Author: Nada El Gallad
Respiratory Syncytial Virus (RSV) is widely recognized as a leading cause of acute lower respiratory tract infections (ALRTIs), such as bronchiolitis, in young children, leading to significant morbidity, mortality, and a substantial burden on healthcare systems. Italian data (2014–2023) show that over 70% of hospitalizationsconcern infants under 1 year of age, with a seasonal peak between November and March. Increasing scientific evidence highlights the long-term effects of the acute phase of RSV infection, particularly recurrent wheezing and asthma. Understanding the connection between early-life RSV infection and chronic respiratory sequelae is crucial for pediatricians to improve risk stratification, early intervention, and long-term outcomes, especially concerning the future asthma diagnosis in children.
The Clinical Impact of RSV Infection on Hospitalized Infants up to 1 Year of Age
Every year, RSV causes millions of acute respiratory infections and bronchiolitis in children under 5, with the highest impact on infants. A recent 9-year observational study conducted by Lodi et al. (2024)—”Epidemiology of respiratory syncytial virus in hospitalized children over a 9-year period and preventive strategy impact,” published in Frontiers in Pharmacology—in Italy showed that 70% of children hospitalized with RSV were under 1 year old, and approximately 50% were under 3 months old. Furthermore, in premature infants, immune system immaturity and reduced secretory IgA production increase the risk of lung damage and subsequent bronchial hyperresponsiveness.
The clinical presentation of RSV bronchiolitis is characterized by acute inflammation, edema, and necrosis of the small airways, leading to increased mucus production and bronchospasm. Symptoms range from nasal congestion and tachypnea to wheezing and, in severe cases, respiratory failure requiring intensive care. Prematurity is a major comorbidity, as preterm infants have an immature immune system that makes them highly susceptible to severe, potentially life-threatening RSV disease course and its long-term complications.
Clinical Predictive Factors and Risk Factors for Recurrent Wheezing and Asthma
Various clinical, immunological, and environmental factors influence the individual risk and severity of respiratory evolution. For recurrent wheezing and asthma following an RSV infection, the main predictive factors include:
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Prematurity;
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Age under 6 months;
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Severity of the primary RSV infection, indicated by the need for hospitalization, prolonged hospital stays, or intensive care unit (ICU) admission;
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Allergic sensitization and environmental factors such as secondhand smoke and pollution;
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Clinical signs like tachypnea and fever during the acute phase.
These elements contribute to determining the probability of developing chronic asthma after an episode of bronchiolitis, which is key for diagnosing asthma in children effectively.
Molecular, Immunological, and Genetic Mechanisms of Post-RSV Asthma
The risk of asthma in children hospitalized for RSV in the first 6 months can increase up to 40–50% by age 5, highlighting the challenge in pediatric asthma diagnosis.
Age at Infection
Early exposure to RSV, particularly under 6 months of age, is linked to more severe disease and a greater risk of subsequent wheezing and asthma. The study “Epidemiology of respiratory syncytial virus in hospitalized children over a 9-year period and preventive strategy impact” observed that children who were 4 months old during the peak viral season had the highest risk of bronchiolitis and subsequent asthma.
Genetic and Immunological Susceptibility
An immune profile dominated by Th2 and Th17 lymphocytes, which promotes the production of cytokines like IL-4, IL-5, and IL-13, is a predisposing factor for chronic wheezing and asthma. This response mirrors the inflammatory infiltrate observed in atopic and asthmatic subjects. Genetic polymorphisms in genes regulating chemokines (e.g., CCL5) and cytokines (e.g., IL-4, IL-13) can also increase susceptibility.
Environmental and Host-Related Factors
Exposure to secondhand smoke (both prenatal and postnatal), air pollution, and low socioeconomic status constitute additional risk factors. Host-related factors such as a history of atopy (e.g., eczema, food allergies) and microbiome alterations can also strongly contribute to the risk of an eventual asthma diagnosis in children.
Quantitative Data on Post-RSV Respiratory Sequelae
| Category | Quantitative Data Points (Source/Significance) |
| 1. Epidemiological Data | |
| Incidence of Wheezing/Asthma Post-RSV Infection | Longitudinal studies show that 30–50% of children hospitalized for RSV develop recurrent wheezing, and 20–30% develop asthma by age 6 (Sigurs et al., Am J Respir Crit Care Med, 2010). |
| Age of Highest Risk | The highest risk is in infants infected before 6 months, with a 2–3 times greater probability of subsequent wheezing (Stensballe et al., BMJ, 2019). |
| Prematurity | Preterm infants (<35 weeks) have a 3.5x relative risk of RSV hospitalization and 2xof developing asthma compared to full-term infants (Hall et al., Pediatrics, 2013). |
| 2. Immunological and Genetic Data | |
| Th2-Th17 Profile | Studies on nasal and bronchoalveolar samples show a significant increase in IL-4, IL-5, and IL-13 in children who develop post-RSV asthma (Heikkinen et al., J Allergy Clin Immunol, 2020). |
| Genetic Polymorphisms | Mutations in the promoters of IL-13 and CCL5 are associated with an OR 1.8–2.1 for persistent wheezing after RSV (Puthothu et al., J Infect Dis, 2008). |
| 3. Environmental and Socio-Demographic Data | |
| Secondhand Smoke | Prenatal/postnatal exposure to secondhand smoke increases the probability of wheezing after RSV by 25–30% (Carlsen et al., Eur Respir J, 2020). |
| Air Pollution (PM2.5) | Each 10 $\mu$g/m$^3$ increase in PM2.5 is associated with a 12% increase in the risk of chronic post-RSV wheezing (Zhang et al., Lancet Planet Health, 2022). |
| 4. Long-Term Outcomes | |
| Duration of Post-RSV Risk | The RSV–asthma association remains significant up to 10 years of age in longitudinal follow-ups (Sigurs et al., 2010). |
| Overall Relative Risk | Children infected with RSV within the first year of life show an overall 3x risk of developing persistent asthma compared to controls (Stein et al., N Engl J Med, 1999). |
Biomarkers Indicating Risk, Severity, and Predictive Pediatric Asthma Diagnosis
Emerging biomarker research shows a potential approach for identifying children at high risk for severe RSV disease and its long-term sequelae. Various molecules measured in blood, serum, and nasopharyngeal aspirates (NPA) can serve as prognostic indicators. Key biomarkers include:
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Severity Markers: Elevated levels of cytokines and chemokines such as IL-6, IL-8, IL-33, TSLP, and IFN-$\alpha$ in nasopharyngeal aspirates are associated with disease severity. For example, high levels of IL-33 in NPAs are correlated with the need for respiratory support. LDH in nasopharyngeal samples has also shown high predictive value for disease severity.
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Recurrent Wheezing/Asthma Markers: Some biomarkers can help predict the progression towards chronic respiratory disease. Elevated serum levels of periostin and eosinophil-derived neurotoxin (EDN) are linked to the development of future wheezing episodes and asthma, which aids in diagnosing asthma in children early. Similarly, high levels of IL-3 and IL-12 in bronchoalveolar lavage fluid (BALF) of infants with RSV bronchiolitis are associated with the development of these conditions.
| Biomarker | Sample | Clinical Significance |
| IL-33, IL-6, IL-8, IFN-$\alpha$, TSLP | Nasopharyngeal Aspirate / Serum | Predictive of acute severity |
| MUC5AC, LDH | Nasal Aspirate | Epithelial damage and inflammatory response |
| Periostin, EDN, CD14, IL-3, IL-12 | Serum / BAL | Predictive of long-term wheezing or asthma (Crucial for Pediatric Asthma Diagnosis) |
Prevention Strategies: The Pillar of Management
Given the significant short- and long-term disease burden of RSV, prevention is of paramount importance. Key strategies include:
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Immunoprophylaxis: Long-acting monoclonal antibodies like nirsevimab have represented a major breakthrough. Administered in a single dose, nirsevimab provides passive immunity for the entire season and has demonstrated high efficacy in preventing RSV-related hospitalizations in all infants, including healthy term newborns. Real-world studies are confirming its efficacy.
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Maternal Vaccination: The RSVpreF vaccine (Abrysvo®), administered to mothers during pregnancy, induces the production of high levels of neutralizing antibodies that are passed to the newborn, offering crucial protection during the most vulnerable first months of life.
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Non-pharmacological Interventions: Basic hygiene measures, such as frequent hand washing and avoiding crowded places during the RSV season, represent a simple yet effective strategy to limit transmission, especially for the youngest infants.
Conclusions
The link between RSV infection in infancy and the subsequent development of asthma and recurrent wheezing is well-established, caused by a complex interaction of viral, host, and environmental factors. While acute disease poses immediate risks, long-term respiratory morbidity represents a continuous but often unrecognized public health challenge. The discovery of advanced biomarkers offers the potential for personalized risk assessment, allowing clinicians to identify high-risk children early, significantly improving the process of diagnosing asthma in children. By integrating these with powerful preventive tools like monoclonal antibodies and maternal vaccination, we are entering a new era in the fight against RSV. Ultimately, this approach can reduce the global burden of RSV and improve long-term respiratory health for children worldwide.
FAQ
What biomarkers indicate a high risk of severe RSV disease?
Elevated levels of IL-6, IL-8, IL-33, and LDH in nasopharyngeal aspirates are associated with severe forms of bronchiolitis and the need for respiratory support.
Are there biomarkers predictive of asthma in children after RSV?
Yes. Periostin, EDN, and IL-13 are biomarkers associated with the risk of chronic wheezing and asthma 3–5 years post-infection, which is vital for early pediatric asthma diagnosis.
What is the role of the immune system in the development of post-RSV asthma?
A Th2-dominant immune response, with increased IL-4 and IL-5, promotes airway inflammation and bronchial hyperresponsiveness.
What prevention strategies are most effective against RSV in infants?
Immunoprophylaxis with nirsevimab and maternal vaccination with RSVpreF reduce RSV-related hospitalizations in infants by up to 80%.
How long does the protection offered by nirsevimab last?
A single dose ensures protection for approximately 5 months, covering the entire RSV epidemic season.
Is maternal vaccination safe for the mother and the newborn?
Yes, clinical studies show a safety profile comparable to other vaccines in pregnancy, with neonatal protection lasting up to 6 months of life.
Are non-pharmacological hygiene measures truly effective?
Frequent hand washing and limiting exposure to crowded places reduce the transmission of the RSV virus by 35–40%.
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