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Ann Thorac Surg 1996;62:1467-1472
© 1996 The Society of Thoracic Surgeons
Departments of Cardiothoracic Surgery and Pathology, Division of Pulmonary Medicine, Stanford University School of Medicine, Stanford, California
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Abstract |
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 TopFootnotes Abstract IntroductionMethods and ResultsCommentReferences |
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Methods. Since 1981, 135 HLTxs and 61 isolated LTxs were performed in 184 patients at Stanford University.
Results. The overall prevalence of OB in patients surviving longer than 3 months postoperatively was 64% after HLTx and 68% after LTx. The actuarial freedom from OB was 72%, 51%, 44%, and 29% at 1, 2, 3, and 5 years, respectively, after HLTx and LTx. An analysis of potential risk factors revealed that the frequency and severity of acute rejection episodes (p < 0.001) and the appearance of lymphocytic bronchiolitis on biopsy (p < 0.05) were significantly associated with the development of OB. With regard to diagnosis of OB, pulmonary function tests show early reductions of the forced expiratory flow between 25% and 75% of the forced vital capacity with subsequent decreases in the forced expiratory volume in 1 second. The sensitivity of transbronchial biopsies has increased to 71% since 1993. Current treatment consists of augmented immunosuppression. Concurrent acute rejection episodes or active OB on biopsy have been treated aggressively with high-dose steroid pulses. Analysis of data from 73 patients with OB after HLTx and LTx revealed actuarial 1-, 3-, 5-, and 10-year survival of 89%, 71%, 44%, and 17% versus 86%, 77%, 63% and 56% in patients without OB (p < 0.05 by log-rank analysis). The main complication and cause of death in patients with OB was superimposed respiratory tract infection, which was treated aggressively.
Conclusions. Early diagnosis of OB using pulmonary function tests or transbronchial biopsy is possible and important, because immediate treatment initiation has led to acceptable survival rates, with nearly 50% of affected patients still alive 5 years after transplantation. Current experimental research on OB suggests that immune injury is the main pathogenetic event of airway obliteration in animal models; rapamycin and leflunomide are new immunosuppressive agents that may have the potential to prevent and treat airway obliteration.
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Introduction |
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TopFootnotesAbstractIntroductionMethods and ResultsCommentReferences |
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Obliterative bronchiolitis (OB) is currently the main cause of morbidity and mortality in the long-term survivors after heart-lung (HLTx) and lung transplantation (LTx). Posttransplantation OB was first described by Burke and colleagues [1] from Stanford University as an unexpected complication after HLTx. Since then, several reports have been published describing the incidence and prevalence of OB in various transplant centers and after different lung transplant procedures [2, 3]. Obliterative bronchiolitis is currently thought to be predominantly the result of a chronic rejection process leading to obliteration and scarring of the terminal bronchioles. Recently, a review article on the history, pathogenesis, and treatment of this complication has been published, as well as reports from other centers on this long-term complication [4–6]. This article will focus on the current incidence, risk factors, diagnosis, management, and out-come of OB at Stanford University including recent research data.
For the purposes of uniformity in definition, a Working Formulation Group of the International Society for Heart and Lung Transplantation has published criteria for the clinical diagnosis of the bronchiolitis obliterans syndrome (BOS). The term BOS was agreed upon for those patients with a more than 20% decline in their forced expiratory volume in 1 second (FEV1) compared with their previous highest posttransplantation baseline value. This deterioration of pulmonary function after LTx or HLTx should be unexplained by other factors such as infection, acute rejection, or bronchial anastomotic complications. This Working Formulation Group reserves the term OB for histologically proven disease and requires the presence of eosinophilic fibrous scarring in the walls of the small conducting airways, with partial or complete obliteration of the lumen [7, 8].
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Methods and Results |
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TopFootnotesAbstractIntroductionMethods and ResultsCommentReferences |
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In patients surviving longer than 3 months after the transplant procedure, the prevalence of BOS or histologically proven OB is currently 64.6% after HLTx and 67.8% after LTx. The incidence of BOS within the first year after HLTx and LTx is 28.1%. The actuarial freedom from BOS or OB is 82%, 59%, 50%, and 34% at 1, 2, 3, and 5 years after HLTx and 67%, 47%, 42%, and 15% at 1, 2, 3, and 5 years after LTx (Fig 1
). The difference when comparing prevalence and incidence data of BOS or OB after HLTx versus LTx did not show statistical significance.
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Diagnostic Tests
In addition to the above-described changes in FEV1, several different pulmonary function parameters have been evaluated to enable an early and reliable diagnosis of BOS/OB. One of the examined parameters of small airway function has been the forced expiratory flow between 25% and 75% of the forced vital capacity (FEF25–75). A comparison of the Stanford data on the FEF25–75 and FEV1 was performed in 30 patients with progressive BOS. The results of this study revealed that a decrease in the FEF25–75 to less than 70% of predicted occurred before a decline of 20% in the FEV1 was noted. Similarly, when a 20% or greater decline in the FEV1 had occurred, the relative decrease in the FEF25–75 was consistently more severe, showing values of less than 30% of predicted. The data support our opinion that the FEF25–75 is a more sensitive indicator of the presence of mild BOS/OB than are changes in FEV1. We therefore suggest that the criterion for clinical onset of BOS be an irreversible reduction in the FEF25–75 to less than 70% of predicted. Advanced BOS was characterized by irreversible reduction of the FEF25–75 to less than 30% of predicted. The latter condition was consistent with reductions in FEV1 of more than 20%, as suggested by the Working Formulation of the International Society for Heart and Lung Transplantation [7].
In addition, measurement of the specific airway conductance also allowed early diagnostic hints for impending BOS. Specific airway conductance was determined via body plethysmography by measuring airway resistance and intrathoracic gas volume. The mean specific airway conductance in 26 patients without BOS was 0.22 L • s-1 • cm H2O-1 • L-1. In 44 patients with BOS, the value dropped from their posttransplantation best baseline value of 0.21 L • s-1 • cm H2O-1 • L-1 to 0.09 L • s-1 • cm H2O-1 • L-1 (p < 0.0001 compared with non-BOS patients). Further analysis revealed that the specific airway conductance decreased in 42% of patients ultimately diagnosed with BOS or OB, before the changes in FEV1 were noted.
The sensitivity of transbronchial biopsies for diagnosis of OB had previously been analyzed, revealing low sensitivity values [9]. Looking at the overall experience, 69.8% of all patients with BOS had at least one positive transbronchial biopsy with evidence of OB during their follow-up. Of all specimens taken from affected patients, 77 of 251 specimens showed evidence of OB, yielding a total sensitivity of 30.7% for each biopsy specimen taken. Since July 1993, the biopsy protocol has been modified, and at least eight to ten tissue specimens are taken from different pulmonary lobes. Since then, the sensitivity of transbronchial biopsy procedures has improved to 71.4%; in 42.8% of all cases, the transbronchial biopsy was the earliest diagnostic test for OB, even before a change in pulmonary function tests (decrease in FEV1) was observable.
Superimposed bacterial or fungal infections are common complications in patients affected with BOS. Analyzing the data of 51 patients at Stanford University, the percentage of patients with superimposed pulmonary infections caused by gram-negative pathogens was 53% in patients with BOS. For detection and immediate treatment for accompanying infectious complications, bronchoscopy, bronchoalveolar lavage, and transbronchial biopsies have proved to be extremely helpful.
Treatment and Management of Affected Patients
Current treatment of BOS or OB consists of augmentation of immunosuppression. Immediately after the first positive diagnostic signs suggestive of impending BOS/OB, the cyclosporin dose is increased to maximum trough levels (around 200 ng/mL serum level by polyclonal assay), based on close monitoring of any impairment in renal function. In addition, the azathioprine dose is increased to 2 to 4 mg • kg-1 • day-1, aiming at a white blood cell count between 3,500 and 5,000 cells/µL. Particularly in progressive cases, the oral steroid dose is also increased to 1 mg • kg-1 • day-1 in divided doses. The steroid medication is then titrated down according to changes in pulmonary function testing. In the case of concomitant acute rejection episodes diagnosed by biopsy or in the case of histologic proof of active OB, the patients are treated with intravenous pulses of corticosteroids (500 mg to 1 g of methylprednisolone per day for 3 consecutive days); in steroid-resistant cases, monoclonal or polyclonal antilymphocyte preparations have been used for 10 to 14 days on rare occasions. With any increase of the total oral or intravenous steroid dose, patients at risk for CMV disease prophylactically receive ganciclovir as CMV prophylaxis for the duration of the steroid dose increase. If patients are hospitalized, inhaled amphotericin B is used as prophylaxis for fungal infections, because the number of fungal infections has decreased significantly at our institution since the introduction of postoperative inhaled amphotericin prophylaxis [10]. If there is any evidence of superimposed bacterial, viral, or fungal pulmonary infection, specific antimicrobial treatment is initiated immediately.
Altogether 4 patients underwent retransplantation due to severe BOS/OB 421 to 1,646 days after an initial HLTx (3 redo HLTx, 1 single redo LTx). Two patients succumbed early (37 and 102 days after redo Tx). Two patients survived 2 years, and 1 patient is still alive more than 4 years (58 months) after his retransplantation, but shows signs of BOS 51 months after the retransplantation.
Patient Survival
Analyzing the data of 110 recipients who survived longer than 3 months and had complete follow-up after pulmonary transplantation, the survival among patients with BOS/OB was 89%, 71%, 44%, and 17% after 1, 3, 5, and 10 years, respectively, compared with 86%, 77%, 63%, and 56% in patients without BOS/OB (Fig 2). Using the log-rank analysis, the difference between both survival curves was significant (p < 0.05). After HLTx the survival figures after 1, 3, 5, and 10 years were 88%, 71%, 48%, and 12% in patients with BOS/OB and 85%, 73%, 62%, and 54% in patients without BOS/OB (Fig 3A); after LTx the corresponding 1-, 3-, and 5-year survival rates were 89%, 71%, and 29% and 88%, 88%, and 66%, respectively (Fig 3B). At present, the mean follow-up of all patients with BOS/OB is 933.7 ± 141.3 days (range, 45 to 3,656 days). Survival after the diagnosis of BOS/OB among all affected patients has been 75%, 48%, 26%, and 11% after 1, 3, 5, and 10 years, respectively, with no major difference between HLTx and LTx (Fig 4). Divided into the different BOS stages at time of primary diagnosis, the 1-, 3-, 5-, and 10-year survival rates were as follows: BOS stage 1: 100%, 100%, 80%, and 80%; BOS stage 2: 91%, 82%, 24%, and 0; and BOS stage 3: 91%, 58%, 33%, and 11% (Fig 5). Pneumonia and respiratory failure were the causes of death in patients with BOS/OB in 61.1% of cases (bacterial pneumonia, 27.7%; CMV pneumonitis, 11.1%; fungal pneumonia, 22.2%). Diffuse alveolar damage/respiratory failure without evidence of pneumonitis was the cause of death of 16.6% of patients. Among the other deaths, 13.1% of the patients succumbed to sepsis and respiratory failure and another 11.1% to other nonpulmonary causes. Thus, 88.8% of all patients died due to terminal respiratory failure, with or without evidence of pneumonitis. In contrast, 44% of the deaths in the non-BOS group were due to terminal respiratory failure (diffuse alveolar damage or viral pneumonitis). The remaining patients died of other nonpulmonary causes.
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In addition, the immunosuppressive drugs were used for treatment of ongoing obliterative airway disease. In this setting, rapamycin most effectively prevented airway obliteration in contrast to other drugs, such as leflunomide or mycophenolic acid, which were not able to influence an existing obliterative airway process.
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Comment |
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TopFootnotesAbstractIntroductionMethods and ResultsCommentReferences |
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Various pulmonary function tests allow early and sensitive diagnosis of BOS. At our institution, a decrease in the FEF25–75 was found to be one of the earliest signs for impending BOS [16]. In addition, measurement of specific airway conductance has also shown early changes suggesting impending BOS [17]. The FEV1 remains the most consistent test, and the classification of BOS is based on the degree of decrease in FEV1 [7]. In addition to pulmonary function testing, the use of bronchoscopy and transbronchial biopsies is of definite importance in the diagnosis of OB. Our recent experience, as well as reports from other centers, has confirmed that the sensitivity of transbronchial biopsies for diagnosis of OB is greater than 70% [18]. Since 1993, transbronchial biopsy has even shown the earliest sign of OB in 43% of the cases, before changes in the FEV1 were observed. Particularly for the diagnosis of superimposed pulmonary infections, which are the most common complications of OB, bronchoscopy, bronchoalveolar lavage, and transbronchial biopsies have proved to be extremely helpful in initiating early and specific antimicrobial treatment.
Current management and treatment focuses on augmentation of immunosuppression. Concurrent acute rejection or evidence of active OB on biopsy should lead to aggressive intravenous steroid pulse therapy and consideration of monoclonal or polyclonal antilymphocyte agents in cases of steroid resistance. The lack of an acute rejection component leads to maximum doses of cyclosporine and azathioprine. The oral steroid dose is increased up to 1 mg • kg-1 • day-1 and titrated down according to pulmonary function changes. During the period of increase of immunosuppression, prophylaxis against CMV using ganciclovir and hyperimmunoglobulin or against fungal infections using inhaled amphotericin B may be beneficial. Early initiation of treatment at our center led to reasonable survival rates of nearly 50% in patients with BOS/OB 5 years after their transplant procedure. Using the log-rank analysis, however, survival of affected versus nonaffected patients shows a significant difference. The main cause of mortality in the affected patient group has been respiratory failure complicated by bacterial, viral, or fungal pneumonitis. Retransplantation remains an ultimate therapeutic option for affected patients; the results, at least at our institution, are definitely inferior when compared with those of primary transplants.
Experimental data have shown promising results using some of the newer immunosuppressive drugs such as leflunomide and rapamycin [19, 20]. These drugs seem to be promising for future treatment strategies, because they show activities in vivo and in vitro leading to inhibition of proliferation of lymphocytes and mesenchymal cells [21, 22]. Ongoing active research in the field of OB is extremely necessary, because this complication limits long-term survival and affects the quality of life of pulmonary transplant patients.
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Footnotes |
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TopFootnotesAbstractIntroductionMethods and ResultsCommentReferences |
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Address reprint requests to Dr Robbins, Department of Cardiothoracic Surgery, CVRB, Stanford University School of Medicine, Stanford, CA 94305-5247
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