Acute Cellular and Antibody-Mediated Rejection of Lung Allografts
Anja C. Roden, M.D.
Allen P. Burke, M.D.
Joseph J. Maleszewski, M.D.
Acute Cellular Rejection
Acute cellular rejection occurs due to an immune response of the host to donor antigens. This immune response is an alloimmune T-cell response that triggers T-cell cytotoxicity, T-cell-mediated delayed type II hypersensitivity, and potentiation of the B-cell-mediated antibody response.1 About one-third of adult lung allograft recipients have at least one episode of acute rejection between discharge and 1-year follow-up.2 Risk factors for acute rejection include HLA mismatch, type of immunosuppression, infection, and recipient factors including genetic factors and possibly vitamin D deficiency. In adults, acute rejection is most common between ages 18 and 34 years old.2 Although acute rejection is the cause of death in <3% of patients, it is an adverse prognostic parameter in lung allografts. Therefore, routine surveillance for such is important.
Patients with acute cellular rejection may present with cough and shortness of breath, tremors, and problems with activities of daily lives, or they may be asymptomatic.3 Imaging studies might show groundglass opacities, interlobular septal thickening, volume loss, nodules, and/or pleural effusion; however, these findings are not specific or sensitive for acute cellular rejection.4 Lung function in these patients is typically obstructed as manifested by decrease in FEV1 or restricted with reduction in FVC and FEV1.5 However, the sensitivity and specificity of a decrease in FEV1 for detecting acute cellular rejection are low. Therefore, bronchoscopic biopsy is currently the gold standard for evaluation of acute cellular rejection in lung allografts.
The histopathologic grading of acute cellular rejection has been defined as the “A” grade by the International Society of Heart and Lung Transplantation (ISHLT).6 The diagnosis of acute cellular rejection requires the exclusion of an infection because of some overlapping morphologic features. Acute cellular rejection is characterized by an infiltrate of mononuclear lymphoid cells around capillaries and small vessels with or without extension into the surrounding interstitium. These lymphoid cells are predominantly of T-cell phenotype. Acute cellular rejection is graded as minimal, mild, moderate, and severe based upon the extent of the lymphocytic infiltrate and the presence or absence of additional findings such as acute lung injury (Table 52.1; Fig. 52.1).
Histologic findings of acute cellular rejection usually involve more than one vessel; however, on occasion, it might be seen only in a single location.6 Therefore, each H&E level should be carefully reviewed. Furthermore, acute cellular rejection should be recorded even if only one vessel is involved. Foci of acute cellular rejection can be of varying grades, and the highest grade should be recorded. Lymphocytic infiltrates surrounding small vessels in the wall of airways should be regarded as airway inflammation rather than acute cellular rejection. Grades A1 and A2 are considered low-grade rejection; grades A3 and A4 are thought of high-grade rejection.
Acute Small Airway Rejection (Lymphocytic Bronchiolitis)
Acute small airway rejection is characterized by a mononuclear lymphoid cell infiltrate surrounding small airways including terminal and respiratory bronchioles. It is defined as the “B” grade by the International Society of Heart and Lung Transplantation (Table 52.2; Fig. 52.2).6 The “R” behind grades B1 and B2 denotes the revised grading in 2007. Inflammation of large airways should be described separately.
Differential Diagnosis of Acute Cellular Rejection and Acute Small Airway Rejection
The diagnosis of acute rejection requires the exclusion of infection, which can morphologically mimic rejection. Specifically, cytomegalovirus or Pneumocystis jirovecii infection might present with perivascular lymphocytic infiltrates.7 Furthermore, features of acute lung injury as seen in high-grade rejection might also mimic an infectious process including viral, bacterial, or fungal infections. Multinucleated giant cells might occur in high-grade acute cellular rejection; however, well-formed granulomas are not a feature of rejection and are suggestive of an infectious process or aspiration. Careful examination of the H&E slides for viral inclusions or foreign body material is important, and the threshold of adding stains for microorganisms should be low.
Moreover, serology and molecular studies can help to identify infectious organisms.
Moreover, serology and molecular studies can help to identify infectious organisms.
TABLE 52.1 Histopathologic Grading of Acute Cellular Rejection of Lung Allografts, International Society of Heart and Lung Transplantation (2007) | |||||||||||||||||||||
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