Individualized therapy for persistent asthma in young children - 18/04/17
Doi : 10.1016/j.jaci.2016.09.028
Anne M. Fitzpatrick, PhD a, ∗, Daniel J. Jackson, MD b, ∗, David T. Mauger, PhD c, Susan J. Boehmer, MA c, Wanda Phipatanakul, MD, MS d, William J. Sheehan, MD d, James N. Moy, MD e, Ian M. Paul, MD, MSc f, Leonard B. Bacharier, MD g, Michael D. Cabana, MD h, Ronina Covar, MD p, Fernando Holguin, MD i, Robert F. Lemanske, MD j, Fernando D. Martinez, MD k, Jacqueline A. Pongracic, MD l, Avraham Beigelman, MD g, Sachin N. Baxi, MD d, Mindy Benson, MSN, PNP m, Kathryn Blake, PharmD n, James F. Chmiel, MD o, Cori L. Daines, MD k, Michael O. Daines, MD k, Jonathan M. Gaffin, MD q, Deborah Ann Gentile, MD r, W. Adam Gower, MD s, Elliot Israel, MD t, Harsha Vardhan Kumar, MD u, Jason E. Lang, MD, MPH v, Stephen C. Lazarus, MD h, John J. Lima, PharmD n, Ngoc Ly, MD w, Jyothi Marbin, MD x, Wayne Morgan, MD k, Ross E. Myers, MD y, J. Tod Olin, MD p, Stephen P. Peters, MD, PhD s, Hengameh H. Raissy, PharmD z, Rachel G. Robison, MD l, Kristie Ross, MD o, Christine A. Sorkness, PharmD aa, Shannon M. Thyne, MD bb, Stanley J. Szefler, MD cc, ⁎ 
for the
for the
National Institutes of Health/National Heart, Lung, and Blood Institute AsthmaNet‡
Contributions by study personnel are presented in the Acknowledgment section of this article's Online Repository at www.jacionline.org.
a Department of Pediatrics, Emory University, Atlanta, Ga
b Pediatrics, Section of Allergy, Immunology and Rheumatology, University of Wisconsin School of Medicine and Public Health, Madison, Wis
c Department of Public Health Sciences, Penn State University, College of Medicine, Hershey, Pa
f Department of Pediatrics, Penn State University, College of Medicine, Hershey, Pa
d Division of Allergy/Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Mass
q Division of Respiratory Diseases, Boston Children's Hospital, Harvard Medical School, Boston, Mass
e Stroger Hospital of Cook County, Department of Pediatrics, Rush University Medical Center, Chicago, Ill
g Department of Pediatrics, Washington University in St Louis School of Medicine and St Louis Children's Hospital, St Louis, Mo
h Medicine, University of California–San Francisco, Medicine, San Francisco, Calif
i University of Pittsburgh Asthma Institute at UPMC/UPSOM, Pittsburgh, Pa
j Pediatrics, University of Wisconsin School of Medicine and Public Health, Pediatrics, Madison, Wis
k Arizona Respiratory Center, University of Arizona, Tucson, Ariz
l Ann & Robert H Lurie Children's Hospital of Chicago, Chicago, Ill
m University of California–San Francisco Benioff Children's Hospital Oakland, Oakland, Calif
n Nemours Children's Health System, Jacksonville, Fla
o Department of Pediatrics, Case Western Reserve University School of Medicine, Rainbow Babies and Children's Hospital, Cleveland, Ohio
p Pediatrics, National Jewish Health, Denver, Colo
r Department of Pediatrics, Allegheny General Hospital, Pittsburgh, Pa
s Wake Forest School of Medicine, Winston-Salem, NC
t Brigham & Women's Hospital, Harvard Medical School, Boston, Mass
u University of Illinois at Chicago, Chicago, Ill
v Nemours Children's Hospital, University of Central Florida College of Medicine, Orlando, Fla
w Airway Clinical Research Center, University of California–San Francisco, San Francisco, Calif
x University of California–San Francisco, Benioff Children's Hospital Oakland, Oakland, Calif
y Rainbow Babies and Children's Hospital, Cleveland, Ohio
z Pediatrics/Pulmonary, University of New Mexico, Albuquerque, NM
aa University of Wisconsin–Madison, Madison, Wis
bb Olive View–UCLA Medical Center, Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, Calif
cc Children's Hospital Colorado, the Breathing Institute, and the University of Colorado School of Medicine, Aurora, Colo
∗Corresponding author: Stanley J. Szefler, MD, Pediatric Asthma Research Program the Breathing Institute, Children's Hospital Colorado, 13123 E 16th Ave, Box 395, Aurora, CO 80045.Pediatric Asthma Research Program the Breathing InstituteChildren's Hospital Colorado13123 E 16th Ave, Box 395AuroraCO80045
Abstract |
Background |
Phenotypic presentations in young children with asthma are varied and might contribute to differential responses to asthma controller medications.
Methods |
The Individualized Therapy for Asthma in Toddlers study was a multicenter, randomized, double-blind, double-dummy clinical trial in children aged 12 to 59 months (n = 300) with asthma necessitating treatment with daily controller (Step 2) therapy. Participants completed a 2- to 8-week run-in period followed by 3 crossover periods with daily inhaled corticosteroids (ICSs), daily leukotriene receptor antagonists, and as-needed ICS treatment coadministered with albuterol. The primary outcome was differential response to asthma medication based on a composite measure of asthma control. The primary analysis involved 2 stages: determination of differential response and assessment of whether 3 prespecified features (aeroallergen sensitization, previous exacerbations, and sex) predicted a differential response.
Results |
Seventy-four percent (170/230) of children with analyzable data had a differential response to the 3 treatment strategies. Within differential responders, the probability of best response was highest for a daily ICS and was predicted by aeroallergen sensitization but not exacerbation history or sex. The probability of best response to daily ICS was further increased in children with both aeroallergen sensitization and blood eosinophil counts of 300/μL or greater. In these children daily ICS use was associated with more asthma control days and fewer exacerbations compared with the other treatments.
Conclusions |
In young children with asthma necessitating Step 2 treatment, phenotyping with aeroallergen sensitization and blood eosinophil counts is useful for guiding treatment selection and identifies children with a high exacerbation probability for whom treatment with a daily ICS is beneficial despite possible risks of growth suppression.
Le texte complet de cet article est disponible en PDF.Graphical abstract |
Key words : Asthma, asthma treatment, asthma biomarkers, asthma phenotype, inhaled corticosteroid, leukotriene receptor antagonist, personalized medicine, treatment response
Abbreviations used : ACD, ECP, ICS, INFANT, LTE4, LTRA, mAPI, PEAK
Plan
| Supported by grants HL098102, HL098096, HL098075, HL098090, HL098177, HL098098, HL098107, HL098112, HL098103, HL098115, TR001082, TR000439, TR000448, and TR000454 from the National Heart, Lung, and Blood Institute as part of AsthmaNet, a clinical trials network supported by a cooperative agreement with the National Heart, Lung, and Blood Institute (NHLBI). The following were donated: fluticasone propionate and matching placebo by GlaxoSmithKline, Evreux, France; montelukast and matching placebo by Merck and Co, Whitehouse Station, NJ; and albuterol sulfate by GlaxoSmithKline, Research Triangle Park, NC, under a clinical trial agreement with Pennsylvania State University. NHLBI Program Officers participated in study design, conduct, and interpretation of the data. The study was monitored by the AsthmaNet data and safety monitoring board, which also reviewed and approved the final manuscript. INFANT ClinicalTrials.gov number, NCT01606306. |
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| Disclosure of potential conflict of interest: A. M. Fitzpatrick's institution has received grant U10 HL098103 from the National Heart, Lung, and Blood Institute (NHLBI), and she has received consultancy fees from Genentech and Boehringer Ingelheim. D. J. Jackson has received consultancy fees from Vectura and GlaxoSmithKline. D. T. Mauger's institution has received donations from Merck and the National Heart, Lung, and Blood Institute (NHLBI). J. N. Moy has received consultancy fees from Prometric, payment for lectures from Grifols, payment for development of educational presentations from Baxalta, and other forms of support from Octapharma and MacroCure. I. M. Paul has received consultancy fees from McNeil Consumer Healthcare, Procter and Gamble, Pfizer, Perrigo Nutritionals, Boehringer Ingelheim, Rocky Mountain Poison, and the Drug Center. L. B. Bacharier has received consultancy fees from GlaxoSmithKline, Merck, DBV Technologies, TEVA, Boehringer Ingelheim, Sanofi, Vectura, Cephalon, and Meda; received payment for lectures from Genentech/Novartis, TEVA, Boehringer Ingelheim, AstraZeneca, and Merck; and received payment for development of educational presentations from WebMD/Medscape. M. D. Cabana's institution has received grants, support for travel, and fees for participating in review activities and payment for writing or reviewing the manuscript from the NHLBI and he has received consultancy fees from Boehringer Ingelheim and payment for lectures from Merck Speakers Bureau. R. Covar received consultancy fees from Genentech/Novartis and payment for development of educational presentations from Aerogen Webinar and Boehringer Ingelheim, and her institution has received grants from AstraZeneca, Roche, and other support from Merck, GlaxoSmithKline, Boehringer Ingelheim, and TEVA. R. F. Lemanske has received support for travel and payment for manuscript writing or reviewing from the NHLBI; received board membership from the American Academy of Allergy, Asthma, & Immunology; received consultancy fees from Health Star Communications; is employed by University of Wisconsin School of Medicine and Public Health; has personally received payment for lectures from the Kuwait Allergy Society, Lurie Children's Hospital, Boston Children's Hospital, L.A. Children's Hospital, Northwestern University, the Asthma and Allergy Foundation of America, Alaska Chapter, and the Egyptian Allergy Society; and receives royalties from Elsevier and UpToDate, and his institution has received grants from the NHLBI (RO-1) and Pharmaxis. F. D. Martinez's institution has received grants from the National Institutes of Health (NIH)/NHLBI (HL098112, HL056177, HL091889, HL30045, HL132523, AI126614), the NIH/National Institute of Environmental Health Sciences (NIEHS; ES000694), and Johnson & Johnson (UA009253-0001); and has received consultancy fees from Copeval. J. A. Pongracic has received a grant, payment from writing or reviewing manuscripts, and support for travel from Northwestern University, and her institution has received support from Novartis. A. Beigelman and S. N. Baxi's institutions have received a grant from the NIH. M. Benson's institution has received a grant, support for travel, and payment for writing or reviewing the manuscript from UCSF. K. Blake's institution has received a grant and support for travel from AsthmaNet. J. F. Chmiel has received personal fees from Boehringer Ingelheim, Gilead Pharmaceuticals, the American Board of Pediatrics, University of Louisville, Cystic Fibrosis Foundation, NIH, Celtaxsys, and Nivalis Therapeutics and grants from the Cystic Fibrosis Foundation, NIH, AstraZeneca, TEVA, and Roche. M. O. Daines' institution has received a grant from the NIH. D. A. Gentile has received consultancy fees from Mylan and Greer; payment for lectures from Stallergenes/Greer and Merck; and support from the DSMB of AstraZeneca. E. Israel has received consultancy fees from AstraZenenca, Bird Rock Bio, Cowen & Co, Novartis, Nuvelution Pharmaceuticals, Philips Respironics, Regeneron Pharmaceuticals, and TEVA Specialty Pharmaceuticals; expert testimony fees from Campbell, Campbell, Edwards & Conroy, Crammer, Bishop & O'Brien, Fox Rothschild, and Ryan Ryan Deluca; and royalties from UpToDate, and his institution has received a grant from TEVA. J. E. Lang has received consultancy fees from Advisor for RFTO Pharmacologic Interventions for Asthma (UConn), and his institution has received a grant from the Thrasher Research Foundation and American Lung Association. N. Ly has received consultancy fees from Gilead and payment for lectures form Genentech. W. Morgan has received support for travel from and is employed by the University of Arizona; received consultancy fees from Genentech and the Cystic Fibrosis Foundation; and received payment for lectures from the American College of Chest Physicians, American Thoracic Society, and Elsevier, and his institution has received grants from MCHB and the Cystic Fibrosis Foundation. R. E. Myers' institution has received support for travel from the NIH/NHLBI. S. P. Peters has received consultancy fees from Array Biopharm, AstraZeneca, Aerocrine, Boehringer Ingelheim, Experts in Asthma, Gilead, GlaxoSmithKline, Merck, Novartis, Ono Pharmaceuticals, Pfizer, PPD Development, Quintiles, Sunovion, Saatchi & Saatchi, Targacept, TEVA, and Theron; payment for lectures Integrity CE; royalties from UpToDate; and payment for development of educational presentations for the Potomac Center for Medical Education and ACAAI/Haymarket. H. H. Raissy and R. G. Robison's institutions have received a grant from the NHLBI/AsthmaNet and grant UG1HD090878-01. R. G. Robison's institution has received support for travel from the Northwestern University (NIH/NHLBI Subcontract) and donations from TEVA. K. Ross' institution has received a grant and support for travel from the NHLBI, and her the institution has received grants from Nivalis N91115. C. A. Sorkness's institution has received a grant from the NIAID Inner City Asthma Consortium. S. J. Szefler received a grant from the NHLBI; received consultancy fees from Roche, AstraZeneca, Aerocrine, Daiichi Sankyo, Boehringer Ingelheim, Merck, Genentech, Novartis; and has grants pending from GlaxoSmithKline. J. T. Olin, S. P. Peters, W. Phipatanakul, J. A. Pongracic, H. H. Raissy, R. G. Robison, K. Ross, W. J. Sheehan, C. A. Sorkness, S. J. Szefler, S. C. Lazarus, J. J. Lima, J. Marbin, F. D. Martinez, D. T. Mauger, R. E. Myers, J. N. Moy, M. O. Daines, A. M. Fitzpatrick, J. M. Gaffin, W. A. Gower, E. Israel, H. V. Kumar, D. J. Jackson, J. E. Lang, L. B. Bacharier, S. N. Baxi, A. Beigelman, K. Blake, S. J. Boehmer, M. D. Cabana, J. F. Chmiel, and R. Covar's institutions have all received donations from GlaxoSmithKline and Merck. W. Morgan, R. E. Myers, J. N. Moy, and D. J Jackson's institutions have received grants from NIH/NHLBI. S. C. Lazarus, J. A. Pongracic, K. Ross, R. E. Myers, A. M. Fitzpatrick, E. Israel, K. Blake, M. D. Cabana, and J. F. Chmiel institutions have received support from Sunovion, Merck, Boehringer, TEVA, and GlaxoSmithKline. R. Covar and R. F. Lemanske's institutions have received a grant from the NHLBI. W. J. Sheehan, S. P. Peters, S. C. Lazarus, and W. Morgan's institutions have received grant from the NIH/National Instituter of Allergy and Infectious Diseases (NIAID). The rest of the authors declare that they have no relevant conflicts of interest. |
© 2016
American Academy of Allergy, Asthma & Immunology. Publié par Elsevier Masson SAS. Tous droits réservés.
Vol 138 - N° 6
P. 1608 - décembre 2016 Retour au numéro
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