The lost chILD: a case report of delayed diagnosis of Surfactant Protein C Deficiency in a 15-year-old African male

doi:10.21203/rs.3.rs-4680594/v1

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The lost chILD: a case report of delayed diagnosis of Surfactant Protein C Deficiency in a 15-year-old African male

https://doi.org/10.21203/rs.3.rs-4680594/v1

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Background: Childhood interstitial lung disease (chILD) encompasses a heterogeneous group of rare disorders characterized by respiratory distress, hypoxemia, exercise intolerance, and distinctive radiological findings. Despite the variable age of onset, these conditions often present with overlapping symptoms and variable progression, even with identical genetic mutations. Surfactant protein deficiencies fall under the category of child, with Surfactant Protein-C (SP-C) deficiency posing significant diagnostic challenges due to its rarity and nonspecific symptoms that may be overlooked.

Case presentation: We present the case of a 15-year-old male from Senegal who recently arrived in Italy, presenting with severe respiratory distress and hypoxemia. The patient, born full-term, had a long history of chronic cough, recurrent respiratory distress, and poor growth since early infancy.

Upon hospitalization, he tested positive for SARS-CoV-2 and exhibited signs of chronic respiratory failure and severe malnutrition. An extensive diagnostic work-up, including a chest CT scan, revealed small cystic-like air spaces and diffuse ground-glass opacities. Whole-exome sequencing confirmed the diagnosis of SP-C deficiency by identifying a heterozygous missense mutation (c.218t>C, Ile73Thr) in the third exon of the SFTPC gene. Treatment with steroids, azithromycin and hydroxychloroquine was initiated. Despite pharmacological treatments, the patient remained oxygen dependent due to the severity of this condition and required long-term bilevel non-invasive ventilatory support.

Conclusions: This case provides unique insight into the natural course of untreated child, specifically SP-C deficiency, enhancing our understanding of its manifestations and progression. The lack of standardized treatments underscores the critical need for increased awareness among physicians of this rare but potentially life-threatening condition, enabling early diagnosis and timely therapeutic interventions.

childhood interstitial lung disease

chronic respiratory failure

pediatrics

surfactant protein deficiency

case report33

Childhood interstitial lung disease (chILD) encompasses a diverse array of approximately 200 rare and mostly chronic pulmonary disorders affecting pediatric patients. These conditions are characterized by respiratory distress, impaired gas exchange and diffuse lung abnormalities observed on imaging studies. Although the exact prevalence remains difficult to determine due to the wide range of conditions included, is estimated to impact between 1.6 to 46 cases per million children, with a mortality rate hovering around 30%, as per the limited available literature^1,2. Various strategies have been employed to delineate between the different entities within chILD, which frequently overlap. In 2013, the American Thoracic Society (ATS) revised the 2007 chILD classification proposed by Deutsch et al., categorizing pediatric Diffuse Lung Disease (DLD) into two broad groups: disorders more prevalent in infancy and those not specific to infancy³. The former was further subdivided into four categories based on both clinical characteristics and histopathology: diffuse developmental disorders; growth abnormalities; specific conditions of undefined etiology [such as Pulmonary Interstitial Glicogenosys (PIG) and Neuroendocrine HyperpIasia of Infancy (NEHI)], and surfactant dysfunction mutations with related disorders (SPDS)³. Mutations in genes crucial for normal surfactant function (such as SFTPB, SFTPC, ABCA3 and TTF1) represent the most common, and often lethal, cause of DLD and respiratory distress in full-term newborns. Specifically, individuals carrying mutations in surfactant protein C (SFTPC) can exhibit symptoms from the neonatal period to the seventh decade of life. The outcomes can vary significantly, even among individuals with identical mutations, ranging from asymptomatic to progressing to respiratory failure, necessitating chronic ventilation, transplantation, or resulting in fatality⁴.

We present the case of a 15-year-old Senegalese male with severe interstitial lung disease caused by an early symptomatic but previously unrecognized surfactant protein C deficiency.

A 15-year‐old male from Senegal was transferred to our institution from another hospital with a diagnosis of acute-on-chronic respiratory failure and concurrent SARS-CoV-2 infection. He was the seventh child born to first-cousin parents and had recently immigrated to Italy from Africa. His medical history included persistent cough, occasional hemoptysis, chronic exertional dyspnea, and failure to thrive since infancy, with no gastrointestinal alterations, deep tissue infections or dermatological or neurological issues. Upon admission to the first hospital, he tested positive for SARS-CoV-2. His clinical presentation included severe dyspnea with a respiratory rate of 40 breaths per minute but no fever. His heart rate was 100 bpm, and his oxygen saturation was 80% on room air, which improved to 100% with 3 L/min of oxygen via nasal canula. Physical examination revealed severe malnutrition (weight: 24.5 kg; height: 146 cm; BMI 11.5 kg/m²), chest and jugular retractions, pulmonary crackles, and digital clubbing. Complete blood count and chemistry profile were normal, including liver and kidney function, troponin I, pro-BNP, thyroid function, protein electrophoresis and coagulation profile. Chest X-ray showed a diffuse reticulonodular pattern; echocardiogram revealed mild dilatation of the right ventricle with pulmonary insufficiency and indirect signs of increased pulmonary pressions (pulmonary artery acceleration time 70 ms, straightening of the interventricular septum). Chest CT scan documented bilateral multiple small cyst-like areas and a diffuse increase in ground-glass density (Fig. 1). Ventilatory support was initiated using high-flow nasal cannula (HFNC 18 L/min, FIO2 0.30), alongside empirical treatment with intravenous macrolides, cephalosporins and steroids. However, there was no clinical improvement observed. On the fifteenth day of hospitalization, the patient was transferred to our Pediatric Department for further medical assessments.

At the time of admission, his clinical conditions remained unchanged, with respiratory distress, digital clubbing, and severe malnutrition, suggesting chronic lung disease.

Arterial blood gas analysis, performed on supplemental oxygen therapy, showed compensated mild alkalosis (pH 7.46, pCO2 39 mmHg, pO2 81 mmHg, HCO3 27.7); nocturnal transcutaneous capnometry monitoring (TCM) was normal. Bronchoalveolar lavage was negative for both common and rare viral, bacterial and fungal infections, as well as tuberculous mycobacterial infection. Cystic fibrosis and primary ciliary dyskinesia were also ruled out. Serum angiotensin converting enzyme and α1 antitrypsin levels were normal, and no laboratory signs of immunological defects, autoimmune diseases or rheumatic disorders were found. The patient underwent a repeat COVID-19 test, which resulted negative. Pulmonary function test revealed a severe restrictive pattern (forced expiratory volume in 1 second [FEV1]: 0.67 L (29%), forced vital capacity [FVC] 0.91 L (35%), FEV1/FVC: 74.6%, forced expiratory flow [FEF] at 25–75% of FVC: 0.97 L/m (33%), total lung capacity [TLC]: 1.42 L (39%), residual volume [RV] 0.53 L (61%)). A six-minute walk test, conducted with oxygen supplementation and covering a distance of 272 mt, showed a maximal oxygen saturation of 99% with a nadir of 85%, a mean heart rate of 100 bpm (maximum: 136 bpm) and a respiratory rate of 32–40 breaths per minute.

Carbon monoxide diffusion capacity (DLCO) measurement could not be performed due to the patient’s inability to take deep inhalations and hold his breath for 10 seconds. Due to the severity of the patient’s clinical condition, bilevel non-invasive ventilation (NIV) with supplemental oxygen (FiO2: 27%) was initiated, and enteral nocturnal supplementation was started to improve his body weight. Subsequently, the patient underwent a thoracoscopic pulmonary biopsy which showed cystic transformation of lung parenchyma (cystic transformation of lung parenchyma (Fig. 2: A: EE 10x, B: EE 20x, C: EE 40x), with cysts lined by flattened or cuboidal epithelium (positive for cytokeratin 7, figure D, 20x) and moderate interstitial fibrosis, with no significant inflammatory reactive infiltrate. Based on the histological pattern, clinical history, and CT scan findings, a diagnosis of surfactant mutation was suspected.

Whole exome sequencing identified a heterozygous missense mutation, c.218t > C (Ile73Thr) in the third exon of the SFTPC gene. This mutation is documented in the literature to cause chILD due to surfactant deficiency, exhibiting an autosomal dominant pattern with variable penetrance. During hospitalization, the patient gained weight, which allowed for a gradual reduction and eventual cessation of enteral nutrition.

After 40 days of hospitalization, the boy was discharged with continuous oxygen supplementation (3 L/min) via nasal canula during the day and NIV at night. He was also prescribed long-term oral hydroxychloroquine (10 mg/kg/day) and azithromycin (10 mg/kg/day, three times a week). The ventilatory support was immediately accepted and well tolerated, with good adherence to the ventilatory program observed during subsequent follow-up.

Nine months after diagnosis, the patient exhibited significant weight gain (+ 5 kg), and a slight improvement in oxygen dependence. Nocturnal oximetry values during NIV with oxygen supplementation, as well as cardiological evaluations, were normal. Eighteen months after diagnosis, respiratory tests confirmed a severe but slightly improved restrictive syndrome [(FVC 1.32L (42%), FEV1 1.27L (45%)], while the HRCT scan remained substantially unchanged. Currently, the patient continues both pharmacologic treatments and the ventilatory support, with periodic respiratory reassessment.

We report a case of severe interstitial lung disease caused by a SFTPC mutation (IIe73Thr). Notably, the patient exhibited chronic symptoms since early childhood but survived without medical intervention until the age of fifteen, providing valuable insights into the natural progression of this rare condition.

Upon admission to the first hospital, the patient tested positive for SARS-CoV-2; however, his clinical symptoms resembled those of a chronic respiratory condition rather than an acute one. Chest CT scan revealed typical interstitial involvement, and subsequent lung biopsy showed cystic lesions in the lung parenchyma. Genetic testing was crucial in confirming the diagnosis of surfactant dysfunction, identifying the heterozygous Ile73Thr mutation in the SFTPC gene.

Pulmonary surfactant is essential for facilitating breathing efforts and preventing collapse during expiration by reducing surface tension within the alveoli at the air/liquid interface.

It is a complex mixture of phospholipids and proteins, produced by type II pneumocytes starting from 24 weeks of gestation age. The protein components, particularly surfactant proteins A (SP-A) and D (SP-D), play crucial roles for innate host defense. Additionally, surfactant proteins B (SP-B) and C (SP-C), encoded by SFTPB and SFTPC genes respectively, are essential for regulating alveolar surface tension. Pulmonary surfactant is synthesized in the endoplasmic reticulum and transported to the lamellar bodies for storage via the Adenosine triphosphate Binding Cassette (ABCA3). Mutations in the genes encoding surfactant protein B or C, ABCA3 or TTF-1 can lead to surfactant protein dysfunction syndromes (SPDS)^4,5. SP-B deficiency and ABCA3 deficiency typically involve full-term infants, rapidly progressing to respiratory failure and death within the first months of life despite medical treatment ^4,6. SFTPC mutations are the most prevalent surfactant disorders in children, accounting for approximately 17% of chILD. The SFTPC gene is located on chromosome 8, with over 60 dominant mutations. The most prevalent mutation, p.Ile73Thr (or c.218 T > C), occurs in 25% of patients with SP-C mutations⁷. These pathogenetic variants are associated with a broad range of phenotypes, ranging from severe neonatal respiratory distress to interstitial lung disease (ILD) and lung fibrosis in children and adults. Disease progression can vary significantly among individuals carrying the same SFTPC mutation, ranging from asymptomatic cases to respiratory failure, even within the same family⁸. Clinical manifestations can begin in the fifth or sixth decade of life. Moreover, the response to empirical treatments can notably vary among patients with identical genotypes..

Among Diffuse Lung Disease (DLD), the term “chILD” defines a group of heterogeneous conditions that must meet at least three out of four criteria for more than four weeks. These criteria, all present in the described case, include respiratory symptoms (such as cough, rapid or difficult breathing or exercise intolerance), respiratory signs (such as resting tachypnoea, retractions, crackles, digital clubbing, failure to thrive, or respiratory failure), altered gas exchange (hypoxemia), and diffuse abnormalities on imaging^2,3,9,10 In our case, CT scan images were consistent with interstitial lung disease, revealing ground glass opacities, multiple cyst-like areoles, extended interlobar thickening throughout both lungs, and initial fibrotic changes.

Given the severity of the clinical presentation and the patient’s age, we opted to perform a lung biopsy to establish a definitive diagnosis. The examination revealed structural subversion of the lung parenchyma, characterized by widespread cystic spaces and moderate interstitial fibrosis. However, there is an ongoing debate regarding the use and timing of lung biopsy in chILD^1,3. While lung biopsy was previously considered the gold standard for chILD diagnosis, it is now mostly reserved as a last resort, when genetic testing results are inconclusive or negative or, in case of rapid progression of the disease, there is no enough time for genetic testing^1,9,11. This shift in approach is due to the invasive nature of lung biopsy, particularly in pediatric patients, and the significant variability in results depending on the expertise of the institution. Some studies suggest that an absent or low level of SP-C (and SP-B) in bronchoalveolar lavage (BAL), may indicate the need for focused genetic analysis^11,12,13

Treatment strategies for SPDS are varied and not standardized due to the heterogeneity and rarity of these conditions. There are two primary clinical practice guidelines, both based on consensus among clinicians derived from case series, reviews, and expert opinions¹⁴. The European guidelines provide recommendations for children up to sixteen years old¹⁵, developed through consensus among clinicians from Europe and Australasia. The second set of guidelines, developed by the American Thoracic society, is specific for children under two years of age³

According to both guidelines, supportive therapy is essential and includes oxygen supplementation, ventilation, respiratory physiotherapy, good nutrition, and regular vaccinations. Anti-inflammatory and immunomodulatory therapies, such as high-dose corticosteroids, hydroxychloroquine and/or azithromycin, are commonly used to treat SPDS^{3,4,9,10,12,15}. Glucocorticoids, which are expected to reduce inflammation and have been shown to increase the expression of ABCA3, may be considered as first line treatment^16–18

An individualized therapeutic regimen is essential for optimizing outcomes and minimizing side effects in SPDS treatment. This regimen should include an initial high-dose therapy (oral prednisolone at 1–2 mg/Kg/day or pulse methylprednisolone at 10–30 mg/Kg/day for three consecutive days, repeated at monthly intervals), a careful tapering phase, and maintenance therapy, along with regular monitoring. While responses can vary depending on the individual and the severity of the disease, some patients begin to respond to systemic steroids within 7 to 28 days¹⁹.

The European guidelines recommend hydroxychloroquine as a first or second-line treatment for mild, stable child, with a dosage range of 6–10 mg/Kg/day. Hydroxycloroquine’s suggested mechanism of action includes its anti-inflammatory properties and potential inhibition of the intracellular processing of the precursor of SP-C²⁰.

Azithromycin, known for its anti-inflammatory and immunomodulatory effects, is also recommended as second-line therapy, either alone or in combination with hydroxychloroquine, for mild chILD. The suggested dose is 10 mg/kg, up to a maximum of 500 mg per dose, administered three days a week¹⁹.

Notably, emerging therapeutic strategies from adult patients may be of interest for certain forms of chILD in the near future.

Nintedanib is a tyrosine kinase inhibitor currently used to treat idiopathic pulmonary fibrosis in adults due to its activity against fibroblasts. It has an acceptable safety profile and appears to reduce the progression of fibrosis and lung function deterioration, including in children^21,22. However, its use in the pediatric population has not yet been approved.

Additionally, mesenchymal stromal cells have been proposed as a novel therapeutic approach to treat respiratory failure associated with SP-C dysfunction in pediatric populations.²³ Encouraging results have also been observed with the use of viral-mediated gene therapy to treat SP-B deficiencies in murine models.^4,9. When medical management and supportive therapies fail to stabilize the disease, lung transplantation may be considered a viable treatment option, although outcomes can vary based on several factors, including the timing of transplantation and the presence of comorbidities²⁴

ChILD are rare yet potentially severe conditions that should be suspected whenever specific clinical and radiological criteria are present. Our case illustrates the consequences of delayed recognition and diagnosis, which can result in significant impairment, poor growth, frequent hospitalizations, loss of lung function, oxygen dependence, and diminished quality of life. ChILD can manifest at any age, including adulthood, and is associated with numerous mutations of variable prevalence.

This case highlights the importance of maintaining a high index of suspicion for chILD, based on the patient’s history, physical examination, and characteristic radiological findings, to initiate treatment promptly. Unfortunately, due to the rarity and heterogeneity of these conditions, diagnosis and treatment pose significant challenges. Addressing these challenges requires future efforts focused on standardizing diagnostic protocols through large-scale, multicenter, international cohort studies.

SPDS Surfactant Protein Dysfunction Syndromes

DIP Desquamative Interstitial Pneumonia

NSIP Non Specific Interstitial Pneumonia

CPI Chronic Pneumonitis of Infancy

PIG Pulmonary Interstitial Glycogenosis

NEHI Neuro Endocrine cell Hyperplasia of Infancy

UIP Usual Interstitial Pneumonia

Consent for publication A written informed consent was signed by the parents who agreed to have the case published.

Authors’ contributions: Nadia Faelli elaborated the manuscript; Federica Chironi followed the patient during the diagnostic work-up; Betrice Andrenacci reviewed and approved the final manuscript; Francesca Patria collaborated on the conception of the manuscript, reviewed and approved all drafts and the final manuscript; Stefano Ferrero dealt with histological diagnosis; Irene Borzani dealt with radiological diagnosis; Costanza Pucci followed the patients during the diagnostic work-up; Daniela Civeriati followed the patient during the diagnostic work-up; Mara Lelii reviewed and approved the final manuscript; Barbara Madini approved the final manuscript; Alessia Rocchi reviewed the final manuscript; Valeria Daccò collaborated on the conception of the manuscript, reviewed and approved all drafts and the final manuscript

All the authors read and approved the final manuscript.

Authors’ information Not applicable.

Funding This study was (partially) supported by a grant from the Italian Ministry of Health (Ricerca Corrente 2024), Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico.

Availability of data and materials Not applicable.

Ethics approval and consent to participate Not applicable.

Competing interests No competing interests for all authors.

Acknowledgements Not applicable.

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Editorial decision: Minor revision
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The lost chILD: a case report of delayed diagnosis of Surfactant Protein C Deficiency in a 15-year-old African male

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