Attained adult height after childhood asthma" Effect of glucocorticoid therapy

Transcription

1 Attained adult height after childhd asthma" Effect f gluccrticid therapy Marc D. Silverstein, MD, a, b Jhn W. Yunginger, MD, c Charles E. Reed, MD, a Tanya Pettersn, MS, b Dnald Zimmerman, MD, c James T. C. Li, MD, PhD, a and W. Michael 'Falln, PhD b Rchester, Minn. Backgrund: Althugh ral and inhaled gluccrticid therapy may impair grwth in children with asthma, the effect f gluccrticid therapy and asthma n attained adult height has nt been extensively studied in representative children in the cmmunity. bjectives: The study was designed t cmpare the attained adult height f children with asthma with the attained adult height f nnasthmatic children and t cmpare the attained adult height f asthmatic children treated with gluccrticids with the attained adult height f asthmatic children wh did nt receive gluccrticids. Methds: Residents f Rchester, Minnesta, with nset f asthma frm 1964 t 1987 and age- and sex-matched nnasthmatic residents f Rchester were studied. Gluccrticid expsure was assessed frm medical recrds. The mean f 5 stadimeter measurements f adult height, adjusted fr sex and parental height, was analyzed. Results: ne hundred fifty-three patients with asthma (mean age at nset, 6.1 _+ 4.8 years) and 153 age- and sex-matched nnasthmatic subjects were studied. Adult height f patients with asthma (mean age at measurement, years) was nt significantly different frm the adult height f nnasthmatic subjects; the verall difference, adjusted fr midparental height, was -.2 cm (95% cnfidence interval frm -.27 t 1.64). The adult height f asthmatic children treated with gluccrticids was nt significantly different frm the adult height f patients with asthma nt treated with gluccrticids; the difference after adjusting fr mid-parental height was -.2 cm (95% cnfidence interval frm -.1 t.6). Cnclusins: We cnclude that the attained adult height f patients with asthma is nt different frm the adult height f age- and sex-matched nnasthmatie subjects and that the attained adult height f asthmatic children treated with glucerticids is nt significantly different frm the adult height f children nt treated with glucerticids. (J Allergy Cliu Immunl 1997;99: ) Key wrds: Asthma, height, grwth, gluecrticids Frm athe Divisin f Area General Internal Medicine, bthe Department f Health Sciences Research, ~the Department f Pediatric and Adlescent Medicine, and dthe Divisin f Allergic Diseases and Internal Medicine, May Clinic and May Fundatin, Rchester. Supprted by a grant frm Schering-Plugh Research, a grant frm the Natinal Institutes f Health (AI-25187), and the May Fundatin. Received fr publicatin Apr. 19, 1996; revised Sept. 24, 1996; accepted fr publicatin Sept. 3, Reprint requests: Marc D. Silverstein, MD, Center fr Health Care Research, Medical University f Suth Carlina, 171 Ashley Ave., Charlestn, SC Cpyright 1997 by Msby-Year Bk, Inc /97 $5. + 1/1/78571 Asthma is a cmmn cnditin with a prevalence in Rchester, Minnesta, f apprximately 8%. 1 The incidence f asthma is highest in the early years f life, and asthma may be active thrughut a child's grwing years. Children with asthma have been reprted t have shrter stature and smaller increase in height fr age (slwer height velcity) than children withut asthma? Althugh it is well recgnized that daily and alternateday administratin f gluccrticids may impair grwth, 3-6 shrter stature fr age has been bserved in children with asthma wh have nt been treated with gluccrticids. 7-1 Mechanisms ther than the effect f gluccrticid treatment have been pstulated t explain the shrter stature f children with asthma including chrnic hypxia, diminished lung functin, chrnic infectin, undernutritin, sleep disturbance, and lngterm stress In additin t grwth retardatin, children with asthma have been reprted t have delayed maturatin as measured by time f appearance f secndary sexual characteristics and by skeletal age. 7,14 Sme investigatrs have fund that althugh change in height (i.e., height velcity) is transiently reduced, catch-up grwth ccurs, 7 and asthmatic children attain nrmal adult height?, ~4, 15 ther investigatrs have nt fund evidence f catch-up grwth? 6, 17 Whether the attained adult height f children with asthma, especially children wh have received gluccrticids, is equal t predicted height and cmparable t attained adult height f children withut asthma is cntrversial. With increasing recgnitin f the imprtance f the rle f inflammatin in asthma and the efficacy f gluccrticid therapy in reducing inflammatin, gluccrticids are presently prescribed mre ften and earlier in the treatment f patients with asthma. Inhaled gluccrticid therapy is ften used t avid the adverse effects f lng-term ral gluccrticid treatment? 8 Beclmethasne and triamcinlne have nt been assciated with reduced height r grwth in previus studies?9, 2 Hwever, a recent randmized clinical trial f aersl beclmethasne cmpared with ral thephylline in treatment f children, ages 6 t 17 years, with mild t mderately severe asthma demnstrated reduced grwth in the beclmethasne grup cmpared with the ral thephylline grup. 21 N ppulatin-based study, hwever, has reprted the adult height f children treated with gluccrticids. 466

2 J ALLERGY CLIN [MMUNL Silverstein et al. 467 VLUME 99, NUMBER 4 We previusly identified a ppulatin-based chrt f Rchester, Minnesta, residents with nset f asthma between 1964 and This chrt, updated thrugh 1987, includes 778 children with definite asthma whse symptms began during childhd and wh have nw attained their adult height. An advantage f studying this retrspective chrt is that the subjects will have already experienced the utcme f interest (i.e., attained adult height). Fr this study we invited all available members f this chrt t participate in a study f asthma and adult height. We evaluated whether patients with nset f asthma during childhd have shrter adult height than nnasthmatic subjects and whether patients with asthma wh received gluccrticids fr treatment f their asthma during childhd had shrter adult height than patients with asthma wh did nt receive gluccrticids. METHDS Study setting Rchester, Minnesta, is lcated 9 miles sutheast f Minneaplis and is centrally lcated in lmsted Cunty. In 199 the ppulatin f Rchester was 7,745 (94% white). With the exceptin f a higher prprtin f residents emplyed in the health care industry, the characteristics f Rchester are similar t thse f the U.S. white ppulatin. Ppulatin-based epidemilgic research is pssible in this setting because essentially all medical care fr Rchester residents is prvided by the May Clinic and its affiliated hspitals, by the lmsted Medical Grup and its affiliated hspital, and by a small number f ther physicians. The medical diagnses and surgical prcedures fr all prviders are recrded in autmated databases, and the riginal medical recrds f all prviders are available fr review thrugh the resurces f the Natinal Institutes f Healthfunded Rchester E pidemilgy Prject. Study design The first study aim was t cmpare the adult height f asthmatic children with the adult height f children withut asthma. Fr this aim, a retrspective chrt study design was selected t cmpare the utcme f adult height f the chrt with asthma with the adult height f an age- and sex-matched chrt f nnasthmatic subjects. The secnd study aim was t cmpare the adult height f asthmatic children wh received gluccrticids with the adult height f asthmatic children wh did nt receive gluccrticids. Fr this aim, a retrspective chrt study design was als selected in which the expsure f interest was gluccrticid therapy and the utcme was attained adult height. Subjects We previusly identified the chrt f Rchester residents with nset f asthma frm 1964 thrugh and have partially updated the chrt thrugh Fr this study, Rchester residents with definite asthma, by the predetermined criteria used fr the previus study f the epidemilgy f asthma, 1 wh experienced the nset f their asthma during childhd and wh attained adult height (age -<17 years fr girls and -<19 years fr bys) were eligible and were asked t participate. With the resurces f the Rchester Epidemilgy Prject, an age- and sex-matched subject withut asthma wh resided in Rchester in the same year as the nset f asthma fr the crrespnding asthmatic study subject was identified frm the list f Rchester residents wh had ever received care at the May Clinic and was invited t vlunteer fr the study. All subjects gave infrmed cnsent t be enrlled in the study. The study was apprved by the May Clinic Institutinal Review Bard. Data cllectin Infrmatin fr the study was cllected frm three surces: (1) directly frm study subjects by means f a pretested structured questinnaire, (2) frm nurse abstractr review f all inpatient and utpatient medical recrds f Rchester prviders f care fr study subjects, and (3) frm direct measurements f adult height fr all study subjects and pulmnary functin test results fr study subjects. Date f birth and gender f all subjects were available frm the medical recrds. All asthma medicatins listed anywhere in the medical recrd frm nset f asthma until age f attaining adult height were recrded fr all subjects. All data cncerning the date, dse, rute, frequency, amunt prescribed, and number f refills were recrded. The recrded height and the date the height was recrded were abstracted frm medical recrds fr at least ne visit each year fr all years in which there was a clinic visit until the study subject attained adult height r was lst t fllw-up. When mre than ne measurement was available, the first measurement in each year was recrded. All subjects were asked t accurately reprt their current height and the height f their natural parents and t estimate their parents' height in relatin t their wn height. Measurement f adult height All subjects had a stadimeter measurement f standing height with shes remved measured by the same study nurse, using a single stadimeter that was calibrated peridically against a knwn standard. The measurements were repeated five times, and the mean f five recrdings was analyzed. Data analysis Fr each study subject, mid-parental height was used t adjust fr subject's mther's and father's height. 2z 23 The frmula used was: Mid-parental height (bys) = (Mther's height + Father's height + 13 cm) + 2 Mid-parental height (girls) = (Mther's height + Father's height - 13 cm) + 2 The height f asthmatic subjects was cmpared with the height f nnasthmatic subjects in tw ways, bth f which adjusted fr survey-reprted mid-parental height. The first cmparisn ignred the matching and assessed the relatinship between the mean f the five measurements f adult height and asthma status by means f analysis f cvariance. The secnd cmparisn used a paired analysis t accunt fr the matching. Here, the difference between a subject's mean measured height and mid-parental height was calculated. This difference frm midparental height was cmpared between the asthmatic subjects and the age- and sex-matched nnasthmatic subjects by using a signed-rank test. Amng asthmatic subjects, the relatinship between mean measured adult height and gluccrticid expsure was assessed by using analysis f cvariance. Each subject's gluccrticid expsure was classified as any chart-recrded expsure r

3 468 Silverstein et al. J ALLERGY CLIN IMMUNL APRIL 1997 TABLE I. Patient and parental height fr asthmatic chrt and age- and sex-matched nnasthmatic chrt Asthmatic chrt Nnasthmatic chrt Variable & sex n Mean -+ SD n Mean -+ SD p Value* Mean measured height (cm) Female Male _ Survey-reprted father's height (cm) Female _ _ Male _ Survey reprted mther's height (cm) Female Male _ Mid-parental height (cm) Female _ Male _ *Rank sum test. n chart-recrded expsure and separately classified as any chart-recrded ral expsure, nly inhaled gluccrticid expsure recrded in the chart, r n chart-recrded expsure. Additinally, the relatinship between mean measured adult height and cumulative gluccrticid expsure was assessed in an analysis f cvariance mdel. Cumulative childhd expsure t gluccrticids was calculated by using all recrded expsures befre subjects attained adult height (age 17 years fr girls and age 19 years fr bys). Fr each episde f gluccrticid use, expsure was calculated by multiplying the dse in milligrams by the number f dses per day and by the ttal number f days expsed. A tapering dse was treated as half the initial dse multiplied by the number f days ver which the dse was tapered. All f the individual episdes f gluccrticid expsure were then added tgether t yield a cumulative expsure t gluccrticids. In an additinal analysis, gluccrticid ptency adjustment was made by adjusting each specific gluccrticid expsure by the ptency f the gluccrticid relative t the ptency f prednisne; all adjusted expsures were then summed t arrive at a cumulative adjusted expsure. Cumulative gluccrticid expsure and cumulative adjusted gluccrticid expsure were als separately calculated fr subjects with any ral gluccrticid expsure and fr subjects with nly inhaled gluccrticid expsure. The distributins f cumulative gluccrticid expsure and cumulative adjusted gluccrticid expsure were highly skewed, and accrdingly, the natural lgarithms f cumulative gluccrticid expsure and adjusted gluccrticid expsure were used in the analysis f cvariance mdels. Analyses were perfrmed by using SAS sftware (SAS Institute). A p value less than.5 was cnsidered statistically significant. RESULTS At the time the study was initiated, 778 members f the updated asthma chrt had experienced nset f asthma during childhd and had attained adult height (age 17 in girls and age 19 in bys) and were therefre eligible fr the study. Fifty-six members f the riginal chrt were excluded because f unavailable current addresses (37 cases), revised diagnses (4 cases), deaths (2 cases), r ther miscellaneus reasns (13 cases). The remaining 722 Rchester residents with nset f asthma befre attaining adult height were invited t participate. Letters t 99 chrt members were returned frm the pst ffice as "unclaimed," indicating that a current address fr these patients was nt available. Thus 623 members f the riginal chrt were assumed t have been cntacted. Sixty-tw (1%) declined t participate, 3 (48%) did nt respnd, and 261 (42%) cmpleted the study questinnaire. ne hundred fifty-three (25%) were available fr height measurement, were enrlled in the study, and cmprise the asthma chrt. There were 153 study subjects with asthma, 78 wmen (51%) and 75 men (49%). The asthmatic subjects' mean age at nset f asthma was 6.1 _+ 4.8 years (median, 5.2 years). The asthmatic subjects' mean age at first gluccrticid expsure was years; the mean interval between nset f asthma and first gluccrticid expsure was years. The mean age at last gluccrticid expsure befre attaining adulthd was 14.6 _+ 3.7 years, and the mean interval between first and last gluccrticid expsure was 7.3 ± 4.8 years. Age at time f measurement f adult height was 25.7 _+ 5.2 years. Table I summarizes the mean f the five stadimeter measurements f adult height, the reprted father's height and mther's height, and the calculated mid-parental height fr the asthmatic chrt and fr the age- and sex-matched cmparisn chrt f Rchester residents withut asthma. The measured height, survey-reprted father's height and mther's height, and calculated mid-parental height f the asthmatic chrt were nt significantly different frm crrespnding values fr the nnasthmatic chrt as determined by the rank-sum test. Nte that the mean measured height was greater than the mean mid-parental height fr wmen and men fr bth the chrt with asthma and the cmparisn chrt. Asthma and adult height In the unmatched analysis, the height f patients with asthma, after adjusting fr sex and mid-parental height, was nt significantly different frm the height f nnasthmatic subjects (p =.82). The adult height f the

4 J ALLERGY CUN IMMUNL Silverstein et al. 469 VLUME 99, NUMBER 4 C,I // / z= -r X3 I D [] ~C D i ~ u ~ ~ elc i c e~ f~ d~ ~D D i i e i i. id~ I D ]m ii ~e dpell D D 9... Males, Asthmatics... Males, Nn-asthmatics... Female, Asthmatics [] Female, Nn-Asthmatics Mid-Parental Height (cm) FIG. 1. Adult height f men and wmen with asthma and age- and sex-matched nnasthmatic subjects by mid-parental height. Lines indicate the fllwing equatin: Adult height = 48.2 cm + (.15 cm) Asthma + (3.44 cm) Male + (.73 cm) x Mid-parental height, where Asthma = 1 if asthmatic, if nnasthmatic; Male = 1 if male, if female, asthmatic chrt and the age- and sex-matched nnasthmatic chrt by mid-parental height, and the lines indicating predicted adult height, are shwn in Fig. 1. After adjustment fr sex and mid-parental height, patients with asthma were.15 cm (.6 inches) taller than nnasthmatic subjects. The difference in the measured height between the asthmatic subjects and matched nnasthmatic subjects was nly.21 _ cm (p =.95). The measured heights f bth the chrt with asthma and the nnasthmatic cmparisn chrt are greater than their expected mid-parental heights ( cm and cm, respectively; bth p <.1). Finally, the paired cmparisn f difference in the measured adult height (adjusted fr mid-parental height) f the asthmatic subjects cmpared with the nnasthmatic subjects was nly.2 _ 8.17 cm; p =.78). In all cmparisns results were cnsistent fr bth wmen and men. Gluccrticids and adult height f patients with asthma verall, 58 (38%) f the patients with asthma had expsure t gluccrticids recrded in their medical recrds. Gluccrticid expsure was similar fr wmen (28 f 78 r 36%) and men (3 f 75 r 4%). The patients with asthma wh received inhaled gluccrticids had a mean f 3.3 dses (median, 4 dses) prescribed per day. The patients with asthma wh received ral r parenteral gluccrticids had a mean f 2.4 curses (median, 1 curse) f ral r parenteral gluccrticids during their childhd years. The mean f the five measurements f adult height, survey-reprted parental height, mid-parental height, and difference between measured height and mid-parental height fr wmen and men by any gluccrticid expsure r n gluccrticid expsure is shwn in Table II. Amng the 58 patients with asthma wh were expsed t gluccrticids, 4 had received ral gluccrticids (19 wmen and 21 men), and 18 had received nly inhaled gluccrticids (9 wmen and 9 men). The adult height f patients with asthma treated with gluccrticids was nt significantly different frm the adult height f patients with asthma wh did nt receive gluccrticids. After adjusting fr mid-parental height, the adult height f patients with asthma treated with gluccrticids was apprximately 1.2 cm (apprximately.5 inch) less than the height f patients with asthma nt treated with sterids. The 95% cnfidence interval fr gluccrticid therapy was (-3.1 cm,.6 cm). The adult height f patients with asthma by mid-parental height and the lines indicating predicted adult height fr thse with any gluccrticid therapy and thse with n gluccrticid therapy are shwn in Fig. 2. In the analysis that classified gluccrticid expsure as any ral gluccrticid use, inhaled gluccrticid use nly, r n gluccrticid use, neither expsure t ral gluccrticids (ever) nr expsure t inhaled gluccrticids nly was assciated with adult height after ad-

5 47 Silverstein et al. J ALLERGY CLIN IMMUNL APRIL "" '" z~ "'""*"" + + z~t ~ z~..,,"" E= a) -r - 2 r,. ~ ~ (D ~ ~ J..~-'~ + z~.,-'" A A..,' + z~+ + +, ~, ~...'" ~- + z~ rp'"'"' z~ z~ *"A + +~.,.z~ / ~...,.+z~ + z+],+..4-" f + u3 j. A... Sterid Treated N Sterid Treatment Mid-Parental Height (cm) FIG. 2. Adult height f patients with asthma wh received any gluccrticid therapy during childhd r adlescence and patients with asthma wh received n gluccrticid therapy during childhd r adlescence by mid-parental height. Lines indicate the fllwing equatin: Adult height = 23.2 cm - (1.26 cm) x Gluccrticid + (.89 cm) Mid-parental height, where Gluccrticid = 1 if gluccrticid recrded in medical recrded, if n gluccrticid therapy recrded in medical recrd. TABLE II. Patient and parental height f patients with asthma by gluccrticid use and sex Gluccrticid use N gluccrticid use Variable n Mean -~ SD n Mean + SD p Value* Measured adult height (cm) Female t Male _ Calculated mid-parental height (cm) Female ± ± Male ± _ t Difference in measured height and mid-parental height (cm) Female ± Male ± t *t test. trank sum test. justing fr mid-parental height. In an analysis that adjusted fr mid-parental height, the adult height f patients with asthma wh received ral gluccrticids (ever) was 1.4 cm less than the height f patients with asthma nt treated with sterids. The 95% cnfidence interval f the difference was (-3.5 cm,.7 cm). The adult height f patients with asthma wh received nly inhaled gluccrticids was.9 cm less than the height f patients with asthma nt treated with gluccrticids. The 95% cnfidence interval f the difference was (-3.8 cm, 2. cm). The adult height f patients with asthma by mid-parental height and the lines indicating predicted adult height f thse wh received ral r parenteral gluccrticids, inhaled gluccrticids nly, r n gluecrticid therapy are shwn in Fig. 3. Cumulative gluecrticid expsure and adult height Gluccrticid expsure is summarized fr all patients with asthma and fr thse wh received ral

6 J ALLERGY CLIN ]MMUNL Silverstein et al. 471 VLUME 99, NUMBER 4 (kl + + ~ / T= "1" " b~ N ( ~7 v /.2e + + /~',/-'~ + + <> + +.~.< V ~ 7 V <>+ ~7"++ _v<~+v + v + +<~ ~ + V v i~/>" v ~ // ;/"-" V --- ral Sterids ">... Inhaled Sterids nly + N Sterid Therapy,, J i, Mid-Parental Height (cm) FIG. 3. Adult height f patients with asthma wh received ral r parenteral gluccrticid therapy during childhd r adlescence, patients with asthma wh received nly inhaled gluccrticids during childhd r adlescence, and patients with asthma wh had n gluccrticid expsure by mid-parental height. Lines indicated the fllwing equatin: Adult height = 23. cm - (1.4 cm) ral - (.9 cm) Inhaled + (.89 cm) Mid-parental height, where ral = 1 if any gluccrticid expsure, if n expsure t ral gluccrticids; and Inhaled = 1 if nly inhaled gluccrticid expsure, if n expsure t any inhaled sterids. TABLE III. Cumulative childhd gluccrticid expsure and gluccrticid ptency-adjusted expsure after nset f asthma until attaining adult height Cumulative gluccrticid expsure Adjusted cumulative gluccrticid expsure Median Mean _+ SD Median Mean -+ SD n (ttal mg) (ttal mg) n (ttal mg) (ttal mg) All gluccrticid use Wmen ± ± 27 Men _ ral gluccrticids (any) Wmen ± _~ 2445 Men ± Inhaled gluccrticids (nly) Wmen ± Men ± ± 125 f the 19 wmen in the ral gluccrticid grup, 12 als received inhaled gluccrticids. Fr these 12 wmen, the mean -+ SD cumulative inhaled gluccrticid expsure was mg (median, 28 mg); the cumulative inhaled ptency-adjusted gluccrticid expsure was mg (median, 87 rag). f the 21 men in the ral gluccrticid grup, 1 als received inhaled gluccrticids. Fr these 1 men, the mean _+ SD cumulative inhaled gluccrticid expsure was mg (median, 83 rag); the cumulative inhaled ptency-adjusted gluccrticid expsure was mg (median, 459 mg). gluccrticids (ever) r inhaled gluccrticids nly fr men and wmen in Table III. The distributin f expsures is quite skewed, and therefre median and mean ± SD are reprted. Nte that patients with asthma whse treatment included curses f ral gluccrticids generally had higher cumulative expsure (p =.3) and adjusted cumulative expsure (p =.3) t gluccrticlds than patients with asthma wh received nly inhaled gluccrticids. After adjusting fr mid-parental height, measured adult height was nt statistically significantly assciated with cumulative gluccrticid expsure r with cumulative gluccrticid expsure ad-

7 472 Silverstein et al. J ALLERGY CLIN IMMUNL APRIL 1997 justed fr gluccrticid ptency (p =.89 and.79, respectively). The relatinship between measured height, adjusted by mid-parental height, and gluccrticld expsure is shwn in Fig. 4. Height f asthma chrt and enrlled subjects This study enrlled patients frm a ppulatin-based chrt f Rchester residents with nset f asthma befre attaining adult height. T assess whether the sample f patients enrlled in the study differs frm riginal chrt members nt enrlled, adult height reprted in the medical recrds f enrlled patients was cmpared with the adult height reprted in the medical recrds f members f the riginal chrt nt enrlled in the study. The medical recrd height f enrlled wmen (mean, cm; n = 72) and men (mean, cm; n = 54) was nt significantly different frm the medical recrd height f chrt wmen (mean, _+ 6.7 cm; n = 134) and men (mean, _+ 7.5 cm; n = 16) nt enrlled in the study. T assess whether the sample f patients wh cmpleted questinnaires but did nt enrll in the study differed frm enrlled subjects wh cmpleted questinnaires and had a stadimeter measurement f adult height, we cmpared the self-reprted height f enrlled subjects with the self-reprted height f thse wh nly respnded t the questinnaire. The self-reprted height f enrlled wmen (mean, cm; n = 78) and men (mean, _+ 7. cm; n = 75) was nt significantly different frm the self-reprted height f wmen (mean, _ 6.2 cm; n = 5) and men (mean, cm; n = 57) wh nly respnded t the questinnaire. DISCUSSIN This study used a ppulatin-based incidence chrt f patients with asthma as a sampling frame t enrll subjects with nset f asthma befre attaining adult height. The adult height f patients with asthma, adjusted fr parental height, was nt significantly different frm the height f nnasthmatic subjects, suggesting that, verall, asthma des nt have an imprtant effect n attained adult height. The attained adult height f patients with asthma wh received gluccrticids was nt significantly different frm the adult height f patients with asthma nt treated with gluecrticids. The actual magnitude f the bserved difference, 1.22 cm r apprximately.48 inch, was small, suggesting n clinically imprtant differences in adult height. Analyses f the attained adult height f patients with asthma wh had received any ral r parenteral gluccrticid treatment and patients with asthma wh had received nly inhaled gluccrticid treatment cmpared with patients with asthma nt treated with gluccrticids als cnfirmed that differences in height were nt statistically significant. The actual magnitudes f any differences were small (1.4 cm r.55 inch and.9 cm r.35 inch, respectively) and are nt likely t be clinically imprtant. Finally, additinal analyses based n cumulative gluccrticid expsure and gluccrticid ptency-ad- justed expsure shwed n significant dse-respnse effect. ur findings are reassuring in that they suggest that, verall, asthma per se and gluccrticid treatment f asthma d nt have a clinically imprtant impact n attained adult height. ur findings suggest that, verall, patients with asthma treated with gluccrticids may be 1.2 cm (.5 inch) shrter than patients with asthma nt treated with gluccrticids. We can use the 95% cnfidence interval t interpret the range that may include the actual difference. Thus patients with asthma treated with gluccrticids culd be as much as -3.1 cm (1.2 inches) shrter r.6 cm (.2 inches) taller than patients with asthma nt treated with sterids. ur best estimate f the difference in attained adult height (1.2 cm r apprximately.5 inch) is small and in ur judgment nt clinically imprtant. The lwer limit f the 95% cnfidence interval, 3.1 cm, is less than ne half f the standard deviatin f adult height. ur study had a 96% pwer t detect a difference f 2 inches between the tw grups but nly a 47% pwer t detect a difference f 1 inch between the tw grups. ur findings are nt incnsistent with results f studies that dcument impaired grwth during gluccrticid expsure. The effect f gluccrticids n attained adult height may depend n the particular gluccrticlds used, rute f delivery dse, duratin f use, and whether gluccrticids were given cntinuusly r intermittently during childhd and adlescence. ur findings indicate that fr mst patients with asthma, the actual use f gluccrticids in management f asthma was nt assciated with a clinically imprtant effect n attained adult height. It is pssible that the gluccrticld expsure f patients with asthma may be t small t prduce a substantial effect n attained adult height r that patterns f use in curses f gluccrticids with intervening perids withut gluccrticid expsure included adequate perids f grwth t allw children and adlescents t attain expected adult height. Gluccrticid expsure was assessed frm review f all the inpatient and ambulatry medical recrds f all prviders f care fr the patients with asthma. Access t the patients' riginal recrds, which is available thrugh the Rchester Epidemilgy Prject, assures a high level f ascertainment f gluccrticid prescriptins. Medical recrd dcumentatin f gluccrticid use may underestimate actual use because refills may nt be cmpletely recrded in the medical recrd. Cnversely, medical recrd dcumentatin f gluccrticid use may verestimate actual use because f nncmpliance. Unfrtunately, we are nt able t directly verify actual medicatin expsure in this lng-term bservatinal study. Nevertheless, we believe that the striking effectiveness f gluccrticids in treatment f asthma, clinical cncerns abut adverse effects f high dses r prlnged gluccrticid use, and general cncern abut treatment with medicatin in children result in reasnably accurate dcumentatin f gluccrticid expsure fr the analyses f the relatinship f any

8 J ALLERGY CLIN IMMUNL Silverstein et al. 473 VLUME 99, NUMBER 4 15 E r.- 1 " a_ i.-._~ C ql,1b i -1 Females Males -15,,, ' ' ', i,,,,,,, I ' ' ',,,, I Cumulative Ptency Adjusted Sterid Expsure FIG, 4. Difference between measured adult height f patients with asthma and mid-parental height versus lgarithm f cumulative ptency-adjusted gluccrticid frm nset f asthma t age f adult height (17 years fr girls and 19 years fr bys). expsure, type f expsure, r cumulative expsure t attained adult height. T evaluate ptential selectin bias in recruitment and enrllment f study subjects, we cmpared the medical recrd adult height f the eligible patients frm the riginal chrt and the medical recrd adult height f enrlled study subjects and fund n significant differences. We als cmpared self-reprted adult height f ptential subjects wh cmpleted the questinnaire with the self-reprted height f enrlled study subjects and again fund n significant differences. Thus we believe that enrlled study subjects are a representative selectin f children treated with gluccrticids. Interestingly, bth patients with asthma and nnasthmatic subjects exceeded their expected (mid-parental) height; patients with asthma were 3.7 cm (apprximately 1.5 inches) taller than expected, and nnasthmatic subjects were 3.6 cm (apprximately 1.4 inches) taller than expected. This increase in stature has been bserved histrically in the United States 24 and has been bserved recently in the Japanese ppulatin. 25 We enrlled subjects frm a ppulatin-based chrt with nset f asthma frm 1964 thrugh 1983 wh had attained adult height by December During this perid, there were changes in physicians' use f gluccrticids fr treatment f childhd asthma. In the 196s and 197s, ral gluccrticids were used in the lwest pssible dsages fr nly the mst severe cases; whereas in the 198s and 199s, inhaled gluccrticids with less ptential fr inducing systemic effects were used in children with mild t mderate asthma. Althugh generally regarded as safe at cnventinal dses, higher dses f inhaled gluccrticids may nt be risk-free. 26 In additin, suppressin f grwth velcity has been reprted in sme children receiving recmmended pharmaclgic dses f these preparatins.6, 21, Findings frm ur retrspective study are cnsistent with thse f previusly published prspective studies invlving fewer children but mre hmgeneus treatment regimens. In a lng-term study invlving 66 asthmatic children, 29 required treatment with 4 t 6 p~g/day f beclmethasne diprpinate, 33 required treatment with crmlyn sdium, and fur required nly brnchdilatr therapy. 7 f the 6 children wh were fllwed up until they attained adult height, all eventually attained nrmal predicted final adult height, althugh the reprt did nt list grup mean r individual data. A recently reprted meta-analysis f the effect f ral and inhaled gluccrticids n the grwth f asthmatic children included 21 studies and 81 patients. 3 As expected, significant weak grwth impairment was bserved fr prednisne and ther ral gluccrticids, but a significant mderate tendency was bserved fr inhaled beclmethasne diprpinate therapy t be assciated with attaining nrmal stature. In particular, there was n statistical evidence fr beclmethasne diprpinate t be assciated with grwth impairment at higher

9 474 Silverstein et al. J ALLERGY CLtN IMMUNL APRIL 1997 dses, fr lnger therapy duratin, r amng patients with mre severe asthma. ur study was limited by reliance n medical recrd dcumentatin f ral gluccrticid expsure, recruit- ment f nly 25% f eligible cntacted members f the riginal chrt, and use f self-reprted parental height. ur study had several strengths. The clinically relevant end pint f attained adult height was accurately measured. Adult height f patients with asthma was cm- pared with the adult height f age- and sex-matched nnasthmatic subjects. Parental height was used t ad- just measured height. Gluccrticid expsure was analyzed by rute f gluccrticid expsure, cumulative expsure, and ptency-adjusted cumulative expsure. Finally, it shuld be nted that prspective studies f the impact f gluccrticids n the clinically relevant end pint (attained adult height) are unlikely t be frth- cming in the near future because f the many years needed t fllw up a chrt until the end pint f final adult height is attained. Thus we believe that ur retrspective chrt prvides a unique pprtunity t assess the effect f gluccrticid expsure n adult height. ur findings shuld reassure physicians, parents, and patients that gluccrticids, as cmmnly prescribed fr treatment f childhd asthma, d nt have an imprtant impact n adult height. We thank Janne Mair, RN, and Judy Blmgren, RN, fr their untiring effrt in recruiting eligible members f the riginal asthma chrt and age- and sex-matched nnasthmatic residents f Rchester, Minnesta, fr the study. We als thank Lee Bellrichard, RN, and Mary Lu Ntermann, RN, fr reviewing the subjects' medical recrds. REFERENCES 1. Yunginger JW, Reed CE, 'Cnnell EJ, Meltn LJ, 'Falln WM, Silverstein MD. 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