Children's interstitial lung disease (chILD) involves the alveoli and surrounding tissues, leading to gas exchange issues. It was previously called interstitial lung disease but diffuse infiltrative lung disease is a more accurate term. Common causes of chILD include surfactant dysfunction disorders, lung growth abnormalities, neuroendocrine cell hyperplasia of infancy, and pulmonary interstitial glycogenosis. Diagnosis involves clinical evaluation, imaging like HRCT, pulmonary function tests, and sometimes lung biopsy. Management is generally supportive care though corticosteroids may help in some cases. Prognosis depends on the underlying condition but some forms of chILD have high mortality.

1. Children's Interstitial
Lung Disease [ ChILD]
MOHAMED ALFAKI

2. Interstitial lung diseases (ILDs) in childhood are
a diverse group of conditions that primarily
involve the alveoli and perialveolar tissues,
leading to derangement of gas exchange,
restrictive lung physiology, and diffuse
infiltrates on radiographs.

3. Because ILDs can involve the distal airspaces as
well as the interstitium, the term diffuse
infiltrative lung disease has been suggested.
This nomenclature may be more accurate than
ILD, but children's interstitial lung disease
(chILD) has become the preferred term.

4. Interstitium
Connective tissues within the lung
–Basement membrane of alveoli and
capillaries
–Perivascular and peri lymphatic tissues.
Function of interstitium
•Supporting lung
•Fluid balance
•Repair and remodeling
Pediatric radiology website.

5. Interstitium
3 zones
–Peripheral connective tissue(pleural)
–Axial connective tissue(central, Broncho
vascular)
–Parenchymal connective tissue(intra
lobular

9. Epidemiology: STILL LIMITTED DATA

10. Pathophysiology:
The pathophysiology is more complex
than adult disease because the injury
occurs during the process of lung
growth and differentiation.

11. In ILD, the initial injury causes damage to the
alveolar epithelium and capillary endothelium.
Abnormal healing of injured tissue may be more
prominent than inflammation in the initial steps
of the development of chronic ILD.

12. The development of a chronic inflammatory
response was thought to perpetuate the
recruitment of inflammatory and
immunoregulatory cells into the interstitium,
alveolar walls and perialveolar tissues,
progressively leading to a thickened alveolar
wall with extensive fibrosis and loss of the
alveolar gas exchange function.

13. Granulomas.
Honeycombing and cavity formation.
Fibrocalcific pleural plaques(in asbestosis ).
Bronchospasm.
Excessive bronchial secretions (caused by
inflammation of airways)

16. Schematic representation of the proposed
mechanism of diffuse alveolar damage and
fibrosis in the developing lung:

18. CLASSIFICATION OF
ChILD

19. Based on the expertise of Dr. Claire Langston

25. Clinico-pathologic classification of interstitial and
diffuse lung disease in childhood

26. I. Disorders more prevalent in infancy
Diffuse developmental disorders Acinar/alveolar dysgenesis;
alveolar capillary dysplasia with
misalignment of pulmonary
veins (ACD-MPV)
Lung growth abnormalities Pulmonary hypoplasia, chronic
neonatal lung disease (BPD)
Specific conditions of unknown or poorly
understood etiology
Neuroendocrine cell hyperplasia
of infancy (NEHI), pulmonary
interstitial glycogenosis (P.I.G.)
Surfactant dysfunction disorders SFTPB, SFTPC, ABCA3, NKX2
.1/TTF1, other genetic mutations

27. II. Disorders not specific to infancy
Disorders of the normal host
("immune intact")
Infectious/post-infectious processes,
aspiration, related to environmental agents
(hypersensitivity pneumonitis),
eosinophilic pneumonia
Disorders of the
immunocompromised host
Opportunistic infections, related to
therapeutic intervention, related to
transplantation or rejection syndromes
Disorders related to systemic
disease processes
Immune-mediated disorders (eg,
connective tissue disorders such as SLE,
polymyositis/dermatomyositis, and
systemic sclerosis), storage disease,
sarcoidosis, Langerhans cell histiocytosis,
malignant infiltrates
Disorders masquerading as ILD Arterial, venous, lymphatic disorders
Unclassified Captures cases of ILD that cannot be
classified for any reason. Common reasons
include end-stage disease, no diagnostic
biopsies, or inadequate biopsy material.

28. General diagnostic approach
Any newborn or child presenting with diffuse lung disease
should have a complete (H&P) performed.
Important history questions should include:
1)Birth history.
2)Complete family history for use of oxygen or pulmonary
deaths in any age family member.
3)Previous pulmonary infections.
4)Family history of autoimmune disease.
5)Environmental history.

29. •A careful family history is critical because
some forms of ChILD may have a genetic
basis, which may be associated with neonatal
deaths, unexplained childhood respiratory
disease, or ILD in adults

31. General physical findings
•Growth retardation, signs of weight loss, and/or
failure to thrive may be evident.
•Hypoxemia on room air is common (87% of
patients with saturation below 90% in one
series).
•Desaturation may occur during sleep, during
feeding (infants), or with exercise.
•Auscultation may reveal normal findings or dry
crackles.

32. CXR are nonspecific and not helpful for specific
diagnoses.
HRCT has been the most helpful images and may
suggest bronchiolitis obliterans, pulmonary alveolar
proteinosis, hypersensitive pneumonitis, and NEHI.
Echo. should be completed to rule out CHD and
pulmonary vein abnormalities and to identify the
presence of pulmonary HTN.

33. Patterns of Interstitial Lung Disease

41. Some chILD centers currently use iPFT in conjunction with
other testing (HRCT , bronchoscopy, and clinical findings) to
determine the need for a lung biopsy in a child with classic
findings for NEHI.
Genetic testing has emerged as a significant consideration in
the evaluation of children with chILD, especially for in
surfactant disorders.
Bronchoscopy and BAL remain important diagnostic tools in
the evaluation of children with chILD syndrome.

46. Evaluation of ILDs in children HRCT, high-resolution thin out computed tomography ACE,
angiotensin-converting enzyme; ANCA anti neutrophil cytoplasmic antibody pHT (idiopathic)
pulmonary hemosiderosis V/Q ventilation/perfusion, EPA erect posterior anterior DLCO
diffusion capacity of lung for carbon monoxide

47. Alveolar capillary dysplasia with
misalignment of pulmonary veins
A rare lethal developmental disorder of the lung that
typically causes very early postnatal respiratory distress and
persistent pulmonary hypertension unresponsive to
supportive measures.
FOXF1 gene mutation and deletions were described.
The majority of affected infants with ACDMPV have
additional malformations with :
1) Cardiac (commonly hypoplastic left heart).
2) GI (intestinal malrotation and atresia).
3) Renal abnormalities.

49. Epidemiology :
Approximately 200 cases of ACDMPV have been
reported in the literature to date.
Some cases (10%) are familial, usually with affected
siblings.
No sex predominance has been identified.
Clinical Presentation :
Affected infants are usually term or near term, and the
initial presentation is indistinguishable from PPHN.
Infants with ACDMPV respond only transiently, to
extensive therapeutic interventions, including inhaled
NO and ECMO.

50. Radiographic Findings :
Initial CXR is often normal with subsequent development of
diffuse hazy opacities.
Findings also are dependent on concurrent anomalies.

52. ACD-MPV =pulmonary veins that are normally in the interlobular septa are
malposition and accompany pulmonary arteries (A) and bronchioles (b), there is
lobular maldevelopment with no alveoli and interstitial widening .

53. ACD-MPV= the marked decrease in alveolar well capillaries is highlighted
by the endothelial cell marker

54. Diagnostic Approach :
The diagnosis of ACDMPV should be considered in infants who
present with severe hypoxemia and idiopathic pulmonary
hypertension for which no anatomic cause can be established.
Diagnosis can only be established by lung biopsy or autopsy.
Treatment and Prognosis :
Therapy is supportive.
Mechanical ventilation.
Inhaled nitric oxide.
ECMO.
The longest reported survival is 101 days.

55. Lung Growth Abnormalities Presenting as
Childhood ILD :
Etiology and Pathogenesis :
Prenatal and postnatal insults can impact lung maturation
and growth.
Distension of the lung with liquid and fetal respiratory
movements is required for normal fetal lung growth, so any
mechanism that interferes with these processes can result in
a prenatal growth disorder.

56. Early insults (before 16 weeks) :
(renal anomalies, congenital diaphragmatic hernia) may
interfere with airway branching and acinar development.
Late insults :
(premature rupture of membranes) will impact acinar
development only.
Postnatal onset growth abnormalities impact late
alveolarization, which is most evident in the subpleural space.

58. Clinical Presentation :
Tachypnea, retractions, hypoxemia, and often diffuse
radiographic abnormalities overlap with other forms of chILD.
Most infants diagnosed with lung growth abnormalities by
lung biopsy.
Radiographic findings :
Radiographic findings are variable based on the etiology, age
of the infant, and severity of the growth abnormality.
Subpleural cysts may be present and are frequently seen in
pulmonary hypoplasia associated with Down syndrome.

59. Histologic Findings :
The ratio of lung weight to body weight is the most reliable
parameter of lung growth.
The radial alveolar count in a full term infant should average
five alveolar spaces.
In prenatal onset pulmonary hypoplasia, there is a reduction
of alveolar spaces for gestational age.
Lobular simplification with alveolar enlargement, often
accentuated in the sub pleural space, characterizes
deficient alveolarization of postnatal onset.

61. Diagnostic Approach :
IPFT tests may suggest pulmonary hypoplasia but do not
exclude concurrent processes.
For infants with respiratory morbidity out of proportion to their
clinical context, lung biopsy may still be required for diagnosis
and to exclude alternative diagnoses.
Treatment and Prognosis :
Supportive care.
Treat underlying conditions.
Lung growth abnormalities are associated with considerable
morbidity and mortality when compared with other causes of
diffuse lung disease.

62. Pulmonary Interstitial Glycogenosis
Epidemiology :
The initial report of PIG included 7 neonates, 5 of whom
presented in the first 24 hours of life.
Mean age at biopsy was 1.3 ± 0.4 months.
Etiology and Pathogenesis :
The etiology of this condition is poorly understood.
Accumulation of immature mesenchymal cells within the
interstitium may represent a selective delay in the maturation
of pulmonary mesenchymal cells.

63. Clinical Presentation :
Form of chILD unique to neonates and young infants.
Most infants with PIG are symptomatic in the first days to
weeks of life, which may follow an initial period of well being
after birth.
PIG is often a self limited disorder.
Diagnosis is typically made by 6 months of age.
The clinical presentation can be highly variable.

64. PIG can occur in either term or preterm infants.
Isolated disorder or a component of other congenital
conditions.
PIG commonly occurs in the setting of lung growth
abnormalities, such as BPD and pulmonary hypoplasia.
May be observed in infants with CHD; pulmonary
hypertension; and meconium aspiration.

65. Radiographic Findings :
CXR have diffuse infiltrates or hazy opacities, but no
common (HRCT) scan pattern has been identified.

68. Histologic Findings :
Term pulmonary interstitial glycogenosis based on the
histologic finding of increased glycogen laden mesenchymal
cells in the alveolar interstitium.
Lung biopsy shows a patchy or diffuse expansion of the
alveolar walls by bland spindle-shaped cells with pale or
bubbly cytoplasm.
The cells are strongly immune positive for vimentin, a
mesenchymal marker, and periodic acid Schiff (PAS) stain
may demonstrate PAS positive material within the cytoplasm
of the cells.
Electron microscopy is considered the best approach to reveal
the accumulation of monoparticulate glycogen in these
interstitial cells

69. Currently, lung biopsy is the only way to diagnose PIG.

70. Treatment and Prognosis :
Supportive care is a mainstay of therapy.
Most children will require supplemental oxygen, and some will
require aggressive support, including mechanical ventilation and
therapy for pulmonary hypertension.
High dose pulse corticosteroids have been reported to have
benefit in case reports and case series.

71. Epidemiology :
The incidence and prevalence of NEHI are unknown.
In the ChILDRN study, NEHI cases represented 10% of all lung
biopsies from children younger than 2 years of age.
Neuroendocrine Cell Hyperplasia of Infancy
Etiology and Pathogenesis :
The etiology of NEHI is unknown, but familial cases with affected
siblings have been identified.
Neuroendocrine cells may lead to V/Q mismatch within the lung.

72. Clinical Presentation :
NEHI is a rare disorder previously termed persistent tachypnea of
infancy.
Occurs in otherwise healthy term or near term infants who present
with tachypnea and retractions, generally of insidious onset, in the
first few months to one year of life.
Crackles are prominent and hypoxemia is common, while
wheezing is rare.
Many patients develop FTT, and upper respiratory infections may
lead to exacerbation of symptoms.
iPFT in NEHI patients has been reported to reveal a mixed
physiologic pattern, including profound air trapping.

73. Radiographic Findings :
CXR may be normal or may reveal hyperinflation.
HRCT findings are distinctive with ground glass opacities
centrally and in the right middle lobe and lingula.
Air trapping is often demonstrated in expiratory images.

75. Histologic Findings :
Lung biopsies in NEHI often show minimal to no pathologic
alterations and may be initially interpreted as normal.
Patchy mild inflammation or fibrosis.
Increased proportion of neuroendocrine cells within distal
airways, best seen by bombesin and serotonin
immunohistochemistry.

77. guidelines for histologic diagnosis include:
1- neuroendocrine cells in at least 75% of total airway profile.
2- neuroendocrine cells representing at least 10% of
epithelial cells .
3-large and /or numerous neuroepithelial bodies.
4- absence of other significant airway or interstitial disease .

78. Diagnostic Approach :
Lung biopsy is currently considered the definitive diagnostic
approach.
Increasing clinical experience with the disorder and the
characteristic constellation of patient findings, radiographic
appearance, and iPFT data have led many clinicians to
confidently suggest the diagnosis without a lung biopsy.

79. The presence of an increased number of neuroendocrine
cells on lung biopsy is not sufficient for the diagnosis
because neuroendocrine cell prominence is associated
with various other pulmonary conditions, including BPD,
sudden infant death syndrome, pulmonary hypertension,
and cystic fibrosis.

80. Treatment and Prognosis :
No known definitive therapy for NEHI.
Management largely consists of general supportive care.
Most children will require supplemental oxygen, and many will
require nutritional supplementation.

82. Surfactant dysfunction disorders :

83. Surfactant production errors:
SP-B deficiency :
-AR, presents early in life with progressive respiratory distress
and failure.
-fatal by 3-6 months of age .
-The typical histopathology is
-Alveolar proteinosis with foamy , eosinophilic ,
lipoproteinaceous material filling alveoli, thickened alveolar
septa with alveolar epithelial hyperplasia.
-abnormal lamellar bodies on electron microscopy.

84. Surfactant protein C
Encoded by the SFTPC gene on chromosome 8.
The presentation of SP-C deficiency is variable .
It is AD sporadic.
Infancy early childhood , although some present in early
infancy.
Dutch study SP-C mutations accounted for approximately
25% of adult familial pulmonary fibrosis ,
Treatment include pulse corticosteroids, hydroxychloroquine
and azithromycin.

85. SP-C show a chronic pneumonitis with uniform alveolar epithelial hyperplasia,
mild interstitial widening , antra – alveolar accumulation of foamy
macrophages and cholestrol cleft .

86. Surfactant protein ABCA3
-are the most common genetic cause of respiratory failure in
full –term infant.
-inheritance AR
-ATP-binding transporter of lipids found in the membrane of
lamellar bodes in type 2
-Children varied from birth to 4 years.
-clinical features found included cough, crackles, clubbing
and FTT.
TTF1 deficiency.

87. Surfactant clearance disorder
Autoimmune PAP immune attack directed at GSM-CSF
PAP caused by CSF2RA Mutation.
PAP caused by CSF2RB Mutation.