Phenotypes, early-life factors characterize difficult-to-control asthma in urban children

PHOENIX — Certain phenotypes are associated with difficult-to-control asthma in urban children, which may be characterized by specific early-life factors and patterns of nasal epithelial cell gene expression, according to a speaker here.

James E. Gern, MD, FAAAAI, professor of pediatrics and medicine at University of Wisconsin School of Medicine and Public Health, spoke at the American Academy of Allergy, Asthma & Immunology Annual Meeting to review the data that has been gathered thus far on where difficult-to-control asthma may originate in children living in urban environments.

Characteristics, phenotypes

Difficult-to-control asthma in urban children can be characterized by greater symptoms and exacerbations, airway obstruction and highly expressed type 2 markers, although there are also some low type 2 phenotypes in early life, Gern said.

He reviewed data from the Asthma Phenotypes in Inner-City Children (APIC) study, which involved 619 children with asthma aged 6 to 17 years. Researchers defined difficult-to-control asthma as that that required at least 500 µg fluticasone, which comprised 41% of the cohort.

Researchers from that study identified 44 variables in 12 domains that predicted difficult-to-control asthma, with the most influential factors being demographics; family, allergy and asthma history; allergen sensitization; allergic inflammation; rhinitis; pulmonary physiology; environmental exposure; BMI; stress; and vitamin D.

Also, bronchodilator response and asthma control test were important distinguishing baseline characteristics between patients with difficult-to-control vs. easy-to-control asthma, with rhinitis medication and symptom scores also playing a role.

Data from the APIC study also revealed five clusters of different asthma phenotypes, which differ based on indicators of asthma and rhinitis severity, pulmonary physiology, allergy sensitization and total serum IgE, and allergic inflammation.

Gern highlighted two groupings that stood out in terms of asthma severity — Clusters B and E — driven by increased nighttime symptoms and albuterol use, with greater medication use to achieve control.

Pulmonary physiology also appeared somewhat low in cluster B, Gern said, but quite low in Cluster E. Also, rhinitis severity, number of allergen sensitizations, total serum IgE, blood eosinophil count all appeared to indicate greater allergen sensitization and allergic inflammation in Cluster E.

Early-life factors

To discuss how these phenotypes relate to early-life environmental exposures, Gern reviewed data from the URECA study which involved 560 children (Black, 72%; Hispanic, 20%; other, 8%) from allergic families living in urban neighborhoods with at least 20% of the residents living in poverty.

The researchers created six clusters of asthma differentiated by patterns of wheezing, atopy and lung function. The largest group (22%) was defined by low wheeze and atopy and normal lung function. Other groups included those with transient wheeze, low atopy and normal lung function (17%); moderate wheeze, low atopy and normal lung function (17%); low wheeze, high atopy and normal lung function (20%); moderate wheeze, high atopy and normal lung function (12%); and high wheeze, high atopy and obstructed lung function (12%).

The latter group had the most comorbidities — including 82% with asthma, 66% with chronic nasal symptoms at age 10 and 44% with any eczema — as well as higher rates of inhaled and oral corticosteroids usage.

When researchers looked at environmental exposures, they found two correlations, Gern said, the first being that the moderate wheeze, low atopy group had significantly higher maternal depression scores and maternal perceived stress score in the child’s early life.

Secondly, the high wheeze, high atopy and low lung function group showed lower exposure to common allergens — including house dust, cat, dog, mouse and cockroach allergens — and higher exposure to ergosterol in house dust, a mold marker.

“It is interesting to think what the mechanisms might be to increase the probability of developing the moderate wheeze, low atopy phenotype, perhaps through endocrine or neurological mechanisms,” Gern said. “But with this high wheeze, high atopy, low lung function group, the decreased exposure to allergens and increased exposure to mold in the house suggest these might be important factors in developing immune responses as these children are growing.”

Epithelial cell gene expression

Researchers also used these groups from URECA to evaluate nasal epithelial cell gene expression using RNA extraction and sequencing, and they identified 26 modules of differentially expressed genes.

Their network analysis of gene modules showed that several modules were overexpressed in the high wheeze, high atopy, low lung function group, with an overall different pattern than what researchers observed for the moderate wheeze, low atopy group. The former group was defined by modules that included typical type 2 inflammatory pathways, Gern said, such as epithelium response to IL-13, MUC5AC hypersecretion, and leukotriene and lipid metabolism.

“MUC5AC hypersecretion was a really unique increase in the group with high wheeze, high atopy and low lung function,” Gern said.

Conversely, the moderate wheeze, low atopy group had underexpression of antioxidant activity and epithelial integrity and leukocyte migration, but an increase in injury response.

“Based on epithelial gene module expression, we get some evidence that these phenotypes may actually be endotypes, with increased expression of injury, reduced expression of integrity and antioxidant activity in the moderate wheeze, low atopy phenotype, whereas the high wheeze/atopy phenotype was associated with an increase in type 2 modules and MUC5AC expression, which could play a direct role in airway closure.”

References:

• Altman MC, et al. J Allergy Clin Immunol. 2021;doi:10.1016/j.jaci.2021.02.040.
• Gern JE, et al. BMC Pulm Med. 2009;doi:10.1186/1471-2466-9-17.
• Pongracic JA, et al. J Allergy Clin Immunol. 2016;doi:10.1016/j.jaci.2016.06.059.
• Zoratti EM, et al. J Allergy Clin Immunol. 2016;doi:10.1016/j.jaci.2016.06.061.