Langerhans Cell Granulomatosis and Smoking-Related Interstitial Lung Diseases

Cigarette smoke contains a mixture of thousands of chemicals, including nicotine, chemical poisons, toxic gases, small particles, and carcinogens. This complex mixture of substances is a leading cause of preventable deaths, causing approximately 650,000 premature deaths each year in the European Union [1]. Inhalation of the toxic particles associated with cigarette smoking and the subsequent immune response leads to a variety of pathological manifestations. Cardiovascular diseases, Chronic Obstructive Pulmonary Disease (COPD), and lung cancer are the most frequent causes of smoking-related deaths [2]. Cigarette smoking has also been implicated as a major cause of interstitial lung diseases (ILDs). ILDs such as respiratory bronchiolitis-associated interstitial lung disease (RB-ILD) and desquamative interstitial pneumonia (DIP), although considered by the current ATS/ERS classification to be idiopathic forms of ILD [3], are clearly associated with cigarette smoking and may be more appropriately defined as “smoking-related interstitial lung diseases” (SR-ILD). Another clinical entity causatively associated with smoking is Pulmonary Langerhans Cell Histiocytosis (PLCH) [4]. More than 90% of all PLCH reported cases and 85-90% of RB-ILD and DIP patients are smokers [4, 5]. In addition, several epidemiological studies have shown evidence for disease remission when smoking ceases [6]. In spite of that, the pathogenic mechanism(s) explaining the association between these diseases and tobacco smoke exposure have not been completely elucidated. Respiratory Bronchiolitis (RB) is a common histopathological finding in smokers, characterized by the accumulation of pigmented macrophages in respiratory bronchioles and alveoli. It has been postulated that a small proportion of smokers may develop an excessive response to smoke provoking interstitial and airspace inflammation as well as fibrotic thickening of the alveoli. These events can eventually lead to symptoms such as cough and dyspnea and to impaired lung function. RB-ILD is usually associated with a good prognosis with radiological and clinical resolution often occurring after smoking cessation; some cases with severe clinical involvement are often treated with corticosteroid therapy, albeit with unknown benefits. Similarly, DIP is characterized by macrophage accumulation in bronchioles and alveoli, although it is much more diffuse than seen in RB-ILD. DIP has a worse prognosis than RB-ILD, and is more often treated with corticosteroid therapy, despite the absence of controlled studies evaluating the efficacy of this approach. PLCH is characterized by the presence of bronchiolocentric interstitial lesions which form nodules that ultimately cavitate and evolve to form cysts, the predominant feature of the disease. PLCH has a good prognosis with smoking cessation alone, though chronic progressive disease or rapid clinical deterioration may sometimes require the use of chemotherapeutic agents. Although SR-ILDs have several distinctive histopathological and radiological features, mixed patterns of SR-ILDs may frequently coexist in the same patient. These observations support the concept that RB-ILD, DIP, and PLCH form a spectrum of interstitial patterns of lung injury related to cigarette smoke [7].