Late-onset pulmonary complications following allogeneic hematopoietic cell transplantation in pediatric patients: a prospective multicenter study.

The primary objective of our multicenter prospective study was to describe the incidence of late-onset non-infectious pulmonary complications (LONIPCs) in children undergoing hematopoietic cell transplantation (HCT) using sensitive criteria for pulmonary function test (PFT) abnormalities including the non-specific pattern of airflow obstruction. Secondary objectives were to assess the factors associated with LONIPC occurrence and the sensitivity of the 2014 NIH-Consensus Criteria of bronchiolitis obliterans syndrome (BOS). PFT and clinical assessment were performed prior to HCT and at 6, 12, 24, and 36 months post-HCT. LONIPC diagnosis was validated by an Adjudication Committee. The study comprised 292 children from 12 centers. Thirty-two individuals (11%, 95% CI: 8-15%) experienced 35 LONIPCs: 25 BOS, 4 interstitial lung diseases, 4 organizing pneumonia and 2 pulmonary veno-occlusive diseases. PFT abnormalities were obstructive defects (FEV1/FVC z-score < -1.645; n = 12), restrictive defects (TLC < 80% predicted, FEV1 and FVC z-scores < -1.645; n = 7) and non-specific pattern (FEV1 and FVC z-score< -1.645, FEV1/FVC z-score > -1.645, and TLC > 80% predicted; n = 8). HCT for malignant disease was the only factor associated with LONIPC (P = 0.04). The 2014 NIH-Consensus Criteria would only diagnose 8/25 participants (32%) as having BOS. In conclusion, 11% of children experienced a LONIPC in a prospective design. Clinical Trials.gov identifier (NCT number): NCT02032381.

Recommendations for surveillance of pulmonary dysfunction among childhood, adolescent, and young adult cancer survivors: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group.

Childhood, adolescent, and young adult (CAYA) cancer survivors are at risk of pulmonary dysfunction. Current follow-up care guidelines are discordant. Therefore, the International Late Effects of Childhood Cancer Guideline Harmonization Group established and convened a panel of 33 experts to develop evidence-based surveillance guidelines. We critically reviewed available evidence regarding risk factors for pulmonary dysfunction, types of pulmonary function testing, and timings of surveillance, then we formulated our recommendations. We recommend that CAYA cancer survivors and healthcare providers are aware of reduced pulmonary function risks and pay vigilant attention to potential symptoms of pulmonary dysfunction, especially among survivors treated with allogeneic haematopoietic stem cell transplantation, thoracic radiotherapy, and thoracic surgery. Based on existing limited evidence and current lack of interventions, our panel recommends pulmonary function testing only for symptomatic survivors. Since scarce existing evidence informs our recommendation, we highlight the need for prospective collaborative studies to address pulmonary function knowledge gaps among CAYA cancer survivors.

Theratyping cystic fibrosis patients to guide elexacaftor/tezacaftor/ivacaftor out-of-label prescription.

BACKGROUND: Around 20% of people with cystic fibrosis (pwCF) do not have access to the triple combination elexacaftor/tezacaftor/ivacaftor (ETI) in Europe because they do not carry the F508del allele on the CF transmembrane conductance regulator (CFTR) gene. Considering that pwCF carrying rare variants may benefit from ETI, including variants already validated by the US Food and Drug Administration (FDA), a compassionate use programme was launched in France. PwCF were invited to undergo a nasal brushing to investigate whether the pharmacological rescue of CFTR activity by ETI in human nasal epithelial cell (HNEC) cultures was predictive of the clinical response. METHODS: CFTR activity correction was studied by short-circuit current in HNEC cultures at basal state (dimethyl sulfoxide (DMSO)) and after ETI incubation and expressed as percentage of normal (wild-type (WT)) CFTR activity after sequential addition of forskolin and Inh-172 (ΔI ETI/DMSO%WT). RESULTS: 11 pwCF carried variants eligible for ETI according to the FDA label and 28 carried variants not listed by the FDA. ETI significantly increased CFTR activity of FDA-approved CFTR variants (I601F, G85E, S492F, M1101K, R347P, R74W;V201M;D1270N and H1085R). We point out ETI correction of non-FDA-approved variants, including N1303K, R334W, R1066C, Q552P and terminal splicing variants (4374+1G>A and 4096-3C>G). ΔI ETI/DMSO%WT was significantly correlated to change in percentage predicted forced expiratory volume in 1 s and sweat chloride concentration (p<0.0001 for both). G85E, R74W;V201M;D1270N, Q552P and M1101K were rescued more efficiently by other CFTR modulator combinations than ETI. CONCLUSIONS: Primary nasal epithelial cells hold promise for expanding the prescription of CFTR modulators in pwCF carrying rare mutants. Additional variants should be discussed for ETI indication.

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.

French national cohort of neuroendocrine cell hyperplasia of infancy (FRENCHI) study: diagnosis and initial management.

Early diagnosis of neuroendocrine cell hyperplasia of infancy (NEHI) is crucial as, conversely to the other causes of intersititial lung disease, corticosteroids are not recommended. Diagnosis is historically based on lung biopsy (NEHI), but in current practice, a clinical and radiological approach is more and more preferred (NEHI syndrome). This national study aimed to address diagnosis and initial management of patients followed up for a NEHI pattern in pediatric centers for rare lung diseases (RespiRare, France). Data on neonatal and familial events, symptoms at diagnosis, explorations performed and results, and therapeutic management were collected by questionnaire. Fifty-four children were included (boys 63%). The mean onset of symptoms was 3.8 ± 2.6 months. The most frequent symptoms at diagnosis were tachypnea (100%), retraction (79.6%), crackles (66.7%), and hypoxemia (59.3%). The mean NEHI clinical score, evocative when ≥ 7/10, was 7.9 ± 1.4 (76% with a score ≥ 7). All chest CT-scans showed ground glass opacities evolving at least the middle lobe and the lingula. Lung biopsy was performed in 38.9% of the cases and was typical of NEHI in only 52.4%, even when the clinical presentation was typical. Initial treatments were oxygen (83.6%) and more curiously intravenous pulses of steroids (83.3%) and azithromycin (70.2%). CONCLUSION: This national cohort of patients underlines diagnosis difficulties of NEHI. A composite clinical and radiological score should help clinicians for limiting the use of anti-inflammatory drugs. WHAT IS KNOWN: •Neuroendocrine cell hyperplasia of infancy (NEHI) is an interstitial lung disease whose diagnosis is essential to limit corticosteroids therapy. WHAT IS NEW: •In this national cohort of 54 patients with a NEHI pattern, diagnosis is mainly based on clinical symptoms and chest CT-scan results. The newly proposed clinical score and, when performed, the lung biopsies are faulted in 25 and 50% of the cases, respectively. •Corticosteroids are widely used. Such results plead for a new composite score to formally diagnose NEHI.

Beneficial short-term effect of autogenic drainage on peripheral resistance in childhood cystic fibrosis disease.

BACKGROUND: Airway clearance techniques are supposed to be a necessary adjunct for the enhancement of impaired peripheral clearance in cystic fibrosis (CF). The objective was to assess the effect of one physiotherapy session (autogenic drainage: AD) on mucus clearance (sputum wet weight) and impulse oscillometry system (IOS) indices, including those obtained from extended Resistance-Inertance-Compliance (eRIC) modelling, considering the degree of bronchial congestion. METHODS: Thirty children with CF (median age: 12.7 years) in a stable condition prospectively underwent IOS measurements at baseline and after AD. They were divided in two groups: with (visual analog scale of bronchial congestion by the physiotherapist ≥ 5/10) and without (scale < 5/10) bronchial congestion. Paired-comparison of the effects of AD on airway resistance measurements was done with Wilcoxon test. RESULTS: The congestion scale correlated with the wet weight of sputum production during the session (Pearson test: p < 0.0001, R = 0.66). Ten children had bronchial congestion and 20 were without congestion. In the whole group, R5-20 Hz significantly decreased after AD (P = 0.049), which was related to a decrease in the children with congestion (P = 0.025), whereas it was not significantly modified in the children without congestion (P = 0.327). The eRIC model allowed the calculation of the peripheral resistance of the respiratory system, which also decreased in the children with congestion (P = 0.037), however, not modified in the children without congestion (P = 0.390). CONCLUSION: One session of autogenic drainage has the ability to decrease peripheral resistance obtained from IOS measurements, more specifically in children with CF with moderate to severe bronchial congestion. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04094441.

Cumulative Incidence and Risk Factors for Severe Coronavirus Disease 2019 in French People With Cystic Fibrosis.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections are closely monitored in people with cystic fibrosis (pwCF), especially severe cases. Previous studies used hospitalization rates as proxy for severity. METHODS: We evaluated data from coronavirus disease 2019 (COVID-19) cases diagnosed in French pwCF over the first pandemic year. Objective criteria were applied for defining severity (eg, respiratory failure and/or death). Data were compared to all French pwCF using the National Registry. RESULTS: As of 30 April 2021, 223 pwCF were diagnosed with COVID-19, with higher risks in adults (odds ratio [OR], 2.52 [95% confidence interval {CI}, 1.82-3.48]) and transplant recipients (OR, 2.68 [95% CI, 1.98-3.63]). Sixty (26.9%) patients were hospitalized, with increased risk in transplant recipients (OR, 4.74 [95% CI, 2.49-9.02]). In 34 (15%) cases, COVID-19 was considered severe; 28 (46.7%) hospitalizations occurred without objective criteria of severity. Severe cases occurred mostly in adult (85.3%) and posttransplant pwCF (61.8%; OR, 6.02 [95% CI, 2.77-13.06]). In nontransplanted pwCF, risk factors for severity included low lung function (median percentage of predicted forced expiratory volume in 1 second, 54.6% vs 75.1%; OR, 1.04 [95% CI, 1.01-1.08]) and CF-related diabetes (OR, 3.26 [95% CI, 1.02-10.4]). While 204 cases fully recovered, 16 were followed for possible sequelae, and 3 posttransplant females died. CONCLUSIONS: Severe COVID-19 occurred infrequently during the first pandemic year in French pwCF. Nontransplanted adults with severe respiratory disease or diabetes and posttransplant individuals were at risk for severe COVID-19. Thus, specific preventive measures should be proposed.

Evaluation of prognostic scores for respiratory syncytial virus infection in a French multicentre cohort of allogeneic haematopoietic stem cell transplantation recipients.

Haematopoietic stem cell transplantation (HSCT) recipients are at risk for severe respiratory syncytial virus (RSV) infection. Two prognostic scores have been proposed to predict the risk of progression from upper respiratory tract infection (URTI) to lower respiratory tract infection (LRTI) and death. This was a multicentre study of allogeneic HSCT recipients diagnosed with an RSV infection between 2010 and 2019 who were retrospectively stratified by the immunodeficiency scoring index (ISI) and the severe immunodeficiency (SID) score. Endpoints were overall survival, RSV-attributable mortality and progression to LRTI after URTI. Prognostic analyses were performed using Cox regression models. We included 147 consecutive patients, including 94 (63.9%) initially diagnosed with URTI and 53 (36.1%) with LRTI. At 90 days, 14 patients had died (survival rate, 90.5%; 95% CI: 85.9-95.3), and nine deaths were attributable to RSV (attributable mortality rate, 5.4%; 95% CI: 2.5-10.0). The cumulative 90-day incidence of LRTI after URTI was 13.8% (95% CI: 7.8-21.6). Neither score showed prognostic value for mortality, while the ISI allowed the prediction of progression to LRTI (p = 0.0008). Our results do not fully replicate the results previously reported in cohorts of HSCT recipients. This may reflect the recent epidemiology of RSV infections in this HSCT cohort.

Very early glucose tolerance abnormalities in children with cystic fibrosis.

Diabetes is a comorbidity of cystic fibrosis (CF) that worsens prognosis. Abnormal glucose tolerance is associated with decreased lung function and poorer nutritional status. Data are lacking on glucose tolerance abnormalities in young children. We report three infants with abnormal glucose tolerance, beginning under the age of one year, including two cases of very early diabetes which started before the age of six months. None of our patients required long-term insulin treatment, and glycaemia spontaneously improved. All three patients had early pulmonary infection with Pseudomonas aeruginosa and poor nutritional status. This case series presents three unique patients with early dysglycaemia, then improvement over time. This adds to the understanding of the spectrum of early dysglycaemia in CF and highlights the difficulty of diagnosis in this age group.

Impulse oscillometry indices to detect an abnormal lung clearance index in childhood cystic fibrosis.

The objective of our cross-sectional study was to assess the relationships between indices of multiple breath washout (MBW) and impulse oscillometry system (IOS) in cystic fibrosis in forty consecutive children (median age 8.1 years) in stable conditions and to evaluate whether cut-off values of IOS indices may help to avoid MBW, which is time-consuming. IOS measurements took a median duration of 3 min, while MBW measurements took a median duration of 49 min. Lung Clearance Index (LCI2.5% ) depicted significant linear correlations with z-scores of R5Hz, R5-20Hz, X5Hz, AX, and Fres (r2 = 0.27 to 0.51). Receiver-operator characteristic curves were constructed and showed that the best compromise was obtained with the z-score of Fres, with a cut-off value of -1.37 that had a sensitivity of 0.966, a specificity of 0.636, and a negative predictive value of 0.875. This z-score is useful for excluding increased LCI2.5% when below -1.37 using the reference set of Gochicoa et al. In conclusion, IOS measurement is easily and rapidly obtained in children and may be clinically useful for excluding increased LCI2.5% , thus allowing the time-consuming MBW test to be avoided.

Frequent lower respiratory tract disease in hematological patients with parainfluenza virus type 3 infection.

Human parainfluenza virus type 3 (HPIV-3) may cause lower respiratory tract infection disease (LRTI-D) after hematopoietic stem cell transplantation (HSCT). Most previous have studies focused on recipients of HSCT whereas data on characteristics and outcomes in patients with hematological malignancies (HMs) compared to non-hematological patients are limited. The prognostic value of viral load in respiratory specimens remains elusive. In a 2-year retrospective study, we determined the frequencies of LRTI-D in HM, HSCT, and in non-hematological patients, and HPIV-3 levels in respiratory tract secretions. Among 98 patients with HPIV-3 infection, including 31 HSCT and 40 HM, 36 had a diagnosis of LRTI-D. LRTI-D was significantly more frequent in patients with HM or HSCT (n = 32, 45.1%) than in non-hematological patients (n = 4, 14.8%) (p = 0.006). The median HPIV-3 loads were high in upper respiratory tract secretions regardless of the presence or absence of LRTI-D (8.3 log10 vs. 7.6 log10 TCID50 /106 cells). HPIV-3 loads in respiratory tract samples in HM were not significantly higher than those found in HSCT but significantly higher than in non-hematological patients (p = 0.007). In conclusion, LRTI-D was frequent in HM patients who were diagnosed with HPIV-3 infection.

Phenotypic Presentations of Cystic Fibrosis in Children of African Descent.

The Robert Debre Pediatric Cystic Fibrosis (CF) centre, located in the North East of Paris, a multicultural area, is in charge of a cohort of around a hundred and sixty children diagnosed with CF. Between 2000 and 2019, the proportion of children of African descent in this centre increased from 2% to 10%. We report the clinical features of 17 children of African descent diagnosed with CF: 4 (23%) were diagnosed after a meconium ileus, 14 (83%) had exocrine pancreatic insufficiency, and 7 (41%) had early Pseudomonas aeruginosa infection before the age of two. Even though the majority of patients were diagnosed through NBS, the twenty-nine-mutation testing kit proved less effective in non-Caucasian populations, with a false negative rate of 25% in this series. CF is definitely not solely a Caucasian disease and the literature reveals similar phenotypes in Caucasian and African people provided that they present the same CFTR mutations. Clinicians have to keep in mind that the diagnosis of CF in patients of African descent must be evoked in the case of symptoms and a sweat test must be performed, despite a negative result for NBS.

Chest physiotherapy enhances detection of Pseudomonas aeruginosa in nonexpectorating children with cystic fibrosis.

Lung damage in cystic fibrosis (CF) is strongly associated with lower airway infections. Early treatment of Pseudomonas aeruginosa is recommended. Pathogen detection requires sampling of lower airway secretions, which remains a challenge in nonexpectorating patients. Our hypothesis was that chest physiotherapy would improve the quality of airway secretion samples and increase the rates of pathogens detected in nonexpectorating patients. This prospective multicentre study compared three successive methods for sampling airway secretions applied through the same session: 1) an oropharyngeal swab (OP), 2) a chest physiotherapy session followed by a provoked cough to obtain sputum (CP-SP) and 3) a second oropharyngeal swab collected after chest physiotherapy (CP-OP). Haemophilus influenzae, Staphylococcus aureus and P. aeruginosa growth cultures were assessed. Accuracy tests and an equivalence test were performed to compare the three successive methods of collection. 300 nonexpectorating children with CF were included. P. aeruginosa was detected cumulatively in 56 (18.9%) children, and according to the different collection methods in 28 (9.8%), 37 (12.4%) and 44 (14.7%) children by using OP, CP-OP and CP-SP, respectively. Compared with OP, the increased detection rate was +22% for CP-OP (p=0.029) and +57% for CP-SP (p=0.003). CP-SP had the best positive predictive value (86.3%) and negative predictive value (96.0%) for P. aeruginosa compared with the overall detection. The results of this adequately powered study show differences in the rates of pathogens detected according to the sampling method used. Chest physiotherapy enhanced detection of P. aeruginosa in nonexpectorating children with CF.

First Wave of COVID-19 in French Patients with Cystic Fibrosis.

Viral infections are known to lead to serious respiratory complications in cystic fibrosis (CF) patients. Hypothesizing that CF patients were a population at high risk for severe respiratory complications from SARS-CoV-2 infection, we conducted a national study to describe the clinical expression of COVID-19 in French CF patients. This prospective observational study involves all 47 French CF centers caring for approximately 7500 CF patients. Between March 1st and June 30th 2020, 31 patients were diagnosed with COVID-19: 19 had positive SARS-CoV-2 RT-PCR in nasopharyngeal swabs; 1 had negative RT-PCR but typical COVID-19 signs on a CT scan; and 11 had positive SARS-CoV-2 serology. Fifteen were males, median (range) age was 31 (9-60) years, and 12 patients were living with a lung transplant. The majority of the patients had CF-related diabetes (n = 19, 61.3%), and a mild lung disease (n = 19, 65%, with percent-predicted forced expiratory volume in 1 s (ppFEV1) > 70). Three (10%) patients remained asymptomatic. For the 28 (90%) patients who displayed symptoms, most common symptoms at admission were fever (n = 22, 78.6%), fatigue (n = 14, 50%), and increased cough (n = 14, 50%). Nineteen were hospitalized (including 11 out of the 12 post-lung transplant patients), seven required oxygen therapy, and four (3 post-lung transplant patients) were admitted to an Intensive Care Unit (ICU). Ten developed complications (including acute respiratory distress syndrome in two post-lung transplant patients), but all recovered and were discharged home without noticeable short-term sequelae. Overall, French CF patients were rarely diagnosed with COVID-19. Further research should establish whether they were not infected or remained asymptomatic upon infection. In diagnosed cases, the short-term evolution was favorable with rare acute respiratory distress syndrome and no death. Post-lung transplant patients had more severe outcomes and should be monitored more closely.

Usefulness of bronchoalveolar lavage in a French pediatric cohort with hypersensitivity pneumonitis.

BACKGROUND: Hypersensitivity pneumonitis (HP) is a rare interstitial lung disease in children, and very little data are available on the frequency, diagnosis, and outcomes of HP. In a pediatric cohort with HP, the characteristics of the CD4/CD8 lymphocyte ratio are often described as nonspecific. METHODS: We used the National French Database (RespiRare) to collect data from the last decade on HP. The diagnosis of HP was defined by the presence of a relevant exposure, clinical symptoms, and compatible lung imaging radiology and was usually defined by positive precipitins antibodies. RESULTS: A total of 16 children with a mean age of 10 years (4-13) presented with HP. All children presented with dyspnea on exertion. Diffuse ground-glass opacity was present in all computed tomography (CT) scans. Research guided by a questionnaire and precipitins antibodies against the corresponding antigens showed that patients were positive for contact with birds with or without fungi. Bronchoalveolar lavage (BAL) was performed in 12 children. The total cell counts were elevated in BAL fluid, with a mean value of 36% lymphocytes. The CD4/CD8 lymphocyte ratio was below one for all children. CONCLUSION: BAL in our pediatric cohort with HP had the same characteristics as that of adults with HP. An HP diagnosis must be considered when dyspnea on exertion and diffuse ground-glass opacity are observed. Carrying out BAL and serological tests can help diagnose and avoid lung biopsy.

Lung evaluation in 10 year survivors of pediatric allogeneic hematopoietic stem cell transplantation.

There is little data on the long-term respiratory development of children after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We describe the respiratory assessment 10 years after allo-HSCT of 35 children transplanted between 2000 and 2004. During this period, 90 children were transplanted at our center. Twenty-five children died, thirty were lost to follow-up, and thirty-five came to have a pulmonary investigation. The thirty-five participants answered a questionnaire asking if they had pulmonary symptoms, and pulmonary function tests (PFTs) were performed. The median age of these children 10 years after the transplant was 16 years old. Just over a third of them had pulmonary symptoms. Among them, 5/13 (38%) had bronchiolitis obliterans syndrome (BOS). The majority of children (62.8%) did not have respiratory symptoms. PFTs were abnormal in one-third of asymptomatic children, revealing restrictive lung disease that was always mild to moderate (p = 0.02).Conclusion: In the long term, research at the time of the medical examination for the presence of chronic cough, shortness of breath on exertion, or wheezing helps to guide the clinician as to the need for further lung exploration. Similarly, informing patients and their families about these symptoms, which can be underestimated, should allow for more specific management.What is Known:• Pulmonary complications are a major cause of hematopoietic stem cell transplantation (HSCT) morbidity and mortality.• A long time after allogeneic HSCT, pulmonary function tests abnormalities may occur in children, but it is not always related to symptoms.What is New:• The occurrence of respiratory symptoms: cough, dyspnea on exertion, chronic bronchitis, and wheezing should be systematically investigated in the follow-up of allografted patients, even at a distance.• The presence of respiratory symptoms should lead to a respiratory functional investigation to detect the presence of an obstructive syndrome.

Whole exome sequencing in three families segregating a pediatric case of sarcoidosis.

BACKGROUND: Sarcoidosis (OMIM 181000) is a multi-systemic granulomatous disorder of unknown origin. Despite multiple genome-wide association (GWAS) studies, no major pathogenic pathways have been identified to date. To find out relevant sarcoidosis predisposing genes, we searched for de novo and recessive mutations in 3 young probands with sarcoidosis and their healthy parents using a whole-exome sequencing (WES) methodology. METHODS: From the SARCFAM project based on a national network collecting familial cases of sarcoidosis, we selected three families (trios) in which a child, despite healthy parents, develop the disease before age 15 yr. Each trio was genotyped by WES (Illumina HiSEQ 2500) and we selected the gene variants segregating as 1) new mutations only occurring in affected children and 2) as recessive traits transmitted from each parents. The identified coding variants were compared between the three families. Allelic frequencies and in silico functional results were analyzed using ExAC, SIFT and Polyphenv2 databases. The clinical and genetic studies were registered by the ClinicalTrials.gov - Protocol Registration and Results System (PRS) ( https://clinicaltrials.gov ) receipt under the reference NCT02829853 and has been approved by the ethical committee (CPP LYON SUD EST - 2 - REF IRB 00009118 - September 21, 2016). RESULTS: We identified 37 genes sharing coding variants occurring either as recessive mutations in at least 2 trios or de novo mutations in one of the three affected children. The genes were classified according to their potential roles in immunity related pathways: 9 to autophagy and intracellular trafficking, 6 to G-proteins regulation, 4 to T-cell activation, 4 to cell cycle and immune synapse, 2 to innate immunity. Ten of the 37 genes were studied in a bibliographic way to evaluate the functional link with sarcoidosis. CONCLUSIONS: Whole exome analysis of case-parent trios is useful for the identification of genes predisposing to complex genetic diseases as sarcoidosis. Our data identified 37 genes that could be putatively linked to a pediatric form of sarcoidosis in three trios. Our in-depth focus on 10 of these 37 genes may suggest that the formation of the characteristic lesion in sarcoidosis, granuloma, results from combined deficits in autophagy and intracellular trafficking (ex: Sec16A, AP5B1 and RREB1), G-proteins regulation (ex: OBSCN, CTTND2 and DNAH11), T-cell activation (ex: IDO2, IGSF3), mitosis and/or immune synapse (ex: SPICE1 and KNL1). The significance of these findings needs to be confirmed by functional tests on selected gene variants.