Paucigranulocytic asthma: Uncoupling of airway obstruction from inflammation

Among patients with asthma, heterogeneity exists regarding the pattern of airway inflammation and response to treatment, prompting the necessity of recognizing specific phenotypes. Based on the analysis of inflammatory cell counts in induced sputum, asthmatic patients can be classified into 4 unique phenotypes: eosinophilic asthma, neutrophilic asthma, mixed granulocytic asthma, and paucigranulocytic asthma (PGA). PGA is an asthma phenotype with no evidence of increased numbers of eosinophils or neutrophils in sputum or blood and in which anti-inflammatory therapies are ineffective at controlling symptoms. Although underinvestigated, PGA is the most common asthma phenotype in patients with stable asthma. However, PGA is sometimes underestimated because of the exclusive reliance on induced sputum cell counts, which are variable among cohorts of studies, prompting the necessity of developing improved biomarkers. Importantly, investigators have reported that inhaled corticosteroids had a limited effect on airway inflammatory markers in patients with PGA and therefore defining PGA as a potentially "steroid-insensitive'' phenotype that requires exploration of alternative therapies. PGA manifests as an uncoupling of airway obstruction from airway inflammation that can be driven by structural changes within the airways, such as airway smooth muscle tissue hypertrophy. Animal models provide evidence that processes evoking airway hyperresponsiveness and airway smooth muscle thickening occur independent from inflammation and might be a consequence of a loss of negative homeostatic processes. Collectively, further understanding of PGA with a focus on the characterization, prevalence, clinical significance, and pathobiology derived from animal studies will likely provide precision therapies that will improve PGA clinical outcomes.