Early lung disease in CF
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Transcript of Early lung disease in CF
EARLY LUNG DISEASE IN CF
Peter D. Sly MBBS, MD, FRACP, DSc
THE AREST CF PROGRAM
Comprehensive early surveillance program• CF diagnosed following detection by NBS
• Initial assessment soon after diagnosis ( 3 months)
• Annual assessment close to birthday until 6 years
• Clinical and research components
• Separate consent for each component• Assessments undertaken when clinically stable
• Very well accepted, >95% complete participation
AREST CF ASSESSMENTS
CT/BAL• GA; EI (25 cmH2O), EE (0 cmH2O)• 3-slice scans; low-dose volumetric scans• BAL after CT
Infant lung function• SF6MBW, LF-FOT, RVRTC
Preschool lung function• FOT, spirometry from 5 years
Biomarker discovery and validation• Matched BAL, serum, urine• Infection, inflammation, metabolomics
AREST CF ASSESSMENTS
Bronchoalveolar lavage
• Following CT, via LMA• 3 x 1ml/kg RML, 1 x1ml/kg LLL or most affected
• Microbiology (aliquots 1 & 4)
− Standard culture-based assessment
− Metagenomics• Inflammation (aliquots 2 & 3)
BAL: WHAT ARE WE TRYING TO MEASURE?
What constitutes normality?
Kanakoudi1 (n=20)
Midulla2 (n=16)
Armstrong3 (n=19)
Gangell4 (n=65, CF never infected)
Age range (y) 0.25-14 0.17-2.67 0.17-4 1.06-1.83
TCC (x103/ml) 199.2±8.12 599 (200-1300)
151(102,223) 242 (194,301)
Neuts (%) 2.94±2.82 5.5 (0-17) 8.2 (4.6,15) 13.6 (11.3,15.6)
IL-8 (pg/ml) 234.9±528.44
24 (12,47) 322 (234,444)
1Hippokratia 2010;14:109-14. 2Pediatr Pulmonol 1995;20:112-118. 3Pediatr Pulmonol 2005;40:500-10. 4Clin Infect Dis 2011;53:425-32.
AREST CF RESULTS
Overall results•1285 BAL (305 children), 869 CT (258 children)•Lung disease begins early in CF
−Bx, air trapping from 3 months−Infection, including with P. aeruginosa from 3 months−May occur in asymptomatic children
•Neutrophilic inflammation prominent− Free NE activity from 3 months− Associated with presence, extent and progression of Bx
•Infection common− At least one infection in 78% by 6 years− Successful eradication of P. aeruginosa if treated early
•Early infection on BAL associated with− Structural lung disease− Abnormal lung function in infancy− Low BMI
Assessment over the first 3y (longitudinal) 127 consecutive infants with CF (NBS) AREST CF ESP
CT, BAL 3m (n=127), 1 (n=109), 2 (n=92), 3y (n=81)
longitudinal analyses 3m-3y
Sly et al NEJM 2013
Early Lung Disease in CF
EARLY LUNG DISEASE IN CF
Bx defined as B:A>1
• A 15 month old child with no abnormalities in inspiration or B expiration • C 2 year old child with bronchiectasis in inspiration • D 2 year old child with gas-trapping in expiration
DEMOGRAPHIC AND CLINICAL DATA
3m (n=127)
1y (n=109) 2y (n=92) 3y (n=81)
BMI Z-score -1.34±1.19 -0.42±1.29 -0.16±1.46 0.22±0.96
NE +ve 28 (23.3%) 19 (18.1%) 20 (21.7%) 19 (25.0%)
Neuts x103/ml 416±810 482±761 1441±2822
2334±5618
Any infection 22.4% 21.1% 40.2% 46.9%
Bx prevalence 29.3% 31.5% 44.0% 61.5%
GT prevalence 68.0% 68.5% 71.6% 69.5%
Sly et al NEJM 2013
EARLY LUNG DISEASE IN CF
Inflammation is increased in those with respiratory symptoms and infection.
Respiratory symptoms Pulmonary infection
Absent (n=93)
Present (n=19)
p Absent (n=94)
Present (n=27)
p
Neutrophils (x103/ml)
326.4 947.5 0.031 303.3 822.4 0.02
Neutrophils (%) 17.9 30.5 0.017 17.5 28.8 0.013
IL-8 (pg/ml) 815.4 1607.9 0.03 988.0 1123.3 0.22
NE activity (%) 19.4 52.6 0.007 19.1 40.7 0.021
Bx (%) 23.7 55.0 0.005 24.2 46.2 0.029
GT (%) 72.0 68.4 0.40 68.1 74.1 0.46
3M DATA STRATIFIED BY NE STATUS
NE positive (n=28)
NE negative (n=92)
p
Sex (M/F) 15/13 47/45 0.82
Severe genotype 100% 88.5% 0.11
BMI Z-score -1.45±0.84 -1.33±1.23 0.66
Respiratory symptoms
35.7% 10.7% 0.007
Meconium Ileus 25.9% 17.7% 0.40
Pancreatic insufficient
100% 78.2% 0.006
Any infection 39.3% 17.4% 0.021
S. aureus 10.7% 4.3% 0.35
P. aeruginosa 10.7% 3.3% 0.14
Sly et al NEJM 2013
3M DATA STRATIFIED BY BX STATUS
Bx positive (n=36)
Bx negative (n=91)
p
Sex (M/F) 15/21 48/40 0.12
Severe genotype 100% 88.5% 0.11
BMI Z-score -1.34±1.05 -1.33±1.25 0.98
Respiratory symptoms
33.3% 12.0% 0.014
Meconium Ileus 40.0% 12.3% 0.002
Pancreatic insufficient 93.1% 78.8% 0.094
Any infection 34.3% 17.8% 0.028
S. aureus 8.6% 5.6% 0.69
P. aeruginosa 14.3% 2.2% 0.018
Sly et al NEJM 2013
Inflammatory markers
No current infection (n=213) [0-6y old]
Past infection* (n=112)
Never infected* (n=101)
Single organism (n=292)
Multiple organisms (n=148)
Total cell count (x103 cells/ml)
254 (218-295) 260 (212-320) 242 (194-301) 296 (258-338)p=0.13
408 (342-487)p=0.001
Neutrophils (x103 cells/ml)
33 (26-43) 28 (20-40) 33 (22-47) 207 (165-260)p<0.001
181 (132-248)p<0.001
Neutrophil elastase (ng/ml)
155 (126-190) 159 (120-210) 144 (106-195) 239 (198-287)p<0.001
346 (272-441)p<0.001
Interleukin-8 (pg/ml)
404 (324-503) 470 (348-636) 322 (234-444) 672 (552-819)p<0.001
856 (660-1112)p<0.001
Inflammatory response score
4.36 (4.22-4.49) 4.36 (4.17-4.56) 4.28 (4.08-4.48) 4.97 (4.84-5.10)p< 0.001
5.12 (4.96-5.29)p<0.001
Inflammatory response is associated with current infection
* Subgroups of no current infection
Gangell. Clin Infect Dis 2011;53:525-32.
Organism Any Bacterial Density Bacterial Density ≥105 cfu/mln Coefficient Std error p n Coefficient Std error p
Aspergillus spp. 19 0.89 0.24 <0.001 7 1.19 0.33 <0.001Candida spp. 7 0.46 0.32 0.15 0 - - -
H. influenzae 12 0.68 0.27 0.01 8 0.59 0.31 0.05P. aeruginosa 29 1.07 0.24 <0.001 25 1.32 0.22 <0.001Staph aureus 31 1.05 0.20 <0.001 17 1.12 0.23 <0.001
Strep pneumoniae 6 1.38 0.37 <0.001 5 1.31 0.38 <0.001
Mixed oral flora 165 0.42 0.11 <0.001 97 0.51 0.12 <0.001Multiple organisms 148 0.58 0.14 <0.001 - - - -
* Regression analyses, adjusted for pancreatic insufficiency, detection by newborn screening, age and the presence of respiratory symptoms, comparing the inflammatory response score associated with the presence of individual organisms in BAL compared with the inflammatory response score associated with BAL from children in the never infected group.
Increased inflammation with some organisms
Gangell. Clin Infect Dis 2011;53:525-32.
AREST CF ESP653 BAL samples from 215 children 3m to 6y old
Longitudinal risk factors for Bx: 3m to 3y
Odds Ratio (95% CI)
GEE with binomial family, logit link and AR(1) correlation matrix
Sly et al NEJM 2013
Univariate analysis
Sly et al NEJM 2013
Odds Ratio (95% CI)
GEE with binomial family, logit link and AR(1) correlation matrix
Longitudinal risk factors for Bx from 3m to 3y
Multivariate analysis
GAS TRAPPING ON CT
What does Gas trapping mean? Uneven emptying of lung units
Is it associated with disease? Increases risk of bronchiectasis Weak association with M2/MO but not LCI
[Hall PLoS ONE 2011;6:e23932]
Can it be treated? No data in infants
Those with NE in BAL develop Bx earlier
Sly et al NEJM 2013
Initial scan Subsequent scan Bx label
DetectedDetected Persistent
Not detected Resolved
Not detectedDetected Acquired
Not detected Negative
Persistent Bx
Odds Ratio (95% CI)
Risk factors at 3m for persistent Bx: 12m
Logistic regression; Blue=univariate; Red=multivariate
Sly et al NEJM 2013
Odds Ratio (95% CI)
Risk factors at 3m for persistent Bx: 3y
Logistic regression; Blue=univariate; Red=multivariate
Sly et al NEJM 2013
CONCLUSION
Lung disease begins early in CF Respiratory symptoms and infection are associated
with more disease Inflammation, Bx and gas trapping can occur in
asymptomatic infants Free NE activity in BAL at 3M increases risk for
persistent Bx 7 fold at 12 months 4 fold at 3y
Prevention of lung disease requires early intervention