Running Like Water — The Omnipresence of Hepatitis E
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《新英格兰医药杂志》
Hepatitis E virus (HEV), originally identified as the culprit in massive waterborne epidemics of acute hepatitis in Asia, is now commanding attention in regions of Sudan and Iraq. And once again, contaminated water is implicated. Between May and August of 2004, almost 4000 suspected cases of hepatitis E were reported by health clinics in the Greater Darfur region of Sudan, where civil conflict has forced the internal displacement of approximately 15 percent of the population. Sudanese refugees who fled to camps in neighboring Chad have fared no better, and more than 1000 suspected cases of hepatitis E were identified between June and September. In Iraq, where conflict also rages, probable cases of hepatitis E were identified in Sadr City in March and, more recently, in Mahmudiya, about 25 miles south of Baghdad. Although the number of reported cases in Iraq is in the hundreds rather than the thousands, the lower numbers could well reflect underreporting and the lack of a routine diagnostic test for hepatitis E. The crowded, unsanitary conditions faced by the Sudanese refugees and the inadequate sewage treatment and erratic water supplies in Iraq have permitted the virus to thrive.
It is not surprising that hepatitis E is now erupting in Sudan and Iraq. The conditions are conducive to viral dissemination, and outbreaks of hepatitis E have occurred previously in Africa (see map). More than 2000 cases occurred in 1985 and 1986 in Ethiopian refugee camps in Somalia and Sudan. Hepatitis E also causes sporadic hepatitis and is the second most common cause of such disease in North Africa and the Middle East. There is no treatment for hepatitis E, and there is not yet a vaccine to prevent it, although a recombinant vaccine has just undergone clinical trials in Nepal. Diagnosis cannot be made on the basis of clinical presentation but, rather, requires laboratory amplification of viral genomes found in serum and feces during the acute phase of the disease or detection of specific antibodies during the convalescent phase. Diagnostic serologic tests are available in some parts of the world but are not licensed in many countries, including the United States. Fortunately, HEV is not commonly transmitted from person to person, so improving sanitation and boiling or chemically purifying the water can substantially reduce the burden of disease.
The virus that causes hepatitis E was identified only recently (see diagram). The first evidence that HEV existed was obtained in 1980 through a process of exclusion. Once specific tests had been developed for hepatitis A virus (HAV), the other enterically transmitted hepatitis virus, it became clear that major waterborne epidemics of hepatitis in India were caused not by HAV but, rather, by a previously unrecognized agent. We now know that the hepatitis caused by these two viruses is clinically indistinguishable and that many outbreaks originally attributed to HAV, including some as far back as the Crusades, were most likely due to HEV.
Model of a Hepatitis E Virus Particle.
The hepatitis E virus has not been studied at high resolution; this model is based on current knowledge about recombinant particles. Adapted from Xing et al.1
Patients with hepatitis E can present with signs and symptoms common to all viral hepatitis: jaundice, anorexia, hepatomegaly, abdominal pain, nausea, vomiting, and fever. The incubation period ranges from three to eight weeks, and jaundice can persist for several weeks. Although hepatitis E never progresses to a chronic condition and full recovery is usual in most groups, mortality rates of 0.5 to 4 percent in the general population and, for unknown reasons, up to 20 percent among pregnant women have been reported.
Much about the epidemiology of hepatitis E is unknown. Outbreaks are most common in tropical and subtropical regions and are rare in temperate climates. Contaminated water supplies have been a frequent source of epidemics and reflect the fact that HEV, like HAV, is excreted in the feces and can survive in sewage. Intuitively, one would expect these two hepatitis viruses to have similar epidemiology, but this is not the case. In India, as in many other developing countries where both viruses are endemic, infection with HAV, as measured by antibody seroprevalence, is almost universally acquired by five years of age, when most infections are inapparent, whereas HEV most commonly infects young adults. Surprisingly, antibodies to HEV are found in only 30 to 40 percent of adults. In contrast, in Egypt, where similar environmental conditions that are conducive to fecal–oral transmission exist, the prevalence of antibodies to HEV already exceeds 60 percent by 10 years of age. Why the pattern of antibody acquisition should be so different in these two countries remains unexplained — and is as puzzling as the question of why the age-stratified seroprevalence of anti-HAV antibodies in India is so dissimilar to that of anti-HEV antibodies.
Although exceedingly rare, locally acquired hepatitis E has now been found in many industrialized countries, including the United States, Japan, and countries of the European Union. However, the prevalence of antibodies to HEV is much higher than expected in these countries (as high as 20 percent among blood donors in some regions of the United States), given the rarity of the disease. Also, many species of animals, from rodents to monkeys, have similar antibodies. A virus closely related to human HEV has been isolated from swine in many developing and industrialized countries, including the United States. Therefore, the specter of hepatitis E as a zoonotic disease that can be acquired from animals has arisen. Indeed, recent clusters of cases of hepatitis E in Japan have been traced to the ingestion of undercooked deer meat and pig liver. It remains to be determined how commonly and by what other mechanism the virus may be transmitted from animals to humans, but in view of the large number of species potentially involved, it is an area that requires exploration.
HEV is perhaps best described as an opportunistic pathogen. Both the virus and the disease appear to be virtually everywhere, but the frequency of disease varies tremendously according to region. Strains that cause sporadic cases of hepatitis E in many developing countries have the potential to cause explosive epidemics when the infrastructure breaks down, as it has in Sudan and Iraq. One might surmise that the strains that are already present in industrialized countries have the same potential; it is simply our good fortune that they have so far been held in check by better sanitation.
Drs. Emerson and Purcell are listed as coinventors on a patent for hepatitis vaccine owned by the U.S. government.
Source Information
From the Molecular Hepatitis Section (S.U.E.) and the Hepatitis Viruses Section (R.H.P.), Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
References
Xing L, Kato K, Li T, et al. Recombinant hepatitis E capsid protein self-assembles into a dual-domain T=1 particle presenting native virus epitopes. Virology 1999;265:35-45.(Suzanne U. Emerson, Ph.D.)
It is not surprising that hepatitis E is now erupting in Sudan and Iraq. The conditions are conducive to viral dissemination, and outbreaks of hepatitis E have occurred previously in Africa (see map). More than 2000 cases occurred in 1985 and 1986 in Ethiopian refugee camps in Somalia and Sudan. Hepatitis E also causes sporadic hepatitis and is the second most common cause of such disease in North Africa and the Middle East. There is no treatment for hepatitis E, and there is not yet a vaccine to prevent it, although a recombinant vaccine has just undergone clinical trials in Nepal. Diagnosis cannot be made on the basis of clinical presentation but, rather, requires laboratory amplification of viral genomes found in serum and feces during the acute phase of the disease or detection of specific antibodies during the convalescent phase. Diagnostic serologic tests are available in some parts of the world but are not licensed in many countries, including the United States. Fortunately, HEV is not commonly transmitted from person to person, so improving sanitation and boiling or chemically purifying the water can substantially reduce the burden of disease.
The virus that causes hepatitis E was identified only recently (see diagram). The first evidence that HEV existed was obtained in 1980 through a process of exclusion. Once specific tests had been developed for hepatitis A virus (HAV), the other enterically transmitted hepatitis virus, it became clear that major waterborne epidemics of hepatitis in India were caused not by HAV but, rather, by a previously unrecognized agent. We now know that the hepatitis caused by these two viruses is clinically indistinguishable and that many outbreaks originally attributed to HAV, including some as far back as the Crusades, were most likely due to HEV.
Model of a Hepatitis E Virus Particle.
The hepatitis E virus has not been studied at high resolution; this model is based on current knowledge about recombinant particles. Adapted from Xing et al.1
Patients with hepatitis E can present with signs and symptoms common to all viral hepatitis: jaundice, anorexia, hepatomegaly, abdominal pain, nausea, vomiting, and fever. The incubation period ranges from three to eight weeks, and jaundice can persist for several weeks. Although hepatitis E never progresses to a chronic condition and full recovery is usual in most groups, mortality rates of 0.5 to 4 percent in the general population and, for unknown reasons, up to 20 percent among pregnant women have been reported.
Much about the epidemiology of hepatitis E is unknown. Outbreaks are most common in tropical and subtropical regions and are rare in temperate climates. Contaminated water supplies have been a frequent source of epidemics and reflect the fact that HEV, like HAV, is excreted in the feces and can survive in sewage. Intuitively, one would expect these two hepatitis viruses to have similar epidemiology, but this is not the case. In India, as in many other developing countries where both viruses are endemic, infection with HAV, as measured by antibody seroprevalence, is almost universally acquired by five years of age, when most infections are inapparent, whereas HEV most commonly infects young adults. Surprisingly, antibodies to HEV are found in only 30 to 40 percent of adults. In contrast, in Egypt, where similar environmental conditions that are conducive to fecal–oral transmission exist, the prevalence of antibodies to HEV already exceeds 60 percent by 10 years of age. Why the pattern of antibody acquisition should be so different in these two countries remains unexplained — and is as puzzling as the question of why the age-stratified seroprevalence of anti-HAV antibodies in India is so dissimilar to that of anti-HEV antibodies.
Although exceedingly rare, locally acquired hepatitis E has now been found in many industrialized countries, including the United States, Japan, and countries of the European Union. However, the prevalence of antibodies to HEV is much higher than expected in these countries (as high as 20 percent among blood donors in some regions of the United States), given the rarity of the disease. Also, many species of animals, from rodents to monkeys, have similar antibodies. A virus closely related to human HEV has been isolated from swine in many developing and industrialized countries, including the United States. Therefore, the specter of hepatitis E as a zoonotic disease that can be acquired from animals has arisen. Indeed, recent clusters of cases of hepatitis E in Japan have been traced to the ingestion of undercooked deer meat and pig liver. It remains to be determined how commonly and by what other mechanism the virus may be transmitted from animals to humans, but in view of the large number of species potentially involved, it is an area that requires exploration.
HEV is perhaps best described as an opportunistic pathogen. Both the virus and the disease appear to be virtually everywhere, but the frequency of disease varies tremendously according to region. Strains that cause sporadic cases of hepatitis E in many developing countries have the potential to cause explosive epidemics when the infrastructure breaks down, as it has in Sudan and Iraq. One might surmise that the strains that are already present in industrialized countries have the same potential; it is simply our good fortune that they have so far been held in check by better sanitation.
Drs. Emerson and Purcell are listed as coinventors on a patent for hepatitis vaccine owned by the U.S. government.
Source Information
From the Molecular Hepatitis Section (S.U.E.) and the Hepatitis Viruses Section (R.H.P.), Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
References
Xing L, Kato K, Li T, et al. Recombinant hepatitis E capsid protein self-assembles into a dual-domain T=1 particle presenting native virus epitopes. Virology 1999;265:35-45.(Suzanne U. Emerson, Ph.D.)