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ARTICLE |
a Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
b Department of Health Policy and Management, Harvard School of Public Health, Boston, Massachusetts
c Yale School of Medicine, New Haven, Connecticut
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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METHODS. Using data that are available from the Childhood Asthma Management Program, we examined the relationship between prebronchodilator FEV1% and important clinical outcomes. Multiple observations of FEV1 were available for each patient; multivariate regression analysis, using a general estimating equation approach, was used to control for the correlation between repeated measurements among individuals and potential confounders. FEV1% was categorized into 4 levels and as a continuous variable. Outcomes of interest included mean symptom score (0–3), episode-free days, and asthma-related events (oral steroid use, emergency department visits, and hospitalizations) during the ensuing 4-month period. Our analysis was limited to the placebo group (N = 417).
RESULTS. We observed a clear relationship between prebronchodilator FEV1% and important clinical outcomes. In multivariable models that simultaneously controlled for covariates of interest, age at baseline, time, previous event history, and nocturnal awakenings, a significant relationship between FEV1% and asthma symptoms and serious asthma exacerbations (oral steroids, emergency department visits, and hospitalizations) was observed. Compared with children with an FEV1% 
100%, children with FEV1% 80% to 99%, 60% to 79%, and <60% were 1.3, 1.8, and 4.8, respectively, more likely to have a serious asthma exacerbation during the ensuing 4 months.
CONCLUSIONS. In children with mild to moderate asthma, FEV1% predicted is independently associated with future asthma symptoms and health care utilization. Previous asthma-related hospitalizations and nocturnal symptoms also were independently associated with risk for future adverse events. FEV1 is an important component of asthma health status and asthma severity classification.
Key Words: asthma • spirometry • treatment outcome • severity classification
Abbreviations: NAEPP—National Asthma Education and Prevention Program • FEV1—forced expiratory volume in 1 second • FEV1%—forced expiratory volume in 1 second percentage • CAMP—Childhood Asthma Management Program • EFD—episode-free day
Severity classification methods can serve a number of useful functions in the description, analysis, and management of asthma. They allow us to define a set of measures by which we can understand physiologic differences between patients that translate into differences in important clinical outcomes both across patients and across time within a given patient. They also provide objective markers and contribute to better standardization of clinical studies. Accurate classification helps ascertainment of whether outcome differences can be attributed to intervention rather than observations that are made in more heterogeneous groups of patients. For decision-analytic purposes, they can be used to relate an objective measure of disease to likely costs and/or health gains that are associated with interventions. Finally, they can be used to guide patient care and decision about therapy. For all of these reasons, there has been considerable effort devoted to developing disease severity classification schemes in asthma.
Spirometry is recommended for the screening, diagnosis, and monitoring of respiratory disease and is increasingly advocated in primary care practice1–4 as a useful tool for the diagnosis and monitoring of individuals with lung disease. The National Asthma Education and Prevention Program (NAEPP) Expert Panel Report 2 Guidelines5 recommend spirometry for diagnosing and assessing the severity of asthma to make "appropriate therapeutic recommendations." The advantages of forced expiratory volume in 1 second (FEV1) as a marker of asthma severity include its objectivity and reproducibility6,7 with an intraclass correlation in the range of 0.85, comparable to values for BMI (0.85) and height (0.95). Because many downstream consequences of asthma are the direct result of airway obstruction, it is intuitively appealing to use a test that measures the level of baseline obstruction. In the Pediatric Asthma Care Patient Outcomes Research Team trial, baseline spirometry predicted asthma symptom days during 1 year of observation.8 However, the evidence for a relationship between FEV1 percentage (FEV1%) and risk for asthma outcomes is mixed. An association between lung function and serious asthma exacerbations has been demonstrated in adult and pediatric observational cohorts.9,10 A strong association between FEV1% predicted and risk for an asthma attack in the subsequent year was found in a pediatric population that was followed longitudinally in the Six City Population, supporting the emphasis on FEV1% in the risk assessment for adverse asthma outcomes.10 In 2 similarly designed but independent adult populations, FEV1% predicted was significantly associated with risk for an asthma attack during the 3 years after its measurement. After adjustment for current smoking and gender, FEV1% predicted remained an independent predictor of subsequent asthma attacks.11 However, this work was based on general population samples, and the diagnosis of asthma was obtained by self-report only. Our goal was to strengthen the evidence regarding the use of FEV1, particularly among a pediatric population. We examined the relationship between lung function and serious asthma exacerbations in a well-characterized cohort of children with documented asthma, the Childhood Asthma Management Program (CAMP).
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Outcome Measures
The children (or their parents or guardians) completed a diary card each day that recorded night awakenings that were caused by asthma, morning and evening peak flows as measured by a peak-flow meter (Assess; HealthScan Products, Cedar Grove, NJ), use of study medication, use of albuterol for symptoms and to prevent exercise-induced bronchospasm, use of prednisone, absences from school as a result of asthma, visits to a physician's office or a hospital because of asthma, and severity of symptoms. Children rated their asthma symptoms on a daily basis throughout the clinical trial. An asthma episode was defined as a single period of 1 or more asthma "stop signs": wheezing, coughing, chest tightness, or shortness of breath. Asthma symptom score was measured on a scale from 0 to 3: 0, no asthma episodes; 1, 1 to 3 asthma episodes each lasting 2 hours or less, all mild; 2, 4 mild asthma episodes or 1 episode that temporarily interfered with activity, play, school, or sleep; and 3, 1 episode that lasted longer than 2 hours or resulted in shortening normal activity or in an urgent doctor visit. An episode-free day (EFD) was defined as a day with an asthma diary asthma score of 0 and no report of a night awakening, morning and evening peak flow >80% personal best, no albuterol use for symptoms or prednisone use, absence from school as a result of asthma, or physician contact as a result of asthma. Data also were collected regarding demographics, history of asthma symptoms and severity, treatment of asthma, allergy history, characteristics of the home environment, and relevant family history. Follow-up visits occurred 2 and 4 months after randomization and at 4-month intervals thereafter.
Prebronchodilator spirometry was performed 3 times per year, and methacholine challenge was performed annually. Spirometry and methacholine testing met the American Thoracic Society standards. Equations that were used to predict the average value of lung function measures for age, gender, and height were race-corrected according to Coultas et al13 for Hispanic individuals, and an adjustment (0.88) was made for black patients according to Knudson et al.14 The children's height (measured by stadiometer) and weight were recorded at every visit.
Analysis
In the CAMP study after an initial 2- and 4-month visit, follow-up visits occurred at 4-month intervals. For the purposes of this analysis, the FEV1 value that was recorded at a given visit was paired with the report of symptoms during the subsequent 4-month period. Prebronchodilator FEV1 was analyzed as the percentage of the FEV1% predicted.
FEV1% predicted was analyzed as a categorical response (FEV1% <60%, FEV1% 60%–79%, FEV1% 80%–99%, and FEV1% 100%) and as a continuous variable. The cut points for FEV1% mirrored the guideline recommendations, except the highest category (FEV1% >80) was subdivided into 2 subcategories; previous analysis suggested differences in the risk for future asthma exacerbations in children with FEV1% of 80% to 99% compared with children who have a FEV1% 100%.10
Multiple observations of FEV1% were used in available patients. Multivariate regression analyses, using a general estimating equation approach, were used to control for the correlation between repeated measurements among individuals and important covariates (Proc GENMOD, SAS 6.12; SAS Institute, Cary, NC). All analyses were performed by using the SAS statistical software program (SAS Institute).
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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100% predicted, children with FEV1% 80% to 99%, FEV1% 60% to 79%, and FEV1% <60% were 1.3, 1.8, and 4.8, respectively, more likely to have an asthma-related event during the ensuing 4 months (Table 3).
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The relationship among FEV1%, asthma symptoms, and serious asthma exacerbations was observed whether FEV1% was modeled as a continuous variable or categorized as recommended in the NAEPP guidelines. Nocturnal awakenings and previous asthma-related hospitalizations also were independently associated with future events (Table 3). When a modified FEV1% classification was used, splitting the highest category into children with FEV1% 80% to 99% and FEV1% 100%, the relationship persisted, although the absolute difference in the risk for future exacerbations in the group of children with FEV1% 100% compared with those <100% was small.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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The cut points studied mirrored those published in the NAEPP guideline recommendations. In addition, we subdivided the highest category, FEV1% >80, on the basis of a previous analysis that suggested differences in risk could be identified among this group of children.10 In our current analysis, both the categorical scheme and FEV1% as a continuous variable captured variation in risk and were informative in predicting risk for future asthma morbidity. Furthermore, when we evaluated the use of a 4-tier classification scheme, there was a trend for an additional decrease in the risk in asthma-related events for FEV1% 100%. Additional evaluation may be important to identify the ideal cut points for distinguishing categories of risk.
Office spirometry is 1 of the NAEPP Expert Panel Report 2 Guideline recommendations that is underused. Although there has been no systematic study of the use of office spirometry in primary care offices, various studies report use by only 5% to 45% of practitioners on 1 occasion in the previous year.15–19 Grant et al20 found that only 20% of physicians used spirometry in asymptomatic patients, whereas Finkelstein et al15 found that 59% of pediatricians never used spirometry. In all studies, rates of spirometry testing are low. Many factors may be associated with failure to adhere to guideline recommendations such as spirometry, with some providers concerned about the recommendations that are based on expert panel consensus rather than being evidence based.21 Our analysis adds objective evidence supporting the NAEPP recommendations.
An advantage of FEV1% as a marker of asthma severity is its objectivity and reproducibility,6,7 In addition, FEV1% predicted is reported frequently in clinical trials and in studies of the efficacy of new therapies. The clinical trials literature suggests that improvements in FEV1% are paralleled by improvements in clinical asthma outcomes such as symptoms, health-related quality of life, rescue medication use, and health care utilization.22–29
Previous data demonstrated the importance of nocturnal awakenings30 and previous asthma-related hospitalization.31–33 Our analysis confirmed the independent effects of FEV1% and nocturnal awakening on the risk for future asthma symptoms and serious asthma exacerbations. Race/ethnicity and socioeconomic status also have been postulated to be associated with risk for exacerbations. However, household income, educational level, and race/ethnic status did not demonstrate consistent relationships with serious asthma exacerbations or symptoms in our population.
Our analysis has limitations. The CAMP population was targeted to include children with mild to moderate persistent asthma. Therefore, relatively few patients met FEV1% criteria for severe persistent disease. However, the consistency of our findings with a previous analysis among a general population sample supports an association between lung function and risk for serious exacerbation. Lung function alone may not characterize fully the severity of disease or risk for future morbidity, yet the inclusion of spirometry in the classification of disease severity adds important information in the management of asthma.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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ACKNOWLEDGMENTS |
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Members of the CAMP Research Group
Clinical centers: Asthma, Inc, Seattle, WA: Gail G. Shapiro, MD (director), Thomas R. DuHamel, PhD (co-director), Mary V. Lasley, MD (co-director), Tamara Chinn, MSN, ARNP (coordinator), Michele Hinatsu, MSN, ARNP, Clifton T. Furukawa, MD, Leonard C. Altman, MD, Frank S. Virant, MD, Paul V. Williams, MD, Michael S. Kennedy, MD, Jonathan W. Becker, MD, Grace White, C. Warren Bierman, MD (1992–1997), Dan Crawford, RN (1996–2002), Heather Eliassen, BA (1996–1999), Babi Hammond (1996–1999), Dominick A. Minotti, MD (1992–2003), Chris Reagan (1992–2003), Marian Sharpe, RN (1992–1994), and Timothy G. Wighton, PhD (1994–1998); Brigham & Women’s Hospital, Boston, MA: Scott Weiss, MD, MS (director), Anne Fuhlbrigge, MD (principal investigator), Anne Plunkett, NP, MS (coordinator), Nancy Madden, RN, BSN, Peter Barrant, MD, Christine Darcy, Kelly Thompson, MD, Walter Torda, MD (co-investigator director, 1993–2003), Martha Tata, RN (1993–2002), Sally Babigian, RN (1997–1999), Linda Benson (1998–2004), Jose Caicedo (1998–1999), Tatum Calder (1998–2001), Anthony DeFilippo (1994–2000), Cindy Dorsainvil (1998–2001), Julie Erickson (1998–1999), Phoebe Fulton (1997), Mary Grace, RN (1994–1996), Jennifer Gilbert (1997–1998), Dirk Greineder, MD (1993–2000), Stephanie Haynes (1993–1998), Margaret Higham, MD (1996–1998), Deborah Jakubowski (1999), Susan Kelleher (1993–1997), Jay Koslof, PhD (1993–1995), Dana Mandel (1996–1998), Patricia Martin (2001–2003), Agnes Martinez (1994–1997), Jean McAuliffe (1994–1995), Erika Nakamoto (2002–2004), Paola Pacella (1993–1998), Paula Parks (1993–1995), Johanna Sagarin (1998–1999), Kay Seligsohn, PhD (1995–2004), Susan Swords (2003–2005), Meghan Syring (1998–2001), June Traylor, MSN, RN (1996–1998), Melissa Van Horn, PhD (1996–1999), Carolyn Wells, RN (1993–1995), and Ann Whitman, RN (1994–1996); Hospital for Sick Children, Toronto, Ontario, Canada: Ian MacLusky, MD, FRCP(C) (director), Joe Reisman, MD, FRCP(C), MBA (director, 1996–1999), Henry Levison, MD, FRCP(C) (director, 1992–1996), Anita Hall, RN (coordinator), Jennifer Chay, Melody Miki, RN, BScN, Renée Sananes, PhD, Yola Benedet (1994–1999), Susan Carpenter, RN (1998–2001), Michelle Collinson, RN (1994–1998), Jane Finlayson-Kulchin, RN (1994–1998), Kenneth Gore, MA (1993–1999), Noreen Holmes, RRT (1998–1999), Sharon Klassen, MA (1999–2000), Joseé Quenneville, MSc (1993–1995), and Christine Wasson, PhD (1999); Johns Hopkins Asthma & Allergy Center, Baltimore, MD: N. Franklin Adkinson, Jr, MD (director), Peyton Eggleston, MD (co-director), Elizabeth H. Aylward, PhD, Karen Huss, DNSc (co-investigator), Leslie Plotnick, MD (co-investigator), Margaret Pulsifer, PhD (co-investigator), Cynthia Rand, PhD (co-investigator), Nancy Bollers, RN (coordinator), Deborah Bull, LPN, Robert Hamilton, PhD, Kimberly Hyatt, Susan Limb, MD, Mildred Pessaro, Stephanie Philips, RN, and Barbara Wheeler, RN, BSN; National Jewish Medical and Research Center, Denver, CO: Stanley Szefler, MD (director), Harold S. Nelson, MD (co-director), Bruce Bender, PhD (co-investigator), Ronina Covar, MD (co-investigator), Andrew Liu, MD (co-investigator), Joseph Spahn, MD (co-investigator), D Sundström (coordinator), Melanie Phillips, Michael P. White, Kristin Brelsford (1997–1999), Jessyca Bridges (1995–1997), Jody Ciacco (1993–1996), Michael Eltz (1994–1995), Jeryl Feeley, MA (coordinator, 1992–1995), Michael Flynn (1995–1996), Melanie Gleason, PA-C (1992–1999), Tara Junk-Blanchard (1997–2000), Joseph Hassell (1992–1998), Marcia Hefner (1992–1994), Caroline Hendrickson, RN (1995–1998, coordinator, 1995–1997), Daniel Hettleman, MA (1995–1996), Charles G. Irvin, PhD (1992–1998), Jeffrey Jacobs, MD (1996–1997), Alan Kamada, PharmD (1994–1997), Sai Nimmagadda, MD (1993–1996), Kendra Sandoval (1995–1997), Jessica Sheridan (1994–1995), Trella Washington (1993–1997), and Eric Willcutt, MA (1996–1997). University of California, San Diego and Kaiser Permanente Southern California Region, San Diego, CA: Robert S. Zeiger, MD, PhD (director), Noah Friedman, MD (co-investigator), Michael H. Mellon, MD (co-investigator), Michael Schatz, MD (co-investigator), Kathleen Harden, RN (coordinator), Elaine M. Jenson, Serena Panzlau, Eva Rodriguez, RRT. James G. Easton, MD (co-director, 1993–1994), M. Feinberg (1997–1998), Linda L. Galbreath (1991–2002), Jennifer Gulczynski (1998–1999), Ellen Hansen (1995–1997), Al Jalowayski, PhD (co-investigator, 1991–2005), Alan Lincoln, PhD (co-investigator, 1991–2003), Jennie Kaufman (1994), Shirley King, MSW (1992–1999), Brian Lopez (1997–1998), Michaela Magiari-Ene, MA (1994–1998), Kathleen Mostafa, RN (1994–1995), Avraham Moscona (1994–1996), Catherine A. Nelle, RN (1991–2005), Jennifer Powers (2001–2003), Karen Sandoval (1995–1996), and Nevin W. Wilson, MD (co-director, 1991–1993), University of New Mexico, Albuquerque, NM: H. William Kelly, PharmD (director), Aaron Jacobs (co-investigator), Mary Spicher, RN (coordinator), Hengameh H. Raissy. Robert Annett, PhD (co-investigator, 1993–2004), Teresa Archibeque (1994–1999), Naim Bashir, MD (co-investigator, 1998–2005), H. Selda Bereket (1995–1998), Marisa Braun (1996–1999), Shannon Bush (2002–2006), Michael Clayton, MD (co-investigator, 1999–2001), Angel Colon-Semidey, MD (co-investigator, 1997–2000), Sara Devault (1993–1997), Roni Grad, MD (co-investigator, 1993–1995), David Hunt, RRT (1995–2004), Jeanne Larsson, RN (1995–1996), Sandra McClelland, RN (coordinator, 1993–1995), Bennie McWilliams, MD (co-investigator, director, 1992–1998), Elisha Montoya (1997–2000), Margaret Moreshead (1996–1999), Shirley Murphy, MD (co-investigator, 1992–1994), Barbara Ortega, RRT (1993–1999), David Weers (1997–1998), and Jose Zayas (1995–1996); Washington University, St Louis, MO: Robert C. Strunk, MD (director), Leonard Bacharier, MD (co-investigator), Gordon R. Bloomberg, MD (co-investigator), James M. Corry, MD (co-investigator), Denise Rodgers, RFPT (coordinator), Lila Kertz, MSN, RN, CPNP, Valerie Morgan, RRT, Tina Oliver-Welker, CRTT, Deborah K. White, RPFT, RRT.
Resource centers: Chair’s Office, National Jewish Medical and Research Center, Denver, CO: Reuben Cherniack, MD (study chair); Coordinating Center, Johns Hopkins University, Baltimore, MD: James Tonascia, PhD (director), Curtis Meinert, PhD (co-director), Patricia Belt, Karen Collins, Betty Collison, Ryan Colvin, MPH, John Dodge, Michele Donithan, MHS, Judith Harle, Rosetta Jackson, Hope Livingston, Jill Meinert, Kapreena Owens, Michael Smith, Alice Sternberg, ScM, Mark Van Natta, MHS, Margaret Wild, Laura Wilson, ScM, Robert Wise, MD, and Katherine Yates, ScM; Project Office, National Heart, Lung, and Blood Institute, Bethesda, MD: Virginia Taggart, MPH (Project Officer), Lois Eggers, James Kiley, PhD, Gang Zheng, PhD. Paul Albert, PhD (1991–1999), Suzanne Hurd, PhD (1991–1999), Sydney Parker, PhD (1991–1994), Pamela Randall (1992–2003), and Margaret Wu, PhD (1991–2001).
Committees: Data and Safety Monitoring Board: Howard Eigen, MD (chair), Michelle Cloutier, MD, John Connett, PhD, Leona Cuttler, MD, David Evans, PhD, Meyer Kattan, MD, Rogelio Menendez, MD, F. Estelle R. Simons, MD, Clarence E. Davis, PhD (1993–2003), and Sanford Leikin, MD (1993–1999); Executive Committee: Reuben Cherniack, MD (chair),Robert Strunk, MD, Stanley Szefler, MD, Virginia Taggart, MPH, James Tonascia, PhD, and Curtis Meinert, PhD (1992–2003); Steering Committee: Reuben Cherniack, MD (chair), Robert Strunk, MD (vice-chair), N. Franklin Adkinson, MD, Robert Annett, PhD (1992–1995, 1997–1999), Bruce Bender, PhD (1992–1994, 1997–1999), Mary Caesar, MHS (1994–1996), Thomas R. DuHamel, PhD (1992–1994, 1996–1999), H. William Kelly, PharmD, Henry Levison, MD (1992–1996), Alan Lincoln, PhD (1994–1995), Ian MacLusky, MD, Bennie McWilliams, MD (1992–1998), Curtis L. Meinert, PhD, Sydney Parker, PhD (1991–1994), Joe Reisman, MD, FRCP(C), MBA (1991–1999), Denise Rodgers (2003–2005), Kay Seligsohn, PhD (1996–1997), Gail G. Shapiro, MD, Marian Sharpe (1993–1994), D Sundström (1998–1999), Stanley Szefler, MD, Virginia Taggart, MPH, Martha Tata, RN (1996–1998), James Tonascia, PhD, Scott Weiss, MD, MS, Barbara Wheeler, RN, BSN (1993–1994), Robert Wise, MD, Robert Zeiger, MD, PhD.
We also thank the pediatric allergy and immunology fellows for their participation (Kirstin Carel, MD, Neal Jain, MD, Harvey Leo, MD, Beth Macomber, MD, Chris Mjaanes, MD, Lora Stewart, MD, and Ben Song, MD).
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FOOTNOTES |
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Address correspondence to Anne L. Fuhlbrigge, MD, Channing Laboratory, 181 Longwood Ave, Boston, MA 02115. E-mail: anne.fuhlbrigge{at}channing.harvard.edu
The authors have indicated they have no financial relationships relevant to this article to disclose.
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