Evaluation of Exercise Capacity and Exercise Limitation in Patients With Pulmonary Langerhans Cell Histiocytosis

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.