Age-dependent Interactions Among Clinical Characteristics, Viral Loads and Disease Severity in Young Children With Respiratory Syncytial Virus Infection

Abstract

Background: Age-dependent differences in clinical presentation and viral loads in infants and young children with respiratory syncytial virus (RSV) infection, and their correlation with disease severity are poorly defined.

Methods: Previously healthy children <2 years old with mild (outpatients) and severe (inpatients) RSV infection were enrolled and viral loads measured by polymerase chain reaction in nasopharyngeal swabs. Patients were stratified by age in 0-<3, 3-6 and >6-24 months, and multivariable analyses were performed to identify clinical and viral factors associated with severe disease.

Results: From 2014 to 2018, we enrolled 534 children with RSV infection, 130 outpatients with mild RSV infection and 404 inpatients with severe RSV disease. Median duration of illness was 4 days for both groups, yet viral loads were higher in outpatients than in inpatients (P < 0.001). In bivariate analyses, wheezing was more frequent in outpatients of older age (>3 months) than in inpatients (P < 0.01), while fever was more common in inpatients than outpatients (P < 0.01) and its frequency increased with age. Adjusted analyses confirmed that increased work of breathing and fever were consistently associated with hospitalization irrespective of age, while wheezing in infants >3 months, and higher RSV loads in children >6-24 months were independently associated with reduced disease severity.

Conclusions: Age had a significant impact defining the interactions among viral loads, specific clinical manifestations and disease severity in children with RSV infection. These observations highlight the importance of patient stratification when evaluating interventions against RSV.

Figure 1.. Sign and Symptoms according to disease severity and age in infants with RSV infection.

Most relevant signs and symptoms were stratified in outpatients (orange) vs inpatients (blue) by age in (A) <3 months, (B) between 3 and 6 months, and (C) > 6 to 24 months of age. The Y axis represents the signs and symptoms in the two disease severity groups and the X axis the frequency of that specific symptom (%). Numbers next to bars represent the exact number of patients with that specific sign/symptom. Comparisons by Fisher exact test. Symbol (*) indicate significant 2-sided p values. WOB: work of breathing; bP: by parental report; PR: by physician report.

Figure 2.. Viral load differences according to age in infants with RSV infection.

The Y axis represents RSV loads in log10 copies/mL and the X axis differences in viral loads in outpatients (orange) and inpatients (blue) in the three age groups. Comparisons by Mann Whitney test, two-tailed p values are provided in the graphs.

Figure 3.. Association between viral loads and age in inpatients and outpatients with RSV infection.

Viral loads for RSV inpatients (left panel; tile dots) and outpatients (right panel; orange dots) according to age are represented using locally estimated scatterplot smoothing (LOESS) curves (in blue), which summarize the association into a single line without imposing constraints such as linearity. Based on polynomial and restricted cubic spline regression there were no significant non-linearity associations, and so linear regression lines (in black) were also fitted to the data. Mean RSV loads (log₁₀ copies/mL) are lower by 0.02 per month for the inpatient cohort, and are higher by 0.02 per month among the outpatient group.