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Ann Thorac Surg 1995;60:1845-1853
© 1995 The Society of Thoracic Surgeons
Department of Cardiothoracic Surgery, Division of Pulmonary Medicine, and Department of Pathology, Stanford University School of Medicine, Stanford, California
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Abstract |
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 TopFootnotes Abstract IntroductionHistoryDefinition of Obliterative...PrevalenceClinical DiagnosisHistologic Features and...PathogenesisNatural Course and TreatmentThe Stanford ExperienceExperimental ResearchConclusionReferences |
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Introduction |
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TopFootnotesAbstractIntroductionHistoryDefinition of Obliterative...PrevalenceClinical DiagnosisHistologic Features and...PathogenesisNatural Course and TreatmentThe Stanford ExperienceExperimental ResearchConclusionReferences |
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History |
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TopFootnotesAbstractIntroductionHistoryDefinition of Obliterative...PrevalenceClinical DiagnosisHistologic Features and...PathogenesisNatural Course and TreatmentThe Stanford ExperienceExperimental ResearchConclusionReferences |
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Obliterative bronchiolitis was classified into three types [5]. (1) infectious, particularly of viral origin in children (eg, respiratory syncytial virus, adenovirus) [4, 6]; (2) toxic, such as from inhalation of toxic fumes (eg, nitrogen dioxide, nitric acid, ozone) [7, 8]; and (3) idiopathic. This latter group has a slower progression of the disease, and this cause has also been observed in patients with autoimmune diseases or connective tissue disorders, such as rheumatoid arthritis, eosinophilic fasciitis, and Sjögren syndrome [9–11].
The first report on OB after lung transplantation (LTx) dates back to 1968, when Hardy's group observed classic histopathologic features of OB after lung autotransplantation in dogs with extended ischemic times [12]. The first successful human pulmonary transplantation with long-term survival was achieved with combined HLTx by Reitz and associates in 1981 [13]. Burke and co-workers [14] published the clinical and histologic features of OB as a long-term complication after HLTx for the first time in 1984.
Obliterative bronchiolitis was initially thought to be a complication restricted to HLTx, and would not occur after isolated LTx. However, only a few years later, the first reports of OB in single lung transplantation (SLTx) and bilateral LTx (BLTx) were published [15, 16].
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Definition of Obliterative Bronchiolitis After Pulmonary Transplantation |
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TopFootnotesAbstractIntroductionHistoryDefinition of Obliterative...PrevalenceClinical DiagnosisHistologic Features and...PathogenesisNatural Course and TreatmentThe Stanford ExperienceExperimental ResearchConclusionReferences |
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The term BOS will be used to describe deterioration of graft function after (H)LTx secondary to progressive airway disease that is otherwise unexplained by other factors such as infection, acute rejection, or anastomotic complications. Based on the severity of pulmonary function changes (change of forced expiratory volume in 1 second [FEV1] from previous best value), BOS can be subdivided into four different categories (0: FEV1 80% to 100%; 1: 65% to 80%; 2: 50% to 65%; 3: less than 50%). The term BOS does not necessarily require histologic confirmation. The term OB is reserved for histologically proven diagnoses. This histologic diagnosis is restricted anatomically to the membranous and respiratory bronchioles and requires the presence of eosinophilic fibrous scarring of the wall of these small conducting airways with partial or complete obliteration of the lumen [18].
Thus, in this article, OB based on a clinical diagnosis will be termed BOS, whereas OB indicates a histopathologically proven diagnosis.
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Prevalence |
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TopFootnotesAbstractIntroductionHistoryDefinition of Obliterative...PrevalenceClinical DiagnosisHistologic Features and...PathogenesisNatural Course and TreatmentThe Stanford ExperienceExperimental ResearchConclusionReferences |
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As stated above, OB occurs not only after HLTx but also after isolated LTx. In the Toronto experience, the prevalence of histologically proven OB was 20% after SLTx and 14% after BLTx, with a shorter follow-up period for BLTx patients [15]. The Hannover Medical School reported a prevalence of clinically diagnosed BOS of 45% after HLTx, 37% after BLTx, and 28% after SLTx, with a tendency for earlier development of this disorder in the BLTx group [23].
In addition, pediatric patients after (H)LTx are not resistant to this long-term complication. The reported prevalence of BOS in children ranges from 25% to 47% [24, 25].
Thus, BOS or OB is a common complication after HLTx and LTx, limiting the long-term success of these procedures.
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Clinical Diagnosis |
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TopFootnotesAbstractIntroductionHistoryDefinition of Obliterative...PrevalenceClinical DiagnosisHistologic Features and...PathogenesisNatural Course and TreatmentThe Stanford ExperienceExperimental ResearchConclusionReferences |
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On examination, few clinical signs can be detected in the early stages of BOS. The expiratory phase of the breath sound is prolonged, with expiratory rhonchi becoming evident in the advanced stages [26]. Late inspiratory high-pitched sounds-``inspiratory squeaks''-are classic clinical features of BOS and are thought to be related to late opening of small airways secondary to accumulation of excess mucus and altered elastic properties of the bronchiolar wall [26]. Because of a ventilation/perfusion mismatch, hypoxemia develops as a late clinical manifestation of BOS, and hypercapnia is a preterminal finding.
Noninvasive Diagnostic Tests
The radiographic changes in patients with posttransplantation BOS are nonspecific and indistinguishable from other infectious and noninfectious processes [27]. The presence of central bronchiectasis may be a common radiographic finding in cases of advanced BOS.
High-resolution computed tomography or thin-section computed tomography may show clear abnormalities consisting of bronchial dilatation, bronchiectasis, air trapping, and patchy areas of consolidation even before any changes are visible in the chest radiograph or routine chest computed tomography [28, 29]. In addition, a progressive decline in ventilation can be detected in ventilation/perfusion scans of the lung [28, 30]. This observation becomes most notable after SLTx in patients with pretransplantation pulmonary hypertension. In these patients, BOS results in a marked ventilation/perfusion mismatch.
The most sensitive noninvasive diagnostic index of BOS is pulmonary function testing. Advanced cases of BOS have significant changes in regard to the forced vital capacity (FVC), FEV1, forced expiratory flow between 25% and 75% of FVC (FEF25-75), ratio of forced expiratory flow at 50% vital capacity to FVC (FEF50/FVC), and arterial oxygen tension compared with unaffected patients [31]. A persistent decline in FEF50/FVC and FEF25-75 without significant impairment of other indices serves as a predictor of impeding airway disease [32]. The Working Formulation on OB considered FEV1 as the most commonly used indicator of graft dysfunction [17]. Daily graft monitoring with FVC and FEV1 can be done easily at home using home spirometers [33]. The maximum inspiratory and expiratory flow-volume contour has been reported to be the most sensitive index for differentiating BOS from stenosis of the airway anastomosis [34].
Invasive Tests
Bronchoalveolar lavage (BAL) is a useful tool for diagnosis of pulmonary infections, but of limited value in diagnosing chronic rejection. However, BAL has provided valuable insight into the acute and chronic host immune response to the allograft [35, 36]. Recently, the use of transbronchial biopsies via flexible bronchoscopy has been described for diagnosis of OB. The sensitivity ranges from 17% to 87% in various centers according to the time of biopsy in relation to the onset of clinical symptoms, with higher sensitivity values in cases of clinically diagnosed BOS [37–39; Berry GJ, personal communication, 1994]. In cases of unclear diagnosis, open lung biopsies can be performed using thoracoscopy after HLTx, BLTx, and SLTx without substantial morbidity and mortality [40].
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Histologic Features and Classification |
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TopFootnotesAbstractIntroductionHistoryDefinition of Obliterative...PrevalenceClinical DiagnosisHistologic Features and...PathogenesisNatural Course and TreatmentThe Stanford ExperienceExperimental ResearchConclusionReferences |
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This classification is difficult to use in pulmonary transplantation because of an overlap between these subtypes. In 1990, a Working Formulation for the Standardization of Nomenclature in the Diagnosis of Heart and Lung Rejection published a subdivision of posttransplantation OB into two broad categories: subtotal or total OB, depending on the degree of bronchiolar obliteration. Each group was further subdivided into active (a) and inactive (b) OB depending on the presence or absence of intra- or peribronchial mononuclear cell infiltrates [42].
The histologic diagnosis of OB has been restricted anatomically to the membranous and respiratory bronchioles and requires the presence of dense fibrous scarring, which may either partially or completely obliterate the lumen of the airway (Figs 1, 2
) [18]. Because of obstruction of the small airways, the distal air spaces may become distended, and secondary acute infectious processes may be noted. Active OB has a mononuclear cell infiltrate accompanying the scarring process, reflecting ongoing damage by alloreactive lymphocytes. In contrast, inactive OB presents without these accompanying cellular infiltrates. Whether inactive OB is a consequence of active OB or a primary feature of OB remains unanswered. Large airway scarring and bronchiectasis (Fig 3) with exuberant production of mucus and potential fungal colonization are present in advanced stages of the disease.
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). Both entities must, however, be distinguished from the dense fibrous scarring representing the pathohistologic hallmark of posttransplantation OB. In cases of lymphocytic bronchiolitis, about 40% develop OB at a later stage [37].
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). The pulmonary vascular changes after HLTx correspond well with coronary graft atherosclerotic features in the transplanted heart [37, 43; Berry GJ, personal communication, 1994].
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Pathogenesis |
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TopFootnotesAbstractIntroductionHistoryDefinition of Obliterative...PrevalenceClinical DiagnosisHistologic Features and...PathogenesisNatural Course and TreatmentThe Stanford ExperienceExperimental ResearchConclusionReferences |
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This connection is understood more easily considering the fact that during acute rejection episodes, an increased number of CD 57-positive cytotoxic/natural killer cells has been found within the submucosa and the epithelium of airways [48]. Acute rejections may lead to OB either by airway-directed allograft injury or by recruitment and activation of other immune cells (delayed-type hypersensitivity) [36].
In 1987, Burke and co-workers [49] hypothesized that OB is a form of chronic rejection, resulting from an expression of major histocompatibility complex (MHC) class II antigens on the bronchial epithelium with subsequent activation of T lymphocytes and initiation of an airway-centered rejection process. In 1992, it was demonstrated that bronchial epithelium can express class II antigens and can increase this expression in case of immunologic stimulation [50]. These antigens usually are detected only on lymphoid cells, endothelial cells, or antigen-presenting cells (eg, macrophages, dendritic cells). In autopsy examinations of transplant recipients, an increased number of MHC class II antigen-positive dendritic cells was found in patients with OB compared with those without OB [51]. In addition, MHC class II-directed lymphocyte reactivity was detected in the BAL specimens of patients with OB [52]. The same group was able to differentiate between class I antigen-specific lymphocyte reactivity in patients with progressive OB and class II reactivity in patients with stable OB [53]. Thus, different immunopathogenetic events may occur in different forms of OB.
Lymphocytes infiltrating the airways in cases of active OB have also been shown to be positive for CD 57, a marker for antigen-reactive cytotoxic lymphocytes [48]. The immunohistologic findings from transbronchial or open lung biopsies in patients with OB demonstrated the predominance of CD8-positive cytotoxic/suppressor T cells [54]. Lymphocytes from both BAL specimens and peripheral blood in patients with OB were shown to express donor-specific alloreactivity using primed lymphocyte testing; patients in whom this response persisted after augmented immunosuppression therapy were at risk for progressive OB [35, 36]. In another study, donor-antigen-specific lymphocyte hyporeactivity was demonstrated in patients without OB, in contrast to those in whom OB did develop [55].
Cytokine mRNA profiles of BAL cells revealed interleukin-2 and interleukin-6 mRNA during acute rejection and in patients with OB. Transcription for interleukin-1
and interferon-
was increased in patients with OB alone [36, 56].
The role of donor/recipient human leukocyte antigen mismatch on the incidence of OB has been investigated several times, with no firm conclusion drawn from these data [22, 44]. In a recent study, however, the development of anti-HLA antibodies was demonstrated in patients with OB, implicating a humoral component in the immunologic pathogenesis of OB [57].
These theories of OB as a rejection-mediated process are supported by the fact that clinical symptoms of BOS can be improved using corticosteroids as enhanced immunosuppression therapy [20, 58]. The expression of MHC class II on bronchial epithelium has also been shown to be reversed by corticosteroid treatment [50]. The addition of azathioprine to the immunosuppressive protocol has also decreased the incidence of OB after HLTx [20].
In this context, it is worthwhile to mention that OB has also been detected in patients after bone marrow transplantation with evidence of graft versus host disease and in patients with autoimmune disorders such as rheumatoid arthritis [9, 59].
The presence of donor-derived cells in the lung allograft and other recipient organs has recently been of interest in OB-related research. Dauber and colleagues [60] showed an association between the incidence of OB and a relatively low percentage of donor-derived macrophages in the BAL specimen. In addition, patients with OB had less evidence of microchimerism in blood, lymph nodes, and skin [61]. These data suggest that the presence of microchimerism might protect LTx recipients from chronic rejection.
Other Pathogenetic Factors
A connection between cytomegalovirus (CMV) infections and the incidence of OB has been suggested. A correlation between either CMV serologic status or CMV infection and the incidence of OB has been demonstrated at the University of Pittsburgh [62]. Other institutions have also described a coincidence of CMV infections and OB [33, 63, 64]. A delayed onset of OB using gancyclovir anti-CMV prophylaxis has also been described [65, 66]. The theoretic background for this correlation between CMV and OB is obvious, considering that infection with CMV increases the number and activity of antigen-presenting cells in the graft, upregulates the immune response, and enhances donor-specific alloreactivity [35, 67]. An upregulation of interferon- has been shown in BAL cells during CMV infections, in addition to an increased expression of MHC class II antigens [36]. However, other institutions, such as the Papworth group, were not able to demonstrate a correlation between CMV infection and the incidence of OB [22].
Graft and airway ischemia have been discussed as possible causes of OB after (H)LTx [12, 68]. This theory suggests that epithelial cell injury and necrosis caused by ischemia, in addition to lymphatic disruption and chronic irritation (by impaired secretion clearance due to the denervation and poor mucociliary function), leads to the release of inflammatory mediators and growth factors and the initiation of a healing process with the production of granulation tissue.
To elucidate further the role of growth factors, increased concentrations of platelet-derived growth factors have been verified in the BAL specimens of patients with posttransplantation OB [69].
In summary, alloimmune responses are of fundamental importance in the pathogenesis of OB. This response process may be modified or accelerated by the presence of severe and persistent acute rejection episodes, certain infections such as CMV, and other causes of epithelial cell injury, such as graft or airway ischemia. All events may lead to a common pathway with release of inflammatory mediators and growth factors, resulting in luminal obliteration and fibrous scarring of the airway.
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Natural Course and Treatment |
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TopFootnotesAbstractIntroductionHistoryDefinition of Obliterative...PrevalenceClinical DiagnosisHistologic Features and...PathogenesisNatural Course and TreatmentThe Stanford ExperienceExperimental ResearchConclusionReferences |
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The main complications of OB are superimposed infections, which cause rapid deterioration in the condition of the patient and are responsible for up to 70% of OB-related deaths [71]. In this regard, recurrent airway infections and late bacterial pneumonia caused by Pseudomonas species are major concerns.
Treatment of patients with BOS remains a challenge to transplantation physicians. The first reports date back to 1986, when the beneficial effect of corticosteroids was described in patients with BOS after HLTx [58]. Subsequently, steroids have been used for the treatment of BOS either by increasing the oral steroid dosage or by administering intravenous bolus therapy [33, 72]. The effect of steroids is based on their antiinflammatory and immunosuppressive properties; in addition, the expression of MHC class II antigens on the bronchial epithelium is reversible using corticosteroids [50]. As mentioned above, the addition of azathioprine to the immunosuppressive regimen has led to a decreased incidence of OB and has slowed the rate of progression of the disease [73]. The use of antilymphocyte antibody preparations has proved effective in several cases [72]. Primary treatment with FK506-based immunosuppression therapy has so far not resulted in a decreased incidence of OB after (H)LTx [74]. However, the number of acute rejection episodes was less in the FK506-treated group; thus, with a longer follow-up, this might have an influence on the development of OB as well. A recent report on 2 patients with BOS who were switched from cyclosporine to FK506 treatment described a retarded progression of the disease with stabilization of the pulmonary function indices and subjective improvement of the patients' condition [75]. Regardless of the treatment used, early diagnosis of BOS and immediate initiation of enhanced immunosuppression protocols are crucial for therapeutic success [20, 26, 46].
Despite these efforts, retransplantation often remains the ultimate therapeutic option. The results, however, are clearly inferior to first-time transplantation procedures, with actuarial survival rates of 41% at 1 year and 33% at 2 years [76]. In patients who develop OB after SLTx, retransplantation of the affected graft offers superior survival compared with replacement of the contralateral native lung. After HLTx, the most effective method of retransplantation seems to be SLTx, as compared with repeat HLTx [77].
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The Stanford Experience |
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TopFootnotesAbstractIntroductionHistoryDefinition of Obliterative...PrevalenceClinical DiagnosisHistologic Features and...PathogenesisNatural Course and TreatmentThe Stanford ExperienceExperimental ResearchConclusionReferences |
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). The incidence of BOS within the first 3 years after transplantation decreased from 57.8% before 1986 to 36.3% thereafter. No significant difference was found in the incidence of BOS comparing HLTx and LTx recipients.
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The diagnosis of BOS has been based primarily on pulmonary function tests. Particularly after HLTx and LTx, a decline of the FEF25-75 to less than 70% predicted was the earliest predictor of BOS. Moderate to severe BOS was characterized by an irreversible reduction of the FEF25-75 to less than 30% predicted. The latter condition was consistent with reductions in FEV1 of more than 20%, as suggested by the above-cited Working Formulation of the International Society for Heart and Lung Transplantation [17].
The sensitivity of transbronchial biopsy with regard to the diagnosis of OB varies with the number of biopsy specimens taken per procedure. Since July 1992, at least eight to ten specimens were taken from different lobes. Looking at the overall experience, 70% (44 of 63) of all patients with BOS had at least one transbronchial biopsy specimen demonstrating OB. Of all specimens taken from affected patients, 77 of 251 showed OB, yielding a sensitivity of 33% for each biopsy procedure.
Superimposed bacterial, fungal, or viral infections occur frequently in patients with BOS. In the Stanford series, the incidence of gram-negative lower respiratory tract infections was increased significantly in patients with BOS. Bronchoscopy and BAL have proved helpful in the recognition and diagnosis of these superimposed infections.
Current treatment of BOS or histologically proven OB consists of augmentation of immunosuppression, aiming at high therapeutic cyclosporine levels, and a maximum dosage of azathioprine (2–4 mg•kg-1•day-1, aiming at a white blood cell count between 3,000 and 5,000 cells/µL). In cases with a progressive decrease in lung function, the dosage of corticosteroids has been augmented up to 1 mg•kg-1•day-1 and titrated according to the changes in pulmonary function tests. Concurrent acute rejection episodes have been treated aggressively with high-dose intravenous steroid pulses with or without monoclonal or polyclonal anti-thymocyte antibodies. Patients at risk for CMV disease are given a prophylactic course of ganciclovir during rejection treatment to avoid CMV reactivation as a consequence of augmented immunosuppression. Superimposed bacterial, fungal, or viral infections require immediate and aggressive antimicrobial treatment.
Analyzing the data of 122 recipients with or without BOS or OB who survived longer than 3 months after transplantation and who received the above treatment regimen, we found an actuarial survival of 83%, 66%, 46%, and 22% after 1, 3, 5, and 10 years, respectively, compared with 86%, 83%, 67%, and 67% in patients without OB (Fig 7; p < 0.05, log rank analysis). At present, the mean follow-up of patients with OB is 927.7 ± 139.9 days (range, 45 to 3,346 days). After the diagnosis of BOS, the mean survival of all affected patients has been 66%, 44%, 37%, and 10% after 1, 3, 5, and 10 years, respectively. Of all patients who died from OB, the mean survival after the diagnosis was 655.9 ± 124.2 days (range, 0 to 2,952 days). The cause of death in the patients with OB was related to pneumonia (bacterial, viral, or fungal) and respiratory failure in 61.1%, to respiratory failure from diffuse alveolar damage in 16.6%, to septicemia in 13.8%, and to other nonpulmonary causes in only 11.1%.
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Experimental Research |
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TopFootnotesAbstractIntroductionHistoryDefinition of Obliterative...PrevalenceClinical DiagnosisHistologic Features and...PathogenesisNatural Course and TreatmentThe Stanford ExperienceExperimental ResearchConclusionReferences |
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In the miniature swine model, evidence of OB was reported 6 months after SLTx, with initial immunosuppression for 4 months after operation [82]. Immunohistochemistry results revealed similar immunologic changes as described above after rat-SLTx.
In 1993, Hertz and colleagues [83] published a reproduction of the OB lesion after heterotopic transplantation of mouse tracheae. Characteristic features of OB were described as soon as 21 days after subcutaneous implantation of these airways. Using this model, the same group was able to reproduce the same obliterative lesion in isografts by local application of various growth factors [84].
This model of obliterative airway disease was reproduced at Stanford University in rats using different implantation sites of rat airways (subcutaneous tissue, renal capsule, major omentum) [85]. This is a simple and easily reproducible surgical technique that produces characteristic features of posttransplantation OB as early as 14 to 28 days after implantation. Immunohistochemistry studies revealed a possible immunologic origin of this airway obliteration. The role of growth factors in the pathogenesis of the lesion was demonstrated using in situ hybridization techniques. Treatment with some of the newer immunosuppressive drugs was able to change the histopathologic picture of the implanted airways; some drugs were able to slow down the obstructive process, whereas other drugs (eg, rapamycin) even prevented luminal obliteration completely [86]. This model not only aids understanding of the biology and pathogenesis of airway obliteration, but also allows study of its prevention and therapy and the nature of the drug action on the pathologic process.
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Conclusion |
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TopFootnotesAbstractIntroductionHistoryDefinition of Obliterative...PrevalenceClinical DiagnosisHistologic Features and...PathogenesisNatural Course and TreatmentThe Stanford ExperienceExperimental ResearchConclusionReferences |
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Footnotes |
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TopFootnotesAbstractIntroductionHistoryDefinition of Obliterative...PrevalenceClinical DiagnosisHistologic Features and...PathogenesisNatural Course and TreatmentThe Stanford ExperienceExperimental ResearchConclusionReferences |
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References |
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TopFootnotesAbstractIntroductionHistoryDefinition of Obliterative...PrevalenceClinical DiagnosisHistologic Features and...PathogenesisNatural Course and TreatmentThe Stanford ExperienceExperimental ResearchConclusionReferences |
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H. Reichenspurner, R. E. Girgis, R. C. Robbins, K. L. Yun, M. Nitschke, G. J. Berry, R. E. Morris, J. Theodore, and B. A. Reitz Stanford Experience With Obliterative Bronchiolitis After Lung and Heart-Lung Transplantation Ann. Thorac. Surg., November 1, 1996; 62(5): 1467 - 1472. [Abstract] [Full Text]
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E. M. Baudet, C. Dromer, J. Dubrez, J. B. Jougon, X. Roques, J.-F. Velly, C. Deville, L. Couraud, and T. B. L. a. H.-L. T. Group INTERMEDIATE-TERM RESULTS AFTER EN BLOC DOUBLE-LUNG TRANSPLANTATION WITH BRONCHIAL ARTERIAL REVASCULARIZATION J. Thorac. Cardiovasc. Surg., November 1, 1996; 112(5): 1292 - 1300. [Abstract] [Full Text]
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