Pulmonary Langerhans Cell Histiocytosis in the Elderly Smoker.
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ABSTRACT:
SUBMITTER: Jeelani HM
PROVIDER: S-EPMC7489450 | biostudies-literature | 2020 Sep
REPOSITORIES: biostudies-literature
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Pulmonary Langerhans Cell Histiocytosis in the Elderly Smoker.
Jeelani Hafiz Muhammad HM Ehsan Hamid H Sheikh Muhammad Mubbashir MM Riaz Adeel A Mahboob Hafiz H
Cureus 20200911 9
Langerhans cell histiocytosis (LCH), formally referred to histiocytosis X, is a histiocytic disorder with unknown etiology. The pathogenesis is believed to originate from myeloid dendritic cells and is now considered an inflammatory myeloid neoplasm within the revised 2016 Histiocyte Society classification. Pulmonary Langerhans cell histiocytosis (PLCH) is a rare and isolated form of LCH with a strong affiliation with smoking in adults of 20-40 years of age. Characteristic CT chest and histologi ...[more]
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Project description:BACKGROUND:Pulmonary Langerhans-cell histiocytosis (PLCH) is a rare interstitial lung disease characterized by clusters of Langerhans cells, organized in granulomas, in the walls of distal bronchioles. It is a diffuse lung disease related to tobacco smoking but otherwise of unknown etiopathogenesis. METHODS:In this study we used a proteomic approach to analyze BAL protein composition of patients with PLCH and of healthy smoker and non-smoker controls to obtain insights into the pathogenetic mechanisms of the disease, to study the effect of cigarette smoking on susceptibility to PLCH and to identify potential new biomarkers. RESULTS:Two-dimensional electrophoresis and image analysis revealed proteins that were differently expressed (quantitatively and qualitatively) in the three groups of subjects. The proteins were identified by mass spectrometry and have various functions (antioxidant, proinflammatory, antiprotease) and origins (plasma, locally produced, etc.). Many, such as protease inhibitors (human serpin B3) and antioxidant proteins (glutathione peroxidase and thioredoxin) are already linked to PLCH pathogenesis, whereas other proteins have never been associated with the disease. Interestingly, numerous proteolytic fragments of plasma proteins (including kininogen-1 N fragments and haptoglobin) were also identified and suggest increased proteolytic activity in this inflammatory lung disease. Differences in protein expression were found between the three groups and confirmed by Principal Component Analysis (PCA). CONCLUSION:Analysis of BAL proteomes of PLCH patients and of smoker and non-smoker controls also proved to be useful for researching the pathogenetic mechanisms and for identifying biomarkers of this rare diffuse lung disease.
| S-EPMC3240815 | biostudies-literature
Project description:Pulmonary Langerhans cell histiocytosis (PLCH) is a rare disorder characterised by granulomatous proliferation of CD1a-positive histiocytes forming granulomas within lung parenchyma, in strong association with tobacco smoking, and which may result in chronic respiratory failure. Smoking cessation is considered to be critical in management, but has variable effects on outcome. No drug therapy has been validated. Cladribine (chlorodeoxyadenosine, 2-CDA) down-regulates histiocyte proliferation and has been successful in curbing multi-system Langerhans cell histiocytosis and isolated PLCH.We retrospectively studied 5 patients (aged 37-55 years, 3 females) with PLCH who received 3 to 4 courses of cladribine therapy as a single agent (0.1 mg/kg per day for 5 consecutive days at monthly intervals). One patient was treated twice because of relapse at 1 year. Progressive pulmonary disease with obstructive ventilatory pattern despite smoking cessation and/or corticosteroid therapy were indications for treatment. Patients were administered oral trimethoprim/sulfamethoxazole and valaciclovir to prevent opportunistic infections. They gave written consent to receive off-label cladribine in the absence of validated treatment.Functional class dyspnea improved with cladribine therapy in 4 out of 5 cases, and forced expiratory volume in 1 second (FEV1) increased in all cases by a mean of 387 ml (100-920 ml), contrasting with a steady decline prior to treatment. Chest high-resolution computed tomography (HRCT) features improved with cladribine therapy in 4 patients. Hemodynamic improvement was observed in 1 patient with pre-capillary pulmonary hypertension. The results suggested a greater treatment effect in subjects with nodular lung lesions and/or thick-walled cysts on chest HRCT, with diffuse hypermetabolism of lung lesions on positron emission tomography (PET)-scan, and with progressive disease despite smoking cessation. Infectious pneumonia developed in 1 patient, with later grade 4 neutrocytopenia but without infection.Data interpretation was limited by the retrospective, uncontrolled study design and small sample size.Cladribine as a single agent may be effective therapy in patients with progressive PLCH.
| S-EPMC4268858 | biostudies-literature
Project description:BackgroundAn important objective on diagnosis of patients with Langerhans cell histiocytosis (LCH) is to determine the extent of disease. However, whether systematic extrathoracic investigation is needed in adult patients with clinically isolated pulmonary LCH (PLCH) has not been evaluated.MethodsIn this prospective, multicentre study, 54 consecutive patients with newly diagnosed clinically isolated PLCH were systematically evaluated at inclusion by bone imaging and blood laboratory testing to search for subclinical extrapulmonary LCH involvement. The patients were followed over a 2-year period. At each visit, they were asked about the presence of extrapulmonary manifestations of LCH.ResultsIn the absence of bone symptoms, the skeletal X-ray survey results were normal for all but two patients who had a localised bone lesion consistent with possible LCH involvement, that remained unchanged over 2 years of follow-up. Whole-body bone scintigraphy did not add information to the plain radiography findings for the detection of asymptomatic bone involvement in isolated PLCH. Conversely, it showed nonspecific focal bone uptake in 18% of the patients, mainly corresponding to post-traumatic or degenerative abnormalities unrelated to LCH. Mild leucocytosis due to neutrophilia was observed in 22% of the patients and was not related to their smoking habits. Three patients had mild isolated lymphocytosis without haematological disease, whereas two patients had mild lymphopaenia. A mild inflammatory biological syndrome was observed in a minority of patients without infection or constitutional symptoms and was not associated with progressive disease. A substantial proportion (24.5%) of the patients had abnormal biological liver test results, including elevated liver enzymes and/or cholestasis, which were not linked to LCH involvement in this cohort.ConclusionsObtaining a thorough history and performing comprehensive physical examination are essential for staging patients diagnosed with PLCH. In the absence of symptoms or signs suggestive of extrapulmonary LCH involvement, the systematic performing of recommended bone imaging does not appear informative. Although the observed blood laboratory abnormalities were not specifically related to LCH, performing these tests in the diagnostic workup for PLCH is useful because some of these alterations may impact patient management.Trial registrationClinicalTrials.gov: No. NCT01225601; URL: www.clinicaltrials.gov.
| S-EPMC4736248 | biostudies-literature
Project description:The natural history of pulmonary Langerhans cell histiocytosis (PLCH) has been unclear due to the absence of prospective studies. The rate of patients who experience an early progression of their disease is unknown. Additionally, conflicting effects of smoking cessation on the outcome of PLCH have been reported.In this prospective, multicentre study, 58 consecutive patients with newly diagnosed PLCH were comprehensively evaluated over a two-year period. Our objectives were to estimate the incidence of early progression of the disease and to evaluate the impact of smoking status on lung function outcomes. Lung function deterioration was defined as a decrease of at least 15% in FEV1 and/or FVC and/or DLCO, compared with baseline values. At each visit, smoking status was recorded based on the patients' self-reports and urinary cotinine measurements that were blinded for the patients. The cumulative incidence of lung function outcomes over time was estimated using the non-parametric Kaplan-Meier method. Multivariate Cox models with time-dependent covariates were used to calculate the hazards ratios of the lung function deterioration associated with smoking status with adjustment for potential confounders.The cumulative incidence of lung function deterioration at 24 months was 38% (22% for FEV1 and DLCO, and 9% for FVC). In the multivariate analysis, smoking status and PaO2 at inclusion were the only factors associated with the risk of lung function deterioration. The patients' smoking statuses markedly changed over time. Only 20% of the patients quit using tobacco for the entire study period. Nevertheless, being a non-smoker was associated with a decreased risk of subsequent lung function deterioration, even after adjustment for baseline predictive factors. By serial lung computed tomography, the extent of cystic lesions increased in only 11% of patients.Serial lung function evaluation on a three- to six-month basis is essential for the follow-up of patients with recently diagnosed PLCH to identify those who experience an early progression of their disease. These patients are highly addicted to tobacco, and robust efforts should be undertaken to include them in smoking cessation programs.ClinicalTrials.gov: No: NCT01225601 .
| S-EPMC4438520 | biostudies-literature
Project description:Pulmonary Langerhans cell histiocytosis (PLCH) is a rare smoking-related lung disease characterized by dendritic cell (DC) accumulation, bronchiolocentric nodule formation, and cystic lung remodeling. Approximately 50% of patients with PLCH harbor somatic BRAF-V600E mutations in cells of the myeloid/monocyte lineage. However, the rarity of the disease and lack of animal models have impeded the study of PLCH pathogenesis. Here, we establish a cigarette smoke-exposed (CS-exposed) BRAF-V600E-mutant mouse model that recapitulates many hallmark characteristics of PLCH. We show that CD11c-targeted expression of BRAF-V600E increases DC responsiveness to stimuli, including the chemokine CCL20, and that mutant cell accumulation in the lungs of CS-exposed mice is due to both increased cellular viability and enhanced recruitment. Moreover, we report that the chemokine CCL7 is secreted from DCs and human peripheral blood monocytes in a BRAF-V600E-dependent manner, suggesting a possible mechanism for recruitment of cells known to dominate PLCH lesions. Inflammatory lesions and airspace dilation in BRAF-V600E mice in response to CS are attenuated by transitioning animals to filtered air and treatment with a BRAF-V600E inhibitor, PLX4720. Collectively, this model provides mechanistic insights into the role of myelomonocytic cells and the BRAF-V600E mutation and CS exposure in PLCH pathogenesis and provides a platform to develop biomarkers and therapeutic targets.
| S-EPMC7101136 | biostudies-literature
Project description:BackgroundReduced exercise capacity severely impacts quality of life in pulmonary Langerhans cell histiocytosis. Ascertaining mechanisms that impair exercise capacity is necessary to identify targets for symptomatic treatments.MethodsDyspnea, pulmonary function tests and cardiopulmonary exercise test were analysed in 62 study participants. Data were compared between subjects with impaired and normal aerobic capacity (V'O2 peak less than 84% versus 84% predicted or more). Data were reduced using a principal component analysis. Multivariate analysis included V'O2 peak as the dependent variable and principal components as covariates.ResultsV'O2 peak was reduced in 44 subjects (71%). Subjects with impaired aerobic capacity presented: (i) decreased FEV1, FVC, FEV1/FVC, DLCO and DLCO/VA and increased AaDO2, (ii) increased ventilatory equivalents at ventilatory threshold, VD/VT peak, AaDO2 peak and PaCO2 peak and decreased ventilatory reserve and PaO2 peak. There was no difference between groups in dyspnea scores. Principal component analysis extracted 4 principal components interpreted as follows: PC1: gas exchange; PC2: "pseudorestriction"; PC3: exercise-induced hyperpnea; PC4: air trapping. Multivariate analysis explained 65% of V'O2 peak. The 4 principal components were independently associated with V'O2 peak (βcoefficients: PC1: 9.3 [4.6; 14], PC2: 7.5 [3; 11.9], PC3: -5.3 [-9.6;-1.], PC4: -9.8 [-14,9;-4.7]).ConclusionImpaired exercise capacity is frequent in pulmonary Langerhans cell histiocytosis. It is mainly caused by pulmonary changes but is not associated with increased dyspnea intensity. Therefore, treating the lung represents a relevant approach for improving exercise capacity, even in patients experiencing mild dyspnea.
| S-EPMC5225005 | biostudies-literature
Project description:Langerhans cell histiocytosis (LCH) has a broad spectrum of clinical behaviors; some cases are self-limited, whereas others involve multiple organs and cause significant mortality. Although Langerhans cells in LCH are clonal, their benign morphology and their lack (to date) of reported recurrent genomic abnormalities have suggested that LCH may not be a neoplasm. Here, using 2 orthogonal technologies for detecting cancer-associated mutations in formalin-fixed, paraffin-embedded material, we identified the oncogenic BRAF V600E mutation in 35 of 61 archived specimens (57%). TP53 and MET mutations were also observed in one sample each. BRAF V600E tended to appear in younger patients but was not associated with disease site or stage. Langerhans cells stained for phospho-mitogen-activated protein kinase kinase (phospho-MEK) and phospho-extracellular signal-regulated kinase (phospho-ERK) regardless of mutation status. High prevalence, recurrent BRAF mutations in LCH indicate that it is a neoplastic disease that may respond to RAF pathway inhibitors.
| S-EPMC3173987 | biostudies-literature
Project description:Background and objectiveDisease-specific outcomes following lung transplantation (LT) in patients with pulmonary Langerhans cell histiocytosis (PLCH) are not well established. We queried the Organ Procurement and Transplantation Network database to identify adult PLCH patients who had undergone LT in the United States.MethodsOverall survival data were analysed with Kaplan-Meier curves. Cox proportional hazard model was used to determine the effect of demographic, clinical and physiological variables on post-transplant survival.ResultsA total of 87 patients with PLCH underwent LT in the United States between October 1987 and June 2017, accounting for 0.25% of the total LT during this period. The mean age at LT for PLCH patients was 49 years (range: 19-67 years), with a near equal gender distribution. Bilateral sequential LT was performed in 71 patients (82%). Pulmonary hypertension was present in 85% of patients, with a mean pulmonary artery pressure of 38.5 ± 14.1 mm Hg. The mean pre-transplant forced expiratory volume in 1 s (FEV1 ) was 41 ± 21% predicted and the mean 6-min walk distance was 221 ± 111 m. Median post-LT survival for PLCH patients was comparable to patients with other lung diseases (5.1 vs 5.5 years, P = 0.76). The actuarial Kaplan-Meier post-LT survival for PLCH patients was 85%, 65%, 49% and 22% at 1, 3, 5 and 10 years, respectively. Female sex (hazard ratio (HR): 0.40, 95% CI: 0.22-0.72), pre-transplant serum bilirubin (HR: 1.66, 95% CI: 1.23-2.26) and serum creatinine (HR: 4.03, 95% CI: 1.01-14.76) were independently associated with post-LT mortality in our cohort.ConclusionPost-LT survival in patients with PLCH is similar to patients with other lung diseases and is significantly affected by patient gender.
| S-EPMC8643712 | biostudies-literature
Project description:BackgroundThe study aimed to investigate the clinical features and prognosis factors of adult patients with Langerhans cell histiocytosis (LCH) with pulmonary involvement, especially multisystem (MS) LCH with pulmonary involvement.MethodsWe retrospectively analyzed the demographic materials, clinical features and treatment outcomes of 119 adult LCH patients with pulmonary involvement at our center from January 1990 to November 2019.ResultsAmong 119 patients, 13 (10.9%) had single-system (SS) LCH, and 106 (89.1%) had MS-LCH with pulmonary involvement. SS-LCH patients had higher smoking rate (84.6% vs 52.8%, P = 0.026) and smoking index (300 vs 200, P = 0.019) than MS-LCH patients. The percentage of respiratory symptoms of SS-LCH patients was higher than MS-LCH patients (84.6% vs 53.8%, P = 0.034). Pulmonary function was impaired in 83.8% of the patients, and DLCO was the parameter most frequently impaired, accounting for 81.1%. The median DLCO was 65.1% predicted. Patients with pneumothorax had significantly worse DLCO (P = 0.022), FEV1 (P = 0.000) and FEV1/FVC (P = 0.000) than those without pneumothorax. During the follow-up, 72.4% of the patients had stable pulmonary function, and 13.8% showed improvements after chemotherapy. The estimated 3-year OS and EFS were 89.7 and 58.3%, respectively. Patients with a baseline FEV1 ≤ 55% predicted had worse OS. A history of pneumothorax indicated worse EFS and cytarabine based therapy predicted better EFS.ConclusionsAn FEV1 ≤ 55% predicted and a history of pneumothorax at diagnosis indicated a poor prognosis. Cytarabine based regimen may arrest the decline in pulmonary function in LCH patients with pulmonary involvement and improve EFS.
| S-EPMC7513534 | biostudies-literature
Project description:Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocyte disorder most commonly characterized by multifocal osteosclerotic lesions of the long bones demonstrating sheets of foamy histiocyte infiltrates on biopsy with or without histiocytic infiltration of extraskeletal tissues. ECD can be difficult to diagnose since it is a very rare disease that can affect many organ systems. Diagnosis is based on the pathologic evaluation of involved tissue interpreted within the clinical context. Patients who have the BRAF V600E mutation are treated first line with vemurafenib. For those without the mutation with symptomatic ECD, conventional or PEGylated interferon alpha is recommended. For patients who are either intolerant or nonresponsive to interferon alpha, systemic chemotherapy with or without corticosteroids can be used. We present a rare case of Erdheim-Chester disease with concurrent Langerhans cell histiocytosis which occurs in only one fifth of the cases and often presents as a diagnostic and therapeutic challenge.
| S-EPMC5977054 | biostudies-literature