Treatment options in type-2 low asthma

Abstract

Monoclonal antibodies targeting IgE or the type-2 cytokines interleukin (IL)-4, IL-5 and IL-13 are proving highly effective in reducing exacerbations and symptoms in people with severe allergic and eosinophilic asthma, respectively. However, these therapies are not appropriate for 30-50% of patients in severe asthma clinics who present with non-allergic, non-eosinophilic, "type-2 low" asthma. These patients constitute an important and common clinical asthma phenotype, driven by distinct, yet poorly understood pathobiological mechanisms. In this review we describe the heterogeneity and clinical characteristics of type-2 low asthma and summarise current knowledge on the underlying pathobiological mechanisms, which includes neutrophilic airway inflammation often associated with smoking, obesity and occupational exposures and may be driven by persistent bacterial infections and by activation of a recently described IL-6 pathway. We review the evidence base underlying existing treatment options for specific treatable traits that can be identified and addressed. We focus particularly on severe asthma as opposed to difficult-to-treat asthma, on emerging data on the identification of airway bacterial infection, on the increasing evidence base for the use of long-term low-dose macrolides, a critical appraisal of bronchial thermoplasty, and evidence for the use of biologics in type-2 low disease. Finally, we review ongoing research into other pathways including tumour necrosis factor, IL-17, resolvins, apolipoproteins, type I interferons, IL-6 and mast cells. We suggest that type-2 low disease frequently presents opportunities for identification and treatment of tractable clinical problems; it is currently a rapidly evolving field with potential for the development of novel targeted therapeutics.

Figure 1. Suggested algorithm for defining type-2 low asthma in clinical practice.

CF, cystic fibrosis; COPD, chronic obstructive pulmonary disease; Eos, eosinophils; FeNO, fractional exhaled nitric oxide; HRCT, high-resolution computed tomograph; PCD, primary ciliary dyskinesia; PCR, polymerase chain reaction.

Figure 2. Key pathways mediating neutrophilic airway inflammation in type 2-low asthma.

APO, apolipoprotein; CXCL, C-X-C motif chemokine ligand; CXCR, C-X-C motif chemokine receptor; FPR, N-formyl peptide receptor; G-CSF, granulocyte colony-stimulating factor; G-CSFR, granulocyte colony-stimulating factor receptor; GM-CSF, granulocyte/monocyte colony-stimulating factor; GM-CSFR, granulocyte/monocyte colony-stimulating factor receptor; gp130, glycoprotein 130; ICS, inhaled corticosteroid; IFN interferon; IL, interleukin; ILC, innate lymphoid cell; IL-6TS, interleukin-6 trans-signaling; LXA, lipoxin; NLRP, nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain containing; sIL-6R, soluble interleukin-6 receptorm; SAA, serum amyloid A; SLPI, secretory leukocyte protease inhibitor; Th, T helper CD4+ lymphocyte; TNF, tumor necrosis factor; TSLP, thymic stromal lymphopoietin.

Figure 3. Clinical trial data for azithromycin data in severe asthma and for induction of resistance in healthy volunteers.

(a) Proportion of subjects with non-eosinophilic severe asthma (FeNOHaemophilus influenzae copy number before and after either placebo (left, red) or azithromycin (right, blue) in AMAZES. Reproduced from Taylor SL[91] with permission from American Thoracic Society.