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.