Published ahead of print on January 30, 2004, doi:10.1164/rccm.200309-1234OE
© 2004 American Thoracic Society
Is Forced Expiratory Volume in One Second the Best Measure of Severity in Childhood Asthma?Ira J. and Jacqueline Neimark Laboratory of Clinical Pharmacology in Pediatrics, Divisions of Clinical Pharmacology, Pulmonary Medicine, Department of Medicine, and Allergy-Clinical Immunology, Departments of Pediatrics, National Jewish Medical and Research Center, University of Colorado Health Sciences Center, Denver, Colorado Correspondence and requests for reprints should be addressed to Joseph D. Spahn, M.D., National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206. E-mail: spahnj{at}njc.org This essay focuses on whether FEV1 is the best measure of asthma severity in childhood asthma. For better or worse, FEV1 has become the gold standard lung function measurement in asthma, as it can be easily and quickly measured with relatively simple equipment. The current asthma guidelines use FEV1 in addition to daytime and nighttime symptoms in judging asthma severity (1, 2). Patients with mild persistent asthma are said to have FEV1 values of more than 80% of predicted, patients with moderate persistent asthma have values of 60 to 80% of predicted, whereas those with severe persistent asthma have values of less than 60% of predicted (1, 2). Despite widespread acceptance, neither are these criteria evidence-based nor is the basis of criteria described. FEV1 is also the outcome variable favored by the U.S. Food and Drug Administration to judge efficacy of asthma-controller medications. Thus, nearly all studies evaluating response to medications in asthma require subjects to have FEV1 values of 60 to 80% of predicted as essential entry criteria. Although this approach provides objective data to evaluate efficacy, it may not be the best measure for children with asthma. This is in large part because children with asthma are likely to have FEV1 values within the normal range when clinically stable. NORMAL FEV1 VALUES ARE THE RULE, NOT THE EXCEPTION IN CHILDHOOD ASTHMA That children with asthma often have normal FEV1 values when clinically stable is demonstrated by several studies, some being more than 30 years old. In 3,626 children with asthma, Fuhlbrigge and coworkers found that those with FEV1 values less than 60% had approximately a 70% chance of having an acute asthma exacerbation in the subsequent year (57 attacks in 77 observations), whereas children with FEV1 values of more than 80% had a 25–30% chance of having a subsequent attack (6,823 attacks in 23,209 observations). Because 94% of the FEV1 values were more than 80% of predicted, the vast majority of attacks occurred in children with normal FEV1s (3). Additional data come from the Childhood Asthma Management Program study, which evaluated 1,041 children with mild to moderate asthma. Over 50% of the cohort had moderate persistent asthma based on frequency of symptoms, yet the mean prebronchodilator and postbronchodilator FEV1 values at randomization were 94 and 103% of predicted, respectively (4). In a comparison of asthma severity based on symptom frequency with FEV1, Bacharier and coworkers found that the mean FEV1 was 95.1% of predicted in children with mild persistent asthma, 90.2% in those with moderate persistent asthma, and 83.8% in those with severe persistent asthma (5). Finally, Jenkins and coworkers compared the lung function of children and adults who had been referred to the National Jewish Medical and Research Center because of severe asthma (6). Despite similar need for chronic oral and high-dose inhaled glucocorticoid therapy between the children and adults, the mean prebronchodilator FEV1 value was 74% of predicted for children compared with 57% of predicted for adults.
That children—even those with severe persistent asthma—do not have significantly impaired FEV1s during periods of disease stability might be expected if one considers that asthma is a slowly progressive disease. It is well established that in adults, individuals with asthma have a greater decline in FEV1 ( HOW WELL DOES FEV1 CORRELATE WITH OTHER CLINICAL PARAMETERS? Although the spirometric criteria for asthma severity may match symptomatic criteria in adults, they may not correlate well in children. Sharek and coworkers examined the relationship between spirometry and parent-reported symptoms, health care utilization, and functional health status using the Child Health Survey for Asthma and diary data in a group of children with moderate to severe asthma (11). These investigators found that parent-reported symptoms, health care utilization, and the individual domains of the Child Health Survey for Asthma correlated with each other throughout the study period. In contrast, clinic spirometry did not correlate with any of the other parameters at any time during the study. Thus, asthma status may be better characterized by parent-reported symptoms, health care utilization, and functional health status measures than by FEV1. Children with asthma often have normal lung function at steady state, yet develop severe airflow obstruction during acute exacerbations. This lability in lung function is likely a reflection of their underlying airway hyperresponsiveness. Weiss and coworkers studied the relationship between airway hyperresponsiveness and asthma severity in the Childhood Asthma Management Program cohort at randomization (12). Despite a normal pre–ß-agonist FEV1 of 94% predicted, the cohort had evidence of significant airway hyperresponsiveness with a median provocative concentration of methacholine producing a 20% drop in FEV1 of 1.16 mg/ml. WHAT ARE THE DIAGNOSTIC AND THERAPEUTIC IMPLICATIONS? Currently, studies required to gain U.S. Food and Drug Administration approval of asthma medications in children use change in FEV1 over placebo as the primary efficacy measure in children who have compromised lung function (FEV1 60–85% of predicted). Because only a small percentage of children with asthma have significant impairment of FEV1, studies evaluating the efficacy of an asthma medication are based on an unrepresentative group of children. In the Childhood Asthma Management Program study, FEV1 had to be greater than 60% predicted but there was no upper limit. Consequently, the mean FEV1 at randomization was 94% of predicted. Figure 1 compares FEV1 with asthma duration at randomization (13). As can be seen, FEV1 values ranged from 60% to about 140% of predicted. More importantly, the majority of children would not have qualified for Phase III studies because their FEV1 was too high.
Because it is not widely appreciated that FEV1 is often in the normal range in childhood asthma, there is a risk that the diagnosis of asthma will either not be made or the severity of the disease will be underestimated. In both scenarios, there is a potential to underdiagnose and undertreat children with asthma. This has important clinical ramifications as there has been increasing emphasis on performing spirometry in primary care settings. Therefore, clinical decisions based on a single prebronchodilator FEV1 value are likely to contribute to, not lessen, the underdiagnosis and undertreatment of asthma. Inhaled glucocorticoids are effective in individuals with asthma having compromised lung function (14–17). Whether they were effective in children with normal lung function was determined in the Childhood Asthma Management Program study (4), where children received treatment with budesonide, nedocromil, or matching placebo for 4 to 6 years. Long-term budesonide therapy improved baseline FEV1, but the change (3%) was not clinically significant, and it failed to improve post–ß-agonist FEV1. On the other hand, budesonide was effective not only in reducing airway hyperresponsiveness, need for rescue ß-agonist, and symptoms but also in reducing hospitalizations, urgent care visits, and need for rescue prednisone. Thus, significant improvement in asthma control can occur with inhaled glucocorticoid therapy in the absence of any meaningful improvement in FEV1. SHOULD ONE NO LONGER RELY AS HEAVILY ON FEV1? Clearly, a child with asthma can have normal FEV1 values. As a result, a single prebronchodilator FEV1 is likely insufficient to accurately assess asthma severity. Prebronchodilator and postbronchodilator spirometry should be performed in all children, as the change in FEV1 after ß-agonist administration provides valuable information regarding the child's airway lability. The degree of ß-agonist reversibility has been shown to correlate with airway inflammation as measured by exhaled nitric oxide and sputum eosinophilia, whereas no such relationship was seen with baseline FEV1 (18). Marotta and coworkers performed spirometry and prebronchodilator and postbronchodilator impulse oscillometry in young children at risk for asthma and found no difference in baseline FEV1 or resistance between children with or without asthma (19). After a bronchodilator, however, the percentage change in resistance was significantly different in the children with asthma. Szefler and coworkers found patients with the greatest response to inhaled glucocorticoids were those with the greatest ß-agonist response independent of baseline FEV1 (20). Lastly, the degree of ß-agonist reversibility may also predict those at risk for disease progression as demonstrated by Ulrik and coworkers (21). These investigators found ß-agonist reversibility at baseline to be a significant risk factor for the development of fixed airflow obstruction in patients with severe asthma. In addition, patients with the greatest ß-agonist reversibility at baseline had a more rapid decline in their FEV1 during the course of the study. Whether the same is true for children with asthma is not known, as adequate longitudinal studies have yet to be performed. Rather than relying on a single FEV1 measure to assess severity, serial FEV1s (pre– and post–ß-agonist) should be obtained over time. Serial measurements will not only provide objective data with respect to current lung function but will help determine disease progression by evaluation of change in FEV1 over time. If a child's FEV1 is less than expected, changes in medications, identification of aggravating factors, and more vigilant surveillance should be in effect to determine the effectiveness of the intervention. Spirometry should be plotted graphically in a manner analogous to what is done with linear growth. If an individual's FEV1 falls below a certain percentile, investigation into the cause should follow. CONCLUSIONS The majority of children with asthma will have FEV1 values that are within the normal range. If one considers the slowly progressive nature of lung function decline in asthma, it is not surprising that even children with severe asthma based on symptoms and health care utilization will demonstrate FEV1 values in the mild to moderate persistent asthma range, according to the NHLBI lung function criteria for asthma severity. This is important for all who care for children with asthma for a number of reasons. First, children with persistent asthma can have normal or nearly normal FEV1 values. As a result, asthma may be undiagnosed if one solely relies on FEV1 values when stable to make the diagnosis. Similarly, there may be a number of children with known asthma who will be undertreated for the same reasons. Second, in clinical research, FEV1 criteria for inclusion/exclusion into pediatric asthma studies must be adjusted so as to include fully representative populations of children with asthma in efficacy studies. Third, the existing National Institutes of Health guidelines need to be reevaluated to assess what constitutes mild, moderate, and severe asthma in children. In children, normal lung function at steady state does not exclude marked impairment in lung function during acute (often viral-induced) exacerbations. As such, the number of and severity of acute exacerbations should be taken into account when assessing asthma severity. Lastly, the need for and dose of inhaled glucocorticoid required to achieve adequate control (normal lung function and few exacerbations) should also be considered when determining the level of asthma severity in children. To advance care, research should focus on developing and evaluating more appropriate lung function measures in childhood asthma (for example, exhaled nitric oxide measurements, impulse oscillometry) and to critically assess ß-agonist reversibility, FEV1/FVC ratio, and serial before– and after–ß-agonist FEV1 values over time while at the same time monitoring the rate of lung function decline. FOOTNOTES Conflict of Interest Statement: J.D.S. has no declared conflict of interest; R.C. has no declared conflict of interest; K.P. has no declared conflict of interest; E.W.G. has no declared conflict of interest. Received in original form September 5, 2003; accepted in final form January 26, 2004 REFERENCES
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1% of predicted per year) than individuals without asthma (
