Global Mortality Associated with Rotavirus Disease among Children in 2004

Abstract

BackgroundAs new rotavirus vaccines are being introduced in immunization programs, global and national estimates of disease burden, especially rotavirus-associated mortality, are needed to assess the potential health benefits of vaccination and to monitor vaccine impact

MethodsWe identified 76 studies that were initiated after 1990, lasted at least 1 full year, and examined rotavirus among >100 children hospitalized with diarrhea. The studies were assigned to 5 groups (A-E) with use of World Health Organization classification of countries by child mortality and geography. For each group, the mean rotavirus detection rate was multiplied by diarrhea-related mortality figures from 2004 for countries in that group to yield estimates of rotavirus-associated mortality

ResultsOverall, rotavirus accounted for 527,000 deaths (95% confidence interval, 475,000–580,000 deaths) annually or 29% of all deaths due to diarrhea among children <5 years of age. Twenty-three percent of deaths due to rotavirus disease occurred in India, and 6 countries (India, Nigeria, Congo, Ethiopia, China, and Pakistan) accounted for more than one-half of deaths due to rotavirus disease

ConclusionsThe high mortality associated with rotavirus disease underscores the need for targeted interventions, such as vaccines. To realize the full life-saving potential of vaccines, it will be vital to ensure that they reach children in countries with high mortality. These baseline figures will allow future assessment of vaccine impact on rotavirus-associated mortality

Rotavirus is the leading cause of severe gastroenteritis in children worldwide. Because of the tremendous health burden of rotavirus gastroenteritis, vaccines have been developed against this pathogen. Two new rotavirus vaccines have recently demonstrated promising efficacy and safety results in clinical trials [1, 2]. These vaccines have already been introduced into national immunization programs in several industrialized and middle-income countries (eg, United States, Australia, Brazil, and Mexico) and are being considered for use in low-income countries that are eligible for support for vaccine purchase through the GAVI Alliance (formerly known as the Global Alliance for Vaccines and Immunization). A key consideration for global health agencies, policy makers, and donor groups in evaluating the value and health benefits of these vaccines will be their potential impact in preventing severe rotavirus disease and childhood deaths from rotavirus disease. At the national level, decision makers may want to review estimates of mortality associated with rotavirus disease in their own setting to help prioritize and facilitate decision making for vaccine introduction. Furthermore, as vaccines are introduced into immunization programs globally, baseline estimates of mortality are needed to monitor vaccine impact

In 1985, de Zoysa and Feachem [3] estimated from a literature review that rotavirus accounted for ∼25% of severe cases of diarrhea among children <5 years of age in developing countries. By applying this proportion to a contemporary estimate of diarrhea-associated mortality of 3.2 million deaths, the Institute of Medicine estimated that, each year, rotavirus caused ∼873,000 deaths among young children [4]. On the basis of a review of studies published during 1986–1999 that indicated that rotavirus accounted for a median of 22% of severe diarrhea cases among young children, Parashar et al [5] estimated that rotavirus caused 440,000 of the ∼2.1 million annual deaths from diarrhea among children <5 years of age worldwide during the same period. An updated review of the literature published during 2000–2004 indicated a median rotavirus detection rate among children with severe diarrhea of 39% [6]. Application of this higher proportion to the contemporary World Health Organization (WHO) estimate of 1.56 million diarrhea-related childhood deaths yielded a substantially greater figure of ∼611,000 global deaths from rotavirus disease

Although the figure of 611,000 deaths due to rotavirus disease is based on more-recent data that should better reflect current trends in the etiology of severe diarrhea, firm conclusions could not be derived for several reasons. First, because the analysis was limited to studies published over a 5-year period, relatively few studies were examined. Second, because the studies were selected on the basis of the year of publication and not the period during which the studies were actually conducted, it was possible that the study periods overlapped with studies included in the previous review. Third, countries were divided into groups based on income level to extrapolate data to countries in the same income group for which data were not available. Although, in general, income level for a country correlates well with other parameters, such as child mortality, that have been used for extrapolation of data for other conditions, certain exceptions exist. For example, Vietnam is a country with a very low income of US$500 per capita, but the child mortality in Vietnam is comparable to that seen in countries with incomes of $4000–$8000 per capita. Finally, the WHO revised the diarrhea-associated mortality figures to 1.9 million deaths among children <5 years of age during 2004 [7], and rotavirus-associated mortality figures need to be updated on the basis of this new estimate of diarrhea-related mortality

To derive updated estimates of rotavirus-associated mortality, we reviewed studies conducted after 1990 that assessed rotavirus among children hospitalized with severe diarrhea. We then applied the observed rotavirus detection rates to 2004 WHO figures of overall childhood mortality associated with diarrhea. We also provide country-specific estimates of the mortality associated with rotavirus disease, based on WHO estimates of overall mortality associated with diarrhea in each country. These data should help donors and policy makers in assessing the magnitude of the problem of rotavirus disease both globally and in each country and in prioritizing the need for interventions against this disease. As rotavirus vaccines are implemented globally, comparison of future mortality estimates against baseline figures presented in this report should help assess the impact of vaccination in reducing childhood mortality

Methods

We examined studies previously identified through computer searches of the scientific literature (in English and other languages) published from 1986 through June 2004 [5, 6]. We conducted our primary search using the keyword “rotavirus” and the truncated stem “rota-.” To ensure the completeness of our review, we cross-checked the citations and consulted with experts in the field. We restricted the final analysis to studies that met each of the following criteria: (1) were initiated after 1990 (for studies conducted over multiple years, only those with a midpoint after 1990 were selected), (2) were conducted for at least 1 full calendar year, and (3) examined rotavirus among at least 100 children hospitalized with diarrhea

For each study, we determined the proportion of children hospitalized with diarrhea who had samples that tested positive for rotavirus. On the basis of the country in which the study was conducted, studies were assigned into 5 groups (A–E) that were formed using a WHO classification of countries by levels of child mortality and by location (Table 1) [8]. For each group, we calculated the random effect mean and 95% confidence intervals (CIs) of the proportion of hospitalizations for diarrhea among children who had samples that tested positive for rotavirus with use of the R metalibrary (http://www.r-project.org) [9, 10]. We then multiplied the mean and 95% CI of the proportion of hospitalizations for diarrhea due to rotavirus in each group by the number of estimated deaths from diarrhea among children <5 years of age in each country in that group to yield country-specific estimates of mortality associated with rotavirus disease. These country-specific estimates were added to calculate mortality associated with rotavirus disease in each group and globally. The 95% CI of the global mortality estimate was derived by sampling 10,000 times from the group-specific 95% CI, multiplying the sampled estimates by the country-specific number of deaths from diarrhea among children <5 years of age, and then ordering the resulting product and selecting the 250th and 9750th results

Table 1

World Health Organization Member States, by Region and Mortality Stratum

Results

Seventy-six studies from 39 countries met the inclusion criteria. The overall rotavirus detection rates ranged from 16% to 66%. Detection rates were greater in countries with lower levels of child mortality (A-C) than in those with higher mortality (D–E) (Figure 1)

Figure 1

Rotavirus detection rates by mortality stratum. For each group, the outer bars indicate the range of estimates from different studies, the box plot shows the 95% confidence interval of the estimates, and the bold line indicates the random effects mean estimate

To estimate the number of deaths from rotavirus disease in each country in each group, we applied the group-specific random effect mean and 95% CI of the rotavirus detection rates to the 2004 country-specific estimates of the number of deaths due to diarrhea among children <5 years of age in that group (Table 2). By adding all country-specific estimates of the number of deaths due to diarrhea among children <5 years of age, we estimated that, overall, rotavirus accounted for 527,000 deaths per year (95% CI, 475,000–580,000 death per year) and 29% of all deaths due to diarrhea among children <5 years of age during 2004

Table 2

Deaths Due to Diarrhea and Rotavirus Disease, by World Health Organization Child Mortality Stratum and Region

National estimates of the number of deaths due to rotavirus disease among children <5 years of age ranged from 122,270 in India to <5 in 58 countries (Figure 2). Twenty-three percent of all deaths due to rotavirus disease occurred in India, and 6 countries (India, Nigeria, the Democratic Republic of the Congo, Ethiopia, China, and Pakistan) accounted for more than one-half of all deaths due to rotavirus disease (Figure 3)

Figure 2

Estimated distribution of deaths due to rotavirus disease among children <5 years of age, by country. Each dot represents 1000 deaths

Figure 3

Number of deaths due to rotavirus disease (and percentage of the global total) in 10 countries with the greatest number of deaths due to rotavirus disease

The rotavirus-associated mortality rate among children <5 years of age among various countries ranged from 439 deaths per 100,000 children in Sierra Leone to <1 death per 100,000 children in 50 countries (Figure 4). Seven countries had a rotavirus-associated mortality rate among children <5 years of age of >300 deaths per 100,000 children (Sierra Leone, Niger, Angola, Afghanistan, Liberia, Somalia, and Mali)

Figure 4

Rotavirus-associated mortality rates among children <5 years of age, by country

Discussion

This review, based on a standard WHO process for estimation of burden of vaccine-preventable diseases, reaffirms the high mortality associated with rotavirus disease among young children. We estimated that 527,000 children (range, 475,000–580,000 children) <5 years of age die of rotavirus disease each year; this translates into ∼1440 deaths due to rotavirus disease per day (1 of 237 children born each year would die of rotavirus disease by 5 years of age). Although rotavirus is ubiquitous and the incidence of disease is similar among children in industrialized and developing countries, we observed a great disparity in mortality associated with rotavirus disease that is likely related to differences in access to appropriate and timely medical care and hydration therapy. Whereas very few deaths due to rotavirus disease occurred in affluent countries, countries with the greatest level of child mortality (D and E) accounted for ∼86% of all deaths due to rotavirus disease. In fact, 6 countries (India, Nigeria, China, Pakistan, Ethiopia, and Democratic Republic of Congo) accounted for >50% of all deaths due to rotavirus disease, with India alone accounting for one-fourth of the deaths. To realize their full life-saving potential, it will be vital to ensure that interventions, such as rotavirus vaccines, reach children in countries with the greatest mortality

As the overall global mortality associated with diarrhea among young children has decreased over the past 2 decades, rotavirus has assumed a more important etiologic role. Reviews of the literature published during 1975–1985 and during 1986–1999 estimated that rotavirus accounted for ∼25% and ∼22% of severe cases of diarrhea [3, 5], respectively, whereas the current review of studies conducted after 1990 showed that this proportion has increased to 29%. In fact, a review of even more-recent studies, published during 1999–2004, found a median rotavirus detection rate of 39% [6], although firm conclusions could not be derived, because only a relatively small number of studies was examined. A recent study that examined data from a unique and stable diarrhea surveillance in Bangladesh during the period 1993–2004 confirmed these changing etiologic trends [11], noting that the proportion of severe diarrhea cases attributable to rotavirus increased from 22% during 1993–1995 to 42% during 2002–2004. When new data from sentinel hospital-based rotavirus surveillance that is ongoing in >40 countries globally becomes available (such as the reports included in this supplement), the estimates in the present report should be reexamined and updated

The increasing role of rotavirus in the etiology of severe childhood diarrhea is likely attributable to the fact that this pathogen is often transmitted from person to person and is difficult to control through improvements in hygiene and sanitation, which have had greater impact on the prevention of diarrhea caused by bacterial and parasitic agents over the past 2 decades. This hypothesis is supported by observations from an evaluation in Mexico that demonstrated that, although diarrhea-associated mortality decreased substantially during 1989–1995, the decrease was less evident during winter among children <2 years of age whose illness met the epidemiologic features of rotavirus diarrhea [12]. In fact, the summer peaks in the number of diarrhea-related deaths that were likely attributable to bacterial and parasitic infections were replaced over the study period by winter peaks in deaths that were likely attributable to rotavirus infection. These observations reinforce the need for targeted interventions, such as vaccines, against rotavirus to further reduce morbidity and mortality associated with rotavirus diarrhea among children

Because very limited data on diarrhea-related death with laboratory confirmation of the etiologic agent are available, our assessment relies on the fundamental assumption that the spectrum of etiologic agents seen in children with severe diarrhea who require hospitalization is representative of the etiology of death due to diarrhea. Because deaths from diarrhea primarily occur in settings where access to medical care is limited, collection of appropriate clinical specimens to perform a microbiologic evaluation is extremely challenging. Although it is more feasible to examine etiologic agents causing death due to diarrhea in hospital settings, only a small proportion of all deaths due to diarrhea occur in hospitals. Furthermore, it is likely that the etiologic picture derived from in-hospital deaths due to diarrhea would be biased toward agents that are less likely to respond to medical care. In addition, the microbiologic composition involved in these deaths may not be representative of that involved in deaths in the community, because these children may have more comorbid conditions (eg, severe malnutrition and immunodeficiency) that could predispose to infection with certain pathogens. With improvement in techniques for the detection of rotavirus in autopsy tissue, serum, and fecal specimens [13, 14], the feasibility of establishing a diagnosis of rotavirus disease in children with severe diarrhea through specialized studies should be assessed. Of note, a recent study from Venezuela that used polymerase chain reaction methods to examine fecal specimens collected from children who died of diarrhea found that 21% had detectable evidence of rotavirus [15], supporting the estimates presented in the present report

As rotavirus vaccines are implemented in routine childhood immunization programs, assessment of the impact of vaccination on severe morbidity and mortality associated with childhood diarrhea will be a priority. Vaccines will have a substantial impact on rotavirus-associated mortality when they are introduced in low-income countries in Asia and Africa, which could occur through support from the GAVI Alliance over the next 2–3 years if favorable efficacy results are obtained from ongoing trials. For the same reasons that make it hard to directly measure the burden of laboratory-confirmed deaths due to rotavirus disease, measurement of the direct impact of vaccines on rotavirus-associated mortality will be challenging. The anticipated reduction in mortality could be modeled on the basis of data on vaccine coverage and efficacy against severe rotavirus disease. However, it is possible that available estimates of vaccine coverage may not be suitable for populations in a country that are most at risk of death from rotavirus disease. Where available, assessment of national or regional data on trends in overall hospitalizations for diarrhea and deaths due to diarrhea could be useful, especially in settings where rotavirus disease is seasonal. Direct assessment of the effectiveness of rotavirus vaccines on diarrhea-associated mortality will likely require specialized epidemiologic assessments (eg, case-control studies) or intervention trials. The baseline mortality figures presented in the present report will allow future assessment of vaccine impact

Potential conflicts of interest: none reported

Financial support: none reported

Supplement sponsorship: This article was published as part of a supplement entitled “Global Rotavirus Surveillance: Preparing for the Introduction of Rotavirus Vaccines,” which was prepared as a project of the Rotavirus Vaccine Program, a partnership between PATH, the World Health Organization, and the US Centers for Disease Control and Prevention, and was funded in full or in part by the GAVI Alliance

Presented in part: Vaccines for Enteric Disease Conference, Lisbon, Portugal, April 2007

The findings and conclusions in this report are those of the authors and do not necessarily represent the views of Centers for Disease Control and Prevention

Present affiliations: Program for Applied Technology in Health, Seattle, Washington (D.S.); and Fogarty International Center, National Institutes of Health, Bethesda, Maryland (R.I.G.)