Norovirus-associated diarrhea and asymptomatic infection in children aged under 4 years: a community-cohort study in the Philippines

Abstract

Objectives: This study aimed to estimate the incidence of norovirus (NoV)-associated diarrhea and asymptomatic infections in children under 4 years of age and identify the genotypes of multiple NoV infections.

Methods: A community-based cohort study was conducted in Tarlac, Philippines. Children aged 0-2 years were followed up for 2 years. The prevalence and incidence rates of NoV-associated diarrhea and asymptomatic infections were calculated. Risk factors were assessed using the Cox proportional hazards model. The genotypes and immunotypes of repeated infections were tabulated.

Results: A total of 338 children aged 6208 child-months were analyzed. NoV was detected in 17.4% (84 of 527, 95% confidence interval [CI]: 12.7-19.7%) of diarrheal episodes and 10.8% (219 of 2031, 95% CI: 9.4-12.3%) of asymptomatic stool samples. The highest incidence of NoV-associated diarrhea occurred in children aged 6-11 months (2.31 per 100 child-months, 95% CI: 1.30-3.32) and 18-23 months (2.34 per 100 child-months, 95% CI: 1.57-3.12), whereas the highest incidence of asymptomatic NoV infection was observed in children aged 12-23 months (4.49 per 100 child-months, 95% CI: 3.41-5.56). Repeated NoV infections were detected between different genotypes, except in two children who had repeated NoV GI.3 and two children with GI.9 infections.

Conclusions: Children had the highest risk of NoV-associated diarrhea during their first year of life, whereas asymptomatic NoV infections persisted after the second year. Repeated NoV infections suggest genotype-specific immunity after NoV infection.

Keywords: Asymptomatic; Children; Community; Diarrhea; Norovirus; Repeated infection.

Figure 1

Prevalence and incidence rate of NoV infection by age. (a) Prevalence (%) of NoV in diarrheal episodes and non-diarrheal stool samples by age group. In total, 2558 stool samples were included from 338 cohort children aged less than 2 years, including 527 diarrheal stool samples and 2031 non-diarrheal stool samples. Error bars represent standard error of the prevalence. (b) Incidence of NoV infection every 6 months of age. The overall incidence rates for NoV-associated diarrhea and asymptomatic infection were 1.35 and 3.53 per 100 child-months, respectively. Error bars represent the 95% confidence interval of incidence. NoV, norovirus.

Figure 2

Pairwise comparison of NoV repeated infection by capsid genotype and immunotype. (a) The matrix shows the pairwise comparison of NoV genotypes in previous and later infections. The columns represent previous infections and rows represent later infections in the repeated infection pairs. The numbers in the cells show the number of infections observed. (b) Matrix tabulated by immunotype in previous and later infections. Three repeated infections were observed in immunotype C and three repeated infections in immunotype J. (c) The difference in symptom between previous and later infections by genotypes. Red represents symptom in later infection increased, whereas green stands for symptom in later infection reduced. The symptom in the repeated infections was compared by computing the difference from clinical score. Severity of infection was evaluated based on the Vesikari clinical score. The severity of asymptomatic infections was considered as 0. Nine infections without fulfilling diarrhea criteria but with other gastroenterological symptoms within 7 days were scored 1 in the clinical score. The changes of symptom increased, reduced, or the same in the later infection were marked as +1, −1, or 0, respectively. The mean of the sum of differences were computed to describe the pattern of symptom changing in repeated infections using heatmap. (d) The difference in symptom between previous and later infections by immunotypes. Same color in panel a and b represents same immunotype: immunotype A (white), GI.1; immunotype B (light blue), GI.2, GI.4, GI.5 and GI.6; immunotype C (yellow), GI.3, GI.7 and GI.9; immunotype E (red), GII.2; immunotype F (purple), GII.3; immunotype G (green), GII.4; immunotype H (indigo), GII.6; immunotype I (brown), GII.7 and GII.14; immunotype J (grey), GII.13 and GII.17; immunotype K (deep blue), GIX.1. Genotype IX.1 was previously named as GII.15 and recently redesigned as GIX.1. GI: Genogroup I; GII: Genogroup II; NoV: norovirus.