- Email: [email protected]
Chile, India: evidence-based tropical medicine
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
THE LANCET
advances. Multicentre trials and systematic views have yet to make a significant impact in tropical medicine although this should change in the near future. The application, to a tropical illness, of the Cochrane Collaboration's approach to systematic reviews is illustrated in the accompanying vignette. For the future the main challenge is to keep the wealthier parts of the world, where most medical research and development takes place, interested in the problems of their less affluent tropical neighbours. We should appeal to altruism, and also to self-interest. Many of these drugresistant tropical infections do not respect international borders, and their ecology is likely to change with increasing international travel and global warming.
References 1
Sack DA, Chowdhury AMAK, Eusof A, et al. Oral rehydration in rotavirus diarrhoea: a double blind comparison of sucrose with glucose electrolyte solution. Lancet 1978; ii: 280-83.
2
W H O Study Group. Chemotherapy of leprosy for control programmes. WHO Tech Rep Ser 1982; no 675.
3
Greene BM. M o d e m medicine versus an ancient scourge. J Infect Dis 1992; 166: 15-21. King CH, Mahmoud AAF. Drugs five years later: praziquantel. Ann Intern Med 1989; l l 0 : 290-96.
4 5
World Health Organization. Control of tropical diseases: severe and complicated malaria. Trans R Soe Trop Med Hyg 1990; (suppl).
6
Keystone JS, Mnrdoch JK. Mebendazole. Ann Intern Med 1979; 91: 582-86.
7
Hien T T , White NJ. Qinghaosu. Lancet 1993; 341: 603-08.
Reemerging pathogens and diseases out of control David L Heymann, Gu6na~l Rodier In the 1970s and 1980s monkeypox virus was shown to infect humans periodically. It became attenuated as it was transmitted through no more than three generations of infection. In early 1997 results of an investigation of a monkeypox outbreak in central Zaire (now Democratic Republic of the Congo) suggested that it had become significantly more threatening to man. 1 This was thought in part to be due to the fact that smallpox vaccine, which also protected against human monkeypox, has not been used in Zaire since 1980, as recommended after the eradication of smallpox. The 1997 investigation was interrupted by civil war, but more thorough inquiry should tell us whether or not regional immunisation programmes with vaccinia vaccine should be envisaged to prevent outbreaks. In 1980 such a decision would have been straightforward. In 1997, however, vaccinia vaccine is no longer a simple issue because of the emergence of HIV and the occurrence in 1984 of fatal vaccinia infection after administration of this vaccine to an HIV-infected adult) A decision whether or not to vaccinate would require careful evaluation of the risk of fatal vaccinia when the prevalence of HIV is as high as 7% while the case fatality rate in human monkeypox is as high as 20%. 20-year
perspective
The reemergence of monkeypox in the context of the emergence of AIDS demonstrates that infectious diseases are constantly in transition: new diseases emerge, known diseases reemerge, and other are eradicated or eliminated as public health problems. Emergence and reemergence place increased demands on health systems already strained by endemic diseases such as malaria, childhood diarrhoea, lower respiratory infections and HIV. They increase the prevalence of other endemic infectious disease such as tuberculosis among those with HIV infection. Many factors contribute to the emergence and re-
Lancet 1997; 3 4 9 (suppl III): 8 - 1 0 Division of Emerging and Other Communicable Diseases, World Health Organization, CH-1211 Gene~,a 27, Switzerland (D L HeYmannMD,G Rodier MD) Correspondence to: Dr David L Heymann
SIII8
emergence of infectious disease. Population growth, urbanisation and poverty are key among these. They are compounded by inadequate or deteriorating public health infrastructures (see vignette from Zaire); and increased exposure to infectious agents due to changes in human behaviour, alterations in land use, agricultural and food preparation practices, climate and environmental conditions.
Emergence Legionella infection was first identified in 1976 in an outbreak among war veterans in North America. Legionellosis is now known to occur world wide and poses a threat to travellers exposed to poorly maintained air conditioning systems. During 1995 in Europe, 172 travellers thought to have been infected in hotels during travel were identified with legionellosis. Th e Ebola virus caused at least four severe epidemics and numerous smaller outbreaks after its identification in 1976 during simultaneous outbreaks in Zaire and Sudan. In major outbreaks transmission has been amplified by failure of hospital infection control. At the same time HIV seroprevalence in rural Zaire was almost 1%, shown retrospectively in blood which had been drawn from persons living in communities around the site of the 1976 outbreak3 HIV has since been amplified by unprotected sexual intercourse and is a preoccupying public health problem worldwide. Th e hepatitis C virus was first identified in North America in 1989. It is now known to be worldwide, and W H O estimates that there may be as many as 170 million chronic carriers throughout the world. Th e major route of transmission is thought to be infected blood transfusions and the use of unsterilised injection equipment. In 1986 a new disease in cattle, bovine spongiform encephalopathy, was recognised in Europe and has been associated in time and place with a previously unknown variant of Creutzfeldt-Jakob disease. Infectivity of BSE is associated with the food chain. Food borne infection with Escherichia coli O157, unknown twenty years ago, has become a food safety concern in Japan, Europe, and the Americas. Lyme borreliosis, first identified in North America in 1982, is now known to be endemic in North America and Europe, being transmitted
Vol 349 o June • 1997
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
THE LANCET
advances. Multicentre trials and systematic views have yet to make a significant impact in tropical medicine although this should change in the near future. The application, to a tropical illness, of the Cochrane Collaboration's approach to systematic reviews is illustrated in the accompanying vignette. For the future the main challenge is to keep the wealthier parts of the world, where most medical research and development takes place, interested in the problems of their less affluent tropical neighbours. We should appeal to altruism, and also to self-interest. Many of these drugresistant tropical infections do not respect international borders, and their ecology is likely to change with increasing international travel and global warming.
References 1
Sack DA, Chowdhury AMAK, Eusof A, et al. Oral rehydration in rotavirus diarrhoea: a double blind comparison of sucrose with glucose electrolyte solution. Lancet 1978; ii: 280-83.
2
W H O Study Group. Chemotherapy of leprosy for control programmes. WHO Tech Rep Ser 1982; no 675.
3
Greene BM. M o d e m medicine versus an ancient scourge. J Infect Dis 1992; 166: 15-21. King CH, Mahmoud AAF. Drugs five years later: praziquantel. Ann Intern Med 1989; l l 0 : 290-96.
4 5
World Health Organization. Control of tropical diseases: severe and complicated malaria. Trans R Soe Trop Med Hyg 1990; (suppl).
6
Keystone JS, Mnrdoch JK. Mebendazole. Ann Intern Med 1979; 91: 582-86.
7
Hien T T , White NJ. Qinghaosu. Lancet 1993; 341: 603-08.
Reemerging pathogens and diseases out of control David L Heymann, Gu6na~l Rodier In the 1970s and 1980s monkeypox virus was shown to infect humans periodically. It became attenuated as it was transmitted through no more than three generations of infection. In early 1997 results of an investigation of a monkeypox outbreak in central Zaire (now Democratic Republic of the Congo) suggested that it had become significantly more threatening to man. 1 This was thought in part to be due to the fact that smallpox vaccine, which also protected against human monkeypox, has not been used in Zaire since 1980, as recommended after the eradication of smallpox. The 1997 investigation was interrupted by civil war, but more thorough inquiry should tell us whether or not regional immunisation programmes with vaccinia vaccine should be envisaged to prevent outbreaks. In 1980 such a decision would have been straightforward. In 1997, however, vaccinia vaccine is no longer a simple issue because of the emergence of HIV and the occurrence in 1984 of fatal vaccinia infection after administration of this vaccine to an HIV-infected adult) A decision whether or not to vaccinate would require careful evaluation of the risk of fatal vaccinia when the prevalence of HIV is as high as 7% while the case fatality rate in human monkeypox is as high as 20%. 20-year
perspective
The reemergence of monkeypox in the context of the emergence of AIDS demonstrates that infectious diseases are constantly in transition: new diseases emerge, known diseases reemerge, and other are eradicated or eliminated as public health problems. Emergence and reemergence place increased demands on health systems already strained by endemic diseases such as malaria, childhood diarrhoea, lower respiratory infections and HIV. They increase the prevalence of other endemic infectious disease such as tuberculosis among those with HIV infection. Many factors contribute to the emergence and re-
Lancet 1997; 3 4 9 (suppl III): 8 - 1 0 Division of Emerging and Other Communicable Diseases, World Health Organization, CH-1211 Gene~,a 27, Switzerland (D L HeYmannMD,G Rodier MD) Correspondence to: Dr David L Heymann
SIII8
emergence of infectious disease. Population growth, urbanisation and poverty are key among these. They are compounded by inadequate or deteriorating public health infrastructures (see vignette from Zaire); and increased exposure to infectious agents due to changes in human behaviour, alterations in land use, agricultural and food preparation practices, climate and environmental conditions.
Emergence Legionella infection was first identified in 1976 in an outbreak among war veterans in North America. Legionellosis is now known to occur world wide and poses a threat to travellers exposed to poorly maintained air conditioning systems. During 1995 in Europe, 172 travellers thought to have been infected in hotels during travel were identified with legionellosis. Th e Ebola virus caused at least four severe epidemics and numerous smaller outbreaks after its identification in 1976 during simultaneous outbreaks in Zaire and Sudan. In major outbreaks transmission has been amplified by failure of hospital infection control. At the same time HIV seroprevalence in rural Zaire was almost 1%, shown retrospectively in blood which had been drawn from persons living in communities around the site of the 1976 outbreak3 HIV has since been amplified by unprotected sexual intercourse and is a preoccupying public health problem worldwide. Th e hepatitis C virus was first identified in North America in 1989. It is now known to be worldwide, and W H O estimates that there may be as many as 170 million chronic carriers throughout the world. Th e major route of transmission is thought to be infected blood transfusions and the use of unsterilised injection equipment. In 1986 a new disease in cattle, bovine spongiform encephalopathy, was recognised in Europe and has been associated in time and place with a previously unknown variant of Creutzfeldt-Jakob disease. Infectivity of BSE is associated with the food chain. Food borne infection with Escherichia coli O157, unknown twenty years ago, has become a food safety concern in Japan, Europe, and the Americas. Lyme borreliosis, first identified in North America in 1982, is now known to be endemic in North America and Europe, being transmitted
Vol 349 o June • 1997