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In recent years, a wide range of preclinical and clinical studies has led to important insights regarding the role of viruses in asthma pathogenesis and exacerbations, as well as mediating factors involved in these processes. In a paper published in May 2020 in the Journal of Allergy and Clinical Immunology, the Microbes in Allergy Committee of the American Academy of Allergy, Asthma & Immunology reviewed notable findings in this area.1
Polymorphisms and Innate Immune Genes
Across multiple cohorts, researchers have identified polymorphisms in antiviral and innate immune genes including STAT4, JAK2, MX1, VDR, DDX58, and EIF2AK2, and these polymorphisms are associated with respiratory virus susceptibility and severity, virus-induced asthma exacerbations, and asthma or virus-induced wheezing phenotypes.2 In addition, various genes including ADAM33, IL4R, CD14, TNF, IL13, and IL1RL1 have been linked with both illness severity and asthma risk.1
Rhinoviruses
Rhinovirus virulence has been found to vary by species, with 1 study showing greater odds of moderate to severe illnesses with rhinovirus A (odds ratio [OR], 8.2; 95% CI, 2.7-25.0] and rhinovirus C (OR, 7.6; 95% CI, 2.6-23.0) compared with rhinovirus B in nasal lavage samples collected from 209 infants.3 The findings further showed that a greater number of wheezing illnesses were caused by rhinovirus A (n=27) and C (n=14) compared with rhinovirus B (n=0).
Rodent studies have found that rhinovirus infection “leads to the expression of epithelial-derived cytokines IL-25, IL-33, and thymic stromal lymphopoietin, as well as to an increase in ILC2 cells as an important source of airway IL-13,” as explained in the new review.1 These pathways are also known to be involved in the response to rhinovirus and associated asthma exacerbations in humans. Mice treated with anti-IL-25 demonstrated attenuation of ILC2 expansion, mucous metaplasia, and airway responsiveness.4
Respiratory Syncytial Virus
In research published in 2017, the use of palivizumab to prevent severe respiratory syncytial virus (RSV) in high-risk infants led to a reduction in physician-diagnosed recurrent wheezing during the first 6 years of life (15.3% vs 31.6% in the treated vs untreated groups, respectively [P =.003]).5 However, this strategy did not affect the risk of asthma development. “Ultimately, RSV appears to have the greatest impact on asthma risk during a critical window of lung development for infants born during the fall (in the Northern Hemisphere), who are at approximately 4 months of age during the peak of the winter RSV season,” according to the AAAAI paper.1
The Role of Specific Bacteria
A range of findings suggest a connection between the presence of specific bacteria and illness severity, including results of multiple infant studies indicating that the presence of Streptococcus, Moraxella, or Haemophilus within the upper airway during upper respiratory infections was associated with a greater likelihood of lower airway symptoms. RSV bronchiolitis has been linked to an increased abundance of Streptococcus and Haemophilus, while rhinovirus-bronchiolitis has been linked to an increased abundance of Moraxella and Haemophilus.
Findings point to a connection between the presence of bacteria and airway inflammation. For example, researchers have noted an association between Haemophilus influenzae colonization of the infant airway before viral infection and increased expression of local inflammatory cytokines. In mouse models, intranasal administration of Lactobacillus rhamnosus was associated with improved immune response, which may indicate that certain bacteria could have protective and prophylactic effects against viral infection.6
The Gut Microbiome
Accumulating evidence suggests that the gut microbiome influences antiviral immune defense and the development of asthma, including an earlier study demonstrating that intact commensal microbiota were required for the proper activation of inflammasomes in response to respiratory influenza virus infection.7
Studies have elucidated that “unique components of the viral genome contribute to respiratory illness, and knowledge of these factors may also assist in development of vaccine and therapeutic strategies aimed at the proteins responsible for specific disease characteristics.”1
Potential of Pre-Seasonal Treatment
In the PROSE study (ClinicalTrials.gov Identifier: NCT01430403) of children with atopic asthma, pre-seasonal treatment with omalizumab decreased fall exacerbations compared with placebo and inhaled corticosteroid boost.8 Omalizumab also improved interferon-α responses to rhinovirus, and greater increases in interferon-α were associated with fewer exacerbations (OR, 0.14; 95% CI, 0.01-0.88).
Vitamin D Supplementation
In a meta-analysis of 2 clinical trials, vitamin D supplementation (2400 or 4000 IU per day) during pregnancy led to a 25% reduction in asthma and/or the risk of recurrent wheeze in infants during the first 3 years of life, especially in women with adequate serum vitamin D levels at baseline.9 “It was suggested that the beneficial effects of vitamin D may be related to enhancement of in utero lung growth and development and promotion of antimicrobial effects, thereby reducing early-life respiratory infections and/or providing immune modulation effects,” wrote the authors of the AAAI report.1
The authors anticipate that research in the next 5 years will further clarify the role of respiratory and gut microbiota in the development of virally induced asthma. They also emphasize the importance of primary prevention a major goal to minimize the effect of viral infections on wheezing and asthma.
For additional discussion regarding the effect of viruses on asthma, we checked in with James E. Gern MD, professor of pediatrics and medicine; Chief of the Allergy, Immunology, and Rheumatology Division; and Vice Chair of Research in the Department of Pediatrics at the University of Wisconsin School of Medicine and Public Health in Madison. Dr Gern coauthored a 2017 review on the role of viral infections in asthma development and exacerbation in children.10
What is known thus far about the effects of respiratory viruses on asthma, and what has been noted thus far with COVID-19 in particular?
Dr Gern: Viruses are linked to asthma in all age groups. Infants who wheeze with respiratory viruses are very likely to go on to develop asthma. RSV may be linked to nonallergic asthma, while children with allergies who wheeze with rhinoviruses are at very high risk of developing asthma.
In children and adults with established asthma, respiratory viruses are common causes of acute exacerbations of asthma. COVID-19 illnesses can also cause wheezing illnesses but are more likely to cause cold or flu-like symptoms.
What are some of the treatment challenges in treating respiratory viruses in asthma patients, and how should these be addressed in clinical practice?
Dr Gern: Patients with asthma who contract a respiratory virus infection are at risk for acute wheezing, and this can sometimes progress to an acute exacerbation. At present, there are no antiviral treatments to prevent or treat an ongoing virus-induced exacerbation of asthma. Instead, prevention is focused on minimizing baseline airway inflammation using treatments such as inhaled corticosteroids and — for more severe asthma — treatments with biologics.
What are your thoughts about the new AAAAI workgroup report on this topic?
Dr Gern: This paper is a nice summary of which individuals are at risk for virus-induced wheezing and exacerbations, current strategies for treatment and prevention, and ongoing research into mechanisms and new approaches to treatment.
What should be the focus of future research regarding the effect of viruses on asthma?
Dr Gern: Antivirals with efficacy against rhinoviruses would be a welcome treatment option and could also help to prevent asthma in infants prone to recurrent wheezing. The airway microbiome is an important cofactor for virus-induced wheeze, and more information in this area could lead to treatments. Since allergic inflammation increases the risk for virus-induced wheezing illnesses, treating baseline inflammation in asthma makes a lot of sense. Finally, better understanding of natural resistance mechanisms against respiratory viruses is likely to yield new targets for therapy.
References
1. Altman MC, Beigelman A, Ciaccio C, et al. Evolving concepts in how viruses impact asthma: a Work Group Report of the Microbes in Allergy Committee of the American Academy of Allergy, Asthma & Immunology. J Allergy Clin Immunol. 2020;145(5):1332-1344.
2. Loisel DA, Du G, Ahluwalia TS, et al. Genetic associations with viral respiratory illnesses and asthma control in children. Clin Exp Allergy. 2016;46(1):112-124.
3. Lee WM, Lemanske RF Jr, Evans MD, et al. Human rhinovirus species and season of infection determine illness severity. Am J Respir Crit Care Med. 2012;186(9):886-891.
4. Hong JY, Bentley JK, Chung Y, et al. Neonatal rhinovirus induces mucous metaplasia and airways hyperresponsiveness through IL-25 and type 2 innate lymphoid cells. J Allergy Clin Immunol. 2014;134(2):429-439.
5. Mochizuki H, Kusuda S, Okada K, et al. Palivizumab prophylaxis in preterm infants and subsequent recurrent wheezing. Six-year follow-up study. Am J Respir Crit Care Med. 2017;196(1):29-38.
6. Tomosada Y, Chiba E, Zelaya H, et al. Nasally administered Lactobacillus rhamnosus strains differentially modulate respiratory antiviral immune responses and induce protection against respiratory syncytial virus infection. BMC Immunol. 2013;14:40.
7. Ichinohe T, Pang IK, Kumamoto Y, et al. Microbiota regulates immune defense against respiratory tract influenza A virus infection. Proc Natl Acad Sci U S A. 2011;108(13):5354-5359.
8. Teach SJ, Gill MA, Togias A, et al. Preseasonal treatment with either omalizumab or an inhaled corticosteroid boost to prevent fall asthma exacerbations. J Allergy Clin Immunol. 2015;136(6):1476-1485.
9. Wolsk HM, Chawes BL, Litonjua AA, et al. Prenatal vitamin D supplementation reduces risk of asthma/recurrent wheeze in early childhood: A combined analysis of two randomized controlled trials. PLoS One. 2017;12(10):e0186657.
10. Jartti T, Gern JE. Role of viral infections in the development and exacerbation of asthma in children. J Allergy Clin Immunol. 2017;140(4):895-906.
