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Request for Proposals (RFPs)

Enterovirus Epidemic, Taiwan, 1998



The National Health Research Institutes (NHRI) is requesting research proposals designed to answer important questions about the Enterovirus epidemic, Taiwan, 1998. Such questions may be divided in three categories. They concern the epidemiologic, clinical-virologic-pathologic and virologic aspects of the epidemic.

This epidemic, which extended from April to August, involved thousands of cases of clinical disease compatible with enterovirus infection (i.e. hand-foot-month disease, herpangina and various central nervous syndromes) in all parts of Taiwan. There were 64 reported deaths. Most of the 15 deaths with positive viral isolations incriminate enterovirus type 71, although the majority of deaths have not been studied virologically. Most deaths present a syndrome undescribed in the literature of enterovirus infection; pulmonary edema, cardiac decompensation, shock, metabolic acidosis and central nervous system disturbances.

NHRI welcomes applications, which can improve our ability to predict, monitor and prevent future epidemics, which can improve the medical care of individual patients and which enhance our basic scientific understanding.

Questions to be Addressed

  1. Epidemiologic questions

A basic question is the precise role of enterovirus type 71 in this epidemic. What role do other viruses play in the infection, morbidity and mortality of the epidemic? Questions arise concern the nature and movement of enterovirus type 71 and other enteroviruses viruses within the Taiwan population as an annual phenomenon but particularly what happened this year. A description of the epidemic is needed in terms of its behavior on the whole island, and locally in different communities in terms of age-specific incidence of infection and disease, ratio of inapparent to apparent infections and case fatality ratio. An important unknown underlying this epidemic is the number of inapparently infected cases. This may be approached by seroepidemiologic studies of selected populations before and after the epidemic. Such studies should also provide estimates of the acquisition of immunity to enterovirus type 71 in various Taiwan communities, categorized according to age and other demographic characteristics. Can estimates be made about the proportion of populations, stratified by age, still susceptible to enterovirus type 71 after this epidemic? Such estimates, if comprehensive, are essential for predictions about the recurrence of an epidemic by type 71 in the future.

The mode of transmission of enterovirus 71 is assumed to be oral-fecal and/or respiratory. Design studies to determine the precise method or methods of transmission. This knowledge is critical for selecting precise preventive measures during an epidemic.

Enteroviruses usually affect a large number of individuals of whom only a few are symptomatic. In view of the severity of the symptomatic cases this year there is unusual interest in a study of the risk factors contributing to disease, and to deaths caused by enterovirus type 71. These include coinfection by other viruses, and the gamut of host factors, including external factors.

2. Clinical-Virological-Pathological Questions

From studies of clinical-virological correlations we should derive a clear picture of different clinical syndromes associated with each different circulating enterovirus, including type 71. Can a presumptive diagnosis of a viral infection be made based on clinical pictures alone? If so, such knowledge can be useful for community viral surveillance.

Enterovirus type 71 has often been associated with deaths in other epidemics. However the presentations of the lethal cases have been unique in this epidemic. Explain the pathogenesis of disease and death in cases associated with enterovirus type 71, based on pathological and autopsy studies. Provide a comparative analysis of deaths with enterovirus type 71 in other epidemics abroad. Provide a similar study of patient deaths associated with other viruses. Which changes could be attributed to the virus directly or indirectly? Which cannot be explained by viral infection?

  1. Virological Questions

Document and describe the best methods to diagnose enterovirus type 71 and related viruses. Which is the most rapid, cost-effective and reliable method? Discuss types of samples to take and which are most productive and convenient. Compare infection diagnosed by virologic and serologic methods and by molecular diagnostics (PCR).

A popular theory of this epidemic is that the virulence and altered clinical manifestations of enterovirus type 71 are due to mutations of the virus. How do the genotypes (base-sequences) vary with clinical manifestations, severity of disease and with different epidemics in other parts of the world? Postulate the pathogenic function of critical genetic variations, if any. Are there any definable serologic differences associated with changes in base sequences? What important specific conclusions can be made about genotype variations?


Qualification of Personnel and Methods of Investigation

From the three categories of questions asked, it is apparent that only qualified scientists, especially epidemiologists, clinicians, pathologists and virologists should apply. They must have access to medical records or virologic and clinical materials concerning patients, who were infected, became sick or died. To elucidate the epidemiology, they must be ready to do surveys among the families or within the community of the afflicted. They must have access to hospital and laboratory records, and records of the Department of Health and local health departments. To study population immunity they must perform systematic and meaningful serologic surveys of patients, contacts and community groups. To elucidate clinical-pathologic-virologic correlations, clinical, pathologic and virologic data must be studied and integrated. To answer the virologic questions, cell culture methods, molecular diagnostic methods as well expertise in molecular genetics is needed.

Single or multiple institutions may apply in one application. Not all questions need to be addressed in any one application. However, applicants should try to answer comprehensively questions from one or more categories. To maximize the use of materials available and to maximize the scope of investigation, collaboration between two or more institutions with different types of materials and expertise is encouraged. Hospital investigators should consider seeking the collaboration or advice of epidemiologists in the Department of Health or universities if they wish to address questions in category 1.



Applications will be reviewed and scored by a committee of experts in infectious disease epidemiology, virologic infectious diseases and virology. They will be judged by two criteria: (1) the completeness with which questions from the three categories will be answered, and (2) the quality of the science demonstrated in the application.



Awards will be made shortly after review within 1998.

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Last updated 1998/08/05