- Email: [email protected]
Bronchiectasis in Infants and Preschool Children Diagnosed with Cystic Fibrosis after Newborn Screening
Bronchiectasis in Infants and Preschool Children Diagnosed with Cystic Fibrosis after Newborn Screening Stephen M. Stick, MA, MB BChir, PhD, Siobhain Brennan, BSc (hons), PhD, Conor Murray, MBBS, Dip Ch, FRANZCR, Tonia Douglas, MBChB (hons), FRACP, Britta S. von Ungern-Sternberg, MD, DEAA, Luke W. Garratt, BSc (hons), Catherine L. Gangell, BSc (hons), PhD, Nicholas De Klerk, BSc, MSc, F Ed TC, PhD, Barry Linnane, MD, PhD, Sarath Ranganathan, MB ChB, MRCP, PhD, FRCPCH, FRACP, Phillip Robinson, BMed Sc, MBBS, FRACP, MD, PhD, Colin Robertson, MBBS, FRACP, MSc (Epi), MD, and Peter D. Sly, MBBS, FRACP, MD, DSci, on behalf of the Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF)* Objectives To determine the prevalence of bronchiectasis in young children with cystic fibrosis (CF) diagnosed after newborn screening (NBS) and the relationship of bronchiectasis to pulmonary inflammation and infection.
Study design Children were diagnosed with CF after NBS. Computed tomography and bronchoalveolar lavage were performed with anesthesia (n = 96). Scans were analyzed for the presence and extent of abnormalities. Results The prevalence of bronchiectasis was 22% and increased with age (P = .001). Factors associated with bronchiectasis included absolute neutrophil count (P = .03), neutrophil elastase concentration (P = .001), and Pseudomonas aeruginosa infection (P = .03). Conclusions Pulmonary abnormalities are common in infants and young children with CF and relate to neutrophilic inflammation and infection with P. aeruginosa. Current models of care for infants with CF fail to prevent respiratory sequelae. Bronchiectasis is a clinically relevant endpoint that could be used for intervention trials that commence soon after CF is diagnosed after NBS. (J Pediatr 2009;155:623-8). See related article, p 629
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ewborn screening (NBS) for cystic fibrosis (CF) is widely established, with approximately 2 million newborns screened annually in the United States.1 In CF, bronchiectasis that results from chronic inflammation and infection is associated with increased morbidity rate2 and accelerated decline in pulmonary function.2,3 Because death is most commonly a result of suppurative lung disease, the development of bronchiectasis has important clinical implications. Computed tomography (CT) scans are sensitive to changes in the lung associated with bronchiectasis.4,5 Therefore the detection of bronchiectasis by CT could be a useful early marker of disease progression and a relevant endpoint in intervention studies. However, it is not known how commonly bronchiectasis occurs in the first years of life, and no matter how sensitive a test for bronchiectasis might be, if the condition is rare, the test would have limited utility. Therefore the aims of this study were to determine the prevalence of bronchiectasis in a young population of screened children with CF and to determine whether CT scanning evidence of bronchiectasis was associated with known pathophysiological risk factors (inflammation and infection). We used data collected as part of a unique early surveillance program (ESP) of newborns diagnosed with CF after NBS in Perth and Melbourne, Australia. The ESP includes annual bronchoalveolar lavage (BAL) and chest CT scans. We used cross-sectional analyses to examine the hypotheses that (1) bronchiectasis is common in the first years of life and (2) children in whom bronchiectasis develops have more severe airway inflammation.
Methods The study was conducted by the Australian Respiratory Early Surveillance Team for CF (AREST CF) at the Princess Margaret Hospital for Children, Perth and
From the Princess Margaret Hospital for Children (S.S., C.M., T.D., B.U.), TVW Institute for Child Health Research (S.S., S.B., T.D., L.G., C.G., N.D., P.S.), School of Paediatrics and Child Health, University of Western Australia (S.S.), Perth and Royal Children’s Hospital (B.L., S.R., P.R., C.R.), Melbourne, Australia
*Additional members of AREST CF are available at www. AREST CF BAL BWT CF CT ESP NBS
Australian Respiratory Early Surveillance Team for Cystic Fibrosis Bronchoalveolar lavage Bronchial wall thickening Cystic fibrosis Computed tomography Early surveillance program Newborn screening
jpeds.com (Appendix 1). This study is supported by Cystic Fibrosis Foundation (USA) (Project grant support), National Health and Medical Research Council (Australia) (Project grant support and Fellowships [S.M.S., P.D.S.]), and) Cystic Fibrosis (Australia) (Project grant support). The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright Ó 2009 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2009.05.005
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the Royal Children’s Hospital, Melbourne, and was approved by the Ethics Committees of both hospitals. Parents of children in the program provided written informed consent. Cross-sectional data presented here are from a clinic survey of children from Perth and Melbourne who underwent highresolution CT scanning during the period of August 2005 and March 2008 including all children to the age of 6 years (n = 125). Ninety-five percent of eligible children took part in the study. To be eligible for the analyses reported here, children had to be diagnosed after NBS6 and be referred to the participating center for multidisciplinary care. Perth is the only referral center in Western Australia. Children were referred to the Melbourne center from a geographically defined area of Victoria. Fourteen children were excluded from the primary analysis because they were diagnosed before the introduction of NBS in Perth during 2001, and an additional 15 children were excluded who presented with meconium ileus before their NBS results were known. Each child was included in the analysis once (n = 96) by use of data from their first available CT scan and BAL (Table I). High-resolution CT scanning was included in the ESP in Perth for all children from diagnosis up to 6 years from August 2005 and prospectively for newly diagnosed children with CF in Melbourne from April 2006. Hence, there are a greater number of children in the first 2 years of life than in older age groups. For newly diagnosed infants the first CT/BAL was performed when children reached approximately 4 kg. Protocols for staphylococcal prophylaxis, eradication of Pseudomonas aeruginosa, mucolytic use, nutrition, and enzyme replacement have been harmonized at each center and are consistent with the Standards of Care, Australia, guidelines.7 A validated questionnaire was used to assess symptoms of cough and wheeze and the presence or not of acute respiratory illness at the time of the BAL/CT.8 The CT scan and BAL were performed during the same anaesthetic according to a standardized total intravenous anesthetic protocol (Appendix 2; available at www.jpeds.com) with children intubated. Lung images were acquired with a 3slice protocol during inspiration at an airway pressure of 25 cm H20 and then 3 additional slices at end expiration (0 cm H20). The x-ray energy was 120 kV and the tube current 60 milliamperes per second (mAs). The gantry rotation time was 0.4 seconds per slice and collimation 0.63 mm. The tube current is the chief modifiable contributor to CT scan dose and has a linear relationship to the effective dose of a scan. The maximum effective radiation dose of each 3-slice scan was calculated as 0.14 to 0.2 millisievert (mSv), depending on body size, and 0.28 to 0.4 mSv for combined inspiratory and expiratory scans.9 Images were reported by an experienced pediatric thoracic radiologist (C.M.). Each lung was considered in 6 zones, (upper, mid, and lower; right and left) corresponding to each axial slice. The presence of bronchiectasis, air-trapping, inflammatory nodules and bronchial wall thickening (BWT) was recorded in a binary fashion for each abnormality for each zone (no = 0, yes = 1) and then weighted by multiplication according to the proportion of visible airways in each zone that were affected for bronchiectasis/BWT (<50% = 1, >50% = 2) and area of each zone affected (<50% = 1, >50% = 2) for 624
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Table I. Anthropometric and clinical information on subjects at the time of assessment Characteristic
Total population
Sex, M:F Age at diagnosis (days) [Median (IQR)] CFTR genotype DF508 homozygous DF508 heterozygous Other Age at CT scan (years) [Median (IQR)] Antistaphylococcal prophylaxis [n (%)] Microbiology [n (%)] Uninfected (<102 CFU/mL) Mixed oral flora only Isolated colonies only (102 104 CFU/mL)* Infected >104 CFU/mL Pseudomonas aeruginosa Staphylococcus aureus Haemophilus influenzae Stenotrophomonas maltophilia Streptococcus pneumoniae Aspergillus fumigatus Other infection† Respiratory symptoms [n (%)]z
55:41 30 (16.5, 37.0) 50 43 3 1.11 (0.30, 3.31) 43/72 (60%) 32 (33%) 33 (34%) 4 (4%) 27 (28%) 5 11 2 0 0 1 14 17 (17.7%)
*Candida sp. (n = 1), H. influenzae (n = 1), S. aureus (n = 2). †Candida sp. (n = 1), Escherichia coli (n = 4), Enterobacter sp. (n = 1), herpes simplex virus 1 (n = 1), Moraxella catarrhalis (n = 2), H. parainfluenzae (n = 2), respiratory syncytial virus (n = 2), Scedosporium sp. (n = 1). zSymptoms include presence of cough, upper/lower respiratory tract infection or wheeze or crackles on auscultation.
air-trapping, as an indication of the extent of each abnormality. Bronchiectasis, BWT and nodules were assessed on inspiratory scans. Bronchiectasis was defined as a bronchus– to–pulmonary artery diameter ratio of >1. Bronchial wall thickening was assessed subjectively. Inflammatory nodules were defined as clusters of small centrilobular nodules conforming to a ‘‘tree in bud’’ or rosette pattern or nonclustering ill-defined centrilobular nodules. Air trapping was defined as geographic foci of reduced density evident on expiratory images.10 Each zone from 20 scans was reassessed (120 individual zones), in random order, 6 to 12 months after the original assessment to determine repeatability of the clinical report. A non-radiologist member of the research team chose 20 individuals from the database with a range of abnormalities (Figure 1). The BAL was performed after the CT scan with a fiberoptic video-bronchoscope. (Olympus, Tokyo, Japan) as previously described.11,12 BAL samples were cultured on blood, CLED, Fildes agar, and Sarabouds agar with chloramphenicol. P. aeruginosa colonies were isolated from Horse Blood Agar and Ticarcillin agar plates incubated in a 5% CO2 atmosphere at 34 C for 48 to 72 hours. Colonies of P. aeruginosa were described as mucoid, smooth or rough by their appearance on horse blood agar. Fungi were identified by growth on wet mount and Sabarouds agar. Infection with a specific organism was considered as >104cfu/mL. Samples that cultured mixed oral flora (MOF) and colonies <104 CFU/mL were classified as uninfected. Immunofluorescence and viral cell culture were used to attempt identification of respiratory syncytial virus, parainfluenzae 1,2&3, influenzae A&B, and adenovirus. Stick et al
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Figure 1. Histogram to indicate the frequency distributions of abnormalities in the sample of 120 zones from 20 individuals selected for rescoring to determine repeatability of the computed tomography assessment.
BAL fluid was used for total and differential cell counts and free neutrophil elastase (NE) activity was measured with enzyme-linked immunosorbent assay.12 Primary comparisons were between children with and without bronchiectasis. Similar analyses were undertaken for children with air-trapping and BWT. Variables were checked for normality and log-transformed before analysis where required. Data are presented as median (25% to 75% interval) or as number (percent) as appropriate. Comparisons between binary variables were made by use of c2 tests. Multivariate ordinal logistic regression analyses were conducted to determine associations between extent of CT abnormalities and inflammation, respiratory symptoms, days hospitalized, sex and infection. Days in hospital were calculated for children $1 year as a percentage of days between annual BALs spent in hospital. CT report agreement was determined using a kappa co-efficient test for binary scores.13 Analyses were performed with either SigmaStat (Systat, Chicago, Illinois) or Stata (StatCorp, College Station, Texas).
Results The population characteristics are shown in Table I. Bronchiectasis and air trapping were commonly observed and easy to recognize in this population of children (Figure 2). Repeatability for reports of bronchiectasis, air trapping and BWT on CT scans were 82.5% (kappa = 0.64), 77.9% (kappa = 0.55) and 61.95% (kappa = 0.237) respectively. Nodules were very uncommon on the CT scans (identified in 7% of children assessed) and were only apparent in children with more severe bronchiectasis, therefore no further analysis of this component was undertaken. There were significant associations of bronchiectasis with air trapping (r = 0.37, P = .0002) and BWT (r = 0.34, P = .0006). Bronchiectasis was common and increased with age (P = .001). The incidence of bronchiectasis in the first year of life was 8.5%, and the prevalence reached 36% by 4 years
(Table II). The extent of bronchiectasis also increased with age (P = .001) (Figure 3; available at www.jpeds.com). Neither the presence, nor the extent of bronchiectasis was associated with poor growth determined by Z-score BMI. There was no relationship between bronchiectasis and days hospitalized for respiratory disease nor reported symptoms at the time of the BAL. Univariate analyses demonstrated relationships between the presence of bronchiectasis and log total cell count (OR 3.39 per one log unit increase in TCC 103 cell mL1; [CI: 1.15, 10.03], P = .027), log absolute number of neutrophils (OR 2.42 per one log unit increase in neutrophils 103cell mL1 [CI: 1.00, 5.81), P = .049), and NE activity (OR: 4.21 per 1 log unit increase in ngmL1 [CI: 1.79, 9.90], P = .001; Table III). There were no associations between the presence of air trapping and any markers of inflammation. The presence of bronchial wall thickening was associated with increased levels of NE activity (OR: 2.31 [CI:1.01, 5.30]), but no other inflammatory markers. The extent of bronchiectasis was associated with indicators of neutrophilic inflammation, with relationships seen between bronchiectasis and total cell count (r = 0.21, P = .04); absolute number of neutrophils (r = 0.25, P = .03), and NE activity (r = 0.43, P = .001). The extent of air trapping was associated with percent neutrophils (r = 0.41, P = .0002) and NE activity (r = 0.25, P = .016). Bronchial wall thickening was associated with NE activity (r = 0.31, P = .003), but no other markers of inflammation. Five children (5.2%) had P. aeruginosa detected in BAL. The presence of bronchiectasis was associated with infection with P. aeruginosa (P = .034). Bronchiectasis was not associated with infection with any other organism. There were no associations between the presence of air-trapping and P. aeruginosa infection. Air-trapping was associated with infection of >104 CFU/mL (P = .016) with organisms other than P. aeruginosa. The presence of bronchial wall thickening was not associated with infection with any organism.
Discussion Structural abnormalities of the lung in infants and young children with CF have been reported previously.14-17 We report the prevalence of CT-defined bronchiectasis in a population of infants and preschool children with CF, diagnosed after NBS. We also report associations between structural changes on CT with airway inflammation and infection with P. aeruginosa. Compared with bronchiectasis and airtrapping the assessment of bronchial-wall thickening had poor repeatability. The poor repeatability will obviously contribute to the population variability of this variable and reduce the likelihood of detecting associations with possible explanatory variables. We believe that the lack of repeatability is due to the very subjective nature of this assessment in our study compared with other studies.16,17 We observed an increase with age in the proportion of children with bronchiectasis. Twenty-two percent of our population, 8.5% of infants and 56% of the 4- to 6-year-olds, have
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Figure 2. Representative images of CT scans showing normal inspiratory, A and expiratory scan, B; bronchiectasis (indicated by white circles) with an extent of 1 in both the right and left lung C, and extent of 1 in the right lung and extent of 2 in the left lung, B; and air trapping with an extent of 1 in the right and not present in the left lung E, and an extent of 1 in the right lung and extent of 2 in the left lung, F. Images A, C, and D were obtained at full inspiration, and images B, E, and F were obtained at end-expiration.
evidence of bronchiectasis and bronchiectasis can be observed in children as young as 3 months. These observations are likely to be representative of outcomes achievable with modern CF management because data from the Australian National CF Registry and U.S. CF Registry indicate that outcomes for patients in Perth and Melbourne are similar to outcomes from the best centers in the world.18,19 We believe these data represent a good estimate of the prevalence of bronchiectasis because more than 95% of eligible children take part in the ESP. Furthermore, the population has a greater number of children at a younger age when CT abnormalities are less common. The associations with neutrophilic inflammation support our argument that the observed CT changes represent clinically relevant CF-related lung damage. The extent of neutrophilic inflammation (Table III) is similar to that observed previously11,20 in young children with CF. These associations were statistically very significant, although the strength of the relationships were only moderate. This is not surprising because
a number of predictable factors will have affected the strength of the associations. These include but are not limited to the sensitivity of the scanning method to identify abnormalities, particularly in smaller peripheral airways; factors that affect CT appearance at this age, such as reversible dilation of airways,21 the mild nature of the disease, and possible lag between onset of significant inflammation and destructive lung disease. We observed an association between the presence of P. aeruginosa in BAL and bronchiectasis. We have a low prevalence of P. aeruginosa in this cohort. Possibly our BAL technique is insensitive for detecting lower airway pathogens.15 However, the prevalence of P. aeruginosa infection was similar to that reported from Melbourne previously with a BAL technique that specifically included additional sampling for pathogens.22 We did not observe any relationships between organisms other than P. aeruginosa with bronchiectasis. Infection with P. aeruginosa was not associated with other CT abnormalities. Whether other organisms play a role in the development
Table II. Prevalence of CT abnormalities as a function of age Age
1st year of life
2nd year of life
3rd year of life
4th year of life
5th year of life
6th year of life
Number of patients by age group Bronchiectasis, n (%) Air trapping, n (%) Bronchial wall thickening, n (%)
47 4 (8.5%) 29 (61.7%) 17 (36.2%)
13 1 (7.7%) 6 (46.2%) 6 (46.2%)
7 2 (28.6%) 4 (57.1%) 5 (71.4%)
11 4 (36.4%) 7 (63.6%) 7 (63.6%)
11 7 (63.6%) 6 (54.5%) 5 (45.5%)
7 3 (42.9%) 4 (57.1%) 5 (71.4%)
Data indicate the number (percent) of children in each age group with the presence of structural abnormality identified by CT. An individual child may have more than one structural abnormality detected.
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Table III. Inflammatory variables from BAL fluid Bronchiectasis Absent
Present
Air trapping Absent
Bronchial wall thickening Present
Absent
Present
N 75 21 40 56 51 45 Total cell count (per mL 103) 225 (107, 400) 356 (220, 490) 300 (166, 448) 227 (120, 422) 263 (153, 487) 255 (118, 389) 30.98 (11.7, 101.2) 43.23 (21.8, 181.4) 43.48 (11.9, 116.4) 30.98 (16.9, 100.8) 32.40 (13.9, 106.3) 32.60 (11.9, 108.0) Neutrophils (per mL 103) Neutrophils (%) 13.99 (9.1, 26.1) 16.33 (10.7, 42.7) 13.33 (7.5, 23.5) 16.33 (10.5, 38.0) 13.50 (7.6, 24.1) 16.33 (10.3, 38.0) Neutrophil elastase (mg/mL) 0.10 (0.10, 0.10) 0.10 (0.10, 1.98) 0.10 (0.10, 0.10) 0.10 (0.10, 0.14) 0.10 (0.10, 0.10) 0.10 (0.10, 0.33) Detectable Neutrophil elastase 10 (13.7%) 8 (47.1%) 5 (13.2%) 13 (25.0%) 5 (10.0%) 13 (32.5%) Respiratory symptoms 12 (16.0%) 5 (23.8%) 7 (17.5%) 10 (17.9%) 10 (19.6%) 5 (15.6%) Infection with organism at any 48 (64.0%) 16 (76.2%) 23 (57.5%) 41 (73.2%) 33 (64.7%) 31 (68.9%) density including MOF* 4 (13.8%) 0 (0.0%) 1 (5.3%) 3 (20.0%) 3 (16.7%) 1 (6.3%) Infection with organism 102 104 CFU/mL† 17 (22.7%) 10 (47.6%) 6 (15.0%) 21 (37.5%) 13 (25.5%) 14 (31.1%) Infection with organism >104 CFU/mLz Pseudomonas infection [n (% of those infected)] 2 (11.8%) 3 (30.0%) 1 (16.7%) 4 (19.1%) 2 (15.4%) 3 (21.4%) Data are reported as median (interquartile range) and number (percent). Numbers in bold indicate significant differences (P < .05) in inflammatory variables between present and absence of structural abnormalities. *Compared with ‘‘uninfected’’ defined as no detectable infection on BAL, MOF = mixed oral flora. †Compared with ‘‘uninfected’’ defined as no detectable infection on BAL, infection excludes MOF (note: n = 4 therefore Fisher’s exact test was used for comparison), children with infection >104 CFU/mL were excluded from this analysis. zCompared with ‘‘uninfected’’ defined as <104 CFU/mL detected on BAL, infection defined as >104 CFU/mL with organism excluding MOF.
of significant lung disease is unclear largely because of the relatively low prevalence of pathogens in this cohort. In this population only air-trapping was associated with detection of organisms other than P. aeruginosa. We acknowledge that our methods for detecting endobronchial infection might be relatively insensitive. Therefore we cannot conclude that bronchiectasis occurs in the absence of infection, nor can we assume that P. aeruginosa is the only or most significant pathogen associated with early lung damage. The presence of bronchiectasis was not associated with routine clinical outcomes commonly used to assess progress including growth, respiratory symptoms or pulmonary exacerbations. The relative insensitivity of symptoms as an indicator of lung disease in young children has been reported previously.12 We used an approach to assess CT abnormalities similar to that previously published.23-26 However, we chose not to compile a composite score in our analyses because none of the previously published algorithms used in this age-group have been adequately validated in young children with mild disease and because we do not know the relative clinical importance at this age of the individual abnormalities. Furthermore, our assessment for BWT indicated poor repeatability of this component of the assessment. We believe that bronchiectasis on a CT scan in this group of young children with CF is likely to represent clinically significant airway damage because there are strong associations with age, severity of airway inflammation (neutrophils and NE) and occurrence of other CT abnormalities. We did not observe some of the components of previously published scores such as bullae and cysts in our population and nodules were only apparent in children with extensive bronchiectasis. The association with age of CT abnormalities agrees with previously published observations.16 Because we have only evaluated scans with 3 discrete slices, we believe we are likely to
have underestimated the severity of lung disease and might not have detected all occurrences of bronchiectasis.27 Because scans were assessed by a single observer, we cannot rule out a systematic bias in the reporting of abnormalities. However, the presence of abnormalities in our population is similar to that in a selected population of young children reported previously.16 We are not proposing that a composite score using the methods we have used reasonably represents the severity of lung disease in an individual. However, given that techniques are emerging to better quantify CT abnormalities28 a score that includes elements that reflect bronchiectasis, air-trapping, and BWT could form the basis, in the future, of a score to be used for infants including those with very mild disease. Improvements in imaging technology and diagnostic algorithms are likely to provide more sensitive and quantitative information regarding structural lung changes,29-32 and periodic assessments will allow a better understanding of the changes that herald progressive lung damage. Probably the most important clinical implication of this study is that it emphasizes that current practice fails to prevent lung disease in infants and there is an urgent need to develop effective strategies from diagnosis after NBS to prevent the respiratory sequelae of CF. There have been few intervention studies in this population of children with CF because of the relatively poor understanding of disease progress in the months following diagnosis and treatment and the lack of appropriate outcome measures at this age. An additional value of our findings is the demonstration of CT scans as a clinically applicable outcome variable for randomized controlled trials. For example, on the basis of our data, a randomized, controlled study from diagnosis that has a 50% reduction in the prevalence of bronchiectasis at 4 years as a primary end-point would require 100 infants per group
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(power 85%; P = .05). Such studies are now feasible given the widespread adoption of NBS and the clinical trial networks that are developing in the United States, Europe, and Australasia. n
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15.
Submitted for publication Oct 29, 2008; last revision received Mar 19, 2009; accepted May 5, 2009.
16.
Reprint requests: Stephen Stick, Department of Respiratory Medicine, Princess Margaret Hospital for Children, Box D184, Perth 6010, Western Australia. E-mail: [email protected].
17.
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Appendix 1 Additional members of AREST CF include: Elizabeth Balding, Luke J. Berry, Dr. Claudia Calogero, Professor John B. Carlin, Rosemary Carzino, A/Professor Graham L Hall, Dr. Anthony Kicic, Dr. Ingrid A. Laing, Karla M. Logie, A/Professor John Massie, Dr. Lauren S. Mott, Dr. David Mullane, Gary Nolan, Dr. Naveen Pillarisetti, Dr. Srinivas R. Poreddy, Professor Roy Robins-Browne, Billy Skoric, Dr. Erika N Sutanto and Dr. Elizabeth Williamson.
Appendix 2 Anesthesia is induced with either propofol or sevoflurane according to the clinical judgement of the anesthetist. The child is then intubated with a cuffed tube, for CT scanning and a standardized recruitment maneuver that consists of 10 consecutive slow breaths up to total lung capacity (3740 cm H2O) over a positive end expiratory pressure of 5 cm H2O for 1-2 seconds per inspiration. For the inspiratory scans the airway opening pressure is held steady at 25 cm H2O. For bronchoscopy and BAL, the endotracheal tube is replaced by a disposable laryngeal mask airway to facilitate passage of the bronchoscope. Lignocaine is not given before the end of the bronchoscopy as it is bacteriostatic and interferes with the microbiology testing. During the procedure total intravenous anesthesia with propofol and remifentanil is maintained as follows: Propofol 12 mg/kg/h for first 10 minutes, then 9 mg/kg/h for an additional 10 minutes, then 6 mg/ kg/h; remifentanil dilution 20 mg/mL and ‘‘Kg body weight’’ in mL/h of remifentanil solution as starting dosage, adapted to clinical needs. If anesthesia needs to be deepened, the remifentanil is increased rather than the propofol.
Figure 3. The relationship between age and extent of bronchiectasis.
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Study design Children were diagnosed with CF after NBS. Computed tomography and bronchoalveolar lavage were performed with anesthesia (n = 96). Scans were analyzed for the presence and extent of abnormalities. Results The prevalence of bronchiectasis was 22% and increased with age (P = .001). Factors associated with bronchiectasis included absolute neutrophil count (P = .03), neutrophil elastase concentration (P = .001), and Pseudomonas aeruginosa infection (P = .03). Conclusions Pulmonary abnormalities are common in infants and young children with CF and relate to neutrophilic inflammation and infection with P. aeruginosa. Current models of care for infants with CF fail to prevent respiratory sequelae. Bronchiectasis is a clinically relevant endpoint that could be used for intervention trials that commence soon after CF is diagnosed after NBS. (J Pediatr 2009;155:623-8). See related article, p 629
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ewborn screening (NBS) for cystic fibrosis (CF) is widely established, with approximately 2 million newborns screened annually in the United States.1 In CF, bronchiectasis that results from chronic inflammation and infection is associated with increased morbidity rate2 and accelerated decline in pulmonary function.2,3 Because death is most commonly a result of suppurative lung disease, the development of bronchiectasis has important clinical implications. Computed tomography (CT) scans are sensitive to changes in the lung associated with bronchiectasis.4,5 Therefore the detection of bronchiectasis by CT could be a useful early marker of disease progression and a relevant endpoint in intervention studies. However, it is not known how commonly bronchiectasis occurs in the first years of life, and no matter how sensitive a test for bronchiectasis might be, if the condition is rare, the test would have limited utility. Therefore the aims of this study were to determine the prevalence of bronchiectasis in a young population of screened children with CF and to determine whether CT scanning evidence of bronchiectasis was associated with known pathophysiological risk factors (inflammation and infection). We used data collected as part of a unique early surveillance program (ESP) of newborns diagnosed with CF after NBS in Perth and Melbourne, Australia. The ESP includes annual bronchoalveolar lavage (BAL) and chest CT scans. We used cross-sectional analyses to examine the hypotheses that (1) bronchiectasis is common in the first years of life and (2) children in whom bronchiectasis develops have more severe airway inflammation.
Methods The study was conducted by the Australian Respiratory Early Surveillance Team for CF (AREST CF) at the Princess Margaret Hospital for Children, Perth and
From the Princess Margaret Hospital for Children (S.S., C.M., T.D., B.U.), TVW Institute for Child Health Research (S.S., S.B., T.D., L.G., C.G., N.D., P.S.), School of Paediatrics and Child Health, University of Western Australia (S.S.), Perth and Royal Children’s Hospital (B.L., S.R., P.R., C.R.), Melbourne, Australia
*Additional members of AREST CF are available at www. AREST CF BAL BWT CF CT ESP NBS
Australian Respiratory Early Surveillance Team for Cystic Fibrosis Bronchoalveolar lavage Bronchial wall thickening Cystic fibrosis Computed tomography Early surveillance program Newborn screening
jpeds.com (Appendix 1). This study is supported by Cystic Fibrosis Foundation (USA) (Project grant support), National Health and Medical Research Council (Australia) (Project grant support and Fellowships [S.M.S., P.D.S.]), and) Cystic Fibrosis (Australia) (Project grant support). The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright Ó 2009 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2009.05.005
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the Royal Children’s Hospital, Melbourne, and was approved by the Ethics Committees of both hospitals. Parents of children in the program provided written informed consent. Cross-sectional data presented here are from a clinic survey of children from Perth and Melbourne who underwent highresolution CT scanning during the period of August 2005 and March 2008 including all children to the age of 6 years (n = 125). Ninety-five percent of eligible children took part in the study. To be eligible for the analyses reported here, children had to be diagnosed after NBS6 and be referred to the participating center for multidisciplinary care. Perth is the only referral center in Western Australia. Children were referred to the Melbourne center from a geographically defined area of Victoria. Fourteen children were excluded from the primary analysis because they were diagnosed before the introduction of NBS in Perth during 2001, and an additional 15 children were excluded who presented with meconium ileus before their NBS results were known. Each child was included in the analysis once (n = 96) by use of data from their first available CT scan and BAL (Table I). High-resolution CT scanning was included in the ESP in Perth for all children from diagnosis up to 6 years from August 2005 and prospectively for newly diagnosed children with CF in Melbourne from April 2006. Hence, there are a greater number of children in the first 2 years of life than in older age groups. For newly diagnosed infants the first CT/BAL was performed when children reached approximately 4 kg. Protocols for staphylococcal prophylaxis, eradication of Pseudomonas aeruginosa, mucolytic use, nutrition, and enzyme replacement have been harmonized at each center and are consistent with the Standards of Care, Australia, guidelines.7 A validated questionnaire was used to assess symptoms of cough and wheeze and the presence or not of acute respiratory illness at the time of the BAL/CT.8 The CT scan and BAL were performed during the same anaesthetic according to a standardized total intravenous anesthetic protocol (Appendix 2; available at www.jpeds.com) with children intubated. Lung images were acquired with a 3slice protocol during inspiration at an airway pressure of 25 cm H20 and then 3 additional slices at end expiration (0 cm H20). The x-ray energy was 120 kV and the tube current 60 milliamperes per second (mAs). The gantry rotation time was 0.4 seconds per slice and collimation 0.63 mm. The tube current is the chief modifiable contributor to CT scan dose and has a linear relationship to the effective dose of a scan. The maximum effective radiation dose of each 3-slice scan was calculated as 0.14 to 0.2 millisievert (mSv), depending on body size, and 0.28 to 0.4 mSv for combined inspiratory and expiratory scans.9 Images were reported by an experienced pediatric thoracic radiologist (C.M.). Each lung was considered in 6 zones, (upper, mid, and lower; right and left) corresponding to each axial slice. The presence of bronchiectasis, air-trapping, inflammatory nodules and bronchial wall thickening (BWT) was recorded in a binary fashion for each abnormality for each zone (no = 0, yes = 1) and then weighted by multiplication according to the proportion of visible airways in each zone that were affected for bronchiectasis/BWT (<50% = 1, >50% = 2) and area of each zone affected (<50% = 1, >50% = 2) for 624
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Table I. Anthropometric and clinical information on subjects at the time of assessment Characteristic
Total population
Sex, M:F Age at diagnosis (days) [Median (IQR)] CFTR genotype DF508 homozygous DF508 heterozygous Other Age at CT scan (years) [Median (IQR)] Antistaphylococcal prophylaxis [n (%)] Microbiology [n (%)] Uninfected (<102 CFU/mL) Mixed oral flora only Isolated colonies only (102 104 CFU/mL)* Infected >104 CFU/mL Pseudomonas aeruginosa Staphylococcus aureus Haemophilus influenzae Stenotrophomonas maltophilia Streptococcus pneumoniae Aspergillus fumigatus Other infection† Respiratory symptoms [n (%)]z
55:41 30 (16.5, 37.0) 50 43 3 1.11 (0.30, 3.31) 43/72 (60%) 32 (33%) 33 (34%) 4 (4%) 27 (28%) 5 11 2 0 0 1 14 17 (17.7%)
*Candida sp. (n = 1), H. influenzae (n = 1), S. aureus (n = 2). †Candida sp. (n = 1), Escherichia coli (n = 4), Enterobacter sp. (n = 1), herpes simplex virus 1 (n = 1), Moraxella catarrhalis (n = 2), H. parainfluenzae (n = 2), respiratory syncytial virus (n = 2), Scedosporium sp. (n = 1). zSymptoms include presence of cough, upper/lower respiratory tract infection or wheeze or crackles on auscultation.
air-trapping, as an indication of the extent of each abnormality. Bronchiectasis, BWT and nodules were assessed on inspiratory scans. Bronchiectasis was defined as a bronchus– to–pulmonary artery diameter ratio of >1. Bronchial wall thickening was assessed subjectively. Inflammatory nodules were defined as clusters of small centrilobular nodules conforming to a ‘‘tree in bud’’ or rosette pattern or nonclustering ill-defined centrilobular nodules. Air trapping was defined as geographic foci of reduced density evident on expiratory images.10 Each zone from 20 scans was reassessed (120 individual zones), in random order, 6 to 12 months after the original assessment to determine repeatability of the clinical report. A non-radiologist member of the research team chose 20 individuals from the database with a range of abnormalities (Figure 1). The BAL was performed after the CT scan with a fiberoptic video-bronchoscope. (Olympus, Tokyo, Japan) as previously described.11,12 BAL samples were cultured on blood, CLED, Fildes agar, and Sarabouds agar with chloramphenicol. P. aeruginosa colonies were isolated from Horse Blood Agar and Ticarcillin agar plates incubated in a 5% CO2 atmosphere at 34 C for 48 to 72 hours. Colonies of P. aeruginosa were described as mucoid, smooth or rough by their appearance on horse blood agar. Fungi were identified by growth on wet mount and Sabarouds agar. Infection with a specific organism was considered as >104cfu/mL. Samples that cultured mixed oral flora (MOF) and colonies <104 CFU/mL were classified as uninfected. Immunofluorescence and viral cell culture were used to attempt identification of respiratory syncytial virus, parainfluenzae 1,2&3, influenzae A&B, and adenovirus. Stick et al
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Figure 1. Histogram to indicate the frequency distributions of abnormalities in the sample of 120 zones from 20 individuals selected for rescoring to determine repeatability of the computed tomography assessment.
BAL fluid was used for total and differential cell counts and free neutrophil elastase (NE) activity was measured with enzyme-linked immunosorbent assay.12 Primary comparisons were between children with and without bronchiectasis. Similar analyses were undertaken for children with air-trapping and BWT. Variables were checked for normality and log-transformed before analysis where required. Data are presented as median (25% to 75% interval) or as number (percent) as appropriate. Comparisons between binary variables were made by use of c2 tests. Multivariate ordinal logistic regression analyses were conducted to determine associations between extent of CT abnormalities and inflammation, respiratory symptoms, days hospitalized, sex and infection. Days in hospital were calculated for children $1 year as a percentage of days between annual BALs spent in hospital. CT report agreement was determined using a kappa co-efficient test for binary scores.13 Analyses were performed with either SigmaStat (Systat, Chicago, Illinois) or Stata (StatCorp, College Station, Texas).
Results The population characteristics are shown in Table I. Bronchiectasis and air trapping were commonly observed and easy to recognize in this population of children (Figure 2). Repeatability for reports of bronchiectasis, air trapping and BWT on CT scans were 82.5% (kappa = 0.64), 77.9% (kappa = 0.55) and 61.95% (kappa = 0.237) respectively. Nodules were very uncommon on the CT scans (identified in 7% of children assessed) and were only apparent in children with more severe bronchiectasis, therefore no further analysis of this component was undertaken. There were significant associations of bronchiectasis with air trapping (r = 0.37, P = .0002) and BWT (r = 0.34, P = .0006). Bronchiectasis was common and increased with age (P = .001). The incidence of bronchiectasis in the first year of life was 8.5%, and the prevalence reached 36% by 4 years
(Table II). The extent of bronchiectasis also increased with age (P = .001) (Figure 3; available at www.jpeds.com). Neither the presence, nor the extent of bronchiectasis was associated with poor growth determined by Z-score BMI. There was no relationship between bronchiectasis and days hospitalized for respiratory disease nor reported symptoms at the time of the BAL. Univariate analyses demonstrated relationships between the presence of bronchiectasis and log total cell count (OR 3.39 per one log unit increase in TCC 103 cell mL1; [CI: 1.15, 10.03], P = .027), log absolute number of neutrophils (OR 2.42 per one log unit increase in neutrophils 103cell mL1 [CI: 1.00, 5.81), P = .049), and NE activity (OR: 4.21 per 1 log unit increase in ngmL1 [CI: 1.79, 9.90], P = .001; Table III). There were no associations between the presence of air trapping and any markers of inflammation. The presence of bronchial wall thickening was associated with increased levels of NE activity (OR: 2.31 [CI:1.01, 5.30]), but no other inflammatory markers. The extent of bronchiectasis was associated with indicators of neutrophilic inflammation, with relationships seen between bronchiectasis and total cell count (r = 0.21, P = .04); absolute number of neutrophils (r = 0.25, P = .03), and NE activity (r = 0.43, P = .001). The extent of air trapping was associated with percent neutrophils (r = 0.41, P = .0002) and NE activity (r = 0.25, P = .016). Bronchial wall thickening was associated with NE activity (r = 0.31, P = .003), but no other markers of inflammation. Five children (5.2%) had P. aeruginosa detected in BAL. The presence of bronchiectasis was associated with infection with P. aeruginosa (P = .034). Bronchiectasis was not associated with infection with any other organism. There were no associations between the presence of air-trapping and P. aeruginosa infection. Air-trapping was associated with infection of >104 CFU/mL (P = .016) with organisms other than P. aeruginosa. The presence of bronchial wall thickening was not associated with infection with any organism.
Discussion Structural abnormalities of the lung in infants and young children with CF have been reported previously.14-17 We report the prevalence of CT-defined bronchiectasis in a population of infants and preschool children with CF, diagnosed after NBS. We also report associations between structural changes on CT with airway inflammation and infection with P. aeruginosa. Compared with bronchiectasis and airtrapping the assessment of bronchial-wall thickening had poor repeatability. The poor repeatability will obviously contribute to the population variability of this variable and reduce the likelihood of detecting associations with possible explanatory variables. We believe that the lack of repeatability is due to the very subjective nature of this assessment in our study compared with other studies.16,17 We observed an increase with age in the proportion of children with bronchiectasis. Twenty-two percent of our population, 8.5% of infants and 56% of the 4- to 6-year-olds, have
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Figure 2. Representative images of CT scans showing normal inspiratory, A and expiratory scan, B; bronchiectasis (indicated by white circles) with an extent of 1 in both the right and left lung C, and extent of 1 in the right lung and extent of 2 in the left lung, B; and air trapping with an extent of 1 in the right and not present in the left lung E, and an extent of 1 in the right lung and extent of 2 in the left lung, F. Images A, C, and D were obtained at full inspiration, and images B, E, and F were obtained at end-expiration.
evidence of bronchiectasis and bronchiectasis can be observed in children as young as 3 months. These observations are likely to be representative of outcomes achievable with modern CF management because data from the Australian National CF Registry and U.S. CF Registry indicate that outcomes for patients in Perth and Melbourne are similar to outcomes from the best centers in the world.18,19 We believe these data represent a good estimate of the prevalence of bronchiectasis because more than 95% of eligible children take part in the ESP. Furthermore, the population has a greater number of children at a younger age when CT abnormalities are less common. The associations with neutrophilic inflammation support our argument that the observed CT changes represent clinically relevant CF-related lung damage. The extent of neutrophilic inflammation (Table III) is similar to that observed previously11,20 in young children with CF. These associations were statistically very significant, although the strength of the relationships were only moderate. This is not surprising because
a number of predictable factors will have affected the strength of the associations. These include but are not limited to the sensitivity of the scanning method to identify abnormalities, particularly in smaller peripheral airways; factors that affect CT appearance at this age, such as reversible dilation of airways,21 the mild nature of the disease, and possible lag between onset of significant inflammation and destructive lung disease. We observed an association between the presence of P. aeruginosa in BAL and bronchiectasis. We have a low prevalence of P. aeruginosa in this cohort. Possibly our BAL technique is insensitive for detecting lower airway pathogens.15 However, the prevalence of P. aeruginosa infection was similar to that reported from Melbourne previously with a BAL technique that specifically included additional sampling for pathogens.22 We did not observe any relationships between organisms other than P. aeruginosa with bronchiectasis. Infection with P. aeruginosa was not associated with other CT abnormalities. Whether other organisms play a role in the development
Table II. Prevalence of CT abnormalities as a function of age Age
1st year of life
2nd year of life
3rd year of life
4th year of life
5th year of life
6th year of life
Number of patients by age group Bronchiectasis, n (%) Air trapping, n (%) Bronchial wall thickening, n (%)
47 4 (8.5%) 29 (61.7%) 17 (36.2%)
13 1 (7.7%) 6 (46.2%) 6 (46.2%)
7 2 (28.6%) 4 (57.1%) 5 (71.4%)
11 4 (36.4%) 7 (63.6%) 7 (63.6%)
11 7 (63.6%) 6 (54.5%) 5 (45.5%)
7 3 (42.9%) 4 (57.1%) 5 (71.4%)
Data indicate the number (percent) of children in each age group with the presence of structural abnormality identified by CT. An individual child may have more than one structural abnormality detected.
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Table III. Inflammatory variables from BAL fluid Bronchiectasis Absent
Present
Air trapping Absent
Bronchial wall thickening Present
Absent
Present
N 75 21 40 56 51 45 Total cell count (per mL 103) 225 (107, 400) 356 (220, 490) 300 (166, 448) 227 (120, 422) 263 (153, 487) 255 (118, 389) 30.98 (11.7, 101.2) 43.23 (21.8, 181.4) 43.48 (11.9, 116.4) 30.98 (16.9, 100.8) 32.40 (13.9, 106.3) 32.60 (11.9, 108.0) Neutrophils (per mL 103) Neutrophils (%) 13.99 (9.1, 26.1) 16.33 (10.7, 42.7) 13.33 (7.5, 23.5) 16.33 (10.5, 38.0) 13.50 (7.6, 24.1) 16.33 (10.3, 38.0) Neutrophil elastase (mg/mL) 0.10 (0.10, 0.10) 0.10 (0.10, 1.98) 0.10 (0.10, 0.10) 0.10 (0.10, 0.14) 0.10 (0.10, 0.10) 0.10 (0.10, 0.33) Detectable Neutrophil elastase 10 (13.7%) 8 (47.1%) 5 (13.2%) 13 (25.0%) 5 (10.0%) 13 (32.5%) Respiratory symptoms 12 (16.0%) 5 (23.8%) 7 (17.5%) 10 (17.9%) 10 (19.6%) 5 (15.6%) Infection with organism at any 48 (64.0%) 16 (76.2%) 23 (57.5%) 41 (73.2%) 33 (64.7%) 31 (68.9%) density including MOF* 4 (13.8%) 0 (0.0%) 1 (5.3%) 3 (20.0%) 3 (16.7%) 1 (6.3%) Infection with organism 102 104 CFU/mL† 17 (22.7%) 10 (47.6%) 6 (15.0%) 21 (37.5%) 13 (25.5%) 14 (31.1%) Infection with organism >104 CFU/mLz Pseudomonas infection [n (% of those infected)] 2 (11.8%) 3 (30.0%) 1 (16.7%) 4 (19.1%) 2 (15.4%) 3 (21.4%) Data are reported as median (interquartile range) and number (percent). Numbers in bold indicate significant differences (P < .05) in inflammatory variables between present and absence of structural abnormalities. *Compared with ‘‘uninfected’’ defined as no detectable infection on BAL, MOF = mixed oral flora. †Compared with ‘‘uninfected’’ defined as no detectable infection on BAL, infection excludes MOF (note: n = 4 therefore Fisher’s exact test was used for comparison), children with infection >104 CFU/mL were excluded from this analysis. zCompared with ‘‘uninfected’’ defined as <104 CFU/mL detected on BAL, infection defined as >104 CFU/mL with organism excluding MOF.
of significant lung disease is unclear largely because of the relatively low prevalence of pathogens in this cohort. In this population only air-trapping was associated with detection of organisms other than P. aeruginosa. We acknowledge that our methods for detecting endobronchial infection might be relatively insensitive. Therefore we cannot conclude that bronchiectasis occurs in the absence of infection, nor can we assume that P. aeruginosa is the only or most significant pathogen associated with early lung damage. The presence of bronchiectasis was not associated with routine clinical outcomes commonly used to assess progress including growth, respiratory symptoms or pulmonary exacerbations. The relative insensitivity of symptoms as an indicator of lung disease in young children has been reported previously.12 We used an approach to assess CT abnormalities similar to that previously published.23-26 However, we chose not to compile a composite score in our analyses because none of the previously published algorithms used in this age-group have been adequately validated in young children with mild disease and because we do not know the relative clinical importance at this age of the individual abnormalities. Furthermore, our assessment for BWT indicated poor repeatability of this component of the assessment. We believe that bronchiectasis on a CT scan in this group of young children with CF is likely to represent clinically significant airway damage because there are strong associations with age, severity of airway inflammation (neutrophils and NE) and occurrence of other CT abnormalities. We did not observe some of the components of previously published scores such as bullae and cysts in our population and nodules were only apparent in children with extensive bronchiectasis. The association with age of CT abnormalities agrees with previously published observations.16 Because we have only evaluated scans with 3 discrete slices, we believe we are likely to
have underestimated the severity of lung disease and might not have detected all occurrences of bronchiectasis.27 Because scans were assessed by a single observer, we cannot rule out a systematic bias in the reporting of abnormalities. However, the presence of abnormalities in our population is similar to that in a selected population of young children reported previously.16 We are not proposing that a composite score using the methods we have used reasonably represents the severity of lung disease in an individual. However, given that techniques are emerging to better quantify CT abnormalities28 a score that includes elements that reflect bronchiectasis, air-trapping, and BWT could form the basis, in the future, of a score to be used for infants including those with very mild disease. Improvements in imaging technology and diagnostic algorithms are likely to provide more sensitive and quantitative information regarding structural lung changes,29-32 and periodic assessments will allow a better understanding of the changes that herald progressive lung damage. Probably the most important clinical implication of this study is that it emphasizes that current practice fails to prevent lung disease in infants and there is an urgent need to develop effective strategies from diagnosis after NBS to prevent the respiratory sequelae of CF. There have been few intervention studies in this population of children with CF because of the relatively poor understanding of disease progress in the months following diagnosis and treatment and the lack of appropriate outcome measures at this age. An additional value of our findings is the demonstration of CT scans as a clinically applicable outcome variable for randomized controlled trials. For example, on the basis of our data, a randomized, controlled study from diagnosis that has a 50% reduction in the prevalence of bronchiectasis at 4 years as a primary end-point would require 100 infants per group
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(power 85%; P = .05). Such studies are now feasible given the widespread adoption of NBS and the clinical trial networks that are developing in the United States, Europe, and Australasia. n
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15.
Submitted for publication Oct 29, 2008; last revision received Mar 19, 2009; accepted May 5, 2009.
16.
Reprint requests: Stephen Stick, Department of Respiratory Medicine, Princess Margaret Hospital for Children, Box D184, Perth 6010, Western Australia. E-mail: [email protected].
17.
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ORIGINAL ARTICLES
November 2009
Appendix 1 Additional members of AREST CF include: Elizabeth Balding, Luke J. Berry, Dr. Claudia Calogero, Professor John B. Carlin, Rosemary Carzino, A/Professor Graham L Hall, Dr. Anthony Kicic, Dr. Ingrid A. Laing, Karla M. Logie, A/Professor John Massie, Dr. Lauren S. Mott, Dr. David Mullane, Gary Nolan, Dr. Naveen Pillarisetti, Dr. Srinivas R. Poreddy, Professor Roy Robins-Browne, Billy Skoric, Dr. Erika N Sutanto and Dr. Elizabeth Williamson.
Appendix 2 Anesthesia is induced with either propofol or sevoflurane according to the clinical judgement of the anesthetist. The child is then intubated with a cuffed tube, for CT scanning and a standardized recruitment maneuver that consists of 10 consecutive slow breaths up to total lung capacity (3740 cm H2O) over a positive end expiratory pressure of 5 cm H2O for 1-2 seconds per inspiration. For the inspiratory scans the airway opening pressure is held steady at 25 cm H2O. For bronchoscopy and BAL, the endotracheal tube is replaced by a disposable laryngeal mask airway to facilitate passage of the bronchoscope. Lignocaine is not given before the end of the bronchoscopy as it is bacteriostatic and interferes with the microbiology testing. During the procedure total intravenous anesthesia with propofol and remifentanil is maintained as follows: Propofol 12 mg/kg/h for first 10 minutes, then 9 mg/kg/h for an additional 10 minutes, then 6 mg/ kg/h; remifentanil dilution 20 mg/mL and ‘‘Kg body weight’’ in mL/h of remifentanil solution as starting dosage, adapted to clinical needs. If anesthesia needs to be deepened, the remifentanil is increased rather than the propofol.
Figure 3. The relationship between age and extent of bronchiectasis.
Bronchiectasis in Infants and Preschool Children Diagnosed with Cystic Fibrosis after Newborn Screening
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