SA medical schools. Supervision was ranked as the aspect of internship that respondents would change the most, with 33.0% performing an interventional procedure for the first time without supervision and 25.6% experiencing an adverse event where senior help was not available. More than half the interns had an entire shift supervised by a medical officer with less than 3 years’ clinical training in that specialty. Conclusions. This survey identified deficiencies of supervision as directed by the HPCSA. It also highlighted difficulties with workload and teaching opportunities. A significant proportion of interns did not feel that patients were safe under their care. A national annual HPCSA survey would highlight hospitals where closer investigation may be required. S Afr Med J 2015;105(7):535-539. DOI:10.7196/SAMJnew.7923

The South African (SA) medical internship is des igned to bridge the gap between the knowledge and skills learned at university and the clinical skills set required for the community service officer (CSO) year, which may involve working as an independent medical practitioner in a rural area. The internship was introduced in 1950 by the South African Medical and Dental Council, which was responsible for overseeing the registration and conduct of medical practitioners. It is now regulated by the Health Professions Council of South Africa (HPCSA).[1] In 2005, after identifying a deficiency in all-round competence among doctors completing a 1-year internship pro gramme,[2] the internship was changed to a 2-year structured curriculum involving rotations in key medical domains chosen by the HPCSA (Table 1) and a syllabus of logbook requirements. Recognising the significant transition from medical school, accredited internship hospitals are charged with the responsibility of providing suitable supervision, guidance and evaluation of clinical work in medical and surgical rotations. Each accredited

facility has an assigned curator to act as a spokesperson for the newly qualified doctors and to assist the hospital chief executive (or equivalent) in the role of organising orientation and ensuring continuous evaluation of clinical skills. The HPCSA provides guidelines and restrictions on the level of clinical work a medical intern can carry out independently. Selected examples are listed in Table 2.[3] Acknowledging that working without sufficient supervision compromises patient safety and promotes incorrect learning, the HPCSA guidelines are there to protect both the patient and the newly qualified doctor. For this reason, interns are not permitted to undertake locum work or be employed at unaccredited facilities. Despite this there have been reports of inadequate supervision, as a result of which the HPCSA has rescinded accreditation of some previously accredited facilities.[4] This study aimed to investigate whether HPCSA guidelines are being complied with in accredited institutions across SA.

Methods

A pilot 30-question electronic survey was designed to cover topics similar to those addressed in the annual National General

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Medical Council training survey in the UK, which is a validated survey adopted and developed to ascertain trainee perception of compliance with General Medical Council standards.[5] The pilot topics included clinical supervision, educational supervision (teaching), handover, induction and patient safety concerns. The questions directly reflected standards from the HPCSA Handbook on Internship Training.[3] The questionnaire was electronically sent to a pilot group of ten CSOs who had completed their internship in December 2013. The feedback from the pilot indicated Table 1. The recommended SA internship programme Specialty General medicine

4 months

Orthopaedics

2 months

Anaesthetics

2 months

Obstetrics and gynaecology

4 months

Family medicine or general practice 3 months Psychiatry

1 month

Paediatrics

4 months

General surgery

4 months

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Table 2. Selected examples of HPCSA guidelines for internship training Supervision

All interns should be supervised by a registered medical practitioner with at least 3 years of post-internship clinical experience in that specific domain of training Ratio of interns per supervisor should be on a basis of 4:1. Access to supervisors should be available 24 hours per day. Interns should be supervised by a medical officer or registrar on hospital premises Interns should not work alone in any critical areas such as casualty, intensive care unit or labour ward

Workload

Maximum overtime of 80 hours per month

Training

Time should be devoted to the training of interns Hospitals should make it possible for all interns to attend an Advanced Trauma Life Support course

Results

50 45 40 35

Respondents, n

lesser concerns for handover and induction guidelines but greater concerns regarding supervision during internship and patient safety. Feedback was also received regarding the length of the survey, which was reduced to 20 questions reflecting the following: (i) levels of supervision; (ii) workload and overtime; (iii) teaching and training; and (iv) perception of patient safety under the respondentâ&#x20AC;&#x2122;s care. This survey was sent to 150 doctors who had completed their internship in December 2013. Email addresses were obtained through the hospital administrations of HPCSA-accredited facilities and from university alumni networks (we were unable to obtain more than 150 email addresses, owing to a poor response from hospital administrations). The survey was open from 1 January 2014 to 1 March 2014, to limit recall bias. All contacts were emailed a reminder 2 weeks before the survey closed. Non-responders were not followed up. We aimed to reach graduates from all SA medical schools. All responses were anonymous and there was an opportunity to comment at the end of each question. Eleven surveys were excluded because respondents had experienced delays in completing their internship, either through choice (e.g. unpaid leave) or from failing to meet specialty requirements in a rotation, therefore requiring extra training time.

30 25 20 15 10 5 0

UCT

Free State

KZN

Limpopo Pretoria Stellenbosch Walter Witwatersrand Sisulu

South African university

Fig. 1. Medical schools from which the respondents had graduated. (UCT = University of Cape Town; KZN = University of KwaZulu-Natal.)

The response rate was 60.0% (n=90), with responses from interns who had graduated from all eight SA medical schools (Fig. 1) and had received internship training across 24 teaching hospitals.

Table 3. Procedures performed by interns without supervision throughout the procedure

Supervision and safety

Procedure

Interns performing procedure for the first time without supervision, n

Chest drain

Central venous line

Lumbar puncture

Administration of local anaesthetic

Umbilical vein catheter

Suprapubic catheterisation

Lymph node biopsy

Bone marrow aspirate

Shoulder reduction

Amputation of finger

A third (33.0%) of respondents reported that they had performed an interventional or surgical procedure for the first time without supervision from start to finish. For 5 respondents, this occurred on more than one occasion. These procedures are listed in Table 3. Anaesthetics was listed as the most supervised specialty, and medicine and family medicine as the least supervised (Fig. 2). Contrary to HPCSA recommendations, over half of the interns (55.5%) reported that they were regularly supervised by a medical practitioner with less than 3 yearsâ&#x20AC;&#x2122; post-graduation experience. In addition, 25.6% had experienced an event where they required senior help but the senior was not on the hospital premises.

Workload

While the majority of respondents (88.9%) felt that their medical school had prepared them for internship, some commented about not being prepared for the responsibility or the workload. Surgery, medicine and obstetrics and gynaecology most frequently required interns to work outside their contracted hours; this was consistent across the 24 teaching hospitals (Fig. 3). When asked why they worked outside contracted hours, 74.4% attributed it to staff shortages, a heavy patient load or little help from

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nursing colleagues (Fig. 4). Other reasons included poor personal organisation, uncertainty about patient management, and difficulty in obtaining results of investigations. The typical on-call shift consisted of 24 hours on call followed by a half day of normal duties; 65.6% of respondents said that they frequently had to stay at work after this shift finished, meaning

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that the majority of interns were frequently working a shift of more than 30 hours in duration and exceeded the recommended 80 hours of overtime per month. When asked about their daily tasks, respondents stated that the majority of daily working hours were spent undertaking basic procedures such as venepuncture, gaining intravenous access and inserting catheters.

Medicine Family medicine/GP Psychiatry Orthopaedics Casualty/A&E Surgery

Teaching

Paediatrics Obstetrics and gynaecology Anaesthetics 0 5 10 15 20 25 Respondents ranking specialty as the most supervised, n

Fig. 2. Repondents’ perceptions of the most supervised specialties. (A&E = accident and emergency; GP = general practice.) Every day

Surgery

1 - 2 times/week 1 - 2 times/month Never

Medicine Casualty/A&E Obstetrics and gynaecology Orthopaedics Paediatrics Anaesthetics Family medicine/GP Psychiatry 0

40 50 Respondents, n

Fig. 3. Responses to question ‘How often did you work outside your contracted hours?’ (A&E = accident and emergency; GP = general practice.)

Little help from seniors 7%

Other 6%

Anaesthetics, orthopaedics, obstetrics and gynaecology and surgery scored the highest in terms of frequency of departmental teaching, with 33 participants (36.7%) stating that they received scheduled teaching daily or multiple times in the week. Casualty and family medicine were ranked lowest for teaching, with 18 (20.0%) reporting teaching sessions as ‘rare’ or ‘never.’

Perception of patient safety

With regard to whether they had ever made a mistake on a drug chart (Fig. 5), most respondents commented that their errors were picked up by the nursing staff before the incorrect drug or dose was given. The most common drug errors were antibiotic dosage errors and prescribing medication to which the patient had an established allergy. The survey asked respondents if they had ever felt that patient safety was compromised under their care as an intern. Only 22.2% felt that patient safety was never compromised, and 4.4% reported feeling that patient safety was compromised on a ‘daily’ basis. The most common reason for the perception of poor patient safety was poor supervision (n=17), which led to uncertainty in medical decisionmaking. The second most common reason was shortage of medical resources (n=12).

The final results Short-staffed department 27%

Poor hospital organisation 13%

By the end of the 2-year internship programme, 73 respondents (81.1%) felt prepared for their CSO year. When asked what single aspect of the internship they would choose to change (Fig. 6), the majority selected ‘More supervision’.

Discussion

Little help from nursing staff 24%

Too many patients 23%

Fig. 4. Responses to question ‘Why do you think you worked outside your contracted hours?’ (‘Other’ = poor personal organisation, delayed scan/blood results, uncertainty with management plan.)

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Medical internships are designed to provide the foundation for future independent clinical work. Despite the intern programme having been lengthened to 2 years in 2005, deficiencies in supervision and safety exist across all rotations and hospitals. The HPCSA sets standards for the supervision and workload of interns, but our survey demonstrates non-compliance with the HPCSA standards for intern clinical work.

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Respondents, n

50 40 30

20 10 0

Yes. The drug was not administered

Yes. The drug was administered

Fig. 5. Responses to question ‘Have you ever made a mistake on a drug chart?’ 35

Respondents, n

Supervision Increased help from nurses

Reduced hours

Teaching

Senior Intern staff numbers numbers

Breaks

Nothing

Fig. 6. Responses to question ‘What aspect of your internship would you most like to change?’

In particular, there was significant failure in providing supervision of interns performing interventional procedures for the first time. This has obvious safety implications for both the patient, who is receiving an inadequate level of care for procedures that carry the potential for morbidity and mortality,[6] and for the intern, who may learn and repeat the procedure incorrectly or experience an adverse event, which is not only traumatic but carries the risk of medicolegal action.[7] The HPCSA clearly states that all doctors must ‘Acknowledge the limits of their professional knowledge

and competence’.[8] However, there may be pressure on interns to carry out procedures for which the guidelines are blurred when there are no seniors available. Previous qualitative studies have described internship concerns regarding teaching, workload and supervision.[9] This survey demonstrates that patient safety was the biggest concern for a large majority of respondents. There was non-compliance to rules set out by the HPCSA with regard to the seniority of the intern supervisor, with more than half of the respondents reporting supervision from another intern or a CSO on a regular basis.

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This situation has been reported in a previous study, where the procedural skills gained by the intern were recognised as inferior,[10] and is not a surprising occurrence considering the staff shortages in many health departments across SA. As SA doctors are able to practise in an unsupervised environment after their CSO year (or even during this year in many rural settings), other provisions should be made to ensure that internship provides a protected working space to exercise clinical skills under supervision (with feedback) to ensure that patients are treated in a safe and appropriate manner. Although the majority of respondents felt prepared for their CSO year, which is in keeping with other research,[11] a largely unsupervised internship turning into a completely unsupervised CSO year will promote a cycle of confident incompetence[12] in medical decision-making and compromise patient safety further. According to the SA National Department of Health, ‘The main objective of Community Service is to ensure improved provision of health services to all the citizens of our country.’[13] However, it is important to note that the rural areas only have each CSO for one year, with very few staying longer; the majority make plans to enter private sector medical work or travel abroad.[14-15] At present, only 30% of all doctors undertake public sector duties for the vast majority of SA citizens who cannot afford private healthcare.[16] It is therefore important to promote other factors that may influence hospital selection and public sector work, such as job satisfaction, manageable workload, teaching and career advancement opportunities. Across all hospitals, the anaesthetics rotation was ranked the most supervised specialty and also scored highly in terms of teaching and workload. This may reflect the fact that the rotation is too short to acquire competency for independent clinical work. The primary responsibility for the interns and their training rests with the chief executive and the senior medical staff of the accredited hospital or facility, and it is quite clear that reducing workload will in turn leave more potential time for teaching. To address the workload discrepancies across the specialties, a number of solutions can be suggested to relieve the interns of tasks that can be undertaken by allied health professionals.

Recommendations

For the clinical manager: • Establish a phlebotomy service. • Use hospital assistants to help nursing staff with non-medical daily tasks such as patient clothing, simple dressings and bed linen changes, to help nursing staff utilise their skills set and free the time of the intern.

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• Have ward clerks to distribute and chase up patient results and formulate patient lists. • Ensure weekly protected intern teaching that is separate from departmental teaching to ensure continued learning throughout the year and to cover generic topics such as drug prescribing and technical skills. • Offer pastoral support, assigning each intern a clinical supervisor for the 2-year programme who is separate to the intern curator. • Employ a co-ordinator to arrange patient transport and discharge. For the HPCSA: • Increase the number of medical officer posts per internshipaccredited hospital. • Undertake annual national training surveys to identify centres where interns are subject to inadequate levels of supervision and teaching.

Study limitations

As with any survey, self-reported data are subject to recall bias and subjectivity. It was difficult to find contact details for doctors who had completed their internship, as many hospitals did not agree to distribute the survey or no longer kept records for previous employees. Because we therefore relied heavily on university alumni networks to distribute the web link for the survey, respondents were mostly graduates from the Western Cape, imposing a potential bias. The study did not aim to provide objective validation of doctor training, like the GMC survey on which it is based, but to provide an insight into how HPCSA guidelines are not being met or may not represent realistic goals. As the pilot group requested fewer questions, we did not collect data on important areas such as intern induction and bullying, which would be addressed by developing a formal national survey.

Conclusion

Medical education for interns is based on the apprenticeship model of ‘learning on the job’, and supervisors should be available to assess

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skills and gradually increase responsibility according to interns’ developing abilities. According to the survey results, this model is being grossly neglected, with particular concern about supervision. Despite staff shortages in the SA health service and a maldistribution of private and public sector workers, interns must receive the correct clinical supervision, teaching and inspiration to encourage them to continue with public sector work. 1. De Vries H, Sanderson P, Barbara J, et al. International Comparison of Ten Medical Regulatory Systems. Commissioned by the UK General Medical Council. Cambridge, UK: Rand Corporation, 2009:121-133. 2. Cameron D, Blitz J, Durrheim D. Teaching young docs old tricks – was Aristotle right? An assessment of the skills training needs and transformation of interns and community service doctors working at a district hospital. S Afr Med J 2002;92(4):276-278. 3. Medical and Dental Professions Board, Health Professions Council of South Africa, Handbook on Internship Training. Guidelines for Interns, Accredited Facilities and Health Authorities [Brochure]. Pretoria: HPCSA, 2013. 4. Medical and Dental Professions Board South Africa. Medic Dent News 2012 – HPCSA removes interns from hospital. http://www.hpcsa.co.za/Uploads/editor/UserFiles/downloads/publications/ newsletters/mdb/medicdent_newsletter_april_2012.pdf (accessed 12 November 2014). 5. General Medical Council. National training surveys: Background. http://www.gmc-uk.org/education/ survey_background.asp (accessed 10 January 2015). 6. Maritz D, Wallis L, Hardcastle T. Complications of tube thoracostomy for chest trauma. S Afr Med J 2009;99(2):114-117. 7. Medical Protection Society South Africa. Junior Doctor 2013;4(1). http://www.medicalprotection.org/docs/ default-source/pdfs/sa-junior-doctor-pdfs/may-2013.pdf?sfvrsn=2 (accessed 12 November 2014). 8. Health Professions Council of South Africa. General Ethical Guidelines for the Health Care Professions. Booklet 1 (2008). www.hpcsa.co.za/downloads/conduct_ethics/rules/generic_ethical_ rules/ booklet_1_guidelines_good_prac.pdf (accessed 12 November 2014). 9. Sein N, Tumbo J. Determinants of effective medical intern training at a training hospital in North West Province, South Africa. African Journal of Health Professions Education 2012;4(1):10-14. [http://dx.doi.org/10.7196/ ajhpe.100] 10. Jaschinski J, de Villiers MR. Factors influencing the development of practical skills of interns working in regional hospitals of the Western Cape province of South Africa. S Afr Fam Pract 2008;50(1):70a-70d. [http://dx.doi.org/10.1080/20786204.2008.10873676] 11. Nkabinde TC, Ross A, Reid S, Nkwanyana NM. Internship training adequately prepares South African medical graduates for community service – with exceptions. S Afr Med J 2013;103(12):930-934. [http://dx.doi.org/10.7196/samj.6702] 12. Mateau TM, Wynne G, Kaye W, Evans TR. Resuscitation: Experience without feedback increases confidence but not skill. BMJ 1990;300(6728):849-850 [http://dx.doi.org/10.1136/bmj.300.6728.849] 13. Reid S. Compulsory community service for doctors in South Africa – an evaluation of the first year. S Afr Med J 2001;91(4):329-336. 14. Hagopian A, Thompson MJ, Fordyce M, Johnson KE, Hart LG. The migration of physicians from subSaharan Africa to the United States of America: Measures of the African brain drain. Hum Resour Health 2004;2(1):17. [http://dx.doi.org/10.1186/1478-4491-2-17] 15. Centre for Rural Health, University of Natal. Reid S. Community service for health professionals 2002. http://reference.sabinet.co.za/webx/access/electronic_journals/healthr/healthr_2002_a10.pdf (accessed 30 November 2014). 16. Health Economics and HIV & AIDS Research Division (HEARD). Human Resources of Health: A Needs and Gaps Analysis of HRH in South Africa. Durban: HEARD, University of KwaZulu-Natal, 2009.

Accepted 11 June 2015.

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GENETICS

A South African family with oculopharyngeal muscular dystrophy: Clinical and molecular genetic characteristics C M Schutte, C M Dorfling, R van Coller, E M Honey, E J van Rensburg Clara Schutte is Head of the Department of Neurology in the Faculty of Health Sciences, University of Pretoria, South Africa. She has a special interest in genetic neurological conditions. Lizette van Rensburg, Associate Professor of Human Genetics in the Department of Genetics, Faculty of Health Sciences, University of Pretoria, has been involved in molecular genetic research for the past 20 years, with a special interest in genetic susceptibility to cancer. Celmari Dorfling is a Research Officer in Lizette van Rensburg’s Cancer Genetics Research Group. Riaan van Coller is a neurologist in private practice who is affiliated to the Department of Neurology at the University of Pretoria, and Engela Honey, a paediatrician with a special interest in human genetics, has been working in the Department of Genetics for the past 15 years. Corresponding authors: clinical data – C M Schutte (cschutte@medic.up.ac.za); genetic data – E J van Rensburg (lizette.jansenvanrensburg@up.ac.za)

Autosomal dominantly inherited oculopharyngeal muscular dystrophy (OPMD) is caused by a trinucleotide repeat expansion in exon 1 of the polyadenylate binding protein nuclear 1 (PABPN1) gene on chromosome 14q. A large family with OPMD was recently identified in Pretoria, South Africa (SA). Molecular studies revealed a (GCG)11(GCA)3GCG or (GCN)15 mutant allele. The (GCN)15 mutation detected in this family has been described previously in families from Uruguay and Mexico as a founder effect. To our knowledge, this is the first report of an SA Afrikaner family with molecularly confirmed OPMD. The proband, a 64-year-old woman, presented to the neurology outpatient department at Steve Biko Academic Hospital, Pretoria. A sibship of 18 individuals was identified, of whom eight had OPMD. Four patients were interviewed and examined clinically, and electromyographic studies were performed. Molecular analysis of the PABPN1 gene was performed by polymerase chain reaction amplification and direct sequencing of exon 1 in three of the patients. Patients presented with ptosis, external ophthalmoplegia, dysphagia, dysarthria and mild proximal weakness. High foot arches and absent ankle reflexes raised the possibility of peripheral neuropathy, but electromyography showed only mildly low sensory amplitudes, and myopathic units in two patients. S Afr Med J 2015;105(7):540-543. DOI:10.7196/SAMJnew.7880

Oculopharyngeal muscular dystrophy (OPMD) (OMIM #164300) is a late-onset (>45 years) myopathy characterised by progressive ptosis, dysphagia and varying degrees of proximal muscle weakness. The ptosis is mostly restricted to the levator palpebrae and later involves other extraocular muscles. Complete external ophthalmoplegia is rare. The dysphagia is initially for solids only, but steadily progresses to an extent that patients may become malnourished. In later life these patients may suffer from bouts of aspiration pneumonia. Although proximal muscle weakness, facial weakness and dysarthria may occur, smooth and cardiac muscles appear to be spared. Pathologically, intranuclear inclusions are observed in the muscle fibres.[1] Early descriptions of families with ptosis and dysphagia drew attention to the hereditary basis of the disorder, and after the 1962 publication by Victor et al.[2] the condition was recognised as a form of muscular dystrophy and given the name OPMD. The condition is mainly inherited in an autosomal dominant manner, although uncommon recessive forms have been described.[1] OPMD has been recognised as a trinucleotide repeat expansion disorder.[3] The PABN1 gene, also known as PABP2, encoding the polyadenylate binding protein nuclear 1, has a polyalanine tract in the N-terminal end. The wild-type allele is (GCG)6(GCA)3GCG, adding up to a total of ten alanine residues (GCNs). Abnormal expansion of this tract results in OPMD.[3] The expansion usually occurs in the (GCG)6 repeat, but repeats of the (GCA)3 have been documented. Individuals with OPMD have expansions ranging from 12 to 17 GCNs.[1] Normal PABN1 is a nuclear protein that is involved

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in the polyadenylation of messenger RNA.[4] It associates with RNA polymerase II during transcription and facilitates movement of the released transcript through the nuclear pore, thus acting as a molecular chaperone for the proper export of poly(A) RNA from the nucleus.[5] Additionally, PABN1 was found to bind to SKIP (ski-interacting protein), and together they directly control the expression of muscle-specific genes. Following on from this, Apponi et al.[6] demonstrated that the normal protein plays an important role in myoblast proliferation and differentiation, whereas the extended polyalanine tract causes clumping or the PABN1 protein and accumulation in the nuclei of the skeletal muscle fibres.[7] Recently Davies and Rubinsztein[8] reported that apoptosis is directly involved in the pathology of OPMD, and that it is a major contributor to the muscle dysfunction in the disease. The incidence of OPMD varies widely, ranging from 1/200 000 in France to 1/600 in Israel (Bukhara Jewish population). The disease has been described in more than 35 countries worldwide, with some variations in clinical presentation. To our knowledge, this is the first South African (SA) OPMD family to be described. We report on the clinical and molecular genetic characteristics of this family. The proband was a 64-year-old woman who presented with ptosis, progressive dysphagia and some proximal weakness to the neurology outpatient department at Steve Biko Academic Hospital in Pretoria, SA. With the assistance of the patient, a family pedigree was drawn up and contact details of as many family members as possible were obtained. All were then contacted and invited to take part in this study. After informed consent had been obtained,

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four individuals were subsequently inter viewed and examined clinically, and had electromyographic (EMG) studies per formed. In addition, blood samples were taken from three individuals. Genomic DNA was extracted from peripheral blood using standard protocols. Exon 1 of PABN1, containing the region where the GCN repeat is located, was ampli fied using primers previously described[9] with the Failsafe PCR Enzyme mix with buffer J (Epicentre Biotechnologies, USA). Cycle sequencing of the amplicons was performed with BigDyeV3.1 (Applied Biosystems, USA) and analysed on an ABI 3130 (Applied Biosystems). The study was approved by the Ethics Committee of the Faculty of Health Sciences, University of Pretoria.

I 1 II

III

3 10

Fig. 1. Pedigree of SA Afrikaner family with OPMD.

Family pedigree

An abbreviated pedigree of this Afrikaner family is depicted in Fig. 1. The index patient (III:17) was one of a sibship of 18, eight of whom are affected with OPMD. Their mother (II:2) was affected from the age of approximately 40 years. Noteworthy is the offspring of III:2, an unaffected daughter, who happened to marry her maternal cousin (III:3) who had OPMD. Their children (IV:1 and IV:2) inherited the disorder from their father.

Patient III:17

This 64-year-old woman reported that her first symptoms of ptosis had started at the age of about 40 years, but really interfered with her vision only 10 years later, when she needed eyelid surgery to correct the ptosis. Dysphagia was also present from age 40 years and progressed slowly up to a point where she now has to be very selective about the food she eats. On examination, she had normal higher functions (Mini Mental State Examination (MMSE) 27/30). She had dysarthria with somewhat nasal speech and often had to clear her throat while speaking. The range of eye movements was restricted, especially upwards in that she could not elevate her eyes beyond the neutral position. Ptosis was not prominent after the eyelid surgery. Mild facial weakness was present, as well as weakness of neck flexion (4/5) and mild proximal weakness in the upper and lower limbs. Deep tendon reflexes could only be elicited with augmentation, but ankle reflexes were absent. The patient had higharched feet, but the findings on sensory examination were unremarkable. On EMG, peroneal, tibial and radial motor responses were normal. The sural response showed slightly low amplitude, as

Fig. 2. Sequence chromatograph of exon 1 of the PABN1 gene. The disease causing heterozygous expansion (GCG)11(GCA)3GCG (patient) is shown in the upper chromatograph. The lower chromatograph depicts a homozygous normal (GCG)6(GCA)3GCG tract in an unaffected individual.

did the medial and lateral plantar responses. The peripheral autonomic sensory potentials (PASPs) were present, and the response to repetitive stimulation of the ulnar nerve was within normal limits. A needle examination showed normal motor units in the deltoid muscle.

Patient III:9

This woman was 75 years old when examined. Her data were retrieved retrospectively from her neurologist’s patient record files because she lived far away. She had severe dysphagia and had lost 15 kg over the past few months. On examination, she had an almost total external ophthalmoplegia and ptosis, more marked on the left. There was weakness of the soft palate and tongue, and her speech was hoarse and dysarthric. Mild proximal and distal weakness was present, but this was difficult to interpret owing to her weak general condition. Findings on EMG conduction studies of the median and ulnar motor and sensory nerves were normal. Myopathic units were found in the deltoid muscle, and needle examination of the tongue revealed normal insertional activity and normal motor unit potentials.

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The findings on repetitive stimulation studies of the accessory nerve were also normal. The patient underwent insertion of a gastrostomy tube to facilitate feeding.

Patient III:14

As with III:17, this 70-year-old woman’s ptosis had started at approximately 40 years of age. She had experienced the first symptoms of dysphagia at around 50 years, after which it progressively worsened. Eyelid repair surgery had been performed twice in the past 20 years. On examination, higher mental functions were normal (MMSE 28/30), but the patient had marked dysarthria with prominent nasal speech and lip weakness; the eye movements were full except for some mild restriction of lateral gaze to both sides. There was asymmetry on elevation of the soft palate and severe dysphagia. She had a clearly myopathic face with weakness of the frontalis, levator palpebrae superioris and orbicularis oculi muscles and severe weakness of the upper lip levators and levator anguli oris. Limb weakness was very mild: the deltoids, pectorals, biceps, triceps and hip flexors and extensors were grade 4+/5 and, interestingly,

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foot dorsiflexion and finger extension was also weak at grade 4/5. The deep tendon reflexes of the upper limbs were only present as a flicker with augmentation manoeuvres, the patella reflex was 2+/4, and the ankle reflexes were absent. The findings on sensory examination were normal. The patient also had high-arched feet. EMG showed normal responses of the peroneal, tibial and radial motor nerves, the medial and lateral plantar responses showed low amplitudes, and the sural responses were normal. The PASPs were present and the response to repetitive stimulation of the ulnar nerve was normal. A needle examination of the left deltoid muscle showed some small myopathic units but no fibrillation potentials.

Patient III:18

Consistent with her sisters, this 63-year-old woman had noted ptosis at the age of 40 years and started complaining of dysphagia approximately 10 years later. She had had eyelid repair operations at least 15 years previously, and had also had oesophageal sphincter botulinum toxin injections and myotomy for severe dysphagia at the age of 56. She did not complain of limb muscle weakness. However, she noted that she had felt tired after bypass surgery following a myocardial infarction 2 months prior to her visit to neurology. On examination, her higher mental functions were normal (MMSE 30/30). She had very mild limitation of upward and lateral gaze, and a mild dysarthria was noticeable. Orbicularis oculi muscle power was slightly decreased and mild ptosis was present. Power of the latissimus dorsi and hip extensors was mildly reduced (4+/5), deep tendon reflexes in the upper limbs were a flicker with augmentation, the patella reflex was 2+/4, and the ankle reflexes were absent bilaterally. Findings on sensory examination and the co-ordination and gait were normal. On EMG, the peroneal, tibial and radial motor responses as well as the response to repetitive stimulation of the ulnar nerve were normal, and PASPs were present. The amplitude of the medial and lateral plantar responses was somewhat decreased, but conduction velocities were normal. The amplitude of the sural response was also slightly decreased at point A. A needle examination showed normal muscle unit potentials in the deltoid muscle.

Molecular analysis

As shown in Fig. 2, cycle sequencing of exon 1 of the PABPN1 gene of the three patients (III:14, III:17 and III:18) from whom blood samples were available revealed that they were heterozygous for a (GCG)11(GCA)3GCG or (GCN)15 mutant allele. This expansion therefore increases the total number of alanine residues (GCNs) from the normal ten to 15.

Discussion

We describe the first SA Afrikaner family with genetically proven OPMD. The Afrikaners are mainly descended from Dutch, German and some French immigrants to the Cape during the 17th century. It is estimated that the founding Afrikaner population consisted of approximately 90 families by 1687. We therefore expected to find that our family would share a mutation with one of these founding populations. Many individuals with OPMD from North America and Europe carry a mutant (GCG)9 or (GCN)13 allele.[3] Studies from the UK showed an equal distribution of (GCG)9 and (GCG)10 (or (GCN)13 and (GCN)14) mutations,[10] and in Hispanic New Mexicans, the (GCG)9 mutation was also commonly identified.[11] Our SA Afrikaner family has the (GCG)11(GCA)3GCG (or (GCN)15) mutation, which has been established to be a founder mutation in Uruguayan and Mexican families.[12] Both the genealogical and molecular data suggested that the ancestors of the Uruguayan

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population with OPMD were settlers in the Canary Islands in the 19th century,[12] with the possibility that the mutation arose between the 10th and 14th centuries in the Old World. In the Mexican population, the possibility of two independent founder effects has been suggested, since the (GCG)11(GCA)3GCG (or (GCN)15) and (GCG)9 or (GCN)13 mutant alleles both occurred in the investigated patients.[13] Interestingly, in the study from Uruguay, one of the patients was an individual from SA who also carried the (GCG)11(GCA)3GCG (or (GCN)15) mutation, but no further details on this patient are available. The patients in the current study presented with typical symptoms and signs of autosomal dominant OPMD. Ptosis started around the age of 40 years, closely followed by progressive dysphagia. Corrective surgery for ptosis was performed on three patients, and one also had oesophageal surgery. The mutant (GCG)11(GCA)3GCG (or (GCN)15) allele may be associated with an earlier onset of symptoms, specifically ptosis, than the mutant (GCG)9 or (GCN)13 allele. Our patients reported an onset of ptosis at around 40 years, which has also been described in the Mexican population, where the mean age at onset of ptosis was 46.5 years in subjects with the (GCG)11(GCA)3GCG (or (GCN)15) mutation, compared with 54.7 years in those with the (GCG)9 or (GCN)13 mutation.[13] All patients showed signs of external ophthalmoplegia, which was severe in two cases. Additionally, all patients had dysarthria, which ranged from very mild to moderate. Dysarthria is a finding that has been reported in patients with OPMD, but is rarely emphasised. A study by Young and Durant-Jones[14] evaluated voice intensity, resonance and pitch range in five patients with OPMD, showing changes in voice, articulation and resonance in all individuals, which was worse in those older than 70 years. Hyper-nasality, as a finding of the dysarthria, was reported in three of their patients. Of our four patients, the older two, at 70 and 75 years, also had the worst dysarthria. Mild proximal weakness, often described in OPMD, was noted in all our patients and neck flexion weakness in two. Interestingly, two of our patients also showed mild weakness of the tibialis anterior muscles, and one of the older patients also had clear weakness of finger extension, uncommonly seen in OPMD. The high foot arches in two patients and the absent ankle reflexes raised the clinical possibility of a peripheral neuropathy. On electrophysiological studies, clear myopathic units were seen in two of our patients, and findings on all motor nerve conduction studies were normal. Low amplitudes of the medial and lateral plantar responses were noted in the three patients in whom these were tested, but the abnormalities were mild; in two, the amplitudes of the sural nerve responses were also minimally reduced. Involvement of the peripheral nerves in OPMD has been debated in the past decade. Finsterer[15] concluded in a recent editorial that involvement of peripheral nerves in OPMD should be evaluated further by studying only patients with genetically confirmed OPMD, since many of the patients with electrophysiological abnormalities were reported in the pre-genetic era. The significance of our electrophysiological findings is unclear; motor nerves and autonomic responses were not involved electrophysiologically, and if anything the lower amplitudes of the plantar responses may indicate a mild sensory neuropathy. However, all our patients were older than 60 years, age perhaps influencing the amplitude of sensory nerve responses, although the medial plantar responses should not be absent before the age of 70 years.

Conclusion

In conclusion, we have described the clinical and genetic features of the first SA family with OPMD.

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Author contributions. CMS initiated the project, interviewed the patients, examined them and wrote up the clinical part of the paper; CMD and EJvR did the genetic analysis and wrote the genetic part of the article; and EMH and RvC helped with the clinical management of patients and reviewing of the manuscript. 1. Brais B. Oculopharyngeal muscular dystrophy: A polyalanine myopathy. Curr Neurol Neurosci Rep 2009;9(1):76-82. [http://dx.doi.org/10.1007/s11910-009-0012-y] 2. Victor M, Hayes R, Adams RD. Oculopharyngeal muscular dystrophy: A familial disease of late life characterized by dysphagia and progressive ptosis of the eyelids. N Engl J Med 1962;267(25):12671272. [http://dx.doi.org/ 10.1056/NEJM196212202672501] 3. Brais B, Bouchard J-P, Xie Y-G, et al. Short GCG expansions in the PABP2 gene cause oculopharyngeal muscular dystrophy. Nat Genet 1998;18(2):164-167. [http://dx.doi.org/ 10.1038/1304] 4. Wahle E, Lustig A, Jeno P, Maurer P. Mammalian poly(A)-binding protein II: Physical properties and binding to polynucleotides. J Biol Chem 1993;268(4):2937-2945. 5. Bear DG, Fomproix N, Soop T, Bjorkroth B, Masich S, Daneholt B. Nuclear poly(A)-binding protein PABN1 is associated with RNA polymerase II during transcription and accompanies the released transcript to the nuclear pore. Exp Cell Res 2003;286(2):332-344. [http://dx.doi.org/10.1016/S00144827(03)00123-X] 6. Apponi LH, Leung SW, Williams KR, Valentini SR, Corbett AH, Pavlath GK. Loss of nuclear poly(A)-binding protein 1 causes defects in myogenesis and mRNA biogenesis. Hum Mol Genet 2010;19(6):1058-1065. [http://dx.doi.org/10.1093/hmg/ddp569]

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7. Uyama E, Tsukahara T, Goto K, et al. Nuclear accumulation of expanded PABP2 gene product in oculopharyngeal muscular dystrophy. Muscle Nerve 2000;23(10):1549-1554. [http://dx.doi. org/10.1002/1097-4598(200010)23:10<1549::AID-MUS11>3.0.CO;2-0] 8. Davies JE, Rubinsztein DC. Over-expression of BCL2 rescues muscle weakness in a mouse model of oculopharyngeal muscular dystrophy. Hum Mol Genet 2011;20(6):1154-1163. [http://dx.doi. org/10.1093/hmg/ddq559] 9. Bae JS, Ki C-S, Kim J-W, Kim BJ. Identification of a novel mutation in a Korean patient with oculopharyngeal muscular dystrophy. J Clin Neurosci 2007;14(1):89-92. [http://dx.doi.org/10.1016/j. jocn.2005.12.036] 10. Hill ME, Creed GA, McMullan TF, et al. Oculopharyngeal muscular dystrophy: Phenotypic and genotypic studies in a UK population. Brain 2001;124(3):522-526. [http://dx.doi.org/10.1093/brain/124.3.522] 11. Becher MW, Morrison L, Davis LD, et al. Oculopharyngeal muscular dystrophy in Hispanic New Mexicans. JAMA 2001;286(19):2437-2440. [http://dx.doi.org/10.1001/jama.286.19.2437] 12. Rodriguez M, Camejo C, Bertoni B, et al. (GCG)11 founder mutation in the PABPN1 gene of OPMD Uruguayan families. Neuromuscular Disorders 2005;15(2):185-190. [http://dx.doi.org/10.1016/j. nmd.2004.10.012] 13. Rivera D, Mejia-Lopez H, Pompa-Mera EN, et al. Two different PABPN1 expanded alleles in a Mexican population with oculopharyngeal muscular dystrophy arising from independent founder effects. Br J Ophthalmol 2008;92(7):998-1002. [http://dx.doi.org/10.1136/bjo.2007.131482] 14. Young EC, Durant-Jones L. Gradual onset of dysphagia: A study of patients with oculopharyngeal muscular dystrophy. Dysphagia 1997;12(4):196-201. [http://dx.doi.org/10.1007/PL00009536] 15. Finsterer J. Involvement of the peripheral nerves in oculopharyngeal muscular dystrophy. Clin Neurophysiol 2010;121(6):803-804. [http://dx.doi.org/10.1016/j.clinph.2010.01.022]

Accepted 6 November 2014.

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EDITORIAL

Understanding the genetic diversity of South Africa’s peoples The diverse nature of the peoples living in South Africa (SA) and their history has offered unique opportunities over the years to its researchers, particularly those working in the field of human and medical genetics. Many genetic conditions and/or genetic causative mutations have been demonstrated to have interesting population-specific distributions. This is well demonstrated by two articles in this issue of the SAMJ.[1,2] Apart from research opportunities, this diversity of genetic disease has major relevance when offering diagnostic testing. Frequencies of disease may differ between groups, and the mutational basis may be different. Unless clinicians and laboratories are aware of these differences, and offer testing appropriate to the origins of patients, inappropriate testing may be performed and important diagnoses may be missed. Different mutation-specific therapies may also be required in the future. The trinucleotide or dynamic repeat disorders, as a group, illustrate many of these points very clearly. They are a group of disorders, first described in the early 1990s, with a similar underlying mutation mechanism. The majority of the conditions have some neurological or neurodegenerative manifestations, but in many cases other systems are involved. Although only approximately 20 of these conditions have been identified, they include some of the commoner genetic conditions, such as fragile X mental retardation syndrome, myotonic dystrophy, Huntington disease (HD) and a number of the spinocerebellar ataxias. All these conditions are characterised by similar mutations – an area within or close to the gene where there is a repetitive DNA sequence, usually three base pairs. These repeat areas occur in everyone, but the number of repeat units is critical. Less than a defined threshold and the number of repeat units is inherited unchanged, like any other genetic material. Greater than a threshold and they are unstable and the repeat number changes from one generation to the next, hence dynamic. Typically they expand, but contractions also occur. Greater numbers of repeats are associated with increased severity, earlier age of onset and in some cases different disease manifestations. These diseases are therefore characterised by marked clinical variability within and between families. The origins of these mutations are uncertain, with a combination of ‘tip-over’ from the normal range and underlying genetic background appearing important. Fragile X mental retardation syndrome is the commonest cause of intellectual disability in all the local SA populations,[3] as it is worldwide. It was previously thought to be rare in blacks, but this was due to under-ascertainment.[4] Although the disease frequencies are uncertain, the diagnosis should be considered in individuals of either gender with intellectual disability, developmental delay or autism, especially if they have physical or behavioural characteristics of fragile X syndrome and/or a family history of undiagnosed intellectual disability. Mutations can also result in premature ovarian insufficiency and a late-onset ataxia, fragile X-associated tremor/ataxia syndrome. Importantly, these individuals may be at risk of having children and grandchildren with severe intellectual disability. Further, the condition is X-linked but has some unusual features. The familial nature therefore needs to be recognised and the implications for other family members conveyed once an expansion is identified in an individual.

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On the other hand, there are a number of trinucleotide dynamic repeat disorders that show population differences at some level. At least two of the common conditions, myotonic dystrophy and HD, are said to occur at higher frequency in the Afrikaansspeaking population, owing to founder mutations.[5,6] The Afrikaner population of SA has many features of a founder population. They originated from a small number of individuals, German, Dutch and Huguenot settlers who immigrated to the Cape Colony in the 1600s and then underwent a period of rapid growth. Genetic mutation frequencies in the new population may differ significantly from those in the original population. There are many diseases for which such founder mutations have been described in the Afrikaner population, including porphyria variegata, familial hypercholesterolaemia, Fanconi’s anaemia, Gaucher disease and autosomal recessive polycystic kidney disease.[7-11] In this issue, Schutte et al.[1] report a rare dynamic repeat disorder, oculopharyngeal muscular dystrophy (OPMD), for the first time in a family with Afrikaner ancestry. Preliminary evidence, not surprisingly, suggests a founder effect. It remains to be seen whether other families will be recognised, and awareness of the possibility of the condition is therefore important. Myotonic dystrophy is the commonest adult neuromuscular disorder, but affected individuals may also present with cataracts, cardiac conduction defects or neonatal hypotonia. It is an autosomal dominant condition and therefore has significant implications for family members. Further, its diverse presentation means that different family members may be treated by different specialists, and the familial nature of the condition may not be recognised. Similarly, some interesting population-specific findings among people of African ancestry in SA have been reported for the trinucleotide repeat disorders – myotonic dystrophy, Friedreich’s ataxia, HD and spinocerebellar ataxia type 7. Neither myotonic dystrophy nor Friedreich’s ataxia has ever been reported in a black patient in South Africa[12] (and Jacquie Greenberg, personal communication, 2015). Its absence is ascribed to the absence of a predisposing chromosomal background (haplotype) and possibly fewer large repeats close to the critical expansion threshold. Further, HD, a progressive autosomal dominant neuro degenerative disorder characterised by abnormal movements, cognitive decline and psychiatric symptoms, shows some unique features in black individuals. This condition was previously thought to be rare in this ethnic group, and the few cases described were reported to be due to admixture.[13,14] Although the frequency of HD remains uncertain, many cases have now been documented. HD in people of African ancestry has been shown to be genetically heterogeneous. HD due to mutations in the HTT gene occurs, but on African-specific haplotypes that differ from those in white patients.[15] In addition, a second HD gene (JPH3) has been implicated in African patients with an HD-like phenotype (HDL2), who do not have an expansion in the HTT gene. Individuals with HDL2 share many clinical features with individuals with HD and are clinically indistinguishable in many individual cases, although the average age of onset and diagnosis in HDL2 is approximately 5 years later than HD and individual clinical features may be more prominent.[16] While mutations at

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the HTT locus account for all confirmed HD diagnoses in white patients, about two-thirds of patients with African ancestry have mutations in HTT and one-third mutations in JPH3. Genetic testing in black African patients with an HD phenotype, and in those with African origins, even if distant, should therefore include routine testing of both HTT and JPH3 to avoid falsenegative diagnoses. Spinocerebellar ataxias are also differently distributed in SA populations, with SCA1 being most common in individuals of mixed ancestry and whites, and SCA7 and SCA2 being most common in blacks.[17] SCA7 has only been reported in black patients in SA.[18] As genetic testing expands with the introduction of new technologies, the number of examples of population- or regionalspecific disease and/or mutation distributions is likely to increase. These findings should be incorporated so that appropriate diagnostic testing is offered to South Africans and Africans, and all patients are given the best available information to make a diagnosis and to guide treatment, genetic counselling and reproductive decisions. Amanda Krause Division of Human Genetics, National Health Laboratory Service and School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa Corresponding author: A Krause (amanda.krause@nhls.ac.za) 1. Schutte CM, Dorfling CM, van Coller R, Honey EM, van Rensburg EJ. A South African family with oculopharyngeal muscular dystrophy: Clinical and molecular genetic characteristics. S Afr Med J 2015;105(7):540-543. [http://dx.doi.org/10.7196/SAMJnew.7880]

2. Watson CM, Crinnion LA, Gleghorn L, et al. Identification of a mutation in the ubiquitin-fold modifier 1-specific peptidase 2 gene, UFSP2, in an extended South African family with Beukes hip dysplasia. S Afr Med J 2015;105(7):558-563. [http://dx.doi.org/10.7196/SAMJnew.7917] 3. Essop F, Krause A. Diagnostic, carrier and prenatal genetic testing for Fragile X syndrome in Johannesburg, South Africa: A 20-year review. S Afr Med J 2013;103(12, Suppl 1): 994-998. [http:// dx.doi.org/10.7196/SAMJ.7144] 4. Goldman A, Krause A, Jenkins T. Fragile X syndrome occurs in the South African black population. S Afr Med J 1997;87(4):418-420. 5. Hayden MR, Hopkins HC, Macrae M, et al. The origin of Huntington’s chorea in the Afrikaner population of South Africa. S Afr Med J 1980;58(5):197-200. 6. Goldman A, Krause A, Ramsay M, et al. Founder effect and the prevalence of myotonic dystrophy in South Africans: Molecular studies. Am J Hum Genet 1996;59(2):445-452. 7. Meissner P, Dailey TA, Hift RJ, et al. A R59W mutation in human protoporphyrinogen oxidase results in decreased enzyme activity and is prevalent in South Africans with variegate porphyria. Nat Genet 1996;13(1):95-97. 8. Callis M, Jansen S, Thiart R, et al. Mutation analysis in familial hypercholesterolaemia patients of different ancestries: Identification of three novel LDLR gene mutations. Mol Cell Probes 1996;12(3):149-152. 9. Tipping AJ, Pearson T, Morgan NV, et al. Molecular and genealogical evidence for a founder effect in Fanconi anaemia families of the Afrikaner population of South Africa. Proc Natl Acad Sci USA 2001;98(10): 5734-5739. 10. Morar B, Lane AB. The molecular characterization of Gaucher disease in South Africa. Clin Genet 1996;50(2):78-84. 11. Lambie L, Amin R, Essop F, et al. Clinical and genetic characterization of a founder PKHD1 mutation in Afrikaners with ARPKD. Pediatr Nephrol 2015;30(2):273-279. [http://dx.doi.org/10.1007/s00467014-2917-1] 12. Goldman A, Ramsay M, Jenkins T. Ethnicity and myotonic dystrophy: A possible explanation for its absence in sub-Saharan Africa. Ann Hum Genet 1996;60(1):57-65. 13. Hayden MR, MacGregor JM, Beighton PH, et al. The prevalence of Huntington’s chorea in South Africa. S Afr Med J 1980;58(5):193-196. 14. Harper PS. The epidemiology of Huntington’s disease. Hum Genet 1992;89(4):365-376. 15. Baine FK, Kay C, Ketelaar ME, et al. Huntington disease in the South African population occurs on diverse and ethnically distinct genetic haplotypes. Eur J Hum Genet 2013;21(10):1120-1127. [http:// dx.doi.org/10.1038/ejhg.2013.2] 16. Krause A, Mitchell CL, Essop F, et al. Junctophilin 3 (JPH3) expansion mutations causing Huntington disease like 2 (HDL2) are common in South African patients with African ancestry and a Huntington disease phenotype. Am J Med Genet 2015 (in press). 17. Smith DC, Bryer A, Watson LM, et al. Inherited polyglutamine spinocerebellar ataxias in South Africa. S Afr Med J 2012;102(8):683-686. [http://dx.doi.org/10.7196/SAMJ.5521] 18. Greenberg J, Solomon GAE, Vorster AA, et al. Origin of the SCA7 gene mutation in South Africa and implications for molecular diagnostics in the South African indigenous black population. Clin Genet 2006;70(5):415-417. [http://dx.doi.org/10.1111/j.1399-0004.2006.00680.x]

S Afr Med J 2015;105(7):544-545. DOI:10.7196/SAMJnew.8041

Genomics in medicine: From promise to practice The culmination of the Human Genome Project, with the publication of two ‘reference’ genomes, introduced the genomic era.[1,2] Before this, human genetics concerned itself with techniques to analyse the chromosomes (cytogenetics) and to detect the genes causing Mendelian diseases such as cystic fibrosis or sickle cell anaemia (molecular genetics), and was largely the preserve of human geneticists. Genetic testing was accurate, but slow and costly. Chromosome analysis was limited by its low resolution (a DNA deletion of 5 million base pairs of DNA may be undetectable), and molecular genetics by the inability to sequence more than a few hundred DNA bases at a time. The growth of genomics has been facilitated by the development of much more rapid and large-scale methods to analyse genetic information, including microarray and next-generation sequencing (NGS) technologies. Available from the early 2000s, microarrays permitted testing for several million preselected items of genetic information in a single test. This allowed the development of approaches such as ‘molecular karyotyping’ and genome-wide association studies (GWASs).

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The arrival of NGS in 2007 took this further, allowing sequencing of millions of segments of DNA in a single experiment. NGS may be used to test preselected genetic sequences, but may also be used for open-ended testing of the entire genome or large subsets thereof. This has been facilitated by great reductions in cost: since 2014 it has been possible to sequence a whole human genome for less than USD1 000. Since each haploid genome comprises three billion base pairs of DNA, and any two human genomes are expected to have at least three million points of difference (genetic variants), the development of computational ‘bioinformatic’ methods has also been crucial. Computational algorithms using a range of public access databases provide the potential for clinically meaningful interpretation of genomic information. Comparison of a genomic test with the ‘reference sequence’ and with databases of normal and pathogenic variants allows for classification of each piece of genomic information as ‘normal’, ‘pathogenic’ or a ‘variant of unknown significance’ (VOUS).

Cytogenetic disorders and microarray

Since microarray has been the forerunner to other genomic methods, it is instructive to track its role in cytogenetics. Molecular

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karyotyping or array competitive genomic hybrid (array CGH) was introduced as a research technique for childhood intellectual disability over a decade ago. Compared with conventional karyotyping, array CGH can detect much smaller deletions or duplications of chromosome material (known as ‘copy number variants’). Evidence has accumulated that the cause of intellectual disability is detected in 15 - 20% of cases by array CGH compared with 3% by karyotyping. Over several years, array CGH transitioned into diagnostic practice as laboratories became more familiar with the methods involved, companies produced more user-friendly array platforms, and databases defined the normal and pathogenic genetic variants more clearly. Array CGH is now rapidly supplanting chromosome analysis for investigation of intellectual disability, autism and multiple dysmorphic features of unknown cause,[3] and other indications.

Multifactorial disease and GWASs

Multifactorial diseases, resulting from the cumulative effect of multiple genetic and environmental predispositions, are a major contributor to the burden of disease in South Africa.[4] The GWAS research design allowed specific genetic loci to be linked to specific multifactorial diseases, and to date over 4 000 such loci have been detected.[5] Detection of a relevant locus permits further research to detect the specific genes and biochemical pathways involved, and potentially allows for new treatments to be developed.

Mendelian disorders and NGS

The arrival of NGS greatly accelerated inter alia the discovery of the genetic causes of Mendelian (single-gene) disorders. The genetic causes of over 3 600 single-gene disorders have been described to date.[5] Making a genetic diagnosis has many practical benefits. It clarifies the cause of the condition and ends the ‘diagnostic odyssey’. It allows for genetic counselling relating to options for preventing recurrence of the condition, including carrier testing, prenatal diagnosis, or possibly even preimplantation genetic diagnosis. In some instances the genetic test may alter treatment (e.g. a genetic diagnosis of Dravet’s syndrome indicates that certain antiepileptic drugs should be avoided). In a few instances it may allow for gene therapy that, although not a cure, significantly improves function. This is the case with RPE65 gene therapy for individuals with a particular cause of blindness, Leber’s congenital amaurosis.[6] The laboratory method most often used to detect new or unidentified Mendelian disorders has been whole-exome sequencing (WES), since most mutations causing these disorders are within the 1% of the genome that codes for proteins (i.e. the exome). WES is no longer just a research tool, and has gained an accepted diagnostic role for rare probably genetic disorders, with a 25% detection rate described by Yang et al.[7] In some instances the result has significantly changed clinical management – in one case prompting a curative bone marrow transplant for a child with intractable inflammatory bowel disease.[8] Mendelian disorders that may be caused by mutations in any one of a number of known genes, such as familial cancers, visual loss, epilepsies or immunodeficiencies, can increasingly be diagnosed by means of sequencing a panel of genes known to cause that condition. Prior to the advent of NGS, such gene panels were impractical. Compared with WES, gene panels have the advantage of giving greater accuracy and less excess information.

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Cell-free DNA and non-invasive prenatal testing (NIPT)

The detection of cell-free fetal DNA in the maternal plasma[9] allowed the development of NIPT. Early NIPT tested DNA sequences unique to the fetus, e.g. the presence of Y-chromosome DNA identified the fetus as male. More recently it has been possible to test for aneuploidies such as Down syndrome. The high sensitivity and specificity of NIPT for Down syndrome led to its rapid acceptance as a first-line screening method for women at high risk of having a child with Down syndrome.[10] Uptake of NIPT in the USA has been very rapid, with over 800 000 tests performed in 2014, to the extent that there have been concerns that testing is proceeding ahead of the clinical evidence.[11]

Cancer genomics

Cancer is a fundamentally genomic disorder, with tumorigenesis resulting from multiple mutations involving a variety of genes involved in control of the cell cycle and DNA repair. Historically, tumour prognosis and treatment decisions have almost exclusively been determined by clinical staging and histological grading of the tumour. It has since become evident that tumours that look clinically and pathologically similar may have a very different molecular basis, which may be associated with different clinical outcomes. An early example was the finding that breast cancers over-expressing the HER-2 receptor are sensitive to treatment with a monoclonal antibody (Herceptin). More recently gene-expression profiles for multiple genes, using mRNA extracted from tumour tissue, have become available to refine the prognosis of early-stage breast cancers, thereby improving decision-making regarding the need for chemotherapy.[12] For a range of cancers there is increasing evidence that the ‘molecular signature’ has great practical potential for determining diagnosis, prognosis and treatment.13] Analogous to NIPT, it is possible to test for cell-free tumour DNA. This has a possible role as a biomarker for a variety of cancers, with potentially important implications for screening and monitoring.

Pharmacogenomics

Pharmacogenomics is the study of how genes affect a person’s response to particular drugs, and it aims to improve the efficacy, safety and dosing of medications. The efficacy of drugs as currently used is limited. Across a range of disorders, the proportion of patients who respond to treatment varies from 25% to 80%.[14] It is anticipated that improved molecular knowledge will improve drug targeting and increase the range of available drugs. Accurate dosing is particularly important for drugs with a narrow therapeutic index, such as warfarin. Incorporating genetic information into decision-making on the warfarin dose was found to reduce the need for hospitalisations for haemorrhage by 28% in the 6 months after initiating therapy.[15] As a result, the Food and Drug Administration in the USA revised the label on warfarin to recommend the use of genotype information when prescribing warfarin and, based on this information, provision of genotype-specific dose ranges.[16] In some cases, severe adverse events have been linked to specific genetic variants (e.g. HLA types). The finding that the HLA-B*5701 allele has good predictive value for abacavir hypersensitivity, and that this allele has a 5% prevalence in Caucasians, led to widespread implementation of genetic testing prior to initiation of therapy.[17]

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EDITORIAL

To date, the uptake of pharmacogenomic tests by clinicians has been relatively low internationally. Various reasons are cited, including uncertainty about the clinical utility of the test and the lack of simple clinical algorithms. A further complexity is that the prevalence of pharmacologically relevant variants is often not well characterised in local populations.[18]

Conclusion

Precision medicine

Michael F Urban Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Cape Town, South Africa

Precision medicine is set to become a paradigm for the medicine of the future. It builds upon several of the approaches described above, and involves more precise identification of a person’s illness at a genetic and biochemical level, whether it be hypertension or prostate cancer. More precise diagnosis will facilitate more precise treatment, using a currently available drug or perhaps a drug designed to take advantage of new biological knowledge. In addition, precision medicine should facilitate earlier diagnosis and prevention. The recent announcement of a Precision Medicine Initiative by President Barack Obama[13] has given a significant boost to the field. It includes funding for a cohort of up to 1 million individuals who will be receiving extensive genomic testing and long-term clinical follow-up, in order to correlate genotypes, phenotypes and responses to treatment. The implications of the precision medicine paradigm are farreaching in the long term. Everything, from the International Classification of Diseases to the use of electronic medical records to medical education to medical aid benefits, will change accordingly.[19]

Ethical and implementation challenges

Conventionally, diagnostic laboratory tests are assessed to ensure that they meet criteria for analytical validity (the assay should be accurate) and clinical validity (the test should be clinically meaningful).[20] Genomic testing challenges this paradigm because of the vast amount of information it produces. Genomic tests regularly detect VOUS, and it will take years to identify the clinical relevance of each variant. The need is for a flexible regulatory environment that stimulates rather than stifles research, while not condoning tests that are without clinical value. The Precision Medicine Initiative envisages an emphasis on developing collaborative public access databases to efficiently increase knowledge of the clinical implications of specific genetic variants.[13] A related challenge is how best to report the range of possible genetic variants detected, e.g. VOUS or ‘actionable’ incidental findings.[21] As the ethical issues are solved and the evidence for clinical utility and cost-effectiveness becomes clearer, the use of genomic and precision medicine approaches will scale up. Given the complexities of implementation, it will initially require a multidisciplinary approach that includes both state-of-the-art molecular genomics and bioinformatic components, and insightful clinical and genetic counselling components.[22]

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Genomics is a complex field that is taking an increasing role in many aspects of healthcare. Genomic medicine is expected to transition into the broader paradigm of precision medicine, with profound long-term implications for the practice of medicine and the training of future practitioners.

Corresponding author: M F Urban (urban@sun.ac.za) 1. Venter JC, Adams MD, Myers EW, et al. The sequence of the human genome. Science 2001;291(5507):1304-1351. [http://dx.doi.org/10.1126/science.1058040] 2. International Human Genome Sequencing Consortium. Initial sequencing and analysis of the human genome. Nature 2001;409(6822):860-921. [http://dx.doi.org/10.1038/35057062] 3. Miller DT, Adam MP, Aradhya S, et al. Consensus statement: Chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet 2010;86(5):749-764. [http://dx.doi.org/10.1016/j.ajhg.2010.04.006] 4. Mayosi BM, Flischer AJ, Lalloo UG, Sitas F, Tollman SM, Bradshaw D. The burden of noncommunicable diseases in South Africa. Lancet 2009;374(9693):937-947.[http://dx.doi.org/10.1016/ S0140-6736(09)61087-4] 5. Lander ES. Cutting the Gordian Helix – regulating genomic testing in the era of precision medicine. N Engl J Med 2015;372(13):1185-1186. [http://dx.doi.org/10.1056/NEJMp1501964] 6. Jacobson SG, Cideciyan AV, Roman AJ, et al. Improvement and decline in vision with gene therapy in childhood blindness. N Engl J Med 2015;372(20):1920-1926. [http://dx.doi.org/10.1056/NEJMoa1412965] 7. Yang Y, Muzny DM, Reid JG, et al. Clinical whole-exome sequencing for the diagnosis of Mendelian disorders. N Engl J Med 2013;369(16):1502-1511. [http://dx.doi.org/10.1056/ NEJMoa1306555] 8. Worthey EA, Mayer AN, Syverson GD, et al. Making a definitive diagnosis: Successful clinical application of whole exome sequencing in a child with intractable inflammatory bowel disease. Genet Med 2011;13(3):255-262. [http://dx.doi.org/10.1097/GIM.0b013e3182088158] 9. Lo YM, Corbetta N, Chamberlain PF, et al. Presence of fetal DNA in maternal plasma and serum. Lancet 1997;350(9076):485-487. [http://dx.doi.org/10.1016/S0140-6736(97)02174-0] 10. American College of Obstetricians and Gynecologists Committee on Genetics. Committee Opinion No. 545: Non-invasive prenatal testing for fetal aneuploidy. Obstet Gynecol 2012;120(6):1532-1534. [http://dx.doi.org/10.1097/01.AOG.0000423819.85283.f4] 11. Morain S, Greene MF, Mello MM. A new era in noninvasive prenatal testing. N Engl J Med 2013;369(6):499-501. [http://dx.doi.org/10.1056/NEJMp1304843] 12. Sotiriou C, Pusztai L. Gene-expression signatures in breast cancer. N Engl J Med 2009;360(8):790-800. [http://dx.doi.org/10.1056/NEJMra0801289] 13. Collins FS, Varmus H. A new initiative on precision medicine. N Engl J Med 2015;372(9):793-795. [http://dx.doi.org/10.1056/NEJMp1500523] 14. Spear BB, Heath-Chiozzi M, Huff J. Clinical application of pharmacogenetics. Trends Mol Med 2001;7(5):201-204. [http://dx.doi.org/10.1016/S1471-4914(01)01986-4] 15. Epstein RS, Moyer TP, Aubert RE, et al. Warfarin genotyping reduces hospitalization rates: Results from the MM-WES (Medco-Mayo Warfarin Effectiveness Study). J Am Coll Cardiol 2010;55(25):2804-2812. [http://dx.doi.org/10.1016/j.jacc.2010.03.009] 16. Wang L, McLeod HL, Weinshilboum RM. Genomics and drug response. N Engl J Med 2011;364(12):1144-1153. [http://dx.doi.org/10.1056/NEJMra1010600] 17. Phillips EJ, Chung WH, Mockenhaupt M, Roujeau JC, Mallal SA. Drug hypersensitivity: Pharmacogenetics and clinical syndromes. J Allergy Clin Immunol 2011;127(3 Suppl):S60-S66. [http:// dx.doi.org/10.1016/j.jaci.2010.11.046] 18. Drogemoller B, Plummer M, Korkie L, et al. Characterization of the genetic variation present in CYP3A4 in three South African populations. Front Genet 2013;4:17. [http://dx.doi.org/10.3389/ fgene.2013.00017] 19. Mirnezami R, Nicholson J, Darzi A. Preparing for precision medicine. N Engl J Med 2012;366(6):489491. [http://dx.doi.org/10.1056/NEJMp1114866] 20. Khoury MJ, Gwinn M, Yoon PW, Dowling N, Moore CA, Bradley L. The continuum of translational research in genomic medicine: How can we accelerate the appropriate integration of human genome discoveries into healthcare and disease prevention? Genet Med 2007;9(10):665-674. [http://dx/doi. org/10.1097/gim.0b013e31815699d0] 21. Green RC, Berg JS, Grody WW, et al. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med 2013;15(7):565-574. [http://dx.doi.org/10.1038/gim.2013.73] 22. Manolio TA, Chisholm RL, Ozenberger B, et al. Implementing genomic medicine in the clinic: The future is here. Genet Med 2013;15(4):258-267. [http://dx.doi.org/10.1038/gim.2012.157]

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EDITORIAL

The Cochrane Corner in the SAMJ: Summaries of Cochrane systematic reviews for evidence-informed practice Despite substantial gains in the implementation of evidence-based practice in the past few decades, it has recently been referred to as a ‘movement in crisis’.[1] This is not because the principle of using rigorous relevant evidence to inform healthcare decisions is in doubt, but rather that the ethos of evidence-based healthcare (EBHC) is being misrepresented or subverted by groups with vested interests, such as the pharmaceutical industry. The overwhelming volume of information from research and guidelines, which is difficult for practitioners to digest, as well as the notion that an evidence-based approach may undermine clinical judgement or experience, are additional barriers to the adoption of EBHC. These challenges notwithstanding, the principles of EBHC must continue to be promoted as the basis for honestly appraising the strengths and limitations of existing evidence and making informed healthcare decisions. Key to the success of EBHC is the integration of the best available, up-to-date research evidence with clinical judgement, and the incorporation of information regarding patient preferences and values.[2] So what constitutes ‘best available research evidence’? This depends on the question being asked. The randomised controlled trial remains the most reliable method for evaluating whether a treatment is effective, whereas questions about risk factors for a particular condition will best be answered by means of cohort and case-control studies. Studying patient preferences, on the other hand, will often require qualitative research. Understanding the value and limitations of each of the different research designs is therefore crucial for appropriate application of evidence in a particular context. The systematic review is a relatively new research methodology which, along with the usual caveats regarding methodological quality, is recognised as a more trustworthy source of evidence than any single study. Unlike single studies, systematic reviews attempt to answer important healthcare questions by identifying and evaluating all relevant research studies and synthesising their results. Using rigorous and explicit methods, such reviews avoid biases resulting from ‘cherry picking’ certain studies and minimise the risk of being misled by studies with flawed methods, selective outcome reporting and small sample size. They also help to address publication bias through conducting comprehensive searches for both published and unpublished studies. Well-conducted, up-to-date systematic reviews therefore constitute the cornerstone of reliable evaluations of what works and what does not work in healthcare. They are now widely accepted as important for the development of evidence-informed guidelines and policies, alongside other information relevant to healthcare decision making, such as costs, feasibility and patient preferences.[3,4] The application of systematic review methods is not limited to research addressing questions of efficacy or effectiveness, but extends to other healthcare questions including diagnosis, aetiology and prognosis, to name just a few. Methods for conducting systematic reviews of the effects of interventions, such as those produced by the Cochrane Collaboration www.cochrane.org are, however, the most developed, and typically employ rigorous approaches that have been empirically tested and validated. Furthermore, Cochrane reviews are subjected to extensive peer review, follow a standard format and are regularly

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updated in response to new information.[5,6] These reviews are then published in an electronic database known as the Cochrane Database of Systematic Reviews (together with other databases of interest to healthcare decision makers) in the form of the Cochrane Library.

A Cochrane Corner for the SAMJ

The Cochrane Library currently contains more than 9 000 reviews covering a wide range of healthcare topics. While these reviews are readily available for use by decision makers, busy clinicians and policy makers may not have the time to access, appraise, interpret and apply them. This editorial introduces a regular contribution from Cochrane South Africa (http://www.mrc.ac.za/cochrane/cochrane.htm) to the South African Medical Journal, which will be called the ‘Cochrane Corner’. Our contribution takes the form of technical summaries of Cochrane systematic reviews handpicked for their relevance to South Africa and the African region. Our goal is to help ensure that the high-quality evidence in Cochrane reviews reaches a wider audience. We hope readers will find these future summaries helpful. Tamara Kredo Cochrane South Africa, South African Medical Research Council, Tygerberg, Cape Town, South Africa Taryn Young, Charles S Wiysonge Cochrane South Africa, South African Medical Research Council, Tygerberg, Cape Town, South Africa, and Centre for Evidence-Based Health Care, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Cape Town Michael McCaul Centre for Evidence-Based Health Care, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Cape Town, South Africa Jimmy Volmink Cochrane South Africa, South African Medical Research Council, Tygerberg, Cape Town, South Africa, and Centre for Evidence-Based Health Care, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Cape Town Corresponding author: T Kredo (tamara.kredo@mrc.ac.za) 1. Greenhalgh T, Howick J, Maskrey N. Evidence based medicine: A movement in crisis? BMJ 2014;348:g3725. [http://dx.doi.org/10.1136/bmj.g3725] 2. Sackett DL, Rosenberg WMC, Gray JAM, Haynes RB, Richardson WS. Evidence based medicine: What it is and what it isn’t. BMJ 1996;312(7023):71-72. [http://dx.doi.org/10.1136/bmj.312.7023.71] 3. Oxman AD, Schünemann HJ, Fretheim A. Improving the use of research evidence in guideline development: 16. Evaluation. Health Res Policy Syst 2006;4:28. [http://dx.doi.org/10.1186/1478-4505-4-28] 4. World Health Organization. WHO Handbook for Guideline Development. 2008. http://www.who.int/ hiv/topics/mtct/grc_handbook_mar2010_1.pdf (accessed 15 March 2015). 5. Jørgensen AW, Hilden J, Gøtzsche PC. Cochrane reviews compared with industry supported meta-analyses and other meta-analyses of the same drugs: Systematic review. BMJ 2006;333:782. [http://dx.doi.org/10.1136/bmj.38973.444699.0B] 6. Jadad AR, Cook DJ, Jones A, Klassen TP, Tugwell P, Moher M, Moher D. Methodology and reports of systematic reviews and meta-analyses: A comparison of Cochrane reviews with articles published in paper-based journals. JAMA 1998;280(3):278-280. [http://dx.doi.org/10.1001/jama.280.3.278]

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RESEARCH

Impact of fibrinolytics on the outcome of empyema in South African children M Zampoli, MD; A Kappos, MD; C Verwey, MD; R Mamathuba, MD; H J Zar, PhD Division of Paediatric Pulmonology, Department of Paediatrics and Child Health, Faculty of Health Sciences, University of Cape Town, South Africa Corresponding author: M Zampoli (m.zampoli@uct.ac.za)

Background. Childhood pneumonia is common in all countries, and empyema is one of the commonest complications. The role of routine intrapleural fibrinolytics in the management of childhood empyema is not well established in low- and middle-income countries. Methods. We did a prospective observational study of children sequentially hospitalised with empyema between December 2006 and December 2011 in South Africa (SA). Intrapleural tissue plasminogen activator (TPA), administered according to a standard protocol, was introduced in September 2009. Outcomes in children treated with TPA after 2009 were compared with the historical cohort not treated with TPA who met the treatment criteria. Results. One hundred and forty-two children with empyema, median age 17 months (interquartile range 8 - 43), were admitted during the study period. Excluding children who did not have a chest tube inserted and those in whom fibrinolysis was contraindicated, there were 99 patients, 52 of whom received fibrinolytics. Clinical characteristics and empyema aetiology were similar in those who received fibrinolysis and those who did not. Eighteen children (38.3%) not treated with TPA required surgery v. 5 (9.6%) treated with TPA (relative risk 0.25; 95% confidence interval 0.1 - 0.6). The median duration of hospitalisation was similar in both groups. Complications occurred rarely and with a similar incidence in both groups. In-hospital mortality was low, with two deaths in each group. Conclusion. Intrapleural TPA resulted in a four-fold reduction in surgery. Fibrinolytics should be used for management of empyema in children in SA. S Afr Med J 2015;105(7):549-553. DOI:10.7196/SAMJnew.7796

Community-acquired pneumonia (CAP) is a leading cause of childhood morbidity and mortality, with an estimated global incidence of 0.22 episodes per child year in 2010 in low-and middle-income countries (LMICs).[1] Empyema is an important complication of CAP, with Streptococcus pneumoniae and Staphylococcus aureus leading causes. Although an increase in the incidence of empyema has been reported from some high-income countries following introduction of 7-valent pneumococcal conjugate vaccine (PCV7), the incidence of empyema in the USA following introduction of 13-valent PCV (PCV13) has dropped by 50% in children <2 years of age.[2-4] In South Africa (SA), the incidence of invasive pneumococcal disease has similarly fallen following the introduction of PCV13 into the national immunisation programme in 2011.[5,6] Intrapleural fibrinolytic therapy as first-line treatment of empyema has been reported in two randomised controlled trials in children. In a study in the UK, Thomson et al.[7] reported that urokinase resulted in a 2-day reduction in length of hospital stay compared with normal saline, but the rate of treatment failure was similar in both treatment groups. Singh et al.[8] compared streptokinase with normal saline and reported that the need for surgical decortication was higher at 30 days in the normal-saline groups. Intrapleural fibrinolysis as the primary intervention for empyema has an outcome equivalent to videoassisted thorascopic surgery (VATS).[9] However, surgery, whether VATS or thoracotomy, is invasive and expensive, and requires specific expertise that is often unavailable in LMICs.[10] There are no data on the efficacy of fibrinolytics in an African setting where the burden of childhood pneumonia is high and comorbid illness such as HIV infection, tuberculosis (TB) and malnutrition lead to more severe disease. The aim of this study was to compare the outcome of children with empyema before and after routine fibrinloysis was introduced at a tertiary paediatric hospital in SA in 2009.

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Methods

Study design and setting

This was a prospective study of children sequentially hospitalised for empyema between December 2006 and December 2011 at Red Cross War Memorial Childrenâ&#x20AC;&#x2122;s Hospital (RCWMCH), a large public paediatric referral hospital in Cape Town, SA. Eligible patients were identified through direct referral to the pulmonology service and daily active surveillance of all admissions for empyema. Patient care was supervised by the same medical and surgical teams throughout the study period. Children with pleural effusion after surgery or trauma were excluded. Patients admitted directly to the paediatric intensive care unit on presentation were also excluded. Children presenting with confirmed, suspected or probable TB pleural effusions were not enrolled. However, those with TB presenting clinically as empyema where TB was not initially suspected but was confirmed by culture after the child received fibrinolytics were included in the treatment analysis.

Empyema definition and management

Empyema was diagnosed if the pleural fluid met any of the following criteria: frank pus or turbid fluid on inspection; neutrophil predominance or pus cells present on microscopy; bacterial organism seen by Gram stain or isolated by culture; or loculated pleural collection on chest ultrasound. TB empyema was diagnosed if the pleural effusion met any of the above criteria and Mycobacterium tuberculosis was detected in the pleural fluid by direct microscopy or liquid culture. Routine management of empyema included general supportive measures and broad-spectrum antibiotics for 14 days (intravenous followed by oral). Empirical intravenous ampicillin (50 mg/kg 6-hourly) and cloxacillin (50 mg/kg 6-hourly) was the standard of care.

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Children with suspected or proven staphylo coccal empyema were treated for 6 weeks with cloxacillin or the oral equivalent. An aminoglycoside (gentamycin 5 mg/kg/d) was added in children who were malnourished, HIV-infected or under 3 months of age, according to local guidelines. Antibiotics were adjusted according to clinical response and microbiological results. TB treatment was initiated in cases where TB co-infection was clinically suspected or microbiologically proven. Before 2009, empyema was managed by chest tube drainage without fibrinloysis. In 2009, a protocol for intrapleural fibrinolysis was introduced. The protocol and indications for chest tube insertion, fibrinloysis and referral for surgery are summarised in Fig. 1. A chest tube to drain the pleural space was inserted under sedation and local anaesthesia if any of the following were present: large pleural effusion causing symptoms (pain or tachypnoea) or mediastinal shift; turbid fluid or pus aspirated during pleurocentesis; pleural effusion associated with clinical signs of sepsis; pyopneumothorax; or effusion with persistent pyrexia (>48 hours) despite appropriate antibiotic treatment. Large hardbore chest tubes (10 - 14F gauge) attached to an underwater drainage system were initially the standard of care, but percutaneous pigtail catheters (12F gauge) became available in 2010 and were subsequently preferentially used. After confirmation of the correct chest tube position by X-ray and exclusion of contraindications (Fig. 1), tissue plasminogen activator (TPA) (Alteplase, Boehringer Ingelheim) was instilled into the pleura via the chest tube according to a standard protocol (Fig. 1) within 24 hours after insertion of the chest tube. A dose of 4 mg TPA in 40 mL 0.9% saline (2 mg in 20 mL for children <5 kg) was instilled once a day for 3 consecutive days (Fig. 1).

Clinical data collection, investigations and outcomes

Clinical, aetiological and outcome data were prospectively collected. All patients had a chest X-ray done on admission. A chest ultrasound scan was requested at the discretion of the attending clinician. Pleural fluid, obtained by pleurocentesis or at the time of chest tube insertion, was sent for routine microscopy and bacterial culture. TB investigations, including a tuberculin skin test, gastric lavage and pleural fluid TB microscopy and culture, were performed when TB was clinically suspected and at the discretion of the attending clinicians. Analysis of the pleural fluid included total protein

Empyema diagnosed by defined crtiteria* Routine investigations, empirical antibiotics and supportive care Chest tube inserted or indicated? No

YES Contraindications to fibrinloysis • Pyopneumothorax/pneumatocele • Bleeding diathesis • TB empyema

Conservative medical management and observation

YES

TPA 4 mg in 40 ml 0.9% saline instilled into pleural space Drain clamped/closed to dwell for 1 hour Drain unclamped/opened to low suction for 24 hours TPA dose repeated daily for 3 consecutive days

Free drainage and observation only

Treatment failure

TPA discontinued if: • Adverse effects, e.g. excessive pleural bleeding • Clinical deterioration • Unintentional removal of chest tube with minimal residual pleural fluid

• Persistent fever >38°C more than 48 - 72 hours after drainage • Persistent or worsening symptoms, e.g. pain, tachypnoea • Inadequate drainage of residual fluid

YES

Referred for surgery Continue routine care Remove chest tube if clinical plus radiological improvement and: • No fever for 48 hours and • <30 ml pleural fluid drainage/day

Fig. 1. Chest tube and fibrinloysis protocol. (*Empyema definition: frank pus or turbid fluid; neutrophil predominance, pus cells or bacteria on microscopy; or loculated pleural collection on chest ultrasound scan.)

and lactate dehydrogenase where possible. A blood culture was performed routinely. HIV testing with consent was routinely done according to the current standard of care, unless the HIV status of the child was known. An HIV DNA polymerase chain reaction (Amplicor HIV-1 DNA test version 1.5; Roche Diagnostics, GmbH, Germany) was done in those younger than 18 months, and an HIV enzyme-linked immunosorbent assay (ArchitectHIV Ag/Ab Combo ELISA; Abbott Laboratories, USA) in older children. A CD4 count was done in HIV-infected children. Weight-for-age z-scores (WAZs) (World Health Organization) were calculated for children <5 years of age; malnutrition was defined as a WAZ <–2. The primary outcome was need for surgical intervention. The indications for surgical referral are described in Fig. 1. Secondary outcomes were length of hospital stay and in-hospital mortality. Complications relating to the underlying empyema and treatmentrelated complications were also recorded.

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The study was approved by the Human Research Ethics Committee of the Faculty of Health Sciences, University of Cape Town (HREC 230/2009).

Statistical analysis

Data were analysed using STATA (version 10.0, Statcorp, USA). Continuous variables were expressed as means (standard deviation (SD)) for normally distributed variables or medians and interquartile ranges (IQRs) for non-normally distributed variables. The Mann-Whitney U-test was used for comparing non-normally distributed measures. Categorical variables were compared using the χ2 test. Relative risk (RR) and 95% confidence intervals (CIs) were calculated where applicable.

Results

Clinical characteristics

One hundred and forty-two children (59 in the pre-fibrinolysis period) with a median age of 17.4 months (IQR 8 - 43) were hospitalised

RESEARCH

for empyema during the study period; 81 (57.0%) were male. Most (n=112, 78.9%) were referred from a primary care setting and 30 (21.1%) from other hospitals. Sixtysix/127 (52.0%) received oral, intramuscular or intravenous antibiotics prior to admission to RCWMCH. PCV immunisation status could not be determined in 11 cases; 6 children were partially immunised and the remainder were unimmunised. Twenty-eight patients (19.7%) were HIV-infected, with a mean CD4 count of 18.4% (SD 9.5%), and 44/114 children (38.6%) were malnourished. Pyopneumothorax was present in 22 cases (15.5%) and pneumatocele(s) in 9 (6.3%).

Empyema aetiology

Table 1. Bacterial isolates from pleural fluid and blood culture (N=142 patients) Pleural fluid culture

Frequency n (%)

Blood culture

Frequency n (%)

Staphylococcus aureus

19 (13.4)

S. pneumoniae

18 (12.7)

Streptococcus pneumoniae

14 (9.9)

S. aureus

9 (6.3)

Other streptococci

3 (2.1)

H. influenzae

2 (1.4)

Staphylococcus aureus/Escherichia coli

1 (0.7)

S. aureus/K. pneumoniae

1 (0.7)

Haemophilus influenzae

1 (0.7)

S. pneumoniae/S. aureus

1 (0.7)

H. influenzae/E. coli

1 (0.7)

S. hominis

1 (0.7)

Klebsiella pneumoniae

1 (0.7)

Pantoea spp.

1 (0.7)

Anaerobes

1 (0.7)

S. pyogenes

1 (0.7)

No growth

94 (66.2)

No growth

98 (69.0)

Not done

7 (4.9)

Not done

10 (7.0)

The culture-positive rates of pleural fluid and blood culture were 45/142 (31.7%) and 33/132 (25.0%), respectively (Table 1). The commonest bacterial pathogens identified on blood or pleural culture were S. aureus and S. pneumoniae (Table 1). Ninety and 104 patients, respectively, had gastric lavage and pleural fluid investigated for TB. Overall, 12/142 (8.4%) children had culture-confirmed TB, of whom 10/104 (9.6%) were diagnosed with TB empyema. Two additional cases of culture-confirmed TB were detected through gastric lavage cultures. Bacterial-TB empyema was confirmed by culture in 5 patients.

N=142 patients n=7 excluded as no chest drain

n=135 patients with chest drain n=36 excluded as fibrinolytics contraindicated

Clinical course and outcome

One hundred and thirty-five patients (95.1%) had a chest tube inserted and 9 (6.6%) required two or more chest tubes during their hospitalisation. The median duration of chest tube placement was 5 days (IQR 3 - 10). Large-bore hard chest tubes were used in most patients (107, 79.3%) and pigtail catheters in 27 (20.0%), all in the TPA treatment group. Nineteen patients (13.4%) were referred to the intensive care unit. Overall, 29 (20.5%) patients needed surgery and 6 died in hospital (4.2%). Excluding patients who did not have a chest tube inserted because their disease was mild and those in whom fibrinolysis was contraindicated (22 pyopneumothorax, 9 pneumatoceles and 5 TB empyema), data on 99 patients from the pre- and postfibrinolysis periods (TPA 52, no TPA 47) were available for comparative analysis (Fig. 2). Baseline clinical characteristics and empyema aetiology were similar in the two groups (Table 2). Eighteen of 47 children (38.3%) not treated with fibrinolytics required surgery compared with 5/52 (9.6%) of those treated with TPA (RR 0.25; 95% CI 0.1 - 0.6). There was a trend towards shorter hospital stay in the TPA group, but the difference was not statistically significant

n=99 patients

No TPA n=47

TPA n=52

Fig. 2. Study population selection.

(Table 3). Surgery, however, was associated with a longer hospital stay (median 16 days (IQR 13 - 29) v. 12 days (IQR 8 - 17); p=0.001). The median time to surgery from admission was similar in the two groups (7 days each). Complications relating to empyema or treatment occurred rarely in both groups (Table 3). Compared with children who were eligible for fibrinolysis, a longer period of hospitalisation (median 18 days (IQR 11 29) v. 12 days (IQR 8 - 16); p<0.01), more disease complications (10/32 (31.3%) v. 11/102 (10.8%); p<0.01) and a longer time to surgery (median 13 days (IQR 9 20) v. 7 days (IQR 4 - 8); p=0.02) were observed in children in whom fibrinolysis

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was contraindicated. Six of these 36 patients (16.7%) needed surgery. Mortality was low and similar to the rest of the cohort (2/36 (5.6%) v. 4/106 (3.8%); p=0.6).

Discussion

This study found a four-fold reduction in surgical intervention with the imple mentation of routine fibrinloysis using TPA in SA children with empyema. The results also suggest a trend towards shorter hospital stay and fewer chest drains in children receiving fibrinolytics. This is the first study describing the use of fibrinolytics in an African setting where the prevalence of childhood malnutrition, HIV and infectious diseases is high, as shown by the comorbidity

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Table 2. Baseline and clinical characteristics of patients with and without TPA treatment TPA (N=52)

No TPA (N=47)

p-value

Age (months), median (IQR)

21 (8 - 42)

17 (8 - 52)

0.9

HIV infected, n (%)

14/50 (28.0)

10/40 (25.0)

0.7

WAZ (<5 years), median (IQR)

–1.08 (–2.4 - –0.3)

–1.72 (–2.6 - –0.4)

0.3

Community referral, n (%)

42 (80.8)

37 (78.7)

0.8

Prior antibiotics, n (%)

24/52 (46.2)

24/40 (60.0)

0.1

No PCV, n (%)

43/47 (91.5)

46/46 (100.0)

0. 1

Streptococcus pneumoniae*, n (%)

11/52 (21.2)

10/47 (21.3)

0.9

Staphylococcus aureus*, n (%)

7/52 (13.5)

5/47 (10.6)

0.6

TB co-infection, n (%)

3/30 (10.0)

2/35 (5.7)

0.6

Total WCC (× 109/L), median (IQR)

18.5 (11.5 - 31.2)

24.4 (16.9 - 35.4)

0.07

Haemoglobin (g/dL), median (IQR)

8.7 (7.2 - 10) (n=49)

9 (8 - 10) (n=46)

0.4

C-reactive protein (mg/L), mean (SD)

258 (101) (n=26)

193 (91) (n=22)

0.02

Fluid lactate dehydrogenase (U/L), median (IQR)

1 251 (596 - 5 040) (n=39)

2 743 (1 181 - 10 144) (n=14)

0.2

Fluid total protein (g/L), mean (SD)

46 (17) (n=36)

49 (19.5) (n=14)

0.5

Underlying comorbidity, n (%)

7/52 (13.5)

6/47 (12.8)

0.9

WCC = white cell count. *Combined blood and pleural fluid culture.

Table 3. Outcomes of patients treated with and without fibrinolysis TPA (N=52)

No TPA (N=47)

Statistical significance

Surgery, n (%)

5 (9.6)

18 (38.3)

RR (95% CI) 0.25 (0.1 - 0.6)

Days in hospital, median (IQR)

9.5 (7 - 16)

12 (10 - 20)

p=0.08

Disease complications, n (%)

5 (9.6)

5 (10.6)

Treatment complications, n (%)

4 (7.7)*

2 (4.3)†

Mortality, n (%)

2 (3.8 )

2 (4.2)

NS = not significant. *2 episodes of intermittent occlusion due to catheter twisting; 1 blocked catheter needing replacement; 1 episode of severe pleural bleeding needing blood transfusion. † 1 incident where chest tube incorrectly inserted and needed replacement; 1 postoperative bronchopleural fistula.

present in children. The prevalence of TB was nearly 10%, highlighting the importance of TB as an unrecognised cause of empyema in this setting. These findings are consistent with other reports, mostly from high-income countries, despite the high rate of comorbid illness, including HIV and malnutrition, in children in our study. Several observational studies have compared the outcome of empyema in children treated with fibrinolytics (TPA, urokinase or streptokinase) with historical cohorts not treated with fibrinolytics. With the exception of an Australian study, all reported a similar reduction in need for surgical intervention.[11-14]

The pre-fibrinolysis treatment failure rate reported in our study (38.3%) is higher than the average rate (23.6%) found in a large meta-analysis of non-operative outcomes of 2 793 empyema cases published between 1982 and 2004.[15] Mortality and complication rates were 3.3% and 5.6%, respectively, similar to our study. The rate of treatment failure without fibrinloysis is variable, however, and has been reported in more recent studies to be as high as 74 - 87%.[13,16] The higher than average treatment failure rate in the pre-fibrinolytics era in our study could be attributed to several factors. First, children in our cohort were considerably younger than those

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in most published studies (median age 17.4 months v. 5 years).[15] Furthermore, the high prevalence of HIV infection and malnutrition in our cohort are probable contributing factors. Complicated or severe empyema is a consequence of the increased risk of severe invasive pneumococcal disease in children who are young, HIVinfected or malnourished.[17] Higher rates of empyema in indigenous children compared with national populations have been reported elsewhere, suggesting that poverty, environmental exposure or malnutrition contribute to the pathogenesis and severity of empyema.[18] Secondly, referral for surgery in our practice was relatively early (median 7 days), increasing the likelihood of treatment failure as defined by our protocol. Lastly, 21.1% of patients were referred from other hospitals and represented complicated empyema cases. However, direct comparison of treatment failure rates between studies cannot be made, as definitions of treatment failure and indications for surgery differ between studies. The fibrinloysis treatment failure rate of 9.6% in our study is comparable to other published reports. However, few prospective paediatric studies define failure of primary fibrinolysis as the primary outcome. Need for surgery is an important outcome in children, especially in settings such as subSaharan Africa, where paediatric surgical resources are scarce. Two studies comparing fibrinolysis with VATS reported a fibrinolysis failure rate of 17% each.[19,20] Other prospective studies comparing fibrinolysis with normal saline or various doses of urokinase report fibrinolysis failure rates of 7 - 24%.[7,8,21] A meta-analysis published in 2005 calculated the average failure rate of 64 empyema cases treated with primary fibrinolysis to be 9.3%.[15]

Study limitations

The main limitation of this study is the use of a historical cohort as the control group. However, the prospective approach to patient recruitment, data collection and implementation of a standard fibrinolysis protocol strengthens the validity of our findings. Furthermore, the study was conducted at a single centre where senior medical staff and treatment protocols remained unchanged throughout the study period. The introduction of PCV7 in the national immunisation programme in 2009 may have influenced the spectrum of empyema in our cohort. However, this is unlikely to have had an impact on the study findings, as very few patients had received

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at least one dose of PCV7 because most were not an age eligible for immunisation when this was introduced into the programme and there was no catch-up campaign during this period. A second limitation is the potential bias towards delayed surgery and longer hospitalisation in the treatment group, but the similar time to surgery in both arms excludes this bias in our study. Lastly, although we attempted to exclude suspected or known TB empyema cases from treatment and analysis, a few children with TB empyema inadvertently received fibrinolysis because the diagnosis was not suspected at the time of presentation. These few cases were included in the analysis, as all were co-infected with a bacterial pathogen.

Conclusion

The findings of our study have important implications for managing childhood empyema in settings where access to paediatric surgical expertise is limited. This study adds to the accumulating evidence for a beneficial role of primary fibrinolysis in childhood empyema. Fibrinolytics should be used for management of children with empyema who require drainage in LMIC settings. Acknowledgements. We thank Henri Carrara for his expert guidance and review of the statistical methodology in this study, and the staff of RCWMCH for their support of the study. Funding information. None/not applicable. Prior abstract presentation. This paper was presented as a poster at the Congress International of Paediatric Pulmonology (CIPP), 26 - 30 June 2014, Bruges, Belgium. Abstract published in Pediatric Pulmonology 2014;49(S37):S66. References 1. Rudan I, O’Brien KL, Nair H, et al. Epidemiology and etiology of childhood pneumonia in 2010: Estimates of incidence, severe morbidity, mortality, underlying risk factors and causative pathogens for 192 countries. J Glob Health 2013;3(1):10401. [http://dx.doi.org/10.7189/jogh.03.010401; 10.7189/ jogh.03.010401] 2. Li ST, Tancredi DJ. Empyema hospitalizations increased in US children despite pneumococcal conjugate vaccine. Pediatrics 2010;125(1):26-33. [http://dx.doi.org/10.1542/peds.2009-0184]

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3. Fletcher MA, Schmitt HJ, Syrochkina M, Sylvester G. Pneumococcal empyema and complicated pneumonias: Global trends in incidence, prevalence, and serotype epidemiology. Eur J Clin Microbiol Infect Dis 2014;33(6):879-910. [http://dx.doi.org/10.1007/s10096-014-2062-6] 4. Simonsen L, Taylor RJ, Schuck-Paim C, Lustig R, Haber M, Klugman KP. Effect of 13-valent pneumococcal conjugate vaccine on admissions to hospital 2 years after its introduction in the USA: A time series analysis. Lancet Respir Med 2014;2(5):387-394. [http://dx.doi.org/10.1016/S2213-2600(14)70032-3] 5. Von Gottberg A, de Gouveia L, Tempia S, et al. Effects of vaccination on invasive pneumococcal disease in South Africa. N Engl J Med 2014; 371(20):1889-1899. [http://dx.doi.org/10.1056/NEJMoa1401914] 6. Madhi SA, Bamford L, Ngcobo N. Effectiveness of pneumococcal conjugate vaccine and rotavirus vaccine introduction into the South African public immunisation programme. S Afr Med J 2014;104(3 Suppl 1):228-234. [http://dx.doi.org/10.7196/SAMJ.7597] 7. Thomson AH, Hull J, Kumar MR, Wallis C, Balfour Lynn IM. Randomised trial of intrapleural urokinase in the treatment of childhood empyema. Thorax 2002;57(4):343-347. [http://dx.doi. org/10.1136/thorax.57.4.343] 8. Singh M, Mathew JL, Chandra S, Katariya S, Kumar L. Randomized controlled trial of intrapleural streptokinase in empyema thoracis in children. Acta Paediatr 2004;93(11):1443-1445. [http://dx.doi. org/10.1080/08035250410033989] 9. Mahant S, Cohen E, Weinstein M, Wadhwa A. Video-assisted thorascopic surgery vs chest drain with fibrinolytics for the treatment of pleural empyema in children: A systematic review of randomized controlled trials. Arch Pediatr Adolesc Med 2010;164(2):201-203. [http://dx.doi.org/10.1001/ archpediatrics.2009.271] 10. Cohen E, Weinstein M, Fisman DN. Cost-effectiveness of competing strategies for the treatment of pediatric empyema. Pediatrics 2008;121(5):e1250-e1257. [http://dx.doi.org/10.1542/peds.2007-1886] 11. Yao CT, Wu JM, Liu CC, Wu MH, Chuang HY, Wang JN. Treatment of complicated parapneumonic pleural effusion with intrapleural streptokinase in children. Chest 2004;125(2):566-571. [http://dx.doi. org/10.1378/chest.125.2.566] 12. Van Loo A, van Loo E, Selvadurai H, Cooper P, van Asperen P, Fitzgerald DA. Intrapleural urokinase versus surgical management of childhood empyema. J Paediatr Child Health 2014;50(10):823-826. [http://dx.doi.org/10.1111/j.1440-1754.2010.01931.x] 13. Faber DL, Best LA, Orlovsky M, Lapidot M, Nir RR, Kremer R. Streptokinase fibrinolysis protocol: The advantages of a non-operative treatment for stage II pediatric empyema patients. Isr Med Assoc J 2012;14(3):157-161. 14. Gasior AC, Knott EM, Sharp SW, Ostlie DJ, Holcomb GW 3rd, St Peter SD. Experience with an evidence-based protocol using fibrinolysis as first line treatment for empyema in children. J Pediatr Surg 2013;48(6):1312-1315. [http://dx.doi.org/10.1016/j.jpedsurg.2013.03.029] 15. Avansino JR, Goldman B, Sawin RS, Flum DR. Primary operative versus nonoperative therapy for pediatric empyema: A meta-analysis. Pediatrics 2005;115(6):1652-1659. [http://dx.doi.org/10.1542/peds.2004-1405] 16. Tagbo O, Uchenna O, Anthony H. Childhood parapneumonic pleural effusion in Enugu. Niger Postgrad Med J 2005;12(1):28-32. 17. Von Gottberg A, Cohen C, de Gouveia L, et al. Epidemiology of invasive pneumococcal disease in the pre-conjugate vaccine era: South Africa, 2003-2008. Vaccine 2013;31(38):4200-4208. [http://dx.doi. org/10.1016/j.vaccine.2013.04.077] 18. Singleton RJ, Holman RC, Wenger J, et al. Trends in hospitalization for empyema in Alaska native children younger than 10 years of age. Pediatr Infect Dis J 2011;30(6):528-530. [http://dx.doi. org/10.1097/INF.0b013e3182075e74] 19. Sonnappa S, Cohen G, Owens CM, et al. Comparison of urokinase and video-assisted thoracoscopic surgery for treatment of childhood empyema. Am J Respir Crit Care Med 2006;174(2):221-227. [http:// dx.doi.org/10.1164/rccm.200601-027OC] 20. St Peter SD, Tsao K, Spilde TL, et al. Thoracoscopic decortication vs tube thoracostomy with fibrinolysis for empyema in children: A prospective, randomized trial. J Pediatr Surg 2009;44(1):106-111. [http:// dx.doi.org/10.1016/j.jpedsurg.2008.10.018] 21. Wang JN, Yao CT, Yeh CN, et al. Once-daily vs. twice-daily intrapleural urokinase treatment of complicated parapneumonic effusion in paediatric patients: A randomised, prospective study. Int J Clin Pract 2006;60(10):1225-1230. [http://dx.doi.org/10.1111/j.1742-1241.2006.01110.x]

Accepted 27 January 2015.

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The impact of highly active antiretroviral therapy on the burden of bacterial lower respiratory tract infections in children K R de Campos,1 MB ChB, MMed (Paed), Dip Allerg (SA); D D Granga,1 MB ChB, MMed (Paed); S Olorunju,2 PhD; R Masekela,1,3 MB BCh, MMed (Paed), Dip Allerg (SA), Cert Pulmonol (SA) Paed, FCCP, PhD epartment of Paediatrics and Child Health, Faculty of Health Sciences, University of Pretoria, South Africa, and Steve Biko D Academic Hospital, Pretoria 2 Biostatistics Unit, Medical Research Council, Pretoria, South Africa 3 Department of Paediatrics and Child Health, School of Clinical Medicine, College of Health Sciences, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa 1

Corresponding author: R Masekela (masekelar@ukzn.ac.za)

Background. Respiratory diseases are common and associated with significant morbidity and mortality in children. Objective. To evaluate the prevalence and outcome of bacterial lower respiratory tract infections (LRTIs) in HIV-infected and uninfected children at a primary level hospital. Methods. A cross-sectional descriptive study of children aged 6 months - 18 years was conducted. Recruitment included HIV-positive children who had been on highly active antiretroviral therapy (HAART) for at least 6 months. A comparator group of HIV-negative children admitted with bacterial pneumonia was included. Laboratory data collected included CD4+ T-cell counts, HIV viral load and C-reactive protein (CRP). Data collected in both groups included demographic data, immunisation status, zinc supplementation, previous LRTIs, environmental exposures and treatment. Results. Fifty-nine HIV-infected and 20 uninfected children were enrolled. The HIV-positive children were older, with a mean age of 107.2 (standard deviation 50.0) months v. 12.0 (5.8) months (p<0.005). The HIV-infected group had a mean CD4 percentage of 31.5%, and had had an average of 3.9 visits for bacterial LRTIs. All were treated with amoxicillin with no complications. In the HIV-uninfected group, cough and rapid breathing were the most common presenting symptoms, and the mean CRP level was 463.0 mg/L. The mean hospital stay was 4 days. Conclusion. HAART is effective in reducing the burden of LRTIs in HIV-positive children, even when the diagnosis is delayed. Cough and fast breathing are still the most reliable presenting symptoms of pneumonia. The majority of children still respond to amoxicillin as first-line therapy, with low complication rates. S Afr Med J 2015;105(7):554-557. DOI:10.7196/SAMJnew.7820

Respiratory diseases are common in children and carry a significant burden of morbidity and mortality in this age group worldwide.[1] Lower respiratory tract infections (LRTIs) are defined as infections that affect airways below the epiglottis. The term is often used as a synonym for pneumonia, which is defined as inflammation of the lung parenchyma with cough, dyspnoea and indrawing of the chest wall the most common presenting symptoms and signs.[2] Healthy children are vulnerable to pneumonia when the immune system is weakened by factors such as immunosuppression, malnutrition, measles, overcrowded homes, parental smoking or indoor pollution. Several steps have been established by the World Health Organization (WHO) to reduce mortality and morbidity due to pneumonia. These include immunisation, promotion of adequate nutrition (including breastfeeding and zinc intake), reduction of indoor air pollution, and implementation of the Integrated Management of Childhood Illness (IMCI) programme.[3] Pneumonia currently accounts for 20% of deaths of children under 5 years of age in developing countries every year, and remains an important condition in HIV-infected children.[4] An estimated 330 000 children acquired HIV infection in 2011, and more than 90% of these lived in sub-Saharan Africa.[5] In South Africa (SA), between 410 000 and 520 000 children aged 0 - 14 years

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are living with HIV.[6] Of the approximately 2.1 million children who are infected with HIV type 1, more than 80% will develop a respiratory illness at some stage during the course of their disease.[7] The advent of highly active antiretroviral therapy (HAART) has changed the natural progression of the disease, reducing viral replication, increasing the number of CD4 lymphocytes, and thus re-establishing host defences and improving survival.[8] Nevertheless, even on HAART children remain more vulnerable to infections than their healthy uninfected peers.[9] A reduction in the rate of opportunistic infections and hospitalisations in adults with AIDS after 6 - 12 months of HAART intervention is well documented.[10] Decreases in hospitalisations and deaths result in a substantial reduction in the healthcare costs associated with infection. The Children with HIV Early Antiretroviral TherapyÂ Trial showed that early diagnosis and early antiretroviral therapy (ART) reduced early infant mortality by 76% and HIV progression by 75%.[11] Worldwide, very few studies on the impact of HAART on vertically infected children and adolescents have been done.[10] The other major intervention to reduce pneumonia-related morbidity and mortality among all children is implementation of preventive strategies. Routine immunisations against Streptococcus pneumoniae, Haemophilus influenzae and varicella are safe and effective even in HIV-infected children, in whom the primary

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immunological response is inferior and there is faster decay in immunological memory.[3] The role of nutritional inventions, such as exclusive breastfeeding and zinc supplements, in the prevention of pneumonia among HIV-infected children needs to be explored more thoroughly.[11,12]

Objective

The primary aim of this study was to assess the prevalence of bacterial LRTIs in HIVinfected and uninfected children. The secondary aim was to assess the outcome of bacterial LRTIs in infected and uninfected children managed at a primary level hospital.

Table 1. Demographic and clinical variables of the HIV-positive children (N=59) Variable Age (months), mean (95% CI)

107.2 (94.20 - 120.26)

Gender (M/F), n (%)

21/38

Age at diagnosis (months), mean (95% CI)

34.5 (24.33 - 44.71)

Duration of HAART (months), mean (95% CI)

66.0 (59.09 - 72.18)

CD4 T-cell percentage, mean (95% CI)

31.5 (29.38- 33.71)

CD4+ T-cell (cells/ÂľL), mean (95% CI)

1 032.9 (877.86 - 1 188.22)

HIV viral load (copies/mL), mean (95% CI)

47 884 (0.0 - 108 947.60)

Visits,* mean (95% CI)

3.9 (3.79 - 4.17)

CI = confidence interval; M = males; F = females. *Number of visits for an LRTI since birth.

Methods

Statistical analysis

Data analysis was performed using Stata 12 (StataCorp LP, 2011; Statistical Software, USA). Summary statistics for all variables were done. Fisherâ&#x20AC;&#x2122;s exact test was used for assessing the association between categorical variables in the HIV-infected and uninfected children, and a two-sample independent t-test for proportions for comparisons of proportions of patients, both HIV-infected and uninfected, who had records of antibiotic therapy, zinc supplementation and immunisation. Similarly, a two-sample t-test

250.0 200.0 Means of variable

It was hypothesised that there is no difference in the rate of LRTIs in HIV-positive children on HAART compared with HIV-negative children. A cross-sectional descriptive study of children aged 6 months - 18 years was conducted at Tshwane District Hospital (TDH), Pretoria, SA, from January 2014 to September 2014. Two cohorts of children were recruited: a group of HIV-infected children who had been on HAART for at least 6 months, and a comparator group consisting of HIV-negative children admitted to the inpatient paediatric ward with a diagnosis of bacterial pneumonia. For both groups of children, data collected included demographic information, number of healthcare visits for LTRIs in the past, number of antibiotic courses given for LRTIs, immunisation status (confirmed by assessment of the Road to Health card (RTHC)), documented zinc supplementation on the RTHC, and finally exposure to biomass fuels and environmental tobacco smoke. For the HIV-positive group, data collected included an assessment of HIV stage, which included CD4+ T-cell counts, HIV viral load and duration of HAART. Patients were excluded if their HIV status was unknown or if consent could not be obtained for HIV testing.

150.0 100.0 50.0 0.0 F

Age (months) Duration of ART (months)

Age at diagnosis (months) CD4 percentage

Fig. 1. Demographic and laboratory parameters of HIV-infected children according to gender.

was used for gender comparisons in the HIV-uninfected group. Testing was done at the 0.05 level of significance.

Results

A total of 59 HIV-infected children were recruited. Of 623 children screened for the HIV-uninfected group, only 20 met the inclusion criteria. The majority of children who were screened had either bronchiolitis or asthma. The children in the HIV-uninfected group were younger (mean age 12.0 (standard deviation (SD) 5.8) months) than the HIVinfected children (mean age 107.2 (50.0) months) (p<0.005). The majority of the HIV-infected children had been diagnosed after the age of 2 years, with most having been on HAART for over 5 years and having immune restoration with normal CD4+ T-cell counts (Table 1). When all the demographic and clinical variables in the HIV-infected group of children were compared, there was no

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statistically significant difference in any of the variables when comparisons were performed according to gender (all p>0.05) (Fig. 1). None of the HIV-infected patients received oxygen therapy, as they were seen and managed at an outpatient department or local clinics, with only one child requiring admission. Thirty-one (52.5%) of these children received antibiotics for LRTIs; only one had complicated pneumonia. None of these HIV-infected children had a record of zinc supplementation. The majority of the HIV-infected group (66.7%) also did not have a complete immunisation record. Twelve (20.3%) of the HIV-infected children had had five visits to the TDH clinic for an LRTI, and 15.3% had had three visits. Amoxicillin was the antibiotic of choice in 98.3% of cases. One patient had only received erythromycin. Of the HIV-uninfected children who were admitted with an LRTI and screened during the study period, only 3.2% had bacterial pneumonia. The gender distribution was

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Table 2. Demographic and clinical characteristics of the HIVnegative children with pneumonia (N=20)

Table 3. Comparison of variables between HIV-uninfected and HIV-infected children presenting with pneumonia

Variable

HIV-positive

HIV-negative

12/8 (60.0/40.0)

Gender (F/M), n

21/38

8/12

20 (100.0)

Age (months), mean (SD)

12.0 (5.8)

107.0 (50.0)

<0.005

Fast breathing, n (%) (95% CI)

16 (80.0) (0.55 - 0.93)

Zinc supplementation, %

Chest indrawing, n (%) (95% CI)

14 (70.0) (0.45 - 0.87)

Antibiotics, %

100

0.0001

Admission (days), mean (95% CI)

4.4 (3.77 - 5.03)

Immunisation, %

33.3

85.0

0.0002

CRP (mg/L), mean (95% CI)

463.0 (333.1 - 592.9)

M = males; F = females; NS = not statistically significant.

Supplemental oxygen, n (%) (95% CI)

5 (25.0) (0.10 - 0.50)

Antibiotics, n (%)

20 (100.0)

Breastfeeding, n (%) (95% CI)

19 (95.0) (0.67 - 0.99)

Immunisation, n (%) (95% CI)

17 (85.0) (0.59 - 0.95)

Zinc supplementation, n (%)

0 (0.0)

Age (months), mean (95% CI)

12.0 (9.27 - 14.72)

Gender (M/F), n (%) Cough, n (%)

unbalanced, with 60.0% males, and the average age of the children was 12 months (Table 2). There was no difference in mean age at admission when the males and females were compared (13.87 months (95% confidence interval (CI) 9.62 - 18.12) v. 10.75 months (95% CI 6.84 - 14.66), respectively) (p=0.233). The most common presenting symptoms of pneumonia were cough, found in all children (100.0%), fast breathing (n=16, 80.0%) and chest indrawing (n=14, 70.0%). More females than males presented with chest indrawing (n=6 (33.3%) v. n=5 (25.0%)), but this was not statistically significant (p=0.41). Of the children with pneumonia, five required oxygen therapy. The mean CRP level was 463.0 mg/L, with no significant difference in CRP levels between males and females (450.8 mg/L (95% CI 327.7 - 573.9) v. 481.2 mg/L (95% CI 158.1 - 804.3), respectively) (p=0.841). The average number of admission days was 4.4, with no difference in number of days when the males and females were compared (p=0.663). Intravenous ampicillin was the first-line antibiotic of choice, with only 12.5% receiving ampicillin and amikacin and only one patient initiated on second-line therapy (ceftriaxone) owing to failed first-line treatment. Exposure to biomass fuels was low in this study population (only 7.0%), the majority of the children’s homes having electric stoves. No children were exposed to tobacco smoke. There was no record of zinc supplementation in any of the children’s RTHCs. Breastfeeding rates were high, with 95.0% of all children being breastfed. Overall, 85.0% of the children were fully immunised, the proportion being higher among males than females (91.7% v. 75.0%), although this did not reach statistical significance (p=0.085). When the HIV-uninfected and HIV-infected groups were compared, all the HIV-uninfected children had been treated with antibiotics as opposed to 52.5% of the HIV-infected group (p<0.005). There was no documented record of zinc supplementation in either group. Immunisation rates differed between the groups, with more HIV-positive children than HIV-negative children having an incomplete record (62.0% v. 15.0%); this was statistically significant (p=0.002).

Discussion

This study shows that diagnosis of HIV infection and initiation of HAART may still be delayed in children; despite this, however, once HAART is initiated the burden of bacterial LTRIs is low, with children experiencing an average of less than one bacterial infection per year

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p-value

in the first 8 years of their lives. Admission rates for pneumonia were also very low, with no serious sequelae. Of concern are relatively low clinic attendance rates, with two-thirds of HIV-infected children having an incomplete immunisation record. For the HIV-uninfected group, viral LRTIs were the most common cause for admission, with children who presented with bacterial LRTIs being younger than 2 years and typically having uncomplicated pneumonia with good outcomes. Cough and fast breathing remain the major presenting symptoms for bacterial pneumonia. Penicillinbased antibiotics were the first-line therapy in most cases, with the average duration of treatment being less than 5 days. Immunisation and breastfeeding rates were high and biomass exposures low. HAART improves survival in HIV-infected children. The majority of HIV-infected children in the current study had been on HAART for over 5 years and had a normal CD4+ T-cell count and a suppressed HIV viral load. This may account for the low levels of recorded bacterial LRTIs and low complication rates. Sánchez et al.[13] found that HAART results in a lower risk of death at 5 years’ follow-up. The impact of ART on lung health of HIVinfected persons is not well understood. Systemically, treatment with ART decreases HIV replication, immune activation and chronic inﬂammation and increases CD4+ T-lymphocyte counts. Within the alveolar space, ART decreases the pulmonary HIV viral load and decreases pulmonary inﬂammatory responses.[8] The present study confirms the effectiveness of HAART as the best intervention for the prevention of pneumonia, and consequently of hospitalisations and deaths, in children and adolescents living with HIV/AIDS. This is supported by the findings of Candiani et al.[10] According to the WHO, pneumonia accounts for 19% of deaths of children aged under 5 and for 4% of neonatal deaths worldwide.[14] In SA, the mortality rate from pneumonia in children increased from 21/1 000 to 103/1 000 between 2003 and 2009. The annual incidence of pneumonia in children younger than 5 years of age in SA remains high, and pneumonia is one of the major causes of mortality in this age group.[15] Determining the causation of bacterial pneumonia in children is difficult, as specimens for culture are difficult to obtain and often yield negative results. For this reason several studies have advocated the use of empirical treatment, since S. pneumoniae is the most common bacterial pathogen identified in children aged 4 weeks and older in developing countries. The role of S. pneumoniae in serious infections has decreased significantly since the introduction of the pneumococcal conjugate vaccine (PCV).[16,17] In SA the PCV7 vaccine was included in the immunisation schedule in the public sector (which caters for over 80% of the population) in 2009.[18] In the current study, the majority of HIV-negative children were under 5 years of age and therefore fell into the group that would have benefited from this vaccine. Vaccination with PCV is a public health intervention to prevent pneumococcal disease, and it was licensed in the USA for use in

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children in 2000. This vaccine is suitable for use in infants and includes the most commonly identified serotypes, namely 4, 6B, 9V, 14, 18C, 19F and 23F.[19] Recently two new vaccines covering other serotypes such as 1 and 5, which are highly invasive and responsible for severe illness and hospitalisation in young children, have been implemented, i.e. PCV10 and PCV13.[20] Several studies on the PCV vaccine have shown that it is effective in reducing invasive pneumococcal disease and hopitalisations.[21] We have observed that the majority of children admitted with ‘pneumonia’ and screened had viral bronchiolitis, with very few having bacterial pneumonia. Most guidelines suggest treatment with amoxicillin as first-line antibiotic therapy for community-acquired bacterial pneumonia.[22] In our cohort, amoxicillin was the antibiotic of choice for both groups, while the first choice for inpatient therapy for the HIV-negative group was ampicillin. The response to treatment was good, based on the short length of hospital stay and the lack of significant complications observed, probably because S. pneumoniae remains the most common bacterial pathogen causing community-acquired pneumonia. Healthy children are vulnerable to pneumonia when their immune system is weakened. Factors involved include parental smoking and indoor pollution, which is a huge problem in Africa, where about 700 million people burn biomass fuels to provide energy to cook. Smith et al.[23] have demonstrated in a randomised controlled trial that biomass exposure is a significant risk factor for pneumonia. We found low levels of biomass exposure, which may explain the low levels of bacterial pneumonia found in our study. Other preventive strategies to reduce pneumonia morbidity and mortality include the use of the IMCI programme. In SA, use of this programme at primary care level has been shown to be very effective for the diagnosis and management of pneumonia.[24] In the current study, cough and fast breathing were the most common presenting symptoms, as per the WHO definition of pneumonia, confirming the value of these clinical symptoms for the diagnosis of pneumonia at primary care level. Acute-phase reactants such as CRP have been extensively studied in the evaluation and prognostication of pneumonia. Various cut-points for diagnosis have been suggested, with values ranging between 300 and 560 mg/L.[25] Youssef et al.[26] demonstrated a correlation between a high CRP level (mean in their study 916.8 mg/L) and severity of pneumonia and the need for intensive care unit (ICU) admission. In the current study, the mean CRP level was 460 mg/L and none of the patients had a prolonged hospital stay or required ICU admission. The value of zinc supplementation as an adjuvant therapy for pneumonia prevention is still not well established. Shah et al.[27] performed a randomised double-blind placebo-controlled study and concluded that there was no significant reduction in duration of hospital stay. The majority of children in the current study did not receive any zinc supplementation; this did not seem to impact upon the severity or number of LRTIs experienced by children in this cohort, although our numbers were small.

Study limitations

The limitations of this study were the small numbers of children, particularly in the HIV-uninfected group, as the majority of children admitted had a viral LRTI. The fact that the HIV-infected children were older makes it difficult to compare them with a younger HIVuninfected group, as younger children generally experience more LRTIs.

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Recommendations

Future randomised controlled trials focusing on the role of zinc supplementation on the prevention of bacterial LRTIs in both HIVinfected and uninfected children should be conducted. In the current study, the HIV-infected children were older and a follow-up study of the same cohort of children in 5 years’ time would be interesting to assess the ongoing protective role of HAART and its impact on lung health in adolescence.

Conclusion

HAART is effective in reducing the burden of LRTIs in children, even when the diagnosis of HIV infection is delayed. Cough and fast breathing are the most reliable presenting symptoms for pneumonia. The majority of children respond to amoxicillin as first-line therapy. References 1. Roth DE, Caulfield LE, Ezzati M, Black RE. Acute lower respiratory infections of childhood. www.who. int/bulletin/volumes (accessed 14 May 2013). 2. Shah N. Pneumonia: The forgotten killer. Pediatr Infect Dis 2010;11:145-157. [http://dx.doi. org/10.1016/S2212-8328(10)80004-9] 3. Greenwood B. A global action plan for the prevention and control of pneumonia. Bull World Health Organ 2008;86(5):322-2A. [http://dx.doi.org/10.2471/BLT.08.053348] 4. Sazawa S, Black R. Effect of pneumonia case management on mortality in neonates, infants and preschool children: A meta-analysis of community-based trials. Lancet Infect Dis 2003;3(9):547-556. [http://dx.doi.org/10.1016/S1473-3099(03)00737-0] 5. Global report UNAIDS on the global AIDS epidemic: 2012. www.unaidsorg (accessed 13 May 2013). 6. Averting HIV and AIDS. HIV and AIDS in South Africa. International HIV and AIDS charity from AVERT. www.avert.org/aidssouthafrica.htm (accessed 13 May 2013). 7. Jeena PM. Can the burden of pneumonia among HIV-infected children be reduced? Bull World Health Organ 2008;86(5):323A-333A. [http://dx.doi.org/10.2471/BLT.08.053223] 8. Crothers K, Thompson BW, Burkhardt K, et al. HIV-associated lung infections and complications in the era of combination antiretroviral therapy. Proc Am Thorac Soc 2011;8(3):275-281. [http://dx.doi. org/10.1513/pats.201009-059WR] 9. Gray DM, Zar HJ. Community-acquired pneumonia in HIV-infected children: A global perspective. Curr Opin Pulm Med 2010;16(3):208-216. [http://dx.doi.org/10.1097/MCP.0b013e3283387984] 10. Candiani TM, Pinto J, Cardoso CA, et al. Impact of highly active antiretroviral therapy (HAART) on the incidence of opportunistic infections, hospitalizations and mortality among children and adolescents living with HIV/AIDS in Belo Horizonte, Minas Gerais State, Brazil. Cad Saude Publica 2007;23(Suppl 3):S414-S423. [http://dx.doi.org/10.1590/S0102-311X2007001500009] 11. Violari A, Cotton MF, Gibb DM, Babiker AG, Steyn J, Madhi SA. 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] 12. Fataki MR, Kisenge RR, Sudfeld CR, et al. Effect of zinc supplementation on duration of hospitalization in Tanzanian children presenting with acute pneumonia. J Trop Pediatr 2014;60(2):104-111. [http:// dx.doi.org/10.1093/tropej/fmt089] 13. Sánchez JM, Ramos Amador JT, Fernándes de Miquel SR, et al. Impact of highly active antiretroviral therapy on the morbidity and mortality in Spanish human immunodeficiency virus-infected children. Pediatr Infect Dis J 2003;22(10):863-877. [http://dx.doi.org/10.1097/01.inf.0000091282.70253.5f] 14. Zar HJ, Jeena PM, Argent A, Gie R, Madhi SA. Diagnosis and management of community-acquired pneumonia in childhood: South African Thoracic Society guidelines. S Afr J Epidemiol Infect 2009;24(1):25-36. 15. Global action plan for prevention and control of pneumonia (GAAP). www.unicef.org (accessed 14 May 2013). 16. Zar HJ. Prevention of HIV-associated respiratory disease in developing countries: Potential benefits. Int J Tuberc Lung Dis 2003;7(10):820-827. 17. Statistical Services South Africa. South Africa 2005. Millenium Development Goals Country Report. www.statssa.gov.za (accessed 14 May 2013). 18. Zar HJ, Madhi S. Pneumococcal conjugate vaccine – advancing child health in South Africa. S Afr J Child Health 2008;2(3):94-95. 19. Hausdorff WP, Bryant J, Paradiso PR, Siber GR. Which pneumococcal serogroups cause the most invasive disease: Implications for conjugate vaccine formulation and use, part 1. Clin Infect Dis 2000;30(1):100-121. [http://dx.doi.org/10.1086/313608]) 20. Gessner BD, Adegbola RA. The impact of vaccines on pneumonia: Key lessons from Haemophilus influenzae type b conjugate vaccine. Vaccine 2008;26(Suppl):B3-B8. [http://dx.doi.org/10.1016/j. vaccine.2008.04.013] 21. Von Gottberg A, de Gouveia L, Madhi S, et al. The impact of conjugate Haemophilus influenza type B (Hib) vaccine introduction in South Africa. Bull World Health Organ 2006;84(10):811-818. [http:// dx.doi.org/10.2471/BLT.06.030361] 22. Mc Cracken GH. Diagnosis and management of pneumonia in children. Pediatr Infect Dis J 2000;19(9):924-928. [http://dx.doi.org/10.1097/00006454-200009000-00036] 23. Smith KR, McCraken JP, Weber MW, et al. Effect of reduction in household air pollution in childhood pneumonia in Guatamala: A randomized controlled trial. Lancet 2011;378(9804):1717-1726. [http:// dx.doi.org/10.1016/S0140-6736(11)60921-5] 24. KZN IMCI Guidelines. Integrated Management of Childhood Illness. www.kznhealthgov.za/imci (accessed 14 May 2013). 25. Van Vugt SF, Broekhuizen BD, Lammens C, et al. Use of serum C reactive protein and PCT concentration in addition to symptoms and signs to predict pneumonia in patients presenting to primary care with acute cough: Diagnostic study. BMJ 2013;346:F2450. [http://dx.doi.org/10.1136/bmj.f2450] 26. Youssef HA, Nasseh S, Hafiz AH, Gawesh A. Evaluation of diagnostic and prognostic value of high sensitivity C reactive protein (hsCRP) in community acquired pneumonia. Egyptian Journal of Chest Diseases and Tuberculosis 2013;62(2):301-304. [http://dx.doi.org/10.1016/j.ejcdt.2013.05.011] 27. Shah GS, Dutta AK, Shah D, Mishra OP. Role of zinc in severe pneumonia: A randomized double blind placebo controlled study. Ital J Pediatr 2012;38:36. [http://dx.doi.org/10.1186/1824-7288-38-36]

Accepted 20 March 2015.

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Identification of a mutation in the ubiquitin-fold modifier 1-specific peptidase 2 gene, UFSP2, in an extended South African family with Beukes hip dysplasia C M Watson,1 BSc, PhD; L A Crinnion,1 BSc; L Gleghorn,2 BSc, PhD; W G Newman,3 PhD, FRCP; R Ramesar,4 BSc, MSc, MBA, PhD; P Beighton,4 OMB, MD, PhD, FRCP, FRSSA; G A Wallis,2 BSc, MA, PhD Yorkshire Regional Genetics Service and School of Medicine, University of Leeds, St James’s University Hospital, Leeds, UK Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Manchester, UK 3 Centre for Genomic Medicine, Manchester Academic Health Science Centre, University of Manchester and Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK 4 MRC Human Genetics Research Unit, Division of Human Genetics, Institute for Infectious Diseases and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, South Africa 1 2

Corresponding author: C M Watson (c.m.watson@leeds.ac.uk)

Background. Beukes hip dysplasia (BHD) is an autosomal dominant disorder of variable penetrance that was originally identified in a large South African family of European origin. BHD is characterised by bilateral dysmorphism of the proximal femur, which results in severe degenerative osteoarthropathy. Previous studies mapped the disorder to a 3.34 Mb region on chromosome 4q35. Objective. To fine-map the BHD locus and identify the disease-causing mutation by direct sequencing. Results. The linked BHD allele was refined to 1.33 Mb, reducing the number of candidate genes from 25 to 16. Analysis of protein coding and invariant splice-site sequences in three distantly related individuals identified a single-candidate disease-causing variant c.868T>C within exon 8 of the ubiquitin-fold modifier 1 (Ufm1)-specific peptidase 2 gene, UFSP2. The presence of this unique mutation was confirmed in all 17 affected members of the BHD family who were genotyped. The mutation segregated with the BHD phenotype in the extended family with a two-point (single marker) LOD score of 10.4 (θ = 0.0 and 80% penetrance). The mutation predicts the substitution of a highly conserved amino acid, p.Tyr290His, in the encoded protein. In vitro functional assays performed using purified recombinant wild-type and mutant UFSP2 protein demonstrated that the BHD mutation abolishes UFSP2-mediated C-terminal cleavage of its substrate, Ufm1. Conclusion. We report a unique UFSP2 mutation that segregates with the BHD phenotype. The predicted amino acid substitution inactivates UFSP2 proteolytic function, thus implicating the ubiquitin-fold modifier 1 cascade in this form of severe hip osteoarthropathy. The facile polymerase chain reaction-based assay we describe could be used to confirm the diagnosis of BHD, or for presymptomatic testing of members of the extended BHD family. S Afr Med J 2015;105(7):558-563. DOI:10.7196/SAMJnew.7917

Skeletal development is controlled by extracellular matrix synthesis and deposition in combination with a complex regulatory network of cellular differentiation. Understanding these processes has been aided by mapping human disease genes, which have revealed fundamental insights into a number of the biological mechanisms underlying skeletogenesis. To date, more than 450 skeletal conditions have been identified and classified based on molecular, biochemical and/or radiographic criteria.[1] One such disorder is Beukes hip dysplasia (BHD) (OMIM #142669), a rare autosomal dominant condition that was originally identified in a large, multigeneration South African (SA) family of European descent.[2] BHD is characterised by severe progressive degenerative osteoarthritis (OA) of the hip joint in early adulthood. The condition is unique in that the underlying dysplasia and subsequent OA are confined to this region. Affected individuals are of normal stature and have no associated health problems. As described in detail previously, symptoms of hip joint discomfort usually develop in infancy or later childhood, but in a single individual initial presentation was as late as 35 years of age.[2] Phenotypic expression is age-related and variable in severity. The penetrance of this disorder is incomplete and has been estimated to be 80%. The earliest primary radiographic features of BHD include bilateral shortening and broadening of the femoral

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neck, delayed appearance of the secondary ossification centre, coxa vara, displacement of the femoral head in the acetabulum, and overgrowth of the greater trochanters. Following onset of symptoms, the characteristic signs of secondary OA (including bone sclerosis, cyst formation and narrowing of the joint space) develop and the joint deteriorates rapidly. We have previously mapped the BHD locus to a 3.34 Mb region of chromosome 4q35.[3] This locus has not been linked to other forms of familial acetabular dysplasia, indicating that BHD is a distinct disorder.[4,5] To reduce the complexity of disease gene identification, we finemapped the chromosome 4q35 locus with polymorphic DNA markers. A combined Sanger and next-generation sequencing approach was used to screen coding and invariant splice-site sequences located within the linked interval for candidate pathogenic mutations. The development of ‘next-generation sequencing’ has accelerated the identification of disease-causing variants. This technology enables millions of DNA fragments covering all known protein coding and splice-site sequences of multiple individuals to be sequenced in a single experiment. This is typically achieved following a targeted enrichment reaction in which a sheared genomic DNA sample is hybridised to a pool of RNA baits that are complementary to the genomic region of interest. Through the application of this technology, we were able to confirm the presence of a single-

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candidate disease-causing variant within the BHD locus, which we subsequently characterised in vitro.

Methods

Archived DNA samples (extracted from blood samples obtained following informed consent for the purpose of molecular genetic analysis) were available from earlier investigations of the family, as reported previously.[3] A standard salting-out protocol was used to extract DNA from peripheral blood lymphocytes of 40 family members.

Fine-mapping the BHD locus

Microsatellite sizing and restriction fragment polymorphism genotyping of markers D4S1535 (Chr4: 185 235 750 - 185 236 098) and rs7663196 (Chr4: 186 570 521) was performed on members of the BHD family (Applied Biosystems, UK). Primer sequences are available on request. Two-point LOD scores were calculated using Linkage v5.1 (http://www.jurgott.org/linkage/LinkagePC.html).

Mutation screening and bioinformatic analysis

Comprehensive mutation screening of coding and flanking intron bases of three genes within the linked locus, CASP3, LRP2BP and UFSP2, was initially undertaken by Sanger sequencing (further details available on request). With the ubiquitous availability of

next-generation sequencing, three distantly related individuals (VII:9, VII:10 and VI:24) were then selected for exome sequencing. Approximately 3 μg of genomic DNA was sheared using a Covaris S2 (Covaris Inc., USA) before standard whole-genome library preparation was performed, following the manufacturer’s protocols throughout (Agilent Technologies, UK). Two enrichment polymerase chain reaction (PCR) reactions were necessary to obtain the required mass of genomic library for enrichment hybridisation, which was carried out using a SureSelect All Exon V5 (no UTRs) bait set. Final exome-enriched libraries were confirmed using an Agilent Bioanalyser prior to being pooled in equimolar concentrations. The pool was sequenced on a HiSeq2500 across three lanes of rapid mode flow cells in a run configuration that generated paired-end 100-bp reads (Illumina Inc., USA). Raw data were demultiplexed and converted to FASTQ.gz format using CASAVA v1.8.2. To analyse each individual, sequence reads were first aligned to an indexed human reference genome (hg19) using bwa v0.6.2. Duplicate reads were removed using Picard v1.85 (http://picard.sourceforge.net), and SAM/BAM file processing was performed using samtools v0.1.18 (http://samtools.sourceforge.net). GATKLite v2.3-4 was used to perform indel realignment, base quality recalibration, variant calling with the UnifiedGenotyper and read-depth analysis (http://www. broadinstitute.org/gatk/index.php). Variant call format files were annotated with position, frequency (incorporating dbSNP and the

Fig. 1. The BHD pedigree, with disease-linked alleles highlighted in red. The smallest disease interval was identified in individual VI:24. Symbols containing a question mark (?) are probably non-penetrant carriers of the BHD allele. The marker order from top to bottom is: D4S1554, D4S1535, D4S171, UFSP2 c.868T>C, D4S2924, rs7663196 and D4S3051. The genotypes for D4S1554, D4S171, D4S2924 and D4S3051 are as previously published.[3] The UFSP2 c.868 ‘C’ allele is notated ‘1’ and the ‘T’ allele as ‘2’ (displayed in bold). The pedigree has been compressed to show only those individuals who contributed to the linkage analysis.

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ESP5400 dataset) and in silico variant effect predictions using Alamut Batch v1.1.5 (http://www.interactive-biosoftware.com/software/ alamut/overview). Interpretation of the annotated variant dataset was aided using AgileExomeFilter (http://dna.leeds.ac.uk/agile)[6] and the variant-decision support software Alamut Visual. To assess exon copy number variation, FishingCNV v2.1 (http://sourceforge.net/ projects/fishingcnv/) was used to compare the sequenced read depth of BHD individuals to a pooled reference control comprising 65 BHD disease-free patients.

Molecular assay for UFSP2 mutation analysis

A 341-bp PCR amplicon spanning the UFSP2 c.868T>C mutation was generated using forward primer dCATTAAACATAATTCGGGAGCA and reverse primer dTCTGCACCATGAGGTAACAAA. Each PCR reaction consisted of 1 μL of 15 ng/μL DNA, 2.5 μL of 10× PCR buffer, 1 μL of 50 mM MgCl2, 1 μL of 10 mM dNTPs, 0.5 μL of BIOTAQTM DNA polymerase (5 U/μL), 17 μL of nuclease-free water, 1 μL of 10 μM forward primer and 1 μL of 10 μM reverse primer (Bioline Reagents Ltd., UK and Eurogentec Ltd., UK). Thermocycling conditions consisted of 95oC for 3 minutes followed by 36 cycles of 95oC for 30 seconds, 55oC for 45 seconds, 72oC for 45 seconds, and a final extension at 72oC for 10 minutes. The UFSP2 c.868T>C mutation introduced an NdeI (CATATG) restriction site that was detected by incubating PCR products with NdeI for 1 hour at 37oC and, if the mutation was present, generated 219-bp and 122-bp PCR fragments (NEB, UK). PCR products were resolved by tris-borateEDTA agarose gel electrophoresis.

deformity, and his general health was good. Specifically, he did not have joint hypermobility, cleft palate, or visual or hearing deficit. A skeletal survey revealed no evidence of abnormality other than in both of his hip joints, where the features were characteristic of BHD and associated OA was evident (Fig. 2). In keeping with the variable penetrance of the disorder, the progression of the clinical and radiological manifestations of VII:10 were less severe than those described for other family members. In addition, his father, although an obligate carrier of the BHD allele, was reported to be asymptomatic apart from mild joint discomfort at the age of 63 years. BHD was previously linked to an 11-cM locus on chromosome 4q35.[3] Subsequently, we fine-mapped the locus using proximal and distal markers D4S1535 and rs7663196, respectively. Recombination

Functional analysis of the UFSP2 mutation

A previously described expression construct for mouse UFSP2 (NM_138668.2) was modified to incorporate the heterologous BHD mutation (c.844T>C, p.Tyr282His).[7] The wild-type (WT) (UFSP2 WT) and mutant (UFSP2 BHD) constructs together with a GSTUfm1-HA construct were expressed in Escherichia coli and purified. Purified proteases were incubated with GST-Ufm1-HA at 37oC for 1 hour and the products were separated by SDS-PAGE gel electrophoresis (Invitrogen Ltd., UK). Protein bands were visualised by staining with Coomassie blue R-250.

Results

Since the original description of BHD in a multigeneration SA family, the pedigree has been extended to include family members in Canada, New Zealand and the UK. A condensed pedigree is shown in Fig. 1. A recent addition to the pedigree was affected individual VII:10, who was diagnosed at 31 years of age while resident in the UK. He presented with severe hip joint discomfort and pain that had increased progressively since the age of 13 years. Consistent with a diagnosis of BHD, his symptoms were confined to his hip joints; he was of normal stature, had no evidence of other

Fig. 2. Anteroposterior radiographs of the pelvis of (A) an unaffected adult and (B) a 31-year-old affected man (VII:10). In (B) the shortening and broadening of the femoral neck, coxa vara and displacement of the femoral head in the acetabulum are characteristic of BHD. The joint space narrowing, presence of marginal osteophytes, cyst formation and sclerosis are indicative of degenerative OA, which is more evident on the right.

Table 1. Performance metrics for exome sequencing experiments Sample ID

Total sequenced reads, n

Duplicate rate, %

Total aligned reads,* n

Proportion of reads mapped to coding exons, %

Variants located in coding exons and invariant splice sites, n

VII:9

295 153 748

43.5

163 283 145

58.9

20 750

VII:10

208 896 212

33.7

136 027 844

59.8

20 863

VI:24

239 488 548

57.4

99 711 251

62.5

20 591

*Following removal of duplicate sequences.

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Fig. 3. (A) Sanger sequencing confirmation of the heterozygous UFSP2 c.868T>C (NM_018359.3) variant. The chromosome 4 human genome co-ordinate corresponds to build hg19. (B) A molecular assay was established for cascade screening of the extended family. A 341-bp PCR fragment was amplified and restricted with NdeI. PCR fragments of 219 bp and 122 bp indicate the presence of the mutant allele. (C) Alignment of partial protein sequences of UFSP2 for a range of multicellular organisms. The tyrosine (Y) residue at position 290 is highly conserved and located in close proximity to the conserved protease Cys domain.

Fig. 4. In vitro biochemical analysis of UFSP2 function. (A) Increasing concentrations of purified UFSP2 WT correlated with increased cleavage of the HA tag from GST-Ufm1-HA. In contrast, even at high concentrations the enzymatic activity of UFSP2 BHD was abolished. (B) Increasing concentrations of UFSP2 BHD were incubated with constant concentrations of UFSP2 WT and GST-Ufm1-HA. No evidence for a dominantnegative effect on the cleavage of GST-Ufm1-HA by UFSP2 WT was observed. ((-) = absence of protein.)

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events (see individual VI:24, Fig. 1) reduced the size of the linked region from 3.34 Mb to 1.33 Mb and decreased the number of candidate genes from 25 to 16. To identify the BHD mutation, systematic sequence analysis of the coding exons and intron splice sites of CASP3, LRP2BP and UFSP2 located in the linked region was conducted. This analysis identified a single novel heterozygous variant, c.868T>C, in UFSP2 exon 8 (NM_018359.3) (Fig. 3, A). To ensure that no additional candidate disease-causing variants were present within the linked interval, whole-exome sequencing was performed on three distantly related individuals (VII:9, VII:10 and VI:24). Exome sequencing performance metrics (Table 1) demonstrated that the hybridisation capture efficiencies, as determined by the percentage of sequence reads mapping to each exome, were comparable to those reported elsewhere.[8] To determine the proportion of target nucleotides that were sufficiently well sequenced to exclude the presence of non-reference nucleotides, read-depth analysis was performed. For two of the three sequenced individuals, >98% of target bases had a read depth that was ≥30×, which is a conservative read-depth metric that has been widely adopted by the diagnostic sequencing community[9] (Table 2). Variants with a reported minor allele frequency <0.2 located within the finemapped BHD locus (Chr4: 185 235 750 186 570 521) were assessed for diseaserelated pathogenicity. This yielded a filtered dataset comprising one variant in individual VII:9, one in VII:10 and four in VI:24. The single variant found in common between the affected individuals was the UFSP2 c.868T>C variant that had been identified by the initial sequencing screen. This c.868T>C variant was not identified in publicly accessible variant databases including dbSNP and the ESP5400 dataset. In addition, exon-based copy number analysis did not identify any dosage variants within the linked interval in any of the three individuals. To explore familial segregation, all available members of the BHD family were genotyped for presence of the UFSP2 c.868T>C variant using PCR followed by restriction enzyme digestion with NdeI (see Fig. 3, B for a representative genotyping gel and Fig. 1 for the genotypes). All 17 individuals with a confirmed diagnosis of BHD were hetero zygous for the c.868T>C mutation. There was evidence of non-penetrance in one obligate carrier (VII:4), and the mutation was found in two individuals (VII:8 and VII:14) in whom BHD had not been excluded or confirmed owing to their young age at time

165

120 83.7 91.7 171 98.0 99.7 203 98.3 99.8 1 477 10 *Chr4: 185 235 750 - 186 570 521, co-ordinates reported according to hg19. † Read depth calculated for linked target nucleotides only.

Mean

160 100.0

95.7 97.0

100.0 204

198 100.0

100.0 100.0

100.0 225

239 100.0

100.0 100.0

100.0 1 092

3 300 21

8 NM_014476.4

NM_021069.4 186 877 870

186 421 815 186 456 712 PDLIM3

SORBS2†

186 506 598

151

29 26.2

99.0 100.0

50.1 113

222 100.0

100.0 100.0

100.0 269

128 100.0

100.0 100.0

100.0 2 499

927 7

7 NM_152775.3

NM_001114357.1 + 186 370 821

186 366 338

186 350 545

186 392 913

C4orf47

CCDC110

174

113 84.0

95.2 100.0

96.3 186

211 100.0

100.0 100.0

100.0 281

217 100.0

100.0 100.0

100.0 1 407

474 5

12 NM_018359.3

NM_181726.2 +

186 320 694

186 317 840

186 347 139

ANKRD37

UFSP2

186 321 390

113

133 100.0

87.4 96.4

100.0 178

162 95.0

100.0 100.0

99.8 194

218 100.0

96.6 100.0

100.0 1 041

2 520 19

8 NM_018409.3

NM_031953.2 +

186 131 284

186 300 152

SNX25

LRP2BP

186 285 120

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186 285 032

142

146 98.6

96.5 98.6

100.0 245

172 100.0

100.0 100.0

100.0 196

302 100.0

98.7 100.0

100.0 1 596

894 4

5 NM_020827.1

NM_001151.3 +

186 125 182

186 064 417

186 080 816

SLC25A4

CFAP97

186 071 538

73 76.5 82.5 113 100.0 100.0 113 95.5 100.0 981 4 NM_001029887.1 + 185 940 083 HELT

185 941 926

159

51 78.8

98.4 100.0

98.9 89

189 99.0

99.3 100.0

100.0 226

107 99.8

99.1 100.0

100.0 1 254

2 094 21

13 NM_024629.3

NM_001995.2 -

185 655 286

185 676 749

185 615 219

185 747 268

CENPU

ACSL1

133 89.9

52.8 80.0

96.3 186

112 78.7

95.0 97.7

98.8 121

239 96.4

85.1 100.0

98.0 1 680

831 8

14 NM_152683.2

NM_004346.3 -

Mean, n

185 548 850 185 570 629

185 570 767

CASP3

PRIMPOL

185 616 113

93.4

30×, % 15×, %

98.6 161

Mean, n 30×, %

95.5 98.9

15×, % Mean, n

181 95.9

30×, % 15×, %

98.8 1 047 9 NM_002199.3

Exons, n Strand

185 308 876 185 395 726 IRF2

Stop Start Gene

VI:24 VII:10 VII:9

562

Coding nucleotides, n

BHD is a unique Mendelian disorder that has to date been described in only a single SA family of European origin.[2] The size and structure of the pedigree enabled the initial mapping of the linked locus to Chr4q35. [3] However, this locus did not contain any obvious candidate genes. To reduce the burden of variant interpretation following mutation screening, we fine-mapped the region and thereby reduced the number of candidate genes from 25 to 16. Initial mutation screening of genes located within the locus by Sanger sequencing identified a unique UFSP2 c.868T>C variant. This variant was identified in all individuals tested who had a confirmed diagnosis of BHD, but there was evidence of non-penetrance of BHD in the pedigree. The segregation of this variant with BHD generated a LOD score of 10.4 (at θ = 0.0 and 80% penetrance). As no other forms of skeletal dysplasia had been mapped to the linked locus on Chr4q35, no other families with BHD had been reported and the UFSP2 c.868T>C variant appeared to be unique to the BHD family, independent verification that the variant was indeed the BHD mutation was not possible. We therefore undertook comprehensive exome analysis of the linked allele in three distantly related individuals. This analysis confirmed that

Annotated transcript

Discussion

Table 2. Read-depth analysis for coding and invariant splice-site nucleotides within the BHD-linked locus*

of consultation. Linkage analysis between BHD and the c.868T>C mutation generated a two-point (single marker) LOD score of 10.4 (at θ = 0.0 and 80% penetrance). The UFSP2 c.868T>C variant predicts a tyrosine to histidine substitution at position 290 of the encoded protein, which is highly conserved across multiple species (Fig. 3, C). The effect of the p.Tyr290His substitution on UFSP2 protease activity was assayed in vitro as previously described by incubating recombinant purified mouse UFSP2 with Ufm1 that had been modified by the addition of an N-terminal GST tag and a C-terminal HA tag.[7] For this purpose, the heterologous mutation (c.844T>C, p.Tyr282His in the mouse) was inserted into the UFSP2 WT construct and expressed, and both the WT and UFSP2 BHD proteases were purified. Increasing concentrations of UFSP2 WT resulted in increased cleavage of the GSTUfm1-HA tag (Fig. 4, A). In contrast, UFSP2 BHD did not cleave GST-Ufm1-HA, even at high concentrations. The processing activity of UFSP2 WT was not affected in the presence of increasing concentrations of UFSP2 BHD, indicating that UFSP2 BHD does not exert a dominant-negative effect at the level of Ufm1 processing in vitro (Fig. 4, B).

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there were no other candidate disease-causing mutations in linkage disequilibrium with UFSP2 c.868T>C, suggesting that this variant is the BHD mutation. The identification of this mutation will enable diagnostic accuracy of BHD, aid predictive testing of at-risk family members, and underpin future longitudinal studies aimed at correlating the progression of radiological features with the onset of clinical symptoms. The cysteine protease encoded by UFSP2 is highly conserved and is homologous to a second cysteine protease, UFSP1, that has a similar C-terminal domain but a shorter N-terminal domain.[7] Neither protease shares sequence homology to other identified proteases. UFSP1 and UFSP2 have been shown previously to cleave two C-terminal residues (S101 and C102) from the protein ubiquitin-fold modifier 1 (Ufm1).[7] Ufm1 is a post-translational modifier protein that is classified as a member of the family of ubiquitin-like proteins (Ubls). Following modification through an E1-E2-E3 multienzyme cascade, Ufm1 is attached to its target protein. The conjugation and deconjugation of target proteins by Ubls modulates their function and thereby the regulation of cellular processes.[10] In the Ufm1 modification pathway, Ufm1 is activated by either UFSP1 or UFSP2 to expose a C-terminal glycine residue.[7] Activated Ufm1 then reacts with Uba5 (E1-like enzyme) and is transferred to Ufc1 (E2-like enzyme) before being transferred to its target protein by Ufl1 (E3-like enzyme). At present, the full repertoire of Ufm1 target proteins remains to be identified. Although there are currently no reported studies detailing the tissue specificity or time course of UFSP2 expression, analysis of multiple mouse tissues has revealed that Ufm1 expression is abundant in protein-secreting cells.[11] Further, there is increasing evidence that the Ufm1 pathway has a role in the regulation of endoplasmic reticulum (ER) stress responses.â&#x20AC;&#x160;[12] Interestingly, ER stress is a recognised pathogenic mechanism underlying a number of forms of osteochondrodysplasia, and the ER stress response has been proposed as a therapeutic target for such disorders.[13] This reported evidence therefore suggests a putative mechanistic link between the Ufm1/UFSP2 pathway and the BHD phenotype. Alignment of multiple UFSP2 protein sequences from different multicellular organisms, including plants and animals, demonstrated that the p.Tyr290 residue has been conserved for at least 1.6 billion years.[14] In an in vitro assay we found that purified mouse UFSP2 containing the mouse equivalent of the p.Tyr290His BHD substitution did not cleave Ufm1, even at high concentrations. Lack

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of activity of the mutated protease is consistent with predictions made from the crystal structure of UFSP2 that the p.Tyr290 amino acid is a crucial residue within the UFSP2 active site.[15] In this in vitro assay, however, the mutated UFSP2 did not appear to exert a dominantnegative effect. Confirmation of the functional consequences of the BHD mutation on the Ufm1/UFSP2 pathway therefore requires further investigation.

Conclusion

In summary, genetic and functional data support that UFSP2 c.868T>C is the mutation causing BHD. The facile PCR-based assay that we have described could be used to confirm the diagnosis of BHD, or for presymptomatic testing of members of the extended BHD family. References 1. Warman ML, Cormier-Daire V, Hall C, et al. Nosology and classification of genetic skeletal disorders: 2010 revision. Am J Med Genet A 2011;155A(5):943-968. [http://dx.doi.org/10.1002/ajmg.a.33909] 2. Cilliers, HJ, Beighton P. Beukes familial hip dysplasia: An autosomal dominant entity. Am J Med Genet 1990;36(4):386-390. [http://dx.doi.org/10.1002/ajmg.1320360403] 3. Roby P, Eyre S, Worthington J, et al. Autosomal dominant (Beukes) premature degenerative osteoarthropathy of the hip joint maps to an 11-cM region on chromosome 4q35. Am J Hum Genet 1999;64(3):904-908. [http://dx.doi.org/10.1086/302291] 4. Ingvarsson T, StefĂĄnsson SE, Gulcher JR, et al. A large Icelandic family with early osteoarthritis of the hip associated with a susceptibility locus on chromosome 16p. Arthritis Rheum 2001;44(11):25482555. [http://dx.doi.org/10.1002/1529-0131(200111)44:11%3C2548::AID-ART435%3E3.0.CO;2-S] 5. Mabuchi A, Nakamura S, Takatori Y, Ikegawa S. Familial osteoarthritis of the hip joint associated with acetabular dysplasia maps to chromosome 13q. Am J Hum Genet 2006;79(1):163-168. [http://dx.doi. org/10.1086/505088] 6. Watson CM, Crinnion LA, Morgan JE, et al. Robust diagnostic genetic testing using solution capture enrichment and a novel variant-filtering interface. Hum Mutat 2014;35(4):434-441. [http://dx.doi. org/10.1002/humu.22490] 7. Kang SH, Kim GR, Seong M, et al. Two novel ubiquitin-fold modifier 1 (Ufm1)-specific proteases, UfSP1 and UfSP2. J Biol Chem 2007;282(8):5256-5262. [http://dx.doi.org/10.1074/jbc.M610590200] 8. Bodi K, Perera AG, Adams PS, et al. Comparison of commercially available target enrichment methods for next-generation sequencing. J Biomol Tech 2013;24(2):73-86. [http://dx.doi.org/10.7171/jbt.13-2402-002] 9. Weiss MM, van der Zwaag B, Jongbloed JD, et al. Best practice guidelines for the use of next-generation sequencing applications in genome diagnostics: A national collaborative study of Dutch genome diagnostic laboratories. Hum Mutat 2013;34(10):1313-1321. [http://dx.doi.org/10.1002/humu.22368] 10. Daniel J, Liebau E. The ufm1 cascade. Cells 2014;3(2):627-638. [http://dx.doi.org/10.3390/ cells3020627] 11. Lemaire K, Moura RF, Granvik M, et al. Ubiquitin fold modifier 1 (UFM1) and its target UFBP1 protect pancreatic beta cells from ER stress-induced apoptosis. PLoS One 2011;6(4):e18517. [http:// dx.doi.org/10.1371/journal.pone.0018517] 12. Zhang Y, Zhang M, Wu J, Lei G, Li H. Transcriptional regulation of the Ufm1 conjugation system in response to disturbance of the endoplasmic reticulum homeostasis and inhibition of vesicle trafficking. PLoS One 2012;7(11):e48587. [http://dx.doi.org/10.1371/journal.pone.0048587] 13. Boot-Handford RP, Briggs MD. The unfolded protein response and its relevance to connective tissue diseases. Cell Tissue Res 2010;339(1):197-211. [http://dx.doi.org/10.1007/s00441-009-0877-8] 14. Wang DY, Kumar S, Hedges SB. Divergence time estimates for the early history of animal phyla and the origin of plants, animals and fungi. Proc Biol Sci 1999;266(1415):163-171. [http://dx.doi.org/10.1098/rspb.1999.0617] 15. Ha BH, Jeon YJ, Shin SC, et al. Structure of ubiquitin-fold modifier 1-specific protease UfSP2. J Biol Chem 2011;286(12):10248-10257. [http://dx.doi.org/10.1074/jbc.M110.172171]

Accepted 11 June 2014.

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Impact of an educational intervention and clinical performance dashboard on neonatal bloodstream infections M S Raban,1 FCPaed (SA), MPhil Neonatol, Cert Neonatol (SA); C Bamford,2 MB ChB, DCH (SA), MPhil, FCPath (Micro), MMed (Med Micro); Y Joolay,1 FCPaed (SA), MPhil Neonatol, Cert Neonatol (SA); M C Harrison,1 MRCP, FRCPCH 1 2

ivision of Neonatal Medicine, Department of Paediatrics, Faculty of Health Sciences, University of Cape Town, South Africa D National Health Laboratory Service, Groote Schuur Hospital and Division of Medical Microbiology, Department of Clinical Laboratory Sciences, Faculty of Health Sciences, University of Cape Town, South Africa

Corresponding author: M S Raban (shukriraban@yahoo.co.uk)

Background. Blood cultures are the most direct method of detecting bacteraemia. Reducing contamination rates improves the specificity and positive predictive value of the blood culture. Clinical performance dashboards have been shown to be powerful tools in improving patient care and outcomes. Objectives. To determine whether prospective surveillance of bloodstream infections (BSIs), introduction of an educational intervention and the use of a clinical performance dashboard could reduce BSIs and blood culture contamination rates in a neonatal nursery. Methods. We compared two time periods, before and after an intervention. Blood culture data were extracted from the local microbiology laboratory database. The educational intervention included the establishment of hand-washing protocols, blood culture techniques and video tools. A clinical performance dashboard was developed to demonstrate the monthly positive blood culture and contamination rates, and this was highlighted and referred to weekly at the unit staff meeting. Results. Before the intervention, 1 460 blood cultures were taken; 206 (14.1%) were positive, of which 104 (7.1% of the total) were contaminants. In the period following the intervention, 1 282 blood cultures were taken; 131 (10.2%) were positive, of which 42 (3.3% of the total) were contaminants. The number of positive blood cultures and contamination rates after the intervention were both statistically significantly reduced (p=0.002 and p<0.001, respectively). Conclusion. This study demonstrates that adopting a relatively simple educational tool, making use of a clinical performance dashboard indicator and benchmarking practice can significantly reduce the level of neonatal sepsis while also reducing contaminated blood cultures. S Afr Med J 2015;105(7):564-566. DOI:10.7196/SAMJnew.7764

Advances in neonatal intensive care have improved survival of preterm infants.[1] Despite these advances, neonatal infection remains an important cause of mortality, morbidity and prolonged hospital stays.[2,3] Blood cultures are the most direct method of detecting bacteraemia in patients.[4] Contaminated blood culture results can be troublesome for clinicians attempting to determine whether the organism represents a significant infection requiring intervention or is merely a false-positive result with no consequence to the patient. Reducing contamination rates will improve the specificity of the blood culture and result in a higher positive predictive value, resulting in a significantly more useful test.[5] To guide empirical antibiotic treatment, infection surveillance is important to monitor infection rates, patterns of sensitivity profiles and infection control measures. It can also be used for benchmarking practice and for interventional studies.[6] Clinical performance dashboards that present and benchmark performance against a series of key indicators have been shown to be powerful tools in improving patient care and outcomes.[7] We evaluated the impact of prospective surveillance of bloodstream infections (BSIs), the introduction of an educational intervention and the use of a clinical performance dashboard on the total number of BSIs and blood culture contamination rates.

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Methods

The study was conducted at the tertiary-level neonatal unit at Groote Schuur Hospital (GSH), Cape Town, South Africa (SA), over a 31-month period. The study was approved by the Human Research Ethics Committee, Faculty of Health Sciences, University of Cape Town. The total number of blood cultures performed and the number of cultures yielding growth were extracted from the National Health Laboratory Service microbiology laboratory database on a monthly basis. BSI was defined as a positive blood culture including fungal organisms. If multiple blood cultures were taken within a 48-hour period and contained the same organism, we considered this a single BSI. A positive blood culture was considered to be a contaminant if any of the following organisms was detected: alpha-haemolytic streptococci, Micrococcus spp., Propionibacterium spp., Corynebacterium spp., Bacillus spp., and sometimes enterococci and Acinetobacter spp., depending on the clinical status of the patient.[5] In cases of coagulasenegative Staphylococcus-positive blood cultures, the cultures were classified as contaminants if serial serum C-reactive protein levels measured 24 hours apart were <10 mg/L, if repeated blood cultures remained negative, or if the attending clinician did not initiate antibiotic treatment because the infant did not have clinical features of sepsis.[8] We examined and compared two time periods, period 1 (January 2010 - April 2011) before any intervention, and period 2 (May 2011Â -

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July 2012) following the introduction of an educational intervention and use of a clinical performance dashboard. The intervention included written policies prioritising and re-enforcing hand washing and a ‘bare-below-elbows’ approach, establi shing uniform blood culture technique, appropriate antibiotic use, and insertion and management of central lines according to a standardised protocol. Video material was used to demonstrate the techniques described in the above protocols. A clinical performance dashboard was developed as a visual aid to demonstrate the monthly positive blood culture and contamination rates, and this was highlighted and referred to weekly at the neonatal unit staff meeting. We calculated a baseline median for the number of BSIs in the unit for the period January - December 2010. The median was calculated annually and only adjusted if it was less than that in the previous year. This ‘rolling’ median served as the benchmark against which performance was monitored. The clinical performance dashboard provided the nursing and medical staff in the neonatal unit with a real-time, instantaneous picture of their performance with regard to the total number of positive blood cultures and the contamination rates. These data were visually displayed using a colour-coded system: green, when the total number of positive blood cultures was less than the median; blue, when the total number of positive blood cultures equalled the median; and red, when the total number of positive blood cultures breached the median. Fig. 1 illustrates how the dashboard was utilised in the neonatal unit.

Fig. 1. The performance dashboard, a visual indicator tool displayed in the neonatal unit at Groote Schuur Hospital. Values written in green indicate months in which positive cultures were below the median number of positive cultures. Red values are used to indicate months when positive cultures were above the median benchmark.

During period 1, 1 460 blood cultures were taken; 206 (14.1%) were positive, of which 104 (7.1% of the total) were contaminants. During period 2, following the introduction of an educational intervention and use of a clinical performance dashboard, 1 282 blood cultures were taken; 131 (10.2%) were positive, of which 42 (3.3% of the total) were contaminants. There were statistically significant reductions in BSIs (p=0.002) and

Trend of % contaminated cultures

Trend of % positive cultures

Trend of % positive cultures post intervention

30% 25% 20% 15% 10% 5% 0% Jul 2009

Jan 2010

Aug 2010

Feb 2011

Sep 2011

Apr 2011

Oct 2012

Months

Fig. 2. Percentages of positive cultures and contaminants before and after intervention. 130 120

Blood cultures, n

110 100

Total cultures taken Contaminated cultures Linear (positive cultures)

Positive cultures Linear (total cultures taken) Linear (contaminated cultures)

90 80 70 60 50 40 30 20 10 0 Ja n Fe 201 b M 20 0 a 1 Ap r 20 0 1 M r 20 0 a 1 Ju y 20 0 n 1 Ju 20 0 Au l 2 10 g 01 Se 20 0 p 10 O c 20 1 No t 20 0 1 D e v 20 0 c 1 Ja 201 0 n 0 Fe 201 M b 20 1 a 1 Ap r 20 1 1 M r 20 1 a 1 Ju y 20 1 n 1 Ju 20 1 Au l 2 11 g 01 S e 20 1 p 11 O c 20 1 No t 20 1 v 2 11 De 0 c 11 Ja 201 n 1 Fe 201 M b 20 2 a 1 Ap r 20 2 1 M r 20 2 ay 1 Ju 20 2 n 1 Ju 2012 l2 2 01 2

Results

Positive cultures

Trend % contaminated cultures post intervention

35%

Data analysis

The microbiology laboratory data were exported to a Microsoft Excel file. Data were analysed with Stata version 12 (Stata Corporation, USA). Chi-square and Fisher’s exact tests were used for comparison of categorical variables. Descriptive results are expressed as numbers and proportions (%). A p-value of <0.05 was considered significant.

% contaminated cultures

Months

Fig. 3. Monthly trend of total, positive and contaminated blood cultures.

blood culture contamination rates (p<0.001) between the pre- and post-intervention periods. Fig. 2 illustrates the decline in BSIs and blood culture contamination

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rates following the intervention. While the total number of blood cultures taken in the neonatal unit fluctuated from month to month, over the study period the

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general trend between period 1 and period 2 remained unchanged. Importantly, the admission rates and referral patterns remained unchanged during the two study periods, suggesting that the workload and clinical indications for taking the blood culture were similar for period 1 and period 2. Fig. 3 illustrates the relationship between the total number of blood cultures taken, BSIs and contaminated blood cultures.

Study limitations

Discussion

Conclusion

Improving the quality and safety of healthcare services is of para mount importance. Surveillance and monitoring of key indicators is central in achieving this, as it allows for benchmarking and performance comparison. Even more important is identifying and implementing interventions that impact significantly on these key indicators. A rapidly growing body of evidence suggests that quality improvement strategies in a variety of clinical settings, including neonatal care, are effective and improve patient outcomes while also reducing costs.[6] Our study demonstrates a significant measurable reduction in the total number of neonatal BSIs and blood culture contamination rates. This is an important outcome, as Modi and Carr[9] and Stoll et al.[10] documented neonatal BSI rates for all neonates of 10 - 25% and rates as high as 50% in extremely preterm infants. In a recent meta-analysis, Bakhuizen et al.[11] concluded that neonatal BSI is associated with an increased risk of mortality and severe short- and long-term outcomes. Contaminated blood cultures have a significant impact on the patient and, also importantly, on cost. Compared with truly negative cultures, false-positive cultures increase laboratory workload, prolong patient stay and increase the use of broad-spectrum antibiotics, with negative consequences for antibiotic resistance and patient morbidity.[12] The American Society for Microbiology suggests contamination rates of <3% for all blood cultures taken.[5] We reduced the blood culture contamination rate from 7% to 3.3%. Hand washing is recognised as the single most effective method of reducing the transmission of micro-organisms between patients, and is an integral part of hospital infection control measures.[13] Blood culture contamination is a result of poor techniques of hand washing, skin cleaning and venepuncture.[12] An essential part of our stratagem of reducing BSI and contamination was the clinical performance dashboard. The high visual impact of the dashboard permitted nursing and medical staff to benchmark their performance against the set threshold and helped drive performance excellence. The dashboard also served as an excellent communication tool; night staff in particular benefited from this, as they were often unable to attend the neonatal unit staff meetings during normal working hours. The dashboard provided the unit with real-time data allowing us to anticipate and recognise problems earlier (e.g. when BSI results equalled the median or breached the median) and consequently to rectify these problems more timeously.

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This study does have limitations. It did not quantify the impact of the intervention on hospital resource utilisation, particularly length of hospital stay, antibiotic utilisation and cost-effectiveness. In addition, it did not explore the impact that reduction of BSIs and blood culture contamination rates had on mortality and short- and long-term morbidities.

This study demonstrates that adopting a relatively simple educational tool, utilisation of a clinical performance dashboard indicator and benchmarking practice can significantly reduce the level of neonatal sepsis while also reducing contaminated blood cultures. This stratagem was based on intensive collaboration with, and among, all levels of staff over the study period and continues to prove successful in our endeavours to reduce infection rates in the GSH neonatal unit. Given the impact of neonatal BSIs on patient outcomes and hospital resource utilisation, the establishment of local and national neonatal infection surveillance networks, with similar interventions to those we report, is imperative to monitor the epidemiology of neonatal infections in SA and inform policy and clinical practice. Integrating and leveraging quality improvement benchmarks derived from surveillance and monitoring into clinical performance dashboards can drive initiatives aimed at excellence within all spheres of healthcare services, at both local and national levels. References 1. Hack M, Fanaroff AA. Outcomes of children of extremely low birthweight and gestational age in the 1990s. Semin Neonatol 2000;5(2):89-106. [http://dx.doi.org/10.1053/siny.1999.0001] 2. Modi N, Doré CJ, Saraswatula A, et al. A case definition for national and international neonatal bloodstream infection surveillance. Arch Dis Child Fetal Neonatal Ed 2009;94(1):F8-F12. [http:// dx.doi.org/10.1136/adc.2007.126458] 3. Adams-Chapman I, Stoll BJ. Neonatal infection and long-term neurodevelopmental outcome in the preterm infant. Curr Opin Infect Dis 2006;19(3):290-297. [http://dx.doi.org/10.1097/01. qco.0000224825.57976.87] 4. Ruge DG, Sandin RL, Siegelski S, et al. Reduction in blood culture contamination rates by establishment of policy for central intravenous catheters. Lab Med 2002;33(10):797-800. 5. Hall KK, Lyman JA. Updated review of blood culture contamination. Clin Microbiol Rev 2006;19(4):788-802. [http://dx.doi.org/10.1128/CMR.00062-05] 6. Horbar JD, Rogowski J, Plsek PE, et al. Collaborative quality improvement for neonatal intensive care. Pediatrics 2001;107(1):14-22. [http://dx.doi.org/10.1542/peds.107.1.14] 7. Egan M. Clinical dashboards impact on workflow, care quality, and patient safety. Crit Care Nurs Q 2006;29(4):354-361. 8. Weinbaum FI, Lavie S, Danek M, Sixsmith D, Heinrich GF, Mills SS. Doing it right the first time: Quality improvement and the contaminant blood culture. J Clin Microbiol 1997;35(3):563-565. 9. Modi N, Carr R. Promising stratagems for reducing the burden of neonatal sepsis. Arch Dis Child Fetal Neonatal Ed 2000;83(2):F150-F153. [http://dx.doi.org/10.1136/fn.83.2.F150] 10. Stoll BJ, Hansen N, Fanaroff AA, et al. Late-onset sepsis in very low birth weight neonates: The experience of the NICHD Neonatal Research Network. Pediatrics 2002;110(2):285-291. [http://dx.doi. org/10.1542/peds.110.2.285] 11. Bakhuizen SE, de Haan TR, Teune MJ, et al. Meta-analysis shows that infants who have suffered neonatal sepsis face an increased risk of mortality and severe complications. Acta Paediatr 2014;103(12):1211-1218. [http://dx.doi.org/10.1111/apa.12764] 12. Roth A, Wiklund AE, Pålsson AS, et al. Reducing blood culture contamination by a simple informational intervention. J Clin Microbiol 2010;48(12):4552-4558. [http://dx.doi.org/10.1128/ JCM.00877-10] 13. Larson E. Skin hygiene and infection prevention: More of the same or different approaches? Clin Infect Dis 1999;29(5):1287-1294. [http://dx.doi.org/10.1086/313468]

Accepted 15 September 2014.

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Prevalence of Blomia tropicalis allergy in two regions of South Africa A C Jeevarathnum,1 MB BCh, FCPaed (SA), Dip Allerg (SA), MMed (Paed); A van Niekerk,1 MB ChB, MMed (Paed); R J Green,1 MB BCh, DCH (SA), FCPaed (SA), MMed (Paed), FCCP, PhD, Dip Allergy (SA), FAAAAI, FRCP, DSc; P Becker,2 BSc Hons, MSc, PhD; R Masekela,3 MB BCh, MMed (Paed), Dip Allerg (SA), Cert Pulmonol (SA) Paed, FCCP, PhD epartment of Paediatrics and Child Health, Division of Pulmonology, Faculty of Health Sciences, University of Pretoria, South Africa D Faculty of Health Sciences, University of Pretoria, South Africa 3 Department of Maternal and Child Health, School of Clinical Medicine, College of Health Sciences, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa 1 2

Corresponding author: R Masekela (masekelar@ukzn.ac.za)

Background. Asthma and allergic rhinitis affect 15% and 38% of South African (SA) children, respectively. The housedust mite (HDM) is the most significant indoor aeroallergen. Typical HDM species include Dermatophagoides pteronyssinus, D. farinae and Blomia tropicalis. Conventional skin-prick testing (SPT) panels only test for Dermatophagoides. B. tropicalis has been described in the tropical and subtropical regions, but is not routinely tested for in SA. Objective. To ascertain the significance of B. tropicalis as an aeroallergen in northern coastal KwaZulu-Natal Province (KZN), a tropical environment, and in Johannesburg in the highveld, where the climate is milder and less humid. Methods. Children aged 1 - 18 years with features of allergic rhinitis and/or asthma were recruited over a 6-month period from Alberlito Hospital in northern KZN and the Clinton Clinic in Johannesburg. SPTs included Dermatophagoides and B. tropicalis. Sensitisation was defined as a wheal 3 mm greater than the negative control. Results. Eighty-five subjects were included, 50 in northern KZN and 35 in the Johannesburg arm; 52% of subjects in northern KZN and 3% in Johannesburg were sensitised to B. tropicalis, with a significant difference between these centres (p<0.05). Of the 52% sensitised to B. tropicalis in northern KZN, half were sensitised only to B. tropicalis. Conclusion. There is a high prevalence of B. tropicalis allergy in the tropical northern KZN region and a much lower prevalence in the Johannesburg region. Routine testing for B. tropicalis allergy should be employed in northern KZN. S Afr Med J 2015;105(7):567-569. DOI:10.7196/SAMJnew.7786

Atopy and allergic disease form part of an expanding field of medicine and include conditions such as asthma, allergic rhinitis, allergic conjunctivitis, atopic eczema and food and drug allergies, to name just a few. The prevalences of allergic rhinitis and asthma among South African (SA) children are as high as 38.5% and 15%, respectively.[1,2] Asthma and allergic rhinitis are closely linked, and physicians are well aware of this link in the form of the ‘united airway’ theory.[3] It has been well described that co-management of these two conditions will reduce disease severity and improve quality of life.[3] Aeroallergens have been implicated in the pathophysiology of both these disease processes.[4] Those implicated include housedust mite (HDM), grass, mould and cockroach, among others. However, HDM allergy is the most important indoor aeroallergen in SA, affecting allergic patients with asthma and allergic rhinitis.[4-6] One study in the Durban region found the incidence of HDM allergy among asthmatics to be as high as 95%.[7] Worldwide, there are a number of HDM species involved in these atopic disease processes. These include Dermatophagoides pteronyssinus, D. farinae, Euroglyphus maynei and Blomia tropicalis. The prevalence of these mite species differs geographically.[8] Dermatophagoides spp. occur worldwide, and prefer a warm and temperate climate with humidity of >55%.[8] Generally the prevalence of D. pteronyssinus is higher in areas with higher humidity than that required by D. farinae. Australia, New Zealand,

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the UK and Mauritius have a predominance of D. pteronyssinus,[9] while D. farinae predominates in South Korea, Jakarta, Indonesia and Italy.[9] E. maynei is thought to occur worldwide, but it has been poorly studied and the exact incidence and predominance are unknown.[8] B. tropicalis is thought to occur most commonly in the tropical and subtropical regions of the world, such as Singapore, Malaysia, the Philippines and Hong Kong.[9] B. tropicalis allergy can be proven via in vivo or in vitro methods. In vivo methods involve use of skinprick testing (SPT) and in vitro methods use of ImmunoCAP (ThermoFisher) assays. The SPT and ImmunoCAP test panels currently in use for the identification of HDM allergy in SA test only for Dermatophagoides spp. unless specifically requested. Dermatophagoides is therefore the most studied HDM species in SA, and data relating to the other species are poorly defined. There is limited cross-reactivity between Dermatophagoides spp. and B. tropicalis, both on SPTs in vivo and IgE binding on ImmunoCAP studies in vitro.[10-12] However, there is marked crossreactivity between D. pteronyssinus and D. farinae on both tests.[11,12] It therefore stands to reason that a positive SPT for D. pteronyssinus or D. farinae does not indicate a positive result for B. tropicalis, and individual testing for B. tropicalis is necessary to prove B. tropicalis allergy. Current testing practices in SA do not include B. tropicalis testing other than in the Western Cape region.[2] Specific immunotherapy offers the only potential cure for HDM allergy. Immunotherapy can comprise either sublingual or subcutaneous therapy, both of which have been found to be effective

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in the treatment of HDM allergy.[2] However, separate reagents for Dermatophagoides and Blomia are required. Current routine testing will not identify patients who suffer from B. tropicalis allergy, and the correct immunotherapy will therefore not be ordered for patients who need it. However, these patients can potentially be cured if a diagnosis of B. tropicalis allergy is made. B. tropicalis should be individually tested for in areas of the world in which it is highly prevalent.[10] If the parts of SA in which B. tropicalis is of significance can be identified, testing in these regions can be advocated.

Objective

Table 1. Characteristics of all participants with asthma and allergic rhinitis included in the study Variable

Johannesburg

KZN

Patients, n

Age (years), mean (range)

7.4 (1 - 18)

7.4 (1 - 15)

Gender (M/F), n

27/8

30/20

Dermatophagoides (%)*

22.9

40.0

B. tropicalis (%)*

2.9

52.0

A retrospective cross-sectional study design was employed. The study was undertaken at two private paediatric practices run by AVN, one situated at the Clinton Clinic in Johannesburg and the other at Alberlito Hospital in northern KZN. All the patients who presented with features of allergic rhinitis and/or asthma and had SPTs for aeroallergens between September 2013 and February 2014 were included in the study. Only SPTs were utilised in this study to confirm sensitisation. Two reagents were utilised for the SPTs at both centres to test specifically for HDM allergy. Both are manufactured by Stallergenes, France. The first was the conventional reagent used by most centres in SA that test for D. pteronyssinus and D. farinae allergy (D. pteronyssinus and D. farinae mix). The second was a specific reagent that tested for B. tropicalis allergy specifically. A positive SPT result was defined as a wheal 3 mm greater than the negative control.

Statistical analysis

For both B. tropicalis and D. pteronyssinus/D. farinae, data were reported by province and the proportions of positive tests along with 95% confidence intervals (CIs). Comparisons between the two settings with respect to the proportions of positive B. tropicalis and D. pteronyssinus/D. farinae tests, respectively, were done using Fisher’s exact test. The association between allergens and site was expressed in terms of odds ratios with 95% CIs. Testing was done at the 0.05 level of significance.

Ethical considerations

Full ethical approval was obtained from the Faculty of Health Sciences Research Ethics Committee of the University of Pretoria. Consent for use of clinical data was obtained from AVN, who was the primary physician at both study sites.

Results

A total of 87 charts from the two centres were screened; two were excluded because only ImmunoCAP testing for inhaled allergens was performed and not SPT analysis. All the patients were between 1 and 18 years of age, with a male-to-female ratio of 2:1 (Table 1). The mean age of the study population was 7.4 years. There was sensitisation to Dermatophagoides in 40.0% (95% CI 26.4 - 54.8) of children in the Alberlito arm as opposed to 22.9% (95% CI 10.4 - 40.1) in the Clinton Clinic arm (Fig. 1). The

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Negative 35 30 25 20 15 10 5 0

Positive

27 20 8

Coastal KZN

Johannesburg

Fig. 1. A comparison between positive SPTs for Dermatophagoides spp. at Alberlito Hospital (KZN) and Clinton Clinic (Johannesburg). Negative Positive skinprick tests, n

Methods

40 35 30 25 20 15 10 5 0

Positive

34 24

1 Coastal KZN

Johannesburg

Fig. 2. A comparison between positive SPTs for B. tropicalis at Alberlito Hospital (KZN) and Clinton Clinic (Johannesburg). Patients sensitised to mites, n

To determine the significance of B. tropicalis allergy among patients with allergic rhinitis and/or asthma in two different regions of SA, namely the northern coastal region of KwaZulu-Natal province (KZN) and the Johannesburg area. The northern KZN region is located at sea level and has a warm subtropical climate all year round. Johannesburg is situated in the highveld at 1 753 m above sea level, and the climate is milder and dry during most of the year.

Positive skinprick tests, n

*% of patients with sensitisation to the specific HDM.

60 50 17

40 30

20 10 0

7 13 Coastal KZN Blomia

Dermatophagoides

1 7 0 Johannesburg B+D

Nil

Fig. 3. A summary of sensitisation to B. tropicalis and Dermatophagoides mites according to site.

difference between the two groups was not statistically significant (p=0.077). For B. tropicalis there was sensitisation in 52.0% (95% CI 37.4 - 66.3) of children in the Alberlito arm as opposed to 2.9% (95% CI 0.1 - 14.9) in the Clinton Clinic arm (Fig. 2). The difference between the two groups was statistically significant (p<0.001). On further analysis of the 33 patients in the Alberlito arm who tested positive for any HDM, 13/50 (26.0%) tested positive for only B. tropicalis, 7/50 (14.0%) positive for only Dermatophagoides spp., and 13/50 (26.0%) positive for both

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Blomia and Dermatophagoides (Fig. 3). In contrast, on analysis of the 8 patients in the Clinton Clinic group sensitised to any HDM, 7/35 (20.0%) tested positive only for Dermatophagoides and 1/35 (2.9%) tested positive for B. tropicalis. The only patient who tested positive for B. tropicalis was also positive for Dermatophagoides.

Discussion

This study demonstrates that allergy to Dermatophagoides spp. occurs both on the subtropical northern KZN coast of SA and in the temperate highveld region, with no statistical difference between the two regions. However, the proportion of B. tropicalis sensitisation was significantly higher in northern KZN, with 52% of individuals as opposed to only 2.9% for the highveld. Previous studies have shown a higher prevalence of HDM allergy (Dermatophagoides spp.) along the coastline of SA compared with the highveld region.[5,6] However, the current study showed no statistical difference in the prevalence of Dermatophagoides between the KZN coast and the highveld. Reasons for the high prevalence of Dermatophagoides spp. in all regions include indoor heating in highveld houses, favouring proliferation of the mites. From this study it is evident that Dermatophagoides plays a significant role in allergic rhinitis and asthma among children both in the highveld and on the KZN coast. Guidelines should therefore require that routine testing for Dermatophagoides spp. is employed all over SA. Around the world, B. tropicalis is abundant in the tropical and subtropical regions where there is high humidity and warm temperatures. One of the reasons Blomia is so prevalent along the KZN coastline may be the weather patterns in this region. The northern KZN area is located at sea level and has a humid climate much like that experienced in the tropical and subtropical belt. The warm Mozambique current that flows along the coast is responsible for warmer seas, warmer temperatures and higher humidity.[7] This warm and humid climate is much like that in the subtropical belt and could explain the high prevalence of B. tropicalis along this coastline. A 2010 study in Mexico City, which does not have a temperate climate, showed B. tropicalis allergy to be highly prevalent in patients with allergic rhinitis and asthma.[13] It therefore seems possible that there may be reasons in addition to humidity and temperature why Blomia may become significant in a particular area. Further studies are required to determine these reasons. Routine testing for B. tropicalis is suggested in warm, tropical environments.[10] There are no formal studies from SA that describe the exact incidence of this mite in different regions of the country. According to expert opinion, 40% of allergic patients in the Western Cape are estimated to be allergic to B. tropicalis. Further studies to delineate the exact importance of B. tropicalis in this region are under way.[5,6] We have demonstrated that another region in SA, namely northern KZN, also has a high prevalence of HDM sensitisation (66.0% overall). B. tropicalis prevalence is high, with 26.0% of new subjects presenting with features of allergic rhinitis or asthma being sensitised to both Blomia and Dermatophagoides and 26.0% to Blomia alone. The routine testing currently employed in SA, either by in vivo or in vitro methods, would miss these cases. B. tropicalis requires a specific reagent during SPT analysis. This is not usually included in most SPT panels for aeroallergens done in SA. The ImmunoCAP screening assay most commonly done for inhaled allergens in SA is the Phadiatop assay. While this is an excellent screening tool for the diagnosis of aeroallergen sensitisation in SA, and includes testing for grass, trees, cockroach,

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cat, dog and HDM, it tests only for allergy to Dermatophagoides spp. and not to Blomia. Since neither routine SPTs nor the Phadiatop assay screen for B. tropicalis allergy, current testing strategies are deficient in view of our finding of a high prevalence of Blomia sensitisation in northern KZN. One of the strategies for treatment of allergic disease is avoidance of the known allergen. However, HDM allergen avoidance is not an option because HDMs are so abundant in the indoor environment. [2] As avoidance strategies are not possible, definitive treatment for HDM allergy, with the possibility of a cure, can be undertaken in the form of immunotherapy. Just as the diagnosis of HDM allergy differs between Dermatophagoides and Blomia, with specific regents required on SPT analysis, so too does immunotherapy for the two species differ, particular agents being required for each species. If routine testing is employed for Blomia in the northern KZN region, patients who are allergic to it can be offered the appropriate immunotherapy.

Study strengths and limitations

One of the strengths of this study is that it utilised SPT and not ImmunoCAP testing. SPT is a much more affordable option and can therefore be done on a wider scale. However, the specific reagent for Blomia should be included in highly prevalent areas. The study is limited by the relatively small sample size and the relatively short period of time during which it was conducted. It also has geographical limitations in that it only involved two private paediatric practices in the each of the regions investigated.

Recommendations

It is recommended that more studies be undertaken to ascertain the significance of B. tropicalis as an aeroallergen in coastal and tropical parts of SA. This would offer a countrywide assessment of the prevalence of B. tropicalis and indicate those areas in which it should be routinely tested for.

Conclusion

There is a high prevalence of B. tropicalis allergy in tropical northern KZN and a much lower prevalence in the non-tropical Johannesburg region. Routine testing for B. tropicalis allergy should be employed in northern KZN. References 1. Motala C, Green RJ, Manjra AI, Potter PC, Zar HJ. Guidelines for the management of chronic asthma in children: 2009 update. S Afr Med J 2009;99(12):898-912. 2. Manjra AI. Allergic rhinitis in children. CME 2011;29(1):25-29. 3. Green RJ, Hockman M, Friedman R, et al. Allergic rhinitis in South Africa: 2012 Guidelines. S Afr Med J 2012;102(8):693-696. [http://dx.doi.org/10.7196/samj.5810] 4. Potter PC. Allergic evaluation and management of the atopic patient. S Afr Fam Pract 2008;50(5):1826. [http://dx.doi.org/10.1080/20786204.2008.10873755] 5. Potter PC. Overview of the indigenous allergens of South Africa. Curr Allergy Clin Immunol 2007;20(4):174-176. 6. Potter PC, Davis G, Manjra A, Luyt D. House dust mite allergy in South Africa – historical perspective and current status. Clin Exp Allergy 1996;26(2):132-137. [http://dx.doi.org/10.1111/j.1365-2222.1996. tb00071.x] 7. Potter PC. Common indoor and outdoor aero-allergens in South Africa. CME 2010;28(9):426-430. 8. Arlian LG, Morgan MS, Neal JS. Dust mite allergens: Ecology and distribution. Curr Allergy Asthma Rep 2002;2(5):401-411. [http://dx.doi.org/10.1007/s11882-002-0074-2] 9. Thomas WR. Geography of house dust mite allergens. Asian Pac J Allergy Immunol 2010;28(4):211224. 10. Caraballo L, Puerta L, Matrinez B, Moreno L. Identification of allergens from the mite Blomia tropicalis. Clin Exp Allergy 1993;24(11):1056-1060. [http://dx.doi.org/10.1111/j.1365-2222.1994.tb02743.x] 11. Chew FT, Yi FC, Chua KY, Fernandez-Caldas E, et al. Allergenic differences between the domestic mites Blomia tropicalis and Dermatophagoides pteronyssinus. Clin Exp Allergy 1999:29(7):982-988. [http://dx.doi.org/10.1046/j.1365-2222.1999.00543.x] 12. Farnandez-Caldas, Lockey RF. Blomia tropicalis, a mite whose time has come. Allergy 2004;59(11):11611164. [http://dx.doi.org/10.1111/j.1398-9995.2004.00727.x] 13. Martinez JNE, Aquilar AD, Rojas RE. Sensitization to Blomia tropicalis and Dermatophagoides pteronyssinus, farinae and siboney prevalence in patients with rhinitis, allergic asthma, or both, in a population of a metropolitan area of Mexico City. Rev Alerg Mex 2010;57(1):3-10.

Accepted 13 January 2015.

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Nodular thyroid disease and thyroid malignancy: Experience at Polokwane Mankweng Hospital Complex, Limpopo Province, South Africa M M Z U Bhuiyan, FRCSG, MMed; A Machowski, MD, PhD Department of General Surgery, Polokwane Mankweng Hospital Complex and Faculty of Health Sciences, University of Limpopo, Polokwane campus, Limpopo Province, South Africa Corresponding author: M M Z U Bhuiyan (bhuiyanmirza@gmail.com)

Background. Nodular thyroid disease is common throughout the world. Numbers of patients with goitre are increasing worldwide, as also noted in Limpopo Province, South Africa (SA). Globally, thyroid nodules have been reported in 4 - 7% of the population on neck palpation and in 30 - 50% by ultrasonography. Objectives. To review the profile of thyroid disease in patients with goitre presenting to the Department of Surgery at Polokwane Mankweng Hospital Complex (PMHC), Limpopo, SA, to characterise the pattern of malignancy in patients with goitre, and to determine the most common thyroid cancer. Method. A 6-year retrospective study (2003 - 2008) of all patients with thyroid nodules who underwent thyroid surgery at PMHC. Results. The study group included 90 patients (mean age 45 years, range 4 - 80). The male-to-female ratio was 1:17 (5 men, 85 women). Of these patients, 80 (89.9%) had benign lesions, of which 52 (57.8% of the total) were adenomas, 25 (27.8%) multinodular goitres (MNGs), 2 (2.2%) hyperplastic nodules and 1 (1.1%) Hashimoto’s thyroiditis. Ten patients (11.1%) had malignant lesions (7 follicular carcinomas and 3 papillary carcinomas), of which 2 were found in MNGs. Conclusions. Adenoma and MNG were the predominant non-malignant conditions (85.6%). The prevalence of thyroid cancer in our study was 11.1%, and of all 90 patients, 7.8% had follicular carcinoma. The risk of malignancy in MNG was 8.9%. Rates of thyroid nodules and carcinoma were highest in women aged 41 - 60 years. We advocate that total thyroidectomy be considered for MNG, because MNG can harbour incidental carcinoma. S Afr Med J 2015;105(7):570-572. DOI:10.7196/SAMJnew.7885

Nodular thyroid disease is common throughout the world, and the incidence has been rising in recent decades. Worldwide, thyroid nodules have been reported in 4 - 7% of the population on neck palpation and in 30 - 50% when investigated by ultrasonography.[1,2] Usually patients with nodular thyroid disease present to a surgical clinic with a neck mass, with or without toxic symptoms, with pressure symptoms or for cosmetic reasons. Treatment options depend on the cause and the clinical presentation and include medication, radioactive iodine and surgery. Thyroid nodules can be benign (adenoma, nodules of multinodular goitres (MNGs), or localised thyroiditis, including autoimmune disease and cysts) or malignant (papillary adenocarcinoma, follicular adenocarcinoma, medullary carcinoma, undifferentiated carci noma or lymphoma). In the hands of experienced surgeons, surgery for nodular thyroid disease has low mortality and morbidity.[3] Operations include lobectomy/hemithyroidectomy, subtotal thyroidectomy and total thyroidectomy. There has been no formal study on these diseases in Limpopo Province, South Africa (SA), which has a population of 5.5 million.

Objectives

To review the profile of thyroid disease in patients with goitre who presented to the Department of Surgery at Polokwane Mankweng Hospital Complex (PMHC), tertiary hospitals in Limpopo, to characterise the pattern of malignant disease in patients presenting with goitre, and to determine the most common thyroid cancer in the Limpopo population study group.

Methods

A 6-year retrospective study (2003 - 2008) of all patients with thyroid nodules who underwent thyroid surgery at PMHC was done. All the patient files were reviewed, and cases in which histological results were not available were excluded. Data were collected from the theatre and hospital information systems, the National Health Laboratory Service and the patient files.

Results

Of 117 patient files, 27 lacked histological results and were excluded from the study. The study group therefore consisted of 90 patients, ranging in age from 4 to 80 years (mean 45); 85 (94.4%) were women and 5 men (5.6%) (male-to-female ratio 17:1). Thyroid function tests were done in all cases, ultrasound scans in 42, isotope nuclear

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scans in 59 and fine-needle aspiration cytology (FNAC) in 11. The histopathological diagnoses in all 90 patients are shown in Table 1. Indications for surgery were cosmetic reasons, suspected malignancy, and compression of adjacent areas. Surgical operations included 53 lobec tomies, 31 subtotal thyroidectomies and 6 total thyroidectomies. There were no operative deaths. Ten patients (11.1% of the total) had malignant lesions (7 follicular Table 1. Histopathological diagnoses of thyroid lesions (N=90) Histological findings

Patients n (%)

Benign conditions Adenoma

52 (57.8)

MNG

25 (27.8)

Hyperplastic nodules

2 (2.2)

Hashimoto’s thyroiditis

1 (1.1)

Subtotal

80 (88.9)

Malignant conditions Follicular carcinoma

7 (7.8)

Papillary carcinoma

3 (3.3)

Subtotal

10 (11.1)

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Table 2. Demographics of patients with benign and malignant thyroid lesions Benign disease n (%)

Malignant disease n (%)

Males

4/5 (80.0)

1/5 (20.0)

Females

76/85 (89.4)

9/85 (10.6)

≤20

21 - 40

1/28 (3.6)

41 - 60

7/50 (14.0)

>60

2/11 (18.2)

Demographic Gender

p-value 0.453*

Age group (years)

0.259*

*Fisher’s exact test.

carcinomas and 3 papillary carcinomas). There were 80 patients (88.9%) with benign lesions, of which 52 (57.8% of the total) were adenomas, 25 (27.8%) MNGs, 2 (2.2%) hyperplastic nodules and 1 (1.1%) Hashimoto’s thyroiditis. Two papillary carcinomas were found in MNGs (8.0% of MNGs). Of all the patients, 7.8% had follicular carcinoma (7 cases). Adenomas and MNGs were the most common non-malignant conditions, occurring in 77 patients (85.6%). In our study, thyroid nodules, whether benign or malignant, occurred more frequently in women (94.4%) than in men. The age group most affected was 41 - 60 years (Table 2).

Discussion

The prevalence of thyroid nodules is rising globally. According to the World Health Organization, at least 1.6 billion people are at risk of iodine deficiency disorders, and of these 655 million are affected by goitre.[4] Most thyroid nodules are benign. The worldwide prevalence of MNG in the general population is estimated to be 4 - 7%, and these lesions are often caused by iodine deficiency.[5] The incidence of thyroid malignancy ranges from 0.9% to 20.5% in different parts of the world.[6,7] Globally, the most common thyroid cancer is papillary carcinoma.[8,9] Follicular carcinoma, while relatively less frequent, is reported to be more common in iodine-deficient areas where MNG is endemic.[10-17] Thyroid cancer is the most common endocrine carcinoma, and the risk factors for malignancy are age <30 or >60 years, male gender (8% males v. 4% females),[2,18] and a history of irradiation to the head and neck.[19] Limpopo Province is located far from the sea, and the iodine content in the diet is low. Our 11.1% rate of thyroid cancer in Limpopo is consistent with the literature.[6,7] In our study, the predominant thyroid cancer was follicular carcinoma (7.8% of patients), comparable to reports from Durban and Burkina Faso.[20-22] The two cancers in MNGs in our study were papillary carcinomas. The risk of malignancy in cases of MNG in our study was 8.9%, similar to findings reported in the literature of 2 - 12%.[6,8,10,23-27] Although there were few males in our study, figures indicate that men are at twice the risk of developing cancer compared with females. FNAC was not reliable in Limpopo; as a result we could not use it regularly, so it is difficult to draw conclusions in this regard. Cytology reports for our 11 patients who underwent FNAC fell into categories 1 - 3 of the Bethesda classification.[28] On histological examination, these lesions were found to be non-malignant. The value of FNAC in thyroid cancers and thyroid nodules is well established,[29-31] including

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at PMHC. It is known that the rate of false-negative results for FNAC ranges from 0.7% to 2.2% if ultrasound-guided FNAC is used,[32,33] the rate rising to 44.7% without ultrasonography.[10,21,34-39] FNAC significantly reduces the number of unnecessary operations,[30,31,40] but the problem of its missing malignant lesions remains unsolved. Five of our 59 patients who had isotope nuclear scans were suspected to have a malignant lesion, but in only one case was carcinoma histologically confirmed, which is similar to previously reported findings.[41] Radioisotope investigations for malignant disease have an important role, but only if they are taken together with clinical findings and other investigations such as ultrasonography, FNAC, computed tomography, magnetic resonance imaging or positron emission tomography.[7,42] Benign thyroid disorders are common, and often affect younger females. Subtotal thyroidectomy/hemithyroidectomy are the surgical procedures most frequently offered.[21,43,44] In our study the majority of patients were females, in whom benign conditions predominated; the operations performed were either lobectomy or subtotal thyroidectomy. The approach to the surgical management of benign goitre is progressively becoming more radical owing to the risk of recurrent goitre[3] and the safety of surgery.[30,45-48] Furthermore, the rate of incidental malignancy in MNG is high (8.9% in our study), and re-operation for recurrent goitre following subtotal thyroidectomy is associated with a significantly increased risk of permanent recurrent laryngeal nerve injury.[48]

Conclusions

Adenoma and MNG were the most common non-malignant conditions in our study (85.6%). The prevalence of thyroid cancer in our study was 11.1%, and of all the lesions 7.8% were follicular carcinomas. Malignant lesions were found in 8.9% of patients with MNG. We advocate that total thyroidectomy be considered for MNG because of the risk of incidental carcinoma. Acknowledgements. We are grateful to Dr B Interewicz and Mrs Maggi Landman for their contribution to data collection, and to Dr F L M Hyera for his valuable comments on this manuscript. We thank Mr S Ntuli for statistical assistance. References 1. Pang H-N, Chen C-M. The incidence of cancer in nodular goiters. Ann Acad Med Singapore 2007;36(4):241-243. 2. Belfiore A, La Rosa GL, Padova G, Sava L, Ippolito O, Vigneri R. The frequency of cold thyroid nodules and thyroid malignancies in patients from an iodine-deficient area. Cancer 1987;60(12):3096-3102. [http://dx.doi.org/10.1002/1097-0142(19871215)60:12<3096::AID-CNCR2820601240>3.0.CO;2-V] 3. Schmitz-Winnenthal FH, Schimmack S, Lawrence B, et al. Quality of life is not influenced by the extent of surgery in patients with benign goiter. Langenbecks Arch Surg 2011;396(8):1157-1163. [http://dx.doi.org/10.1007/s00423-011-0822-7] 4. WHO reaffirms goal for sustainable IDD elimination. IDD Newsletter 1996;12(7):1-3. 5. Bron IP, O’Brien CJ. Total thyroidectomy for clinically benign disease of the thyroid gland. Br J Surg 2004;91(5):569-574. [http://dx.doi.org/10.1002/bjs.4507] 6. Najum ul Haq R, Ali Khan B, Ahmed Chaudhry I. Prevalence of malignancy in goiter – a review of 718 thyroidectomies. J Ayub Med Coll Abbottabad 2009;21(4).315-21 7. Czepczyński R. Nuclear medicine in the diagnosis of benign thyroid diseases. Nucl Med Rev Cent East Eur 2012;15(2):113-119. 8. Hanumanthappa MB, Gopinathan S, Rithin S, et al. Incidence of malignancy in multi-nodular goitre: A prospective study at a tertiary academic centre. J Clin Diagn Res 2012;6(2):267-270. [http://dx.doi. org/ JCDR/2012/4048:1955] 9. Pisanu A, Reccia I, Nardello O, Uccheddu A. Risk factors for nodal metastasis and recurrence among patients with papillary thyroid microcarcinoma: Differences in clinical relevance between nonincidental and incidental tumors. World J Surg 2009;33(3):460-468. [http://dx.doi.org/10.1007/ s00268-008-9870-8] 10. Bombil I, Bentley A, Kruger D, Luvhengo TE. Incidental cancer in multinodular goitre post thyroidectomy. S Afr J Surg 2014;52(1):5-9. [http://dx.doi.org/ 10.7196/SAJS.1970] 11. Woodruff SL, Arowolo OA, Akute OO, et al. Global variation in the pattern of differentiated thyroid cancer. Am J Surg 2010;200(4):462-466. [http://dx.doi.org/10.1016/j.amjsurg.2010.03.009] 12. Thyroid Cancer. American Cancer Society. Updated 20 January 2012. http://www.cancer.org/acs/ groups/cid/documents/webcontent/003144-pdf.pdf (accessed 8 March 2012). 13. Takashima S, Sone S, Takayama F, et al. Papillary thyroid carcinoma: MR diagnosis of lymph node metastasis. AJNR Am J Neuroradiol 1998;19(3):509-513. 14. Doherty G. Current Diagnosis and Treatment Surgery. 13th ed. (Lange Current Series). New York: McGraw-Hill Medical, 2009.

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33. Grant CS, Hay ID, Gough IR, et al. Long term follow-up of patients with benign thyroid: Fine needle aspiration cytologic diagnosis. Surgery 1989;106(6):980-985. 34. Mistry SG, Mani N, Murthy P. Investigating the value of fine needle aspiration cytology in thyroid cancer. J Cytol 2011;28(4):185-190. [http://dx.doi.org/10.4103/0970-9371.86345] 35. Perros P, ed. Report of the Thyroid Cancer Guidelines Update Group: Guidelines for the Management of Thyroid Cancer. 2nd ed. London: Royal College of Physicians, 2007. 36. Cobin RH, Gharib H, Bergman DA, et al. AACE/AAES medical/surgical guidelines for clinical practice: Management of thyroid carcinoma. American Association of Clinical Endocrinologists. American College of Endocrinology. Endocr Pract 2001;7(3):202-220. 37. Kopald KH, Layfield LJ, Mohrmann R, Foshaq LJ, Giuliano AE. Clarifying the role of fineneedle aspiration cytologic evaluation and frozen section examination in the operative management of thyroid cancer. Arch Surg 1989;124(10):1201-1205. [http://dx.doi.org/ 10.1001/ archsurg.1989.01410100107018.] 38. Gharib H. Fine-needle aspiration biopsy of thyroid nodules: Advantages, limitations, and effect. Mayo Clin Proc 1994;69(1):44-49. 39. Jeffrey PB, Miller TR. Fine-needle aspiration cytology of the thyroid. Pathology (Phila) 1996;4(2):319-335. 40. Netea-Maier RT, Aben KKH, Casparie MK, et al. Trend in incidence and mortality of thyroid carcinoma in the Netherlands between 1989 and 2003: Correlation with thyroid fine needle aspiration cytology and thyroid surgery. Int J Cancer 2008;123(7):1681-1684. [http://dx.doi. org/10.1002/ijc.23678] 41. Sabel MS, Staren ED, Gianakakis LM, Dwarakanathan S, Prinz RA. Effectiveness of thyroid scan in evaluation of the solitary thyroid nodule. Am Surg 1997;63(7):660-663. 42. Khanzada TW, Memon W, Kumar B, Samad A. Thyroid scintigraphy: An overused investigation. Gomal Journal of Medical Sciences 2009;7(1):39-41. 43. Saaiq M, Shah SA, Zubair M. Clinical audit of the presentation and outcome of benign thyroid disorders in a tertiary care setting in Pakistan. J Pak Med Assoc 2013;63(9):1172-1175. 44. Hossain MM, Haque MR, Rashid A, et al. Surgical management of thyroid diseases – a study of 78 cases. Mymensingh Med J 2002;11(1):6-8. 45. Colak T, Akca T, Kanik A, Yapici D, Avdin S. Total versus subtotal thyroidectomy for the management of benign multinodular goiter in an endemic region. Aust N Z J Surg 2004;74(11):974-978. [http:// dx.doi.org/10.1111/j.1445-1433.2004.03139.x] 46. Gál I, Solymosi T, Lukács-Tóth G, Wéber G. [Effectiveness and safety of total thyroidectomy in the management of benign multinodular goiters]. Magy Seb 2013;66(5):245-249. [http://dx.doi. org/10.1556/MaSeb.66.2013.5.3] 47. Rudolph N, Dominguez C, Beaulieu A, de Wailly P, Kraimps JL. The morbidity of reoperative surgery for recurrent benign nodular goitre: Impact of previous unilateral thyroid lobectomy versus subtotal thyroidectomy. J Thyroid Res 2014;2014:231857. [http://dx.doi.org/10.1155/2014/231857] 48. Barczyński M, Konturek A, Hubalewska-Dydejczyk A, Gołkowski F, Cichoń S, Nowak W. Five-year follow-up of a randomized clinical trial of total thyroidectomy versus Dunhill operation versus bilateral subtotal thyroidectomy for multinodular nontoxic goiter. World J Surg 2010;34(6):1203-1213. [http://dx.doi.org/10.1007/s00268-010-0491-7]

Accepted 3 April 2015.

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Household fuel use and child respiratory ill health in two towns in Mpumalanga, South Africa P N Albers,1,2 MSc; C Y Wright,1,3,4 PhD; K V V Voyi,2 PhD; A Mathee,1,5 PhD nvironment and Health Research Unit, Medical Research Council, Johannesburg, South Africa E School of Health Systems and Public Health, Faculty of Health Sciences, University of Pretoria, South Africa 3 Climate Studies, Modelling and Environmental Health Research Group, Council for Scientific and Industrial Research, Pretoria, South Africa 4 Department of Geography, Geoinformatics and Meteorology, Faculty of Natural and Agricultural Sciences, University of Pretoria, South Africa 5 Faculty of Health Sciences, University of Johannesburg, South Africa 1 2

Corresponding author: P N Albers (pnalbers@gmail.com)

Background. This cross-sectional study examined respiratory health outcomes and associated risk factors in children living in a part of South Africa characterised by high levels of air pollution. Methods. A questionnaire was used to collect self-reported respiratory health and risk factor data from the parents/guardians of children between the ages of 9 and 11 years attending primary schools in the study area. Six government schools were selected based on their location, class size and willingness to participate. Univariate and bivariate analyses as well as logistic regression analysis were performed on the data, using a p-value of 0.25 and biological plausibility. Results. The overall prevalence of respiratory ill-health symptoms was 34.1%. The prevalence of respiratory ill-health conditions was significantly elevated among children from households using non-electrical fuels v. electricity for cooking (43.9% v. 31.6%; adjusted p-value 0.005). The same was noted among those using non-electrical fuels for heating (37.8% v. 29.0%). Conclusion. The elevated prevalence of some respiratory health outcomes among schoolchildren, especially in conjunction with domestic fossil fuel burning, is of concern. The data collected in this study may be used to complement or form a basis for future policy regarding indoor or ambient air quality in the area. S Afr Med J 2015;105(7):573-577. DOI:10.7196/SAMJnew.7934

Children are particularly vulnerable with regard to exposure to both indoor and outdoor air pollution. They are also a high-risk group in terms of the illhealth outcomes associated with exposure to poor air quality. Their elevated vulnerability is attributable to their spending a relatively high proportion of their time in the home environment, which in South Africa (SA) may be an important source of air pollution from the combustion of solid and liquid fuels for daily cooking and space heating. Children also spend much time engaged in play and physical activities that cause them to breathe deeply and at an increased rate.[1] In addition to the combustion of fossil fuels, indoor air quality may be affected by factors such as indoor smoking, emissions of volatile organic compounds from home furnishing and dĂŠcor materials, poor ventilation, and the presence of mould and pests. Indoor air quality may also be affected by outdoor risk factors such as the proximity of dwellings to heavily used roads and proximity to industrial sites, power plants or mine tailings dams.[2,3] For example, Dong et al.[2] found an association between respiratory morbidity in children and their proximity to traffic-related air pollution. In developing countries such as SA, the indoor combustion of fossil fuels and the associated decline in indoor air quality is a major public health concern. According to a census undertaken in SA in 2011, around 26% of households still use fuels other than electricity for daily cooking.[4] A recent review on household air pollution and child survival concluded that reducing household air pollution could reduce the risk of acute lower respiratory infections (including severe and fatal pneumonia), low birth weight and stillbirth by up to 35%.[5] A risk factor analysis study undertaken in 2002 conservatively indicated

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that just over 1% of the burden of mortality in young children resulted from exposure to indoor air pollution,[6] while a burden of disease study carried out in SA in 2012 showed that lower respiratory tract infections ranked among the top five causes of mortality in children under the age of 4 years.[7]

Objective

To undertake a cross-sectional analysis of domestic fuel use and child respiratory health and associated risk factors in two towns in Mpumalanga Province, SA. The towns are located in an area referred to as the Highveld Priority Area (HPA) because it has a recognised air pollution problem and it is believed that the populations living and working there are exposed to air that is harmful to their health and wellbeing.

Methods

The study was conducted in the towns of eMalahleni (formerly known as Witbank) and Middelburg. They are approximately 25 km apart. As part of the HPA initiative, air quality monitoring stations were set up in both eMalahleni and Middelburg. A cross-sectional study was conducted during September 2010. The study population comprised children aged between 9 and 11 years attending grades 4 and 5 in public (government) primary schools. At this age males and females have similar and high breath rates of 14 m3/day and 13 m3/day, respectively, putting them at increased risk of the harmful effects of air pollution.[8] Schools within a 10 km radius of the air quality monitoring stations in eMalahleni and Middelburg were selected for inclusion in the study. All schools in the study area were identified and ranked according

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to the total number of grade 4 and 5 learners. For logistic and economic reasons, the schools with the highest numbers of grade 4 and 5 students were preferred for inclusion until the required total sample size of 1 334 was reached, involving four schools in eMalahleni and two in Middelburg. All children present on the day of fieldwork were given prestructured questionnaires in their preferred language (where possible) to take home for completion by their parents, caregivers or guardians. A structured questionnaire, based on those used previously by Oosthuizen et Table 1. Profile of the study population (N=627) Variable

n/N (%)*

Town Witbank

189/627 (30.1)

Middelburg

438/627 (69.9)

Gender of the child Female

349/617 (56.6)

Male

268/617 (43.6)

Language Afrikaans

13/621 (2.1)

English

10/621 (1.6)

Zulu

436/621 (70.2)

Sotho

72/621 (11.6)

Other

90/621 (14.5)

Type of housing Brick dwelling

476/574 (82.9)

Flat

12/574 (2.1)

Other (asbestos/wood/ clay)

86/574 (15.0)

Water source Municipality

573/618 (92.7)

Private borehole

12/618 (1.9)

Community borehole

33/618 (5.3)

Fuel used for cooking Electricity

459/614 (74.8)

Gas/paraffin (kerosene)

48/614 (7.8)

Wood/coal

107/614 (17.4)

Fuel used for heating Electricity

31/506 (6.1)

Gas/paraffin

104/507 (20.6)

Wood/coal

371/506 (73.3)

al.[9] and the Vaal Triangle Air Pollution and Health Study, was used for this study.[10] These were based on those by Ferris (ATSDLD-78),[11] the Canadian Air Quality and Health Study (NHW/HPB-190-03040), and the Harvard School of Public Health’s Children’s Health Study (NHW/HPB-19003210). The questionnaire, translated into Afrikaans and Zulu, included sections on demographic information, indoor risk factors (such as the fuels used for cooking and heating) and the child’s health. A total of 1 400 questionnaires was distributed to the schools.

Ethical considerations

The study was granted ethical approval by the University of Pretoria Ethics Committee on 12 April 2011 (S152/2010). The provincial Department of Education granted approval for the study to take place in the selected schools. Questionnaires were distributed together with a subject information sheet providing details of the study, explaining that participation was voluntary and could be withdrawn at any stage, and that completion and return of the questionnaire implied consent to participate.

Data management and statistical analysis

Returned questionnaires were assigned a unique code and entered into a prepared database in Epidata 3.1 (StataCorp, USA). Stata Statistical Software: Release 9 (StataCorp) was used to perform the statistical analysis. The age of the child was calculated using the date of birth and the date of fieldwork. Respondents falling outside the predetermined age range of 9 - 11 years were excluded. Univariate Table 2. Prevalence of respiratory illhealth conditions (N=627) Health outcome

n/N (%)*

Past 6 months Doctor diagnosed Bronchitis

66/422 (15.6)

‘Ever’ during childhood to date Doctor diagnosed Asthma

39/551 (7.1)

Self-reported

Mould present inside the house

Chest wheeze

59/519 (11.4)

149/563 (26.5)

Chest cough

45/445 (10.1)

Smoking inside the house

51/613 (8.3)

Phlegm on the chest

123/481 (25.6) 214/627 (34.1)

110/530 (20.8)

Any respiratory health condition

Absent 1 or more days over the past 2 weeks *Information missing for some children.

*Information missing for some children.

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analysis was carried out, including the calculation of frequencies and examination of missing data. Bivariate analysis using the χ2 test or Fisher’s exact test was then undertaken; p-values, odds ratios (ORs) and the accompanying 95% confidence intervals (CIs) were examined in this step. Logistic regression was undertaken where risk factors were modelled with associated outcomes, adjusting for other associated risk factors. The results of the bivariate analysis were used to inform logistic regression using a p-value of 0.25 and biological plausibility.[12] A probability for entry of 0.05 was used to maintain the strength of the models.

Results

Six schools participated in the study. A total of 859 completed questionnaires were returned, resulting in a response rate of 61.4% (859/1 400). Only 627 of these were finally included in the analysis, because the remaining children fell outside the predefined age range. Table 1 provides a profile of the study population (note that for many variables, information was missing for some children). The majority of the sample lived in the town of Middelburg, and girls outnumbered boys. Three-quarters of the study subjects lived in dwellings in which the main fuel used for daily cooking was electricity, and a further 17.4% used coal. With regard to space heating, solid fuels (coal and wood) were most frequently used, while a relatively small proportion used electricity. A further 20.6% used paraffin or gas to heat their homes. The majority (92.7%) of dwellings were supplied with water through a reticulated municipal system. A relatively low percentage (8.3%) of respondents reported that someone smoked inside the dwelling, and the presence of mould was reported in 26.5% of dwellings. A total of 20.8% of the children in the study were reported to have been absent from school on one or more days using a 2-week recall period. Table 2 gives the reported levels of selec ted respiratory ill-health outcomes (infor mation missing for some children). Overall 16.5% of respondents said that the study child had been diagnosed by a doctor with the condition bronchitis in the preceding 6-month period; 25.6% of the children were reported to have had phlegm on their chests, and 21.5% to have suffered a chest cough or wheezing, using an ‘ever’ recall period. Thirty-four per cent of the study children had experienced a respiratory ill-health condition, over the past 6 months or ‘ever’, during their childhood to date.

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Respiratory ill-health burden in relation to fuel use

any respiratory ill-health condition was significantly associated (p=0.005) with the use of non-electrical fuel sources for cooking. The relationship remained significant (p=0.002) when controlling for town, having mould growth in the home and smoking in the home. Having phlegm on the chest was also significantly associated (p=0.029) with using non-electrical fuels for cooking, even after controlling for town, the presence of mould in the home and smoking (p=0.018). Bronchitis was nearly significantly associated with cooking fuel at bivariate level (p=0.061). Table 5 examines the relationship between using wood or coal and gas or paraffin for space heating and respiratory ill-health outcomes. Having phlegm on the chest (p=0.031) and bronchitis (p=0.008) were significantly associated with using wood or coal at bivariate level, and remained significant (p=0.013 and 0.007, respectively) when controlling for town, mould growth in the home or smoking in the home. Having any respiratory condition and wood or coal burning was weakly associated at bivariate level, but became significant (p=0.018) after controlling for the other factors. Gas or paraffin use for space heating was significantly (p=0.01) associated with only wheeze at bivariate level, and this remained significant (p=0.018) when adjusting for other factors.

Table 3 gives a breakdown of reported respiratory ill-health conditions in relation to the type of fuel used for cooking and space heating (information missing for some children). There was a higher prevalence of any respiratory ill-health conditions among those using non-electrical fuels for cooking than among electricity users, with the prevalence being highest (45.5%) among those using coal. The use of coal for cooking was associated with an increased prevalence of phlegm on the chest (36.9% in coal users v. 23.5% in electricity users) and bronchitis (26.9% v. 13.9%). The use of paraffin for cooking was associated with elevated levels of chest cough (25.7%) and being absent from school for 1 or more days over the past 2 weeks (39.7%). Levels of asthma did not vary according to the type of fuel used. As was the case for cooking fuel, elevated levels of phlegm on the chest (29.3% v. 15.8% in electricity users) and bronchitis (19.7% v. 11.1% in electricity users) were reported in children from homes where wood and coal were used for space heating. Among gas and paraffin users, levels of wheezing (20.9% v. 16.0% among electricity users) and asthma (11.6% v. 7.1% among electricity users) were elevated. Table 4 examines the relationship between respiratory ill health and cooking fuel types other than electricity. It is evident that overall,

Table 3. Reported ill-health conditions according to main fuel used for cooking and space heating Ill-health conditions, n/N (%)*

Asthma

Any respiratory ill-health condition

Absent 1 or more days over the past 2 weeks

44/316 (13.9)

32/407 (7.9)

145/459 (31.6)

77/390 (19.7)

4/33 (12.1)

0/41 (0.0)

19/48 (39.6)

11/42 (29.7)

8/79 (10.1)

17/63 (26.9)

6/90 (6.7)

49/107 (45.5)

18/87 (20.7)

41/122 (33.6)

17/114 (14.9)

21/96 (21.9)

6/131 (4.6)

68/155 (43.9)

29/129 (22.5)

4/25 (16.0)

3/19 (15.8)

2/19 (10.5)

2/18 (11.1)

2/28(7.1)

9/31 (29.0)

9/26 (34.6)

18/86 (20.9)

21/82 (25.6)

8/74 (10.8)

9/77 (11.7)

10/86 (11.6)

40/104 (38.5)

21/92 (22.8)

Wood/coal (N=371)

32/296 (10.8)

82/280 (29.3)

29/256 (11.3)

46/233 (19.7)

23/320 (7.2)

136/354 (38.4)

65/298 (21.8)

ny fuel other than A electricity (N=431)

42/357 (11.8)

97/339 (28.6)

35/309 (11.3)

50/287 (17.4)

30/383 (7.9)

163/431 (37.8)

80/368 (21.7)

Wheeze

Phlegm on chest

Chest cough

Bronchitis

Electricity (N=459)

45/380 (11.8)

82/349 (23.5)

28/323 (8.7)

Gas/paraffin (N=48)

5/37 (13.5)

10/38 (26.3)

9/35 (25.7)

Wood/coal (N=107)

8/90 (9.6)

31/84 (36.9)

ny fuel other than A electricity (N=155)

13/127 (10.2)

Electricity (N=31) Gas/paraffin (N=104)

Fuel used Cooking

Heating

*Information missing for some children.

Table 4. p-values, ORs and 95% CIs for the relationship between fuel used for cooking and respiratory ill-health outcomes Use of fuels other than electricity Health outcome

n/N (%)*

p-value

OR (95% CI)

Adjusted p-valueâ&#x20AC;

Adjusted OR (95% CI)â&#x20AC;

Any respiratory ill-health condition

68/155 (43.9)

0.005

1.69 (1.16 - 2.47)

0.002

1.88 (1.25 - 2.82)

Absenteeism

29/129 (22.5)

0.504

1.18 (0.72 - 1.91)

0.837

1.06 (0.62 - 1.81)

Wheeze

13/127 (10.2)

0.623

0.85 (0.44 - 1.63)

0.524

0.79 (0.38 - 1.64)

Phlegm on the chest

41/122 (33.6)

0.029

1.65 (1.04 - 2.59)

0.018

1.81 (1.11 - 2.94)

Chest cough

17/114 (14.9)

0.059

1.85 (0.96 - 3.53)

0.128

1.74 (0.85 - 3.53)

Bronchitis

21/96 (21.9)

0.061

1.73 (0.96 - 3.09)

0.180

1.56 (0.81 - 2.97)

Asthma

6/131 (4.6)

0.202

0.56 (0.22 - 1.34)

0.296

0.58 (0.21 - 1.61)

*Information missing for some children. â&#x20AC; Adjusted for town, having mould growth in the house and smoking.

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Table 5. p-values, ORs and 95% CIs for the relationships between fuel used for space heating and respiratory ill-health outcomes Wood/ coal burning Health outcome

n/N (%)*

Any respiratory health condition

Gas/paraffin heater

Adjusted p-value†

Adjusted OR (95% CI)†

n/N (%)*

Adjusted p-value†

Adjusted OR (95% CI)†

1.41 (0.83 - 2.4)

0.322

1.34 (0.75 - 2.4)

0.304

1.41 (0.73 - 2.75)

0.837

1.08 (0.52 - 2.27)

18/86 (20.9)

0.01

2.82 (1.24 - 6.41)

0.018

2.67 (1.18 - 6.02)

2.57 (1.22 - 5.41)

21/82 (25.6)

0.238

1.5 (0.76 - 2.94)

0.293

1.48 (0.71 - 3.06)

0.110

2.76 (0.79 - 9.57)

8/74 (10.8)

0.515

1.38 (0.52 - 3.69)

0.601

1.3 (0.48 - 3.49)

3.16 (1.28 - 7.78)

0.007

3.79 (1.45 - 9.92)

9/77 (11.7)

0.895

0.94 (0.39 - 2.26

0.896

0.94 (0.39 - 2.26)

1.01 (0.4 - 2.56)

0.823

1.13 (0.4 - 3.2)

10/86 (11.6)

0.249

1.71 (0.68 - 4.32)

0.253

1.71 (0.68 - 4.31)

p-value

OR (95% CI)

p-value

OR (95% CI)

136/354 (38.4)

0.071

1.58 (0.96 - 2.62)

0.018

1.93 (1.12 - 3.32)

40/104 (38.5)

0.197

Absenteeism

65/298 (21.8)

0.131

1.7 (0.85 - 3.41)

0.104

1.89 (0.88 - 4.09)

21/92 (22.8)

Wheeze

32/296 (10.8)

0.855

0.93 (0.42 - 2.04)

0.883

1.07 (0.43 - 2.65)

Phlegm on the chest

82/280 (29.3)

0.031

2.07 (1.05 - 4.07)

0.013

Chest cough

29/256 (11.3)

0.110

2.85 (0.84 - 9.73)

Bronchitis

46/233 (19.7)

0.008

Asthma

23/320 (7.2)

0.989

*Information missing for some children. † Adjusted for smoking, having mould growth in the house, and town.

Discussion

This study aimed to explore fuel use and child respiratory health and associated risk factors in two towns in SA’s Mpumalanga Province. The results indicate that domestic use of non-electrical fuels for both cooking and space heating have negative consequences for child respiratory health, as seen by the increased prevalence of ill-health conditions reported in Table 3. The prevalence of any one of the examined respiratory ill-health conditions (wheeze, phlegm on the chest, chest cough, bronchitis or asthma) was 12.3% higher among children in whose homes non-electrical fuels were predominantly used for cooking. An 8.8% increase in respiratory ill health was seen among those using non-electrical fuels for heating. The data indicate that paraffin (kerosene) had a greater influence on wheeze than wood or coal, as seen by the higher prevalence among those using it for either cooking or heating. Coal or wood use, for either cooking or heating, appears to be more strongly associated with the presence of phlegm on the chest and bronchitis. Having asthma and absenteeism did not appear to be strongly related to any particular fuel use, indicating other possible risks not examined here. Statistics South Africa indicates that the number of households countrywide using electricity for cooking has increased since 1996 to just over 70% in 2011.[4] Although the majority of this study population reported using electricity as their primary fuel for cooking, it is likely that many households still use multiple fuels to meet all their energy needs.[13] For example, 93.9% of this study population reported using non-electrical fuels such as wood, coal, paraffin or gas for heating. Even though provided with electricity, this study population, and similar communities, are likely to remain at risk of exposure to indoor air pollution and the associated respiratory ill-health risks. According to a burden of disease study in SA, which used data from 2007, lower respiratory tract infections (LRTIs) ranked as the second largest cause of death in children <5 years of age, accounting for 16.2% of deaths in this age group.[7] For children aged 1 - 4 years, LRTIs ranked third highest, accounting for 15% of all deaths. The report also noted that mortality from LRTIs and other infectious diseases increased considerably over the 11-year period 1996 - 2007. A comparative risk assessment conducted by Norman et al.[14] in 2007

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to establish the burden of respiratory ill health in SA from indoor air pollution found that approximately 24% of acute respiratory tract infections in children under the age of 5 years were attributable to this risk factor, after adjusting for ventilation. A similar study to the one reported in this article was conducted in the Vaal Triangle area of SA, showing the prevalence of upper respiratory disease in children aged 8 - 12 years to be 66%, while a prevalence of 29% was found for lower respiratory tract disease.[10] Data collected in Cape Town through the International Study of Asthma and Allergies in Children found a prevalence of 16% for asthma for the 13 - 14-year age group; this prevalence had increased to 20% approximately 5 years later.[15] While Cape Town had a prevalence of 20%, Limpopo Province in the north-east of SA had a prevalence of 18%.[16] Furthermore, the prevalence of severe wheeze in Cape Town was 5% while in Limpopo it was 7%. In a study including other African countries, Limpopo had the highest prevalence of wheeze.[17] It is therefore evident that the results from this study are comparable to those from elsewhere in SA. The findings reported in this paper serve to highlight the ongoing public health significance of exposure to indoor air pollution from the use of non-electrical fuels. Additionally, children living in areas such as the HPA are probably exposed to poor ambient air quality. In homes where fossil fuels are used for cooking or heating, children may be at increased risk of other injuries or illnesses such as burns from fires and poisoning from drinking paraffin. Death from carbon monoxide poisoning, as a result of open fires indoors being left unattended overnight, is also a concern. Studies such as these may be used to lobby for accelerated action to improve residential air quality. Further research is needed to examine the impact on respiratory ill health of, for example, traffic-related pollution or specific industry-related sources of pollution.

Study limitation

A limitation of this study was the use of a self-completed questionnaire completed by the parent or guardian of the child to collect respiratory ill-health information retrospectively. This may have introduced response bias.

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Conclusion

The data presented here highlight the risk of respiratory ill health in children living in homes where fossil fuels are burnt indoors for cooking and space heating. There is a need for scaled-up action to ensure universal use of electricity, associated with poverty elimination in SA. Acknowledgements. The authors thank the Council for Scientific and Industrial Research for funding this study and Juanette John and Loveness Dzikiti for statistical advice. They also thank the schools, principals, teachers, students and parents for participating in this study. This research was carried out as part of PNA’s MSc degree in the School of Health Systems and Public Health, University of Pretoria. Author contributions. PNA – study design, data collection, analysis and interpretation, paper write up; CYW – study design, data interpretation, paper write up; KVVV – study design, data interpretation, paper write up; AM – data interpretation, paper write up. All the authors read and approved the final manuscript. References 1. Bearer CF. How are children different from adults? Environ Health Perspect 1995;103(6):7-12. 2. Dong GH, Ma YN, Ding HL, et al. Housing characteristics, home environmental factors and respiratory health in 3945 pre-school children in China. Int J Environ Health Res 2008;18(4):267-282. [http://dx.doi.org/10.1080/09603120701842864] 3. Thurstan GD. Outdoor air pollution: Sources, atmospheric transport, and human health effects. International Encyclopaedia of Public Health 2008;4:700-712.

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4. Statistics South Africa, 2012. Statistical release P0301.4. http://www.statssa.gov.za/publications/ P03014/P030142011.pdf (accessed 26 May 2015). 5. Bruce NG, Dherani MK, Das JK, et al. Control of household air pollution for child survival: Estimates for intervention impacts. BMC Public Health 2013;13(Suppl 3):S8. [http://dx.doi.org/10.1186/1471-245813-S3-S8] 6. Norman R, Cairncross E, Witi J, et al. Estimating the burden of disease attributable to urban outdoor air pollution in South Africa in 2000. S Afr Med J 2007;97(8):782-790. 7. Nannan N, Dorrington RE, Laubscher R, et al. Under-5 Mortality Statistics in South Africa: Shedding Some Light on the Trends and Causes 1997-2007. Cape Town: South African Medical Research Council, 2012. 8. US Environmental Protection Agency, Exposure Factors Handbook. Washington, DC: National Centre for Environmental Assessment, 1997. 9. Oosthuizen MA, Jinabhai CC, Terblanche APS, Beck PJ. A transition in health status from childhood to adulthood and associated lifestyle risk factors: A 13-year interval follow-up study in South Africa. International Journal of Environmental Health Research, 2008; 18(1): 65–72 10. Terblanche APS, Opperman L, Nel CME, et al. Preliminary results of exposure measurement and health effects of the Vaal Triangle Air Pollution Health Study. S Afr Med J 1992;81(11):550-556. 11. Ferris BG. Epidemiology Standardization Project. Contract No 1-HR-5-3028. Report HR-53028-F. New York: Division of Lung Diseases, National Heart, Lung and Blood Institute, USA, 1978. 12. Hosmer DW, Lemeshow S. Applied Logistic Regression. 2nd ed. Canada: John Wiley & Sons, 2000. 13. Barnes B, Mathee A, Thomas E, Bruce N. Household energy, indoor air pollution and child respiratory health in South Africa. Journal of Energy in Southern Africa 2009;20(1):4-13. 14. Norman R, Barnes B, Mathee A, et al. Estimating the burden of disease attributable to indoor air pollution from household use of solid fuels in South Africa in 2000. S Afr Med J 2007;97(8):764-771. 15. Asher MI, Montefort S, Björkstén B, et al. Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC phases one and three repeat multicountry cross-sectional surveys. Lancet 2006;368(9537):733-743. [http://dx.doi.org/doi:10.1016/ S0140-6736(06)69283-0] 16. Ait-Khaled N, Odhiambo J, Pearce N, et al. Prevalence of symptoms of asthma, rhinitis and eczema in 13- to 14-year-old children in Africa: the International Study of Asthma and Allergies in Childhood Phase III. Allergy 2007;62(3):247-258. [http://dx.doi.org/10.1111/j.1398-9995.2007.01325.x] 17. Wichmann J, Wolvaardt JE, Maritz C, Voyi KVV. Household conditions, eczema symptoms and rhinitis symptoms: Relationship with wheeze and severe wheeze in children living in the Polokwane area, South Africa. J Asthma 2007;44(8):659-666. [http://dx.doi.org/10.1007/s10995007-0309-x]

Accepted 11 June 2015.

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Maternal near miss and maternal death in the Pretoria Academic Complex, South Africa: A population-based study P Soma-Pillay,1 MB ChB, Dip (Obstet) SA, MMed (OetG), FCOG, Cert Maternal and Fetal Medicine (SA); R C Pattinson,2 MD, FRCOG, FCOG (SA); , L Langa-Mlambo,3 MB ChB, FCOG; B S S Nkosi,4 BSc, MB ChB, FCOG, MMed; A P Macdonald,5 MB ChB, MMed (OetG), FCOG, FRCOG epartment of Obstetrics and Gynaecology, Faculty of Health Sciences, University of Pretoria, South Africa, and Steve Biko Academic D Hospital, Pretoria 2 South African Medical Research Council Maternal and Infant Health Care Strategies Unit, Department of Obstetrics and Gynaecology, Faculty of Health Sciences, University of Pretoria, South Africa 3 Maternal and Fetal Medicine Unit, Department of Obstetrics and Gynaecology, Faculty of Health Sciences, University of Pretoria, South Africa 4 Department of Obstetrics and Gynaecology, Mamelodi Hospital, Pretoria, South Africa 5 District Clinical Specialist and Department of Obstetrics and Gynaecology, Faculty of Health Sciences, University of Pretoria, South Africa 1

Corresponding author: P Soma-Pillay (priya.somapillay@up.ac.za)

Background. In order to reduce maternal mortality in South Africa (SA), it is important to understand the process of obstetric care, identify weaknesses within the system, and implement interventions for improving care. Objective. To determine the spectrum of maternal morbidity and mortality in the Pretoria Academic Complex (PAC), SA. Methods. A descriptive population-based study that included all women delivering in the PAC. The World Health Organization definition, criteria and indicators of near miss and maternal death were used to identify women with severe complications in pregnancy. Results. Between 1 August 2013 and 31 July 2014, there were 26 614 deliveries in the PAC. The institutional maternal mortality ratio was 71.4/100 000 live births. The HIV infection rate was 19.9%, and 2.7% of women had unknown HIV status. Of the women, 1 120 (4.2%) developed potentially life-threatening conditions and 136 (0.5%) life-threatening conditions. The mortality index was 14.0% overall, 30.0% for non-pregnancy-related infections, 2.0% for obstetric haemorrhage and 13.6% for hypertension. Of the women with life-threatening conditions, 39.3% were referred from the primary level of care. Vascular, uterine and coagulation dysfunctions were the most frequent organ dysfunctions in women with life-threatening conditions. The perinatal mortality rate was 26.9/1 000 births overall, 23.1/1 000 for women with non-life-threatening conditions, and 198.0/1 000 for women with life-threatening conditions. Conclusion. About one in 20 pregnant women in the PAC had a potentially life-threatening condition; 39.3% of women presented to a primary level facility as an acute emergency and had to be transferred for tertiary care. All healthcare professionals involved in maternity care must have knowledge and skills that equip them to manage obstetric emergencies. Review of the basic antenatal care protocol may be necessary. S Afr Med J 2015;105(7):578-583. DOI:10.7196/SAMJnew.8038

There were 4 452 maternal deaths in South Africa (SA) for the period 2011 - 2013.[1] The institutional maternal mortality ratio (iMMR) in SA decreased from 176.22/100 000 live births in the 2008 - 2010 triennium to 154.06/100 000 for 2011 - 2013, but further work needs to be done to meet the fifth Millennium Development Goal. In order to reduce maternal mortality, it is important to understand the process of obstetric care, identify weaknesses within the system, and finally implement interventions for improving care.[2] A woman who experiences and survives a severe health condition during pregnancy, during childbirth or after delivery is classified as a maternal near miss.[3] By studying cases of maternal deaths and near misses, important information can be obtained about the processes that take place in healthcare systems responsible for the care of pregnant women. While near-miss cases share many pathological and circumstantial characteristics with maternal deaths, they provide additional information about obstacles that have to be overcome after the onset of an acute complication. [2,4] Although a maternal near-miss case can only be identified retrospectively, it is clinically useful to prospectively identify women with potentially life-threatening conditions. A woman who develops a life-threatening condition will either become a maternal near-miss case or a maternal death.

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Objectives

To determine the spectrum of severe maternal morbidity and mortality in the Pretoria Academic Complex (PAC), SA, and compare the data with previous surveys and the World Health Organization (WHO) Multicountry Survey on Maternal and Newborn Health.[5] The WHO study was used as a comparison because it is the only study to characterise maternal morbidity occurring in a worldwide network of health facilities.

Methods

This was a descriptive population-based study that took place from 1 August 2013 to 31 July 2014 at nine delivery facilities in central, south-western and eastern Tshwane, Gauteng Province, SA. The following delivery units were included in the study: Steve Biko Academic Hospital (SBAH) (level 3), Kalafong Provincial Tertiary Hospital Hospital (KAH) (level 3), Mamelodi Hospital (level 2), Tshwane District Hospital (TDH) (level 1), Pretoria West Hospital (level 1), Laudium Community Health Centre (CHC) with midwife obstetric unit (MOU), Eersterust MOU, and Stanza Bopape and Dark City clinics (CHCs). SBAH and KAH are tertiary referral hospitals that receive referrals from outside Gauteng, but data were only analysed for women living in the Tshwane region; those living outside were excluded. Cases of abortion and ectopic pregnancy were also

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excluded from the study. Delivery data were recorded on a daily basis at all the health facilities, and daily audit meetings were held at SBAH and KAH to identify women with life-threatening conditions and organ dysfunction in pregnancy. The following WHO indicators were used to quantify women with severe complications in pregnancy:[2,6] Maternal near miss. A woman who nearly died but survived a complication that occurred during pregnancy or childbirth, or within 42 days of termination of pregnancy. The WHO near-miss criteria are listed in Table 1. Maternal death. A maternal death is the death of a woman while pregnant or within 42 days of termination of pregnancy, irrespective of the duration and the site of pregnancy, from any cause related to or aggravated by the pregnancy or its management, but not from accidental or incidental causes. Life-threatening conditions/severe maternal outcome (SMO). This refers to all women who either qualified as having a maternal near miss or who died. It is the sum of maternal near misses and maternal deaths. Potentially life-threatening condition. The five potentially lifethreatening conditions described by the WHO are severe postpartum haemorrhage, severe pre-eclampsia, eclampsia, sepsis/severe systemic infection, and ruptured uterus. The operational definitions of the five potentially life-threatening conditions are: • Severe postpartum haemorrhage. Genital bleeding after delivery, with at least one of the following: perceived abnormal bleeding (1 000 mL or more) or any bleeding with hypotension or blood transfusion. • Severe pre-eclampsia. Persistent systolic blood pressure of ≥160 mmHg or a diastolic blood pressure of ≥110 mmHg; proteinuria of ≥5 g in 24 hours; oliguria of <400 mL in 24 hours; and HELLP (haemolysis, elevated liver enzymes, low platelets) syndrome or pulmonary oedema. Excludes eclampsia. • Eclampsia. Generalised fits in a patient without previous history of epilepsy. Includes coma in pre-eclampsia. • Severe sepsis/systemic infection. Presence of fever (body temperature >38oC), a confirmed or suspected infection (e.g. chorioamnionitis, septic abortion, endometritis, pneumonia), and at least one of the following: heart rate >90 bpm, respiratory rate >20/min, leucopenia (white blood cells <4 × 109/L), leucocytosis (white blood cells >12 × 109/L). • Uterine rupture. Rupture of uterus during labour confirmed by laparotomy. Severe maternal outcome ratio (SMOR). This refers to the number of women with life-threatening conditions per 1 000 live births. This indicator gives an estimation of the amount of care that would be needed in an area. Mortality index (MI). The number of maternal deaths divided by the number of women with life-threatening conditions, expressed as a percentage. Descriptive statistics in the form of means and standard deviations in the case of continuous data and frequencies and percentages in the case of categorical data were calculated. Ethical approval was obtained from the University of Pretoria Ethics Committee (No. 125/2013).

Results

There were 26 614 deliveries in the PAC (SBAH, KAH, Mamelodi Hospital, TDH, Pretoria West Hospital, Laudium CHC with MOU, Eersterust MOU, Stanza Bopape MOU and Dark City clinics) during the study period. One hundred and thirty-six women developed

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Table 1. The WHO near-miss criteria[6] Clinical criteria Acute cyanosis Oliguria unresponsive to fluids or diuretics Jaundice concomitantly with pre-eclampsia Shock Cerebrovascular accident Breathing rate >40 - <6/min Loss of consciousness, no pulse/heartbeat Gasping Coagulation disorders Total paralysis Laboratory criteria Oxygen saturation <90% for >60 minutes Creatinine >300 µmol/L or >3.5 mg/dL Unconscious, presence of glucose and ketoacidosis in urine PaO2/FiO2 <200 mmHg Acute thrombocytopenia (platelets <50 × 109/L) Bilirubin >100 µmol/L or >6.0 mg/dL Lactate >5 mg/dL pH <0.1 Management criteria Use of continuous vasoactive drug Puerperal hysterectomy due to infection or haemorrhage Transfusion >5 units of red cell concentrate Dialysis for treatment of acute kidney failure Cardiopulmonary resuscitation Intubation and ventilation for >60 minutes, unrelated to anaesthesia PaO2/FiO2 = ratio of partial pressure of arterial oxygen and fraction of inspired oxygen.

life-threatening conditions, and there were 19 maternal deaths. The SMOR was 5.1/1 000 births and the MI 14.0%. The caesarean section rate was 25.2% overall and 61.0% for women with life-threatening conditions. The HIV infection rate was 19.9% for the general population, 23.1% for near misses and 36.8% for mothers who died. HIV status was unknown in 2.7% of patients. The spectrum of morbidity from uncomplicated pregnancies to maternal death is illustrated in Fig. 1. Most of the patients with potentially life-threatening and lifethreatening conditions were treated at the two PAC tertiary level hospitals. Forty-six women (39.3%) who were classified as near misses and 7 (36.8%) who died had to be transferred to the tertiary level hospitals after initially presenting at a lower level of care. The most frequent indications for emergency transfer of women with life-threatening conditions to the tertiary hospitals were severe preeclampsia (15.4%, n=21), obstetric haemorrhage (13.2%, n=18) and organ dysfunction in women with underlying medical disease (6.6%, n=9) (Table 2). The MI was 18.6% for SBAH, 10.2% for KAH and 12.5% for Mamelodi Hospital. Twenty-six women (22.2%) who were classified as a near miss had not booked with antenatal care services or had had infrequent visits. Medical practitioners caring for these patients believed that lack of antenatal care may have contributed to the life-threatening event. The distribution of patients with potentially life-threatening

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Potentially life-threatening conditions 1 120 (4.21%) Life-threatening conditions 136 (0.51%) Non-near miss Severe morbidity 984 (3.70%)

25 467 (95.70%)

Near miss 117 (0.43%) Maternal death 19 (0.07%)

Non-life-threatening conditions All pregnancies 26 614 Fig.1. The spectrum of morbidity from uncomplicated pregnancies to maternal death (not drawn to scale).

Table 2. Acute life-threatening conditions necessitating tertiary care (N=136)

Condition

Patients referred to tertiary centre from lower levels of care n (%)

Patients already in tertiary care n (%)

Obstetric haemorrhage

18 (13.2)

26 (19.1)

Pre-eclampsia

21 (15.4)

22 (16.2)

Sepsis

3 (2.2)

11 (8.1)

Medical/surgical disorders

9 (6.6)

Non-pregnancy-related infections

3 (2.2)

8 (5.9)

Anaesthetic disorders

4 (2.9)

Other

2 (1.5)

Total

54 (39.7)

82 (60.3)

400 350

SBAH KAH

Patients, n

300 250

Mamelodi TDH Pta West Laudium Dark City Stanza Bopape Eersterust

200 150 100 50 0

Potentially life-threatening conditions

Life-threatening conditions

Maternal death

Fig. 2. Distribution of potentially life-threatening conditions, near misses and maternal deaths in relation to the different levels of care.

conditions in relation to the different levels of care is shown in Fig. 2. The frequency of potentially life-threatening disorders is shown in Table 3. (Antepartum haemorrhage and non-pregnancy-related infections that are not part of the WHO definition of potentially life-threatening conditions have been included.)

The MI for non-pregnancy-related infections was 30.0%, for obstetric haemorrhage 2.0%, for hypertension 13.6% and for medical and surgical disorders 19.0% (Table 4). The near-miss markers and distribution of organ dysfunction are shown in Tables 5 and 6. The average age of the women who were classified as a near miss was

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30.3 years (minimum 16, maximum 43); 34 (29.1%) were primigravidas and 83 (70.9%) were multigravidas. There were 6 maternal deaths related to HIV and AIDS; 4 patients had respiratory failure secondary to TB pneumonia, 1 had bacterial meningitis and 1 died after presenting with multiorgan failure and milliary tuberculosis. Six women died of complications related to pre-eclampsia: 1 patient had a liver rupture, 2 had intracranial bleeds, 2 had respiratory failure due to pulmonary oedema and 1 had a cardiac arrest. The patient who died as a result of postpartum haemorrhage had a placenta praevia and had had two previous caesarean sections. Although an antenatal ultrasound scan had confirmed the location of the placenta, the diagnosis of placenta accreta was missed. Surgeons encountered a major bleed at caesarean section, and despite two re-look laparotomies the bleeding could not be controlled. Four patients died due to underlying medical disease, 1 each due to breast cancer, acute-on-chronic pancreatitis and an anaesthetic complication in a diabetic patient, while the 4th patient had a prosthetic heart valve. There were no maternal deaths at the level 1 hospitals or CHCs and only one death at a level 2 hospital. This was a patient with advanced-stage breast cancer who was unable to obtain transport to a tertiary-level facility. The MIs for the two tertiary hospitals were 18.6% (SBAH) and 10.15% (KAH), and that for the level 2 hospital was 12.5%. Table 7 compares the indices of severe acute maternal morbidity at the PAC for the periods 1997 - 1998, 2002 - 2004 and 2013 - 2014. Although the SMOR for the general population has remained the same since 1997 - 1998, both the iMMR and the MI have decreased. These findings are consistent for postpartum haemorrhage and hypertension. The SMOR for puerperal sepsis has remained constant despite the HIV epidemic with a decrease in MI. The SMOR and MI for medical and surgical conditions remain unchanged. Fig. 3 illustrates the perinatal mortality related to maternal morbidity. The women with severe maternal morbidity and mortality had a much high perinatal mortality rate (PNMR); however, for every woman with a complicated pregnancy, almost five women had no life-threatening condition. This explains the relatively small difference between the total PNMR and the PNMR of the non-life-threatening conditions. The primary obstetric causes of perinatal death were unexplained intrauterine death (30.3%), spontaneous preterm labour (25.5%), antepartum haemorrhage

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(12.3%), intrapartum asphyxia (9.3%), hypertensive disorders (7.4%), fetal abnor mality (6.9%) and maternal disease (3.7%).

Discussion

To our knowledge, this is the first study in SA assessing the spectrum of morbidity

Table 3. Frequency of potentially life-threatening disorders

Severe haemorrhage

All women (N=26 614) n (%)

Women with SMO (N=136) n (%)

HIV infection in women with SMO n (%)

660 (2.5)

51 (37.5)

7 (13.7)

Antepartum haemorrhage

301 (1.1)

17 (12.5)

1 (5.9)

Postpartum haemorrhage

336 (1.3)

31 (22.7)

4 (12.9)

Ruptured uterus Severe hypertensive disorders

23 (0.1)

3 (2.2)

2 (66.7)

682 (2.6)

44 (32.4)

4 (9.1)

Pre-eclampsia

457 (1.7)

40 (29.4)

4 (10.0)

Eclampsia

225 (0.8)

4 (2.9)

35 (0.1)

14 (10.3)

2 (14.3)

20 (14.7)

20 (100.0)

Other complications Puerperal sepsis Non-pregnancy-related infections

Table 4. MIs for different disease conditions Underlying condition

Maternal near miss, n

Maternal death, n

MI, %

Obstetric haemorrhage

2.0

Antepartum haemorrhage

Ruptured uterus

Postpartum haemorrhage

3.2

Hypertension

13.6

Chronic

Pre-eclampsia

10.0

Eclampsia

50.0

Puerperal sepsis

Non-pregnancy-related infections

30.0

Medical/surgical disorders

19.0

Table 5. Markers for classification of a maternal near miss (N=117) Near-miss marker

n (%)

Cerebrovascular accident

2 (1.7)

Total paralysis

1 (0.9)

Oxygen saturation <90% for >60 minutes

6 (5.1)

Acute thrombocytopenia (platelets <50 × 109/L)

26 (2.2)

Creatinine >300 µmol/L or > 3.5 mg/dL

4 (3.4)

Bilirubin >100 µmol/L or > 6.0 mg/dL

1 (0.9)

Ketoacids in urine

4 (3.4)

Use of continuous vasoactive drug

3 (2.6)

Dialysis for acute renal failure

2 (1.7)

Hysterectomy following infection or haemorrhage

35 (29.9) (infection 14, haemorrhage 21)

Cardiopulmonary resuscitation

3 (2.6)

Transfusion of >5 units red cells

31 (26.5)

Intubation and ventilation for >60 minutes

18 (15.4)

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for a specific region. There were 26 614 deliveries over a 12-month period (2013 2014). This represents almost a doubling of deliveries since 1997 - 1998, when the total number of births for the biennium was 27 025, and a 35% increase since 2002 - 2004 (51 469 births).[7] Just over 4% of women developed a potentially lifethreatening condition and 0.5% developed a life-threatening condition. This is lower than the WHO Multicountry Survey on Maternal and Newborn Health, which reported an incidence of 7% for potentially life-threatening conditions and 1% for lifethreatening conditions.[5] However, the difference between the two studies was that ours was population based while the WHO study was hospital based. About 40% of women with acute lifethreatening conditions did not present directly to the two tertiary level hospitals during the acute stage of disease. These patients were booked at a level 1 or 2 facility and then developed an acute condition requiring urgent transfer. Similarly, the England Collaborative Group reported that a significant proportion of serious complications occur in women with no recognisable risk factors.[8] Severe preeclampsia, obstetric haemorrhage and organ dysfunction due to an underlying medical condition were the most important reasons for emergency transfer. This indicates the need to have all healthcare professionals involved in care of pregnant women trained in the initial stabilisation and management of obstetric and neonatal emergencies. The antenatal care protocol used in our complex is based on the WHO recommendation of four antenatal visits for low-risk patients.[9] The low frequency of visits possibly means Table 6. Organ system dysfunction in women with life-threatening conditions (N=136)* Dysfunction

n (%)

Vascular dysfunction (hypovolaemia)

54 (39.7)

Uterine dysfunction

35 (25.7)

Coagulation dysfunction

27 (19.9)

Respiratory dysfunction

24 (17.7)

Cardiovascular dysfunction

9 (6.6)

Immunological dysfunction

8 (5.9)

Renal dysfunction

8 (5.9)

Cerebral dysfunction

7 (5.2)

Hepatic dysfunction

5 (3.7)

Metabolic dysfunction

5 (3.7)

*Some women had more than one organ dysfunction.

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Table 7. Comparison of the indices of severe acute morbidity rates at the PAC for the periods 1997 - 1998, 2002 - 2004 and 2013 - 2014 1997 - 1998

2002 - 2004

2013 - 2014

SMOR

iMMR

SMOR

iMMR

SMOR

iMMR

Antepartum haemorrhage

1.0

0.9

1.9

2.1

0.6

Postpartum haemorrhage

1.4

7.4

5.3

2.1

15.5

7.5

1.2

3.8

3.2

Hypertension

1.5

33.3

22.5

1.57

19.4

12.3

1.6

22.5

13.6

Puerperal sepsis

0.4

7.4

20.0

0.5

5.8

10.7

0.5

Non-pregnancy-related infections

0.3

22.2

66.7

0.4

19.4

47.6

0.8

22.5

30.0

Medical and surgical disorders

0.8

11.1

14.3

0.8

11.7

14.3

0.8

15.0

19.0

Total (excluding early pregnancy losses)

5.8

96.2

16.6

7.0

85.5

12.2

5.1

71.4

14.0

Total deliveries 26.94/1 000 (n=717)

Potentially life-threatening conditions 114.26/1 000 (n=128)

Non-life-threatening conditions 23.13/1 000 (n=589)

Life-threatening conditions 198.0/1 000 (n=27)

Near miss 196.6/1 000 (n=23)

Non-near miss Severe morbidity 102.64/1 000 (n=101)

Maternal death 210/1 000 (n=4)

Fig. 3. Perinatal mortality rate (for babies >500 g).

that cases of pre-eclampsia in the early stages of the disease process were missed, leading to patients presenting at a later stage with acute complications requiring tertiary care. Early detection of pre-eclampsia may require revision of our current antenatal care protocol and is supported by the recent Cochrane review on patterns of routine antenatal care for low-risk pregnancy.[10] There has been a decrease in the iMMR and MI at the PAC since 1997. This has been associated with decreases in MI for postpartum haemorrhage, hypertension, puerperal sepsis and non-pregnancy-related infections. The MI for non-pregnancyrelated infections in the PAC was 66.7% in 1997 - 1999, 75% in 2000, 47.6% in

2002 - 2004 and 30% in 2013 - 2014.[8,11] The decrease reflects the implementation of the antiretroviral programme by the National Department of Health and better handling of respiratory complications. Of significance is the low MI for postpartum haemorrhage (3.2%), which is less than half of the rate (7.5%) reported in 2002 - 2004 and significantly lower than the rate (5.3%) reported for 1997 - 1998.[11,12] The decrease in MI for severe postpartum haemorrhage and puerperal sepsis is probably a result of the introduction of strict protocols. The frequency of postpartum haemorrhage in women with life-threatening conditions (22.7%) was similar to that in the WHO study (26.7%).[6] However, the rates of pre-

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eclampsia (29.4%) and non-pregnancyrelated infections (14.7%) were greater in our study (WHO 16.3% and 1.6%, respectively). The rate of pre-eclampsia in women with life-threatening conditions was consistent with reports from Nigeria (32.5%) and Mozambique (32.9%).[13,14] Vascular (hypovolaemia), uterine (hyster ectomy) and coagulation (low platelets) dysfunction were the most frequent organ system dysfunctions in women with lifethreatening conditions (Table 6). Many women had multiple complications. The disease profile in our complex has changed since the year 2000, when vascular, cardiac, immunological and coagulation dysfunction were the most important organ systems causing obstetric morbidity.[15] Obstetric haemorrhage was the potentially lifethreatening condition most frequently encountered in our complex (37.5%), and vascular dysfunction as a result of hypovolaemia was the most common organ system dysfunction seen. The low MI for postpartum haemorrhage suggests that although postpartum haemorrhage is an important problem, the condition is well managed by our clinicians. Of the five potentially life-threatening conditions, hypertensive disorders contri buted to 7.4% of perinatal deaths. Ninety-three per cent of perinatal deaths were not related to antepartum and intrapartum maternal lifethreatening conditions, and if postpartum maternal life-threatening conditions are included, 80% of the women with perinatal deaths did not have severe morbidity. These findings are consistent with those of Allanson et al.[16] describing perinatal mortality in Mpumalanga Province, SA, and Vogel et al.[17] in the WHO Multicountry Survey, who found that a significant proportion of women have no recognisable obstetric or medical condition at the time of perinatal death. Allanson et al.[16] found a rate of maternal complications in macerated stillbirths, fresh stillbirths and early neonatal deaths of 50.4%,

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50.7% and 25.8%, respectively. The WHO Multicountry Survey found a maternal complication rate of 22.9%, 27.7% and 21.2% in late macerated stillbirths, late fresh stillbirths and early neonatal deaths, respectively. Current early antenatal identification of both severe maternal morbidity and perinatal mortality is inadequate.

Study strengths and limitations

The strength of this study is the robust method of data collection. The new national birth register records maternal complications, facilitating the collection of data. The PAC has been collecting and reviewing data on life-threatening conditions for more than 15 years, and all doctors are familiar with the WHO near-miss criteria. Women who were classified as a near miss were interviewed about barriers encountered in accessing healthcare. This information will be presented in a separate article. A limitation of this study is the exclusion of cases of early pregnancy loss (abortions and ectopic pregnancies). Some cases of sepsis may have been missed if patients presented late in the postpartum period. Furthermore, maternal infections such as pneumonia, tuberculosis and meningitis were not on the list of potentially life-threatening conditions, so the SMOR could not be calculated for these disease conditions. The list of potentially life-threatening conditions should be expanded to include medical conditions and non-pregnancyrelated infections. This is supported by Lumbiganon et al.,[18] who demonstrated that indirect causes of maternal deaths are increasingly important in developing countries, with indirect causes being responsible for about one-fifth of severe maternal outcomes.

Recommendations

• The WHO has identified five potentially life-threatening conditions: severe postpartum haemorrhage, severe pre-eclampsia, eclampsia, sepsis/severe infection and ruptured uterus.[2] Our study has shown that conditions such as abruptio placentae, nonpregnancy-related infections and medical and surgical disorders are also important causes of obstetric morbidity, and the WHO should therefore consider expanding its categories of potentially life-threatening conditions. • Forty per cent of patients with life-threatening conditions presented to a level 1 or 2 facility before being transferred for tertiary care. Cases of postpartum haemorrhage and severe pre-eclampsia could not be predicted antenatally. In addition, no recognisable obstetric condition was present in the majority of pregnancies that ended in a perinatal death. Health workers in level 1 and 2 centres must therefore be able to recognise, stabilise and transfer pregnant women and neonates presenting with an acute obstetric emergency. • Strategies to prevent and screen for pre-eclampsia and improvement of emergency transport for women are essential in order to reduce obstetric morbidity and mortality. • Review of the reduced visits protocol put forward by the WHO should be considered, as increasing the frequency of antenatal

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visits for low-risk women may increase detection of pre-eclampsia at an earlier stage of the disease process.[8] However, this would require a considerable increase in resources.

Conclusion

In this study we were able to identify the proportion of pregnancyrelated morbidity in our population and compare it with other studies. The MI and prevalence of potentially life-threatening conditions were similar to those in the WHO Multicountry Survey. Although there has been a decrease in the MI for non-pregnancy-related infection, further interventions need to be implemented to reduce morbidity and mortality associated with HIV disease and tuberculosis. A significant proportion of women who developed severe maternal conditions were not identified during the antenatal period, indicating the need to ensure that all levels of care can manage the initial steps in obstetric and neonatal emergencies and that an efficient emergency transport system is available. References 1. Pattinson RC, ed. Saving Mothers 2011-2013: Sixth Report on Confidential Enquiries into Maternal Deaths in South Africa. Pretoria: Department of Health, 2014. 2. World Health Organization. Evaluating the Quality of Care for Severe Pregnancy Complications. The WHO Near-miss Approach for Maternal Health. Geneva: WHO Press, 2011. 3. Pattinson RC, Hall MH. Near Misses: A useful adjunct to maternal death enquiries. Br Med Bull 2003;67(1):231-243. [http://dx.doi.org/10.1093/bmb/ldg007] 4. Chhabra P. Maternal near miss: An indicator for maternal health and maternal care. Indian J Community Med 2014;39(3):132-137. [http://dx.doi.org/10.4103/0970-0218.137145] 5. Souza JP, Gulmezoglu AM, Vogel J, et al. Moving beyond essential interventions for reduction of maternal morbidity (the WHO Multicountry Survey on Maternal and Newborn Health): A crosssectional study. Lancet 2013;381(9879):1747-1755. [http://dx.doi.org/10.1016/S0140-6736(13)60686-8] 6. Say L, Souza JP, Pattinson RC. Maternal near-miss – towards a standard tool for monitoring quality of maternal care. Best Pract Res Clin Obstet Gynaecol 2009;23(3):287-296. [http://dx.doi.org/10.1016/j. bpobgyn.2009.01.007] 7. Pattinson RC, Macdonald AP, Backer F, Kleynhans M. Effect of audit on critically ill pregnant women. Clinical Governance: An International Journal 2006;11(4):278-288. [http://dx.doi. org/10.1108/14777270610708814. 8. Birthplace in England Collaborative Group. Perinatal and maternal outcomes by planned place of birth for healthy women with low risk pregnancies: The Birthplace in England national prospective cohort study. BMJ 2011;343:d7400. [http://dx.doi.org/10.1136/bmj.d7400] 9. Villar J, Bergsjo P. WHO Antenatal Care Randomised Trial: Manual for the Implementation of the New Model. Geneva: WHO, 2003. 10. Dowswell T, Carroli G, Duley L, et al. Alternative versus standard packages of antenatal care for lowrisk pregnancy (Review). Cochrane Database Syst Rev 2010, Issue 10. Art. No.: CD000934. [http:// dx.doi.org/10.1002/14651858.CD000934.pub2] 11. Vandecruys HIB, Pattinson RC, Macdonald AP, Mantel GD. Severe acute maternal morbidity and mortality in the Pretoria Academic Complex: Changing patterns over 4 years. Eur J Obstet Gynecol Reprod Biol 2002;102(1):6-10. [http://dx.doi.org/10.1016/S0301-2115(01)00558-9] 12. Lombaard H, Pattinson RC. Common errors and remedies in managing postpartum haemorrhage. Best Pract Res Clin Obstet Gynaecol 2009;23(3):317-326. [http://dx.doi.org/10.1016/j. bpobgyn.2009.01.006] 13. Daru PH, MU J, Achara P, et al. Near miss maternal mortality in Jos University Teaching Hospital, Jos, Plateau State Nigeria. Ibom Medical Journal 2008;3(1):18-21. 14. David E, Machungo F, Zanconato G et al. Maternal near miss and maternal deaths in Mozambique: A cross sectional, region-wide study of 635 consecutive cases assisted in health facilities of Maputo Province. BMC Pregnancy Childbirth 2014;14:401. [http://dx.doi.org/10.1186/s12884-014-0401-3] 15. Mantel GD, Buchmann E, Rees H, Pattinson RC. Severe acute maternal morbidity: A pilot study of a definition for a near-miss. BJOG 1998;105(9):985-990. [http://dx.doi.org/10.1111/j. 1471-0528] 16. Allanson ER, Muller M, Pattinson RC. Causes of perinatal mortality and associated maternal complications in a South African province: Challenges in predicting poor outcomes. BMC Pregnancy Childbirth 2015;15:37. [http://dx.doi.org/10.1186/s12884-015-0472-9] 17. Vogel JP, Souza JP, Mori R, et al. Maternal complications and perinatal mortality: Findings of the World health Organisation Multicountry Survey on Maternal and Newborn Health. BJOG 2014;121(Suppl. 1):76-88. [http://dx.doi.org/10.1111/1471-0528.12633] 18. Lumbiganon P, Laopaiboon M, Intarut N, et al. Indirect causes of severe adverse maternal outcomes: A secondary analysis of the WHO Multicountry Survey on Maternal and Newborn Health. BJOG 2014;121(Suppl. 1):32-39. [http://dx.doi.org/10.1111/1471-0528.12647]

Accepted 27 March 2015.

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Intracranial suppuration: Review of an 8-year experience at Umtata General Hospital and Nelson Mandela Academic Hospital, Eastern Cape, South Africa M A Anwary, MMed (DRad) Department of Radiology, Walter Sisulu University, Nelson Mandela Academic Hospital and Umtata General Hospital, Mthatha, Eastern Cape, South Africa Corresponding author: M A Anwary (radiologynmah@gmail.com)

Background. Intracranial suppuration (ICS) is a life-threatening condition caused by various disease processes and consisting of brain abscess and extradural and subdural empyema. The major causes have changed over the decades. To the authorâ&#x20AC;&#x2122;s knowledge, the incidence of ICS in South Africa (SA) has not been established. Objective. To determine the incidence of ICS, overall and according to age and gender, and to identify the source and distribution of ICS. Method. The archive of the radiology departments at Umtata General Hospital and Nelson Mandela Academic Hospital in the Transkei region, Eastern Cape Province, SA, was searched retrospectively for computed tomography (CT) reports of patients diagnosed with ICS. Cases in which the CT images, patientsâ&#x20AC;&#x2122; clinical information and CT reports were available for an uninterrupted period of at least 1 year were included. Results. Five time frames were established, encompassing 8 years of data. The first time frame established an incidence of ICS of 1/100 000/year for the Transkei region. All the time frames were utilised to determine the incidence according to gender and age, and the source and distribution of ICS. The incidence of ICS was higher among males than females, and highest in the age groups 0 - 10 and 11 - 20 years. A seasonal variation in the incidence of sinusitis- and meningitis-related ICS was noted. Numbers of cases declined during the last 3 years of the study period. Conclusion. Sinusitis, head trauma, ear infection and meningitis were the major sources of ICS. A pulmonary source was not a major feature. In the last 4 years, trauma became the commonest source of ICS. A steady decline in ear infection- and meningitis-related ICS was noted. S Afr Med J 2015;105(7):584-588. DOI:10.7196/SAMJnew.7881

Intracranial suppuration (ICS) is a serious and lifethreatening complication of various disease processes. It consists of extradural empyema (EDE), subdural empyema (SDE) and brain abscess. The main causes of ICS are paranasal sinusitis, ear infection, head injury, meningitis, and metastatic spread from distant foci.[1-5] In some cases, the source of ICS is not identifiable.[1-5] Computed tomography (CT) is the main imaging modality used in the diagnosis of

ICS. With adequate clinical information and CT examination an accurate diagnosis can be achieved in the majority of cases, magnetic resonance imaging being reserved for cases in which a conclusive diagnosis cannot be made with CT. Brain abscess appears on the CT scan as an isodense or hyperdense ring, typically of uniform thickness with a hypodense centre (Fig. 1). Following intravenous injection of contrast medium, mild to intense ring enhancement of the abscess wall is seen. A hypodense area may be present surrounding

the abscess, and represents vasogenic oedema. The presence of ventriculitis is seen as enhancement of the ependyma. On the CT scan, SDE appears as a hypodense or isodense crescentic or lenticular area adjacent to the inner table of the skull (Fig. 2). On a contrast-enhanced CT scan, enhancement of the medial rim is usually seen. EDE appears as a biconvex hypodense area between the inner table of the skull and the brain (Fig. 3). Contrast-enhanced scans show a well-demarcated rim of enhancement representing the dura.

Fig. 1. Axial contrast-enhanced CT image of the brain showing rim-enhancing abscess (arrow) in the right frontal lobe with surrounding brain oedema (arrow head).

Fig. 2. Axial contrast-enhanced CT image of the brain showing subdural empyema (arrow head) and right parafalx empyema (arrow).

Fig. 3. Axial contrast-enhanced CT image of the brain showing left frontal extradural empyema (arrow).

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Table 1. Cases of ICS according to age, n Age groups (years)

1993 - 1994

1996

2001

2005 - 2006

2007- 2008

2008 - 2009

2009 - 2010

2010 - 2011

0 - 10

11 - 20

21 - 30

31 - 40

41 - 50

51 - 60

>60

In July 1992, the then government of the Republic of Transkei purchased and installed the first and the only CT scanner in Transkei at Umtata General Hospital, to serve a population of approximately three million people. Umtata General Hospital, being the only referral and teaching hospital in Transkei, received patients from 32 peripheral hospitals. The referral system was such that all patients needing specialist care were first referred to Umtata General Hospital for diagnosis and management and only then referred to other South African (SA) hospitals as needed. Umtata General Hospital therefore received most, if not all, of its patients from a well-defined and largely rural geographical area. Since the incidence of ICS in SA has not been established, this study sought to determine the overall incidence of ICS as well as the incidence according to age and gender. The sources and distribution of ICS were also identified.

Methods

This was a retrospective study. The archive of the radiology departments at Umtata General Hospital and Nelson Mandela Academic Hospital in the Transkei region, Eastern Cape Province, SA, was searched for CT scan reports of the patients diagnosed with ICS. Cases in which the CT images, patients’ clinical information and CT reports were available for an uninterrupted period of at least 1 year were included in the study. The following time frames fitted the latter cri terion: (i) June 1993 - May 1994; (ii) January 1996 - December 1996; (iii) January 2001 December 2001; (iv) June 2005 - May 2006; and (v) July 2007 - June 2011. Time frame (i) (June 1993 - May 1994) represents patients from the entire Transkei region serviced by Umtata General Hospital and 32 peripheral hospitals. After May 1994, Transkei became incorporated into SA, with the result that some patients presented at non-Transkei hospitals and clinics. Also, following the formation of the five regions

of the Eastern Cape Province in 1995, the peripheral hospitals of Transkei could refer patients to Frere Hospital (East London), Cecilia Makiwane Hospital (Mdantsane) and Queenstown Hospital, the province’s designated referral hospitals. Time frames (ii) - (iv) therefore represent the postregionalisation period and a smaller referral base consisting of Umtata General Hospital and 22 peripheral hospitals. The overall incidence of ICS for Transkei was therefore determined using the first time frame. The other incidences, causes and distribution of ICS were determined using a combination of all the time frames. All consecutive cases diagnosed as brain abscess, extradural and subdural empyema, or combinations thereof were included in the study. Cases in which a conclusive CT diagnosis was not possible were excluded. The CT images for all the cases were stored on magnetic tape, a magnetic optic disc or a picture archiving system. The clinical information on all the patients was copied and archived.

Results Incidence

During time frame June 1993 - May 1994, Umtata General Hospital and 32 peripheral hospitals served a population of approximately 3 million; 31 cases of intracranial suppuration were diagnosed, giving an incidence of approximately 1/100 000/year.

Presentation

During the five time frames, consisting of 8 years, 145 patients with ICS were diagnosed, of whom 93 were male and 52 female. Their ages ranged from 1 month to 61 years (Table 1); 75% of the patients were in the age group 0 - 20 years and 46% in the age group 11 - 20 years.

Signs and symptoms

The common presenting signs and symptoms are shown in Table 2. The most common symptoms were headache (31%) and vomiting (11%). The most common signs

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Table 2. Signs and symptoms of ICS (N=145) n (%) Headache

45 (31.0)

Fever

42 (29.0)

Seizures

30 (20.7)

Neck stiffness

37 (25.6)

Orbital cellulitis

27 (18.6)

Cranial nerve palsy

14 (9.7)

Hemi/monoparesis

45 (31.0)

Altered level of consciousness

33 (22.8)

Forehead swelling

7 (4.8)

Vomiting

16 (11.0)

included fever (29%), hemi/monoparesis (31%), neck stiffness (26%) seizures (21%), altered level of consciousness (23%) and orbital cellulitis (19%). Of 27 patients who had orbital cellulitis, sinusitis was the cause in 23. Of the 45 presenting with hemi/ monoparesis, 25 had brain abscess, 19 empyema and 1 a combination of abscess and empyema. There were 14 cases of cranial nerve palsy, of which 10 were caused by abscess and 4 by subdural empyema.

Sources of ICS

The sources of ICS are listed in Table 3. The most common sources were sinusitis (n=38), head trauma (n=33), ear infection (n=22) and meningitis (n=24). In 15 cases (10%) the source of sepsis was not found. The incidence of sinusitis-related ICS as a percentage of all the cases per year remained stable within a range of 21 - 36% ,while a general increase in head trauma-related ICS was noted (range 4.5 - 44%). During the last 4 years of the study period, only 4 cases of ear infection-related and 5 cases of meningitis-related ICS were seen. The sources of ICS according to age are listed in Table 4. Common sources in the first decade of life were meningitis, sinusitis, trauma and ear infection. In the

RESEARCH

Table 3. Sources of ICS, n Source

1993 - 1994 (n=31)

1996 (n=17)

2001 (n=22)

2005 - 2006 (n=22)

2007 - 2008 (n=19)

2008 - 2009 (n=13)

2009 - 2010 (n=9)

2010 - 2011 (n=12)

Total (N=145)

Sinusitis

Ear infection

Meningitis

Trauma

Unknown

Postoperative

Bronchopneumonia

Soft-tissue infection

Congenital heart disease

Table 4. Sources of ICS according to age, n Age group (years)

Sinusitis

Ear infection

Meningitis

Trauma

Unknown

Soft-tissue infection

Bronchopneumonia

Congenital heart disease

Postoperative

0 - 10

11 - 20

21 - 30

31 - 40

41 - 50

51 - 60

>60

second decade, sinusitis was the commonest cause, followed by ear infection, trauma and meningitis. Head trauma was the commonest source of ICS above the age of 20 years, 54% of trauma-related ICS occurring in the age group 0 - 20 years and 79% in the age group 0 - 30 years. Unknown causes of ICS were more frequent in older patients (8 of the 35 patients aged >20 years as opposed to 7/110 patients aged ≤20 years), i.e. the source of ICS tended to become more obscure with older patient age. Of the known common causes of ICS, sinusitis and trauma were more prevalent in males than in females (Table 5); in fact, traumarelated ICS was seven times more common in males, in keeping with the high incidence of trauma in this group.[9] Sinusitis-related ICS was twice as common in males than in females, and meningitis was a more common source in females than in males.

Types of ICS (Table 6)

During the review period, there were 65 cases of abscess, 15 of EDE, 46 of SDE, 8 combinations of EDE and SDE, and 11 combinations of abscess and empyema. In total there were 76 cases of abscess (D + E in Table 6) and 80 cases of empyema (A + B + C + D). SDE (B + C) was more than twice as common as EDE (A + C). There were 16 patients with multiple abscesses.

Sources of abscess

The common sources of abscess were trauma (n=25), meningitis (n=17) and ear infection (n=11). There were 15 cases of ICS in which the source of sepsis could not be determined; of these, 12 were abscesses and 3 empyemas. In 16% of the abscesses the source of sepsis could not be found, while this was the case in only 3% of the empyemas. This finding highlights the occult nature of some of the sources of brain abscess.

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Table 5. Major sources of ICS according to gender, n Males

Females

Trauma

Sinusitis

Ear infection

Meningitis

Empyema + abscess (D)

Abscess (E)

Table 6. Types of ICS, n Year

EDE (A)

SDE (B)

EDE + SDE (C)

1993 - 1994

1996

2001

2005 - 2006

2007 - 2008

2008 - 2009

2009 - 2010

2010 - 2011

Total

Sources of empyema

The common sources of EDE were sinusitis (n=13) and ear infection (n=8). The common sources of SDE were sinusitis (n=29), trauma

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through to April. Of the 22 cases, only 2 were seen during these summer and autumn months. Other causes of ICS did not vary significantly in seasonal occurrence.

Cases of ICS, n

25 20 15

Distribution of ICS

10 Series 1

5 Dec

Nov

Oct

Sep

Aug

Jul

Jun

May

Apr

Mar

Feb

Jan

Month

7 6 5 4 3 2 1 0

Dec

Nov

Oct

Sep

Aug

Jul

Jun

May

Apr

Mar

Feb

Series 1 Jan

Cases of ICS, n

Fig. 4. Cumulative monthly (seasonal) occurrence of all ICS.

Month

Discussion

7 6 5 4 3 2 1 0 Dec

Nov

Oct

Sep

Aug

Jul

Jun

May

Apr

Mar

Feb

Series 1 Jan

Cases of ICS, n

Fig. 5. Cumulative monthly (seasonal) occurrence of sinusitis-related ICS.

Month Fig. 6. Cumulative monthly (seasonal) occurrence of meningitis-related ICS.

(n=10), meningitis (n=9) and ear infection (n=5).

Cumulative monthly occurrence of ICS

During the process of data analysis, it was found that the incidence of ICS was higher during certain months. Fig. 4 shows the cumulative monthly occurrence of ICS from all causes. The incidence was highest from June through to October, accounting for 58%

of the cases. Further analysis of the causes of ICS during this period revealed that sinusitis was a major contributor. The cumulative monthly occurrence of sinusitis-related ICS (Fig.Â 5) shows that the incidence was highest during the winter months of June, July and August; 47% of all sinusitisrelated ICS occurred during these months. The cumulative monthly occurrence of meningitis-related ICS (Fig. 6) revealed a relatively low incidence from December

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Abscesses commonly occurred in the frontal (n=27), temporal (n=21) and parietal lobes (n=15) and the cerebellum (n=15). Of the 15 cerebellar abscesses, 9 were caused by ear infection. The major sources of frontal lobe abscess were trauma (n=11), meningitis (n=7) and sinusitis (n=5). Temporal lobe abscesses were related to meningitis (n=7), trauma (n=5) and ear infection (n=3). Parietal lobe abscesses were mainly trauma related (n=9). The abscesses of unknown source showed no predilection for any particular area. EDE was predominantly seen in the frontal area (n=18), followed by the temporal area (n=7) and posterior fossa (n=5). Of the 18 cases of frontal EDE, 13 were related to sinusitis. There were 5 EDEs in the posterior fossa, all caused by ear infection. SDE predominantly occurred in the frontal (n=43), temporal (n=28), parietal (n=24) and parafalx areas (n=38), and was linked to sinusitis (n=29), trauma (n=10) and meningitis (n=9). The parafalx empyemas were mainly caused by sinusitis (n=19), trauma (n=8) and meningitis (n=5).

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The incidence of 1/100 000/year for ICS in the Transkei region is similar to the incidences of 1.1/100 000/year in Olmstead County, Minnesota, USA[6] and 1/100 000/ year in Edinburgh, UK.[7] However, it is much higher than the incidences of 0.3/100Â 000/ year in Wimbledon, London, UK,[3] and 0.3 0.5/100 000/year in Northern Ireland.[8] The higher incidence of ICS in males than in females in this study is reflected in other SA studies, which showed ratios of 2:1[4] and 2.8:1.[1] The ratio was 2:1 in Merseyside, UK,[2] and 4:1 in Olmstead County, USA.[6] Gender analysis of traumarelated ICS revealed a male bias of 7:1, in keeping with the higher incidence of head trauma among males.[9] This study revealed a high incidence of ICS in the first two decades of life, accounting for 75% of all the cases over the study period. Other SA studies found that 52% of cases were in this age group[1] and that 23% were in the age group 0 - 13 years.[5] In Edinburgh, 43% of cases were in the age group 10 - 29 years.[2] Common signs and symptoms in the studies reviewed vary substantially, and include headache (26 - 82%), fever (26 - 51%), focal neurological deficit (70%), neck stiffness (36 - 45%) and seizures (25 - 34%).[1-3]

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The major causes of ICS in this study were sinusitis (26%), head trauma (23%), ear infection (15%) and meningitis (16%), which is similar to a study by Alegria et al.[1] in Johannesburg, SA, during January 1977 - December 1979 that showed sinusitis (25%), trauma (24%) and ear infection (20%) to be the major sources of ICS. These figures are comparable to ours despite a gap of more than 14 years between the two studies. The higher incidence of ICS due to meningitis in our study appears to be related to the increased incidence of tuberculosis. The increased incidence of sinusitis-related ICS in June, July and August is in keeping with the fact that sinusitis is commonest during winter. Numbers of cases of ICS in this study fell from 31 in 1993 - 1994 to 17 in 1996 as a result of a smaller referral base. The number of cases seen then stabilised at 22 for 2001 and 2005 - 2006, but a further decline was seen to 9 cases in 2009 - 2010, with 12 in 2010 - 2011. The decrease may reflect the general improvement in healthcare delivery in the Transkei region. A significant decrease in meningitis- and ear infection-related ICS was noted, with one case of meningitis-related and two cases of ear infection-related ICS seen during the last 2 years of the study. The incidence of

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sinusitis-related ICS was stable, while trauma-related ICS showed a steady increase. Further follow-up is required to confirm these trends. References 1. Alegria C, Lipschitz R, Zwonninkoff G. Intracranial suppuration: A review of 79 cases seen at Baragwanath hospital over 3 years. S Afr J Surg 1982;20(1):25-35. 2. Bradley PJ, Shaw MDM. Three decades of brain abscess in Merseyside. J R Coll Surg Edinb 1983;28(4):223-229. 3. Miller ES, Dias PS, Uttley D. CT scanning in the management of intracranial abscess: A review of 100 cases. Br J Neurosurg 1988;2(4):439-446. [http://dx.doi.org/10.3109/02688698809029597] 4. Danziger A, Price H, Schecter MM. An analysis of 113 intracranial infections. Neuroradiology 1980;19(1):31-34. 5. Snyman H, Kruger P, van den Heever CM. Intracranial sepsis: A microbiological review. S Afr J Surg 1986;24(2):78-80. [http://dx.doi.org/10.1093/infdis/154.3.399] 6. Nicolosi A, Hauser WA, Beghi E, Kuland LT. Epidemiology of central nervous system infection in Olmstead County, Minnesota, 1950-1981. J Infect Dis 1986;154(3):399-408. [http://dx.doi. org/10.1093/infdis/154.3.399] 7. Small M, Dale BAB. Intracranial suppuration 1968-1982: A 15-year review. Clin Otolaryngol 1984;9(6):315-321. [http://dx.doi.org/10.1111/j.1365-2273.1984.tb01514.x] 8. McClelland C, Craig BF, Crockard HA. Brain abscesses in Northern Ireland: A 30 year community review. J Neurol Neurosurg Psychiatry 1978;41(11):1043-1047. [http://dx.doi.org/10.1136/ jnnp.41.11.1043] 9. Nell V, Brown DSO. Epidemiology of traumatic brain injury in Johannesburg: II. Morbidity, mortality and etiology. Soc Sci Med 1991;33(3):289-296. [http://dx.doi.org/10.1016/0277-9536(91)90363-H]

Accepted 8 November 2014.

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Observed full blood count and lymphocyte subset values in a cohort of clinically healthy South African children from a semi-informal settlement in Cape Town D Lawrie,1 MSc (Med), PhD; H Payne,2,3 BSc Hons, MB ChB Hons, MRCPCH; M Nieuwoudt,4 PhD (Bioengineering), Dip Nucl Med Tech, BSc (Physiology, Psychology); D K Glencross,1 MB BCh, MMed epartment of Molecular Medicine and Haematology, National Health Laboratory Service and Faculty of Health Sciences, University of the D Witwatersrand, Johannesburg, South Africa 2 Institute of Child Health, University College London, UK 3 Children’s Infectious Diseases Clinical Research Unit, Department of Paediatrics, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Cape Town, South Africa 4 South African Department of Science and Technology/National Research Foundation Centre of Excellence in Epidemiological Modelling and Analysis, Faculty of Science, Stellenbosch University, Stellenbosch, Western Cape, South Africa 1

Corresponding author: D Lawrie (denise.lawrie@nhls.ac.za)

Background. The paediatric full blood count and lymphocyte subset reference intervals used by the National Health Laboratory Service (NHLS), South Africa (SA), are taken from two international reference interval publications. Differences in reference intervals suggest that international data sets may not be appropriate for use in SA. Objective. To study immunohaematological values of a group of clinically healthy children from an informal settlement in Cape Town, SA, to assess whether international paediatric reference intervals used by the NHLS are appropriate. Methods. A cross-sectional study of 207 female and 174 male HIV-uninfected children living in an informal settlement in Cape Town was performed. Full blood counts, automated differential counts and lymphocyte subset analysis were done using internationally accepted technologies. Data were categorised by age and reference intervals compiled using medians and 95% confidence intervals (CIs). Gender comparisons were calculated by non-parametric tests. Results. Although median and 95% CI values differed slightly, physiological trends for red cell, platelet, white blood cell differential and lymphocyte subsets were similar to international reference intervals currently in use at the NHLS. Benign ethnic neutropenia was not a significant finding, and gender-specific intervals were not necessary until 12 years of age. Lower overall median values for haemoglobin and haematocrit, and higher median values for mean cell volume and red cell distribution width, were noted. Assessment of haemoglobin, red cell distribution width and calculated Mentzer ratios suggested underlying iron deficiency in 14.2% of participants. Conclusion. Paediatric immunohaematological reference intervals observed in this study are similar to, and support continued use of, international paediatric reference intervals. Underlying iron and related nutritional deficiencies may be contributing to lower haemoglobin levels noted in local children. A larger nationwide study, including all ethnic groups, is recommended. S Afr Med J 2015;105(7):589-595. DOI:10.7196/SAMJnew.7914

Integrated productive haemopoeisis is fundamental to a successful immune response. Neutrophils, monocytes, eosinophils and basophils are essential components of the primary innate immune response and, further, initiate the secondary immune response by processing and presenting pathogenic antigens to the adaptive immune cells in the lymph nodes. After antigenic stimulation, the lymphocytes respond via T-cell-dependent cellular and B-cell-dependent humoral immune reactions.[1] A laboratoryderived immunohaematological profile usually includes full blood count parameters, a white blood cell (WBC) differential count and lymphocyte subsets (T, B and natural killer cells). Lymphocyte subsets are further defined to provide important physiological and functional information such as the proportions of naïve, memory and activated T and B cells. Comprehensive immunohaematological analysis is therefore used to screen paediatric patients for underlying immune suppression associated with primary immunodeficiency such as X-linked agammaglobulinaemia and severe combined

589

immunodeficiency. It can also be used to exclude secondary immunodeficiency caused by overwhelming infections such as HIV, parvovirus, hepatitis B and tuberculosis,[2] and primary T-cell and B-cell as well as post-transplantation[3,4] lymphoproliferative disorders. Although the optimal approach to assessing and monitoring immunohaematological status is to record individual patient baseline values prior to infection or clinical illness, this is not generally feasible. Standard clinical and laboratory practice is to compare the patient’s results with established reference intervals (that reveal the expected immunohaematological intervals of 90 - 95% of a ‘normal healthy population’[5]). Currently, the paediatric full blood count and lymphocyte subset reference intervals used by the National Health Laboratory Service (NHLS) in South Africa (SA) are taken from two international reference interval publications.[2,6] Differences in reference intervals attributed to ethnicity, diet, endemic infections, altitude, laboratory testing protocols and statistical methodologies used[7,8] suggest that international data sets may not necessarily be appropriate for local use in SA.

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Objective

An opportunity to establish whether the reference interval sets[2,6] used are representative of local children’s full blood count and lymphocyte subset reference intervals presented itself during a recent clinical paediatric study at a child wellness clinic in Cape Town (H Payne et al. – unpublished data). The aim of this report was to establish reference intervals of full blood count and lymphocyte subset values in a cohort of apparently healthy SA children of diverse ethnicity, residing in a semi-informal settlement in Cape Town, SA, to assess the appropriateness of the full blood count and lymphocyte subset paediatric reference intervals currently used in the NHLS.

Methods

This was a cross-sectional study performed on 381 clinically healthy, HIV-uninfected children from the Wesbank semi-informal settlement in Cape Town. In Wesbank,[9] 27% of adults are unemployed, 62% have not completed their complete education to grade 12 level, and 39% of households earn <R19 200 per year. Sixteen per cent of the population lives in informal dwellings, and 5% of the population is >65 years of age. The infant mortality rate is 23.2/1 000 live births, 7% of babies are born to mothers aged <18 years, and 20% of babies weigh <2 500 g at birth. There were 207 female and 174 male participants, with an age range of 2 weeks - 12.6 years. Each age group had an approximately 50:50 male-to-female ratio. The children were black Africans (n=85) or of mixed ethnic ancestry (n=296). An attending paediatrician confirmed that the children were clinically healthy and well nourished on the day of phlebotomy. Wellness criteria included: (i) previous registration at the child wellness clinic; (ii) attendance with the biological mother and Road-to-Health card; (iii) a documented clinical history without current infection (defined as within the last week) or chronic medical conditions; and (iv) no prescribed medications. The Stellenbosch University Human Ethics Committee approved the study (M12/01/005). Venous blood samples were collected into dipotassium EDTA, transported and stored at 20ºC (standard deviation 4ºC) prior to preparation and analysis. All testing was completed within 24 hours of collection. Rapid HIV antibody analysis (Alere Determine, USA) confirmed that the participants were HIV-seronegative on the day of phlebotomy. An automated full blood count and white cell differential analysis was performed using a Beckman Coulter LH-750 Haematology Analyser (Beckman Coulter, USA). Samples were examined for the following parameters: total white blood cell (WBC) count and five-part automated differential count, red blood cell (RBC) count, haemoglobin (Hb), haematocrit (Hct), mean cell volume (MCV), red cell distribution width (RDW) and platelet (Plt) count. Blood films were reviewed manually to visually confirm automated differential counts and exclude gross morphological abnormalities. A Mentzer index (MCV/RBC)[10-12] was calculated for each participant. Dual-platform absolute lymphocyte subset counts and percentages were prepared using the Becton Dickinson FACSLyse/wash method (BDIS, USA). Samples were stained using the following directly labelled antibodies: CD3 APC, CD3 FITC, CD16 PE, CD19 FITC, CD45 PerCP, CD45RO PE, CD45RA FITC, HLA DR APC (BDIS) and CD4 FITC, CD8 PE and CD56 PE (Beckman Coulter). All samples were analysed on a FACSCalibur flow cytometer (Becton Dickinson, USA) using CellQuest analysis software (Becton Dickinson). The accuracy of the full blood count and lymphocyte subset values was subject to strict manufacturer and internationally recommended internal and external quality assurance procedures. Laboratories performing testing are accredited under the South African National Accreditation System

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(certificate numbers M0025A and M0106B) and subscribe to the NHLS National Quality Assessment programmes and the UK National External Quality Assessment Schemes to confirm longitudinal accuracy of all laboratory parameters.

Statistical analysis

The Clinical and Laboratory Standards Institute Approved Guideline (3rd edition) for defining and establishing reference intervals was used to determine and calculate the reference intervals.[5] No data points were removed from statistical analysis, as sample integrity and testing quality were closely monitored (and ensured) throughout the study. The data were categorised into the following age groups: 0 - 3 months, 3 - 6 months, 6 - 12 months, 1 - 2 years, 2 - 6 years, 6 - 12 years and >12 years, in keeping with similar international publications. Differences between genders were calculated with the non-parametric Mann-Whitney U-test and the reference intervals were reported as medians with 95% confidence intervals (CIs). Data analysis was performed using Microsoft Excel (Frontline Systems Inc., USA), Stata version 12 (StataCorp LP, USA) and GraphPad Prism 5 Software (GraphPad Software, USA).

Results

Table 1 summarises the values obtained for the full blood count and white cell differential parameters. Table 2 summarises the immune monitoring values, i.e. lymphocyte subsets, activated T cells and naive and memory subsets. No gender-specific statistically significant differences (Mann-Whitney p-values <0.05) were noted across any of the age groups for any of the full blood count parameters or lymphocyte subsets analysed. The Mentzer index, RDW and Hb values for participants identified with possible iron deficiency are summarised in Table 3.

Discussion

RBC parameters

In this study, the overall median RBC, Hb and Hct values increased from infancy to 12 years of age, with a cumulative increase of ±24% for RBCs (3.50 v. 4.60 × 1012/L), ±17% for Hb (10.6 v. 12.8 g/dL) and ±18% for HCT (0.31 v. 0.38 L/L between 0 - 3 months and 12 years of age. The median MCV (92.2 fL) was highest at 0 - 3 months, decreasing steadily until approximately 2 years of age (72.5 fL); subsequently values increased, reaching previously reported adult values. Although the median RDW values were variable, no specific trends were noted across any of the paediatric age groups, falling within an interval of 13.5 - 16.3 fL. Analysis of the median values for RBC parameters and comparison with published literature confirms that the RBC parameters noted (Fig. 1) are in keeping with ‘normal’ physiological anaemia of childhood.[1] Increasing physiological demands for RBCs result in an overall decreased median Hb concentration and production of smaller RBCs (decreased median MCV),[6] with greater variation in size (increased median RDW). The MCV begins to decrease in healthy neonates after ±1 week, and RBC production increases when the Hb drops to a level of about 11 g/dL (at ±2 months of age), attributable to reduced red cell lifespan (60 80 days v. 120 days for an adult), influence of erythropoietin,[1] etc. No statistically significant gender-related differences in RBC parameters were noted until 12 years of age (p>0.05). Although genderspecific discrepancies have been noted previously in the literature, they are more evident from puberty and are attributed to the hormonal influences of oestrogen and androgens (Hb in males is reported to increase by as much as 2 g/dL in response to testosterone[13]). Although not shown in this study, ethnicity and altitude have been noted to contribute to RBC parameter variation[6] in other studies.

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Table 1. Full blood count calculated medians and 95% CIs for the study group Age ranges 0 - 3 months (n=45)

3 - 6 months (n=40)

6 - 12 months (n=54)

1 - 2 years (n=79)

2 - 6 years (n=118)

6 - 12 years (n=37)

>12 years (n=8)

RBCs (× 1012/L)

3.5 (2.7 - 4.4)

4.2 (3.1 - 4.9)

4.4 (3.9 - 5.2)

4.4 (3.9 - 5.1)

4.3 (3.9 - 4.8)

4.2 (3.8 - 4.7)

4.6 (4.0 - 5.2)

Hb (g/dL)

10.6 (8.7 - 14.7)

11.4 (8.5 - 12.7)

10.8 (9.5 - 13.1)

10.8 (8.7 - 12.5)

11.2 (9.4 - 12.5)

11.8 (10.0 - 13.1)

12.8 (11.1 - 13.3)

Hct (L/L)

0.31 (0.25 - 0.41)

0.34 (0.25 - 0.38)

0.32 (0.28 - 0.39)

0.32 (0.27 - 0.37)

0.34 (0.29 - 0.38)

0.35 (0.31 - 0.38)

0.38 (0.32 - 4.00)

MCV (fL)

92.2 (82.2 - 99.4)

79.2 (68.7 - 88.6)

73.5 (66.8 - 81.2)

72.5 (64.5 - 82.2)

78.9 (64.5 - 86.4)

83.2 (74.3 - 87.7)

81.1 (75.4 - 86.8)

RDW (%)

14.7 (12.8 - 18.2)

13.5 (11.7 - 16.8)

15.9 (13.4 - 21.3)

16.3 (14.1 - 20.8)

14.8 (12.8 - 19.4)

13.9 (12.7 - 15.9)

13.9 (13.3 - 16.3)

Plt (× 109/L)

420 (243 - 581)

390 (228 - 687)

367 (253 - 610)

349 (192 - 551)

326 (197 - 471)

319 (206 - 454)

280 (180 - 371)

WBCs (× 109/L)

9.6 (5.7 - 14.9)

10.4 (6.9 - 19.7)

12.0 (5.3 - 20.0)

10.7 (6.9 - 18.5)

8.7 (5.8 - 13.6)

7.6 (4.0 - 10.0)

8.6 (4.9 - 13.0)

Neutrophils (%)

24.1 (15.6 - 39.0)

29.6 (11.6 - 48.8)

31.7 (13.0 - 52.3)

31.5 (20.0 - 51.1)

42.0 (25.0 - 61.2)

48.2 (28.4 - 65.3)

54.4 (45.5 - 57.2)

Neutrophils (× 109/L)

2.36 (1.26 - 5.20)

2.88 (1.22 - 8.11)

3.99 (1.13 - 8.08)

3.55 (1.79 - 7.87)

3.63 (1.59 - 6.64)

3.69 (1.85 - 6.33)

4.19 (2.60 - 7.30)

Lymphocytes (%)

60.0 (49.0 - 72.8)

58.8 (42.3 - 77.5)

58.0 (36.8 - 73.9)

57.0 (37.7 - 69.0)

43.4 (26.1 - 62.1)

37.5 (21.5 - 60.9)

35.1 (27.7 - 45.8)

Lymphocytes (× 109/L)

5.56 (3.23 - 11.07)

6.12 (3.79 - 12.43)

6.20 (3.10 - 11.45)

5.75 (3.58 - 10.58)

3.81 (1.93 - 6.11)

2.71 (1.50 - 3.89)

2.85 (1.78 - 3.95)

Monocytes (%)

11.0 (5.0 - 18.3)

7.9 (3.2 - 16.6)

8.0 (2.8 - 13.4)

7.0 (3.0 - 12.0)

6.0 (2.5 - 11.0)

5.3 (1.6 - 11.2)

6.1 (4.2 - 8.0)

Monocytes (× 109/L)

1.03 (0.52 - 2.40)

0.97 (0.32 - 2.37)

0.89 (0.30 - 1.93)

0.73 (0.29 - 1.61)

0.53 (0.20 - 1.06)

0.38 (0.12 - 0.97)

0.46 (0.22 - 0.75)

Eosinophils (%)

3.0 (1.0 - 6.3)

3.0 (0 - 10.0)

3.1 (1.0 - 8.0)

3.1 (0 - 10.0)

5.9 (1.5 - 18.1)

4.8 (0.9 - 12.9)

6.8 (1.1 - 16.0)

Eosinophils (× 109/L)

0.25 (0.07 - 0.89)

0.33 (0 - 1.24)

0.29 (0.05 - 1.34)

0.32 (0 - 1.37)

0.51 (0.11 - 1.20)

0.27 (0.10 - 1.16)

0.50 (0.06 - 1.05)

Basophils (%)

0.2 (0 - 1.1)

0.2 (0.1.1)

0.3 (0 - 1.3)

0.2 (0 - 1.0)

0.3 (0 - 1.0)

0.3 (0 - 0.8)

0.3 (0 - 0.4)

Basophils (× 109/L)

0.02 (0 - 0.11)

0.03 (0 - 0.12)

0.03 (0 - 0.17)

0.02 (0 - 010)

0.03 (0 - 0.08)

0.02 (0 - 0.04)

0.03 (0 - 0.10)

The RBC parameter variation, particularly in median Hb (~1 - 2 g/ dL lower) and Hct (~4 - 7% lower), across all age groups may be attributed to a combination of ethnicity and altitude. However, subclinical iron deficiency and/or mild anaemia could not be ruled out. Although iron deficiency and other metabolic disorders, including vitamin B12 and folate deficiencies, were not formally excluded in this cohort, haematological indices and the Mentzer index calculation were assessed.[10] Iron deficiency was suspected if a concurrent Hb <10 g/ dL, RDW >15%[11] and Mentzer index >13[10,12] was found. As noted in another local adult reference interval study,[14] the findings suggested that 14.2% (54/381) of the children tested in this study had possible iron deficiency (Table 3). Further studies are required to confirm this finding.

Platelets

The overall median Plt counts were highest at 0 - 3 months (420 × 109/L) and were comparable to adult values described

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previously.[1,6] However, although the Plts remained within adult reference limits, they showed a steady decrease of approximately 33% until 12 years of age (280 × 109/L) (Fig. 2). The median Plt count of the cohort appeared to stabilise at ±12 years of age, similar to reference intervals currently in use and a previously published local adult study.[15] Individual gender-specific differences become apparent at puberty as a result of hormonal influences. In girls, Plt counts increase by approximately 25 × 109/L owing to the effect of the hormone oestradiol.[13] Additional increases are linked to the onset of menstruation and prevalence of iron deficiency anaemia.[1,6]

WBC parameters

Total white cell and differential count The median total WBC count increased from 9.6 × 109/L at 0 - 3 months, reaching a peak of 12 × 109/L at 12 months. Thereafter, median WBC counts declined to reach adult values[6] at 12 years

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Table 2. Measured immune monitoring data for the study group, medians and 95% CIs Age ranges 0 - 3 months (n=45)

3 - 6 months (n=40)

6 - 12 months (n=54)

1 - 2 years (n=79)

2 - 6 years (n=118)

6 - 12 years (n=37)

>12 years (n=8)

CD3+

3 650 (2 028 - 7 625)

3 999 (2 341 - 8 451)

4 212 (1 795 - 7 334)

3 787 ( 2 392 - 6 616)

2 652 (1 360 - 4 202)

1 853 (1 017 - 2 913)

1 944 (1 146 - 2 544)

CD4+

2 656 (1 520 - 5 160)

2 927 (1 573 - 5 441)

2 474 (1 085 - 4 562)

2 190 (1 374 - 3 928)

1 579 (816 - 2 705)

1 092 (568 - 2 013)

1 205 (724 - 1 785)

CD8+

949 (428 - 2 478)

1 135 (593 - 3 176)

1 355 (622 - 3 244)

1 280 (669 - 3 247)

970 (414 - 1 599)

648 (340 - 1 210)

704 (318 - 980)

Ratio CD4+/CD8+

2.58 (1.29 - 5.49)

2.33 (1.19 - 4.96)

1.70 (0.90 - 3.92)

1.69 (0.78 - 3.88)

1.80 (0.91 - 3.13)

1.67 (0.95 - 2.47)

1.74 (1.58 - 2.63)

CD19+

835 (351 - 1823)

1 179 (666 - 3 310)

1 037 (485 - 2 348)

1 156 (610 - 2 699)

584 (274 - 1 468)

322 (163 - 563)

303 (105 - 623)

CD3+HLA–DR+

172 (94 - 709)

222 (90 - 1 361)

387 (157 - 916)

365 (142 - 1 069)

217 (92 - 507)

124 (56 - 284)

157 (54 - 205)

CD4+HLA–DR+

117 (45 - 228)

129 (45 - 380)

107 (44 - 229)

125 (56 - 282)

84 (34 - 153)

49 (20 - 137)

60 (23 - 77)

CD8+HLA–DR+

46 (10 - 487)

99 (21 - 950)

213 (58 - 699)

199 (44 - 849)

112 (29 - 414)

65 (29 - 168)

84 (27 - 131)

CD4+CD45+RA+

1 828 (954 - 4 064)

2 383 (1 200 - 4 049)

1 749 (793 - 3 700)

1 687 (930 - 2 655)

944 (388 - 2 018)

603 (92 - 1 278)

551 (344 - 1 086)

CD4+CD45+RO+

868 (261 - 1 801)

634 (314 - 1 384)

576 (359 - 1 293)

634 (343 - 1 218)

562 (343 - 1 218)

523 (305 - 845)

660 (311 - 708)

atio CD4+ naive/ R memory

2.6 (0.74 - 7.00)

3.72 (1.55 - 6.45)

2.83 (1.19 - 5.51)

2.57 (1.35 - 5.64)

1.76 (0.71 - 3.69)

1.15 (0.10 - 2.48)

1.21 (0.76 - 1.60)

CD8+CD45+RA+

812 (370 - 2 044)

873 (402 - 2 323)

974 (443 - 1 939)

964 (459 - 2 688)

719 (295 - 1 247)

466 (258 - 800)

425 (200 - 731)

CD8+CD45+RO+

146 (50 - 683)

259 (81 - 1174)

337 (83 - 1 583)

292 (72 - 1 162)

188 (69 - 532)

159 (48 - 455)

213 (68 - 339)

Ratio CD8+ naive/ memory

4.93 (1.48 - 14.00)

3.40 (0.94 - 10.60)

3.36 (0.81 - 14.30)

3.43 (1.16 - 12.90)

3.56 (1.25 - 9.98)

2.86 (1.24 - 6.92)

2.52 (1.06 - 3.66)

CD16+CD56+

489 (179 - 1 310)

399 (137 - 1 699)

367 (117 - 1 860)

435 (111 - 1 372)

284 (120 - 782)

214 (52 - 697)

277 (128 - 642)

CD3–CD56+

448 (189 - 1 450)

396 (126 - 1 647)

368 (123 - 1 840)

385 (125 - 1 253)

283 (119 - 744)

219 (61 - 680)

294 (136 - 624)

CD3+

69.3 (58.0 - 79.2)

67.8 (47.0 - 79.7)

68.3 (47.3 - 76.2)

67.0 (52.4 - 76.2)

70.5 (54.6 - 79.3)

71.8 (50.7 - 80.5)

64.5 (56.2 - 74.5)

CD4+

49.5 (37.6 - 63.0)

45.9 (37.6 - 63.0)

41.2 (26.7 - 57.8)

39.7 (26.5 - 56.3)

41.6 (30.2 - 53.8)

41.9 (29.2 - 54.2)

42.0 (37.7 - 55.3)

CD8+

18.2 (10.7 - 28.1)

19.6 (11.4 - 30.2)

24.1 (12.7 - 33.9)

24.4 (13.7 - 35.3)

24.5 (15.1 - 35.7)

25.9 (15.2 - 32.3)

23.3 (17.2 - 26.8)

Ratio CD4+/CD8+

2.58 (1.29 - 5.49)

2.33 (1.19 - 4.96)

1.70 (0.90 - 3.92)

1.69 (0.78 - 3.88)

1.80 (0.91 - 3.13)

1.67 (0.95 - 2.47)

1.74 (1.58 - 2.63)

CD19+

15.5 (8.0 - 29.5)

20.1 (10.5 - 38.7)

18.6 (9.3 - 33.5)

20.0 (10.7 - 33.0)

15.7 (9.4 - 30.5)

11.5 (8.4 - 18.0)

12.1 (5.9 - 17.1)

CD3+HLA–DR+

5.1 (2.6 - 14.9)

5.6 (2.4 - 20.7)

9.7 (3.6 - 19.3)

9.0 (3.0 - 19.6)

8.0 (4.0 - 19.9)

6.9 (3.1 - 16.0)

7.3 (4.0 - 10.4)

Cell marker (cells/ml), median (95% CI)

Cell marker, % (95% CI)

Continued ...

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Table 2. (Continued) Measured immune monitoring data for the study group, medians and 95% CIs Age ranges 0 - 3 months (n=45)

3 - 6 months (n=40)

6 - 12 months (n=54)

1 - 2 years (n=79)

2 - 6 years (n=118)

6 - 12 years (n=37)

>12 years (n=8)

CD4+HLA–DR+

4.0 (2.0 - 8.1)

4.2 (1.8 - 8.7)

4.3 (2.3 - 8.9)

5.6 (2.3 - 12.0)

5.7 (2.2 - 10.0)

4.3 (1.9 - 15.0)

4.2 (2.5 - 6.5)

CD8+HLA–DR+

4.5 (1.6 - 28.7)

10.0 (1.5 - 38.9)

16.9 (5.4 - 35.1)

14.4 (4.5 - 46.2)

12.5 (4.6 - 30.1)

9.3 (5.1 - 23.9)

11.4 (6.4 - 17.8)

CD4+CD45+RA+

72.2 (42.6 - 87.5)

78.8 (60.8 - 86.6)

73.9 (54.4 - 84.6)

72.0 (57.4 - 84.9)

63.8 (41.6 - 78.7)

53.5 (8.9 - 71.3)

54.6 (43.1 - 61.5)

CD4+CD45+RO+

27.8 (12.5 - 57.4)

21.2 (13.4 - 39.2)

26.1 (15.4 - 45.6)

28.0 (15.1 - 42.6)

36.2 (21.3 - 58.4)

46.5 (28.7 - 91.1)

45.4 (38.5 - 56.9)

atio CD4+ naive/ R memory

2.6 (0.7 - 7.0)

3.7 (1.6 - 6.5)

2.8 (1.2 - 5.5)

2.6 (1.4 - 5.6)

1.8 (0.7 - 3.7)

1.2 (0.1 - 2.5)

1.2 (0.8 - 1.6)

CD8+CD45+RA+

83.1 (59.6 - 93.3)

77.3 (48.3 - 91.4)

77.1 (44.8 - 93.5)

77.4 (53.6 - 92.8)

78.1 (55.6 - 90.9)

74.9 (55.4 - 87.9)

71.6 (51.4 - 78.6)

CD8+CD45+RO+

16.9 (6.7 - 40.4)

22.7 (8.6 - 51.7)

22.9 (6.5 - 55.2)

22.6 (7.2 - 46.4)

21.9 (9.1 - 44.4)

25.9 (12.6 - 47.0)

28.4 (21.4 - 48.6)

Ratio CD8+ naive/ memory

4.9 (1.5 - 14.0)

3.4 (0.9 - 10.6)

3.4 (0.8 - 14.3)

3.4 (1.2 - 12.9)

3.6 (1.3 - 10.0)

2.9 (1.2 - 6.9)

2.5 (1.1 - 3.7)

CD16+CD56+

9.3 (3.6 - 22.5)

6.5 (3.0 - 17.7)

7.0 (3.2 - 18.4)

7.1 (2.4 - 20.0)

7.9 (3.4 - 18.1)

7.9 (2.9 - 26.9)

9.9 (6.0 - 19.2)

CD3–CD56+

9.2 (4.0 - 20.7)

6.5 (3.0 - 18.5)

7.0 (3.2 - 17.8)

6.4 (2.5 - 19.1)

7.9 (3.6 - 17.5)

8.2 (3.1 - 26.3)

10.6 (5.9 - 19.8)

of age, with an overall 10% decrease in median total WBC counts between 0 - 3 months and 12 years of age (9.6 v. 8.6 × 109/L). Between 0 - 3 months and 12 years of age, the overall median absolute neutrophils increased by 44% (2.36 × 109L v. 4.19 × 109L) and lymphocytes decreased by 49% (5.56 × 109L v. 2.85 × 109L). Monocyte counts decreased by 55% (1.03 × 109L v. 0.46 × 109L), while eosinophils and basophils increased by 50% (0.25 × 109L v. 0.50 × 109L) and 33% (0.02 × 109L v. 0.03 × 109L), respectively. These trends were also noted in the corresponding relative neutrophil, lymphocyte, monocyte, eosinophil and basophil percentage values. Lymphocytes are the predominant WBC until ±4 years of age and then decline, with neutrophils becoming increasingly predominant as the child grows.[6] This study confirmed this observation, showing a median lymphocyte count of 5.75 × 109/L v. 3.55 × 109/L for neutrophils at 1 - 2 years, with lymphocyte numbers decreasing to 2.71 × 109/L and neutrophils increasing to 3.69 × 109/L by 6 - 12 years of age (Fig. 3). Neutrophil reference intervals calculated from this local paediatric population were in keeping with those reported from westernised countries.[6] These are higher than intervals reported from other African countries,[7,8] where benign genetic neutropenia, which

may be linked to the Duffy-null trait, is thought to confer protection against Plasmo dium vivax malaria.[16] The similarity of this locally derived neutrophil reference interval to westernised countries could also be attributed to the large number of participants of mixed ethnic ancestry in this study (n=296). Baseline eosinophil counts are reported to be increased in some African countries as a result of endemic parasitic infections.[8] Endemic parasitic infections are reported to be prevalent in children from the neighbouring Eastern Cape Province and, with the reported rapid influx of migrants from the Eastern Cape into Cape Town, increased eosinophil counts may have been expected in this study. However, the results from this and a previous SA study[15,17] reveal that eosinophil counts are low and in keeping with westernised countries. This is possibly the result of successful local implementation of deworming programmes in children that has ensured minimal helminthiasis, despite reports that >90% of children from the Eastern Cape region are infected by Ascaris and/or Trichuris.[18] Further, although a schistosomiasis prevalence of 73.2% was reported in a study of schoolchildren in the rural Eastern Cape, the eosinophil counts of this cohort of children suggest that schistosomiasis is also not prevalent in this population group.[19]

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Table 3. Summary of Mentzer index, RDW and Hb values for boys and girls identified as having possible iron deficiency Mentzer index

RDW (%)

Hb (g/dL)

27.0

15.5

7.3

15.8

16.9

7.7

17.5

18.4

7.9

27.1

15.5

8.2

14.5

19.4

8.3

15.6

16.8

8.7

15.4

17.1

8.8

12.4

19.8

8.8

13.0

19.4

8.8

35.6

15.6

8.9

16.0

8.9

14.0

9.2

18.8

20.5

9.2

16.4

9.2

19.5

21.5

9.3

15.5

18.4

9.4

32.8

15.3

9.4

14.5

20.8

9.5

Boys

Continued ...

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Table 3. (Continued) Summary of Mentzer index, RDW and Hb values for boys and girls identified as having possible iron deficiency Mentzer index

5.0 4.5 4.0 3.5 3.0 2.5 2.0

RBCs (× 1012/L)

1.5 1.0 0.5 0

Hb (g/dL)

RDW (%)

Hb (g/dL)

17.4

16.2

9.5

16.9

17.8

9.6

15.6

20.9

9.6

17.2

18.9

9.6

11.1

23.6

9.7

16.6

17.9

9.7

17.6

16.4

9.7

16.1

18.1

9.7

14.7

16.8

9.7

17.9

20.5

9.8

16.8

17.7

9.8

20.6

16.6

9.8

16.8

9.9

15.3

17.3

9.9

15.4

18.9

8.2

32.9

17.9

8.5

12.5

20.0

8.5

27.2

16.1

8.5

37.3

16.6

8.7

26.8

15.4

9.0

26.6

19.0

9.2

13.7

16.8

9.4

16.3

18.6

9.4

20.9

15.3

9.4

18.9

21.3

9.5

16.2

18.4

9.5

15.5

17.1

9.5

16.2

17.7

9.6

17.2

17.3

9.7

35.0

17.1

9.5

17.5

9.8

15.9

19.5

9.9

15.7

18.7

9.9

14.7

21.0

9.9

13.8

20.3

9.9

16.6

17.5

9.9

Girls

Lymphocyte subsets (T, B and natural killer cells) Analysis of the absolute T, B and natural killer lymphocyte subset numbers showed a decreasing trend with age, in keep ing with previously described normal physiological total WBC and lymphocyte count intervals. [6] The median T-cell

12 10 8

2 0-3 mo.

3-6 mo.

6 - 12 mo.

1-2 yr

2-6 yr

6 - 12 yr

<12 yr

Fig. 1. Graphical representation of childhood physiological anaemia in this study group, similar to that previously described.[1] From ~3 - 6 months of age until 6 - 12 years of age, there is an inverse relationship between the median Hb and median RBC cell count. Between 6 and 12 years of age, the parameters converge and increase proportionally until adulthood.

450 400 350 300 250 200 150 100

14 12 10 8 6

Plts (× 109/L)

Hb (g/dL)

50 0

0 0-3 mo.

3 - 6 6 - 12 1 - 2 mo. mo. yr

2-6 yr

6 - 12 <12 yr yr

Fig. 2. Comparison of the median Hb trend v. the median Plt count trend. As illustrated, while Hb increases steadily with age, Plts show a decreasing trend with age and only stabilise at puberty.

4.5 4 3.5 3 2.5 2 1.5 1 0.5 0

3 2 1 0

Granulocytes (× 109/L) Lymphocytes (× 109/L)

0 - 3 3 - 6 6 - 12 1 - 2 2 - 6 6 - 12 <12 mo. mo. mo. yr yr yr yr Fig. 3. Comparison of median granulocyte numbers v. lymphocyte numbers. As illustrated, from about 2 years of age lymphocyte numbers decrease markedly while granulocyte numbers stabilise and slowly begin to increase, in keeping with normal childhood physiological development.[1]

numbers decreased by ±47%, CD4positive cells by 55% and CD8-positive cells by 26%. As reported elsewhere, developmental changes in the composition of the peripheral B-cell pool are most noticeable up to 5 years of age, and the total number of B cells decreases with age. [1] In this cohort, the median number

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of CD19-positive B cells decreased by 36%, in keeping with international reports. [2] The median number of CD3 –/CD16 +/ CD56+ natural killer cells decreased by 43% between 0 - 3 months and 12 years of age, in keeping with international trends and the current reference intervals used for reporting.[2]

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T-cell activation To assess T-cell activation, HLA-DR expression was measured on the total CD3+ T-cell population, on CD3+/CD8+ cytotoxic T lymphocytes and on CD3+/CD4+ helper T lymphocytes. HLA-DR expression is typically increased on T cells during activation and on CD8+ lymphocytes, specifically with increasing age.[20] In this cohort of children, an overall decrease of 9% in the total number of activated T cells between 0 - 3 months and 12 years of age (172 × 106/L v. 157 × 106/L) was noted. However, further investigation of the T-cell subsets showed a 51% decrease in activated CD3+/CD4+ lymphocytes (117 × 106/L v. 60 × 106/L) and a 55% increase in activated CD3+/ CD8+ cytotoxic T cells (46 × 106/L v. 84 × 106/L), as reported elsewhere.[2] Naive and memory subsets Analysis of CD45RA and CD45RO expression on CD3+/CD4+ T-helper lymphocytes in this study group was in keeping with international reports and showed consistent conversion of naive T-helper cells to memory T-helper cells from 0 - 3 months (ratio 2.6) across the range of paediatric age groups, to achieve a ratio of 1.21 by 12 years of age.[2] Expression of CD45 isoforms, CD45RA and CD45RO, on CD4- and CD8-positive T-cells varies depending on the stage of maturation and the T-cell receptor response to antigenic stimulation.[21] CD45RA has been shown to be associated with CD4 and be more efficient at promoting T-cell activation after T-cell receptor stimulation. Analysis of the CD45RA and CD45RO isoforms therefore remains important for monitoring immune suppression associated with infections such as HIV.[21]

Conclusion

Paediatric full blood count and lymphocyte subset reference intervals often differ between laboratories and across centres, and vary between populations and regions. Locally, a lack of comprehensive local paediatric full blood count and lymphocyte subset reference intervals has led to the use of internationally published reference intervals, which may not be appropriate for our local populations. Reference intervals reported here, derived from a cohort of children from an informal settlement in the Western Cape Province, SA, confirm expected active immunohaemopoeisis of childhood.[1,6] Locally established reference intervals,[17,22] using limited participants from a single area (where a multitude of unknown factors may affect outcome), may not necessarily be appropriate for defining whether a particular individual’s blood counts are ‘normal’ (or not) if the individual is of different ethnic origin or socioeconomic background or lives in a different region. International Clinical Laboratory Standards Institute study guidelines are also not specific enough to exclude all variables that could affect each parameter studied.[5] The reference intervals reported here, although limited, do provide important insight into local paediatric reference intervals. In the absence of a local fully representative population study, including paediatric participants from across SA (with known ethnic, social

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and economic demographics), this study serves to validate the use of the published international reference intervals provided with NHLS paediatric immunohaematology laboratory reports. Ethical considerations will preclude studies on healthy, normal children. However, conducting similar studies during paediatric clinical trials in different regions across SA could provide valuable opportunities to extend this work. In the meantime, this article supports the continued use of the international paediatric reference intervals currently used by the NHLS for full blood count, white cell differential and lymphocyte subsets. References 1. Kaushansky K, Lichtman MA, Beutler E, Kipps TJ, Seligsohn U, Prchal JT. Williams Hematology. 8th ed. McGraw-Hill, 2010. 2. Shearer WT, Rosenblatt HM, Gelman RS, et al. Lymphocyte subsets in healthy children from birth through 18 years of age: The Pediatric AIDS Clinical Trials Group P1009 study. J Allergy Clin Immunol 2003;112(5):973-980. [http://dx.doi.org/10.1016/j.jaci.2003.07.003] 3. Yang F, Li Y, Braylan R, Hunger SP, Yang LJ. Pediatric T-cell post-transplant lymphoproliferative disorder after solid organ transplantation. Pediatr Blood Cancer 2008;50(2):415-418. [http://dx.doi. org/10.1002/pbc.21072] 4. Kaleem Z, Hassan A, Pathan MH, White G. Flow cytometric evaluation of posttransplant B-cell lymphoproliferative disorders. Arch Pathol Lab Med 2004;128(2):181-186. [http://dx.doi. org/10.1043/1543-2165(2004)128<181:FCEOPB>2.0.CO;2] 5. Clinical Laboratory Standards Institute. Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory: Approved Guideline. 3rd ed. Vol. 28, No. 20. Wayne, PA: CLSI, 2010:61. 6. Bates I, Lewis SM. Reference ranges and normal values. In: Bain BJ, Bates I, Laffan MA, Lewis M, eds. Dacie and Lewis Practical Haematology. Philadelphia, PA: Elsevier Churchill Livingstone, 2012:11-22. [http://dx.doi.org/10.1016/B978-0-7020-3408-4.00002-3] 7. Buchanan AM, Muro FJ, Gratz J, et al. Establishment of haematological and immunological reference values for healthy Tanzanian children in Kilimanjaro Region. Trop Med Int Health 2010;15(9):10111021. [http://dx.doi.org/10.1111/j.1365-3156.2010.02585.x] 8. Lugada ES, Mermin J, Kaharuza F, et al. Population-based hematologic and immunologic reference values for a healthy Ugandan population. Clin Diagn Lab Immunol 2004;11(1):29-34. [http://dx.doi. org/10.1128/CDLI.11.1.29-34.2004] 9. Gie J, Small K, Haskins C. Planning District Profiles. Cape Town: City of Cape Town, 2007:1-16. 10. Mentzer WC, Jr. Differentiation of iron deficiency from thalassaemia trait. Lancet 1973;1(7808):882. [http://dx.doi.org/10.1016/S0140-6736(73)91446-3] 11. Sazawal S, Dhingra U, Dhingra P, et al. Efficiency of red cell distribution width in identification of children aged 1-3 years with iron deficiency anemia against traditional hematological markers. BMC Pediatr 2014;14(8):1-6. [http://dx.doi.org/10.1186/1471-2431-14-8] 12. Vehapoglu A, Ozgurhan G, Demir AD, et al., Hematological indices for differential diagnosis of beta thalassemia trait and iron deficiency anemia. Anemia 2014(2014), article ID 576738. [http://dx.doi. org/10.1155/2014/576738] 13. Sikaris KA. Physiology and its importance for reference intervals. Clin Biochem Rev 2014;35(1):314. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&li st_uids=24659833 (accessed 9 June 2015). 14. Lawrie D, Coetzee LM, Glencross DK. Iron deficiency anaemia in healthy South African women despite iron fortification. S Afr Med J 2008;98(8):606-607. 15. Lawrie D, Coetzee LM, Becker P, Mahlangu J, Stevens W, Glencross DK. Local reference ranges for full blood count and CD4 lymphocyte count testing. S Afr Med J 2009;99(4):243-248. 16. Reich D, Nalls MA, Kao WH, et al. Reduced neutrophil count in people of African descent is due to a regulatory variant in the Duffy antigen receptor for chemokines gene. PLoS Genet 2009;5(1):e1000360. [http://dx.doi.org/10.1371/journal.pgen.1000360] 17. Badenhorst CJ, Fourie J, Steyn K, et al. The haematological profile of urban black Africans aged 15-64 years in the Cape Peninsula. East Afr Med J 1995;72(1):19-24. http://www.ncbi.nlm.nih.gov/entrez/ query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=7781549 (accessed 9 June 2015). 18. Adams VJ, Markus MB, Adams JF. Paradoxical helminthiasis and giardiasis in Cape Town, South Africa: Epidemiology and control. Afr Health Sci 2005;5(3):276-280. [http://dx.doi.org/10.5555/ afhs.2005.5.3.276] 19. Meents EF, Boyles TH. Schistosoma haematobium prevalence in school children in the rural Eastern Cape Province, South Africa. S Afr J Epidemiol Infect 2010;25(4):28-29. 20. O’Gorman MR, Millard DD, Lowder JN, Yogev R. Lymphocyte subpopulations in healthy 1-3-day-old infants. Cytometry 1998;34(5):235-241. [http://dx.doi.org/10.1002/(SICI)10970320(19981015)34:5<235::AID-CYTO5>3.0.CO;2-0 [pii] 21. Altin JG, Sloan EK. The role of CD45 and CD45-associated molecules in T cell activation. Immunol Cell Biol 1997;75(5):430-445. [http://dx.doi.org/10.1038/icb.1997.68] 22. Kiepiela P, Coovadia HM, Coward P, Woodhead R, Abdool-Karim SS, Becker P. Age-related lymphocyte sub-population changes among healthy Africans from birth to adulthood. Ann Trop Paediatr 1989;9(4):199-205. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=Pub Med&dopt=Citation&list_uids=2482000 (accessed 9 June 2015).

Accepted 19 January 2015.

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Evaluation of the diagnostic accuracy of the HemoCue device for detecting anaemia in healthy schoolaged children in KwaZulu-Natal, South Africa T P Gwetu, MB ChB, MPH; M K Chhagan, FCPaed, PhD Department of Public Health, School of Clinical Medicine, College of Health Sciences, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa Corresponding author: T P Gwetu (tgwetu@gmail.co.za)

Background. The prevalence of anaemia in school-aged children is reported to be high (>10%), yet neither the onset of anaemia nor the disease causing it is easily established. Any form of anaemia, even if mild, can compromise children’s health and survival. This study was conducted to generate data to support or reject use of the HemoCue device as a potential point-of-care method for haemoglobin (Hb) assessment in field and primary healthcare settings. Objective. To assess the validity of the HemoCue in relation to the gold-standard laboratory method. Methods. A cross-sectional study of children aged 6 - 8 years, analysing the diagnostic accuracy of the HemoCue in determining Hb levels in venous blood. Agreement between the HemoCue and laboratory techniques was evaluated using the Bland-Altman plot. The intra-class correlation coefficient was used to assess within-subject variability of measured Hb. Results. A trend of underestimation of Hb values was noted. The mean Hb with the HemoCue was 11.70 g/dL and that with the laboratory method 12.19 g/dL. The mean difference between the two methods was 0.49 g/dL, with a standard deviation of 0.77 g/dL (95% confidence interval –0.59 - –0.38). Discrepancies >1 g/dL were identified in 14.1% of cases. Bias increased with increasing Hb values. Conclusion. The HemoCue was found to be comparable to the standard laboratory method for determining Hb concentrations in school-aged children. Its usefulness for screening healthy children was demonstrated, although a full blood count is recommended if anaemia or iron deficiency is suspected. S Afr Med J 2015;105(7):596-599. DOI:10.7196/SAMJnew.7919

Anaemia frequently occurs in association with an underlying condition and is linked to poor clinical outcomes. In school-aged children in sub-Saharan Africa, the prevalence of anaemia is reported to be high (affecting 25.4%).[1] There is, however, a notable paucity of data relating to haemoglobin (Hb) levels, onset and duration of anaemia, and the underlying illness causing the anaemia in schoolaged children. This is a significant deficiency, as any anaemia, even if it is mild, can compromise growth and development, irrespective of the underlying condition causing it. The Hb level is endorsed by the World Health Organization (WHO) as the universal indicator of anaemia at individual and population levels.[2] However, most reliable ways of measuring it require some automated equipment that is not readily available in primary healthcare centres or resource-poor settings. An accurate diagnostic test is essential for identifying suboptimal Hb levels and monitoring the response to interventions. The HemoCue method has some key advantages over the routinely used laboratory method. The HemoCue device measures Hb in a small sample of undiluted capillary or venous blood, is portable and user friendly, does not require access to refrigeration or electricity, gives immediate digitally displayed results, and is relatively inexpensive. This study assessed the HemoCue as an alternative point-of-care (POC) test for diagnosing anaemia and as a potential vehicle to improve coverage for anaemia screening programmes. We also determined a practical initial diagnostic approach that could assist in selecting an appropriate management strategy.

Methods

Design and participants

We carried out a cross-sectional survey in a rural community living in an isolated mountainous part of western KwaZulu-Natal Province

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(KZN), South Africa. This study was an ancillary investigation in a larger longitudinal study measuring various health indicators and psychosocial needs of preschool and school-aged children. Data collection was integrated into the usual services at the research site as far as possible. One hundred and eighty-four consecutive children attending follow-up over a 4-month period were invited to take part in the current study.

Diagnostic testing

Hb values of children in this study were determined using two methods: the conventional laboratory method and the HemoCue device. Samples for the laboratory method and the HemoCue were collected simultaneously from the cephalic vein of seated participating children using a Vacutainer needle. Hb determination with the HemoCue was conducted at the research site by the principal investigator (TPG), who had received training on the standardised use of a portable HemoCue Hb-201+ system (Angelholm, Sweden). The child’s venous blood in the Vacutainer was used to fill a HemoCue cuvette and placed on the HemoCue. The result was read within 10 minutes and recorded to two decimal places. The device was calibrated each morning using the standard guideline provided. For every tenth participant, two HemoCue cuvettes were filled and the Hb values of the samples compared for quality control purposes. The HemoCue device readings were interpreted without knowledge of the results of the reference standard or clinical examination. Corresponding blood samples were sent for analysis according to standard protocol to a local accredited laboratory that measured Hb values using an automated analyser, the Siemens Advia 2120 machine. Anaemia cut-off values used were based on WHO recommen dations.[2] For the outcome measure of anaemia, Hb <11.5 g/dL was

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used. Anaemia was classified as mild (Hb 11.0 - 11.4 g/dL), moderate (8.0 - 10.9 g/dL) or severe (<8.0 g/dL).

Data management and analysis

Ethical considerations

Ethical approval for this study was obtained from the official review board of the University of KwaZulu-Natal Biomedical Research Ethics Committee. Informed consent was obtained from each child’s parent or caregiver before inclusion in the study. Children with anaemia were referred to their local health centre for further management.

Results

One hundred and eighty-four children participated in the study. The participants’ ages ranged from 72 to 102 months (mean 83.7 (standard deviation (SD) 7.3)). There were more boys (108/184, 58.7%) than girls (76/184, 41.3%). The children all had symptoms of anaemia, and none were reported to be taking iron supplements. The prevalence of anaemia using the laboratory method was 43/184 (23.4%) (mean Hb 12.17 g/dL, range 7.80 - 19.20; 95% CI 10.06 - 14.52). Anaemia was predomin

HemoCue, g/dL

16.00 14.00 12.00 10.00 8.00 6.00

8.00

10.00 12.00 14.00 16.00 18.00 20.00 Laboratory, g/dL

Fig. 1. Representation of linear regression of Hb concentrations between the HemoCue device and the laboratory method.

4.00 HemoCue, g/dL

Data were entered daily into a predesigned electronic database using the SPSS Statistics for Windows package, version 22.0 (IBM, USA), and cleaned regularly. SPSS was used to perform the statistical analysis. The distribution of Hb values was assessed using descriptive statistics and graphical plots. The paired Student’s t-test was used to compare mean Hb differences between the HemoCue device and the laboratory method. The intra-class correlation coefficient (ICC) and Pearson’s correlation coefficient were computed to assess the agreement and correlation between the Hb values provided by the two instruments. The Bland-Altman limits of agreement method was also applied to the numerical data to assess agreement between the two methods.[3] The Bland-Altman analysis was demonstrated in MS Excel. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) with 95% confidence intervals (CIs) were used to determine diagnostic accuracy of the categorical data. Clinical intervention for anaemia is generally provided for cases with moderate and severe anaemia. Hence the assessment of HemoCue performance takes into consideration its ability to detect clinically significant anaemia with Hb values that are ≤10.9 g/dL according to the laboratory method.

3.00 2.00 1.00 .00 -1.00

-4.00

-3.00

-2.00

-1.00

.00

1.00

Laboratory, g/dL Fig. 2. Bland-Altman representation of comparison analysis between the HemoCue device and the laboratory method.

antly mild (24/43, 55.8%) or moderate (18/43, 41.9%). Severe anaemia was rare (1/43, 2.3%). According to the HemoCue device, the mean Hb was 11.70 g/dL (range 6.60 - 15.50; 95% CI 9.45 - 14.13) and the prevalence of anaemia was 41.3% (76/184); 1/76 children (1.3%) had severe, 45/76 (59.2%) moderate and 30/76 (39.5%) mild anaemia.

Accuracy

The HemoCue device was generally precise and showed good correlation with the

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reference laboratory method (Figs 1 and 2); 158/184 (85.9%) of Hb values measured with the HemoCue were within 1 g/dL of those measured with the laboratory reference method, and 182/184 (98.9%) were within 2 g/dL. The sensitivity for anaemia of the HemoCue device was 93%, meaning that only 7% of children with anaemia were missed by the device. The NPV was 97%, indicating that children with an optimal HemoCue reading were probably not

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Table 1. Performance of the HemoCue device in detecting anaemia and severe anaemia relative to the laboratory method HemoCue performance n/N (%) Anaemia detection

Table 2. Diagnostic accuracy and precision of the HemoCue device HemoCue

Laboratory analyser

Hb (g/dL), mean

11.70

12.17

Range (g/dL)

6.6 - 15.5

7.8 - 19.20

0.189

0.187 0.087

0.088

Sensitivity

40/43 (93.0)

Mean difference (g/dL)

0.47 – statistically significant

Specificity

105/141 (74.5)

Coefficient of variation

1.63 – wide variation

PPV

40/76 (52.6)

95% limit of agreement

–1.07 - 2.02

NPV

105/108 (97.2)

SD (g/dL) (precision)

0.77

Discrepancies >1 g/dL, % of cases

14.1

Discrepancies >2 g/dL, % of cases

1.1

Anaemia severity Sensitivity

18/19 (94.7)

Specificity

138/165 (83.6)

PPV

18/45 (40.0)

NPV

138/139 (99.3)

anaemic. Specificity was good (94%), but the PPV was low (52.6%), indicating that among the children with suboptimal HemoCue readings only 52.6% actually had the condition (Table 1).

Precision

The HemoCue device demonstrated good reproducibility. Generally no differences were observed between repeat procedures on the same sample of blood at the same time. Sequential samples in the same patient did not differ significantly. The mean difference for repeat HemoCue readings using the BlandAltman method was 0.1 g/dL (95% CI 0.1 0.2). The 95% limits of agreement were –1.4 1.5 g/dL. Instrument error was therefore ruled out as a substantial contributor of error due to unreliability. The Bland-Altman mean difference for Hb values between the HemoCue device and the laboratory method was 0.47 g/dL (95% CI 0.36 - 0.59), with 95% limits of agreement ranging from –1.07 to 2.02 (Table 2). The SD (precision 0.77) and Pearson correlation coefficient (r=0.79) were high and significant (p=0.000). The ICC was 0.88 (95% CI 0.84 - 0.91). This was statistically significant (p=0.00). The ICC is calculated on a range of 0 - 1, with 1 representing complete reliability without any measurement errors and 0 reflecting unreliability. Variation was noted in mean Hb values depending on anaemia status. The mean Hb for anaemic participants was 0.32 g/ dL (95% CI –0.51 - –0.14) with a Pearson correlation coefficient of r=0.81 and SD 0.60, and statistically significant (p=0.001). The standard error (SE) was low (0.092). The mean difference in Hb values among the non-anaemic participants was 0.52 g/dL (95%

CI –0.66 - –0.39). The correlation among the non-anaemic participants was lower than among those who were anaemic (r=0.64, SD 0.81 and SE 0.068; p=0.000).

Discussion

This study showed that the HemoCue device was less accurate than the laboratory method and that its variability was significant. The hypothesis that the device is equivalent to the laboratory method has to be rejected. Nevertheless, it must be kept in mind that automated laboratory Hb analysis and the HemoCue are not competing techniques but complementary methods for Hb assessment. Laboratory analysis represents the goldstandard reference method for Hb assessment. An acceptable mean difference between the HemoCue and the laboratory method would be <1 g/dL;[4] our results therefore show a significant difference (14.1%; p<0.05) between the two methods when monitoring Hb values. The relevance of this limit should be interpreted with caution, however, as a 1 g/ dL error will have different consequences for interpretation of Hb values depending on the circumstances. In evaluating the results of this study, one also needs to keep in mind the usefulness of the HemoCue as a POC anaemia screening tool that is portable, displays Hb results rapidly within 1 minute, and uses a tiny blood sample. The HemoCue tended to underestimate Hb values compared with the laboratory method, which may result in overestimation of anaemia. Although the device gave lower Hb values, these measurements varied widely. Discrepancies in Hb values of >1.0 g/ dL were identified in 14.1% of participants and differences of >2 g/dL in 1.1%. Outliers of >2 g/dL are significant because they could result in altered clinical management, with children being overtreated or over investigated. Although such large differences in Hb values were

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infrequent, we recommend that clinical decisions should not be based solely on HemoCue results. While the differences noted could not definitely be attributed to any individual factor, they may be due to factors such as biological variation, collection mistakes during sampling, environmental factors or device error. Previous studies have generally reported a difference between the means, although most did not reach statistical significance. The range in the mean difference of Hb values in this study was 0.1 - 0.5 g/ dL (SD 0.37 - 1.1). A trend towards underestimation of Hb values has frequently been reported,[5-7] although some studies found no difference,[8] some overestimation,[9] and another both under- and overestimation, Neufield et al.[10] reporting underestimation of Hb values with capillary samples for concentrations <12.5 g/ dL and overestimation at higher values. The HemoCue device showed good sensitivity in detecting anaemia in the population studied (Table 2). Children with optimal Hb concentrations (>11.5 g/dL, the anaemia cut-off) are more likely to be misclassified than those with low values. The accuracy of the HemoCue was not affected by the presence of anaemia, although bias increased in non-anaemic participants with increasing Hb values. The mean difference in Hb values among non-anaemic children was 0.52 g/dL and that among anaemic children 0.32 g/dL. The sensitivity of the HemoCue for detecting anaemia was 93%, and the NPV was 97.22%. These values are near the top of the range reported in earlier studies, where sensitivity ranged from 75% to 91%, specificity from 88% to 100%, and PPVs from 75% to 86%.[11] Differences in anaemia detection and estimates of severity could influence statistical estimates in screening initiatives and surveys. When screening for anaemia, a high sensitivity as

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opposed to a high specificity is desirable, because poor outcomes are likely with untreated chronic anaemia. Although the HemoCue did not match the laboratory method, it can be expected to be useful as a screening tool and a reliable predictor of the need for a laboratory full blood count (FBC) in resource-poor populations. An FBC may be essential when anaemia is identified or iron deficiency is suspected in the presence of a normal HemoCue Hb reading. It is unlikely that clinically important anaemia will go unnoticed, either by the clinician or by the HemoCue. The HemoCue would therefore seem to be a useful screening method for anaemia in appropriate situations such as in primary healthcare, routine surveillance, field survey operations, or evaluation of interventions for iron nutrition. The HemoCue device was not expected to match the laboratory gold-standard method, but simply to provide an alternative technique in prescribed circumstances. The Clinical Laboratories Improvement Act of 1988 recommends that the estimated percentage difference between a number of devices measuring Hb levels in a laboratory setting should be about 7% of the actual value.[12] We found a very high coefficient of variation (1.63) for the HemoCue, which was higher than that documented by other researchers investigating the performance of the device under fieldwork conditions.[11] The mean difference for Hb values was 0.47 g/dL and the 95% limits of agreement between the HemoCue and laboratory Hb values were –1.07 - 2.02 g/dL, indicating that the two measurement methods agreed closely in estimating small values but disagreed with larger values (Fig. 2). This finding suggests that for any child in this study population, the Hb assessments could have differed between –1.07 and 2.02 g/dL. This is too wide-ranging to be clinically acceptable – it would mean, for example, that a child with an Hb value of 10 g/dL according to the HemoCue would be expected to have a laboratory measurement between 8.93 and 12.02 g/dL. Both the ICC and Pearson’s correlation coefficient were determined, because it is possible to have a high degree of correlation while agreement is poor. We demonstrated a significant correlation (r=0.85; p=0.001) and a significant bias of 0.47 g/dL (SD 0.77) between the HemoCue and the laboratory method in a field setting (Table 2). Accordingly, data obtained from the field can be assumed to be of the same level of reliability as data obtained in laboratory settings. The diagnostic precision of the HemoCue in laboratory settings is widely acknowledged,[11] but its performance outside the laboratory setting has been questioned. Morris et al.[13] suggested the use of repeat sampling to minimise the effect of unreliability. However, this is unlikely to be practical during fieldwork and in settings where large numbers are surveyed.

Study limitations

This study analysed blood samples obtained from healthy children, so the results are limited to the screening of well children and should not be translated into a setting where acutely ill children need a reliable result and speedy intervention. The HemoCue test is widely conducted with a finger-prick capillary sample. In children, Hb levels between venous and capillary samples have been reported to vary, with the largest discrepancies being in the neonatal period and in

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acutely ill children. The largest difference between the two sample types has been observed in anaemic children.[10,11]

Recommendations

Studies have shown that iron deficiency anaemia can result in impaired psychomotor and behavioural development, which may not be reversible.[14] National screening of all children for anaemia during infancy and later when they start school may be a logical and productive approach to anaemia control. Screening of children around the stage of school entry gives an adequate time interval for anaemia of chronic disease to become apparent. The feasibility of routine large-scale screening of children for anaemia has not been investigated. Further studies are required to address this significant challenge. Until such screening investigations are implemented, the National Department of Health needs to highlight and endorse the appropriate execution of the Integrated Management of Childhood Illness programme for identification and management of anaemia in children. Our study suggests that the HemoCue test is comparable to the reference laboratory method as a practical technique for detecting anaemia in school-aged children. For the device to be used widely and successfully, the interpretation of Hb values may need to be adjusted. The definition of anaemia in children may be improved by basing it on an Hb range linked to negative potential health outcomes. This approach to defining anaemia may, however, result in larger numbers of children being categorised as anaemic. Further research is required before recommending this diagnostic approach, with studies that regulate confounding variables such as comorbidities. References 1. De Benoist B, McLean E, Egli I, Cogswell M. Worldwide Prevalence of Anaemia 1993-2005: WHO Global Database on Anaemia. Geneva: World Health Organization, 2008. 2. World Health Organization. Haemoglobin Concentrations for the Diagnosis of Anaemia and Assessment of Severity. Vitamin and Mineral Nutrition Information System. Geneva: WHO, 2011. http://www.who.int/vmnis/indicators/haemoglobin.pdf (accessed 20 March 2015). 3. Altman DG. Practical Statistics for Medical Research. London: Chapman & Hall, 1991. 4. Radtke H, Polat G, Kalus U, Salama A, Kiesewetter H. Haemoglobin screening in prospective blood donors: Comparison of different blood samples and different quantitative methods. Transfus Apher Sci 2005;33(1):31-35. [http://dx.doi.org/10.1016/j.transci.2004.11.004] 5. Lara MAM, Kandulu J, Chisuwo L, Bates I. Evaluation and costs of different haemoglobin methods for use in district hospitals in Malawi. J Clin Pathol 2005;58:56-60. [http://dx.doi.org/10.1136/jcp.2004.018366] 6. Rechner IJ, Twigg A, Davies AF, Imong S. Evaluation of the HemoCue compared with the Coulter STKS for measurement of neonatal haemoglobin. Arch Dis Child Fetal Neonatal Ed 2002;86(3):F188-F189. [http://dx.doi.org/10.1136/fn.86.3.F188] 7. Cohen AR, Seidl-Friedman J. HemoCue system for haemoglobin measurement: Evaluation in anaemic and non-anaemic children. Am J Clin Pathol 1988;90(3):302-305. 8. Nkrumah B, Nguah SB, Sarpong N, et al. Haemoglobin estimation by the HemoCue portable haemoglobin photometer in a resource poor setting. BMC Clin Pathol 2011;11:5. [http://dx.doi. org/10.1186/1472-6890-11-5] 9. Spielmann N, Mauch J, Madjdpour C, Schmugge M, Weiss M, Haas T. Accuracy and precision of haemoglobin point-of-care testing during major paediatric surgery. International Journal of Laboratory Haematology 2012;34(1):86-90. [http://dx.doi.org/10.1111/j.1751-553X.2011.01363.x] 10. Neufeld L, García-Guerra A, Sánchez-Francia D, Newton-Sánchez O, Ramírez-Villalobos MD, RiveraDommarco J. Haemoglobin measured by HemoCue and a reference method in venous and capillary blood: A validation study. Salud Publica Mex 2002;44(3):219-227. [http://dx.doi.org/10.1590/S003636342002000300005] 11. Gwetu TP, Chhagan MK, Craib M, Kauchali S. HemoCue validation for the diagnosis of anaemia in children: A semi-systematic review. Pediat Therapeut 2013;4:187. [http://dx.doi.org/10.4172/2161-0665.1000187] 12. Medicare, Medicaid and CLIA programs. Regulations implementing the Clinical Laboratory Improvement Amendments of 1988 (CLIA)–HCFA. Final rule with comment period. Fed Regist 1992;57:7002-7186. 13. Morris SS, Ruel MT, Cohen RJ, Dewey KG, de la Briere B, Hassan MN. Precision, accuracy and reliability of haemoglobin assessment with use of capillary blood. Am J Clin Nutr 1999;69(6):1243-1248. 14. Lozoff B, Jimenez E, Hagen J, Mollen E, Wolf AW. Poorer behavioural and developmental outcome more than 10 years after treatment for iron deficiency in infancy. Paediatrics 2000;105(4):e51. http:// www.pediatrics.org/cgi/content/full/105/4/e51 (accessed 10 March 2015).

Accepted 11 June 2015.

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RESEARCH

Use of EMLA cream as a topical anaesthetic before venepuncture procedures in field surveys: A practice that helps children, parents and health professionals T P Gwetu, MB ChB, MPH; M K Chhagan, FCPaed, PhD Department of Public Health, School of Clinical Medicine, College of Health Sciences, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa Corresponding author: T P Gwetu (tgwetu@gmail.co.za)

Background. Topical analgesia is becoming essential as the number of invasive screening procedures involving children rises steadily. Little is known about the frequency of these procedures, or about interventions to ease the pain. Methods. We investigated the use of EMLA cream in 184 school-aged children in KwaZulu-Natal Province, South Africa. Another group of 20 children did not receive any local analgesia and was assessed as a control. Anticipatory anxiety, pain, adverse reactions and ease of procedure were assessed using a subjective visual analogue scale (VAS) pain score generated by the researcher and obtained from each child immediately after the procedure. Results. The use of EMLA cream resulted in reduced pain and distress. The pain-relieving influence of EMLA was good (91.3% analgesic effect). Participants who received EMLA cream reported significantly lower VAS pain scores (p=0.001). Pain scores generated by the researcher were also significantly lower in the EMLA group than in the control group (p=0.000). No adverse reactions were observed, and the children could continue with other research activities during the application time and after the procedure. Parent or caregiver scores were in favour of EMLA cream. Conclusion. EMLA cream was safe and effective for alleviating the pain associated with venepuncture in a fieldwork setting. We therefore believe that it merits a place in the routine premedication of children before phlebotomy and cannulation procedures in clinical settings, research studies and field surveys. Further research is recommended to assess whether EMLA cream can be used for immunisations. S Afr Med J 2015;105(7):600-602. DOI:10.7196/SAMJnew.7797

Children in healthcare settings endure painful procedures daily. Venepuncture of paediatric participants is also becoming increasingly common in many research studies and surveys. Several researchers have stated that venepuncture procedures are distressing to children and their families, and may affect the ease of performing the procedure,[1,2] the success rate and the child-healthcare provider relationship. We could find no reports documenting the efficacy of EMLA cream in a field setting for the management of pain related to short procedures. Discomfort associated with these procedures continues to be inadequately managed. Topical analgesia is becoming essential as the number of invasive screening procedures and health surveys involving children rises steadily. Children often do not understand why they are subjected to needle procedures such as phlebotomy.[2] Little is known about the frequency of these invasive procedures, or about the use of interventions to ease the pain. A eutectic mixture of local anaesthetics (EMLA), which consists of 2.5% lidocaine and 2.5% prilocaine, is a topical analgesic that works by blocking pain transmission to the brain. Few studies have addressed whether use of a local anaesthetic influences venepuncture success and hence enrolment and retention rates of children in research studies and surveys. This study describes the efficacy of EMLA cream in preventing pain in school-aged children in a field setting. When carried out in a reassuring environment, this non-invasive means of delivering analgesia is expected to minimise distress during venepuncture procedures. The implications for practice and the benefits to both researchers and participants are expected to result in improved public health screening.

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Methods

This study was an ancillary investigation in a larger longitudinal study measuring various health indicators and psychosocial needs of preschool and school-aged children. As far as possible, data collection was integrated into the usual services at the research site. One hundred and eighty-four consecutive children aged 6 - 8 years attending for follow-up over a 4-month period were invited to join the current study. Another group of 20 children who did not receive any local analgesia was assessed as a control. EMLA application was limited to children requiring needle puncture of intact skin for phlebotomy procedures. The collected venous blood samples were used to assess the childrenâ&#x20AC;&#x2122;s anaemia and iron status by laboratory assays for haemoglobin, serum ferritin and soluble transferrin receptor. These results are reported in another article.[3]

Application

The EMLA cream was applied at the research site before the phlebotomy procedure. The cream was applied to the skin surface under occlusion with a Tegaderm patch (3M). The dressing was placed at least 60 minutes before the phlebotomy procedure to allow for adequate local cutaneous absorption. A maximum of 120 minutesâ&#x20AC;&#x2122; application time was allowed to avoid significant systemic absorption of the lidocaine and prilocaine; 1 - 2 cm3 of cream was applied per cm2 of skin, up to a maximum of 10 mL on the same participant. During the application time the children continued with other scheduled research activities. The cream was removed and the skin disinfected before a venous blood sample was collected using a 22 G Vacutainer needle. The participant was repeatedly asked about any skin or systemic reactions during and up to 2 hours after the application time.

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Outcome assessment

The primary outcome was analgesic efficacy for acute procedurerelated pain. Anticipatory anxiety, pain, adverse reactions and ease of procedure were assessed. A subjective visual analogue scale (VAS) pain score of 0 - 3 was generated by the researcher and obtained through direct enquiry from each participant immediately after the phlebotomy procedure was completed. Pain responses were documented by the principal investigator (TPG) using subjective pain scores expressed through the VAS. A wry face was assessed as indicating mild pain, limb withdrawal as indicating moderate pain, and crying or resisting the procedure as indicating severe pain. The children were also asked about any pain they had experienced. The children’s responses and the observations made by the clinician were both scored on a four-point verbal scale (pain-free – 0, mild pain – 1, moderate pain – 2, severe pain – 3). The parent or caregiver observer ratings for the efficacy of EMLA cream in relieving pain were also considered.

Statistical analysis

The SPSS Statistics for Windows package, version 22.0 (IBM, USA), was used for data entry and analysis. Findings from the study were assessed with the variables characterised as either categorical or continuous. Categorical variables such as parental ratings of EMLA efficacy and anticipatory anxiety were analysed using a two-tailed Fisher’s exact test. Continuous variables such as VAS provider and self-reported scores were assessed using Student’s t-test and graphical plots. The study reported on the effects of EMLA with regard to the mean difference in pain, anxiety and ease of procedure during phlebotomy between the group that received EMLA and the control group with no intervention, relative risk (RR), and whether the effect on pain reduction was significant or non-significant.

Ethical considerations

This research received ethical clearance from the official review board of the University of KwaZulu-Natal Biomedical Research Ethics Committee. Informed consent was obtained from the children’s caregivers before they were included in the study.

Results

One hundred and eighty-four children participated in the study. The participants’ ages ranged from 72 to 102 months (mean 83.65, standard deviation 7.32). There were 109 males (59.2%) and fewer females (n=75, 40.8%). The mean application time was 72 minutes (range 60 - 104).

Anticipatory anxiety

The children were individually counselled before application of the cream, and told that it would help reduce the pain. This, together with a reassuring environment, resulted in the children co-operating with the phlebotomy procedure; 24/184 (13.0%) were noted to be mildly anxious, although they allowed the phlebotomy procedure to continue. The children in the control group were generally anxious (12/20, 60.0%) and showed some distress despite the reassuring environment.

Pain and distress

EMLA cream was effective in reducing pain during phlebotomy in 91.3% of participants compared with 25.0% in the control group. Of children who underwent procedures conducted with EMLA, only 3/184 (1.6%) complained of moderate pain and 13/184 (7.1%) of mild discomfort. The rest (n=168, 91.3%) were without pain. No child reported severe pain. The researcher’s pain scores

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were significantly lower in the EMLA group than in the control group (p=0.000). The participants who received EMLA also selfreported significantly lower pain scores (p=0.001). With regard to anaesthetic efficacy, EMLA significantly reduced the risk of pain compared with the control group (RR 0.11; 95% confidence interval (CI) 0.05 - 0.27), self-reporting of pain (RR 0.12; 95% CI 0.04 0.24), and observations by the investigators of responses indicating pain (RR 0.13; 95% CI 0.02 - 0.22).

Adverse reactions

EMLA cream was well tolerated and non-toxic in this study population. No adverse dermatological or systemic reactions were noted, and no itching or local reactions were observed. The children were able to continue with other scheduled research activities during the application time and also after the phlebotomy procedure.

Ease of procedure

Of phlebotomies with EMLA, 172/184 (93.5%) were graded as ‘easy’ compared with 12/20 (60.0%) in the control group. Easier needle insertion was noted with EMLA cream, and this was statistically significant (R=0.417; p=0.000).

Parent or caregiver ratings

The ratings of EMLA cream efficacy by parent or caregiver observer scales were in favour of the cream. They felt that EMLA cream was effective in decreasing the distress associated with the phlebotomy procedure in 180/184 children (97.8%).

Discussion

This study found the use of EMLA cream to be an effective strategy for managing acute procedure-related pain in children participating in field surveys. EMLA also improved the ease of the procedure. The reduced trouble and effort associated with restraining a struggling child has been reported by other researchers.[4] The 33.5% increase in ease of drawing blood when EMLA was used (93.5% for the EMLA group minus 60.0% for the control group) suggests that topical analgesia offers a substantial benefit. The analgesic effect of EMLA for this study population was 91.3%, comparable to other studies conducted in outpatient settings.[5,6] Errors that may cause inadequate analgesia include inappropriate application, a short waiting time, using a small volume of cream, and poor occlusion strategies such as a loose Tegaderm dressing.[1,2] These errors were minimised in this study by controlling the application time to between 1 and 2 hours, measuring the volume of cream used, and having trained medical personnel apply the cream and dressing. EMLA was well tolerated and non-toxic. No participants developed side-effects, although this could be due to the small sample size and/ or the short follow-up period. Although EMLA is generally reported to be non-toxic after infancy, local adverse outcomes have been described by other researchers and include erythema, oedema, allergic contact dermatitis and hyperpigmentation.[7] Seizures and respiratory depression were described in one case report.[8] Methaemoglobinaemia was the most dangerous and potentially fatal complication reported in neonates.[9] The limitations of EMLA use observed in this study included the need to wait for at least 60 minutes from application of the cream to the venepuncture procedure. The considerable waiting time required before an adequate analgesic effect could be overcome by allowing capable children and their caregivers to participate in the application after being instructed in the proper use of the cream.[10] The application of EMLA could also be scheduled earlier, while the child participates in other research activities or in the

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RESEARCH

waiting area. It was not possible to distinguish between problematic venepunctures that necessitated numerous needle insertions and anticipatory anxiety resulting in the child struggling even when pain relief was adequate. Anticipatory anxiety can be expected to lessen with widespread use of pharmacological and nonpharmacological strategies to reduce needle phobias.[11] If adequate pain relief is provided, children can be expected to become less fearful of needle-related procedures. The cost-effectiveness of the cream may be an issue if it is used in on a large scale, and needs to be weighed against the benefits of a stress-free, easier and safer venepuncture procedure. Needle phobia is a recognised medical disorder, affecting approximately 10% of the world population and resulting in fear and avoidance behaviour.[12] In the current study, 13.0% of the children who received EMLA cream were anxious about the procedure v. 60.0% in the control group. In an era when health of children in underdeveloped countries is being prioritised, with large-scale screening and intervention initiatives, avoidance of healthcare in order to avoid needle experience would be unfortunate.[12] Many screening tests and interventions rely on the hypodermic needle. Health professionals need to be mindful of the fact that needle phobia, although infrequent, may lead to avoidance of health initiatives. The use of topical analgesia in children should be prioritised, and health professionals need to be aware of available options to prevent the pain associated with needle procedures. The use of EMLA cream can be expected to result in safer and more effective venepuncture procedures in children by lessening the discomfort experienced by the child and making it easier to perform these procedures. Numerous other non-invasive topical anaesthetic options are available that can be measured against EMLA. Welldesigned clinical trials are necessary in order to assess EMLA further with regard to relative efficacy, safety and feasibility in children in a large-scale field setting in national surveys and also for childhood

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immunisations. Further studies, such as case-control studies, are also necessary to determine whether a waiting time of <60 minutes can be used without compromising the efficacy of the cream.

Conclusion

Use of EMLA cream can reduce pain, make venepuncture easier, and improve the therapeutic relationship with health professionals. Further research is recommended to assess whether EMLA can be used for childhood immunisations. References 1. Chen BK, Cunningham BB. Topical anaesthetics in children: Agents and techniques that equally comfort patients, parents, and clinicians. Current Opinion in Paediatrics 2001;13(4):324-330. [http:// dx.doi.org/10.1097/00008480-200108000-00007] 2. Rogers TL, Ostrow CL. The use of EMLA cream to decrease venepuncture pain in children. J Pediatr Nurs 2004;19(1):33-39. [http://dx.doi.org/10.1016/j.pedn.2003.09.005] 3. Gwetu TP, Chhagan MK. Evaluation of the diagnostic accuracy of the HaemoCue device for detecting anaemia in healthy school-aged children in KwaZulu-Natal, South Africa. S Afr Med J 2015;105(7):596599. [http://dx.doi.org/10.7196/SAMJnew.7919] 4. Choy L, Collier J, Watson AR. Comparison of lidocaine-prilocaine cream and amethocaine gel for local analgesia before venepuncture in children. Acta Paediatr 1999;88(9):961-964. [http://dx.doi. org/10.1111/j.1651-2227.1999.tb00190.x] 5. Hellgren U, Kihamia CM, Premji Z, Danielson K. Local anaesthetic cream for the alleviation of pain during venepuncture in Tanzanian schoolchildren. Br J Clin Pharmacol 1989;28(2):205-206. 6. Young SS, Schwartz R, Sheridan MJ. EMLA cream as a topical anaesthetic before office phlebotomy in children. South Med J 1996;89(12):1184-1187. [http://dx.doi.org/10.1097/00007611-19961200000010] 7. Godwin Y, Brotherston M. Hyperpigmentation following the use of EMLA cream. Br J Plast Surg 2001;54(1):82-83. [http://dx.doi.org/10.1054/bjps.2000.3466] 8. Rincon E, Baker RL, Iglesias AJ, et al. CNS toxicity after topical application of EMLA cream on a toddler with molluscum contagiosum. Pediatr Emerg Care 2000;16(4):252-254. [http://dx.doi. org/10.1097/00006565-200008000-00009] 9. Essink-Tebbes CM, Wuis EW, Liem KD, et al. Safety of lidocaine-prilocaine cream application four times a day in premature neonates: A pilot study. Eur J Pediatr 1999;158(5):421-423. [http://dx.doi. org/10.1007/s004310051106] 10. Koh JL, Fanurik D, Stoner PD, et al. Efficacy of parental application of eutectic mixture of local anesthetics for intravenous insertion. Pediatrics 1999;103:e79. [http://dx.doi.org/10.1542/ peds.103.6.e79] 11. Sokolowski CJ, Giovannitti JA, Boynes SG. Needle phobia: Etiology, adverse consequences, and patient management. Dent Clin North Am 2010;54(4):731-744. [http://dx.doi.org/10.1016/j.cden.2010.06.012] 12. Hamilton JG. Needle phobia: A neglected diagnosis. J Fam Pract 1995;41(2):169-175.

Accepted 2 February 2015.

July 2015, Vol. 105, No. 7

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GUEST EDITORIAL

Nutrition in toddlers This issue of CME is dedicated to nutrition and malnutrition in young children. It is an important topic in paediatric medicine and child health, because toddlers start feeding independently and lifelong feeding patterns for health are thus set in motion. Malnutrition as a result of protein or energy deficiency or chronic illness is relatively common in this age group, even in our modern world. The establishment of normal nutritional patterns in toddlers is precariously balanced between the legacy of infancy, genetic determinants, environmental inputs and social and cultural norms. Healthy nutrition is both physically and emotionally manipulated. While disease is reflected in growth, it is equally revealed in both micronutrient deficiency, intellectual dysfunction, immune disorders and behavioural pathology. A number of overt and subtle physical conditions are consequences of malnutrition. This issue of CME focuses on obvious gross malnutrition, malnutrition as a result of subtle deficiencies, and deficiencies associated with chronic illness. There are many national programmes and policies that address feeding and malnutrition. In the state healthcare delivery sector, severe acute malnutrition has received national priority and hospitals that treat children are required to keep detailed monthly admission data that include anthropometric details according to the new World Health Organization z-scores.[1] Mortality data for children are collected nationally according to the Child Healthcare Problem Identification Programme (CHPIP) data summary; this information determines the modifiable factors, including malnutrition. These data are critical to ensure that health priorities focus on the consequences of poverty, including malnutrition in children. Malnutrition in the modern world does not only comprise the consequences of protein energy shortage. There is also recognition of a growing concern for obesity in children and teenagers and insights into the health consequences of vitamin and trace element

deficiencies, including iron, vitamin D and vitamin A, although every vitamin and mineral is critical to good health. It is my pleasure to collate and present the articles in this issue of CME in the SAMJ. I thank the authors for outstanding contributions and trust that readers will find this issue constructive and educational. I have included an article by Jeane Cloete[2] on ‘Management of severe acute malnutrition’, in which she motivates for the implementation of a multifocus set of interventions for feeding, but also that one should not ignore the social needs of children with the condition. Colleagues Tony Westwood,[3] Etienne Nel and Alta Terblanche,[4] and Rajendra Thejpal[5] share their wealth of knowledge on ‘Nutrition in children with long-term health conditions’ (chronic illness), ‘Nutritional support of children with chronic liver disease’ and ‘Iron deficiency in children’, respectively. The review article relates to vitamin D deficiency in young people. Ultimately, our goal is improved health for South African children and potential achievement of the Millennium Development Goals of improved child health in our country and on our continent. R J Green Department of Paediatrics and Child Health Faculty of Health Sciences University of Pretoria South Africa robin.green@up.ac.za 1. http://www.who.int/childgrowth/en/ (accessed 10 January 2015). 2. Cloete J. Management of severe acute malnutrition. S Afr Med J 2015;105(7):605. [http://dx.doi. org/10.7196/SAMJnew.7782] 3. Westwood A. Nutrition in children with long-term health conditions. S Afr Med J 2015;105(7):606. [http:// dx.doi.org/10.7196/SAMJnew.7784] 4. Nel ED, Terblanche AJ. Nutritional support of children with chronic liver disease. S Afr Med J 2015;105(7):607. [http://dx.doi.org/10.7196/SAMJnew.7783] 5. Thejpal R. Iron deficiency in children. S Afr Med J 2015;105(7):607. [http://dx.doi.org/10.7196/SAMJnew.7781]

S Afr Med J 2015;105(7):603. DOI:10.7196/SAMJnew.7915

REVIEW

Vitamin D deficiency and insufficiency in Africa and the Middle East, despite year-round sunny days R J Green,1 PhD, DSc; G Samy,2 MD, PhD; M S Miqdady,3,4 MD; M El-Hodhod,5 MD; O O Akinyinka,6 MB BS, PhD; G Saleh,7 MD; J Haddad,8 MD; S A Alsaedi,9 MD; A Y Mersal,10 MB BS, FRCPC; A Edris,11 MD; M Salah,12 MD epartment of Paediatrics and Child Health, Faculty of Health Sciences, University of Pretoria, South Africa D Department of Child Health and Nutrition, Institute of Postgraduate Childhood Studies, Ain Shams University, Cairo, Egypt 3 Division of Hepatology and Nutrition, Department of Pediatric Gastroenterology, Sheikh Khalifa Medical City, United Arab Emirates 4 Adjunct Staff, Cleveland Clinic, USA 5 Department of Pediatric Gastroenterology and Endoscopy, Faculty of Medicine, Ain Shams University, Cairo, Egypt 6 Department of Paediatrics, College of Medicine, University of Ibadan, Ibadan, Nigeria 7 National Nutrition Institute, Cairo, Egypt 8 Department of Pediatrics, Faculty of Medicine, Balamand University, Beirut, Lebanon 9 Department of Pediatrics in ICU Section, King Abdulaziz University, Jeddah, Saudi Arabia 10 Department of Pediatrics, King Faisal Specialist Hospital and RC, Jeddah, Saudi Arabia 11 Department of Pediatrics and Neonatology, Faculty of Medicine, Cairo University, Cairo, Egypt 12 Medical Affairs and R&D Department, Wyeth Nutrition, Nestlé (Middle East), United Arab Emirates 1 2

Corresponding author: R J Green (robin.green@up.ac.za)

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CONTINUING MEDICAL EDUCATION

Exposure to sunlight, specifically ultraviolet B (UVB), is essential for cutaneous vitamin D synthesis. Despite significant daily sunlight availability in Africa and the Middle East, persons living in these regions are frequently vitamin D insufficient or deficient. Vitamin D insufficiency (25-hydroxyvitamin D (25(OH)D) between 15 and 20 ng/mL (37.5 - 50 nmol/L)) has been described in various population groups, ranging from 5% to 80%. Risk factors include traditional dress and avoidance of sunlight exposure, and multiple dietary factors as a result of specific cultural beliefs. Vitamin D resistance due to calcium deficiency mechanisms has been described in similar population groups, which may lead to hypovitaminosis D. Should the new diseases related to hypovitaminosis D prove to be truly associated, Africa and the Middle East will become an epicentre for many of these conditions. Urgent attention will need to be paid to cultural dress and dietary behaviours if hypovitaminosis D is to be taken seriously. Should such factors not be correctable, new strategies for supplementation or food fortification will have to be devised. S Afr Med J 2015;105(7):603-605. DOI:10.7196/SAMJnew.7785

The subject of vitamin D insufficiency has become topical since an increase in the number of reports in the medical literature of health-related problems in children and adults with vitamin D insufficiency. It is important to assess vitamin D status before frank deficiency, because many conditions are linked to this condition. Vitamin D insufficiency and deficiency are extremely common in Africa and the Middle East, despite these regions having high levels of sunlight exposure in summer and winter. This important paradox may have many explanations, which need to be defined for corrective action to be taken for children and adults at risk of hypovitaminosis D.

Vitamin D metabolism

Exposure to sunlight, specifically ultraviolet B (UVB), is essential for cutaneous vitamin D synthesis; UVB radiation is higher at midday than at other times of the day. During spring, summer and autumn, 10 - 15 minutes of sun exposure between 10h00 and 15h00 are sufficient for adequate vitamin D synthesis in light-skinned individuals.[1] However, most Asian Indians require three times as much sun exposure as lightskinned individuals to achieve equivalent vitamin D concentrations, and individuals with very dark skin pigmentation (e.g. some with African ancestry) require 6 - 10 times as much exposure as lightskinned individuals.[2,3] The use of sunscreens and sunblock with a sun protection factor of 30 may decrease vitamin D synthetic capacity by as much as 95%.[4] Staying indoors for long periods can also cause reduced vitamin D synthesis,[5] which may lead to low vitamin D levels in disabled children and those who stay primarily indoors.[6] Less than 10% of vitamin D is derived from dietary sources in the absence of food fortification or use of supplements. Both the D2 and D3 forms are used for food fortification. The primary natural (unfortified) dietary sources of vitamin D are oily fish (salmon, mackerel, sardines), cod liver oil, liver and organ meats, and egg yolk. Children typically consume few of these sources consistently. Because of the scarcity of natural dietary sources, vitamin D is fortified in many foods, particularly milk and milk products, orange juice, bread and cereals. Infant formulas in the USA are required to contain 40 - 100 IU vitamin D/100 kcal (usually providing at least 400 IU/L), and milk and orange juice that are labelled vitamin D fortified are required to contain at least 400 IU/L. The third trimester in pregnancy is a critical time for vitamin D transfer, because this is when the fetal skeleton becomes calcified, requiring increased activation of 25-hydroxyvitamin D (25(OH)D) to 1,25(OH)2D in the maternal kidneys and placenta. Vitamin D levels are particularly low in premature infants, who have less time to accumulate vitamin D from the mother through placental transfer.[7] The vitamin D content of breastmilk is low (15 - 50 IU/L), even in a mother with sufficient vitamin D, and exclusively breastfed infants consuming an average of 750 mL of breastmilk daily ingest only 10 - 40 IU vitamin D in the absence of sun exposure or

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supplement use. Vitamin D content of breastmilk is even lower in dark-skinned mothers or mothers with other causes of vitamin D deficiency.[8] A study that included black and white infants estimated that most breastfed infants need to be exposed to sunlight for at least 30 minutes/week while wearing only a nappy in order to maintain 25(OH)D levels at >20 ng/mL (50 nmol/L).[9] This amount of sun exposure is unlikely, given current recommendations to limit sun exposure in infants <6 months old. The advantage of sun exposure in providing vitamin D needs to be balanced against the potential risk of skin cancer from excessive exposure to UV radiation, particularly melanoma, which is one of the most common forms of cancer among young adults – especially lightskinned individuals. These concerns have led to recommendations that direct sunlight exposure should be avoided in infants <6 months old, and that sun exposure should be limited in older children through the use of protective clothing and sunscreen.[10]

High-risk groups

A number of previously recognised risk factors for vitamin D deficiency and insufficiency are listed in Table 1. These factors, however, fail to emphasise the problem of insufficiency in regions with high sunlight exposure. Based on many considerations, currently accepted standards for defining vitamin D status in children and adolescents are as follows:[11-13] • Vitamin D sufficiency: 25(OH)D ≥20 ng/mL (50 nmol/L) • Vitamin D insufficiency: 25(OH)D between 15 and 20 ng/mL (37.5 - 50 nmol/L) • Vitamin D deficiency: 25(OH)D ≤15 ng/mL (37.5 nmol/L). Table 1. Known risk factors for vitamin D deficiency and insufficiency in children • E xclusively breastfed infants, particularly if the mothers were vitamin D deficient during pregnancy • Premature infants • Children with chronic illnesses, especially liver and kidney disease • Malnourished children • Dark-skinned children • Living at higher latitudes • Limited sun exposure • Developed nations; if sufficient vitamin D intake is not ensured through the use of supplements and fortified foods, particularly if exposure to sunlight is limited • Use of certain medications, e.g. anticonvulsants or antiretrovirals • Malabsorptive conditions • Children on glucocorticoid treatment, which inhibits intestinal vitamin D-dependent calcium absorption

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Prevalence of vitamin D insufficiency in Africa and the Middle East

Vitamin D insufficiency and deficiency are common across these regions, with studies in South Africa (SA) reporting insufficiency in 19% of 10-year-old children and deficiency in 7%.[14] In Nigeria, 83% of Fulani women were reported to by deficient[15] and in the United Arab Emirates (UAE) a study reported 50% of pregnant women being deficient.[16] In Saudi Arabia, a study found 59% of healthy 4 - 15-year-old schoolchildren to be deficient and 28% insufficient in vitamin D.[17] Studies in every country in this region reveal significant numbers of individuals with vitamin D insufficiency and deficiency.

Aetiological factors for vitamin D insufficiency and deficiency in Africa and the Middle East

The following factors have been reported to be associated with vitamin D insufficiency and deficiency in Africa and the Middle East: black race and seasonality in SA children;[14] inactivity; smoking; injectable progestin contraceptive use; high alcohol consumption and diets low in calcium and high in animal protein; phosphorus and sodium intake in SA adults;[18] diets rich in corn and cassava;[19] diets rich in unfortified dairy products in Nigerian adults;[15] fast-food diets in the UAE;[20] women in purdah,[21] traditional or religious dress;[15,21] socioeconomic status in Nigerian adults;[22] exclusive breastfeeding in Nigerian children;[15,20,21] indoor lifestyle in Nigeria;[15,20] chronic disease in Egyptian adults,[23] and adolescent girls in Iran and Saudi Arabia;[24,25] anaemia in a group of adults living in Riyadh, Saudi Arabia;[26] lack of sunlight exposure[16] and body mass index in the UAE.[27]

Conclusion

Should the new diseases related to hypovitaminosis D prove to be truly associated, then Africa and the Middle East will become an epicentre for many of these conditions. Urgent attention will need to be paid to cultural dress and dietary behaviours if hypovitaminosis D is to be taken seriously. Should such factors not be correctable, new strategies for supplementation or food fortification will urgently need to be devised.

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References 1. Misra M, Pacaud D, Petryk A, Collett-Solberg PF, Kappy M. Vitamin D deficiency in children and its management: Review of current knowledge and recommendations. Pediatrics 2008;122(2):398-417. [http://dx.doi.org/10.1542/peds.2007-1894] 2. Hollis BW. Circulating 25-hydroxyvitamin D levels indicative of vitamin D sufficiency: Implications for establishing a new effective dietary intake recommendation for vitamin D. J Nutr 2005;135:317-322. 3. Holick MF. Photosynthesis of vitamin D in the skin: Effect of environmental and life-style variables. Fed Proc 1987;46:1876-1882. 4. Matsuoka LY, Ide L, Wortsman J, MacLaughlin JA, Holick MF. Sunscreens suppress cutaneous vitamin D3 synthesis. J Clin Endocrinol Metab 1987;64:1165-1168. 5. Tangpricha V, Turner A, Spina C, Decastro S, Chen TC, Holick MF. Tanning is associated with optimal vitamin D status (serum 25-hydroxyvitamin D concentration) and higher bone mineral density. Am J Clin Nutr 2004;80:1645-1649. 6. Del Arco C, Riancho JA, Luzuriaga C, González-Macías J, Flórez J. Vitamin D status in children with Down’s syndrome. J Intellect Disabil Res 1992;36:251-257. 7. Greer FR. Fat-soluble vitamin supplements for enterally fed preterm infants. Neonatal Netw 2001;20:7-11. 8. Specker BL, Tsang RC, Hollis BW. Effect of race and diet on human-milk vitamin D and 25-hydroxyvitamin D. Am J Dis Child 1985;139:1134-1137. 9. Specker BL, Valanis B, Hertzberg V, Edwards N, Tsang RC. Sunshine exposure and serum 25-hydroxyvitamin D concentrations in exclusively breast-fed infants. J Pediatr 1985;107:372-376. 10. Committee on Environmental Health. Ultraviolet light: A hazard to children. Pediatrics 1999;104:328333. 11. Misra M, Pacaud D, Petryk A, et al. Vitamin D deficiency in children and its management: Review of current knowledge and recommendations. Pediatrics 2008;122:398-417. [http://dx.doi.org/10.1542/ peds.2007-1894] 12. Boonen S, Rizzoli R, Meunier PJ. The need for clinical guidance in the use of calcium and vitamin D in the management of osteoporosis: A consensus report. Osteoporos Int 2004;15:511-519. 13. Lips P. Vitamin D deficiency and secondary hyperparathyroidism in the elderly: Consequences for bone loss and fractures and therapeutic implications. Endocr Rev 2001;22:477-501. 14. Poopedi MA, Norris SA, Pettifor JM. Factors influencing the vitamin D status of 10-year-old urban South African children. Public Health Nutr 2011;14(2):334-339. [http://dx.doi.org/10.1017/ S136898001000234X] 15. Glew RH, Crossey MJ, Polanams J, Okolie HI, VanderJagt DJ. Vitamin D status of seminomadic Fulani men and women. J Natl Med Assoc 2010;102(6):485-490. 16. Dawodu A, Dawson KP, Amirlak I, et al. Diet, clothing, sunshine exposure and micronutrient status of Arab infants and young children. Ann Trop Paediatr 2001;44:39-44. 17. Mansour MM, Alhadidi KM. Vitamin D deficiency in children living in Jeddah, Saudi Arabia. Indian J Endocrinol Metabol 2012;16:263-269. [http://dx.doi.org/10.4103/2230-8210.93746] 18. Kruger MC, Kruger IM, Wentzel-Viljoen E, Kruger A. Urbanization of black South African women may increase risk of low bone mass due to low vitamin D status, low calcium intake, and high bone turnover. Nutr Res 2011;31(10):748-758. [http://dx.doi.org/10.1016/j.nutres.2011.09.012] 19. Maziya-Dixon BIO, Akinyele EB, Oguntona S, et al. Nigeria Food Consumption and Nutrition Survey 2001 - 2003. Summary. Ibadan, Nigeria: International Institute of Tropical Agriculture (IITA), 2005. 20. Okonofua F, Houlder S, Bell J, Dandona P. Vitamin D nutrition in pregnant Nigerian women at term and their newborn infants. J Clin Pathol 1986;39(6):650-653. 21. Sanchez PA, Idrisa A, Bobzom DN, et al. Calcium and vitamin D status of pregnant teenagers in Maiduguri, Nigeria. J Natl Med Assoc 1987;89(12):805-811. 22. Ene-Obong HN, Enugu GI, Uwaegbute AC. Determinants of health and nutritional status of rural Nigerian women. J Health Popul Nutr 2001;19(4):320-330. 23. Gannagé-Yared MH, Chedid R, Khalife S, Azzi E, Zoghbi F, Halaby G. Vitamin D in relation to metabolic risk factors, insulin sensitivity and adiponectin in a young Middle-Eastern population. Eur J Endocrinol 2009;160:965-971. [http://dx.doi.org/ 10.1530/EJE-08-0952] 24. Moussavi M, Heidarpour R, Aminorroaya A, et al. Prevalence of vitamin D deficiency in Isfahani High School students in 2004. Horm Res 2005;64:144-148. 25. Siddiqui AM, Kamfar HZ. Prevalence of vitamin D deficiency rickets in adolescent school girls in Western region, Saudi Arabia. Saudi Med J 2007;28:441-444. 26. Abdulkareem O, Alsuwaida YM, Farag, et al. Prevalence of vitamin D deficiency in Saudi adults. Saudi Med J 2013;34(8):814-818. 27. Muhairi SJ, Mehairi AE, Khouri AA, et al. Vitamin D deficiency among healthy adolescents in Al Ain, United Arab Emirates. BMC Public Health 2013;13:33. [http://dx.doi.org/10.1186/1471-2458-13-33]

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ARTICLE

Management of severe acute malnutrition J Cloete, MB ChB, MMed (Paediatrics and Child Health), DCH (SA), Dip HIV Man (SA) Department of Paediatrics and Child Health, Faculty of Health Sciences, University of Pretoria, South Africa Corresponding author: J Cloete (jeane.cloete@up.ac.za )

Malnutrition remains a global health concern and contributes significantly to childhood mortality. Nearly half of all deaths in children <5 years of age are attributed to undernutrition, especially in developing countries. It is important to differentiate between acute and chronic malnutrition, as the management and mortality for these two conditions differ. Management should follow integrative management protocols to ensure that mortality and morbidity are minimised. General principles for inpatient management of acute malnutrition can be divided into two phases, i.e. the initial stabilisation phase (usually in the first week) for acute complications, and the much longer rehabilitation phase. The initial phase lasts approximately 1 week and involves intensive monitoring and treatment. Severe acute malnutrition remains a problem in public health, especially in developing countries. Adhering to programmatic approaches for diagnosis and management ensures lower mortality rates and better outcomes. S Afr Med J 2015;105(7):605. DOI:10.7196/SAMJnew.7782

Malnutrition remains a global health concern and contributes significantly to childhood mortality. Nearly half of all deaths in children <5 years of age are attributed to undernutrition, especially in developing countries.[1,2] Implementation of programmatic management approaches developed by the World Health Organization (WHO) and United Nations Children’s Fund (UNICEF) has markedly reduced fatalities due to severe acute malnutrition (SAM). Further expansion of the existing programmes to include community-based initiation of treatment should decrease the mortality even further. This has been documented in numerous studies as being successful in rural regions of Africa and Asia.[1,3-7] Acute malnutrition develops when under nutrition occurs in an essential period of childhood growth, and is exacerbated by coexistent infection and metabolic abnor malities.

children aged 6 months - 5 years can be divided into three groups, as shown in Fig. 1. Marasmic patients have signs of wasting in the axilla, groin and buttock areas, and subsequently on the face. Kwashiorkor is mainly diagnosed by the presence of bilateral symmetrical pitting oedema (the degree should be graded for severity). These patients often have additional signs, such as hyperpigmented dermatosis that may desquamate, which in turn may become secondarily infected. It is important to consider other possible diagnoses in patients who demonstrate a poor response to treatment or may have additional conditions. Children with marasmic kwashiorkor are often severely ill and have a higher risk of mortality.

Treatment

Every patient with SAM should be assessed to decide whether in- or outpatient management is best. In developing countries, with the highest incidence of undernutrition, lack of resources limits the ability to admit every child. Effective screening to correctly enrol patients in outpatient programmes has been shown to improve survival.[3-7,10-14] Classifying patients according to anthropometry, presence or absence of symmetrical bilateral pitting MUAC <11.5 cm

Marasmus WFH z-score >3 SD below the mean

Diagnosis

It is important to differentiate between acute and chronic malnutrition, as man agement and mortality of these two conditions differ. [3,6] The hallmark of chronic malnutrition is stunted growth, while in acute malnutrition there is wasting, with or without the presence of symmetrical bilateral pitting oedema and other signs, such as sparse hair, skin changes or an enlarged smooth liver. Patients with chronic malnutrition occasionally develop acute malnutrition owing to the presence of infection or a sudden change in food security. SAM in

Management of the three categories of acute malnutrition should be approached in the same manner by following inte grative management protocols to ensure that mortality and morbidity are kept as low as possible.[3,4,6,8,9]

MUAC <12.5 cm Acute malnutrition

Kwashiorkor

WFH z-score >2 SD below the mean Clinical signs Severe wasting

Marasmic kwashiorkor

Symmetrical bilateral pitting oedema Other signs of malnutrition

Bilateral pitting oedema

Fig. 1. Clinical forms of acute malnutrition (MUAC = mid-upper-arm circumference; WFH = weight for height; SD = standard deviation).

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Anthropometry WFH z-score and/or MUAC MUAC 11.5 - 12.5 cm WFH z-score -2 to -3

MUAC <11.5 cm WFH z-score <-3 SD

Table 1. General approach to inpatient management of severe acute malnutrition (World Health Organization 10-step approach) Stabilisation phase • Prevention and treatment of hypoglycaemia

Presence of bilateral pitting oedema?

• Prevention and treatment of hypothermia • Prevention and treatment of dehydration • Correction of electrolyte imbalance

Severe acute malnutrition*

Yes

• Treatment of infection • Correction of micronutrient deficiencies • Feeding

Moderate acute malnutrition

Complications present?

Yes

Inpatient management

• Provide sensory stimulation and emotional support

Good appetite

• Preparation for discharge

Outpatient management

Fig. 2. In- or outpatient management for severe acute or moderate acute malnutrition (RTUF = readyto-use therapeutic food). *Severe acute malnutrition can be treated on an inpatient basis, irrespective of complications, especially in the presence of oedema.

oedema and complications (pneumonia, sepsis, severe diarrhoea with shock and metabolic complications, i.e. hypoglycaemia and hypothermia) assists with decisionmaking with regard to in- or outpatient management (Fig. 2).[2,3,8,9,15-18] The beneficial principles for inpatient management of acute malnutrition can be divided into two phases, i.e. the initial stabilisation phase (usually in the first week, when acute complications are managed) and a much longer rehabilitation phase (Table 1). Table 1 reflects the general approach to the inpatient management of SAM (WHO 10-step approach).

Stabilisation phase

Prevention and treatment of hypoglycaemia It is of the utmost importance to monitor glucose levels in patients with SAM; their blood glucose should be assessed on admission. Ongoing glucose evaluation is important, especially when hypothermia is present. If facilities are not available for sideroom or laboratory investigation of blood glucose, patients should be treated as though hypoglycaemia is present. Regular feeding must be continued over a 24-hour period (not interrupted at night) as an important preventive measure for

• Continued feeding • Achieve catch-up growth

Appetite test with RTUF Not good appetite

Rehabilitation phase

hypoglycaemia. If it is present, the patient should be actively managed, preferably with oral feeds or fluids, as mortality can thus be prevented.[4,9] Prevention and treatment of hypothermia As hypothermia is associated with mortality, it is important to monitor body temperature on admission and during rewarming. This should occur 2-hourly until the child’s temperature remains >36.5oC. Prevention of hypothermia, by ensuring that the patient is covered at all times and kept away from draughts, and avoiding prolonged exposure during bathing and medical examination, is critical. Wet nappies, clothes and bedding must be changed quickly and it is important to check blood glucose levels during episodes of hypothermia. The patient should be fed immediately or rehydration should be commenced as needed. Rewarm children with a warmed blanket and place a heater or lamp nearby. To rewarm infants, they must be placed on their mother’s bare chest.[2] Treatment of dehydration and diarrhoea Assessment of dehydration in severely malnourished children in the presence of oedema may be challenging. Small

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volumes of unformed stools may be passed as a consequence of the underlying malnutrition; this should not be confused with profuse watery diarrhoea. To prevent dehydration when a child has continuing watery diarrhoea, breastfeeding or starter formula feeding should be encouraged. Stool losses should be replaced with approximate volumes of oral rehydration solution, which is much safer than intra venous fluids.[3,4,7,8,10,11,19-21] All children with profuse watery diarrhoea should be assumed to be dehydrated and managed with rehydration measures. These patients have low cardiac reserves – intravenous fluids may lead to volume overload and possibly cardiac failure. Oral rehydration is a much safer option for correction of dehydration. Shock from dehydration and sepsis are also likely to coexist in severely malnourished children. Overhydration and repeated intravenous boluses during resus citation increase mortality. The amount of fluid administered is determined by the child’s response and monitored by pulse and respiratory rates. With improvement in these rates, intravenous fluid boluses should be discontinued. Intravenous fluids (halfstrength Darrow’s solution with 5% dextrose) should be administered at a conservative rate, rehydrating slowly, or alternatively oral or nasogastric rehydration with an oral rehydration solution should be employed. It is imperative to frequently re-evaluate the patient to ensure that overhydration does not occur, which is a frequent cause of death. Continued rapid breathing and a rapid

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pulse during rehydration suggest coexisting infection or overhydration. The following are signs of excess fluid (overhydration): increased respiratory and pulse rates, increased oedema and puffy eyelids. In these instances, fluids must be discontinued immediately.[3,4,7,8,10,11,19,20] Additional treatment modalities for diarrhoea include the use of zinc supplementation. This has been shown to be beneficial, shortening the duration of the illness. In dysentery, the administration of intravenous cefotaxime or ceftriaxone must be considered.[3,8,18-20,22-24] Correction of electrolyte imbalances All severely malnourished children have excess body sodium, even though plasma sodium may be low. Fluids, or feeds containing excessive sodium, may cause mortality. Potassium and magnesium deficiencies are also present and may take at least 2 weeks to correct (Box 1). Oedema is partly due to these imbalances and is consequently not treated with a diuretic. Treatment of infection In severe malnutrition the usual signs of infection, such as fever, are often absent, and infections are often occult. Therefore, broad-spectrum antibiotics with adequate Gram- positive and -negative cover should be provided. Where specific infections are identified, specific antimicrobials should be administered, e.g. antimalarial treatment for malaria and metronidazole for gastrointestinal infections and infestations.[7,8,19,25] Box 1. Dosage of potassium chloride and magnesium supplementation Potassium chloride solution 25 - 50 mg/kg/dose orally 3 times daily until oedema subsides: <10 kg - 250 mg >10 kg - 500 mg Extra magnesium: 0.4 - 0.6 mmol/kg/day

Correction of micronutrient deficiencies Vitamin and mineral deficiencies are common in malnutrition. Supplementation (Table 2) should be given for at least 2 weeks. Although anaemia is frequently present, iron supplementation should not be commenced initially, but delayed until the child has a good appetite and starts gaining weight – usually by the second week. Early iron supplementation may aggravate infection status. Start cautious feeding Feeding a malnourished child takes place in two phases. During the stabilisation phase a cautious approach is required because of the child’s compromised physiological state and reduced homeostatic capacity. Feeding should start as soon as possible, but in small volumes. Starting with feeds that are too large places the child at greater risk of developing the ‘refeeding syndrome’. A starter formula of ~75 kcal/100 mL and 0.9 g protein/100 mL should, ideally, be initiated. The child should be weighed daily and it is useful to monitor the amount of feed remaining after a meal and the frequency and consistency of stools. These should diminish progressively. Signs of progression to the rehabilitation phase include a return of appetite and a loss of all oedema, which usually occurs about 1 week after admission. A gradual transition to the rehabilitation phase is recommended to avoid the risk of heart failure, which may occur if malnourished children suddenly consume large-volume feeds.

Rehabilitation phase

In the rehabilitation phase, a vigorous approach to feeding is required to achieve high intakes and rapid weight gain of 10 g/kg/day. Ready-to-use therapeutic food (RTUF) packages have been successful, not only during outpatient management programmes, but also during the rehabilitation phase. An alternative option is a higher energy and protein-containing formula, such as the WHO

Table 2. Micronutrient and vitamin replacements Micronutrient or vitamin

Dosage

Vitamin A • Orally on day 1, unless there is definite evidence that a dose has been given in the last month

<6 months: 50 000 IU 6 - 12 months: 100 000 IU >12 months: 200 000 IU

Multivitamin supplement • Give daily for at least 2 weeks Folic acid

1 mg/day (give 5 mg on day 1)

Zinc

2 mg/kg/day

Copper

0.3 mg/kg/day

Iron

3 mg/kg/day, but only when gaining weight

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F-100 formula. Continued monitoring after transition would include weight assessment every morning. If weight gain is poor, the patient would benefit from a full nutritional assessment; otherwise an alternative diagnosis should be considered.[4,8,15,17,26] Provide sensory stimulation, emotional support and follow-up after recovery In severe malnutrition, there is delayed mental and behavioural development. A cheerful and stimulating environment should be provided for the patient, with provision of structured play therapy for 30 minutes per day as soon as the child is well enough to be active. Maternal involvement, where possible, is important and an essential education contact point before discharge to ensure continued stimulating play at home. Discharge should occur with a clear follow-up plan, including frequent weight assessment. Furthermore, ensure that booster immunisations and vitamin A are given.[21]

Conclusion

SAM remains a problem in public health, especially in developing countries. Adhering to programmatic approaches for diagnosis and management ensures lower mortality rates and better outcomes. References 1. Blo M, Borghi E, Frongillo E, Morris R. Underweight in 1990 and 2005. J Am Med Assoc 2004;291:2600-2606. 2. World Health Organization (WHO) and United Nations Children’s Fund (UNICEF). WHO Child Growth Standards and the Identification of Severe Acute Malnutrition in Infants and Children. Geneva: WHO, 2009. 3. Collins S, Dent N, Binn P, et al Management of severe acute malnutrition in children. Lancet 2006;368:1992-2000. 4. Trehan I, Manary MJ. Management of severe acute malnutrition in low-income and middle-income countries. Arch Dis Child 2014;100:283-287. [http://dx.doi.org/10.1136/ archdischild-2014-306026] 5. Kouam CE, Delisle H, Ebbing HJ, et al. Perspectives for integration into the local health system of community-based management of acute malnutrition in children under 5 years: A qualitative study in Bangladesh. Nutr J 2014;13:1-15. [http:// dx.doi.org/10.1186/1475-2891-13-22] 6. Collins S. Treating severe acute malnutrition seriously. Arch Dis Child 2007;92:453-461. 7. Bhan MK, Bhandari N, Bahl R. Management of the severely malnourished child: Perspective from developing countries. BMJ 2003;326:146-151. 8. WHO. Guideline: Update on the management of severe acute malnutrition in infants and children. 2013. www.who.int/ entity/maternal_child_adolescent/documents/severe-acutemalnutrition/en/ (accessed 15 April 2015). 9. WHO. Management of severe malnutrition: A manual for physicians and other senior health workers. www.who.int/entity/ nutrition/publications/guidelines/updates_management_SAM_ infantandchildren/en/ (accessed 15 April 2015). 10. Ashworth A, Chopra M, McCoy D, et al. WHO guidelines for management of severe malnutrition in rural South African hospitals: Effect on case fatality and the influence of operational factors. Lancet 2004;363:1110-1115. 11. Bernal C, Velásquez C, Alcaraz G, Botero, J. Treatment of severe malnutrition in children: Experience in implementing the World Health Organization guidelines in Turbo, Colombia. J Pediatr Gastroenterol Nutr 2008;46:322-328. [http://dx.doi.org/10.1097/ MPG.0b013e318156c2c3] 12. Chinkhumba J, Tomkins A, Banda T, Mkangama C, Ferguson P. The impact of HIV on mortality during in-patient rehabilitation of severely malnourished children in Malawi. Trans R Soc Trop Med Hyg 2008;102:639-644. [http://dx.doi.org/10.1016/j. trstmh.2008.04.028] 13. UNICEF. Improving child nutrition. The achievable imperative for global progress. 2013. www.unicef.org/nutrition/index_68661. html (accessed 15 April 2015).

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14. Norman K, Pichard C, Lochs H, Pirlich M. Prognostic impact of disease-related malnutrition. Clin Nutr 2008;27:5-15. 15. Prudhon C, Briend A, Prinzo Z, et al. WHO, UNICEF and SCN informal consultation on communitybased managment of severe acute malnutrition in children. Food Nutr Bull 2006;27(3 Suppl):S99-S104. 16. De Onis M, Onyango AW, Borghi E, Garza C, Yang H. Comparison of the World Health Organization (WHO) Child Growth Standards and the National Center for Health Statistics/ WHO international growth reference: Implications for child health programmes. Public Health Nutr 2006;9:942-947. 17. Hendricks M, Bourne L. An integrated approach to malnutrition in childhood. S Afr Gauge 2010;2:46-52. 18. Iannotti LL, Trehan I, Clitheroe KL, Manary MJ. Diagnosis and treatment of severely malnourished children with diarrhoea. J Paediatr Child Health 2014;51:387-395. [http://dx.doi.org/10.1111/jpc.12711] 19. Amadi B, Kelly P, Mwiya M, et al. Intestinal and systemic infection, HIV, and mortality in Zambian children with persistent diarrhea and malnutrition. J Pediatr Gastroenterol Nutr 2001;32:550-554. 20. Bhutta ZA, Bird S, Black R, et al. Therapeutic effects of oral zinc in acute and persistent diarrhea in children in developing countries: Pooled analysis of randomized controlled trials. Am J Clin Nutr 2000;72:1516-1522.

21. Ashworth A, Khanum S, Jackson A, Schofield C. WHO Guidelines for the inpatient treatment of severely malnourished children. 2003. www.who.int/entity/nutrition/publications/severemalnutrition/9241546093/ en/ (accessed 15 January 2015). 22. Bahl R, Bhandari N, Saksena M, et al. Efficacy of zinc-fortified oral rehydration solution in 6- to 35-month-old children with acute diarrhea. J Pediatr 2002;141:677-682. 23. Bhatnagar S, Bahl R, Sharma P, et al. Zinc with oral rehydration therapy reduces stool output and duration of diarrhea in hospitalized children: A randomized controlled trial. J Pediatr Gastroenterol Nutr 2004;38:34-40. 24. Kerac M, Bunn J, Seal A, et al. Probiotics and prebiotics for severe acute malnutrition (PRONUT study): A double-blind efficacy randomised controlled trial in Malawi. Lancet 2009;374:136-144. [http://dx.doi.org/10.1016/S0140-6736(09)60884-9] 25. Trehan I, Goldbach H, LaGrone L, et al. Antibiotics as part of the management of severe acute malnutrition. N Engl J Med 2013;368:425-435. [http://dx.doi.org/10.1056/NEJMoa1202851] 26. Lenicek Krleza J, Misak Z, Jadresin O, Skaric I. Refeeding syndrome in children with different clinical aetiology. Eur J Clin Nutr 2013;67:883-886. [http://dx.doi.org/10.1038/ejcn.2013.58]

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Nutrition in children with long-term health conditions A Westwood, MB ChB, DCH (SA), FCPaed (SA), MD School of Child and Adolescent Health, Department of Paediatrics and Child Health, Faculty of Health Sciences, University of Cape Town, and Deparmtent of Paediatrics, New Somerset Hospital, Cape Town, South Africa Corresponding author: A Westwood (anthony.westwood@uct.ac.za)

Long-term health conditions (LTHCs) in children may affect nutrition and growth by means of multiple mechanisms. Both undernutrition and overweight/obesity are risk factors. Direct effects of the condition that may cause undernutrition include increased resting energy expenditure, excess losses through malabsorption, difficulty ingesting food, and decreased appetite. Indirect effects of LTHCs may be mediated by learnt or adaptive behaviours, secondary anorexia, inappropriate diets, or conditions that aggravate existing social nutritional risks to the child. Undernutrition may have significant consequences for the child, including reduced life expectancy. Overweight is a particular risk in children with neurological LTHCs. Regular clinical assessment, including anthropometry, is required to prevent and detect malnutrition. Anticipatory nutritional guidance to the child and caregivers is required and must be adapted to the specific LTHC. Controlling the disease processes that contribute to malnutrition and optimising energy intake are fundamental elements of prevention and management. Interventional feeding regimens, such as surgical approaches, may be required. A mutidisciplinary team, which includes a dietitian, should manage complex LTHCs and LTHC-associated malnutrition. S Afr Med J 2015;105(7):606. DOI:10.7196/SAMJnew.7784

A significant proportion of children in any community have long-term health conditions (LTHCs). This term is preferred to ‘chronic disease’. Firstly, chronic has a connotation of severity. Secondly, many children with long-term health problems do not have a disease, as the problem may be a congenital condition or an acquired disability with health consequences. Up to 20% of children have an LTHC, while <5% have a severe LTHC.[1] There is a wide range of conditions that share a set of potential secondary effects mediated by the presence of the condition (regardless of its specific characteristics) and the long duration of evolving childhood. • For children with LTHCs there is a need for greater involvement with healthcare services than in the case of their peers. • There are potential effects on neurodevelopment, self-image and self-efficacy, and other psychological functioning. • There are potential effects on the family. • There are potential effects on growth and/or nutrition. Not all of these effects may be present and they may vary in intensity. Many may be preventable by anticipatory interventions. The effects may act synergistically to produce secondary disabilities. This synergistically negative effect is especially important if the LTHC has an intrinsic effect on nutrition and growth; optimal outcomes for a child with an LTHC can only be achieved if optimal growth is achieved. In the absence of an LTHC having an intrinsic effect on growth (e.g. untreated growth hormone deficiency or skeletal disorder), nutrition is the main arbiter of growth. In many severe conditions, undernutrition is directly linked to life expectancy, even in conditions such as sickle cell disease,[2] which are not always regarded as having a major nutritional aspect. Another consequence of undernutrition – delayed puberty – is associated with problems such as decreased bone mineral density and negative selfimage, which have potential consequences in adult life. Over- and undernutrition are risks in a wide range of LTHCs. Chronic deficits of micro- or macronutrients can limit somatic growth and have varying direct effects on organ function, depending

on the specific LTHC. For example, decreased muscle bulk secondary to undernutrition may limit neurodevelopment in a child with a cardiorespiratory or neurological condition. Overweight can produce secondary disability in these conditions by aggravating any limitation of activity due to the LTHC. Therefore, special consideration must be given to nutrition for most children with LTHCs as part of any management plan that aims to optimise a child’s quality of life. This article explores the mechanisms by which nutritional problems may occur in LTHCs. It provides pointers to the prevention and management of such problems. Specific micronutrient deficiencies are not discussed.

The normal situation

It is a fundamental precept of auxology (the study of human growth) that the growth of a developing organism can only occur if energy intake exceeds energy expenditure. Genetic growth potential will only be realised if there is a sufficiently positive energy balance to allow optimal growth. In healthy children energy is expended as follows: • Resting energy expenditure (REE) – energy used in metabolic (e.g. protein synthesis, ion pumps) and resting mechanical activities (e.g. heartbeat and breathing) that are necessary to maintain body integrity. This comprises 50 - 60% of total energy expenditure (TEE). • Diet-induced thermogenesis (5 - 8% of TEE). • Activities of daily living (30 - 40% of TEE). • Faecal energy losses, which vary with dietary energy intake. Fig. 1 demonstrates the normal energy balance in a healthy child. Inadequate energy intake relative to expenditure limits growth. Excess energy intake relative to expenditure may lead to fat deposition and overweight.

Mechanisms of suboptimal nutrition

Fig. 2 summarises the many mechanisms that can lead to under nutrition in children with LTHCs; there may be more than one in a

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Energy expenditure Energy intake

Growth Fig. 1. Energy balance and growth. Acute and chronic inflammation Recurrent infections Sputum losses Increased work of breathing Uncoupled oxidative phosphorylation

Energy expenditure

Energy intake Anorexia Unwillingness to eat Aberrant eating patterns Disorders of the upper gastrointestinal tract Recurrent infections Depression Psychosocial problems Maldigestion Increased faecal losses Cardiorespiratory failure

Decreased activity Weakness Depression Limited opportunities Limited expectations Poor growth

Fig. 2. Mechanisms of negative energy balance in long-term health conditions.

child. When present together, some may be more than additive in their effect, e.g. recurrent infections leading to recurrent anorexia. The potential mitigating energy balance effect of reduced activities of daily living has risks, such as aggravation of depression or anorexia. Not shown in Fig. 2 is the inability to use available nutrient-derived energy, because this contributor to limitation of growth in some LTHCs (especially endocrine disorders such as hypothyroidism) is not mediated through nutrition.

Decreased intake

Anorexia and decreased appetite These are often primary effects in LTHCs affecting the gastrointestinal tract (GIT). The child with primary GIT dysmotility or that which arises secondary to malabsorption in liver, gut or pancreatic diseases learns that eating produces bloating or discomfort and reduces the quantity and frequency of food intake. Chronic renal failure produces primary anorexia. Children with immune deficiencies are prone to opportunistic mouth or oesophageal infections (e.g. thrush), which produce dysphagia. Recurrent infections also reduce appetite for significant periods. Secondary anorexia may occur owing to micronutrient (especially iron and zinc) deficiencies. These deficiencies may be

secondary to poor intake or malabsorption. Uncontrolled perennial allergic rhinitis reduces taste differentiation and appetite. Secondary anorexia also occurs when a child fails to cope with living with an LTHC and becomes depressed. Long-term medication effects on the GIT, such as nausea, vomiting or abdominal pain, may decrease appetite.[3] Unwillingness to eat Unwillingness to eat is often seen in patients with conditions such as cystic fibrosis, where high-energy intake is promoted to overcome excess energy losses or energy expenditure. Poorly managed parental zeal produces an oppositional response in the child. This may set a pattern for life, unless it is recognised and dealt with. Children and adolescents with type 1 diabetes mellitus can be adept at limiting intake – which may not be nutritionally optimal – to achieve a thin body habitus. Inability to eat enough Children with congenital or acquired abnormalities of the upper GIT or the mouth, such as cleft palate, are at risk of undernutrition. Likewise, in neurological disorders, such as quadriplegic cerebral palsy, inadequate oral phase of swallowing and inco-ordinate deglutition limit energy intake of liquids and/or solids. Without multidisciplinary interventions in such

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conditions the risk of undernutrition is high. Cardiorespiratory disorders, such as left-toright congenital heart shunts in small infants, may cause tachypnoea and fatigue that limit the infant’s ability to breastfeed or bottle-feed adequately. Chronic anaemia may have the same effect in infancy, e.g. in sickle cell disease. Therefore, careful attention to nutrient intake and eating habits is required in most children with LTHCs. Additional attention is required in children from economically deprived homes, as reduced intake due to poverty or social disruption has a greater effect on a child with an LTHC than on an otherwise healthy child. Malabsorption While the potential contribution of mal absorption to decreased food energy availability and consequent undernutrition is obvious in GIT conditions such as coeliac disease and obstructive biliary disorders, malabsorption is a factor in many other LTHCs. Recurrent diarrhoea (including undiagnosed giardiasis) is common in immunodeficiencies. Uncontrolled cardiac failure and chronic hypoxaemia affect the absorptive function of the small intestine. Psychological disorders While psychiatric LTHCs such as anorexia nervosa have clear nutritional consequences, other LTHCs may be associated with enough primary or secondary psychopathology to affect energy intake.[3] This is especially the case with depression – often the result of dys functional adaptation to the presence of an LTHC – and its consequences for the child and family. Awareness of this risk and screening for its early manifestations should be part of standard clinical care for children with LTHCs. Inappropriate diets Medical practitioners need to be aware that families of children with an incurable or severe LTHC may use dietary remedies to ‘cure’ or ameliorate the condition. Parents may remove milk from the diet of a child with chronic lung disease because it is perceived to ‘increase mucus’. Some LTHCs, such as coeliac disease, require special diets. In such cases the input of a dietitian is necessary to avoid an energy-poor diet.

Increased energy expenditure

Increased inflammation Diversion of nutrient energy into inflam mation is a potent contributor to suboptimal nutrition and growth in many LTHCs. This is an especially important consideration in conditions that render children prone to recurrent or chronic infections. Examples are HIV-associated diseases and chronic

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suppurative disorders of the lung, such as those that occur with chronic Pseudomonas aeruginosa infection in cystic fibrosis. Nutritional losses from chronic sputum production can be significant. Noninfective chronic inflammation in autoimmune disorders may add to the intrinsic risk of underweight and growth restriction caused by musculoskeletal pain and reduced movement. Increased energy utilisation As with inflammation, energy diversion to other non-growth activities occurs in many LTHCs. The most common of these is utilisation of abovenormal amounts of energy for maintenance of oxygenation in congenital and acquired cardiac and respiratory diseases. REE can be >20% higher than normal owing to increased cardiorespiratory effort. In some diseases this diversion is not recognised because the level of disease activity is not correctly assessed. A common example of this phenomenon is undertreated asthma. If not compensated for, this diversion will contribute to suboptimal growth and possible overt malnutrition. In LTHCs such as hyperthyroidism and mitochondrial disorders increased REE is intrinsic to the disease and needs to be compensated for. REE may be raised in some patients with HIV infection despite good disease control.

Prevention and early detection of undernutrition

Undernutrition should be prevented in children with LTHCs. Clinical assessment of the risk to an individual is an essential part of comprehensive care. Continuity of the healthcare team is an important component, as the risk changes with phases of the child’s life and the LTHC. Therefore, attention to nutrition and growth should be a regular and planned part of clinical consultations. The essential elements of the nutritional assessment include: • Dietary history. • Review of eating and mealtime habits. • Evidence of GIT dysfunction. • Anthropometric assessment: weight, height, weight-for-height or body mass index, mid-upper-arm circumference (6 months - 5 years). • Plotting these measures and assessing trends on appropriate growth charts. • Physical examination. Measurement of height is especially important in detecting longerterm nutritional effects of LTHCs that may not be acute enough to manifest as overt weight loss or wasting. Overall evaluation of the status of the LTHC may also raise issues that could result in nutritional depletion if not remedied or compensated for, e.g. frequent infections or disease exacerbations. Anticipatory guidance is an essential part of long-term care for children with LTHCs. Such guidance is required for nutritional problems and issues of development, mental health and transition to adult-orientated healthcare. The clinician is required to make an assessment of a child’s nutritional risk, which is then used to construct a counselling approach. For example, a baby with a leftto-right cardiac shunt or malabsorption syndrome requires more frequent weighing than other infants. Special guidance on energy intake may be required in children with chronic infections. Educators may need to play a role in the child’s nutrition during the school day. Advice on how to handle expected eating behavioural patterns may assist a parent with these common challenges. Dietitians can play a crucial role in anticipatory guidance and specific dietary and eating advice. They should be included in the healthcare team at an early stage to assist with children who have an LTHC and a significant risk of undernutrition.

Management of undernutrition

Most of the principles of management of undernutrition in children are applicable to children with LTHCs. These principles include: • Controlling the disease processes that contribute to the energy deficit, where possible. • Optimising energy intake through: • attention to the form and balance of the diet, including the possible use of supplements • improving eating behaviour where necessary • deciding whether an interventional form of feeding is required (discussed below) • ensuring that energy intake during hospital admissions and disease exacerbations is maximised. • Use of the World Health Organization 10-step intervention (suitably modified for the specific LTHC) for severely malnourished children. • Avoiding refeeding syndrome in children with severe malnutrition. • Regular follow-up and assessment by a multidisciplinary team. A dietitian is indispensable in nutritional rehabilitation. Expertise in assessing the nature and extent of the problem, constructing appropriate diets, counselling on eating habits and reviewing progress are essential elements in the care of a child with an LTHC and undernutrition. South Africa (SA)’s primary healthcare nutrition National Therapeutic Programme provides supplements to children with LTHCs on the advice of a dietitian employed by the Department of Health.[4] A psychologist may be required if eating behaviours cannot be ameliorated by the standard healthcare team, or if there is a significant psychological component to the causation of the undernutrition. Speech therapists can assist with feeding and sensory and other problems that lead to limited energy intake. Specialist nurses often play a pivotal role in nutritional management of children with LTHCs in well-resourced countries, but there are very few such nurses in SA. Doctors must not abdicate responsibility for canvassing and co-ordinating such advice and inputs in the comprehensive care of a child. Interventional feeding regimens may be required, such as specialised bottles for children with cleft lips and palates, and nasogastric or gastrostomy feeds. The last may be used to bypass upper GIT and facial anomalies. Overnight supplementary feeds are valuable for children whose energy requirements are so high that they cannot reasonably be expected to consume enough food and supplements (e.g. in cystic fibrosis), or if their appetite is poor (e.g. in chronic renal failure). All of these interventions require the input of nurses and dietitians, again emphasising the role of the multidisciplinary team in the management of children with LTHCs.

Overweight and obesity

Problems of overweight are not uncommon among children with LTHCs, especially those with a neurological component. The risk arises from a combination of compensatory eating behaviours and inappropriately high-calorie, low-residue diets, because these are easier for the child to masticate and swallow, and relatively lowenergy use in activities of daily living. Again, prevention is better than cure. Awareness of the risk and anticipatory guidance allow the clinician and healthcare team to work with the parents, family and child to prevent the child from becoming overweight. The dietitian’s role can be pivotal.

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Conclusion

Nutritional problems, especially undernutrition, are probable in many children with LTHCs. These problems arise from the direct effects of the LTHC and the secondary effects common to most LTHCs â&#x20AC;&#x201C; often in combination. Awareness is essential and prevention must be an aim of comprehensive care. Management of potential and actual nutritional problems requires a planned approach and includes contributions from many members of a multidisciplinary team over the entire period that an LTHC is present.

References 1. Westwood T, Robertson A. A child with a long-term health condition. In: Kibel M, Saloojee H, Westwood T. Child Health for All. 5th ed. Cape Town: Oxford University Press, 2012. 2. Al-Saqladi AW, Cipolotti R, Fijnvandraat K, Brabin BJ. Growth and nutritional status of children with homozygous sickle cell disease. Ann Trop Paediatr 2008;28:165-189. [http:// dx.doi.org/10.1179/146532808X335624] 3. Quick VM, Byrd-Bredbenner C, Neumark-Sztainer D. Chronic illness and disordered eating: A discussion of the literature. Adv Nutr 2013;4:277-286. [http://dx.doi.org/10.3945/ an.112.003608] 4. Labadarios D, Steyn NP, Mgijima C, Daldla N. Review of the South African nutrition policy 1994 2002 and targets for 2007: Achievements and challenges. Nutrition 2005;21:100-108. [http://dx.doi. org/10.1016/j.nut.2004.09.014]

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ARTICLE

Nutritional support of children with chronic liver disease E D Nel,1 MB ChB, MMed (Paed), BSc Hons (Epidemiology); A J Terblanche,2 MB ChB, Dip Allerg (SA), MMed (Paed), FCPaed (SA), Cert Gastroenterol (SA) Paed, Dip Pal Med (Paed) (SA) Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa Department of Paediatrics and Child Health, Faculty of Health Sciences, University of Pretoria, South Africa

1 2

Corresponding author: E D Nel (edn@sun.ac.za)

Anorexia, malabsorption and metabolic derangements contribute to the malnutrition that occurs in most children with chronic liver disease. Nutritional support should be started early in the management of these children with the co-operation of a paediatric dietitian to improve quality of life and decrease post-transplant mortality. Nutritional assessment entails a detailed dietary history, physical examination and anthropometry. Weight-based anthropometric measures are unreliable while mid-upper-arm circumference and skinfold thickness provide more reliable estimates of nutritional status. Special investigations such as serum vitamin levels and skeletal X-rays further guide management. High energy (130 - 150% of recommended daily intake (RDI)) and protein (3 - 4 g/kg/day) intakes are recommended. Diets are usually enriched with medium-chain fatty acids because of their better absorption in cholestatic liver disease. High-dose fat-soluble vitamin supplements are given while care is taken to avoid toxicity. Initial doses are two to three times the RDI and then adjusted according to serum levels or international normalised ratio (INR) in the case of vitamin K. Children with good appetites are fed orally. Feeds should be more regular than for other children to avoid prolonged periods of fasting and improve energy intake. Some children require supplementary nasogastric feeds to increase energy intake and avoid overnight fasting. S Afr Med J 2015;105(7):607. DOI:10.7196/SAMJnew.7783

A large variety of conditions cause chronic liver disease (CLD) in children. In infants, biliary atresia is the most common cause followed by inherited metabolic disease, genetic abnormalities, and other biliary abnormalities. Auto-immune hepatitis, nonalcoholic fatty liver disease, chronic viral hepatitis and inherited metabolic disease are leading causes in older children. The effect that chronic liver disease has on a child’s nutritional status and health is determined by the cause and severity of the liver disease and the age of onset. There is a bidirectional interaction between CLD and malnutrition: CLD often leads to malnutrition, and malnutrition adversely affects the course of liver disease. The progressive loss of liver function and development of cirrhosis in children with CLD causes haemodynamic and metabolic disturbances and severe complications such as hepatopulmonary syndrome and renal failure. Liver transplantation is the only curative option for many children. For these children nutritional support improves quality of life, improves post-transplant survival, and prevents serious complications such as rickets, severe muscle loss, and haemorrhagic disease. In some children the liver disease requires specific nutritional therapy such as a galactose-free diet. However, even children with less severe liver disease require nutritional assessment and intervention to prevent osteopenia and the complications of micronutrient deficiency. Current recommendations are based on our understanding of the effect of CLD on nutritional status, digestion and absorption of nutrients, metabolism and limited clinical trials.

Prevalence of malnutrition

Approximately 60 - 80% of children with CLD awaiting liver transplantation are malnourished;[1] weight, height, head circum ference, skinfold thickness and mid-upper-arm circumference are

reduced.[2,3] These changes are particularly prominent in children with severe cholestatic liver disease such as biliary atresia and the severe intrahepatic causes of CLD.

Effect of malnutrition on prognosis

The degree of malnutrition reflects the severity of liver disease and is included in the assessment of end-stage liver disease in children (paediatric end-stage liver disease (PELD) score).[4] Malnourished children have increased post-transplant mortality and morbidity. [4] In addition, specific nutrient deficiencies can cause serious complications, e.g. vitamin deficiencies (A, E, D, K) and essential fatty acid deficiency.

Nutritional consequences of CLD

CLD significantly alters body composition and metabolism. Fat mass is reduced and eventually lean body mass as well. Resting energy expenditure and total energy expenditure are increased by approximately 30% in young children with CLD.[5,6] Children preferentially oxidise fat in the postabsorptive phase.[5,7] Oxidation of branched-chain amino acids such as leucine is increased. Hormonal changes contribute to poor growth and changes in body composition. Growth hormone receptor expression is reduced, leading to low insulin-like growth factor 1 (IGF-1). In adolescents, puberty is often delayed and hypogonadism is common.[8] Considered together, these changes have important implications for nutritional support: energy intake should be high, periods of fasting avoided, protein intake not restricted, and branched-chain amino acids supplemented. Initiation of nutritional support should not be delayed as nutritional recovery may be difficult to achieve once children have developed severe malnutrition. Liver-associated metabolic bone disease with pathological fractures is a significant complication in children with cirrhotic and non-cirrhotic CLD.[9] The term ‘hepatic osteodystrophy’ describes

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this complex of structural and metabolic bone changes, including osteoporosis and osteomalacia or rickets in children. Osteoporosis, where the bone mineral density (BMD) is decreased, is a common cause for fractures (prevalence 10 - 28%),[8] and although mostly asymptomatic, has a significant negative impact on morbidity and quality of life.[10] In contrast to adults, children have a greater potential for spontaneous recovery of BMD after liver

transplant, usually after 1 year.[8] Immobility and low muscle force in this population further contribute to the low bone mass.[8] In children, not only the existing bone is affected, but also the growth plates, adding rickets (the consequence of vitamin D deficiency on growing bone), spine abnormalities and growth failure to the equation.[8] Vitamin D deficiency is thought to be a major causative factor for hepatic osteodystrophy. Malabsorption of fat-soluble vitamins due to deficient

Table 1. Clinical nutritional assessment in paediatric chronic liver disease Nutritional element/factor

Assessment tools

Deficiency

Toxic effects

Specific recommendations

Macronutrients Energy/caloric intake

Anthropometric measurements Mid-upper-arm circumference Triceps and subscapular skinfold thickness Serial measurements weight/height Indirect calorimetry Fat malabsorption

Reduced muscle bulk Reduced subcutaneous fat Alopecia, thin sparse hair Pigmentary changes skin Parotid enlargement Steatorrhoea

Financial burden Essential fatty acid deficiency

Calorie goal of 130 - 180% of RDI based on weight or height 50th centile MCT oil 1 - 2 mL/kg/d in 2 - 4 doses Add glucose polymers (Polycose powder or solutions) and supple mental night-time nasogastric drip feeds MCT infant formulas (Pregestimil, Alimentum, Prenan)

Carbohydrate

Serum glucose

Protein

Mid-upper-arm circumference Serum albumin, prealbumin, RBP, transferrin

Reduced muscle bulk Alopecia, thin sparse hair Pigmentary changes skin Parotid enlargement Peripheral oedema Psychomotor changes, irritability

Infants: protein intake 3 - 4 g/kg/d Hepatic encephalopathy: protein intake 0.5 - 1.0 g/kg/d Branched-chain amino acid supplements

Triene:tetraene ratio >0.3 Decreased linoleic acid

Skin dryness, peeling Alopecia

Oral vegetable/corn oil or intravenous lipid emulsions

Fat Essential fatty acid deficiency

Monitor for hypoglycaemia during fasting, illness or reduced intake

Micronutrients Vitamin A

Deficiency: Retinol: RBP molar ratio <0.8 or serum retinol <20 µg/dL

Xerosis Bitot spots Night blindness Dry skin Follicular keratosis Possible immune dysfunction

Liver fibrosis Hypercalcaemia Pseudotumor cerebri Painful bone lesions

Vitamin A 5 000 - 25 000 U/d po

Vitamin D

Deficiency: 25-OH vitamin D level <30 ng/mL Calcium, phosphorus levels

Hypocalcaemia Hypophosphatemia Muscle hypotonia Poor dentition Rickets: Bowed legs Epiphyseal enlargement Rachitic rosary Craniotabes Frontal bossing Delayed fontanel closure

Hypercalcaemia Pseudotumor cerebri Nephrocalcinosis

Ergocalciferol: 3 - 10 times RDI Cholecalciferol based on weight and vitamin D levels Weight <40 kg

Weight >40 kg

<10 ng/mL: 100 U/kg/d

<10 ng/mL: 5 000 U/d

11 - 19 ng/mL: 75 U/kg/d

11 - 19 ng/mL: 4 000 U/d

20 - 29 ng/mL: 50 U/kg/d

20 - 29 ng/mL: 3 000 U/d Continued ...

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Table 1. (continued) Clinical nutritional assessment in paediatric chronic liver disease Nutritional element/ factor

Assessment tools

Deficiency

Toxic effects

Specific recommendations

Micronutrients Vitamin E

Deficiency: Vitamin E:total lipid ratio <0.6 mg/g (<1 y) <0.8 mg/g (>1 y)

Poor nerve conduction Hypo/areflexia Ataxia Peripheral neuropathy Loss of vibratory sense Myopathy Vision loss Haemolytic anaemia

Vitamin K

Deficiency: Prolonged PTT/INR Elevated PIVKA-II

Haemorrhagic disease Excessive bruising

Impaired neutrophil chemotaxis Potentiation vitamin K deficiency Coagulopathy Diarrhoea Hyperosmolality (TPGS)

Alpha-Tocopherol (acetate) 25 - 200 IU/kg/d TPGS (Luiqi E) 15 - 25 IU/kg/d

Vitamin K 2.5 - 5 mg, 2 - 7 times/wk Intravenous vitamin K 2 - 10 mg may be required

Water-soluble vitamins

Multivitamin preparation providing 1 - 2 times RDI Minerals and trace elements

Iron

Deficiency: Decreased iron level, increased total ironbinding capacity

Pallor Koilonychia Stomatitis

Teeth staining Haemorrhagic gastroenteritis Metabolic acidosis Coma, liver failure

Elemental iron 5 - 6 mg/kg/d

Zinc

Deficiency: Plasma zinc level <60 µg/dL

Alopecia, thin sparse hair Acrodematitis enterohepatica

Decreased intestinal absorption copper and iron

Zinc sulphate solution 10 mg/mL elemental zinc Elemental zinc 1 mg/kg/d

Selenium

Deficiency: Plasma selenium <40 µg/L

Dermatological changes Diarrhoea Dyspepsia Anorexia

1 - 2 µg/kg/d oral sodium selenite or 1 - 2 µg/kg/d selenium in TPN

Magnesium

Deficiency: Serum magnesium <0.7 mmol/L

Respiratory depression Lethargy Coma

Magnesium oxide 0.5 - 1 mmol/kg daily po, or 50% solution of magnesium sulphate 0.01 - 0.25 mmol/kg IV over 3 - 6 h

Calcium

Deficiency in steatorrhoea despite corrected vitamin D status

Hypercalcaemia Hypercalciuria

25 - 100 mg/kg/d up to 800 - 1 200 mg/d

Phosphorus

Low serum phosphorus level despite corrected vitamin D and calcium status

Gastrointestinal intolerance

25 - 50 mg/kg/d up to 500 mg/d

Poor dentition

MCT = medium-chain triglyceride; po = orally; PTT = partial thromboplastin time; TPN = total parenteral nutrition; RDI = recommended daily intake. Adapted from Nightingale & Ng,[6] Suchy et al.,[9] Sultan et al.,[15] Cameron & Kogan-Liberman,[16] Murray & Horslen.[17]

intraluminal bile acids, decreased exposure to direct sunlight and poor 25-hydroxylation in end-stage liver failure, are all contributing factors. Secondary hyperparathyroidism, in response to low serum calcium, increases bone resorption and intestinal calcium absorption but also increases phosphate loss in the kidney. Other contributing factors are suboptimal calcium intake, hypogonadism, vitamin K deficiency (important role in osteocalcin homeostasis), and corticosteroid treatment.[11]

recommended.[2] Nausea, anorexia, mucosal congestion, decreased intestinal motility, early satiety due to organomegaly and ascites, and dietary modifications that require unpalatable diets all contribute to reduced intake. Infants and young children derive approximately 50% of their energy from dietary fat. Absorption of long-chain fatty acids is reduced as a result of reduced luminal bile acid concentration depriving children of this important source of energy and often leading to essential fatty acid deficiency.[12]

Causes of malnutrition

Assessment of nutritional status

The cause of malnutrition in CLD is multifactorial. Intake in children is poor, with as many as 70% of children consuming less than

The nutritional status of children is assessed to identify those who require additional nutrition support and monitor response to

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treatment. Nutritional status is assessed at the first and all subsequent visits. A dietary history identifies the type and quantity of feeds taken. In the case of formula-fed infants calculation of daily intake is easier than in the toddler and older child on a mixed diet. Determining the variety of foods ingested is important as children with restricted diets are at risk of micronutrient deficiency. Asking parents to keep a dietary diary is useful to obtain this information. Symptoms such as vomiting, anorexia, diarrhoea or steatorrhoea, and pale stools further identify those children at risk of poor intake and malabsorption. Assessment of the nutritional status also includes assessment of subcutaneous fat and muscle mass and signs of micronutrient deficiency. Anthropometry, the mainstay of nutritional assessment in most children, is influenced by changes in body composition in children with CLD. Weight-for-age and weight-for-height-for-age measurements usually underestimate the degree of malnutrition because of coexisting organomegaly, ascites and fluid retention. Stunting reflects chronic undernutrition; length or height should be accurately measured. However, in the presence of genetic conditions such as Alagille syndrome, stunting may be due to the underlying defect rather than malnutrition. Skinfold thickness and mid-upper-arm circumference are less influenced by oedema and provide a more reliable estimate of nutritional status in these children. Skinfold thickness, measured over the triceps and subscapular areas, allows assessment of fat mass. These measurements require use of specialised calipers and appropriate training. Mid-upper-arm circumference is a useful tool that assesses muscle mass and can be compared with normal values for age. Essential fatty acids or the triene:tetraene ratio can be determined in children with suspected essential fatty acid deficiency. These tests are often not available in routine laboratories in South Africa (SA). Fat-soluble vitamin status should be assessed every 6 months or more frequently in the presence of deficiency. Biochemical vitamin A deficiency occurs before the deficiency becomes clinically overt. Serum retinol does not always accurately estimate vitamin A status in children with liver disease. The relative dose response may be more reliable but is not routinely performed.[13] The molar ratio of plasma retinol:retinolbinding protein (RBP) has been suggested as an alternative (serum retinol (µg/dL)/serum RBP (mg/dL) × 0.0734: normal 0.8 - 2.0);[14] results of studies assessing this measure are however equivocal and most laboratories in SA do not routinely determine RBP. Children with CLD require regular assessment for evidence of vitamin D deficiency and bone disease. This includes a history of bone pain and fractures, palpation of the spine and assessment of pubertal stage. Laboratory evaluation would include 25-OH vitamin D, parathyroid hormone, calcium, phosphate, magnesium, and alkaline phosphatase. Hand X-rays are valuable to evaluate the severity of osteodystrophy and the growth potential. Dual-energy X-ray absorptiometry to detect low bone mass and lateral spine X-ray to determine the presence of vertebral fractures may be required in older children. Vitamin E deficiency is common in cholestatic liver disease. Initially asymptomatic, children develop peripheral neuropathy, spinocerebellar degeneration, and ataxia. Early in the disease these changes are reversible but, if treatment is delayed, may become permanent. In the presence of hyperlipidaemia, a frequent finding in cholestatic liver disease, vitamin E levels may be falsely normal; the ratio of tocopherol:total lipids or tocopherol:cholesterol should therefore be assessed to screen for vitamin E deficiency. Laboratories in SA do not determine protein induced in vitamin K absence (PIVKA) for vitamin K deficiency. Prothrombin time or inter national normalised ratio (INR) are frequently used to assess for vitamin K deficiency; it should be kept in mind that these measures are

also influenced by liver synthetic function. The response to parenteral vitamin K supplementation indicates whether abnormalities are due to liver failure or vitamin K deficiency. Although coagulopathy is the major complication of vitamin K deficiency, bone disease may also be due to carboxylation defects in vitamin K deficiency. Trace-element deficiency occurs in children with CLD. Zinc and selenium deficiencies are common and serum zinc levels should be determined in children who are not growing satisfactorily. Iron deficiency also commonly occurs, particularly in children with portal hypertension. Plasma proteins (albumin, prealbumin, RBP) are less useful in children with CLD as their levels are influenced by hepatocellular function and systemic inflammation. Bioelectrical impedance has little value in the nutritional assessment of these children. Table 1 summarises the clinical nutritional assessment of children with CLD.

Nutritional support

The goals of nutritional support in children with CLD are normal growth and body composition and the prevention of vitamin and trace-element deficiency. Nutritional support should not be delayed, particularly in young infants. Intake should be reviewed regularly. Severity of disease, presence of complications, levels of activity and age-related changes in nutritional requirements should be taken into account. This requires expertise that is often beyond the scope of the family physician and paediatrician. A dietitian, experienced in the management of children, should be involved early in the course of the child’s disease. In the absence of malnutrition, energy requirements can initially be considered to be normal. However, if growth is not satisfactory, high energy intake is encouraged. Intakes of 130 - 150% of normal energy intake are recommended. This is achieved by increasing fat and carbohydrate intake. Increasing the fat intake increases total fat absorption. Mediumchain fatty acid absorption is not dependent on bile salts and diets are supplemented with these fatty acids. They should not exceed 80% of the total fat intake as essential fatty acid deficiency may ensue. Longchain polyunsaturated fatty acids are essential for normal growth and brain development. Diets are enriched with foods that are rich in these fatty acids, e.g. egg yolk and vegetable oils. Carbohydrates are an important energy source in children. Diets should contain adequate carbohydrate to meet the child’s energy requirements without causing osmotic diarrhoea. This is usually not a problem in children receiving normal foods; however, for those receiving enteral feeds, selection of a formula with glucose polymers and not sugars may be necessary. In children with galactossaemia, galactose-free diets are required. Protein restriction limits normal growth and should be avoided. Intakes of 3 - 4 g/kg/day (minimum 2 g/kg/day)[14] are encouraged. Although moderate elevations of ammonia are often present, this should not prompt prolonged protein restriction in the absence of encephalopathy. Branched-chain amino acid supplementation has been shown to improve lean body mass gain. However, formulas enriched with these amino acids are expensive and are not readily available in SA. Fat-soluble vitamin deficiencies frequently occur in children with cholestatic liver disease. This is predominantly due to fat mal absorption. These children often require high-dose supplementation and in some cases parenteral administration of vitamins. A watersoluble preparation of vitamin E (TPGS) improves the absorption of other fat-soluble vitamins. Unfortunately this preparation is not available in SA.

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Children are supplemented with 5 000 - 10 000 IU of vitamin A daily. Occasionally higher doses (up to 25 000 IU/day) are required,[1] particularly in infants who have severe cholestatic liver disease. Care should be taken to avoid vitamin A toxicity which may cause pseudotumor cerebri, hypercalcaemia, painful bone lesions and liver toxicity. Vitamin E deficiency is particularly difficult to treat in children with severe cholestasis. In the absence of TPGS, high-dose vitamin E supplementation is often required to prevent vitamin E deficiency. The starting dose is usually 10 - 25 IU/kg/day; this is increased as required to 100 - 200 IU/kg/day. Regular assessment of serum levels is required for dose titration. Oral vitamin K supplementation is usually adequate to prevent severe vitamin K deficiency-associated coagulopathy. Children are given 2.5 - 5 mg/day although supplementation three times per week is often adequate to prevent coagulopathy. All children with CLD require vitamin D supplementation. The dose is determined by age, severity of liver disease, and the presence of complications such as rickets. Cholecalciferol is most frequently used to replenish vitamin D stores and prevent the complications of vitamin D deficiency. Alphacalcidol or calcitriol, active vitamin D metabolites, do not replace vitamin D stores, but are used to increase calcium absorption or to treat coexisting renal failure. These metabolites are usually added in children who have failed standard cholecalciferol supplementation and should not be used in isolation to treat vitamin D deficiency. Serum calcium and phosphate levels and urinary calcium should be monitored to avoid vitamin D toxicity. Children with vertebral fractures and evidence of low BMD may benefit from treatment with bisphosphonates and should be referred to bone specialists where possible.[8] Supplementation aims to maintain a serum 25-OH vitamin D level of >50 nmol/L and a parathyroid hormone of <55 pg/mL. Children with a 25-OH vitamin D level >25 nmol/L are given 3 - 10 times the normal requirement (1 200 - 4 000 U/day); if the 25-OH vitamin D level is <25 nmol/L, the dose is increased to 6 000 - 25 000 U/day until normal levels are achieved. In the event of unsuccessful oral therapy, intramuscular vitamin D can be given monthly until normalisation of the serum vitamin D.[8] Dietary support of children with CLD also addresses trace element deficiency and sodium load. Supplementation with zinc, as well as other trace elements such as selenium, improves appetite and growth. Sodium intake is restricted, particularly in those children with ascites. Fluid intake is not routinely restricted with the exception of children in hepatic failure.

Routes of feeding

Most children can be fed orally. Although liver-specific enteral feeds are not available in SA, modular feeds and other specialised infant formulas are useful in their management. Formulas developed for preterm infants have a high energy and mineral content and are enriched with medium-chain fatty acids. These formulas are often used to feed infants with cholestatic liver disease who are unable to breastfeed. Breastfed infants may require fortification or supplementation with medium-chain fatty acids.

Children with advanced liver disease require more frequent feeds as a result of rapid glycogen depletion in the fasting state and the risk of hypoglycaemia. These children often also have significant anorexia and require supplemental nasogastric feeds. Overnight nasogastric feeds are recommended in children who are unable to take in enough food to supply energy requirements. Nasogastric tubes are well tolerated by most of these children and do not increase the risk of bleeding in portal hypertension. If enteral feeds fail, parenteral nutrition is considered in consultation with a paediatric gastroenterologist and paediatric dietitian. Although not an absolute contraindication, placement of a percutaneous endoscopic gastrostomy (PEG) is usually avoided in these children. Constant infusion feeds are given to children who are unable to tolerate bolus feeds. Regardless of the route or manner of feeding, oral feeding skills should be maintained to allow easier transition to full oral feeds at a later stage. The assistance of a speech and language therapist may be warranted.

Conclusions

Malnutrition is an important complication of CLD in children. Survival and quality of life are improved with early initiation of an active nutritional support programme. Most components of nutritional monitoring and supplementation can competently be implemented by the family physician and general paediatrician. However, given the complexity of the diseases, a paediatric gastro enterologist or hepatologist, together with a paediatric dietitian, should be involved in the treatment of these children from an early stage of their disease. References 1. Young S, Kwarta E, Azzam R, Sentongo T. Nutrition assessment and support in children with end-stage liver disease. Nutr Clin Pract 2013;28(3):317-329. [http://dx.doi.org/10.1177/0884533612474043] 2. Chin SE, Shepherd RW, Thomas BJ, et al. The nature of malnutrition in children with end-stage liver disease awaiting orthotopic liver transplantation. Am J Clin Nutr 1992;56(1):164-168. 3. Sokol RJ, Stall C. Anthropometric evaluation of children with chronic liver disease. Am J Clin Nutr 1990;52(2):203-208. 4. Los EL, Lukovac S, Werner A, Dijkstra T, Verkade HJ, Rings EH. Nutrition for children with cholestatic liver disease. Nestle Nutr Workshop Ser Pediatr Program 2007;59:147-157. [http://dx.doi. org/10.1159/000098533] 5. Greer R, Lehnert M, Lewindon P, Cleghorn GJ, Shepherd RW. Body composition and components of energy expenditure in children with end-stage liver disease. J Pediatr Gastroenterol Nutr 2003;36(3):358-363. [http://dx.doi.org/10.1097/00005176-200303000-00010] 6. Nightingale S, Ng VL. Optimizing nutritional management in children with chronic liver disease. Pediatr Clin North Am 2009;56(5):1161-1183. [http://dx.doi.org/10.1016/j.pcl.2009.06.005] 7. Mager DR, Wykes LJ, Roberts EA, Ball RO, Pencharz PB. Mild-to-moderate chronic cholestatic liver disease increases leucine oxidation in children. J Nutr 2006;136(4):965-970. 8. Hogler W, Baumann U, Kelly D. Endocrine and bone metabolic complications in chronic liver disease and after liver transplantation in children. J Pediatr Gastroenterol Nutr 2012;54(3):313-321. [http:// dx.doi.org/10.1097/mpg.0b013e31823e9412] 9. Suchy FJ, Sokol SR, Balistreri WF, eds. Liver Disease in Children: Cambridge University Press, 2014. 10. Mansueto P, Carroccio A, Seidita A, Di Fede G, Craxi A. Osteodystrophy in chronic liver diseases. Intern Emerg Med 2013;8(5):377-388. [http://dx.doi.org/10.1007/s11739-012-0753-5] 11. Pappa HM, Bern E, Kamin D, Grand RJ. Vitamin D status in gastrointestinal and liver disease. Curr Opin Gastroenterol 2008;24(2):176-183. [http://dx.doi.org/10.1097/mog.0b013e3282f4d2f3] 12. Socha P, Koletzko B, Swiatkowska E, Pawlowska J, Stolarczyk A, Socha J. Essential fatty acid metabolism in infants with cholestasis. Acta Paediatr 1998;87(3):278-283. 13. Feranchak AP, Gralla J, King R, et al. Comparison of indices of vitamin A status in children with chronic liver disease. Hepatology 2005;42(4):782-792. [http://dx.doi.org/10.1002/hep.20864] 14. Baker A, Stevenson R, Dhawan A, Goncalves I, Socha P, Sokal E. Guidelines for nutritional care for infants with cholestatic liver disease before liver transplantation. Pediatr Transplant 2007;11(8):825834. [http://dx.doi.org/10.1111/j.1399-3046.2007.00792.x] 15. Sultan MI, Leon CD, Biank VF. Role of nutrition in pediatric chronic liver disease. Nutr Clin Pract 2011;26(4):401-408. [http://dx.doi.org/10.1177/0884533611405535] 16. Cameron R, Kogan-Liberman D. Nutritional considerations in pediatric liver disease. Pediatr Rev 2014;35(11):493-496. [http://dx.doi.org/10.1542/pir.35-11-493] 17. Murray KF, Horslen S, eds. Diseases of the Liver in Children. New York: Springer, 2014.

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ARTICLE

Iron deficiency in children R Thejpal, MB ChB, FCPaed (SA), Cert Clin Haematology (SA) Department of Paediatrics and Child Health, Faculty of Health Sciences, University of KwaZulu-Natal, Durban, South Africa Corresponding author: R Thejpal (thejpal@ukzn.ac.za)

A search (MEDLINE/PubMed) was conducted of recent and relevant articles on iron deficiency in childhood. Iron deficiency remains a global health problem. In South Africa, multiple interventions, including mandatory fortification and a programme for deworming and supplementation, have significantly reduced the prevalence of anaemia. Studies continue to show that iron deficiency in infancy and early childhood is associated with negative neurocognitive, motor and behavioural effects, some of which persist despite treatment. Maternal iron deficiency has negative effects during pregnancy and in the postpartum period, which affects maternal health (e.g. depression, stress, interaction) and has negative effects on the baby (e.g. behavioural and immunological effects). Newer tests include the soluble transferrin receptor, reticulocyte haemoglobin and hepcidin assays. The hepcidin level is useful in differentiating iron deficiency from anaemia of chronic disease with and without iron deficiency. Screening is a challenge and no firm recommendations have been made. The mainstay of treatment remains oral iron (commonly ferrous sulphate). Failure to respond to treatment, refractory iron deficiency and use of parenteral iron are briefly covered. S Afr Med J 2015;105(7):607. DOI:10.7196/SAMJnew.7781

Anaemia is a worldwide health problem affecting developed and developing countries. Children <5 years of age and women of child-bearing age are the most vulnerable. Iron deficiency anaemia (IDA) ranked 15th and 14th in the global disability-adjusted life-years in 1990 and 2010, respectively.[1] Globally, the prevalence of anaemia was 32.9% in 2010.[2] Anaemia contributed to 8.8% of the total disability from all conditions. Although the prevalence of anaemia has decreased since 1990, it has increased in children <5 years of age during this period; the poorest countries have an unacceptably high prevalence. Anaemia in childhood is defined as a haemoglobin (Hb) concentration below cutoff levels established by the World Health Organization: <11 g/dL in children aged 6 - 59 months, <11.5 g/dL in children aged 5 - 11 years and <12 g/dL in children aged 12 - 14 years. Causes of anaemia vary by age, sex and geographical region, but IDA remains the leading cause of anaemia worldwide. Regions with a high prevalence of anaemia (Asia and subSaharan Africa) have a larger burden of infections and iron deficiency. In childhood, anaemia is more prevalent in boys owing to parasite infestation, mainly hookworm. In adults, anaemia is more prevalent and severe in women. High-income regions have a higher incidence of anaemia caused by haemoglobinopathy, chronic kidney disease and gastrointestinal haemorrhage. In sub-Saharan Africa, malaria is a major cause (24.7%) of anaemia. Almost half of the world’s anaemia burden is caused by iron deficiency.[3,4] IDA represents the extreme end of the spectrum of iron deficiency and a large burden of iron deficiency without anaemia is present in the background. In South Africa (SA), the prevalence of anaemia in children <5 years of age has decreased by approximately 63% since 2005.[5]

Iron physiology

Iron is a major component of the earth’s crust and an essential element for all living organisms in an oxygen-rich environment. Environmental iron exists as ferric iron (Fe3+) or ferrous iron (Fe2+). Ferric iron is almost insoluble in water at a neutral pH, and as a polar hydrophilic ion is unable to cross membranes. Iron can readily convert from one form to the other (Fe2+ and Fe3+) by losing or gaining an electron. This is useful in all reactions requiring the loss or gain of electrons, but potentially toxic when reactive oxygen species are generated.

Iron is required for many metabolic processes, such as oxygen transport, drug metabolism, as a cofactor for essential enzymatic reactions (including synthesis of steroid hormones and neurotransmitters), cellular respiration, electron transport within cells, DNA synthesis, gene regulation and cell proliferation and differentiation.

Iron absorption and distribution

Three pathways exist in enterocytes for the uptake of food iron. Haem iron and non-haem iron are absorbed into the enterocyte non-competitively. Haem is maintained in a soluble state and digested enzymatically free of globin. Haem enters the enterocyte as a metalloporphyrin. Within the cell, iron is released from haem by haem oxygenase to pass into the body as inorganic iron. Most non-haem dietary iron is ferric iron. Some ferric iron enters the absorptive cell via the integrin-mobilferrin pathway. Iron is reduced in the gut lumen by the action of duodenal cytochrome b or ferric reductase and enters the enterocyte via the divalent metal transporter-1 (DMT-1). The DMT-1 is found mainly at the apical surface of the enterocytes of the first part of the duodenum, in endodermal vesicles in erythroid and other cells and on macrophages. DMT-1 also transports zinc, copper, cobalt, manganese, cadmium and lead. Ferroportin (basolateral transporter) in association with hephaestin (ferroxidase) is responsible for iron export from cells (enterocytes, placenta, macrophages and hepatocytes). Absorption varies with iron stores (stores regulator), erythroid activity (erythropoietic regulator), tissue iron deficiency and changes in mucosal oxygen tension. The enterocyte is informed of body requirements for iron and programmed accordingly at the base of the crypt. Intracellular ferritin controls the amount of iron retained by the cell and excess iron is stored as ferritin to protect the cell from oxidative damage. Iron leaves the enterocyte via the ferroportin transporter. Transferrin is the receiving protein that transports iron in the plasma. Severe IDA results in a marked increase in erythropoiesis. Inadequate haemoglobinisation results in ineffective erythropoiesis, as these cells are not viable and an increase occurs in effective iron turnover and the serum transferrin receptor. More than two-thirds of the body’s iron (28 - 30 mg/kg) is in Hb and myoglobin (5 mg/kg). The remainder is storage iron ferritin (4 - 8 mg/kg), haemosiderin (2 - 4 mg/kg) and iron bound to transferrin (<1 mg/kg).

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Losses, approximately 1 - 2 mg daily (skin, menses), need to be balanced by intestinal absorption of 1 - 2 mg daily. Hepcidin is a key protein in iron homeostasis.[6,7] Intra- and extra cellular iron concentrations and infection/inflammation increase the hepcidin concentration, while increased erythropoiesis suppresses hepcidin production. Hepcidin regulates plasma iron by its effect on ferroportin concentrations in the enterocyte, macrophage and hepatocyte. Elevated hepcidin levels in anaemia associated with infection, inflammation, chronic kidney disease and cancer cause down-regulation of the ferroportin exporter and sequestration of iron in the enterocyte, hepatocyte and macrophage. In IDA, hepcidin levels are suppressed to low or undetectable levels.

Sources of iron

Haem iron, which is readily available for absorption, is found in clams, oysters, liver and red meat. In the USA and Europe, most of the dietary iron is from haem. Non-haem iron is mainly available from vegetables and is less bioavailable. Sources are fortified cereals, beans, soya, spinach, lentils and asparagus. The presence of haem iron, vitamin C or citrus juice in the diet enhances absorption of dietary iron. Eggs, soya, bran, phytates, phosphates, tannates, oxalates, carbonates and other iron chelators reduce absorption of dietary iron. Rice is a poor source of dietary iron.

Causes of iron deficiency anaemia in childhood

In adults about 95% of the iron required for new red cell Hb is recycled from aged red cells and only 5% comes from the diet. Because infants grow so rapidly, <70% of iron is recycled and 30% is required from dietary sources. Factors contributing to the development of iron deficiency include ante- and perinatal factors that influence infant iron status, increased iron requirements for the expanding red cell mass during growth, and blood loss. Women of reproductive age are at risk because of menstruation, fetal and placental requirements, and bleeding during delivery. Children of anaemic mothers are a vulnerable group. Maternal iron deficiency is associated with increased maternal and infant mortality; it also influences birth weight and duration of gestation in mothers of low birth weight or premature infants.

Milk feeds and iron deficiency

The dietary iron requirement of infants up to 6 months of age has been estimated at 0.27 mg/day; the iron in breastmilk is adequate for most babies. Breastmilk iron is bioavailable and up to 50% of the ingested iron is absorbed. Iron stores are depleted when the baby doubles its birth weight. Children 6 - 12 months of age require 11 mg/day, which is not met by breastmilk. The iron requirement decreases to 7 mg/day between the ages of 1 - 3 years, an amount that may be readily supplied by the introduction of iron-rich foods.[8] Exclusive breastfeeding, without supplementation, beyond 6 months is a risk factor for IDA. Iron in cow’s milk and formula milk is poorly absorbed. Formula feeds are therefore suitably fortified. However, the use of undiluted cow’s milk and a predominant cow’s milk intake in later infancy is associated with IDA. Contributory factors are allergy and proportionately less intake of weaning feeds containing iron. Iron stores are directly proportional to birth weight, i.e. low birth weight babies have lower iron stores at birth and are at increased risk of IDA. Infants of diabetic mothers, babies with a low cord ferritin level and twin and multiple pregnancies are also at risk.

Impact of postpartum maternal iron deficiency

Maternal anaemia has been observed to be significantly related to postpartum depression and fatigue.[9] A conservative estimate of anaemia in adult women in an urban SA environment is 15% (10% IDA).[10]

Maternal iron deficiency is associated with impaired cognition and interaction and mother-child interaction is negatively affected. The potential child health risks associated with maternal anaemia and iron deficiency may not be limited to the prenatal period. In HIV, anaemia and iron deficiency are common and independent predictors of HIV disease progression and mortality. Maternal anaemia in the postpartum period strongly predicted child mortality and immune status in children born to HIV-infected women.[11,12]

Iron deficiency anaemia in infancy

Iron deficiency can impair growth and intellectual development. Iron has been documented to have an effect on normal myelination and basal ganglia function. The brain is most vulnerable during rapid brain growth, especially in the third trimester of pregnancy and the first 2 years of life. Iron deficiency, even without anaemia, can result in neuropsychological effects and has been linked to cognitive impairment in later childhood and in adolescence.[13] Iron deficiency in infants resulted in poorer motor function.[14] Infants with iron deficiency test lower in cognitive, motor, social-emotional and neurophysiological development than controls. Of concern is the occurrence of motor defects in non-anaemic infants with iron deficiency, persistence of some of these defects and failure to consistently improve with iron therapy.[15] Iron deficiency affects cell-mediated immunity and myeloperoxidase activity in phagocytes. It has also been reported to increase susceptibility to common infections. Some patients with life-threatening infections received ‘vigorous iron therapy’.[16] The defect in cell-mediated immunity corrects with iron therapy. Fungal infections, herpes, other viral infections and repeated bacterial infections have been reported. Treatment of iron deficiency may predispose to the development of malaria in certain settings. Maternal IDA was associated with significantly lower CD4 counts in exposed but uninfected babies.[12] Iron deficiency has effects on epithelial surfaces. Glossitis, stomatitis, oesophageal webs and malabsorption reflect direct involvement of the gastrointestinal tract; pica and koilonychia may also be present.

Prevention and treatment

There is no ideal age for the screening of children. At any given point there would be infants who are anaemic for a period, while others would become anaemic thereafter. A number of countries in sub-Saharan Africa, India and Afghanistan have ‘an alarmingly high level of hidden hunger, with stunting, iron deficiency anaemia and vitamin A deficiency all being highly prevalent’.[17] These numbers are likely to increase with economic recession and climate change, and other poverty-related factors will result in inequalities in early childhood development. The effects prenatally and in the first year of life will have long-lasting negative consequences on intellectual development and motor functioning.[18] There is a real need for multiple micronutrient interventions (e.g. iron, zinc, vitamin A) to tackle this hidden burden of disease. To ameliorate iron deficiency, fortified supplementary foods, deworming and prophylactic iron treatment are indicated. In SA, mandatory food fortification (iron, zinc, vitamin A, thiamine, riboflavin and vitamin B6) was introduced in 2003 for maize and wheat flour. Furthermore, a national programme to provide deworming and school feeding has been implemented. Additional intervention with a micronutrient-fortified beverage reduced iron deficiency (based on serum ferritin) from 29.2% to 5.5%.[19] In this study, improvement in cognitive test scores was also documented. Baseline prevalence of anaemia improved from 27.9% to 5.8 - 8.8% in the different groups.

Prophylaxis

Prophylaxis is indicated for high-risk groups, including low birth weight and premature babies, infants of diabetic mothers, exclusively breastfed infants (especially beyond 6 months of age), babies who

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Table 1. Intravenous iron preparations Preparation

Iron sucrose (Venofer)

LMW iron dextran (CosmoFer)

Ferric carboxymaltose (Ferinject)

Iron isomaltose (Monofer)

Test dose

Required

Dosage and administration

Maximum: 200 mg in 30 minutes 3 times a week

100 - 200 mg in 30 minutes 2 - 3 times a week TDI 4 - 6 hours

TDI or 15 mg/kg slow intravenous injection 100 mg/min injection Up to 1 000 mg in 15 minutes

200 - 1 000 mg once weekly 200 mg in 4 minutes TDI over 60 minutes

Contraindications

Drug hypersensitivity, asthma, atopy, pregnancy

Drug hypersensitivity, asthma, atopy, cirrhosis, renal failure, infection, rheumatoid arthritis (active)

Drug hypersensitivity

Drug hypersensitivity, asthma, atopy, cirrhosis, rheumatoid arthritis

Cost

Cheap

Cheaper

More expensive

Expensive

LMW = low molecular weight; TDI = total dose infusion (up to 20 mg/kg).

are introduced to cow’s milk early, and in multiple pregnancies and peripartum blood loss. The requirement for prophylaxis for premature and low birth weight babies is higher. The suggested iron intake for term infants is 1 mg/kg body weight per day to a maximum of 15 mg, starting no later than 4 months and continuing until 3 years of age. The recommendation for low birth weight infants is 2 mg/kg/day to a maximum of 15 mg, starting no later than 2 months of age. Delayed cord clamping is advocated. In older children there is a place for intermittent prophylaxis (once or twice a week).

Presentation and diagnosis

Presentation with severe anaemia is easily recognised, as these patients have pallor, a high cardiac output state and are sometimes in cardiac failure. Irritability, fatigue, poor concentration, gastrointestinal effects, pica and koilonychia may be present. Microcytosis and anaemia (Hb <11.5 g/dL) are the most severe stages of deficiency. Confirmatory tests include low serum iron (there may be a diurnal variation), elevated transferrin and transferrin saturation <16%. A low serum ferritin is confirmatory (at all ages <10 - 12 µg/mL), but elevation occurs with inflammation, infection and liver disease. The challenge is to detect patients with subclinical or latent iron deficiency, without anaemia (stage 1, where stores are depleted, and stage 2, where iron transport for erythropoiesis is decreased). Tests include serum ferritin (<15 µg/L), soluble transferrin receptor concentration (>8.3 mg/L) and zinc protoporphyrin concentration (>70 µmol/mol haem). Zinc protoporphyrin is also affected by inflammation and lead poisoning. The newer tests (soluble transferrin receptor and reticulocyte Hb content) have not added much to diagnosing iron deficiency. The hepcidin assay has promise in diagnosing pure IDA (low levels) from anaemia of chronic disease (ACD) or combined IDA/ ACD, where the levels are higher. The assessment of stainable iron on bone marrow smear or biopsy for the definitive diagnosis of IDA is still widely regarded as the gold standard, but reliability is suboptimal. Because of the high prevalence of dietary iron deficiency, it is justified to diagnose IDA by a therapeutic trial of iron treatment. A baseline Hb is done and 5 - 6 mg/kg/day elemental iron is administered. Systemic improvement occurs within days, the reticulocyte response peaks at 5 - 10 days (roughly 10%), Hb increases with 1 - 2 g in the first 3 weeks and Hb and smear normalise in 2 months, irrespective of severity. A failed trial requires further testing to confirm the diagnosis and aetiology. Failure to respond to oral iron may be owing to failure to take medication, discontinuation of medication, persisting blood loss, infection, missed diagnosis (malabsorption, ACD), misdiagnosis of or accompanying folate deficiency.

The preferred treatment is with oral iron for a further 2 - 3 months after the Hb normalises to replenish stores. Concomitant vitamin C enhances absorption. The medication is ideally taken on an empty stomach. Side-effects (nausea, vomiting, diarrhoea, heartburn) can be reduced by administering the treatment with meals, dose modification or a change in preparation.

Indications for parenteral iron

Refractory IDA requires exclusion of bowel pathology (coeliac disease, gastritis, Helicobacter pylori infection, bleeding) and often an endoscopic examination is indicated. True malabsorption is rare, but rapid transit times and failure to absorb enteric-coated tablets may occur. Moreover, oral iron intolerance, poor compliance, kidney disease with erythropoietin, bowel disease and ongoing blood loss are indications for parenteral iron. Various intravenous preparations are available (Table 1). The more expensive preparations enable total dose infusions within an hour. References 1. Murray CJL, Lopez AD. Measuring the global burden of disease. N Engl J Med 2013;169:448-457. [http://dx.doi.org/10.1056/NEJMra1201534] 2. Kassebaum NJ, Jasrasaria R, Naghavi M, et al. A systematic analysis of global anemia burden from 1990 to 2010. Blood 2014;123(5):615-624. [http://dx.doi.org/10.1182/blood-2013-06-508325] 3. World Health Organization (WHO)/UNICEF/UNU. Iron Deficiency Anaemia: Assessment, Prevention, and Control. A Guide for Programme Managers. Geneva:WHO, 2001. 4. Pasricha S-R, Drakesmith H, Black J, et al. Control of iron deficiency anemia in low- and middleincome countries. Blood 2013;121(14):2607-2617. [http://dx.doi.org/10.1182/blood-2012-09-453522] 5. Shisana O, Labadarios D, Rehle T, et al. South African National Health and Nutrition Examination Survey (SANHNES-1). Cape Town: HSRC Press, 2013. 6. Ganz T, Nemeth E. Hepcidin and iron homeostasis. Biochim Biophys Acta 2012;1823:1434-1443. [http://dx.doi.org/10.1016/j.bbamcr.2012.01.014] 7. Theuri I, Aigner E, Theuri M, et al. Regulation of iron homeostasis in anemia of chronic disease and iron deficiency anemia: Diagnostic and therapeutic implications. Blood 2009;113:5277-5286. [http:// dx.doi.org/10.1182/blood-2008-12-195651] 8. Baker RD, Greer FR. Diagnosis and prevention of iron deficiency and iron-deficiency anemia in infants and young children (0 - 3 years of age). Pediatrics 2010;126:1040-1050. [http://dx.doi.org/10.1542/peds.2010-2576] 9. Corwin EJ, Murray-Kolb L, Beard JL. Low haemoglobin level is a risk factor for postpartum depression. J Nutr 2003;133:4139-4132. 10. Lawrie D, Coetzee LM, Glencross DK. Iron deficiency anaemia in healthy South African women despite iron fortification. S Afr Med J 2008;98(8):606-607. 11. Levine AM, Berhane K, Masri-Lavine L, et al. Prevalence and correlates of anemia in a large cohort of HIV infected women: Women’s Interagency HIV Study. J Acquir Immune Defic Syndr 2001;26:28-35. 12. Isanaka S, Spiegelman D, Aboud S. Post-natal anaemia and iron deficiency in HIV-infected women and the health and survival of their children. Matern Child Nutr 2012;8(3):287-298. [http://dx.doi. org/10.1111/j.1740-8709.2011.00389.x] 13. Grantham-McGregor S, Ani C. A review of studies on the effect of iron deficiency on cognitive development in children. J Nutr 2001;131:649S-648S. 14. Shafir T, Angulo-Barrosa R, Jing Y, et al. Iron deficiency and motor development. Early Hum Dev 2008;84:479-485. [http://dx.doi.org/10.1016/j.earlhumdev.2007.12.009] 15. Lozoff B, Georgieff MK. Iron deficiency and brain development. Semin Pediatr Neurol 2006;13:158-165. 16. Cook JD, Lynch SR. The liabilities of iron deficiency. Blood 1986;68(4):803-809. 17. Muthayya S, Rah JH, Sugimoto JD, et al. The global hidden hunger indices and maps: An advocacy tool for action. PLoS One 2013;8(6):e67860. [http://dx.doi.org/10.1371/journal.pone.0067860] 18. Walker SP, Wachs TD, Grantham-McGregor S, et al. Inequality in early childhood: Risk and protective factors for early childhood development. Lancet 2011;378:1325-1338. [http://dx.doi.org/10.1016/ S0140-6736(11)60555-2] 19. Taljaard C, Covic NM, van Graan AE, et al. Effects of a multi-micronutrient-fortified beverage, with and without sugar, on growth and cognition in South African schoolchildren: A randomised, double-blind, controlled intervention. Br J Nutr 2013;110: 2271-2284. [http://dx.doi.org/10.1017/ S000711451300189X]

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Tel: 012 481 2121 | E-mail: ladinev@samedical.org http://www.hmpg.co.za | www.professionalads.co.za We accept credit card payments - Visa or MasterCard.

GP REQUIRED GP required to join a multi-disciplinary practice serving the local community, University & Schools. Based in Grahamstown which is close to the coast and boasts several good schools. Please contact Dr. Murray Gainsford at 046 6362063 or Alix Whittington-Jones (Whittington-jones@highstmed.co.za)

RECRUITMENT AND PLACEMENT OF RECRUITMENT PLACEMENT OF • Medical personnel for permanentAND placements • Non-medical personnel forforpermanent • Medical personnel permanent placements placements

VACANCY FOR FEMALE GYNAECOLOGIST Excellent opportunity for female gynaecologist to take over a well-established private obstetric and gynaecological practice in a mainly Afrikaans speaking environment in Bloemfontein. Contact: MFI, Jannie Fourie, Cell no: 082 788 1995 Email: gemini@gemini.bfnmcc.co.za

PRACTICE FOR SALE IN KENTON-ON-SEA

• Non-medical for permanent placements • Locum placement of personnel General Practitioners • Locum of General Practitioners • After-hour coverplacement at hospitals and clinics • After-hour cover at hospitals and clinics

Phone Lélane for Dr yourfor personal, professional solution to personnel URGENTLY REQUIRING Emergency unit in Limpopo. Salary negotiable. Placements at the lowest rates.

Busy financially stable practice for sale in medical complex at Kenton-on-Sea along the Sunshine Coast. Excellent location. Enough work for two doctors. Very little after hours work

: 082 Cell: 082Cell 92 106 92 92 106 92 Tel: 011 660 Tel :7702 011 660 7702 Fax: 088 Fax 011 :660 0887702 011 660 7702 Email: info@medserve.co.za email : info@medserve.co.za

Contact 0825743446. Owner retiring

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Tel: 021 681 7000 | E-mail: bronlyne.granger@hmpg.co.za www.hmpg.co.za | www.professionalads.co.za We PROFESSIONAL accept credit card payments -ADVERTISING Visa or MasterCard.

Klerksdorp/Welkom/Kimberley

As a creative, dynamic and passionate professional, you will join our highly successful team. Responsive customer needs, are responsible, respectable accountable, possessing a well-deAs to a creative dynamic andyou passionate professional, you will join&our highly successful team. Responsive to customer veloped work ethic. needs, you are respectable & accountable, possessing a well developed work ethic. Laboratories have a available position available for a Clinical Pathologist Microbiologist the PathCare PathCare Laboratories have a position for an Anatomical Pathologist in or Claremont (CapeinTown), Potchefstroom/Klerksdorp area and a Clinical Pathologist/ Microbiologist/any specific discipline for Namibia and Nigeria. Welkom and Kimberley.

If you believe you would thrive in a multi-disciplinary private laboratory, and have similar goals and valIf you believe you would thrive in a multi-disciplinary private laboratory and have similar goals and ues to ourvalues own,towe encourage you to contact us for this position. our own, we encourage you to contact us for this position. Requirements: Requirements: • orM.Med or FC Pathology • M.Med FC Pathology (SA) (SA) • Current with the as aasPathologist • registration Current registration withHPCSA the HPCSA a Pathologist • and willingness toworking registerexperience with the NHPC • Relevant • Relevant working experience • High level of ethics and integrity. • Excellent communication and interpersonal skills “Pathology • AbilityInterested to maintain confidentiality and impartiality. applicants who meet the criteria may email a CV to:

that Adds Value”

lindyg@pathcare.co.za

Interested applicants who meet the criteria may email a CV to: lindyg@pathcare.co.za

MEDICAL OFFICER The Food Workers Medical Benefit Fund is a joint Worker / Management Fund providing primary health care for Food Workers. We invite applications for the above position at our Ashton based Clinic and the successful applicant is to commence employment on the 3rd AUGUST 2015. Requirements • Registration as a Medical Practitioner with the SAMDC / HPCSA; Have a current dispensing licence; • Fluency in Afrikaans and English (writing and verbal); Professional liability insurance (e.g. MPS); Previous experience in Primary Health Care/ Community Health Care; Computer skills (Windows: MSWord, MSOutlook, MSPowerPoint, MSExcel,); Ability to work under pressure; Ability to foster good relations with members, service providers and co-workers; Ability to identify problems and being proactive; Sound work ethic. Duties • Manage the Ashton Clinic and Clinic Staff of the Fund; Provide a general practitioner service including dispensing medicine; Manage other health related services of the Fund; Assist with resolving members’ queries; Assist with general administrative duties Remuneration The Fund offers an attractive salary package and leave entitlement.

Persons who meet the requirements of this position may forward their written applications including a CV with covering letter, certified copies of qualifications, at least two references and contactable telephone numbers to: THE PRINCIPAL OFFICER CLOSING DATE FOR APPLICATIONS: 17 JULY 2015 Food Workers Medical Benefit Fund P.O. Box 1067 Please note: If you have not heard from us by 28 PAROW July 2015, please accept that your application 7499 has been unsuccessful. Tel: 021-930 3550 Fax: 086-551 4064 Email: appollis@foodmed.co.za The Food Workers Medical Benefit Fund strives towards equal opportunities. The Fund is not obliged to fill the position.

partner knowledge your • partner knowledge your 123603

Faculty of Medicine and Health Sciences Professor/Associate Professor and Executive Head of Department: Anaesthesiology and Critical Care (Ref: TGB01/184/0615) Duties: Strategic leadership and operational management of the Department • teaching and guidance of undergraduate and postgraduate students in Anaesthesiology and Critical Care • guiding and participating in the design, execution and publication of research • rendering of clinical service in the field of Anaesthesiology and Critical Care. Requirements: A postgraduate qualification in Anaesthesiology and Critical Care • registration/compliance with the criteria for registration with the Health Professions Council of South Africa as Specialist in Anaesthesiology • management experience within an academic environment • teaching experience in Anaesthesiology and Critical Care at both undergraduate and postgraduate levels • experience in and a proven record of independent and innovative research and guidance of research. Recommendations: A doctoral degree.

Professor/Associate Professor and Executive Head of Department: Obstetrics and Gynaecology (Ref: TGB10/185/0615) Duties: Strategic leadership and operational management of the Department • teaching and guidance of undergraduate and postgraduate students in Obstetrics and Gynaecology • guiding and participating in the design, execution and publication of research • rendering of clinical service in the field of Obstetrics and Gynaecology. Requirements: A postgraduate qualification in Obstetrics and Gynaecology • registration/compliance with the criteria for registration with the Health Professions Council of South Africa as Specialist in Obstetrics and Gynaecology • management experience within an academic environment • teaching experience in Obstetrics and Gynaecology at both undergraduate and postgraduate levels • experience in and a proven record of independent and innovative research and guidance of research. Recommendations: A doctoral degree.

Professor/Associate Professor and Head of Division: Surgery (Ref: TGB03/186/0615) Duties: Strategic leadership and operational management of the Division • teaching and guidance of undergraduate and postgraduate students in Surgery • guiding and participating in the design, execution and publication of research • rendering of clinical service in the field of Surgery. Requirements: A postgraduate qualification in Surgery • registration/compliance with the criteria for registration with the Health Professions Council of South Africa as Surgeon • management experience within an academic environment • teaching experience in Surgery at both undergraduate and postgraduate levels • experience in and a proven record of independent and innovative research and guidance of research. Recommendations: A doctoral degree.

Professor/Associate Professor and Head of Division: Neurosurgery (Ref: TGB03/187/0615) Duties: Strategic leadership and operational management of the Division • teaching and guidance of undergraduate and postgraduate students in Neurosurgery • guiding and participating in the design, execution and publication of research • rendering of clinical service in the field of Neurosurgery. Requirements: A postgraduate qualification in Neurosurgery • registration/compliance with the criteria for registration with the Health Professions Council of South Africa as Specialist in Neurosurgery • management experience within an academic environment • teaching experience in Neurosurgery at both undergraduate and postgraduate levels • experience in and a proven record of independent and innovative research and guidance of research. Recommendations: A doctoral degree. Commencement of duties: January 2016 Closing date: 31 July 2015 Enquiries regarding the job content: Prof JA Volmink, Dean, Faculty of Medicine and Health Sciences on +27 21 938 9200 Enquiries regarding remuneration/benefits as well as technical assistance with the electronic application process: Human Resources Division, Tygerberg Campus on +27 21 938 9636 The University will consider all applications in terms of its Employment Equity Plan, which acknowledges the need to diversify the demographic composition of the staff corps, especially with regard to the appointment of suitable candidates from the designated groups. The University reserves the right not to make an appointment.Your application, comprising a comprehensive curriculum vitae (including the names and contact details of at least two referees), must reach the University before or on the closing date of the advertised post. Applicants should request their referees to send confidential reports by the closing date directly to the following address: Manager: Human Resources (Satellite Campuses), Stellenbosch University, PO Box 19063, Tygerberg 7505; e-mail: hrtygerberg@sun.ac.za; fax: +27 21 932 9266 Apply online at www.sun.ac.za/english/careers Candidates may be subjected to appropriate psychometric testing and other selection instruments. Should no feedback be received from the University within six weeks of the closing date, kindly accept that your application did not succeed. www.ayandambanga.co.za

CPD

JULY 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 Impact of fibrinolytics on the outcome of empyema in South African (SA) children 1. Empyema is one of the commonest complications of childhood pneumonia. 2. The commonest bacterial pathogen identified on pleural culture was Mycobacterium tuberculosis. 3. In SA, the incidence of invasive pneumococcal disease has declined following the introduction of PCV13 into the national immunisation programme in 2011. The impact of highly active antiretroviral therapy (HAART) on the burden of bacterial lower respiratory tract infections (LRTIs) in children, and household fuel use and child respiratory ill health 4. A burden of disease study undertaken in SA in 2012 showed that lower respiratory infections is ranked among the top five causes of mortality in children under the age of 4 years. 5. Despite initiation of HAART, the burden of bacterial LTRIs remains high. 6. The risk of respiratory ill health is high in children living in homes where indoor fossil burning is taking place for residential cooking and space heating. Nodular thyroid diseases and thyroid malignancy 7. The risk of malignancy in cases of multinodular goitre ranges from 2% to 12%. Intracranial suppuration (ICS) at Umtata General Hospital and Nelson Mandela Academic Hospital 8. Sinusitis and ear infection are major sources of ICS. 9. An accurate diagnosis of ICS can be achieved in the majority of cases with adequate clinical information and computed tomography (CT) scans, magnetic resonance imaging being reserved for cases in which a conclusive diagnosis cannot be made with CT. 10. Common signs and symptoms of ICS include headache, fever, focal neurological deficit, neck stiffness and seizures.

CME Vitamin D deficiency and insufficiency in Africa and the Middle East, despite year-round sunny days 11. Vitamin D deficiency has been linked to children with recurrent wheeze and asthma. 12. Vitamin D insufficiency is not common in children in countries with long daytime sunlight hours. Management of severe acute malnutrition 13. The hallmarks of acute malnutrition include wasting, sparse hair, skin changes and an enlarged smooth liver. 14. Kwashiorkor is diagnosed, in the main, by the presence of bilateral symmetrical pitting oedema. Nutrition in children with long-term health conditions (LTHCs) 15. Up to 20% of children have an LTHC, with <5% having a severe LTHC. 16. Diversion of nutrient energy into inflammation is a potent contributor to suboptimal nutrition and growth in children with LTHCs. Nutritional support of children with chronic liver disease 17. Most children with chronic liver disease require parenteral feeding. 18. Children with advanced liver disease require less frequent feeds owing to attendant gut malabsorption. Iron deficiency in children 19. Low birth weight infants are at higher risk of developing iron deficiency and iron deficiency anaemia than infants born at normal weights. 20. Introducing cowâ&#x20AC;&#x2122;s milk feeds before the age of 12 months increases the risk of the child developing iron deficiency anaemia.

Readers please note: articles may appear in summary/abstract form in the print edition of the journal, with the full article available online via www.hmpg.co.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

July 2015, Vol. 105, No. 7

COMMON CLINICAL PROBLEMS AND THEIR SOLUTIONS

SAMA CONFERENCE | EXHIBITION

ANNUAL DOCTORâ&#x20AC;&#x2122;S AWARDS 2015 18 - 20 September 2015 Early bird registrations end 1 July 2015

SAMA is the largest medical association in South Africa, representing more than 17 000 medical practitioners, both generalists and specialists, in private practice and public sector. The SAMA conference will focus on clinical issues, tools and solutions in order to deliver a better healthcare system to the nation. This conference has become bigger and better over the years. The quality of the speakers, combined with the depth and breadth of topics discussed, continues to exceed the expectations of participants and experts alike. The conference attracts, not only doctors but representatives from important healthcare stakeholders such as the National Department of Health, regulators, funders, administrators and managed healthcare entities.

FOR MORE INFORMATION:

www.samedical.org/events | Registration opens online 1 June 2015