A roadmap to precision treatments for familial pulmonary fibrosis.

Interstitial lung diseases (ILDs) in adults and children (chILD) are a heterogeneous group of lung disorders leading to inflammation, abnormal tissue repair and scarring of the lung parenchyma often resulting in respiratory failure and death. Inherited factors directly cause, or contribute significantly to the risk of developing ILD, so called familial pulmonary fibrosis (FPF), and monogenic forms may have a poor prognosis and respond poorly to current treatments. Specific, variant-targeted or precision treatments are lacking. Clinical trials of repurposed drugs, anti-fibrotic medications and specific treatments are emerging but for many patients no interventions exist. We convened an expert working group to develop an overarching framework to address the existing research gaps in basic, translational, and clinical research and identified areas for future development of preclinical models, candidate medications and innovative clinical trials. In this Position Paper, we summarise working group discussions, recommendations, and unresolved questions concerning precision treatments for FPF.

High risk of lung cancer in surfactant-related gene variant carriers.

BACKGROUND: Several rare surfactant-related gene (SRG) variants associated with interstitial lung disease are suspected to be associated with lung cancer, but data are missing. We aimed to study the epidemiology and phenotype of lung cancer in an international cohort of SRG variant carriers. METHODS: We conducted a cross-sectional study of all adults with SRG variants in the OrphaLung network and compared lung cancer risk with telomere-related gene (TRG) variant carriers. RESULTS: We identified 99 SRG adult variant carriers (SFTPA1 (n=18), SFTPA2 (n=31), SFTPC (n=24), ABCA3 (n=14) and NKX2-1 (n=12)), including 20 (20.2%) with lung cancer (SFTPA1 (n=7), SFTPA2 (n=8), SFTPC (n=3), NKX2-1 (n=2) and ABCA3 (n=0)). Among SRG variant carriers, the odds of lung cancer was associated with age (OR 1.04, 95% CI 1.01-1.08), smoking (OR 20.7, 95% CI 6.60-76.2) and SFTPA1/SFTPA2 variants (OR 3.97, 95% CI 1.39-13.2). Adenocarcinoma was the only histological type reported, with programmed death ligand-1 expression ≥1% in tumour cells in three samples. Cancer staging was localised (I/II) in eight (40%) individuals, locally advanced (III) in two (10%) and metastatic (IV) in 10 (50%). We found no somatic variant eligible for targeted therapy. Seven cancers were surgically removed, 10 received systemic therapy, and three received the best supportive care according to their stage and performance status. The median overall survival was 24 months, with stage I/II cancers showing better survival. We identified 233 TRG variant carriers. The comparative risk (subdistribution hazard ratio) for lung cancer in SRG patients versus TRG patients was 18.1 (95% CI 7.1-44.7). CONCLUSIONS: The high risk of lung cancer among SRG variant carriers suggests specific screening and diagnostic and therapeutic challenges. The benefit of regular computed tomography scan follow-up should be evaluated.

Similarities and differences of interstitial lung disease associated with pathogenic variants in SFTPC and ABCA3 in adults.

BACKGROUND AND OBJECTIVE: Variants in surfactant genes SFTPC or ABCA3 are responsible for interstitial lung disease (ILD) in children and adults, with few studies in adults. METHODS: We conducted a multicentre retrospective study of all consecutive adult patients diagnosed with ILD associated with variants in SFTPC or ABCA3 in the French rare pulmonary diseases network, OrphaLung. Variants and chest computed tomography (CT) features were centrally reviewed. RESULTS: We included 36 patients (median age: 34 years, 20 males), 22 in the SFTPC group and 14 in the ABCA3 group. Clinical characteristics were similar between groups. Baseline median FVC was 59% ([52-72]) and DLco was 44% ([35-50]). An unclassifiable pattern of fibrosing ILD was the most frequent on chest CT, found in 85% of patients, however with a distinct phenotype with ground-glass opacities and/or cysts. Nonspecific interstitial pneumonia and usual interstitial pneumonia were the most common histological patterns in the ABCA3 group and in the SFTPC group, respectively. Annually, FVC and DLCO declined by 1.87% and 2.43% in the SFTPC group, respectively, and by 0.72% and 0.95% in the ABCA3 group, respectively (FVC, p = 0.014 and DLCO , p = 0.004 for comparison between groups). Median time to death or lung transplantation was 10 years in the SFTPC group and was not reached at the end of follow-up in the ABCA3 group. CONCLUSION: SFTPC and ABCA3-associated ILD present with a distinct phenotype and prognosis. A radiologic pattern of fibrosing ILD with ground-glass opacities and/or cysts is frequently found in these rare conditions.

Objectives for algorithmic decision-making systems in childhood asthma: Perspectives of children, parents, and physicians.

Objectives: To identify with children, parents and physicians the objectives to be used as parameters for algorithmic decision-making systems (ADMSs) adapting treatments in childhood asthma. Methods: We first conducted a qualitative study based on semi-structured interviews to explore the objectives that children aged 8-17 years, their parents, and their physicians seek to achieve when taking/giving/prescribing a treatment for asthma. Following the grounded theory approach, each interview was independently coded by two researchers; reconciled codes were used to assess code frequency, categories were defined, and the main objectives identified. We then conducted a quantitative study based on questionnaires using these objectives to determine how children/parents/physicians ranked these objectives and whether their responses were aligned. Results: We interviewed 71 participants (31 children, 30 parents and 10 physicians) in the qualitative study and identified seven objectives associated with treatment uptake and five objectives associated with treatment modalities. We included 291 participants (137 children, 137 parents, and 17 physicians) in the quantitative study. We found little correlation between child, parent, and physician scores for each of the objectives. Each child's asthma history influenced the choice of scores assigned to each objective by the child, parents, and physician. Conclusion: The identified objectives are quantifiable and relevant to the management of asthma in the short and long term. They can therefore be incorporated as parameters for future ADMS. Shared decision-making seems essential to achieve consensus among children, parents, and physicians when choosing the weight to assign to each of these objectives.

Lung biopsies in infants and children in critical care situation.

INTRODUCTION: Lung biopsy is considered as the last step investigation for diagnosing lung diseases; however, its indication must be carefully balanced with its invasiveness. The present study aims to evaluate the diagnostic yield of lung biopsy in critically ill patients hospitalized in the pediatric intensive care unit (ICU). MATERIAL AND METHODS: Children who underwent a lung biopsy in the ICU between 1995 and 2022 were included. Biopsies performed in the operating room and post-mortem biopsies were excluded. RESULTS: Thirty-one patients were included, with a median age of 18 days (2 days to 10.8 years); 21 (67.7%) were newborns. All patients required invasive mechanical ventilation, 26 (89.7%) had a pulmonary hypertension, and 22 (70.9%) were placed under extracorporeal membrane oxygenation (ECMO). The lung biopsy led to a diagnosis in 81% of the patients. The diagnostic reliability seemed to decrease with age (95% in newborns, 71% in 1 month to 2 years and 0/3 patients aged over 2 years old). Diffuse developmental disorders of the lung accounted for 15 (49%) patients, primarily alveolar capillary dysplasia, followed by surfactant disorders in 5 (16%) patients. Complications occurred in 9/31 (29%) patients including eight under ECMO, with massive hemorrhages in seven cases. DISCUSSION AND CONCLUSION: In critical situations, lung biopsy should be performed. Lung biopsy is a reliable diagnostic procedure for neonates in critical situation when a diffuse developmental disorder of the lung is suspected. The majority of lung biopsy complication was associated with the use of ECMO. The prospective evaluation of the complications of such procedure under ECMO, and particularly over 10 days of ECMO and in children over 2-year-old remains to be ascertained.

Pulmonary mucoepidermoid carcinoma in a 7-year-old child.

A 7-year-old boy presented with exertional dyspnea and cough, initially misdiagnosed as asthma. Imaging revealed a mass obstructing the left main bronchus, later identified as a pulmonary mucoepidermoid carcinoma (MEC). Following surgical sleeve resection, complete tumor removal occurred without malignancy in surrounding lymph nodes, resulting in symptom resolution without additional therapy. Pulmonary MEC, uncommon in pediatric patients, poses diagnostic challenges due to nonspecific symptoms, resulting in delayed diagnosis. Typically managed via complete surgical resection, MEC offers a favorable prognosis, primarily affecting central airways and requiring conservative surgical approaches to preserve lung tissue. This case underscores the diagnostic challenges of primary pulmonary MEC in pediatric patients. It stresses the need to consider unusual causes in pediatric respiratory symptoms and highlights the critical role of precise diagnostic methods and personalized surgical strategies in managing such rare pulmonary malignancies for optimal outcomes.

Acinar Dysplasia in a Full-Term Newborn with a NKX2.1 Variant.

Acinar dysplasia (AcDys) is one of the three main diffuse developmental disorders of the lung. The transcription factor NK2 homeobox 1 (NKX2.1) partly controls the synthesis of surfactant proteins by type 2 alveolar epithelial cells (AEC2), and germline mutations are known to be associated with brain-lung thyroid syndrome. We report the case of a full-term neonate who developed refractory respiratory failure with pulmonary hypertension requiring venoarterial extracorporeal membrane oxygenation. Histological examination of the lung biopsy specimen was consistent with the diagnosis of AcDys. Molecular analyses led to the identification of the missense heterozygous variant in NKX2.1 (NM_001079668) c.731A>G p.(Tyr244Cys), which is predicted to be pathogenic. After 5 weeks, because AcDys is a fatal disorder and the patient's status worsened, life-sustaining therapies were withdrawn, and she died after a few hours. This study is the first to extend the phenotype of NKX2.1 pathogenic variant, to a fatal form of AcDys.

The significance of multidisciplinary team meetings in diagnosing and managing childhood interstitial lung disease within the RespiRare network.

INTRODUCTION: Childhood Interstitial Lung Disease (chILD) represents a rare and severe group of diseases for which the etiologic workup, classification, and management remain a challenge for most pediatric pulmonologists. In France in 2018, the RespiRare network established the first multidisciplinary team meetings (MDTm) dedicated to chILD. This study aims to investigate the impact of MDTm in chILD diagnosis and management as well as user satisfaction. METHODS: The MDTm took place on a monthly basis through video conferences. The participants consisted of a quorum and included pediatric pulmonologists, radiologists, geneticists, and pulmonologists, with an average of 10.5 participants per meeting. Patients provided consent to participate in MDTm and for data collection. Data were retrospectively extracted from MDTm reports. To evaluate the usefulness of the MDTm and the satisfaction of the participants, a survey was sent by email at least 3 months after the MDTm to the participants. RESULTS: A total of 216 chILD cases were discussed during 56 MDTm sessions. The median age of onset was 0.5 years (interquartile range 0-7). The MDTm sessions resulted in the correction of chILD etiology in 25% of cases (neuroendocrine cell hyperplasia of infancy 17%, surfactant metabolism disorder 8%, pulmonary alveolar proteinosis 4%, hemosiderosis 3%, sarcoidosis 3%, and others 34%), and chILD was ruled out in 7% of cases. A change in therapy was proposed for 46% of cases. User satisfaction was significant, particularly regarding their confidence in managing these rare diseases. DISCUSSION AND CONCLUSION: Dedicated MDTm sessions offer a unique opportunity to enhance chILD etiologic diagnosis and management, leading to increased physician knowledge and confidence in managing these patients.

CSF2RB mutation-related hereditary pulmonary alveolar proteinosis: the "long and winding road" into adulthood.

Genetic analysis pre-lung transplantation diagnosed a case of hereditary pulmonary alveolar proteinosis (PAP) complicated by fibrosis in adulthood. The need for genetic testing in GM-CSF autoantibody negative and unclassifiable PAP is highlighted. https://bit.ly/3QcsYwM.

An evaluation of an open access iPSC training course: "How to model interstitial lung disease using patient-derived iPSCs".

BACKGROUND: Interstitial lung diseases (ILD) are a group of rare lung diseases with severe outcomes. The COST Innovator Grant aims to establish a first-of-a-kind open-access Biorepository of patient-derived induced pluripotent stem cells (iPSC) and to train researchers in the skills required to generate a robust preclinical model of ILD using these cells. This study aims to describe and evaluate the effectiveness of a training course designed to train researchers in iPSC techniques to model ILD. METHODS: 74 researchers, physicians and stakeholders attended the training course in Dublin in May 2022 with 31 trainees receiving teaching in practical iPSC culturing skills. The training course learners were divided into the Hands-on (16 trainees) and Observer groups (15 trainees), with the Observers attending a supervised live-streamed experience of the laboratories skills directly delivered to the Hands-on group. All participants were asked to participate in an evaluation to analyse their satisfaction and knowledge gained during the Training Course, with means compared using t-tests. RESULTS: The gender balance in both groups was predominantly females (77.4%). The Hands-on group consisted mainly of researchers (75%), whereas all participants of the Observer group described themselves as clinicians. All participants in the Hands-on group were at least very satisfied with the training course compared to 70% of the participants in the Observer group. The knowledge assessment showed that the Hands-on group retained significantly more knowledge of iPSC characteristics and culturing techniques compared to the Observers (* < 0.05; p = 0.0457). A comprehensive learning video detailing iPSC culturing techniques was produced and is included with this manuscript. CONCLUSIONS: The majority of participants were highly or very satisfied with the training course and retained significant knowledge about iPSC characteristics and culturing techniques after attending the training course. Overall, our findings demonstrate the feasibility of running hybrid Hands-on and Observer teaching events and underscore the importance of this type of training programme to appeal to a broad spectrum of interested clinicians and researchers particularly in rare disease. The long-term implications of this type of training event requires further study to determine its efficacy and impact on adoption of iPSC disease modelling techniques in participants' laboratories.

Outcome of lung transplantation for adults with interstitial lung disease associated with genetic disorders of the surfactant system.

Background: Interstitial lung disease associated with genetic disorders of the surfactant system is a rare entity in adults that can lead to lung transplantation. Our objective was to describe the outcome of these patients after lung transplantation. Methods: We conducted a retrospective, multicentre study, on adults who underwent lung transplantation for such disease in the French lung transplant centres network, from 1997 to 2018. Results: 20 patients carrying mutations in SFTPA1 (n=5), SFTPA2 (n=7) or SFTPC (n=8) were included. Median interquartile range (IQR) age at diagnosis was 45 (40-48) years, and median (IQR) age at lung transplantation was 51 (45-54) years. Median overall survival after transplantation was 8.6 years. Two patients had a pre-transplant history of lung cancer, and two developed post-transplant lung cancer. Female gender and a body mass index <25 kg·m-2 were significantly associated with a better prognosis, whereas transplantation in high emergency was associated with a worst prognosis. Conclusions: Lung transplantation in adults with interstitial lung disease associated with genetic disorders of surfactant system may be a valid therapeutic option. Our data suggest that these patients may have a good prognosis. Immunosuppressive protocol was not changed for these patients, and close lung cancer screening is needed before and after transplantation.

Hypomorphic pathogenic variant in SFTPB leads to adult pulmonary fibrosis.

Biallelic pathogenic variants in the surfactant protein (SP)-B gene (SFTPB) have been associated with fatal forms of interstitial lung diseases (ILD) in newborns and exceptional survival in young children. We herein report the cases of two related adults with pulmonary fibrosis due to a new homozygous SFTPB pathogenic variant, c.582G>A p.(Gln194=). In vitro transcript studies showed that this SFTPB synonymous pathogenic variant induces aberrant splicing leading to three abnormal transcripts with the preservation of the expression of a small proportion of normal SFTPB transcripts. Immunostainings on lung biopsies of the proband showed an almost complete loss of SP-B expression. This hypomorphic splice variant has thus probably allowed the patients' survival to adulthood while inducing an epithelial cell dysfunction leading to ILD. Altogether, this report shows that SFTPB pathogenic variants should be considered in atypical presentations and/or early-onset forms of ILD particularly when a family history is identified.

Diffuse alveolar haemorrhage in children: an international multicentre study.

Background: Paediatric diffuse alveolar haemorrhage (DAH) is a rare heterogeneous condition with limited knowledge on clinical presentation, treatment and outcome. Methods: A retrospective, descriptive multicentre follow-up study initiated from the European network for translational research in children's and adult interstitial lung disease (Cost Action CA16125) and chILD-EU CRC (the European Research Collaboration for Children's Interstitial Lung Disease). Inclusion criteria were DAH of any cause diagnosed before the age of 18 years. Results: Data of 124 patients from 26 centres (15 counties) were submitted, of whom 117 patients fulfilled the inclusion criteria. Diagnoses were idiopathic pulmonary haemosiderosis (n=35), DAH associated with autoimmune features (n=20), systemic and collagen disorders (n=18), immuno-allergic conditions (n=10), other childhood interstitial lung diseases (chILD) (n=5), autoinflammatory diseases (n=3), DAH secondary to other conditions (n=21) and nonspecified DAH (n=5). Median (IQR) age at onset was 5 (2.0-12.9) years. Most frequent clinical presentations were anaemia (87%), haemoptysis (42%), dyspnoea (35%) and cough (32%). Respiratory symptoms were absent in 23%. The most frequent medical treatment was systemic corticosteroids (93%), hydroxychloroquine (35%) and azathioprine (27%). Overall mortality was 13%. Long-term data demonstrated persistent abnormal radiology and a limited improvement in lung function. Conclusions: Paediatric DAH is highly heterogeneous regarding underlying causes and clinical presentation. The high mortality rate and number of patients with ongoing treatment years after onset of disease underline that DAH is a severe and often chronic condition. This large international study paves the way for further prospective clinical trials that will in the long term allow evidence-based treatment and follow-up recommendations to be determined.

Diagnostic workup of childhood interstitial lung disease.

Childhood interstitial lung diseases (chILDs) are rare and heterogeneous diseases with significant morbidity and mortality. An accurate and quick aetiological diagnosis may contribute to better management and personalised treatment. On behalf of the European Respiratory Society Clinical Research Collaboration for chILD (ERS CRC chILD-EU), this review summarises the roles of the general paediatrician, paediatric pulmonologists and expert centres in the complex diagnostic workup. Each patient's aetiological chILD diagnosis must be reached without prolonged delays in a stepwise approach from medical history, signs, symptoms, clinical tests and imaging, to advanced genetic analysis and specialised procedures including bronchoalveolar lavage and biopsy, if necessary. Finally, as medical progress is fast, the need to revisit a diagnosis of "undefined chILD" is stressed.

Children's views on artificial intelligence and digital twins for the daily management of their asthma: a mixed-method study.

New technologies enable the creation of digital twin systems (DTS) combining continuous data collection from children's home and artificial intelligence (AI)-based recommendations to adapt their care in real time. The objective was to assess whether children and adolescents with asthma would be ready to use such DTS. A mixed-method study was conducted with 104 asthma patients aged 8 to 17 years. The potential advantages and disadvantages associated with AI and the use of DTS were collected in semi-structured interviews. Children were then asked whether they would agree to use a DTS for the daily management of their asthma. The strength of their decision was assessed as well as the factors determining their choice. The main advantages of DTS identified by children were the possibility to be (i) supported in managing their asthma (ii) from home and (iii) in real time. Technical issues and the risk of loss of humanity were the main drawbacks reported. Half of the children (56%) were willing to use a DTS for the daily management of their asthma if it was as effective as current care, and up to 93% if it was more effective. Those with the best computer skills were more likely to choose the DTS, while those who placed a high value on the physician-patient relationship were less likely to do so.   Conclusions: The majority of children were ready to use a DTS for the management of their asthma, particularly if it was more effective than current care. The results of this study support the development of DTS for childhood asthma and the evaluation of their effectiveness in clinical trials. What is Known: • New technologies enable the creation of digital twin systems (DTS) for children with asthma. • Acceptance of these DTSs by children with asthma is unknown. What is New: • Half of the children (56%) were willing to use a DTS for the daily management of their asthma if it was as effective as current care, and up to 93% if it was more effective. •Children identified the ability to be supported from home and in real time as the main benefits of DTS.

COVID-19 and pediatric pulmonology: Feedback from an expert center after the first year of the pandemic.

The coronavirus disease 2019 (COVID-19) outbreak has evolved with different waves corresponding to subsequent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mutations. While the most severe cases have been observed in the elderly and in individuals with underlying comorbidities, severe pediatric and young adult cases have been observed, as well as post-infectious inflammatory syndromes and persistent symptoms leading to long-COVID. This manuscript describes the experience of a pediatric respiratory unit during the first year of the pandemic and reviews the corresponding literature with a special emphasis on children and young people with underlying conditions, such as immunosuppression, sickle cell disease, and cystic fibrosis.

Long-term evolution of neuroendocrine cell hyperplasia of infancy: the FRENCHI findings.

Only few studies report long-term evolution of patients with neuroendocrine cell hyperplasia of infancy (NEHI). We report data from a 54-patient cohort followed up in the French network for rare respiratory diseases (RespiRare). Demographic characteristics and respiratory and nutritional evolution were collected at the time of the patient's last scheduled visit. The mean duration of follow-up was 68 months (5 months to 18 years). Fifteen patients (27.8%) were considered clinically cured. During follow-up, hospitalizations for wheezy exacerbations were reported in 35 patients (55%), and asthma diagnosed in 20 (37%). Chest CT scan improvement was noted in 25/44 (56.8%). Spirometry showed a persistent obstructive syndrome in 8/27 (29.6%). A sleep disorder was rare (2/36, 5.5%). Oxygen weaning occurred in 28 of the 45 patients initially treated (62.2%) and was age-dependent (35.7% under 2 years, 70.5% between 2 and 6 years, and 100% after 7 years). Oxygen duration was linked to a biopsy-proven diagnosis (p = 0.02) and to the use of a nutritional support (p = 0.003). Corticosteroids were largely prescribed at diagnosis, with no evident respiratory or nutritional effect during follow-up. Among 23 patients with an initial failure to thrive, 12 (52.2%) had no weight recovery. Initial enteral feeding (17/54, 31.5%) was stopped at a mean age of 43 months (3 to 120), with no effect on cure and oxygen liberation at the last visit.  Conclusion: Our results show that NEHI has a globally positive, but unequal, improvement over time. Further prospective studies are needed to better clarify the different trajectories of patients with NEHI. What is Known: • Neuroendocrine cell hyperplasia of infancy (NEHI) is an interstitial lung disease whose long-term outcome is considered positive from very few studies including heterogeneous populations. What is New: • The 68-month follow-up of our 54-patient cohort showed respiratory/nutritional symptom persistence in 72.2%, oxygen requiring in 34%, and asthma in 37%. When controlled, radiological or functional improvement was noted in 56.8 and 40.7%. Further prospective studies are needed to better clarify the different trajectories of patients with NEHI.