Incidence of Severe Rotavirus Diarrhea in New Delhi, India, and G and P Types of the Infecting Rotavirus Strains
- Rajiv Bahl1,
- Pratima Ray1,
- Swati Subodh1,
- Prashant Shambharkar1,
- Manju Saxena1,
- Umesh Parashar2,
- Jon Gentsch2,
- Roger Glass2 and
- 1 Center for Diarrheal Disease and Nutrition Research, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India
- 2 Viral Gastroenteritis Division, Centers for Disease Control and Prevention, Atlanta, Georgia
- Reprints or correspondence: Prof. M. K. Bhan, Dept. of Pediatrics, All India Institute of Medical Sciences, New Delhi 110029, India (mkbhan_rv{at}bol.net.in).
Abstract
A total of 62,475 children <5 years old from a defined population of ∼500,000 children and adults from slums in New Delhi, India, were assessed for 1 year by means of passive surveillance, to identify children who were hospitalized for diarrhea. The incidence of severe rotavirus diarrhea was estimated, and the G and P types of the infecting rotavirus strains were determined and were correlated with the clinical severity of diarrhea. Of 584 children who were hospitalized with diarrhea, 137 (23.5%) had rotavirus detected in stool specimens (incidence of rotavirus diarrhea-associated hospitalizations, 337 hospitalizations/100,000 children <5 years of age). Most cases of diarrhea (98%) occurred during the first 2 years of life, peaking at 9–11 months of age. Rotavirus-associated diarrhea occurred year-round but was predominant in winter. Among the strains that could be G-typed, G1 was the most common serotype, followed by G9 and G2; 10% of cases of diarrhea were due to mixed G-type infections. Common strains identified in the present surveillance study were P[8]G1, P[4]G2, P[8]G9, P[6]G1, P[6]G9, and P[6]G3. Children infected with G1 strains had a greater risk of developing more-severe cases of diarrhea than did children infected with other rotavirus strains (odds ratio, 2.95; 95% confidence interval, 1.3–6.67).
Rotavirus is the most common cause of severe diarrhea in children worldwide [1]. In India, health care facility-based studies of children have indicated that rotavirus infection accounts for ∼26% of all diarrhea-related hospitalizations [2]. There are no population-based data from which to estimate the incidence of severe rotavirus diarrhea and related hospitalizations. These data would be valuable not only to determine sample sizes for the evaluation of rotavirus vaccines but, also, to define policy regarding the priority of rotavirus vaccines among the available interventions in public health programs aimed at reducing mortality and morbidity among children and the associated health care costs. Also, because rotaviruses show unusual genomic diversity in India and in other developing countries [3–8], continuous surveillance for different serotypes is important to assess the appropriateness to the local population of the antigenic makeup of the vaccines under development. We conducted a longitudinal study in which all children <5 years old from a defined population of ∼500,000 children were monitored after being admitted with diarrhea to 6 hospitals, to determine the incidence of severe rotavirus disease and the proportion of G types and P types among infecting rotavirus strains and their association with the clinical severity of diarrhea.
Materials and Methods
Study population and census
A population of ∼120,000 households (median household size, 4.5 individuals) of low socioeconomic status from south New Delhi, India, was chosen for the present study. A door-to-door survey was conducted by trained field-workers, to identify the number of children <5 years of age in the study population. This number was the denominator used in the calculation of the overall and age-specific incidences of severe rotavirus diarrhea.
Selection of hospitals for passive surveillance
By means of a door-to-door survey, information was collected about any hospitalization that had occurred since the birth of any child ⩽5 years of age who resided in the household. These data indicated that ∼65% of hospitalizations of children in the study population were covered by 6 hospitals in the southern part of New Delhi and that the remaining children were hospitalized in numerous small nursing homes located in and around the study area. Data from a previous study [9], in which 4000 newborns were followed until age 1 year, also suggested that approximately two-thirds of hospitalized infants were admitted to the following 6 hospitals in south Delhi (M.K.B., unpublished data): Safdarjang Hospital, All India Institute of Medical Sciences, Batra Hospital, Majeedia Hospital, Holy Family Hospital, and Jeevan Hospital. We therefore monitored these hospitals during the present study, anticipating that ∼65% of admissions of children from the selected population would be captured.
Surveillance for identification of hospitalized children with diarrhea
Surveillance for the identification of children hospitalized for diarrhea was conducted for the calendar year from 1 August 2000 through 31 July 2001. All hospitals selected for inclusion in the study were visited on all work days by a study team led by a physician. All children admitted to the emergency department, diarrhea treatment unit, or pediatrics ward of each hospital were screened. Children residing in the study area who were admitted for diarrhea and who were hospitalized for at least 6 h were included in the study. The addresses of the children were confirmed by the parent(s) and were matched with the address recorded on each child's case report form. Clinical information was recorded for and a stool sample was obtained from each of the children studied.
Laboratory studies
Stool specimens were screened for the presence of rotavirus by use of a monoclonal antibody-based EIA kit (Premier Rotaclone; Meridian Diagnostics), which was used according to the manufacturer's instructions. Of the 137 rotavirus-positive stool specimens tested, 135 were characterized for the G and P outer capsid proteins; the remaining 2 stool specimens could not be tested because the amount of the sample obtained was insufficient. Rotavirus double-stranded RNA was extracted from stool specimens by use of the standard glass powder method described elsewhere [10]. G and P types were determined using seminested reverse-transcription polymerase chain reaction performed with the use of primers specific for G1–G4 and G9 (G type) and for P4, P6, P8, and P11 (P type) [10, 11].
Analysis
We calculated the incidence of hospitalizations due to rotavirus diarrhea by using the number of hospitalized children who had rotavirus-positive stool specimens as the numerator and the total number of children in the relevant age category as the denominator. The value that was calculated was adjusted for the 65% coverage of hospitalizations anticipated to be captured by the 6 hospitals participating in the study.
A 20-point clinical severity score was calculated for each child with diarrhea: mild diarrhea was defined by a score of 1–8; moderate diarrhea, by a score of 9–14; and severe diarrhea, by a score of >14, as described elsewhere [12, 13]. The proportion of children with severe diarrhea (severity score, >14) and the proportion of children with severe dehydration (according to World Health Organization criteria) at admission to the hospital were compared for the groups of children infected with different rotavirus strains. Adjustment for age and sex was done in logistic regression models.
Ethics
The study was reviewed and approved by the ethical review committee of the All Indian Institute of Medical Sciences in New Delhi, India.
Results
Overall and age-specific incidences of severe rotavirus diarrhea
There were 62,475 children <5 years of age in the study population, with approximately equal numbers of children in each 1-year age group up to 5 years of age. A total of 584 children from study households who were hospitalized with diarrhea were identified during 1 calendar year of surveillance at the 6 study hospitals. Of these 584 children, 137 (23.5%) had a stool specimen that tested positive for rotavirus, yielding an incidence of rotavirus diarrhea-associated hospitalization of 337 hospitalizations/100,000 children <5 years of age. This incidence indicates that ∼1 in 59 children in this population is likely to be hospitalized with rotavirus diarrhea between birth and 5 years of age.
Most (98%) of the children who were hospitalized with rotavirus diarrhea were <2 years of age. The incidence of rotavirus diarrhea was 1270, 534, and 12 cases/100,000 children during the first, second, and third to fifth years of life, respectively. The incidence was low during the first 3 months of life, peaked at age 9–11 months, and decreased sharply after age 18 months (table 1).
View this table:
Table 1
Age-specific incidence of severe rotavirus diarrhea among 62,475 children <5 years of age in new delhi, india.
None of the hospitalized children with rotavirus diarrhea had disease of mild severity, 101 (73.7%) had moderately severe disease, and 36 (26.3%) had severe disease. None of the 137 children died during the study period; 133 (97.1%) were discharged from the hospital, and 4 (2.9%) left the hospital against medical advice.
Seasonality of rotavirus infection
Hospitalizations for rotavirus-associated diarrhea occur year-round in Delhi, but we identified a distinct peak in winter (i.e., from November through February) (">@@@@figure 1). In contrast, the number of hospitalizations not associated with rotavirus peaked during the summer months.
Figure 1
Seasonality of severe rotavirus diarrhea in New Delhi, India
During the winter months, G1 and G9 strains were the most common strains identified, accounting for 45% and 29% of typeable strains, respectively. G1 (42%) and G2 (36%) strains were the most common strains identified during July–October, whereas G9 (33%), G1 (27%), and G2 (27%) strains were most commonly isolated during the summer months (March–June).
Strain characterization
A G or P type, or both types, could be determined for 105 of the 135 stool specimens tested. For 20 of 30 untypeable specimens, RNA was not detected by PAGE. Among the strains that could be G-typed, G1 was the most common type identified, followed by types G9 and G2. Mixed G-type infections were identified in 10% of the stool specimens. P-typing was used to indicate the diversity of strains in circulation and to identify the frequency of the 4 most common strains worldwide—namely, P[8] combined with G1, G3, or G4; P[4]G2; and P[6] or P[8] combined with G9 (table 2). Only strains P[8]G1, P[4]G2, P[8]G9, and P[6]G9 were commonly isolated in the present study. Other strains that are not common globally but that were frequently identified during this surveillance study were P[6]G1 and P[6]G3.
View this table:
Table 2
Distribution of G and P serotypes of rotavirus strains isolated from 137 stool specimens obtained from children from the slums of New Delhi, India, who were hospitalized for severe rotavirus diarrhea.
Association of G types with clinical severity of diarrhea
Compared with all other rotavirus-positive children, a higher proportion of children infected with the G1 strain had severe diarrhea, as defined by a severity score of >14 (age- and sex-adjusted odds ratio [OR], 2.95; 95% confidence interval [CI], 1.3–6.67) (table 3). The mean severity score was also higher for children infected with G1 strains (difference in means, 0.8; 95% CI, 0–1.5). Similarly, the prevalence of severe dehydration at admission was significantly higher for children infected with G1 strains than for children infected with other G-type strains (age- and sex-adjusted OR, 3.03; 95% CI, 1.11–8.26 (table 4). We did not find any association of P type with clinical severity of diarrhea.
View this table:
Table 3
Association of the G serotype of rotavirus strains with severe diarrhea.
View this table:
Table 4
Association of the G serotypes of rotavirus strains with severe dehydration at admission to the hospital.
Discussion
We believe the present study to be the first study from a developing country to report the population-based incidence of hospitalization for rotavirus diarrhea in a well-defined catchment area. The high incidence of rotavirus diarrhea requiring patient hospitalization confirms the immense importance of rotavirus diarrhea with regard to public health. If the estimates of incidence obtained from the present study were applied to the total birth cohort of ∼25 million children in India, then ∼450,000 hospitalizations for rotavirus diarrhea would be expected to occur annually. An effective rotavirus vaccine, in addition to preventing 100,000 rotavirus disease-associated deaths annually, as estimated elsewhere [14], could prevent most of these hospitalizations and result in large savings in health care costs. The findings also reiterate the need for effective oral rehydration therapy for the prevention of the serious consequences of diarrhea and, in particular, rotavirus diarrhea.
In Europe and North America, rotavirus disease is predominant in winter; however, previous studies from India have reported that the disease occurs year-round [15–19]. Those studies found either a peak in the occurrence of rotavirus disease in winter [15, 16], the occurrence of 2 peaks in a year [17, 18], or no seasonal pattern [19]. The findings of the present study confirm that the disease occurs year-round in New Delhi and that it is clearly predominant in winter. Although the ratio of rotavirus diarrhea to nonrotavirus diarrhea during the winter months of November through February (average maximum daily temperature, 21°C–24°C) was almost 1 : 1, it was >1 : 10 for the summer months from March through June (average maximum daily temperature, 36°C–41°C). The predominance of rotavirus diarrhea in winter may have implications for treatment.
In previous hospital-based studies performed in India, the most common rotavirus strains had G2 and G9 serotypes [3]. Although we also found these strains to be common, G1 was the most common type identified in the present study. G1 rotavirus strains are also, epidemiologically, the most common circulating strains globally [20]. The findings of the present study may differ from those of previous studies, because we assessed only hospitalized children, whereas many previous studies also evaluated outpatients. Furthermore, if G1 strains are associated with greater clinical severity of disease, as indicated by the current data, then outpatient-based surveillance is likely to yield a lower prevalence of infections with strains of the G1 type. Nevertheless, because our observations covered only a 1-year period, some of the differences in serotype distributions from previous studies may be attributable to year-to-year variations. In addition, a significant proportion of strains could not be G- or P-typed, indicating a need to search for other serotypes. In southern India, G8 and, recently, G10 strains have also been implicated as the cause of gastroenteritis in children [21, 22].
Several studies have attempted to associate the type of infecting rotavirus strain with the clinical severity of disease [23–34]: 7 studies found no association [23–29], 1 study found that strains in subgroup 2 (G1, G3, and G4 strains) were associated with greater clinical severity [30], 1 study reported that G1 and G3 strains were associated with more-prolonged diarrheal illness [31], 2 studies found that G2 strains were associated with greater clinical severity [32, 33], and 1 study reported that the P type, rather than the G type, was associated with clinical severity [34]. Our findings indicate that G1 strains cause greater clinical severity, both in terms of the overall severity score and the associated development of severe dehydration. If true, this finding may be potentially important for the development of rotavirus vaccines. Candidate vaccines must be shown to be effective against G1 strains, in addition to other rotavirus strains, to have a maximal effect on the prevention of deaths and hospitalizations due to rotavirus diarrhea. Clinical severity may be influenced not only by viral factors but, also, by such host factors as nutritional and immune status. However, there was no association of the infecting rotavirus strain with any of the host factors assessed.
Some limitations of the present study require consideration. Surveillance was conducted only for 1 year, and, therefore, we cannot be certain of the year-to-year variation in strain types. Also, the study population included residents of the slums of New Delhi, and the rate of migration in and out of the slums could be up to 10%–15% during the year. Finally, although we used a corrective factor of 65% to estimate incidence on the basis of our survey results, this factor may not have been totally accurate.
In conclusion, the findings of the present study imply that the development of a safe and effective rotavirus vaccine that is efficacious against multiple serotypes is a public health priority in India. These data should facilitate trials of candidate vaccines and should assist in the estimation of the cost-effectiveness of such vaccines.
Delhi Rotavirus Study Group Members
The members (hospital affiliation in New Delhi, India) of the Delhi Rotavirus Study Group are M. Saxena and S. Bhatnagar (All India Institute of Medical Sciences); N. Gupta, S. Paul, G. Srivastav, S. Saraf, A. S. Bakshi, and S. Bagai (Batra Hospital); S. Warsi (Holy Family Hospital); S. Shakdhar (Jeevan Hospital); B. Oberoi, P. Dewan, and S. K. Sethi (Majeedia Hospital); and M. S. Prasad and I. P. Chaudhary (Safdarjang Hospital).
Footnotes
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Financial support: Department of Vaccines and Biologicals, World Health Organization; Children's Vaccine Program at the Program for Appropriate Technology in Health.
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Potential conflicts of interest: none reported.
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↵a Members of the study group are listed at the end of the text.
- © 2005 by the Infectious Diseases Society of America
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