Independent and interactive effects of viral species on risk for lower respiratory tract illnesses in early life.

All children experience upper respiratory tract illnesses (URI) caused by viral infections. However, some of these illnesses progress to the lower airways. Although studies have found infection with certain viral species are more likely to trigger lower respiratory illnesses (LRIs), a comprehensive analysis of viruses underlying early-life LRIs is lacking. Determine the incidence of URIs, mild and severe LRIs (mLRI, sLRI) during the first 2 years of life and the association between viral respiratory pathogens and odds of LRIs versus URIs in Puerto Rican children, a population at high risk for respiratory disease. Healthy mother-infant pairs were enrolled in the Puerto Rican Infant Metagenomic and Epidemiologic Study of Respiratory Outcomes birth cohort, in Caguas, Puerto Rico. Infants (n=2,061) were surveilled for respiratory illnesses during the first two years of life (March 2020 to April 2024). Nasal swabs from a subset of 1,363 illnesses from 774 participants were screened for 21 pathogens. Infection with respiratory pathogens. URI, mLRI, and sLRI in the first two years of life. RSV infections occurred in 23% of sLRIs and were associated with dramatically increased odds of sLRI vs URI (OR=9.28; 95% CI, 5.43-15.85). Metapneumovirus, parainfluenza, and non-SARS-CoV-2 coronavirus infections also increased odds of sLRIs. SARS-CoV-2 was associated with lower risk of sLRIs vs. URIs (OR=0.33; 95% CI, 0.16-0.68). Though rhinovirus (43%) and bocavirus (16.1%) were commonly detected in sLRIs, neither was associated with increased sLRI risk. Infection with multiple viral species (i.e. co-infection) occurred in one-third of sLRIs and was associated with 2.92-fold greater odds of sLRI (95% CI, 2.05-4.16) compared to single viral species infections. Rhinovirus-bocavirus was the most common co-infection (32.4%), and interaction between these viral infections was associated with increased sLRI risk (OR=2.21; 95% CI, 1.20-4.09) relative to illnesses that were negative for rhinovirus and bocavirus. A diversity of viral pathogens drive early-life sLRIs. Some viral pathogens (e.g. RSV and metapneumovirus) have intrinsic propensity to cause sLRIs, whereas many sLRIs are caused by viruses whose lower airway pathogenicity is dependent on other factors, including co-infection. Question: How do common respiratory viruses differ in their prevalence and risk of causing severe lower respiratory illnesses (LRIs) during early childhood?Findings: RSV, metapneumovirus, and parainfluenza are independent risk factors for early childhood severe LRIs. While rhinovirus and bocavirus infections alone do not increase the risk of severe LRIs, these two viruses significantly elevate risk when they occur as co-infections.Meaning: Our findings highlight significant variability in viruses that drive severe early-life LRIs. Some viral species appear to inherently predispose individuals to lower airway disease, while for others, the development of disease likely depends on co-infections and/or host susceptibility.