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

Abstract

BACKGROUND: In young children, rates of community-acquired alveolar pneumonia (CAAP) or invasive pneumococcal disease (IPD) have been associated with respiratory syncytial virus (RSV), human metapneumovirus (hMPV), influenza (flu), and parainfluenza (PIV) (collectively termed here as pneumococcal disease-associated viruses [PDA-viruses]). However, their contribution to the pathogenesis of pneumococcal-associated disease has not yet been elucidated. The COVID-19 pandemic provided a unique opportunity to examine the question. METHODS: This prospective study comprised all children <5 years, living in southern Israel, during 2016 through 2021. The data were derived from multiple ongoing prospective cohort surveillance programs and include: hospital visits for CAAP, non-CAAP lower respiratory infections (LRI); nasopharyngeal pneumococcal carriage (<3 years of age); respiratory virus activity; all-ages COVID-19 episodes; and IPD in children <5 years (nationwide) A hierarchical negative binominal regression model was developed to estimate the proportion of the disease outcomes attributable to each of the viruses from monthly time series data, stratified by age and ethnicity. A separate model was fit for each outcome, 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. FINDINGS: During 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 outcomes 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 outcomes 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 outcomes. 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 outcomes, especially in infants. Pneumococcal carriage prevalence remained largely stable throughout the study. INTERPRETATION: RSV 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 disease burden typically attributed to bacteria.

Bacterial nasopharyngeal colonisation in children in South Africa before and during the COVID-19 pandemic: an observational study

“…Furthermore, there was a lower density of overall and non-typeable S pneumoniae colonisation during the COVID-19 compared with pre-COVID-19 periods. This finding is in contrast to an Israeli study which did not report any reductions in the pneumococcal carriage density in children younger than 5 years, 13 although in that study semi-quantitative methods were used to measure density, which could have contributed to the difference between the studies. Nevertheless, it is plausible that the lower rates of invasive pneumococcal disease reported in our setting during the COVID-19 pandemic were a result of the net reduction in overall pneumococcal density, as higher density of colonisation is a risk factor for pneumococcal disease.…”

“…This possible effect is further corroborated by findings in Israel which reported a temporary decline in invasive pneumococcal disease in children during the COVID-19 pandemic that was associated with the decline in the prevalence of respiratory virus infections. 13 …”

RSV and Rhinovirus asymptomatic upper airway infection increases pneumococcal carriage acquisition rates and density in adults whereas nasal inflammation is associated with bacterial shedding

“…The non-specified time of viral infection onset and the lack of symptoms may have masked viral-induced nasal inflammation and the optimum effect that certain respiratory viruses have on carriage acquisition. However, our results reflect some of the viral-pneumococcal associations described in large epidemiological studies, as in the case of highly influential RSV [8,10,51,52] protect against a limited number of the most invasive serotypes. After interaction with certain viruses, less invasive, non-vaccine serotypes may exhibit heightened ability to invade or exit the human host.…”

Anstieg invasiver Erkrankungen durch Streptokokken und komplizierte Pneumonien zum Ende der COVID-19-Pandemie

“…Die resultierende Hypothese war, dass die verringerte Infektionsrate von Viren, die mit Pneumokkokken interagieren, eine Folge des Rückgangs der Inzidenz von IPD während der Pandemie mit NPI ist [14] (Übersicht auch bei Chow EJ et al [5]). Die gleiche Arbeitsgruppe konnte in einer prospektiven Untersuchung zeigen, das RSV, hMPV, Parainfluenzavire (PIV) und Influenza mit dem Auftreten von pCAP und PID assoziiert sind, RV, herkömmliche Coronaviren und Adenoviren (AV) dagegen nicht [24]. Konfirmiert werden diese Daten u. a. durch eine in Quebec/Kanada durchgeführte populationsgestützte Analyse von IPD-Surveillance-und Labor-Surveillance-Daten, die einen Anstieg der IPD-Inzidenz weit über die präpandemischen Zahlen koinzident mit der RSV-Saison bei Kindern unter 5 Jahren, nicht aber bei älteren Menschen mit deutlich geringerer Inzidenz von RSV-Nachweisen zeigte [25] sowie eine französische multizentrische Untersuchung [15].…”