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