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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2019, Vol. 13 Issue (2) : 259-266
Clinical characteristics in lymphangioleiomyomatosis-related pulmonary hypertension: an observation on 50 patients
Xiuxiu Wu1, Wenshuai Xu1, Jun Wang1, Xinlun Tian1, Zhuang Tian2, Kaifeng Xu1()
1. Department of Respiratory Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
2. Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
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Lymphangioleiomyomatosis (LAM) is a rare diffuse cystic lung disease. Knowledge on LAM-related pulmonary hypertension (PH) is limited. This study aimed to analyze the clinical characteristics of LAM with elevated pulmonary artery pressure (PAP) and evaluate the potential efficacy of sirolimus. The study involved 50 LAM patients who underwent echocardiography. According to the tricuspid regurgitation velocity (TRV), these patients were divided into the TRV≤2.8 m/s group and TRV>2.8 m/s group. Both groups comprised 25 females with an average age of 38.6±8.1 and 41.5±8.9 years. In the TRV>2.8 m/s group, the estimated systolic PAP (SPAP) was significantly elevated (52.08±12.45 mmHg vs. 30.24±5.25 mmHg, P<0.01). Linear analysis showed that SPAP was correlated with forced expiratory volume in 1 s (FEV1), diffusing capacity of the lungs for carbon monoxide, alveolar arterial oxygen gradient (PA-aO2), and 6 min walking distance (r = −0.392, −0.351, 0.450, and −0.591, respectively; P<0.05), in which PA-aO2 was a risk factor for SPAP elevation (β = 0.064, OR= 1.066, P<0.05). Moreover, in 10 patients who received sirolimus therapy, SPAP decreased from 57.0±12.6 mmHg to 35.2±11.1 mmHg. The study showed that LAM patients with PH exhibit poor pulmonary function and hypoxemia and may benefit from sirolimus treatment.

Keywords lymphangioleiomyomatosis      pulmonary hypertension      pulmonary function      hypoxemia      sirolimus     
Corresponding Authors: Kaifeng Xu   
Just Accepted Date: 09 March 2018   Online First Date: 18 April 2018    Issue Date: 28 March 2019
 Cite this article:   
Xiuxiu Wu,Wenshuai Xu,Jun Wang, et al. Clinical characteristics in lymphangioleiomyomatosis-related pulmonary hypertension: an observation on 50 patients[J]. Front. Med., 2019, 13(2): 259-266.
Fig.1  Patient screening chart. TRV, tricuspid regurgitation velocity; SPAP, pulmonary artery systolic pressure; PFT, pulmonary function test; ABG, arterial blood gas; 6MWD, 6 min walking distance; SGRQ, St George’s respiratory questionnaire.
Variables TRV≤2.8m/s
n = 25
TRV>2.8 m/s
n = 25
P value
Age (mean years) 38.64±8.10 41.48±8.93 0.245
Cigarette smoking 0 0 1
Weight (kg) 53.66±5.65 51.68±7.15 0.283
Body mass index (kg/m2) 20.97±2.21 20.51±2.71 0.512
LAM diagnosis
Definite (%)
Probable (%)
Tuberous sclerosis complex (%) 8% 8% 1
Renal angiomyolipoma (%) 20% 12% 0.702
History of pneumothorax (%) 32% 28% 0.758
History of chylothorax (%) 28% 40% 0.370
WHO functional class
I–II (%) 92% 76% 0.247
III–IV (%) 8% 24%
SPAP (mmHg) 30.24±5.25 52.08±12.45 0.000
Supplemental oxygen 20% 72% 0.000
Tab.1  Demographics and clinical characteristics of TRV≤2.8 m/s group and TRV>2.8 m/s group
Fig.2  Correlation between systolic pulmonary artery pressure (SPAP) and pulmonary function, oxygenation, and 6 min walking distance (6MWD). SPAP was negatively correlated with forced vital capacity (FVC) % predicted, forced expiratory volume in 1 s (FEV1) % predicted, diffusing capacity of the lungs for carbon monoxide (DLCO) % predicted, arterial oxygen pressure (PaO2), arterial oxygen saturation (SaO2), and 6MWD (A–F) and positively correlated with alveolar arterial PO2 difference (PA-aO2) (G).
Variables TRV≤2.8 m/s
n = 25
TRV>2.8 m/s
n = 25
P value
Pulmonary function
FVC% pred 87.82±16.3 69.82±20.21 0.001
FEV1% pred 67.63±24.30 43.71±19.97 0.000
FVC/FEV1% 66.66±22.00 52.62±14.82 0.012
TLC% pred 109.66±19.29 112.42±19.73 0.646
RV% pred 157.08±66.20 191.53±75.65 0.115
RV/TLC% 44.61±1 2.06 53.54±14.46 0.031
DLCO% pred 45.92±18.75 30.42±16.78 0.005
Arterial blood gas
PaO2 (mmHg) 78.10±13.39 60.60±14.31 0.000
PA-aO2 (mmHg) 30.61±15.60 56.24±26.14 0.000
PaCO2 (mmHg) 34.96±4.31 35.40±8.97 0.827
SaO2 (%) 94.53±2.72 90.45±5.07 0.001
6MWD (m) 476.15±88.62 344.11±104.19 0.000
Borg dyspnea index 1.94±2.40 2.77±2.22 0.217
Symptom (score) 40.04±24.82 47.68±20.48 0.241
Activity ability (score) 45.88±26.43 67.80±16.92 0.001
Disease impact (score) 33.84±22.15 54.80±21.94 0.001
Total score (score) 38.80±21.89 57.52±17.13 0.002
Tab.2  Evaluations of the TRV≤2.8 m/s and TRV>2.8 m/s groups
Variables β OR (95%CI) P value
FEV1% pred −0.029 0.971 (0.922–1.023) 0.276
DLCO% pred 0.028 1.028 (0.963–1.097) 0.404
PA-aO2 0.064 1.066 (1.006–1.129) 0.031
6MWD −0.0.007 0.993 (0.984–1.002) 0.105
Tab.3  Multivariate logistic analyses for predicting the probability of PH in LAM
Variables Baseline After sirolimus Paired t test
d t P value
SPAP (mmHg) 57.00±12.59 35.17±11.07 −21.83±10.21 −6.755 0.000
FVC% pred 55.62±14.23 82.85±25.07 27.23±19.36 4.446 0.002
FEV1% pred 30.52±12.00 45.11±23.47 14.59±15.68 2.941 0.016
DLCO% pred 22.75±6.69 29.69±19.13 6.94±14.32 1.52 0.16
PaO2 (mmHg) 55.03±6.59 71.53±10.75 16.50±15.18 3.436 0.007
SaO2 (%) 87.01±4.38 94.02±2.23 7.01±5.22 4.244 0.002
PA-aO2 (mmHg) 54.40±9.11 38.13±13.37 −16.27±15.86 −3.243 0.01
6MWD (m) 294.75±83.45 394.40±71.69 99.65±68.29 4.614 0.001
Tab.4  Improvement in clinical features after sirolimus treatment
Fig.3  Improvement in clinical features after sirolimus treatment. (A) Pulmonary artery systolic pressure (SPAP) was significantly decreased after treatment with sirolimus. (B, C) Pulmonary function, including forced vital capacity (FVC) % pred and forced expiratory volume in 1 s (FEV1) % pred, were significantly increased. (D, E, F) Oxygenation indicators, such as arterial oxygen pressure (PaO2) and arterial oxygen saturation (SaO2), were significantly increased, and alveolar arterial oxygen gradient (PA-aO2) was significantly decreased. (G) Six minute walking distance (6MWD) was significantly improved after sirolimus treatment compared with the baseline.
1 ECHarknett, WY Chang, SByrnes, JJohnson, RLazor, MMCohen, BGray, S Geiling, HTelford, AETattersfield, RBHubbard, SRJohnson. Use of variability in national and regional data to estimate the prevalence of lymphangioleiomyomatosis. QJM 2011; 104(11): 971–979 pmid: 21764810
2 SRJohnson, AM Taveira-DaSilva, JMoss. Lymphangioleiomyomatosis. Clin Chest Med 2016; 37(3): 389–403 pmid: 27514586
3 AMTaveira-DaSilva, OMHathaway, VSachdev, YShizukuda, CWBirdsall, JMoss. Pulmonary artery pressure in lymphangioleiomyomatosis: an echocardiographic study. Chest 2007; 132(5): 1573–1578 pmid: 17890459
4 FXMcCormack. Lymphangioleiomyomatosis: a clinical update. Chest 2008; 133(2): 507–516 pmid: 18252917
5 AMTaveira-DaSilva, JMoss. Clinical features, epidemiology, and therapy of lymphangioleiomyomatosis. Clin Epidemiol 2015; 7: 249–257 pmid: 25897262
6 SHarari, O Torre, JMoss. Lymphangioleiomyomatosis: what do we know and what are we looking for? Eur Respir Rev 2011; 20(119): 34–44 pmid: 21357890
7 VCottin. Pulmonary hypertension in chronic respiratory diseases. Presse Med 2014; 43(9): 945–956 pmid: 25123317
8 SHarari, G Simonneau, EDe Juli, FBrenot, JCerrina, PColombo, EGronda, EMicallef, FParent, PDartevelle. Prognostic value of pulmonary hypertension in patients with chronic interstitial lung disease referred for lung or heart-lung transplantation. J Heart Lung Transplant 1997; 16(4): 460–463
pmid: 9154958
9 CSGFreitas, BG Baldi, CJardim, MSAraujo, JBSobral, GIHeiden, RAKairalla, RSouza, CRRCarvalho. Pulmonary hypertension in lymphangioleiomyomatosis: prevalence, severity and the role of carbon monoxide diffusion capacity as a screening method. Orphanet J Rare Dis 2017; 12(1): 74 pmid: 28427470
10 CFBarnett, P Alvarez, MHPark. Pulmonary arterial hypertension: diagnosis and treatment. Cardiol Clin 2016; 34(3): 375–389 pmid: 27443135
11 NGaliè, M Humbert, JLVachiery, SGibbs, ILang, A Torbicki, GSimonneau, APeacock, AVonk Noordegraaf, MBeghetti, AGhofrani, MAGomez Sanchez, GHansmann, WKlepetko, PLancellotti, MMatucci, TMcDonagh, LAPierard, PTTrindade, MZompatori, MHoeper. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint 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: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Respir J 2015; 46(4): 903–975 pmid: 26318161
12 SRJohnson, JF Cordier, RLazor, VCottin, UCostabel, SHarari, MReynaud-Gaubert, ABoehler, MBrauner, HPopper, FBonetti, CKingswood; Review Panel of the ERS LAM Task Force. European Respiratory Society guidelines for the diagnosis and management of lymphangioleiomyomatosis. Eur Respir J 2010; 35(1): 14–26 pmid: 20044458
13 MRMiller, J Hankinson, VBrusasco, FBurgos, RCasaburi, ACoates, RCrapo, PEnright, CPvan der Grinten, PGustafsson, RJensen, DCJohnson, NMacIntyre, RMcKay, DNavajas, OFPedersen, RPellegrino, GViegi, JWanger; ATS/ERS Task Force. Standardisation of spirometry. Eur Respir J 2005; 26(2): 319–338 pmid: 16055882
14 HFNadrous, PA Pellikka, MJKrowka, KLSwanson, NChaowalit, PADecker, JHRyu. Pulmonary hypertension in patients with idiopathic pulmonary fibrosis. Chest 2005; 128(4): 2393–2399 pmid: 16236900
15 FXMcCormack, N Gupta, GRFinlay, LRYoung, AMTaveira-DaSilva, CGGlasgow, WKSteagall, SRJohnson, SASahn, JHRyu, C Strange, KSeyama, EJSullivan, RMKotloff, GPDowney, JTChapman, MKHan, JM D’Armiento, YInoue, EPHenske, JJBissler, TVColby, BWKinder, KAWikenheiser-Brokamp, KKBrown, JFCordier, CMeyer, VCottin, JLBrozek, KSmith, KCWilson, JMoss; ATS/JRS Committee on Lymphangioleiomyomatosis. Official American Thoracic Society/Japanese Respiratory Society Clinical Practice Guidelines: Lymphangioleiomyomatosis Diagnosis and Management. Am J Respir Crit Care Med 2016; 194(6): 748–761 pmid: 27628078
16 VCottin, S Harari, MHumbert, HMal, P Dorfmüller, XJaïs, MReynaud-Gaubert, GPrevot, RLazor, CTaillé, JLacronique, SZeghmar, GSimonneau, JFCordier; Groupe d'Etudes et de Recherche sur les Maladies "Orphelines" Pulmonaires (GERM"O"P). Pulmonary hypertension in lymphangioleiomyomatosis: characteristics in 20 patients. Eur Respir J 2012; 40(3): 630–640 pmid: 22362861
17 SDNathan, PM Hassoun. Pulmonary hypertension due to lung disease and/or hypoxia. Clin Chest Med 2013; 34(4): 695–705 pmid: 24267299
18 RNaeije, C Dedobbeleer. Pulmonary hypertension and the right ventricle in hypoxia. Exp Physiol 2013; 98(8): 1247–1256 pmid: 23625956
19 YNakahara, H Taniguchi, TKimura, YKondoh, SArizono, KNishimura, KSakamoto, SIto, M Ando, YHasegawa. Exercise hypoxaemia as a predictor of pulmonary hypertension in COPD patients without severe resting hypoxaemia. Respirology 2017; 22(1): 120–125 pmid: 27471142
20 TWang, Y Mao, YSun, WHou, Y Feng, HQu. Pulmonary hypertension in patients with chronic obstructive pulmonary disease: clinical characteristics and risk factors. Chin J Intern Med (Zhonghua Nei Ke Za Zhi) 2015; 54(12): 1037–1040
pmid: 26887371
21 FJMeyer, R Ewert, MMHoeper, HOlschewski, JBehr, J Winkler, HWilkens, CBreuer, WKübler, MMBorst; German PPH Study Group. Peripheral airway obstruction in primary pulmonary hypertension. Thorax 2002; 57(6): 473–476 pmid: 12037220
22 XGSun, JE Hansen, RJOudiz, KWasserman. Pulmonary function in primary pulmonary hypertension. J Am Coll Cardiol 2003; 41(6): 1028–1035 pmid: 12651053
23 YCLai, KC Potoka, HCChampion, ALMora, MTGladwin. Pulmonary arterial hypertension: the clinical syndrome. Circ Res 2014; 115(1): 115–130 pmid: 24951762
24 WSeeger, Y Adir, JABarberà, HChampion, JGCoghlan, VCottin, TDe Marco, NGaliè, SGhio, S Gibbs, FJMartinez, MJSemigran, GSimonneau, AUWells, JLVachiéry. Pulmonary hypertension in chronic lung diseases. J Am Coll Cardiol 2013; 62(25 Suppl): D109–D116 pmid: 24355635
25 GRuocco, B Cekorja, PRottoli, RMRefini, MPellegrini, CDi Tommaso, GDel Castillo, BFranci, RNuti, A Palazzuoli. Role of BNP and echo measurement for pulmonary hypertension recognition in patients with interstitial lung disease: An algorithm application model. Respir Med 2015; 109(3): 406–415 pmid: 25613108
26 MRFisher, GJ Criner, APFishman, PMHassoun, OAMinai, SMScharf, HEFessler; NETT Research Group. Estimating pulmonary artery pressures by echocardiography in patients with emphysema. Eur Respir J 2007; 30(5): 914–921 pmid: 17652313
27 CSFreitas, BG Baldi, MSAraújo, GIHeiden, RAKairalla, CRCarvalho. Use of sirolimus in the treatment of lymphangioleiomyomatosis: favorable responses in patients with different extrapulmonary manifestations. J Bras Pneumol 2015; 41(3): 275–280 pmid: 26176526
28 FXMcCormack, Y Inoue, JMoss, LGSinger, CStrange, KNakata, AFBarker, JTChapman, MLBrantly, JMStocks, KKBrown, JPLynch 3rd, HJGoldberg, LRYoung, BWKinder, GPDowney, EJSullivan, TVColby, RTMcKay, MMCohen, LKorbee, AMTaveira-DaSilva, HSLee, JP Krischer, BC;TrapnellNational Institutes of Health Rare Lung Diseases Consortium; MILES Trial Group. Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N Engl J Med 2011; 364(17): 1595–1606 pmid: 21410393
29 DAGoncharov, TV Kudryashova, HZiai, KIhida-Stansbury, HDeLisser, VPKrymskaya, RMTuder, SMKawut, EAGoncharova. Mammalian target of rapamycin complex 2 (mTORC2) coordinates pulmonary artery smooth muscle cell metabolism, proliferation, and survival in pulmonary arterial hypertension. Circulation 2014; 129(8): 864–874 pmid: 24270265
30 WWang, J Liu, AMa, RMiao, Y Jin, HZhang, KXu, C Wang, JWang. mTORC1 is involved in hypoxia-induced pulmonary hypertension through the activation of Notch3. J Cell Physiol 2014; 229(12): 2117–2125 pmid: 24825564
31 APWang, XH Li, YMYang, WQLi, W Zhang, CPHu, ZZhang, YJLi. A critical role of the mTOR/eIF2a pathway in hypoxia-induced pulmonary hypertension. PLoS One 2015; 10(6): e0130806 pmid: 26120832
32 VPKrymskaya, J Snow, GCesarone, IKhavin, DAGoncharov, PNLim, SC Veasey, KIhida-Stansbury, PLJones, EAGoncharova. mTOR is required for pulmonary arterial vascular smooth muscle cell proliferation under chronic hypoxia. FASEB J 2011; 25(6): 1922–1933 pmid: 21368105
33 AHoussaini, S Abid, NMouraret, FWan, D Rideau, MSaker, EMarcos, CMTissot, JLDubois-Randé, VAmsellem, SAdnot. Rapamycin reverses pulmonary artery smooth muscle cell proliferation in pulmonary hypertension. Am J Respir Cell Mol Biol 2013; 48(5): 568–577 pmid: 23470622
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