SAMJ Vol 105, No 2 (2015) by HMPG

FEBRUARY 2015

VOL. 105 NO. 2

Digitalis reappraised

Quality improvement â&#x20AC;&#x2DC;toolâ&#x20AC;&#x2122; for trauma services

The South African National Cancer Registry

103, 107

End-stage kidney disease and HIV positivity

105, 110

Linking cervical cancer screening to HPV vaccination

115

Predictors of mortality following non-cardiac surgery

126

Human myiasis

129

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FEBRUARY 2015

FROM THE EDITOR

On getting published in the SAMJ J Seggie

EDITOR’S CHOICE

VOL. 105 NO. 2

EDITOR Janet Seggie, BSc (Hons), MD (Birm), FRCP (Lond), FCP (SA) EDITOR EMERITUS Daniel J Ncayiyana, MD (Groningen), FACOG, MD (Hon), FCM (Hon) CONSULTING EDITOR JP de V van Niekerk, MD, FRCR

CORRESPONDENCE 80

Helpful hints for writing SI units M Coetzee, J Joubert

Implications of Cochrane Review on restricting or banning alcohol advertising in South Africa C Parry, D Pienaar, J Ataguba, J Volmink, T Kredo, M Jere, N Siegfried

Full circle R-I Caldwell

DEPUTY EDITOR Bridget Farham, BSc (Hons), PhD, MB ChB SCIENTIFIC EDITOR Ingrid Nye, BSc TECHNICAL EDITORS Emma Buchanan, BA Paula van der Bijl, BA, HDipLib

IZINDABA 82 83 85

HMPG secures top-drawer CEO Hands-on student training in private hospitals has arrived Honing healthcare leaders’ competence and attitudes equals facility-level delivery

OBITUARY Mannie Stein, 1920 - 2014

BOOK REVIEW Dance with Suitcase: A Memoir resting on Movement

NEWS EDITOR Chris Bateman | Email: chrisb@hmpg.co.za HEAD OF PUBLISHING Robert Arendse PRODUCTION MANAGER Emma Jane Couzens ART DIRECTOR Brent Meder DTP & DESIGN Carl Sampson

SAMJ FORUM

CLINICAL PRACTICE Digitalis reappraised: Still here today, but gone tomorrow? L H Opie

DRUG ALERT Recommendations pertaining to the use of influenza vaccines and influenza antiviral drugs: Influenza 2015 S Walaza, C Cohen

TRAUMA CARE Trauma quality improvement: The Pietermaritzburg Metropolitan Trauma Service experience with the development of a comprehensive structure to facilitate quality improvement in rural trauma and acute care in KwaZulu-Natal, South Africa D L Clarke

MEDICINE AND THE LAW Must doctors disclose their fees before treatment? D J McQuoid-Mason

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

EVIDENCE REVIEW Evidence insufficient to confirm the value of population screening for diabetes and hypertension in low- and-middle-income settings S Durão, O Ajumobi, T Kredo, C Naude, N S Levitt, K Steyn, D Bradshaw, T Young

ISSN 0256-9574

EDITORIALS 103

Why is cancer not a priority in South Africa? D C Stefan

105

Morbidity and mortality of black HIV-positive patients with end-stage kidney disease receiving chronic haemodialysis in South Africa N Wearne

RESEARCH 107

South African National Cancer Registry: Effect of withheld data from private health systems on cancer incidence estimates E Singh, J M Underwood, C Nattey, C Babb, M Sengayi, P Kellett

February 2015, Vol. 105, No. 2

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Publisher website: www.hmpg.co.za SAMA website: www.samedical.org Journal website: www.samj.org.za

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For further product information contact PHARMA DYNAMICS: P O Box 30958 Tokai 7966 • Tel 021 707 7000 • Fax 021 701 5898 • www.pharmadynamics.co.za Customer Care 0860-PHARMA (742 762). SINTAIR 4 mg: Each chewable tablet contains montelukast sodium, equivalent to 4 mg montelukast. Reg. No.: RSA S3 44/10.2.2/0829 NAM NS2 13/10.2.2/0214. SINTAIR 5 mg: Each chewable tablet contains montelukast sodium, equivalent to 5 mg montelukast. Reg. No.: RSA S3 44/10.2.2/0830 NAM NS2 13/10.2.2/0215. SINTAIR 10 mg: Each tablet contains montelukast sodium, equivalent to 10 mg montelukast. Reg. No.: RSA S3 44/10.2.2/0831 NAM NS2 13/10.2.2/0216. For full prescribing information, refer to the package insert approved by the MedicinesControl Council. SRA65/10/2014.

110

Morbidity and mortality of black HIV-positive patients with end-stage kidney disease receiving chronic haemodialysis in South Africa J Fabian, H A Maher, C Clark, S Naicker, P Becker, W D F Venter

115

121

Prevalence of gastrointestinal pathogenic bacteria in patients with diarrhoea attending Groote Schuur Hospital, Cape Town, South Africa B Kullin, R Meggersee, J D’Alton, B Galvão, N Rajabally, A Whitelaw, C Bamford, S J Reid, V R Abratt

126

Predictors of in-hospital mortality following non-cardiac surgery: Findings from an analysis of a South African hospital administrative database Y Moodley, B M Biccard

129

Human myiasis in rural South Africa is under-reported* S K Kuria, H J C Kingu, M H Villet, A Dhaffala

134

Multimorbidity in non-communicable diseases in South African primary healthcare* H Lalkhen, R Mash

139

Prospective analysis of the medicine possession ratio of antidepressants in the private health sector of South Africa, 2006 - 2011* F N Slabbert, B H Harvey, C B Brink, M S Lubbe

145

Integrated positron emission tomography/computed tomography for evaluation of mediastinal lymph node staging of non-small-cell lung cancer in a tuberculosis-endemic area: A 5-year prospective observational study* J A Shaw, E M Irusen, F von Groote-Bidlingmaier, J M Warwick, B Jeremic, R du Toit, C F N Koegelenberg

Please submit all letters and articles for publication online at www.samj.org.za

CONTINUING MEDICAL EDUCATION

151

EDITORIAL The medical case report B Farham

Use of editorial material is subject to the Creative Commons Attribution – Noncommercial Works License. http://creativecommons.org/licenses/bync/3.0

152

CASE REPORTS The unsuspected killer: Liquefied petroleum gas overexposure in South Africa L W J Sampson, N van der Schyff, C Cupido

153

The utility of urine sulphosalicylic acid testing in the detection of non-albumin proteinuria S Ndamase, R Freercks

154

Digoxin therapy in the modern management of cardiovascular disease: An unusual but serious complication P Mkoko, N Mokhele, M Ntsekhe, N A B Ntusi

154

Arthritis mutilans: A rare phenomenon M C Madua

155

For external use only P Mkoko

155

A tale of two viruses M C Madua

156

Schistosomiasis misdiagnosed as abdominal tuberculosis S N Botes, S B Ibirogba, D Kahn

156

An additional X chromosome M C Madua

157

Wernicke’s encephalopathy as a complication of gastroparesis after emergency partial antrectomy N S Ganie, E Janse van Rensburg

157

Fever, sore throat and myalgia P Ive, M Mendelson, S Dlamini

*Full article available online only.

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Plagiarism is defined as the use of another’s work, words or ideas without attribution or permission, and representation of them as one’s own original work. Manuscripts containing plagiarism will not be considered for publication in the SAMJ. For more information on our plagiarism policy, please visit http://www.samj.org.za/ index.php/samj/about/editorialPolicies Printed by Creda Communications

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February 2015, Vol. 105, No. 2

FIRST PUBLISHED IN 1884

On getting published in the SAMJ ‘Work; finish; publish’ (Michael Faraday[1] ) The SAMJ proudly publishes research that impacts on clinical practice in (South) Africa, reflecting the journal’s byline ‘Leading research impacting clinical care in Africa’, which implies that we have been pleased, as readers will know, to have entertained work from researchers in other countries in Africa (see ‘Sources of articles published in SAMJ/CME during 2014’[2]). One of the pleasures of my role as Editor is to accept and publish the work of (South) Africa’s young clinical scientists, recently established in their chosen field and embarking on their research, or even having undertaken research during community service. Common to the manuscript that is successful is clear evidence of mentorship[3] in the undertaking of the research. It is interesting to note The Lancet’s growing insistence on what they term ‘Research in context’:[4] offering a description of all the evidence that the author(s) considered before undertaking the study, a description of how the findings add value to the existing evidence, and a statement of the implications for practice or policy, and future research, of their study. In the generation of the article submitted for publication, some fundamental rules need to be followed: going into the SAMJ’s website and reading the Author Guidelines, and submitting in the belief that the research is a good ‘fit’ for the journal, whose readership is ‘generalist’ at a general practice and specialist level; ensuring that the abstract is crafted with special attention (given that it is all that may be read, it must convey the ‘whole story’ of the research); and accepting with grace and humility the comments of reviewers who suggest revisions, and complying – as far as is possible – with those suggestions. The SAMJ rejects some 50 - 70% of submissions, and authors need to prepare for, and graciously accept, the journal’s decision not to publish an article. The chief reason for rejection is that an article is not suitable for the journal … that its subject matter is too parochial and not generalisable, or too highly specialised for the readership and more suited to a specialist journal. Clear evidence that the Author Guidelines have not been read, or even that previous SAMJs and similar articles have not been studied for the ‘SAMJ format’, immediately signals problems. Also, shorter is always better! We have good reasons for not accepting lengthy articles with countless references, which, if they were to be accepted, would delay publication of others in the queue and add to the copyediting, and proofreading, workload. Simply put … research the SAMJ before submission, and research again. The best response to rejection is to consider whether another journal, perhaps one of the SAMJ’s siblings,[5] might not be a better choice and getting on with rewriting the article with that journal in mind, paying heed to the advice of reviewers, if available. It bears mentioning that the SAMJ will entertain a request for reconsideration following rejection, if soundly motivated. Some 10 - 20% of submissions are accepted at ‘first-pass review’ by the journal’s Editorial Advisory Committee, the remainder proceeding to review by expert, discipline-specific peer reviewers, of whom, it must be said, there is an insufficient number willing to spend the 4 - 8 hours (typically of down and relaxation time) on the academic task of adjudicating a paper’s worthiness and scientific strength. We are grateful to those generous national

and international colleagues who support the journal by under taking peer review for us, seeing it as part of their academic endeavour. Our expert reviewers criticise lack of originality, unclear hypotheses, poor or weak design, a too-small sample, inappropriate or misapplied statistics, unjustified conclusions and outdated or overlooked references. A rash of MMed theses, offered for publication, all too often reveal these deficiencies, and importantly absence of the mentorship referred to above. We are on the lookout for conflicts of interest[6] and ethical breaches (though these are rare). Too often, local authors have a tendency to lean heavily on differences between racial cohorts without sound reasons. The SAMJ’s Emeritus Editor Daniel J Ncayiyana has offered advice:[7] ‘In unequal societies with a history of institutionalised racism, particular health and medical problems have a particular prevalence in ethnic groups that are longstanding victims of material deprivation and health care inequities. In this context, research into health disparities of social groups that are victims of discrimination is both legitimate and important. However, the researcher should be quite clear as to what is being measured. The research should not lead to “social and economic variables [being] mixed up with, and confused with genetic determinants” in the mind of the researcher, and should not lead to the misperception that being black (for example) – rather than poverty, limited education, poor housing, lack of sanitation, poor nutrition and other deprivations – is the “explanation” for ill health.’ Then there are author ‘crimes’: duplicate publication (the same article, modestly reframed and offered to more than one journal), ‘salami’ publishing (the same body of work divided into several segments in an attempt to achieve multiple publications), and plagiarism, especially from websites. All articles submitted to all the HMPG titles are ‘seen’ by the iThenticate plagiarism screening system, which screens submitted papers for originality and can tell whether a paper contains passages of text that also appear in other publications or resources.[8] This means that we can (generally, but not always) catch articles with plagiarised content. Publishing worldwide has run into financial difficulties for a number of reasons. And, for a journal that is circulated by post to some 17 000 SAMA members, it does not help that postal and distribution costs are escalating and that the postal service fails because of strikes. Moreover, cost containment requires that the print volume of the journal is held to a finite page allocation, limiting the number of research papers that can be published in any one print edition. This is why, since January 2014, CME has been co-joined with SAMJ and is limited to printed summaries, the full articles being published online, and why, since November 2014, the SAMJ has published printed abstracts of papers (randomly selected) with the full paper available online. A loose canvassing of the opinion of one’s younger, and even older, colleagues reveals their comfort with this, and unashamed admission that the journal often remains in its plastic sleeve and is read instead on one or another computer platform. As suggested in my inaugural editorial,[9] the entire journal will in time go this way. In 2005, George D Lundberg, former Editor of JAMA, provided advice during a seminar to hundreds of student authors[1] on ‘How to write a medical paper to get it published in a good journal’ (the video that accompanies this reference is worth looking at). Lundberg says this: ‘Writing is hard work. So you want to write a paper? What

February 2015, Vol. 105, No. 2

FROM THE EDITOR

do you have to say? Is it worth writing? Has the information already been published? What format should it be? What is the audience? What journal is appropriate? Expect peer review, a process that began some 300 years ago in France and in England and revolutionized science by creating a culture of peer criticism and self-criticism. Peer reviewers are asked: Is the manuscript original, important, interesting; are the data valid; are the conclusions justified by the data; is the writing clear; and what is the priority and timing? Is it new? Is it true? All journals make messes. They clean them up in the letters column and by corrections and retractions.’ Lundberg goes on to highlight the presence of a vade mecum for would-be authors adapted from Tierney of Indiana University and available by clicking on http://images.medscape.com/images/515/525/ mgm515525.attachment.doc In his Offline commentary entitled ‘Think English’,[10] the Editor of The Lancet last year addressed a question frequently posed to him: ‘How can I publish my paper in The Lancet?’ Horton’s answer was ‘But the question is ridiculous. Who cares about getting published in The Lancet?’ Invoking Michael Faraday, one of the world’s greatest scientists, Horton stated: ‘Getting published at all is what ought to count for a young scientist.’

Janet Seggie

Editor janet.seggie@hmpg.co.za 1. Lundberg GD. How to write a medical paper to get it published in a good journal. MedGenMed 2005;7(4):36. 2. Sources of articles published in SAMJ/CME during 2014. S Afr Med J 2015;105(1): between pages 34 and 35. 3. Seggie J. On mentorship. S Afr Med J 2014;104(7):453. [http://dx.doi.org/10.7196/SAMJ.8437] 4. Kleinert S, Benham L, Collingridge D, Summerskill W, Horton R. Further emphasis on research in context. Lancet 2014;384(9961):2176-2177. http://dx.doi.org/10.1016/S01406736(14)62047-X] 5. Health and Medical Publishing Group. List of journals. http://www.hmpg.co.za/journals (accessed 12 January 2015). 6. Blockman M, Parrish A. Who will guard the guards? Medical leadership and conflict of interest in South African healthcare. S Afr Med J 2014;104(11):757-758. [http://dx.doi.org/10.7196/SAMJ.8546] 7. Ncayiyana DJ. Racial profiling in medical research: What are we measuring? S Afr Med J 2007;97(12):1225-1226. 8. iThenticate. Plagiarism blog. http://www.ithenticate.com/plagiarism-detection-blog/bid/63534/ CrossCheck-Plagiarism-Screening-Understanding-the-Similarity-Score#.VFyoQPSUe9g (accessed 12 January 2015). 9. Seggie J. There are no schools for medical editors. S Afr Med J 2013;103(2):65-66. [http://dx.doi. org/10.7196/SAMJ.6618] 10. Horton R. Offline: Think English. Lancet 2013;381(9880):1800. [http://dx.doi.org/10.1016/S01406736(13)61085-5]

S Afr Med J 2015;105(2):77-78. DOI:10.7196/SAMJ.9348

EDITOR’S CHOICE CME: Case reports

February’s CME consists of a series of case reports that have been received over the past 12 months. Many journals, local and international, feature case reports within their pages, and younger doctors in particular are encouraged to write up their more interesting cases in this format. According to Wikipedia, ‘in medicine, a case report is a detailed report of the symptoms, signs, diagnosis, treatment and follow-up of an individual patient’. Case reports are usually written to provide an unusual or novel occurrence of a set of signs and symptoms, or, as is the case in some of the reports published this month, unusual presentations of a particular disease entity. Case reports often contain some kind of literature review of other reported cases, even if only to say that the report is of a rare occurrence. Case reports are, by their very nature, anecdotal and are placed at the foot of the hierarchy of clinical evidence, together with case series. However, case reports are usually thought to have genuinely useful roles in medical research and in evidence-based medicine. However, one of the most useful roles of case reports is that of medical education, both formally, providing a structure for casebased learning (which we all did at medical school), and informally, for the general reader. In both cases, interesting and unusual presentations are helpful to day-to-day practice and will often trigger recognition of a diagnosis or pathology in a puzzling clinical case. All the case reports presented in this issue of CME are local, and selected for their particular usefulness to our younger and less experienced colleagues.

Renal disease and haemodialysis in HIV-positive patients

An article on morbidity and mortality of black HIV-positive patients with end-stage kidney disease receiving chronic haemodialysis in South Africa (SA)[1] and an accompanying editorial[2] reveal the extent

of renal disease in the HIV-positive population. Renal disease affects up to 30% of HIV-infected patients. HIV-associated nephropathy (HIVAN) is most common and, unless treated with antiretroviral therapy (ART), progresses rapidly to end-stage renal disease (ESRD). ESRD is projected to increase further now that HIV-positive patients are living longer on ART and are increasingly manifesting the diseases of lifestyle, including hypertension and diabetes. All HIV-positive patients should be screened for chronic kidney disease at first encounter with any health service. This is particularly important in view of the fact that HIVAN can occur with high CD4 counts. Screening should include urinalysis and measurement of kidney function. Patients manifesting renal involvement should be fast-tracked for ART. Furthermore, being HIV-positive is no longer a contraindication to renal transplantation, provided patients are established on ART and achieve acceptable CD4 counts and suppressed viral loads.

Linking cervical cancer screening to human papillomavirus (HPV) vaccination

This issue of SAMJ features the second article on the Vaccine and Cervical Cancer Screen (VACCS) project, on linking cervical cancer screening to HPV vaccination in the South-West District of Tshwane, Gauteng, SA.[3] This study provided the novel opportunity to investigate the outcome of cervical cancer screening in mothers and guardians by linking this to the vaccination of the grade 4 - 7 girls in their care. New molecular screening technology was utilised, permitting self-sampling in a home setting with a screen kit offered to female parents and guardians (plus an extra one for a friend or family member). The screen kit consisted of a tampon with user instructions: women inserted the tampon vaginally and removed it after one hour. The used tampon was placed in a container with buffer and, together with personal information, was returned to the school in a sealed envelope. DNA

February 2015, Vol. 105, No. 2

12106

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EDITOR’S CHOICE

60 000 Cancer cases, n

was extracted from the tampon specimens and tested for any of the 15 high-risk viral types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, 82), HPV 16 and 18 being the two most oncogenic. Roughly half of the women took up the screening opportunity, and molecular screening identified cervical cancer risk in 30% and a high risk of future disease in 9.1%. Using the school infrastructure as well as mobile phone technology, all women received their screen results. This is an important development, given the limited success registered by the national cervical cancer prevention programme, launched in 2000, which offers three Papanicolaou smears per lifetime (starting after the age of 30, at 10-year intervals).

50 000 40 000 30 000 20 000 10 000 0

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 Year

NCR projected

Digitalis reappraised

Still here today, but gone tomorrow? Opie[4] suggests that there are very few arguments left in favour of the use of digitalis in the control of heart rate in atrial fibrillation. Following negative mortality data from one large recent study of digitalis in heart failure (HF), enthusiasm for further testing for the benefit of digitalis that would necessitate a large, multicentre, prospective randomised controlled trial is waning. Opie suggests that digoxin, for the indication of HF, would not be passed by regulatory agencies on the basis of present data. (See also in CME ‘Digoxin therapy in the modern management of cardiovascular disease: An unusual but serious complication’[5].)

Why is cancer not a priority in South Africa?

An editorial asks the above question.[6] The National Cancer Registry (NCR) is an invaluable source of cancer data for the country. Established in 1986 as a voluntary, pathology-based cancer reporting system, the Registry within the National Health Laboratory Service is the principal cancer surveillance system in SA. Regulation 380 of the 2011 National Health Act formally established the NCR as the main cancer surveillance agency and mandated reporting of all confirmed cancers in SA to the NCR. The NCR receives over 100 000 cancer reports annually; approxi mately 80 000 are new cases, on the basis of which cancer incidence is calculated. Registry data have been used to highlight cancers of importance in the SA context. Data from the Johannesburg Cancer Case Control Study (JCCCS), conducted by the Cancer Epidemiology Research Group, have been used to extensively describe the epidemiology of HIV-related cancers and particularly to explore the relationship between Kaposi’s sarcoma and HIV. The JCCCS has also contributed to risk factor analysis in the International Collaboration of Epidemiological Studies of Cervical Cancer. The NCR manages cancer surveillance in the context of SA’s dual health system, comprising a large public health infrastructure serving approximately 84% of the population and a smaller private health system catering to 16%. It is dismaying to learn from Singh et al.[7] that private laboratory cancer data reporting, which was consistent throughout the early 2000s, was withheld from 2005 to 2007, resulting in a 28% under-reporting from private healthcare centres (see Fig. 1, reproduced below). Fortunately the impact of withheld private data appears to have been minimal in that there was only a 4% decrease in overall cancer reporting, reflecting the reality that four out of every five SA citizens receive care in public healthcare systems. Fortunately, too, relationships with private sector laboratories have been renewed and a standard system has been established to receive private sector pathology data electronically. In an era of growing prioritisation of NCDs and with global cancer burdens estimated to increase significantly, the NCR has an invaluable role to play in the health and health planning landscape of SA. In view of the progressive health developments in the country,

NCR reported

Private projected

Private reported

Fig. 1. Actual and projected case reporting from private laboratories and to the NCR, 1995 - 2007.

such as the introduction of National Health Insurance, there is an imperative to accurately quantify the cancer burden, and thus the cost of cancer services to be provided to the SA population.

Non-communicable diseases (NCDs)

Two articles in this issue address comorbidity and multimorbidity in NCDs in the SA setting,[8,9] the former suggesting that future clinical guidelines, training of primary care nurses and involvement of doctors in the continuum of care should address the complexity of patients with NCDs and multimorbidity, and the latter warning against mobilisation of scarce resources to implement mass screening for diabetes and hypertension in the absence of adequate evidence of benefit. As is well recognised, the SA healthcare system faces a quadruple burden of disease, characterised by HIV/AIDS and tuberculosis, injury and violence, maternal and child health issues and NCDs. The World Health Organization estimates the burden of NCDs to be two to three times higher in SA than in high-income countries. NCDs are estimated to contribute 28% to the total burden of disease, and this is predicted to increase substantially over the next few decades. In the Western Cape, NCDs account for five of the ten leading causes of death: ischaemic heart disease, diabetes, cerebrovascular disease, lung cancer and chronic obstructive pulmonary disease. NCD distribution reflects socioeconomic disparities, with the heaviest burden among poor communities in urban areas, posing a developmental challenge to the country.[10] JS 1. Fabian J, Maher HA, Clark C, Naicker S, Becker P, Venter WDF. Morbidity and mortality of black HIVpositive patients with end-stage kidney disease receiving chronic haemodialysis in South Africa. S Afr Med J 2015;105(2):110-114. [http://dx.doi.org/10.7196/SAMJ.8369] 2. Wearne N. Morbidity and mortality of black HIV-positive patients with end-stage kidney disease receiving chronic haemodialysis in South Africa. S Afr Med J 2015;105(2):105-106. [http://dx.doi. org/10.7196/SAMJ.9068] 3. Snyman LC, Dreyer G, Botha MH, van der Merwe FH, Becker PJ. The Vaccine and Cervical Cancer Screen (VACCS) project: Linking cervical cancer screening to HPV vaccination in the South-West District of Tshwane, Gauteng, South Africa. S Afr Med J 2015;105(2):115-120. [http://dx.doi.org/10.7196/ SAMJ.8418] 4. Opie LH. Digitalis reappraised: Still here today, but gone tomorrow? S Afr Med J 2015;105(2):88-89. [http://dx.doi.org/10.7196/SAMJ.8634] 5. Mkoko P, Mokhele N, Ntsekhe M, Ntusi NBA. Digoxin therapy in the modern management of cardiovascular disease: An unusual but serious complication. S Afr Med J 2015;105(2):154. [http:// dx.doi.org/10.7196/SAMJ.8638] 6. Stefan DC. Why is cancer not a priority in South Africa? S Afr Med J 2015;105(2):103-104. [http:// dx.doi.org/10.7196/SAMJ.9301] 7. 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] 8. Lalkhen H, Mash R. Comorbidity and multimorbidity in non-communicable diseases in South African primary healthcare. S Afr Med J 2015;105(2):134-138. [http://dx.doi.org/10.7196/SAMJ.8696] 9. Durão S, Ajumobi O, Kredo T, et al. Evidence insufficient to confirm value of screening for diabetes and hypertension in low- and-middle-income settings. S Afr Med J 2015;105(2):98-102. [http://dx.doi. org/10.7196/SAMJ.8819] 10. Hoffman K. Non-communicable diseases in South Africa: A challenge to economic development. S Afr Med J 2014;104(10):647. [http://dx.doi.org/10.7196/SAMJ.8727]

February 2015, Vol. 105, No. 2

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Metropolitan Health, a division of MMI Group Limited, an authorised financial services provider.

CORRESPONDENCE

Helpful hints for writing SI units

To the Editor: We often read medical writing, e.g. assignments, dissertations and manuscripts, where the International System of Units (SI) is not used optimally. The abbreviation ‘SI’ is derived from Le Système International d’Unités, which refers back to the Metre Convention of 1875 in Paris. We want to share four hints that have helped us. The best resource for SI units is the latest edition of the SI Brochure of the International Bureau of Weights and Measures (BIPM).[1] South Africa is a full member state of the BIPM. The Author Guidelines of the SAMJ[2] in fact follow the SI Brochure. Always insert a space between the numeral and the unit. The SI units of measurement are treated as mathematical entities (e.g. ‘3.5 kg’ and not ‘3.5kg’). The value of a quantity is the product of the numerical value multiplied by the unit.[3] One of the exceptions is that degrees Celsius (°C) are written without the space between the numeral and unit (e.g. 5°C). To prevent the unit wrapping to the next line and losing contact with the numeral, use a ‘hard space’ that does not break (Ctrl + Shift + Space in Microsoft Word).[4] The litre can be abbreviated as ‘l’ or ‘L’, and ‘millilitre’ as ‘ml’ or ‘mL’. The symbol for litre was designated ‘l’ in 1879.[5] Some countries were afraid that ‘l’ might be confused with ‘1’, and therefore changed the ‘l’ to ‘L’ [SAMJ has recently changed to ‘L’ – Editor]. The litre is not a base unit of the SI system any longer. It is defined as a cubic decimetre.[6] Numbers with many digits can be divided into groups of three by a space.[7] Do not use commas. When numbers are in a table, the format of the numbers in a column must remain constant. Marius Coetzee

Department of Haematology and Cell Biology, University of the Free State and National Health Laboratory Service, Bloemfontein, South Africa coetzeemj@ufs.ac.za

Jaco Joubert

Department of Haematology and Cell Biology, University of the Free State and National Health Laboratory Service, Bloemfontein, South Africa

1. BIPM. The SI Brochure: The International System of Units (SI). 8th ed. Paris: Bureau International des Poids et Mesures (BIPM), 2014:1-180. http://www.bipm.org/en/publications/si-brochure/ (accessed 29 December 2014). 2. Health and Medical Publishing Group. Author Guidelines, South African Medical Journal, 2014. http:// www.samj.org.za/index.php/samj/about/submissions#authorGuidelines (accessed 29 December 2014). 3. BIPM. Formatting the value of a quantity. In: BIPM: The SI Brochure: The International System of Units (SI). 8th ed. Paris: Bureau International des Poids et Mesures (BIPM), 2014:133. http://www. bipm.org/en/publications/si-brochure/ (accessed 29 December 2014). 4. Brownridge D. A Practical Guide to the International System of Units. Colorado State University: US Metric Association, 2008. http://lamar.colostate.edu/~hillger/brownridge.html] (accessed 29 December 2014). 5. Resolution 6 of the 16th CGPM: Symbols for the Litre 1979. Paris: Bureau International des Poids et Mesures (BIPM). http://www.bipm.org/en/CGPM/db/16/6/ (accessed 29 December 2014) 6. BIPM. Non-SI units accepted for use with the SI, and units based on fundamental constants. In: BIPM: The SI Brochure: The International System of Units (SI). 8th ed. Paris: Bureau International des Poids et Mesures (BIPM), 2014:123-129. http://www.bipm.org/en/publications/si-brochure/ (accessed 29 December 2014). 7. BIPM. Formatting numbers, and the decimal marker. In: BIPM: The SI Brochure: The International System of Units (SI). 8th ed. Paris: Bureau International des Poids et Mesures (BIPM), 2014:133. http:// www.bipm.org/en/publications/si-brochure/ (accessed 29 December 2014).

As part of the review, 8 902 articles were screened and 107 scrutinised. Many well-known regression analyses for Organisation for Economic Co-operation and Development (OECD) and US data on advertising and consumption did not meet the study inclusion criteria, largely because the timing of the intervention could not be determined.[2] Of four eligible studies, one was a small randomised controlled trial (RCT) that evaluated drinking behaviour of 80 young Dutch men who were exposed to movies having either low or high alcohol content together with commercials for alcohol products or neutral content (surrogate for a ban on alcohol advertising). The others were interrupted time series (ITS) studies conducted in Canada, with one evaluating what happened after a 58-year ban was lifted and the remaining two evaluating what happened after advertising bans were implemented in two provinces. The ITS studies evaluated different forms of banning with the effects of either full or partial bans of advertising and in some cases for specific types of alcohol. The low-quality data from these studies did not show clear effects either for or against restricting or banning alcohol advertising. The RCT[3] showed that men exposed to commercials with a neutral alcohol content drank significantly less than men exposed to alcohol commercials during a 1.5-hour follow-up period. However, this study and the three ITS studies all suffered from methodological biases. The Cochrane Review found a lack of robust evidence for or against advertising bans or restrictions. It does not say that bans do not work; we do not know. Given that evidence is one component informing policy, decisions to ban alcohol advertising should transparently reflect other important factors, including resource considerations, feasibility, values and preferences that may inform the final recommendation.[4,5] If the political appetite in SA is for banning advertising, we recommend that this be implemented in a research context. This should be a rigorous ITS study where data are collected at at least three time-points before and after implementation of a ban and include monthly industry (sales) data supplemented with household surveys to assess individual-level consumption. Charles Parry

Alcohol, Tobacco and Other Drug Research Unit, Medical Research Council, Tygerberg, Cape Town, South Africa, and Department of Psychiatry, Stellenbosch University, Tygerberg, Cape Town cparry@mrc.ac.za

David Pienaar

Department of Health, Western Cape Government, Cape Town, South Africa

John Ataguba

Health Economics Unit, School of Public Health and Family Medicine, University of Cape Town, Cape Town, South Africa

Jimmy Volmink

S Afr Med J 2015;105(2):80. DOI:10.7196/SAMJ.9337

Centre for Evidence-based Health Care, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Cape Town, South Africa, and South African Cochrane Centre, South African Medical Research Council, Cape Town, South Africa

Implications of Cochrane Review on restricting or banning alcohol advertising in South Africa

Tamara Kredo

South African Cochrane Centre, South African Medical Research Council, Cape Town, South Africa

To the Editor: A letter in The Lancet in June 2014 reported on delays in legislating an alcohol advertising ban in South Africa (SA).[1] These delays resulted from the addition of an independent regulatory impact assessment due to be completed in 2014. A Cochrane Review on restricting or banning alcohol advertising to reduce alcohol consumption[2] was published in November 2014 and should inform policy deliberations.

Mlenga Jere

Graduate School of Business, University of Cape Town, Cape Town, South Africa

Nandi Siegfried

Alcohol, Tobacco and Other Drug Research Unit, Medical Research Council, Tygerberg, Cape Town, South Africa, Department of Psychiatry and Mental Health, Faculty of Health Sciences, University of Cape Town, and Department of Epidemiology and Biostatistics, University of California, San Francisco, USA

February 2015, Vol. 105, No. 2

Air Liquide Southern Africa Tel: +27 (0)11 389 7262, Celeste Gopaul (Executive Healthcare Assistant) Fax: +27 (0)11 389 7394 www.airliquide.co.za

CORRESPONDENCE

1. Parry C, London L, Myers B. Delays in South Africa’s plans to ban alcohol advertising. Lancet 2014;383(9933):1972. [http://dx.doi.org/10.1016/S0140-6736(14)60954-5] 2. Siegfried N, Pienaar DC, Ataguba JE, et al. Restricting or banning alcohol advertising to reduce alcohol consumption in adults and adolescents (Review). Cochrane Database of Systematic Reviews 2014;11(CD010704). [http://dx.doi.org/10.1002/14651858.CD010704.pub2] 3. Engels RC, Hermans R, van Baaren RB, Hollenstein T, Bot SM. Alcohol portrayal on television affects actual drinking behavior. Alcohol 2009;44(3):224-249. [http://dx.doi.org/ 10.1093/alcalc/agp003] 4. Lavis JN. How can we support the use of systematic reviews in policymaking? PLoS Med 2009;6(11):e1000141. [http://dx.doi.org/10.1371/journal.pmed.1000141] 5. Oxman AD, Fretheim A, Schünemann HJ and SURE. Improving the use of research evidence in guideline development: Introduction. Health Res Policy Syst 2006;4:12. [http://dx.doi. org/10.1186/1478-4505-4-12]

S Afr Med J 2015;105(2):80-81. DOI:10.7196/SAMJ.9260

Full circle

To the Editor: At a junior school reunion in Port Elizabeth a few years ago I renewed friendship with Philip Bateman, whom I so clearly remembered from my first evening as a boarder in 1956, far away from home. He had held out something edible and said: ‘Quis?’ ‘Ego!’ had yelled everyone but me. I learnt Latin fast after that. I visited Cape Town, and Philip invited me home for dinner. There I met his wife Caroline, and her father, Edward Gale. Edward and I discovered a synchronicity when he learnt that I was a flying doctor of sorts, and that one of my regular visits was to the Church of Scotland Hospital at Tugela Ferry – COSH in modern parlance. A Church of Scotland mission station had been established for many years near Pomeroy, Natal, when its new medical facility was moved to nearby Tugela Ferry for better water supply. In the early 1930s, COSH was established on an undeveloped site by Dr George William Gale, who was born in Durban but had studied medicine on a scholarship in Edinburgh. He was a pioneer of primary healthcare, and in time became Secretary for Health in the Smuts government. He was also instrumental in the establishment of the medical school at the University of Natal in Durban, and became its first dean in 1952. He died in 1976 after a most distinguished career, both in South Africa and internationally. His son Edward remembers COSH with great fondness, as he lived there from the age of three. His four years at the mission hospital determined his choice of profession, and he returned there to work and learn during vacations as a Wits medical student. He has taken his own family back to visit the dramatic aloe-clad valley where it is situated. One such visit was for the memorial service for George Gale. There could have been no more fitting place in which to remember this extraordinary man than the chapel there, on a hot African afternoon, with Zulu song ringing out: the place where he had worked and cared with such fervour.

From small beginnings COSH has become a remarkable hospital in a remote and impoverished part of KwaZulu-Natal. Of course it is famous, not merely notorious, for the discovery, characterisation and management of extensively drug-resistant tuberculosis in 2005, and it has consequently become an important facility for research into HIV-AIDS and TB, in association with Yale University. Until recently, when Theo van der Merwe moved to Mossel Bay, he, Tony Moll and Francois Eksteen were a trio of doctors with combined continuous service of almost 70 years. COSH attracts young doctors and medical students, and enjoys a heyday similar to that of Charles Johnson Memorial Hospital, Nqutu, when Anthony and Maggie Barker ran it as a mission hospital in the 1960s and 1970s. Dr Edward Gale is a cardiologist, and retired from his Johannesburg practice not that long ago. He wondered whether his still modern and functional ECG machine would be of value to COSH. The transfer by air of a largeish heavy suitcase from Cape Town to Durban was organised by the Red Cross Air Mercy Service (AMS), which is the transport arm of the outreach programme in KZN. Mr Meshach Nehemiah, who drives the Pietermaritzburg AMS vehicle, picked it up. His next trip to COSH coincided with my regular second-Tuesday-ofthe-month visit. Dr Gale Junior’s ECG machine arrived safely and appropriately at COSH on 11 November 2014, to an enthusiastic reception at the eight o’clock morning meeting – with the photograph below to prove it.

Medical staff, Church of Scotland Hospital.

Robert-Ian Caldwell

Sessional Physician for Internal Medicine Outreach, Grey’s Hospital, Pietermaritzburg, South Africa robertcaldwell@telkomsa.net S Afr Med J 2015;105(2):81. DOI:10.7196/SAMJ.9250

February 2015, Vol. 105, No. 2

IZINDABA

HMPG secures top-drawer CEO The Health and Medical Publishing Group (HMPG), owned by the South Afri can Medical Association (SAMA), has scored a coup in securing Hannah Kikaya, a former senior editor at The Lancet and a top South African (SA) health systems and communications strategist, as its new CEO.

Hannah Kikaya, HMPG’s new CEO.

She will succeed Gert Steyn, the new SAMA General Manager, who over the past two years, both before and during his current tenure, revitalised HMPG, the country’s leading medical publishing group, by taking it from a net loss-making enterprise to a thriving, financially sound, technologically relevant and income-diverse platform. Kikaya will use this springboard to apply her unique combination of academic publishing experience, global policy development and practical implementation skills (seemingly tailor-made for her new job). With 14 years’ experience in public health, she has specialised in multisectoral publicprivate relationship building in challenging environments, been intimately involved in helping lay the groundwork for SA’s national health system reforms, co-ordinated regional country planning to discuss tuberculosis (TB) in the mining sector, and organised community participation in health systemsstrengthening initiatives. She is also the inaugural editor of HMPG’s latest journal title, Strengthening Health Systems, an exciting new international open-access journal and publishing support resource for developing countries, launched in July last year.

Bringing rare handson experience to our journals

Kikaya will bring rare hands-on experience to shaping the texture and content of HMPG’s 12 journals, of which SAMJ is the flagship. While a consultant to the World Bank (2011 - 2013) and the Stop TB Partnership (World Health Organization and Global Business Coalition, Health (SA)) (2013/14), she designed and successfully implemented a revenue and administrative efficiency-boosting programme for Gauteng’s main referral hospitals and supported the drafting of the Southern African Development Community (SADC) Declaration on TB in the Mining Sector. She provided technical guidance for a regional project to establish minimum standards for national policies on the management of paediatric HIV, TB and malaria treatment protocols in SADC member states, and finalised a mid-term review and various donor reports for the Lesotho Country Office of UNICEF. She has more than 50 publications in scientific journals, with a further 50 editorial contributions to The Lancet (most as the main leader writer). Her publishing and media experience include a year as part-time Managing Editor of Molecular Oncology (2008/9), a 2½-year stint as Senior Editor of Lancet Oncology (2001 - 2003), Editor at Current Drugs Limited (1999 - 2000), and speech writer and researcher for Ian Taylor, an MP in the British House of Commons (part of a 4-month internship in 1999). Fluent in French and English and holder of dual South African-British citizenship, she holds a BSc with joint honors in Physiology and Pharmacology from University College London.

HMPG 2020

Kikaya’s vision for HMPG is to put the needs of SA’s scientists and health practitioners at centre stage by transforming the company into a diverse provider of publishing and educational services to support academic enquiry, knowledge exchange and prof essional development across the region. She explains that academic publishing was first established to facilitate the exchange of new knowledge between scien tists and investigators, usually in the context of learned societies. However, as the field developed and commercial incentives took hold, the money required for scientists to be able to communicate their work,

February 2015, Vol. 105, No. 2

and the subscription costs for others to read it, led to a situation where knowledge exchange was effectively hindered rather than supported by the publication process – especially for researchers in low-resource environments. Under Kikaya, who recognises the company’s strong history of supporting academic societies and research in South Africa, HMPG will re-emphasise its commitment to open-access publication of all journal content and pledges to maintain its much-lauded policy of no author fees for submissions. ‘I strongly believe that the free exchange of knowledge among academics and health and medical practitioners is crucial to the betterment of public health, both in this country and worldwide. However, achieving publication in established academic journals is still a significant challenge for many of SA’s aspiring scientists and practitionerinvestigators. These publication barriers hinder the kinds of knowledge exchange that could catalyse rapid advancements in health and medicine. We at HMPG pledge to support the growth of academic enquiry and scientific publication in this country and find innovative solutions to professional learning that promote, rather than hinder, the generation and use of new knowledge,’ says Kikaya. Key to her five-year strategy is to bring the company up to date with the internet age. Online publishing presents a huge opportunity for sharing of information among academic communities, but techno logical challenges and infrastructure weaknesses have so far prevented academics from reaping the full benefits of these developments. Understanding the crucial role of the internet for current and future knowledge exchange, Kikaya has pledged to give HMPG’s online publishing interface and web-based library the prominence it deserves under her leadership. ‘We want to ensure that all academic investigators, no matter how big or small their research grant, or how powerful or weak their institution, can share and access the knowledge that helps move the country forward to better health. It is as simple as that,’ she says. Chris Bateman chrisb@hmpg.co.za S Afr Med J 2015;105(2):82. DOI:10.7196/SAMJ.9383

™

IZINDABA

Hands-on student training in private hospitals has arrived Mediclinic and Stellenbosch University have successfully piloted the first standardised rotation of 4th- and 5th-year medical students through a private hospital – and plan to quadruple the intake to broaden the inadequate national training platform and diversify student disease profile exposure. The partnership, enthusiastically backed by the Western Cape health department, saw 32 Matie medical undergraduates each spending a month at the Durban ville Mediclinic in an internal medicine (IM) rotation during 2014, supervised by locals: radiologist Dr Rene Truter and IM specialist Dr Rust Theron. All the private specialists (who volunteered their time) underwent a special short course at the Stellenbosch University Faculty of Medicine and Health Sciences (FMHS) to ‘ensure they would optimally transfer the right skills and knowledge’ to their young charges. From next year the plan is to put 140 Matie medical undergraduates through the four Mediclinic hospitals in the northern suburbs (adding Cape Gate, Louis Leipoldt and Panorama hospitals to the list) via a ‘memorandum of agreement’ signed by the two contracting parties. According to Prof. Marietjie de Villiers, Deputy Dean of Education at the FHMS, this is not the first time the private sector has contributed to the training of medical undergraduates – but the ‘scale and standardisation’ of the current project is a major departure from the historical norm.

Outdated training laws not serving the National Development Plan

The Wits Donald Gordon Medical Centre in Gauteng (in which Mediclinic is a minority shareholder) is an accredited training hospital, and various other initiatives across the country have involved the private sector in the training of medical undergraduates. The Health Professions Council of South Africa (HPCSA) does not prohibit training of undergraduates in the private sector – private general practitioners have been helping out with training for years. However, in terms of existing legislation, postgraduate training remains confined to public sector tertiary and regional hospitals, something of which both the academic and private medical communities at the launch of the latest undergraduate private initiative were highly critical, given the dire shortage of qualified healthcare professionals. Koert Pretorius, CEO of Mediclinic Southern Africa, said that the HPCSA would not accredit private hospitals for training purposes (Wits Donald Gordon being an exception). ‘They made it clear to us that if Mediclinic ever became a majority shareholder at Wits Donald Gordon, their training accreditation would fall away – so from that perspective it’s been problematic.’ He said that if the country was to deliver on the over-arching National Development Plan, outdated legislation, including the prohibition on hiring doctors by private hospitals, would have to be urgently revised. ‘We operate private

hospitals in Dubai and Switzerland where we employ the doctors. We fundamentally do not understand why doctors are not allowed to choose where they may be employed. Our experience is also that most of our supporting specialists are very interested in giving back via training. By definition, because of their years of training, they’re academics – and they’re keen to plough their skills back in and mentor, creating an enabling environment for healthcare delivery in this country,’ he added. Asked to elaborate on Mediclinic’s view on the current ethical rules around employ ment of doctors, fee-sharing and doctor co-ownership of facilities, Pretorius said the point of departure ‘should not be that all doctors are susceptible to over-servicing pressures’. He saw the future of healthcare as embracing a more integrated approach between service providers instead of the current approach where the hospital, clinical radiologists and pathologists worked ‘in silos’. Clinical independence and decision making should remain with doctors while allowing them to take part in other business models that would create ‘better and more informed decision making, enabling them to be part of the solution’. While he understood the HPCSA’s ethical concerns, an enabling environment for more integrated and efficient models would keep costs down and improve the quality of healthcare delivery. ‘I think the concern from the HPCSA is that once you have corporate involvement or ownership of doctors’ practices, there will be pressure to over-service and generate unnecessary income – but that can be dealt with.’ He alluded to the R20 million Da Vinci robotic surgery system, of which Mediclinic recently imported five (used mainly for prostatectomies), saying that his company sacrificed short- to medium-term profits in favour of exposing urologists to the best available research and technology – hugely benefiting patient outcomes and recovery periods. ‘We want funders to contribute, but we’re also prepared in the initial introductory phase to make a contribution in the sense that we’ll not recover our full costs,’ he added.

Even more collaboration needed – Volmink Stellenbosch University medical undergraduates Gys Neethling and Victoria van der Schyff, with their internal medicine consultant tutor Dr Rust Theron, check on ‘patient’ Mariana Wilders.

February 2015, Vol. 105, No. 2

Prof. Jimmy Volmink, Dean of the Stellen bosch University FHMS, said the HPCSA was ‘out of line with what’s happening

IZINDABA

in the rest of the world – this [private training] is an idea whose time has come. The public and private sectors needed to collaborate to help solve some of the fundamental problems South Africa [SA] faced. I think we’re pushing the envelope here; there simply wasn’t a push for the private sector to become involved before,’ he added, alluding to national health minister Dr Aaron Motsoaledi’s numerous overtures to and partnerships with the private sector.

According to Prof. Marietjie de Villiers, Deputy Dean of Education at the FHMS, this is not the first time the private sector has contributed to the training of medical undergraduates – but the ‘scale and standardisation’ of the current project is a major departure from the historical norm. Asked what was behind the HPCSA’s seem i ng aversion to open up doctor training to both sectors, Volmink said there was ‘probably reluctance that somehow the private sector would cannibalise the public sector – I think we need to do more to try and reassure them – and the private sector needs to be more clear about its goals in addressing the broader needs of the population. Also if you look at education generally in the private sector, there are a number of degree and certification programmes that are very poor, with quality assurance not always what it should be – that could be another reason.’ Previous Western Cape Health MEC Theuns Botha, who attended the announcement of the pilot scheme’s success at Durbanville Hospital on 18 November 2014, said there had been a radical political shift from the days of apartheid when there was a ‘differentiated level of responsibility towards different population groups’. ‘The argument was we have enough in terms of what is required to look after the white population of the country’. This had shifted towards universal health coverage, yet the legislation was ‘not developed for this purpose’ and needed urgent renewal. Botha said that while ensuring that every South African had access to decent quality healthcare, there was ‘no reason’ why people should not be able to choose

private healthcare services. ‘In my opinion a normal, growing, vibrant economy will result in 10% of the population driving luxury sedans and 85% of the population driving an affordable Japanese model car. Why should healthcare be any different? You should be able to decide where you get your healthcare service. This is not Cuba.’ Botha predicted that the entire medical training platform would soon look very different, with his province probing the addition of newly established primary healthcare facilities to public tertiary hospital doctor training. De Villiers said they were not expecting any bureaucratic resistance or interference with their initiative because all doctors taking part were accredited by the HPCSA as teachers, with the hospital easily meeting the required minimum training standards.

Ageing doctor cohort – and training pipeline ‘thin’

Theron said he and his colleagues had realised that the doctors coming through the Mediclinic hospitals were ‘ageing and there were not a lot of new people coming through – a reflection of the shortages nationwide’. All eight medical schools were currently producing at maximum capacity, with Motsoaledi adding pressure by asking them to expand to help ‘reorientate’ what will soon be 1 000 per annum Cuban-trained SA undergraduates returning to local conditions and disease profiles. The programme that trains South Africans as doctors in Cuba will expand nearly tenfold over the next 5 years, pouring 1 000 undergraduates into our currently under-resourced local medical campuses every year from 2018 onwards. For the past 3 years, the annual output of Cuban-trained South Africans, ‘polished up’ in their final year at local medical schools, came to about 8% of the 1 300 graduates fully trained locally. The sudden acceleration in Cuban training is a crisis intervention aimed at buying time to adjust and expand our local medical training platform so that it can increase local doctor output while continuing to better reorientate the Cuban ‘returnees’ towards SA’s very different disease profile. Theron described the response from all role-players in the current local private training initiative as ‘overwhelmingly posi tive’, with students exposed to a disease profile significantly different to what they would have seen at a major public sector hospital (e.g. HIV/TB v. diseases of

February 2015, Vol. 105, No. 2

lifestyle). Theron said the student group gained hands-on experience in interpreting X-rays, pathology, microbiology and haematology, accompanying him and his colleagues on daily ward rounds. ‘They spent more time explaining to patients what was going on, forcing us to explain our decisions and actions – so everyone got a better service,’ he joked. Theron said that the paediatrics and cardiology consultants in the other Northern Suburbs Mediclinic hospitals had already expressed willingness to come aboard pro bono as the programme evolved. ‘They’re all willing to give time and expertise to make this really viable,’ he added. One of the medical students who took part in the pilot programme, Victoria van der Schyff, said that initially she and her colleagues were worried that the different (private) patient profile might ‘threaten their marks’ at the end of their academic block. However, every student performed above their own expectations, ‘probably because of the excellent one-on-one teaching’.

Theron said that the paediatrics and cardiology consultants in the other northern suburbs Mediclinic hospitals had already expressed willingness to come aboard pro bono as the programme evolved. ‘They’re all willing to give time and expertise to make this really viable,’ he added. Volmink said that his faculty’s teaching approach emphasised social accountability and the social determinants of health, plus exposure to rural healthcare. ‘But I think they need to also see what happens in the private sector, the profile of patients and disease and how to function in it,’ he added. Mediclinic, responding to the nurse production crisis in the early 1990s, began importing Indiantrained nurses to supplement their own staff and have since established six learning centres with satellite facilities that train more than 1 000 nurses per annum, with accreditation by the Department of Higher Education and Training. Chris Bateman chrisb@hmpg.co.za S Afr Med J 2015;105(2):83-84. DOI:10.7196/SAMJ.9314

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Honing healthcare leaders’ competence and attitudes equals facility-level delivery Just when you thought there was enough evidence to give up on our public and private healthcare sectors ever partnering to deliver quality, affordable care to a critical mass of South Africans – National Health Insurance (NHI) notwithstanding – along come several potentially game-changing training initiatives. Izindaba can now reveal that at least three healthcare facility management and training courses are already impacting on until recently woeful public sector facility leadership. They are providing vital support to hospital, clinic and community healthcare workers, often highly clinically skilled but under-equipped and struggling to manage the day-to-day running of their facilities

Prof. Marion Jacobs.

It all (officially) began in 2012 with a national audit of public healthcare facility operational managers. Under-qualified and/or underperforming chiefs were either redeployed or slotted into existing ‘upgrade’ courses. Former Dean of Medicine at the University of Cape Town, Prof. Marion Jacobs, was appointed by national health minister Dr Aaron Motsoaledi to set up the Academy of Leadership and Management of Health, training student healthcare managers and up-skilling existing healthcare facility CEOs, pulling together and standardising numerous existing programmes into a single, needs-appropriate ‘virtual institution’, and drawing on the best available expertise. Long before this however (in 2005), the South African Medical Association (SAMA)’s highly successful Foundation

for Professional Development (FPD) was running two externally funded and fully subsidised courses: an advanced certificate in health management (partnering with Yale University) – a virtual hospital management mini-MBA – and an entry-level certificate in healthcare management, which has churned out 5 000 trainees to date. Both are distance education courses with face-to-face student support tutorials in the cities they work in, focusing on monitoring and evaluation, project management, communication skills, human resources and resource mobilisation. Anton le Grange, head of the FPD’s Quality Assurance Academic Program Development and Management Training, has several uplifting stories that strongly illustrate the impact their courses are having, particularly in the public sector. ‘Initially it was difficult to measure, so we started following our students to see if the knowledge they were receiving was having results.’

However, if there is no management or leadership expertise to push the process forward, it stalls. COHSASA spokesperson Marilyn Keegan said there were ‘numerous experiences’ of hospitals being given standards, shown how to use them and encouraged to use the tools provided, ‘but nothing happens’. ‘The missing factor is a good manager or leader who understands why using standards to measure what does and does not happen in a healthcare facility represents the best of all worlds: he/ she can see what is wrong and do something about it.’

The power of one

One doctor running a primary healthcare clinic in the Sekukhune district of Limpopo Province chose to begin monitoring and evaluating the National Core Standards audit of his facility by the national Office for Healthcare Standards Compliance (OHSC) – part of the work-up towards setting minimum healthcare delivery standards in advance of the ambitious NHI implementation. His clinic initially received a 64% score (70% being the minimum

February 2015, Vol. 105, No. 2

threshold for norms and standards). He set to work implementing the FPD training he was concurrently receiving as part of his yearlong studies, and by October 2014 (with his graduation due in July 2015), his clinic scored 80% – a direct result of his interventions. Says Le Grange: ‘Most of our students come back and say they find the project management and monitoring and evaluation aspects the most useful. This was exactly why we started the courses (currently 900 students enrolled, equally divided between courses and all fully subsidised from among 3 000 annual applications). He adds: ‘You have doctors and nurses with excellent clinical skills but pushed into running a facility or unit without any managerial experience. We teach them how to be leaders, what a supervisor is, how to present yourself. They also come away talking better and more effectively to their staff and to patients.’

Identifying and plugging the gaps

Then cut to the private equivalent of the OHCSC – a veteran quality assurance outfit, the Council for Healthcare Service Accreditation of South Africa (COHSASA). Based in Pinelands, Cape Town, COHSASA has been beavering away quietly for the past 18 years, teaching healthcare workers how to cost-effectively monitor improvements using quality improvement methods, inter nationally accredited standards and a webbased information system. It has accredited 600 healthcare facilities throughout Africa (hundreds of them in the South African (SA) public healthcare sector) and regularly audits and supports facilities to help them stay on track and retain accreditation. Its forte is in improving patient safety and quality of care by identifying deficiencies, guiding interventions and monitoring progress, and providing quality improvement plans. Its founder and director, Prof. Stuart Whittaker, sits on the board of the OHSC, providing invaluable input and guidance to the current national core standards process that has completed audits of 20% of all public sector hospitals so far. Patch into COHSASA’s work a recent academic innovation at Stellenbosch University (SU). Headed by Dr Jurgen Seifert, course co-ordinator of the new Executive Development for Healthcare Leaders on the SU campus at Bellville Park, the programme was born out of filling a pragmatic need in COHSASA’s work. COHSASA’s baseline

IZINDABA

evaluation of facilities identifies where there are gaps in providing safe and quality care. Senior hospital managers and unit leaders are supplied with a clear blueprint of how to address these gaps, prioritising the most critical ones. However, if there is no management or leadership expertise to push the process forward, it stalls. COHSASA spokesperson Marilyn Keegan said there were ‘numerous experiences’ of hospitals being given standards, shown how to use them and encouraged to use the tools provided, ‘but nothing happens’. ‘The missing factor is a good manager or leader who understands why using standards to measure what does and does not happen in a healthcare facility represents the best of all worlds: he/she can see what is wrong and do something about it.’ Siefert said his course provided the pragmatic know-how on what it takes to be a leader. ‘How do the receptionists, radiotherapists, ordinary doctors, get themselves into a leadership mindset? How do they apply situational awareness that goes beyond protocols, check-lists and computer programs to apply considered human judgment?’ he asks. With a PhD in aviation, Seifert says the health sector is ‘about 40 years’ behind aviation in applied human judgement backed by technology. ‘You need to build an acute awareness of what needs to be done – and have excellent “flying skills”, he says, citing the instant decision of

the pilot who impeccably landed his plane in the icy Hudson River after his engine ingested a flock of geese, forcing a stall at low altitude. Seifert said continuous training and upskilling was ‘essential’ in healthcare to prevent leaders ‘falling back on bad habits’. ‘You need to stay in the forefront of what’s happening in your operating environment. We’re moving from transactional management to transformational leadership. It’s all about attitude and outlook complementing appropriate skills,’ he added.

He set to work implementing the FPD training he was concurrently receiving as part of his year-long studies, and by October 2014 (with his graduation due in July 2015), his clinic scored 80% – a direct result of his interventions.

Leading under ‘conditions of complexity and uncertainty’

competence (knowledge, skills and attitudes) necessary for an organisational leader to function ‘under conditions of complexity and uncertainty’. Case studies from the students’ own facilities will be used to develop solutions to problems, and a full assignment is expected to be handed in a month after completing the course. So what is the initial evidence that the combination of these and other similar courses are beginning to improve healthcare delivery in South Africa? A recent survey of five critical patient care areas in the public sector conducted by an agent for the OHCSC showed a 40.1% leap in ‘positive caring attitudes’ held by public health facility staff members (from 30% to the 70% threshold) in the past 2 years. This was followed by a 27% improvement in patient safety and security (34% to 61%), with availability of medicines and supplies increasing by 12% (54% to 65.5%), this last improvement a hopeful sign that woefully inadequate supply management systems, corruption and theft might actually be yielding slightly to a raft of new National Department of Health initiatives.

The primary aim of the 5-day Stellenbosch course is ‘to explore, analyse and unpack the advanced topics in current leadership thinking as it applies to the healthcare system’. The course will focus on the

Chris Bateman chrisb@hmpg.co.za

hard to come by, but a brother of Mannie’s mother, Sam Hackner, had emigrated earlier and sponsored the family. At the age of six Mannie set sail from Hamburg with his mother, his older brother Morris, and Hymie aged one. They arrived in Durban to join Mannie’s father, who had preceded them six months earlier and started a small eatery. Mannie matricu lated at Durban High School at the age of 16 with distinctions in Mathematics and Latin. He studied medicine at the University of the Wit watersrand, graduating in 1942. In 1945 he married Lola Jankelson, with whom he had three children, Michael, David and Linda. After graduating he obtained his FRCS in Edinburgh. He spent a year at the Rotunda in Dublin, where he acquired his Diploma in Gynaecology and Obstetrics and a DA in anaesthesiology. All in all he spent 11 years doing surgical registrar ships and a stint in general practice as required by the South African Council to be registered as a specialist surgeon.

Mannie opened a surgical practice in 1953 and shared rooms with Barry Adams, who became the first Professor of Medicine at the newly established medical school in Durban. By his sheer competence, ability and work ethic he built up a thriving practice. His workload became so heavy that he invited me to join him in partnership, which I did in 1960. Up to that point I had only come under his influence when he gave teaching ward rounds and lectures to medical students. Mannie’s rapid rise to become the best and busiest surgeon in Durban was greeted with resentment by the old Durban families, and as his partner I was subjected to the same discrimination. Like me he was nurtured by the two leading surgeons at that time, Aubrey Radford and Lawrence V Pearson. In 1963 Harold Duncan joined the practice and introduced a breath of fresh air from Pretoria. Once the practice was firmly established, Mannie took long breaks. He visited Profs Rob and Eastcott at St Mary’s, Prof. Milnes

S Afr Med J 2015;105(2):85-86. DOI:10.7196/SAMJ.9316

OBITUARY Mannie Stein, 1920 - 2014

Mannie Stein was born in Lithuania a few days after Pesach (Passover), but as no exact records were kept, he celebrated his birthday on 1 April. Although the worst of the pogroms were over, there was still overt anti-Semitism and great economic hardship and many Jews emigrated. Emigration papers were

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Walker in Bristol, Drs Moore and Linton in Boston and Drs de Bakey and Cooley in Houston, and brought back his new knowledge to widen the scope of the practice. Enthused by this knowledge, he established a large vascular practice. He did the first repair of aortic aneurysms, bypasses, peripheral bypasses and carotid endarterectomies in Durban. He was very adept at portocaval shunts, although we knew little about hepatic encephalopathy at that time. When thinking of Mannie, the following attributes come to my mind. His technical excellence and high work ethic. His insistence on punctuality. If an operation was scheduled for 7.30 a.m., that was cutting time and if the anaesthetist, assistant and theatre staff were late they were left in no doubt about his displeasure. He had excellent surgical judgement. In the days before computed tomography scans and magnetic resonance imaging, he had an intuitive ability to know whether a post operative problem could be treated conservatively or required a re-look operation.

He was the epitome of the old surgical adage ‘The good doctor knows when to operate and to do so decisively, and the very good doctor knows when not to operate and stay his hand’. He was bold and decisive. I am not sure whether the title of his autobiography, Mindful of a Miracle, relates to a particular patient, Rev. Yule. Dr Jack Rossiter, Yule’s physician, had phoned Mannie to tell him that the Reverend had collapsed with a ruptured aortic aneurysm. Mannie arranged his admission to St Augustine’s Hospital. He was taken straight to the operating theatre, and to all intents and purposes was dead: no pulse, no recordable blood pressure, and no easy venous access. Mannie opened the abdomen, rapidly isolated the aorta, and then took the blood trans fusion being held by the startled physician and plunged it into the vena cava. Four units of blood were rapidly infused, and the pulse and BP returned. A stained glass window in the church commemorates this surgical feat. His compassion, dedicated after-care and generosity. My wife and I were taken into his family, and we became not only partners but good friends. I learnt a great deal from him.

In Mannie’s autobiography there is a fore word by the Editor of the Canadian Jewish News, Moredchai Ben Dal, in which he quotes the American writer and philosopher Ralph Emerson: ‘There is properly no history, only biography’. Had Emerson known Mannie Stein he would have been doubly pleased, at the acquaintanceship with so rare an individual and that this aphorism could be so splendidly affirmed. Mannie retired at the age of 65, and after a short stay in Israel moved to Toronto where his two sons had established themselves. Although he became increasingly frail, he retained his cognitive abilities and regularly did Sudoko and played bridge. In his 93rd year he became more and more tired, and eventually passed away. We extend our sympathies to Michael, David and Linda, and their spouses and children. Mannie will be sorely missed by the Jewish community, the medical fraternity and his friends. Roy O Wise Entabeni Hospital, Durban, South Africa wisel@mweb.co.za

BOOK REVIEW Dance with Suitcase: A Memoir resting on Movement

By Dawn Garisch. Cape Town: Tiber Tree Press, 2013. ISBN 978-0-9921922-6-6

Dawn Garisch is a medical doctor, writer, creative methods facilitator and dancer, who,

in this memoir about the power of the body in motion, explores the connections between the body, mind and emotions. She courageously shares the personal narratives that have shaped her own life, and illustrates how dance has had different meanings for her – as escape and a way to cope with the difficulties of life, but also as a way to express exuberance and creativity. Like Eloquent Body,[1] her book that explores the science and poetry of the body, this too is a process book. It is not only about the practice of movement but investigates freedom and limitation, desire and restraint, as they have shaped her life. Dawn is fascinated by the body as metaphor, as dream, as a map of the unconscious. She is intrigued by the creative process, and by how everything, including the hardest life events, are ‘gifts’ that can be used for personal growth by those who choose to do so. She shares her own experiences of how creative capacities can be used to enrich life and to channel disturbances creatively for healing. Creative projects, such as writing, doing art and dancing, are tools to manage the anxiety of the unknown, to live more balanced and less destructive lives. Writing about dancing is a challenge: how to translate a non-verbal practice into words? Dawn accomplishes this with light ness and

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authenticity as she weaves her life narrative around the metaphor of dance and movement as symbols of life and self-expression and a way of being during times of intense personal challenge. Dance is a form of movement, and the way we move through the world is part of who we are. Movement practice enhances the capacity to have fun and to confront and process fears. Spontaneous dance is a process of both selfdiscovery and self-recovery, bringing healing and playfulness into awareness. Memoir is a way to express openness and to make one’s self vulnerable, which can be a healing process. Sharing emotional truths can help others heal as they realise that they are not alone. For a busy doctor, Dance with Suitcase is a quick read because it is a slim volume and also because of the fluent style of writing. The book has the double benefit of being a prompt for personal reflection by the doctor and also offering a recommendation for patients who would like to explore alternative ways to process their personal issues. Janet Giddy Mowbray, Cape Town, South Africa janetgiddy@gmail.com 1. Garisch D. Eloquent Body. Cape Town: Modjaji, 2012.

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CLINICAL PRACTICE

Digitalis reappraised: Still here today, but gone tomorrow? L H Opie Prof. Lionel Opie, MD, DSc, FRCP, is a research scholar at the University of Cape Town, South Africa, and Emeritus Director at the Hatter Institute for Cardiovascular Research in Africa, Faculty of Health Sciences, University of Cape Town. Corresponding author: L H Opie (lionel.opie@uct.ac.za)

Digoxin is one of the oldest of drugs acting on the heart and still one of the most frequently used. While in atrial fibrillation digoxin continues to have a valid role in the control of ventricular rate when added to beta-blockers and calcium antagonists, digoxin for heart failure is no longer a supportable option in view of the negative recent meta-analysis. S Afr Med J 2015;105(2):88-89. DOI:10.7196/SAMJ.8634

In 1673, William Harvey wrote that ‘the heart is to be regarded as the primary cause of life’.[1] In 1705, Thomas Sydenham, an English physician, linked dropsy to difficulty in breathing,[2] marking the beginnings of the concept of heart failure (HF) for which digitalis, described by Withering in 1801, was the first natural remedy to be used.[3] Withering was most impressed with its diuretic effects, but he also observed that ‘digitalis had power over the motion of the heart to a degree, yet unobserved in any other medicine’. Despite this auspicious history, the use of digoxin is now in serious question as shown by the most recent largest and longest study, from Quebec, in which digoxin use over 14 years was associated with a 14% greater risk of all-cause mortality in patients aged ≥65 years with atrial fibrillation (AF) regardless of concomitant HF.[4] The present article, and other reports since digoxin therapy was last reviewed in the SAMJ in 2011,[5] forcefully bring to our attention that the decision to treat with digoxin potentially exposes the patient to serious risks such as drug toxicity and even death,[4] as also shown in a recent study on American veterans.[6]

Swings in digitalis use

Digitalis has gone through several phases. Historically it has been long regarded as essential first-line therapy for HF, together with the diuretics. As data on ineffectiveness or tolerance came in, its use declined, especially in the UK. Thereafter use declined again for several reasons, the first of which was that there were no recent studies to eliminate major doubts regarding the ideal dose and blood levels.[4-6] Even in the large Digitalis Investigation Group (DIG) trial in 1997, when HF therapy was relatively primitive and did not have the benefit of beta-blockade and angiotensin-converting enzyme inhibitors, there were only limited benefits.[7] Thereafter, positive haemodynamic data in several small studies and the major withdrawal studies re-established the reputation of digoxin, but that was 21 years ago.[8] Currently the declining use relates in part to the increasing realisation that digoxin is a very complex drug with a very narrow therapeutic-toxic window and numerous drug interactions (see Tables 6-6 and 6-7 in Teerlink et al.[9]). These many problems have relegated digoxin to an optional extra in the management of heart failure, given, if at all, in lower doses than previously, with the aim of achieving symptomatic rather than mortality benefit.

Digoxin kinetics, toxicity and contraindications

Digoxin is rapidly absorbed into the circulation where it is unbound to plasma proteins, with a therapeutic level of 0.65 - 1.3 nmol/L, which is about half of the previous toxic level as shown in Fig. 6-12 in Teerlink et al.[9] Also of note, is the role of the plasma potassium level in the expression of digoxin toxicity, whereby low potassium levels sensitise the heart to the prevailing digoxin level. The blood half-life is about 36 hours. About 70% is excreted unchanged in the urine after tubular excretion, with the remainder undergoing non-renal clearance by the liver and in the stools.[9] In brief, toxicity and major contraindications are as follows: • Digitalis toxicity is the major complication, pending a full history of digitalis dosage, blood tests for renal failure, and measurement of serum digoxin and potassium. Digoxin has a blood half-life of 36 hours, so toxicity is not readily reversed and requires digoxin antibodies which are not widely available. • Hypertrophic obstructive cardiomyopathy • Some cases of Wolff-Parkinson-White syndrome • Atrioventricular nodal heart block if significant.

Recent studies

There are four recent studies, of which the largest and the most recent in clinical practice, in Quebec, showed that digoxin use over 14 years was associated with a 14% greater risk of all-cause mortality in patients aged ≥65 years with AF, regardless of concomitant HF.[10] This study reached the public arena via the New York Times, which reported on 8 August 2014 that ‘the investigators followed more than 100,000 people with newly diagnosed AF and found that those prescribed digoxin were more likely to die over the next several years than those who received other treatments’.[11] Further population studies may never be undertaken owing to lack of funding and lack of urgency. The three other recent reports are of note.[12-14] In the first, the authors identified adults with incident systolic HF between 2006 and 2008 within the Kaiser Permanente Northern California group who had no prior digoxin use.[12] The important result was that digoxin use, during a median 2.5 years of follow-up in 2 891 patients with incident systolic HF, was independently associated with an increased risk of death (hazard ratio 1.72; 95% confidence interval 1.25 - 2.36), although there was no difference in HF hospitalisation.

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The researchers had controlled for medical history, laboratory results, medications, HF disease severity, and the propensity for digoxin use in their patient population.

Digoxin to control ventricular rate in HF

Even those authorities who still hold that there a place for digoxin in HF therapy[15] admit that the place of digoxin in AF is insecure and will probably diminish further in the future, because of the drug’s inability to reduce heart rate during exercise on the one hand, and the outcome of studies such as the defective negative study of Whitbeck et al.[13] on the other. Regarding the other major use of digoxin to control the heart rate in HF, in a recent single-centre study on 1 269 unselected consecutive patients with both AF and HF, therapy with a beta-blocker alone or with a beta-blocker plus digoxin was associated with a similar decrease of just over 40% in risk of death (p=0.005).[16] Of further note, digoxin given alone was associated with a worse survival probability, similar to that of patients without any rate control treatment.

Conclusions

There are very few arguments left in favour of the use of digitalis in the control of heart rate in AF. After the negative mortality data from one large recent study of digitalis in HF, enthusiasm for its further testing in HF has diminished further. Ideally an even larger, multicentre, prospective randomised controlled trial could add new conclusive data. Such a trial is, however, very unlikely to be done in view of the low likelihood of digoxin’s finding a prominent place in the current increasingly sophisticated therapy of HF.[9] In the

absence of such a trial, it would be safe to predict that digoxin for the indication of HF would not be passed by regulatory agencies on the basis of present data. 1. Willis R. The Works of William Harvey MD. London: Sydenham Society, 1847. 2. Sydenham T. The Whole Works. London, 1705. 3. Wilkins MR, Kendall MJ, Wade OL. William Withering and digitalis, 1785 to 1985. BMJ 1985;290(6461):7-8. 4. Shah M, Avgil Tsadok M, Jackevicius CA, Essebag V, Behlouli H, Pilote L. Relation of digoxin use in atrial fibrillation and the risk of all-cause mortality in patients ≥65 years of age with versus without heart failure. Am J Cardiol 2014;114(3):401-406. [http://dx.doi.org/10.1016/j.amjcard.2014.05.013] 5. Opie LH. Dilated cardiomyopathy and potentially deadly digoxin. S Afr Med J 2011;101(6):388-390. 6. Georgiopoulou VV, Kalogeropoulos AP, Giamouzis G, et al. Digoxin therapy does not improve outcomes in patients with advanced heart failure on contemporary medical therapy. Circ Heart Fail 2009;2:90-97. [http://dx.doi.org/10.1161/CIRCHEARTFAILURE.108.807032] 7. Dec GW. Digoxin remains useful in the management of chronic heart failure. Med Clin North Am 2003;87(2):317-337. 8. The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997;336(80):525-533. 9. Teerlink JR, Sliwa K, Opie LH. Heart failure. In: Opie LH, Gersh BJ. Drugs for the Heart. 8th ed. Philadelphia: Elsevier Saunders, 2013:169-223. 10. Shah M, Tsadok MA, Jackevicius CA, Essebag V, Behlouli H, Pilote L. Relation of digoxin use in atrial fibrillation and the risk of all-cause mortality in patients ≥65 years of age with versus without heart failure. Am J Cardiol 2014;114(3):401-406. [http://dx.doi.org/10.1016/j.amjcard.2014.05.013] 11. Digoxin tied to increased risk of death in new atrial fibrillation patients. New York Times (8/11, D4, O’Connor). 12. Freeman JV, Yang J, Sung SH, Hlatky MA, Go AS. Effectiveness and safety of digoxin among contemporary adults with incident systolic heart failure. Circ Cardiovasc Qual Outcomes 2013;6(5):525-533. [http://dx.doi.org/10.1161/CIRCOUTCOMES.111.000079] 13. Whitbeck MG, Charnigo RJ, Khairy P, et al. Increased mortality among patients taking digoxin – analysis from the AFFIRM study. Eur Heart J 2013;34(20):1481-1488. [http://dx.doi.org/10.1093/ eurheartj/ehs348] 14. Gheorghiade M, Fonarow GC, van Veldhuisen DJ, et al Lack of evidence of increased mortality among patients with atrial fibrillation taking digoxin: Findings from post hoc propensity-matched analysis of the AFFIRM trial. Eur Heart J 2013;34(20):1489-1497. [http://dx.doi.org/10.1093/eurheartj/eht120] 15. Van Veldhuisen DJ, van Gelder IC, Ali A, Gheorghiade M. Digoxin for patients with atrial fibrillation and heart failure: Paradise lost or not? Eur Heart J 2013;34(20):1468-1470. [http://dx.doi.org/10.1093/ eurheartj/ehs483] 16. Fauchier L, Grimard C, Nonin P, et al. Comparison of beta blocker and digoxin alone and in combination for management of patients with atrial fibrillation and heart failure. Am J Cardiol 2009;103(2):248-254. [http://dx.doi.org/10.1016/j.amjcard.2008.09.064]

Accepted 8 September 2014.

This month in the SAMJ ... Nicola Wearne* is a consultant nephrologist in the Department of Nephrology and Hypertension at Groote Schuur Hospital, Cape Town. She completed a bachelor’s degree in medical science and an undergraduate medical degree with honours at the University of Sydney, Australia. Her training as a specialist physician and in nephrology was done at the University of Cape Town. She is involved in all aspects of nephrology, including transplantation, and has a particular clinical interest in peritoneal dialysis, running the unit at Groote Schuur. She has a keen interest in HIV-associated kidney disease and has published in this field, and is involved in research activities involving peritoneal dialysis outcomes in South Africa. She is also very involved in both postgraduate and undergraduate teaching programmes at the University of Cape Town. * Wearne N. Morbidity and mortality of black HIV-positive patients with end-stage kidney disease receiving chronic haemodialysis in South Africa. S Afr Med J 2015;105(2):105-106. [http://dx.doi.org/10.7196/SAMJ.9068]

June Fabian* currently heads up the Research Office at the Wits Donald Gordon Medical Centre, Johannes burg. She trained in nephrology at the University of the Witwatersrand, Johannesburg, and has worked as a nephrologist in both the public and private sectors. * Fabian J, Maher HA, Clark C, Naicker S, Becker P, Venter WDF. Morbidity and mortality of black HIV-positive patients with end-stage kidney disease receiving chronic haemodialysis in South Africa. S Afr Med J 2015;105(2):110-114. [http://dx.doi.org/10.7196/SAMJ.8369]

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DRUG ALERT

Recommendations pertaining to the use of influenza vaccines and influenza antiviral drugs: Influenza 2015 S Walaza, C Cohen Sibongile Walaza and Cheryl Cohen are medical epidemiologists at the Centre for Respiratory Diseases and Meningitis, National Institute for Communicable Diseases (NICD), Johannesburg, South Africa, and have compiled this article on behalf of the Centre for Respiratory Diseases and Meningitis, NICD and the National Department of Health, Pretoria, South Africa. Corresponding author: S Walaza (sibongilew@nicd.ac.za)

Prevention of influenza is the most effective management strategy. Influenza vaccine is administered each year before the influenza season. Here we provide recommendations for the use of influenza vaccines in anticipation of the 2015 Southern Hemisphere influenza season. For a review of the 2014 influenza season, please refer to the website of the National Institute for Communicable Diseases of the National Health Laboratory Service, www.nicd.ac.za S Afr Med J 2015;105(2):90-91. DOI:10.7196/SAMJ.9367

Recommended vaccine formulation

The following strains have been recommended by the World Health Organization (WHO) for the 2015 Southern Hemisphere influenza season: • an A/California/7/2009 (H1N1)pdm09-like virus • an A/Switzerland/9715293/2013 (H3N2)-like virus (A/South Aus tralia/55/2014, A/Norway/466/2014 and A/Stockholm/6/2014 are A/Switzerland/9715293/2013-like viruses) • a B/Phuket/3073/2013-like virus. Vaccines should contain 15 μg of each haemagglutinin antigen in each 0.5 ml dose.

Indications

• Pregnant women irrespective of stage of pregnancy, or postpartum (within 2 weeks after delivery) • Persons (adults or children) who are at high risk for influenza and its complications because of underlying medical conditions and who are receiving regular medical care for conditions such as chronic pulmonary (including tuberculosis) and cardiac diseases, chronic renal diseases, diabetes mellitus and similar metabolic disorders, individuals who are immunosuppressed (including HIV infected persons), and individuals who are morbidly obese (body mass index ≥40 kg/m2) • Healthcare workers • Residents of old-age homes and chronic care and rehabilitation institutions • Persons aged >65 years • Children aged 6 months - 59 months • Persons aged 6 months to ≤18 years on long-term aspirin therapy • Adults and children who are family contacts of high-risk cases • Any persons wishing to minimise the risk of influenza acquisition, especially in industrial settings, where large-scale absenteeism could cause significant economic losses. Older people, children aged <2 years and severely immuno compromised individuals often have lower protective immune response to trivalent influenza vaccines compared with younger

healthy adults. However, even for these people influenza vaccine still provides some protection.

Dosage

• Adults: Whole or split-product or subunit vaccine: one dose intramuscularly (IM) • Children (<12 years): Split-product or subunit vaccine: one dose IM • Children (6 months - 8 years) who have never been vaccinated or when vaccine status is unknown: two doses, 1 month apart • Children (6 months - 8 years) who have received two or more doses of seasonal influenza vaccine since March 2010 should receive one dose • Children <3 years of age should receive half the adult dose on two occasions separated 1 month apart • Influenza vaccine is not recommended for infants <6 months of age.

Contraindications

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

Precautions

• Persons with moderate illness with or without fever should preferably be immunised after symptoms have disappeared. • History of Guillain-Barré syndrome within 6 weeks of receipt of influenza vaccine.

Timing

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

Antiviral chemotherapy

At present influenza A(H1N1)pdm09, A(H3N2) and B viruses remain sensitive to oseltamivir and zanamivir. A small proportion of A(H1N1) pdm09 viruses with highly reduced inhibition (HRI) by oseltamivir have been detected globally. High levels of resistance to adamantanes among influenza A viruses have been detected in a number of countries. The use of amantadine and rimantadine in the treatment of

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Table 1. Recommended dosage of antiviral agents for treatment Age group

Weight (kg)

Adults

Oseltamivir dosage*

Zanamivir dosage*

75 mg twice per day

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

Premature neonates† <38 weeks

1 mg/kg twice per day

38 - 40 weeks

1.5 mg/kg twice per day

Infants (14 days - 12 months) Children

3 mg/kg twice a day ≤15 kg

30 mg twice per day

>15 - 23 kg

45 mg twice per day

>23 - 40 kg

60 mg twice per day

>40 kg

75 mg twice per day

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

*Recommended duration of treatment is 5 days. Zanamivir is recommended for treatment in children ≥7 years of age. †

Corrected gestational age.

influenza is therefore not recommended. The dosages for treatment with oseltamivir and zanamivir are provided in Table 1.

Antiviral chemoprophylaxis

Annual influenza vaccine is the best way to prevent influenza, because it can be given

in advance before the possible exposures to the influenza viruses occur and it can provide safe and effective immunity throughout the influenza season. Antiviral chemoprophylaxis for contacts of persons with influenza is currently not recommended. WHO recommendations advise presumptive treatment using the treatment regimen

described below, for a duration of 7 days, for higher-risk (patients with severe immunosuppression or transplant patients) individuals exposed to influenza instead of the previously recommended long-term lower-dose chemoprophylaxis regimen. These higher-risk individuals need to be carefully monitored during the influenza season for early signs of influenza and should be treated immediately on suspicion of infection. For a more detailed description of antiviral management and chemoprophylaxis of influenza, please refer to the Healthcare Workers Handbook on influenza on the NICD website http://www.nicd.ac.za/ assets/files/Healthcare%20Workers%20 Handbook%20on%20Influenza%20in%20 SA%20_12%20May%202014%281%29.pdf For the full report on recommended influenza vaccine, refer to the WHO website http://www.who.int/influenza/ vaccines/virus/recommendations/201409_ recommendation.pdf?ua=1

Accepted 9 January 2014.

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TRAUMA CARE

Trauma quality improvement: The Pietermaritzburg Metropolitan Trauma Service experience with the development of a comprehensive structure to facilitate quality improvement in rural trauma and acute care in KwaZulu-Natal, South Africa D L Clarke Before 2006, Damian Clarke was a surgeon at Durban’s South Beach, also known as Addington Hospital. Since fleeing the ongoing attempts to gentrify and ‘Disneyfy’ the beachfront, he has tried to reinvent himself as a faux Midlands farmer and member of the landed gentry in the misty foothills of the Drakensberg. Corresponding author: D L Clarke (damianclar@gmail.com)

Improving the delivery of efficient and effective surgical care in rural South Africa is a mammoth task bedevilled by conflict between the stakeholders, who include rural doctors, surgeons, ancillary staff, researchers, educators and administrators. Management training is not part of most medical school curricula, yet as they progress in their careers, many clinicians are required to manage a healthcare system and find the shift from caring for individual patients to managing a complex system difficult. Conflict arises when management-type interventions are imposed in a top-down manner on surgical staff suspicious of an unfamiliar field of study. Another area of conflict concerns the place of surgical research. Researchers are often accused of not being sufficiently focused on or concerned about the tasks of service delivery. This article provides an overview of management theory and describes a comprehensive management structure that integrates a model for healthcare systems with a strategic planning process, strategic planning tools and appropriate quality metrics, and shows how the Pietermaritzburg Metropolitan Trauma Service in KwaZulu-Natal Province, South Africa, successfully used this structure to facilitate and contextualise a diverse number of quality improvement programmes and research initiatives in the realm of rural acute surgery and trauma. We have found this structure to be useful, and hope that it may be applied to other acute healthcare systems. S Afr Med J 2015;105(2):92-95. DOI:10.7196/SAMJ.8792

The strategic planning process and healthcare systems

include the SWOT analysis, the balanced scorecard, and strategic drift and gap analysis.

Strategic planning is a systematic process designed to assist organisational decision-making by taking account of the micro environment(s) within an organisation, as well as the macroenvironment in which the organisation exists.[1-5] Healthcare systems are complex and tightly coupled. Strategic planning within such a system, without an overarching framework to provide a structure for quality improvement programmes, risks becoming ad hoc, haphazard, ineffectual and even counterproductive. The strategic planning process must identify the organisation’s vision and mission or the system’s aims and objectives. The mission statement explains the reasons for the healthcare system’s existence. The vision statement identifies a potential more ideal ‘future state’ that the system aspires to achieve. Situational analysis follows and analyses the external environment to identify threats and opportunities, then looks inwards to assess the organisation’s resources and capabilities.[1-6] The stage of synthesis follows, in which the strategic plan is crafted. The plan must then be implemented, and after that outcomes must be audited. There are a number of generic strategic planning tools that are of relevance to developing a structured systemic approach to quality improvement programmes. These

SWOT

This acronym stands for Strengths, Weaknesses, Opportunities and Threats (SWOT) and identifies internal strengths and weaknesses, and threats and opportunities in the external environment, that may affect the organisation.

The balanced scorecard

The balanced scorecard is a forward-looking management system that views the organisation from four perspectives, namely learning and growth, process, the customer point of view, and results.

Strategic drift and gap analysis

The final outcome of a strategic plan is a result of the interaction of the external environment and three internal factors, namely the plan, the leadership and the culture of the organisation. A gap analysis model helps identify reasons for the strategic gap.

A healthcare system model

There is a well-established model for thinking about healthcare systems (Table 1) that breaks a healthcare system down into inputs,

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Table 1. The components of a healthcare system (Donabedian[5]) Inputs

Process

Outcome

Macroeducational programmes University funding Nursing colleges Ambulance training colleges

Application process Admission process Academic support for disadvantaged students Type of education

Newly qualified staff Doctor/nurse/paramedic to patient ratios

Microeducational programmes at hospital level

Staff attending Staff completing course

Improvement in patient care Compliance with guidelines

Hospital morbidity and mortality meetings

Staff attending Cases discussed

Decreased rates of adverse events

CT scanner Radiology staffing

Call list Protocols for use Waiting time

Patients scanned Treatment influenced Accuracy of reporting

ICU beds ICU staffing

Triage policy Referral system

Patients treated Mortality rates Length of stay Readmission rate

CT = computed tomography; ICU = intensive care unit.

process and outcome.[4,5] Table 1 attempts to give examples of the various constituents of a healthcare system and to categorise them according to which component they reflect. The system comprises two variables and a product of those two variables. Healthcare outcomes are a direct product of the interaction between inputs and processes. The only components of the healthcare system that planners can directly influence are the inputs and the processes. The relationship between inputs and process is not linear, and increasing inputs without altering process will not necessarily improve outputs. Conversely, improving the process of care without increasing the resources available may result in a dramatic improvement in outcomes.

Metrics to measure outcomes of a healthcare system

A good quality indicator provides a platform to improve pro足 cesses and outcomes and can be classified according to type or according to which component of a healthcare system it measures. Table 2 attempts to contextualise the type of quality indicators against the component of the healthcare system being analysed.[5,6]

A comprehensive strategic planning structure for healthcare systems

I have developed an overarching structure or grid (Table 3) that allows planners to contextualise the strategic planning process against the various components of the healthcare system, to plan accordingly, and to evaluate improvements over time. It integrates the planning process, the components of the system, and quality metrics. The structure comprises a composite grid with an x axis and a y axis. Along the y axis are the components of the strategic planning process (analysis, synthesis and implementation), and along the x axis are the three components of a healthcare system (inputs, processes, outcomes). Within each cell of the grid there is room for the appropriate strategic planning tool as well as the specific quality improvement intervention, and for the appropriate metric. The model allows a planner to identify each metric according to its role in the strategic planning process and according to the component of the system it is measuring. Above and below the grid are columns for the mission and vision of the organisation. These should inform each grid. Table 3 attempts to

Table 2. Examples of types of indicators available Generic and disease-specific indicators

Injury per capita

Rate-based indicators

Caseload

Sentinel indicators

Wrong-site surgery

Input/structural indicators

Ambulance-to-patient ratio

Process indicators

Time to theatre Time till admission

Outcome indicators

Mortality rates Length of stay

show how the grid could be used to situate each tool, intervention or metric according to the stage of the strategic planning process and the component of the healthcare system it is addressing. Planners can situate each planning tool in its appropriate grid. Each proposed intervention can also be placed in a grid according to whichever component of the system it is intended to address. Table 4 illustrates how such a structure may be used in practice to contextualise data from a number of sources in rural trauma and acute care.

Applying the grid to the Pietermaritzburg Metropolitan Trauma Service (PMTS)

Since its inception in 2006, the PMTS in KwaZulu-Natal Province, South Africa (SA), has run a research and a quality improvement programme aimed at uplifting trauma care at Edendale Hospital and in the rural Sisonke health district. This programme is a multifaceted one, as it is obvious that no single intervention will address all the deficits in trauma and acute surgical care in our system. The grid structure has helped to contextualise all programmes within an overarching structure. This is represented in Table 4, which places a number of research projects into context. Commencing by measuring the resources available to deal with trauma and the burden of disease,[7] I then adopted a number of theoretical constructs, taken from fields outside surgery, and used them to both measure quality of care and to inform potential interventions. These theoretical constructs included error theory and the idea of developing a suitable quality

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Table 3. Comprehensive structure for a quality improvement programme looking at improving the quality of care of acute trauma patients in a rural health district in SA Vision*

Quality metric

Mission

Inputs

Processes

Outcomes cannot be directly targeted but must be audited

Analysis SWOT Strategic drift Balanced scorecard

What is the load of trauma? What is the capacity of the rural hospitals to deal with this load? Can we develop new metrics? Can we use new constructs to help us?

What is the delay from injury to arrival at the district hospital? What is the delay from district hospital to regional hospital? Quality of documentation Quality of care

What is the mortality rate compared with elsewhere? What is the error rate compared with elsewhere? What is the length of stay? What is the cost?

Metrics

Synthesis and implementation Generic quality improvement strategies Increase resources Improve process

Can we decrease the load? (injury prevention) Can we increase the number of staff available? Can we improve the quality of the staff available with educational programmes? Can we improve monitoring systems? Will better reporting and feedback to staff improve care?

Should we change the referral patterns? Should specific trauma patients bypass the small district hospital? Can we change the way we deliver care? Restructuring morbidity and mortality meetings

Have we improved the mortality rate? Have we reduced the error rate? Have we reduced the length of stay? Have we improved cost?

Develop targeted quality improvement programmes

Vision

Quality metric

†

*Vision: To have a single high standard of care for urban and rural trauma patients. † Mission: To identify deficits in care and provide pragmatic and sustainable interventions to address these deficits. Note: Planners may need to develop innovative quality metrics. Using the comprehensive structure will help them think about what they wish to measure and how they should measure it.

marker for surgery.[8,9] These systems were used to assess the quality of care in the area.[10-15] Once this situational analysis was done, I moved on to the stage of synthesis of strategies and interventions, introducing educational programmes and refinement of morbidity and mortality meetings with the intention of driving quality improvement;[16,17] a number of innovative registries, which allowed us to capture data for research and to quantify the burden of disease and the outcome more accurately;[18,19] use of the data from these registries to further inform morbidity and mortality meetings and educational initiatives; and a surgical outreach programme (that has run for over a decade), designed to uplift surgical care in the rural hospitals of western KwaZulu-Natal.[20] The grid structure helped in understanding the role of this latter programme and auditing its efficacy in transferring skills to the district hospitals. There are ongoing efforts to refine the process of care by developing burns teams, trauma teams and acute physiological support teams.[21,22] The last introduction was an innovative attempt to provide improved care to surgical patients who were deemed to be too sick for the general ward but too well for the intensive care unit.[22] Ongoing audit has revealed some successes and some failures.[23,24] The grid enabled contextualisation of each research project and each intervention within the overarching system, and closure of the loop between research and strategy.

Conclusion

I have developed a grid structure that integrates the strategic planning process, the associated strategic planning tools, a model of the healthcare system, and the many quality metrics available to measure components of the system as they relate to acute care. As shown, each step in the strategic planning process and each individual quality metric can be placed within the grid to provide a system-wide overview. I believe that this grid will facilitate the development and

implementation of successful quality improvement programmes in a variety of settings in the SA healthcare system. 1. Souba WW, Weitekamp MR, Mahon JF. Political strategy, business strategy, and the academic medical center: Linking theory and practice. J Surg Res 2001;100(1):1-10. [http://dx.doi.org/10.1006/ jsre.2001.6249] 2. Glickman SW, Bagget KA, Krubert CH, et al. Promoting quality: The health-care organization from a management perspective. Int J Qual Health Care 2007;19(3):341-348. [http://dx.doi.org/10.1093/ intqhc/mzm047] 3. Jacobs T, Shepherd J, Johnson G. Strengths, weaknesses, opportunities and threats (SWOT) analysis. In: Ambrosini V, Johnson G, Scholes K, eds. Exploring Techniques of Analysis and Evaluation in Strategic Management. London: Prentice Hall, 1998:122-133. 4. Kaplan RS, Norton DP. The balanced scorecard – measures that drive performance. Harv Bus Rev 1992;70(1):71-79. 5. Donabedian A. The quality of care. How can it be assessed? JAMA 1988;260(12):1743-1748. [http:// dx.doi.org/10.1001/jama.260.12.1743] 6. Mainz J. Defining and classifying clinical indicators for quality improvement. Int J Qual Health Care 2003;15(6):523-530. [http://dx.doi.org/10.1093/intqhc/mzg081] 7. Clarke DL, Aldous C, Thomson SR. Assessing the gap between the burden of trauma in Sisonke District and the surgical capacity of the district hospitals: What are the implications for planning? Eur J Trauma Emerg Surg 2014;40(3):303-308. [http://dx.doi.org/10.1007/s00068-013-0369-0] 8. Clarke DL, Gouveia J, Thomson SR, Muckart DJ. Applying modern error theory to the problem of missed injuries in trauma. World J Surg 2008;32(6):1176-1182. 9. Clarke DL, Kong VY, Handley J, Aldous C. A concept paper: Using the outcomes of common surgical conditions as quality metrics to benchmark district surgical services in South Africa as part of a systemic quality improvement programme. S Afr J Surg 2013;51(3):84-86. [http://dx.doi.org/10.7196/SAJS.1476] 10. Alexander T, Fuller G, Hargovan P, Clarke DL, Muckart DJ, Thomson SR. An audit of the quality of care of traumatic brain injury at a busy regional hospital in South Africa. S Afr J Surg 2009;47(4):120122, 124-126. 11. Stewart WW, Farina Z, Clarke DL, Thomson SR. Variations in levels of care within a hospital provided to acute trauma patients. S Afr J Surg 2011;49(4):194-198. 12. Clarke DL, Allorto NL, Thomson SR. An audit of failed non-operative management of abdominal stab wounds. Injury 2010;41(5):488-491. [http://dx.doi.org/10.1016/j.injury.2009.10.022] 13. Clarke DL, Aldous C, Thomson SR. The implications of the patterns of error associated with acute trauma care in rural hospitals in South Africa for quality improvement programs and trauma education. Injury 2013;45(1):285-288. [http://dx.doi.org/10.1016/j.injury.2013.04.011] 14. Allorto NL, Oosthuizen GV, Clarke DL, Muckart DJ. The spectrum and outcome of burns in a regional hospital in South Africa. Burns 2009;35(7):1004-1008. [http://dx.doi.org/10.1016/j.burns.2009.01.004] 15. Kong VY, van der Linde S, Handley J, Aldous C, Clarke DL. Quantifying the disparity in outcome between urban and rural patients with acute appendicitis in South Africa. S Afr Med J 2013;103(10):742-745. [http://dx.doi.org/10.7196/SAMJ.7109] 16. Aldous C, Searle R, Clarke DL. An error awareness program for junior doctors. African Journal of Health Professions Education 2014;6(2):161. [http://dx.doi.org/10.7196/AJHPE.350] 17. Clarke DL, Furlong H, Laing GL, Aldous C, Thomson SR. Using a structured morbidity and mortality meeting to understand the contribution of human error to adverse surgical events in a South African regional hospital. S Afr J Surg 2013;51(4):122-126. [http://dx.doi.org/10.7196/SAJS.1537] 18. Clarke DL, Aldous C. Surgical outreach in rural South Africa: Are we managing to impart surgical skills? S Afr Med J 2013;104(1):57-60. [http://dx.doi.org/10.7196/SAMJ.7252] 19. Laing GL, Bruce JL, Aldous C, Clarke DL. The design, construction and implementation of a computerized trauma registry in a developing South African metropolitan trauma service. Injury 2014;45(1):3-8. [http://dx.doi.org/10.1016/j.injury.2013.05.013]

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Table 4. Using the comprehensive structure for quality improvement programmes to contextualise a number of diverse research projects Vision

Quality metric

Mission Analysis SWOT Strategic drift Balanced scorecard

Inputs

Processes

Outcomes

Grid 1 Assessing the gap between the acute trauma workload and the capacity of a single rural health district in SA. What are the implications for systems planning?[7] A concept paper: using the outcomes of common surgical conditions as quality metrics to benchmark district surgical services in SA as part of a systemic quality improvement programme[8] Applying modern error theory to the problem of missed injuries in trauma[9]

Grid 2 An audit of the quality of care of traumatic brain injury at a busy regional hospital in SA[10] Variations in levels of care within a hospital provided to acute trauma patients[11]

Grid 3 An audit of failed nonoperative management of abdominal stab wounds[12] The implications of the patterns of error associated with acute trauma care in rural hospitals in SA for quality improvement programmes and trauma education[13] The spectrum and outcome of burns in a regional hospital in SA[14] Quantifying the disparity in outcome between urban and rural patients with acute appendicitis in SA[15]

Metrics

Synthesis and implementation Generic quality improvement strategies Increase resources Improve process

Grid 4 An educational programme for error awareness in acute trauma for junior doctors[16] Using a structured morbidity and mortality meeting to understand the contribution of human error to adverse surgical events in an SA regional hospital[17] Surgical outreach in rural SA: are we managing to impart surgical skills?[18] The design, construction and implementation of a computerised trauma registry in a developing SA metropolitan trauma service[19] Development, implementation and evaluation of a hybrid electronic medical record system specifically designed for a developing-world surgical service[20]

Grid 5 Tick-box admission forms improve the quality of documentation of surgical emergencies, but have limited impact on clinical behaviour[21] The introduction of an acute physiological support service for surgical patients is an effective error reduction strategy[22]

Grid 6 A multifaceted quality improvement programme results in improved outcomes for the selective nonoperative management of penetrating abdominal trauma in a developing world trauma centre[23] Challenges and merits of improving burn care in SA[24]

Develop targeted quality improvement programmes

Vision

Quality metric

Grid 1 represents projects analysing the inputs of care; Grid 2 represents projects analysing the process of care; Grid 3 represents projects analysing the outcomes of the process of care and the inputs of care; Grid 4 represents projects designed to improve the inputs of care; Grid 5 represents projects designed to improve the process of care; Grid 6 represents projects designed to measure the outcomes after inputs and processes have been improved. 20. Laing GL, Bruce JL, Skinner DL, Allorto NL, Clarke DL, Aldous C. Development, implementation and evaluation of a hybrid electronic medical record system specifically designed for a developing world surgical service. World J Surg 2014;38(6):1388-1397. [http://dx.doi.org/10.1007/s00268-0132438-2] 21. Laing GL, Bruce JL, Clarke DL. Tick-box admission forms improve the quality of documentation of surgical emergencies, but have limited impact on clinical behavior. S Afr Med J 2014;104(6):435-438. [http://dx.doi.org/10.7196/SAMJ.7673] 22. Clarke DL, Kong VY, Naidoo LC, Furlong H, Aldous C. The introduction of an acute physiological support service for surgical patients is an effective error reduction strategy. Int J Surg 2013;11(9):989992. [http://dx.doi.org/10.1016/j.ijsu.2013.06.003]

23. Laing GL, Skinner DL, Bruce JL, Bekker W, Oosthuizen GV, Clarke DL. A multi faceted quality improvement programme results in improved outcomes for the selective non-operative management of penetrating abdominal trauma in a developing world trauma centre. Injury 2014;45(1):327-332. [http://dx.doi.org/10.1016/j.injury.2013.08.021] 24. Allorto N, Clarke DL. Merits and challenges in the development of a dedicated burn service at a regional hospital in South Africa. Published online 20 August 2014. http://dx.doi.org/10.1016/j. burns.2014.07.021

Accepted 18 August 2014.

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MEDICINE AND THE LAW

Must doctors disclose their fees before treatment? D J McQuoid-Mason David McQuoid-Mason is Professor of Law at the Centre for Socio-Legal Studies, University of KwaZulu-Natal, Durban, South Africa, and publishes and teaches in medical law. Corresponding author: D J McQuoid-Mason (mcquoidm@ukzn.ac.za)

The bioethical principles of patient autonomy, beneficence, non-maleficence and justice or fairness require doctors to disclose their fees before treating patients. The provisions regarding disclosures about fees in the Health Professions Act and National Health Act are in conflict. Those in the National Health Act are likely to be applied by the courts to impose a legal duty on healthcare practitioners to disclose their fees before treating patients. This is because the National Health Act is consistent with the access to healthcare provision in the Constitution, as the nature of the access is often determined by the patient’s ability to afford the treatment. Given the unequal bargaining power between doctors and patients, very few patients may ask doctors what their fees are before being treated. It is feasible for doctors to provide such information, or an estimate, and ethically and legally they have a duty to do so. S Afr Med J 2015;105(2):96-97. DOI:10.7196/SAMJ.9096

Whether there is an ethical and legal duty on doctors to inform their patients of their fees before treat ment depends on the ethical principles applied to healthcare practitioners and interpretation of the Health Professions Act[1] and the National Health Act.[2] The courts must resolve the conflict where statutes dealing with the same topic differ, e.g. with regard to healthcare practitioners providing information about their fees. This begs the question whether it is feasible for doctors to implement such ethical and legal duties. Bioethical principles require that doctors respect their patients’ autonomy and apply the principles of beneficence, non-maleficence and fairness or justice.[3] These can also be used to justify whether doctors should inform patients about their fees. Patient autonomy[4] concerning payment of fees requires doctors to respect the freedom of patients to decide what form of payment they wish to use or whether they can afford it. Patients are entitled to know the costs of their treatment because these affect: (i) their future available medical aid cover; (ii) how much they will need to co-pay when a doctor has contracted out of medical scheme rates; (iii) how much it will cost should they pay the doctor directly; and (iv) whether they should approach the public sector. The principles of beneficence[5] and non-maleficence[6] also support the principle of patient autonomy concerning information about fees. Patients benefit by knowing how much of their medical aid or cash reserves will be used by the fees for the treatment or procedure. Some patients may then inform their doctor(s) that they cannot afford their services because they are not members of a medical scheme, they have consulted a doctor who has contracted out of medical scheme tariffs, or they are financially unable to pay for the consultation directly. In emergencies the principles of beneficence and non-maleficence apply, regardless of the patient’s ability to pay – the doctor must stabilise the patient before referral, as the Constitution states that nobody may be refused emergency medical treatment.[7] In non-emergency cases, the doctor is still required to do good for the patient, and avoid harm, e.g. by referral to the public sector or, if the doctor has contracted out of medical scheme rates, to a colleague who has not contracted out. The principle of fairness or justice[8] also requires doctors to inform patients how much their medical treatment or procedure is going to cost when done in their rooms, as such costs impact on the patient’s

medical scheme or private purse. Doctors, however, cannot be expected to inform patients of fees to be charged by other healthcare professionals when they refer them. However, they may be able to advise a patient that the other practitioner charges medical scheme tariffs, or has contracted out of them, or to provide an estimate for the costs of tests or procedures. The referring doctor should warn patients that the other practitioner or testing agency will also charge a fee. Sometimes patients do not understand this, and complain to the Health Professions Council of South Africa that they were not told by the referring doctor that there would be additional costs.

The Health Professions Act and National Health Act

The Health Professions Act states that, unless it is impossible, practi tioners shall inform their patients (or the person responsible for them) of the fee to be charged before providing professional services.[1] However, this is qualified by stating that information about fees must be given when requested by the person concerned, or when such fee exceeds that usually charged.[1] In the latter case, the doctor must inform the patient or responsible person of ‘the usual fee’.[1] The Act does not define ‘usual fee’, but presumably means ‘the fees used by a professional board as the norm’.[9] Except where the doctor charges a higher than usual fee, the onus of requesting information is placed on the patient. This is in conflict with the National Health Act, which requires the provider to disclose the costs to the patient.[2] The National Health Act requires a healthcare provider to inform ‘users’ (patients and persons acting on their behalf) not only about ‘the range of diagnostic procedures and treatment options generally available’ but also about ‘the benefits, risks, costs [my italics] and consequences associated with each option’.[2] This statement is not qualified by stating that such information must be given if requested by the patient.[1] The obligation on healthcare providers to mention their costs is mandatory – ‘[every] health care provider must inform [my italics] a user of … the costs of the diagnostic procedure and treatment options’[1] – unlike the Health Professions Act,[2] which implies that it is discretionary except where the patient requests them. The courts must decide whether the provisions in the National Health Act supersede those in the Health Professions Act.

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Resolving the conflict between the Acts

When interpreting a general statute, the courts presume that, if there is a conflict between the provisions in an earlier general statute and a later general statute dealing with the same topic, the provisions in the later statute revoke the earlier statute. This is applied where the provisions in the later statute are inconsistent and irreconcilable with an earlier statute.[9] However, the courts invoke this presumption sparingly because ‘it is also presumed that a statutory provision is not aimed at altering or abrogating the existing law more than necessary’.[10] An alteration or abrogation must also be consistent with the Constitution.[7] There is a conflict between the provision in the Health Professions Act that information regarding fees must be given by a healthcare practitioner ‘when so requested’ [my italics],[1] and the provision in the National Health Act which states that the health care provider ‘must inform’ [my italics] the user of ‘the costs associated with each option’ regarding the ‘diagnostic procedures and treatment options’.[2] The National Health Act provides ‘a framework for a structured uniform health system … taking into account the obligations imposed by the Constitution and other laws’.[11] The Constitution provides that everyone has the right of access to healthcare services.[12] Whether or not patients can exercise their constitutional right of access to healthcare may depend on their ability to afford the practitioner’s services by paying the practitioner directly, relying on their medical scheme, or approaching the public sector. Patients may only be able to make this choice after being informed about the likely fees. The constitutional right of access to information[13] would be satisfied if doctors made information about fees available on request from their patients where an equal power relationship exists. However, given the generally unequal power relationship between doctors and their patients, particularly when patients are ill and vulnerable, many may not make such requests, thus undermining the patient’s right of access to healthcare. The doctor’s duty to disclose the costs of procedures and treatment as required by the National Health Act[1] therefore concurs with the constitutional[12] right of access to healthcare, and should be adhered to by healthcare practitioners. Some provisions in the Health Professions Act regarding fees charged by healthcare professionals[1] were amended after the National Health Act came into effect. However, the National Health Act provision[2] is more consistent with the spirit of the Constitution[12] than the unchanged provision in the Health Professions Act[1] that places the onus on patients to request information about the practitioner’s fees.

Is it feasible for doctors to inform patients about their treatment cost?

Some practitioners argue that it is not feasible always to advise their patients beforehand regarding the cost of their treatment. However,

it must be possible to specify what their consultation, procedures, hourly fees, etc. are, or to provide an approximate fee. It is sometimes said that doctors cannot estimate how much the scheme will cover for a medical scheme member, because this is a matter between the patient and their medical scheme and depends on their contract.[14] However, when obtaining preauthorisation for medical or surgical procedures or hospital stays, practitioners should be able to ascertain whether the medical scheme will cover these, and advise their patients accordingly. Similarly, when patients are referred to another practitioner they must be warned that the other practitioner will charge a fee additional to that of the referring doctor. Doctors can also sometimes give a reasonably accurate estimate of what the procedure or test is likely to cost, e.g. radiology or pathology tests. In any event, where doctors charge rates above those ‘usually charged for such services’, e.g. when they have contracted out of medical scheme rates, the Health Professions Act legally requires them to inform their patients of their fee, and the fee that would usually be charged.[1] If such doctors must inform their patients of their intended fee and the ‘usual rates’, it seems reasonable for doctors who charge the ‘usual rates’ to do likewise, or to provide an estimate. In the USA, patients are increasingly likely to demand disclosure of the cost of care, and the websites of organisations such as Clear Health Care Beta[15] and Pricing Healthcare[16] have databases of the fees charged by different doctors to enable patients to estimate their healthcare costs in advance of consultations.[14] 1. Section 53(1) of the Health Professions Act No. 56 of 1974. www.hpcsa.co.za/…/legislations/acts/ health_professions-ct-56-1974.pdf (accessed 17 December 2014). 2. Section 6(1)(b) and (c) of the National Health Act No. 61 of 2003. (www.lawsofsouthafrica.up.ac.za/… health/national-health-act-61-of-2003/ (accessed 17 December 2014). 3. Beauchamp TL, Childress JF. Principles of Biomedical Ethics. 3rd ed. Oxford: Oxford University Press, 1994:67-113 (autonomy), 194-249 (beneficence), 120-184 (non-maleficence), 256-302 (justice). 4. Beauchamp TL, Childress JF. Principles of Biomedical Ethics. 3rd ed. Oxford: Oxford University Press, 1994:67-113. 5. Beauchamp TL, Childress JF. Principles of Biomedical Ethics. 3rd ed. Oxford: Oxford University Press, 1994:194-249. 6. Beauchamp TL, Childress JF. Principles of Biomedical Ethics. 3rd ed. Oxford: Oxford University Press, 1994:120-184. 7. Section 27(3) of the Constitution of the Republic of South Africa, 1996. www.justice.gov.za/legislation/ constitution/constitution.htm (accessed 17 December 2014). 8. Beauchamp TL, Childress JF. Principles of Biomedical Ethics. 3rd ed. Oxford: Oxford University Press, 1994:256-302. 9. Section 53(3)(d) of the Health Professions Act No. 56 of 1974. www.hpcsa.co.za/…/legislations/acts/ health_professions-ct-56-1974.pdf (accessed 17 December 2014). 10. Du Plessis LM. Statute law and interpretation. In: Joubert WA, Faris JA, eds. The Law of South Africa. Vol 25, part 1. 2nd ed. Durban: LexisNexis, 2011. 11. Preamble to the National Health Act No. 61 of 2003. 12. Section 27(1)(a) of the Constitution of the Republic of South Africa, 1996. 13. Section 32(1) of the Constitution of the Republic of South Africa, 1996. 14. Ubel P. Doctors must discuss the cost of care with their patients. Policy July 10 2014. http://www. kevinmd.com/blog/2014/07/doctors-must-discuss-cost-care-patients.html (accessed 28 October 2014). 15. Clear Health Costs Beta. http://www.clearhealthcosts.com (accessed 28 October 2014). 16. Pricing Healthcare. http://www.pricinghealthcare.com (accessed 28 October 2014).

Accepted 20 November 2014.

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EVIDENCE REVIEW

Evidence insufficient to confirm the value of population screening for diabetes and hypertension in low- and middle-income settings S Durão, O Ajumobi, T Kredo, C Naude, N S Levitt, K Steyn, D Bradshaw, T Young Solange Durão, BSc Dietetics, MPH, is a senior scientist at the South African Cochrane Centre, South African Medical Research Council, Cape Town. Her interests include public health nutrition, evidence synthesis and evidence-informed policies and practice, and capacity building for using and conducting systematic reviews. Oluwayemisi Ajumobi, MS, MPH, is an epidemiologist working at the World Bank, Health, Nutrition and Population Global Practice. Her interests include designing sustainable health innovations, impact evaluations to assess development effectiveness, the impact of health interventions at population level, and strengthening the capacity of the health systems in developing countries for improved multi-disease surveillance. Tamara Kredo, MB ChB, MMed (Clinical Pharmacology), HIV Dip Man, is a senior specialist scientist at the South African Cochrane Centre, Cape Town. Her interests include capacity building in evidence-based healthcare and clinical guideline development and implementation. Celeste Naude, PhD, MNutr, BSc Dietetics, works at the Centre for Evidence-based Health Care, Stellenbosch University, Tygerberg, Cape Town, South Africa. She is a dietitian and senior researcher and her interests include public health nutrition, evidence synthesis, knowledge translation and evidence-informed decision-making. Prof. Naomi (Dinky) Levitt, MB ChB, MD, FCP (SA), Fellow of the University of Cape Town, heads the Division of Diabetic Medicine and Endocrinology, Department of Medicine, UCT and Groote Schuur Hospital and is Director of Chronic Disease Initiative for Africa, Department of Medicine, UCT. Krisela Steyn, MSc, MD, NED, is Associate Director of the Chronic Disease Initiative for Africa, Department of Medicine, UCT. She has conducted research on the public health aspects of non-communicable diseases since 1982. Debbie Bradshaw, DPhil (Oxon), is Director of the Burden of Disease Research Unit, Medical Research Council, Cape Town. She is an expert in disease patterns and has a broad interest in evidence for reducing the burden of disease. Taryn Young, MB ChB, FCPHM, MMed (Public Health) is a public health specialist at the Centre for Evidence-based Health Care at Stellenbosch University and the South African Cochrane Centre. She has considerable experience in building capacity for and promoting the conduct and use of research evidence in healthcare decision-making. Corresponding author: S Durão (solange.durao@mrc.ac.za)

To assess the evidence from systematic reviews on the effect on morbidity and mortality of blanket screening for hypertension or diabetes mellitus compared with targeted, opportunistic or no screening, we searched for relevant systematic reviews and conducted duplicate study selection, data extraction and quality appraisal. Results were summarised narratively. We included two completed reviews of moderate quality and one ongoing Cochrane review. In one completed review, general health checks had no effect on total morbidity or mortality or on healthcare services compared with no health checks. In the other, intensive hypertension screening methods were ineffective in increasing screening uptake or detecting new cases compared with less intensive methods. Both reviews included studies in high-income settings. There is insufficient evidence from currently available systematic reviews to confirm a beneficial effect of blanket screening for hypertension and/or diabetes compared with other types of screening methods in low- and middle-income settings. Scarce resources are being mobilised to implement mass screening intervention for diabetes and hypertension without adequate evidence of its effects. A systematic review is needed to assess clinical effectiveness, cost-effectiveness and overall impact on the health system of screening strategies, especially in low- and middle-income settings such as exist in South Africa. Robust evaluation of these outcomes would then be necessary to inform secondary prevention strategies. S Afr Med J 2015;105(2):98-102. DOI:10.7196/SAMJ.8819

In efforts to address the rising burden of diabetes and hypertension,[1-6] some provincial departments of health in South Africa (SA) are implementing population-level screening programmes for cardiovascular risk factors, including diabetes and hypertension. In addition, the National Ministry of Health included screening for diabetes and hypertension as part of the HIV counselling and testing campaign that commenced in April 2010. Screening seeks to identify apparently healthy individuals who have, or are at increased risk of, cardiovascular disease but do not yet manifest symptoms, with the aim of instituting treatment and impacting favourably on the disease course.[7] Although screening for diabetes and hypertension has the potential to improve health, its effectiveness depends on whether blanket screening (population-wide screening for every individual,

irrespective of gender, age group and health conditions), targeted screening (screening targeted at individuals known to be at increased risk for certain conditions/diseases), or opportunistic screening (screening provided at point of care for other related conditions) is undertaken.[1] Population-wide screening programmes are associated with high implementation costs, wastage of resources due to ineffective programmes, and inconveniences and psychological distress resulting from false-positive results.[7] To ensure implementation of screening interventions with population-wide benefits, and that are clinically effective and cost-effective, any screening method requires evidence of its effectiveness.[7,8] Since systematic reviews of randomised controlled trials are the gold standard of evidence for the effectiveness of healthcare interventions, we analysed current systematic reviews that have

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evaluated the effects of blanket (population-wide) screening for diabetes and hypertension, compared with targeted or opportunistic screening, or no screening. In this context, it bears noting that systematic reviews use explicit, systematic methods to collate all existing studies that meet prespecified eligibility criteria, and assess the validity of the findings in included studies, to address a clearly stated objective or research question.[9]

Methods

Criteria for study selection

We included systematic reviews of population screening (also called blanket or community-wide screening) for diabetes mellitus and/ or hypertension, using any type or combination of screening tests implemented in the general healthy population. These interventions could have been compared with targeted, opportunistic or no screening. Our primary outcomes included all-cause mortality and diabetesand hypertension-related morbidity. Our secondary outcomes of interest included uptake of the screening, incident cases of hypertension and correctly diagnosed diabetes, impact on the healthcare services, cost-effectiveness and quality of life.

Searching for systematic reviews

We searched the electronic databases MEDLINE (PubMed), the Cochrane Library, the TRIP database, McMaster Health Evidence. org, the EPPI library and the Campbell Library up to August 2013. We used a comprehensive search strategy, without language restrictions, to identify all existing relevant systematic reviews. Reference lists of included studies were also examined for any other relevant reviews.

Study selection, data extraction and analysis

Two authors (SD and YA) independently screened search results and extracted data from eligible studies. Disagreements were resolved by discussion with a third author (TK). The methodological quality of included reviews was evaluated using AMSTAR, an 11-item validated tool.[10] Each item on AMSTAR is rated as yes (clearly done), no (clearly not done), unclear or not applicable. Each item rated ‘yes’ was awarded one point, and points were summed to calculate a total score. Total scores of 0 - 4 indicated low quality, 5 - 8 moderate quality, and 9 - 11 high quality.[11] Information from the included reviews was summarised narratively.

Results

The database search retrieved 875 records. Two completed systematic reviews and one ongoing review were included: Krogsboll et al.[12] assessed the benefits and harms of general health checks in adults, compared with no health checks, on morbidity and mortality, and Ebrahim[13] compared the effectiveness of more and less intensive methods of detecting hypertension. Both reviews involved adult participants and were conducted in highincome settings. The third ongoing study involves a protocol of a Cochrane review that plans to assess the effects of screening for type 2 diabetes on reducing morbidity and mortality, compared with no screening.[14] Table 1 summarises the characteristics of these three reviews. The Krogsboll and Ebrahim reviews were of high and moderate quality (AMSTAR scores 9/11 and 7/10, respectively). In the case of Ebrahim, it was unclear whether unpublished as well as published studies had been searched for. Neither review reported on publication bias, or assessed possible conflict of interest in the studies they included.

Effects of interventions

Ebrahim[13] did not address screening for diabetes. Krogsboll et al.[12] assessed interventions that screened for many diseases, including diabetes and hypertension. Table 2 summarises the results of both these reviews. Effects on mortality and morbidity Krogsboll et al.[12] found no effects of general health checks on mortality, either total (risk ratio (RR) 0.99, 95% confidence interval (CI) 0.95 - 1.03; meta-analysis of nine studies, 155 899 participants, I2 = 0%) or cardiovascular (RR 1.03, 95% CI 0.91 - 1.17; meta-analysis of eight studies on 152 435 participants, I2 = 64%). The duration of follow-up was 4 - 22 years, varying within each trial for different outcomes. Health checks compared with no health checks had no effect on morbidity (coronary heart disease, stroke or myocardial infarction). Ebrahim[13] did not evaluate the effect of screening for hypertension on mortality or morbidity. Uptake of screening Ebrahim[13] found that less rigorous studies, or those conducted in areas with poor healthcare coverage, showed that intensive screening methods (e.g. door-to-door) were more effective at increasing coverage of the population compared with less intensive methods (e.g. routine case finding). However, in well-conducted trials, or in populations with reasonable access to healthcare, this was not the case. Krogsboll et al.[12] did not assess uptake of screening. Detection of incident cases of hypertension and diabetes mellitus Ebrahim[13] found no difference in the yield of unknown hypertensive patients through screening compared with routine case finding. Krogsboll et al.[12] reported that health checks are likely to increase the number of diagnoses, but noted that this outcome was poorly documented in most studies. Impact on the health service Krogsboll et al.[12] found that general health checks had no effect on hospital admission rates, number of people admitted to the hospital once or more, number of days in hospital, or number of physician visits. Cost-effectiveness and quality of life Neither review reported on cost-effectiveness or quality-of-life outcomes.

Discussion

We found two completed systematic reviews that addressed some aspects of our question regarding population screening v. targeted, opportunistic or no screening for diabetes and hypertension. Krogsboll et al.[12] found that health checks for the general population did not reduce general or cardiovascular-related morbidity and mortality, and results were poorly reported for the effect on new diagnoses and the impact on the healthcare system. Ebrahim[13] found increased coverage with intensive screening in areas with poor healthcare coverage. We also found an ongoing review, the aim of which is to assess the efficacy of screening for type 2 diabetes compared with regular care in reducing morbidity and mortality related to diabetes. These findings urge caution regarding the implementation of population-based screening interventions. Evidence from a systematic review of economic studies assessing the costeffectiveness of interventions to prevent and control diabetes

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Table 1. Characteristics of included studies Krogsboll et al.[12]

Ebrahim[13]

Woolthuis et al.[14] (protocol)

Objectives of the review

To quantify the benefits and harms of general health checks with an emphasis on patientrelevant outcomes such as morbidity and mortality, rather than on surrogate outcomes such as blood pressure and serum cholesterol levels

To determine the most effective methods of detecting hypertension, improving patient adherence with treatment, improving control of blood pressure, and improving professional compliance with standards of good practice

To determine the efficacy of screening for type 2 diabetes in reducing morbidity and mortality associated with diabetes compared with no screening. Secondary objectives include assessing the effects of screening for type 2 diabetes on adverse events, healthcare consumption, quality of life, and costs.

Date of last search

July 2012

July 1996

N/A

Study designs included and number of studies included

14 RCTs

4 RCTs, 5 quasiexperimental comparisons with contemporary control groups, and 2 before-andafter studies

This review will include only randomised controlled trials with a minimum duration of 3 months.

Participant characteristics

Adults, regardless of gender and ethnicity, in the general population or participants within a narrow group (e.g. employees of a company)

Age ranged from â&#x2030;Ľ16 years to adults of all ages.

This review will include people without known diabetes mellitus. The authors will assess the precise diagnostic criteria from the report, or from the authors in case there are missing data.

Setting

High-income countries Primary care or community

High-income countries (England, Canada, Wales, Scotland)

No specific setting mentioned in the protocol.

Intervention features

General health checks (defined as screening for more than one disease or risk factor in more than one organ system, whether performed only once or repeatedly) compared with no health checks. They included trials that included lifestyle interventions, such as advice on diet, smoking and exercise, in addition to the screening. The interventions could have been administered by doctors, nurses, or other health professionals.

Interventions comparing more intensive screening methods for detection of hypertension (e.g. nurse screening, home blood pressure screening, housewife or door-to-door screening) with less intensive methods (e.g. usual care, routine health services check or case-findings, targeted screening, computer doctor prompts)

This review will include any studies of diabetes screening, including mass, targeted and opportunistic screening approaches, that use the fasting plasma glucose or the 2-hour plasma glucose as a screening test, individually or in combination. This includes studies using stepwise screening procedures, for example questionnaires or database selection, followed by those two tests. Comparison interventions will be diagnosis of type 2 diabetes during regular care.

Outcomes assessed

Primary: All-cause mortality, disease-specific mortality (cardiovascular and cancer mortality) Secondary: Morbidity (myocardial infarction), new diagnosis (total and condition specific), admission to hospital, disability, patient worry, selfreported health, number of referrals to specialists, number of non-scheduled visits to GP, number of additional diagnostic procedures due to positive screening tests, new medications prescribed and frequency and type of surgery, absence from work

Coverage of the population achieved and the detection rates of new and known hypertensive patients

Primary: Incidence of type 2 diabetes (as diagnosed at the time of the diagnosis with prevailing diagnostic criteria), diabetesrelated mortality (myocardial infarction, stroke, peripheral vascular disease, renal disease, hyper- or hypoglycaemia or sudden death), total mortality, all morbidity and diabetes and cardiovascular morbidity (vascular complications, neuropathy, retinopathy, nephropathy, erectile dysfunction, amputation) Secondary: Adverse events, healthcare consumption (e.g. use of medication, number of consultations), quality of life, and costs. Outcomes will be assessed in the short (3 6 months), medium (6 - 12 months) or long term (>12 months)

N/A = not applicable; RCT = randomised controlled trial; GP = general practitioner.

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Table 2. Summary of the results of the included completed reviews Krogsboll et al.[12]

Ebrahim[13]

Effects on mortality

Total mortality: RR 0.99 (95% CI 0.95 - 1.03); meta-analysis of 9 studies, 155 899 participants, I2 = 0% Cardiovascular mortality: RR 1.03 (95% CI 0.91 - 1.17); metaanalysis of 8 studies on 152 435 participants, I2 = 64%)

Effects on morbidity

Health checks had no effect on morbidity in terms of actual illness, but they may increase the number of people diagnosed with elevated risk factors.

ffects on uptake/ E coverage of screening

Results synthesised narratively. More intensive screening methods (e.g. door-to-door) were more effective at increasing coverage if studies were done in areas where coverage was likely to be poor (e.g. poor black people in US housing blocks) or with less rigorous BAS. Intensive screening did not increase coverage greatly in trials that were well conducted or done in populations with reasonable access to healthcare.

ffect on incident E cases diagnosed

Results synthesised narratively. General health checks likely to increase the number of new diagnoses, but these results were poorly reported in most trials.

More intensive screening had no effect on the detection rates, or yield of unknown hypertensive patients, compared with routine case finding.

ffects on health E services

Health checks had no effects on admission rates, number of people admitted once or more, or number of days in hospital, when compared with no health checks. There were also no effects on physician visits.

Process evaluation data/costeffectiveness results

Quality of life

Primary outcomes

Secondary outcomes

NR = not reported; BAS = before-and-after studies.

further emphasises this.[15] In this review, three cost-effectiveness studies, one of universal opportunistic screening for undiagnosed type 2 diabetes compared with targeted screening for those with hypertension, and two of universal opportunistic screening for undiagnosed type 2 diabetes with ensuing treatment compared with no screening in a US population aged ≥45 years, showed that universal opportunistic screening was not cost-effective. These cost-effectiveness studies also showed that screening proved cost-effective only when it targeted persons with additional risk factors, such as hypertension, or of specific ethnicities, e.g. African Americans aged 45 - 54 years. The lack of an effect of general health checks on the healthcare system was surprising, as screening is expected to lead to increased use of healthcare services, to confirm diagnosis and initiate treatment as necessary. Only one trial, conducted in a high-income setting and included in the Krogsboll review, reported an increase in new diagnoses with general health checks compared with no health checks; it is possible that most cases identified in this way were known cases that did not have an additional impact on the health system.

Overall completeness, quality and applicability of evidence

Neither of the included reviews report on all the specified out comes. Ebrahim’s[13] literature search was conducted in 1996,

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and is outdated and likely to have missed important new trials addressing the question. The trials included in the reviews were conducted in high-income settings, potentially rendering their results inapplicable to the lower- or middle-income settings that characterise SA. Krogsboll et al.[12] did not assess screening of diabetes and hypertension specifically, but rather screening for multiple diseases or risk factors, including diabetes or hypertension. The results of these interventions may differ from those addressing only hypertension or diabetes.

Conclusion

Screening interventions should be selected on the basis of evidence of their effects in terms of clinical and healthcare system outcomes. This is particularly important where under-resourced health services are already pressurised to provide care for chronic management of both infectious and non-communicable diseases. There is insufficient evidence from currently available systematic reviews to confirm a beneficial effect of blanket screening for hypertension and/or diabetes compared with other types of screening methods in low- and middle-income settings. Scarce resources are being mobilised to implement a mass screening intervention for diabetes and hypertension without adequate evidence of its effects. A systematic review is needed to consider the outcomes of clinical effectiveness, cost-effectiveness and impact on the healthcare system overall of screening strategies, especially in lower- and middle-income

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settings such as exist in SA. Robust evaluation of these outcomes would then be necessary to inform secondary prevention strategies. Author contributions. All authors contributed to the development of the protocol for this study. SD and YA performed literature searches. SD and YA selected studies for inclusion and TK resolved disagreements in study selection. SD and YA extracted and synthesised data. SD drafted the manuscript. All authors contributed to finalisation of the manuscript, and all reviewed and approved the manuscript. Acknowledgements. The Cochrane Collaboration’s Global Evidence Synthesis Initiative for funding this project. 1. Mohan V, Seedat YK, Pradeepa R. The rising burden of diabetes and hypertension in South East Asian and African regions: Need for effective strategies for prevention and control in primary health care settings. Int J Hypertens 2013;2013: article ID 409083. [http://dx.doi.org/10.1155/2013/409083] 2. Bradshaw D, Norman R, Pieterse D, Levitt NS. Estimating the burden of disease attributable to diabetes in South Africa in 2000. S Afr Med J 2007;97(7):700-706. 3. Norman R, Gaziano T, Laubscher R, et al. Estimating the burden of disease attributable to high blood pressure in South Africa in 2000. S Afr Med J 2007;97(8):692-698. 4. Peer N, Steyn K, Lombard C, Lambert EV, Vythilingum B, Levitt NS. Rising diabetes prevalence among urban-dwelling black South Africans. PLoS One 2012;7(9):e43336. [http://dx.doi.org/10.1371/journal. pone.0043336]

5. Peer N, Steyn K, Lombard C, Gwebushe N, Levitt N. A high burden of hypertension in the urban black population of Cape Town: The Cardiovascular Risk in Black South Africans (CRIBSA) Study. PLoS One 2013;8(11):e78567. [http://dx.doi.org/10.1371/journal.pone.0078567] 6. Mayosi B, Flisher AJ, Lalloo UG, Sitas F, Tollman SM, Bradshaw D. The burden of non-communicable diseases in South Africa. Lancet 2009;374(9693):934-947. [http://dx.doi.org/10.1016/S0140-6736(09)61087-4] 7. Grimes D, Schulz K. Use and abuses of screening tests. Lancet 2002;359(9309):881-884. [http://dx.doi. org/10.1016/S0140-6736(02)07948-5] 8. Australian Population Health Development Screening Committee. Population based screening framework. Australia: Commonwealth of Australia, 2008. http://www.screening.nhs.uk/criteria (accessed 10 December 2013). 9. Higgins JPT, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. www.cochrane-handbook.org (accessed 13 December 2013). 10. Shea BJ, Hamela C, Wells GA, et al. AMSTAR is a reliable and valid measurement tool to assess the methodological quality of systematic reviews. J Clin Epidemiol 2009;62(10):1013-1020. [http://dx.doi. org/10.1016/j.jclinepi.2008.10.009] 11. Van der Linde RM, Stephan BCM, Savva GM, Dening T, Brayne C. Systematic reviews on behavioural and psychological symptoms in the older or demented population. Alzheimers Res Ther 2012;4(4):123. [http://dx.doi.org/10.1186/alzrt131] 12. Krogsboll LT, Jorgensen K, Gronhoj L, Gotzsche P. General health checks in adults for reducing morbidity and mortality from disease (Review). Cochrane Database of Systematic Reviews 2013; Issue 10. Art. No.: CD009009. [http://dx.doi.org/10.1002/14651858.CD009009.pub2] 13. Ebrahim S. Detection, adherence, and control of hypertension for the prevention of stroke: A systematic review. Health Technol Assess 1998;2(11):1-78. [http://dx.doi.org/10.3310/hta2110] 14. Woolthuis EPK, de Grauw WJC, van de Laar FA, Akkermans RP. Screening for type 2 diabetes mellitus (Protocol). Cochrane Database of Systematic Reviews 2005; Issue 2. Art. No.: CD005266. [http:// dx.doi.org/10.1002/14651858.CD005266] 15. Li R, Zhang P, Barker LE, Chowdhury FM, Zhang X. Cost-effectiveness of interventions to prevent and control diabetes mellitus: A systematic review. Diabetes Care 2010;33(8):1872-1894. [http://dx.doi. org/10.2337/dc10-0843]

Accepted 25 August 2014.

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EDITORIAL

Why is cancer not a priority in South Africa? Every year on our planet, 8.2 million people die of cancer.[1] That number equals the population of a whole country such as Rwanda, Austria or Haiti. By 2050 it is estimated that the figure will more than double to approximately 17.5 million.[2] As personal incomes increase in the developing world, lifestyles evolve towards the pattern seen in high-income populations, with obesity, excessive alcohol consumption, air pollution and smoking, all of which increase the risk of cancer. Already around 60% of all new cancer cases and 70% of related deaths occur in low- and middle-income countries.[1] Globally, cancer kills more people than HIV/AIDS, tuberculosis and malaria.[2] In the hierarchy of causes of death, it occupies a place close to the top in most countries. Is the cancer incidence in South Africa (SA) following the global trend? Anyone who consults the latest list of all underlying causes of death (in 2013) in our country, published by Statistics South Africa recently,[3] would be surprised to see that cancer does not appear among the ten most frequent causes. A cursory examination of the list may create the impression that SA enjoys the unique privilege of having been spared the increase in the incidence of malignant disease seen in the rest of the world. For the more inquisitive mind, however, the joy would be shortlived, as it would soon become clear that malignant disease has been reported according to its anatomical location: ‘malignant neoplasm of digestive organs’, ‘malignant neoplasm of respiratory and intrathoracic organs’, and so on. The reporting was based on the International Statistical Classification of Diseases and Related Health Problems (10th edition) (ICD-10).[4] As the ICD-10 does not provide for an all-encompassing ‘malignant diseases’ category, the total deaths from cancer are distributed over 15 anatomical sites, with the resulting smaller figures. Without disputing the epidemiological value of classifying malignant neoplasms by their anatomical location, when strategising for optimal healthcare delivery the total number of deaths from all these neoplasms would be required in order to understand the magnitude of the problem. The total number of deaths from cancer in 2013, arrived at by adding together the numbers corresponding to various anatomical locations, was 36 726 (8% of all deaths). This figure reveals that malignant neoplasms were in fact the second most frequent cause of death in SA, second only to tuberculosis. Also, cancer killed more people than other non-communicable diseases such as cerebrovascular pathology, hypertension and diabetes. This sobering finding has far-reaching implications. First of all, the second place of cancer in the hierarchy of causes of death will have to be acknowledged. At present it does not even appear on the list of the ten most frequent causes. Thereafter, adequate planning followed by effective measures will be needed in order to address the already considerable and steadily increasing threat of malignant disease. Likewise, the top national research priorities should reflect the need for cancer control. In order to increase our resolve to implement such significant changes, we need to evaluate the economic impact of cancer on SA more precisely. At present the magnitude of this impact in the country is not known, but the figures may be considerable. In the USA, where almost 600 000 people die of cancer every year, the losses to the economy were estimated at USD216.6 billion in 2009. While the total healthcare costs were impressive at USD86.6 billion, the costs of lost productivity from premature deaths were even higher, amounting to USD130 billion.[5] Worldwide, it has been estimated

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that cancer has the highest economic impact, from premature death and disability, of all causes of death.[6] The total annual loss for the world economy was evaluated at USD1.16 trillion in 2010.[1] A major contributor to the fight against the increased burden of malignant disease is the National Cancer Registry. Established in 1986 as a pathology-based registry, its activity was impaired by lack of funding and reluctance to communicate data on the part of numerous stakeholders such as private laboratories, among others, mainly out of fear of consequences arising from disclosure of information that could be regarded as private and confidential.[7] The registry was revitalised in 2009, with the intention of transforming it into a hospital-based and later a population-based one. Although the reporting of cases was made compulsory by law in 2011, its completeness still needs to be tested. There remains a long distance to be covered to establishing a population-based registry. Continuing to face challenges, the registry has not yet processed its backlog of data since 2008, nor has it issued a comprehensive report. A co-ordinated, evidence-based national approach to prevent ing and treating cancer is necessary today more than ever before. This should be framed by a National Cancer Control Plan,[8] formulated along the guidelines established by the World Health Organization.[9] The Cancer Association of South Africa under took to formulate a cancer control plan as early as 1993. Although the plan was supported by representatives of academia, national medical research organisations, provincial administrations, hospice organisations and non-governmental organisations, it was not adopted by the National Department of Health until 1999. The National Cancer Control Plan is currently being updated, and although the Department of Health faces many new challenges, such as antimicrobial resistance, rapid implementation is expected to address the scourge of cancer. It has to be acknowledged that a number of policies aimed at limiting the risk of malignant disease in SA have been implemented in the past two decades. The Tobacco Products Control Act and the Liquor Act have sought to limit the use of these recognised carcinogenic products. The cervical cancer screening programme and more recently the vaccination programme against human papillomavirus (in its pilot phase at present) will contribute to reducing the incidence of cervical cancer.[10] Another significant measure was the establishing of the Ministerial Advisory Committee on Cancer in 2013. Further, the Department of Health’s Strategic Plan for 2014/15 - 2018/19[11] prioritises the fight against cancer of the cervix. The effectiveness of these measures needs to be evaluated by the National Cancer Registry. In February 2014, the International Agency for Research on Cancer (IARC) launched the latest edition of a respected publication, the World Cancer Report 2014,[1] which deals with numerous facets of cancer epidemiology, prevention, treatment and research. The most salient conclusion of this report was, as defined by one of its editors, Dr Christopher Wild, Director of the IARC, that ‘we cannot treat our way out of the cancer problem’.[12] The costs of adequate treatments are progressively becoming unsustainable, even for high-income countries:[12] cancer control must therefore resort to concerted action against the main risk factors – tobacco use, obesity and lack of physical activity, excessive exposure to sunlight, radiation, infectious agents, and chemicals in food and in the environment. Such action would require adequate policies, proper implementation and sustained monitoring, all supported by a comprehensive National Cancer Control Plan.

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The SA Medical Research Council (MRC) is poised to support research aimed at reducing the cancer burden. To this purpose, it plans to support research that provides reliable and up-to-date figures on the burden of cancer in our country to augment the surveillance measures. The MRC will also promote research into the prevalence and geographical distribution of cancer to better understand risk factors, as well as funding research addressing effective ways of mitigating the effects of carcinogens. Through its Strategic Health Innovation Partnerships division, the MRC is already funding translational research into new medicines and devices for the prevention, diagnosis and management of cancer. Addressing malignant disease as one of the national health priorities, the MRC will fund dedicated cancer centres in SA under the leadership of prominent scientists, which will respond to the most pressing and relevant cancer research questions. The time has arrived to acknowledge the impact of cancer on the SA population, at present as well as in future decades. The data published by Stats SA clearly place malignant disease as the second most frequent cause of death in our country in 2013. Death from cancer may rise to first place once tuberculosis and HIV have been more efficiently controlled. To improve the health of South Africans, adequate attention to cancer is required, and should include a holistic approach that addresses research, effective management and prevention modalities.

D Cristina Stefan Vice-President, South African Medical Research Council, and Visiting Senior Research Associate in the Nuffield Division of Clinical Laboratory Sciences, Oxford University, UK Â Corresponding author: D C Stefan (cristina.stefan@mrc.ac.za) 1. Stewart BW, Wild CP, eds. World Cancer Report 2014. Lyon, France: International Agency for Research on Cancer, 2014. 2. American Cancer Society. Overview of the global cancer and tobacco burden, and our global programs. www.cancer.org/aboutus/globalhealth/ourglobalprograms/index (accessed 15 December 2014). 3. Statistics South Africa. Mortality and Causes of Death in South Africa, 2013: Findings from Death Notification. Statistical release P03039.3. Pretoria: Statistics South Africa, 2014. 4. World Health Organization. Classifications. International Classification of Diseases (ICD). www.who. int/classifications/icd/en (accessed 11 December 2014). 5. American Cancer Society. Cancer Facts & Figures 2014. Atlanta, Ga.: ACS, 2014. 6. American Cancer Society and Livestrong. The global economic cost of cancer. http://www.cancer.org/acs/ groups/content/@internationalaffairs/documents/document/acspc-026203.pdf (accessed 14 December 2014). 7. Singh E, Underwood JM, Nattey C, et al. 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] 8. National Cancer Registry. www.nioh.co.za (accessed 15 December 2014). 9. World Health Organization. Cancer. National cancer control programmes. www.who.int/cancer/nccp/ en (accessed 15 December 2014). 10. Botha MH, van der Merwe FH, Snyman LC, Dreyer G. The Vaccine and Cervical Cancer Screen (VACCS) project: Acceptance of human papillomavirus vaccination in a school-based programme in two provinces of South Africa. S Afr Med J 2015;105(1):40-43. [http://dx.doi.org/10.7196/SAMJ.8419] 11. Department of Health. Strategic Plan 2014/15 - 2018/19. http://www.health.gov.za/docs/strategic/2013/ strategicplan.pdf (accessed 11 December 2014). 12. IARC Press Release No. 224. Global battle against cancer wonâ&#x20AC;&#x2122;t be won with treatment alone. Effective prevention measures urgently needed to prevent cancer crisis. http://www.iarc.fr/en/media-centre/ pr/2014/pdfs/pr224_E.pdf (accessed 12 December 2014).

S Afr Med J 2015;105(2):103-104. DOI:10.7196/SAMJ.9301

SASUOG

South African Society for Ultrasound in Obstetrics and Gynaecology

Congress 2015 Protea Hotel Stellenbosch Western Cape Thursday 12 March - Sunday 15 March

www.sasuog.org.za

Congress Organisers Londocor Event Management Sonja du Plessis Tel: 011 954 5753 / Fax: 011 954 6100 OR E-mail: sonja@londocor.co.za

Professor Lut Geerts Convenor

REGISTRATION IS NOW OPEN

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February 2015, Vol. 105, No. 2

EDITORIAL

Morbidity and mortality of black HIV-positive patients with end-stage kidney disease receiving chronic haemodialysis in South Africa South Africa (SA) has the highest prevalence of HIV/AIDS of any country in the world, with 6.3 million people living with HIV.[1] This high rate of infection adds complexity to a health system already overwhelmed by chronic kidney disease (CKD), particularly that caused by hypertension, diabetes and chronic glomerulonephritis. Renal disease is common in HIV-infected individuals, affecting up to 30% of patients, and is associated with increased morbidity and mortality.[2-5] In SA, the spectrum of renal disease in HIV has been accumulating from renal biopsy data.[4,6] HIV-associated nephro pathy (HIVAN)[7,8] is the most common renal biopy finding and progresses rapidly to end-stage renal disease (ESRD) if the patient does not receive antiretroviral therapy (ART).[4] Other causes of renal disease in HIV-positive patients include tubulointerstitial nephritis from tuberculosis, drugs (tenofovir, rifampicin, sulfamethoxazole plus trimethoprim, amphotericin), and acute kidney injury due to sepsis.[9] The prevalence of ESRD is projected to increase further, as there is an emerging collision of epidemics of communicable and non-communicable diseases. HIV-positive patients are living longer on ART, with a rising incidence of the diseases of lifestyle including hypertension and diabetes.[10] Black Africans, who are most affected by the HIV epidemic, also have a genetic predisposition to HIVAN. Epidemiological data confirm that African Americans in the USA are more prone to CKD than any other ethnic group.[11] The risk of ESRD has been reported to be three- to six-fold higher in African American than in Caucasian HIV-infected patients.[12] HIVAN represents a huge disease burden and is ranked as the third leading cause of ESRD among blacks aged 20 - 64 years in the USA, lagging behind diabetes and hyperten sion.[13] Fortunately, ART has reduced the incidence of HIVAN and ESRD among African Americans[14] and black South Africans.[4] Until recently, the magnitude of CKD and the number of persons accessing renal replacement therapy in SA have been poorly documented. However, SA has taken positive steps to reinstate a functional renal registry, which confirms that currently 8.5% of 4 637 chronic dialysis patients in the country are HIV-positive.[15] However, this number is underestimated owing to exclusion of a substantial number of HIV-positive patients from state sector dialysis units, because state hospitals require their patients to be transplantable in order to gain access to chronic dialysis. Given the risk of posttransplant comorbidities, it is mandatory for HIV-positive patients to have a CD4 count >200 cells/µL, to have a suppressed viral load, and to have been stable on ART for 6 months in order to be considered for most state sector chronic dialysis.[16] Patients who do not fulfil these criteria are excluded from most state units. Prior to availability of ART, HIV was a death sentence for individuals with CKD. Several studies suggested that survival rates were dismal, and owing to the poor prognosis, chronic renal replacement therapy (RRT) was rarely offered to patients.[17] This was particularly true in SA. Since introduction of ART, the overall survival of HIV-positive patients has increased dramatically. SA, which has the largest HIV treatment programme in the world and average treatment initiation rates of 30 000 per month,[1] now has a parallel need for increased access to RRT.

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Since ART roll-out there has been growing evidence of little difference in survival between HIV-infected patients who are receiving efficacious ART compared with the general population on dialysis.[17] After comparing survival between 5 299 patients who received haemodialysis and 716 who received peritoneal dialysis (PD), the United States Renal Data System has also reported that dialysis modality is not a factor in survival of patients with HIVAN (hazard ratio: peritoneal dialysis v. haemodialysis 1.04, 95% confidence interval (CI) 0.96 - 1.13).[18] However, the study was limited by the lack of information regarding CD4 counts and viral loads. In the pre-ART era, the proportion of patients with peritonitis in the HIV-infected population treated with PD was not different from that of the HIVnegative population treated with PD.[19] Gorrin et al.[20] demonstrated an increase in overall survival and a decrease in PD-associated complications compared with previous studies. In this small study of eight HIV-positive patients, cardiovascular events were the main cause of death (two patients, 25%). However, until large studies are conducted, controlling for stage of HIV infection and other comorbidities, selecting dialysis modality for HIV-infected patients should be similar to other patients with ESRD. Although the evidence is encouraging regarding RRT in HIVpositive patients, the Dialysis Outcomes and Practice Patterns Study (DOPPS)[21] concluded that HIV-positive patients are at increased risk on haemodialysis. This study pooled data among haemodialysis patients in Europe, Japan and the USA and confirmed a nearly three-fold greater mortality risk on haemodialysis among individuals with HIV infection (relative risk (RR) 2.96; p<0.0001), with most deaths during the first year of dialysis (RR 5.60; p<0.01), but once again did not distinguish between those currently receiving or not receiving ART.[21] It is well documented that transplantation is the best treatment option for CKD in patients without HIV. In spite of the cost of the operation and of immunosuppressive medication, it is also the most cost-effective treatment option. Given the high haemodialysis mortality seen in the DOPPS, should we not be striving for dialysis to be the bridge to transplantation in HIV-positive patients? Being HIV-positive was previously an absolute contraindication to renal transplantation. With the advent of ART, renal transplantation using HIV-negative donor kidneys in positive recipients has been employed successfully for HIV-infected patients with ESRD.[22] In a prospective study by Mysore et al.[23] (presented at the American Transplant Congress 2008) long-term survival was described in 132 HIV-positive patients with ESRD listed for kidney transplantation during February 2001 and December 2006. Half the cohort (65 patients) received kidney transplants and the other half (67 patients) remained on dialysis while waiting for kidney donation. The selection criteria for waiting list placement included maintenance on ART with a suppressed viral load and an absolute CD4 count of 200 cells/µL. The primary endpoint was patient death. Patient survival in the transplant v. the dialysis group at 1 year was 91% v. 89% (p=0.9) and at 5 years 80% v. 26% (p=0.000). Despite equal therapeutic suppression of HIV infection with ART and similar comorbid factors, kidney transplantation significantly prolonged 5-year patient survival in HIV-positive patients compared with dialysis in this study.

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EDITORIAL

In SA, places on state dialysis programmes are severely restricted. There are additional problems of long waiting lists for transplantation and limited consent to organ donation. HIV-infected patients, like many others with comorbidity, are often denied treatment, while kidneys from HIV-infected deceased donors are discarded.[24] Transplantation of kidneys from HIV-positive donors to positive recipients has been pioneered at Groote Schuur Hospital, Cape Town, SA, significantly increasing the pool of donor kidneys to the advantage of both HIV-positive and HIV-negative patients.[25] To date, 29 HIV-positive individuals have been transplanted with kidneys from HIV-infected cadaver donors. Preliminary data are extremely promising: 1-year patient survival is 86.36% and 3-year survival 72.73%, and graft survival is 90.91% at 1 year and 80.81% at 3 years.[26] Transplanting HIVinfected patients with kidneys from HIV-positive donors represents a significant advance in our resource-constrained environment. In this issue of the SAMJ, Fabian et al.[27] demonstrate that haemodialysis in black African HIV-positive patients in the private sector in SA imparts excellent overall survival in spite of higher hospital admission rates and higher morbidity from infection (particularly vascular access-related infections) compared with HIV-negative patients. This study contributes to the growing data reflecting good outcomes for HIV-positive patients on dialysis. However, in Fabian’s cohort a high proportion of patients had unexplained suboptimal viral suppression rates that would disqualify them as transplant recipients. In resource-restricted settings such as SA, attention needs to be geared towards prevention of CKD and slowing progression towards ESRD. HIV contributes to a high risk of CKD, and as such HIV-positive patients should be screened for CKD at their first encounter with any health service. This is particularly important in view of the fact that HIVAN can occur with high CD4 counts.[4] Screening should include urinalysis and measuring kidney function. Strategies should include fast-tracking for ART for patients manifesting renal involvement, awareness of tenofovir and sulfamethoxazole-trimethoprim toxicity, avoidance of nephrotoxic agents such as non-steroidal anti-inflammatory drugs, adequate fluid resuscitation when necessary, and efficient treatment of sepsis.[9] Patients are living longer on ART and as such are at increased risk of developing hypertension and diabetes.[10] Diseases of lifestyle may emerge as a new epidemic in the HIV-positive population. Those who provide healthcare to HIV-positive patients need to be aware of the special renal issues relevant to HIV, and the potential for evolution to ESRD, and should work actively with HIV and nephrology specialists to improve the outcome and quality of life of patients. Nicola Wearne Division of Nephrology, Department of Medicine, Groote Schuur Hospital, Cape Town, South Africa Corresponding author: N Wearne (nicola.wearne@uct.ac.za)

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1. UNAIDS. Country progress report 2012 – South Africa 2014 http://www.unaids.org/en/ regionscountries/countries/southafrica (accessed 4 October 2014). 2. Gupta SK, Mamlin BW, Johnson CS, Dollins MD, Topf JM, Dube MP. Prevalence of proteinuria and the development of chronic kidney disease in HIV-infected patients. Clin Nephrol 2004;61(1):1-6. [http:// dx.doi.org/10.5414/CNP61001] 3. Wyatt CM, Hoover DR, Shi Q, et al. Pre-existing albuminuria predicts AIDS and non-AIDS mortality in women initiating antiretroviral therapy. Antivir Ther 2011;16(4):591-596. [http://dx.doi. org/10.3851/IMP1766] 4. Wearne N, Swanepoel CR, Boulle A, Duffield MS, Rayner BL. The spectrum of renal histologies seen in HIV with outcomes, prognostic indicators and clinical correlations. Nephrol Dial Transplant 2012;27(11):4109-4118. [http://dx.doi.org/10.1093/ndt/gfr702] 5. Szczech LA, Hoover DR, Feldman JG, et al. Association between renal disease and outcomes among HIV-infected women receiving or not receiving antiretroviral therapy. Clin Infect Dis 2004;39(8):11991206. [http://dx.doi.org/10.1086/424013] 6. Gerntholtz TE, Goetsch SJ, Katz I. HIV-related nephropathy: A South African perspective. Kidney Int 2006;69(10):1885-1891. [http://dx.doi.org/10.1038/sj.ki.5000351] 7. D’Agati V, Suh JI, Carbone L, Cheng JT, Appel G. Pathology of HIV-associated nephropathy: A detailed morphologic and comparative study. Kidney Int 1989;35(6):1358-1370. [http://dx.doi.org/10.1038/ ki.1989.135] 8. Rao TK, Friedman EA. AIDS (HIV)-associated nephropathy: Does it exist? An in-depth review. Am J Nephrol 1989;9(6):441-453. [http://dx.doi.org/10.1159/000168011] 9. Swanepoel CR, Wearne N, Duffield MS, Okpechi IG. The evolution of our knowledge of HIVassociated kidney disease in Africa. Am J Kidney Dis 2012;60(4):668-678. [http://dx.doi.org/10.1053/j. ajkd.2012.04.034] 10. Kalyesubula R, Wearne N, Semitala FC, Bowa K. HIV-associated renal and genitourinary comorbidities in Africa. J Acquir Immune Defic Syndr 2014;67(Suppl 1):S68-S78. [http://dx.doi.org/10.1097/ QAI.0000000000000259] 11. United States Renal Data System 2010 Annual Data Report: Atlas of Chronic Kidney Disease & EndStage Renal Disease in the United States. Am J Kidney Dis 2011;57(1, Suppl 1):e1-e526. 12. Lucas GM, Lau B, Atta MG, Fine DM, Keruly J, Moore RD. Chronic kidney disease incidence, and progression to end-stage renal disease, in HIV-infected individuals: A tale of two races. J Infect Dis 2008;197(11):1548-1557. [http://dx.doi.org/10.1086/587994] 13. Ross MJ, Klotman PE. Recent progress in HIV-associated nephropathy. J Am Soc Nephrol 2002;13(12):2997-3004. [http://dx.doi.org/10.1097/01.ASN.0000040750.40907.99] 14. Cosgrove CJ, Abu-Alfa AK, Perazella MA. Observations on HIV-associated renal disease in the era of highly active antiretroviral therapy. Am J Med Sci 2002;323(2):102-106. [http://dx.doi. org/10.1097/00000441-200202000-00009] 15. Davids MR, Marais N, Jacobs JC. South African Renal Registry Annual Report 2012. Cape Town: South African Renal Society, 2014. 16. Swanepoel CR, Wearne N, Okpechi IG. Nephrology in Africa – not yet uhuru. Nat Rev Nephrol 2013;9(10):610-622. [http://dx.doi.org/10.1038/nrneph.2013.168] 17. Mandayam S, Ahuja TS. Dialyzing a patient with human immunodeficiency virus infection: What a nephrologist needs to know. Am J Nephrol 2004;24(5):511-521. [http://dx.doi.org/10.1159/000081041] 18. Ahuja TS, Collinge N, Grady J, Khan S. Is dialysis modality a factor in survival of patients with ESRD and HIV-associated nephropathy? Am J Kidney Dis 2003;41(5):1060-1064. [http://dx.doi.org/10.1016/ S0272-6386(03)00204-X] 19. Kimmel PL, Umana WO, Simmens SJ, Watson J, Bosch JP. Continuous ambulatory peritoneal dialysis and survival of HIV infected patients with end-stage renal disease. Kidney Int 1993;44(2):373-378. [http://dx.doi.org/10.1038/ki.1993.254] 20. Gorrin MR, Rivas JLM, Garcelán MCA, et al. Outcome of HIV-infected patients of peritoneal dialysis: Experience in a center and literature review. [Evolución de los pacientes infectados por el VIH en diálisis peritoneal: Experiencia de un centro y revisión de la literatura] Nefrología 2008;28(5):505-510. 21. Goodkin DA, Bragg-Gresham JL, Koenig KG, et al. Association of comorbid conditions and mortality in hemodialysis patients in Europe, Japan, and the United States: The Dialysis Outcomes and Practice Patterns Study (DOPPS). J Am Soc Nephrol 2003;14(12):3270-3277. [http://dx.doi.org/10.1097/01. ASN.0000100127.54107.57] 22. Stock PG, Barin B, Murphy B, et al. Outcomes of kidney transplantation in HIV-infected recipients. N Engl J Med 2010;363(21):2004-2014. [http://dx.doi.org/10.1056/NEJMoa1001197] 23. Mysore S, Anil K, Shahid M, et al. In HIV+ patients with end stage renal disease (ESRD) kidney transplantation significantly prolongs long-term patient survival compared to chronic dialysis treatment. Presented at the plenary session (1 June) at the American Transplantation Congress 2008, Toronto, Canada, 31 May - 4 June 2008. 24. Benatar SR. Health care reform and the crisis of HIV and AIDS in South Africa. N Engl J Med 2004;351(1):81-92. [http://dx.doi.org/10.1056/NEJMhpr033471] 25. Muller E, Barday Z, Mendelson M, Kahn D. Renal transplantation between HIV-positive donors and recipients justified. S Afr Med J 2012;102(6):497-498. 26. Muller M. HIV positive to positive transplantation. Presented at the World Congress of Transplantation, San Francisco, 30 July 2014. 27. Fabian J, Maher HA, Clark C, Naicker S, Becker P, Venter WDF. Morbidity and mortality of black HIVpositive patients with end-stage kidney disease receiving chronic haemodialysis in South Africa. S Afr Med J 2015;105(2):110-114. [http://dx.doi.org/10.7196/SAMJ.8369]

S Afr Med J 2015;105(2):105-106. DOI:10.7196/SAMJ.9068

February 2015, Vol. 105, No. 2

RESEARCH

South African National Cancer Registry: Effect of withheld data from private health systems on cancer incidence estimates E Singh,1,2 MMed, FCPHM; J M Underwood,3 PhD; C Nattey,2,4 MSc; C Babb,1 PhD; M Sengayi,1,5 MSc; P Kellett,1 DipMedTech ancer Epidemiology Research Group, National Cancer Registry, National Health Laboratory Service, Johannesburg, South Africa C Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa 3 Division of Cancer Prevention and Control, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, GA, USA 4 National Institute for Occupational Health, National Health Laboratory Service, Johannesburg, South Africa 5 Graduate School for Cellular and Biomedical Sciences, University of Bern, Switzerland 1 2

Corresponding author: E Singh (elvira.singh@nioh.nhls.ac.za) Background. The National Cancer Registry (NCR) was established as a pathology-based cancer reporting system. From 2005 to 2007, private health laboratories withheld cancer reports owing to concerns regarding voluntary sharing of patient data. Objectives. To estimate the impact of under-reported cancer data from private health laboratories. Methods. A linear regression analysis was conducted to project expected cancer cases for 2005 - 2007. Differences between actual and projected figures were calculated to estimate percentage under-reporting. Results. The projected NCR case total varied from 53 407 (3.8% net increase from actual cases reported) in 2005 to 54 823 (3.7% net increase) in 2007. The projected number of reported cases from private laboratories in 2005 was 26 359 (19.7% net increase from actual cases reported), 27 012 (18.8% net increase) in 2006 and 27 666 (28.4% net increase) in 2007. Conclusion. While private healthcare reporting decreased by 28% from 2005 to 2007, this represented a minimal impact on overall cancer reporting (net decrease of <4%). S Afr Med J 2015;105(2)107-109. DOI:10.7196/SAMJ.8858

The National Cancer Registry (NCR) within the National Health Laboratory Service (NHLS) is the principal cancer surveillance system in South Africa (SA) and maintains the largest repository of cancer data in the country. The NCR is mandated through recent (2011) legislation to monitor SA’s national cancer burden.[1] Established in 1986 as a voluntary, pathology-based cancer reporting system, it now receives over 100 000 cancer reports annually. Approximately 80 000 are new cases, on the basis of which cancer incidence is calculated. Data collected from the system are used for research, for educational purposes and to inform decision-making for cancer prevention and control policies in SA. Surveillance and research activities at the NCR have made a significant contribution to the scope of cancer knowledge both locally and internationally. In addition to describing the overall cancer burden in SA, the registry data have been used to highlight cancers of special interest such as skin, prostate and oral cancers.[2-4] Of importance in the SA context, the data from the Johannesburg Cancer Case Control Study (JCCCS), conducted by the research arm of the NCR, the Cancer Epidemiology Research Group (CERG), have been used to extensively describe the epidemiology of HIV-related cancers in SA and particularly to explore the relationship between Kaposi’s sarcoma and HIV.[5-11] The JCCCS has also contributed to risk factor analysis in the International Collaboration of Epidemiological Studies of Cervical Cancer, including the link between oral and injectable contraceptive use and female cancers.[12-18] The NCR manages cancer surveillance in the context of a dual health system in SA: a large public health infrastructure serving approximately 84% of the population, and a smaller private health

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system catering to 16%.[19] The NCR achieves its objectives by estimating cancer incidence rates by age, race and gender, using pathology reports received from all public and private healthcare laboratories nationally.[20] Data reporting among private systems was consistent throughout the early 2000s. However, concerns regarding voluntary sharing of patient data led some private healthcare laboratories to withhold cancer pathology reports, beginning in 2005. We undertook an analysis to measure the impact of withheld private data on cancer surveillance in SA.

Methods

NCR methodology

The NCR methodology follows that recommended by the International Agency for Research on Cancer.[21] Pathology reports are received in electronic or hard-copy format, and from these appropriate data items, namely demographic and tumour information, are abstracted. A hot-deck imputation method[22] is used to allocate population group to cases without this information. Following international practice, cancers are classified by anatomical site/topography using the International Classification of Diseases – Oncology, Version 3 (ICD-O-3).[23] Mid-year population estimates from Statistics South Africa are used as the denominator, stratified by population, gender and 5-year age groups. Analyses include crude incidence rates, agestandardised incidence rates (ASRs) using the Doll et al.[24] world population as the standard, 95% confidence intervals for the ASRs, and cumulative lifetime incidence risk (the likelihood of developing a cancer in one’s lifetime if one lives to age 74).[25] The ASR and

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RESEARCH

the lifetime incidence risk are adjusted for the proportion of cases in the unknown age category. The rate calculations represent incident cancers, excluding basal and squamous cell carcinomas of the skin.

Analysis of under-reporting

Using actual numbers of cases reported by private health laboratories for 1995 - 2004, a linear regression analysis was performed. Based on this analysis, we were able to project the expected cases for 2005, 2006 and 2007 from private laboratories. The calculated number of projected cases for each year was used to estimate the number of missed cases reported per annum from private laboratories. Differences between actual and projected figures were calculated to establish the percentage of under-reporting.

Results

In 1995, a total of 46 769 cases of cancer were reported from all laboratories (both private and public system laboratories), which increased to 52 887 cases in 2004, then decreased to 52 816 in 2007 (Fig. 1). The projected increase in cases in 2005 was 53 407 (3.8% net increase from actual cases reported), followed by 56 679 (3.5% net increase) in 2006 and 54 823 (3.7% net increase) in 2007. In 1995, a total of 19 137 cases of cancer were reported from private laboratories, which increased to 24 473 cases in 2004, then decreased to 19 803 in 2007. The projected number of reported cases of cancer in 2005 was 26 359 (19.7% net increase from actual cases reported), followed by 27 012 (18.8% net increase) in 2006 and 27 666 (28.4% net increase) in 2007.

Discussion

This is the first study to assess the impact of missing cancer cases from private healthcare

laboratories on NCR surveillance in SA. While private healthcare reporting decreased by 28% from 2005 to 2007, this represented a minimal impact on overall cancer reporting (net decrease of <4%). Despite missing data, the NCR cancer data therefore provide an accurate estimation of overall pathologydiagnosed cancer incidence in SA. This finding can be explained by healthcare use patterns, particularly the two-tiered healthcare system mentioned previously. Given that a relatively large proportion of the population accesses the public healthcare system (84%) as opposed to private healthcare facilities,[19] the bulk of cancer reports to the NCR originate in the public health system from the more than 300 laboratories operated by the NHLS. While the overall decrease in reporting may represent a small proportion, missing data may be over-represented in certain population groups. Membership in medical schemes, and therefore ability to access private healthcare, is concentrated in the wealthiest 20% of the SA population[26] and correlates with population group. More than two-thirds of white South Africans belong to a medical aid, as opposed to 8% of blacks.[27] The NCR may therefore be underreporting cancers in these groups for the specified period. Our results also reflect some underreporting or under-diagnosis of cancer among public healthcare facilities. Sixteen per cent of South Africans (all race groups) belong to a medical aid,[19] yet the private health service represents just under half of the cancer cases reported. Despite the lifestyle risk factors for cancer associated with higher socioeconomic status, one would expect more cancer cases from the public health service than the approximately 40 000 received by the NCR. The NCR receives and processes all cancer pathology

Cancer cases, n

60 000 50 000 40 000 30 000 20 000 10 000 0

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 Year

NCR projected

NCR reported

Private projected

Private reported

Fig. 1. Actual and projected case reporting from private laboratories and to the NCR, 1995 - 2007.

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reports from the public healthcare facilities. The rate of under-diagnosis and underascertainment of cancers in the SA health service must be quantified so that a more accurate illustration of the cancer burden can be provided. Several strengths and limitations are evident in this study. The NCR is the largest and most representative cancer surveillance system in SA. The registry methods are robust, with staff available to process the country’s cancer burden with a quality-assured output. Since the registry is pathology based, specific and detailed histological diagnoses are available. However, this also implies that cases without a pathology diagnosis will be missed, resulting in underestimates of cancer burden. Although publication of cancer incidences for SA is delayed, the reporting time will soon be comparable to more comprehensive international registries such as the US Centers for Disease Control’s National Program of Cancer Registries, which has a reporting time of approximately 3 years from the time a patient is diagnosed to the time national data are reported.[28] The delays in cancer reporting are attributable to a number of factors, including lack of a champion for cancer registration. The NCR was without a director from 2002 to 2009, which led to leadership inconsistencies and high staff turnover. During this time, competing health priorities such as HIV prevention and control emerged as the public health priority in SA. As a result, the NCR did not receive the same level of resources for cancer surveillance as in the past, which impacted negatively on cancer reporting and data analysis. However, with the appointment of the new management in 2009 and promulgation of new legislation in 2011, there have been significant gains in efficiency. The NCR has established electronic receipt of pathology data from public sector laboratories, thereby ensuring a more timely acquisition of morbidity information. Relationships with private sector laboratories have been renewed, and a standard system has been established to receive private sector pathology data electronically. Promulgation of Regulation 380 of the National Health Act[1] by the Department of Health in 2011 marked a milestone in cancer care and control by formally establishing the NCR as the main cancer surveillance agency and requiring mandatory reporting of all confirmed cancers in SA to the NCR. The legislation ensured that cancer reporting to the NCR was no longer voluntary and precluded the drop-off of reporting that has occurred in the past.

RESEARCH

Regulation 380 also allows the NCR to implement population-based cancer registration in selected surveillance sites. In response to the legislation, the NCR has developed a 10-year business plan for the implementation of the population-based registries for the country, as well as tackling the pathology-based registry backlog. Fund-raising activities have commenced, and a pilot population-based registry is operational in Ekurhuleni District, Gauteng Province. Populationand pathology-based cancer registration complemented by novel research from the NCR’s CERG will provide a comprehensive description of the cancer burden across SA. In an era of growing prioritisation of non-communicable dis eases, and with global cancer burdens estimated to increase signi ficantly,[29] the NCR has an invaluable role to play in the health and health planning landscape of SA. In view of the progressive health developments in the country, such as introduction of National Health Insurance,[5] there is an imperative to accurately quantify the cancer burden, and thus the cost of cancer services to be provided to the SA population.

Conclusion

The withholding of private laboratory cancer data from 2005 to 2007 resulted in a 4% decrease in overall cancer reporting to SA’s NCR, despite a relatively larger amount (28%) of under-reporting of private healthcare cancers. This probably reflects the reality that four out of every five SA citizens receive care in the public healthcare system. This analysis does not address undiagnosed cancer cases in the public health system, an issue that requires further investigation. The NCR is an invaluable source of cancer data for the country. Recent parliamentary legislation, investment in the NCR and improved access to quality healthcare will allow the NCR to remain SA’s leading resource for national cancer data. Authorship. All authors have read and approved the manuscript, and there are no financial disclosures, conflicts of interests and/or acknowledgements necessary. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. References 1. National Department of Health. National Health Act (Act No. 61 of 2003): Regulations Relating to Cancer Registration. No. R 380. Republic of South Africa, 2011. http://www.nioh.ac.za/assets/files/ Gazetted%20Version%2026_4_2011%20(2).pdf (accessed 12 January 2015). 2. Norval M, Kellett P, Wright CY. The incidence and body site of skin cancer in the population groups of South Africa. Photodermatol Photoimmunol Photomed 2014;30(5):262-265. [http://dx.doi.org/10.1111/phpp.12106] 3. Abram MH, van Heerden WFP, Rheeder P, Birdler-Brown BV, van Zyl W. Epidemiology of oral squamous cell carcinoma. SADJ 2012;67(10):550-553. 4. Babb C, Urban M, Kielkowski D, Kellett P. Prostate cancer in South Africa: Pathology based National Cancer Registry data (1986-2006) and mortality rates (1997-2009). Prostate Cancer 2014;2014, Article ID 419801. [http://dx.doi.org/10.1155/2014/419801] 5. Sitas F, Pacella-Norman R, Carrara H, et al. The spectrum of HIV-1 related cancers in South Africa. Int J Cancer 2000;88(3):489-492. [http://dx.doi.org/10.1002/1097-0215(20001101)88:3<489::AIDIJC25>3.0.CO;2-Q]

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6. Stein L, Urban MI, O’Connell D, et al. The spectrum of human immunodeficiency virus-associated cancers in a South African black population: Results from a case-control study, 1995-2004. Int J Cancer 2008;122(10):2260-2265. [http://dx.doi.org/10.1002/ijc.23391] 7. Sitas F, Newton R. Kaposi’s sarcoma in South Africa. J Natl Cancer Inst Monogr 2000;2000(28):1-4. [http://dx.doi.org/10.1093/oxfordjournals.jncimonographs.a024250] 8. Sitas F, Bezwoda WR, Levin V, et al. Association between human immunodeficiency virus type 1 infection and cancer in the black population of Johannesburg and Soweto, South Africa. Br J Cancer 1997;75(11):1704-1707. [http://dx.doi.org/10.1038/bjc.1997.290] 9. International Collaboration on HIV and Cancer. Highly active retroviral therapy and incidence of cancer in human immunodeficiency virus-infected adults. J Natl Cancer Inst 2000;92(22):1823-1830. [http://dx.doi.org/10.1093/jnci/92.22.1823] 10. Weiss RA, Sitas F. Kaposi’s sarcoma in AIDS. J Registry Manage 2001;28(2):93-96. 11. Beral V, Newton R, Sitas F. Human herpesvirus 8 and cancer. J Natl Cancer Inst 1999;91(17):14401441. [http://dx.doi.org/10.1093/jnci/91.17.1440] 12. Plummer M, Peto J, Franceschi S for International Collaboration of Epidemiological Studies of Cervical Cancer (incl. Urban MI). Time since first sexual intercourse and the risk of cervical cancer. Int J Cancer 2012;130(11):2638-2644. [http://dx.doi.org/10.1002/ijc.26250] 13. Plummer M, Peto J, Franceschi S for International Collaboration of Epidemiological Studies of Cervical Cancer (incl. Urban MI). Cervical carcinoma and sexual behaviour: Collaborative reanalysis of individual data on 15,461 women with cervical carcinoma and 29,164 women without cervical carcinoma from 21 epidemiological studies. Cancer Epidemiol Biomarkers Prev 2009;18(4):10601069. [http://dx.doi.org/10.1158/1055-9965.EPI-08-1186] 14. Plummer M, Peto J, Franceschi S for International Collaboration of Epidemiological Studies of Cervical Cancer (incl. Urban MI). Cervical cancer and hormonal contraceptives: Collaborative reanalysis of individual data for 16,573 women with cervical cancer and 35,509 women without cervical cancer from 24 epidemiological studies. Lancet 2007;370(9599):1609-1621. [http://dx.doi.org/10.1016/S01406736(07)61684-5] 15. Plummer M, Peto J, Franceschi S for International Collaboration of Epidemiological Studies of Cervical Cancer (incl. Urban MI). Cervical carcinoma and reproductive factors: Collaborative reanalysis of individual data on 16,563 women with cervical carcinoma and 33,542 women without cervical carcinoma from 25 epidemiological studies. Int J Cancer 2006;119(5):1108-1124. [http:// dx.doi.org/10.1002/ijc.21953] 16. Plummer M, Peto J, Franceschi S for International Collaboration of Epidemiological Studies of Cervical Cancer (incl. Urban MI). Carcinoma of the cervix and tobacco smoking: Collaborative reanalysis of individual data on 13 541 women with carcinoma of the cervix and 23 017 woman without carcinoma of the cervix from 23 epidemiological studies. Int J Cancer 2006;118(6):1481-1495. [http://dx.doi.org/10.1002/ijc.21493] 17. Plummer M, Peto J, Franceschi S for International Collaboration of Epidemiological Studies of Cervical Cancer (incl. Urban MI). Comparison of risk factors for invasive squamous cell carcinoma and adenocarcinoma of the cervix: Collaborative reanalysis of individual data on 8,097 women with squamous cell carcinoma and 1,374 women with adenocarcinoma from 12 epidemiological studies. Int J Cancer 2006;120(4):885-891. [http://dx.doi.org/ 10.1002/ijc.22357] 18. Urban M, Banks E, Egger S, Canfell K, O’Connell D, Beral V, Sitas F. Injectable and oral contraceptive use and cancers of the breast, cervix, ovary, and endometrium in black South African women: Cancer case-control. PLoS Med 2012;9(3):e1001182. [http://dx.doi.org/10.1371/journal.pmed.1001182] 19. Green Paper: National Health Insurance in South Africa. A Policy Paper. National Department of Health, Republic of South Africa. http://www.hst.org.za/publications/green-paper-national-healthinsurance-south-africa (accessed 25 April 2014). 20. Cancer in South Africa Full Reports: 2000 - 2007. www.ncr.ac.za (accessed 9 July 2014). 21. National Health Laboratory Service. National Cancer Registry Methodology. 2006. www.nioh.ac.za/ assets/files/NCR_methodology.pdf (accessed 1 July 2014). 22. Little RJA, Rubin DB. The analysis of social science data with missing values. In: Fox J, Long JS, eds. Modern Methods of Data Analysis. London: Sage Publications, 1990. 23. Fritz A, Percy C, Jack A, Kanagaratnam S, Sobin L, Parkin DM et al., eds. International Classification of Diseases for Oncology. 3rd ed. Geneva: World Health Organization, 2000. 24. Doll R, Payne PM, Waterhouse JAH. Cancer Incidence in Five Countries. International Union Against Cancer. Berlin: Springer-Verlag, 1966. [http://dx.doi.org/10.1007/978-3-642-85849-9] 25. Jensen OM, Parkin DM, Maclennan R, Muir CS, Skeet RG, eds. Cancer Registration: Principles and Methods. IARC Scientific Publications No. 95. Lyon: International Agency for Research on Cancer, 1991. [http://dx.doi.org/10.1038/bjc.1991.142] 26. McIntyre D. Private Sector Involvement in Funding and Providing Health Services in South Africa: Implications for Equity and Access to Health Care. EQUINET Discussion Paper Series 84. Health Economics Unit, University of Cape Town; ISER, Rhodes University, Grahamstown, Eastern Cape; EQUINET, Harare, 2010. 27. Statistics South Africa. General Household Survey 2011. Statistical Release P0318. www.statsa.gov.za (accessed 25 June 2014). 28. US Cancer Statistics Working Group. United States Cancer Statistics: 1999-2010. Incidence and Mortality Web-based Report. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention and National Cancer Institute, 2013. www.cdc.gov/uscs (accessed 9 July 2014). 29. Bray F, Jemal A, Grey N, Ferlay J, Forman D. Global cancer transitions according to the Human Development Index (2008-2030): A population-based study. Lancet Oncology 2012;13(8):790-801. [http://dx.doi.org/10.1016/S1470-2045(12)70211-5]

Accepted 4 September 2014.

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Morbidity and mortality of black HIV-positive patients with end-stage kidney disease receiving chronic haemodialysis in South Africa J Fabian,1,2 MD, MMed; H A Maher,1 Registered Nurse; C Clark,3 MTech Clinical Technology, BSc, PhD; S Naicker,2 MD, PhD; P Becker,4 PhD; W D F Venter,2,5 MD, MMed its Donald Gordon Medical Centre, Parktown, Johannesburg, South Africa W Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa 3 National Renal Care, South Africa 4 Biostatistics Unit, South African Medical Research Council, Tshwane, South Africa 5 Wits Reproductive Health and HIV Institute, Johannesburg, South Africa 1 2

Corresponding author: J Fabian (june.fabian@mweb.co.za)

Introduction. There are few published data from South Africa (SA) on the outcomes of black HIV-positive patients receiving chronic haemodialysis. Methods. This retrospective study compared the incidences of vascular and infectious morbidity and mortality in black HIV-positive patients with those in a group of HIV-negative patients matched for ethnicity, age and gender. All the patients were receiving chronic haemodialysis in the medically insured healthcare sector of SA. Results. The incidence of tuberculosis and hospital admission rates for vascular access-related infections were significantly higher in the HIV-positive group than the HIV-negative group. The HIV-positive group had significantly lower albumin (p<0.05) and haemoglobin levels (p<0.01), but this did not impact on mortality. Survival in both groups was excellent. In the HIV-positive group, viral suppression rates were suboptimal with <50% of patients on antiretroviral therapy completely virally suppressed. Conclusion. This study has shown that black HIV-positive patients receiving chronic haemodialysis in a healthcare-funded environment in SA have excellent overall survival in spite of higher hospital admission rates and higher infectious morbidity compared with HIV-negative patients. S Afr Med J 2015;105(2):110-114. DOI:10.7196/SAMJ.8369

Outcomes of HIV-positive patients with end-stage kidney disease (ESKD) in the era prior to antiretroviral therapy (ART) were dismal.[1] In the USA before 1995, when ART was not freely available, median survival of HIV-positive patients on chronic haemodialysis ranged from 1.4 to 12 months.[2] After 1995, as access to effective ART improved, studies began to show progressive improvements in survival in HIV-positive patients receiving chronic haemodialysis, but survival was still significantly lower than in their HIV-negative counterparts.[3,4] In 2006, French researchers showed that the 2-year survival of HIVpositive patients on haemodialysis with access to ART was comparable (89%) to a cohort of HIV-negative patients.[5] Survival rates of black HIV-positive patients with ESKD in sub-Saharan Africa are unknown. ART became freely available in the state health sector in South Africa (SA) in 2004, with access expanding dramatically so that over 2 million people were on ART by 2013.[6,7] Before 2008, it was standard policy in SA public sector hospitals to exclude HIV-positive patients from access to chronic dialysis. In 2008, this policy was reviewed. The SA renal and transplant societies jointly acknowledged that HIV-positive patients could not be excluded on the basis of their HIV status alone, and the guidelines were revised.[8] Unfortunately the majority of patients with ESKD in the public healthcare system, including HIV-positive patients, have extremely limited access to chronic dialysis because of limited resources, whereas those with medical health insurance have unrestricted access.[9,10] There are no published data from SA on the outcomes of either of these groups of patients. This study was conducted to assess the outcomes of black HIV-positive individuals with ESKD on chronic haemodialysis, who have access to medical health insurance in SA.

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Methods

This study was a national, retrospective cohort study. Approval was obtained from the Human Research Ethics Committee of the University of the Witwatersrand, approval No. M101120. National Renal Care (NRC) was the dialysis service provider for all the chronic haemodialysis centres that participated in the study. Adult HIV-positive patients over the age of 18 who had started chronic haemodialysis between 1 January 2006 and 31 October 2010 and had continued for at least 6 months were eligible for inclusion in the study. Informed consent was obtained from 48 of the HIV-positive patients (consent rate 24.5%). The date of the first dialysis session in the chronic dialysis unit was taken as commencement of the first year of dialysis, and each subsequent year on dialysis was defined from this point. Before commencement of the study, staff in the dialysis centres were trained by two of the authors on how to obtain informed consent in accordance with Good Clinical Practice guidelines.[11] Only those who had completed the training were eligible to obtain informed consent and were delegated by one of the authors to do so. Both HIV-positive and HIV-negative patients were asked to participate in the study. They were supplied with a patient information leaflet, and written informed consent was obtained from those who agreed to participate. All patients who were HIV-positive and gave consent were included in the study. Participants with incorrectly completed consent forms were excluded. A group of HIV-negative patients who had given consent were then selected as matching controls in a 2:1 ratio. Dialysis prescriptions were individualised with respect to size of the dialysis membrane, blood flow rate and pump speed and reviewed as needed by the attending doctor, based upon the condition of the patient and his/her blood results. All patients received haemodialysis three times a week for

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4 hours. Polysulfone haemodialysis membranes were used in all dialysis centres, and there was no re-use policy regarding membranes. The following data were routinely collected on all patients: demographics (access to running water was defined as access within the proximity of the house/dwelling), medical history, blood tests performed at various intervals as standard of care, and medical information regarding acute/emergency hospital admissions. The following blood tests were done: corrected serum calcium (mmol/L), serum phosphate (mmol/L), haemoglobin (g/dL), serum ferritin (µg/L), serum albumin (g/L); and KT/V (K (urea clearance of dialyser (ml/min)) × T (dialysis time in minutes) ÷ V (volume (ml)), calculated as a measure of dialysis adequacy). Values for each year the patients were on the study were collected and an average was calculated per year of follow-up. Vascular access and transplant listing was defined at a single point in time, 31 October 2010. The prevalence of HIV infection (positive ELISA), chronic hepatitis B infection (hepatitis B surface antigen positivity for >6 months), hepatitis C infection (hepatitis C antibodies), and the total number of patients receiving chronic haemodialysis with NRC were defined at a single point in time, 31 October 2010. For the HIV-positive group, CD4 counts (cells/µl) were recorded per year of follow-up, and in the case of more than one value an annual average was calculated; the log HIV viral load (copies/ml) was determined using a single value as close as possible to the single point in time, 31 October 2010. Medication regimens were obtained from patient records in the dialysis units, from the NRC database, and in some cases from the attending doctors’ patient files. With regard to each hospital admission, the following data were collected (where appropriate): date of admission, date of discharge, and reason for admission (as determined by the admitting doctor);

number of hospital admissions for the current year; date of infection and site of infection; date on which the dialysis access was created or removed; and how many previous dialysis access-related events the patient had. In the case of laboratory testing, the respective laboratories were accessed for information where necessary, e.g. for histology and tuberculosis (TB) culture results. A positive diagnosis of TB was determined via either a clinical diagnosis with confirmatory laboratory results (histology, culture) or commencement of empiric anti-TB treatment based on the patient’s clinical presentation. Hypertension was defined as a diagnosis of hypertension by the attending doctor or evidence from patient records that the patient was receiving antihypertensive treatment. Coronary artery disease was defined by the need for admission and included a diagnosis of either unstable angina or acute myocardial infarction from the attending doctor. Cerebrovascular events were defined by the need for admission and a diagnosis of a stroke (either thrombotic or haemorrhagic) or a reversible ischaemic neurological event as determined by the attending doctor. Average duration of follow-up was calculated by taking the total months on chronic dialysis of all patients and dividing this by the total number of patients. Incidence rate ratios were calculated by dividing the incidence in HIV-positive patients by the incidence in HIV-negative patients. ‘Patient-days’ were calculated by dividing the total number of days that patients were admitted during the period of follow-up divided by the number of patients in each group. Statistical analysis was performed using the statistical package Stata 11 Data Analysis and Statistical Software. Descriptive statistical analysis was performed, as well as linear regression analysis comparing differences between the HIV-positive and HIV-negative groups, for each year on dialysis, over the 5-year study period.

Table 1. Demographics and comorbidity of the HIV-positive and HIV-negative patient groups Parameter

HIV-positive (N=48)

HIV-negative (N=96)

p-value

Follow-up (months), mean (95% CI for mean)

30.6 (25.4 - 35.9)

30.6 (26.8 - 34.5)

0.71

Age (years), mean (95% CI for mean)

43.4 (40.6 - 46.2)

45.1 (43.1 - 47.1)

0.82

Female gender, n (%)

20 (41.7)

39 (40.6)

0.84

Black

47 (97.9)

81 (84.4)

0.03

Mixed

1 (2.1)

11 (11.5)

Ethnicity, n (%)

4 (4.1)

0.15

Housing, n (%)

Asian 45 (93.8)

94 (97.9)

0.47

Members per household, mean (95% CI for mean)

3.9 (3.41 - 4.33)

4.2 (3.82 - 4.52)

0.53

Access to running water, n (%)

41 (85.4)

84 (87.5)

0.98

Employed, n (%)

35 (72.9)

61 (63.5)

0.50

Diabetes mellitus (prevalence), n (%)

9 (18.8)

18 (18.8)

0.60

Hypertension (prevalence), n (%)

33 (68.8)

82 (85.4)

0.09

Arteriovenous fistula

30 (62.5)

58 (60.4)

0.32 (df = 2)

Arteriovenous graft

1 (2.1)

7 (7.3)

Vascular access, n (%)

Tunnelled catheter

13 (27.1)

19 (19.8)

Unknown

4 (8.3)

12 (12.5)

2/48 (4.2)

18/96 (18.8)

On transplant wait list, n/N (%)

Continuous variables were compared using the unpaired t-test and categorical variables using the χ2 test. df = degrees of freedom.

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Results

A total of 2 010 patients received chronic haemodialysis nationally with NRC during the study period. Prevalence rates for infections were as follows: HIV 9.75% (196/2 010), hepatitis C 0.95% (19/2 010) and hepatitis B 1.59% (32/2 010). Comorbidity and demographic comparators between HIV-positive and HIV-negative patients are set out in Table 1. The two groups were well matched, apart from a significantly higher proportion of black patients in the HIV-positive group. Significantly fewer HIV-positive than HIVnegative patients were wait-listed for kidney transplantation. Incident disease while on the study is summarised in Table 2. The total number of patient days admitted, independent of cause for admission, was significantly higher for the HIV-positive group. Vascular access rates and accessrelated admission rates with respect to arteriovenous fistula, arteriovenous graft and tunnelled catheter were similar in both groups, but the number of access-related infections that required hospital admission was statistically higher in the HIV-positive group. The incidence of treated TB infection was also significantly higher in the HIVpositive group. In the HIV-positive group, log HIV viral suppression rates and mean CD4 counts per year of follow-up are set out in Table 3. The mean duration of ART was 30.1 months (n=31) (95% confidence interval (CI) for the mean 23.7 - 36.5). No data regarding ART exposure were available in 14/48 (29.2%) patients, and 3/48 (6.3%) were not on ART. In those documented on ART, 19/37 (51.4%) were not virally suppressed using log <2.0 as a cut-off. Linear regression analysis showed that average haemoglobin levels (p<0.01) and serum albumin levels (p<0.05) were statistically significantly lower in the HIV-positive group for the duration of follow-up, although the average serum albumin level in the HIVpositive group was nevertheless higher than 30 g/L. There was no statistical difference between the groups for serum ferritin, calcium, phosphate and KT/V values (Table 4). Survival during follow-up in the two groups was comparable at 100% for HIV-positive and 99% for HIV-negative patients. One patient died and one received a kidney transplant.

Discussion

In this study, survival of medically insured black HIV-positive patients receiving chronic haemodialysis in SA was excellent, in spite of longer durations of hospital stay and higher infectious morbidity. Infectious morbidity was associated with

Table 2. Incident disease during follow-up in HIV-positive and HIV-negative patient groups Parameter

HIV-positive (N=48)

Cerebrovascular accident

0/123 person-years

Incidence rate Coronary artery disease

p-value

4/238 person-years

0.15

1.7:100 0/123 person-years

Incidence rate Tuberculosis

HIV-negative (N=96)

7/238 person-years

0.06

2.9:100 9/123 person-years

2/238 person-years

Incidence rate

7.3:100

0.8:100

Incidence rate ratio

8.7

0.001

Comparison done using Fisher’s exact test.

Table 3. HIV viral suppression and mean CD4 counts during follow-up Log HIV viral load

HIV-positive patients on ART (N=37) n (%)

<2.0

18 (48.6)

2.1 - 3.0

4 (10.8)

3.1 - 4.0

5 (13.5)

4.1 - 5.0

8 (21.6)

>5.0

2 (5.5)

Year of follow-up

Mean CD4 count (cells/µl)*

95% CI for mean

1 (n=29)

293

207 - 378

2 (n=23)

335

246 - 423

3 (n=19)

306

202 - 409

4 (n=13)

309

200 - 416

5 (n=8)

320

134 - 505

*One-way analysis of variance p=0.27 (no significant difference between CD4 counts and year of follow-up).

higher hospital admission rates for vascular access-related infections, higher incidence rates for TB and inadequate HIV viral load suppression in those on ART. Limitations of this study include the small sample size, inability to match the HIV-positive and negative groups perfectly with respect to ethnicity, and restriction of participants to a healthcarefunded environment. These factors limit generalisation of the findings and do not accurately reflect the socioeconomic circumstances of the general population in SA. The consent rates for HIV-positive participants were unexpectedly low. It was thought that training staff to obtain consent would increase the recruitment rate, but these staff disclosed that they felt uncomfortable asking HIV-positive patients to participate and believed that a high patient load compromised their capacity for research-related activity. Survival in the HIV-positive group was excellent. To date, the only other data available in SA on survival of black HIVpositive patients receiving chronic dialysis are from a study conducted in the state-funded

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Helen Joseph Hospital in Johannesburg. [12] In this study, 59 HIV-positive patients received chronic dialysis from 2001 to 2012, and although the demographics with respect to age, gender, ethnicity and mean follow-up were similar to those in the current study, mortality was much higher at 51% (30/59). [12] Potential reasons for this discrepancy are probably multifactorial and may be related to a lower median CD4 count of 231 cells/µl and higher prevalences of co-infection with hepatitis B at 22% (13/59) and hepatitis C at 5% (3/59), making the relative frequencies 14 and five times more common, respectively, in the Helen Joseph study than in the current study. A further explanation for the discrepant survival was the choice of chronic renal replacement therapy – in our study only HIVpositive patients on chronic haemodialysis were recruited, while in the Helen Joseph cohort chronic ambulatory peritoneal dialysis (CAPD) was the predominant mode of dialysis (63% (37/59)). Sixty-three per cent of deaths occurred in the CAPD group, the most common causes of death being fluid overload (38%) and peritonitis (31%), which are potentially preventable and easily treated.

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Table 4. Summary data for blood indices on all patients HIV-negative mean (SD)

HIV-positive mean (SD)

p-value

1.23 (0.27)

1.21 (0.29)

0.079

1.33 (0.29)

1.16 (0.26)

1.21 (0.23)

1.16 (0.25)

1.31 (0.42)

1.22 (0.35)

1.33 (0.31)

1.27 (0.21)

586 (711)

699 (917)

667 (841)

644 (723)

700 (1 063)

748 (660)

962 (1 499)

931 (1 068)

769 (1 065)

946 (928)

10.3 (14)

9.4 (12)

11.0 (16)

10.3 (15)

11.0 (26)

10.3 (14)

10.3 (29)

10.4 (13)

10.6 (25)

9.5 (15)

34.8 (4.7)

32.5 (5.7)

35.8 (4.1)

33.6 (5.8)

36.4 (4.1)

35.1 (6.1)

36.6 (4.0)

35.2 (6.5)

36.3 (4.2)

35.4 (5.4)

Parameter/year of follow-up KT/V

Serum ferritin (µg/L) 0.497

Serum haemoglobin (g/dL)

Serum albumin (g/L)

<0.001

0.015

Serum calcium (mmol/L)

0.462

2.2 (0.19)

2.26 (0.25)

2.18 (0.25)

2.19 (0.22)

2.21 (0.20)

2.16 (0.21)

2.16 (0.29)

2.12 (0.20)

2.21 (0.25)

2.21 (0.15)

1.58 (0.47)

1.55 (0.47)

1.52 (0.40)

1.60 (0.58)

1.64 (0.41)

1.64 (0.54)

1.59 (0.39)

1.52 (0.52)

3.12 (6.8)

1.56 (0.40)

Serum phosphate (mmol/L)

0.98

These deaths may reflect a combination of lower socioeconomic status and poor access to healthcare facilities when acutely ill. Our survival rate for HIV-positive patients on chronic haemodialysis is better than international figures. In the international literature, survival of HIV-positive patients receiving chronic haemodialysis in various cohorts in the USA ranged from 74% at 1 year to 30% at 2 years.[2,4] In Europe, 1- and 2-year survival rates were 93.8% and 89.4%,

respectively, with the strongest predictors of survival being CD4 counts >200 cells/µl and serum albumin >30 g/L,[2,5] which are comparable to the CD4 counts and serum albumin levels in the patients in our study. Our HIV-positive patients did have increased rates of infection. TB was the most common opportunistic pathogen in the HIV-positive group, and this was also seen in the study at Helen Joseph Hospital.[12] There are very few data regarding susceptibility to TB in HIV-

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positive dialysis patients.[13,14] HIV status alone, independent of chronic dialysis, can explain the increased predilection to inci dent TB and has been well described.[15] This study confirmed a much higher relative risk of incident TB in HIV-positive patients (incidence rate ratio 8.7), even with relatively well-preserved CD4 counts and good socio economic circumstances. HIV-positive patients were admitted more frequently for vascular access-related infections than HIV-negative patients. There are conflicting reports on the impact of HIV on vascular access infection rates in HIV. [16] Some studies have shown no differences between HIV-positive and HIV-negative patients, while others have shown that vascular access-related infections were more prevalent in those with lower CD4 counts, hepatitis B antigenaemia and injecting drug use.[17,18] The results of our study are different to these findings, as there were increased rates of admission for access-related infection in the HIV-positive group in spite of relatively well-preserved CD4 counts and low levels of hepatitis B antigenaemia. The impact of injecting drug use in our setting is unknown. The USA has the third highest prevalence of injecting drug use in the world (0.96%), and an associated HIV prevalence among injectors of 16%.[19] A study in 2012 showed that there were 67 000 injecting drug users in SA. This translates to a population prevalence of 0.13%, which is approximately seven times less frequent than that in the USA. The HIV prevalence in this group was 19.4%.[20,21] There are no data from SA on injecting drug use in chronic dialysis populations, but based on the national prevalence rates it is possible to infer that the prevalence in dialysis units is low, and the impact of injecting drug use on outcomes in this patient group would be minimal. An unexpected finding was the treatment response in the HIV-positive patients on ART. The HIV viral load was incompletely suppressed in 51% of participants on treatment. Regular testing of CD4 counts and HIV viral loads after initiation of ART was not standardised and data were scanty. Poor HIV viral suppression with chronic dialysis has been documented, with rates of complete HIV suppression ranging from 44% to 88%. This has been correlated with higher mortality.[12,22-24] Reasons for incomplete HIV viral suppression have been ascribed to inexperience with HIV treatment and poor prescribing practices by nephrologists, with both under- and over-prescription of ART, and infrequent consultation and follow-up with an infectious diseases specialist.[24] These factors must be

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considered as possible explanations in this study, as many nephrolo gists initiate and continue ART without input from an infectious diseases specialist in the medically insured setting. The impact of suboptimal practice may adversely affect the outcomes of this group of HIV patients, not only with respect to mortality but also eligibility for kidney transplantation. Although poorer outcomes were not reflected in this study, the effect may have been masked by small numbers. These preliminary findings deserve further scientific exploration in future studies and in the development of clinical practice guidelines for nephrologists who care for HIV patients in SA.

Conclusion

Black HIV-positive patients on chronic haemodialysis in a healthcare-funded environment in SA had excellent survival rates that were comparable with those in their HIV-negative counterparts despite suboptimal HIV viral suppression, lower serum albumin and haemoglobin levels, and a higher incidence of TB and vascular access-related infections that required hospital admission. Sources of support. Unrestricted research grants from NRC, SA, and Roche, SA. WDFV is supported by PEPFAR. Acknowledgements. The authors thank all those who supported the project: NRC senior management, the staff and patients in the NRC chronic dialysis units, and the doctors in the NRC units who facilitated access to patients and assisted with clinical information on patients who participated in the study. Conflict of interest. The results presented in this article have not been published previously in whole or in part, except in abstract format. References 1. Ortiz C, Meneses R, Jaffe D, Fernandez JA, Perez G, Bourgoignie JJ. Outcome of patients with human immunodeficiency virus on maintenance hemodialysis. Kidney Int 1988;34(2):248-253. [http://dx.doi. org/10.1038/ki.1988.172] 2. Rodriguez RA, Mendelson M, O’Hare AM, Hsu LC, Schoenfeld P. Determinants of survival among HIVinfected chronic dialysis patients. J Am Soc Nephrol 2003;14(5):1307-1313. [http://dx.doi.org/10.1097/01. ASN.0000062963.56513.28]

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3. Perinbasekar S, Brod-Miller C, Pal S, Mattana J. Predictors of survival in HIV-infected patients on hemodialysis. Am J Nephrol 1996;16(4):280-286. [http://dx.doi.org/10.1097/01] 4. Ahuja TS, Grady J, Khan S. Changing trends in the survival of dialysis patients with human immunodeficiency virus in the United States. J Am Soc Nephrol 2002;13(7):1889-1893. [http://dx.doi.org/10.1097/01] 5. Tourret J, Tostivint I, du Montcel ST, et al. Outcome and prognosis factors in HIV-infected hemodialysis patients. Clin J Am Soc Nephrol 2006;1(6):1241-1247. [http://dx.doi.org/0.2215/CJN. 02211205] 6. Pillay Y. Launch of the 2013 WHO Consolidated ARV Guidelines: What’s the evidence? Presented at the 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention, Kuala Lumpur, Malaysia, 30 June - 3 July 2013. 7. South African National Department of Health. National Antiretroviral Treatment Guidelines. 1st ed. South Africa: Jacana, 2004. 8. South African Renal Society, SATS, Southern African HIV Clinicians Society. Guidelines for renal replacement therapy in HIV-infected individuals in South Africa. Southern African Journal of HIV Medicine 2008;Autumn:34-42. 9. ProPublica. Life and death choices as South Africans ration dialysis care. 15 December 2010. www.propublica. org/article/dialysis-south-africa (accessed 28 October 2011). 10. Moosa MR, Kidd M. The dangers of rationing dialysis treatment: The dilemma facing a developing country. Kidney Int 2006;70(6):1107-1114. [http://dx.doi.org/10.1038/sj.ki.5001798] 11. South African National Department of Health. Guidelines for Good Practice in the Conduct of Clinical Trials with Human Participants in South Africa. 2nd ed. Pretoria: Department of Health, 2006. 12. Zako F, Wambugu B, Radev M, Naicker S. Outcomes of chronic dialysis in HIV-infected patients. Presented at the ISN World Congress of Nephrology, Hong Kong, 31 May - 4 June 2013. 13. Dobler CC, McDonald SP, Marks GB. Risk of tuberculosis in dialysis patients: A nationwide cohort study. PloS One 2011;6(12):e29563. [http://dx.doi.org/10.1371/journal.pone.0029563] 14. Hussein M, Mooij J, Roujouleh H. Tuberculosis in hemodialysis patients. Saudi J Kidney Dis Transpl 1996;7(1):6-9. 15. Lawn SD, Myer L, Bekker LG, Wood R. Burden of tuberculosis in an antiretroviral treatment programme in sub-Saharan Africa: Impact on treatment outcomes and implications for tuberculosis control. AIDS 2006;20(12):1605-1612. 16. Castro CE, Madariaga MG. Vascular access-related infections in HIV patients undergoing hemodialysis: Case description and literature review. Braz J Infect Dis 2008;12(6):531-535. [http://dx.doi.org/10.1590/ S1413-86702008000600017] 17. Mitchell D, Krishnasami Z, Allon M. Catheter-related bacteraemia in haemodialysis patients with HIV infection. Nephrol Dial Transplant 2006;21(11):3185-3188. [http://dx.doi.org/10.1093/ndt/gfl425] 18. Mokrzycki MH, Schroppel B, von Gersdorff G, Rush H, Zdunek MP, Feingold R. Tunneled-cuffed catheter associated infections in hemodialysis patients who are seropositive for the human immunodeficiency virus. J Am Soc Nephrol 2000;11(11):2122-2127. 19. Mathers BM, Degenhardt L, Phillips B, et al. Global epidemiology of injecting drug use and HIV among people who inject drugs: A systematic review. Lancet 2008;372(9651):1733-1745. [http://dx.doi.org/10.1016/ S0140-6736(08)61311-2] 20. Petersen Z, Pluddeman A, van Hout MC, et al. Availability of HIV prevention and treatment services for people who inject drugs: Findings from 21 countries. Harm Reduct J 2013;10(13). [http://dx.doi. org/10.1186/1477-7517-10-13] 21. Statistics SA. 2012. www.statssa.gov.za/publications/SAStatistics/SAStatistics2012pdf (accessed 25 May 2013). 22. Trullas JC, Barril G, Cofan F, et al. Prevalence and clinical characteristics of HIV type 1-infected patients receiving dialysis in Spain: Results of a Spanish survey in 2006: GESIDA 48/05 study. AIDS Res Hum Retroviruses 2008;24(10):1229-1235. 23. Trullas JC, Mocroft A, Cofan F, et al. Dialysis and renal transplantation in HIV-infected patients: A European survey. J Acquir Immune Defic Syndr 2010;55(5):582-589. [http://dx.doi.org/10.1097/ QAI.0b013e3181efbe59] 24. Tourret J, Tostivint I, Tezenas du Montcel S, et al. Antiretroviral drug dosing errors in HIV-infected patients undergoing hemodialysis. Clin Infect Dis 2007;45(6):779-784. [http://dx.doi.org/10.1086/521168]

Accepted 16 July 2014.

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The Vaccine and Cervical Cancer Screen (VACCS) project: Linking cervical cancer screening to HPV vaccination in the South-West District of Tshwane, Gauteng, South Africa L C Snyman,1 MB ChB, MPraxMed, MMed (O&G), FCOG (SA); G Dreyer,1 MB ChB, MMed (O&G), MCOG (SA), PhD; M H Botha,2 MB ChB, MMed (O&G), FCOG (SA), PhD; F H van der Merwe,2 MB ChB, MMed (O&G), FCOG; P J Becker,1,3 BSc (Hons), MSc, PhD epartment of Obstetrics and Gynaecology and Gynaecological Oncology Unit, Faculty of Health Sciences, University of Pretoria, South Africa D Department of Obstetrics and Gynaecology and Unit for Gynaecological Oncology, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Cape Town, South Africa 3 Biostatistics Unit, South African Medical Research Council, Pretoria, South Africa 1

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

Background. Cervical cancer is preventable, but still highly prevalent in South Africa (SA). Screening strategies in the country have been ineffective, and new ways to prevent the disease are needed. Objectives. To investigate the feasibility of linking cervical cancer screening in adult women to human papillomavirus (HPV) vaccination in schoolgirls. Methods. Ten primary schools in the South-West District of Tshwane, Gauteng Province, SA, took part in the study. Cervical cancer and HPV vaccine information was provided to schoolgirls and their parents. Consented schoolgirls were vaccinated and their female parents were invited to participate in self-screening. Results. Among 1 654 girls invited for vaccination, the consented and invited uptake rates were 99.4% and 64.0%, respectively. Vaccine completion rates were higher in schools where the vaccination programme was completed in the same calendar year than in those where it was administered over two calendar years. Of 569 adult females invited, 253 (44.5%) returned screen tests; 169 (66.8%) tested negative and 75 (29.6%) positive for any high-risk HPV (hrHPV). There were no differences in level of education, employment status or access to healthcare between women with positive and those with negative screen results. Conclusions. Implementation of HPV vaccination in a primary school-based programme was successful, with high vaccine uptake and completion rates. Self-screening reached the ideal target group, and it is possible to link cervical cancer screening to the cervical cancer vaccine by giving women the opportunity of self-sampling for hrHPV testing. This is a novel and feasible approach that would require some adaptive strategies. S Afr Med J 2015;105(2):115-120. DOI:10.7196/SAMJ.8418

Secondary population-based cervical cancer screening has not been implemented successfully in resourcepoor settings or developing countries anywhere in the world.[1] Reasons for this failure include the difficulties of conventional cytology screening and the fact that many prerequisites need to be in place and functioning well for population-based screening to be implemented; if any one of the components fails to deliver, the whole screening programme fails.[2] Cervical cancer screening in South Africa (SA) is mainly opportunistic, and although the National Department of Health has a cervical cancer screening policy, it has not been implemented at any level. Opportunistic screening tends to over-screen some sub-populations, while many others do not take part. In addition, the main target groups are often not well represented, including age and sociodemographic groups.[3,4] In SA, the communication of results and follow-up of screen-positive women are known to be very problematic. Consequently, the incidence of cervical cancer remains high and the majority of women who are diagnosed present with advanced-stage disease. To improve screening efforts in SA, new approaches to screening need to investigate improvements in uptake, inclusion of the correct target population, and successful communication of results. Primary prevention of cervical cancer is now possible with the availability of human papillomavirus (HPV) vaccines targeting HPV types 16 and 18, which cause the majority of cervical cancers

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worldwide, as well as in Africa.[5] The target population for primary prevention is initially girls between the ages of 9 and 11 years attending primary school. The Vaccine and Cervical Cancer Screen (VACCS) project was a cervical cancer vaccine implementation study, which also provided the opportunity to investigate the outcome of cervical cancer screening when linked to the vaccination of schoolgirls. Potential advantages of this approach are the linking of two relevant, but different, health interventions aimed at cervical cancer prevention and the possibility of exploiting the educational and logistic opportunities inherent to school-based programmes. In addition, this project utilised new molecular screening technology that offered the opportunity to use self-sampling in a home setting.

Methods

This was a national study conducted in Gauteng and Western Cape provinces, SA, with the approval of the national and provincial departments of Basic Education and Health. The study methodology differed slightly between the two provinces, and in this report the method and results of the Gauteng arm of the study are described. In Gauteng, ten primary schools were identified in Atteridgeville and the South-West District of Tshwane. After obtaining consent from the governing body and principal of each school, information events were held at the schools during 2011 and 2012. All the girls in grades 4 - 7 and their female parents or guardians were invited to attend these events.

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The ages and previous screening histories of women who accepted the invitation to screen were determined to assess whether an appropriate target population for secondary prevention was reached. HPV test results were interpreted as positive if DNA of any of the 15 high-risk viral types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, 82) were demonstrated, and as invalid if no DNA amplification occurred as tested by the internal control. Women testing positive for the two most oncogenic HPV types (16 and 18) were reported separately.

During the information event, attending female parents and guardians were interviewed and completed questionnaires (Appendix 1, available in the online version of this article), after which they attended a session at which information on cervical cancer, the vaccine for primary prevention and screening for the disease was provided by a medical doctor in the form of a 15-minute PowerPoint presentation as well as through the distribution of information leaflets in English or Tswana. During the vaccination programme, telephonic interviews were conducted, repeating the questions that tested knowledge and screening behaviour (Appendix 1, available in the online version of this article). Female parents and guardians attending the information events were invited to take part in self-administered HPV screening and to take a screen kit for themselves as well as for a friend or family member. The screen kit consisted of a tampon with user instructions; women were to insert the tampon vaginally and remove it after one hour. The used tampon was placed in a container with buffer and, together with personal information, returned to the school in a sealed envelope. DNA was extracted from the tampon specimens and tested using Roche linear array for HPV DNA testing as described previously.[6] Parents and guardians of girls aged 9 years and older in grades 4 - 7 were invited to provide consent, and all girls were requested to provide consent for HPV vaccination. The vaccine was administered per protocol by a team of registered nurses during school hours. Both bivalent and quadrivalent vaccines donated by the manufacturing companies were available to be administered.

Definitions

The invited cohort (IC) was defined as all female learners enrolled in the selected schools in grades 4 - 7. The consented cohort (CC) was defined as participants with written consent and assent from the learner. Girls with consent whose parents or guardians did not attend vaccine events were included in the CC. The vaccinated cohort (VC) was defined as all girls who received one vaccine dose. Vaccine uptake rates were calculated in a number of ways in order to allow comparison with other published HPV vaccine reports. The consented uptake rate (CUR) was calculated as VC/CC, with the invited uptake rate (IUR) calculated as VC/IC. Vaccine completion was calculated using the vaccinated cohort as denominator. The vaccine completion rate (VCR) was calculated using all girls who received all three vaccine doses. Girls who received only two vaccine doses within a short period of time were then separated from those who received the two vaccines at least 6 months apart, and the latter group was considered sufficiently vaccinated based on recent data suggesting protective antibody levels against vaccine HPV

Table 1. Uptake, vaccination and completion rates in schools vaccinated over one and two calendar years

Description

All girls in grades 4-7

All girls with Received consent at least and assent one dose

Doses 1 Single dose and 2

Doses 2 and 3

Doses 1 and 3

Doses 1 and 3, All 3 doses +/- dose 2

Received only 1 vaccine dosage

Received 2 doses, Received 2 <6 months dosages, 6 apart months apart

Received all 3 doses

Received at least 2 doses, min. 6 months apart

Received 2 doses, 6 weeks apart

Three vaccine doses administered within one calendar year: eight schools B1

183

118

119

108

114

223

127

117

120

123

166

181

136

131

155

Subtotal

1 179

742

739

639

698

Vaccination rates

IUR 62.9% CUR 99.6% IVR 5.5%

VCR 86.5% SVR 94.5%

Three vaccine doses administered over two calendar or school years: two schools B5

225

159

103

114

B10

250

158

155

128

129

Subtotal

475

317

314

231

243

Vaccination rates

IUR 66.7% CUR 99.1% IVR 22.6%

VCR 73.5% SVR 77.4%

Total Gauteng cohort: ten schools Total Vaccination rates

1 654

1 059

1 053

IUR 64.0% CUR 99.4%

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IVR 10.6%

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870

941

VCR 82.6% SVR 89.4%

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Statistical analysis

Questionnaire data were obtained from women who participated in the study and consisted of basic demographic data as well as data on access to and use of healthcare facilities. In addition, knowledge about cervi cal cancer and prevention of the disease was tested before and after the information event. Knowledge scores were calculated by awarding points for correct answers to a maximum score of 5 marks each for symptoms of, screening for and vaccination against cervical cancer. Changes in knowledge as tested by the same questions asked before and after the information event were measured and compared between groups. A p-value of <0.05 was regarded as statistically significant. Women who participated in self-screening were compared with a matched control group of women who did not participate. Within the participants of self-screening, data from all women with positive screen results were compared with a matched subgroup of those who screened negative. Matching of both control groups was done using age and the school attended by the child. There were no significant differences with regard to level of education, employment status and access to healthcare between the three groups of women. The study was approved by the Research Ethics Review Committee of the Faculty of Health Sciences, University of Pretoria (219/2009).

same calendar year. Vaccine completion rates were superior in these schools compared with the two schools in which vaccination was scheduled over two calendar years. Vaccine uptake and VCRs per school as well as the effect of scheduling over one and two calendar years are shown in Table 1. No serious adverse events related to vaccination were reported.

hrHPV. The hrHPV results are shown in Fig. 2. Twenty-three samples (9.1%) were positive for HPV type 16 and/or 18, and 52 (20.5%) were positive for one or more of the remaining 13 high-risk types. Of the 75 positive specimens, 43 (57.3%) had a single type and 32 (42.7%) tested positive for more than one hrHPV.

Screening results

Knowledge scores for cervical cancer symptoms, screening and vaccines for the total group before and after the educational intervention are shown in Fig. 3. Initial knowledge of all aspects was insufficient, but improved scores were obtained in the second questionnaire. Considering the screened and unscreened groups, there was no difference in initial knowledge of cervical cancer and its symptoms, which was poor in both groups. Around 70% in both groups obtained 0 or 1 out of the potential 5 marks awarded. Among women who participated in self-screening, the level of cervical cancer knowledge improved signifi cantly after the information event (n=132;

The 569 female parents or guardians attending the information events at the different schools were invited to take selfscreening kits home. A total of 795 screen tests were handed out, of which 253 (44.5%) were returned and tested for the presence of high-risk HPV (hrHPV) DNA. The mean age (standard deviation) of the screened population (Fig. 1) was 38.3 (10.2) years (95% confidence interval 37.0 - 39.6), and the median age was 38.5 years. Of the 253 samples tested, 9 (3.6%) were reported as invalid, 169 (66.7%) tested negative for hrHPV and 75 (29.6%) were positive for any 120

108

80 61 60 40 20

Results

Vaccination data

In the ten schools included in the project, the IC consisted of 1 654 girls, of whom 1 059 had given full consent (CC); 1 053 girls received the first vaccine dose (VC). The CUR was 99.4% and the IUR 64.0%. In the CC group, 498 parents or guardians provided informed parental consent during the information events held at the different schools, while 561 provided written informed consent on the basis of the information leaflet that learners took home. Five hundred and sixty-nine parents or guardians attended the information events and questionnaire interviews, while 1 085 received only leaflet information. Consent for vaccination was therefore provided by 561 of 1 085 parents (51.7%) who received only leaflet information, and by 498 of 569 (87.5%) who attended the information events (p<0.0001). In eight of the ten schools, all three doses of the vaccination were completed in the

Cervical cancer knowledge

100 Participants, n

types in similar recipients.[7,8] The insufficiently vaccinated rate (IVR) was calculated using the number of girls who received only one dose, or two doses <6 months apart.

Unknown

≤25

26 - 35

36 - 45

46 - 55

56 - 65

>65

Age, years

Fig. 1. Age distribution of screened women.

3.6% 9.1% HPV 16- and/or 18-positive 21% Non-16/18 hrHPV-positive

hrHPV-negative 67% Invalid

Fig. 2. Molecular results of self-collected cervical screening tests.

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Knowledge: screening

60 50

Questionnaire 1

Questionnaire 2

30 20 10 0

Score

Discussion

Knowledge: protection

70 60

Questionnaire 1 Questionnaire 2

50 40 30 20 10 0

Score

Knowledge: vaccine

90 80 70 60

Questionnaire 1 Questionnaire 2

50 40 30 20 10 0

Score

Fig. 3. Improvement in knowledge scores for cervical cancer symptoms, screening and vaccines.

p<0.001) (Table 2), while among unscreened women the improvement was not statistically significant (n=41; p=0.06) (Table 2). With regard to knowledge of cervical cancer prevention, knowledge of screening and vaccination improved significantly after the information event among screened

those who did not (p=0.169); 51.2% of women who participated in self-screening reported no previous screening ever or did not know whether they had had screening in the past, compared with 48.8% of non-participants. It is interesting that after participating in the project, 45 of 131 screened women (34.3%) reported that their last ‘cervical cancer test’ was more than 5 years ago. Despite this disparity, there was still a significant improvement in reported screening behaviour in this group between the two questionnaires (p<0.001) (Table 3) compared with the control group, which did not show significant improvement (p=0.036) (Table 3).

and unscreened groups (data not shown, p<0.001).

Screening behaviour

Self-reported previous screening behaviour did not differ significantly between women who participated in self-screening compared with

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Vaccine uptake data differ worldwide and are influenced by numerous social, religious and economic factors. In addition, vaccine programme and communication strategies have a very large effect on uptake. Uptake of HPV vaccines is low in the USA and Germany[9,10] and high in Australia,[11] while uptake rates in Africa vary.[12-14] Vaccine uptake, calculated as the proportion of girls who received one vaccine dose from the total IC, was 64.0% for the total group in this study. The project protocol allowed for the provision of only sketchy information to prospective participants, because another aim of the study was to test baseline knowledge. Although it can be argued that interested and informed parents were more likely to attend, the relatively low vaccine uptake (51.7%) among parents who did not attend the information event compared with those who did attend (87.5%) could probably be attributed in part to this lack of information. Moodley et al.[15] reported overall HPV vaccine uptake in an implementation study in KwaZulu-Natal Province, SA, of 99.7%, 97.9% and 97.8% for the first, second and third vaccination doses, respectively. These data represent the uptake and completion rates of those who consented, but uptake as a proportion of girls available for vaccination was not provided. In the current study, similar success in vaccination of consented girls of 99.4%, 98.6% and 82.6% for one, two and all three doses, respectively, was achieved. In addition to uptake and completion rates, the proportion of the VC that received at least two vaccine doses at least 6 months apart was calculated. To our knowledge it is the first time that HPV vaccine data from an implementation or demonstration project have been presented in this way, and these results therefore cannot be compared. In a school-based programme, it is acknowledged that VCRs are largely influ enced by the number of follow-up visits to

RESEARCH

Table 2. Improved knowledge on cervical cancer and its symptoms (upper triangles of table, above the grey tint) among screened and unscreened women Knowledge about cervical screening: scores after information event Screened women* nowledge about cervical K screening: scores before information event

Score

Total

132

Score

Total

Unscreened women

†

nowledge about cervical K screening: scores before information event

Score 0 = no correct answer; scores 1 - 5: one mark for each correct answer. *p<0.001. † p=0.06.

Table 3. Improvement in self-reported screening behaviour (upper triangles of table, above the grey tint) among screened women but not among unscreened women Self-reported screening behaviour after intervention Screened women* Self-reported screening Score behaviour before 0 intervention 1

Total

131

Total

Unscreened women† Self-reported screening Score behaviour before 0 intervention 1

Scores: 0 = never; 1 = don’t know; 2 = >10 years ago; 3 = 6 - 10 years ago; 4 = 1 - 5 years ago; 5 = <1 year ago. *p<0.001. † p=0.036.

the school. In an attempt to simulate large-scale rollout of schoolbased vaccination, extra follow-up visits to schools where unforeseen

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school activities and absenteeism prevented a large number of girls from attending scheduled vaccination were limited to one. In view

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of this limited effort to improve vaccine completion, the attained VCR of 82.6% and a sufficiently vaccinated rate (SVR) of 89.4% are considered very satisfactory. Vaccination in a single calendar year was more successful than vaccination scheduled over two years, as reflected by better VCRs (86.5% v. 73.5%) and SVRs (94.5% v. 77.4%). The difference can possibly be attributed to the December holiday break, children changing schools and promotion to secondary schools, which resulted in fewer girls receiving the important third dose. Although not surprising, this is to our knowledge the first confirmation of this effect reported from SA. The projected large loss of immune response and resulting herd immunity caused by an inefficiently vaccinated population is of huge importance for the planning of all vaccine rollout programmes using school-based infrastructure. Screening uptake, calculated as the proportion of women screened from those invited, was 44.5% in this study. Furthermore, in this study 253 women took up screening, of whom more than half reported no previous cervical cancer screening. Molecular screening results identified cervical cancer risk in 28.8% and a high risk for future disease in 9.1%. Using the school infrastructure as well as mobile phone technology, all women received screen results and this was confirmed for all screen-positive women. All five of these parameters compare favourably to the limited data available for the existing cytology-based countrywide screening programme. According to the World Health Organization, cervical cytology coverage of eligible women in SA for the period 2000 - 2006 was estimated to be 17%.[16] Screening will have the largest effect on cancer incidence if coverage is large, the correct high-risk target group is reached, and the biggest possible number of screen-positive women can get results and receive preventive therapy. HPV screening in low-resource settings is feasible, and self-sampling offers the added benefits of eliminating a clinic visit, speculum examination and the need for a healthcare provider to perform screening. In addition to screening, education about cervical cancer symptoms and screening was successfully linked to the cervical cancer vaccine by the provision of information to parents or guardians of girls invited to be vaccinated. Knowledge about cervical cancer-related matters was lacking in this group of urban mothers, but improved following the provision of information. Neither demographics nor baseline knowledge predicted screening uptake in this study. Positive screening behaviour was associated with an improvement in knowledge about cervical cancer. As expected, most screening participants reported an improvement in screening behaviour after the tampon test, reflecting an understanding of the intention of the test. The finding that some women who took part in self-screening were not aware of the fact that they were screened could be attributed to a lack of knowledge or the structure of the questionnaire.

Conclusion

Implementation of HPV vaccination in a primary school-based programme was hugely successful. No serious adverse events were reported, and uptake rates of 64.0% of the IC and 99.4% of the CC were achieved. Vaccine completion was optimal when all vaccine doses were offered within a single calendar year. Self-screening tests reached the ideal target group, and results were successfully reported to all participants. Linking cervical cancer screening to the cervical cancer vaccine was possible by providing women the opportunity to self-sample. This is a novel approach that would require some adaptive strategies, but was feasible and practical in the setting of this trial.

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Knowledge about cervical cancer, its symptoms and prevention is generally poor, and school-based vaccine programmes offer a unique opportunity to provide appropriate information. This report of the Gauteng part of the VACCS project confirmed a measurable improvement in knowledge following health education. In addition, it was demonstrated that improved knowledge correlated with the uptake of screening. Acknowledgements. The assistance of the following groups and persons that enabled the successful completion of this project is gratefully acknowledged. Financial support was received from the Cancer Research Initiative of South Africa, a national collaborative research programme supported by the South African Medical Research Council and the Cancer Association of South Africa, and First for Women Insurance for screening and treatment of screen-positive women and investigator support. The vaccine manufacturing companies GlaxoSmithKline/Aspen SA and Merck supported this investigator-initiated study by generously donating all vaccines used in this project. Ms Debbie Constant of the School of Public Health, University of Cape Town, assisted with development of the questionnaire, Prof. Gerhard Lindeque provided valuable advice, Ms Bertha Grond managed the finances; Ms Riekie Burden and her team of registered nurses handled study and vaccine processes, Dr Karin Richter managed laboratory screening data, Ms Cathy Visser collated and analysed the vaccination and screening data, consultants and registrars of the Department of Obstetrics and Gynaecology, University of Pretoria, presented lectures at the information events, undergraduate medical students administered the questionnaires, and Ms Barbara English of the Faculty of Health Sciences, University of Pretoria, assisted with language editing. References 1. Gakidou E, Nordhagen S, Obermeyer Z. Coverage of cervical cancer screening in 57 countries: Low average levels and large inequalities. PLoS Med 2008;5(6):e132. [http://dx.doi.org/10.1371/journal.pmed.0050132] 2. Richter KL. Understanding and incorporating human papillomavirus testing in cervical cancer screening: A South African perspective. South African Journal of Gynaecological Oncology 2011;3(1):9-14. 3. Seidel D, Becker N, Rohrmann S, Nimptsch K, Linseisen J. Socio-demographic characteristics of participation in the opportunistic German cervical cancer screening programme: Results from the EPIC-Heidelberg cohort. J Cancer Res Clin Oncol 2009;135(4):533-541. [http://dx.doi.org/10.1007/s00432-008-0485-0] 4. Freitas RA, Carvasan GA, Morais SS, Zeferino LC. Excessive Pap smears due to opportunistic cervical cancer screening. Eur J Gynaecol Oncol 2008;29(5):479-482. 5. Denny L, Adewole I, Anorlu R, et al. Human papillomavirus prevalence and type distribution in invasive cervical cancer in sub-Saharan Africa. Int J Cancer 2014;134(6):1389-1398. [http://dx.doi.org/10.1002/ijc.28425] 6. Richter K, Becker P, Horton A, Dreyer G. Age-specific prevalence of cervical human papillomavirus infection and cytological abnormalities in women in Gauteng Province. S Afr Med J 2013;103(5):313317. [http://dx.doi.org/10.7196/SAMJ.6514] 7. Dobson SR, McNeil S, Dionne M, et al. Immunogenicity of 2 doses of HPV vaccine in younger adolescents vs 3 doses in young women: A randomized clinical trial. JAMA 2013;309(17):1793-1802. [http://dx.doi.org/10.1001/jama.2013.1625] 8. Lazcano-Ponce E, Stanley M, Munoz N, et al. Overcoming barriers to HPV vaccination: Non-inferiority of antibody response to human papillomavirus 16/18 vaccine in adolescents vaccinated with a two-dose vs. a threedose schedule at 21 months. Vaccine 2014;32(6):725-732. [http://dx.doi.org/10.1016/j.vaccine.2013.11.059] 9. Delere Y, Bohmer MM, Walter D, Wichmann O. HPV vaccination coverage among women aged 18-20 years in Germany three years after recommendation of HPV vaccination for adolescent girls: Results from a crosssectional survey. Hum Vaccin Immunother 2013;9(8):1706-1711. [http://dx.doi.org/10.4161/hv.24904] 10. Dorell C, Yankey D, Jeyarajah J, et al. Delay and refusal of human papillomavirus vaccine for girls, national immunization survey-teen, 2010. Clin Pediatr 2014;53(3):261-269. [http://dx.doi. org/10.1177/0009922813520070] 11. Brotherton JM, Murray SL, Hall MA, et al. Human papillomavirus vaccine coverage among female Australian adolescents: Success of the school-based approach. Med J Aust 2013;199(9):614-617. [http://dx.doi.org/10.5694/mja13.10272] 12. Binagwaho A, Wagner CM, Gatera M, Karema C, Nutt CT, Ngabo F. Achieving high coverage in Rwandaâ&#x20AC;&#x2122;s national human papillomavirus vaccination programme. Bull World Health Organ 2012;90(8):623-628. [http://dx.doi.org/10.2471/BLT.11.097253] 13. Jumaan AO, Ghanem S, Taher J, Braikat M, Al Awaidy S, Dbaibo GS. Prospects and challenges in the introduction of human papillomavirus vaccines in the extended Middle East and North Africa region. Vaccine 2013;31(Suppl 6):G58-G64. [http://dx.doi.org/10.1016/j.vaccine.2012.06.097] 14. Watson-Jones D, Baisley K, Ponsiano R, et al. Human papillomavirus vaccination in Tanzanian schoolgirls: Cluster-randomized trial comparing 2 vaccine-delivery strategies. J Infect Dis 2012;206(5):678-686. [http://dx.doi.org/10.1093/infdis/jis407] 15. Moodley I, Tathiah N, Mubaiwa V, Denny L. High uptake of Gardasil vaccine among 9 - 12-yearold schoolgirls participating in an HPV vaccination demonstration project in KwaZulu-Natal, South Africa. S Afr Med J 2013;103(5):318-321. [http://dx.doi.org/10.7196/SAMJ.6414] 16. World Health Organization. World Health Statistics 2008. World Health Organization, 2008. http:// www.who.int/whosis/whostat/EN_WHS08_Full.pdf (accessed 12 February 2014).

Accepted 8 September 2014.

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Appendix 1 Study No. ___ ___ ___ ___

Vaccination and Cervical Cancer Screening Project COMPLETE THIS TOP SECTION BEFORE STARTING THE INTERVIEW Participant Study number: Interviewer number: Code for school attended by daughter: Code for Site: Date of Interview:

Introductory remarks

Hello, my name is .....................……….… Thank you for agreeing to this interview. I am going to ask you a few questions about your understanding of cervical cancer. It will take about 15 minutes. Your name and contact details that I write down here will be kept separate from the questionnaire so anything you tell me will be anonymous and be kept confidential. Thank you.

Participant name

____________________________________

Participant ID Participant Contact Numbers

Daughter’s Name

___________________________________

Daughter’s ID/Birth date Instructions to the interviewer

   

Circle the appropriate number/s or fill in the appropriate response. Follow skip patterns carefully. DO NOT read words in BOLD or CAPS OR ITALICS Use probes where necessary Circle the NOT MENTIONED options after completion of the interview, before signing completion of form

NB: FILL IN STUDY NUMBERS ON NEXT PAGES AND DETACH THIS FRONT PAGE FROM THE QUESTIONNAIRE AND STORE SEPARATELY

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Study No. ___ ___ ___ ___ SECTION-1: Socio-Demographic Characteristics No. 101

READ: “To start I am going to ask you some questions about yourself” Questions and filters How old are you?

Coding categories

Code Age in years

[___|___]

Missing 102

What is the highest level of education you have completed? CIRCLE ONLY ONE

-66

No formal schooling Grade 1/Sub A to Grade 7/Std 5 Grade 8/Std 6 to Grade 11/Std 9 Grade 12/Std 10 Diploma course Technikon degree University degree Other course: Specify________________________________

1 2 3 4 5 6 7

Missing 103

What is your source of income, if any? READ RESPONSES ONE BY ONE CIRCLE MORE THAN ONE IF NEEDED

Are you paid a salary Are you self employed Do you receive a grant Do you receive financial support from other members of the family Other Other: Specify_____________________________________

-66 Yes 1 1 1

No 0 0 0

1 1

0 0

No Income

Missing

No. 201

SECTION-2: Use of Health Care Facilities READ: Now I would like to ask you some questions about your use of health care facilities. Questions and filters When did you last visit any health care centre?

Coding categories

CIRCLE ONLY ONE

202

Why have you not visited a health care centre for more than 5 years DO NOT READ RESPONSES CIRCLE

 IF MENTIONED

Probes: Anything else?

In the last month In the last 6 months In the last year In the last 5 years Unsure

-66

Code 1 2 3 4 88

More than 5 years ago Missing No health problem Don’t have the money Too far away No transport to get there Don’t have enough time to go there Don’t believe they can help my me with my health problem Have to wait too long at the clinic The service at the clinic is poor The clinic is not open when I can go there Other Other: Specify__ _________________________________ Missing

Page 2 of 9

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Instructions

5 -66 M 1 1 1 1 1 1 1 1 1 1

NM 0 0 0 0 0 0 0 0 0 0 -66

Instructions Skip to 203

Skip to 202

Skip to 301

RESEARCH

Study No. ___ ___ ___ ___ No. 203

Questions and filters Which service do you most often visit when you go for health care? READ ALL RESPONSES THEN CIRCLE ONLY ONE

Coding categories

Government clinics Government hospitals Private doctors/hospitals Traditional healers Other Other: Specify________________________________ Missing

204

What is the name of the health care centre you most often visit?

Is it easy to get to this facility?

Missing

READ RESPONSES ONE BY ONE CIRCLE MORE THAN ONE IF NEEDED

-66

Walk Taxi Public transport Car

How do you usually travel to this facility?

What was the reason for your most recent visit to any health care centre?

No 0

Yes 1

CIRCLE ONLY ONE

205

-66

NAME_______________________________________

Missing c)

Code 1 2 3 4 5

For treatment of a disease For medicines for yourself For family planning for yourself For a Pap Smear or gynaecological examination for yourself To accompany someone else Other

1 2 3 4 -66 Yes 1 1 1 1 1 1

Other: Specify_______ ________________________ Missing

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February 2015, Vol. 105, No. 2

-66

No 0 0 0 0 0 0

Instructions

RESEARCH

Study No. ___ ___ ___ ___

No. 301

SECTION-3: Knowledge of Pap Smears and cancer of the cervix READ: “Now I would like to talk to you about cervical cancer and how to prevent it.” Questions and filters a) Can you explain what you understand about cervical cancer – that is cancer of the mouth of the womb?

IF CLIENT SAYS SHE KNOWS NOTHING ABOUT CERVCAL CANCER, SKIP TO SECTION 4

OPEN RESPONSE

Coding categories

Code

Instructions

302

What changes in your body would make you think that you had cervical cancer? DO NOT READ RESPONSES CIRCLE  FOR ALL RESPONSES MENTIONED Probe: Anything else?

Pain Discharge from vagina Odour from vagina Ulcers/sores on private parts Unusual bleeding There are no signs Don’t know Other

M 1 1 1 1 1 1 1 1

NM 0 0 0 0 0 0 0 0

Other: Specify_______________________________

303

304

Do you know how a woman can protect herself against developing cervical cancer?

How can a woman protect herself against developing cervical cancer? DO NOT READ RESPONSES CIRCLE  FOR ALL RESPONSES MENTIONED Probe: Anything else?

Missing

-66

Yes No Unsure

1 0 88

Missing

-66

Regular pap smear Regular examination of womb Seeing a special doctor Regular visit to General Practitioner Not having sex Using condoms Vaccine/injection Other screening tests Other

M 1 1 1 1 1 1 1 1

NM 0 0 0 0 0 0 0 0

Other: Specify_______ ________________________

305

Do you think cervical cancer can be cured with treatment?

Missing

-66

Yes No Unsure

1 0 88

Missing

-66

Page 4 of 9

February 2015, Vol. 105, No. 2

Skip to 304 Skip to 305 Skip to 304

RESEARCH

Study No. ___ ___ ___ ___

No. 401

402

SECTION-4: Cervix cancer screening History READ: “Now I would like to ask you about any cervix cancer screening tests you may have had” Questions and filters Have you ever had a test for cervical cancer?

Coding categories

If YES What test did you have? DO NOT READ RESPONSES CIRCLE  FOR ALL RESPONSES MENTIONED Probe: Anything else?

Yes No Unsure

Code 1 0 88

Missing

-66

Pap smear Vaginal Examination Tampon test Other

M 1 1 1 1

If NO Why have you never had a test for cervical cancer? DO NOT READ RESPONSES CIRCLE  FOR ALL RESPONSES MENTIONED Probe: Anything else?

Skip to 404

Other: specify______________________________ Missing

403

NM 0 0 0 0

Instructions Skip to 402 Skip to 403 Skip to 501

Scared Embarrassed My partner wouldn’t like it I don’t have the money I don’t like having these kinds of tests I have never heard about this before Didn’t know where to go Didn’t think it would help me Did not have a reason to go for one Other

-66 M 1 1 1 1 1 1 1 1 1 1

NM 0 0 0 0 0 0 0 0 0 0

Skip to 501

Other specify____________________________ __________________________________________

404

How many years ago was your last test for cervical cancer? CIRCLE ONLY ONE

405

What was the result of your last test? CIRCLE ONLY ONE

406

Did you have any treatment for this? CIRCLE ONLY ONE

Missing

-66

Less than 1 year ago 1-5 years 6-10 years > 10 years ago Don’t know

1 2 3 4 88

Missing

-66

Normal Abnormal Don’t know

1 0 88

Missing

-66

Yes No Unsure

1 0 88

Missing

-66

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Skip to 501 Skip to 406 Skip to 501

RESEARCH

Study No. ___ ___ ___ ___ SECTION-5: Vaccination Knowledge and attitudes READ: “Now I would like to ask you about your opinions about vaccination and cervical cancer” No. 501

502

Questions and filters Have you ever heard of a vaccine or injection to prevent cervical cancer?

IF YES: Who is the vaccine or injection for?

DO NOT READ RESPONSES CIRCLE  FOR ALL RESPONSES MENTIONED Probe: Anybody specific?

Coding categories

Code Yes No Unsure

1 0 88

Missing

-66

Women/girls only Men and women/girls Women/girls under a certain age Women/girls who have not had sexual intercourse yet Don’t know enough about it Other Other: Specify_______________________________

M 1 1 1 1 1 1

Skip To Skip to 502 Skip to 503 Skip to 503

NM 0 0 0 0 0 0

___________________________________________

503

504

505

Do you think a vaccine to prevent cervical cancer would be good to have?

IF NO or unsure: Why do you think it would not/ might not be good to have a vaccination to prevent cervical cancer? End interview. Thank the client for her help and ask: “Do you have any questions?”

Missing

-66

Yes No Unsure Missing

1 0 88

Skip to 505 Skip to 504 Skip to 504

-66

OPEN RESPONSE _________________________________________ _________________________________________ __________________________________________

SAY: There is such a vaccine: ASK: Would you advise primary school girls to have it? End interview. Thank the client for her help and ask: “Do you have any questions?”

Yes No Unsure

1 0 88

Missing

-66

______________________________________ Signature of Interviewer (post-interview) (Your signature verifies that you have reviewed the responses given by the interviewee, corrected any problems, and that ALL questions have a response marked.) INTERVIEWER: Is this survey complete? 1 = Complete 2 = Incomplete If not complete please give reasons:

_____________________________________________________________________________________________ _____________________________________________________________________________________________ _____________________________________________________________________________________________ End of first Interview Page 6 of 9

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Study No. ___ ___ ___ ___

VACCS Project – Second Interview No. 601

SECTION-6: Knowledge of Pap Smears and cancer of the cervix READ: “Now I would like to talk to you about cervical cancer and how to prevent it.” Questions and filters a) Can you explain what you understand about cervical cancer – that is cancer of the mouth of the womb?

IF CLIENT SAYS SHE KNOWS NOTHING ABOUT CERVCAL CANCER, SKIP TO SECTION 4

OPEN RESPONSE

Coding categories

Code

Instructions

602

What changes in your body would make you think that you had cervical cancer? DO NOT READ RESPONSES CIRCLE  FOR ALL RESPONSES MENTIONED Probe: Anything else?

Pain Discharge from vagina Odour from vagina Ulcers/sores on private parts Unusual bleeding There are no signs Don’t know Other

M 1 1 1 1 1 1 1 1

NM 0 0 0 0 0 0 0 0

Other: Specify_______________________________

603

604

Do you know how a woman can protect herself against developing cervical cancer?

How can a woman protect herself against developing cervical cancer? DO NOT READ RESPONSES CIRCLE  FOR ALL RESPONSES MENTIONED Probe: Anything else?

Missing

-66

Yes No Unsure

1 0 88

Missing

-66

Regular pap smear Regular examination of womb Seeing a special doctor Regular visit to General Practitioner Not having sex Using condoms Vaccine/injection Other screening tests Other

M 1 1 1 1 1 1 1 1

NM 0 0 0 0 0 0 0 0

Other: Specify_______ ________________________

605

Do you think cervical cancer can be cured with treatment?

Missing

-66

Yes No Unsure

1 0 88

Missing

-66

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Skip to 304 Skip to 305 Skip to 304

RESEARCH

Study No. ___ ___ ___ ___

No. 701

702

SECTION-7: Cervix cancer screening History READ: “Now I would like to ask you about any cervix cancer screening tests you may have had” Questions and filters Have you ever had a test for cervical cancer?

Coding categories

If YES What test did you have? DO NOT READ RESPONSES CIRCLE  FOR ALL RESPONSES MENTIONED Probe: Anything else?

Yes No Unsure

Code 1 0 88

Missing

-66

Pap smear Vaginal Examination Tampon test Other

M 1 1 1 1

If NO Why have you never had a test for cervical cancer? DO NOT READ RESPONSES CIRCLE  FOR ALL RESPONSES MENTIONED Probe: Anything else?

Skip to 404

Other: specify______________________________ Missing

703

NM 0 0 0 0

Instructions Skip to 402 Skip to 403 Skip to 501

-66 M 1 1 1 1 1 1 1 1 1 1

NM 0 0 0 0 0 0 0 0 0 0

Skip to 501

Other specify____________________________ __________________________________________

704

How many years ago was your last test for cervical cancer? CIRCLE ONLY ONE

705

What was the result of your last test? CIRCLE ONLY ONE

706

Did you have any treatment for this? CIRCLE ONLY ONE

Missing

-66

Less than 1 year ago 1-5 years 6-10 years > 10 years ago Don’t know

1 2 3 4 88

Missing

-66

Normal Abnormal Don’t know

1 0 88

Missing

-66

Yes No Unsure

1 0 88

Missing

-66

Page 8 of 9

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Skip to 501 Skip to 406 Skip to 501

RESEARCH

Study No. ___ ___ ___ ___ SECTION-8: Vaccination Knowledge and attitudes READ: “Now I would like to ask you about your opinions about vaccination and cervical cancer” No. 801

802

Questions and filters Have you ever heard of a vaccine or injection to prevent cervical cancer?

IF YES: Who is the vaccine or injection for?

DO NOT READ RESPONSES CIRCLE  FOR ALL RESPONSES MENTIONED Probe: Anybody specific?

Coding categories

Code Yes No Unsure

1 0 88

Missing

-66

M 1 1 1 1 1 1

Skip To Skip to 502 Skip to 503 Skip to 503

NM 0 0 0 0 0 0

___________________________________________

803

804

805

Do you think a vaccine to prevent cervical cancer would be good to have?

Missing

-66

Yes No Unsure Missing

1 0 88

Skip to 505 Skip to 504 Skip to 504

-66

OPEN RESPONSE _________________________________________ _________________________________________ __________________________________________

SAY: There is such a vaccine: ASK: Would you advise primary school girls to have it? End interview. Thank the client for her help and ask: “Do you have any questions?”

Yes No Unsure

1 0 88

Missing

-66

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Prevalence of gastrointestinal pathogenic bacteria in patients with diarrhoea attending Groote Schuur Hospital, Cape Town, South Africa B Kullin,1 PhD; R Meggersee,1 PhD; J D’Alton,1 BSc (Hons); B Galvão,1 PhD; N Rajabally,2 MB ChB, FCP (SA), Cert Gastroenterol; A Whitelaw,3 MB ChB, MSc, FCPath (Micro); C Bamford,3 MB ChB, MMed (Med Micro), FCPath (Micro); S J Reid,1 PhD; V R Abratt,1 PhD epartment of Molecular and Cell Biology, Faculty of Science, University of Cape Town, South Africa D Division of Gastroenterology, Department of Medicine, Groote Schuur Hospital and Faculty of Health Sciences, University of Cape Town, South Africa 3 National Health Laboratory Service, Groote Schuur Hospital and Division of Medical Microbiology, Faculty of Health Sciences, University of Cape Town, South Africa 1 2

Corresponding author: V R Abratt (valerie.abratt@uct.ac.za)

Background. Diarrhoea due to gastrointestinal infections is a significant problem facing the South African (SA) healthcare system. Infections can be acquired both from the community and from the hospital environment itself, the latter acting as a reservoir for potential pathogenic bacteria. Objectives. To examine the prevalence of a panel of potential diarrhoea-causing bacteria in patients attending a tertiary healthcare facility in Cape Town, SA. Methods. Polymerase chain reaction (PCR) primers specific for Clostridium difficile, Shigella spp., Salmonella spp., Klebsiella oxytoca, enteropathogenic and enterohaemorrhagic Escherichia coli (EPEC/EHEC), Staphylococcus aureus, enterotoxigenic Bacteroides fragilis and Campylobacter spp. were used to screen total bacterial genomic DNA extracted from stool samples provided by 156 patients with diarrhoea attending Groote Schuur Hospital, Cape Town, SA. Results. C. difficile was the most frequently detected pathogen (16% of cases) in the 21 - 87-year-old patient range, but was not present in samples from the 16 - 20-year-old range. K. oxytoca (6%), EPEC/EHEC strains (9%) and S. aureus (6%) were also detected. The remaining pathogens were present at low frequencies (0 - 2.9%), and the occurrence of mixed infections was 5%. The majority of non-C. difficile-related diarrhoeas were community acquired. Conclusion. C. difficile was the main cause of infectious diarrhoea in the sampled patients, while K. oxytoca and EPEC/EHEC strains were present as relatively minor but potentially significant pathogens. S Afr Med J 2015;105(2):121-125. DOI:10.7196/SAMJ.8654

Diarrhoea as a result of gastrointestinal tract infections is a significant problem facing much of Africa.[1] In 2000 alone, almost 4% of the deaths in South Africa (SA) were attributable to infectious diarrhoea, representing the fifth leading cause of years of life lost.[2] The causes of infectious diarrhoea are varied. Nosocomial infections are chiefly caused by Clostridium difficile and to a lesser extent by Klebsiella oxytoca, typically after anti biotic therapy, which allows the organisms to proliferate and cause disease.[3] Community-acquired diarrhoea resulting from personto-person transmission or the consumption of contaminated and poorly prepared foodstuffs and water can be caused by a range of bacterial agents. These include several pathotypes of Escherichia coli, non-typhoidal Salmonella spp., Shigella spp., enterotoxigenic Bacteroides fragilis, Campylobacter spp. and Staphylococcus aureus, as well as several viruses (rotavirus, norovirus and adenovirus) and parasites (e.g. Giardia lamblia and Entamoeba spp.).[4] Despite their potential to cause disease, there have been relatively few SA studies examining the prevalence of pathogenic microorganisms in ‘non-outbreak’ situations, particularly in the hospital environment. In addition, the majority of surveillance studies have examined paediatric populations that are at increased risk of developing diarrhoeal disease. There is little information regarding the prevalence of potential pathogens in adults. The aim of this

121

study was therefore to identify the prevalence of a selected panel of potential pathogenic bacteria in routine stool samples provided by patients with diarrhoea attending Groote Schuur Hospital (GSH), Cape Town, SA.

Methods

Sample collection and study participants

Stool samples (N=139) were collected as part of a larger study from in- and outpatients presenting to GSH with diarrhoea between March 2012 and March 2013. Patients <16 years old were excluded from the study. Samples were transferred to the National Health Laboratory Service (NHLS) unit at GSH, where they were stored at –20°C until further processing. The presence of blood in stool samples was assessed visually. Ethics approval was obtained from the University of Cape Town, Human Research Ethics Committee (HREC Number 310/2008).

Genomic DNA extraction

Total faecal genomic DNA was extracted from stool samples using the GXT Stool Extraction Kit (Hain Lifesciences, SA) and the GenoXtract automated extraction instrument following the manufacturer’s instructions. The quantity and purity of the DNA were assessed using a Nanodrop 1000 instrument (Nanodrop, USA). The quality of the genomic DNA and the absence of polymerase chain reaction (PCR)

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RESEARCH

of K. oxytoca (pehX), enteropathogenic and enterohaemorrhagic Escherichia coli (EPEC/EHEC) (eaeA) and the various pathogenic Shigella spp. (invC) were used as positive amplifications controls in the respective reactions.

inhibitors were further assessed by PCR amplification of each sample using 50 ng template and the F27/R5 primer pair, which target the bacterial 16S rRNA gene.

Preparation of positive amplification controls

Screening for potential pathogens

Bacterial-specific genomic DNA for use as a positive amplification control in the PCR screening amplifications was prepared from pure cultures of C. difficile (toxigenic isolate R20291), C. jejuni (a laboratory isolate provided by the NHLS, SA), S. aureus (a laboratory isolate) and S. enterica subsp. enterica serovar Typhimurium (ATCC 14028), using a genomic DNA extraction kit (ThermoScientific, USA) following the manufacturer’s instructions. For the B. fragilis bft screening experiment, plasmids containing the cloned target region of the bft-1 subtype (prepared in this study) and the bft-2 subtype (kindly provided by Prof. Cynthia Sears), were used as positive amplification controls.[5] Plasmids containing cloned target regions

Total faecal genomic DNA (50 ng) prepared from each stool sample was used as template in a series of PCR amplifications using primers specific to each pathogen (Table 1). No template control reactions were included for each different primer set. PCR cycling parameters for the universal bacterial 16S rRNA gene, C. jejuni/C. coli, S. aureus, Salmonella spp., Shigella spp., K. oxytoca and EHEC/EPEC reactions were as follows: denaturation at 95°C for 5 minutes, followed by 35 cycles of denaturation at 94°C for 30 seconds, annealing at primerspecific temperature for 30 seconds, and extension at 72°C for 1 minute, and finally 72°C for 7 minutes.

Table 1. Primers used in this study

Primer

Sequence (5ʹ - 3ʹ)

Annealing temperature (°C)

Target/description

Size (bp)

Reference

Bacterial 16S rRNA gene

1 500

65 - 55*

C. difficile tpi gene

230

65 - 55*

C. difficile tcdA gene

369/110†

65 - 55*

C. difficile tcdB gene

160

Common forward primer

F27

AGA GTT TGA TCI TGG CTC AG

ACG GIT ACC TTG TTA CGA CTT

Tpi-F

AAA GAA GCT ACT AAG GGT ACA AA

Tpi-R

CAT AAT ATT GGG TCT ATT CCT AC

TcdA-F

AGA TTC CTA TAT TTA CAT GAC AAT AT

TcdA-R

GTA TCA GGC ATA AAG TAA TAT ACT TT

TcdB-F

GGA AAA GAG AAT GGT TTT ATT AA

TcdB-R

ATC TTT AGT TAT AAC TTT GAC ATC TTT

GBF-201

GAA CCT AAA ACG GTA TAT GT

GBF-312

CCT CTT TGG CGT CGC

Reverse primer for bft-1 gene

190

GBF-322

CGC TCG GGC AACT AT

Reverse primer for bft-2 gene

175

GBF-334

TGT CCC AAG TTC CCC AG

Reverse primer for bft-3 gene

287

K. oxytoca pehX polygalacturonase gene

344

EHEC/EPEC E. coli eaeA intimin gene

248

C. jejuni/C. coli 16S rRNA gene

854

S. aureus nuc gene

280

Salmonella spp. invA gene

281

Shigella spp. invC gene

875

Peh-C

GAT ACG GAG TAT GCC TTT ACG GTG

Peh-D

TAG CCT TTA TCA AGC GGA TAC TGG

eaeA-F

ATG CTT AGT GCT GGT TTA GG

eaeA-R

GCC TTC ATC ATT TCG CTT TC

CCCJ609-F

AAT CTA ATG GCT TAA CCA TTA

CCCJ1442-R

GTA ACT AGT TTA GTA TTC CGG

nuc-F

GCG ATT GAT GGT GAT ACG GTT

nuc-R

AGC CAA GCC TTG ACG AAC TAA AGC

invA-F

GTG AAA TTA TCG CCA CGT TCG GGC AA

invA-R

TCA TCG CAC CGT CAA AGG AAC C

SgenDF1

TGC CCA GTT TCT TCA TAC GC

SgenDR1

GAA AGT AGC TCC CGA AAT GC

bp = base pairs. * Touchdown PCR procedure: An initial annealing temperature of 65°C dropping to 55°C by 1°C per cycle for the first 11 cycles. † The full-length tcdA gene fragment is 369 bp, whereas the truncated tcdA gene fragment in toxin A – B + C. difficile strains is 110 bp.

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Multiplex PCR reactions were used to screen for bft-positive B. fragilis strains and toxigenic C. difficile. For the B. fragilis bft screening protocol, a common forward primer and three specific reverse primers that target the three different bft subtypes were used. The PCR cycling parameters were as follows: denaturation at 95°C for 5 minutes, followed by 35 cycles of denaturation at 94°C for 1 minute, annealing at 62°C for 30 seconds and extension at 72°C for 1 minute, and finally 72°C for 7 minutes. For the C. difficile screening protocol, primers targeting the species-specific tpi gene as well as the two toxin genes tcdA and tcdB were used to identify toxigenic strains. A touchdown PCR procedure was employed. An initial denaturation at 95°C for 5 minutes was performed, followed by 40 cycles of denaturation at 95°C for 30 seconds, annealing for 30 seconds at temperatures decreasing from 65°C to 55°C (decreasing by 1°C per cycle for the first 11 cycles) and extension at 72°C for 30 seconds. A final extension step was then carried out at 72°C for 7 minutes. All reaction products were analysed by electrophoresis through 2% (w/v) agarose gels and imaged using a ChemiDoc EC imager (Bio-rad, SA). Positive controls (50 ng of pure genomic DNA from target strains or 50 ng of plasmid DNA containing the relevant target fragment) and negative controls containing no template were included in each PCR experiment.

Results

Basic demographic data

A total of 139 stool samples were analysed, of which 80 (57.6%) were from female patients. Patient ages ranged from 16 to 87 years, with the majority of the patients (73%) between 20 and 60 years of age.

Prevalence of selected pathogenic bacteria in diarrhoea samples

All samples showed the predicted 1.5 kb product when screened using the universal bacterial 16S rRNA gene primers (result not shown). Each of the primer sets gave the specific, expected product when used to amplify control target DNA under the study conditions (Fig. 1). The results of screening the study samples are summarised in Fig. 2. Of the 139 samples screened, 53 (approximately 38%) contained one or more

Size (kb)

Bf1

Bf2

of the target organisms possibly linked to the patient symptoms, while the remainder gave a negative result reflecting a diarrhoea of unknown origin. Toxigenic C. difficile was the most prevalent potential pathogen. It was found in approximately 16% of samples overall and in all age groups except the 16 - 20 years group. EPEC/EHEC E. coli were present in approximately 9% of cases and occurred across all age groups. K. oxytoca and S. aureus both occurred in 6% of samples, Salmonella spp., Shigella spp., and bft-positive B. fragilis together were present in approximately 8% of the samples, and Campylobacter spp. were not detected in any of them (Fig. 2). Mixed populations of potential pathogens were found in approximately 5% of the samples. Of the patient cohort, ten individuals (7%) showed evidence of blood in their stool. Two of these stools came from patients colonised by Shigella spp. and one from a patient colonised by S. aureus, while the remaining seven bloody stools did not contain any of the pathogens included in the screening procedures.

Discussion

Routine surveillance of bacteria that are known agents of infectious diarrhoea is very seldom carried out for organisms other than Shigella spp. and non-typhoidal Salmonella spp. In this study, we sought to examine the prevalence of other potential bacterial pathogens present in diarrhoea samples from patients attending a hospital in Cape Town. The results suggested that C. difficile was the most prevalent pathogen among patients in the 21 - 87-year-old range, with the rest of the selected potential pathogens making up a relatively small percentage of the cases. C. difficile is a frequent cause of nosocomial diarrhoea, accounting for up to 20% of such cases worldwide.[3] There have also been reports suggesting that the prevalence of community-acquired cases of C. difficile is increasing.[6] Importantly, there are few data on the prevalence of C. difficile in SA. A previous study, also carried out at GSH but employing an enzyme-immunoassay (EIA)-based technique, determined a prevalence of 9.2% for toxigenic C. difficile in patients with diarrhoea.[7] It is possible, however, that some C. difficile cases were overlooked in this earlier study, as EIA-based tests have been reported to suffer from inferior diagnostic sensitivity.[8]

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1

Fig. 1. Positive control reactions for each primer set. Lanes: Mw (100 bp DNA ladder), Cd (C. difficile), Bf1 (B. fragilis bft-1), Bf2 (B. fragilis bft-2), Ko (K. oxytoca), Ec (EHEC/EPEC E. coli), Sl (Salmonella spp.), Sg (Shigella spp.), Cm (C. jejuni/C. coli), Sa (S. aureus).

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Samples containing selected pathogen, n

1 3

2 4

1 3

1 1 6

2 1 5

1 16

1 1 1 4 1 2

2 1 1 1 1 4

13 11

0 16 - 20

21 - 30

31 - 40

41 - 50

51 - 60

61 - 70

71 - 87

Patient age groups, years Unknown C. jejuni/C. coli

C. difficile S. aureus

B. fragilis bft Salmonella spp.

K. oxytoca Shigella spp.

EPEC/EHEC E. coli

Fig. 2. Prevalence of selected pathogenic bacteria in diarrhoea samples. The numbers of samples containing the selected pathogen are given next to the histograms for each age group. Samples that did not contain any of the selected pathogens investigated in the study were reported as ‘Unknown’.

The only other PCR-based analysis reported a prevalence of 11.4% of toxigenic C. difficile in individuals with diarrhoea in the Vhembe district, suggesting that C. difficile-related infections are an important but possibly under-reported cause of diarrhoea in SA.[9] A more detailed analysis of the prevalence and epidemiology of C. difficile at GSH as well as a comparison of various diagnostic testing modalities is currently being prepared for publication. Pathogenic E. coli are traditionally divided into several different pathotypes. While enteroaggregative E. coli are increasingly recog nised as an important cause of diarrhoea in both Africa and the rest of the world, their broad genetic diversity means that in order to detect them using a PCR-based screening method, several primer combinations detecting different targets need to be employed.[10] We therefore limited our screening procedure to detect EPEC and EHEC strains, both of which have been known to cause outbreaks of diarrhoea in Africa and can be detected by the presence of the eaeA gene.[11] In the current study, EPEC and EHEC strains were present in just under 9% of the diarrhoea cases. Of these cases, 8/12 (67%) developed prior to hospital admission, suggesting that the majority of the E. coli infections were community acquired. Blood in the stool was not evident in any of the patients colonised by EPEC/EHEC strains. A previous study by Bisi-Johnson et al.[12] identified EPEC and EHEC strains in approximately 13% of patients with diarrhoea attending a tertiary hospital in the Eastern Cape Province, SA. However, that study had a large proportion of young patients (30% of

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the patients were between the ages of 7 and 13), who are at increased risk of developing E. coli-related diarrhoea. K. oxytoca has been implicated as a cause of antibiotic-associated haemorrhagic colitis. Clinical isolates have been shown to constitutively produce β-lactamases, which confer resistance to both amino- and carboxypenicillins and allow the organism to survive antibiotic therapy and initiate infection.[13] A small proportion of healthy individuals (1.6%) are asymptomatic carriers of K. oxytoca, although the carriage rate in non-symptomatic patients attending GSH is currently unknown.[14] None of the samples positive for K. oxytoca showed evidence of blood in the stool, suggesting that K. oxytoca was not a major cause of diarrhoea among the patients examined. Non-typhoidal Salmonella spp. and Shigella spp. are responsible for a significant number of cases of diarrhoea in Africa and are regarded by the World Health Organization as organisms of global significance.[1,15] Shigella spp. in particular have been known to cause outbreaks of bloody diarrhoea among adults in much of the developing world.[4] Of the four patients colonised by pathogenic Shigella spp., two showed strong evidence of blood in the stool. Although occasional nosocomial outbreaks have been reported in SA, both pathogens are predominantly acquired through the ingestion of contaminated food and water or from person-toperson transmission via the faecal-oral route. In the current study, all the diarrhoea cases in which either pathogen was present

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were community acquired. However, the combined prevalence of approximately 5% suggests that neither pathogen was a major cause of diarrhoea in the sample group. B. fragilis is a human gut commensal that is also able to cause opportunistic invasive infections. In addition, certain strains also produce a metalloprotease enterotoxin encoded by the bft gene that enables the bacterium to cause diarrhoea.[5] Screening of the samples in the current study using primers that target all three subtypes of the bft gene revealed a low prevalence of bft-positive B. fragilis strains. Enterotoxin-producing S. aureus is a fairly rare cause of diarrhoea, but is of particular significance in the hospital environment owing to its role in postoperative infections. There have also been reports that many samples from patients with antibiotic-associated diarrhoea that were positive for enterotoxin-producing S. aureus were also positive for C. difficile.[16] In the current study, 5/8 (62.5%) of the samples positive for S. aureus also harboured at least one of the other potential pathogens that were included in the screen. C. difficile was co-present in three of these samples and is presumed to be the main cause of diarrhoea in these patients. It is not clear from these results whether the presence of S. aureus promoted colonisation by other potential pathogens or vice versa. In developing countries, Campylobacter spp., predominantly C. jejuni and C. coli, are the most common bacterial cause of diarrhoea in babies in the first year of life.[4] A previous study by Samie et al.[17] repor ted prevalences of 12.5% and 7% for C. jejuni and C. coli, respectively, among patients between the ages of 0 and 88 attending hospitals in the Venda region of SA. However, in the patient group examined in our study, it was not possible to detect either species in the stool samples using the described primer set, the specificity of which was validated using the C. jejuni-positive control DNA. An initial screening of the purified DNA using universal primers targeted to the bacterial 16S rRNA gene yielded positive products for each of the samples, indicating that the quality of the extracted DNA was suitable for PCR analysis. However, it is possible that in cases where targets were not abundant in the samples, these may not have been detected by the individual PCR screening experiments. In addition, other bacterial strains, parasites and viruses as well as non-infectious factors (e.g. direct gut toxicity of administered antibiotics) were not included in this pilot study and are reflected as being of unknown origin (Fig. 2). These might be contributing to the diarrhoea cases observed and should be included in further studies. In particular, protocols to detect the prevalence of rotavirus (which has an RNA not a DNA genome) should be used during stool analysis. Nevertheless, the results presented here suggest that, in addition to C. difficile, other bacterial pathogens such as EPEC/EHEC strains that are not routinely screened for in the hospital setting may be responsible for a number of episodes of diarrhoea among adults in SA, and this warrants further investigation. Acknowledgements. The authors acknowledge funding from the National Research Foundation of South Africa. BK acknowledges bursary funding

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from the Carnegie Corporation and the Claude Leon Foundation. The authors are grateful to Hain Lifescience for the loan of the GenoXtract automated extraction instrument and extraction kits for use in the study, and to the staff of the NHLS at GSH for assistance in the collection of samples. References 1. Lamberti LM, Bourgeois AL, Fischer Walker CL, Black RE, Sack D. Estimating diarrheal illness and deaths attributable to Shigellae and enterotoxigenic Escherichia coli among older children, adolescents, and adults in South Asia and Africa. PLoS Negl Trop Dis 2014;8(2):e2705. [http://dx.doi.org/10.1371/ journal.pntd.0002705] 2. Bradshaw D, Groenewald P, Laubscher R, et al. Initial burden of disease estimates for South Africa, 2000. S Afr Med J 2003;93(9):682-688. 3. Lemee L, Dhalluin A, Testelin S, et al. Multiplex PCR targeting tpi (triose phosphate isomerase), tcdA (toxin A), and tcdB (toxin B) genes for toxigenic culture of Clostridium difficile. J Clin Microbiol 2004;42(12):5710-5714. [http://dx.doi.org/10.1128/JCM.42.12.5710-5714.2004] 4. Pfeiffer ML, DuPont HL, Ochoa TJ. The patient presenting with acute dysentery – a systematic review. J Infect 2012;64(4):374-386. [http://dx.doi.org/10.1016/j.jinf.2012.01.006] 5. Franco AA, Cheng RK, Goodman A, Sears CL. Modulation of bft expression by the Bacteroides fragilis pathogenicity island and its flanking region. Mol Microbiol 2002;45(4):1067-1077. [http://dx.doi. org/10.1046/j.1365-2958.2002.03077.x] 6. Eyre DW, Cule ML, Wilson DJ, et al. Diverse sources of C. difficile infection identified on whole-genome sequencing. N Engl J Med 2013;369(13):1195-1205. [http://dx.doi.org/10.1056/NEJMoa1216064] 7. Rajabally NM, Pentecost M, Pretorius G, Whitelaw A, Mendelson M, Watermeyer G. The Clostridium difficile problem: A South African tertiary institution’s prospective perspective. S Afr Med J 2013;103(3):168-172. [http://dx.doi.org/10.7196/SAMJ.6012] 8. Humphries RM, Uslan DZ, Rubin Z. Performance of Clostridium difficile toxin enzyme immunoassay and nucleic acid amplification tests stratified by patient disease severity. J Clin Microbiol 2013;51(3):869-873. [http://dx.doi.org/10.1128/JCM.02970-12] 9. Samie A, Obi CL, Franasiak J, et al. PCR detection of Clostridium difficile triose phosphate isomerase (tpi), toxin A (tcdA), toxin B (tcdB), binary toxin (cdtA, cdtB), and tcdC genes in Vhembe District, South Africa. Am J Trop Med Hyg 2008;78(4):577-585. 10. Okeke IN. Diarrheagenic Escherichia coli in sub-Saharan Africa: Status, uncertainties and necessities. J Infect Dev Ctries 2009;3(11):817-842. [http://dx.doi.org/10.3855/jidc.586] 11. Wang G, Clark CG, Rodgers FG. Detection in Escherichia coli of the genes encoding the major virulence factors, the genes defining the O157:H7 serotype, and components of the type 2 Shiga toxin family by multiplex PCR. J Clin Microbiol 2002;40(10):3613-3619. [http://dx.doi.org/10.1128/JCM.40.10.3613-3619.2002] 12. Bisi-Johnson MA, Obi CL, Vasaikar SD, Baba KA, Hattori T. Molecular basis of virulence in clinical isolates of Escherichia coli and Salmonella species from a tertiary hospital in the Eastern Cape, South Africa. Gut Pathog 2011;3(1):9. [http://dx.doi.org/10.1186/1757-4749-3-9] 13. Decré D, Burghoffer B, Gautier V, Petit J-C, Arlet G. Outbreak of multi-resistant Klebsiella oxytoca involving strains with extended-spectrum beta-lactamases and strains with extended-spectrum activity of the chromosomal beta-lactamase. J Antimicrob Chemother 2004;54(5):881-888. [http:// dx.doi.org/10.1093/jac/dkh440] 14. Högenauer C, Langner C, Beubler E, et al. Klebsiella oxytoca as a causative organism of antibiotic-associated hemorrhagic colitis. N Engl J Med 2006;355(23):2418-2426. [http://dx.doi.org/10.1056/NEJMoa054765] 15. Morpeth SC, Ramadhani HO, Crump JA. Invasive non-typhi Salmonella disease in Africa. Clin Infect Dis 2009;49(4):606-611. [http://dx.doi.org/10.1086/603553] 16. Ackermann G, Thomalla S, Ackermann F, Schaumann R, Rodloff AC, Ruf BR. Prevalence and characteristics of bacteria and host factors in an outbreak situation of antibiotic-associated diarrhoea. J Med Microbiol 2005;54(2):149-153. [http://dx.doi.org/10.1099/jmm.0.45812-0] 17. Samie A, Obi CL, Barrett LJ, Powell SM, Guerrant RL. Prevalence of Campylobacter species, Helicobacter pylori and Arcobacter species in stool samples from the Venda region, Limpopo, South Africa: Studies using molecular diagnostic methods. J Infect 2007;54(6):558-566. [http://dx.doi. org/10.1016/j.jinf.2006.10.047] 18. Weisburg WG, Barns SM, Pelletier DA, Lane DJ. 16S ribosomal DNA amplification for phylogenetic study. J Bacteriol 1991;173(2):697-703. 19. Kato N, Liu CX, Kato H, et al. A new subtype of the metalloprotease toxin gene and the incidence of the three bft subtypes among Bacteroides fragilis isolates in Japan. FEMS Microbiol Lett 2000;182(1):171176. [http://dx.doi.org/10.1016/S0378-1097(99)00585-6] 20. Kovtunovych G, Lytvynenko T, Negrutska V, Lar O, Brisse S, Kozyrovska N. Identification of Klebsiella oxytoca using a specific PCR assay targeting the polygalacturonase pehX gene. Res Microbiol 2003;154(8):587-592. [http://dx.doi.org/10.1016/S0923-2508(03)00148-7] 21. Linton D, Lawson AJ, Owen RJ, Stanley J. PCR detection, identification to species level, and fingerprinting of Campylobacter jejuni and Campylobacter coli direct from diarrheic samples. J Clin Microbiol 1997;35(10):2568-2572. 22. Brakstad OG, Aasbakk K, Maeland JA. Detection of Staphylococcus aureus by polymerase chain reaction amplification of the nuc gene. J Clin Microbiol 1992;30(7):1654-1660. 23. Rahn K, de Grandis SA, Clarke RC, et al. Amplification of an invA gene sequence of Salmonella typhimurium by polymerase chain reaction as a specific method of detection of Salmonella. Mol Cell Probes 1992;6(4):271-279. [http://dx.doi.org/10.1016/0890-8508(92)90002-F] 24. Ojha SC, Yean Yean C, Ismail A, Singh K-KB. A pentaplex PCR assay for the detection and differentiation of Shigella species. Biomed Res Int 2013;2013:412370. [http://dx.doi.org/10.1155/2013/412370]

Accepted 9 December 2014.

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Predictors of in-hospital mortality following noncardiac surgery: Findings from an analysis of a South African hospital administrative database Y Moodley, MMedSci; B M Biccard, MB ChB, FCA (SA), FFARCSI, MMedSci, PhD Perioperative Research Group, Department of Anaesthetics, College of Health Sciences, Nelson R Mandela School of Medicine, University of KwaZulu-Natal and Inkosi Albert Luthuli Central Hospital, Durban, South Africa Corresponding author: Y Moodley (moodleyyo@ukzn.ac.za)

Background. Predictors of in-hospital mortality (IHM) following non-cardiac surgery in South African (SA) patients are not well described. Objective. To determine the association between patient comorbidity and IHM in a cohort of SA non-cardiac surgery patients. Methods. Data related to comorbidity and IHM for 3 727 patients aged ≥45 years were obtained from a large administrative database at a tertiary SA hospital. Logistic regression analysis was used to determine independent predictors of IHM. In addition, population-attributable fractions (PAFs) were calculated for all clinical factors identified as independent predictors of IHM. Results. Renal dysfunction, congestive heart failure, cerebrovascular disease, male gender and high-risk surgical specialties were independently associated with IHM (odds ratios (95% confidence intervals) 7.585 (5.480 - 10.50); 2.604 (1.119 - 6.060); 2.645 (1.414 - 4.950); 1.433 (1.107 1.853); and 1.646 (1.213 - 2.233), respectively). Ischaemic heart disease, diabetes and hypertension were not identified as independent predictors of IHM in SA non-cardiac surgery patients. Renal dysfunction had the largest contribution to IHM in this study (PAF 0.34), followed by high-risk surgical specialties (PAF 0.15), male gender (PAF 0.08), cerebrovascular disease (PAF 0.03) and congestive heart failure (PAF 0.03). Conclusion. Renal dysfunction, congestive heart failure, cerebrovascular disease, male gender and high-risk surgical specialties were major contributors to increased IHM in SA non-cardiac surgery patients. Prospectively designed research is required to determine whether ischaemic heart disease, diabetes and hypertension contribute to IHM in these patients. S Afr Med J 2015;105(2):126-129. DOI:10.7196/SAMJ.8268

Weiser et al.[1] estimated the global number of patients undergoing surgery in 2004 to be over 234 million, with 0.5% of these patients dying during or shortly after their surgical procedure. These alarming statistics emphasise the importance of surgical safety and the need to identify risk factors associated with in-hospital mortality (IHM) in patients before their surgery, so that these risk factors may be appropriately managed to reduce the risk of perioperative IHM. Studies of perioperative mortality have been confined primarily to European[2] and North American[3] surgical popu lations. Interestingly, the clinical importance of comorbi dities in the pathology of adverse outcomes may differ between South African (SA) patients and patients from Europe and North America.[4] The current epidemiological transition towards a higher burden of non-communicable disease in SA patients appears to explain these observed differences.[4,5] For example, while hypertension has been associated with an almost four-fold increased risk of postoperative mortality in SA non-cardiac vascular surgery patients,[5] similar research by a vascular surgery research group in New England, USA, did not identify hypertension as a predictor of adverse perioperative events.[6] It is therefore imperative that SA non-cardiac patients be stratified for perioperative risk through a country-specific list of appropriate comorbid risk factors. We sought to determine the relationship between several common comorbid conditions and IHM in a cohort of SA non-cardiac surgery patients.

Methods

This study was conducted at Inkosi Albert Luthuli Central Hospital (IALCH), Durban, SA. The hospital provides a tertiary service to patients living in the province of KwaZulu-Natal.

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Ethical approval was obtained from the Biomedical Research Ethics Committee of the University of KwaZulu-Natal before commencing the study. The hospital’s administrative database was used to identify all patients aged ≥45 years who underwent elective non-cardiac surgery at the hospital between 2005 and 2012. International Statistical Classification of Diseases and Related Health Problems (10th edition) (ICD-10) codes were then used to extract data related to comorbidities from patient electronic medical records and create a database for statistical analysis. We used an age of ≥45 years as an inclusion criterion for this study, in keeping with other large studies of perioperative outcomes.[7] The effects of the following comorbidities on IHM were investigated: hypertension, diabetes, renal dysfunction, ischaemic heart disease, congestive heart failure and cerebrovascular disease/stroke. Hypertension was included because it is highly prevalent in the SA surgical population.[5] The other five comorbidities are established risk factors for poor perioperative outcomes and form part of Lee’s Revised Cardiac Risk Index (RCRI),[8] which is commonly used as a perioperative risk stratification tool at IALCH. In-hospital death was determined by evaluating each patient’s discharge record following their surgery. Vascular surgery, thoracic surgery and general surgery were classified as high-risk surgical specialties.[2] Duplicate records, patients aged <45 years, cardiac surgery patients and non-surgical patients were excluded from the final data set. Categorical data were analysed using the χ2 test or Fisher’s exact test, where appropriate. Binary logistic regression was used to identify independent associations between comorbidities and IHM. A result was considered statistically significant at a p-value of <0.05. Results for the logistic regression analysis are presented as odds ratios (ORs) with 95% confidence intervals (CIs). The

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population-attributable fraction (PAF) for each factor independently associated with a higher incidence of IHM was also calculated.[9] Univariate and multivariate statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS) version 21 (SPSS Inc., USA).

The results of the PAF analysis for each predictor of IHM are shown in Table 4. Renal

dysfunction had the largest contribution to IHM in this study (PAF 0.34), followed by

7 646 adult patients admitted for cardiac and non-cardiac procedures registered on hospital administrative database (2005 - 2012) Excluded patients: (i) 598 duplicates (ii) 166 patients aged <45 years

Results

The final study cohort comprised 3 727 non-cardiac surgery patients. Reasons for excluding patients from the final data set are shown in Fig. 1. Overall, the cumulative incidence of IHM in this study was 7.5%. Table 1 shows the proportion of patients in the final study cohort by surgical specialty. Almost half of all patients underwent surgery that fell within a high-risk surgical specialty group. Renal surgery and vascular surgery were the surgical specialties associated with the highest levels of IHM (incidences of 24.3% and 7.0%, respectively). The preoperative clinical characteristics of the study cohort are shown in Table 2. There was a high prevalence of diabetes and hypertension in the cohort (46.7% and 79.1%, respectively). Statistically significant univariate associations were observed between IHM and male gender (p<0.001), elderly age (p<0.001), diabetes (p<0.001), cerebrovascular disease (p=0.007) and renal dysfunction (p<0.001) (Table 2). Three comorbid conditions (renal dys f unction, congestive heart failure and cerebrovascular disease) were inde pendently associated with an increased risk of IHM following non-cardiac surgery (Table 3). In addition, male gender and high-risk surgical specialties were also independently associated with an increased risk of IHM in this study (Table 3).

6 882 patients ≥45 years old undergoing cardiac and non-cardiac procedures Excluded patients: (ii) 1 727 patients undergoing cardiac procedures (iv) 1 428 patients transferred postoperatively to medical/ non-surgical wards 3 727 patients ≥45 years old undergoing non-cardiac procedures transferred postoperatively to surgical wards

Fig. 1. Study profile.

Table 1. Proportion of patients in the final study cohort by surgical specialty Surgical specialty

n (% of final study cohort)

Gynaecological surgery

130 (3.5)

General surgery

481 (12.9)

Vascular surgery

1 164 (31.2)

Plastic surgery

91 (2.4)

Orthopaedic surgery

321 (8.6)

Urological surgery

370 (9.9)

Ear, nose and throat surgery

96 (2.6)

Renal surgery

494 (13.3)

Thoracic surgery

162 (4.4)

Ophthalmological surgery

418 (11.2)

Total

3 727 (100.0)

Table 2. Baseline patient clinical characteristics expressed as a frequency (%)

Patient characteristic

Total cohort (N=3 727) n (%)

Patients with in-hospital mortality (N=278) n (%)

Patients without in-hospital mortality (N=3 449) n (%)

p-value*

Male gender

1 591 (42.7)

150 (54.0)

1 441 (41.8)

<0.001

Age >65 years

1 265 (33.9)

65 (23.4)

1 200 (34.8)

<0.001

Ischaemic heart disease

420 (11.3)

23 (8.3)

397 (11.5)

0.101

Diabetes

1 739 (46.7)

98 (35.3)

1 641 (47.6)

<0.001

Congestive heart failure

50 (1.3)

7 (2.5)

43 (1.2)

0.095

Renal dysfunction

487 (13.1)

119 (42.8)

368 (10.7)

<0.001

Cerebrovascular disease/stroke

87 (2.3)

13 (4.7)

74 (2.1)

0.007

Hypertension

2 948 (79.1)

209 (75.2)

2 739 (79.4)

0.095

High-risk surgical specialty

1 807 (48.5)

125 (45.0)

1 682 (48.8)

0.222

*p<0.05 was considered statistically significant.

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Table 3. Results of multivariate analysis: clinical variables independently associated/ not independently associated with IHM Clinical variable

OR (95% CI)

p-value*

Male gender

1.433 (1.107 - 1.853)

0.006

Age >65 years

0.840 (0.616 - 1.147)

0.273

Ischaemic heart disease

0.815 (0.515 - 1.290)

0.383

Diabetes

0.832 (0.634 - 1.092)

0.185

Congestive heart failure

2.604 (1.119 - 6.060)

0.026

Renal dysfunction

7.585 (5.480 - 10.50)

<0.001

Cerebrovascular disease/stroke

2.645 (1.414 - 4.950)

0.002

Hypertension

1.119 (0.823 - 1.522)

0.474

High-risk surgical specialty

1.646 (1.213 - 2.233)

<0.001

*p<0.05 was considered statistically significant.

Table 4. PAFs for clinical variables associated with IHM in SA non-cardiac surgery patients Comorbidity

PAF

Congestive heart failure

0.03

Renal dysfunction

0.34

Cerebrovascular disease/stroke

0.03

High-risk surgical specialty

0.15

Male gender

0.08

high-risk surgery (PAF 0.15), male gender (PAF 0.08), cerebrovascular disease (PAF 0.03) and congestive heart failure (PAF 0.03).

Discussion

The incidence of postoperative IHM in our study was much higher than that reported for most Nothern and Western European countries.[10] This may be explained in part by the fact that almost half our patient population underwent surgery in a high-risk specialty, placing them at increased risk of IHM after the procedures. We found univariate associations between increased IHM and male gender, age >65 years, diabetes, renal dysfunction, cerebrovascular disease and high-risk surgery. Interestingly, while our observation that renal dysfunction and cerebrovascular disease were more common in patients who died in hospital was in agreement with the studies of Pearse et al.,[10] Charlson et al.[11] and Elixhauser et al.,[12] our observation that diabetes was significantly more common in patients who did not suffer IHM was in contrast to the findings of these studies. Following multivariate statistical analysis, male gender, renal dysfunction, congestive heart failure, cerebrovascular disease and high-risk surgical specialties were identified as independent predictors of IHM in SA non-cardiac surgery patients. While the

importance of renal dysfunction has been described in overseas surgical populations, its contribution to IHM in SA non-cardiac surgery patients is of concern, with just over one-third of the risk associated with IHM being attributed to renal dysfunction. Waikar et al.[13] found that although IHM rates among patients with acute renal dysfunction had decreased between 1988 and 2002, mortality rates for patients not requiring dialysis and those requiring dialysis were >20% and >30%, respectively. In the perioperative setting, a serum creatinine level of >177 µmol/L has previously been shown to be an independent predictor of perioperative cardiovascular morbidity and mortality in non-cardiac surgery patients.[8] ‘Renal disease’ and ‘renal failure’ were also associated with IHM in the studies of Charlson et al.[11] and Elixhauser et al.,[12] respectively. In addition to the risk stratification studies of Charlson et al.[11] and Elixhauser et al.,[12] congestive heart failure was also identified as an independent predictor of cardiovascular morbidity and mortality in patients undergoing non-cardiac surgery by Lee et al.,[8] as well as in the validation study of Lee’s RCRI.[14] Hernandez et al.[15] observed substantial levels of morbidity and mortality in older patients with congestive heart failure who underwent non-cardiac surgery. Similarly, Hammill et al.[16] found that patients with heart failure were at higher risk of operative mortality than those without (adjusted OR 1.63; 95% CI 1.52 - 1.74). It is estimated that up to 14% of patients with a first-time stroke may have stroke recurrence within a year.[17] Patients with recurrent stroke have a higher mortality rate than those with a first-time stroke,[18] with surgery and its associated physiological stresses likely to increase the risk of mortality. The findings of this study are once again in agreement with the studies by Lee et al.[8] and Charlson et al.,[11] who observed a higher risk

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of perioperative mortality in patients with a history of cerebrovascular disease. High-risk surgical specialties were also found to be associated with an increased risk of IHM in our study, which is in agreement with a large database study of 3.7 million surgical procedures conducted in 102 Dutch hospitals by Noordzij et al.[2] We did not find ischaemic heart disease, diabetes or hypertension to be independently associated with IHM in this study. It is likely that these comorbidities were under-diagnosed in our non-cardiac surgery population, in particular in the group of patients who suffered IHM. The problem of under-diagnosis of comorbidities has been established by a number of studies,[19-21] although the reasons for underdiagnosis, as in our study, remain unclear. In addition, we did not observe elderly age to be an independent predictor of IHM following non-cardiac surgery in SA patients, although this finding may be related to the fact that only a third of our cohort was >65 years old.

Study limitations

This study was not without limitations. The identification of comorbidities in this study was based on a physician’s diagnosis at admission and the subsequent coding of this diagnosis on the hospi tal administrative database. As such, we were unable to measure the extent of undiagnosed comorbidity in our study, which is likely to be an important determinant of the findings for ischaemic heart disease, diabetes and hypertension. Also, the admini strative database was limited by the accuracy with which perioperative medication was recorded; we were therefore unable to investigate the impact of medication use on IHM following non-cardiac surgery. A prospectively designed study that includes appropriate measures to diagnose patient comorbidity, as well as perioperative medication use, is required.

Conclusion

The incidence of IHM following non-cardiac surgery in our study was much higher than that reported for several developed-world European countries. This finding highlights the importance of identifying independent predictors of IHM in non-cardiac surgery patients, so that attempts can be made to optimise a patient’s condition prior to their surgery and reduce their risk of postoperative IHM. Adequate preoperative management of renal dysfunction, congestive heart failure and cerebrovascular disease may improve outcome after surgery. It is likely that ischaemic heart disease, diabetes and hypertension are underdiagnosed in SA non-cardiac surgery patients. Further prospectively designed research is required to confirm our findings.

RESEARCH

Acknowledgements. This work forms a component of the doctoral studies of Y Moodley, who is the recipient of a doctoral scholarship awarded by the South African National Research Foundation. Referencew 1. Weiser TG, Regenbogen SE, Thompson KD, et al. An estimation of the global volume of surgery: A modelling strategy based on available data. Lancet 2008;372(9633):139-144. [http://dx.doi. org/10.1016/S0140-6736(08)60878-8] 2. Noordzij PG, Poldermans D, Schouten O, Bax JJ, Schreiner FA, Boersma E. Postoperative mortality in The Netherlands: A population-based analysis of surgery-specific risk in adults. Anesthesiology 2010;112(5):1105-1115. [http://dx.doi.org/10.1097/ALN.0b013e3181d5f95c] 3. Barnett S, Moonesinghe SR. Clinical risk scores to guide perioperative management. Postgrad Med J 2011;87(1030):535-541. [http://dx.doi.org/10.1136/pgmj.2010.107169] 4. Steyn K, Sliwa K, Hawken S, et al. Risk factors associated with myocardial infarction in Africa: The INTERHEART Africa study. Circulation 2005;112(23):3554-3561. [http://dx.doi.org/10.1161/ CIRCULATIONAHA.105.563452] 5. Biccard BM, Nepaul S. Risk factors associated with intermediate and long-term mortality following vascular surgery in South African patients. Cardiovasc J Afr 2010;21(5):263-267. [http://dx.doi.org/CVJ-21.004] 6. Bertges DJ, Goodney PP, Zhao Y, et al. The Vascular Study Group of New England Cardiac Risk Index (VSG-CRI) predicts cardiac complications more accurately than the Revised Cardiac Risk Index in vascular surgery patients. J Vasc Surg 2010;52(3):674-683. [http://dx.doi.org/10.1016/j.jvs.2010.03.031] 7. Devereaux PJ, Chan MT, Alonso-Coello P, et al. Association between postoperative troponin levels and 30-day mortality among patients undergoing noncardiac surgery. JAMA 2012;307(21):2295-2304. [http://dx.doi.org/10.1001/jama.2012.5502] 8. Lee TH, Marcantonio ER, Mangione CM, et al. Derivation and prospective validation of a simple index for prediction of cardiac risk of major noncardiac surgery. Circulation 1999;100(10):1043-1049. [http://dx.doi.org/10.1161/01.CIR.100.10.1043] 9. Steenland K, Armstrong B. An overview of methods for calculating the burden of disease due to specific risk factors. Epidemiology 2006;17(5):512-519. [http://dx.doi.org/10.1097/01. ede.0000229155.05644.43]

10. Pearse RM, Moreno RP, Bauer P, et al. Mortality after surgery in Europe: A 7 day cohort study. Lancet 2012;380(9847):1059-1065. [http://dx.doi.org/10.1016/S0140-6736(12)61148-9] 11. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: Development and validation. J Chronic Dis 1987;40(5):373-383. [http://dx.doi. org/10.1016/0021-9681(87)90171-8] 12. Elixhauser A, Steiner C, Harris DR, Coffey RM. Comorbidity measures for use with administrative data. Med Care 1998;36(1):8-27. 13. Waikar SS, Curhan GC, Wald R, McCarthy EP, Chertow GM. Declining mortality in patients with acute renal failure, 1988 to 2002. J Am Soc Nephrol 2006;17(4):1143-1150. [http://dx.doi.org/10.1681/ASN.2005091017] 14. Boersma E, Kertai MD, Schouten O, et al. Perioperative cardiovascular mortality in noncardiac surgery: Validation of the Lee cardiac risk index. Am J Med 2005;118(10):1134-1141. [http://dx.doi. org/10.1016/j.amjmed.2005.01.064] 15. Hernandez AF, Whellan DJ, Stroud S, Sun JL, O’Connor CM, Jollis JG. Outcomes in heart failure patients after major noncardiac surgery. J Am Coll Cardiol 2004;44(7):1446-1453. [http://dx.doi. org/10.1016/j.jacc.2004.06.059] 16. Hammill BG, Curtis LH, Bennett-Guerrero E, et al. Impact of heart failure on patients undergoing major noncardiac surgery. Anesthesiology 2008;108(4):559-567. [http://dx.doi.org/10.1097/ALN.0b013e31816725ef] 17. Dickerson LM, Carek PJ, Quattlebaum RG. Prevention of recurrent ischemic stroke. Am Fam Physician 2007;76(3):382-388. 18. Jorgensen HS, Nakayama H, Reith J, Raaschou HO, Olsen TS. Stroke recurrence: Predictors, severity, and prognosis. The Copenhagen Stroke Study. Neurology 1997;48(4):891-895. [http://dx.doi. org/10.1212/WNL.48.4.891] 19. Ashworth M, Lloyd D, Smith RS, Wagner A, Rowlands G. Social deprivation and statin prescribing: A cross-sectional analysis using data from the new UK general practitioner ‘Quality and Outcomes Framework’. J Public Health (Oxf) 2007;29(1):40-47. [http://dx.doi.org/10.1093/pubmed/fdl068] 20. Soljak M, Samarasundera E, Indulkar T, Walford H, Majeed A. Variations in cardiovascular disease under-diagnosis in England: National cross-sectional spatial analysis. BMC Cardiovasc Disord 2011;11:12. [http://dx.doi.org/10.1186/1471-2261-11-12] 21. Ward PR, Noyce PR, St Leger AS. Are GP practice prescribing rates for coronary heart disease drugs equitable? A cross sectional analysis in four primary care trusts in England. J Epidemiol Community Health 2004;58(2):89-96. [http://dx.doi.org/10.1136/jech.58.2.89]

Accepted 9 December 2014.

Human myiasis in rural South Africa is under-reported S K Kuria,1 PhD; H J C Kingu,2 MD, MMed (Surg); M H Villet,3 PhD; A Dhaffala,2 MB ChB, MMed (Surg) epartment of Biological Sciences, Faculty of Natural Sciences, Walter Sisulu University, Mthatha, Eastern Cape, South Africa D Department of Surgery, Faculty of Health Sciences, Walter Sisulu University, Mthatha, Eastern Cape, South Africa 3 Department of Entomology and Zoology, Faculty of Science, Rhodes University, Grahamstown, Eastern Cape, South Africa 1 2

Corresponding author: S K Kuria (kkuria@wsu.ac.za)

Background. Myiasis is the infestation of live tissue of humans and other vertebrates by larvae of flies. Worldwide, myiasis of humans is seldom reported, although the trend is gradually changing in some countries. Reports of human myiasis in Africa are few. Several cases of myiasis were recently seen at the Mthatha Hospital Complex, Mthatha, Eastern Cape Province, South Africa (SA). Objective. Because of a paucity of literature on myiasis from this region, surgeons and scientists from Walter Sisulu University, Mthatha, decided to document myiasis cases presenting either at Nelson Mandela Academic Hospital or Umtata General Hospital from May 2009 to April 2013. The objective was to determine the incidence, epidemiology, patient age group and gender, and fly species involved. The effect of season on incidence was also investigated. Results. Twenty-five cases (14 men and 11 women) were recorded in the 4-year study period. The fly species involved were Lucilia sericata, L. cuprina, Chrysomya megacephala, C. chloropyga and Sarcophaga (Liosarcophaga) nodosa, the latter being confirmed as an agent for human myiasis for the first time. The patients were 3 - 78 years old (median 56). Cases were most numerous during spring and summer, and were associated with underlying pathologies typical of ageing. Conclusion. Myiasis is a more common medical condition than expected in the Mthatha region. The study shows that human myiasis is still frequently encountered in SA, and there is a need to understand its epidemiology better. S Afr Med J 2015;105(2):129-133. DOI:10.7196/SAMJ.8118

Infestation of live tissue of humans and other verte brates by larvae (maggots) of flies is termed myiasis. The disease most commonly occurs in the tropics and subtropics.[1-2] Clinically, human myiasis may be classified according to the location of the body invaded by maggots (ocular, nasal, oral, intestinal, etc.).[1-2] Cutaneous

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myiasis may be divided further into three main types: furuncular, creeping and wound myiasis.[3] Wound myiasis is the most prevalent type.[4] Different fly species cause myiasis in different regions of the world. There are approximately 50 species of Diptera (mostly in the families Oestridae, Calliphoridae and Sarcophagidae) that regularly

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scientists from Walter Sisulu University (WSU) and a decision to document the incidence of myiasis in the Eastern Cape, especially the Transkei region, and to identify the fly species responsible.

Methods

The study group constituted patients presenting with cutaneous myiasis and admitted between May 2009 and April 10

8 7

2013 to the MHC, which comprises Nelson Mandela Academic Hospital (NMAH) and Umtata General Hospital (UGH). Biodata for relevant patients were captured and included gender, age, geographical location, diagnosis and management. Examination of patients was carried out by surgeons and their diagnoses were recorded. Samples of live maggots were extracted from the wounds, which were then irrigated

Cases, n

cause myiasis in humans.[1] Flies of the genus Lucilia are the most common causes of myiasis.[1,5] Cases of human myiasis have been documented from many countries in Africa, most of them caused by the blowfly Cordylobia anthropophaga (Table 1). Some of the earliest cases of myiasis reported in Africa involved livestock and larvae of the family Oestridae, with several outbreaks reported between 1920 and 1960 in South Africa (SA) and Namibia.[6] Myiasis is usually treated by removal of the larvae and treatment of associated infections. However, some maggots are deliberately used in wound treatment, technically referred to as maggot debridement therapy.[7] Maggots are known to benefit wounds by removing dead and necrotic tissue, secreting antimicro足 bial compounds and sometimes stimulating wound healing.[8] The commonest species used for this purpose is L. sericata,[7] which is distributed throughout the world, infesting humans in the Americas, Africa, Europe and Asia.[1,8] From May 2009, surgeons working in the Mthatha Hospital Complex (MHC), Mthatha, Eastern Cape Province, SA, noted several patients presenting with cutaneous myiasis. This led to the involvement of

6 5

4 3

Diabetic foot

Other

2 1 0 Burns

Peripheral vascular disease

Cancerous skin ulcer Medical diagnosis

Fig. 1. Medical conditions predisposing to human myiasis.

Fig. 2. Distribution of patients with myiasis, classified by associated fly species.

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with weak hydrogen peroxide to kill any remaining maggots. Subsequent treatment depended on the patient’s diagnosis. Live maggots were submitted to the WSU entomology laboratory. Since identification of fly larvae is difficult, the extracted maggots were fed on minced beef in the laboratory until they pupated. The emerging adult flies were collected and identified to species level. In a few cases, maggot samples failed to survive in the laboratory. Since adult myiasis-causing flies are poikilothermic, their activity is affected by weather conditions (mainly temperature[9]). Temperature data for Mthatha were obtained from the South African Weather Service to determine the relationship of season to human myiasis.

Results

In total, 25 cases (14 men and 11 women) of cutaneous myiasis were recorded. Cases most commonly occurred in February and March, almost all in summer and autumn (Table 2). The ages of the patients ranged from 3 to 78 years (median 56) (Table 2). The most commonly diagnosed medical condition predisposing to human myiasis in this series was lower limb gangrene due to peripheral vascular disease, followed by burns, cancerous ulcers and diabetic ulcers (Fig. 1). Anatomically, lower limb infestation was the most common (Table 2). The distribution of patients with myiasis, classified by associated fly species, is shown in Fig. 2. Five fly species were identified from the infestations: L. sericata (Meigen) (n=3), L. cuprina (Wiedemann) (n=14), Chrysomya chloropyga (n=1), C. megacephala (n=1), and Sarcophaga (Liosarcophaga) nodosa Engel (n=2); in five cases the maggots died before reaching adulthood (Table 2). In two cases maggots belonging to two fly species were collected from one patient: L. cuprina and S. nodosa in one case and C. megacephala and C. chloropyga from the other. The cases were drawn from a wide area of the Eastern Cape (Fig. 2), which is the catchment area that falls under the management of the MHC located in Mthatha. There was little difference between summer and autumn temperatures in Mthatha during the study period (Table 3). The highest temperature recorded for summer was 38.6°C in 2009/2010 and for autumn 38.1°C in 2012. There were no extreme weather conditions in Mthatha (Table 3).

Discussion

Human cutaneous myiasis may be more widespread in the Eastern Cape than previously reported (Fig. 2). In 4 years

25 cases were seen, represen ting to our knowledge the highest number of individuals with human myiasis to be reported from SA. Owing to the paucity of literature on myiasis literature from this region, it is difficult to estimate the incidence of myiasis

in the country. The majority of cases were concentrated around NMAH and UGH, but given the widespread occurrence of the species involved,[1,10] there is a strong possibility that cases are seen in other medical facilities in the Eastern Cape but

Table 1. Cases of human myiasis reported in Africa, classified by infestation site Type of myiasis

Species of fly

Locality

Reference

Ocular

Oestrus ovis

Libya – Aljabal Algharbi

South Africa

Botswana – Kalahari Desert

South Africa – Onderstepoort

Zimbabwe – Gwale

South Africa

Ocular and nasal

O. ovis

Morocco

Cutaneous

Cordylobia anthropophaga

Cameroon

Congo

DR Congo

Namibia

Nigeria – Harcourt

Nigeria – Niger Delta

Senegal (3 cases)

28, 29, 30

Sierra Leone

Sudan – Gazira state

The Gambia – Fajara

Zimbabwe – Harare

C. rodhaini

Ethiopia

Cordylobia spp.

South Africa – Pretoria

C. anthropophaga

Angola

East Africa

Gabon

Ghana

Ghana – Accra

Nigeria – Aba, South East

Southern Africa

Tanzania – Ntagatcha

Uganda

Furuncular

West Africa

C. rodhaini

Ghana

Gasterophilus sp.

Zimbabwe – Harare

Sarcophaga spp. and Oestrus sp.

Egypt – Minia Governorate

Intestinal

Chrysomya chloropyga

South Africa

Rectal

Muscina stabulans

Zimbabwe

Urinogenital

Sarcophaga sp. and Eristalis tenax

Zimbabwe

Sanguinivorous

Auchmeromyia luteola

Zimbabwe – Harare, Mutare and Hwange

Gastrointestinal

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Table 2. Details of patients presenting with cutaneous myiasis at the MHC Age (years)

Gender

Diagnosis and anatomical part involved

Maggot collection date

Fly species

Post skin graft, chest

24 November 2010

Maggots died

Contracture release, neck

19 December 2011

Maggots died

Donor skin, right thigh

7 March 2011

L. cuprina

Burns, left knee

5 May 2009

S. nodosa

Kaposiâ&#x20AC;&#x2122;s sarcoma, both lower limbs

21 February 2011

L. cuprina

Gangrenous autoamputation, left foot

4 March 2013

L. cuprina, S. nodosa

Biobrane dressing, facial burns

28 March 2011

L. cuprina

Ulcerative cancer, right breast

2 April 2013

L. cuprina

Burns, right hand

20 February 2013

L. cuprina

Cancer, mouth floor

29 October 2010

L. cuprina

Gangrene, right foot

28 February 2011

L. cuprina

Diabetic ulcer, right foot

11 March 2011

L. cuprina

Necrotising fasciitis, penis, perineum and anterior abdominal wall

8 March 2011 (afternoon)

L. sericata

Gangrene, right dorsum of foot

7 May 2009

L. cuprina

Diabetic ulcer, right foot

23 May 2011

L. cuprina

Amputated stump, left leg

2 March 2011

L. cuprina

Burns, right foot

12 May 2009

Maggots died

Lymphoedema, left leg

11 August 2011

L. sericata

Dog bite, left leg

18 February 2011

L. cuprina

Symes amputation stump, right foot

8 March 2011 (morning)

L. sericata

Diabetic ulcer, left foot

21 February 2011

L. cuprina

Cancerous ulcer, right leg

3 June 2010

C. megacephala, C. chloropyga

Gangrene, right foot

17 January 2012

Maggots died

Gangrene, left leg

24 April 2012

Maggots died

Burns, back

17 January 2012

L. cuprina

F = female; M = male.

Table 3. Seasonal mean (standard error of the mean), minimum and maximum temperatures (oC) obtained from the Mthatha weather station (May 2009 - May 2013) (South African Weather Service) Seasons Summer (December - February) Year

Mean (SE)

2009/2010

22.06 (0.37)

38.6

10.9

2010/2011

21.76 (0.28)

35.7

2011/2012

22.24 (0.31)

37.6

2012/2013

21.74 (0.32)

37.1

Autumn (March - May)

Winter (June - August)

Spring (September - November)

Mean (SE)

21.03 (0.30)

36.0

9.9

14.12 (0.36)

31.4

-0.9

17.84 (0.41)

37.5

3.5

19.72 (0.37)

36.6

3.2

14.59 (0.37)

36.0

1.1

18.83 (0.41)

38.6

4.8

12.2

18.90 (0.41)

35.5

3.2

12.49 (0.29)

34.5

-0.1

17.88 (0.35)

39.4

4.0

10.8

18.56 (0.38)

38.1

1.7

13.50 (0.36)

35.2

0.3

16.99 (0.33)

35.0

1.8

9.4

18.44 (0.42)

37.9

4.3

14.74 (0.33)

35.3

-0.2

2009

Mx = maximum; Mn = minimum.

are not reported. To estimate the extent of human myiasis in SA in general, there is a need to sensitise medical practitioners to document and report all human myiasis cases across the other provinces. Several fly species are known to cause human myiasis. The commonest species in Africa is C. anthropophaga (Table 1), which does not occur in Eastern Cape because the climate is too cool. Outside the geographical distribution of C. anthropophaga, the usual causes of human myiasis worldwide are L. sericata and

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L. cuprina.[1] Our study has shown that L. cuprina is the most commonly involved species around Mthatha. C. chloropyga and C. megacephala have been reported in myiasis cases elsewhere (Table 1), so their occurrence in the Eastern Cape is not surprising. However, S. nodosa, previously only suspected of causing myiasis in animals,[1] was shown to cause human myiasis for the first time only in 2009.[11] The collection of two species from the same case is an unusual infestation that is rarely reported.[7] All species

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are associated with decaying animal material and have wide distributions in Africa. All the cases we recorded were cutaneous myiases. There was no obvious gender bias. Previously identified factors that predispose humans to myiasis include poverty, an immunosuppressed state, alcohol, unhygienic conditions and old age.[3] Results suggest that debilitating diseases, especially in advanced age (the elderly being prone to infection, cancer and diabetes), predispose to cutaneous myiasis. Older patients may be more frail or sleep more than younger individuals, and may fail to fend off flies that lay their eggs in open wounds.[12] Maintenance of cleanliness in both homes and hospitals may reduce the incidence of myiasis. There is therefore a need to educate people who care for the elderly on how to avoid or minimise fly infestations. In the USA, it has been reported that myiasis infestations tend to occur in late summer (August - October).[13] In the Eastern Cape the observation was different, with 52% of cases (n=13) occurring in autumn (March - May) and 32% (n=8) in summer. In summer and autumn, the weather conditions recorded at Mthatha are favourable for fly activity and reproduction. However, in the current study, infestations were also reported in spring (n=2) and winter (n=2), before adult fly populations would have built up significantly,[14] because the generally warmer weather conditions in Mthatha allow flies to be active throughout most of the year.[9] Only cutaneous wound myiasis was recorded in our study, probably because the surgeons involved in the study are attached to the burns and general surgery specialties and do not see patients managed by specialties such as otorhinolaryngology or ophthalmology, who are more likely to encounter nasal or ocular myiasis, respectively. Acknowledgements. We are grateful to Mr S Mguni for maintaining the rearing facilities. We also thank Mr S Swanepoel for his expert assistance in GIS and Mr G Sampson of the South African Weather Service for weather data for Mthatha. This project was funded by a research grant from WSU through the Research Directorate. References 1. Zumpt FKE. Myiasis in Man and Animals in the Old World: A Textbook for Physicians, Veterinarians and Zoologists. London: Butterworths, 1965. 2. Francesconi F, Lupi O. Myiasis. Clin Microbiol Rev 2012;25(1):79-105. [http://dx.doi.org/10.1128/ CMR.00010-11] 3. Robbins K, Khachemoune A. Cutaneous myiasis: A review of the common types of myiasis. Int J Dermatol 2010;49(10):1092-1098. [http://dx.doi.org/10.1111/j.13654632.2010.04577.x] 4. Sherman RA. Wound myiasis in urban and suburban United States. Arch Intern Med 2000;160(13):20042014. [http://dx.doi.org/10.1001/archinte.160.13.2004] 5. Zumpt FKE. The problem of intestinal myiasis in humans. S Afr Med J 1963;23:305-307. 6. Basson PA. Studies on specific oculo-vascular myiasis of domestic animals (UITPEULOOG). J S Afr Vet Assoc 1962;33(13):347-349. 7. Vilcinskas A. From traditional maggot therapy to modern biosurgery. In: Vilcinskas A, ed. Insect Biotechnology. Dordrecht: Springer, 2011:67-75. 8. Service MW. Medical Entomology for Students. London: Chapman & Hall, 2008:152-167. [http:// dx.doi.org/10.1017/CBO9780511811012] 9. Richards CS, Price BW, Villet MH. Thermal ecophysiology of seven carrion-feeding blowflies in Southern Africa. Entomol Exp Appl 2009;131(1):11-19. [http://dx.doi.org/10.1111/j.15707458.2009.00824.x] 10. Richards CS, Williams KA, Villet MH. Predicting geographic distribution of seven blowfly species (Diptera: Calliphoridae) in South Africa. Afr Entomol 2009;17(2):170-182. [http://dx.doi. org/10.4001/003.017.0207]

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11. Kuria SK, Kingu HJC, Vasaikar SD, et al. New fly species causing human myiasis identified in Eastern Cape, South Africa. S Afr Med J 2010;100(9):580-581. 12. Kingu HJ, Kuria SK, Villet MH, Mkhize JN, Iisa JM, Dhaffala A. Cutaneous myiasis: Is Lucilia cuprina safe and acceptable for maggot debridement therapy? Journal of Cosmetics, Dermatological Sciences and Applications 2012;2(2):79-82. [http://dx.doi.org/10.4236/jcdsa.2012.22018] 13. Delshad E, Rubin AI, Almeida L, et al. Cuterebra cutaneous myiasis: Case report and world literature review. Int J Dermatol 2008;47(4):363-366. [http://dx.doi.org/10.1111/j.1365-4632.2008.03532.x] 14. Williams KA. Spatial and temporal occurrence of forensically important South African blowflies (Diptera: Calliphoridae). MSc thesis. Grahamstown: Rhodes University, 2003. 15. Abdellatif MZM, Elmazar HMF, Essa AB. Oestrus ovis as a cause of red eye in Aljabal Algharbi, Libya. Middle East Afr J Ophthalmol 2011;18(4):305-308. 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The second case of cutaneous myiasis caused by Cordylobia anthropophaga (Tumbu fly) in Sri Lanka. Ceylon J Med Sci 2000;43(2):31-33. 23. Hakeem MJML, Bhattacharyya DN. Exotic human myiasis. Travel Med Infect Dis 2009;7(4):198-202. [http://dx.doi.org/10.1016/j.tmaid.2009.05.007] 24. Koźminska-Kubakska A. Cordylobia anthropophaga infestation. Int J Dermatol 1981;20(7):495-496. [http://dx.doi.org/10.1111/j.1365-4362.1981.tb04912.x] 25. Zumpt F. The Tumbu fly, Cordylobia anthropophaga (Blanchard), in southern Africa. S Afr J Med Sci 1959;33:862-865. 26. Du Toit ML. A mission doctor’s experiences in West Africa. S Afr Med J 1984;66(20):775-778. 27. Ogbalu OK, Achufusi, TG, Adibe C. Incidence of multiple myiases in breasts of rural women and oral infection in infants from the human warble fly larvae in the humid Tropic-Niger Delta. Int J Dermatol 2006;45(9):1069-1070. [http://dx.doi.org/10.1111/j.1365-4632.2006.02983.x] 28. Veraldi S, Brusasco A, Süss L. Cutaneous myiasis caused by larvae of Cordylobia anthropophaga (Blanchard). Int J Dermatol 1993;32(3):184-187. [http://dx.doi.org/10.1111/j.1365-4362.1993. tb02789.x] 29. Lodi A, Bruscagin C, Gianni C, Mancini LL, Crosti C. Myiasis due to Cordylobia anthropophaga (Tumbufly). Int J Dermatol 1994;33(2):127-128. [http://dx.doi.org/10.1111/j.1365-4362.1994.tb01542.x] 30. Dalton MT, Haldane DJM. Unusual dermal arthropod infestations. Can Med Assoc J 1990;143(2):113-114. 31. Muneizel S, Weshah S. Cutaneous myiasis among Jordanian soldiers in Sierra Leone. Journal of the Royal Medical Services 2003;10(1):75-77. 32. Musa HA, Allah EMW. Cutaneous myiasis caused by Cordylobia anthropophaga: Description of a case from Gazira State – Sudan. Sudanese Journal of Public Health 2008;3(2):91-93. 33. Onyeama CO, Njai PC. Cutaneous myiasis (Tumbu fly larvae): A case report. Niger J Paediatr 2005;32(1):26-27. [http://dx.doi.org/10.4314/njp.v32i1.12097] 34. Mpofu SM. Active cutaneous myiasis: A case report. Cent Afr J Med 1984;30(8):153-154. 35. Goldsmid JM, Phelps RJ. A review of myiasis of man in Rhodesia. Cent Afr J Med 1977;23(8):174-179. 36. Hannam P, Khairnar K, Downey J, Powis J, Ralevski F. Pillai DR. Cutaneous myiasis in traveler returning from Ethiopia. Emerg Infect Dis 2011;17(12):2385-2386. [http://dx.doi.org/10.3201/eid1712.111062] 37. Van Niekerk G, Henning M, Coetzee M. Outbreak of myiasis. S Afr Med J 2007;97(2):112-113. 38. Lee EJK, Robinson F. Furuncular myiasis of the face caused by larva of the Tumbu fly (Cordylobia anthropophaga). Eye 2007;21(2):266-268. [http://dx.doi.org/10.1038/sj.eye.6702507] 39. Jelinek T, Nothduret HD, Rieder N, Löscher T. Cutaneous myiasis: Review of 13 cases in travelers returning from tropical countries. Int J Dermatol 1995;34(9):624-626. [http://dx.doi. org/10.1111/j.1365-4362.1995.tb01088.x] 40. Günther SH. Furuncular Tumbu-fIy-myiasis of man in Gabon, Equatorial Africa. J Trop Med Hyg 1967;70(7):169-174. 41. Calvert H. Myiasis from the Tumbu fly: Two cases recorded in Britain. BMJ 1961;1(5238):1513-1514. [http://dx.doi.org/10.1136/bmj.1.5238.1513] 42. Biggar RJ, Morrow H, Morrow RH. Extensive myiasis from Tumbu fly larvae in Ghana, West Africa. Clin Pediatr 1980;19(3):231-232. [http://dx.doi.org/10.1177/000992288001900311] 43. Adisa CA, Mbanaso A. Furuncular myiasis of the breast caused by the larvae of the Tumbu fly (Cordylobia anthropophaga). BMC Surg 2004;4(5):1-4. [http://www.biomedcentral.com/14712482/4/5] 44. Palmieri JR, North D, Santo A. Furuncular myiasis of the foot caused by the Tumbu fly, Cordylobia anthropophaga: Report in a medical student returning from a medical mission trip to Tanzania. Int Med Case Rep J 2013;6:25-28. [http://dx.doi.org/10.2147/IMCRJ.S44862] 45. Hasegawa M, Harada T, Kojima Y, et al. An imported case of furuncular myiasis due to Cordylobia anthropophaga which emerged in Japan. Br J Dermatol 2000;143(4):912-914. [http://dx.doi. org/10.1046/j.1365-2133.2000.03809.x] 46. Tamir J, Haik J, Schwartz E. Myiasis with Lund’s fly (Cordylobia rodhaini) in travellers. J Travel Med 2003;10(5):293-295. [http://dx.doi.org/10.2310/7060.2003.2732] 47. Ahmad AK, Abdel-Hafeez EH, Makhloof M, Abdel-Raheem EM. Gastrointestinal myiasis by larvae of Sarcophaga sp. and Oestrus sp. in Egypt: Report of cases, and endoscopical and morphological studies. Korean J Parasitol 2011;49(1):51-57. [http://dx.doi.org/10.3347/kjp.2011.49.1.51] 48. De Meillon B, Osburn HS. A case of intestinal myiasis caused by the larva of Chrysomyia chloropyga Wied. (Diptera: Calliphorinae). S Afr Med J 1935;9(9):654-655.

Accepted 9 December 2014.

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Multimorbidity in non-communicable diseases in South African primary healthcare H Lalkhen, MB ChB, MMed; R Mash, MB ChB, DRCOG, DCH, FRCGP, FCFP, PhD Division of Family Medicine and Primary Care, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Cape Town, South Africa Corresponding author: R Mash (rm@sun.ac.za)

Background. Multimorbidity in non-communicable diseases (NCDs) is a complex global healthcare challenge that is becoming increasingly prevalent. In Africa, comorbidity of communicable diseases and NCDs is also increasing. Objectives. To evaluate the extent of multimorbidity among patients with NCDs in South African (SA) primary healthcare (PHC). Methods. A dataset obtained from a previous morbidity survey of SA ambulatory PHC was analysed. Data on conditions considered active and ongoing at consultations by PHC providers were obtained. Results. Altogether 18 856 consultations were included in the dataset and generated 31 451 reasons for encounter and 24 561 diagnoses. Hypertension was the commonest NCD diagnosis encountered (13.1%), followed by type 2 diabetes (3.9%), osteoarthritis (2.2%), asthma (2.0%), epilepsy (1.9%) and chronic obstructive pulmonary disease (COPD) (0.6%). The majority of patients (66.9%) consulted a nurse and 33.1% a doctor. Overall 48.4% of patients had comorbidity and 14.4% multimorbidity. Multimorbidity (two or more conditions) was present in 36.4% of patients with COPD, 23.7% with osteoarthritis, 16.3% with diabetes, 15.3% with asthma, 12.0% with hypertension and 6.7% with epilepsy. Only 1.1% also had HIV, 1.0% TB, 0.4% depression and 0.04% anxiety disorders. Conclusion. About half of the patients with NCDs had comorbidity, and multimorbidity was most common in patients with COPD and osteoarthritis. However, levels of multimorbidity were substantially lower than reported in high-income countries. Future clinical guidelines, training of PHC nurses and involvement of doctors in the continuum of care should address the complexity of patients with NCDs and multimorbidity. S Afr Med J 2015;105(2):134-138. DOI:10.7196/SAMJ.8696

Non-communicable diseases (NCDs) are the leading cause of global mortality, and their prevalence is rising in low- and middle-income countries.[1] This is because of increasing life expectancy, urbanisation and globalisation of the food industry, which drive the four main underlying risk factors of unhealthy diet, physical inactivity, tobacco smoking and harmful use of alcohol.[1] In sub-Saharan Africa, communicable diseases such as HIV, tuberculosis (TB) and malaria have been the leading causes of death in the past.[2] However, because of the prevention and treatment of communicable diseases, particularly HIV, which is now seen as a chronic disease, life expectancy is increasing and enables the emergence of NCDs in middle age.[2] In developing countries, the age of onset of NCDs is younger than in developed countries, and, because of their early age of onset, they lead to more premature deaths.[3] Communicable diseases and NCDs are also interconnected and there is, for example, evidence of a relationship between the treatment of HIV/AIDS and cardiometabolic disorders; between smoking, diabetes and tuberculosis; and between smoking, TB and chronic obstructive pulmonary disease (COPD).[4] The South African (SA) healthcare system faces a quadruple burden of disease, characterised by HIV/AIDS and TB, injury and violence, maternal and child health issues, and NCDs.[2] Currently NCDs are estimated to contribute 28% to the total burden of disease, and this is predicted to increase substantially over the next few decades if measures are not taken to combat the trend.[2] In the Western Cape, NCDs make up five of the ten leading causes of death: ischaemic heart disease, diabetes, cerebrovascular disease, lung cancer and COPD.[5] The World Health Organization estimates the burden of NCDs to be two to three times higher in SA than in high-income countries.[6] The distribution of NCDs displays socioeconomic disparities, with the

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heaviest burden among poor communities in urban areas. The rising morbidity and mortality related to NCDs have major implications for the delivery of both acute and chronic healthcare services.[2] In addiÂ tion, NCDs have economic consequences for individuals, households and society, and are therefore also a developmental challenge.[6] Primary healthcare (PHC) is the foundation of the SA healthcare system and where the majority of patients with NCDs are managed, usually by nurses.[7] The most common NCDs are hypertension, diabetes, asthma, osteoarthritis, COPD and epilepsy.[7] NCDs are generally poorly managed and controlled.[6] Poorly organised healthcare systems, intermittent disruption of drug supplies and lack of capability to manage NCDs on the part of healthcare workers (HCWs) all contribute to patient morbidity and mortality.[8] In high-income countries with elderly populations, the issue of multimorbidity has become a major challenge. In Scotland, for example, over half of the population over the age of 65 years have two or more NCDs.[9] Effective management of multimorbidity and NCDs may require a shift from problem-orientated to goal-orientated care.[10] This means that treatment of patients with multimorbidity should be tailored to each individual patient, that each patientâ&#x20AC;&#x2122;s socioeconomic circumstances and preferences should be taken into account, and that protocols should not be followed blindly.[11] Furthermore, general practitioners believe that using approaches focused on a single disease is not adequate when multiple conditions and their recommended treatments need to be brought together and priorities established, which is a complex task. In people with multimorbidity, some decisions will still be made within a single-disease framework, but decisionmaking will often require balancing competing considerations.[11] At any one moment, there may be a single condition that dominates the clinical picture in a patient with multimorbidity, but over time

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The International Classification of Primary Care, 2nd edition (ICPC-2)[12] was used to code all reasons for encounter and diagnoses. The ICPC-2 was developed by the World Organization of National Colleges, Academies and Academic Associations of General Practitioners/Family Physicians (WONCA) as a classification system uniquely suited to PHC. The system enables classification of the reasons for encounter and diagnoses using a biaxial structure. The first axis codes the body system involved by means of a letter derived from 17 possible chapters. The second axis contains seven components related to different aspects of the consultation. Within each component a menu of standardised rubrics are listed with definitions and inclusion and exclusion criteria. These rubrics provide a two-digit numerical code that is combined with the letter to give the final classification. For example, HIV/AIDS is coded as B90, type 2 diabetes as T90 and tuberculosis as A70. In this study, the data on NCDs were analysed further with the help of a statistician. Using an Excel spreadsheet, it was possible to analyse the frequency of the following variables for each of the targeted NCDs (hypertension, asthma, COPD, epilepsy and diabetes): age distribution and mean age, gender distribution, other comorbid diseases, and whether the consultation was with a nurse or a doctor. Finally, it was possible to calculate the percentage of patients with different numbers of comorbid conditions for

100 90 80 70 60 %

50 40

Female

Male

20 10

NCDs

Fig. 1. Gender distribution of patients with selected NCDs.

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CO PD

ps y Ep ile

ar Os

te o

As th

rit

m a

et es

The sample size was based on: (i) the number of HCWs a research assistant could train and support across a number of facilities; and (ii) ensuring that the secondary encounters would occur in large enough numbers. The sample size per province was therefore the product of the number of HCWs that could be handled (60), the number of sampling days for each HCW (5) and the number of patients per day (20), resulting in 6 000 encounters per province and 24 000 overall. One district was purposefully selected from each province, based on the location of the research assistants. Out of these districts, four subdistricts were purposively selected, with at least one of the subdistricts an urban area. Urban subdistricts were defined as having a town or metropolitan area and a population of more than 200 000 people. In the Western Cape, subdistricts were selected from the

Sampling and sample size

The original study was implemented during 2010 in PHC facilities in the Western Cape, North West, Northern Cape and Limpopo provinces of SA. These provinces were chosen because postgraduate students were available to act as research assistants and because they traversed the country from east to west and north to south. Sequential ambulatory patients who presented to nurses or doctors were included in the study.

Data analysis

At each selected facility, the research assistant explained the project and invited PHC providers (either doctors or nurses) to participate. HCWs were provided with a data collection tool that allowed them to record the age and gender of each patient and up to five reasons for each encounter and five diagnoses for that consultation. No distinction was made between primary and secondary or ongoing diagnoses. HCWs had access to the medical record and recorded all the reasons for the encounter and diagnoses pertinent to the consultation. While chronic conditions that were considered active and ongoing would have been recorded, everything in the past medical history may not have been captured. HCWs were not expected

Setting

to screen patients for undiagnosed disease. Data were collected on all sequential ambulatory patients seen by the HCW on that day. HCWs were expected to be working in general PHC and not in a specialised vertical programme or emergency department.

Data collection

sio

The study analysed a dataset obtained from a previous morbidity survey of SA PHC.[7] The design of the study from which the dataset was derived is outlined below.

te n

Study design

pe r

Methods

metropolitan and West Coast districts to enable a mix of rural and urban populations. The sample size required from each subdistrict to make up the total of 6 000 for the province was stratified according to the population of the subdistrict. The facilities in each subdistrict were then listed and divided into community health centres (CHCs), fixed clinics or mobile clinics. It was assumed that a larger CHC would have five HCWs participating in the survey, a fixed clinic two and a mobile clinic one. It was also assumed that each HCW would see at least 20 patients a day and collect data on 5 separate days. The number of HCWs required to deliver the sample size was then determined and distributed between the different types of facilities in proportion to the total number of different facilities in the subdistrict. The required number of CHCs, fixed clinics and mobile clinics were then randomly selected. In the Tygerberg and Klipfontein subdistricts, the City of Cape Town, which runs the clinics, refused permission for the survey and four CHCs were therefore selected.

this often changes. Additionally, where a patient has many conditions, single-disease guideline recommendations are sometimes discordant. Different courses of action may be contradictory, for example, prescribing a short course of steroids to a patient with asthma and diabetes, in which situation the multimorbidity creates complexity that requires clinical judgement beyond that offered in guidelines. In the SA context, there is active debate on how to integrate chronic care for HIV, which is currently organised as a separate vertical service, with TB services and with NCDs. HCWs anticipate a scenario in which large numbers of people have concurrent communicable and non-communicable diseases that need to be treated, and controlled, in an integrated approach. This study, which is based on a national PHC morbidity survey,[7] aimed to measure the current degree of multimorbidity among patients diagnosed with NCDs in SA.

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2 (0.4) Elevated blood pressure (K85) 3 (2.1) Ischaemic heart disease with angina (K74) 3 (0.6) Lower back symptoms (L03) 2 (0.5) Stroke (K90) 5 (0.5)

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*ICPC codes in parentheses.

3 (0.1) Oesophagus disease (D84)

Epilepsy (N88)

2 (0.4) Sweating problem (A09) 3 (2.1) Tobacco abuse (P17) 3 (0.6) Sleep problem (P06) 2 (0.5) Intellectual disability (P85) 6 (0.6) 3 (0.1) Neurological symptom (N29)

Ischaemic heart disease (K76)

2 (0.4) Convulsions (N07) 3 (2.1) Lipid dysfunction (T93) 5 (1.0) Respiratory infection (R83) 2 (0.5) Headache (N01) 7 (0.7) 48 (1.5) Heart failure (K77)

Muscle pain (L18)

2 (0.4) Stroke (K90) 3 (2.1) Tuberculosis (A70) 6 (1.2) Epilepsy (N88) 2 (0.5) Memory disturbance (P20) 8 (0.8) 54 (1.7) Lipid disorder (T93)

Schizophrenia (P72)

4 (0.8) Rheumatoid arthritis (L88) 5 (3.6) Ischaemic heart disease without angina (K76) 11 (2.2) Tuberculosis (A70) 3 (0.8) Schizophrenia (P72) 8 (0.8) 55 (1.7) Epilepsy (N88)

HIV infection/AIDS (B90)

4 (0.8) Peripheral neuritis (N94) 5 (3.6) Epilepsy (N88) 15 (3.1) Allergic rhinitis (R97) 3 (0.8) Acute otitis media (H71) 10 (1.1) 66 (2.1) Ischaemic heart disease (K76)

Dermatitis contact/ allergic (S88)

5 (0.9) Gout (T92) 9 (6.4) Tuberculosis (A70) 23 (4.7) Acute bronchitis (R78) 3 (0.8) Psychosis (P98) 13 (1.4) 67 (2.1) COPD (R95)

Sleep problem (P06)

6 (1.1)

9 (1.7) Heart failure (K77)

Stomach function disorder (D87) 13 (9.3)

17 (12.1) Osteoarthritis (L91)

Diabetes (T90) 26 (5.4)

28 (5.8) Osteoarthritis (L91)

Diabetes (T90) 5 (1.3)

9 (2.4) Osteoarthritis (L91)

Tuberculosis (A70) 14 (1.5)

41 (4.3)

116 (3.6) Asthma (R96)

Osteoarthritis (L91) 256 (8.0) Osteoarthritis (L91)

Lipid disorder (T93)

12 (2.3) Ischaemic heart disease (K76) 67 (47.9) Hypertension (K86) 139 (28.7) Hypertension (K86) 54 (14.4) Hypertension (K86) 597 (63.1) 587 (18.2) Diabetes (T90)

Hypertension (K86)

Comorbid condition n (%) n (%) Comorbid condition

Comorbid condition

n (%)

Comorbid condition

n (%)

Comorbid condition

COPD N=140 (R95) Asthma N=485 (R96) Epilepsy N=375 (N88) Type 2 diabetes N=946 (T90) Hypertension N=3 219 (K86, K87)

Table I. The top ten conditions that were comorbid with each NCD*

Altogether 18 856 consultations were included in the survey and generated 31 451 reasons for encounter and 24 561 diagnoses. Limpopo provided 6 678 of the consultations (35.4%), the Northern Cape 1 504 (7.9%), North West 5 082 (26.9%) and the Western Cape 5 592 (29.6%). Women accoun ted for 12 526 (66.6%) of consultations and men for 6 288 (33.4%). In the original morbidity study, hypertension was the most common diagnosis encountered in PHC, with 2 957 (12%) having uncomplicated and 262 (1.1%) complicated hypertension. Another six NCDs were in the top 25 diagnoses seen in PHC: type 2 diabetes 946 (3.9%), osteoarthritis 530 (2.2%), asthma 485 (2.0%), epilepsy 375 (1.9%) and COPD 140 (0.6%). The total number of patients with these NCDs was 5 695, of whom 3 811 (66.9%) were seen by nurses and 1 884 (33.1%) by doctors. The mean age (standard devia tion) of patients with osteoarthritis was 56.9 (13.1) years, while that for COPD was 56.8 (10.1) years, for type 2 diabetes 56.6 (12.9) years, for hypertension 56.4 (13.3) years, for asthma 45.5 (18.1) years and for epilepsy 37.9 (16.4) years. Fig. 1 shows the gender distribution of patients with NCDs. Women were in the majority for hypertension, diabetes and osteoarthritis, whereas there were more men with COPD and epilepsy. Table 1 illustrates the top ten condi tions, in descending order of occurrence, that were comorbid with each of the selected NCDs. Hypertension was the commonest comorbid condition in type 2 dia betes, epilepsy, asthma and COPD. Diabetes and hypertension was the commonest combination. Table 2 and Fig. 2 show the extent of multimorbidity for each NCD. This table includes patients with type 1 and type 2 diabetes as well as all forms of osteoarthritis. Comorbidity with ICPC codes for other diseases and tumours were included in the calculation, while

n (%)

Results

Comorbid condition

Osteoarthritis N=530 (L91)

each index condition. In this analysis, comorbidity refers to the presence of another disease at the consultation in addition to the selected NCD, while multimorbidity refers to the presence of two or more such diseases.

n (%)

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Table 2. Multimorbidity in NCDs Comorbid diseases, n 0

Hypertension (N=3 219), n (%)

1 822 (56.6)

1 012 (31.4)

294 (9.1)

89 (2.8)

2 (0.1)

Diabetes (N=999), n (%)

348 (34.8)

488 (48.8)

109 (10.9)

52 (5.2)

2 (0.2)

Asthma (N=485), n (%)

265 (54.6)

146 (30.1)

61 (12.6)

13 (2.7)

0 (0.0)

Epilepsy (N=375), n (%)

283 (75.5)

67 (17.9)

18 (4.8)

7 (1.9)

0 (0.0)

COPD (N=140), n (%)

51 (36.4)

38 (27.1)

35 (25.0)

15 (10.7)

1 (0.7)

Osteoarthritis (N=575), n (%)

218 (37.9)

221 (38.4)

100 (17.4)

35 (6.1)

1 (0.2)

All (N=5 793), n (%)

2 987 (51.6)

1 972 (34.0)

617 (10.7)

211 (3.6)

6 (0.1)

All Osteoarthritis

Epilepsy

Hypertension

>2 Asthma COPD 0

Discussion

Comorbidity was present in almost half of the patients with NCDs and presents a challenge that all HCWs should be aware of. Comorbidity in patients with NCDs ranged from 65.2% of people with diabetes to 24.5% of people with epilepsy. Hypertension was the commonest comorbid condition. Multimorbidity was found in 14.4% of patients, varying from 36.4% in COPD to 6.7% in those with epilepsy. Patients of older age had greater levels of comorbidity. Although multimorbidity is clearly an issue, the extent of the challenge to clinical care is not on the same scale as that in Europe or North America. For example, in Scotland 47% of patients with diabetes were found to have three or more comorbid NCDs compared with only 5% of patients in this study,[9] a possible reason being a more elderly Scottish population, with longer life expectancy. Better access to and quality of PHC may also have led to better diagnosis and documentation of comorbid conditions in Scotland. It is likely that many NCDs went undiagnosed in contemporary SA PHC and were therefore not counted, the level of comorbidity reported here almost certainly being an underestimate of the true picture. It is also likely that multimorbidity will increase as SA life expectancy increases. Mental health disorders such as depression and anxiety were found in 40% of patients in

Diabetes NCDs

infections, injuries and congenital conditions were excluded. Overall, 48.4% of patients presented with comorbid conditions at the consultation, although the majority (34.0%) had only one additional condition. Multimorbidity was present overall in 14.4% of consultations: in 36.4% of patients with COPD, 23.7% with osteoarthritis, 16.3% with diabetes, 15.3% with asthma, 12.0% with hypertension and 6.7% with epilepsy. Of the patients with NCDs, only 1.1% were also diagnosed with HIV, 1.0% with TB, 0.4% with depression and 0.04% with anxiety disorders.

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Fig. 2. The extent of multimorbidity in patients with NCDs.

the Scottish study, but were hardly recognised in the SA context.[7] A recent study of people with hypertension in SA found that 8.1% had had an anxiety disorder and 4.9% a depressive disorder during the previous 12 months.[13] Psychological problems also increase in relation to the extent of multimorbidity.[14] The low comorbidity with mental disorders found in this study therefore probably reflects poor ability to recognise these disorders. Despite concerns in SA about emerging co足 morbidity between HIV and NCDs, this study suggested that the problem appears very small among patients with NCDs attending ambu足latory PHC. In the age group 50 - 60 years, the prevalence of HIV in the population is between 10% and 15%,[15] and as the morbidity survey excluded patients with HIV who were being seen in a separate vertical programme, the results cannot shed light on comorbidity among patients with HIV.[7] Notably, there is work that suggests that 30% of older patients with HIV may have comorbidity with other chronic diseases.[16] It is also possible that treatment for NCDs is being given to HIV-positive patients in HIV clinics. Future research is required to investigate these comorbid conditions within the HIV context,

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especially as HIV-positive patients who were diagnosed in young adulthood mature. Most patients with TB are also treated separately and yet would still need to attend ambulatory PHC for treatment of any comorbid NCDs. The current incidence of TB of approximately 1%[17] would be broadly consistent with the rate found among patients with NCDs in this study. Multimorbidity increases the complexity of clinical care, as guidelines for different diseases must be integrated and rationalised for management of a specific patient with their own preferences and perspective. Patients should be managed holistically, and all their medical problems attended to by a competent generalist, rather than risk fragmenting care between different services and consultations; patients also deserve their own goals, concerns and preferences to be taken into account.[10] The ability to deliver such care is a challenge, as most are seen by nurses with limited training in the management of NCDs.[18] The PHC system will need to look at guidelines that support a more integrated approach, such as the PC101 PHC guidelines,[19] and the availability of PHC doctors to assist with more complex patients.[20]

RESEARCH

Improved training, especially when it comes to prescribing, will be necessary as multimorbidity increases. Clinicians often find it difficult to balance the benefits of certain medications with the potential risks of the specific medication or the interaction it may have with existing medications.[21] For example, in patients with hypertension in PHC, 73% of scripts have potential drugdrug interactions, with 7% of these being potentially severe; in patients with diabetes, 81% of patients have potential drugdrug interactions, 12% of which are potentially severe. [21] Guidelines take individual conditions into account, but combining recommendations can potentially be harmful in patients with several NCDs. The question whether nurses are adequately trained to manage the potentially complicated patient with numerous NCDs therefore arises. The evidence tends to suggest that nurses/ nurse practitioners do well when using guidelines to manage single diseases,[22] but little evidence exists to suggest the same when it comes to multimorbidity. The role of the family physician may be important in assisting with the clinical care of these patients through consultations, mentoring of nurses/nurse practitioners, and clinical governance activities.[23] Family physicians may offer a more patient-centred and biopsychosocial approach, as a result of their generalist training.

Study limitations

Not all the provinces in SA were represented in the study, so the findings may not be applicable to the entire population. Districts and subdistricts were not randomly selected, which could influence the results. The sample in the Northern Cape, because of a shortage of staff, was significantly smaller than originally anticipated. The findings are derived from the public sector and are likely to be different in the private sector. The data represent what has been recognised and documented in PHC and is not necessarily an accurate picture of multimorbidity in the community overall. Some regions in SA are better resourced for the screening and diagnosis of NCDs (e.g. the Western Cape), as a result of which the degree of multimorbidity recognised might be greater than in other areas. The findings represent conditions that had been diagnosed (no screening for undiagnosed conditions was asked for) and were considered to be active and ongoing at that consultation. The results therefore represent the practical comorbidity that needed to be managed, rather than the total comorbidity that might have been present had all conditions been looked for and included.

Implications and recommendations

• Guidelines for the management of patients with NCDs should take cognisance of the common comorbid conditions found in SA PHC. • Multimorbidity in patients with NCDs needs to be monitored, as it is likely to increase as life expectancy increases. • Further research is needed to evaluate the capability of nurses/ nurse practitioners in managing comorbidity and to consider care pathways in PHC that involve doctors appropriately. • Future research may aim to accurately determine the degree of multimorbidity, when all diseases of interest may be actively looked for under ideal study conditions, as opposed to the pragmatic, reallife conditions employed in this study. This would throw light on the extent to which PHC is currently recognising comorbidity and the quality of care provided. • Because recognition of mental disorders in patients with NCDs is likely to be low, attention should be given to better recognition, diagnosis and management of such conditions.

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Conclusion

The study set out to determine the prevalence of multimorbidity among patients with common NCDs (diabetes, hypertension, asthma, osteoarthritis, epilepsy, COPD) in SA. Overall 48.4% of patients consulted had at least one comorbid condition, while 14.4% had multimorbidity. Findings showed a lower prevalence of multimorbidity relative to that found in high-income countries. Rates of comorbidity ranged from 65.2% of patients with diabetes to 24.5% of patients with epilepsy. There was a lower than expected relationship between NCDs and psychiatric conditions. Hypertension was strongly comorbid with diabetes, COPD, asthma and epilepsy. Since patients with NCDs were mostly seen by nurses, future training and guidelines should address the complexity inherent in their consultations. Greater involvement of doctors in managing more complicated patients with multimorbidity should also be considered. Acknowledgements. RM was the principal investigator in the original primary care morbidity study and made the dataset available. HL analysed the dataset and wrote the initial report. Both authors contributed to and approved the final manuscript. The authors thank Dr Justin Harvey from the Centre for Statistical Consultation at Stellenbosch University for assistance with the analysis. References 1. Bradshaw D, Steyn K, Levitt N, Nojilana B. Non-communicable diseases – a race against time. Chronic Disease Initiative for Africa, Department of Medicine, University of Cape Town, 2011. http://www.health. uct.ac.za/usr/health/research/groupings/cdia/downloads/MRC_policy_brief.pdf (accessed 11 April 2014). 2. Mayosi BM, Flisher AJ, Lalloo UG, Sitas F, Tollman SM, Bradshaw D. The burden of noncommunicable diseases in South Africa. Lancet 2009;374(9693):934-947. [http://dx.doi.org/10.1016/ S0140-6736(09)61087-4] 3. Miszkurka M, Haddad S, Langlois EV, Freeman E, Kouanda E, Zunzunegui M. Heavy burden of noncommunicable diseases at early age and gender disparities in an adult population of Burkina Faso: World health survey. BMC Public Health 2012;12:24. [http://dx.doi.org/10.1186/1471-2458-12-24] 4. Van Zyl Smit RN, Pai M, et al. Global lung health: The colliding epidemics of tuberculosis, tobacco smoking, HIV and COPD. Eur Respir J 2010;35(1):27-33. [http://dx.doi.org/10.1183/09031936.00072909] 5. Naledi T. Progress in NCD programmes in the Western Cape. Presented at the Annual Chronic Disease Initiative for Africa Network Meeting, Cape Town, 11-12 November 2013. 6. Department of Health. South African Declaration on the Prevention and Control of Noncommunicable Diseases. Pretoria: Department of Health, 2011. http://www.doh.gov.za/docs/dcl/2011/ draft_declaration_sa.pdf (accessed 11 April 2014). 7. Mash B, Fairall L, Adejayan O, et al. A morbidity survey of South African primary care. PLoS One 2012;7(3):1-11. [http://dx.doi.org/10.1371/journal.pone.0032358] 8. Harries A, Jahn A, Zachariah R, Enarson D. Adapting the DOTS Framework for Tuberculosis Control to the management of non-communicable diseases in sub-Saharan Africa. PLoS Med 2008;5(6):859862. [http://dx.doi.org/10.1371/journal.pmed.0050124] 9. Barnett K, Mercer S, Norbury M, Watt G, Wyke S, Guthrie B. Epidemiology of multimorbidity and implications for health care, research, and medical education: A cross-sectional study. Lancet 2012;380(9836):37-43. [http://dx.doi.org/10.1016/S0140-6736(12)60240-2] 10. De Maeseneer J, Boeckxstaens P. James Mackenzie Lecture 2011: Multimorbidity, goal-oriented care, and equity. Br J Gen Pract 2012;62(600):e522-e524. [http://dx.doi.org/10.3399/bjgp12X652553] 11. Luijks HD, Loeffen MJW, Lagro-Janssen AL, van Weel C, Lucassen PL, Schermer TR. GPs’ consideration in multimorbidity management: A qualitative study. Br J Gen Pract 2012;62(600):e503-e510. [http:// dx.doi:10.3399/bjgp12X652373] 12. WONCA International Classification Committee. International Classification of Primary Care (ICPC2). Oxford: Oxford University Press, 1998. 13. Grimsrud A, Stein DJ, Seedat S, Williams D, Myer L. The association between hypertension and depression and anxiety disorders: Results from a nationally-representative sample of South African adults. PLoS One 2009;4(5):e5552. [http://dx.doi.org/10.1371/journal.pone.0005552] 14. Mendenhall E, Richter LM, Stein A, Norris SA. Psychological and physical co-morbidity among urban South African women. PLoS One 2013;8(10):e78803. [http://dx.doi.org/10.1371/journal.pone.0078803] 15. Simbayi LC, Shisana O, Rehle T, et al. South African National HIV Prevalence, Incidence and Behaviour Survey, 2012. Pretoria: Human Sciences Research Council, 2014. 16. Negin J, Martiniuk A, Cumming RG, et al. Prevalence of HIV and chronic comorbidities among older adults. AIDS 2012;26(Suppl 1):S55-S63. 17. Headline TB statistics for South Africa. http://www.tbfacts.org/tb-statistics-south-africa.html (accessed 16 August 2014). 18. Parker W, Steyn NP, Levitt NS, Lombard CJ. They think they know but do they? Misalignment of perceptions of lifestyle modification knowledge among health professionals. Public Health Nutr 2010;14(8):1429-1438. [http://dx.doi.org/10.1017/S1368980009993272] 19. University of Cape Town Lung Institute, Knowledge Translation Unit. Primary Care 101 Integrated Guideline: Symptom-based Approach to the Adult in Primary Care. Cape Town: Department of Health, 2011. 20. Howe AC, Mash RJ, Hugo JFM. Developing generalism in the South African context. S Afr Med J 2013;103(12):899-900. [http://dx.doi.org/10.7196/SAMJ.7509] 21. Kapp PA, Klop AC, Jenkins LS. Drug interactions in primary health care in the George area, South Africa: A cross-sectional study. MMed dissertation. Tygerberg, Cape Town: Stellenbosch University, 2011. 22. Coleman R, Gill G, Wilkinson D. Non-communicable disease management in the resource-poor settings: A primary care model from rural South Africa. Bull World Health Organ 1998;76(6):633-640. 23. Mash B. Reflections on the development of family medicine in the Western Cape: A 15-year review. S Afr Fam Pract 2011;53(6):557-562.

Accepted 12 September 2014.

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Prospective analysis of the medicine possession ratio of antidepressants in the private health sector of South Africa, 2006 - 2011 F N Slabbert,1 MSc, B H Harvey,2 PhD, C B Brink,3 PhD, M S Lubbe,1 PhD edicine Usage in South Africa (MUSA), School of Pharmacy, Faculty of Health Sciences, North-West University, Potchefstroom, M North West, South Africa 2 Centre of Excellence for Pharmaceutical Sciences, School of Pharmacy, Faculty of Health Sciences, North-West University, Potchefstroom, North West, South Africa 3 Division of Pharmacology, School of Pharmacy, Faculty of Health Sciences, North-West University, Potchefstroom, North West, South Africa 1

Corresponding author: M S Lubbe (martie.lubbe@nwu.ac.za)

Background. Major depressive disorder (MDD) is a disabling mental illness with high morbidity and mortality rates. Inadequate treatment efficacy, unfavourable side-effect profiles and consequent shortfalls in compliance are major stumbling blocks in its treatment. Noncompliance data in low- to middle-income countries are lacking. Objective. To investigate the prevalence of antidepressant (AD) non-compliance in the private healthcare sector of South Africa (SA). Methods. We conducted a prospective cohort study analysing AD medicine claims (N=35 175) for 14 135 patients, obtained from a nationally representative pharmaceutical benefit management company, over a 6-year study period (1 January 2006 - 31 December 2011). The medicine possession ratio (MPR) was used as a proxy to determine compliance with AD medication. Only patients >18 years of age whose treatment had been initiated by a psychiatrist following an appropriate International Classification of Diseases (10th edition) (ICD10) diagnosis of a mood disorder were included. A patient was considered compliant if the MPR was between ≥80% and ≤110% over a >4-month treatment period. Results. After the first 4 months, only 34% of patients were compliant. A statistically significant association was found between active ingredient consumed and compliance (p<0.0001). Only 26.2% of patients who received amitriptyline-containing products were compliant, compared with 38.8% and 38.7% for venlafaxine and duloxetine, respectively. Conclusion. Compliance data collected from pharmacy claims provide a workable estimate of the broader clinical scenario they represent. Although differences between classes of AD were evident, non-compliance was found to be high in the private healthcare environment of SA, comparable with global trends. S Afr Med J 2015;105(2):139-144. DOI:10.7196/SAMJ.8394

Major depressive disorder (MDD) is a disabling ill ness affecting people worldwide. The lifetime prevalence for major depression in South Africa (SA) is 9.8%,[1] as opposed to 16.7%[2] and ~13% for the USA and Europe, respectively.[3] MDD not only decreases general health but impairs quality of life, performance at work and at school, and everyday social interactions. MDD poses a substantial risk for suicide,[4] with an estimated 15 - 20% mortality rate.[4] The economic impact of affective disorders in Europe (major depression and bipolar depression) amounts to EUR106 billion (2004 figures).[5] Of this amount, nearly EUR29 billion was spent on direct healthcare costs such as hospitalisation, visits to doctors and drug treatment, whereas EUR77 billion was attributable to indirect costs including premature death, sick leave and workdays lost.[5] The economic cost of depressive disorders in the USA in 2007 was estimated to be over USD83 billion,[6] with direct and indirect costs on health expenditure of USD26 billion and 57 billion, respectively. Projections done in 2011 indicated that the total annual cost to South Africans living with severe depression and anxiety disorders amounted to USD3.6 billion.[7] These estimates suggest either that mental illness has a major economic impact, through the effect of disability and stigma on earnings, or that people in lower income groups are at increased risk of mental illness. The management of MDD is severely compromised by noncompliance.[8] It is recommended that treatment of depression

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continue for at least 4 - 6 months from the time of remission, to prevent relapse.[9,10] This is extended in high-risk patients, those with recurrent illness and/or those with a history of treatment resistance. Several studies have shown that remission rates for compliant patients with depression are higher than for non-compliant patients,[11,12] and furthermore that sustained antidepressant (AD) use over 12 36 months may decrease the risk of relapse further by up to 70% compared with non-compliant patients.[13] In a Spanish study, 56% of patients discontinued their AD treatment within the first 4 months, whereas only 22% maintained satisfactory adherence over a 5-year period.[14] Many studies concur that between 30% and 60% of patients do not comply with AD treatment,[15-16] and that up to 30% are likely to stop taking ADs within the first month after the start of treatment. In addition, 45 - 60% of patients will have stopped their prescribed treatment by the end of the third month.[17-19] Without adequate treatment, patients may experience further relapses of depressive episodes.[20] Furthermore, preclinical studies demonstrate that premature discontinuation may evoke a specific sequence of neurobiological events that underlie relapse and treatment resis tance.[21,22] Compliance and persistence are therefore key concerns in the pharmacological management of MDD. No studies have investigated AD compliance in low- to middleincome countries. We therefore studied the prevalence of noncompliance with AD treatment in the private healthcare sector in

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SA, using the medicine possession ratio (MPR) as a proxy for patient compliance with ADs, and also looking at possible changes in the prescribed daily dosage (PDD) between compliant and non-compliant patients, and whether class of AD is an additional determinant.

Methods

We conducted a prospective, descriptive cohort study analysing nationally representative medicine claims data submitted to a privately owned SA pharmaceutical benefit management (PBM) company. The database included all prescriptions for an AD (Monthly Index of Medical Specialities classification 1.4)[23] for 407 586 patients over a 6-year study period, 1 January 2006 - 31 December 2011. We extracted data for patient demographics (gender and date of birth) and pertinent prescription information (such as drug trade name, days supplied, dispensing date, quantity of medicine prescribed, initial dose, final dose and ICD-10 code per claim). The quality of data was ascertained by several automated validation processes that were applied by the PBM company. There were no missing data fields in the data sets. The variables ‘birth date’ and ‘dispensing date’ were used to calculate the age of patients on the date of treatment and the number of days between refills. A study population was selected according to the inclusion criteria illustrated in Fig. 1. The ICD-10 codes are based on the International Statistical Classification of Diseases and Related Health Problems, 10th edition, published by the World Health Organization.[24] In this study the ICD-10 codes F32 (depressive episode) and F33 (recurrent depressive disorder) were used to identify patients with MDD as diagnosed by a psychiatrist. Thereby it was ensured that data were excluded where ADs may have been used for other illnesses, such as amitriptyline for the treatment of chronic pain. The study population was older than 18 years and consisted of a total of 14 135 patients receiving 35 175 AD medicine items dispensed on more than two occasions. The MPR is a well-established method of calculating drug com pliance in pharmcoepidemiological studies, including chronic diseases such as depression,[14] hypertension[25] osteoporosis[26] and schizophrenia.[27] However, it is important to note that the compliance value obtained from the MPR only gives an indication of the possession of medicine by the patient, and that appropriate consumption of medicine is assumed to ensue from possession. The use of medicine claims data in MPR calculations is helpful in that this information is acceptably accurate, convenient, objective, non-invasive and relatively inexpensive to obtain when a large study population is needed. It is therefore suitable for the calculation of the MPR as an indication of patient compliance with medication therapy. The MPR is defined as the total number of days for which medication is supplied (medicine treatment period), divided by the number of days in the refill interval, multiplied by 100.[28,29] The MPR is considered acceptable if the calculated value is ≥80% but ≤110%.[14] An

Patients received AD 2006 - 2011 (N=407 586)

Patients received >1 AD prescriptions for a specific active ingredient

Patients should be >18 years of age

MPR of <80% indicates the presence of refill gaps, so that possession is considered unacceptably low (undersupply), whereas an MPR >110% is considered unacceptably high (oversupply). Data management and analysis were performed using SAS Version 9.1.3 (SAS Institute, USA). All statistical significance was considered with a probability of p<0.05. The practical significance of the results was computed when the p-value was statistically significant (p≤0.05). For the purpose of the study, the MPR and the medicine treatment period were used to determine AD compliance of patients. In order to treat MDD effectively and prevent relapse, patients must be on chronic treatment for at least 120 days.[9,10,28] All patients with an MPR of <80% or >110% and/or an AD treatment period of <120 days were therefore deemed non-compliant. Conversely, a patient was considered compliant with his/her AD treatment if the MPR was between ≥80% and ≤110%, and the AD treatment period was >120 days. Variables (age, age groups, gender, treatment period and active ingredients) were expressed using descriptive statistics such as frequencies (n), percentages (%), means, standard deviations (SDs) and 95% confidence intervals (CIs). Patient age was determined at time of first dispensing and divided into three groups: 18 - 40 years, 41 - 60 years and ≥61 years. Treatment duration was calculated as the time (in days) from the first prescription of the ADs until the last. It was divided into three groups: ≤30 days, between ≥31 days and ≤120 days, and >120 days. The χ2 test was used to determine whether an association existed between proportions of two or more groups (age groups v. MPR groups). Cramer’s V statistics were used to test the practical significance of this association. The two-sample t-test allowed us to compare the mean MPR of male and female patients. One-way analysis of variance was used to test differences between three or more means and to calculate differences in the adjusted PDD changes between compliant and non-compliant patients. It was operationalised with the general linear model procedure of the SAS Version 9.1.3 system. If a difference was indicated, a Tukey multiple comparison test was performed to determine which groups most significantly influenced the overall difference between groups. Cohen’s d was used to evaluate effect size between means (with d≥0.8 defined as practically significant).[30] The PDD (in mg) of an AD was calculated by multiplying the number of tablets (or volume of suspension or syrup) dispensed during the treatment period and the strength per tablet (or per mL), divided by the number of days supplied. Possible PDD changes from the first until the last prescription on the database were determined. The correlation coefficient, r, indicated a negative association between the initial PDD and change in PDD (r<–0.5; p=0.0001). Possible PDD changes were therefore adjusted for variations in initial dosage. The study was approved by the Ethics Committee of North-West University, Potchefstroom Campus, North West Province, SA (NWU0046-08-A5), and the boards of directors of the PBM. Data were analysed anonymously.

Patients should be diagnosed with MDD (ICD-10 F32 and F33)

Fig. 1. The inclusion criteria used in the study.

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Only MDD patients diagnosed by a psychiatrist

Total number of patients included N=14 135

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Results

MPRs of ADs

The mean (SD) age of the patients was 50.4 (15.9) years, 71.1% were women, and 71.1% received AD medication for >4 months (Table 1). The mean MPR of the 35 175 ADs was 98.2% (95% CI 96.6 - 99.9) (Table 2). Only 49.6% of dispensed ADs were associated with an acceptable MPR of between 80% and 110% (Table 1). No statistically significant differences were found between the MPRs of male and female patients: 98.4% (95% CI 95.4 - 101.4) v. 98.2% (95% CI 96.2 - 100.1) (Table 2). Patients older than 60 years had a lower MPR than those aged 18 - 40 years (p=0.0169) (Table 2). Table 2 clearly indicates that the treat ment period had a statistical (p=0.0001) and practically significant (d>0.8) influence on the MPR of ADs. An abnormally large number of patients were noted to be on treatment for <30 days (255.4%; 95% CI 235.7 - 275.1). This increase in MPR was also practically significant compared with patients on therapy for between 30 and 120 days (94.1%; 95% CI 93.3 - 94.9) and those on therapy for >120 days (81.1%; 95% CI 80.7 - 81.5) (d>1.0).

Patient compliance with AD therapy

Only 34% of patients were compliant with the AD treatment. In the majority of cases (66%), the MPRs were not in the acceptable range (80 - 110%) and the treatment period was <120 days (Table 3); these patients were therefore deemed non-compliant. No statistically significant association was found between gender and patient compliance (p=0.1342). Of practical significance (p<0.0001; Cramer V=0.0734), the results reveal that a larger percentage (38.9%) of patients aged >60 years receiving ADs, and who were likely to have chronic comorbidities such as hypertension or diabetes, were compliant compared with those in the 18 - 40 years age group (Table 3). The ten most dispensed AD medications represented 86.1% of all those dispensed during the study period (Table 1). These include venlafaxine, escitalopram, duloxetine, mirtazapine, citalopram, fluoxetine, bupro pion, sertraline, amitriptyline and trazodone. A statistically significant association was found between the type of active ingredients consumed and compliance (p<0.0001) (Table 3). Only 26.2% of patients who received amitriptyline-containing products were com pliant compared with 38.8% and 38.7% in the case of the ADs with the highest compliance, viz. venlafaxine and duloxetine, respectively (Table 3).

Table 1. Patient demographics and medicine use data Age (years), mean (SD)

50.4 (15.9)

Age groups (years), n (% of 14 135) >18 - ≤40

3 449 (24.4)

>40 - ≤60

6 537 (46.2)

>60

4 149 (29.4)

Gender, n (% of 14 135) Female

10 003 (70.8)

Male

4 132 (29.2)

Treatment period (days), n (% of 14 135) ≤30

830 (5.9)

>30 - ≤120

3 256 (23.0)

>120

10 049 (71.1)

Top ten active ingredients (medicine items), n (% of 35 175) Venlafaxine

5 222 (14.9)

Escitalopram

5 117 (14.6)

Duloxetine

3 351 (9.5)

Mirtazapine

2 992 (8.5)

Citalopram

2 919 (8.3)

Fluoxetine

2 433 (6.0)

Bupropion

2 153 (6.1)

Sertraline

2 137 (6.1)

Amitriptyline

2 105 (6.0)

Trazodone

1 834 (5.2)

Antidepressant MPR, n (% of 35 175) >0 - <80

12 490 (35.5)

≥80 - ≤110

17 435 (49.6)

>110

5 250 (14.9)

Table 2. MPRs of ADs by age group, gender and treatment period Variable

Mean MPR (%)

95% CI

Overall

35 175

98.2

96.6 - 99.9

Age group (years)

p-value 0.0169

>18 - ≤40

7 419

102.4*

98.1 - 106.8

>40 - ≤60

16 911

98.0

95.7 - 100.4

>60

10 845

95.6*

93.0 - 98.3

Male

9 739

98.4

95.4 - 101.4

Female

25 536

98.2

96.2 - 100.1

Gender

0.9200

Treatment period (days)

0.0001

≤30

2 769

255.4

235.7 - 275.1

>30 - ≤120

9 208

94.1

93.3 - 94.9

>120

23 198

81.1

80.7 - 81.5

*Significant difference in mean MPR (p=0.0169).

Changes in PDDs and compliance

Negative correlations between the initial PDD and PDD changes were found for

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all ADs (p=0.0001), with r>–0.5 for venlafaxine, escitalopram, mirtazapine and amitriptyline. Statistically significant

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differences (p<0.05; d<0.8) in the adjusted PDD changes were found between com pliant and non-compliant patients on ven lafaxine, escitalopram, mirtazapine and ami triptyline therapy (Table 4). The adjusted mean decrease of 6.7 mg (95% CI –10.2 –3.2) in the PDD of venlafaxine in the non-compliant patients was significantly different compared with the mean increase of 1.2 mg (95% CI –3.2 - 5.6) in the compliant patients (Table 4). The PDD of mirtazapine

also decreased, with an adjusted mean of 0.2 mg (95% CI –1.2 - –0.06) in the noncompliant patients and 1.2 mg (95% CI 0.3 2.0) in the compliant patients (Table 4). The mean adjusted PDD for amitriptyline also decreased, with an adjusted mean of 1.3 mg (95% CI –2.5 - –0.06) in the non-compliant patients and a 1.5 mg (95% CI –0.5 - 3.6) increase in the compliant patients (Table 4). The mean PDD of escitalopram increased more in the compliant patients (1.7 mg; 95%

Table 3. Patient compliance with ADs by age group, gender and active ingredient Variable

Compliant

Non-compliant

Overall, n (% of 35 175)

11 953 (34.0)

23 222 (66.0)

>18 - ≤40

202/5 419 (29.7)

5 217/5 419 (70.3)

>40 - ≤60

5 534/16 911 (32.7)

11 377/16 911 (67.3)

>60

4 217/10 845 (38.9)

6 628/10 845 (61.1)

Male

3 369/9 739 (34.6)

6 370/9 739 (65.4)

Female

8 584/25 436 (33.8)

16 852/25 436 (66.3)

p-value

Age group (years), n (%)

0.0001

Gender, n (%)

0.1342

Top ten active ingredients, n (%)

0.0001

Venlafaxine

2 026/5 222 (38.8)

3 196/5 222 (61.2)

Escitalopram

1 796/5 117 (35.1)

3 321/5 117 (64.9)

Duloxetine

1 295/3 351 (38.7)

2 056/3 351 (61.4)

Mirtazapine

862/2 992 (28.8)

2 130/2 992 (71.2)

Citalopram

1 032/2 929 (35.4)

1 887/2 919 (64.7)

Fluoxetine

763/2 433 (31.4)

1 670/2 433 (68.6)

Bupropion

724/2 153 (33.6)

1 429/2 153 (66.4)

Sertraline

701/2 137 (32.8)

1 436/2 137 (67.2)

Amitriptyline

552/2 105 (26.2)

1 553/2 105 (73.8)

Trazodone

602/1 834 (32.8)

1 232/1 834 (67.2)

CI 1.2 - 2.2) than in those who were noncompliant (0.1 mg; 95% CI –0.3 - 0.5) from the first prescription to the last prescription (Table 4).

Discussion

The most important findings of this study are that: (i) compliance with chronic AD treatment is poor (34%) in the SA private healthcare population; and (ii) use of medicine claims data may be a feasible and reliable way to assess medicine possession ratios and subsequent compliance with ADs. Non-compliance in patients taking ADs is a major concern. The 34% compliance rate described here is especially poor, although Bambauer et al.[31] found that 42% of patients stopped their treatment within the first 30 days, and by day 90, 72% of patients had done so. Our study not only emphasises that non-compliance is a major obstacle in the successful management of MDD, but to our knowledge demonstrates for the first time that this hindrance to a successful outcome is evident in a middle-income country and is comparable to data reported for developed countries. Interestingly, this observation has prompted studies geared to isolating possible reasons for the poor compliance,[15,32,33] such as feeling better, side-effects, fear of addiction and lack of efficacy.[32] We found the prevalence of MDD in female patients to be almost double that in males, in keeping with previous studies.[34-36] Stressful life events are implicated in the emergence and persistence of gender differences associated with MDD,[34-36] and it has been postulated that women have a biological and/or psychological vulnerability towards developing an anxiety or mood disorder.[34-36] We have noted earlier that non-compliance

Table 4. PDD adjusted for possible change in initial AD dosage in both compliant and non-compliant patients Compliant patients

Non-compliant patients

Final PDD (mg)

Adjusted change in dosage (mg)

Compliant patients

Non-compliant patients

Top ten active ingredients

Initial PDD (mg)

95% Cl

Adjusted change in dosage (mg)

95% Cl

p-value

Venlafaxine

1 986

136.1

137.2

3 179

135.9

129.3

1.2

–3.2 - 5.6

–6.7

–10.2 - –3.2

0.006

Escitalopram

1 796

20.7

21.9

3 321

19.7

20.1

1.7

1.2 - 2.2

0.1

–0.3 - 0.5

0.0001

Duloxetine

1 295

60.7

61.8

2 056

56.3

57.3

3.9

2.0 - 5.9

1.7

0.1 - 3.2

0.08

Mirtazapine

862

26.3

2 126

25.1

24.7

1.2

0.3 - 2.0

–0.2

–1.2 - –0.06

0.0007

Citalopram

1 012

26.5

29.1

1 871

28.7

29.1

2.4

1.5 - 3.3

1.5

0.8 - 2.2

0.12

Fluoxetine

731

32.9

1 654

33.1

0.8

–0.5 - 2.1

0.5

–0.4 - 1.4

0.76

Bupropion

724

235

242.8

1 429

238.6

246.7

27.0

11.2 - 42.8

26.8

16.5 - 37.1

0.98

Sertraline

675

78.7

82.6

1 418

80.5

84.4

5.8

3.6 - 8.1

5.7

4.1 - 7.2

0.90

Amitriptyline

522

43.2

43.3

1 553

40.6

37.9

1.5

–0.5 - 3.6

–1.3

–2.5 - –0.06

0.02

Trazodone

602

274.6

284.2

1 232

390.7

362.5

-13.9

–34.8 - 7.0

4.2

–10.4 - 18.8

0.16

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and inappropriate discontinuation evoke a stress response that may adversely affect long-term outcomes.[21,22] It could also be argued that males would be more likely to discontinue their AD medication voluntarily, owing to a stronger negative bias associated with the psychological stigma of the illness. However, we did not observe any significant association between compliance and gender. Two earlier studies have also noted that the gender of ambulatory patients treated with AD is a weak predictor of non-compliance.[18,37] Our study also reveals that elderly patients (>60 years) may be more compliant than younger populations taking ADs. In fact, elderly patients demonstrate reduced dropout ratios and are more likely to comply with their medication, and in some cases respond better to treatment, than younger patients.[38] Younger patients have a stronger negative bias towards issues such as weight gain, sexual dysfunction and dissatisfaction with the physician.[39,40] We also demonstrated that the treatment period has a definite influence on the MPR and patient compliance. We found that patients were prescribed an oversupply of AD during the first month of treatment. This is an interesting observation, especially since giving excessive medication may constitute a risk in patients with suicidal ideation. However, issues of dosage instability, side-effects and changing the regimen or dosage may explain this observation. Moreover, hospitalisation and co-prescription of medicines may also occur. These findings should be considered when calculating the MPR as a measure of patient compliance, taking into account that patients on AD treatment first need to be stabilised on the correct AD and dose. However, it is of great concern that patients became gradually less compliant in the latter part of the 4-month treatment period. The serotonin re-uptake inhibitors (SSRIs), represented here by escitalopram, citalopram, fluoxetine and sertraline, are first-line treatÂ ments for MDD because of improved safety and reduced cost,[10] and are the most frequently dispensed class of ADs for this disorder.[41] Furthermore, in the SA private health sector they have compliance rates of between 32.8% and 34% (this study), which is slightly higher than the 25.5% reported elsewhere.[42] The low compliance with SSRIs in this study population is a noteworthy observation. We found compliance ratios for venlafaxine and duloxetine to be significantly better (p<0.001) (38.8% and 38.7%) than that for amitriptyline (26.2%). Amitriptyline was found to have the worst compliance, perhaps because of its greater side-effect burden.[43-45] A negative correlation was found between the initial PDD and the change in PDD, implying that the higher the initial PDD the smaller the change in PDD, particularly for venlafaxine, escitalopram, mirtazapine and amitriptyline. A higher initial PDD was also associated with better compliance with AD treatment. This finding is supported in the literature, as several studies have found that MDD is commonly treated with inadequate doses of ADs.[46-48] Furthermore, a study by Marcus et al.[49] found that a lower initial dose of AD was associated with subsequent switching to another AD or to an entirely new class of AD, suggesting that an inadequate dose at the start of treatment may contribute to a suboptimal response to initial AD treatment and therefore increase the possibility of AD switching and relapse.

Conclusion

We established that compliance with AD treatment remains a major obstacle in the treatment of MDD in a middle-income developing country like SA. These findings are worrying, as such non-compliance may have significant negative effects not only on the long-term treatment outcome of MDD but also that of comorbid disorders. Some of these aspects are currently under study by our research

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group. We found that only a third of patients suffering from MDD are compliant with their AD treatment, with newer-generation ADs (particularly serotonin noradrenaline reuptake inhibitors (SNRIs)) performing better. We also verified that data from medicine claims may be used as a measure of patient compliance in the clinical setting. Furthermore, the treatment period has a statistically significant effect on the MPR when used as a measure of compliance. Conflict of interest. BHH has participated in speakers/advisory boards and received honoraria from Organon, Pfizer and Servier, and has received research funding from Lundbeck and Servier. Except for income from the primary employer and research funding to BHH from the SA Medical Research Council, and the exceptions noted earlier, no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional services, and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest. Acknowledgements. We thank Dr Suria Ellis from Statistical Consultation Services, North-West University, Potchefstroom Campus, for statistical support, and Anne-Marie Bekker for administrative support regarding the database. The authors thank North-West University, the National Research Foundation and the South African Medical Research Council for financial support. References 1. Tomlinson M, Grimsrud AT, Stein DJ, et al. The epidemiology of major depression in South Africa: Results from the South African stress and health study. S Afr Med J 2009;99(5):367-373. 2. Kessler RC, Chiu WT, Demler O, et al. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 2005;62(6):617-627. [http://dx.doi.org/10.1001/archpsyc.62.6.617] 3. Alonso J, Angermeyer MC, Bernert S, et al. Disability and quality of life impact of mental disorders in Europe: Results from the European Study of the Epidemiology of Mental Disorders (ESEMeD) project. Acta Physiol Scand Suppl 2004;109(Suppl S420):38-46. [http://dx.doi.org/10.1111/j.1600-0047.2004.00329.x] 4. Goodwin FK, Jamison KR. Suicide in Manic-depressive Illness. New York: Oxford University Press, 1990:227-244. 5. Andlin-Sobocki P, Jonsson B, Wittchen HU, et al. Cost of disorders of the brain in Europe. Eur J Neurol 2005;12 (Suppl 1):1-27. [http://dx.doi.org/10.1111/j.1468-1331.2005.01202.x] 6. National Institute of Mental Health. The numbers count: Mental disorders in America. 2011. http:// www.nimh.nih.gov/health/publications/the-numbers-count-mentaldisorders-in-america/index. shtml#Intro (accessed 15 June 2012). 7. Lund C, Myer L, Stein DJ, et al. Mental illness and lost income among adult South Africans. Soc Psychiatry Psychiatr Epidemiol 2013;48(5):845-851. [http://dx.doi.org/10.1007/s00127-012-0587-5] 8. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med 2005;353(5):487-497. [http://dx.doi. org/10.1056/NEJMra050100] 9. National Institute for Health and Clinical Excellence. Depression: The treatment and management of depression in adults. Partial update of NICE clinical guideline 2009. http://www.nice.org.uk/ nicemedia/pdf/CG90NICEguideline.pdf (accessed 2 May 2013). 10. Keller MB, Hirschfeld RM, Demyttenaere K, et al. Optimizing outcomes in depression: Focus on antidepressant compliance. Int Clin Psychopharmacol 2002;17(6):265-271. 11. Akerblad AC, Bengtsson F, von Knorring L, et al. Response, remission and relapse in relation to adherence in primary care treatment of depression: A 2-year outcome study. Int Clin Psychopharmacol 2006;21(2):117-124. 12. Akerblad AC, Bengtsson F, Holgersson M, et al. Identification of primary care patients at risk of nonadherence to antidepressant treatment. Patient Prefer Adherence 2008;2:379-386. 13. Geddes JR, Carney SM, Davies C, et al. Relapse prevention with antidepressant drug treatment in depressive disorders: A systematic review. Lancet 2003;361(9358):653-661. [http://dx.doi.org/10.1016/ s0140-6736(03)12599-8] 14. Serna MC, Cruz I, Real J, et al. Duration and adherence of antidepressant treatment (2003 to 2007) based on prescription database. Eur Psychiatry 2010;25(4):206-213. [http://dx.doi.org/10.1016/j. eurpsy.2009.07.012] 15. Demyttenaere K. Compliance during treatment with antidepressants. J Affect Disord 1997;43(1):27-39. [http://dx.doi.org/10.1016/S0165-0327(96)00095-X] 16. Cramer JA. Optimizing long-term patient compliance. Neurology 1995;45(2 Suppl 1):S25-S28. 17. Hotopf M, Hardy R, Lewis G. Discontinuation rates of SSRIs and tricyclic antidepressants: A meta-analysis and investigation of heterogeneity. Br J Psychiatry 1997;170:120-127. [http://dx.doi. org/10.1192/bjp.170.2.120] 18. Lin EH, von Korff M, Katon W, et al. The role of the primary care physician in patientsâ&#x20AC;&#x2122; adherence to antidepressant therapy. Med Care 1995;33(1):67-74. [http://dx.doi.org/10.1097/00005650-199501000-00006] 19. Robinson P, Bush T, von Korff M, et al. Primary care physician use of cognitive behavioral techniques with depressed patients. J Fam Pract 1995;40(4):352-357. 20. Frank E, Perel JM, Mallinger AG, et al. Relationship of pharmacologic compliance to long-term prophylaxis in recurrent depression. Psychopharmacol Bull 1992;28(3):231-235. 21. Harvey BH, McEwen BS, Stein DJ. Neurobiology of antidepressant withdrawal: Implications for the longitudinal outcome of depression. Biol Psychiatry 2003;54(10):1105-1117. [http://dx.doi. org/10.1016/S0006-3223(03)00528-6] 22. Harvey BH. Adaptive plasticity during stress and depression and the role of glutamate-nitric oxide pathways. S Afr Psychiatry Rev 2006;9:132-139. http://www.ajol.info/index.php/ajpsy/article/ viewFile/30214/22831 (accessed 27 December 2014). 23. MIMS: Monthly Index of Medical Specialities 2012;51(2):13-28.

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24. World Health Organization. ICD-10 Version: 2010. http://apps.who.int/classifications/icd10/ browse/2010/en (accessed 23 November 2012). 25. Cramer JA, Benedict A, Muszbek N, et al. The significance of compliance and persistence in the treatment of diabetes, hypertension and dyslipidaemia: A review. Int J Clin Pract 2008;62(1):76-87. [http://dx.doi.org/10.1111/j.1742-1241.2007.01630.x] 26. Weycker D, Macarios D, Edelsberg J, et al. Compliance with osteoporosis drug therapy and risk of fracture. Osteoporos Int 2007;18(3):271-277. [http://dx.doi.org/10.1007/s00198-006-0230-y] 27. Weiden PJ, Kozma C, Grogg A, et al. Partial compliance and risk of rehospitalization among California Medicaid patients with schizophrenia. Psychiatr Serv 2004;55(8):886-891. [http://dx.doi.org/10.1176/ appi.ps.55.8.886] 28. Paterson DL, Swindells S, Mohr J, et al. Adherence to protease inhibitor therapy and outcomes in patients with HIV infection. Ann Intern Med 2000;133(1):21-30. [http://dx.doi.org/10.7326/00034819-133-1-200007040-00004] 29. Steiner JF, Prochazka AV. The assessment of refill compliance using pharmacy records: Methods, validity, and applications. J Clin Epidemiol 1997;50(1):105-116. [http://dx.doi.org/10.1016/S08954356(96)00268-5]. 30. Steyn HS. Manual for the Determination of Effect Size Indices and Practical Significance. Potchefstroom: North-West University. http://www.nwu.ac.za/content/statcs-effect-size (accessed 25 September 2012). 31. Bambauer KZ, Adams AS, Zhang F, et al. Physician alerts to increase antidepressant adherence: Fax or fiction? Arch Intern Med 2006;166(5):498-504. [http://dx.doi.org/10.1001/archinte.166.5.498] 32. Demyttenaere K, Enzlin P, Dewe W, et al. Compliance with antidepressants in a primary care setting. 1: Beyond lack of efficacy and adverse events. J Clin Psychiatry 2001;62(Suppl 22):30-33. 33. Pampallona S, Bollini P, Tibaldi G, et al. Combined pharmacotherapy and psychological treatment for depression: A systematic review. Arch Gen Psychiatry 2004;61(7):714-719. [http://dx.doi.org/10.1001/ archpsyc.61.7.714] 34. Kessler RC. Epidemiology of women and depression. J Affect Disord 2003;74(1):5-13. [http://dx.doi. org/10.1016/S0165-0327(02)00426-3] 35. Harvey BH, Hamer M, Louw R, et al. Metabolic and glutathione redox markers associated with brainderived neurotrophic factor in depressed African men and women: Evidence for counterregulation? Neuropsychobiology 2013;67(1):33-40. [http://dx.doi.org/10.1159/000343501] 36. Hankin BL, Abramson LY. Development of gender differences in depression: An elaborated cognitive vulnerability-transactional stress theory. Psychol Bull 2001;127(6):773-796. [http://dx.doi. org/10.1037/0033-2909.127.6.773] 37. Simon GE, von Korff M, Wagner EH, et al. Patterns of antidepressant use in community practice. Gen Hosp Psychiatry 1993;15(6):399-408.

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38. Birrer RB, Vemuri SP. Depression in later life: A diagnostic and therapeutic challenge. Am Fam Physician 2004;69(10):2375-2382. 39. Akincigil A, Bowblis JR, Levin C, et al. Adherence to antidepressant treatment among privately insured patients diagnosed with depression. Med Care 2007;45(4):363-369. [http://dx.doi.org/10.1097/01. mlr.0000254574.23418.f6] 40. Tamburrino MB, Nagel RW, Chahal MK, et al. Antidepressant medication adherence: A study of primary care patients. J Clin Psychiatry 2009;11(5):205-211. [http://dx.doi.org/10.4088%2FPCC.08m00694] 41. Gelenberg AJ, Freeman MP, Markowitz JC, et al. American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 3rd ed. 2010. http://www. psychiatryonline.com/pracGuide/pracGuideTopic_7.aspx (accessed 17 July 2013). 42. Liu X, Chen Y, Faries DE. Adherence and persistence with branded antidepressants and generic SSRIs among managed care patients with major depressive disorder. Clinicoecon Outcomes Res 2011;2011(3):63-72. [http://dx.doi.org/10.2147%2FCEOR.S17846] 43. Baldwin DS. Unmet needs in the pharmacological management of depression. Hum Psychopharmacol Clin Exp 2001;16(S2):S93-S99. [http://dx.doi.org/10.1002/hup.337] 44. Hirschfeld RM. Antidepressants in long-term therapy: A review of tricyclic antidepressants and selective serotonin reuptake inhibitors. Acta Psychiatr Scand Suppl 2000;101(S403):35-38. [http:// dx.doi.org/10.1111/j.1600-0447.2000.tb10946.x] 45. Masand PS. Tolerability and adherence issues in antidepressant therapy. Clin Ther 2003;25(8):22892304. [http://dx.doi.org/10.1016/S0149-2918(03)80220-5] 46. Dew RE, Kramer SI, McCall WV. Adequacy of antidepressant treatment by psychiatric residents: The antidepressant treatment history form as a possible assessment tool. Acad Psychiatry 2005;29(3):283288. [http://dx.doi.org/10.1176/appi.ap.29.3.283] 47. Mulsant BH, Haskett RF, Prudic J, et al. Low use of neuroleptic drugs in the treatment of psychotic major depression. Am J Psychiatry 1997;154(4):559-561. [http://ajp.psychiatryonline.org/doi/ pdfplus/10.1176/ajp.154.4.559] 48. Shasha M, Lyons JS, Oâ&#x20AC;&#x2122;Mahoney MT, Rosenberg A, Miller SI, Howard KI. Serotonin reuptake inhibitors and the adequacy of antidepressant treatment. Int J Psychiatry Med 1997;27(2):83-92. [http://dx.doi. org/10.2190/YVBE-MXAF-Q09Q-Y02Q] 49. Marcus SC, Hassan M, Olfson M. Antidepressant switching among adherent patients treated for depression. Psychiatr Serv 2009;60(5):617-623. [http://dx.doi.org/10.1176/appi.ps.60.5.617]

Accepted 22 October 2014.

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Integrated positron emission tomography/computed tomography for evaluation of mediastinal lymph node staging of non-small-cell lung cancer in a tuberculosisendemic area: A 5-year prospective observational study J A Shaw,1 MB ChB; E M Irusen,1 MB ChB, FCP (SA), PhD; F von Groote-Bidlingmaier,1 MD; J M Warwick,2 BSc, MB ChB, FCNP (SA), MMed, PhD; B Jeremic,3 MD, PhD; R du Toit,1 MB ChB; C F N Koegelenberg,1 MB ChB, MMed (Int), FCP (SA), FRCP (Lond), Cert Pulm (SA), PhD ivision of Pulmonology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University and D Tygerberg Academic Hospital, Tygerberg, Cape Town, South Africa 2 Division of Nuclear Medicine, Department of Medical Imaging and Clinical Oncology, Faculty of Medicine and Health Sciences, Stellenbosch University and Tygerberg Academic Hospital, Tygerberg, Cape Town, South Africa 3 Division of Radiation Oncology, Department of Medical Imaging and Clinical Oncology, Faculty of Medicine and Health Sciences, Stellenbosch University and Tygerberg Academic Hospital, Tygerberg, Cape Town, South Africa 1

Corresponding author: J A Shaw (jane.shaw@stonedragon.co.za)

Background. Integrated positron emission tomography/computed tomography (PET-CT) is a well-validated modality for assessing mediastinal lymph node metastasis in non-small-cell lung cancer (NSCLC), which determines management and predicts survival. Tuberculosis (TB) is known to lead to false-positive PET-CT findings. Objectives. To assess the diagnostic accuracy of PET-CT in identifying mediastinal lymph node involvement of NSCLC in a high TB-endemic area. Methods. Patients who underwent both PET-CT and lymph node tissue sampling for the investigation of suspected NSCLC were prospectively included in this observational study. Results were analysed per patient and per lymph node stage. A post-hoc analysis was performed to test the validity of a maximum standardised uptake value (SUVmax) cut-off for lymph node positivity. Results. PET-CT had a sensitivity of 92.6%, specificity of 48.6%, positive predictive value of 56.8% and negative predictive value (NPV) of 90.0% in the per-patient analysis. Diagnostic accuracy was 67.2%. Similar values were obtained in the per-lymph node stage analysis. TB was responsible for 21.1% of false-positive results. A SUVmax cut-off of 4.5 yielded an improvement in diagnostic accuracy from 64.0% to 84.7% compared with a cut-off of 2.5, but at the cost of decreasing the NPV from 90.6% to 83.5%. Conclusion. In a high TB-endemic area, PET-CT remains a valuable method for excluding mediastinal lymph node involvement in NSCLC. Patients with a negative PET-CT may proceed to definitive management without further invasive procedures. However, PET-CT-positive lymph nodes require pathological confirmation, and the possibility of TB must be considered. S Afr Med J 2015;105(2):145-150. DOI:10.7196/SAMJ.8357

Lung cancer is the most common cause of death from cancer worldwide, with equally poor survival in developed and developing regions.[1] Non-small-cell lung cancer (NSCLC) comprises 75 - 80% of lung cancer cases.[2] Determining mediastinal lymph node involvement is fundamental in the staging of NSCLC and has been shown to have prognostic significance.[3] The node (N) stage determines the treatment strategy, as patients with N2 lymph node metastasis are considered inoperable and only selected patients with this stage are eligible for chemotherapy and/or radiotherapy with curative intent.[4,5] At present, integrated positron emission tomography/computed tomography (PET-CT) is recognised as being superior to PET alone, CT alone, or visual comparison of PET and CT images for the assessment of mediastinal lymph node involvement in NSCLC,[6] with an average sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 73%, 80%, 78% and 91%, respectively.[2] This imaging modality has been available in the Western world since the 1990s, forming an integral part of mediastinal lymph node staging in those regions,[7] but has only recently become standard practice in South Africa (SA). It has been suggested that

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negative PET-CT for mediastinal lymph node involvement requires no further invasive staging and surgical resection may proceed.[8] Developing regions, particularly high tuberculosis (TB)-endemic areas, face the potential challenge of interpreting PET-CT images as false positive in TB-involved lymph nodes.[2,5,9,10] The effect of TB on PET-CT staging of NSCLC has previously been investigated in areas with an incidence of TB of approximately 73/100 000 popula tion.[5,11,12] Two studies from Korea showed that the sensitivity (75% and 46%, respectively) and PPV (27% and 72%) of PET-CT were adversely affected, but that a high specificity (85% and 98%) and NPV (98% in both studies) were maintained, especially when calcification and attenuation of nodes on CT was taken into account.[5,11] Recent data from China demonstrated a similar pattern of results, with a relatively low sensitivity (61.8% and 78.6% for adenocarcinoma and squamous cell carcinoma, respectively) and specificity (66.3% and 45.5%), and a high NPV (80.9% and 87%). The authors stated that the high incidence of granulomatous disease in their region impacted significantly on the rate of false-positive results in their study.[12] According to the World Health Organization, the incidence of TB in SA is 1 000/100 000 population.[13] To date, no study of the efficacy

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granted by the Health Research Ethics Committee of Stellenbosch University. Patients with an intermediate to high pretest probability of malignancy according to clinical guidelines[14] were referred for PET-CT according to the standardised diagnostic algorithm that was used at the time of the study, with the PET-CT generally performed before tissue sampling (Fig. 1). Patients who had no lymph node tissue sampling performed were excluded. Patients were followed up to the point of referral for definitive treatment or palliation.

of this modality for mediastinal lymph node staging in NSCLC in an area with such a high incidence of TB has been conducted. The aim of this study was to assess the diagnostic accuracy of integrated PET-CT in detecting NSCLC metastases in mediastinal lymph nodes in patients from a high TB-endemic area.

Methods

Study design and patient population

Tygerberg Academic Hospital (TAH), Cape Town, provides tertiary services for approximately 2 million people in the Western Cape Province of SA, draining the eastern subdistrict of the Cape Town metropole and surrounding areas. All patients referred with a suspicion of NSCLC to the Division of Pulmonology at TAH from January 2009 to December 2013 were eligible for inclusion in this observational study. Ethical approval for the study was

PET-CT scanning

All studies were performed from the base of skull to the upper thigh with a Siemens Biograph or Philips Gemini PET-CT system with 16-slice uncontrasted CT (Fig. 2). The procedure was performed according to European Association of Nuclear Medicine guidelines.[15] Patients fasted for at least 6

hours prior to the study. Blood glucose levels were tested prior to the scan, which was postponed if the patient had a level of >11.1 mmol/L. Patients lay supine for 30 minutes prior to the study, and for a further 60 minutes, without talking, after injection of 18 fluorodeoxyglucose (FDG). An FDG dose of 7 - 13 mCi was administered according to body weight. All images were interpreted by an experienced nuclear medicine physician and at least one radiologist, and independently by a respiratory physician. Lymph node positivity was defined as any increase in FDG uptake compared with the mediastinal blood pool. Nodes were considered negative if they demonstrated a lower or equal FDG uptake compared with the mediastinal blood pool. The intensity of the FDG uptake in lymph nodes of interest was quantified using a Philips EBW workstation. A cursor was manually placed at the site of highest visual uptake within the

Suspicion of lung cancer (history, clinical signs, CXR) YES

Tumour-specific treatment considered?

Potenially curable

Contrasted CT

Incurable

Rule out other pathology

Pos. for M+

Poor PS

Integrated PET-CT

Neg. for M+ Neg. for mediast. LNs+

Pos. for mediast. LNs+

Sample PT (FB ± EBUS, EUS/CT-TTNA)

Sample most accessible site

Sample LNs ± PT (FB ± EBUS) N0/1

Mediastinoscopy N0/1

T1 - 3

Functional assessment Operable

Inoperable

Surgical resection ± adjuvant therapy

Radical radiotherapy ± chemotherapy

Palliative oncological therapy

Best supportive care

Fig. 1. Algorithm utilised during the study period for the evaluation of patients with suspected lung cancer. (CXR = chest radiograph; neg. = negative; pos. = positive; M = distant metastases; mediast. LNs = mediastinal lymph nodes; PT = primary tumour; FB = flexible bronchoscopy; EBUS = endobronchial ultrasound; EUS = endoscopic ultrasound; TTNA = transthoracic needle aspiration; N = lymph node metastases; T = tumour stage.)

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lymph node, and the maximum standardised uptake value (SUVmax) was obtained from this slice using a circular region of interest with an 8 mm diameter. Lymph nodes were identified by accepted nomenclature according to the International Association for the Study of Lung Cancer lymph node map.[4] These were further grouped into N1, N2 and N3 zones for prognostic purposes.[4]

Tissue sampling

Fig. 2. (a) PET-CT scan demonstrating a left hilar lymph node with positivity due to proven tuberculosis. (b) PET-CT scan demonstrating a subcarinal lymph node with positivity due to metastatic non-small-cell lung cancer.

Cells were obtained from lymph nodes of interest by an experienced interventional pulmonologist via endoscopic transbronchial needle aspiration, or fine-needle aspiration where accessible. Cytologically positive samples were considered to be evidence for the presence of metastatic malignancy, but negative samples were not considered sufficient evidence for the absence of malignancy. Where further sampling was required, biopsy of suspicious lymph nodes was performed by mediastinoscopy. Alternatively, the entire lesion with surrounding lymph

nodes was resected in an attempt at cure. All histological specimens thus obtained were considered definitive for both lymph node positivity and negativity. Biopsy specimens were concurrently tested for TB via staining for acid-fast bacilli. Bronchial lavage and/or sputum samples were obtained from each patient and tested for TB via Ziehl-Neelsen staining (this being replaced by GeneXpert in 2013) and mycobacterial culture. These samples were also sent for routine microscopy, culture and sensitivity.

Statistical aspects

Descriptive statistics were performed. Analyses were conducted of data collected per patient, as well as per lymph node stage sampled (N1, N2, N3). The sensitivity, specificity, PPV, NPV, likelihood ratios (LRs) and diagnostic accuracy of PET-CT were calculated using standard methods. A post-hoc secondary analysis of the SUVmax of all individual lymph nodes sampled was undertaken with the aim

PET-CT performed in patients with intermediate/high clinical probability of lung cancer (N=224)

Excluded (n=160) 72 metastatic disease 52 alternative diagnosis 16 loss to follow up 9 poor performance status 8 unresectable tumour 3 small-cell carcinoma

LN sampled NO YES 64 patients 111 LN stages

PET-CT positive LN 44 patients 80 LN stages

YES

20 patients 31 LN stages

Tissue pos. (true pos.)

Tissue neg. (false pos.)

Tissue pos. (false neg.)

Tissue neg. (true neg.)

25 patients 41 LN stages

19 patients 33 LN stages

2 patients 3 LN stages

18 patients 34 LN stages

Fig. 3. Consort diagram. Alternative diagnoses included 21 patients with pulmonary infection of which 16 were tuberculosis, 28 patients with post-infectious changes with no organism identified, and 3 patients with non-carcinomatous tumours. (LN = lymph node; neg. = negative; pos. = positive.)

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of identifying the SUVmax cut-off for designation of lymph nodes as ‘positive’ or ‘negative’ that would prove most clinically relevant. A receiver operating characteristic (ROC) curve was used to identify the SUVmax cut-off with the highest diagnostic accuracy. The SUVmax cut-off of 2.5 has been used in previous studies as a comparison value. It was therefore subsequently compared with the value identified by the ROC curve with regard to sensitivity, specificity, PPV, NPV and diagnostic accuracy.[16]

Results

Study population

During the study period, a total of 224 patients were referred for PET-CT based on an intermediate or high pre-test probability of lung cancer (Fig. 3). A total of 64 patients underwent extensive lymph node sampling and were therefore included in the study, with 111 separate lymph node stages sampled. Demographic data are depicted in Table 1.

PET-CT findings

In the per-patient analysis, PET-CT was found to have a sensitivity of 92.6%, specificity of 48.6%, PPV of 56.8%, NPV of 90.0%, positive LR of 1.8 and negative LR of 0.15 (Table 2). The diagnostic accuracy was 67.2%. Of the false positives, 21.1% were attributed to active TB infection and 78.9% were reactive lymph nodes. In the perlymph node stage analysis, the sensitivity was 93.2%, specificity 50.0%, PPV 55.4% and NPV 91.7%, with a positive LR of 1.9, and negative LR of 0.14. Diagnostic accuracy was 67.6%. In the secondary analysis of SUVmaxes of individual nodes, the ROC curve identified a SUVmax cut-off of 4.5 as offering the highest overall diagnostic accuracy (Fig. 4). The comparison SUVmax cut-off of 2.5 was analysed and found to have a sensitivity of 95.7%, specificity of 36.3%, PPV of 56.8% and NPV of 90.6% when applied to these data. The diagnostic accuracy was 64.0%. A SUVmax cut-off of 4.5 yielded a sensitivity of 80.0%, specificity of 88.8%, PPV of 86.2% and NPV of 83.5% (Table 3). The diagnostic accuracy was 84.7%.

Discussion

In this first study of PET-CT for evaluation of mediastinal lymph node staging in NSCLC in SA, we have demonstrated that PET-CT had a high sensitivity of 92.6% and 93.2% per patient and per lymph node stage, respectively, and a high NPV of 90% and 91.7%. It had a low specificity of 48.6% and 50.0% and a low PPV of 56.8% and 55.4%. Moreover, we found favourable negative LRs. The diagnostic

accuracy was 67.2% and 67.6%, respectively. More than 20% of false-positive PET-CT scan results were attributable to active TB, once again highlighting that TB can mimic lung cancer in the clinical setting. These results confirm the value of PETCT for excluding lymph node involvement in NSCLC in a high TB-endemic area. The role of PET-CT can therefore be considered the same as in non-TB-endemic areas,

where it is used to direct node biopsy rather than to aid in diagnosis. A patient with a PET-CT that is negative for any lymph node involvement may be considered to be accurately staged and therefore proceed to definitive management of the cancer without further invasive staging investigations. Importantly, in the SA context a positive lymph node on PETCT has an approximately 50% chance of

Table 1. Demographic data: characteristics of the population screened during the study period, with patients included in the study compared with patients excluded Study population

Patients excluded

Males, n (%)

39 (60.9)

96 (60.0)

Females, n (%)

25 (39.1)

64 (40.0)

<40

2 (3.1)

5 (3.1)

40 - 50

11 (17.2)

17 (10.6)

51 - 60

21 (32.8)

52 (32.5)

61 - 70

20 (31.3)

49 (30.6)

71 - 80

10 (15.6)

32 (20.0)

>80

0 (0.0)

5 (3.1)

59.3 (10.2)

61.6 (10.7)

Adenocarcinoma

34 (59.7)

49 (45.4)

Squamous cell carcinoma

16 (28.1)

38 (35.2)

Undifferentiated large-cell carcinoma

4 (7.0)

17 (15.7)

Other

3 (5.3)

1 (0.9)

Stage I

10 (17.5)

3 (2.9)

Stage II

18 (31.6)

4 (3.8)

Stage III

22 (38.6)

41 (39.0)

Stage IV

7 (12.3)

57 (54.3)

Age range (years), n (%)

Mean age (years) (standard deviation) Histological type*, n (%)

Clinical stage*, n (%)

*In patients with proven NSCLC.

Table 2. PET-CT results: data acquired from the comparison of PET-CT findings and tissue sampling, grouped per patient and per lymph node stage, and statistical analysis thereof Per-patient analysis

Per-lymph node stage analysis

True positive, n (%)

25 (39.1)

41 (36.9)

True negative, n (%)

18 (28.1)

34 (30.6)

False positive, n (%)

19 (29.7)

33 (29.7)

False negative, n (%)

2 (3.1)

3 (2.7)

Sensitivity (95% CI)

92.6 (0.743 - 0.987)

93.2 (0.803 - 0.982)

Specificity (95% CI)

48.6 (0.322 - 0.653)

50.0 (0.376 - 0.624)

PPV (95% CI)

56.8 (0.411 - 0.713)

55.4 (0.434 - 0.668)

NPV (95% CI)

90.0 (0.669 - 0.983)

91.7 (0.764 - 0.978)

Positive likelihood ratio (95% CI)

1.803 (1.295 - 2.511)

1.864 (1.445 - 2.403)

Negative likelihood ratio (95% CI)

0.152 (0.038 - 0.611)

0.136 (0.044 - 0.419)

CI = confidence interval.

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RESEARCH

being a false positive. All such patients therefore require further investigations for pathological confirmation before they can be accurately staged and appropriately managed. Initial studies involving this modality in other regions of the world found a pooled average sensitivity, specificity, PPV and NPV of 73%, 80%, 78% and 91%, respectively.[2] The present study in

a high TB-endemic region demonstrated the anticipated reduction in specificity and PPV, which is attributable to the high rate of false-positive TB-infected or reactive nodes. However, our sensitivity and NPV are equal or superior to these international values. We postulate that the higher rate of pick-up of true-negative nodes in our study may be due to our method of combined analysis of PET-

1.0

4.495

0.8

Sensitivity

0.6

0.4

0.2

0.0 0.0

0.2

0.4

0.6

0.8

1.0

1– specificity

Fig. 4. ROC curve of SUVmaxes of individual lymph nodes. The value 4.495 is identified as having the highest overall diagnostic accuracy.

Table 3. Proposed SUVmax cut-off value results: data acquired from grouping individually sampled lymph nodes as positive or negative according to proposed SUVmax cut-off values of 2.5 and 4.5 (identified by ROC curve in the present study), and statistical analysis thereof True positive, n (%)

SUVmax cut-off 2.5

SUVmax cut-off 4.5

67 (44.7)

56 (37.3)

True negative, n (%)

29 (19.3)

71 (47.3)

False positive, n (%)

51 (34.0)

9 (6.0)

False negative, n (%)

3 (2.0)

14 (9.3)

Sensitivity (95% CI)

95.7 (0.872 - 0.989)

80.0 (0.684 - 0.883)

Specificity (95% CI)

36.3 (0.260 - 0.478)

88.8 (0.792 - 0.944)

PPV (95% CI)

56.8 (0.474 - 0.658)

86.2 (0.748 - 0.931)

NPV (95% CI)

90.6 (0.738 - 0.976)

83.5 (0.736 - 0.904)

Positive likelihood ratio (95% CI)

1.501 (1.264 - 1.784)

7.111 (3.801 - 13.306)

Negative likelihood ratio (95% CI)

0.118 (0.037 - 0.373)

0.225 (0.141 - 0.361)

CI = confidence interval.

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CT images by a nuclear medicine physician and a radiologist, who take into account their own judgement of the appearance of the lymph nodes and attenuation of the nodes on CT, as well as interpreting the PET. Studies have demonstrated that lymph nodes with higher attenuation (>70 Hounsfield units) or calcification on CT have a much higher probability of being benign. Using these additional criteria for interpretation of images on PET-CT improves diagnostic accuracy, even in a TB-endemic area.[5,11,12] Previous studies conducted in high TB-endemic areas did not demonstrate the anticipated reduction in specificity. In fact, these studies found a reduction in sensi tivity.[5,11,12] These authors proposed that this may have been due to the selective inclusion of patients of lower clinical stage with possible micrometastases to lymph nodes that did not demonstrate positivity on PET-CT, as well as the designation of all calcified lymph nodes as benign. It is worth considering that the present study was inadvertently subject to the same selective inclusion, although not to the same degree, and did not suffer corresponding losses in sensitivity. The present study does, however, agree with the previous studies[5,11,12] in the reduction of PPV, with preservation of NPV. An ROC curve has been utilised in previous studies to identify the SUVmax cutoff with the highest diagnostic accuracy for the prediction of malignancy in mediastinal lymph nodes on PET-CT. Values identified in these studies included 4.4 and 5.3, yielding a diagnostic accuracy of 92% and 98%, respectively.[16,17] Although our posthoc analysis of proposed SUVmax cut-offs suggested that a cut-off of 4.5 conferred an improvement in diagnostic accuracy from 64.0% to 84.7% compared with a cut-off of 2.5, it came at the cost of decreasing the sensitivity from 95.7% to 80.0% and the NPV from 90.6% to 83.5%. As PET-CT is used to exclude mediastinal spread rather than diagnose it, the reduction in NPV renders the cut-off of 4.5 less appropriate for clinical use. The strength of the present study lies in the substantial number of lymph nodes sampled, and the prospective method in which the data were collected. A potential limitation was the necessary exclusion of a large number of patients – especially those in higher clinical stages of disease – prior to lymph node sampling. However, this was unavoidable as the study was conducted within the parameters of a normal clinical setting, and all decisions regarding invasive investigations were made in the interests of providing best patient care.

RESEARCH

Conclusion

PET-CT remains a valuable method for excluding mediastinal lymph node metastases in the staging of NSCLC in a high TB-endemic area, because of its high sensitivity and NPV. A patient with negative PETCT for mediastinal lymph node involvement may therefore safely and swiftly proceed to curative surgical intervention without undergoing further invasive staging procedures. However, the low specificity and PPV indicate that the finding of a positive lymph node on this imaging modality requires pathological confirmation, and that the possibility of TB must be considered. References 1. Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11. Lyon: International Agency for Research on Cancer, 2013. http:// globocan.iarc.fr (accessed 9 February 2014). 2. De Wever W, Stroobants S, Coolen J, Verschakelen JA. Integrated PET/CT in the staging of non-smallcell lung cancer: Technical aspects and clinical integration. Eur Respir J 2009;33(1):201-212. [http:// dx.doi.org/10.1183/09031936.00035108] 3. Detterbeck FC, Postmus PE, Tanoue LT. The stage classification of lung cancer. Diagnosis and management of lung cancer, 3rd ed. American College of Chest Physicians evidence-based clinical practice guideline. Chest 2013;143(5, suppl):e191S-e210S [http://dx.doi.org/10.1378/chest.12-2354] 4. Detterbeck FC, Boffa DJ, Tanoue LT. The new lung cancer staging system. Chest 2009;136(1):260-271. [http://dx.doi.org/10.1378/chest.08-0978] 5. Lee JW, Kim BS, Lee DS, et al. 18F-FDG PET/CT in mediastinal lymph node staging of non-smallcell lung cancer in a tuberculosis-endemic country: Consideration of lymph node calcification and distribution pattern to improve specificity. Eur J Nucl Med Mol Imaging 2009;36(11):1794-1802. [http://dx.doi.org/10.1007/s00259-009-1155-4] 6. Lardinois D, Weder W, Hany TF, et al. Staging of non-small-cell lung cancer with integrated positronemission tomography and computed tomography. N Engl J Med 2003;348(25):2500-2507 [http:// dx.doi.org/10.1056/nejmoa022136]

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7. Beyer T, Townsend DW, Brun T, et al. A combined PET/CT scanner for clinical oncology. J Nucl Med 2000;41(8):1369-1379. 8. Perigaud C, Bridji B, Roussel JC, et al. Prospective preoperative mediastinal lymph node staging by integrated positron emission tomography-computerised tomography in patients with nonsmall-cell lung cancer. Eur J Cardiothorac Surg 2009;36(4):731-736. [http://dx.doi.org/10.1016/j. ejcts.2009.05.044] 9. Chang JM, Lee HJ, Goo JM, et al. False positive and false negative FDG-PET scans in various thoracic diseases. Korean J Radiol 2006;7(1):57-69. [http://dx.doi.org/10.3348/kjr.2006.7.1.57] 10. Sathekge MM, Maes A, Pottel H, Stolz A, van de Wiele C. Dual time-point FDG PET/CT for differentiating benign from malignant solitary pulmonary nodules in a TB-endemic area. S Afr Med J 2010;100(9):598-601. 11. Kim YK, Lee KS, Kim BT, et al. Mediastinal nodal staging of non-small-cell lung cancer using integrated 18F-FDG PET/CT in a tuberculosis-endemic country: Diagnostic efficacy in 674 patients. Cancer 2007;109(6):1068-1077. [http://dx.doi.org/10.1002/cncr.22518] 12. Lu P, Sun Y, Sun Y, Yu L. The role of 18F-FDG PET/CT for evaluation of metastatic mediastinal lymph nodes in patients with lung squamous-cell carcinoma or adenocarcinoma. Lung Cancer 2014;85(1):5358. [http://dx.doi.org/10.1016/j.lungcan.2014.04.004] 13. World Health Organization. Global Tuberculosis Report 2013. Geneva: World Health Organisation, 2013. http://www.who.int/tb/publications/global_report/en/ (accessed 9 February 2014). 14. Gould MK, Donington J, Lynch WR, et al. Evaluation of individuals with pulmonary nodules: When is it lung cancer? Diagnosis and management of lung cancer, 3rd ed. American College of Chest Physicians evidence-based clinical practice guideline. Chest 2013;143(5, suppl):e78S-e92S. [http:// dx.doi.org/:10.1378/chest.12-2350] 15. Boellaard R, Oâ&#x20AC;&#x2122;Doherty MJ, Weber WA, et al. FDG PET and PET/CT: EANM procedure guidelines for tumour PET imaging: version 1.0. Eur J Nucl Med Mol Imaging 2010;37(1):181-200. [http://dx.doi. org/10.1007/S00259-009-1297-4] 16. Bryant AS, Cerfolio RJ, Klemm KM, Buddhiwardhan O. Maximum standard uptake value of mediastinal lymph nodes on integrated FDG-PET-CT predicts pathology in patients with non-small cell lung cancer. Ann Thorac Surg 2006;82(2):417-423. [http://dx.doi.org/10.1016/j.athoracsur.2005.12.047] 17. Vansteenkiste JF, Stroobants SG, de Leyn PR, et al. Lymph node staging in non-small-cell lung cancer with FDG-PET scan: A prospective study on 690 lymph node stations from 68 patients. J Clin Oncol 1998;16(6):2142-2149.

Accepted 28 July 2014.

February 2015, Vol. 105, No. 2

EDITORIAL

The medical case report February’s CME consists of a series of case reports that I have been sent over the past 12 months. Many journals – local and international – feature case reports within their pages, and younger doctors in particular are encouraged to write up their more interesting cases in this format. According to Wikipedia,[1] ‘In medicine, a case report is a detailed report of the symptoms, signs, diagnosis, treatment and follow-up of an individual patient’. Case reports are usually written to provide an unusual or a novel occurrence of a set of signs and symptoms, or, as is the case in some of the reports published this month, unusual presentations of a particular disease entity. Case reports generally contain a literature review of other reported cases, even if only to say that the report is of a rare occurrence. Case reports are, by their very nature, anecdotal and placed at the foot of the hierarchy of clinical evidence, together with case series. However, case reports are usually thought to have a genuinely useful role in medical research and evidence-based medicine. A good example is the recognition of the link between giving thalidomide to pregnant women and malformations in their babies, which was triggered by a case report. Case reports have a role in pharmacovigilance and can contribute to the understanding of the clinical spectrum of rare diseases and unusual presentations in common ones. These anecdotal

reports often help researchers to generate study hypotheses – including plausible mechanisms of disease. However, one of the most useful roles of case reports is that of medical education, both formally, providing a structure for casebased learning (which we all did at medical school), and informally, for the general reader. In both cases, interesting and unusual presentations are helpful for day-to-day practice and often trigger recognition of a diagnosis or pathology in a puzzling clinical case. All the case reports in this issue of CME are local, and I have tried to publish reports that will be particularly useful to our younger and less experienced colleagues. Please keep sending in your case reports. They are always welcome and interesting to read. Bridget Farham Editor, CME ugqirha@iafrica.com 1. http://en.wikipedia.org/wiki/Case_report (accessed 6 January 2015).

S Afr Med J 2015;105(2):151. DOI:10.7196/SAMJ.9350

ABSTRACT

Intimate partner violence and HIV in women In 2011, the Joint United Nations Programme on HIV/ AIDS (UNAIDS) World AIDS Day Report showed that 1 in 7 new HIV infections in South Africa could have been avoided through the prevention of intimate partner violence. Several studies have shown an association between intimate partner violence and HIV infection in women and reports from the World Health Organization (WHO) and UNAIDS conclude that research has documented an undeniable link between intimate partner violence and HIV infection. However, the authors of a recent paper in The Lancet Global Health report that adjusted analyses have produced inconsistent results. In this study, Dick Durevall and Annika Lindskog systematically assessed the association, and under what condition it holds, using nationally representative data from 10 sub-Saharan African countries. They focused on physical, sexual and emotional violence and the role of male controlling behaviour. The authors assessed cross-sectional data from 12 Demographic and Health Surveys from 10 countries in sub-Saharan Africa. The data are nationally representative for women aged 15 - 49 years. Exposure was measured using physical, sexual, and emotional violence, male controlling

behaviour, and combinations of these. The samples used were ever-married women, married women, and women in their first union. Depending on specification, the sample size varied between 11 231 and 45 550 women. There were consistent and strong associations between HIV infection in women and physical violence, emotional violence, and male controlling behaviour. The evidence for an association between sexual violence and HIV was weaker and only significant in the sample with women in their first union. The associations were dependent on the presence of controlling behaviour and a high regional HIV prevalence rate; when women were exposed to only physical, sexual, or emotional violence, and no controlling behaviour, or when HIV prevalence rates were <5%, the adjusted odds ratios were, in general, close to 1 and insignificant. The findings indicate that male controlling behaviour in its own right, or as an indicator of ongoing or severe violence, puts women at risk of HIV infection. HIV prevention interventions should focus on high-prevalence areas and men with controlling behaviour, in addition to violence. Durevall D, Lindskog A. The Lancet Global Health. Early Online Publication, 21 November 2014. [http:// dx.doi.org/10.1016/S2214-109X(14)70343-2]

The full version of this article is available online. Use the QR code above to access.

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February 2015, Vol. 105, No. 2

CONTINUING MEDICAL EDUCATION

CASE REPORT

The unsuspected killer: Liquefied petroleum gas overexposure in South Africa L W J Sampson;1 N van der Schyff,2 MB ChB, MPhil Emerg Med, FCP (SA); C Cupido,2 MB ChB, FCP (SA) Sixth-year medical student, Faculty of Health Sciences, University of Cape Town, South Africa Department of Internal Medicine, Victoria Hospital, Wynberg, Cape Town, South Africa

1 2

Corresponding author: L Sampson (sampson.mbchb@gmail.com)

A 21-year-old woman with no past medical history of note was found unconscious together with five of her family members after prolonged exposure to liquefied petroleum gas. She was admitted to the intensive care unit at Victoria Hospital, Wynberg, Cape Town, South Africa, following resuscitation for pulseless electrical activity. On examination the following was found: coma without focal neurology; shock requiring fluid resuscitation and adrenaline; probable pneumonitis or aspiration pneumonia; acute rhabdomyolysis with severe metabolic acidosis; and raised serum K+. A carboxyhaemoglobin test was unable to confirm or exclude carbon monoxide poisoning. S Afr Med J 2015;105(2):152. DOI:10.7196/SAMJ.9267

Liquefied petroleum gas (LPG) contains propane and butane gas and is generally used as an alternative to electricity for cooking and heating. Because of increasing energy costs, it is now more commonly used in South Africa (SA).[1] Although it is a cheaper source of energy, there are specific health risks to the uninformed user. In SA, LPG is sold in pressurised, sealed canisters, and includes a warning/instruction leaflet from the South African Bureau of Standards, requiring that all LPG systems be installed by a professional.[2] The gas is odourless and colourless, but an odourant is added to the container before sale.[3] Besides being highly flammable, the gas can create a hypoxic environment by consuming atmospheric oxygen (O2) (especially in small enclosures) to form carbon monoxide (CO), which is toxic; therefore, when used there must be adequate ventilation and no leakages. LPG is also a simple asphyxiant with anaesthetic properties. However, the gas itself is non-toxic.[2,3] A literature search found only two cases of LPG overexposure, with resultant rhabdomyolysis.

Case report

The first objective in the management of our patient was to identify the insulting agent by means of a collateral history from her boyfriend and the emergency services personnel – the latter reported a ‘musty’ smell and found an open gas canister in her kitchen. CO poisoning could not be excluded because of laboratory and transit errors, preventing a carboxyhaemoglobin level from being obtained. However, after consulting the literature, we confirmed LPG overexposure as the likely cause because of the following: • the collateral history indicated the gas as the possible agent • the patient had a reduced level of consciousness and signs of a probable pneumonitis – both fitting the effects commonly associated with overexposure to LPG. Furthermore, significant rhabdomyolysis was present; it is, however, a rare presentation in cases of LPG overexposure.[4,5] This was coupled with pulseless electrical activity, which is related to rhabdomyolysis.

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In our patient it was caused by hypoxia, severe metabolic acidosis, hyperkalaemia and long-term immobility. After resuscitation, which included the administration of 100% oxygen and adrenaline, the patient’s electrocardiogram was normal, which is rather unusual in the light of the hyperkalaemia. Although adrenaline is contraindicated in the management of a patient present ing with overexposure to LPG, as it causes tachyarrhythmias,[6] in this case it may have been protective as adrenaline reduces serum potassium levels.[7] Further management in this case was supportive, maintaining ventilation and renal function. With increased use of LPG in SA and the lack of end-user education regarding risks and correct installation, LPG overexposure could become a likely and unnecessary contributor to morbidity and mortality in SA. The points taken from our case are that a collateral history is important, removal from the compromised environment is the first step in management, and CO poisoning should be excluded where possible. Initial hospital management is resuscitation, 100% oxygen and monitoring of renal function and fluid status. Although a rare presentation, rhabdomyolysis should always be excluded, and special attention given to serum K+ levels. As was seen in our patient, adrenaline inadvertently aided treatment, but management of hyperkalaemia should be by more conventional methods such as intravenous insulin and glucose, furosemide, chelation and inhaled salbutamol with 100% oxygen, depending on the level of hyperkalaemia. Patients should be educated regarding the possible dangers of LPG use before discharge from hospital. References 1. Mohlakoana N, Annecke W. Finally breaking the barriers: South African case study on LPG use by lowincome urban households. http://www.hsrc.ac.za/en/research-outputs/view/3951 (accessed 17 July 2013). 2. South African Bureau of Standards (SABS). The Handling, Storage, Distribution and Maintenance of Liquefied Petroleum. SANS 10087-2:2011. 3rd ed. Pretoria: SABS, 2011:20. 3. AFROX. Material safety and data sheet (MSDS) liquefied petroleum gas & propane. http://www.afrox.co.za/ internet.global.corp.zaf/en/images/LiquefiedPetroleumGas_Propane266_27684.pdf (accessed 17 July 2013). 4. Prasad S, Singh R, Manocha R, et al. Acute massive rhabdomyolysis due to inhalation of LPG. Journal of the Association of the Physicians of India 2009;57:472-473. 5. Frangides CY, Tzortzatos GV, Koulouras V, Pneumatikos IA. Acute massive rhabdomyolysis due to prolonged inhalation of liquid gas. Eur J Emerg Med 2003;10(1):44-46. 6. Safety Data Sheet for Liquefied Petroleum Gas (LPGas). http://www.unigas.com.au/downloads/Safety_ Data_Sheet_for_LPG_Jan_2011.pdf (accessed 17 July 2013). 7. Editorial. Adrenaline and potassium: Everything in flux. Lancet 1983;322(8364):1401-1403.

February 2015, Vol. 105, No. 2

Zytomil 10 mg. Each film coated tablet contains 10 mg escitalopram. Reg. No./Nr.: RSA S5 42/1.2/0912. NAM NS3 10/1.2/0479. Zytomil 20 mg. Each film coated tablet contains 20 mg escitalopram. Reg.No./Nr.: RSA S5 42/1.2/0914. NAM NS3 10/1.2/0481. For full prescribing information, refer to the package insert approved by the Medicines Regulatory Authority. ZLA17/01/2014.

CONTINUING MEDICAL EDUCATION

CASE REPORT

The utility of urine sulphosalicylic acid testing in the detection of non-albumin proteinuria S Ndamase, MB ChB; R Freercks, MB ChB, FCP (SA), Cert Nephrology (SA), MPhil Division of Nephrology and Hypertension, Department of Medicine, Faculty of Health Sciences, University of Cape Town, and Renal Unit, Livingstone Hospital, Port Elizabeth, South Africa Corresponding author: R Freercks (robert.freercks@uct.ac.za)

We report two cases of immunoglobulin light chain proteinuria (Bence Jones proteinuria) detected by simple side-room investigations: urine dipstick negative/1+, but with strong positive precipitation on addition of an equal volume of sulphosalicylic acid (SSA) 3%. We highlight a significant limitation of urine dipstick testing, namely specificity for albumin, and the utility of SSA testing for the detection of urinary free light chain immunoglobulins. S Afr Med J 2015;105(2):153. DOI:10.7196/SAMJ.9270

Case 1

A 51-year-old woman with hypertension and type 2 diabetes mellitus was referred for evaluation of her chronic kidney disease. Her creatinine was 124 µmol/L, urea 5.6 mmol/L and estimated glomerular filtration rate 40 mL/min. She had a severe normocytic anaemia, with a haemoglobin of 6.5 g/dL. On further enquiry she gave a history of unintentional weight loss of 9 kg. She was pale, with no lymphadenopathy or oedema. Urine dipstick was negative for proteinuria, but the urine protein:creatinine ratio was 0.8 g/mmol (normal range <0.02 g/mmol), indicating nephrotic range proteinuria. The addition of sulphosalicylic acid (SSA) to her urine caused immediate turbidity (Fig. 1). A diagnosis of multiple myeloma was

therefore suspected and serum and urine electrophoresis confirmed a monoclonal lambda peak. Serum free kappa light chains were 12.9 mg/L (3.3 - 19.4), and free lambda light chains 5 688 mg/L (5.7 - 26.3).

Case 2

A 54-year-old man presented with a 2-day history of headache and epistaxis. He was pale, with no lymphadenopathy and an otherwise normal physical examination. Initial testing revealed a severe bicytopenia: haemoglobin 6.2 g/dL, mean corpuscular volume 85.8 fL, and platelets 10 × 109/L. A peripheral smear showed occasional tear drop cells with a leuco-erythroblastic reaction and no fragments or platelet clumping. His urea was 14.9 mmol/L and creatinine 460 µmol/L. Urinary dipstick testing showed only 1+ proteinuria, while the urine protein:creatinine ratio was markedly elevated at 1.3 g/mmol. On addition of SSA, dense turbidity was immediately noted. A diagnosis of multiple myeloma was subsequently confirmed on bone marrow biopsy. Serum free kappa light chains were 8.2 mg/L (3.3 - 19.4) and lambda light chains 27 098.0 mg/L (5.5 - 26.3).

Discussion

The urine dipstick is specific for albumin and will miss positively charged proteins in the urine, such as immunoglobulin light chains.[1] The bedside detection of non-albumin proteinuria is aided by the use of a simple, inexpensive and often-overlooked investigation: addition of SSA 3% to urine. The degree of turbidity provides a semiquantitative method for proteinuria detection.[2] Discordance between SSA and dipstick testing (where SSA is strongly positive and dipstick negative or low positive) mainly suggests the presence of non-albumin proteinuria, usually immunoglobulin light chain excretion.[3] This reminder may be of particular interest to clinicians in the South African public sector, where serum and urine electrophoresis results can take 3 - 4 weeks to become available. However, SSA should not substitute urine electrophoresis, as small quantities of monoclonal free light chains may be missed.[4] References

Fig. 1. Case 1. Turbidity with the urine sulphosalicylic acid 3% precipitation test. Negative dipstick test for proteinuria (white arrow-head).

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1. Kashif W, Siddiqi N, Dincer HE, et al. Proteinuria: How to evaluate an important finding. Cleve Clin J Med 2003;70(6):535-547. [http://dx.doi.org/10.3949/ccjm.70.6.535] 2. Arnulfo J, Penagos V, Jairo J, et al. Use of sulfosalicylic acid in the detection of proteinuria and its application to hypertensive problems in pregnancy. Iatreia 2011;24(3):259-266. 3. Gyure W. Comparison of several methods for semiquantitative determination of urinary protein. Clin Chem 1977;23(5):876-879. 4. Said A, Naderi A, Reilly RF. Primary care approach to proteinuria. J Am Board Fam Med 2008;21(6):569-574. [http://dx.doi.org/10.3122/jabfm.2008.06.070080]

February 2015, Vol. 105, No. 2

CONTINUING MEDICAL EDUCATION

CASE REPORT SUMMARY

Digoxin therapy in the modern management of cardiovascular disease: An unusual but serious complication P Mkoko, MB ChB; N Mokhele, MB ChB; M Ntsekhe, MD, PhD; N A B Ntusi, FCP (SA), DPhil Cardiac Clinic, Department of Medicine, Faculty of Health Sciences, Groote Schuur Hospital and University of Cape Town, South Africa Corresponding author: N A B Ntusi (ntobeko.ntusi@gmail.com)

A 67-year-old woman presented to the Emergency Unit, Groote Schuur Hospital, Cape Town, South Africa, with a 1-week history of poor appetite, vomiting and fatigue. Her background history was notable for infundibular pulmonary stenosis resection, pulmonary embolism and atrial flutter. Two days before, she complained to her general practitioner of recentonset, recurrent syncope and worsening gastrointestinal upset. Her medical treatment included warfarin 5 mg daily, enalapril 5 mg twice daily, furosemide 40 mg twice daily, atenolol 50 mg twice daily, amiodarone 200 mg daily and digoxin 0.125 mg daily. The digoxin was added to her therapy 8 months earlier to optimise rate control. A final diagnosis of digoxin toxicity complicated by ventricular tachycardia, sinus arrest and 1st-degree atrioventricular block was

made. The patient was discharged from hospital feeling much better and digoxin therapy was discontinued. First described in 1785 by William Withering, cardiac glycosides have been used in the treatment of heart failure for >200 years, and digoxin had been the most commonly used of these compounds. Owing to adverse effects and the availability of improved drugs for heart failure, its popularity as the drug of choice has declined. In summary, this case serves as a timely reminder that careful consideration and thought should be given before the use of cardiac glycosides. Indeed, in an article in the Forum section of this edition of SAMJ, Opie states that there are few arguments in favour of the use of digoxin to control rate in atrial fibrillation.

S Afr Med J 2015;105(2):154. DOI:10.7196/SAMJ.8638

CASE REPORT SUMMARY

Arthritis mutilans: A rare phenomenon M C Madua, MB ChB, FCP (SA) Charlotte Maxeke Johannesburg Academic Hospital, and Division of Rheumatology, Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa Corresponding author: M C Madua (chasneyza@yahoo.com)

A 67-year-old woman presented to the Department of Surgery, Charlotte Maxeke Johannesburg Academic Hospital, South Africa, with an incarcerated umbilical hernia and a 12-year history of hypertension and psoriasis. She received indomethacin for her arthritis and steroid creams for her psoriasis. Gastroscopy revealed a prepyloric ulcer. She had generalised plaque psoriasis and arthritis of the small joints of the hands, wrist and feet. Psoriatic arthritis is a member of the spondyloarthropathy family and may be defined as an inflammatory arthropathy associated with

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psoriasis, usually negative for rheumatoid factor. Between 5% and 30% of psoriasis patients develop arthritis. Plaque psoriasis is the most common skin phenotype in patients with psoriatic arthritis. Psoriasis manifests after arthritis in 15% of patients. The literature reports that arthritis mutilans is a rare phenomenon. Dactylitis and enthesitis are typical features of psoriatic arthritis, and there is no known laboratory test that is diagnostic of the condition.

S Afr Med J 2015;105(2):154. DOI:10.7196/SAMJ.9263

February 2015, Vol. 105, No. 2

CONTINUING MEDICAL EDUCATION

CASE REPORT SUMMARY

For external use only P Mkoko, MB ChB Department of Internal Medicine, Faculty of Health Sciences, Groote Schuur Hospital and University of Cape Town, South Africa Corresponding author: P Mkoko (mkoko25@me.com)

A previously well 28-year-old woman presented to Groote Schuur Hospital, Cape Town, South Africa, with a history of hair dye ingestion, thus intending to end her life. She had not passed urine for 12 hours, but appeared comfortable. Her face was oedematous, blood pressure 110/80 mmHg, and pulse 80/min, with a clear chest and raised jugular venous pressure. Her arterial blood gas showed a pH of 7.31, an HCO3- of 19 mmol/L, a base excess of –6 mmol/L and a lactate level of 0.7 mmol/L. The urine volume and electrolyte levels are shown in Table 1 in the online case report. A diagnosis of acute kidney injury secondary to hair dye poisoning was made. The patient received haemodialysis from day 3 of her hospital stay, and started passing urine on day 8. She was discharged home on day 14 and was followed up at the nephrology outpatient clinic. Hair dye poisoning is a common problem in West Africa, in North Africa and on the Indian subcontinent. In Morocco, acute hair dye poisoning is the most frequent reason for hospitalisation for attempted suicide. In adults, 70 - 90% of episodes of hair dye

poisoning are suicide attempts. The reported mortality rate range for acute hair dye poisoning is 10.6 - 38.7%. Para-phenylenediamine (PPD) is a major ingredient of oxidisable permanent hair dyes. It is a derivative of para-nitroaniline. On oxidation, PPD produces Bandrowski’s base, which is an allergen and possibly mutagenic. Acute ingestion of PPD causes angioneurotic oedema of the neck and face, often requiring an emergency tracheostomy in children, and anuric or oliguric renal failure with chocolate-brown urine and rhabdomyolysis. Acute renal failure develops in 70.5% of patients and 50% require renal replacement therapy. PPD is a dangerous poison and is widely available over the counter. It is imperative that we are aware of its clinical manifestations on acute ingestion and that it may potentially cause chronic renal impairment when recurrently applied to unprotected skin.

S Afr Med J 2015;105(2):155. DOI:10.7196/SAMJ.9264

CASE REPORT SUMMARY

A tale of two viruses M C Madua, MB ChB, FCP (SA) Chris Hani Baragwanath Academic Hospital, and Division of General Medicine, Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa Corresponding author: M C Madua (chasneyza@yahoo.com)

A 30-year-old woman presented to Tshepong Hospital, Klerksdorp, South Africa, with a history of rash with papules and pustules, which started on her face and spread to her entire body. There was a typical varicella lesion on the trunk. She was newly diagnosed as HIV-positive, with a CD4 count of 232 cells/µL, and was not yet on antiretroviral therapy. The diagnosis was that of disseminated varicella in a woman newly diagnosed with HIV. Varicella in an immunocompromised patient often presents as severe disease.

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Disseminated zoster is associated with immunosuppression. In our setting, HIV is the most common association, although there are other causes for the immunosuppression. Dissemination of zoster in an immunocompromised patient may present mainly with cutaneous dissemination and visceral dissemination in the form of zoster pneumonitis, hepatitis and encephalitis.

S Afr Med J 2015;105(2):155. DOI:10.7196/SAMJ.9292

February 2015, Vol. 105, No. 2

CONTINUING MEDICAL EDUCATION

CASE REPORT SUMMARY

Schistosomiasis misdiagnosed as abdominal tuberculosis S N Botes,1 MB ChB; S B Ibirogba,2 FCS (SA), MMed; D Kahn,2 MB ChB, FCS (SA), ChM 1

Surgical Unit, Rob Ferreira Hospital, Nelspruit, South Africa Department of Surgery, Faculty of Health Sciences, Groote Schuur Hospital and University of Cape Town, South Africa

Corresponding author: S N Botes (snbotes@gmail.com)

Schistosomiasis (also termed bilharzia, after the tropical disease specialist Theodor Bilharz) is a waterborne parasitic infection. It was first described in the appendix in 1909, but despite awareness of the disease for more than a century, few data on its exact incidence are available. We report a case of a missed diagnosis of the disease. A 36-year-old woman presented to her general practitioner on 2 March 2012, complaining of a 2-week history of abdominal pain. Clinically, she had a right iliac fossa (RIF) mass, which was confirmed on an ultrasound scan. On 24 April 2012, an ultrasound scan at Rob Ferreira Hospital (RFH), Nelspruit, South Africa (SA), revealed a poorly circumscribed RIF mass with para-aortic lymph nodes. The liver and spleen were normal and no renal calculi were seen. The gynaecology team ruled out pelvic inflammatory disease. The Surgery Unit requested a computed tomography (CT) scan of the abdomen and a sputum specimen for tuberculosis (TB) diagnosis. Colonoscopy with biopsy of the mass was performed, as well as a pregnancy test, which was negative. The patient was newly diagnosed as HIV-positive, with a CD4 count of <50 cells/μL. She was started on TB therapy and then lost to follow-up. On 17 June 2013, the patient presented to the RFH casualty department with an acute abdomen and generalised peritonitis.

She had a C-reactive protein level of 205 mg/L, a white cell count of 7.89 × 109/L, and an erythrocyte sedimentation rate (ESR) of 65 mm/h. On 19 June 2013, the patient underwent an emergency laparotomy, which revealed a perforated jejenum and terminal ileum. A limited right hemicolectomy was performed, and an ileostomy was made. On 27 June 2013, the histology report confirmed schistosomiasis (Schistosoma haematobium). The patient was started on praziquantel, and discharged on day 13 after the laparotomy. The diagnosis of TB of the abdomen was never confirmed, and was based on the clinical findings, raised ESR, low CD4 count, and radiological findings (even though the ultrasound scan was not convincing of TB of the abdomen). The diagnosis of schistosomiasis was, however, confirmed on histological examination, and the patient showed significant improvement after a course of praziquantel. It is therefore assumed that the original diagnosis was incorrect, and that the patient suffered from abdominal schistosomiasis. The incidence of this disease at RFH is unknown, but as the Lowveld region of SA is an endemic area, schistosomiasis should always be considered in the differential diagnosis of a patient with a chronic, vague abdominal mass. S Afr Med J 2015;105(2):156. DOI:10.7196/SAMJ.9269

CASE REPORT SUMMARY

An additional X chromosome M C Madua, MB ChB, FCP (SA) Charlotte Maxeke Johannesburg Academic Hospital, and Division of Rheumatology, Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa Corresponding author: M C Madua (chasneyza@yahoo.com)

A 35-year-old man presented with symmetrical inflammatory polyarthritis of the small and large joints and associated early-morning stiffness. He gave a history of leg ulcers 8 years ago. He had never been to school and never been sexually active. Examination revealed a tall man with a normal blood pressure, pulse, respiratory rate and temperature, but with orbital hypertelorism, a prognathic jaw, a eunichoid stature and long arms. Other clinical findings were gynaecomastia (greater on the right), infantile genitalia, lack of secondary sexual characteristics, facial atrophy,

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hyperpigmented knuckles and generalised erythema nodosum. He was assessed as having features in keeping with Klinefelter’s syndrome, with a possible underlying connective tissue disease (systemic lupus erythematosus (SLE), rheumatoid arthritis or Sjögren’s syndrome). There is a strong association between Klinefelter’s syndrome and rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, dermatomyositis/polymyositis, SLE, systemic sclerosis, ankylosing spon dylitis, primary biliary cirrhosis and mixed connective tissue disease. S Afr Med J 2015;105(2):156. DOI:10.7196/SAMJ.9266

February 2015, Vol. 105, No. 2

CONTINUING MEDICAL EDUCATION

CASE REPORT SUMMARY

Wernicke’s encephalopathy as a complication of gastroparesis after emergency partial antrectomy N S Ganie, MB ChB; E Janse van Rensburg, MB ChB, MMed (Neurology) Department of Neurology, Faculty of Health Sciences, University of the Free State, Bloemfontein, South Africa Corresponding author: E Janse van Rensburg (vanrense@ufs.ac.za)

Wernicke’s encephalopathy is a common comp lication of malnutrition, alcohol abuse and gastric outlet obstruction. We describe a patient who developed Wernicke’s encephalopathy secondary to gastroparesis, with no significant evidence of malnutrition, alcohol abuse, or gastric outlet obstruction.

Case report

A 64-year-old woman with a history of hypertension and peptic ulcer disease was admitted to hospital. She had a 2-month history of vomiting, with difficulty eating and drinking, and felt bloated. These symptoms affected her appetite, resulting in a loss of 10 kg since symptom onset. Her presentation was further complicated by a recent 1-week history of visual hallucinations and new-onset generalised tonic-clonic seizures. Her past surgical history revealed an emergency laparotomy for a perforated gastric ulcer for which a partial gastrectomy had been performed. She had a history of severe alcohol abuse, but stopped drinking alcohol >5 years ago. A series of haematological, radiological and invasive investigations were performed to investigate the delirium and clinical malnutrition with associated gastrointestinal symptoms. All the haematological investigations were normal, including urea and electrolyte levels, liver function enzymes, albumin levels, white cell count, and haemoglobin level with mean cell volumes. Iron studies and vitamin B12 levels were within normal limits, indicating an acute

clinical malnutrition without biochemical evidence suggesting otherwise. An endoscopic examination revealed a small stomach and a healed gastric ulcer with a fibrotic base on the greater curvature. There was also evidence of the anastomosis created by previous surgery. Histological examination of gastric tissue showed no features of dysplasia or malignancy. A water-soluble contrast swallow study was performed, which demonstrated features in keeping with delayed gastric emptying, as contrast media was still notably present in the stomach 5 hours later. In view of the delirium, a computed tomography scan of the brain was performed, which was reported as normal. Subsequently, a lumbar puncture was done, which was also normal. As the delirium and new-onset seizures could not be explained, magnetic resonance imaging of the brain was performed. Axial T2-weighted images with fluid attenuated inversion recovery (FLAIR) at the level of the basal ganglia showed an increased signal of the fornix and periventricular region around the third ventricle and the medial thalamic nuclei. Images at the level of the midbrain and pons, showed an increased signal of the tectal plate. On the sagittal T2-weighted image with FLAIR, an increased signal was noted in the parietal cortex in the post-central gyrus and fornix, mamillary bodies and peri-aqueductal region. These changes were in keeping with Wernicke’s encephalopathy. S Afr Med J 2015;105(2):157. DOI:10.7196/SAMJ.9271

CASE REPORT SUMMARY

Fever, sore throat and myalgia P Ive, FCP (SA); M Mendelson, PhD, FRCP; S Dlamini, FCP (SA), Cert ID (SA) Phys Division of Infectious Diseases and HIV Medicine, Department of Medicine, Faculty of Health Sciences, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa Corresponding author: P Ive (prue.ive@gmail.com)

A 20-year-old man presented with a severely sore throat and myalgia, which were unresponsive to antibiotics. Ten days into his illness he was admitted to a regional hospital with an ongoing painful throat, generalised myalgia, fever (38.5°C) and a transient, recurring, salmon-pink rash on his hands and trunk. He did not respond to ceftriaxone and had a continual significant fever daily. Shotty cervical lymphadenopathy was noted.

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The patient fulfilled the Yamaguchi criteria (Table 3 in the online Case report) for adult-onset Still’s disease (AOSD), with a good clinical and laboratory response to prednisone 80 mg once daily. When the aetiological diagnosis eludes the clinician, patients with pyrexia of unknown origin are often diagnosed as having AOSD. S Afr Med J 2015;105(2):157. DOI:10.7196/SAMJ.9262

February 2015, Vol. 105, No. 2

PULSE

Diabetes tsunami threatens South Africa

The World Health Organization predicts that diabetes will become a leading global killer in the next 25 years – and South Africa (SA) is no exception. Recent data from the Council for Medical Schemes show an alarming rise in lifestyle diseases over a 5-year period, with the prevalence of type 2 diabetes increasing by a staggering 84%. Increasing urbanisation and rising unhealthy lifestyle risk factors are major contributors to this growing diabetes epidemic in SA. Of particular concern are the large numbers of South Africans with diabetes who are not diagnosed. Without diagnosis, treatment and appropriate management, complications from diabetes rise at an alarming rate. Many medical schemes offer members free access to diabetes management programmes, which are specifically designed to improve the wellbeing of patients through education and awareness. Dr Ali Hamdulay, who heads up the Metropolitan Health Diabetes Special Care programme, says: ‘Unfortunately, general patient indifference and lack of knowledge means some patients miss out on accessing the benefits available through these programmes. Patients diagnosed with the disease should be encouraged to register.’ As part of these programmes, patients usually have access to a special care case manager. The Metropolitan Health Diabetes Special Care programme provides patients with access to a trained healthcare professional who promotes appropriate health behaviour by answering questions related to benefits, medicine, blood sugar levels and general health. ‘These professionals also assist by providing advice and motivation on healthy lifestyle choices, such as diabetes-smart eating choices and appropriate physical exercise. They also help patients with medication compliance, advising them how and when they should be taking their medicines and how to manage any side-effects they may experience, as well as assist in obtaining medical scheme authorisation for appropriate healthcare services. ‘Case managers usually work closely with the patient’s doctor and other healthcare providers to ensure that treatment is co-ordinated – and delivers the best possible results,’ explains Dr Hamdulay.

Understanding the insured benefit funds available

As part of the prescribed minimum benefit (PMB) Chronic Diseases List, the diagnosis, treatment and care of patients’ diabetes will be paid from their schemes’ insured benefits in line with PMB regulations. Covered care interventions often include: • consultations with the patient’s treating doctor • lifestyle assistance, such as dietary advice • an annual eye examination • an annual comprehensive foot examination • pathology tests • home glucose monitoring. ‘Medical schemes may limit the number of care interventions. Depending on patients’ risk rating and the medical scheme agreement, they may receive a care plan, which clearly shows the list of services and care interventions relating to the management of their diabetes that will be paid from their scheme’s insured benefits.’

The process

Metropolitan Health Risk Management automatically identifies patients who have been diagnosed with diabetes. The patients are then requested to complete an enrolment form and are granted access to the programme at no extra cost. Risk rating based on strong evidence-based analytical tools ensures that they receive the appropriate level of intervention and care.

‘A patient’s doctor can proactively enrol patients onto the programme, by contacting the relevant medical scheme’s chronic department or via the online provider portal. Early enrolment onto the programme is highly recommended, particularly for high-risk individuals, as the combined efforts of the treating practitioner and the case manager have a greater impact on disease management to ensure positive health outcomes,’ explains Dr Hamdulay. While patients are encouraged to take ownership of their condition, their primary doctor is also encouraged to take control of their care plan and ensure that they access the authorised services specified in the plan. ‘If a doctor believes their patient’s care plan does not adequately address their patients’ needs, they are encouraged to motivate for additional services. ‘In an era of growing obesity, rapid urbanisation and an ageing HIVpositive population in SA, it is vital for doctor, patient, managed care provider and medical scheme to align closely in terms of diagnosing, treating and managing the disease,’ concludes Dr Hamdulay.

Over two-thirds of women admit that their sex lives are suffering due to a hidden symptom of menopause

A first-of-its-kind study, known as CLarifying vaginal atrophy’s impact On SEx and Relationships (CLOSER), has revealed that over two-thirds (69%) of postmenopausal women and a higher proportion of their partners (76%) agree that they are having less sex because of vaginal atrophy – a common condition that affects around half of all postmenopausal women and is caused by a decline in oestrogen. Symptoms include vaginal dryness, itching and painful intercourse. Vaginal atrophy can have a significant impact on quality of life and, if left untreated, may also be associated with serious long-term urogenital problems, including incontinence. The CLOSER research was an online survey conducted by StrategyOne (partnering with Ipsos MORI) between 13 December 2011 and 7 February 2012. The survey was completed by 4 100 postmenopausal women aged 55 - 65 who had ceased menstruating for at least 12 months and had experienced vaginal atrophy, and 4 100 male partners of such women. The participants were located across nine countries: the USA, the UK, Canada, Denmark, Sweden, Finland, Norway, Italy and France. The objectives of the research were to improve understanding of the impact of vaginal atrophy on intimacy and relationships, both physically and emotionally, and to find out how to encourage positive communication between men and women about this topic. The research also looked at the positive impact that local oestrogen treatment can have on the sufferer’s relationship. The results were first presented at the European Menopause and Andropause Society meeting in March 2012. • The research highlights that approximately seven out of 10 women (69%) avoided being physically intimate with their partner because of vaginal atrophy, and almost half of them (41%) had lost confidence in themselves as a sexual partner as a result. • Although vaginal atrophy is a common condition, nearly threequarters (73%) of the women surveyed felt there was not enough information available about the symptoms and treatment. Previous studies have shown that it is still considered to be a taboo subject. • Nearly half (40%) of women with vaginal atrophy found sex more satisfying after trying local oestrogen treatment.

February 2015, Vol. 105, No. 2

PULSE

‘It is clear from this research that too many postmenopausal women and their partners are putting up, unnecessarily, with less satisfying sex because of vaginal atrophy,’ says Dr Trudy Smith, a Johannesburgbased gynaecologist. ‘It is saddening that, for a number of reasons, women are not seeking help when treatment is available. This is especially frustrating considering how commonplace discussion of erectile dysfunction has become – but women continue to suffer in silence.’

Four out of every ten women worry about their future sex life

Over a third of women (39%) with vaginal atrophy are concerned that it will never go away, so the impact on their relationship will remain, and they are worried that they will have no future sex life with their partner. The impact of vaginal atrophy is clearly emotional as well as physical, with more than half of women surveyed (60%) feeling upset that their body no longer works as it did and more than a third (41%) having lost confidence in themselves as a sexual partner. Vaginal atrophy also has a negative impact on partners. Almost one in three men (29%) believed that vaginal discomfort had created a big problem for their sex life, and consequently the relationship. Twelve per cent of men said that it had created an emotional distance between them and their partner. Over threequarters (76%) of men agreed that their partner had avoided physical intimacy because of vaginal atrophy. Additionally, over one in five men and women (22%) reported that the condition had aggravated male sexual health issues.

Seeking help

‘Vaginal atrophy is still considered a taboo subject, with many women not seeking treatment because they are either too embarrassed to talk to their healthcare provider or partner, or simply accept it as a natural part of ageing that can’t be treated,’ says Dr Smith. ‘It is important for couples to recognise the impact vaginal atrophy is having on their relationship and, more importantly, to speak to a healthcare provider, because effective treatments are available.’ Instead of speaking with a healthcare provider, many women selftreat using over-the-counter lubricants and moisturisers, measures that may only provide temporary relief of symptoms and do not treat the underlying condition.

Once the condition has been diagnosed, many healthcare providers may recommend oestrogen treatments that are available in systemic and local forms. Local oestrogen (e.g. cream or vaginal tablets) is the preferred treatment, according to the International Menopause Society. It is applied directly to the vagina via an applicator, as opposed to orally administered preparations, which increase systemic exposure to oestrogen. Consequently, local oestrogen avoids the side-effects that can potentially occur with systemic therapy. Because vaginal atrophy is a chronic condition, treatment needs to be continued to maintain the benefits. Vagifem vaginal tablets are a convenient, easy-to-use option for women who will benefit from local oestrogen. With the applicator that is provided, they are easy and comfortable to insert – once daily for the first 2 weeks and twice weekly thereafter. In a recent clinical survey, women who had been using vaginal cream for approximately a year and a half were switched to Vagifem. After a treatment period of approximately 21 months, two-thirds of the women said that they were much more likely to use their current vaginal tablet compared with the cream that they had previously used. The preference for Vagifem was, among other reasons, because the tablets were effective in reducing symptoms; convenient to use, neat, clean and not messy to apply; and the lowest dose of oestrogen available. ‘Women need to routinely discuss vaginal atrophy with healthcare providers,’ says Dr Smith. ‘Once women are using local oestrogen treatment, it is crucial that they continue if they want to improve their vaginal health and maintain the benefits.’ According to the CLOSER research, local oestrogen therapy can provide effective relief, which leads to a positive impact on the sufferer’s physical relationships, such as less painful and more satisfying sex. Vagifem vaginal tablets (25 µg oestradiol, Reg. No: 27/21.8.1/98, indicated for the treatment of atrophic vaginitis due to oestrogen deficiency) are marketed and distributed on behalf of Novo Nordisk by Adcock Ingram in South Africa. For full prescribing information, refer to the package insert approved by the medicines regulatory authority. Enquiries: Kerry Simpson, Bespoke Strategic Communications, (011) 280-6679, Kerry@bespokecomms.co.za. References available on request.

February 2015, Vol. 105, No. 2

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True (A) or false (B): Digitalis reappraised: Still here today, but gone tomorrow? 1. Digoxin is a very complex drug with a very narrow therapeutictoxic window and numerous drug interactions. 2. Digoxin is rapidly absorbed into the circulation, bound to plasma proteins, and largely excreted by the liver and in the stools.

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South African National Cancer Registry: Effect of withheld data from private health systems on cancer incidence estimates 3. Regulation 380 of the National Health Act by the Department of Health in 2011 formally established the National Cancer Registry (NCR) as the main cancer surveillance agency, requiring mandatory reporting of all confirmed cancers to the NCR.

Digoxin therapy in the modern management of cardiovascular disease: An unusual but serious complication 13. At toxic concentrations, digoxin leads to arrhythmias secondary to increased cell excitability from decreased resting cellular membrane potentials and after depolarisations.

Morbidity and mortality of black HIV-positive patients with endstage renal disease (ESRD) receiving chronic haemodialysis 4. Renal disease affects up to 30% of HIV-infected patients and is associated with increased morbidity and mortality. 5. HIV-associated nephropathy is most common and, unless treated with antiretroviral therapy, progresses rapidly to ESRD. 6. Being HIV-positive is an absolute contraindication to renal transplantation. 7. Because of the high risk of chronic kidney disease (CKD), all HIVpositive patients, even those with high CD4 counts, should be screened for CKD at first encounter with any health service. The Vaccine and Cervical Cancer Screen (VACCS) project: Linking cervical cancer screening to HPV vaccination 8. There are 15 HPV high-risk viral types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, 82), with the two most oncogenic being HPV 16 and 18. Human myiasis in rural SA is under-reported 9. Myiasis is infestation of live tissue of humans by larvae (maggots), with ocular myiasis being the most prevalent type. Multimorbidity in non-communicable diseases (NCDs) 10. The World Health Organization estimates the burden of NCDs to be two to three times higher in SA than in high-income countries. The unsuspected killer: Liquefied petroleum gas overexposure in South Africa 11. Besides being highly flammable, liquefied petroleum gas can create a hypoxic environment by consuming atmospheric oxygen (especially in small enclosures) to form carbon monoxide, which is toxic; therefore, its use requires adequate ventilation and no leaks.

Arthritis mutilans: A rare phenomenon 14. Psoriatic arthritis is an inflammatory arthropathy associated with psoriasis and usually positive for rheumatoid factor. For external use only 15. The reported mortality rates for acute hair dye poisoning range between approximately 10% and 40%. A tale of two viruses 16. Herpes zoster in an immunocompromised patient may present with cutaneous and visceral dissemination, the latter in the form of pneumonitis, hepatitis and encephalitis. Schistosomiasis misdiagnosed as abdominal tuberculosis 17. Schistosomiasis is a waterborne trematode infection that spreads through direct contact with the human skin. 18. The symptoms of schistosomiasis are caused by the host’s immune response to the antigens secreted by the schistosoma eggs, leading to a granulomatous reaction. An additional X chromosome 19. Most patients with Klinefelter’s syndrome do not come to medical attention and therefore do not receive a diagnosis. Wernicke’s encephalopathy as a complication of gastroparesis after emergency partial antrectomy 20. In the clinical presentation of Wernicke’s encephalopathy, the typical classic triad of ataxia, confusion and nystagmus is present in less than half of all patients.

CPD questions include articles from CME. The full versions of each article can be found on the SAMJ website (http://www.samj.org.za)

A maximum of 3 CEUs will be awarded per correctly completed test.

INSTRUCTIONS 1. Read the journal. All the answers will be found there. 2. Go to www.mpconsulting.co.za to answer the questions. Accreditation number: MDB001/007/01/2014 (Clinical)

February 2015, Vol. 105, No. 2