Effect of C1‐inhibitor in adults with mild asthma: A randomized controlled trial

Abstract

To the Editor, Several newly approved monoclonal antibodies targeting type 2 inflammation have shown remarkable beneficial effects in patients with severe asthma. Biologics directed against IL‐5 (mepolizumab, resli‐ zumab), IL‐5 receptor (benralizumab), or IL‐4 receptor α (dupilumab) have shown to reduce asthma exacerbation rate by about 50%.1,2 Though promising, these drugs are unable to completely alleviate in‐ flammation‐induced asthma symptoms. Moreover, a substantial subset of patients without a pronounced type 2 airway inflammation does not benefit from the currently available biologics. Therefore, novel anti‐ inflammatory treatments targeting other relevant asthma‐associated pathways are still warranted. In recent years, the complement system has been implicated in the pathogenesis of type 2 asthma.3 Elevated levels of anaphylatoxins, activation products of the complement sys‐ tem, have been found in the airways of asthma patients following local allergen provocation.4 Functional roles for the anaphylatoxins in asthma have been established in experimental studies in mice, show‐ ing that these proinflammatory mediators act synergistically and drive allergic inflammation.3 C1‐inhibitor (C1‐INH) is an endogenous pro‐ tein with a pivotal regulatory function in the complement system by inhibiting both the classical and lectin pathways. We hypothesized that C1‐INH administration inhibits complement activation and attenuates allergen‐induced airway eosinophilia in patients with mild asthma. In this randomized, double‐blind, placebo‐controlled, parallel study, 24 adults with asthma and house dust mite (HDM) allergy received a continuous intravenous infusion with human plasma‐de‐ rived C1‐INH 100 U kg−1 h−1 or placebo followed after 2 hours by segmental challenge with HDM and lipopolysaccharide (LPS) in one lung and saline in the contralateral lung as control. Bronchoalveolar lavage fluid was obtained seven hours after HDM/LPS or saline chal‐ lenge. The primary outcome was influx of eosinophils and neutro‐ phils, defined as number of cells/mL, into the bronchoalveolar space. Further details of the study design, subject selection criteria, bron‐ choalveolar lavage handling, assays, and statistical analysis are de‐ scribed in the supplemental section. Baseline patient characteristics were similar across treatment groups (Table S1). Two hours after the initiation of C1‐INH infusion, median plasma C1‐INH antigen concentrations were four times higher in C1‐INH‐ infused patients compared to vehicle‐infused controls (Figure S1A). Segmental HDM/LPS challenge resulted in increased C1‐INH antigen Monica C. Lopez4 M. Celeste Ferreira‐Cornwell1 John A. Getsy1