early lung disease in cystic fibrosis
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Early Lung Disease in Cystic Fibrosis
Sarath Ranganathan
Defective CF gene
Defective/deficient CFTR
Bronchial obstruction
Infection
Bronchiectasis
Inflammation
Abnormal airway surface milieu
UK cystic fibrosis population. Proportion of a) males and b) females of each 3-yr cohort surviving until 2003. : 1968–1970; : 1971–1973; : 1974–1976; : 1977–1979; : 1980–1982; : 1983–1985; : 1986–1988; •: 1989–1991; : 1992–1994.
Survival in UK CF CohortsDodge et al Eur Respir J 2007
100908070605040
400
300
200
100
0
Prior LRI
No prior LRI
Control
Length (cm))
FEV 0
.4(m
L)
FEVFEV0.40.4 vs length in healthy infants and infants with CF vs length in healthy infants and infants with CF with and without prior lower respiratory with and without prior lower respiratory illnessillness
Ranganathan et al Lancet 2001Ranganathan et al Lancet 2001
Median FEV1 has improved more than 10 percentage points at all ages from 6 to 30 since 1990.
4 0
60
80
100
6 8 10 12 14 16 18 2 0 2 2 2 4 2 6 2 8 30
Perc
ent P
redi
cted
Age (Years)
Median FEV1 Percent Predicted vs. Age, 1990 and 2009
1990 2009
The early surveillance program
Early Surveillance Program
Early Bronchiectasis detected by surveillance CT Pillarisetti et al Respirology 2010;6:1009‐11
How early does disease occur?
Prevalence of symptoms, infection, inflammation and structural changes at diagnosis
Sly et al Am J Respir Crit Care Med 2009;180:146‐142
Number studied 57
Age 3.6 months
Respiratory symptoms 9 (16%)
Bacterial infection 12 (20%)
Free neutrophil elastase 17 (30%)
Bronchial dilatation 11 (19%)
• Lung structure
• Pulmonary infection
• Pulmonary inflammation
• Lung function
Prevalence of BronchiectasisStick et al J Pediatr 2009;155:623-28
Stick et al J Pediatr 2009;155:623-28
Progression of structural changesMott et al. Thorax 2011
Subsequent scan
Initial scan
• Lung structure
• Pulmonary infection
• Pulmonary inflammation
• Lung function
Inflammation responses to individual organismsGangell et al Clin Infect Dis 2011;53:425‐432
Organism Number of BAL Significance
Aspergillus spp. 19 <0.001
Candida spp. 7 0.18
Escherichia coli 8 0.36
Enterobacter spp. 4 0.38
H. influenzae 12 0.017
Moraxella spp. 4 0.76
P. aeruginosa 29 <0.001
S. aureus 31 <0.001
Strep. pneumoniae 6 <0.001
Mixed Oral Flora 165 0.22
Multiple organisms 148 0.001
• Lung structure
• Pulmonary infection
• Pulmonary inflammation
• Lung function
Associations with BMI z‐score (n=42)Ranganathan et al Thorax 2011;66:408‐13
Coefficient 95% CI P‐value
Free NE ‐0.4 ‐0.8 to ‐0.1 0.02
S. aureus (25%)
‐1.0 ‐1.6 to ‐0.4 0.001
PsA
(10%)
0.04 ‐0.7 to 1.7 0.9
Anti-staphylococcal antibiotics (70%): better BMI z-score (p=0.01)
• Lung structure
• Pulmonary infection
• Pulmonary inflammation
• Lung function
Linnane et al. Am J Respir Crit Care Med 2008
Linnane et al. Am J Respir Crit Care Med 2008
Associations with lung function over timePillarisetti et al. Am J Respir Crit Care Med 2011
Comparison of outcomes between infants with CF and controls at 3 months
Hoo et al. Thorax 2012
Interventions aiming to prevent or arrest lung disease, rather than just damage limitation, must be the new paradigm for those
diagnosed with CF
Evidence that we need to do betterWainwright et al. JAMA. 2011;306(2):163-171
Conclusions• Lung disease (including structural changes) are common
at diagnosis.
• Lung function is diminished early and progression is related to lower respiratory infection
• ? Need to be more aggressive in preventing, detecting, eradicating and treating early S. aureus infection
• Early intervention studies essential to prevent structural changes and lung function decline.
• Can we target those at greatest risk of progression early in life?
Acknowledgements
• United States Cystic Fibrosis Foundation
• National Health and Medical Research Council, Australia
• Cystic Fibrosis Australia
• National Institutes for Health
• Murdoch Children’s Research Institute
• Royal Children’s Hospital CF Trust
PerthStephen StickPeter SlyElizabeth BaldingLuke BerryCindy Branch-SmithBarry ClementsTonia DouglasClara FooCatherine GangellLuke GarrattSamantha GroganGraham HallMilena JokicNick de KlerkAnthony Kicic
MelbourneSarath RanganathanColin RobertsonPhil RobinsonJohn CarlinRosemary CarzinoAnne-Marie EbdonAnne-Marie GibsonJo HarrisonEmily HartJohn MassieRoy Robins-BrowneBilly SkoricJohn Wong
www.arestcf.org
Ingrid LaingClair LeeKarla LogieLauren MottConor MurraySrinivas PoreddyLynn PriddisJudy ParkAnneli RobbshawLinda ShieldsShannon SimpsonErika Sutanto
UBC, Uni of British Columbia; UNC, Uni of North Carolina; UWA, Uni Western Australia; WEHI, Walter & Eliza Hall Institute; ECFS CTN, European CF Society Clinical Trial Network; USCFF , US CF Foundation
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