Respiratory viral infections in infants: causes, clinical symptoms, virology, and immunology

Abstract

In global terms, respiratory viral infection is a major cause of morbidity and mortality. Infancy, in particular, is a time of increased disease susceptibility and severity. Early-life viral infection causes acute illness and can be associated with the development of wheezing and asthma in later life. The most commonly detected viruses are respiratory syncytial virus (RSV), rhinovirus (RV), and influenza virus. In this review we explore the complete picture from epidemiology and virology to clinical impact and immunology. Three striking aspects emerge. The first is the degree of similarity: although the infecting viruses are all different, the clinical outcome, viral evasion strategies, immune response, and long-term sequelae share many common features. The second is the interplay between the infant immune system and viral infection: the immaturity of the infant immune system alters the outcome of viral infection, but at the same time, viral infection shapes the development of the infant immune system and its future responses. Finally, both the virus and the immune response contribute to damage to the lungs and subsequent disease, and therefore, any prevention or treatment needs to address both of these factors.

FIG. 1.

Interplay of factors that cause disease following respiratory viral infection and impact of infancy. The ultimate cause of illness/disease following respiratory viral infection is airway occlusion, which leads to a reduction in gaseous exchange, leading to respiratory distress. This airway occlusion can be either immune or virally mediated and most probably is a combination of both. Early life has an effect on both virus- and immune-mediated damage. The infant immune system is skewed to a hyporesponsive phenotype, with a reduced type I interferon response leading to a higher viral load. The adaptive immune response is also skewed and limited in its effect. These factors act in combination with small body size and small airways to further increase disease severity.

FIG. 2.

Viral detection and viral evasion. (A) Viral detection by the innate immune system. Respiratory viruses are detected extracellularly by TLR2, TLR4, and TLR6; in the endosome by TLR3, TLR7, and TLR9; and in the cytoplasm by RIG-I (retinoic acid-inducible gene I), MDA-5 (melanoma differentiation-associated gene 5), and NLRP3 (NLR family, pyrin domain-containing 3). (B) Viral evasion of the innate immune system. Viruses inhibit the pattern recognition receptors RIG-I and MDA-5 and the downstream molecules IRF3, NF-κB, and JAK/STAT. In some cases the viral protein that inhibits the response has been identified. Abbreviations: AV, adenovirus; CoV, SARS coronavirus; hMPV, human metapneumovirus; IV, influenza virus; PIV, parainfluenza virus, RSV, respiratory syncytial virus; RV, rhinovirus; TLR, Toll-like receptor; IFNAR, interferon alpha receptor; ORF, open reading frame; CASP-1, caspase 1; NS, nonstructural.

FIG. 3.

The paradox of early-childhood immune hyporesponsiveness and virally induced immunopathology. Shown are possible mechanisms by which increased immunopathology may occur in the context of dampened responses to infection in infants. Similar levels of pattern recognition receptors are detectable for infant and adult leukocytes. However, the molecules that transduce the signal, e.g., IRF3 and IRF7, have reduced function. This leads to an altered immune response, with higher viral load, decreased immunoregulation (via IDO [indoleamine 2,3-dioxygenase]), and skewed cytokine production, all of which may increase damage caused by the immune response. Abbreviations: PRR, pattern recognition receptor; IRF, interferon response factor.