Other nonneoplastic disease

Transplantation / rejection

Editorial Board Member: Carolyn Glass, M.D., Ph.D.
Editor-in-Chief: Debra L. Zynger, M.D.
Rachel Bowden, M.B.B.S.
M. Ángeles Montero-Fernández, M.D., Ph.D.

Last author update: 27 October 2020
Last staff update: 6 January 2023 (update in progress)

Copyright: 2003-2023,, Inc.

PubMed search: pulmonary transplantation [title] rejection

Rachel Bowden, M.B.B.S.
M. Ángeles Montero-Fernández, M.D., Ph.D.
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Cite this page: Bowden R, Montero MA. Transplantation / rejection. website. Accessed March 22nd, 2023.
Definition / general
  • Lung transplant is the treatment for end stage lung nontumoral diseases
  • Lung allograft rejection is a significant cause of acute graft dysfunction and eventually chronic graft failure (Arch Pathol Lab Med 2017;141:437)
Essential features
  • Lung allograft rejection is a significant cause of acute graft dysfunction and eventually chronic graft failure
  • Rejection of allograft through cellular mediated response or antibody mediated response
  • Acute cellular rejection resolves in 80 - 90% with immunosuppression
  • Chronic lung allograft dysfunction is the main cause of mortality in 50% of lung transplant recipients after 5 years
  • ACR - acute cellular rejection
  • CLAD - chronic lung allograft dysfunction (irreversible graft loss, 20% fall in forced expiratory volume in 1 second [FEV1])
  • BOS - bronchiolitis obliterans syndrome (85% of chronic lung allograft dysfunction)
  • OB - obliterative bronchiolitis (clinical bronchiolitis obliterans syndrome)
  • RAS (rCLAD) - restrictive allograft syndrome (15% of chronic lung allograft dysfunction)
  • MHC - major histocompatibility complex
ICD coding
  • ICD-10:
    • T86.810 - Lung transplant rejection
    • T86.811 - Lung transplant failure
    • T86.812 - Lung transplant infection
    • T86.818 - Other complications of lung transplant
    • T86.819 - Unspecified complication of lung transplant
  • Respiratory system
  • Immune response to the allograft is characterized by the following processes:
    • Hyperacute rejection:
      • Due to preformed donor specific antibodies (DSAs), which activate the complement system and platelet aggregation leading to vascular thrombosis and graft necrosis (J Heart Lung Transplant 2016;35:397)
    • Acute cellular rejection:
      • Recipient T lymphocytes recognize donor human leukocyte antigen (HLAs) or other antigens
      • Pathways: direct (donor dendritic cells presenting major histocompatibility complex directly to recipient T cells) and indirect (recipient dendritic cells presenting alloantigen from donor antigen presenting cells to T cells) (J Thorac Dis 2017;9:5440)
    • Antibody mediated rejection:
      • Donor specific antibodies produced by B cells and plasma cells, target foreign HLA on the donor capillary endothelial cells
      • HLA-DSA cause persistent insult to the graft epithelium, resulting in epithelial ischemia and antibodies to self antigens such as K-α-1-tubulin (Kα1T) and collagen V (Col-V0) (Arch Pathol Lab Med 2017;141:437)
Clinical features
  • Shortness of breath
  • Pulmonary edema
  • Diffuse alveolar hemorrhage (J Thorac Dis 2019;11:S1732)
  • Fever
  • Cough
  • Decline in pulmonary function tests
  • Bronchoscopy:
    • Bronchoalveolar lavage (BAL) - cytological and microbiological analysis
    • Transbronchial biopsy forceps and cryobiopsy (Ann Thorac Surg 2019;108:1052)
  • Clinical:
  • Eosinophilia, neutrophilia, leukocytosis
Radiology description
  • Chest Xray:
    • Ground glass opacities, pulmonary edema and pleural effusions
  • High resolution computer tomography:
    • Ground glass opacities with interlobular septal thickening, without consolidation and atelectasis (J Thorac Dis 2017;9:5440)
Radiology images

Images hosted on other servers:

Hyperacute lung transplant rejection

Acute rejection A1

Restrictive allograft syndrome

Prognostic factors
  • Hyperacute rejection has high mortality (J Heart Lung Transplant 2016;35:397)
  • Acute rejection resolves in 80 - 90% with immunosuppression
  • Chronic lung allograft dysfunction is a major cause of death after 6 months posttransplant
  • Immunosuppressant therapy causes secondary infections (CMV, EBV) and posttransplant lymphoproliferative disorder (Respiration 2015;90:451)
  • Posttransplant lymphoproliferative disorder:
    • Majority occur within the first year posttransplant (> 85%)
    • Risk factors include immunosuppressive burden and the oncogenic nature of the Epstein-Barr virus (EBV) (World J Transplant 2020;10:29)
    • Treatment includes reduction of immunosuppressive therapy, rituximab, antivirals and chemotherapy
Case reports
  • Reserved for symptomatic grades of acute cellular rejection (> A2) and consists of methylprednisolone IV, tapering to oral
  • Consider tacrolimus if on cyclosporine or addition of a mammalian target of rapamycin (mTOR) inhibitor, such as everolimus (J Thorac Dis 2017;9:5440)
  • Extracorporeal photophoresis stimulates and expands the number of peripheral regulatory T cells, stabilizing acute cellular rejection and reducing lung function decline in chronic lung allograft dysfunction / bronchiolitis obliterans syndrome (Clin Transplant 2017;31:e13041)
Gross description
  • Antibody mediated rejection: unfixed lungs are hyperemic and heavy
  • Chronic rejection: hyperinflated lungs, with bronchiectasis, fibrosis of lung parenchyma (J Thorac Dis 2017;9:2684)
Gross images

Contributed by M. Angeles Montero, M.D., Ph.D.

Explant lung with diffuse alveolar damage

Idiopathic pleuroparenchymal fibroelastosis

Chronic lung allograft dysfunction

Microscopic (histologic) description
  • Acute cellular rejection characterized by infiltration of lymphocytes / monocytes around blood vessel endothelium (A grade) and airways / bronchioles (B grade) (J Thorac Dis 2017;9:5440)
  • Classified by the International Society for Heart and Lung Transplantation (ISHLT) working party (see table below)
  • Perivascular inflammation:
    • Minimal: 2 - 3 layers perivascular lymphocytes
    • Mild: > 3 perivascular lymphocytes, eosinophils and plasma cells
    • Moderate: extension of perivascular inflammation into neighboring alveolar septa
    • Severe acute rejection: diffuse inflammation, hemorrhage, necrosis and hyaline membrane formation (J Thorac Dis 2017;9:5440)
  • Airway inflammation:
    • Low grade: submucosal lymphocytic inflammation, without epithelial injury
    • High grade: submucosal lymphocytic inflammation, with epithelial injury with or without ulceration
  • Chronic rejection is characterized as present or absent
    • Bronchiolitis obliterans: partial or complete occlusion of bronchiole lumen, with patchy submucosal fibrosis, with or without inflammatory infiltrates
    • Restrictive allograft syndrome: pleuroparenchymal fibroelastosis with or without bronchiolitis obliterans or diffuse alveolar damage

Revised working formulation for classification and grading of pulmonary allograft rejection:
A: Perivascular inflammation B: Airway inflammation C: Chronic airway rejection
Grade 0 - none Grade 0 - none 0 - absent
Grade 1 - minimal Grade 1R* - low grade 1 - present
Grade 2 - mild Grade 2R* - high grade
Grade 3 - moderate Grade X - ungradable
Grade 4 - severe
*R denotes new revised stage
Reference: J Heart Lung Transplant 2007;26:1229
Microscopic (histologic) images

Contributed by M. Angeles Montero, M.D., Ph.D.

Alveolar septal capillaritis


Minimal acute cellular rejection (A1)

Moderate acute cellular rejection (A3)

Severe acute cellular rejection (A4)

Lymphocytic bronchiolitis (B2R)

Obliterative bronchiolitis

Acute fibrinous and organizing pneumonia

Acute lung injury

Cytology description
  • Allograft rejection is associated with increased neutrophils and epithelial cells in bronchoalveolar lavage (Respir Res 2018;19:102)
Immunofluorescence description
  • In antibody mediated rejection, capillary C4d staining in alveolar tissue may support the presence of an antibody mediated process (Am J Transplant 2018;18:936)
Immunofluorescence images

Contributed by M. Angeles Montero, M.D., Ph.D.


Positive stains
  • Proposed scoring threshold for positive C4d
    • Diffuse staining (> 50%) of alveolar interstitial capillaries
Negative stains
  • Proposed scoring threshold for negative C4d
    • Focal staining (< 50%) of alveolar interstitial capillaries
Molecular / cytogenetics description
  • MicroRNA has shown promising potential in distinguishing patients with acute cellular rejection from those without rejection (Transplant Direct 2015;1:e44)

Indications, patient selection and outcomes

Sample pathology report
  • Left lung, lower lobe, transbronchial biopsy:
    • Mild acute cellular rejection, mild lymphocytic bronchiolitis and no evidence of antibody mediated rejection (A2 B1R C0, pAMR0, see comment)
    • Comment: There are 5 adequate pieces of lung, including 1 bronchiole and several vessels. Two perivascular lymphocytic infiltrates that extend to the septa are noted. Occasional eosinophils and focal endotheliitis are noted. Bronchiolar submucosal lymphocytic infiltrate without epithelial injury is also seen. No bronchiolitis obliterans or capillaritis identified. Immunohistochemistry stain for C4d is negative.
Differential diagnosis
Board review style question #1

Which is the main cause of mortality in lung allograft patients, shown here?

  1. Acute cellular rejection
  2. Antibody mediated rejection
  3. Chronic lung allograft dysfunction
  4. Hyperacute rejection
Board review style answer #1
C. Chronic lung allograft dysfunction is the main cause of mortality, affecting 50% of transplant recipients after 5 years (J Thorac Dis 2017;9:2684)

Comment Here

Reference: Lung transplantation / rejection
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