NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Aronson N, Lefevre F, Piper M, et al. Management of Chronic Asthma. Rockville (MD): Agency for Healthcare Research and Quality (US); 2001 Sep. (Evidence Reports/Technology Assessments, No. 44.)

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

Cover of Management of Chronic Asthma

Management of Chronic Asthma.

Show details

3Results and Conclusions Part 1: Long-Term Management of Asthma in Children

Key Question 1a. Does chronic use of ICS improve long-term outcomes for children with mild-to-moderate asthma, compared to:

  • "as needed" beta-2 agonists
  • long-acting beta-2 agonists
  • theophylline
  • cromolyn/nedocromil
  • combinations of above drugs

Overview

This question addresses long-term outcomes of ICS treatment. 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 measurement of postbronchodilator FEV1 provides the best indicator of long-term progression of asthma (Childhood Asthma Management Program Research Group, 1999). Prebronchodilator FEV1 and PEF can also indicate long-term progression, but both 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, are also likely to correlate with long-term progression of disease over time, but are highly subject to changes in short-term control of bronchospasm. The review of evidence for this question includes the various outcomes reflecting both short-term control and long-term progression of disease. However, the primary outcomes of interest will be lung function measurements, with postbronchodilator FEV1 being the preferred measure. (See Evidence Tables 1-1 through 1-10.)

Ten studies enrolling a total of 2,210 patients met the inclusion criteria for this key question. Tables 2-5 summarize the study characteristics and key findings for these studies. Nine of the 10 studies were randomized, double-blind, parallel group trials. The most robust of these, the CAMP (Childhood Asthma Management Program Research Group, 2000a) study, is a three-arm trial enrolling 1,041 patients followed for 224 weeks that compared ICS with 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" (Childhood Asthma Management Program Research Group, 1999). The remaining eight randomized trials are considerably smaller in size (range: 14-102 per study arm) and duration of followup (range: 12-95 weeks). The tenth trial, by Agertoft and Pedersen (1994) was not randomized.

Table 2. Study characteristics and outcomes reported.

Table

Table 2. Study characteristics and outcomes reported.

Table 3. Change in lung function outcomes reported.

Table

Table 3. Change in lung function outcomes reported.

Table 4. Symptom outcomes.

Table

Table 4. Symptom outcomes.

Table 5. Medication use and utilization outcomes.

Table

Table 5. Medication use and utilization outcomes.

The majority of patients included in these studies were followed for a year or longer. Studies of several years' duration are needed to measure the long-term effects of ICS on lung function relative to "as needed" treatment or other long-term controller medications; and, in particular, to address the question of whether asthma is characterized by a pattern of progressive decline in lung function that can be prevented by ICS treatment. Lung function measures in studies of less than 1-year duration can assess the effects of ICS on short term control of underlying bronchospasm, but are unlikely to reflect any meaningful changes in long term progression of disease. Moreover, lung function measurements taken within the first few months of treatment capture the marked early improvement associated with initiating ICS treatment and cannot be directly compared with measurements taken later in the course of treatment.

Four of 10 studies reported both pre- and postbronchodilator FEV1 outcomes; and six studies did not specify which measure of FEV1 was reported. The prebronchodilator FEV1 assesses the patient's lung function under treatment, and the postbronchodilator FEV1 assesses the patient's maximal lung function. Of the four included studies reporting both measures, two compared ICS to placebo (Childhood Asthma Management Program Research Group, 2000a; van Essen-Zandvliet, Hughes, Waalkens et al., 1992) and two compared ICS to another long-term controller medication (Verberne, Frost, Roorda et al., 1997; Tinkelman, Reed, Nelson et al., 1993). In all cases, treatment difference in percent predicted FEV1 was greater with the prebronchodilator measure than by the postbronchodilator measure; and prebronchodilator treatment difference was approximately 2 times greater (Table 6). Thus, comparisons between studies that report prebronchodilator FEV1 results and those that report postbronchodilator results should be avoided. Although it is likely that studies not specifying how FEV1 was measured actually reported prebronchodilator results, no comparisons across such studies can be made with any reasonable confidence.

Table 6. Differences in pre- and postbronchodilator outcomes in studies reporting both measures.

Table

Table 6. Differences in pre- and postbronchodilator outcomes in studies reporting both measures.

The 10 trials reported 12 comparisons relevant to this key question. Eight (n=1,511) comparisons were of treatment with ICS versus as-needed beta-2 agonists alone, seven of which were placebo-controlled and one which compared ICS to usual care (Agertoft and Pedersen, 1994). Two of these eight trials (n=69) were limited to children under 5 years of age and had followup of 26 weeks (Storr, Lenney, and Lenney, 1986; Connett, Warde, Wooler et al., 1993). There was one comparison of nedocromil versus placebo, in a three-arm study, which thus permits indirect comparisons of ICS with nedocromil (Childhood Asthma Management Program Research Group, 2000a). Two comparisons (n=202) were ICS versus salmeterol, with followup of 48 and 52 weeks (Verberne, Frost, Roorda et al., 1997; Simons, 1997). One trial, enrolling 195 patients with 36 weeks' followup, compared ICS with theophylline (Tinkelman, Reed, Nelson et al., 1993).

Three of the studies were based in the Netherlands (Hoekstra, Grol, Hovenga et al., 1998; van Essen-Zandvliet, Hughes, Waalkens et al., 1992; Verberne, Frost, Roorda et al., 1997), two were from Scandinavia (Jonasson, Carlsen, Blomqvist et al., 1998; Agertoft and Pedersen, 1994), two from the United Kingdom (Storr, Lenney, and Lenney, 1986; Connett, Warde, Wooler et al., 1993), two from the United States (Childhood Asthma Management Program Research Group, 2000a; Tinkelman, Reed, Nelson et al., 1993) and one from Canada (Simons, 1997). Six reported funding from a pharmaceutical industry source (Childhood Asthma Management Program Research Group, 2000a; Simons, 1997; Hoekstra, Grol, Hovenga et al., 1998; van Essen-Zandvliet, Hughes, Waalkens et al., 1992; Verberne, Frost, Roorda et al., 1997; Tinkelman, Reed, Nelson et al., 1993), five from a government or academic source (Childhood Asthma Management Program Research Group, 2000a; Hoekstra, Grol, Hovenga et al., 1998; van Essen-Zandvliet, Hughes, Waalkens et al., 1992; Storr, Lenney, and Lenney, 1986; Tinkelman, Reed, Nelson et al., 1993), and three (Connett, Warde, Wooler et al., 1993; Jonasson, Carlsen, Blomqvist, et al. 1998; Agertoft and Pedersen, 1994) did not specify a funding source. Several trials indicated multiple funding sources.

One of the inclusion criteria for this key question was that patients should not have had prior ICS treatment; or, alternatively, that there was a washout period of at least 4 weeks prior to initiation of treatment on study (see the "Methodology" chapter). The studies excluded for failure to meet these criteria included several large, recent trials (Baker, Mellon, Wald et al., 1999; Kemp, Skoner, Szefler et al., 1999; Shapiro, Mendelson, Kraemer et al., 1998; White, Cruz-Rivera, Walton-Bowen, 1999).

Patient Populations

In seven of the 10 studies, the mean age was similar, in the range of 9-12 years, with -1SD approximately 7 years of age in most studies. For two of the studies of ICS versus no ICS (Storr, Lenney, and Lenney, 1986; Connett, Warde, Wooler et al., 1993), enrollment was restricted to patients younger than 5 years of age, with mean ages of 3.5 and 1.8 years, respectively. The results of these studies in very young children will be reported separately. In the tenth trial (Agertoft and Pedersen, 1994), the mean age was approximately 6 years (range 3-11 years), but results of older and younger children were not reported separately. This study is the only one that appears to overlap the categories for children older and younger than 5 years of age.

The study eligibility criteria varied, with various combinations of lung function, symptom-based and utilization-based eligibility criteria. Eight trials included symptom-based eligibility criteria, six trials had lung function measures as eligibility criteria, and three included utilization based measures. Specific criteria within these broad categories varied as well. For example, among the studies using lung function eligibility, five of six used FEV1, with the minimum FEV1 ranging between 50 and 75 percent. One of the six trials (Childhood Asthma Management Program Research Group, 2000a) used only bronchial hyperreactivity as a lung function eligibility criterion.

Severity of illness at the time of enrollment was estimated using the NHLBI classification system to the extent possible given the information contained in the reports. Only one study was judged to be restricted to patients with mild asthma (Jonasson, Carlsen, Blomqvist et al., 1998). Four of the studies included a population predominantly in the mild-moderate range (Childhood Asthma Management Program Research Group, 2000a; Simons, 1997; Hoekstra, Grol, Hovenga et al., 1998; Verberne, Frost, Roorda et al., 1997), while three studies included patients with severity ranging from mild to severe (Agertoft and Pedersen, 1994; van Essen-Zandvliet, Hughes, Waalkens et al., 1992; Tinkelman, Reed, Nelson et al., 1993). In the two studies of very young children (Storr, Lenney, and Lenney, 1986; Connett, Warde, Wooler et al., 1993), severity could not be estimated due to a lack of sufficient data on lung function and/or symptom levels. However, both of these trials selected patients whose symptoms were judged to be inadequately controlled, making it likely that these patients were representative of the more severe end of the disease spectrum.

Baseline mean FEV1 was reported for the eight studies that enrolled children over 5 years of age, ranging from a mean of 74.1 to 105 percent of predicted. In four studies, it was not specifically stated whether this was a pre- or postbronchodilator measure; in most cases it was probably a prebronchodilator measure. In the remaining four studies (Childhood Asthma Management Program Research Group, 2000a; van Essen-Zandvliet, Hughes, Waalkens et al., 1992; Verberne, Frost, Roorda et al., 1997; Tinkelman, Reed, Nelson et al., 1993) both pre- and postbronchodilator mean baseline FEV1 values were reported. The difference between pre- and postbronchodilator measures ranged from 8.9 to 19.1 percent predicted, which in several cases could change the classification of severity, depending on which measure was used. For the purpose of classifying severity in this evidence report, the prebronchodilator measure was used where both were reported, since this was used most consistently and allowed better comparison of severity level across studies.

Six of the trials reported baseline symptom scores and/or symptom frequency measures. Because of differences in units and type of reporting, these measures were not helpful in comparing severity levels across studies.

Interventions

All 10 trials included treatment with ICS in at least one study arm. The control arms of these studies all included treatment with short-acting beta-2 agonists on an as-needed basis, thus making the comparison primarily ICS versus as-needed beta-2 agonists alone. Three different ICS agents were employed: budesonide in five studies, beclomethasone in four studies, and fluticasone in one study.

Using current classification schemes for ICS dose level (NHLBI), 6 of the 10 studies used doses within the medium dose range. One study of children older than 5 years with three treatment groups (Jonasson, Carlsen, Blomqvist et al., 1998) used dosages of budesonide within the low range (100-200 mcg/d). A second study, in children younger than 5 years, used a low dose of beclomethasone (330 mcg/d). Two studies, both in children older than 5 years, used ICS dosages in the high range. Agertoft and Pedersen (1994) treated patients with 800 mcg/d of budesonide, while van Essen-Zandvliet, Hughes, Waalkens et al. (1992) treated patients with 600 mcg/d of budesonide. In the two studies that used salmeterol in one of the study arms, the dose was 50 mcg twice per day. Nedocromil was administered at a dose of 8 mg twice per day in the CAMP study (Childhood Asthma Management Program Research Group, 2000a), and the theophylline dosage was titrated to blood levels by Tinkelman, Reed, Nelson et al. (1993).

Outcomes

As summarized in Table 2, the 10 included trials reported the following outcomes and outcome measures:

  • Lung function outcomes were reported in 8 of the 10 studies. The two studies that did not report lung function outcomes (Storr, Lenney, and Lenney, 1986; Connett, Warde, Wooler et al., 1993) were the studies with patients younger than 5 years of age, in which performing lung function measures is not feasible. All eight of these studies reported FEV1 outcomes and all but one (Agertoft and Pedersen, 1994) reported PEF outcomes. The units of reporting varied (percent predicted, absolute value in liters or L/min) for FEV1 and PEF, although the majority of studies reported FEV1 as percent predicted and PEF as L/min. Five studies reported bronchial hyperresponsiveness outcomes in various ways (e.g., mg of medication required for PC20, doubling dose).
  • Nine of the 10 studies reported on symptom outcomes, either as symptom scores or symptom frequencies. Eight studies reported some measure of symptom frequency, either as the percentage of days and/or nights with symptoms, the percentage of days needing rescue medication, or the percentage of days with a symptom score greater than a threshold level. Five studies reported daytime symptom scores and three reported nighttime symptom scores. The units of the symptom scores varied considerably, with one study using a 0-2 scale, two studies using a 0-3 scale, one study using a 0-6 scale, and one study using a 0-32 scale.
  • Medication use outcomes were reported in 8 of the 10 studies. Six of these reported oral corticosteroid usage and five reported beta-2 agonist usage.
  • Utilization outcomes were reported in 5 of the 10 studies. The utilization outcomes reported were either hospitalizations (reported as number of patients with event, number of events/person, total number of events over study), or missed days of work/school (reported as percent of patients with any missed days, or total number of missed days over entire study).

Study Quality

Quality of study design and conduct were assessed as described in the "Methodology" chapter. The objective was to identify a group of higher quality trials for purposes of sensitivity analysis. The definition for higher quality studies is applicable only to randomized controlled trials and excluded nonrandomized controlled trials and single arm studies. It includes general quality indicators that have been shown to be associated with a bias in magnitude of effect, and asthma specific study features that control for potential confounders of outcomes.

To be defined as a higher quality study, a trial needed to meet three general quality indicators: (1) double blinding; (2) appropriate handling of exclusions and withdrawals as demonstrated by percentage of excluded patients below threshold or results analyzed by intent-to-treat analysis; and (3) concealment of treatment allocation.

In addition, the presence of six features specific to the setting of asthma was assessed. The first was that power calculations for primary outcomes were specified prospectively. The second criterion was whether the study accounted for the reasons that patients withdrew from the study, particularly regarding the number of patients that were withdrawn due to lack of efficacy. Next, the presence of specific study features designed to control for potential confounders of outcome was assessed. These were: (1) whether reversibility of lung obstruction was established at study entry; (2) whether use of asthma medications other than the study medication was controlled for; (3) whether measures of patient compliance were reported; (4) and whether the influence of seasonal differences on outcomes was addressed.

Only the CAMP (Childhood Asthma Management Program Research Group, 2000a) trial met all general quality indicators for defining a higher quality study (Table 7). This trial also met all asthma-specific study quality indicators except addressing the effects of seasonality. Of the 2,210 patients enrolled in the 10 studies that met the study inclusion criteria for this key question, 1,041 (47 percent) of the total patients were enrolled in the CAMP trial (Childhood Asthma Management Program Research Group, 2000a). Of studies comparing ICS to as-needed beta-2 agonists, CAMP contributed 40 percent of ICS patients (n=311) and 64 percent of controls (n=418) (Childhood Asthma Management Program Research Group, 2000a). The CAMP trial also had the longest duration of treatment (4 years), the most complete set of outcome measures, and the most detailed reporting of study design and statistical analysis (Childhood Asthma Management Program Research Group, 2000a).

Table 7. Assessment of study quality.

Table

Table 7. Assessment of study quality.

Of the eight other randomized controlled trials, all were double-blinded but only the trial by Jonasson, Carlsen, Blomqvist et al. (1998) met the criterion for percentage of subjects excluded from analysis below the specified threshold. This study also analyzed results by intent-to-treat analysis, but did not specify whether allocation to treatment arm was concealed. Jonasson, Carlsen, Blomqvist et al. (1998) also reported power calculations and accounted for excluded patients, but did not fulfill any of our other asthma specific study quality indicators.

A high number of patients excluded from the analysis of results was typical for this group of studies. With one exception (Simons, 1997), all gave an accounting of the reasons patients were excluded from the analysis. Overall, the preponderance of exclusions from analysis were patients withdrawn for the placebo arm due to lack of treatment effect (i.e., symptoms, exacerbations). Thus, the relatively high withdrawal rates from the placebo arm are an indicator that ICS treatment is more effective in controlling the symptoms of asthma. Only the CAMP (Childhood Asthma Management Program Research Group, 2000a) and Jonasson, Carlsen, Blomqvist et al. (1998) studies used an intent-to-treat analysis to control for bias related to withdrawals. Several other studies stated that intent-to-treat analysis was used, but it was evident from close review of the results sections of these papers that this was not the case.

Two trials other than CAMP reported on allocation concealment (van Essen-Zandvliet, Hughes, Waalkens et al., 1992; Verberne, Frost, Roorda et al., 1997); overall, six of the nine trials did not specify whether allocation to treatment arm was concealed. Verberne, Frost, Roorda et al. (1997) also met all the asthma-specific quality indicators, except addressing the effects of seasonality. van Essen-Zandvliet, Hughes, Waalkens et al. (1992) fulfilled three of the six asthma-specific indicators: accounting for excluded patients, establishing reversibility of lung obstruction and controlling for other medication use.

Five trials met no general quality criteria other than double-blinding (Simons, 1997; Hoekstra, Grol, Hovenga et al., 1998; Storr, Lenney, and Lenney, 1986; Connett, Warde, Wooler et al., 1993; Tinkelman, Reed, Nelson et al., 1993), and three of the five reported power calculations. Tinkelman, Reed, Nelson et al. (1993) also established reversibility, accounted for excluded patients, and controlled for other medication use. The trials by Storr, Lenney, and Lenney (1986) and Connett, Warde, Wooler et al. (1993) were of younger children, where lung function tests cannot be preformed to establish reversibility. Both accounted for excluded patients; Storr, Lenney, and Lenney (1986) also addressed seasonality. Neither study controlled for other medications or reported compliance. Storr, Lenney, and Lenney (1986) is the only trial of the 10 included in this key question that addressed seasonality. Of the two remaining trials, Hoekstra, Grol, Hovenga et al. (1998) and Simons (1997) both established reversibility and reported on compliance. But only Hoekstra, Grol, Hovenga et al. (1998) accounted for excluded patients and controlled for other medication use.

Results

Trials Comparing ICS to "As-Needed" Beta-2 Agonists: Children Older Than 5 Years

There were six trials in this category, enrolling a total of 790 patients treated with ICS and 652 controls; 40 percent of ICS patients (n=311) and 64 percent of controls (n=418) were contributed by the CAMP study (Childhood Asthma Management Program Research Group, 2000a). Except for Agertoft and Pedersen (1994), all trials were randomized, double-blinded, and placebo-controlled. Agertoft and Pedersen (1994) enrolled 216 ICS patients but only 62 controls; which comprises 27 percent and 10 percent, respectively, of the total population of the included studies. Asthma severity in these studies was generally mild to moderate. Three studies had a population that was estimated to be confined to mild-to-moderate patients (Childhood Asthma Management Program Research Group, 2000a; Simons, 1997; Hoekstra, Grol, Hovenga et al., 1998); together, these studies contributed 50 percent of ICS patients and 75 percent of controls. One study, which contributed 16 percent of ICS patients and 6 percent of controls, had a population that was clearly limited to mild asthma (Jonasson, Carlsen, Blomqvist et al., 1998). Two studies, enrolling 35 percent of ICS patients and 18 percent of controls, had populations spanning the range of severity from mild to severe (Agertoft and Pedersen, 1994; van Essen-Zandvliet, Hughes, Waalkens et al., 1992). The range of mean baseline FEV1 was 75.7 to 105 percent predicted.

Most patients (estimated 90 percent) were followed for a year or longer. Three trials reported followup greater than 1 year; 224 weeks in CAMP (Childhood Asthma Management Program Research Group, 2000a), mean of 192.4 weeks in the ICS arm of Agertoft and Pedersen (1994), and median of 95.3 weeks in van Essen-Zandvliet, Hughes, Waalkens et al. (1992). Simons (1997) reported 52 weeks of followup; the trials by Jonasson, Carlsen, Blomqvist et al. (1998) and Hoekstra, Grol, Hovenga et al. (1998) were each only 12 weeks in duration.

Lung Function Outcomes

All six studies report FEV1 outcomes; all but Agertoft and Pedersen (1994) also report PEF and PC20 outcomes. Two studies (Childhood Asthma Management Program Research Group, 2000a, van Essen-Zandvliet, Hughes, Waalkens et al., 1992) report FEV1 outcomes in both pre- and postbronchodilator values; the others did not specify whether the FEV1 outcomes were pre- or postpostbronchodilator measurements.

The CAMP study (Childhood Asthma Management Program Research Group, 2000a), because of its 4-year followup, large number of patients, and completeness in reporting lung function outcomes, provides the most robust available evidence on the effect of ICS on long-term lung function outcomes. CAMP found no significant changes in postbronchodilator FEV1 between the ICS and placebo groups (0.6 vs. −0.1 percent predicted, p=NS) (Childhood Asthma Management Program Research Group, 2000a). Baseline postbronchodilator FEV1 measures were in the normal range (>100 percent) for both groups and there was little overall change in these after 4 years of followup. An initial rise in FEV1 was observed in the ICS group, which diminished over time. After 1 year of followup, the difference between groups for postbronchodilator FEV1 was reported to be significant in favor of ICS, although specific data were not reported. This significant difference was not present, however, at the final time point.

These primary analyses of lung function outcomes were performed in an intent-to-treat manner. Since over 25 percent of patients in the placebo group received beclomethasone due to inadequate control, this intent-to-treat analysis may underestimate the true difference in lung function between groups. Supplementary comparisons were also performed (Childhood Asthma Management Program Research Group, 2000b) on a treatment-received basis and for patients who were compliant with treatment. The range of treatment difference in FEV1 was −0.3 to 0.6 percent predicted for these analyses, indicating that the lack of treatment effect was not the result of contamination of the placebo group or noncompliance in the treatment group.

The CAMP study reported statistically significant differences in prebronchodilator FEV1 and bronchial hyperreactivity at the 4-year time point that favored ICS over placebo (Childhood Asthma Management Program Research Group, 2000a). Change in prebronchodilator FEV1 was 2.9 vs. 0.9 percent predicted (p=0.02); an increase from baseline of 93.6 percent predicted to 96.5 percent in the ICS group, compared with 94.2 percent to 95.1 percent in the placebo group. For bronchial hyperreactivity, the ratio of final to initial concentration of methacholine that caused a 20 percent decrease in FEV1 was 3.0 in the ICS group compared with 1.9 in the placebo group (p<0.0001). The change in PEF was not significantly different for the ICS and placebo groups (131 L/min vs. 132 L/min).

The other five trials each reported a statistically significant difference in FEV1 outcomes in favor of the ICS group. Four of these trials did not specify whether the FEV1 measured was pre- or postbronchodilator. Of these four trials, two measured FEV1 at 12 weeks (Jonasson, Carlsen, Blomqvist et al., 1998; Hoekstra, Grol, Hovenga et al., 1998); one had 31 percent withdrawal in the placebo arm and 17 percent in the ICS arm (Simons, 1997); and the fourth trial was not randomized (Agertoft and Pedersen, 1994). Moreover, the trial by Jonasson, Carlsen, Blomqvist et al. (1998), which had three ICS arms at different dosages, reported final FEV1 only for the ICS arm that had significant results (budesonide 100 mcg twice daily). Thus, differences cannot be calculated for the two ICS arms that had nonsignificant results. Among these five trials, the difference in the change in FEV1 between ICS and control groups ranged from 5.2 percent to 14.8 percent.

It is difficult to compare the magnitude of change in FEV1 across these trials, or with the CAMP trial, due to several factors. Not all studies reported postbronchodilator FEV1 and, as discussed previously, results of studies reporting prebronchodilator FEV cannot be directly compared with those of studies that report postbronchodilator FEV1. The only study other than CAMP that reported both pre- and postbronchodilator measurements had a 43 percent rate of patient withdrawal in the placebo arm due to lack of treatment effect (van Essen-Zandvliet, Hughes, Waalkens et al., 1992). Likewise, comparisons of lung function outcomes at different lengths of followup is problematic. The effect of ICS on lung function parameters over time is not linear, therefore, comparisons of these outcomes need to be made at similar points in time in order to be meaningful. A further difficulty in comparing results across trials is that different doses of ICS may have an impact on the magnitude of effect. While the data contained in these studies are not robust enough to permit quantitative analysis, it is interesting to note that the two studies employing high doses of ICS (Agertoft and Pedersen, 1994; van Essen-Zandvliet, Hughes, Waalkens et al., 1992) reported the largest differences in FEV1 between groups (14.8 percent and 10.0 percent difference in prebronchodilator FEV1 between groups), while the single study using low ICS dosages in older children was largely negative (Jonasson, Carlsen, Blomqvist et al., 1998).

Among these same five trials, PEF was reported in four (Jonasson, Carlsen, Blomqvist et al., 1998; Simons, 1997; Hoekstra, Grol, Hovenga et al., 1998; van Essen-Zandvliet, Hughes, Waalkens et al., 1992). In three of these studies (Simons, 1997; Hoekstra, Grol, Hovenga et al., 1998; van Essen-Zandvliet, Hughes, Waalkens et al., 1992), there were significant differences in favor of the ICS group. PC20 outcomes were reported for four of these trials (Jonasson, Carlsen, Blomqvist et al., 1998; Simons, 1997; Hoekstra, Grol, Hovenga et al., 1998; van Essen-Zandvliet, Hughes, Waalkens et al., 1992), with significant differences found in favor of ICS in all four cases. PC20 outcomes were reported in various units (e.g., mg of medication, treatment ratio, doubling dose), precluding comparison of treatment effect across studies.

Symptom and Medication Use Outcomes

Three of the six studies reported symptom score outcomes (Childhood Asthma Management Program Research Group, 2000a; Jonasson, Carlsen, Blomqvist et al., 1998; Hoekstra, Grol, Hovenga et al., 1998), four reported symptom frequency outcomes (Childhood Asthma Management Program Research Group, 2000a; Jonasson, Carlsen, Blomqvist et al., 1998; Simons, 1997; van Essen-Zandvliet, Hughes, Waalkens et al., 1992), and four reported medication use outcomes (Childhood Asthma Management Program Research Group, 2000a; Jonasson, Carlsen, Blomqvist et al., 1998; Simons, 1997; van Essen-Zandvliet, Hughes, Waalkens et al., 1992). Statistically significant differences in symptom scores in favor of ICS were reported in two of the three studies (Childhood Asthma Management Program Research Group, 2000a; Jonasson, Carlsen, Blomqvist et al., 1998). In one of these two (Jonasson, Carlsen, Blomqvist et al., 1998), significant differences were found for only one of three ICS groups and not for the other two. CAMP reports a difference between groups in the improvement of symptom scores between groups of 0.07 on a 0-3 scale (p=0.005) (Childhood Asthma Management Program Research Group, 2000a).

Symptom frequency outcomes were significant in favor of ICS for two of the four studies reporting this class of outcomes. The CAMP study reported a significant difference in the improvement in episode-free days per month for the ICS group as compared to the placebo group (11.3 per month vs. 9.3 per month, respectively, p<0.01) (Childhood Asthma Management Program Research Group, 2000a). This difference represents a gain of two episode-free days per month associated with ICS use. CAMP reported no significant difference between the ICS and placebo groups in the number of night awakenings (−0.7 per month vs. −0.6 per month, p=NS) (Childhood Asthma Management Program Research Group, 2000a). Simons (1997) also reported no difference between groups in the percentage of symptom-free nights (99 percent in both arms). In contrast, Jonasson, Carlsen, Blomqvist et al. (1998) reported a significant difference in symptom-free nights for one of three ICS arms (treatment difference −0.11 nights/week without symptoms, p<0.05). This treatment difference represents a gain of approximately three symptom-free nights per month associated with ICS use. This treatment arm in the Jonasson, Carlsen, Blomqvist et al. (1998) study (budesonide 100 mcg twice daily) was the same arm that showed significant differences on lung function outcomes.

Four studies reported on supplemental beta-2 agonist use. CAMP reported a greater reduction in beta-2 agonist use for the ICS group as compared to the placebo group (7.4 puffs/week vs. 5.3 puffs/week, p<0.001), representing approximately two fewer puffs per week of beta-2 agonist associated with ICS use (Childhood Asthma Management Program Research Group, 2000a). Simons (1997) reported a difference of 9 percent (p=0.03) between groups on the overall percentage of days free of rescue medication use. This represents a gain of approximately 3 days per month in which rescue medication is not required. Jonasson, Carlsen, Blomqvist et al. (1998) and Simons (1997) reported no significant group differences in beta-2 agonist use.

Three studies reported on oral corticosteroid usage, two reporting a significant difference. CAMP reported 122 courses of oral corticosteroid use per 100 patient-years in the placebo group compared with 70 courses per 100 patient-years in the ICS group (p<0.001) (Childhood Asthma Management Program Research Group, 2000a). In the van Essen-Zandvliet, Hughes, Waalkens et al. (1992) trial, 48 percent of patients on placebo required at least one course of oral corticosteroids, compared with 14 percent of patients on ICS (p<0.001). In the Simons (1997) study, oral corticosteroid use was greater in the placebo group, but no test of statistical significance was reported.

Utilization Outcomes

Four trials reported some measure of utilization outcomes (Childhood Asthma Management Program Research Group, 2000a; Simons, 1997; Agertoft and Pedersen, 1994; van Essen-Zandvliet, Hughes, Waalkens et al., 1992), two of which were significantly better for the ICS group. CAMP reported a decrease in hospitalizations for the ICS group as compared to placebo (2.5/100 patient-years vs. 4.4/100 patient-years, p=0.04) (Childhood Asthma Management Program Research Group, 2000a). Agertoft and Pedersen (1994) also reported a decreased rate of hospitalizations associated with ICS use (0.004/pt/year vs. 0.03/pt/yr, p<0.001). Simons (1997) reported the percentage of patients with no missed school days to be 81 percent in the ICS group and 66 percent in the placebo group (p=NS). van Essen-Zandvliet, Hughes, Waalkens et al. (1992) reported no significant differences in the total number of hospitalizations and no significant difference in the total number of missed school days.

Summary

The evidence on the efficacy of ICS in children older than 5 years is from six trials, five of which were placebo controlled and randomized. These six trials enrolled a total of 790 patients treated with ICS and 652 controls. Overall, these studies demonstrate that, compared to as-needed beta-2 agonists without long-term controller medication, ICS improve control in patients with mild-to-moderate asthma. ICS-treated patients demonstrate reduced airway hyperresponsiveness (e.g., prebronchodilator FEV1, PC20), less frequent symptoms (e.g., daytime frequency, as-needed beta-2 agonist use), fewer courses of oral corticosteroids, and lower utilization (e.g., hospitalization). However, these improvements in asthma control may not translate into long-term benefits in lung function. In the CAMP trial, no difference among groups was observed in change in postbronchodilator FEV1 after 4 years of treatment (Childhood Asthma Management Program Research Group, 2000a).

The most robust evidence is from the CAMP trial, which contributed 40 percent of ICS patients (n=311) and 64 percent of controls (n=418) to the total patient population for this body of literature (Childhood Asthma Management Program Research Group, 2000a). This study also had the longest duration of treatment (4 years), the most complete outcome measures, and the most detailed reporting of study design and statistical analysis. All results reported by CAMP were adjusted for characteristics at study entry, including baseline value, severity and duration of asthma, age, sex, race, and ethnicity (Childhood Asthma Management Program Research Group, 2000a). Although lacking the power, followup and completeness of the CAMP study, the other five studies also reported statistically significant measures of asthma control that favored ICS. No study reported any statistically significant result that favored the control arm.

The CAMP study is unique, however, in demonstrating that there was no statistically significant change in postbronchodilator FEV1, which is a measure of long-term disease progression (Childhood Asthma Management Program Research Group, 2000a).

Of the five other studies, four did not specify whether pre- or postbronchodilator FEV1 was being reported; although it is likely that the measure was prebronchodilator. Moreover, two of these studies were only 12 weeks in duration and the third was 1 year; and thus insufficient to observe the long-term effects of disease or treatment. The fourth study followed 116 patients for 22 months and had a high rate of withdrawal. The fifth was a nonrandomized trial that enrolled only 62 patients in the control arm. Thus, none of these predecessors to the CAMP study were adequate to address the question of whether ICS can alter the course of the disease in patients with mild-to-moderate asthma.

Trials Comparing ICS to "As-Needed" Beta-2 Agonists: Children Younger Than 5 Years

Two studies (n=69) compared ICS to placebo in children less than 5 years of age, with treatment duration of 26 weeks (Storr, Lenney, and Lenney, 1986; Connett, Warde, Wooler et al., 1993). The main outcomes reported in these trials of very young children were symptom-based outcomes. Both reported symptom score and symptom frequency outcomes as recorded by the parents or caretakers. Both trials also reported beta-2 agonist use. Connett, Warde, Wooler et al. (1993) also reported oral corticosteroid usage and the total number of hospital visits. Lung function outcomes were not reported, as these are infeasible to measure in children younger than 5 years of age.

Both trials reported statistically significant differences favoring ICS in some symptom subscores. Storr, Lenney, and Lenney (1986) measured three symptom subscores: daytime wheezing, nighttime wheezing, and cough, on a 0-3 scale. Significant differences were found in favor of ICS on the final scores for daytime wheezing (0.26 vs. 0.33, p<0.05) and nighttime wheezing (0.26 vs. 0.35, p<0.05). Connett, Warde, Wooler et al. (1993) reported on five symptom score subscales: daytime cough, nighttime cough, daytime wheeze, nighttime wheeze, and days of limited activity, each measured on a 0-2 scale. Significant differences were found in favor of ICS on the change in two of these subscales, daytime cough (−0.5 vs. 0.05, p<0.03) and nighttime cough (−0.4 vs. 0.07, p<0.05). No differences were found on daytime or nighttime wheeze or on days of limited activity.

Other measures favored ICS use, but were not consistently statistically significant in these two small trials. Storr, Lenney, and Lenney (1986) reported significantly less beta-2 agonist use for the ICS group as compared to placebo (0.52 puffs/day vs. 0.98 puffs/day), but the difference was not significant in the trial by Connett, Warde, Wooler et al. (1993). Storr, Lenney, and Lenney (1986) found no differences in the percentage of symptom-free days or the percentage of symptom-free nights. But Connett, Warde, Wooler et al. (1993) found that the ICS group had a significantly greater percentage of symptom-free days as compared to placebo (54 percent vs. 31 percent, p<0.0001). The Connett, Warde, Wooler et al. (1993) study found less oral corticosteroid use and fewer hospitalizations in the ICS group, but the differences were not statistically significant.

Summary

Two small trials (n=69) compared ICS treatment to placebo in children under 5 years of age. The available evidence is scant, but the results reported appear to be consistent with those reported for children over 5 years of age.

Trials Comparing ICS with Salmeterol

Two randomized and double-blinded trials compared ICS to salmeterol in children (Verberne, Frost, Roorda et al., 1997; Simons, 1997). One of these (Verberne, Frost, Roorda et al., 1997) was designed as a direct comparison between the two agents. The second trial (Simons, 1997) was a three-arm study in which both ICS and salmeterol were compared with placebo, but for most outcomes, direct statistical comparisons were not reported between ICS and salmeterol. An indirect comparison of the two agents can be made by comparing the relative efficacy of each with placebo and by examining the magnitude of difference in outcomes between the two medications. Both of these trials included patient severity levels in the mild-to-moderate range and were of approximately 1-year duration. The total number of patients enrolled was 308 (including 80 patients in the placebo arm of Simons, 1997), with 237 patients evaluable. Both reported lung function outcomes, symptom frequency outcomes, and medication use outcomes. Simons (1997) also reported on the percentage of patients with missed school days.

Verberne, Frost, Roorda et al. (1997) found a significant difference in favor of ICS on the change in FEV1 over the course of the study. This study reported both pre and postbronchodilator FEV1 values and found a significant difference on both measures. There was a difference of 12 percent in the final prebronchodilator FEV1 in favor of the ICS group compared to salmeterol (95 percent vs. 83 percent, p<0.0001). A significant difference in postbronchodilator FEV1 was also reported, although this difference of 5.0 percent was a smaller absolute benefit in favor of the ICS group (102.5 percent vs. 97.5 percent, p=0.007). In contrast, the second study (Simons, 1997) reported an identical change in FEV1 (+10 percent predicted) for the ICS and salmeterol groups, and both were statistically significant compared to compared to placebo (+5 percent, p=0.001). Simons (1997) did not state whether the measure was pre or postbronchodilator.

Both trials reported PEF outcomes. Verberne, Frost, Roorda et al. (1997) reported a rise in PEF of 60.9 L/min in the ICS group as compared to 48.8 L/min in the salmeterol group, a difference that was not statistically significant. Simons (1997) reported a rise in PEF of 35 L/min for the ICS group and a slightly higher rise of 41 L/min for the salmeterol group, both significant compared to placebo. For PC20 outcomes, Verberne, Frost, Roorda et al. (1997) reported a significant difference in favor of the ICS group (increase of 2.02 doubling doses, as compared to a decrease of 0.73 doubling doses, p<0.0001). Simons (1997) reported change in mean mg of methacholine required for PC20, and reported a statistical comparison between ICS and salmeterol for this outcome in favor of ICS (increase of 1.37 mg vs. increase of 0.84 mg, p=0.01).

Symptom frequency measures were reported by Verberne, Frost, Roorda et al. (1997) as days/week with symptoms, nights/week with symptoms, and the percentage of patients with no symptoms over a 2-week period. There were no differences between groups in days/week or nights/week with symptoms. The percentage of patients with no symptoms over a 2-week period was 55 percent for the ICS group and 36 percent for the salmeterol group. This comparison was reported as "only significant at some time points," but not at others. Simons (1997) reported the percent of days in which beta-2 agonist was not required as rescue medication: 92 percent for ICS and 88 percent for salmeterol. The difference between the ICS group and the placebo group (92 versus 83 percent, p<0.001) was statistically significant, while the difference between the salmeterol group and the placebo group was not (88 percent vs. 83 percent, p=NS). There was no statistical comparison reported between the ICS and salmeterol groups.

In both studies, overall withdrawals and withdrawals for exacerbation were higher in the salmeterol group than the ICS group. Verberne, Frost, Roorda et al. (1997) reported that 10 patients withdrew from the trial. Of the seven patients who withdrew because of exacerbations, six were in the salmeterol group. Simons (1997) reported that overall withdrawals were 17 percent in the ICS group, 28 percent in the salmeterol group, and 31 percent in the placebo group (ICS vs. placebo, p=0.03). The percent of patients for whom the primary reason for withdrawal was asthma exacerbation was 5 percent in the ICS group, 15 percent in the salmeterol group, and 15 percent in the placebo group.

Beta-2 agonist use, as measured by the median number of puffs per day during the treatment period, was reduced in the ICS group as compared to salmeterol in the Verberne, Frost, Roorda et al. (1997) study (0.07 puffs/day vs. 0.44 puffs/day, p=0.0001). Simons (1997) reported that median percent albuterol-free days was significantly lower for ICS compared to placebo (92 vs. 83, p<0.001), but the difference between salmeterol and placebo (88 vs. 83) was not significant. Oral corticosteroid usage was reported in both studies. Both studies reported fewer courses of oral corticosteroids in the ICS group (2 versus 17 courses in Verberne, Frost, Roorda et al., 1997, 10 vs. 15 courses in Simons, 1997), but neither study reported a statistical comparison. Simons (1997) reported on the percentage of patients who did not miss any school days due to asthma, 88 percent in the ICS group vs. 81 percent in the salmeterol group and 66 percent in the placebo group. No statistical comparisons were reported for this outcome.

Summary

There is little evidence available to compare ICS and salmeterol in children with mild to moderate asthma. Two randomized and double-blinded trials enrolled 116 (99 evaluable) patients treated with ICS, 112 (83 evaluable) patients treated with salmeterol, and 80 (55 evaluable) patients treated with placebo. One of these is a three-arm trial in which most comparisons were indirect and reported as ICS vs. placebo and salmeterol vs. placebo. Most of the results that were statistically significant were from only one of the two trials; and statistical data were lacking for many comparisons of interest. These two trials are not adequate to determine the relative effectiveness of the two agents. However, all statistically significant results reported favored ICS over salmeterol and none favored salmeterol over ICS.

Trials Comparing ICS with Theophylline

One trial compared ICS use to theophylline (Tinkelman, Reed, Nelson et al., 1993). This was a 36-week trial enrolling 195 patients whose asthma severity ranged from mild to severe. Outcomes reported included pre- and postbronchodilator FEV1, PEF, bronchial hyperreactivity, symptom scores, symptom frequencies, oral corticosteroid usage, and ER visits. There was a high dropout rate in both arms of this trial: 25 percent of the patients in the ICS arm and 26 percent in the theophylline arm were not included in the final analysis.

There were no statistically significant differences found between groups on the majority of the outcome measures abstracted. Prebronchodilator FEV1 increased to a similar degree in both groups, while post bronchodilator FEV1 remained largely unchanged in both groups. PEF improved by 6 percent predicted in the ICS group compared with 2 percent predicted in the theophylline group (p=NS). The PC20 also showed a larger increase in the ICS group (9.04 mg methacholine vs 3.7 mg methacholine) but this difference did not reach statistical significance either. Baseline and final symptom scores were virtually identical between groups. Similarly, there were no significant differences in symptom frequencies, or ER visits. The ICS group had less oral corticosteroid use as compared to the theophylline group, with 81.4 percent of patients in the ICS group not requiring oral corticosteroids, as compared to 63.4 percent of patients in the theophylline group (p=0.007).

Summary

One trial (n=195) compared ICS use to theophylline. Because of the lack of additional trials and large numbers of withdrawals, these data are not sufficient to judge the comparative efficacy of ICS vs. theophylline; neither are the data sufficient to conclude that these agents have equivalent efficacy.

Trials Comparing ICS with Nedocromil/Cromolyn

The third arm of the CAMP (Childhood Asthma Management Program Research Group, 2000a) study compared nedocromil to placebo, enrolling 312 patients in the nedocromil arm and comparing outcomes to the 418 patients in the placebo group. As described previously, this was a population of mild-to-moderate asthmatics followed for over 4 years. No direct comparisons of the ICS arm with the nedocromil arm were reported. However, examination of the comparison to placebo in each of the two treatment arms allows an indirect determination of the relative efficacy of ICS vs. nedocromil

The majority of comparisons of nedocromil vs. placebo were not significantly different. These included pre- and postbronchodilator FEV1, PEF, PC20, symptom scores, symptom frequencies, and beta-2 agonist use. There were two outcome measures that showed a significant difference in favor of the nedocromil group. The amount of oral corticosteroid use was less in the nedocromil group (102 courses/100 patient-years vs. 122 courses/100 patient-years, p=0.01). The frequency of ER use was also lower in the nedocromil group as compared to placebo (16 visits/100 patient-years vs. 22 visits/100 patient-years, p=0.02).

Summary

The CAMP trial found no difference between nedocromil and placebo in lung function or symptom outcomes, although courses of oral corticosteroids and urgent care visits were reduced (Childhood Asthma Management Program Research Group, 2000a). Therefore, it can be concluded that ICS are more effective than nedocromil in reducing the frequency and severity of symptoms, supplemental beta-2 agonist use, and the frequency of hospitalizations due to asthma. The data do not suggest that either agent leads to improved long-term lung function outcomes, as measured by change in postbronchodilator FEV1, for children with mild-to-moderate asthma.

Conclusions

Most of the studies in the evidence base for this systematic review evaluated outcomes related to asthma control; the outcome measures and duration of followup in most studies were not adequate to assess the effects of treatment on disease progression over the long term. The available evidence is sufficient to conclude that ICS are superior to "as needed" beta-2 agonists in improving short term lung function measures, symptoms, ancillary medication use, and utilization. However, the CAMP study, which provides the most robust evidence to date on long-term changes in lung function, found no difference between ICS and control groups after 4 years of treatment (Childhood Asthma Management Program Research Group, 2000a). Thus improvements in short-term parameters of control may not translate to long-term improvements in lung function, at least in the population and treatment duration addressed by CAMP. The evidence is not sufficient to permit conclusions on the comparative benefit of ICS vs. salmeterol or ICS vs. theophylline. The CAMP study found that ICS are superior to the mast-cell stabilizing agent nedocromil (Childhood Asthma Management Program Research Group, 2000a).

Inhaled Corticosteroids Compared to As-Needed Beta-2 Agonists

Children Age 5 Years or Older

The evidence on the efficacy of ICS in children older than 5 years is from six trials, five of which were placebo controlled and randomized. These six trials enrolled a total of 790 patients treated with ICS and 652 controls. The most robust evidence is from the CAMP trial, which contributed 40 percent of ICS patients (n=311) and 64 percent of controls (n=418), had the longest duration of treatment (4 years), the most complete outcome measures, and the most detailed reporting of study design and statistical analysis (Childhood Asthma Management Program Research Group, 2000a).

Overall, these studies demonstrate that compared to as-needed beta-2 agonists without long-term controller medication, ICS improve control in patients with mild-to-moderate asthma. ICS-treated patients demonstrate improvement in prebronchodilator FEV1, reduced airway hyperresponsiveness, improvements in symptom scores and symptom frequency, less supplemental beta-2 agonist use, fewer courses of oral corticosteroids, and lower utilization (hospitalization). The evidence does not suggest, however, that ICS use is associated with improved long-term postbronchodilator FEV1. The CAMP trial reported no difference in the change in postbronchodilator FEV1, which is a measure of disease progression, after 4 years of treatment (Childhood Asthma Management Program Research Group, 2000a).

Children Age 5 Years or Younger

Two small trials (n=69) compared ICS treatment to placebo in children under 5 years of age. The available evidence is scant, but the results reported appear to be consistent with those reported for children over 5 years of age: that ICS improve short-term control of asthma. There is no evidence addressing the long-term effect of ICS on lung function in this age group.

Inhaled Corticosteroids Compared to Alternative Long-Term Control Medications

Salmeterol

The available evidence is not adequate to determine the relative effectiveness of the ICS and salmeterol in children with mild to moderate asthma. Two randomized and double-blinded trials enrolled 116 (99 evaluable) patients treated with ICS, 112 (83 evaluable) patients treated with salmeterol, and 80 (55 evaluable) patients treated with placebo. One of these is a three-arm trial in which most comparisons were indirect and reported as ICS vs. placebo and salmeterol vs. placebo. Of the statistically significant results reported, most were significant in only one of the two trials; however, all favored ICS over salmeterol.

Theophylline

One trial (n=195) compared ICS use to theophylline. Because of the lack of additional trials and large numbers of withdrawals, these data are not sufficient to judge the comparative efficacy of ICS vs. theophylline; neither are the data sufficient to conclude that these agents have equivalent efficacy.

Nedocromil

The CAMP trial found no difference between nedocromil and placebo in lung function or symptom outcomes, although courses of oral corticosteroids and urgent care visits were reduced (Childhood Asthma Management Program Research Group, 2000a). Therefore, it can be concluded that ICS are more effective than nedocromil in reducing the frequency and severity of symptoms, supplemental beta-2 agonist use, and the frequency of hospitalizations due to asthma.

Key Question 1b. What are the lon g-term adverse effects of chronic ICS use in children on the following outcomes:

  • vertical growth
  • BMD
  • ocular toxicity
  • suppression of adrenal/pituitary axis

Overview

This systematic review addresses the long term adverse effects of ICS use in children on four outcomes: vertical growth; BMD; ocular toxicity, including posterior subcapsular cataract and glaucoma; and suppression of adrenal/pituitary axis function.

The difficulties of systematically assessing adverse effects of drugs 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. To assess the adverse effects of ICS on the outcomes of interest, evidence from controlled clinical trials was used; however, other sources of data also were sought.

Numerous factors can confound the interpretation of growth and bone density effects, including individual variation, effects of puberty, severity of asthma, and oral corticosteroid use. Furthermore, among the various ICS preparations, each agent may have somewhat different effects due to differences in per-unit potency, absorption, and solubility. Thus, for growth outcomes and effects on bone density, the evidence was limited to controlled studies that incorporated plausibly constructed adjustments for confounders. In contrast, for rarely occurring events such as cataracts in childhood or iatrogenic Cushing's syndrome, the literature was searched broadly for observational data, including case reports. While such reports cannot establish the frequency of occurrence of an adverse effect, they can show an association between intervention and event and may, under some conditions, permit causal inferences.

Effect on Vertical Growth

Evidence was found on three measures of vertical growth in children: short term growth velocity measured over a period of 1 year or less; growth velocity and change in height measured over longer duration (4-6 years), and final attained adult height. The evidence on short-term growth velocity is from a published meta-analysis that pooled data from five 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 longer duration is from the CAMP trial (Childhood Asthma Management Program Research Group, 2000a), a randomized trial comparing ICS, nedocromil, and placebo in 1,041 children with mild-to-moderate asthma who were followed for 4 to 6 years. 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, Yunginger, Reed et al., 1997; Van Bever, Desager, Lijssens et al., 1999). Together, these three studies included a total of 243 asthmatics treated with ICS, 154 asthmatics who had not been treated with ICS, and 204 nonasthmatic controls.

Growth Velocity < 1 Year

The effect of ICS on short-term growth velocity has been evaluated in several randomized clinical trials. Randomized controlled trials constitute the most rigorous evidence of an effect on growth velocity, free from effects of confounding caused by asthma status and severity of disease. A previous synthesis of randomized, clinical trials was located that combines the results of studies that would have qualified for inclusion in the review of evidence.

A meta-analysis of the relevant randomized controlled trials was published by Sharek and Bergman (2000). Studies were included in the meta-analysis if they met the following criteria: subjects 0 to 18 years of age with a clinical diagnosis of asthma; subjects randomized to inhaled beclomethasone, budesonide, flunisolide, fluticasone, or triamcinolone versus a nonsteroidal inhaled control for a minimum of 3 months; single- or double-blinded; and outcome convertible to linear growth velocity.

Out of 92 full-text studies initially reviewed by Sharek and Bergman (2000), five trials met study selection criteria. Of the five trials, four used beclomethasone and one used fluticasone. The studies all included patients with mild-to-moderate asthma that was thought to be clinically stable at the time of enrollment. Characteristics of the subjects in all five trials, representing 855 subjects, revealed a mean age of 9.5 years, a mean percentage of males of 67.0 percent, and a mean baseline FEV1 of 85.4 percent. All five studies calculated growth velocity using a regression coefficient of height on time.

Studies by Doull, Freezer, and Holgate (1995), Simons (1997), Tinkelman, Reed, Nelson et al. (1993), and Verberne, Frost, Roorda et al. (1997) all evaluated beclomethasone. Each study by itself showed a statistically significant effect of ICS on growth velocity. The summary weighted mean difference between children treated with beclomethasone and children treated with nonsteroidal medication was −1.51 cm/year (95 percent CI: −1.15 to −1.87). Due to the small number of studies and the lack of data on subgroups, analyses examining treatment duration, ICS dose, subject age and pubertal status were not performed.

One study by Allen, Bronsky, LaForce et al. (1998) evaluated fluticasone at a moderate-strength dose of 200 mcg/day. The mean difference between 96 children treated with fluticasone and 87 children treated with placebo was −0.43 cm/year (95 percent CI: −0.01 to −0.85).

Thus, the conclusion of the meta-analysis by Sharek and Bergman (2000) is that there is a consistent effect of ICS on growth velocity when assessed over a period of 1 year or less. The limitations of the meta-analysis are important to note. Because the measurement of growth was limited to 1 year, no firm conclusions can be made about the effect of ICS beyond 1 year. If growth delay upon initiation of therapy is compensated for by increased later growth, then the implications for growth in long-term therapy are less significant. Secondly, the small number of trials did not allow for analysis of subgroup and interaction effects, that could clarify the independent effects, if any, of treatment duration, ICS dose, and subject age or pubertal status. Third, the meta-analysis reflects largely the effect of beclomethasone, and may not be generalizable to other drugs.

Long-Term Growth Velocity and Change in Height

There is one study that examined growth velocity and changes in height in a rigorous randomized clinical trial over longer than 1 year. The CAMP study (Childhood Asthma Management Program Research Group, 2000a) randomized 1,041 children with mild-to-moderate asthma to receive budesonide, nedocromil, or placebo, and followed growth parameters for 4 to 6 years.

At the end of the study period, the children receiving ICS had 1.1 cm less growth than those in the placebo group and 1.0 cm less growth than those in the nedocromil group (p=0.005). Such differences also expressed as final height percentiles were also statistically significant (p<0.001). These analyses were performed on an intent-to-treat basis, providing a conservative estimate of the differences between groups. Supplementary analysis was performed on a treatment-received basis (Childhood Asthma Management Program Research Group, 2000b). In this analysis, children who had received any ICS over the course of the study had 1.8 cm less growth compared with children who had only taken "as needed" beta-2 agonists (p=0.0001).

The investigators also calculated a "projected" final height for each subject, which is a prediction of final adult height based on age, attained height, bone age, and age of onset of menses for girls. Such estimates do not take into account uncertainty of the prediction, and if the components from which the estimate is made are affected by treatment, comparisons between treatment groups may be biased. These projected final height estimates did not differ for all treatment groups.

In CAMP, growth velocity was much slower in the ICS group over the first year of the study (Childhood Asthma Management Program Research Group, 2000a). By 2 years of followup, growth velocity appeared to have converged, and after 4 years it was essentially identical in all three study groups.

The comparisons between treatment groups were analyzed on an intent-to-treat basis, regardless of the treatment actually received by the study subjects. It is notable in the CAMP study that over the 4 years of the study, over 25 percent of the subjects in the nedocromil and placebo groups eventually required initiation of additional therapy, usually ICS (Childhood Asthma Management Program Research Group, 2000a). Thus, the results comparing heights include a fair proportion of patients that crossed over into the other treatment arm, thus, producing a possibly conservative measure of effect. On the other hand, it is unknown to what degree growth may have been impaired if asthma therapy had not been intensified in patients whose disease was not adequately controlled.

Final Attained Adult Height

There are three studies that attempted to evaluate the effect of ICS on final attained adult height (Agertoft and Pedersen, 2000; Silverstein, Yunginger, Reed et al., 1997; Van Bever, Desager, Lijssens et al., 1999). None of the studies are randomized controlled trials. All are retrospective cohort studies, which cannot evaluate potential sources of confounding such as severity of asthma or other factors which may be associated with both final attained adult height and treatment for asthma. Only studies that accounted for potential confounding of parental height were included in the analysis. All of the studies reviewed here controlled for parental height by calculating a predicted attained height for each subject based on the height of both parents.

The study by Silverstein, Yunginger, Reed et al. (1997) enrolled 153 patients from Rochester, Minnesota with a clinical diagnosis of asthma during childhood. Adult height of asthma subjects was directly measured, data on types of treatments received were obtained from questionnaire and medical records, and height of parents was based on subjects' self-report. An age- and sex-matched control group of 153 subjects without asthma were recruited from Rochester residents who had ever received care at the Mayo Clinic.

Comparisons of adult height adjusting for parental height were carried out for asthmatics versus nonasthmatics. Among asthmatic subjects, comparisons were carried out for any corticosteroid (n=58) use versus noncorticosteroid (n=95) use, oral corticosteroid (n=40) use versus no corticosteroid (n=95) use, and ICS (n=18) use versus no corticosteroid (n=95) use. All comparisons showed small differences that were not statistically significant. In particular, the comparison among asthmatic subjects between ICS use and no corticosteroid use showed that ICS users were 0.9 cm shorter (95 percent CI, −3.8 to 2.0). However, this estimate is based on only 18 subjects who used ICS and 95 subjects who did not use any corticosteroids.

A similar study also based on a retrospectively collected sample by Van Bever, Desager, Lijssens et al. (1999) compared final adult heights among subjects with asthma treated during childhood with different treatment regimens. One group of subjects had been treated with ICS (n=43) during childhood, and the other group had not received inhaled or oral corticosteroids (n=42) during childhood. Both subjects' height and their parents' heights were directly measured by the investigators.

Although the mean adult heights between subjects who had taken ICS and those who had not were not statistically different, adjustment for parental height made a critical difference in the analysis. Overall, after adjusting for parental height, those who had taken ICS were 2.54 cm shorter than those who had not (p=0.03). Stratifying by gender, males who had taken ICS were 3.09 cm shorter than those who had not (p=0.04), and females who had taken ICS were 1.99 cm shorter than those who had not (p=0.31).

In additional secondary analyses, there was no association between height and age at which ICS were started, and no association between total dose of ICS and height. Using hospitalization as a proxy for severity of asthma, among the ICS users, the 11 subjects who had been hospitalized for asthma had a statistically lower adult height minus target height than did the 31 subjects who had never been hospitalized (difference of 2.02 cm, p=0.046).

The study by Agertoft and Pedersen (2000) assessed final adult height in 211 children: 142 treated from childhood with ICS, 18 control patients with asthma who had never been treated with ICS, and 51 healthy siblings of the children treated with ICS. Although an original cohort of subjects with asthma was followed prospectively for several years, due to dropouts and changes in treatment, the study is equivalent to a retrospectively defined cohort, based on data availability and actual treatment given.

The 142 subjects who took ICS were 0.3 cm taller than target adult height, whereas the 18 asthmatic subjects who never took ICS were −0.2 shorter than target adult height, so the net difference between the two groups was 0.5 cm (no differences statistically significant). The healthy siblings were 0.9 cm taller than target adult height, so the net difference between subjects receiving ICS and their healthy siblings was −0.6 (p=NS).

In analysis of the longitudinal data, the investigators found that the growth rate during years 1 and 2 was significantly slower than during the run-in period of the study (run-in 6.1 cm/year, year one 5.1 cm/year, year two 5.5 cm/year). During the third year, the growth rate was not statistically significantly slower than the run-in period.

Conclusions on Vertical Growth

The body of research regarding the effect of ICS on growth velocity over a relatively short period of 1 year is consistent in showing a difference of average height of 1cm/year over a period of about 1 year. This difference is demonstrated in several studies using the most rigorous study design, i.e., randomized clinical trials. In the one clinical trial extending beyond 1 year (Childhood Asthma Management Program Research Group, 2000a), a difference consistent with this magnitude also occurred in the first year of the study. However, in subsequent long-term followup, the difference in growth velocity was not maintained, and by the end of the 4- to 6-year observation period, there was still an approximately 1 cm difference in cumulative growth between the study groups.

The evidence regarding final adult height appears to be fairly consistent as well. However, this evidence is based on retrospective cohort studies, where the confounding effects of severity of asthma cannot be adjusted for. Selection biases cannot be assessed in retrospective studies, because only subjects who are available at the end of the study can be assessed. More severe asthma patients are more likely to use ICS. Finally, the small sample size of ICS users in the Silverstein, Yunginger, Reed et al. (1997) study make the conclusions of a negative study less firm. The studies of Silverstein, Yunginger, Reed et al., (1997) and Agertoft and Pedersen (2000) showed no difference in final attained adult height, whereas the study of Van Bever, Desager, Lijssens et al. (1999) showed a difference between ICS users and nonusers. However, the difference in adult height in the Van Bever, Desager, Lijssens et al. (1999) study, 2.54 cm, is much less than would be expected if the 1 cm/year growth velocity difference demonstrated in the short-term studies was maintained over several years (Table 8).

Table 8. Difference between adult-target height.

Table

Table 8. Difference between adult-target height.

The differences between the studies on short-term growth velocity and final attained adult height appear to be explained by the fact that the initial difference in growth velocity is not sustained over longer periods of time. Although there is no evidence for an initial compensatory acceleration of growth rate (i.e., "catch-up" growth), after the first year, there appears to be resumption of normal growth rates.

Effect on Bone Mineral Density

Selection criteria for this outcome required that BMD alone be considered the appropriate outcome, and that studies have sufficient size (n=25) in each group for sufficient comparison. Studies that evaluated adults were included if it was felt that the outcomes largely reflected treatment in childhood or young adulthood. Studies of adults were thus included if the mean age of the population was less than 40 years and if the duration of asthma and/or ICS treatment was sufficiently long enough to conclude that ICS exposure had primarily occurred during childhood or early adulthood. Two of the studies are cross-sectional studies that evaluate BMD at a single time, and one of the studies is a randomized clinical trial which assesses changes in BMD over a period of 4-6 years.

Agertoft and Pedersen (1998) compared 157 asthmatic children treated with inhaled budesonide at a mean daily dose of 504 mcg to 111 age-matched children also suffering from asthma but who had never been treated with oral corticosteroids for more than 14 days. The children receiving ICS had been taking medication for 3 to 6 years. The mean age of the ICS users was 10.3 years. There was no difference in mean total body BMD between children taking ICS and the control group (0.92 g/cm2 vs. 0.92 g/cm2). In addition, there were no significant differences in bone mineral capacity and total bone calcium.

Ip, Lam, Yam et al. (1994) studied 30 young adults with a mean duration of asthma of 14 years who had been on ICS an average of 40 months (range: 3-180 months). They were compared to a control group without asthma matched on sex, age, body mass index and menopausal status. BMD measured at the spine, femoral neck, and hip of the ICS users were all significantly lower than that of the control patients. When the subjects were stratified by sex, only females showed a significant difference in all BMD measurements. Among the female patient group, there was a significant correlation between the average daily dose of ICS and BMD of the lumbar spine (r= −0.46, p=0.054) and BMD of the femoral trochanter (r= −0.47, p=0.047).

The one randomized clinical trial, the CAMP study (Childhood Asthma Management Program Research Group, 2000a) evaluated 1,041 children who received budesonide, nedocromil, or placebo. Mean age was 9.5 years and BMD of the spine was assessed at baseline and the end of followup at 4 to 6 years. None of the patients groups had significantly different changes in spinal BMD (budesonide 0.17 g/cm2, nedocromil 0.17 g/cm2, placebo 0.17 g/cm2).

Conclusions on Bone Mineral Density

The CAMP study (Childhood Asthma Management Program Research Group, 2000a), with large numbers, randomization, assessment of longitudinal changes, provides very strong evidence that there is no effect of ICS on BMD in the doses given in that study (Table 9). The other studies are subject to potential confounding because of unmeasured differences between groups that are risk factors for low BMD. In the Ip, Lam, Yam et al. (1994) study, patients' BMD was measured during adulthood, making it uncertain as to whether the effect of ICS was due to an effect during childhood (i.e., slowing the increase in BMD during growth) or adulthood (i.e., accelerating the loss of BMD due to aging). In addition, the clinical significance of the differences in BMD are unknown. Subtle differences in BMD would not have clinical impact until additive to other risk factors such as aging. It is uncertain whether differences observed during young adulthood would persist to old age, or whether small changes in childhood would lead to clinically meaningful differences in fracture risk at older ages.

Table 9. Effects of ICS on bone mineral density.

Table

Table 9. Effects of ICS on bone mineral density.

Effects on Posterior Subcapsular Cataract and Glaucoma

A total of seven studies enrolling approximately 1,000 asthmatic subjects receiving ICS therapy examined occurrence of subcapsular cataracts. Because the incidence and prevalence of cataracts is expected to be zero in children and young adults, clinical trials, comparative cross-sectional studies, and single-group cross-sectional studies were all selected for review. Three studies were randomized clinical trials that examined subjects for incidence of cataracts during the trial period. Two studies were cross-sectional studies examining the prevalence of cataracts in groups already being treated with ICS compared with control groups never treated with ICS. Two studies were cross-sectional studies examining the prevalence of cataracts only among subjects already taking ICS.

Several of the clinical trials that evaluated cataracts were of relatively short duration. The randomized clinical trials by Allen, Bronsky, LaForce et al. (1998) and Tinkelman, Reed, Nelson et al. (1993) only treated and followed patients for 1 year. The CAMP study (Childhood Asthma Management Program Research Group, 2000a) assessed the incidence of cataracts over 4 to 6 years of treatment with ICS. The four cross-sectional studies evaluating subjects who had already been treated with ICS reported a mean prior treatment duration between 2.1 and 6.7 years.

Occurrence of cataract was a rare outcome in all studies. Three of the seven studies evaluating a total of 360 subjects taking ICS reported no cataracts among users (Agertoft Larsen, and Pedersen, 1998; Tinkelman, Reed, Nelson et al., 1993; Simons, Persaud, Gillespie et al., 1993). Four of the studies reported the occurrence of a single cataract that could possibly be attributed to ICS. In the randomized clinical trial by Allen, Bronsky, LaForce et al. (1998), a single patient out of 219 treated with fluticasone developed a trace subcapsular cataract at the 24th week of the study. Before enrolling in the study, the patient had been treated with ICS for 2 years. In the cross-sectional study of Nassif, Weinberger, Sherman et al. (1987), a single subcapsular cataract was noted in one patient out of 31 taking ICS. In the study of Abuikteish, Kirkpatrick, and Russell (1995), one cataract in one patient out of 140 patients taking ICS was identified, but this patient had a past history of oral corticosteroid use. In the CAMP study (Childhood Asthma Management Program Research Group, 2000a), no patients had cataracts according to lens-photography criteria, but a single patient out of 311 on ICS had a posterior subcapsular cataract detected in an ophthalmologic exam conducted 5 months after the photographs were taken. The patient had been receiving budesonide and beclomethasone, and had received 38 days of oral prednisone during the study.

Thus, the studies appear to rule out a large effect of ICS on the short-term incidence of cataract, but are insufficient to rule out an increased risk of a small absolute magnitude.

Two of these studies also reported findings on measurements of ocular pressure. In the randomized, controlled trial of Tinkelman, Reed, Nelson et al. (1993), no cases of glaucoma were detected. In the cross-sectional study by Nassif, Weinberger, Sherman et al. (1987), ocular pressures were normal in all cases and mean ocular pressures did not differ between patients taking ICS and patients not on ICS (14.0 vs. 14.0).

Conclusions on Posterior Subcapsular Cataract and Glaucoma

These very limited data available show no relationship between glaucoma or increased intraocular pressure and ICS. However, these studies only examined children and young adults. Evidence is lacking on adverse effect occurrence of these complications when the subjects are older and the baseline risk of cataracts and glaucoma is much greater. A small increased risk of senile cataracts or glaucoma because of childhood treatment with ICS would be of great public health importance because of the high prevalence of ICS use and the high incidence of senile cataracts.

Effect on Hypothalamic-Pituitary-Adrenal Axis Function

Two types of evidence on the effects of ICS on HPA axis function were found. The first type of evidence consists of case reports of iatrogenic Cushing's syndrome, possibly related to ICS. The second type consists of six studies evaluating 413 patients treated with ICS where HPA axis function was followed for or assessed at least 1 year after initiation of treatment. Three studies are randomized clinical trials (or extensions or subsets of randomized clinical trials), two are cross-sectional studies, and one is a single-arm pre-post study. Each study evaluates from one to three different measures of HPA function. The three randomized clinical trials and the one pre-post study assessed HPA function over the 1-year period of trial. The two cross-sectional studies assessed HPA function at 1.4 and 2.1 mean years of treatment with ICS.

Case Reports of Iatrogenic Cushing's Syndrome

Several case reports describe children presenting with signs and symptoms of iatrogenic Cushing's syndrome possibly related to ICS (Zimmerman, Gold, Wherrett et al., 1998; Taylor, Jensen, Kanabar et al., 1999; Priftis, Everard, and Milner, 1991; Hollman and Allen, 1988). In each of these four case reports, patients presented with signs and symptoms of Cushing's syndrome; and at the time of clinical presentation, patients' plasma cortisol levels were low and out of the normal range. Stimulation tests were not always performed on the patients but were normal in at least one of the patients (Hollman and Allen, 1988). The case for causality of the symptoms in all of these case reports is further strengthened by the fact that signs and symptoms regressed after reduction or withdrawal of ICS and retesting confirmed return to normal plasma cortisol levels.

The case reports show that systemic effects can occur in clinically detectable ways, with a strong case for causality in these individual patients by the accompanying laboratory tests and response when ICS were withdrawn. Case reports such as these provide strong evidence that systemic effects on the HPA axis can occur, but provide no evidence on the frequency of such effects. However, if a particular adverse effect is rare, then most randomized clinical trials or cohort studies are also unable to determine the frequency of such events.

Studies of HPA Axis Function in Clinical Trials and Cross-Sectional Studies

Out of the large number of studies examining some aspect of HPA axis function in patients taking ICS, study selection criteria limited the reviewed studies to those in which at least 25 patients were evaluated, and where HPA axis function was followed for at least 1 year after initiation of treatment.

The designs of the included studies vary. Three studies are randomized clinical trials (or extensions or subsets of randomized clinical trials), two are cross-sectional studies, and one is a single-arm pre-post study. Each study evaluates from one to three different measures of HPA function.

Four studies (Scott and Skoner 1999; Tinkelman, Reed, Nelson et al., 1993; Nassif, Weinberger, Sherman et al., 1987; Ribeiro 1993) evaluating 312 patients taking ICS reported findings on serum cortisol levels. None of the studies reported significant differences in serum cortisol values, whether the findings were expressed as comparison of changes between groups between baseline and followup, a cross-section comparison during treatment, or a single-group pre-post comparison.

Three studies (Price, Russell, Hindmarsh et al., 1997; Gonzalez Perez-Yarza, Mintegui, Garmendia et al., 1996; Nassif, Weinberger, Sherman et al., 1987) evaluating 132 patients taking ICS reported findings on 24-hour urinary cortisol, a measure which is a more sensitive measure of difference in adrenal function than serum cortisol, because it is correlated with cortisol excretion over a 24-hour period of time. Although the study of Price, Russell, Hindmarsh et al. (1997) was a randomized clinical trial, all three studies reported only cross-sectional comparisons of urinary cortisol. Two of the studies, the studies of Gonzalez Perez-Yarza, Mintegui, Garmendia et al. (1996) and Nassif, Weinberger, Sherman et al. (1987) reported significant differences in the mean value of urinary cortisol between groups treated with ICS versus control groups.

Three studies (Scott and Skoner 1999; Tinkelman, Reed, Nelson et al., 1993; Ribeiro 1993) evaluating 281 patients taking ICS reported the results of normal dose ACTH stimulation tests between ICS users and control groups. None of the studies reported a change in ACTH-stimulated cortisol levels consistent with adrenal suppression, either between baseline and followup between study groups or between baseline and followup in a single-arm study. In the single-arm study by Ribeiro (1993), the results were statistically significant in the opposite direction, indicating better responsiveness to ACTH in the period after ICS were started. In the study by Gonzalez Perez-Yarza, Mintegui, Garmendia et al. (1996), only patients with low urinary cortisol levels were subjected to ACTH stimulation tests. Tests were abnormal in 3.1 percent of patients (n=2). However, control subjects were not tested, so it is unknown whether this is attributable to ICS treatment.

Conclusions on Effect of Inhaled Corticosteroids on HPA Axis

The findings of these studies, although varying widely as to whether a statistically significant effect of ICS on adrenal function exists, could be explained by differences in the sensitivity of the different tests used to evaluate adrenal function and the different aspects of adrenal function that are being evaluated. Measures of low cortisol, either serum or urinary, reflect diminished cortisol excretion due to the effect of exogenous steroids on the feedback mechanism which regulates cortisol excretion. Stimulation tests, on the other hand, reflect the ability of the adrenal gland to respond to stimulation by increasing cortisol excretion.

All the studies assessing adrenal function using serum cortisol level or conventional dose ACTH stimulation tests showed no effect of ICS (Table 10). However, when using more sensitive tests of such as 24-hour urinary cortisol, two out of three studies showed a statistically significant effect of ICS. It should be noted that these statistically significant results occur as comparisons of mean values between groups. Few or no patients in most studies have laboratory values out of the "normal" range. However, the clinical significance of these more sensitive indicators of adrenal function is unknown.

Table 10. Effects of ICS on HPA function.

Table

Table 10. Effects of ICS on HPA function.

The question, then, is how to reconcile the case reports with the results of clinical trials and cohort studies. The case reports appear to be reasonably causally attributable to ICS 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 have only clinically insignificant effects of ICS on the HPA axis, there may be individuals acutely susceptible to their effects. The relatively short duration of the reviewed studies precludes any conclusion regarding the effects of years of ICS use on HPA function.

Conclusions

This systematic review addresses the long term adverse effects of chronic ICS use in children on four outcomes: vertical growth; BMD; ocular toxicity, including posterior subcapsular cataract and glaucoma; and suppression of adrenal/pituitary axis. 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, while effects on vertical growth are not a concern for adults, ocular toxicity is likely to occur more frequently as age increases.

As summarized, the available evidence suggests that the use of ICS 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 ICS initiated in childhood might have cumulative effects that increase the relative risk of certain events, such as osteoporosis, cataracts, or glaucoma, in later life. However, none of the available studies has sufficient followup duration or numbers of patients to definitively assess this possibility. It is also likely that the probability of adverse effects is related to the dose of ICS. However, no studies identified in the published literature were appropriately designed to test the dose-response relationship of ICS to adverse effects.

Vertical Growth

Evidence on 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 (4-6 years), and final attained adult height. The evidence on short-term growth velocity is from a published meta-analysis which pooled data from five randomized controlled trials representing 855 subjects, with a mean age of 9.5 years. Evidence on growth velocity and height over longer duration is from the CAMP trial (Childhood Asthma Management Program Research Group, 2000a) randomized trial comparing ICS, nedocromil, and placebo in 1,041 children with mild-to-moderate asthma followed for 4 to 6 years. For final attained adult height, evidence is from three retrospective cohort studies that adjusted for the potential confounding factor of parental height. Together, these three studies included a total of 243 asthmatics treated with ICS, 154 asthmatics who had not been treated with ICS, and 204 non-asthmatic controls.

Evidence on growth velocity over 1 year is consistent in showing a difference of average height of 1 cm/year between children treated with ICS and controls. In the only trial extending beyond 1 year (Childhood Asthma Management Program Research Group, 2000a), a difference consistent with this magnitude also occurred in the first year of the study. However, in subsequent long term followup, the difference in growth velocity was not maintained. At the end of the 4 to 6 year observation period there was still an approximately 1 cm difference in cumulative growth between the study groups.

The evidence on final adult height appears to be fairly consistent, as well. However, this evidence is based on retrospective cohort studies, which are subject to selection bias and the confounding effects of severity of asthma cannot be adjusted for. Some comparisons in these studies were also limited by small sample size. One study showed a difference in final attained adult height between ICS users and nonusers. However, the difference is much less than would be expected than if a 1 cm/year growth velocity difference was maintained over several years.

Bone Mineral Density

The CAMP study (Childhood Asthma Management Program Research Group, 2000a) followed a population of mild to moderate asthmatics, mean age approximately 9 years treated for 4 years with ICS. This study, with large numbers, randomization and assessment of longitudinal changes, provides very strong evidence that there is no effect of ICS on BMD and in the doses given and time duration in that study. One retrospective study of 30 young adults found a significant correlation between BMD and ICS dosage among female patients. 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 clinical impact until additive to other risk factors such as aging, and it is uncertain whether differences observed during young adulthood would persist to old age. Alternatively, it is possible that subtle changes during critical periods of bone mineral accretion that occur in childhood could magnify the risk of osteoporotic fracture in later life.

Posterior Subcapsular Cataract and Glaucoma

Studies that report the occurrence of posterior subcapsular cataracts consist mostly of small cohorts and cross-sectional studies, with the exception of the CAMP study (Childhood Asthma Management Program Research Group, 2000a). The expected incidence rate of subcapsular cataract in any population of normal young children and adults is zero. These studies are sufficient to rule out a large effect of ICS on short-term incidence of cataract, but are not capable of detecting a small increase in risk of an event which has a baseline risk of essentially zero. Also, 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. The very limited data available show no relationship between glaucoma or raised intraocular pressure and ICS.

Effect on Hypothalamic-Pituitary-Adrenal Axis Function

Two types of evidence on the effects of ICS on HPA axis function were found. These were case reports of iatrogenic Cushing's syndrome related to ICS and six studies (n=413 treated with ICS) regarding HPA axis function. Each study evaluates from one to three different measures of HPA 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 in individuals, with a strong case for causality in these individual patients by the accompanying laboratory tests and response when ICS were withdrawn. In the controlled clinical studies, when using more sensitive tests of cortisol such as 24-hour urinary cortisol, two out of three studies of HPA axis function showed a statistically significant effect of ICS. It should be noted that these statistically significant results occur as comparisons of mean values between groups. Few or no patients in most studies have laboratory values out of the "normal" range. However, the clinical significance of these more sensitive indicators of adrenal function is unknown.

The case reports appear to be reasonably causally attributable to ICS 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 have only clinically insignificant effects of ICS on the HPA axis, there may be individuals acutely susceptible to their effects.

Views

  • PubReader
  • Print View
  • Cite this Page

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...