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Infection as a treatable cause for asthma- Where do we go from here?

Workshop - September 2012. Infection as a treatable cause for asthma- Where do we go from here?. David L Hahn, MD MS. Conflict of interest disclosure. I have no conflicts of interest that relate to this presentation. Agenda.

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Infection as a treatable cause for asthma- Where do we go from here?

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  1. Workshop - September 2012 Infection as a treatable cause for asthma- Where do we go from here? David L Hahn, MD MS

  2. Conflict of interest disclosure • I have no conflicts of interest that relate to this presentation

  3. Agenda • Goal or purpose: Looking towards the future of research into azithromycin as a novel treatment for asthma • Aim#1: Brief background of rationale and research to date • Aim#2: Open discussion about your perspectives of the possible role(s) for PBRN research

  4. Background • Current asthma treatments are palliative, not curative • Anti-inflammatory treatments • Despite treatment, half of patients have uncontrolled asthma • Demoly et al 2010

  5. Asthma Control Test (ACT)

  6. Asthma Control in Five European Countries Not Well Controlled (ACT≤19) • More activity limitations (40.8% vs 1.5%) • More breathlessness ≥3 times weekly (72.5% vs 5.4%) • More sleep difficulties ≥1 times weekly (60.3% vs 4.6%) • More rescue medication ≥2-3 times weekly (77.4% vs 15.9%) • More healthcare utilization (17.4% vs 9.9%) • More absenteeism (12.2% vs 5.5%) • More work impairment (30.0% vs 15.4%) • Decreased quality-of-life (P<.001) Compared to Controlled (ACT≥20) Demoly et al. Update on asthma control in five European countries. Eur Respir Rev 2010

  7. Lack of Asthma Control is Common Asthma prevalence = 6.1% (France,Germany, Italy, Spain and UK, 2008) All asthma Treated asthma Demoly et al. Update on asthma control in five European countries. Eur Respir Rev 2010

  8. Background • A subset of asthma (20%) progresses to COPD • Increasing the burden of morbidity and mortality • Preventive and curative treatments are desirable

  9. Macrolides for asthma • Growing interest in second generation macrolides/azalides for asthma • To offer greater control • Possibly preventive or curative • Unresolved debate about mechanisms • Anti-inflammatory v antimicrobial (atypicals) • 10 trials published: mixed results • Methodologic limitations • Small, short-term, different drug/duration, no post-treatment observation period, disease-oriented outcomes, limited external validity (poor generalizability)

  10. Macrolides for asthma • Growing interest in second generation macrolides/azalides for asthma • To offer greater control • Possibly preventive or curative • Unresolved debate about mechanisms • Anti-inflammatory v antimicrobial (atypicals) • 10 trials published: mixed results • Methodologic limitations • Small, short-term, different drug/duration, no post-treatment observation period, disease-oriented outcomes, limited external validity (poor generalizability)

  11. Guideline treatment trials: Lacking external validity The proportion of people with asthma eligible for the major RCTs (n=17) cited in the Global Initiative for Asthma (GINA) guidelines. • Current asthma • Current asthma on treatment Travers et al. External validity of randomised controlled trials in asthma: to whom do the results of the trials apply?. Thorax 2007;62:219-223

  12. Guideline treatment trials: Lacking external validity Typical exclusions: • Comorbidity • FEV1 not 50-85 %predicted • ≤12% reversibility • Current smoking • Past hx >10 pack years Additional exclusions: • Being asymptomatic • No regular use of ICS Herland et al. How representative are clinical study patients with asthma or COPD for a larger “real life” population of patients with obstructive lung disease?. Respiratory Med 2005; 99:11-19

  13. Generalizable studies of macrolides in asthma are limited • Two prospective observational (before-after) trials • Hahn JFP 1995 • Hahn et al. PLoS ONE 2012 • Two randomized, controlled trials (RCTs) • Hahn et al, PLoS Clinical Trials 2006 • Hahn et al. JABFM 2012

  14. Treatment of Chlamydia pneumoniae infection in adult asthma: a before-after trial. J Fam Pract 1995; 41:345-351 Of 46 patients with moderate to severe stable asthma symptoms, 25 (54%) had PFT and clinically confirmed persisting improvement: • Prior acute C. pneumoniae* 4/4: complete response o Possible chronic C. pneumoniae* 21/42: 3 complete response 18 major improvement Positive response assoc w/ Less disease duration (P=.01) Less fixed obstruction (P<.01) * Dots represent multiple measures for individuals

  15. Chlamydia pneumoniae-specific IgE is prevalent in asthma and is associated with disease severity. PLoS ONE 2012; 7:e35945. Of 66 uncontrolled asthma patients: • 33 (50%) were Cp-IgE+ • 16 (24%) were Cp-PCR+ 39/66 elected azithromycin Rx. Of those 39: • 33 (85%) reported lasting improvement • No association with IgE status *P=0.002, **P<0.0001

  16. Secondary outcomes of a pilot randomized trial of azithromycin treatment for asthma. PLoS Clin Trials 2006; 1:e11 • 45 patients with mostly mild to moderate persistent asthma symptoms: • Baseline Cp IgA antibodies predicted worsening asthma symptoms at end study (P=.04) • Symptom improvement attributable to AZ was 28% in high IgA v 12% in low IgA subjects (interaction P=0.27) • • Binary measure for improvement (≥1 unit increased AQLQ and/or ≥50% decreased rescue BD) was: • 53% AZ v 13% PLA (P=0.03) • NNT=3 * *P=0.04 by linear regression analysis

  17. Azithromycin for bronchial asthma in adults: An effectiveness trial. J Am Bd Fam Med 2012; 25:442-459 • 97 subjects enrolled • 3 months Rx, 9 months post-Rx observation • Open-label cohort, n = 22 (23%) • Declined randomization after learning of a 50% chance of receiving placebo • IRB approval for an open-label (OL) observational arm • More severe asthma than randomized subjects

  18. Asthma severity

  19. Asthma Symptoms (5-point scale)

  20. AQL: Asthma Quality of Life (Juniper)

  21. Asthma Control (Juniper)

  22. Change From Baseline in AQL 48 Weeks Post-Enrolment

  23. Summary • Randomized trial was negative • Underpowered (Potential NNT=7) • Open-label subjects reported significant prolonged benefit compared to placebo group • NNT = 2-3 for AQL improvement ≥ 2 units at one year

  24. Unanswered questions • Are the open label results spurious, or did these subjects correctly self-identify themselves as good candidates? • Was the RCT biased towards a null effect due to self- exclusion of subjects most likely to benefit? • Results support further azithromycin trials

  25. Open for Discussion • What kinds of asthma? • What study designs? • What role for PBRNs?

  26. What kinds of asthma? • New-Onset • Well-controlled • Uncontrolled and/or treatment resistant (refractory) What study designs? • Before-After (Registries) • RCTs • Including large simple trials

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