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:Pulmonary Langerhans cell (LC) histiocytosis (PLCH) has unknown cause and is a rare neoplastic disorder characterized by the infiltration of lungs and various organs by bone marrow-derived Langerhans cells with an accompanying strong inflammatory response. These cells carry somatic mutations of BRAF gene and/or NRAS, KRAS, and MAP2K1 genes, which cause activation of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling pathway. PLCH occurs predominantly in young smokers, without gender predominance. Lungs might be involved as an isolated organ or as part of a multiorgan disease. High-resolution computed chest tomography plays an outstanding role in PLCH diagnosis. The typical radiological picture of PLCH is the presence of small intralobular nodules, "tree in bud" opacities, cavitated nodules, and thin- and thick-walled cysts, frequently confluent. Histological examination of the lesion and demonstration of characteristic eosinophilic granulomas with the presence of LCs that display antigen CD1a or CD207 in immunohistochemistry are required for definite diagnosis. Smoking cessation is the most important recommendation for PLCH patients, but treatment of progressive PLCH and multisystem disease is based on chemotherapy. Recently, new targeted therapies have been implemented.
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Project description:Pulmonary Langerhans cell histiocytosis (PLCH) is a rare sporadic cystic lung disease of unknown aetiology that is characterised by the infiltration and destruction of the wall of distal bronchioles by CD1a+ Langerhans-like cells. In adults, PLCH is frequently isolated and affects young smokers of both sexes. Recent multicentre studies have led to the more standardised management of patients in clinical practice. Smoking cessation is essential and is occasionally the only suitable intervention. Serial lung function testing is important because a significant proportion of patients may experience an early decline in forced expiratory volume in 1 s and develop airflow obstruction. Cladribine was reported to dramatically improve progressive PLCH in some patients. Its efficacy and tolerance are currently being evaluated. Patients who complain of unexplained dyspnoea with decreased diffusing capacity of the lung for carbon monoxide should be screened for pulmonary hypertension by Doppler echocardiography, which must be confirmed by right heart catheterisation. Lung transplantation is a therapeutic option for patients with advanced PLCH.The identification of the BRAFV600E mutation in approximately half of Langerhans cell histiocytosis lesions, including PLCH, and other mutations of the mitogen-activated protein kinase (MAPK) pathway in a subset of lesions has led to targeted treatments (BRAF and MEK (MAPK kinase) inhibitors). These treatments need to be rigorously evaluated because of their potentially severe side-effects.
| S-EPMC9489169 | biostudies-literature
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| S-EPMC6334777 | biostudies-literature
Project description:BackgroundPulmonary 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.MethodsIn 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.ResultsTwo-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).ConclusionAnalysis 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: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:BackgroundPulmonary 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.Methods and patientsWe 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.ResultsFunctional 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.DiscussionData interpretation was limited by the retrospective, uncontrolled study design and small sample size.ConclusionCladribine as a single agent may be effective therapy in patients with progressive PLCH.
| S-EPMC4268858 | biostudies-literature
Project description:Children with Langerhnans cell histiocytosis (LCH) develop granulomatous lesions with characteristic clonal CD207+ dendritic cells that can arise as single lesions or life-threatening disseminated disease. Despite the wide range of clinical presentations, LCH lesions are histologically indistinguishable based on severity of disease, and uncertain classification as an immune versus neoplastic disorder has historically challenged the development of optimal clinical strategies for patients with LCH. Recently, activating somatic mutations in MAPK pathway genes, most notably BRAFV600E, have been discovered in almost all cases of LCH. Further, the stage of myeloid differentiation in which the mutation arises defines the extent of disease and risk of developing LCH-associated neurodegeneration. MAPK activation in LCH precursor cells drives myeloid differentiation, inhibits migration, and inhibits apoptosis, resulting in accumulation of resilient pathologic dendritic cells that recruit and activate T cells. Recurrent somatic mutations in MAPK pathway genes have also been identified in related histiocytic disorders: juvenile xanthogranuloma, Erdheim-Chester disease, and Rosai-Dorfman disease. New insights into pathogenesis support reclassification of these conditions as a myeloid neoplastic disorders. Continued research will uncover opportunities to identify novel targets and inform personalized therapeutic strategies based on cell of origin, somatic mutation, inherited risk factors, and residual disease.
| S-EPMC9150752 | 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.
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Project description:BackgroundThe 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.MethodsIn 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.ResultsThe 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.ConclusionsSerial 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.Trial registrationClinicalTrials.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