BMJ 2014;348:g3846 doi: 10.1136/bmj.g3846 (Published 19 June 2014)
Page 1 of 2
Editorials
EDITORIALS Rapid diagnostic tests for malaria A useful tool for managing fever in countries with endemic disease, but not necessarily a substitute for good microscopy 1
1
Zeno Bisoffi director , Federico Gobbi physician , Jef Van den Ende professor
2
Ospedale Sacro Cuore, Centro per le Malattie Tropicali, Verona, Italy; 2Institute of Tropical Medicine, Antwerp, Belgium
1
Despite a decline in incidence, malaria remains one of the leading infectious causes of mortality worldwide.1 Although Asia accounts for the largest proportion of the world’s population exposed to malaria,1 most clinical cases and deaths from the disease occur in sub-Saharan Africa. This is due to a higher, average intensity of malaria transmission in sub-Saharan Africa and to the infective species involved. Plasmodium falciparum, the parasite responsible for the most severe form of malaria and the majority of deaths from the disease, largely occurs in Africa, whereas Plasmodium vivax, the parasite that generally causes a more benign disease, is the predominant species in most of Asia.
The management of malaria, especially in Africa, has long relied on clinical, presumptive management, as most patients are seen at remote dispensaries with no laboratory facility. In early 2000 the widespread introduction of the rapid diagnostic test (RDT) for malaria, a test that is easy to use and requires no equipment, led to the current recommendation of testing all suspected cases and treating only those patients with a positive test result.2 This should limit the misuse of antimalarials, especially the effective but also comparatively expensive artemisinin combination treatments, which are the first choice for treating falciparum malaria. The current policy for treatment has been the subject of hot debate.3 A limited number of randomised controlled trials have so far compared test based management of patients with clinical management alone.
A Cochrane review of seven trials has just been published.4 All the trials were conducted in Africa, indicating that in general, but not in all settings, RDT substantially reduced the over-prescription of antimalarials while not showing a consistent effect on the prescription of antibiotics or the short term outcome for patients. In a linked paper (doi:10.1136/bmj.g3730), Leslie and colleagues report the results of the first such trial conducted in central Asia—namely, in Afghanistan.5 The study was carried out in two areas, one in the north of the country where malaria is now rare, and one in the east with a moderate incidence of malaria. In the north only half of the 10 clinics were equipped with
microscopy, whereas in the east, microscopy was available in all 12 clinics.
An observational study found that, where microscopy was not available, only 1 patient out of over 400 treated for malaria was confirmed to be positive (for P vivax) at subsequent reference microscopy.6 In the clinics equipped with microscopy up to half of those patients found to be negative for malaria by reference laboratory testing were nevertheless administered antimalarials, partly as a result of errors in microscopy and partly to non-adherence to negative test results. The main purpose of the new trial was to show whether the introduction of RDT could substantially improve the management of febrile patients.5
Patients with suspected malaria based on clinical signs and symptoms were randomised to be managed on the basis of a malaria RDT result or in the usual way (clinically or after microscopy according to local availability). Overall, 1696 patients of all ages were enrolled in the northern region with low transmission (1044 and 652 in clinics with and without microscopy, respectively), and 4053 in the eastern region with moderate transmission (all in clinics with microscopy).
Not surprisingly, the RDT arm performed better than the clinical management arm (65% v 12.5% of patients, respectively, were correctly managed). In clinics equipped with microscopy, the difference in the main outcome was smaller, with 84% and 80% of patients in the RDT arm (in the moderate and low transmission areas, respectively) correctly managed compared with 76% (in both areas) in the microscopy arm. A further, marginal advantage of the RDT in the moderate transmission area was improved identification (and consequent treatment with artemisinin combination treatments) of rare P falciparum cases. Significantly more participants in the RDT arm than clinical arm received antibiotics (57% v 14%), whereas the RDT and microscopy arms did not differ significantly. In contrast with most African trials, no information was available on clinical outcomes. This first trial to be conducted in Central Asia confirms that the adoption of RDT may substantially improve the management of malaria in areas of low transmission that lack laboratory
Correspondence to: Z Bisoffi [email protected] For personal use only: See rights and reprints http://www.bmj.com/permissions
Subscribe: http://www.bmj.com/subscribe
BMJ 2014;348:g3846 doi: 10.1136/bmj.g3846 (Published 19 June 2014)
Page 2 of 2
EDITORIALS
facilities. It also provides a comparison with microscopy that was unavailable in most African trials, showing that the advantage of RDT over microscopy is much less clear cut.
Should rapid diagnostic tests replace microscopy? Leslie and colleagues’ trial did not report cost effectiveness, but results from African trials have been mixed.7 8 Moreover, good quality microscopy has potential added values that are generally not taken into account in cost effectiveness studies, such as the estimation of parasite density and the diagnosis of other conditions such as tuberculosis.9
Leslie and colleagues’ study provides further evidence that malaria has become a rare cause of fever in most countries with endemic malaria in Asia. This has also become true for many parts of Africa. Excluding malaria is good but could also lead to overuse of antibiotics if facilities for diagnosing other febrile conditions are lacking.
Investigating non-malarial causes of fever is therefore a new priority. A few good examples have been published recently.10 11 Research is also urgently needed on accurate, point of care tools for non-malarial fevers,12 including the cost effectiveness of competing diagnostic strategies, with the ultimate aim of providing the best base of evidence to inform clinical management of fevers and training in the field. Competing interests: We have read and understood the BMJ Group policy on declaration of interests and declare the following interests: none.
For personal use only: See rights and reprints http://www.bmj.com/permissions
Provenance and peer review: Commissioned; not externally peer reviewed. 1 2 3 4 5 6 7 8
9 10 11 12
WHO. World malaria report 2013. www.who.int/malaria/publications/world_malaria_report_ 2013/report/en/. WHO. Guidelines for the treatment of malaria. 2nd edn. 2010. http://whqlibdoc.who.int/ publications/2010/9789241547925_engpdf?ua=1. English M, Reyburn H, Goodman C, Snow RW. Abandoning presumptive antimalarial treatment for febrile children aged less than five years—a case of running before we can walk? PLoS Med 2009;6:e1000015. Odaga J, Sinclair D, Lokong JA, Donegan S, Hopkins H, Garner P. Rapid diagnostic tests versus clinical diagnosis for managing people with fever in malaria endemic settings. Cochrane Database Syst Rev 2014;4:CD008998. Leslie T, Mikhail A, Mayan I, Cundill B, Anwar M, Bakhtash SH, et al. A patient-randomised effectiveness trial of malaria rapid diagnostic tests to improve treatment for malaria and other febrile illnesses in primary care clinics in Afghanistan. BMJ 2014;348:g3730. Leslie T, Mikhail A, Mayan I, Anwar M, Bakhtash S, Nader M, et al. Overdiagnosis and mistreatment of malaria among febrile patients at primary healthcare level in Afghanistan: observational study. BMJ 2012;345:e4389. Uzochukwu BS, Obikeze EN, Onwujekwe OE, Onoka CA, Griffiths UK. Cost-effectiveness analysis of rapid diagnostic test, microscopy and syndromic approach in the diagnosis of malaria in Nigeria: implications for scaling-up deployment of ACT. Malar J 2009;8:265. Ansah EK, Epokor M, Whitty CJ, Yeung S, Hansen KS. Cost-effectiveness analysis of introducing RDTs for malaria diagnosis as compared to microscopy and presumptive diagnosis in central and peripheral public health facilities in Ghana. Am J Trop Med Hyg 2013;89:724-36. WHO. Determining cost effectiveness of malaria rapid diagnostic tests in rural areas with high prevalence. 2014. www.wpro.who.int/malaria/sites/rdt/. Mayxay M, Castonguay-Vanier J, Chansamouth V, Dubot-Pérès A, Paris DH, Phetsouvanh R, et al. Causes of non-malarial fever in Laos: a prospective study. Lancet Glob Health 2013;1:e46-54. D’Acremont V, Kilowoko M, Kyungu E, Philipina S, Sangu W, Kahama-Maro J, et al. Beyond malaria−causes of fever in outpatient Tanzanian children. N Engl J Med 2014;370:809-17. Bisoffi Z, Buonfrate D. When fever is not malaria. Lancet Glob Health 2013;1:e11-3.
Cite this as: BMJ 2014;348:g3846 © BMJ Publishing Group Ltd 2014
Subscribe: http://www.bmj.com/subscribe
Page 1 of 2
Editorials
EDITORIALS Rapid diagnostic tests for malaria A useful tool for managing fever in countries with endemic disease, but not necessarily a substitute for good microscopy 1
1
Zeno Bisoffi director , Federico Gobbi physician , Jef Van den Ende professor
2
Ospedale Sacro Cuore, Centro per le Malattie Tropicali, Verona, Italy; 2Institute of Tropical Medicine, Antwerp, Belgium
1
Despite a decline in incidence, malaria remains one of the leading infectious causes of mortality worldwide.1 Although Asia accounts for the largest proportion of the world’s population exposed to malaria,1 most clinical cases and deaths from the disease occur in sub-Saharan Africa. This is due to a higher, average intensity of malaria transmission in sub-Saharan Africa and to the infective species involved. Plasmodium falciparum, the parasite responsible for the most severe form of malaria and the majority of deaths from the disease, largely occurs in Africa, whereas Plasmodium vivax, the parasite that generally causes a more benign disease, is the predominant species in most of Asia.
The management of malaria, especially in Africa, has long relied on clinical, presumptive management, as most patients are seen at remote dispensaries with no laboratory facility. In early 2000 the widespread introduction of the rapid diagnostic test (RDT) for malaria, a test that is easy to use and requires no equipment, led to the current recommendation of testing all suspected cases and treating only those patients with a positive test result.2 This should limit the misuse of antimalarials, especially the effective but also comparatively expensive artemisinin combination treatments, which are the first choice for treating falciparum malaria. The current policy for treatment has been the subject of hot debate.3 A limited number of randomised controlled trials have so far compared test based management of patients with clinical management alone.
A Cochrane review of seven trials has just been published.4 All the trials were conducted in Africa, indicating that in general, but not in all settings, RDT substantially reduced the over-prescription of antimalarials while not showing a consistent effect on the prescription of antibiotics or the short term outcome for patients. In a linked paper (doi:10.1136/bmj.g3730), Leslie and colleagues report the results of the first such trial conducted in central Asia—namely, in Afghanistan.5 The study was carried out in two areas, one in the north of the country where malaria is now rare, and one in the east with a moderate incidence of malaria. In the north only half of the 10 clinics were equipped with
microscopy, whereas in the east, microscopy was available in all 12 clinics.
An observational study found that, where microscopy was not available, only 1 patient out of over 400 treated for malaria was confirmed to be positive (for P vivax) at subsequent reference microscopy.6 In the clinics equipped with microscopy up to half of those patients found to be negative for malaria by reference laboratory testing were nevertheless administered antimalarials, partly as a result of errors in microscopy and partly to non-adherence to negative test results. The main purpose of the new trial was to show whether the introduction of RDT could substantially improve the management of febrile patients.5
Patients with suspected malaria based on clinical signs and symptoms were randomised to be managed on the basis of a malaria RDT result or in the usual way (clinically or after microscopy according to local availability). Overall, 1696 patients of all ages were enrolled in the northern region with low transmission (1044 and 652 in clinics with and without microscopy, respectively), and 4053 in the eastern region with moderate transmission (all in clinics with microscopy).
Not surprisingly, the RDT arm performed better than the clinical management arm (65% v 12.5% of patients, respectively, were correctly managed). In clinics equipped with microscopy, the difference in the main outcome was smaller, with 84% and 80% of patients in the RDT arm (in the moderate and low transmission areas, respectively) correctly managed compared with 76% (in both areas) in the microscopy arm. A further, marginal advantage of the RDT in the moderate transmission area was improved identification (and consequent treatment with artemisinin combination treatments) of rare P falciparum cases. Significantly more participants in the RDT arm than clinical arm received antibiotics (57% v 14%), whereas the RDT and microscopy arms did not differ significantly. In contrast with most African trials, no information was available on clinical outcomes. This first trial to be conducted in Central Asia confirms that the adoption of RDT may substantially improve the management of malaria in areas of low transmission that lack laboratory
Correspondence to: Z Bisoffi [email protected] For personal use only: See rights and reprints http://www.bmj.com/permissions
Subscribe: http://www.bmj.com/subscribe
BMJ 2014;348:g3846 doi: 10.1136/bmj.g3846 (Published 19 June 2014)
Page 2 of 2
EDITORIALS
facilities. It also provides a comparison with microscopy that was unavailable in most African trials, showing that the advantage of RDT over microscopy is much less clear cut.
Should rapid diagnostic tests replace microscopy? Leslie and colleagues’ trial did not report cost effectiveness, but results from African trials have been mixed.7 8 Moreover, good quality microscopy has potential added values that are generally not taken into account in cost effectiveness studies, such as the estimation of parasite density and the diagnosis of other conditions such as tuberculosis.9
Leslie and colleagues’ study provides further evidence that malaria has become a rare cause of fever in most countries with endemic malaria in Asia. This has also become true for many parts of Africa. Excluding malaria is good but could also lead to overuse of antibiotics if facilities for diagnosing other febrile conditions are lacking.
Investigating non-malarial causes of fever is therefore a new priority. A few good examples have been published recently.10 11 Research is also urgently needed on accurate, point of care tools for non-malarial fevers,12 including the cost effectiveness of competing diagnostic strategies, with the ultimate aim of providing the best base of evidence to inform clinical management of fevers and training in the field. Competing interests: We have read and understood the BMJ Group policy on declaration of interests and declare the following interests: none.
For personal use only: See rights and reprints http://www.bmj.com/permissions
Provenance and peer review: Commissioned; not externally peer reviewed. 1 2 3 4 5 6 7 8
9 10 11 12
WHO. World malaria report 2013. www.who.int/malaria/publications/world_malaria_report_ 2013/report/en/. WHO. Guidelines for the treatment of malaria. 2nd edn. 2010. http://whqlibdoc.who.int/ publications/2010/9789241547925_engpdf?ua=1. English M, Reyburn H, Goodman C, Snow RW. Abandoning presumptive antimalarial treatment for febrile children aged less than five years—a case of running before we can walk? PLoS Med 2009;6:e1000015. Odaga J, Sinclair D, Lokong JA, Donegan S, Hopkins H, Garner P. Rapid diagnostic tests versus clinical diagnosis for managing people with fever in malaria endemic settings. Cochrane Database Syst Rev 2014;4:CD008998. Leslie T, Mikhail A, Mayan I, Cundill B, Anwar M, Bakhtash SH, et al. A patient-randomised effectiveness trial of malaria rapid diagnostic tests to improve treatment for malaria and other febrile illnesses in primary care clinics in Afghanistan. BMJ 2014;348:g3730. Leslie T, Mikhail A, Mayan I, Anwar M, Bakhtash S, Nader M, et al. Overdiagnosis and mistreatment of malaria among febrile patients at primary healthcare level in Afghanistan: observational study. BMJ 2012;345:e4389. Uzochukwu BS, Obikeze EN, Onwujekwe OE, Onoka CA, Griffiths UK. Cost-effectiveness analysis of rapid diagnostic test, microscopy and syndromic approach in the diagnosis of malaria in Nigeria: implications for scaling-up deployment of ACT. Malar J 2009;8:265. Ansah EK, Epokor M, Whitty CJ, Yeung S, Hansen KS. Cost-effectiveness analysis of introducing RDTs for malaria diagnosis as compared to microscopy and presumptive diagnosis in central and peripheral public health facilities in Ghana. Am J Trop Med Hyg 2013;89:724-36. WHO. Determining cost effectiveness of malaria rapid diagnostic tests in rural areas with high prevalence. 2014. www.wpro.who.int/malaria/sites/rdt/. Mayxay M, Castonguay-Vanier J, Chansamouth V, Dubot-Pérès A, Paris DH, Phetsouvanh R, et al. Causes of non-malarial fever in Laos: a prospective study. Lancet Glob Health 2013;1:e46-54. D’Acremont V, Kilowoko M, Kyungu E, Philipina S, Sangu W, Kahama-Maro J, et al. Beyond malaria−causes of fever in outpatient Tanzanian children. N Engl J Med 2014;370:809-17. Bisoffi Z, Buonfrate D. When fever is not malaria. Lancet Glob Health 2013;1:e11-3.
Cite this as: BMJ 2014;348:g3846 © BMJ Publishing Group Ltd 2014
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