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The
journal of medicine
established in 1812 may 23, 2013 vol. 368 no. 21
A bs t r ac t
Background
Bronchiectasis develops early in the course of cystic fibrosis, being detectable in From Queensland Childrens Medical Re-
infants as young as 10 weeks of age, and is persistent and progressive. We sought search Institute (P.D.S., C.L.G., L.C.,
R.S.W.), and the School of Population
to determine risk factors for the onset of bronchiectasis, using data collected by the Health, University of Queensland (R.S.W.),
Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF) in- Brisbane; Murdoch Childrens Research
tensive surveillance program. Institute, the Department of Respiratory
Medicine, Royal Childrens Hospital, and
the Department of Paediatrics, Universi-
Methods ty of Melbourne, Melbourne, VIC (S.R.);
We examined data from 127 consecutive infants who received a diagnosis of cystic and the Departments of Respiratory Med-
icine (L.S.M., S.M.S.) and Diagnostic Im-
fibrosis after newborn screening. Chest computed tomography (CT) and bronchoal- aging (C.P.M.), Princess Margaret Hospi-
veolar lavage (BAL) were performed, while the children were in stable clinical con- tal for Children, and Telethon Institute
dition, at 3 months and 1, 2, and 3 years of age. Longitudinal data were used to de- for Child Health Research, Centre for
Child Health Research, University of
termine risk factors associated with the detection of bronchiectasis from 3 months Western Australia (L.S.M., S.M.S.), Perth
to 3 years of age. all in Australia. Address reprint re-
quests to Dr. Sly at Queensland Chil-
drens Medical Research Institute, Level
Results 4, Foundation Building, Royal Childrens
The point prevalence of bronchiectasis at each visit increased from 29.3% at 3 months Hospital, Herston Rd., Herston, QLD
of age to 61.5% at 3 years of age. In multivariate analyses, risk factors for bronchi- 4029, Australia, or at p.sly@uq.edu.au.
ectasis were presentation with meconium ileus (odds ratio, 3.17; 95% confidence * Members of the Australian Respiratory
interval [CI], 1.51 to 6.66; P=0.002), respiratory symptoms at the time of CT and Early Surveillance Team for Cystic Fibro-
BAL (odds ratio, 2.27; 95% CI, 1.24 to 4.14; P=0.008), free neutrophil elastase activ- sis (AREST CF) are listed in the Supple-
mentary Appendix, available at NEJM.org.
ity in BAL fluid (odds ratio, 3.02; 95% CI, 1.70 to 5.35; P<0.001), and gas trapping
on expiratory CT (odds ratio, 2.05; 95% CI, 1.17 to 3.59; P=0.01). Free neutrophil This article was published on May 21, 2013,
at NEJM.org.
elastase activity in BAL fluid at 3 months of age was associated with persistent
bronchiectasis (present on two or more sequential scans), with the odds seven N Engl J Med 2013;368:1963-70.
DOI: 10.1056/NEJMoa1301725
times as high at 12 months of age and four times as high at 3 years of age. Copyright 2013 Massachusetts Medical Society.
Conclusions
Neutrophil elastase activity in BAL fluid in early life was associated with early bron-
chiectasis in children with cystic fibrosis. (Funded by the National Health and Medi-
cal Research Council of Australia and Cystic Fibrosis Foundation Therapeutics.)
I
llness and death from cystic fibrosis could be accurately determined by measuring
are due primarily to progressively destructive biomarkers of inflammation and infection in BAL
lung disease resulting in bronchiectasis and fluid at 3 months of age.
respiratory failure. Computed tomography (CT)
can detect changes in the lungs associated with Me thods
bronchiectasis1,2 and evidence of structural lung
disease in children with cystic fibrosis as young Study Population
as 10 weeks of age.3-8 The true prevalence of bron- We examined data from 127 consecutive infants
chiectasis among children with cystic fibrosis is who received a diagnosis of cystic fibrosis on the
unknown; however, studies conducted by the Aus- basis of newborn screening and who were par-
tralian Respiratory Early Surveillance Team for ticipants in the AREST CF surveillance program.
Cystic Fibrosis (AREST CF) and the Australasian Assessments were undertaken when the children
Cystic Fibrosis Bronchoalveolar Lavage study group were in stable clinical condition. We sought to
have shown that 50 to 70% of patients have CT- determine whether pulmonary inflammation and
defined bronchiectasis by 3 to 5 years of age.3,5,9 infection detected in BAL fluid at 3 months and
Once present, bronchiectasis persists and pro- 1, 2, and 3 years of age were associated with the
gresses in approximately 75% of young children,3 development of bronchiectasis by 3 years of age.
despite receipt of the best current therapy.
A coordinated approach to early surveillance in CT and BAL
young children with cystic fibrosis has been de- Chest CT and BAL were performed while the in-
veloped by the AREST CF, a collaborative program fants were under general anesthesia.3-5 Children
of the pediatric cystic fibrosis clinics at Princess were initially intubated with a cuffed tracheal
Margaret Hospital for Children, Perth, and the tube; a standardized recruitment maneuver, con-
Royal Childrens Hospital, Melbourne. The clinics sisting of 10 consecutive slow breaths up to total
serve the entire populations of Western Australia lung capacity (transrespiratory pressure [PRS], 37
and Victoria, respectively, apart from the southern to 40 cm of water) over a positive end-expiratory
metropolitan region of Melbourne. The program pressure of 5 cm of water for 1 to 2 seconds after
includes assessments soon after diagnosis (average each inspiration, was used to reduce procedure-
age, 3 months) and annually until 6 years of age, related atelectasis. A volume-controlled, limited-
encompassing clinical assessment, lung-function slice CT scan (initial scan at 3 months of age; see
testing, chest CT with the use of a low-radiation Table S1 in the Supplementary Appendix) was ob-
protocol, bronchoalveolar lavage (BAL), and col- tained, with three slices obtained at both end in-
lection of blood and urine samples (see the Sup- spiration (PRS, 25 cm of water) and end expiration
plementary Appendix, available with the full text (PRS, 0 cm of water); a volume-controlled volu-
of this article at NEJM.org). metric CT scan was obtained at end inspiration
Previous studies from the AREST CF, using for older children (starting in 2007 in Perth and
largely cross-sectional data, have shown that 2010 in Melbourne). Details of the scanners and
neutrophilic inflammation (characterized by the settings used have been published previously.3,15
presence of free neutrophil elastase activity in CT images were scored, as previously reported,
BAL fluid) and pulmonary infection (especially with no knowledge of the childs clinical status
with Pseudomonas aeruginosa) are the major risk or the results of any previous scans or tests to
factors for early disease in cystic fibrosis, includ- detect infection or inflammation.3-5 Each scan
ing the development and progression of bronchi- was considered in six zones (upper, middle, and
ectasis,3-5 a reduction in the body-mass index,10 lower areas of the left and right lungs), and each
and lung-function decline.11 BAL-based studies zone was scored for the presence or absence and
have shown that lung disease begins early in extent of bronchiectasis (on inspiratory scans)
life4-6,12,13 and is associated with increased levels and gas trapping (on expiratory scans). Bronchi-
of proinflammatory cytokines, such as CXCL8 ectasis was defined as a bronchus-to-artery ratio
(interleukin-8),4,14 and that more extensive in- of more than 1.0 or the presence of a nontaper-
flammation is found in lung lobes with more ing bronchus in the transverse plane.3,5 To avoid
severe bronchiectasis.6 We conducted the current overinterpretation of radiologically defined dis-
study to test the hypothesis that the risk of bron- ease, especially from limited-slice scans in early
chiectasis, especially persistent bronchiectasis, life, we defined persistent bronchiectasis as bron-
Table 1. Demographic and Clinical Characteristics of the Study Population, According to Time of Assessment.*
smaller numbers of children with increasing age age to 61.5% at 3 years of age (P<0.001) (Table 1).
was that the children had not yet reached the as- The cumulative prevalence of bronchiectasis
sessment age by the end of the data-collection reached 83.7% by 3 years of age. The point preva-
period (Fig. 1). Demographic and clinical data are lence of CT-defined gas trapping at each visit was
shown in Table 1. The point prevalence of bron- 68.0% at 3 months, 68.5% at 1 year, 71.6% at
chiectasis increased from 29.3% at 3 months of 2 years, and 69.2% at 3 years (Table 1).
Table 2. Characteristics of the Study Participants at the 3-Month Assessment, According to Status with Respect
to Neutrophil Elastase Activity and Bronchiectasis at That Time.*
* Fishers exact test was used for all analyses, unless otherwise noted.
Bronchiectasis could not be assessed on three CT scans owing to procedure-related atelectasis, and these scans were
considered to be negative.
Severe genotype was defined as a lack of predicted function of residual cystic fibrosis transmembrane conductance reg-
ulator (CFTR) on the basis of mutation class.
Plusminus values are means SD. Analysis of variance was used for the comparisons.
At the initial assessment, at 3 months of age, eus at presentation (odds ratio, 3.17; 95% confi-
28 of 120 children (23.3%) had detectable neu- dence interval [CI], 1.51 to 6.66; P=0.002),
trophil elastase activity in BAL fluid, and 36 of respiratory symptoms at the time of CT and BAL
123 (29.3%) had bronchiectasis on the chest CT (odds ratio, 2.27; 95% CI, 1.24 to 4.14; P=0.008),
scan. Demographic and clinical data stratified neutrophil elastase activity in BAL fluid (odds ra-
according to status with respect to neutrophil tio, 3.02; 95% CI, 1.70 to 5.35; P<0.001), and gas
elastase activity and bronchiectasis at the initial trapping on expiratory CT (odds ratio, 2.05; 95%
assessment are shown in Table 2. Neutrophil elas- CI, 1.17 to 3.59; P=0.01). There were no signifi-
tase activity in BAL fluid was associated with the cant interactions between any of the risk factors
presence of respiratory symptoms at the time of and the age at which BAL was performed. A sen-
BAL (P=0.007), pancreatic insufficiency (P=0.006), sitivity analysis, with the assumption that once
and pulmonary infection (P=0.02). Bronchiectasis bronchiectasis was detected, all subsequent
on the initial CT scan was associated with respi- scans would be positive, had similar results
ratory symptoms (P=0.01), meconium ileus at (Table S2 in the Supplementary Appendix), with
presentation (P=0.002), and any pulmonary in- the presence of neutrophil elastase activity in
fection (P=0.03) or infection with P. aeruginosa BAL fluid and initial presentation with meconi-
(P=0.02) (Table 2). um ileus as significant predictors in multivariate
analyses.
Risk Factors for Bronchiectasis
Risk factors associated with the development of Risk Factors for Persistent Bronchiectasis
bronchiectasis from 3 months to 3 years of age Persistent bronchiectasis was observed in 15 of
are shown in Table 3. Risk factors for bronchiec- 104 children (14.4%) at 12 months of age and in
tasis on multivariate analysis were meconium il- 25 of 78 children (32.1%) at 3 years of age. Risk
No potential conflict of interest relevant to this article was We thank the clinical fellows who performed the bronchosco-
reported. pies and the laboratory staff members who processed and ana-
Disclosure forms provided by the authors are available with lyzed the samples, in particular Luke Berry, Rosemary Carzino,
the full text of this article at NEJM.org. and Dr. John Wong.
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