International Practice Patterns by Age and Severity ofLung Disease in Cystic Fibrosis: Data From theEpidemiologic Registry of Cystic Fibrosis (ERCF)

Christian Koch, MD Dr Med Sci ,1* Sheila G. McKenzie, PhD,2 Haley Kaplowitz, PhD,3Margaret E. Hodson, MD, FRCP,4 H. Karsten Harms, MD,5 Jean Navarro, MD,6 and

Gianni Mastella, MD7

Summary. The Epidemiologic Registry of Cystic Fibrosis provides clinical profiles for more than6,800 patients and descriptions of practice patterns across eight European countries. Prelimi-nary cross-sectional analysis has been performed by age and pulmonary function as an as-sessment of disease severity. In general, pulmonary treatments including inhaled bronchodila-tors and rhDNase increased as lung disease became more severe. Use of a number of treat-ments, including mucolytic agents and inhaled corticosteroids, varied markedly from country tocountry. Several widely used therapies are not yet supported by controlled clinical trials, par-ticularly in patients under 6 years of age. Nutritional intervention was more common in patientswith advanced lung disease regardless of age. Patients with nasal polyps had less severe lungdisease at each age than patients without polyps. It is clear that studies of early interventions areneeded to determine the optimal types of treatments and the ages at which to begin treatment.Pediatr. Pulmonol. 1997; 24:147–154. © 1997 Wiley-Liss, Inc.

Key words: cystic fibrosis; treatment; pulmonary function; nasal polyps; diabetesmellitus.

INTRODUCTION

Accurate information on the clinical characteristics oflarge numbers of CF patients and the practice patterns ofCF Centers in different regions around the world is im-portant to understand the scope of the disease as well asto evaluate therapeutic trials. The ERCF is a databasesponsored by F. Hoffmann-La Roche Ltd. that collectsdata on the clinical status and treatment of individual, butnot personally identifiable patients with CF attendingcenters in several European countries. The database (ad-ministered by Quintiles) consists of data entered for eachpatient in a set of forms, starting with an enrollment formand followed in a prospective manner by follow-upforms, ideally at each clinic visit. Enrollment of patientsinto ERCF began in January, 1994 in the UK and Den-mark, with other countries joining in subsequent years.

ERCF has a sister database in North America, theESCF, which is sponsored by Genentech, Inc. and whichalso began enrolling patients in January 1994. As morethan 90% of the categories of data collected are commonto both registries, the enrollment data for the period Janu-ary, 1994 to December, 1995 were pooled in May 1996to produce an International ERCF/ESCF Data Reportfor distribution to participating institutions. The reportcompared enrollment characteristics of 7,403 CF patients

enrolled in ERCF with those of 18,264 patients in ESCF,and also compared patients and practice patterns indifferent countries. This paper describes the Europeandata that were contributed to the International ERCF/ESCF Data Report according to age and severity ofillness.

1Department of Pediatrics, Rigshospitalet, Copenhagen, Denmark.

2Hoffmann-La Roche Ltd., Basle, Switzerland.

3Genentech, Inc., South San Francisco, California.

4Cystic Fibrosis Department, Royal Brompton National Heart & LungHospital, London, United Kingdom.

5University Children’s Hospital, Munich, Germany.

6Hopital Robert Debre´, Paris, France.

7Veneto Regional Cystic Fibrosis Center, Verona, Italy.

Presented at the International Cystic Fibrosis Congress, Roche/Genentech Satellite Symposium: ‘‘The Rationale for Early Interven-tion in Cystic Fibrosis,’’ June 18, 1996, Jerusalem, Israel.

*Correspondence to: Dr. Christian Koch, Department of PediatricsGGK-5002, Rigshospitalet University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.

Pediatric Pulmonology 24:147–154 (1997)

© 1997 Wiley-Liss, Inc.

METHODS

After exclusion of a minority of patients because ofmissing data, data from 6,858 patients in ERCF could beanalyzed. These patients were distributed among eightcountries: The United Kingdom (3,433), Austria (77),Denmark (290), France (820), Germany (1,701), Ireland(439), The Netherlands (22), and Sweden (73), plus threepatients whose country of origin was not given. There-fore, the data are dominated by the United Kingdom,which contributed 50% of the patient data.

The types of scientific analysis that can be performedon the database are limited at present. The duration offollow-up is still too short to allow longitudinal compari-sons between individual countries, or to support cause-effect comparisons between differences in long-termprognosis in control and treated groups. In particular, thisis true for the analysis of differences in the approach toantibiotic treatment of bronchopulmonary infections, butthis will hopefully be possible in the near future. Amongcurrent obstacles are differences in the date of enroll-ment, the duration of follow-up, and the number of pa-tients enrolled compared with the projected number ofpatients, which is still incomplete in some countries. Alow reporting/projected ratio carries a significant risk ofselection bias. Equivalent reporting, random selection,and a high ratio of reported patients to total number ofpatients are mandatory for valid comparative studies. Forthese reasons no statistical calculations have been madeat this stage.

On the other hand, several important parameters canbe analyzed on the basis of data recorded at the time ofenrollment into the registry. Among these are some treat-ment modalities commonly employed in patients withCF. The sheer size of the database offers the opportunityto look at components of basic CF treatment that are lesslikely to change over time than antibiotic treatment. An-tibiotic treatment often changes from week to week inindividual patients and is influenced by the nature oflower respiratory tract pathogens, which may vary fromcenter to center; it can also show seasonal variation. In-formation that can usefully be reported at this stage in-cludes use of airway clearance techniques, pancreatic en-zyme therapy, treatments consisting of mucolytics andexpectorants, systemically or topically administered anti-

inflammatory agents, nutritional supplements, and insu-lin and/or oral hypoglycemic agents. We are not present-ing data at this time on use of antibiotics or sputumculture status because these analyses are not sufficientlyadvanced for comment.

For the present cross-sectional analysis of treatmentpatterns, patients have been grouped according to ageand pulmonary function as assessed by FEV1 at enroll-ment (see Tables). Enrollment values of FEV1 should notbe considered as optimal values, since centers may haveenrolled patients at the time of a routine clinic visit, at avisit because of exacerbation of illness, or at acute hos-pitalization.

RESULTS

Baseline Patient Data

The mean age, FVC, and FEV1 at time of enrollmentare shown in Table 1. The distribution of patients inERCF according to four age groups and three age groupswith FEV1 is given in Table 2. The number of patients insome subgroups is very small, and the material is farfrom being evenly distributed. For the subsequent analy-sis of treatment patterns, the consequences of any selec-tion bias will therefore have far greater impact in terms of

TABLE 2—Distribution by Age Group and Lung Functionat Enrollment (N = 6,858)

Age (yr)FEV1

(% predicted) No. %

<6 1,662 24.26–12 >100 275 4.0

71–100 913 13.340–70 504 7.3

<40 127 1.913–17 >100 80 1.1

71–100 464 6.840–70 461 6.7

<40 219 3.2ù18 >100 77 1.1

71–100 494 7.240–70 841 12.3

<40 741 10.8

Abbreviations

ABPA Allergic bronchopulmonary aspergillosisCF Cystic fibrosisCFTR Cystic fibrosis transmembrane conductance regulatorERCF Epidemiologic Registry of Cystic FibrosisESCF Epidemiologic Study of Cystic FibrosisFEV1 Forced expiratory volume in 1 secondFVC Forced vital capacityrhDNase I Human recombinant DNase

TABLE 1—Age and Lung Function at Enrollment in ERCF(N = 6,858)

Parameter

Age (yr)Mean 13.6Median 12

FVC (% predicted)Mean 78.0Median 80.3

FEV1 (% predicted)Mean 65.5Median 66.5

148 Koch et al.

error of interpretation in groups that are very small thanin large patient groups. The size of each of the 12 sub-groups >6 years of age varies from 1.1% to 13.3% of thetotal patient population (absolute numbers 77 and 913patients, respectively).

Treatment Patterns

Bronchodilators

The use oforal bronchodilators increased from 3% ofpatients <6 years to 19% of adult patients with severelung disease (Table 3). The corresponding values forin-haledbronchodilators were 36% and 80% (Table 3). Theuse of oral bronchodilators increased moderately withage, whereas the use ofinhaledbronchodilators showedminimal age dependency (Table 3). Both showed a minorincrease with increasing disease severity (Table 3). Thenumber of patients on bronchodilators far exceeded thenumber of patients with a reported diagnosis of compli-cating asthma-like symptoms, which did not exceed 27%in any age group. This clinical diagnosis was based onthe reported presence of bronchial hyper-reactivity (withor without histamine challenge) or asthma-like symp-toms (prolonged exhalation with crepitations and wheez-ing). Bronchial hyper-reactivity has been reported to bepresent in up to 43% of patients <18 years, and in an evenhigher percentage of older patients.1 Reports in the lit-erature on the prevalence of bronchial hyper-reactivity,although often yielding conflicting results, may thus haveled to the liberal use of bronchodilators, as reported to theregistry. Bronchodilators may also have been prescribedfor reasons other than airway obstruction reversed byb2-agonists, namely, to increase mucociliary clearance.Studies on the effect ofb2-agonists on mucociliary clear-ance have, however, yielded conflicting results at best.2

It is noteworthy that bronchodilators were most oftenused in older patients with severely impaired FEV1, since

presumably this group is the one with the highest degreeof irreversible airflow obstruction (Table 3). The groupof patients least often treated with bronchodilators in-cluded those <6 years of age, possibly because of thescarcity (due to technical limitations) of studies on theeffect of b2-agonists in CF patients in this age group.New techniques to permit routine recording of lung func-tion, including quantitation of bronchoconstriction in re-sponse to stimulants and reversibility byb2-agonists,could lead to major improvements in treatment withbronchodilators and other forms of therapy in the nearfuture. If bronchodilators are being used as prophylaxisagainst the retention of the secretions that lead to infec-tion, atelectasis, and bronchiectasis, it would appear thatthey are at present being administered to the group ofpatients that is least likely to benefit from this therapy.The relatively frequent use oforal bronchodilators (con-sidered to have more side effects than inhaled broncho-dilators) in older patients with severe lung disease maybe due to physicians’ assumptions that poor regional ven-

TABLE 3—Percentage of Patients in Each Age Group TreatedWith Bronchodilators at Enrollment (N = 6,858)

Age (yr)FEV1

(% predicted)

Oralbronchodilators

(%)

Inhaledbronchodilators

(%)

Asthma-likesymptoms

(%)

<6 3 36 146–12 >100 5 48 11

71–100 4 47 1740–70 7 57 22

<40 5 63 2513–17 >100 5 45 10

71–100 6 53 1440–70 7 63 21

<40 13 74 27ù18 >100 10 46 13

71–100 12 52 1540–70 15 68 21

<40 19 80 24

TABLE 4—Percentage of Patients in Each Age GroupTreated With Corticosteroids at Enrollment (N = 6,858)

Age(yr)

FEV1

(% predicted)ABPA

(%)

Oralcorticosteroids

(%)

Inhaledcorticosteroids

(%)

<6 <1 2 176–12 >100 3 5 26

71–100 5 4 2140–70 8 7 26

<40 7 10 2413–17 >100 1 1 21

71–100 4 6 2640–70 7 9 34

<40 5 12 28ù18 >100 3 4 17

71–100 4 7 2240–70 6 13 31

<40 8 21 41

International Practice Patterns in CF 149

tilation and other barriers to adequate deposition ofin-haledbronchodilator in the lungs leads to a suboptimaleffect of inhaled drugs.

Corticosteroids

The use oforal corticosteroids increased substantiallywith severity of the lung disease, but usage turned out tobe rather independent of age (Table 4). Particularly inolder age groups, the use oforal steroids exceeded thenumber of patients with a diagnosis of ABPA (Table 4),suggesting that there were other indications for oral ste-roids than the presence of ABPA. The use oforal ste-roids was about twice as high in patients with severe lungdisease as in patients with mild and moderate disease(Table 4), suggesting that they are often used in severelyinfected patients as nonspecific anti-inflammatoryagents.

Except for patientsù18 years, the use ofinhaledcor-ticosteroids varied much less with disease severity thandid oral steroids, and again there was little variation withage (Table 4). Interestingly, inhaled steroids were pre-scribed 3 to 4 times as often to patients of all ages andseverities of lung disease in the United Kingdom (36%)as in Germany (12%) or France (10%) (Table 5). Thesefindings may reflect traditional differences in Europeanapproaches toward the use of inhaled steroids in bron-chial asthma. The surprisingly widespread use of inhaledsteroids clearly contrasts with the scarcity of formalclinical trials in patients with CF.3

Pancreatic Enzymes

Pancreatic enzymes were used in 93–97% of patientsbelow 13 years of age, regardless of severity of lungdisease (Table 6). However, in patients 13–17 years old,only 86% of patients with normal FEV1, as opposed to94% of patients with severe lung disease, were takingpancreatic enzymes; this correlation with severity of lungdisease became even more pronounced in patientsù18years (Table 6). A likely interpretation of these data isthat the numerically small (Table 2) group of patientswho reach adulthood and still have mild lung disease areoften pancreatic sufficient. This suggests that pancreaticsufficiency may be associated with a milder long-termcourse of lung disease, possibly through a common linkto CFTR mutations that give rise to residual CFTR func-

tion. It will be possible to address this issue in the futurewhen the registry data are analyzed in terms of type ofCFTR mutation.

Insulin/Oral Hypoglycemics

As expected, the use of insulin and oral hypoglycemicswas strongly associated with increasing age of the pa-tients (Table 6).4 What was surprising, however, was aclear correlation between severity of lung disease and useof insulin/oral hypoglycemics in patients >18 years(Table 6, Fig. 1). A more severe course of lung disease inCF patients with diabetes has been suggested by severallarge studies.5,6 The findings in our large database sug-gest that insulin deficiency is correlated with severe lungdisease, although it is also possible that insulin and hy-poglycemic agents are given more readily to patientswith severe lung disease than to those with a mildercourse. More detailed analysis will be performed whenmore data are available.

Mucolytics and Expectorants

Overall, the use of mucolytics and expectorants wascommon and showed no consistent changes with age orseverity of disease (Tables 5 and 7). There were largevariations in usage among European countries: use ofthese agents was seldom reported in the United Kingdom(<1%), but much more frequently in France (24%) andGermany (90%) (see Table 5). It would appear that use ofthese agents depends on a general, possibly traditionalapproach that differs between countries and possibly alsobetween CF centers. A misinterpretation may be presentif N-acetyl-cysteine is reported as a mucolytic/expecto-rant when it is in fact given for constipation and/or toprevent distal intestinal obstruction syndrome.

TABLE 5—Percent of Patients in the Three LargestContributing Countries Receiving Treatment at EnrollmentWith Inhaled Corticosteroids or Mucolytics Expectorants

France(n 4 820)

Germany(n 4 1,701)

UK(n 4 3,433)

Inhaled corticosteroids 10% 12% 36%Mucolytics/expectorants 24% 90% <1%

TABLE 6—Percent of Patients in Each Age Group TreatedWith Pancreatic Enzymes, Insulin, or Oral Hypoglycemicsat Enrollment (N = 6,858)

Age(yr)

FEV1

(% predicted)

Pancreaticenzymes

(%)

Insulin/oralhypoglycemics

(%)

<6 93 <16–12 >100 94 1

71–100 94 <140–70 95 1

<40 97 213–17 >100 86 5

71–100 93 540–70 94 8

<40 94 7ù18 >100 78 10

71–100 84 1040–70 87 16

<40 90 21

150 Koch et al.

rhDNase I

Overall, the prescription of rhDNase I (dornase alfa,Pulmozymet) varied considerably between Europeancountries from 16% of patients in the United Kingdom to49% in France (Table 8). There was a marked increase inuse of rhDNase with increasing severity of lung disease,but no increase with age (Table 8). The low usage ofrhDNase in children below 6 years can be explained byits being approved only in patients above 5 years of age.The higher use of rhDNase I in some countries is notexplained by its date of introduction. The pattern of pre-scription of rhDNase I is consistent with its effect ofdecreasing the viscosity and furthering removal of puru-lent secretions.7,8 Since, however, rhDNase I seems toprevent exacerbations of lung disease caused by viraland/or bacterial infections,9 it may at present be under-used in young patients with mild lung disease.

Nutritional Supplementation

The use of all forms of nutritional supplementationincreased with severity of lung disease in all age groups(Table 9). From 36% to 48% of patients aged 6 years orolder with severe lung disease were taking oral supple-mentation, and from 9% to 17% received enteral supple-mentation (Table 9). For oral supplements, there was amodest decline in use with increasing age, which prob-

ably reflects the particular concern of adequate nutritionin growing individuals. It should be mentioned that oralsupplementation may encompass the active recommen-dation of a high-fat, high-calorie diet adopted by manycenters, and it may not necessarily imply prescription ofcommercial predigested comprehensive nutritional for-mulations. The present data cannot yet answer the im-portant question of whether nutritional supplementationfavorably modifies the course of lung disease, but theydo suggest that patients with severe lung disease second-

Fig. 1. Percentage of patients >6 years treated with insulin and/or oral hypoglycemics at time of enrollment, presented accordingto age and severity of lung disease . n = 5,196. Normal, FEV 1 > 100% predicted; mild, 71–100%; moderate, 40–70%; severe, <40%predicted.

TABLE 7—Percentage of Patients in Each Age Group TreatedWith Mucolytics or Expectorants at Enrollment (N = 6,858)

Age(yr)

FEV1

(% predicted)

Mucolytics andexpectorants

(%)

<6 226–12 >100 26

71–100 3140–70 30

<40 3013–17 >100 26

71–100 3040–70 30

<40 36ù18 >100 35

71–100 2540–70 29

<40 29

International Practice Patterns in CF 151

ary to long-standing infection are the ones most in needof the extra calories supplied by nutritional supple-ments.10

Airway Clearance/Chest Physiotherapy

Use of airway clearance techniques was reported in87–93% of patients <13 years. In patients >12 years therelative frequency of use of these techniques was depen-dent partly on the severity of lung disease, and partlyupon age (Fig. 2). Thus, among patientsù18 years, 70%with a normal FEV1 received such treatment, whereas thecorresponding figure for patients with severe disease was83%.

Nasal Polyposis vs. Severity of Lung Disease

One particularly interesting finding is the negative cor-relation between the presence of nasal polyps (nasal pol-yposis) and severity of lung disease in age groups >6years (Fig. 3). Although no statistical calculations havebeen performed at present, the data suggest that the pres-ence or absence of nasal polyps is a predictor of thecourse of lung disease. The nature of this relationship isunknown, but more may be learned when the material isanalyzed further in terms of CFTR genotype. It may bespeculated that genetic factors outside the CFTR locusmay modify the electrolyte abnormalities in the airways,leading to a greater degree of nasal polyp formation, aswell as to a milder course of lung disease. Further elu-cidation of this observation, if confirmed, will requireelectrophysiological studies in vivo and in vitro.

DISCUSSION

This cross-sectional analysis of data from 6,858 pa-tients with CF, distributed among a large number of CF

centers from several European countries, reveals impor-tant aspects of the use of some aspects of everyday man-agement in patients of different ages and with differentseverities of lung disease. In general, the frequency ofmost treatment modalities increased with increasing se-verity of lung disease, an observation that suggests mosttreatments are implemented for symptomatic diseasecontrol. Notable exceptions were mucolytics and inhaledcorticosteroids, which demonstrated regional differencesin usage that appeared to be unrelated to disease severity.

Patient age was a factor in utilization of most treat-ments. As expected, usage of insulin or oral hypoglyce-mics increased with age. Furthermore, the frequency ofadministration of oral bronchodilators increased with in-creasing patient age, while usage of oral nutritionalsupplements and airway clearance techniques were sur-prisingly less frequent in adult patients than in childrenwith similar pulmonary function. In older patients withmild lung disease, the use of pancreatic enzymes was lessthan in other patient groups.

TABLE 8—Percentage of Patients in Each Age Group Treated With rhDNase I at Enrollment

Age(yr)

FEV1

(% predicted)

ERCF(N 4 6,858)

(%)

UK(N 4 3,433)

(%)

Germany(N 4 1,701)

(%)

France(N 4 820)

(%)

<6 5 2 2 146–12 >100 13 5 15 52

71–100 17 6 15 5840–70 38 21 30 80

<40 50 40 36 8113–17 >100 9 5 4 20

71–100 21 9 20 6740–70 44 34 31 73

<40 57 54 47 74ù18 >100 5 0 8 14

71–100 17 7 19 5340–70 34 21 40 62

<40 53 45 60 65Overall 25 16 25 49

TABLE 9—Percentage of Patients in Each Age Group TreatedWith Nutritional Supplementation at Enrollment (N = 6,858)

Age(yr)

FEV1

(% predicted)Oral(%)

Enteral(%)

<6 32 16–12 >100 33 1

71–100 37 240–70 46 6

<40 44 1513–17 >100 21 1

71–100 28 140–70 38 5

<40 48 17ù18 >100 21 1

71–100 18 140–70 29 3

<40 36 9

152 Koch et al.

Fig. 2. Percentage of patients being treated with airway clearance or chest physiotherapy techniques at time of enrollment,presented according to age and severity of lung disease . N = 6,858. Normal, FEV 1 >100% predicted; mild, 71–100%; moderate,40–70%; severe, <40% predicted.

Fig. 3. Percentage of patients >6 years with nasal polyps at time of enrollment, shown according to age and severity of lungdisease . n = 5,196. Normal, FEV 1 >100% predicted; mild, 71–100%; moderate, 40–70%; severe, <40% predicted.

International Practice Patterns in CF 153

Some routine treatments were used more frequentlythan has been proposed in the literature, namely, morethan half of all patients receivedinhaledbronchodilators,a proportion clearly in excess of those reported to haveasthma-like symptoms or bronchial hyper-reactivity. Us-age of oral corticosteroids also exceeded the reportedprevalence of ABPA in patients with severe lung disease.

There has been increasing interest in treatment ofyoung patients with CF. We found that patients under 6years of age were generally treated with pancreatic en-zymes (93%), chest physiotherapy (89%), inhaled bron-chodilators (36%), and oral nutritional supplements(32%). Prescription ofinhaled corticosteroids variedfrom 6% to 26%, depending on the reporting country.This appears to be a high rate, considering that there arealmost no studies on the benefits ofinhaled corticoste-roids in this age range. Among patients older than 6 yearswith FEV1 >70% predicted (the mild category), the mostfrequent additional treatment was rhDNase in 5–21%, againwith considerable variability in usage among countries.

Although the practice patterns described here suggestthat routine treatments are implemented as necessary tocontrol symptoms, some therapies, i.e., rhDNase, bron-chodilators, and inhaled corticosteroids, may have pro-phylactic efficacy by intervening in the vicious cycle ofaccumulating viscous secretions, atelectasis, increasingpathogen load, and inflammatory lung damage. Since itis now recognized that this pathogenic process beginsearly in the course of CF lung disease, it is necessary toalign current practice with the aim of prophylactic as wellas therapeutic management. New methodology is re-quired to monitor lung pathophysiology and function inyoung patients, particularly in those under 6 years of age,to evaluate the effects of early treatment.

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