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Severe Asthma Research - August 2015

Christina E Ciaccio, MD, MSc

Christina E Ciaccio, MD, MSc
Allergist/Immunologist
Assistant Professor of Pediatrics
University of Chicago Medicine
Comer Children’s Hospital
Chicago, Illinois, United States

Severe asthma is associated with airway dysbiosis

This study profiled the microbiome from bronchial brushings from 40 subjects ages 20 to 63 with severe asthma (SA) and compared it to previously studied healthy subjects (n=7) and those with mild-to-moderate disease (n=41). The authors found bronchial bacterial composition to be associated with body mass index, changes in Asthma Control Questionnaire (ACQ), sputum total leukocyte values, and bronchial biopsy eosinophil values. The presence of Proteobacteria was associated with worsening ACQ and total leukocyte values. The presence of Actinobacteria was associated with improving/stable ACQ score and bronchial epithelial gene expression of FK506 binding protein, an indicator of steroid responsiveness. Patients with SA were observed to have a significant increase (7.8 fold) in a Klebsiella genus member. This study confirms that airway dysbiosis in those with SA differs from those with milder asthma also on inhaled corticosteroids. Whether manipulation of the airway microbiota will influence the severity of disease remains to be seen.

Source: Huang YJ, Nariya S, Harris JM, Lynch SV, Choy DF, Arron JR, Boushey H. The airway microbiome in patients with severe asthma: Associations with disease features and severity. Journal of Allergy Clinical Immunology 2015; article in press. (doi:http://dx.doi.org/10.1016/j.jaci.2015.05.044)

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IFNɣ/SLPI axis dysregulation marks severe asthma

In this study, the authors collected broncho-alveolar (BAL) fluid from 66, predominantly Caucasian, adult subjects (33 with mild-moderate asthma and 33 with severe asthma). BAL cells were analyzed in a subset, and they found that IFNɣ (Th1) immune responses are increased in severe asthma (SA). The group then established a mouse model of SA by sensitizing mice to house dust mite and cyclic-di-GMP. This model proved to have airway hyperresponsiveness (AHR) resistant to dexamethasone compared to mice sensitized to house dust mite alone. When Ifng-/- mice were subjected to this protocol they did not mount AHR compared to wild type (WT) mice.  Computer-assisted pathway analysis linked IFNɣ to secretory leukocyte protease inhibitor (SLPI), and the two were found to be inversely correlated in both SA patients and the mouse model. Forced secretory leukocyte protease inhibitor (SLPI) expression was then found to decrease AHR in the mouse model. This study successfully clarifies the role of IFNɣ in SA and provides an exciting new potential target for therapeutic intervention.

Source: Raundhal M, Morse C, Khare A, Oriss TB, Milosevic J et al. High IFN-gamma and low SLPI mark severe asthma in mice and humans. The Journal of Clinical Investigation 2015; 125(8): 3037-3050. (doi:10.1172/JCI80911)

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Tralokinumab (anti-IL 13) found to be safe and well tolerated but failed to reduce asthma exacerbation in phase 2b trial   

This double-blind, randomized, placebo-controlled study included 452 patients with severe asthma (SA), ages 18-75, who received tralokinumab or placebo every 2 weeks or every 4 weeks for 1 year. The asthma exacerbation rate was not significantly different between tralokinumab (q 2 weeks), tralokinumab (q 4 weeks) and placebo. Pre-bronchodilator FEV1 was significantly increased compared to placebo in the tralokinumab (q2 week) group. Post-hoc analysis showed improvement in secondary endpoints in subgroups with: (1) an elevated baseline dipeptidyl peptidase-4 (DDP-4), and (2) an elevated baseline periostin level. Phase 3 trials are ongoing to investigate improvement in certain subgroups of patients with SA and potentially utilizing DPP-4 and periostin as biomarkers of IL-13 pathway activation. Although new treatments for SA are long overdue, biologic therapies which target a single cytokine pathway have been underwhelming. (Funded by MedImmune)

Source: Brightling CE, Chanez P, Leigh R, O’Byrne PM, Korn S et al. Efficacy and safety of tralokinumab in patients with severe uncontrolled asthma: a randomised, double-blind, placebo-controlled, phase 2b trail. The Lancet Respiratory Medicine 2015; published online ahead of print, 28 July. (doi:http://dx.doi.org/10.1016/S2213-2600(15)00197-6)

Summary