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2016 ; 10
(3
): 211-34
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Novel approaches to the management of noneosinophilic asthma
#MMPMID26929306
Thomson NC
Ther Adv Respir Dis
2016[Jun]; 10
(3
): 211-34
PMID26929306
show ga
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 (PPAR?) 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)-? are disappointing. Greater understanding of the mechanisms of
noneosinophilic inflammation in asthma should lead to improved therapies.
|Animals
[MESH]
|Anti-Asthmatic Agents/administration & dosage/*therapeutic use
[MESH]
|Asthma/*drug therapy/physiopathology
[MESH]
|Biological Factors/administration & dosage/therapeutic use
[MESH]
|Eosinophils/metabolism
[MESH]
|Glucocorticoids/administration & dosage/therapeutic use
[MESH]
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