Allergic asthma results from an exaggerated immune response to inhaled allergens. This response leads to eosinophilic airway inflammation, excessive mucus secretion, and bronchial hyperresponsiveness. In early life, many children are sensitized to house dust mite allergens, animal dander, pollen, and fungal spores. Sensitization is established through interactions between epithelial and dendritic cells: epithelial cells respond to allergens by releasing cytokines that activate dendritic cells. These cells migrate to lung-draining lymph nodes and induce the differentiation of naive T cells into type 2 T helper (Th2) cells, which promote asthma pathogenesis.
Asthma most often develops in early childhood and is shaped by multiple risk factors and environmental conditions, including mode of delivery, family size, maternal diet and smoking status, and air pollution. Although early-life infections generally reduce the likelihood of allergy, respiratory diseases – such as those caused by rhinovirus or respiratory syncytial virus (RSV) – are associated with an increased risk of asthma. RSV is highly prevalent among infants, and most experience mild disease; however, 2–3% develop severe bronchiolitis requiring hospitalization. Severe RSV infection early in life can have long-term consequences and is considered a significant risk factor for asthma, particularly in atopic children, although assessing these effects is challenging due to the need for long-term follow-up.
Genetic predisposition also plays an important role: parental asthma markedly increases the risk of asthma in offspring, especially when the mother is affected. Despite this well-established association, the underlying mechanisms remain poorly understood.
A nationwide analysis of nearly 1.5 million Danish children, including approximately 25,000 cases of RSV hospitalization within the first six months of life, showed that parental asthma or allergic rhinitis increases the likelihood of severe RSV infection and subsequent asthma development in children.
Mouse experiments revealed a likely mechanism underlying this association. Maternal allergen-specific antibodies are transferred to newborns and enhance allergen uptake by dendritic cells, leading to subsequent Th2 activation. Th2 activation occurs only in the context of viral infection, which induces increased expression of Fc receptors on neonatal dendritic cells. This mechanism illustrates how inherited allergy and early RSV infection may interact to promote asthma development in high-risk newborns.
Parental Asthma Amplifies the Impact of Early RSV Bronchiolitis on Childhood Asthma Risk
Researchers from Belgium and Denmark analyzed data from more than 1.5 million children in the Danish National Patient Registry. The analysis showed that hospitalization due to RSV bronchiolitis during the first six months of life significantly increased the likelihood of an asthma diagnosis later in childhood. In children without a family history of asthma, this risk was threefold higher compared with uninfected peers.
Parental asthma nearly doubled the risk of asthma development in children who had not been hospitalized with RSV bronchiolitis, compared with children of non-asthmatic parents.
The highest risk was observed in children who experienced both severe RSV bronchiolitis and had an asthmatic mother or father: in this group, the probability of developing asthma exceeded that of control groups by more than four- to fivefold.
Using prescriptions for intranasal corticosteroids as a proxy for allergy revealed that parental allergic rhinitis also increased asthma risk in children. The most significant risk was observed in children with early severe RSV infection and parental allergic rhinitis, particularly maternal.
Thus, severe RSV infection in infancy and familial allergic rhinitis or asthma represent risk factors for future asthma, and their combination confers the highest risk of asthma development.
Mouse Experiments: Neonatal Pneumovirus Infection Promotes Asthma Development
Infection alone enhanced eosinophilic airway inflammation; however, key features of asthma – mucus hyperproduction, bronchial hyperresponsiveness, and enhanced Th2 responses – developed only in offspring of allergic mothers. This effect was accompanied by increased activation and differentiation of allergen-specific Th2 cells, as well as a reduction in regulatory T cells. Paternal asthma had no such effect. These results confirm that early pneumovirus infection and maternal allergy synergistically increase asthma risk in offspring.
Pneumovirus Infection Activates Inflammatory Dendritic Cells That Efficiently Capture Inhaled Allergens
Neonatal pneumovirus infection led to activation of lung dendritic cells (cDCs), which usually maintain tolerance to microbial colonization. In the lungs of infected neonatal mice, inflammatory cDC2 accumulated and expressed activating Fcγ receptors as well as high levels of the costimulatory molecules CD80 and CD86. These cells most effectively stimulated the proliferation of virus-specific CD4 T cells. Inflammatory cDC2 developed only following pneumovirus infection. In offspring of allergic mothers, these cDC2 enhanced the uptake of inhaled allergens via allergen-specific IgG.
Maternal Allergen-Specific Antibodies Amplify Allergic Responses in Newborns After Respiratory Viral Infection
Maternal allergen-specific IgG antibodies are transferred to offspring primarily through lactation via the FcRn receptor. These IgG antibodies enhance antigen uptake and T cell activation in the lungs of pneumovirus-infected neonatal mice.
In offspring that experienced pneumovirus infection, maternal IgG1 and IgG2c increased the proliferation of allergen-specific CD4 T cells and their differentiation into Th2 cells. This effect was abolished when antibodies were not transferred via FcRn or were unable to activate Fcγ receptors. A similar enhancement of Th2 responses was observed when allergen-specific IgG was administered to neonatal mice before infection.
Collectively, these data show that early-life respiratory viral infection programs lung dendritic cells to utilize circulating allergen-specific IgG, thereby amplifying immune responses that underlie the development of allergic asthma.
Immunoprophylaxis of Pneumovirus Infection in Neonatal Mice Markedly Reduces Asthma Risk
Because RSV bronchiolitis is the leading cause of hospitalization during the first year of life and has long-term consequences for lung development, pregnant women are recommended to receive RSV vaccination during the third trimester. For newborns, recommendations include administration of long-acting RSV-neutralizing antibodies to prevent severe bronchiolitis. Both strategies aim to provide newborns with passive immunity to RSV through neutralizing antibodies.
Mouse experiments showed that transfer of RSV-neutralizing antibodies from mothers treated with the monoclonal antibody MPE8 to newborns attenuated virus-induced activation of T cells and dendritic cells. This prophylaxis prevented enhancement of allergen-specific T cell responses, eosinophilic airway inflammation, mucus hyperproduction, and bronchial hyperresponsiveness.
Conclusion
An extensive population-based analysis of nearly 1.5 million children demonstrated that hospitalization with RSV bronchiolitis during the first six months of life significantly increases the risk of subsequent asthma, including in children without a family history of the disease. The risk was highest when early RSV infection was combined with parental asthma or allergic rhinitis.
Mouse experiments confirmed a causal relationship: neonatal pneumovirus infection activates dendritic cells and enhances allergen presentation, leading to pronounced asthma-like changes. RSV immunoprophylaxis in neonatal mice reduced the risk of asthma.
