No rejection; there are no significant perivascular inflammatory cell infiltrates. The presence of a few small noncircumferential infiltrates is not sufficient for a diagnosis of A1 (Figs. 3.1 and 3.2).

Minimal rejection; there are scattered and infrequent perivascular mononuclear cell infiltrates in alveolar tissue with only few eosinophils and no endotheliitis. The presence of endotheliitis would indicate at least grade A2 rejection. Some (if not all) infiltrates should be entirely circumferential around vessels. If many vessels are involved, this may not be “minimal” rejection and we tend to regard this as grade A2 (Figs. 3.3 and 3.4).

Mild rejection; this grade is characterized by more frequent and larger perivascular chronic inflammatory cell infiltrates around venules and arterioles, often with accompanying eosinophils and endotheliitis. Venules appear to be more frequently involved than arterioles. The presence of only rare eosinophils is not sufficient to warrant a diagnosis of A2 rejection by itself, but it should prompt careful review of the biopsy material for more features of grade A2. Furthermore, the absence of endotheliitis does not exclude grade A2 rejection if other features are present. There is obviously room for interpretive differences in frequency and size of perivascular inflammatory cell infiltrates between grades A1 and A2; the ISHLT guidelines suggest the perivascular infiltrates of A2 are more easily recognizable at lower scanning power. This is fair advice, but experienced pathologists are able to detect small A1 perivascular infiltrates at low power and must be able to adjust their grading criteria accordingly (Figs. 3.5 and 3.6).

Moderate rejection; this grade is defined by the extension of the inflammatory cell infiltrate into the alveolar septa. There are usually concurrent endotheliitis and frequent eosinophils but not always. There may be features of mild acute lung injury with fibrin deposition but there are no hyaline membranes (Figs. 3.7, 3.8, and 3.9).

Severe rejection: this grade of rejection is characterized by concurrent severe acute lung injury with features of acute cellular rejection, specifically perivascular and interstitial mononuclear cell infiltrates with or without endotheliitis and eosinophils. The acute lung injury demonstrates hyaline membranes and reactive pneumocyte injury. Paradoxically, the rejection-associated inflammatory cell infiltrates may be diminished, compared with grade A3 or A2 rejection, and distinction from nonrejection causes of lung injury may be difficult. Pathological confirmation of perivascular infiltrates and exclusion of infection by special stains and/or microbiology studies, and clinical correlation are usually sufficient to confirm the diagnosis of severe rejection (Figs. 3.10, 3.11, and 3.12).

No significant inflammation; there may be scattered chronic inflammatory cells associated with the small airways but the infiltrate would be within normal limits.

Low-grade bronchiolar inflammation; there are varying degrees of mononuclear cells within the submucosa and muscular layers of the small airway. There may be mild lymphocytic infiltration of the epithelium but there is no significant epithelial cell injury. Small vessels around the airway may have circumferential perivascular infiltrates suggestive of acute rejection grade A1. If these vessels are part of the airway, the inflammation should be considered a component of the airway inflammation and not acute rejection (Figs. 3.13 and 3.14).

High grade; this grade is characterized by more intense intraepithelial lymphocytic infiltration and epithelial cell injury manifesting as metaplasia or frank necrosis. Eosinophils are more common than in grade B1R. If there are abundant neutrophils, an infectious etiology should be considered and, if proven or favored, grade BX should be rendered (Figs. 3.15 and 3.16).

Ungradeable; when no airway is present on the biopsy or is obscured by handling artifact or infection-associated inflammation, this is designated as grade BX. Data from the Banff Study of Pathologic Findings Associated with HLA Antibodies found 38 % of cases, from a pool of 253 biopsies, were graded BX [4].

BOS manifests as a decrease in forced expiratory volume per 1 second (FEV₁), may result in eventual graft loss and contributes to the 5-year graft survival of approximately 50 % [6]. The development of BOS is not reliably evaluated by the transbronchial biopsy and is best monitored by clinical and radiological evaluation. Nevertheless, the presence of airway scarring, termed bronchiolitis obliterans (BO), should be reported if discovered on a transbronchial biopsy. If there is no evidence of airway scarring, the grade is C0; if scarring is present, the grade is C1. The scarring begins as subepithelial granulation tissue with small vessels within an edematous fibrous stroma. The process may be concentric or eccentric. Eventually, the granulation tissue is replaced by dense fibrous scar tissue that causes progressive obstruction of the small airways and may ultimately lead to complete obliteration. The findings may be difficult to appreciate on a hematoxylin and eosin (H&E) stain and the features can be highlighted with special connective tissue stains, such as Movat, Masson trichrome, or elastic stains (Figs. 3.19 and 3.20).

Distal to the lesion, postobstructive changes, such as clusters of foam cells or cholesterol clefts with granulomas, may be seen (Fig. 3.21). However, these are nonspecific findings and, although these features are suggestive, do not indicate a diagnosis of BO without sampling of the lesion in the airway. Pathological features of BO are more easily discovered in larger resection specimens such as allograft explants (Figs. 3.22 and 3.23).