Asthma Pathogenesis: Phenotypes, Therapies, and Gaps: Summary of the Aspen Lung Conference 2023

Abstract

Although substantial progress has been made in our understanding of asthma pathogenesis and phenotypes over the nearly 60-year history of the Aspen Lung Conferences on asthma, many ongoing challenges exist in our understanding of the clinical and molecular heterogeneity of the disease and an individual patient's response to therapy. This report summarizes the proceedings of the 2023 Aspen Lung Conference, which was organized to review the clinical and molecular heterogeneity of asthma and to better understand the impact of genetic, environmental, cellular, and molecular influences on disease susceptibility, heterogeneity, and severity. The goals of the conference were to review new information about asthma phenotypes, cellular processes, and cellular signatures underlying disease heterogeneity and treatment response. The report concludes with ongoing gaps in our understanding of asthma pathobiology and provides some recommendations for future research to better understand the clinical and basic mechanisms underlying disease heterogeneity in asthma and to advance the development of new treatments for this growing public health problem.

Keywords: asthma; endotype; environment; genetics; phenotype.

Figure 1.

Schematic representation of the intersection of genetics and environmental exposures over the lifespan. Genetic factors are likely to be of greater relevance in early life, with increasing contributions of the environment over time. The environment is likely to interact with the genome through epigenetic mechanisms to broadly impact asthma heterogeneity and progression. The figure was created using BioRender. RSV = respiratory syncytial virus; RV = rhinovirus.

Figure 2.

Airway epithelial cell diversity and function in the proximal and distal airways. The figure highlights the differences in distribution of cell types in the proximal airway epithelium as compared with the distal airway epithelium. The marker genes expressed by each of the major and rare cell types and their cellular function are highlighted in the accompanying table.

Figure 3.

Airway smooth muscle (ASM) function and dysfunction in asthma. Canonical contractile and relaxation functions of ASM integrate with asthma-associated signals, leading to downstream phenotypic changes, including altered contraction and relaxation, hypertrophy and hyperplasia, secretion of cytokines, and modified deposition of extracellular matrix. In severe asthma, these changes in ASM phenotype can result in fixed airway obstruction.

Figure 4.

Multiomics profiling of cells obtained via bronchoscopy can define new asthma subtypes and cellular mechanisms. Unsupervised clustering from BAL samples can define profiles for healthy patients, characterized by IL-10–producing M2-like macrophages, and severe asthma, exemplified here by IFN-γ–producing CD4 and CD8 cells and IL-4–producing innate immune cells. Specific CD4 and CD8 phenotypes, such as cytotoxic CD8⁺ tissue resident memory cells, can be characterized using antibody-based profiling or single-cell sequencing. These methods can be extended to characterize abnormalities in the airway epithelium in asthma in the context of specific immune cell populations and phenotypes.

Figure 5.

Schematic representation of the evolving complexities of the use of bioinformatics and multiomics to interrogate disease pathogenesis and heterogeneity. Although most current work relies on single intra-compartmental approaches, the full promise of bioinformatics awaits the integration of multiple different cells, compartments, time sequencing, and treatment effects. The figure was created using BioRender.

Figure 6.

Illustration of type 2-low asthma with current understanding of phenotypes. A major feature of type 2-low asthma is lack of T2 biomarkers, potentially due to effects of obesity, metabolic dysfunction, neutrophilic inflammation, and/or use of high-dose oral or inhaled CSs. Phenotypes under the type 2-low asthma umbrella include stable mild asthma, possibly mast cell–driven and easily treated with ICS, and an early-onset, long-duration phenotype with few markers of inflammation and airflow limitation with poor reversibility. Possible treatments include bronchial thermoplasty and/or anti–TSLP; late-onset asthma in the setting of obesity characterized by IL-1 and IL-6 and best treated with weight loss and possibly anti–IL-6 therapies; and a late-onset asthma phenotype characterized by sputum production and neutrophilic inflammation in the setting of high pollution, smoking, and/or infection treated with smoking cessation and possibly macrolides and/or pulmonary hygiene approaches. Adapted with permission from Reference . BD = bronchodilator; BMI = body mass index; CSs = corticosteroids; ICS = inhaled corticosteroids; Rx = treatment; T2 = type 2; TSLP = thymic stromal lymphopoietin.