Rapid Responses to:
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Rapid Responses: Rapid Responses published:
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Value of Pf antigen rapid assay over thick and thin smear examination in malaria detection & treatment
- Professor Pranab kumar Bhattacharya, Bhattacharya, Rupak, Bhattacharya, Ritwik, Bhattacharya Upasana,Pathak Swapan,Mukherjee Dipankar (31 January 2007)
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Stop ambiguous messages on malaria diagnosis
- Valérie D'Acremont, Christian Lengeler, Blaise Genton (2 February 2007)
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Malaria diagnosis and management in endemic countries: a still unsolved problem.
- Zeno Bisoffi, Jef Van den Ende (24 February 2007)
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Guiding out-patient treatment of malaria in Africa
- Ayokunle.T. Abegunde (1 March 2007)
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Professor Pranab kumar Bhattacharya, Professor of Pathology, Incharge ofCytogenetics, Ex- in charge Ronald Ross Malaria Clinic, Institute of Post Graduate Medical Education& Research ,244A, AJC Bose Road, Kolkata-20, India, Bhattacharya, Rupak, Bhattacharya, Ritwik, Bhattacharya Upasana,Pathak Swapan,Mukherjee Dipankar
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We went through the article “Rapid diagnostic tests compared with malaria microscopy for guiding outpatient treatment of febrile illness in Tanzania: randomised trial” By Hugh Reyburn 1*, Hilda Mbakilwa 2, Rose Mwangi 3, Ombeni Mwerinde 3, Raimos Olomi 4, Chris Drakeley 1, Christopher J M Whitty 1 BMJ, doi:10.1136/bmj.39073.496829.AE (published 26 January 2007) Malaria remains today one of the major health problems in the tropics including in India with increased mortality and morbidity. Falciparum malaria presents with protean manifestations and is associated with variety of complications and has a high mortality. P. Falciparum, in contrast to benign malaria P. Vivax may progress to a life threatening multi-system organ failure & thus possesses serious complications. In the West Bengal State Of India Malaria must be considered in any patients presenting with high fever unless proved otherwise as many areas of the state are highly endemic. Although the first symptoms usually begin in 10 days to 4 weeks after transmission by an infected mosquito, in children and often in adults particularly in Plasmodium falciparum infection the symptoms begin with non specific flu-like symptoms that include malaise, vomiting and even with diarrhea. We in our institute IPGMER, Kolkata, West Bengal, at first look for the parasite in thin and thick Blood smear with Romansky stain. Many times though we miss trophozoites of Plasmodium falciparum malaria in blood slides and often may confuse with artifacts stain deposits, so we perform Rapid Test by Pf Rapid antigen assay. This test is very sensitive and specific for Histidine protein of P. Falciparum species. The Diagnosis of Malaria, particularly the P. Falciparum, must be prompt. Failure to expedite appropriate referral may lead to development of life threatening complications like in severe malaria. Thick and thin blood films processed in EDTA sample by local hematological laboratory are the main stay of diagnosis. Generally 3 (three) blood films at height of temperature are required to exclude malaria. But they require a laboratory to prepare a good smear, good stain, good microscopy with light and expert Technician on identification of malaria parasites & or qualified clinical pathologist, which are not usually found in suburbs of greater Kolkata even, or in subdivision or in villages of West Bengal. This Rapid Antigen Assay for PF is very easy to perform and interpret even in the field and even by a technician and is very sensitive. Unless the Report of Malaria comes negative, we give the patients a dose of chloroquine immediate after collecting blood for malaria in all fever cases as the standard protocol in our institute. Malaria is still a big problem in India, including in one of its province West Bengal. West Bengal, one of the eastern provinces in India, has an area of 88752 sq. kilometer, having twenty( 20) districts towns, 40782 villages and 375 towns. It has 8.2 cores population and density of population is 903 per Sq kilometer. Percentage of population in urban set up up is 28% and rest (72%) in rural set up. Highest density of population are in Kolkata (24718) followed by in Haora (2913), South 24 Parganas (2182), North-24 Parganas(1173). Percentage of Population in below poverty line [considering World Bank 1991 criteria Us$<1,08 i.e< 47 Indian Rupees per-day per-capita income] is 47% [ 16% in urban and 32% in rural set up] In West Bengal a statistical analysis on malaria shows that in in 1991 numbers of slide positive cases were 40452, of which P. Falciparum cases were 7913 and death was only in 13 cases. Since 1991 to 2004, there was a steady rise of incidence of malaria cases, Pf cases and death due to P falciparum. In 2004 Number of slide positive cases of malaria was 2,21,617 cases, when Pf cases was 60,643 having Pf%27.4 and death due to P. falciparum was 190. The SPR% in 1985 was 2.9; it rose to a peak of 7.9 in 1991, fell in 2001 to 4.3 and further rose to 5.7 in 2004. The Pf% in West Bengal in 1985 was 23.3, rose to a peak of 32 in 1999, fell in 2000 to 22.3 and further rosed to 32.9 in 2004. The highest incidence of Pf cases was found in Kolkata urban/semiurban then in Jalpaiguri areas, followed by Kolkata municipal corporation areas then in Bankura, Hoara, Birbhum districts of West Bengal respectively. But highest incidence of death in 2004 was noted in Jalpaiguri (88), Kolkata (19) Pashim Mednapur districts in-spite of insecticide spray under National Malaria Control Program in West Bengal2. In view of global distribution of cholorquine resistance WHO has already disapproved of the use of chloroquine for treatment of severe malaria in general and where chloroquine sensitivity is not known3. For treatment of P. Falciparum (severe or uncomplicated) the physician does not want to take any risk and in tertiary institute the physician uses either Artesunate [available in trade name as “Falcigo” of Cadila as 60 mg vial injectable form in standard recommended doses of 120mg Iv or im on day 1 followed by 60 mg Iv or im in next 4-6 days]. This is also practice in our Institute. One vial of 60 mg cost around Indian currency Rs 170/= as such total costs for drugs only is 1100/= in Indian Rupees. The drug is safe except occasional abdominal pain vomiting and prolongation of Q-T interval and first degree heart block in very rare cases. Otherwise the treatment is done with Quinine di-hydrochloride injection [available in the market in 2ml vial cost Rs 14/=] This injection is given initially 20 mg/kg iV infusion over 4 hours, then 8 hours after the loading dose in adults. A maintenance dose of 10 mg/kg over 4 hours is then given. This maintenance dose is repeated every 8 hourly for adults. The side effect may be atrial fibrillation, heart block. Resistance to Quninine is not known in West Bengal yet. Use of both these drugs requires hospitalization of patients in either a private or in nursing home or in public set up hospital where the IV infusion arrangement to give the loading dose, maintenance dose and ECG monitoring is possible. However these are not possible in the rural set up or in semi urban set up [ in home set up also] where 72% population of West Bengal live. Therapeutic efficacy study with chloroquine and with sulfa doxine-pyrimethamine were conducted in falciparum malaria according to standard WHO protocol in Orrisa, North Eastern states of India and across the international boarders of the country by ICMR3. The analysis of data showed good efficacy of chloroquine and of sulfadoxine pyrimethamine in Keonjhar town and in Podmapur of Orrisa state. However high failure rate up to 50% were observed in Birsa and in Kaurmunda of Sundergarh with sulfa doxine pyrimethamine. Moreover there is fear of Steven- Jhonsons syndrome with this drug. In Assam State of India, failure rate of 34% and 30% was observed in Sonapur (Kamrup district) and Kathitali (Nawgao district) respectively with chloroquine. However efficacy of the drug was found good in Boko. The efficacy of Choloroquine was also evaluated in Indo-Nepal boarder in Darjeeling district of West Bengal. Cumulative failure rate was 66% and 33% respectively in Sukna & in Naxal Bari Block PHC. But therapeutic efficacy of chloroquine in P. Vivax is 100% in Goutam Buddha Nagar of UP, in Mumbai, Chennie & in Kolkata. References 1)Miram. K. Laufer, Philip. C Thesing and Nicole. D. Eddington et al Return of choloroquine anti-malarial efficacy in Malwai: New Eng. J. Med Nov9, 1959-1966;2006 2)Health on March 2004-2005 of state Bureue of Health intelligence, directorate of Health Services, government of West Bengal, India, Pages 3,6,9,127-133, 282-83;2006 3)Annual Report 2003-2004 of Indian council of Medical Research, New Delhi published by Director General ICMR ,2005 Page 30 Authors: 1) Professor Pranab kumar Bhattacharya MD (cal)
2) Mr. Rupak Bhattacharya Bsc (Cal) MSC(JU)
3) Mr. Ritwik Bhattacharya B.Com(Cal)
4) Dr. Dipankar Mukherjee MD(Cal) DM ( Cardio)
Acknowledgement--Authors are grateful for all help from Miss Upasana Bhattacharya of mahamayatala Garia, Mr Debasis Mukherjee Bsc(Cal) of South Habra, North 24 parganas, W.B, and DR. Swapan Pathak, Associate professor, pathology, IPGMER, Kolkata. Competing interests: None declared |
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Valérie D'Acremont, Research physician, specialist in infectious diseases Ifakara Health Research & Development Centre, PO Box 78373, DSM Tanzania; Swiss Tropical Institute, Christian Lengeler, Blaise Genton
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We welcome the paper of Reyburn et al[1] that addresses a hot topic in malaria case management in endemic areas: should the clinician rely on the malaria test to give antimalarials or not? Reyburn’s findings that about half of the febrile patients were given antimalarials in spite of a negative test, and this irrespective of the technique used [Rapid Diagnostic Test (RDT), microscopy] and of the level of endemicity, is definitely worrying. It shows clearly that clinicians do not think in terms of pre- or post-test probabilities to decide on treatment. The authors conclude soundly that the issue to address now is to find out how to change clinicians’ behaviour, i.e. how to stop them over-prescribing antimalarial drugs. We believe that part of the problem is due to ambiguous messages provided by malaria experts and national guidelines on how to take action on the result of a malaria test. The diagnostic performance of RDTs is not any more an issue: meta-analyses have shown the performance to be excellent and consistently reliable[2]; RDTs based on HRP-2 detection have even proved to be more sensitive than microscopy in malaria endemic areas[3]. Despite the strength of this evidence, a rationale argument is clearly not strong enough to convince clinicians. Hence, training needs to focus on the other reasons that lead them to prescribe antimalarials in case of a negative RDT. Undoubtedly, an important one is the ambiguity of national malaria control programme guidelines on the management of suspected malaria in children under 5 years. In Tanzania, the recommendation is: perform microscopy/RDT for malaria -> Negative -> No signs and symptoms of severe disease -> Under five years: treat as uncomplicated malaria; look for other condition[4]. Similar inconsistency is found in the Ugandan guidelines. It is pretty unusual in medical history to recommend a laboratory test and in the same sentence to propose not to take into account the result… Even Reyburn et al state that ‘…in areas of very high malaria transmission, withholding antimalarial drugs from children under 5 with febrile illness is potentially hazardous even in the face of negative test results…’[1]. A case management strategy should not be based on extremely rare events, such as a true malaria episode with a negative test in semi- immune populations (because of sequestration etc.), in other terms based on fears (putting children at risk of severe malaria if not treated as soon as they get fever). Evidence is now provided that the safety issue is not where malaria experts think. Indeed the same authors and others have shown that more patients are dying of non-malarial causes of fever that are missed because of sticking to the diagnosis of malaria than of severe malaria[5;6]. The risk of missing a true malaria case in the event of a negative test, and the resulting consequences has been recently evaluated thoroughly in Uganda[7]. In this study, febrile children were not given antimalarials when the microscopy was negative (rate of malaria test positivity: 32%). Only 2 malaria cases out of 2359 febrile episodes were missed; both consulted the next day because of persisting fever and were treated for uncomplicated malaria based on a new test that was positive. In parallel, 464 non-malaria causes of fever in need of antibiotic treatment were identified[7]. Hence, the assertion that feverish children under five years should be treated with antimalarials irrespective of the test result, because the disease has a more rapid course, is inadequate. Indeed it is the clinical assessment to identify early enough danger signs that is crucial, but the performance of the test, and hence the trust we can have in its result, is the same in all age groups. Teaching material and guidelines should not be based on beliefs and fears but updated using most recent evidence. There is an urgent need to give a uniform and unambiguous message for uncomplicated febrile illness: positive malaria test -> Malaria; negative malaria test -> NO malaria. This is where we are in 2007… References 1. Reyburn H, Mbakilwa H, Mwangi R, Mwerinde O, Olomi R, Drakeley C et al. Rapid diagnostic tests compared with malaria microscopy for guiding outpatient treatment of febrile illness in Tanzania: randomised trial. BMJ 2007. 2. Marx A, Pewsner D, Egger M, Nuesch R, Bucher HC, Genton B et al. Meta-analysis: accuracy of rapid tests for malaria in travelers returning from endemic areas. Ann.Intern.Med. 2005;142:836-46. 3. Ochola LB, Vounatsou P, Smith T, Mabaso ML, Newton CR. The reliability of diagnostic techniques in the diagnosis and management of malaria in the absence of a gold standard. Lancet Infect.Dis. 2006;6:582- 8. 4. National Malaria Control Programme MoH, Tanzania. National guidelines for malaria diagnosis and treatment 2006. 5. Makani J, Matuja W, Liyombo E, Snow RW, Marsh K, Warrell DA. Admission diagnosis of cerebral malaria in adults in an endemic area of Tanzania: implications and clinical description. QJM. 2003;96:355-62. 6. Reyburn H, Mbatia R, Drakeley C, Carneiro I, Mwakasungula E, Mwerinde O et al. Overdiagnosis of malaria in patients with severe febrile illness in Tanzania: a prospective study. BMJ 2004;329:1212. 7. Njama-Meya D, Clark TD, Nzarubara B, Staedke S, Kamya MR, Dorsey G. Treatment of malaria restricted to laboratory confirmed cases: a prospective cohort study in Ugandan children. Malar.J. 2007;6:7. Competing interests: None declared |
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Zeno Bisoffi, Head, Centre of Tropical Diseases S. Cuore Hospital, Negrar (Verona), Italy, Jef Van den Ende
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The last issue of BMJ focuses on the critical issue of the clinical management of malaria in endemic countries (1,2). With a group of researchers from Europe and Burkina Faso we just concluded a randomised trial on malaria diagnosis and management both in the dry and the rainy season (NCT00317590). Febrile patients were randomised either to be managed clinically, or after a rapid diagnostic test (RDT) for malaria (Paracheck®). Data are currently analysed, and will be published after a full report has been submitted to the Ministry of Health of Burkina Faso. Preliminary results for the dry season show no difference in malaria management between the two groups: clinical officers don’t appear to take into account test results. On the other hand there is a significant decrease in “double diagnosis” (i.e., malaria plus a second diagnosis) in patients submitted to the test. Since test-negative patients are anyhow suspect for another diagnosis, even if they are treated as malaria, the explanation for this overall drop in double diagnosis can only be that a patient with a positive RDT is taken as a confirmed malaria case, without considering another possibly life threatening condition. In a highly endemic zone a positive RTD does not automatically mean that malaria is the true cause of fever: these tests are very sensitive and may detect low to very low parasitaemias without any clinical significance. Consequently, there could be a risk of under treatment of other causes of fever, with a potential harm to the patient. In conclusion, as Reyburn and Coll. correctly affirm, the problem of malaria diagnosis and management is complex and unlikely to be solved by any magic bullet. We believe that this is a research issue of high priority. 1.Hugh Reyburn, Hilda Mbakilwa, Rose Mwangi, Ombeni Mwerinde, Raimos Olomi, Chris Drakeley, Christopher J M Whitty. Rapid diagnostic tests compared with malaria microscopy for guiding outpatient treatment of febrile illness in Tanzania: randomised trial. BMJ 2007;334:375-376 2.Talisuna A O and Meya D N. Diagnosis and treatment of malaria. BMJ 2007;334:403 Competing interests: None declared |
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Ayokunle.T. Abegunde, GP registrar Directorate of Child Health,William Harvey Hospital, Kennington Road, Ashford, Kent TN24 OLZ
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Sir, Over diagnosis of malaria has been identified as one of the contributory factors which may make delivery of Artemisinin combination treatments (ACT) unsustainable in Africa.(1) The paper by Reyburn et al is timely and answered a very relevant question in the on going debate about the sustainability of widespread introduction of ACTs in sub-saharan Africa. Intervention with rapid diagnostic tests (RDT) did not lead to an improvement in clinician decision making and reduction in over-diagnosis of malaria. This is a significant finding which argues against promoting RDTs( added cost implication) as the only means of preventing wastage of ACTs if deployed widely in sub-saharan Africa, highlighting the need for a change in prescribing behavior by health workers and the recognition of alternative treatable diagnoses as key issues for success. Delivery of ACTs is likely to depend on international subsidy.(1) However it is unclear if this subsidy will extend to ACTs bought in the informal retail sector (shops) where a substantial proportion of the population purchase antimalarials.(2-4) Guiding treatment of malaria in these informal settings is likely to be the bigger challenge. However, changing practice in hospitals is a very vital first step. In theory, pairing delivery of ACTs with rapid diagnostic tests (RDT) for malaria may reduce over diagnosis of malaria and improve the cost effectiveness of the delivery of ACT in Africa by ensuring that only patients with a positive test get antimalarials. This strategy may also be useful in drug shops where diagnosis of malaria is by clinical symptoms alone. However, studies have shown that a significant proportion of shop bought antimalarials are purchased on behalf of others, this negates the opportunity to use the RDT to guide treatment in these settings.(2-4) Formal health services without facilities for microscopic diagnosis of malaria appear to be the best setting for the RDT/ACT combination strategy. Strategies to safely and cost effectively deploy ACTs in the informal retail sector in Africa need to be devised and studied. References (1)Reyburn H, Mbakilwa H, Mwangi R et al. Rapid diagnostic tests compared with malaria microscopy for guiding outpatient treatment of febrile illness in Tanzania: randomised trial. BMJ.2007 Feb 24;334 (2)Patrick Kachur S, Schulden J et al. Prevalence of malaria parasitaemia among clients seeking treatment for fever or malaria at drug stores in rural Tanzania.Trop Med Int Health. 2006 Apr;11(4):441-51. (3)Afolabi BM, Brieger WR, Salako LA. Management of childhood febrile illness prior to clinic attendance in urban Nigeria. J Health Popul Nutr. 2004 Mar;22(1):46-51. (4)Nshakira N, Kristensen M, Ssali F et al. Appropriate treatment of malaria? Use of antimalarial drugs for children's fevers in district medical units, drug shops and homes in eastern Uganda.Trop Med Int Health,7(4):309-16. 2002. Competing interests: None declared |
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