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Practice of clinical medicine in the tropics
THE LANCET
Practice of clinical medicine in the tropics Nicholas J White
The specialty of tropical medicine reminds me of an old house in a new and rapidly developing city. Once at the forefront of architectural design, it now lies quaint and secluded, dwarfed by shining, tall temples of medical modernity. A time capsule where prescriptions are still sometimes in grains, and poisons such as antimony and arsenic have no worthy successors in a small and infrequently edited pharmacopoeia. But this is the medical practice that serves a large proportion of the world's population, and for the most part comprises the prevention and treatment of infectious diseases and malnutrition in people with little or no money. The past thirty years have seen losses and gains. The great campaign to eradicate malaria failed, and there has been a resurgence of the disease throughout the tropics. Currently malaria infects about 250 million people. The explosion of AIDS has spawned a resurgence in tuberculosis throughout the tropical world. Successes include the Expanded Programme of Immunisation, the eradication of smallpox, and major reductions in the incidence of poliomyelitis, yellowfever, plague, leprosy, yaws, South America trypanosomiasis, onchocerciasis (river blindness), elephantiasis, guineaworm infestation, and, in Asia, schistosomiasis and other trematode infections (liver and lung fluke). Economic improvements in Asia and South American have had dividends for the health of indigenous people, but the end of the millennium sees us grappling with the consequences of economic decline in Africa, and the evolution of drug resistance in major pathogens such as
Streptococcus pneumoniae, Mycobacterium tuberculosis, Salmonella typhi, Shigella spp, Plasmodium falciparum, and HIV. The practice of tropical medicine varies considerably. Clinicians working in rural West Africa see a very different spectrum of disease from the one faced by those who work, as I do, in South-East Asia. The spectrum may even vary within a country, depending on social, environmental, and economic circumstances, the density and behaviour of the insect vectors, and the availability of health care. It is difficult, therefore, to generalise, so this is a personal perspective of the changes in clinical practice over the past 30 years. Diagnosis
Unfortunately, diagnostic imaging (other than simple Xrays) and functioning biochemistry and microbiology laboratories are still rare in tropical countries, and most infections are diagnosed clinically The microscope Lancet 1997; 3 4 9 (suppl III): 6 - 8 Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; and Wellcome Trust Clinical Research Unit, He Chi Minh City, Viet Nam (Prof N J White FRCP) Correspondence to: Prof Nicholas J White, Faculty of Tropical Medicine, Mahidol University, 4 2 0 / 6 Rajvithi Road, Bangkok 10400, Thailand i
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remains the single most useful diagnostic tool in tropical medicine. Several antigen, antibody, or nucleic-acid based diagnostic tests have been devised for tropical infections; unfortunately, not many of these have been (or ever will be) employed in routine diagnostic practice in the tropics. They tend to be too cumbersome, expensive, or slow. Notable exceptions have been the widespread deployment of screening for and the introduction of simple card tests for the diagnosis of syphilis, and the C A T T test for the diagnosis of African trypanosomiasis. Another is the recent introduction of a rapid and simple assay for P falciparum histidine-rich protein 2. This allows the diagnosis of malaria, where microscopes are not available, with a sensitivity and specificity that is similar to that of a diligent microscopist examining a blood film. The future must lie in the development of simple, inexpensive, and robust "stick" or "card" tests which require little preparation of clinical specimens and provide a result quickly. Fortunately in most tropical countries screening of donated blood for HIV and hepatitis B virus is now available. Clinical practice
It is disappointing how little clinical tropical medicine practice has changed for some diseases over the past 30 years. The considerable increases in our understanding of the immunology and pathophysiology of parasitic diseases, accumulated during attempts to develop effective vaccines, have had little impact on practice. The major advances in health care have come from improvements in public health (immunisation, vector control) and drugs. But perhaps the greatest advance in clinical management has been the recognition that nearly all diarrhoeal disease can be treated with simple sugar (or starch) and salt solutions. ~ Oral rehydration has saved the lives of many thousands of children, and prompt intravenous fluid replacement has reduced the case fatality rate in dengue shock syndrome from 20% to less than 3%. New, and therefore expensive, antibiotics have improved the treatment of several bacterial infections (eg, fluoroquinolones in enteric fever, ceffazidime in melioidosis). However, it has been the widespread deployment of affordable and simply administered formulations that has probably had the greater impact overall; examples here are slow-release penicillins, co-trimoxazole for acute respiratory-tract infections and oil formulations of chloramphenicol for epidemic meningococcal meningitis. 30 years ago tuberculosis required 18 months of treatment and lepromatous leprosy was a life sentence. Now we can treat most cases of tuberculosis effectively in 4-6 months; and, with multiple drug treatment, cure is available to patients across the immunological spectrum of leprosy. 2 There is now a real prospect that leprosy will be eradicated. There have been major advances in the prevention of blindness. Trachoma diagnosis and treatment has Vol 349 • June • 1997
THE LANCET
Chile, India: e v i d e n c e - b a s e d t r o p i c a l m e d i c i n e Epilepsy is common in developing countries. Where computed tomography is available and epilepsy can be properly investigated, neurocysticercosis is sometimes found to be the cause. This parasitic infection of the brain causes considerable illness and its management is costly. Yet we know little about treatment and outcome, other than the fact that the disease may be asymptomatic and cysts commonly resolve spontaneously. Albendazole is usually recommended but there are case-reports suggesting that antiparasitic drugs can cause severe side-effects and even sudden death. With reports of adverse effects in mind, we started to question the effectiveness of current regimens. Working through links made by the stroke and infectious diseases groups of the Cochrane Collaboration we produced a review protocol, prespecifying clinical outcomes that made sense to us as clinicians (and to patients with the disease) and also radiological evidence of brain cysts. We did an extensive literature search and contacted people doing trials on neurocysticercosis in India, Chile, and Ecuador, and liaised with specialists at the US Centers for Disease Control and Prevention and WHO. We identified only three small trials, and only one examined clinical outcomes. The data synthesis showed that the evidence for or against therapy (when compared with placebo) was very limited, 1 and this indicated the need for a large, placebo-controlled randomised trial with clinically relevant outcomes, including survival and disability. This almost certainly means a multicentre study in several countries, and the contacts we made in the process of our review are helping us set this up. Until this trial is complete, we improved considerably. Recognition of the importance 6f vitamin A deficiency (especially when complicating measles in childhood) and the donation of ivermectin for the treatment of onchocerciasis have saved the sight, and probably the lives, of enormous numbers of children. Praziquantel has transformed the treatment of trematode infections; 4 where it has been deployed it has had a major impact on the incidence of schistosomiasis, and also liver and lung fluke infections in Asia. In the war against the larger parasites, we now have mebendazole, a broadspectrum agent for soil-transmitted helminth infections which costs less than 2 US cents a dose, 6 and, more recently, albendazole, which is proving to be the anthelminthic equivalent of a third-generation cephalosporin. The diagnosis and management of severe malaria has been standardised on the basis of studies of pathophysiology and treatment2 We have seen the introduction of sulphadoxine-pyrimethamine and then mefloquine and halofantrine for the treatment of multidrug-resistant malaria and, most recently, the artemisinin derivatives for the treatment of severe falciparum malaria and for uncomplicated multidrugresistant P falciparum infections. 7 The artemisinins are the most rapidly acting of all antimalarial drugs. They have proved to be remarkably well tolerated, they are highly effective by the oral, parenteral, and rectal routes, and they have also been shown to reduce transmission of malaria. Their use in some parts of South-East Asia has
Vol 349 • June • 1997
Cyst persistence in patients given cysticidal therapy (active) or placebo (control) in three randomised trials For individual trials the odds ratio (Peto OR) and 95% Cl (fixed) are shown; boxes reflect size of trial, For three trials with scans at less than 6 months OR = 0,73 (95% CI 0.38 - 1.43); this is not significant. For the one trial with scans at more than 6 months OR = 0.67 (95% Cl 0.29 - 1.57); this is not significant. (Adapted from Cochrane Database [updated July 15, 1997].)
will remain uncertain as to whether treatments that have become routine practice really do help or harm patients.
Rodrigo Salinas, Kameshwar Prasad, Paul Garner Departamento de Ciencias Neurol6gicas, Universidad de Chile, Santiago, Chile; Department of Neurology, All India Institute of Medical Sciences, Delhi, India; and Liverpool School of Tropical Medicine, Liverpool, UK
Salinas R, Prasad K. Curative d r u g therapy in h u m a n neurocysticercosis. In: G a r n e r P, Gelband H , Olliaro P, Salinas R, Volmink J, Wilkinson D, eds. Infectious diseases module of the Cochrane Database of Systemic Reviews (updated July 15, 1997). Oxford: Update Software, 1997.
been associated with a marked reduction in the incidence of falciparum malaria. In some parts of Thailand P falciparum has developed resistance to chloroquine, pyrimethamine-sulphadoxine, and to mefloquine and halofantrine, but the artemisinin derivatives have saved the day. The spectre of untreatable malaria has receded, but it still waits in the shadows.
Clinical p h a r m a c o l o g y Tropical medicine, and antiparasitic chemotherapy in particular, has been slow to adopt the advances made in other areas of anti-infective therapeutics. We still do not know enough about the pharmacokinetics and pharmacodynamics of many drugs used to treat tropical parasitic diseases. Studies of parasite population dynamics have been used to improve the use of anthelminthics in the prevention of soil-transmitted helminth infections, but pharmacokineticpharmacodynamic modelling is in its infancy, and strategies such as the use of drug combinations to delay resistance have been seldom applied outside tuberculosis. Recommended treatment regimens, often with toxic drugs, have varied considerably. Between the 1970s and the 1980s recommended dose regimens for chloroquine in the treatment of severe falciparum malaria varied by a factor of 6 and for quinine by a factor of 8. As in other branches of medicine, randomised controlled trials have formed the basis for therapeutic
sII[7
Practice of clinical medicine in the tropics Nicholas J White
The specialty of tropical medicine reminds me of an old house in a new and rapidly developing city. Once at the forefront of architectural design, it now lies quaint and secluded, dwarfed by shining, tall temples of medical modernity. A time capsule where prescriptions are still sometimes in grains, and poisons such as antimony and arsenic have no worthy successors in a small and infrequently edited pharmacopoeia. But this is the medical practice that serves a large proportion of the world's population, and for the most part comprises the prevention and treatment of infectious diseases and malnutrition in people with little or no money. The past thirty years have seen losses and gains. The great campaign to eradicate malaria failed, and there has been a resurgence of the disease throughout the tropics. Currently malaria infects about 250 million people. The explosion of AIDS has spawned a resurgence in tuberculosis throughout the tropical world. Successes include the Expanded Programme of Immunisation, the eradication of smallpox, and major reductions in the incidence of poliomyelitis, yellowfever, plague, leprosy, yaws, South America trypanosomiasis, onchocerciasis (river blindness), elephantiasis, guineaworm infestation, and, in Asia, schistosomiasis and other trematode infections (liver and lung fluke). Economic improvements in Asia and South American have had dividends for the health of indigenous people, but the end of the millennium sees us grappling with the consequences of economic decline in Africa, and the evolution of drug resistance in major pathogens such as
Streptococcus pneumoniae, Mycobacterium tuberculosis, Salmonella typhi, Shigella spp, Plasmodium falciparum, and HIV. The practice of tropical medicine varies considerably. Clinicians working in rural West Africa see a very different spectrum of disease from the one faced by those who work, as I do, in South-East Asia. The spectrum may even vary within a country, depending on social, environmental, and economic circumstances, the density and behaviour of the insect vectors, and the availability of health care. It is difficult, therefore, to generalise, so this is a personal perspective of the changes in clinical practice over the past 30 years. Diagnosis
Unfortunately, diagnostic imaging (other than simple Xrays) and functioning biochemistry and microbiology laboratories are still rare in tropical countries, and most infections are diagnosed clinically The microscope Lancet 1997; 3 4 9 (suppl III): 6 - 8 Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; and Wellcome Trust Clinical Research Unit, He Chi Minh City, Viet Nam (Prof N J White FRCP) Correspondence to: Prof Nicholas J White, Faculty of Tropical Medicine, Mahidol University, 4 2 0 / 6 Rajvithi Road, Bangkok 10400, Thailand i
SlII6
remains the single most useful diagnostic tool in tropical medicine. Several antigen, antibody, or nucleic-acid based diagnostic tests have been devised for tropical infections; unfortunately, not many of these have been (or ever will be) employed in routine diagnostic practice in the tropics. They tend to be too cumbersome, expensive, or slow. Notable exceptions have been the widespread deployment of screening for and the introduction of simple card tests for the diagnosis of syphilis, and the C A T T test for the diagnosis of African trypanosomiasis. Another is the recent introduction of a rapid and simple assay for P falciparum histidine-rich protein 2. This allows the diagnosis of malaria, where microscopes are not available, with a sensitivity and specificity that is similar to that of a diligent microscopist examining a blood film. The future must lie in the development of simple, inexpensive, and robust "stick" or "card" tests which require little preparation of clinical specimens and provide a result quickly. Fortunately in most tropical countries screening of donated blood for HIV and hepatitis B virus is now available. Clinical practice
It is disappointing how little clinical tropical medicine practice has changed for some diseases over the past 30 years. The considerable increases in our understanding of the immunology and pathophysiology of parasitic diseases, accumulated during attempts to develop effective vaccines, have had little impact on practice. The major advances in health care have come from improvements in public health (immunisation, vector control) and drugs. But perhaps the greatest advance in clinical management has been the recognition that nearly all diarrhoeal disease can be treated with simple sugar (or starch) and salt solutions. ~ Oral rehydration has saved the lives of many thousands of children, and prompt intravenous fluid replacement has reduced the case fatality rate in dengue shock syndrome from 20% to less than 3%. New, and therefore expensive, antibiotics have improved the treatment of several bacterial infections (eg, fluoroquinolones in enteric fever, ceffazidime in melioidosis). However, it has been the widespread deployment of affordable and simply administered formulations that has probably had the greater impact overall; examples here are slow-release penicillins, co-trimoxazole for acute respiratory-tract infections and oil formulations of chloramphenicol for epidemic meningococcal meningitis. 30 years ago tuberculosis required 18 months of treatment and lepromatous leprosy was a life sentence. Now we can treat most cases of tuberculosis effectively in 4-6 months; and, with multiple drug treatment, cure is available to patients across the immunological spectrum of leprosy. 2 There is now a real prospect that leprosy will be eradicated. There have been major advances in the prevention of blindness. Trachoma diagnosis and treatment has Vol 349 • June • 1997
THE LANCET
Chile, India: e v i d e n c e - b a s e d t r o p i c a l m e d i c i n e Epilepsy is common in developing countries. Where computed tomography is available and epilepsy can be properly investigated, neurocysticercosis is sometimes found to be the cause. This parasitic infection of the brain causes considerable illness and its management is costly. Yet we know little about treatment and outcome, other than the fact that the disease may be asymptomatic and cysts commonly resolve spontaneously. Albendazole is usually recommended but there are case-reports suggesting that antiparasitic drugs can cause severe side-effects and even sudden death. With reports of adverse effects in mind, we started to question the effectiveness of current regimens. Working through links made by the stroke and infectious diseases groups of the Cochrane Collaboration we produced a review protocol, prespecifying clinical outcomes that made sense to us as clinicians (and to patients with the disease) and also radiological evidence of brain cysts. We did an extensive literature search and contacted people doing trials on neurocysticercosis in India, Chile, and Ecuador, and liaised with specialists at the US Centers for Disease Control and Prevention and WHO. We identified only three small trials, and only one examined clinical outcomes. The data synthesis showed that the evidence for or against therapy (when compared with placebo) was very limited, 1 and this indicated the need for a large, placebo-controlled randomised trial with clinically relevant outcomes, including survival and disability. This almost certainly means a multicentre study in several countries, and the contacts we made in the process of our review are helping us set this up. Until this trial is complete, we improved considerably. Recognition of the importance 6f vitamin A deficiency (especially when complicating measles in childhood) and the donation of ivermectin for the treatment of onchocerciasis have saved the sight, and probably the lives, of enormous numbers of children. Praziquantel has transformed the treatment of trematode infections; 4 where it has been deployed it has had a major impact on the incidence of schistosomiasis, and also liver and lung fluke infections in Asia. In the war against the larger parasites, we now have mebendazole, a broadspectrum agent for soil-transmitted helminth infections which costs less than 2 US cents a dose, 6 and, more recently, albendazole, which is proving to be the anthelminthic equivalent of a third-generation cephalosporin. The diagnosis and management of severe malaria has been standardised on the basis of studies of pathophysiology and treatment2 We have seen the introduction of sulphadoxine-pyrimethamine and then mefloquine and halofantrine for the treatment of multidrug-resistant malaria and, most recently, the artemisinin derivatives for the treatment of severe falciparum malaria and for uncomplicated multidrugresistant P falciparum infections. 7 The artemisinins are the most rapidly acting of all antimalarial drugs. They have proved to be remarkably well tolerated, they are highly effective by the oral, parenteral, and rectal routes, and they have also been shown to reduce transmission of malaria. Their use in some parts of South-East Asia has
Vol 349 • June • 1997
Cyst persistence in patients given cysticidal therapy (active) or placebo (control) in three randomised trials For individual trials the odds ratio (Peto OR) and 95% Cl (fixed) are shown; boxes reflect size of trial, For three trials with scans at less than 6 months OR = 0,73 (95% CI 0.38 - 1.43); this is not significant. For the one trial with scans at more than 6 months OR = 0.67 (95% Cl 0.29 - 1.57); this is not significant. (Adapted from Cochrane Database [updated July 15, 1997].)
will remain uncertain as to whether treatments that have become routine practice really do help or harm patients.
Rodrigo Salinas, Kameshwar Prasad, Paul Garner Departamento de Ciencias Neurol6gicas, Universidad de Chile, Santiago, Chile; Department of Neurology, All India Institute of Medical Sciences, Delhi, India; and Liverpool School of Tropical Medicine, Liverpool, UK
Salinas R, Prasad K. Curative d r u g therapy in h u m a n neurocysticercosis. In: G a r n e r P, Gelband H , Olliaro P, Salinas R, Volmink J, Wilkinson D, eds. Infectious diseases module of the Cochrane Database of Systemic Reviews (updated July 15, 1997). Oxford: Update Software, 1997.
been associated with a marked reduction in the incidence of falciparum malaria. In some parts of Thailand P falciparum has developed resistance to chloroquine, pyrimethamine-sulphadoxine, and to mefloquine and halofantrine, but the artemisinin derivatives have saved the day. The spectre of untreatable malaria has receded, but it still waits in the shadows.
Clinical p h a r m a c o l o g y Tropical medicine, and antiparasitic chemotherapy in particular, has been slow to adopt the advances made in other areas of anti-infective therapeutics. We still do not know enough about the pharmacokinetics and pharmacodynamics of many drugs used to treat tropical parasitic diseases. Studies of parasite population dynamics have been used to improve the use of anthelminthics in the prevention of soil-transmitted helminth infections, but pharmacokineticpharmacodynamic modelling is in its infancy, and strategies such as the use of drug combinations to delay resistance have been seldom applied outside tuberculosis. Recommended treatment regimens, often with toxic drugs, have varied considerably. Between the 1970s and the 1980s recommended dose regimens for chloroquine in the treatment of severe falciparum malaria varied by a factor of 6 and for quinine by a factor of 8. As in other branches of medicine, randomised controlled trials have formed the basis for therapeutic
sII[7