The interdependencies of viral load, the innate immune response, and clinical outcome in children presenting to the emergency department with respiratory syncytial virus-associated bronchiolitis

Abstract

Respiratory syncytial virus (RSV) causes significant infant morbidity and mortality. For decades severe RSV-induced disease was thought to result from an uncontrolled host response to viral replication, but recent work suggests that a strong innate immune response early in infection is protective. To shed light on host-virus interactions and the viral determinants of disease, copy numbers of five RSV genes (NS1, NS2, N, G, F) were measured by quantitative real-time polymerase chain reaction (qPCR) in nasal wash samples from children with RSV-associated bronchiolitis. Correlations were sought with host cytokines/chemokines and biomarkers. Associations with disposition from the emergency department (hospitalized or sent home) and pulse oximetry O2 saturation levels were also sought. Additionally, RNase P copy number was measured and used to normalize nasal wash data. RSV gene copy numbers were found to significantly correlate with both cytokine/chemokine and biomarker levels; and RNase P-normalized viral gene copy numbers (NS1, NS2, N and G) were significantly higher in infants with less severe disease. Moreover, three of the normalized viral gene copy numbers (NS1, NS2, and N) correlated significantly with arterial O2 saturation levels. The data support a model where a higher viral load early in infection can promote a robust innate immune response that protects against progression into hypoxic RSV-induced lower respiratory tract illness.

Viral Load Dynamics and Clinical Disease Severity in Infants With Respiratory Syncytial Virus Infection

“…On the other hand, it could also be possible that higher RSV loads promote an early robust innate immune response that can protect from disease progression. Supporting the latter, and in agreement with our findings, a recent study conducted in older infants with RSV infection showed that those with milder disease not requiring hospitalization had higher RSV loads, and that VL was significantly correlated with mucosal concentrations of proinflammatory cytokines [5,20].…”

“…Moreover, steroid use is not mentioned in the majority of studies that have analyzed RSV load dynamics. Although with the current study design it not possible to determine whether steroids are responsible for the slower viral decay, indicative of sicker children, or a combination of both, our study suggests that this is an important cofounding factor [5,6,27] that may have contributed to the differences observed. For these models, we used RSV loads and the CDSS at enrollment.…”

“…The variability in clinical presentations is likely the result of a complex interplay between viral factors and the host immune response [4][5][6][7][8][9]. A number of studies with variable designs have examined the association between viral loads (VL) and disease severity, with conflicting results.…”

IL-33 and ST2 as predictors of disease severity in children with viral acute lower respiratory infection

“…On the other hand, a recent publication reported an association between ALRI in children by coronavirus alone or in co-detection with rhinovirus C and severity of the disease, defined as need for admission to the pediatric intensive care unit in our hospital [41]. On regards to viral load, many studies have assessed the role of RSV viral load in predicting worse outcomes, with conflicting results [42]. It has been recently suggested that higher RSV viral loads at presentation elicits a more robust inflammatory response, resulting in faster viral clearance, which could be associated with milder disease [43].…”

Nasopharyngeal CCL5 in infants with severe bronchiolitis and risk of recurrent wheezing: A multi‐center prospective cohort study

“…To examine the robustness of the findings, we conducted a series of sensitivity analyses. First, to address potential dilutions of the specimens, we normalized the CCL5 level by using RNase P (host housekeeping gene) copy number, as we have previously described (6). Second, we performed a subgroup analysis excluding patients who had a breathing problem before the index hospitalization.…”