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Original Research: Pulmonary Vascular Disease |

Pulmonary Langerhans Cell Histiocytosis-Associated Pulmonary HypertensionPulmonary Langerhans Cell Histiocytosis: Clinical Characteristics and Impact of Pulmonary Arterial Hypertension Therapies FREE TO VIEW

Jérôme Le Pavec, MD, PhD; Gwenaël Lorillon, MD; Xavier Jaïs, MD; Colas Tcherakian, MD; Séverine Feuillet, MD; Peter Dorfmüller, MD, PhD; Gérald Simonneau, MD; Marc Humbert, MD, PhD; Abdellatif Tazi, MD, PhD
Author and Funding Information

From the Centre National de Référence de l’Histiocytose Langerhansienne (Drs LePavec, Lorillon, Feuillet, and Tazi), Univ Paris Diderot, Sorbonne Cité, Assistance Publique Hôpitaux de Paris, Service de Pneumologie, Hôpital Saint Louis, Paris; Université Paris-Sud (Drs Jaïs, Dorfmüller, Simonneau, and Humbert), Faculté de Médecine, Kremlin-Bicêtre; Assistance Publique Hôpitaux de Paris (Drs Jaïs, Simonneau, and Humbert), Centre National de Référence de l’Hypertension Pulmonaire Sévère, Service de Pneumologie et Réanimation Respiratoire, Hôpital Antoine, Béclère, Clamart; INSERM U999 (Drs Jaïs, Dorfmüller, Simonneau, and Humbert), Clamart; Service de Pneumologie (Dr Tcherakian), Hôpital Foch, Suresnes; and the Service d’Anatomie et Cytologie Pathologiques (Dr Dorfmüller), Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France.

Correspondence to: Abdellatif Tazi, MD, PhD, Service de Pneumologie, Hôpital Saint Louis, 1 Avenue Claude Vellefaux, 75475, Paris cedex 10, France; e-mail: abdellatif.tazi@sls.aphp.fr


For editorial comment see page 1087

Funding/Support: The authors have reported to CHEST that no funding was received for this study.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2012;142(5):1150-1157. doi:10.1378/chest.11-2490
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Background:  Precapillary pulmonary hypertension (PH) is a complication of pulmonary Langerhans cell histiocytosis (PLCH) associated with increased mortality. However, outcomes and efficacy of pulmonary arterial hypertension (PAH) therapies in patients with PH complicating PLCH (PLCH-PH) remain unknown.

Methods:  Consecutive patients with PLCH with PH confirmed by right-sided heart catheterization were included in the study. Characteristics at baseline and during follow-up as well as survival were analyzed.

Results:  Twenty-nine patients were studied. Baseline characteristics of patients with PLCH-PH were as follows: 83% of patients in World Health Organization (WHO) functional class III to IV, mean 6-min walk distance of 355 ± 95 m, mean pulmonary arterial pressure (mPAP) of 45 ± 14 mm Hg, cardiac index of 3.2 ± 0.9 L/min/m2, and pulmonary vascular resistance (PVR) of 555 ± 253 dyne/s/cm5. Use of PAH therapy in 12 patients was followed by an improvement in mPAP (56 ± 14 mm Hg and 45 ± 12 mm Hg, P = .03) and PVR (701 ± 239 dyne/s/cm5 and 469 ± 210 dyne/s/cm5, P = .01) between baseline and follow-up evaluations. No significant oxygen worsening was observed in the treated group. The 1-, 3-, and 5-year survival estimates of the 29 patients were 96%, 92%, and 73%, respectively. Except a trend toward a better survival rate associated with the use of PAH therapy, WHO functional class was the only variable significantly associated with death.

Conclusions:  In this group of patients, PAH therapies improved hemodynamics without oxygen worsening or pulmonary edema. WHO functional class was the only prognostic factor identified. Prospective clinical trials focusing on this population of patients are warranted.

Figures in this Article

Pulmonary Langerhans cell histiocytosis (PLCH) is an uncommon lung disease that primarily affects young adults, almost exclusively with a history of current or prior cigarette smoking.14 Although PLCH may regress spontaneously or after smoking cessation,14 in a minority of patients the disease may progress, ultimately leading to chronic respiratory failure for which lung transplantation may be considered as the only therapeutic option.57

Precapillary pulmonary hypertension (PH) is a common and severe complication occurring in the course of patients with PLCH with advanced lung disease.810 Thus, in the study by Dauriat et al,8 PH confirmed by right-sided heart catheterization (RHC) was present in 92% of the 36 patients with PLCH referred for lung transplantation, and mean pulmonary arterial pressure (mPAP) was > 35 mm Hg in 72.5% of cases. However, Chaowalit et al11 suggested that PLCH-associated PH (PLCH-PH) may not be limited to patients with end-stage pulmonary disease. In this retrospective cohort of 123 patients with PLCH, echocardiography carried out in 17 symptomatic patients identified an estimated systolic pulmonary arterial pressure > 35 mm Hg (systolic pulmonary arterial pressure > 65 mm Hg in seven patients) in 13 cases (76.5%).11

Survival in PLCH-PH remains to be determined. Indeed, depending on PH definition, median survival after PH diagnosis may extend from 7.6 months11 to > 50 months.12 Additionally, prognostic factors in PLCH-PH have never been specifically investigated.

Although currently available pharmacologic agents may be associated with some beneficial effects in idiopathic PAH,13 the efficacy of PAH therapies has not been evaluated in the setting of PLCH-PH. Given the high incidence of pulmonary venular obstruction and the risk of acute pulmonary edema in advanced PLCH-PH,9 the use of vasodilators has long been considered hazardous in these patients. Therefore, we sought to evaluate our experience with PLCH-PH and describe clinical characteristics, efficacy, and safety of PAH therapies and survival in these patients.

Patient Population

This was a retrospective analysis of patients with PLCH-PH. The group of patients was identified from the Pulmonary Hypertension Program in the Pulmonary Division at Hôpital Antoine Béclère (Clamart, France) and from the PLCH program in the Pulmonary Division at Hôpital Saint Louis (Paris, France), which maintain a registry of all patients evaluated at their centers. The study was approved by our Institutional Review Board (CEPRO No. 2011-035). Each registry was queried for subjects with a diagnosis of PLCH and PH. Consecutive patients with PCLH-PH as confirmed by RHC evaluated between January 1998 and February 2010 were included. The diagnosis of PLCH was either histologically confirmed or based on the association of an appropriate clinical setting, a typical lung high-resolution CT (HRCT) scan showing the combination of multiple cysts and nodules with a mid- to upper-zone predominance, and exclusion of alternative diagnoses.1

Evaluation

Baseline evaluation included demographics, medical history, physical examination, World Health Organization (WHO) functional score, and a 6-min walk test (6MWT) as previously described.14 Precapillary PH was defined during RHC as mPAP ≥ 25 mm Hg, pulmonary capillary wedge pressure ≤ 15 mm Hg, and pulmonary vascular resistance (PVR) ≥ 240 dyne/s/cm5 in the absence of another known cause of PH.15 Pulmonary function tests (PFTs) obtained closest to the diagnosis of PLCH and PH were included in the analysis. Lung volumes were evaluated by plethysmography, and FEV1 and FVC were evaluated by a flow curve volume. Diffusing capacity of lung for carbon monoxide (Dlco) was measured using the single-breath method. Predictive values were determined as previously described.16 HRCT scan of the chest obtained closest to the date of the diagnostic RHC was included in the analysis. The lung lesions were classified as previously described.17

Exclusion criteria were as follows: chronic thromboembolic pulmonary hypertension, pulmonary hypertension secondary to left-sided heart diseases, PAH associated with connective tissue diseases, portal hypertension, HIV infection, congenital heart disease, and exposure to anorexigens. Follow-up investigations included WHO functional class, oxygen saturation, and 6MWT within the first 6 months after baseline and then every 6 months. Repeated RHC was performed at the discretion of the treating clinician to assess response to therapy.

Treatment

All patients were treated with conventional therapy, including oral anticoagulation in the absence of contraindication, diuretics, and oxygen as needed. In the absence of formal recommendations for patients with PLCH-PH, the choice of PAH-specific therapies was established in accordance with standards of practice and based on the availability of different treatments across the years.

Statistical Analysis

Continuous variables are shown as mean ± SD. Group comparisons were made using Student t test or Wilcoxon rank test as appropriate for continuous variables, and χ2 statistics or Fisher exact test, as appropriate for categorical variables. Paired proportions were compared using McNemar test. A P value < .05 was considered significant. A Pearson correlation method was used to evaluate correlation between baseline hemodynamic and PFT variables and change in PVR in response to therapy. Survival analysis was performed using the Kaplan-Meier method. Comparisons between groups were assessed by log-rank test. Univariable Cox proportional hazards modeling was performed to determine the variables associated with mortality. Hazard ratio and 95% CI for continuous variables are displayed per each unit increase in SD. Patients who underwent lung transplantation were censored at the date of the surgical procedure. All computations were performed using Stata statistical software (version 10; StataCorp LP).

Baseline Characteristics

A total of 29 patients meeting the inclusion criteria were included in the study. Diagnosis of PLCH was histologically confirmed in 16 patients as follows: surgical lung biopsies (n = 10), lung samples obtained at the time of lung transplantation (n = 3), bone biopsies (n = 3). In the remaining 13 patients, PLCH diagnosis was based on combined results of the clinical evaluation and HRCT scan of the chest. Extrapulmonary localizations of the disease were diagnosed in seven patients (bone, n = 3; pituitary stalk, n = 4). At the time of diagnostic RHC, pulmonary lesions on HRCT scan were predominantly cystic in 27 patients, and a nodular pattern was only present in five patients. Table 1 summarizes the clinical, hemodynamic, and functional features of the overall population. The degree of PH was considerable, with an average mPAP of 45 mm Hg. Moreover, 19 had an mPAP ≥ 40 mm Hg, indicative of severe PH.18

Table Graphic Jump Location
Table 1 —Baseline Characteristics of the Overall Population, Treated and Untreated Groups

Except where indicated otherwise, values are the mean ± SD. 6MWT = 6-min walk test; bpm = beats per min; CO = cardiac output; Dlco = diffusing capacity of lung for carbon monoxide; HR = heart rate; mPAP = mean pulmonary arterial pressure; PAH = pulmonary arterial hypertension; PCWP = pulmonary capillary wedge pressure; PLCH-PH = pulmonary Langerhans cell histiocytosis-associated pulmonary hypertension; PVR = pulmonary vascular resistance; RAP = right atrial pressure; RV = residual volume; TLC = total lung capacity; WHO = World Health Organization.

a 

Comparison between treated and untreated groups by paired t test or Fisher exact test as appropriate.

Histologic Evaluation

Lungs from two patients with PLCH were obtained at the time of transplantation for PLCH-PH. Several hematoxylin-eosin-stained slides (37 for the first one and 38 for the other) were retrospectively analyzed by an experienced pathologist (P. D.). Both cases displayed a partial destruction of the parenchymal architecture by interstitial fibrosis and bronchocentric fibrous remodeling, sometimes associated to typical aggregates of Langerhans cells and inflammatory infiltrate. Pulmonary arterial remodeling was present in both cases with predominance of medial hypertrophy and concentric nonlaminar intimal fibrosis. Several histologic pattern of postcapillary involvement were present in both cases. Indirect signs of postcapillary remodeling, including hemangiomatosis-like multiplication of capillaries and intraalveolar accumulation of siderin-laden macrophages, were a prominent feature. Septal veins and small preseptal venules focally presented with loose intimal fibrosis and partial muscularization, although frequently associated with prominent interstitial fibrosis.

PFT According to the Time of PH Diagnosis

In the overall population, mean FEV1/FVC was 63% ± 16% with a mean FEV1 of 52% ± 20% predicted, indicating a moderate to severe obstructive lung disease at the time of PH diagnosis (Table 1). In 23 patients, PLCH was diagnosed before PH with a mean delay of 11.1 ± 6.4 years (range, 1-26 years). Interestingly in this group, significant declines in Dlco (51% ± 13% and 29% ± 7% predicted, P < .01), FEV1 (58% ± 16% and 50% ± 21% predicted, P = .05), FEV1/FVC ratio (72% ± 11% and 62% ± 17%, P = .02) occurred between PLCH and PH diagnoses (Table 2). In the remaining six patients, PLCH and PH were diagnosed simultaneously within a period of 1.8 ± 1.7 months (range 0-3 months). Importantly, the severity of PH at baseline was comparable regardless of the time of PH diagnosis (results not shown).

Table Graphic Jump Location
Table 2 —PFTs According to PH Diagnosis

Except where indicated otherwise, values are the mean ± SD. PFT = pulmonary function test; PH = pulmonary hypertension; PLCH = pulmonary Langerhans cell histiocytosis. See Table 1 legend for expansion of other abbreviations.

a 

Delay between PLCH and PH diagnoses was 11.1 ± 6.4 y.

b 

Comparison of PFT variables by paired t test between PCLH and PH diagnoses in patients in whom PLCH was diagnosed before PH.

c 

Delay between PLCH and PH diagnoses was 1.8 ± 1.7 mo.

d 

Comparison of PFT variables by unpaired t test at PH diagnoses in both groups.

Effects of PAH Therapy on WHO Functional Class, Exercise Capacity, and Hemodynamics

Fourteen patients underwent PAH therapies after baseline evaluation. Most patients received initial therapy with an endothelin receptor antagonist (n = 10) or phosphodiesterase 5 inhibitor (n = 5). Two patients of these received a combination therapy. Only one patient was treated by inhaled iloprost. Five patients (35%) ultimately received a second PAH agent, either instead of or in combination with the initial drug. Compared with the treated group, patients in the untreated group had a less severe PH, a lower FEV1/FVC ratio, and a higher residual volume (Table 1). Of note, in the overall population, 13 patients were treated with oral anticoagulation, and no patient received any corticosteroids.

A follow-up assessment was available in 12 patients at an average of 5.5 ± 2.5 months after baseline and included WHO functional class, 6MWT, and RHC (Table 3). WHO functional class improved by at least one functional class in eight patients (67%). At follow-up evaluation, six patients (50%) were in WHO functional class I to II, and six were in WHO functional class III to IV (P = .12 compared with baseline). Five subjects (45%) experienced ≥ 10% increase in 6MWT, and three (27%) of these demonstrated ≥ 20% improvement. All 12 patients underwent a follow-up RHC. Among these, mPAP (P = .03) and pulmonary vascular resistance (P = .01) improved significantly compared with baseline (Table 3). The significant improvement in hemodynamics was sustained over the time according to a third invasive evaluation performed 16 ± 4 months after baseline in 10 patients (Table 3).

Table Graphic Jump Location
Table 3 —Response to PAH Therapy at Follow-up Evaluations

Except where indicated otherwise, values are the mean ± SD. PAH = pulmonary arterial hypertension. See Table 1 legend for expansion of other abbreviations.

a 

Short- and long-term evaluations performed at 5.5 ± 2.5 mo and 16 ± 4 mo after baseline in 12 and 10 patients, respectively.

b 

McNemar test or paired t test as appropriate, comparison between baseline and short-term evaluations.

c 

McNemar test or paired t test as appropriate, comparison between baseline and long-term evaluations.

An exploratory analysis was performed to ascertain if any baseline variables were predictive of a better therapeutic response. There was no association between any functional parameters and subsequent changes in PVR.

Survival and Lung Transplantation

During a median observation period following the initial RHC of 35 months (range 2.7-130 months), five patients died and six underwent lung transplantation with a mean delay of 43 ± 30 months and 20 ± 15 months, respectively. Median survival was 35.2 months. The 1-, 3-, and 5-year survival rates were 96%, 92%, and 73%, respectively (Fig 1). Table 4 lists the effects of selected variables on overall survival in the univariate analysis. Except a trend toward a better survival associated with the use of PAH therapy (P = .09) and increase in FEV1/FVC ratio (P = .06), WHO functional class was the only variable significantly associated with death (P = .03) (Table 4). Two deaths were attributed to right-sided heart failure. The cause of death remained unknown in three patients.

Table Graphic Jump Location
Table 4 —Univariate Model of Risk Factors for Mortality in the Overall Population

HR = hazard ratio. See Table 1 and 3 legends for expansion of other abbreviations.

a 

Hazard ratio and 95% CI for continuous variables are displayed per each unit increase in SD.

Figure Jump LinkFigure 1. Kaplan-Meier overall survival estimates from date of diagnosis of pulmonary hypertension obtained by right-sided heart catheterization in the overall population of 29 patients with pulmonary Langerhans cell histiocytosis-associated pulmonary hypertension. The 1-, 3-, and 5-year overall survival were 96%, 92%, and 73%, respectively.Grahic Jump Location

This study provides a longitudinal analysis of well-characterized population of patients with PCLH with severe PH, suggesting that PAH therapies may improve WHO functional class and hemodynamics. PH was diagnosed after PLCH in 23 patients (79.5%) and simultaneously in the remaining patients. Mean interval between PH and PLCH diagnoses was comparable to that of the study by Fartoukh et al9 (11.1 ± 6.4 years and 11 ± 2.6 years, respectively). Here, we provide further information regarding the natural history of PLCH before the development of PH. Thus, except for a moderate decrease in FEV1, Dlco was the only parameter affected by a significant decline between PLCH and PH diagnoses. Accordingly, several reports indicate that Dlco is reduced in idiopathic PAH19,20 and has been identified as an independent prognostic factor in various forms of PAH.21 These results suggest that an isolated decline in Dlco may be indicative of the development of PH and should prompt a search for this complication in patients with PLCH.

Great strides have been made in the development of effective medical therapy for idiopathic PAH. However, very little information is available on the treatment of PLCH-PH. One case was reported of a patient who improved with corticosteroids.22 Conversely, another patient deteriorated rapidly and died despite corticosteroids.23 In our experience, the use of PAH-specific therapies was associated with a significant improvement in hemodynamics, which was sustained over the time. Although there was no significant effect on 6MWT, there was a trend toward improvement in WHO functional class in the treated group. Accordingly, Kiakouama et al24 recently reported a case of a patient with PLCH-PH treated by bosentan with clinical, functional, and hemodynamic improvements. These benefits were sustained over a 7-year period of follow-up.

Of note, these clinical improvements occurred without significant worsening oxygenation among these patients. Indeed, vasodilators may improve pulmonary hemodynamics but have the potential to worsen arterial oxygenation in chronic respiratory diseases associated with PH as a result of greater imbalance in ventilation/perfusion due to inhibition of hypoxic pulmonary vasoconstriction.25 More specifically in PLCH, the use of vasodilators may be associated with an additional risk for pulmonary edema. Direct involvement of the pulmonary venules by the disease process appears to account for this phenomenon.9,23 Interestingly, this complication did not occur in our group of patients.

Prognosis of PLCH-PH remains to be determined.11,12 In our group of patients, the 1-, 3-, and 5-year overall survival estimates were 96%, 92%, and 73%, respectively, with a median survival rate of 35.2 months. Compared with PH associated with other chronic respiratory diseases such as granulomatous respiratory disorders and airflow-limited or diffuse cystic lung diseases, these results may be of various significance. In the retrospective study by Nunes et al26 including 22 patients with sarcoidosis-related PH, 5-year survival rate was 59% and lower than in our group of patients. Similarly, in the study by Chaouat et al27 including 11 patients with COPD and an out-of-proportion PH (ie, mPAP > 40 mm Hg), the 5-year survival rate was poorer and < 20%. Last, Cottin et al28 recently conducted a retrospective multicenter study and included 20 patients with lymphangioleiomyomatosis and precapillary PH. Interestingly, the 1-, 2-, and 3-year survival estimates in their series were 94%, 94%, and 78%, respectively, which were close to ours.28

WHO functional class was significantly associated with prognosis in our group of patients. This result is in agreement with many reports that have clearly identified WHO functional class as a strong prognostic factor in PAH.29 Of note, the use of PAH therapy was associated with a trend toward a lower risk of death in the univariate analysis but, possibly because of the limited number of patients, failed to reach significance.

Mechanisms that account for PH in patients with PLCH-PH remain unclear. The degree of PH complicating PLCH is independent from pulmonary function parameters and is usually higher than PH associated with other chronic respiratory disease.912 Based on histologic5,30,31 or functional31 evidence, compelling data further suggest that pulmonary vascular lesions may develop in PLCH. However, in a subset of patients with PLCH-PH, a proliferative and widespread vasculopathy including intimal fibrosis and medial hypertrophy of small arteries and pulmonary venoocclusive disease patterns has also been identified on lung samples.9 Interestingly, these vascular abnormalities are observed in areas remote from PLCH lesions.9 In our study, the analysis of lung samples in two patients showed pulmonary arterial remodeling associated in both cases with postcapillary involvement. Whether inflammation induced by PLCH granuloma plays a significant role in the vascular remodeling process needs to be further investigated.

There are several limitations of this study that may influence the generalization of the results. First, all subjects were referred to two referral centers, and thus selection bias toward inclusion of those patients may have occurred. Further, since this study extended over 12 years, and the availability and effectiveness of PAH therapies varied over the time, the extrapolation of our data concerning specific PAH treatment in PLCH-PH may be impaired. In addition, because of the limited number of events, a multivariate analysis could not be performed. This may have included confounding factors in the survival analysis.

In summary, this study represents, to our knowledge, the largest series to date in which baseline characteristics, impact of PAH therapies, and survival were examined in a well-characterized population of patients with PCLH-PH. In this group of patients, PAH therapies improved hemodynamics without oxygen worsening or pulmonary edema. WHO functional class at baseline was the only prognostic factor identified in the survival analysis. Safety and efficacy of PAH therapies in PLCH-PH need to be properly evaluated by prospective clinical trials focusing on this group of patients.

Author contributions: Drs Le Pavec and Tazi take responsibility for the integrity of the data and the accuracy of the data analysis.

Dr Le Pavec: contributed to study design and interpretation of data, drafting the article, revising the paper, and final approval of the manuscript.

Dr Lorillon: contributed to acquisition of the data and final approval of the manuscript.

Dr Jaïs: contributed to acquisition of the data and final approval of the manuscript.

Dr Tcherakian: contributed to acquisition of the data and final approval of the manuscript.

Dr Feuillet: contributed to manuscript revision and final approval of the manuscript.

Dr Dorfmüller: contributed to the histopathologic analysis and final approval of the manuscript.

Dr Simonneau: contributed to manuscript revision and final approval of the manuscript.

Dr Humbert: contributed to manuscript revision and final approval of the manuscript.

Dr Tazi: contributed to study design and interpretation of data, drafting the article, revising the paper, and final approval of the manuscript.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Jaïs has relationships with drug companies including Actelion Pharmaceuticals Ltd, GlaxoSmithKline, and Pfizer, Inc. In addition to being an investigator in trials involving these companies, relationships include consultancy service and membership on scientific advisory boards. Dr Dorfmüller participates as a speaker in academic courses organized biannually and financed by Actelion Pharmaceuticals Ltd. Dr Simonneau has relationships with drug companies including Actelion Pharmaceuticals Ltd; Bayer; Schering-Plough; GlaxoSmithKline; Eli Lilly and Company; Novartis AG; Pfizer, Inc; and United Therapeutics Corp. In addition to being an investigator in trials involving these companies, relationships include consultancy service and membership on scientific advisory boards. Dr Humbert has relationships with drug companies including Actelion Pharmaceuticals Ltd; AstraZeneca; Bayer; Schering-Plough; Chiesi Ltd; GlaxoSmithKline; Eli Lilly and Company; Merck Sharp & Dohme; Novartis AG; Takeda Pharmaceuticals International GmbH; Pfizer, Inc; and United Therapeutics Corp. In addition to being an investigator in trials involving these companies, relationships include consultancy service and membership on scientific advisory boards. Drs LePavec, Lrillon, Tcherakian, and Feuillet have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

6MWT

6-min walk test

Dlco

diffusing capacity of lung for carbon monoxide

HRCT

high-resolution CT

mPAP

mean pulmonary arterial pressure

PAH

pulmonary arterial hypertension

PFT

pulmonary function tests

PH

pulmonary hypertension

PLCH

pulmonary Langerhans cell histiocytosis

PLCH-PH

pulmonary Langerhans cell histiocytosis-associated pulmonary hypertension

PVR

pulmonary vascular resistance

RHC

right-sided heart catheterization

WHO

World Health Organization

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Cottin V, Harari S, Humbert M, et al.. Pulmonary hypertension in lymphangioleiomyomatosis: characteristics in 20 patients.Eur Respir J 2012;40(3):630-640.
 
Galiè N, Hoeper MM, Humbert M, et al;; ESC Committee for Practice Guidelines (CPG) ESC Committee for Practice Guidelines (CPG). Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J. 2009;30(20):2493-2537. [CrossRef] [PubMed]
 
Colby TV, Lombard C. Histiocytosis X in the lung. Hum Pathol. 1983;14(10):847-856. [CrossRef] [PubMed]
 
Travis WD, Borok Z, Roum JH, et al. Pulmonary Langerhans cell granulomatosis (histiocytosis X). A clinicopathologic study of 48 cases. Am J Surg Pathol. 1993;17(10):971-986. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1. Kaplan-Meier overall survival estimates from date of diagnosis of pulmonary hypertension obtained by right-sided heart catheterization in the overall population of 29 patients with pulmonary Langerhans cell histiocytosis-associated pulmonary hypertension. The 1-, 3-, and 5-year overall survival were 96%, 92%, and 73%, respectively.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 —Baseline Characteristics of the Overall Population, Treated and Untreated Groups

Except where indicated otherwise, values are the mean ± SD. 6MWT = 6-min walk test; bpm = beats per min; CO = cardiac output; Dlco = diffusing capacity of lung for carbon monoxide; HR = heart rate; mPAP = mean pulmonary arterial pressure; PAH = pulmonary arterial hypertension; PCWP = pulmonary capillary wedge pressure; PLCH-PH = pulmonary Langerhans cell histiocytosis-associated pulmonary hypertension; PVR = pulmonary vascular resistance; RAP = right atrial pressure; RV = residual volume; TLC = total lung capacity; WHO = World Health Organization.

a 

Comparison between treated and untreated groups by paired t test or Fisher exact test as appropriate.

Table Graphic Jump Location
Table 2 —PFTs According to PH Diagnosis

Except where indicated otherwise, values are the mean ± SD. PFT = pulmonary function test; PH = pulmonary hypertension; PLCH = pulmonary Langerhans cell histiocytosis. See Table 1 legend for expansion of other abbreviations.

a 

Delay between PLCH and PH diagnoses was 11.1 ± 6.4 y.

b 

Comparison of PFT variables by paired t test between PCLH and PH diagnoses in patients in whom PLCH was diagnosed before PH.

c 

Delay between PLCH and PH diagnoses was 1.8 ± 1.7 mo.

d 

Comparison of PFT variables by unpaired t test at PH diagnoses in both groups.

Table Graphic Jump Location
Table 3 —Response to PAH Therapy at Follow-up Evaluations

Except where indicated otherwise, values are the mean ± SD. PAH = pulmonary arterial hypertension. See Table 1 legend for expansion of other abbreviations.

a 

Short- and long-term evaluations performed at 5.5 ± 2.5 mo and 16 ± 4 mo after baseline in 12 and 10 patients, respectively.

b 

McNemar test or paired t test as appropriate, comparison between baseline and short-term evaluations.

c 

McNemar test or paired t test as appropriate, comparison between baseline and long-term evaluations.

Table Graphic Jump Location
Table 4 —Univariate Model of Risk Factors for Mortality in the Overall Population

HR = hazard ratio. See Table 1 and 3 legends for expansion of other abbreviations.

a 

Hazard ratio and 95% CI for continuous variables are displayed per each unit increase in SD.

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Cottin V, Harari S, Humbert M, et al.. Pulmonary hypertension in lymphangioleiomyomatosis: characteristics in 20 patients.Eur Respir J 2012;40(3):630-640.
 
Galiè N, Hoeper MM, Humbert M, et al;; ESC Committee for Practice Guidelines (CPG) ESC Committee for Practice Guidelines (CPG). Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J. 2009;30(20):2493-2537. [CrossRef] [PubMed]
 
Colby TV, Lombard C. Histiocytosis X in the lung. Hum Pathol. 1983;14(10):847-856. [CrossRef] [PubMed]
 
Travis WD, Borok Z, Roum JH, et al. Pulmonary Langerhans cell granulomatosis (histiocytosis X). A clinicopathologic study of 48 cases. Am J Surg Pathol. 1993;17(10):971-986. [CrossRef] [PubMed]
 
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