We confirmed 2 risk factors common to self-reported blacks and non-Hispanic whites: a history of prior exacerbations and lower lung function. We also found risk factors unique to each individual ethnic group, and exacerbation rates were not significantly different between blacks and whites. However, blacks with a higher African ancestry above the median (≥82%) had more frequent asthma exacerbations compared with blacks with lower African ancestry. This study illustrates the complex risk factors that underlie the mechanisms for more frequent asthma exacerbations, including the yet-to-be-defined interactions between the socioeconomic, environmental, geographic, cultural, and genetic factors that track with African ancestry.6

Pulmonology Advisor: What would you recommend to clinicians regarding the evaluation of these patients?

Dr Ortega: When evaluating individuals with recurrent asthma exacerbations despite appropriate treatment, important considerations include the recognition of diseases that mimic severe asthma (including vocal cord dysfunction, bronchiectasis, and allergic bronchopulmonary aspergillosis), occupational or environmental exposures that trigger symptoms or exacerbations, and comorbidities that associate with recurrent exacerbations such as gastroesophageal reflux disease and chronic sinusitis.


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Important factors to consider for the treatment of individuals with frequent asthma exacerbations include the intensity and combination of current drug treatments, adherence to prescribed therapies, socioeconomic or cultural barriers to compliance, interventions to minimize or reduce the effect of exposures to allergic or irritant triggers, and whether the appropriate strategies are in place to treat comorbid diseases. More advanced biologic therapies targeting allergic inflammatory pathways are reserved for patients with biomarker evidence of eosinophilic asthma after the above considerations have been addressed, preferably in a clinic specializing in the care of severe asthma.

Pulmonology Advisor: What are remaining challenges and needs in this area?

Dr Ortega: Clinical trials evaluating different asthma treatments have primarily been performed in whites of European descent, and the vast minority of participants have been from underrepresented minorities. This is important because of the disproportionate burden of asthma morbidity experienced by African Americans and Puerto Ricans, for whom the most effective step-up treatment strategy to control asthma may differ.6

The complex environmental and geographic factors that influence asthma risk and severity are an emerging area of research and highlight the role of diet, allergens, secondhand tobacco smoke, and pollutants from the level of a household to entire neighborhoods and cities as determinants of asthma severity. In more recent studies, cultural and socioeconomic factors such as experiences of racism and psychosocial stressors have also been identified as determinants of asthma severity and drug response in underrepresented minorities.7,8

One of the biggest challenges will be the identification of how genetic factors that track with African ancestry interact or track with the different socioeconomic, environmental, geographic, and cultural factors and contribute to exacerbation frequency and interethnic differences. With the advent of high-throughput whole-genome and gene scanning technologies, there has been an exponential increase in genetic studies that have contributed to our understanding of the distribution of genetic ancestry between individuals and how genes influence interindividual differences in asthma severity and responsiveness to drugs (pharmacogenetic studies).

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Unfortunately, fewer than 5% of genetic studies have included African descent or Hispanic ethnic groups, resulting in an underrepresentation of these groups.6 Differences in genes across the human genome have permitted us to estimate African ancestry, which is associated with more frequent asthma exacerbations. The small number of genetic studies in minority groups has demonstrated both shared and unique genetic factors that influence asthma risk and responsiveness to commonly used drugs, such as inhaled beta agonists.6 At least one gene variant in Puerto Rican children was found to influence beta agonist response through an interaction with stress levels.9

Research aimed at definitively understanding and addressing the ancestry-specific genomic and environmental factors that influence exacerbation risk will require a combination of longitudinal studies in well-characterized minority cohorts and multi-omic approaches that evaluate whole-genome DNA sequence, epigenetic, RNA, and protein expression differences.

References

1. Barnes PJ. Recent advances in asthma treatment. Eur Respir Pulm Dis. 2018;4(1):15-16.

2. Loymans RJ, Sterk PJ. Exacerbation-prone asthma: a separate bioclinical phenotype? Am J Respir Crit Care Med. 2017;195(3):275-277.

3. Denlinger LC, Heymann P, Lutter R, Gern JE. Exacerbation-prone asthma [published online November 22, 2019]. J Allergy Clin Immunol Pract. doi:10.1016/j.jaip.2019.11.009

4. ten Brinke A, Sterk PJ, Masclee AA, et al. Risk factors of frequent exacerbations in difficult-to-treat asthma. Eur Respir J. 2005;26(5):812-818.

5. Bønnelykke K, Sleiman P, Nielsen K, et al. A genome-wide association study identifies CDHR3 as a susceptibility locus for early childhood asthma with severe exacerbations. Nat Genet. 2014;46(1):51-55.

6. Grossman NL, Ortega VE, King TS, et al. Exacerbation-prone asthma in the context of race and ancestry in Asthma Clinical Research Network trials. J Allergy Clin Immunol. 2019;144(6):1524-1533.

7. American College of Allergy, Asthma & Immunology. Racism a factor for asthma control in young African American children. https://acaai.org/news/racism-factor-asthma-control-young-african-american-children. September 17, 2019. Accessed December 22, 2019.

8. Jones BL, Staggs V, Woods-Jaeger B, et al. Chronic stress exposure among young African American children with asthma: Racism is a factor. Ann Allergy Asthma Immunol. 2019;123(5):507-508.

9. Brehm JM, Ramratnam SK, Tse SM, et al. Stress and bronchodilator response in children with asthma. Am J Respir Crit Care Med. 2015;192(1):47-56.