NOVEMBER 2014
VOL. 104 NO. 11
Mediation, not litigation Ebola – update on the epidemic New editors for SAJCH and SAJOG Blood-borne infections in healthcare workers Consequences of increasing medical negligence litigation Recommendations for the management of sickle cell disease Khat (Catha edulis) chewing and orodental health CME: Immunology Surgical aspects of liver disease in children
717 722, 754 724, 730 732 736, 752 743 773 785-796 797-832
HOW MUCH IS ENOUGH TO GET THE BIG FAMILY HOME
&
STILL GROW YOUR INVESTMENT PORTFOLIO?
How much is enough? An age-old question that needs a new answer. Old Mutual Wealth has it and it’s called Integrated Wealth Planning. It’s a wealth map that puts you and your goals at its core, helping you plan how much is enough for you – for now, for your life and for your legacy. Contact your Financial Adviser about your Old Mutual Wealth Integrated Wealth Plan .
Call 0860 WEALTH (932584) or go to www.howmuchisenough.co.za
ADVICE | INVESTMENTS | WEALTH
Old Mutual Wealth is brought to you through several Licenced Financial Services Providers in the Old Mutual Group who make up the elite service offering 10015764JB/
/E
NOVEMBER 2014
GUEST EDITORIAL
717
Mediation – an alternative to litigation in medical malpractice J Walters
718
EDITOR’S CHOICE
VOL. 104 NO. 11
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 720
Bureaucracy and clinical performance J V Larsen
720
A puzzling case of cryptococcal meningitis S J Brown, S George, K Braithwaite
721
Dr Mary Gordon J Metz
DEPUTY EDITOR Bridget Farham, BSc (Hons), PhD, MB ChB EDITORIAL SYSTEMS MANAGER Melissa Raemaekers, BSc (Hons), PhD SCIENTIFIC EDITOR Ingrid Nye, BSc
IZINDABA 722 725 727 729
Ebola global response: ‘not in my back yard’ Emergency care doctors – ‘off-task and in the wrong places’ The smell of coffee, blood and disinfectant … Discard the placenta at your peril, pathologist warns doctors
731 731
BOOK REVIEWS Principles of Medicine in Africa Creative Arts in Humane Medicine
SAMJ FORUM
732
CLINICAL ALERT Blood-borne infections in healthcare workers in South Africa T M Rossouw, M van Rooyen, J M Louw, K L Richter
TECHNICAL EDITORS Paula van der Bijl, BA, HDipLib Emma Buchanan, BA NEWS EDITOR Chris Bateman | Email: chrisb@hmpg.co.za HEAD OF PUBLISHING Robert Arendse PRODUCTION COORDINATOR Bronlyne Granger ART DIRECTOR Brent Meder
OPINION 736 Impressions of defensive medical practice and medical litigation among South African neurosurgeons D Roytowski, T R Smith, A G Fieggen, A Taylor 738
The impact of the Consumer Protection Act on pharmacists K du Toit, E van Eeden
741
MEDICINE AND THE LAW Interference with the clinical independence of doctors in hospitals faced with a shortage of resources: What should doctors do? D J McQuoid-Mason
743
CLINICAL PRACTICE Recommendations for the management of sickle cell disease in South Africa N A Alli, M Patel, H D Alli, F Bassa, M J Coetzee, A Davidson, M R Essop, A Lakha, V J Louw, N Novitzky, V Philip, J E Poole, R D Wainwright
DTP & DESIGN Carl Sampson ONLINE MANAGER Gertrude Fani DISTRIBUTION MANAGER Edward Macdonald | Tel. 021-681-7085 HEAD OF SALES AND MARKETING Diane Smith | Tel. 012-481-2069 Email: dianes@samedical.org PROFESSIONAL ADVERTISING Bronlyne Granger | Tel. 021-681-7000 E-mail: bronlyne.granger@hmpg.co.za HMPG BOARD OF DIRECTORS Prof. M G Veller (Chair), Prof. M Lukhele, Dr M Mbokota, Prof. A A Stulting, Dr M R Abbas, Dr G Wolvaardt ASSOCIATE EDITORS Q Abdool Karim, A Dhai, N Khumalo R C Pattinson, A Rothberg, A A Stulting, J Surka, B Taylor, M Blockman
EDITORIALS
ISSN 0256-9574
752
Public somnambulism: A general lack of awareness of the consequences of increasing medical negligence litigation G R Howarth, B Goolab, R N Dunn, A G Fieggen
Publisher website: www.hmpg.co.za SAMA website: www.samedical.org Journal website: www.samj.org.za
754
Ebola virus disease in West Africa – South African perspectives J Weyer, L H Blumberg
755
Compensation for research injuries: Thoughts from a human research ethics committee chair P Cleaton-Jones
757 Who will guard the guards? Medical leadership and conflict of interest in South African healthcare A Parrish, M Blockman
715
November 2014, Vol. 104, No. 11
RESEARCH 759
Compensation for research-related harm: The implications of Venter v Roche Products (Pty) Limited and Others for research ethics committees A Strode, P P Singh
762
Appropriateness of computed tomography and magnetic resonance imaging scans in the Eden and Central Karoo districts of the Western Cape Province, South Africa J Becker, L S Jenkins, M de Swardt, R Sayed, M Viljoen
766
A laboratory-based study to identify and speciate non-tuberculous mycobacteria isolated from specimens submitted to a central tuberculosis laboratory from throughout KwaZulu-Natal Province, South Africa L Sookan, Y M Coovadia
769
Determining need for hospitalisation: Evaluation of the utility of the CRB-65 score in patients with community-acquired pneumonia presenting to an emergency department* D M Kabundji, A Musekiwa, M Mukansi, C Feldman
773
The association of khat (Catha edulis) chewing and orodental health: A systematic review and meta-analysis* A Astatkie, M Demissie, Y Berhane
779
Duchenne muscular dystrophy: High-resolution melting curve analysis as an affordable diagnostic mutation scanning tool in a South African cohort* A I Esterhuizen, J M Wilmshurst, R G Goliath, L J Greenberg
CONTINUING MEDICAL EDUCATION
785
GUEST EDITORIAL Immunology as a medical discipline in South Africa: Why, how and what form? J Peter, S Ress, C Gray
787
REVIEW Superheroes in autoimmune warfare: Biologic therapies in current South African practice G Tarr, B Hodkinson, H Reuter
791
ARTICLES Investigation of adult immunodeficiency and indications for immunoglobulin replacement therapy S Ress
793 Investigation and management of primary immunodeficiency in South African children B Eley, M Esser 794
Advances in the diagnosis and management of allergic disease: Applications to South African practice A Pentz, R J Green
795
Immune tolerance and immunosuppression in solid organ transplantation C W N Spearman, Z A Barday
796
Recommendations for the use of immunoglobulin therapy for immunomodulation and antibody replacement
J G Peter, J M Heckmann, N Novitzky
CONTENTS LISTED IN Index Medicus (Medline). Excerpta Medica (EMBASE). Biological Abstracts (BIOSIS). Science Citation Index (SciSearch). Current Contents/Clinical Medicine SAMJ SUBSCRIPTION RATES Local subscriptions R1 044.00 p.a. Foreign subscriptions R2 352.00 p.a. Single copies R95.00 Members of the Association receive the SAMJ only on request, as part of their membership benefit. Subscriptions: Tel. 012-481-2071 E-mail: members@samedical.org The SAMJ is published monthly by the Health and Medical Publishing Group (Pty) Ltd, Co. registration 2004/0220 32/07, a subsidiary of SAMA. 28 Main Road (Cnr Devonshire Hill Road), Rondebosch, 7700 Tel. (021) 681-7200. E-mail: publishing@hmpg.co.za Website: www.samedical.org Please submit all letters and articles for publication online at www.samj.org.za © Copyright: Health and Medical Publishing Group (Pty) Ltd, a subsidiary of the South African Medical Association Use of editorial material is subject to the Creative Commons Attribution – Noncommercial Works License. http://creativecommons.org/licenses/bync/3.0 Plagiarism is defined as the use of another’s work, words or ideas without attribution or permission, and representation of them as one’s own original work. Manuscripts containing plagiarism will not be considered for publication in the SAMJ. For more information on our plagiarism policy, please visit http://www.samj.org.za/ index.php/samj/about/editorialPolicies Printed by Creda Communications
Part 2 797- 832
Surgical aspects of liver disease in children
*Full article available online only.
PROFESSIONAL ADVERTISING
CPD QUESTIONS
Stars over Kogel Bay. Photo and text: Eric Nathan Email: eric@ericnathan.com
716
November 2014, Vol. 104, No. 11
GUEST EDITORIAL
Mediation – an alternative to litigation in medical malpractice ‘… may we live in a world without lawyers and court cases …’ (Confucius) Interestingly, by the end of the communist era in China there were only 10 000 lawyers serving the needs of that entire nation. But that did not mean people were without justice. Confucius said a lot of things, and his take on the legal side of life was spot on. Adherence to Confucianism, with the core values of ‘perfect virtue, middle ground and authority admiration [respect]’, is still part of Chinese culture today.[1] Positioned in every community were people whose task it was to resolve conflict as it arose. Reportedly, there was one counsellor for every 100 souls throughout the country. While one can speculate as to how these disputes were resolved, what is interesting is that the community developed a system that essentially ensured justice for all. How is it that we have allowed ourselves to end up where we are? The evolution of the justice system in the Western world seems to have taken a very different path to that of the Chinese. Our legal system has focused firmly on applying the ‘law’, and not necessarily on seeking justice. An SAMJ editorial last year[2] outlined very clearly the dilemma currently facing doctors over much of the world. Two publications in this issue, an editorial by Howarth et al.[3] and an article by Roytowski et al.,[4] further underline the magnitude of the problem. Through our legal system, the cost of doctors protecting themselves from possible legal action has reached breaking point, as evidenced by the threat that obstetricians might abandon the practice of obstetrics becoming an ever-increasing reality. The problem does not affect doctors alone. For healthcare institutions, in particular those managed by the state and ‘covered’ by taxpayers’ money, the position is just as dire. The Gauteng government has recently settled claims in excess of R2 billion, with about as much still pending. That these funds were destined for the health budget underscores the crisis in the public sector as well. So how did we get here? There are numerous cost drivers that are taking healthcare beyond our reach. An easily identifiable and prominent cost-driving factor can be attributed to the law, or rather the implementation thereof. Khan et al.[5] have suggested, somewhat pointedly, that apart from the role played by the changing expectations of the public, a growing legal services industry plays an active role in the cost escalation. Fear of litigation fuels cost-inefficient defensive practice. The upward spiral of escalating legal fees and costs is indicative of a ‘dispute’ resolution process that we can no longer afford. This process has affected the very nature of the healthcare we provide. The profession, once characterised by the generosity of altruism, has, with the passage of time and a multitude of events involving a few, become transformed into a fearful and defensive band of practitioners constantly watching their backs. A recent survey of orthopaedic surgeons in the USA disclosed that 96% of participants practised defensive medicine.[6] It is estimated that the cost of defensive orthopaedic practice in the USA is around $2 billion per year, while Mello et al.[7] reported this to have reached $45 billion in 2010. What was once a dilemma is now a crisis. Our legal structure is based on the ‘tort’ system, meaning that in terms of the law of delict, if patients suffer as a result of failure of a hospital or a doctor to provide reasonable care due to negligence, compensation can be sought.[8] In an editorial in the SA Orthopaedic Journal,[9] I presented the arguments against litigation as the appropriate oversight system, citing that it is expensive, that most of the money spent accrues to the legal teams, and that it is cumbersome and time consuming without necessarily reaching the desired goal, which, as Confucius would have put it, should be fairness in righting the wrong. In addition, litigation means that the
717
plaintiff will only succeed in the event of negligent practice being proven against the practitioner, but enjoys no compensation or benefit when an inherent or unavoidable error has occurred. This is not the case when alternative dispute resolution methods are employed. The call for change is strong. But what are the alternatives to the litigation system under which we operate? Arguments for changes in the tort system are being heard around the world, such as a shift of liability from physician to enterprise, while momentum is gathering for the introduction of health courts, for no-fault compensation, and towards arbitration and mediation. There are two core factors informing this shift. Firstly, there is an increasing acknowledgement that not every complication or error is ‘avoidable’. We work in systems that are frequently beyond our control and have boundaries that are not ideal. Innovations to minimise the ‘human factor’ are being usefully introduced, such as the ‘surgical safety checklist’. Introduced under the auspices of the World Health Organization to reduce system errors for patients undergoing surgery, this system of checks and balances to eliminate errors ensures accurate communication and interaction with all involved in the management of patients.[10] Secondly, a major advantage of some of the alternative systems proposed to replace litigation is that a great deal of the money spent on the legal process will be directed at redressing the wrongs where help is needed, and that ultimately this benefit accrues to the healthcare system rather than disappearing down a legal drain. The plaintiff is more likely to derive benefit without falling foul of legal technicalities. Sohn[11] suggests that ideally whatever system operates should ensure appropriate compensation for the medical injury and correctly identify the error, and that knowledge gained from the adverse effects should help to build systems that eliminate errors. This is not always the case with litigation, especially disputes settled on the courtroom steps. The major problem is the disjuncture between the costs associated with defensive practice, mounting a claim and the defence thereof, and how much is directed to restitution of what caused the problem in the first place. As in the USA, we have no repository for medical malpractice claims, so determining the actual amounts directed to the legal process is a difficult task. For the USA, this is estimated to be in the order of 2.4% of the total national healthcare expenditure.[12] Only about 30 - 45% of money involved in the settlement of a claim finds its way to the claimant.[13] Obviously healthcare would be much better off if the money spent on the legal process was channelled instead into the healthcare system itself. It is this realisation that has led to the pursuit of alternative dispute resolution (ADR) mechanisms. Arbitration and mediation are two possibilities that may serve this purpose. Of these two, mediation is perhaps the most effective. The essence of mediation is that it involves the two parties communicating through a facilitator. The complainant or aggrieved party has an opportunity to define and address the complaint to the respondent, while the respondent has an equal chance to explain the events that led to it. A trained mediator facilitates the process, guiding both parties to a point of mutual agreement or acceptance. The majority of complaints against healthcare workers or institutions are issues that arise out of miscommunication. Such issues are ideal for the mediation process. While most complaints involving negligence or malpractice are also amenable to mediation, in certain instances the nature of the injury or offence is of such a nature that official censure will need to be applied. Such penalty or censorship can only be effectively instituted by the relevant governing
November 2014, Vol. 104, No. 11
GUEST EDITORIAL
body, namely the Health Professions Council of South Africa, or the law courts, where a full legal inquiry into such conduct needs to be undertaken. In medical matters, as with commercial civil suits, only a minority of cases truly require the full process of the law. The estimated cost of mediation is an order of magnitude less than litigation, both financially and in terms of time. This financial cost saving will directly benefit the healthcare system. Medical malpractice insurance will diminish significantly, as the associated costs of litigation, namely the court and ‘silk’ costs, will not apply. What is paid will to a large extent cover the direct costs or costs of restitution that may arise out of malpractice or negligence. At present the USA, Canada and the UK have embraced mediation for settling medical disputes, which are increasingly being resolved in this fashion. The courts in Florida, USA, are duty bound to first refer the complaint for mediation; if this fails, litigation can proceed. In the 2013 Medical Malpractice Annual Report[13] the mechanisms by which claims were settled are reported as 31% abandoned, 42% settled by parties, 15% court settled and 12% settled by ADR. Interest in alternatives to litigation is increasing: the SA government is showing great interest in ADR, and legislation has been passed to ensure that court-annexed mediation at magisterial level is in place by December 2014. For additional information on mediation, see http:// www.mediate.com There is no doubt that we are in deep trouble. Our profession cannot be expected to continue along this path for much longer. With the assistance of a pinch of Confucianism, we have at our disposal very positive solutions to address this medicolegal crisis. The ball is in our court.
Johan Walters Division of Orthopaedic Surgery, Department of Surgery, Faulty of Health Sciences, University of Cape Town, South Africa johan.walters@uct.ac.za 1. Qin G. The thinking way of Confucianism and the rule of law. Journal of Politics and Law 2008;1(1):68-72. [http://dx.doi. org/10.5539/jpl.v1n1p68] 2. Seggie J. The ‘boom’ in medical malpractice claims – patients could be the losers. S Afr Med J 2013;103(7):433. [http:// dx.doi.org/10.7196/SAMJ.7127] 3. Howarth GR, Goolab B, Dunn RN, Fieggen AG. Public somnambulism: Public lack of awareness of the consequences of increasing medical negligence litigation. S Afr Med J 2014;104(11):752-753. [http:// dx.doi.org/10.7196/SAMJ.8568] 4. Roytowski D, Smith TR, Fieggen AG, Taylor A. Impressions of defensive medical practice and medical litigation among South African neurosurgeons. S Afr Med J 2014;104(11):736-738. [http://dx.doi. org/10.7196/SAMJ.8336] 5. Khan IH, Jamil W, Lynn SM, Khan OH, Markland K, Giddins G. Analysis of NHSLA claims in orthopedic surgery. Orthopedics 2012;35(5):e726-e731. [http://dx.doi.org/10.3928/01477447-20120426-28] 6. Sethi MK, Obremskey WT, Natividad H, Mir HR, Jahangir AA. Incidence and costs of defensive medicine among orthopedic surgeons in the United States: A national study survey. Am J Orthop 2012;41(2):69-73. 7. Mello MM, Chandra A, Gawanda AA, Studdert DM. National costs of the medical liability system. Health Aff 2010;20(9):1569-1577. [http://dx.doi.org/10.1377/hlthaff.2009.0807] 8. Coetzee L, Carstens P. Medical malpractice and compensation in South Africa. University of Chicago Law Review 2011;86(3):1263-1301. 9. Walters J. Medical malpractice litigation: Is there an alternative? SA Orthopaedic Journal 2013;12(3):13. http://www.scielo.org.za/scielo.php?script=sci_arttext&pid=S1681-150X2013000300001&lng=en& nrm=iso (accessed 8 September 2014). 10. World Health Organization. WHO surgical safety checklist and implementation manual. www.who. int/patientsafety/safesurgery/ss_checklist/en (accessed 8 August 2014). 11. Sohn D. Negligence, genuine error, and litigation. Int J Gen Med 2013;3(6):49-56. 12. Studdert DM, Mello MM, Gawande AA, et al. Claims, errors, and compensation payments in medical malpractice litigation. N Engl J Med 2006;354(19):2024-2033. [http://dx.doi.org/10.1056/ NEJMsa054479] 13. Kreidler M. 2013 Medical Malpractice Annual Report. http://www.insurance.wa.gov/about-oic/commissionerreports/2009-present/documents/2013-med-mal-annual-report.pdf (accessed 14 August 2014).
S Afr Med J 2014;104(11):717-718. DOI:10.7196/SAMJ.8851
EDITOR’S CHOICE CME: Immunology
Immunology underlies most of the biological and clinical disciplines in medicine. This includes autoimmune diseases, infectious diseases and HIV, primary immunodeficiency, cancer and transplantation medicine. Indeed, the formalised use of immunology knowledge, laboratory techniques and targeted immunotherapies in routine clinical practice is now commonplace in much of the world. It is the most rapidly advancing field, and generalists need to keep up with advances in knowledge that impact on patient management. This is the impetus behind this month’s CME, entitled ‘Updates in immunology and allergy’. The medical community, both clinical and pathology disciplines, can no longer afford to see immunology as a ‘black box’ discipline irrelevant to day-to-day patient management or only applicable to the uncommon case of immunodeficiency or autoimmune disease. For South African (SA) doctors this means considering immunology beyond HIV medicine. Is it time for immunology in SA, amid competing public health needs, to be established as a distinct specialty or sub-specialty? This issue of CME provides an overview and an update on clinical immunology that will be indispensable to all practitioners.
‘… may we live in a world without lawyers and court cases’ (Confucius)
A year ago, I wrote an editorial[1] lamenting the current SA penchant for suing health practitioners, sometimes clearly justified and warranted, but
718
often as a means to easy enrichment. I predicted that patients would be the losers.[2] This issue of SAMJ carries much that confirms this sentiment. Howarth et al.[3] ask whether the public is unknowingly sleepwalking into a dystopian future. In the face of escalating costs of liability cover for specialists offering obstetric and neonatal care, spinal surgery and neurosurgery, they predict fewer doctors in these high-risk fields, with those remaining practising defensive medicine; an absence or severe curtailing of private specialist obstetric care; paediatricians and ophthalmologists reluctant to manage neonates; and fewer neurosurgeons in private practice, all restricted to the larger urban areas. Patients would have to be treated in already busy state facilities and would have to compete for resources. Any medicolegal liabilities would move across to the state sector hospitals and staff. As Howarth et al. emphatically state, the medical profession cannot be expected to resolve the situation, as there is no medical answer. Rather, private patients, private providers, public patients, public providers, politicians and policy pundits all have a vested interest in resolving the problem – the issue has to enter the public debate. Smith et al.[4] point out that the annual premium for neurosurgeons in 2013 was R250 900, second only to that of obstetricians (R254 230), this rise having paralleled the increase in the number and amount of awards in malpractice litigation. (SA’s highest-ever medical damages settlement of R25 million was awarded in June 2013, to a patient who had undergone neurosurgery). Neurosurgeons are indicating that they would not have chosen the specialty had they envisaged the current
November 2014, Vol. 104, No. 11
EDITOR’S CHOICE
medical liability situation. A third of their number have discontinued performing highrisk procedures because of the associated liability risk. Walters[5] suggests mediation as an alternative to litigation in medical malpractice, and states the obvious – that healthcare would be much better off if the money spent on the legal process were rather channelled into the healthcare system itself. This realisation has led to pursuit of alternative dispute resolution through arbitration or mediation. Walters believes that mediation is perhaps the most effective, since the majority of complaints against healthcare workers or institutions arise out of miscommunication. Such issues are ideal for the mediation process, involving the two parties, complainant and respondent, communicating through a facilitator. The complainant or aggrieved party defines and addresses his or her complaint to the respondent; the respondent then has the opportunity to explain the events that led to the complaint or grievance. A trained mediator guides both parties to a point of mutual agreement or acceptance. Looking at the implications of Venter v Roche Products (Pty) Limited and Others for research ethics committees, Strode and Singh[6] address what type of compensation research participants would be entitled to in a clinical trial when they have signed an informed consent document excluding certain forms of compensation. In this recent case, the court considered whether the plaintiff was entitled to claim for non-medical costs (pain and suffering, loss of income and general damages). His application for damages was dismissed because he had voluntarily agreed to the limited compensation as set out in the informed consent form, which had been approved by both the local research ethics committees and the Medicines Control Council. The article warns that research ethics committees have the obligation both to ensure
that compensation clauses in informedconsent documents are carefully reviewed and that these are made clear to potential research participants. Asking ‘Who will guard the guards?’, Parrish and Blockman[7] aim to raise awareness of conflict of interest (COI) issues, including some tactics used by the pharmaceutical industry to influence thought leaders. COI exists when professional judgement in a primary interest is unduly influenced by a secondary interest and fosters a conflict in loyalties that translates into a biased decision, with the potential for harm. A good practical example is that, in the wake of reports regarding the risk of myocardial infarction in diabetics treated with rosiglitazone, authors who had favourable views on the safety of rosiglitazone were three times more likely to have a financial conflict of interest with a pharmaceutical company than were authors who had unfavourable views.[8]
The Ebola epidemic rages on …
As the Ebola epidemic rages,[9,10] clinicians should ask every febrile patient: ‘Which African country(ies) have you recently visited?’ We are also reminded that the occupational risk of infection by blood-borne viruses (BBVs) in healthcare practitioners (HCPs) and students is significant, especially in the developing world.[11] Three viral pathogens are known to pose the most serious risk: HIV, hepatitis B virus (HBV) and hepatitis C virus (HCV). The route of transmission can be percutaneous or mucosal, and is related to the work environment and practices of HCPs. Not only are HCPs at risk of acquiring these infections, but they also pose a risk to patients once infected. Rossouw et al.[11] offer these recommendations: all HCPs and all healthcare students should know their infection and immune status (as appropriate) for all three major BBVs, and all who are not infected with HBV should be vaccinated and have their immune status confirmed prior to initiation of training.
450 400
Scans, n
350 Private CT Hospital CT Total Private MRI Expon. (total)
300 250 200 150 100 50 Ap M r ay Ju Ju n l Auy g O Se c t pt No Dev c Ja n Fe b M a Ap r M r ay Ju Ju n l Auy g Oc Se t pt No Dev c Ja n Fe Mb Apar M r ay Ju Ju n l Auy g Oc Se t pt No v
0
Fig. 2. CT and MRI scans done in the Eden and Central Karoo districts of the Western Cape Province, SA, from April 2011 to November 2013. (CT = computed tomography; MRI = magnetic resonance imaging; SA = South Africa.)
719
November 2014, Vol. 104, No. 11
Appropriateness of CT and MRI scans
Computed tomography (CT) and magnetic resonance imaging (MRI) are now an essential part of modern healthcare, enabling the practitioner to make non-invasive diagnoses. Imaging is one of the fastest-growing services in medicine, amounting to $100 000 billion annually in the USA. The clinical information obtained, and their increased accessibility, has made these modalities attractive to both patients and referring physicians. However, marked increases in imaging utilisation are now straining healthcare expenditure and threatening health system sustainability. Becker et al.[12] question the appropriateness of CT and MRI scans in the Eden and Central Karoo districts of the Western Cape. The increased utilisation of diagnostic imaging (see Fig. 2 of the article, reproduced below) has brought with it significant economic risks, plus medical risks through increased radiation exposure, with its accompanying carcinogenic potential, and the unforeseen gadoliniumrelated nephrogenic systemic fibrosis, over and above the well-known mild allergies and anaphylactoid responses. The recommendation is that consultants be required to grant permission for CT or MRI, as at George Hospital, but with awareness of the American College of Radiologists Appropriateness Criteria and and the Royal College of Radiology Guidelines. JS 1. Seggie J. The ‘boom’ in medical malpractice claims – patients could be the losers. S Afr Med J 2013;103(7):433. [http://dx.doi. org/10.7196/SAMJ.7127] 2. Malherbe J. Counting the cost: The consequences of increased medical malpractice litigation in South Africa. S Afr Med J 2013;103(2):83-84. [http://dx.doi.org/10.7196/SAMJ.6457] 3. Howarth GR, Goolab B, Dunn RN, Fieggen AG. Public somnambulism: Public lack of awareness of the consequences of increasing medical negligence litigation. S Afr Med J 2014;104(11):752-753. [http://dx.doi.org/10.7196/SAMJ.8568] 4. Roytowski D, Smith T, Fieggen AG, Taylor A. Impressions of defensive medical practice and medical litigation among South African neurosurgeons. S Afr Med J 2014;104(11):736-738. [http://dx.doi.org/10.7196/SAMJ.8336] 5. Walters J. Mediation – an alternative to litigation in medical malpractice. S Afr Med J 2014;104(11):717-718. [http://dx.doi. org/10.7196/SAMJ.8851] 6. Strode A, Singh PP. Compensation for research-related harm: The implications of Venter v Roche Products (Pty) Limited and Others for research ethics committees. S Afr Med J 2014;104(11):759761. [http://dx.doi.org/10.7196/SAMJ.8596] 7. Parrish A, Blockman M. Who will guard the guards? Medical leadership and conflict of interest in South African healthcare. S Afr Med J 2014;104(11):757-758. [http://dx.doi.org/10.7196/SAMJ.8546] 8. Wang AT, McCoy CP, Murad MH, Montori VM. Association between industry affiliation and position on cardiovascular risk with rosiglitazone: Cross sectional systematic review. BMJ 2010;340:c1344. [http://dx.doi.org/10.1136/bmj.c1344] 9. Bateman C. Ebola global response: ‘not in my back yard’. S Afr Med J 2014;104(11):722-724. [http://dx.doi.org/10.7196/SAMJ.9021] 10. Weyer J, Blumberg L. Ebola virus disease in West Africa – South African perspectives. S Afr Med J 2014;104(11):754-755. [http:// dx.doi.org/10.7196/SAMJ.9045] 11. Rossouw TM, van Rooyen M, Louw JM, Richter KL. Blood-borne infections in healthcare workers in South Africa. S Afr Med J 2014;104(11):732-735. [http://dx.doi.org/10.7196/SAMJ.8518] 12. Becker J, Jenkins LS, de Swardt M, Sayed R, Viljoen M. Appropriateness of computed tomography and magnetic resonance imaging scans in the Eden and Central Karoo districts of the Western Cape Province, South Africa. S Afr Med J 2014;104(11):762-765. [http://dx.doi.org/10.7196/SAMJ.8158]
CORRESPONDENCE
Bureaucracy and clinical performance
To the Editor: There currently seems to be a view among managers in the Department of Health that the best way to improve the clinical performance of staff, particularly in peripheral clinics, is to increase the bureaucratic demands upon them. Consider, for instance, the plight of the midwife working in a small clinic in KwaZulu-Natal. Hers is a very demanding task. For each new patient (I hate the word client) she must take the history, do the lab tests (haemoglobin, HIV, rhesus, a syphilis test, urine dipstick), take blood specimens for CD4+ and creatinine if the patient is HIVpositive and for rhesus antibodies if she is Rh-negative, check blood pressure and weight, do a complete medical examination, including a Pap smear if the patient is booking early enough, provide the necessary health and post-test counselling, dispense the necessary medications, and in addition fill in no less than nine documents if the patient has HIV. They are: (i) the huge antenatal register; (ii) the daily clinic attendance register; (iii) the isoniazid prevention therapy register; (iv) the antenatal record; (v) the HAST (HIV/AIDS, sexually transmitted infection, tuberculosis) record; (vi) the TB screening checklist; (vii) the antenatal checklist; (viii) the health education checklist; and (ix) the MomConnect register. These are regarded as necessary so that managers can have easy access to statistics, and they seem to be the main, often only, measure of clinical compliance and competence. It is no mystery that midwives, even when assisted by enrolled nurses to fulfil some of these roles, struggle to keep in focus the obstetric problem the patient has presented with, battle to concentrate on relationship building, and find it hard to create time to structure a really logical and effective management plan. Too often the paperwork is intact but the clinical responses are defective, and the exercise has ended up defeating itself by its complexity. This problem is not confined to the clinics. In many hospital wards, registered nurses spend more time meeting the bureaucratic demands of their employers than they do directly caring for their patients, and forests are decimated to produce the paper involved! A careful rethink by senior management is required, because all this bureaucracy probably increases rather than decreases the rate of litigation, quite apart from not improving the standard of care. J V Larsen
Howick, KwaZulu-Natal, South Africa jon.larsen@iuncapped.co.za S Afr Med J 2014;104(11):720. DOI:10.7196/SAMJ.8957
A puzzling case of cryptococcal meningitis
To the Editor: We recently admitted a young immunocompetent man with cryptococcal meningitis. He presented alone, and a combination of language barrier and blunted cerebral function hampered history taking. He described 1 week of headache and fever, and gave a vague account of a penetrating head injury 6 months previously. It was difficult to explain why this otherwise healthy young man, with no evident risk factors for poor T-cell function, had encapsulated yeasts growing in his cerebrospinal fluid. Multiple HIV rapid antigen tests were negative, and 2 weeks of intravenous amphotericin B and oral fluconazole did little to improve his condition.
720
Fig. 1. Cryptococcal meningitis in an otherwise healthy young man – the puzzle solved.
We were poised to embark on the somewhat lengthy referral procedure for a computed tomography brain scan at our tertiary centre when our patient noticed a small amount of pus discharging from a scar on his scalp. A firm prominence was palpated just under the scar, and a subsequent X-ray solved the mystery (Fig. 1). After surgical removal of the knife blade, the meningitis resolved within several days. The patient was then able to give a more detailed history, and it transpired that he had not come to hospital after the initial injury 6 months earlier because of transport and financial constraints. A retained foreign body is an often-overlooked differential diagnosis in patients who present with atypical infection.[1] A good history is the single most useful tool in making the diagnosis. This has been well described in the context of inhaled objects in the paediatric population.[2] Difficulty in obtaining a complete history can delay diagnosis and definitive treatment. Maintaining a high index of suspicion, and early use of simple imaging where there is any possibility of prior penetrating trauma, may assist in early exclusion of a retained foreign body. Making a delayed diagnosis by means of unnecessary and expensive investigations at tertiary referral centres can then be avoided. Stewart James Brown Simon George Kate Braithwaite
Tintswalo Hospital, Acornhoek, Mpumalanga, South Africa simongeorge@hotmail.co.uk 1. Anderson MA, Newmeyer WL 3rd, Kilgore ES Jr. Diagnosis and treatment of retained foreign bodies in the hand. Am J Surg 1982;144(1):63-67. 2. Hilliard T, Sim R, Saunders M, Hewer SL, Henderson J. Delayed diagnosis of foreign body aspiration in children. Emerg Med J 2003;20(1):100-101. [http://dx.doi.org/10.1136/emj.20.1.100]
S Afr Med J 2014;104(11):720. DOI:10.7196/SAMJ.8804
November 2014, Vol. 104, No. 11
The role of dairy consumption in preventing Type 2 Diabetes Mellitus Diabetes Mellitus (DM) is considered one of the most common chronic diseases worldwide. The prevalence of DM (HbA1c > 6.5%) in South Africa is reported to be 9.6%, while 19% of the population has impaired glucose homeostasis (6.1% < HbA1c < 6.5%).1
R
esearch shows that poor diet and lifestyle factors (lack of exercise and obesity) seem to play the biggest role in the development of type 2 DM. Medical nutrition therapy guide lines recommended for the management of DM includes following a healthy, balanced eating plan, with the optimal combination of macronutrients individualized for carbo hydrates and fat2. It is advised that a variety of protein sources be consumed, which is associated with a reduction in the intake of red meat3,4 and a concomitant increase in the intake of nuts and lowfat dairy products.1,2,5
The role of dairy consumption in DM has received considerable attention lately. However, con flicting results have been reported in the literature, ranging from a significant inverse association between dairy consumption and the risk of developing type 2 DM610 to no significant associa tions.11–14 An Australian study run over five years found that dairy intake independently reduced the risk of DM.6 In another longterm study (10 years), people with the highest intake of dairy had a 59% lower risk of developing Metabolic Syndrome.10 Although the risk for DM was also lower in this group, it was neither consistent nor significant. Other studies reported the intake of cheese and fermented dairy products to be inversely associated with fasting plasma glucose and two hour postprandial glucose values.11,12 Similarly, total dairy intake was not significantly associated with the incidence of type 2 DM in the 10year Whitehall II cohort study. Although an inverse as sociation was found between fermented dairy product intake and mortality, no such association was observed with type 2 DM incidence.13
Association between the intake of dairy products and the risk of type 2 DM Recent metaanalyses have reported consistent and significant evidence that the consumption of dairy products reduces the risk of type 2 DM. High intake of dairy products in general was associated with a significant reduction – between 11% and 15% – in the risk of type 2 DM7–9,14,15 and lowfat dairy consumption specifically was associated with a 10–19% lower risk of type 2 DM.7–9,15 The association appears to be independent of type of lowfat dairy product, as intakes of lowfat milk, cheese, yoghurt and fermented dairy products were all associated with reducing the risk of type 2 DM.7–9 In contrast, no significant association was found between the intake of fullfat dairy, total milk and fullfat milk7,8 and the risk of type 2 DM.
Dose–response association between dairy consumption and risk of type 2 DM The best risk reduction was reported for total dairy intake up to 200 g per day, with the largest reduction associated with lower intakes.7,8 Although the association was still significant with higher intakes, risk reduction was more modest. No additional benefit was found with intakes exceeding 300–400 g per day.8 For low-fat dairy, 300 g per day was reported to be associated with the best risk reduction.7 No additional benefit was found for intakes exceeding 400 g per day.7 Yoghurt intakes exceeding 120–140 g per day provided no further risk reduction.8
Conclusion The prevalence of DM in South Africa is alarmingly high, with nearly 10% of the popu lation suffering from the condition. Every effort should be made to curb the growth in cases effectively. Medical nutrition therapy guidelines include being physically active and following a balanced diet that includes a wide variety of foods. As the daily intake of dairy products, especially lowfat options, signifi cantly reduces the risk of developing DM, dairy should be emphasised as part of a healthy diet. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.
Shisana O, et al. 2013. South African National Health and Nutrition Examination Survey (SANHANES-1). Cape Town: HSRC Press. American Dietetic Association. Standards of medical care in diabetes – 2013. Diab Care 2013; 36 (suppl 1):S11–S66. Pan A, Sun Q, et al. 2011. Am J Clin Nutr. 94: 1088–1096. Feskens EJM, et al. 2013. Curr Diab Rep. DOI 10.1007/s11892-0130365-0. Lazarou C, et al. 2012. Crit Rev Food Sc Nutr. 52: 382–389. Grantham NM, et al. 2012. Public Health Nutr. 16: 339–345. Gao D, et al. 2013. PLoS ONE. 8: e73965. Aune D, et al. 2013. Am J Clin Nutr. 98: 1066–1083. Tong X, et al. 2011. Eur J Clin Nutr. 65: 1027–1031. Louie JCY, et al. 2013. Nutr Metab Cardiovasc Dis. 23: 816–821. Struijk EA, et al. 2013. Nutr Metabol Cardiovasc Dis. 23: 822–828. Sluijs I, et al. 2012. Am J Clin Nutr. 96: 382–390. Soedamah-Muthu SS, et al. 2013. Br J Nutr. 109: 718–726. Elwood PC, Pickering JE, Givens DA et al. 2010. Lipids. 45: 925–939. Cândido FG, et al. 2013. 28(5): 1384–1395.
A more comprehensive referenced review is available on www.rediscoverdairy.co.za under Dairy-based nutrition.
Possible mechanisms of action The question can be asked whether the positive association found between dairy consumption and reduced risk of DM could be due to the higher intake of protein and amino acids in general, or whether it should be ascribed to the individual nutrient components of dairy. Lowerfat dairy products produced stronger associations than fullfat dairy products, suggesting that dairy fat is not the only important nutrient to consider.16 For an intervention to be effective, it would need to address the risk factors resulting in the development of type 2 DM. Hence, mani pulating insulin receptor sensitivity, regulating insulin secretion and reducing insulin resistance could all be effective in targeting primary causes of DM. On the contrary, any changes in lifestyle associated risk factors (e.g. weight loss or prevention of weight gain, lower blood pressure, increased satiety) could be equally effective.2,17,18 Various mechanisms could therefore explain the inverse association between the intake of dairy products and the reduced risk of type 2 DM. Milk and dairy products have an abundance of calcium, magnesium and vitamin D*. The positive effects of these nutrients include their role in increasing insulin receptor expression, improving insulin sensitivity and beta cell function, decreasing fat absorption, increasing weight loss and reducing blood pressure. Dairy consumption also aids in weight loss by means of increasing the thermic effect of a meal and fat oxidation. Dairy protein, such as whey protein, is specifically known to increase satiety and lower blood pressure pressure.7–9,14,17,19,20 *
Take note: South African milk is not fortifiedwith vitamin D
AN INITIATIVE BY THE CONSUMER EDUCATION PROJECT OF MILK SA For further information contact:
Tel: 012 991 4164 • Fax: 012 991 0878
www.rediscoverdairy.co.za info@rediscoverdairy.co.za
CORRESPONDENCE
Dr Mary Gordon
To the Editor: We are researching and writing a book on my late aunt, Dr Mary Gordon. When she immigrated to South Africa (SA) from England in 1917, she became the first woman doctor to be appointed to Johannesburg Hospital. She was later to establish a large private practice in Johannesburg while also teaching at the then newly founded medical school at the University of the Witwatersrand, where she remained one of the members of staff until 1946. During World War II Dr Gordon enlisted in the South African Medical Corps, serving as the Officer Commanding, Medical Division, Cottesloe Military Hospital, and then as a physician at No. 110 Military Hospital, Roberts Heights (Voortrekkerhoogte), where she was promoted to major. After her discharge from the army in 1946 she went to Palestine, where she served in various medical capacities. Dr Gordon returned to SA in 1958 and established a clinic for children at the Bluegill Waters farm school, one of the first
of its kind in the country, while also serving as a medical officer at the Tladi and Senoane children’s clinics, Soweto, and heading the Department of Physical Medicine and Rehabilitation at Tara Hospital. She practised until she died in the very week of her retirement at the age of 80, in 1971. During her long and distinguished career as a pioneering woman doctor in SA, Dr Gordon interacted with many across her profession and in the broader community. We would very much appreciate hearing from anyone who is willing to share their memories of her, and such contributions will no doubt significantly enhance the telling of the story of this remarkable woman. Jack Metz
Melbourne, Australia jac1911@optusnet.com.au S Afr Med J 2014;104(11):721. DOI:10.7196/SAMJ.8982
This month in the SAMJ ...
Dr Graham Howarth* qualified as a doctor at Stellenbosch University, went on to qualify as an obstetrician and gynaecologist there, and subsequently completed their master’s in bioethics. Before moving to the UK, where he works for the Medical Protection Society as a full-time medicolegal advisor and is now Head of Medical Services – Africa, he was an associate professor in the Department of Obstetrics and Gynaecology at the University of Pretoria and was also founding head of the faculty’s Bioethics Department. * Howarth GR, Goolab B, Dunn RN, Fieggen AG. Public somnambulism: Public lack of awareness of the consequences of increasing medical negligence litigation. S Afr Med J 2014;104(11):752-753. [http://dx.doi.org/10.7196/SAMJ.8568]
Dr Juanita Becker* completed her 2-year medical internship at George Provincial Hospital in the Western Cape and is currently a community service medical officer at Knysna Provincial Hospital. She completed her MB ChB at the University of Cape Town, graduating top of her class. This is her third publication in SAMJ, her first having been as a 5th-year medical student. Juanita has a special interest in public health and developing world medicine, and hopes to do an MSc in global health at Oxford University in the future. * Becker J, Jenkins LS, De Swardt M, Sayed R, Viljoen M. Appropriateness of computed tomography and magnetic resonance imaging scans in the Eden and Central Karoo districts of the Western Cape Province, South Africa. S Afr Med J 2014;104(11):762-765. [http://dx.doi.org/10.7196/SAMJ.8158]
721
November 2014, Vol. 104, No. 11
IZINDABA
Ebola global response: ‘not in my back yard’ As the 8-month West Afri can Ebola outbreak death tally accelerated beyond 4 500 (of 9 000 people infec ted) by mid-October, Spain and the USA became the first nonAfrican countries to record secondary domestic infections after entry by Ebolainfected people. In the original West African outbreak countries of Liberia, Guinea and Sierra Leone the number of cases is doubling every 3 weeks, overwhelming thinly equipped facilities, with rotting bodies lying in the streets and countryside. By mid-October, some 6 000 frontline healthcare workers were infected and 240 had died, eliciting loud protests from the World Medical Association (WMA), holding its annual meeting in Durban. The US Centers for Disease Control (CDC) estimates that unless better controlled, Ebola could affect up to 1.4 million people by January.
By mid-October, some 6 000 healthcare workers were infected and 240 had died, eliciting loud protests from the World Medical Association (WMA), holding its annual meeting in Durban. The international rescue and relief effort began to quicken only after the handful of Ebola infections had crossed European and North American borders, causing secondary infections on both continents. Back in West Africa the vanguard of the treatment and contatinment effort, Médecins Sans Frontières, were paying a deadly price for their ‘against-all-odds’ battle, losing nine healthcare workers, with 16 infected among their 3 000 staff in the region. On 9 October, the USA boosted its response by dispatching six military cargo planes carrying 100 soldiers from its 101 Airborne Division to join the 250 already in Liberia and Senegal, together with equipment and medical staff to set up and run 17 treatment centres and seven mobile laboratories. It also put 3 900 more soldiers on standby to join them, but army commanders initially said this would probably not be necessary. The soldiers will not treat but help set up facilities, distribute equipment and contribute logistical support. In the USA, wall-to-wall cable network TV
coverage ran unabated, focusing almost entirely on the domestic Ebola ‘incursion’. One of the US Ebola-infected duo, Liberian Thomas Eric Duncan, visiting family in Dallas-Fort Worth, Texas, arrived in the USA displaying no symptoms and was sent home from a clinic visit bearing only antibiotics, to return days later in a severely weakened condition, dying within weeks. The correct initial history taking (but failure to respond appropriately to his listed country of origin) and diagnosis put North Dallas hospital and public health authorities onto high alert, eliciting initial threats of prosecution from Liberia and the USA for his not having declared contact with Ebola victims before boarding his US-bound flight. Two Dallas nurses who helped treat him, Nina Pham, 26, and Amber Vinson, 29, became infected a fortnight apart and were in a ‘clinically stable’ condition, Pham after receiving a blood plasma transfusion from Dr Kent Brantly, a Texan who survived the virus. CDC officials said a ‘breach of [treatment] protocol’ was responsible for Pham contracting the disease, launching an urgent probe into how Vinson was allowed to board a plane from Dallas to Cleveland for the weekend – after reporting her slightly elevated temperature to the CDC. The plane was hangared, disinfected and returned to service, its crew put on paid leave. In spite of Vinson having flown while ‘asymptomatic’, all passengers on her return flight to Dallas were asked to call the CDC for follow-up interviews. Containment measures and vigilance on the 78 healthcare workers who treated Duncan were urgently stepped up. Duncan had reportedly taken his landlord’s 19-year-old pregnant daughter to an Ebola treatment unit in Liberia’s capital, Monrovia, where she was turned away because of insufficient space. Duncan brought her home, where she died hours later. Four of his
722
November 2014, Vol. 104, No. 11
immediate relatives were under quarantine in their Fort Worth home with temperatures taken twice daily over the 21-day incubation period, while up to 50 other Americans he came into brief contact with were also being ‘closely monitored’ for signs of the disease. President Barack Obama resisted loud calls to impose a ban on incoming passengers from the three most affected countries, instead ordering the CDC to expand precautions at relevant airports and to use US point-oforigin filters and thermal screening. The initial lack of urgency shown by much of the international community was worsened by relatively recent budget cuts at the World Health Organization (WHO). After the 2009 global financial crisis, the WHO’s budget dropped by roughly $1 billion, nearly 25% of its budget today. By March this year, when the current Ebola outbreak began, staff levels at the WHO had been cut by 35%, further hampering the organisation’s ability to prepare for and respond to health emergencies and prompting drastic cuts to its infectious diseases budget, now considered absurdly inadequate. The other two newer Ebola victims on ‘foreign’ soil were Teresa Romero Ramos, a nursing assistant in Madrid who cared for one of two Ebola-infected missionary priests flown from Sierra Leone to Spain in September (both priests subsequently died, and she was reportedly ‘serious but stable’), and Ashoka Mukpo, an American freelance cameraman who checked into a Nebraska hospital in Omaha, suspecting he had been infected either while spray-washing a vehicle in Liberia in which an Ebola victim died, or while filming in an Ebola clinic (reportedly ‘improving’). All human contacts of both victims were being isolated and monitored, with no initial signs of the disease. An Ebola-infected British male nurse, Will Pooley, discharged from the Royal
FOCUS ON NUTRIENT DENSITY FOR HEALTHY WAISTLINES
PART OF THE RED MEAT IN NUTRITION & HEALTH SERIES
Choose a wide variety of nutrient dense foods to ensure that all the needed vitamins, minerals, phytochemicals and antioxidants for a healthy body are consumed. Visual examples of the recommended daily intake for a small-frame female for an energy restricted diet of 5000kJ per day (aimed to assist her with weight loss) are displayed below. Note the high variety of food types in a prudent, balanced daily diet focused on nutrient density.
Nutrient density is defined as the ratio of the nutrient content (in grams) to the total energy content (in kiloJoules) which a specific food product would contribute to the human body after ingestion The more nutrients present and the fewer the kiloJoules, the higher the nutrient density The higher the nutrient density of your daily diet, the higher the probability that you ingest all the required vitamins, minerals, fiber, phytochemicals and antioxidants needed for a healthy body, without ingesting to much energy Focus on the nutrient density of local red meat Today, lean red meat contains less fat and therefore, more nutrients per edible portion (high nutrient density) Recent local scientific research has found that lean South African lamb and mutton are: - Significant sources of many essential nutrients, which can contribute meaningfully to an individualâ&#x20AC;&#x2122;s daily nutrient requirements (RDA) - Contain less than 10% fat, making it a lean protein choice
Prudent diet focused on nutrient density
High protein diet
High fat diet
45% carbohydrates 20% protein 35% fat
10% carbohydrates 35% protein 55% fat
10% carbohydrates 15% protein 75% fat
Provided by C Julsing-Strydom. 2014. Registered Dietitian â&#x20AC;&#x201C; www.nutritionalsolutions.co.za
Important nutrients provided by 100g cooked portion of lean South African lamb and mutton Nutrient
Unit
Recommended Dietary Allowance (RDA)
Lamb
Mutton
Energy
kJ
-
715
889
Protein
g
56
25.4*
28.1*
Fat
g
-
7.67
7.20
Magnesium
mg
420
22.9#
24.2#
>5%
Iron
mg
18
3.12^
3.81^
>15%
Zinc
mg
11
3.38*
4.41*
>30%
Healthy Meat
HealthyMeatZA
Contribution to RDA per 100g portion
>45%
www.healthymeat.co.za
An educational campaign translating current science into consumer friendly messages. Supported by the Red Meat Industry of South Africa.
SAMJ_RM_Oct2014
Lamb & Mutton South Africa
IZINDABA
Free Hospital in London in early September, was granted an emergency passport to fly to the USA, where he also donated blood in an initial attempt to help treat the two victims there. A predictable animal-rights debate erupted when the Madrid health authorities obtained a court order to kill the Spanish nurse’s dog instead of quarantining it.
SADC countries unite to prepare for Ebola incursions
The 15-country South African Development Community (SADC) ‘home front’ – with the exception of the Democratic Republic of Congo (DRC) – remained clear of any Ebola intrusions. The DRC outbreak is of a strain unrelated to the West African pandemic, with relatively small numbers (70 cases and 42 deaths as of 28 September 2014), but strongly underscores the need for rapidly accelerated surveillance and control preparedness measures in sub-Saharan Africa. The outbreaks in Nigeria (20 cases, eight deaths) and Senegal (one survivor), swiftly controlled, are believed to be ‘over,’ with no further recorded infections. Meanwhile, the National Institute for Communicable Diseases (NICD) in Sandring ham, Johannesburg, conducted its first 2-day ‘hands-on’ Ebola training session for SADC member states on 23 and 24 September, with at least three people from every member country attending. This followed an earlier SADC health ministers’ Ebola ‘Indaba’ in Gauteng, where co-operation, training, funding and equipment procurement topped the agenda. The NICD workshop delegates ranged from physicians, laboratory directors and specimen couriers to public health and port control officials. Speaking from the SADC’s headquarters in Gaborone, Botswana, Mr Joseph Mthethwa, SADC Programme Director: Health and Pharmaceuticals, said that emphasis was being laid on port health, adherence to international infection control standards, identifying responsible public health officials, disease containment, specimen-taking and couriering procedures, integrated disease surveillance and response, and clinical care. ‘We’ll have to come up with a combined strategy, financial model and procurement plan that will stand in for everybody,’ he said. An initial ‘train the trainer’ healthcare and prevention strategy was being put into place, while a secure internet portal had been set up for senior government health officials and ministers. He said that the SADC ministers of health had met twice on Ebola, and were due to meet again in late October. ‘We also have to rely on what’s happening at the WHO – not just at our level,’ he opined. The NICD training programme was ‘all about the
practicality of managing this problem, evolving the roles and responsibilities of medical health services, and what the role of the military should be (raising public awareness, crowd control, containment measures)’, he added. Most speakers were South African (SA) experts, but included several from the renowned Pasteur Institute in Madagascar. Local Director-General of Health, Ms Precious Matsoso, opened the programme. National Minister of Health Dr Aaron Motsoaledi meanwhile pulled together a multidisciplinary Ebola advisory team of SA’s top scientists to support the SADC region, announcing a R32.5 million Ebola ‘preparedness and response’ budget. Together with the private sector, he also set up an almost certainly larger West African Ebola rescue fund to secure and airlift into the most affected West African regions critically needed medical equipment, including thousands of personal protection suits, mobile crematoria, some ambulances and 12 scooters. Speaking at the launch of these efforts on 10 October, he described the local West African rescue effort as ‘helping shut off a global problem at source – better we all go to West Africa than deal with it at home’. He added that Ebola outbreak response teams had now been set up in every province in SA.
SA’s VHF record: ‘we’ve contained every outbreak at source’
Dr Lucille Blumberg, head of the NICD’s Surveillance and Outbreak Response Unit, said that, contrary to claims in the October Izin daba Ebola report that SA had ‘no outbreak laurels to rest on’, several viral haemorrhagic
fever (VHF) cases or ‘outbreaks’ had been successfully contained over the past decade and a half. The Izindaba report was based on opinions expressed by former CDC staffer and now local disease surveillance expert Dr Andrew Medina-Marino on his return from helping out in Liberia. He posited the theory that SA’s history with HIV (pre antiretroviral drugs) and extensively drug-resistant tuberculosis (XDR TB) (also no proven drugs available) boded ill for any scattered West African-type local urban Ebola outbreak. While disagreeing with the comparisons, Blumberg conceded that a scattered urban Ebola outbreak here would pose considerable problems. However, she stressed that ‘so far we’ve contained every outbreak at source and we hope to continue doing so’. There had not been a single secondary case of Crimean Congo fever (endemic here), of which between zero and ten local cases were recorded annually over ‘the last decade or so’. Her unit had also identified and named the novel ‘Lujo’ (Lusaka/ Johannesburg) virus that caused the deaths of five people, four of them with Johannesburg hospital-acquired infections, in 2008 (for further local VHF containment history, see the editorial[1] in this issue). Blumberg said that the NICD had the capacity for rapid, reliable and specialised differential diagnoses of VHFs, including Ebola, which was integral to the response to any suspected case(s) that might present to SA healthcare facilities. The NICD had tested ‘less than a dozen’ local blood samples for Ebola (all negative) since the West African outbreak, mainly because ‘very strong filters’ were in place, including travel history and potential exposure. ‘Having said that, people don’t have to beg us for a test,’ she emphasised.
NICD funding claim explained
Prof. Lucille Blumberg, head of the NICD’s Surveillance and Outbreak Response Unit.
723
November 2014, Vol. 104, No. 11
The contention of Medina-Marino and SA’s leading expert on drug-resistant TB, Prof. Keertan Dheda, that alarm bells should be ringing more loudly around XDR TB than Ebola was ‘very well made – the question that should be asked is why isn’t this kind of effort going into XDR TB?’, Blumberg said. However, using these diseases as evidence that SA would struggle with an Ebola outbreak was ‘just wrong … we’re talking about an endemic chronic disease versus an acute outbreak’, she added. MedinaMarino, reported as saying that the NICD was mainly funded by the US government, has explained to Izindaba that he was referring to the NICD’s Field Epidemiology and Laboratory Training Programme being predominantly funded by US PEPFAR and the Global Disease Detection Program for
IZINDABA
the past 7 years. ‘The SA health department needs to take ownership of this funding in order to make it sustainable. It’s meant to increase the country’s capacity for outbreak investigations – the current Ebola outbreak simply highlights this,’ he said. MedinaMarino addressed the WMA’s annual assembly in Durban in mid-October on his recent Liberian experiences. The WMA (40 national medical associations) passed an emergency resolution urging governments to do ‘far more’ to fight the viral disease. It said that evidence from those treating patients in affected communities was that a shortage of healthcare workers, personal protective equipment and beds, plus poor ability to initiate control measures, was bedeviling efforts. It called on the United Nations and its agencies to provide these immediately, emphasising that healthcare workers needed adequate supplies of gloves, masks and gowns. These should be urgently dispatched to every functional treatment centre to prevent the cross-infections of healthcare workers that were currently crippling an effective treatment response.
Human rights moves centre stage
Meanwhile, the ethical and human rights dimension of the outbreak has moved centre stage. Prof. Frans Viljoen, Director of the Centre for Human Rights at the University of Pretoria, says that HIV has taught South Africans that ‘coercion and compulsion is not the way to go’, driving patients underground and exposing the population to greater risk. Instead, education, raising of awareness and making clinics ‘open and desirable, places where you go to be healed, not to die’ were crucial to an effective response to Ebola. Viljoen says that a balance needs to be struck, instead of seeing Ebola victims solely as vectors or victims: ‘If you over-emphasise the community’s interests in curbing the disease, you can miss taking the victim seriously. We have a duty of care – a totalitarian approach can never work.’ He says that healthcare workers cannot be forced to treat Ebola patients, using the metaphor of a lifeguard declining to rescue a blood-soaked swimmer floundering one kilometre out to sea in the midst of a pack of hungry sharks. ‘However, if the swimmer is half that distance away in a very strong sea,
you still have to go.’ He said that ‘clearly’ not all health care workers could be issued with infection-hazard suits. Reasonable, commonsense precautions should prevail around asymptomatic patients, with risk-benefit analysis taking priority. ‘You have to ask to what extent you can uphold the Hippocratic Oath while at the same time considering the risks,’ he said, adding that ‘it’s all contextual; it depends on what equipment you have. There will be optimal conditions and other contexts where you and other healthcare workers are at great risk.’ He took issue with President Obama typifying Ebola as a global security threat, saying that it had been around since 1976 and that malaria had killed 300 000 Africans over the time of the latest Ebola outbreak. He said Ebola was being ‘othered’ by the global developed world – and by African leaders. ‘At first it was restricted to rural areas, now it’s urban and suddenly they’re taking notice – woken up. Lagos (Nigeria) is a perfect example. The political elite couldn’t have bothered initially. The positive is that we can hopefully now prioritise these neglected diseases.’ Putting a travel ban on all Nigerians, for example, was ‘just one step away from stigmatisation’. ‘You can’t see the pandemic as this monolithic presence that turns all those affected into vectors – you have to create the intellectual and mental space to take rational, reasonable decisions.’ Chris Bateman chrisb@hmpg.co.za S Afr Med J 2014;104(11):722-724. DOI:10.7196/SAMJ.9021 1. Weyer J, Blumberg L. Ebola virus disease in West Africa – South African perspectives. S Afr Med J 2014;104(11):754-755. [http:// dx.doi.org/10.7196/SAMJ.9045]
New editor for SA Journal of Obstetrics and Gynaecology Dr William Edridge, FCOG (SA), MRCOG (UK), MBBChir (Cantab), a long-time consultant in obstetrics and gynaecology at Chris Hani Baragwanath Hospital and lecturer at the University of the Witwatersrand, Johannesburg, has taken up the editorship of SAJOG. Born in Sussex, England, in 1960 and educated at Tonbridge School and Corpus Christi College, Cambridge, Edridge originally studied history at Cambridge University, but after a year decided to change to medicine. Leaving Cambridge to re-matriculate in science subjects, he returned the following year. After moving to Liverpool to work in casualty and play for ‘a particular rugby club’, he then went to Newcastle to start training in obstetrics and gynaecology, which he was completing at the Royal Free Hospital in London when he came to Johannesburg on a one-year exchange in 1998. He never returned to the UK, and has been a consultant at Chris Hani Baragwanath Hospital, attached to the University of the Witwatersrand, for the past 14 years. Edridge lists his interests as oncology, endoscopy, anything in obstetrics and gynaecology, ‘and anything that’s not quite true’.
724
November 2014, Vol. 104, No. 11
SAFETY FIRST Protecting healthcare workers. Protecting South Africa. South Africa’s high burden of communicable diseases poses a major occupational hazard for healthcare workers1. There is an ever-present risk of the transmission of blood borne pathogens such as HIV, Hepatitis B and Hepatitis C among healthcare workers. Needlestick injuries, poorly ventilated consulting rooms, inadequate protective clothing, inconsistent standards for infection control measures and poor application of infection control measures, all elevate the risk. Healthcare workers have the power to protect themselves against this risk. But only if they are well informed, committed and unfailing in applying tried and tested safeguards.
Awareness and education Understand the nature of risk
SAFETY
Access and share information on how to limit risk
A culture of safety Implement simple safety precautions and existing policies Adopt safety engineered devices
WORK ENVIRONMENT
Advocacy and collective action Collaborate through professional organisations
OCCUPATIONAL RISK
Participate in initiatives for uniform guidelines 1
POLICY & PROCEDURE
http://www.mediclinic.co.za/about/Documents/ECONEX%20NHI%20note%202.pdf
TO FIND OUT MORE: Tel: (+27 11) 603-2620
●
Email: safetyza@bd.com
●
www.bd.com/za
IZINDABA
Emergency care doctors – ‘off-task and in the wrong places’ It’s virtually impossible to calculate whether South Africa (SA) has a shortage of emergency care doctors and nurses until they are properly deployed to where the greatest needs are – and have sufficient ancillary support to ensure that they don’t spend chunks of their time doing ‘other people’s jobs’.
portaging patients and answering telephones (as one unpublished internal Western Cape government health quality study at three emergency centres in the relatively well-staffed and equipped Cape Town metropole shows). ‘Everybody thinks we need more clinicians, but this [doing inappropriate tasks] is a problem nobody likes to address,’ he stressed. The Cape Town study (which suggests that the situation could be infinitely worse in lesser-resourced and staffed emergency centres) also looked at how many minutes it took for a doctor to assess the different levels of injury severity in patients (triage-coded red, orange and green), enabling a rough estimate of how many doctors were needed. The results suggest that ‘we don’t fully staff our emergency centres’ – but more critically that 40% of their actual workload was ‘non-value-adding’ (the menial tasks referred to earlier). ‘If our doctors were doing what they’re supposed to be doing all the time, we could quantify the gap much better,’ he explained.
Ludicrous deployment
Prof. Lee Wallis, Western Cape Head of Emerg ency Medicine.
Thi s is the view of Prof. Lee Wallis, head of the emergency medicine divisions of the universities of Cape Town and Stellenbosch and Western Cape Head of Emergency Medicine. Appointed in 2012 by national health minister Dr Aaron Motsoaledi to chair a committee reviewing emergency care nationally, Wallis spent over a year methodically visiting emer gency centres across the length and breadth of the country. This September he also co-led the largest-ever peacetime evacuation of its citizens by an SA Defence Force medical team – the repatriation of the 25 survivors of the tragic Nigerian Pentecostal church hostel collapse in Lagos that claimed 85 of their compatriots among the 115 killed. Izindaba called Wallis to test our assumption that SA’s lack of emergency doctors and nurses is crippling our ability to deal with our internationally recognised huge burden of violence and trauma. Wallis quickly cautioned against this. He said that SA was actually ‘taskshifting the wrong way’, resulting in emergency care doctors spending up to 40% of their time doing menial tasks such as clerical duties,
Giving an example of dismally inefficient deployment of emergency care clinicians, Wallis cited two (anonymous) hospitals of roughly the same size, situated cheek-byjowl, one a district hospital and the other a tertiary. The tertiary hospital had a brand-new emergency centre and four doctors, tending to only about 20 patients daily – because of the strict referral criteria. The doctors and nurses consequently had ‘spare time on their hands’. The other nearby (district) hospital had crumbling infrastructure and a casualty
ward typical of those at its sister hospitals countrywide. Here, two doctors handled nearly 200 emergency patients per day. ‘Probably between those two emergency centres they have close to the right number of doctors, but they are inappropriately placed. Granted it’s not this dramatic country wide, but it’s clear that the bigger academic centres have better staffing ratios than district hospitals [90% of emergency patients are seen at district hospitals]. We also need to be putting resources closer to where the communities live,’ Wallis added, citing the already overburdened but hugely successful modern Khayelitsha Hospital (opened in April 2012) in the eponymous sprawling township outside Cape Town. Asked how the imbalance had developed, he speculated that it was ‘probably a throwback to how the balance of power lay and the historical lack of investment in the district health system’.
Mid-level workers will mitigate pressures
Wallis said that because doctors were ‘very expensive’, the 5-year-old clinical associate training programme (3-year hands-on training) was proving invaluable wherever its graduates were being deployed, KwaZuluNatal being an early example. Although no data were available yet, surveys in that province showed that ‘patients and staff are happier’ wherever mid-level medical workers supplemented healthcare staff. ‘There’s a perception that we can afford doctors, and while that’s partly true, we can’t retain them when other countries are always paying more. Instead of this spiral of retention of
Just hours before survivors of the Lagos church hostel disaster arrive for evacuation by a SA Air Force Hercules C130 transport plane.
725
November 2014, Vol. 104, No. 11
IZINDABA
doctors and salary hikes, we should think a bit more cleverly.’ His standpoint reflects the government’s White Paper on Healthcare Human Resources remedial options of overhauling management (accountability), design (task shifting, as in using midlevel workers such as clinical associates to fill the skills gap between the nurse-based delivery system and doctors), and increased productivity.[1] This is preferred over simply hiring more healthcare professionals and clumsily inserting them into the system without an overall needs analysis. Since the clinical associates training programme began at Walter Sisulu University in the Eastern Cape in 2008 (extended to the universities of Pretoria and the Witwatersrand a year later), 408 students have graduated and have been deployed to every province except the better-staffed Western Cape. Another 504 are currently in training at the three campuses. According to John Capiti, Country Director of the American International Health Alliance, which underpins pre-service educational programmes in Africa, the mid-level medical workers can perform 80% of a doctor’s tasks (except prescribing drugs, surgery and some other high-level tasks), and ‘certainly have an impact on patient waiting times’. Their introduction has aroused predictable controversy in the medical profession, but with a clear scope of practice, supervision and experience they will inevitably help address the healthcare human resource crisis, freeing up doctors in district hospitals to attend outlying clinics and releasing them to handle more complicated cases. For the country as a whole, the doctor-to-population ratio is estimated to be 0.77/1 000. However, because 73% of all GPs work in the private sector, there is just one practising doctor per every 4 219 people for the vast majority of the population. Capiti said that the existing cadre of clinical associates had not yet had an opportunity to work in emergency care, ‘but we have a large interest in supporting them [emergency care workers] overall’. Wallis said that another supplementary strategy would be to base paramedics in emergency centres in the more rural district hospitals – but only when they were not responding to call-outs. ‘Normally in rural towns you have nurses seeing these emergency cases and calling in sessional doctors [private GPs] to help,’ he explained. Writing in a March 2011 SAMJ editorial,[2] Wallis said there was no doubt that trauma was an endproduct of multiple complex interactions between education levels, unemployment, poverty, alcohol and drug abuse, poor law enforcement, societal norms and multiple other factors. At a national government
Loading of survivors begins.
level, this complexity and multisectoral nature seemed to be the obstacle to a strong, co-ordinated response: ‘it is every ministry’s responsibility, hence it appears to be no mini stry’s responsibility’, he wrote. Trauma is the second-commonest cause of death in SA and has millions of living secondary victims, being responsible for up to 40% of hospital emergency centre attendances every year. ‘Look a little deeper, and we see that it affects those who potentially have the most to offer to developing societies – the young and healthy,’ Wallis added. Reducing the overall rate of trauma was ‘critical’. However, no less important (and a whole lot simpler to achieve) was improving the co-ordinated medical care of victims.
Nigerian rescue mission a huge success
Asked about his role in September’s evacuation after the Nigerian church hostel collapse, Wallis said that initially he thought that his flying into Lagos 3 days before a specially fitted out Hercules C130 SA air force plane was due to land would put his specialist skills to little practical use. This was because it was well beyond the 72-hour optimal lifesaving window period for seriously injured patients. However, he was forced to reconsider. The poorly resourced, under-staffed hospitals with limited equipment in Lagos’s sprawling shanty towns meant that at least three SA survivors had developed lifethreatening complications that he and the military medical team were able to resolve. Wallis, a former British naval officer and battle-hardened medical veteran, said: ‘It was touch and go for a while. One man was on dialysis with a spinal injury and
726
November 2014, Vol. 104, No. 11
proved a challenge to stabilise. A woman had deteriorated very badly with septic shock and was critical by the day we arrived in Lagos. We brought her to the [airport] hangar and the military team spent a good couple of hours trying to stabilise her. Then a third patient developed a haemothorax which had gone undetected and was intensively treated on the flight home, being admitted to Steve Biko Academic Hospital (along with the others) in a dramatically improved condition.’ Flying all night to Lagos, spending 9 hours on the ground, and flying back to Pretoria (again overnight), Wallis said that the five other doctors, three SA National Defence Force commanders, eight paramedics and eight nurses worked incredibly hard to locate, retrieve via muddy, pot-holed township roads, assess and stabilise their precious cargo. He was full of praise for his military counterparts, who he described as ‘superbly efficient, well-equipped and a pleasure to work with’. The Hercules C130 aircraft was fitted out with two large intensive care beds and operated as an aerial hospital platform. ‘I actually had goose-bumps, I wouldn’t be surprised to see that level of expertise and equipment on a British military plane dropping into Iraq.’ Wallis knows what he’s talking about; he was a medical officer with 40 Commando Royal Marines who secured the Al-Faw Peninsula (Iraq’s land-sea oil-tanker hub) in the 2003 allied invasion of Saddam Hussein’s Iraq. His contingent ‘turned off the oil taps’ before fighting their way to Basra, suffering 40 casualties, all of whom he helped treat.
Learning from our disaster responses
Wallis punted the idea of a single SA national emergency response team priori
IZINDABA
tising African medical emergencies, adding that setting up a disaster medicine component at the national health depart ment could play ‘a key role in these situations’. ‘I think there’s value in having a senior disaster management person and a clinician to get to the site quickly, do an assessment and provide good on-theground intelligence.’ When called upon to help assemble the Lagos medical evacuation team, he found that many of his colleagues were not up to date with yellow fever injections, effectively ruling them out. ‘We need people available at short notice,’ he stressed. Asked whether his emergency care recommendations to the National Health Committee were being
taken up, he said that extending entrylevel training from a 4-week course to a year had been accepted in principle (the minimum requirement for ambulance paramedics). Other suggestions such as expanding emergency medical service staff and locating staff correctly were being ‘taken very seriously’, he added. Chris Bateman chrisb@hmpg.co.za S Afr Med J 2014;104(11):725-727. DOI:10.7196/SAMJ.8989
Strapped in, ready for take-off.
1. Bateman, C. Denying reality no longer an option – stark HR report. S Afr Med J 2011;101(10):700-702. 2. Wallis LA. Trauma care in South Africa – a call to arms. S Afr Med J 2011;101(3):171.
The smell of coffee, blood and disinfectant … He’s the guy who ‘makes and loves the coffee’ – which is probably just as well, because he’s one of only two emergency medicine specialists on night duty at Khayelitsha Hospital, and will soon have to hyper-focus; it’s pay-day weekend.
four other doctors and 15 nurses make snap decisions that will save the lives of 80% of their patients, most of whom are inebriated. The million-plus-strong township thrums on a payday weekend as shackland taverns, open houses and street parties generate music, frivolity and profit, belying the chaos that inevitably ensues as disinhibited energies (read: pent-up frustrations) spill over into multiple episodes of uncontrolled violence. Small worked-up crowds ebb and flow between venues, and long-standing gang animosities often explode, sparked by seemingly minor incidents. At the same time, domestic disputes boil over behind brick, corrugated-iron or cardboard walls, incurring multiple casualties as neighbours also living on or below the breadline try to intervene or take sides. Lahri and his colleagues meanwhile savour what could at any second be their last cup of his much-loved special coffee blend as the admission rate begins to pick up …
Mending hearts in more ways than one Dr Sa’ad Lahri and colleague Dr Hendrik Lategan.
The against-the-odds saving of lives that takes place is as unbelievable to less trauma-hardened medics, as is the sure-fire predictability of this month-end patient influx, says Dr Sa’ad Lahri. Only the types of severe trauma differ as he, consultant colleague Dr Hendrik Lategan,
‘Most of our cases are penetrating traumatic injury to the chest – these criminals read the anatomy books, they know where to stab.’ His team’s stab-heart survival rate is 75%, an incredible 60% above the international survival norm listed in the medical literature. They’ve had 60 stabbed hearts at the emergency centre over the past 2 years, and have saved 45 of the patients. One case he’ll never forget: the youth’s left anterior descending coronary artery was
727
November 2014, Vol. 104, No. 11
severed. ‘We managed to stabilise and get him into theatre. The surgeon used a feeding tube to create an artificial artery, and we were then able to get him to Groote Schuur for a bypass.’ The second highest trauma category is traumatic brain injury from community assaults, ‘and then we get the car accident patients, mostly off the [nearby N2]’, Lahri says, pausing to field the barrage of questions that countless interviews have taught him will ensue. Yes, 90% of the trauma cases are alcohol-related, but the thing that has stood out during his 2-year tenure is the timing of this human tidal wave of patients: ‘It’s very clear; it’s the first or second day of every month; whenever there’s money and alcohol.’ What ‘bugs’ him most, though, are the three to four new patients with drug-induced psychosis admitted every day (about 110 per month), most of whom have committed active crimes. Very few have schizophrenia or other psychiatric conditions. Police baulk at arresting these people because they are ‘deurmekaar’ (confused) and need to brought down first – meaning that the emergency unit staff faces the brunt of their destructive behaviour. Says Lahri: ‘They break windows, equipment, assault staff. We had one guy fall through the ceiling after he somehow got into the roof through a trapdoor. It’s a major issue. They also sell their parents’ stuff. One mum came in crying, saying he’d sold everything in the house, fridge, stove and chandeliers – the lot. We just treat symptomatically and wait for the psychiatric professionals to come. They sometimes lie with
IZINDABA
An aerial view of Khayelitsha’s new hospital.
us for days. We try to interact with FAMSA and SANCA and the community health centres (who have psychiatric nurse practitioners), but our job is to deal with the critically ill. Drug abuse gets in the way of everything else.’ Asked to quantify the problem, he responds: ‘It’s about 3% of my load but 70% of my problem.’
Vigilante violence puts police in the shade
The other disturbing phenomenon for Lahri is the community assaults. ‘We have people being beaten for stealing chickens. The community gets hold of them and beats them to a pulp, mostly resulting in severe traumatic brain injury, or just simply burns them alive via the necklace method’ (a legacy of the civil warfare that raged in townships during the apartheid years, when suspected ‘impimpis’ (sell-outs) were beaten, and a petrol-filled car tyre slung around their necks and set alight). Asked to quantify the mob attacks, he puts the figure at around ten victims per weekend and ‘at least 30’ per month. Lahri counts himself lucky staffing-wise (he only has to compare his situation with similar hospitals anywhere in the country), but cannot escape the dearth of appropriately trained nurses. Many of his are agency or locum nurses, which he, like many of his frustrated colleagues nationally, considers unsustainable when it comes to quality control. Six are traumatrained, a result of smart forward thinking when he and Lategan sent two a year on trauma and resuscitation courses, leading to short-term work pressure but substantive long-term relief. Given a magic wand, he’d conjure up a third consultant, giving himself and his colleague more time to handle admin and write up some of their more noteworthy resuscitations and treatment (he’s managed to get just four papers published in over 2 years). Both he and Lategan are family men with young children. ‘We’re the only two, so we have to have one another’s backs; it gets rough sometimes – it’s not just
the volumes, the patients are complicated, we have polytrauma, airway injuries, patients with gunshot-face and stabbed neck, it’s not simple stuff.’ Then there are the medical admissions, also driven by poor housing, lack of potable water and sanitation, and other povertyrelated factors. ‘We see a lot of the massive HIV/tuberculosis (TB) burden via presenting emergencies. They will arrive in septic shock, with cardiac tamponade from TB or have massive diarrhoea with a potassium count of 0.5 mmol/l.’ The unit sees about 700 children a month on average, rising to 1 200 per month in the December - April ‘surge season’ when diarrhoea and pneumonia are most prevalent. Overall, paediatric mortality in the township has dropped by more than 50% since the hospital opened its doors in on 17 April 2012 (all traumarelated deaths have plummeted by 80%). Lahri’s team deals with an unusual amount of pulmonary embolisms and has thrombolised ‘at least 20’ patients over the past 2 years (compared with, say, Victoria Hospital or the ultra-modern and also relatively new Mitchell’s Plain Hospital, where thrombolysis is normally associated with myocardial infarction).
Most memorable cases
Besides one horrific night when a crazed knifeman slit the throats of several local residents, Lahri’s most memorable cases include a child who was playing with an electric live wire and was electrocuted. ‘A member of the community ran in with him and we immediately defibrillated the child. We intubated, ventilated and got him to Tygerberg – he survived,’ he says with barely disguised pride. The ‘night of the knifeman’ included a patient whose neck had been ‘slit open like a sheep at the Adam’s apple’. Emblazoned in the memories of all who helped save him are his gurgling screams and the blood spray-painted across themselves, the room and the walls. Overseas doctors who ‘parachute in’ for the unparalleled work experience are generally the most ‘freaked
728
November 2014, Vol. 104, No. 11
out’, Lahri says (there’s a waiting list of foreignqualified doctors stretching to 2016). Asked about the prevalence of posttraumatic stress disorder among his colleagues, Lahri responds: ‘We actively manage all the situations. Whenever stuff happens, we actively debrief. We go through about 5 kg of coffee a week! We begin by asking them what they think they did well, what could have been done better, and then ask if there’s anything troubling them about the case. It always comes down to “Hey! You didn’t shoot the guy, you did your best!”’ The unit’s caseload stands at about 3 000 patients a month and has remained relatively static, peaking at over 100 patients per day on month-end weekends. Asked about travelling to and from the hospital and security at the hospital itself, Lahri says he has ‘no issues’. ‘To come in and travel out has been fine, and our hospital security is awesome. They tend to block a lot of the nonsense, with guns and knives usually handled by the ambulance staff or our security searching patients. We’ve had patients coming in with weapons, but it’s sorted out very quickly.’ Contrary to a widely held negative perception following reportage of an official probe into the township’s police force, he has nothing but gratitude for Khayelitsha’s policemen and women. ‘Every time we’ve called, they’re here within 10 - 15 minutes. Take an alleged rapist the community beat up: the cops come in, take a statement and then guard him. We had one cop here the other day who stepped into the middle of a mob that was busy savaging one guy and saved him, promising on his life that the suspect would go back to jail from the courts and giving the crowd his personal cell phone number. He stayed here well past his shift – until the guy was discharged – and then took him back to a holding cell.’ Lahri, a former consultant at the notori ously busy GF Jooste Hospital Emergency Unit in the heart of the Cape Flats ganglands, shut down in a rationalisation/modernisation initiative early last year, knows that the latter only partially contributes to his hospital’s 131% overall bed occupation level. The other major factor is Khayelitsha’s highly migrant population, whose healthcare in the Eastern Cape cannot match that available locally. About 70% of the adults living in the township come from the Eastern Cape, while most people under 19 were born locally. ‘We have a major influx from the Eastern Cape, often chronic patients, especially cancer, many in the last stages.’ He gave one heroic example of a child with a fractured femur, brought in via longdistance taxi from Umtata by his barely older sister, who had extracted him from a hospital where he had lain unattended for ‘weeks’.
IZINDABA
International study dovetails with trauma profile
Khayelitsha and Rio de Janeiro were recen tly the subjects of a 32-month international comparative study by the Human Sciences Research Council, (HSRC) on the role of social cohesion (or social solidarity) in understanding the link between inequality, poverty and urban violence.[1] The report cited Khayelitsha’s murder rate as between 76 and 108/100 000 at the township’s various police stations (the South African average being 31), and said there were ‘high levels of fear of violence in all social spheres, including many public spaces’. Evidence at the recent Commission of Inquiry into policing in Khayelitsha indicated that the police perceived the township as an impenetrable space that they could not police. As a result, they failed to intervene and appeared to police ‘at the margins’ of the community. The HSRC report said that youth gangs were ‘a significant form of social
organisation’. Although not organised in the same way as the gangs on the Cape Flats, they were shaping the nature and meaning of public space in places such as parks and schools. They were ‘highly territorial and shape identity, as young boys in particular areas feel obligated to join their local gang’. These gangs had a particular language of violence, which was very much about a public display of power. The report said that the collective violence residents engaged in was also organised as a public spectacle, intended to enforce a moral community against an ‘other’. This ‘other’ shifted, and might be a foreigner, a criminal or some other category of person.
Asked what his core message was for his emergency medicine colleagues (70% of them female), who work 9-hour days and every second weekend, Lahri replied: ‘I tell the younger ones there are very few chances in life to be a hero(ine) – and sometimes being a doctor here is just that. I define a hero as someone who finds the strength to persevere in spite of the obstacles – that’s certainly my motto. Things will always be difficult – it’s about persisting. When you see that mother hug her child, it’s all worth it. I sometimes tell my guys on night shift, when they’re really tired and irritated: “Just remember someone else still has a family member because of you … so stop whining!”’
Embrace your heroic work – and stop whining
Chris Bateman chrisb@hmpg.co.za
Lahri’s 47-bed accident and emergency unit is 30% larger than a standard district hospital trauma unit, and the hospital has a heliport and a fleet of 11 ambulances and 110 paramedics and drivers.
S Afr Med J 2014;104(11):727-729. DOI:10.7196/SAMJ.9004 1. Barolsky V. Violence in Khayelitsha: Finding a way out. HSRC Review 2014;12(4):8-11.
Discard the placenta at your peril, pathologist warns doctors Doctors who discard the placenta after a newly born infant dies or is permanently impaired – seemingly during the birth process – could potentially be throwing away their last chance of a legitimate defence should the angry and grieving parents decide to sue. Prof. Colleen Wright, an anatomical patho logist at the National Health Labora tory Services in Port Elizabeth, had specialists and GPs paying close attention at the South African Medical Association’s Millennium
Prof. Colleen Wright, anatomical pathologist.
Development Goals conference this August. Reminding them that the oft-discarded afterbirth placenta was a crucially important fetal organ and therefore a ‘map’ of what had happened to the infant in utero, she said it was a priceless tool in determining the pathophysiology of an adverse pregnancy outcome. The placenta could uniquely show whether injuries were primarily related to labour/delivery or to an in utero insult long before the onset of labour. Determining the timing of such injuries was invaluable in the medicolegal assessment of cases. Without placental pathology, the attending doctor could be left high and dry in responding to litigation. Wright said numerous studies had shown that babies who had ‘an event’ during the course of their mother’s pregnancy went into labour already compromised. The placenta was normally ‘relegated to the sink’. Her experience at Tygerberg Hospital in the year 2000 was that she saw just six placentas from an ‘excellent’ and extremely busy neonatal unit that year. Through her advocacy and that of her colleagues, this improved to 848 placentas a year (still just 15% of deliveries) by 2004/5, when there were only 30 cases of clinically suspected intrapartum hypoxia. On examination, the placenta was normal
729
November 2014, Vol. 104, No. 11
in only one of these 30 cases, the remainder all showing some degree of pathology unsuspected by the attending clinician. Existing data from developing countries showed that 90% of neonatal injury occurred before the onset of labour, while the only existing comparative data (from developed countries) showed the percentage of injury due to intrapartum hypoxia to be just 6 10% (estimated to be higher in developing countries). Wright said that the commonest causes of intrapartum hypoxia were placental abruption and cord accidents (i.e. cord prolapse), both sudden and unpredictable events. Where she was now working (Dora Nginza Regional Hospital in Port Elizabeth), nearly every baby delivered with a low Apgar score was labelled as having birth hypoxia. ‘If that’s seen by a lawyer, it’s a field day because you then have to prove it was not,’ she warned.
US insurance companies insist on placental pathology
Wright cited some insurance companies in the USA as suggesting that every placenta delivered by their clients be sent for pathology, as some adverse outcomes may not be immediately
IZINDABA
apparent at birth – a highly pragmatic and effective means of saving on litigation payouts. More practical in our setting, however, was for each hospital to agree on guidelines for submission of placentas appropriate for their setting and budget, based on internationally published and accepted guidelines. She also outlined four essential criteria needed to define an acute intrapartum event as being sufficient to cause cerebral palsy, one of these being the exclusion of any other identifiable cause, saying that this further pointed to a need for placental pathology. Placentas with decreased reserve would still function adequately, yet be unable to cope with the stress of a normal delivery, she emphasised. Among the reasons the placenta was ignored was the limited exposure students and doctors had to it during training, difficulties in terminology, interpreting findings and examination, and the dearth of qualitative studies. Another reason it had become ‘the outcast’ among pathology specimens was that ‘there are simply too many of them’. She said that some indications for placental examination would not be obvious at the time of delivery. Not only did determining the pathophysiology of an adverse pregnancy outcome help determine the timing of events to assist in a medicolegal assessment, but it also contributed significantly to the management of subsequent pregnancies and the management of the newborn child in the acute and longer term. It also helped define health policies and the allocation of resources.
Seventy-three per cent of US obstetricians sued more than once
Driving home her message, she cited a 1985 National Institutes of Health report putting the number of mentally retarded children in the USA at 850 000, cerebral-palsied young children at 750 000 (with 10% of all schoolchildren disabled), and 42 million neurological, communicative disorders. In 2003, a full 73% of obstetricians in the USA reported being sued at least once – most often related to cerebral palsy. The median award for ‘medical negligence in childbirth cases’ was $2.3 million (just over R23 million). Wright proposed that in South Africa (SA), where litigation is on a sharp upward curve given the predisposing conditions for adverse events in public hospitals, ‘we pay more attention to our own placentas and their role in contributing to the statistics we have in our neonatal and perinatal deaths. If we do, I think you’ll find the placenta has a great deal to contribute to reducing the shocking statistics we have.’ The SA Saving Babies 2010 - 2011 report puts the early perinatal mortality rate as 21/1 000 live births, with the majority of these deaths occurring in the 1 000 - 1 499 g weight category. Deaths due to intrapartum asphyxia are reported as being linked to healthcare provider-associated avoidable factors in 44% of cases. The top five health worker-related factors were: (i) fetal distress monitored but not
detected; (ii) fetal distress not monitored and not detected; (iii) no intervention for prolonged second stage of labour; (iv) delay in referring the patient; and (v) delay in calling for expert assistance. Wright told her doctor audience that the only time a placenta would not help them was if they were negligent. The ‘ideal’ would be to identify problems prior to delivery. Here the Doppler ultrasound scan may prove to be of great assistance in avoiding having to tell parents ‘sorry, you have a dead baby, but we can point to the cause’. She was involved in a large international study trying to correlate data on Doppler ultrasound use v. placental pathology, and added: ‘In SA we are in the early stages of identifying our problems, but there is much more we can do.’ ‘I believe when a baby is compromised, everybody is the loser – the baby, the obstetrician, the neonatologist and the parents. Sometimes the best you can do is sit down with the parents and say we looked at everything we could, there was a natural cause for it. If you don’t have an answer for them, they will take you to court – they’re angry. But if you can truly say it was nobody’s fault, that nature can be cruel, they won’t sue,’ she said. Chris Bateman chrisb@hmpg.co.za S Afr Med J 2014;104(11):729-730. DOI:10.7196/SAMJ.8991
New editor for SA Journal of Child Health Dr John Pettifor, new editor of the SAJCH, was until his retirement 4 years ago head of the Department of Paediatrics at Chris Hani Baragwanath Hospital and the University of the Witwatersrand, Johannesburg, and director of the Medical Research Council (MRC) Mineral Metabolism Research Unit and the Birth to Twenty longitudinal study. He is a National Research Foundation A-rated scientist, serves on the editorial boards of a number of international bone and nutrition journals, and has received national and international research awards. Pettifor qualified as a doctor from the University of the Witwatersrand in 1968 and then specialised in paediatrics, which he completed in 1974. In 1978/9 he spent a year as a clinical research fellow at the Shriners Hospital in Montreal with Dr Francis Glorieux studying paediatric bone diseases, the first of many to have honed their skills in paediatric metabolic bone disease at that institution. On his return to South Africa (SA) he established the Mineral Metabolism Research Unit and was appointed its director by the SA MRC in 1985, a position he held until his retirement. In 1981 he obtained the PhD (Med) for studies into the role of low dietary calcium intake in the pathogenesis of rickets in children in rural areas of SA. Pettifor’s major research interests have focused on metabolic bone diseases in children, and in particular the roles of vitamin D and dietary calcium intake in the pathogenesis of rickets. He is currently involved in a longitudinal study of ethnic differences in bone mass in children and the factors influencing bone growth and acquisition during puberty. He has over 200 publications in accredited journals, has written 30 chapters in books, and is co-editor of the only book published internationally on paediatric bone diseases. Pettifor is an Emeritus Professor at the University of the Witwatersrand, has been appointed an Honorary Professorial Researcher in the Department of Paediatrics, and is a member of the Developmental Pathways for Health Research Unit. He is also director of the Carnegie Clinician PhD Fellowship Programme in the Wits Faculty of Health Sciences.
730
November 2014, Vol. 104, No. 11
IZINDABA
BOOK REVIEWS Principles of Medicine in Africa
Ed. by David Mabey, Geoffrey Gill, Eldryd Parry, Martin W Weber and Christopher JM Whitty. 4th ed. Cambridge: Cambridge University Press, 2013. ISBN 978-1-107-00251-7
Creative Arts in Humane Medicine Ed. by Cheryl McLean. Alberta: Brush Education Inc., 2014. ISBN 978155059454-6
‘… the medical toolkit offers not the way of engaging with or alleviating patient suffering, but one way, a one-dimensional
This is the 4th edition of this important book, which was first published in 1976, and a far thicker tome than the original. As implied by the title, the scope of the publication is huge – medicine in Africa, arguably one of the more interesting continents in terms of pathology. And that pathology is not always driven by disease-causing organisms, as the opening section of the book reminds us, covering people and the environment, food and nutrition, refugees and disasters, and how to manage a health service. Mother and child health has a complete section, mirroring the concerns of the Millennium Development Goals – sadly missed in most African countries for myriad reasons, poor health systems being one of the most pertinent. Infections come next, with the major infections such as HIV and tuberculosis singled out from the sections on viral, bacterial, protozoal, helminth and fungal infections. Non-communicable diseases are of course becoming all too common, even in the developing world, and are covered in detail, along with the diseases of the body systems,
tool for three-dimensional problems.’ (Louise Younie, p. 166) Certain tenets of traditional medical education and practice are under review. Best practice tended to focus on scientific fact alone, discarding the complex story and emotional detail of a patient’s circumstances as either falling outside the domain of medicine or being irrelevant to care. The relationship between patient and medical practitioner was left unexamined, except by a few pioneers like Balint. Recent developments in transdisciplinary fields such as medical humanities bring creative practice, emotional life and narratives of illness back into the argument for improved care for both patients and health professionals. Creative Arts in Humane Medicine is a reference book for medical educators. The editor has grouped the chapters in a useful way: 1. Using the arts to teach and stimulate empathy. Contributors argue for training in empathy in medical schools as an essential tool in patient care. The book contains many interesting ideas for those who wish to both enliven and deepen their teaching of undergraduates. 2. The use of artistic practice in practitioner self-care. The multiple stressors encountered in most medical fields can lead to depression, addiction and burnout. Incorporating the arts
731
November 2014, Vol. 104, No. 11
cancer and palliative care (the latter poorly provided in most parts of the continent), and venoms and poisons. Like all Cambridge University Press publications the book is laid out well, with easy-to-read text, plus text boxes, illustrations, tables and graphs where these add to the text. Colour photographs are used to aid understanding and diagnosis, and are of high quality. My only criticism is the make-up of contributors to the book. Africa is poorly represented. The sections on HIV and tuberculosis, for example, are provided predominantly by authors from the UK and Europe. This is strange when there is such expertise in these common infections right here in Africa. I would urge the publishers to look more broadly for authors when putting together the next edition of this excellent textbook. Bridget Farham Deputy Editor, SAMJ ugqirha@iafrica.com
into the medical curriculum emphasises the value of play and creativity as means to manage stress, ambiguity and uncertainty. Artistic practice assists medics to reflect, debrief, and form a community with their peers. 3. How the experience of illness, disability or accident affects the shape of a person’s life, and how they can communicate that experience to others through artistic projects to improve understanding and empathy. 4. The creative arts in action for change in medical education – assessing how artsbased inquiry can be incorporated into the curriculum. ‘… all illness narratives speak of an interrupted life ... Constructing an illness narrative is an attempt to “discover, or create, a meaning that can bind it together again”1’ (J K Schwind, p. 125). ‘Engaging with patient suffering takes us beyond the physical, into the social, emotional and existential realms, beyond the biomedical, into the biographical …’ (Louise Younie, p. 166). The book makes a strong case for broadening the base from which we as medical professionals live and work. Dawn Garisch Author of Eloquent Body (Modjaji, 2012), Cape Town, South Africa dawn.garisch@gmail.com
FORUM
CLINICAL ALERT
Blood-borne infections in healthcare workers in South Africa T M Rossouw, M van Rooyen, J M Louw, K L Richter Dr Theresa Rossouw is an HIV clinician and researcher in the departments of Family Medicine and Immunology at the University of Pretoria, South Africa. She has been involved in the management of HIV-infected patients and students since 2004 and has a special interest in drug-resistant HIV and biomedical ethics. Dr Marietjie van Rooyen is a family physician working with both undergraduate and postgraduate students in the Department of Family Medicine, University of Pretoria. She has a special interest in medical education and student support, including post-exposure prophylaxis. Dr Murray Louw co-ordinates the training of clinical associates and manages healthcare students after accidental exposures to bloodborne pathogens at the University of Pretoria. He is a family physician experienced in providing antiretroviral therapy and in rural medicine. Dr Karin Richter is a clinical virologist/consultant pathologist and senior lecturer in the Department of Medical Virology, University of Pretoria and National Health Laboratory Service. Her passion is the prevention of infectious diseases and empowerment through knowledge and education. Corresponding author: K L Richter (karin.richter@up.ac.za)
The risks associated with infection of healthcare workers and students with blood-borne pathogens, specifically HIV, hepatitis B virus and hepatitis C virus, are often neglected. South Africa (SA) currently has no official policies or guidelines in place for the prevention and management of these infections. This article reviews the available data and international guidelines with regard to infected healthcare practitioners and makes minimum recommendations for the SA setting. S Afr Med J 2014;104(11):732-735. DOI:10.7196/SAMJ.8518
The occupational risk of blood-borne infection in healthcare workers and students – collectively termed healthcare professionals (HCPs) – is a significant yet under-researched area in medical practice, especially in the developing world. Although many viral pathogens have been associated with occupational exposure, three are known to pose the most serious risk: HIV, hepatitis B virus (HBV) and hepatitis C virus (HCV). The route of transmission can be percutaneous or mucosal and is related to the work environment and practices of HCPs.[1] Importantly, not only are HCPs at risk of acquiring these infections, but once infected they also pose a risk to patients. This has serious policy implications and raises significant ethical challenges. HCPs and patients in developing countries, especially South Africa (SA), are particularly vulnerable to occupational and nosocomial exposure because the prevalence of HIV and HBV is much higher than in the developed world. The work environment may contribute further to this risk, because injection routes are frequently used for administration of medication and improper venesection practices and inadequate facilities for sharps disposal are common.[1,2] Medical and dental students and junior doctors are at high risk owing to their developing skills level, frequent exposure to invasive procedures and long working hours. Two studies in large teaching hospitals in SA reported that 55% and 64% of interns, respectively, reported one or more episodes of occupational exposure. Exposures were more common among first- than second-year interns (62% v. 38%), and only 64% of percutaneous injuries involving HIV-infected blood were reported.[3,4] Many international bodies have developed guidelines for the prevention and management of infection with blood-borne viruses (BBVs) in HCPs. SA, however, does not have management guidelines in place, and large disparities in disease burden, work practices and healthcare resources complicate adoption of international guidelines. This article attempts to frame BBVs in the local context and suggests
732
strategies for prevention, reporting and management responsibilities in a developing-world context.
Prevalence and transmission risk
The exact prevalence of BBV infection in SA HCPs is unknown, but is estimated to mimic that of the general population: HBV 0.2 - 16%, HIV 17.9% and HCV ~2.4%. The risk of occupational infection is highest for HBV (30%), followed by HCV (1 - 2%) and HIV (0.3%). It has been estimated that globally 66 000 HCPs have been infected with HBV through occupational exposure, 1 000 with HIV and 16 000 with HCV.[5] Rare cases of patients contracting HIV from infected HCPs have been documented, but the exact risk of provider-topatient transmission has not been quantified.[6] Estimated figures are derived from settings of low HCP HIV prevalence (0.4% and 0.7%), and figures may well be higher in settings where high prevalence is coupled with late diagnosis. Transmission of BBVs is associated with exposure-prone invasive procedures (EPPs) (Table 1), inadequate infection control precautions and drug diversion by HCPs who abuse injection drugs, and determined by the circulating viral burden.[7]
Prevention
Standard universal precautions (Table 2) should always be followed, regardless of the perception of risk of the procedure or the patient. The use of safety-engineered devices such as retractable syringes, needle-free intravenous systems and winged butterfly needles is encouraged. The following disease-specific measures are also advised.
Hepatitis B virus
Proof of immunity (arbitrarily defined as a hepatitis B surface antibody (anti-HBs) level >10 IU/L) or knowledge of infection status should be a mandatory requirement for all HCPs. HCPs are required to be vaccinated against HBV before they start their training, but no compulsory systems are in place to document immunity or to exclude pre-existing chronic HBV infection. HBV
November 2014, Vol. 104, No. 11
FORUM
Table 1. Classification of EPPs* Procedures and techniques
Examples
Major abdominal surgery
General surgery, nephrectomy, small-bowel resection, cholecystectomy, transplantation surgery
Obstetric/gynaecological surgery
Abdominal and vaginal hysterectomy, caesarean sections and vaginal deliveries, cone biopsy, ovarian cyst removal, other transvaginal obstetric and gynaecological procedures involving hand-guided sharps
Cardiothoracic surgery
Valve replacement, coronary artery bypass grafting, other bypass surgery, heart transplantation, repair of congenital heart defects, thymectomy, open lung biopsy
Orthopaedic surgery
All orthopaedic surgery, total knee arthroplasty, total hip arthroplasty, major joint replacement surgery, open spine surgery, open pelvic surgery
Head and neck surgery
Subtotal thyroidectomy and all surgery involving bones, including oncological procedures
Neurosurgery
Craniotomy, other intracranial procedures, open spine surgery
Plastic surgery
Extensive cosmetic procedures, e.g. abdominoplasty and thoracoplasty
Oral or maxillofacial surgery
Surgical extractions, hard- and soft-tissue biopsy, apicoectomy, root amputation, gingivectomy, periodontal curettage, mucogingival and osseous surgery, alveoplasty or alveoectomy, endosseous implant surgery
Trauma surgery and procedures performed in the emergency department
Open head injuries, facial and jaw fracture reductions, extensive soft-tissue trauma, ophthalmic trauma, open resuscitation efforts, deep suturing to arrest haemorrhage, internal cardiac massage
Procedures and techniques in poorly visualised areas
Digital palpation of a needle tip in a body cavity and/or the simultaneous presence of an HCPâ&#x20AC;&#x2122;s fingers and a needle or other sharp instrument or object in a poorly visualised or highly confined anatomical site
Situations with significant risk of the patient biting the HCP
Interactions with violent patients or patients experiencing an epileptic seizure
EPPs = exposure-prone procedures; HCP = healthcare professional. *Adapted from Centers for Disease Control[15] and Henderson et al.[7]
Table 2. Standard universal precautions* Barrier precautions
Wear gloves when: in contact with blood and body fluids, mucous membranes, or non-intact skin of all patients handling items or surfaces soiled with blood or body fluids performing venepuncture and other vascular access procedures Double-glove for all invasive procedures Change gloves: during long procedures after contact with each patient Wear masks, protective eyewear or face shields when: performing procedures likely to generate droplets of blood or other body fluids Wear gowns or aprons when: performing procedures likely to generate splashes of blood or other body fluids
Hand washing
Wash hands and other skin surfaces immediately and thoroughly if contaminated with blood or other body fluids directly after gloves are removed
Prevent sharps injuries
Do not recap, remove from disposable syringes, or manipulate needles by hand Immediately place all disposable syringes and sharp items in puncture-resistant containers for disposal Locate puncture-resistant containers as close as practical to the use area
Minimise mouth-to-mouth resuscitation
Equip all areas where resuscitation is likely to be performed with mouthpieces, resuscitation bags or other ventilation devices
HCP with exudative lesions or weeping dermatitis
Refrain from all direct patient care and handling patient care equipment until the condition resolves
HCP = healthcare professional. *Adapted from Centers for Disease Control.[19]
733
November 2014, Vol. 104, No. 11
FORUM
vaccination is approximately 92% effective in immunocompetent adults <40 years of age, and only 84% effective in those aged ≥40 years.[7] All vaccine recipients with anti-HBs <10 IU/L after the primary vaccine series should be investigated for chronic HBV infection (hepatitis B surface antigen) and non-vaccine exposure (hepatitis B core antibody (anti-Hbc)). If both tests are negative, a second series of single or double vaccine doses can be given.[8] If anti-HBs remains <10 IU/L after the second vaccine series, the indi vidual is classified as a non-responder and should receive hepatitis B-specific immunoglobulin after exposure to a known HBV-infected individual.[8] As from 2014, a new cohort of potentially Extended Program on Immunization (EPI)vaccinated healthcare students started their training. Only 16% of persons vaccinated at age <1 year are estimated to have detectable anti-HBs ≥10 mIU/mL 18 years later. However, they generally show good immunological memory, with 60 - 97.4% showing protective anti-HBs levels after a booster dose of HBV vaccine, and are then considered protected.[8,9]
HIV
In 2006, patients with HIV-related diseases occupied more than half of the hospital beds in sub-Saharan Africa, and in SA, even in the era of widely available antiretroviral therapy (ART), at least 44% of medical admissions are of HIV-infected patients.[10] Post-exposure prophylaxis (PEP) is advised in all cases of occupational exposure with perceptible risk. The Southern African HIV Clinicians Society 2008 PEP guidelines[11] recommend the use of two nucleos(t)ide reverse transcriptase inhibitors together with either a non-nucleoside reverse transcriptase inhibitor (NNRTI), efavirenz, or a protease inhibitor (PI), lopinavir/ritonavir. The newly revised 2013 US Public Health Services PEP guidelines[12] advise the use of tenofovir (TDF) and emtricitabine together with the integrase strand transfer inhibitor raltegravir (RAL). This regimen is effective and better tolerated than NNRTI- and PI-based regimens. RAL has the additional advantage that restricted availability limits the likelihood of drug resistance. A combination of zidovudine (AZT)/lamivudine (3TC)/RAL can be used in HCPs with pre-existing renal disease, and an HIV expert should be consulted in cases of pregnancy, breastfeeding, serious medical disease in the HCP, and known or suspected HIV drug resistance in the source patient. It is vital to ensure that the full 28-day course is completed. This can be achieved
through active management of side-effects and anxiety.[11] Follow-up is essential and should specifically address condom use, as well as the timing of subsequent HIV and hepatitis tests. Post-PEP HIV testing should be performed by serial enzyme-linked immunosorbent assay (ELISA) testing, and there is currently no consensus on the use of polymerase chain reaction testing in this setting. A case may be made for the use of the HIV viral load (VL) for testing HCPs presenting with possible acute HIV infection after exposure to high-risk patients. These tests do, however, have several limitations such as a window period (albeit shorter than for ELISA) and considerable cost. Finally, it is essential to exclude active HBV in all HCPs on PEP, because the effect of withdrawing TDF or 3TC after 1 month of treatment in the setting of active HBV is uncertain.
Hepatitis C virus
There is currently no vaccine or effective PEP to protect against HCV after exposure. Effective treatment of HCV is available, however, and it is important to identify and document HCV exposure and monitor for acute infection.
Management of HCPs infected with HBV/HIV/ HCV
The optimal management of HCPs infected with BBVs has always been controversial because so few cases have been documented and randomised controlled clinical trials are not feasible. Management is further complicated by the absence of a comprehensive SA policy or guideline. By default, cases are managed on an ad hoc basis and monitoring is sparse or absent. Using international guidelines as a point of reference, with due cognisance of the local context, we suggest specific management strategies in the following sections, as well as in Table 3.
Any management programme should start with acknowledging the importance of HCPs knowing their infection status with respect to all three BBVs, and their obligation to know it, especially when performing EPPs.[7] This approach allows for protection of patients from nosocomial transmission, but also enables appropriate and timely access to care for HCPs. HCPs are at greater risk of active tuberculosis (TB), as well as drug-resistant TB, than the general population, a situation exacerbated by the presence of immunodeficiency.[13,14] In SA, owing to the burden of infectious diseases and the general lack of adequate infection control practices, HCPs are exposed to extra ordinary risk in their work environment and every effort should be made to protect them. Once HCPs are aware that they are infected with one of the BBVs, they should be supported by the medical fraternity, e.g. through expert review panels in their institution or health department or by a designated specialist in the field.[7] The role of such a panel or expert should be supportive, not punitive, and they should be governed by the professional rules of confidentiality and non-discrimination. Expert advisers can assist infected students and practitioners in minimising the risk of transmission and disease progression by advising on appropriate treatment, monitoring and infection control practices. International guidelines advise monitoring of infectivity by means of DNA serum levels, i.e. VL, with restriction of EPP above a certain cut-off point (Table 3). Activities not classified as exposure prone are not restricted, provided the HCP does not have a medical condition, such as HIV-related neurocognitive dysfunction, resulting in the inability to perform tasks; there is no prior evidence of transmission of a BBV by the HCP to a patient; and the HCP follows standard infection control guidelines, is able to perform regular duties, and is closely monitored by an expert review panel, occup
Table 3. VL criteria and testing frequency for HCPs infected with HBV/HCV/HIV* HBV†
HCV
HIV
No restrictions
VL <104‡
VL <104
VL <5 × 102§
Restriction of EPPs
VL ≥104 or HBeAg+
VL ≥104
VL ≥5 × 102
VL testing frequency
Twice a year
Twice a year
Twice a year
VL = viral load; HCPs = healthcare professionals; HBV = hepatitis B virus; HCV = hepatitis C virus; EPPs = exposure-prone invasive procedures (Table 1); HBeAg = hepatitis B e antigen. *Adapted from Henderson et al.[7] † Standardised guidelines based on VL are constrained by the following factors: (i) variability of HBV DNA levels among chronically infected individuals; (ii) paucity of data linking levels of viraemia to risk of transmission; (iii) variable reliability and reproducibility of the molecular tests used to measure HBV DNA; (iv) lack of standardisation among the different tests used to detect HBV DNA; and (v) the variability and durability of therapeutic antiviral effects, and specifically the length of time viraemia can be effectively suppressed before ‘escape’ mutant viruses emerge.[7] ‡ Unit of measurement for VL = copies/mL. § In HIV a VL threshold of 500 copies/mL is selected, since this is the cut-off level for viral ‘blibs’.
734
November 2014, Vol. 104, No. 11
FORUM
ational safety staff and a physician. Importantly, infection with any of the three BBVs per se is not viewed as sufficient to warrant preclusion of the study or practice of medicine.[7,15]
Reporting and management responsibilities
Neither the Health Professions Council of South Africa nor the South African Medical Association (SAMA) oblige HCPs to know their HIV infection status or disclose this status to an employer. Both encourage voluntary counselling and testing after an exposure incident.[16,17] Infected practitioners are encouraged to seek counselling from an ‘appropriate professional source’ familiar with current recommendations, who can advise on the need for restricting professional practice. The SAMA guidelines stress the importance of upholding confidentiality, especially in healthcare institutions, and the right to non-discrimination, as delineated in the SA Constitution (1996) and the Employment Equity Act.[17] The ethics of managing infected HCPs are complex and will not be discussed in detail. The debate is strongly influenced by the ethical, professional and fiduciary responsibility HCPs have towards their patients. Suffice it to say that balance should be sought between the HCP’s right to confidentiality and non-discrimination and the patient’s right to non-maleficence and a safe environment. While we support voluntary and confidential testing of HCPs, we argue that structures and procedures should be in place to facilitate such testing and that the individual should not be held responsible for the cost of testing. Ideally, institutions should have an expert review panel, or at minimum an occupational health officer, to monitor testing and take responsibility for follow-up of infected HCPs. Restriction of scope of practice should be evidence based and should not be applied if the HCP is adequately treated and is able to practise safely and competently. An HCP who has been the source of patient exposure should report such an exposure to the occupational health officer and undergo testing for infection with BBVs. The patient should be informed of the exposure and of the outcome of the source’s BBV results, and be offered counselling and PEP as appropriate.[7] In order to protect confidentiality and in line with international guidelines, patients need not be informed of the name of the source or the exact circumstances of the exposure. Pre-notification of patients regarding their HCP’s infection status is also not indicated, provided infection is appropriately managed. In addition, the following precautions are advised in HIV-infected HCPs: (i) screen for active TB every 6 - 12 months; (ii) isoniazid prophylactic therapy (treat tuberculin skin test (TST)-negative HCPs for 6 months and TST-positive HCPs for 18 months); (iii) pneumococcal vaccine as per current recommendations;[18] and (iv) influenza vaccine annually. HIV-infected healthcare students deserve further mention. Given that students are more likely to experience exposure incidents, they should be offered special assignments while working in high-risk environments such as surgery and TB wards. They should be allowed to withdraw without penalty from any clinical setting they feel poses a high risk of transmission. Students who are not on optimal treatment should be encouraged to seek such treatment, and VL results and ART regimen changes should be reported to the dean or a designated person on an annual basis. The teaching institution should assist students in selecting career paths best suited to their specific situation, and students whose HBV, HCV and/or HIV cannot be effectively cleared or suppressed below the recommended thresholds should be encouraged to select careers that do not involve the highest-risk procedures.
735
Recommendations
In the absence of SA guidelines, we suggest the following basic principles as minimum requirements: • All healthcare providers and all healthcare students should know their infection and immune status (as appropriate) for all three major BBVs. • All HCPs not infected with HBV should be vaccinated and have their immune status confirmed prior to initiation of training. Chronic HBV infection must be excluded in non-responders. • HCPs infected with HIV, HBV or HCV should seek treatment and obtain expert advice, whether through an institutional expert review panel, occupational health officer or specialist in the field. • Institutions and healthcare facilities should be familiar with current international guidelines on the management of occupational exposures. • All institutions should have a dedicated person, such as an occupational health officer, who can monitor and support infected HCPs. • All occupational injuries need to be documented and the data used to adapt training programmes and introduce innovative ways to prevent such injuries. • HCPs should have easy and confidential access to testing and treatment for all three BBVs in their place of work. • PEP should be individualised as more patients are on ART and should be accompanied by adequate medical and psychological support. 1. Deuffic-Burban S, Delarocque-Astagneau E, Abiteboul D, et al. Blood-borne viruses in health care workers: Prevention and management. J Clin Virol 2011;52(1):4-10. [http://dx.doi.org/10.1016/j. jcv.2011.05.016] 2. Mendelson M, Meintjies G. Increasing the risk of nosocomial transmission of HIV: Pitfalls and practices at a busy secondary level hospital with a high burden of HIV. South Afr J Epidemiol Infect 2009;24(1):8-11. 3. Karani H. Occupational exposure to blood-borne or body fluid pathogens among medical interns at Addington Hospital, Durban. S Afr Fam Pract 2011;53(5):462-466. [http://dx.doi.org/10.1080/20786 204.2011.10874135] 4. Karstaedt AS, Pantanowitz L. Occupational exposure of interns to blood in an area of high HIV seroprevalence. S Afr Med J 2001;91(1):57-61. 5. Pruss-Ustun A, Rapiti E, Hutin Y. Estimation of the global burden of disease attributable to contaminated sharps injuries among health-care workers. Am J Ind Med 2005;48(6):482-490. 6. Centers for Disease Control and Prevention. Surveillance of occupationally acquired HIV/AIDS in healthcare personnel, as of December 2010. http://www.cdc.gov/HAI/organisms/hiv/SurveillanceOccupationally-Acquired-HIV-AIDS.html (accessed 12 April 2013). 7. Henderson DK, Dembry L, Fishman NO, et al. SHEA guideline for management of healthcare workers who are infected with hepatitis B virus, hepatitis C virus, and/or human immunodeficiency virus. Infect Control Hosp Epidemiol 2010;31(3):203-232. [http://dx.doi.org/10.1086/650298] 8. Centers for Disease Control and Prevention. CDC guidance for evaluating health-care personnel for hepatitis B virus protection and for administering postexposure management. MMWR Morb Mortal Wkly Rep 2013;62(10):1-19. 9. Chiara F, Bartolucci GB, Mongillo M, et al. Hepatitis B vaccination at three months of age: A successful strategy? Vaccine 2013;31(13):1696-1700. [http://dx.doi.org/10.1016/j.vaccine.2013.01.046] 10. Long L, Sauls C, Sanne I, Rosen S. HIV-related burden on South African hospitals in the era of largescale access to antiretroviral therapy. Abstract Z - 140, CROI 2012. http://www.retroconference. org/2012b/PDFs/659.pdf (accessed 12 April 2013). 11. Andrews S, Mendelson M, Hefer E, et al. Southern African HIV Clinicians Society post-exposure prophylaxis guidelines. Southern African Journal of HIV Medicine 2008;9(1):36-45. 12. Kuhar DT, Henderson DK, Struble KA, et al. Updated US Public Health Service guidelines for the management of occupational exposures to human immunodeficiency virus and recommendations for postexposure prophylaxis. Infect Control Hosp Epidemiol 2013;34(9):875-892. [http://dx.doi. org/10.1086/672271] 13. Menzies D, Joshi R, Pai M. Risk of tuberculosis infection and disease associated with work in health care settings. Int J Tuberc Lung Dis 2007;11(6):593-605. 14. O’Donnell MR, Jarand J, Loveday M, et al. High incidence of hospital admissions with multidrug resistant and extensively drug resistant tuberculosis among South African health care workers. Ann Intern Med 2010;153(8):516-522. [http://dx.doi.org/10.7326/0003-4819-153-8-201010190-00008] 15. Centers for Disease Control and Prevention. Updated CDC recommendations for the management of hepatitis B virus-infected health-care providers and students. MMWR Morb Mortal Wkly Rep 2012;61(No. RR-3):1-12. 16. Health Professions Council of South Africa. Guidelines for Good Practice in the Health Care Professions. Ethical Guidelines for Good Practice with Regard to HIV. Booklet 11. Pretoria: HPCSA, May 2008. 17. South African Medical Association. Human Rights and Ethical Guidelines on HIV and AIDS: A Manual for Medical Practitioners. Pretoria: SAMA, 2006. 18. Souter J. An update on pneumococcal vaccination in children and adults. S Afr Pharm J 2014;81(2):15-18. 19. Centers for Disease Control and Prevention. Recommendations for prevention of HIV transmission in health-care settings. MMWR Morb Mortal Wkly Rep 1987;36(25):S3-S18.
Accepted 1 July 2014.
November 2014, Vol. 104, No. 11
FORUM
OPINION
Impressions of defensive medical practice and medical litigation among South African neurosurgeons D Roytowski, T R Smith, A G Fieggen, A Taylor David Roytowski, Graham Fieggen and Allan Taylor all work in the Division of Neurosurgery, Faculty of Health Sciences, University of Cape Town, South Africa. Timothy Smith is from the Department of Neurological Surgery at Northwestern University in Chicago, Illinois, USA. Corresponding author: A Taylor (allan.taylor@uct.ac.za)
From a litigation perspective, neurosurgery is considered a ‘super high-risk’ field, and this has been associated with rapidly increasing malpractice cover costs. In 2013 the annual Medical Protection Society fee for cover was R250 900. We wished to determine whether high malpractice cover was influencing how neurosurgeons managed patients. A 40-question online survey asking questions on defensive medicine was distributed to determine perceptions around liability risk and whether these influenced how patients were managed. Eightyfour per cent of respondents agreed that a medicolegal crisis existed, and over half (53.8%) had been sued for malpractice during their career. Altering practice behaviour to minimise the risk of a lawsuit is common. The increasing number of legal claims against respondents in this survey has resulted in most neurosurgeons practising defensive medicine. Arguably this will result in increased healthcare costs, inferior patient care and decreased access to skilled surgeons. S Afr Med J 2014;104(11):736-738. DOI:10.7196/SAMJ.8336
All medical practitioners are at risk of malpractice claims, but fields involving acute illness where rapid decision-making is required and outcomes may be unavoidably poor are at more risk of attracting litigation. Neurosurgery is one of those fields.[1] The annual premium charged by the Medical Protection Society for malpractice cover has increased three-fold between 2008 and 2013, with neurosurgery now classified as ‘super high risk’. The annual premium (R250 900 for 2013) is second only to that for obstetricians (R254 230).[2] This rise in premiums has paralleled the recent increase in the number and amount of awards in malpractice litigation.[3] The scale of the problem is reflected in South Africa’s highest-ever medical damages settlement of R25 million in June 2013, to a patient who had undergone neurosurgery.[4] The net result of increased litigation and increased premiums is thought to have several consequences where medical practice is concerned: • A change in practice to more defensive behaviour, with the effect of increasing costs to patients and funders, ultimately driving up healthcare inflation[5] • Limiting practice to patients and conditions that are thought to be ‘lower risk’ rather than taking on complex or surgically demanding cases[1] • Discouraging specialisation in high-risk disciplines and seeking activities with reduced liability risk, such as non-clinical legal, insurance or road accident fund work. A recent study in the USA confirmed that neurosurgeons had changed their practice to minimise malpractice risk and that this could ultimately lead to increased costs for patients and reduced access to neurosurgical care.[1] To establish the impact of the medicolegal environment on the behaviours and perceptions of South African (SA) neurosurgeons, a 40-question online survey was distributed to registered SA neurosurgeons. The questions covered seven broad categories, namely surgeon characteristics, patient characteristics, practice type,
736
liability cover aspects, surgeon liability profile, surgeons’ perceptions, and defensive practice behaviour.
Findings
Sixty-six responses were received from neurosurgeons registered to practise in SA. This reflects a 41.7% response rate from the 158 surgeons contacted. More than 70% had been in practice for over 10 years. The majority of respondents were from Gauteng (37.9%) and the Western Cape provinces (34.8%). Sixty-three per cent described themselves as generalist neurosurgeons and a quarter (26.2%) as having a spine-dominant practice. A small number described their practice as paediatric, cerebrovascular or functional. Annual operative caseloads were reported as being between 200 and 300 by 30%, with over a quarter (26.6%) reporting more than 10 000 cases over their practice lifetime. Most respondents (72.7%) were in private practice with just under a quarter (22.5%) in state service, of whom two-thirds did some form of limited private practice. Of the respondents, 18.2% of respondents did not know whether their institution mandated that they have minimum liability cover, 10.6% stated they were required to have unlimited cover, and 69.7% reported that there was no institutional mandate for liability cover. The remainder (1.5%) reported a required minimum cover of R1 million - R10 million. Two-thirds (67.7%) of the practitioners had an annual cost of indemnity of between R200 000 and R300 000. Three per cent did not have liability cover, and a further 3% paid in excess of R300 000. The cost of malpractice indemnity as a percentage of income varied widely depending on the practice type of the neurosurgeon. Eighty per cent of neurosurgeons in state practice paid less than 5% of their gross annual revenue (GAR) for malpractice cover (Fig. 1). This probably reflects the fact that some may not have taken any indemnity cover, as the state does not require it, or have cover but pay a reduced fee. Forty per cent of neurosurgeons in limited private practice paid 6 - 10% of their GAR for indemnity cover.
November 2014, Vol. 104, No. 11
FORUM
100
Respondents, %
80
State service
60
State service with limited private practice (RWOPS)
40
Private practice
20
0
<5
6 - 10
10 - 19
20 - 29
30 - 39
GAR spent on annual indemnity, %
Fig. 1. Malpractice premiums as a percentage of GAR. (GAR = gross annual revenue; RWOPS = remunerative work outside the public sector.)
Sixty-three per cent of private practitioners contributed 6 - 20% of their GAR towards their malpractice cover, while 6.3% paid 30 - 39%. A single respondent indicated that malpractice indemnity costs constituted >60% of his GAR. Over half (53.8%) of the neurosurgeons surveyed had been sued, with 31.8% of respondents having faced claims in the past 3 years. Just over a quarter (27.3%) had faced 1 - 2 claims over the past year, and 4.5% had faced 3 - 4 claims. Eighty-four per cent of respondents agreed that there was a medicolegal crisis in their specialty, 6% disagreed, and the remainder stated that they were neutral. The majority of the neurosurgeons (58.5%) indicated that they would have chosen differently if the current medical liability situation had existed when they decided to train in the specialty, 28% indicated that they would not have chosen a different speciality, and some respondents remained neutral on this issue. Changing practice behaviour to try to minimise the risk of a lawsuit is a common occurrence. The most common activity undertaken solely to minimise the risk of a lawsuit was requesting imaging studies (when not clinically indicated), with the majority of the respondents (89%) acknowledging that they had done so. Referring patients was the next most common defensive practice, with 76% of practitioners claiming to have done so in the past. Sixty-four per cent had ordered extra laboratory tests, and 39% had prescribed medication that was not clinically
indicated. A quarter of the respondents had undertaken a procedure for purely defensive purposes. Spinal surgery and paediatrics were considered the most risky disciplines with respect to lawsuits. Skull convexity tumour resection was thought to have the lowest risk. Thirty-one per cent of the neurosurgeons had discontinued providing what they considered to be high-risk procedures owing to the liability that these present.
Discussion
Medical malpractice litigation is increasing. There are various possible reasons for this, including problems relating to the way doctors treat patients, the expectations of patients, and increased targeting of medical professionals by lawyers. More than 50% of the neurosurgeons in this survey had been sued, and the data confirm that claim rates are increasing, with the result that almost 90% of respondents felt that they were practising defensive medicine through ordering unnecessary investigations, referring patients, or doing a procedure that was not clinically required. Requesting extra investigations has been described as positive defensive practice, implying that despite added cost it can’t hurt to be more careful.[6] In our survey the most widely used defensive practice was requesting additional imaging. A classic example would be ordering a magnetic resonance imaging (MRI) scan for a patient presenting with headache. The patient’s
737
November 2014, Vol. 104, No. 11
history and clinical examination may be typical of tension headache, but the doctor can never be 100% certain. Given the tiny chance that there could be pathology, an MRI scan is requested. This is done so that there can be no accusation of delaying a diagnosis should there be a positive scan finding. The patient may be on a comprehensive medical aid, the scan is fully funded and it shows no abnormality, so everyone is reassured and happy. Even in this good outcome, however, the cost of the scan still has to be paid, and if this happens often enough it will ultimately result in increased medical aid contributions. The alternative scenario is one where the medical aid does not fully fund the scan, and the patient can’t afford the cost either. In this situation the doctor feels safe in that the scan was ordered, but the patient feels more anxious because the responsibility for not having the scan is theirs. A better outcome may result if the doctor feels free to say ‘I’m sure this is a tension headache, which we will treat and follow up.’ A more vexing scenario can occur: MRI shows a small benign cyst that was never the cause of the patient’s symptoms. The doctor is convinced about this, but now there is a patient with headache and something on the MRI scan. To avoid potential litigation, the surgeon suggests operating on the cyst (an unnecessary procedure). The costs of this will again reflect in increasing medical aid premiums, with the patient at risk of complications of surgery for an incidental finding. Interestingly, it is precisely this situation that may lead to a lawsuit if the patient develops a surgical complication. Clearly, in this instance defensive practice is bad for both patients and doctors. Negative defensive practice is seen as avoiding certain patients or procedures. Seventy-six per cent of respondents reported referring patients rather than treating them in order to reduce the risk of litigation. This would typically occur in a field of practice considered high risk, such as paediatric neurosurgery. Unfortunately in SA, because of spiralling malpractice cover costs, paediatric neurosurgeons have withdrawn from private practice altogether. Although this information did not come directly from the survey, it came to light during subsequent discussions initiated by the survey. Private patients may still consult these specialists, but only at a state hospital, which increases the burden on already overstretched facilities. Concern has been raised that obstetricians will be unwilling to perform deliveries in the private sector by the end of the decade as a result of risk
FORUM
avoidance.[7] Given the experience in neurosurgery, this is a real concern that will ultimately impact on other disciplines. Almost 60% of respondents would not choose to train in neurosurgery if they were starting over; sadly, this attitude is likely to filter to prospective trainees. We face a future in which there may not be a specialist to remove the extradural bleed from a child who has fallen off a swing, or decompress the nerve crushed by a disc fragment in a patient who is in unbearable pain. This survey confirms that there is a crisis in neurosurgery, and probably also in other practices considered super high risk. Urgent action is required. There is an obligation for doctors to avoid defensive practice, care for their patients, manage patient expectations and behave as professionals. However, even if doctors were able to address all these points, malpractice litigation would be likely to continue. Unrealistic patient expectations, increased access to malpractice representation through the Contingency Fee Act (No. 66 of 1997) and a shift from road accident fund work to malpractice litigation are all litigation drivers.[8] Legal reform in some of the states of the USA is an approach that has helped control personal injury liability costs and could be implemented in SA.[9]
Conclusion
Neurosurgery is considered a super high-risk field in terms of malpractice claims and indemnity cover. The increasing number of legal claims against respondents in this survey has resulted in most neurosurgeons practising defensive medicine. Arguably this will result in higher healthcare costs, inferior patient care, and reduced access to skilled surgeons. 1. Nahed BV, Babu MA, Smith TR, Heary RF. Malpractice liability and defensive medicine: A national survey of neurosurgeons. PLoS ONE 2012;7(6):1-7. [http://dx.doi.org/10.1371/journal.pone.0039237] 2. Medical Protection Society. MPS Subscription rates (1 January 2013 - 31 December 2013). www. medicalprotection.org/southafrica (accessed 6 December 2013). 3. Howarth GR, Bown S, Whitehouse S. The importance of comprehensive protection in today’s healthcare environment. S Afr Med J 2013;103(7):453-454. [http://dx.doi.org/10.7196/SAMJ.7106] 4. Botched brain ops lead to SA’s highest-ever medical payout. Sunday Times, 16 June 2013. 5. Hermer LD, Brody H. Defensive medicine, cost containment, and reform. J Gen Intern Med 2010;25(5):470-473. [http://dx.doi.org/10.1007/s11606-010-1259-3] 6. Summerton N. Positive and negative factors in defensive medicine: A questionnaire study of general practitioners. BMJ 1995;310(6971):27-29. [http://dx.doi.org/http://dx.doi.org/10.1136/bmj.310.6971.27] 7. Howarth GR. Obstetric risk avoidance: Will anyone be offering obstetrics in private practice by the end of the decade? S Afr Med J 2013;103(8):513-514 [http://dx.doi.org/10.7196/SAMJ.7233] 8. Malherbe J. Counting the cost: The consequences of increased medical malpractice litigation in South Africa. S Afr Med J 2013;103(2):83-84. [http://dx.doi.org/10.7196/SAMJ.6457] 9. Congressional Budget Office. Limiting Tort Liability for Medical Practice. http://www.cbo.gov/sites/ default/files/cbofiles/ftpdocs/49xx/doc4968/01-08-medicalmalpractice.pdf (accessed 13 April 2014).
Accepted 1 July 2014.
OPINION
The impact of the Consumer Protection Act on pharmacists K du Toit, E van Eeden Karen du Toit is a pharmacist with a PhD degree in applied chemistry. She is an honorary associate professor in the Discipline of Pharmaceutical Sciences, University of KwaZulu-Natal, Durban, South Africa, and an admitted attorney. Evert van Eeden of Van Eeden Inc., Pretoria, is an attorney with a PhD degree in consumer law. He is the author of a book on consumer protection law in South Africa and also contributes to international legal journals. Corresponding author: K du Toit (karen@pharmalaw.co.za)
The Consumer Protection Act of 2008 has had far-reaching consequences for suppliers of goods and services in South Africa. The implementation of the Act has important implications for all suppliers who enter into ‘consumer transactions’. This article aims to stimulate awareness of the legal consequences of the Act arising from day-to-day situations occurring in the pharmacy, and to highlight the compliance obligations that the Act creates for pharmacists. S Afr Med J 2014;104(11):738-740. DOI:10.7196/SAMJ.8488
The purpose of the Consumer Protection Act (CPA),[1] in so many words, is to promote and advance the social and economic welfare of consumers in South Africa (SA). Specific protection is given to certain classes of people such as the illiterate, minors, seniors, people living in remote areas and those of low income. Most of the provisions of the Act came into effect on 1 April 2011. The provisions of the Act relating to harm caused to consumers by defective products apply only to goods supplied on or after 1 April 2011. Interpretation of any law must promote the spirit and the objectives of the Bill of Rights,[2] which protects the fundamental rights of every person in SA, and the CPA is no exception to this
738
rule. For example, a pharmacist may not discriminate unfairly between patients by prioritising supply of medicines, supplying goods or services of different quality, or charging different prices to different patients on the grounds of race, gender, pregnancy, marital status, ethnic or social origin, colour, sexual orientation, age, disability, religion, conscience, belief, culture, language or birth. Furthermore, to protect his or her right to privacy the consumer may refuse to be contacted for purposes of direct marketing through electronic and postal advertising media. The consumer has a right to choose his/her supplier in that a supplier is not permitted to require, as a condition of the supply of any goods or services to a consumer, that the consumer must purchase particular goods either from that supplier or from another party. Such ‘bundling’ of
November 2014, Vol. 104, No. 11
FORUM
goods and services is only permitted if the supplier can show that the convenience to the consumer outweighs the limitation of the consumer’s right to choice, that the bundling results in economic benefit for the consumer, or that the bundled goods or services are also offered separately. The Act should also be interpreted to give effect to its stated purposes. However, if there is inconsistency with other acts, such as the Medicines and Related Substances Act,[3] the two acts will be applied together and inconsistencies will be dealt with by applying the provision in whichever of the acts affords greater protection to the consumer.
Who are the supplier and the consumer?
With certain exceptions, the CPA[1] applies to all transactions entered into in SA as well as to the promotion and supply of goods and services. Pharmacies regularly advertise goods and services and enter into transactions for the supply of services such as blood pressure monitoring or goods such as medicines, and are therefore deemed to be suppliers in terms of the Act. For the purposes of the CPA,[1] a consumer is a ‘natural person’ (i.e. a human being) as well as certain ‘legal persons’ (typically companies). A consumer is one to whom goods or services are marketed, and/or who enters into a transaction, and/or who is the user of goods or the recipient/beneficiary of services. For purposes of the supplier’s liability for harm caused by defective products (product liability), it is irrelevant whether or not the person who has been harmed was a party to the transaction in which the goods or services were procured. The result is that a supplier (including the manufacturer, an importer, a wholesaler and the pharmacy) will be liable to the ‘consumer’ for harm suffered as a result of defects in the product supplied, for example to a patient who has received free medication. A pharmacy may also be considered a consumer because it enters into transactions and procures medicines and other goods and services from suppliers. A pharmacy belonging to the government or that is a company and has an asset value or annual income of ≥R2 000 000 is not regarded as a consumer.
Protection afforded by the CPA
A consumer may select goods displayed in open shelves and is not responsible for loss or damage of these goods unless this results from the consumer’s gross negligence, recklessness, or malicious or criminal behaviour. Generally, goods may not be displayed for sale unless their prices are also displayed. Prices may be displayed in various ways, ranging from being applied to goods to being published in relation to goods in a catalogue indicating a period during which the prices will be valid. False or misleading representations concerning the nature, advantages or price of goods or services are prohibited. The Medicines and Related Substances Act[3] also deals with false advertisements concerning medicines. Information in notices, documents, promotional offers and loyalty programmes must be provided in plain, understandable language, taking into account the class of consumer for whom such a document is intended. The class of consumer is determined by the literacy skill and minimum experience as a consumer of the person procuring the goods or services offered. Advantage may not be taken of consumers suffering from physical or mental disabilities, and no agreements may be made with persons lacking
739
legal capacity, such as minors. A consumer must be provided with a written record of each transaction regarding supplied goods or services. The supplier may not enter into an agreement to supply goods/services to a consumer at unfair, unreasonable or unjust prices or terms. Since medicines are inherently unsafe, instructions and warnings are extremely important. Information requirements in terms of labelling information, package inserts and patient information leaflets are laid down in the Regulations to the Medicines and Related Substances Act.[4] Furthermore, staff members of a pharmacy dealing with consumers should be sufficiently trained before they are allowed to advise consumers, as is also recommended in the Good Pharmacy Practice guidelines[5] provided by the South African Pharmacy Council. Any consumer has the right to the good-quality service that people are generally entitled to expect. The Good Pharmacy Practice guidelines[5] also deal with this issue and should be applied. If a pharmacy fails to supply good service, the consumer may insist on such service or ask for a reasonable refund, depending on the extent to which the pharmacy failed. Furthermore, a consumer also has the right to good-quality, safe goods without defects, which are suitable for the intended purpose and durable. In the situation where a consumer communicated the need for goods suitable for a particular purpose to the pharmacy and after delivery finds the goods unsuitable, they may be returned for a refund within 10 business days. The refund price may be reduced, for example due to consumption, but no reduction is allowed when goods are returned unopened and in the original packaging. The CPA[1] will not apply in the above circumstances if the return of goods holds a threat to public health or is prohibited by a public regulation. The return of medicines is not prohibited by the Medicines and Related Substances Act.[3] Unsafe and defective goods may be returned within 6 months for repair, replacement or refund without penalty under all circumstances. These returned goods can be sent back by the pharmacy to the distributors or to other entities in the supply chain if the pharmacy meets the requirements of being a consumer. This is possible because of an implied warranty of quality that is embodied in any transaction or agreement pertaining to the supply of goods to a consumer. It is also in line with the Medicines and Related Substances Act.[3] However, if the original goods were tampered with, for example repacked in the pharmacy, return to the other entities in the distribution chain will probably not be possible. It must be noted that the Good Pharmacy Practice guidelines,[5] as well as the Regulations to the Medicines and Related Substances Act,[4] do allow repacking if certain requirements are fulfilled. In terms of returned goods, it is clear from the Code of Conduct for Pharmacists[6] and the Good Pharmacy Practice guidelines[5] that medicines that have been in a patient’s possession and returned must not be redispensed. A reasonable deposit may be charged in advance for procured goods to be collected or delivered at a later date. Advance reservations, bookings or orders may be cancelled by a consumer, with the exception of special-order goods, such as medicine, that the pharmacy was required or expected to procure to satisfy the consumer’s requirements and that it does not ordinarily stock. A reasonable cancellation fee may be charged depending on factors such as the nature of the goods and the length of notice, except in cases of death or hospitalisation of the consumer. Goods must be delivered and services supplied on the date agreed upon between the pharmacist and the patient, or within a
November 2014, Vol. 104, No. 11
FORUM
reasonable time, at the agreed place, as is also clear from the Good Pharmacy Practice guidelines.[5] Goods must be delivered at the cost of the pharmacy unless expressly otherwise agreed, according to the CPA.[1] If delivery takes place on a date or at a place not agreed upon, the consumer may require that the delivery takes place as agreed upon or cancel the agreement without penalty. The person delivering goods to the consumer must be identifiable or provide suitable identification. If goods are substituted by other goods, the transaction will apply to the substituted goods from the date of their delivery and the sales record will have to be amended. Safety monitoring and recall of goods also forms part of the CPA.[1] The Consumer Commission will play a role in the develop ment of codes of practice for the investigation of defects of goods, warning of the public against these goods, and recall of goods.
Liabilities and remedies
The producer, importer, distributor and retailer of goods are all liable if the goods supplied by them were unsafe, defective or hazardous, or if inadequate instructions or warnings were provided to the consumer. They will be liable for harm in the form of death, injury, illness, loss or damage of property, or any economic loss experienced by the consumer arising therefrom. Consumers may claim from them separately or jointly. It is irrelevant whether they were negligent or not. This is often referred to as ‘no-fault liability’ or ‘strict liability’. Complaints of infringement of consumer rights may be lodged by any person acting on behalf of him/herself, on behalf of another person who cannot act in his/her own name, as a member of, or in the interests of, a group or class making class actions possible, or in the public interest. An association can act in the interests of its members. Consumers have a wide range of options when lodging a complaint. Complaints must first be lodged through the supplier’s internal procedure where possible, with a relevant ombudsman, or in terms of an alternative dispute resolution process where this is provided for. If these processes do not result in the resolution of a dispute, a complaint can be lodged with the National Consumer Commission (NCC) to be investigated further at no cost to the consumer. In time, various industry bodies are expected to submit industry codes and
740
ombud schemes for approval by the Minister of Trade and Industry. Once approved, a consumer will be obliged to make use of such an ombud and to await the outcome before escalating the complaint to the Commission or the courts. After investigating a dispute, the NCC may decide to issue a compliance notice or to refer the matter to the National Consumer Tribunal (NCT) or a consumer court. The Commission may also issue a notice of non-referral where complaints are frivolous or vexatious. If the matter is referred to the NCT and it is found that the consumer’s rights with regard to the CPA have been contravened, an administrative fine of up to 10% of the supplier’s annual turnover or R1 million, whichever is the greater amount, may be imposed. An employer of an employee who infringed a consumer’s rights may be held liable separately, or jointly with the employee, for the employee’s actions. A pharmacy owner will therefore be liable for infringements by staff members. To prevent complaints from escalating and reaching the NCC and the NCT or the court, it is essential for pharmacies to deal with possible problems early. Systems should be in place to prevent infringements of consumers’ rights or to detect such infringements where they do occur. Staff members should be sufficiently trained and must be able to deal with consumer complaints effectively and as soon as possible. It is also recommended that pharmacies advertise their compliance with the CPA to assure the public that they have taken the necessary action to adhere to the provisions of the Act.[1] 1. Consumer Protection Act, Act No. 68 of 2008. http://www.thenct.org.za/NCTDocs/foundinglegislation/f8d6f6aa-994d-4305-b3d0-ea056416bbd0.pdf (accessed 2 September 2014). 2. Constitution of the Republic of South Africa, Act No. 108 of 1996. http://www.gov.za/documents/ constitution/1996/a108-96.pdf (accessed 2 September 2014). 3. Medicines and Related Substances Act, Act No. 101 of 1965. http://www.mccza.com/genericDocuments/ Act_101_of_1965_published_2003.pdf. (accessed 2 September 2014). 4. Regulations to Medicines and Related Substances Act, Act No. 101 of 1965. http://www.saflii.org/za/ legis/consol_reg/marsa101o1965rangnr510723/ (accessed 2 September 2014). 5. South African Pharmacy Council. Good Pharmacy Practice in South Africa. 4th ed. Pretoria: South African Pharmacy Council, 2010. 6. Code of Conduct for Pharmacists and Other Persons Registered in Terms of the Pharmacy Act, Act No. 53 of 1974. http://www.mm3admin.co.za/documents/docmanager/0C43CA52-121E-4F58-B8F681F656F2FD17/00010774.pdf (accessed 2 September 2014).
Accepted 1 July 2014.
November 2014, Vol. 104, No. 11
FORUM
MEDICINE AND THE LAW
Interference with the clinical independence of doctors in hospitals faced with a shortage of resources: What should doctors do? D J McQuoid-Mason David McQuoid-Mason is Professor of Law at the Centre for Socio-Legal Studies, University of KwaZulu-Natal, Durban, South Africa, and publishes and teaches in medical law. Corresponding author: D J McQuoid-Mason (mcquoidm@ukzn.ac.za)
In the face of interference with their clinical independence in hospitals with a shortage of resources, what should doctors do? The question can be answered by considering: (i) the constitutional right to healthcare and emergency treatment; (ii) the common-law position regarding unlawful homicide and the doctrine of ‘superior orders’; (iii) the ethical rules of the Health Professions Council of South Africa; and (iv) whether there is any protection for doctors who refuse to carry out unprofessional, unethical or unlawful directives from their superiors. While this article focuses on the public sector, some of the legal principles, where relevant, apply equally to doctors in the private sector. S Afr Med J 2014;104(11):741-742. DOI:10.7196/SAMJ.8868
Constitutional right of access to healthcare and emergency medical treatment
The South African (SA) Constitution[1] provides that everyone has the right of access to healthcare services within available resources (section 27(1)) and that nobody may be unfairly discriminated against (section 9(3)). It also provides that ‘[n]o one may be refused emergency medical treatment’, which is not defined (section 27(3)). The National Health Act[2] similarly mentions that ‘[a] health care provider, health worker or health establishment may not refuse a person emergency medical treatment’, but also does not define what this means (section 5). The Constitutional Court, however, has defined ‘emergency medical treatment’ as treatment required for ‘a dramatic, sudden situation or event which is of a passing nature in terms of time’ (which means that it may be cured), and not a chronic terminal illness.[3] One of the reasons for this is that doctors are expected not to engage in futile treatment[4] and waste valuable resources – particularly in the resource-constrained public hospitals of SA. In the case of public officials and institutions, the Public Finance Management Act[5] provides that accounting authorities are required to ‘prevent irregular expenditure, fruitless and wasteful expenditure … and expenditure not complying with the operational policies’ of the public entity (section 51).
The common-law position regarding unlawful homicide and the doctrine of ‘superior orders’
The common law states that a doctor who intentionally or negligently and unlawfully causes the death of another – whether by an act or an omission – may be criminally and civilly liable for homicide. In the case of an intentional unlawful act or omission causing death, the perpetrator may be guilty of the crime of murder[6] and civilly liable for a dependant’s action if the deceased person was supporting lawfully recognised dependants. In the case of a negligent act or omission causing death, the perpetrator may be guilty of the crime of culpable homicide[7] and liable to a dependant’s action.[8] The question
741
of what is unlawful depends on the legal convictions or boni mores of society, which in a constitutional democracy such as SA is influenced by the values in the Constitution.[9] Hence an intentional or negligent breach of a person’s constitutional rights may well be evidence of an unlawful act or omission. The common law also states that ‘superior orders’ are not a defence to an unlawful act or omission where the person carrying out the order knew, or ought to have known, that what they were doing was unlawful.[10] Doctors cannot raise the defence that their employer or superior directed them to engage in conduct that was unprofessional, unethical or illegal – unless their act, or failure to act, was under duress (e.g. they were forced to act unlawfully in order to prevent greater harm to themselves or their immediate family).[11]
Vicarious liability
In order for employers such as provincial authorities or hospitals to be vicariously liable for the wrongful conduct of their employees, the persons suing them must show that the employees had committed an unlawful act or omission while acting in the course and scope of their employment – even if the work was carried out in an improper way.[12] Consequently, hospitals will be liable if their employees intentionally disobey hospital protocols or standard operating procedures where such acts or omissions fall within the course and scope of the employees’ employment. Although a provincial authority or a hospital is vicariously liable for the conduct of its employees, the employees themselves may be held personally liable.[13] Employees may therefore be personally sued, or, depending on their employment contract, may be liable to reimburse their employers for any damages paid out to injured or harmed patients. According to the State Liability Act,[14] the state is vicariously liable for the delictual acts or omissions of state employees on the same basis as other employers (section 1).[15]
The ethical rules of the medical profession
The ethical rules of the Health Professions Council of South Africa (HPCSA)[16] require doctors not to permit themselves ‘to be exploited in any manner’ (rule 22), to ‘act in the best interests’ of their patients
November 2014, Vol. 104, No. 11
FORUM
at all times (rule 27A(a)), and to ‘maintain the highest standards of personal conduct and integrity’ (rule 27A(c)). Doctors who allow themselves to ignore these ethical rules of their profession, under pressure from their superiors, are therefore clearly acting unprofessionally and unethically. Not only may such doctors be sanctioned by the HPCSA for unethical behaviour, but their conduct may also result in criminal or civil liability. In addition, the HPCSA rules require doctors to report any unprofessional, unethical or illegal conduct by colleagues (rule 25(1)(c)). The World Medical Association Declaration of Seoul on Professional Autonomy and Clinical Independence[17] states that ‘professional autonomy [i]s an essential component of high quality medical care’ and ‘maintaining and assuring the continuation of professional autonomy in the care of patients … is an essential principle of medical ethics’. This principle is fundamentally undermined if the professional autonomy of doctors is interfered with.
Protection of doctors who refuse to carry out unprofessional, unethical or unlawful directives from their superiors
Conclusion
Doctors who refuse to carry out unprofessional, unethical or illegal directives from their superiors, or anyone else, may not be victimised for their actions. The Constitution provides that everyone is entitled to fair labour practices (section 23(1)), and this is enshrined in the Labour Relations Act.[18] The Act regulates the relationship between employers and employees and protects the rights of employees against potential abuse by employers. An employee who is disciplined, discriminated against or dismissed for failing to carry out an unprofessional, unethical or unlawful directive from a superior would clearly have an action for an unfair labour practice (chapter VIII). By obeying such a directive, the employee risks being disciplined by his/her professional body and held criminally or civilly liable, and moreover cannot raise the defence of having acted under ‘superior orders’.[9] Likewise, a doctor who carries out the HPCSA ethical duty to report unprofessional, unethical or unlawful conduct by a fellow practitioner[16] – even if he or she is a ‘superior’ such as an MEC for health, a provincial head of health, a hospital manager, or any other person in authority, who is registered with the HPCSA – will be protected by the common-law principle of ‘qualified privilege’. A qualified privilege exists where the person making disclosure has a moral, legal or social duty to make the disclosure to a person who has a reciprocal interest in receiving the information,[19] provided this is in circumstances not actuated by malice.
742
Doctors who report unprofessional, unethical or unlawful conduct by fellow practitioners may also be protected by the Protected Disclosures Act,[20] which is designed to protect whistle-blowers in both the public and private sectors. The Act protects whistle-blowers from disciplinary action, dismissal, suspension, demotion, harassment, intimidation, transferral against their will, refusal of transfer or promotion, or any other form of victimisation that affects their employment, profession, office, employment opportunities or work security. In terms of the Act, such disclosures to a specified person or body such as the Public Protector or Auditor-General (section 8), or as a ‘general protected disclosure’ (section 9), will be protected. In the latter situation, a report to the HPCSA in terms of its ethical rules would clearly be a ‘protected disclosure’ provided the communication is made in good faith, is believed to be substantially true, and is not made for personal gain (section 9(1)). Whistle-blowers are also protected by the Labour Relations Act,[18] which states that a person who is dismissed for reporting abuse in terms of the Protected Disclosures Act[20] will have an action for unfair dismissal (chapter VIII).
Doctors who allow their legal and ethical obligations to patients to be subverted risk being subjected to criminal and civil sanctions, as well to disciplinary action by the HPCSA, and cannot raise the defence of ‘superior orders’. 1. Constitution of the Republic of South Africa, 1996. www.gov.za/documents/constitution/1996/a10896.pdf (accessed 30 August 2014). 2. National Health Act 2004 (Act 61 of 2004). www.gov.za/documents/download.php?f=68039 (accessed 30 August 2014). 3. Soobramoney v Minister of Health, KwaZulu-Natal 1998 (1) SA 765 (CC) 778. 4. Cf. Airedale NHS Trust v Bland [1993] 1 All ER 821 (HL). 5. Public Finance Management Act No. 1 of 1999. www.treasury.gov.za/legislation/PMFA/act.pdf (accessed 30 August 2014). 6. S v Hartmann 1975 (3) SA 532 (C). 7. S v Mkwetshana 1965 (2) SA 493 (N). 8. Cf. Union Government v Warneke 1911 AD 657. 9. Faircape Property Developers (Pty) Ltd v Premier, Western Cape 2000 (2) SA 54 (C). 10. Cf. S v Banda 1990 (3) SA 466 (B). 11. McQuoid-Mason D, Mahomed D. A-Z of Medical Law. Cape Town: Juta & Co., 2011:172-173. 12. Minister of Police v Rabie 1986 (1) SA 117 (A). 13. Cf. Feldman (Pty) Ltd. v Mall 1945 AD 733. 14. State Liability Act No. 20 of 1957. www.justice.gov.za/legislation/acts/1957-20.pdf (accessed 30 August 2014). 15. Mhlongo v Minister of Police 1978 (2) SA 551 (A). 16. Ethical Rules of Conduct for Practitioners Registered under the Health Professions Act, 1974. Government Notice R717 of 4 August 2006. Pretoria: Government Printer, 2006. 17. World Medical Association. Declaration of Seoul on Professional Autonomy and Clinical Independence. Adopted by the 59th WMA General Assembly, Seoul, Korea, October 2008. www.wma. net/en/30publications/10policies/a30/ (accessed 26 August 2014). 18. Labour Relations Act No. 66 of 1995. www.gov.za/documents/download.php?f=70985 (accessed 30 August 2014). 19. Cf. Jansen van Vuuren v Kruger 1993 (4) SA 842 (A). 20. Protected Disclosures Act No. 26 of 2000. www. justice.gov.za/legislation/acts/2000-026.pdf (accessed 30 August 2014).
Accepted 28 August 2014.
November 2014, Vol. 104, No. 11
FORUM
CLINICAL PRACTICE
Recommendations for the management of sickle cell disease in South Africa N A Alli, M Patel, H D Alli, F Bassa, M J Coetzee, A Davidson, M R Essop, A Lakha, V J Louw, N Novitzky, V Philip, J E Poole, R D Wainwright Dr Nazeer Alli is principal consultant in the Department of Molecular Medicine and Haematology, National Health Laboratory Service (NHLS) and School of Pathology, University of the Witwatersrand, Johannesburg, South Africa; Prof. Moosa Patel is head of the Clinical Haematology Unit, Chris Hani Baragwanath Hospital, Johannesburg, and academic head of clinical haematology, Department of Medicine, Faculty of Health Sciences, University of the Witwatersrand; Dr Hassan Dawood Alli is a senior consultant in the Department of Opthalmology, St John’s Eye Hospital, Johannesburg; Dr Fatima Bassa is a principal consultant and head of the Division of Clinical Haematology, Department of Medicine, Tygerberg Academic Hospital, Cape Town, South Africa; Associate Prof. Marius Coetzee is head of the Department of Haematology and Cell Biology, NHLS Universitas Tertiary Laboratories, University of the Free State, Bloemfontein, South Africa; Prof. Alan Davidson is head of Paediatric HaematologyOncology, Red Cross War Memorial Children’s Hospital, Cape Town, and University of Cape Town; Prof. Mohammed Essop is head of the Department of Cardiology, Chris Hani Baragwanath Hospital, Johannesburg; Dr Atul Lakha is a consultant in the Department of Haematology, Chris Hani Baragwanath Hospital; Prof. Vernon Louw is head of the Department of Internal Medicine, University of the Free State; Prof. Nicolas Novitzky is head of the Division of Haematology, Department of Medicine and Pathology, Faculty of Health Sciences, University of Cape Town; Dr Vinitha Philip is a senior consultant in the Department of Haematology, Chris Hani Baragwanath Hospital; Prof. Janet Poole is head of the Department of Paediatric Haematology-Oncology, Charlotte Maxeke Johannesburg Academic Hospital, Johannesburg; and Dr Rosalind Wainwright is a consultant in and head of the Division of Paediatric Haematology-Oncology, Department of Paediatrics, Chris Hani Baragwanath Hospital. Corresponding author: N A Alli (nazeer.alli@nhls.ac.za)
The spectrum of sickle cell disease (SCD) encompasses a heterogeneous group of disorders that include: (i) homozygous SCD (HbSS), also referred to as sickle cell anaemia; (ii) heterozygous SCD (HbAS), also referred to as sickle cell trait; and (iii) compound heterozygous states such as HbSC disease, HbSβ thalassaemia, etc. Homozygous or compound heterozygous SCD patients manifest with clinical disease of varying severity that is influenced by biological and environmental factors, whereas subjects with sickle cell trait are largely asymptomatic. SCD is characterised by vaso-occlusive episodes that result in tissue ischaemia and pain in the affected region. Repeated infarctive episodes cause organ damage and may eventually lead to organ failure. For effective management, regular follow-up with support from a multidisciplinary healthcare team is necessary. The chronic nature of the disease, the steady increase in patient numbers, and relapsing acute episodes have cost implications that are likely to impact on provincial and national health budgets. Limited resources mandate local management protocols for the purposes of consistency and standardisation, which could also facilitate sharing of resources between centres for maximal utility. These recommendations have been developed for the South African setting, and it is intended to update them regularly to meet new demands and challenges. S Afr Med J 2014;104(11):743-751. DOI:10.7196/SAMJ.8470
1. Introduction
Sickle cell disease (SCD) is the commonest inherited haemoglobin disorder, with approximately 70 million affected individuals worldwide. The highest gene frequencies are encountered in tropical regions, particularly equatorial Africa, the Arabian peninsula, India, the Mediterranean, the Caribbean and South America. The protective effect of the heterozygous state against malaria has led to persistence of the sickle gene in malarial endemic areas. South Africa (SA) is not a malarial endemic area, and so has a predictably low prevalence of SCD (<1%). However, with relaxed border controls since 1994, the influx of people from other African states has been accompanied by an influx of the sickle gene. Clinicians are therefore encountering an increasing number of patients with the disease. Under conditions of decreased oxygen tension, HbS polymerises linearly in an alpha-helical fashion to form ‘tactoids’ that force red cells to elongate at two opposite ends and eventually assume a sickle shape (or variants thereof). Upon re-entry to the pulmonary
743
circulation and subsequent reoxygenation of HbS, sickle cells revert to their original shape. Repeated cycles of sickling and unsickling cause membrane damage and increased rigidity, which ultimately leads to formation of irreversibly sickled cells. Normal biconcave red cells are pliable and can easily squeeze through the microcirculation, but owing to their elongated shape, sickle cells are not as flexible. In addition, sickle cells have exposed receptors that bind to integrins on the endothelial surface, which makes them ‘sticky’. In the presence of predisposing factors, e.g. infection, sickle cells therefore get trapped in the microcirculation and cause obstruction to flow, with resulting ischaemia. The severe pain that may be experienced at the site of ischaemia, commonly referred to as an ‘acute pain crisis’ or ‘acute sickle crisis’, is a hallmark of the disease. Chronic organ damage results from repeated infarctive episodes. The only intervention that may be curative is stem cell trans plantation (SCT), but this comes at considerable cost and requires expertise (Appendix 4). Gene therapy is experimental and if successful would overcome some of the hurdles of SCT.
November 2014, Vol. 104, No. 11
FORUM
2. Acute crises
2.1 Acute vaso-occlusive crisis (VOC) (synonyms: acute pain crisis, acute sickle crisis)[1]
Acute VOC is the hallmark of SCD, and is the most common acute presentation. Long bones are the most common sites for acute VOC, but any other site or organ may be involved, including the axial skeleton, abdomen, chest, kidneys, central nervous system and soft tissues. In infants and young children, acute VOC involving small bones of the hands and feet (dactylitis), typically occurring between the ages of 6 months and 3 years, may be the first presenting manifestation of SCD. This causes acute pain as well as swelling and tenderness of the affected regions, often dubbed the ‘hand-foot syndrome’. Any drop in oxygen tension or related events can precipitate a sickle crisis. Precipitating factors include: A. A cidosis, anaesthesia, anxiety, (high) altitude B. Bouts of infection, bad habits, e.g. smoking, alcohol C. C old exposure D. Dehydration E. E xercise (vigorous) F. Folate deficiency (e.g. megaloblastic crisis) G. General surgery H. Hypoxia I. Infection O. O ther – trauma, menstruation. Fever frequently accompanies a pain crisis. As the temperature rarely exceeds 38oC, temperatures above this level should be investigated, guided by the clinical findings and further investigations, e.g. chest radiograph, and blood/urine culture. Empiric antibiotics should be administered until culture results are known, and adjusted where necessary. Acute VOC often causes excruciating pain and can lead to despair and panic. Pain is experienced as a result of tissue ischaemia that results from sludging or occlusion of the microcirculation by sickled red cells. Vaso-occlusion of cerebral vessels results in clinical stroke or silent cerebral infarcts. • Vigorous hydration with intravenous fluids (normal saline or 5% dextrose in saline) is necessary. • Check oxygen saturation and administer oxygen if <95%. 2.1.1 Acute pain Pain management should be individualised, as patients have varying thresholds of pain and different levels of tolerance from past exposure to analgesics. Management: • Prehospital care: bed rest, hydration and simple oral analgesia should be instituted by the patient. Failure of self-treatment should mandate prompt referral to hospital (emergency department/ casualty/admission ward). • Upon admission, rapid clinical assessment and reassurance are important. • Analgesics should be administered as soon as possible, and within 30 minutes of arrival at hospital. • For mild to moderate pain, paracetamol with codeine, nonsteroidal anti-inflammatory drugs (NSAIDs) or tramadol (tilidine in the case of children) may be used as single agents or in combination, bearing in mind the World Health Organization (WHO) three-step ladder for pain management: • Step 1: Mild pain – non-opioid ± adjuvant • Step 2: Moderate pain – weak opioid (or low dose of strong opioid) ± non-opioid ± adjuvant • Step 3: Severe pain – strong opioid ± non-opioid ± adjuvant).
744
• Opioids are generally required for severe pain. Morphine is the drug of choice, except where contraindicated (e.g. allergy, intracranial disease, liver disease, etc.). Ideally morphine should be administered parenterally at fixed intervals. Table 1 serves as a general guide to dosing. Close monitoring of vital signs, pain control and sedation is essential at 15 - 20-minute intervals for the first hour, then at 30-minute intervals, and thereafter 2-hourly once pain control has been achieved. After 24 - 48 hours of pain relief, parenteral morphine should be weaned off over the next 2 - 3 days. A nonopioid analgesic, such as paracetamol or an NSAID, may be added as an adjunct. For breakthrough pain, oral morphine solution can be used (e.g. 5 - 10 mL 4 - 6-hourly). The frequency of and response to pain-relieving medication should be documented with pain charts or scales appropriate to the patient’s age and cognitive abilities. Patient-controlled analgesia pumps are particularly useful for frequent, ongoing pain and should be offered where available. For morphine-related side-effects and their management, see Table 1. Routine use of sedatives should be avoided. For extremely anxious and agitated patients, anxiolytics such as haloperidol, benzodiazepines or antihistamines may be used with caution. Chronic pain is discussed under complications and organ damage (3.8). 2.1.2 Stroke[2,3] The incidence of stroke is highest between 2 and 11 years of age, with up to 30% of individuals being affected (the SA experience however, seems to suggest a lower incidence). • Haemorrhagic stroke. Adults with SCD and moya-moya are at risk of recurrent intracranial haemorrhage. Bleeding aneurysms have been successfully treated with interventional neuroradiology (embolisation with coils) or surgery (craniotomy and clipping). • Arterial stroke. In the acute phase, SCD patients with arterial stroke should undergo exchange transfusion, with the aim of achieving an HbS percentage <30%. As there is a high prevalence of a second stroke, it is recommended that these patients be put onto a chronic transfusion regimen, either top up or exchange transfusion (see below). There is no clear guidance on when to stop the transfusions. • Primary stroke prevention. Long-term red cell transfusion is the mainstay of stroke prevention in SCD. It is possible to identify patients at high risk for developing stroke. Cerebral vessel velocities, as measured by transcranial Doppler (TCD) imaging, exceeding 200 cm/s increase the risk (high risk) for developing stroke. The predictive value of TCD velocity is limited to children, as the velocity rarely exceeds 200 cm/s in adults. • Secondary stroke prevention. Following a first ischaemic stroke, the risk of recurrence in untreated cases is 50 - 92%. This risk is reduced to about 10% by regular transfusions to maintain an HbS level <30%. The initial transfusion should be an exchange transfusion and may be followed by simple transfusions. Chronic transfusion is superior to hydroxyurea in stroke prevention. • Covert infarction. The incidence of silent cerebral infarcts is 7.06/100 patient-years. There should be a high index of suspicion when patients present with cognitive abnormalities. Detection of cerebral infarcts is possible on magnetic resonance imaging (MRI). • Epilepsy. There is a ten-fold increase in the occurrence of seizures in SCD compared with the general population. These are associated with silent infarcts and overt cerebrovascular disease. Seizures should be managed with anticonvulsants.
November 2014, Vol. 104, No. 11
FORUM
Table 1. Suggested dosing of morphine for pain in SCD and management of side-effects Suggested dosing
Side-effects
Morphine
Adult
Paediatric
Initial dose (administered until pain control achieved)
0.1 mg/kg IV every 15 - 30 min OR 10 μg/kg/h as a continuous IV infusion
0.1 - 0.15 mg/kg (max 7.5 mg/dose) Repeat morphine once after 60 min if inadequate pain relief
Subsequent dosing after pain control achieved
0.05 - 0.1 mg/kg IV every 2 - 4 hours
Additional IV boluses of morphine can be given – 0.05 mg/kg 1 - 2-hourly as required
If unable to obtain venous access
Initial dose: 0.1 mg/kg SC followed by 0.05 - 0.1 mg/kg SC 2 - 4-hourly
0.1 - 0.2 mg/kg SC 4-hourly
Constipation
Lactulose 10 mL bid OR Senna 2 - 4 tablets daily
Lactulose 5 mL bid Senna 1 - 2 tabs daily (>6 yr)
Nausea and vomiting
Prochlorperazine 5 - 10 mg tds OR Cycline 50 mg tds
Prochlorperazine 7.5 mg daily oral/ rectal
Pruritus
Hydroxyzine 25 mg bid OR Cetrizine 10 mg nocte OR Promethazine 25 mg tds
Hydroxyzine 5 - 15 mg/day (<6 yr) Cetrizine 5 mg/d Promethazine 5 - 15 mg/day (CI <2 yr)
Respiratory depression
Stop opioid analgesics Naloxone 0.4 - 2 mg IV Repeat when necessary
Stop opioid analgesic Naloxone 0.01 mg/kg IV Repeat with 0.1 mg/kg when necessary
SCD = sickle cell disease; IV = intravenous; SC = subcutaneous; bid = 12-hourly; tds = 8-hourly; CI= contraindicated.
2.1.3 Acute chest syndrome (ACS)[4] ACS is the leading cause of death in SCD, and is characterised by: • Fever – temperature >38.5oC • Respiratory symptoms and signs, including cough, chest pain, dyspnoea or wheezing • A new pulmonary infiltrate on chest X-ray (e.g. consolidation, segmental changes, etc.) • ACS may begin as a pain crisis affecting the ribs, chest or shoulders. The pathogenesis involves vaso-occlusion, fat embolism and pulmonary thromboembolism. There is also a bronchoreactive component. Complications of an ACS include respiratory failure, central nervous system injury (from anoxia, infarction or haemorrhage), seizures, non-cardiogenic pulmonary oedema and multiorgan failure (from hypoxia, resulting in widespread sickling and VOC). Patients with ACS are best cared for in a high-care facility. Management of ACS: • Bed rest, hydration and analgesia • Oxygen supplementation – oxygen may be administered to moderately hypoxaemic patients (arterial oxygen tension 70 - 80 mmHg; oxygen saturation 92 - 95%) nasally at a rate of 2 L/min • Antibiotics are indicated as infection is a common precipitant of ACS, and should include a macrolide (e.g. erythromycin) to cover atypical organisms, combined with a second- or third-generation cephalosporin. The choice of antibiotics may be modified based on the age of the patient and the institutional sensitivity and resistance patterns. • Bronchodilators should be prescribed for patients with evidence of bronchospasm. • Blood transfusion. Where there is severe anaemia or significant drop in haemoglobin concentration (≥2 g/dL), a blood transfusion is required. An exchange transfusion is indicated if there is evidence of hypoxia (±5 - 10% drop from the baseline oxygen saturation level or paO2 <70 mmHg) and in deteriorating patients,
745
since acute respiratory failure can supervene rapidly. Exchange transfusion in this setting often results in dramatic improvement. • For severe hypoxia (paO2 <60 mmHg), continuous positive airways pressure (CPAP) and mechanical ventilation may be necessary. • Incentive spirometry is useful in preventing complications such as atelectasis and pulmonary infiltrates in patients experiencing pain above the diaphragm. 2.1.4 Abdominal crisis An abdominal crisis most commonly arises from occlusion or infarction of mesenteric vessels and can mimic an acute abdomen, e.g. intestinal obstruction, cholecystitis, acute appendicitis or pancreatitis. Bowel ischaemia often causes abdominal pain that has a girdle distribution, called the ‘girdle syndrome’. Ischaemic colitis causes thickening of the intestinal wall that can be detected on an abdominal computed tomography scan. Angiography does not image smaller vessels reliably and has limited diagnostic value. Conservative management with rehydration and analgesia generally leads to resolution within 2 - 4 days. Colonoscopy is indicated if infarction is suspected. Progression to severe ischaemic colitis necessitating colonic resection is rare and can be avoided by optimising colonic perfusion with exchange blood transfusion, intravenous broad-spectrum antibiotics and several days of bowel rest. However, there is a risk of bowel perforation if there is no response within 2 weeks. Patients who develop peritonitis, sepsis or gangrene (identified through endoscopy) or whose clinical condition deteriorates despite conservative management should undergo laparotomy for resection of the affected bowel segment. 2.1.5 Priapism[5,6] Priapism is an unwanted, persistent, painful erection of the penis. By the age of 20 years, 30 - 45% of men with SCD will have suffered at least one episode of priapism. It can occur as an acute sustained attack or as recurrent shorter episodes (stuttering). If an episode lasts more than 3 - 4 hours, it can lead to erectile dysfunction. It is
November 2014, Vol. 104, No. 11
FORUM
important for patients to be educated to abort attacks of priapism. Newer management ensures that more than 70% of men with SCD remain potent. Management principles of priapism include: • Simple measures: urination, hydration, hot baths, adequate analgesia (including morphine for severe pain in hospitalised patients – see management of acute pain above). Do not apply ice, as this will slow the circulation. • Aspiration and irrigation of the corpora cavernosa. • Intracavernous injection of sympathomimetic agents, such as phenylephrine (add 1 mL of a 10 mg/mL solution to 500 mL of 0.9% saline; administer 1 mL of the solution every 3 - 5 minutes for up to an hour, before proceeding to the next step), or as a second option epinephrine (add 1 mL of a 1:1 000 solution to 1 000 mL saline). • Surgical shunting (performed by a urologist) would be indicated for ongoing, refractory ischaemic priapism. • Once the acute episode has settled, review and optimise the comprehensive care of the patient. • If stuttering priapism persists despite optimal treatment, specific prophylaxis and home treatment should be considered. This includes oral pseudoephedrine (30 mg at night if <10 years of age; 60 mg at night if >10 years) or oral etilefrine (25 mg at night for adults). • A urologist and a clinical psychologist should be involved in the management of patients who develop erectile dysfunction. There are various medical and prosthetic options available for such patients. 2.2 Splenic sequestration crisis This is a life-threatening emergency where the spleen enlarges very rapidly, sometimes within hours, and causes massive pooling of blood. The effect is synonymous with internal exsanguination with development of acute anaemia. Splenic sequestration is most common in early childhood but may be encountered in older children and adults, particularly those with compound heterozygous sickle-β thalassaemia or HbSC disease. Early and urgent blood transfusion is life-saving. Splenectomy is generally indicated for recurrent life-threatening episodes (usually after 4 - 6 years of age). When the spleen regresses to its original size, the blood returns to the main circulation, which may increase the haemoglobin to above baseline levels. This is known as reverse sequestration and poses a risk for developing acute cardiac failure, acute hypertension or stroke. Care should therefore be taken not to aim for baseline haemoglobin levels during transfusion. Education of parents to palpate for splenomegaly from infancy/ early childhood allows for early recognition and prompt intervention of this emergency situation.[7]
2.3 Aplastic crisis
In the context of SCD, as in other haemolytic states, aplastic crisis refers to pure red cell aplasia, where there is selective erythroid hypoplasia or aplasia with resultant reticulocytopenia. The most common cause is infection with parvovirus type B19, which infects early erythroid precursors through the glycophorin receptor. In normal individuals this infection rarely causes anaemia, but in haemolytic states where there is maximal erythropoietic activity, destruction of erythroid precursors leads to rapid development of severe anaemia. Blood transfusion is the mainstay of management. Intravenous gamma globulin and/or corticosteroids may be indicated for the treatment of parvovirus B19 infection.
746
2.4 Haemolytic crisis
Haemolytic crisis may be caused by an acute VOC, malarial infection or oxidant drug exposure in individuals with concomitant glucose-6-phosphate dehydrogenase (G6PD) deficiency. Haemolytic crisis may be distinguished from aplastic crisis by the finding of a reticulocytosis as opposed to a reticulocytopenia. Rarely, a hyperhaemolysis syndrome may be triggered by a red cell transfusion. Here the haemoglobin concentration drops to below pretransfusion levels as a result of destruction of allogeneic as well as autologous red cells without any evidence of an antibodymediated transfusion reaction. The mechanism of hyperhaemolysis is not known, but it is thought to result from hyperactive macrophage activity. Corticosteroids (first line) and intravenous immunoglobulin are the mainstays of treatment. Since red cell transfusion during an episode of hyperhaemolysis can accelerate the haemolytic process, additional transfusions should be limited to situations of life-threatening anaemia.
3. Complications and organ damage 3.1 Infection
Increased susceptibility to infection in SCD patients may be due to a number of predisposing factors, including functional asplenia (hyposplenism), impaired complement activity, zinc deficiency, iron overload and the presence of necrotic tissue. The spleen is an early casualty of organ damage from repeated infarctive episodes, which reduce it to a nubbin of fibrous tissue. Functional asplenia in particular increases the propensity to infections with encapsulated bacteria and malaria, which may be life-threatening. Key to a successful outcome is early recognition and prompt therapeutic intervention. Osteomyelitis is often a result of vaso-occlusion, ischaemia and infarction, with consequent bone necrosis and secondary infection. In addition, bacteraemia may lead to osteomyelitis or septic arthritis. Management of osteomyelitis entails: • Supportive care including bed rest, splinting of the affected limb, analgesia, hydration and oxygenation • Surgical drainage where necessary • Administration of intravenous antibiotics for 2 - 6 weeks. Appropriate antibiotics include the cephalosporins such as ceftriaxone and the quinolones in Salmonella osteomyelitis, and cloxacillin where Staphylococcus aureus is suspected. See below for preventive measures against infection.
3.2 Cardiovascular complications
Cardiovascular complications have become more evident with increasing longevity in patients with SCD and include pulmonary hypertension, left and right ventricular dysfunction, myocardial infarction, arrhythmias and sudden death.[8]
3.2.1 Pulmonary hypertension (PHT)[9]
PHT occurs in 5 - 30% of patients with SCD and is a risk factor for sudden cardiac death. Although the precise mechanism has not been defined, chronic haemolytic anaemia and release of free haemoglobin, which inactivates nitric oxide, may have an important role in the causation of pulmonary vasculopathy. Proliferation of smooth-muscle cells with resultant vascular obliteration leads to a pathological picture almost identical to that seen in idiopathic PHT. Other factors that contribute to the development of PHT in this population include functional asplenia, thromboembolism, lung fibrosis, hypoxia and left ventricular dysfunction.
November 2014, Vol. 104, No. 11
FORUM
Echocardiography is the most useful screening test when PHT is suspected on clinical grounds, but it should be emphasised that definitive confirmation requires invasive right-heart catheterisation. The echocardiographic definition of PHT is a pulmonary artery systolic pressure >40 mmHg, while the haemodynamic definition of PHT is a mean pulmonary artery pressure (MPAP) >25 mmHg at rest, measured at cardiac catheterisation. A raised tricuspid regurgitant velocity (TRV) (>2.5 m/s) on Doppler echocardiography correlates well with an increased MPAP, and is more suitable for regular screening of patients owing to the non-invasive nature of the test. However, a diagnosis of PHT based on an elevated TRV needs to be confirmed with cardiac catheterisation, as not all patients with a raised TRV have PHT. Several studies have confirmed that a TRV >2.5 m/s is associated with a 9 - 16 times increased risk of death. These patients should be referred to a cardiologist for further management and follow-up. Therapeutic interventions include: • Prostacyclin analogues (e.g. epoprostenol, iloprost) • Phosphodiesterase type 5 inhibitors (e.g. sildenafil) • Endothelin receptor antagonists (e.g. bosentan).
3.4 Avascular necrosis (AVN)
3.2.2 Left ventricular dysfunction (LVD) LVD is not infrequent and is largely related to the duration and severity of anaemia. Compensatory left ventricular hypertrophy and dilatation are accompanied by both systolic and diastolic dysfunction and consequent heart failure. Other factors contributing to the heart failure phenotype include systemic hypertension, chronic inflammation, and possibly direct myocardial damage as a result of microvasculopathy. The treatment of LVD and heart failure should follow standard guidelines and include diuretics, digitalis, beta-blockers and angiotensin-converting enzyme (ACE) inhibitors. 3.2.3 Myocardial infarction (MI) MI has been documented in SCD, but the mechanisms are unclear because coronary angiography rarely reveals obstructive coronary disease. Other mechanisms that have been postulated include microvascular obstruction and endothelial dysfunction. The role of standard therapies for MI such as antiplatelets and thrombolytics remain unclear, although most patients improve with standard management of the sickle cell crisis.
3.3 Renal complications
Patients may present with symptoms early on in life and may manifest with the following complications: 3.3.1 Hyposthenuria Hyposthenuria refers to an inability to concentrate urine maximally and is a common renal abnormality in SCD. Hyposthenuria typically manifests as enuresis in early childhood (in rare cases it may continue into the teenage years) and may cause nocturia in adults. Maintaining good hydration is important, as these patients are more susceptible to dehydration than normal individuals. 3.3.2 Haematuria Haematuria may occur in homozygous SCD (HbSS) as well as hetero zygous SCD (HbAS) and is caused by renal papillary necrosis resulting from ischaemic damage to the renal medulla. Treatment involves bed rest, maintenance of a high urinary flow, and blood transfusion if blood loss is significant. In the event of excessive or life-threatening bleeds, local resection of the bleeding segment in the kidney is preferable. It is, however, important to exclude other causes of haematuria.
747
3.3.3 Proteinuria Screening for proteinuria should be performed annually with a urine dipstick. If positive, a 24-hour protein estimation or urine albumin/creatinine ratio is indicated. For patients with albuminuria, ACE inhibitors or angiotensin-II receptor antagonists are usually beneficial. Renal function should be monitored annually (urine for microalbuminuria, blood urea, electrolyte and creatinine levels). Serum creatinine levels are generally low in SCD, so a rise in the creatinine level to within the normal range often signals the onset of renal impairment. Long-term use of NSAIDs should be avoided, particularly in patients with evidence of renal impairment. Renal transplantation may be considered in patients with end-stage renal failure. Patients with renal dysfunction should be assessed and followed up by a renal physician.
Osteonecrosis or AVN occurs when repetitive vaso-occlusion results in the infarction of articular surfaces and juxta-articular bone, e.g. the head of a long bone. The most common sites are heads of femoral bones and humeri, followed by the knee (tibial condyles) and small joints of the hands and feet. The femoral head is highly vulnerable to ischaemic damage because its blood supply depends solely on an endartery. Multiple joints are often affected. Pain due to AVN is most noticeable during weight bearing and there may also be functional limitation of the joint. Early disease is best detected by MRI (signal intensity changes, irregular bony and articular outline). Plain X-rays detect only more advanced disease (flattening of the head, coarsening of the bone architecture, cystic areas, sclerosis). Isotope bone scans may detect osteonecrosis as focal areas of increased activity. Without treatment it is expected that most affected femoral heads will collapse within 5 years of diagnosis. Treatment options include a more conservative approach in children, with analgesia (paracetamol, mild opiates, NSAIDs), physiotherapy and protected weight bearing (avoidance of weight bearing) for approximately 3 - 6 months. Secondary degenerative arthritis can compound the osteonecrosis in adults and a conservative approach is less effective. Analgesia, core decompression and realignment osteotomy with aggressive physiotherapy are used in early disease, while joint replacement is reserved for patients with severe manifestations of advanced disease. There is a high rate of perioperative complications, which include blood loss, acute chest syndrome, infection and failure of the prosthesis.
3.5 Leg ulceration
Leg ulceration is a frequent complication of SCD in adults and most commonly occurs over the shins and malleoli. Leg ulcers should be treated promptly to minimise progression to a chronic state. Investigation and management of leg ulcers include the following: • Swab for culture if infected, and treat as per sensitivity results. Osteomyelitis should be excluded if there is fever and bone tenderness. An MRI scan may be indicated to establish a diagnosis of osteomyelitis. • Topical emollients and wound dressings to promote moist wound healing. Graduated compression bandages will reduce venous hypertension. Zinc supplementation may be of benefit in terms of wound healing, as the patients tend to be in negative zinc balance. Topical antibiotics should be avoided to prevent sensitisation. • Arterial insufficiency should be excluded. If discovered, the patient must be referred to a vascular surgeon.
November 2014, Vol. 104, No. 11
FORUM
• For those who fail to respond to the above measures, the attending doctor should consider: • Regular blood transfusions until wound healing occurs (a costly option) • Wound dressings with Thrombostim, a product developed and manufactured by the South African National Blood Service (SANBS). Thrombostim is a dual-component treatment system containing lyophilised platelet-rich plasma, which is rich in platelet-derived growth factor (PDGF), and lyophilised thrombin. PDGF is essential for the wound healing process.
4. Preventive measures 4.1 Patient education
The surgical team should be involved in the management of patients with chronic leg ulcers.
Patients as well as caring family members need to be informed about the disease process, with particular attention being paid to the following: • Precipitating factors • Home management. The aim is to recognise symptoms or signs that require hospital admission, and at the same time abort the various forms of acute crises. A supply of simple analgesics should be made available for managing milder forms of sickle crises. Parents should be taught the art of palpating for the spleen in order to pre-empt a splenic sequestration crisis. • Genetic counselling.
3.6 Gallstones
4.2 Infection control
Formation of gallstones is a common complication of SCD, and if the patient is symptomatic, cholecystectomy should be performed. A laparoscopic procedure is preferred.
3.7 Ocular complications
In the early stages ocular complications are usually clinically silent. Anterior- and posterior-segment changes of the eye can occur. Retinal changes are broadly categorised as follows: 3.7.1 Non-proliferative retinopathy Non-proliferative retinopathy includes ‘salmon patches’ and ‘black sunbursts’. These changes occur as a result of peripheral retinal haemorrhages due to arteriolar occlusion and rupture of the blood vessel. This does not normally lead to visual loss. 3.7.2 Proliferative retinopathy Proliferative retinopathy is predominantly encountered in young adults with SCD (including HbSS and HbSC disease). Neovascularisation occurs in response to microvascular occlusion and ischaemia. This may lead to complications such as vitreous haemorrhage and retinal detachment, which is a cause of sudden loss of vision. Pan-retinal photocoagulation laser therapy is effective in preventing vision-threatening complications such as vitreous haemorrhage and retinal detachments. Antivascular endothelial growth factor (antiVEGF) agents such as bevacizumab have also been used in the treatment of proliferative retinopathy. Annual ophthalmic assessment is recommended.
3.8 Chronic pain
A multidisciplinary team is required for the optimal management of chronic pain. The cause of the pain should be determined. Where circumstances permit, home management should be encouraged. • Pharmacological management should include medium- to long-acting opioids, as the use of frequent short-acting opioids is less effective. NSAIDs should be used judiciously with 3-monthly monitoring of renal function. For breakthrough pain, alternative analgesia such as fentanyl or oxycodone may be used, where available. • Non-pharmacological measures should be considered where necessary, such as physiotherapy, acupuncture, etc. • Surgical options may be exercised where indicated, e.g. decompression or total hip replacement for avascular necrosis of the hip and cholecystectomy for gallstones. Perioperative thromboprophylaxis is imperative. • Chronic headache is common in SCD, and any exacerbation or change in the nature of the pain warrants neurological assessment (to exclude potentially life-threatening events such as intracranial haemorrhage or venous sinus thrombosis).
748
Globally, infection is the leading cause of death in developing countries. The factors responsible for increased susceptibility to infections in SCD have been mentioned previously. In particular, hyposplenism renders patients more susceptible to the detrimental effects of encapsulated organisms and malaria. In addition, infection is a common precipitant of an acute crisis, and prompt treatment with appropriate antibiotics is therefore essential. 4.2.1 Antibiotics There is debate on the prophylactic use of oral antibiotics in all patients with SCD. However, penicillin VK 125 mg twice daily orally for children under 3 years of age and 250 mg bid for children older than 3 years of age is recommended, and continued until adolescence. Erythromycin is recommended for patients who are allergic to penicillin. 4.2.2 Immunisation • Pneumococcal vaccine. Adults and children >2 years of age should receive the unconjugated vaccine (Pneumovax 23®). Conjugated vaccine (Prevenar 13®) is provided to children under the age of 2 years as part of the national immunisation schedule. Children who have missed the conjugated vaccine should have two doses of the conjugated vaccine followed by a dose of the unconjugated vaccine, at 6 - 8-week intervals. • Conjugated meningococcal C vaccine. If not given as part of the childhood immunisation programme, a single dose should be given. • Haemophilus influenzae type B vaccine. If not given as part of the childhood immunisation programme, a single dose should be given. • Annual influenza vaccination is recommended.
4.3 Nutritional supplements
• Folic acid becomes depleted owing to its high turnover as well as loss from chronic haemolysis. A dose of 1 - 2 mg daily is adequate to supplement the increased requirements of folate. • Zinc is a constituent of the metalloenzyme carbonic anhydrase, which is lost in intravascular haemolytic states. Zinc should be supplemented in individuals displaying symptoms of zinc deficiency, viz. malaise, listlessness and fatigue or repeated infections. • Repeated transfusions can lead to iron overload. However, individuals who are not regularly transfused can develop a negative iron balance, necessitating supplementation.
4.4 Family screening
Family members and prospective partners should be screened. Cultural and societal sensitivities often pose a challenge to effective screening programmes, largely owing to stigma associated with the
November 2014, Vol. 104, No. 11
FORUM
disease. An aggressive education drive is necessary to overcome such barriers. The most convenient method of screening for SCD is high-performance liquid chromatography (HPLC), since it is reliable, automated and allows for high throughput. Hb electrophoresis may be used as a confirmatory test. The slide sickle and solubility tests, although still used in some under-resourced centres, are far from ideal because they may not distinguish HbAS from HbSS and also cannot detect compound heterozygous states.
4.5 Antisickling agents
There are various antisickling agents, such as hydroxyurea (HU), statins, clotrimazole and butyrate. Of the available agents, HU has proven to be the most effective. HU is a cytotoxic agent that acts by inhibiting the enzyme ribonucleotide reductase. The mechanisms of action of hydroxyurea include: • Increase in HbF concentration. HbF does not participate in formation or elongation of the sickle tactoids and as such retards the sickling process. • Increase in the mean cell volume, which prolongs the delay time (time taken for a red cell to sickle). • Reduction of cell counts and adhesion molecules, thereby improving the rheology and flow of blood. HU is indicated in all adult patients with SCD. Use in children has been less definitive, however, primarily owing to concerns regarding fertility and potential mutagenicity. There is no clear-cut evidence that long-term use of HU (when used for the treatment of benign disorders) leads to an increased risk of secondary malignancies. Although infertility is not a recognised complication, reduced sperm counts and a decrease in sperm motility have been demonstrated, which appear to improve or reverse after discontinuation of HU. On the contrary, numerous studies have demonstrated the benefits of HU, viz. a decreased number of acute crises, decreased transfusion requirements and organ preservation in children. Institution of HU therapy is therefore recommended in children with SCD >2 years of age.[7] The dosage scheme of HU is as follows: Start at 10 - 15 mg/kg/d and increase to a maximum of 30 mg/kg/d. The dose should be titrated against the neutrophil count and increased by 5 mg/kg increments at 3-monthly intervals. The dose should be decreased if the neutrophil count drops below 1.5 × 109/L, and stopped if it drops below 1 × 109/L or when conception is planned.
4.6 Gout prevention
Elevation of uric acid levels are closely linked with the degree of haemolysis. There may also be a contribution from the use of hydroxyurea or renal dysfunction. A uric acid-lowering agent such as allopurinol is recommended where the uric acid levels are elevated.
4.7 Outpatient visits
Regular outpatient visits are essential for monitoring and early detection of organ dysfunction. (See Appendix 3 for a recommended schedule of outpatient visits.) Disclaimer. The advice and information in these guidelines is largely evidence based and believed to be true and accurate at the time of going to press. The authors or publishers therefore cannot accept any legal responsibility for these recommendations. It should also be noted that, for reasons of conscience, not all the authors agree on termination of pregnancy beyond situations where the life of the pregnant woman is endangered.
749
References. Please note that only key references are cited as per publisher’s requirements. Detailed referencing is available on request from the authors. 1. Rees DC, Olujohungbe AD, Parker NE, et al. Guidelines for the management of acute painful crisis in sickle cell disease. Br J Haematol 2003;120(5):744-752. [http://dx.doi.org/10.1046/j.13652141.2003.04193.x] 2. Adams RJ, McKie VC, Hsu L, et al. Prevention of a first stroke by transfusions in children with sickle cell anaemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med 1998;339(1):5-11. [http://dx.doi.org/10.1056/NEJM199807023390102] 3. Ware RE, Helms RW. SWITCH investigators. Stroke with transfusions changing to hydroxyurea (SWITCH). Blood 2012;119(17):3925-3932. [http://dx.doi.org/10.1182/blood-2011-11-392340] 4. Vichinsky EP, Neumayr LD, Earles AN, et al. Causes and outcomes of the acute chest syndrome in sickle cell disease. National Acute Chest Syndrome Study Group. N Engl J Med 2000;342(25):18551865. [http://dx.doi.org/10.1056/NEJM200006223422502] 5. Emond AM, Holman R, Hayes RJ, et al. Priapism and impotence in homozygous sickle cell disease. Arch Intern Med 1980;140(11):1434-1437. [http://dx.doi.org/10.1001/archinte.1980.00330220022011] 6. Montague DK, Jarow J, Broderick GA, et al. American Urological Association guideline on the management of priapism. J Urol 2003;170(4):1318-1324. [http://dx.doi.org/10.1097/01. ju.0000087608.07371.ca] 7. Wang WC, Ware RE, Miller ST, et al., for the BABY HUG investigators. Hydroxycarbamide in very young children with sickle cell anaemia: A multicentre, randomised, controlled trial (BABY HUG). Lancet 2011;377(9778):1663-1672. [http://dx.doi.org/10.1016/S0140-6736(11)60355-3] 8. Gladwin MT, Sachdev V. Cardiovascular abnormalities in sickle cell disease. J Am Coll Cardiol 2012;59(13):1123-1133. [http://dx.doi.org/10.1016/j.jacc.2011.10.900] 9. Gladwin MT, Sachev V, Jison ML, et al. Pulmonary hypertension as a risk factor for death in patients with sickle cell disease. N Engl J Med 2004;350(9):886-895. [http://dx.doi.org/10.1056/NEJMoa035477] 10. Oteng-Ntim E, Babarinsa I, Bagot C, et al. Management of Sickle Cell Disease in Pregnancy. Green-top Guideline No. 61. London: Royal College of Obstetricians and Gynaecologists, 2011:1-20. 11. Smith LA, Espeland M, Bellevue R, et al. Pregnancy in sickle cell disease: Experience of the Cooperative Study of Sickle Cell Disease. Obstet Gynecol 1996;87(2):199-204. [http://dx.doi.org/10.1016/00297844(95)00367-3] 12. Wenko SO, Telen MJ. Transfusion management in sickle cell disease. Hematol Oncol Clin North Am 2005;19(5):803-826. [http://dx.doi.org/10.1016/j.hoc.2005.07.002] 13. Bolton-Maggs PHB. Transition of care from paediatric to adult services in haematology. Arch Dis Child 2007;92(9):797-801. [http://dx.doi.org/10.1136/adc.2006.103804] 14. Lucarelli G, Clift RA, Galimberti M, et al. Bone marrow transplantation in patients with thalassemia. N Engl J Med 1990;322(7):417-421. [http://dx.doi.org/10.1056/NEJM199002153220701] 15. Panepinto JA, Walters MC, Carreras J, et al. Matched-related donor transplantation for sickle cell disease: Report from the Center for International Blood and Transplant Research. Br J Haematol 2007;137(5):479-485. [http://dx.doi.org/10.1111/j.1365-2141.2007.06592.x]
Accepted 20 June 2014.
Appendix 1. Pregnancy and contraception in SCD
Pregnancy is a major decision for a woman with SCD, since it is associated with a number of maternal and fetal complications. Maternal complications include VOC (30 - 50%), infections (28%), anaemia (34%), pre-eclamptic toxaemia (PET)/eclampsia (9%), preterm labour (24%), etc. Fetal complications include miscarriage, abruptio placentae, placenta praevia, preterm delivery (24%), low birth weight (20%), fetal distress (14%), stillbirths (0.9%), etc. Improvements in obstetric and perinatal care have resulted in a decrease in maternal and perinatal mortality (from 11.5% in the 1970s to <2%). The philosophy of avoidance of pregnancy in the past has now shifted to one of support and comprehensive stepwise care, for which a multidisciplinary team including the haematologist and obstetrician is required. This is summarised below.
Management of SCD in pregnancy[10,11]
1. Screening and counselling of young women at risk • Education • Issues surrounding fertility, contraception and pregnancy • Choice and screening of spouse/partner • Discussion of potential maternal and fetal complications. • Planning of the pregnancy prior to conception – discuss discon tinuation of HU prior to conception, pneumococcal vaccination, and need for continuation or termination of pregnancy (TOP). 2. Antenatal diagnosis. This is not without risk of complications and should be undertaken if TOP is a realistic option. Techniques include chorionic villous sampling at 9 - 13 weeks, amniocentesis at 15 - 16 weeks and fetal blood sampling at 18 - 20 weeks.
November 2014, Vol. 104, No. 11
FORUM
3. Antepartum management • Early booking is advised, ideally by 12 - 14 weeks. Recommended followup frequency: monthly until 28 weeks, fortnightly until 34 weeks and weekly after 34 weeks. • Close monitoring of mother and fetus is needed for early detection of recognised complications. Perform growth scans/ ultrasound monthly until 34 weeks, then fortnightly until delivery. Weekly nonstress testing from 32 weeks’ gestation is recommended. • Folic acid 5 mg daily, and iron supple mentation if indicated. • Blood transfusion – prophylactic trans fusion for uncomplicated pregnancy is not recommended. Indications for blood transfusion include: anaemia associated with cardiorespiratory disease, acute chest syndrome, refractory PET, preparation for caesarean section (CS) and other medical or obstetric indications. 4. Labour and delivery • Timing and route of delivery should be based on obstetric indications as in nonSCD cases. • During labour ensure good pain relief, adequate hydration, oxygen, and fetal and maternal monitoring. • Avoid long and exhausting labour and delivery. • For CS, optimise surgical and anaesthetic risks (e.g. transfusion, hydration, oxygen ation, temperature control, etc.). Beware of acute chest syndrome post-surgery (peak 48 hours post surgery). • Where opiates are used, be aware of the sedative and depressive effects. If they are used prior to or during labour and delivery, a neonatologist should be alerted, and be present at delivery in case of fetal sedation. 5. After delivery • Owing to the increased risk of thromboembolic disease, aim for early ambulation and use of stockings, with thromboprophylaxis in high-risk indivi duals. • During breastfeeding, avoid HU and ensure good hydration. • It is important to offer family planning advice with the various options on contraception, viz. oral contraceptive pill (including combined and progesteroneonly pill), depot medroxyprogesterone acetate, barrier methods and copper intrauterine contraceptive devices, which are all acceptable in SCD.
6. Neonate • Establish early diagnosis – an umbilical cord blood sample may be used for con venience. • In the case of a child born with SCD, institute a comprehensive care programme where both the paedia trician and the haematologist are invol ved in manage ment.
Appendix 2. Blood transfusion and iron overload in SCD[12]
Blood transfusion remains an important component of the management of patients with SCD. The rationale behind transfusion is to improve microvascular perfusion and oxygen-carrying capacity and decrease the proportion of sickle cells in the circulation. Indications for transfusion are set out in Table 2. Transfusion for anaemia is generally indicated in symptomatic patients with a >20% drop in haemoglobin or a decrease in oxygen saturation. The goal of transfusion should be to reduce the level of HbS to <30% and in order to prevent the problems of hyperviscosity, achieve a post-transfusion haemoglobin concentration not exceeding 9 - 10 g/dL. The role of transfusion in stroke is discussed under ‘Acute VOC’ (2.1.2). Controversial indications for transfusion include priapism, pregnancy and patients with chronic leg ulcers (cf. respective sections). Simple v. exchange transfusion. The deci sion with regard to each of the modalities of transfusion will depend on the indication, clinical circumstances and available resources. Exchange transfusion has the added advantage of reducing HbS effectively without the risk of increasing viscosity or causing volume overload. Simple transfusion has the advantage of ease of administration, as well as accessibility outside major medical centres. The disadvantages include the potential to
increase viscosity, as well as the risk of iron and volume overload. The optimal management strategy should also include measures to limit the complications associated with blood transfusion, the most important being alloimmunisation and iron overload. Alloimmunisation is a commonly encoun tered complication in patients with SCD, and extended phenotyping has been shown to reduce the incidence of this complication. Testing for at least D, C/c, E/e and K antigens is recommended before commencing transfusions, and phenotypically matched, leucodepleted blood should be administered. Patients receiving regular transfusions should have regular monitoring of their iron status, and chelation therapy should be commenced appropriately. The iron chelators available are deferoxamine (given parenterally), deferiprone and deferasirox (given orally). Oral iron chelators are preferred, as they improve patient compli ance. Deferiprone should be avoided in patients with aplastic crisis or neutropenia because it is known to cause agranulocytosis in some patients.
Appendix 3. Outpatient follow-up and transition of care in SCD Outpatient follow-up
In the initial stages, patients should be seen at the haematology outpatient clinic on a monthly basis. Intervals between visits may be increased to 3 months once the patient is stable and therapy is optimised. Investigations conducted at outpatient level for monitoring purposes are listed in Table 3.
Transition of care[13]
Transfer of care from a paediatric to an adult team is a major life-changing event for the young patient with HbSS. With advances in medical care, >90% of patients with SCD now reach adulthood, with the majority living into their forties.
Table 2. Indications for blood transfusion in SCD Acute
Chronic
Symptomatic anaemia Splenic/hepatic sequestration crisis Acute chest syndrome Acute neurological syndromes Perioperative (major surgery) Acute multiorgan failure Sepsis
Primary or secondary stroke prevention Pulmonary hypertension Recurrent sequestration crisis/chest syndrome Anaemia associated with chronic renal failure Congestive cardiac failure
SCD = sickle cell disease.
750
November 2014, Vol. 104, No. 11
FORUM
Table 3. Guide to outpatient monitoring of SCD Baseline
Monthly
FBC + differential
×
×
6-monthly
Annual
Biennial
U+E
×
LFTs
×
Urine for microalbumin
×
Chest X-ray
×
×
TRV (>10 yr)
×
×
Lung function tests (>10 yr)
×
TCD (paediatric population)
×
×
Ocular assessment
×
× Adults
Serum ferritin (if regularly transfused)
× × ×
× × Older children with HbSC
×
SCD = sickle cell disease; FBC = full blood count; U + E = urea and electrolytes; LFTs = liver function tests; TRV = tricuspid regurgitant velocity; TCD = transcranial Doppler.
Longer survival has increased the need for successful transition of care from paediatric to adult services. The handover from paediatric to adult services should be planned and managed as a process and should begin after the age of 12 years. The optimal time for transition should be individualised and requires assessment of the level of readiness as well as patient and parent education about their illness and the transition process. The anxiety of patients during a transfer process centres around transfer of their history, the adult service’s attitude to issues pertaining to pain management, and practical issues such as appointments, etc. Methods to facilitate the process include printed literature, meeting with a support group or someone who has successfully transitioned, visiting the adult service before the first appointment, and the establishment of special combined clinics.
Appendix 4. Haematopoietic SCT for SCD[14,15]
Allogeneic SCT offers the only chance of cure in SCD. Gene therapy is still in the development phase and is currently not a realistic option. The indications for transplantation in SCD remain poorly defined owing to the variable phenotypic expression of the disease with age. The general experience in transplantation for this disease is also less than in thalassaemia. As a rule, in the absence of severe organ dysfunction, this treatment option should be considered in all moderately or severely symptomatic children if an HLA-identical donor is available. Results are better if transplantation is performed at an earlier age, particularly before irreversible sickle vasculopathy is established. While the outcome of transplantation for SCD has been favourable, the main limiting factors for its wider use are lack of HLAcompatible donors, infrastructure and expertise, and cost. Outcomes depend on certain risk factors associated with the treatment of the haemoglobinopathy, such as irregular iron chelation therapy, which significantly increases transplant-related mortality. In addition,
751
transplantation for SCD may have unique complications such as cerebrovascular occlusive/haemorrhagic episodes with stroke, convulsions requiring prophylaxis with anticonvulsive therapy, meticulous control of electrolytes, and maintaining higher than baseline blood haemoglobin levels and platelet counts throughout the procedure. For the success of this type of therapy, two barriers must be overcome, viz. graft rejection and graft-versus-host disease (GVHD). For effective engraftment myeloablative conditioning is preferred, particularly in view of the highly cellular marrow as a consequence of chronic haemolysis and the brisk immune response resulting from exposure to allogeneic antigens during blood transfusions. The specifics of myeloablation are beyond the scope of this review. The probabilities of overall survival, sickle cell-free survival and transplant-related mortality are 92%, 86% and 5%, respectively. Despite the appropriate use of immunosuppressive agents, approximately one-third of patients will develop clinically relevant scores of GVHD, necessitating further therapy with corticosteroids and immunosuppressive agents. Adult patients usually have more advanced disease, and therefore greater comorbidities and higher treatment-related mortality. A proportion of patients may have re-emergence of their own haematopoiesis with persistent and stable chimerism, which is generally associated with an asymptomatic state. In contrast to transplantation for malignancies, mixed chimerism in haemo globinopathies therefore does not necessarily mean treatment failure. Allogeneic SCT is an effective treatment option, and currently the only proven curative therapy for patients with SCD. By removing the sickle cell phenotype, the vasculopathy is reversed and patients are likely to have a normal quality of life. Challenges remain the broader availability of this procedure with the use of alternative donors, as well as enhancing engraftment and preventing GVHD.
November 2014, Vol. 104, No. 11
SAMAREC/CPD SERVICES AVAILABLE: 타
South Africa Medical Association Research and Ethics Committee SAMAREC
타
타
WHAT WE ARE ABOUT SAMAREC:
CPD:
Evaluating the ethics of research
Assisting health professionals to
protocols developed for clinical
maintain and acquire new and
South African Medical Association
trials conducted in the private
updated levels of knowledge, skills
Continued Professional
healthcare sector. Ensuring the
and ethical attitudes that will be of
Development Accreditation
protection and respect of rights,
measurable benefit in professional
safety and well-being of
practice and to enhance and
participants involved in clinical
promote professional integrity. The
trials and to provide public
SA Medical Association is one of
health to the nation
assurance of the protection by
the institutions that have been
o
Excellent Service
reviewing, approving and providing
appointed by the Medical and
o
Quick Turnaround
comment on clinical trial protocols,
Dental Professions Board of the
o
Efficiency
the suitability of investigators,
Health Professions Council of SA
facilities, methods and procedures
to review and approve CPD
used to obtain informed consent.
applications.
Our Mission: o
Empowering Doctors to bring
For further information please contact the SAMAREC/CPD Secretariat on 012 481 2000 OR email us on samarec@samedical.org or cpd@samedical.org
EDITORIAL
Public somnambulism: A general lack of awareness of the consequences of increasing medical negligence litigation Attend any meeting of obstetricians, spinal surgeons, neurosurgeons or neonatologists, and talk soon turns to the burgeoning costs of cover for negligence claims. Local medical academic and trade journals are increasingly addressing the issue: the whys, the consequences, and possible solutions.[1-4] Although there are regular newspaper headlines and articles on litigation costs, seldom if ever does an article in the lay press address the consequences of increasing medical negligence litigation. Is the public unknowingly sleep-walking into a dystopian future with regard to obstetrics, spinal surgery, neurosurgery and neonatology? Claims costs depend on the number of claims, the value of those claims, and legal costs.[5] In South Africa (SA), all have increased in recent years. Improved but expensive and sophisticated care has considerably extended life expectancy for extremely compromised patients. Generally speaking, the worse the injury and the longer the survival, the more the costs of care. Those specialties where injuries may be the most severe and survival is likely to be the longest are at greatest risk of extremely high claims; indemnity costs for this group are therefore the highest. It is not surprising, then, that the costs of liability cover for those offering obstetric and neonatal care, spinal surgery and neurosurgery are high and have been increasing rapidly. Is this a matter that is restricted to obstetricians, spinal surgeons, neurosurgeons or neonatologists in private practice, affecting the income of these specialists, or are there broader issues? While not restricted to these high-risk specialties, there is a tendency for doctors in the current medicolegal environment to practise defensively in an attempt to diminish their medicolegal risk. Defensive medicine is not without its problems, including unnecessary increased costs, the risk attendant to the tests themselves and undue anxiety, to name but a few. In saving on indemnity costs, some doctors may consider practising without any cover. However, they would be poorly advised to do so, because although an individual may be at a relatively low risk of being claimed against, a single claim, even successfully defended, may ruin them financially.[6] Additionally, there is the question about the ethics of being unindemnified, as deserving patients could be inadequately compensated. Furthermore, it is unlikely that any hospital group would knowingly allow a doctor without adequate indemnity or insurance to practise in a high-risk specialty at one of their hospitals, as claimant lawyers would undoubtedly try to shift the liability onto the hospital group. The deterioration in claims experience and the impact it has on increasing indemnity costs have impacted on careers across the spectrum of high-risk specialties, and concerns have been raised with regard to recruiting new candidates.[7] Recently qualified specialists may decide that local private practice is unsustainable and remain in state practice (a positive), or leave the country, exacerbating the shortage of doctors, to say nothing of losing the money spent on training them. Established practitioners may either change their practice or retire earlier than anticipated, sometimes directing their attention to medicolegal work and aggravating the situation. A numerically small but extremely important specialty such as neurosurgery is particularly vulnerable to these changes.[8,9]
Orthopaedics
Doctors who operate as a group are more at risk of litigation than those who do not, and orthopaedic surgery is no exception;
752
indeed, they are at relatively high risk even within the context of surgery. Spinal surgery, however, is more expensive to cover as the complications tend to be severe and expensive to compensate. As performing spinal surgery is not universal among orthopaedic surgeons, it would be unfair to expect them all to cover the associated risks and liabilities. An orthopaedic surgeon who performs spinal surgery therefore pays more for cover than one who does not. Initially the difference was relatively modest – a small percentage of the nonspinal rate. Owing to the rapid deterioration in claims experience, the difference has now increased to such an extent that the difference alone is a multiple of the standard orthopaedic rate. Increasing indemnity costs are already negatively impacting on the orthopaedic spinal surgical community. The differential cost of cover between general orthopaedics, with and without spinal cover, has forced many orthopaedic surgeons to reconsider continuing to perform spinal surgery. This trend is manifested by many resignations of orthopaedic surgeons from the South African Spine Society, citing this very reason. Traditionally, general orthopaedic surgeons would perform the fusion component of spine surgery while operating with a neurosurgical colleague performing the decompressive work. This allowed spinal surgery to function in the smaller cities and towns where there may have been no dedicated spine surgeons. The revenue generated by these procedures often no longer compensates for the additional indemnity cost and risk, resulting in orthopaedic surgeons being unwilling or unable to provide this service. Often the local neurosurgeon is not trained in fusion surgery, with the result that surgery requiring stabilisation is no longer possible outside big cities. Although some may argue that forcing this surgery to the bigger centres and high-volume dedicated spine surgeons is not a bad thing, it disrupts the trauma environment. Spinal trauma frequently presents in smaller towns as a result of high-speed motor vehicle accidents, and there is now paucity of cover. The unindemnified orthopaedic surgeon is reluctant to assess the patient based on the attendant risk; historically neurosurgeons have little to no spine trauma training. This indemnity cost therefore has a direct impact in terms of reducing patient care.
Neurosurgery
Neurosurgery faces the ‘perfect storm’ of a numerically small specialty facing high medicolegal risk.[9] While the majority of a private neurosurgeon’s operative caseload is adult spinal surgery (which is certainly reflected in their medicolegal risk profile), neurosurgeons also play an important and much broader role in the overall medical community.[9] For example, a private neurosurgeon also treats a wide range of common ailments, many of which are life- or functionthreatening conditions such as traumatic brain injury, stroke or brain tumours.[8,9] Paediatric neurosurgery may be a harbinger of the future. Although society may consider children to be its most precious benisons, this doesn’t translate into expenditure on medical care, with paediatric disciplines typically being ‘loss leaders’ for private hospitals. Remuneration for paediatric surgical procedures often lags far behind that for adult degenerative conditions, to the extent that a private practice limited exclusively to paediatric neurosurgery is unsustainable. Until recently, only three full-time paediatric neurosurgeons in our country offered care to a limited number of highly complex cases from the private sector, but the cost of
November 2014, Vol. 104, No. 11
EDITORIAL
liability cover rendered this unviable. At present, specific paediatric neurosurgery expertise is only available at Red Cross War Memorial Children’s Hospital in Cape Town, where the mismatch between operative time and workload now precludes acceptance of patients from the private sector.
Neonatology
Indemnity costs for paediatricians working with neonates have started to rise. Paediatricians are now being drawn into cerebral palsy claims where had the neonatal care not allegedly been negligent the outcome would have been better. Any neonatal work already increases the cost of cover for a paediatrician by a multiple of the basic paediatric rate. Retinopathy of prematurity claims are high claims, and often involve paediatricians performing neonatal work; ophthalmologists are also increasingly being drawn in. If the cost of covering ophthalmologists who perform neonatal work escalates substantially, ophthalmologists may decline to become involved in the care of these children.
Obstetrics
Obstetrics is the area where the problem and the consequences are most acute. In the absence of definitive intervention, it is not alarmist to ask who will perform private deliveries by the end of the decade.[10,11] Women will continue to fall pregnant and require delivery, but where will those 100 000-plus deliveries occur? If private obstetricians are unwilling to deliver them, or precluded from doing so, patients will have to deliver in state facilities. Private parturients are unlikely to be enamoured by state hospitals, and the already busy state facilities will be confronted with an increased workload of demanding patients. There is an additional cost burden for the state, as not only will they have to provide the facilities for the extra deliveries, but there will also be a shift of the liability burden for these patients. If and when these patients sue, they will now sue the state. As well as the inconvenience of having to deliver in busier labour wards, state patients will be further disadvantaged, as money allocated to the state’s health budget includes provision for litigation. Every rand lost to litigation is a rand lost from state healthcare – money set aside for the care of indigent patients. Significant inflation in the cost of cover for obstetrics has spread further than those performing deliveries. Advances in obstetric ultrasound have enabled identification of fetal anomalies, some of which may lead to severe disabilities.[12] Missing such a case deprives the parents of the opportunity to consider termination of pregnancy. If such a child is delivered and the parents did not have the chance to consider termination, they may sue to cover the costs of the care of the child. Claims for missed abnormalities are emerging as a group that is potentially as expensive a liability as cerebral palsy claims, and this has led to a substantial increase in the cover for obstetric ultrasound. Few non-obstetricians can justify the cost of cover for fetal scanning, thus limiting patients’ access to obstetric scanning, and particularly access for those patients living outside urban areas.
What’s next?
So what could the dystopian future entail? Fewer specialists in highrisk specialties, with those remaining practising defensive medicine. An absence, or severe curtailing, of private specialist obstetric care. Paediatricians and ophthalmologists reluctant to manage neonates.
753
Fewer neurosurgeons in private practice, fewer still with a primary interest in anything other than spinal surgery, and all restricted to the larger urban areas. Likewise few, if any, spinal surgery services outside major urban areas. The problem is not restricted to the private arena, as those patients would now have to be treated in state facilities. Not only are these facilities already busy, but private patients would have to compete for resources and their medicolegal liabilities would move across to the state. Clearly the issue is far broader than merely affecting the income of doctors in these high-risk specialties. Private patients, private providers, public patients, public providers, politicians and policy pundits all have a vested interest in resolving the problem. The medical profession cannot resolve the issues alone. There is not a medical answer – it has to enter the public debate. Conflict of interest. GRH is a full-time employee of the Medical Protection Society (MPS). The MPS is not an insurance company but a non-profit mutual organisation.
G R Howarth Head of Medical Services – Africa, Medical Protection Society, 2 Victoria House, Victoria Place, Leeds, UK B Goolab President, South African Society of Obstetrics and Gynaecology; Department of Obstetrics and Gynaecology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa R N Dunn Pieter Moll and Nuffield Chair of Orthopaedic Surgery, Department of Orthopaedic Surgery, Faculty of Health Sciences, University of Cape Town, South Africa A G Fieggen Professor and Head, Division of Neurosurgery, Faculty of Health Sciences, University of Cape Town, South Africa Corresponding author: G R Howarth (graham.howarth@mps.org.uk) 1. Pepper MS, Slabbert MN. Is South Africa on the verge of a medical malpractice litigation storm? South African Journal of Bioethics and Law 2011;4(1):29-35. 2. Malherbe J. Counting the cost: The consequences of increased medical practice litigation. S Afr Med J 2013;103(2):83-84. [http://dx.doi.org/10.7196/SAMJ.6457] 3. Medical litigation: A national health crisis requiring urgent solutions. Medical Chronicle November 2011. http://www.medicalchronicle.co.za/medical-litigation-a-national-health-crisis-requiring-urgentsolutions/ (accessed 1 September 2014). 4. Obstetric noose tightens. Medical Chronicle April 2014. http://medicalchronicle.co.za/magazine/2014/ April/MC%20April/ (accessed 1 September 2014). 5. Bateman C. Medical negligence pay-outs soar by 132% – subs follow. S Afr Med J 2011;101(4):216-217. 6. Howarth GR, Bown S. The importance of comprehensive protection in today’s healthcare environment. S Afr Med J 2013;103(7):453-454. [http://dx.doi.org/10.7196/SAMJ.7106] 7. Koller AB (as SASOG President). Letter to the Minister of Health regarding the consequences of increasing litigation. 25 April 2011. 8. Fieggen G. What can a neurosurgeon do for you? CME 2013;31(3):74. 9. Fieggen G. Neurosurgery in South Africa. S Afr Med J 2014;104(4):254. [http://dx.doi.org/10.7196/ SAMJ.8213] 10. Howarth GR. Obstetric risk avoidance: Will anyone be offering obstetrics in private practice by the end of the decade? S Afr Med J 2013;103(8):513-514. [http://dx.doi.org/10.7196/SAMJ.7233] 11. Howarth GR, Carstens P. Can private obstetric care be saved in South Africa? South African Journal of Bioethics and Law (in press). 12. Howarth GR. Obstetric ultrasound – its risks and the cost of addressing them. South African Journal of Radiology 2013;17(3):98-99. [http://dx.doi.org/10.4102/sajr.v17i3.274]
S Afr Med J 2014;104(11):752-753. DOI:10.7196/SAMJ.8568
November 2014, Vol. 104, No. 11
EDITORIAL
Ebola virus disease in West Africa – South African perspectives The outbreak of Ebola virus disease (EVD) in West Africa has been raging for nearly a year at the time of writing. The likely index case of the outbreak was a 2-year-old child who died on 6 December 2013, having acquired the infection late in November 2013, although the outbreak was only formally announced in March 2014.[1] On 13 October 2014, a total of 8 400 suspected and confirmed cases of EVD, culminating in more than 4 000 deaths, has been reported.[2] This case count is nearly three times the total number of cases of EVD reported in 20 earlier outbreaks from 1976 to 2013. Although it may seem logical to believe that the present virus has mutated to become more lethal and transmissible since previous outbreaks, this epidemic is widely recognised to be fuelled by socioeconomic and public health-related issues that have complicated conventional containment efforts.[3-5] Full genome characterisation of Ebola virus isolates from Guinea and Sierra Leone has revealed that they are Zaire ebolavirus.[1,6] This strain has been associated with haemorrhagic fever outbreaks in central African countries since 1976, with case fatality rates of up to 90%. The current fatality rate is estimated to be between 60% and 70%; describing it as ‘the most lethal outbreak of EVD to date’ therefore relates more to the scale of the epidemic than the actual death rate.[7] In recent months, nations worldwide have been bolstering their capacity to detect and manage EVD. Although the outbreak remains largely confined to Guinea, Liberia and Sierra Leone, the exportation of EVD to Nigeria in July 2014 has fuelled international fears of further spread beyond the affected countries in West Africa. In retrospect, with the outbreak nearing the one-year time mark, only four cases of EVD have been introduced to countries outside Guinea, Liberia and Sierra Leone, of which three resulted in transmission to secondary cases.[2] The outbreak in Nigeria affected healthcare workers in contact with a patient who travelled to Lagos from Liberia. A total of 20 cases (19 confirmed) were reported, with no additional ones since 5 September. A case of EVD was confirmed in Dakar, Senegal, involving a Guinean national who travelled via bus to the city, with no secondary cases. All those linked to the EVD cases in Nigeria and Senegal have completed a 21-day follow-up period, so it may be reasonable to assume adequate containment of the outbreak in these countries. In September 2014, a patient travelling from Liberia (where he tended to sick family members) to the USA was diagnosed and hospitalised for EVD. To date, two additional cases of EVD have been noted in nurses who tended to this patient. Likewise, there has been a secondary infection involving a nurse who cared for a patient evacuated for treatment of EVD in Spain. These cases have highlighted some weaknesses in response to EVD in West Africa – for example, the cases that introduced EVD to Nigeria and the USA were known contacts of EVD patients in Liberia, and should have been prohibited from travelling in the first place. Nevertheless, it is clear that systems are available for the detection of EVD, at least in these countries affected by the importation of EVD, and the responses are reassuring in that these outbreaks were contained, as was the case in Nigeria. The exportation of cases has coincided with the explosion of EVD in Liberia and Sierra Leone. On 2 July 2014, there was a cumulative total of 759 reported cases from the three affected countries. This total rose to 1 323 on 31 July, 3 069 on 28 August, and 8 400 in early October. It is reasonable to believe that the risk of exporting the disease will continue to rise as the epidemic evolves in these countries and containment measures struggle to keep up with it.
754
How does South Africa (SA) measure up to the challenge of responding to imported cases? A review of SA’s track record in dealing with imported cases of haemorrhagic fever and rapid containment of these infections may provide some degree of reassurance. The first importation of haemorrhagic fever to SA was in 1975. The case involved an Australian backpacker who travelled from Zimbabwe (then Rhodesia) to SA. The cause of death was Marburg virus disease, and two secondary cases (neither fatal) were identified and managed.[8] In 1996, a Gabonese doctor working with EVD patients during an outbreak in Gabon fell ill, travelled to SA and presented to a Johannesburg hospital. The patient did not reveal his connections to the EVD outbreak and was discharged from hospital undiagnosed. When a nurse involved in his management presented with signs and symptoms of haemorrhagic fever, laboratory and epidemiological investigations indicated EVD as the cause of her death. [9] In 2007, a Nigerian doctor was evacuated to SA for medical treatment and admitted to a Pretoria hospital with a presumptive diagnosis of complicated typhoid fever. Upon admission, the risk of viral haemorrhagic fever was recognised. Immediate isolation and rapid laboratory confirmation of Lassa fever ensued. The outcome was fatal, but the infection was contained and no secondary cases occurred. In 2008, an SA expatriate living in Zambia was evacuated to SA for medical treatment, and died without a definitive diagnosis. When a contact presented with a similar clinical picture within 2 weeks of the death of the first patient, the possibility of a viral haemorrhagic fever was followed up. Within a 3-week period, three further cases were recognised. Initial specific laboratory testing was confounding and provided limited insights. Nevertheless, isolation procedures and contact tracing were followed, and the total case tally was limited to five (including the index case). Intensive laboratory investigation attributed the outbreak to a novel arenavirus, dubbed ‘Lujo’ (i.e. Lusaka-Johannesburg) virus.[10] SA’s capacity to deal with haemorrhagic fever cases has developed against the backdrop of endemic Crimean-Congo haemorrhagic fever (CCHF). Since it was originally diagnosed in SA in 1981, nearly 200 cases have been recognised and managed at various hospitals and confirmed by specialised laboratory testing at the National Institute for Communicable Diseases (NICD).[11] Each of these cases has involved isolation management and intensive case tracing and monitoring. Apart from two small nosocomial outbreaks and one secondary case of CCHF in a laboratory worker, cases have not resulted in secondary spread.[12,13] Importantly, the NICD has the only biosafety level 4 laboratory in Africa, a facility with established experience in dealing with haemorrhagic fever viruses.[9-11] Notably, this facility and all other core work at the NICD is in fact funded directly by the National Health Laboratory Service and the National Department of Health (NDoH), and not through external funding as was recently suggested in the SAMJ.[14] Similarly, the NICD has been at the forefront of supporting laboratory diagnostics for EVD by deployment of a staffed mobile laboratory to Sierra Leone, which too is funded by the NDoH. In an interconnected world, while any country runs the risk of importation of EVD, the risk of a community outbreak will be low if the index case is recognised early and appropriate infection prevention and control measures are applied. SA is well prepared for the possibility of imported EVD, including traveller health screening at entry points and training of air, sea and land port health staff. There are 11 designated public sector health facilities (at least one in each province), with staff trained and provided with personal
November 2014, Vol. 104, No. 11
EDITORIAL
protective equipment, but realistically, we must understand that patients may arrive at any hospital or clinic. The most important factor is early recognition of potential cases and especially protection of front-line health workers, who are the most vulnerable. In patients with unexplained acute febrile illness, a history of travel involving the three affected countries, together with the likelihood of exposure to blood and body fluids of ill persons, should raise the suspicion of EVD. There would seem to be high awareness of EVD among health practitioners in SA, fuelled by intense publicity from West Africa. Malaria remains the commonest cause of febrile illness in travellers for whom Ebola virus testing has been requested of the NICD. It is important that the threshold for laboratory testing be at a level that provides a degree of confidence and assurance to health workers, while balancing the absolute need for accurate histories, exclusion and management of other common infectious diseases, and unnecessary testing and waste of expensive resources. At this stage it is not possible to predict either a timeline or number of cases as the outbreak continues unabated in Guinea, Sierra Leone and Liberia. Safety and efficacy trials of experimental vaccines are currently in progress. The value of experimental therapeutic agents such as monoclonal antibodies (ZMapp) remains unclear, and convalescent sera have been used with some success on a limited number of cases. While measures to prevent the introduction of EVD into countries are important, the focus has to be on ensuring an accelerated, co-ordinated and intense international response, using well-tried methods to break the chain of transmission in the three affected countries, where a humanitarian, health and economic disaster is unfolding. It is important, however, not to lose sight of other high-burden communicable diseases that continue to exact a far greater annual toll on the African continent, including millions of deaths annually from HIV, tuberculosis, malaria, pneumonia and diarrhoeal diseases, even as Ebola captures the headlines. The public health response to the Ebola outbreak must be used to strengthen surveillance and response to other communicable disease threats.
Acknowledgement. The authors thank Prof. John Frean for his expertise and advice in preparation of this editorial.
Jacqueline Weyer Centre for Emerging and Zoonotic Diseases, National Institute for Communicable Diseases, National Health Laboratory Service, Sandringham, Johannesburg, South Africa Lucille H Blumberg Division for Surveillance and Outbreak Response, National Institute for Communicable Diseases, National Health Laboratory Service, Sandringham, Johannesburg, South Africa Corresponding author: L H Blumberg (lucilleb@nicd.ac.za) 1. Baize S, Pannetier D, Oestereich L, et al. Emergence of Zaire Ebola virus disease in Guinea – preliminary report. N Engl J Med 2014;371(15):1418-1425. [http://dx.doi.org/10.1056/NEJMoa1404505] 2. Centers for Disease Control and Prevention. 2014 Ebola outbreak West Africa. http://www.cdc.gov/ vhf/ebola/outbreaks/2014-west-africa/index.html (accessed 14 October 2014). 3. Weyer J, Blumberg LH, Paweska JT. Ebola virus disease in West Africa – an unprecedented outbreak. S Afr Med J 2014;104(8):555-556. [http://dx.doi.org/10.7196/SAMJ.8672] 4. Fauci AS. Ebola – underscoring the global disparities in health care resources. N Engl J Med 2014;371(12):1084-1086. [http://dx.doi.org/10.1056/NEJMp1409494] 5. Chan M. Ebola virus disease in West Africa – no early end to the outbreak. N Engl J Med 2014;371(13):1183-1185. [http://dx.doi.org/10.1056./NEJMp1490859] 6. Gire SK, Goba A, Andersen KG, et al. Genomic surveillance elucidates Ebola virus origin and transmission during the 2014 outbreak. Science 2014;345(6202):1369-1372. [http://dx.doi.org/10.1126/science.1259657] 7. Kucharski AJ, Edmunds WH. Case fatality rate for Ebola virus disease in West Africa. Lancet 2014;384(9950):1260. [http://dx.doi.org/10.1016/S0140-6736(14)61706-2] 8. Gear JSS, Cassel GA, Gear AJ, et al. Outbreak of Marburg virus disease in Johannesburg. BMJ 1975;4:489-493. 9. Richards GA, Murphy SRN, Jobson R. Unexpected Ebola virus in tertiary setting: Clinical and epidemiological aspects. Crit Care Med 2000;28(1):240-244. [http://dx.doi.org/10.1097/00003246200001000-00041] 10. Paweska JT, Sewlall NH, Kziasek TJ, et al. Nosocomial outbreak of novel arenavirus infection, southern Africa. Emerg Infect Dis 2009;15(10):1598-1602. [http://dx.doi.org/10.3201/eid1510.090211] 11. Kemp A, Msimang V, Weyer J, Paweska JT. Crimean-Congo haemorrhagic fever and tick bite fever in South Africa, 2012-2014. National Institute for Communicable Diseases, Infectious Diseases Bulletin 2014;12(3):59-62. 12. Van Eeden PJ, Joubert JR, van de Wal BW, et al. A nosocomial outbreak of Crimean-Congo haemorrhagic fever at Tygerberg Hospital. Part I: Clinical features. S Afr Med J 1985;68(10):711-717. 13. Van Eeden PJ, van Eeden SF, Joubert SF, et al. A nosocomial outbreak of Crimean-Congo haemorrhagic fever at Tygerberg Hospital. Part II: Patient management. S Afr Med J 1985;68(10):718-721. 14. Bateman C. Ebola: SA has no outbreak ‘laurels’ to rest on. S Afr Med J 2014;104(10):653-655. [http:// dx.doi.org/10.7196/SAMJ.8894]
S Afr Med J 2014;104(11):754-755. DOI:10.7196/SAMJ.9045
Compensation for research injuries: Thoughts from a human research ethics committee chair The Venter case for research injury compensation following a clinical trial[1] is the first I am aware of in South African (SA) courts during my service on research ethics committees (RECs) since 1974. Moreover, of the several thousand clinical trials approved in the past 40 years by the Human Research Ethics Committee (Medical) at the University of the Witwatersrand, there has been only one claim for compensation for a research injury of an enduring nature. In this case, about a decade ago, a participant in a clinical trial developed idiopathic hypertension; the sponsor agreed that this was trial related, and has provided long-term care for the hypertension without a need to approach the courts. With this limited knowledge I did an online search for court cases for compensation due to research injury, particularly during clinical trials under the Association of the British Pharmaceutical Industry (ABPI) guidelines.[2] My search was disappointing because the outcome was swamped with claims
755
associated with medical ‘negligence’; linkage to clinical trials and the ABPI guidelines was hidden, if present at all. However, one case in the UK involving the ABPI guidelines (Wyle vs Grosset Greater Glasgow Health Board 2011 CSOH 89) was mentioned in the Venter judgement. This limited compensation to ‘appropriate medical treatment’.[3] Section 10 of the Declaration of Helsinki 2013[4] states that ‘Appropriate compensation and treatment for subjects who are harmed as a result of participating in research must be ensured.’ Under this principle, what types of compensation are available in different countries? I found so much variation between and within countries that it would be impossible to discuss this in an editorial, or even a full article. However, a recent report from the US Presidential Commission for the Study of Bioethical Issues,[5] which has two summary appendices listing compensation methods in four US federal agencies and 45 ‘international and transnational requirements’, is useful.
November 2014, Vol. 104, No. 11
EDITORIAL
A US federal agency that supports much research in SA is the National Institutes of Health (NIH). For in-house research, ‘the Clinical Centre of the NIH will provide short-term medical care … In general, no long-term medical care or financial compensation for research-related injuries will be provided …’[5] Those serving on RECs in SA will be familiar with the absence of research injury compensation in NIH-sponsored research, something challenged by SA REC chairs in 2006.[6] In fact, little has changed since 20 years ago, when it was reported that in the USA ‘there is no comprehensive program to cover injuries resulting from privately and publically funded research’.[7] Is alteration in research injury compensation policy also slow in the USA outside the federal system? Resnik et al.[8] looked for change in compensation policy over a decade by secondary analysis of data sets from surveys in US research institutions in 2002 (N=127) and 2012 (N=169). There was minimal change in compensation policies, the percentage without compensation (including treatment) being 56.1% in 2000 and 51.2% in 2012. Importantly, Resnik et al.[8] noted that a ‘significant percentage of policies contain language that can reasonably interpreted as waiving, or appearing to waive, legal rights’. Examination of the summaries of the 45 international requirements listed in the Commission’s report[5] shows that 62% require insurance, 36% want treatment to be provided for a research injury, 20% offer economic compensation, 13% indemnify researchers and sponsors, 11% have vague statements that compensation is needed, and only 1% offer both treatment and economic compensation as stated by the Declaration of Helsinki.[5] None of the requirement summaries mention quantum of compensation, which is not surprising. It is a complex and difficult matter, since variables to be considered include who should be compensated, for what (will known complications be excluded?), by whom, at what quantum, and who will decide. For the latter, Denmark, Finland and New Zealand cite general laws and government bodies dealing with compensation that would be used.[5] Collaboration between legal experts, bioethicists, clinicians and insurers will be necessary. The current Presidential Commission[5] noted that ‘Almost all other developed nations have instituted policies to require treatment, or compensation for treatment, for injuries suffered by research subjects.’ The Commission acknowledged past recommendations by presidentially appointed bioethics commissions and other groups for the USA to establish federal compensation policies, and the lack of progress in fulfilling this. In the absence of these policies, local researchers in Africa rely on insurance during NIH-sponsored HIV/AIDS clinical trials. [9] The current Commission report advised a cautious, systematic approach towards establishment of policies.[5] There is no reason to believe that change of compensation requirements in SA would not follow a similar slow course.
756
Strode and Singh[1] believe that ‘RECs … protect the rights and welfare of research participants by carefully reviewing compen sation clauses in informed-consent documents.’ I agree. Since change in compensation policy in our country is likely to take time to fulfil the requirements of the Declaration of Helsinki,[4] what should RECs do now? My view is that potential participants need to have a better understanding of the ABPI-based compen sation policy. What happens at present is that late in an information sheet, perhaps in the last few of many pages, there is a paragraph or two that describes compensation available from the sponsor, under certain conditions including the ABPI guidelines, should there be a trial-related injury. Included is a statement that ‘this does not affect the right of a participant to pursue a legal remedy in respect of injury alleged to have been suffered as a result of participation’.[10] This is surely similar to the confusing language found in the USA by Resnik et al.[8] What some sponsors have been saying in recent times seems clearer to me, namely that a participant’s right to claim for compensation is not affected, but negligence must be proven. Whatever information on compensation is provided to a potential participant in a clinical trial information sheet, my belief is that it should be on a separate page requiring a signature and preferably combined with questioning to ensure that the potential participant understands it. Perhaps this should be in the front of an informed consent form, which would certainly help RECs reviewing an application, as well as the potential participant. Peter Cleaton-Jones Chair, Human Research Ethics Committee (Medical), University of the Witwatersrand, Johannesburg, South Africa Corresponding author: P Cleaton-Jones (peter.cleaton-jones@wits.ac.za) 1. Strode A, Singh PP. Compensation for research-related harm: The implications of Venter v Roche Products (Pty) Limited and Others for research ethics committees. S Afr Med J 2014;104(11):759-761. [http://dx.doi.org/10.7196/SAMJ.8596] 2. Clinical Trial Compensation Guidelines. The Association of the British Pharmaceutical Industry. 1994. http://www.abpi.org.uk/our-work/library/guidelines/Pages/ct-compensation.aspx (accessed 18 August 2014). 3. Venter vs Roche Products (Pty) Limited and Others (case no. 12285/08). 4. Declaration of Helsinki 2013. http://www.wma.net/en/30publications/10policies/b3/ (accessed 7 January 2014). 5. Presidential Commission for the Study of Bioethical Issues. Moral Science Protecting Participants in Human Subjects Research. Updated version June 2012. http://www.bioethics.gov (accessed 21 August 2014). 6. Cleaton-Jones P, Wassenaar D, Hammann E, et al. Research injury in clinical trials in South Africa. Lancet 2006;367(9509):458-459. [http://dx.doi.org/10.1016/S0140-6736(06)68158-0] 7. Institute of Medicine. Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies, Vol. 1. Washington, DC: National Academies Press, 1994:243. http://www.nap.edu/ openbook.php%record_id=2304&page=243 (accessed 22 August 2014). 8. Resnik DB, Parasidis E, Carroll K, Evans JM, Pike ER, Kissling GE. Research-related injury compensation policies of US research institutions. IRB 2014;36(1):12-19. http://www.ncbi.nlm.gov/ pubmed/24649739 (accessed 18 August 2014). 9. Mamotte N, Wassenaar D, Singh N. compensation for research-related injury in NIH-sponsored HIV/AIDS clinical trials in Africa. J Empir Res Hum Res Ethics 2013;8(1):45-54. [http://dx.doi.org/10.1525/jer.2013.8.1.45] 10. 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, 2006:43.
S Afr Med J 2014;104(11):755-756. DOI:10.7196/SAMJ.8939
November 2014, Vol. 104, No. 11
EDITORIAL
Who will guard the guards? Medical leadership and conflict of interest in South African healthcare The pharmaceutical industry has filled a vacuum. A few decades ago, medical leaders would set research directions and would lobby for products to treat problems faced by their patients. Today, in an era of disease mongering and priority setting by pharmaceutical firms, leaders often react to industry rather than setting clear priorities in worthwhile diagnostic and therapeutic spend. Conflict of interest (COI) may cause harm if it influences the quality of patient care, the integrity of research, the objectivity of education, or community trust in healthcare.[1] There is a need for transformational medical leadership[2] that unifies followers, restores professionalism and takes back control of the direction and purpose of medical care. We aim to raise awareness of COI issues that may have been incompletely explored during medical training, including some tactics used by the pharmaceutical industry to influence thought leaders.
What is COI?
COI happens if the interests of clinicians do not align with those of their patients.[3] More broadly, it is a condition where professional judgement in a primary interest may be unduly influenced by a secondary interest. It is a set of conditions rather than an established behaviour,[4] in that it identifies potential for harm rather than making a judgement of established wrong-doing.[5] Harm occurs if conditions fostering a conflict in loyalties translate into a biased decision. COI will always be present when healthcare is practised as a marketable commodity.[6] Healthcare provision differs from other financial transactions in that there is both asymmetry of information and patient vulnerability. Patients struggle to balance benefit and harm, many decisions are urgent, and decisions may have lasting and very personal physical consequences. Patients trust the skill and integrity of clinicians, and this is reflected in societal respect for professional status and clinical autonomy.[7] However, erosion of this trust may be increasing, although changes happening over decades are difficult to measure. In the USA, polls during the last quarter of the 20th century reflect a 20 - 30% reduction in public faith in the authority of medicine.[8]
Manifestations of COI
Revelations of conflicts leading to serious patient harms have renewed public interest in managing COI. Many of these revelations arose not so much from directed research but from public disclosures as part of legal proceedings against the pharmaceutical industry.[9] Further stimulus may have been from a flurry of books covering aspects of pharmaceutical company influence[10-12] and a website designed to document some of these influences.[13]
Key opinion leaders
Key opinion leaders (KOLs, ‘thought leaders’) are identified by the pharmaceutical industry as clinicians who are regularly asked for advice by colleagues, often speak at conferences, have a good publication record, consider themselves early adopters of new treatments, and assist in guideline development.[14] There is an ‘influence cascade’ of KOLs, starting with an international panel of advisory board members brought together strategically early in the
757
product development cycle. These link to national and then local KOLs, with the performance and market worth of the latter being assessed by influence on prescription numbers.[15] KOLs are nurtured by pharmaceutical manufacturers, with a sub-industry devoted to their selection, as stated on one website: ‘With centers of excellence assessments we take a drill-down approach, starting at the academic medical centers, then moving into affiliated hospitals and clinics, and, finally, providing identification and in-depth analysis of significant affiliated physicians in educational and clinical roles.’[16] Some companies have developed software to aid in thought-leader selection, and also use social network analysis.[17] KOLs influence practice, with a Cochrane review finding that they contributed to a 12% overall improvement in compliance with clinical practice guidelines.[18]
Gifting
Clinicians generally do not think that small gifts influence their own behaviour, but are less charitable about the effect on their colleagues. A study in 2001 revealed that 61% of doctors thought they would not be influenced personally, but the same individuals thought that only 16% of their colleagues would remain uninfluenced.[19] Even small gifts have an effect – raters who denied conscious awareness of influence scored artwork higher if accompanied by the logo of the group subsidising their participation in the trial, and accompanying magnetic resonance images showed clear evidence of increased venteromedial prefrontal cortex activity (an area considered to influence preference judgements).[20]
Ghost writing
This happens when an individual writes a portion of a manuscript but is not listed as an author or contributor. Ghost writing is an industry in its own right,[21] and writers may be contracted by the pharmaceutical industry to prepare a manuscript for publication as part of a process organised by ‘publication planners’ employed by medical education and communication companies. Such articles may then be gifted to KOLs to ‘assist’ with final editing.[22] A study comparing protocols approved by the Scientific-Ethical Committee for Copenhagen and Frederiksberg with the corresponding publications of industry-initiated trials found evidence of ghost authorship in 75% (95% confidence interval (CI) 60 - 87%).[23]
Impact of COI
Evidence of the impact of marketing on patient-level outcomes is still scanty, but it does influence prescribing and doctors’ attit udes.[24] There is clear evidence that the position of opinion leaders may correlate with industry affiliation. A recent systematic review of positions taken on the safety of rosiglitazone in the wake of reports questioning its cardiovascular harms found a rate ratio of 3.36 (95% CI 1.94 - 5.83) in support of the agent in those with financial COI compared with those without. Nearly a quarter of these articles with authors with COI did not disclose this, with 3.3% actively declaring no COI when one did in fact exist.[25]
Interventions for dealing with COI Disclosure
Much of the information on the effect of disclosure is derived from social science experiments on university student volunteers.
November 2014, Vol. 104, No. 11
EDITORIAL
There is little work on clinicians. What evidence there is suggests that declaration does exactly the opposite of what is intended, and enhances the effect of bias. Reasons for this include insinuation anxiety (‘burden of disclosure’ – if you don’t take the advice of somebody who has declared a potential COI, it is impolite because it implies that you believe that such conflict really exists), inadequate discounting[26] by recipients of the COI information with no independent measure of truth, moral licensing (‘I have told you I am biased, now I can really exaggerate to compensate for your expected reaction’ – i.e. ‘strategic exaggeration’), and the panhandler effect[27] (‘Now that I have told you about my financial interests, don’t you feel obliged to help me make a bit of money here?’). The 2010 US Physician Payments Sunshine Act requires that payers report any payment of more than $10, including meals, entertainment, consultancy fees, speaker payments, research grants and stock options. This Act was implemented in 2013, but earlier reports of disclosure are somewhat disheartening – for example, one study looking at clinicians receiving more than $100 000 per annum from industry found that nearly a quarter of their publications failed to declare this conflict.[28]
Creating awareness
In the face of evidence that self-awareness of conflict is usually inadequate, a structured non-punitive and nationally consistent approach to recognising and handling COI should be seen as integral to both undergraduate and postgraduate medical education.
Academic counter-detailing
Although this has statutory funding in both the USA and Canada, there is as yet little evidence that it can compete against the marketing might of the industry in its own right. A change in mindset might be helpful. If, for instance, in all local conferences there was a unanimous and consistent call for evidence-based and unconflicted debate, this might allow a culture of true academic review to be reborn.
Fostering professionalism
This has evolved from being seen as an innate characteristic to being measurable as a series of observable behaviours – being ‘in service’ to patients, demonstrating integrity and accountability, pursuing clinical excellence, and practising fair and ethical stewardship of healthcare resources.[29] This approach disaggregates professionalism into separate competencies that clinicians should continue to develop over time and includes a specific recommendation that potential conflicts of interest should be actively managed.
Conclusion
In the absence of good leadership, we will remain in perpetual conflict between the aim of best serving our patients and the desire to remain funded by a profit-driven industry. Clinicians who recognise and manage conflict of interest are better equipped to lead the profession on a more impartial and patient-centred course. Colleagues, funders and patients should feel confident that decision makers and opinion leaders make evidence-based decisions without pecuniary or other conflicts.
758
Andy Parrish Department of Internal Medicine, Frere and Cecilia Makiwane hospitals, East London, Eastern Cape, South Africa Marc Blockman Department of Internal Medicine, Division of Clinical Pharmacology, Faculty of Health Sciences, Groote Schuur Hospital and University of Cape Town, South Africa Corresponding author: A Parrish (andygp@mweb.co.za) 1. Lo B, Field MJ. Conflict of Interest in Medical Research, Education, and Practice. National Academies Press, 2009. http://www.nap.edu/catalog.php?record_id=12598 (accessed 30 May 2014). 2. Aarons GA. Transformational and transactional leadership: Association with attitudes towards evidence-based practice. Psychiatr Serv 2006;56(8):1162-1169. [http://dx.doi.org/10.1176/appi. ps.57.8.1162] 3. Tonelli MR. Conflict of interest in clinical practice. Chest 2007;132(2):664-670. [http://dx.doi. org/10.1378/chest.07-0315] 4. Thompson DF. Understanding financial conflicts of interest. N Engl J Med 1993;329(8):573-576. [http://dx.doi.org/10.1056/NEJM199308193290812] 5. Smith R. Conflicts of interest: How money clouds objectivity. J Royal Soc Med 2006;99(6):292-297. [http://dx.doi.org/10.1258/jrsm.99.6.292] 6. Nguyen H. The principal-agent problems in health care: Evidence from prescribing patterns of private providers in Vietnam. Health Policy Plan 2011;26(Suppl 1):i53-i62. [http://dx.doi.org/10.1093/heapol/czr028] 7. Clark CC. Trust in medicine. J Med Philos 2002;27(1):11-29. [http://dx.doi.org/10.1076/ jmep.27.1.11.2975] 8. Schlesinger M. A loss of faith: The sources of reduced political legitimacy for the American medical profession. Milbank Q 2002;80(2):185-235. [http://dx.doi.org/10.1111/1468-0009.t01-1-00010] 9. Steinman MA, Bero LA, Chren MM, Landefeld CS. Narrative Review: The promotion of gabapentin: An analysis of internal industry documents. Ann Intern Med 2006;145(2):284-293. [http://dx.doi. org/10.7326/0003-4819-145-4-200608150-00008] 10. Angell M. The Truth About the Drug Companies: How They Deceive Us and What To Do About It. New York: Random House, 2004. 11. Kassirer JP. On the Take: How Medicine’s Complicity With Big Business Can Endanger Your Health. Oxford: Oxford University Press, 2005. 12. Goldacre B. Bad Pharma: How Medicine Is Broken and How We Can Fix It. London: Harper Collins, 2013. 13. ProPublica. Dollars for Docs: How Industry Dollars Reach Your Doctors. http://projects.propublica. org/docdollars/ (accessed 30 May 2014). 14. PR Web. What makes a key opinion leader a KOL? http://www.prweb.com/releases/2012/3/ prweb9250355.htm (accessed 26 March 2014). 15. Sismondo S. Corporate disguises in medical science: Dodging the interest repertoire. Bull Sci Technol Soc 2011;31(6):482-492. [http://dx.doi.org/10.1177/0270467611422838] 16. Thought Leader Select. http://www.thoughtleaderselect.com (accessed 30 May 2014). 17. KOL, L.L.C. The key to opinion leader development. http://www.kolonline.co (accessed 30 May 2014). 18. Flodgren G, Parmelli E, Doumit G, et al. Local opinion leaders: Effects on professional practice and health care outcomes. Cochrane Database Syst Rev 2011;8:CD000125. [http://dx.doi. org/10.1002/14651858.CD000125.pub4] 19. Steinman MA, Shlipak MG, McPhee SJ. Of principles and pens: Attitudes of medicine housestaff towards pharmaceutical industry promotions. Am J Med 2001;110(7):551-557. [http://dx.doi. org/10.1016/S0002-9343(01)00660-X] 20. Harvey AH, Kirk U, Denfield GH, Montague PR. Monetary favours and their influence on neural responses and revealed preference. J Neuroscience 2010;30(28):9597-9602. [http://dx.doi.org/10.1523/ JNEUROSCI.1086-10.2010] 21. Sismondo S. Ghost management: How much of the medical literature is shaped behind the scenes by the pharmaceutical industry? PLoS Med 2007;4(9):e286. [http://dx.doi.org/10.1371/journal. pmed.0040286] 22. Berenson A Evidence in Vioxx suits shows intervention by Merck officials. New York Times, 24 April 2005. http://www.nytimes.com/2005/04/24/business/24drug.html (accessed 26 March 2014). 23. Gøtzsche PC, Hrobjartsson A, Johansen HK, et al. Ghost authorship in industry-initiated randomised trials. PLoS Med 2007;4(1):e19. [http://dx.doi.org/10.1371/journal.pmed.0040019] 24. Wazana A. Physicians and the pharmaceutical industry. Is a gift ever just a gift? JAMA 2000;283(3):373380. [http://dx.doi.org/10.1001/jama.283.3.373] 25. Wang AT, McCoy CP, Murad MH, Montori VM. Association between industry affiliation and position on cardiovascular risk with rosiglitazone: Cross sectional systematic review. BMJ 2010;340:c1344. [http://dx.doi.org/10.1136/bmj.c1344] 26. Daylian M, Loewenstein G, Moore DA. The dirt on coming clean: Perverse effects of disclosing conflicts of interest. J Legal Stud 2005:34(1):1-25. [http://dx.doi.org/10.1086/426699] 27. Sah S, Loewenstein G, Cain DM. The burden of disclosure: Increased compliance with distrusted advice. J Personality Soc Psychol 2013;104(2):289-304. [http://dx.doi.org/10.1037/a0030527] 28. Norris SL, Holmer HK, Ogden LA, Burda BU, Fu R. Characteristics of physicians receiving large payments from pharmaceutical companies and the accuracy of their disclosures in publications: An observational study. BMC Med Ethics 2012;13:24. [http://dx.doi.org/10.1186/1472-6939-13-24] 29. Lesser CS, Lucey CR, Egener B, Braddock CH, Linas SL, Levinson W. A behavioural and systems view of professionalism. JAMA 2010;304(24):2732-2737. [http://dx.doi.org/10.1001/jama.2010.1864]
S Afr Med J 2014;104(11):757-758. DOI:10.7196/SAMJ.8546
November 2014, Vol. 104, No. 11
RESEARCH
Compensation for research-related harm: The implications of Venter v Roche Products (Pty) Limited and Others for research ethics committees A Strode, BA, LLB, LLM, PhD; P P Singh, BCom, LLB, LLM School of Law, University of KwaZulu-Natal (Pietermaritzburg), and HIV/AIDS Vaccines Ethics Group, School of Applied Human Sciences, University of KwaZulu-Natal, Pietermaritzburg, South Africa Corresponding author: A Strode (strodea@ukzn.ac.za) Background. The issue of what type of compensation a research participant would be entitled to in a clinical trial when they have signed an informed consent document excluding certain forms of compensation recently came before our courts in the matter of Venter v Roche Products (Pty) Limited and Others (Case No. 12285/08). In this case, the court had to consider whether the plaintiff, Mr Venter, was entitled to claim for non-medical costs such as pain and suffering, loss of income and general damages, even though the informed-consent document expressly excluded such claims. Objectives. To set out the facts, issues and judgment in the case, concluding with a discussion of the implications of the judgment for research ethics committees (RECs). Methods. Critical review of a judgment of the Western Cape High Court. Results. The court concluded that Mr Venter’s application for damages should be dismissed because he had voluntarily agreed to the limited compensation as set out in the informed consent form that had been approved by both the local RECs and the Medicines Control Council. Conclusions. The Venter case has shown that delictual claims for research-related injuries will not be successful if plaintiffs have agreed to limit their own rights through signing an informed-consent form that limits compensation. This places an important obligation on RECs to ensure that they carefully review compensation clauses in informed-consent documents and that these are made clear to potential research participants. S Afr Med J 2014;104(11):759-761. DOI:10.7196/SAMJ.8596
Section 27 of the South African (SA) Constitution provides that: (i) everyone has the right to have access to healthcare services, including reproductive health care; and (ii) the state must take reasonable legislative and other measures – within its available resources – to achieve the progressive realisation of each of these rights.[1] The provision of medicine and healthcare services plays a central role in ensuring that individuals have access to quality healthcare. Given that access to effective medicines and quality healthcare services underpin this right, great value has been attached to health research which is aimed at developing medicines and improving such services.[2] The mission statement of the national Health Research Policy in SA reflects this by providing that the state must ‘promote research that contributes towards the improvement of human health and welfare’.[2] Health research frequently requires the use of human volunteers, who may bear some risk in order to generate new knowledge. Their interests are often pitted against those of science and broader public health goals.[3] As a result, a central concern in the regulation of health research is that the interests of society and of science do not override the interests of individual research participants.[4] The issue of the interests of science and society v. those of individual research participants recently came before our courts in the matter of Venter v Roche Products (Pty) Limited and Others (Case No. 12285/08) (hereafter ‘Venter’). In this case, the court had to consider whether the plaintiff, Mr Venter, was entitled to claim for non-medical costs such as pain and suffering, loss of income and general damages, even though the informed-consent document that he had signed expressly excluded such claims.[5]
759
This article sets out the facts, issues and judgment in the case. It concludes with a discussion of the implications of the judgment for research ethics committees (RECs).
The facts of the case
In 2005, Mr Venter agreed to participate in a study on the safety and efficacy of an experimental cancer drug for the treatment of colon, breast and lung cancer (paragraphs (paras) 1 and 8 – all paragraph numbers refer to the relevant paragraphs in the Venter case). The study was a global one sponsored by F Hoffman-La Roche AG (FHLR), a Swiss company (para 8). FHLR entered into a written agreement with Roche SA to conduct the study on their behalf in SA (para 11). Roche SA in turn, entered into a sub-agreement with a Dr Raats at GVI Oncology in the Western Cape to act as the principal investigator and trial site (para 15). Regulatory approval for the clinical trial was obtained from the Medicines Control Council (MCC) and two RECs, of the University of the Witwatersrand and Pharma Ethics (para 12), both of which approved the study and the informed-consent document that was to be used (para 14). Mr Venter was invited to participate in the study by a Dr Van der Merwe from GVI Oncology. He was given a copy of the informedconsent document to read at home, and 5 days later Dr Van der Merwe went through it with him point by point (para 17). Mr Venter thereafter agreed to be a participant in the study and signed the consent form (para 17). The consent document expressly provided that the sponsor, FHLR, would pay for the cost of medical treatment directly linked to any trial-related injury, and that no other compensation would be
November 2014, Vol. 104, No. 11
RESEARCH
available (para 3). Furthermore, any claims for compensation would be determined in line with the guidelines issued by the Association of British Pharmaceutical Industry (ABPI), on which the SA Good Clinical Practice guidelines (GCP) are based (para 3). Mr Venter subsequently suffered a research-related injury and had to be hospitalised (paras 5 and 18). He claimed that he had suffered damages as a result of this research-related injury, and instituted a civil action against Roche SA and GVI Oncology (para 5).
Issues
Given that the informed-consent document expressly limited compensation to medical costs (para 21), in dispute was whether Mr Venter was entitled to claim for non-medical costs such as pain and suffering, loss of income, and general damages.
Judgment
The first issue before the court was determining whether a tacit contract existed between the parties in which it was agreed that compensation beyond the stipulated medical costs would be paid in the event of a research-related injury (paras 31 - 37). In this instance, the court found that there was no tacit agreement between Mr Venter and Roche SA on the issue of compensation. This was because: (i) in terms of the arrangement between FHLR and Roche SA, FHLR was to obtain insurance for the trial – this was in line with clause 4.11 of the GCP, which requires the sponsor to pay compensation for any trialrelated injuries; (ii) the informed-consent document provided that FHLR, as the sponsor of the trial, was responsible for compensation and it could be assumed that the reasonable person in the position of the plaintiff would have been aware of this clause before signing; (iii) there was no evidence that Dr Van der Merwe or GVI Oncology had the authority to conclude a tacit agreement, or that Mr Venter intended to conclude a contract with a party not listed on the informed-consent form; and (iv) clause 15 of the informed-consent form contained an indemnity for GVI, for trial-related injuries (paras 40 - 42). The second issue considered by the court was whether the wording of the compensation clause in the informed-consent document gave rise to a broader obligation to pay compensation beyond medical costs (para 43). This part was headed ‘compensation’ and stated that FHLR (the sponsor) would pay for the costs of medical treatment following a research-related injury. Any compensation provided would be determined in terms of the ABPI guidelines, with no other compensation being payable (para 44). Although the court held that the term ‘compensation’ had a broad meaning and included compensation for loss suffered as a result of a trial-related injury, i.e. damages (para 47 - 48), it found that the informed-consent document required any compensation to be determined according to the ABPI guidelines (para 53). A review of the ABPI guidelines found a recommendation for payment without legal commitment, i.e. an ex gratia payment by the sponsor and not by the researchers (paras 39 and 58). The court quoted with approval the English decision of Morton James Wylie v Dr Donald Grosset, Greater Glasgow Health Board (2011), where it was held that the ABPI guidelines on compensation were a procedural rather than a substantive guide to sponsors (para 61). Based on the above, the court concluded that there was no legal obligation to pay compensation beyond the medical costs in Mr Venter’s case (para 62). The third issue addressed by the court was whether a stipulato alteri (an offer to a third party that comes into effect when the agreement is signed) existed (para 66). Mr Venter alleged that, as the MCC application stated that all regulatory requirements would
760
be met and that the trial would be conducted in accordance with the GCP guidelines, there existed a stipulato alteri in favour of the trial participants (para 67). The court again rejected this, finding that there was no evidence that Mr Venter had either seen the MCC application or had intended to accept a third-party offer by signing the consent form (para 67). The fourth issue was whether Roche SA and GVI Oncology breached a legal duty that they owed to Mr Venter. The court found that there was no evidence that Roche SA and GVI Oncology’s failure to include an agreement to provide broader compensation was wrongful (para 71). In particular, the court noted that expert evidence had indicated that the MCC regularly approved studies without such compensation obligations (para 72). In the light of the above, the court concluded that Mr Venter’s application for damages should be dismissed (para 94).
Discussion
The outcome of the Venter matter is important, as it is our first judgment on compensation for non-medical injuries following a research-related injury. This matter has clarified the approach that the courts will take to such disputes by highlighting a number of applicable principles. Firstly, the obligation to assess and approve the nature of the compensation for research-related injuries falls on the regulators reviewing and approving the study. Secondly, participants are bound by the express terms of the informed-consent document that have been approved by these regulators, and any verbal or tacit amendments to such documents would need to be reduced to writing if they are to be enforceable. Both these principles have significant implications with regard to the way in which RECs review clinical trials.
Role of RECs in establishing what forms of compensation for harm are ethical
The court held that regulatory approval had been obtained from the MCC and two ethics committees (para 12). All three regulatory bodies had approved the content and wording of the informedconsent document (para 14). The court appeared to accept that limiting compensation in this way was reasonable because, firstly, such bodies had the legal authority to approve/not approve research, and, secondly, this stance on compensation in this instance reflected an accepted practice in the field (para 72). It is submitted that the court was correct in viewing the responsibility to set the normative standards for compensation as being in the hands of the regulators. The MCC must ensure that clinical trials are scientifically valid and that they comply with certain ethical standards such as obtaining consent from participants,[6,7] while RECs must grant ethical approval if a protocol is found to be ethical.[8] Compensation for research-related harm is clearly an ethical issue, which is referred to in both the national ethical guidelines[9] and the GCP.[7] This seems to imply that the MCC and RECs should ensure that adequate compensation arrangements are in place, as part of the assessment of whether health research is ethical. However, there is limited ethical guidance on this point, and possibly there are divergent approaches in practice. Neither the national ethical guidelines[9] nor the GCP[7] set a substantive standard on compensation for harm. However, the national ethical guidelines require arrangements to ‘ensure adequate compensation to participants for injury suffered as a result of participation in the trial’.[9] These arrangements must be specified in the informed-consent document,[9] while the GCP guidelines focus on the procedures and substantive standards that should be followed if there is a dispute regarding the nature of compensation to be paid.[7]
November 2014, Vol. 104, No. 11
RESEARCH
This lack of specific ethical guidance on compensation leaves open the question of whether limiting compensation to medical costs is ethical. The court found that as the regulators had approved the study with this specific limitation on the kinds of compensation that could be claimed and Mr Venter had agreed to this, he could not at a later point argue that the researchers or sponsors had acted wrongfully (para 71). This means that RECs must specifically consider the issue of the compensation standards when approving research as part of their ethical obligation to protect research participants and promote their welfare. Furthermore, members of RECs should ensure that they carefully consider the express wording of the compensation clause and that they are satisfied with it if it limits a participant’s rights by excluding certain forms of damages. This is because once the informed-consent document is approved and consented to by a participant, a participant cannot argue later that the researchers or sponsors had acted wrongfully (para 71).
Implications of the express terms of the informed-consent document
Our law is clear regarding the obligation to obtain consent from research participants. The National Health Act provides that when a health service is experimental and is being undertaken at a health establishment, there is a duty on that establishment to inform the user that the service is a form of research.[8] Researchers are also required to inform research volunteers of the ‘objects of the research or experimentation and any possible positive or negative consequences on his or her health’.[8] With regard to compensation, point 3.5 of the GCP provides that the informed-consent document should specify the ‘compensation and/or treatment available to the participant in the event of trial related injury’.[9] In summary, these norms require information on compensation, but do not set a substantive norm on what types of compensation should be provided by sponsors. The court made it clear that it would not recognise terms that were not expressly provided for in the informed-consent document. It is submitted that this is the correct approach from a public policy point of view, and it would be inappropriate if research participants could ‘negotiate’ alternative conditions under which they would participate in a study. Furthermore, the court held that as the defendant, Mr Venter, had given informed consent, this excluded wrongfulness, thus excluding the possibility of a civil claim. The above facts and issues considered, it is submitted that RECs must ensure that researchers implement an adequate informedconsent process that brings to the attention of participants the distinction between the researchers and sponsors, and the limitation of compensation – as defined by the express wording in the consent document. Furthermore, informed-consent documents should confirm that the participant is aware that any verbal or other changes to the content of the signed consent document would only be legally binding on the researchers and sponsors if they were reduced to writing and brought to the attention of the REC concerned.
Claims in terms of the GCP
It is submitted that the court erred in so far as it viewed the GCP as being only procedural in nature and misinterpreted the role of GCP norms within the context of the wording of the specific informedconsent document. It is considered that the guidance in the GCP is not just procedural in nature. Although it does not specifically state what forms of damages should be covered by the sponsors of research, there are two principles indicating that the drafters intended a broader approach. Firstly, they state that sponsors must obtain
761
‘comprehensive’ insurance. Secondly, they refer to the need to ensure that the amount of compensation will be ‘appropriate to the nature, severity and persistence of the injury and should in general terms be consistent with the quantum of damages commonly awarded for similar injuries by a South African Court in cases where legal liability is admitted’.[9] It is argued that these are substantive rather than procedural obligations, implying that a broad approach to compensation is not excluded. Finally, it is submitted that the wording of the informedconsent document indicated that any dispute regarding the specified compensation would be determined in terms of the ABPI guidelines. This indicates that disputes regarding issues such as whether certain medical costs could be covered would be resolved by reference to the substantive norms in the GCP – which provide that, for example, a participant may only claim for serious bodily injury of an ‘enduring character’.[10] It is circular logic to state that there is no legal obligation to pay compensation beyond that set out in the GCP, as these guidelines provide that the ‘fact that a sponsor has agreed to abide by these Guidelines in respect of a trial does not affect the right of a participant to pursue a legal remedy in respect of injury alleged to have been suffered as a result of participation’.[7]
Conclusions
The Venter case has shown that delictual claims for research-related injuries will not be successful if the plaintiff has agreed to limit his/ her own rights through signing an informed-consent form that limits compensation. This places an important obligation on RECs to protect the rights and welfare of research participants by carefully reviewing compensation clauses in informed-consent documents. The national ethical guidelines require that compensation arrangements be ‘adequate’,[9] and in light of this, RECs should consider what is just in the circumstances. Is it in fact appropriate to limit compensation to medical costs when participants may lose earnings and endure pain and suffering and other forms of harm in the event of a serious adverse event? RECs are obligated to ensure that participants are made aware that if compensation is limited to medical costs, they will not be able to claim other delictual damages at a later stage. Acknowledgements. The authors are grateful for the assistance of Professor Douglas Wassenaar, who provided insightful comments. Mr Amin Matola is thanked for his assistance with preparing the manuscript for publication. References 1. Constitution of the Republic of South Africa, 1996. Gazette No. 17678, Notice No. 2083, 18 December 1996. Commencement date 4 February 1997 – unless otherwise indicated [Proc. No. R6, Gazette No. 17737, 24 January 1997]. http://www.gov.za/documents/constitution/1996/a108-96.pdf (accessed 19 May 2014). 2. Department of Health. Health Research Policy in South Africa, 2001. http://www.doh.gov.za/docs/ index.html (accessed 25 August 2008). 3. Fisher F. Medical Ethics Today: Its Practice and Philosophy. London: BMJ Publishing Group, 1993:195. 4. Declaration of Helsinki. http://www.wma.net/e/policy/b3.htm (accessed 19 May 2014). 5. Venter v Roche Products (Pty) Limited and Others (case no. 12285/08). 6. Medicines and Related Substances Act, No 101 of 1965. Gazette No. 1171, Notice No. 1002, 7 July 1965. Commencement date 1 April 1966 [Proc. No. 94, Gazette No. 1413]. http://www.saflii.org/za/legis/ consol_reg/marsa101o1965rangnr510723/ (accessed 12 May 2014). 7. Department of Health. Guidelines for Good Practice in the Conduct of Clinical Trials with Human Participants in South Africa. 2006:56. http://www.hsrc.ac.za/uploads/pageContent/181/ SAgoodclinicalpracticeguidelines.pdf (accessed 14 May 2014). 8. The National Health Act, No. 61 of 2003. Government Gazette 2004;469(26595). http://www.doh.gov.za/ docs/legislation-f.html and http://www.info.gov.za/gazette/acts/2003/a61-03.pdf (accessed 18 May 2014). 9. Department of Health. Ethics in Health Research: Principles, Structures and Processes (Research Ethics Guidelines – 2004). 2004:59. http://www.doh.gov.za/docs/index.html (accessed 12 May 2014). 10. Slack C, Singh P, Strode A, Essack Z. Compensation for research-related injury in South Africa: A critique of the Good Clinical Practice (GCP) guidelines. South African Journal of Bioethics and Law 2012;5(2):91-94. [http://dx.doi.org/10.7196/SAJBL.211]
Accepted 15 July 2014.
November 2014, Vol. 104, No. 11
RESEARCH
Appropriateness of computed tomography and magnetic resonance imaging scans in the Eden and Central Karoo districts of the Western Cape Province, South Africa J Becker,1 MB ChB; L S Jenkins,2 MB ChB, MFamMed, FCFP (SA), PhD; M de Swardt,2 MB ChB; R Sayed,3 MSc; M Viljoen,4 MB ChB Knysna Provincial Hospital, Western Cape, South Africa Department of Family Medicine, George Provincial Hospital, Western Cape, South Africa 3 School of Public Health and Family Medicine, Faculty of Health Sciences, University of Cape Town, South Africa 4 George Provincial Hospital, Western Cape, South Africa 1 2
Corresponding author: J Becker (juanitabecker7@gmail.com)
Introduction. Computed tomography (CT) and magnetic resonance imaging (MRI) are an essential part of modern healthcare. Marked increases in clinical demand for these imaging modalities are straining healthcare expenditure and threatening health system sustainability. The number of CT and MRI scans requested in the Eden and Central Karoo districts of the Western Cape Province, South Africa (SA), almost doubled from 2011 to 2013. Objective. To determine the appropriateness of CT and MRI scans and relate this to the requesting department and clinician. Methods. This was a retrospective analytical cohort study. All scans during October 2012 were analysed as a sample. Appropriateness of scans was determined using the American College of Radiologists (ACR) Appropriateness Criteria and the Royal College of Radiology Guidelines. Appropriateness was also correlated back to the requesting department and clinician. Results. Of a total of 219 scans, 53.0% were abnormal. Overall 6.4% of scans were considered inappropriate. Interns and registrars requested no inappropriate scans. The orthopaedics department scored the highest rate of appropriate scans (80.0%) and the oncology department the highest rate of inappropriate scans (20.8%). Conclusion. The limited resources available for healthcare in a developing country like SA should be a motivation to implement control mechanisms aimed at appropriate utilisation of imaging examinations. The Eden and Central Karoo districts have a low rate of inappropriate scans (6.4%). We recommend that the current preauthorisation system by consultants and other senior clinicians continues, but with increased clinician awareness of the ACR Appropriateness Criteria and the Royal College guidelines. S Afr Med J 2014;104(11):762-765. DOI:10.7196/SAMJ.8158
Computed tomography (CT) and magnetic resonance imaging (MRI) have become an essential part of modern healthcare.[1] It would seem intuitive that, by enabling the practitioner to make non-invasive diagnoses, these investigations should improve health outcomes in many individuals, but this is often difficult to prove. However, marked increases in imaging utilisation are now straining healthcare expenditure and threatening health system sustainability.[1] Imaging is one of the fastest-growing services in medicine; it is estimated that imaging costs amount to $100 000 billion annually in the USA.[2] In the past decade technological advances in CT and MRI have further increased their clinical utilisation.[3] The clinical information obtained and their greater accessibility have made them attractive to both patients and referring doctors. However, the increased utilisation of diagnostic imaging has brought with it significant economic and medical risks. Brenner and Hall[4] have highlighted the alarming increase in radiation exposure through CT and the accompanying carcinogenic potential. Recent work also emphasised the growing concern about unforeseen contrast-related severe reactions such as gadolinium-related nephrogenic systemic fibrosis, over and above the well-known mild allergies and anaphylactoid responses.[5] According to a World Bank report in 2009, health expenditure in South Africa (SA) was 8.5% of the gross domestic product. This was considerably higher than the 5% recommended by the World Health Organization. The national Minister of Health, Dr Aaron Motsoaledi, has stated that ‘We
762
exceed our healthcare costs ... We are a country spending more on health but having poor outcomes.’ It is therefore essential to regulate costs in our health system, which includes the cost of imaging.[6] Levy et al.[7] investigated the effect of the American College of Radiologists (ACR) Appropriateness Criteria and found an increase in appropriate MRI examinations after applying these criteria. It has been shown that a telephonic preauthorisation process for radiological studies also produced a statistically significant change in the rate of ordering MRI studies, but not CT scans.[8] A study undertaken in Israel[9] assessed the effect of a managed care preauthorisation programme based on the ACR Appropriateness Criteria and the Royal College of Radiology Guidelines. Before preauthorisation was compulsory, CT and MRI utilisation rates were constantly increasing, by 20% and 5% per year for CT and MRI, respectively. After implementation of preauthorisation, CT and MRI annual request rates decreased from 25.9 and 7 examinations per 1 000 patients in 2000 to 17.3 and 5.6 in 2003. CT was more commonly inappropriately utilised by the paediatric group, while medical subspecialties more commonly utilised MRI inappropriately. Preauthorisation of CT and MRI requests resulted in a substantial decrease in utilisation and imaging costs.[9] In the Eden and Central Karoo districts in the Western Cape Province of SA, CT and MRI services requested in the public sector were historically outsourced to the private sector (Fig. 1). In 2011 the Eden District had a population of approximately 563 573 people, of whom 89% had no medical insurance.
November 2014, Vol. 104, No. 11
RESEARCH
Methods
Fig. 1. Map of the health districts and subdistricts in the Western Cape Province, SA. (SA = South Africa.) 450 400
Scans, n
350 Private CT Hospital CT Total Private MRI Expon. (total)
300 250 200 150 100 50 Ap M r ay Ju Ju n l Auy g Oc Se t pt No Dev c Ja n Fe b M a Ap r M r ay Ju Ju n l Auy g Oc Se t pt No Dev c Ja n Fe Mb Apar M r ay Ju Ju n l Auy g Oc Se t pt No v
0
Fig. 2. CT and MRI scans done in the Eden and Central Karoo districts of the Western Cape Province, SA, from April 2011 to November 2013. (CT = computed tomography; MRI = magnetic resonance imaging; SA = South Africa.)
25
23.29
20 15
18.72
45 - 54
55 - 64
Results
13.24
% 10
19.63
8.68
9.59 6.85
5 0
≤12
13 - 24
25 - 34
35 - 44
≥65
Age group, years Fig. 3. Age distribution of the study population.
In November 2010, George Hospital obtained and started operating its own CT scanner. Subsequently the number of CT and MRI scans requested in the Eden and Central Karoo districts almost doubled between April 2011 and November 2013 (Fig. 2). There
were no data available on the appropriateness of CT and MRI scans in these districts. The aim of this study was to determine the appropriateness of CT and MRI scans in the districts and relate their appropriateness score to the requesting department and clinician.
763
This was a retrospective analytical cohort study. All public sector scans done in the Eden and Central Karoo districts during October 2012 were included. The folders of all patients at George Hospital who underwent private or state sector CT or MRI scans were retrieved from the hospital. The demographic data, type of scan, indication for the scan, requesting practitioner and requesting department were obtained from the notes. Folders with incomplete data were excluded from the study. Public sector patients who had scans done in private practice at Knysna or Mossel Bay provincial hospitals were not included in the study, as it was not possible to access their folders. During the study period 25 and 42 state patients had CT and MRI scans done in private practice in Mossel Bay and Knysna, respectively. Appropriateness of CT and MRI scans was determined by using the ACR Appropriateness Criteria and the Royal College of Radiology Guidelines.[10] The ACR Appropriateness Criteria uses the following rating scale: 1, 2, 3 ‘usually not appropriate’, 4, 5, 6 ‘may be appropriate’, and 7, 8, 9 ‘usually appropriate’. Cases in which an ACR code could not be assigned were labelled ACR non-codable. Data were captured and analysed using Microsoft Excel 2003 software. Statistical support was offered by the School of Public Health and Family Medicine, University of Cape Town. The study was approved by the Human Ethics Committee of the University of Cape Town (HREC REF: 132/2013).
November 2014, Vol. 104, No. 11
A total of 251 scans were performed during the study period, 219 of which were included in the study. The mean age of the population sampled was 47.6 years (Fig. 3). The Eden district has seven subdistricts. Table 1 compares the total population size of each subdistrict (2011)[11] with the number of CT and MRI scans requested. Scans performed in the private sector are not included. The majority of CT scans requested were of the brain (48.4%), and a total of 27 MRI scans were requested (Table 2). As judged by the reports, 31.5% of scans were normal, 53.0% were abnormal and 15.5% were ‘abnormal as expected’ (scans in patients who had known pathology, but no new pathology noted). Using the ACR criteria, 6.4% of scans were found to be inappropriate, 15.5%
RESEARCH
Table 1. Population size of each subdistrict (2011) in relation to the number of scans requested
Subdistrict
Total population
Scans, n
% of subdistrict population scanned in October 2012
George
188 236
114
0.06
Hessequa
46 296
13
0.02
Kannaland
28 505
7
0.02
Knysna
60 564
28
0.05
Bitou
48 763
2
0.004
Mossel Bay
101 544
19
0.02
Oudtshoorn
92 545
27
0.03
Other
9
Total
219
Table 2. Anatomical areas scanned Type of scan
n (%)
CT Brain
106 (48.4)
Chest
27 (12.3)
Abdomen
23 (10.5)
Cervical spine
7 (3.2)
Abdomen and pelvis
6 (2.7)
Angiogram of legs
5 (2.3)
Whole body
4 (1.8)
Renal arteries/renal tract
4 (1.8)
Brain and orbits
3 (1.4)
Pulmonary angiogram
2 (0.9)
Brain and facial bones
2 (0.9)
Pelvis
1 (0.5)
Sinuses
1 (0.5)
Cerebral angiogram
1 (0.5)
MRI Lumbar spine
11 (5.0)
Brain
4 (1.8)
Cervical spine
4 (1.8)
Pelvis
4 (1.8)
Whole spine
2 (0.9)
Thoracic spine
1 (0.5)
Femur
1 (0.5)
Total
219 (100)
CT = computed tomography; MRI = magnetic resonance imaging.
‘may be appropriate’, 63.5% were appropriate and 14.6% were ACR non-codable. Table 3 relates appropriateness to the rank of the requesting practitioner. Interns and registrars requested no inappropriate scans.
764
Table 4 relates appropriateness to the requesting department. The orthopaedics department had the highest percentage of appropriate scans (80.0%), while the oncology department had the highest percentage of inappropriate scans (20.8%).
Discussion
Almost two-thirds (64%) of the scans performed at George Hospital were found to be appropriate using the ACR Appropriateness Criteria. This compares favourably with a study from the University of Washington that retrospectively analysed 459 CT and MRI scans for appropriateness using evidence-based guidelines.[12] In this study, clinical history submitted at the time of interpretation, the clinical notes and laboratory results preceding the date of the imaging were evaluated. The radiology reports and subsequent clinic visits were measured for outcomes, and 74% of scans were found to be appropriate. Examples of inappropriate scans included brain CT for chronic headache, lumbar spine MRI for acute back pain, knee or shoulder MRI in patients with osteoarthritis, and CT scans for haematuria during a urinary tract infection.[12] It is essential that doctors know how to select the appropriate imaging technique to ensure cost-effective, high-quality patient care.[13] The ACR developed its Appropriateness Criteria in 1993, and ongoing revisions have kept them relevant. These are expertgenerated, evidence-based guidelines intended to guide referring doctors in the correct use of diagnostic and interventional radiology for given clinical situations.[10] However, it has been shown that in the USA there is low utilisation of the ACR Appropriateness Criteria by clinicians when ordering imaging studies for their patients.[14] In our study, most of the scans were performed in the >65 years age group and very few were performed in patients aged <12 years. This is excellent practice in terms of reducing radiation exposure in children, yet the paediatrics department was found to have an 18.7% rate of inappropriate scans, despite a general perception that the department is very judicious in the ordering of CT scans. According to the ACR Appropriateness Criteria, MRI scans are preferred in children because of the reduced radiation exposure. It is, however, difficult to order MRI scans for children at George Hospital, as they have to be performed in the private sector, necessitating transport to the private hospital, and a doctor has to accompany the child for sedation purposes due to the claustrophobic tunnel and the noise generated by the MRI machine. CT scans, which can be done at George Hospital, therefore tend to be preferred. When comparing the numbers of scans on patients from the various subdistricts in Eden, there is a clear discrepancy. Far more scans are requested from George Hospital compared with the peripheral hospitals, but this probably reflects the referral nature of George Hospital. The George region has a population of 188 236 and generated 114 scans (0.06% of the population), while Oudtshoorn, with a population of 92 545, generated only 27 scans (0.03%). Patients have to travel 65 km from Oudtshoorn to George Hospital via ambulance to have a scan, while patients in George have easier access to scans. The question arises whether George is perhaps doing too many scans, or the peripheral hospitals are doing too few. Looking at appropriateness of scans in relation to the requesting practitioner, we found that interns ordered no inappropriate scans, while 5.4% of those ordered by consultants were inappropriate. One explanation could be that interns tend to make decisions on the more straightforward scans with clear appropriateness guidelines, while scans that need approval by a consultant typically include more difficult clinical situations. Alternatively, the intern may have only been directed to request the scan after senior clinician input.
November 2014, Vol. 104, No. 11
RESEARCH
Table 3. Appropriateness of scan in relation to requesting practitioner rank Practitioner
Inappropriate n (%)
May be appropriate n (%)
Appropriate n (%)
Non-codable n (%)
Total N (%)
Consultant
6 (5.4)
13 (11.6)
71 (63.4)
22 (19.6)
112 (100)
Intern
0 (0)
3 (33.3)
6 (66. 7)
0 (0)
9 (100)
Medical officer
4 (4.8)
15 (18.3)
54 (65.8)
9 (11.0)
82 (100)
Registrar
0 (0)
3 (33.3)
6 (66.7)
0 (0)
9 (100)
Unknown
4 (57.1)
0 (0)
2 (28.6)
1 (14.3)
7 (100)
Total
14 (6.4)
34 (15.5)
139 (63.5)
32 (14.6)
219 (100)
Table 4. Appropriateness of scans in relation to the requesting department Department
Inappropriate n (%)
May be appropriate n (%)
Appropriate n (%)
Non-codable n (%)
Total N (%)
Cardiothoracic outreach
0 (0)
0 (0)
0 (0)
1 (100)
1 (100)
Ear, nose and throat
0 (0)
1 (50.0)
1 (50.0)
0 (0)
2 (100)
Family medicine
1 (4.2)
5 (20.8)
17 (70.8)
1 (4.2)
24 (100)
Internal medicine
0 (0)
15 (20.8)
49 (68.1)
8 (11.1)
72 (100)
Oncology
5 (20.8)
6 (25.0)
9 (37.5)
4 (16.7)
24 (100)
Ophthalmology
0 (0)
1 (100)
0 (0)
0 (0)
1 (100)
Orthopaedics
1 (4.0)
1 (4.0)
20 (80.0)
3 (12.0)
25 (100)
Paediatrics
3 (18.7)
1 (6.2)
5 (31.2)
7 (43.7)
16 (100)
Psychiatry
0 (0)
1 (33.3)
0 (0)
2 (66.7)
3 (100)
Surgery
4 (8.3)
3 (6.2)
35 (72.9)
6 (12.5)
48 (100)
Urology
0 (0)
0 (0)
3 (100)
0 (0)
3 (100)
Total
14 (6.4)
34 (15.5)
139 (63.5)
32 (14.6)
219 (100)
Recommendations
References
While almost two-thirds of scans were considered appropriate, and no inappropriate scans were requested by interns or registrars, we recommend that the current ‘preauthorisation’ system, where consultants are required to grant permission in complex clinical cases, continue at George Hospital, but with an increased sensitivity and awareness of the ACR Appropriateness Criteria. This is particularly true for the oncology department, where a more in-depth study may reveal reasons for requests for some apparently inappropriate scans. Finally, improved access for scans from district hospitals may warrant attention.
Conclusions
The introduction and ongoing improvement of sophisticated new diagnostic imaging modalities, particularly CT and MRI, have increased utilisation by clinicians dramatically over the past decade. The limited resources available for healthcare in a developing country like SA ought to be motivation to implement control mechanisms aimed at appropriate utilisation of imaging examinations. While this study showed 63.5% of scans to be appropriate, we also identified concerns around access to scans for district hospitals in the periphery, and a relatively high proportion of inappropriate scans requested by clinicians in the departments of oncology and paediatrics. Acknowledgements. The authors thank George Hospital management for their support of this study.
765
1. You JJ. Appropriateness: The next frontier in the quest for better access to CT and MRI. Healthc Q 2009;12(4):25-27. [http://dx.doi.org/10.12927/hcq.2013.21122] 2. Mishori R. The danger of too many tests. Parade, 6 July 2008. www.parade.com/articles/editions/2008/ edition_07-06 2008/3Too_Many_Tests (accessed 28 January 2013). 3. Bhargavan M, Sunshine JH. Utilization of radiology services in the United States: Levels and trends in modalities, regions, and populations. Radiology 2005;234(3):824-832. [http://dx.doi.org/10.2214/ AJR.08.1622] 4. Brenner DJ, Hall EJ. Computed tomography: An increasing source of radiation exposure. N Engl J Med 2007;357(22):2277-2284. [http://dx.doi.org/10.1056/NEJMra072149] 5. Wiginton CD, Kelly B, Oto A, et al. Gadolinium-based contrast exposure, nephrogenic systemic fibrosis, and gadolinium detection in tissue. Am J Radiol 2008;190(4):1060-1068. [http://dx.doi.org/10.2214/ AJR.07.2822] 6. Motsoaledi: South Africa’s healthcare declining. Mail & Guardian, 7 September 2012. http://mg.co.za/ article/2012-09-07-motsoaledi-sa-health-care-declining (accessed 2 February 2013). 7. Levy G, Blachar A, Goldstein L, et al. Nonradiologist utilization of American College of Radiology Appropriateness Criteria in a preauthorization center for MRI requests: Applicability and effects. Am J Radiol 2005;187(4):855-858. [http://dx.doi.org/10.2214/AJR.05.1055] 8. Smulowitz PB, Ngo L, Epstein SK. The effect of a CT and MR preauthorization program on ED utilization. Am J Emerg Med 2008;27(3):328-332. [http://dx.doi.org/10.1016/j. ajem.2008.03.012] 9. Blachar A, Tal S, Mandel A, et al. Preauthorization of CT and MRI examinations: Assessment of a managed care preauthorization program based on the ACR Appropriateness Criteria and the Royal College of Radiology Guidelines. J Am Coll Radiol 2006;3(11):851-859. [http://dx.doi.org/10.1016/j.jacr.2006.04.005] 10. American College of Radiology. ACR Appropriateness Criteria. http://www.acr.org/Quality-Safety/ Appropriateness-Criteria (accessed 2 February 2013). 11. Eden District Municipality: Integrated Development Plan 2014/2015. Found at www.westerncape.gov. za/text/2014/April/eden-draft-idp-2014-15.pdf (accessed 26 September 2014). 12. Lehnert BE, Bree RL. Analysis of appropriateness of outpatient CT and MRI referred from primary care clinics at an academic medical center: How critical is the need for improved decision support? J Am Coll Radiol 2012;7(3):192-197. [http://dx.doi.org/10.1016/j.jscr.2009.11.010] 13. Bettmann M. The ACR appropriateness criteria: View from the committee chair. J Am Coll Radiol 2006;3(7):510-512. [http://dx.doi.org/10.1016/j.jscr.2006.03.024] 14. Bautista AB, Burgos A, Nickel BJ, Yoon JJ, Tilara AA, Amorosa JK. Do clinicians use the American College of Radiology Appropriateness Criteria in the management of their patients? AJR Am J Roentgenol 2008;192(6):1581-1585. [http://dx.doi.org/10.2214/AJR.08.1622]
Accepted 1 July 2014.
November 2014, Vol. 104, No. 11
RESEARCH
A laboratory-based study to identify and speciate nontuberculous mycobacteria isolated from specimens submitted to a central tuberculosis laboratory from throughout KwaZulu-Natal Province, South Africa L Sookan, MB BCh, FCPath (SA) Micro; Y M Coovadia, MB ChB, FCPath (SA) Micro Department of Medical Microbiology, Nelson Mandela School of Medicine, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa, and National Health Laboratory Service, KZN Academic Complex, KwaZulu-Natal Corresponding author: L Sookan (lishasookan@hotmail.com)
Background. Non-tuberculous mycobacteria (NTM) are important environmental pathogens capable of causing a spectrum of infection. The different species exhibit varied geographical prevalence worldwide. Identification of the infecting organism may be helpful in determining the clinical significance of the isolate. Objective. To describe the spectrum of NTM isolated from clinical specimens received at the National Health Laboratory Service central tuberculosis laboratory in KwaZulu-Natal Province, South Africa. Method. In a laboratory-based prospective study, 200 suspected NTM were randomly selected over a period of 1 year and identified to species level using a commercially available DNA strip assay (GenoType Mycobacterium, CM/AS; Hain Lifescience, Germany). Results. Of the 200 suspected NTM, 133 (66.5%) were confirmed to be NTM by the molecular test. The most frequently isolated NTM species were Mycobacterium intracellulare (45.9%), M. avium subspecies (11.3%), M. gordonae (6.0%) and M. kansasii (4.5%). Conclusion. It is important for laboratories to document the local spectrum of NTM because of the geographical variation in the different NTM species isolated. Although molecular tests for identifying NTM are relatively expensive, they have the advantage of providing rapid and accurate identification of the various NTM species. S Afr Med J 2014;104(11):766-788. DOI:10.7196/SAMJ.8017
Non-tuberculous mycobacteria (NTM) is a term used to refer to species of the genus Mycobacterium that are not included in the Mycobacterium tuberculosis complex (MTBc). These organisms are ubiquitous in nature, and can be recovered from a wide array of environmental sources.[1] NTM species are now increasingly being recognised as opportunistic pathogens capable of causing a spectrum of infections including pulmonary, lymphatic, skin and soft-tissue, and disseminated disease.[2] More than 140 NTM species have been identified to date. Of these, 25 have been linked to human disease, exhibiting geographical variability with regard to prevalence of disease, species isolated and sites of infection. Identifying the NTM species, together with the site from which it was cultured, may be helpful in determining the clinical significance of the isolate.[3] In the USA, M. avium complex was found to be the most common cause of NTM lung disease, followed by M. kansasii.[4] In England and Wales, disease is most commonly caused by M. kansasii, and in Scotland by M. malmoense.[5] In a locally based study, M. kansasii was the commonest isolate recovered from the sputum of miners.[6] To the best of our knowledge, there are no data available in South Africa (SA) on the spectrum of NTM species recovered from all clinical specimens. It is well recognised that clinicians have great difficulty in distin guishing between disease caused by NTM and MTBc. Although microscopy for acid-fast bacilli (AFB) enables rapid diagnosis of mycobacteria, it cannot differentiate M. tuberculosis from NTM. This requires culture, which may take up to 6 weeks. Speciation of NTM in a routine laboratory traditionally required a battery of biochemical tests and observation of growth rate and colony morphology. However,
766
this is time consuming, error prone and labour intensive, and requires experienced personnel for interpretation of results.[7] The introduction of molecular methods has led to a marked improvement in accuracy as well as turnaround time. The GenoType Mycobacterium CM/AS (Hain Lifescience, Germany) is a commercial DNA strip assay based on reverse hybridisation of polymerase chain reaction products to their complementary probes. Although this molecular method is more expensive than the traditional methods, mycobacteria from positive liquid or solid cultures can be identified to species level rapidly and accurately. The combination of the GenoType CM (for common mycobacteria) and Genotype AS (for additional species) allows for the detection of more than 40 clinically relevant mycobacteria species from cultured samples.[8]
Methods
This was a laboratory-based, prospective study to identify and speciate NTM isolated from specimens submitted to the National Health Laboratory Service (NHLS) central tuberculosis (TB) lab oratory at Inkosi Albert Luthuli Central Hospital (IALCH) from patients throughout the province of KwaZulu-Natal Province (KZN), SA. This is the only laboratory performing mycobacterial culture on specimens received from public healthcare centres in KZN. Ethical approval was obtained from the Biomedical Research Ethics Committee at the University of KwaZulu-Natal. A retrospective analysis of laboratory records for the year 2009 revealed that the IALCH TB laboratory was isolating ±1 200 suspec ted NTM and ±10 000 MTBc annually from clinical specimens. In consultation with a statistician, it was agreed that 200 suspected
November 2014, Vol. 104, No. 11
RESEARCH
NTM, which comprised ±17% of the total number of NTM cultured annually, should be speciated to provide a statistically significant sample. Random sampling for a period of 1 year was performed (January 2010 - December 2010). All specimens submitted for TB culture were processed according to the TB laboratory standard operating procedure. Samples included sputum, endotracheal aspirates, brochoalveolar lavage, sterile fluid, biopsy tissue, blood and cerebrospinal fluid. Isolates suspected to be NTM by colony morphology, biochemical tests (niacin and nitrate) and/or the SD Bioline TB Ag MPT64 Rapid Test were investigated further by a commercially available molecular test that speciates NTM. The GenoType Mycobacterium CM/AS was used to identify suspected NTM from liquid (BACTEC MGIT 960, Becton Dickinson, USA) or solid (Middlebrook 7H11; Becton Dickinson) culture media. DNA was extracted from the stored cultures according to the manufacturer’s instructions. The GenoType assay was performed strictly according to the manufacturer’s package insert. The demographic characteristics of patients from whom the NTM was recovered were extracted from the NHLS TB laboratory database, and data analysis was performed using Microsoft Excel. Confidentiality of patient information was maintained throughout the study.
Results
Of a total of 200 suspected NTM cultures from 200 individual patients, 133 (66.5%) were confirmed as NTM by the molecular assay. Of these 133 NTM, 114 were fully speciated by the molecular assay; 8 could not be speciated further as the molecular assays only contain probes that allow for the detection of 40 commonly isolated NTM, and the remaining 11 represented mixed NTM species. An additional 6 cultures were identified as MTBc, and the remaining 61 cultures could not be speciated owing to contamination or an absence of mycobacterial DNA (Table 1). Of the 133 NTM species, M. intracellulare (n=61, 45.9%), M. avium subspecies (ssp.) (n=15, 11.3%), M. gordonae (n=8, 6.0%) and M. kansasii (n=6, 4.5%) accounted for 90 (67.7%) of isolates (Fig. 1).
All NTM were cultured from respiratory specimens, with the exception of an M. gordonae isolate that was cultured from a biopsy sample and an M. intracellulare isolate from a gastric washing. Fifty-eight (43.6%) of the NTM isolates were cultured from patients attending healthcare facilities in the eThekwini (Durban)
Table 1. Identification of suspected NTM Organism
Isolates, n
NTM
133
M. abscessus
5
M. asiaticum
2
M. avium ssp.
15
M. chelonae
5
M. fortuitum
4
M. gordonae
8
M. heckeshornense
1
M. interjectum
2
M. intracellulare
61
M. kansasii
6
M. lentiflavum
1
M. malmoense
1
M. scrofulaceum
3
NTM not speciated
8
Mixed NTM species
11
MTBc
6
Cultures with no mycobacterial DNA
54
Contaminated cultures
7
Total
200
NTM = non-tuberculous mycobacteria; M. = Mycobacterium; MTBc = M. tuberculosis complex.
12
10
Isolates, n
8 M. intracellulare M. avium M. gordonae
6
Mycobacterium spp. M. kansasii
4
2
0
Jan
Feb
March
April
May
June
July
Aug
Sept
Month
Fig. 1. Common Mycobacterium species isolated during the year 2010.
767
November 2014, Vol. 104, No. 11
Oct
Nov
Dec
RESEARCH
district. This was followed by 20 (15.0%) and 11 (8.3%) isolates from the Umkhanyakude and Uthungulu districts, respectively.
Discussion
In recent years there has been an increased awareness of NTM as disease-causing agents, especially in the growing HIV-infected population as well as in other immunosuppressed patients. In countries with high prevalence rates of M. tuberculosis, patients in whom AFB are detected on microscopy or culture are generally assumed to have TB and treated as such. The incorrect diagnosis leads to unnecessary and/or incorrect treatment of many patients who are in fact colonised or infected with NTM.[9] The most common species of NTM identified during the study period was M. intracellulare (45.9%), followed by M. avium ssp. (11.3%). These two species are often referred to as M. avium complex (MAC) and cannot be differentiated using phenotypic tests. There are, however, specific DNA probes in the molecular tests that allow for speciation of these two closely related and commonly isolated NTM. In this study, MAC accounted for 76 (57.1%) of the 133 NTM isolates. Six per cent of the cultured NTM were identified as M. gordonae. In the majority of cases this organism is considered to be nonpathogenic, and it is the most commonly isolated mycobacterial contaminant.[10] M. kansasii, which is the most common agent causing NTM disease in England and Wales, made up only 4.5% of NTM isolated in this study. Generally, tap water is reported to be the most frequent environmental source of this organism; infection may lead to lung disease that closely resembles tuberculosis.[10] The spectrum and distribution of NTM in sub-Saharan Africa is not well known, as most data originate from the more developed nations in Northern Europe and North America. This may not necessarily be due to a low incidence of NTM disease in developing countries, but rather result from less priority being given to NTM in regions where the TB burden is overwhelming. Buijtels et al.[11] reported that in Zambia, a country with a high prevalence of TB, MAC was the most frequently isolated NTM. Similarly, a study identifying NTM from clinical specimens in Ethiopia showed MAC to be the predominant species, followed by M. abscessus, M. gordonae, M. simiae and M. fortuitum.[12] The high frequency of isolation of MAC in both studies is in keeping with our findings. In an SA study of NTM in miners, the two most common isolates were M. kansasii (n=56) and M. scrofulaceum (n=14); only three of the isolates were identified as M. avium ssp.[6] This is in contrast to our study, where MAC predominated, with M. kansasii making up only 4.5% of NTM recovered. Ninety-three per cent of the NTM isolates were cultured from sputum. This is not surprising, as pulmonary TB remains the commonest form of TB in SA, hence the predominance of sputum samples being submitted for TB culture. Lung disease is also regarded as the most frequent clinical manifestation of NTM disease.[10] The province of KZN is divided geographically into 11 healthcare districts. Fifty-eight (43.6%) of the NTM originated from patients presenting to healthcare facilities in the eThekwini (Durban) district. Twenty-one (36.2%) of these isolates were identified as M. intracellulare. This organism was also found to be the predominant
768
NTM in all districts with the exception of Uthukela, where M. avium ssp. was the most common isolate. The high burden of TB disease in the eThekwini district, which has a large TB clinic as well as a TB referral hospital, may have resulted in a larger number of specimens being submitted for TB culture. This possibly accounted for the highest proportion of NTM being found in this district, rather than indicating a greater risk of NTM exposure.
Study limitations
This study had certain limitations. The absence of clinical and radiological data precluded determining the clinical significance of the NTM isolates. As a result, we could not determine whether disease was indeed due to a NTM, or if the organism was merely a contaminant. Furthermore, as a result of the long incubation period required for mycobacteria, many of the culture plates were found to be overgrown with non-mycobacterial contaminants, hindering the molecular process of identification.
Conclusion
The most common NTM isolated from patients with suspected mycobacterial disease were M. intracellulare and M. avium ssp., which is in keeping with findings elsewhere in the world. We believe that it is important for laboratories to document the local spectrum of NTM, even in developing countries, because of the geographical variation in the different NTM species isolated. Although the molecular tests for identifying NTM are relatively expensive and require expertise, they have the advantage of providing rapid and accurate identification of the various NTM species. Acknowledgement. This research was conducted at the NHLS central tuberculosis laboratory, IALCH, KwaZulu-Natal, SA. References 1. Falkinham JO III. The changing pattern of nontuberculous mycobacterial disease. Can J Infect Dis 2003;14(5):281-286. 2. Chetchotisakd P, Kiertiburanakul S, Mootsikopun P, Assanasen S, Chaiwarith R, Anunnatsiri S. Disseminated nontuberculous mycobacterial infection in patients who are not infected with HIV in Thailand. Clin Infect Dis 2007;45(4):421-427. [http://dx.doi.org/10.1086/520030] 3. Van Ingen J. Diagnosis of nontuberculous mycobacterial infections. Semin Respir Crit Care Med 2013;34(1):109-109. [http://dxdoi.org/10.1055/s-0033-1333569] 4. Oâ&#x20AC;&#x2122;Brien RJ, Geiter LJ, Snider DE Jr. The epidemiology of nontuberculous mycobacterial diseases in the United States: Results from a national survey. Am Rev Respir Dis 1987;135(5):1007-1014. 5. British Thoracic Society. Management of opportunistic mycobacterial infections: Joint Tuberculosis Committee Guidelines 1999. Thorax 2000;55(3):210-218. [http://dx.doi.org/10.1136/thorax.55.3.210] 6. Corbett EL, Blumberg L, Churchyard GJ, et al. Nontuberculous mycobacteria: Defining disease in a prospective cohort of South African miners. Am J Respir Crit Care Med 1999;160(1):15-21. [http:// dx.doi.org/10.1164/ajrccm.160.1.9812080] 7. Cook VJ, Turenne CY, Wolfe J, Pauls R, Kabani A. Conventional methods versus 16S ribosomal DNA sequencing for identification of nontuberculous mycobacteria: Cost analysis. J Clin Microbiol 2003;41(3):1010-1015. [http://dx.doi.org/10.1128/JCM.41.3.1010-1015.2003] 8. Hain Lifescience. GenoTypeÂŽ Mycobacterial CM/AS. http://www.hain-lifescience.co.za/products/ microbiology/mycobacteria/genotype-mycobacterium-cmas.html (accessed 10 March 2010). 9. Jesudason MV, Gladstone P. Non tuberculous mycobacteria isolated from clinical specimens at a tertiary care hospital in South India. Indian J Med Microbiol 2005;23(3):172-175. [http://dx.doi. org/10.4103/0255-0857.16589] 10. Griffith DE, Aksamit T, Brown-Elliot BA, et al. An official ATS/IDSA statement: Diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 2007;175(4):367416. [http://dx.doi.org/10.1164/rccm.200604-571ST] 11. Buijtels PCAM, van der Sande MAB, de Graaff CS, et al. Nontuberculous mycobacteria, Zambia. Emerg Infect Dis 2009;15(2):242-249. [http://dx.doi.org/10.3201/eid1502.080006] 12. Girmachew F. Identification on nontuberculosis mycobacteria from clinical specimens referred to national TB reference laboratory, Ethiopia. Presented at the 8th TB Research Advisory Committee (TRAC) Conference, 23 March 2013, Addis Ababa, Ethiopia. http://ehnri.gov.et/TRAC%20CON/ Day%20Three/Feven%20EDITED%20Presentation.pdf (accessed 12 June 2013).
Accepted 2 June 2014.
November 2014, Vol. 104, No. 11
RESEARCH
Determining need for hospitalisation: Evaluation of the utility of the CRB-65 score in patients with community-acquired pneumonia presenting to an emergency department D M Kabundji,1 MB BCh, MSc Med (Emergency Medicine); A Musekiwa,2 MSc (Math Statistics); M Mukansi,3 MB BCh, FCP (SA); C Feldman,3 MB BCh, DSc, PhD, FRCP, FCP (SA) elen Joseph Hospital and Division of Emergency Medicine, Department of Family Medicine, Faculty of Health Sciences, H University of the Witwatersrand, Johannesburg, South Africa 2 Wits Reproductive Health and HIV Institute, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa 3 Division of Pulmonology, Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa 1
Corresponding author: D M Kabundji (jdmulombe@yahoo.fr)
Background. The CRB-65 severity of illness score, used for assessing patients with community-acquired pneumonia (CAP), may be of particular benefit in resource-constrained areas, since it relies purely on clinical parameters. Objective. To assess the potential accuracy of the CRB-65 score when used in deciding whether to hospitalise patients with CAP presenting to an emergency department (ED). Methods. Prospective, observational study in an academic hospital in Johannesburg, South Africa. Data from adult patients with radiologically confirmed CAP were analysed. Results. Overall, 152 patients were enrolled (79 females, 73 males; median age 36.5 years). Several diverse criteria had been used by the ED doctors in admission decisions, while the CRB-65 score had been used in only 3/152 patients (1.6%). Overall, 68/152 patients (44.7%) had been managed as inpatients and 84/152 (55.3%) as outpatients. If the CRB-65 had been used as the sole criterion for site-of-care decisions, 107/152 patients (70.4%) would potentially have been managed as outpatients and 45/152 (29.6%) as inpatients. Achieving a stable clinical condition took longer (p=0.037) and mortality was higher (p<0.001) in patients with higher than lower CRB-65 scores. All five patients who died were inpatients. Of these, three (60.0%) would have been classified by the CRB-65 as having an intermediate mortality risk and two (40.0%) as having a high mortality risk. Conclusions. This study demonstrates the utility of the CRB-65 score in accurately determining the need for admission of patients with CAP presenting to an ED in a resource-constrained environment. S Afr Med J 2014;104(11):769-772. DOI:10.7196/SAMJ.8150
Despite recent advances in the management of community-acquired pneumonia (CAP), it remains a common and potentially lethal infectious disease. CAP mortality is variable, depending on the site of care. It is <1% in the outpatient setting, about 5 - 15% in inpatients not requiring intensive care unit (ICU) care, up to 25% in intubated patients, and nearly 50% in ICU patients requiring vasopressors.[1-4] Determination of disease severity is crucial in the assessment and management of patients with CAP in the emergency department (ED), since it guides various interventions and decisions, including the optimal site of care (i.e. need for hospital or ICU admission or suitability for home care). Several tools have been developed to assist in the prediction of severity of CAP, including the CRB-65 score.[3] This scoring system was developed from the CURB-65 score and derived from the British Thoracic Society rule, but is simpler to use. It has been recommended for use in the community setting in the UK, and has an accuracy similar to that of the CURB-65 score and the Pneumonia Severity Index (PSI).[1,3,5] However, since it does not require measurement of the blood urea level, it may be of particular value in areas with limited resources. We wished to assess the potential accuracy of the CRB-65 score used to determine the need for admission to hospital of patients with CAP
769
presenting to the ED at Helen Joseph Hospital (HJH), Johannesburg, South Africa (SA), in an area with a high prevalence of HIV infection.
Materials and methods Study design and population
This was a prospective, observational, hospital-based study of a consecutive sample of 152 adult patients aged ≥18 years with CAP seen in the ED at HJH between February 2011 and April 2011. It was purely an observational study and the researchers did not play any role in clinical management of the patients, including decisions regarding severity of illness or need for hospital admission. Once the ED doctors had diagnosed a patient as having CAP and personally managed the case (including determining, by whatever criteria they used, whether the patient needed to be admitted to hospital or not), they informed the primary study investigator (DMK) about the patient. After obtaining written informed consent from the patient, DMK evaluated each case for purposes of the study, in the first instance confirming that the patient actually had CAP. For the purposes of the study the following criteria were used for the definition of CAP, as described previously:[6] two or more of the following: altered breath sounds and/or signs of lung consolidation, fever, rigors, sweats and cough, with or without sputum production,
November 2014, Vol. 104, No. 11
RESEARCH
pleuritic chest pain, cyanosis, shortness of breath and tachypnoea, together with radiological confirmation of the diagnosis of pneumonia. Chest radiographs (CXRs) were initially evaluated by the attending ED doctors or registrars, and confirmed for study purposes as demonstrating pneumonia by DMK. Excluded were cases of suspected or confirmed aspiration pneumonia, chemical pneumonitis, Pneumocystis jirovecii pneumonia and pulmonary tuberculosis. Patients with any acute or active comorbid illness such as diabetes mellitus, renal failure, cardiac failure or end-stage AIDS were similarly excluded. Thereafter, DMK found out from the ED doctors what criteria they had used to assess the severity of illness and/or determine the need or not for hospital admission of the patients. The CRB-65 severity of illness score was then evaluated in each CAP study patient by the primary researcher. In this scoring system, one point is assigned for each of the following parameters, if present: confusion, respira tory rate (RR) ≥30/min, systolic blood pressure (BP) <90 mmHg and/or diastolic PB ≤60 mmHg, and age ≥65 years.[3,5] The abbreviated mental test, modified for SA conditions (AMTMSA), was used for objective assessment of the presence/ absence of confusion.[3,4,7] Confusion was further defined as an AMTMSA score of ≥8 or presence of new disorientation for place or time.[7-9] It has previously been suggested that patients with a CRB-65 score of 0 are at low risk of mortality and may be suitable for management as outpatients. Patients with a score of 1 or 2 are at intermediate risk of mortality and should be considered for hospital-supervised treatment, while those with scores of 3 or 4 are at high risk of mortality and may require high care or ICU care.[3,5] The study patients were therefore classified into low, moderate and high mortality risk groups. DMK documented demographic and clinical features, including age, gender, the AMTMSA score, systolic and diastolic blood pressure, heart rate, respiratory rate, body temperature, site of care (outpatient or inpatient) and outcome. These parameters were used to determine the CRB-65 score, as well as the time to clinical stability and the mortality rate. Time to clinical stability was determined according to a validated rule, described previously, that defined clinical stability as the first day on which most of the following criteria were simultaneously achieved: systolic BP ≥90 mmHg; RR ≤24/ min; heart rate ≤100 bpm, oxygen saturation (on room air) ≥92%, temperature ≤37.2°C,
ability to tolerate oral intake, and baseline mental status.[10] Admission day was day 0, with the second admission day as day 1 and so on. Patients who were treated as outpatients were personally contacted telephonically 2 weeks after the ED visit, with prior consent, to determine their outcome. The numbers of patients admitted and discharged by the ED physicians were compared with the numbers who would have been admitted or discharged if the CRB-65 score had been used in this decision-making process. Furthermore, the CRB-65 scores were evaluated in relation to the time to clinical stability among the patients who were admitted, and to the outcome of all cases, including those treated at home. These outcome variables were used to evaluate the potential accuracy, and hence the utility, of the CRB-65 score.
Statistical methods
For the analysis of the data, descriptive statistics were summarised using frequencies and cross-tabulations. For non-normally distributed continuous variables, medians and their associated ranges were calculated and reported. Associations between categorical outcomes were formally tested using the χ2 test and Fisher’s exact test. The latter was used when the expected numbers of subjects in the cells were less than 5. Results were presented using p-values. Throughout the analysis, two-sided statistical tests were
used at the 5% level of significance. STATA 11.0 was used in the analysis of the data.
Results
A total of 152 patients were enrolled into the study. There were 79 females (52.0%) and 73 males (48.0%), age range 20 - 87 years (median 36.5). The majority of the patients (98.0%) had a normal AMTMSA score (10/10). The median systolic blood pressure was 114 mmHg (range 86 - 172), diastolic blood pressure 72 mmHg (35 100), heart rate 103 bpm (58 - 158), RR 23.5/min (14 - 38) and temperature 37.8ºC (36 - 41). As shown in Table 1, the most common criterion used by the HJH ED doctors to decide whether patients should be admitted to hospital or not was the appearance of the CXR (41.5%), followed by the haemodynamic parameters of the patients (25.9%) and thereafter, somewhat less frequently, various other parameters. The CRB-65 score was used in only 1.6% of cases. On the basis of these criteria, 68/152 (44.7%) of all the enrolled patients had been managed in hospital by the ED physicians, with the remaining 84/152 (55.3%) treated as outpatients. Had the CRB-65 score been the sole criterion on which this decision had been based, 107/152 patients (70.4%) would potentially have been managed as outpatients and 45/152 (29.6%) in hospital. Table 2 shows the association between the CRB-65 score and the time to clinical
Table 1. Criteria used for decisions regarding admission or discharge of CAP patients Criterion
Admitted n (%)
Discharged n (%)
Total n (%)
CXR
47 (49.0)
33 (34.0)
80 (41.5)
Haem. para.
3 (3.0)
47 (48.0)
50 (25.9)
Blood
6 (6.0)
15 (15.0)
21 (10.9)
O2 sat.
20 (21.0)
_
20 (10.4)
Fever
5 (5.0)
_
5 (2.6)
CURB-65
2 (2.0)
2 (2.0)
4 (2.1)
CRB-65
2 (2.0)
1 (1.0)
3 (1.6)
Adv. RVD
2 (2.0)
_
2 (1.0)
Tachycardia
2 (2.0)
_
2 (1.0)
RD
2 (2.0)
_
2 (1.0)
IV antibiotic
1 (1.0)
_
1 (0.5)
Dehydration
1 (1.0)
_
1 (0.5)
Ren. dysf.
1 (1.0)
_
1 (0.5)
SOB
1 (1.0)
_
1 (0.5)
Total
95 (100.0)
98 (100.0)
193 (100)
CAP = community-acquired pneumonia; CXR = chest radiograph; Haem. para. = haemodynamic parameters; Blood = blood test results; O2 sat. = saturation of oxygen on room air; Adv. RVD = advanced retroviral disease; RD = respiratory distress; IV antibiotic = need for intravenous antibiotics; Ren. dysf. = renal dysfunction; SOB = shortness of breath.
770
November 2014, Vol. 104, No. 11
RESEARCH
Table 2. Association between time to clinical stability and CRB-65 scores among the CAP patients Time to clinical stability (days) n (%) CRB-65 score
1
2
3
Total, n
0
16 (47.0)
17 (50.0)
1 (3.0)
34
1-2
6 (21.5)
16 (57.0)
6 (21.5)
28
3-4
_
1 (100.0)
_
1
Total
22 (35.0)
34 (54.0)
7 (11.0)
63
CAP = community-acquired pneumonia.
Table 3. CRB-65 scores in patients stratified according to outcome (alive/dead) CRB-65 score
Alive, n (%)
Dead, n (%)
0
107 (100.0)
_
107
1-2
39 (93.0)
3 (7.0)
42
3-4
1(33.0)
2 (67.0)
3
Total
147 (97.0)
5 (3.0)
152
stability. There was a significantly shorter time to clinical stability in patients with a lower CRB-65 score (Fisher’s exact test p=0.037). The total of 63 in-hospital patients in the table excludes the five deaths that occurred in the overall total of 68 in-hospital patients. These five patients did not reach clinical stability at any time during their hospital stay and therefore could not be used in the assessment of this parameter. Table 3 shows the association between mortality and the CRB-65 score in the CAP patients. There were no deaths among the outpatients, but five of the in-hospital patients died. Three of these five patients would have been classified by the CRB-65 score as having an intermediate mortality risk and two as having a high mortality risk, which would have required that they be admitted. Patients with a higher CRB-65 score were at a significantly higher risk of death than patients with a lower CRB-65 score (Fisher’s exact test p<0.001).
Discussion
Main study findings
The main findings of this study, which we believe is the first in a resource-constrained environment, were as follows: (i) the CRB-65 score was used very infrequently by the ED doctors at this hospital; (ii) had the CRB-65 score been used as the criterion for hospital admission, far fewer patients would have been admitted (all the additional patients who were admitted to hospital having had a good outcome), (iii) all the discharged patients had a CRB-65 score confirming that they could indeed be considered for treatment
Total, n
safely at home (notably, all survived); (iv) the patients admitted to hospital with a lower CRB-65 score had a shorter time to clinical stability and a lower mortality compared with patients with a higher CRB-65 score; and (v) all the patients who ultimately died would have been admitted on the basis of their CRB-65 scores.
Interpretation of findings in relation to previously published work
The CRB-65 score was used very infrequently by the ED doctors, being utilised in only 3/152 cases (1.6%), while the CURB-65 score was utilised in only 4/152 cases (2.6%). Surprisingly, there have been very few studies investigating the use of severity of illness scoring systems by ED clinicians, but at least one study documen ted low utilisation and compliance with a validated ED triage system.[11] Furthermore, even when severity of illness scoring systems are used for assessment of patients with pneumonia in the ED, ED providers often do not rely on them for decision-making regarding hospitalisation.[12] However, we did not address the question of why the doctors did not use the scoring system more frequently. The CXR was the most frequently used criterion used by the ED doctors for admitting CAP patients to hospital for treatment, whereas haemodynamic criteria were most commonly used for discharge decisions. The specific CXR criteria that encouraged HJH ED doctors to admit patients were not specifically investigated in the current study.
771
November 2014, Vol. 104, No. 11
However, when we subsequently reviewed the CXR findings of all the patients (data not shown), we noted that the most common radiographic features among the patients who had been admitted were bilateral infiltration, multilobar consolidation and significant pleural effusion. Interestingly, in the study by Espana et al.,[13] multilobar/ bilateral lung involvement on the CXR and abnormal haemodynamic parameters (systolic BP <90 mmHg, RR >30/min and altered mental status) were among eight independent predictive factors for severe CAP. Had the CRB-65 score been used, fewer patients would have been admitted to hospital. ED doctors admitted 68/152 patients (44.7%) and discharged 84/152 (55.3%), whereas had the CRB-65 score been used for admission decisions, a total of 107/152 patients (70.4% – all classified as at low mortality risk) would potentially have been managed as outpatients, while 45/152 (29.6% – 42 classified as at intermediate mortality risk and three as at high mortality risk) would have been managed as inpatients. Similarly, in the study described above documenting that ED providers did not rely on the PSI for determining the initial site of care for patients with CAP, many lowrisk cases (258/689; 37.4%) were admitted to hospital.[12] Evidence suggests that ED physicians tend to overestimate the risk of death among patients with CAP, consequently leading to hospitalisation of many patients at low risk of mortality. Importantly, in the current study the outcome of all these additional low-risk patients who had been hospitalised was good, and there were no deaths among them. It is clear that this may have considerable cost implications, as demonstrated in many studies. In their study of the cost of treating patients with CAP, Lave et al.[14] concluded that hospital admission of low-risk patients with CAP is far more costly than outpatient treatment. A documented example given was $264 for outpatients and $7 500 for inpatients (including hospital and physician care and follow-up care). In a study of preferences of home v. hospital care among low-risk patients with CAP, Coley et al.[15] came to a similar conclusion. Among the patients admitted to hospital, those with a lower CRB-65 score had a significantly shorter time to clinical stability (p=0.037) and lower mortality. All the deaths were of inpatients: 3/5 (60.0%) would have been classified by the CRB-65 score as having an intermediate mortality risk, with the remaining 2/5 (40.0%) having a high mortality risk. If the CRB-65 score had been used as the
RESEARCH
sole criterion for hospital admission, all the deaths would have occurred among patients who would have been assessed as needing hospital, and possibly even high-care or ICU, admission. The CRB-65 score would therefore have appeared to perform well, being able to predict the time to clinical stability and the risk of death for hospitalised patients with CAP. Others have arrived at the same conclusion. For example, in their study of predictive accuracy of the PSI versus the CRB-65 for time to clinical stability, Arnold et al.[16] found that the CRB-65 score was a powerful yet simple tool for predicting time to clinical stability and death among patients with CAP. In a study of 338 406 patients with CAP from Germany, Ewig et al.[17] came to a similar conclusion. As international studies have done, our study therefore showed that the CRB-65 severity of illness score, which is based exclusively on three bedside clinical signs and age, appears to accurately predict the time to clinical stability and the risk of death in patients with CAP. Importantly, this scoring tool worked well in a resource-constrained environment that is also an area of high HIV prevalence.
Limitations and strengths of the study
The study has limitations. While undertaken in SA, a country with a high prevalence of HIV and resource constraints, it encompassed only one institution. The findings may therefore not be generalisable to other countries or other institutions. Furthermore, the ethnic origin of the patients, their socioeconomic status and home circumstances, and their habits (with regard to alcohol consumption, drug use and cigarette smoking) were not recorded. It is possible that these factors may have impacted on our findings. The study has strengths. It was a prospective investigation, and therefore all the information that was required for the study analysis was collected. It is also the first study we are aware of that used the CRB-65 score in a resource-constrained environment.
Conclusion
In conclusion, this study demonstrates the potential ability of the CRB-65 severity of illness scoring system to assist ED physicians with decisions regarding the optimal site of care of patients with CAP in a resource-constrained environment. Further studies are required, in particular an interventional study in which the CRB65 score is implemented for decision-making in some patients, and its performance compared with cases in which decision-making is based on the usual standard of care, whatever that may be. Lastly, it is important to remember that severity of illness scoring systems are a guide and cannot take the place of sound clinical judgement. Acknowledgements. This study formed the basis of DMKâ&#x20AC;&#x2122;s research report for the MSc Med degree in the specialty of Emergency Medicine from the
772
University of the Witwatersrand. The authors thank the study participants, Helen Joseph Hospital and the University of the Witwatersrand staff who assisted in this study. Authorsâ&#x20AC;&#x2122; contributions. DMK planned the study, wrote the protocol, performed data processing, evaluated and interpreted the results and wrote the article. AM performed the statistical analysis and assisted in the writing up of the statistical methods and results. He also assisted in the writing of the article. MM assisted in the writing of the protocol and the article. CF conceived the study, and assisted in the writing up of the protocol, in evaluation and interpretation of the results, and in the writing of the article. Funding. CF is supported by the National Research Foundation of South Africa. References 1. Restrepo MI, Anzueto A. Severe community-acquired pneumonia. Infect Dis North Am 2009;23(3):503-520. [http://dx.doi.org/10.1016/j.idc.2009.04.003] 2. Moran GJ, Talan DA, Abrahamian FM. Diagnosis and management of pneumonia in the emergency department. Infect Dis Clin North Am 2008;22(1):53-72. [http://dx.doi.org/10.1016/j.idc.2007.10.003] 3. Angus DC, Marrie TJ, Obrosky DS, et al. Severe community-acquired pneumonia: Use of intensive care services and evaluation of American and British Thoracic Society diagnostic criteria. Am J Respir Crit Care Med 2002;166(5):717-723. [http://dx.doi.org/10.1164/rccm.2102084] 4. Rodriguez A, Mendia A, Sirvent JM, et al. Combination antibiotic therapy improves survival in patients with community-acquired pneumonia and shock. Crit Care Med 2007;35(6):1493-1498. [http://dx.doi.org/10.1097/01.CCM.0000266755.75844.05] 5. Feldman C, Brink AJ, Richards GA, et al. Management of community-acquired pneumonia in adults. South Afr J Epidemiol Infect 2008;23(2):31-42. [http://dx.doi.org/10.1016/S1473-3099(07)70242-6] 6. RD Bulletin. June 2007, volume 14 issue 5. www.ich.ucl.ac.uk/bulletin (accessed 27 December 2013). 7. Moran G. Approaches to treatment of community-acquired pneumonia in the emergency department and the appropriate role of fluoroquinolones. J Emerg Med 2006;30(4):377-387. [http://dx.doi. org/10.1016/j.jemermed.2005.07.009] 8. Hodkinson HM. Evaluations of a mental test score for assessment of mental impairment in the elderly. Age Ageing1972;1(4):233-8. [http://dx.doi.org/10.1093/ageing/1.4.233] 9. Wikipedia. Abbreviated mental state score. 2009. http://en.wikipedia.org/wiki/abbreviated_mental_ test_score#cite_note-hodkinson72-0 (accessed 22 December 2013). 10. Menendez R, Torres A, Rodriguez de Castro F, et al. Reaching stability in community-acquired pneumonia: The effects of the severity of disease, treatment, and the characteristics of patients. Clin Infect Dis 2004;39(12):1783-1790. [http://dx.doi.org/10.1086/426028] 11. Christensen D, Jensen NM, Maaloe R, et al. Low compliance with a validated system for emergency department triage. Dan Med Bull 2011;58(6):A4294. 12. Aujesky D, McCausland JB, Whittle J, et al. Reasons why emergency department providers do not rely on pneumonia severity index to determine the initial site of treatment for patients with pneumonia. Clin Infect Dis 2009;49(10):e100-e108. [http://dx.doi.org/10.1086/644741] 13. Espana PP, Capelastegui A, Gorordo I, et al. Development and validation of a clinical predictive rule for severe community-acquired pneumonia. Am J Respir Crit Care Med 2006;174(11):1249-1256. [http:// dx.doi.org/10.1164/rccm.200602-177OC] 14. Lave JR, Lin CJ, Hughes-Cromwish P, et al. The cost of treating patients with communityacquired pneumonia. Semin Respir Crit Care Med 1999;20(3):189-198. [http://dx.doi. org/10.1055/s-2007-1021315] 15. Coley CM, Li YH, Medsger AR, et al. Preferences for home vs hospital care among low-risk patients with community-acquired pneumonia. Arch Intern Med 1996;156(14):1565-1571. [http://dx.doi. org/10.1001/archinte.1996.00440130115012] 16. Arnold FW, Brock GN, Peyrani P, et al. Predictive accuracy of the pneumonia severity index vs CRB65 for time to clinical stability: Results from the Community-Acquired Pneumonia Organization (CAPO) international cohort study. Resp Med 2010;104(11):1736-1743. [http://dx.doi.org/10.1016/j. rmed.2010.05.022] 17. Ewig S, Birkner N, Strauss R, et al. New perspectives on community-acquired pneumonia in 388 406 patients. Results from a nationwide mandatory performance measurement programme in healthcare quality. Thorax 2009;64(12):1062-1069. [http://dx.doi.org/10.1136/thx.2008.109785]
Accepted 12 May 2014.
November 2014, Vol. 104, No. 11
RESEARCH
The association of khat (Catha edulis) chewing and orodental health: A systematic review and meta-analysis A Astatkie,1 BSc, MPH; M Demissie,2 MD, MPH, PhD; Y Berhane,2 MD, MPH, PhD 1 2
School of Public and Environmental Health, College of Medicine and Health Sciences, Hawassa University, Hawassa, Ethiopia Addis Continental Institute of Public Health, Addis Ababa, Ethiopia
Corresponding author: A Astatkie (ayalewastatkie@gmail.com)
Background. It has been claimed that chewing khat (Catha edulis), a plant common in parts of eastern and southern Africa and the Arabian Peninsula, is associated with a range of orodental problems. Objective. To provide a synthesis of the evidence on the association between khat chewing and orodental health. Method. A systematic review and meta-analysis of studies that reported on the association of khat chewing and outcomes related to orodental health identified through a systematic search using web-based electronic search engines. Results. Nineteen studies were found suitable for this review. Of these, between two and five (based on the type of outcome measured) were suitable for meta-analysis. The rest were used only for qualitative synthesis. A meta-analysis of the association of khat chewing with mucosal white lesions, gum recession, periodontal pocketing and gum bleeding showed that chewing increased the odds of the respective oral problems. However, qualitative synthesis of the findings on the effect of khat chewing on oral micro-organisms showed no evidence that the practice favours the presence of pathogenic micro-organisms in the oral cavity – instead, it seems to favour the proliferation of micro-organisms compatible with orodental health. Conclusion. Khat chewing is associated with adverse orodental health outcomes. While literature on the topic is scarce and there is a need for generation of more evidence from different countries, on the basis of the evidence accumulated to date, public health officials and health practitioners should consider khat a threat to orodental health and take appropriate action. S Afr Med J 2014;104(11):773-779. DOI:10.7196/SAMJ.8070
Khat (Catha edulis) is a green shrub that grows in several countries in eastern and southern Africa and the Arabian Peninsula.[1-3] The leaves and tender shoots are commonly chewed by people in these regions, and by ethnic minorities who have emigrated from these areas to other parts of the world.[3,4] Psychostimulation and euphoria result from the chewing and seem to reinforce the habit.[5] While there are more than 40 chemical constituents in khat, the alkaloid called cathinone is the active principle and responsible for its stimulant effect.[6,7] Many health problems have been attributed to the khat chewing habit,[4,7,8] including a range of orodental problems[9] ranging from stomatitis[10] and plasma cell gingivitis[11,12] to oral cancer.[13] However, much of the literature is inconclusive and contradictory. For example, Mengel et al.[14] and Ali[15] found khat chewing to have adverse effects on periodontal health, and Al-Sharabi et al.[16] found that heavy chewing is associated with clinical attachment loss. In contrast, based on an experimental study of 17 people (eight khat chewers and nine non-chewers), Al-Hebshi and Al-Ak’hali[17] showed khat chewing to have antiplaque and antigingivitis properties; similarly, Jorgensen and Kaimenyi[18] found that the oral hygiene status of khat chewers was better than that of non-chewers, and that there was no evidence that khat chewing was detrimental to periodontal health. Such contradictions in the literature call for a systematic qualitative and quantitative synthesis of the evidence in the literature available to date. We report a systematic review and meta-analysis of the evidence on the association between khat chewing and orodental health, which to our knowledge is the first such work.
773
Methods
Literature search strategy
To search the available literature for this review and meta-analysis, we carried out a web-based search using the advanced features of PubMed, Google Scholar, Embase, Scopus and the Directory of Open Access Journals (DOAJ). The PubMed search was carried out using the EndNote bibliographic software. In Google Scholar, search results were downloaded using the Zotero software and then exported to EndNote. Pertinent search results from Embase, Scopus and the DOAJ were individually downloaded and manually archived in EndNote. We used various key words for the search. Khat, Catha edulis, qat, q’at, qaat, kath, kat, gat, miraa, murungu, tohai, herari, jaad, kaad, oral, oral health, dental, dental health, periodontal, periodontal health, tooth, tooth loss, gingivitis and periodontal pocketing were used as key words in various combinations using a Boolean search technique. For example, in PubMed we used the following combinations of key terms for the search: khat AND oral, khat AND dental, khat AND oral health, khat AND dental health, khat AND periodontal, khat AND periodontal health, khat AND periodontal pocketing, khat AND tooth, khat AND tooth loss, and khat AND gingivitis. The term khat was subsequently alternated with the search terms Catha edulis, qat, q’at, qaat, kath, kat, gat, miraa, murungu, tohai, herari, jaad and kaad. In Google Scholar, Embase, Scopus and the DOAJ, the following combination of search terms was used in one go: khat AND (oral OR dental OR ‘oral health’ OR ‘dental health’ OR periodontal OR ‘periodontal health’ OR ‘periodontal pocketing’ OR tooth OR ‘tooth loss’ OR gingivitis). As in PubMed, here also the term khat was alternated with other terms. We also used Google search, mainly
November 2014, Vol. 104, No. 11
RESEARCH
to identify ‘grey literature’; the World Health Organization (WHO) database (HINARI) and specific journal websites were also searched. The references of the relevant literature so obtained were consulted in order to locate additional literature (ancestry search). The literature identified through Google, HINARI, journal-specific websites and the ancestry search was manually entered into EndNote. Finally, the EndNote libraries created for the different search strategies were merged and duplicate retrievals removed. The last literature search for this systematic review and metaanalysis was undertaken on 10 February 2014.
Inclusion and exclusion criteria
To be included into this systematic review and meta-analysis, the study had to be original, could be observational or experimental, had to include both khat chewers and non-chewers (except in studies designed to investigate the in vitro effect of khat extract on oral micro-organisms at varying concentrations of the extract), and should have measured oral health-related outcomes in both groups. In vitro experiments that investigated the potential effect of khat on orodental health were also included. Both articles published in peer-reviewed journals and unpublished research outputs such as theses (‘grey literature’) were included. Not only studies that reported the statistical association between khat chewing and oral health-related outcomes were included; studies were considered for inclusion as long as they presented the outcomes for khat chewers and non-chewers. No time limit was imposed for the search, in order to identify as much literature as possible, and there were no restrictions regarding the language in which articles were published. Case reports and studies that included only khat chewers, those that did not report sufficient and clear findings on the association of the dependent and independent variables, those that used a purely convenience selection of study participants, commentaries, letters to the editor and debates were excluded. In the case of duplicate publications, later versions of the duplicated articles were excluded.
Selection of relevant references
For all studies identified through the search strategies described above, the title was examined first. Studies with irrelevant titles were excluded outright. For studies with titles that seemed relevant, the abstracts, and if necessary the objectives, methods and key variables, were examined. Subsequently, studies that failed to fulfil the inclusion criteria described above were excluded. In the case of unpublished reports that were relevant but where a full report could not be found online, an attempt was made to contact the authors; if no contact addresses of the authors could be found, the reports were excluded.
Data extraction
Required data were extracted from the studies selected, according to the criteria described above, using a format prepared for this purpose by one of the authors (AA). Various attributes of the studies selected such as the author(s), year of publication, country where the study was conducted, study design, sample size, cell frequencies for a 2 × 2 cross-tabulation of the relationship between the exposure of interest (i.e. khat chewing) and the presence or absence of the outcome of interest (i.e. a specific oral health-related outcome), etc. were extracted from the studies. When 2 × 2 cross-tabulations were not readily available in the studies, they were constructed based on the information provided in the text. As the oral health-
774
related outcome/s measured differed from study to study, the data extraction was performed separately based on the type of outcome measured (oral mucosal white lesions, gingival recession, gum bleeding, etc.).
Data analysis and reporting
The extracted data that could be combined by means of metaanalysis were entered into a computer as separate data files based on the type of outcome measured using the statistical software IBM SPSS Statistics version 20 (IBM, USA) and then exported to Stata 12 (StataCorp LP, USA) for analysis. Generally, we performed four separate meta-analyses on the association of khat chewing and oral white lesions (n=5 studies), the association of khat chewing and gum recession (n=4), the association of khat chewing and periodontal pocketing (n=2) and the association of khat chewing and gum bleeding (n=2). Tests for heterogeneity in effect size among the original studies were carried out using the χ2-based test statistic (Q-test) and the I2 test statistic. For three of the meta-analyses, the χ2 tests were significant (p<0.001) and I2 ≥95% in the fixed-effects model, and the random-effects model was therefore used to determine the DerSimonian and Laird summary effect (i.e. odds ratio (OR)). It is also logical to assume that the studies were heterogeneous, as they were carried out at different times, by different researchers, on different populations and in different settings. For the model for which the test of heterogeneity was not significant, the summary effect measure obtained from the fixed-effect model using the inverse-variance method was retained. To determine whether the effect sizes were small, medium or large, we converted the overall OR of each metaanalysis to effect size using the formula suggested by Chinn[19] and applied Cohen’s cut-offs.[20] The possible presence of publication bias was investigated by visual inspection of funnel plot symmetry and by using a regression test (based on Egger’s test). However, the regression test could be performed only in the analyses that used three or more studies. For analyses that used only two studies, the possible existence of publication bias was based on visual inspection of funnel plot symmetry alone. For studies that were relevant but could not be included in the meta-analysis, a synthesis of the findings is reported. Reporting of the present systematic review and meta-analysis is in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guideline.[21]
Results
Description of the original studies
After removing duplicate retrievals, 2 369 articles, including ‘grey literature’, were obtained. Of these, 30 were eligible for full article reading. Eleven[13,22-31] of the 30 articles were excluded because they did not meet the inclusion criteria. Nineteen studies were therefore found appropriate for this systematic review and meta-analysis (only eight of the 19 studies were suitable for metaanalysis) (Fig. 1). Based on the outcomes measured, the studies can be grouped into six categories: (i) studies that measured oral white lesions (n=5); (ii) studies that measured gingival recession (n=4); (iii) studies that measured periodontal pocketing (n=2); (iv) studies that investigated gum bleeding (n=2); (v) studies that investigated oral micro-organisms (n=4); and (vi) studies that measured other oral health-related outcomes (n=7). As some studies measured more than one outcome, the sum of the number of studies falling into the different categories was more than 19.
November 2014, Vol. 104, No. 11
RESEARCH
360 articles retrieved through PubMed search
7 525 articles and grey literature obtained via Google Scholar, Embase, Scopus, DOAJ, Google, HINARI, journal-specific websites and ancestry search
After removing duplicates, 2 369 articles and grey literature obtained
2 339 articles excluded because they were irrelevant (did not meet the inclusion criteria)
All 2 369 articles assessed based on titles and abstracts
30 full-text articles assessed for eligibility
19 studies included in qualitative synthesis
8 studies included in quantitative synthesis (meta-analysis)
11 full-text articles excluded for various reasons: • 2 studies[13,22] included only cancer cases. Comparison was impossible • 1 study[23] was a case report • 3 studies[24,25,28] included only khat chewers. Comparison was impossible • In 1 study,[26] the outcome measured and the presentation of results were ambiguous • 1 study[27] investigated the effect of khat extract on in vitro-reconstructed oral mucosa • 1 study[29] involved volunteers • For 1 study,[30] a full report could not be found • 1 study[31] was a duplicate of another[45]
Fig. 1. Flow diagram showing article retrieval for this review. (DOAJ = Directory of Open Access Journals.)
Of the 19 studies, 15[14-17,32-42] were carried out in Yemen, three[18,43,44] were from Kenya and one[45] was from Israel (conducted among people of Yemeni origin). In terms of design, 15 were cross-sectional, three were experimental (both in vivo and in vitro) and one was a case-control study. Eighteen of the 19 studies were journal articles and only one[40] fell into the ‘grey’ category. Year of publication ranged from 1990[18] to 2013.[16] Details of the studies are given in Table 1.
The association of khat chewing and orodental health
Of the 19 studies in this review, five investigated the association of khat chewing with oral mucosal white lesions. Four[38,40,41,45] of the five studies showed a statistically significant association between khat chewing and oral mucosal white lesions (i.e. there was a higher relative frequency of occurrence of oral mucosal white lesions in chewers than in non-chewers). Only Macigo
et al.[43] reported an association that was not statistically significant. Although the point estimate of the effect size they reported is closer to 2, the 95% confidence interval (CI) embraced 1, rendering the association insignificant. Of the 19 studies, four[15,39,41,42] investigated the association between khat chewing and gum recession. In all four studies, khat chewing had a statistically significant posi tive association with the presence of gum recession. Similarly, two[15,39] of the 19 studies repor ted on the association between khat chewing and periodontal pocketing. Both studies documented that a significantly higher proportion of chewers than non-chewers were affected by periodontal pocketing. These same studies also investigated the association between khat chewing and gum bleeding. One[15] of the studies used periodontal examination to establish the presence or absence of bleeding, while the other[39] was based on participants’ selfreport. Both showed that the occurrence of
775
November 2014, Vol. 104, No. 11
gum bleeding was significantly higher in khat chewers than in non-chewers. Of the 19 studies included in this review, four[33-36] investigated the in vitro effect of crude khat extracts on oral micro-organ isms and the effect of khat chewing on periodontal bacteria identified from suband supra-gingival plaques. All four studies, undertaken by Al-Hebshi and colleagues, demonstrated a possible antimicrobial effect of khat on oral micro-organisms. In one of the in vitro studies,[33] the authors showed a selective antimicrobial effect of crude khat extracts on oral microorganisms. They demonstrated that while bacteria associated with periodontal disease were sensitive to the extracts, bacteria associated with periodontal health were less sensitive, and cariogenic bacteria were not susceptible. They further showed that the khat extracts resulted in a two- to four-fold potentiation of tetracycline and penicillin G activities against some oral bacterial strains. In another study, Al-Hebshi et al.[35] showed that crude khat extracts interfered with the ability of Streptococcus mutans to form adherent biofilms, implying that khat may have anticariogenic effects. In two other studies,[34,36] investigating the effect of khat chewing on sub- and supra-gingival bacteria from chewers and non-chewers, Al-Hebshi and colleagues showed that khat chewing did not seem to increase colonisation of gingival plaque by periodontal pathogens[36] but rather decreased the total pathogen burden and increased the total sub-gingival bacterial count,[34] implying that khat chewing may favour the presence of bacterial species compatible with periodontal health. Seven[14,16-18,32,37,44] of the 19 studies compared various oral health-related outcomes between khat chewers and non-chewers. Al-Bayaty et al.[32] analysed the association between khat chewing and mean number of teeth lost, stratified by gender, and showed that among female chewers the mean was significantly higher than among female non-chewers. The mean difference was not statistically significant (at an alpha value of 0.05) between male chewers and male non-chewers. Similarly, Mengel et al.[14] studied 1 001 subjects selected randomly from schools, clinics, university and private dental practice in four different areas of Yemen, and reported that the mean community periodontal index of treatment need (CPITN) index, mean attachment loss and mean calculus index were all higher in khat chewers than in non-chewers. However, these authors did not report on the statistical significance of the differences.
RESEARCH
Table 1. Overview of the studies included in this systematic review and meta-analysis Study (author, year)
Country
Study design
Sample size
Literature type
Ali et al., 2004
Yemen
Cross-sectional
2 500
Journal article
Gorsky et al., 2004[45]
Israel
Cross-sectional
102
Journal article
Macigo et al., 1995
Kenya
Case-control
226
Journal article
Al-Sharabi, 2011[41]
Yemen
Cross-sectional
650
Journal article
Al-Sanabani, 2011[40]
Yemen
Cross-sectional
162
Grey
[15]
Ali, 2007
Yemen
Cross-sectional
2 500
Journal article
Al-Kholani, 2010[39]
Yemen
Cross-sectional
730
Journal article
Ali et al., 2006
Yemen
Cross-sectional
50 (70 biopsies)
Journal article
Al-Bayaty et al., 2011[32]
Yemen
Cross-sectional
2 506
Journal article
Jorgensen and Kaimenyi, 1990
Kenya
Cross-sectional
430
Journal article
Mengel et al., 1996[14]
Yemen
Cross-sectional
1 001
Journal article
Al-Hebshi and Al-Ak’hali, 2010
Yemen
Experimental
17
Journal article
Al-Sharabi et al., 2013[16]
Yemen
Cross-sectional
500
Journal article
[33]
Al-Hebshi et al., 2006
Yemen
In vitro experiment
33 oral microbial strains
Journal article
Al-Hebshi et al., 2005[35]
Yemen
In vitro experiment
1 bacterial strain (Streptococcus mutans)
Journal article
Al-Hebshi et al., 2005[36]
Yemen
Cross-sectional
51 (408 sub- and supra-gingival plaques)
Journal article
Al-Hebshi et al., 2010
Yemen
Cross-sectional
20 (40 sub-gingival plaque)
Journal article
Amran and Ataa, 2011[42]
Yemen
Cross-sectional
602
Journal article
Nyanchoka et al., 2008
Kenya
Cross-sectional
167
Journal article
[38]
[43]
[37]
[18]
[17]
[34]
[44]
We tried to test the statistical significance of the mean differences, but it was not possible as the authors of the original study had not reported the standard deviations of the respective means. Nyanchoka et al.,[44] in their study in Kenya (N=162), found a significantly higher caries rate, as measured by the decayed, missing and filled teeth (DMFT) index, in khat chewers than in non-chewers. They found the mean DMFT score in current chewers to be 8.778, while that in subjects who never chewed khat was 6.529. The authors suggested that the higher DMFT score in chewers could be a result of cariogenic substances such as soft drinks that are often consumed with khat. Al-Sharabi et al.[16] also found that khat chewing significantly increased the odds of clinical attachment loss. However, they found that the community periodontal index (CPI) was not significantly associated with khat chewing. Ali et al.,[37] in a study of biopsies taken from the oral mucosa of khat chewers and non-chewers, showed clear histopathological changes in biopsies taken from the chewing side of the mouths of chewers, while such changes were almost non-existent in biopsies from non-chewers. On the other hand, Jorgensen and Kaimenyi[18] and Al-Hebshi and Al-Ak’hali[17] reported what could be considered a ‘beneficial’ effect of khat chewing on periodontal health. Jorgensen
% Study
Sample size
OR (95% CI)
weight
Ali et al., 200438
2 500
46.43 (20.62 - 104.53)
20.31
Gorsky et al., 200445
102
24.92 (8.78 - 70.75)
19.83
Macigo et al., 1995
226
1.83 (0.72 - 4.63)
20.09
Al-Sharabi, 2011
650
1 267.07 (410.75 - 3 908.66) 19.64
162
19.96 (8.06 - 49.40)
20.13
34.62 (5.21 - 230.22)
100.00
43
41
Al-Sanabani, 201140
Overall (I2=95.0%; p=0.000) NOTE: Weights are from random effects analysis. 0.01 Reduce lesions
1
100 Increase lesions
Fig. 2. Forest plot of the effect measure of khat chewing on oral mucosal white lesions. (OR = odds ratio; CI = confidence interval.)
and Kaimenyi[18] reported lower mean gingivitis scores and lower mean surface plaque scores among khat chewers than among non-chewers, while documenting no significant difference in terms of attachment loss, while Al-Hebshi and Al-Ak’hali[17] reported lower mean scores for plaque index, gingival index and bleeding on probing among chewers than among non-chewers.
Meta-analysis
The effect measure (both in individual studies and in pooled form) of khat chewing on various oral health-related outcomes is
776
November 2014, Vol. 104, No. 11
shown in the forest plots in Figs 2 - 5. The pooled effect measure of khat chewing on oral mucosal white lesions, gum recession, periodontal pocketing and gum bleeding is summarised in Table 2. In all cases, the pooled effect of chewing is an increase in the odds of the outcome of interest. The effect sizes for oral mucosal white lesions and gum recession were large (1.95 and 1.33, respectively), while those for periodontal pocketing and gum bleeding were medium (0.61 and 0.56, respectively). Although the 95% CIs of two of the effect measures are very wide, signalling lack of robustness of
RESEARCH
% weight
Study
Sample size
OR (95% CI)
Ali , 200715
2 500
3.63 (2.18 - 6.04)
28.82
Al-Sharabi, 201141
650
34.87 (19.07 - 63.74)
28.36
730
2.86 (2.10 - 3.89)
29.59
602
240.96 (14.90 - 3 896.48) 13.23
Al-Kholani, 201039 Amran and Ataa, 2011
42
11.19 (2.89 - 43.31)
Overall (I2=95.1%; p=0.000)
100.0
NOTE: Weights are from random effects analysis. 0.01 1 Reduce recession
100 Increase recession
Fig. 3. Forest plot of the effect measure of khat chewing on gingival recession. (OR = odds ratio; CI = confidence interval.) % Study
Sample size
OR (95% CI)
weight
Ali, 200715
2 500
3.26 (2.61 - 4.07) 64.99
Al-Kholani, 201039 730
2.70 (1.99 - 3.65) 35.01
Overall (I2=0.0%; p=0.326)
3.05 (2.55 - 3.65) 100.00
0.01
Reduce pocketing
1
100 Increase pocketing
Fig. 4. Forest plot of the effect measure of khat chewing on periodontal pocketing. (OR = odds ratio; CI = confidence interval.) % Study
Sample size
OR (95% CI)
weight
Ali, 200715
2 500
4.08 (3.42 - 4.87) 51.39
Al-Kholani, 201039 730
1.85 (1.35 - 2.53) 48.61
Overall (I2=94.6%; p=0.000)
2.78 (1.28 - 6.03) 100.00
NOTE: Weights are from random effects analysis. 0.01
Reduce bleeding
1
100 Increase bleeding
Fig. 5. Forest plot of the effect measure of khat chewing on gum bleeding. (OR = odds ratio; CI = con fidence interval.)
the effect size estimates (probably owing to the small number of studies used for the meta-analyses), looking at the lower bounds of the intervals alone shows that the effects are considerable. Assessment of the possible presence of publication bias by visual inspection of
funnel plots revealed no evidence of bias, though it was difficult to judge the symmetry reliably owing to the small number of studies included in the meta-analysis. A regression test using Egger’s test for the possible presence of publication bias showed no evidence of bias for the meta-analyses
777
November 2014, Vol. 104, No. 11
that pooled five and four studies. For the two meta-analyses that used two studies each, a regression test was not possible.
Discussion
This systematic review and meta-analysis presents a synthesis of the evidence regard ing the association between khat chewing and various orodental health-related outcomes, based on the best studies available at the time the review was conducted. On the basis of the evidence presented, khat chewing is shown to be associated with various adverse oral and dental health outcomes such as oral mucosal white lesions, gingival recession, periodontal pocketing and gum bleeding. The summary effect size of khat chewing on the various outcomes was shown to be considerable. It has been claimed that continuous mechanical friction and exposure to the chemical content in khat[46] may result in adverse consequences in the oral cavity. Continuous exposure of the oral mucosa to a high concentration of the alkaloids in khat[47] could account for the effects on the oral mucosa observed. Date et al.[48] have suggested that pesticides on khat may cause acute and chronic adverse health outcomes, implying that pesticides applied to khat in the process of production could constitute an additional insult to the oral cavity. Although two studies[17,18] reported what appears to be a ‘beneficial’ effect of khat chewing on periodontal health, the findings were not substantiated by subsequent studies and could not counteract the evidence that demonstrated khat chewing to be associated with adverse orodental health. Regarding the effect of khat chewing on oral micro-organisms, the available evidence consistently indicates that chewing did not favour the proliferation of pathogenic oral micro-organisms. Rather, it was shown to have selective antimicrobial effects and to favour the presence of micro-organisms compatible with oral health. This does not imply that its use should be encouraged, as two of these four studies were conducted under in vitro conditions and may not be replicable in vivo. Additionally, the mechanical and chemical insults to the oral tissues resulting from chewing khat may create fertile conditions for infection of tissues of the oral cavity, as abraded tissues can be susceptible to infection even by the normal flora of the oral cavity. Given that only a few studies were identified for the present review, and that most of them were just from one country, there appears to be a paucity of evidence on the association of the dependent and independent variables that were the focus of the review. While khat chewing is common in several African
RESEARCH
Table 2. Summary effect size of khat chewing on oral mucosal white lesions, gum recession, periodontal pocketing and gum bleeding Outcome
Studies included, n
Summary effect measure OR (95% CI)
Oral mucosal white lesions
5
34.62 (5.21 - 230.22)
Gum recession
4
11.19 (2.89 - 43.31)
Periodontal pocketing
2
3.05 (2.55 - 3.65)
Gum bleeding
2
2.78 (1.28 - 6.03)
OR = odds ratio; CI = confidence interval.
countries such as Ethiopia, Somalia, Eritrea, Kenya, Djibouti and Uganda, in countries of the Arabian Peninsula such as Yemen and Saudi Arabia, and in other parts of the world,[1-3] the fact that most of the evidence is based on studies conducted in one country (Yemen) suggests that the issue has not been prioritised as a subject for research in other countries where the habit is commonplace. Additionally, the fact that most (15/19) of the studies included in this review were conducted in Yemen may limit generalisability of the evidence to a broader context, as aspects of the chewing habit and its effects may differ from country to country. However, in spite of the possibility of contextual differences in the habit, we maintain that the mechanisms (chemical, mechanical or other) by which khat chewing may result in the aforementioned orodental outcomes do not change significantly. While the amount of khat chewed and the duration of chewing, as well as other habits such as smoking and concomitant use of sweet substances such as sugar, soft drinks, tea, coffee, etc., may modify the orodental effect of khat chewing in any direction, we consider that the net effect attributable to khat remains the same. We therefore believe that the findings of the present review may apply to contexts beyond those in which the original studies were conducted. Most of the studies included in our metaanalysis did not control for the effects of possible confounding variables such as cigarette smoking and consumption of sweet substances. We therefore did a meta-analysis of the crude ORs. If adjusted effect measures were available and used, the effect sizes might have differed (at least might have been slightly lower). Furthermore, different studies measured different orodental health-related outcomes. Even a single outcome was measured in different ways. Some authors measured the outcomes as ‘present/absent’ or ‘yes/no’, while others used scoring systems and reported outcomes numerically. These inconsistencies in reporting outcomes, coupled with the scarcity of studies investigating the asso
ciation of khat chewing with orodental health, make synthesis of evidence and pooling effect measures problematic. We were therefore able to pool effect measures for only four outcomes (oral white lesions, periodontal pocketing, gingival recession and gum bleeding). The association of khat chewing with the multitude of other orodental health-related outcomes remains scant and unclear. This calls for proper investigation of the association of khat chewing with different oral and dental health-related outcomes in a consistent way.
Conclusion
Khat chewing has been shown to be associated with adverse orodental health outcomes such as oral mucosal white changes, gum recession, periodontal pocketing and gum bleeding, with effect sizes ranging from medium to large. It has also been shown that chewing is associated with other indicators of periodontal health and tooth loss. The evidence that khat chewing is associated with adverse orodental health consequences outweighs that of studies reporting what seemed to be beneficial effects of khat. Public health officials and health practitioners should therefore consider khat a threat to orodental health and take appropriate action. Further studies on the association of khat chewing and orodental health should come from countries that have overlooked the issue so far. High-powered cohort and/ or case-control studies that control for the confounding effect of variables such as smoking are required to come up with stronger evidence of the association between khat chewing and orodental health. Finally, the present review should be updated in the light of studies that will emerge in the future. Acknowledgement. There was no funding support to conduct this review. We are grateful to the authors of the original studies upon which this review is based. References 1. Fitzgerald J. Khat: A Literature Review. Centre for Culture, Ethnicity & Health, and Louise Lawrence Research, 2009. http:// www.ceh.org.au/downloads/khat_report_final.pdf (accessed 25 September 2014).
778
November 2014, Vol. 104, No. 11
2. Lemessa D. Khat (Catha edulis): Botany, Distribution, Cultivation, Usage and Economics in Ethiopia. Addis Ababa: United Nations Development Programme, Emergencies Unit for Ethiopia (UNDP-EUE), 2001. 3. Advisory Council on the Misuse of Drugs (ACMD). Khat (Qat): Assessment of Risk to the Individual and Communities in the UK. London: Home Office, 2005. 4. Al-Motarreb A, Baker K, Broadley KJ. Khat: Pharmacological and medical aspects and its social use in Yemen. Phytother Res 2002;16(5):403-413. [http://dx.doi.org/10.1002/ptr.1106] 5. Brenneisen R, Fisch HU, Koelbing U, Geisshusler S, Kalix P. Amphetamine-like effects in humans of the khat alkaloid cathinone. Br J Clin Pharmacol 1990;30(6):825-828. [http:// dx.doi.org/10.1111/j.1365-2125.1990.tb05447.x] 6. Kalix P, Khan I. Khat: An amphetamine-like plant material. Bull World Health Organ 1984;62(5):681-686. 7. Dhaifalah I, Šantavý J. Khat habit and its health effect: A natural amphetamine. Biomedical Papers 2004;148(1):11-15. [http:// dx.doi.org/10.5507/bp.2004.002] 8. Cox G, Rampes H. Adverse effects of khat: A review. Advances in Psychiatric Treatment 2003;9(6):456-463. [http://dx.doi. org/10.1192/apt.9.6.456] 9. El-Wajeh YAM, Thornhil MH. Qat and its health effects. Br Dent J 2009;206(1):17-21. [http://dx.doi.org/10.1038/ sj.bdj.2008.1122] 10. Halbach H. Medical aspects of the chewing of khat leaves. Bull World Health Organ 1972;47(1):21-29. 11. Marker P, Krogdahl A. Plasma cell gingivitis apparently related to the use of khat: Report of a case. Br Dent J 2002;192(6):311-313. [http://dx.doi.org/10.1038/sj.bdj.4801364] 12. Rawal SY, Rawal YB, Anderson KM, Bland PS, Stein SH. Plasma cell gingivitis associated with khat chewing. Perio 2008;5(1):21-28. 13. Soufi HE, Kameswaran M, Malatani T. Khat and oral cancer. J Laryngol Otol 1991;105(8):643-645. [http://dx.doi.org/10.1017/ S0022215100116913] 14. Mengel R, Eigenbrodt M, Schunemann T, Flores-de-Jacoby L. Periodontal status of a subject sample of Yemen. J Clin Periodontol 1996;23(5):437-443. [http://dx.doi.org/10.1111/ j.1600-051X.1996.tb00571.x] 15. Ali AA. Qat habit in Yemen society: A causative factor for oral periodontal diseases. Int J Environ Res Public Health 2007;4(3):243-247. [http://dx.doi.org/10.3390/ijerph2007030008] 16. Al-Sharabi AK, Shuga-Aldin H, Ghandour I, Al-Hebshi NN. Qat chewing as an independent risk factor for periodontitis: A crosssectional study. Int J Dent 2013;2013: Article ID 317640. [http:// dx.doi.org/10.1155/2013/317640] 17. Al-Hebshi NN, Al-Ak’hali MS. Experimental gingivitis in male khat (Catha edulis) chewers. J Int Acad Periodontol 2010;12(2):56-62. 18. Jorgensen E, Kaimenyi JT. The status of periodontal health and oral hygiene of Miraa (Catha edulis) chewers. East Afr Med J 1990;67(8):585-590. 19. Chinn S. A simple method for converting an odds ratio to effect size for use in meta-analysis. Stat Med 2000;19(22):3127-3131. [http:// dx.doi.org/10.1002/1097-0258(20001130)19:22%3C3127::AIDSIM784%3E3.3.CO;2-D] 20. Cohen J. A power premier. Psychol Bull 1992;112(1):155-159. [http://dx.doi.org/10.1037/0033-2909.112.1.155] 21. Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group. Preferred Reporting Items for Systematic Reviews and MetaAnalyses: The PRISMA Statement. BMJ 2009;339:b2535. [http:// dx.doi.org/10.1136/bmj.b2535] 22. Sawair FA, Al-Mutwakel A, Al-Eryani K, et al. High relative frequency of oral squamous cell carcinoma in Yemen: Qat and tobacco chewing as its aetiological background. Int J Environ Health Res 2007;17(3):185-195. [http://dx.doi. org/10.1080/09603120701254813] 23. Fasanmade A, Kwok E, Newman L. Oral squamous cell carcinoma associated with khat chewing. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;104(1):e53-e55. [http://dx.doi. org/10.1016/j.tripleo.2007.01.010] 24. Sultan M, Alhadad KA, Alsanaban F. Tooth lost and gingival recession as a risk factor of khat chewing in Yemen. Cairo Dental Journal 2008;24(2):171-176. 25. Cobián OG, Triguero RJP, Pérez HS, Salgado KMR. Trastornos temporomandibulares en adictos al qat [Temporomandibular disorders in qat addicted people]. Rev Cubana Estomatol 2012;49(4):268-275. 26. Halboub E, Dhaifullah E, Abdulhuq M. Khat chewing and smoking effect on oral mucosa: A clinical study. Acta Medica (Hradec Kralove) 2009;52(4):155-158. 27. Lukandu OM, Neppelberg E, Vintermyr OK, Johannessen AC, Costea DE. Khat alters the phenotype of in vitro-reconstructed human oral mucosa. J Dent Res 2010;89(3):270-275. [http:// dx.doi.org/10.1177/0022034509354980] 28. Ali AA. Histopathologic changes in oral mucosa of Yemenis addicted to water-pipe and cigarette smoking in addition to takhzeen al-qat. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;103(3):e55-e59. [http://dx.doi.org/10.1016/j. tripleo.2006.10.008] 29. Hill CM, Gibson A. The oral and dental effects of q’at chewing. Oral Surg Oral Med Oral Pathol 1987;63(4):433-436. [http:// dx.doi.org/10.1016/0030-4220(87)90255-6] 30. Ayagah IN, Dimba E, Macigo F, Wanzala P. Effect of khat chewing in the oral cavity. https://iadr.confex.com/iadr/ afrmde05/preliminaryprogram/abstract_69180.htm (accessed 15 November 2012). 31. Yarom N, Epstein J, Levi H, Porat D, Kaufman E, Gorsky M. Oral manifestations of habitual khat chewing: A case-control study.
RESEARCH
Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010;109(6):e60-e66. [http://dx.doi.org/10.1016/j. tripleo.2010.02.022] 32. Al-Bayaty FH, Ali NAW, Bulgiba AM, Masood M, Hussain SF, Abdulla MA. Tooth mortality in khat and non khat chewer in Sana’a Yemen. Scientific Research and Essays 2011;6(5):1039-1045. 33. Al-Hebshi N, Al-Haroni M, Skaug N. In vitro antimicrobial and resistance-modifying activities of aqueous crude khat extracts against oral microorganisms. Arch Oral Biol 2006;51(3):183-188. [http:// dx.doi.org/10.1016/j.archoralbio.2005.08.001] 34. Al-Hebshi NN, Al-Sharabi AK, Shuga-Aldin HM, Al-Haroni M, Ghandour I. Effect of khat chewing on periodontal pathogens in subgingival biofilm from chronic periodontitis patients. J Ethnopharmacol 2010;132(3):564-569. [http://dx.doi.org/10.1016/j.jep.2010.08.051] 35. Al-Hebshi NN, Nielsen Ø, Skaug N. In vitro effects of crude khat extracts on the growth, colonization, and glucosyltransferases of Streptococcus mutans. Acta Odontol Scand 2005;63(3):136-142. [http:// dx.doi.org/10.1080/00016350510019838] 36. Al-Hebshi NN, Skaug N. Effect of khat chewing on 14 selected periodontal bacteria in sub- and supragingival plaque of a young male population. Oral Microbiol Immunol 2005;20(3):141-146. [http://dx.doi.org/10.1111/j.1399-302X.2004.00195.x] 37. Ali AA, Al-Sharabi AK, Aguirre JM. Histopathological changes in oral mucosa due to takhzeen alqat: A study of 70 biopsies. J Oral Pathol Med 2006;35(2):81-85. [http://dx.doi.org/10.1111/j.16000714.2006.00362.x] 38. Ali AA, Al-Sharabi AK, Aguirre JM, Nahas R. A study of 342 oral keratotic white lesions induced by qat chewing among 2500 Yemeni. J Oral Pathol Med 2004;33(6):368-372. [http://dx.doi.org/10.1111/ j.1600-0714.2004.00145.x] 39. Al-Kholani AI. Influence of khat chewing on periodontal tissues and oral hygiene status among Yemenis. Dent Res J 2010;7(1):1-6.
40. Al-Sanabani JSM. Oral white lesions due to qat chewing among women in Yemen. Doctor Medicinae Dentariae thesis. Berlin: Universitätsmedizin, 2011. 41. Al-Sharabi AK. Conditions of oral mucosa due to takhzeen al-qat. Yemeni Journal of Medical Sciences 2011;5:1-6. 42. Amran AG, Ataa MAS. Statistical analysis of the prevalence, severity and some possible etiologic factors of gingival recessions among the adult population of Thamar city, Yemen. RSBO (Online) 2011;8(3):305-313. 43. Macigo FG, Mwaniki DL, Guthua SW. The association between oral leukoplakia and use of tobacco, alcohol and khat based on relative risks assessment in Kenya. Eur J Oral Sci 1995;103(5):268-273. [http://dx.doi.org/10.1111/j.1600-0722.1995.tb00025.x] 44. Nyanchoka IN, Dimba EAO, Chindia ML, Wanzala P, Macigo FG. The oral and dental effects of khat chewing in the Eastleigh area of Nairobi. Journal of the Kenya Dental Association 2008;1(1):37-42. 45. Gorsky M, Epstein JB, Levi H, Yarom N. Oral white lesions associated with chewing khat. Tob Induc Dis 2004;2(3):145-150. [http://dx.doi.org/10.1186/1617-9625-2-3-145] 46. Hassan NAGM, Gunaid AA, Murray-Lyon IM. Khat (Catha edulis): Health aspects of khat chewing. East Mediterr Health J 2007;13(3):706-718. 47. Al-Habori M. The potential adverse effects of habitual use of Catha edulis (khat). Expert Opin Drug Saf 2005;4(6):1145-1154. [http://dx.doi.org/10.1517/14740338.4.6.1145] 48. Date J, Tanida N, Hobara T. Qat chewing and pesticides: A study of adverse health effects in people of the mountainous areas of Yemen. Int J Environ Health Res 2004;14(6):405-414. [http://dx.doi. org/10.1080/09603120400012884]
Accepted 3 July 2014.
Duchenne muscular dystrophy: High-resolution melting curve analysis as an affordable diagnostic mutation scanning tool in a South African cohort A I Esterhuizen,1,2 MSc (Med); J M Wilmshurst,3 MB BS, MD, MRCP (Lond), FCPaed (SA); R G Goliath,1,2 PhD; L J Greenberg,1 PhD ivision of Human Genetics, Department of Clinical Laboratory Sciences, Institute of Infectious Diseases and Molecular Medicine, D Faculty of Health Sciences, University of Cape Town, South Africa 2 National Health Laboratory Service, Groote Schuur Hospital, Cape Town, South Africa 3 Paediatric Neurology and Neurophysiology, Red Cross Children’s War Memorial Hospital, School of Child and Adolescent Health, Faculty of Health Sciences, University of Cape Town, South Africa 1
Corresponding author: A I Esterhuizen (alina.esterhuizen@nhls.ac.za)
Background. Duchenne/Becker muscular dystrophy (D/BMD) is an X-linked recessive muscle disorder affecting 1/3 500 live male births worldwide. Up to 70% of all D/BMD cases are caused by exonic deletions or duplications routinely identified in diagnostic laboratories worldwide. The remaining patients harbour other sequence alterations for which testing availability is limited owing to the expense of interrogating the large DMD gene. Genetic screening for D/BMD in South Africa currently includes multiple ligase-dependent probe amplification (MLPA) for exonic deletions and duplications and linkage analysis. No genetic testing for small mutations in the DMD gene is offered, leaving a third of D/BMD families without genetic closure. The advent of potential mutation-specific therapies for DMD necessitates comprehensive testing protocols. Objective. To investigate the effectiveness and affordability of high-resolution melting curve analysis (hrMCA) for detection of small/point mutations in the DMD gene, for possible inclusion into the local public health-funded diagnostic service. Methods. DNA from 24 patients who had previously tested deletion-negative with multiplex polymerase chain reaction (mPCR) was analysed by MLPA and hrMCA. Results. MLPA revealed eight previously undetected exonic rearrangements: five deletions and three duplications. HrMCA of the remaining samples revealed three nonsense, four frameshifts, one splice-site, one missense and one single-base substitution in the Dp427promoter/ exon1 of the DMD gene. In addition, 41 polymorphisms and three changes of uncertain significance were detected. Conclusion. These findings identify hrMCA as an affordable and effective mutation scanning tool for incorporation into the local diagnostic setting, allowing for better genetic counselling of more DMD families and selection of potential candidates for future therapies. S Afr Med J 2014;104(11):779-784. DOI:10.7196/SAMJ.8257
Duchenne muscular dystrophy (DMD) (OMIM #310200) is the most common of the inherited muscular dystrophies and is caused by lack or faulty production of the dystrophin protein, which is a vital component of the dystrophin-associated protein complex, critical to the maintenance of the structural integrity of muscle fibres. DMD is an X-linked recessive disorder,
779
occurring at an incidence of 1/3 500 live male births worldwide.[1] It generally manifests in boys between the ages of 2 and 5 years and is typically marked by delayed motor milestones and symptoms such as frequent falling, difficulty in getting up, gait problems, toewalking and flat-footedness.[2] In untreated patients, respiratory and cardiac complications result in death at a mean age of 19 years. The milder, allelic form of DMD, Becker’s muscular dystrophy
November 2014, Vol. 104, No. 11
RESEARCH
A
X chromosome Xp21
0 B
500 M
1500
1000
P
Dp4278B Dp427M Dp427P
R
B3
Dp260
Dp140
NH2
B
2500kb
2000 S
G
Dp116
Dp71
CYS COOH Full length Muscle, brain, Purkinje neurons NH2 NH2 NH2 NH2
CYS COOH Dp260
Retina
CYS COOH Dp140
Brain3, kidney
CYS COOH Dp116
Peripheral nerve
CYS COOH Dp71
Ubiquitous
Fig. 1. The DMD gene and its products. A: Linear representation of the DMD gene located at Xp21 and its products (adapted from Muntoni et al.[11]). The black vertical lines represent the 79 exons of the dystrophin gene, distributed over about 2.5 million bases. The arrows indicate the various promoters: the full-length Dp427 brain (B), muscle (M), and Purkinje (P) promoters; Dp260 (retinal, R), Dp140 (brain3, B3), Dp116 (Schwann cells, S), and Dp71 (general, G) promoters. B: The domain composition of the various dystrophin proteins is indicated. The amino-terminal domain is followed by the spectrinlike, the cysteine-rich, and the carboxy-terminal domains. (DMD = Duchenne muscular dystrophy.) 1
2
3
4
5
6
7
8
9
10
11
12
13
14
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
23
24
25
26
27
28
29
30
37
38
39
40
A
B
18
31
19
20
21
22
32
33
34
35
36
C
Fig. 2. Exon phasing of relevant sections of the DMD gene and the predicted effect of the deletions detected in the cohort. The phase of each exon is represented by the shape of extremity of the box representing the exon. A vertical line represents an exon starting (or ending) at the 1st (or 3rd) nucleotide of a codon. An arrow shape represents an exon starting (or ending) at the 2nd or 3rd nucleotide of a codon. A: Out-of-frame deletion of exons 5 - 7. B: Out-of-frame deletion of exon 7. C: Out-of-frame deletion of exons 22 - 33. (Adapted with permission from www.humgen.nl/lab-aartsma-rus/. DMD = Duchenne muscular dystrophy.)
(BMD), occurs at a lower frequency (1/18 450 live male births), with a later age of onset, a more diverse presentation and a longer life expectancy.[3] D/BMD is a monogenic disease, caused by mutations in the dystrophin-encoding DMD gene, which encompasses ~2.5 Mb
of genomic sequence and a ~14 kb RNA transcript, comprising 79 exons and eight tissue-specific promoters (Fig. 1). Owing to its large size, the DMD gene is prone to mutations, of which approximately 70% are exonic deletions and duplications. These tend to cluster within two hotspot
780
November 2014, Vol. 104, No. 11
regions, spanning exons 44 - 53 and 2 - 20. The remaining 25 - 35% of the disease-associated changes are small/point alterations, mostly nonsense, frameshift or splice-site mutations.[4] These do not appear to exhibit any clustering effect, and because of the large size of the DMD gene, continue to present a significant diagnostic challenge. The genetic service for D/BMD at Groote Schuur Hospital, Cape Town, South Africa (SA) and the Division of Human Genetics, University of Cape Town (UCT), commenced in 1987 and was the first of its kind to be offered nationally by the state health services in SA.[5] The early testing protocol involved tracking the inheritance of the putative X chromosome using intragenic linkage markers and later included the deletion hotspot screen with multiplex polymerase chain reaction (mPCR), based on the work published by Chamberlain et al.[6] In 2000, the Human Genetics Laboratory in Johannesburg (now also incorporated into the National Health Laboratory Service (NHLS)) began diagnostic testing for D/BMD, using a similar protocol of mPCR and linkage analysis. [7] The genetic service for D/ BMD, currently offered by both centres, is extended to state and private patients in and outside SA. Introduction of the multiple ligasedependent probe amplification (MLPA) in 2007 by the NHLS in Cape Town and Johannesburg significantly improved the level of service, as the detection range of the assay spans all exons of the DMD gene, allowing for identification of exonic rearrangements across the gene, not just the hotspots. Furthermore, the dosage component of the MLPA enables identification of duplications in males and determination of female carrier status, which could not be achieved with the mPCR.[8] Determining the female carrier status is a significant aspect of any mole cular genetic service for D/BMD, not only for the purpose of effective genetic counselling but also for clinical monitoring and management of D/BMD carriers, who develop symptoms in approximately 22% of all cases. These may involve a cardiac pathology (dilated cardiomyopathy) with or without muscle weakness, which varies from very mild to a DMD-like clinical course.[9] Another advantage of the MLPA analysis for D/BMD is better delineation of the extent of the exonic deletion/duplication in an individual. Genotype-phenotype correlation studies in D/BMD have shown that the disease severity is influenced not so much by the
RESEARCH
Objective
The project was conducted as a pilot study aimed at investigating the effectiveness and affordability of high-resolution melting curve analysis (hrMCA) as a presequencing scanning tool for detection of small/point
mutations in the DMD gene, for possible inclusion into the local public health-funded diagnostic service.
on the ABI 3130xl Genetic Analyser (Life Technologies, USA) and the data files analysed with the GeneMapper v4.1 (Applied Biosystems, USA) and the Coffalyser.NET software (www.mlpa.com) (details available on request). The probable effect of the exonic changes on the ORF was predicted using the Reading Frame Checker (http://www.humgen.nl/scripts/ DMD_frame.php).
Methods
Patients and controls
The study panel included 24 unrelated boys diagnosed with D/BMD on the basis of clinical presentation and elevated creatine kinase levels. Laboratory confirmation of the diagnosis by immunohistochemistry (IHC) of muscle biopsy samples was available in 13 cases. IHC results were not available or muscle biopsies were not performed on the remaining 11 patients. Of the 24 boys, all of whom had previously tested deletionnegative with the mPCR hotspot screen offered routinely before 2007, 19 had been referred from the Neuromuscular Clinic at Red Cross War Memorial Children’s Hospital in Cape Town and five from other centres in the country. The cohort ethnicity reflected the patient base of the referral centres. Where available, archived DNA was retrieved from the DNA Registry (REC/REF 234/2010) at the Division of Human Genetics, UCT. Alternatively, DNA was extracted from blood lymphocytes, using standard techniques. DNA samples from two healthy male volunteers were obtained for inclusion as wild-type controls. The study protocol was approved by the Human Research Ethics Committee, UCT (REC/REF 416/2008), in keeping with the tenets of the Declaration of Helsinki (2008).
Mutation scanning with hrMCA
Principle HrMCA is based on the natural process of DNA denaturation or ‘melting’ upon exposure to a gradual increase in tempera ture. Double-stranded DNA (dsDNA) dissociates into single-stranded DNA (ssDNA) in the presence of an intercalating dye, which fluoresces only while incorpor ated into dsDNA. The melting process can be monitored by measuring the gradually diminishing amount of fluorescence during strand dissociation, and a melting curve is derived by plotting fluorescence v. temperature (Fig. 3). It has been recognised that the precise shape of the melting curve is a function of the DNA sequence. The observed thermal denaturation profile is characteristic of a specific DNA fragment and is dependent on its sequence length, base and guanine-cytosine (GC) content.[14] Successful hrMCA requires specialised instru m entation capable of collecting data with exquisite real-time and thermooptical precision. In this study, DNA of patients who tested MLPA-negative for exonic rearrangements was subjected to hrMCA on the RotorGene™6000 (Corbett Research, Australia), which is a real-time PCR and hrMCA platform suitable for a reliable high-resolution melting (HRM) analysis.[15]
MLPA analysis
Owing to the limitations of the mPCR method, all samples were retested for exonic rearrangements using the MLPA (PO34 and P035 probe mixes (MRC-Holland, Netherlands). The MLPA products were separated by capillary electro p horesis
100
Normalised Fluorescence
Normalised Minus C
size of the mutation, as by: (i) the location of the mutation in relation to the critical functional domains of the dystrophin protein; and (ii) the effect of the mutation on the DNA translational open reading frame (ORF).[10,11] This so-called ‘readingframe hypothesis’ argues that mutations that disrupt the ORF result in more severe phenotypes (DMD) than those where the reading frame is retained (BMD). The effect of an exonic rearrangement on the ORF and possibly the phenotype can be predicted, as the intron-exon boundaries have been well characterised and show that some exons of the DMD gene do not contain an integral number of triplet codons and if deleted will result in a frameshift of the mRNA (Fig. 2). While such predictions made on DNA-based test results should be approached with caution, they are thought to add value, especially in early diagnoses of cases with no family history, where possible anticipation of the disease severity may influence the approach to treatment. Nevertheless, molecular confirmation of the clinical diagnosis of B/DMD remains elusive to approximately a third of the SA D/BMD patient population, i.e. those carrying small/point mutations. Recent advances in the development of mutation-specific therapies for DMD support routine availability of testing for most D/BMD-causing mutations. While next generation sequencing and microarray studies present the ultimate technological approach and have been successfully employed by investigators abroad,[12,13] the platforms are prohibitively expensive in the local public health context and the bioinformatic support structure required for routine implementation is largely unavailable at present, though much effort is being made in that direction. Similarly, while the cost of direct BigDye Terminator sequencing (Life Technologies, USA) is no longer seen as high in the developed countries, it is still an expensive option in SA, especially considering the amount of sequencing required for analysis of the vast DMD gene. The work presented here was undertaken in response to the call from the clinical community in SA for local availability of affordable testing for all, or most, B/DMDcausing mutations.
0
-5
-10
76
Colour
77
78
79
80
Name
81
82
83
84
80 60 40 20
85
Genotype
Confidence %
wild type exon 47
control
100.00
female carrier exon 47
variation
59.82
DMD male exon 47
variation
55.56
A 76
77
78
79
80
81
82
83
84
210 220 230 A G A C A A A T C T C C A G T A G A T A A A G G T TA G A C A T T A G C
Fig. 3. High-resolution melting curve analysis and sequencing analysis of a family with a nonsense mutation in exon 47. A: A difference curve. B: A fluorescence normalised HRM curve. The darkest blue line represents the melting profile of the wild type (normal) DNA; the proband is in light blue and his mother (a DMD carrier) in medium blue. C: Sanger sequencing trace of exon 47 in the affected proband (c.6905G>A). (HRM = high-resolution melting; DMD = Duchenne muscular dystrophy.)
781
November 2014, Vol. 104, No. 11
Beyond the scope of mPCR Disrupted* Dp427m-unique N-terminus × 1/black Duplication (ex 1) c.-244-?_31+?dup 8
782
MLPA = multiple ligase-dependent probe amplification; HGVS = Human Genome Variation Society; DMD = Duchenne muscular dystrophy; mPCR = multiplex polymerase chain reaction. *The reading-frame predictions based on DNA findings may not reflect the actual changes at the mRNA level. Predictions for duplications are particularly risky, as non-tandem or complex duplications are frequently reported and the orientation of the duplicated fragment cannot be determined by DNA analysis.[10] † Diagrammatically represented in Fig. 2. ‡ The deletion may extend beyond the DMD gene, and its effect on the open reading frame or applicability to any potential therapy cannot be predicted with the data available here.
Beyond the scope of mPCR Disrupted* Dp427m-unique N-terminus Duplication (ex 1) c.-244-?_31+?dup 7
× 1/black
DMD; calf hypertrophy
Beyond the scope of mPCR Maintained* Actin-binding domain and central rod domain ending mid-repeat 13 Duplication (ex 3 - 36) c.94-?_5154+?dup 6
× 1/black
Not confirmed; late presentation
Outside of the hotspot Uncertain‡ Central rod domain, repeat 24 and hinge 4 cystein-rich domain carboxy-terminus Deletion (ex 61 -79) c.9085- ?_(*2691_?)del 5
× 1/black
DMD; calf hypertrophy, waddling, toe-walking
Outside of the hotspot Disrupted* Central rod domain hinge 4 Deletion (ex 61-63) c.9085-?_9286+?del 4
× 1/coloured
DMD; severe course, posterior cardiac infarction, good intellect
Outside of the hotspot Disrupted† Central rod domain repeats 6 - 11 Deletion (ex 22 - 33) c.2804-?_4674+?del 3
× 1/coloured
DMD; learning difficulties from early on
Exon 7 not included in mPCR Disrupted† Actin-binding domain Deletion (ex 7) c.531-?_649+?del 2
× 1/black
DMD; poor respiratory function, overweight, stopped walking at 11 years
? analytical error
DMD; waddling, toe-walking
Previously undetected due to Reading frame
Disrupted†
Dystrophin domain/s
Actin-binding domain
Clinical details
DMD; learning difficulties, calf hypertrophy, waddling gait × 1/black Deletion (ex 5 - 7) c.265-?_649+?del 1
Times detected/ ethnicity Variant (HGVS notation) No.
Table 1. Exonic deletions/duplications detected with the MLPA
RESEARCH
November 2014, Vol. 104, No. 11
PCR amplification and hrMCA The entire coding region of the DMD gene in each patient was PCR-amplified and subjected to hrMCA on the RotorGene™600, using 96 sets M13-tailed primer pairs and the EvaGreen (Biotum Inc.) intercalating dye. The primers were specifically designed for hrMCA and subsequent sequencing as published by Almomani et al.[16] Amplification efficiency in real time and hrMCA profiles of the test v. the wild-type DNA samples were compared by visual scrutiny and RotorGene™6000 Series Analysis Software (details available on request). Sequencing Fragments exhibiting altered HRM prof iles were sequenced with the uni versal M13 sequencing primers and the BigDye®Terminator v3.1 mix (Life Tech nologies, USA), using standard methods. The sequences were compared to the Leiden coding reference sequence (www.dmd. nl), based on the GenBank reference file NM_004006.1 of the Dp427m dystrophin isoform (with one difference: 12505G>A). The output files were analysed with the BioEdit Sequence Alignment Editor and the NCBI Basic Local Alignment Search Tool (BLAST) (www.ncbi.nlm.nih.gov). Bioinformatic analysis Possible disease association of the sequence variants was determined in silico using the ESEfinder 2.0, Human Splicing Finder (HSF), Sorting of Intolerant From Tolerant (SIFT), Transcription Element Search System (TESS). It must be emphasised that the results of such analyses are indicators of probable effects rather than definitive proof thereof. The final effect of a given mutation may be influenced by a combination of factors not necessarily taken into account during a computational search for a specific effect.
Results
MLPA analysis
The MLPA revealed eight exonic changes (five deletions and three duplications) previously undetected with the mPCR assay (Table 1), which was not capable of detecting duplications or deletions located outside of its range, largely limited to the deletion hotspots. The superior informativity of the MLPA in comparison with the previously used mPCR was clearly demonstrated here (as also shown by colleagues in Johannesburg).[7] The MLPA findings were confirmed by repeat MLPA and single-exon PCRs. No further analyses were carried out to confirm pathogenicity, as exonic rearrangements are an accepted cause of D/BMD.
RESEARCH
Table 2. Disease-associated small mutations detected No.
Variant
Translational effect
Times detected/ ethnicity Dystrophin domain
New?*
1
c.620T>G (exon 7)
Nonsense p.(Leu207X)
× 1/coloured
Actin-binding domain
Yes
2
c.4729C>T (exon 34)
Nonsense p.(Arg1577X)
× 1/coloured
Central rod domain repeat 12
No*
3
c.6905G>A (exon 47)
Nonsense p.(Trp2302X)
× 1/white
Central rod domain repeat 18
No*
4
c.503delC (exon 6)
Frameshift p.(Ala168fsX2)
× 1/coloured
Actin-binding domain
Yes
5
c.836_837delCG (exon 9)
Frameshift p.(Thr278fsX8)
× 1/black
Central rod domain repeat 1
Yes
6
c.8284dupA (exon 56)
Frameshift p.(Iso2762fsX10)
× 1/coloured
Central rod domain repeat 22
Yes
7
c.8028_8031dupGGTG (exon 55)
Splice/frameshift p.Val2677fsX4 × 1/black
Central rod domain repeat 22
Yes
8
c.2293-1G>A (exon 19)
Splice
× 1/coloured
Central rod domain repeat 4
Yes
9
c.-85T>C (Dp427m/exon1)
5ʹUTR
× 1/coloured
Transcription factor binding site
Yes
10
c.587T>C (exon 7)
Missense p.(Leu196Pro)
× 1/unknown
Actin-binding domain
Yes
*As per literature search and the Leiden Open Variation Database (LOVD), Leiden muscular dystrophy pages (http://www.dmd.nl).
[4]
Interestingly, the predicted effects of both duplication mutations detected were in conflict with the recorded phenotype. This is in fact consistent with the literature, where authors warn that while readingframe predictions are useful, DNA-based predictions of duplications in particular should be viewed with caution, as the true nature of the rearrangements may not be known owing to events such as nontandem rearrangements or altered splicing.[10]
HrMCA and sequencing
At least one hrMCA variant profile was noted in each of the 16 patients screened and variant profiles were noted in 218 (14%) of all the analysed PCR fragments (96 per patient). Cycle sequencing revealed sequence alterations in 54 (3%) of these hrMCA variants. This high number of false variants was attributed to the variable quality of the available DNA, as fresh blood specimens could not be obtained in every case. Also, the criteria applied for variant selection erred on the side of caution, to avoid missing disease-associated mutations. Ten of the sequence alterations found were classified as diseasecausing (Table 2) and comprised seven truncating mutations (three nonsense and four frameshifts), one splice-site, one missense and one point substitution in the Dp427 promoter/exon1 region of the DMD gene. Of these, only two (c.4729C>T and c.6905G>A) (Fig. 3) had previously been recorded in the Leiden Open Variation Database (LOVD), Leiden muscular dystrophy pages (http://www.dmd.nl).[4] The remaining eight mutations were accepted as novel, based on the LOVD and a literature search. Truncating mutations (nonsense and frameshifts) in the DMD gene are generally accepted as pathogenic, as are mutations affecting splicing (Table 2). Bioinformatics tools (previously listed) were used to confirm this, and to determine the probable pathogenicity of the novel missense mutation in exon 7 and the 5ʹUTR sequence change (Table 2). Testing of population cohorts of affected and wild-type samples yielded negative results, providing further evidence towards the pathogenic and private (i.e. patient/family specific) nature of both these mutations. It must again be mentioned that while the disease association suggested by such analyses is likely, a definitive elucidation of their role in disease pathogenesis can only be achieved with mRNA expression and functional studies, all of which were beyond the scope of this project. Where possible, archived DNA from family members was tested with PCR, restriction endonuclease (RE) or sequence analysis for the putative change identified in the proband. In each case, the mutation was shown to segregate with the affected phenotype. This did not
783
provide definitive proof as the variant could simply segregate with the inherited chromosome, but went towards strengthening the case for pathogenicity. Also identified were 41 benign polymorphisms, two of which were novel (data not shown). The assumption of non-pathogenicity was based their presence in multiple patients, co-segregation with pathogenic mutations, and/or previous reports of non-pathogenicity in the LOVD. Study findings also revealed three sequence alterations of uncertain clinical significance (data not shown), viewed as probably benign owing to their location at the 3ʹUTR and close proximity to other changes listed as non-pathogenic in the DMD LOVD. However, since no other pathogenic changes were found in these patients, additional studies are required to definitively exclude or establish their significance. No disease-associated mutations were identified in eight patients in the cohort. The reasons for this may be threefold. Firstly, the clinical diagnosis was not confirmed with muscle biopsies in four of these cases and in the absence of genetic diagnoses, clinical reassessments may be warranted. Secondly, in some cases only archived DNA extracted using different methods was available, which may have resulted in missed variants owing to compromised DNA integrity or the presence of impurities known to influence the outcomes of hrMCA. Lastly, some of the patients could carry deep intronic mutations resulting in novel splice sites and inclusion of intronic sequences into the mRNA. These ‘pseudoexon mutations’ cannot be picked up with DNA-based testing and the methods used here, owing to the exceptionally large size of the DMD introns, and require analysis of mRNA from muscle tissue.[17]
Discussion
In recent years, much effort has gone into investigating method ologies for comprehensive mutation detection in D/BMD, driven by the prospects of availability of mutation-based therapies. With that in mind, the major aim of this study was testing hrMCA as a screening tool for detection and characterisation of small/point mutations in the DMD gene in the local laboratory environment. We view identification of pathogenic mutations in ten out of 16 patients tested as a positive outcome, which has provided a significant part of the cohort and their families with previously unavailable genetic diagnoses. The method employed (hrMCA) was chosen for its ease and cost-effectiveness as a mutation scanning tool. In contrast to the diagnostic laboratories in developed countries, where
November 2014, Vol. 104, No. 11
RESEARCH
DNA sequencing is relatively inexpensive, the local cost of direct sequencing is high, at approximately ZAR100.00 per PCR fragment at the time of the study. This is a conservative estimate, which only partially factors in the cost of consumables and the analyst’s time. The size of the DMD gene, where approximately 96 PCR fragments must be sequenced to cover its coding region (with genomic DNA as a template), makes direct sequencing in the local context prohibitively expensive. This cost is considerably reduced with the use of a presequencing mutation scanning tool such as the hrMCA, at ~R7.00 per PCR fragment. Once a putative ‘family’ mutation is identified in the proband, testing of other members of the family can be performed cheaply by targeting a specific region of the gene with PCR, RE or sequencing analysis. Research involving point mutation detection in the DMD gene has previously been conducted locally. However, this is the first study in SA, and to our knowledge on the African continent, to take an all-encompassing approach to mutation profiling across the coding region of the DMD gene, i.e. detection of exonic rearrangements with the MLPA and small/point mutation detection with hrMCA and sequencing. Future plans for the molecular genetic service for DMD include establishing massive parallel sequencing as a diagnostic platform, which will further improve local mutation detection capabilities. An additional consideration is the superior nature of RNA-based analysis for definitive determination of the downstream effects of sequence alterations.[16] However, this requires muscle tissue sampling, which is invasive and is typically undertaken only in cases of clinically suspected D/BMD with negative results of molecular studies. This may change in the future, should RNA analysis become essential for ascertainment of eligibility for a mutation-based therapy. Until such time, however, DNA extracted from blood lymphocytes is likely to remain the mainstay of diagnostic testing.
Conclusion
The work described here provides the foundation for establishing a cost-effective, comprehensive and specific testing strategy for every D/BMD family. Furthermore, defining the mutations underlying the D/BMD phenotype in the SA population will facilitate establishing trends within the various population subgroups of SA, possibly correlating molecular features to the disease course and facilitating a more strategised approach to the
784
clinical and laboratory diagnostic protocols. The knowledge of the disease-causing mutations detected during this study provides patients and their families with a considerable head-start in the future, when mutation-based genetic therapy becomes a veritable therapeutic avenue. Acknowledgments. The study was funded by the Muscular Dystrophy Foundation, SA. The authors wish to thank the Foundation for their enthusiasm and support throughout. References 1. Emery AE. The muscular dystrophies. Lancet 2002;359(9307):687-695. [http://dx.doi.org/10.1016/ S0140-6736(02)07815-7] 2. Bushby K, Finkel R, Birnkrant DJ, et al. Diagnosis and management of Duchenne muscular dystrophy, part 1: Diagnosis, and pharmacological and psychosocial management. Lancet Neurol 2010;9(1):77-93. [http://dx.doi.org/10.1016/S1474-4422(09)70271-6] 3. Blake DJ, Kroger S. The neurobiology of Duchenne muscular dystrophy: Learning lessons from muscle? Trends Neurosci 2000;23(3):92-99. [http://dx.doi.org/10.1016/S0166-2236(99)01510-6] 4. Aartsma-Rus A, van Deutekom JC, Fokkema IF, van Ommen GJ, den Dunnen JT. Entries in the Leiden Duchenne muscular dystrophy mutation database: An overview of mutation types and paradoxical cases that confirm the reading-frame rule. Muscle Nerve 2006;34(2):135-144. [http://dx.doi. org/10.1002/mus.,20586] 5. Ballo R, Viljoen D, Beighton P. Duchenne and Becker muscular dystrophy prevalence in South Africa and molecular findings in 128 persons affected. S Afr Med J 1994;84(8):494-497. 6. Chamberlain JS, Gibbs RA, Ranier JE, Nguyen PN, Caskey CT. Deletion screening of the Duchenne muscular dystrophy locus via multiplex DNA amplification. Nucleic Acids Res 1988;16(23):1114111156. [http://dx.doi.org/10.1093/nar/16.23.11141] 7. Kerr R, Robinson C, Essop FB, Krause A. Genetic testing for Duchenne/Becker muscular dystrophy in Johannesburg, South Africa. S Afr Med J 2013;103(12):999-1004. [http://dx.doi.org/10.7196/samj.7274] 8. Gatta V, Scarciolla O, Gaspari AR, et al. Identification of deletions and duplications of the DMD gene in affected males and carrier females by multiple ligation probe amplification (MLPA). Hum Genet 2005;117(1):92-98. [http://dx.doi.org/10.1007/s00439-005-1270-7] 9. Brioschi S, Gualandi F, Scotton C, et al. Genetic characterization in symptomatic female DMD carriers: Lack of relationship between X-inactivation, transcriptional DMD allele balancing and phenotype. BMC Med Genet 2012;13(1):73. [http://dx.doi.org/10.1186/1471-2350-13-73] 10. Kesari A, Pirra LN, Bremadesam L, et al. Integrated DNA, cDNA, and protein studies in Becker muscular dystrophy show high exception to the reading frame rule. Hum Mutat 2008;29(5):728-737. [http://dx.doi.org/10.1002/humu.20722] 11. Muntoni F, Torelli S, Ferlini A. Dystrophin and mutations: One gene, several proteins, multiple phenotypes. Lancet Neurol 2003;2(12):731-740. [http://dx.doi.org/10.1016/S1474-4422(03)00585-4] 12. Ishmukhametova A, van Kien PK, Méchin D, et al. Comprehensive oligonucleotide array-comparative genomic hybridization analysis: New insights into the molecular pathology of the DMD gene. Eur J Hum Genet 2012;20(10):1096-1100. [http://dx.doi.org/10.1038/ejhg.2012.51] 13. Vasli N, Bohm J, Le Gras S, et al. Next generation sequencing for molecular diagnosis of neuromuscular diseases. Acta Neuropathol 2012;124(2):273-283. [http://dx.doi.org/10.1007/s00401-012-0982-8] 14. Erali M, Voelkerding KV, Wittwer CT. High resolution melting applications for clinical laboratory medicine. Exp Mol Pathol 2008;85(1):50-58. [http://dx.doi.org/10.1016/j.yexmp.2008.03.012] 15. White H, Potts G. Mutation Scanning by High Resolution Melt Analysis. Evaluation of Rotor-Gene 6000 (Corbett Life Science), HR-1 and 384-well LightScanner (Idaho Technology). Wessex: National Genetics Reference Laboratory, 2006. 16. Almomani R, van der Stoep N, Bakker E, den Dunnen JT, Breuning MH, Ginjaar IB. Rapid and cost effective detection of small mutations in the DMD gene by high resolution melting curve analysis. Neuromuscul Disord 2009;19(6):383-390. [http://dx.doi.org/10.1016/j.nmd.2009.03.004] 17. Gurvich OL, Tuohy TM, Howard MT, et al. DMD pseudoexon mutations: Splicing efficiency, phenotype, and potential therapy. Ann Neurol 2008;63(1):81-89. [http://dx.doi.org/10.1002/ana.21290]
Accepted 26 June 2014.
November 2014, Vol. 104, No. 11
GUEST EDITORIAL
Immunology as a medical discipline in South Africa: Why, how and what form? Immunology underlies most of the biological and clinical disciplines in medicine, including autoimmune diseases, infectious diseases and HIV, primary immunodeficiency, allergy, cancer and transplantation medicine. The formalised use of immunology knowledge, laboratory techniques and targeted immunotherapies in routine clinical practice is currently commonplace in most parts of the world. It is the most rapidly advancing field in medicine, and there is a definite need for generalists to keep up with advances in knowledge that impact on patient management. This is the impetus behind this month’s CME entitled ‘Updates in immunology and allergy’. The medical community, both clinical and pathology disciplines, can no longer afford to see immunology as a ‘black box’ discipline irrelevant to day-to-day patient management or only applicable to the uncommon case of immunodeficiency or autoimmune disease. For South African (SA) doctors this means considering immunology beyond HIV medicine. Is it time for immunology in SA, amidst competing public health needs, to be established as a distinct specialty or sub-specialty discipline? Globally, an expanding knowledge base continues to identify fundamental roles for the immune system in the pathogenesis and pathology of an increasing number of common non-communicable and communicable diseases, e.g. asthma, rheumatic heart disease, inflammatory bowel diseases, multiple sclerosis, type 1 diabetes, rheumatoid arthritis, and immune cytopenias. Following this, and with parallel technological advance, there is an explosion in the development and clinical use of targeted immunotherapies. For instance, in just three decades, over 30 different monoclonal antibodies have been licensed in the USA and Europe for conditions such as cancer and rheumatoid arthritis and for the prevention of transplant rejection.[1] More importantly, some of these are now standard of care – not only in resource-rich tertiary care settings. Approximately 2 500 patients in SA, including 1 - 2% in the public sector, receive biologic therapy (SARA registry, B Hodkinson – personal communication). Tarr et al.[2] review registered biologics and their use in this issue of the journal. The abovementioned number of patients will likely increase in the future owing to confirmed efficacy in patients whose disease has not been controlled with conventional medication. Numerous other monoclonal antibodies are in the advanced stages of
785
development, and the ‘biosimilar’ market is growing; this will mean increased accessibility and affordability for developing countries. Furthermore, our ability and insight on how to interrogate patients’ immune functioning and their underlying genotype are becoming increasingly more specialised and affordable. Over 200 inborn errors of immunity have been described with protean clinical manifestations; 30 novel genetic defects have been described in the past three years alone.[3] Increasingly, molecular studies are also contributing to the diagnosis of primary immunodeficiency. The need for a specialist immunology knowledge base and clinical service is expanding. We believe that practising clinicians, from generalists to subspecialists across a number of disciplines, already require a good understanding of immunology in the context of the HIV epidemic, but will increasingly require an improved understanding of immunological concepts and therapies for good clinical practice. Immunology laboratory and pathology infrastructure and services are essential to support advanced diagnosis and treatment. What may not be clear is how a growing need for clinical and pathology immunology training, services and infrastructure development can be met within the context of competing public health needs. Perhaps a medical crisis, such as the Ebola outbreak, represents a good example of where immunology knowledge and an understanding of immunotherapy and vaccination is at the cutting edge of public health. The current state of immunology in SA, outside of HIV and tuberculosis (TB), is worrying. There is no established immunology medical specialty or sub-specialty. This was shown in a 2001 survey of university hospitals in Africa, identifying only seven clinical immunologists.[4] The co-ordination of immunology teaching to medical and science students at undergraduate and postgraduate level in SA is fragmented. Curricula vary from university to university, with some programmes incorporating minimal and outdated immunology teaching at undergraduate level owing to lack of relevant faculty. Postgraduate training also varies, with the focus at well-established research-intensive universities on laboratorybased MSc and PhD immunology projects, which track students on a research career path only. Consequently, SA has some of the world’s leading researchers in infectious disease immunology and vaccinology, particularly in TB and HIV medicine. Many of these
November 2014, Vol. 104, No. 11
GUEST EDITORIAL
laboratories use very advanced molecular and cellular immunology tools and equipment. Here lies the dichotomy, which is the concern. Few, if any, of these tools and infrastructure are available or geared to investigative patient care and for routine patient management. With the rationalisation of testing within provincial and national structures, it continues to be a struggle to maintain even a limited repertoire of tests to evaluate immune function, given their relative expense and low-test volumes. Not only does this mean that in many provinces immunodeficiency other than HIV is simply not diagnosed, with consequent morbidity and mortality, but that critical human resource capacity is being lost with impact on the future growth of training and service. A number of approaches are needed to address these concerns. Academic institutions should strive for a model of seamless integration of immunology research, research and development, a clinical service, provision of tertiary specialised immune diagnostic assays, and teaching of immunology to under- and postgraduate students. In addition, we believe that the establishment of immunology into its own medically registered discipline would be a key component for growth and long-term sustainability of pathology and clinical services, research and continuing medical education. In the USA and UK, the discipline of Clinical Immunology, linked with allergy training, is more than three decades old, with over 4Â 000 registered specialists in a 2004 USA survey.[5] International training curricula are well established.[6] Recognition as a distinct discipline has offered a number of advantages, including: (i) improved patient care through unification of practitioners, allowing for better advocacy; (ii) improved training and teaching through co-ordination at a national level; (iii) improved research via the development of centres of excellence; and (iv) growth of the discipline. There remains considerable heterogeneity in the set-up of the discipline across countries, including: (i) whether allergy and clinical immunology are considered as unified or separate disciplines; (ii) whether the discipline is a primary specialty or sub-specialty; and (iii) whether it is administered in the colleges of pathology, medicine or paediatrics. Therefore, the Health Professions Council of SA will be approached to register immunology as a sub-specialty, and the National Health Laboratory Service Immunology Expert Committee is embarking on a scoping exercise to identify how immunology is considered in the SA medical community and how best to move forward towards such registration. Please participate in this survey by accessing https://www.surveymonkey.com/s/RVPW5RM. It is hoped that in the coming years immunology as a discipline will find a strong and distinct identity integrated into the fabric of high-quality SA healthcare.
786
Jonathan Peter Guest editor Division of Allergology and Clinical Immunology, Department of Medicine, Faculty of Health Sciences, University of Cape Town, South Africa jonny.peter@uct.ac.za Stanley Ress Guest editor Emeritus Associate Professor of Medicine, Faculty of Health Sciences, University of Cape Town, and UCT Private Academic Hospital, Cape Town, South Africa stan.ress@uct.ac.za Clive Gray Guest editor Wernher Beit Chair of Immunology, Division of Immunology, Institute of Infectious Disease and Molecular Medicine, Department of Clinical Laboratory Sciences and National Health Laboratory Service, University of Cape Town, South Africa clive.gray@uct.ac.za
1. Buss NA, Henderson SJ, McFarlane M, Shenton JM, de Haan L. Monoclonal antibody therapeutics: History and future. Curr Opin Pharmacol 2012;12(5):615-622. [http://dx.doi.org/10.1016/j. coph.2012.08.001] 2. Tarr G, Hodkinson B, Reuter H. Superheroes in autoimmune warfare: Biologic therapies in current South African practice. S Afr Med J 2014;104(11):787-791. [http://dx.doi.org/10.7196/SAMJ.8947] 3. Al-Herz W, Aldhekri H, Barbouche MR, Rezaei N. Consanguinity and primary immunodeficiencies. Hum Hered 2014;77(1-4):138-143. [http://dx.doi.org/10.1159/000357710] 4. Sibanda EN. Research and clinical aspects of immunology in Africa. Curr Opin Immunol 2001;13(5):528-532. 5. Marshall GD, American Academy of Asthma and Allergy, Immunology Workforce Committee. The status of US allergy/immunology physicians in the 21st century: A report from the American Academy of Allergy, Asthma and Immunology Workforce Committee. J Allergy Clin Immunol 2007;119(4):802-807. 6. World Health Organization/International Union of Immunological Societies/International Association of Allergy and Clinical Immunology. Clinical immunology: Guidelines for its organization, training and certification; relationships with allergology and other medical disciplines â&#x20AC;&#x201C; a WHO/IUIS/IAACI report. Clin Exp Immunol 1993;93(3):484-491.
S Afr Med J 2014;104(11):785-786. DOI:10.7196/SAMJ.9003
November 2014, Vol. 104, No. 11
CONTINUING MEDICAL EDUCATION
REVIEW
Superheroes in autoimmune warfare: Biologic therapies in current South African practice G Tarr,1 MB BCh, FCP (SA), Cert Rheum (SA), MMed (Int Med); B Hodkinson,2 MB BCh, FCP (SA), Cert Rheum (SA), PhD; H Reuter,1,3 MB ChB, FCP (SA), MMed (Int), FRCP (Edin), PhD Winelands Rheumatology Research Centre, Stellenbosch, South Africa Department of Medicine, Groote Schuur Hospital and University of Cape Town, and Division of Rheumatology, Chris Hani Baragwanath Academic Hospital, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa 3 Division of Rheumatology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa 1 2
Corresponding author: B Hodkinson (drbridget@gmail.com)
Biologic drugs targeting immune cells or cytokines underlying systemic inflammation have dramatically improved outcomes in patients with rheumatological and autoimmune diseases. Nine biologic drugs are currently available in South Africa (SA) – all showing good efficacy and safety profiles. Their high cost and potential adverse events preclude them from being used as first-line agents. They are therefore indicated for severe disease refractory to standard therapies, and their use must be initiated by a specialist. The most important adverse effect of this class of drugs is infection and, in SA, tuberculosis is of particular concern. As new targets in the immune system are identified, new biologics will be developed. The current challenges are to optimise standard care for all patients with autoimmune diseases, and to offer the appropriate biologic to patients with refractory disease. S Afr Med J 2014;104(11):787-791. DOI:10.7196/SAMJ.8947
Everyone who reads comics knows that winning is about recognising the villains, choosing the superhero with precisely the right ‘superpowers’ to overcome the bad guy, and sitting back to enjoy the action. The last two decades have been exciting times in the battle against autoimmune diseases. The villains have been elucidated owing to a growing understanding of the immunological mechanisms underlying the co-ordinated interaction between T and B cells and pro-inflammatory cytokines responsible for systemic inflammation, followed by the development of targeted biologic drugs with ‘superpowers’ against specific immune cells or cytokines. These biologic therapies have dramatically improved outcomes in patients with a range of autoimmune conditions, including rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriasis and psoriatic arthritis (PsA), and inflammatory bowel disease (IBD), as well as systemic inflammatory diseases such as lupus erythematosus (SLE) and the vasculitides. The biologic disease-modifying anti-rheumatic drugs (DMARDs) are classified according to their target. There are currently eight registered biologic drugs in South Africa (SA), of which four are tumour necrosis factor alpha inhibitors (TNFi) and four are non-
787
TNFi, including ustekinumab, which is currently registered for the treatment of psoriasis but not for the arthritides (Table 1). Their structure is specified by the abbreviation at the end of their name: ‘-cept’ = fusion of a receptor to the Fc part of human IgG1; ‘-mab’ = monoclonal antibody; ‘-ximab’ = chimeric monoclonal antibody; and ‘-umab’ = humanised monoclonal antibody. Many patients respond to the conventional synthetic DMARDs. Because of the high cost and potential adverse events, biologic drugs are reserved for patients with severe disease who fail to respond to standard treatments. In SA, the use of biologic therapies needs to be initiated by a specialist, who follows the guidelines published online by the relevant specialist associations, including the South African Gastroenterology Society (www.SAGES.co.za), the South African Rheumatology Association (www.SARAA.co.za),[1] and the Dermatology Society of South Africa (www.DERMA.co.za).[2]
Rheumatoid arthritis
Biologic therapies have made an enormous impact on severe RA by modulating disease activity and retarding radiographic damage, thus preventing disability. Patients with active disease despite synthetic DMARDs over at least six months can be considered candidates
November 2014, Vol. 104, No. 11
CONTINUING MEDICAL EDUCATION
Table 1. Biologic drugs in South Africa Mechanism of action
Route of administration
Registered indications
Infliximab (Revellex)
Mouse/human chimeric mab against TNF-α
IV every 8 weeks
RA, AS, PS, PSA, CD, UC, PaedCD, PaedUC
Etanercept (Enbrel)
Soluble TNF- α receptor fusion protein
SC weekly
RA, AS, PS, PSA, JIA
Adalimumab (Humira)
Mab against TNF-α
SC every other week
RA, AS, axial spondyloarthropathies, PS, PSA,CD, UC, JIA, PaedCD
Golimumab (Simponi)
Human mab against TNF-α
SC monthly
RA, AS, PSA, UC*
Certolizumab pegol†
Human mab against TNF- α
SC monthly
RA,* CD,* AS,* PSA*
Abatacept (Orencia)
Receptor fusion protein inhibiting T-cell co-stimulation
IV monthly or SC weekly
RA, JIA
SLE
Rituximab (Mabthera)
Mouse/human chimeric mab against CD 20+ B cells
IV 6-monthly
RA, ANCAassociated vasculitis, haematological malignancies, NHL, CLL
SLE, pemphigus vulgaris, inflammatory myopathies
Serious infections: hepatitis B reactivation, progressive multifocal leukoencephalopathy
Tocilizumab (Actemra)
Humanised IL-6 receptor antibody
IV monthly
RA, SJIA, JIA*
Castleman’s, CD, relapsing polychondritis, SLE, SScL, PMR, RS3PE
Infection: neutropenia, transaminitis, dyslipidaemia, GI perforation
Ustekinumab (Stelara)
IL-12/23 monoclonal antibody
PS, PSA,* CD*
UC
Serious infections
Biologic drug
Off-label indications
Major adverse effects
JIA, SJIA, uveitis, Takayasu arteritis, GCA, pyoderma gangrenosum, sarcoidosis
Serious infections, including: tuberculosis, hepatitis B reactivation, demyelinating disorders
ANCA = anti-neutrophilic cytoplasmic antibody; AS = ankylosing spondylitis; CD = Crohn’s disease; CLL = chronic lymphocytic lymphoma; GCA = giant cell arthritis; GI = gastrointestinal; IL = interleukin; IV = intravenous; JIA = juvenile idiopathic arthritis; NHL =non-Hodgkin lymphoma; PAED = paediatrics; PMR = polymyalgia rheumatica; PS = psoriasis; PsA = psoriatic arthritis; RA = rheumatoid arthritis, RS3PE = relapsing seronegative symmetrical synovitis with pitting oedema; mab = monoclonal antibody; SC = subcutaneous; SJIA = systemic juvenile idiopathic arthritis; SLE = systemic lupus erythematosus; SScL = systemic sclerosis; TNF = tumour necrosis factor; UC = ulcerative colitis. *Registration pending. † Currently not available in South Africa.
for biologic therapy. Seven of the currently available biologics are registered for first-line use in RA, and systemic reviews suggest that these biologics have similar efficacies.[3,4] The choice of drug depends on the side-effect profile, disease characteristics, patient preferences for route of administration, and cost. Because of the high risk of tuberculosis (TB) in SA, particularly associated with TNFi, biologic
788
drugs with an alternative mode of action may be the most appropriate choice as first-line therapy.[5] In addition, certain disease features may guide the choice of drug, e.g. rheumatoid factor-negative patients are less likely to respond to rituximab, and those with pronounced systemic symptoms (such as anaemia of chronic disorders, high C-reactive protein and fatigue) are likely to have a good response to
November 2014, Vol. 104, No. 11
CONTINUING MEDICAL EDUCATION
tocilizumab. Methotrexate or leflunomide should be co-prescribed with biologics, except in the case of tocilizumab, where there is good evidence for monotherapy. The Janus kinase (JAK) inhibitor tofacitinib is a new synthetic DMARD with equivalent efficacy to the biologic agents used in the treatment of RA, but it is not yet registered in SA.
Ankylosing spondylitis
The TNFi drugs dramatically improve the symptoms and reduce the radiographic progression of AS. Randomised controlled studies of all four TNFi have shown good efficacy in early and advanced disease. Younger age, shorter disease duration, high inflammatory markers, human leukocyte antigen (HLA) B27 positivity and minimal baseline functional disability are associated with better outcomes.[6] Loss of response to TNFi over time is well documented in AS, probably related to TNFi antibody production. In these patients, switching to an alternative TNFi may be efficacious. Other biologics (rituximab, abatacept and tocilizumab) have shown only limited success in AS. In future, secukinumab (an interleukin (IL)17A inhibitor) may be useful.
Psoriasis
Persistent severe plaque psoriasis resistant to standard therapies is an indication for TNFi therapy.[2] Similarly, PsA (including peripheral arthritis, axial disease, enthesitis and dactylitis) has shown a rapid and significant response to TNFi with inhibition of radiographic disease progression.[7] More recently, ustekinumab, an IL-12/IL-23 monoclonal antibody, has been shown to be effective in psoriasis and PsA, but is currently only registered for plaque psoriasis. In addition, drugs inhibiting IL-17 seem promising, particularly for skin disease and enthesitis.[8]
Inflammatory bowel disease
In Crohn’s disease, monoclonal antibodies that inhibit TNF (but not TNF receptor blockers) are beneficial in steroid-refractory, steroid-dependent, or complex fistulising disease. This induction therapy needs to be continued for at least 12 months in patients who show a response.[9] The TNFi is usually prescribed together with an immunosuppressive agent, with evidence particularly favouring azathioprine.[10] Similarly, TNFi are also effective for treatmentrefractory, moderate, or severely active ulcerative colitis. Patients with IBD-associated axial or peripheral arthritis refractory to sulfasalazine may also benefit from TNFi. Ustekinumab has been shown to be useful in TNF-resistant Crohn’s disease.[11] Abatacept and natalizumab (an integrin receptor antagonist) may also be effective in Crohn’s disease and trials are ongoing.
Juvenile idiopathic arthritis
Biologic drugs have greatly improved outcomes in refractory polyarticular and oligoarticular juvenile idiopathic arthritis (JIA), and TNFi have been the most widely studied biologics in these
789
diseases. A recent systematic review demonstrated that etanercept, adalimumab and abatacept were equally efficacious.[12] Refractory systemic JIA has shown good response to tocilizumab, and to IL-1 inhibitors including anakinra, canakinumab and rilonocept and encouraging study results have been reported with tofacitinib. The IL-1 inhibitors and tofacitinib are not yet licensed in SA.
Systemic lupus erythematosus
Despite initial optimism that biologic drugs would lead to new therapeutic options, most clinical trials in SLE have missed their primary endpoints.[13] Belimumab inhibits B-cell activation factor, which is also known as B-lymphocyte stimulator. It has been shown to reduce flares and antibody titres in mild to moderate SLE (excluding renal or central nervous system (CNS) involvement) and is the only biologic registered in the USA for use in SLE. Rituximab (for haematological, renal and CNS involvement), abatacept (for arthritis), and TNFi (for skin and joint disease) have been successfully used off-label.
ANCA-associated vasculitis, uveitis and Behçet’s syndrome
Rituximab is one of the few biologics to have been studied in antineutrophilic cytoplasmic antibody (ANCA)-associated vasculitis, and has been shown to be non-inferior to cyclophosphamide for induction therapy.[14,15] Although no randomised controlled trials have been published, observational studies have shown benefit in cyclophosphamideresistant disease. In refractory Behçet’s disease, both TNFi infliximab and adalimumab were effective, also for severe ocular inflammation, whereas etanercept was less effective for ocular or gastrointestinal manifestations.[16]
IgG4 sclerosing-related disease
Immunoglobulin (Ig) G4-related disease is a rare, recently character ised, immune-mediated fibrosing disorder, with varying clinical manifestations depending on the specific organ system involved. Mainstay treatment is corticosteroids, but immunosuppressants may be added in relapsing patients or as steroid-sparing agents. Rituximab may be useful in refractory patients.[17]
Adverse effects of biologics
While the efficacy of biologic drugs has been clearly established, the risk of adverse effects has been uncertain, and has only recently been clarified by Cochrane meta-analysis and by literature review.[18,19] Table 1 summarises the major adverse effects of various biologics available in SA. A great concern with all biologic treatments, with the exception of abatacept, is the increased risk of community-acquired and opportunistic infections. Of particular importance in SA is the risk of TB infection or reactivation, which is only partially addressed
November 2014, Vol. 104, No. 11
CONTINUING MEDICAL EDUCATION
by screening for latent TB infection and isoniazid prophylaxis. In studies conducted in countries with a low TB prevalence, the risk of TB seems highest among patients receiving monoclonal TNFi during their first year of treatment and rises as high as a 56-fold increased incidence compared with the general population.[20-22] Although initially of concern, malignancies do not seem to increase in patients using biologics except for a possible increase in melanoma associated with TNFi.[23]
Switching and withdrawing biologic therapy
Despite impressive results in the majority of patients, response to a specific biologic drug is unpredictable and up to one-third of patients with an autoimmune disease requiring biologic therapy have a poor response or lose their response. These patients may respond to switching to another biologic drug. The search for biomarkers to allow optimal selection of biologic drugs is ongoing. Given the costs and potential adverse effects, withdrawal or reduction of biologic therapy is a goal of many patients and physicians. In RA, AS and PsA, this may be possible in a subset of patients who have achieved long-term remission, particularly in those with early disease, and studies are ongoing.[24] In the case of IBD, withdrawal of TNFi therapy in patients who have been in clinical remission ≥12 months appears safe in the majority of patients.
Vaccination
Because of the increased risk of serious infections in patients using biologics, vaccination is an important preventive strategy.[25,26] Current recommendations are that vaccines, particularly influenza and pneumococcal vaccines, be given prior to biologic therapy where possible, and that live vaccines (including measles, mumps, rubella, live attenuated influenza, varicella zoster, yellow fever, Ty21a oral typhoid, bacillus Calmette-Guérin (BCG), and rotavirus vaccines) are contraindicated.[27]
Cost of biologic drugs
One of the major problems restricting biologic use in SA is their cost, ranging between R110 000 and R160 000 annually. Offset against this cost is the benefit of early disease control, thus reducing the impact of the disease on functional capabilities and work productivity. A recent French study demonstrated that even though early biologic therapy in RA was costly, it resulted in lower health-associated costs (including physician consultations, investigations and hospitalisation) over a 4-year period owing to better disease control.[28] Long-term studies in SA are needed to evaluate the cost of biologics against the economic burdens of poorly controlled disease. Healthcare providers and patient groups in SA need to lobby for wider access to biologics for patients who require them, in both the
790
private and state sectors. This might entail pharmaceutical companies offering drugs at reduced prices, greater flexibility by medical schemes for patients with limited cover, and the use of biosimilar drugs.
Biologic registries
Biologic registries are a major source of efficacy and safety data, and a registry of rheumatology patients who are on biologic therapy has been in operation in SA since 2008. A recent paper describes the SA experience of TNFi therapy in RA, showing results similar to those seen elsewhere in the world.[29] Further clinical research, using the epidemiological data from the SA registry, will help to develop evidence-based treatment guidelines with regard to TB risks and latent TB detection, strategies to monitor patients on biologics, and long-term cost-effectiveness of treatment.
Conclusion
Ben Parker, uncle to Peter Parker aka Spiderman, remarked ‘With great power comes great responsibility’. So it is with biologic drugs. As our knowledge of the underlying mechanisms of autoimmune diseases expands, we can expect more targeted therapies to be developed. Our growing experience with biologics and their adverse events will include development of clinical and laboratory biomarkers to allow selection of optimal therapy for each patient. The current and future challenges in SA are to optimise the standard care for patients with autoimmune diseases, with careful selection of patients with severe refractory disease and provision of the appropriate biologic drugs. References 1. Hodkinson B, Van Duuren E, Pettipher C, Kalla A, South African Rheumatism and Arthritis Association. South African recommendations for the management of rheumatoid arthritis: An algorithm for the standard of care in 2013. S Afr Med J 2013;103:576-585. [http://dx.doi.org/10.7196/samj.7047] 2. Raboobee N, Aboobaker J, Jordaan HF, et al. Guideline on the management of psoriasis in South Africa. S Afr Med J 2010;100:257-282. 3. Singh JA, Christensen R, Wells GA, et al. Biologics for rheumatoid arthritis: An overview of Cochrane reviews. Cochrane Database Syst Rev 2009;(4):CD007848. 4. Nam JL, Winthrop KL, van Vollenhoven RF, et al. Current evidence for the management of rheumatoid arthritis with biological disease-modifying antirheumatic drugs: A systematic literature review informing the EULAR recommendations for the management of RA. Ann Rheum Dis 2010;69(6):976986. [http://dx.doi.org/10.1136/ard.2009.126573] 5. Tikly M, Hodkinson B, Dheda K. Biologic therapy for rheumatoid arthritis in developing countries – a place for non-TNF inhibitors as first-line treatment? Rheumatology [Epub ahead of print 31 March 2014]. [http://dx.doi.org/10.1093/rheumatology/keu040] 6. Vastesaeger N, van der Heijde D, Inman RD, et al. Predicting the outcome of ankylosing spondylitis therapy. Ann Rheum Dis 2011;70(6):973-981. [http://dx.doi.org/10.1136/ard.2010.147744] 7. Thorlund K, Druyts E, Avina-Zubieta JA, Mills EJ. Anti-tumor necrosis factor (TNF) drugs for the treatment of psoriatic arthritis: An indirect comparison meta-analysis. Biologics: Targets & Therapy 2012;6:417-427. 8. Huynh D, Kavanaugh A. Psoriatic arthritis: Current therapy and future approaches. Rheumatology [Epub ahead of print 14 August 2014]. [http://dx.doi.org/10.1093/rheumatology/keu237] 9. D’Haens GR, Panaccione R, Higgins PD, et al. The London Position Statement of the World Congress of Gastroenterology on Biological Therapy for IBD with the European Crohn’s and Colitis Organization: When to start, when to stop, which drug to choose, and how to predict response? Am J Gastroenterol 2011;106(2):199-212. [http://dx.doi.org/10.1038/ajg.2010.392] 10. Lakatos PL. Is there a benefit from the concomitant use of immunosuppression with anti-TNF in Crohn’s disease; heads or tails? Rev Recent Clin Trials 2009;4(3):152-158. [http://dx.doi. org/10.2174/157488709789957664] 11. Sandborn WJ, Feagan BG, Fedorak RN, et al. A randomized trial of Ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate-to-severe Crohn’s disease. Gastroenterology 2008;135(4):1130-1141. [http://dx.doi.org/10.1053/j.gastro.2008.07.014]
November 2014, Vol. 104, No. 11
CONTINUING MEDICAL EDUCATION
12. Otten MH, Anink J, Spronk S, van Suijlekom-Smit LW. Efficacy of biological agents in juvenile idiopathic arthritis: A systematic review using indirect comparisons. Ann Rheum Dis 2013;72(11):1806-1812. [http://dx.doi.org/10.1136/annrheumdis-2012-201991] 13. Gatto M, Kiss E, Naparstek Y, Doria A. In-/off-label use of biologic therapy in systemic lupus erythematosus. BMC Med 2014;12:30. [http://dx.doi.org/10.1186/1741-7015-12-30] 14. Stone JH, Merkel PA, Spiera R, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med 2010;363(3):221-232. [http://dx.doi.org/10.1056/NEJMoa0909905] 15. Jones RB, Tervaert JW, Hauser T, et al. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med 2010;363(3):211-220. [http://dx.doi.org/10.1056/NEJMoa0909169] 16. Bawazeer A, Raffa LH, Nizamuddin SH. Clinical experience with adalimumab in the treatment of ocular Behçet disease. Ocul Immunol Inflamm 2010;18(3):226-332. [http://dx.doi.org/10.3109/09273948.2010.483314] 17. Khosroshahi A, Carruthers MN, Deshpande V, Unizony S, Bloch DB, Stone JH. Rituximab for the treatment of IgG4-related disease: Lessons from 10 consecutive patients. Medicine 2012;91(1):57-66. [http://dx.doi.org/10.1097/MD.0b013e3182431ef6] 18. Singh JA, Wells GA, Christensen R, et al. Adverse effects of biologics: A network meta-analysis and Cochrane overview. Cochrane Database Syst Rev 2011;(2):CD008794. 19. Ramiro S, Gaujoux-Viala C, Nam JL, et al. Safety of synthetic and biological DMARDs: A systematic literature review informing the 2013 update of the EULAR recommendations for management of rheumatoid arthritis. Ann Rheum Dis 2014;73(3):529-535. [http://dx.doi. org/10.1136/annrheumdis-2013-204575] 20. Tubach F, Salmon D, Ravaud P, et al. Risk of tuberculosis is higher with anti-tumor necrosis factor monoclonal antibody therapy than with soluble tumor necrosis factor receptor therapy: The threeyear prospective French Research Axed on Tolerance of Biotherapies registry. Arthritis Rheum 2009;60(7):1884-1894. http://dx.doi.org/10.1002/art.24632]
21. Dixon WG, Hyrich KL, Watson KD, et al. Drug-specific risk of tuberculosis in patients with rheumatoid arthritis treated with anti-TNF therapy: Results from the British Society for Rheumatology Biologics Register (BSRBR). Ann Rheum Dis 2010;69(3):522-528. [http://dx.doi.org/10.1136/ard.2009.118935] 22. Lee SK, Kim SY, Kim EY, et al. Mycobacterial infections in patients treated with tumor necrosis factor antagonists in South Korea. Lung 2013;191(5):565-571. [http://dx.doi.org/10.1007/s00408-013-9481-5] 23. Raaschou P, Simard JF, Holmqvist M, Askling J, Group AS. Rheumatoid arthritis, anti-tumour necrosis factor therapy, and risk of malignant melanoma: Nationwide population based prospective cohort study from Sweden. BMJ 2013;346:f1939. 24. Kadar G, Balazs E, Soos B, et al. Disease activity after the discontinuation of biological therapy in inflammatory rheumatic diseases. Clin Rheumatol 2014;33(3):329-333. [http://dx.doi.org/10.1007/s10067-014-2508-3] 25. Doran MF, Crowson CS, Pond GR, O’Fallon WM, Gabriel SE. Frequency of infection in patients with rheumatoid arthritis compared with controls: A population-based study. Arthritis Rheum 2002;46(9):2287-2293. [http://dx.doi.org/10.1002/art.10524] 26. Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: Systematic review and metaanalysis of rare harmful effects in randomized controlled trials. J Am Med Ass 2006;295(19):22752285. [http://dx.doi.org/10.1001/jama.295.19.2275] 27. Ferreira I, Isenberg D. Vaccines and biologics. Ann Rheum Dis 2014;73(8):1446-1454. [http://dx.doi. org/10.1136/annrheumdis-2014-205246] 28. Chevreul K, Haour G, Lucier S, et al. Evolution of direct costs in the first years of rheumatoid arthritis: Impact of early versus late biologic initiation – an economic analysis based on the ESPOIR cohort. PloS One 2014;9(5):e97077. [http://dx.doi.org/10.1371/journal.pone.0097077] 29. Pettipher C, Rudolph R, Musenge E, Tikly M. A prospective study of anti-tumor necrosis factor therapy in South African rheumatoid arthritis patients. Int J Rheum Dis 12 February 2014. [Epub ahead of print]
ARTICLE SUMMARY
Investigation of adult immunodeficiency and indications for immunoglobulin replacement therapy S Ress, MB ChB, FCP (SA) Department of Medicine, Faculty of Health Sciences, University of Cape Town, and University of Cape Town Private Academic Hospital, Cape Town, South Africa Corresponding author: S Ress (stan.ress@uct.ac.za)
Underlying immunodeficiency needs to be excluded in adults presenting with recurrent infections. These patients fall into one of three groups: (i) with recurrent localised infections, it is mandatory to exclude an underlying predisposing, anatomical defect, e.g. base of skull fractures presenting with recurrent pneumococcal meningitis, urinary tract obstruction presenting with recurrent urinary infections, and recurrent sinusitis after previous extensive surgery that results in bacterial colonisation on abnormal mucosal surfaces; (ii) secondary immune deficiency, which can be due to underlying diseases or a complication of immune suppression, e.g. HIV, diabetes, liver cirrhosis and nephrotic syndrome, haematological diseases, autoimmunity and malignancy; (iii) primary immune disorders, which can present for the first time in adulthood, involving defects in antibody production, T-cell function, complement deficiencies,
791
or phagocytic function. Defects in humoral immunity are most commonly encountered in clinical practice, involving the following conditions: Selective immunoglobulin (Ig) A deficiency. Patients may be asymptomatic or present with recurrent sinopulmonary and gastrointestinal infections, e.g. recurrent giardiasis. Abnormalities in serum IgM levels. Patients with selective IgM deficiency may present with septicaemia or recurrent respiratory infections. Those with hyper-IgM syndrome usually present in childhood with elevated serum IgM but reduced IgG and IgA levels owing to mutations in the CD40-mediated signalling pathway. Milder mutations may result in a less severe clinical course later in life. Common variable immunodeficiency (CVID) is the most common primary intrinsic disorder of antibody production in both children and adults.
November 2014, Vol. 104, No. 11
CONTINUING MEDICAL EDUCATION
IgG subclass deficiency and specific antibody deficiency (SAD). Diagnosis of clinically significant IgG subclass deficiency requires a significant reduction in one or more IgG subclass concentrations, together with evidence of antibody dysfunction evidenced by recurrent infections, and an inadequate antibody response to vaccine challenge. SAD can cause recurrent infections despite normal total serum immunoglobulin as well as IgG subclass levels owing to defective specific antibody production against protein or polysaccharide organisms. Selective IgG deficiency. Patients with borderline serum IgG are commonly referred for immune evaluation. They may have allergic rhinitis and recurrent sinusitis, and are also often asthmatic, with significant steroid use. Chronic infections are usually poorly defined and accompanied by fatigue and a modest reduction in serum IgG of 5 - 7 g/L (normal range 7 - 16 g/L). Defective cellular immunity often accompanies hypogamma globulinaemia in CVID, while patients with acquired antibodies to inteferon (IFN)-γ are increasingly being described and can present with disseminated Mycobacterium avium or Salmonella infections. Defects in phagocytocis are usually diagnosed in childhood with recurrent pyogenic infections, deep-seated abscesses and sepsis, but these can also present in adults.
Immune investigations
• Quantification of IgA, IgM, IgG and IgE. • Myeloma often needs exclusion with serum protein electrophoresis and free serum light-chain assay, and urine light chains.
792
• IgG subclasses and a baseline vaccination status are obtained by requesting serum IgG ‘memory’-specific antibody levels against capsular polysaccharide organisms and tetanus toxoid and diphtheria. • Defective phagocytic function can be diagnosed by flow cytometry to measure phagocytic index and respiratory burst of polymorph neutrophils and monocytes. • Measurement of peripheral blood subsets provides percentage and absolute numbers of circulating T cell, B cell and natural killer cells. A reduction in ‘switched’ memory B cells in CVID correlates with recurrent respiratory infections and bronchiectasis more than actual serum immunoglobulin concentration. • T-cell function can be assessed by measuring proliferative responses to stimulation by mitogens (phytohaemagglutinin/Con-A), antigens (purified protein derivative) and Candida. Patients with recurrent infections despite optimal management of predisposing conditions, such as allergic rhinitis and asthma, and a trial of prophylactic antibiotics, can be considered for immuno globulin replacement therapy. Documented suboptimal responses to vaccination with polysaccharide and/or protein antigens are generally a prerequisite for funding by medical aids, as treatment is costly, can be associated with side-effects, and is usually lifelong. S Afr Med J 2014;104(11):791-792. DOI:10.7196/SAMJ.8948
November 2014, Vol. 104, No. 11
CONTINUING MEDICAL EDUCATION
ARTICLE SUMMARY
Investigation and management of primary immunodeficiency in South African children B Eley,1 MB ChB, FCPaed, BSc (Hons); M Esser,2 MB ChB, MMed Paed (Cert Rheum) Paediatric Infectious Diseases Unit, Red Cross War Memorial Children’s Hospital and Department of Paediatrics and Child Health, University of Cape Town, South Africa 2 Immunology Unit, National Health Laboratory Service, Tygerberg, and Department of Pathology, Tygerberg Hospital and Stellenbosch University, Cape Town, South Africa 1
Corresponding author: B Eley (brian.eley@uct.ac.za)
The primary immunodeficiency diseases (PIDs) are inherited, non-communicable diseases causing immunological dysfunction. They primarily manifest with a wide range of infections. The pattern, frequency and severity of infection depend on the underlying immunological defect. PIDs are seldom reported in South Africa (SA). Based on a mid2013 population estimate of 52.98 million and assuming that the prevalence of PIDs is similar to that in well-resourced settings, the total number of individuals with PIDs in our country should range between 2 850 and 45 723. However, fewer than 500 cases of PID have been reported in SA.
Classification of PIDs
The latest international classification includes nearly 250 different PIDs spanning nine categories, including a new category, phenocopies of PIDs, which contains conditions caused by somatic mutations and autoantibody-mediated PIDs.
Investigation
A high level of awareness of PIDs is key to investigation and diagnosis and a family history is an important warning sign. While the majority of significant PIDs can be diagnosed with basic investigations, a normal testing profile does not always exclude these conditions.
Management
Most interventions for managing PIDs are available in SA in varying degrees. Immunisation with live viral or bacterial
793
vaccines poses an infection risk to individuals with severe PIDs of T-cell, B-cell and phagocytic origin, requiring modification to routine immunisation practices in children and changes to the immunisation of household contacts of patients with the diseases. Several patients with PIDs may benefit from antimicrobial prophylaxis. Many predominantly antibody deficiencies and combined immunodeficiencies in which quantitative and/or qualitative immunoglobulin G deficiency occurs, may benefit from immunoglobulin replacement therapy. General advice aimed at reducing the risk of infection will benefit many immunodeficient patients, including advice on personal, hand and dental hygiene, avoidance of exposure to individuals with active infections, and annual influenza immunisation for household contacts. In SA, there is limited access to haematopoietic stem cell transplantation in the public sector – the treatment of choice for many severe PIDs, including severe combined immunodeficiencies. Other therapeutic modalities include cytokine therapy, enzyme replacement and interleukin 1-blocking agents. Gene therapy offers hope as a potential treatment and cure for PIDs in the future.
Conclusion
Worldwide, PIDs are more common than is generally believed. In SA, their diagnosis may be masked by a high background prevalence of infectious diseases. It is hoped that this article increases awareness among general practitioners and paediatricians. S Afr Med J 2014;104(11):793. DOI:10.7196/SAMJ.8946
November 2014, Vol. 104, No. 11
CONTINUING MEDICAL EDUCATION
ARTICLE SUMMARY
Advances in the diagnosis and management of allergic disease: Applications to South African practice A Pentz, MB ChB, DCH (SA), FCPaed (SA), MMed (Paed), Dip Allergology (SA), Cert Pulmonolgy (Paed) (SA), FCCP; R J Green, MB BCh, DCH, FCPaed (SA), DTM&H, MMed, FCCP, PhD, Dip Allergology (SA), FAAAAI, FRCP, DSc Department of Paediatrics and Child Health, Faculty of Health Sciences, University of Pretoria, South Africa Corresponding author: R J Green (robin.green@up.ac.za)
Allergic diseases are on the increase globally and locally. New allergens are identified and reported regularly, and recently there have been significant advances in the diagnosis and management of allergic disorders. There are a host of new South African (SA) guidelines for the diagnosis and management of all the allergic diseases; these might be considered as the ‘practical advances’. There are also new diagnostic and therapeutic approaches that may be considered the ‘possible advances’. ‘Possible’, because even though these advanced tests and therapies are available they should not be utilised without proper cause.
• previous anaphylaxis to a food, insect sting, latex or unavoidable aeroallergen • food-dependent exercise-induced anaphylaxis • idiopathic anaphylaxis • coexistent unstable or moderate to severe, persistent asthma and a food allergy.
Practical advances
ISAC microarray test
A number of SA ‘guidelines’ have been published in the past year and should form the basis of any rational decision-making in the diagnosis and management of allergic disorders. Diagnosis of atopic dermatitis requires a typical skin rash with pruritus. Once the diagnosis is made, treatment starts with liberal use of emollients, therapies that control pruritus and inflammation, adjunctive therapies and patient education. Maintenance of normal healthy skin is the goal of long-term care. With regard to the management of chronic rhinitis (CR), the SA Allergic Rhinitis Working Group published the following statement: ‘Consider CR as a multifactorial condition of which allergic rhinitis is only one cause, medication should be tailored to individual patients and patient education for CR is very important.’ The Allergy Society of SA has been involved with the National Pathology Group to revise suggestions for investigating allergic patients. Where immunoglobulin (Ig) E-mediated allergy is possible, consider screening with a Phadiatop, specific ImmunoCAP testing or specific skin-prick tests. The absolute indications for use and carriage of adrenaline autoinjectors include:
794
Possible advances
There have been a number of advances in allergy diagnostics and therapy. Two of these are the development of a new diagnostic modality, the multiplex microarray chip, and in the therapeutic realm new progress in immunotherapy.
The immuno-solid-phase allergen chip (ISAC) test is a multiplex microarray chip in which IgE is detected to multiple recombinant allergen components. The current ISAC microchip is a miniaturised immunoassay platform using only 20 µl of serum to measure specific IgE to 112 different recombinant allergen components. This test should not be used as a screening test in patients with a history that indicates a low suspicion of allergy, but as a diagnostic tool in those with suspected allergen cross-reactivity such as combined food and pollen allergies or in cases of multiple allergies.
Immunotherapy
Recent advances have improved the safety and efficacy of immunotherapy. The addition of omalizumab or toll-like receptor agonists to standard subcutaneous immunotherapy has proved beneficial. For patients with certain allergic profiles immunotherapy may be an important treatment modality. Such patients include those with bee venom anaphylaxis, allergic rhinitis and mild asthma. S Afr Med J 2014;104(11):794. DOI:10.7196/SAMJ.8959
November 2014, Vol. 104, No. 11
CONTINUING MEDICAL EDUCATION
ARTICLE SUMMARY
Immune tolerance and immunosuppression in solid organ transplantation C W N Spearman,1 FCP (SA), PhD; Z A Barday,2 MB ChB, FCP (SA), Cert Nephrology (SA) 1 2
ivision of Hepatology, Department of Medicine, Faculty of Health Sciences, University of Cape Town, South Africa D Division of Nephrology, Department of Medicine, Faculty of Health Sciences, University of Cape Town, South Africa
Corresponding author: Z A Barday (zunaid.barday@uct.ac.za)
Solid organ transplantation (SOT) is the treatment of choice for patients with end-stage organ failure. Most of them will require lifelong immunosuppression to prevent acute and chronic rejection. Immunosuppressive regimens currently used in clinical practice are nonspecific and target T-cell activation, clonal expansion or differentiation into effector T cells. While these therapeutic regimens have advanced considerably and one-year graft survival figures for most SOTs are >90%, the long-term graft survival remains fair owing to graft loss from chronic rejection. These immunosuppressive drugs are associated with significant longterm side-effects, such as opportunistic infections, malignancies, nephrotoxicity, hypertension and diabetes mellitus. Experimental models suggest that induction of tolerance can prevent chronic rejection. The ‘holy grail’ of SOT is therefore the development of a permanent specific immune tolerance against donor allogeneic antigens without long-term use of immunosuppression. Clinically, this is called operational tolerance, defined as a well-functioning graft lacking histological signs of acute or chronic rejection in the absence of immunosuppression for at least one year in an immunocompetent person capable of responding to infections. This, however, occurs infrequently and is difficult to predict, and the incidence varies by allograft type. It occurs in up to 20% of liver transplant recipients, much less commonly in renal transplant recipients, and only rarely in lung and heart transplant recipients. Operationally tolerant transplant recipients have been shown to exhibit signature transcriptional gene profiles that differ in liver and kidney transplant recipients. Clinically, operational tolerance can be divided into: (i) spontaneous tolerance in patients who have been non-compliant and discontinued all immunosuppression; (ii) planned weaning under medical super vision to reduce side-effects and toxicity of immunosuppression; and (iii) active application of tolerogenic protocols. Various experimental tolerogenic protocols based on the mechanisms of central and peripheral tolerance that normally maintain immune homeostasis and self-tolerance have been tested in animal and non-human primate models, with only a few entering clinical trials and clinical practice. Tolerogenic protocols in clinical practice include the induction of microchimerism, T-cell depletion and co-stimulatory blockade. Immune tolerance remains difficult to achieve and disruption of a single pathway is usually insufficient to promote tolerance or long-term allograft survival. Most SOT recipients require life-long immunosuppression, which includes induction therapy at the time of transplantation (usually an intravenous antibody preparation) and maintenance immunosuppression (usually oral). The guiding principle with immunosuppression in SOT is to achieve a balance between preventing rejection and avoiding side-effects.
795
Induction agents include the interleukin-2 receptor (CD25) blocker, basiliximab, an anti-CD25 monoclonal antibody and anti-thymocyte globulin (ATG). ATG, being polyclonal, targets multiple molecules and receptors on thymocytes and is considered the most potent induction agent for preventing and treating acute cellular rejection, but also plays a role in preventing antibody-mediated rejection. ATG increases the risk of opportunistic infections and post-transplant lymphoproliferative disease and should be reserved for patients at highest immunological risk of acute rejection. Maintenance immunosuppression is started at the time of transplant and can be divided into five classes: glucocorticosteroids; anti-metabolites; calcineurin inhibitors (CNIs); mammalian target of rapamycin inhibitors (mTORi); and co-stimulatory inhibitors. Patients usually receive glucocorticosteroids and a combination of two agents from the four other classes. Most patients continue oral prednisone (which is rapidly weaned to a low maintenance dose) after the initial pulses of intravenous (IV) methylprednisolone. The CNIs cyclosporin A (CYA) and tacrolimus (TAC) form the cornerstone of immunosuppression, around which the other drugs are added. Calcineurin is a key enzyme transmitting the activation signal from the T-cell receptor to the nucleus. TAC is a more potent immunosuppressive with a slightly different side-effect profile (more risk of new-onset diabetes after transplant and neurological side-effects) to CYA (more risk of hypertension, hyperuricaemia, hirsuitism, gingival hypertrophy and hyperlipidaemia). Both are potentially nephrotoxic. The oncedaily prolonged-release TAC formulation potentially improves compliance. The anti-metabolites include azathioprine (AZA) and myco phenolates. AZA is considered to be the ‘safest’ immunosuppressant in pregnancy. Mycophenolate mofetil (MMF) or sodium (MPS) have lower acute rejection rates and are replacing AZA in the transplant setting, but are teratogenic and contraindicated in pregnancy. The mTORIs, sirolimus and everolimus, are not nephrotoxic, but are not as potent at preventing acute rejection as CNIs. Also called antiproliferative drugs, they have useful anti-cancer properties, and have been used in the treatment of post-transplant lymphoproliferative disorders and renal cell carcinoma. There is a high rate of side-effects and discontinuation. Co-stimulatory inhibitors currently include only one drug, i.e. belatacept (CTLA-4-Ig), which is given IV monthly lifelong and allows for the omission of CNIs. Operational tolerance remains difficult to achieve and most transplant recipients require lifelong immunosuppression, with the most common immunosuppressive regimen being a combination of prednisone with CYA-AZA or TAC-MMF. S Afr Med J 2014;104(11):795. DOI:10.7196/SAMJ.8960
November 2014, Vol. 104, No. 11
CONTINUING MEDICAL EDUCATION
ARTICLE SUMMARY
Recommendations for the use of immunoglobulin therapy for immunomodulation and antibody replacement J G Peter,1 MB ChB, MMed, FCP (SA), PhD; J M Heckmann,2 MB BCh, MMed, FCN (SA), PhD; N Novitzky,3 PhD, Dip Med, FCP (SA), Cert Clin Haematol (SA) Division of Immunology, Department of Medicine, Faculty of Health Sciences, University of Cape Town, South Africa Division of Neurology, Department of Medicine, Faculty of Health Sciences, University of Cape Town, South Africa 3 Division of Haematology, Department of Medicine, Faculty of Health Sciences, University of Cape Town, South Africa 1 2
Corresponding author: J G Peter (jonny.peter@uct.ac.za)
Immunoglobin therapy, administered via the intra venous, subcutaneous or intramuscular route, is standard of care in the treatment of a number of immune-mediated pathologies. However, the use of immunoglobulin therapy in South Africa (SA) is restricted, and will likely remain so given the cost involved. Clinicians need to motivate for therapy on a case-by-case basis. The incremental benefit over other forms of immunosuppression must be carefully assessed to justify the additional expense. Therefore, clinicians should have an understanding of the therapy, considerations for use and evidence-based quality of data in specific disciplines. In this short review we discuss these in the context of current use in SA. Polyvalent immunoglobulin is purified from pooled human plasma, and this origin as a plasma-derived product underpins the majority of general clinical considerations.
Manufacture
The need for human plasma donors, together with the complex production process to exclude unwanted vasoactive and infectious substances, makes immunoglobulin therapy expensive and limits availability. Regulatory and licensing procedures are also challenging and costly. SA has only four registered products.
Mechanism of action
In immunodeficiency, antibody replacement therapy reconstitutes fundamental humoral immunity, while a number of mechanisms of action have been proposed for the immunomodulatory benefits and are likely to differ depending on the specific autoimmune pathogenesis and individual genetic background.
Side-effects
Major side-effects with modern immunoglobulin preparations are rare, but mild systemic (intravenous) or infusion-site reactions (subcutaneous) are common (20 - 40%) and can be managed with simple analgesics. More serious problems tend to be associated with higher immunomodulatory dosing. One needs to particularly monitor for renal impairment, which is usually reversible. Prehydration is important in patients with pre-existing renal disease or the elderly; in these situations it may be preferable to use a subcutaneous preparation.
796
Current use and conditions with highquality evidence
Immunoglobulin use is supported by randomised control trials (RCTs) for certain conditions in neurology, haematology, immunology and dermatology. In SA, the largest volume of intravenous immunoglubulin (IV Ig) is used in neurology (~40%), followed by haematology. In immunodeficiencies, immunoglobulin replacement is used in lower volumes, but therapy tends to be lifelong, with the attendant issues of chronic medication. Grade A (established evidence-based RCT) recommendations support the use of immunoglobulins in Guillain-Barré syndrome (0.4 g/kg for 5 days) and chronic inflammatory demyelinating polyradiculopathy. In Guillain-Barré syndrome IV Ig or plasma exchange show similar efficacy and use depends on local preferences. Similarly, Grade A recommendations are available to guide use in acute idiopathic thrombocytopenia, Kawasaki disease and immunobullous diseases. However, in the cost-constrained SA health system, the incremental benefit over corticosteroid immunosuppression is often not seen to justify the additional expense. Therefore, with the exception of Kawasaki disease, where IV Ig is first-line therapy to prevent coronary artery abnormalities, corticosteroids remain used as frontline immunosuppression with IV Ig reserved for certain emergency situations and steroid-resistant cases. Similarly, there is consensus that immunoglobulin therapy offers benefit in a number of other conditions, including, but not limited to, myasthenia gravis, autoimmune limbic encephalitis, some paraprotein-associated demyelinating neuropathies, autoimmune and newborn haemolytic anaemia and pure red cell aplasia (autoimmune or secondary to parvovirus B19), as well as secondary antibody deficiency. IV Ig therapy for these uncommon indications is also used as second-line or ‘rescue’ therapy. In contrast, lifelong immunoglobulin replacement therapy (0.4 - 0.6 g/kg monthly) in patients with primary antibody deficiencies such as X-linked agammaglobulinaemia or common variable immunodeficiency has been proven to be both efficacious and cost-effective. We hope that this article will help clinicians to improve their use of immunoglobulin therapy and aid motivations where thera peutic benefit is well established. The development of formal SA immunoglobulin therapy guidelines to improve and advocate for appropriate use is ongoing. S Afr Med J 2014;104(11):796. DOI:10.7196/SAMJ.8965
November 2014, Vol. 104, No. 11
PROFESSIONAL ADVERTISING Tel: 021 681 7000 | E-mail: bronlyne.granger@hmpg.co.za www.hmpg.co.za | www.professionalads.co.za We accept credit card payments - Visa or MasterCard.
GP REQUIRED
GP REQUIRED
GP required to join a multi-disciplinary practice serving the local community, University & Schools. Based in Grahamstown which is close to the coast and boasts several good schools.
Full time employment opportunities available for GP’s in a 24 hour Emergency Unit situated in a new private hospital in Midstream.
Please contact Dr. Barbara Bull (bull@highstmed.co.za) or Alix Whittington-Jones (Whittington-jones@highstmed.co.za) at 046 636 2063.
Valid ACLS,ATLS and APLS will be advantageous, interested parties to please e mail CV to info@careatmidstream.co.za
GYNAECOLOGIST OPPORTUNITY Uitenhage Eastern Cape Hospital looking for a gynaecologist to start a practice and to admit patients at their facility. Huge demand for services. Young dynamic candidate required. Please contact Hospital Manager, Walter Kurten on (041) 995 9002 or email walter.kurten@netcare.co.za for more details.
ESTABLISHED FAMILY PRACTICE WE OFFER AN OPPORTUNITY TO JOIN A WELL EQUIPPED FAMILY PRACTICE WITH A VIEW TO JOINING THE PRACTICE ON A LOND TERM BASISI ALTHOUGH FLEXI TIME ALSO A POSSIBILITY POST COMMUNITY APPLICATION WELCOME CONTACT DOCTOR ON: 082 702 9985 EMAIL: MEDIVIEW1@GMAIL.COM
PROFESSIONAL ADVERTISING
GLOUCESTERSHIRE HOSPITALS NHS FOUNDATION TRUST
3 Full-time Consultants in General/ Cross-Sectional Imaging Radiology (special interests in Interventional, Paediatric, Head & Neck/ Neuro) This is an opportunity to join a forward-thinking radiology team in an outstanding area of the country. The posts have arisen as a consequence of one retirement, one overseas relocation and workload growth. Experience in general radiology, general cross-sectional imaging and acute radiology are essential. Interests in Paediatric imaging, Head and Neck and Neuro imaging would suit the department best but we can be flexible. There is a new paediatric wing at Gloucestershire Royal hospital that provides integrated care for the whole county and we work closely with our paediatric colleagues. ENT and neurology services are also based at the same site and both have excellent reputations in the region with ENT providing a specialist regional service for tumour resection. Radiology supports one-stop ENT neck lump clinics with cytology support and there are opportunities to participate in research in radiotherapy planning for head and neck cancer IMRT cases.
We work closely with other departments to provide active urology, renal RFA, GI, biopsy, drainage and general interventional support. We already run a seven day service in radiology, use outsourcing of reporting to ease workload pressures and are about to outsource overnight on call. Whole-time, part-time or job share applicants welcome. Gloucestershire Hospitals NHS Trust was formed in April 2002 and became a Foundation Trust in July 2004. A successful Trust with a strong track record of achievement and financial stability, we are situated mainly on the two larger operational sites, Gloucestershire Royal Hospital and Cheltenham General Hospital, providing acute services to Gloucestershire. With its close proximity to the Cotswolds and the Forest of Dean, its excellent cultural and recreational facilities, housing and schools, you will find Gloucestershire a highly desirable place to live and work. For an informal discussion please contact Dr Frank Jewell (03004 225093). To apply, please visit www.jobs.nhs.uk (Job Ref 318-845). You should also attach a CV to your online application form.
Closing Date: 27 November 2014 Anticipated Interview Date: 9 January 2015
The interventional radiology post will be part of an exciting expansion of the vascular services that we provide as a specialist vascular surgical centre. We have developed a large EVAR practice and participate in the training of new vascular surgical trainees. As a team we provide a thrombolysis service for venous and arterial disease, a large fistula service to support the two local dialysis units and we adopt innovative techniques where appropriate. A new £2.5million hybrid theatre project opened in February 2014 and an additional new build IR room is planned to underpin the provision of these services.
Working for PathCare always produces excellent results!!
Clinical Microbiologist/Clinical Pathologist Midrand, Gauteng
Responsibilities: ▪ Grow the business from an in-house hospital laboratory perspective as well as a geographical perspective ▪ Initiate and contribute to the hospital’s antimicrobial stewardship programme according to the needs of the hospital group ▪ Contribute to clinical ward rounds as required by clinicians. Requirements: ▪ M.Med Degree in either Microbiology or Clinical Pathology OR a College of Medicine South Africa equivalent ▪ Clinical Microbiologist or Clinical Pathologist with a specific interest in clinical microbiology ▪ At least 5 years’ private practice experience ▪ Current registration with HPCSA as a pathologist ▪ Partnership will be offered pending certain performance criteria. Please note: Preference will be given to candidates currently working in Gauteng. To apply, please email lindyg@pathcare.co.za Closing date: 30 November 2014. www.pathcare.co.za
www.strate
o.za gy-rm.c y-r www.strateg
m.
CPD
NOVEMBER 2014
Effective in 2014, the CPD programme for SAMJ will be administered by Medical Practice Consulting: CPD questionnaires must be completed online at www.mpconsulting.co.za
True (A) or false (B): Recommendations for the management of sickle cell disease (SCD) 1. Because of the influx of people from other African states into South Africa (SA) and an influx of the sickle gene, clinicians are likely to encounter an increasing number of patients with SCD. 2. The ‘hand-foot syndrome’ in infants and young children represents an acute vaso-occlusive crisis (VOC) involving small bones of the hands and feet. 3. The incidence of stroke, as a manifestation of VOC, is highest between the ages of 20 and 40 years. Medical leadership and conflict of interest in SA healthcare 4. Ghost writing occurs when writers are contracted by the pharma ceutical industry to prepare a manuscript for publication. 5. In the wake of reports regarding the potential cardiovascular harms of rosiglitazone, authors who had favourable views on the safety of rosiglitazone were more than three times more likely to have a financial conflict of interest with a pharmaceutical company than those who had unfavourable views. Appropriateness of computed tomography (CT) and magnetic resonance imaging scans in the Eden and Central Karoo districts of the Western Cape 6. CT involves larger radiation doses than the more common con ventional X-ray imaging procedures, with an attendant (albeit low) risk of radiation-induced carcinogenesis. Identification and speciation of non-tuberculous mycobacteria (NTM) isolated from specimens submitted to a tuberculosis lab oratory 7. NTM are ubiquitous in nature, and can be recovered from a wide range of environmental sources. 8. NTM species are increasingly recognised as opportunistic patho gens (causing a spectrum of infections including pulmonary, lymphatic, skin and soft-tissue, and disseminated disease). The association of khat (Catha edulis) chewing and orodental health 9. Khat chewing is shown to be associated with adverse orodental health outcomes such as oral mucosal white changes, gum recession, periodontal pocketing and gum bleeding. 10. The available evidence consistently indicates that khat chewing favours the proliferation of pathogenic oral micro-organisms.
Superheroes in autoimmune warfare: Biologic therapies in current SA practice 11. Biologic drugs are reserved for patients with severe disease who fail to respond to standard treatments. 12. In rheumatoid arthritis, patients with active disease despite synthetic disease-modifying anti-rheumatic drugs over at least 6 months can be considered for biologic therapy. Investigation of adult immunodeficiency and indications for immunoglobulin replacement therapy 13. In patients presenting with recurrent localised infections, it is mandatory to exclude an underlying predisposing, regional anatomical defect. 14. Rare disorders such as cystic fibrosis and chronic granulomatous disease never present for the first time in adults. Investigation and management of primary immunodeficiency in SA children 15. Respiratory infections are the commonest presenting symptom of primary immunodeficiency, and a positive family history is recorded in 30% of cases. Advances in the diagnosis and management of allergic disease 16. Previous anaphylactic reaction to a food, insect sting, latex or unavoidable aeroallergen is an absolute indication for an injectable adrenaline device. 17. Children allergic to shellfish may outgrow the allergy. Immune tolerance and immunosuppression in solid organ trans plantation 18. Immunosuppressive drugs are also associated with significant long-term side-effects such as opportunistic infections, malig nancies, nephrotoxicity, hypertension and diabetes mellitus. Recommendations for the use of immunoglobulin therapy for immunomodulation and antibody replacement 19. Intravenous immunoglobulin therapy is highly effective in a number of neuromuscular diseases, but the substantial cost must be taken into account in developing a treatment plan. 20. It is unnecessary to check for hepatitis B/C or HIV before starting immunoglobulin therapy.
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)
2
November Month2014, 20xx,Vol. Vol.104, xxx, No. 11 x
south africa 1941
HAVASWW-D63655/E
Put the right people together, and a group of dentists can lead the way to financial protection.
Created in 1941 by 8 pioneering South African dentists looking for a better way to protect their earning potential and ensure their financial security, PPS today provides unique, tailor-made insurance, investment and healthcare solutions specifically created for graduate professionals. And because PPS belongs to our graduate professional members*, they also share all our profits.
Find out why it pays to keep the right company www.pps.co.za
#joinourtable