The International Variation in Asthma Phenotypes

Asthma is a heterogeneous disease with distinct phenotypes that result from a combination of genetic factors and environmental exposures.¹,² With the globalization of medical research, it has become apparent that evidence generated from specific ethnic groups or countries might not reflect the genetic composition and environments of other populations, with important consequences in risk assessments and therapeutic responses. Even within the US, there are racial and ethnic groups underrepresented in clinical research for whom current clinical knowledge might not be generalizable.³ Different racial and ethnic groups have distinct prevalences of genetic variants that can increase the risk of asthma morbidity and impact treatment responses.⁴,⁵ However, many pharmaceutical companies testing cutting-edge asthma therapies are recruiting patients internationally, which can help with the generalizability of study results. Efforts to understand the phenotypic variation of asthma across countries are important because the relevance of the mechanistic targets being tested might vary by population. Recent work has noted wide international variation in asthma exacerbation rates, and importantly, that the predictors of exacerbation-proneness seem to vary by country.⁶

The article featured in this issue by Park et al.⁷ contributes important knowledge in this regard by comparing asthma phenotypes across severe asthma cohorts from 4 continents. This is one of the first instances of a comparison of asthma phenotypes using clustering analyses that combines international cohorts. The authors included cohorts from Asia (Cohort for Reality and Evolution of Adult Asthma in Korea, COREA), South America (The Program for Control of Asthma in Bahia, ProAR), Europe (Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes, U-BIOPRED), and North America (the Severe Asthma Research Program, SARP). In order to compare characteristics across clusters, they focused on data common across all cohorts and included age, gender, smoking history, family history of asthma, allergic rhinitis status, aeroallergen sensitization, asthma age of onset, total immunoglobulin E (IgE), lung function, absolute eosinophil count, number of exacerbations in the last year, and sputum cell counts from adults 18 years and older.

A few differences stand out between cohorts. First, the Korean cohort had an older age of onset, with a mean in middle age and most of its range in adulthood. In contrast, other cohorts had a mean age of onset in either early adulthood or adolescence, with a range covering childhood. Adult and pediatric asthma are phenotypically different and likely driven by distinct mechanisms,⁸ suggesting that there are fundamental differences in the pathobiology of asthma across these countries. Second, most patients from Korea are lean, while most patients from the US are either overweight or obese. If the results of the study by McDowell et al.⁹ extend to all populations and predict greater likelihood of on-biologic remission for patients with severe asthma with shorter disease duration and for those who are lean, then attention should be paid to initiating biologic therapy in patients in the COREA cohort with the hope of a more likely remission. However, these positive predictive factors for on-biologic remission might be offset by the greater proportion of heavy smokers in the Korean cohort. Third, cohorts differed in their atopic frequency and their allergen sensitization patterns. More detailed patient characterization might explain these differences. For example, the relatively high prevalence of intestinal parasitic infections in Brazil could contribute to the ProAR cohort having the highest total IgE levels yet the second lowest proportion of patients with atopy.¹⁰

These results are also influenced by several aspects of the study design. The lower lung function and greater number of exacerbations in UBIOPRED might reflect differences in selection criteria across the 4 cohorts. The prevalence of asthma biologic use is likely different across countries due to varying indication criteria, with impacts on overall asthma exacerbation rates. Further, since our current definition of severe asthma according to the European Respiratory Society/American Thoracic Society 2014 task force report relies on controller therapy prescriptions,¹¹ the high proportion of patients without any controller therapy (e.g., 50% in ProAR) raises questions about whether these patients should truly be categorized as severe. On the other hand, low adherence to controller therapy is a well-documented phenomenon in asthma management, and therefore, this finding makes these cohorts more representative of real-world circumstances. More importantly, the high prevalence of non-adherence to controller therapy regardless of world region and ethnicity highlights the universality of this barrier to optimal care and accentuates the need for therapies and system-wide approaches that can sidestep low adherence to daily therapy. Lastly, as acknowledged by the authors, patients from these cohorts are unlikely to be representative of all patients in their respective continents, considering the vast geographic, ethnic, cultural, healthcare system, and many other differences in every continent.

The work by Park et al.⁷ takes an important step towards understanding international phenotypic differences in asthma. Future studies should also take advantage of the multi-omic phenotypic characterization available to the SARP and UBIOPRED cohorts, and perhaps other cohorts, which extend to variables not incorporated into the principal component analysis. Otherwise, this approach would miss the opportunity to delve deeper into mechanistic differences across cohorts. Longitudinal data would overcome the limitations of cross-sectional analyses and address the issue of the stability of clinical and mechanistic phenotypes across countries.

Continued efforts in understanding international differences in asthma are important for the development of future asthma therapeutics aimed at personalized medicine by targeting precise mechanistic signatures at a global level.