Pediatric Interstitial Lung Disease and Hermansky-Pudlak Syndrome



Pediatric Interstitial Lung Disease and Hermansky-Pudlak Syndrome


Allen P. Burke, M.D.

Jennifer M. Boland, M.D.



Pediatric Interstitial Lung Disease


Terminology and Classification

Children’s interstitial lung disease (ChILD) can generally be divided into disorders more prevalent in infancy and those that can that can occur anytime during childhood but are more commonly seen in older children (>2 years).1,2,3 Diffuse lung diseases of infancy include disorders of surfactant metabolism, alveolar growth abnormalities (deficient alveolarization), diffuse developmental disorders (conditions that catastrophically affect alveolar development or vascular development), and several specific conditions of unknown etiology (neuroendocrine cell hyperplasia of infancy [NEHI] and pulmonary interstitial glycogenosis [PIG]).1,2,3

There are a variety of primary and secondary disorders that may occur throughout childhood, which can be classified based on the presence of an underlying systemic disease and the host immune status.1,3 There are also disorders that may masquerade as interstitial lung disease in children, including various causes of pulmonary hypertension, lymphatic disorders, vasculitis, and congestive heart disease.1,3 ChILD with a known genetic basis includes alveolar capillary dysplasia (see Chapter 13), surfactant disorders, disorders of macrophages resulting in alveolar proteinosis, and usual interstitial pneumonia (UIP).4,5 The last entity rarely occurs in children; familial IPF and its genetic basis are discussed in Chapter 17.

Interstitial lung diseases that primarily involve infants are generally classified separately from those occurring in children and adolescents (Table 15.1).1,2,3,6,7 For older children and young adults, a classification similar to that used in adults has been proposed.6 However, idiopathic interstitial pneumonias (acute interstitial pneumonia, UIP, nonspecific interstitial pneumonia [NSIP], and respiratory bronchiolitis-interstitial lung disease) rarely if ever occur in young children. A particularly confusing factor is the historical use of “desquamative interstitial pneumonia,” or DIP, for one of the typical histologic appearances of congenital surfactant disorders. The use of terms such as “cryptogenic alveolitis,” DIP, and early interstitial pneumonia in the context of pediatric lung disease is now obsolete.8 The term DIP should be reserved for the typical smoking-related interstitial lung disease seen in adults (Chapter 18).








TABLE 15.1 Classification of Pediatric Interstitial Lung Diseasea













































Condition (Diseases of Infancy in Bold)

Comment


Diffuse developmental disorders (i.e., dysplasias)

Acinar and alveolar dysplasias are rare, associated with pulmonary hypoplasia (see Chapter 12). Acinar dysplasia resembles arrest at pseudoglandular phase of development; alveolar dysplasia resembles arrest at saccular phase.

Acinar dysplasia


Congenital alveolar dysplasia

Alveolar capillary dysplasia with misalignment of pulmonary veins

Alveolar capillary dysplasia (see Chapter 13)


Surfactant disorders

See Table 15.2


Alveolar growth abnormalities (AGA)

Alveolar simplification often with cystic change, most commonly observed in context of chronic lung disease of prematurity (see Chapter 14); similar changes may occur in trisomy 21 and congenital heart disease.


Pulmonary interstitial glycogenosis

Glycogen-rich mesenchymal cells in the interstitium; usually occurs as a secondary change (nonspecific change), but may be idiopathic


Neuroendocrine cell hyperplasia of infancy

Normal histologic findings; increased bombesin-secreting neuroendocrine cells in >75% of airways, >10% of airway epithelium


Cryptogenic organizing pneumonia

Overlaps with adult disease (see Chapter 19)


Hypersensitivity pneumonitis

Overlaps with adult disease (see Chapter 23)


Eosinophilic lung disease

Loeffler syndrome (transient infiltrates, often precipitated by parasitic infection)


Eosinophilic pneumonitis (acute and chronic); dramatic response to corticosteroids


Diffuse alveolar hemorrhage syndromes

See Chapter 29


Systemic disorders

Collagen vascular disease


Storage diseases


Sarcoidosis


Langerhans cell histiocytosis


aA similar classification for interstitial lung disease as used in adults has also been applied to children, although the idiopathic interstitial pneumonias occur rarely if at all in infants and young children. The table presents those that occur with any frequency in children6.


Modified from Cazzato S, et al. Interstitial lung disease in children. Early Hum Dev. 2013;89(suppl. 3):S39-S43.



Incidence

The incidence of pediatric interstitial lung disease has been estimated at 3 to 4 per million.7,8 Prior to routine genetic testing, the frequency of familial pediatric interstitial lung disease (ILD) was less than 25%.8


Disorders of Surfactant Metabolism


Clinical Features

Infants with congenital disorders of surfactant metabolism classically present with a syndrome similar to neonatal respiratory distress syndrome (NRDS)/hyaline membrane disease, occurring in a term infant (rather than the typical premature infant where NRDS would be expected due to functional surfactant deficiency).9 Symptoms include respiratory distress with cough and tachypnea.9 There is generally hypoxemia with diffuse bilateral infiltrates on chest radiographs and CT scans,7 which may include ground-glass opacities, “crazy paving” pattern, or complete whiteout of the bilateral lung fields. However, as more is learned about surfactant-related disorders and genetic testing for causative mutations is more readily available, it is becoming apparent that the clinical course is variable, and some children may present after infancy or even into teenage years and young adulthood with chronic pulmonary disease.9









TABLE 15.2 Genetic Basis for Children’s Interstitial Lung Disease





























































Genetic Syndrome

OMIM

Gene, Chromosomal Location, Mechanism

Inheritance

Pathology

Age at Onset and Clinical Course


SP-B deficiency

#265120

SMDP1 SFTPB 2p12-p11.2 Loss of function

Autosomal recessive

Surfactant dysfunction

Neonatal onset, severe, fatal


ABCA3 deficiency

#610921 SMDP3

ABCA3 16p13.3 Loss of function

Autosomal recessive

Surfactant dysfunction

Neonatal to childhood onset, variable


SP-C dysfunction

#610913 SMDP2

SFTPC 8p21 Toxic gain in function

Autosomal dominant

Surfactant dysfunction

Neonatal to young adult, variable


Brain-thyroid-lung syndrome

#610978

TTF1 (NKX2.1) 14q13.3 Haploinsufficiency

Autosomal dominant, sporadic

Surfactant dysfunction

Newborn, hypothyroid, variable


GM-CSF receptor deficiency, α chain

#300770 SMDP4

CSF2RA Xp22.32, Yp11.3 Loss of function

Autosomal recessive

Alveolar proteinosis

Childhood, variable


Lysinuric protein intolerance

#222700

SLC7A7 14q11.2 Loss of function

Autosomal recessive

Alveolar proteinosis

Infancy to childhood, hyperammonemia, progressive course


Alveolar capillary dysplasia (see Chapter 13)

#265380

FOXF1 16q24.1 Haploinsufficiency

Autosomal dominant, sporadic

Misalignment of pulmonary veins, alveolar capillary dysplasia

Neonatal, severe, and fatal


Adapted from Nogee LM. Genetic basis of children’s interstitial lung disease. Pediatr Allergy Immunol Pulmonol. 2010;23(1):15-24



Etiology and Genetics of Surfactant-Related Disorders

Most genetic interstitial lung diseases of infancy are attributed to genes that encode proteins involved in surfactant metabolism (Table 15.2). These include ABCA3 (ATP-binding cassette transporter protein A3), SP-B, SP-C, and TTF-1 (thyroid transcription factor 1), also known as NKX2.1, which is involved in transcription of surfactant proteins.5,7

Surfactant is a mixture of lipids and proteins whose function is to reduce alveolar surface tension. It is produced by type II pneumocytes within lamellar bodies and secreted by exocytosis. The lipid portion, largely disaturated phosphatidylcholine, requires hydrophobic proteins SP-B and SP-C in addition to more hydrophilic proteins SP-A and SP-D. Because surfactant is catabolized by alveolar macrophages by a mechanism dependent on GM-CSF (granulocyte-monocyte colony-stimulating factor) signaling, macrophage defects may also result in lung disease, usually resembling pulmonary alveolar proteinosis (PAP). In adults, PAP occurs from antibodies to GM-CSF (see Chapter 28), whereas in infants and children, the defect is usually genetic.5,7

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  4. Miscellaneous Carcinomas of the Thymus

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Aug 19, 2016 | Posted by in CARDIOLOGY | Comments Off on Pediatric Interstitial Lung Disease and Hermansky-Pudlak Syndrome

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