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N Engl J Med. 2018 Mar 8;378(10):891-901. doi: 10.1056/NEJMoa1710988. Epub 2018 Mar 3.

Quintupling Inhaled Glucocorticoids to Prevent Childhood Asthma Exacerbations.

Collaborators (156)

Cardet JC, Burke-Roberts E, Hauptman M, Hron B, Kopel L, Osganian S, Permaul P, Wright L, Burke C, Cavanaugh M, Cunningham A, Dimas A, Gerald A, Nisbett L, Peterson B, Regos D, Ryan T, Schierembergg D, Volonte B, Kumar R, Makhija M, Szychlinski C, Flexas I, Koridek-Phillips K, Lane J, Codispoti C, Yu B, Kayaloglou A, Li G, Stevens S, Zitzer S, Nyenhuis S, Gonzalez V, Morales-Perez M, Morken V, Spears G, Szefler S, Wechsler ME, Davies L, Jump S, Ruybal J, Sundstrom D, White M, Caffey L, Batson C, Kelly F, Redway A, Ramratnam S, Knutson M, Olson S, Schend V, Watson T, Denlinger L, Bach J, Celedon J, Chong H, Forno E, Green T, Kurland G, Larkin A, Spahr J, Weiner D, Granny C, Kasubinski E, Kufen A, Lanzo R, Richey S, Hart M, Gluvna A, Logan L, Veri L, Skoner D, Butler E, Misplay S, Sossong N, Coverstone A, Ellis A, Horner C, Kertz L, Rivera-Spoljaric K, Strunk R, Navin M, Norris T, Siegel M, Caldwell W, Bentz M, Carmona N, Gonzalez-Vargas J, Herm A, Sparatta A, Ross J, DelToro R, Harris C, Mok R, Nelson-Purdy C, Stessel H, Aguilar P, Carr T, Daines C, Daines M, Gerald L, Goforth M, Goodwin J, Grad R, Hiranratta A, Mathur A, Benavides A, Bloss V, Castro S, Cooper C, David S, Lopez S, Oremelendez P, Posada M, Preciado M, Priefert J, Provencio N, Ryan E, Schunk R, Shareef F, Thomas I, Vasquez M, Wences J, Gower W, Ortega V, Wilmoth C, Bruce A, Dodds J, Schaeffer D, Batalla J, Joyce K, LaFave G, Littlefield M, Ponthieux K, Riber B, Rutledge S, Ali-Dinar T, Livingston F, Brown S, Oquendo O, Pena-Rufino M, Walker K, Chinchilli V, Craig T, King T, Paul I, Dyer AM, Kunselman S, Merchlinski A, Updegrave A, Nelson J, Nye K, Baab K, Zimmerman R, Ferrari L, Texter L.

Author information

From the Department of Pediatrics, University of Wisconsin School of Medicine and Public Health (D.J.J., R.F.L.J.), and the University of Wisconsin-Madison (C.A.S.) - both in Madison; the Department of Pediatrics, Washington University in St. Louis School of Medicine and St. Louis Children's Hospital, St. Louis (L.B.B., A.B.); the Department of Public Health Sciences, Penn State University, Hershey (D.T.M., S.B.), and the University of Pittsburgh Asthma Institute at University of Pittsburgh Medical Center-University of Pittsburgh School of Medicine (F.H.) and the Department of Pediatrics, Allegheny General Hospital (D.A.G.), Pittsburgh - all in Pennsylvania; the Department of Pediatrics, Case Western Reserve University School of Medicine, Rainbow Babies and Children's Hospital, Cleveland (J.F.C., R.E.M., K.R.); the Department of Pediatrics, Emory University, Atlanta (A.M.F.); the Divisions of Respiratory Diseases (J.M.G.) and Allergy-Immunology, Boston Children's Hospital (W.P., W.J.S., S.N.B.), Harvard Medical School, and Brigham and Women's Hospital, Harvard Medical School (E.I.) - all in Boston; the Arizona Respiratory Center, University of Arizona, Tucson (W.J.M., F.D.M.); Wake Forest University School of Medicine, Winston-Salem, NC (S.P.P.); the Departments of Pediatrics (M.D.C., N.L.), Epidemiology (M.D.C.), Biostatistics (M.D.C.), and Medicine (S.C.L.), University of California, San Francisco (UCSF), and UCSF Benioff Children's Hospital (M.D.C.) - both in San Francisco; Ann and Robert H. Lurie Children's Hospital of Chicago (J.A.P., R.G.R.), University of Illinois at Chicago (J.A.K., H.V.K.), and the Department of Pediatrics, Stroger Hospital of Cook County, Rush University Medical Center (J.N.M.) - all in Chicago; UCSF Benioff Children's Hospital Oakland, Oakland (M.B., D.L., J.M.); Nemours Children's Health System, Jacksonville (K.B., J.J.L.), and Nemours Children's Hospital, University of Central Florida College of Medicine, Orlando (J.E.L.) - both in Florida; the Department of Pediatrics, National Jewish Health, Denver (R.C., J.T.O.); and the Department of Pediatrics, University of New Mexico, Albuquerque (H.H.R.).



Asthma exacerbations occur frequently despite the regular use of asthma-controller therapies, such as inhaled glucocorticoids. Clinicians commonly increase the doses of inhaled glucocorticoids at early signs of loss of asthma control. However, data on the safety and efficacy of this strategy in children are limited.


We studied 254 children, 5 to 11 years of age, who had mild-to-moderate persistent asthma and had had at least one asthma exacerbation treated with systemic glucocorticoids in the previous year. Children were treated for 48 weeks with maintenance low-dose inhaled glucocorticoids (fluticasone propionate at a dose of 44 μg per inhalation, two inhalations twice daily) and were randomly assigned to either continue the same dose (low-dose group) or use a quintupled dose (high-dose group; fluticasone at a dose of 220 μg per inhalation, two inhalations twice daily) for 7 days at the early signs of loss of asthma control ("yellow zone"). Treatment was provided in a double-blind fashion. The primary outcome was the rate of severe asthma exacerbations treated with systemic glucocorticoids.


The rate of severe asthma exacerbations treated with systemic glucocorticoids did not differ significantly between groups (0.48 exacerbations per year in the high-dose group and 0.37 exacerbations per year in the low-dose group; relative rate, 1.3; 95% confidence interval, 0.8 to 2.1; P=0.30). The time to the first exacerbation, the rate of treatment failure, symptom scores, and albuterol use during yellow-zone episodes did not differ significantly between groups. The total glucocorticoid exposure was 16% higher in the high-dose group than in the low-dose group. The difference in linear growth between the high-dose group and the low-dose group was -0.23 cm per year (P=0.06).


In children with mild-to-moderate persistent asthma treated with daily inhaled glucocorticoids, quintupling the dose at the early signs of loss of asthma control did not reduce the rate of severe asthma exacerbations or improve other asthma outcomes and may be associated with diminished linear growth. (Funded by the National Heart, Lung, and Blood Institute; STICS number, NCT02066129 .).

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