Lung Transplantation The State of the Airways Aliya N. Husain, MD; Edward R. Garrity, MD
Context.—Lung transplantation has become a viable option for definitive treatment of several end-stage lung diseases for which there are no other options available. However, long-term survival continues to be limited by chronic lung allograft dysfunction, which primarily affects the airways. Objective.—To highlight the complications occurring mainly in the airways of the lung transplant recipient from the early to late posttransplant periods. Data Sources.—Review literature focusing on the airways in patients with lung transplants and clinical experience of the authors. Conclusions.—Postsurgical complications and infections
of the airways have decreased because of better techniques and management. Acute cellular rejection of the airways can be distinguished from infection pathologically and on cultures. Separating small from large airways need not be an issue because both are risk factors for bronchiolitis obliterans. Grading of airway rejection needs to be standardized. Chronic lung allograft dysfunction consists of both bronchiolitis obliterans and restrictive allograft syndrome, neither of which can be treated very effectively at present. (Arch Pathol Lab Med. 2016;140:241–244; doi: 10.5858/ arpa.2015-0295-SA)
L
to differentiate acute rejection from infection; thus clinicians would prefer biopsy evidence of rejection to guide therapy. The pathologic definition of acute rejection of lung has remained essentially the same during the past 3 decades (Figure 1, A and B). It is assessed by evaluation of tissue obtained by transbronchial biopsy (hematoxylin-eosin– stained sections). According to the 1990 Working Formulation for the Standardization of Nomenclature in the Diagnosis of Heart and Lung Rejection: Lung Rejection Study Group report, ‘‘acute rejection is characterized by both perivascular mononuclear infiltrates and a lymphocytic bronchitis/bronchiolitis.’’ 1(p594) The 1996 revision states, ‘‘Acute rejection is characterized by perivascular and subendothelial mononuclear infiltrates and by lymphocytic bronchitis and bronchiolitis.’’ 2(p2) In the 2007 revision, ‘‘acute rejection is characterized by perivascular mononuclear cell infiltrates, which may be accompanied by subendothelial infiltration, so-called endothelialitis or intimitis and also by lymphocytic bronchitis and bronchiolitis.’’ 3(p1230) However, the 2007 working formulation also states that ‘‘A diagnosis of acute rejection is based exclusively on the presence of perivascular and interstitial mononuclear cell infiltrates.’’ 3(p1230) This statement is the result of controversy among pathologists as to the significance of airway inflammation, distinguishing infection from acute rejection, and separating bronchioles from cartilage containing airways. Grading of acute rejection has been done for perivascular infiltrates from none (A0) to severe (A4). Airway grading has been changing over time from absent/present (in 1990) to B0B4 (1996) to B0-B2R (2007). In the most recent formulation, the B grades are low grade (B1R) and high grade (B2R) small airway inflammation/lymphocytic bronchiolitis.
ung transplantation has been practiced since the early 1980s after a moratorium by the US National Institutes of Health ended with the introduction of cyclosporine for use in clinical practice. Since then, lung transplantation has become an option for patients with very advanced lung diseases of various etiologies offering an opportunity for longer life spans and an improved quality of life. In recent years, management and modulation of the immune system via immunosuppressive drugs and subsequent improvement in surgical management and postoperative care have significantly improved outcomes. There is significant literature regarding perivascular rejection and its management. However, the focus of this article is to review the airway pathology of lung transplantation, including surgical and infectious complications and acute and chronic rejection, with special emphasis on those areas that directly affect clinical decision-making and management. DEFINITIONS AND GRADING Acute Rejection The clinical definition of acute rejection depends on recognition of abnormalities in gas exchange (hypoxemia) or airflow (lung function tests) from the transplanted lung. Caution always needs to be exercised, however, in attempting
Accepted for publication November 13, 2015. From the Departments of Pathology (Dr Husain) and Medicine (Dr Garrity), University of Chicago, Chicago, Illinois. The authors have no relevant financial interest in the products or companies described in this article. Reprints: Aliya N. Husain, MD, Department of Pathology, University of Chicago, 5841 S Maryland Ave, MC 6101, Room S627, Chicago, IL 60637 (email: [email protected]). Arch Pathol Lab Med—Vol 140, March 2016
Airways After Lung Transplantation—Husain & Garrity 241
Figure 1. Acute rejection is characterized by perivascular (A) and airway (B) inflammatory infiltrates (hematoxylin-eosin, original magnification 3200 [A and B]). Figure 2. Bronchiolitis obliterans with almost complete occlusion of the airway lumen from submucosal fibrosis. The adjacent branch of the pulmonary artery is not affected (hematoxylin-eosin, original magnification 3100). Figure 3. Restrictive allograft syndrome shows patchy fibrosis as shown here with a gross photograph of the cut surface of a transplanted lung at autopsy.
CHRONIC LUNG ALLOGRAFT DYSFUNCTION The term chronic lung allograft dysfunction (CLAD) was introduced to cover all forms of chronic graft dysfunction, including obstructive and restrictive forms, and it has been defined recently.4 Bronchiolitis Obliterans Syndrome Bronchiolitis obliterans syndrome (BOS) was first defined in the early 1990s, and is the leading cause of death in patients at 1 year after transplant.5 Its presentation is progressive obstructive physiology, with forced expiratory volume at the end of the first second of expiration (FEV1) decreasing more rapidly than forced vital capacity (FVC) on spirometry. There is usually relative hyperinflation or air trapping in the allograft because of inadequate expiratory airflow induced by small airway disease. Clinical grading of BOS may be helpful in guiding therapy. The pathology of BOS is well described and consists of patchy, submucosal fibrosis, which may partially or totally occlude the airway 242 Arch Pathol Lab Med—Vol 140, March 2016
lumen (Figure 2). It may be accompanied by varying degrees of inflammation. Restrictive Allograft Syndrome Restrictive allograft syndrome is the interstitial counterpart of BOS, manifesting as progressive, restrictive physiology with an appearance of increasing fibrosis on imaging studies.6 In this entity, the FVC decreases in conjunction with the FEV1, so restriction is the key finding on pulmonary function tests. It most often coexists with BOS. The main pathologic finding is pleuropulmonary fibrosis (Figure 3), which is progressive.7,8 It constitutes a significant minority of cases of allograft dysfunction after lung transplantation, and the understanding of this problem is still evolving. COMMENT Surgical Complications In the early postoperative period, the airway is most vulnerable at the new anastomosis of the donor-recipient Airways After Lung Transplantation—Husain & Garrity
Figure 4. A cartilage-containing airway seen on transbronchial biopsy; on the first level, cartilage was not evident, and this would have been called a bronchiole. However, at deeper levels, cartilage is present, and this would now be called a bronchus by the pathologist (hematoxylin-eosin, original magnification 3100). Figure 5. Predominant submucosal neutrophils as seen in this airway suggest infection (hematoxylin-eosin, original magnification 3400).
bronchus. Surgical technique has evolved with time, leading to the most current practice of making the anastomosis as distal in the recipient airway as possible, resulting in fewer complications at this site. Anastomotic injury is thought to be the result of ischemia of the donor airway, leading to varying degrees of necrosis, sloughing of airway epithelium, infection, and dehiscence. Healing of the injury may leave stenosis requiring intervention by dilatation, stenting, and repeated endoscopy to clean the area involved. This early injury likely has a role in the development of CLAD, dependent on its extent and severity. The other sequelae of surgery are more apt to be represented by primary graft dysfunction than by specific airway pathology, but the 2 types of injury are surely linked by common cause.9 Infectious Complications The anastomosis can be a significant site for infectious complications that may contribute to necrosis of the anastomosis and potential dehiscence. The sources of early bacterial infection can be either donor or recipient with the predominant infections in patients with bronchiectasis coming from their own flora. Airway fungal infections tend to be due to either Candida sp. or Aspergillus with those from Aspergillus considered far more serious. Candida sp. tends to be derived from the donor, whereas Aspergillus tends to occur as a hospital- or community-acquired infection with varying incidence, depending on geography. Each can cause anastomotic infection, acute bronchitis with plaque formation, and sometimes pneumonia. Because the treatment may vary, specific identification of the causative fungus is important. Routine use of combined systemic and aerosol prophylaxis during the past 2 decades has contributed to a much lower incidence of fungal infection.10 Antibody Mediated Rejection Antibody mediated rejection seems to occur rarely in recipients of lung transplants11 and is mainly a clinical diagnosis based on the presence of antibodies in the serum and a decrease in lung function. The pathologic features are rather nonspecific, and use and interpretation of staining for Arch Pathol Lab Med—Vol 140, March 2016
C4d is difficult.12,13 Thus, it is not known whether the airways are affected in this form of rejection. Airway Cellular Rejection: Grading and Impact on Therapy The significance of airway inflammation after lung transplantation remains controversial. However, there are data to suggest that any airway inflammation is an important contributor to the development of CLAD.14 These experimental data provide support to the concept that any epithelial damage in the airways leads to neoantigen exposure and the potential for development of further alloimmune and autoimmune phenomena.5 Part of the controversy arises from the site of biopsies and surrounding abnormalities. When transbronchial biopsies are performed, they are taken from the most-distal lung tissue accessible via bronchoscopy, invisible from the end of the scope, usually from airways 2 mm and smaller. Endobronchial biopsies, on the other hand, tend to be taken from airways that are more proximal and, thus, sample airways that are larger and contain cartilage.15 The absolute distinction between small and large airways cannot always be made, and some hold that the inflammation present is unimportant if it involves obviously large airways. The presence of cartilage in an airway appears to be what the pathologists are using as the definition of large airways3; it is important to emphasize that any airways sampled during transbronchial biopsy are small enough to be biopsied together with the alveoli and thus provide the continuum of airways into the parenchyma and need not be separately evaluated (Figure 4). Thus, the presence of characteristic inflammatory infiltrates (whether perivascular and/or airway) is what should define acute cellular rejection. We suggest that the term acute cellular airway rejection, rather than lymphocytic bronchiolitis/bronchitis, would simplify the evaluation process. The inflammatory infiltrate seen in acute cellular rejection has consistent characteristics and is composed primarily of activated lymphocytes with fewer eosinophils, neutrophils, and plasma cells. Acute cellular rejection is the general term for rejection and includes both perivascular and airway Airways After Lung Transplantation—Husain & Garrity 243
inflammation. Use of this term implies that airway inflammation is likely to be equally important because of perivascular inflammation in later development of submucosal airway fibrosis (bronchiolitis obliterans), and thus, it needs to be treated in a similar manner.16–18 Distinguishing infection from airway rejection remains difficult. One helpful feature is the presence of predominant neutrophils in the epithelium and submucosa, which may indicate infection (Figure 5). More recently, the presence of greater than 15% neutrophils in the bronchial alveolar lavage fluid, absent infection, has been termed neutrophilic reversible allograft dysfunction, which may be part of the etiology of restrictive allograft syndrome.19 Thus, it seems that any inflammation, regardless of cause, predisposes the patient to the development of CLAD and needs to be part of the pathologic evaluation. Once the characteristic inflammation associated with acute cellular rejection is seen in the airways, it needs to be graded in a manner similar to perivascular rejection. Because many transplant centers treat mild airway rejection (B2), which may occur with or without perivascular rejection, lumping it together with minimal airway rejection in one category (B1R as recommended in 2007 revision3) appears to be unhelpful. More studies are needed to determine the effect of airway rejection/lymphocytic bronchitis/bronchiolitis on the development of CLAD and the long-term outcome of lung transplant recipients. Chronic Lung Allograft Dysfunction Bronchiolitis obliterans syndrome is the most common form of CLAD and is diagnosed in 50% and 76% of adult patients by 5 and 10 years after transplantation, respectively.20 In children, its incidence is greater than 50% at 5 years.21 Its incidence has not significantly decreased, and it remains the most common cause of death despite incremental improvements in all aspects of patient management and medical therapies. However, during the past 15 years or so, some patients are living longer with the diagnosis. The etiology of CLAD is multifactorial and needs to be better understood before there can be major improvement in longterm outcomes after lung transplantation. CONCLUSIONS In current practice, postsurgical complications and infections of the airways are rarely seen because of better techniques and management. Acute cellular rejection of the airways can be distinguished from infection by the presence of predominant neutrophils in the latter and from microbial cultures. It is not necessary to separate small from large airways because both are risk factors for bronchiolitis obliterans. Grading of airway rejection needs to be standardized. Chronic lung allograft dysfunction consists of both bronchiolitis obliterans and restrictive allograft
244 Arch Pathol Lab Med—Vol 140, March 2016
syndrome, neither of which can be treated very effectively at present. References 1. Yousem SA, Berry GJ, Brunt EM, et al. A working formulation for the standardization of nomenclature in the diagnosis of heart and lung rejection: Lung Rejection Study Group. The International Society for Heart Transplantation. J Heart Transplant. 1990;9(6):593–601. 2. Yousem SA, Berry GJ, Cagle PT, et al. Revision of the 1990 working formulation for the classification of pulmonary allograft rejection: Lung Rejection Study Group. J Heart Lung Transplant. 1996;15(1):1–15. 3. Stewart S, Fishbein MC, Snell GI, et al. Revision of the 1996 working formulation for the standardization of nomenclature in the diagnosis of lung rejection. J Heart Lung Transplant. 2007;26(12):1229–1242. 4. Verleden GM, Raghu G, Meyer KC, Glanville AR, Corris P. A new classification system for chronic lung allograft dysfunction. J Heart Lung Transplant. 2014;33(2):127–133. 5. Weigt SS, DerHovanessian A, Wallace WD, Lynch JP III, Belperio JA. Bronchiolitis obliterans syndrome: the Achilles’ heel of lung transplantation. Semin Respir Crit Care Med. 2013;34(3):336–351. 6. Sato M, Waddell TK, Wagnetz U, et al. Restrictive allograft syndrome (RAS): a novel form of chronic lung allograft dysfunction. J Heart Lung Transplant. 2011;30(7):735–742. 7. Ofek E, Sato M, Saito T, et al. Restrictive allograft syndrome post lung transplantation is characterized by pleuroparenchymal fibroelastosis. Mod Pathol. 2013;26(3):350–356. 8. Pakhale SS, Hadjiliadis D, Howell DN, et al. Upper lobe fibrosis: a novel manifestation of chronic allograft dysfunction in lung transplantation. J Heart Lung Transplant. 2005;24(9):1260–1268. 9. Machuzak M, Santacruz JF, Gildea T, Murthy SC. Airway complications after lung transplantation. Thorac Surg Clin. 2015;25(1):55–75. 10. Laghi F, Yeldandi V, McCabe M, Garrity ER Jr. Common infections complicating lung transplantation. N J Med. 1993;90(4):317–319. 11. Saint Martin GA, Reddy VB, Garrity ER, et al. Humoral (antibodymediated) rejection in lung transplantation. J Heart Lung Transplant. 1996;15(12): 1217–1222. 12. Wallace WD, Weigt SS, Farver CF. Update on pathology of antibodymediated rejection in the lung allograft. Curr Opin Organ Transplant. 2014;19(3): 303–308. 13. Roden AC, Maleszewski JJ, Yi ES, et al. Reproducibility of Complement 4d deposition by immunofluorescence and immunohistochemistry in lung allograft biopsies. J Heart Lung Transplant. 2014;33(12):1223–1232. 14. Verleden SE, Ruttens D, Vandermeulen E, et al. Bronchiolitis obliterans syndrome and restrictive allograft syndrome: do risk factors differ? Transplantation. 2013;95(9):1167–1172. 15. Greenland JR, Jones KD, Hays SR, et al. Association of large-airway lymphocytic bronchitis with bronchiolitis obliterans syndrome. Am J Respir Crit Care Med. 2013;187(4):417–423. 16. Yousem SA. Lymphocytic bronchitis/bronchiolitis in lung allograft recipients. Am J Surg Pathol. 1993;17(5):491–496. 17. Husain AN, Siddiqui MT, Holmes EW, et al. Analysis of risk factors for the development of bronchiolitis obliterans syndrome. Am J Respir Crit Care Med. 1999;159(3):829–833. 18. Glanville AR, Aboyoun CL, Havryk A, Plit M, Rainer S, Malouf MA. Severity of lymphocytic bronchiolitis predicts long-term outcome after lung transplantation. Am J Respir Crit Care Med. 2008;177(9):1033–1040. 19. Verleden SE, Vandermeulen E, Ruttens D, et al. Neutrophilic reversible allograft dysfunction (NRAD) and restrictive allograft syndrome (RAS). Semin Respir Crit Care Med. 2013;34(3):352–360. 20. Yusen RD, Edwards LB, Kucheryavaya AY, et al; International Society for Heart and Lung Transplantation. The registry of the International Society for Heart and Lung Transplantation: thirty-first adult lung and heart-lung transplant report— 2014; focus theme: retransplantation. J Heart Lung Transplant. 2014;33(10): 1009–1024. 21. Benden C, Goldfarb SB, Edwards LB, et al; International Society for Heart and Lung Transplantation. The registry of the International Society for Heart and Lung Transplantation: seventeenth official pediatric lung and heart-lung transplantation report—2014; focus theme: retransplantation. J Heart Lung Transplant. 2014;33(10):1025–1033.
Airways After Lung Transplantation—Husain & Garrity
Context.—Lung transplantation has become a viable option for definitive treatment of several end-stage lung diseases for which there are no other options available. However, long-term survival continues to be limited by chronic lung allograft dysfunction, which primarily affects the airways. Objective.—To highlight the complications occurring mainly in the airways of the lung transplant recipient from the early to late posttransplant periods. Data Sources.—Review literature focusing on the airways in patients with lung transplants and clinical experience of the authors. Conclusions.—Postsurgical complications and infections
of the airways have decreased because of better techniques and management. Acute cellular rejection of the airways can be distinguished from infection pathologically and on cultures. Separating small from large airways need not be an issue because both are risk factors for bronchiolitis obliterans. Grading of airway rejection needs to be standardized. Chronic lung allograft dysfunction consists of both bronchiolitis obliterans and restrictive allograft syndrome, neither of which can be treated very effectively at present. (Arch Pathol Lab Med. 2016;140:241–244; doi: 10.5858/ arpa.2015-0295-SA)
L
to differentiate acute rejection from infection; thus clinicians would prefer biopsy evidence of rejection to guide therapy. The pathologic definition of acute rejection of lung has remained essentially the same during the past 3 decades (Figure 1, A and B). It is assessed by evaluation of tissue obtained by transbronchial biopsy (hematoxylin-eosin– stained sections). According to the 1990 Working Formulation for the Standardization of Nomenclature in the Diagnosis of Heart and Lung Rejection: Lung Rejection Study Group report, ‘‘acute rejection is characterized by both perivascular mononuclear infiltrates and a lymphocytic bronchitis/bronchiolitis.’’ 1(p594) The 1996 revision states, ‘‘Acute rejection is characterized by perivascular and subendothelial mononuclear infiltrates and by lymphocytic bronchitis and bronchiolitis.’’ 2(p2) In the 2007 revision, ‘‘acute rejection is characterized by perivascular mononuclear cell infiltrates, which may be accompanied by subendothelial infiltration, so-called endothelialitis or intimitis and also by lymphocytic bronchitis and bronchiolitis.’’ 3(p1230) However, the 2007 working formulation also states that ‘‘A diagnosis of acute rejection is based exclusively on the presence of perivascular and interstitial mononuclear cell infiltrates.’’ 3(p1230) This statement is the result of controversy among pathologists as to the significance of airway inflammation, distinguishing infection from acute rejection, and separating bronchioles from cartilage containing airways. Grading of acute rejection has been done for perivascular infiltrates from none (A0) to severe (A4). Airway grading has been changing over time from absent/present (in 1990) to B0B4 (1996) to B0-B2R (2007). In the most recent formulation, the B grades are low grade (B1R) and high grade (B2R) small airway inflammation/lymphocytic bronchiolitis.
ung transplantation has been practiced since the early 1980s after a moratorium by the US National Institutes of Health ended with the introduction of cyclosporine for use in clinical practice. Since then, lung transplantation has become an option for patients with very advanced lung diseases of various etiologies offering an opportunity for longer life spans and an improved quality of life. In recent years, management and modulation of the immune system via immunosuppressive drugs and subsequent improvement in surgical management and postoperative care have significantly improved outcomes. There is significant literature regarding perivascular rejection and its management. However, the focus of this article is to review the airway pathology of lung transplantation, including surgical and infectious complications and acute and chronic rejection, with special emphasis on those areas that directly affect clinical decision-making and management. DEFINITIONS AND GRADING Acute Rejection The clinical definition of acute rejection depends on recognition of abnormalities in gas exchange (hypoxemia) or airflow (lung function tests) from the transplanted lung. Caution always needs to be exercised, however, in attempting
Accepted for publication November 13, 2015. From the Departments of Pathology (Dr Husain) and Medicine (Dr Garrity), University of Chicago, Chicago, Illinois. The authors have no relevant financial interest in the products or companies described in this article. Reprints: Aliya N. Husain, MD, Department of Pathology, University of Chicago, 5841 S Maryland Ave, MC 6101, Room S627, Chicago, IL 60637 (email: [email protected]). Arch Pathol Lab Med—Vol 140, March 2016
Airways After Lung Transplantation—Husain & Garrity 241
Figure 1. Acute rejection is characterized by perivascular (A) and airway (B) inflammatory infiltrates (hematoxylin-eosin, original magnification 3200 [A and B]). Figure 2. Bronchiolitis obliterans with almost complete occlusion of the airway lumen from submucosal fibrosis. The adjacent branch of the pulmonary artery is not affected (hematoxylin-eosin, original magnification 3100). Figure 3. Restrictive allograft syndrome shows patchy fibrosis as shown here with a gross photograph of the cut surface of a transplanted lung at autopsy.
CHRONIC LUNG ALLOGRAFT DYSFUNCTION The term chronic lung allograft dysfunction (CLAD) was introduced to cover all forms of chronic graft dysfunction, including obstructive and restrictive forms, and it has been defined recently.4 Bronchiolitis Obliterans Syndrome Bronchiolitis obliterans syndrome (BOS) was first defined in the early 1990s, and is the leading cause of death in patients at 1 year after transplant.5 Its presentation is progressive obstructive physiology, with forced expiratory volume at the end of the first second of expiration (FEV1) decreasing more rapidly than forced vital capacity (FVC) on spirometry. There is usually relative hyperinflation or air trapping in the allograft because of inadequate expiratory airflow induced by small airway disease. Clinical grading of BOS may be helpful in guiding therapy. The pathology of BOS is well described and consists of patchy, submucosal fibrosis, which may partially or totally occlude the airway 242 Arch Pathol Lab Med—Vol 140, March 2016
lumen (Figure 2). It may be accompanied by varying degrees of inflammation. Restrictive Allograft Syndrome Restrictive allograft syndrome is the interstitial counterpart of BOS, manifesting as progressive, restrictive physiology with an appearance of increasing fibrosis on imaging studies.6 In this entity, the FVC decreases in conjunction with the FEV1, so restriction is the key finding on pulmonary function tests. It most often coexists with BOS. The main pathologic finding is pleuropulmonary fibrosis (Figure 3), which is progressive.7,8 It constitutes a significant minority of cases of allograft dysfunction after lung transplantation, and the understanding of this problem is still evolving. COMMENT Surgical Complications In the early postoperative period, the airway is most vulnerable at the new anastomosis of the donor-recipient Airways After Lung Transplantation—Husain & Garrity
Figure 4. A cartilage-containing airway seen on transbronchial biopsy; on the first level, cartilage was not evident, and this would have been called a bronchiole. However, at deeper levels, cartilage is present, and this would now be called a bronchus by the pathologist (hematoxylin-eosin, original magnification 3100). Figure 5. Predominant submucosal neutrophils as seen in this airway suggest infection (hematoxylin-eosin, original magnification 3400).
bronchus. Surgical technique has evolved with time, leading to the most current practice of making the anastomosis as distal in the recipient airway as possible, resulting in fewer complications at this site. Anastomotic injury is thought to be the result of ischemia of the donor airway, leading to varying degrees of necrosis, sloughing of airway epithelium, infection, and dehiscence. Healing of the injury may leave stenosis requiring intervention by dilatation, stenting, and repeated endoscopy to clean the area involved. This early injury likely has a role in the development of CLAD, dependent on its extent and severity. The other sequelae of surgery are more apt to be represented by primary graft dysfunction than by specific airway pathology, but the 2 types of injury are surely linked by common cause.9 Infectious Complications The anastomosis can be a significant site for infectious complications that may contribute to necrosis of the anastomosis and potential dehiscence. The sources of early bacterial infection can be either donor or recipient with the predominant infections in patients with bronchiectasis coming from their own flora. Airway fungal infections tend to be due to either Candida sp. or Aspergillus with those from Aspergillus considered far more serious. Candida sp. tends to be derived from the donor, whereas Aspergillus tends to occur as a hospital- or community-acquired infection with varying incidence, depending on geography. Each can cause anastomotic infection, acute bronchitis with plaque formation, and sometimes pneumonia. Because the treatment may vary, specific identification of the causative fungus is important. Routine use of combined systemic and aerosol prophylaxis during the past 2 decades has contributed to a much lower incidence of fungal infection.10 Antibody Mediated Rejection Antibody mediated rejection seems to occur rarely in recipients of lung transplants11 and is mainly a clinical diagnosis based on the presence of antibodies in the serum and a decrease in lung function. The pathologic features are rather nonspecific, and use and interpretation of staining for Arch Pathol Lab Med—Vol 140, March 2016
C4d is difficult.12,13 Thus, it is not known whether the airways are affected in this form of rejection. Airway Cellular Rejection: Grading and Impact on Therapy The significance of airway inflammation after lung transplantation remains controversial. However, there are data to suggest that any airway inflammation is an important contributor to the development of CLAD.14 These experimental data provide support to the concept that any epithelial damage in the airways leads to neoantigen exposure and the potential for development of further alloimmune and autoimmune phenomena.5 Part of the controversy arises from the site of biopsies and surrounding abnormalities. When transbronchial biopsies are performed, they are taken from the most-distal lung tissue accessible via bronchoscopy, invisible from the end of the scope, usually from airways 2 mm and smaller. Endobronchial biopsies, on the other hand, tend to be taken from airways that are more proximal and, thus, sample airways that are larger and contain cartilage.15 The absolute distinction between small and large airways cannot always be made, and some hold that the inflammation present is unimportant if it involves obviously large airways. The presence of cartilage in an airway appears to be what the pathologists are using as the definition of large airways3; it is important to emphasize that any airways sampled during transbronchial biopsy are small enough to be biopsied together with the alveoli and thus provide the continuum of airways into the parenchyma and need not be separately evaluated (Figure 4). Thus, the presence of characteristic inflammatory infiltrates (whether perivascular and/or airway) is what should define acute cellular rejection. We suggest that the term acute cellular airway rejection, rather than lymphocytic bronchiolitis/bronchitis, would simplify the evaluation process. The inflammatory infiltrate seen in acute cellular rejection has consistent characteristics and is composed primarily of activated lymphocytes with fewer eosinophils, neutrophils, and plasma cells. Acute cellular rejection is the general term for rejection and includes both perivascular and airway Airways After Lung Transplantation—Husain & Garrity 243
inflammation. Use of this term implies that airway inflammation is likely to be equally important because of perivascular inflammation in later development of submucosal airway fibrosis (bronchiolitis obliterans), and thus, it needs to be treated in a similar manner.16–18 Distinguishing infection from airway rejection remains difficult. One helpful feature is the presence of predominant neutrophils in the epithelium and submucosa, which may indicate infection (Figure 5). More recently, the presence of greater than 15% neutrophils in the bronchial alveolar lavage fluid, absent infection, has been termed neutrophilic reversible allograft dysfunction, which may be part of the etiology of restrictive allograft syndrome.19 Thus, it seems that any inflammation, regardless of cause, predisposes the patient to the development of CLAD and needs to be part of the pathologic evaluation. Once the characteristic inflammation associated with acute cellular rejection is seen in the airways, it needs to be graded in a manner similar to perivascular rejection. Because many transplant centers treat mild airway rejection (B2), which may occur with or without perivascular rejection, lumping it together with minimal airway rejection in one category (B1R as recommended in 2007 revision3) appears to be unhelpful. More studies are needed to determine the effect of airway rejection/lymphocytic bronchitis/bronchiolitis on the development of CLAD and the long-term outcome of lung transplant recipients. Chronic Lung Allograft Dysfunction Bronchiolitis obliterans syndrome is the most common form of CLAD and is diagnosed in 50% and 76% of adult patients by 5 and 10 years after transplantation, respectively.20 In children, its incidence is greater than 50% at 5 years.21 Its incidence has not significantly decreased, and it remains the most common cause of death despite incremental improvements in all aspects of patient management and medical therapies. However, during the past 15 years or so, some patients are living longer with the diagnosis. The etiology of CLAD is multifactorial and needs to be better understood before there can be major improvement in longterm outcomes after lung transplantation. CONCLUSIONS In current practice, postsurgical complications and infections of the airways are rarely seen because of better techniques and management. Acute cellular rejection of the airways can be distinguished from infection by the presence of predominant neutrophils in the latter and from microbial cultures. It is not necessary to separate small from large airways because both are risk factors for bronchiolitis obliterans. Grading of airway rejection needs to be standardized. Chronic lung allograft dysfunction consists of both bronchiolitis obliterans and restrictive allograft
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syndrome, neither of which can be treated very effectively at present. References 1. Yousem SA, Berry GJ, Brunt EM, et al. A working formulation for the standardization of nomenclature in the diagnosis of heart and lung rejection: Lung Rejection Study Group. The International Society for Heart Transplantation. J Heart Transplant. 1990;9(6):593–601. 2. Yousem SA, Berry GJ, Cagle PT, et al. Revision of the 1990 working formulation for the classification of pulmonary allograft rejection: Lung Rejection Study Group. J Heart Lung Transplant. 1996;15(1):1–15. 3. Stewart S, Fishbein MC, Snell GI, et al. Revision of the 1996 working formulation for the standardization of nomenclature in the diagnosis of lung rejection. J Heart Lung Transplant. 2007;26(12):1229–1242. 4. Verleden GM, Raghu G, Meyer KC, Glanville AR, Corris P. A new classification system for chronic lung allograft dysfunction. J Heart Lung Transplant. 2014;33(2):127–133. 5. Weigt SS, DerHovanessian A, Wallace WD, Lynch JP III, Belperio JA. Bronchiolitis obliterans syndrome: the Achilles’ heel of lung transplantation. Semin Respir Crit Care Med. 2013;34(3):336–351. 6. Sato M, Waddell TK, Wagnetz U, et al. Restrictive allograft syndrome (RAS): a novel form of chronic lung allograft dysfunction. J Heart Lung Transplant. 2011;30(7):735–742. 7. Ofek E, Sato M, Saito T, et al. Restrictive allograft syndrome post lung transplantation is characterized by pleuroparenchymal fibroelastosis. Mod Pathol. 2013;26(3):350–356. 8. Pakhale SS, Hadjiliadis D, Howell DN, et al. Upper lobe fibrosis: a novel manifestation of chronic allograft dysfunction in lung transplantation. J Heart Lung Transplant. 2005;24(9):1260–1268. 9. Machuzak M, Santacruz JF, Gildea T, Murthy SC. Airway complications after lung transplantation. Thorac Surg Clin. 2015;25(1):55–75. 10. Laghi F, Yeldandi V, McCabe M, Garrity ER Jr. Common infections complicating lung transplantation. N J Med. 1993;90(4):317–319. 11. Saint Martin GA, Reddy VB, Garrity ER, et al. Humoral (antibodymediated) rejection in lung transplantation. J Heart Lung Transplant. 1996;15(12): 1217–1222. 12. Wallace WD, Weigt SS, Farver CF. Update on pathology of antibodymediated rejection in the lung allograft. Curr Opin Organ Transplant. 2014;19(3): 303–308. 13. Roden AC, Maleszewski JJ, Yi ES, et al. Reproducibility of Complement 4d deposition by immunofluorescence and immunohistochemistry in lung allograft biopsies. J Heart Lung Transplant. 2014;33(12):1223–1232. 14. Verleden SE, Ruttens D, Vandermeulen E, et al. Bronchiolitis obliterans syndrome and restrictive allograft syndrome: do risk factors differ? Transplantation. 2013;95(9):1167–1172. 15. Greenland JR, Jones KD, Hays SR, et al. Association of large-airway lymphocytic bronchitis with bronchiolitis obliterans syndrome. Am J Respir Crit Care Med. 2013;187(4):417–423. 16. Yousem SA. Lymphocytic bronchitis/bronchiolitis in lung allograft recipients. Am J Surg Pathol. 1993;17(5):491–496. 17. Husain AN, Siddiqui MT, Holmes EW, et al. Analysis of risk factors for the development of bronchiolitis obliterans syndrome. Am J Respir Crit Care Med. 1999;159(3):829–833. 18. Glanville AR, Aboyoun CL, Havryk A, Plit M, Rainer S, Malouf MA. Severity of lymphocytic bronchiolitis predicts long-term outcome after lung transplantation. Am J Respir Crit Care Med. 2008;177(9):1033–1040. 19. Verleden SE, Vandermeulen E, Ruttens D, et al. Neutrophilic reversible allograft dysfunction (NRAD) and restrictive allograft syndrome (RAS). Semin Respir Crit Care Med. 2013;34(3):352–360. 20. Yusen RD, Edwards LB, Kucheryavaya AY, et al; International Society for Heart and Lung Transplantation. The registry of the International Society for Heart and Lung Transplantation: thirty-first adult lung and heart-lung transplant report— 2014; focus theme: retransplantation. J Heart Lung Transplant. 2014;33(10): 1009–1024. 21. Benden C, Goldfarb SB, Edwards LB, et al; International Society for Heart and Lung Transplantation. The registry of the International Society for Heart and Lung Transplantation: seventeenth official pediatric lung and heart-lung transplantation report—2014; focus theme: retransplantation. J Heart Lung Transplant. 2014;33(10):1025–1033.
Airways After Lung Transplantation—Husain & Garrity
