Selected Pulmonary Disorders byDr Harry Kozakewich.pdf

Presented by Dr Harry Kozakewich M.D.
Children’s Hospital Boston
Harvard Medical School

1. Harry Kozakewich M.D.
Children’s Hospital Boston
Harvard Medical School

2. Post Mortem Evaluation of Pre-
and Postnatal Pulmonary
Development
•Weight (somewhat informative but may also be
misleading). Lung weight/body weight ratios also
available.
•Inflated volume very informative
•Hypoplasia best detected by this method
•Inflated volume might be decreased in diffuse
fibrosing or destructive processes
•Virtually all hypoplastic lungs have a decreased
number of airways

3. Airway Development
•Development between 5-“16” wk gestation
•One or 2 respiratory bronchioles added between
16 and 24 weeks gestation
•Number of generations varies between 15 and 26
depending on segment (this includes terminal and
respiratory bronchioles)
•Axial and non-axial branching
•Number of airways without cartilage support
varies between 3 to 9

4. Airway Generation Methodology
•Airway number may be desirable
•Gross dissection of airway +/- submission of block
for step sectioning for determination of last few
generations

5. Alveolar Development

•Alveolar development begins after 16 wk
gestation
•Type I and type II cells detectable at 6 mo
gestation
•At birth, 8% of alveoli present
•Alveoli increase in number until 8 yr of age
•Thereafter, alveoli increase in size until chest wall
growth ceases with onset of adulthood

6. Radial Alveolar Count
•Not a substitute for lung volume
•Values and methodology vary somewhat

•Alveolar size- difficult to evaluate in lungs
not fixed under continuous pressure

7. Evaluation of Pulmonary Arteries
for Hypertensive Change
•Barium-gelatin arterial injection and radiography rarely
done because conditions need to be strictly controlled
•Values of pulmonary arterial medial thickness of arteries
of different size at different prenatal and postnatal ages are
available in routine sections
•Note extension of muscle beyond respiratory bronchiolar
level in newborn
•Note alveolar-artery ratio
•Reid-Rabinowitz classification of hypertension (detects
early hypertensive changes
•Heath-Edwards classification is typically used

8. Some Examples of Pulmonary
Entities

9. CASE 1
•PNUS at 20 wk.showed echogenic mass in
posterior-medial portion of RLL with aortic
branch.
•Intralobar sequestration diagnosis.
•Slight initial enlargement followed by
decrease towards term.
•RLL posterior segmentectomy at 7 mo.

11. DEFINITIONS

•extralobar sequestration (extralobar mass with
systemic blood supply and invariable bronchial
atresia. CCAM often present.
•intralobar sequestration (intralobar segment(s)
with systemic arterial supply; CCAM and BA
usually present).
•congenital cystic adenomatoid malformation
(intralobar segment(s) with pulmonary blood
supply; BA usually present).
•lobar emphysema (normal blood supply;
emphysema or polyalveolar change; bronchial
obstruction sometimes present).

12. PROSPECTIVE STUDY OF BRONCHIAL
ATRESIA IN LUNG SPECIMENS
(lobar, segmental or subsegmental)
• (47 specimens in 4 years at CHB assessed
with aid of dissecting microscope).

• 100 % in extralobar sequestration.
• 82 % in intralobar sequestration.
• 70 % in congenital cystic adenomatoid
malformation.
• 50 % in lobar emphysema (minor CCAM).

13. BRONCHIAL ATRESIA AND
CCAM NEARLY ALWAYS
ACCOMPANY EACH
OTHER
•Bronchial atresia:

•100 % of ELS
•82 % of ILS
•70 % of CCAM
•“LE” with minor
CCAM
•CCAM:

•91 % of ELS
•91 % of ILS
•100 % of CCAM
•“LE” with BA

14. COMMENT
•ILS and CCAM probably have their onset during
6-16 weeks of fetal life when the bronchial tree
develops.
•?Does BA cause CCAM because of “obstruction”.
•?Are BA and CCAM manifestations of the same
etiology.
•Experimental model of tracheal obstruction in first
trimester trimester not reported.
•Tracheal occlusion in human fetuses in second
trimester or beyond produces polyalveolar change
•Experimental genetic models have not produced
convincing CCAM.

15. CASE 2
•PNUS diagnosis of HLHS.
•Term, balloon ASD on first day.
•Difficulty with oxygenation and ventilation
requiring VV ECMO.
•Stage I Norwood day 8 (also lung biopsy).
•Could not be weaned off bypass and
remained on ECMO.

21. ALVEOLAR-CAPILLARY
DYSPLASIA
•Typical presenttaion is respiratory distress
within hours after birth and persistent
pulmonary hypertension.
•Poor response to NO requiring ECMO.
•Invariably fatal.

23. PULMONARY PATHOLOGY
•Large, heavy, pale, poorly fissured lungs.
•Large inflated volumes.
•Diminished bronchial branching.
•Small caliber pulmonary arterial tree.
•Simplified acinus.
•Variable expansion of alveolar septa with stromal
cells.
•Diminished capillaries , many not fused with
alveolar basement membrane.
•Medial muscular hyperplasia of small pulmonary
arteries.
•Misaligned small pulmonary veins.

25. COMMENTS
•Two thirds have one or more associated
malformations such as CHD, absent gall
bladder, intestinal malrotation, annular
pancreas, Hirschsprung, hydronephrosis,
internal genital anomalies.
•May be autosomal recessive.
•Gene not yet identified.
•26 infants at CHB in 90 years.

26. CASE 3
•PROM, born at 28 weeks.
•Mother had been treated for Wilms when
she was 8 weeks of age.
•Respiratory distress at 10 minutes, thought
to have respiratory distress syndrome.
•Respiratory failure and death at 35 hours.

31. PATHOLOGY

•Major abnormality in this newborn is excess
of pulmonary interstitial mesenchymal cells.
•These cells are prominent in the developing
lung up to about 28 weeks.
•Cells have few organelles and abundant
glycogen; thought to participate in matrix
production and surfactant synthesis.
•Excess may affect pulmonary compliance.
•No good marker for these cells

32. CELLULAR INTERSTITIAL
PNEUMONITIS IN INFANTS/
PULMONARY INTERSTITIAL
GLYCOGENOSIS

•Described by Shroeder et al in 1992 and Canakis
et al in 2002 respectively.
•Infants generally present in the first day, weeks or
months of life with tachypnea and desaturation.
•Xrays show interstitial infiltrates and
hyperinflation.
•Response to steroids.
•Long term outcome is favorable.

33. CHB EXPERIENCE
•Three newborns were identified at CHB during a
recent review of lung sections in over 1600
children (mostly autopsies) in a search for
alveolar-capillary dysplasia spanning eight
decades.
•These newborns (1 preterm, 2 term) were born in
1973, 1974 and 1981 had marked and diffuse
involvement and died within 48 hours after birth.
•Confounding effects of therapy after several days
of life probably preclude confident identification
of similar cases in the modern era.

34. Excess of Interstitial Mesenchymal
Cells
•Also found in some cases of
sequestration/congenital cystic adenomatoid
malformation.
•Miscellaneous

35. CASE 4
•Born at term with no problems.
•In retrospect, “breathing fast” since birth
•Failure to thrive at two months and extensive
investigation negative.
•Admitted at 5.5 mo. with hypoxia and pulmonary
infiltrates with RSV but infiltrates of ground glass
type failed to clear.
•BAL showed absent surfactant C.
•Mutation in gene for surfactant C found.
•Lung biopsy done at 7mo.

43. CASE 4 (cont’d)
•Required nasal oxygen.
•Chloroquine started with good improvement
•At 3 yr, off oxygen but abnormal radiograph
•Parents had repeated pneumothoraces in
adolesecnce; father has clubbing.
•Patient’s two siblings have “asthma”.
•Father and one sibling have identical
mutations.

44. SP-C PATHOLOGY
•Marked, diffuse alveolar cell hyperplasia.
•Variable PAS+ material in alveolar spaces.
•Variable alveolar macrophages including
foamy macrophages and cholesterol clefts.
•Mild interstitial mononuclear infiltrate.
•Increased interstitial reticulin.
•Normal lamellar bodies by ultrastructure.

45. SP-C PHYSIOLOGY
•Stored and synthesized in type II cells.
•Minor component of lamellar bodies.
•Recycled by type II or catabolized by type
II or macrophages.

46. SURFACTANT C
DEFICIENCY
•Autosomal dominant, heterogeneous.
•Much milder disease than Sp-B deficiency.
•Only rarely present in newborn period.
•Usually present later in infancy as well as
childhood or even adulthood with tachypnea
and cough with gradual disease progression.
•Steroids and chloroquine helpful.

47. CASE 5
•Born at 35.5 weeks by C-section for PROM and
PIH.
•Respiratory distress within minutes requiring
intubation for 3 wk. and nasal oxygen thereafter.
•At 3 mo., CT showed diffuse alveolar-interstitial
disease and small, symmetrical diffuse cysts not
consistent with the usual BPD.
•Lung biopsy done at 3 mo.

48. CASE 5 (cont’d)
•Infant also had hypothyroidism, hemihypertrophy,
developmental delay, and CNS findings including
pachygyria.
•Karyotpye showed an interstitial deletion on
chromosome 14(14Q 12-21.3) which encompasses
thyroid transcription factor-1 gene.
•Died at 8 mo. with pneumonia and respiratory
failure.

53. ADDITIONAL AUTOPSY
FINDINGS
•Normally fissured lungs.
•Slightly heavy (pneumonia).
•Nearly normal inflated volume.
•Diminished bronchial generation count
• (15 obs./21 exp. in lateral segment of LLL)
•Irregular, marked “emphysema”.
•Absent left lobe of thyroid.
•Partially intrapericardial thymus.

54. Photo of lung

57. ROLE OF TTF-1 IN LUNG
DEVELOPMENT
•Essential for morphogenesis of thyroid, lungs and
parts of brain.
•Knockout mice fail to develop these organs.
•Expressed in primitive lung bud epithelium and
differentiating epithelium.
•Postnatally, expression abundant in type II cells.
•Essential for complete induction of embryonic
lung branching, epithelial proliferation, and distal
structures including type II cells.
•Regulatory role in expression of genes for
surfactant and Clara cell secretory protein.

58. CASE 6
•Born at term to a opiate addicted, HIV-, Hep C+
mother.
•Episodic tachpnea with retractions, and cyanosis
prompted visit at 2 mo.
•Chest radiograph showed hyperinflation.
•Extensive work-up negative.
•Some benefit with nebulized albuterol.
•Lung biopsy done at 4 mo.; lungs looked normal
to the surgeon.

64. Immunopositive cells 22/29 (76%)airways

65. NEUROENDOCRINE
HYPERPLASIA OF
INFANCY
•Infants and children under 2 years.
•Tachypnea, retractions, hypoxia, crackles
upon auscultation, patchy interstitial
infiltrates and hyperinflation by imaging.
•Various therapies have little effect.
•Most children improve over several years.

66. NEUROENDOCRINE
HYPERPLASIA OF
INFANCY
•Pulmonary neuroendocrine cells appear at 8 wk.
gestation, peak at mid-gestation and drop to adult
levels by term.
•Bombesin-like peptide is the most common
neuropeptide; plays a role in lung development,
affects airway and arterial tone, and plays a role in
macrophage function.
•Neuroendocrine cells increased in BPD, Wilson-
Mikity syndrome, SIDS, CF, asthma and
mechanical ventilation.

67. PATHOLOGY OF NEHI
•Relatively minor changes in lung biopsy.
•Slightly increased airway smooth muscle.
•Increased alveolar macrophages.
•Occasional mild periairway infiltrates.
•Increased “clear cells” in distal airways.
•Bombesin-like peptide particularly
increased.

68. FOLLOW-UP
•Inhalational therapies.
•Symptoms worsened over the next year
with focal pulmonary interstitial markings.
•Repeat lung biopsy done at 17 mo.

70. SYNAPTOPHYSIN

71. FOLLOW-UP (cont’d)
•Child now 3.5 yr.
•Symptoms have improved over the past
year.

72. Other Disorders

73. EXTRALOBAR SEQUESTRATION

74. CYSTIC ADENOMATOID
MALFORMATION

75. CYSTIC ADENOMATOID
MALFORMATION

76. “LOBAR EMPHYSEMA”

77. END