Discussion
We previously reported three term infants with SFTPC pathogenic variants who presented with post-neonatal respiratory failure and were supported with tracheostomy and chronic mechanical ventilation(1). At the time, chronic invasive mechanical ventilation was a novel, alternative approach to lung transplantation (12). However, tracheostomy placement carries significant risks including bleeding, infection, and sudden death resulting from tube occlusion and parents assume a huge burden of care(13).
Historically, home NIV was suboptimal for children due to limitations surrounding ventilator size, mask size and fit, skin breakdown, midface hypoplasia, impeding developmental skills, and insurance approval. In two infants with SFTPC pathogenic variants, we used NIV which avoided additional medical complexity associated with tracheostomy while still permitting developmental therapies. Infant 2 was treated with enteral corticosteroids (instead of intravenously), further decreasing medical complexity and family burden. As ventilator technology improves with less dead space, better synchrony, and smaller, infant-appropriate masks, NIV may be an effective therapy for infants with respiratory insufficiency.
SFTPC pathogenic variants act in an autosomal dominant manner with variable penetrance or arise de novo .(7) Among families with the same inherited SFTPC variant, age of presentation varies, ranging from neonatal respiratory failure to adult pulmonary fibrosis(8). SFTPC encodes a 191 or 197-amino acid precursor protein (proSP-C), which undergoes proteolytic processing resulting in an extremely hydrophobic, 35-amino mature protein. The c.Gly97Cys and c.Cys189Tyr variants identified in these infants are located within the BRICHOS domain which mediates folding and processing of proSP-C (9-11).SFTPC variants within the BRICHOS domain result in retention of mutant proSP-C in the endoplasmic reticulum and subsequent cellular stress, activation of the unfolded protein response, AEC2 apoptosis, increased cytokine production, macrophage recruitment, polycellular alveolitis, and fibrosis (11).
Histologic findings among children with SFTPC pathogenic variants include alveolar proteinosis, non-specific interstitial pneumonia or desquamative interstitial pneumonia, depending on timing of biopsy(14). The alveolar proteinosis associated with infantile SFTPCpathogenic variants typically will improve with time through macrophage catabolism, visualized with clearance of ground-glass opacities on chest CT (15). SFTPC pathogenic variants result in diverse respiratory phenotypes, and affected infants and children may require prolonged hospitalization due to slow improvement: families and care providers should be prepared for this. Like bronchopulmonary dysplasia, infants with SFTPC pathogenic variants benefit from higher positive end expiratory pressure (PEEP) to prevent atelectasis, but conversely, may benefit from lower tidal volumes and higher rates to limit further alveolar injury. Clinical phenotype varies dramatically, and discussions of transplantation and comfort care may still be appropriate with treatment course personalized to each child. ChILD Centers of Excellence have expertise with these rare and complex patients and may help guide these decisions. We present two infants with SFTPC pathogenic variants managed with NIV as an alternative therapy to transplantation, comfort care, or tracheostomy placement.
The authors wish to acknowledge Dr. Lawrence Nogee for his additional expertise in SFTPC pathogenic variants.
Figure 1. Clinical courses of our two patients withSFTPC pathogenic variants
Figure 2. Chest CT imaging from two cases with SFTPCpathogenic variants. 2A: Case 1 at 2 weeks of age with diffuse ground-glass opacities. 2B: Case 1 at 2 years of age with clearing of ground-glass opacities. 2C: Case 2 at 3 months of age with diffuse ground-glass opacities.