AZithromycin Therapy in Preschoolers With a Severe Wheezing Episode Diagnosed at the Emergency Department (AZ-SWED)

AZithromycin Therapy in Preschoolers With a Severe Wheezing Episode Diagnosed at the Emergency Department

AZithromycin Therapy in Preschoolers With a Severe Wheezing Episode Diagnosed at the Emergency Department (AZ-SWED)

University of Utah, Emory University, Morgan Stanley Children's Hospital, University of Pittsburgh, Children's Hospital and Health System Foundation, Wisconsin, Children's Hospital of Philadelphia, Children's Hospital Medical Center, Cincinnati, Boston Children's Hospital

AZ-SWED is a parallel group, double blind, placebo control efficacy clinical trial with two separate hypotheses. The trial will compare the 5-day outcome of preschool children presenting to an Emergency Department (ED) with an acute, severe wheezing episode and treated with either once daily oral Azithromycin (12 mg/kg/day for 5 days) or placebo. The AZ-SWED researchers will make separate comparisons in children in whom specific pathogenic bacteria are isolated from nasopharyngeal swabs, and in those in whom they are not isolated. The primary outcome will be the Asthma Flare-up Diary for Young Children (ADYC), a validated instrument that caregivers will transmit electronically daily after discharge from the ED. Families will be contacted daily during the five-day treatment to collect the ADYC, and to assess compliance and complications. A randomly chosen subset of enrolled children will participate in two follow-up visits 5-8 days and 14-21 days after visit 1 to assess development of resistance to study drug and treatment response related changes in the airway microbiome.

This Phase III trial is designed as a parallel group, placebo-controlled, double-blind, randomized, multi-center evaluation of AZ for the treatment of acute wheezing episodes. The study will recruit eligible patients from an estimated six EDs and enroll up to 2,000 patients. We will test two primary hypotheses: 1) AZ (12 mg/Kg/day) given for 5 days to preschool children with severe acute wheezing and harboring any of three specific pathogenic bacteria (H influenzae, M catarrhalis, or S pneumonia) in their nasopharynx will decrease the severity of the acute episode; and 2) AZ given on an identical schedule and dose will decrease the severity of wheezing episodes in children who do not harbor any of these three pathogenic bacteria in their nasopharynx. We will also explore whether variants in the genes encoding for Cadherin Related Family Member 3 (CDHR3), Interleukin-8 (IL-8) and in the 17q asthma-related gene cluster predict response to AZ. This short-term study has three planned visits. All enrolled patients will participate on the Day 0 visit for screening, the informed consent process, enrollment, randomization, treatment initiation and dispensing drug. A sub-group of 370 randomly selected patients will participate in two follow-up visits on Day 5 - 8 and Day 14 - 21 where they will be tested for antibiotic resistance. The primary outcome will be the sum of the Asthma Flare-up Diary for Young Children (ADYC) score, a validated instrument completed by the parent or guardian of the enrolled children during the 5-day treatment period. Secondary outcomes will include (1) ED length of stay (2) hospital length of stay, and (3) return ED visits or hospitalizations within 72 hours after randomization.

This Phase III trial is designed as a parallel group, placebo-controlled, double-blind, randomized, multi-center evaluation of AZ for the treatment of acute wheezing episodes. This short-term study has three planned visits. All enrolled patients will participate on the Day 0 visit for screening, the informed consent process, enrollment, randomization and dispensing. A sub-group of 370 randomly selected patients will participate in two follow-up visits on Day 5 - 8 and Day 14 - 21 where they will be tested for antibiotic resistance.

Equal allocation randomization tables will be provided by the Data Coordinating Center (DCC) to the central research pharmacy. The central research pharmacy will prepare consecutively numbered study kits according to the randomization schedule. Study kits will be sent to the clinical sites. Study products will be labeled with numerical codes that will maintain allocation concealment. Blinding/labeling of study medication bottles will be completed at the site pharmacy prior to dispensing to the patient. Randomization tables will be created at the Data Coordinating Center using permuted-block randomization stratified by clinical site and baseline severity of symptoms. Permuted blocks of random lengths 2, 4, and 6 will be used. The randomization number will be recorded in the database.

Eligible patients will be randomly assigned to one of two treatment groups (1:1) and one arm will be administered the active drug per the randomization schedule. Study medication will be provided to parents/guardians, along with instructions, for home-based administration. The first dose of the study medication will be administered before discharge from the ED.

Eligible patients will be randomly assigned to one of two treatment groups (1:1) and one arm will be administered placebo per the randomization schedule. Study medication will be provided to parents/guardians, along with instructions, for home-based administration. The first dose of the study medication will be administered before discharge from the ED.

oral azithromycin (12 mg/kg per day for 5 days) Local investigational drug pharmacies will be provided with active study medication (azithromycin) from a central pharmacy. Azithromycin will be reconstituted with water at the local pharmacy, and will resemble placebo with regards to appearance, flavor, consistency and packaging.

oral placebo (12 mg/kg per day for 5 days) Local investigational drug pharmacies will be provided with placebo from a central pharmacy. Placebo will be reconstituted with water at the local pharmacy, and will resemble azithromycin with regards to appearance, flavor, consistency and packaging.

The Asthma Flare-up Diary for Young Children (ADYC) is a validated instrument that consists of a 17-item questionnaire scored from 1 (best) to 7 (worst). The parent or guardian of the enrolled child (up to 60 months of age) will fill out the diary daily for 5 days, starting from the first day following the first dose of Azithromycin (AZ). The cumulative score at the end of 5 days will be used to assess response to the intervention (e.g. time to exacerbation, acute-care visit, hospitalization and no wheeze), with a higher score indicating a worse outcome.

Secondary outcomes will include (1) ED length of stay (2) hospital length of stay, and (3) return ED visits or hospitalizations.

Presence of azithromycin-resistant organisms will be assessed at baseline, and again at two follow-up visits 5-8 days and 14-21 days after enrollment in a randomly selected subset of trial subjects. A total of 370 subjects will be selected for this follow-up. Subjects in whom resistance is detected at baseline will not be included in the analysis of development of bacterial resistance at follow-up. Among subjects that are negative for bacterial resistance at baseline, follow-up resistance will be tabulated by treatment. The absolute risk difference, together with a 95% one-sided confidence interval, will be used to summarize treatment difference. Participants who harbor or do not harbor the three pathogenic bacteria will be included in these analyses.

Inclusion Criteria: Age 18 months to <60 months. The presence of expiratory wheezing as ascertained by a physician or nurse practitioner at admission to the ED. A Pediatric Respiratory Assessment Measurement (PRAM) score of greater than or equal to 4 at any time during the ED admission. Exclusion Criteria: Presence of acute infection that requires systemic antibiotics, as determined by the physician. Current or previous use of systemic antibiotics within the last 2 weeks. Current or previous use of a steroid for wheezing within the last 2 weeks. Suspected foreign body induced aspiration during the last 2 weeks. A known systemic illness (other than allergy) including but not limited to: Recurrent seizures Gastroesophageal reflux (GER) requiring medical treatment Major congenital anomalies Physical and intellectual delay Cerebral palsy A history of chest surgery Tuberculosis or other chronic infections Primary or secondary immunodeficiency Gastrointestinal malformation or disease Cardiac disorder (except for a hemodynamically insignificant atrial septal defect (ASD), ventricular septal defect (VSD) or benign heart murmur) Born at less than 36 weeks estimated gestational age. Received oxygen for more than 5 days in the neonatal period, or received mechanical ventilation. Significant developmental delay / failure to thrive, defined as a child plotting less than 3rd percentile. Any chronic lung disease. The study intervention poses undue risk to patient in the opinion of the treating physician Known sensitivity or allergy to AZ. Participation in the evaluation of a drug or medical device currently or within the last 30 days. Previous enrollment into this trial. Inability to speak English or Spanish.

After subject enrollment and follow up have been completed, the DCC may prepare a final study database for analysis. A releasable database will be produced and completely de-identified in accordance with the definition provided in the Health insurance Portability and Accountability Act (HIPAA). HIPAA will be recoded in a manner that will make it impossible to deduce or impute the specific identity of any patient. The database will not contain any institutional identifiers. This releasable database will be forwarded to the Biologic Specimen and Data Repository Information Coordinating Center (BIOLINCC) or, in case AZ-SWED samples and data are not deposited in BIOLINCC, to users in electronic form, in accordance with policies determined by the investigators and funding sponsors.

Nath JB, Hsia RY. Children's emergency department use for asthma, 2001-2010. Acad Pediatr. 2015 Mar-Apr;15(2):225-30. doi: 10.1016/j.acap.2014.10.011. Epub 2015 Jan 14.

Hasegawa K, Tsugawa Y, Brown DF, Camargo CA Jr. Childhood asthma hospitalizations in the United States, 2000-2009. J Pediatr. 2013 Oct;163(4):1127-33.e3. doi: 10.1016/j.jpeds.2013.05.002. Epub 2013 Jun 12.

Castro-Rodriguez JA, J Rodrigo G, E Rodriguez-Martinez C. Principal findings of systematic reviews of acute asthma treatment in childhood. J Asthma. 2015;52(10):1038-45. doi: 10.3109/02770903.2015.1033725. Epub 2015 Aug 24. Erratum In: J Asthma. 2016;53(3):339.

Castro-Rodriguez JA, Beckhaus AA, Forno E. Efficacy of oral corticosteroids in the treatment of acute wheezing episodes in asthmatic preschoolers: Systematic review with meta-analysis. Pediatr Pulmonol. 2016 Aug;51(8):868-76. doi: 10.1002/ppul.23429. Epub 2016 Apr 13.

Foster SJ, Cooper MN, Oosterhof S, Borland ML. Oral prednisolone in preschool children with virus-associated wheeze: a prospective, randomised, double-blind, placebo-controlled trial. Lancet Respir Med. 2018 Feb;6(2):97-106. doi: 10.1016/S2213-2600(18)30008-0. Epub 2018 Jan 17. Erratum In: Lancet Respir Med. 2018 Jan 31;:

Fleming-Dutra KE, Demirjian A, Bartoces M, Roberts RM, Taylor TH Jr, Hicks LA. Variations in Antibiotic and Azithromycin Prescribing for Children by Geography and Specialty-United States, 2013. Pediatr Infect Dis J. 2018 Jan;37(1):52-58. doi: 10.1097/INF.0000000000001708.

Bisgaard H, Hermansen MN, Buchvald F, Loland L, Halkjaer LB, Bonnelykke K, Brasholt M, Heltberg A, Vissing NH, Thorsen SV, Stage M, Pipper CB. Childhood asthma after bacterial colonization of the airway in neonates. N Engl J Med. 2007 Oct 11;357(15):1487-95. doi: 10.1056/NEJMoa052632.

Bisgaard H, Hermansen MN, Bonnelykke K, Stokholm J, Baty F, Skytt NL, Aniscenko J, Kebadze T, Johnston SL. Association of bacteria and viruses with wheezy episodes in young children: prospective birth cohort study. BMJ. 2010 Oct 4;341:c4978. doi: 10.1136/bmj.c4978.

Kloepfer KM, Lee WM, Pappas TE, Kang TJ, Vrtis RF, Evans MD, Gangnon RE, Bochkov YA, Jackson DJ, Lemanske RF Jr, Gern JE. Detection of pathogenic bacteria during rhinovirus infection is associated with increased respiratory symptoms and asthma exacerbations. J Allergy Clin Immunol. 2014 May;133(5):1301-7, 1307.e1-3. doi: 10.1016/j.jaci.2014.02.030. Epub 2014 Apr 1.

Bacharier LB, Guilbert TW, Mauger DT, Boehmer S, Beigelman A, Fitzpatrick AM, Jackson DJ, Baxi SN, Benson M, Burnham CD, Cabana M, Castro M, Chmiel JF, Covar R, Daines M, Gaffin JM, Gentile DA, Holguin F, Israel E, Kelly HW, Lazarus SC, Lemanske RF Jr, Ly N, Meade K, Morgan W, Moy J, Olin T, Peters SP, Phipatanakul W, Pongracic JA, Raissy HH, Ross K, Sheehan WJ, Sorkness C, Szefler SJ, Teague WG, Thyne S, Martinez FD. Early Administration of Azithromycin and Prevention of Severe Lower Respiratory Tract Illnesses in Preschool Children With a History of Such Illnesses: A Randomized Clinical Trial. JAMA. 2015 Nov 17;314(19):2034-2044. doi: 10.1001/jama.2015.13896. Erratum In: JAMA. 2016 Jan 12;315(2):204. JAMA. 2016 Jan 26;315(4):419.

Stokholm J, Chawes BL, Vissing NH, Bjarnadottir E, Pedersen TM, Vinding RK, Schoos AM, Wolsk HM, Thorsteinsdottir S, Hallas HW, Arianto L, Schjorring S, Krogfelt KA, Fischer TK, Pipper CB, Bonnelykke K, Bisgaard H. Azithromycin for episodes with asthma-like symptoms in young children aged 1-3 years: a randomised, double-blind, placebo-controlled trial. Lancet Respir Med. 2016 Jan;4(1):19-26. doi: 10.1016/S2213-2600(15)00500-7. Epub 2015 Dec 17.

Mandhane PJ, Paredes Zambrano de Silbernagel P, Aung YN, Williamson J, Lee BE, Spier S, Noseworthy M, Craig WR, Johnson DW. Treatment of preschool children presenting to the emergency department with wheeze with azithromycin: A placebo-controlled randomized trial. PLoS One. 2017 Aug 3;12(8):e0182411. doi: 10.1371/journal.pone.0182411. eCollection 2017.

Parnham MJ, Erakovic Haber V, Giamarellos-Bourboulis EJ, Perletti G, Verleden GM, Vos R. Azithromycin: mechanisms of action and their relevance for clinical applications. Pharmacol Ther. 2014 Aug;143(2):225-45. doi: 10.1016/j.pharmthera.2014.03.003. Epub 2014 Mar 11.

Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M, Morgan WJ. Asthma and wheezing in the first six years of life. The Group Health Medical Associates. N Engl J Med. 1995 Jan 19;332(3):133-8. doi: 10.1056/NEJM199501193320301.

Henderson J, Granell R, Heron J, Sherriff A, Simpson A, Woodcock A, Strachan DP, Shaheen SO, Sterne JA. Associations of wheezing phenotypes in the first 6 years of life with atopy, lung function and airway responsiveness in mid-childhood. Thorax. 2008 Nov;63(11):974-80. doi: 10.1136/thx.2007.093187. Epub 2008 Aug 4.

Gibson PG, Yang IA, Upham JW, Reynolds PN, Hodge S, James AL, Jenkins C, Peters MJ, Marks GB, Baraket M, Powell H, Taylor SL, Leong LEX, Rogers GB, Simpson JL. Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial. Lancet. 2017 Aug 12;390(10095):659-668. doi: 10.1016/S0140-6736(17)31281-3. Epub 2017 Jul 4.

Teo SM, Mok D, Pham K, Kusel M, Serralha M, Troy N, Holt BJ, Hales BJ, Walker ML, Hollams E, Bochkov YA, Grindle K, Johnston SL, Gern JE, Sly PD, Holt PG, Holt KE, Inouye M. The infant nasopharyngeal microbiome impacts severity of lower respiratory infection and risk of asthma development. Cell Host Microbe. 2015 May 13;17(5):704-15. doi: 10.1016/j.chom.2015.03.008. Epub 2015 Apr 9.

Bonnelykke K, Sleiman P, Nielsen K, Kreiner-Moller E, Mercader JM, Belgrave D, den Dekker HT, Husby A, Sevelsted A, Faura-Tellez G, Mortensen LJ, Paternoster L, Flaaten R, Molgaard A, Smart DE, Thomsen PF, Rasmussen MA, Bonas-Guarch S, Holst C, Nohr EA, Yadav R, March ME, Blicher T, Lackie PM, Jaddoe VW, Simpson A, Holloway JW, Duijts L, Custovic A, Davies DE, Torrents D, Gupta R, Hollegaard MV, Hougaard DM, Hakonarson H, Bisgaard H. A genome-wide association study identifies CDHR3 as a susceptibility locus for early childhood asthma with severe exacerbations. Nat Genet. 2014 Jan;46(1):51-5. doi: 10.1038/ng.2830. Epub 2013 Nov 17.

Sleiman PM, Annaiah K, Imielinski M, Bradfield JP, Kim CE, Frackelton EC, Glessner JT, Eckert AW, Otieno FG, Santa E, Thomas K, Smith RM, Glaberson W, Garris M, Gunnlaugsson S, Chiavacci RM, Allen J, Spergel J, Grundmeier R, Grunstein MM, Magnusson M, Bisgaard H, Grant SF, Hakonarson H. ORMDL3 variants associated with asthma susceptibility in North Americans of European ancestry. J Allergy Clin Immunol. 2008 Dec;122(6):1225-7. doi: 10.1016/j.jaci.2008.06.041. Epub 2008 Aug 28. No abstract available.

Chalut DS, Ducharme FM, Davis GM. The Preschool Respiratory Assessment Measure (PRAM): a responsive index of acute asthma severity. J Pediatr. 2000 Dec;137(6):762-8. doi: 10.1067/mpd.2000.110121.

Ducharme FM, Zemek R, Chauhan BF, Gravel J, Chalut D, Poonai N, Guertin MC, Quach C, Blondeau L, Laberge S; DOORWAY research group of the Pediatric Emergency Research in Canada (PERC) network. Factors associated with failure of emergency department management in children with acute moderate or severe asthma: a prospective, multicentre, cohort study. Lancet Respir Med. 2016 Dec;4(12):990-998. doi: 10.1016/S2213-2600(16)30160-6. Epub 2016 Jul 20.

Jartti T, Kuneinen S, Lehtinen P, Peltola V, Vuorinen T, Leinonen M, Ruuskanen O. Nasopharyngeal bacterial colonization during the first wheezing episode is associated with longer duration of hospitalization and higher risk of relapse in young children. Eur J Clin Microbiol Infect Dis. 2011 Feb;30(2):233-41. doi: 10.1007/s10096-010-1075-z. Epub 2010 Oct 13.

Hacking D, Knight JC, Rockett K, Brown H, Frampton J, Kwiatkowski DP, Hull J, Udalova IA. Increased in vivo transcription of an IL-8 haplotype associated with respiratory syncytial virus disease-susceptibility. Genes Immun. 2004 Jun;5(4):274-82. doi: 10.1038/sj.gene.6364067.

Goetghebuer T, Isles K, Moore C, Thomson A, Kwiatkowski D, Hull J. Genetic predisposition to wheeze following respiratory syncytial virus bronchiolitis. Clin Exp Allergy. 2004 May;34(5):801-3. doi: 10.1111/j.1365-2222.2004.1947.x.

Beigelman A, Mikols CL, Gunsten SP, Cannon CL, Brody SL, Walter MJ. Azithromycin attenuates airway inflammation in a mouse model of viral bronchiolitis. Respir Res. 2010 Jun 30;11(1):90. doi: 10.1186/1465-9921-11-90.

Beigelman A, Isaacson-Schmid M, Sajol G, Baty J, Rodriguez OM, Leege E, Lyons K, Schweiger TL, Zheng J, Schechtman KB, Castro M, Bacharier LB. Randomized trial to evaluate azithromycin's effects on serum and upper airway IL-8 levels and recurrent wheezing in infants with respiratory syncytial virus bronchiolitis. J Allergy Clin Immunol. 2015 May;135(5):1171-8.e1. doi: 10.1016/j.jaci.2014.10.001. Epub 2014 Nov 18.

Bonnelykke K, Coleman AT, Evans MD, Thorsen J, Waage J, Vissing NH, Carlsson CJ, Stokholm J, Chawes BL, Jessen LE, Fischer TK, Bochkov YA, Ober C, Lemanske RF Jr, Jackson DJ, Gern JE, Bisgaard H. Cadherin-related Family Member 3 Genetics and Rhinovirus C Respiratory Illnesses. Am J Respir Crit Care Med. 2018 Mar 1;197(5):589-594. doi: 10.1164/rccm.201705-1021OC.

Bochkov YA, Watters K, Ashraf S, Griggs TF, Devries MK, Jackson DJ, Palmenberg AC, Gern JE. Cadherin-related family member 3, a childhood asthma susceptibility gene product, mediates rhinovirus C binding and replication. Proc Natl Acad Sci U S A. 2015 Apr 28;112(17):5485-90. doi: 10.1073/pnas.1421178112. Epub 2015 Apr 6.

Demenais F, Margaritte-Jeannin P, Barnes KC, Cookson WOC, Altmuller J, Ang W, Barr RG, Beaty TH, Becker AB, Beilby J, Bisgaard H, Bjornsdottir US, Bleecker E, Bonnelykke K, Boomsma DI, Bouzigon E, Brightling CE, Brossard M, Brusselle GG, Burchard E, Burkart KM, Bush A, Chan-Yeung M, Chung KF, Couto Alves A, Curtin JA, Custovic A, Daley D, de Jongste JC, Del-Rio-Navarro BE, Donohue KM, Duijts L, Eng C, Eriksson JG, Farrall M, Fedorova Y, Feenstra B, Ferreira MA; Australian Asthma Genetics Consortium (AAGC) collaborators; Freidin MB, Gajdos Z, Gauderman J, Gehring U, Geller F, Genuneit J, Gharib SA, Gilliland F, Granell R, Graves PE, Gudbjartsson DF, Haahtela T, Heckbert SR, Heederik D, Heinrich J, Heliovaara M, Henderson J, Himes BE, Hirose H, Hirschhorn JN, Hofman A, Holt P, Hottenga J, Hudson TJ, Hui J, Imboden M, Ivanov V, Jaddoe VWV, James A, Janson C, Jarvelin MR, Jarvis D, Jones G, Jonsdottir I, Jousilahti P, Kabesch M, Kahonen M, Kantor DB, Karunas AS, Khusnutdinova E, Koppelman GH, Kozyrskyj AL, Kreiner E, Kubo M, Kumar R, Kumar A, Kuokkanen M, Lahousse L, Laitinen T, Laprise C, Lathrop M, Lau S, Lee YA, Lehtimaki T, Letort S, Levin AM, Li G, Liang L, Loehr LR, London SJ, Loth DW, Manichaikul A, Marenholz I, Martinez FJ, Matheson MC, Mathias RA, Matsumoto K, Mbarek H, McArdle WL, Melbye M, Melen E, Meyers D, Michel S, Mohamdi H, Musk AW, Myers RA, Nieuwenhuis MAE, Noguchi E, O'Connor GT, Ogorodova LM, Palmer CD, Palotie A, Park JE, Pennell CE, Pershagen G, Polonikov A, Postma DS, Probst-Hensch N, Puzyrev VP, Raby BA, Raitakari OT, Ramasamy A, Rich SS, Robertson CF, Romieu I, Salam MT, Salomaa V, Schlunssen V, Scott R, Selivanova PA, Sigsgaard T, Simpson A, Siroux V, Smith LJ, Solodilova M, Standl M, Stefansson K, Strachan DP, Stricker BH, Takahashi A, Thompson PJ, Thorleifsson G, Thorsteinsdottir U, Tiesler CMT, Torgerson DG, Tsunoda T, Uitterlinden AG, van der Valk RJP, Vaysse A, Vedantam S, von Berg A, von Mutius E, Vonk JM, Waage J, Wareham NJ, Weiss ST, White WB, Wickman M, Widen E, Willemsen G, Williams LK, Wouters IM, Yang JJ, Zhao JH, Moffatt MF, Ober C, Nicolae DL. Multiancestry association study identifies new asthma risk loci that colocalize with immune-cell enhancer marks. Nat Genet. 2018 Jan;50(1):42-53. doi: 10.1038/s41588-017-0014-7. Epub 2017 Dec 22.

Caliskan M, Bochkov YA, Kreiner-Moller E, Bonnelykke K, Stein MM, Du G, Bisgaard H, Jackson DJ, Gern JE, Lemanske RF Jr, Nicolae DL, Ober C. Rhinovirus wheezing illness and genetic risk of childhood-onset asthma. N Engl J Med. 2013 Apr 11;368(15):1398-407. doi: 10.1056/NEJMoa1211592. Epub 2013 Mar 27.

Semic-Jusufagic A, Belgrave D, Pickles A, Telcian AG, Bakhsoliani E, Sykes A, Simpson A, Johnston SL, Custovic A. Assessing the association of early life antibiotic prescription with asthma exacerbations, impaired antiviral immunity, and genetic variants in 17q21: a population-based birth cohort study. Lancet Respir Med. 2014 Aug;2(8):621-30. doi: 10.1016/S2213-2600(14)70096-7. Epub 2014 May 14.

Cohen RT, Pelton SI. Individual Benefit vs Societal Effect of Antibiotic Prescribing for Preschool Children With Recurrent Wheeze. JAMA. 2015 Nov 17;314(19):2027-9. doi: 10.1001/jama.2015.14953. No abstract available.