Children's Interstitial Lung Disease [ ChILD]

MOHAMED ALFAKI

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.

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.

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.

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

Epidemiology: STILL LIMITTED DATA

Pathophysiology:

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

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.

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.

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

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

CLASSIFICATION OF ChILD

Based on the expertise of Dr. Claire Langston

Clinico-pathologic classification of interstitial and diffuse lung disease in

childhood

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

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.

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.

•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

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.

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.

Patterns of Interstitial Lung Disease

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.

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

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.

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.

Radiographic Findings :

Initial CXR is often normal with subsequent development of diffuse hazy opacities.

Findings also are dependent on concurrent anomalies.

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 .

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

Radiographic Findings :

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

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

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

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.

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.

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.

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.

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.

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 .

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.

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.

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.

Surfactant dysfunction disorders :

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.

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.

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

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.

Surfactant clearance disorder

Autoimmune PAP immune attack directed at GSM-CSFPAP caused by CSF2RA Mutation.PAP caused by CSF2RB Mutation.