Pulmonary hypertension in lymphangioleiomyomatosis: characteristics in 20 patients

Vincent Cottin, Sergio Harari, Marc Humbert, Hervé Mal, Peter Dorfmüller, Xavier Jaïs, Martine Reynaud-Gaubert, Grégoire Prevot, Romain Lazor, Camille Taillé, Jacques Lacronique, Sabrina Zeghmar, Gérald Simonneau, Jean-François Cordier, the Groupe d'Etudes et de Recherche sur les Maladies “Orphelines” Pulmonaires (GERM“O”P)
European Respiratory Journal 2012 40: 630-640; DOI: 10.1183/09031936.00093111

Abstract

This retrospective, multicentre study evaluated patients with lymphangioleiomyomatosis (LAM) and pre-capillary pulmonary hypertension (PH) by right heart catheterisation.

It was conducted in 20 females with a mean±sd age of 49±12 yrs and a mean±sd time interval between LAM and PH diagnoses of 9.2±9.8 yrs. All, except for one patient, were receiving supplemental oxygen. 6-min walking distance was mean±sd 340±84 m. Haemodynamic characteristics were: mean pulmonary artery pressure (PAP) 32±6 mmHg, cardiac index 3.5±1.1 L·min−1·m−2 and pulmonary vascular resistance (PVR) 376±184 dyn·s·cm−5. Mean PAP was >35 mmHg in only 20% of cases. The forced expiratory volume in 1 s was 42±25%, carbon monoxide transfer factor was 29±13%, and arterial oxygen tension (Pa,O2) was 7.4±1.3 kPa in room air. Mean PAP and PVR did not correlate with Pa,O2. In six patients who received oral pulmonary arterial hypertension (PAH) therapy, the PAP decreased from 33±9 mmHg to 24±10 mmHg and the PVR decreased from 481±188 dyn·s·cm−5 to 280±79 dyn·s·cm−5. The overall probability of survival was 94% at 2 yrs.

Pre-capillary PH of mild haemodynamic severity may occur in patients with LAM, even with mild pulmonary function impairment. PAH therapy might improve the haemodynamics in PH associated with LAM.

Lymphangioleiomyomatosis (LAM), a disease that mostly affects young and middle-aged females [1–3], is characterised by the proliferation of abnormal smooth muscle-like cells (so-called LAM cells) along lymphatics in the lungs and abdomen. Manifestations of LAM include: diffuse cystic lung disease; recurrent pneumothoraces; benign renal tumours (e.g. angiomyolipomas); and lymphatic abnormalities, which include pleural and peritoneal chylous effusion as well as abdominal lymphangioleiomyomas. Pulmonary involvement is dominated by the formation and progression of thin-walled cysts, the pathogenesis of which may implicate metalloprotease secretion by LAM cells, leading to airflow obstruction, impairment of carbon monoxide diffusion capacity, and chronic respiratory insufficiency [1–4]. Although sirolimus (a mammalian target of rapamycin (mTOR) inhibitor) has recently been demonstrated to slow the rate of lung function decline [5], lung transplantation is the sole treatment for LAM patients with advanced disease [6–9]. Kaplan–Meier analysis estimated transplantation-free survival to be ∼80–90% at 10 yrs in a recent series of LAM patients [10, 11]. However, the rate of disease progression is highly variable among patients [12–15].

Pulmonary hypertension (PH), which may occur in LAM patients [16], is included in the PH group with unclear and/or multifactorial mechanisms in the Dana Point clinical classification of PH (group 5) [17]. Likely multifactorial [18] PH pathogenesis in LAM patients is related, at least in part, to hypoxia and reduced pulmonary vascular capacitance caused by cystic lesions [19]. In addition, mTOR expression is up-regulated in LAM [20], and activation of mTOR complexes 1 and 2 is further enhanced by hypoxia, contributing to smooth muscle cell proliferation [21] and conceivably to PH pathogenesis. Taveira-DaSilva et al. [19] reported 7% PH prevalence in 95 patients with LAM, as defined by estimated systolic pulmonary artery pressure (PAP) >35 mmHg on echocardiography. PH, confirmed by right heart catheterisation (RHC) (mean PAP >25 mmHg), was diagnosed in nine (45%) out of the 20 patients evaluated for lung transplantation [7]. Little information is available regarding the haemodynamic profile of PH in LAM, and there are no data on the effect of pulmonary arterial hypertension (PAH)-specific therapy, such as endothelin receptor antagonists, phosphodiesterase type-5 inhibitors and prostacyclin derivatives.

This study aimed to: 1) evaluate by RHC the haemodynamic characteristics of patients with LAM and PH not explained otherwise; 2) determine whether haemodynamics may be related to pulmonary function; 3) ascertain the survival of PH patients with LAM; and 4) explore whether PH-specific therapy, given off-label on an individual basis, can bring about significant clinical and/or haemodynamic improvements.

PATIENTS AND METHODS

Study design

This multicentre study was undertaken by the French Reference Centre for Rare Pulmonary Diseases (Lyon, France; coordinator J-F. Cordier), the French Reference Centre for Pulmonary Hypertension (Clamart, France; coordinator G. Simonneau), the Centre for Rare Pulmonary Diseases (Milan, Italy; coordinator S Harari), the Network of French Competence Centres for Rare Pulmonary Diseases (Lyon, France; coordinator J-F. Cordier) and Competence Centres for Pulmonary Hypertension (Clamart, France; coordinator G. Simonneau), and the Groupe d'Etudes et de Recherche sur les Maladies "Orphelines" Pulmonaires (GERM"O"P), a collaborative group dedicated to research on rare (so-called “orphan”) pulmonary diseases. Participating physicians prospectively reported all cases of LAM to the GERM"O"P registry (coordinator J-F. Cordier). PH was screened by echocardiography at the discretion of the physicians; however, most groups in France and Italy perform echocardiography once a year in LAM patients with impaired lung function. RHC was implemented in cases of suspected PH (with estimated systolic PAP of ≥40 mmHg on echocardiography) or evaluation for lung transplantation.

Data on PH were collected prospectively from the Registry of the French Network of Pulmonary Hypertension that now comprises of 24 university pulmonary vascular centres [22]. The registry was opened in 2002 and enrolled all consecutive patients aged ≥18 yrs with pre-capillary PH seen at these centres. Additional results on LAM were obtained, retrospectively, and data collection ended in December 2010. A control group of patients with LAM (without PH) was obtained from the active file of the centres. This study was compliant with the requirements of the Commission nationale de l'informatique et des libertés (Paris, France) the organisation dedicated to privacy, information technology, and civil rights in France. All patients provided informed consent before participation [22]. The study was approved by the Institutional Review Board of the French Learned Society for Respiratory Medicine and registered at www.clinicaltrials.gov (NCT00960895).

Inclusion criteria

The following inclusion criteria applied: 1) Definite or probable LAM diagnosed according to European Respiratory Society (ERS) recommendations [6]. 2) Pre-capillary PH, defined by mean PAP ≥25 mmHg and pulmonary artery wedge pressure ≤15 mmHg at RHC [23].

Patients with PAH, either idiopathic, heritable, or associated with connective tissue diseases related to portal hypertension, congenital heart disease, human immunodeficiency virus infection, or PH due to left heart disease or chronic thromboembolic PH, were excluded. Chronic thromboembolic PH was ruled out by ventilation perfusion scanning and high resolution computed tomography (HRCT) of the chest. “Out-of-proportion” pre-capillary PH was defined by mean PAP >35–40 mmHg.

Investigations

RHC was performed as described elsewhere [24] with values obtained at end of expiration. Cardiac output was measured by the standard thermodilution technique. A vasodilator test with inhaled nitric oxide (10 ppm for 5–10 min) was carried out, and positive acute responses were defined as a decrease in mean PAP of >10 mmHg compared with baseline mean PAP (with mean PAP <40 mmHg), and normal or increased cardiac output [24].

Pulmonary function tests followed the joint guidelines of the American Thoracic Society and the ERS [25–27]. Lung volume was measured by whole-body plethysmography (Jaeger Masterscreen Body®; Sebbac, Wuerzburg, Germany), and data were expressed as percentages of predicted values [28]. A non-encouraged 6-min walk test (6MWT) was performed according to recommendations [29].

The date of PH diagnosis was defined as the date of RHC, and all data (symptoms including New York Heart Association (NYHA) functional class, 6MWT, pulmonary function, echocardiography) were obtained within 2 months of RHC. PH treatment was left to the physicians' discretion, including the management of pleural and other LAM manifestations, oxygen supplementation as needed, oral anticoagulation, diuretics, and possible PAH-specific therapy initiated after RHC.

Pathology

Explanted lungs of transplanted patients were reviewed by a pathologist with particular expertise in pulmonary vascular disease. The presence of LAM/perivascular epithelioid cells (PEComa cells) was semi quantified as absent, mild, moderate, or high, along cyst edges, alveolar walls, bronchioles, pulmonary arteries, veins and lymphatics. Cells within the remodelled pulmonary arteries were further characterised by HMB45 immunostaining.

Statistical analysis

The data were analysed by Microsoft Excel 2003 and SPSS 17.0 (SSPS Inc., Chicago, IL, USA). All values were expressed as mean±sd. Correlations were calculated with Pearson's correlation coefficient. The probability of survival at each time-point was estimated according to the Kaplan–Meier method, from the date of the first haemodynamic evaluation demonstrating PH to the end-point of death or censoring. All-cause mortality was included in survival statistics. For overall survival calculation, transplanted subjects were censored at the time of transplantation. Living patients were censored at the date of the last visit. Categorical data were compared using the Fisher's exact test. Haemodynamic and pulmonary function variables were compared by the two-tailed paired t-test. Statistical significance was established at p<0.05.

RESULTS

Patient population

29 LAM patients with suspected PH at echocardiography underwent RHC. The estimated systolic PAP at echocardiography significantly correlated with the systolic PAP (r=0.66, p=0.001) and with the mean PAP measured at RHC (r=0.69, p=0.0006). The mean difference between the systolic PAP estimated at echocardiography and the systolic PAP measured at RHC was -5.4 mmHg (95% CI -13– -2 mmHg). The systolic PAP at echocardiography was overestimated by ≥10 mmHg when compared with RHC in four cases (14%), and was underestimated by ≤10 mmHg in nine cases (31%). The difference between the estimated systolic PAP at echocardiography and the measured systolic PAP at RHC was mainly >10 mmHg in patients with a mean PAP <25 mmHg (fig. 1).

Figure 1–
Figure 1–

The correlation between systolic pulmonary artery pressure (PAP), estimated at echocardiography and a) systolic PAP measured at right heart catheterisation (RHC) or b) measured mean PAP. c) Accuracy of estimated systolic PAP compared with systolic PAP measured by RHC in relation to PAP. -----: −10 mmHg and +10 mmHg, respectively.

Nine patients had mean PAP between 20 mmHg and 24 mmHg and were excluded from the subsequent analysis. Thus, the study population comprised of 20 patients, including 18 with sporadic LAM and two with LAM associated with tuberous sclerosis complex; all were female, with a mean age of 49±12 yrs and not reported previously [7, 16]. In total, 270 LAM patients were included in the GERM“O”P registry (n=222) or followed in the Milan referral centre (n=48) during the study period; therefore, it was estimated that PH patients represented a minimum of 7% of LAM patients. The reasons for RHC were evaluation for transplantation (n=9) and/or suspicion of PH based on systematic echocardiography (n=11).

The baseline clinical data are reported in table 1. The diagnosis of LAM was definitive in 19 patients, and probable in one nonsmoker with characteristic chest imaging, obstructive ventilatory defect, and compatible medical history. A pattern characteristic of LAM [6] was present on HRCT of the chest in all patients. The diagnosis was confirmed by video-assisted thoracoscopic lung biopsy in 13 cases (65%). 15 patients were ex-smokers, with a median of 10 pack-yrs. One patient had a history of splenectomy and another had taken anorexigens. One patient had undergone unilateral nephrectomy for angiomyolipoma. When compared with LAM patients without PH, patients with LAM and PH had more severe dyspnoea and presented more frequently with right heart failure or haemoptysis.

View this table:
Table 1– Characteristics, clinical manifestations and pulmonary function tests at diagnosis of pre-capillary pulmonary hypertension (PH) in 20 patients with lymphangioleiomyomatosis (LAM) compared with 72 patients with LAM without PH

LAM was treated as follows: inhaled bronchodilators, 75% of patients; progesterone derivatives and/or anti-oestrogen therapy, 45%; doxycycline, 30%; sirolimus, 25%.

Clinical and functional evaluation

The mean time interval between LAM diagnosis and the first RHC demonstrating PH was 9.2±9.8 yrs (range 0–36 yrs), and the mean time period between first respiratory symptoms and PH was 10.4±7.5 yrs (range 3.0–22.1 yrs). NYHA functional class was III or IV in 95% of these patients.

Echocardiography revealed dilated right heart cardiac cavities in seven (35%) out of 20 patients. The mean value of systolic PAP estimated at echocardiography was 56±18 mmHg (range 40–108). Mild pericardial effusion was reported in one patient. B-type natriuretic peptide (BNP) level was normal in all of the seven patients tested. Haemoglobin was >160 g·L−1 in two patients (10%).

The 6-min walking distance (6MWD) was 340±84 m, with mean desaturation of 10±8%. The median Borg index value of dyspnoea at the end of the 6MWT, available in 11 patients, was 4 (range, 3–6). Table 2 presents the pulmonary function test results. Obstructive ventilatory defect, defined by forced expiratory volume in 1 s (FEV1): forced vital capacity (FVC) <70%, was present in 83% of patients. FEV1 was <80% predicted value in 84% of patients, and <50% pred value in 63% of patients. Gas exchange was severely impaired, with a mean single-breath diffusing capacity of the lung for carbon monoxide (DL,CO) of 29±13% pred value. When compared with LAM patients without PH, patients with LAM and PH had more severe airflow obstruction, lower diffusion capacity for CO, more severe hypoxaemia and impairment of exercise capacity.

View this table:
Table 2– Pulmonary functions and 6-min walking test (6MWT) in patients with lymphangioleiomyomatosis (LAM) and pulmonary hypertension (PH) compared with 72 patients with LAM without PH

Haemodynamics

Table 3 reports the results of RHC. Mean PAP was 32±6 mmHg, and pulmonary vascular resistance (PVR) was 376±184 dyn·s·cm−5. None of the eight patients tested were acutely vasoreactive to inhaled NO. Mean PAP was >35 mmHg in four patients with definite LAM (20%), two of whom had normal FEV1, and one with mean PAP of 40 mmHg and FEV1 of 52% pred had a history of anorexigen intake. Mean PAP was >40 mmHg in one patient (5%) who had normal FEV1.

View this table:
Table 3– Haemodynamic data at the time of pulmonary hypertension diagnosis

Significant correlations were observed between haemodynamic parameters and pulmonary function (table S1, fig. 2), especially between PVR and FEV1 and DL,CO and the transfer coefficient for the lung for carbon monoxide (KCO), but not with arterial oxygen tension (Pa,O2) or arterial oxygen saturation measured by pulse oximetry (Sp,O2) at the end of the 6MWT. Mean PAP correlated with estimated systolic PAP at echocardiography (r=0.583, p=0.063).

Figure 2–
Figure 2–

Correlation between mean pulmonary arterial pressure (PAP) or pulmonary vascular resistance (PVR) and forced expiratory volume in 1 s (FEV1), single breath diffusing capacity of the lungs for carbon monoxide (DL,CO), or single breath transfer factor of the lungs for carbon monoxide (KCO). Regression lines are indicated.% pred: % predicted.

Outcome and survival analysis

95% of patients received long-term supplemental nasal oxygen therapy; 30% received diuretics and 25% were given oral anticoagulant therapy, for PH.

Six (30%) out of the 20 patients received first-line therapy for PAH with dual endothelin receptor antagonist (bosentan n=5) or phosphodiesterase type-5 inhibitors (sildenafil n=1) with no concomitant change in supplemental oxygen therapy. No patient was administered prostacyclin derivatives. In this subgroup of six treated patients, no statistically significant difference was observed on NYHA functional class (p=0.987), 6MWD (p=0.983), cardiac index (p=0.786), FEV1 (p=0.530), Pa,O2 (p=0.179) or Sp,O2 (p=0.880) between the evaluation before PAH therapy and the last evaluation on therapy (fig. 3). Right heart cavities were dilated in three out of six patients, with no change upon PH therapy. Mean PAP decreased significantly in the six treated patients with PAH therapy from 33±9 mmHg to 24±10 mmHg (mean difference 9 mmHg, 95% CI 5–14; p=0.003) after a median of 38 months (interquartile range (IQR) 14.5–34 months). PVR declined in the six treated patients from 481±188 dyn·s·cm−5 to 280±79 dyn·s·cm−5 (mean difference 201 dyn.s.cm−5, 95% CI 18–384; p=0.037). Overall, an improvement (predefined by NYHA functional class reduction and/or a 20% increase in 6MWD and/or a 20% decrease in PVR with 20% diminution of mean PAP) was seen in the five patients who received bosentan, but not in the patient given sildenafil.

Figure 3–
Figure 3–

Outcome of six patients who received bosentan or sildenafil. NYHA FC: New York Heart Association Functional Class; 6MWD: 6-min walking distance; PAP: pulmonary arterial pressure; PVR: pulmonary vascular resistance; FEV1: forced expiratory volume in 1 s; Sp,O2: arterial oxygen saturation measured by pulse oximetry; (room air); Pa,O2: arterial oxygen tension (room air). *: p<0.05 versus baseline.

In addition, one patient was treated with sirolimus (but no PAH treatment) for LAM progression and had a follow-up evaluation after 10 months of therapy; NYHA functional class had changed from IV to III, 6MWD from 330 m (Sp,O2 of 84%) to 350 m (SpO2 of 90%), FEV1 from 27% to 53% pred, FVC from 63% to 102%, mean PAP from 35 mmHg to 23 mmHg, PVR from 168 dyn·s·cm−5 to 178 dyn·s·cm−5, and cardiac index from 5.2 L·min−1·m−2 to 3.9 L·min−1·m−2.

Overall, the study subjects were followed for a mean of 2.5±2.1 yrs from the diagnosis of PH. No patient was lost to follow-up. At the end of follow-up, one patient had died from cardiac arrest and five patients had undergone single or double lung transplantation (three and two patients, respectively). The overall probability of survival was 94% at 1 yr, 94% at 2 yrs, and 78% at 3 yrs (fig. 4). The transplant-free probability of survival was 87% at 1 yr, 78% at 2 yrs, and 56% at 3 yrs.

Figure 4–
Figure 4–

Transplant-free and overall survival in patients with lymphangioleiomyomatosis and pulmonary hypertension.

Pathology assessment of explanted lungs

Pathological assessment of explanted lungs in five patients demonstrated pronounced vascular remodelling, with involvement of the pulmonary arterial walls by characteristic LAM cells (so-called PEComa cells) (table 4, fig. 5). Cells within the remodelled pulmonary arteries were further characterised as LAM/PEComa cells by positive HMB45 immunostaining in 3/3 cases available. As expected, LAM/PEComa cells were also observed along the edges of the lung cysts, bronchioles, and pulmonary lymphatics.

Figure 5–
Figure 5–

Pathological assessments of lungs at the time of transplantation in three patients with pulmonary lymphangioleiomyomatosis (LAM). a–d) Haematoxylin-eosin staining in one patient. a) Two bronchioles (#) and their adjacent pulmonary arteries (arrows). Both structures show remodelling; the bronchioles are directly involved with characteristic LAM/ perivascular epithelioid cells (PEComa)-cell proliferation (arrowheads), while pulmonary arteries display intimal fibrosis and some minor LAM/PEComa involvement. b) Two pulmonary veins with paucicellular collagen-rich intimal fibrosis (arrows). Note the two LAM/PEComa-foci (arrowheads) surrounding the blood vessels. c) Two pulmonary arteries displaying medial hypertrophy and intimal fibrosis (arrows) and adjacent bronchiole (#). d) A pulmonary artery showing tortuosity and intimal fibrosis. Note involvement of the artery with PEComa cell proliferation at the periphery of the vessel (arrowheads). e) Immunohistochemical staining for HMB45 demonstrating a pulmonary artery with HMB-45+ cells within the remodelled vessel-wall. f) Immunohistochemical staining for HMB45 showing a small arteriole or venule presenting muscularisation and involvement of HMB-45+ LAM cells.

View this table:
Table 4– Semiquantitative assessment of lymphangioleiomyomatosis/perivascular epithelioid cells (LC) and their distribution in the diseased lungs of five transplanted patients

DISCUSSION

The present study is the first to report the haemodynamic evaluation of LAM patients with pre-capillary PH confirmed by RHC, the gold standard for PH diagnosis [23].

The main findings were as follows: 1) PH was generally of only mild haemodynamic severity, with mean PAP of 32±6 mmHg and PVR of 376±184 dyn·s·cm−5, and only 20% of patients had mean PAP >35 mmHg (out-of-proportion PH); 2) PH was diagnosed after a mean of 9.2±9.8 yrs following the LAM diagnosis in patients with mean FEV1 of 46.4±26% pred value, chronic hypoxaemia (mean Pa,O2 of 7.4±1.1 kPa), and moderate-to-severe exercise intolerance as shown by mean 6mwd of 340 ± 84 m with mean Sp,O2 of 81.3±9.3% at the end of the test; 3) patients with PH had more severe dyspnoea, airflow obstruction, hypoxaemia, and impairment of exercise capacity than patients with LAM but without PH; 4) haemodynamic parameters correlated with pulmonary function and especially with FEV1, DL,CO, and KCO; 5) significant remodelling of the pulmonary arteries was observed with involvement by HMB45 positive LAM/PEComa cells; 6) the overall probability of survival was 94% at 2 yrs, and transplant-free survival was 78% at 2 yrs; 7) off-label oral PAH therapy in a subgroup of patients was associated with a significant decrease in mean PAP and PVR without a significant difference in exercise capacity or dyspnoea.

Impairment of pulmonary function in our study population was more severe than in most recent series of LAM patients, who had mean FEV1 of 65% to 75% pred at the time of diagnosis [10, 12, 13, 30, 31]. Patients with PH had more airflow obstruction than LAM patients without PH, indicating that PH generally occurs in subjects with more advanced pulmonary disease. Consistent with this hypothesis, LAM diagnosis preceded PH diagnosis by almost a decade, and five patients (25%) underwent lung transplantation within 2 yrs after being diagnosed with PH.

However, unexpected correlations were found between lung function and haemodynamic parameters, with greater mean PAP, superior PVR, and lower cardiac index in patients with improved preserved FEV1 and DL,CO, indicating that PH may progress independently of parenchymal lung disease. In contrast, systolic or mean PAP correlates inversely with DL,CO in idiopathic pulmonary fibrosis patients, although it correlates poorly with lung volume [32–35]. Sp,O2was significantly decreased during exercise, and most LAM and PH patients required long-term oxygen therapy. However, mean PAP did not correlate with Pa,O2 at rest, consistent with a previous observation that PH (during exercise) cannot be predicted from resting pulmonary function testing [19]. Although our small sample size prevents firm conclusions, our study indicates that PH can occur in patients with mild-to-severe lung function impairment and may reflect intrinsic vasculopathy in an unknown proportion of patients, as suggested by pathological findings in five patients and earlier descriptions of the involvement of pulmonary arteries by cell proliferation in LAM [36, 37]. It is conceivable that mTOR activation in LAM may contribute to PH in patients with LAM [21], as in patients with neurofibromatosis type 1 [38].

The mean PAP in our patients (32±6 mmHg) was strikingly similar to that reported by Reynaud-Gaubert et al. [7] (33±8 mmHg) in nine patients evaluated for lung transplantation, and higher than that observed by Harari et al. [16] (26.0±2.5 mmHg) in six patients also evaluated for lung transplantation, but not included in the present series. PH in the context of chronic parenchymal lung disease is usually mild or moderate (i.e. with mean PAP <35–40 mmHg). However, subgroups of patients with chronic obstructive pulmonary disease (COPD) [39–41], idiopathic pulmonary fibrosis [42], or combined pulmonary fibrosis and emphysema syndrome [43] have severe “out-of-proportion” pre-capillary PH, usually defined by mean PAP >35–40 mmHg [17, 39]. These subjects are prone to right heart failure and may share similarities with idiopathic PAH [43, 44]. Only 20% of patients in the present study had mean PAP >35 mmHg with 5% disclosing mean PAP >40 mmHg, fulfilling this definition. Interestingly, two of these patients had normal FEV1 with PH and were thus “out-of-proportion”. The highest mean PAP recorded in our study was 51 mmHg, and 47 mmHg in that of Reynaud-Gaubert et al. [7]. The mean haemodynamic profile of LAM patients in the present series was much less severe than that of PAH patients in the national French registry (with a higher PVR index of 1,640 dyn·s·cm−5·m−2 and cardiac index of 2.5 L·min−1·m−2) [22]. It was also less severe than in patients with pre-capillary PH and pulmonary Langerhans cell histiocytosis [45, 46], combined pulmonary fibrosis and emphysema [43], or sarcoidosis [47], and somewhat comparable to that of PH associated with idiopathic pulmonary fibrosis [32, 35, 42]. However, although mean PAP was only mildly elevated, some patients with mild lung-function impairment had severe and “out-of-proportion” PH.

The clinical relevance of PH in patients with LAM is currently unknown. In a study by Taveira-DaSilva et al. [19], peak exercise PAP correlated negatively with Sp,O2, indicating that PH may contribute to exercise-induced hypoxaemia and exercise limitation; increased systolic PAP was observed during low-level exercise corresponding to daily living activities. Predictors of a more severe prognosis could not be evaluated in the present series, because of the small sample size. However, LAM patients with PH had lower DL,CO, more severe hypoxaemia, and impaired exercise capacity when compared with LAM patients without PH, suggesting that a low diffusion capacity in LAM should prompt to perform an echocardiography. A significant proportion of our PH and LAM patients died or underwent lung transplantation within 2 yrs of PH diagnosis. Although no formal survival comparison was made to a group of LAM patients without PH, the present finding questions whether PH might have prognostic significance in LAM, similar to what has been reported in idiopathic pulmonary fibrosis [42, 48], COPD [49], and combined pulmonary fibrosis and emphysema [50, 51]. The 10-yr survival rate of patients with LAM has been reported to 71%, 79%, and 91% from the time of diagnosis in large series [10, 11, 52]. Thus, the potential impact of PH on long-term survival in LAM deserves further analysis in prospective studies.

The potential benefit of PAH-specific therapy is not known in PH patients with associated pulmonary parenchymal disorders, as these drugs have not been approved in this setting. It is unlikely that the rare occurrence of PH in LAM (an “orphan” disease) will be investigated in a dedicated clinical trial. A minority of patients in the present series were treated off-label on an individual basis, providing some interesting preliminary information on the efficacy and safety of PAH therapy in this condition. PAH treatment with bosentan or sildenafil was well tolerated, especially since gas exchange was not significantly impaired as has been observed in some COPD and PH patients [53]. Although involvement of pulmonary veinules was observed pathologically, pulmonary oedema was not observed at initiation of PH therapy. Haemodynamics improved significantly with a 28% decrease in mean PAP and a 42% reduction of PVR, but no significant effect of therapy was apparent on dyspnoea or exercise capacity (although such analysis was underpowered). Sirolimus, which has proven beneficial in lung function and clinically-relevant parameters [5], should be considered in LAM patients with progressive disease. The present study did not allow us to evaluate whether sirolimus may also contribute to improvement in PH patients with LAM. Nasal oxygen supplementation should be considered whenever appropriate [6]. Younger LAM patients should be evaluated early for lung transplantation, which remains the issue in advanced disease [6–9].

This study sheds light on the utility of non-invasive methods screening for PH in LAM patients. No patients tested in the present series had elevated serum BNP levels, and only 35% had dilated right heart cavities on echocardiography. All patients with mean PAP >25 mmHg at RHC had estimated systolic PAP of ≥40 mmHg based on systolic regurgitation of the tricuspid valve. Conversely, patients who eventually manifested mean PAP between 20 mmHg and 25 mmHg had estimated systolic PAP ≤40 mmHg on echocardiography. Although this study was not designed to evaluate the diagnostic value of echocardiography, we suggest that LAM patients with estimated systolic PAP ≥40 mmHg on echocardiography undergo RHC. It is known that echocardiography lacks specificity and accuracy in patients with advanced lung disease, including emphysema [54] and idiopathic pulmonary fibrosis [55, 56]. No patients in the present study had post-capillary PH. Although the current study was not designed to evaluate the prevalence of PH, a conservative 7% was estimated for PH prevalence in LAM patients, consistent with a previous similar assessment based on echocardiography [19].

Our investigation has some limitations, especially its observational and uncontrolled design owing to the rarity of this condition. However, LAM cases were prospectively included in the GERM“O”P registry, and haemodynamic data were collected prospectively in the setting of the French national PH registry. Haemodynamic and pulmonary functions were not evaluated during exercise. As indications for echocardiography and treatment were left to the physicians' discretion, the data presented here are potentially subject to bias and should not be interpreted as proper evaluation of therapeutic efficacy. However, data on haemodynamic parameters and survival were unlikely to be affected by the study design.

In conclusion, PH may occur in a small subset of LAM patients after a mean of 9 yrs after diagnosis. It can affect LAM patients with mildly to severely-impaired lung function, most of them requiring long-term oxygen therapy. However, mean PAP and PVR did not correlate with Pa,O2, indicating that factors other than hypoxia, and especially LAM/PEComa cell vasculopathy, may contribute to PH. Whether PAH-specific therapy may be beneficial in LAM patients with PH deserves further study.

Acknowledgments

The authors are indebted to all the patients who participated in this study, the French Association of Patients with Lymphangioleiomyomatosis (F-LAM), and all physicians who took care of these patients. The authors would also like to thank C. Silarakis for bibliographic assistance, O. Da Silva for editing this manuscript, and F. Thivolet-Béjui (Lyon, France), F. Calabrese (Padova, Italy), M.J. Payan (Marseille, France) and C. Danel (Paris, France) who contributed the pathology slides. Other collaborators who were also involved in the study included B. Crestani (Paris, France), S. Günther (Clamart, France), S. Hirschi (Strasbourg, France), and C. Khouatra (Lyon, France).

The affiliations for the authors are as follows: V Cottin, S. Zeghmar and J-F Cordier: Hospices Civils de Lyon, Hôpital Louis Pradel, Service de pneumologie – Centre de référence national des maladies pulmonaires rares et Centre de compétences de l'hypertension artérielle pulmonaire, Lyon, and Université de Lyon, Université Lyon I, INRA, UMR754 INRA-Vetagrosup EPHE IFR 128, Lyon, France. S. Harari: Unita operativa di pneumologia e terapia semi-intensiva respiratoria, Servizio di fisiopatologia respiratoria ed emodinamica polmonare, Ospedale San Giuseppe, Milano, Italy. M. Humbert, X. Jaïs and Gérald Simonneau: Université Paris-Sud, Faculté de médecine, Le Kremlin Bicêtre, Service de pneumologie – Centre de référence de l'hypertension pulmonaire sévère, Hôpital Bicêtre, AP-HP and INSERM UMR 999, Clamart, France. H. Mal and C. Taillé: Hôpital Bichat, Centre de compétences des maladies pulmonaires rares, Paris, France. P. Dorfmüller: Service d'Anatomie et de cytologie pathologiques, Hôpital Marie Lannelongue, INSERM UMR 999, Le Plessis Robinson, France. M. Reynaud-Gaubert: AP-HM, CHU Nord, Service de pneumologie, Centre de compétences des maladies pulmonaires rares et Centre de compétences de l'hypertension artérielle pulmonaire; and URMITE CNRS- UMR 6236, Université Aix-Marseille II, Marseille, France. G. Prevot: Hôpital Larrey, Centre de compétences de l'hypertension artérielle pulmonaire, Toulouse, France. J. Lacronique: Service de pneumologie, Hôpital Cochin, AP-HP , Université Paris Descartes, Sorbonne Paris Cité, Paris, France. R. Lazor: Hospices Civils de Lyon, Hôpital Louis Pradel, Service de pneumologie – Centre de référence national des maladies pulmonaires rares et Centre de compétences de l'hypertension artérielle pulmonaire, Université de Lyon, Université Lyon I, INRA, UMR754 INRA-Vetagrosup EPHE IFR 128, Lyon, France, and Consultation des pneumopathies interstitielles et maladies pulmonaires rares, Service de pneumologie, Centre hospitalier universitaire vaudois, Lausanne, Switzerland.

Footnotes

  • This article has supplementary material available from www.erj.ersjournals.com

  • Support Statement

    Funding was provided by the Comité national contre les maladies respiratoires (CNMR) and the Seventh Framework Program of the European Commission

  • Statement of Interest

    A statement of interest for V. Cottin, M. Humbert, X. Jaïs, G. Simonneau and J-F Cordier can be found at www.erj.ersjournals.com/site/misc/statements.xhtml

  • Received June 1, 2011.
  • Accepted December 7, 2011.

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Pulmonary hypertension in lymphangioleiomyomatosis: characteristics in 20 patients
Vincent Cottin, Sergio Harari, Marc Humbert, Hervé Mal, Peter Dorfmüller, Xavier Jaïs, Martine Reynaud-Gaubert, Grégoire Prevot, Romain Lazor, Camille Taillé, Jacques Lacronique, Sabrina Zeghmar, Gérald Simonneau, Jean-François Cordier, the Groupe d'Etudes et de Recherche sur les Maladies “Orphelines” Pulmonaires (GERM“O”P)
European Respiratory Journal Sep 2012, 40 (3) 630-640; DOI: 10.1183/09031936.00093111
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