Role of deficient type III interferon-λ production in asthma exacerbations

Contoli, Marco; Message, Simon D.; Laza-Stanca, Vasile; Edwards, Michael R.; Wark, Peter; Bartlett, Nathan W.; Kebadze, Tatiana; Mallia, Patrick; Stanciu, Luminita A.; Parker, Hayley L.; Slater, Louise; Lewis-Antes, Anita; Kon, Onn Min; Holgate, Stephen T.; Davies, Donna E.; Kotenko, Sergei V.; Papi, Alberto; Johnston, Sebastian L.

doi:10.1038/nm1462

Cited by 949 publications

(983 citation statements)

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“…18,19 Viral infection impairs antibacterial innate immune responses 20 and increases bacterial adherence to bronchial epithelium. 21 Thus, bacterial infections are more common and more severe in patients with asthma, viruses increase susceptibility to bacterial infection, and acute wheezing episodes in children younger than 3 years were associated with both bacterial and viral infection.…”

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confidence: 99%

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Azithromycin for Acute Exacerbations of Asthma

et al. 2016

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IMPORTANCEGuidelines recommend against antibiotic use to treat asthma attacks. A study with telithromycin reported benefit, but adverse reactions limit its use.OBJECTIVE To determine whether azithromycin added to standard care for asthma attacks in adults results in clinical benefit. DESIGN, SETTING, AND PARTICIPANTSThe Azithromycin Against Placebo in Exacerbations of Asthma (AZALEA) randomized, double-blind, placebo-controlled clinical trial, a United Kingdom-based multicenter study in adults requesting emergency care for acute asthma exacerbations, ran from September 2011 to April 2014. Adults with a history of asthma for more than 6 months were recruited within 48 hours of presentation to medical care with an acute deterioration in asthma control requiring a course of oral and/or systemic corticosteroids.INTERVENTIONS Azithromycin 500 mg daily or matched placebo for 3 days. MAIN OUTCOMES AND MEASURESThe primary outcome was diary card symptom score 10 days after randomization, with a hypothesized treatment effect size of −0.3. Secondary outcomes were diary card symptom score, quality-of-life questionnaires, and lung function changes, all between exacerbation and day 10, and time to a 50% reduction in symptom score. RESULTSOf 4582 patients screened at 31 centers, 199 of a planned 380 were randomized within 48 hours of presentation. The major reason for nonrecruitment was receipt of antibiotics (2044 [44.6%] screened patients). Median time from presentation to drug administration was 22 hours (interquartile range, 14-28 hours). Exacerbation characteristics were well balanced across treatment arms and centers. The primary outcome asthma symptom scores were mean (SD), 4.14 (1.38) at exacerbation and 2.09 (1.71) at 10 days for the azithromycin group and 4.18 (1.48) and 2.20 (1.51) for the placebo group, respectively. Using multilevel modeling, there was no significant difference in symptom scores between azithromycin and placebo at day 10 (difference, −0.166; 95% CI, −0.670 to 0.337), nor on any day between exacerbation and day 10. No significant between-group differences were observed in quality-of-life questionnaires or lung function between exacerbation and day 10, or in time to 50% reduction in symptom score. CONCLUSIONS AND RELEVANCEIn this randomized population, azithromycin treatment resulted in no statistically or clinically significant benefit. For each patient randomized, more than 10 were excluded because they had already received antibiotics.TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01444469

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“…19,27 A mechanistic and exploratory aim of AZALEA was to determine whether treatment benefited patients with these infections.…”

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Azithromycin for Acute Exacerbations of Asthma

et al. 2016

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“…In fact, impaired antiviral immunity has been reported in both asthmatic (Contoli et al. 2006; Edwards et al. 2012b; Uller et al.…”

Section: Discussionmentioning

confidence: 99%

Anti‐inflammatory effects of the novel inhaled phosphodiesterase type 4 inhibitor CHF6001 on virus‐inducible cytokines

Edwards

Facchinetti

Civelli

et al. 2016

Pharmacology Res & Perspec

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Respiratory virus infections precipitate asthma and chronic obstructive pulmonary disease (COPD) exacerbations, with most exacerbations due to rhinovirus infection. Both asthma and COPD exacerbations are not well controlled by steroid therapies, and there is a much research interest in finding improved therapies or combinations of therapies for controlling exacerbations. CHF6001 is a new, inhaled highly potent and selective phosphodiesterase type 4 (PDE4) inhibitor. Using in vitro human bronchial epithelial cells (BEAS‐2B), we investigated the potential anti‐inflammatory effects of CHF6001 on rhinovirus (RV1B)‐induced cytokines. Cytokine mRNA was measured by real‐time PCR, while protein release was measured by ELISA. CHF6001 was used in a 7‐point dose–response curve (1000–0.001 nmol/L) as a 1.5‐h pretreatment prior to infection in comparison with roflumilast. Both roflumilast and CHF6001 reduced RV1B‐induced IL‐8, IL‐29, IP‐10, and RANTES mRNA and protein in a concentration‐dependent manner. Generally, CHF6001 was 13‐ to 16‐fold more potent (subnanomolar EC 50 values) than roflumilast at reducing IL‐8, IL‐29, IP‐10, and RANTES mRNA and protein release, but had similar efficacies. In combination with the steroid fluticasone propionate (1 nmol/L), CHF6001 had additive effects, significantly reducing RV‐induced cytokines when compared with steroid or CHF6001 alone. Combined low‐dose steroid and low‐dose CHF6001 had a similar efficacy as high‐dose steroid or CHF6001 alone, indicating the combination had steroid and PDE4 inhibitor sparing effects. Overall results indicate that PDE4 inhibitors have anti‐inflammatory activity against virus‐induced inflammatory mediators and that CHF6001 is more potent than roflumilast.

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“…We hypothesized that atopy, particularly to indoor allergens, would be associated with increased antigen‐induced Th2‐like cytokine responses, and that these responses would be especially prominent in women with allergic asthma. We also expected that asthma in this population would be associated with deficient Th1‐like cytokine (IFN‐γ and IL‐12p40) and reduced type 1 interferon responses in response to viral and microbial stimuli, as reported in other studies 18, 19, 20.…”

Section: Introductionmentioning

confidence: 74%

The influence of atopy and asthma on immune responses in inner‐city adults

Kakumanu

Jaffee

Visness

et al. 2016

Immunity, Inflammation and Disease

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Asthma in the inner‐city population is usually atopic in nature, and is associated with significant morbidity and mortality. However, the underlying immune abnormalities that underlie asthma in urban adults have not been well defined. We investigated the influence of atopy and asthma on cytokine responses of inner‐city adult women to define immune abnormalities associated with asthma and atopy. Blood samples were collected from 509 of 606 inner‐city women enrolled in the Urban Environment and Childhood Asthma (URECA) study. We tested for associations between atopy and asthma status and cytokine responses in peripheral blood mononuclear cells incubated ex vivo with a panel of innate and adaptive immune stimulants. Atopic subjects had heightened Th2 cytokine responses (IL‐4, IL‐5, IL‐13) to cockroach and dust mite antigens, tetanus toxoid, and phytohemagglutinin (P < 0.05 for all). Differences in cytokine responses were greatest in response to stimulation with cockroach and dust mite. In a multivariate analysis, atopy was broadly related to increased Th2‐like responses to all antigens and PHA, while asthma was only weakly related to mitogen‐induced IL‐4 and IL‐5 responses. There were few asthma or allergy‐related differences in responses to innate stimuli, including IFN‐α and IFN‐γ responses. In this inner‐city adult female population, atopy is associated with enhanced Th2 responses to allergens and other stimuli, and there was little or no additional signal attributable to asthma. In particular, these data indicate that altered systemic interferon and innate immune responses are not associated with allergies and/or asthma in inner‐city women.

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Role of deficient type III interferon-λ production in asthma exacerbations

Cited by 949 publications

References 14 publications

Azithromycin for Acute Exacerbations of Asthma

Azithromycin for Acute Exacerbations of Asthma

Anti‐inflammatory effects of the novel inhaled phosphodiesterase type 4 inhibitor CHF6001 on virus‐inducible cytokines

The influence of atopy and asthma on immune responses in inner‐city adults

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