Table 1.
Characteristics of randomized controlled trials using macrolides on children with asthma, recurrent wheezing and bronchiolitis
| Reference | Country | Population (M%:F%) | Age (range/mean±SD) | Intervention:control | Intervention | Concomitant/baseline medication (I:C) % | Outcome measure | Severe adverse events (%) |
|---|---|---|---|---|---|---|---|---|
|
| ||||||||
| Ball et al 199049 | USA | 15 children severe, steroid-requiring asthma | 8–18 years (13.1±3.0) 13.8±3.0 vs 12.4±3.2 | 5:5:5 | Troleandomycin 250 mg QD × 2 days the QOD × 7 times, totally 2 weeks | Methyl-prednisolone 40 mg/1.73 m2 | Steroid dose reduction, symptoms scores, morning plasma cortisol concentration, FEV1, FVC, TGV, methacholine PC20, eosinophil count after 2 weeks, methylprednisolone clearance | Nil |
| Kamada et al 199350 | USA | 18 children severe, steroid- requiring asthma (36%:64%) | 6–17 years 14.3±2.9 vs 11.3±2.7 | 6:7:5 | Troleandomycin 250 mg QD or QOD depending on steroid protocol for 12 weeks | Prednisolone ≥20 mg QOD, bronchodilator ≥4 times/day, theophylline, ICS 500–1,000 µg BID | Steroid dose reduction, symptoms scores, need for extra prednisolone, PEFR, pre-bronchodilator FEV1, FEF 25%–75%, methacholine PC20, morning plasma cortisol concentration, urinary cortisol excretion, bone density, hip flexor strength after 12 weeks | Abnormal liver function (7.6%) |
| Fonseca-Aten et al 200632 | USA | 43 children history of recurrent wheezing/asthma with an AE to ED (74%:26%) | 4–17 years 112.5 (62–187) vs 100 (50–181) months | 22:21 | Clarithromycin 15 mg/kg/day, BID for 5 days, orally | SABA (39 of 43), LABA (3 of 43), and/or ICS (12 of 43) | serum/nasopharyngeal aspirates: TNF-α, IFN-γ, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, GM-CSF, RANTES, eotaxin, MIP-1α, MIP-1β, MCP-1; Mycoplasma pneumoniae, Chlamydia pneumoniae detection in nasopharyngeal swabs/serologic test; dyspnea, wheeze, cough, asthma score | NR |
| Piacentini et al 200762 | Italy | 16 children hospitalized for asthma (75%:25%) | 13.9±2.4 vs 12.9±2.6 | 8:8 | Azithromycin 10 mg/kg QD for 3 consecutive days/week × 8 weeks | ICS (fluticasone, 100–200 µg/day; beclomethasone dipropionate, 200–400 µg/day), SABA as needed | FEV1, FVC, FEF 25%–75%, bronchial hyper-responsiveness (expressed as the dose– response slope of FEV1 fall after hypertonic saline inhalation, and induced sputum) | NR |
| Tahan et al 200760 | Turkey | 21 infants hospitalized for RSV bronchiolitis, first episode of wheezing (57%:43%) | ≥7 months 2 (1–6) vs 2 (1–7) | 12:9 | Clarithromycin (15 mg/kg) QD × 3 weeks | β2-agonist (when SpO <94%, 2 RR >60 breaths/min, wheezing on auscultation, respiratory distress) | Primary outcome: LOS; duration of need for O2, IVF and β2-agonist Secondary outcomes: changes in the IL-4, IL-8, eotaxin, IFN-γ levels, readmission rate 6 months after discharge | NR |
| Rasul et al 200857 | Bangladesh | 60 children hospitalized for bronchiolitis (72%:28%) | 0–2 years (80% below 6 months) | 15:22:23 | Erythromycin orally | O2(for those with SpO2, 95%) and nebulization | Progress of the symptoms after 72 hours, progress of the signs after 72 hours, outcomes of bronchiolitis (improved, deteriorated, hospital stay) | NR |
| Strunk et al 200851 | USA | 55 children moderate-to-severe persistent asthma (58%:42%) | 6–18 years (11.2±2.6) | 17:19:19 | Azithromycin 250 mg QD (for those 25–40 kg) or 500 mg QD (for those .40 kg) | Budesonide 400–800 µg BID; Serevent Diskus® 50 µg BID (run-in/post randomized) | Primary outcome: time to inadequate asthma control M. pneumoniae, C. pneumoniae detection in nasal washes: PCR assays | NR |
| Kabir et al 200958 | Bangladesh | 295 children hospitalized for breathing difficulty/chest indrawing (73%:27%) | ,24 months | 99:99:97 IV ampicillin: oral erythromycin: no antibiotics (P-Ab: O-Ab: N-Ab) | P-Ab (50 mg/kg/dose 6 hourly IV) O-Ab (10 mg/kg/dose 6 hourly) | Nebulized salbutamol at 0.15 mg/kg/6–8 hours, O2 inhalation (SpO2 <90%), IVF maintenance | 18 symptoms/signs which were graded on a two-point recovery scale of “rapid” and “gradual”, indicating improvement within “four days” and “beyond four days”, respectively | NR |
| Koutsoubari et al 201261 | Greece | 40 children intermittent/mild persistent asthma with an acute AE (45%:55%) | 6–14 years 9.1±2.7 vs 8.4±2.5 | 18:22 | Clarithromycin 15 mg/kg × 3 weeks | Prophylactic treatment according to asthma control level (GINA) ICS (61.1:59.1) | Primary outcome: days without symptoms within subsequent 12 weeks. Secondary outcome: symptom-free days after first AE, number/severity of periods with loss of control, time to first loss of control, PEFR variability, duration of the index episode, FEV1, mean daily morning PEFR; RT-PCR in nasal wash samples | NR |
| Pinto et al 201252 | Brazil | 184 infants hospitalized with AB (60%:40%) | ≥2 months 3.1±2.2 vs 3.1±2.3 | 88:96 | Azithromycin 10 mg/kg/day × 7 days | Antibiotics (4.5:6.3); Steroid (4.5:7.3); bronchodilator (20.5:21.8) | Primary outcomes: LOS, duration of O2 Other variables: antibiotic use, broncho-dilators use, admission to the PICU, immunofluorescence for adenovirus, parainfluenza, influenza, RSV | NR |
| Mccallum et al 201355 | Australia/New Zealand | 96 children hospitalized, O2-required bronchiolitis (68%:32%) | ≥18 months 5.3 (3–9.4) vs 5 (3–8.5) | 50:46 | Azithromycin (30 mg/kg), single large dose of oral liquid | Antibiotics (72.0:70.0); Supplemental IVF (38.0:41.0) | Primary endpoints: LOS, duration of O2 Other outcomes: any respiratory-related readmissions in 6 months of discharge, identification of respiratory viruses and bacterial pathogens (RT-PCR/culture) | Nil |
| Chiong-Manaysay and Andaya 201459,a | Philippines | 23 children with FEV1 <80% before treatment | Children | 13:10 | Clarithromycin 15 mg/kg/day bid × 3 weeks | NR | Asthma Control Test questionnaires and spirometry (FVC, FEV1, FEV1/FVC, FEF 25%–75% and PEFR) prior medication and after the study period | NR |
| Bacharier et al 2015 42 | USA | 443 children histories of recurrent, severe wheezing (62%:38%) | 12–71 months (41.5±16.5) 42.5±16.4 vs 40.2±16.6 | 223:220 RTIs 473:464 | Azithromycin 12 mg/kg/day × 5 days | Albuterol 4 times daily for the first 48 hours/whenever needed at any time during the RTI | Primary outcome: number of RTIs not progressing to a severe LRTI (prescription of oral corticosteroids) Secondary outcome: numbers of urgent care/ED visits, hospitalizations. Symptom scores, albuterol use, time to second RTI | Nil |
| Beigelman et al 2015 37 | USA | 39 infants hospitalized with RSV bronchiolitis (59%:41%) | 1–18 months (3.8±2.9) 3.7±3.7 vs 3.9±2.0 | 19:20 | Azithromycin 10 mg/kg/day × 7 days then 5 mg/kg/day × 7 days | Antibiotic treatment (0:2); hypertonic saline treatment (1:0) | Primary outcomes: serum and nasal lavage IL-8 levels, proportion of participants with ≥2 additional wheezing episodes after treatment Secondary outcomes: proportion of participants with ≥3 wheezing episodes, with diagnosed asthma, being-prescribed with ICS, the time to second and third episode, the number of, ED visits for respiratory symptoms, courses of OCS, days of rescue albuterol, days with respiratory symptoms | Nil |
| Beigelman et al 2015 63 | USA | 39 children hospitalized with RSV infection (59%:41%) | 1–18 months (3.8±2.9) 3.7±3.7 vs 3.9±2.0 | 19:20 | Azithromycin 10 mg/kg/day × 7 days then 5 mg/kg/day × 7 days | Antibiotic treatment (0:2); hypertonic saline treatment (1:0) | RSV load in nasal lavage samples obtained on randomization, day 8, and day 15 | Nil |
| Mccallum et al 2015 56 | Australia/New Zealand | 219 children hospitalized with bronchiolitis (62%:38%) | ≥24 months 5.7 (3–10) vs 5.6 (3–9) | 106:113 (LOS/6-month readmission) 59:74 (O2 duration) 100:110 (day 21 clinical review) | Azithromycin 30 mg/kg/dose weekly × 3 times | Nonmacrolide antibiotics prescribed prior to hospital (45.0:42.0); during hospital (61.0:60.0); IVF (23.0:20.0) | Primary endpoint: LOS, duration of O2, day 21 clinical review, 6 months readmission; microbiology: Nasopharyngeal swabs for virus/bacteria (RT-PCR/culture) | Nil |
| Silveira D’Azevedo V et al 201653,a | Brazil | 91 infants hospitalized with AB | <12 months | 51:40 | Azithromycin × 7 days | NR | Wheezing and hospitalization in a follow-up 1, 3, and 6 months after the AB | NR |
| Stokholm et al 2016 43 | Denmark | 72 children recurrent asthma- like symptoms, troublesome lung symptoms ≥3 days (65%:35%) | 1–3 years 2.0±0.6 | 74:74 episodes | Azithromycin 10 mg/kg/day × 3 days | ICS (84%:80%); Montelukast (64.0:57.0) | Primary outcome: duration of episodes of troublesome lung symptoms after initiation of treatment Secondary outcomes: time from treatment to the next episode of troublesome lung symptoms, episodes that turned into severe AE (need for oral steroids/hospitalization), and the duration of β2 agonist use after treatment | 1:1 Hospitalized for AGE: 4 days after randomized Hospitalized for pneumonia: 20 days after randomized |
| Wan et al 2016 40 | Taiwan | 56 children with mild persistent asthma (63%:37%) | 5–16 years 10.1±3.1 vs 10.2±3.1 | 36:20 | Clarithromycin 5 mg/kg/day × 4 weeks | Fluticasone propionate 50 µg/puff bid | Childhood asthma control test, FEV1, FEF 25%–75%, FeNO, total IgE, absolute eosinophil count, ECP level | NR |
| Zhou et al 2016 64 | USA | 39 infants hospitalized with first RSV bronchiolitis (59%:41%) | 1–18 months (3.8±2.9) 3.7±3.7 vs 3.9±2.0 | 19:20 | Azithromycin 10 mg/kg/day × 7 days then 5 mg/kg/day × 7 days | Antibiotic treatment (0:2); hypertonic saline treatment (1:0) | Recurrent wheezing: assessed monthly over a year following the initial episode Microbiome sequencing ≥ changes in nasal lavage microbial communities following the study treatments | Nil |
| Mandhane et al 2017 41 | Canada | 222 children presenting to ED with wheezing (72%:28%) | 12–60 months 34.8±13.6 vs 30.5±13.9 | 110:112 (primary analysis); 87:82 (secondary analysis) | Azithromycin 10 mg/kg/day at day 1 then 5 mg/kg/day × 4 days (day 2–5) | Prior ED: ICS (62.7:58.9) SABA (35.5:36.6); At ED discharge: SABA (79.1:73.2) OCS (59.1:62.5) ICS (57.3:50.9) | Primary outcome: time (days) to respiratory symptoms resolution Secondary outcomes: the number of days children used a SABA during the 21 day follow-up, time to disease exacerbation during the following 6 months | Nil |
| Pinto et al 2017 54,a | Brazil | 83 infants hospitalized with AB | <12 months | 46:37 | Azithromycin × 7 days | NR | LOS, identification of respiratory viruses, recurrent wheezing/hospital readmission post-AB | NR |
Note:
a
Studies have been only reported as abstracts.
Abbreviations: AB, acute bronchiolitis; AE, acute exacerbation; AGE, acute gastroenteritis; BHR, bronchial hyper-responsiveness; BID, twice per day; C, control; DRS, dose response slope; ECP, eosinophil cation protein; ED, emergency department; F, female; FEV1, forced expiratory volume in one second; FVC, forced vital capacity; FeNO, fractional exhaled nitric oxide; FEF 25%–75%, forced expiratory flow between 25% and 75% of vital capacity; GINA, Global Initiative For Asthma; GM-CSF, granulocyte-macrophage colony stimulating factor; I, intervention; ICS, inhaled corticosteroid; IL, interleukin; ICU, intensive care unit; IFN, interferon; IV, intravenous; IVF, intravenous fluid; LABA, long-acting inhaled β-agonist; LOS, length of stay; LRTI, lower respiratory tract infection; LTRA, leukotriene receptor antagonist; M, male; MCP, monocyte chemoattractant protein; MIP, macrophage inflammatory protein; methacholine PC20, concentration of methacholine required to induce a 20% decrease in FEV1; NR, not reported; PEFR, peak expiratory flow rate; QD, every day; QOD, every other day; RR, respiratory rate; RSV, respiratory syncytial virus; RTI, respiratory tract infection; RT-PCR, real-time polymerase chain reaction; SpO2, saturation of peripheral oxygen; SABA, short-acting β-agonist; TGV, thoracic gas volume.