Epidemiologic factors

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Norovirus

Noroviruses are prevalent worldwide. The burden of disease is unknown, but it is hypothesized that over 90% of adults have been exposed to norovirus. This hypothesis is based on antibody acquisition data indicating that antibody prevalence to norovirus is lowest in children 0-5 years old and increases with age. In industrialized countries such as the United States and the United Kingdom, antibody prevalence ranged from undetectable to 20% in the 0-5 year old age group to 65-70% in the 11-15 year old age group.84-87 In developing countries such as Bangladesh and Ecuador, antibody prevalence ranged from 75 to 100% in the first 5 years of life and remained in this high range throughout childhood.84,85 Based on RT-PCR analyses of stool specimens, several cohort studies have identified NoV prevalence rates of 7-20% in developing countries

12 88 89

among symptomatic and asymptomatic children.12 88 89 It is important to note that these studies are preliminary and antibody acquisition data will differ from RT-PCR results because of the assay measurement, sensitivity, and specificity. These differences suggest higher rates of exposure in developing countries than industrialized countries perhaps due to differences in water quality, sanitation and hygiene practices. Children may be reinfected several times with different strains of virus in a short period of time.12

Noroviruses are divided into five different genogroups, three of which cause human disease: genogroups I, II, and IV. Genogroups I and II are most commonly associated with human disease. Genogroup IV, while associated with human disease, is rarely found.90 Each genogroup has multiple strains categorized by phylogenetic analysis (based on either polymerase or capsid sequences) into prototype clusters. In 2004, genogroup I had over 8 prototype clusters and genogroup II had 17 prototype clusters (CDC, personal communication). New strains of NoV are routinely identified, and therefore this number is expected to increase. Among the genogroup II viruses, strains in the GII/4 cluster are most commonly associated with outbreaks in the United States and Europe. Certain NoV strains may appear in a region, predominate among outbreaks, and later be replaced by other strains. It is hypothesized that different strains have different predominant transmission routes, infectivity, and clinical manifestations. We speculate that virus strains differ in other virulence aspects including longer shedding times, shedding higher titers, and longer persistence in the environment. In addition, host determinants of resistance and susceptibility (genetic and immunologic) are probably different for each strain (reviewed in Hutson et al90). The genetic differences among NoV strains create challenges for the development of a pan NoV vaccine (reviewed in Hutson et al. ,90 Matsui and Greenberg,91 Tacket et al.,92 Estes et al.,93 and Tacket94). It is possible that NoV vaccine development may follow the influenza vaccine model, in which yearly flu vaccines are developed for the predominant strains.

Surveillance data from Europe and the United States indicate that novel virulent NoV strains may emerge and cause pandemics. Why pandemics are caused by certain strains and not others is not understood. For example, in 1995 to 1996, a norovirus strain, belonging to genogroup II/4, was detected in the United States and spread throughout South America, Europe, Asia, and Australia.95 In 2002, the European surveillance network detected a rise in norovirus outbreaks among ten European countries caused by the emergence of a new genogroup II/4 norovirus strain.96 This strain had a consistent mutation in its polymerase region that set it apart from other genogroup II/4 strains detected in Europe. The factors that contribute to norovirus genetic diversity are also not understood. Several groups have suggested that within-genogroup recombination gives rise to hybrid strains capable of causing outbreaks in human populations. For example, the strain Arg320 was suggested to be a recombinant of Lordsdale (II/4) virus and Mexico virus (II/3).97 In summary, noroviruses are highly virulent and have broad genetic diversity, and these features contribute to their epidemic and pandemic spread across the world.

Hepatitis A virus

Hepatitis A virus is present worldwide and may cause sporadic and epidemic disease. Different rates of prevalence and endemicity are observed in various world regions. In the United States, one-third of the general population has serologic evidence of prior hepatitis A infection; while in some parts of southeast Asia, over 90% of the general population has serologic evidence of infection.33 In developing countries, hepatitis A is endemic, and most individuals are infected in early childhood without symptoms. A single hepatitis A infection renders immunity to the virus. Because of this, in developing countries, most adults are usually immune, and epidemics of hepatitis A are uncommon. As socioeconomic or sanitation conditions improve, the prevalence of hepatitis A infections decreases, and the average age of reported cases increases because people are more likely to be exposed later in life and have symptomatic infections. In industrialized countries, transmission is largely person-to-person (fecal-oral), but large common source outbreaks can occur. Hepatitis A infection often occurs in crowded institutions such as schools, prisons, and the military. Disease transmission is frequent among households, sexual contacts of acute cases, travelers to endemic countries, injecting drug users, and men who have sex with men. Foodborne outbreaks have been reported in most parts of the world except those with the highest hepatitis A endemicity. In outbreaks, up to 20% of cases are due to secondary transmission of hepatitis A (reviewed in Koopmans et al8).

Only one serotype of hepatitis A virus has been found of which the antigenicity is determined by an immunodominant epitope. Four distinct genotypes of hepatitis A virus have been identified in humans. These four genotypes have no important biologic differences, and all belong to the same single serotype. The hepatitis A vaccine or infection confers lifelong immunity to the virus. In the United States, increased hepatitis A vaccination has decreased the incidence rate by 76%, between the baseline period (1990-1997) and 2003.98 In 2003, rates in the United States were 2.6 for every 100 000 individuals (61 000 new infections in 2003) compared with 1992, when rates were 9.1 for every 100 000 individuals (288 000 new infections in 1992). Hepatitis A vaccinations and immunoglobulins are also effective interventions in hepatitis A outbreak situations and may shorten outbreak duration.62,99

Infectious dose

An exact determination of the infectious dose of viruses in humans is difficult because conducting necessary investigations requires human challenge studies. For hepatitis A, it is believed that 10-100 virus particles are sufficient to infect an individual. For norovirus, 10 RT-PCR detectable units, or approximately two genome copies, are sufficient to infect an individual (Moe C, et al. unpublished). In these studies, volunteers were infected with three different strains of noro-viruses. Challenge with different NoV viruses induced different dose-infectivity curves and dose-illness curves (Moe C, et al. unpublished). These results suggest that individual NoV strains may have different infectivity and severity.

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