Background Since the inflammatory response to chronic infectioncontributes to lung destruction in patients with cystic fibrosis,we hypothesized that antiinflammatory therapy might slow theprogression of lung disease.
Methods In a double-blind trial, 85 patients, 5 to 39 yearsof age, with mild lung disease (forced expiratory volume inone second [FEV1], >60 percent of the predicted value) wererandomly assigned to receive ibuprofen or placebo orally twicedaily for four years. Doses were adjusted individually to achievepeak plasma concentrations of 50 to 100 µg per milliliter.Changes in pulmonary function, the percentage of ideal bodyweight, the chest-radiograph score, and the frequency of hospitalizationwere assessed.
Results Patients randomly assigned to ibuprofen had a slowerannual rate of change in FEV1 than the patients assigned toplacebo (mean [±SE] slope, -2.17±0.57 percentvs. -3.60±0.55 percent in the placebo group; P = 0.02),and weight (as a percentage of ideal body weight) was bettermaintained in the former group (P = 0.02). Among the patientswho took ibuprofen for four years and had at least a 70 percentrate of compliance, the annual rate of change in FEV1 was evenslower (-1.48±0.69 percent vs. -3.57±0.65 percentin the placebo group, P = 0.03), and this group of patientsalso had a significantly slower rate of decline in forced vitalcapacity, the percentage of ideal body weight, and the chest-radiographscore. There was no significant difference between the ibuprofenand placebo groups in the frequency of hospitalization. Onepatient was withdrawn from the study because of conjunctivitis,and one because of epistaxis related to ibuprofen.
Conclusions In patients with cystic fibrosis and mild lung disease,high-dose ibuprofen, taken consistently for four years, significantlyslows the progression of the lung disease without serious adverseeffects.
Lung disease in patients with cystic fibrosis is characterizedby persistent bacterial infection leading to bronchitis andbronchiectasis. The airways are plugged with thick mucopurulentsecretions containing abundant bacteria and neutrophils, anddeath results from progressive destruction of the lungs.1 Patientswith pancreatic insufficiency or a lower-than-normal weightfor their height have shorter lives.2,3 Vigorous antibiotictherapy, clearance of mucus, and nutritional repletion havebeen the pillars of conventional therapy.4 Recently, attentionhas been focused on the inflammatory response in the lungs,which not only damages the lungs directly but impairs localhost defenses, preventing the clearance of infection. Bluntingthe inflammatory response might preserve lung function.1
In a pilot study, the administration of high doses of corticosteroidson alternate days in patients with cystic fibrosis and mildlung disease slowed the progression of the lung disease.5 Asubsequent, larger trial was terminated, however, because ofgrowth retardation and glucose intolerance in the group of patientsreceiving the high doses of corticosteroids.6 Nonsteroidal antiinflammatorydrugs should be considered as an alternative treatment.
In high doses, ibuprofen inhibits the migration, adherence,swelling, and aggregation of neutrophils, as well as the releaseof lysosomal enzymes.7,8,9,10,11,12,13,14,15,16 The safety recordfor ibuprofen has made it acceptable for over-the-counter sale,and there is more experience with this drug than with othernonsteroidal antiinflammatory drugs in children. In a rat modelthat mimics the infection and inflammation seen in cystic fibrosis,high-dose ibuprofen significantly reduced lung inflammationwithout increasing the burden of pseudomonas.17 Suitable bloodlevels of ibuprofen can be obtained in patients with cysticfibrosis, but the appropriate dose can be determined only bypharmacokinetic analysis.18 The present trial was designed todetermine whether high-dose ibuprofen, taken consistently, slowsthe decline of pulmonary function in patients with cystic fibrosisand mild lung disease.
Methods
Study Subjects
From 1988 to 1989, 85 patients with cystic fibrosis, rangingfrom 5 to 39 years of age, were recruited for the study; 74were from the Cystic Fibrosis Center at Rainbow Babies and Children'sHospital, Cleveland, and 11 were from the Cystic Fibrosis Centerat Children's Hospital Medical Center, Akron, Ohio. Patientswere eligible for enrollment if they had cystic fibrosis thathad been diagnosed according to the conventional criteria19and a forced expiratory volume in one second (FEV1) that wasat least 60 percent of the predicted value, with no use of intravenousantibiotics during the previous two months. Patients were excludedif they had used corticosteroids (systemic or inhaled) or nonsteroidalantiinflammatory drugs for more than two weeks within the previoustwo years or had inhaled cromolyn sodium during the six-monthperiod before enrollment. Other criteria for exclusion werehypersensitivity to nonsteroidal antiinflammatory drugs, allergicbronchopulmonary aspergillosis, a respiratory tract culturecontaining Burkholderia cepacia, and hepatic, cardiovascular,renal, neurologic, hematologic, or peptic ulcer disease. Informedconsent was obtained from all the patients, and the protocolsfor the study were approved by the institutional review boardsat both hospitals.
Study Design and Tests
The study was a randomized, double-blind, placebo-controlledtrial. Randomization was carried out with permuted blocks offour patients each stratified by age (<13, 13 to 18, and>19 years). Two patients in each block were randomly assignedto receive ibuprofen orally twice daily for four years, andtwo were assigned to receive placebo. The randomization codewas known only by the pharmacologist, who made the treatmentassignments, and the pharmacist, who dispensed the ibuprofenand placebo.
The initial evaluation included a medical-history taking, physicalexamination, pulmonary-function testing, chest radiography,sputum or throat culture, blood chemical measurements, a completeblood count, analysis of bleeding time, urinalysis, and a stooltest for occult blood. Concomitant therapies were documented.The pharmacokinetics of ibuprofen were measured, and adverseeffects were determined with a questionnaire.
Follow-up evaluations were scheduled every three months duringyear 1 and every six months thereafter. All base-line evaluationswere repeated at every visit except pulmonary-function tests(performed every six months), chest radiography (performed yearly),and pharmacokinetic studies of ibuprofen (performed during year3 or if body weight changed by at least 25 percent). All measurementswere performed in Cleveland.
Pulmonary-function testing was performed in patients with clinicallystable disease with the use of the MedGraphics Pulmonary FunctionSystem 1070-1085 (Medical graphics, St. Paul, Minn.), accordingto published standards.20 Bronchodilators were withheld forat least 12 hours before testing. FEV1, forced vital capacity(FVC), and forced expiratory flow at 25 to 75 percent of vitalcapacity (FEF25-75%) were each expressed as a percentage ofthe predicted normal value for the patient's age, sex, and height.21Residual volume as a proportion of total lung capacity (RV/TLC)was determined by plethysmography.
The patients' physicians prescribed medications for clinicalcare (antibiotics, bronchodilators, pancreatic enzymes, andso forth). The use of corticosteroids, nonsteroidal antiinflammatorydrugs, salicylates, and cromolyn sodium was specifically limited.None of the patients received other experimental drugs. Thestudy drug was discontinued for any of the following reasons:the development of an illness affecting the response to thestudy drug or assessment of clinical status, especially an illnessrequiring prolonged treatment with corticosteroids, nonsteroidalantiinflammatory drugs, or cromolyn sodium; the occurrence ofsevere adverse effects or hypersensitivity to the study drug;or noncompliance with the protocol.
Pharmacokinetics of Ibuprofen and Dose Determinations
The study drugs consisted of ibuprofen tablets (200 mg) andplacebo tablets that were identical in appearance (Upjohn, Kalamazoo,Mich.). Pharmacokinetic analysis was used to determine the dosefor each patient that would result in a peak plasma concentrationof 50 to 100 µg per milliliter. The dose was determinedat base line, during year 3, and if there was a weight gainof 25 percent or more. Dose determinations were performed forall patients, whether they were assigned to placebo or ibuprofen,to keep the treatment assignment concealed. Plasma was obtainedbefore and every 30 minutes after the administration of ibuprofen(20 to 30 mg per kilogram of body weight, to a maximum of 1600mg) for 3 hours. The patients did not eat or take pancreaticenzymes for two hours after the dose had been administered.The ibuprofen concentration was measured by high-performanceliquid chromatography.22 If the peak concentration of 50 to100 µg per milliliter was achieved at a particular dose,that was the dose given to the patient. If the peak concentrationwas not achieved, the dose was altered by the pharmacologist,and the pharmacokinetic studies were repeated. The number ofpills to be taken was calculated on the basis of these studies.
Assessment of Compliance
Compliance was determined by pill counts and blood monitoring.Tablets were dispensed every three months. At each visit, thepatients returned all containers received since the previousvisit so that unused pills could be counted. Overall compliancewas calculated as the mean compliance during each interval betweenvisits, weighted by the length of the interval. Plasma was obtainedat each visit for measurements of ibuprofen and salicylate concentrations,and the history was taken to monitor the use of other restrictedmedications.
Analysis of Outcome Measures
The primary outcome measure was the annual rate of change (asassessed by the slope) of FEV1. Secondary outcome measures werethe annual rate of change in FVC, FEF25-75%, and RV/TLC; theannual rate of change in the percentage of ideal body weight;the change in the chest-radiograph score at four years; andthe number of hospital admissions and days of care, includingthe number of days on which intravenous antibiotics were administeredat home.
For changes in pulmonary-function measures and the percentageof ideal body weight, a mixed-model analysis of variance (SASInstitute, Cary, N.C.) was used to fit a model that includedtime, treatment group, and the interaction between time andtreatment simultaneously, with the results weighted for eachpatient according to the number of missing data and the variabilityof the outcome measures. The coefficient of time (the slope,or rate of change) estimated for each treatment group and theinteraction between time and treatment were used to test fordifferences between the groups. Base-line pulmonary functionand age were included as covariates if their contribution tothe fit of the model was significant according to likelihood-ratiotests.
Chest radiographs obtained at base line and year 4 were scoredwith the method of Brasfield et al.23 by a radiologist and anothertrained observer; identifying information and dates on the radiographswere concealed. The mean differences between the scores at baseline and year 4 in the treatment groups were determined witha t-test. Hospital admissions and days of care were comparedwith the Mann–Whitney U test. For all statistical tests,two-tailed P values less than 0.05 were considered to indicatestatistical significance.
Use of Concomitant Therapies
Differences in the frequency of concomitant therapies in theyear before enrollment in the study were compared with a chi-squaretest. Changes in the frequency of concomitant therapy from theyear before enrollment to year 4 were assessed by categorical-datamodeling (SAS Institute), which is similar to a two-way analysisof variance for qualitative data.
Analysis of Adverse Effects
A comprehensive questionnaire, based on the table of adverseeffects of ibuprofen,24 was administered by the same researchnurse at all visits. A base-line profile of the frequency andseverity of symptoms that might be attributable to ibuprofenwas established for each patient and compared with symptomsreported during the trial. Differences in the frequency of adverseeffects between the ibuprofen and placebo groups were comparedwith a chi-square test.
Results
Assignment of Subjects
Forty-two patients were randomly assigned to ibuprofen, and43 to placebo. A 13-year-old girl assigned to ibuprofen withdrewat month 3 because of abdominal pain and poor compliance withthe protocol; all other patients returned for follow-up andwere included in the intention-to-treat analysis. Fifty-sevenpatients (67 percent) met the prospective criteria for completionof the trial and were included in the completed-treatment analysis.The ibuprofen and placebo groups were similar at base line forboth the intention-to-treat analysis (Table 1) and the completed-treatmentanalysis (data not shown). Reasons for failure to complete thestudy did not differ between the two groups (Table 1). Therewere no deaths.
Table 1. Characteristics of 84 Subjects with Cystic Fibrosis and Mild Lung Disease Who Were Randomly Assigned to Receive Ibuprofen or Placebo.
Pharmacokinetics and Doses of Ibuprofen
The peak plasma ibuprofen concentration of 50 to 100 µgper milliliter was achieved in all patients at doses of 16.2to 31.6 mg per kilogram of body weight (Figure 1). In 11 patients,the values fell outside this range during the first study; thepeak concentrations were less than 50 µg per milliliterat doses of 20.4 to 26.5 mg per kilogram in 8 patients and morethan 100 µg per milliliter at doses of 24.4 to 28.6 mgper kilogram in 3 patients. During the four years of the study,37 patients required a dose adjustment because of a weight gainof 25 percent or more. Follow-up pharmacokinetic studies duringyear 3 confirmed that the peak plasma ibuprofen concentrationsremained within the target range in all the other patients.
Figure 1. Relation between the Dose and Peak Plasma Concentration of Ibuprofen in 84 Patients with Cystic Fibrosis and Mild Lung Disease.
The plotted points represent the doses of ibuprofen necessary to achieve a peak plasma concentration between 50 and 100 µg per milliliter in all subjects before enrollment. The dashed lines at doses of 20 and 30 mg of ibuprofen per kilogram indicate this dose range. With a mean dose (±SE) of 25.4±0.3 mg per kilogram, the mean peak plasma concentration of ibuprofen was 71.8±1.3 µg per milliliter.
Compliance
In the intention-to-treat analysis, the mean (±SE) compliancewas 68±5 percent for the ibuprofen group and 72±4percent for the placebo group. Compliance did not vary withage. Salicylate was detected once in each of four patients (onein the ibuprofen group and three in the placebo group). Noneof the patients in the placebo group had detectable plasma concentrationsof ibuprofen on routine monitoring that could not be accountedfor by the history. The use of ibuprofen (aside from the studydrug) and other restricted medications was within the protocolguidelines in both treatment groups. For four patients, theuse of corticosteroids exceeded the protocol guidelines, andthese patients were therefore excluded from the completed-treatmentanalysis.
Outcome Measures
Pulmonary Function
The primary outcome measure, FEV1, declined significantly moreslowly in the patients assigned to ibuprofen than in those assignedto placebo (Table 2). Among the patients in the placebo group,the rate of change in FEV1 was similar in the intention-to-treatand completed-treatment analyses. Among the patients in theibuprofen group, however, those who completed treatment hada slower decline in FEV1 than those who did not complete treatment;in the completed-treatment analysis, FEV1 declined 59 percentmore slowly in the ibuprofen group than in the placebo group.
Table 2. Results of Outcome Measures for All Patients and for Those Who Completed Treatment.
The other pulmonary-function measures, FVC, FEF25-75%, and RV/TLC,showed a concordant trend in the intention-to-treat analysis(Table 2). In the completed-treatment analysis, FVC declinedsignificantly more slowly in the ibuprofen group than in theplacebo group, and FEF25-75% and RV/TLC showed similar trends.
For patients who were less than 13 years old at the time ofenrollment, the effect of ibuprofen was even greater, slowingthe rate of decline in FEV1 by 65 percent in the intention-to-treatanalysis and by 88 percent in the completed-treatment analysis(Table 3). The results of other pulmonary-function measureswere similar. Among the older patients, there were no differencesin pulmonary function between the treatment groups (Table 4).
Table 4. Results of Outcome Measures for Patients Initially 13 Years of Age or Older.
Other Outcome Measures
The percentage of ideal body weight declined in the placebogroup, but not in the ibuprofen group. This difference was mostpronounced in the completed-treatment analysis and among thepatients who were less than 13 years old. The chest-radiographscore tended to decline less in the ibuprofen group than inthe placebo group (P = 0.06) and declined significantly lessamong those who completed treatment with ibuprofen. These changesdid not differ significantly among the three age subgroups.
Forty-nine percent of the patients in the ibuprofen group and40 percent of those in the placebo group were not hospitalizedduring the trial, but a few patients spent considerable timein the hospital. Although the patients in the ibuprofen grouptended to have fewer hospital admissions and days of care thanthe patients in the placebo group, the differences were notsignificant, even when only hospitalizations for respiratorysymptoms were considered.
Concomitant Therapies
The use of concomitant therapies was similar in the two treatmentgroups during the one-year period before enrollment. At year4 there was a greater increase in the use of bronchodilatorsand intravenous antibiotics among the patients in the placebogroup (Table 5).
Table 5. Use of Concomitant Therapies at Base Line and Year 4.
Adverse Effects
Nine patients (five in the ibuprofen group and four in the placebogroup) discontinued the study drug because of adverse effects(Table 1). However, there was a high prevalence of these symptomsat base line (Table 6). Adverse effects were clearly relatedto the use of ibuprofen in one patient with conjunctivitis andin one with epistaxis. These preexisting problems worsened withthe administration of the study drug, improved with the withdrawalof the drug, and worsened on repeated challenge.
Table 6. Prevalence of Possible Adverse Effects of Ibuprofen Therapy during the Four-Year Study Period.
Of the seven patients with abdominal pain (including epigastricpain and heartburn) severe enough to discontinue the study drug,one patient in the placebo group had severe esophagitis on endoscopy.However, abdominal pain, which is nearly universal in patientswith cystic fibrosis, decreased in many cases. The proportionof patients in whom abdominal pain increased was similar inthe two treatment groups (Table 6). The use of antacids or H2-receptorantagonists increased no more in the ibuprofen group than inthe placebo group (Table 5). The frequency or severity of otherpossible adverse effects did not differ between the two groups.
Discussion
A regimen of high-dose ibuprofen for four years significantlyslowed the progression of lung disease in patients with cysticfibrosis who were over five years of age and whose disease wasmild at the outset. The effect was particularly evident in patientswho completed treatment and in those who were initially lessthan 13 years old. In addition, weight (expressed as a percentageof ideal body weight) was better maintained in the ibuprofengroup. The effect of ibuprofen was sustained throughout thefour-year trial, and the values for the outcome measures betweenthe treatment groups continued to diverge at the end of thetrial.
FEV1 was selected as the primary outcome measure because multivariateanalyses, including those performed in the patient populationat our center, indicated that, of the pulmonary-function measures,FEV1 best predicts mortality.25,26 In the intention-to-treatanalysis, FEV1 declined significantly more slowly in the ibuprofengroup than in the placebo group, and there was a trend towardsimilar improvement in the other measures. In the completed-treatmentanalysis, the rate of decline in FEV1 and FVC differed significantlybetween the treatment groups.
Consideration of the results of the completed-treatment analysisis appropriate for several reasons. First, this subgroup analysiswas specified prospectively on the assumption that the drugwould not benefit those who did not take it, particularly duringa period of four years. Second, in the completed-treatment analysis,the decline in pulmonary function was slower only in the ibuprofengroup, not in the placebo group, suggesting that the drug, notsimply compliance, makes the difference. Third, adverse effects,which make an intention-to-treat analysis critical in trialsin which adverse effects of drugs are severe, were similar inthe two treatment groups. In addition, the results of the intention-to-treatand completed-treatment analyses were similar.
The effect of ibuprofen is clinically important, significantlyaffecting two characteristics that have been associated withmortality among patients with cystic fibrosis: FEV1 and thepercentage of ideal body weight. In the intention-to-treat analysis,FEV1 declined 40 percent less among the patients assigned toibuprofen than among those assigned to placebo. Moreover, thepatients in the ibuprofen group maintained their weight, whereasthe patients in the placebo group lost 4 percentage points ofideal body weight during the trial. The effect of ibuprofenwas concentrated among the younger patients: there was no significanttreatment effect among the older patients. Among the patientsin the ibuprofen group who were less than 13 years old initiallyand who completed treatment, the rate of decline in FEV1 wasreduced by 88 percent, so that by the end of four years, FEV1had declined by less than 2 percent of the predicted value,as compared with a decline of over 15 percent of the predictedvalue in the placebo group. Similarly, whereas the younger patientstreated with ibuprofen gained almost 1 percentage point of idealbody weight over a period of four years, the younger patientstreated with placebo lost 6 percentage points. If FEV1 and relativeunderweight predict mortality among patients with cystic fibrosis3,25,26and if ibuprofen slows the decline in these measures, then ibuprofenmay prolong survival.
The better results in the ibuprofen group cannot be attributedto more intensive conventional treatment or to a lower frequencyof pseudomonas infection, since these variables were similarin the two treatment groups at base line, and the frequencyof new cases of pseudomonas infection was similar in the twogroups during the trial (data not shown). The use of concomitanttherapies was also similar, except that the use of bronchodilatorsand intravenous antibiotics increased significantly in the placebogroup.
We evaluated antiinflammatory therapy in patients with mildlung disease because such patients have substantial airway inflammationeven when they appear to be clinically stable.27 Antiinflammatorytherapy should have the greatest effect before fixed structuraldamage develops. Also, FEV1 declines more rapidly in patientswith mild disease than in those with more severe disease, sofewer subjects are required to demonstrate a benefit from aneffective intervention.
We chose a peak plasma ibuprofen concentration of 50 to 100µg per milliliter as a target on the basis of concentration–responsedata in the literature and our own previous work. Our goal wasto achieve the inhibitory effect of ibuprofen on neutrophilactivation and migration, which generally occurs at concentrationsover 50 µg per milliliter.7,8,9,10,11,12,13,14,15,16 Inpseudomonas-infected rats treated with ibuprofen twice daily,a mean peak plasma concentration of 55 µg per millilitersignificantly reduced lung inflammation, as compared with thatin controls, and resulted in better weight gain without worseinfection.17 With a dose of 20 to 30 mg of ibuprofen per kilogram,the influx of neutrophils to the alveolar crevices of the oralmucosa was reduced in subjects with cystic fibrosis and in normalcontrols.28 However, low doses of ibuprofen (2 to 3 mg per kilogram)increased the influx of neutrophils, arousing concern that inadequatepeak concentrations might be detrimental. This dose-relatedresponse was also observed in a rat model of endotoxin-inducedalveolitis.12 Because low peak concentrations might be detrimental,we chose 50 µg per milliliter as the lower limit of ourdose range. Although the target peak concentration was ultimatelyachieved with a dose of 20 to 30 mg per kilogram in 90 percentof our patients, it was not possible to predict the dose inan individual patient.
Adverse effects and study dropouts were evenly distributed betweenthe two treatment groups. Abdominal pain is reportedly commonwith ibuprofen therapy.24 It also occurs in association withcystic fibrosis. During this trial, as we observed previously,18more patients in both treatment groups reported improvementthan worsening of abdominal pain. The use of antacids and H2-receptorantagonists was evenly distributed between the two groups. Thus,we have no evidence of an ibuprofen-related increase in abdominalpain. However, this study was too small to detect reliably evena common drug-related complication, and negative data shouldbe interpreted with caution.
Two adverse effects, conjunctivitis and epistaxis, appearedto be directly related to ibuprofen. The mechanism underlyingconjunctivitis is unknown. Preexisting epistaxis may be exacerbatedby ibuprofen, since it interferes with platelet aggregation.Ibuprofen should be used cautiously during episodes of epistaxisand possibly hemoptysis.
In summary, high doses of ibuprofen significantly slowed theprogression of lung disease during a period of four years inpatients with cystic fibrosis who had initially mild lung disease,without unacceptable adverse effects. These results are clinicallyimportant and warrant the evaluation of patients who have cysticfibrosis with an FEV1 of at least 60 percent of the predictedvalue, particularly younger patients, for therapy with high-doseibuprofen. Monitoring by physicians for adverse effects andadequate doses is essential. Ibuprofen therapy will not addmuch to the cost of care (less than $200 annually for the highestdose).
Antiinflammatory agents represent a new strategy in the treatmentof patients with cystic fibrosis and mild lung disease, augmentingconventional therapy as practiced in the two centers participatingin this study. Our results should encourage further researchwith other dose schedules or other agents directed against lunginflammation in patients with cystic fibrosis.
Supported by grants from the Cystic Fibrosis Foundation andthe National Institutes of Health (P30-DK27651 and MO1 RR-00080).
We are indebted to Louise Strauss, R.N., the research nursecoordinator; to Ann Salvator, M.S., the data manager; to CarlDoershuk, M.D., Robert Stern, M.D., and the physicians of theCystic Fibrosis Center in Cleveland for the recruitment andcare of patients; to Robert Stone, M.D., principal investigatorat the Cystic Fibrosis Center in Akron, Ohio, for the recruitmentand care of patients; to Gail Anthony, Georgette DeRivera, MarvinLough, and Angel Martinez for pulmonary-function testing; toBetsy Bryson, Joanne Celestina, Cathy Demko, Zenovia Fakkas,Jay Hilliard, Kate Hilliard, Steve Ingalls, Jeanne Knesebeck,Sandi Lederman, Paul Minkler, Maria Occhionero, and StephanieSupers for assistance with the conduct of the trial; to SaulMillman and Tom Irwin, the research pharmacists; to the nursesand administrative staff of the Clinical Research Center; toRobert Konstan, M.D., for scoring the chest radiographs; toStacey FitzSimmons, Ph.D., Arnold Smith, M.D., and Bruce Thompson,Ph.D., the Data Review Committee; to Peter Chelune and associatesat the Upjohn Company for providing the ibuprofen and placebotablets and the randomization code; to the Cystic Fibrosis Foundationfor their support; and to the patients and families for theirparticipation.
Source Information
From the Departments of Pediatrics (M.W.K., P.J.B., P.B.D.), Medicine (C.L.H., P.B.D.), and Pharmacology (C.L.H.), Case Western Reserve University School of Medicine, Rainbow Babies and Children's Hospital, and the Veterans Affairs Medical Center, Cleveland.
Address reprint requests to Dr. Konstan at the Rainbow Babies and Children's Hospital, 2101 Adelbert Rd., Cleveland, OH 44106.
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