CF Epidemiology: Australia

Cystic Fibrosis

1938

CYSTIC FIBROSIS OF THE PANCREAS

AND ITS RELATION TO CELIAC

DISEASE.

D ANDERSEN.

American Journal Diseases Children.

Cystic Fibrosis : The beginning

0

5

10

15

20

25

Nos of cases

0.5 1 1.5 2 2.5 3 3.5 4 4.5 5

Age at death

May 1938: 49 cases

Cystic Fibrosis

Commonest lethal inherited condition in WW

Life limiting and incurable.

600 patients in Victoria with CF.

One in every 2,500 live births

About 15-25 new born pts per year in Vict

Cystic Fibrosis

Median age survival late 30’s

95% survive till 20 years

80% till 30 years

Cystic Fibrosis

New Born screening: Hits

All states of Australia

Day 3

2 part test: IRT and CF gene

Positive results by 4-6 weeks

Cystic Fibrosis

New Born screening

2 part test: IRT top 1%

CF genotype

Cystic Fibrosis

State

New South Wales + ACT

Victoria + Tasmania

Queensland

South Australia + Northern Territory

Western Australia

Mutations screened

508

p.F508, del,c.489+1G>T, c.1585-1G>A,

c.3718-2477C>T, p.1507del, p.W1282X,

p.R553X, p.R560T, p.N1303K, p.G542X,

p.G551D, p.V520F

508, I507, G551D, G542X, 621+1GT

R553X N1303K, R117H, p.V520F

508, I507, G551D, G542X, R553X

508, G551D, G542X, 621+1GT

Cystic Fibrosis

CF gene:

Over 1900 different mutations

508 commonest - present in 90% pts in Australia

Current Vic program screens for 12 commonest

Mutations screened for differ between states

Cystic Fibrosis Transmembrane Regulator

CYSTIC FIBROSIS

GENOTYPES

Class 1: Premature termination of mRNA translation

due to base substitution causing stop codons

or mutations that shift the reading frame

Producing defective proteins

CYSTIC FIBROSIS

GENOTYPES

Class 2: Defects in protein processing

CFTR is degraded in ER and does not reach

apical membrane

508 and N1303K

CYSTIC FIBROSIS

GENOTYPES

Class 3: Regulatory mutations

CFTR reaches apical membrane but fails

respond to activation signals

G551D

CYSTIC FIBROSIS

GENOTYPES

Class 4: Defective protein conduction

Reaches apical membrane but has altered

channel properties

R117H and R347P

CYSTIC FIBROSIS

GENOTYPES

Class 5: Reduced levels of RNA for CFTR

Cystic Fibrosis

New Born screening: Misses

Chronic Cough

Cystic Fibrosis


Chronic Cough

Failure to thrive

Cystic Fibrosis


Chronic Cough

Failure to thrive

Chronic Diarrhoea

Underlying defect in CF

Mechanisms of lung damage in CF

Infection Inflammation

Lung damage

Abnormal lung function

Death

Viscous

secretions

CFTR

dysfunction

CF : Early lung disease

Aim to minimise/ delay onset disease

thru new born screening

Early intervention in CF patients

prevents severe malnutrition

• Wisconsin CF Neonatal Screening Study

• Randomised controlled trial with 650,000 newborns.

Split into two groups:

– an early-diagnosis screened cohort

– a standard diagnosis control group

• Newborns screened for CF by

– immunoreactive trypsinogen (IRT) test (1985-91)

– IRT test + DNA-based detection of F508 (1991-94)

Effect of screening on weight

-1.8

-1.6

-1.4

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

Screened

Unscreened

We

igh

t S

DS

p<0.05

CF update: Early lung disease

Aim to minimise thru NBS

Regular assessments: BAL

CT Scans

PFT’s



30% infants will have Pseudomonas by age 3

Linnane B



30% infants will have Pseudomonas by age 3 despite

aggressive cross infection policies





Aggressive eradication programs – 85% successful





Aggressive eradication programs – 85% successful

Pseudomonas EVER is a bad prognostic factor


Regular assessments: CT scans

90% infants will show signs of bronchiectasis

on CT at age 5 years

Wainwright C


Regular assessments: PFT’s

Changes occur very early and are progressive

Linnane B

CF update Antibiotic therapy in CF

Targeted

Non Pseudomonal: Staph/ H Inf

Incidence airway pathogens by age

0

20

40

60

80

100

0-1 2-5 6-10 11-15 16-20 21-25 26-30 31-35 >35

S. aureus

H. influenzae

Age group (years)

To

tal cu

ltu

res (

%)

CYSTIC FIBROSIS

B. CEPACIA

Genomovars (1-9)

Aggressive lung disease (cenocepacia type 3)

Non 3 mild disease

Bactrim/Colistin/minocycline

Some clearance

CYSTIC FIBROSIS

ASPERGILLUS

ABPA

Airway colonisation

Aspergilloma

Infection in pre existing cyst

ABPA

(ABPA) Allergic bronchopulmonary aspergillosis is a condition

characterised by an exaggerated TH2 CD4+ immune response to the fungus

Aspergillus (most commonly Aspergillus fumigatus).

Diagnosis of ABPA in CF is difficult, and may often be delayed, because many

of the diagnostic criteria overlap with common manifestations of CF

ABPA Classic case(all five required)

1. Acute or subacute clinical deterioration (cough, wheeze, exercise intolerance, exercise-induced asthma, decline in pulmonary function, increased sputum) not attributable to another etiology.

2. Serum total IgE concentration of >1000 IU/mL (2400 ng/mL), unless patient is receiving systemic corticosteroids

3. Immediate cutaneous reactivity to Aspergillus (prick skin test wheal of >3 mm with surrounding erythema, or elevated IgE antibody to A. fumigatus

4. Precipitating antibodies to A. fumigatus or serum IgG antibody to A. fumigatus

5. New or recent abnormalities on chest radiography (infiltrates or mucus plugging) or chest CT (bronchiectasis) that do not clear with Ab’s and physio.

ABPA Minimal diagnostic criteria (all four required)

1. Acute or subacute clinical deterioration (cough, wheeze, exercise intolerance, exercise-induced asthma, change in pulmonary function, or increased sputum production) not attributable to another etiology.

2. Total serum IgE concentration of >500 IU/mL (1200 ng/mL) off steroids.

3. Immediate cutaneous reactivity to Aspergillus (prick skin test wheal of >3 mm or elevated specific IgE antibody to A. fumigatus.

4. One of the following: (a) precipitins to A. fumigatus or in vitro demonstration of IgG antibody to A. fumigatus; or (b) new or recent abnormalities on chest radiography

Incidence airway pathogens by age

0

20

40

60

80

100

0-1 2-5 6-10 11-15 16-20 21-25 26-30 31-35 >35

P. aeruginosa

S. aureus

H. influenzae

Age group (years)

To

tal cu

ltu

res (

%)

CF update Antibiotic therapy in CF

Targeted

Main challenge is Pseudom

Still limited to Tobra/ Cipro (Colistin)

Cayston – BD ineffective

Initial eradication phase

Regular cycling suppressive courses

Pseudomonas therapy

Reculture:

Sputum or BAL

POSITIVE NEGATIVE

2 weeks of IV anti-

pseudomonal

antibiotics and then

repeat

No further treatment or

back to prophylactic

antibiotics

If following second attempt of eradication sputum or

BAL is still positive is likely chronic Pa infection

+ve sample

culture for

P.

aeruginosa

Nebulised tobramycin

Cipro Cipro

3 months

? IV’s

P. aeruginosa:

Early colonisation to chronic infection

Progression from intermittent colonisation to chronic

infection coincides with activation of gene coding

for alginate production

Pseudomonas treatment

Compared the clinical and microbiological effectiveness

as well as the safety of 4 antibiotic treatment strategies

for newly identified P aeruginosa infection isolated

from respiratory cultures in children with CF.

Treggiari Arch Pediatr Adolesc Med. 2011;165(9):847-856


10 end point: Time to pulmonary exacerbation requiring IV’s

and

% of P aeruginosa +ve cultures.



304 pts there were no statistically significant differences in

exacerbation rates or in prevalence of Pseud between cycled and culture-based groups.


Pseudomonas treatmentAdding ciprofloxacin produced no benefits.


P. aeruginosa: From early colonisation

to chronic infection

Progression from intermittent colonisation to chronic

infection coincides with activation of gene coding

for alginate production

Transition coincides with increase in specific serum

anti-P. aeruginosa antibodies (exotoxin A)



Progression from intermittent colonisation to chronic infection coincides with activation of gene coding for alginate production

Transition coincides with increase in specific serum anti-P. aeruginosa antibodies (exotoxin A)

Activation of alginate gene may be caused by hydrogen peroxide released from activated PMNs

Cumulative age of patients with

chronic P. aeruginosa infection

0

20

40

60

80

100

0 5 10 15 20 25 30 35 40 45 50

1975 (n=55)

1980 (n=107)

1985 (n=123)

1990 (n=130)

1995 (n=131)

Age (years)

%

40

50

60

70

80

90

100

7 8 9 10 11 12 13 14 15 16 17Age in years

Percen

t p

red

ictd

FVC FEV

P. aeruginosa negative - Mean %

predicted of spirometry parameters

40

50

60

70

80

90

100

7 8 9 10 11 12 13 14 15 16 17

Age in years

Percen

t p

red

ictd

FVC FEV

P. aeruginosa positive - Mean %

predicted of spirometry parameters

Small airways and lung function

Stenotrophomonas maltophilia in CF

Pts with chronic S. maltophilia infection had significantly

increased risk of pulmonary exacerbation requiring

hospitalization and antibiotics compared pts who had never

had S. maltophilia.



Macrolide antibiotics suppress alginate production in vitro

Azithromycin treatment leads to increase in FVC and FEV1 in patients with chronic P. aeruginosa infection

Not effective in non Pseudomonas cases (Saiman)

AZT therapy now widey used to stabilise established

lung disease M,W,F or daily 250 or 500 mg

Other macrolides not effective

Macrolide therapy in CF

Clarithromycin Therapy for Patients With Cystic Fibrosis:

A Randomized Controlled Trial

P. Robinson, et al Pediatric Pulmonology 47:551–557 (2012).

Prevalence of AES-1

0.0

10.0

20.0

30.0

40.0

50.0

60.0

70.0

80.0

A1(n=20)

A2(n=117)

A3(n=52)

A4(n=20)

A5(n=14)

B1(n=68)

B2(n=85)

B3(n=47)

C1(n=57)

C2(n=174)

C3(n=20)

C4(n=38)

C5(n=16)

C6(n=6)

D1(n=72)

D2(n=24)

E1(n=93)

F1(n=28)

Overall(n=951)

Pe

rce

nt

pre

va

len

ce

State/Centre

AES-1Range:0.0% – 44.7% AES-1 detected in 17/18 centres

Prevalence of AES-2

0.0

10.0

20.0

30.0

40.0

50.0

60.0

70.0

80.0

A1(n=20)

A2(n=117)

A3(n=52)

A4(n=20)

A5(n=14)

B1(n=68)

B2(n=85)

B3(n=47)

C1(n=57)

C2(n=174)

C3(n=20)

C4(n=38)

C5(n=16)

C6(n=6)

D1(n=72)

D2(n=24)

E1(n=93)

F1(n=28)

Overall(n=951)

Pe

rce

nt

pre

va

len

ce

State/Centre

Range:0.0% – 66.7%

AES-2AES-2 detected in 16/18 centres

CF updateAntibiotic therapy in CF:

Prophylactic

Anti Staph treatment till 2 years age

50% treatment dose of Augmentin or Fluclox

CF updateAntibiotic therapy in CF:

Prophylactic

Anti Staph treatment till 2 years age

50% treatment dose of Augmentin or Fluclox

Anti Pseudomonal therapy (neb tobra)

in select cases

CF update

New therapies

Mucolytic therapies – new ones

CF update

Mucolytic therapies

New ones

Inhaled mannitol

Denufosol

CF update

Mucolytic therapies

New ones

Inhaled mannitol

Pulmozyme over 5 years age

Hypertonic saline 3-6%

Elkins M et al. N Engl J Med 2006;354:229-240

Elkins M

Inhaled mannitol

Mannitol - A naturally occurring sugar alcohol.

• A potent osmotic agent

• Mannitol dry powder

– Respirable particles - 3µm

– No carrier

– Small portable inhaler

– No cleaning or preparation time

– 400mg = 10 x 40mg caps (bd)

– 3 – 5 minutes dosing time

Healthy Mucociliary System

Thin film of mucus

Airway Surface Liquid

Submucosal glands

Cilia

Goblet Cell

Ciliated Cell

Mucociliary system (normal)

Thin film of mucus

Airway Surface Liquid

Submucosal glands

Cilia

Goblet Cell

Ciliated Cell

Mucus surface

properties

changed

Airway Surface

Liquid

reconstituted

Cilia

function

improved

H2OH2O H2O H2O

H2O

Goblet Cell

Ciliated Cell

1

3

2

4 Cough60 mm/s

1. Mannitol alters the rheological properties of mucus

2. Mannitol increases the volume of airway surface liquid (ASL)

3. Mannitol has shown to have an indirect effect on cilia beat frequency in

in-vitro studies

4. Mannitol promotes productive cough and assists in clearing mucus- Difference between productive cough and impact cough

Mode of Action of Mannitol

CF-301 Mean % change in FEV1

Bilton D, Robinson P et al. European Respiratory Journal 2011:38:1071-1080

CF update

Mucolytic therapies – new uses for old ones

Pulmozyme (dornase alpha)

CF update: Pulmozyme (dornase alpha)

Over 5 years age:

1 month trial showing 10% increase in FEV1 for continued therapy

CF update: Pulmozyme (dornase alpha)

Over 5 years age:

1 month trial showing 10% increase in FEV1 for continued therapy

Removed 2013 now clinical grounds only

Under 5 years age:

Severe clinical course with > 3 admits

Signif bronchiectasis on CT scan

Severe CF bronchiolitis with persistent, resistant wheeze

Severe impairment on spirometry (FOT or MBW)

CF update

New therapies: Mutation specific therapies

Vertex trials: G551D

Vx 102 and 103 trials

Evaluate the efficacy of VX-770 after 24 weeks of

treatment in subjects with CF who have the G551D-cystic

fibrosis trans membrane conductance regulator (CFTR)

mutation on at least 1 allele

102 CF pts above 12 years

103 CF 6-12 years

105 open label extension

VX-770 Phase III Study Design 102

• Randomized, double-blind, placebo-controlled

• Recruitment: 161 subjects

• Key inclusion criteria

– G551D mutation on at least one CFTR allele

– Aged ≥ 12 years

– FEV1 40% to 90% predicted

Run-inScreening

Randomization(1:1)

Or

2-yr Follow-up

VX-770 150 mg q12h

Open-label

rollover study

Placebo Placebo

Day -35 -14 0 48Week 24

VX-770 150 mg q12h

VX-770 150 mg q12h

Treatment period Extension period

Primary analysis

Day 15 Week 8 Week 16 Week 24 Week 32 Week 40 Week 48

-5

0

5

10

15Placebo

VX-770

Ab

so

lute

ch

an

ge in

% p

red

icte

d F

EV

1

(mea

n,

95

% C

I)

Absolute Change in FEV1 % Predicted

Treatment effect through Week 24

+ 10.6 %P < 0.0001


+ 10.5 %P < 0.0001


-60

-55

-50

-45

-40

-35

-30

-25

-20

-15

-10

-5

0

5

Placebo

VX-770

Ch

an

ge in

sw

eat

ch

lori

de c

on

cen

trati

on

mm

ol/

L (

me

an

, 9

5%

CI)

Change from Baseline in Sweat Chloride


– 47.9 mmol/LP < 0.0001


– 48.1 mmol/L P < 0.0001

Change from Baseline in CFQ-R Resp Domain


-10

-8

-6

-4

-2

0

2

4

6

8

10

12

Placebo

VX-770Ch

an

ge

in

CF

Q-R

re

sp

irato

ry d

om

ain

po

ints

(m

ean

, 95

% C

I)

* MCID, minimal clinically important difference (Quittner et al 2009)

MCID = 4*


+ 8.1P < 0.0001


+ 8.6P < 0.0001

Time to First Pulmonary Exacerbation

Week 24

Hazard Ratio

0.40 P = 0.0016

Week 48

Hazard Ratio

0.46 P = 0.0012

0.78

0.51

0.67

0.41

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 28 56 84 112 140 168 196 224 252 280 308 336 364

Hazard Ratio: 0.45 ( 0.28, 0.73) P=0.0012

PLACEBO VX-770

Event-Free Rate At Week 48 0.41 0.67

PLACEBO VX-770

Event-Free Rate At Week 48

Placebo

VX-770

Pro

po

rtio

n o

f e

ve

nt-

fre

e s

ub

jec

ts

Study day

Change from Baseline in Weight


-1

0

1

2

3

4

5Placebo

VX-770

Ch

an

ge

in

we

igh

tkg

(m

ea

n,

95%

CI)

Treatment effect at Week 24

+ 2.8 kgP < 0.0001

Treatment effect at Week 48

+ 2.7 kgP = 0.0001

Lumicaftor

2 part medication

809 + Ivacaftor

3-4% increase in lung function

CF updateComplications of getting older

Diabetes

20% CFRD by age of 20 years and up to 50% by mid thirties

Annual endocrine review after age 12 with consideration of

OGTT annually

CF Related Diabetes mellitus (CFRD)

60% non-diabetic pts vs 25% diabetic pts lived to 30 yrs

US study, 21% CF patients with long-term diabetes had

microangiopathy, retinopathy, neuropathy, nephropathy

Miscellaneous GI manifestations

Cancer:

Increased freq of small bowel, colon, biliary tract

No increase in stomach or rectum

Coeliac:

Previously thought to be increased but now found 10 times less common.

C. Difficile:

High carriage rate 20 to broad spectrum Ab’s

Crohn’s:

IBD 7 times more common, Crohns 17 times.

Osteoporosis in CF

Increasingly recognised in adults and children > 12

Children: 62 pts mean Z score -1.03 (spine) and 0.71

femoral neck. (Henderson).

Adults: mean Z score -1.21 (spine) and -1.25

(femoral neck)

Osteoporosis in CF

Multifactorial

Malabsorption of Vit D and Calcium

Low body weight,

Decreased physical activity

Hypogonadism,

Osteolytic activity circulating cytokines,

Amenorrhea

Steroid usage

diabetes

Chronic infection,

Delayed puberty

Osteoporosis in CF

CYSTIC FIBROSIS

DIAGNOSIS

Gold standard sweat test

Clinically think fat malabsorption

Prop develop PI nearer 12 months

5-10% PS – 95% destrn

CYSTIC FIBROSIS

PANCREATIC INSUFFICENCY

Steathorrea most clinical obvious

Enzymes contain all 3 enzymes

Enteric coated

Acidic small bowel

Acid reducing agents

Cystic Fibrosis

BOSTON TORONTO

n=499 (15.9yrs) n=534 (15.2yrs)

58% males 57% males

Fat restriction High fat diet

FEV1 = FEV1

Cystic Fibrosis

BOSTON TORONTO

n=499 (15.9yrs) n=534 (15.2yrs)

58% males 57% males

Fat restriction High fat diet

FEV1 = FEV1

BUT

Median survival

21 years 30 years

ASL

ASL

In newborn wild-type pigs, the ASL rapidly kills bacteria

in vivo, when removed from the lung and in primary

epithelial cultures.

Lack of CFTR reduces bacterial killing.

AA Pezzulo et al. Nature 487, 109-113 (2012)

AA Pezzulo et al. Nature 487, 109-113 (2012)

P. aeruginosa-coated

grids placed on HBE S. Aureus-coated

grids placed on HBE

ASL

Found that the ASL pH was more acidic in CF pigs, and

reducing pH inhibited the antimicrobial activity of ASL.

ASL

Without CFTR, airway epithelial HCO3 secretion is

defective, the ASL pH falls and inhibits antimicrobial

function, thereby impairing the killing of bacteria that

enter the newborn lung.

Hypertonic saline

Nebulised Hypertonic Saline (HTS)

CF lung inflammation mediated inflam chemokines, incl IL-8.

IL8 protected proteolytic degradation by binding to

glycosaminoglycans

Reeves Am J Respir Crit Care Med 2011; 183


? anti-inflammatory effect of HTS in CF lung by focusing on IL-8

CF IL-8 levels significantly higher than the control group

Digesting glycosaminoglycans in CF BALF displaced IL-8 from

glycosaminoglycan matrices, rendering the chemokine susceptible

to proteolytic cleavage.

Reeves Am J Respir Crit Care Med 2011; 183

Reeves Am J Respir Crit Care Med Vol 2011 183


Nebulized HTS tx disrupts the interaction between IL-8

and glycosaminoglycans, rendering IL-8 susceptible to

proteolytic degradation with subsequent decrease in

neutrophil chemotaxis, facilitating resolution of

inflammation.

Reeves Am J Respir Crit Care Med Vol 2011 183

Inhaled hypertonic saline in CF children < 6 yrs.

Multicenter, randomized, double-blind, placebo-controlled trial at 30 US CF centers in children 4 - 60 months.

Active treatment (158) received 7% HTS

Control group (163) received 0.9% isotonic saline,

nebulized bd for 48 weeks.

Mean pulmonary exacerbation rate was;

2.3 in HTS group and

2.3 in controls pts.

Rosenfeld ISIS Study Group. JAMA. 307(21):2269-77, 2012

Inhaled hypertonic saline in CF children < 6 yrs

No significant difference in secondary end points including height, weight, respiratory rate, oxygen saturation, cough, or respiratory symptom scores.

Rosenfeld ISIS Study Group. JAMA. 307(21):2269-77, 2012

Bugs and drugs

Pseudomonas and Females

Estradiol and estriol induced alginate production in P. aeruginosa strain 01 and in clinical isolates obtained from patients with and those without CF.

After prolonged exposure to estradiol, P. aeruginosa adopts mucoid morphology

Frameshift mutation was identified in mucA, a key regulator of alginate biosynthesis in P. aeruginosa

In vivo levels of estradiol correlated with infective exacerbations in

women with CF, with majority occurring during the follicular phase

Chotirmall N Eng J Med May 2012


Pseudomonas and Females

Predominantly nonmucoid P. aeruginosa was isolated from sputum

during exacerbations in the luteal phase (low estradiol).

Increased proportions of mucoid bacteria were isolated during

exacerbations occurring in the follicular phase (high estradiol),


Azt autophagy

Autophagy: degradation of a cell's own components through the lysosomal system.

Autophagy appears crucial for an effective cellular response against mycobacteria including NTM.

Macrolide bafilomycin is known to disrupt autophagy in vitro.

Renna The Journal of Clinical Investigation 2011;121;(9)

Azt autophagyStudies have identified synchronous increase in mycobacterial

infection of CF pts, predominantly with the multi-drug-resistant,

highly pathogenic nontuberculous mycobacteria Mycobacterium

abscessus.

Postulated azithromycin paradoxically impairs host immunity

against mycobacteria.


Azt autophagyStudies have identified synchronous increase in mycobacterial

infection of CF pts, predominantly with the multi-drug-resistant,

highly pathogenic nontuberculous mycobacteria Mycobacterium

abscessus.

Postulated azithromycin paradoxically impairs host immunity

against mycobacteria.


RENAL DISEASE IN CF

CFRD requiring insulin therapy substantially increased

the risk of chronic kidney disease.

Pulmonary exacerbations did not significantly increase

the risk of chronic kidney disease.

Pseudomonas aeruginosa Type-3 Secretion

System Dampens Host Defense by Exploiting

the NLRC4-coupled Inflammasome

Structures of needle proteins and their complexes.

Blocker A J et al. PNAS 2008;105:6507-6513

©2008 by National Academy of Sciences

By “capping’ the TSSS there would be less intracellular

injection of bacterial toxins and less cell injury.

Cellular inflammation

During an infection, one of the first forms of defense employed by the

innate immune response is a group of pattern recognition receptors

(PRRs) encoded in the germline to recognize molecular patterns expressed

by invading pathogens.

May either be on the membrane surface e.g. Toll-like receptors (TLRs)

and C-type Lectin Receptors (CLRs) or inside the cytoplasm e.g. Nod-like

receptors (NLRs).

Nod = nucleotide-binding oligomerization domain receptors

Oligomerization (chemistry) The formation of an oligomer from a

monomer

INFLAMMASOME

In 2002, it was reported that a subset of NLRs named NLRP1 were able to

assemble and oligomerize into a common structure which collectively activated

the caspase-1 cascade, thereby leading to the production of pro-inflammatory

cytokines especially IL-1B and IL-18. This NLRP1 multi-molecular complex

was dubbed the ‘inflammasome’.

Since then, several other inflammasomes were discovered, two of which are also

NLR subsets—NLRP3 and NLRC4

Pseudomonas aeruginosa triggers, through a

functional type-3 secretion system (T3SS), the

activation of an intracellular cytosolic sensor

of innate immunity, NLRC4.

Pseudomonas aeruginosa triggers through a functional type-3 secretion system (T3SS), the activation of an intracellular cytosolic sensor of innate immunity, NLRC4.

However,

NLRC4-inflammasome–dependent response contributes to increased clearance of intracellular pathogens, while Pseudomonas is an extracellular pathogen.

Congenital abnormalities

Laryngomalacia

Clinical diagnosis

Bronchoscopy for Diff Dx

Resolution 2-3 years

Residual insp flow limitation


Laryngomalacia

Clinical diagnosis

Bronchoscopy for Diff Dx

Resolution 2-3 years

Residual insp flow limitation

Diff Dx: tracheomalacia, sub-glottic haemangioma,

sug glottic cyst, paralysed vocal cord


Tracheomalacia:

Isolated, 20 TOF,

Cartilage rings, stenosis

aberrant airway anatomy

External compression

Bronchogram vs bronchoscopy

Stenting


Tracheomalacia:

20 TOF, vascular ring

Surgical repair does not improve

Pulm fnctn in short term

Dying spells


Pulmonary hypoplasia:

Isolated

Compression – diaph hernia

Reduced lung function

Check vascular anatomy

Bronchopulmonary Sequestration

A non-functioning mass of lung tissue that lacks normal communication with the tracheobronchial tree and receives its arterial blood supply from the systemic circulation usually from the thoracic or abdominal aorta.

2 types based on the nature of their pleural covering.

Extralobar sequestration is a mass of pulmonary parenchyma with a distinct pleura covering separating it from the adjacent normal lung.

Intralobar sequestration is located within a normal lobe and lacks its own visceral pleura. Both types are composed of normal lung tissue, including airway and alveolar elements.


Histologically, pulmonary sequestrations demonstrate immature lung

development.

Extralobar sequestrations have anomalous blood supply from an

infradiaphragmatic source in about 20% of patients.


Intralobar sequestrations appear similar, on prenatal ultrasound, to a

CPAM. Can be associated with pleural effusion, polyhydraminos,

and nonimmune hydrops fetalis. Can be difficult to differentiate

from a CPAM or CDH by prenatal ultrasound. 60% occur on the

left side, most commonly left lower lobe.

90% extralobar sequestrations are located in the left hemithorax

within the posterior mediastinum. Sequestration in the upper lobe

occurs in only 10–15%, and bilateral sequestrations are rare.


Extralobar sequestrations generally present earlier than intralobar.

Infants with extralobar sequestrations typically present with respiratory distress and less commonly with recurrent pneumonia.

Intralobar sequestration usually present in late

childhood or adolescence with recurrent pulmonary infections.


Extralobar sequestrations often identified on antenatal U/S or in

infancy during surgery for other congenital anomalies such as

CPAM or CDH.

Most intralobar sequestrations present later in childhood due to

recurrent pulmonary infections.

The abnormally developed lung tissue is ineffective in gas exchange

and therefore is not of benefit to the patient. Spontaneous

involution of extralobar sequestrations has been described


Symptomatic patients, treatment is surgical excision, curative and is

associated with minimal morbidity.

Sx may be immediately after birth in severe RDS. Or electively in

older children who present with recurrent infections.

Intralobar pulmonary sequestration. CT scan showing calcified mass in left lower lobe

Congenital pulmonary airway malformations (CPAM)

Previously congenital cystic adenomatoid malformations (CCAM)

Benign hamartomas or dysplastic tumors characterized by

overgrowth of terminal bronchioles in a glandular/adenomatoid

pattern.

Constitute 10–30% of congenital lung malformations.

Thought to result from marked overgrowth of the terminal bronchioles at the expense of alveoli development.


Generally unilobar with a slight predilection for the lower lobes,

with right and left sides affected equally.

Typically, have normal pulmonary arterial and venous blood

supply and communicate with the tracheobronchial tree.

Prenatal diagnosis by sonography is relatively common


Natural history determined more by overall size and

degree of compression of adjacent structures than by their

gross appearance.

Prenatal DDx includes congenital diaphragmatic hernia,

pulmonary sequestration, and bronchogenic cyst.

U/S findings associated with CPAM include

polyhydramnios, mediastinal shift, pleural effusions, and

fetal hydrops

In antenatal and immediate postnatal period, main physiologic consequence of CPAM results from compression of the mediastinum and adjacent normal lung by the mass lesion.

Fetal hydrops identified in 40% of fetuses with CPAM and historically was an ominous finding, associated with a high risk of fetal or neonatal demise. Mortality approaches zero for a fetus with a CPAM but without hydrops

Spontaneous resolution in-utero of an antenatally diagnosed CPAM is reported in up to 15% of patients

Congenital pulmonary airway

malformations (CPAM)

Congenital pulmonary airway

malformations (CPAM)

Most asymptomatic or undiagnosed CPAM will present

with infectious complications during childhood or

adolescence if not resected.

10% infectious complications by 3 yrs with unresected CPAM.

Pneumothorax and bronchiectasis are reported in association

with an untreated CPAM. Less commonly, a CPAM is

diagnosed in a child or during adulthood in association with a

pulmonary malignancy.

Congenital Lobar Emphysema (CLO)

Characterized by expiratory air trapping within affected lobe.

Air trapping leads to overdistension of the affected lobe and

compression of the adjacent lung and mediastinal structures.

Lung parenchyma is typically normally developed, bronchial

collapse is commonly seen due to a focal deficiency or

absence of the cartilaginous components of the lobar

Bronchus.

Congenital Lobar Emphysema

Dx CLE is rarely made by antenatal US or MRI as

process of air trapping occurs postnatally.

Most commonly, the Dx CLE is made by plain chest X-ray

in newborn with RDS.

Most often affects the left upper lobe (40–50%), followed

by right middle lobe (30–40%), right upper lobe (20%).

Congenital Lobar Emphysema

Associated with congenital heart disease in approximately

15% of patients and therefore screening echocardiography

is recommended.

50% affected infants will demonstrate signs of respiratory

distress in the first few days of life; the remainder develop

symptoms within the first few months or years of life.

Bronchogenic Cysts

Bronchogenic cysts are typically thick walled, unilocular

cysts that originate from either the trachea or bronchus.

Believed to occur as a result of abnormal budding of the

tracheobronchial tree; hence can be found anywhere along the

conducting airways.

Bronchogenic Cysts

Most often located within the lung parenchyma, mediastinum, or

in the neck; but ectopic bronchogenic cysts have been reported in

paravertebral, paraesophageal, pericardial, subcarinal, and

subcutaneous locations.

Many bronchogenic cysts are asymptomatic and discovered

incidentally by chest radiography.

Bronchogenic Cysts

Most infants present with wheezing, tachypnea, dyspnea, and

cyanosis or less commonly, failure to thrive as a result of

compression of adjacent mediastinal structures. Older children

typically present with infectious complications.

Resection is typically indicated to alleviate symptoms, prevent

future infection, and to provide pathologic identification.

Documents

CF Epidemiology: Australia