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Although the eosinophilic asthma phenotype is well-established and typically responds to corticosteroids and other therapies, noneosinophilic neutrophilic asthma is still poorly understood. This subtype has been linked to greater disease severity, chronic airflow obstruction, and corticosteroid insensitivity, underscoring the critical need for effective therapies for this patient population.1 Treatment options for neutrophilic asthma are scant, partly because of a lack of biomarkers to inform diagnosis and management.
“Beyond clinical characteristics that do not suggest type 2 asthma, there is no way to identify neutrophilic asthma except for analyzing airway samples for the presence of neutrophils, and this type of testing is not widely available,” Mark C. Liu, MD, associate professor of pulmonary and critical care medicine at Johns Hopkins University School of Medicine in Baltimore, commented. “Hence, this classification has not had a practical impact on clinical practice, and these patients are treated as most other patients with asthma.”
Although there are currently no approved therapies that target neutrophilic asthma, addressing exacerbating factors may help limit inflammation in affected patients. “Some factors and exposures, including smoking, workplace exposures, pollution, infections, and obesity, have been associated with neutrophilic inflammation and should be identified and treated,” Dr Liu said.
A range of potential therapies for neutrophilic asthma has been the focus of emerging research, with promising results thus far. In a new paper funded by the National Heart, Lung, and Blood Institute, Kalchiem-Dekel et al reviewed studies pertaining to agents that target mediators of neutrophilic inflammation in asthma.1 They suggest that these findings may ultimately guide the development of treatments that could be used in a precision medicine approach, with specific therapies administered to each patient based on which pathways are active in that individual.
Selected results explored in the review are summarized below.
- Th1/ILC1 cytokines. Findings indicate that dysregulated interferon γ production by Th1 CD4+ T cells and group 1 innate lymphoid cells may promote severe asthma. In addition, interferon γ “induces C-X-C motif chemokine ligand (CXCL) 10 expression, which is a chemokine with chemoattractant activity towards Th1 CD4+ T cells and neutrophils, and also decreases airway epithelial cell production of secretory leukocyte protease inhibitor (SLPI), which may promote increases in airway hyperresponsiveness, exhaled nitric oxide production, and airway remodeling,” as explained in the paper.1 “Therefore, an [interferon γ]/CXCL10-mediated type 1 bias may exist in severe, steroid unresponsive asthmatics that might be targeted to reduce neutrophilic airway inflammation.”
- Tumor necrosis factor (TNF)-α. TNF-α, which is produced by macrophages, Th1 CD4+ T cells, and other cell types, has also been shown to promote neutrophilic inflammation. A clinical trial investigating the effects of the TNF-α inhibitor golimumab on lung function and disease control in patients with severe asthma did not demonstrate improvement before the study was terminated early because of increased incidence of infection, cancer, and other adverse events.2,1 The review authors note that enrollment in this study was not limited to TNF-α-high asthmatics.
“While the unfavorable risk-benefit profile related to TNF-α inhibition suggested that this approach may not be suitable for all asthmatics, it is not known whether anti-TNF-α therapies with fewer side effects might be utilized for the targeted treatment of asthmatics with an endotype of TNF-α-mediated neutrophilic airway inflammation,” they stated.1
- Interleukin-1β (IL-1β). Studies have linked IL-1β, a pro-inflammatory cytokine produced by the NLRP3 inflammasome, with neutrophilic inflammation and greater asthma severity. A phase 1/2 clinical trial (ClinicalTrials.gov identifier: NCT03513458) is now underway to investigate the effect of anakinra, an IL-1 receptor antagonist, on airflow obstruction in patients with mild allergic asthma. In a previous study, anakinra was associated with reductions in endotoxin-induced neutrophilic airway inflammation, as well as sputum levels of IL-1β, IL-6, and IL-8 in a sample of healthy volunteers.1,3
- IL-6. Recent findings have led to the identification of a new asthma endotype involving elevated systemic inflammation, increased plasma IL-6 levels, and metabolic dysfunction.1,4 These IL-6-high patients with asthma were also found to have worse asthma control and lung function compared with IL-6-low patients, as well as elevated blood neutrophils, suggesting a “role for systemic IL-6-mediated neutrophilic inflammation in mediating an ‘outside-in mechanism of lung dysfunction,’ ” wrote Kalchiem-Dekel et al.1
Anti-IL-6 receptor humanized monoclonal antibodies are currently being used for other inflammatory diseases such as rheumatoid arthritis, and future research should examine whether IL-6-neutralizing therapies can reduce disease severity in IL-6-high patients with asthma.1,5 “These studies can also assess whether plasma IL-6 levels mediate increased airway neutrophils in asthma,” the researchers wrote.
- Macrolides. In a trial described in the American Journal of Respiratory and Critical Care Medicine, azithromycin was found to reduce exacerbations and improve quality of life in adults with persistent uncontrolled asthma, including those with noneosinophilic asthma.6 The precise mechanisms underlying these effects have yet to be fully elucidated; various mechanisms involving alterations in IL-8, calcineurin, and mammalian target of rapamycin have been proposed.
Although the use of prolonged macrolide therapy is common in clinical practice, the “potential of inducing antibiotic resistant bacteria should be considered with long-term macrolide therapy for asthma, as an analysis of the AMAZES study showed that azithromycin increased the carriage of macrolide- and tetracycline-resistance genes by the airway microbiome.”1,7
One of the key challenges in exploring potential new therapies for neutrophilic asthma is “finding a convenient way of identifying patients with neutrophilic asthma for participation in clinical trials,” said Dr Liu. In future research, agents that “target pathways involved in neutrophilic inflammation should be studied in groups where neutrophils are a defined part of their inflammatory response.”
The review authors note that neutralizing certain pathways could increase the risk for infectious complications, highlighting the need to carefully titrate such therapies to preserve host defense.
References
1. Kalchiem-Dekel O, Yao X, Levine SJ. Meeting the challenge of identifying new treatments for type 2-low neutrophilic asthma [published online September 13, 2019]. Chest. doi:10.1016/j.chest.2019.08.2192
2. Wenzel SE, Barnes PJ, Bleecker ER, et al; T03 Asthma Investigators. A randomized, double-blind, placebo-controlled study of tumor necrosis factor-alpha blockade in severe persistent asthma. Am J Respir Crit Care Med. 2009;179(7):549-558.
3. Hernandez ML, Mills K, Almond M, et al. IL-1 receptor antagonist reduces endotoxin-induced airway inflammation in healthy volunteers. J Allergy Clin Immunol. 2015;135(2):379-385.
4. Peters MC, McGrath KW, Hawkins GA, et al. Plasma interleukin-6 concentrations, metabolic dysfunction, and asthma severity: a cross-sectional analysis of two cohorts. Lancet Respir Med. 2016;4(7):574-584.
5. Avci AB, Feist E, Burmester GR. Targeting IL-6 or IL-6 receptor in rheumatoid arthritis: What’s the difference? BioDrugs. 2018;32(6):531-546.
6. Gibson PG, Yang IA, Upham JW, et al. Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial. Lancet. 2017;390(10095):659-668.
7. Taylor SL, Leong LEX, Mobegi FM, et al. Long-term azithromycin reduces haemophilus influenzae and increases antibiotic resistance in severe asthma. Am J Respir Crit Care Med. 2019;200(3):309-317.
