Azithromycin for Bronchial Asthma in Adults: An Effectiveness Trial

David L. Hahn; Mike Grasmick; Scott Hetzel; Steven Yale

doi:10.3122/jabfm.2012.04.110309

Article Figures & Data

Figures

Tables

Download figure
Open in new tab
Figure 1.
CONSORT diagram. *Unavailable pulmonary function tests (PFTs) as the only disqualification of 67 of 170. ^†Nonqualifying PFTs in 10 of 24.
Download figure
Open in new tab
Figure 2.
Differences from baseline for asthma symptoms, quality of life, and control. A: Symptoms—rating of overall asthma symptoms for the past 24 hours (negative numbers indicate decreased symptoms and hence improvement). B: Quality of life— Juniper Asthma Quality of Life Questionnaire (AQLQ); positive numbers indicate higher quality of life scores and hence improvement). C: Control—Juniper Mini-Asthma Control Questionnaire (ACQ; negative numbers indicate better control and hence improvement). See Methods for details. Symbols represent the mean paired differences from baseline. Bars represent 95% confidence intervals. *P < 0·05, **P < 0·01, ***P < 0·001 (t tests, placebo versus open label).
Download figure
Open in new tab
Figure 3.
Improvement in asthma quality of life (AQL) after azithromycin treatment may be “all or none.” AQL change scores from baseline to 12 months after enrollment (9 months after treatment completion) are defined as follows: “AQL change <0” = AQL change worse than baseline; “AQL change 0 < .5” = change between 0 to <.5 units; “AQL change 0.5 < 1” = change between 0.5 to <1 (change of 0.5 unit is considered the minimum clinically important change); “AQL change 1 < 2” = change between 1 and 2 (change >1.5 units represents a large change); “AQL change ≥2” = change of 2 units or more. The contrasting patterns between placebo and open-label azithromycin were statistically significant, as noted in the text. The differences between randomized azithromycin and placebo were not statistically significant, as noted in the text.

Tables

Figures

View popup

Table 1. Inclusion, Exclusion, and Outcome Criteria

	Criteria
Inclusions	Adults ≥18 years of age with physician-diagnosed asthma (symptomatic ≥2 days per week and/or ≥2 nights per month or in exacerbation) Objective evidence for reversible airway obstruction (≥12% and ≥200 mL change in FEV₁⁸ and/or a 25% and 60 L/min change in PEFR⁹) either spontaneously or after treatment Asthma for at least 6 months before enrollment
Exclusions	Not English literate or has no email address or Internet access Macrolide allergy Pregnant or lactating ≥4 weeks of continuous use of macrolides, tetracyclines, or quinolones within 6 months of randomization Asthma symptoms less than 6 months' duration Unstable asthma requiring immediate emergency care Comorbidities likely to interfere with study assessments or follow-up (eg, cystic fibrosis, obstructive sleep apnea requiring CPAP, cardiomyopathy, congestive heart failure, terminal cancer, alcohol or other drug abuse, or any other serious medical condition that, in the opinion of the study physician, would seriously interfere with or preclude assessment of study outcomes or completion of study assessments) Medical conditions for which macrolide administration may possibly be hazardous (eg, acute or chronic hepatitis, cirrhosis, or other liver disease; chronic kidney disease; or history of prolonged cardiac repolarization and QT interval or torsades de pointes). Specified medications for which close monitoring has been recommended in the setting of macrolide administration (digoxin, theophylline, warfarin, ergotamine or dihydroergotamine, triazolam, carbamazepine, cyclosporine, hexobarbital, or phenytoin)
Outcomes	Asthma symptom scores (0 = none, 1 = mild, 2 = moderate, 3 = severe, 4 = worst ever) within the past 24 hours; every 1.5 months AQL (Juniper AQL questionnaire)¹⁰ within the past 2 weeks; every 3 months Asthma control (mini-Juniper Asthma Control Questionnaire, without pulmonary function)^11,12 within the past week; every 3 months Exacerbations (a steroid burst, an unscheduled or emergency visit and/or a hospitalizations for asthma) within the past 1.5 months; every 1.5 months Other respiratory illnesses within the past 1.5 months; every 1.5 months Off-study antibiotic use within the past 1.5 months; every 1.5 months Adverse events within the past 1.5 months; every 1.5 months Use of asthma-controller medications (oral or inhaled steroids, LABAs, or antileukotriene agents) within the past 3 months; every 3 months Self-reported improvement in asthma (compared with baseline) within the past 3 months; every 3 months

AQL, asthma quality of life; CPAP, continuous positive airway pressure; FEV₁, forced expiratory volume in 1 second; LABA, long-acting bronchodilators; PEFR, peak expiratory flow rate.

View popup

Table 2. Patient Characteristics

Characteristic	Randomized Placebo (n=37)	Randomized Azithromycin (n=38)	Open-Label Azithromycin (n=22)	P^*
Age(years), mean(SD)	47.4 (14.2)	45.7 (15.5)	45.4 (15.2)	.621/.745
At asthma diagnosis	24 (<1–59)	24 (<1–58)	28 (11–59)	.603/.104
Diagnosis at age ≥18 years	21 (57)	24 (63)	19 (86)	.641/.023
Male sex	13 (35)	11 (29)	12 (55)	.626/.078
Smoking status				.187/.028
Never	13 (35)	20 (53)	16 (73)
Former	19 (51)	12 (32)	6 (27)
Current	5 (14)	6 (16)	0 (0)
White race	33 (89)	36 (95)	18 (82)	.430/.227
Education, median years (range)	15 (10–20)	14 (12–22)	17 (12–25)	.550/<.001
≥High school graduate	35 (95)	38 (100)	21 (100)	.240/1.000
Chronic sinusitis	11 (30)	14 (37)	17 (77)	.626/<.001
Atopy
Allergy tested	18 (53)	18 (49)	19 (86)	.814/.003
Negative	2 (11)	1 (6)	6 (32)	.759/.003
Positive for 1–3 positive	4 (22)	3 (17)	8 (42)
Positive for ≥4	12 (67)	14 (78)	5 (26)
Infectious asthma^{^†}	6 (16)	17 (46)	13 (59)	.011/.024
Exacerbations (previous 2 years), n (%)	24 (65)	26 (68)	14 (64)	.809/.802
Hospitalized	0 (0)	2 (5)	4 (18)	.493/.023
Emergency visit	14 (38)	19 (50)	9 (41)	.355/1.000
Steroid burst	22 (59)	24 (63)	13 (59)	.815/1.000
Baseline asthma severity, n (%)
Day symptom frequency^{^‡}				.675/.009
Mild to moderate	35 (95)	34 (89)	15 (68)
Severe	2 (5)	4 (11)	7 (32)
Night symptom frequency^{^‡}				1.000/.046
Mild to moderate	33 (89)	33 (87)	15 (68)
Severe	4 (11)	5 (13)	7 (32)
Coexisting COPD	8 (22)	5 (13)	2 (9)	.375/.509
Lung function, mean (SD)
FEV₁, L (n)	18	19	7
Low^{^§}	2.24 (1.25)	2.33 (1.05)	2.48 (1.19)	.812/.688
% Change^{^‖}	42 (47.4)	26 (25.9)	33 (26.8)	.214/.969
PEFR, L/min (n with value)	25	25	18
Low^{^§}	258 (110)	276 (110)	300 (105)	.566/.281
% Change^{^‖}	62 (56)	63 (49)	85 (63)	.927/.140
Any controller medication	33 (89)	25 (66)	19 (86)	.026/.549
Inhaled corticosteroid	30 (81)	24 (63)	18 (82)
Long-acting bronchodilator^{^¶}	26 (70)	14 (37)	15 (68)
Leukotriene inhibitor	8 (22)	9 (24)	6 (27)
Oral prednisone	4 (11)	2 (5)	1 (5)
Baseline asthma measures, mean (SD)^**
Overall asthma symptoms	1.48 (0.94)	1.42 (0.77)	2.06 (0.73)	.744/.005
Asthma quality of life	4.97 (1.28)	4.98 (1.27)	4.12 (1.29)	.988/.023
Asthma control	1.56 (1.02)	1.75 (0.93)	2.26 (1.35)	.424/.090

Values provided as n (%) unless otherwise indicated.
↵* P values comparing randomized placebo versus randomized azithromycin/randomized cohort versus open-label cohort.
↵† History showed first asthma symptoms began after an acute respiratory illness.
↵‡ Day: mild = ≥2 days/week to less than daily; moderate = ≥1 per day to less than continuous; severe = continuous. Night: mild = ≥2 per month to ≤1 per week; moderate = >1 per week to ≤1 per night; severe = >1 per night.
↵§ Before bronchodilator use or lowest spontaneous value.
↵‖ Based on data after bronchodilator use or highest spontaneous value. Some subjects had either FEV₁ or PEFR values, not both.
↵¶ All subjects using a long-acting bronchodilator also were using an inhaled corticosteroid.
↵** See Methods for definitions.
COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in 1 second; PEFR, peak expiratory flow rate.

View popup

Table 3. Asthma Outcomes^*

	Randomized Placebo	Randomized Azithromycin	Open-label Azithromycin	P, Placebo vs Randomized Azithromycin	P, Placebo vs Open-Label
Change in overall asthma symptoms, from baseline
Week 6	−0.60 (1.07) (n=30)	−0.15 (0.83) (n=33)	−0.88 (0.81) (n=16)	.071/.071^{^†}	.333/.428^{^†}
Week 12	−0.48 (1.16) (n=23)	−0.31 ((0.74) (n=32)	−1.0 (1.37) (n=16)	.551/.580^{^†}	.223/.723^{^†}
Week 18	−0.15 (1.13) (n=27)	0.10 (0.75) (n=31)	−0.94 (1.12) (n=16)	.344/.178^{^†}	.034/.161^{^†}
Week 24	−0.08 (0.95) (n=25)	−0.10 (0.96) (n=30)	−1.0 (1.17) (n=17)	.939/.599^{^†}	.012/.013^{^†}
Week 30	−0.05 (1.09) (n=22)	−0.34 (1.01) (n=29)	−0.81 (1.17) (n=16)	.322/.280^{^†}	.048/.870^{^†}
Week 36	−0.21 (1.14) (n=24)	−0.22 (0.70) (n=27)	−1.27 (0.70) (n=15)	.959/.942^{^†}	.001/.017^{^†}
Week 42	−0.04 (0.88) (n=23)	−0.12 (0.93) (n=25)	−1.21 (0.70) (n=14)	.770/.858^{^†}	<.001/.001^{^†}
Week 48	−0.10 (1.07) (n=20)	−0.07 (0.88) (n=29)	−1.07 (0.95) (n=13)	.916/.758^{^†}	.011/.067^{^†}
Change in AQL, from baseline
Week 12	0.50 (0.95) (n=22)	0.67 (1.10) (n=26)	1.54 (1.91) (n=15)	.584/.682^{^†}	.067/.180^{^†}
Week 24	0.31 (1.36) (n=22)	0.49 (1.11) (n=27)	1.36 (1.75) (n=17)	.618/.382^{^†}	.049/.151^{^†}
Week 36	0.23 (1.02) (n=23)	0.58 (1.04) (n=22)	2.05 (1.40) (n=15)	.261/.342^{^†}	<.001/.001^{^†}
Week 48	0.40 (1.33) (n=19)	0.50 (1.10) (n=25)	1.70 (1.42) (n=13)	.784/.929^{^†}	.015/.068^{^†}
Change in asthma control, from baseline
Week 6	−0.37 (0.88) (n=30)	−0.46 (0.60) (n=33)	−1.24 (1.14) (n=16)	.634/.654^{^†}	.014/.009^{^†}
Week 12	−0.41 (1.01) (n=23)	−0.40 (0.80) (n=32)	−1.38 (1.87) (n=16)	.946/.998^{^†}	.075/.324^{^†}
Week 18	−0.40 (1.05) (n=27)	−0.28 (0.88) (n=31)	−1.18 (1.53) (n=16)	.637/.573^{^†}	.085/.179^{^†}
Week 24	−0.37 (1.12) (n=25)	−0.34 (1.03) (n=30)	−1.35 (1.69) (n=17)	.925/.536^{^†}	.045/.034^{^†}
Week 30	−0.25 (1.22) (n=22)	−0.56 (0.81) (n=29)	−1.04 (1.38) (n=16)	.307/.281^{^†}	.078/.163^{^†}
Week 36	−0.39 (1.00) (n=24)	−0.39 (0.79) (n=27)	−1.63 (1.41) (n=15)	1.000/.852^{^†}	.007/.015^{^†}
Week 42	−0.22 (1.32) (n=23)	−0.38 (0.72) (n=25)	−1.42 (1.41) (n=14)	.604/.817^{^†}	.016/.068^{^†}
Week 48	−0.45 (1.00) (n=20)	−0.34 (0.88) (n=29)	−1.08 (1.20) (n=13)	.692/.525^{^†}	.132/.379^{^†}
AQL improved ≥1 unit, n/N (%)
Week 12	5/22 (23)	11/26 (42)	9/15 (60)	.221/.136^{^‡}	.038/.098^{^‡}
Week 24	6/22 (27)	8/27 (30)	11/17 (65)	1.000/.745^{^‡}	.026/.048^{^‡}
Week 36	5/23 (22)	6/22 (27)	12/15 (80)	.738/.738^{^‡}	.001/.003^{^‡}
Week 48	4/19 (21)	9/25 (36)	7/13 (54)	.335/.386^{^‡}	.072/.116^{^‡}
Asthma control improved ≥1 unit, n/N (%)
Week 6	6/30 (20)	4/33 (12)	9/16 (56)	.498 /.421^{^‡}	.021/.010^{^‡}
Week 12	7/23 (30)	7/32 (22)	11/16 (69)	.539/.531^{^‡}	.025/.045^{^‡}
Week 18	7/27 (26)	4/31 (13)	9/16 (56)	.315/.437^{^‡}	.059/.054^{^‡}
Week 24	6/25 (24)	10/30 (33)	10/17 (59)	.556/.144^{^‡}	.029/.017^{^‡}
Week 30	5/22 (23)	9/29 (31)	8/16 (50)	.546/.502^{^‡}	.098/.105^{^‡}
Week 36	5/24 (21)	6/27 (22)	10/15 (67)	1.000/.875^{^‡}	.007/.009^{^‡}
Week 42	6/23 (26)	7/25 (28)	8/14 (57)	1.000/.862^{^‡}	.085/.152^{^‡}
Week 48	5/20 (25)	8/29 (28)	5/13 (38)	1.000/.980^{^‡}	.461/.998^{^‡}

All values are mean (SD) unless otherwise indicated.
↵* See Methods for definitions.
↵† Univariate (t test)/multivariate (analysis of variance); controlled for age, sex, and ever-smoking at each time point, as well as for controller medication use at weeks 12, 24, 36, and 48 (controller data is unavailable for other time points).
↵‡ Univariate (Fisher exact test)/multivariate (logistic regression); controlled for age, sex, and ever-smoking at each time point, as well as for controller medication use at weeks 12, 24, 36, and 48 (controller data is unavailable for other time points).
AQL, asthma quality of life.

View popup

Table 4. Side Effects^*

Side Effects, n (%)	Randomized Placebo	Randomized Azithromycin	Open-Label Azithromycin	P^{^†}
Nausea				.016/.008/.458
None	31 (91)	25 (71)	12 (60)
Mild to moderate	1 (3)	9 (26)	6 (30)
Severe	2 (6)	1 (3)	2 (10)
Vomiting				1.000/.128/.456
None	32 (94)	33 (94)	18 (90)
Mild to moderate	0 (0)	1 (3)	2 (10)
Severe	2 (6)	1 (3)	0 (0)
Stomach pain				.076/.001/.196
None	30 (88)	24 (69)	9 (45)
Mild to moderate	3 (9)	10 (29)	10 (50)
Severe	1 (3)	1 (3)	1 (5)
Diarrhea				.106/.002/.196
None	29 (85)	23 (66)	9 (45)
Mild to moderate	3 (9)	10 (29)	10 (50)
Severe	2 (6)	2 (6)	1 (5)
Rash				.743/.046/.420
None	33 (97)	33 (94)	16 (80)
Mild to moderate	0 (0)	2 (6)	3 (15)
Severe	1 (3)	1 (3)	1 (5)
Swelling				.239/.716/.128
None	32 (94)	35 (100)	18 (90)
Mild to moderate	1 (3)	0 (0)	2 (10)
Severe	1 (3)	0 (0)	0 (0)
Hearing loss				.743/1.000/.999
None	32 (94)	34 (97)	19 (95)
Mild to moderate	1 (3)	1 (3)	1 (5)
Severe	1 (3)	0 (0)	0 (0)
Vaginal candidiasis				.670/1.000/.999
None	20 (91)	21 (84)	7 (88)
Mild to moderate	3 (9)	4 (16)	1 (13)
Severe	0 (0)	0 (0)	0 (0)

↵* Worst reported severity during the 12-week treatment period.
↵† Fisher exact tests: randomized placebo versus randomized azithromycin/randomized placebo versus open-label azithromycin/randomized azithromycin versus open-label azithromycin.

View popup

Table 5. Randomized Trials of Second-Generation Macrolides/Azalides for Asthma: Study Designs

Reference	Age Group	Sampling Frame	Asthma Severity	Subjects (n)	Design	R_X/Duration	Observation after R_X
Shoji (1999)¹⁷	Adults	Hospital asthma clinic	Mild/moderate	14	Single site; double-blind cross-over (4-week washout)	Roxithromycin, 300 mg daily or placebo/8 weeks	None
Shoji (1999)¹⁷	Adults	Hospital asthma clinic	Aspirin-intolerant asthma	14	Single site; double-blind cross-over (4-week washout)	Roxithromycin, 300 mg daily or placebo/8 weeks	None
Amayasu (2000)¹⁸	Adults	Not stated (hospital asthma clinic[s]?)	Mild/moderate	17	Single site; double-blind cross-over (4-week washout)	Clarithromycin, 200 mg daily or placebo/8 weeks	None
Black (2001)¹⁹	18–60 years old	Majority of subjects recruited from the general population; recruitment method(s) not specified	Moderate/severe	232	Multinational; double-blind, parallel groups (Australia, New Zealand, Italy, Argentina)	Roxithromycin, 300 mg daily or placebo/6 weeks	24 weeks
Kraft (2002)²⁰	Young adults	Subjects recruited from the general population via advertising	Not stated Mean FEV₁%pred = 69.3 35% were taking ICS	52	Single site; double-blind parallel groups All subjects underwent bronchoscopy before and after prescription	Clarithromycin, 1000 mg daily or placebo/6 weeks	None
Kostadima (2004)²¹	18–70 years old	Not stated (referral speciality setting)	Not stated, probably mild	63	Single site; double-blind, parallel groups	Clarithromycin, 500 or 750 mg daily or placebo/8 weeks	None
Kostadima (2004)²¹	18–70 years old	Not stated (referral speciality setting)	Mean FEV₁%pred ∼85% Subjects using albuterol >2 times weekly were excluded	63	Single site; double-blind, parallel groups	Clarithromycin, 500 or 750 mg daily or placebo/8 weeks	None
Hahn (2006)²²	≥18 years old	Community-based healthcare settings	Mostly mild/moderate	46	Multisite; double-blind, parallel groups	Azithromycin, 600 mg daily for 3 days then 600 mg weekly or placebo/6 weeks	12 weeks
Piacentini (2007)²³	Children	Inpatient setting	Not stated	16	Single site; double-blind, parallel groups	Azithromycin, 10 mg/kg/day for 3 of 7 days or placebo/8 weeks	None
Simpson (2008)²⁴	Adults	Specialty outpatient clinic	Severe refractory	45	Single site; double-blind, parallel groups	Clarithromycin, 1000 mg daily or placebo/8 weeks	4 weeks
Simpson (2008)²⁴	Adults	Specialty outpatient clinic	Severe refractory	45	Stratified by high (>61%)/low induced sputum neutrophil proportion	Clarithromycin, 1000 mg daily or placebo/8 weeks	4 weeks
Strunk (2008)²⁵	Children	Academic asthma centers	Moderate/severe	55	Multisite; double-blind, parallel groups This was a study of macrolide as a “steroid-sparing” agent, not as an antimicrobial	Azithromycin, 250–500 mg daily or montelukast 5–10 mg daily of placebo/24 weeks	6 weeks
Sutherland (2010)²⁶	18–60 years old	Academic asthma centers	Suboptimally controlled asthma	92	Multisite; double-blind, parallel groups Stratified on Mpn or Cpn PCR± (bronchoscopic sampling) The study was underpowered to test PCR+ cases	Clarithromycin, 1000 mg daily or placebo/16 weeks	None
Hahn (2012), current study	≥18 years old	Community-based healthcare settings	Mild/moderate (randomized)	75 randomized 22 open-label	Multisite; double-blind, parallel groups	Azithromycin, 600 mg daily for 3 days then 600 mg weekly or placebo/12 weeks	36 weeks
Hahn (2012), current study	≥18 years old	Community-based healthcare settings	Severe (open-label)	75 randomized 22 open-label	Multisite; double-blind, parallel groups		36 weeks

%pred, percent of the predicted value; Cpn, Chlamydia pneumoniae; FEV₁, forced expiratory volume in 1 second; ICS, inhaled corticosteroid; Mpn, Mycoplasma pneumoniae; PCR, polymerase chain reaction.

View popup

Table 6. Randomized Trials of Second-Generation Macrolides/Azalides for Asthma: Exclusions, Outcomes, and Results

Reference	Exclusions^*	Outcomes Reported	Results of Macrolide Treatment
Shoji (1999)¹⁷	Smokers	Blood eosinophils and ECP	Decreased eosinophils/ECP
	Controller medication	Sputum cell counts and ECP	Decreased eosinophils/ECP
			(No differences in sputum neutrophils)
		Sulpyrine provocation test	Not improved
		Sulpyrine provocation test	(No patient-oriented outcomes reported)
Amayasu (2000)¹⁸	Smokers	Blood eosinophils and ECP	Decreased eosinophils/ECP
	Aspirin sensitivity	Sputum cell counts and ECP	Decreased eosinophils/ECP
	ARI for 6 weeks	BHR	Improved
	Any asthma controller medication	Pulmonary function	Not improved
	Any asthma controller medication	Overall asthma symptoms	Improved
Black (2001)¹⁹	FEV₁ <50% predicted	Pulmonary function(PEF)	Improvement at end of prescription that waned after prescription
	C. pneumoniae IgG < 1:64 and IgA < 1:16	Pulmonary function(FEV₁)	Not improved
	Smoking ≥20 pack-years	Asthma symptoms	Not improved
	Bronchiectasis	AQL	Not improved
	Prednisone burst in previous month
	Respiratory illness
Kraft (2002)²⁰	Smoking >5 pack years	PCR+ for Mpn or Cpn	31 of 55 were PCR+ for Mpn and/or Cpn
	Any cigarette within 2 years	Pulmonary function	Improved FEV₁ in PCR+ subject subgroup
	Any lung comorbidity	Lung inflammation	Decreased inflammatory cytokines
	Any LRTi within 3 months	Lung inflammation	(No patient-oriented outcomes reported)
Kostadima (2004)²¹	Asthma diagnosis <1 year ago	BHR	Decreased BHR
	Not on ICS	Pulmonary function	Not improved
	Rescue inhaler >2 times weekly	Serum free cortisol	Not affected
	Any smoking history		(No patient-oriented outcomes reported)
	Any other medication
	FEV₁ < 50% predicted
	Any ARI or exacerbation within 4 weeks before or during the study
Hahn (2006)²²	None	AQL	No improvement
		Rescue medication use	No improvement
		Cpn IgG and IgA antibodies	Baseline IgA predicted worsening symptoms
		Overall asthma symptoms	Improved at end of prescription and persisted after prescription
Piacentini (2007)²³	Oral steroids in the preceding 3 months or during the study	Lung function	No improvement
	Signs of airway infection in the preceding month or during the study	BHR	Improved
		Lung inflammation	Reduced induced sputum neutrophils
Simpson (2008)²⁴	Current smoking	Sputum inflammatory markers	Decreased airway IL-8 and neutrophils
	History of smoking, >5 pack-years	Pulmonary function	No improvement
	Antihistamine medication	BHR	No improvement
		Asthma control	No improvement
		Asthma symptoms	Decreased wheezing after prescription
		AQL	Improved (NNT = 6 for ≥0.5 units improvement)
		AQL	It was unclear whether the AQL was reported at the end of the prescription or after the prescription
Strunk (2008)²⁵	No controller medication	Time to inadequate control after steroid step-down	No improvement in asthma control (futility analysis)
	FEV₁ < 50%pred		Recruitment was discontinued early (292 screened, only 55 randomized)
	>3 hospitalizations in past year
	Sinus surgery in past year
	Lung comorbidities
Sutherland (2010)²⁶	Exacerbation within 6 weeks	Asthma control	No differences in asthma control
	ARI within 6 weeks	Pulmonary function	No improvement
	>2 exacerbations or ARI prior to entry	Exhaled nitric oxide	No improvement
	Smoking	BHR	Improved
	History of smoking, ≥10 pack-years	Rescue medication use	No improvement
	Lung comorbidities	AQL	No improvement
Hahn (2012), current study	None	Overall asthma symptoms	Randomized: no improvements in any outcome
		AQL	Open label: improved overall asthma symptoms and AQL score at end of prescription that persisted after prescription (improvements maximal at the 9-month study point)
		ACQ

↵* Other than for safety and logistics.
ACQ, asthma control questionnaire; ARI, acute respiratory illness; AQL, asthma quality of life; BHR, bronchial hyperresponsiveness; Cpn, Chlamydia pneumoniae; ECP, eosinophil cationic protein; FEV₁, forced expiratory volume in 1 second; ICS, inhaled corticosteroid; Ig, immunoglobulin; IL, interleukin; LRTi, lower respiratory tract illness; Mpn, Mycoplasma pneumoniae; NNT, number needed to treat; PCR, polymerase chain reaction; PEF, peak expiratory flow.