U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health

National Heart, Lung, and Blood Institute

National Asthma Education and Prevention Program

Update on 

Selected Topics 2002

Asthma Expert Panel Report:

Guidelines for the

Diagnosis and

Management of

Asthma

Archive

for historical Reference Only
Archive

for historical Reference Only
Update on 

Selected Topics 2002

Asthma Expert Panel Report:

Guidelines for the

Diagnosis and

Management of

Asthma

National Asthma Education and Prevention Program

U.S. DEPARTMENT OF HEALTH

AND HUMAN SERVICES

National Institutes of Health

National Asthma Education 

and Prevention Program

National Heart, Lung, 

and Blood Institute

NIH Publication No. 02-5074

June 2003

Archive

for historical Reference Only
Archive

for historical Reference Only
iii

Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .ix

National Asthma Education and Prevention Program Science Base Committee 

and Expert Panel on the Management of Asthma . . . . . . . . . . . . . . . . . . . . . . . . . . . . .ix

National Heart, Lung, and Blood Institute Staff and American Institutes for 

Research/Prospect Center Support Staff . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .ix

National Asthma Education and Prevention Program Coordinating Committee . . . . . . .ix

Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .xii

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3

Methods Used To Develop This Report . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7

Overview of the Pathogenesis of Asthma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .11

Inflammation of Asthma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .11

An Imbalance Between Th1 and Th2 in the Origins of Asthma . . . . . . . . . . . . . . . . . .12

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .14

1. Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .17

Long-Term Management of Asthma in Children: 

Effectiveness of Inhaled Corticosteroids Compared to Other Medications . . . . . . . . . . .17

Question . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .17

Summary Answer to the Question . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .17

Rationale for the Question . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .18

Systematic Review of the Evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .18

Methods of Literature Search . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .18

Summary of Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .19

Additional Literature/Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .21

Recommendations for EPR Update . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .22

Recommendations for Future Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .29

Key Evidence Tables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .30

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .34

Long-Term Management of Asthma in Children: 

Safety of Inhaled Corticosteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .37

Question . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .37

Summary Answer to the Question . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .37

Rationale for the Question . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .37

Systematic Review of the Evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .37

Methods of Literature Search . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .37

Summary of Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .38

Additional Literature/Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .40

Recommendations for EPR Update . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .40

Linear Growth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .40

Bone Mineral Density . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .41

Cataracts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .41

Hypothalamic-Pituitary-Adrenal Axis Function . . . . . . . . . . . . . . . . . . . . . . . . . .41

Recommendations for Future Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .41

Key Evidence Tables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .42

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .46

Contents

Archive

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iv

Contents

Combination Therapy: Addition of Other Long-Term Control 

Medications to Inhaled Corticosteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .49

Question . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .49

Summary Answer to the Question . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .49

Rationale for the Question . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .49

Systematic Review of the Evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .49

Methods of Literature Search . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .49

Summary of Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .50

Additional Literature/Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .52

Recommendations for EPR Update . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .55

Recommendations for Future Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .58

Key Evidence Tables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .59

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .61

Use of Antibiotics To Treat Asthma Exacerbations . . . . . . . . . . . . . . . . . . . . . . . . . . . .63

Question . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .63

Summary Answer to the Question . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .63

Rationale for the Question . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .63

Systematic Review of the Evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .63

Methods of Literature Search . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .63

Summary of Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .64

Additional Literature/Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .64

Recommendations for EPR Update . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .64

Recommendations for Future Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .65

Key Evidence Tables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .66

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .70

2. Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .73

Written Action Plans Compared to Medical Management Alone . . . . . . . . . . . . . . . . .73

Question . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .73

Summary Answer to the Question . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .73

Rationale for the Question . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .73

Systematic Review of the Evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .74

Methods of Literature Search . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .74

Summary of Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .74

Additional Literature/Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .75

Recommendations for EPR Update . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .75

Recommendations for Future Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .76

Key Evidence Tables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .78

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .84

Peak Flow-Based Compared to Symptom-Based Written Action Plans . . . . . . . . . . . . .85

Question . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .85

Summary Answer to the Question . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .85

Rationale for the Question . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .85

Systematic Review of the Evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .85

Methods of Literature Search . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .85

Summary of Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .85

Recommendations for EPR Update . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .86

Recommendations for Future Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .87

Key Evidence Tables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .89

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .92

3. Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .95

Effects of Early Treatment on the Progression of Asthma . . . . . . . . . . . . . . . . . . . . . . .95

Question . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .95

Summary Answer to the Question . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .95

Rationale for the Question . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .95

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Contents

Background Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .96

Natural History of Persistent Asthma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .96

Systematic Review of the Evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .97

Methods of Literature Search . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .97

Summary of Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .98

Recommendations for EPR Update . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .101

Recommendations for Future Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .104

Key Evidence Tables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .106

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .110

Appendix A: Updated Charts for the Management of Asthma . . . . . . . . . . . . . . . .113

Appendix A–1. Stepwise Approach for Managing Asthma . . . . . . . . . . . . . . . .115

Figure 1. Stepwise Approach for Managing Infants and Young Children 

(5 Years of Age and Younger) With Acute or Chronic Asthma 

(Updates EPR-2 Figures 3–4a and 3–6) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .115

Figure 2. Stepwise Approach for Managing Asthma in Adults and Children 

Older Than 5 Years of Age: Treatment (Updates EPR-2 Figures 3–4a and 3–4b) . .116

Appendix A–2. Usual Dosages for Asthma Medications . . . . . . . . . . . . . . . . . . .117

Figure 1. Usual Dosages for Long-Term-Control Medications 

(Updates EPR-2 Figure 3–5a) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .117

Figure 2. Estimated Comparative Daily Dosages for Inhaled Corticosteroids 

(Updates EPR-2 Figure 3–5b) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .119

Figure 3. Usual Dosages for Quick-Relief Medications 

(Updates EPR-2 Figure 3–5d) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .120

Figure 4. Dosages of Drugs for Asthma Exacerbations in Emergency Medical 

Care or Hospital (Updates EPR-2 Figure 3–10) . . . . . . . . . . . . . . . . . . . . . . . . . . .122

Appendix A–2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .124

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .124

Appendix B: Acronyms and Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .129

Archive

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Archive

for historical Reference Only
Acknowledgments

Asthma Expert Panel Report:

Guidelines for the

Diagnosis and

Management of

Asthma

Archive

for historical Reference Only
Archive

for historical Reference Only
ix

National Asthma Education and

Prevention Program Science Base

Committee and Expert Panel on the

Management of Asthma

William W. Busse, M.D., Chair

University of Wisconsin Medical School

Madison, WI

Homer A. Boushey, M.D.

University of California at San Francisco

San Francisco, CA

Sonia Buist, M.D.

Oregon Health Sciences University

Portland, OR

Noreen M. Clark, Ph.D.

University of Michigan 

School of Public Health

Ann Arbor, MI

H. William Kelly, Pharm.D.

University of New Mexico 

Health Sciences Center

Albuquerque, NM

Robert F. Lemanske, M.D.

University of Wisconsin 

Hospital and Clinics

Madison, WI

Fernando D. Martinez, M.D.

University of Arizona Medical Center

Tucson, AZ

Harold S. Nelson, M.D.

National Jewish Medical and 

Research Center

Denver, CO

Gail Shapiro, M.D.

University of Washington

Seattle, WA

Stuart Stoloff, M.D.

University of Nevada School of Medicine

Reno, NV

Stanley Szefler, M.D.

National Jewish Medical and 

Research Center

Denver, CO

National Heart, Lung, and Blood

Institute Staff 

Robinson Fulwood, Ph.D., M.S.P.H.

Senior Manager

Office of Prevention, Education, and Control

James P. Kiley, Ph.D.

Director

Division of Lung Diseases

Gregory J. Morosco, Ph.D., M.P.H.

Associate Director

Office of Prevention, Education, and Control

Diana K. Schmidt, M.P.H.

Coordinator

National Asthma Education and 

Prevention Program

Virginia S. Taggart, M.P.H.

Health Scientist Administrator

Division of Lung Diseases

Prospect Associates Ltd. Staff 

(now part of American Institutes

for Research Health Program, 

Silver Spring, MD)

Susan Bratten

Senior Editor

Teresa Wilson, M.P.H., R.N.

Senior Partnership Leader

National Asthma Education and

Prevention Program Coordinating

Committee

Claude Lenfant, M.D., Chair

National Heart, Lung, and Blood Institute

Denise Dougherty, Ph.D.

Agency for Health Care Policy and Research

Nancy J. Sander

Allergy and Asthma Network/Mothers of

Asthmatics, Inc.

Gail Shapiro, M.D.

American Academy of Allergy, Asthma, 

and Immunology

Barbara P. Yawn, M.D., M.Sc.

American Academy of Family Physicians

Gary S. Rachelefsky, M.D.

American Academy of Pediatrics

Gabriel R. Ortiz, M.P.A.S., PA-C

American Academy of Physician Assistants

Thomas J. Kallstrom, R.R.T.

American Association for Respiratory Care

Pam Carter, R.N., C.O.H.N.-S.

American Association of Occupational 

Health Nurses

William Storms, M.D.

American College of Allergy, Asthma, 

and Immunology

John P. Mitchell, M.D., F.A.C.P.

American College of Chest Physicians

Richard M. Nowak, M.D., M.B.A.,

F.A.C.E.P.

American College of Emergency Physicians

Noreen M. Clark, Ph.D.

American Lung Association

Paul V. Williams, M.D.

American Medical Association

Acknowledgments

Archive

for historical Reference Only
x

Acknowledgments

Karen Huss, R.N., D.N.Sc.

American Nurses Association

Dennis M. Williams, Pharm.D.

American Pharmaceutical Association

Pamela J. Luna, Dr.P.H., M.Ed.

American Public Health Association

Lani S.M. Wheeler, M.D., F.A.A.P.,

F.A.S.H.A.

American School Health Association

Leslie Hendeles, Pharm.D.

American Society of Health-System Pharmacists

Stephen C. Lazarus, M.D.

American Thoracic Society

Barbara L. Hager, M.P.H., C.H.E.S.

Association of State and Territorial Directors of

Health Promotion and Public Health

Education

Mary E. Worstell, M.P.H.

Asthma and Allergy Foundation of America

Sarah Lyon-Callo, M.A., M.S.

Council on State and Territorial

Epidemiologists

Carol Costante, R.N., M.A., C.S.N.,

F.N.A.S.N.

National Association of School Nurses

Susan B. Clark, R.N., M.N.

National Black Nurses Association, Inc.

Mary Vernon-Smiley, M.D., M.P.H.

National Center for Chronic 

Disease Prevention

Centers for Disease Control and Prevention

Leslie P. Boss, Ph.D., M.P.H.

National Center for Environmental Health

Centers for Disease Control and Prevention

Lara Akinbami, M.D.

National Center for Health Statistics

Centers for Disease Control and Prevention

Gregory R. Wagner, M.D.

National Institute for Occupational Safety 

and Health

Centers for Disease Control and Prevention

Kenneth Adams, Ph.D.

National Institute of Allergy and Infectious

Diseases

J. Patrick Mastin, Ph.D.

National Institute of Environmental 

Health Sciences

Michael Lenoir, M.D.

National Medical Association

Ruth I. Quartey, M.A., R.R.T.

NHLBI Ad Hoc Committee on Minority

Populations

Carlos A. Camargo, M.D., Dr.P.H.

Society for Academic Emergency Medicine

Estelle Bogdonoff, M.P.H., C.H.E.S.

Society for Public Health Education

Doris Sligh

U.S. Department of Education

David E. Jacobs, Ph.D.

U.S. Department of Housing and Urban

Development

Mary T. Smith, J.D.

U.S. Environmental Protection Agency

Robert J. Meyer, M.D.

U.S. Food and Drug Administration

Olivia Carter-Pokras, Ph.D.

U.S. Public Health Service

Archive

for historical Reference Only
Preface

Asthma Expert Panel Report:

Guidelines for the

Diagnosis and

Management of

Asthma

Archive

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Archive

for historical Reference Only
xiii

Expert Panel Report: Guidelines for the Diagnosis

and Management of Asthma—Update on 

Selected Topics 2002 (EPR—Update 2002)

provides timely information on several

selected priority asthma topics. It updates

recommendations of the Expert Panel Report

2: Guidelines for the Diagnosis and Management

of Asthma (EPR-2).

The current update was developed using 

a new approach that will make the asthma

guidelines a dynamic and timely guide for

practicing clinicians. The National Asthma

Education and Prevention Program (NAEPP)

Science Base Committee regularly reviews the

scientific literature as an ongoing process to

identify topics that warrant a more in-depth

and systematic review. For this update, the

Committee has focused on a few of the more

pressing asthma issues rather than updating

all topics at once. This approach should provide more expeditious updates in the future,

thus adding to the value of the guidelines as

a living document.

The Committee recommends to the NAEPP

Coordinating Committee when a review is

warranted and, upon concurrence by the CC,

an expert panel is convened. Expert panel

members are independent thinkers who represent a multidisciplinary group of clinicians

and scientists possessing expertise in clinical

management. They make recommendations

based on their interpretation of the best and

most current evidence available.

The 2002 update to the asthma guidelines

has been developed under the able leadership

of Dr. William Busse, Panel Chair. The

National Heart, Lung, and Blood Institute

sincerely appreciates the work of Dr. Busse

and all members of the Expert Panel in

developing this report. Sincere appreciation

also goes to the 40 organizations (professional

societies, voluntary organizations, Federal

agencies) that comprise the NAEPP-CC for

their thoughtful review and comments in

approving content of this report.

Ultimately, broad change in clinical practice

depends on the influence of local physicians

and other health professionals who not only

provide state-of-the-art care to their patients,

but also communicate to their peers the

importance of doing the same. We are optimistic that over the next several years, the

joint efforts of the NAEPP, its CC member

organizations, and committed professionals

at the local level will result in extensive

implementation of the recommendations in

the EPR—Update 2002 and EPR-2. We ask

for the assistance of every reader in reaching

our ultimate goal: improving asthma care

and the quality of life for every patient with

asthma and their families.

Publications from the NAEPP can be ordered

through the National Heart, Lung, and Blood

Institute Information Center, P.O. Box 30105,

Bethesda, MD 20924-0105. Publications are

also available through the Internet at

http://www.nhlbi.gov.nhlbi/nhlbi.htm.

Claude Lenfant, M.D. 

Director

National Heart, Lung, and Blood Institute

Chair, National Asthma Education and 

Prevention Program Coordinating Committee

Preface

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Introduction

Asthma Expert Panel Report:

Guidelines for the

Diagnosis and

Management of

Asthma

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3

Asthma is a chronic inflammatory disease 

of the airways that has created a significant

public health burden. In the United States,

more than 11 million people reported

having an asthma attack in the year 2000,

and more than 5 percent of all children

younger than age 18 reported having

asthma attacks. In 1999, asthma was

responsible for 2 million emergency department visits, 478,000 hospitalization with

asthma as a primary diagnosis, and 4,426

deaths. The rates of hospitalization have

remained the same or lower since 1980 for

all age groups, except children younger than

age 15. Mortality rates have declined overall

since 1995, but a disparity among ethnic

groups remains: Asthma mortality is nearly

3 times higher in black males than in white

males and 2.5 times higher in black females

than in white females (Centers for Disease

Control and Prevention).

Scientific advances over the last 15 years have

led to a greater understanding of the mechanisms of asthma and the development of

therapeutic approaches that can reduce 

morbidity and improve the quality of life

among persons with asthma. To help health

care professionals bridge the gap between current knowledge and practice, the National

Heart, Lung, and Blood Institute’s (NHLBI’s)

NAEPP has convened expert panels to prepare clinical practice guidelines for the

diagnosis and management of asthma. The

NAEPP Coordinating Committee, under the

leadership of Claude Lenfant, M.D., director

of the NHLBI, convened the first Expert

Panel in 1989. The Panel was charged with

developing a report that would provide a general approach to diagnosing and managing

asthma based on current science. The NAEPP

Expert Panel Report: Guidelines for the Diagnosis

and Management of Asthma (NAEPP 1991)

was published in 1991. Recommendations 

for the treatment of asthma were organized

around the following four components of

effective asthma management:

■ Use of objective measures of lung function to assess the severity of asthma and

to monitor the course of therapy

■ Environmental control measures to avoid

or eliminate factors that contribute to

asthma severity

■ Comprehensive pharmacologic therapy

for long-term management designed to

reverse and prevent the airway inflammation characteristic of asthma, as well as

pharmacologic therapy to manage asthma

exacerbations

■ Patient education that fosters a partnership among the patient, his or her family,

and clinicians.

The NAEPP convened a second Expert

Panel in 1995 to review the entire 1991

report and update it, if necessary, based 

on review of the literature published since

1991 and on clinical experience with implementation of the report’s recommendations

for clinical practice. The NAEPP Expert

Panel Report 2: Guidelines for the Diagnosis

and Management of Asthma (EPR-2) was

published in 1997.

The NAEPP recognizes that the value of

clinical practice guidelines lies in their presentation of recommendations based on the

best and most current evidence available.

However, high-quality research on all areas

of asthma management is not available, and

scientific examination and discovery often is

focused on only a few areas at any given

time. The NAEPP concluded that an efficient approach to updating the clinical

practice guidelines would be to identify

selected questions that warrant intensive

review and possible update, based on either

the level of research activity reflected in the

published literature or the level of concern

or controversy in clinical practice. Position

statements on these topics would be 

published as NAEPP Expert Panel Report

Updates, and would be incorporated into the

Introduction

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4

Introduction

Web-based version of EPR-2. Thus, the NAEPP

Expert Panel Report is a dynamic document that will

be updated continuously with position statements 

on topics of interest to the community of patients,

clinicians, and organizations dedicated to improving

asthma care.

The NAEPP charged its Science Base Committee with

the responsibility for monitoring the scientific literature, identifying topics for review, determining the

need for changes in the EPR-2, and preparing appropriate updates. The Science Base Committee is a

multidisciplinary group of clinicians and scientists with

expertise in asthma management. The group includes

health professionals in the areas of general medicine,

family practice, pediatrics, emergency and critical care,

allergy, pulmonary medicine, pharmacy, and health 

education. The Science Base Committee reports to the

NAEPP Coordinating Committee, which comprises

representatives from 40 professional societies, voluntary

organizations, and Federal agencies.

This report, the NAEPP Expert Panel Report: Guidelines

for the Diagnosis and Management of Asthma—Update on

Selected Topics 2002 (EPR—Update 2002), presents 

recommendations for the management of asthma that

will help clinicians and patients make appropriate

decisions about asthma care on the following topics:

■ Medications

• Long-term management of asthma in children:

– Effectiveness of inhaled corticosteroids for

children with mild or moderate persistent

asthma compared with other medications

– Safety of long-term use of inhaled 

corticosteroids

• Combination Therapy: The addition of other

long-term-control medications to inhaled 

corticosteroids

• The effect of antibiotics on acute asthma 

exacerbations

■ Monitoring

• Written asthma management plans compared 

to medical management alone

• Peak flow-based compared to symptom-based

written action plans

■ Prevention

• Effects of early treatment on the progression 

of asthma.

The appendices to this report contain updated stepwise and dosage charts and a list of abbreviations 

and acronyms.

This report revises the EPR-2 Stepwise Approach for

Managing Asthma to incorporate findings from the

review of the scientific evidence. These guidelines are

intended to inform, not replace, clinical judgment.

Of course, the clinician and patient need to develop

individual treatment plans that are tailored to the

specific needs and circumstances of the patient. 

This report is not an official regulatory document 

of any Government agency.

Methods Used To Develop This Report

The NAEPP Science Base Committee met in April

1999 to identify priority areas for review and possible

update of recommendations in EPR-2. The Committee

used a modified Delphi technique to rank all major

EPR-2 clinical recommendations according to

whether major new studies had been published in that

area or the area was of considerable clinical interest

but lacking in consistent evidence at the time EPR-2

was developed. At the same time, the Agency for

Healthcare Research and Quality (AHRQ), through

its own routine process of soliciting questions from

the medical community for the development of 

evidence reports, received questions on asthma from

the American Academy of Pediatrics and the

American Academy of Family Physicians. Several of

the topics were comparable to those identified by

NAEPP Science Base Committee, so the NHLBI

worked with the AHRQ to develop a contract with an

AHRQ Evidence-Based Practice Center. An AHRQ

contract was awarded to the Blue Cross Blue Shield

Association Technology Evaluation Center to conduct

a systematic review of the evidence (SRE) on the

topics listed earlier.

In August 1999, the AHRQ Evidence-Based Practice

Center began to perform comprehensive review of the

literature on each of the selected topics; to prepare 

evidence tables depicting study design, research 

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5

Introduction

variables, and reported outcomes; and to summarize the

literature findings in a narrative report. This report,

however, was not intended to make judgments about

the implications of the findings for clinical practice.

The Evidence-Based Practice Center’s methods for 

conducting the SRE are described in detail elsewhere

(Blue Cross and Blue Shield Association Technology

Evaluation Center) and are summarized here.

■ The Evidence-Based Practice Center formed a

Technical Advisory Group composed of asthma 

specialists and primary care physicians, including

several members of the NAEPP Science Base

Committee. The literature search included fulllength reports published in peer-reviewed medical

journals and articles in English or published in 

foreign languages with English abstracts. Studies

that did not include control groups in the research

design were excluded from review (except for those

that dealt with the topic of adverse effects of inhaled

corticosteroids), and most of the included trials were

randomized. Specific criteria that defined patient

populations of interest, outcomes of interest, types 

of interventions, and study design were established

for each topic. A comprehensive literature search was

performed using key text words and MeSH terms

(Medical Subject Heading) to identify all relevant

controlled clinical trials. (Key words included, for

example, all long-term-control asthma medications,

antibiotics in asthma, peak expiratory flow rate meter,

action plan, and self-care monitoring.) Both the

MEDLINE and EMBASE databases were searched for

all articles published from 1980 through August

2000. In addition, the search included potentially

relevant studies published before 1980 but referenced

in the post-1980 literature.

■ The search retrieved 4,235 English and 343 

non-English language references. One member of

the Evidence-Based Practice Center’s study team

reviewed abstracts; a second team member

reviewed any excluded abstracts. On the basis of

this abstract review, 668 full-length journal articles were retrieved and rated independently by

two study team members against study selection

criteria. Eighty-seven articles met the study selection criteria to be included in the SRE. Data from

these 87 articles were abstracted for evidence

tables by two reviewers and were recorded in 

an electronic database. Data elements included categories such as study design and methods, patient

characteristics, lung function outcomes, symptom

outcomes, medication outcomes, utilization 

outcomes, and adverse events.

■ A quality assessment of the studies was performed

to enable sensitivity analysis comparing the results

and conclusions reached from all included studies

with the results and conclusions of a subgroup of

higher quality studies. Quality was assessed on

three domains: concealment of treatment allocation

during randomization, double-blinding, and handling of withdrawals and exclusions. Quality also

was assessed on domains deemed pertinent to

asthma research, such as establishing reversibility of

airway obstruction, controlling for other medication

use, reporting compliance, addressing seasonality,

and a priori reporting of power calculations.

■ A meta-analysis was performed to assess the benefits

of adding long-acting inhaled beta2 agonist medication to inhaled corticosteroids as treatment of

moderate persistent asthma.

In February 2001, the Evidence-Based Practice Center

submitted a draft report of the SRE to the AHRQ.

The NAEPP Science Base Committee, serving as an

Expert Panel, met in March to review the EvidenceBased Practice Center’s report and to interpret the

implications for clinical practice and the recommendations included in EPR-2. The Expert Panel reached

consensus on whether the evidence supported the 

recommendations made in EPR-2 or indicated a need

for revision. The Expert Panel then assigned writing

committees to develop position statements on each of

the topics. Each Panel member was assigned to one of

the writing committees. The Expert Panel noted that,

for some topics, significant studies had been published

in the 7-month period between the Evidence-Based

Practice Center’s search of the literature and the submission of its report. The Expert Panel agreed that the

writing committees would include their own review of

additional literature published since August 2000 and

use MEDLINE searches as appropriate. The distinction between the two literature reviews is noted in the

position statements by separating discussion of the

Evidence-Based Practice Center’s SRE and the Expert

Panel’s Additional Literature or Information. Further, the

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6

Introduction

source and level of the evidence used to justify Panel recommendations for sustaining or revising EPR-2 are noted

in parentheses following the recommendation. (That is, the

level of evidence is categorized A, B, C, or D according to

the description below. If the source of the evidence is from

the SRE, the category is preceded by the notation “SRE”;

if the source is the Expert Panel’s additional literature,

there is no prefix.) The system used to describe the level

of evidence is as follows (Jadad et al. 2000):

■ Evidence Category A: Randomized controlled

trials (RCTs), rich body of data. Evidence is from

end points of well-designed RCTs that provide a

consistent pattern of findings in the population for

which the recommendation is made. Category A

requires substantial numbers of studies involving

substantial numbers of participants.

■ Evidence Category B: RCTs, limited body of

data. Evidence is from end points of intervention

studies that include only a limited number of

patients, post hoc or subgroup analysis of RCTs, 

or meta-analysis of RCTs. In general, Category B

pertains when few randomized trials exist, they are

small in size, they were undertaken in a population

that differs from the target population of the recommendation, or the results are somewhat inconsistent.

■ Evidence Category C: Nonrandomized trials

and observational studies. Evidence is from outcomes of uncontrolled or nonrandomized trials or

from observational studies.

■ Evidence Category D: Panel consensus 

judgment. This category is used only in cases

where the provision of some guidance was deemed

valuable, but the clinical literature addressing the

subject was insufficient to justify placement in one

of the other categories. The Panel consensus is based

on clinical experience or knowledge that does not

meet the criteria for categories A through C.

As the Expert Panel members reviewed the scientific

evidence and considered revisions to EPR-2, they identified areas that require further investigation to either

fill important gaps found in the data or to pursue

promising areas of research revealed by study findings.

Each position statement includes recommendations for

further research.

The Expert Panel prepared draft position statements in

its respective writing committees during summer and

fall 2001, and the drafts were edited during the winter.

A series of drafts were discussed in three telephone

conference calls (June 2001, October 2001, and

February 2002) among the full Panel membership.

Final agreement on each position statement was

reached during these calls, including the specific 

recommendations within the position statements to

either retain or revise EPR-2. A vote confirmed the

unanimous agreement of the Panel. In March 2002, 

a draft was mailed to the NAEPP Coordinating

Committee members for their review, comment, and

approval. In April 2002, the Expert Panel reviewed the

Coordinating Committee’s suggested edits by e-mail

and by telephone conference call and incorporated suggestions that were within the scope of the Coordinating

Committee’s approval. Expert Panel members’ agreement on the final text was unanimous. The NAEPP

EPR—Update 2002 was released in June 2002.

This report was funded by the NHLBI, National

Institutes of Health. Expert Panel members disclosed

relevant financial interests to each other prior to their

deliberations. Expert Panel members and reviewers

participated as volunteers and were compensated only

for travel expenses related to the Expert Panel meeting.

In summary, the NAEPP Expert Panel Report: Guidelines

for the Diagnosis and Management of Asthma—Update on

Selected Topics 2002 represents the NAEPP’s ongoing

effort to keep recommendations for clinical practice up

to date and based on systematic review and consideration of the best available scientific evidence, as well as

on the collective expertise of the Expert Panel and

Coordinating Committee members in asthma management. The NAEPP hopes that this report will assist

clinicians and patients as they work together to achieve

asthma control.

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7

Introduction

Blue Cross and Blue Shield Association Technology Evaluation Center. Evidence Report/Technology

Assessment Number 44. Agency for Healthcare Research and Quality Publication No. 01-EO-44.

Rockville, MD, 2001.

Centers for Disease Control and Prevention.

Jadad AR, Moher M, Browman GP, Booker L, Sigouin C, Fuentes M, Stevens R. Systematic

reviews and meta-analyses on treatment of asthma: critical evaluation. BMJ

2000;320(7234):537–40.

Mannino DM, Homa DM, Akinbami LJ, Moorman JE, Gwynn C, Redd SC. Surveillance for

Asthma—United States, 1980–1999. MMWR Surveillance Summaries 2002;51(SS01):1–13.

National Asthma Education and Prevention Program. Expert Panel Report: Guidelines for the

Diagnosis and Management of Asthma. National Institutes of Health Publication No. 91-3642.

Bethesda, MD, 1991.

National Asthma Education and Prevention Program. Expert Panel Report 2: Guidelines for the

Diagnosis and Management of Asthma. National Institutes of Health Publication No. 97-4051.

Bethesda, MD, 1997.

References

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Overview of the 

Pathogenesis of Asthma

Asthma Expert Panel Report:

Guidelines for the

Diagnosis and

Management of

Asthma

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11

An overview of current insights into 

the pathophysiology of asthma is presented here in order to provide a context

in which recommendations regarding

asthma treatment were made for the 

EPR—Update 2002.

The working definition of asthma, as 

proposed in the EPR-2 in 1997 (page 3)—

Asthma is a chronic inflammatory disorder of

the airways in which many cells and cellular

elements play a role, in particular, mast cells,

eosinophils, T lymphocytes, neutrophils, and

epithelial cells. In susceptible individuals, 

this inflammation causes recurrent episodes 

of wheezing, breathlessness, chest tightness,

and cough, particularly at night and in the

early morning. These episodes are usually

associated with widespread but variable airflow obstruction that is often reversible either

spontaneously or with treatment. The inflammation also causes an associated increase in

the existing bronchial hyperresponsiveness to 

a variety of stimuli (NHLBI 1997).

—continues to capture the features of

asthma and underscores the importance 

of airway inflammation to the pathogenesis,

pathophysiology, and treatment of this 

disease. Important additions to this definition include recent observations that

reversibility may be incomplete in some

patients with asthma, and other individuals with features of chronic bronchitis

may manifest some degree of reversibility

in airflow obstruction (Bousquet J. et al.

2000). Nonetheless, the study of asthma

pathogenesis and its treatment continues

to focus on inflammation as a target to

control and regulate airflow obstruction

and the resulting symptoms.

Recent studies have begun to categorize

airway inflammation into phases, which

although somewhat arbitrary in demarcation, provide insights into the possible

progression of the disease as well as its

management. Acute symptoms of asthma

usually arise from bronchospasm and

require and respond to bronchodilator

therapy. Acute and chronic inflammation

can affect not only the airway caliber and

airflow but also underlying bronchial

hyperresponsiveness, which results in 

susceptibility to bronchospasm. Treatment

with anti-inflammatory drugs can, to a large

extent, reverse some of these processes; however, the successful response to therapy often

requires weeks to achieve and, in some situations, may be incomplete. Finally, some

patients may have persistent airflow limitations for which no current therapy has been

found to be effective. Therefore, the paradigm of asthma has been expanded from

bronchospasm and airway inflammation 

to include airway remodeling in some

patients. The concept that asthma may be a

continuum of these processes that can lead

to moderate and severe persistent disease is

of critical importance to understanding this

disease’s pathogenesis and pathophysiology.

As these questions undergo a constant evaluation, current treatment recommendations

also must be reassessed.

Inflammation of Asthma

Airway inflammation in asthma is found in

patients with mild, moderate, and severe

disease. Although there are some universal

features of this inflammatory response in

the airway, the specifics of the bronchial

reaction show variations, which are dependent upon the disease’s severity, treatment,

and duration. Infiltration of the airway by

inflammatory cells such as activated lymphocytes and eosinophils, denudation of the

epithelium, deposition of collagen in the

subbasement membrane area, and mast cell

degranulation are often, but not always, features of mild or moderate persistent asthma.

In fatal disease and severe persistent asthma,

other conditions occur, such as occlusion of

the bronchial lumen by mucus, hyperplasia

and hypertrophy of the bronchial smooth

muscle, and goblet cell hyperplasia.

Overview of the

Pathogenesis

of Asthma Archive

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Overview of the Pathogenesis of Asthma

The cellular profile of inflammation in asthma provides evidence for the nature of the immune reaction

of injury and remodeling or repair, the potential

mechanisms by which such responses occur, the

resulting alteration in physiology, and the possible

therapeutic targets necessary to regulate, reverse, or

prevent such events. IgE antibodies have been found

to have a relationship to the severity of asthma and

the airway’s early response to allergens. The ability to

synthesize IgE antibodies to environmental allergens

(i.e., atopy) remains a major risk factor in asthma

pathogenesis. Synthesized IgE binds to mast cells and

basophils via high-affinity IgE receptors, and the

bridging of these attached molecules signals the cells

to release preformed and newly generated mediators,

including histamine and cysteinyl leukotrienes, to

rapidly contract airway smooth muscle. In addition,

the mast cell can produce a variety of cytokines,

including interleukin (IL)-1, -2, -3, -4, and -5 along

with granulocyte-macrophage colony-stimulating

factor, interferon (IFN)-γ, and tumor necrosis factor-α.

The generation of these pro-inflammatory proteins

suggests that mast cells can contribute to both acute

and chronic inflammation.

Eosinophilic infiltration of the airway remains a 

consistent feature of acute inflammation and also is

found in mucosal airway tissue from many patients

with chronic, persistent asthma. The granule proteins

of the mature eosinophil are sources of inflammatory

mediators, including major basic protein, which can

injure airway epithelium, enhance bronchial responsiveness, and affect the regulation of acetylcholine

release. In addition, the eosinophil can release 

cysteinyl leukotrienes, such as C4, to contract airway

smooth muscle. The production of eosinophils and

their release from the bone marrow are regulated by

IL-5. Migration of these cells to the airway involves

an interaction of eosinophil surface-bound integrins,

β1 and β2, with endothelial cell and matrix tissue

counterligands. Finally, recently identified families

of chemokines (RANTES) eotaxin, and macrophage

inflammatory protein-1α, participate in the migration of these cells to the airway. Although the

eosinophil is a feature of asthma pathology that 

is known to be affected by anti-inflammatory

therapy in a manner that improves airway physiology, its precise role in the pathophysiology of

asthma is still under investigation.

An Imbalance Between Th1 and Th2 in the

Origins of Asthma

The role of lymphocytes in the inception and progression of asthma continues to be of considerable

importance. Since the 1997 EPR-2, there has been

interest in the idea that an imbalance in T-helper

(Th) 1 and Th2 cytokines may help explain and even

predict the subsequent development of asthma.

Airway inflammation in asthma may represent a loss

of normal balance between two “opposing” populations of Th lymphocytes. Two types of Th

lymphocytes have been characterized: Th1 and Th2.

Th1 cells produce IL-2 and IFN-γ, which are critical

in cellular defense mechanisms in response to infection. Th2, in contrast, generates a family of cytokines

(IL-4, -5, -6, -9, and -13) that can mediate allergic

inflammation. The current “hygiene hypothesis” of

asthma illustrates how this cytokine imbalance may

explain some of the dramatic increases in asthma

prevalence in Westernized countries. This hypothesis

is based on the assumption that the immune system

of the newly born is skewed towards Th2 cytokine

generation. Following birth, environmental stimuli

such as infections will activate Th1 responses and

bring the Th1/Th2 relationship to an appropriate

balance. There is evidence that the incidence of

asthma is reduced in association with certain infections (M. tuberculosis, measles, or hepatitis A);

exposure to other children (e.g., presence of older

siblings and early enrollment in childcare); and less

frequent use of antibiotics. Furthermore, the

absence of these lifestyle events is associated with

the persistence of a Th2 cytokine pattern. Under

these conditions, the genetic background of the

child, with a cytokine imbalance toward Th2, will

set the stage to promote the production of IgE

antibody to key environmental antigens, such as

house dust mite, cockroach, Alternaria, and 

possibly cat. Therefore, a gene-by-environment

interaction occurs in which the susceptible host is

exposed to environmental factors that are capable of

generating IgE, and sensitization occurs. Precisely

why the airways of some individuals are susceptible

to these allergic events is not established.

There also appears to be a reciprocal interaction

between the two subpopulations in which Th1

cytokines can inhibit Th2 generation and vice versa.

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Overview of the Pathogenesis of Asthma

Allergic inflammation may be the result of an

excessive expression of Th2 cytokines. Alternately,

the possibility that the loss of normal immune balance arises from a cytokine dysregulation in which

Th1 activity in asthma is diminished has been 

suggested in recent studies. The focus and actions 

of cytokines and chemokines to regulate and activate

the inflammatory profile in asthma has provided

ongoing and new insight into the pattern of airway

injury that may lead to new therapeutic targets.

Because of the importance of IgE to the pathogenesis of allergic diseases and inflammation, the

development of humanized monoclonal antibodies

has become a possible treatment. Early studies in

asthma have indicated that this approach can

reduce serum IgE, inhibit the immediate and late

airway response to inhaled antigen, and allow for 

a withdrawal of inhaled corticosteroids without

deterioration in lung function or precipitation of

an asthma exacerbation. The findings of anti-IgE

monoclonal antibody therapy support the importance of IgE-mediated responses in asthma and

suggest that IgE-regulated processes may encompass processes that influence inflammation other

than mast-cell-dependent responses.

In addition, monoclonal antibodies against IL-5

recently have been tested in asthma. Anti-IL-5 has

reduced circulating concentrations of eosinophils and

their presence in sputum. However, despite the

reduction (but not elimination) of eosinophils, there

was no change in the development of the late-phase

response to an inhaled antigen. These preliminary

studies have raised questions about the specific role of

IL-5 in mechanisms of airflow obstruction and of

eosinophils in the pathophysiology of asthma. It

appears to be an omnipresent cell in asthma, but how

it participates in the disease process is not yet clear.

A soluble IL-4 receptor (IL-4R) has been developed

for inhaled administration. This molecule acts as a

decoy and is capable of binding to IL-4 and thus

acting as an antagonist for that molecule. Although

early studies that administered nebulized IL-4R

showed that inhaled corticosteroid doses can be

reduced without a loss of asthma control or lung

function, subsequent trials with this molecule have

failed to demonstrate effectiveness in asthma control.

A number of lessons can be learned from these early

studies directed toward a single cytokine. Although

modification of features of allergic inflammation can

be seen in animals with genes that have “knocked

out” selected cytokines, similar benefits have not necessarily been seen in human asthma. These findings

underscore the relevancy of multiple factors regulating inflammation in asthma and the redundancy

of these processes. Moreover, these clinical studies in

human asthma also serve to indicate that phenotypes

of asthma exist and that these phenotypes may have

very specific patterns of inflammation. Nonetheless,

as more clinical trials with modifiers of inflammation in asthma are performed, it is likely that a more

comprehensive insight into the mechanisms of this

disease will occur.

In summary, recent evidence continues to underscore

the importance of immune factors in the development

of asthma and resulting inflammation processes.

Insight into the mechanisms of these processes will

be important for future therapy. In the meantime,

asthma therapy continues to focus on controlling

underlying airway inflammation.

Archive

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Bousquet J, Jeffery PK, Busse WW, Johnson M, Vignola AM. Asthma. From bronchoconstriction to

airways inflammation and remodeling. Am J Respir Crit Care Med 2000;161(5):1720–45.

References

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Overview of the Pathogenesis of Asthma

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1. Medications

Asthma Expert Panel Report:

Guidelines for the

Diagnosis and

Management of

Asthma

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Several clinical questions were considered 

by the NAEPP Expert Panel regarding

medications used in asthma therapy,

including questions about the effectiveness

of inhaled corticosteroids compared to other

long-term-control medications in the management of asthma in children, the safety of

long-term use of inhaled corticosteroids in

children, the use of combination therapy

in treating moderate persistent asthma,

and the use of antibiotics in treating acute

exacerbations of asthma. This section on

medications will present each clinical

question separately, and each discussion

will include a statement of the specific

question; a summary answer to the question; the rationale for the question; a

summary of the SRE, as well as additional

literature considered by the Expert Panel

after the systematic review was completed;

recommendations for updating the EPR-2

and recommendations for future research.

Long-Term Management 

of Asthma in Children:

Effectiveness of Inhaled

Corticosteroids Compared 

to Other Medications

Question

Does chronic use of inhaled corticosteroids improve long-term outcomes

for children with mild or moderate 

persistent asthma, in comparison 

to the following treatments?

■ “As-needed” beta2-agonists?

■ Long-acting beta2-agonists?

■ Theophylline?

■ Cromolyn/nedocromil?

■ Combinations of above drugs?

Leukotriene modifiers (leukotriene

receptor antagonists [LTRAs] and 

5-lipoxygenase inhibitors) were not

included in the SRE because no published

data meeting minimal inclusion criteria

for children were available to compare this

class of compounds directly to any other

long-term-control medications, including

inhaled corticosteroids. Studies on LTRAs

in children that were published subsequent to the SRE were considered by the

Expert Panel as additional information and

included in the comprehensive review of

the question.

Summary Answer to the Question

Strong evidence establishes that inhaled 

corticosteroids improve long-term outcomes

for children of all ages with mild or moderate persistent asthma, compared to

as-needed beta2-agonists, as measured by

prebronchodilator forced expiratory

volume in 1 second (FEV1), reduced

hyperresponsiveness, improvements in

symptom scores, fewer courses of oral 

corticosteroids, and fewer urgent care visits

or hospitalizations (SRE-Evidence A).

Studies comparing inhaled corticosteroids to

cromolyn, nedocromil, theophylline, or

LTRAs are limited, but available evidence

shows that none of these long-term-control

medications is as effective as inhaled

corticosteroids in improving asthma outcomes (SRE-Evidence B; Evidence B, C).

(See Appendix A, Stepwise Approach for

Managing Asthma, for the definition of

asthma severity classifications.) A revision

to the EPR-2 stepwise approach to therapy

is recommended. The Expert Panel recommends the following therapy for children

with mild persistent asthma:

■ For children older than 5 years of age,

the preferred therapy is inhaled corticosteroids (low dose) (SRE-Evidence A).

Alternative therapies (listed alphabetically because there are insufficient data

to enable ranking) include cromolyn,

LTRAs, nedocromil, or sustainedrelease theophylline (SRE-Evidence A,

B; Evidence A, B).

1. Medications

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18

Medications: Effectiveness in Children

■ For children 5 years of age and younger, no studies

compare inhaled corticosteroids to other long-termcontrol medications. Therefore, recommendations

are based on extrapolations of studies in older children. The preferred therapy is low-dose inhaled

corticosteroids, with nebulizer, dry powder inhaler

(DPI), or metered-dose inhaler (MDI) with holding

chamber, with or without a face mask. Alternative

therapies (listed alphabetically) include cromolyn or

LTRA (SRE-Evidence B).

Rationale for the Question

The NAEPP recognizes the need for continual

appraisal of the benefits and potential risks of asthma

medications in children. The EPR-2 recommends

inhaled corticosteroids, cromolyn, and nedocromil 

as preferred treatment, with acknowledgement of a

potential but small risk of adverse events with the use

of inhaled corticosteroids. The NAEPP considers it

important to update information regarding the effectiveness and safety of inhaled corticosteroids in

children. A review of evidence on the safety of inhaled

corticosteroids is presented in another section. To enrich

the evaluation of effectiveness, the SRE searched the

literature for studies comparing the effectiveness of

inhaled corticosteroids used as monotherapy to shortacting beta2-agonists taken as needed, and to other

long-term-control medications used as monotherapy

in children with mild or moderate persistent asthma.

Such a review enables the NAEPP to consider the

most appropriate position of various medications in

the stepwise approach to asthma management, based

on the current evidence. At the time that the EPR-2

was published, the following long-term-control medications were available for treatment in children:

inhaled corticosteroids, long-acting inhaled beta2-agonists (salmeterol), theophylline, cromolyn,

nedocromil, and leukotriene modifiers (zafirlukast and

zileuton); not all were approved for use in children

younger than 5 years of age. Since the publication of

the EPR-2, a third leukotriene modifier, montelukast,

has become available for children 2 years of age and

older, and a nebulized form of inhaled corticosteroids

has become available for children as young as 1 year

of age. The DPI forms of salmeterol and fluticasone,

available for older children, also were approved down

to 4 years of age.

Systematic Review of the Evidence

The following description of the SRE is an adaptation of the evidence report, including direct

excerpts, submitted by the Blue Cross Blue Shield

Association Evidence-Based Practice Center. (See

Introduction, Methods.)

❙ Methods of Literature Search

This question addresses long-term outcomes of treatment for children with mild or moderate persistent

asthma. Outcomes of primary interest are those that

indicate the progression of underlying disease; 

short-term measures of symptom control cannot 

adequately address this question. Of the available

measures, longitudinal determination of postbronchodilator FEV1 provides the best available measure 

of lung growth (CAMP Research Group 2000).

Epidemiologic studies often use prebronchodilator

FEV1, which has been one of the strongest correlates

with long-term outcomes. Peak expiratory flow

(PEF) also can indicate long-term progression; both

prebronchodilator FEV1 and PEF are more subject to

short-term changes in control and, of the two, PEF

is the more variable measure. Other outcome measures, such as symptoms, medication use, and

utilization measures, also are likely to correlate with

long-term progression of disease over time, but are

highly subject to changes in short-term control of

bronchospasm.

In addition to the eligibility criteria for selecting

studies related to all topics in the SRE (described in

the Introduction), the following criteria were used to

select studies for this question:

■ Study design is a comparative or crossover clinical

efficacy trial, with a concurrent control group.

■ Study compares the use of inhaled corticosteroids

vs. placebo; OR compares inhaled corticosteroids

vs. no treatment control; OR compares inhaled

corticosteroids vs. alternative medication for mild

asthma (as-needed beta2-agonists, theophylline,

cromolyn, nedocromil, or combinations of these

medications); OR compares the addition of inhaled

corticosteroids to other medication for mild asthma

(as-needed beta2-agonists, theophylline, cromolyn,

nedocromil, or combinations of these medications).

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19

Medications: Effectiveness in Children

■ Includes at least 10 evaluable, similarly treated

patients per study arm or crossover phase with

mild or moderate persistent asthma, with the 

following defined limits:

• FEV1 more than 60 percent of predicted; PEF

variability more than 20 percent

OR

• Symptoms more than 2 times a week to daily

OR

• Nocturnal symptoms more than 2 times 

a month

OR

• Population cannot be classified into the above

categories but appears to include primarily 

persons with mild or moderate persistent

asthma

OR

• Population is mixed, but the majority appears 

to consist of persons with mild or moderate 

persistent asthma.

■ Study duration is of at least 12 weeks.

■ At least 90 percent of included patients have not

been treated with other long-term-control medications (LTRAs, long-acting inhaled beta2-agonists,

inhaled corticosteroids) for at least 4 weeks before

beginning to take inhaled corticosteroids.

■ Enrolls only patients younger than 18 years of age

or stratifies outcomes for patients younger than

18 years of age.

■ Study addresses relevant outcomes.

❙ Summary of Findings

Studies

Ten studies enrolling 2,210 patients met the inclusion

criteria for this question. Three of the studies were

based in the Netherlands (Hoekstra et al. 1996; Van

Essen-Zandvliet et al. 1992; Verberne et al. 1997);

two were from Scandinavia (Jonasson et al. 1998;

Agertoft and Pedersen 1994); two from the United

Kingdom (Storr et al. 1986; Connett et al. 1993);

two from the United States (CAMP 2000;

Tinkelman 1993); and one from Canada (Simons

1997). Nine of the 10 studies were randomized, 

double-blind, parallel-group trials. The most robust

of these, the Childhood Asthma Management

Program (CAMP) Research Group (CAMP 2000), 

is a three-arm trial enrolling 1,041 patients followed

for 4 to 6 years that compared inhaled corticosteroids

to nedocromil and with placebo. At present, the

CAMP trial is the “largest, longest, and most comprehensive multicenter treatment trial for asthma

ever attempted in the United States”(CAMP 2000).

The remaining eight randomized trials are considerably smaller in size (range: 14 to 102 patients per

study arm) and duration of followup (range: 1 to 2

years). The tenth trial (Agertoft and Pedersen 1994)

was not randomized. (See the key evidence tables in

this section for a summary description of the 10

studies that met the eligibility criteria for evaluation.) Publications comparing the use of LTRA in

children to other long-term-control medications were

not available at the time of the SRE.

Results of Studies

Inhaled Corticosteroids Compared to 

As-Needed Beta2-Agonists

Children Older than 5 Years of Age

The evidence of the efficacy of inhaled corticosteroids in children older than 5 years of age was

obtained from six trials, five of which were

placebo controlled and randomized. These six

trials enrolled a total of 790 patients treated with

inhaled corticosteroids and 652 controls. The most

robust evidence is from the CAMP trial, which

contributed 40 percent (311) of the total inhaled

corticosteroid patients and 64 percent (418) of the

total controls, documented the longest duration 

of treatment (4 years), used the most complete

outcome measures, and reported in the greatest

detail the study design and statistical analysis.

Overall, these studies demonstrate that inhaled

corticosteroids improve asthma control compared

to as-needed beta2-agonists without any other

long-term-control medication. Inhaled corticosteroid-treated patients with mild or moderate 

persistent asthma demonstrate improvements in

prebronchodilator FEV1, reduced airway hyperresponsiveness, symptom scores and symptom

frequency, less supplemental beta2-agonist use,

fewer courses of oral corticosteroids, and lower

hospitalization utilization. The evidence does not

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20

Medications: Effectiveness in Children

suggest, however, that inhaled corticosteroid use is

associated with improved long-term postbronchodilator FEV1 which is a surrogate measure of

lung growth. The CAMP trial reported no difference in the change in postbronchodilator FEV1

after 4 years of treatment (CAMP 2000). No study

reported any statistically significant result that

favored the as-needed beta2-agonist control group.

Children 5 Years of Age or Younger

Two small trials (69 participants, combined) 

compared inhaled corticosteroid treatment to

placebo in children younger than 5 years of age.

The available evidence is scant, but the results

reported appear to be consistent with those

reported for children older than 5 years of age:

that inhaled corticosteroids improve short-term

control of asthma. No studies that examine the

long-term impact of inhaled corticosteroids on

lung function in this age group are available.

Inhaled Corticosteroids Compared to

Alternative Long-Term-Control Medications

No comparison studies are available for children

younger than 5 years of age.

Long-Acting Inhaled Beta2-Agonist (Salmeterol)

The available evidence is inadequate to make

definitive conclusions about relative effectiveness

of inhaled corticosteroids and salmeterol in children with mild or moderate persistent asthma.

Two randomized and double-blinded trials

enrolled 116 (99 evaluable) children treated with

inhaled corticosteroids, 112 (83 evaluable) 

children treated with salmeterol, and 80 (55

evaluable) children treated with placebo. One of

these is a three-arm trial in which most comparisons were indirect and reported as inhaled

corticosteroids vs. placebo and salmeterol vs.

placebo. Of the statistically significant results

reported, most were significant in only one of 

the two trials; however, all results clearly favored

inhaled corticosteroids over salmeterol as

monotherapy. In one of the trials, measurements 

of FEV1 deteriorated over time in those children

receiving monotherapy with salmeterol (Verberne

et al. 1997).

Theophylline

One trial compared the effectiveness of 1 year of

treatment with theophylline or low-dose inhaled

corticosteroids in 747 patients, 185 of whom were

children (Reed 1998). Although conclusions are

limited because of the large numbers of withdrawals

and the absence of additional trials, the data from

this study support the superior effectiveness for

low-dose inhaled corticosteroids compared to 

theophylline. The inhaled corticosteroids were 

significantly more effective in reducing symptoms,

supplemental bronchodilators and systemic corticosteroid doses, bronchial hyperresponsiveness, and

eosinophilia. No outcomes were significantly 

superior with theophylline, which caused more

headaches, nervousness, insomnia, and gastrointestinal distress; and more patients discontinued

treatment because of side effects that occurred

while they were taking theophylline.

Nedocromil

The CAMP trial found no differences between

nedocromil and placebo in lung function or

symptom outcomes, although courses of oral 

corticosteroids and urgent care visits were reduced

(CAMP 2000). The primary analysis in this study

compares two medications—nedocromil and

inhaled corticosteroids—to placebo, rather than 

to each other. However, the magnitude of the

effect of inhaled corticosteroids on all clinical 

outcomes, along with the marginal effect of

nedocromil on just two, supports the conclusion

that inhaled corticosteroids are more effective than

nedocromil in reducing the frequency and severity

of symptoms, supplemental beta2-agonist use, and

the frequency of hospitalizations due to asthma.

Additional Literature/Information

Additional data were reviewed to include information that was published since the SRE was

performed and to consider leukotriene modifiers.

Inhaled Corticosteroids

A recent study confirmed the effectiveness of

inhaled corticosteroids in improving symptoms,

airway hyperresponsiveness, and lung function 

in children 2 to 5 years of age (Nielsen and

Bisgaard 2000).

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Medications: Effectiveness in Children

Cromolyn and Nedocromil

A consideration of the precise relationship of 

cromolyn and nedocromil among other long-termcontrol medications in the treatment of persistent

asthma continues to be difficult based on the 

few available comparison studies. These two 

medications have distinct properties but similar

mechanisms of action. They have been shown to

provide symptom control greater than placebo in

some clinical trials (Konig 1997; Petty et al. 1989)

and to confer protection against exacerbations of

asthma leading to hospitalization, particularly in

children (Donahue et al. 1997) and emergency

department visits (Adams et al. 2001). These

results, along with the excellent safety profile, 

justify consideration of these medications as treatment options. However, when data regarding the

efficacy of cromolyn recently were systematically

reviewed (Tasche et al. 2000), the authors 

concluded that insufficient evidence existed to

conclude that cromolyn had a beneficial effect on

maintenance treatment of childhood asthma.

Compared to placebo, nedocromil reduces urgent

care visits as well as the need for prednisone,

which are meaningful clinical outcomes. However,

nedocromil is no different than placebo on all

other outcome measures (CAMP 2000). Overall,

nedocromil is significantly less effective in

improving outcome measures than inhaled 

corticosteroids (CAMP 2000). Nedocromil has not

been adequately studied in children younger than

5 years of age.

As a result of these disparate findings on cromolyn

and nedocromil (i.e., some, but limited effectiveness and strong safety profile), the Expert Panel’s

opinion is that cromolyn for children of all ages

and nedocromil for children older than 5 years of

age could be considered in the treatment of persistent asthma, but they are not preferred therapies

(SRE-Evidence A; Evidence B, C).

Leukotriene Modifiers

Leukotriene modifiers comprise two pharmacologic

classes of compounds: 5-lipoxygenase pathway

inhibitors (e.g., zileuton), and LTRAs (e.g., zafirlukast and montelukast). Only zafirlukast (for

children as young as 7 years of age) (Pearlman et

al. 2000; Weinberger 2000) and montelukast (for

children as young as 2 years of age) (Knorr et al.

1998; Knorr et al. 2001) are approved for use in

children. Zileuton has been demonstrated to control asthma more effectively than placebo (Israel 

et al. 1996) and comparably to theophylline

(Schwartz et al. 1998) in adult patients with 

persistent symptoms; studies in children have not

been reported yet.

The LTRAs have been demonstrated to provide

statistically significant but modest improvement

in lung function when used as monotherapy in

both adults and children as young as 6 years of age

and in asthma control outcomes other than lung

function in patients as young as 2 years of age

(Pearlman et al. 2000; Knorr et al. 1998; Knorr et

al. 2001; Israel et al. 1996; Schwartz et al. 1998;

Altman et al. 1998; Busse et al. 2001; Kemp et al.

1998; Nathan et al. 1998; Tashkin et al. 1999;

Bleecker et al. 2000; DuBuske et al. 1997). In

general, these studies included patients with either

mild or moderate persistent asthma, although the

classification of severity was not always clear in the

studies, nor consistently applied. When comparing overall efficacy of LTRAs to inhaled

corticosteroids in adult patients with persistent

asthma, most outcome measures significantly and

clearly favored inhaled corticosteroids (Busse et al.

2001). Therefore, based on the available data 

comparing LTRAs to inhaled corticosteroids, the

Expert Panel concludes that inhaled corticosteroids

should be the preferred treatment option for mild

persistent asthma in adults and, by extrapolation

until published comparison data become available,

for children (Evidence B, C). (See Medications:

Combination Therapy for recommendations on the

use of LTRAs in moderate asthma.) Due to the

lack of randomized controlled trials (RCTs) in

children less than 12 years of age, zileuton cannot

be recommended for use in children.

Long-Acting Inhaled Beta2-Agonists

In a recent study, 164 patients ages 12 through 65

years whose asthma was well controlled on 400 mcg

twice daily of inhaled corticosteroids were randomly

assigned to continue inhaled corticosteroids or

switch to long-acting inhaled beta2-agonists, 42

mcg twice daily. During the 16-week study, clinical

outcomes did not differ significantly. However, those

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on long-acting inhaled beta2-agonists experienced

significantly more treatment failures (24 percent vs.

6 percent) and asthma exacerbations (20 percent vs.

7 percent) than those remaining on inhaled corticosteroids (Lazarus et al. 2001). These results,

favoring use of inhaled corticosteroids over longacting beta2-agonists as monotherapy, support the

findings of the studies in children that were noted

in the SRE.

Recommendations for EPR Update

The Expert Panel recommends revising EPR-2, based

on review of the SRE and additional data and clinical

experience. The following key changes are described:

■ Based on the SRE, inhaled corticosteroids are 

the preferred treatment for initiating therapy in

children of all ages with persistent asthma (SREEvidence A, B). Thus, the Expert Panel no longer

recommends consideration of an initial therapeutic trial with cromolyn or nedocromil.

Current scientific evidence demonstrates the

superiority of inhaled corticosteroids.

■ LTRAs are available for children as young as 

2 years of age, and studies have demonstrated

improved outcomes (Evidence B). LTRAs are an

alternative—although not preferred—treatment

(Evidence B) and are considered if patient 

circumstances regarding administration of

inhaled corticosteroids warrants selection of oral

treatment (Evidence D).

■ Based on epidemiologic study of wheezing in

early childhood, it is the opinion of the Expert

Panel that the initiation of long-term-control

therapy should be considered strongly for infants

and young children who in the past year have had

more than three episodes of wheezing that lasted

more than 1 day and affected sleep, and who in

addition have identifiable risk factors for the

development of asthma (Evidence D). This is in

addition to previously recommended indications

for initiating long-term-control therapy (i.e., children requiring symptomatic treatment more than

2 times a week or experiencing severe exacerbations less than 6 weeks apart).

Specifically, the Expert Panel recommends that the

text of EPR-2 be revised to read as follows in the

EPR-2 sections: The Medications and the Stepwise

Approach for Managing Asthma; the blue text 

indicates new text. 

Recommended changes to The Medications

(pages 59 through 67 in EPR-2)

Key Points: The Medications (page 59 in EPR-2):

■ Cromolyn and nedocromil: Used as alternative,

but not preferred, medications for the treatment

of mild persistent asthma (Evidence A, B). Can

also be used as preventive treatment prior to exercise or unavoidable exposure to known allergens.

■ Long-acting inhaled beta2-agonists: Longacting bronchodilator used concomitantly with

inhaled corticosteroids is the preferred combination therapy for long-term control and prevention

of symptoms in moderate and severe persistent

asthma (Evidence A, B). Also prevents exerciseinduced bronchospasm (EIB).

■ Leukotriene modifiers: The leukotriene receptor

antagonists (LTRAs) montelukast (for patients ≥ 2

years of age) and zafirlukast (for patients ≥ 7 years

of age), or the 5-lipoxygenase inhibitor zileuton

(for patients ≥12 years of age), are alternative, but

not preferred, therapies for the treatment of mild

persistent asthma (Evidence B). Leukotriene modifiers also may be used with inhaled corticosteroids

as combination therapy in the treatment of moderate persistent asthma (Evidence B).

Corticosteroids (page 60 in EPR-2)

Insert after the third sentence.

The evidence of the efficacy of inhaled corticosteroids

in children older than 5 years of age was obtained

from six trials, five of which were placebo controlled

and randomized (see EPR Update-2002 for complete

references). Overall, these studies demonstrate that

inhaled corticosteroids improve asthma control compared to as-needed beta2-agonists without any other

long-term-control medication (Evidence A). Inhaled

corticosteroid-treated patients with mild or moderate

persistent asthma demonstrate improvements in prebronchodilator FEV1, reduced airway

22

Medications: Effectiveness in Children

Archive

for historical Reference Only
hyperresponsiveness, symptom scores and symptom

frequency, less supplemental beta2-agonist use, fewer

courses of oral corticosteroids, and lower hospitalization utilization. The evidence does not suggest,

however, that inhaled corticosteroid use is associated

with improved long-term postbronchodilator FEV1,

which is a surrogate measure of lung growth. 

No study reported any statistically significant result

that favored the as-needed beta2-agonist control

group. Studies comparing inhaled corticosteroids to

cromolyn, nedocromil, theophylline, or LTRAs are

limited, but available evidence shows that none of

these long-term-control medications appear to be as

effective as inhaled corticosteroids in improving

asthma outcomes (Evidence A, B).

Cromolyn Sodium and Nedocromil 

(page 60 in EPR-2)

Replace the third paragraph of text with the following.

Cromolyn sodium and nedocromil have been shown

to provide symptom control greater than placebo in

some clinical trials (Konig 1997; Petty et al. 1989)

and to confer protection against exacerbations of

asthma leading to hospitalization, particularly in

children (Donahue et al. 1997) and emergency

department visits (Adams et al. 2001) These results,

along with the excellent safety profile, justify consideration of these medications as treatment options.

However, when data regarding the efficacy of cromolyn recently were systematically reviewed (Tasche

et al. 2000), the authors concluded that insufficient

evidence existed to conclude that cromolyn had a

beneficial effect on maintenance treatment of 

childhood asthma. Compared to placebo, nedocromil

reduces urgent care visits as well as the need for 

prednisone, which are meaningful clinical outcomes.

However, nedocromil is no different than placebo on

all other outcome measures (CAMP 2000). Overall,

nedocromil is significantly less effective in improving

outcomes measures than inhaled corticosteroids

(CAMP 2000). Nedocromil has not been adequately

studied in children younger than 5 years of age. 

As a result of these disparate findings on 

cromolyn and nedocromil (i.e., some, but limited

effectiveness and strong safety profile), the Expert

Panel’s opinion is that cromolyn for children of all

ages and nedocromil for children older than 5 years

of age could be considered in the treatment of persistent asthma, but they are not preferred therapies

(Evidence A, B, C).

Leukotriene Modifiers (page 65 in EPR-2)

Replace the second paragraph of text with 

the following.

Three leukotriene modifiers—montelukast, 

zafirlukast and zileuton—are available as oral tablets

for the treatment of asthma. Leukotriene modifiers

comprise two pharmacologic classes of compounds:

5-lipoxygenase pathway inhibitors (e.g., zileuton),

and LTRAs (e.g., montelukast and zafirlukast). Only

zafirlukast (for children as young as 7 years of age)

and montelukast (for children as young as 2 years of

age) are approved for use in children. Zileuton has

been demonstrated to control asthma more effectively than placebo (Israel et al. 1996) and

comparably to theophylline (Schwartz et al. 1998) 

in adult patients with persistent symptoms; studies

in children have not been reported yet.

The LTRAs have been demonstrated to provide 

statistically significant but modest improvement in

lung function when used as monotherapy in both

adults and children as young as 6 years of age and in

asthma control outcomes other than lung function in

patients as young as 2 years of age (Pearlman et al.

2000; Knorr et al. 1998; Knorr et al. 2001; Israel et

al. 1996; Schwartz et al. 1998; Altman et al. 1998;

Busse et al. 2001; Kemp et al. 1998; Nathan et al.

1998; Tashkin et al. 1999; Bleecker et al. 2000;

DuBuske et al. 1997). In general, these studies

included patients with either mild or moderate 

persistent asthma, although the classification of

severity was not always clear in the studies, nor consistently applied. When comparing overall efficacy

of LTRAs to inhaled corticosteroids in adult patients

with persistent asthma, most outcome measures significantly and clearly favored inhaled corticosteroids

(Busse et al. 2001).

Insert as the final paragraph.

Therefore, based on the available data comparing

LTRAs to inhaled corticosteroids, the Expert Panel

concludes that inhaled corticosteroids should be the

preferred treatment option for mild persistent asthma

in adults, and by extrapolation until published com23

Medications: Effectiveness in Children

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24

Medications: Effectiveness in Children

parison data become available, for children (Evidence

B, C). Five published studies evaluated the addition

of leukotriene modifiers to fixed doses of inhaled

corticosteroids; none compared the combination to

increasing the dose of inhaled corticosteroids.

Limitations of these studies preclude definitive 

conclusions, but they reveal a trend showing

improvement in lung function and, in some, symptoms from the combination of leukotriene modifiers

and inhaled corticosteroids compared with a fixed

dose of inhaled corticosteroids alone. 

Figure 3–1. Long-Term-Control Medications

(page 63 in EPR-2)

Long-Acting Inhaled Beta2-Agonists. Add in

“Therapeutic Issues” column: Treatment of choice in

combination with inhaled corticosteroids for treatment of moderate persistent asthma in adults and

children over 5 years of age. 

Leukotriene Modifiers. Add: Montelukast tablets:

long-term control and prevention of symptoms in

mild persistent asthma for patients ≥2 years of age.

May also be used with inhaled corticosteroids as combination therapy in moderate persistent asthma.

Zafirlukast: Change age zafirlukast to ≥7 years of age.

And add: May also be used with inhaled corticosteroids as combination therapy in moderate

persistent asthma. Zileuton: add: May also be used

with inhaled corticosteroids as combination therapy

in moderate persistent asthma.

Figure 3–2. Quick-Relief Medications 

(page 64 in EPR-2)

Short-Acting Inhaled Beta2-Agonists. Add:

Levalbuterol

Recommended changes to The Stepwise

Approach to Managing Asthma; mild persistent

asthma (step 2 care) (pages 85 through 97 

in EPR-2). 

Revisions of EPR-2 on moderate persistent asthma

(step 3 care) are presented in the section

“Medications: Combination Therapy.”

Figure 3–4b. Stepwise Approach for Managing

Asthma in Adults and Children Older than

5 Years of Age: Treatment (page 85 in EPR-2)

Step 2

Mild Persistent

One daily long-term-control medication

Preferred treatment:

Inhaled corticosteroids (low dose)

Alternative treatment (listed alphabetically):

Cromolyn

OR

Leukotriene modifier (only LTRAs are 

recommended for use in children)

OR

Nedocromil

OR

Sustained release theophylline to serum 

concentrations of 5–15 μg/mL.

Step 3 and Step 4

Please refer to the Medications: Combination

Therapy on page 56 of this report.

Key Recommendations box for managing

asthma in school-age children and adolescents

(page 97 in EPR-2)

■ Pulmonary function testing should use appropriate reference populations. Adolescents compare

better to childhood than to adult predicted norms.

■ When initiating daily long-term-control therapy

for mild or moderate persistent asthma, the choice

of medication includes consideration of treatment

effectiveness, the individual patient’s history of

previous response to therapies, the ability of the

patient and family to correctly use the medication,

and anticipated patient and family adherence with

the treatment regime (Evidence D).

■ Adolescents (and younger children when appropriate) should be directly involved in establishing

goals for therapy and developing their asthma

management plans.

■ Active participation in physical activities, exercise, and sports should be promoted.

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Medications: Effectiveness in Children

■ A written asthma management plan should be

prepared for the student’s school and should

include plans to ensure reliable, prompt access to

medications. Either encourage parents to take a

copy to the child’s school or obtain parental permission and send a copy to the school nurse or

designee (Evidence D).

Figure 3–6. Stepwise Approach for Managing

Infants and Young Children (5 Years of Age and

Younger) With Acute or Chronic Asthma

Symptoms (page 96 in EPR-2)

Step 2

Mild Persistent

One daily long-term-control medication

Preferred treatment:

Low-dose inhaled corticosteroids (with nebulizer OR MDI with holding chamber with or

without a face mask OR DPI)

Alternative treatment (listed in alphabetical order):

Cromolyn (nebulizer is preferred; or MDI with

holding chamber)

OR

Leukotriene receptor antagonist.

Step 3

Moderate Persistent

Preferred treatments:

Low-dose inhaled corticosteroids and longacting inhaled beta2-agonists

OR

Medium-dose inhaled corticosteroids

Alternative treatment:

Low-dose inhaled corticosteroids and either

LTRA or theophylline.

If needed (particularly in patients with recurring

severe exacerbations):

Preferred treatment: 

Medium-dose inhaled corticosteroids and

long-acting beta2-agonists.

Alternative treatment: 

Medium-dose inhaled corticosteroids and either

LTRA or theophylline.

Special considerations for managing asthma 

in different groups: infants and young children

(5 years of age and younger), key recommendations (pages 94 through 97 in EPR-2)

■ Diagnosing asthma in infants is often difficult,

yet underdiagnosis and undertreatment are key

problems in this age group. Thus, a diagnostic

trial of inhaled bronchodilators and antiinflammatory medications may be helpful.

■ Treatment for infants and young children with

asthma has not been adequately studied.

Recommendations for treatment are based on

extrapolations from studies in older children and

adults.

■ The initiation of long-term-control therapy

should be strongly considered in the following

circumstances, in the opinion of the Expert Panel

(Evidence D):

• Infants and young children who had more

than three episodes of wheezing in the past

year that lasted more than 1 day and affected

sleep AND who have a high risk of developing

persistent asthma as indicated by either (a) a

physician diagnosis of atopic dermatitis or a

parental history of asthma OR (b) two of the

following conditions: physician-diagnosed

allergic rhinitis, greater than 4 percent peripheral blood eosinophilia, or wheezing apart from

colds (Martinez et al. 1995; Martinez 1995;

Castro-Rodriguez 2000).

• Infants and young children consistently

requiring symptomatic treatment more than 

2 times per week should be given daily longterm-control therapy.

• Infants and young children who have severe

exacerbations (requiring inhaled beta2-agonist

more frequently than every 4 hours over 24

hours) that occur less than 6 weeks apart.

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26

Medications: Effectiveness in Children

■ When initiating daily long-term-control therapy,

inhaled corticosteroids are the preferred treatment

(SRE-Evidence B). Alternative treatment options

(listed here in alphabetical order because there are

insufficient data to enable ranking) include cromolyn and LTRA (montelukast) (Evidence B).

The initial choice of long-term-control medication

includes consideration of treatment effectiveness,

the individual patient’s history of previous

response to therapies, the ability of the patient

and family to correctly use the medication, and

anticipated patient and family adherence to the

treatment regimen (Evidence D).

■ Response to therapy should be carefully monitored. Once control of asthma symptoms is

established and sustained, a careful step down in

therapy should be attempted. If clear benefit is not

observed within 4 to 6 weeks, alternative therapies

or diagnoses should be considered (Evidence D).

Diagnosis

Several studies show that as many as 50 to 80 

percent of children with asthma develop symptoms

before their fifth birthdays. Diagnosis can be difficult

in this age group and has important implications. 

On the one hand, asthma in early childhood is 

frequently underdiagnosed (receiving such labels 

as chronic bronchitis, wheezy bronchitis, recurrent

pneumonia, gastroesophageal reflux, and recurrent

upper respiratory tract infections), and thus many

infants and young children do not receive adequate

therapy. On the other hand, not all wheezes and

coughs are caused by asthma, and caution is needed

to avoid giving infants and young children inappropriately prolonged asthma therapy. Episodic or

chronic wheezing, coughing, and breathlessness also

may be seen in other less common conditions,

including cystic fibrosis, vascular ring, tracheomalacia, primary immunodeficiency, congenital heart

disease, parasitic disease, and foreign body aspiration.

Among children 5 years of age and younger, the

most common cause of asthma-like symptoms is

viral respiratory infection. At present, the relative

contributions of airway inflammation, bronchial

smooth-muscle abnormalities, or other structural

factors in producing wheeze with acute viral upper

respiratory infections are unknown. There appear to

be two general patterns of illness in infants and children who wheeze with acute viral upper respiratory

infections: a remission of symptoms in the preschool

years and persistence of asthma throughout childhood. No clear markers are available to predict the

prognosis of an individual child; however, in infants

and young children under 5 years of age with frequent wheezing (for example, more than three

episodes in the past year that lasted more than 1 day

and affected sleep), risk factors significantly associated with persistent asthma at 6 years of age include

having either (a) parental asthma history or a physician diagnosis of atopic dermatitis or (b) two of the

following conditions: physician-diagnosed allergic

rhinitis, peripheral blood eosinophilia, or wheezing

apart from cold (Evidence C) (Castro-Rodriguez et

al. 2000; Martinez 1995). Although currently not

established, it is conceivable that early recognition

and treatment of these high-risk children could

result in secondary prevention of childhood asthma.

Diagnosis is complicated by the difficulty in

obtaining objective measurements of lung function

in this age group. Essential elements in the evaluation include the history, symptoms, physical

examination, and assessment of quality of life. 

A therapeutic trial with medications listed in figure

3–5d also will aid in the diagnosis.

Treatment

Figure 3–6 illustrates the Expert Panel’s recommendations for a stepwise approach to managing acute

and chronic asthma symptoms, regardless of the

prognosis for the wheezing infant or young child.

It is the opinion of the Expert Panel that, in

general, daily long-term-control therapy should

be initiated in infants and young children consistently requiring symptomatic treatment more

than 2 times per week and in infants and young

children who experience severe exacerbations

(requiring inhaled beta2-agonist more frequently

than every 4 hours over 24 hours) that occur

less than 6 weeks apart. It is the opinion of the

Expert Panel that the initiation of long-termcontrol therapy should also be strongly

considered in infants and young children who

had more than three episodes of wheezing in

the past year that lasted more than 1 day and

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27

Medications: Effectiveness in Children

affected sleep AND who have risk factors for

developing persistent asthma: either (a) parental

history of asthma or a physician diagnosis of

atopic dermatitis or (b) two of the following

conditions: physician-diagnosed allergic rhinitis,

greater than 4 percent peripheral blood

eosinophilia, or wheezing apart from colds

(Evidence D).

The following have been Food and Drug Administration (FDA)-approved for young children: the

inhaled corticosteroids budesonide nebulizer solution

(approved for children 1 to 8 years of age) and fluticasone DPI (approved for children 4 years of age and

older); the long-acting beta2-agonist salmeterol DPI

(approved for children 4 years of age and older); and,

based on safety data rather than efficacy data, the

LTRA montelukast 4 mg chewable tablet (approved

for children 2 to 6 years of age).

At present, there are few studies of medications in

children younger than 3 years of age. A therapeutic

trial of anti-inflammatory medications should be

monitored carefully. Treatment should be stopped if 

a clear beneficial effect is not obvious within 4 to 6

weeks. Inhaled corticosteroids have been shown to be

effective in long-term clinical studies with infants; in

contrast, cromolyn has inconsistently demonstrated

symptom control in children younger than 5 years of

age (Tasche et al. 2000). A LTRA (montelukast) 4

mg chewable tablet has shown some effectiveness in

children 2 to 5 years of age (Knorr et al. 2001).

Sustained-release theophylline is not recommended 

as an alternative long-term-control medication for

young children with mild persistent asthma because

it may have particular risks of adverse side effects in

infants who frequently have febrile illnesses, which

increase theophylline concentrations. Theophylline

may be considered as adjunctive therapy in young

children with moderate or severe persistent asthma 

if there are cost considerations, but only if serum 

concentration levels will be carefully monitored.

In deciding when to initiate daily long-term-control

therapy, the clinician must weigh the possible longterm effects of inadequately controlled asthma vs.

the possible adverse effects of medications given over

prolonged periods. There is evidence that antiinflammatory treatment can reduce morbidity from

wheezing in early childhood (Connett et al. 1993).

Long-term studies in children 5 to 12 years of age 

at the time of enrollment conclude that inhaled 

corticosteroids improve health outcomes for children

with mild or moderate persistent asthma and that

the potential albeit small risk of delayed growth

from the use of inhaled corticosteroids is well balanced by their effectiveness (CAMP 2000). Further,

available long-term data indicate that most children

treated with recommended doses of inhaled corticosteroids achieve their predicted adult heights

(Agertoft and Pedersen 2000). It is noted that the

long-term prospective studies on growth involved

budesonide, and that the retrospective analyses

included studies on beclomethasone, but the results

have been generalized to include all inhaled corticosteroid preparations. Although different preparations

and delivery devices may have a systemic effect at 

different doses, all short-term studies on numerous

preparations suggest that the effect of inhaled corticosteroids on growth is a drug class effect. In children

with demonstrable adverse effects related to inhaled

corticosteroid therapy, other options (cromolyn,

LTRA, nedocromil, or theophylline) for initiating

and maintaining long-term-control therapy are

available. Thus, based on high-quality evidence,

the Expert Panel recommends long-termcontrol therapy for children with mild or 

moderate persistent asthma because it provides

control and prevention of asthma symptoms

(SRE-Evidence A). However, evidence to date 

is insufficient to permit conclusions regarding

whether early vs. delayed intervention with

daily long-term-control medication will alter 

the underlying course of the disease. Although a

preliminary study suggests that appropriate control

of childhood asthma may prevent more serious

asthma or irreversible obstruction in later years

(Agertoft and Pedersen 1994), these observations

were not verified in a recent long-term randomized

controlled trial in children ages 5 to 12 years

(CAMP 2000). The best available evidence does not

support the assumption that children 5 to 12 years

of age with mild or moderate persistent asthma have

a progressive decline in lung function that can be

prevented by early initiation of long-term-control

medications. Observational prospective data from

other large groups of children suggest that the

timing of the CAMP intervention was too late, as

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Medications: Effectiveness in Children

most loss of lung function in early childhood

asthma appears to occur during the first 3 to 5 years

of life (Martinez et al. 1995). However, it has not

yet been determined whether early recognition of

children at high risk of developing persistent

asthma coupled with early therapeutic intervention

will either prevent the loss of lung function or prevent the development of persistent disease.

Currently, critical prospective studies to address

these issues are in progress.

Recommendations for treating infants and young

children at different steps of care include:

■ The patient’s response to therapy should be

monitored carefully. When benefits are sustained for 2 to 4 months, a step down in

therapy should be attempted. If there are no

clear benefits within 4 to 6 weeks, treatment

should be stopped and alternative therapies or

diagnoses should be considered (Evidence D).

■ For step 2 care (mild persistent asthma), daily

long-term-control therapy with an inhaled

corticosteroid is the preferred option; cromolyn and LTRA are alternative therapies,

(SRE-Evidence A, B; Evidence B). A trial of

LTRA in children 2 years of age or older can

be considered in situations in which inhaled

medication delivery is suboptimal due to

poor technique or adherence (Evidence D).

■ When inhaled corticosteroids are introduced

in step 2 care, doses should be in the low

range. Inhaled corticosteroids are now available in both MDI and nebulizer preparations.

(See figures 3–5b and 3–5c in EPR-2 for discussion of equivalency among preparations.)

■ For step 3 care (moderate persistent asthma), there

are no data available that compare treatments in

step 3 care for infants and young children whose

asthma is not well controlled on low doses of

inhaled corticosteroids. Recommendations are based

on expert opinion and extrapolation from studies

in older patients. (See Medications: Combination

Therapy.) There are two main choices for step

3 care therapy: adding long-acting inhaled

beta2-agonists to low-dose inhaled corticosteroids (SRE-Evidence B; extrapolation from

studies in older children) OR increasing the

dose of inhaled corticosteroids within the

medium-dose range (Evidence D). Alternative

but not preferred options are adding either a

LTRA or theophylline (if serum concentrations are

monitored) to low-to-medium doses of inhaled

corticosteroids (Evidence D).

Comparative studies in older children and adults

consistently favor combination therapy over

increasing doses of inhaled corticosteroids.

Because studies indicate that the potential for

side effects of inhaled corticosteroids, though

small, appears to be dose related and has been

demonstrated in this age group at the mediumdose range of inhaled corticosteroids (Bisgaard

2002), the approach of adding long-acting

inhaled beta2-agonists to a lower dose of inhaled

corticosteroids is one preferred option (Evidence

B-extrapolating from adult studies). On the other

hand, there are no data on long-acting beta2-

agonists in children under 4 years of age, and

studies in infants and young children have shown

medium doses of inhaled corticosteroids to be

effective in treating moderate and severe asthma

(Connet 1993, de Blic 1996, Bisgaard 1999,

Nielsen 2000). The few studies available in this

age group that have directly compared different

doses of inhaled corticosteroids have shown that

increasing the dose is most effective in reducing

asthma exacerbations (Bisgaard 1999) and less

consistently effective in improving other outcomes (Bisgaard 1999, Baker 1999, Kemp 1999).

These results also have been found in studies of

adults. Therefore, it is the opinion of the Expert

Panel that using medium doses of inhaled corticosteroids as monotherapy for moderate asthma is

another preferred treatment option. 

For all treatments, it is essential to monitor

the child’s response to therapy. If there is no

clear response within 4 to 6 weeks, the

therapy should be discontinued and alternative therapies or alternative diagnoses

considered. If there is a clear and positive

response after 2 to 4 months, a step down in

therapy should be undertaken to the lowest

possible doses of medication required to

maintain asthma control (Baker 1999; Kemp,

Skoner, Szefler et al. 1999).

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Medications: Effectiveness in Children

■ Exacerbations caused by viral respiratory infections may be intermittent yet severe. Consider

systemic corticosteroids if the exacerbation is

moderate to severe or at the onset of a viral

respiratory infection if the patient has a history of severe exacerbations.

■ Consultation with an asthma specialist

should be considered for infants and young

children requiring step 2 care; consultation 

is recommended for those requiring step 3 or

step 4 care.

■ Several delivery devices are available for infants

and young children. The dose received may vary

considerably among devices and age groups. (See

figure 3–3 for a summary of therapeutic issues

regarding aerosol delivery devices.) The child’s

caregivers must be instructed in the proper use of

appropriately sized face masks, spacers/holding

chambers with face masks, and spacers/holding

chambers for medication delivery to be effective

and efficient. For children 2 years of age and

younger, nebulizer therapy with mask may be

preferred for administering aerosol medications.

Children between 3 and 5 years of age may begin

therapy with MDI and spacer/holding chamber

alone, but if the desired therapeutic effects are not

achieved, they may require a nebulizer or an MDI

plus spacer/holding chamber and face mask.

Recommendations for Future Research

■ How do LTRAs and inhaled corticosteroids compare in safety and efficacy in both the short term

and long term in the treatment of mild persistent

asthma in children younger than 5 years of age?

■ Do anticipated differences in adherence to medication regimens (for example, inhalation therapy

vs. oral tablet dose therapy) translate into significant clinical differences in overall asthma control?

■ What is the best form of adjunctive therapy in

children with moderate persistent asthma who 

are not adequately controlled on inhaled corticosteroid therapy alone? Long acting beta2-agonists?

LTRAs? Theophylline?

■ Can response to various long-term-control 

medications be predicted prior to initiating

treatment? Phenotype and genotype characterizations and definitions are needed to address 

this question.

■ What is the most effective way of treating 

children who have only viral-induced asthma

symptoms?

■ Is drug delivery using an MDI with spacer 

equal in efficacy to nebulizer treatments in 

childhood asthma?

■ Can early recognition and treatment of an infant

or young child at high risk of developing asthma

prevent development of persistent asthma?

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30

Medications: Effectiveness in Children

Key Evidence Tables

Childhood Asthma 

Management Research 

Group 2000a

Randomized, parallel-arm, 

double-blinded, 

placebo-controlled trial 

Jonasson, Carlsen, 

Blomqvist 1998

Randomized, parallel-arm, 

double-blinded, 

placebo-controlled trial 

Simons 1997

Randomized, parallel-arm, 

double-blinded, 

placebo-controlled trial 

Hoekstra, Grol, 

Hovenga et al. 1998

Randomized, parallel-arm, 

double-blinded, 

placebo-controlled trial

Agertoft and Pedersen 1994

Parallel-arm-controlled trial 

van Essen-Zandvliet, Hughes,

Waalkens et al. 1992

Randomized, parallel-arm, 

double-blinded, 

placebo-controlled trial 

Children younger than 5 years

Storr, Lenney, Lenney 1986

Randomized, parallel-arm, 

double-blinded, 

placebo-controlled trial 

Connett, Warde, 

Wooler et al. 1993

Randomizitrolled trial 

Placebo 418 411 9 +/- 2.2 Mild or Moderate 

BUD 311 306 9 +/- 2.1 Mild or Moderate 

Placebo 40 40 9.6 Mild 

BUD 1 40 40 10.2 Mild 

BUD 2 42 42 10.0 Mild 

BUD 3 41 41 9.8 Mild 

Placebo 55 52 9.5 +/- 2.4 Mild or Moderate 

BDP 81 67 9.6 +/- 2.6 Mild or Moderate 

Placebo 19 15 11 +/- 1.8 Mild or Moderate 

FP 15 25 10.6 +/- 1.8 Mild or Moderate 

Placebo 62 NR 6.1 Mild or Severe 

BUD 216 NR 6.2 Mild or Severe 

Placebo 58 17 10.9 +/- 1.9 Mild or Severe 

BUD 58 29 11 +/- 1.9 Mild or Severe 

Placebo 14 13 3.4 +/- 1.5 Unable to estimate 

BDP 15 15 3.6 +/- 1.2 Unable to estimate 

Placebo 20 19 1.9 +/- 0.5 Unable to estimate 

BUD 20 17 1.7 +/- 0.6 Unable to estimate 

Table 1-1. Inhaled Corticosteroids vs. No Inhaled Corticosteroids

Citation/Study Type Study Arm Number Enrolled Number Evaluable Mean Age +/- SD Estimated Disease 

Severity 

Children older than 5 years

Key:

BDP = beclomethasone dipropionate BUD = budesonide FEV1 = forced expiratory flow volume in 1 second

FP = fluticasone propionate NR = not reported PC20 = provocative concentration of bronchoconstrictor that induces a 20% drop in FEV1

SD = standard deviation Sx = symptom PEF = peak expiratory flow 

X = outcome reported

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Medications: Effectiveness in Children

224 X X X X X 

224 X X X X X 

12 X X X X Not stated how patients with moderatesevere asthma were excluded. 

12 X X X X 

12 X X X X 

12 X X X X 

52 X X X X X 

52 X X X X X 

12 X X X 

12 X X X 

270.4 (mean) X X Control patients were those patients who

declined recommendation to take inhaled 

corticosteroids.

Inhaled corticosteroid-free period after 

diagnosis is referred to as the run-in period, 

equal to at least 1 year. 

192.4 (mean) X X 

95.3 (median) X X X X 

95.3 (median) X X X X Pharmaceutical company supplied study 

medication.

26 X Study took place over an 18-month period 

in an attempt to eliminate seasonal bias.

26 X 

26 X X Patients treated for up to 6 months, included 

in analysis if treated at least 5 weeks.

26 X X Study medication adjusted to 200–400 mcg 

2x/day budesonide or 1–2 puffs 2x/day 

placebo depending on clinical need.

Study Duration Lung Function Outcomes Sx/Meds Utilization Outcomes Comments

(weeks) FEV1 PEF PC20

Source:

Blue Cross and Blue Shield Association Technology Evaluation Center. Management of Chronic Asthma:

Evidence Report/Technology Assessment Number 44. AHRQ Publication No. 01–EO44. Rockville, MD:

Agency for Healthcare Research and Quality. September 2001.

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Medications: Effectiveness in Children

Verberne, Frost, 

Roorda et al. 1997

Randomized, parallel-arm, 

double-blinded, 

controlled trial 

Simons 1997

Randomized, parallel-arm, 

double-blinded, 

placebo-controlled trial 

Salmeterol 35 25 10.6 +/- 2.9 Mild or Moderate 

BDP 35 32 10.5 +/- 2.3 Mild or Moderate 

BDP 81 67 9.6 +/- 2.6 Mild or Moderate

Salmeterol 80 58 8.8 +/- 2.1 Mild or Moderate

Table 1-2a. Inhaled Corticosteroids vs. Long-Acting Inhaled Beta2-Agonists

Citation/Study Type Study Arm Number Enrolled Number Evaluable Mean Age +/- SD Estimated Disease 

Severity 

Tinkelman, Reed, Nelson,

et al. 1993

Randomized, parallel-arm, 

double-blinded, 

placebo-controlled trial 

Theophylline 93 69 11.9 +/- 2.8 Mild or Severe

BDP 102 76 11.9 +/- 2.7 Mild or Severe 

Table 1-2b. Inhaled Corticosteroids vs. Theophylline

Citation/Study Type Study Arm Number Enrolled Number Evaluable Mean Age +/- SD Estimated Disease 

Severity 

Childhood Asthma

Management Program 

Research Group 2000a

Randomized, parallel-arm, 

double-blinded, 

placebo-controlled trial 

Placebo 418 411 9 +/- 2.2 Mild or Moderate

BUD 311 306 9 +/- 2.1 Mild or Moderate

Table 1-2c. Inhaled Corticosteroids vs. Nedocromil

Citation/Study Type Study Arm Number Enrolled Number Evaluable Mean Age +/- SD Estimated Disease 

Severity 

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Medications: Effectiveness in Children

48 X X X 

48 X X X 

52 X X X X

52 X X X X

Study Duration Lung Function Outcomes Sx/Meds Utilization Outcomes Comments

(weeks) FEV1 PEF PC20

Source:

Blue Cross and Blue Shield Association Technology Evaluation Center. Management of Chronic Asthma: Evidence Report/Technology Assessment Number 44.

AHRQ Publication No. 01–EO44. Rockville, MD: Agency for Healthcare Research and Quality. September 2001

36 X X X X X

36 X X X X X

Study Duration Lung Function Outcomes Sx/Meds Utilization Outcomes Comments

(weeks) FEV1 PEF PC20

Source:

Blue Cross and Blue Shield Association Technology Evaluation Center. Management of Chronic Asthma: Evidence Report/Technology Assessment Number 44.

AHRQ Publication No. 01–EO44. Rockville, MD: Agency for Healthcare Research and Quality. September 2001

224 X X X X X

224 X X X X X

Study Duration Lung Function Outcomes Sx/Meds Utilization Outcomes Comments

(weeks) FEV1 PEF PC20

Source:

Blue Cross and Blue Shield Association Technology Evaluation Center. Management of Chronic Asthma: Evidence Report/Technology Assessment Number 44.

AHRQ Publication No. 01–EO44. Rockville, MD: Agency for Healthcare Research and Quality. September 2001.

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Storr J, Lenney CA, Lenney W. Nebulized beclomethasone dipropionate in preschool asthma. Arch Dis

Child 1986;61(3):270–3.

Tasche MJ, Uijen JH, Bernsen RM, de Jongste JC, van der Wouden JC. Inhaled disodium cromoglycate (DSCG) as maintenance therapy in children with asthma: a systematic review. Thorax 

2000;55(11):913–20.

Tashkin DP, Nathan RA, Howland WC, Minkwitz MC, Simonson SG, Bonuccelli CM. An evaluation

of zafirlukast in the treatment of asthma with exploratory subset analyses. J Allergy Clin Immunol

1999;103(2 Pt 1):246–54.

Tinkelman DG, Reed CE, Nelson HS, Offord KP. Aerosol beclomethasone dipropionate compared

with theophylline as primary treatment of chronic, mild to moderately severe asthma in children.

Pediatrics 1993;92(1):64–77.

van Essen-Zandvliet EE, Hughes MD, Waalkens HJ, Duiverman EJ, Pocock SJ, Kerrebijn KF. Effects

of 22 months of treatment with inhaled corticosteroids and/or beta-2-agonists on lung function,

airway responsiveness, and symptoms in children with asthma. The Dutch Chronic Non-specific

Lung Disease Study Group. Am Rev Respir Dis 1992;146(3):547–54.

Verberne AA, Frost C, Roorda RJ, van der Laag H, Kerrebijn KF. One year treatment with salmeterol

compared with beclomethasone in children with asthma. The Dutch Paediatric Asthma Study

Group. Am J Respir Crit Care Med 1997;156(3 Pt 1):688–95.

Weinberger M. Zafirlukast and cromolyn are effective first-line therapies for child asthma. Ann Allergy

Asthma Immunol 2000;84(6):638–9.

36

Medications: Effectiveness in Children

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37

Medications: Safety of Inhaled Corticosteroids in Children

Long-Term Management of Asthma 

in Children: Safety of Inhaled

Corticosteroids

Question

What are the long-term adverse effects 

of chronic inhaled corticosteroid use in children 

on the following outcomes?

■ Vertical growth?

■ Bone mineral density (BMD)?

■ Ocular toxicity?

■ Suppression of adrenal/pituitary axis?

Summary Answer to the Question

Strong evidence from clinical trials following 

children for up to 6 years suggests that the use of

inhaled corticosteroids at recommended doses does

not have long-term, clinically significant, or irreversible effects on any of the outcomes reviewed.

Inhaled corticosteroids do improve health outcomes

for children with mild or moderate persistent

asthma, and the potential but small risk of delayed

growth is well balanced by their effectiveness (SREEvidence A, B). Updated text is recommended for

the EPR-2 incorporating the results of the SRE, but

this update does not change the EPR-2 statements.

Rationale for the Question

Inhaled corticosteroids have been proven to be beneficial

in the treatment of mild or moderate persistent asthma

in children. Because this class of compounds has the

potential for producing adverse side effects, however,

a SRE on the potential long-term adverse effects would

help guide consideration of potential risks and benefits

in the therapeutic decisionmaking process.

Systematic Review of the Evidence

The following description of the SRE is an 

adaptation of the evidence report, including direct

excerpts, submitted by the Blue Cross Blue Shield

Association Evidence-Based Practice Center. (See

Introduction, Methods.)

❙ Methods of Literature Search

To be eligible for consideration in the SRE, each

study was required to meet the following criteria: 

■ It reported on inhaled corticosteroid treatment.

■ The treatment duration/observation was at least 

1 year.

■ For prospective studies:

• Enrolled only patients younger than 18 years

of age.

OR

• Stratified outcomes for patients younger than

18 years of age and reported baseline demographics for the stratified subgroup.

■ For retrospective studies:

• Enrolled children and/or young adults younger

than 40 years of age and indicated that a substantial proportion of the exposure to inhaled

corticosteroids had been during childhood.

• Study design was a comparative clinical trial,

cohort study, case control study, or crosssectional study.

■ Reported on a group of at least 25 evaluable, 

similarly treated asthma patients per study arm.

■ For growth outcomes:

• Studies of short-term growth were restricted 

to randomized clinical trials.

• Studies of long-term growth were restricted to

studies that assessed final attained adult height

and controlled for confounding variables.

• For bone density, studies were restricted to 

controlled trials.

• For subcapsular cataract, clinical series studies

were also included.

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Medications: Safety of Inhaled Corticosteroids in Children

• For hypothalamic-pituitary-adrenal (HPA) axis

function, studies also were included that used

a pre-post single-arm design, where baseline

HPA axis function was measured before initiation of inhaled corticosteroids.

❙ Summary of Findings

Studies

The SRE addressed the long-term adverse effects of

chronic inhaled corticosteroid use in children on four

outcomes: vertical growth; bone mineral density;

ocular toxicity, including posterior subcapsular

cataract and glaucoma; and suppression of adrenal/

pituitary axis. (See the key evidence tables in this

section for a description of the studies reviewed for

vertical growth [three retrospective cohort/studies 

on final height]; bone-mineral density [two crosssectional studies and one randomized controlled

trial]; and HPA axis function [six studies, including

three randomized controlled trials]). The difficulties of

systematically assessing adverse effects are well known.

Most clinical trials are not designed to specifically

address adverse effects and thus may be statistically

underpowered and of insufficient duration to detect

long-term adverse effects. In addition, the results of

this evidence review do not apply to adults. For the

adult population, particularly elderly adults, adverse

effects may differ qualitatively and quantitatively. For

example, although effects on vertical growth are not a

concern for adults, ocular toxicity is likely to occur

more frequently as age increases.

Results of Studies

The available evidence suggests that the use of

inhaled corticosteroids at recommended doses 

does not have frequent, clinically significant, or 

irreversible effects on any of the outcomes reviewed. 

It is possible that chronic use of inhaled corticosteroids initiated in childhood and continued through

adulthood might have cumulative effects that increase

the relative risk of certain conditions—such as osteoporosis, cataracts, or glaucoma—in later life.

However, none of the available studies had sufficient

followup duration or numbers of patients to assess

this possibility definitively. It is also likely that the

probability of adverse effects is related to inhaled

corticosteroids dosage. No studies identified in the

published literature, however, were designed to test

the dose-response relationship of inhaled corticosteroids to adverse effects.

Vertical Growth

The long-term prospective studies on growth

involved budesonide, and the retrospective analyses

included studies on beclomethasone, but the results

have been generalized to all inhaled corticosteroid

preparations. Although different preparations and

delivery services may have a systemic effect at 

different doses, all short-term studies of numerous

preparations suggest that the effect of inhaled 

corticosteroids on growth is a drug class effect.

Evidence addressing three measures of vertical

growth in children was found: short-term growth

velocity measured over a period of 1 year or less,

growth velocity and change in height measured

over longer duration (4 to 6 years), and final

attained adult height. The evidence on short-term

growth velocity is from a published meta-analysis,

which pooled data from 5 randomized controlled

trials representing 855 subjects, with a mean age

of 9.5 years (Sharek and Bergman 2000). Evidence

on growth velocity and height over a longer

period of time is from the CAMP trial, comparing

inhaled corticosteroids (budesonide), nedocromil,

and placebo in 1,041 children with mild or moderate persistent asthma, who were followed for 4

to 6 years (CAMP 2000). For final attained adult

height, evidence is from three retrospective cohort

studies that adjusted for the potential confounding

factor of parental height (Agertoft and Pedersen

2000; Silverstein et al. 1997; Van Bever et al.

1999). Together, these three studies included a

total of 243 patients with asthma treated with

inhaled corticosteroids, 154 asthmatic patients

who had not been treated with inhaled corticosteroids, and 204 nonasthmatic controls.

Evidence on growth velocity when evaluated

during the first year of therapy is consistent in

showing a difference in height averaging approximately 1 cm between children treated with

inhaled corticosteroids and controls. The magnitude of this change in height (≈0.5→1.5 cm) has

varied between studies using different inhaled 

corticosteroid preparations, indicating that either

the study design or specific steroid preparation/

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39

Medications: Safety of Inhaled Corticosteroids in Children

dose may be important considerations (Doull et al.

1995; Allen et al. 1998; Verberne et al. 1997). In

the only trial extending beyond 1 year (CAMP

2000), a difference consistent with this magnitude

also occurred during the first year of the study.

However, in subsequent long-term followup, the

difference in growth velocity was not maintained;

all groups had similar growth velocity at the end

of treatment. At the end of the 4- to 6-year treatment period, there was still an approximately 1

cm difference in cumulative growth between the

study groups, but a slight difference in bone age

suggests the potential for catchup for the inhaled

corticosteroid group.

The evidence on final adult height appears to be

fairly consistent as well. However, this evidence 

is based on cohort studies that are subject to selection bias and the confounding effects of severity 

of asthma cannot be adjusted. Some comparisons

in these studies also were limited by small sample

size. Of the three studies, two showed no difference, and one showed a difference in final attained

adult height between inhaled corticosteroid users

and nonusers. However, the difference was much

less than would be expected if a 1 cm/year growth

velocity difference noted in the 1-year studies were

maintained over several years.

Bone Mineral Density

The CAMP study followed children with mild or

moderate persistent asthma and a mean age of

approximately 9 years who were treated for 4 to 6

years with inhaled corticosteroids. This study, with

large numbers, randomization, and assessment of

longitudinal changes, provides strong evidence

that there is no effect of inhaled corticosteroids on

bone mineral density (BMD) in the doses given

and in the duration in the study (CAMP 2002).

One retrospective study of 30 young adults found

a significant correlation between BMD and dose 

of inhaled corticosteroids among female patients 

(Ip et al. 1994). Such studies are subject to potential

confounding because of unmeasured differences

between groups that are risk factors for low BMD.

In addition, the clinical significance of any observed

differences in BMD are unknown. Subtle differences in BMD would not have a clinical impact

until they were added to other risk factors such as

aging, and it is uncertain whether differences

observed during young adulthood would persist

into old age.

Posterior Subcapsular Cataract and Glaucoma

Studies that report on the occurrence of posterior

subcapsular cataracts consist mostly of small

cohorts and cross-sectional studies (Allen et al.

1998; Tinkelman et al. 1993; Agertoft et al. 1998;

Simons et al. 1993; Nassif et al. 1987; Abuekteish

et al. 1995), with the exception of the CAMP

study. The expected incidence rate of subcapsular

cataract in any population of normal young 

children and adults is none. These studies are 

sufficient to rule out a large effect of inhaled 

corticosteroids on the short-term incidence of

cataract, but they are not capable of detecting a

small increase in risk of an event that has a baseline risk of essentially zero. In addition, several of

the clinical trials that evaluated development of

cataracts were of relatively short duration.

Two of these studies also reported on measurements

of ocular pressure (Tinkelman et al. 1993; Nassif et

al. 1987). The limited data available show no relationship between glaucoma or increased intraocular

pressure and inhaled corticosteroids.

Effect on Hypothalamic-Pituitary-Adrenal 

Axis Function

Two types of evidence on the effects of inhaled 

corticosteroids on HPA axis function have been

reported: three case reports of iatrogenic Cushing

syndrome that were possibly related to inhaled 

corticosteroids (Zimmerman et al. 1998; Taylor et

al. 1999; Priftis et al. 1991; Hollman and Allen

1988) and six controlled clinical trials regarding

HPA axis function (Tinkelman et al. 1993; Nassif

et al. 1987; Scott and Skoner 1999; Ribeiro 1993;

Price et al. 1997; Gonzalez Perez-Yarza et al. 1996).

Each study evaluated from one to three different

measures of HPA axis function, with followup for 

at least 1 year after initiation of treatment.

The case reports show that systemic effects can

occur in clinically detectable ways, with a strong

case for causality indicated in the case studies by

the accompanying laboratory tests and response

when inhaled corticosteroids were withdrawn. 

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Medications: Safety of Inhaled Corticosteroids in Children

In the controlled clinical studies, four studies 

of serum control values identified no differences.

However, three other studies used more sensitive

tests of cortisol, such as 24-hour urinary cortisol,

and two showed a statistically significant effect 

of inhaled corticosteroids. It should be noted that

these statistically significant results occur as 

comparisons of mean values between groups. Few

or no patients in most studies produce laboratory

values out of the normal range. However, the clinical significance of these more sensitive indicators

of adrenal function is unknown.

The results of the case reports appear to be

causally attributable to inhaled corticosteroids

based on clinical presentation, consistency with

laboratory findings, and clinical response to reduction or withdrawal of treatment. Although the

studies show that, on average, persons may only

have clinically insignificant effects of inhaled corticosteroids on the HPA axis, some individuals may

be acutely susceptible to their effects.

Additional Literature/Information

Since the release of the EPR-2, a FDA-based committee convened to review the safety of inhaled

corticosteroid therapy, with particular emphasis on

growth effects. The FDA committee recommended

inserting the following cautionary wording in

package inserts for all (both nasal and oral) inhaled

corticosteroid medications: “A reduction in growth

velocity in children or teenagers may occur as a

result of inadequate control of chronic diseases such

as asthma or from use of corticosteroids for treatment. Physicians should follow closely the growth 

of adolescents taking corticosteroids by any route

and weigh the benefits of corticosteroid therapy and

asthma control against the possibility of growth 

suppression if an adolescent’s growth appears slowed

(http://www.fda.gov).”

Two additional studies on the effect of inhaled 

corticosteroids were completed after the SRE; the

studies involved primarily adults but included some

children and thus were considered by the Expert

Panel. One report pertaining to the risk of cataract

formation among patients 3 to 90 years of age was

based on a large retrospective cohort study in the

United Kingdom-based General Practice Research

Database population, with a nested case-control

analysis among users of inhaled corticosteroids and

patients without previous steroid use who were

younger than 90 years of age. All users of inhaled

corticosteroids were at a marginally increased risk

of cataract formation (risk ratio = 1.3) compared

to patients who did not use corticosteroids.

Among individuals 40 years of age or older, the

risk ratio increased as numbers of inhaled corticosteroid prescriptions increased after controlling for

other variables. These trends were not evident for

those individuals younger than 40 years of age

(Jick et al. 2001).

A prospective cohort study on bone loss in women

18 to 45 years of age reported that bone-density loss

at the total hip and the trochanter—but not at the

femoral neck or spine—increased with the number

of puffs per day of an inhaled corticosteroid (Israel 

et al. 2001). However, the clinical significance of

these findings is uncertain because the rate of loss

reported was small, any association of this small loss

with increased risk of bone fracture has not been

established, and the rates varied among the women

taking the inhaled corticosteroids.

Recommendations for EPR Update

Based on this information from the SRE and 

additional studies, the Expert Panel recommends 

the following text (the blue text indicates new text)

as an update to pages 71 through 73 of EPR-2 

(The Medications, Special Issues on Safety, Systemic

Adverse Effects). This text updates—but does not

change—the EPR-2 recommendations.

Linear Growth

A reduction in growth velocity in children or adolescents may occur as a result of inadequate control 

of chronic diseases such as asthma or from the use 

of corticosteroids for treatment. Overall, however,

the available cumulative data in children suggest

that, although low-to-medium doses of inhaled 

corticosteroids may have the potential of decreasing

growth velocity, the effects are small, nonprogressive, and may be reversible (SRE-Evidence A, B, C).

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41

Medications: Safety of Inhaled Corticosteroids in Children

The long-term prospective studies on growth

involved budesonide, and the retrospective analyses

included studies on beclomethasone, but the results

have been generalized to include all inhaled corticosteroid preparations. Although different preparations

and delivery devices may have a systemic effect at

different doses, all short-term studies on numerous

preparations suggest that the effect of inhaled 

corticosteroids on growth is a drug-class effect. When

high doses of inhaled corticosteroids are necessary to

achieve satisfactory asthma control, the use of adjunctive long-term-control therapy should be initiated in

order to reduce the dose of inhaled corticosteroids

and thus minimize possible dose-related long-term

effects on growth. Physicians should monitor the

growth of children and adolescents taking corticosteroids by any route and weigh the benefits of

corticosteroid therapy and asthma control against the

possibility of growth suppression or delay if a child’s

or an adolescent’s growth appears slowed.

Bone Mineral Density

Low-to-medium doses of inhaled corticosteroids

appear to have no serious adverse effects on BMD 

in children (SRE-Evidence A) (CAMP 2000). 

A small, dose-dependent reduction in BMD may 

be associated with inhaled corticosteroid use in

patients older than 18 years of age (SRE-Evidence 

C; Evidence B) (Ip et al. 1994; Israel et al. 2001), but

the clinical significance of these findings is not clear.

Cataracts

In children, low-to-medium dose inhaled corticosteroid therapy has no significant effects on the

incidence of subcapsular cataracts or glaucoma 

(SRE-Evidence A, C) (CAMP 2000; Jick et al.

2001). High (greater than 2000 mg) cumulative

lifetime doses of inhaled corticosteroids may increase

slightly the prevalence of cataracts as suggested 

in two retrospective studies of adult and elderly

patients (SRE-Evidence C; Evidence C) (Cumming

et al. 1997; Jick et al. 2001).

Hypothalamic-Pituitary-Adrenal Axis Function

The available evidence indicates that, on average,

children may experience only clinically insignificant,

if any, effects of low-to-medium dose inhaled

corticosteroids on the HPA axis (SRE-Evidence A,

C). Rare individuals, however, may be more susceptible to their effects even at conventional doses.

Recommendations for Future Research

■ What are the long-term effects of inhaled corticosteroid therapy on BMD and cataract formation

if it is initiated at a young age and continued for

prolonged periods of time?

■ Are potential growth effects of inhaled corticosteroid therapy more pronounced during certain

developmental periods (e.g., first 3 years of life,

preadolescence)?

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Medications: Safety of Inhaled Corticosteroids in Children

Key Evidence Tables

Silverstein, Yunginger, 

Reed et al. 1997 

Van Bever, Desager, 

Lijssens et al. 1999 

Agertoft and Pedersen 2000 

All asthmatics (n = 153) vs. nonasthmatics (n = 153) 0.2 

All corticosteroid users (n = 58) vs. noncorticosteroid asthmatics (n = 95) -1.2 

Males: All corticosteroid users (n = 30) vs. noncorticosteroid asthmatics (n = 45) -1.8 

Females: All corticosteroid users (n = 28) vs. noncorticosteroid asthmatics (n = 50) -0.8 

Oral corticosteroid users (n = 40) vs. never used corticosteroids (n = 95) -1.4 

Inhaled corticosteroid users (n = 18) vs. never used corticosteroids (n = 95) -0.9 

All inhaled corticosteroid users (n = 43) vs. never used corticosteroids (n = 42) -2.542

Males: Inhaled corticosteroid users (n = 23) vs. never used corticosteroids (n = 26) -3.092

Females: Inhaled corticosteroid users (n = 20) vs. never used corticosteroids (n = 16) -1.99 

All inhaled corticosteroid users (n = 142) vs. noncorticosteroid using 

asthmatics (n = 18) +0.5 

All inhaled corticosteroid users (n = 142) vs. healthy sibling control 

group (n = 51) -0.6 

Males: All inhaled corticosteroid users (n = 86) vs. healthy sibling 

control group (n = 24) -0.6 

Females: All inhaled corticosteroid users (n = 56) vs. healthy sibling 

control group (n = 27) -0.8

Table 1-3. Differences in Adult Target Height in Cohort Studies

Study Group (n) Comparison Difference in (Adult

Target) Height (cm)1

1 A negative number indicates that corticosteroid users had lower attained adult height than the comparison group, controlling for parental height. 

2 p < 0.05

Source:

Blue Cross and Blue Shield Association Technology Evaluation Center. Management of Chronic Asthma: Evidence Report/Technology Assessment Number

44. AHRQ Publication No. 01–EO44. Rockville, MD: Agency for Healthcare Research and Quality. September 2001.

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43

Medications: Safety of Inhaled Corticosteroids in Children

Budesonide 

504 mcg per day

Nonsteroid 

asthma therapies

Beclomethasone 

or budesonide

Normal control

subjects, matched 

by sex, age, BMI,

menopausal status

Budesonide 

400 mcg/day 

Nedocromil 

16 mg/day 

Placebo

157 157 3.0 (minimum) Total body 

BMD:

0.92 g/cm2

111 111 3.0 (minimum) Total body NS 

BMD:

0.92 g/cm2

30 30 3.3 Spine:

0.944 0.041

Femur Neck:

0.769 0.007

Trochanter:

0.676 0.034

Ward’s 

Triangle:

0.729 0.016

30 30 NA Spine:

1.011 

Femur Neck:

0.835 

Trochanter:

0.724 

Ward’s 

Triangle:

0.729 

311 311 4–6 Change in 0.53 vs. 

spine BMD: placebo

0.17 g/cm2

312 312 4–6 Change in 0.15 vs. 

spine BMD: placebo

0.17 g/cm2

418 418 4–6 Change in 

spine BMD:

0.18 g/cm2

No significant difference

between groups or

between boys and girls in

bone mineral capacity or

total bone calcium

Mean treatment time 4.4

(3–6) years 

Stratified by sex, all differences significant for

females but not for males 

Agertoft,

Larsen, and

Pedersen 1998

Ip, Lam, Yam,

et al. 1994 

Childhood

Asthma

Management

Program

Research

Group 2000a

Table 1-4. Effects of Inhaled Corticosteroids on Bone Mineral Density

Citation Treatment Arm Number Number Treatment Bone P Value Comment

Enrolled Evaluable Duration (years)

Source:

Blue Cross and Blue Shield Association Technology Evaluation Center. Management of Chronic Asthma: Evidence Report/Technology Assessment Number

44. AHRQ Publication No. 01–EO44. Rockville, MD: Agency for Healthcare Research and Quality. September 2001.

Archive

for historical Reference Only
BUD 

500 mcg/day (n = 132)

vs.

conventional treatment (n = 57) 

FP 

50 mcg/day (n = 36)

vs.

cromolyn

20 mg/day (n = 27) 

BDP

84 mcg/day (n = 102)

vs.

theophylline (n = 93) 

Budesonide or beclomethasone

mean dose 676 +/- 280 mcg/day (range,

226–1800) (n = 250)

vs.

normal controls (n = 108)

Beclomethasone 358 mcg/day (n = 17)

vs.

Beclomethasone 726 mcg/day (n = 14)

vs.

asthmatic control group (n = 20) and normal

control groups (n = 21) 

Budesonide

200 mcg/day (n = 47)

Serum cortisol at baseline and 12 mo. 

ACTH-stimulated cortisol at baseline 

and 12 mo. 

Percentage of patients from normal 

to abnormal stimulation test between

baseline and 12 mo.

Urinary cortisol geometric mean 

ratio between patient groups at 6 and 

12 mo. 

Serum cortisol at baseline, 6 and 

12 mo.

ACTH-stimulated cortisol at baseline, 

6 and 12 mo. 

Urinary cortisol 

Number of abnormal ACTH stimulation

tests in subset with urinary cortisols 

below 1 standard deviation 

Serum cortisol 

Urinary cortisol

Serum cortisol at baseline and 12 mo. 

ACTH-stimulated cortisol at baseline and

12 mo. 

Scott and Skoner 1999

Price, Russell, Hindmarsh et al. 1997 

Tinkelman, Reed, Nelson et al. 1993 

Gonzales Perez-Yarza, Mintegui,

Garmendia et al. 1996

Nassif, Weinberger, Sherman et al. 1987

Ribiero 1993

Table 1-5. Effects of Inhaled Corticosteroids on HPA Function

Citation Treatment Arms Measure of HPA Axis Function

Randomized Clinical Trials

Single Arm Pre-Post Study

Cross-Section Studies

44

Medications: Safety of Inhaled Corticosteroids in Children

Archive

for historical Reference Only
Results P Value Comments

BUD (0, 12 mo): 320, 300 

Conventional (0, 12 mo.): 250, 315 

BUD (0, 12 mo.): 695, 655 

Conventional (0, 12 mo.): 690, 720

BUD: 24% 

Conventional: 21% 

Ratio of urinary cortisol at 6 mo.: 0.85 

Ratio of urinary cortisol at 12 mo.: 0.96 

BDP 336 mcg/day 

(0, 6, 12 mo.): 328, 306, 309 

Theophylline 

(0, 6, 12 mo.): 309, 322, 334

BDP 336 mcg/day 

(baseline): 726 (6, 12 mo. NA) 

Theophylline 

(baseline): 723 (6, 12 mo. NA)

BUD/BDP: 58.69 nmol/m2/day

Control: 81.98 nmol/m2/day 

BUD/BDP group: 2 abnormal tests (3.1%) 

Control group: Not done 

BDP <450 mcg/day: 403 

BDP >450 mcg/day: 353 

Asthmatic controls: 353 

Normal controls: 367 

BDP <450 mcg/day: 22 mcg/g creatinine

BDP >450 mcg/day: 16.5 mcg/g creatinine 

Asthmatic controls: 43 mcg/g creatinine

Normal controls: 29.5 mcg/g creatinine

Basal cortisol

(0, 12 mo.): 497, 497 

4-hr. stimulated cortisol 

(0, 12 mo.): 1104, 1131 

5-hr. stimulated cortisol 

(0, 12 mo.): 1242, 1380 

“No significant differences” 

“No significant differences” 

“Not different” 

NS: 95% CI includes 1 

NS: 95% CI includes 1 

Not stated: “similar” 

Not stated: “almost identical” 

p <0.05 

Not applicable 

Not specifically stated: presumed NOT 

statistically significant 

Text: 

“Statistically significant” from controls 

Not stated, presumed not statistically 

significant 

p = 0.02 for increase from baseline, 

both tests

Subset of full trial 

Subset of full trial 

One of the two patients with abnormal 

test had chronic oral corticosteroids. 

Source:

Blue Cross and Blue Shield Association Technology Evaluation Center. Management of Chronic Asthma: Evidence Report/Technology Assessment Number

44. AHRQ Publication No. 01–EO44. Rockville, MD: Agency for Healthcare Research and Quality. September 2001.

45

Medications: Safety of Inhaled Corticosteroids in Children

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Nassif E, Weinberger M, Sherman B, Brown K. Extrapulmonary effects of maintenance corticosteroid

therapy with alternate-day prednisone and inhaled beclomethasone in children with chronic

asthma. J Allergy Clin Immunol 1987;80(4):518–29.

References

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Medications: Safety of Inhaled Corticosteroids in Children

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Medications: Safety of Inhaled Corticosteroids in Children

Price JF, Russell G, Hindmarsh PC, Weller P, Heaf DP, Williams J. Growth during one year of 

treatment with fluticasone propionate or sodium cromoglycate in children with asthma. Pediatr

Pulmonol 1997;24(3):178–86.

Priftis K, Everard ML, Milner AD. Unexpected side-effects of inhaled steroids: a case report. Eur J

Pediatr 1991;150(6):448–9.

Ribeiro LB. Budesonide: safety and efficacy aspects of its long-term use in children. Pediatr Allergy

Immunol 1993;4(2):73–8.

Scott MB, Skoner DP. Short-term and long-term safety of budesonide inhalation suspension in infants

and young children with persistent asthma. J Allergy Clin Immunol 1999;104(4 Pt 2):200–9.

Sharek PJ, Bergman DA. The effect of inhaled steroids on the linear growth of children with asthma: 

a meta-analysis. Pediatrics 2000;106(1):E8.

Silverstein MD, Yunginger JW, Reed CE, Petterson T, Zimmerman D, Li JT, O’Fallon WM. Attained

adult height after childhood asthma: effect of glucocorticoid therapy. J Allergy Clin Immunol

1997;99(4):466–74.

Simons FE, Persaud MP, Gillespie CA, Cheang M, Shuckett EP. Absence of posterior subcapsular

cataracts in young patients treated with inhaled glucocorticoids. Lancet 1993;342(8874):776–8.

Taylor DA, Jensen MW, Kanabar V, Engelstatter R, Steinijans VW, Barnes PJ, O’Connor BJ. 

A dose-dependent effect of the novel inhaled corticosteroid ciclesonide on airway responsiveness

to adenosine-5’-monophosphate in asthmatic patients. Am J Respir Crit Care Med

1999;160(1):237–43.

Tinkelman DG, Reed CE, Nelson HS, Offord KP. Aerosol beclomethasone dipropionate compared

with theophylline as primary treatment of chronic, mild to moderately severe asthma in children.

Pediatrics 1993;92(1):64–77.

Van Bever HP, Desager KN, Lijssens N, Weyler JJ, Du Caju MV. Does treatment of asthmatic children

with inhaled corticosteroids affect their adult height? Pediatr Pulmonol 1999;27(6):369–75.

Verberne AA, Frost C, Roorda RJ, van der Laag H, Kerrebijn KF. One year treatment with salmeterol

compared with beclomethasone in children with asthma. The Dutch Paediatric Asthma Study

Group. Am J Respir Crit Care Med 1997(3 Pt 1);156:688–95.

Zimmerman B, Gold M, Wherrett D, Hanna AK. Adrenal suppression in two patients with asthma

treated with low doses of the inhaled steroid fluticasone propionate. J Allergy Clin Immunol

1998;101(3):425–6.

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Medications: Combination Therapy

Combination Therapy:

Addition of Other Long-Term-Control

Medications to Inhaled Corticosteroids

Question

In patients with moderate persistent asthma 

who are receiving inhaled corticosteroids, does

addition of another long-term-control agent

improve outcomes?

Summary Answer to the Question

Strong evidence consistently indicates that 

long-acting inhaled beta2-agonists added to lowto-medium-dose inhaled corticosteroids improve 

outcomes (SRE-Evidence A). Adding a leukotriene

modifier or theophylline to inhaled corticosteroids 

or doubling the dose of inhaled corticosteroids also

improves outcomes, but the evidence is not as 

substantial (SRE-Evidence B). The EPR-2 recommendations for moderate persistent asthma have been

revised: The preferred treatment for adults and children older than 5 years of age is the addition of

long-acting inhaled beta2-agonists to low-to-mediumdoses of inhaled corticosteroids. Adjunctive therapy

combinations have not been studied in children

younger than 5 years of age. For this age group, it is

the opinion of the Expert Panel that there are two

preferred options for treating moderate asthma: either

the addition of long-acting inhaled beta2-agonists to

a low dose of inhaled corticosteroids or medium-dose

inhaled corticosteroids as monotherapy.

Rationale for the Question

There are an increased number of studies evaluating

combination therapy primarily as a result of the

development of fixed-dose combinations of the 

long-acting inhaled beta2-agonists and inhaled 

corticosteroids (salmeterol plus fluticasone proprionate, now FDA-approved, and formoterol plus

budesonide, under development). The ongoing 

preference to minimize the dose of corticosteroids,

especially for patients taking high doses, and to

reduce the possibility of adverse side effects, has stimulated studies of adjunctive therapies. The question

of interest is whether, for patients requiring more

than low doses of inhaled corticosteroids, equal or

better asthma control could be achieved by adding an

additional medication rather than by increasing the

dose of inhaled corticosteroids. An extensive body of

literature addressing the question of adjunctive

therapy has become available since the publication of

EPR-2 and has thus warranted Expert Panel Review.

Systematic Review of the Evidence

The following description of the SRE is an adaptation of the evidence report, including direct excerpts,

submitted by the Blue Cross Blue Shield Association

Evidence-Based Practice Center. (See Introduction,

Methods.)

❙ Methods of Literature Search

The SRE divided the studies into three study design

categories:

1. The addition of a long-term-control medication 

to a fixed dose of inhaled corticosteroids compared

with the same dose of inhaled corticosteroids alone.

This design simply assesses whether combination

therapy is better than monotherapy with inhaled

corticosteroids. The potential bias from this study

design is seen when patients can be controlled on

inhaled corticosteroids alone, resulting in a negative study because of the inability to improve.

2. The addition of a long-term-control medication to

inhaled corticosteroids with subsequent downward

titration of the dose of inhaled corticosteroids to the

lowest dose that maintains control. This design is

even more problematic because it may be raising 

a fundamentally different question—i.e., “Can the

other long-term-control medication act as a substitute for the inhaled corticosteroids following

initial control of the asthma?” However, if the

goal is simply to lower the dose of inhaled corticosteroids by some increment (usually half), then

the study design addresses the primary question

more directly.

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Medications: Combination Therapy

3. The addition of the long-term-control medication

compared with increasing the dose of inhaled 

corticosteroids to improve asthma control. This

design most directly addresses the question,

because eligible patients first demonstrated a lack

of adequate control during an open run-in period

on inhaled corticosteroids. The definition of inadequate control varied among studies, however,

and this variance could introduce some bias.

In addition to the eligibility criteria for selecting

studies related to all topics in the SRE (described 

in the Introduction), the criteria for selecting studies

for this question were as follows:

■ Study comparisons included:

• Inhaled corticosteroids alone compared to

inhaled corticosteroids plus leukotriene modifiers, or long-acting beta2-agonists, or

theophylline

OR

• Two different long-term-control medications 

in patients using inhaled corticosteroids

OR

• The addition of an alternative medication to 

an increased dose of inhaled corticosteroids for

patients already on inhaled corticosteroids.

■ Treatment duration was at least 4 weeks. 

■ At least 90 percent of patients in the study were

on inhaled corticosteroids, or the subgroup of

patients on inhaled corticosteroids was analyzed

separately, and this subgroup otherwise met the

eligibility criteria for this question.

■ No more than 10 percent of the patients in the

population or in a subgroup were on oral corticosteroids.

❙ Summary of Findings

Studies

The majority of the studies reviewed by the SRE fit

into study design categories 1 and 3. Thirty-nine

studies involving 45 comparisons and a total of

9,020 patients were selected for the SRE. (See the

key evidence tables in this section.) Overall, 34 of

the 45 comparisons evaluated the addition of a 

long-acting beta2-agonist to inhaled corticosteroids. 

All but one of the studies were randomized trials.

The following comparisons were made:

■ Twenty-six compared the addition of a drug to a

fixed dose of inhaled corticosteroids (18 [3,163

patients] compared long-acting inhaled beta2-

agonists; 4 [234 patients] compared theophylline;

and 4 [885 patients] compared LTRAs).

■ Four compared a titrated dose of inhaled corticosteroids after the addition of a drug (3 [268

patients] compared long-acting inhaled beta2-

agonists; 1 [226 patients] compared LTRA).

■ Fifteen compared a low-to-moderate dose of

inhaled corticosteroids with an additional drug 

to high-dose inhaled corticosteroids (13 [4,285

patients] compared long-acting inhaled beta2-

agonists and 2 [252 patients] compared

theophylline).

■ No studies were found that compared long-acting

oral beta2-agonists.

■ No studies meeting SRE quality criteria were 

found that compared the addition of cromolyn 

or nedocromil.

Results of Studies

Addition of long-acting inhaled beta2-agonists

A sufficient number of quality studies in both

design categories 1 and 3 were completed to enable

meta-analyses of lung function and as-needed

short-acting beta2-agonist use outcomes in each

category. (See the key evidence tables in this section for a description of eligible studies.) Both the

systematic review and meta-analyses confirmed the

superiority of combination therapy to inhaled 

corticosteroids monotherapy. In particular, the

findings of the meta-analysis for the addition of

long-acting inhaled beta2-agonist compared with

increasing the inhaled corticosteroid dosage were

consistent with a previously reported meta-analysis

(Shrewsbury et al. 2000). In addition to similar

findings on lung function, Shrewsbury and colleagues had access to the original data and were

able to assess the rate of asthma exacerbations,

reporting a positive benefit of the combination

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Medications: Combination Therapy

therapy. The data are robust and convincing that

the addition of long-acting inhaled beta2-agonists

to inhaled corticosteroids improves lung function

and asthma control in patients inadequately 

controlled with low-to-medium doses of inhaled

corticosteroids.

Of note is the paucity of pediatric trials in the

database. One pediatric study by Verberne et al.

(1998) was completed in older children (mean 

11 years of age). Following a 6-week run-in, 120

patients were randomized to either low-dose inhaled

corticosteroid—beclomethasone dipropionate (BDP)

(400 mcg/day), medium-dose BDP (800 mcg/day),

or low-dose BDP plus the long-acting inhaled

beta2-agonist salmeterol for 1 year. No significant

difference was found among any of the three arms

in postbronchodilator FEV1 or PC20 FEV1 methacholine provocation. These results suggest that the

children’s asthma was adequately controlled with

low-dose inhaled corticosteroids and that the addition of the long-acting inhaled beta2-agonist neither

improved nor worsened airway responsiveness.

Thus, due to the design, this study cannot refute

the potential benefit of the drug combination for

those children inadequately controlled on low-dose

inhaled corticosteroids alone.

A multicenter double-blind trial of salmeterol 

as added therapy for children who were not well

controlled with inhaled corticosteroids (mean dose

of 750 mcg/day) demonstrated significant

improvement in morning PEF and symptom-free

days in the long-acting inhaled beta2-agonist plus

inhaled corticosteroid group, compared to the

placebo plus inhaled corticosteroid group (Russell

1995). Although this study did not compare the

addition of a long-acting inhaled beta2-agonist to

an increased dose of inhaled corticosteroids, the

patients were already receiving doses of inhaled

corticosteroids ranging from 400 to 2,400 mcg a

day. Thus, this study established a need for further

asthma control in children already receiving

inhaled corticosteroids; it also more directly

addresses the question posed by the SRE.

Addition of long-acting oral beta2-agonists

No studies were found.

Addition of cromolyn/nedocromil

No studies meeting the quality criteria of the SRE

were found. No new studies since the publication

of the EPR-2 were found.

Addition of theophylline

Six studies evaluated the addition of theophylline,

including two more recent studies that compared

the addition to increased inhaled corticosteroid

dosage. The results indicate that the combination

of drugs and the increased dose of the inhaled 

corticosteroids result in equivalent outcomes, 

suggesting that theophylline has only a modest

steroid-sparing effect. None of the four studies

(two in children 6 to 19 years of age) comparing

the addition of theophylline to a fixed dose of

inhaled corticosteroids met the quality criteria of

the SRE, because all had study-design and statistical problems. No studies were found that

included children younger than 6 years of age.

Addition of leukotriene modifiers

Five published studies evaluated the addition 

of leukotriene modifiers to fixed doses of inhaled 

corticosteroids; none compared the combination to

increasing the dose of inhaled corticosteroids. Two

of these studies used pranlukast, an LTRA unavailable in the United States, and one used zafirlukast

in a dose four times the dosage recommended on

the package label. None of the studies included

children younger than 12 years of age. The most

relevant of the five studies (Laviolette et al. 1999),

which contributed the most patients and had the

longest duration, failed to meet the definition of

high quality for the SRE because it met only one

of the quality indicators (double blinding).

Limitations of these studies preclude definitive

conclusions, but they reveal a trend showing

improvement in lung function and, in some,

symptoms from the combination of leukotriene

modifiers and inhaled corticosteroids compared

with a fixed dose of inhaled corticosteroids alone.

Addition of an adjunctive agent and down

titration of the inhaled corticosteroids

This group of studies is discussed separately, 

as some of the trials were designed to ask a 

fundamentally different question (i.e., could the

adjunctive therapy ultimately replace inhaled 

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Medications: Combination Therapy

corticosteroid therapy?). An example is the study

that attempted to wean patients from the inhaled

corticosteroids after beginning a long-acting

inhaled beta2-agonist until they had an exacerbation or the inhaled corticosteroid therapy was

discontinued (McIvor et al. 1998). Ten of the 13

patients in the long-acting inhaled beta2-agonist

arm experienced an exacerbation only after discontinuing their inhaled corticosteroids, providing

further evidence that the long-acting inhaled

beta2-agonist should not be used as a substitute for

anti-inflammatory therapy. One trial attempted to

wean patients from the inhaled corticosteroids

after addition of the LTRA montelukast, with the

goal of maintaining adequate asthma control

(Lofdahl et al. 1999). The mean percentage reduction in the dose of inhaled corticosteroids was 47

percent—a 17 percent increase over placebo—and

40 percent of patients were able to discontinue

their inhaled corticosteroids compared with 29 

percent in the placebo arm, which was not statistically significant. Thus, data are inconclusive about

the “steroid sparing” effect of adjunctive therapy, and

data show that patients cannot be entirely weaned

from inhaled corticosteroids. In addition, data from

these studies are insufficient to determine the relative “steroid-sparing” effect of the various adjunctive

therapies. Finally, none of the studies included 

children younger than 5 years of age.

Additional Literature/Information

In addition to reviewing studies published after the

SRE, the Expert Panel considered four other issues

relevant to the question of the use of combination

therapy for the treatment of persistent asthma: the

effect of the different combinations on the rate of

exacerbations of asthma; the comparison of different

combinations to determine relative effectiveness; the

use of combination therapy in children 5 years of age

and younger; and the use of combination therapy in

severe persistent asthma.

Studies Published After the SRE

The addition of montelukast to inhaled corticosteroids was evaluated in 279 children 6 to 14

years of age with moderate asthma whose symptoms were not completely controlled on 400 mcg

budesonide daily (Simons et al. 2001). This study

was a double-blinded, randomized, placebocontrolled, crossover trial with a 4-week open-label

run-in period to establish the need for adjunctive

therapy. Each treatment period also consisted of 4

weeks. The trial had sufficient power (95 percent)

to detect a 4.4-percent difference between the

placebo and the active drug in the primary end

point, FEV1 percent predicted. In the intentionto-treat analysis, no significant difference was

found between the placebo and montelukast for

the primary end point (1.3 percent difference). 

A post hoc censure of the data revealed a statistically significant 1.9 percent difference between 

the active drug and the placebo. Other significant

differences reported in favor of montelukast were a

decrease in beta2-agonist usage (.33 puffs/day 

difference) and exacerbation days that also were

defined by beta2-agonist usage—an improvement

in morning and evening PEFs (9.7 L/min and 10.7

L/min, respectively). It was not indicated whether

these were intention-to-treat analyses. Outcomes

found to be the same at the end of the study

included worsening asthma, global evaluations,

number of asthma attacks requiring intervention,

and quality of life.

Another study compared the addition of theophylline to low-dose BDP (400 mcg daily) with

increasing the dose of BDP to 1,000 mcg daily or

maintaining patients on the low-dose BDP alone

for 7 months (Lim et al. 2000). The study found

no difference between the high-dose inhaled

corticosteroids and the theophylline group for any

outcome, thus confirming the SRE findings.

Effect of Combination Therapy on the Rate 

of Exacerbations of Asthma

Reduction in the rate of asthma exacerbations has

been suggested as a surrogate for an anti-inflammatory effect. Compared with placebos, leukotriene

modifiers have been reported to reduce the

number of exacerbations treated with prednisone

(zileuton, zafirlukast, and montelukast package

inserts). Both of the long-acting inhaled beta2-

agonists—formoterol and salmeterol—have been

reported to reduce exacerbations of asthma when

administered in conjunction with inhaled corticosteroids (Pauwels et al. 1997; Shrewsbury et al.

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Medications: Combination Therapy

2000). In one study, the addition of formoterol 

to either low-dose (100 mcg bid) or high-dose

(400 mcg bid) budesonide significantly reduced

both mild and severe exacerbations. Further, fewer

exacerbations occurred in the high-dose inhaled

corticosteroid group compared with the lower dose

group, though statistical analysis was not done

(Pauwels et al. 1997). A meta-analysis of studies in

which the addition of salmeterol to a lower dose of

inhaled corticosteroids was compared with a higher

dose of inhaled corticosteroids demonstrated that

exacerbations were significantly lower with the

combination therapy (Shrewsbury et al. 2000).

It has been suggested that this reduction in 

exacerbations may be attributed to an enhanced

corticosteroid effect due to priming of the glucocorticoid receptor by the long-acting inhaled

beta2-agonist (Eickelberg et al. 1999). Two

recently published studies (Lazarus et al. 2001;

Lemanske et al. 2001) also are pertinent to the

issue of using asthma exacerbation as an outcome.

In the first trial, those patients adequately controlled on low-dose inhaled corticosteroids were

left on the inhaled corticosteroids, switched to the

long-acting beta2-agonist salmeterol, or switched

to placebo. Although the conventional outcomes

(morning and evening PEFs) for the salmeterol

and inhaled corticosteroid arms were not different,

the salmeterol group had a significantly greater

number of exacerbations and treatment failures—

again demonstrating that the long-acting inhaled

beta2-agonists cannot substitute for inhaled corticosteroids (Lazarus et al. 2001). The companion

study evaluated the ability to reduce the dose of

inhaled corticosteroids following the introduction

of a long-acting inhaled beta2-agonist in those

patients initially suboptimally controlled on the

inhaled corticosteroids (Lemanske et al. 2001). In

this group, the dose of inhaled corticosteroids was

reduced by one-half in those patients responding

to the addition without any significant change in

asthma control, yet a significant treatment failure

rate was noted when the inhaled corticosteroids

were stopped.

Although clinical studies in the SRE suggest that

the addition of a long-acting inhaled beta2-agonist

to a low-to-medium dose of inhaled corticosteroids

is the most effective treatment for moderate persistent asthma (step 3 care), there may be situations

where both the addition of a long-acting inhaled

beta2-agonist and an increase in the dose of

inhaled corticosteroids are indicated. The studies

of Sont et al. (1999) and Pauwels et al. (1997)

support the added benefit of a higher dose of

inhaled corticosteroids in reducing asthma exacerbations. Thus, for patients considered to be at

higher risk for exacerbations (suggested by a history of repeated short courses of prednisone,

emergency department visits, or hospitalizations),

both the addition of a long-acting inhaled beta2-

agonist and an increase in the dose of inhaled

corticosteroids may be indicated.

Comparison of Combinations To Determine

Relative Effectiveness

Not included in the SRE were direct comparative

studies of the effectiveness of the various drugs

used as adjuncts to inhaled corticosteroids. Studies

comparing the long-acting inhaled beta2-agonist

to sustained-release theophylline are numerous

(Davies et al. 1998), and generally involve patients

receiving inhaled corticosteroids. A meta-analysis

of these studies (Davies et al. 1998) demonstrated

that both pulmonary function and asthma symptoms showed more improvement with the

long-acting inhaled beta2-agonist as adjunctive

therapy than with theophylline. In the three 

published studies included in the meta-analysis,

between 50 percent and 97 percent of the subjects

were receiving regular inhaled corticosteroid

therapy (Fjellbirkeland et al. 1994; Muir et al.

1992; Paggiaro et al. 1996). 

A comparison of the addition of the long-acting

beta2-agonist salmeterol to the addition of the

LTRA zafirlukast (Busse et al. 1999) also examined

a mixed population; however, this study was not

included in the SRE because more than 80 percent

of the patients in both arms were using inhaled

corticosteroids, rather than 90 percent required by

the SRE selection criteria. The study otherwise met

the criteria for a high-quality study and should be

considered. The results indicate that salmeterol

improved both pulmonary function and asthma

symptoms significantly more than did zafirlukast.

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Medications: Combination Therapy

Another direct comparison of long-acting inhaled

beta2-agonists and a leukotriene modifier as combination therapy was published after the SRE

(Nelson et al. 2000). This study also met the SRE

criteria for high quality and should be considered.

The investigators evaluated patients who were still

symptomatic on low-dose inhaled corticosteroids

(fluticasone 88 mcg bid), before and after the

addition of the long-acting beta2-agonist salmeterol or the LTRA montelukast over 3 months.

Those patients receiving salmeterol plus fluticasone, compared with those on montelukast and

fluticasone, had greater improvement in pulmonary function and in some asthma symptoms,

and experienced significantly fewer exacerbations.

Although the addition of sustained-release theophylline or a leukotriene modifier to treatment

with inhaled corticosteroids generally is not as

effective as the addition of a long-acting inhaled

beta2-agonist, there may be circumstances when

these combinations would be indicated for selected

patients. Among the considerations favoring one

of these alternative combinations would be the

patient’s intolerance of the side effects of the longacting inhaled beta2-agonist, marked preference for

oral therapy, demonstration of superior responsiveness to the alternate class of drug, as well as

financial considerations (theophylline is the least

expensive). Finally, although the recently marketed fixed-dose combination of fluticasone

propionate and salmeterol in a DPI may provide

an advantage in terms of ease of use (one inhaler

instead of two), there is no evidence of superiority

of this particular combination over that of other

inhaled corticosteroids and long-acting inhaled

beta2-agonists.

Combination Therapy in Children 5 Years of

Age and Younger

None of the adjunctive therapy combinations have

been adequately studied in children 5 years of age

and younger. Indeed, only one study, a study

adding the long-acting inhaled beta2-agonist 

salmeterol to inhaled corticosteroids, included

patients as young as 4 years of age (Russell 1995).

The lower age limit of all other combination

therapy studies in children is 6 years of age

(Simons et al. 2001; Meltzer et al. 1992; Nassif 

et al. 1981). The data are thus inadequate to provide definitive recommendations on combination

therapy in young children, and recommendations

must be extrapolated from studies in older children and adults, which support the combination 

of inhaled corticosteroids and long-acting inhaled

beta2-agonists. Because patients in this age range

may be at greater risk for systemic effects from

high doses of inhaled corticosteroids, the use of

combination therapy seems prudent when goals 

of therapy are not attained with low or the lower

range of medium doses of inhaled corticosteroids.

However, as noted in the section on effectiveness 

of long-term-control medications, there are no data

available on the use of long-acting inhaled beta2-

agonists in infants and young children, whereas

studies of medium doses of inhaled corticosteroids

demonstrate effectiveness in this age group.

The following medications have been FDAapproved for young children: the inhaled

corticosteroids budesonide nebulizer solution

approved for children 1 to 8 years of age and fluticasone DPI approved for children 4 years of age

and older; the long-acting inhaled beta2-agonist

salmeterol DPI approved for children 4 years of

age and older; and, based on safety data rather

than efficacy data, the LTRA montelukast 4 mg

chewable approved for children 2 to 6 years of age.

Combination Therapy in Patients With Severe

Persistent Asthma

Current recommendations for treatment include

adding oral systemic corticosteroids if a patient

cannot achieve and maintain control with high

doses of inhaled corticosteroids and long-acting

bronchodilators. An alternative approach may be 

to add a third long-term-control medication to a

combination of medium-to-high-dose corticosteroids and long-acting inhaled beta2-agonists in

severe persistent asthma. However, few trials

regarding this approach and of sufficient quality are

available. A double-blind, crossover trial of LTRA

(10 mg montelukast or placebo) in 72 adults with

severe persistent asthma found no benefit from the

addition of montelukast to other medication

(Robinson et al. 2001). In this study, the concurrent medication varied among the patients: All

patients received medium-to-high-dose inhaled

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Medications: Combination Therapy

corticosteroids; 85 percent also received either

theophylline, a long-acting inhaled beta2-agonist,

or both; and 47 percent also received oral systemic

corticosteroids. No attempt was made to eliminate

the oral corticosteroids. The treatment period of 

14 days for LTRA and 14 days for placebo was 

relatively short, although leukotriene modifiers

usually produce a rapid response. This study 

indicates that there is no additional benefit to

adding LTRA as a third medication. Similar 

controlled clinical trials have not been conducted

to evaluate other long-term-control medications

added to the combination of medium-to-high

doses of inhaled corticosteroids and long-acting

inhaled beta2-agonists in severe persistent asthma.

Until more research is conducted, recommendations for managing severe persistent asthma are

based on extrapolations from studies of the 

combination of inhaled corticosteroids and one

other long-term-control medication in treating

moderate persistent asthma. 

Recommendations for EPR Update

Based upon the assessment of evidence provided by

the SRE and the additional evidence considered by

the Expert Panel, the following changes to step 3

care in EPR-2 are recommended:

■ The preferred treatment for those adults and children older than 5 years of age whose asthma is

inadequately controlled on low-dose inhaled

corticosteroids is combination therapy: the addition of a long-acting inhaled beta2-agonist

(SRE-Evidence A) to a low-to-medium dose of

inhaled corticosteroids. Scientific evidence from

studies of children older than 12 years of age and

adults indicates that patients with moderate persistent asthma benefit from two different types of

daily medication in order to achieve and maintain

optimal control of their asthma: (1) medication

aimed at suppressing underlying airway inflammation and (2) a medication whose primary action

is bronchodilation. This approach is preferred to

increasing the dose of inhaled corticosteroids.

The exception is indicated for those patients who

experience recurring severe exacerbations that

require oral prednisone, emergency department

visits, or hospitalizations. For these patients,

increasing the dose of inhaled corticosteroids along

with the addition of a long-acting inhaled beta2-

agonist should be considered (SRE-Evidence B).

For children 5 years of age or younger, combination therapy has not been adequately studied.

Therefore, recommendations for step 3 care for

this age group are based on extrapolations of data

from older children and adults, as well as expert

opinion. For children 5 years of age and younger

with moderate persistent asthma, there are two

equally preferred options: low-dose inhaled corticosteroids and a long-acting beta2-agonist

(Evidence B, extrapolation from studies in older

children and adults) OR inhaled corticosteroids as

monotherapy with an increase of the dose within

the medium-dose range (Evidence D).

■ Alternative—but not preferred—approaches that

may be considered include doubling the dose of

inhaled corticosteroids within the medium-dose

range (this is an alternative but not preferred

option for older children and adults; for children

5 years of age and younger, increasing the

inhaled corticosteroid dose is an equally preferred

option); adding sustained-release theophylline; or

adding a leukotriene modifier (SRE-Evidence B).

Leukotriene modifiers or theophylline may be

considered if the patient displays intolerance of

long-acting inhaled beta2-agonists, has a marked

preference for oral therapy, and demonstrates

superior responsiveness to the alternative class 

of drug through a therapeutic trial. Other issues

may include financial considerations (theophylline

is the least expensive).

■ The recommendations for the use of nedocromil

and long-acting oral beta2-agonists as alternatives

to increasing the dose of inhaled corticosteroids

are untenable at this time due to lack of data and

should be removed as therapeutic options.

Specifically, the Expert Panel recommends that step

3 in figure 3–4b, Stepwise Approach for Managing

Asthma in Adults and Children Older Than 5 Years

of Age, be revised as follows with the revision noted

in blue text. 

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Figure 3–6. Stepwise Approach for Managing

Infants and Young Children (5 Years of Age and

Younger) With Acute or Chronic Asthma. (See

Medications: Effectiveness in Children on page 25

of this report for revisions to step 3.)

Figure 3–4b. Stepwise Approach for Managing

Asthma in Adults and Children Older Than

5 Years of Age: Treatment (pages 84 through 85

in EPR-2)

Step 3: Moderate Persistent

Daily Medication:

Preferred treatment:

Low-to-medium-dose inhaled corticosteroids

and long-acting inhaled beta2-agonists

Alternative treatment (listed alphabetically):

Increase inhaled corticosteroids within 

medium-dose range

OR

Low-to-medium-dose inhaled corticosteroids and

either a leukotriene modifier OR theophylline

If needed (particularly in patients with recurring

severe exacerbations)

Preferred treatment: 

Increase inhaled corticosteroids within

medium-dose range and add a long-acting

beta2-agonist

Alternative treatment:

Increase inhaled corticosteroids within mediumdose range and add either a leukotriene modifier

OR 

Theophylline

Step 4: Severe Persistent

Daily Medication:

Preferred treatment:

High-dose inhaled corticosteroids

AND

Long-acting inhaled beta2-agonists

AND, if needed

Corticosteroid tablets or syrup long term (1 to 2

mg/kg/day; generally do not exceed 60 mg/day).

(Make repeat attempts to reduce systemic corticosteroids and maintain control with high-dose

inhaled corticosteroids.)

The text in EPR-2 on pages 93 and 94 regarding

step 3 and step 4 care for adults and children older

than 5 years of age should be revised as follows, with

the blue text indicating new text. (See Medications:

Effectiveness in Children on page 25 for revisions to

step 3 for children 5 years of age and younger.)

Step 3: Moderate Persistent Asthma

Consultation with an asthma specialist may be 

considered because the therapeutic options at this

juncture pose a number of challenging risk-benefit

outcomes. Before increasing therapy, however, the

clinician should review the patient’s inhaler technique and adherence, as well as determine whether

environmental factors are contributing to the

patient’s worsening asthma. If a step-up in therapy 

is required, there are at least four options for initiating step 3 therapy.

■ Add a long-acting inhaled beta2-agonist to 

a low-to-medium-dose of inhaled corticosteroids (SRE-Evidence A, B). This is the

preferred treatment. Early investigations suggested

that the addition of a long-acting inhaled beta2-

agonist to a low (Greening et al. 1994) or

medium (Woolcock et al. 1996) dose of inhaled

corticosteroids resulted in greater improvement in

lung function and overall asthma control than

doubling the dose of inhaled corticosteroids. Since

that time, numerous studies have confirmed the

superiority of combination therapy over

increasing the dose of inhaled corticosteroids,

even for reducing severe asthma exacerbations

(SRE 2001, Shrewsbury et al. 2000). Use of combination therapy has not been shown to mask

worsening of inflammation and asthma. Indeed,

the combination has consistently been shown to

reduce the number of severe asthma exacerbations

(Pauwels et al. 1997; Shrewsbury et al. 2000).

This approach has proved so successful that it has

spawned the development of two fixed-dose combinations of long-acting inhaled beta2-agonists

and inhaled corticosteroids in one inhaler, one currently marketed. The fixed-dose combination may

be easier to use and hence facilitate adherence to

the regimen, but there is no evidence of clinical

superiority over using the inhaled corticosteroids

and long-acting inhaled beta2-agonists in separate

inhalers.

OR

56

Medications: Combination Therapy

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57

Medications: Combination Therapy

■ Increase the dose of inhaled corticosteroids

and add a long-acting inhaled beta2-agonist

(SRE-Evidence B). This approach should be

reserved for those patients experiencing recurring

severe exacerbations requiring oral prednisone,

emergency department visits, or hospitalizations.

In a 1-year trial of combination therapy, the addition of long-acting inhaled beta2-agonists to

either low-dose or high-dose inhaled corticosteroids significantly reduced both mild and

severe exacerbations (Pauwels et al. 1997). In

addition, fewer exacerbations occurred in the

high-dose inhaled corticosteroid group compared

with the lower-dose group, although statistical

analysis was not done.

OR

■ Give inhaled corticosteroids as monotherapy by

increasing the dose within the medium-dose

range (SRE-Evidence A, B). This approach is

another preferred treatment option for young

children; it is an alternative, but not preferred,

treatment option for older children and adults.

Studies of adults in which the dose of inhaled 

corticosteroids was at least doubled consistently

demonstrate improved lung function and other

outcomes in those patients not completely 

controlled on low-to-medium-doses of inhaled

corticosteroids, but these results are consistently

less effective than adding a long-acting inhaled

beta2-agonist (SRE-Evidence A, B).

OR

■ Add a leukotriene modifier or theophylline 

to inhaled corticosteroids (SRE-Evidence B;

Evidence B). The addition of leukotriene modifiers and theophylline has produced modest

improvement in lung function and some other

outcomes in patients not completely controlled

on inhaled corticosteroids. The addition of theophylline, however, has not been shown to be

more effective than doubling the dose of inhaled

corticosteroids (Evans et al. 1997; Ukena et al.

1997). The leukotriene modifiers have produced

improvements in lung function and in some but

not all measures of asthma control in patients

incompletely controlled on inhaled corticosteroids (Laviolette et al. 1999). In addition, the

leukotriene modifiers allow slightly more patients

to be taken off inhaled corticosteroids than does

placebo (11 percent difference) (Lofdahl et al.

1999). The addition of the leukotriene modifiers

to inhaled corticosteroids has not been compared

with doubling the dose of inhaled corticosteroids.

Direct comparisons of the addition of a leukotriene

modifier or a long-acting inhaled beta2-agonist to

therapy for patients incompletely controlled on

inhaled corticosteroids show significantly greater

improvement in lung function and other measures of asthma control for patients receiving the

long-acting inhaled beta2-agonist and inhaled

corticosteroid combination (Busse et al. 1999;

Nelson et al. 2000). Thus, although the combination of inhaled corticosteroids and either

theophylline or leukotriene modifier is not the

preferred approach, considerations favoring one 

of these alternative combinations would be the

patient’s intolerance of the side effects of the longacting inhaled beta2-agonist, marked preference

for oral therapy, and demonstration of superior

responsiveness to the alternative class of drug, 

as well as financial considerations (theophylline 

is the least expensive).

Specific issues for children. Recommendations on

combination therapy for children younger than

12 years of age with moderate persistent asthma

are based on extrapolations from studies in

older children and adults and on expert opinion

(Evidence B, D). None of the adjunctive therapy

combinations have been adequately studied in children younger than 12 years of age, and they have not

been studied at all in children younger than 4 years

of age. One negative study of combination therapy

in children with mild or moderate persistent asthma

failed to establish a need in the study participants at

baseline for more therapy than low-dose inhaled 

corticosteroids and thus did not sufficiently address

the question of combination therapy (Verberne et al.

1998). In one study in children 4 to 16 years of age

with moderate or severe asthma, the addition of a

long-acting beta2-agonist produced a clear benefit

compared to placebo (Russell et al. 1995). In a

recent crossover comparison of children 6 to 14 years

of age on inhaled corticosteroids, no significant difference was found with the addition of the LTRA

montelukast in the primary outcome measure FEV1,

but a small reduction in as-needed short-acting

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58

Medications: Combination Therapy

beta2-agonist use (.33 puffs/day) in favor of LTRA

was found. No difference was found for worsening

asthma, asthma attacks, or quality of life (Simons et

al. 2001). Studies of the addition of theophylline to

inhaled corticosteroids in children 6 to 19 years of

age showed both a benefit (Nassif et al. 1981) and

no benefit (Meltzer et al. 1992). Neither of these

theophylline studies is of high enough quality to

generate a recommendation. Finally, there is only

one study on adjunctive therapy that included children as young as 4 years of age, and there are no

studies in children younger than 4 years of age.

Step 4: Severe Persistent Asthma

Patients with severe persistent asthma require

high doses of inhaled corticosteroids and a longacting inhaled beta2-agonist and, if needed, an

oral corticosteroid (Evidence B). It is the

opinion of the Expert Panel that consultation

with an asthma specialist is recommended for

patients with severe persistent asthma. Evidence

to date does not support using a third long-termcontrol medication added to inhaled corticosteroids

and long-acting inhaled beta2-agonists in order to

avoid using systemic corticosteroid therapy

(Evidence C). A study found no benefit for the 

addition of an LTRA to high doses of inhaled 

corticosteroids and, for most patients in the study,

another medication (either theophylline, a longacting beta2-agonist, oral corticosteroid, or a

combination) (Robinson et al. 2001). Similar studies

of other long-term-control medications added to the

combination of medium-to-high doses of inhaled

corticosteroids and long-acting inhaled beta2-

agonists in severe persistent asthma are not available.

Patients whose asthma is not controlled on high

doses of inhaled corticosteroids and the addition of

long-acting inhaled beta2-agonists also will need oral

systemic corticosteroids on a regularly scheduled,

long-term basis. For patients who require long-term

systemic corticosteroids:

■ Use the lowest possible dose (single dose daily or,

preferably, on alternate days).

■ Monitor patients closely for corticosteroid adverse

side effects (see component 3-Medications).

■ When control of asthma is achieved, make persistent attempts to reduce systemic corticosteroids.

High doses of inhaled corticosteroids are preferable to systemic corticosteroids because inhaled

corticosteroids have fewer systemic effects.

■ Recommend consultation with an asthma 

specialist.

Recommendations for Future Research

The Panel recommends the following research to

clarify treatment options:

■ Long-term studies to examine the effect of

adjunctive therapy on possible loss in pulmonary

function and the natural history of asthma—

hospitalization, exacerbations, and decline in 

pulmonary function.

■ Studies of noninvasive markers that would give 

a composite picture of both disease activity (e.g.,

inflammation) and disease control. These could 

be used as surrogate markers for overall asthma

control to guide therapy. Ideally, such markers

would be more efficient than gauging a patient’s

response to therapy following a relatively long

therapeutic trial.

■ Long-term studies to examine the importance of

the greater suppression of inflammation achievable

with higher doses of inhaled corticosteroids compared with adjunctive therapy. Low doses of

inhaled corticosteroids usually are sufficient for

improvement in lung function and control of

asthma symptoms but may not suppress inflammation to the same extent as higher doses. Studies

to assess the value of maximum suppression of

inflammation vis-à-vis therapeutic control will

contribute to understanding the appropriate use 

of inhaled corticosteroids and adjunctive therapy.

■ Evaluations of adjunctive therapies in children

younger than 12 years of age.

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Table 1-7. Meta-Analysis: Medication Use Outcomes for Studies

Comparing the Addition of Long-Acting Beta2-Agonists to a 

Fixed Dose of Inhaled Corticosteroids

59

Medications: Combination Therapy

FEV1: Combined Studies (n = 14) 0.334 0.241, 0.428 0.10 0.17 L 0.12, 0.22

3.71% pred 2.67, 4.75 

FEV1: Sensitivity analysis by quality: 0.319 0.139, 0.499 0.14 0.17 L 0.07, 0.26

Studies that meet all generic quality 3.43% pred 1.54, 5.54

criteria except allocation concealment and meet most 

(>4) asthma-specific criteria (n = 3) 

FEV1: Sensitivity analysis by quality: 0.368 0.257, 0.478 0.20 0.19 L 0.13, 0.25

Studies that meet all generic quality criteria except 4.08% pred 2.85, 5.30 

allocation concealment (N = 11)

PEF: Combined studies (n = 9) 0.581 0.417, 0.745 0.0034 24.68 L/min 17.70, 31.65

7.26% pred 5.21, 9.31 

PEF: Sensitivity analysis by quality: 0.643 0.460, 0.826 0.17 27.33 L/min 19.55, 35.10

Studies that meet all generic quality criteria except 8.04% pred 5.75, 10.32

allocation concealment and meet most (>4) asthma-specific 

criteria (n = 4) 

PEF: Sensitivity analysis by quality: 0.630 0.478, 0.781 0.06 26.77 L/min 20.32, 33.19

Studies that meet all generic quality criteria except 7.88% pred 5.98, 9.76

allocation concealment (n = 8) 

Table 1-6. Meta-Analysis: Lung Function Outcomes for Studies

Comparing the Addition of Long-Acting Beta2-Agonists to a 

Fixed Dose of Inhaled Corticosteroids

Meta-Analysis Effect Size 95% CI Test for Treatment 95% Cl

Estimate Homogeneity Effect 

P-Value Estimate

Source:

Blue Cross and Blue Shield Association Technology Evaluation Center. Management of Chronic Asthma: Evidence Report/Technology Assessment Number

44. AHRQ Publication No. 01–EO44. Rockville, MD: Agency for Healthcare Research and Quality. September 2001.

Puffs/day: Combined studies (n = 6) -1.18 -1.56, -0.80 0.018 

Puffs/day: Sensitivity analysis by quality: -1.34 -1.87, -0.84 0.20 

Studies that meet all generic quality criteria except 

allocation concealment and meet most (>4) asthma-specific 

criteria (n = 3) 

Puffs/day: Sensitivity analysis by quality: -1.00 -1.34, -0.66 0.14

Studies meet all generic quality criteria except allocation 

concealment (n = 5) 

Meta-Analysis Treatment Effect Estimate 95% CI Test for Homogeneity 

P-Value

Source:

Blue Cross and Blue Shield Association Technology Evaluation Center. Management of Chronic Asthma: Evidence Report/Technology Assessment Number

44. AHRQ Publication No. 01–EO44. Rockville, MD: Agency for Healthcare Research and Quality. September 2001.

Key Evidence Tables

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FEV1: Combined Studies (n = 8) 0.209 0.133, 0.285 0.93 0.11 L 0.07, 0.15

2.32% pred 1.48-3.16 

FEV1: Sensitivity analysis by quality: 0.203 0.107, 0.299 0.94 0.11 L 0.06, 0.16

Studies that that meet all generic quality criteria except 2.25% pred 1.19, 3.32

allocation concealment and meet most (>4) asthma-specific 

criteria (n = 4)

FEV1: Sensitivity analysis by quality: 0.212 0.134, 0.290 0.88 0.11 L 0.07, 0.15

Studies that meet all generic quality criteria except 2.35% pred 1.49, 3.22 

allocation concealment (n = 7) 

PEF: Combined studies (n = 10) 0.310 0.192, 0.429 0.0002 11.6 L/min 5.2-18.0

3.4% pred 1.5-5.3 

PEF: Sensitivity analysis by quality: 0.300 0.030, 0.569 0.000007 12.75 L/min 1.28, 24.18

Studies that meet all generic quality criteria except 3.75% pred 0.38, 7.11

allocation concealment and meet most (>4) asthma-specific 

criteria (n = 4)

PEF: Sensitivity analysis by quality: 0.296 0.143, 0.449 0.00005 12.58 L/min 6.08, 19.08

Studies that meet all generic quality criteria except 3.7% pred 1.79, 5.61

allocation concealment (n = 7) 

Table 1–8. Meta-Analysis: Lung Function Outcomes for Studies

Comparing a Lower Dose of Inhaled Corticosteroids Plus Long-Acting

Inhaled Beta2-Agonists vs. an Increased Dose of Inhaled Corticosteroids

Meta-Analysis Effect Size 95% CI Test for Treatment 95% Cl

Estimate Homogeneity Effect 

P-Value Estimate

Source:

Blue Cross and Blue Shield Association Technology Evaluation Center. Management of Chronic Asthma: Evidence Report/Technology Assessment Number

44. AHRQ Publication No. 01–EO44. Rockville, MD: Agency for Healthcare Research and Quality. September 2001.

60

Medications: Combination Therapy

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Medications: Combination Therapy

Blue Cross and Blue Shield Association Technology Evaluation Center. Management of Chronic Asthma:

Evidence Report/Technology Assessment Number 44. AHRQ Publication No. 01–EO44. Rockville, MD:

Agency for Healthcare Research and Quality. September 2001.

Busse W, Nelson H, Wolfe J, Kalberg C, Yancey SW, Rickard K. Comparison of inhaled salmeterol

and oral zafirlukast in patients with asthma. J Allergy Clin Immunol 1999;103(6):1075–80.

Davies B, Brooks G, Devoy M. The efficacy and safety of salmeterol compared to theophylline: 

meta-analysis of nine controlled studies. Respir Med 1998;92(2):256–63.

Eickelberg O, Roth M, Lorx R, Bruce V, Rudiger J, Johnson M, Block LH. Ligand-independent 

activation of the glucocorticoid receptor by beta2-adrenergic receptor agonists in primary human

lung fibroblasts and vascular smooth muscle cells. J Biol Chem 1999; Jan 8;274(2):1005–10.

Evans DJ, Taylor DA, Zetterstrom O, et al. A comparison of low-dose inhaled budesonide plus 

theophylline and high-dose inhaled budesonide for moderate asthma. N Engl J Med

1997;337(20):1412–8.

Fjellbirkeland L, Gulsvik A, Palmer JB. The efficacy and tolerability of inhaled salmeterol and 

individually dose-titrated, sustained-release theophylline in patients with reversible airways 

disease. Respir Med 1994;88(8):599–607.

Greening AP, Ind PW, Northfield M, Shaw G. Added salmeterol versus higher-dose corticosteroid in

asthma patients with symptoms on existing inhaled corticosteroid. Lancet 1994;344(8917):219–24.

Laviolette M, Malmstrom K, Lu S, Chervinsky P, Pujet JC, Peszek I, Zhang J, Reiss TF. Montelukast

added to inhaled beclomethasone in treatment of asthma. Montelukast/Beclomethasone Additivity

Group. Am J Respir Crit Care Med 1999;160(6):1862–8. 

Lazarus SC, Boushey HA, Fahy JV, Chinchilli VM, Lemanske Jr RF, Sorkness CA, Kraft M, Fish JE,

Peters SP, Craig T et al. Long-acting β2-agonist monotherapy vs. continued therapy with inhaled 

corticosteroids in patients with persistent asthma: a randomized controlled trial. JAMA

2001;285(20):2583–93.

Lemanske Jr RF, Sorkness CA, Mauger EA, Lazarus SC, Boushey HA, Fahy JV, Drazen JM, Chinchilli

VM, Craig T, Fish JE, et al. Inhaled corticosteroid reduction and elimination in patients with persistent asthma receiving salmeterol: a randomized controlled trial. JAMA 2001;285(20):2594–603.

Lim S, Jatakanon A, Gordon D, Macdonald C, Chung KF, Barnes PJ. Comparison of high dose

inhaled steroids, low dose inhaled steroids plus low dose theophylline, and low dose inhaled

steroids alone in chronic asthma in general practice. Thorax 2000;55(10):837–41.

Lofdahl CG, Reiss TF, Leff JA, Israel E, Noonan MJ, Finn AF, Seidenberg BC, Capizzi T, Kundu S,

Godard P. Randomised, placebo controlled trial of effect of a leukotriene receptor antagonist, 

montelukast, on tapering inhaled corticosteroids in asthmatic patients. BMJ 1999;319(7202):87–90.

McIvor RA, Pizzichini E, Turner MO, Hussack P, Hargreave FE, Sears MR. Potential masking effects

of salmeterol on airway inflammation in asthma. Am J Respir Crit Care Med 1998;158(3):924–30.

Meltzer EO, Orgel HA, Ellis EF, Eigen HN, Hemstreet MP. Long-term comparison of three combinations of albuterol, theophylline, and beclomethasone in children with chronic asthma. J Allergy

Clin Immunol 1992 Jul;90(1):2–11.

Muir JF, Bertin L, Georges D. French Multicentre Study Group. Salmeterol versus slow release 

theophylline combined with ketotifen in nocturnal asthma: a multicenter study. Eur Respir J

1992;5(10):1197–200.

Nassif EG, Weinberger M, Thompson R, Huntley W. The value of maintenance theophylline in

steroid-dependent asthma. N Engl J Med 1981; Jan 8;304(2):71–5.

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propionate/salmeterol combination provides more effective asthma control than low-dose inhaled 

corticosteroid plus montelukast. J Allergy Clin Immunol 2000;106(6):1088–95.

Paggiaro PL, Giannini D, Di Franco A, Testi R. European Study Group. Comparison of inhaled salmeterol and individually dose-titrated slow-release theophylline in patients with reversible airway

obstruction. Eur Respir J 1996;9(8):1689–95.

Pauwels RA, Lofdahl CG, Postma DS, Tattersfield AE, O’Byrne P, Barnes PJ, Ullman A. Formoterol

and Corticosteroids Establishing Therapy (FACET) International Study Group. Effect of inhaled 

formoterol and budesonide on exacerbations of asthma. N Engl J Med 1997;337(20):1405–11. 

Pierson WE, LaForce CF, Bell TD, MacCosbe PE, Sykes RS, Tinkelman D. Long-term, double-blind

comparison of controlled-release albuterol versus sustained-release theophylline in adolescents and

adults with asthma. J Allergy Clin Immunol 1990;85(3):618–26. 

Roberts JR, Desai HI, Gillespie CA, Simons FE. Sustained-release terbutaline vs. sustained-release

theophylline in young patients with asthma. Am J Dis Child 1986;140(7):650–54.

Russell G, Williams, DA, Weller P, Price JF. Salmeterol xinafoate in children on high dose inhaled

steroids. Ann Allergy Asthma Immunol 1995;75(5):423–8. 

Shrewsbury S, Pyke S, Britton M. Meta-analysis of increased dose of inhaled steroid or addition of 

salmeterol in symptomatic asthma (MIASMA). BMJ 2000;320(7246):1368–73. 

Simons FE, Villa JR, Lee BW, Teper AM, Lyttle B, Aristizabal G, Laessig W, Schuster A, Perez-Frias

et al. Montelukast added to budesonide in children with persistent asthma: a randomized, doubleblind, crossover study. J Pediatr 2001;138(5):694–8.

Sont JK, Willems LN, Bel EH, van Krieken JH, Vandenbroucke JP, Sterk PJ. The AMPUL Study Group.

Clinical control and histopathologic outcome of asthma when using airway hyperresponsiveness as an

additional guide to long-term treatment. Am J Respir Crit Care Med 1999;159(4 Pt 1):1043–51.

Ukena D, Harnest U, Sakalauskas R, Magyar P, Vetter N, Steffen H, Leichtl S, Rathgeb F, Keller A,

Steinijans VW. Comparison of addition of theophylline to inhaled steroid with doubling of the

dose of inhaled steroid in asthma. Eur Respir J 1997;10(12):2754–60.

Verberne AA, Frost C, Duiverman EJ, Grol MH, Kerrebijn KF. Addition of salmeterol versus doubling the dose of beclomethasone in children with asthma. The Dutch Asthma Study Group. 

Am J Respir Crit Care Med 1998;158(1):213–9.

Weinstein SF, Pearlman DS, Bronsky EA, Byrne A, Arledge T, Liddle R, Stahl E. Efficacy of salmeterol xinafoate powder in children with chronic persistent asthma. Ann Allergy Asthma Immunol

1998;81(1):51–8.

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Medications: Use of Antibiotics

Use of Antibiotics To Treat Asthma

Exacerbations

Question

Does routinely adding antibiotics to standard

care improve the outcomes of treatment for

acute exacerbation of asthma? Does the addition

of antibiotics to standard care in the following

populations improve the outcomes of treatment

for an acute exacerbation of asthma: patients

without signs and symptoms of bacterial infection; patients with signs and symptoms of a

bacterial infection; patients with signs and 

symptoms of sinusitis?

Summary Answer to the Question

The available evidence (two randomized, controlled

clinical trials) suggests no benefit from antibiotic

therapy for asthma exacerbations, whether administered routinely or when suspicion of bacterial

infection is low (SRE-Evidence B). No studies

addressed the question of greatest relevance to contemporary clinical practice: whether the addition 

of antibiotics to standard care when signs and 

symptoms suggest the possibility—but do not

clearly indicate the presence—of bacterial infection

improves the outcomes of treatment for acute

asthma exacerbations.

The EPR-2 recommendation has not been changed:

Antibiotics are not recommended for the treatment

of acute asthma exacerbations except as needed for

comorbid conditions—e.g., for the patients with

fever and purulent sputum, evidence of pneumonia,

or suspected bacterial sinusitis.

Rationale for the Question

Asthma exacerbations often are associated with 

clinical signs of infection, such as purulence of

expectorated sputum or nasal discharge. Most

asthma exacerbations are associated with infection 

by a respiratory virus, especially rhinovirus 

(Nicholson et al. 1993; Johnston et al. 1995), but a

small percentage of exacerbations are associated with

infection by an atypical bacterium, like Mycoplasma

pneumoniae or Chlamydia pneumoniae (Freymuth et al.

1999). It is widely believed that coincident bacterial sinusitis contributes to asthma exacerbations,

and some clinicians have postulated that airway

obstruction due to mucus plugging—common in

asthma—predisposes patients to bacterial infection

of nondraining regions of the lungs. 

In the absence of clear signs of bacterial infection

(e.g., lobar pulmonary infiltrate on chest radiography distinguishing viral from bacterial infections),

infection is often difficult to manage. Viral infections

commonly resemble bacterial infections in that they

also cause neutrophilic inflammation of the upper

and lower airways (Teran et al. 1997; Trigg et al.

1996; Fahy et al. 1995). This difficulty, coupled

even with the remote possibility that bacterial 

infection may be associated with an asthma exacerbation, may account for the frequency with which

antibiotics are prescribed in addition to inhaled

bronchodilators, inhaled or systemic corticosteroids,

and supplemental oxygen.

Systematic Review of the Evidence

The following description of the SRE is an adaptation of the evidence report, including direct

excerpts, submitted by the Blue Cross Blue 

Shield Association Evidence-Based Practice Center.

(See Introduction, Methods.)

❙ Methods of Literature Search

In addition to the selection criteria for studies

related to all topics in the SRE (described in the

Introduction section), studies for this question were

included in which standard care (asthma medications)

plus antibiotics was compared with standard care

alone in the treatment of acute asthma exacerbations.

Patient populations included patients without signs

and symptoms of bacterial infection, patients with

signs and symptoms of bacterial infection, and

patients with signs and symptoms of sinusitis.

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Medications: Use of Antibiotics

❙ Summary of Findings

Studies

Only two randomized, double-blind, placebocontrolled, parallel-group trials—with a total enrollment of 121 patients—have addressed the question

of whether routinely adding antibiotics to standard

care improves the outcomes of treatment for acute

asthma exacerbations (Shapiro et al. 1974; Graham

et al. 1982). (See the key evidence tables in this 

section.) Both trials studied patients hospitalized 

for asthma exacerbations. Both used a penicillin

derivative whose activity against atypical bacteria

was unknown. Shapiro and colleagues examined the

effects of hetacillin (an analogue of ampicillin; 100

mg/kg every 24 hours for a minimum of 24 hours,

then 225 mg four times per day for 6 days) in 50

children who did not exhibit clinical evidence of

bacterial infection. Graham and colleagues examined

the effects of amoxicillin (500 mg three times per

day) in 60 adults and adolescents who experienced 

a total of 71 hospital admissions. Whereas the pediatric study explicitly excluded patients with clinical

evidence of bacterial infection, the study of adults

and adolescents excluded only patients with evidence

of pneumonia on chest radiography. Thus, the 

populations in these studies consisted primarily of

patients without signs or symptoms of bacterial

illness, including suspected acute sinusitis.

In both trials, all patients received standard care

that included high-dose oral or intravenous corticosteroids and regularly scheduled beta2-agonist

treatment. In the pediatric study, all patients 

were also treated with intravenous aminophylline

followed by oral theophylline. 

The study design and conduct for these two trials did

not meet the SRE criteria for higher quality because

of deficiencies in allocation concealment, subject

withdrawal, and reporting of power calculations.

The outcomes analyzed included change in FEV1,

symptom scores, and length of hospital stay.

❙ Results of Studies

Neither study reported an association—nor a trend

towards an association—between antibiotic treatment

and greater improvement in any asthma outcome.

Therefore, available evidence suggests no benefit

from the use of antibiotic treatment for asthma exacerbations either routinely or when the suspicion of

bacterial infection is minimal. (See key evidence

tables 1–11 and 1–12.)

Additional Literature/Information

A related question, for which clinical trials data are

unavailable, should ask whether the use of an antibiotic active against Mycoplasma and Chlamydia would

alter outcomes. Some recent studies using polymerase

chain reaction (PCR)-based methods for detecting

specific genomic sequences have suggested that

chronic infection with these organisms may contribute to the severity of chronic asthma (Kraft et al.

1998). These highly sensitive methods have not yet

been applied to the analysis of airway tissue or 

secretions obtained from patients suffering acute 

exacerbations. Thus, there is a theoretical basis for the

concept that a subgroup of patients with asthma 

exacerbations may benefit from treatment with an

antibiotic that is active against these atypical bacteria.

The EPR-2 statement that “the use of antibiotics is

generally reserved for patients with fever and purulent

sputum (discolored because of polymorphonuclear

leukocytes, not eosinophils)” comes under scrutiny

because low-grade fever also may accompany viral 

respiratory infections. Furthermore, a recent study

shows that discoloration of sputum by polymorphonuclear leukocytes is observed in viral

tracheobronchitis, and the sputum from patients

suffering from uncomplicated asthma exacerbations commonly contains high numbers of

polymorphonuclear leukocytes (Fahy et al. 1995).

Recommendations for EPR Update

No evidence supports changing the EPR-2 recommendation (SRE-Evidence B). The parenthetical

statement on page 116 of EPR-2 [“(discolored

because of polymorphonuclear leukocytes, not

eosinophils)”] should be removed (Evidence C). 

The recommendation can otherwise stand and 

is as follows:

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Medications: Use of Antibiotics

Antibiotics are not recommended for the

treatment of acute asthma exacerbations

except as needed for comorbid conditions.

Bacterial, Chlamydia, or Mycoplasma infections infrequently contribute to exacerbations

of asthma and therefore the use of antibiotics

is generally reserved for patients with fever

and purulent sputum and for patients with

evidence of pneumonia. When the presence 

of bacterial sinusitis is suspected, treat with

antibiotics.

Recommendations for Future Research

No studies addressed the question of greatest 

relevance to contemporary clinical practice—

whether the addition of antibiotics to standard care

when signs and symptoms suggest the possibility

but do not clearly indicate the presence of bacterial

infection improves the outcomes of treatment for

acute asthma exacerbations. The two trials reviewed

excluded the patients most likely to be treated with

antibiotics and those with signs or symptoms 

suggestive of bacterial infection, including suspected

acute sinusitis. Studies of the efficacy of antibiotic

treatment in this group are needed.

Several studies are needed to clarify the role of

antibiotics in the treatment of asthma exacerbations.

Questions for research are as follows:

■ What is the efficacy of antibiotic treatment in

asthma patients most likely to be treated with

antibiotics, such as those with signs suggestive 

of bacterial infection, including suspected acute

sinusitis? The role of sinusitis in acute exacerbations of asthma has not been truly defined.

■ What is the role of sinusitis in acute exacerbations of asthma or increased asthma severity?

■ What is the efficacy of using an antibiotic active

against atypical bacteria, given the possibility

that such bacteria commonly contribute to

asthma exacerbations?

■ What would be the value of studies applying

modern sensitive methods of detection of atypical

bacteria (e.g., PCR-based methods) to samples of

airway tissues or secretions obtained at the time

of an asthma exacerbation?

■ Do antibiotics such as macrolides have a nonantibiotic action (e.g., anti-inflammatory) that is

beneficial in asthma patients?

Archive

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66

Medications: Use of Antibiotics

Key Evidence Tables

Graham, Milton,

Knowles et al. 1982

Shapiro, Eggleston,

Pierson et al. 1974 

Randomized, 

double-blind, 

placebo-controlled, 

parallel group trial 

Randomized, 

double-blind, 

placebo-controlled, 

parallel group trial 

Country: 

United Kingdom

Funding: 

Government grant

Tx setting: 

University Hospital,

inpatient setting 

Country: 

United States

Funding: 

Pharm Industry and

Government grant

Tx setting: 

Hospital, inpatient 

setting 

Stated: Not specified

Estimated: Unable to

estimate 

Stated: Not specified

Estimated: 

Unable to estimate 

Eligibility assessed 

on admission to 

hospital with asthma

exacerbation:

• FEV1 of 1.5L or less

and/or PEF of 150

l/min

• Reversibility of FEV1

at least 15% spontaneously or after

inhalation of beta2-

agonist

Exclusions: Evidence of

pneumonia on CXR,

history of penicillin

allergy 

Eligibility assessed 

on admission to 

hospital with asthma

exacerbation:

• Severe bronchospasm,

lack of response 

to subcutaneous 

epinephrine

Exclusions: Clinical

evidence of bacterial

infection; recent use of

antibiotics 

Table 1-9. Study Characteristics

Citation Study Design Study Setting Asthma Severity Eligibility

Source:

Blue Cross and Blue Shield Association Technology Evaluation Center. Management of Chronic Asthma: Evidence Report/Technology Assessment Number

44. AHRQ Publication No. 01–EO44. Rockville, MD: Agency for Healthcare Research and Quality. September 2001.

Archive

for historical Reference Only
67

Medications: Use of Antibiotics

Graham, Milton,

Knowles et al.

1982 

Shapiro,

Eggleston,

Pierson et al.

1974 

Placebo 

Antibiotics 

Placebo 

Antibiotics 

Placebo tablet 3 times per day

Oral prednisolone (20–60 mg/day) and/or 

IV hydrocortisone (100–200 mg every 4 to 

6 hours)

Regularly scheduled beta2-agonists and/or

phosphodiesterase inhibitors

Chest physiotherapy 

Amoxicillin 500 mg 3 times per day

Oral prednisolone (20–60 mg/day) and/or 

IV hydrocortisone (100–200 mg every 4 to 

6 hours)

Regularly scheduled beta2-agonists and/or

phosphodiesterase inhibitors

Chest physiotherapy

Placebo 4 times per day for 6 days

IV hydrocortisone (7 mg/kg/24 hr) for 24

hours, followed by oral prednisone

IV aminophylline (15 mg/kg/24 hr) for 24

hours, followed by oral theophylline

Nebulized beta2-agonists q30 min x 4, 

then as needed 

Hetacillin (100 mg/kg/24 hr) for at least 24

hours, followed by oral hetacillin 225 mg 

4 times per day for 6 days

IV hydrocortisone (7 mg/kg/24 hr) for 24

hours, followed by oral prednisone

IV aminophylline (15 mg/kg/24 hr) for 24

hours, followed by oral theophylline

Nebulized beta2-agonists q30 min x 4, 

then as needed 

60 patients enrolled with 71 exacerbations.

Unit of analysis by exacerbations. 

Culture-proven bacterial source of infection

found in two patients on admission and two

patients on discharge 

37 patients enrolled with 44 exacerbations,

unit of analysis by exacerbation

Table 1–10. Study Parameters

Source:

Blue Cross and Blue Shield Association Technology Evaluation Center. Management of Chronic Asthma: Evidence Report/Technology Assessment Number

44. AHRQ Publication No. 01–EO44. Rockville, MD: Agency for Healthcare Research and Quality. September 2001.

Citation Study Arm Treatment Comments Archive

for historical Reference Only
68

Medications: Use of Antibiotics

Key Evidence Tables

Graham, Milton, Placebo 71* 32* 8 20.9

Knowles (3–16) (<7.3–63)

et al. 1982

Antibiotics 71* 37* 7 23.1

(3–25) (<7.3–45.5)

Shapiro, Placebo 50* 24* 2.9 26.5

Eggleston, (SD 1.4) (SD 15)

Pierson et al.1974

Antibiotics 50* 20* 2.5 28.3

(SD 0.8) (SD 11)

Table 1-11. Lung Function Outcome

Citation Study Arm Number Number Study Duration (days) FEV1 Baseline

Enrolled Evaluable (median/range) (mean)

Graham, Milton, Knowles Placebo 34 32 8

et al. 1982 (3–16)

Antibiotics 37 37 7

(3–25)

Shapiro, Eggleston, Pierson Placebo 24 24 2.9

et al. 1974 (SD 1.4)

Antibiotics 20 20 2.5

(SD 0.8)

Table 1-12. Symptoms/Utilization Outcomes

Citation Study Arm Number Enrolled Number Evaluable Study Duration (days)

(median/range)

Archive

for historical Reference Only
11 4 8

(6–12) (4–8) (3–16)

11 5 NS 7 NS

(5–12) (4–9) (3–25)

7.1 (mean) 2.5 2.9

(SD 2.2) (SD 2.0) (SD 1.4)

7.1 (mean) 2.0 NR 2.4

(SD 1.8) (SD 2.0) (SD 0.8)

Baseline Symptom Score Final Symptom Score P-Value Hospital Length of Stay P-Value

(median/range) (median/range)

Source:

Blue Cross and Blue Shield Association Technology Evaluation Center. Management of Chronic Asthma: Evidence Report/Technology Assessment Number 44.

AHRQ Publication No. 01–EO44. Rockville, MD: Agency for Healthcare Research and Quality. September 2001.

69

Medications: Use of Antibiotics

FEV1 Final (mean) P-Value PEF Baseline (mean/range) PEF Final (mean/range) P-Value

*Unit of analysis was admission. Number enrolled represented total admissions in both groups, information not provided by group. Number evaluated 

represents total number of admissions included in analysis.

Source:

Blue Cross and Blue Shield Association Technology Evaluation Center. Management of Chronic Asthma: Evidence Report/Technology Assessment Number

44. AHRQ Publication No. 01–EO44. Rockville, MD: Agency for Healthcare Research and Quality. September 2001.

65.6 23.8 72.8

(31.5–108.5) (<9.4–83.9) (32.8–108.1)

52.3 0.039 23.8 59 0.052

(10–92.9) (<9.4–47.3) (16.7–95)

49 NR NR

(SD 17)

61 NR NR NR

(SD 19)

Archive

for historical Reference Only
Blue Cross and Blue Shield Association Technology Evaluation Center. Management of Chronic Asthma:

Evidence Report/Technology Assessment Number 44. AHRQ Publication No. 01–EO44. Rockville, MD:

Agency for Healthcare Research and Quality. September 2001.

Fahy JV, Jim KW, Liu J, Boushey HA. Prominent neutrophilic inflammation in sputum from subjects

with asthma exacerbation. J Allergy Clin Immunol 1995;95(4):843–52.

Freymuth F, Vabret A, Brouard J, Toutain F, Verdon R, Petijean J, Gouarin S, Duhamel JF, Guillois

B. Detection of viral, Chlamydia pneumoniae and Mycoplasma pneumoniae infections in exacerbations of asthma in children. J Clin Virol 1999;13(3):131–9.

Graham VA, Milton AF, Knowles GK, Davies RJ. Routine antibiotics in hospital management of

acute asthma. Lancet 1982;1(8269):418–420.

Johnston SL, Pattemore PK, Sanderson G, Smith S, Lampe F, Josephs L, Symington P, O’Toole S,

Myint SH, Tyrell DA, et al. Community study of role of viral infections in exacerbations of asthma

in 9-11 year old children. BMJ 1995;310(6989):1225–9.

Kraft M, Cassell GH, Henson JE, Watson H, Williamson J, Marmion BP, Gaydos CA, Martin RJ.

Detection of Mycoplasma pneumoniae in the airways of adults with chronic asthma. Am J Respir

Crit Care Med 1998;58(3):998–1001.

Labro MT. Anti-inflammatory activity of macrolides: a new therapeutic potential? J Antimicrob

Chemother 1998;41(Suppl B):37–46.

Nicholson K, Kent J, Ireland D. Respiratory viruses and exacerbations of asthma in adults. Br Med J

1993;307:982–6.

Shapiro GG, Eggleston PA, Pierson WE, Ray CG, Bierman CW. Double-blind study of the effectiveness of a broad spectrum antibiotic in status asthmaticus. Pediatrics 1974;53(6):867–72.

Teran LM, Johnston SL, Schroder JM, Church MK, Holgate ST. Role of nasal interleukin-8 in 

neutrophil recruitment and activation in children with virus-induced asthma. Am J Respir Crit Care

Med 1997;155(4):1362–6.

Trigg CJ, Nicholson KG, Wang JH, Ireland DC, Jordan S, Duddle JM, Hamilton S, Davies RJ.

Bronchial inflammation and the common cold: a comparison of atopic and non-atopic individuals.

Clin Exp Allergy 1996;26(6):665–76.

References

70

Medications: Use of Antibiotics

Archive

for historical Reference Only
2. Monitoring

Asthma Expert Panel Report:

Guidelines for the

Diagnosis and

Management of

Asthma

Archive

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Archive

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73

Monitoring: Written Action Plans

Two distinct questions have been raised

regarding the use of written action plans

in the management of asthma. First, does

the use of written action plans make a difference in patient outcomes beyond those

accomplished by appropriate medical/

pharmacologic management? Second, 

is there a difference in patient outcomes

between action plans based on symptom

monitoring and those based on peak flow

monitoring? This section of the EPR

Update considers both questions.

Written Action Plans Compared

to Medical Management Alone

Question

Compared to medical management

alone, does the use of a written asthma

action plan improve outcomes?

Summary Answer to the Question

Data are insufficient to support or refute

the benefits of using written asthma action

plans compared to medical management

alone (SRE-Evidence B). Seven studies

compared medical management with

written action plans to medical management without action plans. Beyond

including instructions on the action plan 

to the intervention groups, four of these

studies did not include asthma education

for either the intervention or control

groups; three of the studies included similar

but limited asthma education for both

intervention and control groups. Only one

study included children. Significant limitations in study designs and methods in

these studies preclude conclusions. For

example, the studies showing no benefits of

written action plans did not have sufficient

power for comparisons between treatment

and control groups, and the two studies

reporting significant improvements with

action plans had potential biases in patient

selection, withdrawals, data collection, 

or analysis.

However, a Cochrane review of 25 studies

comparing asthma self-management education interventions for adults to medical

care without such education also contrasted

those studies with self-management

interventions that included written action

plans to those that did not. The selfmanagement interventions that included

written action plans had the greatest 

benefits, including reduced emergency

department visits and hospitalizations 

and improved lung function.

The EPR-2 recommendations have not

been changed: It is the opinion of the

Expert Panel that use of written action

plans as part of an overall effort to educate

patients in self-management is recommended, especially for patients with

moderate or severe persistent asthma and

patients with a history of severe exacerbations (Evidence B, C).

Rationale for the Question

The use of written action plans is recommended in the EPR-2 and is widely

accepted as good practice. Generally, 

the use of written action plans has been

studied as part of self-management 

education (Gibson et al. 2000). In busy

practices, however, physicians often 

provide their patients with action plans

independent of other asthma education

efforts. This question was posed in order

to identify data that describe the effects of

using written action plans, independent 

of other components of asthma education.

2. Monitoring

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74

Monitoring: Written Action Plans

Systematic Review of the Evidence

The following description of the SRE is an adaptation of the evidence report, including direct excerpts,

submitted by the Blue Cross Blue Shield Association

Evidence-Based Practice Center. (See Introduction,

Methods.)

❙ Methods of Literature Search

For the purpose of the SRE, an action plan is a

written algorithm that identifies specific clinical

indicators that should alert patients to make

adjustments in their medications and provides 

specific instructions on how to make these adjustments. EPR-2 recommends the use of both a daily

self-management plan and an action plan for exacerbations. Generally, studies included in the SRE

involved the use of one plan that combined the

objectives of both. Typically, the plans divided steps

for patient actions into different zones, in which 

recommended actions are correlated with differing

acute signs and symptoms of worsening asthma.

Most of the plans in the available studies used 

four-zone plans, some were three-zone plans that did

not include directions for use of oral corticosteroids

before seeking emergency care.

The evidence review examined studies in which the

intervention used an action plan as defined above

and, if asthma education was given to both treatment

and control groups, the treatment group had no

more than 1 additional hour of education for the

action plan. The treatment/observation duration was

at least 12 weeks, and the intervention and control

groups received the same treatment, except that the

intervention group also received a written action

plan. Studies were excluded if the comparisons were

confounded by additional treatment components in

the intervention group—for example, optimization

of medications in the intervention group only or

education programs of more than 1 hour in the

intervention group only. The literature review

included randomized controlled trials (RCTs) in

which at least 25 evaluable patients (not physicians)

were randomly allocated to the intervention and

control groups.

❙ Summary of Findings

Studies

Seven studies involving more than 1,400 patients

met SRE inclusion criteria for review; only one of

the studies included children. (See the key evidence

tables in this section.) None of the studies met SRE

standards for high quality; each had significant limitations. None was conducted with sufficient power

(i.e., adequate numbers of subjects in each study

arm) to enable comparisons between treatment and

control groups. In one study reporting reduced

emergency department visits, data were unavailable

to control for baseline differences that may have

existed between treatment and control groups, and

the reported effect may be attributed to a subset of

high frequency users. In another study, the design

involved clinicians who both provided plans and 

collected assessment data. Moreover, a large number

of subjects were excluded from the analyses.

All seven studies compared medical management

with written action plans to medical management

without written action plans, and all used a peak

flow meter-based plan. Three of the studies also

included similar but limited asthma education for

both the intervention and control groups, but the

groups still differed as to whether written plans were

used. In two trials, the control group used peak flow

meters but without an action plan.

Results of Studies

Five trials documented no differences in outcomes,

and two trials documented significant benefit of

written action plans, especially in reducing emergency department visits. However, there were notable

limitations to each of these trials, as described earlier.

In summary, SRE study data were insufficient to

support or to refute the advantages of using asthma

action plans independent of self-management 

education when compared with medical 

management alone.

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75

Monitoring: Written Action Plans

Additional Literature/Information

Evidence supporting the use of written plans as a

component of self-management education is reported

in a recent Cochrane Collaboration review (Gibson et

al. 2000). The SRE question on action plans provides

a clearer assessment of isolating the advantages of

providing an action plan. The Cochrane review 

centered on the benefits of self-management 

interventions and regular medical review with the

clinician vs. usual medical care. The Cochrane review,

however, also contrasted those self-management

interventions with written action plans to those

without written action plans. The review included

some of the same studies included in the SRE but

overcame the limitations of study sample sizes by

pooling data. Further, the set of 25 studies in the

Cochrane review was larger than the 7 in the SRE

due to the broader question under review. 

In the Cochrane analysis that compared results of

self-management interventions with action plans to

those without, the interventions with written action

plans demonstrated the greatest benefits, including

reduced asthma-related hospital admissions (odds

ratio 0.35, 95 percent confidence interval) and

reduced emergency department visits (odds ratio

0.55, 95 percent confidence interval). In addition,

patients who managed their asthma by adjusting

medications according to a written action plan had

better lung function than those whose medications

were adjusted by a doctor during regular care visits.

The review concluded that training in asthma selfmanagement that involves self-monitoring by either

peak flow or symptoms, coupled with regular 

medical review and a written action plan, appears 

to improve health outcomes for adults with asthma.

Additional evidence supporting written action plans

coupled with regular patient education and medical

review is available from a recent case control study

(Abramson et al. 2001). This study does not fit the

SRE review criteria because studies that qualified 

for this review were required to be RCTs allowing

inferences of cause and effect, and they were required 

to provide an action plan independent of a multicomponent intervention including education. Although the

Abramson study is not an RCT, it is a well-conducted

study that compared 51 patients who died from asthma

to 202 patients presenting to hospitals with acute

asthma. The study reported that written action plans

for patients with severe persistent asthma were 

associated with a 70 percent reduction in mortality

risk. As such, the study supports the opinion that

providing written action plans as part of asthma 

education is an important element of practice. 

Recommendations for EPR Update

No data from the SRE, in which RCTs compared

written action plans to medical management

alone, indicate the need to change the EPR-2

action plan recommendations (SRE-Evidence B).

Additional data from studies on action plans as 

a part of self-management education support 

the EPR-2 recommendations (Evidence B, C). 

The following blue text indicates revisions that

should be incorporated into the text on pages 33

and 123 in EPR-2.

Component 1: Measures of Assessment and

Monitoring; Periodic Assessment and

Monitoring (page 33 in EPR-2)

Whether peak flow monitoring, symptom monitoring, or a combination of approaches is used, the

Expert Panel believes that self-monitoring is important to the effective self-management of asthma. 

The nature and intensity of self-monitoring should

be individualized, based on such factors as asthma

severity, patient’s ability to perceive airflow obstruction, availability of peak flow meters, and patient

preferences.

It is the opinion of the Expert Panel that,

regardless of the type of monitoring used,

patients should be given a written action plan

and instructed to use it. (See figure 4–5.) It is

the opinion of the Expert Panel that including

action plans as part of an overall effort to educate patients in self-management is the soundest

approach and is especially indicated for patients

with moderate or severe persistent disease or a

history of severe exacerbations (Evidence B, C).

It is the opinion of the Expert Panel that a plan is

important in large part because it enhances clinicianpatient communication. The plan should define a

regimen that meets the medical needs of the patient

Archive

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76

Monitoring: Written Action Plans

and should have a format that facilitates the patient’s

understanding and ability to take appropriate action

to control the disease. Regardless of format, an effective plan should include the following:

■ Explicit, patient-specific recommendations for

environmental control and other preventive

efforts that may be necessary to avoid or reduce

the impact of exacerbations

■ An algorithm of procedures that clearly describes

how to use long-term-control and rescue medicines, given a set of specific circumstances and

conditions, and clear instructions on how to make

medicine adjustments when conditions change

■ Steps the patient should take when medicines are

ineffective or if an emergency situation arises

■ Contacts for securing urgent care, if needed

As emphasized above, it is the opinion of the Expert

Panel that a written action plan is considered part of

ongoing efforts to provide self-management education

and support appropriate to the severity of the

patient’s asthma, the patient’s age, and related 

circumstances (Evidence B, C). The clinician should

periodically review the plan, revise it as necessary,

and confirm that the patient knows what to do if his

or her asthma gets worse.

Component 4: Education for a Partnership in

Asthma Care, Key Points (page 123 in EPR-2)

■ Patient education should begin at the time of

diagnosis and be integrated into every step of

clinical asthma care.

■ It is essential that education be provided by all

members of the health care team. The principal

clinician should introduce the key educational

messages and negotiate agreements with patients;

these messages should be reinforced and expanded

by all members of the health care team.

■ Teach asthma self-management, tailoring the

approach to the needs of each patient. Maintain 

a sensitivity to cultural beliefs and practices.

■ Teach and reinforce at every opportunity:

• Basic facts about asthma

• Roles of medications

• Skills: inhaler/spacer/holding chamber use,

self-monitoring

• Environmental control measures

• When and how to take rescue actions.

■ Jointly develop treatment goals.

■ To encourage an active partnership, provide all

patients with a written daily self-management

plan and an action plan for exacerbations. 

A written action plan is considered part of

ongoing efforts to provide self-management 

education and support appropriate to the severity

of the patient’s asthma, the patient’s age, and

related circumstances (Evidence B, C). Action

plans are especially important for patients with

moderate-to-severe asthma and patients with a

history of severe exacerbations. Provide appropriate patients with a daily asthma diary.

■ Encourage adherence by promoting open 

communication; individualizing, reviewing, and

adjusting plans as needed; emphasizing goals and

outcomes; and encouraging family involvement.

Recommendations for Future Research

Research that may enhance the quality and effect 

of interventions fostering patient self-management

would examine the following questions:

■ Are some action plan formats more effective

than others? What characterizes the most 

effective format?

■ What alternative action plan formats are effective, given specific patient needs, including

disease severity, literacy levels, languages spoken,

ages, and unique management problems (e.g.,

comorbidities)?

■ How much time and emphasis should be given 

to the development of action plans during the

course of clinical counseling? In comprehensive

education programs? In medical review?

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Monitoring: Written Action Plans

■ What are potential means of providing selfmanagement interventions that include action

planning to patients who are members of underserved populations (e.g., reaching them through

worksites, community centers, or churches)?

■ How effective are written action plans in treating

children with asthma?

■ How effective are written action plans in 

different caretaker situations (e.g., daycare, A

camps, or school)?

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78

Monitoring: Written Action Plans

Key Evidence Tables

Jones, Mullee, Middleton et al. 1995

Drummond, Abdalla, Beattie et al. 1994

(GRASSIC) 

Ayres, Campbell, Follows 1995

Cowie, Revitt, Underwood et al. 1997 

Cote, Cartier, Robichaud et al. 1997 

Ignacio-Garcia and Gonzalez-Santos 1995 

Charlton, Antoniou, Atkinson et al. 1994 

Randomized; parallel, controlled 

Randomized; parallel, controlled 

Randomized; parallel, controlled 

Randomized; parallel, controlled 

Randomized; parallel, controlled 

Randomized; parallel, controlled 

Randomized; parallel, controlled 

Country: United Kingdom 

Funding: Pharm. ind. grant 

Tx Setting: Primary/specialty 

combination, university 

Multicenter 

Country: United Kingdom 

Funding: Academic grant 

Tx Setting: Specialty care, nonuniversity 

Multicenter 

Country: United Kingdom 

Funding: Pharm. ind. grant 

Tx Setting: Unknown 

Multicenter 

Country: Canada 

Funding: Hospital 

Tx Setting: Primary/specialty 

combination, university

Multicenter 

Country: Canada

Funding: Pharm. ind. grant

Tx Setting: Specialty care, nonuniversity

Multicenter 

Country: Spain

Funding: Not specified

Tx Setting: Specialty care, nonuniversity 

Country: Australia

Funding: Pharm. ind. and government

and university funding

Tx Setting: Specialty care, nonuniversity 

Table 2-1. Study Characteristics

Citation Study Design Study Setting

Optimal medical management vs. optimal medical management + peak flow meter (PFM)-based action plan

Optimal medical management + (PFM) use (without action plan) vs. optimal medical management + PFM-based action plan

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Monitoring: Written Action Plans

Patient eligibility based on symptoms only

Included patients using inhaled corticosteroids <1,000 mcg per

day for at least 1 month

Exclusions: Patients on oral steroids or using peak flow meters 

at home 

Patient eligibility based on lung function and utilization

Inclusion: FEV1 reversibility 20% or greater

Exclusion: Patients who already owned a PFM 

Patient eligibility based on lung function, symptoms, utilization

Inclusions: PEF variability maximum 0.15%; nights/week with

symptoms minimum 3; use of inhaled corticosteroids or sodium

cromoglycate for a minimum of 3 months 

Patient eligibility based on symptoms and utilization

Inclusions: Treatment for an exacerbation of asthma in an ER or

attending a university asthma clinic; history of receiving urgent

treatment for asthma in the previous 12 months 

Patient eligibility based on lung function and symptoms

FEV1 postbronchodilator 85–100% of predicted 

PEF minimum 85% of predicted; PEF variability minimum 0%;

Methacholine

Exclusion: Patients having previously taken part in an asthma

educational program 

Patient eligibility based on utilization only

Inclusion: Patients from outpatient asthma clinic with asthma for

2 years 

Patient eligibility based on utilization only

Inclusion: Patients who required admission for asthma or attended

the outpatient department

Power based on several outcomes (FEV needed 23 patients, sixfold

reduction in night wakening needed 21 per group, eightfold reduction in days off work or school needed 37 per group).

2-week course of oral steroids given before randomization to 

optimize lung function.

Power based on the 569 randomized, but n varies for each outcome

and in some cases is not specified as to exact n, just that n was

> = 250; may not be powered for all outcomes.

Patients included had less severe asthma on entry than those who

already owned a PFM and were excluded, especially with regard to

social and physical functioning. 

Doctor also graded the overall and individual severity of symptoms

as 0 = none and 3 = severe. 

Subjects were recruited by contacting those who had been treated

for an exacerbation of asthma in an emergency room or those

attending a university asthma clinic who had a history of having

received urgent treatment for their asthma in the previous 12

months. 

In discussion “although the control group received more than the

usual care treatment, none received book, none had written action

plan; none had structured education or PFM at home after run-in.” 

Run-in = 2–6 wks.; diagnosis of asthma included need to take daily

anti-inflammatory agents; were excluded. 

One doctor aware of the group assignment was responsible for

assessment of all patients’ condition, but the paper also says “in control group, the doctor assessing the patient was blinded with regard

to registers of peak flow monitoring until end of study”, random

allocation by order of recruitment.

Randomization was based on age, sex, whether they used asthma

prophylaxis before study. 

Eligibility Comments

Source:

Blue Cross and Blue Shield Association Technology Evaluation Center. Management of Chronic Asthma: Evidence Report/Technology Assessment Number

44. AHRQ Publication No. 01–EO44. Rockville, MD: Agency for Healthcare Research and Quality. September 2001.

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80

Monitoring: Written Action Plans

Jones, Mullee, Middleton 

et al. 1995 

Drummond, Abdalla, Beattie 

et al. 1994

(GRASSIC) 

Ayres, Campbell, Follows 1995 

Cowie, Revitt, Underwood 

et al. 1997 

Cote, Cartier, Robichaud 

et al. 1997 

Ignacio-Garcia and GonzalezSanto 1995 

Charlton, Antoniou, Atkinson 

et al. 1994 

Usual care 

PFM-based action

plan 

Usual care 

PFM-based action

plan 

Usual care 

PFM-based action

plan 

Usual care 

PFM-based action

plan 

Usual care 

PFM-based action

plan 

Usual care + PFM use

Usual care + PFMbased action plan

Usual care + PFM use

Usual care + PFMbased action plan

64

63

284

285

64

61

48

46

54

50

44

50

43

48

39

33

260

250

64

31

35

35

26

26

52

52

24

24

28

28

Table 2-2. Lung Function Outcomes: FEV1

Citation Study Arm Number Enrolled Number Evaluable Treatment Duration

(weeks)

Usual care vs. peak flow meter (PFM)-based action plan

Usual care + PFM use alone vs. usual care + PFM-based action plan

Archive

for historical Reference Only
81

Monitoring: Written Action Plans

Baseline FEV1* Final FEV1 P-Value P-Value Comparison Comments

85.4 +/- 17.5 % of predicted 

87.1 +/- 16.9 % of predicted 

78.1 % of predicted 

77.3 % of predicted 

2 +/- 0.1 L (type predose) 

2.3 +/- 0.1 L (type predose) 

78 +/- 21.3 % of predicted 

82 +/- 20.5 % of predicted 

65.34 +/- 16.6 % of predicted

(type predose) 

69.03 +/- 24.0 % of predicted

(type predose) 

81.2 +/- 18.3 % of predicted 

83.2 +/- 18 % of predicted 

75.4 +/- 27.7 % of predicted 

74.6 +/- 27.8 % of predicted 

2.2 +/- 0.1 L (type predose) 

2.3 +/- 0.2 L (type predose) 

65.48 +/- 24.7 % of predicted 

80.45 +/- 23.3 % of predicted 

NS

NS

NS

<0.0040

Absolute value, 

Tx vs. Ctl

Change, Tx vs. Ctl

Absolute value, 

Tx vs. Ctl

Absolute value, 

Tx vs. Ctl

95% CI for baseline

FEV is 74.8-81.4. 

95% CI for baseline

FEV is 74.1-80.5. 

Unclear number of

patients analyzed on

each end point. 

Unclear number of

patients analyzed on

each end point. 

Number of subjects

with <60% predicted

was 10. 

Number of subjects

with <60% predicted

was 9. 

Source:

Blue Cross and Blue Shield Association Technology Evaluation Center. Management of Chronic Asthma: Evidence Report/Technology Assessment Number

44. AHRQ Publication No. 01–EO44. Rockville, MD: Agency for Healthcare Research and Quality. September 2001.

Archive

for historical Reference Only
Jones, Mullee,

Middleton et al. 1995 

Drummond, Abdalla,

Beattie et al. 1994

(GRASSIC) 

Ayres, Campbell,

Follows 1995 

Cowie, Revitt,

Underwood et al.

1997 

Cote, Cartier,

Robichaud et al. 1997 

Ignacio-Garcia and

Gonzalez-Santos 1995 

Charlton, Antoniou,

Atkinson et al. 1994 

82

Monitoring: Written Action Plans

Usual care 

PFM-based

action plan 

Usual care 

PFM-based

action plan 

Usual care 

PFM-based

action plan 

Usual care 

PFM-based

action plan 

Usual care 

PFM-based

action plan 

Usual care +

PFM use

Usual care +

PFM-based

action plan 

Usual care +

PFM use

Usual care +

PFM-based

action plan 

64

63

284

285

64

61

48

46

54

50

44

50

43

48

45

39

67

54

64

61

48

46

35

35

37

42

26

26

52

52

24

24

24

24

28

28

52

52

1.91 +/- 0.6

(scale, 0-3)

1.77 +/- 0.6

(scale, 0-3)

4.95 (median;

scale, 0-3)

2.85 (median;

scale, 0-3)

1.39 +/- 1.11,

(scale 0-3)

1.38 +/- 0.12

(scale, 0-3)

0.22 (median;

scale, 0-3)

0.26 (median;

scale, 0-3)

Table 2-3. Symptom Score Outcomes

Citation Study Arm Number Number Treatment Duration Baseline Daytime Final Daytime

Enrolled Evaluable (weeks) Symptom Score Symptom Score

Usual care vs. peak flow meter (PFM)-based action plan

Usual care + PFM use alone vs. usual care + PFM-based action plan

Archive

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83

Monitoring: Written Action Plans

NS1

NS1

NS1

NS1

NS1

0.75 (median;

scale, 0-3)

0.35 (median;

scale, 0-3)

0.69 +/- 0.13,

(scale 0-3)

0.67 +/- 0.14

(scale, 0-3)

0.25 (median;

scale, 0-3)

0.15 (median;

scale, 0-3)

Symptom score across study was divided by number of days w/diary data X 28 to give a

monthly rate; sx score day = cough; sx score night = wakening at night; median wheeze =

5.46; shortness of breath = 7.88; asthma restricting normal daily activities = 0.0

Symptom score across study was divided by number of days w/diary data X 28 to give a

monthly rate; sx score day = cough; sx score night = wakenings at night; median wheeze

= 4.39; shortness of breath = 6.50; asthma restricting normal daily activities = 0.17. 

Night and day sx score outcome is only from a subgroup of patients reporting variation in

outcome; 112/246 never reported sleep disturbances; 15/246 reported that their sleep was

disturbed every night. 

Night and day outcome is only from a subgroup of patients reporting variation in outcome, controlled for peak flow, FEV1, duration of asthma; 114/239 never reported sleep

disturbances; 14/239 reported that their sleep was disturbed every night. 

Sx score day = overall severity of asthma. 

Changes in: sleep disturbance scores 1.89 → 0.69; cough at rest 1.08 → 0.69; wheeze at

rest was 1.25 → 0.67; difficulty breathing 1.47 → 0.96; cough with activity = 1.75 →

1.30.

Sx score day = overall severity of asthma.

Changes in: sleep disturbance scores 1.79 → 0.67; cough at rest 1.00 → 0.87; wheeze at

rest was 0.97 → 0.74; difficulty breathing 1.41 → 0.85; cough with activity = 1.48 →

1.28. All comparisons in sx scores between groups NS. 

No significant differences in other indexes of asthma control, including waking with 

asthma, beta2-agonist use, or self-rating of asthma severity differed among the groups at 

3 months or at 6 months after entry. 

No significant differences in other indexes of asthma control, including waking with 

asthma, beta2-agonist use, or self-rating of asthma severity among the groups at 3 months

or at 6 months after entry.

Nighttime symptoms = total nighttime awakenings over total study. (Values not reported

by AHRQ) 

Nighttime symptoms = total nighttime awakenings over total study.

Sx score day = wheeze day; Sx score night = wheeze night; daily score for activity 

restriction was 0.13. 

Sx score day = wheeze day; Sx score night = wheeze night; daily score for activity restriction

was 0.06, p <0.05 compared to control. 

P-Value Final Nighttime P-Value Comments

Symptom Score

Source:

Blue Cross and Blue Shield Association Technology Evaluation Center. Management of Chronic Asthma: Evidence Report/Technology Assessment Number

44. AHRQ Publication No. 01–EO44. Rockville, MD: Agency for Healthcare Research and Quality. September 2001.

Archive

for historical Reference Only
Abramson MJ, Bailey MJ, Couper FJ, Driver JS, Drummer OH, Forbes AB, McNeil JJ, Haydn

Walters E; Victorian Asthma Mortality Study Group. Are asthma medications and management

related to deaths from asthma? Am J Respir Crit Care Med 2001;163(1):12–8.

Ayres JG, Campbell LM, Follows, RMA. A controlled assessment of an asthma self-management plan

involving a budesonide dose regimen. OPTIONS Research Group. Eur Respir J 1996;9(5)886–92.

Blue Cross and Blue Shield Association Technology Evaluation Center. Management of Chronic Asthma:

Evidence Report/Technology Assessment Number 44. AHRQ Publication No. 01–EO44. Rockville, MD:

Agency for Healthcare Research and Quality. September 2001.

Charlton I, Antoniou AG, Atkinson J, Campbell MJ, Chapman E, Mackintosh T, Shapira D. Asthma

at the interface: bridging the gap between general practice and a district general hospital. Arch Dis

Child 1994;70(4):313–8.

Charlton I, Charlton G, Broomfield J, Mullee MA. Evaluation of peak flow and symptoms only self

management plans for control of asthma in general practice. BMJ 1990;301(6765):1355–9.

Cote J, Cartier A, Robichaud P, Boutin H, Malo JL, Rouleau M, Fillion A, Lavalee M, Krusky M, Boulet

LP. Influence on asthma morbidity of asthma education programs based on self-management plans 

following treatment optimization. Am J Respir Crit Care Med 1997;155(5):1509–14.

Cowie RL, Revitt SG, Underwood MF, Field SK. The effect of a peak flow-based action plan in the

prevention of exacerbations of asthma. Chest 1997;112(6):1534–8.

Drummond N, Abdalla M, Beattie JAG, et al. Effectiveness of routine self monitoring of peak flow 

in patients with asthma. Grampian Asthma Study of Integrated Care (GRASSIC). BMJ

1994;308(6928):564–7.

Gibson PG, Coughlan J, Wilson AJ, Abramson M, Bauman A, Hensley MJ, Walters EH. Selfmanagement education and regular practitioner review for adults with asthma. Cochrane Database

Syst Rev 2000(2):CD001117. Review.

Ignacio-Garcia JM, Gonzales-Santos P. Asthma self-management education program by home 

monitoring of peak expiratory flow. Am J Respir Crit Care Med 1995;151(2 Pt 1):353–9.

Jones KP, Mullee MA, Middleton M, Chapman E, Holgate ST. Peak flow based asthma selfmanagement: a randomized controlled study in general practice. British Thoracic Society Research

Committee. Thorax 1995;50(8):851–7.

References

84

Monitoring: Written Action Plans

Archive

for historical Reference Only
85

Monitoring: Peak Flow vs. Symptom

Peak Flow-Based Compared to 

Symptom-Based Written Action Plans

Question

Compared to a written action plan based on symptoms, does use of a written action plan based on

peak flow monitoring improve outcomes?

Summary Answer to the Question

Evidence neither supports nor refutes the benefits 

of written action plans based on peak flow monitoring compared to symptom-based plans in

improving health care utilization, symptoms, 

or lung function. Just four studies, one including

children, were available, and these studies had 

limitations (e.g., inadequate sample sizes and 

power to detect differences or potential bias in

patient selection). The evidence does not clearly

show that a peak flow-based action plan is better,

but equivalent benefits have been demonstrated

(Evidence B). Patient preferences and circumstances

(e.g., inability to recognize or report signs and

symptoms of worsening asthma) may warrant

choosing peak flow monitoring.

The EPR-2 recommendations have not been

changed. It is the opinion of the Expert Panel that

peak flow monitoring for patients with moderate or

severe persistent asthma should be considered because

it may enhance clinician-patient communication and

may increase patient and caregiver awareness of the

disease status and control (Evidence B).

Rationale for the Question

The EPR-2 contains descriptions of the data available

to assess asthma-related outcomes associated with

peak flow monitoring. The EPR-2 Panel made clear

that studies conducted at the time of EPR-2 were

limited in number and quality and that findings were

contradictory. Some guidance was available in the

existing research related to patients with moderate 

or severe asthma who might benefit most from peak

flow monitoring. It was considered useful to search

the literature for additional, more recent studies.

Efforts to teach, encourage, and persuade patients 

to use a peak flow meter can be costly. Review of the

question would help discern whether physician and

patient time, energy, and money are warranted in

terms of disease-related outcomes.

Systematic Review of the Evidence

The following description of the SRE is an adaptation of the evidence report, including direct excerpts,

submitted by the Blue Cross Blue Shield Association

Evidence-Based Practice Center. (See Introduction,

Methods.)

❙ Methods of Literature Search

The evidence review included studies that lasted at

least 12 weeks and that compared the use of a peak

flow meter-based plan plus medical management 

vs. a symptom-based action plan plus medical 

management, different schedules of peak flow 

monitoring, or the use of peak flow monitoring for

routine chronic management vs. acute exacerbations.

The comparison of peak flow monitoring to symptom

monitoring was considered a strong approach, as

there is widespread agreement among clinicians that

patients should closely monitor their asthma symptoms. Peak flow monitoring values are thought to 

be beneficial objective measures that help patients

determine the need to adjust their medicines and

identify potentially urgent situations. Their use in

patient self-management is thus dependent on an

action plan provided by a clinician. Therefore, all

studies included in the SRE compared peak flow

monitoring-based written action plans with

symptom-based written action plans.

❙ Summary of Findings

Studies

Four studies met SRE inclusion criteria to assess 

the differences in outcomes when using a peak flow

monitoring-based written action plan or a symptombased action plan. (See the key evidence tables in

this section). None of the studies met SRE criteria

for high quality. In addition, the studies included in

the review had significant limitations (e.g., all four

studies had insufficient power to detect differences

Archive

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86

Monitoring: Peak Flow vs. Symptom

between treatment and control groups). Further

methodological weaknesses were noted in the question on written action plans, because three of the

studies were included in both reviews (Cowie et al.

1997, Cote et al. 1997, and Charlton et al. 1990).

Results of Studies

Three of the four studies documented no significant

differences on any outcome measure between peak

flow monitoring-based plans and symptom-based

plans. One study reported a difference in total 

emergency department visits in favor of the peak

flow monitoring-based plan (Cowie et al. 1997).

These findings are presented in the key evidence

tables in this section. However, the significant

methodologic weaknesses of the studies, as noted

earlier, limit the conclusions. For example, the study

reporting reduced emergency department visits did

not compare change from baseline among groups,

and the data suggest the effect may be attributable

to a subset of patients who had very high frequency

of emergency department visits.

In summary, the available evidence neither supports

nor refutes the use of peak flow monitoring-based

action plans vs. symptom-based plans in improving

outcomes.

Recommendations for EPR Update

Current EPR-2 recommendations should not be

changed until there is clear evidence that one 

monitoring method is superior to another. The

Expert Panel recommends the following blue text 

be incorporated into EPR-2.

Component 1: Measures of Assessment and

Monitoring; Peak Flow Monitoring 

(pages 28 through 33 in EPR-2)

Peak flow monitoring can be used for short-term

monitoring, managing exacerbation, and daily

long-term monitoring. When used in these ways,

the patient’s measured personal best is the most

appropriate reference value. Thus far, the few

studies that have isolated a comparison of peak

flow and symptom monitoring have not been sufficient to assess the relative contributions of each to

asthma management. The literature does suggest

which patients may benefit most from peak flow

monitoring. (See box 1, Peak Flow Monitoring

Literature Review.)

A systematic review of the evidence conducted in

2002 concluded that evidence at this time does 

not clearly show that a peak flow monitoring-based

action plan is better than a symptom monitoringbased plan in improving outcomes, but it does show

similar benefits (SRE-Evidence B). In the opinion 

of the Expert Panel, there are two distinct arguments

for keeping the recommendations to consider peak

flow monitoring for patients with moderate or severe

persistent asthma: (1) peak flow monitoring appears

to provide a way to enhance clinician-patient communication, and (2) either peak flow or symptom

self-monitoring appears to increase patient awareness

of the disease status and control, thereby helping

patients “tune in” to their disease.

If this is the case, either method, if taught and 

followed correctly, may be equally effective

(Evidence B). Patient preferences for objective 

measures or certain patient circumstances, such as

inability to either perceive or report signs and symptoms of worsening asthma, warrant the use of peak

flow monitoring. It is the opinion of the Expert Panel

that the associated clinician and patient time, energy,

and costs are, therefore, justified (Evidence D). This

does not, however, change the recommendation that

all patients with persistent asthma have a peak flow

meter and know how to use it.

The Expert Panel concludes, on the basis of this 

literature and the Panel’s opinion, that:

■ Patients with moderate or severe persistent

asthma should learn how to monitor their

PEF and have a peak flow meter at home.

■ Peak flow monitoring during exacerbations

of asthma is recommended for patients with

moderate or severe persistent asthma to:

• Determine severity of the exacerbation.

• Guide therapeutic decisions (see component

3, Managing Exacerbations, and figure 4–5) in 

the home, clinician’s office, or emergency

department.

Archive

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87

Monitoring: Peak Flow vs. Symptom

■ Long-term daily peak flow monitoring is

helpful in managing patients with moderate

or severe persistent asthma to:

• Detect early changes in disease status that

require treatment.

• Evaluate responses to changes in therapy.

• Provide assessment of severity for patients

with poor perception of air flow obstruction.

• Afford a quantitative measure of impairment.

■ If long-term daily peak flow monitoring is

not used, a short-term (2- to 3-week) period

of peak flow monitoring is recommended to:

• Evaluate responses to changes in chronic

maintenance therapy.

• Identify temporal relationship between

changes in PEF and exposure to environmental or occupational irritants or

allergens. It may be necessary to record PEF

4 or more times a day (Chan-Yeung 1995).

• Establish the individual patient’s personal

best PEF.

■ The Expert Panel does not recommend longterm daily peak flow monitoring for patients

with mild intermittent or mild persistent

asthma unless the patient, family, and/or 

clinician find it useful in guiding therapeutic

decisions. Any patient who develops severe

exacerbations may benefit from peak flow

monitoring (Evidence B).

Limitations of long-term peak flow monitoring

include:

■ Difficulty in maintaining adherence to monitoring

(Reeder et al. 1990; Chmelik and Doughty 1994;

Malo et al. 1993), often due to inconvenience,

lack of required level of motivation, or lack of a

specific treatment plan based on PEF.

■ Potential for incorrect readings related to poor

technique, misinterpretation, or device failure.

Whether peak flow monitoring, symptom monitoring, or a combination of approaches is used, the

Expert Panel believes that self-monitoring is important to the effective self-management of asthma. 

The nature and intensity of self-monitoring should

be individualized, based on such factors as asthma

severity, patient’s ability to perceive or report airflow

obstruction, availability of peak flow meters, and

patient preferences.

Recommendations for Future Research

The utility of peak flow monitoring and the circumstances where it is beneficial continue to be salient

issues in asthma self-management. The following

questions for research deserve attention:

■ Does peak flow monitoring provide benefits over

symptom monitoring? Studies of adequate power

are needed to settle the question.

■ Which patients (e.g., those with more severe 

disease, of different ages, or with special circumstances or preferred language or literacy concerns)

are most likely to benefit from peak flow monitoring? Studies in children are especially needed

because children may not report symptoms as

easily or readily as adults.

■ What type of benefits can be accrued from peak

flow monitoring? 

• Identification of precipitants to symptoms?

• More timely adjustment of medicines?

• Improved perception of airflow obstruction?

■ Is peak flow monitoring more likely to be used

by patients regularly instead of only during 

exacerbations? Short term vs. long term? What

are the relative benefits of short term use in 

producing disease-related outcomes?

The SRE stimulates questions that go beyond those

related to written action plans and peak flow vs.

symptom monitoring. Answers to the following

related and important research questions may

enhance efforts to educate patients and foster 

self-management:

■ Which components of self-management interventions are most powerful (i.e., account for the

greatest variance in disease-related outcomes)?

Archive

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88

■ What is the minimum core of information and

skills required in self-management interventions

to produce desired outcomes?

■ Which types of interventions (and which of their

components) are most effective given the patient’s

disease severity?

■ Which members of the health care team or 

education partners (e.g., teachers and social

workers) best provide which components of 

self-management education? 

■ What new venues (e.g., worksites, community

centers, churches) might provide greater access 

to patients who are members of underserved 

populations?

Monitoring: Peak Flow vs. Symptom

Archive

for historical Reference Only
89

Monitoring: Peak Flow vs. Symptom

Cowie, Revitt,

Underwood 

et al. 1997

Cote, Cartier,

Robichaud

et al. 1997 

Turner, Taylor,

Bennett et al. 1998 

Charlton, Charlton,

Broomfield 

et al. 1990

Randomized; 

parallel, controlled

Randomized; 

parallel, controlled

Randomized; 

parallel, controlled

Randomized; 

parallel, controlled

Country: Canada 

Funding: Foothills

Hospital, Calgary 

Tx Setting:

Primary/specialty

combination, 

university

Multicenter 

Country: Canada 

Funding: Pharm.

Ind., grant

Tx Setting:

Specialty care,

nonuniversity

Multicenter 

Country: Canada 

Funding: Pharm.

Ind. + other, 

not specified 

Tx Setting: Primary

care, nonuniversity 

Country: United

Kingdom 

Funding: Clare

Wand Fund,

Scientific

Foundation of RCP

Vitalogap 

Tx Setting:

Specialty care,

nonuniversity

Patient eligibility based on

symptoms and utilization.

Inclusions: Treatment for an

exacerbation of asthma in an ER

or attending a university asthma

clinic; history of receiving

urgent treatment for asthma in

the previous 12 months 

Patient eligibility based on lung

function and symptoms.

FEV1 Postbronchodilator

85–100% of predicted; PEF

minimum 85% of predicted;

PEF variability minimum 0%;

Methacholine

Exclusion: Previous enrollment

in an asthma educational 

program 

Patient eligibility based on lung

function and symptoms. 

Inclusions: Methacholine PC20

maximum 7.9; using inhaled

corticosteroids

Exclusions: Previous PFM use;

significant comorbid conditions 

Patient eligibility based on

symptoms only.

Inclusion: Patients on repeat

prescribing register 

Subjects were recruited by 

contacting those who had been

treated for an exacerbation of

asthma in an emergency department or those attending a 

university asthma clinic with a

history of having received urgent

treatment for their asthma in

the previous 12 months. 

In discussion “although the 

control group received more

than the usual care treatment,

none received book, none had

written action plan, none had

structured education or PFM 

at home after run-in”; run-in =

2–6 weeks; diagnosis of asthma

included need to take daily 

anti-inflammatory agents; were

excluded. 

Patients were randomized after

stratification for severity of airway responsiveness using values

of PC20 methacholine <2

mg/mL or >2 mg/mL.

150 screened, 117 enrolled. 

Patients were not randomly

selected for participation.

Letters were sent to patients on

the repeat prescribing register,

and invited them to make an

appointment with a nurse.

Table 2-4. Study Characteristics

Citation Study Design Study Setting Eligibility Comments

PFM-based action plan vs. symptom-based action plan

Source:

Blue Cross and Blue Shield Association Technology Evaluation Center. Management of Chronic Asthma: Evidence Report/Technology Assessment Number

44. AHRQ Publication No. 01–EO44. Rockville, MD: Agency for Healthcare Research and Quality. September 2001.

Key Evidence Tables

Archive

for historical Reference Only
90

Monitoring: Peak Flow vs. Symptom

Turner, Taylor, Bennett et al.

1998 

Charlton, Charlton, Broomfield

et al. 1990 

Cowie, Revitt, Underwood 

et al. 1997 

Cote, Cartier, Robichaud 

et al. 1997

Symptom-based

action plan 

PFM-based action

plan 

Symptom-based

action plan 

PFM-based action

plan 

Symptom-based

action plan 

PFM-based action

plan 

Symptom-based

action plan 

PFM-based action

plan 

48

44

45

46

45

50

48

44

24

24

Table 2-6. Symptom Score Outcomes

Citation Study Arm Number Enrolled Number Evaluable Treatment Duration

(weeks)

Peak flow meter (PFM)-based action plan vs. symptom-based action plan

Turner, Taylor, Bennett et al.

1998 

Charlton, Charlton, Broomfield

et al. 1990 

Cowie, Revitt, Underwood 

et al. 1997 

Cote, Cartier, Robichaud 

et al. 1997

Symptom-based

action plan 

PFM-based action

plan 

Symptom-based

action plan 

PFM-based action

plan 

Symptom-based

action plan 

PFM-based action

plan 

Symptom-based

action plan 

PFM-based action

plan 

48

44

45

46

45

50

48

44

45

46

24

24

24

24

Citation Study Arm Number Enrolled Number Evaluable Treatment Duration

(weeks)

Peak flow meter (PFM)-based action plan vs. symptom-based action plan

Table 2-5. Lung Function Outcomes: FEV1

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91

Monitoring: Peak Flow vs. Symptom

Baseline FEV1* Final FEV1 P-Value P-Value Comparison Comments

78.7 +/- 18.9% of predicted 

78.1 +/- 19.7% of predicted 

79 +/- 18% of predicted 

82 +/- 20.5% of predicted 

86.1 (mean) % of

predicted 

83 (mean) % of

predicted 

NS Absolute value, 

Tx vs. Ctl

FEV1 in L, mean (SD)

was 2.86 (0.88). 

FEV1 in L, mean (SD)

was 2.84 (0.86). 

Number of subjects

with <60% predicted

was 8. 

Number of subjects

with <60% predicted

was 9. 

Baseline Daytime Final Daytime P-Value Final Nighttime P-Value Comments

Symptom Score Symptom Score Symptom Score

9.1 (mean; scale, 0–24) 

8.2 (mean; scale, 0–24) 

5.2 (mean; scale, 

0–24)

3.2 (mean; scale, 

0–24)

NS1

Not sure if reported score is

actually a mean; daytime score

is really overall score where 24

is max and higher value = more

asthma symptoms. 

Not sure if reported score is

actually a mean; daytime score

is really overall score where 24

is max and higher value = more

asthma symptoms. 

* FEV1 pre- or postbronchodilator status unknown unless otherwise indicated.

Source:

Blue Cross and Blue Shield Association Technology Evaluation Center. Management of Chronic Asthma: Evidence Report/Technology Assessment Number

44. AHRQ Publication No. 01–EO44. Rockville, MD: Agency for Healthcare Research and Quality. September 2001.

1 Treatment comparison-absolute value, Tx vs. Ctl 2 Treatment comparison not specified

Source:

Blue Cross and Blue Shield Association Technology Evaluation Center. Management of Chronic Asthma: Evidence Report/Technology Assessment Number

44. AHRQ Publication No. 01–EO44. Rockville, MD: Agency for Healthcare Research and Quality. September 2001.

Archive

for historical Reference Only
Blue Cross and Blue Shield Association Technology Evaluation Center. Management of Chronic Asthma:

Evidence Report/Technology Assessment Number 44. AHRQ Publication No. 01–EO44. Rockville, MD:

Agency for Healthcare Research and Quality. September 2001.

Chan-Yeung M. Assessment of asthma in the workplace. American College of Chest Physicians

Consensus Statement. Chest 1995;108(4):1084–117.

Charlton I, Charlton G, Broomfield J, Mullee, MA. Evaluation of peak flow and symptoms only self

management plans for control of asthma in general practice. BMJ 1990;301(6765):1355–9.

Cote J, Cartier A, Robichaud P, Boutin H, Malo JL, Rouleau M, Fillion A, Lavallee M, Krusky M,

Boulet LP. Influence on asthma morbidity of asthma education programs based on self-management plans following treatment optimization. Am J Respir Crit Care Med 1997;155(5):1509–14.

Cowie RL, Revitt SG, Underwood MF, Field SK. The effect of a peak flow-based action plan in the

prevention of exacerbations of asthma. Chest 1997;112(6):1534–8.

Turner MO, Taylor D, Bennett R, Fitzgerald JM. A randomized trial comparing peak expiratory flow

and symptom self-management plans for patients with asthma attending a primary care clinic. 

Am J Respir Crit Care Med 1998;157(2):540–6.

References

92

Monitoring: Peak Flow vs. Symptom

Archive

for historical Reference Only
3. Prevention

Asthma Expert Panel Report:

Guidelines for the

Diagnosis and

Management of

Asthma

Archive

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Archive

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95

In deciding when to initiate daily therapy

for patients with asthma, clinicians consider

the goals of controlling and preventing

symptoms, as well as the possibility of

preventing further progression of the

underlying disease. This section of the

EPR—Update 2002 addresses the question of whether early initiation of daily

inhaled corticosteroid treatment is warranted to prevent progression of asthma.

Effects of Early Treatment 

on the Progression of Asthma

Question

For patients with mild or moderate 

persistent asthma, does early intervention of long-term-control therapy

(i.e., inhaled corticosteroids) prevent

progression of asthma as indicated by

changes in lung function or severity 

of symptoms?

Summary Answer to the Question

Evidence regarding the benefits of early

treatment of asthma in preventing the

progression of disease is insufficient to

draw conclusions. But available evidence

does not support the assumption that 

children 5 to 12 years of age with mild 

or moderate persistent asthma experience 

a progressive decline in lung function 

(SRE-Evidence A). Further, the evidence

indicates that although inhaled corticosteroids provide superior control and

prevention of asthma symptoms during

treatment of childhood asthma, symptoms

and airway hyperresponsiveness worsen

when treatment is withdrawn (SREEvidence A). This evidence suggests that

the therapy controls but does not modify

the disease in this age group. Studies in

children younger than 3 years of age and in

adults document declines in lung function.

Studies of whether treatment can prevent

these declines in lung function or symptom

severity have not yet been conducted in

young children and are inconclusive in

adults. Revisions to the EPR-2 are recommended to reflect the new understanding

of the progression of asthma.

Rationale for the Question

A common question confronting clinicians

and patients is: At what point in the 

disease process—as reflected by the level 

of clinical signs and symptoms as well the

duration of disease—should daily longterm-control therapy be initiated?

Although the effectiveness of inhaled 

corticosteroids in controlling and preventing symptoms of asthma and

improving pulmonary function is well

documented, an important question is

whether inhaled corticosteroids modify

the natural history of the disease. If the

progression of asthma is from airway

inflammation to airway remodeling and

some irreversible airway obstruction, then

anti-inflammatory medication (i.e., inhaled

corticosteroids) given early in the course of

disease may interrupt this process and prevent permanent declines in lung function.

In order for early initiation of inhaled 

corticosteroids to be more beneficial than

delayed initiation, two assumptions must

be valid: as a group, people with mild or

moderate persistent asthma experience a

progressive decline in lung function that

is measurable and clinically significant,

and treatment with inhaled corticosteroids prevents or slows this decline, in

addition to controlling asthma symptoms.

A SRE was conducted to evaluate the 

current literature on the effect of intervention of inhaled corticosteroids in altering

the progression of disease.

3. Prevention

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Background Information

Addressing the question about the effect of inhaled

corticosteroids on the progression of disease requires

answering a series of questions: What is the 

progression of asthma? Does intervention alter the

progression? When is the appropriate time to 

intervene? The Expert Panel’s review of the literature on the progression of asthma is presented here

as a context for interpreting the studies evaluated 

in the SRE.

❙ Natural History of Persistent Asthma

Children

It has been well established that asthma is a variable

disease: It can vary among individuals, and its 

progression and symptoms can vary within an individual’s experience over time. It has been postulated

that the persistence or increase of asthma symptoms

over time is accompanied by a progressive decline in

lung function. Recent research suggests that this may

not be the case; rather, the course of asthma may vary

markedly between young children, older children and

adolescents, and adults, and this variation is probably

more dependent upon age than symptoms.

A prospective cohort study in which followup began

at birth revealed that in children whose asthma-like

symptoms began before 3 years of age, deficits in

lung growth associated with the asthma occurred 

by 6 years of age (Martinez et al. 1995). Continued

followup on lung function measures taken at 11 to

16 years of age found that compared to the group of

children who experienced no asthma symptoms for

the first 6 years of life, the group of children whose

asthma symptoms began before 3 years of age experienced significant deficits in lung function at 11 to

16 years of age, but the group whose asthma symptoms began after 3 years of age did not experience

deficits in lung function. 

A longitudinal study of children 8 to 10 years of age

found that bronchial hyperresponsiveness was associated with declines in lung function growth in both

children with active symptoms of asthma and children without (Xuan et al. 2000). Thus, symptoms

neither predicted nor determined lung function

deficits in this age group.

Baseline data from the Childhood Asthma

Management Program (CAMP) study support the

finding that the individual’s age at the time of

asthma onset influences declines in lung function

growth. At the time of enrollment of children with

mild or moderate persistent asthma at 5 to 12 years

of age, an inverse association between lung function

and duration of asthma was noted (Zeiger et al.

1999). Although the analysis did not distinguish

between age of onset and duration of asthma, it can

be inferred that because the average duration of

asthma was 5 years and the average age of the 

children was 9 years, most children with the longer

duration of asthma started experiencing symptoms

before 3 years of age. The data suggest that these

were the children with lowest lung function levels.

After 4 to 6 years of followup, the children in the

CAMP study, on average, did not experience deficits

in lung growth (as defined by postbronchodilator

FEV1), regardless of their symptom levels or treatment they received (CAMP 2000).

These results suggest that most of the deficits in

lung function growth observed in childhood asthma

occur in children whose symptoms begin during the

first 3 years of life, and the onset of symptoms after

3 years of age usually is not associated with significant deficits in lung function growth. Further, at

least for children with mild or moderate persistent

asthma, there do not appear to be deficits in lung

function growth from 5 to 17 years of age.

Thus, the most promising target for interventions

designed to prevent deficits in lung function and

perhaps the development of more severe symptoms

later in life would be those children who have 

symptoms before 3 years of age and are destined to

develop persistent asthma. However, it is important

to distinguish this group from the majority of children who wheeze before 3 years of age and do not

experience any more symptoms after 6 years of age

(Martinez et al. 1995). Until recently, no validated

algorithms were available to predict which children

among those with asthma-like symptoms early in

life would go on to have persistent asthma. Data

obtained from long-term longitudinal studies of

children enrolled at birth generated such a predictive

index. This predictive index identified the following

risk factors for developing persistent asthma 

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symptoms among children younger than 3 years of

age who had more than three episodes of wheezing

during the previous year: either physician diagnosis

of atopic dermatitis/eczema or a parental history of

asthma or two out of three of the following asthmaassociated phenotypes—peripheral blood eosinophilia,

wheezing apart from colds, or physician-diagnosed

allergic rhinitis. When the index was applied to a

birth cohort that was followed through 13 years of

age, 76 percent of the children who were diagnosed

with asthma after 6 years of age had a positive predictive index; moreover, 97 percent of the children in

this cohort who did not have asthma after 6 years of

age had a negative asthma predictive index before 3

years of age (Castro-Rodriguez et al. 2000).

Adults

Accelerated loss of lung function appears to occur in

adults with asthma. In a study of adults with asthma

who received 2 weeks of high-dose prednisone if 

airflow obstruction persisted after 2 weeks of bronchodilator therapy, the degree of persistent airflow

obstruction correlated with both the severity and the

duration of their asthma (Finucane et al. 1985).

Two large prospective epidemiological studies 

evaluated the rate of decline in pulmonary function

in adults with asthma. In an 18-year prospective

study of 66 nonsmokers with asthma, 26 smokers

with asthma, and 186 control participants with no

asthma, spirometry was performed at 3-year intervals

(Peat et al. 1987). Seventy-three percent of the study

group underwent at least 6 spirometric evaluations.

The slope for decline in lung function (FEV1) was

approximately 40 percent greater for the participants

with asthma than for those with no asthma. This did

not appear to be the result of extreme measurement

produced by a few participants, because fewer than

25 percent of the participants who had asthma were

measured with a slope less steep than the mean for

those who did not have asthma. In another study,

three spirometry evaluations were performed in

13,689 adults (778 who had asthma, 12,911 who did

not have asthma) over a 15-year period (Lange et al.

1998). The average decline in FEV1 was significantly

greater in those who had asthma (38 mL per year)

than those who did not have asthma (22 mL per

year). Although, in this study, asthma was defined

simply by patient report, the researchers noted that

because the 6 percent prevalence rate for asthma did

not increase in this cohort as they increased in age, 

it is likely that the subjects who reported having

asthma did indeed have asthma rather than chronic

obstructive pulmonary disease (COPD). It is not 

possible to determine from these studies whether the

loss of pulmonary function occurred in those who had

mild or moderate asthma or only in those who had

severe asthma. Nevertheless, the data support the 

likelihood of potential accelerated loss of pulmonary

function in adults who have asthma.

Taken together, these longitudinal epidemiological

studies and clinical trials indicate that the progression

of asthma, measured by declines in lung function,

varies in different age groups. Declines in lung 

function growth observed in children appear to

occur by 6 years of age and occur predominantly 

in those children whose asthma symptoms started

before 3 years of age; children 5 to 12 years of age

with mild or moderate persistent asthma do not

appear to experience declines in lung function

through 11 to 17 years of age. There is also evidence

of progressively declining lung function in adults.

Data on the effect of interventions to influence the

progression of asthma, measured by declines in lung

function, airway hyperresponsiveness, or the severity

of symptoms, were evaluated in the SRE.

Systematic Review of the Evidence

❙ Methods of Literature Search

The following description of the SRE is an 

adaptation of the evidence report, including direct

excerpts, submitted by the Blue Cross Blue Shield

Association Evidence-Based Practice Center. 

(See Introduction, Methods.)

In addition to the eligibility criteria for selecting

studies related to all topics in the SRE (described 

in the Introduction), the criteria for selecting studies

for this question were as follows:

■ Some or all patients started long-term-control

medication (inhaled corticosteroids, leukotriene

modifiers, cromolyn, nedocromil, or theophylline)

during the study 

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AND

• The treatment group was treated immediately

following diagnosis of asthma compared to a

control group that received the same treatment

after a delay

OR

• The population was stratified by the duration 

of asthma prior to the initiation of long-termcontrol medication and outcomes compared

across the different strata.

■ Treatment duration was at least 1 year.

■ At the start of the study, no more than 10 percent

of the population was currently being treated

with or had been continuously (more than 1

month) treated in the past with the longterm-control medication being studied.

❙ Summary of Findings

Studies

Although the objective was to review the literature

on the effects of any long-term-control medications

(e.g., inhaled corticosteroids, leukotriene modifiers,

cromolyn, nedocromil, theophylline), the available

studies were limited to research on inhaled corticosteroids. (See the key evidence tables in this section

for a summary description of the eligible studies.)

Four studies reporting on a total of 475 asthma

patients met the inclusion criteria for this key 

question: two randomized controlled trials (RCTs)

(Haahtela et al. 1994; Overbeek et al. 1996) and two

single-arm studies (Selroos et al. 1995; Agertoft and

Pedersen 1994). Just one of the studies enrolled 

children who were 3 to 11 years of age (Agertoft and

Pedersen 1994). According to EPR-2 classification

of severity, two studies involved mild asthma (baseline FEV1 greater than 80 percent predicted)

(Haahtela et al. 1994; Agertoft and Pedersen 1994),

and two involved moderate asthma (Overbeek et al.

1996; Selroos et al. 1995). Each of the two RCTs

(Haahtela et al. 1994; Overbeek et al. 1996) was an

open-label extension of an RCT originally intended

to evaluate the efficacy of inhaled corticosteroids. 

In these studies, the patients who were initially

assigned to the noncorticosteroid-treated control

group were subsequently administered inhaled 

corticosteroids at the conclusion of the original

RCT. Each of the single-arm studies (Selroos et al.

1995; Agertoft and Pederson 1994) analyzed a

cohort of patients treated in a hospital-based clinic,

where the patients were stratified by the individual’s duration of asthma prior to initiating

inhaled corticosteroids treatment, and outcomes

were compared across the strata.

The duration of the followup was 3 years in the 

randomized trials and 2 and 3.7 years, respectively,

in the single-arm studies. Haahtela et al. (1994)

treated one group with inhaled corticosteroids for 24

months, then treated the delayed inhaled corticosteroid group for 12 months. Overbeek et al. (1996)

treated one group with inhaled corticosteroids for 30

months, initiated treatment with inhaled corticosteroids in the delayed group, and followed both

groups for an additional 6 months. In the single-arm

studies, patients starting on inhaled corticosteroids

were followed for 2 years in one study (Selroos et al.

1995) and for 2 to 6 years (mean: 3.7 years) in the

final study (Agertoft and Pedersen 1994).

All four trials reported lung function outcomes, 

but no two studies used the same measure to report

change in lung function from baseline. Neither of

the two RCTs (Haahtela et al.; Overbeek et al. 1996)

met the SRE criteria that define higher quality

studies. Neither study maintained blinding to treatment throughout the course of the study. For both,

the rate of dropouts/withdrawals exceeded the established threshold. Analyses were not done by intent

to treat or in a manner to minimize dropout bias.

With respect to SRE asthma-specific indicators of

study quality, both randomized trials established

reversibility on lung function measurements and

controlled for use of other asthma medications, but

neither study reported power calculations for outcomes, adequately accounted for excluded patients,

specified a priori which were primary outcomes for

analysis, reported compliance, or controlled for the

effects of seasonality on outcomes.

A major limitation of the single-arm studies is that

patients entered the study at varying time points in

the duration of their disease, making it impossible

to compare outcome data at a uniform time point. 

A second limitation in such studies is the high

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potential for selection bias. It is likely that patients

who have had asthma longer will have more severe 

disease, both because of disease progression and

because asthma is more likely to remit in milder cases.

Finally, the SRE literature search found no prospective

studies to address this key question in the specific

population of interest. As a result, the available 

evidence from studies that compared early with

delayed inhaled corticosteroid treatment has notable

limitations with respect to the study population,

time frames for study entry and followup, clarity 

of reporting with respect to details of interest to the

question, and the use of appropriate control groups.

For some trials, it was impossible to accurately 

calculate the number of enrolled or evaluable patients

of interest, because reporting of one or the other

number was combined with other patient groups

(e.g., patients who have COPD or individuals with

severe asthma).

The SRE also included consideration of results from

CAMP 2000, although the research was not published until after the SRE literature search, and the

study design does not address the question of 

intervention timing (early vs. delayed treatment).

The study is considered in the SRE because it evaluates the long-term (4 to 6 years) effect of treatment

on lung growth and asthma symptoms in more than

1,000 children with mild or moderate asthma. 

The RCT comparing inhaled corticosteroids and

nedocromil with placebo (all groups received asneeded beta2-agonists) met SRE criteria for high

quality. Thus, the study provides robust evidence 

on the course of childhood asthma.

Results of Studies

Of the four studies identified by the SRE literature

search, the randomized trial by Haahtela, although

small (52 evaluable study participants), is the most

relevant in terms of study design and population.

The design includes comparisons that directly

address the key question of interest, and the population is limited to individuals with mild asthma who

were enrolled in the study at a similar point in the

history of their disease—i.e., a diagnosis within the

12 months prior to enrollment. The first phase of

the study was a randomized control comparison of a

group treated daily with inhaled corticosteroids and

a group treated with daily beta2-agonists, and

followed for 24 months. The second phase of the

study was an open-label study in which 67 percent

of the original beta2-agonist treatment group was

given inhaled corticosteroids and followed for 12

more months; the original inhaled corticosteroid

treatment group was either continued on a reduced

dose of steroid or given a placebo. Outcomes at the

end of 3 years indicated improvements in lung function measures and symptom scores in both groups,

with larger increases occurring in the immediate

inhaled corticosteroid group compared to the

delayed inhaled corticosteroid group (FEV1 0.15 L 

vs. 0.02 L; PEF 42 L/min vs. 15 L/min; PC15 5.0 

vs. 4.22 DD histamine; symptom score change of

0.8 vs. 0.4 from a mean baseline of 2.2 on a 1 to

10 point scale). Although these findings appear to

support the hypotheses that an irreversible decline in

lung function can occur in asthma not treated with

an anti-inflammatory medication and that treatment

with inhaled corticosteroids may have an impact on

decline, methodologic features of the study limit the

conclusions that can be reached. No statistical tests

of significance were performed comparing baseline

and 3-year outcomes between the immediate and the

delayed treatment groups, and the differences are of

unknown clinical significance because the magnitude

is of a size that could be explained by bias. Bias may

have occurred due to the lack of strict comparability

between the double-blind and open-label phases of

the trial, lack of controls for doses of inhaled 

corticosteroids, and a high rate of withdrawal from

the study during the open-label phase (36 of 53

patients in the delayed treatment group and 16 of

50 in the immediate treatment group were available

for analysis at 3 years), with no tests of comparability between withdrawals and continuing patients.

The second randomized trial identified in the SRE 

is also an open-label extension of a double-blind

RCT designed to evaluate the efficacy of inhaled 

corticosteroids. The study had three treatment

groups: one received inhaled corticosteroids, a second

received inhaled ipratropium, and a third received

placebo, but all groups received an inhaled beta2-

agonist four times a day (Overbeek et al. 1996).

After 30 months of treatment, the asthma patients

in the groups not receiving inhaled corticosteroids

were given that agent and followed 6 additional

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months in an open-label observation. This allows

comparison of a group (49 patients) receiving immediate vs. a group (53 patients) receiving delayed

inhaled corticosteroids for asthma. Results reported 

a greater but not statistically significant rise in FEV1

during the initial 3 months of inhaled corticosteroid

therapy for the immediate treatment group (13.8

percent increase vs. 8.5 percent increase; p = 0.13),

and a statistically significant rise in PC15 values for

the initial 6 months of inhaled corticosteroids in the

immediate treatment group (1.77 doubling dose vs.

0.79, p = 0.03), and no differences in symptom score

values. The study suggests the possibility of some

benefit for immediate treatment, but conclusions 

are severely limited by several methodologic problems. For example, it is not clear at what point in 

the individual patient’s disease process the treatment 

was started; the study populations include a mix 

of patients with severe asthma and COPD, and there

were no comparisons made relevant to the key 

question—i.e., comparison of baseline and final lung

function measured at the end of the trial. Further,

there was a high dropout rate (less than half the 

eligible patients participated in the extended 

open-label phase) with no analysis of the withdrawals, which may introduce bias.

For the single-arm studies, one study enrolled 105

consecutive patients started on inhaled corticosteroids and observed them for 2 years (Selroos

1995). Changes in lung function outcomes (FEV1

percent predicted and PEF percent predicted) were

compared among the patients, according to groups

stratified by duration of asthma at the onset of treatment (0 to 6 months, 14 patients; 6 to 12 months,

35 patients; 12 to 14 months, 13 patients; 24 to 

60 months, 19 patients; 60 to 120 months, 

15 patients). All strata were compared to the 0- 

to 6-month duration group; no comparison among

strata was reported. The greatest increase in lung

function measures occurred in the group with the

shortest (0 to 6 months) duration of asthma (17 percent increase in FEV1 percent predicted); and the

least increase occurred in the group with the longest

(60 to 120 months) duration of asthma (0 percent

increase, p <0.01). All other strata except the 24- 

to 60-month group had significantly less degree of

lung function improvement than the 0- to 6-month

group, but of varying magnitude. 

For PEF, the 0- to 6-month group had a 21 percent

increase in percent predicted values, compared with

a 2 percent increase in the 60- to 120-month group

(p <0.05), but differences among the other strata

varied in magnitude and significance. Although the

stratification accounted for differences in duration of

disease, it is impossible to compare outcome data at

a uniform time point in the disease. Further, baseline

differences in lung function and asthma severity

indicate some selection bias. Finally, approximately

one-third of the study participants were current or

exsmokers, and the proportion of current smokers

varied from 0 percent to 29 percent in the different

groups. Thus, study design features, variance in final

outcome measures among the strata, and the confounding factors of asthma severity and smoking

limit interpretation of the results.

The second single-arm study identified by the SRE is a

nonrandomized, prospective controlled trial of longterm outcomes in 216 children treated with inhaled

corticosteroids for a mean of 3.7 years compared to 62

children who declined recommendations for inhaled

corticosteroid treatment (Agertoft and Pedersen,

1994). In a supplemental cohort analysis, patients in

the inhaled corticosteroid group were stratified by

prior duration of asthma (0 to 2 years, 2 to 3 years, 

3 to 5 years, and more than 5 years). This allowed 

a comparison relevant to the key SRE question. 

The main reported outcome was annual change in percent predicted FEV1, calculated by linear regression.

Results showed a mean change in FEV1 per year of 8.2

percent for the 0- to-2-year group, 6.7 percent for the

2- to 3-year group, 3 percent for the 3- to 5-year

group, and 2.4 percent for the more than 5-year

group. A statistically significant correlation existed

between the duration of asthma and the estimated

change in FEV1 per year; however, the differences were

not significant between every group (e.g., the less than

2 vs. the 2- to 3-year strata or the 3- to 5-year vs. the

more than 5-year strata). A major difficulty in interpreting these results is that the linear regression

assumes a linear change in outcomes over the entire

course of the study. However, it is well documented

in the literature that there is a pattern of a sharp 

initial rise in FEV1 during the first 3 months of

inhaled corticosteroid treatment that is then followed

by a plateau. Indeed, the final difference in FEV1

percent predicted between the less than 2-year strata

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(101 percent) and the more than 5-year strata (96.2

percent) was 4.8 percent after a mean of 3.7 years 

of treatment. This is considerably less than the 5.8

percent per year difference estimated by the linear

regression model applied to the data.

The results of the CAMP 2000 study influence the

conclusions derived from the SRE (CAMP 2000). 

This study is a three-arm, RCT evaluating the outcome effects of inhaled corticosteroids or nedocromil

sodium compared to placebo in 1,041 children over a

mean followup period of 4.3 years. The primary outcome measure was postbronchodilator FEV1. Although

the design of CAMP does not address the question of

early versus delayed intervention (the average duration

of asthma was 5 years for the study population), it

does address the question of the effect of intervention

with two treatments on disease progression as defined

by loss in FEV1 percent predicted.

CAMP researchers found an initial, highly statistically

significant difference between treatment and control

groups for change in postbronchodilator FEV1 in

the first year of the study, but no difference in

change from baseline to the end of the 4- to 6-year

followup period. This outcome measure was chosen

to minimize the effects of reversible airway constriction and individual variability over time that are

observed with prebronchodilator FEV1. The finding

of no difference in postbronchodilator FEV1 and

minimal change overall in lung function over 4 to 

6 years for the entire study population does not 

support the hypothesis that treatment with inhaled

corticosteroids improves lung growth in children

with mild or moderate persistent asthma. It is of

particular interest that CAMP does not document

progressive decline in lung function in the placebo

group, or significant improvement from baseline 

in the treatment groups (CAMP 2000). Similar to

the findings related to lung function outcomes, no

progressive decline in symptoms with the placebo

groups was noted. Symptom scores and nightawakening scores improved over the course of the

study in both the inhaled corticosteroid and placebo

groups, with greater improvement throughout the

study period shown in the inhaled corticosteroid

group. The improvements in the placebo group may

have been a result of the close medical supervision

and patient education given to all study participants,

but the greater improvements in symptom scores

and airway hyperresponsiveness indicate superior

effectiveness of inhaled corticosteroid treatment.

However, after inhaled corticosteroid treatment was

withdrawn, symptom scores and airway hyperresponsiveness values were no different between groups.

This finding indicates that the inhaled corticosteroids provided superior control and prevention 

of symptoms, but did not modify underlying 

disease. The finding that the placebo group did 

not experience a decline in lung function does not 

support the assumption of such a decline in children

with mild or moderate asthma in this age group.

As noted in the Background Information section, 

it is likely that a progressive decline in lung function occurs in younger children and in adults. It is

also possible it occurs in individuals with more

severe asthma.

The studies identified by the SRE most relevant to

addressing the question of whether early intervention

with inhaled corticosteroids can prevent progression

of disease were suggestive of benefit, but methodologic issues severely limit the conclusions that may

be drawn. Additional consideration of the CAMP

study supports cautious interpretation of the studies

identified in the SRE. Although none of these

studies was designed specifically to compare 

immediate versus delayed treatment in preventing

progression of disease, the results provide critical

insights for future research. At this time, the Expert

Panel concludes that the evidence is insufficient 

to permit conclusions regarding the use of early

intervention vs. long-term-control medication to

prevent progression of disease.

Recommendations for EPR Update

Modifications in the EPR-2 are necessary to reflect

the current understanding of natural history of 

persistent asthma, based on the SRE and review of

additional, recently published studies that provide

insights on the progression of asthma. It is clear

that further research is needed to define the benefits

of early intervention, the appropriate time of intervention, the nature of asthma as a progressive

disease, and the effect of medications on preventing

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progression. Until this information is available, 

the Expert Panel recommends the following revisions

to EPR-2 (the blue text indicates new text), based on

the SRE.

Introduction: Pharmacologic Therapy 

(page 4, column 2, final paragraph in EPR-2)

Observations into the basic mechanisms of asthma

have had a tremendous influence on therapy. Because

inflammation is considered an early and persistent

component of asthma, therapy for persistent asthma

must be directed toward long-term suppression 

of the inflammation. Thus, EPR-2 continues to

emphasize that the most effective medications for

long-term-control are those shown to have antiinflammatory effects. For example, early intervention

with inhaled corticosteroids can improve asthma 

control and normalize lung function. However, it

remains to be determined whether intervention with

inhaled corticosteroids or any other long-termcontrol therapy can prevent irreversible airway

obstruction that may be associated with asthma

(Evidence D).

Pathogenesis and Definition: Child Onset

Asthma (page 10, column 1, paragraph 2 

in EPR-2)

Asthma often begins in childhood, and when it does,

it is frequently found in association with atopy,

which is the genetic susceptibility to produce IgE

directed toward common environmental allergens,

including house-dust mites, animal proteins, and

fungi (Larsen 1992). With the production of IgE

antibodies, mast cells and possibly other airway cells

(e.g., lymphocytes) are sensitized and become 

activated when they encounter specific antigens.

Although atopy has been found in 30 to 50 percent

of the general population, it is frequently found in

the absence of asthma. Nevertheless, atopy is one of

the strongest predisposing factors in the development of asthma (Sporik et al., 1990). Furthermore, 

a large epidemiologic study shows that among 

children who have recurrent episodes of wheezing

during the first 3 years of life and have either one of

two major risk factors (parental history of asthma 

or physician diagnosis of atopic dermatitis) or two of

three minor risk factors (wheezing apart from colds,

peripheral blood eosinophilia, or physician diagnosis

of allergic rhinitis) have a 76 percent probability of

developing asthma during the school years (Evidence

C) (Castro-Rodriguez et al. 2000).

Pathogenesis and Definition. Airway

Remodeling (page 11, column 2, paragraph 3 

in EPR-2)

Airway remodeling. In some patients with asthma,

airflow limitation may be persistent and nonresponsive to treatment. This nonresponsiveness may be

caused by changes in the structure of airways. These

changes include wall thickening, subepithelial

fibrosis, goblet cell hypermetaplasia, myofibroblast

hyperplasia, myocyte hyperplasia and hypertrophy,

vascular neogenesis, and epithelial hypertrophy (Elias

1999). Regulation of the repair and remodeling

process is not well established, but both the process

of repair and its regulation are likely to be key

events in explaining the persistent nature of the 

disease and limitations to a therapeutic response.

Although yet to be fully explored, the importance 

of airway remodeling as a possible cause of persistent

airflow limitation and the possible role of 

chronic inflammation as a cause of remodeling 

suggest a rationale for early intervention with antiinflammatory therapy. This hypothesis must be confirmed with specific, prospective, controlled studies.

Component 1: Measures of Assessment and

Monitoring. Spirometry (page 28, column 1 

in EPR-2)

The Expert Panel recommends that spirometery tests

be done (1) at the time of initial assessment; (2) after

treatment is initiated and symptoms and PEF have

stabilized, to document attainment of (near) “normal”

airway function; and (3) at least every 1 to 2 years to

assess the maintenance of airway function. These

spirometry measures should be followed over the

patient’s lifetime to detect potential for decline and

rate of decline of pulmonary function over time

(Evidence D).

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Component 3: Pharmacologic Therapy. 

Key Points: The Medications, Inhaled

Corticosteroids (page 58 in EPR-2) 

Increased understanding of inhaled corticosteroids

notes that: 

• Early intervention with inhaled steroids likely

will improve overall asthma management, but

its effect on preventing irreversible airway

injury remains to be determined (SREEvidence A, B).

Component 3: Pharmacologic Therapy. 

Special Considerations for Managing Asthma 

in Different Age Groups. Infants and Young

Children, Diagnosis (page 95, column 1, 

paragraph 2 in EPR-2)

Among children 5 years of age and younger the

most common cause of asthma symptoms is viral

respiratory infection. At present, the relative contributions of airway inflammation, bronchial smooth

muscle abnormalities, or other structural factors in

producing wheeze with acute viral upper respiratory

infections are unknown. There appear to be two

general patterns of illness in infants and children

who have wheezing with acute viral upper respiratory infections: a remission of symptoms in the

preschool years and persistence of asthma

throughout childhood.

No clear markers to predict the prognosis for an individual child exist. However, epidemiologic studies

suggest that for children less than 3 years of age who

have more than three episodes of wheezing in a year

(that last more than 1 day and affect sleep), the following predictive index identifies the risk associated

with persistent asthma after 6 years of age. If a child has

either (a) a physician diagnosis of atopic dermatitis or a

parental history of asthma OR (b) two of the following:

physician-diagnosed allergic rhinitis, greater than 4

percent peripheral blood eosinophilia, or wheezing

apart from colds, then the child has a high likelihood

(76 percent probability) of developing persistent

asthma (Evidence C) (Martinez 1995; Castro-Rodriguez

2000). It is conceivable that early recognition and treatment of these high-risk children could result in

secondary prevention of persistent asthma, although

this is not yet established by clinical trials.

Component 3: Pharmacologic Therapy, 

Special Considerations for Managing Asthma 

in Different Age Groups. Infants and Young

Children, Treatment (page 95, column 2 in

EPR-2)

In deciding when to initiate daily long-term-control

therapy, the clinician must weigh the possible 

long-term effects of inadequately controlled asthma

vs. the possible adverse effects of medications given

over prolonged periods. There is evidence that 

anti-inflammatory treatment can reduce morbidity

from wheezing in early childhood (Connett et al.

1993). Long-term studies in children 5 to 12 years

of age at the time of enrollment conclude that

inhaled corticosteroids improve health outcomes for

children with mild or moderate persistent asthma

and that the potential albeit small risk of delayed

growth from the use of inhaled corticosteroids is

well balanced by their effectiveness (SRE-Evidence

A) (CAMP 2000). Further, available long-term data

indicate that most children treated with inhaled 

corticosteroids achieve their predicted adult heights

(Agertoft and Pedersen 2000). It is noted that the

long-term prospective studies on growth involved

budesonide and that the retrospective analyses

included studies on beclomethasone, but the results

have been generalized to include all inhaled corticosteroid preparations. Although different preparations

and delivery devices may have a systemic effect at

different doses, all short-term studies of numerous

preparations suggest that the potential effect of

inhaled corticosteroids on growth is a drug class

effect. In children with demonstrable adverse 

effects related to inhaled corticosteroid therapy, 

other options (cromolyn, LTRA, nedocromil, 

or theophylline) for initiating or maintaining 

long-term-control therapy are available.

Based on high-quality evidence, the Expert

Panel recommends long-term-control therapy

for children with mild or moderate persistent

asthma because it controls and prevents asthma

symptoms (SRE Evidence A). However, evidence

to date is insufficient to permit conclusions

regarding whether early vs. delayed intervention

with daily long-term-control medication will

alter the underlying course of the disease.

Although a preliminary study suggests that 

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104

Prevention

appropriate control of childhood asthma may prevent more serious asthma or irreversible obstruction

in later years (Agertoft and Pedersen 1994), these

observations were not verified in a recent long-term

RCT in children 5 to 12 years of age (CAMP 2000)

(SRE-Evidence A, B). The best available evidence

does not support the assumption that children 5 to

12 years of age with mild or moderate persistent

asthma have a progressive decline in lung function

that can be prevented by early initiation of longterm-control medications. Observational prospective

data from other large groups of children suggest that

the timing of the CAMP intervention was too late,

as most loss of lung function in childhood asthma

appears to occur in the first 3 to 5 years of life

(Martinez et al. 1995). However, it has not yet been

determined whether early recognition of children at

high risk of developing persistent asthma coupled

with early therapeutic intervention will either prevent the loss of lung function or prevent the

development of persistent disease. Currently, critical

prospective studies to address these issues are in

progress. Similarly, to date no studies have evaluated

whether intervention with inhaled corticosteroids can

prevent the more rapid decline in lung function that

can occur in adults with asthma.

Recommendations for Future Research

The SRE revealed methodological problems in

most of the studies that evaluated the effect of

inhaled corticosteroids on the progression of

asthma. RCTs designed explicitly to address the

research question are urgently needed. Further, new

opportunities are now available to treat children

younger than 5 years of age in whom the incidence

of asthma onset is highest (Yuninger et al. 1992)

and the risk for declines in lung function growth is

high (Stern 2000; Castro-Rodriquez 2000). For

example, LTRA is available for children as young as

2 years of age and inhaled corticosteroid nebulizing

suspension for children as young as 1 year of age.

In addition, new classes of medication that may be

feasible for young children currently are being evaluated for their potential to modify disease: e.g.,

anti-IgE agents, cytokine antagonists, and cytokine

receptor antagonists.

Because disease onset is high in children younger

than 5 years of age and because these children are

initially evaluated and managed by primary care

physicians, it is important to establish firm diagnostic criteria for persistent asthma. Further, a

refinement in the definition of disease progression

must occur and methods to monitor progression

should be designed and evaluated for use in clinical

practice.

Specifically, more information in the following areas

is needed to enhance our knowledge about the 

natural progression of asthma in children and adults, 

as well as appropriate interventions to alter it:

■ Additional long-term studies, lasting a minimum

of 2 years, of each medication class (e.g., inhaled

corticosteroids, LTRAs, anti-IgE) in order to

define the impact of treatment on the progression

of asthma. Studies should:

• In young children, be designed to assess for

effect on measures including pulmonary function

• In adults, be designed to examine whether loss

of pulmonary function may be a unique feature

of adult asthma, especially adult-onset asthma.

■ Studies to determine the significance of declines

in lung function and its relevance to other longterm events, including quality of life and severity

of symptoms (acute exacerbations, symptoms,

nighttime awakenings). Identification of the most

appropriate pulmonary function measure to use

for monitoring lung function growth in children

and lung function declines in adults.

■ Studies to identify the prevalence of airway

remodeling and whether it can be predicted by

asthma phenotype and genotype.

■ Studies to identify methods for reliably and easily

measuring and interpreting pulmonary function

in young children. Forced oscillation could

improve the feasibility of pulmonary function

testing in young children, but these tests must 

be verified.

■ Validation of a profile to predict persistent

asthma and levels of asthma severity.

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105

Prevention

■ Studies to identify and compare relevant outcomes that define disease progression and

measure the effects of interventions to alter it.

Pulmonary function, airway hyperresponsiveness,

markers of inflammation, symptoms, medication

use, and disease severity classifications are some

outcomes of interest.

■ Studies to design and evaluate methods for use in

primary clinical practice to monitor individuals

for progression of their disease. Serial measures of

pulmonary function, assessments of medication

requirements and urgent care visits over time,

and, for infants, application of the asthma predictive index are possible approaches.

■ Studies to evaluate when long-term-control

therapy might be discontinued.

■ Studies to evaluate the effectiveness of early use 

of environmental control measures, with or

without pharmacologic therapy, alter the A

progression of disease.

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106

Prevention

Key Evidence Tables

Overbeek, Huib,

Kerstjens et al.

1996 

Haahtela,

Jarvinen, Kava et

al. 1994 

Agertoft and

Pedersen 1994 

Selroos,

Pietinalho,

Lofroos et al.

1995 

Open label extension

of randomized 

parallel arm, doubleblinded, placebo 

controlled trial 

Open label extension

of randomized 

parallel arm, 

double-blinded, 

controlled trial 

Prospective cohort

analysis within

parallel, controlled

trial; patients 

stratified by prior

duration of asthma 

Prospective cohort

study; patients 

stratified by prior

duration of asthma 

Country:

Netherlands

Funding:

Pharmacologic + 

government grant

Tx Setting:

Unknown/Other;

Multicenter 

Country: Scandinavia

Funding: 

Not specified

Tx Setting:

Unknown/Other;

Multicenter 

Country: Scandinavia

Funding: 

Not specified

Tx Setting:

Unknown/Other 

Country: Scandinavia

Funding: 

Not specified

Tx Setting:

Unknown/Other 

Stated: Not specified

Estimated: Unable to

estimate 

Stated: Mild

Estimated: Mild 

Stated: 

Mild-moderate

Estimated: 

Mild-Severe 

Stated: 

Mild-moderate

Estimated: 

Mild-Severe 

Patient eligibility based on lung

function only.

(1) FEV1 (type not specified) minimum 1.2 L and 1.64 to 4.5 residual

SDs below predicted, or FEV1/inspiratory vital capacity ratio >1.64

residual SDs below predicted.

(2) Histamine PC20 maximum 8

mg/mL.

Exclusions: Patients with medication

use or conditions likely to interfere

with the purpose of the study. 

Patient eligibility based on lung

function and symptoms.

FEV1 (postdose) minimum 80% of

predicted; increase of more than 15%

after inhalation of beta2-agonist or

decrease of more than 15% after exercise tolerance test.

Maximum duration of symptoms 

12 months.

Exclusions: History of smoking

within 6 months, regular asthma

treatment, prior treatment with corticosteroids or cromolyn.

Patient eligibility based on utilization and stated severity.

Minimum of three prior visits to

clinic within past year, with mild or

moderate persistent asthma.

Exclusions: Prior use of inhaled 

corticosteroids for more than 2 weeks

per year; other chronic diseases. 

Patient eligibility based on lung

function and symptoms.

FEV1 (type not specified) maximum

75% of predicted or PEF (a.m. clinic) maximum 75% of predicted;

and/or use of inhaled bronchodilators

>3x/week, and/or regular asthma

symptoms during day or night,

and/or reduced exercise tolerance.

Exclusions: Prior use of inhaled corticosteroids; irreversible airway

obstruction. 

Table 3-1. Study Characteristics

Citation Study Design Study Setting Asthma Severity Eligibility

Source:

Blue Cross and Blue Shield Association Technology Evaluation Center. Management of Chronic Asthma: Evidence Report/Technology Assessment Number

44. AHRQ Publication No. 01–EO44. Rockville, MD: Agency for Healthcare Research and Quality. September 2001.

Archive

for historical Reference Only
107

Prevention

Overbeek, Huib,

Kerstjens 

et al. 1996 

Haahtela, Jarvinen,

Kava et al. 1994 

Agertoft and

Pedersen 1994 

Selroos, Pietinalho,

Lofroos et al. 1995 

None 

Run-in 2

weeks to

establish

patient 

eligibility 

Run-in 52

weeks to

establish

patient 

eligibility 

None 

Inhaled corticosteroid—immediate 

Inhaled corticosteroid—delayed

Inhaled corticosteroid—immediate 

Inhaled corticosteroid—delayed

Inhaled corticosteroid—immediate 

Inhaled corticosteroid—delayed 1

Inhaled corticosteroid—delayed 2

Inhaled corticosteroid—delayed 3

Inhaled corticosteroid—immediate 

Inhaled corticosteroid—delayed 1

Inhaled corticosteroid—delayed 2

Inhaled corticosteroid—delayed 3

Inhaled corticosteroid—delayed 4

Inhaled corticosteroid—delayed 5

All patients received 200 mcg

beclomethasone dipropionate 4x daily; 

all patients received 500 mcg terbutaline

4x daily. 

All patients received 500 mcg terbutaline

4x daily for entire study.

Some patients received 40 mcg ipratropium bromide 4x daily for first 30 months

of study.

All patients received 200 mcg

beclomethasone dipropionate 4x daily for

final 6 months of study. 

All patients received 600 mcg budesonide

2x daily for first 24 months, then reduced

to 200 mcg 2x daily for final 12 months

of study. 

All patients received 600 mcg budesonide

2x daily for final 12 months of study. 

All patients received 800 mcg budesonide

daily (frequency of dosing not specified). 

All patients received 800 mcg budesonide

daily (frequency of dosing not specified). 

All patients received 800 mcg budesonide

daily (frequency of dosing not specified). 

All patients received 800 mcg budesonide

daily (frequency of dosing not specified). 

Average daily dose for entire population

454 mcg budesonide 2x daily at start 

of study; 374 mcg 2x daily after 2 years 

of treatment.

Average daily dose for entire population

454 mcg budesonide 2x daily at start 

of study; 374 mcg 2x daily after 2 years 

of treatment.

Average daily dose for entire population

454 mcg budesonide 2x daily at start 

of study; 374 mcg 2x daily after 2 years 

of treatment.

Average daily dose for entire population

454 mcg budesonide 2x daily at start 

of study; 374 mcg 2x daily after 2 years 

of treatment.

Average daily dose for entire population

454 mcg budesonide 2x daily at start 

of study; 374 mcg 2x daily after 2 years 

of treatment.

Average daily dose for entire population

454 mcg budesonide 2x daily at start 

of study; 374 mcg 2x daily after 2 years 

of treatment.

Corticosteroids delayed 

0 months, then administered 

for 36 months 

Corticosteroids delayed 

30 months, then administered 

for 6 months 

Corticosteroids delayed

0 months, then administered 

for 36 months 

Corticosteroids delayed 

24 months, then administered 

for 12 months 

Prior duration of asthma 

0–12 months; inhaled corticosteroids administered for at least

24 months 

Prior duration of asthma 

12–24 months; inhaled corticosteroids administered for at least

24 months 

Prior duration of asthma 

24–36 months; inhaled corticosteroids administered for at least

24 months 

Prior duration of asthma 

12–24 months; inhaled corticosteroids administered for at least

24 months 

Prior duration of asthma 

0–6 months; inhaled corticosteroids administered for 

24 months 

Prior duration of asthma 

6–12 months; inhaled corticosteroids administered for 

24 months 

Prior duration of asthma 

12–24 months; inhaled corticosteroids administered for 

24 months 

Prior duration of asthma 

24–60 months; inhaled corticosteroids administered for 

24 months 

Prior duration of asthma 

60–120 months; inhaled corticosteroids administered for 

24 months 

Prior duration of asthma 

>120 months; inhaled corticosteroids administered for 

24 months 

Table 3-2. Study Parameters 

Citation Pretreatment Study Arm Number Costicosteroid Treatment

Enrolled Delay

Source:

Blue Cross and Blue Shield Association Technology Evaluation Center. Management of Chronic Asthma: Evidence Report/Technology Assessment Number

44. AHRQ Publication No. 01–EO44. Rockville, MD: Agency for Healthcare Research and Quality. September 2001.

Archive

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108

Prevention

Key Evidence Tables

Table 3-3. Lung Function Outcomes: FEV1

Overbeek, Huib, Kerstjens

et al. 1996 

Haahtela, Jarvinen, Kava 

et al. 1994 

Agertoft and Pedersen 1994 

Selroos, Pietinalho, Lofroos 

et al. 1995 

Inhaled corticosteroid—

immediate 

Inhaled corticosteroid—

delayed

Inhaled corticosteroid—

immediate 

Inhaled corticosteroid—

delayed

Inhaled corticosteroid—

immediate 

Inhaled corticosteroid—

delayed 1

Inhaled corticosteroid—

delayed 2

Inhaled corticosteroid—

delayed 3

Inhaled corticosteroid—

immediate 

Inhaled corticosteroid—

delayed 1

Inhaled corticosteroid—

delayed 2

Inhaled corticosteroid—

delayed 3

Inhaled corticosteroid—

delayed 4

Inhaled corticosteroid—

delayed 5

91

183

50

53

14

35

13

19

15

9

49

53

16

36

3.0

3.0

3.0

3.0

3.7

3.7

3.7

3.7

2.0

2.0

2.0

2.0

2.0

2.0

Citation Study Arm Number Enrolled Number Evaluable Study Duration A

(years)

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109

Prevention

Source:

Blue Cross and Blue Shield Association Technology Evaluation Center. Management of Chronic Asthma: Evidence Report/Technology Assessment Number

44. AHRQ Publication No. 01–EO44. Rockville, MD: Agency for Healthcare Research and Quality. September 2001.

FEV1 Baseline FEV1 Final FEV1 P-Value Comments

64.6 +/- 14.1% predicted 

61.2 +/- 15.6% predicted 

3.17 +/- 0.8 L 

3.05 +/- 0.7 L

NR 

NR

NR

NR

70 +/- 21% predicted 

70 +/- 21% predicted 

78 +/- 18% predicted 

60 +/- 16% predicted 

62 +/- 18% predicted 

67 +/- 30.0% predicted 

13.8% pred

(change, 95% CI,

7.7–18.7) 

8.5% pred (change,

95% CI, 3.3–15.9) 

3.32 L 

3.07 L 

8.2% pred/yr

(change, 95% CI,

6.1, 10.3) 

6.7% pred/yr

(change, 95% CI,

5.0, 8.4)

3% pred/yr

(change, 95% CI,

1.8, 4.2)

2.4% pred/yr (95%

CI, 1.1, 3.7) 

87 +/- 18.7% 

predicted 

75 +/- 17.7% 

predicted .

85 +/- 18.0% 

predicted 

68 +/- 21.8% 

predicted 

66 +/- 19.4% 

predicted 

67 +/- 30.0% 

predicted 

NS 

0.100

<.0500

NS

<.0500

<.0100

Number of patients enrolled includes both COPD

and asthma patients; number evaluable includes

only asthma patients. 

Comparison only made of rise in FEV1 during 

initial 3 months’ treatment with inhaled corticosteroids in both groups. 

Values represent FEV1 at start of initial study 

and final FEV1 after 3 years. 

No statistical comparison performed on change 

in FEV1 from start of study until final end-point. 

Final FEV1 % predicted 101 +/- 13.6%

Calculation of % increase/yr in FEV1 by linear

regression probably not appropriate. 

Final FEV1 % predicted 96.2 +/- 9.5%, 

p <0.05 as compared to inhaled corticosteroidimmediate group. 

Comparison of change in FEV1 vs. Ctl 

Comparison of change in FEV1 vs. Ctl 

Comparison of change in FEV1 vs. Ctl 

Comparison of change in FEV1 vs. Ctl 

Comparison of change in FEV1 vs. Ctl 

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pulmonary function in asthmatic children. Respir Med 1994;88(5):373–81.

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Evidence Report/Technology Assessment Number 44. AHRQ Publication No. 01–EO44. Rockville, MD:

Agency for Healthcare Research and Quality, September 2001.

Castro-Rodriguez JA, Holberg CJ, Wright AL, Martinez FD. A clinical index to define risk of asthma

in young children with recurrent wheezing. Am J Respir Crit Care Med 2000;162(4 Pt 1):1403–6.

Childhood Asthma Management Program (CAMP) Research Group. Long-term effects of budesonide

or nedocromil in children with asthma. N Engl J Med 2000;343(15):1054–63.

Connett GJ, Warde C, Wooler E, Lenney W. Use of budesonide in severe asthmatics aged 1–3 years.

Arch Dis Child 1993;69(3):351–5.

Elias JA, Zhu Z, Chupp G, Homer RJ. Airway remodeling in asthma. J Clin Invest 1999;104(8):1001–6.

Finucane KE, Greville HW, Brown PJ. Irreversible airflow obstruction: Evolution in asthma. Med J

Aust 1985;142(11):602–4.

Haahtela T, Jarvinen M, Kava T, Kiviranta K, Koskinen S, Lehtonen K, Nikander K, Persson T,

Selroos O, Sovijarvi A, et al. Effects of reducing or discontinuing inhaled budesonide in patients

with mild asthma. N Engl J Med 1994;331(11):700–5.

Lange P, Parner J, Vestbo J, Schnohr P, Jensen G. A 15-year follow-up study of ventilatory function in

adults with asthma. N Engl J Med 1998;339(17):1194–200.

Lau S, Illi S, Sommerfeld C, Niggemann B, Bergmann R, von Mutius E, Wahn U. Early exposure to

house-dust mite and cat allergens and development of childhood asthma: a cohort study. Lancet

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Overbeek SE, Kerstjens HA, Bogaard JM, Mulder PG, Postma DS. The Dutch Chronic Nonspecific

Lung Disease Study Groups. Is delayed introduction of inhaled corticosteroids harmful in patients

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Peat JK, Woolcock AJ, Cullen K. Rate of decline of lung function in subjects with asthma. Eur J

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Pullan CR, Hey EN. Wheezing, asthma, and pulmonary dysfunction 10 years after infection with 

respiratory syncytial virus in infancy. Br Med J 1982;284(6330):1665–9.

Selroos O, Pietinalho A, Lofroos AB, Riska H. Effect of early vs. late intervention with inhaled 

corticosteroids in asthma. Chest 1995;108(5):1228–34.

Stern DA, Burrows B, Halonen M, Wright AL, Martinez FD. Increased prevalence of asthma in Anglo

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Archive

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Archive

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Appendix A:

Updated Charts for the

Management of Asthma

Asthma Expert Panel Report:

Guidelines for the

Diagnosis and

Management of

Asthma

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115

Appendix A–1. STEPWISE APPROACH FOR MANAGING ASTHMA

Figure 1. Stepwise Approach for Managing Infants and Young Children (5 Years of Age and Younger) 

With Acute or Chronic Asthma (Updates EPR-2 Figures 3–4a and 3–6)

Severe Persistent

Moderate Persistent

Mild Persistent

Mild Intermittent

Step 4

Step 3

Symptoms/Day

Symptoms/Night

Continual

Frequent

Daily

>1 night/week

>2/week but <1x/day

>2 nights/month

≤2 days/week

≤2 nights/month

Daily Medications

■ Preferred treatment:

– High-dose inhaled corticosteroids

AND

– Long-acting inhaled beta2-agonists

AND, if needed,

– Corticosteroid tablets or syrup long term (2 mg/kg/day, generally do not exceed

60 mg per day). (Make repeat attempts to reduce systemic corticosteroids and 

maintain control with high-dose inhaled corticosteroids.)

■ Preferred treatments:

– Low-dose inhaled corticosteroids and long-acting inhaled beta2-agonists

OR

– Medium-dose inhaled corticosteroids.

■ Alternative treatment:

– Low-dose inhaled corticosteroids and either leukotriene receptor antagonist 

or theophylline.

If needed (particularly in patients with recurring severe exacerbations):

■ Preferred treatment:

– Medium-dose inhaled corticosteroids and long-acting beta2-agonists.

■ Alternative treatment:

– Medium-dose inhaled corticosteroids and either leukotriene receptor 

antagonist or theophylline.

■ Preferred treatment:

– Low-dose inhaled corticosteroids (with nebulizer or MDI with 

holding chamber with or without face mask or DPI).

■ Alternative treatment (listed alphabetically):

– Cromolyn (nebulizer is preferred or MDI with holding chamber) 

OR leukotriene receptor antagonist.

■ No daily medication needed.

Note

■ The stepwise approach is intended to assist, not replace, the clinical decisionmaking required to meet individual patient needs.

■ Classify severity: assign patient to most severe step in which any feature occurs. 

■ There are very few studies on asthma therapy for infants.

■ Gain control as quickly as possible (a course of short systemic corticosteroids may

be required); then step down to the least medication necessary to maintain control.

■ Minimize use of short-acting inhaled beta2-agonists. Overreliance on short-acting

inhaled beta2-agonists (e.g., use of short-acting inhaled beta2-agonist every day,

increasing use or lack of expected effect, or use of approximately one canister a 

month even if not using it every day) indicates inadequate control of asthma and the 

need to initiate or intensify long-term-control therapy.

■ Provide parent education on asthma management and controlling environmental 

factors that make asthma worse (e.g., allergens and irritants).

■ Consultation with an asthma specialist is recommended for patients with moderate or 

severe persistent asthma. Consider consultation for patients with mild persistent asthma.

Classify Severity: Clinical Features Before Treatment or

Adequate Control

Medications Required To Maintain Long-Term Control

Step 2

Step 1

■ Bronchodilator as needed for symptoms. Intensity of treatment will depend upon severity of exacerbation. 

– Preferred treatment: Short-acting inhaled beta2-agonists by nebulizer or face mask and space/holding chamber

– Alternative treatment: Oral beta2-agonists

■ With viral respiratory infection

– Bronchodilator q 4–6 hours up to 24 hours (longer with physician consult); in general, repeat no more than 

once every 6 weeks

– Consider systemic corticosteroid if exacerbation is severe or patient has history of previous severe exacerbations

■ Use of short-acting beta2-agonists >2 times a week in intermittent asthma (daily, or increasing use in persistent asthma) 

may indicate the need to initiate (increase) long-term-control therapy. 

Quick Relief

All Patients

Step down

Review treatment every 1 to 6 months; a gradual stepwise 

reduction in treatment may be possible.

Step up

If control is not maintained, consider step up. First, review patient

medication technique, adherence, and environmental control.

■ Minimal or no chronic 

symptoms day or night

■ Minimal or no exacerbations 

■ No limitations on activities; 

no school/parent’s work missed

■ Minimal use of short-acting 

inhaled beta2-agonist 

■ Minimal or no adverse effects 

from medications

Goals of Therapy: Asthma Control

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116

APPENDIX A–1. STEPWISE APPROACH FOR MANAGING ASTHMA (continued)

Figure 2. Stepwise Approach for Managing Asthma in Adults and Children Older Than 5 Years of Age:

Treatment (Updates EPR-2 Figures 3–4a and 3–4b)

Severe Persistent

Moderate Persistent

Mild Persistent

Mild Intermittent

Step 4

Step 3

Symptoms/Day

Symptoms/Night

Continual

Frequent

Daily

>1 night/week

>2/week but < 1x/day

>2 nights/month

≤2 days/week

≤2 nights/month

PEF or FEV1

PEF Variability

≤60%

>30%

>60% – <80%

>30%

≥80%

20–30%

≥80%

<20%

Classify Severity: Clinical Features Before Treatment or 

Adequate Control

Medications Required To Maintain 

Long-Term Control

Step 2

Step 1

Step down

Review treatment every 1 to 6 months; a gradual stepwise

reduction in treatment may be possible.

Step up

If control is not maintained, consider step up. First, review patient

medication technique, adherence, and environmental control.

■ Short-acting bronchodilator: 2–4 puffs short-acting inhaled beta2-agonists as needed for symptoms.

■ Intensity of treatment will depend on severity of exacerbation; up to 3 treatments at 20-minute 

intervals or a single nebulizer treatment as needed. Course of systemic corticosteroids may be needed.

■ Use of short-acting beta2-agonists >2 times a week in intermittent asthma (daily, or increasing use in 

persistent asthma) may indicate the need to initiate (increase) long-term-control therapy. 

Quick Relief

All Patients

Note

■ The stepwise approach is meant to assist, not replace, the clinical decisionmaking 

required to meet individual patient needs.

■ Classify severity: assign patient to most severe step in which any feature occurs 

(PEF is % of personal best; FEV1 is % predicted).

■ Gain control as quickly as possible (consider a short course of systemic corticosteroids);

then step down to the least medication necessary to maintain control.

■ Minimize use of short-acting inhaled beta2-agonists. Overreliance on short-acting inhaled 

beta2-agonists (e.g., use of short-acting inhaled beta2-agonist every day, increasing use or

lack of expected effect, or use of approximately one canister a month even if not using it

every day) indicates inadequate control of asthma and the need to initiate or intensify 

long-term-control therapy.

■ Provide education on self-management and controlling environmental factors that 

make asthma worse (e.g., allergens and irritants).

■ Refer to an asthma specialist if there are difficulties controlling asthma or if step 4 

care is required. Referral may be considered if step 3 care is required.

■ Minimal or no chronic 

symptoms day or night

■ Minimal or no exacerbations 

■ No limitations on activities; no 

school/work missed

■ Maintain (near) normal pulmonary 

function

■ Minimal use of short-acting inhaled 

beta2-agonist 

■ Minimal or no adverse effects 

from medications

Goals of Therapy: Asthma Control

Daily Medications

■ Preferred treatment:

– High-dose inhaled corticosteroids

AND

– Long-acting inhaled beta2-agonists

AND, if needed,

– Corticosteroid tablets or syrup long term (2 mg/kg/day, 

generally do not exceed 60 mg per day). (Make repeat 

attempts to reduce systemic corticosteroids and maintain 

control with high-dose inhaled corticosteroids.)

■ Preferred treatment:

– Low-to-medium dose inhaled corticosteroids and 

long-acting inhaled beta2-agonists.

■ Alternative treatment (listed alphabetically):

– Increase inhaled corticosteroids within medium-dose range

OR

– Low-to-medium dose inhaled corticosteroids and either 

leukotriene modifier or theophylline.

If needed (particularly in patients with recurring severe exacerbations):

■ Preferred treatment:

– Increase inhaled corticosteroids within medium-dose 

range and add long-acting inhaled beta2-agonists.

■ Alternative treatment:

– Increase inhaled corticosteroids within medium-dose range 

and add either leukotriene modifier or theophylline.

■ Preferred treatment:

– Low-dose inhaled corticosteroids.

■ Alternative treatment (listed alphabetically): cromolyn, 

leukotriene modifier, nedocromil, OR sustained release 

theophylline to serum concentration of 5–15 mcg/mL.

■ No daily medication needed.

■ Severe exacerbations may occur, separated by long periods 

of normal lung function and no symptoms. A course of 

systemic corticosteroids is recommended.

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117

APPENDIX A–2. USUAL DOSAGES FOR ASTHMA MEDICATIONS

Figure 1. Usual Dosages for Long-Term-Control Medications (Updates EPR-2 Figure 3–5a)

Medication

Inhaled Corticosteroids (See Estimated Comparative Daily Dosages for Inhaled Corticosteroids.)

Systemic Corticosteroids

Methylprednisolone

Prednisolone

Prednisone

Long-Acting Inhaled Beta2-Agonists 

Salmeterol

Formoterol

Dosage Form

2, 4, 8, 16, 32 mg

tablets

5 mg tablets,

5 mg/5 cc,

15 mg/5 cc

1, 2.5, 5, 10, 20, 50 mg

tablets;

5 mg/cc, 5 mg/5 cc

MDI 21 mcg/puff

DPI 50 mcg/blister

DPI 12 mcg/single-use 

capsule

Adult Dose

7.5–60 mg daily in 

a single dose in a.m. 

or qod as needed for 

control

Short-course “burst”: 

to achieve control 

40–60 mg per day 

as single or 2 divided 

doses for 3–10 days

2 puffs q 12 hours

1 blister q 12 hours

1 capsule q 12 hours

Child Dose*

0.25–2 mg/kg daily in 

single dose in a.m. 

or qod as needed for 

control

Short-course “burst”:

1–2 mg/kg/day, 

maximum 60 mg/day 

for 3–10 days

1–2 puffs q 12 hours

1 blister q 12 hours

1 capsule q 12 hours

Comments

■ For long-term treatment 

of severe persistent 

asthma, administer single

dose in a.m. either daily 

or on alternate days 

(alternate-day therapy 

may produce less adrenal 

suppression). If daily 

doses are required, one 

study suggests improved 

efficiency and no increase in

adrenal suppression when 

administered at 3 p.m.

(Beam et al. 1992).

■ Short courses or “bursts” 

are effective for establishing

control when initiating 

therapy or during a 

period of gradual 

deterioration.

■ The burst should be 

continued until patient 

achieves 80% PEF personal

best or symptoms resolve. 

This usually requires

3–10 days but may 

require longer. There 

is no evidence that 

tapering the dose following

improvement prevents 

relapse.

■ Should not be used for 

symptom relief or 

exacerbations. Use with

corticosteroids.

■ May use one dose nightly 

for symptoms.

■ Efficacy and safety have 

not been studied in 

children <5 years of age.

■ Each capsule is for single 

use only; additional doses 

should not be administered for at least 12 hours.

■ Capsules should be used 

only with the AerolizorTM

inhaler and should not be 

taken orally.

A

(Applies to all three corticosteroids)

rchive

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118

APPENDIX A–2. USUAL DOSAGES FOR ASTHMA MEDICATIONS (continued)

Figure 1. Usual Dosages for Long-Term-Control Medications (Updates EPR-2 Figure 3–5a)

Medication

Combined Medication

Fluticasone/Salmeterol

Cromolyn and Nedocromil

Cromolyn

Nedocromil

Leukotriene Modifiers

Montelukast

Zafirlukast

Zileuton

Methylxanthines

Theophylline

Dosage Form

DPI 100 mcg, 

250 mcg, or 500 mcg/

50 mcg

MDI 1 mg/puff

Nebulizer 

20 mg/ampule

MDI 1.75 mg/puff

4 mg or 5 mg chewable

tablet

10 mg tablet

10 or 20 mg tablet

300 or 600 mg tablet

Liquids, sustained-release

tablets, and capsules

Adult Dose

1 inhalation bid; dose

depends on severity of 

asthma

2–4 puffs tid-qid

1 ampule tid-qid

2–4 puffs bid-qid

10 mg qhs

40 mg daily

(20 mg tablet bid)

2,400 mg daily

(give tablets qid)

Starting dose 10

mg/kg/day up to 300 mg

max; usual max 800

mg/day

Child Dose*

1 inhalation bid; dose

depends on severity of

asthma

1–2 puffs tid-qid

1 ampule tid-qid

1–2 puffs bid-qid

■ 4 mg qhs

(2–5 years of age)

5 mg qhs

(6–14 years of age)

10 mg qhs

(>14 years of age)

■ 20 mg daily

(7–11 years of age)

(10 mg tablet bid)

Starting dose 10

mg/kg/day; usual max:

■ <1 year of age:

0.2 (age in weeks) 

+ 5 = mg/kg/day

■ ≥1 year of age:

16 mg/kg/day

Comments

■ Not FDA approved in 

children <12 years of 

age.

100/50 for patient not 

controlled on low-tomedium dose inhaled 

corticosteroids.

250/50 for patients 

not controlled on 

medium-to-high dose 

inhaled corticosteroids.

■ One dose prior to 

exercise or allergen 

exposure provides 

effective prophylaxis 

for 1–2 hours.

■ See cromolyn above.

■ Montelukast exhibits a

flat dose-response 

curve. Doses >10 mg 

will not produce a 

greater response in 

adults.

■ For zafirlukast, 

administration with 

meals decreases 

bioavailability; 

take at least 1 hour 

before or 2 hours after 

meals.

■ For zileuton, monitor 

hepatic enzymes (ALT).

■ Adjust dosage to 

achieve serum concentration of 5–15 

mcg/mL at steadystate (at least 48 hours

on same dosage).

■ Due to wide interpatient variability in 

theophylline metabolic 

clearance, routine 

serum theophylline 

level monitoring is 

important.

■ See figure 3–5a, 

page 87, EPR-2 for 

factors that can affect 

theophylline levels.

*Children ≤ 12 years of age

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119

APPENDIX A–2. USUAL DOSAGES FOR ASTHMA MEDICATIONS (continued)

Figure 2. Estimated Comparative Daily Dosages for Inhaled Corticosteroids

(Updates EPR-2 Figure 3–5b)

Drug

Beclomethasone CFC

42 or 84 mcg/puff

Beclomethasone HFA

40 or 80 mcg/puff

Budesonide DPI

200 mcg/inhalation

Inhalation suspension for 

nebulization (child dose)

Flunisolide

250 mcg/puff

Fluticasone

MDI: 44, 110, or 220 

mcg/puff

DPI: 50, 100, or 250 mcg/

inhalation

Triamcinolone acetonide

100 mcg/puff

Adult

168–504 mcg

80–240 mcg

200–600 mcg

500–

1,000 mcg

88–264 mcg

100–300 mcg

400–1,000 mcg

Child*

84–336 mcg

80–160 mcg

200–400 mcg

0.5 mg

500–750 mcg

88–176 mcg

100–200 mcg

400–800 mcg

Child*

336–672 mcg

160–320 mcg

400–800 mcg

1.0 mg

1,000–1,250 mcg

176–440 mcg

200–400 mcg

800–1,200 mcg

Low Daily Dose Medium Daily Dose

Adult

> 840 mcg

> 480 mcg

> 1,200 mcg

> 2,000 mcg

> 660 mcg

> 600 mcg

> 2,000 mcg

High Daily Dose

Child*

> 672 mcg

> 320 mcg

> 800 mcg

2.0 mg

> 1,250 mcg

> 440 mcg

> 400 mcg

> 1,200 mcg

Adult

504–840 mcg

240–480 mcg

600–1,200 mcg

1,000–

2,000 mcg

264–660 mcg

300–600 mcg

1,000–2,000 mcg

* Children ≤12 years of age

Note

■ The most important determinant of appropriate dosing is the clinician’s judgment of the patient’s response to therapy.

The clinician must monitor the patient’s response on several clinical parameters and adjust the dose accordingly. The stepwise approach to therapy

emphasizes that once control of asthma is achieved, the dose of medication should be carefully titrated to the minimum dose required to maintain

control, thus reducing the potential for adverse effect.

■ Comparative dosages in the EPR-2 were based on a limited number of published comparative clinical trials and extrapolation of differences in 

topical potency and lung delivery. This updated comparative dosage chart is based on review of recently published clinical trials involving more 

than 5,000 patients and published reviews (Barnes PJ et al. 1998; Kelly 1998; Pedersen 1997). The key differences from the EPR-2 include a 

higher dosage of budesonide and recommendations for two newly available medications: beclomethasone HFA and budesonide suspension for 

nebulization. The rationale for these changes is summarized as follows:

– The high dose is the dose that appears likely to be the threshold beyond which significant hypothalamic-pituitary-adrenal (HPA) axis 

suppression is produced, and, by extrapolation, the risk is increased for other clinically significant systemic effects if used for prolonged 

periods of time (Martin et al. 2002; Szefler et al. 2002). 

– The low and medium dose reflects findings from dose-ranging studies in which incremental efficacy within the low-to-medium dose ranges 

was established without increased systemic effect as measured by overnight cortisol excretion. The studies demonstrated a relatively flat 

dose-response curve for efficacy at the medium-dose range; that is, increasing the dose to high-dose range did not significantly increase 

efficacy but did increase systemic effect (Martin et al. 2002; Szefler et al. 2002). 

– The dose for budesonide dry powder inhaler (DPI) is based on recently available comparative data with other medications, rather than the 

comparison to budesonide metered-dose inhaler (MDI) that was used in the EPR-2. These new data, including a meta-analysis of seven 

studies, show that budesonide DPI is comparable to approximately one-half the microgram dose of fluticasone (Barnes NC et al. 1998; 

Nielsen and Dahl 2000).

– The dose for beclomethasone HFA is one-half the dose for beclomethasone CFC, based on studies demonstrating that the different 

pharmaceutical properties of the medications result in enhanced lung delivery for the HFA (a less forceful spray from the HFA propellant and

a reengineered nozzle that allows a smaller particle size) (Leach et al. 1998; Busse et al. 1999; Gross et al. 1999; Thompson et al. 1998). 

– The dose for budesonide nebulizer suspension is based on efficacy and safety studies (Baker et al. 1999; Kemp et al. 1999; Shapiro et al. 

1998), but no comparative studies with other inhaled corticosteroids are available. It is noted that the efficacy studies did not demonstrate a

clear or consistent dose-response, although the high dose of 2.0 mg was effective in a placebo-controlled study in 40 infants with severe 

asthma (de Blic et al. 1996). In a small open-label long-term safety study, the ACTH stimulated cortisols appeared lower in the 13 infants 

receiving the high dose of 2.0 mg budesonide compared to infants receiving lower doses, but this was not statistically significant due, 

perhaps, to the small study size (Scott and Skoner 1999). 

■ Some doses may be outside package labeling, especially in the high-dose range.

■ MDI dosages are expressed as the actuater dose (the amount of the drug leaving the actuater and delivered to the patient), which is the labeling 

required in the United States. This is different from the dosage expressed as the valve dose (the amount of drug leaving the valve, not all of which

is available to the patient), which is used in many European countries and in some scientific literature. DPI doses are expressed as the amount of 

drug in the inhaler following activation. 

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120

APPENDIX A–2. USUAL DOSAGES FOR ASTHMA MEDICATIONS (continued)

Figure 3. Usual Dosages for Quick-Relief Medications (Updates EPR-2 Figure 3–5d)

Dosage Form

MDI

90 mcg/puff, 

200 puffs

90 mcg/puff, 

200 puffs

200 mcg/puff, 

400 puffs

DPI

200 mcg/capsule

Nebulizer solution

5 mg/mL (0.5%)

2.5 mg/3 mL

1.25 mg/3 mL

0.63 mg/3 mL

Nebulizer solution

2 mg/mL (0.2%)

Nebulizer solution

0.31 mg/3 mL

0.63 mg/3 mL

1.25 mg/3 mL

Adult Dose

■ 2 puffs 5 minutes 

prior to exercise

■ 2 puffs tid-qid prn

1–2 capsules q 4–6 hours

as needed and prior to

exercise

1.25–5 mg in 3 cc of

saline q 4–8 hours

0.5–3.5 mg (0.25–1 cc) 

in 2–3 cc of saline q 

4–8 hours 

0.63 mg–2.5 mg q 

4–8 hours

Child Dose*

■ 1–2 puffs 5 minutes 

prior to exercise

■ 2 puffs tid-qid prn

1 capsule q 4–6 hours 

as needed and prior to 

exercise

0.05 mg/kg (min 1.25 mg,

max 2.5 mg) in 3 cc of

saline q 4–6 hours

Not established

0.025 mg/kg (min. 0.63

mg, max. 1.25 mg) q 

4–8 hours

Comments

■ An increasing use or lack of 

expected effect indicates 

diminished control of asthma.

■ Not generally recommended 

for long-term treatment. 

Regular use on a daily basis 

indicates the need for 

additional long-termcontrol therapy.

■ Differences in potency 

exist, but all products are 

essentially comparable on a 

per puff basis.

■ May double usual dose for 

mild exacerbations.

■ Nonselective agents (i.e., 

epinephrine, isoproterenol, 

metaproterenol) are not 

recommended due to their 

potential for excessive 

cardiac stimulation, 

especially in high doses.

■ May mix with cromolyn or 

ipratropium nebulizer 

solutions. May double dose 

for severe exacerbations.

■ May not mix with other 

nebulizer solutions.

■ 0.63 mg of levalbuterol is equivalent in efficacy and side effects to 

1.25 mg of racemic albuterol. 

The product is a sterile-filled 

preservative-free unit dose vial.

Medication

Short-Acting Inhaled Beta2-Agonists

Albuterol

Albuterol HFA

Pirbuterol

Albuterol Rotahaler

Albuterol

Bitolterol

Levalbuterol

(R-albuterol)

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121

APPENDIX A–2. USUAL DOSAGES FOR ASTHMA MEDICATIONS (continued)

Figure 3. Usual Dosages for Quick-Relief Medications (Updates EPR-2 Figure 3–5d)

Dosage Form

MDI

18 mcg/puff, 200 puffs

Nebulizer solution

0.25 mg/mL (0.025%)

MDI

18 mcg/puff of ipratropium

bromide and 90 mcg/puff

of albuterol.

200 puffs/canister

Nebulizer solution

0.5 mg/3 mL ipratropium

bromide and 2.5 mg/3 mL

albuterol

2, 4, 6, 8, 16, 32 mg

tablets

5 mg tablets, 5 mg/5 cc,

15 mg/5 cc

1, 2.5, 5, 10, 20, 50 mg

tablets; 5 mg/cc, 

5 mg/5 cc

Repository injection

40 mg/mL

80 mg/mL

Adult Dose

2–3 puffs q 6 hours

0.25 mg q 6 hours

2–3 puffs q 6 hours

3 mL q 4–6 hours

■ Short course “burst”:

40–60 mg/day as 

single or 2 divided 

doses for 3–10 days

240 mg IM once

Child Dose*

1–2 puffs q 6 hours

0.25–0.5 mg q 6 hours

1–2 puffs q 8 hours

1.5–3 mL q 8 hours

■ Short course “burst” 

1–2 mg/kg/day, 

maximum 60 mg/day, 

for 3–10 days

7.5 mg/kg IM once

Comments

■ Evidence is lacking 

for anticholinergics 

producing added benefit

to beta2-agonists in

long-term-control 

asthma therapy.

■ Contains EDTA to 

prevent discoloration 

of the solution. This 

additive does not

induce bronchospasm.

■ Short courses or 

“bursts” are effective for

establishing control 

when initiating therapy

or during a period of 

gradual deterioration.

■ The burst should be 

continued until patient 

achieves 80% PEF 

personal best or symptoms resolve. This usually requires 3–10 days 

but may require longer. 

There is no evidence 

that tapering the dose 

following improvement 

prevents relapse.

■ May be used in place of

a short burst of oral 

steroids in patients who

are vomiting or if 

adherence is a problem.

Medication

Anticholinergics

Ipratropium

Ipratropium 

with albuterol

Systemic Corticosteroids

Methylprednisolone

Prednisolone

Prednisone

(Methylprednisolone 

acetate)

(Applies to the first three corticosteroids)

* Children ≤12 years of age

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APPENDIX A–2. USUAL DOSAGES FOR ASTHMA MEDICATIONS 

Figure 4. Dosages of Drugs for Asthma Exacerbations in Emergency Medical Care or Hospital 

(Updates EPR-2 Figure 3–10)

Adult Dose

2.5–5 mg every 20 minutes for

3 doses, then 2.5–10 mg every 

1–4 hours as needed, or 10–15

mg/hour continuously

4–8 puffs every 20 minutes up to

4 hours, then every 1–4 hours as

needed

See albuterol dose

See albuterol dose

1.25–2.5 mg every 20 minutes for

3 doses, then 1.25–5 mg every

1–4 hours as needed, or 5–7.5

mg/hour continuously

See albuterol dose

0.3–0.5 mg every 20 minutes for

3 doses sq

0.25 mg every 20 minutes for

3 doses sq

Child Dose*

0.15 mg/kg (minimum dose 2.5

mg) every 20 minutes for 3 doses,

then 0.15–0.3 mg/kg up to 10

mg every 1–4 hours as needed, or

0.5 mg/kg/hour by continuous

nebulization

4–8 puffs every 20 minutes for

3 doses, then every 1–4 hours

inhalation maneuver. Use

spacer/holding chamber

See albuterol dose; thought to be

half as potent as albuterol on 

a mg basis

See albuterol dose

0.075 mg/kg (minimum dose

1.25 mg) every 20 minutes for 

3 doses, then 0.075–0.15 mg/kg

up to 5 mg every 1–4 hours as

needed, or 0.25 mg/kg/hour by

continuous nebulization

See albuterol dose; thought to be

half as potent as albuterol on a mg

basis

0.01 mg/kg up to 0.3–0.5 mg

every 20 minutes for 3 doses sq

0.01 mg/kg every 20 minutes for

3 doses then every 2–6 hours as

needed sq

Comments

Only selective beta2-agonists are

recommended. For optimal delivery, dilute aerosols to minimum of

3 mL at gas flow of 6–8 L/min.

As effective as nebulized therapy if

patient is able to coordinate.

Has not been studied in severe

asthma exacerbations. Do not mix

with other drugs.

Has not been studied in severe

asthma exacerbations.

0.63 mg of levalbuterol is equivalent to 1.25 mg of racemic albuterol

for both efficacy and side effects.

Has not been studied in severe

asthma exacerbations.

No proven advantage of systemic

therapy over aerosol.

No proven advantage of systemic

therapy over aerosol.

Medication

Short-Acting Inhaled Beta2-Agonists

Albuterol

Nebulizer solution

(5.0 mg/mL,

2.5 mg/3 mL,

1.25 mg/3 mL,

0.63 mg/3 mL)

MDI

(90 mcg/puff)

Bitolterol

Nebulizer solution

(2 mg/mL)

MDI

(370 mcg/puff)

Levalbuterol

(R-albuterol)

Nebulizer solution

(0.63 mg/3 mL, 

1.25 mg/3 mL)

Pirbuterol

MDI

(200 mcg/puff)

Systemic (Injected) Beta2-Agonists

Epinephrine 

1:1000 (1 mg/mL)

Terbutaline

(1 mg/mL)

Dosages Archive

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123

APPENDIX A–2. USUAL DOSAGES FOR ASTHMA MEDICATIONS (continued)

Figure 4. Dosages of Drugs for Asthma Exacerbations in Emergency Medical Care or Hospital 

(Updates EPR-2 Figure 3–10)

Adult Dose

0.5 mg every 30 minutes for 3

doses then every 2–4 hours as

needed

4–8 puffs as needed

3 mL every 30 minutes for 

3 doses, then every 2–4 hours 

as needed

4–8 puffs as needed

120–180 mg/day in 3 or 4

divided doses for 48 hours, then

60–80 mg/day until PEF reaches

70% of predicted or personal

best

Child Dose*

0.25 mg every 20 minutes for 3

doses, then every 2 to 4 hours

4–8 puffs as needed

1.5 mL every 20 minutes for 

3 doses, then every 2–4 hours

4–8 puffs as needed 

1 mg/kg every 6 hours for 48

hours then 1–2 mg/kg/day

(maximum = 60 mg/day) in 2

divided doses until PEF 70% of

predicted or personal best

Comments

May mix in same nebulizer with

albuterol. Should not be used as 

first-line therapy; should be added to

beta2-agonist therapy.

Dose delivered from MDI is low 

and has not been studied in asthma

exacerbations.

Contains EDTA to prevent discoloration. This additive does not induce

bronchospasm.

For outpatient “burst” use 40–60 mg

in single or 2 divided doses for adults

(children: 1–2 mg/kg/day, maximum

60 mg/day) for 3–10 days.

Medication

Anticholinergics

Ipratropium bromide

Nebulizer solution

(0.25 mg/mL)

MDI

(18 mcg/puff)

Ipratropium with albuterol

Nebulizer solution

(Each 3 mL vial contains 

0.5 mg ipratropium 

bromide and 2.5 mg 

albuterol.)

MDI

(Each puff contains 

18 mcg ipratropium 

bromide and

90 mcg of albuterol.)

Systemic Corticosteroids

Prednisone

Methylprednisolone

Prednisolone

Dosages

Note

No advantage has been found for higher dose corticosteroids in severe asthma exacerbations, nor is there any advantage for intravenous administration over oral therapy provided gastrointestinal transit time or absorption is not impaired. The usual regimen is to continue the frequent multiple

daily dose until the patient achieves an FEV1 or PEF of 50 percent of predicted or personal best and then lower the dose to twice daily. This usually

occurs within 48 hours. Therapy following a hospitalization or emergency department visit may last from 3 to 10 days. If patients are then started

on inhaled corticosteroids, studies indicate there is no need to taper the systemic corticosteroid dose. If the followup systemic corticosteroid therapy

is to be given once daily, one study indicates that it may be more clinically effective to give the dose in the afternoon at 3 p.m., with no increase in

adrenal suppression (Beam et al. 1992).

* Children ≤12 years of age

(Dosages and comments apply to all three corticosteroids)

Archive

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safety of budesonide inhalation suspension (Pulmicort Respules) in young children with inhaled

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beclomethasone dipropionate extrafine aerosol. Respir Med 1998;92(suppl):33–39.

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Appendix B: 

Acronyms and Abbreviations

Asthma Expert Panel Report:

Guidelines for the

Diagnosis and

Management of

Asthma

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129

Appendix B: 

Acronyms and

Abbreviations

ACTH adrenocorticotropic hormone

AHRQ Agency for Healthcare Research and Quality

BDP beclomethasone dipropionate

BMD bone mineral density

BUD budesonide

CAMP Childhood Asthma Management Program

CI confidence interval

COPD chronic obstructive pulmonary disease

ctl control arm

DPI dry powder inhaler

EIB exercise-induced bronchospasm

EPR—Update2002

EPR-2 Expert Panel Report-2

FDA Federal Drug Administration

FEV1 forced expiratory volume in 1 second

FP fluticasone propionate

HPA hypothalamic-pituitary-adrenal

IFN interferon

IL interleukin

kg kilogram

LTRA leukotriene receptor antagonist

MDI metered-dose inhaler

MeSH Medical Subject Heading

mg milligram

mL milliliter

NA not available

NAEPP National Asthma Education and Prevention Program

NHLBI National Heart, Lung, and Blood Institute

NR not reported

PEF peak expiratory flow

pharm. ind. pharmaceutical industry

Pred predicted

RCT randomized controlled trial

SD standard deviation

SRE systematic review of the evidence

sx symptoms

TEC Technology Evaluation Center

Th T-helper

tx treatment

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National Heart, Lung, 

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Guidelines for the Diagnosis and Management of Asthma

Expert Panel Report: Update on Selected Topics 2002

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