Epidemiology

• 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

---

Physiology

• 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

---

Diagnosis

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

• Peripheral Eosinophilia (see Peripheral Eosinophilia, [[Peripheral Eosinophilia]]): may be seen

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

• Hypoxemia (see Hypoxemia, [[Hypoxemia]])

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

Thoracentesis

• 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]])

---

Treatment

• Corticosteroids (see Corticosteroids, [[Corticosteroids]]):
  • Intravenous Methylprednisolone (Solumedrol) (see Methylprednisolone, [[Methylprednisolone]])
  • Prednisone (see Prednisone, [[Prednisone]])
• 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]])
  • Everolimus (see Everolimus, [[Everolimus]])
  • Sirolimus (see Sirolimus, [[Sirolimus]])
• Change from Azathioprine (Imuran) to Mycophenolate Mofetil (Cellcept) (see Mycophenolate Mofetil, [[Mycophenolate Mofetil]])
• Aerosolized Cyclosporine A (see Cyclosporine A, [[Cyclosporine A]]): not commercially available

---

Prognosis

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

---

References

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