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 January
2009: VOLUME
1, NUMBER 5
Measurement
of Early Lung Disease in Children With Cystic Fibrosis
In
this Issue...
Significant
advancements in the field of infant and preschool lung
function testing, as well as computed tomography scanning
of the chest, are now providing investigators and clinicians
with an improved understanding of the early manifestations
of cystic fibrosis (CF) lung disease. Sensitive outcome
measures assessing early CF lung disease are critical,
as new therapeutic agents are being developed for the
youngest population. Certainly, the detection of early
disease may lead to more aggressive management at a younger
age, thereby improving long-term prognosis.
In this issue we focus on recent publications describing
imaging and physiologic measures that are currently available
to better demarcate early CF lung disease. |
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Program
Directors
Michael
P. Boyle, MD, FCCP
Associate Professor of Medicine
Director, Adult Cystic Fibrosis Program
The Johns Hopkins University
Baltimore, MD
Peter
J. Mogayzel, Jr., MD, PhD
Associate Professor of Pediatrics
Director, Cystic Fibrosis Center
The Johns Hopkins University
Baltimore, MD
Donna
W. Peeler, RN, BSN
Pediatric Clinical Coordinator
Cystic Fibrosis Center
The Johns Hopkins University
Baltimore, MD
Meghan
Ramsay, MS, CRNP
Adult Clinical Coordinator
Cystic Fibrosis Center
The Johns Hopkins University
Baltimore, MD |
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GUEST
AUTHORS OF THE MONTH |
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Commentary
& Reviews: |
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Stephanie
D. Davis, MD
Associate Professor of Pediatrics
Division of Pediatric Pulmonology
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina |
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Commentary
& Reviews: |
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Jessica
E. Pittman, MD
Fellow, Pediatric Pulmonology University of
North Carolina at Chapel Hill
Chapel Hill, North Carolina |
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Guest
Faculty Disclosures
Dr.
Davis has disclosed no relationships with
commercial supporters.
Dr.
Pittman has disclosed no relationships with
commercial supporters..
Unlabeled/Unapproved Uses
The authors have indicated that there will be references
to unlabeled or unapproved uses of drugs or products
in this presentation.
Program
Directors' Disclosures |
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At
the conclusion of this activity, participants should be
able to:
Newsletter:
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Describe
the evolution of early lung disease in children
with cystic fibrosis (CF) |
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Discuss the techniques currently available for assessing
lung function and disease in young children with
CF |
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Identify
the structural and physiologic changes in the lungs
of young children with CF |
Podcast:
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Discuss
the advantages and disadvantages of early physiologic
and structural measurements available in the infant
and preschooler with CF. |
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Delineate
the clinical and research utility of infant and
preschool pulmonary function testing in the CF population.
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Discuss the clinical implications of structural
abnormalities in the early CF lung. |
To
obtain ACPE credit the post-test
for both newsletter and podcast must be completed successfully. |
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COMPLETE
THE
POST-TEST
Step
1.
Click on the appropriate link below. This will take you
to the post-test.
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If you have participated in a Johns Hopkins on-line course,
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Step
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Complete the post-test and course evaluation.
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* (The post-test for the newsletter & podcast is combined
for a total of 1.5 credit hours.)
Respiratory
Therapists
Visit
this page to confirm that your state will accept the
CE Credits gained through this program or click on the
link below to go directly to the post-test.
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eCysticFibrosis
Review is happy to offer our accredited
PODCASTS for 2009. Listen
here. |
The
eCysticFibrosis Review podcast is
a clinical discussion between our January
authors, Stephanie D. Davis, MD, Jessica Pittman,
MD and Robert Busker, eCysticFibrosis
Review's Medical Editor. The topic is
Measurement of Early Lung Disease in Children
With Cystic Fibrosis.
Participants can now receive 0.5 credits per
podcast after completing an online post-test
via the links provided on this page.
To learn more about podcasting and how to
access this exciting new feature of eCysticFibrosis
Review, please
visit this page.. |
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Podcasts
Please remember that you
don't need this
to listen to our podcasts.
You can listen directly
from your computer. |
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Identifying and tracking early cystic fibrosis (CF) lung
disease has historically been difficult because of the
lack of sensitive techniques that are easy to perform
in a young child. Over the past 10 years, much progress
has been made in this area, with CF clinicians now beginning
to realize that airway disease begins early, often prior
to the manifestation of clinical symptoms.1
Focal, distal mucus plugging causes dilatation of the
peripheral airways, as denoted by physiologic markers
of hyperinflation and airway trapping. The CF clinician
is often unable to detect these subtle changes because
of the inability to auscultate airway abnormalities with
his or her stethoscope, as well as a negative respiratory
history reported by the parents.
In the older child, forced expiratory volume in 1 second
(FEV1
), measured via spirometry, is used to track the progression
of lung disease. In the preschooler, spirometry may be
difficult to perform, since this technique requires active
cooperation (this measure is clearly impossible to perform
during infancy). Recent progress has led to use of a sedated
lung function technique called raised volume rapid thoracoabdominal
compression (RVRTC) in infancy to simulate adult-type
measures. During the performance of this technique, the
infant is sedated and forced expiratory maneuvers are
initiated from an inflated lung volume. The lung parameters
measured are similar to those used in classic spirometry,
except that forced expiratory volume in 0.5 seconds (FEV0.5)
is assessed rather than FEV1
, since infants often cannot exhale for 1 full second.
Published results using FEV0.5
have demonstrated diminished lung function values in the
CF population compared with healthy controls. Using pediatric-friendly
procedures, spirometry in preschoolers has demonstrated
effectiveness. In addition, simpler techniques have been
developed to assist in the use of physiologic measures
in the 3-to-5-year-old age-group. Standardization of the
RVRTC technique and preschool lung function measurements
have been published through a joint effort of the American
Thoracic Society and the European Respiratory Society
Working Group on Infant and Young Children Pulmonary Function
Testing,2,3
thereby encouraging multicenter collaboration and dissemination
of the procedures. The measurement of lung function during
infancy and preschool years using these standardized techniques
is addressed in articles by Kozlowska and colleagues,
and Linnane and associates, reviewed in this issue.
In children with CF, the evaluation of structural damage
through computed tomography (CT) scans of the chest has
evolved over the past decade. Historically, chest radiographs
have been used to assess progression of lung disease in
the CF population; however, compared with conventional
radiography, high-resolution computed tomography (HRCT)
of the chest provides more detailed information on the
regional distribution and severity of parenchymal and
airway changes within the lung. In addition, a dichotomy
between evidence of lung disease as presented on CT scans
and physiologic markers of abnormality has been noted.
Challenges in the young child include the need for sedation
or anesthesia to perform the scan, as well as a respiratory
motion artifact that often occurs. This artifact may lead
to difficulty in interpreting subtle abnormalities of
the airway and lung parenchyma noted in young children
with CF. A controlled breathing technique developed by
Long and coworkers4
allows the infant's ventilation to be controlled non-invasively,
thereby minimizing motion artifact and improving the quality
of interpretation of chest CT findings. Certainly, a limitation
associated with the use of CT scans is exposure to radiation,
and dosing should be thoroughly reviewed with a pediatric
radiologist. The articles by de Jong and colleagues, and
Davis and associates, highlight the presence of early
disease, even bronchiectasis, during infancy, and the
dichotomy between structure and function.
Simple, yet sensitive techniques for the detection of
early CF lung disease are ideal. The multiple-breath washout
(MBW) technique uses inhalation of an inert gas (ie, sulfur
hexafluoride; SF6
) to measure ventilation inhomogeneity. Subjects inhale
a gas mixture containing an inert gas until the inhaled
and exhaled concentrations of the gas are equal (washin
phase). They then breathe room air until the exhaled concentration
of the inert gas is below a certain threshold, typically
0.1% (washout phase). The lung function parameter, lung
clearance index (LCI), is calculated as the cumulative
expired volume in the washout phase divided by the functional
residual capacity. A higher LCI implies increased ventilation
inhomogeneity. MBW is currently being standardized for
infants; the measure has great potential since it may
be an early indicator of peripheral airway disease and
may be used from infancy onward. The article by Aurora
and coworkers outlines the sensitivity of MBW vs spirometry
for the detection of early CF lung disease.
In conclusion, recent progress has shown that lung disease
in children with CF begins early; however, the clinical
manifestations are often silent. The physiologic and structural
measures of disease described in this issue may serve
as useful outcome measures for future clinical trials.
Our current knowledge regarding early CF lung disease
may lead to a more aggressive treatment approach in the
youngest CF population.
Commentary References
| 1. |
Davis
SD, Brody AS, Emond MJ, Brumback LC, Rosenfeld M.Endpoints
for clinical trials in young children with cystic
fibrosis. Proc Am Thorac Soc. 2007;4(4):418-430.
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| 2. |
Beydon N, Davis SD, Lombardi E, et al; on behalf
of the American Thoracic Society/European Respiratory
Society Working Group on Infant and Young Children
Pulmonary Function Testing.
An official American Thoracic Society/European Respiratory
Society statement: pulmonary function testing in
preschool children. Am J Respir Crit Care
Med. 2007;175(12):1305-1345. |
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| 3. |
American
Thoracic Society(ATS)/European Respiratory Society(ERS).
ATS/ERS statement: raised volume forced expirations
in infants: guidelines for current practice.
Am J Respir Crit Care Med. 2005;172(11):1463-1471. |
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| 4. |
Long
FR, Castile RG, Brody AS, et al. Lungs
in infants and young children: improved thin-section
CT with a noninvasive controlled-ventilation technique-initial
experience. Radiology. 1999;212(2):588-593. |
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LUNG
FUNCTION ABNORMALITIES FROM INFANCY THROUGH PRESCHOOL
YEARS IN CHILDREN WITH CYSTIC FIBROSIS |
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Kozlowska
WJ, Bush A, Wade A, et al; London Cystic Fibrosis
Collaboration. Lung function from
infancy to the preschool years after clinical
diagnosis of cystic fibrosis. Am
J Respir Crit Care Med. 2008;178(1):42-49.
(For non-journal subscribers, an additional
fee may apply for full text articles.)
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Kozlowska
and colleagues designed a prospective, longitudinal,
case-control study to determine progression of lung
disease in children with cystic fibrosis (CF) compared
with healthy controls. Infant lung function testing,
using the raised volume technique before 2 years
of age and incentive spirometry between 3 and 5
years of age, were performed, with a median of 3
lung function measurements per subject during the
study period. Spirometric measures obtained included
forced vital capacity (FVC), forced expiratory volume
in 1 second (FEV1)
in preschoolers, forced expiratory flow between
25% and 75% of FVC (FEF25-75),
forced expiratory volume in 0.5 seconds (FEV0.5),
and forced expiratory volume in 0.75 seconds (FEV0.75).
The latter 2 techniques are commonly used for infant
and preschool lung function testing because of the
shorter duration of exhalation required. Logistic
regression was used to investigate the association
between spirometric measures and clinical data,
including height, weight, body mass index (by z-score),
genotype, mode of presentation, wheeze on auscultation,
recent cough, intravenous (IV) antibiotic use, and
infection with Pseudomonas aeruginosa.
The study population included 48 children with CF
and 33 healthy controls. Of the 48 subjects with
CF, 22 (46%) had received at least 1 course of IV
antibiotics (median, 1; range, 1 to 9) for respiratory
exacerbation before 6 years of age. Six children
presented for lung function testing with wheeze
on auscultation but were otherwise asymptomatic;
6 had crackles on auscultation. A total of 37 children
with CF were reported to have cough in the week
prior to testing. By the completion of the study,
67% (32 of 48) of the children with CF had grown
P. aeruginosa by deep pharyngeal culture at
a median age of first growth of 1.4 years; 3 children
grew mucoid P. aeruginosa strains. Of
the 48 children with CF who were evaluated, 20 (42%)
grew Staphylococcus aureus and 19 (39%)
grew Haemophilus influenzae.
Within the multivariable linear regression model,
height was the strongest predictor of all lung function
measures. After adjustment for height, subjects
with CF had mean reductions in FEV0.75
and FEF25-75
of 7.5% (95% confidence interval [CI], 0.9, to 13.6)
and 15.1% (95% CI, 3.6 to 25.3), respectively, compared
with healthy controls, both of which were statistically
significant (p<0.05). Reductions in FVC (2.6%),
FEV0.5
(4.3%), and FEV1 (7.1%) did not reach statistical
significance in the overall population, although
FEV0.5
was a strong predictor of disease among infants.
Positive P. aeruginosa culture prior to
first lung function testing was associated with
a further reduction in all lung function parameters
except FEF25-75;
the presence of P. aeruginosa resulted
in an additional mean reduction in FVC of 10.1%
(95% CI, 4.0 to 15.9) and in FEV0.75
of 9.0% (95% CI, 2.7 to 14.8) compared with healthy
controls. The difference in lung function between
P. aeruginosa -positive subjects and those
who were P. aeruginosa -negative persisted
regardless of culture clearance prior to testing.
Wheeze on auscultation and cough in the week prior
to testing were each independently associated with
a reduction in FEV0.5
and FEF25-75.
This is the first prospective, longitudinal study
using forced expiratory maneuvers to document the
progression of lung disease in patients with CF
vs healthy controls from infancy through the preschool
years. CF was associated with a significant reduction
in FEV0.75
and FEF25-75
in the first 6 years of life, with larger reductions
associated with a history of infection with P.
aeruginosa, wheezing on auscultation, and cough
in the week prior to testing. The authors suggest
that because children with P. aeruginosa
had similar lung function to those without P.
aeruginosa prior to their first infection,
this decline in lung function is a direct result
of the infection itself. However, because subjects
in this study were diagnosed by clinical symptoms,
it is possible that significant lung damage had
occurred prior to the study investigations. The
fact that lung function was diminished regardless
of current P. aeruginosa culture status
is also of concern. These 2 observations leave open
the possibility that P. aeruginosa is serving
as a marker of more severe lung disease. Although
FEV0.5
was strongly correlated with the presence of lung
disease in infancy, it was a poor predictor of disease
in the preschool population. This may be related
to differences in airway anatomy as children age,
with FEV0.5
representing central and peripheral airways in infants,
but more predominantly central airways in older
children. Evidence of decline in lung function in
early childhood despite protocolized care of patients
with CF, including aggressive management of infections,
suggests that new therapies or more aggressive use
of currently available treatments may be necessary
to prevent early morbidity from CF lung disease.
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PULMONARY
FUNCTION TESTING IN INFANTS WITH CYSTIC FIBROSIS DIAGNOSED
BY NEWBORN SCREENING |
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Linnane
BM, Hall GL, Nolan G, et al; AREST-CF. Lung
function in infants with cystic fibrosis diagnosed
by newborn screening. Am J Respir
Crit Care Med. 2008;178(12):1238-1244.
(For non-journal subscribers, an additional
fee may apply for full text articles.) |
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Newborn screening for CF is now widely available in the
United States, the United Kingdom, and Australia, allowing
for the presymptomatic diagnosis of the disease. It has
been shown that early diagnosis of CF by newborn screening
improves nutritional status early in life; however, lung
function in presymptomatic children with CF has not been
evaluated. This study was designed to measure lung function
via use of the raised volume rapid thoracoabdominal compression
technique in infants with CF diagnosed by newborn screening.
Values obtained were compared with those in healthy controls,
and associations with pulmonary infection and inflammation
(determined by bronchoalveolar lavage [BAL] performed
within 24 to 48 hours after lung function testing) were
investigated.
A total of 68 infants with CF and 49 healthy controls
were studied using infant pulmonary function testing;
16 of the CF infants returned 1 year after their initial
study visit for repeat lung function testing. Of the infants
with CF, 96% had a diagnosis rendered or confirmed by
newborn screening (immunoreactive trypsinogen/DNA). Half
of the subjects with CF were homozygous for delta F508;
an additional 46% were heterozygotes. The majority of
infants (63%) were receiving prophylactic antibiotics
at the time of evaluation. Height was similar between
the CF infants and healthy controls; however, individuals
in the CF group had lower mean body weight and body mass
index z-scores.
After adjusting for gender, maternal smoking, and height,
infants with CF had lower FEV0.5
(-31.2 mL; 95% CI, -50.6 to -11.8) and forced expiratory
flow at 75% of exhaled vital capacity (FEF75; -58 mL/s;
95% CI, -96.2 to -19.8) values than did healthy controls,
corresponding to a 17.4% and 39.7% reduction in forced
expiratory measures, respectively (differences in FVC
were not statistically significant). The authors used
data from healthy controls to create a predictive model
for FEV0.5 based on infant height, then generated FEV0.5
z-scores for all infants in the study. The FEV0.5,
z -score in infants with CF decreased by 0.77
per year of age (95% CI, 0.41 to 1.14). Post hoc analysis
revealed no difference in FEV0.5
z-score between healthy controls and subjects
with CF <6 months of age, whereas infants with CF >6
months of age had a mean z -score of -1.13, vs
0.02 in healthy controls (95% CI, -1.57 to -0.72). Similar
differences between infants with CF and healthy controls
were reportedly shown for FVC and FEF75, although the
data are not included in the article. Whereas the majority
of the data were cross-sectional, there was a decline
in FEF0.5
z -score of -0.73 (95% CI, -1.51 to 0.06), in
FVC of -1.35 (95% CI, -2.52 to -0.17), and in FEF75
of -1.3 (95% CI, -2.27 to -0.33) in the 16 infants with
CF who returned for lung function testing 1 year after
their initial evaluation.
BAL fluid cultures grew S. aureus (17.8%), H.
influenzae (8.9%), and P. aeruginosa (6.7%),
as well as other pathogens (19.9%). Neither culture results
nor inflammatory markers (total cell count, neutrophil
percentage, free neutrophil elastase, or interleukin-8
[IL-8]) explained changes in lung function. Clinical symptoms,
hospital admissions, and genotype also failed to show
a significant association with diminished lung function.
This is the first study of lung function in infants with
CF diagnosed by newborn screening. Despite optimized nutrition
and early care, infants with CF appear to have significantly
diminished lung function compared with healthy controls,
which did not correlate with infection or inflammation
as detected by BAL. Differences between CF infants and
controls were first detectable after 6 months of age.
Although the authors acknowledge that the predominantly
cross-sectional nature of this study is a significant
limitation, it is important to note that the decline in
FEF0.5,
per year of age shown in the CF group as a whole (compared
with healthy controls) was similar to that reported in
the subgroup of CF infants in whom lung function testing
was repeated 1 year later (0.77 vs 0.73, respectively).
This study suggests that decline in lung function in children
with CF may begin at a very early age, and there may be
a "therapeutic window" in which lung function is relatively
normal and thus interventions may have a maximum effect.
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PROGRESSION
OF STRUCTURAL AIRWAY DAMAGE ON COMPUTED TOMOGRAPHY IN
CHILDREN WITH CYSTIC FIBROSIS |
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de
Jong PA, Nakano Y, Hop WC, et al. Changes
in airway dimensions on computed tomography scans
of children with cystic fibrosis. Am
J Respir Crit Care Med. 2005;172(2):218-224.
(For non-journal subscribers, an additional
fee may apply for full text articles.) |
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It is believed that the airways of newborns with CF are
structurally normal and that abnormalities develop progressively,
beginning early in life. Computed tomography (CT) scanning
may be more sensitive than pulmonary function testing
(PFT) for the detection of airway abnormalities in children
and adults with mild CF lung disease, and several published
CT scoring systems are currently available. The composite
CT score has the disadvantage of providing an overall
value based on multiple structural findings; thus, following
progression of composite CT scoring may mask particular
patterns of structural change in the lungs of patients
with CF. The authors measured airway wall thickening and
bronchial dilatation in a cohort of CF subjects using
2 scans performed 2 years apart. Comparisons were made
with CT scans from control subjects with normal lungs,
and first and second scans from patients with CF were
compared to assess the progression of structural airway
disease. Among individuals with CF, measures of structural
disease were also compared with changes in PFT parameters
over time.
A total of 23 clinically stable children with CF were
studied, with a mean age at first CT scan of 11.1 years
(range, 4.0 to 15.9 years) and at second CT scan of 12.9
years (range, 6.2 to 17.9 years). Patients with CF were
compared with control subjects (n = 21) without lung disease,
who had a mean age at CT scan of 11.6 years (range, 3.6
to 17.2 years). Airway-artery pairs were identified, and
measurements included airway wall area (WA), airway lumen
area (LA), arterial area (AA), and airway wall thickness
(AWT). AWT and the ratio of WA/AA were considered markers
of airway wall thickening; LA/AA ratio was used to define
bronchial dilatation. PFT data were available on 21 of
the 23 subjects with CF; FEF25-75
data were assessed in 16 subjects. Mean FEV1 at the time
of initial CT was 71% predicted (±16), FVC was 83% predicted
(±16), and FEF25-75
was 54% predicted (±29).
The LA/AA ratio was 1.92 times higher in children with
CF compared with healthy controls. Moreover, the WA/AA
ratio was 1.45 times higher in children with CF compared
with healthy controls. AWT changed significantly between
the first and second CT scans (p=0.02), increasing by
a mean of 0.03 mm in 2 years (no other airway measurements
demonstrated a significant change over time). Four CT
scoring systems (Brody, Helbich, Santamaria, and Bhalla
2-5)
all showed significant progression of airway damage over
time, with a mean change over 2 years of 3% to 4% of the
maximum score (P<.02). Within the composite CT
scores, only the bronchiectasis score worsened significantly
(P=.007). There was no significant change in
PFT parameters over the 2 years between the first and
second CT scans, except for an improvement in residual
volume/total lung capacity of -12% (P=.03). AWT
was the only measure that showed a significant (P=.002)
correlation with PFT data; for each 0.01-mm increase in
AWT, FEF25-75
decreased by 0.45% predicted. LA/AA and WA/AA ratios did
not correlate with global CT scoring, nor did they correlate
with PFT.
This study shows a striking difference in bronchial dilatation
and AWT (as measured by airway LA, and LA/AA and WA/AA
ratios) on CT scans in children with CF compared with
control subjects. Because airways with mucus plugging
(potentially more damaged airways) were excluded from
measurements and there was more mucus plugging on the
second CT scan than on the first (20.5% of airway-artery
pairs excluded vs 7.9%, respectively), changes in LA/AA
and WA/AA ratios may be underestimated. Although these
ratios did not appear to change over the 2-year time span,
AWT and composite CT scores (driven predominantly by change
in the bronchiectasis component) increased significantly.
The lack of correlation between changes in bronchiectasis
scoring and LA/AA ratio may have occurred because the
bronchiectasis scores also reflect peripheral airways
that were not included in LA/AA calculations (because
of lack of visible arteries). Therefore, peripheral airway
damage could be driving changes in the progression of
bronchiectasis. The change in AWT was negatively correlated
with FEF25-75
, suggesting that quantitative measures of AWT may be
useful in assessing structural lung disease in patients
with CF as an adjunct to the qualitative measures used
as part of component scoring systems. This correlation
may be associated with the impact of increased AWT on
airflow, or AWT may serve as a marker for additional pathology,
including small airway destruction. In this study, CT
scans were more sensitive than PFT at tracking progression
of lung disease, suggesting that CT scans may serve as
useful outcome measures in future studies of children
with CF.
References
| 1. |
Bhalla M, Turcios N, Aponte V, Jenkins M, Leitman BS, McCauley DI, Naidich DP. Cystic fibrosis: scoring system with thin-section CT. Radiology 1991;179:783–788.
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| 2. |
Brody AS, Molina PL, Klein JS, Rothman BS, Ramagopal M, Swartz DR.
High-resolution computed tomography of the chest in children with cystic fibrosis: support for use as an outcome surrogate. Pediatr Radiol 1999;29:731–735. |
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| 3. |
Helbich TH, Heinz-Peer G, Fleischmann D, Wojnarowski C, Wunderbaldinger P, Huber S, Eichler I, Herold CJ.
Evolution of CT findings in patients with cystic fibrosis.
AJR Am J Roentgenol 1999;173:81–88. |
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| 4. |
Santamaria F, Grillo G, Guidi G, Rotondo A, Raia V, de Ritis G, Sarnelli P, Caterino M, Greco L. Cystic fibrosis: when should high-resolution computed tomography the chest be obtained? Pediatrics 1998;101: 908–913. |
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COMPUTED
TOMOGRAPHY AND BRONCHOALVEOLAR LAVAGE FINDINGS IN EARLY
CYSTIC FIBROSIS LUNG DISEASE |
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Davis,
SD, Fordham LA, Brody AS, et al. Computed
tomography reflects lower airway inflammation and
tracks changes in early cystic fibrosis.
Am J Respir Crit Care Med. 2007;175(9):943-950.
(For non-journal subscribers, an additional
fee may apply for full text articles.) |
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Brody
AS, Molina PL, Klein JS, Rothman BS, Ramagopal M,
Swartz DR. High-resolution computed tomography
of the chest in children with cystic fibrosis: support
for use as an outcome surrogate.
Pediatr Radiol 1999;29:731–735.
(For non-journal subscribers, an additional
fee may apply for full text articles.) |
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Davis and colleagues conducted a prospective study evaluating
the sensitivity of high- resolution CT (HRCT) of the chest
as an outcome measure in young children with CF. This
study was designed to (1) identify regional distribution
of CF lung disease during a pulmonary exacerbation in
children <4 years of age; (2) correlate BAL cultures and
inflammatory markers with areas of "greatest" and "least"
disease on HRCT; and (3) determine the sensitivity of
HRCT in detecting changes in airway disease following
IV antibiotic therapy and intensified airway clearance.
A total of 17 children with CF aged 2 to 44 months scheduled
to undergo clinically indicated bronchoscopy for pulmonary
exacerbation were enrolled in the study. Each subject
received chest x-ray (CXR) 1 to 2 days prior to bronchoscopy.
On the day of bronchoscopy, a sedated, controlled-ventilation
HRCT was performed, and lobes with the “greatest”
and the “least” disease were identified qualitatively.
These 2 lobes were then independently sampled by BAL,
and the samples were sent for bacterial culture, cell
count and differential, and IL-8 levels. Of the 17 individuals
evaluated, 15 received IV antibiotics and intensified
airway clearance (based on clinical assessment); 13 of
them returned within 1 week of completion of intensified
therapy for a second HRCT and CXR. Modified Brody HRCT
scores (comprising bronchiectasis/bronchial dilatation,
mucus plugging, peribronchial thickening, parenchymal
lung disease, and hyperinflation subscores) were compared
pre- and posttherapy, and regional changes were assessed.
Brasfield CXR scores were also compared pre- and posttreatment.
The right lung consistently had a higher disease burden
than did the left; the lobe identified as having the greatest
disease on qualitative and quantitative (Brody scoring)
evaluation was on the right in 100% and 82% of subjects,
respectively. Similarly, the lobe with the least disease
was on the left in 94% of subjects by qualitative evaluation
and in 76% by quantitative evaluation (p<0.01). Total
Brody score (all lobes) was significantly higher on the
right than on the left. The total HRCT score improved
significantly between visits 1 and 2 (pre- and posttreatment)
(p<0.01), with significant improvements in subscores
for hyperinflation and bronchiectasis/bronchial dilatation(p<0.01
for both). The mean score for the lobe with the greatest
disease showed significant improvement pre- and posttreatment
(p=0.002), whereas the score for the lobe with the least
disease did not change significantly. Brasfield scoring
of plain CXRs was ≥20 (maximum score, 25) in all but
2 subjects and showed a trend toward improvement only
between visits (P=.06). On BAL evaluation, IL-8
levels and neutrophil percentage were significantly higher
in the lobe with the greatest vs the least disease (p<0.01
and p=0.04, respectively). Bacterial count and total cell
count tended to be higher in the lobe with the greatest
disease, but differences did not reach statistical significance.
BAL cultures grew S. aureus (65%), P. aeruginosa
(41%), H. influenzae (18%), and Moraxella
catarrhalis (18%). Two subjects (1 with P. aeruginosa
and S. aureus, 1 with S. aureus alone)
grew organisms from the lobe identified as having the
greatest disease but no organisms from the lobe with the
least disease.
This is the first study to compare BAL findings and HRCT
in the preschool age-group, and the first to compare HRCT
findings pre- and posttherapy for pulmonary exacerbation
in this population. Results demonstrate significant regional
variation in airway inflammation, as evidenced by neutrophil
percentages and IL-8 levels. Improvement in HRCT scoring
following IV antibiotic therapy and intensified airway
clearance suggests that HRCT is a sensitive outcome measure
in this young population with relatively mild lung disease.
Evidence of increased disease burden in the right lung
may be secondary to gastroesophageal reflux disease with
aspiration or to diminished clearance of secretions from
the right lung compared with the left. Regional differences
noted on both HRCT and BAL evaluation underscore the importance
of performing multisite lavage in this population. Reversibility
of HRCT findings, particularly hyperinflation, bronchiectasis,
and bronchial dilatation in the lobe with the greatest
disease, suggests that permanent lung disease in the preschool
population may be prevented or delayed, and highlights
the necessity of aggressive therapy for pulmonary exacerbations.
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USE
OF MULTIPLE-BREATH WASHOUT IN PRESCHOOL CHILDREN WITH
CYSTIC FIBROSIS |
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Aurora
P, Bush A, Gustafsson P; London Cystic Fibrosis
Collaboration. Multiple-breath washout as
a marker of lung disease in preschool children with
cystic fibrosis. Am J Respir Crit
Care Med. 2005;171(3):249-256.
(For non-journal subscribers, an additional
fee may apply for full text articles.) |
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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.
(For non-journal subscribers, an additional
fee may apply for full text articles.) |
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Identifying
early CF lung disease has fueled interest in PFT methods
that may be performed from infancy onward. Several techniques
have been developed for the preschool age-group—preschool
spirometry, plethysmography for the measurement of specific
airway resistance, specific airway resistance (sRaw),
and multiple-breath washout (MBW) measuring lung clearance
index (LCI). Higher LCI and sRaw values are suggestive
of airway disease, whereas lower FEV0.5
and FEF25-75
values indicate obstructive airway disease. The study
by Aurora and coworkers was designed to investigate the
feasibility and sensitivity of each of these measures
in a cohort of children with CF, aged 2 to 5 years, vs
age-matched, healthy control subjects.
A total of 40 children with CF and 37 healthy controls
were recruited for this study, with a mean age of 4.1
years (standard deviation [SD] 0.9) and 4.2 (SD 0.9) years,
respectively. Of these children, 30 in each group were
able to complete all 3 maneuvers (preschool spirometry,
plethysmography, and MBW). The z-scores for FEV0.5,
FEF25-75,
FRC, and sRaw were calculated using reported data from
the healthy control population. The authors also used
healthy control subjects to generate a mean LCI for the
healthy population, with an LCI >1.96 SD above the mean
then classified as abnormal. There was no relationship
between LCI and age in either the control or the CF population.
Children with CF had significantly higher mean LCI (9.61
vs. 6.89, respectively; P<.001) and sRaw (z-score
1.83 vs 0.00; P<.001) values, and significantly lower
FEV0.5
(z-score -0.76 vs 0.00; P< .05) values than
did control subjects. Abnormal LCI values were observed
in 73% (22 of 30) of children with CF; sRaw was abnormal
in 47% (14 of 30), FEV0.5
in 7% (2 of 30), and FEF25-75
in 13% (4 of 30) of children with CF. One child with an
abnormal sRaw had a normal LCI; all other children with
an abnormal sRaw, FEV0.5,
or FEF25-75
had abnormal LCI values as well. LCI was higher in CF
subjects infected with P. aeruginosa than in
uninfected individuals (10.77 vs 8.83, respectively);
however, a comparison of only uninfected CF subjects vs
healthy controls continued to show significant differences
in all measured lung function parameters. There was no
difference in other lung function parameters between P.
aeruginosa -positive and P. aeruginosa -negative
cohorts.
This is the first study to compare spirometry, measures
of airway resistance, and LCI in a large cohort of preschool
patients with CF. The authors demonstrated that MBW could
be successfully performed by skilled operators in a majority
of preschoolers. Results suggest that LCI measured by
MBW may be more sensitive than plethysmography or spirometry
for detection of CF lung disease, and is further affected
by the presence of P. aeruginosa infection. The
clinical relevance of these findings has yet to be determined;
however, recent reports in older children have shown LCI
to be more sensitive than spirometry for structural changes
on CT,2
suggesting that elevated LCI values may be a marker of
early lung disease in children with CF. Because MBW is
now being performed in infants, this measurement may serve
as a single airway function assessment that can be followed
throughout a person's life. |
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| Accreditation
Statement — back
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This activity has been planned and implemented in
accordance with the Essential Areas and Policies
of the Accreditation Council for Continuing Medical
Education through the joint sponsorship of The Johns
Hopkins University School of Medicine, the Institute
for Johns Hopkins Nursing and the Postgraduate Institute
for Medicine. The Johns Hopkins University School
of Medicine is accredited by the ACCME to provide
continuing medical education for physicians.
The Institute for Johns Hopkins Nursing is accredited
as a provider of continuing nursing education by
the American Nurses Credentialing Center's Commission
on Accreditation.
 Postgraduate
Institute for Medicine is accredited by the Accreditation
Council for Pharmacy Education as a provider of
continuing pharmacy education. |
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Physicians
eNewsletter: The Johns Hopkins
University School of Medicine designates this educational
activity for a maximum of 1.0 AMA PRA Category
1 Credit(s)TM.
Physicians should only claim credit commensurate
with the extent of their participation in the activity.
Podcast: The Johns Hopkins University
School of Medicine designates this educational activity
for a maximum of 0.5 AMA PRA Category 1 Credit(s)TM.
Physicians should only claim credit commensurate
with the extent of their participation in the activity.
Nurses
eNewsletter: This 1 contact hour
Educational Activity is provided by The Institute
for Johns Hopkins Nursing. Each Newsletter carries
a maximum of 1 contact hours or a total of 6 contact
hours for the six newsletters in this program.
Podcast: These paired 0.5 contact
hour Educational Activities are provided by The
Institute for Johns Hopkins Nursing. Each podcast
carries a maximum of 0.5 contact hours or a total
of 1.5 contact hours for the three podcasts in this
program.
Dieticians
eNewsletter: The Johns Hopkins
University has approved this activity for 1.0 contact
hours for non-physicians.
Podcast: The Johns Hopkins University
has approved this activity for 0.5 contact hours
for non-physicians.
Physical
Therapists
eNewsletter: The Johns Hopkins
University has approved this activity for 1.0 contact
hours for non-physicians.
Podcast: The Johns Hopkins University
has approved this activity for 0.5 contact hours
for non-physicians.
Pharmacists
Postgraduate Institute for Medicine designates this
continuing education activity for 1.5 contact hour(s)
(0.15 CEUs) of the Accreditation Council for Pharmacy
Education. (Universal Program Number - 809-999-08-267-H01-P).
Respiratory
Therapists
For United States: Visit
this page to confirm that your state will accept
the CE credits gained through this program.
For Canada: Visit
this page to confirm that your province will
accept the CE credits gained through this program.
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| Post-Test
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| To
take the post-test for eCysticFibrosis Review you
will need to visit The
Johns Hopkins University School of Medicine's CME
website, The
Institute for Johns Hopkins Nursing and the
Postgraduate
Institute for Medicine . If you have already
registered for another Hopkins CME program at these
sites, simply enter the requested information when
prompted. Otherwise, complete the registration form
to begin the testing process. A passing grade of
70% or higher on the post-test/evaluation is required
to receive CE credit. |
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| The
Johns Hopkins University School of Medicine takes
responsibility for the content, quality, and scientific
integrity of this CME/CE activity. |
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| Intended
Audience — back
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| This
activity has been developed for Pulmonologists,
Pediatric Pulmonologists, Gastroenterologists, Pediatricians,
Infectious disease specialists, Respiratory Therapists,
Dieticians, Nutritionists, Pharmacists, Nurses,
and Physical therapists. |
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| Learning
Objectives — back
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At
the conclusion of this activity, participants should
be able to:
Newsletter:
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Describe
the evolution of early lung disease in children
with cystic fibrosis (CF) |
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Discuss
the techniques currently available for assessing
lung function and disease in young children
with CF |
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Identify
the structural and physiologic changes in
the lungs of young children with CF |
Podcast:
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Discuss
the advantages and disadvantages of early
physiologic and structural measurements available
in the infant and preschooler with CF. |
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Delineate
the clinical and research utility of infant
and preschool pulmonary function testing in
the CF population. |
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Discuss
the clinical implications of structural abnormalities
in the early CF lung. |
To
obtain ACPE credit the post-test
for both newsletter and podcast must be completed
successfully. |
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CME/CE Policy — back
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The
Office of Continuing Medical Education (CME) at
The Johns Hopkins University School of Medicine,
The Institute for Johns Hopkins Nursing and the
Postgraduate Institute for Medicine are committed
to protect the privacy of its members and customers.
The Johns Hopkins University SOM CME maintains its
Internet site as an information resource and service
for physicians, other health professionals and the
public.
Continuing Medical Education at The Johns Hopkins
University School of Medicine, The Institute for
Johns Hopkins Nursing and the Postgraduate Institute
for Medicine will keep your personal and credit
information confidential when you participate in
a CE Internet-based program. Your information will
never be given to anyone outside of The Johns Hopkins
University School of Medicine's CME program. CME
collects only the information necessary to provide
you with the services that you request. |
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Disclosure — back
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As
a provider accredited by The ACCME, it is the policy
of The Johns Hopkins University School of Medicine
to require the disclosure of the existence of any
significant financial interest or any other relationship
a faculty member or a provider has with the manufacturer(s)
of any commercial product(s) discussed in an educational
presentation. The Program Directors reported the
following:
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Michael
P. Boyle, MD, FCCP has disclosed
no relationship with commercial supporters.
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Peter
J. Mogayzel, Jr, MD, PhD has disclosed
no relationship with commercial supporters.
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Donna
W. Peeler, RN, BSN has disclosed
no relationship with commercial supporters.
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Meghan
Ramsay, MS, CRNP has disclosed no
relationship with commercial supporters. |
PIM Clinical Reviewers Jan Hixon, RN, Trace Hutchison,
PharmD, and Linda Graham, RN have no real or apparent
conflicts of interest to report.
Guest
Author Disclosures |
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| Disclaimer
Statement — back
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The opinions and recommendations expressed by faculty
and other experts whose input is included in this
program are their own. This enduring material is
produced for educational purposes only. Use of Johns
Hopkins University and the Postgraduate Institute
for Medicine name implies review of educational
format design and approach. Please review the complete
prescribing information of specific drugs or combination
of drugs, including indications, contraindications,
warnings and adverse effects before administering
pharmacologic therapy to patients. |
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©
2009 JHUSOM, IJHN, PIM and eCysticFibrosis Review
Created by
DKBmed. |
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To unsubscribe, please visit
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COMPLETE
THE
POST-TEST
Step
1.
Click on the appropriate link below. This will take you to the
post-test.
Step
2.
If you have participated in a Johns Hopkins on-line course,
login. Otherwise, please register.
Step
3.
Complete the post-test and course evaluation.
Step
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* (The post-test for the newsletter & podcast is combined
for a total of 1.5 credit hours.)
Respiratory
Therapists
Visit
this page to confirm that your state will accept the CE
Credits gained through this program or click on the link below
to go directly to the post-test.
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Illustration
© Michael Linkinhoker |
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