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.