CYSTIC FIBROSIS OF THE PANCREAS AND ITS RELATION TO CELIAC DISEASE. D ANDERSEN. American Journal Diseases Children.

Transcription

1 Cystic Fibrosis

2 1938 CYSTIC FIBROSIS OF THE PANCREAS AND ITS RELATION TO CELIAC DISEASE. D ANDERSEN. American Journal Diseases Children.

3 Cystic Fibrosis : The beginning May 1938: 49 cases Nos of cases Age at death

4 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 new born pts per year in Vict

5 Cystic Fibrosis Median age survival late 30 s 95% survive till 20 years 80% till 30 years

6 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

7 Cystic Fibrosis New Born screening 2 part test: IRT top 1% CF genotype

8 Cystic Fibrosis State New South Wales + ACT Victoria + Tasmania Mutations screened 508 p.f508, del,c.489+1g>t, c g>a, c c>t, p.1507del, p.w1282x, p.r553x, p.r560t, p.n1303k, p.g542x, p.g551d, p.v520f Queensland South Australia + Northern Territory Western Australia 508, I507, G551D, G542X, 621+1G T R553X N1303K, R117H, p.v520f 508, I507, G551D, G542X, R553X 508, G551D, G542X, 621+1G T

9 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

10 Cystic Fibrosis Transmembrane Regulator

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12 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

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16 CYSTIC FIBROSIS GENOTYPES Class 2: Defects in protein processing CFTR is degraded in ER and does not reach apical membrane 508 and N1303K

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18 CYSTIC FIBROSIS GENOTYPES Class 3: Regulatory mutations CFTR reaches apical membrane but fails respond to activation signals G551D

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20 CYSTIC FIBROSIS GENOTYPES Class 4: Defective protein conduction Reaches apical membrane but has altered channel properties R117H and R347P

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22 CYSTIC FIBROSIS GENOTYPES Class 5: Reduced levels of RNA for CFTR

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24 Cystic Fibrosis New Born screening: Misses Chronic Cough

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29 Cystic Fibrosis New Born screening: Misses Chronic Cough Failure to thrive

30 Cystic Fibrosis New Born screening: Misses Chronic Cough Failure to thrive Chronic Diarrhoea

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33 Underlying defect in CF

34 Mechanisms of lung damage in CF CFTR dysfunction Viscous secretions Infection Inflammation Lung damage Abnormal lung function Death

35 CF : Early lung disease Aim to minimise/ delay onset disease thru new born screening

36 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 ( ) IRT test + DNA-based detection of F508 ( )

37 Weight SDS Effect of screening on weight Screened Unscreened p<0.05

38 CF update: Early lung disease Aim to minimise thru NBS Regular assessments: BAL CT Scans PFT s

39 CF update: Early lung disease Regular assessments: BAL 30% infants will have Pseudomonas by age 3 Linnane B

40 CF update: Early lung disease Regular assessments: BAL 30% infants will have Pseudomonas by age 3 despite aggressive cross infection policies

41 CF update: Early lung disease Regular assessments: BAL 30% infants will have Pseudomonas by age 3 despite aggressive cross infection policies Aggressive eradication programs 85% successful

42 CF update: Early lung disease Regular assessments: BAL 30% infants will have Pseudomonas by age 3 despite aggressive cross infection policies Aggressive eradication programs 85% successful Pseudomonas EVER is a bad prognostic factor

43 CF update: Early lung disease Regular assessments: CT scans 90% infants will show signs of bronchiectasis on CT at age 5 years Wainwright C

44 CF update: Early lung disease Regular assessments: PFT s Changes occur very early and are progressive

45 Linnane B

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47 Targeted CF update Antibiotic therapy in CF Non Pseudomonal: Staph/ H Inf

48 Total cultures (%) Incidence airway pathogens by age S. aureus H. influenzae >35 Age group (years)

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50 CYSTIC FIBROSIS B. CEPACIA Genomovars (1-9) Aggressive lung disease (cenocepacia type 3) Non 3 mild disease Bactrim/Colistin/minocycline Some clearance

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52 CYSTIC FIBROSIS ASPERGILLUS ABPA Airway colonisation Aspergilloma Infection in pre existing cyst

53 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

54 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.

55 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

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57 Total cultures (%) Incidence airway pathogens by age P. aeruginosa S. aureus H. influenzae >35 Age group (years)

58 Targeted CF update Antibiotic therapy in CF Main challenge is Pseudom Still limited to Tobra/ Cipro (Colistin) Cayston BD ineffective Initial eradication phase Regular cycling suppressive courses

59 Pseudomonas therapy +ve sample culture for P. aeruginosa? IV s 3 months Nebulised tobramycin Cipro Cipro Reculture: Sputum or BAL POSITIVE NEGATIVE 2 weeks of IV antipseudomonal 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

60 P. aeruginosa: Early colonisation to chronic infection Progression from intermittent colonisation to chronic infection coincides with activation of gene coding for alginate production

61 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):

62 Pseudomonas treatment 1 0 end point: Time to pulmonary exacerbation requiring IV s and % of P aeruginosa +ve cultures. Treggiari Arch Pediatr Adolesc Med. 2011;165(9):

63 Pseudomonas treatment 304 pts there were no statistically significant differences in exacerbation rates or in prevalence of Pseud between cycled and culture-based groups. Treggiari Arch Pediatr Adolesc Med. 2011;165(9):

64 Pseudomonas treatment Adding ciprofloxacin produced no benefits. Treggiari Arch Pediatr Adolesc Med. 2011;165(9):

65 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)

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

67 % Cumulative age of patients with chronic P. aeruginosa infection (n=55) 1980 (n=107) 1985 (n=123) 1990 (n=130) 1995 (n=131) Age (years)

68 Small airways and lung function P. aeruginosa negative - Mean % predicted of spirometry parameters P. aeruginosa positive - Mean % predicted of spirometry parameters Percent predictd Percent predictd Age in years Age in years FVC FEV FVC FEV

69 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.

70 P. aeruginosa: From early colonisation to chronic infection Macrolide antibiotics suppress alginate production in vitro Azithromycin treatment leads to increase in FVC and FEV 1 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

71 Macrolide therapy in CF Clarithromycin Therapy for Patients With Cystic Fibrosis: A Randomized Controlled Trial P. Robinson, et al Pediatric Pulmonology 47: (2012).

72 Percent prevalence Prevalence of AES Range: 0.0% 44.7% AES-1 detected in 17/18 centres AES 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) State/Centre

73 Percent prevalence Prevalence of AES Range: 0.0% 66.7% AES-2 detected in 16/18 centres AES 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) State/Centre

74 CF update Antibiotic therapy in CF: Prophylactic Anti Staph treatment till 2 years age 50% treatment dose of Augmentin or Fluclox

75 CF update Antibiotic 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

76 CF update New therapies Mucolytic therapies new ones

77 CF update Mucolytic therapies New ones Inhaled mannitol Denufosol

78 CF update Mucolytic therapies New ones Inhaled mannitol Pulmozyme over 5 years age Hypertonic saline 3-6%

79 Elkins M et al. N Engl J Med 2006;354: Elkins M

80 Inhaled mannitol

81 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

82 Healthy Mucociliary System Mucociliary system (normal) Thin film of mucus Cilia Airway Surface Liquid Ciliated Cell Goblet Cell Submucosal glands

83 Mode of Action of Mannitol Cilia function improved 3 1 Mucus surface properties changed Goblet Cell 60 mm/s Ciliated Cell 4 Cough 2 Airway Surface Liquid reconstituted H 2 O H 2 O H 2 O H 2 O H 2 O 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

84 CF-301 Mean % change in FEV 1 Bilton D, Robinson P et al. European Respiratory Journal 2011:38:

85 CF update Mucolytic therapies new uses for old ones Pulmozyme (dornase alpha)

86 Over 5 years age: CF update: Pulmozyme (dornase alpha) 1 month trial showing 10% increase in FEV1 for continued therapy

87 Over 5 years age: CF update: Pulmozyme (dornase alpha) 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)

88 CF update New therapies: Mutation specific therapies Vertex trials: G551D

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90 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

91 VX-770 Phase III Study Design 102 Screening Randomization (1:1) VX mg q12h Run-in Primary analysis VX mg q12h Open-label rollover study VX mg q12h Placebo Placebo Or 2-yr Follow-up Day Week Treatment period Extension period Randomized, double-blind, placebo-controlled Recruitment: 161 subjects Key inclusion criteria G551D mutation on at least one CFTR allele Aged 12 years FEV 1 40% to 90% predicted

92 Absolute Change in FEV 1 % Predicted 15 Placebo VX-770 Absolute change in % predicted FEV1 (mean, 95% CI) Treatment effect through Week % P < Treatment effect through Week % P < Day 15 Week 8 Week 16 Week 24 Week 32 Week 40 Week 48

93 Change from Baseline in Sweat Chloride 5 0 Change in sweat chloride concentration mmol/l (mean, 95% CI) Placebo VX-770 Treatment effect through Week mmol/l P < Treatment effect through Week mmol/l P < Day 15 Week 8 Week 16 Week 24 Week 32 Week 40 Week 48

94 Change from Baseline in CFQ-R Resp Domain Treatment effect through Week P < Treatment effect through Week P < Change in CFQ-R respiratory domain points (mean, 95% CI) Placebo VX-770 MCID = 4* Day 15 Week 8 Week 16 Week 24 Week 32 Week 40 Week 48 * MCID, minimal clinically important difference (Quittner et al 2009)

95 Proportion of event-free subjects Time to First Pulmonary Exacerbation Week 24 Hazard Ratio 0.40 P = Week 48 Hazard Ratio 0.46 P = Placebo VX PLACEBO VX-770 Event-Free Rate At Week Hazard Ratio: 0.45 ( 0.28, 0.73) P= Study day

96 Change from Baseline in Weight 5 Placebo VX-770 Treatment effect at Week kg P < Treatment effect at Week kg P = Change in weight kg (mean, 95% CI) Day 15 Week 8 Week 16 Week 24 Week 32 Week 40 Week 48

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98 Lumicaftor 2 part medication Ivacaftor 3-4% increase in lung function

99 CF update Complications 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

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104 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

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107 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 2 0 to broad spectrum Ab s Crohn s: IBD 7 times more common, Crohns 17 times.

108 Osteoporosis in CF

109 Osteoporosis in CF Increasingly recognised in adults and children > 12 Children: 62 pts mean Z score (spine) and 0.71 femoral neck. (Henderson). Adults: mean Z score (spine) and (femoral neck)

110 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

111 CYSTIC FIBROSIS DIAGNOSIS Gold standard sweat test Clinically think fat malabsorption Prop develop PI nearer 12 months 5-10% PS 95% destrn

112 CYSTIC FIBROSIS PANCREATIC INSUFFICENCY Steathorrea most clinical obvious Enzymes contain all 3 enzymes Enteric coated Acidic small bowel Acid reducing agents

113 Cystic Fibrosis BOSTON TORONTO n=499 (15.9yrs) n=534 (15.2yrs) 58% males 57% males Fat restriction High fat diet FEV1 = FEV1

114 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

115 ASL

116 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, (2012)

117 P. aeruginosa-coated grids placed on HBE S. Aureus-coated grids placed on HBE AA Pezzulo et al. Nature 487, (2012)

118 ASL Found that the ASL ph was more acidic in CF pigs, and reducing ph inhibited the antimicrobial activity of ASL.

119 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.

120 Hypertonic saline

121 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

122 Nebulised Hypertonic Saline (HTS)? 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

123 Reeves Am J Respir Crit Care Med Vol

124 Nebulised Hypertonic Saline (HTS) 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

125 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): , 2012

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127 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): , 2012

128 Bugs and drugs

129 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

130 Chotirmall N Eng J Med May 2012

131 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), Chotirmall N Eng J Med May 2012

132 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)

133 Azt autophagy Studies 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. Renna The Journal of Clinical Investigation 2011;121;(9)

134 Azt autophagy Studies 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. Renna The Journal of Clinical Investigation 2011;121;(9)

135 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.

136 Pseudomonas aeruginosa Type-3 Secretion System Dampens Host Defense by Exploiting the NLRC4-coupled Inflammasome

137 Structures of needle proteins and their complexes. Blocker A J et al. PNAS 2008;105: by National Academy of Sciences

138 By capping the TSSS there would be less intracellular injection of bacterial toxins and less cell injury.

139 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

140 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

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

145 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.

146 Congenital abnormalities Laryngomalacia Clinical diagnosis Bronchoscopy for Diff Dx Resolution 2-3 years Residual insp flow limitation

147 Congenital abnormalities 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

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149 Congenital abnormalities Tracheomalacia: Isolated, 2 0 TOF, Cartilage rings, stenosis aberrant airway anatomy External compression Bronchogram vs bronchoscopy Stenting

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151 Congenital abnormalities Tracheomalacia: 2 0 TOF, vascular ring Surgical repair does not improve Pulm fnctn in short term Dying spells

152 Congenital abnormalities Pulmonary hypoplasia: Isolated Compression diaph hernia Reduced lung function Check vascular anatomy

153 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.

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155 Bronchopulmonary Sequestration Histologically, pulmonary sequestrations demonstrate immature lung development. Extralobar sequestrations have anomalous blood supply from an infradiaphragmatic source in about 20% of patients.

156 Bronchopulmonary Sequestration 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.

157 Bronchopulmonary Sequestration 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.

158 Bronchopulmonary Sequestration 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

159 Bronchopulmonary Sequestration 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.

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

162 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.

163 Congenital pulmonary airway malformations (CPAM) 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

164 Congenital pulmonary airway malformations (CPAM) 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

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167 Congenital pulmonary airway malformations (CPAM) 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

168 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.

169 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.

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171 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%).

172 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.

173 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.

174 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.

175 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.