Understanding the Links Between Asthma and Viral Infections in Children - Pulmonology Advisor

Posted: 31 Jan 2020 07:31 AM PST

Asthma is the most common chronic respiratory disease in children, affecting approximately 6.1 million US children younger than 18 years.¹ Asthma's hallmark characteristics — chronic inflammation of the airways, bronchial hyperreactivity, airflow obstruction, and excessive mucus production — lead to troublesome episodes of cough, wheezing, and dyspnea² that require ongoing management and pose a consistent burden on the healthcare system.³

Furthermore, asthma can have a negative effect on the daily routines of both children and caregivers and hamper a child's academic performance and ability to attend school. In 2013, the CDC found that 49% of children with asthma reported ≥1 asthma-related missed school days.⁴

Although asthma can develop at any time throughout life, it most often begins in childhood.⁵ A range of childhood risk factors for asthma have been identified in studies to date, including genetic susceptibility, atopy, and microbial and environmental exposures.³

In this interview with Asthma Advisor, translational researcher Mitchell H. Grayson, MD, FAAAAI, FACAAI, chief of the Division of Allergy and Immunology at Nationwide Children's Hospital and professor of pediatrics at The Ohio State University College of Medicine in Columbus, discussed the latest insights about the connection between common viral infections and asthma in children.

Asthma Advisor: Which viral strains have been associated with the development of wheezing episodes in children?

Mitchell H. Grayson, MD, FAAAAI, FACAAI: There are viruses that have been associated with the development of asthma and postviral wheeze, and then there are viruses associated with asthma exacerbations. Respiratory syncytial virus (RSV), rhinovirus, coronaviruses, and influenza have been associated with postviral wheeze and asthma onset; rhinovirus and coronaviruses have been more associated with exacerbations of existing disease than with induction of asthma.² Also, parainfluenza virus types 1 and 3 have been associated with induction of disease, as well as exacerbation of existing asthma.²

Asthma Advisor: How is the number of wheezing episodes in early childhood related to the development of asthma?

Dr Grayson: This is a complicated situation that leads to 2 questions — 1) What is asthma? and 2) What is a postviral wheeze? Obviously, we do not get all excited about a child having asthma if they wheeze once, but the "gray zone" is when they wheeze 2 or more times.

First, there is no magic answer, but in the absence of emergency department visits or hospitalizations, if a patient wheezes more than 2 or 3 times due to viral illnesses, that patient probably has asthma, but there is no hard and fast rule about that.

Asthma Advisor: In cases of true asthma, will asthma episodes also be provoked by other types of environmental stimuli?

Dr Grayson: Possibly; in children at least, almost all asthma is allergic asthma. Part of the problem in clearly defining asthma is that wheezing is actually the lung being "twitchy" and bronchoconstricting to an irritant of some sort — it may be diesel smoke, a cat allergen, or rhinovirus, and that is where it becomes sort of problematic — is this all the same disease? We lump them together because the clinical symptoms are the same, but I would argue that the mechanisms of wheeze due to cat allergen and rhinovirus are very similar (immunoglobulin E [IgE] responses) but that diesel exhaust may not be driving asthma through an IgE response. So, there may be different mechanisms upfront with the same downstream effect on the lung.

Asthma Advisor: How much is known about the connection between allergic sensitization and asthma? What comes first?

Dr. Grayson: Most studies have looked at sensitization at 1 year of age, and the problem is that the children were already wheezing before that. The COAST study (ClinicalTrials.gov Identifier: NCT00204841) investigators, for example, attempted mathematical modeling and proposed that rhinovirus infections cause asthma in children who already have atopic sensitization.⁶

There have also been some recent publications suggesting that RSV infection leads to wheezing in children who are not atopic to begin with vs the rhinovirus that leads to wheezing in children who are atopic.² So, there is a little confusion as to how that mechanism is working. Generally, with RSV, the risk is in the age group between 2 and 6 months² who have a severe RSV infection; that is usually a little young to be producing a lot of IgE vs the risk of asthma from rhinovirus tends to be in children a little older, which would then align with the idea that patients become atopic first.

There is also the "atopic march," in which children develop atopic dermatitis in infancy and then allergic rhinitis by the time they are 3 or 4 years old and, finally, asthma by the time they are 5 or 6 years old. The traditional path to atopic asthma is one that develops with the atopic march, and therefore, clearly, the children are sensitized well before they start wheezing.⁷

Asthma Advisor: What are the risk factors for allergic asthma vs nonallergic asthma?

Dr Grayson: Allergies and allergic disease in the family and in the individual put one at risk for allergic asthma. Nonallergic asthma tends to occur later in life and be more severe and is usually not associated with eosinophils in the peripheral blood and sputum.^8,9 I would put viruses in the allergic asthma pot, although there have been studies that suggested that RSV drives nonallergic asthma. The risk factors for nonallergic asthma are not well defined and, in many ways, nonallergic asthma is the absence of allergic asthma.

Asthma Advisor: What is the long-term outlook for children who develop allergic asthma in early childhood?

Dr Grayson: We do have children who outgrow their asthma. In many cases, it is like a lot of other allergic diseases that, when you get to your 20s, seem to go away only to return in your 30s. In the vast majority of children, asthma gets better and becomes less problematic as the child gets older.¹⁰ We assume that the more severe asthma is, the less likely it is that the child will outgrow it, but we really do not have good predictors of who will outgrow their asthma.

Asthma Advisor: Is there a genetic susceptibility in children who develop asthma after a viral infection?

Dr Grayson: I am not aware of any good studies finding a specific genetic link. There is no good genetic marker to predict if someone will wheeze or not wheeze with a viral infection. With a family history of atopy, you are more likely to have asthma, but whether you would have it with a virus is a different issue.

Asthma Advisor: How much is known about the mechanism by which viral infections cause asthma exacerbations?

Dr Grayson: There are a couple of ideas about this. There was a clinical trial (ICATA Asthma Mechanistic Study; ClinicalTrials.gov Identifier: NCT00377390) where the investigators used anti-IgE therapy in children with allergic asthma and reduced asthma exacerbations in the pollen season, but they also reduced asthma exacerbations basically back to the level seen in the control group during the viral respiratory season in the winter.¹¹ My argument would be that the anti-IgE therapy removes antiviral IgE, preventing mast cell activation and subsequent histamine release, all ending up preventing bronchoconstriction from the viral infection. If you do not have bronchoconstriction, it is likely that you will not have asthma. That is a rationale for using anti-IgE therapy to prevent viral induced wheezing and asthma.

Another explanation, proposed by the Inner-City Asthma Consortium, is that there is a certain type of dendritic cell that makes type I interferon, which is a major player in the antiviral immune response.¹² Crosslinking IgE on these cells reduces the amount of type I interferon that they produce. So, if you are allergic and produce more IgE, you have an impaired immune response because you are making less type I interferon and, therefore, that leads to worsening disease.

I have 2 problems with this: First, I do not know about the mechanistic connection between type I interferon and wheeze, and second, solid data supporting the idea that viral titers are higher, or that type I interferon is markedly suppressed in patients with asthma, are lacking. We do not have a good study using antiviral IgE therapy at the time of initial viral infection to see if it will prevent the development of postviral wheeze or a study where we give individuals a virus, whether they are or are not receiving antiviral IgE therapy, to see if it will prevent them from wheezing.

Disclosure: Dr Grayson reported serving on advisory boards for AstraZeneca, Genentech, Novartis, Genzyme, DBV Technologies, and Aimmune.

References

Centers for Disease Control and Prevention. Most Recent National Asthma Data: National Current Asthma Prevalence (2017). Accessed January 27, 2020.
Mikhail I, Grayson MH. Asthma and viral infections: an intricate relationship. Ann Allergy Asthma Immunol. 2019;123(4):352-358.
Ferrante G, La Grutta S. The burden of pediatric asthma. Front Pediatr. 2018;6:186.
Centers for Disease Control and Prevention. AsthmaStats:Asthma-related Missed School Days among Children aged 5-17 years. Accessed January 27, 2020.
Dharmage SC, Perret JL, Custovic A. Epidemiology of asthma in children and adults. Front Pediatr. 2019;7:246.
Lemanske RF Jr. The Childhood Origins of Asthma (COAST) study. Pediatr Allergy Immunol. 2002;13(s15):38-43.
Paller AS, Spergel JM, Mina-Osorio P, Irvine AD. The atopic march and atopic multimorbidity: many trajectories, many pathways. J Allergy Clin Immunol. 2019;143(1):46-55.
Hekking PP, Bel EH. Developing and emerging clinical asthma phenotypes. J Allergy Clin Immunol Pract. 2014;2(6):671-680.
Peters SP. Asthma phenotypes: nonallergic (intrinsic) asthma. J Allergy Clin Immunol Pract. 2014;2(6):650-652.
Gerritsen J, Koter GH, Postma DS, Schouten JP, Knol K. Prognosis of asthma from childhood to adulthood. Am Rev Respir Dis. 1989;140(5):1325-1330.
Busse WW, Morgan WJ, Gergen PJ, et al. Randomized trial of omalizumab (anti-IgE) for asthma in inner-city children. N Engl J Med. 2011;264(11):1005-1015.
Gill MA, Liu AH, Calatroni A, et al. Enhanced plasmacytoic dendritic cell antiviral responses after omalizumab. J Allergy Clin Immunol. 2018;141(5):1735-1743.

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