StemCell Therapy

Asthma is the most common chronic respiratory disease in children, affecting approximately 6.1 million US children younger than 18 years.1 Asthmas 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 dailyroutines of both children and caregivers and hamper a childs academicperformance and ability to attend school. In 2013, the CDC found that 49% ofchildren with asthma reported 1 asthma-related missed school days.4

Although asthma can develop at any time throughout life, itmost often begins in childhood.5 A range of childhood risk factorsfor asthma have been identified in studies to date, including geneticsusceptibility, atopy, and microbial and environmental exposures.3

In this interview with Asthma Advisor, translationalresearcher Mitchell H. Grayson, MD, FAAAAI,FACAAI, chief of the Division of Allergy and Immunology at NationwideChildrens Hospital and professor of pediatrics at The Ohio State UniversityCollege of Medicine in Columbus, discussed the latest insights about theconnection between common viral infections and asthma in children.

AsthmaAdvisor: Which viral strains have been associated with the development of wheezingepisodes 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

AsthmaAdvisor: How is the number of wheezingepisodes in early childhood related to the development of asthma?

Dr Grayson: This is a complicated situation that leads to 2questions 1) What is asthma? and 2) What is a postviral wheeze? Obviously, wedo not get all excited about a child having asthma if they wheeze once, but thegray 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 apatient wheezes more than 2 or 3 times due to viral illnesses, that patientprobably 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 asthmais allergic asthma. Part of the problem in clearly defining asthma is thatwheezing is actually the lung being twitchy and bronchoconstrictingto an irritant of some sort it may be diesel smoke, a cat allergen, orrhinovirus, and that is where it becomes sort of problematic is this all thesame 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 andrhinovirus are very similar (immunoglobulin E [IgE] responses) but that dieselexhaust may not be driving asthma through an IgE response. So, there may bedifferent mechanisms upfront with the same downstream effect on the lung.

AsthmaAdvisor: How much is known about the connection between allergic sensitization andasthma? 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 recentpublications suggesting that RSV infection leads to wheezing in children whoare not atopic to begin with vs the rhinovirus that leads to wheezing in childrenwho are atopic.2 So, there is a little confusion as to how thatmechanism is working. Generally, with RSV, the risk is in the age group between2 and 6 months2 who have a severe RSV infection; that is usually alittle young to be producing a lot of IgE vs the risk of asthma from rhinovirustends to be in children a little older, which would then align with the ideathat 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

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

Dr Grayson: Allergies and allergic disease in the family andin the individual put one at risk for allergic asthma. Nonallergic asthma tendsto occur later in life and be more severe and is usually not associated witheosinophils in the peripheral blood and sputum.8,9 I would putviruses in the allergic asthma pot, although there have been studies thatsuggested that RSV drives nonallergic asthma. The risk factors for nonallergicasthma are not well defined and, in many ways, nonallergic asthma is theabsence 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. Inmany cases, it is like a lot of other allergic diseases that, when you get toyour 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.10We assume that the more severe asthma is, the less likely it is that the childwill outgrow it, but we really do not have good predictors of who will outgrowtheir asthma.

AsthmaAdvisor: Is there a geneticsusceptibility in children who develop asthma after a viral infection?

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

AsthmaAdvisor: How much is known about themechanism 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 andwheeze, and second, solid data supporting the idea that viral titers are higher,or that type I interferon is markedly suppressed in patients with asthma, arelacking. We do not have a good studyusing antiviral IgE therapy at the time of initial viral infection to see if itwill prevent the development of postviral wheeze or a study where we giveindividuals a virus, whether they are or are not receiving antiviral IgEtherapy, to see if it will prevent them from wheezing.

Disclosure:Dr Grayson reported serving onadvisory boards for AstraZeneca, Genentech,Novartis, Genzyme, DBVTechnologies, and Aimmune.

References

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

This entry was posted on February 1, 2020 at 4:46 am and is filed under Genetic medicine. You can follow any responses to this entry through the RSS 2.0 feed. Both comments and pings are currently closed. |