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.

Respiratory recovery trajectories after severe-to-critical COVID-19: a 1-year prospective multicentre study.

BACKGROUND: Survivors of severe-to-critical coronavirus disease 2019 (COVID-19) may have functional impairment, radiological sequelae and persistent symptoms requiring prolonged follow-up. This pragmatic study aimed to describe their clinical follow-up and determine their respiratory recovery trajectories, and the factors that could influence them and their health-related quality of life. METHODS: Adults hospitalised for severe-to-critical COVID-19 were evaluated at 3 months and up to 12 months post-hospital discharge in this prospective, multicentre, cohort study. RESULTS: Among 485 enrolled participants, 293 (60%) were reassessed at 6 months and 163 (35%) at 12 months; 89 (51%) and 47 (27%) of the 173 participants initially managed with standard oxygen were reassessed at 6 and 12 months, respectively. At 3 months, 34%, 70% and 56% of the participants had a restrictive lung defect, impaired diffusing capacity of the lung for carbon monoxide (D LCO) and significant radiological sequelae, respectively. During extended follow-up, both D LCO and forced vital capacity percentage predicted increased by means of +4 points at 6 months and +6 points at 12 months. Sex, body mass index, chronic respiratory disease, immunosuppression, pneumonia extent or corticosteroid use during acute COVID-19 and prolonged invasive mechanical ventilation (IMV) were associated with D LCO at 3 months, but not its trajectory thereafter. Among 475 (98%) patients with at least one chest computed tomography scan during follow-up, 196 (41%) had significant sequelae on their last images. CONCLUSIONS: Although pulmonary function and radiological abnormalities improved up to 1 year post-acute COVID-19, high percentages of severe-to-critical disease survivors, including a notable proportion of those managed with standard oxygen, had significant lung sequelae and residual symptoms justifying prolonged follow-up.

Dramatic Response After Switching MEK Inhibitors in a Patient With Refractory Mixed Histiocytosis.

We report the case of a patient with progressive multisystem mixed histiocytosis associating Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD) involving the bone marrow, whose lesions harbored the MAP2K1 E102-I103del. After initial improvement under the MEK inhibitor trametinib, the treatment was only partially efficient and poorly tolerated. Eventually, although the trough blood level of trametinib at steady state was within expected ranges, the disease progressed to a life-threatening situation, with peritoneal involvement and anasarca. Switching to the MEK inhibitor cobimetinib as a salvage therapy resulted in a dramatic, rapid disease response, and the patient remains disease-free 3 years later with the treatment. The load of the MAP2K1 deletion in peripheral blood was correlated with the disease activity and strongly declined with cobimetinib, although it remained detectable at the last follow-up.

Long-term outcomes of adult pulmonary Langerhans cell histiocytosis: a prospective cohort.

BACKGROUND: The long-term outcomes of adult pulmonary Langerhans cell histiocytosis (PLCH), particularly survival, are largely unknown. Two earlier retrospective studies reported a high rate of mortality, which contrasts with our clinical experience. METHODS: To address this issue, all patients with newly diagnosed PLCH referred to the French national reference centre for histiocytoses between 2004 and 2018 were eligible for inclusion. The primary outcome was survival, which was defined as the time from inclusion to lung transplantation or death from any cause. Secondary outcomes included the cumulative incidences of chronic respiratory failure (CRF), pulmonary hypertension (PH), malignant diseases and extrapulmonary involvement in initially isolated PLCH. Survival was estimated using the Kaplan-Meier method. RESULTS: 206 patients (mean age 39±13 years, 60% female, 95% current smokers) were prospectively followed for a median duration of 5.1 years (IQR 3.2-7.6 years). Of these, 12 patients (6%) died. The estimated rate of survival at 10 years was 93% (95% CI 89-97%). The cumulative incidences of CRF and/or PH were <5% at both 5 and 10 years, and 58% of these patients died. 27 malignancies were observed in 23 patients. The estimated standardised incidence ratio of lung carcinoma was 17.0 (95% CI 7.45-38.7) compared to an age- and sex-matched French population. Eight (5.1%) of the 157 patients with isolated PLCH developed extrapulmonary involvement. CONCLUSION: The long-term prognosis of PLCH is significantly more favourable than has previously been reported. Patients must be closely monitored after diagnosis to detect severe complications early.

Clarifying the relationship between pulmonary langerhans cell histiocytosis and Alpha 1 antitrypsin deficiency.

Pulmonary Langerhans cell histiocytosis (PLCH) is a rare, smoking related, progressive diffuse cystic lung disease that occurs primarily in smokers. The aim of this study was to determine if there was an increase in alpha-1 antitrypsin deficient alleles or phenotypes in a large series of PLCH patients and whether serum alpha-1 antitrypsin levels correlated with markers of disease severity. Fifty PLCH patients, 24 with a diffuse cystic lung pattern and 26 with a typical nodulo-cystic pattern on imaging were included. The mean alpha-1 antitrypsin levels were in normal range for both the population with diffuse cystic lung pattern population (1.39 g/L ± 0.37) and the nodulo-cystic pattern group (1.41 g/L ± 0.21). Deficiency alleles PiZ and PiS were 1% and 2% respectively in the entire study population of 50 patients, demonstrating no increased incidence of alpha-1 antitrypsin deficiency in PLCH. Alpha-1 antitrypsin levels showed no correlation with lung function parameters or extent of cystic lesions on lung computed tomography.

Psychological features of adult patients with langerhans cell histiocytosis.

BACKGROUND: The prevalence of psychological symptoms and the co-occurrence of substance abuse disorders in adult patients with Langerhans cell histiocytosis (LCH) has not been previously explored. We aimed to use validated scales to evaluate depression and anxiety symptoms experienced by adult LCH patients. METHODS: In this cross-sectional study, all consecutive adult LCH patients seen at our national reference center between January 2012 and January 2013 were asked to complete the following instruments: the Hospital Anxiety and Depression scale (HADS); Barratt Impulsiveness Scale, Version 10 (BIS-10); and Cannabis Use Disorders Identification Test (CUDIT). Self-reported scores on these scales were used to determine the point prevalence of clinically significant psychological symptoms and substance use disorders in LCH patients. Patient profiles in terms of psychological features were assessed by principal component analysis including the HADS and BIS-10 instruments values, followed by hierarchical clustering. Fisher exact tests and Wilcoxon tests were used to examine the associations between disease-related parameters and high levels of anxiety and impulsivity. RESULTS: Seventy-one adult LCH patients, mainly with pulmonary LCH (PLCH), completed the evaluations. Clinically significant anxiety and depression symptoms were reported by 22 (31%) and 4 (6%) subjects, respectively. Impulsivity was detected in 14% (10/71) of the patients. Seventeen percent (12/71) of the patients used cannabis on a regular basis, with 50% of these individuals (6/12) exhibiting scores consistent with cannabis use disorder. Three derived clusters of patients were identified in the principal component analysis; these patient clusters differed in successful weaning from tobacco at the time of evaluation (p = 0.03). In univariate analyses, isolated PLCH and the use of psychotropic treatments were statistically associated with clinically significant anxiety symptoms. CONCLUSIONS: High levels of anxiety and impulsivity are common in adult patients with LCH. The consequences of these symptoms for the management of LCH patients warrant further evaluation.

Custom pyrosequencing assay to detect short BRAF deletions in Langerhans cell histiocytic lesions.

Langerhans cell histiocytosis (LCH) is a rare inflammatory myeloid neoplastic disease driven by activating mutations in the mitogen-activating protein kinase signalling pathway, including the BRAF V600E mutation and BRAF deletions (BRAFdel). Next-generation sequencing and whole exome sequencing (WES) are valuable and powerful approaches for BRAFdel identification, but these techniques are costly and time consuming. Pyrosequencing is an alternative method that has the potential to rapidly and reliably identify gene deletions. We developed a custom pyrosequencing assay to detect the exon-12 BRAFdel in 18 biopsies from adult patients with LCH, which were all genotyped in parallel using Sanger sequencing and WES. A BRAFdel was detected in 7/18 (39%), 6/18 (33%) and 3/18 (17%) LCH lesions using WES, pyrosequencing and Sanger, respectively, with good concordance between the WES and pyrosequencing results (Kappa-coefficient=0.88). Therefore, our pyrosequencing assay is reliable and useful for detecting BRAFdel, particularly in BRAF V600E-negative LCH lesions, for which targeted treatment is indicated.

Childhood Langerhans cell histiocytosis with severe lung involvement: a nationwide cohort study.

BACKGROUND: Lung involvement in childhood Langerhans cell histiocytosis (LCH) is infrequent and rarely life threatening, but occasionally, severe presentations are observed. METHODS: Among 1482 children (< 15 years) registered in the French LCH registry (1994-2018), 111 (7.4%) had lung involvement. This retrospective study included data for 17 (1.1%) patients that required one or more intensive care unit (ICU) admissions for respiratory failure. RESULTS: The median age was 1.3 years at the first ICU hospitalization. Of the 17 patients, 14 presented with lung involvement at the LCH diagnosis, and 7 patients (41%) had concomitant involvement of risk-organ (hematologic, spleen, or liver). Thirty-five ICU hospitalizations were analysed. Among these, 22 (63%) were secondary to a pneumothorax, 5 (14%) were associated with important cystic lesions without pneumothorax, and 8 (23%) included a diffuse micronodular lung infiltration in the context of multisystem disease. First-line vinblastine-corticosteroid combination therapy was administered to 16 patients; 12 patients required a second-line therapy (cladribine: n = 7; etoposide-aracytine: n = 3; targeted therapy n = 2). A total of 6 children (35%) died (repeated pneumothorax: n = 3; diffuse micronodular lung infiltration in the context of multisystem disease: n = 2; following lung transplantation: n = 1). For survivors, the median follow-up after ICU was 11.2 years. Among these, 9 patients remain asymptomatic despite abnormal chest imaging. CONCLUSIONS: Severe lung involvement is unusual in childhood LCH, but it is associated with high mortality. Treatment guidelines should be improved for this group of patients: viral infection prophylaxis and early administration of a new LCH therapy, such as targeted therapy.

Functional assessment and phenotypic heterogeneity of SFTPA1 and SFTPA2 mutations in interstitial lung diseases and lung cancer.

INTRODUCTION: Interstitial lung diseases (ILDs) can be caused by mutations in the SFTPA1 and SFTPA2 genes, which encode the surfactant protein (SP) complex SP-A. Only 11 SFTPA1 or SFTPA2 mutations have so far been reported worldwide, of which five have been functionally assessed. In the framework of ILD molecular diagnosis, we identified 14 independent patients with pathogenic SFTPA1 or SFTPA2 mutations. The present study aimed to functionally assess the 11 different mutations identified and to accurately describe the disease phenotype of the patients and their affected relatives. METHODS: The consequences of the 11 SFTPA1 or SFTPA2 mutations were analysed both in vitro, by studying the production and secretion of the corresponding mutated proteins and ex vivo, by analysing SP-A expression in lung tissue samples. The associated disease phenotypes were documented. RESULTS: For the 11 identified mutations, protein production was preserved but secretion was abolished. The expression pattern of lung SP-A available in six patients was altered and the family history reported ILD and/or lung adenocarcinoma in 13 out of 14 families (93%). Among the 28 SFTPA1 or SFTPA2 mutation carriers, the mean age at ILD onset was 45 years (range 0.6-65 years) and 48% underwent lung transplantation (mean age 51 years). Seven carriers were asymptomatic. DISCUSSION: This study, which expands the molecular and clinical spectrum of SP-A disorders, shows that pathogenic SFTPA1 or SFTPA2 mutations share similar consequences for SP-A secretion in cell models and in lung tissue immunostaining, whereas they are associated with a highly variable phenotypic expression of disease, ranging from severe forms requiring lung transplantation to incomplete penetrance.

Lack of evidence for the involvement of Merkel cell polyomavirus in pulmonary Langerhans cell histiocytosis.

Compared to control lung tissues from smokers, MCPyV DNA is rarely detected in PLCH lesions and is not associated with alterations of the MAPK pathway. A viral trigger in PLCH pathogenesis remains elusive. https://bit.ly/2xKmkIo.

Long-term efficacy and safety of 2CdA (cladribine) in extra-pulmonary adult-onset Langerhans cell histiocytosis: analysis of 23 cases from the French Histiocytosis Group and systematic literature review.

Langerhans cell histiocytosis (LCH) is a rare protean disease that usually affects children. Few data are available for management of adult-onset cases. A complete picture of the efficacy and safety of 2CdA (2-chlorodeoxyadenosine, cladribine) is lacking. We report a retrospective multicentre study of 23 adult LCH (a-LCH) patients who received single-agent 2CdA and a systematic literature review. All had previously received systemic therapy (vinblastine, n = 19). Response to 2CdA was evaluable in 22 cases. Overall response rate (ORR) was 91%. Complete response (CR) occurred in 11 cases (50%). Nine patients (39%) developed grade 3-4 neutropenia and/or severe infection. A literature review yielded 48 additional cases. A pooled analysis confirmed our findings (ORR: 88%, CR: 49%). CRs were rare with cumulative dose <50 mg/m2 . Disease progression rates were 20% and 30% at two and five years, respectively. Partial response (PR) to 2CdA was predictive of disease progression. Among eight re-treated patients, five went into CR, two in PR, and one died. Single-agent 2CdA is effective in reactivated a-LCH, including at intermediate doses. Toxicity, significant but acceptable, warrants infectious prophylaxis. Complete responders may enter prolonged remission. Further studies are needed to determine 2CdA sequencing with other agents (vinblastine, cytarabine).

BRAF-mutated histiocytosis of the skull lacking the expression of Langerhans cell markers.

Langerhans cell histiocytosis (LCH) is a rare condition affecting children more frequently than adults. LCH can involve any organ in the body and has a wide spectrum of clinical presentation from a single self-healing bone lesion to a multisystemic life-threatening disease. The diagnosis of LCH requires histology with compatible clinical and radiological findings. Positive immunochemistry for both CD1a and CD207 is required for a definitive diagnosis of LCH. The majority of LCH shares oncogenic BRAFV600E mutation. We report the case of a 55-year-old adult who presented with a single lytic self-healing lesion of the skull, invading adjacent soft tissues. The histology and cytology were also typical of LCH, and tumor cells contained the BRAFV600E mutation. However, histiocytes were negative for CD1a and CD207. We suggest that this case might be considered as LCH, despite its abnormal phenotype.
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Genetic landscape of adult Langerhans cell histiocytosis with lung involvement.

The clinical significance of the BRAF V600E mutation in adult Langerhans cell histiocytosis (LCH), including pulmonary Langerhans cell histiocytosis (PLCH), is not well understood. Similarly, the spectrum of molecular alterations involved in adult LCH has not been fully delineated. To address these issues, we genotyped a large number of adult LCH biopsies and searched for an association of identified molecular alterations with clinical presentation and disease outcome.Biopsies from 117 adult LCH patients, 83 with PLCH (median age 36.4 years, 56 females, 38 multisystem disease, 79 single system disease, 65 current smokers) were genotyped for the BRAF V600E mutation. In 69 cases, LCH lesions were also genotyped by whole-exome sequencing (WES) or targeted gene panel next-generation sequencing (NGS). Cox models were used to estimate the association of baseline characteristics with the hazard of LCH progression.MAPK pathway alterations were detected in 59 out of 69 cases (86%) (BRAF V600E mutation: 36%, BRAF N486_P490 deletion: 28%, MAP2K1 mutations: 15%, isolated NRAS Q61 mutations: 4%), while KRAS mutations were virtually absent in PLCH lesions. The BRAF V600E mutation was not associated with LCH presentation at diagnosis, including smoking status and lung function, in PLCH patients. BRAF V600E status did not influence the risk of LCH progression over time.Thus, MAPK alterations are present in most lesions from adult LCH patients, particularly in PLCH. Unlike reports in paediatric LCH, BRAF V600E genotyping did not provide additional information on disease outcome. The search for alterations involved in the MAPK pathway, including BRAF deletions, is useful for guiding targeted treatment in selected patients with refractory progressive LCH.

Management and outcomes of pneumothorax in adult patients with Langerhans cell Histiocytosis.

BACKGROUND: Pneumothorax may recur during pulmonary Langerhans cell histiocytosis (PLCH) patients' follow-up and its management is not standardised. The factors associated with pneumothorax recurrence are unknown. METHODS: In this retrospective study, PLCH patients who experienced a pneumothorax and were followed for at least 6 months after the first episode were eligible. The objectives were to describe the treatment of the initial episode and pneumothorax recurrences during follow-up. We also searched for factors associated with pneumothorax recurrence and evaluated the effect on lung function outcome. Time to recurrence was estimated by the Kaplan Meier method and the cumulative hazard of recurrence handling all recurrent events was estimated. Univariate Cox models and Andersen-Gill counting process were used for statistical analyses. RESULTS: Fourty-three patients (median age 26.5 years [interquartile range (IQR), 22.9-35.4]; 26 men, 39 current smokers) were included and followed for median time of 49 months. Chest tube drainage was the main management of the initial pneumothorax, which resolved in 70% of cases. Pneumothorax recurred in 23 (53%) patients, and overall 96 pneumothoraces were observed during the study period. In the subgroup of patients who experienced pneumothorax recurrence, the median number of episodes per patient was 3 [IQR, 2-4]. All but one recurrence occurred within 2 years after the first episode. Thoracic surgery neither delayed the time of occurrence of the first ipsilateral recurrence nor reduced the overall number of recurrences during the study period, although the rate of recurrence was lower after thoracotomy than following video-assisted thoracic surgery (p = 0.03). At the time of the first pneumothorax, the presence of air trapping on lung function testing was associated with increased risk of recurrence (hazard ratio = 5.08; 95% confidence interval [1.18, 21.8]; p = 0.03). Pneumothorax recurrence did not predict subsequent lung function decline (p = 0.058). CONCLUSIONS: Our results show that pneumothorax recurrences occur during an "active" phase of PLCH. In this observational study, the time of occurrence of the first ipsilateral recurrence and the overall number of pneumothorax recurrences were similar after conservative and thoracic surgical treatments. Further studies are needed to determine the best management to reduce the risk of pneumothorax recurrence in PLCH patients.

Management of immune-related adverse events resulting from immune checkpoint blockade.

INTRODUCTION: Immune checkpoint inhibitors (ICI) are now a standard of care in the treatment of many cancers leading to durable responses in patients with metastatic disease. These agents are generally well tolerated but may lead to the occurrence of immune-related adverse events (irAEs). As any organ may be affected, clinicians should be aware of the broad range of clinical manifestations and symptoms and keep in mind that toxicities may occur late, at any point along a patient's treatment course. Although the most common irAEs are rarely severe, some of them may be associated with great morbidity and even become life-threatening. The rate of occurrence, type and severity of irAEs may vary with the type of ICI; thus, grade 3 and 4 irAEs are reported in more than 55% of patients treated with the combination of ipilimumab 3 mg/kg and nivolumab 1 mg/kg. Area covered: This review presents the management of irAEs resulting from checkpoint blockade, with a focus on rare irAEs. Expert commentary: With the development of immuno-oncology and the expanding role of ICI, physicians have learnt to diagnose and treat most of the irAEs that can occur. This review provides an overview of current guidelines, previously published studies and our multidisciplinary team based practices.

Noninfectious lung complications after allogeneic haematopoietic stem cell transplantation.

Epidemiological data on late-onset noninfectious pulmonary complications (LONIPCs) following allogeneic haematopoietic stem cell transplantation (HSCT) are derived exclusively from retrospective studies and are conflicting. We aimed to evaluate prospectively the incidence, risk factors and outcomes for LONIPCs.All consecutive patients scheduled to receive allogeneic HSCT between 2006 and 2008 at a university teaching hospital in France were screened for inclusion in the study. Eligible patients were those surviving at day 100. Among 243 screened patients, 198 patients were included in the analysis. The median (interquartile range) follow-up was 72.3 (15.2-88.5) months. 55 LONIPCs were diagnosed in 43 patients. Bronchiolitis obliterans syndrome (n=22) and interstitial lung disease (n=12) were the most common LONIPCs. At 36 months after inclusion, the estimated cumulative incidence of LONIPCs was 19.8% (95% CI 14.2-25.3%). The estimated median survival after the diagnosis of LONIPCs was 78.5 months (95% CI 20.0-not reached). Based on a multivariate Cox model, a history of chest irradiation anytime prior to HSCT, a history of pneumonia within 100 days post-HSCT and a low mean forced expiratory flow at 25-75% of forced vital capacity at day 100 were associated with the development of LONIPCs.Our data provide clues to identify patients at high risk of developing LONIPCs. These patients should be targeted for close monitoring to provide earlier LONIPC treatment or prophylactic treatment.