Multicenter Randomized Controlled Trial of Withdrawal of Inhaled Corticosteroids in Cystic Fibrosis

Abstract

Rationale: Lung inflammation and injury is critical in cystic fibrosis. An ideal antiinflammatory agent has not been identified but inhaled corticosteroids are widely used despite lack of evidence. Objectives: To test the safety of withdrawal of inhaled corticosteroids with the hypothesis this would not be associated with an earlier onset of acute chest exacerbations. Methods: Multicenter randomized double-blind placebo-controlled trial in 18 pediatric and adult UK centers. Eligibility criteria included age Ͼ 6.0 yr, FEV 1 у 40% predicted, and corticosteroid use Ͼ 3 mo. During the 2-mo run-in period, all patients received fluticasone; they then took either fluticasone or placebo for 6 mo. Measurements and Main Results: Fluticasone group: n ϭ 84, median age 14.6 yr, mean (SD) FEV 1 76% (18); placebo group: n ϭ 87, median age 15.8 yr, mean (SD) FEV 1 76% (18). There was no difference in time to first exacerbation (primary outcome) with hazard ratio (95% confidence interval) of 1.07 (0.68 to 1.70) for fluticasone versus placebo. There was no effect of age, atopy, corticosteroid dose, FEV 1 , or Pseudomonas aeruginosa status. There was no change in lung function or differences in antibiotic or rescue bronchodilator use. Fewer patients in the fluticasone group withdrew from the study due to lung-related adverse events (9 vs. 15%); with a relative risk (95% confidence interval) of 0.59 (0.23-1.48) fluticasone versus placebo. Conclusions:In this study population (applicable to 40% of patients with cystic fibrosis in the UK), it appears safe to consider stopping inhaled corticosteroids. Potential advantages will be to reduce the drug burden on patients, reduce adverse effects, and make financial savings.

Primary ciliary dyskinesia: a consensus statement on diagnostic and treatment approaches in children

“…Antiinflammatory strategies such as alternate-day prednisolone have been shown to be effective in CF [99], but need to be formally trialled in PCD before they could be recommended. There are no data on which to recommend or avoid inhaled corticosteroids; by analogy with CF [100], they are probably best avoided unless they can be shown to be of definite benefit in an individual patient.…”

The pros and cons of immunomodulatory IL-10 gene therapy with recombinant AAV in a Cftr−/−-dependent allergy mouse model

“…Although this represents a very high prevalence, asthma is much more common in children with CF, where the rate of bronchial hyper-responsiveness approaches 50%, and up to 10-15% may experience a hyper-IgE asthma variant known as allergic bronchopulmonary aspergillosis (ABPA). [29][30][31][32][33][34][35][36][37][38][39][40] ABPA is characterized by a predominantly Th2-mediated immune response to inhaled Aspergillus antigens in the airways, leading to reversible airway obstruction and bronchial hyper-reactivity. This inflammatory response correlates with the local infiltration of effector cells including mast cells, activated neutrophils, eosinophils, basophils and macrophages into the airway mucosa and the airway lumen.…”

Inhibition of airway proteases in cystic fibrosis lung disease

“…Other studies have demonstrated the ineffectiveness or the occurrence of adverse side-effects of approaches involving inhaled steroids [8] and a leukotriene (LT)B 4 antagonist [9]. A major difficulty in evaluating anti-inflammatory treatments in clinical trials remains selection of appropriate outcome measures (table 1).…”