Neutrophil degranulation and cell lysis is associated with clinical severity in virus-induced asthma

Wark, Peter; Johnston, Sebastian L.; Moric, Ivana; Simpson, Jodie L.; Hensley, Michael; Gibson, Peter G.

doi:10.1183/09031936.02.00226302

Cited by 336 publications

(310 citation statements)

References 29 publications

(41 reference statements)

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“…2 Respiratory viral infections are a frequent cause of asthma exacerbations in children 3,4 and adults. [5][6][7] Atypical bacterial (Mycoplasma pneumoniae and Chlamydophila pneumoniae) infection and/or reactivation is also associated, with serologic positivity rates of 40% to 60% in some studies, [8][9][10][11][12] indicating that viral and atypical bacterial infections may interact in increasing asthma exacerbation risk.…”

mentioning

confidence: 99%

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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confidence: 99%

Azithromycin for Acute Exacerbations of Asthma

et al. 2016

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“…TLR protein expression was assessed in sputum cytospins (alkaline phosphatase anti-alkaline phosphatase (APAAP) technique) with anti-human TLR2 (Clone TLR2.1) and TLR4 (Clone HTA125) antibodies (Serotec, Oxford, UK) as described previously. 24 Cytospins were fixed using paraformaldehyde, L-lysine, periodate and allowed to air dry before being immersed in sucrose solution for storage. 25 Slides were stored at 220˚C until immunocytochemical analysis was undertaken.…”

Section: Specific Target Positive Calibratorsmentioning

confidence: 99%

Innate immune activation in neutrophilic asthma and bronchiectasis

Simpson

Grissell

Douwes

et al. 2007

Thorax

295

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Background: The role of the innate immune system in the pathogenesis of asthma is unclear. Activation of innate immune receptors in response to bacterial lipopolysaccharide, viral infection and particulate matter triggers a pre-programmed inflammatory response, which involves interleukin (IL)8 and neutrophil influx. The inflammatory response in asthma is heterogeneous. Aim: To test the hypothesis that innate immune activation may be a relevant inflammatory mechanism in neutrophilic asthma where IL8 levels are increased. Methods: Induced sputum was obtained from non-smoking adults with asthma (n = 49), healthy controls (n = 13) and a positive reference group with bronchiectasis (n = 9). Subjects with asthma were classified into inflammatory subtypes using induced sputum cell counts. Sputum was examined for mRNA expression of the innate immune receptors toll-like receptor (TLR)2, TLR4 and CD14, and inflammatory cytokines. A separate sputum portion was dispersed and the supernatant assayed for surfactant protein A, IL8, soluble CD14 and endotoxin. Results: Expression of innate immune receptors was increased in subjects with bronchiectasis and neutrophilic asthma compared with other asthma subtypes and controls. Increased expression of the receptors TLR2, TLR4 and CD14, as well as the pro-inflammatory cytokines IL8 and IL1b, was observed. Subjects with neutrophilic asthma had higher airway levels of endotoxin than the other groups studied. Conclusion: There is evidence of activation of the innate immune system in asthma which results in the production of pro-inflammatory cytokines and may contribute to the pathogenesis of neutrophilic asthma.

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“…(Johnston et al, 1995) In a study of 49 Australian adults who were enrolled within 4 hours of an emergency department visit for an asthma exacerbation, 19 (39%) had RSV detected by either PCR or direct fluorescent antigen. (Wark et al, 2002) To our knowledge, there are no other studies which report the RSV detection rate in adults with acute asthma exacerbations; however, a 39% detection rate seems unusually high given that only 8% had detection of rhinovirus, which in most studies is by far the most common virus detected in adult asthmatics. In the Australian study, the subjects were enrolled from February 2-December 1, which should have included the peak times of both RSV and rhinovirus infection in the Southern hemisphere.…”

Section: Identification Of Rsv During Asthma Exacerbations In Peoplementioning

confidence: 97%

Challenges and Opportunities for Respiratory Syncytial Virus Vaccines

2013

Current Topics in Microbiology and Immunology

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Reactive airway disease (RAD) is a general term for respiratory illnesses manifested by wheezing. Respiratory syncytial virus (RSV) results in wheezing, either by causing bronchiolitis or by inducing acute exacerbations of asthma. There has been a long standing interest in whether severe RSV bronchiolitis in infancy is a risk factor for the development of asthma later in childhood. While epidemiologic studies have suggested that such a link exists, a very recent study suggests that infants with greater airways responsiveness to methacholine instead have an increased prevalence of severe RSV bronchiolitis. Increased airways responsiveness to methacholine has been implicated as a key factor for loss of lung function in asthmatic subjects, suggesting that instead of being causal, severe RSV infection may instead be a marker of a predisposing factor for asthma. In this chapter, we will explore the evidence that RSV infection leads to RAD in infants and adults, and how these different forms of RAD may be linked.

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Neutrophil degranulation and cell lysis is associated with clinical severity in virus-induced asthma

Cited by 336 publications

References 29 publications

Azithromycin for Acute Exacerbations of Asthma

Azithromycin for Acute Exacerbations of Asthma

Innate immune activation in neutrophilic asthma and bronchiectasis

Challenges and Opportunities for Respiratory Syncytial Virus Vaccines

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