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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

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Early lung disease in CF

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  1. Early lung disease in CF Peter D. Sly MBBS, MD, FRACP, DSc

  2. 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

  3. 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

  4. 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)

  5. BAL: what are we trying to measure? • What constitutes normality? 1Hippokratia 2010;14:109-14. 2Pediatr Pulmonol 1995;20:112-118. 3Pediatr Pulmonol 2005;40:500-10. 4Clin Infect Dis 2011;53:425-32.

  6. 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

  7. Early Lung Disease in CF • 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

  8. 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

  9. Demographic and clinical data Sly et al NEJM 2013

  10. Early Lung Disease in CF Inflammation is increased in those with respiratory symptoms and infection.

  11. 3m data stratified by NE status Sly et al NEJM 2013

  12. 3m data stratified by Bx status Sly et al NEJM 2013

  13. Inflammatory response is associated with current infection * Subgroups of no current infection Gangell. Clin Infect Dis 2011;53:525-32.

  14. Increased inflammation with some organisms AREST CF ESP 653 BAL samples from 215 children 3m to 6y old * 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. Gangell. Clin Infect Dis 2011;53:525-32.

  15. Longitudinal risk factors for Bx: 3m to 3y Univariate analysis Odds Ratio (95% CI) GEE with binomial family, logit link and AR(1) correlation matrix Sly et al NEJM 2013

  16. Longitudinal risk factors for Bx from 3m to 3y Multivariate analysis Odds Ratio (95% CI) GEE with binomial family, logit link and AR(1) correlation matrix Sly et al NEJM 2013

  17. 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

  18. Those with NE in BAL develop Bx earlier Sly et al NEJM 2013

  19. Persistent Bx

  20. Risk factors at 3m for persistent Bx: 12m Odds Ratio (95% CI) Logistic regression; Blue=univariate; Red=multivariate Sly et al NEJM 2013

  21. Risk factors at 3m for persistent Bx: 3y Odds Ratio (95% CI) Logistic regression; Blue=univariate; Red=multivariate Sly et al NEJM 2013

  22. 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

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