The two forms of bronchiolitis obliterans in heart-lung transplant recipients

Original Contributions The Two Forms of Bronchiolitis Obliterans in Heart-Lung Transplant Recipients EVELYN C. ABERNATHY, MD, RALPH H. HRUBAN, MD, WILLIAM A. BAUMGARTNER, MD, BRUCE A. REITZ, MD, AND GROVER M. HUTCHINS, MD Bronchiolitis ohliterans has emerged as the major long-term complication of heart-lung transplantation. We reviewed the histologic findings in lungs obtained from 11 patients who had received a combined heart-lung transplant at The Johns Hopkins Hospital. Ten lungs were obtained at autopsy, and one was obtained from a patient who was retransplanted because of severe bronchiolitis obliterans. Bronchiolitis obliterans was identified in seven of these 11 lungs. Three of the seven lungs with bronchiolitis obliterans were from patients who had received their transplants more than 6 months previously; the bronchiolitis obliterans in these patients was characterized by a relatively acellular concentric fibrosing process that was limited to the terminal bronchioles. The bronchiolitis obliterans in these three patients was felt to be secondary to chronic lung allograft rejection. Four of the seven patients with bronchiolitis obliterans had received their transplants less than 6 months previously; the bronchiolitis ohliterans in these patients was focal and cellular. It extended into the distal alveolar spaces and, in several cases, was associated with aspirated material and foreign body-type giant cells. All four of these patients had concurrent infections, aspiration, or large airway obstruction, which were felt to be responsible for the development of bronchiolitis obliterans. Bronchiolitis ohliterans in lung allograft recipients may have a variety of etiologies, and the etiology of this process in a particular case can often be deduced by the morphologic appearance of this lesion. HUM PATHOL 22:1102-l 110. Copyright 0 1991 by W.B. Saunders Company

ization of the nomenclature in the diagnosis of pulmonary rejection, chronic rejection is defined by the presence of bronchiolitis obliterans.7 A variety of processes unrelated to rejection may also cause bronchiolitis obliterans. These include viral and bacterial infections, toxic inhalants, bronchial obstruction, and chronic aspiration.‘-‘” While these processes may affect the lung allograft recipient as well as the nontransplanted patient, it is in the lung transplant recipient that bronchiolitis obliterans due to rejection must be distinguished from bronchiolitis obliterans unrelated to rejection. The purpose of this study was to examine the morphologic appearance of bronchiolitis obliterans in lung allograft recipients to determine the clinical and pathologic distinctions between rejection- and nonrejectionrelated bronchiolitis obliterans. This is primarily a morphologic study, and the terms “pure bronchiolitis obliterans” and “bronchiolitis obliterans with organizing pneumonia” are used as descriptive morphologic terms. Their use is not meant to connote specific clinicopathologic entities.

Combined heart-lung transplantation is an effective therapy for otherwise fatal cardiopulmonary disease.‘.2 Despite improvements in patient management, bronchiolitis obliterans remains the major complication in long-term survivors, occurring in up to 50% of these patients.“,” Although a variety of etiologies have been proposed for the development of bronchiolitis obliterans in heart-lung transplant recipients, the most commonly held view is that it reflects chronic lung allograft rejection. This view is supported by the finding that augmented immunosuppressive therapy can slow or arrest the progress of bronchiolitis obliterans in these patients.‘.” Indeed, in a recent proposal for the standard-

METHODS

From the Department of Pathology and the Cardiac Surgery Division of the Department of Surgical Sciences, The Johns Hopkins Medical Institutions, Baltimore, MD. Accepted for publication January 14. 1991. Kq wor& lung transplantation, lung pathology, bronrhiolitis obliterans. bronchiolitis obliterans organizing pneumonia. Address correspondence and reprint requests to Ralph H. Hruban, MD. Depal-tment of Pathology, The Johns Hopkins Hospital, Baltimore, MD 21205. Copyright 0 199 1 by W.B. Saunders Company 0046.8177/91/221 I-0006$.5.00/0

1102

Between November 1983 and October 1990, 18 patients received a total of 19 heart-lung transplants at The Johns Hopkins Hospital. Each of these transplants has been assigned a unique number (HL-1 to HL-19). Sets of lungs from 11 of these transplants have been examined pathologically. 10 at autopsy and one at retransplantation. One lung from each patient (either the left or right lung) was processed in a routine fashion. The other lung was inflation-fixed and air-dried by a method that allows for detailed gross and microscopic examination of the lung parenchyma. ” Bronchiolitis obliterans was identified histologically in seven of these 11 lungs (HL-4, HI,6, HL-8, HL-13, HL-14, HL-16, and HL-18). These seven cases form the basis of this study. All tissue was fixed in 4% buffered formaldehyde solution, processed, sectioned, and stained routinely with hematoxylineosin. At least six histologic sections were examined from each lung. Particular attention was paid to pathologic changes in the distal airways and airspaces. For purposes of classification, terminal bronchioles were defined as tubular airways less than 2 mm in diameter, each of which supplies a pulmonary acinus. Respiratory bronchioles were defined as those bronchioles directly supplying alveoli and lacking ciliated epithelium.

BRONCHIOLITIS

1’1~~plimts

included

OBLITERANS

in this study were followed

IN LUNG TRANSPLANTATION

by home

spir-ornetrv and. with the exception of HLA, formal pulmonary function ;ests were not l~crfornied. RESULTS

‘l‘able 1 summarizes the clinical findings in the seven heart-lung transplant recipients with bronchiolitis obTABLE 2.

-Iii

(hloodt

HSV

(hloodl

et al)

literans. Three of the seven patients with bronchiolitis obliterans (HI.4, HI,-6, and HL-8) survived longer than 6 months (mean, 11 months), while four (HI,-13, HL14. HI,-16, and HL-18) did not (mean, 2.7 months). The mean donor age for the three long-term (>6 months) survivors was 19 years (range, I2 to 32 years) and the mean recipient age was 31 years (range, 26 to

Infections in the Seven Patients With Bronchiolitis

Ill:IS III

(Abernathy

Obliterans

HUMAN PATHOLOGY

Volume 22, No. 11 (November

1991)

FIGURE 1. Gross (A) and microscopic (B) sections of an inflation-fixed and air-dried lung from a long-term survivor (HL-6) with rejection-related pure bronchiolitis obliterans. Note the abrupt termination of the bronchiectatic airways (arrows) at the foci of pure bronchiolitis obliterans (B, arrowhead) and the remarkable preservation of the surrounding alveoli. (Hematoxylin-eosin stain; . magnification X 18.)

40 years). The mean ischemic time for these three patients was 136 minutes (range, 44 to 296 minutes). One of the three had two class I major histocompatibility antigen matches with the donor, one had one match, and one had no matches. None of these three patients was HLA-DR matched with the donor. The infectious complications these patients developed following their transplantations are listed in Table 2. They experienced from one to four episodes of acute pulmonary rejection. The mean length of survival posttransplant for the four patients who survived less than 6 months was 2.7 months (range, 1.4 to 4.5 months). The mean donor age for these patients was 26 years (range, 4 to 45 years), and the mean recipient age was 26 years (range, 7 to 4 1 years). The mean ischemic time for these four patients was 248 minutes (range, 196 to 310 minutes). One of these four patients had two class I major histocompatibility antigen matches with the donor, two had one, and one had none. Two of these patients had at least one HLA-DR match with their donors. The infectious complications these patients developed following their transplants are listed in Table 2. None of these patients had a documented episode of acute pulmonary rejection. Gross Findings Inflation-fixed, air-dried lungs were available for detailed gross examination from six of the seven patients 1104

with bronchiolitis obliterans (HL-6, HL-8, HI,-1 3, HL14, HL-16, and HL-18). The lungs from the two longterm survivors available for review (HL-6 and HL-8) were characterized by severe bronchiectasis. These bronchiectatic airways extended into the peripheral lung parenchyma, where they appeared to end abruptly (Fig 1). In contrast, the alveolar architecture and airspaces in these lungs were remarkably well preserved. Two of the four sets of lungs from the patients who survived less than 6 months (HL-13 and HL-16) were remarkable only for focal fibrosis, while the other two patients’ (HL-14 and HL-18) lungs were characterized by focal bronchiectasis and patchy alveolar airspace consolidation (Fig 2). Histologic

Findings

Histologic material was available from all seven cases. The bronchiolitis obliterans in the three long-term survivors was characterized by a diffuse, relatively acellular fibrosing process, which concentrically narrowed the lumina of the terminal bronchioles (Fig 3). The larger cartilaginous airways proximal to the obliterated bronchioles showed an intraepithelial lymphocytic infiltrate, 1". 13 as did the terminal bronchioles. The airspaces distal to the obliterated bronchioles were patent and generally not involved by the inflammatory process. This histologic appearance has been termed “pure obliter-

BRONCHIOLITIS

OBLITERANS

IN LUNG TRANSPLANTATION

(Abernathy

et ai)

with FIGURE 2. 13oss cross-sections of inflation-fixed and air-dried lungs from two of the short-term survivors [:A mi..-1L’ ~3 Wl8) bronchiolitis obliterans with organizing pneumonia. In contrast to the gross appearance of the lungs from the lang-term survivor with rejecticr-related pure bronchiolifis obliterans (see Fig I), these lungs are remarkable for focal airspace consoklation (arrows)

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HUMAN PATHOLOGY

Volume 22, No. 11 (November

1991)

FIGURE 3. Histologic sections from a long-term survivor (HL-6) with rejection-related pure bronchiolitis obliterans (arrows). Note the concentric narrowing of the bronchiolar lumina and the relative sparing of the airspaces of the surrounding alveoli (Fig 38 corresponds to Fig IB). (Hematoxylin-eosin stains. Magnifications: A, x 100: B, x 125.)

transplant, she developed fever and diffuse interstitial infiltrates on chest radiography. Open lung biopsy revealed perivascular mononuclear cell inflammation while endomyocardial biopsy consistent with rejection,‘, showed no rejection. Temporary improvement was achieved with steroid treatment. Recurrent episodes of respiratory decompensation at 3 weeks, 6 months, 9 months, and 11 months were treated with pulse steroids. Pulmonary function tests performed 9 months after transplantation revealed severe obstructive and mild restrictive ventilator-y defects with a forced vital capacity of 0.87 L, a forced expiratory volume of 0.56 L, an arterial oxygen tension of 70 mm Hg, and an arterial carbon dioxide tension of 35 mm Hg. Pure bronchiolitis obliterans was present on open lung biopsy at 11 months. Pneumocystis carinii and Candida albicans were seen in bronchial washings at 1 year during an episode of severe respiratory failure. Pulmonary function did not improve with amphotericin B and trimethoprim sulfamethoxazole treatment. A second heart-lung transplant (HL-9) was performed 14 months after the first. The patient died 12 hours later. Examination of the first allograft (HL-6) revealed extensive pure bronchiolitis obliterans (Figs 1, 3, and 4) with dense concentric fibrosis of the terminal bronchioles, mild intimal proliferation in medium-sized vessels, severe bronchiectasis, 1106

and a severe lymphocytic bronchitis and bronchiolitis.‘“.“’ These findings are all consistent with severe chronic lung allograft rejection.7 HL-13. Patient HI,-1 3 was a 41-year-old woman with idiopathic primary pulmonary hypertension who underwent combined heart-lung transplantation in 1988. She received 0KT3, cyclosporine, and imuran immunosuppressive therapy. She was cytomegalovirus seronegative and she received cytomegalovirus seropositive organs. She received immune globulin prophylaxis during her entire postoperative course, which was complicated by bronchial cultures positive for Hemophilus influenza and S aureus, with purulent respiratory secretions and exudate around the tracheal anastomosis on bronchoscopic evaluation. One month posttransplant S aureus was cultured from pleural fluid. Mild acute rejection was noted on endomyocardial biopsy. The patient suffered progressive respiratory deterioration and died 7 weeks posttransplantation. Pulmonary function tests were not performed on this patient. Examination of the lungs at autopsy revealed bronchiolitis obliterans with organizing pneumonia (Fig 5) associated with a diffuse cytomegalovirus pneumonitis. Other autopsy findings included cytomegalovirus infection of the spleen, liver, heart, and adrenals. No evidence of pulmonary or cardiac rejection was identified.

BRONCHIOLITIS

OBLITERANS

IN LUNG TRANSPLANTATION

(Abernathy

et al)

FIGURE 4. The end stage of the pure form of bronchiolitis obliter ‘ans is characterized by the complete obliteration of the lumina of the terminal bronchioles, resulting in the appearance of fibrous (:ords. (Hematoxylin-eosin stains. Magnifications: A, ~50; B, X100.)

DISCUSSION Combined heart-lung transplantation is an effective therapy for otherwise fatal pulmonary vascular and parenchymal diseases.‘,’ The major long-term complication of this procedure has been the development of bronchiolitis obliterans. Bronchiolitis obliterans develops in approximately one third to one half of the patients who leave the hospital following heart-lung transplantation,“,4 and it can lead to graft failure and patient death. While considerable debate still exists as to the etiology of the bronchiolitis obliterans in lung transplant recipients, there is a growing body of evidence to suggest that some cases of bronchiolitis obliterans are manifestations of allograft rejection.‘ti,‘7 Heart-lung transplant recipients are, however, also susceptible to the development of nonrejection-related bronchiolitis obliterans.‘” For example, heart-lung transplant recipients are immunosuppressed and therefore susceptible to a variety of infections, including infections by agents like cytomegalovirus, which are themselves associated with the development of bronchiolitis obliterans.‘“~‘” Indeed, in a recent proposal for the standardization of the nomenclature in the diagnosis of pulmonary rejection, it was emph,asized that bronchiolitis obliterans secondaq to lung allograft rejection must be distinguished from bronchiolitis obliterans due to infection and other nonrejection-related processes.7 The purpose of this study 1107

was to examine the morphologic appearance of bronchiolitis obliterans in heart-lung transplant recipients to determine if bronchiolitis obliterans due to rejection differs in any way from bronchiolitis obliterans unrelated to rejection. We examined the gross and microscopic features of the lungs from seven patients who developed bronchiolitis obliterans following heart-lung transplantation. Four of the lungs were obtained from patients who survived less than 6 months following transplantation. The bronchiolitis obliterans in these four patients was directly associated with either an infections process, evidence of aspiration, or proximal airway obstruction. The bronchiolitis obliterans in these four patients was therefore felt to be caused by nonrejection-related processes, and it had the morphologic appearance of “bronchiolitis obliterans with organizing pneumonia.““‘~‘” Three of the lungs were obtained from patients, who survived longer than 6 months following transplantation. The bronchiolitis obliterans in these three cases was not directly associated with proximal airwav obstruction, infectious processes, or aspiration, but’in:jtead was clinically and pathologically typical of the process reported to be secondary to chronic allograft rejection.‘.“.‘” The bronchiolitis obliterans in these cases dif‘usely involved the lung parenchyma and had a morphologic appearance best characterized as “pure obliterative bronchiolitis.“” These observations suggest that bronchiolitis ob-

HUMAN PATHOLOGY

Volume 22, No. 11 (November

1991)

FIGURE 5. In contrast to the pure form of bronchiolitis obliterans seen in the long-term survivors, the bronchiole pathology in this short-term survivor (HL-13) was characterized by the presence of bronchiolitis obliterans with organizing pneumonia (arrows). The fibrosing process extends into the airspaces of the surrounding alveoli (arrowhead). (Hematoxylin-eosin stains. Magnifications: A, ox100: B, ~100.)

literans due to lung- allograft rejection has a morphologic appearance different from bronchiolitis ohliterans unrelated to rejection. While the distinction between the two forms of bronchiolitis obliterans is useful in separating cases of re,jection fiwn those not due to rejection, it must be emphasized that there is some overlap. For example, one of the seven patients we examined (HI,16) had both types of lesions. It is also possible that the two forms of bronchiolitis may represent diRerent stages of obliterans identified obthe same process. In other words. the bronchiolitis literans with organizing pneumonia found in the four patients who died less than 6 months following transplantation may represent an active form of bronchiolitis obliterans, while the pure bronchiolitis obliterans found in the three long-term survivors may represent an inobliterans. While we cannot active [or-111 of bronchiolitis rule out this possibility, we feel it is unlikely for three reasons. First, in the three patients in whom bronchiolitis obhterdns was identified in bronchoscopic or open lung biopsies performed prior to the time of death or retransplantation, the form of bronchiolitis obliterans identified in the biopsies was the same as that found on subsequent examination of the entire lung. Second, the two forms of bronchiolitis obliterans differ not by the presence or absence of an active inflammatory cell infiltrate, but instead by the character and distribution of

1108

the infiltrate. In bronchiolitis obliterans with organizing pneumonia, the infiltrate involves both the terminal bronchioles and the alveolar airspaces and is composed of macrophages, lymphocytes, and spindle-shaped cells. In the pure form of bronchiolitis obliterans, the inflammatory process consists of a lymphocytic infiltrate in the epithelium of the bronchi and terminal bronchioles. Third, the bronchiolitis obliterans in the four lungs obtained from patients who survived less than 6 months was directly associated with nonrejection-related processes known to predispose to the development of bronchiolitis obliterans, while in the three long-term survivors it was not. While we cannot establish with certainty that the bronchiolitis obliterans that developed in the three longterm survivors was due to lung allograft rejection, there is a growing body of evidence which suggests that some cases of bronchiolitis obliterans are due to rejection.“i,‘7 For example, the failure of experimental autografts to develop bronchiolitis obliterans suggests that this lesion is not merely due to the transplant procedure itself, and the development of bronchiolitis obliterans in bone marrow transplant recipients with graft-versus-host disease suggests that bronchiolitis obliterans can be immunologically induced. ‘“z’.” Perhaps the strongest evidence that bronchiolitis obliterans is a manifestation of lung allograft rejection comes from a recent study by

BRONCHIOLITIS

OBLITERANS

IN LUNG TRANSPLANTATION

\

Lymphocyte FIGURE 6. Acute lung allograft rejection is associated with lymphocyte-mediated epithelial cell injury. Proximally (A) this process is manifested by bronchiectasis and a lymphocytic bronchiolitis with individual epithelial cell necrosis, while distally (B) it is characterized by a lymphocytic bronchiolitis and the development of pure bronchiolitis obliterans.


(Abernathy

et al)

HUMAN PATHOLOGY

Volume 22, No. 11 (November

17. Burke CM, Glanville AR, Theodore J, et al: Lung immunog&city. rejection. and obliterative bronchiolitis. Chest 92:547-549, 1987 18. razelaar HD, Yousem SA: The pathology of combined heartlung transplantation: An autopsy study. HUM PATHOI. 19:1403-1416, 1988 19. Fend F, Prior C, Margreiter R. et al: Cytomegalovirus pneumonitis in heart-lung transplant recipients: Histopathology and clinicopathologic considerations. HLIhl PATHOL. 21:918-926. 1990 20. Dutnmer JS. White LT, Ho M, et al: Morbidity of cytomegalovirus infection in recipients of heart or heart-lung transplants who received cyclosporine. J Infect Dis 152: 1182-I 191. 1985 21. Burke CM. Theodore J, Dawkins KD, et al: Post-transplant obliterative bl-onchiolitis and other late lung sequelae in human heartlung transplantation. Chest 86:8?4-829, 1984 22. Hruban RH, Hutchins GM: The patholog)’ of lung transplantation, in Baumgartner WA, Reitr BA, Achuff SC (eds): Heart and Heart-Lung Transplantation. Philadelphia, PA, Saunders, 1990, pp 37?-381) 23. Prop J. Ehrie MG, Crapo I), et al: Reimplantation response in isografted rat lungs. Analysis of causal factors. J Thorax Cardiovasc Surg 87:702-710. 1984 2-4 Urbanski SJ, Kossakowska AE, Curtis J, et al: Idiopathic small airways pathology in patients with graft-versus-host disease following allogeneic bone marrow transplantation. Am J Surg Pathol I 1:965971, 1987

1991)

25. Clelland C, Higenbottam T. Otulana B. et al: Histologic prognostic indicators for the lung altografts of heart-lung transplants. J Heart Transplant 9: 177-l 86, 1990 26. Hruban RH, Beschomer WE, Baumgartner WA, et al: Dagnosis of lung allograft rejection by bronchial intraepithelia] 1.~1-7 positive T lymphocytes. J ‘fhorac Cardiovasc Surg 96:939-946, 1988 27. Hruban RH, Beschorner WE. Hutchins GM: I.ymphoc-ytic bronchitis and lung allograft rejection. Transplantation 50:793, 1990 (letter) 2X. Lane BP, Habicht (3, Jasper GS: I~ymphocyte-epithelirllll interaction during rejection of nonisogeneic rat trachral grafts. Am J Path01 86:71-80. 1977 29. Adamson IYR. Young I,, Bowden DH: Relationship of alveolar epithelial injury and repair to the induction 01 pulmonary tibrosis. Am J Path01 130:377-38X. 1988 30. Adamson IYR. Hedgecock C, Bowden DH: Epithclial ct~llhhroblast interactions in lung injury and repair. Am J Pathnl 137: 385-392, 1990 31. Cathrart MK, Emdur Ll. Ahtiala-Stewart K. et al: Excessivr helper T-cell function in patient5 with idiopathic pulmonan fihl-osis: Correlation with diseasr activity. Clin Immunol Immunopathol 4:3: 382-394, 1987 32. Piguet PF. Collar-t MA. C;rau GE. et al: Requit-ement 01. tumour necrosis fat tor fol- development of silica-induced pulmona~-) fibrosis. Nature 344:2-l.%247, 1990

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