Risk factors and patterns of household clusters of respiratory viruses in rural Nepal

Scott, E. M.; Magaret, A.; Kuypers, J.; Tielsch, J. M.; Katz, J.; Khatry, S. K.; Stewart, L.; Shrestha, L.; LeClerq, S. C.; Englund, J. A.; Chu, H. Y.

Our study has several limitations. Asymptomatic infections were not captured, affecting our ability to fully characterise the transmission chain. We expect that asymptomatic transmission may have impacted our ability to characterise HRV spread, particularly in transmission involving older children and adults, our ability to associate age of index case with transmission risk [30, 39] . Moreover, we likely only captured a minority of adult illness as adults required subjective fever for specimen collection and fever occurs infrequently in adult RSV, MPV and HRV illness [7 40 ]. While we underestimated transmission, specifically spread involving individuals ⩾5 years, due to our symptom criteria, a previous study of RSV transmission demonstrated that the odds of transmission in symptomatic infection is five times that of asymptomatic infections [28] . This suggests that we likely captured index infections. We anticipate that some illness with shedding <7 days may have been missed due to our weekly surveillance. We expect that this represented a small minority of illness episodes as the estimated shedding duration of HRV and RSV in adults is 10 and 9 days, respectively [30, 31] . Shedding for 1-2 weeks is common with paediatric respiratory infections [31] . Moreover, while we performed sequencing on RSV and HRV samples involved in transmission chains, we were not able to phylogenetically verify transmission in the majority of episodes due to high cycle threshold values, and could not use sequencing data to define transmission. Our sequencing results revealed a degree of misclassification with some HRV and RSV transmission events representing illness clusters with multiple virus types circulating in the household simultaneously. This was especially true for HRV, a finding in agreement with previous studies of HRV transmission, including in household and daycare settings [30, 39 41] . Additionally, some households originally selected for the household substudy were not surveyed as intended. Individuals within selected households who were not surveyed were primarily adults. Among adults, males and those <40 years old were surveyed less frequently, a group not considered high risk for household transmission of respiratory viruses in previous studies. A significant proportion of the Sarlahi population, especially men, are reported as absent from home, supporting the possibility that some household members were absent from the community during the study, although these data were not captured [36] . We also surveyed a higher proportion of preschool children compared to school-aged children. The differential exclusion of these subsets may have affected our results, including identification of index cases, especially if these persons were periodically present in the household. Lastly, we did not collect data on the social mixing patterns of individuals in these households which would have provided valuable information regarding possible causal explanations for our findings.