Noroviruses are a major cause of acute gastroenteritis (AGE) across all age groups. In some countries using rotavirus vaccines, noroviruses have surpassed rotavirus to become the leading cause of severe AGE among children.1,2 Scarce data are available on incidence of severe norovirus disease among children in low- and middle-income settings.2 Moreover, limited data are available on the association of socioeconomic status with norovirus disease rates.3,4 Such data are urgently needed to assess the health value of candidate norovirus vaccines that are in development. We conducted prospective, population-based, active surveillance to determine the incidence of norovirus-associated hospital visits among children in southern Israel. Furthermore, we assessed differences in norovirus rates between Jewish and Bedouin populations with different lifestyle and socioeconomic status.
MATERIALS AND METHODS
Two distinct populations inhabit southern Israel: the Jewish population is primarily a higher income, urban population in contrast to the Bedouin population which is primarily of low–middle income, transitioning from seminomadic rural lifestyle to semi urban settings. The Bedouin population is further characterized by lower socioeconomic status, lower education and crowded living conditions of extended families as compared with the Jewish population. While parity rates are lower in the Jewish population, birth cohorts of both populations in southern Israel are similar in size.5 Both Jewish and Bedouin communities have complete free access to full ambulatory and emergency medical services. Nearly all (~95%) children born at the Soroka University Medical Center (SUMC) in southern Israel also receive all hospital services, including emergency department (ED) services and hospitalization, at SUMC.
We conducted active surveillance for pediatric AGE-associated ED visits and hospitalizations at SUMC since April 2006. Children <5 years of age, residing in Southern Israel, who were examined at the ED due to AGE were offered study participation after parental written consent was granted. AGE was defined as ≥3 liquid or semi-liquid stools/24 h or forceful vomiting (excluding post-tussive vomiting) lasting <7 days. Demographic and clinical information was documented including patient disposition and a stool sample was collected from all patients. From April 1, 2006 to March 31, 2013, 6780 patients were enrolled in the study. A stool sample of every 10th consecutive patient was tested for norovirus by using real-time reverse transcriptase-polymerase chain reaction and positive stools were genotyped by conventional reverse transcriptase-polymerase chain reaction and sequencing.
To calculate numerators for norovirus-associated ED visits and hospitalizations, a child discharged from the ED was counted as an ED visit and a child hospitalized was counted as a hospitalization. Because all children are seen at the ED before hospitalization, ED visit or hospitalization was mutually exclusive for incidence numerator counting purposes (ie, a child admitted from the ED to the hospital was counted as a hospitalization but not an ED visit). To extrapolate norovirus rates from the sampled population to the entire population examined at SUMC due to AGE during the study period, first we assumed similar norovirus infection rates among the patients who were tested for norovirus (every 10th enrolled child) and those enrolled but not tested. Then, for eligible children who were not enrolled (eligible children whose parents refused enrollment or children missed due to ED visit during out-of- working hours), we chose to use a conservative approach in which the assumption was that norovirus rates among these patients were only half, compared with children who provided samples. This conservative approach was based on the assumption that some of these patients would not have met the case definition, if they were screened during regular work hours. Preliminary analysis of the data showed 56% of eligible ED patients and 94% of eligible hospitalized patients were enrolled. Extrapolation was conducted separately for each ethnic group (Jewish and Bedouin children), and each age group (0–11, 12–23, 24–35, 36–47 and 48–59 months), and separately for hospitalized children and for ED visits. Study enrollment was interrupted during April to October 2009 due to lack of funding for that period and extrapolation for the interrupted period was conducted as described above for eligible children not enrolled using data for the same calendar months from other years.
Annual population denominators were obtained from the Israel Bureau of Statistics birth registry.5 Because there is little population mobility in southern Israel and child mortality is low, we assumed the number of births serves as a good proxy for population denominators. Incidence was calculated as number of ED visits or hospitalizations per person year by age group and ethnicity. We calculated confidence intervals for proportions using Wilson score interval and used conditional maximum likelihood estimate for rate ratio (RR) calculations.
Overall, norovirus infection was detected in 67 (10%) of 673 children tested, and co-infection with rotavirus was detected in 2 of these 67 norovirus cases. Nearly all norovirus cases (65/67, 97%) were detected among children <2 years of age (see Table, Supplemental Digital Content 1, http://links.lww.com/INF/C175). Norovirus accounted for 44/480 (9%) AGE hospitalizations and 23/193 (12%) AGE ED visits (P = 0.35).
The estimated annual incidences of norovirus hospitalizations and ED visits [95% confidence interval (CI)] among children <5 years were 10.4 (9.5–11.3) and 9.9 (9.0–10.7) per 10,000 person-years, respectively (Table 1). Among children aged <1 years, the annual incidence of norovirus hospitalizations and ED visits was 39.1 (35.4–42.8) and 36.5 (32.9–40.1) per 10,000 person-years, respectively.
Norovirus hospitalization rates among Bedouin children aged <5 were 13.9 (12.4–15.3) per 10,000 person-years as compared with 7.1 (6.1–8.1) among Jewish children (RR 2.0, 95% CI: 1.6–2.3). These differences were most prominent among infants (aged <1 year): norovirus hospitalization rate among Bedouins was 59.7 (53.2–66.2) per 10,000 person-years as compared with 19.7 (16.0–23.4) among Jews (RR: 3.0, 95% CI: 2.5–3.8).
Genogroup II, genotype 3 (GII.3) viruses were detected in 14 (21%) samples, followed by GII.4 Den Haag 2006 (n = 10, 15%), GII.4 Yerseke 2006a (n = 7, 10%), GII.4 New Orleans 2009 (n = 4, 6%), GII.4 Sydney 2012 (n = 4, 6%) and GII.4 Osaka 2007 (n = 3, 4%) GII.4 Farmington Hills (n = 2, 3%) and GII.4 untypeable (n = 1, 1%). Other genotypes were identified in ≤2 patients (see Table, Supplemental Digital Content 2, http://links.lww.com/INF/C176). Genotype distribution was similar between the Jewish and Bedouin populations, except GII.4 Sydney 2012 which was detected only in Bedouin children).
We conducted a prospective, population-based study of norovirus-associated hospitalizations and ED visits among 2 distinct pediatric populations in southern Israel—Jewish and Bedouin. Most norovirus cases and most norovirus-associated hospitalizations occurred among children <2 years of age. While the overall incidence of norovirus hospitalizations among children <5 years in Israel was similar to that reported elsewhere,1 incidence rates were greater among Bedouin compared with Jewish children. In particular, among Bedouin infants (<1 year old), the incidence of norovirus-associated hospitalizations was 3 times that of Jewish children. We estimated that annually, approximately 1 of every 168 Bedouin infants was hospitalized with norovirus as compared with 1 of every 508 Jewish infants.
The Jewish and Bedouin populations of southern Israel are distinctive in socioeconomic, cultural and genetic characteristics. Previous studies have linked the prevalence of norovirus to lower socioeconomic status3 and crowded living conditions that may facilitate norovirus transmission.4 Expression of different histo-blood group antigens may explain the difference in disease incidence between Bedouin and Jewish children.6 Rotavirus-associated hospitalization rates were also shown to be higher among Bedouin infants as compared with Jewish infants in southern Israel.7 Socioeconomic and genetic factors were implicated in clonal distribution of pneumococcal serotypes between the 2 populations.8
The overall rate of norovirus-positivity in children of southern Israel (10%) is similar to that reported in a meta-analysis of pediatric norovirus hospitalizations and ED visits worldwide.9 Higher proportions of norovirus cases were noted in infants and 1 year old children compared with 2–4 year old children. A previous study conducted in northern Israel estimated the incidence of norovirus hospitalizations among children aged that <5 years was 33/10,000;10 however, our results, based on a prospective, population-based surveillance are comparable to results from other studies from high income countries with similar methodology.1
Our study has several limitations. For logistical reasons, norovirus testing was performed on a relatively small sample (10%) of enrolled patients, and, thus, the results may not be fully representative of the entire population. In Israel, global vaccination against rotavirus began in December 2010. Due to the short period of postvaccine study enrollment, we were unable to assess norovirus hospitalization rates in the postrotavirus vaccine period as compared with prevaccine rates. We used a conservative extrapolation method assuming that norovirus rates among children not enrolled were approximately half of those of eligible patients. This may have resulted in an underestimation of disease incidence, especially for ED visits.
In summary, we report a substantial burden of norovirus-associated hospital visits, highest among infants and young children. Higher incidence was observed among Bedouin infants as compared with Jewish infants in Southern Israel. This finding mandates further examination of the possible causes including a comparison of the demographic characteristics and clinical presentation of severe norovirus cases. Better understanding of norovirus disease burden in pediatric population at low–middle income countries is essential for continued prevention and vaccine development efforts.
The authors thank Eileen Brown for excellent technical assistance and Bart A. van der Beek for his hard work and contribution to the manuscript.
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