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