Acute Lung Transplant Rejection


  • Incidence: >33% of lung transplant patients are treated for acute cellular rejection within the first year after transplant
  • Acute Cellular Lung Transplant Rejection is the Predominant Type of Lung Transplant Rejection

Risk Factors for Acute Cellular Rejection

  • Genetic Factors: genetic variants may influence the risk of acute cellular rejection
    • Variants in Interleukin-10 (IL-10)
    • Variants in Multidrug Resistance Genotype
    • Variants in CCL4L Chemokine
    • Variants in Toll-Like Receptor-4 (TLR4)
  • Human Leukocyte Antigen (HLA) Mismatching: increasing HLA mismatch between the donor and recipient increases the risk of acute cellular rejection (mismatch at some loci may be more important than other loci)
  • Immunosuppression Regimen:
    • Cyclosporine-A Regimens (see Cyclosporine A, [[Cyclosporine A]]): risk of acute cellular rejection in the first year is highest in this subgroup
    • Tacrolimus Regimens (see Tacrolimus, [[Tacrolimus]]): lowest risk of acute cellular rejection in the first year is lowest in this subgroup
    • Interleukin-2R Antagonist Regimens: lower risk of acute cellular rejection than other induction regimens
  • Age: rejection occurs more commonly in age 18-34 y/o patient subgroup (although data from the ISHLT registry was not adjusted for underlying disease or other confounding variables)
  • Vitamin De Deficiency (see Vitamin D, [[Vitamin D]]): risk of acute cellular rejection is higher in patients with 25-hydroxyvitamin D deficiency near the time of transplantation


  • T-Cell Recognition of Foreign Donor Human Leukocyte Antigens (HLA) (Major Histocompatibility Antigens, MHC)
    • Lymphocyte-Predominant Inflammatory Response is Centered on the Blood Vessels and Airways
    • Vascular Component: perivascular mononuclear cell infiltrate which may extend to the subendothelium and involve alveolar walls (in higher grades of rejection)
      • Eosinophils may be occasionally present
      • Presence of hyaline fibrosis in airways/vessels is not present -> if it is, this indicates chronic rejection instead
    • Airway Component: lymphocytic response initially in the bronchiolar submucosa, later extending through the basement membrane
      • May occur isolated or with the vascular component
      • Ulceration of the airway epithelium may occur in advanced cases
      • Eosinophils may be occasionally present
      • Presence of hyaline fibrosis in airways/vessels is not present -> if it is, this indicates chronic rejection instead


Complete Blood Count (CBC) (see Complete Blood Count, [[Complete Blood Count]])

Arterial Blood Gas (ABG) (see Arterial Blood Gas, [[Arterial Blood Gas]])

Sputum Culture

  • Indicated

Peripheral Blood Cytomegalovirus (CMV) Viral Load (see Cytomegalovirus, [[Cytomegalovirus]])

  • Indicated

Pulmonary Function Tests (PFT’s) (see Pulmonary Function Tests, [[Pulmonary Function Tests]])

  • General Comments: spirometry does not differentiate infection from acute rejection
  • Obstruction (Decreased FEV1 with Decreased FEV1/FVC Ratio
    • Sensitivity of Decreased FEV1 in Detecting Acute Rejection: 60%
    • Presence of obstruction may also be seen in bronchial stenosis
  • Restriction (Decreased FEV1 and FVC with Preserved FEV1/FVC Ratio)
  • Pattern of Decreased DLCO + Decreased TLC: may be seen in acute rejection in patients with heart-lung transplant

Exercise Testing (see Exercise Testing, [[Exercise Testing]])

  • Exercise-Associated SaO2 Desaturation >5%: suggestive of rejection (or infection)

Chest X-Ray (CXR)

  • Low Sensitivity/Specificity: normal in 80% of cases later in the course of acute rejection

High-Resolution Chest Computed Tomography CT (HRCT) (see High-Resolution Chest Computed Tomography, [[High-Resolution Chest Computed Tomography]])

  • Findings
    • Atelectasis
    • Ground-Glass Infiltrates
    • Pleural Effusion
    • Septal Thickening
  • Low Sensitivity/Specificity: does not reliably differentiate between infection and rejection
    • However, HRCT may be useful to guide sites of BAL or TBB


  • Pleural Effusion is Common in the First Two Weeks After Lung Transplant: sampling is not required unless effusion is large or infection is suspected
  • Lymphocytic Exudate (see Pleural Effusion-Exudate, [[Pleural Effusion-Exudate]])

Bronchoscopy (see Bronchoscopy, [[Bronchoscopy]])

  • Surveillance Bronchoscopy: controversial (varies between centers)
    • May be Useful Given Evidence of Acute Rejection in Asymptomatic Patients
    • However, Surveillance Bronchoscopy Has Not Been Demonstrated to Have a Mortality Benefit
  • Bronchoalveolar Lavage (BAL): useful to rule out infection
  • Transbronchial Biopsy (TBB): gold standard for detecting acute rejection and ruling out infection
    • Sensitivity: 61-94%
    • Specificity: 90-100%
    • Risk of Pneumothorax (see Pneumothorax, [[Pneumothorax]]): 1-3%
    • 2007 ISHLT Grading System
      • A = Acute Rejection (grades 1, 2, 3, 4)
      • B = Airway Inflammation (grades 0, 1R, 2R, X)
      • C = Chronic Airway Rejection (grades 0, 1)
      • D = Chronic Vascular Rejection/Accelerated Graft Vascular Sclerosis (fibrointimal thickening of pulmonary arteries/veins)
        • These lesions are not seen on TBB, as they affect larger blood vessels than those sampled with TBB

Open Lung Biopsy

  • May Be Necessary in Some Cases

Clinical Manifestations

General Comments

  • Onset: within first 6 mo
  • Asymptomatic: common (with diagnosis made by surveillance transbronchial biopsies)

Pulmonary Manifestations

  • Acute Respiratory Distress Syndrome (ARDS) (see Acute Respiratory Distress Syndrome, [[Acute Respiratory Distress Syndrome]]): may occur in severe cases
  • Cough with/without Sputum Production (see Cough, [[Cough]])
  • Hemoptysis/Diffuse Alveolar Hemorrhage (DAH) (see Hemoptysis, [[Hemoptysis]] and Diffuse Alveolar Hemorrhage, [[Diffuse Alveolar Hemorrhage]]): occurs weeks-months post-transplant
    • May be the only manifestation of allograft rejection
  • Dyspnea (see Dyspnea, [[Dyspnea]])
  • Pleural Effusion (see Pleural Effusion-Exudate, [[Pleural Effusion-Exudate]])
  • Crackles/Wheezing

Other Manifestations

  • Malaise
  • Fever (see Fever, [[Fever]])


  • Corticosteroids (see Corticosteroids, [[Corticosteroids]]):
  • Change from Cyclosporine A to Tacrolimus (see Tacrolimus, [[Tacrolimus]]): for patients on a cyclosporine A regimen
  • Anti-Thymocyte Globulin (ATG) (see Anti-Thymocyte Globulin, [[Anti-Thymocyte Globulin]])
  • Alemtuzumab (Campath, MabCampath, Campath-1H, Lemtrada) (see Alemtuzumab, [[Alemtuzumab]])
  • Extracorporeal Photopheresis (ECP)
  • Addition of Mechanistic Target of Rapamycin (mTOR) Inhibitor to Regimen (see Mechanistic Target of Rapamycin Inhibitors, [[Mechanistic Target of Rapamycin Inhibitors]])
  • Change from Azathioprine (Imuran) to Mycophenolate Mofetil (Cellcept) (see Mycophenolate Mofetil, [[Mycophenolate Mofetil]])
  • Aerosolized Cyclosporine A (see Cyclosporine A, [[Cyclosporine A]]): not commercially available


  • Mortality: acute cellular rejection accounts for 4% of deaths in the first 30 days after lung transplant


  • Are symptom reports useful for differentiating between acute rejection and pulmonary infection after lung transplantation? Heart Lung. 2004;33(6):372 [MEDLINE