Novel approaches to the management of noneosinophilic asthma

Abstract

Noneosinophilic airway inflammation occurs in approximately 50% of patients with asthma. It is subdivided into neutrophilic or paucigranulocytic inflammation, although the proportion of each subtype is uncertain because of variable cut-off points used to define neutrophilia. This article reviews the evidence for noneosinophilic inflammation being a target for therapy in asthma and assesses clinical trials of licensed drugs, novel small molecules and biologics agents in noneosinophilic inflammation. Current symptoms, rate of exacerbations and decline in lung function are generally less in noneosinophilic asthma than eosinophilic asthma. Noneosinophilic inflammation is associated with corticosteroid insensitivity. Neutrophil activation in the airways and systemic inflammation is reported in neutrophilic asthma. Neutrophilia in asthma may be due to corticosteroids, associated chronic pulmonary infection, altered airway microbiome or delayed neutrophil apoptosis. The cause of poorly controlled noneosinophilic asthma may differ between patients and involve several mechanism including neutrophilic inflammation, T helper 2 (Th2)-low or other subtypes of airway inflammation or corticosteroid insensitivity as well as noninflammatory pathways such as airway hyperreactivity and remodelling. Smoking cessation in asthmatic smokers and removal from exposure to some occupational agents reduces neutrophilic inflammation. Preliminary studies of 'off-label' use of licensed drugs suggest that macrolides show efficacy in nonsmokers with noneosinophilic severe asthma and statins, low-dose theophylline and peroxisome proliferator-activated receptor gamma (PPARγ) agonists may benefit asthmatic smokers with noneosinophilic inflammation. Novel small molecules targeting neutrophilic inflammation, such as chemokine (CXC) receptor 2 (CXCR2) antagonists reduce neutrophils, but do not improve clinical outcomes in studies to date. Inhaled phosphodiesterase (PDE)4 inhibitors, dual PDE3 and PDE4 inhibitors, p38MAPK (mitogen-activated protein kinase) inhibitors, tyrosine kinase inhibitors and PI (phosphoinositide) 3kinase inhibitors are under development and these compounds may be of benefit in noneosinophilic inflammation. The results of clinical trials of biological agents targeting mediators associated with noneosinophilic inflammation, such as interleukin (IL)-17 and tumor necrosis factor (TNF)-α are disappointing. Greater understanding of the mechanisms of noneosinophilic inflammation in asthma should lead to improved therapies.

Keywords: airway inflammation; asthma; biological agents; biomarkers; cigarette smoking; corticosteroid insensitivity; eosinophils; neutrophils; small molecules.

Figure 1.

Schematic diagram of potential pathways leading to noneosinophilic inflammation and airway damage in severe asthma. Several inflammatory pathways could potentially lead to noneosinophilic inflammation and airway damage in asthma although the exact mechanisms are unclear. Possible pathways are briefly summarized in the schematic diagram. Stimuli such as viruses, cigarette smoke and pollutants could induce the release of chemoattractants including IL-8 to recruit neutrophils to the airways. The release of IL-17A and IL-17F from activated Th17 cells could stimulate the synthesis of neutrophil chemoattractants, such as CXCL1 and IL-8 from the airway epithelium. IFN-γ may also be involved in noneosinophilic asthma, possibly in part through its release from Th1 cells. Inflammatory mediators released by neutrophils are implicated in causing mucus gland hyperplasia and hypersecretion, airway hyperreactivity and remodelling as well as corticosteroid insensitivity in asthma. Th1 and Th17 cells may induce airway hyperreactivity or remodelling independently of neutrophil activation. Abbreviations: CXCL1, chemokine (C-X-C motif) ligand; IFN, interferon; IL, interleukin; LT, leukotriene; MMP, matrix metalloproteinase; MPO, myeloperoxidase; ROC, reactive oxygen species; TNF-α, tumor necrosis factor α.

Figure 2.

Targets and potential therapies for treating noneosinophilic airway inflammation in asthma. Noneosinophilic airway inflammation is found in approximately 50% of patients with asthma. The proportion of this group with neutrophilic inflammation is less certain because of variable cut-off points used to define neutrophilia. The higher the cut-off value used to define sputum neutrophilia the greater the proportion of patients that are classified as having paucigranulocytic inflammation. Pathways that may account for poor asthma control in patients with noneosinophilic asthma including neutrophilic inflammation, associated inflammatory phenotypes (Th1-high inflammation, Th17-high inflammation, a combination of Th2 and Th17 inflammation, mast cell-induced inflammation, and other inflammatory mechanisms) as well as corticosteroid insensitivity. Noninflammatory mechanisms such as airway hyperreactivity and airway remodelling may be important in causing symptoms in some individuals. Potential treatments targeting specific pathways are listed in the diagram. Novel small molecules targeting neutrophilic inflammation, such as CXCR2 antagonists reduce neutrophils, but do not improve clinical outcomes. Smoking cessation in asthmatic smokers and removal from exposure to occupational agents reduces neutrophilic inflammation. The results of clinical trials of biological agents targeting mediators associated with noneosinophilic inflammation, such as IL-17 and TNF-α are disappointing. Preliminary studies of ‘off-label’ use of licensed drugs suggest that macrolides show efficacy in nonsmokers with noneosinophilic severe asthma and statins, low-dose theophylline and PPARγ agonists may benefit asthmatic smokers with noneosinophilic inflammation and associated corticosteroid insensitivity. Inhaled PDE₄ inhibitors, dual PDE₃ and PDE₄ inhibitors, p38MAPK inhibitors, tyrosine kinase inhibitors and PI3kinase inhibitors are under development and these compounds may be of benefit in treating noneosinophilic inflammation and corticosteroid insensitivity. Long-acting bronchodilators or bronchial thermoplasty are possible treatment options for symptomatic patients with paucigranulocytic inflammation in whom there is no evidence of activated inflammatory pathways or corticosteroid insensitivity that could be targeted by specific therapies. Abbreviations: CXCR, C-X-C chemokine receptor; FLAP, 5-lipoxygenase-activating protein; IL, interleukin; PDE, phosphodiesterase; PI3K, phosphoinositide 3-kinase; PPARγ,: peroxisome proliferator-activated receptor-γ.