Pulmonary Hypoplasia and Postnatal Lung Growth. Howard B. Panitch, M.D. Division of Pulmonary Medicine The Children s Hospital of Philadelphia
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1 Pulmonary Hypoplasia and Postnatal Lung Growth Howard B. Panitch, M.D. Division of Pulmonary Medicine The Children s Hospital of Philadelphia
2 Pulmonary Hypoplasia CDH GO Lung Lesion (CPAM)
3 PHP Enrollment by Diagnosis Other 1% (n=6) GO 14% LL 21% CDH 64% DX Number Enrolled CDH 433 CDH/GO 7 CDH/LL 23 GO 90 LL/GO 2 Lung Lesion 125 Other 6 Grand Total 687
4 Congenital Diaphragmatic Hernia 1: live births /10,000 total births 4 types Posterolateral ~90% of all 70-90% left-sided Anterolateral Pars sternalis Morgagni
5 Pulmonary Abnormalities in CDH Lungs physically smaller Fewer airway branches Fewer terminal units Decreased surfactant Smaller and fewer arterioles Abnormally developed Excessive smooth muscle Hypertension Abnormal response to O 2 Hislop A and Reid L. Thorax 31:450; 1976
6 Normal lung, 6 months Aw PA Alveolar surface Density (cm-1) CDH, 7 months 500 Aw 250 PA 0
7 CDH: A Heterogeneous Condition Location of hernia Degree of pulmonary hypoplasia Other organ involvement Cardiac Skeletal Gastrointestinal Associated genetic mutations Chromosomal abnormalities Animal models From Kardon G et al. Dis Model Mech 10:955;2017
8 Selected Genetic Mouse Models of Abnormal Diaphragm Development Model Diaphragm Defect Human Correlate C-Met Amuscular Unknown COUP-TFII (Nkx 3.2 conditional model) Posterior hernia (no sac) Cytogenetic hotspot 15q (D1H1, OMIM #142340) (syndromic) Fog2 (Zfpm2 lil/lil ) Posterior hernia (sac), muscle patterning defect Gab 1 Amuscular Unknown de novo mutation (non-syndromic) Gata4 +/- Central hernia (sac) Suspected, cytogenetic hotspot 8p23.1 LOX Central rupture Unknown MyoD Thin, not functional Unknown Mogen Amuscular Unknown MyoR/Capsulin Posterior hernia (?sac) Unknown Pax3 (Splotch) Amuscular Unknown RARα/RARβ2 (retinoic acid receptors) Compound receptor nulls have posterior hernias Slit3 Central midline hernia (sac) Unknown Unknown, suspected Wt1 Posterior hernia Syndromic Adapted from Ackerman KG and Greer JJ. Am J Med Genet Part C Semin Med Genet 145C: ; 2007
9 Morbidity at Discharge and Defect Size Putnam LR et al. Pediatrics 138:e ; 2016
10 Pulmonary Hypoplasia in CDH: A Two-Hit Hypothesis Space occupying lesion Embryopathy Combination?Accelerated (catch-up) growth?
11 Giant Omphalocele Omphalocele 1 in 6,000 live births - Small, giant, ruptured - Giant contains most of liver - High incidence of respiratory insufficiency
12 Chest Shape in Newborns with Abdominal Wall Defects Gastroschesis Small Omphalocele Giant Omphalocele BW (g) 2515 ± ± ± 566 GA (weeks) 37.4 ± ± ± 2.6 W1/T 1.12 ± ± ± 0.07 W2/T 0.71 ± ± ± 0.06 (H1+H2)/2T 0.68 ± ± ± 0.08 (Ac Ah)/T 2.55 ± ± ± 0.26 P < P < 0.05 Hershenson MB et al. J Pediatr Surg 20:348; 1985
13 Purported Mechanism of Pulmonary Hypoplasia in GO Deformation Sequence Intraabdominal pressure Absence of molding by liver Lateral displacement of abdominal musculature Narrowed chest Abnormal Diaphragm Development Impaired thoracic cage movement in utero Pulmonary Hypoplasia
14
15 Pulmonary Hypertension in GO N = without PH 20 with PH 9 required long term therapy (sildenafil) PH associated with Duration of mechanical ventilation Requirement for tracheostomy Need for bronchodilators Supplemental O 2 at time of NICU discharge Partridge EA et al J Pediatr Surg 49: 1767; 2014
16 Postnatal Alveolar Development Alveolar Number x Alv. No. Dunnill (1962) Alv. No. Davies & Reid (1970) Alv. Size Davies & Reid (1970) Age (years) Alveolar Size 1 ( alv./cc x ) 106 Reid LM. Br J Dis Chest 78:12; 1984
17 3/31/08 4/6/08 POD #2 5/8/08
18 1 day old 2.5 yrs old
19 Pulmonary Outcomes at 1 Yr vs Support at 30d % * * * * ** Invasive Noninvasive RA Any Inhaler ICS Diuretics O 2 Cauley RP et al. J Pediatr Surg 50:849; 2015 Severe V/Q Mismatch *p<0.001 **p<0.002
20 Pulmonary Outcomes at 5 Yr vs Support at 30d ** * * ** Invasive or Noninvasive RA % *p=0.01 **p< Any Inhaler ICS Cauley RP et al. J Pediatr Surg 50:849; 2015 Asthma Severe V/Q Mismatch
21 Standard Lung Function Testing PEFR Flow RV Flow V T FVC TLC FRC FEF Time Volume Time RV
22 CDH Study Population n = 98 (56 males) 11 days 44 months 24 <37 wk GA ( /7 wks) Support 2 no mechanical ventilation 3 prolonged: 22.2, 25.7 and 52.8 mo In remaining 93, MV d 53 ino or sildenafil 20 ECMO Panitch HB et al. Pediatr Pulmonol 50:896; 2015
23 Spirometry FVC and forced flows were lower than normal FEV 0.5 /FVC slightly reduced 23 with FEV 0.5 /FVC < Z scores Panitch HB et al. Pediatr Pulmonol 50:896; 2015
24 Lung Volumes Z scores Panitch HB et al. Pediatr Pulmonol 50:896; 2015
25 Change in Lung Function with Growth For every 1.0 ml/cm in healthy controls: FVC increased 0.78 ml/cm FRC increased 1.76 ml/cm RV increased 2.5 ml/cm 3/31/08 4/6/08 POD #2 Panitch HB et al. Pediatr Pulmonol 50:896; /8/08
26 Forced Expiratory Flows: GO Danzer E et al. J Pediatr Surg 47:1811; 2012
27 Lung Volumes: GO Danzer E et al. J Pediatr Surg 47:1811; 2012
28 Specific Conductance CDH GO Gerhardt T et al. J Pediatr 110:448; 1987
29 Subsequent Lung Growth
30 Expiratory Inspiratory R=962 ml L=792 ml TLC= 1596 ml ( =9%)
31 Long-Term Pulmonary Follow-up Ipsilateral Ventilation Ipsilateral Perfusion Kamata S et al. J Pediatr Surg 40:1833; 2005
32 Pulmonary Blood Flow at 2 Years Pulmonary Blood Flow From: Weis M et al. AJR 206:1315; 2016 Pulmonary Blood Volume
33 New BPD : Arrested Alveolar Development Normal Thin septae Uniform fibrosis Agrons GA et al. RadioGraphics 25:1047; 2005
34 Vascular Growth Factors and Alveolarization Thebaud B and Abman S. Am J Respir Crit Care Med 175:978; 2007
35 Alveolar Development and Angiogenesis Jakkula M et al. Am J Physiol Lung Cell Physiol 279:L600; 2000
36 Change in FRC and RV Over n = 29 6 persistent PAH 8 PAH first study, normal second study 15 never with PAH Time Healy F et al. Pediatr Pulmonol 50:672; 2015
37 PAH and Lung Function Presence of PAH resulted in Normal TLC but Elevated RV and FRC Elevated RV/TLC and FRC/TLC Lower forced expiratory flows Lower sgrs Persistence of PAH correlated with greater changes
38 Long-Term Follow-up 26 CDH ( yrs, X = 13.2 yrs) vs. age- and gender-matched controls _ * ** * cdh control % Predicted * FEV-1 FEV-1 After BD FEF RV / TLC 0 *p<0.001 **p<0.01 Trachsel D et al. Pediatr Pulmonol 39:433; 2005
39 CDH Adult Survivors 2 1,5 1 Z-score 0,5 0-0,5-1 -1,5-2 -2,5-3 FVC FEV 1 FEV 1 /FVC FEF 25-75% TLC RV FRC D L CO D L CO/Va Peetsold MG et al. Pediatr Pulmonol 42:325; 2007
40 How Will New Therapies Change Outcomes? Fetal Endoluminal Tracheal Occlusion (FETO) for CDH Deprest J et al. Ultrasound Obstet Gynecol 24:121; 2004
41 Next Steps: EIT 1. Healthy lung Lung imaging: Air content Lung function imaging: Change of air content
42 Left CDH, Supine
43 Summary Clinical questions regarding pulmonary parenchymal and vascular remodeling remain?function of initial cause of hypoplasia?role of initial mutation Severity of initial impairment predicts long term outcome Most survivors do functionally well Bronchospasm/RAD PAH, GERD Prenatal and postnatal interventions may be possible to alter the course of disease
44 Effect of PAH on Lung Function Healy F et al. Pediatr Pulmonol 50:672; 2015
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