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

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Presentation on theme: "Infection as a treatable cause for asthma- Where do we go from here? David L Hahn, MD MS Workshop - September 2012."— Presentation transcript:

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

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

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

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

5 Asthma Control Test (ACT)

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

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

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

9 Macrolides for asthma l Growing interest in second generation macrolides/azalides for asthma –To offer greater control –Possibly preventive or curative l Unresolved debate about mechanisms –Anti-inflammatory v antimicrobial (atypicals) l 10 trials published: mixed results l 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 l Growing interest in second generation macrolides/azalides for asthma –To offer greater control –Possibly preventive or curative l Unresolved debate about mechanisms –Anti-inflammatory v antimicrobial (atypicals) l 10 trials published: mixed results l 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 Travers et al. External validity of randomised controlled trials in asthma: to whom do the results of the trials apply?. Thorax 2007;62: Current asthma Current asthma The proportion of people with asthma eligible for the major RCTs (n=17) cited in the Global Initiative for Asthma (GINA) guidelines. Current asthma on treatment Current asthma on treatment

12 Guideline treatment trials: Lacking external validity 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 Additional exclusions: Being asymptomatic Being asymptomatic No regular use of ICS No regular use of ICS Typical exclusions: Comorbidity Comorbidity FEV1 not %predicted FEV1 not %predicted ≤12% reversibility ≤12% reversibility Current smoking Current smoking Past hx >10 pack years Past hx >10 pack years

13 Generalizable studies of macrolides in asthma are limited l Two prospective observational (before-after) trials –Hahn JFP 1995 –Hahn et al. PLoS ONE 2012 l 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: Of 46 patients with moderate to severe stable asthma symptoms, 25 (54%) had PFT and clinically confirmed persisting improvement: Prior acute C. pneumoniae* 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:e Of 66 uncontrolled asthma patients: 33 (50%) were Cp-IgE+ 33 (50%) were Cp-IgE+ 16 (24%) were Cp-PCR+ 16 (24%) were Cp-PCR+ 39/66 elected azithromycin Rx. Of those 39: 33 (85%) reported lasting improvement 33 (85%) reported lasting improvement No association with IgE status 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) 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) 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: 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: l 97 subjects enrolled – 3 months Rx, 9 months post-Rx observation l 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 RandomizedN=75 Open Label N=22P-value Hospitalized Previous 2y 3%9%0.02 Day Severity Mild/Mod/Severe 64%/28%/8%32%/36%/32%0.01 Night Severity Mild/Mod/Severe 51%/37%/12%50%/18%/32%0.02 Symptom score QOL score

19 Asthma Symptoms (5-point scale) (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 l Randomized trial was negative –Underpowered (Potential NNT=7) l 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 l Are the open label results spurious, or did these subjects correctly self-identify themselves as good candidates? l Was the RCT biased towards a null effect due to self- exclusion of subjects most likely to benefit? l Results support further azithromycin trials

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

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


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