Pediatric Pulmonology 49:873–877 (2014)

Increased Rate of Lung Function Decline in AustralianAdolescents With Cystic Fibrosis

Liam Welsh, PhD,1,2* Colin F. Robertson, MD,1,2 and Sarath C. Ranganathan, PhD1,2

Summary. Introduction: Though baseline lung function as measured by spirometry in children

with cystic fibrosis (CF) has improved, the annual rate of decline has not changed significantly

during the critical period of adolescence. The aim of this study was to describe factors associated

with longitudinal decline in lung function in a contemporary cohort of children with CF. Methods:

Best annual lung function data from children attending the CF service of the Royal Children’s

Hospital Melbourne were reviewed to determine rate of decline in FEV1 up until time of transfer to

an adult center. Mixed models were used to determine the influence of age, sex, genotype,

newborn screening, respiratory hospitalization, CF related diabetes mellitus (CFRD), pancreatic

insufficiency, Pseudomonas aeruginosa (PsA) infection, and body mass index (BMI) on lung

function decline. Results: Longitudinal lung function data (range 5–20 years) were obtained for 98

patients with CF (55 male). Overall, the annual rate of decline in FEV1 % predicted for the entire

cohort was 1.4% per annum though the greatest rate of FEV1 decline was seen during

adolescence (2.6%). Increasing age, homozygousDF508 genotype,CFRD,mucoidPsA infection,

pancreatic insufficiency and respiratory hospitalizations were all significant predictors of FEV1

decline. Conclusion: FEV1 declines at its sharpest rate during adolescence even in the presenceof

newborn screening. Genotype, increasing age, CFRD, PsA infection, pancreatic insufficiency and

a greater number of respiratory hospitalizations are all associated with an increased rate of lung

function decline in Australian children and adolescents with cystic fibrosis. Pediatr Pulmonol.

2014; 49:873–877. � 2013 Wiley Periodicals, Inc.

Key words: cystic fibrosis; lung function; decline; Pseudomonas aeruginosa.

Funding source: none reported

INTRODUCTION

Though baseline lung function as measured byspirometry has increased over the past 20 years inchildren with cystic fibrosis (CF), the rate of FEV1 declineduring the critical period of adolescence has remainedunchanged at approximately 2.5–3.0% per annum.1 Foradult and pediatric populations alike, several factors havebeen associated with an increased rate of FEV1 declineincluding age, sex, microbiological infection, pancreaticinsufficiency, CF related diabetes (CFRD) and nutritionalstatus.2–7 However, most of the research has focused onEuropean and US cohorts and longitudinal data arecurrently lacking for Australian populations. As newbornscreening was adopted much earlier by Australiancenters8 there is a need to know whether a similarrelationship exists for Australian children and to be able tobetter identify those most at risk of an increased rate ofdecline in the context of previous early diagnosis.Therefore, the aim of this study was to describe factorsassociated with longitudinal decline in lung function in acontemporary cohort of Australian children and adoles-cents with CF.

METHODS

We performed a retrospective analysis of children andadolescents who had transferred from the Royal Child-ren’s Hospital (RCH), Melbourne CF service to adult carewithin the previous 5 years as of June 2011. The CFservice at RCH cares for all children within a geographicregion which covers two thirds of the state of Victoria.The range of birth years included 1987 through 1993(newborn screening was introduced in Victoria in 1989).

1Respiratory Medicine, Royal Children’s Hospital, Melbourne, Australia.

2Murdoch Children’s Research Institute, Melbourne, Australia.

�Correspondence to: Liam Welsh, Respiratory Medicine, Royal Children’s

Hospital, Melbourne Flemington Road, Parkville 3052, Australia.

E-mail: liam.welsh@rch.org.au

Received 25 November 2012; Accepted 13 August 2013.

DOI 10.1002/ppul.22946

Published online 31 October 2013 in Wiley Online Library

(wileyonlinelibrary.com).

� 2013 Wiley Periodicals, Inc.

Children were included in the study if they had aconfirmed diagnosis of CF (regardless of the mode ofpresentation) and were able to perform reproduciblespirometry. The Australian Cystic Fibrosis Data Registrywas used to collect clinical information regardinggenotype, pulmonary function, newborn screening status,pancreatic insufficiency, CF related diabetes mellitus(CFRD), Pseudomonas aeruginosa (PsA) infection, andrespiratory hospitalization. Gastrointestinal hospitaliza-tions and day admissions were not included. Socio-economic status (SES) was determined using the Socio-Economic Index for Areas (SEIFA) from the AustralianBureau of Statistics household census conducted in 2011.SES was categorized according to decile (i.e., 1–10) with1 representing the most disadvantaged and 10 the leastdisadvantaged. Patients who received lung transplanta-tion or died prior to transfer were not included in theanalysis (15 deaths and 3 lung transplantations).Best annual lung function data, defined as the highest

percent predicted FEV19 within a calendar year, were

consecutively collated for children once they hadgraduated from the pre-school laboratory through thetime of transfer to adult care (i.e., �5 to 20 years).

STATISTICS

Statistical analysis was performed using Stata Version11.0 (Stata Corporation, TX). A mixed model, whichadjusted for the correlated nature of individually repeatedmeasures of FEV1, was used to determine the influence of:age, sex, genotype (categorized as homozygous DF508,heterozygous DF508, or other/unknown), newbornscreening, pancreatic insufficiency, CFRD, PsA infectionstratified as ever, non-descript, rough or mucoid, bodymass index (BMI) stratified as underweight, normalor overweight (i.e., <5th centile, 5–95th centile, >95centile),10 respiratory hospitalization stratified by occur-rence (i.e., 0, 1, 2–4, �5 and <10, �10 admissions),hospitalizations adjusted for the number of years studied(categorized as quartiles) and socio-economic status.After adjusting for repeat measures, factors which werenear significant on univariable analysis (i.e., P< 0.15) orthose with a strong a priori hypothesis (e.g., age) wereentered into the mixed model using a step-wise approach.Age, BMI and PsA were treated as time-dependentvariables in the mixed model. The effect of diagnosis bynewborn screening (yes vs. no) was evaluated by testingfor interactions within the mixed model. Variables wereretained in the model if they independently influencedFEV1 decline.Seemingly unrelated regression analysis was per-

formed separately to examine whether the rate of declinein FEV1 differed between age groups (i.e., 5–8.99 years,9–12.99 years, and �13 years). Significance levels wereset at P< 0.05.

RESULTS

Between June 2006 and June 2011, 98 patients withCF (55 male) transferred from the RCH Melbourne toadult care. Study population characteristics are shownin Table 1. In terms of spirometry data, there was amedian of 12 (range 3–16) observations per patient(i.e. 12 years of data) with 1,127 observations in total.The median number of respiratory hospitalizationsper patient was 2 (range 0–72). Those diagnosed bynewborn screening (52 patients) were significantlyyounger at diagnosis than those diagnosed clinically(46 patients) (mean (SD): 0.24 (0.56) years vs. 1.52(3.02) years; P< 0.001).On univariable analysis, the annual rate of decline in

FEV1 % predicted for the entire cohort was 1.4% (95% CI1.2–1.5) per annum. This decline was calculated from thetime that spirometry was first measured through the finalmeasurement prior to transfer. The adjusted coefficientsfor the multivariable analysis are provided in Table 2.Specifically, increasing age, homozygous DF508 geno-type, CFRD, mucoid PsA infection, pancreatic insuffi-ciency and a greater number of respiratory hospitalizationswere all significant factors which increased the rate of

TABLE 1—Study Population Characteristics

Variable

Subjects, n 98

Male 55 (56%)

Total observations 1,127

Follow-up time (years) 10.5 (2.4)

Age at transfer (years) 18.5 (0.9)

Mode of presentation

Newborn screening 52 (53%)

Other 46 (47%)

Genotype

Homozygous DF508 43 (44%)

Heterozygous DF508 41 (42%)

Other 14 (14%)

Pancreatic insufficiency 88 (90%)

Cystic fibrosis-related diabetes mellitus 18 (18.4%)

Pseudomonas aeruginosa infection

Ever 75 (76.5%)

Non-descript 53 (54.1%)

Rough 38 (38.9%)

Mucoid 61 (62.2%)

Hospitalizations

0 27 (27.6%)

1 19 (19.3%)

2–4 22 (22.5%)

�5 and <10 14 (14.3%)

�10 16 (16.3%)

Hospitalizations per year of study 0.45 (0.72)

Body mass index (kg/m2)

Underweight (<5th centile) 16 (16.3%)

Normal weight (5–95th centile) 75 (76.5%)

Overweight (>95th centile) 7 (7.2%)

Data are presented as n, n (%), or mean (SD) unless otherwise stated.

874 Welsh et al.

Pediatric Pulmonology

FEV1 decline. Sex, length of follow-up, age at transfer,BMI, age of diagnosis, newborn screening and SES werenot significantly associated with lung function decline inthe multivariable analysis. The rate of FEV1 decline didnot differ significantly between the groups who had 2–4,5–10, or >10 respiratory hospitalizations.The rate of decline in FEV1 % predicted increased with

age. Patients aged 5–8.99 years had an annual rate ofdecline of 0.80% per annum, compared with 1.53% forthose aged 9–12.99 years and 2.55% for those aged 13 orolder. The two youngest groups did not differ significantlywhile the adolescent group had a significantly greater rateof decline when compared to the younger age categories(P¼ 0.03) (Fig. 1).

DISCUSSION

Our findings demonstrate an increased rate of decline inFEV1 among Australian adolescents with CF when

compared to younger children and draw attention toseveral significant predictors of lung function deteriora-tion during pediatric care includingmucoidPsA infection,increasing age, genotype, pancreatic insufficiency, CFRDand number of hospitalizations. Reassuringly, we haveshown a similar average annual decline in FEV1 of 1.4%per annum throughout childhood compared to previousstudies1,7,11 and have highlighted many of the same riskfactors as earlier reports.2–7 However, themost distressingfinding is that adolescents continue to have an accelerateddecline in lung function of 2.6% per annum despiteadvances in CF care. Also, diagnosis of CF by newbornscreening at a significantly younger age, did not favorslower rates of decline compared with subjects who hadbeen diagnosed clinically.To a certain degree, we can only speculate as to why

there is an increased rate of decline in lung functionthrough adolescence. Adherence to treatment may be animportant factor, though there is no significant change inthe model of care provided to adolescents. Both chronicmicrobiological infection and repeated hospitalizationwere significant predictors of lung function decline inour analysis and these may begin to take their toll.Indeed, recent work has shown that a significantproportion of children, adolescents and young adultsfailed to recover their baseline lung function followinga pulmonary exacerbation3 and cross-sectional datafrom Australia shows a doubling of PsA infection inadolescents compared to children.12 However, theaccelerated decline during adolescence may also be amanifestation of early life events, including early clinicalmanagement prior to the advent of successful eradicationstrategies for PsA.Despite prompt diagnosis and treatment with newborn

screening, abnormal lung function can be detected withinthe first 3 months of life in infants with CF13 and high

TABLE 2—Multivariate Analysis of Factors Influencing theRate of FEV1 % Predicted Decline

Variable Slope (95% CI) P-Value

Age �0.63 (�1.45; �0.19) 0.01

Sex

Male Ref. Ref.

Female 0.85 (�4.4; 6.1) 0.752

Newborn screening

No Ref. Ref.

Yes �0.12 (�0.47; 0.23) 0.511

Genotype

Other Ref. Ref.

Heterozygous DF508 �0.48 (�1.03; 0.06) 0.083

Homozygous DF508 �0.94 (�1.49; �0.40) 0.001

Pancreatic insufficiency �1.01 (�1.57; �0.46) <0.001

Cystic fibrosis-related

diabetes mellitus

�1.30 (�1.68; �0.92) <0.001

Mucoid Pseudomonas

aeruginosa infection

�0.45 (�0.78; �0.12) 0.008

Respiratory hospitalizations

0 Ref. Ref.

1 �0.04 (�0.49; 0.43) 0.880

2–4 �1.22 (�1.66; �0.80) <0.001

�5 and <10 �1.10 (�1.63; �0.58) <0.001

�10 �0.62 (�1.12; �0.12) 0.016

Hospitalizations per year

of study

�3.2 (�9.2; 2.80) 0.294

Hospitalizations per year

of study quartiles

1st 0.11 (�0.13; 0.25) 0.411

2nd 0.31 (�0.93; 1.54) 0.627

3rd �0.32 (�1.19; 0.54) 0.470

4th �0.47 (�1.03; 0.08) 0.093

Body mass index (kg/m2)

Normal weight Ref. Ref.

Underweight 0.21 (�0.21; 0.64) 0.330

Overweight 0.31 (�0.41;1.04) 0.399

Ref., reference.

Fig. 1. Forced expiratory volume in 1 second (FEV1) % predicted

decline stratified by age. Patients aged 5–8.99 years had an

annual rate of decline of 0.80% per annum, compared with 1.53%

for those aged 9–12.99 years and 2.55% for those aged 13 or

older.

Increased Rate of Lung Function 875

Pediatric Pulmonology

resolution computed tomography (HRCT) has revealedbronchiectatic type structural lung changes among infantsand preschool children with CF14 which persist andprogress in most cases.15 Importantly though, we alsoknow that spirometry can be insensitive to early CF lungdisease with several reports of structural abnormalities inthe presence of seemingly preserved lung function.16–19

Perhaps it is only once inhomogeneous lung diseaseworsens to widespread homogenous disease that a moreobvious decline in spirometry becomes apparent, andperhaps this typically occurs during adolescence.Hospitalizations per year of study failed to reach

significance within the mixed model though this may be areflection of low statistical power. Overall, nearly half(46.9%) of our cohort had either never been hospitalizedor had only had one admission throughout the studyperiod. Consequently, this analysis was likely underpow-ered to detect a significant effect.Socio-economic status is another perspective worth

considering with several reports indicating that a low SESis associated with significantly poorer outcome in CF. Forexample, children with CF in the United States who couldnot afford health insurance were reported to have athreefold greater risk of death, poorer pulmonaryfunction, poorer nutrition and were more likely to requirehospitalization for pulmonary exacerbation when com-pared to CF patients with health insurance.20,21 However,SES did not influence the rate of decline in lung functionin our cohort which may be a reflection of the universalhealthcare model in Australia.Taken together, our findings show a combination

of both modifiable and unalterable risk factors fordecline in lung function in children and adolescentswith CF, yet encouragingly there still appears to be scopefor improved therapeutic strategies during several lifestages. Notably, there were only 15 deaths and threetransplantations throughout the period investigated whichsuggests our results are representative of the Melbournecohort.The retrospective nature of this study limited the

information we could gather regarding symptom profileand therefore severity of respiratory hospitalization. Wewere also unable to measure potential confounders suchas smoking status and environmental tobacco exposure. Inaddition, we acknowledge that these results only describea single treatment center and that a multi-centerlongitudinal study incorporating every pediatric CFcenter in Australia would better elucidate the factorsassociated with lung function decline in this group.However, despite these shortcomings our results shouldstrengthen our endeavor to keep young children free ofmicrobiological infection and out of hospital wherepossible. Long term, we should also include assessmentsof FEV1 decline during adolescence as a benchmark ofsuccessful treatment.

CONCLUSION

Genotype, increasing age, CFRD, mucoid PsA infec-tion, pancreatic insufficiency and a greater number ofrespiratory hospitalizations are all associated with anincreased rate of lung function decline in Australianchildren with cystic fibrosis. Though the greatest declinein lung function is seen during adolescence, the criticalperiod to intervene may be during very early life. Howthese findings relate to underlying lung structuralchanges, and whether PsA eradication success can reducethe rate of decline in future cohorts, warrants furtherinvestigation.

ACKNOWLEDGEMENTS

The authors wish to thank A/Prof Susan Donath fromthe Clinical Epidemiology and Biostatistics Unit at theRoyal Children’s Hospital, Melbourne for her statisticaladvice and Ms Louise King who assisted with data entryon this project.

REFERENCES

1. United States Cystic Fibrosis Foundation. Patient registry report;

2010.

2. Konstan MW, Morgan WJ, Butler SM, Pasta DJ, Craib ML, Silva

SJ, Stokes DC, Wohl ME, Wagener JS, Regelmann WE, Johnson

CA. Risk factors for rate of decline in forced expiratory volume in

one second in children and adolescents with cystic fibrosis. J

Pediatr 2007;151:134–139, 139e131.

3. Sanders DB, Bittner RC, Rosenfeld M, Hoffman LR, Redding GJ,

Goss CH. Failure to recover to baseline pulmonary function after

cystic fibrosis pulmonary exacerbation. Am J Respir Crit Care

Med 2010;182:627–632.

4. Sanders DB, Bittner RC, Rosenfeld M, Redding GJ, Goss CH.

Pulmonary exacerbations are associated with subsequent fev1

decline in both adults and children with cystic fibrosis. Pediatr

Pulmonol 2011;46:393–400.

5. Schaedel C, de Monestrol I, Hjelte L, Johannesson M, Kornfalt R,

Lindblad A, Strandvik B, Wahlgren L, Holmberg L. Predictors of

deterioration of lung function in cystic fibrosis. Pediatr Pulmonol

2002;33:483–491.

6. Schluchter MD, Konstan MW, Davis PB. Jointly modelling the

relationship between survival and pulmonary function in cystic

fibrosis patients. Stat Med 2002;21:1271–1287.

7. Waters V, Stanojevic S, Atenafu EG, Lu A, Yau Y, Tullis E,

Ratjen F. Effect of pulmonary exacerbations on long-term

lung function decline in cystic fibrosis. Eur Respir J 2012;40:

61–66.

8. Massie RJ, Curnow L, Glazner J, Armstrong DS, Francis I.

Lessons learned from 20 years of newborn screening for cystic

fibrosis. Med J Aust 2012;196:67–70.

9. Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver B,

Enright PL, Hankinson JL, Ip MS, Zheng J, Stocks J. Multi-ethnic

reference values for spirometry for the 3–95 year age range: the

global lung function 2012 equations. Eur Respir J 2012;40(6):

1324–1343.

10. Cole TJ, Freeman JV, Preece MA. British 1990 growth reference

centiles for weight, height, body mass index and head circumfer-

ence fitted by maximum penalized likelihood. Stat Med 1998;

17:407–429.

876 Welsh et al.

Pediatric Pulmonology

11. Liou TG, Elkin EP, Pasta DJ, Jacobs JR, Konstan MW, Morgan

WJ, Wagener JS. Year-to-year changes in lung function in

individuals with cystic fibrosis. J Cyst Fibros 2010;9:250–256.

12. Bell SC, Bye PT, Cooper PJ, Martin AJ, McKay KO, Robinson PJ,

Ryan GF, Sims GC. Cystic fibrosis in australia, 2009: results from

a data registry. Med J Aust 2011;195:396–400.

13. Hoo AF, Thia LP, Nguyen TT, Bush A, Chudleigh J, Lum S,

Ahmed D, Lynn IB, Carr SB, Chavasse RJ, Costeloe KL, Price J,

Shankar A, Wallis C, Wyatt HA, Wade A, Stocks J. Lung function

is abnormal in 3-month-old infants with cystic fibrosis diagnosed

by newborn screening. Thorax 2012;67:874–881.

14. Stick SM, Brennan S, Murray C, Douglas T, von Ungern-

Sternberg BS, Garratt LW, Gangell CL, De Klerk N, Linnane B,

Ranganathan S, Robinson P, Robertson C, Sly PD. Bronchiectasis

in infants and preschool children diagnosed with cystic fibrosis

after newborn screening. J Pediatr 2009;155:623–628, e621.

15. Mott LS, Park J, Murray CP, Gangell CL, de Klerk NH, Robinson

PJ, Robertson CF, Ranganathan SC, Sly PD, Stick SM.

Progression of early structural lung disease in young children

with cystic fibrosis assessed using CT. Thorax 2012;67:509–516.

16. Brody AS, Klein JS, Molina PL, Quan J, Bean JA, Wilmott RW.

High-resolution computed tomography in young patients with

cystic fibrosis: distribution of abnormalities and correlation with

pulmonary function tests. J Pediatr 2004;145:32–38.

17. de Jong PA, Lindblad A, Rubin L, Hop WC, de Jongste JC, Brink

M, Tiddens HA. Progression of lung disease on computed

tomography and pulmonary function tests in children and adults

with cystic fibrosis. Thorax 2006;61:80–85.

18. de Jong PA, Nakano Y, Lequin MH, Mayo JR, Woods R, Pare PD,

Tiddens HA. Progressive damage on high resolution computed

tomography despite stable lung function in cystic fibrosis. Eur

Respir J 2004;23:93–97.

19. Gustafsson PM, De Jong PA, Tiddens HA, Lindblad A. Multiple-

breath inert gas washout and spirometry versus structural lung

disease in cystic fibrosis. Thorax 2008;63:129–134.

20. Schechter MS, McColley SA, Silva S, Haselkorn T,

Konstan MW, Wagener JS. Association of socioeconomic status

with the use of chronic therapies and healthcare utilization in

children with cystic fibrosis. J Pediatr 2009;155:634–639,

e631–e634.

21. Schechter MS, Shelton BJ, Margolis PA, Fitzsimmons SC. The

association of socioeconomic status with outcomes in cystic

fibrosis patients in the united states. Am J Respir Crit Care Med

2001;163:1331–1337.

Increased Rate of Lung Function 877

Pediatric Pulmonology