Chronic Rejection
Chronic Allograft Rejection
Extensive research efforts have attempted to unravel the pathophysiology of OB and identify key cytokines and growth factors involved in the process. A clinical grading system has been proposed, to divide BOS into four and more recently five categories, depending on the severity of airflow obstruction.
Risk factors for Chronic Rejection - Several risk factors for the development of OB/BOS have been identified, the predominant factors being late or recurrent/refractory acute rejections, lymphocytic bronchitis/bronchiolitis, noncompliance with the immune suppression medication, human leucocyte antigen (HLA) mismatches at the A locus, total human leococyte antigen mismatches, and cytomegalovirus(CMV) pneumonitis. Whether airway ischemia is also a risk factor remains a matter of debate. The single most important clinical risk factor for OB is acute rejection. Late acute rejection is also recognized as an important risk.
Human Leucocyte Antigen Mismatches - Some researchers noted that mismatches at specific loci of the major histocompatibility complex were associate with an increased risk to develop OB, but others found no association.
CMV- Several case studies documented CMV infections as a potential risk factor for the development of OB. Especially in the CMV donor-positive and CMV negative transplant patient.
Pathophysiology of OB - Many papers have highlighted the involvement of neutrophils, which are present in high amounts in bronhoalveolar lavage fluid from OB patients compared with stable lung tranplant recipients.
Airway Epithelium - The airway epithelium seems to play a pivotal role in the intial inflammatory events that lead to OB.
Cytokines and Growth Factors - The development of OB may be hypothesized as follows: an initially immune-mediated response probably damages the epithelium, generating differetn cytokines and chemokines and that attract lymphocytes and neutrophils to the injured airway. After this early stage of inflammation, there gradually appears a fibroproliferative phase, mediated by several growth factors. Nitric Oxide may then further damage the epithelium and stimulate fibroblast activity
OB is consistently characterized by a reduction in pulmonary function parameters, most specifically in FEV1, attributed to airways obstruction. There is no signficant reversibility aftere inhalation of short- acting agonists. The onset of symptoms is mostly insidious, with progressive exertional dyspnea, often accompanied by cough. Sometimes with airways infection seems to have triggered the onset of OB. In the later course of the disease, airways superinfections are frequently seen and colonization with Pseudomonas aeruginosa and Aspergillus fumigatus is common.
Diagnosis of OB - Although OB is a diagnosis that has to be made by the pathologist, it is often impossible to obtain adequate material or a positive transbronchial biopsy. Therefore, a new stage has been incorporated, namely "potential BOS".
Outcome - Early diagnosis and improved management of BOS have led to a better survival, although survival rate is still significantly lower in comparison with lung transplant recipients without BOS.
Conclusion - Chronic rejection remains the most important and challenging problem after heart/lung and lung transplantation because it leads to airways obstruction, loss of qualityof life, increased morbidity and a high mortality.
(Source: Seminars in Respiratory and Critical Care Medicine, 2001)
| Acute Rejection* |
| Grade | Histopathological Findings |
| A0 (None) | No mononuclear inflammation, hemorrhage or necrosis |
| A1 (Minimal) | Scattered infrequent perivascular mononuclear infiltrates not obvious at low magnification (40X). Blood vessels, particularly venules, are cuffed by small round, plasmacytoid, and transformed lymphocytes forming a ring of 2 to 3 cells thick in the perivascular adventitia. |
| A2 (Mild) | Frequent perivascular mononuclear infiltrates surrounding venules and arterioles readily recognizable at low magnification and usually consist of activated lymphocytes, small round lymphocytes, plasmacytoid lymphocytes, macrophages, and eosinophils. Frequent subendothelial infiltration by the mononuclear cells with hyperplastic or regenerative changes in the endothelium (endotheliitis); although there is expansion of the perivascular interstitium by inflammatory cells, there is no obvious infiltration by mononuclear cells into the adjacent alveolar septae or air spaces. Concurrent lymphocytic bronchiolitis is not uncommon. A solitary perivascular mononuclear infiltrate of significant intensity to be noted at low magnification still warrants a diagnosis of grade A2 (or greater) rejection |
| A3 (Moderate) | Readily recognizable cuffing of venules and arterioles by dense perivascular mononuclear cell infiltrates, which are usually associated with endothelialitis; eosinophils and occasional neutrophils are common. By definition, there is extension of the inflammatory cell infiltrate into perivascular and peribronchiolar alveolar septae and air spaces. Collections of alveolar macrophages are common in the airspaces in the zones of septal infiltration. |
| A4 (Severe) | Diffuse perivascular, interstitial, and air space infiltrates of mononuclear cells and prominent alveolar pneumocyte damage usually associated with intra-alveolar necrotic cells, macrophages, hyaline membranes, hemorrhage, and neutrophils; there may be associated parenchymal necrosis, infarction, or necrotizing vasculitis. The obvious presence of numerous perivascular and interstitial mononuclear cells seen with grade A4 rejection permits distinction from peri-operative (reperfusion/ischemic) lung injury. |
| * Pathologists should mention airway inflammation and may choose to grade B lesions (see below). |
| Chronic Airway Rejection (Bronchiolitis Obliterans) |
| Classification | Histopathological Findings |
| Active | In addition to the fibrosis, there are intra and/or peribronchiolar submucosal and peribronchiolar mononuclear cell infiltrates usually associated with ongoing epithelial damage |
| Inactive | Dense fibrous scarring without cellular infiltrates; this represents old cicatricial change in the small airways with a lack of significant submucosal and peribronchiolar inflammatory infiltrates |
Alveolar neutrophilia is a predictor for the bronchiolitis obliterans syndrome, and increases with degree of severity -Background: Bronchiolitis obliterans syndrome (BOS) is a common complication of lung transplantation (LT), associated with a tremendous mortality and morbidity. Recent innovative research has focused on bronchoalveolar lavage (BAL) analysis, assuming that neutrophilia might be a marker of chronic rejection. Patients and methods: To address this issue, we retrospectively analyzed 258 sequential BAL from 44 lung transplant recipients, having survived for more than 3 months after surgery. Results: At the end of the follow-up, 22, 7, 7 and 8 patients had BOS stage 0, 1, 2 and 3, respectively. The total cell count and neutrophilia increased with BOS severity (P<0.01). BOS occurring before and after the 12th month of LT were associated with early and more delayed increases of BAL neutrophils, respectively. Finally, the various kinetic profiles of neutrophil progression were identified, allowing for an earlier identification of BOS stages 2 and 3, by 3 and 6 months, respectively. Conversely, neutrophilia associated to BOS stage 1 remained low, and could not be distinguished from that of stage 0. Conclusions: These results support the possible role of neutrophils in BOS pathogenesis, and may be of interest for an earlier detection and management of chronic rejection. (Source: Transplant Immunology, Vol. 10 (4) (2002))
Scanning for the Diagnosis of Bronchiolitis Obliterans Syndrome After Lung Transplantation- (Added 10/4/04) - High-resolution electron-beam (HREB) CT scanning for diagnosing bronchiolitis obliterans syndrome (BOS) in lung transplant recipients.At the time of follow-up examinations after lung transplantation, 52 patients were examined by dynamic HREB CT scan. Visualsigns of small airway disease were assessed and compared with lung function. On visual analysis, significant parenchymal attenuation inhomogeneities were present in eight of nine patients with manifest BOS, and in two of four patients who developed BOS during follow-up. Conclusions: Dynamic HREB CT of lung transplant recipients correlates wellwith lung function criteria of BOS at the time of the CT examination and with the subsequent progression to BOS (Source: Chest 2004)
