Rotavirus is the most common cause of severe diarrhea in children worldwide.1 2 3 rotavirus vaccines be included in all national immunization programs as part of a comprehensive strategy to control diarrheal diseases.4 5 7
Given the WHO recommendation for inclusion of rotavirus vaccines in all national immunization programs and the increasing evidence of the benefits of rotavirus vaccination in other countries,7
MATERIALS AND METHODS
Sources of Data
For rotavirus disease burden estimates and strain distribution, we identified references through searches of PubMed and 2 Chinese literature databases (China National Knowledge Infrastructure and Wanfang) for articles published from 1 January 1994 to 31 December 2014, by use of the terms (“rotavirus” and “China”) or (“diarrhea” and “China”). The term “China” was used for PubMed search only. Chinese language (“
”
;”
”) was used for the China National Knowledge Infrastructure and Wanfang searches. We then manually screened all English and Chinese language articles resulting from these searches for study population, study duration and rotavirus diagnostic methods. Articles that met the following criteria were fully abstracted and included in this report: (1) data available for 100 or more patients younger than 5 years; (2) study duration of at least 12 month increments (to account for seasonality of disease); and (3) use of the following rotavirus laboratory tests on fecal samples: enzyme-linked immunosorbent assay for rotavirus detection and/or reverse-transcriptase polymerase chain reaction for strain typing. We excluded literature reviews, studies reporting on adults only and reports on outbreaks and nosocomial infections.
Categorization of Rotavirus Disease Burden and Strain Distribution Studies
We stratified rotavirus disease burden studies by health care setting (inpatient and outpatient) and by geographic location (urban and rural). For each study reviewed, we used a standardized form to abstract the rotavirus detection rate, health care setting, geographic location, study duration and study population size. For inpatient studies that provided age-stratified data, we pooled the number of children enrolled by age to determine the cumulative age distribution for rotavirus-related hospitalizations. Because predominant rotavirus strains may change over time, we examined strain distribution by the following time periods for which data were available: 1995–1999, 2000–2004, 2005–2009 and 2010–2013.
RESULTS
Rotavirus Disease Burden
The initial search identified 10,342 rotavirus-related citations from China National Knowledge Infrastructure, Wanfang and PubMed. Forty-five studies met the inclusion criteria for review (Fig. 1 ). Thirty-nine studies were published in Chinese, and 6 were published in English. Of the 45 included studies, 39 provided data on inpatient health care visits, with study periods ranging from 12 to 60 months,6 , 8–45 8 , 9 , 36 , 42 , 46–51
FIGURE 1: Eligibility of studies for inclusion in the systematic review.
For the 39 inpatient studies conducted between 1998 and 2013, a total of 74,846 (range per study: 169–14,511) children younger than 5 years with acute gastroenteritis were evaluated (Table 1 ) for which a median of 44% (range: 7.3%–65.6%) of these children tested positive for rotavirus; the proportion of diarrhea hospitalizations due to rotavirus was stable over the 16-year period (Fig. 2 ). The median proportion of children that tested positive for rotavirus did not vary greatly by geographic region (range for North, Central and Southern regions: 37.7%–47.3%). Thirty-three studies were conducted in urban areas (median rotavirus positive: 39.8%; range: 7.3%–65.6%), and 6 were conducted in rural areas (median rotavirus positive: 46.7%; range: 43.7%–54.3%). For pooled data on cumulative rotavirus hospitalization incidence from 12 studies, 14% of rotavirus gastroenteritis hospitalizations occurred in children younger than 6 months, and 91% of rotavirus gastroenteritis hospitalizations occurred by age less than 24 months (Fig. 3 ).6 , 9 , 13 , 14 , 26 , 29 , 31 , 49 , 52–55
TABLE 1: Rotavirus Detection Rates for 41 Inpatient Studies of Pediatric Diarrhea Among Children Younger Than 5 Years in China, 1998–2013
FIGURE 2: Rotavirus positivity by study midpoint in children younger than 5 years hospitalized with acute gastroenteritis, 1998–2013.
FIGURE 3: Age distribution of children hospitalized with acute rotavirus gastroenteritis in China, 1998–2013. Bars denote the number of hospitalizations in different age groups and the line represents the cumulative rotavirus-positive rate.
In 10 outpatients studies conducted between 1998 and 2013, a total of 16,994 (range per study: 155–10,140), children younger than 5 years with acute gastroenteritis were evaluated (Table 2 ). A median of 30.7% (range: 12.3%–35.4%) of these children tested positive for rotavirus. The proportion of children that tested positive for rotavirus was reported as 27.3%–35.4% in 3 studies conducted in Northern China, 30.8% in 1 study conducted in Central China, 12.3%–30.7% in 5 studies conducted in Southern China and 31% in 1 study conducted in various locations in Gansu Province. All studies were conducted in urban areas.
TABLE 2: Rotavirus Detection Rates for 10 Outpatient Studies of Pediatric Diarrhea Among Children Younger Than 5 Years in Urban China, 1998–2013
Rotavirus Strain Distribution
We examined rotavirus strain distribution data for the years 1995–2013 from 35 studies that met the inclusion criteria6 , 8 , 9 , 11–14 , 17 , 19 , 20 , 24 , 27–29 , 32 , 35 , 38 , 45 , 47 , 52–67 Fig. 4 ). In 3 studies with data for 1995–1999, G1 was the predominant reported G type, accounting for 70% of strains; data on P types were not available for this time period. In 11 studies with data for 2000–2004, G1 and G3 were the predominant reported G types, accounting for 39% and 38% of strains, respectively. In 8 studies for which P types were reported during the same period, P[8] was predominant, accounting for 59% of strains. In 14 studies with data for 2005–2009, G3 was the predominant reported G type, accounting for 62% of strains, while in 11 studies for the same time period, P[8] was the predominant reported P type, accounting for 60% of strains. In 9 studies with data for 2010–2013, G3 was the predominant reported G type, accounting for 42.3% of strains, while in 8 studies for the same time period, P[8] was the predominant reported P type. No uniform differences in genotype predominance by region were seen within each time period.
FIGURE 4: Distribution of common G and P types in children younger than 5 years in China, 1995–2013. MT indicates mixed type; NP, nontypeable.
DISCUSSION
The findings of this comprehensive, up-to-date literature review affirm that rotavirus is a leading cause of severe diarrheal disease among children in China, causing over 40% of diarrhea hospitalizations and ~30% of diarrhea-related outpatient visits in children younger than 5 years. The proportion of diarrhea hospitalizations due to rotavirus was remarkably stable over the 16 year period from 1998 to 2013 and also was similar in different geographic regions and urban/rural settings. Severe rotavirus disease occurs early in life in China with over half of rotavirus-related hospitalizations occurring in the first year of life and 91% of rotavirus-related hospitalizations occurring by 2 years of age. However, it is important to note that only 14% of hospitalizations occurred before the age of 6 months. Therefore, a vaccination program with doses given early in infancy has the potential to prevent the majority of the burden of severe rotavirus disease. Our review also demonstrates that, while there has been natural, temporal variation in circulating rotavirus strains in China, the predominant local strains are the same as those that are globally dominant.68 , 69
Using estimates of approximately 30 million doses of LLR vaccine distributed since 2000 and a birth cohort of 16 million, the crude national LLR vaccination coverage is only 15.6% with 1 dose. This may help explain why we observed steady rotavirus positivity rates in our review of the literature even after 2000, the year of vaccine licensure. However, without accurate national and local population coverage data, it is difficult to gauge the true level of impact that LLR vaccine may have had on rotavirus disease trends in China and whether decreases in rotavirus disease in specific areas were due to vaccine use. More scientifically rigorous studies are essential to evaluate the impact and effectiveness of this vaccine.
This review has some limitations. First, because of its retrospective nature, people in studies are not the same. Second, given strict inclusion and exclusion criteria, a greater proportion of the included studies were from urban location, which limits the generalizability of our findings. Additionally, we were unable to obtain national-level data that would have covered more provinces of China, including the poorest areas in Western China. Third, we were unable to include all studies identified through the literature searches given different study periods, ages of enrollment, case definitions of severity and diagnostic assays used. However, by using a uniform set of inclusion criteria, we were able to compare studies over time, across regions, by urban/rural location and by clinical setting as a marker of disease severity where hospitalizations represent more severe disease. Despite these limitations, we were able to review a large number of studies, and the detection rates observed in this review are similar to those found in the most recent large prospective study in China.70
The introduction of rotavirus vaccines into routine immunization programs worldwide has resulted in substantial declines in rotavirus-related morbidity and mortality in the countries that have introduced vaccine.7 , 71 rotavirus vaccines , Rotarix (GlaxoSmithKline, Rixensart, Belgium) and RotaTeq (Merck and Co. Inc, West Point, PA), have been introduced into over 75 countries worldwide since 2006 and have had good effectiveness against severe rotavirus disease under conditions of routine use and a notable impact in reducing rotavirus hospitalization in many countries.72 , 73 rotavirus vaccines and a new trivalent lamb–human reassortant rotavirus vaccine are in prelicensure clinical trials, and several other locally manufactured rotavirus vaccines are in development.
Our findings affirm that rotavirus is the major cause of childhood diarrheal disease in China and suggest that a vaccination program with doses given early in infancy has the potential to prevent the majority of the burden of severe rotavirus disease. This information should help inform future decisions on national rotavirus vaccine introduction in China.
ACKNOWLEDGMENTS
The authors express their gratitude to Zijian Feng and Zhaojun Duan of the Chinese Center for Disease Control and Prevention for their grant support.
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