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 Table of Contents  
Year : 2021  |  Volume : 16  |  Issue : 5  |  Page : 101-108

Lung transplantation in connective tissue disease associated interstitial lung disease

Department of Heart and Lung Transplantation, Yashoda Hospitals, Secunderabad, Telangana, India

Date of Submission21-Sep-2021
Date of Acceptance05-Nov-2021
Date of Web Publication21-Dec-2021

Correspondence Address:
Dr. Apar Jindal
Department of Heart and Lung Transplantation, Yashoda Hospitals, Alexander Road, Kummari Guda, Shivaji Nagar, Secunderabad - 500 003, Telangana
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-3698.332984

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The science and practice of organ transplant have evolved, and a lung transplant is now a viable option that can add years and quality to life. The connective tissue diseases (CTDs) at present form a very small percentage of the indications for which lung transplants are done today. Patients with interstitial lung disease or those with respiratory failure as a result of pulmonary vascular disease may benefit from transplants if done in the right setting. The various nonpulmonary manifestations of CTDs influence the odds of the success of a lung transplant and need to be taken into account beforehand. Evaluation of the individual candidate, ensuring disease remission at the time of the transplant, anticipating the surgical and anesthetic challenges and the postsurgical intensive care-related challenges is important. Careful patient selection and meticulous preprocedure evaluation are likely to result in good outcomes.

Keywords: Connective tissue disease, interstitial lung disease, lung transplantation, pulmonary hypertension, scleroderma

How to cite this article:
Rajagopala S, Jindal A. Lung transplantation in connective tissue disease associated interstitial lung disease. Indian J Rheumatol 2021;16, Suppl S1:101-8

How to cite this URL:
Rajagopala S, Jindal A. Lung transplantation in connective tissue disease associated interstitial lung disease. Indian J Rheumatol [serial online] 2021 [cited 2023 Feb 2];16, Suppl S1:101-8. Available from:

  Introduction Top

The proportion of lung transplantations (LT) performed for connective tissue diseases (CTD) is small, accounting for 0.9% of all cases being reported to the International Society for Heart and LT in 2019.[1] Rheumatoid arthritis (RA) and undifferentiated CTD (UCTD), followed by scleroderma, account for more than 70% of these transplants.[1] The concern about LT in CTDs is because of the presence of unfavorable risk factors for posttransplant outcomes in these patients (notably esophageal disease, bone marrow involvement, cardiac disease, and pulmonary hypertension [PH]), the association with preformed anti-HLA antibodies, the difficulty in distinguishing posttransplant rejection from severe flares of CTDs and concerns about long-term outcome in this group of patients.[2],[3],[4] Several carefully selected cohorts show excellent outcomes and we review the relevant literature addressing these concerns.

  Connective Tissue Diseases and Associated Pulmonary Syndromes Top

Five major CTDs, namely systemic lupus erythematosus, systemic sclerosis (SSc), inflammatory myositis, RA, and Sjogren's syndrome,[5],[6],[7],[8],[9] can all have associated ILD. In addition, ILD can be associated with overlap syndromes like mixed connective tissue disorder, as well as with UCTD. Further, a significant proportion of patients with ILD manifest some autoimmune features but do not fulfill the criteria for a definitive CTD and are referred to as Interstitial Pneumonia with Autoimmune Features.[10] The pulmonary vasculitis syndromes are diseases characterized by primary damage to the small blood vessels in the pulmonary tree and are included here because the concerns about LT for pulmonary vasculitis are similar to those with the CTD syndromes. A wide variety of pleuropulmonary manifestations have been reported with the CTD syndromes. These manifestations may lead to respiratory failure, necessitating evaluation for LT. Some of the features associated with CTDs may also impact transplant candidacy or are contraindications to LT, e.g., shrinking lung syndrome.[11],[12],[13],[14],[15]

  Extrapulmonary Conditions Associated with Connective Tissue Diseases Relevant to Lung Transplantation Top

The CTD syndromes have characteristic but variable extrapulmonary manifestations. Several of these are absolute contraindications to LT or place prospective lung transplant recipients at substantially higher risk after LT. Specific attention is paid to cardiac involvement, right ventricular function, and PH in SSc-ILD. PH in SSc-ILD can be due to pulmonary arterial hypertension (Group 1), extensive interstitial lung disease and sleep apnea (Group 3), left heart disease or diastolic dysfunction (Group 2), pulmonary thromboembolism (Group 4), or venous-occlusive disease. Phenotyping before LT is important for management in the perioperative period.

  Listing Criteria and Contraindications to Lung Transplantation in General Top

The indications for referral and listing for LT are usually related to interstitial lung disease and PH related to the CTD syndrome. The usual listing criteria for both these indications are summarized in [Table 1]. There are several absolute contraindications to LT as well as factors that place recipients at substantially high-risk posttransplantation; these have been summarized in [Table 2]. Severe esophageal dysmotility, kidney disease with glomerular filtration rate <60 mL/min, bone marrow involvement due to disease or therapy, coronary artery disease related to accelerated atherosclerosis, and severe PH are of particular relevance to patients with CTDs.[16]
Table 1: Criteria for listing for lung transplant in interstitial lung disease and pulmonary hypertension (International Society for Heart and Lung Transplantation 2021 consensus)

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Table 2: Risk factors for poor posttransplant outcomes

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  Candidate Evaluation for Lung Transplantation in Connective Tissue Diseases Top

The evaluation for LT in a patient with CTD proceeds as in any patient for LT; in addition, careful attention is paid to the extrapulmonary manifestations that are of relevance to a patient undergoing transplantation by focused investigations [Table 3]. The specific contraindications or risk factors for poor outcomes in patients with individual CTDs in addition to factors previously listed in [Table 2] are summarized in [Table 4]. In patients with scleroderma, discussion on the expected period of nil per oral after transplant and the use of postpyloric feeds should occur before listing.[2]
Table 3: Specific evaluation of patients with connective tissue disease during transplant evaluation

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Table 4: Specific contraindications to lung transplantation relevant to connective tissue disease syndromes

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Connective tissue disease remission before transplant

The CTD must be in remission before the transplant. This requires coordination between the transplant team and the rheumatologist. Rarely, LT evaluation is undertaken in the setting of recent life-threatening activity like severe lupus pneumonitis or anti-MDA5 syndrome.

Surgical and anesthesia-related challenges

Transplant procedure

Bilateral LT (BLT) is usually the procedure of choice given the younger age and PH in patients with CTD. Patients with severe structural or cardiac functional abnormalities or dysfunction, not likely to improve with normalization of pulmonary pressures, in conjunction with intrinsic lung disease or severe PH, are considered for heart-lung transplant. This decision must be balanced with the likelihood of recovery of right ventricle failure (RV) after BLT in the absence of objective assessment of infarcts or fibrotic changes of the RV.


Patients with right ventricular dysfunction related to PH may need bridging with venoarterial-extracorporeal membrane oxygenation (VA-ECMO), while interstitial lung disease alone can be bridged with venovenous-ECMO (VV-ECMO).

Anaesthesia and intra-operative hemodynamic support and monitoring

Difficult airway and intubation-related cervical subluxation can occur in patients with microstomia and RA respectively, and awareness reduces these complications. Particular care during anesthesia induction in patients with PH is essential to prevent hemodynamic collapse. In this case, awake VA-ECMO provides preoperative cardiovascular support, avoids cardiac arrest related to induction, and is a useful adjunct for continued intraoperative and postoperative support. The goal includes avoiding increasing pulmonary vascular resistance, maintaining preload while avoiding fluid overload, reducing RV afterload, and reducing tachycardia. The use of a pulmonary artery catheter to monitor pressures and cardiac output is essential during surgery.

Patients with CTD-ILD have small chest cavities and PH, and intra-operative central VA-ECMO helps avoid hypotension during cardiac retraction. Transesophageal echocardiography guides the management of right ventricular function intraoperatively.

Patients with CTD are at higher risk of vascular access-related complications such as hematomas, pseudoaneurysms, fistulas, and limb ischemia. Use of ultrasound and restricting radial artery and subclavian access duration along with the use of topical nitroglycerin, warm gloves, blankets as adjuncts can potentially reduce complications. Avoiding vasopressors and optimizing fluid and cardiac function can help avoid extremity vessel and coronary artery spasm as complications.

  Intensive Care Challenges Top

Cardiac management

Cardiac dysfunction can be related to left ventricular diastolic dysfunction; SSc-related right ventricular dysfunction; PH-related post-LT left ventricular systolic dysfunction; tachyarrhythmias and constrictive pericarditis. There is an association between CTD-ILD and primary graft dysfunction (PGD); this is possibly confounded by the association of PH in CTD leading to PGD; optimizing other donor and recipient factors could potentially reduce PGD incidence.

The use of low tidal volume ventilation (6 mL/kg) and donor lung size-guided volume-based ventilation can also reduce PGD incidence. A conservative fluid strategy is preferred to avoid unfavorable right ventricular preload and flooding the allograft; low-dose vasopressors can help if hemodynamic support is required despite appropriate fluid resuscitation. Inhaled nitric oxide has favorable pulmonary vasodilator activity and is useful in the setting of persistent PH with reduced cardiac output. Severe right ventricular dysfunction requires VA-ECMO support postoperatively.


Patients with ILD retain rapid shallow breathing patterns in the early transplant period and patients whose work of breathing during spontaneous breathing is normal should be considered for a trial of extubation.

Acute kidney injury

Acute kidney injury is often a concern in patients with CTD because of renal involvement, especially in SSc-ILD. Scleroderma renal crises can occur in up to 5-10 percent of patients with SSc. Avoiding high dose steroids postoperatively, blood pressure management, and use of tacrolimus (over cyclosporine) can avoid renal injury in this setting. In other CTD patients, good hemodynamic management and aggressive management of infections prevent kidney injury.

Gastroesophageal reflux and gastroparesis

Multidisciplinary management of scleroderma with speech pathologists, gastroenterologists, nutritionists, pulmonologists, and surgeons is required to device a plan for these complex patients as there is no consensus on management of patients with esophageal dysmotility postoperatively. Keeping nil per oral, liberal use of prokinetics, attention to the texture of allowed enteral diet, and exclusive use of postpyloric tubes postoperatively till 3–6 months is recommended to avoid reflux, aspiration, and early allograft dysfunction. Patients with Sjogren's syndrome may require artificial saliva due to xerostomia and attention to oral candidiasis postoperatively.

pH manometry and gastric emptying are repeated 6–12 weeks postoperatively. In patients with severe gastroparesis postoperatively, prokinetics agents and antiemetics are the first-line treatment. In patients with refractory symptoms, placement of a venting gastrostomy-jejunostomy tube allows patients to maintain good nutrition. Gastric electrical stimulation and postpyloric botulinum toxin-A injection have been reported in refractory cases. A surgical fundoplication is an option in patients who are clinically stable about 3 months from their transplantation with refractory gastroparesis.

  Survival and Outcomes of Patients with Connective Tissue Diseases after Lung Transplantation Top

Small single-center series of carefully selected patients with SSc-ILD show similar outcomes with no difference in rates of acute rejection or long-term survival [Table 5]. The data on other CTDs are smaller but promising.[27]
Table 5: Studies evaluating lung transplantation in scleroderma

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  Conclusion Top

Lung transplant has emerged as an option in patients with advanced pulmonary involvement as a result of CTDs. The nonpulmonary manifestations pose a significant challenge in the success of transplant in patients with CTD-related pulmonary disease. A thorough evaluation and selection of the right transplant candidates are important determinants of the success of the procedure.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Khush KK, Cherikh WS, Chambers DC, Harhay MO, Hayes D Jr., Hsich E, et al. The international thoracic organ transplant registry of the international society for heart and lung transplantation: Thirty-sixth adult heart transplantation report-2019; focus theme: Donor and recipient size match. J Heart Lung Transplant 2019;38:1056-66.  Back to cited text no. 1
Crespo MM, Lease ED, Sole A, Sandorfi N, Snyder LD, Berry GJ, et al. ISHLT consensus document on lung transplantation in patients with connective tissue disease: Part I: Epidemiology, assessment of extrapulmonary conditions, candidate evaluation, selection criteria, and pathology statements. J Heart Lung Transplant 2021;40:1251-66.  Back to cited text no. 2
Bermudez CA, Crespo MM, Shlobin OA, Cantu E, Mazurek JA, Levine D, et al. ISHLT consensus document on lung transplantation in patients with connective tissue disease: Part II: Cardiac, surgical, perioperative, operative, and post-operative challenges and management statements. J Heart Lung Transplant 2021;40:1267-78.  Back to cited text no. 3
Crespo MM, Claridge T, Domsic RT, Hartwig M, Kukreja J, Stratton K, et al. ISHLT consensus document on lung transplantation in patients with connective tissue disease: Part III: Pharmacology, medical and surgical management of post-transplant extrapulmonary conditions statements. J Heart Lung Transplant 2021;40:1279-300.  Back to cited text no. 4
Lundberg IE, Tjärnlund A, Bottai M, Werth VP, Pilkington C, de Visser M, et al. 2017 European League Against Rheumatism/American College of Rheumatology classification criteria for adult and juvenile idiopathic inflammatory myopathies and their major subgroups. Arthritis Rheumatol 2017;69:2271-82.  Back to cited text no. 5
Shiboski CH, Shiboski SC, Seror R, Criswell LA, Labetoulle M, Lietman TM, et al. 2016 American College of Rheumatology/European League Against Rheumatism classification criteria for primary Sjögren's syndrome: A consensus and data-driven methodology involving three international patient cohorts. Arthritis Rheumatol 2017;69:35-45.  Back to cited text no. 6
van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, et al. 2013 classification criteria for systemic sclerosis: An American College of Rheumatology/European League against Rheumatism collaborative initiative. Arthritis Rheum 2013;65:2737-47.  Back to cited text no. 7
Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd, et al. 2010 Rheumatoid arthritis classification criteria: An American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 2010;62:2569-81.  Back to cited text no. 8
Aringer M, Costenbader K, Daikh D, Brinks R, Mosca M, Ramsey-Goldman R, et al. 2019 European League Against Rheumatism/American College of Rheumatology classification criteria for systemic lupus erythematosus. Arthritis Rheumatol 2019;71:1400-12.  Back to cited text no. 9
Fischer A, Antoniou KM, Brown KK, Cadranel J, Corte TJ, du Bois RM, et al. An official European Respiratory Society/American Thoracic Society research statement: Interstitial pneumonia with autoimmune features. Eur Respir J 2015;46:976-87.  Back to cited text no. 10
Kokosi M, Lams B, Agarwal S. Systemic lupus erythematosus and Antiphospholipid antibody syndrome. Clin Chest Med 2019;40:519-29.  Back to cited text no. 11
Long K, Danoff SK. Interstitial lung disease in polymyositis and dermatomyositis. Clin Chest Med 2019;40:561-72.  Back to cited text no. 12
Esposito AJ, Chu SG, Madan R, Doyle TJ, Dellaripa PF. Thoracic manifestations of rheumatoid arthritis. Clin Chest Med 2019;40:545-60.  Back to cited text no. 13
Natalini JG, Johr C, Kreider M. Pulmonary involvement in Sjögren syndrome. Clin Chest Med 2019;40:531-44.  Back to cited text no. 14
Perelas A, Arrossi AV, Highland KB. Pulmonary manifestations of systemic sclerosis and mixed connective tissue disease. Clin Chest Med 2019;40:501-18.  Back to cited text no. 15
Leard LE, Holm AM, Valapour M, Glanville AR, Attawar S, Aversa M, et al. Consensus document for the selection of lung transplant candidates: An update from the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 2021;40:1349-79.  Back to cited text no. 16
Massad MG, Powell CR, Kpodonu J, Tshibaka C, Hanhan Z, Snow NJ. et al. Outcomes of lung transplantation in patients with scleroderma. World J Surg. 2005;29:1510-5.  Back to cited text no. 17
Schachna L, Medsger TA Jr, Dauber JH, Wigley FM, Braunstein NA, White B, et al. Lung transplantation in scleroderma compared with idiopathic pulmonary fibrosis and idiopathic pulmonary arterial hypertension. Arthritis Rheum. 2006;54:3954-61. doi: 10.1002/art.22264. PMID: 17133609.  Back to cited text no. 18
Saggar R, Khanna D, Furst DE, Belperio JA, Park GS, Weigt SS, et al. European Respiratory Journal 2010;36:893-900; DOI: 10.1183/09031936.00139809  Back to cited text no. 19
Sottile PD, Iturbe D, Katsumoto TR, Connolly MK, Collard HR, Leard LA, et al. Outcomes in systemic sclerosis-related lung disease after lung transplantation. Transplantation. 2013;95:975-80.  Back to cited text no. 20
Launay D, Savale L, Berezne A, Le Pavec J, Hachulla E, Mouthon L, et al. Working Group on Heart/Lung transplantation in systemic sclerosis of the French Network on Pulmonary Hypertension. Lung and heart-lung transplantation for systemic sclerosis patients. A monocentric experience of 13 patients, review of the literature and position paper of a multidisciplinary Working Group. Presse Med. 2014;43:e345-63.  Back to cited text no. 21
Bernstein EJ, Peterson ER, Sell JL, D'Ovidio F, Arcasoy SM, Bathon JM et al. Survival of adults with systemic sclerosis following lung transplantation: a nationwide cohort study. Arthritis Rheumatol. 2015;67:1314-22.  Back to cited text no. 22
Crespo MM, Bermudez CA, Dew MA, Johnson BA, George MP, Bhama J et al. Lung Transplant in Patients with Scleroderma Compared with Pulmonary Fibrosis. Short- and Long-Term Outcomes. Ann Am Thorac Soc. 2016;13:784-92.  Back to cited text no. 23
Miele CH, Schwab K, Saggar R, Duffy E, Elashoff D, Tseng CH et al. Lung Transplant Outcomes in Systemic Sclerosis with Significant Esophageal Dysfunction. A Comprehensive Single-Center Experience. Ann Am Thorac Soc. 2016;13:793-802.  Back to cited text no. 24
Pradère P, Tudorache I, Magnusson J, Savale L, Brugiere O, Douvry B et al. Working Group on Heart/Lung Transplantation in Systemic Sclerosis. Lung transplantation for scleroderma lung disease: An international, multicenter, observational cohort study. J Heart Lung Transplant. 2018;37:903-11.  Back to cited text no. 25
Chan EY, Goodarzi A, Sinha N, Nguyen DT, Youssef JG, Suarez EE, et al. Long-Term Survival in Bilateral Lung Transplantation for Scleroderma-Related Lung Disease. Ann Thorac Surg. 2018;105:893-900.  Back to cited text no. 26
Courtwright AM, El-Chemaly S, Dellaripa PF, Goldberg HJ. Survival and outcomes after lung transplantation for non-scleroderma connective tissue-related interstitial lung disease. J Heart Lung Transplant. 2017;36:763-9.  Back to cited text no. 27


  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]


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