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Diffuse Lung Diseases in Childhood
See also Chapter 427 .
Inherited Disorders of Surfactant Metabolism
Pulmonary surfactant is a mixture of phospholipids and proteins synthesized, packaged, and secreted by alveolar type II pneumocytes (AEC2s) that line the distal air spaces. This mixture forms a monolayer at the air–liquid interface that lowers surface tension at end-expiration of the respiratory cycle, preventing atelectasis and ventilation–perfusion mismatch. Four surfactant-associated proteins have been characterized: surfactant proteins A and D (SP-A, SP-D) participate in host defense in the lung, whereas surfactant proteins B and C (SP-B, SP-C) contribute to the surface tension–lowering activity of pulmonary surfactant. The adenosine triphosphate–binding cassette protein member A3, ABCA3, is a transporter located on the limiting membrane of lamellar bodies, the storage organelle for surfactant within alveolar type II cells, and has an essential role in surfactant phospholipid metabolism. The proper expression of the surfactant proteins and ABCA3 is dependent on a number of transcription factors, particularly thyroid transcription factor 1 (TTF-1). Two genes for SP-A (SFTPA1, SFTPA2) and 1 gene for SP-D (SFTPD) are located on human chromosome 10, whereas single genes encode SP-B (SFTPB), SP-C (SFTPC), TTF-1 (NKX2-1), and ABCA3 (ABCA3), which are located on human chromosomes 2, 8, 14, and 16, respectively. Inherited disorders of SP-B, SP-C, ABCA3, and TTF-1 have been recognized in humans and are collectively termed surfactant dysfunction disorders ( Table 434.1 ).
Table 434.1
Comparison of Surfactant Dysfunction Disorders
| SP-B DEFICIENCY | SP-C DISEASE | ABCA3 DEFICIENCY | TTF-1 DISORDERS | |
|---|---|---|---|---|
| Gene name | SFTPB | SFTPC | ABCA3 | NKX2-1 |
| Age of onset | Birth | Birth–adulthood | Birth–childhood; rarely adult | Birth–childhood |
| Inheritance | Recessive | Dominant/sporadic | Recessive | Sporadic/dominant |
| Mechanism | Loss of function | Gain of toxic function or dominant negative | Loss of function | Loss of function Gain of function |
| Natural history | Lethal | Variable | Generally lethal, may be chronic | Variable |
| DIAGNOSIS | ||||
| Biochemical (tracheal aspirate) | Absence of SP-B and presence of incompletely processed proSP-C | None | None | None |
| Genetic (DNA) | Sequence SFTPB | Sequence SFTPC | Sequence ABCA3 | Sequence NKX2-1; deletion analysis |
| Ultrastructural (lung biopsy–electron microscopy) | Disorganized lamellar bodies | Not specific; may have dense aggregates | Small dense lamellar bodies with eccentrically placed dense cores | Variable |
| Treatment | Lung transplantation or compassionate care | Supportive care, lung transplantation if progressing | Lung transplantation or compassionate care for infants with biallelic null mutations; lung transplantation for other mutations if progressing | Supportive care; treat coexisting conditions (hypothyroidism) |
SP , Surfactant protein.
Pathology
Histopathologically, these disorders share a unique constellation of features, including AEC2 hyperplasia, alveolar macrophage accumulation, interstitial thickening and inflammation, and alveolar proteinosis. A number of different descriptive terms have historically been applied to these disorders, including ones borrowed from adult forms of interstitial lung disease ( desquamative interstitial pneumonia , nonspecific interstitial pneumonia) as well as a disorder unique to infancy ( chronic pneumonitis of infancy ). These diagnoses in infants and children are strongly indicative of surfactant dysfunction disorders but do not distinguish which gene is responsible. As the prognosis and inheritance patterns differ depending upon the gene involved, genetic testing should be offered when one of these conditions is reported in the lung biopsy or autopsy of a child.
Deficiency of Surfactant Protein B (Surfactant Metabolism Dysfunction, Pulmonary, 1; Smdp1; Omim #265120)
Clinical Manifestations
Infants with an inherited deficiency of SP-B present in the immediate neonatal period with respiratory failure. This autosomal recessive disorder is clinically and radiographically similar to the respiratory distress syndrome (RDS) of premature infants (see Chapter 122.3 ) but typically affects full-term infants. The initial degree of respiratory distress is variable, but the disease is progressive and is refractory to mechanical ventilation, surfactant replacement therapy, and glucocorticoid administration. SP-B deficiency is observed in diverse racial and ethnic groups. Almost all affected patients have died without lung transplantation, but prolonged survival is possible in cases of partial deficiency of SP-B. Humans heterozygous for loss-of-function mutations in SFTPB are clinically normal as adults but may be at increased risk for obstructive lung disease if they also have a history of smoking.
Genetics
Multiple loss-of-function mutations in SFTPB have been identified. The most common is a net 2 base-pair insertion in codon 133 (originally termed “121ins2”, currently termed c.397delCinsGAA, p.Pro133Glu fs *95) that results in a frameshift, an unstable SP-B transcript, and absence of SP-B protein production. This mutation has accounted for 60–70% of the alleles found to date in infants identified with SP-B deficiency and is present in approximately 0.07% of European-descent individuals in large-scale sequencing projects. Most other mutations have been family-specific. A large deletion encompassing 2 exons of the SP-B gene has also been reported.
Diagnosis
A rapid, definitive diagnosis can be established with sequence analysis of SFTPB, which is available through clinical laboratories ( http://www.genetests.org ). While sequencing of SFTPB alone is available, as the phenotype of SP-B deficiency overlaps that of other surfactant dysfunction disorders, multi-gene panels using next generation sequencing (NGS) methods are supplanting sequencing of single genes. For families in which SFTPB mutations were previously identified, antenatal diagnosis can be established by preimplantation genetic diagnosis or molecular assays of DNA from chorionic villous biopsy or amniocytes, which permits advanced planning of a therapeutic regimen. Other laboratory tests remain investigational, including analysis of tracheal aspirate (effluent) for the presence or absence of SP-B protein and for incompletely processed precursor proSP-C peptides that have been identified in SP-B–deficient human infants. Immunostaining of lung biopsy tissue for the surfactant proteins can also support the diagnosis, although immunohistochemical assays for SP-B and SP-C are also generally available only on a research basis. Staining for SP-B is usually absent, but robust extracellular staining for proSP-C because of incompletely processed proSP-C peptides is observed and is diagnostic for SP-B deficiency. Such studies require a lung biopsy in a critically ill child but may be performed on lung blocks acquired at the time of autopsy, allowing for retrospective diagnosis. With electron microscopy, a lack of tubular myelin, disorganized lamellar bodies, and an accumulation of abnormal-appearing multivesicular bodies suggest abnormal lipid packaging and secretion.
Surfactant Protein C Gene Abnormalities (Surfactant Metabolism Dysfunction, Pulmonary, 2; Smdp2; Omim #610913)
SP-C is a very low molecular weight, extremely hydrophobic protein that, along with SP-B, enhances the surface tension–lowering properties of surfactant phospholipids. It is derived from proteolytic processing of a larger precursor protein (proSP-C).
Clinical Manifestations
The clinical presentation of patients with SFTPC mutations is quite variable. Some patients present at birth with symptoms, signs, and radiographic findings typical of RDS. Others present later in life, ranging from early infancy until well into adulthood , with gradual onset of respiratory insufficiency, hypoxemia, failure to thrive, and chest radiograph demonstration of interstitial lung disease, or, in the 5th or 6th decade of life, as pulmonary fibrosis . The age and severity of disease vary even within families with the same mutation. The natural history is also quite variable, with some patients improving either spontaneously or as the result of therapy or prolonged mechanical ventilation, some with persistent respiratory insufficiency, and some progressing to the point of requiring lung transplantation. This variability in severity and course of the disease does not appear to correlate with the specific mutation and also hinders accurate assessment of prognosis.
Genetics
Multiple mutations in SFTPC have been identified in association with acute and chronic lung disease in patients ranging in age from newborn to adult. A mutation on only one SFTPC allele is sufficient to cause disease. Approximately half of these mutations arise spontaneously, resulting in sporadic disease, but the remainder are inherited as a dominant trait . A threonine substitution for isoleucine in codon 73 (termed p.I73T or p.Ile73Thr) has accounted for 25–35% of the cases identified to date but is rare (not identified in gnomAD ~123,000 individuals). SFTPC mutations have been identified in diverse racial and ethnic groups. Mutations in SFTPC are thought to result in production of misfolded proSP-C that accumulates within the alveolar type II cell and causes cellular injury, or alters the normal intracellular routing of proSP-C.
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