Clinical characteristics in lymphangioleiomyomatosis-related pulmonary hypertension: an observation on 50 patients

Abstract

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 (P_A-aO₂), and 6 min walking distance (r = −0.392, −0.351, 0.450, and −0.591, respectively; P<0.05), in which P_A-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

References

[1] Harknett EC, Chang WY, Byrnes S, Johnson J, Lazor R, Cohen MM, Gray B, Geiling S, Telford H, Tattersfield AE, Hubbard RB, Johnson SR. Use of variability in national and regional data to estimate the prevalence of lymphangioleiomyomatosis. QJM 2011; 104(11): 971–979

[2] Johnson SR, Taveira-DaSilva AM, Moss J. Lymphangioleiomyomatosis. Clin Chest Med 2016; 37(3): 389–403

[3] Taveira-DaSilva AM, Hathaway OM, Sachdev V, Shizukuda Y, Birdsall CW, Moss J. Pulmonary artery pressure in lymphangioleiomyomatosis: an echocardiographic study. Chest 2007; 132(5): 1573–1578

[4] McCormack FX. Lymphangioleiomyomatosis: a clinical update. Chest 2008; 133(2): 507–516

[5] Taveira-DaSilva AM, Moss J. Clinical features, epidemiology, and therapy of lymphangioleiomyomatosis. Clin Epidemiol 2015; 7: 249–257

[6] Harari S, Torre O, Moss J. Lymphangioleiomyomatosis: what do we know and what are we looking for? Eur Respir Rev 2011; 20(119): 34–44

[7] Cottin V. Pulmonary hypertension in chronic respiratory diseases. Presse Med 2014; 43(9): 945–956

[8] Harari S, Simonneau G, De Juli E, Brenot F, Cerrina J, Colombo P, Gronda E, Micallef E, Parent F, Dartevelle P. 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

[9] Freitas CSG, Baldi BG, Jardim C, Araujo MS, Sobral JB, Heiden GI, Kairalla RA, Souza R, Carvalho CRR. 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

[10] Barnett CF, Alvarez P, Park MH. Pulmonary arterial hypertension: diagnosis and treatment. Cardiol Clin 2016; 34(3): 375–389

[11] Galiè N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, Simonneau G, Peacock A, Vonk Noordegraaf A, Beghetti M, Ghofrani A, Gomez Sanchez MA, Hansmann G, Klepetko W, Lancellotti P, Matucci M, McDonagh T, Pierard LA, Trindade PT, Zompatori M, Hoeper M. 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

[12] Johnson SR, Cordier JF, Lazor R, Cottin V, Costabel U, Harari S, Reynaud-Gaubert M, Boehler A, Brauner M, Popper H, Bonetti F, Kingswood C; 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

[13] Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Crapo R, Enright P, van der Grinten CP, Gustafsson P, Jensen R, Johnson DC, MacIntyre N, McKay R, Navajas D, Pedersen OF, Pellegrino R, Viegi G, Wanger J; ATS/ERS Task Force. Standardisation of spirometry. Eur Respir J 2005; 26(2): 319–338

[14] Nadrous HF, Pellikka PA, Krowka MJ, Swanson KL, Chaowalit N, Decker PA, Ryu JH. Pulmonary hypertension in patients with idiopathic pulmonary fibrosis. Chest 2005; 128(4): 2393–2399

[15] McCormack FX, Gupta N, Finlay GR, Young LR, Taveira-DaSilva AM, Glasgow CG, Steagall WK, Johnson SR, Sahn SA, Ryu JH, Strange C, Seyama K, Sullivan EJ, Kotloff RM, Downey GP, Chapman JT, Han MK, D’Armiento JM, Inoue Y, Henske EP, Bissler JJ, Colby TV, Kinder BW, Wikenheiser-Brokamp KA, Brown KK, Cordier JF, Meyer C, Cottin V, Brozek JL, Smith K, Wilson KC, Moss J; 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

[16] Cottin V, Harari S, Humbert M, Mal H, Dorfmüller P, Jaïs X, Reynaud-Gaubert M, Prevot G, Lazor R, Taillé C, Lacronique J, Zeghmar S, Simonneau G, Cordier JF; 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

[17] Nathan SD, Hassoun PM. Pulmonary hypertension due to lung disease and/or hypoxia. Clin Chest Med 2013; 34(4): 695–705

[18] Naeije R, Dedobbeleer C. Pulmonary hypertension and the right ventricle in hypoxia. Exp Physiol 2013; 98(8): 1247–1256

[19] Nakahara Y, Taniguchi H, Kimura T, Kondoh Y, Arizono S, Nishimura K, Sakamoto K, Ito S, Ando M, Hasegawa Y. Exercise hypoxaemia as a predictor of pulmonary hypertension in COPD patients without severe resting hypoxaemia. Respirology 2017; 22(1): 120–125

[20] Wang T, Mao Y, Sun Y, Hou W, Feng Y, Qu H. 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

[21] Meyer FJ, Ewert R, Hoeper MM, Olschewski H, Behr J, Winkler J, Wilkens H, Breuer C, Kübler W, Borst MM; German PPH Study Group. Peripheral airway obstruction in primary pulmonary hypertension. Thorax 2002; 57(6): 473–476

[22] Sun XG, Hansen JE, Oudiz RJ, Wasserman K. Pulmonary function in primary pulmonary hypertension. J Am Coll Cardiol 2003; 41(6): 1028–1035

[23] Lai YC, Potoka KC, Champion HC, Mora AL, Gladwin MT. Pulmonary arterial hypertension: the clinical syndrome. Circ Res 2014; 115(1): 115–130

[24] Seeger W, Adir Y, Barberà JA, Champion H, Coghlan JG, Cottin V, De Marco T, Galiè N, Ghio S, Gibbs S, Martinez FJ, Semigran MJ, Simonneau G, Wells AU, Vachiéry JL. Pulmonary hypertension in chronic lung diseases. J Am Coll Cardiol 2013; 62(25 Suppl): D109–D116

[25] Ruocco G, Cekorja B, Rottoli P, Refini RM, Pellegrini M, Di Tommaso C, Del Castillo G, Franci B, Nuti R, Palazzuoli A. 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

[26] Fisher MR, Criner GJ, Fishman AP, Hassoun PM, Minai OA, Scharf SM, Fessler HE; NETT Research Group. Estimating pulmonary artery pressures by echocardiography in patients with emphysema. Eur Respir J 2007; 30(5): 914–921

[27] Freitas CS, Baldi BG, Araújo MS, Heiden GI, Kairalla RA, Carvalho CR. Use of sirolimus in the treatment of lymphangioleiomyomatosis: favorable responses in patients with different extrapulmonary manifestations. J Bras Pneumol 2015; 41(3): 275–280

[28] McCormack FX, Inoue Y, Moss J, Singer LG, Strange C, Nakata K, Barker AF, Chapman JT, Brantly ML, Stocks JM, Brown KK, Lynch JP 3rd, Goldberg HJ, Young LR, Kinder BW, Downey GP, Sullivan EJ, Colby TV, McKay RT, Cohen MM, Korbee L, Taveira-DaSilva AM, Lee HS, Krischer JP, Trapnell BC;National 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

[29] Goncharov DA, Kudryashova TV, Ziai H, Ihida-Stansbury K, DeLisser H, Krymskaya VP, Tuder RM, Kawut SM, Goncharova EA. 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

[30] Wang W, Liu J, Ma A, Miao R, Jin Y, Zhang H, Xu K, Wang C, Wang J. mTORC1 is involved in hypoxia-induced pulmonary hypertension through the activation of Notch3. J Cell Physiol 2014; 229(12): 2117–2125

[31] Wang AP, Li XH, Yang YM, Li WQ, Zhang W, Hu CP, Zhang Z, Li YJ. A critical role of the mTOR/eIF2a pathway in hypoxia-induced pulmonary hypertension. PLoS One 2015; 10(6): e0130806

[32] Krymskaya VP, Snow J, Cesarone G, Khavin I, Goncharov DA, Lim PN, Veasey SC, Ihida-Stansbury K, Jones PL, Goncharova EA. mTOR is required for pulmonary arterial vascular smooth muscle cell proliferation under chronic hypoxia. FASEB J 2011; 25(6): 1922–1933

[33] Houssaini A, Abid S, Mouraret N, Wan F, Rideau D, Saker M, Marcos E, Tissot CM, Dubois-Randé JL, Amsellem V, Adnot S. Rapamycin reverses pulmonary artery smooth muscle cell proliferation in pulmonary hypertension. Am J Respir Cell Mol Biol 2013; 48(5): 568–577

Acknowledgements

This work was supported by the Beijing Municipal Science and Technology Project (No. Z151100003915126) and the National Key Research and Development Program of China (No. 2016YFC0901502).

Compliance with ethics guidelines

Xiuxiu Wu, Wenshuai Xu, Jun Wang, Xinlun Tian, Zhuang Tian, and Kaifeng Xu declare that they have no conflict of interest. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from all patients who were included in the study.

RIGHTS & PERMISSIONS

2018 Higher Education Press and Springer-Verlag GmbH Germany, part of Springer Nature