Airway and serum biochemical correlates of refractory neutrophilic asthma

Abstract

Background: Despite progress in the diagnosis and management of asthma, many patients have poorly controlled or refractory asthma (RA). The mechanism of this RA is not well understood.

Objective: We sought to explore the relationship between neutrophils and other biomarkers of RA.

Method: Sixty patients with RA, 30 patients with nonrefractory asthma (NRA), and 20 healthy subjects were enrolled. We performed a comprehensive characterization of these study subjects, which included laboratory and pulmonary function studies, chest computed tomography, and bronchoscopy with bronchoalveolar lavage (BAL). We analyzed BAL fluid and serum for a total of 244 biomolecules using a multiplex assay and correlated them with clinical and other laboratory parameters.

Results: RA was significantly different from NRA with regard to pulmonary function indices, bronchial basement membrane thickness, and BAL fluid neutrophil and lymphocyte counts but not eosinophil counts. BAL fluid neutrophil counts negatively and positively correlated with forced vital capacity and age, respectively. Of the 244 biomolecules studied, 52 and 14 biomolecules from BAL fluid and serum, respectively, were significantly different among the study groups. Thirteen of these 52 molecules correlated with BAL fluid neutrophil counts. BAL fluid from 40% of patients with RA was positive for a pathogenic microbe. Infection-negative neutrophilic RA was associated with an increase in levels of select biomarkers of inflammation in the serum, suggesting the presence of systemic inflammation.

Conclusions: RA was associated with increased numbers of neutrophils and proneutrophilic biomolecules in the airways. Subclinical infection was present in 40% of patients with RA, which likely contributed to neutrophilic inflammation. A subgroup of patients with noninfected neutrophilic RA was associated with systemic inflammation.

Keywords: Refractory asthma; bronchoalveolar lavage; cytokines; infection; neutrophilic asthma.

Graphical abstract

Fig 1

A-D, Comparison of blood and BAL fluid neutrophil counts among infection-positive (Inf+) and infection-negative (Inf−) patients with RA and patients with NRA, including and excluding patients with RA taking OCSs.

Fig 2

Comparison of biomolecule levels between serum and BAL fluid among infection-positive (Inf+) patients with RA, infection-negative (Inf−) patients with RA, and patients with NRA.

Fig 3

Comparison of systemic inflammatory markers in serum from infection-positive (Inf+) patients with RA, infection-negative (Inf−) patients with RA, and patients with NRA.

Fig E1

Study design and overview of the results. A, Schematic presentation of study design. B, Inserted table summarizes the number of biomolecules studied, not detected, changed, and unchanged in BAL fluid and serum from the study subjects. C, Number of biomolecules in BAL fluid that were significantly (P < .05) different among study populations.

Fig E2

Fold increase in biomolecule level in patients with RA compared with those with NRA (A and B). Patients with RA were subgrouped as having infection (infection positive, black bars) or no infection (infection negative, gray bars). Results in Fig E2, A, were separated from results in Fig E2, B, because of the higher level of increase (see labels on x-axis).