The COVID-19 Pandemic as an Opportunity for Unravelling the Causative Association between Respiratory Viruses and Pneumococcus-Associated Disease in Young Children: A Prospective Study
Authors: Dagan Ron , van der Beek Bart Adriaan , Ben-Shimol Shalom , Greenberg David , Shemer-Avni Yonat , Weinberger Daniel M. , Danino Dana 
Published: September 2022

SummaryBACKGROUNDIn young children, rates of lower respiratory infections (LRI) and invasive pneumococcal disease (IPD) have been associated with respiratory syncytial virus (RSV), human metapneumovirus (hMPV), influenza (flu), and parainfluenza (PIV) (collectively termed here as pneumonia and pneumococcal disease-associated viruses [PDA-viruses]). However, their contribution to the pathogenesis of these disease endpoints has not yet been elucidated. The COVID-19 pandemic provided a unique opportunity to examine the question.METHODSThis prospective study comprised all children <5 years, living in southern Israel, during 2016 through 2021. The data were previously collected in multiple ongoing prospective surveillance programs and include: hospital visits for community-acquired alveolar pneumonia (CAAP), non-CAAP LRI; nasopharyngeal pneumococcal carriage (<3 years of age); respiratory virus activity; and nationwide, all-ages COVID-19 episodes and IPD in children <5 years. A hierarchical statistical model was developed to estimate the proportion of the different clinical endpoints attributable to each virus from monthly time series data, stratified by age and ethnicity. A separate model was fit for each endpoint, with covariates that included a linear time trend, 12-month harmonic variables to capture unexplained seasonal variations, and the proportion of tests positive for each virus in that month.FINDINGSDuring 2016 through 2021, 3,204, 26,695, 257, and 619 episodes of CAAP, non-CAAP LRI, pneumococcal bacteremic pneumonia and non-pneumonia IPD, respectively, were reported. Compared to 2016-2019, broad declines in the disease endpoints were observed shortly after the pandemic surge, coincident with a complete disappearance of all PDA-viruses and continued circulation of rhinovirus (RhV) and adenovirus (AdV). From April 2021, off-season and abrupt surges of all disease endpoints occurred, associated with similar dynamics among the PDA-viruses, which re-emerged sequentially. Using our model fit to the entire 2016-2021 period, 82% (95% CI, 75-88%) of CAAP episodes in 2021 were attributable to the common respiratory viruses, as were 22%-31% of the other disease endpoints. Virus-specific contributions to CAAP were: RSV, 49% (95% CI, 43-55%); hMPV, 13% (10-17%); PIV, 11% (7-15%); flu, 7% (1-13%). RhV and AdV did not contribute. RSV was the main contributor in all endpoints, especially in infants. Pneumococcal carriage prevalence remained largely stable throughout the study.INTERPRETATIONRSV and hMPV play a critical role in the burden of CAAP and pneumococcal disease in children. Interventions targeting these viruses could have a secondary effect on the burden of disease typically attributed to bacteria.FUNDINGThere was no funding for this study.Research in ContextEvidence before this studyLower respiratory infections (LRI) and invasive pneumococcal disease (IPD) in young children, have often been associated with specific respiratory viruses, namely respiratory syncytial virus (RSV), human metapneumovirus (hMPV) influenza viruses (flu), and parainfluenza viruses (PIV) (termed in the current article pneumonia and pneumococcal disease-associated viruses [PDA-viruses]). However, their causative role as co-pathogens has not yet been fully elucidated. There is already ample evidence that bacteria and viruses interact to cause severe disease. This could be seen after the introduction of pneumococcal conjugate vaccines (PCVs), when there was a significant reduction in hospitalisation for viral lower respiratory infections (LRIs). This suggests that viral-pneumococcal coinfections are common and play a role in the pathogenesis of pneumococcal respiratory infections. To demonstrate the contribution of viruses to the burden of pneumococcal disease specifically, and pneumonia in general, it would be necessary to eliminate one or more of the respiratory viruses. Shortly after the start of the COVID-19 pandemic, multiple reports demonstrated reduced IPD and LRI rates among young children, coincident with dramatically reduced rates of the PDA-viruses globally. Initially, the reduced rates of pneumococcal disease were attributed to non-pharmaceutical interventions that might reduce pneumococcal transmission in the community. However, continuous, virtually unchanged pneumococcal carriage rates were reported in multiple studies, strongly suggesting the reduced circulation ofS. pneumoniaewas not significantly contributing to disease reduction. Surprisingly, pneumococcus-associated diseases and PDA-viruses simultaneously re-emerged in 2021 during the off-season. In contrast to PDA-viruses, other viruses, such as adenovirus and rhinovirus did not show any of the patterns discussed above. We searched PubMed on June 1st, 2022, for studies since 2020 using the following terms: (“COVID-19” or “SARS-Cov-2”) and (“S. pneumoniae” or “pneumococcus” or “IPD” or “respiratory virus” or respiratory syncytial virus” or “hMPV” or “influenza” or “parainfluenza” or “adenovirus” or “rhinovirus” or “lower respiratory infection”). The search was for English literature and unrestricted by date.Added value of this studyThree unique characteristics of the COVID-19 pandemic-induced abnormal dynamics, coupled with multiple ongoing cohort studies in young children, contributed to the historic opportunity to model and quantify the attributable role of the various common respiratory viruses to four pneumococcus-associated disease endpoints (in particular community-acquired alveolar pneumonia (CAAP), non-CAAP LRIs, pneumococcal bacteremic pneumonia and non-pneumonia IPD): First, the full seasonal disappearance of all PDA-viruses shortly after the start of the pandemic, in the presence of continuous, uninterrupted pneumococcal carriage and continuous unchanged rhinovirus and adenovirus activity. Second, the off-season resurgence of the PDA-viruses in 2021. Third, the sequential, rather than simultaneous, re-emergence of the PDA-viruses. The analysis in this study suggests that several of the respiratory viruses, particularly RSV and hMPV, play an important causative role in the pathogenesis of pneumococcal diseases and other respiratory infections. Furthermore, the proportion attributable to each of the PDA-viruses for each of the four studied disease endpoints, and each of the age groups (<1, 1, and 2-4 years of age) could be estimated.Implication of all the available findingsOur findings add evidence about the absolute and relative contribution of common respiratory viruses to the burden of pneumonia and pneumococcal diseases and related conditions in young children. The strong contribution of RSV to disease burden compared to other viruses in all studied disease endpoints suggests that interventions that target viruses could have secondary effects on the burden of diseases typically attributed to bacteria.