Pneumococcal carriage is more common in asthmatic than in non‐asthmatic young men

Jounio, Ulla; Juvonen, Raija; Bloigu, Aini; Silvennoinen-Kassinen, Sylvi; Kaijalainen, Tarja; Kauma, Heikki; Peitso, Ari; Saukkoriipi, Annika; Vainio, Olli; Harju, Terttu; Leinonen, Maija

doi:10.1111/j.1752-699x.2009.00179.x

Cited by 52 publications

(34 citation statements)

References 30 publications

(42 reference statements)

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“…People with asthma have increased susceptibility to streptococcal infections, [13][14][15] increased carriage of bacterial pathogens identified by culture 16 and molecular techniques, 17 and impaired interferon and type 1 T helper cell responses to bacterial polysaccharides. 18,19 Viral infection impairs antibacterial innate immune responses 20 and increases bacterial adherence to bronchial epithelium.…”

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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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“…During the immune response to pathogens such as Mycobacterium tuberculosis, Staphylococcus aureus, Listeria monocytogenes, Escherichia coli, and Candida albicans (41-44), ␥␦17 cells stimulated neutrophil recruitment, antibacterial peptide production, and maintenance of epithelial barriers (45). Notably, people with asthma, whose T cells express high levels of STAT6 (46), are at increased risk for invasive bacterial infections and bacterial pneumonia (47)(48)(49)(50). However, the mechanisms by which asthma impairs host defense against bacterial infection are unknown.…”

Section: Discussionmentioning

confidence: 99%

STAT6 Signaling Attenuates Interleukin-17-Producing γδ T Cells during Acute Klebsiella pneumoniae Infection

et al. 2016

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A pproximately 50% of the intraepithelial lymphocyte population is composed of ␥␦ T cells, which constitute a critical first line of defense against bacterial and fungal pathogens (1). In contrast to adaptive ␣␤ T cells, ␥␦ T cells are capable of immediate cytokine release, providing an initial innate layer of protection at mucosal surfaces while influencing the development of subsequent adaptive responses (2, 3). ␥␦17 cells are a subset of ␥␦ T cells that produce large quantities of interleukin-17A (IL-17A), a cytokine crucial to antibacterial and antifungal defense (4). ␥␦17 cells also produce high levels of IL-17A in various models of inflammation and autoimmunity, including experimental autoimmune encephalitis, ischemic brain injury, and psoriasis (2, 3, 5-7). While these data highlight the importance of understanding how ␥␦17 cell function is regulated, this process remains poorly understood.␥␦17 cell function is controlled by multiple immune cell populations and soluble molecules, particularly cytokines. Within 4 to 8 h in the presence of the inflammatory cytokines IL-23 and IL-1␤, ␥␦17 cells secrete IL-17A without the need for T cell receptor (TCR) engagement (2). ␥␦17 cells constitutively express IL-23 receptor (IL-23R) and IL-1R1, providing for an efficient mechanism to induce rapid effector cytokine production. A recent study showed that the serine/threonine kinase Sgk1 is a novel, critical regulator of IL-23R expression (8).Studies from our group and others have established that STAT6 negatively regulates IL-17A expression in Th17 cells (9-13). By extension, we hypothesized that STAT6 also inhibits innate ␥␦17 cell cytokine secretion. STAT6 is a transcription factor important for Th2 differentiation, inhibiting Th1 differentiation and activating the B cell response (14). IL-4 signals through both the type I IL-4 receptor (IL-4R), which consists of IL-4R␣ and the common ␥-chain, and the type II IL-4R, which consists of IL-4R␣ and IL-13R␣, while IL-13 signals through only the type II IL-4R (15, 16). IL-4 binds to the IL-4R␣ subunit and IL-13 binds to the IL-13R␣ subunit of the IL-4 heterodimer receptor with high affinity, leading to the phosphorylation of STAT6 (17,18). STAT6 is expressed at high levels in the settings of parasitic infections (19) and asthma, during which STAT6 induces Th2 differentiation, IgE antibody class switching, goblet cell metaplasia, alternative macrophage activation, mucus expression, and airway remodeling (20). Thus, STAT6 attenuation of ␥␦17 cell function may impair host defenses against bacterial and fungal infections in people with asthma or parasitic infections.We found that ␥␦17 cells expressed the type I IL-4R, and that IL-4 increased STAT6 phosphorylation in ␥␦17 cells. Furthermore, IL-4 signaling attenuated ␥␦17 cell production of IL-17A and IL-17F. IL-4 also decreased ␥␦17 cell expression of IL-23R as well as Sgk1. To determine whether STAT6 regulates ␥␦17 cell cytokine expression in vivo, we used a mouse model of Klebsiella pneumoniae lung infection in mice deficien...

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“…There is little published evidence that standard bacterial infections are important in the aetiology of asthma exacerbations; 14 however, patients with asthma have increased susceptibility to respiratory bacterial infections, [15][16][17] increased carriage of pathogenic respiratory bacteria identified by culture 18 and molecular techniques, 19 and impaired interferon responses to bacterial polysaccharides. 20 In addition, viral infection impairs innate responses that are important in antibacterial immunity 21 and increases bacterial adherence to bronchial epithelial cells.…”

Section: Aetiology Of Asthma Exacerbationsmentioning

confidence: 99%

A randomised, double-blind, placebo-controlled study to evaluate the efficacy of oral azithromycin as a supplement to standard care for adult patients with acute exacerbations of asthma (the AZALEA trial)

et al. 2016

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Declared competing interests of authors: Sebastian L Johnston has received institutional funding for a clinical trial and consultant compensation from Centocor, Sanofi Pasteur, GlaxoSmithKline and Synairgen; institutional funding for a research grant and consultant compensation from Chiesi, Boehringer Ingelheim and Novartis; and consultant compensation from Grünenthal. He is also a shareholder in Synairgen and has nine relevant licensed patents and one relevant patent pending. Christopher Brightling has received institutional grants and consultant compensation from GlaxoSmithKline, AstraZeneca, Boehringher Ingleheim, Novartis, Chiesi and Roche/Genentech. Dave Singh has received grants and personal fees from Almirall, AstraZeneca, Boehringher Ingleheim, Chiesi, GlaxoSmithKline, Glenmark, Johnson & Johnson, Merck, NAPP, Novartis, Pfizer, Takeda, Teva, Theravance and Verona, and personal fees from Genentech and Skyepharma. Bernard Higgins has taken the role of local principal investigator for multicentre studies funded by Novartis and Roche. Christopher Corrigan has received a grant and personal fees for attendance at scientific conferences and payments for lectures from Allergy Therapeutics; a grant and personal fees from Novartis for research collaborations and consultancy not connected with the current research; a grant for attendance at scientific conferences from Stallergenes, Boehringer Ingelheim and Diagenics; and personal fees from AstraZeneca for speaking at conferences. Rekha Chaudhuri reports a grant and personal fees for attendance at scientific conferences and advisory board meetings: Novartis Pharmaceuticals, Astra-Zeneca, Teva and GlaxoSmithKline. Published October 2016 DOI: 10.3310/eme03080This report should be referenced as follows:Johnston SL, Szigeti M, Cross M, Brightling C, Chaudhuri R, Harrison T, et al. A randomised, double-blind, placebo-controlled study to evaluate the efficacy of oral azithromycin as a supplement to standard care for adult patients with acute exacerbations of asthma (the AZALEA trial). Efficacy Mech Eval 2016;3(8). This journal is a member of and subscribes to the principles of the Committee on Publication Ethics (COPE) (www.publicationethics.org/). Efficacy and Mechanism EvaluationEditorial contact: nihredit@southampton.ac.ukThe full EME archive is freely available to view online at www.journalslibrary.nihr.ac.uk/eme. Print-on-demand copies can be purchased from the report pages of the NIHR Journals Library website: www.journalslibrary.nihr.ac.uk Criteria for inclusion in the Efficacy and Mechanism Evaluation journalReports are published in Efficacy and Mechanism Evaluation (EME) if (1) they have resulted from work for the EME programme, and (2) they are of a sufficiently high scientific quality as assessed by the reviewers and editors. EME programmeThe Efficacy and Mechanism Evaluation (EME) programme was set up in 2008 as part of the National Institute for Health Research (NIHR) and the Medical Research Council (MRC) coordinated strategy for clinical trials. The EME pro...

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Pneumococcal carriage is more common in asthmatic than in non‐asthmatic young men

Abstract: Pneumococcal carriage is more common in asthmatic than in non-asthmatic young men.

Cited by 52 publications

References 30 publications

Azithromycin for Acute Exacerbations of Asthma

Azithromycin for Acute Exacerbations of Asthma

STAT6 Signaling Attenuates Interleukin-17-Producing γδ T Cells during Acute Klebsiella pneumoniae Infection

A randomised, double-blind, placebo-controlled study to evaluate the efficacy of oral azithromycin as a supplement to standard care for adult patients with acute exacerbations of asthma (the AZALEA trial)

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