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\begin{document}

\title{Non-invasive management of infants with SFTPC pathogenic variants}



\author[1]{Deborah R. Liptzin}%
\author[2]{Matthew McGraw}%
\author[3]{Timothy Stidham}%
\author[4]{Jennifer Wambach (Guest Editor)}%
\author[1]{Robin Deterding}%
\affil[1]{University of Colorado Anschutz Medical Campus Department of Pediatrics}%
\affil[2]{University of Rochester Medical Center}%
\affil[3]{Logan Health}%
\affil[4]{Washington University in St Louis Department of Pediatrics}%


\vspace{-1em}



  
  \date{May 25, 2024}


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\selectlanguage{english}
\begin{abstract}
Pathogenic variants in the Surfactant Protein C gene ( \emph{SFTPC})
result in fibrotic childhood interstitial lung disease (chILD). We
previously reported three children with \emph{SFTPC} pathogenic variants
with respiratory failure who were supported by chronic invasive
ventilation via tracheostomy as an alternative to lung transplantation
or comfort care {[}(1){]}(\#ref-0001). We present two children with
\emph{SFTPC} pathogenic variants treated with non-invasive ventilation
(NIV) (Figure 1).%
\end{abstract}%



\sloppy


Non-invasive management of infants with \emph{SFTPC} pathogenic variants

Deborah R Liptzin MD MS\textsuperscript{1*}, Matthew D. McGraw,
MD\textsuperscript{2}, Timothy Stidham, MD\textsuperscript{3}, Jennifer
A. Wambach, MD, MS\textsuperscript{4}, Robin R. Deterding,
MD\textsuperscript{1}

\textsuperscript{1}Department of Pediatrics, Section of Pulmonary and
Sleep Medicine, University of Colorado, Aurora,
CO;\textsuperscript{2}Department of Pediatrics, Division of Pulmonology,
University of Rochester Medical Center, Rochester,
NY;\textsuperscript{3}Department of Pediatrics, Division of Pediatric
Critical Care, Logan Health Medical Center, Kalispell,
MT;\textsuperscript{4}Edward Mallinckrodt Department of Pediatrics,
Washington University School of Medicine and St. Louis Children's
Hospital, St. Louis, MO.

Funding Sources: DRL has funding from the National Institute of Health
UG1OD024952. MDM reports grant support from the National Institute of
Environmental Health Sciences (NIEHS) P30ES001247, K08ES033290, and
Boehringer Ingelheim (BI) as a scientific advisory committee member for
childhood interstitial lung disease. JAW reports grant support from the
National Heart, Lung and Blood Institute (R01 HL149853, U01 HL134745)
and the Children's Discovery Institute. TS reports no funding or
conflicts of interest. RRD reports the following:

-Now Vitals, CEO and Founder

-Boehringer Ingelheim, Consultant and Coordinating Investigator

-Earables, Founder and Chief Medical Officer

-EvoEndo, Consultant and Founder

-Roche, Inc., Consultant

-The France Foundation, Consultant

*Corresponding Author: Deborah R Liptzin, dliptzin@yahoo.com

\textbf{To the Editor:}

Pathogenic variants in the Surfactant Protein C gene (\emph{SFTPC} )
result in fibrotic childhood interstitial lung disease (chILD). We
previously reported three children with \emph{SFTPC} pathogenic variants
with respiratory failure who were supported by chronic invasive
ventilation via tracheostomy as an alternative to lung transplantation
or comfort care (1). We present two children with \emph{SFTPC}
pathogenic variants treated with non-invasive ventilation (NIV) (Figure
1).

\emph{Case 1}

A full-term male with unremarkable pregnancy and birth histories
presented at one week of life with tachypnea and hypoxemia that
progressed to respiratory failure requiring invasive mechanical
ventilation with high frequency oscillatory ventilation (HFOV).
Echocardiogram was unremarkable and infectious workup was negative.
Chest computed tomography (CT) demonstrated patchy airspace
consolidation with diffuse parenchymal ground-glass opacities (Figure
2A). Lung biopsy showed alveolar type II cell (AEC2) hyperplasia,
alveolar septal fibrosis, and abundant reactive intra-alveolar
macrophages. Genetic testing revealed a \emph{de novo}
\emph{SFTPC}(NM\_003018.3) pathogenic variant:
c.566G\textgreater{}A,p.Cys189Tyr. This previously reported (2) variant
affects a conserved amino acid within the BRICHOS chaperone domain, is
not present in large adult genomic databases (3, 4), and is predicted
damaging by \emph{in silico}(5, 6).

Following diagnosis, treatment was initiated with high-dose intravenous
methylprednisolone (30mg/kg IV daily for three days every month),
azithromycin (5mg/kg enterally three times weekly), and
hydroxychloroquine (7mg/kg enterally daily). The infant's oxygenation
improved following corticosteroid administrations, transitioning
sequentially from HFOV to conventional mechanical ventilation, NIV, and
ultimately nasal cannula oxygen (Figure 1A). He received feeding
supplementation via nasogastric tube for 7 months, and medications at
time of hospital discharge included azithromycin and hydroxychloroquine.
At 8 months, supplemental oxygen was discontinued. At 2 years, chest CT
showed improved parenchymal infiltrates, and enteral medications were
discontinued (Figure 2B). At time of last follow-up visit, he remained
nonmonic off oxygen and without significant developmental delays.

\emph{Case 2}

A full-term male with unremarkable pregnancy and birth histories was
diagnosed with failure to thrive at his 2-week well child check
prompting hospital admission (Figure 1B). Echocardiogram was
unremarkable. Infectious workup was remarkable for nonspecific chest
radiograph findings. A video fluoroscopic swallow study noted
incoordination, and nasogastric feeds were initiated. He desaturated
with sleep and was discharged with nasal cannula oxygen.

He was readmitted at 3.5 months for fever, emesis, increased work of
breathing, and increased oxygen requirement. Chest CT revealed diffuse
ground-glass opacities and right sided lobar cystic structures (Figure
2C). Genetic testing revealed a novel, \emph{de novo SFTPC} variant:
c.289G\textgreater{}T;p.Gly97Cys that is not present in adult
databases(3, 4), affects a conserved amino acid within the BRICHOS
domain, and is predicted deleterious(5, 6).

His respiratory status continued to decline with multiple
hospitalizations, requiring maximal respiratory support of NIV. He
discharged home at 11 months with nasal cannula oxygen while awake and
NIV 15/7 with oxygen bled-in for sleep. Discharge medications included
prednisolone 9 mg/kg weekly, azithromycin 10 mg/kg three times per week,
and hydroxychloroquine 7mg/kg daily via gastrostomy tube. Growth and
development continue to be typical for age. NIV was discontinued at 21
months, and oxygen was discontinued at 2 years. He tolerated respiratory
syncytial virus infection without hospitalization or oxygen. At 3 years,
he remains on azithromycin and hydroxychloroquine and is normoxic while
comfortably breathing room air.

\emph{Discussion}

We previously reported three term infants with \emph{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 \emph{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.

\emph{SFTPC} pathogenic variants act in an autosomal dominant manner
with variable penetrance or arise \emph{de novo} .(7) Among families
with the same inherited \emph{SFTPC} variant, age of presentation
varies, ranging from neonatal respiratory failure to adult pulmonary
fibrosis(8). \emph{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).\emph{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 \emph{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
\emph{SFTPC}pathogenic variants typically will improve with time through
macrophage catabolism, visualized with clearance of ground-glass
opacities on chest CT (15). \emph{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 \emph{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
\emph{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 \emph{SFTPC} pathogenic variants.

\textbf{Figure 1.} Clinical courses of our two patients with\emph{SFTPC}
pathogenic variants

\textbf{Figure 2.} Chest CT imaging from two cases with
\emph{SFTPC}pathogenic 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.

\emph{}

\emph{References}

1. Liptzin DR, Patel T, Deterding RR. Chronic ventilation in infants
with surfactant protein C mutations: an alternative to lung
transplantation. Am J Respir Crit Care Med. 2015;191(11):1338-40.

2. Guillot L, Epaud R, Thouvenin G, Jonard L, Mohsni A, Couderc R, et
al. New surfactant protein C gene mutations associated with diffuse lung
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3. Genome aggregation database (gnomAD). v.3.1.2 ed.

4. ClinVar {[}Available from: https://www.ncbi.nlm.nih.gov/clinvar/.

5. Kircher M, Witten DM, Jain P, O'Roak BJ, Cooper GM, Shendure J. A
general framework for estimating the relative pathogenicity of human
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6. Ioannidis NM, Rothstein JH, Pejaver V, Middha S, McDonnell SK, Baheti
S, et al. REVEL: An Ensemble Method for Predicting the Pathogenicity of
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7. Nogee LM, Dunbar AE, 3rd, Wert SE, Askin F, Hamvas A, Whitsett JA. A
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8. Thomas AQ, Lane K, Phillips J, 3rd, Prince M, Markin C, Speer M, et
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9. Nerelius C, Martin E, Peng S, Gustafsson M, Nordling K, Weaver T, et
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10. Johansson H, Eriksson M, Nordling K, Presto J, Johansson J. The
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transmembrane segment. Protein Sci. 2009;18(6):1175-82.

11. Katzen J, Wagner BD, Venosa A, Kopp M, Tomer Y, Russo SJ, et al. An
SFTPC BRICHOS mutant links epithelial ER stress and spontaneous lung
fibrosis. JCI Insight. 2019;4(6).

12. Eldridge WB, Zhang Q, Faro A, Sweet SC, Eghtesady P, Hamvas A, et
al. Outcomes of Lung Transplantation for Infants and Children with
Genetic Disorders of Surfactant Metabolism. J Pediatr.
2017;184:157-64.e2.

13. Afolabi FA, Liptzin DR, Sharma PB, Gelfand A, Baker CD. To trach or
not to trach? Ethical considerations for medically complex children
during a home nursing crisis. Pediatr Pulmonol. 2023.

14. Kr\selectlanguage{ngerman}öner C, Reu S, Teusch V, Schams A, Grimmelt AC, Barker M, et al.
Genotype alone does not predict the clinical course of SFTPC deficiency
in paediatric patients. Eur Respir J. 2015;46(1):197-206.

15. DeBoer EM, Liptzin DR, Humphries SM, Lynch DA, Robison K, Galambos
C, et al. Ground glass and fibrotic change in children with surfactant
protein C dysfunction mutations. Pediatr Pulmonol. 2021;56(7):2223-31.\selectlanguage{english}
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