How is lung transplant rejection graded?

Answer

The incidence of acute rejection is low with current immunosuppressive regimens, but chronic rejection remains the main complication that limits long-term survival.^{[1, 2]}The International Society for Heart and Lung Transplantation (ISHLT) grading of lung transplant rejection was updated in 1996^[4]and revised in 2007^[5](see Table 1). Grades B and C are simplified in the latter; however, many clinicians and pathologists still use the former system because it offers more information on which treatment decisions can be based.

In 2018, the ISHLT proposed a grading system for lung posttransplantation airway complications in adults and children that includes ischemia and necrosis (I), dehiscense (D), stenosis (S), and malacia (M).^[6] These categories are further subdivided by location (all) and extent (all but malacia).^[6] (See Table 2, below.)

Table 1. ISHLT Grading of Lung Transplant Rejection—1996 and 2007. (Open Table in a new window)

1996	2007
A. Acute Rejection	A. Acute Rejection
A0 - Normal A1 - Minimal A2 - Mild A3 - Moderate A4 - Severe	Grade 0 - None Grade 1 - Minimal Grade 2 - Mild Grade 3 - Moderate Grade 4 - Severe
B. Airway Inflammation	B. Airway Inflammation
BX - Inadequate sampling B0 - None B1 - Minimal B2 - Mild B3 - Moderate B4 - Severe	Grade 0 - None Grade 1R - Low grade* Grade 2R - High grade* Grade X - Ungradeable
C. Chronic Airway Rejection - Bronchiolitis obliterans	C. Chronic Airway Rejection - Obliterative bronchiolitis
a. Active b. Inactive	0 - Absent 1 - Present
D. Chronic Vascular Rejection – Accelerated graft vascular sclerosis	D. Chronic Vascular Rejection – Accelerated graft vascular sclerosis
*”R" denotes revised grade to avoid confusion with the 1996 scheme.

Table 2. 2018 ISHLT Proposed Grading System for Lung Posttransplantation Airway Complications^[6] (Open Table in a new window)

	Location	Extent
Ischemia and Necrosis (I)	a. Perianastomotic: Within 1 cm of the anastomosis	a. < 50% circumferential ischemia
	b. Extends 41 cm from the anastomosis to the major airways (bronchus intermedius and distal left main stem)	b. >50%-100% of circumferential ischemia
	c. Extends 41 cm from the anastomosis into the lobar or segmental airways	c. < 50% circumferential necrosis
		d. >50%-100% of circumferential necrosis
Dehiscense (D)	a. Cartilaginous	a. 0%-25% of circumference
	b. Membranous	b. >25%-50% of circumference
	c. Both	c. >50%-75% of circumference
		d. >75% of circumference
Stenosis (S)	a. Anastomotic	a. 0%-25% reduction in cross-sectional area
	b. Anastomotic plus lobar/segmental	b. 25%-50% reduction in cross-sectional area
	c. Lobar/segmental only	c. 50% to < 100% reduction in cross-sectional area
		d. 100% distribution
Malacia (M)	a. Perianastomotic: Within 1 cm of the anastomosis
Malacia (M)	b. Diffuse: Involves the anastomosis and extends beyond 1 cm

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Media Gallery

Lung transplantation-related pathology. Intraalveolar multinucleated giant cell indicates microaspiration in this posttransplant transbronchial biopsy specimen (hematoxylin and eosin [H&E], 200x)
Lung transplantation-related pathology. This image depicts minimal acute cellular rejection with incomplete perivascular cuff of inflammatory cells (grade A1) (hematoxylin and eosin [H&E], 200x).
Lung transplantation-related pathology. This image shows mild acute perivascular rejection with a thick complete cuff around a blood vessel (grade A2) (hematoxylin and eosin [H&E], 200x).
Lung transplantation-related pathology. Moderate acute perivascular rejection is revealed: The inflammation extends into adjacent alveolar walls and is accompanied by fibrinous exudates (grade A3) (hematoxylin and eosin [H&E], 200x).
Lung transplantation-related pathology. Note the minimal acute airway rejection shown: There is focal inflammation in the submucosa (grade B1) (hematoxylin and eosin [H&E], 200x).
Lung transplantation-related pathology. This image demonstrates mild acute airway rejection: There is a bandlike infiltrate in the submucosa (grade B2) (hematoxylin and eosin [H&E], 200x).
Lung transplantation-related pathology. Moderate acute airway rejection is revealed: The inflammatory infiltrate extends into the overlying epithelium (grade B3) (hematoxylin and eosin [H&E], 200x).
Lung transplantation-related pathology. This image shows bronchial-associated lymphoid tissue (BALT): A collection of small mature lymphocytes is present which is associated with pigment. Although no airway is seen in this figure, the morphologic appearance is not that of rejection (hematoxylin and eosin [H&E], 100x).
Lung transplantation-related pathology. Bronchiolitis obliterans (chronic rejection) is revealed: The patient underwent retransplantation for chronic rejection, which is seen here as eccentric fibrosis partially occluding the airway lumen. Note the presence of scant inflammatory cells and plump fibroblasts in the lesion (hematoxylin and eosin [H&E], 100x).
Lung transplantation-related pathology. This image demonstrates bacterial infection: The presence of mostly neutrophils in both the submucosa and mucosa is most suggestive of an infection (hematoxylin and eosin [H&E], 200x).
Lung transplantation-related pathology. The image reveals cytomegalovirus (CMV) infection by immunohistochemical (IHC) staining: Both enlarged nuclei and normal-sized infected nuclei stain positively. This feature is helpful when viral inclusions are not readily apparent on hematoxylin and eosin (H&E) stain. (IHC stain using antibody against immediate early antigen, 200x)
Lung transplantation-related pathology. This image demonstrates posttransplant lymphoproliferative disorder (PTLD): There is a diffuse infiltrate of atypical lymphoid cells, obliterating the lung architecture, with a foci of necrosis, as would be seen in a large-cell lymphoma (hematoxylin and eosin [H&E], 200x).

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Table 1. ISHLT Grading of Lung Transplant Rejection—1996 and 2007.

1996	2007
A. Acute Rejection	A. Acute Rejection
A0 - Normal A1 - Minimal A2 - Mild A3 - Moderate A4 - Severe	Grade 0 - None Grade 1 - Minimal Grade 2 - Mild Grade 3 - Moderate Grade 4 - Severe
B. Airway Inflammation	B. Airway Inflammation
BX - Inadequate sampling B0 - None B1 - Minimal B2 - Mild B3 - Moderate B4 - Severe	Grade 0 - None Grade 1R - Low grade* Grade 2R - High grade* Grade X - Ungradeable
C. Chronic Airway Rejection - Bronchiolitis obliterans	C. Chronic Airway Rejection - Obliterative bronchiolitis
a. Active b. Inactive	0 - Absent 1 - Present
D. Chronic Vascular Rejection – Accelerated graft vascular sclerosis	D. Chronic Vascular Rejection – Accelerated graft vascular sclerosis
*”R" denotes revised grade to avoid confusion with the 1996 scheme.

Table 2. 2018 ISHLT Proposed Grading System for Lung Posttransplantation Airway Complications ^[6]

	Location	Extent
Ischemia and Necrosis (I)	a. Perianastomotic: Within 1 cm of the anastomosis	a. < 50% circumferential ischemia
	b. Extends 41 cm from the anastomosis to the major airways (bronchus intermedius and distal left main stem)	b. >50%-100% of circumferential ischemia
	c. Extends 41 cm from the anastomosis into the lobar or segmental airways	c. < 50% circumferential necrosis
		d. >50%-100% of circumferential necrosis
Dehiscense (D)	a. Cartilaginous	a. 0%-25% of circumference
	b. Membranous	b. >25%-50% of circumference
	c. Both	c. >50%-75% of circumference
		d. >75% of circumference
Stenosis (S)	a. Anastomotic	a. 0%-25% reduction in cross-sectional area
	b. Anastomotic plus lobar/segmental	b. 25%-50% reduction in cross-sectional area
	c. Lobar/segmental only	c. 50% to < 100% reduction in cross-sectional area
		d. 100% distribution
Malacia (M)	a. Perianastomotic: Within 1 cm of the anastomosis
Malacia (M)	b. Diffuse: Involves the anastomosis and extends beyond 1 cm

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