What is the recommended diagnostic evaluation and treatment strategy for a newborn or infant with suspected metabolic surfactant dysfunction presenting with persistent hypoxemia, diffuse ground‑glass opacities on high‑resolution chest computed tomography, and recurrent respiratory distress unresponsive to standard therapy?

Metabolic Surfactant Dysfunction in Children

Diagnostic Evaluation

For newborns or infants presenting with persistent hypoxemia, diffuse ground-glass opacities on high-resolution chest CT, and recurrent respiratory distress unresponsive to standard therapy, genetic testing for surfactant protein mutations should be performed immediately, as these findings are pathognomonic for inherited surfactant metabolism disorders. 1

Clinical Recognition Criteria

• Full-term or late-preterm infants with severe, prolonged respiratory failure and diffuse lung infiltrates on chest radiograph or CT scan warrant immediate suspicion for surfactant protein dysfunction syndromes. 1

• The classic presentation includes acute, severe respiratory dysfunction in the neonatal period (for SFTPB, ABCA3, NKX2.1 mutations) or chronic respiratory insufficiency of variable onset and severity in later infancy and childhood (for SFTPC, ABCA3, NKX2.1 mutations). 2, 3

• Persistent respiratory distress despite exogenous surfactant administration is a critical red flag distinguishing genetic surfactant disorders from typical respiratory distress syndrome. 1, 4

Specific Genetic Testing Algorithm

• Order genetic sequencing for the following genes in priority order:

  • SFTPB (surfactant protein B deficiency) 2, 5
  • ABCA3 (ATP binding cassette member A3) 2, 6
  • SFTPC (surfactant protein C) 2, 5
  • NKX2.1 (thyroid transcription factor) 2, 3

• Genetic testing establishes definitive diagnosis and should be sent before proceeding to lung biopsy when the clinical presentation is consistent. 2

Adjunctive Diagnostic Studies

• Lung biopsy with electron microscopy is a useful adjunct when genetic testing is pending or results are equivocal, as it can reveal characteristic ultrastructural abnormalities. 2

• High-resolution chest CT typically shows diffuse ground-glass opacities, which, combined with the clinical picture, strongly suggests surfactant dysfunction. 1

• Echocardiography should be performed to assess for associated pulmonary hypertension, which is commonly described in these disorders. 1

Treatment Strategy

Acute Neonatal Presentation (SFTPB, ABCA3 Deficiency)

For surfactant protein-B deficiency and ABCA3 deficiency presenting with acute neonatal respiratory failure, the only definitive treatment options are lung transplantation or compassionate care, as these conditions are uniformly lethal without transplantation. 2

• Exogenous surfactant replacement is ineffective in these genetic disorders because the underlying defect is in surfactant protein production or function, not quantity. 1, 2

• Supportive mechanical ventilation should be provided as a bridge to lung transplantation evaluation, but families must be counseled that this is temporizing, not curative. 2

• Lung transplantation is the only route to long-term survival for infants with surfactant protein-B deficiency or severe ABCA3 deficiency presenting in the neonatal period. 1, 2

• The natural history of these acute presentations is relentless progression without transplantation, with most infants dying within the first months of life. 1

Chronic Presentation (SFTPC, ABCA3, NKX2.1)

For the more chronic presentations of surfactant protein-C, ABCA3, and NKX2.1-associated disease, individualized supportive care is appropriate because the natural history is highly variable, ranging from mild chronic lung disease to progressive respiratory failure. 2

• Oxygen supplementation targeting saturations of 92-94% to prevent hypoxemia-related pulmonary hypertension. 1

• Aggressive treatment of underlying lung disease including:

  • Evaluation for chronic reflux and aspiration 1
  • Assessment for structural airway abnormalities (tonsillar/adenoidal hypertrophy, vocal cord paralysis, subglottic stenosis, tracheomalacia) 1
  • Bronchodilator therapy for bronchoreactivity 1
  • Diuretics for lung edema 1

• Serial pulmonary function monitoring and growth assessment, as feeding dysfunction and poor growth are markers of severe disease. 1

Management of Associated Pulmonary Hypertension

• Echocardiographic screening should be performed at diagnosis and serially every 4-6 months, as pulmonary hypertension is a common and life-threatening complication. 1

• Pulmonary vasodilator therapy may be considered for documented pulmonary hypertension, though data demonstrating efficacy in this specific population are extremely limited. 1

• Options include inhaled nitric oxide (10-20 ppm, weaned to 2-10 ppm), sildenafil, endothelin receptor antagonists, or calcium channel blockers, but these should only be used after thorough diagnostic evaluation. 1

Critical Pitfalls to Avoid

• Do not assume standard surfactant replacement will be effective in genetic surfactant disorders; failure to respond to exogenous surfactant should immediately trigger genetic evaluation. 1, 2

• Do not delay genetic testing while pursuing empiric therapies; early diagnosis is essential for appropriate counseling and transplant evaluation. 2, 3

• Do not overlook associated conditions in NKX2.1 mutations, which cause brain and thyroid developmental abnormalities in addition to lung disease. 2, 3

• Recognize that SFTPB and severe ABCA3 deficiency are uniformly fatal without lung transplantation; prolonged aggressive support without transplant planning is futile. 1, 2, 6

• Avoid attributing respiratory failure solely to prematurity in late-preterm or term infants with severe, persistent disease; genetic surfactant disorders must be considered. 1, 4