This is the first study that reports the frequency of the four recognized HCoV species among hospitalized children and asymptomatic controls in several regions of the United States during multiple years. No statistically significant increase was observed in the rates of detection for HCoV or for any of the four individual species of HCoV among the hospitalized cases when compared with the controls, regardless of whether the 27% of hospitalized children who were coinfected with IV, RSV, HPIV, or HMPV, were excluded. The children hospitalized for ARI/fever in whom HCoV alone was detected appeared to be less severely ill than children with IV, RSV, HPIV, or HMPV infections, and the particular association observed between species NL63 and croup was consistent with other studies27–29
. In addition, children coinfected with HCoV and other respiratory viruses were clinically similar to those infected only with IV, RSV, HPIV, or HMPV. This suggests that the other viruses rather than HCoV were responsible for the hospitalization.
The prevalence of HCoV species appeared episodic over the five seasons, with two years of lower overall activity separating several years of higher activity. A similar episodic pattern was reported by another study.7
However, a study of HCoV seasonality over 20 years that did not include species HKU1 showed a high degree of year-to-year variability without a clear episodic pattern.17
While we cannot ascertain a definitive epidemic pattern with five years of data, this study confirms the variable nature of HCoV circulation using sensitive methods of molecular detection.
Overall, our finding of no association between HCoV infection and serious illness among hospitalized children bolsters the findings of several prior studies.19–21
A 2004–05 study from Thailand among patients of all ages and asymptomatic outpatient controls found no association between HCoV infection and hospitalization for pneumonia.19
However, they observed fewer cases, with detection rates of 1.8% among cases and 2.1% among controls, and the number of asymptomatic controls enrolled was relatively small compared with our study (280 over one year versus 742 over two years). A more recent study comparing hospitalized Alaskan Native children less than three years of age and asymptomatic community controls found HCoV detection rates were the same for cases and controls (4%).20
In a prospective community-based birth cohort study, species 229E and OC43 were detected at similar frequencies among symptomatic (5.5%) and asymptomatic children (4.4%), and neither species was detected in a specimen taken during an ARI episode that required hospitalization.21
In contrast to our study, a three-year study of pediatric and adult inpatients and outpatients from the United Kingdom noted that 1.71% of those with lower respiratory tract infection were singly infected with HCoV compared with 1.08% among those with no respiratory symptoms.18
However, the age distribution and sample size for those without symptoms were not described and a test for statistical significance was not provided.
Limitations of our study include the fact that the three geographic areas in this study may not be representative of the rest of the United States. Also, we did not assess bacterial coinfections or antibiotic use, which could have impacted the clinical outcomes for those children who were hospitalized. Our study did not collect data about respiratory symptoms before or after enrollment. Both cases and controls may have tested positive for HCoV from a very recent infection and developed symptoms after enrollment. Since prior studies have noted that HCoV may be shed at least 14 days after acute infection30, 31
, it is possible that controls with HCoV detected may have been shedding HCoV from a recent, symptomatic infection. However, this is also true for the hospitalized children, and few children with HCoV had medically-attended visits for respiratory illness in the month prior to enrollment. Another possible limitation is that asymptomatic children were not enrolled year-round, but the peak periods of HCoV circulation were included. Finally, we did not test the controls for the additional respiratory viruses for which the hospitalized children were tested.
This large prospective, multicenter, population-based study of HCoV infections among both cases and controls over several seasons found no association between hospitalization for ARI/fever and HCoV infection. This type of study, however, cannot rule out the possibility that the infection was causal in a subset of the children. It is possible that host factors are of primary importance in responding to HCoV infections, and further study of the relevance of host or other co-factors in symptomatic illness would help move the field forward. Furthermore, since very few studies of the known HCoVs have included a robust sample size, multiple years, and a control group, more studies would be helpful to verify the findings of this study. Given the low prevalence of hospitalized HCoV cases, the frequency of viral coinfection, and the differences in yearly circulation patterns, conducting future studies with larger numbers of cases and well-matched controls will be challenging. However, new multipathogen PCR platforms may provide opportunities for future studies of respiratory disease that include HCoV. Biopsy and autopsy studies with in situ identification of HCoV and microscopic assessment of fatal cases might also help elucidate viral etiology. Studies utilizing a variety of research strategies are needed to better delineate the role of HCoV infections among children.