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.