By Dr. Geoffrey Modest
Although antibiotics should not be routinely used in those with asthma exacerbations, per the British Thoracic Society and Global Initiative for Asthma guidelines, they are frequently prescribed at the pains of increased microbial resistance and microbiome changes, as well as potential adverse effects. A recent study found no efficacy for azithromycin for acute exacerbations of asthma (see doi:10.1001/jamainternmed.2016.5664), the AZALEA study.
Details:
- 4582 patients from 31 centers in the UK, though only 199 patients qualified for the study (from their target of 380) and were randomized
- Mean age 38; 70% female; 85% were on either: regular preventer therapy, initial add-on therapy or persistent poor control (i.e., few with either mild intermittent asthma or on continuous/frequent oral steroids); median FEV1=63% of predicted, FEV1/FVC=70%, peak expiratory flow (PEF) of 67% predicted
- Inclusion criteria: 18-55 yo with any smoking history, 56-65 if less than 20 pack-year smoking, or >65 yo with <5 pack-year; documented asthma for >6 months; recruitment within 48 hours of asthma attack with acute deterioration of asthma control (increased wheeze/dyspnea/cough) necessitating systemic steroids per the attending MDs, and PEF or FEV1 <80% predicted
- Randomized to azithro 500 daily for 3 days vs placebo, with posttherapy assessment at day 5 and 10, as well as serum sampling at 6 weeks
- Primary outcome: diary card summary of symptom score (wheezing, dyspnea, cough assessed at 10 days after randomization). Secondary outcomes: acute Asthma Quality of Life Questionnaire, FEV1, FVC, FEV1/FVC, PEF, and time to 50% reduction of symptoms (and a few other measurements)
Results:
- Primary outcome: asthma symptom score from 0-6, latter being severe symptoms — baseline 4.14 decreasing to 2.09 at day 10 with azithromycin, and 4.18 to 2.20 on placebo; i.e. no difference
- Secondary outcomes: no difference in any (the graphs are basically overlaying for each of the first 10 days, including time to 50% reduction in symptoms)
- Pathogens detected: 58% of patients provided sputum sample. 11% had bacteria or atypicals (e.g. mycoplasma/chlamydia); 18% had virus on nasal or throat swabs. and no difference by these results in azithro vs placebo groups [though numbers of patients were pretty small]
- Adverse events: esp GI in the azithro group (35 vs 24 events). Also 4 vs 2 cardiac events. But respiratory/thoracic/mediastinal disorders were more in the placebo group (37 vs 27), none of these adverse effects were further defined
Commentary:
- It is pretty striking that of the 4582 patients evaluated, 4383 were excluded (96% !!!), and, of these, 2044 (47% !!!!) were excluded because they were already on antibiotics. And this is at 30 secondary care hospitals and 1 primary care center. To me, this is what makes this study important: it is really common practice to give antibiotics to those with asthma exacerbations. Unfortunately the validity of this study was undermined by this recruitment dilemma: they took much longer to recruit patients than expected (took almost 3 years), loosened some of the recruitment exclusions (e.g., allowing people longer time until presentation to the ED), and still did not achieve their target number, getting only 67% of what they planned.
- The expectation going into the study was, I think, that azithromycin would help because:
- Respiratory URIs and atypical bacterial (mycoplasma and chlamydia, which can be as high as 40-60% by serology) are frequently associated with asthma exacerbations
- Asthmatic patients have increased carriage of bacterial pathogens, susceptibility to bacterial infections, and impaired immunologic barriers (impaired interferon and type 1 T-helper cell responses)
- Viral infections themselves impair innate antibacterial immune responses and increase bacterial adhesion to bronchial epithelium
- So, clinically, acute bacterial infections are more common and more severe in asthmatic patients
- Azithro has several appealing traits: it has broad anti-microbial activity (including against the atypicals), is anti-inflammatory (though all of these patients were on steroids), even has anti-viral properties, and augments the production of interferons (deficient in asthmatic patients)
- And, as a marginally related issue, azithro can decrease recurrent COPD exacerbations (see Albert RK. N Engl J Med 2011; 365: 689)
- There was a study showing that the antibiotic telithromycin works in decreasing asthma symptoms and leading to faster recovery (N Engl J Med 2006; 354: 1589), and telithromycin has less anti-viral activity than azithro. And has more hepatotoxicity to boot
- There are some concerns about the AZALEA study: there may have been a real selection bias in who was recruited (i.e., most got antibiotics prior to the study. Were they sicker than the ones in this study, or did they have a disease that really was more amenable to the azithro?); and there were pretty low numbers of patients with atypical bacteria (chlamydia/mycoplasma) compared to many other studies (which also suggests a bias in the previously-treated excluded group). The telithromycin study had a much higher percentage of atypicals, and most patients were not on steroids, which is a possibly major difference with the AZALEA study)
- So, one question is whether there are ways to stratify patients who may or may not benefit. A recent blog (see https://stg-blogs.bmj.com/bmjebmspotlight/2015/01/29/primary-care-corner-with-geoffrey-modest-md-community-acquired-pneumonia/ ) reviewed community acquired pneumonias, noting for example that serum procalcitonin is quite specific for pneumonia (I.e. if <0.1 mg/L, one can either withhold or stop antibiotics). Or perhaps CRP levels are useful.
- The bottom line: it would be great to have a more definitive study, with better recruitment than this one (i.e. early on and before antibiotics were prescribed), and which assessed potential biomarkers for more serious disease (e.g. procalcitonin, crp, ?others) to see if some group of patients might benefit from antibiotics. But at this point it seems that antibiotics are given to patients with acute asthma attacks probably much more often than necessary. My guess is that the patients who did qualify for this study probably should be on a short course of oral steroids and not antibiotics, and that we should be following them closely. Perhaps a phone call the next day or so, with re-evaluation if they are not improving.
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