Evaluation of Exercise Capacity and Exercise Limitation in Patients With Pulmonary Langerhans Cell Histiocytosis
Evaluation of Exercise Capacity and Exercise Limitation in Patients With Pulmonary Langerhans Cell Histiocytosis
Pulmonary Langerhans Histiocytosis Cells (PLCH) is characterized by infiltration of
 Langerhans cells and formation of loose granulomas with lymphocytic infiltrate and formation
 of nodular and cystic lesions on chest CT, and is often associated with smoking.
 Functionally, there may be obstructive and / or restrictive defect, with reduced carbon
 monoxide diffusing capacity. Dyspnea and lower exercise tolerance are common in PLCH, but
 exercise capacity in this disease is poorly understood and has not been compared to controls.
 Besides, the mechanisms involved in limiting exercise are poorly understood and cover
 multiple factors such as change in gas exchange, pulmonary hypertension (PH), dynamic
 hyperinflation, physical deconditioning and left heart failure. The involvement of pulmonary
 circulation in PLCH has unknown prevalence, but contributes to the symptoms. In the PH
 classification, PLCH belongs to the group 5, of multifactorial etiology. The definition of
 the presence and contribution of dyspnea mechanisms in different severities of PLCH is
 important to understanding the disease and individualization of treatment. The objective of
 the study is to evaluate the exercise capacity of patients with HCLP, and determinate
 mechanisms of dyspnea and lower exercise tolerance beyond its impact on quality of life.
Langerhans cells are antigen-presenting cells of monocyte-macrophage lineage present in
 various epithelium like airways. Langerhans cell histiocytosis (LCH), also called
 histiocytosis X or pulmonary eosinophilic granulomatosis, are characterized by proliferation
 and infiltration of Langerhans cells in the affected organs, including skin, lung, bones,
 pituitary gland, liver, lymph nodes and thyroid gland.

 Several clinical presentations have been described. In the pediatric population, clonal
 neoplastic processes are responsible for acute disseminated forms (Letterer-Siwe syndrome) or
 multifocal forms (Syndrome Hand-Schuller-Christian),and both have an unfavorable prognosis.

 In adults, LCH may affect one or several organs in a multisystemic disease. The pulmonary
 form is usually sporadic and occurs almost exclusively in smokers, with smoking history of at
 least 20 pack-years. It is believed that, unlike systemic forms, exposure to tobacco antigens
 generates a polyclonal response with recruitment and accumulation of Langerhans cells
 throughout the interstitium of small airways.

 LCH is a rare condition. The prevalence of 3.4% found in a series of 502 surgical lung
 biopsies may be underestimated, because many patients may improve spontaneously or may be
 asymptomatic and diagnosis is defined based on radiological findings. The main clinical
 features are cough, dyspnea and respiratory failure. The mean age of diagnosis is between 20
 and 40 years. Men and women are equally affected, which probably reflects the characteristics
 of smoking habits nowadays.

 In the study of Vassallo and colleagues, median survival was 12.5 years between diagnosis and
 death in patients with LCH, which is lower than that described in general population. Among
 the predictors of poor prognosis In this study the predictors of worse prognosis include an
 obstructive pattern, air trapping and reduction in carbon monoxide diffusing capacity (DLCO)
 in pulmonary function tests.

 The diagnosis of pulmonary LCH may be established by the combination of compatible clinical
 and radiological findings in smoking patients. In high-resolution computed tomography, the
 typical pattern is the coexistence of cysts and nodules, predominantly in the upper and
 middle lobes, and tends to spare the basal portions of the lungs. Moreover, interstitial
 infiltrates, reticular densities and architectural distortion degrees may be found. Computed
 tomography, such as in others cystic lung diseases, is useful in monitoring the disease
 progression and to assess treatment response.

 In some cases, histopathological examination may be necessary, preferably by surgical biopsy,
 but transbronchial or transthoracic biopsy may be sufficient in selected patients.

 In pathology, LCH presents with focal changes, separated by apparently normal lung
 parenchyma, and diffuse distribution with bronchiolar predominance and the presence of
 Langerhans cells organized into loose granulomas and lymphocytic infiltrate.

 Lesions of apparently different ages can be found: Initially, eccentric infiltration of the
 walls of respiratory bronchioles is found, which promotes gradual destruction. Inflammatory
 cells and Langerhans cells are also present. In advanced disease, lesions are replaced by
 stellar fibrotic scars bordering cystic spaces of different sizes.

 In electron microscopy, Birbeck granules may be identified, which are more numerous in cells
 associated with the disease than in normal Langerhans cells. The immunohistochemical staining
 shows membrane antigens on the cell surface of Langerhans cells, such as S100 and CD1a - the
 latter is more specific - and confirms the diagnosis.

 Up to 15% of pulmonary function tests may be normal in patients with LCH. The earliest
 finding is reduced DLCO. The most frequent changes are airflow obstruction and air trapping.
 Restriction can be found in more advanced cases. In 102 patients with LCH evaluated by
 Vassallo and colleagues, mean DLCO was 64% of predicted, and restrictive and obstructive
 disorders were found in, respectively, 27.2% and 45.7% of all patients.

 Smoking cessation is mandatory in the treatment of patients with pulmonary LCH, and this
 isolated therapy determine partial or complete resolution or stabilization of lesions in the
 majority of patients. In some patients, corticosteroids and cytotoxic agents, such as
 cladribine and etoposide, may be necessary. However, there is lack of robust evidence about
 the benefit of these medications. Lung transplantation should be considered in advanced
 cases.

 Extrapulmonary involvement in LCH occurs in approximately 15% of adults and can affect bones,
 skin or pituitary, which may cause diabetes insipidus. Pneumothorax is one of the most common
 complications of pulmonary LCH, which is found in 4-17% of patients. Recurrence of
 pneumothoraxcan be high, especially if conservative treatment is performed.

 Pulmonary vascular involvement associated with LCH has been increasingly discussed and
 described in the literature. Evidence suggests that its contribution to the pathophysiology
 is more significant than previously believed. Dauriat and colleagues found the presence of
 pulmonary hypertension (PH) in 92% of LCH patients evaluated for lung transplantation.

 Pulmonary hypertension (PH) consists in the involvement of pulmonary vasculature, in which
 mean pulmonary artery pressure (Mpap), measured by right heart catheterization at rest, is
 greater than or equal to 25 mmHg. This criteria may be applied if pulmonary capillary
 pressure at the end of expiration is less than 15 mmHg. In the second International Symposium
 on Pulmonary Hypertension, which occurred in Evian (France) in 1998, PH was classified
 according to pathophysiological basis and divided into five groups: 1 - pulmonary arterial
 hypertension; 2 - related to left heart disease; 3 - secondary to chronic lung disease or
 hypoxemia; 4 - chronic pulmonary thromboembolism and 5 - Miscellaneous. This classification
 had several changes since 1998 until the Fifth Symposium, which occured in 2013 in Nice
 (France).

 LCH is currently included in group 5 of PH, which contain multifactorial etiologies of
 pulmonary hypertension or those with cause not yet fully elucidated.

 However, since LCH presents parenchymal abnormalities, PH in this disease may be secondary to
 hypoxemia and thus belongs to group 3, in which it is believed that remodeling of the
 parenchyma and, as a result, hypoxemia determine reduction in the cross-sectional area of the
 vessels, which promotes increase in pulmonary vascular resistance. This mechanism explains
 why the vast majority of patients with COPD GOLD IV present with mPAP above 20 mmHg, despite
 the fact that the progression of PH in these cases is slow, with rates of less than 1 mmHg
 increase per year. In less than 5% of these patients, mPAP exceeds 40 mmHg, a value from
 which increases the contribution of the cardiovascular component to exercise limitation. In
 group 3, the presence of HP is a strong predictor of mortality, which is directly
 proportional to mPAP. In idiopathic pulmonary fibrosis (IPF), survival is inversely
 proportional to the values of forced vital capacity.

 Vascular changes in distant areas of parenchymal abnormalities typical of LCH suggest that
 there are other mechanisms involved in the pathophysiology of the disease, which still need
 to be elucidated. It is believed that the production of inflammatory cytokines and growth
 factors by activated granulomas cause pulmonary vascular remodeling. Moreover, granulomas can
 directly infiltrate arteries promoting luminal obstruction, fibrosis and hypertrophy of the
 intima and media. Fartoukh and colleagues retrospectively evaluated 12 lung biopsies of
 patients with LCH and found arterial and venular changes, respectively, in 60% and 75%.
 Veno-occlusive-like disease has been seen in one third of these patients.

 In patients with symptoms and limitation to exercise which is not fully explained by
 parenchymal abnormalities, which means disproportionately low DLCO compared with lung
 volumes, the predominant component is pulmonary arterial hypertension, group 1, in which
 benefits of specific therapy are proven. Furthermore, levels of pulmonary artery pressure
 found in patients with HCL are similar of those found in patients of group 1. mPAP levels are
 higher in patients with LCH compared with those found in patients with COPD or IPF, who have
 higher impairment in lung volumes.

 Some reports or case series demonstrate symptomatic improvement, and also in survival, in
 exercise capacity and in parameters of right heart catheterization after using single or
 combined use of pulmonary vasodilators such as phosphodiesterase inhibitors (tadalafil),
 endothelin receptor antagonists (bosentan) or analogues of prostacyclin (epoprostenol) in
 patients with LCH.

 Thus, it very important to establish a correct diagnosis and also classification of pulmonary
 hypertension in order to define appropriate treatment, which may result in an increase in
 survival and an improvement in quality of life after using specific therapy for patients
 classified in group 1. On the other hand, side effects and expenses with these medications
 may be prevented in patients with PH included in group 3, and the main focus should be
 correction of hypoxemia, and treatment of parenchymal disease. Echocardiography is a safe and
 cost-effective method of screening for evaluation of PH in these patients.

 Data about prevalence of PH in patients with LCH is scarce and previous studies only included
 patients with advanced disease or who are undergoing evaluation for transplantation. A study
 that evaluates patients with disease with different severities will certainly contribute to
 the understanding the influence of vascular and parenchymal components in each patient with
 LCH.
Inclusion Criteria:

 -  proven diagnosis of pulmonary Langerhans cell histiocytosis based on histopathological
 or clinical and radiological findings;

 Exclusion Criteria:

 -  lung transplantation

 -  cognitive or musculoskeletal disorders that preclude exercise test;

 -  severe or decompensated heart disease.