Patients with connective tissue disease (CTD) and advanced lung disease are often considered suboptimal candidates for lung transplantation (LTx) due to their underlying medical complexity and potential surgical risk. There is substantial variability across LTx centers regarding the evaluation and listing of these patients. The International Society for Heart and Lung Transplantation-supported consensus document on lung transplantation in patients with CTD standardization aims to clarify definitions of each disease state included under the term CTD, to describe the extrapulmonary manifestations of each disease requiring consideration before transplantation, and to outline the absolute contraindications to transplantation allowing risk stratification during the evaluation and selection of candidates for LTx.
Keywords
According to the 2019 International Society for Heart and Lung Transplantation (ISHLT) Registry report, the proportion of lung transplants performed in patients with end-stage lung disease related to connective tissue disease (CTD) is small (0.9%).
1
Among lung transplant (LTx) recipients with CTD, rheumatoid arthritis (RA)-lung disease is the most common (28.71%), followed by undifferentiated CTD (21.36%). Whether LTx is an acceptable treatment option for patients with CTD can be controversial due to medical and surgical risks. Particular concerns pertain to the potential risk for aspiration due to esophageal dysmotility, gastroesophageal reflux (GERD), and an association between the upper gastrointestinal (GI) pathology and an increased risk for early chronic lung allograft dysfunction (CLAD).- Chambers DC
- Cherikh WS
- Harthay MO
- et al.
The international thoracic organ transplant registry of the international society for Heart and Lung Transplantation: Thirthy-sixth adult lung and heart-lung transplantation report-20019; focus theme: donor and recipient size match.
J Heart Lung Transplant. 2019; 38: 1042-1055
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The 2014 ISHLT consensus document for the selection of LTx candidates suggests that patients with CTD can be acceptable candidates if there are no extrapulmonary contraindications for transplantation,3
however there is substantial variability between LTx centers regarding the evaluation and listing of these patients.The goals of this consensus paper are to clarify definitions of each disease state included under the term CTD, to describe the extrapulmonary manifestations of each disease requiring consideration prior to transplantation, and to outline the absolute contraindications to transplantation as determined by a Delphi consensus methodology.
4
The purpose of this effort is to allow for risk stratification during the evaluation and selection of candidates for LTx and heart-lung transplantation (HLTx). For this document, we classified disease states under the term of CTD as either:- •Systemic sclerosis (SSc)
- •Sjögren's syndrome (SS)
- •Rheumatoid arthritis (RA)
- •Systemic lupus erythematosus (SLE)
- •Inflammatory myopathies (polymyositis (PM), dermatomyositis (DM), and antisynthetase syndrome)
- •Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), including granulomatosis with polyangiitis (GPA), eosinophilic granulomatosis with polyangiitis (EGPA/Churg-Strauss syndrome) and microscopic polyangiitis (MPA)
- •Mixed connective tissue disease (MCTD) and overlap syndromes
Methodology
In 2019, an expert Writing Committee was convened by the ISHLT with the aim to develop a consensus recommendations focusing on specific recommendations for LTx and heart-lung transplant (HLTx) in patients with CTD. After an open invitation to ISHLT members, an international workgroup was created. This consensus represents a collaborative effort from international experts in the specialties of Pulmonary, Pulmonary Hypertension, Pharmacy, Pathology, Nursing and Allied Health, and Rheumatology.
The Writing Committee was divided into 12 subgroups covering the following topics: (1) connective tissue disorders including definitions of disease states, extrapulmonary conditions, LTx evaluation, and contraindications for LTx, (2) CTD -related pulmonary hypertension and cardiomyopathy, (3) surgical management and unique challenges in patients with CTD, (4) Anesthetia considerations in the CTD population, (5) intensive care unit challenges and management in CTD transplant recipients, (6) pharmacology therapy of CTD: pre- and post-transplant, (7) surgical management of esophageal disorders in CTD transplant recipients, (8) post-transplant management of CTD transplant recipients, and (9) pathology of CTD as it pertains to LTx and HLTx. A comprehensive literature search and review was performed for each topic to answer the identified questions based on the published evidence and to provide guidance based on prevailing expert knowledge and experience. This consensus was divided in three parts to provide a comprehensive review of the salient topics within cardiothoracic transplantation of patients with CTD. Part I which is discussed here reviews the epidemiology, extrapulmonary conditions, pathology, candidate evaluation, and selection criteria considerations for transplantation for each CTD.
Recommendations regarding evaluation, testing, and absolute contraindications for transplantation were made based on voting by the members of the workforce. The strength of the workforce agreement was based on a Delphi method voting.
4
The voting range for each participant was from 0 to 9, with 0 as no agreement with the statement and 8 to 9 as high agreement. A consensus agreement was considered to be present when ≥80% of workforce members voted 8 or higher. The percentage of responders was also recorded. Based on poor agreement results for the proposed absolute contraindications in the first survey, a second-round survey was sent using the responder's comments from round I to modify the statements for the round II survey. Of note, only nurses, pulmonologists, and surgeons who were directly involved in the LTx and HLTx clinical evaluation and selection were asked to respond to this second-round survey. For each statement on the round II survey, the agreement was also calculated as the percentage of respondents who endorsed at a level 8 or higher.Connective tissue diseases: Assesment of extrapulmonary conditions, specific recommendations for lung transplant evaluation, and agreement strength
The involvement of a multidisciplinary team in the evaluation of these complex patients is strongly advised. Rheumatology evaluation is recommended to confirm disease diagnosis, assess disease activity, and evaluate for active extra-pulmonary disease. The workgroup's LTx evaluation recommendations specific for each CTD and the agreement strength are summarized below in Table 1, Table 2, Table 3, Table 4, Table 5, Table 6.
Table 1Extrapulmonary Manifestations and Transplant Evaluation Specific to Systemic Sclerosis: Recommendations and Agreement Strength
| Extrapulmonary manifestations(references) | Specific transplant evaluation (Testing agreement strength = 87%) | |
|---|---|---|
| Cardiac 7 |
|
|
| VTE 8 , 9 , 10 , 11 |
|
|
| Renal: Scleroderma renal crisis (SRC) 12 , 13 , 14 , 15 |
|
|
| GI 16 ,17 |
|
|
| Vascular: Raynaud's phenomenon 18 |
|
|
Abbreviations: CT, computed tomography; GERD, gastroesophageal reflux disease; GI, gastrointestinal; LTx, lung transplant; MRI, magnetic resonance imaging; RP, raynaud's phenomenon; SRC, scleroderma renal crisis; SLP, speech and language pathologist; SSc, systemic sclerosis; VTE, venous thromboembolism.
a In those patients with a family or personal history of venous thromboembolism.
Systemic sclerosis
Systemic sclerosis (SSc) is a chronic autoimmune collagen vascular disease that often leads to life-threatening visceral involvement, including interstitial lung disease (ILD), cardiac disease, and renal disease.
5
,6
Patients with SSc can have extrapulmonary clinical manifestations which can negatively impact the patient's transplant candidacy as summarized in Table 1.Sjögren's syndrome
Sjögren's syndrome (SS) is a chronic multi-system autoimmune inflammatory exocrinopathy. Secondary Sjögren's syndrome may accompany other CTDs such as RA, SSc, SLE, and PM/DM. Lung involvement by SS is characterized by constrictive bronchiolitis and lymphoproliferative disease in approximately 9% to 20% of patients with primary SS (pSS).
20
SS patients have important extrapulmonary conditions that may be relevant in the evaluation and management of a potential LTx and HLTx candidate (Table 2).Table 2Extrapulmonary Manifestations and Transplant Evaluation Specific to Primary Sjögren's Syndrome: Recommendations and Agreement Strength
| Extrapulmonary manifestations(references) | Specific transplant evaluation (Testing agreement strength = 82%) | |
|---|---|---|
| Oncologic/Hematologic , 20 , 21 , 22 , 23 , 24 |
|
|
| Immunologic 25 , 26 , 27 |
|
|
| VTE 28 , 29 , 30 , 31 , 32 |
|
|
| GI 33 , 34 , 35 |
|
|
| Vasculitis: Dermatological 36 |
|
|
| Renal 37 , 38 , 39 |
|
|
Abbreviations: BCL, B-cell lymphoma; DVT, deep vein thrombosis; ESSDAI, sjögren's syndrome disease activity index; GERD, gastroesophageal reflux disease; GI, gastrointestinal; GMN, glomerulonephritis; HTN, hypertension; LTx, lung transplant; MALT, mucosa-associated lymphoid tissue; MGUS, monoclonal gammopathy of undetermined significance; MM, multiple myeloma; PE, pulmonary embolism; PET, positron emission tomography; pSS, primary sjögren's syndrome; RTA, renal tubular acidosis; SS, sjögren's syndrome; SLP, speech and language pathologist; SPEP, serum protein electrophoresis; TIN, tubulointerstitial nephritis; UA, urinalysis; UPEP, urine protein electrophoresis; VTE, venous thromboembolism.
a Risk factors for development of BCL in pSS are: recurrent swelling of parotid glands; splenomegaly, lymphadenopathy, or both; purpura; score of >5 on the ESSDAI, rheumatoid factor, cryoglobulinemia; low C4 level; CD4 T cell lymphocytopenia, presence of ectopic germinal centers, focus score >3, germinal mutations in TNFAIDP3. TNFAIP3= tumor necrosis factor alpha–induced protein 3.
b ESSDAI= Sjögren's Syndrome Disease Activity Index. Scores range from 0 to 123, with a score of 5-13 indicating moderate activity and a score of ≥ 14 indicating high activity.
c In those patients with a family or personal history of venous thromboembolism.
Rheumatoid arthritis
RA is the most common systemic autoimmune disease, with an overall prevalence of 0.5% to1%.
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Pulmonary manifestations of RA include ILD, airway disease, pleural disease, pulmonary vascular disease, and musculoskeletal involvement.41
,42
RA-lung disease is the second most common cause of death behind secondary cardiac disease.43
RA also has other non-pulmonary clinical organ involvement, which can be relevant for lung transplant candidacy and post-transplant management. These concerning extrapulmonary conditions are included in Table 3.Table 3Extrapulmonary Manifestations and Transplant Evaluation Specific to Rheumatoid Arthritis: Recommendations and Agreement Strength
| Extrapulmonary manifestations(references) | Specific transplant evaluation (Testing agreement strength = 81%) | |
|---|---|---|
| Upper airway 44 ,45 |
|
|
| MSK involvement 46 ,47 |
|
|
| Neurologic 48 ,49 |
|
|
Abbreviations: CT, computed tomography; LTx, lung transplant; MSK, musculoskeletal; MRI, magnetic resonance imaging; OHNS, otolaryngology head and neck surgery; RA, rheumatoid arthritis.
Systemic lupus erythematosus
Pulmonary involvement in SLE includes ILD, pleural disorders, pulmonary hypertension, and diaphragmatic disorders. Shrinking lung syndrome (SLS) is a rare manifestation of SLE that is typically seen in women. However, if present, this uncommon complication of SLE could have serious implications for lung transplant candidacy. It is manifested by an elevated hemidiaphragm with evidence of restrictive pulmonary function testing. These patients are typically not noted to have a radiographically evident pleural or parenchymal disease on imaging.
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, 51
, 52
Extrapulmonary conditions of SLE which can affect both LTx candidacy and post-transplant clinical outcomes are detailed in Table 4.Table 4Extrapulmonary Manifestations and Transplant Evaluation Specific for Systemic Lupus Erythematosus: Recommendations and Agreement Strength
| Extrapulmonary manifestations(references) | Specific transplant evaluation (Testing agreement strength = 82%) | |
|---|---|---|
| VTE 53 , 54 , 55 , 56 , 57 |
|
|
| Hematologic 58 , 59 , 60 , 61 , 62 , 63 |
|
|
| Neurologic and Psychiatric 64 ,65 |
|
|
| Renal 66 |
|
|
| Cardiac 67 , 68 , 69 |
|
|
Abbreviations: aPL, antiphospholipid antibodies; APS, antiphospholipid syndrome; CT, computed tomography; EEG, electroencephalography; MRI, magnetic resonance imaging; NPSLE, neuropsychiatric systemic lupus erythematosus; NCS, nerve conduction studies; SLE, systemic lupus erythematosus; SLS, shrinking lung syndrome.
Polymyositis, Dermatomyositis, and antisynthetase syndrome
There are four primary types of inflammatory myopathies (IM), but it is PM, DM, and a subset of these termed antisynthetase syndromes that are associated with ILD. Anti-synthetase syndrome has a much higher prevalence of ILD than the other IM, with ILD involvement in approximately 90% of cases.
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,- Lundberg IE
- Tjärnlund A
- Bottai M
- et al.
International Myositis Classification Criteria Project consortium, The Euromyositis register and The Juvenile Dermatomyositis Cohort Biomarker Study and Repository (JDRG) (UK and Ireland). 2017 European League Against Rheumatism/American College of Rheumatology classification criteria for adult and juvenile idiopathic inflammatory myopathies and their major subgroups.
Ann Rheum Dis. 2017; 76: 1955-1964
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The concerning extrapulmonary features of PM/DM which can be relevant during transplant candidate evaluation and listing are sumarized in Table 5.Table 5Extrapulmonary Manifestations and Transplant Evaluation Specific of Polymyositis/Dermatomyositis: Recommendations and Agreement Strength
| Extrapulmonary manifestations(references) | Specific transplant evaluation (Testing agreement strength = 92%) | |
|---|---|---|
| Oncologic 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 |
|
|
| Cardiac 81 ,82 |
|
|
| GI 83 ,84 |
|
|
| MSK 85 ,86 |
|
|
Abbreviations: CAM, cancer associated myositis; CMRI, cardiac magnetic resonance imaging; CT, computed tomography; DM, dermatomyositis; GERD, gastroesophageal reflux disease; GI, gastrointestinal; MSK, musculoskeletal; NHL, non-Hodgkin's lymphoma ;PM, polymyositis; PET, positron emission tomography.
ANCA-Associated Vasculitis
ANCA-associated vasculitis (AAV) includes GPA, EGPA/Churg-Strauss syndrome, and MPA.
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, Vasculitides are often classified by the type (arteriole, venule, etc.) and size (small, medium, or large) of the vessel (s) involved. GPA is the most common vasculitis for which lung transplantation has been reported. However, the multi-organ involvement in GPA can increase the complexity of a lung transplant candidate, which in turn makes the optimal timing of referral hard to define. Patients with AAV can develop granulomatous airway inflammation. Subglotic stenosis, the most common airway complication of vasculitis, can be very severe and requires adequate management before transplantation. A single area of focal stenosis is usually treatable89
; however, multiple mass lesions, multiple areas of stenosis, or tracheobronchomalacia is more problematic.The concerning extrapulmonary features of vasculitis to consider during LTx evaluation and listing are include in Table 6.
Table 6Extrapulmonary Manifestations and Transplant Evaluation Specific to ANCA-Associated Vasculitis: Agreement Strength
| Extrapulmonary Manifestations(references) | Specific Transplant Evaluation (Testing agreement strength = 83%) | |
|---|---|---|
| Neurologic 90 ,91 |
|
|
| Renal 92 , 93 |
|
|
| Rheumatologic 94 , 95 , 96 , 97 , 98 |
|
|
| Upper and Lower Airway 92 ,99 |
|
|
Abbreviations: AAV, ANCA-associated vasculitis; ANCA, anti-neutrophil cytoplasmic antibody; CT, computed tomography; EGPA, eosinophilic granulomatosis with polyangiitis; EMG, electromyography; GPA, Granulomatosis with polyangiitis; MPA, microscopic polyangiitis; MRI, magnetic resonance imaging; NCS, nerve conduction studies; OHNS, otorhinolaryngology surgery; PET, positron emission tomography.
Mixed connective tissue disease
The definitive diagnosis of mixed connective tissue disease (MCTD) is often complicated because the characteristic overlapping features of SLE, SSc, RA, and IM, found in association with high titers of anti-U1 ribonucleoprotein (RNP) antibody, tend to occur sequentially. The extrapulmonary clinical manifestations in patients with CTD relevant for LTx evaluation and selection are primarily associated with the dominant disease of the overlapping CTD.
Survival and prognosis of patients with CTD after lung transplantation
Lung transplant (LTx) outcomes in patients with CTD have been reported in several case series. Transplant centers in both US and Europe have consistently reported that outcomes in patients undergoing LTx for SSc are comparable to those in patients transplanted for other ILD.
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, 101
, 102
, 103
, 104
Despite the high frequency of severe esophageal dysmotility and GERD, patients with SSc do not appear to be at an increased risk for CLAD compared with other patients with ILD. Severe pulmonary arterial hypertension (PAH) and high body mass index (BMI) are high-risk factors for poor LTx survival in SSc.102
Small, retrospective studies have shown that patients with RA have comparable short and long-term LTx outcomes compared with patients with other non-RA ILD.
105
,106
Few centers have reported the experience of LTx for SLE-associated pulmonary disease. Positive outcomes have been reported for a cohort of 6 patients transplanted for SLE-ILD or SLE-PAH with 3-year survival of 83% and no development of extra-pulmonary complications of SLE over a median follow up of 4-years.
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In a larger, scientific registry of transplant recipients (SRTR)- based study of 275 patients who underwent LTx for non-scleroderma CTD, including 24 patients with SLE, there were no differences in survival, the occurrence of acute rejection, CLAD, or extrapulmonary organ dysfunction compared with a cohort of 6,346 patients transplanted for idiopathic pulmonary fibrosis (IPF).106
Knowledge of LTx outcomes in patients with PM/DM is limited to a few case reports and retrospective review studies. The most extensive data available describes patients from the Organ Procurement Transplantation Network (OPTN) database, who underwent LTx between May 2005 and Sep 2016. Similar 30-day, 1-, and 5-year survival was found in PM/DM patients as compared to those transplanted for IPF.
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Very few case reports exist regarding LTx in patients with vasculitis. Published rates of vasculitis relapse following solid organ transplantation are highly variable, with only very few studies available on relapse after LTx. In a case report, a LTx recipient remained relapse-free for 1450 days post-transplant but required treatment with cyclophosphamide and rituximab in addition to post-transplant immunosuppression.
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Contraindications for lung and heart-lung transplantation in patients with CTD
Data regarding specific predictors of prognosis after cardiothoracic transplantation in CTD are limited. The consensus group recognizes that the paucity of evidence precludes any strong conclusions about LTx and HLTx contraindications in patients with CTD. A consensus agreement on absolute contraindication was considered to be present when ≥80% of workforce members voted 8 or higher. The relative contraindications were considered when no absolute contraindication agreement was present. While listing absolute and relative contraindications for lung transplantation, the group acknowledges that the willingness to accept any risk may vary between centers, depending on the center's expertise and the local need to ration the limited organ supply. The absolute and relative contraindications specific for each CTD and the agreement strength of the voting survey's questionaries are summarized below in Table 7, Table 8, Table 9, Table 10, Table 11, Table 12.
Table 7Contraindications for Lung Transplant Specific to SSc: Absolute Agreement Strength
| Absolute Agreement strength (≥80%) | Relative | ||
|---|---|---|---|
| Rheumatologic |
| Renal |
|
| Gastrointestinal |
| Gastrointestinal |
|
| Cardiac |
| Vascular |
|
Abbreviations: CT, computed tomography; CrCl, creatinine clearance; DCI, Distal Contractile Integral; GERD, gastroesophageal reflux; NPO, nil per os; SSc, systemic sclerosis.
Table 8Contraindications for Lung Transplant Specific to SS: Absolute Agreement Strength
| Absolute agreement strength (≥80%) | Relative | ||
|---|---|---|---|
| Gastrointestinal |
| Rheumatologic |
|
| Hematologic |
| Hematologic/oncologic |
|
Abbreviations: BCL, B-cell lymphoma; MALT, mucosa-associated lymphoid tissue; MGUS, monoclonal gammopathy of undetermined significance; SS, Sjögren's syndrome.
Table 9Contraindications for Lung Transplant Specific to RA: Absolute Agreement Strength
| Absolute Agreement strength (≥80%) | Relative | ||
|---|---|---|---|
| Musculoskeletal/ Neurologic |
| Musculoskeletal/ Neurologic |
|
| Rheumatologic |
| ||
Table 10Contraindications for Lung Transplant Specific to SLE: Absolute Agreement Strength
| Absolute Agreement strength (≥80%) | Relative | ||
|---|---|---|---|
| Rheumatologic |
| Hematologic |
|
| Renal |
| Renal |
|
| Cardiac |
| ||
| Neurologic/ Pshychiatric |
| ||
| Musculoskeletal/Respiratory muscle |
| Musculoskeletal/ Respiratory muscle |
|
Abbreviations: CrCl= creatinine clearance; SLE, systemic lupus erythematosus.
Table 11Contraindications for Lung Transplant Specific to PM/DM: Absolute Agreement Strength
| Absolute Agreement strength (≥80%) | Relative | ||
|---|---|---|---|
| Rheumatologic |
| Hematologic/Oncologic |
|
| Gastrointestinal |
| ||
| Cardiac |
| ||
| Musculoskeletal/ Respiratory muscle |
| Musculoskeletal/ Respiratory muscle |
|
Abbreviations: DM, dermatomyositis; PAS, Penetration Aspiration Scale; PM, polymyosytis.
Table 12Contraindications for Lung Transplant Specific to Vasculitis: Absolute Agreement Strength
| Absolute Agreement strength (≥80%) | Relative | ||
|---|---|---|---|
| Rheumatologic |
| Rheumatologic |
|
| Airway |
| Renal |
|
| Neurologic |
| Neurologic |
|
Abbreviations: ANCA, anti-neutrophil cytoplasmic antibody; CrCl, creatinine clearance; EGPA, eosinophilic granulomatosis with polyangiitis; GPA, Granulomatosis with polyangiitis; Hx, history; MPA, microscopic polyangiitis.
Summary and recommendations on lung transplantation in patients with CTD
Lung transplantation should be considered for CTD patients with advanced lung disease whose clinical status has progressively declined despite maximal medical therapy. Ideally, the candidate should be free of any other organ dysfunction or medical problem that would substantially jeopardize the outcome of transplantation. Early referral to a transplant center is recommended due to the medical complexity inherent to this particular patient population and to determine the potential risk and benefits of LTx. An earlier evaluation may identify modifiable risk factors that would influence a patient's candidacy for transplantation or their survival after lung transplantation.
SSc Recipient pulmonary phenotype proposal: Discussion and recommendations
Based on the extent of ILD and hemodynamic profiles, distinct SSc pulmonary phenotypes can be identified (Figure 1). Understanding outcomes as they relate to phenotypes may help understand outcomes. Goh and colleagues developed a staging system of SSc-associated ILD based on HRCT of the chest that defines ILD as “limited” (<20% of lung area) or “extensive” (≥20% of lung area).
6
The 20% cutoff to classify ILD into categories has been associated with mortality differences in patients with SSc.6
Pulmonary hypertension (PH) in SSc is often multifactorial as both pre and postcapillary PH may be present in an individual patient.6
,110
,- Hinchcliff M
- Fisher A
- Schiopu E
- et al.
Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma (PHAROS): baseline characteristics and description of study population. Pulmonary complications including pulmonary hypertension (PH) and interstitial lung disease (ILD) are leading causes of mortality in systemic sclerosis/scleroderma (SSc).
J Rheumatol. 2011; 38: 2172-2179
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Combined ILD and PH in SSc have been associated with greater mortality compared to ILD or PAH alone.101
, 102
, 103
, 104
, 105
, 106
, 107
, 108
, 109
, 110
, - Hinchcliff M
- Fisher A
- Schiopu E
- et al.
Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma (PHAROS): baseline characteristics and description of study population. Pulmonary complications including pulmonary hypertension (PH) and interstitial lung disease (ILD) are leading causes of mortality in systemic sclerosis/scleroderma (SSc).
J Rheumatol. 2011; 38: 2172-2179
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, 112
, 113
, 114
, 115
, 116
Figure 1Systemic Sclerosis (SSc) pulmonary phenotypes: Extent of interstitial lung disease (ILD) and hemodynamic Porfiles.
Recommendation: The working group proposes the following classification of pulmonary phenotypes in LTx and HLTx candidates with SSc as predominant ILD, predominant PAH, and combined ILD and PH (Table 13). Classifying SSc in pulmonary phenotypes as proposed above may allow better risk stratification of candidates for LTx. As more information about the association in SSc of ILD and PH with mortality emerges, the cutoff points of these criteria may be updated.
Table 13Classification of SSc Pulmonary Phenotypes in Lung Transplant Candidates : Proposal
| Predominant ILD | Combined ILD-PH | Predominant PAH | |
|---|---|---|---|
| ILD extent on HRCT | ≤20% | >20% | ≤20% |
| Hemodynamic Profile | mPAP≤ 20 mmHg PVR < 3 WU PAWP≤15 | mPAP >20 mmHg PVR ≥ 3 WU PAWP ≤15 | mPAP > 20 mmHg PVR ≥ 3 WU PAWP≤15 |
Abbreviations: HRCT, high resolution computed tomography; ILD, interstitial lung disease; mPAP, mean pulmonary artery pressure; PH, pulmonary hypertension; PAH, pulmonary arterial hypertension; PAWP, pulmonary artery wedge pressure; WU, wood units.
a when indeterminate, ILD predominance determined by forced vital capacity (FVC).
The team agreement strength voting on the proposed SSc pulmonary phenotypes groups was 91.83%.
Histopathological aspects of connective tissue disease
Although there has been increasing awareness of the pulmonary manifestations of CTD over the last several decades, specific histopathological features have yet to be established that provide diagnostic criterion of any of the rheumatologic disorders in the absence of clinical or serological findings. The histopathological findings can include one or more patterns: interstitial, airway, pleural and/or vascular alterations.
Explanted specimens, though limited, provide a unique opportunity to study this complicated ILD pathology and to correlate the pathology with imaging studies and the clinical course of a particular disease. With this, a clearer picture of how morphology may predict or correlate with the clinical course becomes feasible. Further, given the histopathologic overlap of pulmonary manifestations of many connective tissue diseases with both acute cellular rejection (i.e., lymphocytic inflammation) and antibody-mediated rejection (AMR) (i.e., capillaritis, organizing pneumonia pattern with neutrophils) and obliterative bronchiolitis in the transplanted lung, an understanding of the patient's CTD may be helpful in the evolution of the patient's post-transplant course for evidence of acute cellular rejection, antibody-mediated rejection and/or for possible disease recurrence in the transplanted lung. The recommendations for standardization of pathology protocol of explanted lungs and transbronchial biopsies (TBBx) from CTD recipients are summarized in Table 14.
Table 14Pathology Standardization Protocol of Explanted Lungs and TBBx from CTD Recipients: Recommendations
| Lung Explanted Tissue Preparation | Fresh unfixed sample Fresh tissue blocks Snap frozen for molecular analysis Samples should include areas with both heavily involved and less involved pathology |
| Fixation of Explanted Tissue | Infuse fresh explanted lung through the airways with 10 to 15% buffered formalin at physiologic pressures Fix for a minimum of 3 hours |
| Macroscope Evaluation/Preparation | Evaluate lung parenchyma for nodules/masses, cavities, fibrosis, vascular disease (thrombosis, hemorrhage), airway diseases (bronchiectasis, obliterative/constrictive bronchiolitis), and pleuritis. Follow institutional protocols, we suggest cutting explant into 2 segments along sagittal plane parallel to hilus, photograph and then sequentially at 0.5 to 1.0 cm intervals along axial plane to permit correlation with CT images. |
| Unique Microscopic Features in CTD Explants or TBBx from Recipients with CTD | Presence of vasculitis and/or pulmonary hypertensive vasculopathology: • Elastic stains may be helpful Presence of hemosiderin: • Prussian blue or other iron stains may be helpful Presence of foreign material or a giant cell reaction as a manifestation of aspiration: • Bile acid stains remain controversial • Oil red O stain may highlight aspirated fat vacuoles Pediatric population consider BAL staining |
Abbreviations: CTD, connective tissue disease; TBBx, transbronchial biopsies.
In summary, this protocol proposes a framework for tissue procurement/preservation and sampling to enhance pathological reliability in diagnosis and classification, in the evaluation of pretransplant treatment protocols, and research opportunities in pulmonary manifestation in CTD.
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Disclosure statement
No specific funding was available for this project. Each workforce member disclosure their conflict of interest. The funding sources for each workforce member had no role in study design, data collection, data analysis, or writing of the report.
The author thanks Mrs Megan Barrett for providing administrative support and for helping with the preparation and distribution of the surveys used for this project.
The authors also thank the expert reviewers Dr. Jason Christie, Dr. Joseph Pilewski, and Dr. Paul Corris for their input.
References
- The international thoracic organ transplant registry of the international society for Heart and Lung Transplantation: Thirthy-sixth adult lung and heart-lung transplantation report-20019; focus theme: donor and recipient size match.J Heart Lung Transplant. 2019; 38: 1042-1055
- Impaired esophageal motilitity and clearance post-lung transplant; risk for chronic allograft failure.Clin Transl Gastroenterol. 2017; 8: e102
- A consensus document for the selection of lung transplant candidates: 2014-An update from the Pulmonary Transplantation Council of the International Society for Heart and Lung Transplantation.J Heart Lung Transplant. 2015; 34: 1-15
- An exploration of the use of simple statistics to measure consensus and stability in Delphi studies.BMC Med Res Methodol. 2007; 7: 52
- 2013 classification criteria for systemic sclerosis: An American College of Rheumatology/European League against Rheumatism collaborative initiative.Arthritis Rheum. 2013; 65: 2737-2747
- Interstitial lung disease in systemic sclerosis: a simple staging system.Am J Respir Crit Care Med. 2008; 177: 1248-1254
- Heart involvement in systemic sclerosis: evolving concept and diagnostic methodologies.Arch Cardiovas Dis. 2010; 103: 46-52
- Risk of Pulmonary Embolism and Deep Venous Thrombosis in Systemic Sclerosis: a General Population-Based Study.Arthritis Care Res (Hoboken). 2016; 68: 246-253
- Systemic sclerosis and risk of venous thromboembolism: a systematic review and meta-analysis.Mod Rheumatol. 2015; 25: 893-897
- Systemic sclerosis increases the risk of deep vein thrombosis and pulmonary thromboembolism: a nationwide cohort study.Rheumatology (Oxford). 2014; 53: 1639-1645
- Antiphospholipid antibodies in patients with scleroderma: prevalence and clinical significance.Ann Rheum Dis. 2005; 64: 1795-1796
- Diagnosis, management and prevention of scleroderma renal disease.Curr Opin Rheumatol. 2008; 20: 692-696
- Kidney disease other than renal crisis in patients with diffuse scleroderma.J Rheumatol. 2005; 32: 649-655
- Scleroderma renal crisis.Semin Arthritis Rheumat. 2015; 44: 687-694
- Acute renal failure occurring in scleroderma patients treated with cyclosporine A: a report of three cases.Br J Rheumatol. 1994; 33: 90-92
- Systemic sclerosis gastrointestinal disease and its management.Rheum Dis Clin North Am. 2015; 41: 457-459
- The role of impaired esophageal and gastric motility in end-stage lung diseases and after lung transplantation.J Surg Res. 2014; 186: 201-206
- Raynaud's phenomenon and digital ischemia: a practical approach to risk stratification, diagnosis and management.Int J Clin Rheumatol. 2010; 5: 355-370
- Primary Sjögren's syndrome.N Engl J Med. 2018; 379: 97
- 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.Ann Rheum Dis. 2017; 76: 9-16
- Rate, risk factors and causes of mortality in patients with Sjogren's syndrome: a systematic review and meta-analysis of cohort studies.Rheumatology (Oxford). 2016; 55: 450-460
- Sjögren syndrome: an update on disease pathogenesis, clinical manifestations and treatment.Clin Immunol. 2019; 203: 81-121
- Primary Sjögren syndrome hematologic patterns of disease expression.Medicine (Baltimore). 2002; 81: 281-292
- Hematologic manifestations of primary Sjögren's syndrome.Clin Exp Rheumatol. 2006; 24: 438-448
- Hematologic manifestation and predictors of lymphoma development in primary Sjögren syndrome: clinical and pathophysiologic aspects.Medicine (Baltimore). 2009; 88: 284-293
- Effect of hypogammaglobulinemia after lung transplantation: a single-institution study.Eur J Cardiothorac Surg. 2014; 45: e61-e67
- Bronchiolitis obliterans syndrome, hypogammaglobulinemia, and infectious complications of lung transplantation.J Heart Lung Transplant. 2013; 32: 36-43
- The risk of deep venous thrombosis and pulmonary embolism in primary Sjögren syndrome: a general population-based study.J Rheumatol. 2017; 44: 1184-1189
- Increase risk of deep vein thrombosis and pulmonary embolism in Sjögren syndrome: a nationwide cohort study.J Rheumatol. 2014; 41: 909-915
- Risk of pulmonary embolism in patients with autoimmune disorders: a nationwuide follow-up study from Sweden.Lancet. 2012; 379: 244-249
- Risk of venous thromboembolism in people admitted to hospital with selected immune-mediated diseases: records Linkage Study.BMC Med. 2011; 9: 1
- Autoimmune skin and connective tissue diseases and risk of venous thromboembolism: a population-based case-control study.J Thromb Haemost. 2012; 10: 815-821
- Esophageal function and Sjögren's syndrome.Dig Dis Sci. 2004; 49: 248-253
- Gastrointestinal and hepatic manifestations of Sjögren syndrome.J Clin Gastroenterol. 2012; 46: 25-30
- Patterns of autoimmunity in primary biliary cirrhosis patients and their families: a population based cohort study.QJM. 2004; 97: 397-406
- Cutaneous vasculitis in primary Sjögren syndrome: classification and clinical significance of 52 patients.Medicine (Baltimore). 2004; 83: 96-106
- Renal involvement in primary Sjögren syndrome: a clinicopathologic study.Clin J Am Soc Nephrol. 2009; 4: 1423-1431
- Renal involvement and follow up of 130 patients with primary Sjögren syndrome.J Rheumatol. 2008; 35: 278-284
- Primary Sjögren syndrome in Spain: clinical and immunologic expression in 1010 patients.Medicine (Baltimore). 2008; 87: 210-219
- 2010 Rheumatoid arthritis classification criteria: An American College of Rheumatology/European League Against Rheumatism collaborative initiative.Arthritis Rheum. 2010; 62: 2569-2581
- Review series: Aspects of interstitial lung disease: connective tissue disease-associated interstitial lung disease: how does it differ from IPF? How should the clinical approach differ?.Chron Respir Dis. 2011; 8: 53-82
- Interstitial lung disease in recent onset rheumatoid arthritis.Am J Respir Crit Care Med. 1997; 156: 528-535
- Cardiovascular death in rheumatoid arthritis: a population-based study.Arthritis Rheum. 2005; 52: 722-732
- Laryngeal involvement in rheumatoid arthritis. A clinical, laryngoscopic, and computerized tomographic study.Arthritis Rheum. 1984; 27: 873-882
- Laryngeal involvement in rheumatoid arthritis.Brazilian J Otorhinolaryngology. 2013; 79: 233-238
- Survival and quality of life in rheumatoid arthritis-associated interstitial lung disease after lung transplantation.J Heart Lung Transplant. 2014; 33: 514-520
- Frequency of cervical spine involvement in rheumatoid arthritis.J Indian Med Assoc. 1995; 93: 138-139
- Survival and extrapulmonary course of connective tissue disease after lung transplantation.J Clin Rheumatol. 2012; 18: 283-289
- Prevalence and patterns of peripheral neuropathy in patient of rheumatoid arthritis.J Family Med Prim Care. 2019; 8: 22-26
- Pleuropulmonary manifestations of systemic lupus erythematosus.Thorax. 2000; 55: 159-166
- Pulmonary manifestations of systemic lupus erythematosus.Clin Chest Med. 2010; 31: 479-488
- Pulmonary manifestations of systemic lupus erythematosus.Semin Respir Crit Care. 2014; 35: 249-254
- The clinical significance of antiphospholipid antibodies in systemic lupus erythematosus.Eur J Rheumatol. 2016; 3: 75-84
- Determinants of risk for venous and arterial thrombosis in primary antiphospholipid syndrome and in antiphospholipid syndrome with systemic lupus erythematosus.J Rheumatol. 2009; 36: 1195-1199
- Severe vascular lesions and poor functional outcome in kidney transplant recipients with lupus anticoagulant antibodies.Am J Transplant. 2010; 10: 2051-2060
- Antiphospholipid antibody syndrome in renal transplantation: occurrence of clinical events in 96 consecutive patients with systemic lupus erythematosus.Am J Kidney Dis. 1999; 34: 1040-1047
- Morbidity and mortality in the antiphospholipid syndrome during a 10-year period: a multicenter prospective study of 1000 patients.Ann Rheum Dis. 2015; 74: 1011-1018
- Clinical assessment and management of cytopenias in lupus patients.Curr Rheumatol Rep. 2011; 13: 291-299
- Anaemia in systemic lupus erythematosus: aetiological profile and the role of erythropoietin.Ann Rheum Dis. 2000; 59: 217-222
- Bone marrow findings in systemic lupus erythematosus patients with peripheral cytopenias.Clin Rheumatol. 1998; 17: 219-222
- Autoimmune myelofibrosis: an update on morphologic features in 29 cases and review of the literature.Hum Pathol. 2014; 45: 2183-2191
- A rare cause of cytopenia in a patient with systemic lupus erythematosus: Autoimmune myelofibrosis.Eur J Rheumatol. 2017; 4: 76-78
- Thrombocytopenia in system lupus erythematosus: Clinical manifestations, treatment and prognosis in 230 patients.Medicine. 2016; 95: e 2818
- American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes.Arthritis Rheum. 1999; 42: 599-608
- Neuropsychiatric systemic lupus erythematosus.Curr Neuropharmacol. 2011; 9: 449-457
- American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis.Arthritis Care Res. (Hoboken). 2012; 64: 797-808
- Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham Study.Am J Epidemiol. 1997; 145: 408-415
- Premature coronary-artery atherosclerosis in systemic lupus erythematosus.N Engl J Med. 2003; 349: 2407-2415
- Cardiac pathology of systemic lupus erythematosus.J Clinic Pathol. 2009; 62: 584-592
- International Myositis Classification Criteria Project consortium, The Euromyositis register and The Juvenile Dermatomyositis Cohort Biomarker Study and Repository (JDRG) (UK and Ireland). 2017 European League Against Rheumatism/American College of Rheumatology classification criteria for adult and juvenile idiopathic inflammatory myopathies and their major subgroups.Ann Rheum Dis. 2017; 76: 1955-1964
- The diagnosis and treatment of antisynthetase syndrome.Clin Pulm Med. 2016; 23: 218-226
- Dermatomyositis and malignancy. A review of the literature.Ann Intern Med. 1976; 84: 68-76
- Polymyositis/dermatomyositis and malignancy risk: a metaanalysis study.J Rheumatol. 2015; 42: 282-291
- Risk of cancer in patients with dermatomyositis or polymyositis. A population-based study.N Engl J Med. 1992; 326: 363-367
- Ovarian cancer in patients with dermatomyositis.Medicine (Baltimore). 1994; 73: 153-160
- Frequency of specific cancer types in dermatomyositis and polymyositis: a population-based study.Lancet. 2001; 357: 96-100
- Predicting factors of malignancy in dermatomyositis and polymyositis: a case-control study.Br J Dermatol. 2001; 144: 825-831
- Cutaneous leukocytoclastic vasculitis in dermatomyositis suggests malignancy.Dermatology. 2001; 202: 123-126
- Factors predicting malignancy in patients with polymyositis and dermatomyositis: a systematic review and meta-analysis.PLoS One. 2014; 9: e94128
- Meta-analysis of the association of dermatomyositis and polymyositis with cancer.Br J Dermatol. 2013; 169: 838-847
- The heart in dermatomyositis and polymyositis.Rheumatology (Oxford). 2006; 45: iv18-iv21
- Cardiac involvement in adult polymyositis or dermatomyositis: a systemic review.Clin Cardiol. 2012; 35: 686-691
- Esophageal abnormalities and dysphagia in polymyositis and dermatomyositis.Arthritis Rheum. 1983; 26: 961-968
- Dysphagia in inflammatory myopathy: self-report, incidence, and prevalence.Dysphagia. 2012; 27: 64e9
- Myopathy with anti-Jo-1 antibodies: pathology in perimysium and neighboring muscle fibers.J Neurol Neurosurg Psychiatry. 2000; 68: 472-478
- Pulmonary involvement in PM/DM.Br J Rheumatol. 1990; 29: 1111
- 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides.Arthritis Rheum. 2013; 65: 1-11
- Pulmonary vasculitis.Rheum Dis Clin North Am. 2015; 41: 315-331
- Successful stenting in endobronchial Wegener's granulomatosis.Ulster Med J. 2006; 75: 155-157
- Peripheral neuropathy in systemic vasculitides.Curr Opin Rheumatol. 2005; 17: 41
- Peripheral neuropathy in ANCA-associated vasculitis: outcomes from the European Vasculitis Study Group trials.Rheumatology (Oxford). 2011; 50: 2214-2222
- Wegener granulomatosis: an analysis of 158 patients.Ann Intern Med. 1992; 15 (116): 488-498
- EULAR/ERA-EDTA recommendations for the management of ANCA-associated vasculitis.Ann Rheum Dis. 2016; 75: 1583-1594
- Early mortality in systemic vasculitis: relative contribution of adverse events and active vasculitis.Ann Rheum Dis. 2010; 69: 1036-1043
- Outcome of patients with small vessel vasculitis after renal transplantation: National Database Analysis.Transplant Direct. 2018; 4: e350
- Predictors of relapse and treatment resistance in antineutrophil cytoplasmic antibody-associated small-vessel vasculitis.Ann Intern Med. 2005; 143: 621-631
- Post transplantation presentation of ANCA-associated vasculitis: Granulomatosis with polyangitis.Int J Organ Transplant Med. 2018; 9: 184-191
- Heart transplantation in patients with eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome).J Heart Lung Transplant. 2014; 33: 842-850
- Vasculitis of the upper and lower airway.Best Pract Res Clin Rheumatol. 2009; 23: 403-417
- Outcomes in systemic sclerosis-related lung disease following lung transplantation.Transplantation. 2013; 95: 975-980
- Lung transplant outcomes in systemic sclerosis with significant esophageal dysfunction. A comprehensive single-center experience.Ann Am Thorac Soc. 2016; 13: 793-802
- Lung transplant in patients with scleroderma compared with pulmonary fibrosis. Short- and long-term outcomes.Ann Am Thorac Soc. 2016; 13: 784-792
- Long-term survival in bilateral lung transplantation for scleroderma-related lung disease.Ann Thorac Surg. 2018; 105: 893-900
- 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: 903-911
- Comparison of short-term outcomes for connective tissue disease-related interstitial lung disease and idiopathic pulmonary fibrosis after lung transplantation.J Thorac Dis. 2018; 10: 1538-1547
- Survival and outcomes after lung transplantation for non-scleroderma connective tissue-related interstitial.J Heart Lung Transplant. 2017; 36: 763-769
- Is systemic lupus erythematosus-related lung disease a contraindication to lung transplantation?.J Heart Lung Transplant. 2015; 34: 4S
- Polymyositis and dermatomyositis in lung transplantation: The National U.S. experience.Am J Respir Crit Care Med. 2018; 197: A7373
- Lung transplantation for severe antineutrophilic cytoplasmic antibody-associated vasculitis.Transplant Proc. 2010; 42: 2707-2710
- Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma (PHAROS): baseline characteristics and description of study population. Pulmonary complications including pulmonary hypertension (PH) and interstitial lung disease (ILD) are leading causes of mortality in systemic sclerosis/scleroderma (SSc).J Rheumatol. 2011; 38: 2172-2179
- Diagnosis and assessment of pulmonary arterial hypertension.J Am Coll Cardiol. 2009; 54: S55-S66
- Major lung complications of systemic sclerosis.Nat Rev Rheumatol. 2018; 14: 511-527
- Haemodynamic definitions and updated clinical classification of pulmonary hypertension.Eur Respir J. 2019; 53: 180-1913
- Causes and risk factors for death in systemic sclerosis: a study from the EULAR Scleroderma Trials and Research (EUSTAR) database.Ann Rheum Dis. 2010; 69: 1809-1815
- Survival and prognostic factors in systemic sclerosis-associated pulmonary hypertension: as systematic review and meta-analysis.Arthritis Rheum. 2013; 65: 2412-2423
- Connective tissues disease-associated pulmonary arterial hypertension in the modern treatment ear.Am J Respir Crit Care Med. 2009; 179: 151-157
- Recurrent aspiration in children: lipid-laden alveolar macrophage quantification.Ped Pulm. 1987; 3: 86-89
- Lung section and staining and microscopy.Bio Protocol. 2017; 10: e2286
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Published online: July 28, 2021
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© 2021 International Society for Heart and Lung Transplantation. All rights reserved.
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