BACKGROUND Research has underscored the effects of exposure and sensitization to allergens on the severity of asthma in inner-city children. It has also revealed the limitations of environmental remediation and guidelines-based therapy in achieving greater disease control. METHODS We enrolled inner-city children, adolescents, and young adults with persistent asthma in a randomized, double-blind, placebo-controlled, parallel-group trial at multiple centers to assess the effectiveness of omalizumab, as compared with placebo, when added to guidelines-based therapy. The trial was conducted for 60 weeks, and the primary outcome was symptoms of asthma. RESULTS Among 419 participants who underwent randomization (at which point 73% had moderate or severe disease), omalizumab as compared with placebo significantly reduced the number of days with asthma symptoms, from 1.96 to 1.48 days per 2-week interval, a 24.5% decrease (P<0.001). Similarly, omalizumab significantly reduced the proportion of participants who had one or more exacerbations from 48.8 to 30.3% (P<0.001). Improvements occurred with omalizumab despite reductions in the use of inhaled glucocorticoids and long-acting beta-agonists. CONCLUSIONS When added to a regimen of guidelines-based therapy for inner-city children, adolescents, and young adults, omalizumab further improved asthma control, nearly eliminated seasonal peaks in exacerbations, and reduced the need for other medications to control asthma. (Funded by the National Institute of Allergy and Infectious Diseases and Novartis; ClinicalTrials.gov number, NCT00377572.)

Lung disease is the major cause of morbidity and mortality in patients with cystic fibrosis (CF). Although CF lung disease is primarily an infectious disorder, the associated inflammation is both intense and ineffective at clearing pathogens. Persistent high-intensity inflammation leads to permanent structural damage of the CF airways and impaired lung function that eventually results in respiratory failure and death. Several defective inflammatory responses have been linked to cystic fibrosis transmembrane conductance regulator (CFTR) deficiency including innate and acquired immunity dysregulation, cell membrane lipid abnormalities, various transcription factor signaling defects, as well as altered kinase and toll-like receptor responses. The inflammation of the CF lung is dominated by neutrophils that release oxidants and proteases, particularly elastase. Neutrophil elastase in the CF airway secretions precedes the appearance of bronchiectasis, and correlates with lung function deterioration and respiratory exacerbations. Anti-inflammatory therapies are therefore of particular interest for CF lung disease but must be carefully studied to avoid suppressing critical elements of the inflammatory response and thus worsening infection. This review examines the role of inflammation in the pathogenesis of CF lung disease, summarizes the results of past clinical trials and explores promising new anti-inflammatory options.

IMPORTANCE In asthma and other diseases, vitamin D insufficiency is associated with adverse outcomes. It is not known if supplementing inhaled corticosteroids with oral vitamin D3 improves outcomes in patients with asthma and vitamin D insufficiency. OBJECTIVE To evaluate if vitamin D supplementation would improve the clinical efficacy of inhaled corticosteroids in patients with symptomatic asthma and lower vitamin D levels. DESIGN, SETTING, AND PARTICIPANTS The VIDA (Vitamin D Add-on Therapy Enhances Corticosteroid Responsiveness in Asthma) randomized, double-blind, parallel, placebo-controlled trial studying adult patients with symptomatic asthma and a serum 25-hydroxyvitamin D level of less than 30 ng/mL was conducted across 9 academic US medical centers in the National Heart, Lung, and Blood Institute’s AsthmaNet network, with enrollment starting in April 2011 and follow-up complete by January 2014. After a run-in period that included treatment with an inhaled corticosteroid, 408 patients were randomized. INTERVENTIONS Oral vitamin D3 (100 000 IU once, then 4000 IU/d for 28 weeks; n = 201) or placebo (n = 207) was added to inhaled ciclesonide (320 µg/d). If asthma control was achieved after 12 weeks, ciclesonide was tapered to 160 µg/d for 8 weeks, then to 80 µg/d for 8 weeks if asthma control was maintained. MAIN OUTCOMES AND MEASURES The primary outcome was time to first asthma treatment failure (a composite outcome of decline in lung function and increases in use of β-agonists, systemic corticosteroids, and health care). RESULTS Treatment with vitamin D3 did not alter the rate of first treatment failure during 28 weeks (28%[95% CI, 21%-34%] with vitamin D3 vs 29% [95% CI, 23%–35%] with placebo; adjusted hazard ratio, 0.9 [95% CI, 0.6–1.3]). Of 14 prespecified secondary outcomes, 9 were analyzed, including asthma exacerbation; of those 9, the only statistically significant outcome was a small difference in the overall dose of ciclesonide required to maintain asthma control (111.3 µg/d [95% CI, 102.2–120.4 µg/d] in the vitamin D3 group vs 126.2 µg/d [95% CI, 117.2–135.3 µg/d] in the placebo group; difference of 14.9 µg/d [95% CI, 2.1–27.7 µg/d]). CONCLUSIONS AND RELEVANCE Vitamin D3 did not reduce the rate of first treatment failure or exacerbation in adults with persistent asthma and vitamin D insufficiency. These findings do not support a strategy of therapeutic vitamin D3 supplementation in patients with symptomatic asthma. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01248065

Vertex Pharmaceuticals.

Background Phenotypic presentations in young children with asthma are varied and may contribute to differential responses to asthma controller medications. Methods The Individualized Therapy for Asthma in Toddlers (INFANT) study was a multicenter, randomized, double-blind, double-dummy, clinical trial in children age 12-59 months (n=300) with asthma necessitating treatment with daily controller (Step 2) therapy. Participants completed a 2-8 week run-in period followed by three crossover periods with daily inhaled corticosteroid (ICS), daily leukotriene receptor antagonist (LTRA), and as-needed ICS treatment co-administered with albuterol. The primary outcome was differential response to asthma medication based on a composite measure of asthma control. The primary analysis involved two stages: determination of differential response, and assessment of whether three pre-specified features (aeroallergen sensitization, previous exacerbations, sex) predicted differential response. Results 74% (170 of 230) of children with analyzable data had a differential response to the three treatment strategies. Within differential responders, the probability of best response was highest for daily ICS and was predicted by aeroallergen sensitization, but not exacerbation history or sex. The probability of best response to daily ICS was further increased in children with both aeroallergen sensitization and blood eosinophils ≥300/μL. In these children, daily ICS was associated with more asthma control days and fewer exacerbations compared to the other treatments. Conclusions In young children with asthma necessitating Step 2 treatment, phenotyping with aeroallergen sensitization and blood eosinophils is useful for guiding treatment selection and identifies children with a high exacerbation probability for whom treatment with daily ICS is beneficial despite possible risks of growth suppression.

Inflammation plays a critical role in cystic fibrosis (CF) lung pathology and disease progression making it an active area of research and important therapeutic target. In this review, we explore the most recent research on the major contributors to the exuberant inflammatory response seen in CF as well as potential therapeutics to combat this response. Absence of functional cystic fibrosis transmembrane conductance regulator (CFTR) alters anion transport across CF airway epithelial cells and ultimately results in dehydration of the airway surface liquid. The dehydrated airway surface liquid in combination with abnormal mucin secretion contributes to airway obstruction and subsequent infection that may serve as a trigger point for inflammation. There is also evidence to suggest that airway inflammation may be excessive and sustained relative to the infectious stimuli. Studies have shown dysregulation of both pro-inflammatory mediators such as IL-17 and pro-resolution mediators including metabolites of the eicosanoid pathway. Recently, CFTR potentiators and correctors have garnered much attention in the CF community. Although these modulators address the underlying defect in CF, their impact on downstream consequences such as inflammation are not known. Here, we review pre-clinical and clinical data on the impact of CFTR modulators on inflammation. In addition, we examine other cell types including neutrophils, macrophages, and T-lymphocytes that express CFTR and contribute to the CF inflammatory response. Finally, we address challenges in developing anti-inflammatory therapies and highlight some of the most promising anti-inflammatory drugs under development for CF.

Our objectives were to characterise the microbiota in cystic fibrosis (CF) bronchoalveolar lavage fluid (BALF), and determine its relationship to inflammation and disease status. BALF from paediatric and adult CF patients and paediatric disease controls undergoing clinically indicated bronchoscopy was analysed for total bacterial load and for microbiota by 16S rDNA sequencing. We examined 191 BALF samples (146 CF and 45 disease controls) from 13 CF centres. In CF patients aged <2 years, nontraditional taxa (e.g. Streptococcus, Prevotella and Veillonella) constituted ~50% of the microbiota, whereas in CF patients aged ⩾6 years, traditional CF taxa (e.g. Pseudomonas, Staphylococcus and Stenotrophomonas) predominated. Sequencing detected a dominant taxon not traditionally associated with CF (e.g. Streptococcus or Prevotella) in 20% of CF BALF and identified bacteria in 24% of culture-negative BALF. Microbial diversity and relative abundance of Streptococcus, Prevotella and Veillonella were inversely associated with airway inflammation. Microbiota communities were distinct in CF compared with disease controls, but did not differ based on pulmonary exacerbation status in CF. The CF microbiota detected in BALF differs with age. In CF patients aged <2 years, Streptococcus predominates, whereas classic CF pathogens predominate in most older children and adults.

Cystic fibrosis (CF) lung disease is characterized by a self-perpetuating cycle of airway obstruction, chronic bacterial infection, and vigorous inflammation that results in structural damage to the airway. CF patients have a predilection for infection with a limited spectrum of distinctive bacteria that initiate a vigorous inflammatory response which is more harmful than protective. The airway epithelial cell, which normally expresses the cystic fibrosis transmembrane conductance regulator (CFTR), directs the inflammatory response. Defects in CFTR are associated with increased production of pro-inflammatory mediators including IL-8, a potent neutrophil chemoattractant that stimulates the influx of massive numbers of neutrophils into the airways. These neutrophils are the primary effector cells responsible for the pathological manifestations of CF lung disease. Documented deficiencies in immunoregulatory molecules such as IL-10 likely contribute to the generation of the excessive and persistent inflammatory response. Since inflammation is a key contributor to the pathogenesis of CF lung disease, anti-inflammatory therapy must assume a larger role in CF until a cure is discovered. To date, attention has focused primarily on the therapeutic potential of systemic and inhaled corticosteroids and the non-steroidal anti-inflammatory drug (NSAID) ibuprofen. Development of new anti-inflammatory therapies that impact intracellular signaling pathways and cell-cell communication molecules likely will have the greatest impact on limiting the excessive production of the inflammatory mediators in the CF lung, thereby slowing the decline in lung function and improving survival.