In the present study, 14 (22.6%) patients had an improvement in lung function, although 48 (77.4%) patients remained with persistent obstruction despite high-dose CI plus LABA plus an oral corticosteroid trial (regular treatment at W2). Among the patients who remained with persistent airflow obstruction, we were able to identify 2 distinct functional behaviors: milder lung function impairment and response to anti-inflammatory treatment (MPO) vs. severe lung function impairment with no response to anti-inflammatory treatment (SPO). This last subgroup (25%) was markedly different from the other groups, mainly in relation to pulmonary function parameters, with greater airway resistance, air trapping, and greater heterogeneity of the small airways. Similarly, HRCT measures showed higher bronchial thickness in the SPO group, which was associated with higher airway muscle components in bronchial biopsies.
Our clinical, functional, and inflammatory findings are similar to those of other studies published from SA cohorts 4,25,26, but we identified a subgroup with a more severe fixed airflow obstruction. This trait is associated with severe asthma despite the inflammatory profile, challenging the main target of the asthma treatment concept 27. The heterogeneous response to conventional anti-inflammatory treatment indicates that multiple factors may influence SA evolution. A cluster analysis of the Severe Asthma Research Program (SARP) cohort 28 identified that as asthma severity increases, sputum neutrophil increases, and sputum eosinophil persists, indicating that therapies might target distinct inflammatory cell types. High levels of induced sputum eosinophil were an inflammatory marker in our cohort and did not differentiate patients according to the pattern of airway obstruction. Sputum eosinophilia was found at baseline and persisted after oral corticosteroid burst. The development of persistent obstruction in our asthmatic patients does not seem to depend exclusively on the severity of inflammation.
Some factors that may lead to persistent obstruction phenotype include asthma duration, amount of anti-inflammatory treatment delivered, and some patient characteristics responsible for different inflammatory and remodeling behavior to asthma triggers 29. Our SPO patients have significantly longer asthma duration with at least 3 decades from disease onset. Evidence recognizing that most adult asthma starts in childhood 30,31 is increasing as are data suggesting that exacerbations are a consequence rather than a cause of diminished airway caliber in childhood 11,12, which means that influences of asthma duration on lung function are still poorly understood. There is a clear “black box period” that includes transition between childhood and adulthood 32, with multiple factors that may interfere with asthma behavior. Poor lung development intra utero or irreversible structural changes during longer follow-up could decline lung function at age 21 33, defining an irreversible worsening marker 34. Therefore, lifetime non-controlled asthma may correlate to irreversible airway damage and, ultimately, persistent airflow obstruction.
Higher inhaled corticosteroid doses are associated with better symptoms and inflammation control as well as an impact on better disease progression 35. However, this does not seem to play any important role in our population because no difference in oral or inhaled corticosteroid doses was found at baseline among our subgroups. We are not able to determine the influence of previous treatment in the lives of these patients 10.
The complexity and heterogeneity of asthma is characterized by multiple and distinct inflammatory pathways 27. It is unlikely that all patients have a similar response when exposed to the same trigger. Current data cannot explain all asthma characteristics based purely on genetic data 36. It is well known that asthma phenotypes depend on the interaction of individual genetic profiles with multiple exposures. Increased data on epigenetics are emerging to contribute to the understanding of actual asthma pathophysiology 27,37. Individual characteristics are certainly a determinant of severity and how asthma manifests. Inflammatory predisposition profiles, such as higher expression of IL-13 genes 38, and TNF-alpha, IL-4R-alpha, and IL-4 polymorphisms 39 were linked to severity. The development of persistent obstruction in asthmatic patients should also be influenced by individual predisposing factors. Specific inflammatory profiles may contribute to a subset of patients with a greater component of muscle hypertrophy and remodeling leading to fixed obstructive disorder 15,40.
Thickened Asm, a finding usually identified in early life 41, is a distinguishing feature in this group. Our data 15 show that symptom control was not associated with airway tissue inflammation and remodeling. It is still a controversy whether these features are inflammation independent or arise as a proliferative response. Increase in the proliferating and higher airway smooth muscle cell levels were not related to inflammation, supporting the idea that evolution in smooth muscle in asthma is independent of airway inflammation 42.
Our patients had high BMI, especially in the severe persistent obstruction group. Obesity is a well-recognized phenotype in severe asthma with growing evidence relating to a T2 low inflammatory profile 43. Otherwise, it may also be a consequence of long-term corticosteroid treatment, psychiatric disorders, and physical activity impairment 44. This phenotype is commonly observed in other international cohorts 45,46. Obesity may influence asthma severity and progression due to some factors like gastroesophageal reflux disease (GERD) 47 and static lung volume changes, mainly lower functional residual capacity 48,49.
Our SPO was the group with the worst response to both oral corticosteroid treatment and bronchodilator. The lung function impairment in this group was characterized, not only by large airway involvement (FEV1), but also by significant small airway commitment (airway resistance, airway trapping, and heterogeneity of lung function). Air trapping measured both by HRCT 16 and plethysmography 50, had already been related to persistent obstruction in severe asthma. We were able to go further in the assessment of distal airways by using single breath washout nitrogen maneuvers. These are important data because several studies had already demonstrated the relationship between small airway involvement and poor asthma control as well as high exacerbation rates 51–53.
The SPO subgroup had thicker bronchi, suggesting a more pronounced remodelling process. HRCT imaging may reflect histopathological features related to airway remodeling. We were able to demonstrate that bronchial thickness was associated with airway smooth muscle hypertrophy. We had previously shown the relationship between persistent obstruction phenotype and a more proliferative airway smooth muscle behavior, induced by the evidence of less periostin, TGF-b+ cells and mucosal chymase+ mast cells in bronchial biopsies 15. In this scenario, thorax HRCT emerges as a non-invasive, informative, and useful tool to assess severe asthmatic patients. Kaminska et al 54 and Zhang et al 55 also demonstrated the correlation between persistent obstruction phenotype with airway smooth muscle hypertrophy. However, they were not able to discriminate this phenotype by using CT imaging and showed distinguishable inflammatory sputum profile compared with severe asthmatic patients with reversible airflow obstruction. In our study, the pathological features related to persistent obstruction were unaccompanied by increases in extracellular matrix structural components or a different inflammatory cell profile. Berair et al 40 recently published similar results confirming the association of the fixed obstruction phenotype with airway smooth muscle hypertrophy, lack of significant inflammation, and the possibility of using HRCT as a surrogate marker of airway remodeling.
Our study has some limitations. The small sample size in the subgroups could make the study underpowered to demonstrate a statistical difference in all variables according to their severity. This was a single-center study, and we caution extrapolating our data. Particular features of our population may not be reflected in other cohorts, although our baseline patient profiles are similar to other severe asthmatic populations 25,40,55. To delineate a systematic protocol, we chose a fixed dose of prednisone, which may not have achieved the higher anti-inflammatory effect, related to some patients’ particularities, such as obesity or corticosteroid resistance 46,48. Another point that stands out refers to the fact that, at the time when the study was designed, additional treatments for severe asthmatic patients, such as long-acting muscarinic receptor antagonists (LAMAs), and none of the biologicals were approved for use in asthmatic patients. We used quantitative HRCT measurements and biopsy samples, which are not used in clinical practice. However, these consistent results provide knowledge for severe asthma characterization that may be translated into valuable tools in clinical practice. Finally, we were not able to assess air trapping by HRCT because we did not perform expiratory volumetric scans.