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Ann Thorac Surg 1997;64:945-948
© 1997 The Society of Thoracic Surgeons

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Original Article: General Thoracic

Mycophenolate Mofetil for Obliterative Bronchiolitis Syndrome After Lung Transplantation

Departments of Surgery and Medicine, University of Michigan, Ann Arbor, Michigan

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
Background. The development of obliterative bronchiolitis after lung transplantation portends a poor long-term outcome because of progressive decline in allograft function. There are currently no effective means of treating this condition.

Methods. Thirteen patients in whom obliterative bronchiolitis syndrome developed after lung transplantation were treated with mycophenolate mofetil, an antimetabolite immunosuppressant, at a dose of 1.5 g orally twice daily. Patients were followed up clinically and with pulmonary function testing.

Results. Duration of mycophenolate mofetil therapy ranged from 1 week to 24 months (mean duration, 11.4 months). Pulmonary function test results stabilized in the majority of patients with no significant further decline in forced expiratory volume in 1 second. Two patients died of progressive obliterative bronchiolitis, 1 patient is alive with progressive disease, and 1 patient died of an acute infection. The drug was discontinued in 2 additional patients. In no patient did severe leukopenia or cytomegalovirus infection develop; 1 patient had a fungal infection, and 7 patients experienced gastrointestinal side effects.

Conclusions. In the setting of obliterative bronchiolitis syndrome, mycophenolate mofetil is generally well tolerated and is associated with stabilization of pulmonary function test results. These findings suggest that the otherwise progressive process of obliterative bronchiolitis can be slowed.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
The major long-term problem facing patients undergoing lung transplantation is the development of obliterative bronchiolitis (OB). This condition is characterized pathologically by proliferation of fibrovascular connective tissue in small airways and clinically by a decline in pulmonary function [1, 2]. Because pathologic confirmation of OB is not always available, the concept of obliterative bronchiolitis syndrome (OBS) has been put forth as a method of identifying patients with chronic lung allograft rejection [3]. The natural history of patients with OBS is poor, as the majority demonstrate progressive decline in pulmonary function, often leading to death [2, 4, 5]. Treatment of this condition has been wholly unsatisfactory; no standard immunosuppressive agents have demonstrated a convincing ability to reverse the decline in pulmonary function associated with this condition.

Mycophenolate mofetil (MMF) is a new immunosuppressive agent that has potential advantages over other antimetabolite drugs in preventing or reversing allograft rejection. This agent has been used to treat acute rejection of heart, liver, and kidney allografts, and there is evidence that it may be useful in prevention of chronic vascular rejection [6–10]. In vivo, MMF is rapidly hydrolyzed into its active form, mycophenolic acid, which inhibits inosine monophosphate dehydrogenase, thereby selectively suppressing proliferation of T and B lymphocytes [11]. Because of the novel mechanism of action of MMF and the lack of effective alternative treatments of OBS, MMF was investigated for its ability to alter the progressive decline in pulmonary function associated with this syndrome.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
Starting in July 1995, patients with OBS after lung transplantation at The University of Michigan were offered the opportunity to receive MMF as an alternative to azathioprine as part of their standard immunosuppression regimen. The drug was administered as part of an institutional review board–approved study, and informed consent was obtained. All patients met the criteria for the development of OBS: a greater than 20% drop in forced expiratory volume in 1 second (FEV₁) and temporally associated bronchoscopy (including transbronchial biopsy and bronchoalveolar lavage) showing no evidence of active acute rejection or infection. After the diagnosis of OBS was made, patients were treated with two courses of a high-dose steroid (methylprednisolone sodium succinate, 1 g daily for 3 days) in an attempt to improve lung function. If there was no favorable response, MMF therapy was initiated.

Mycophenolate mofetil was administered orally, 1.5 g twice daily. Azathioprine was discontinued at the onset of MMF therapy, but prednisone (10 to 20 mg/d) and cyclosporine (dose-adjusted to a whole-blood high-performance liquid chromatographic level of 100 to 300 µg/mL) were continued at unchanged doses. Complete blood counts were obtained weekly during the first month of MMF therapy and monthly thereafter. The dose of MMF was decreased if the total leukocyte count decreased to less than 3,500/µL.

All patients had a clinical evaluation and flow–volume loop obtained at the time of diagnosis of OBS and after initial treatment with high-dose steroids. Pulmonary function tests were done at 4- to 6-week intervals after institution of MMF treatment. All spirometric studies were performed on a calibrated pneumotachograph (Medical Graphics Co, St. Paul, MN), and values were expressed as absolute volumes and as a percentage of the predicted values published by Morris and colleagues [12]. Patients were also followed by telephone contact by one of the lung transplant nurse coordinators at biweekly intervals or more frequently if new complaints developed.

Results of pulmonary function tests were compared before and after initiation of MMF therapy using paired t test: a p value of less than 0.05 was considered significant.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
Between June 1995 and August 1996, 13 patients were diagnosed as having OBS after lung transplantation. Baseline patient characteristics, including severity of OB [3], are listed in Table 1. There were 5 men and 8 women; the mean age was 48 years (range, 19 to 60 years). The reason for transplantation was chronic obstructive pulmonary disease in 8 patients, pulmonary fibrosis in 2 patients, sarcoidosis in 2 patients, and primary pulmonary hypertension in 1 patient. Nine patients underwent single-lung transplantation, 3 had bilateral lung transplantation, and 1 patient had heart-lung transplantation. The mean interval from transplantation to initiation of MMF treatment was 31 months (range, 3 to 52 months). Six (46%) of the 13 patients had documented cytomegalovirus (CMV) infection at some point between transplantation and development of OBS.

The pulmonary function test results before and after MMF treatment are summarized in Tables 2 and 3. Duration of treatment ranged from 1 week to 18 months (mean duration, 11 months). Ten patients were treated with MMF for at least 6 months (see Table 2), and 7 patients were followed for at least 12 months (see Table 3). There was no significant change in forced vital capacity, FEV₁, or forced expiratory flow between 25% and 75% of forced vital capacity, either as absolute volumes or as percent predicted, at 3 months, 6 months, or 12 months after institution of MMF therapy. Overall changes in FEV₁ for all patients, including the best FEV₁ after transplantation, are illustrated in Figure 1. The decrease in FEV₁ between "best FEV₁" (best after transplantation) and "PRE" (before MMF therapy) is highly significant (p < 0.0001) using paired t test, but subsequent changes were not significant.

View larger version (10K): [in this window] [in a new window]   Fig 1. . Forced expiratory volume in 1 second (FEV1) versus time. There was a significant difference (p < 0.0001) between BEST FEV1 and PRE. (BEST FEV1 = best FEV1 after transplantation; PRE = before treatment with mycophenolate mofetil.)

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
Bronchiolitis obliterans remains the major cause of late mortality and morbidity in lung transplant recipients. It occurs with increasing frequency the longer patients are followed after transplantation and has a prevalence of greater than 50% in patients with a follow-up longer than 32 months [2, 4]. The majority of patients experience a progressive decline in pulmonary function, and the mortality rate associated with the condition is greater than 40% [2, 4].

Three potential treatment strategies for combating OB are prevention, stabilization, and reversal. Prevention requires either an understanding of the causes of OB or an ability to identify patients at risk. Important risk factors for the development of OB include CMV infection and repeated episodes of acute rejection [13]. Logic dictates that augmented immunosuppression in an attempt to minimize episodes of acute rejection would decrease the incidence of OB; however, such efforts can also lead to increased infectious complications (including CMV infection), which may nullify any benefits. Keenan and co-workers [14] have reported a decreased incidence of OB in patients receiving tacrolimus as an alternative to cyclosporine without a significantly higher overall incidence of infection, and Ross and associates [15] have described a comparison between induction therapy with OKT3 and MALG. In their study, patients treated with OKT3 appeared to have delayed presentation of OB. Many lung transplant centers including ours, have not used induction cytolytic therapy for fear of increasing the incidence of early CMV infection. Greater efforts to prevent CMV infection with prolonged administration of ganciclovir may prove beneficial, although this drug also has side effects and is expensive to administer on a long-term basis.

If OBS cannot yet be prevented, stabilization of pulmonary function, or prevention of further decline, is desirable. It has been reported that pulmonary function can stabilize spontaneously in up to 50% of patients with OB, although their final pulmonary function may be well below their best posttransplantation value [5]. Kesten and associates [16] described the use of an antilymphocyte preparation for treatment of OBS in 15 patients. Two (13%) of these patients experienced an improvement in pulmonary function as measured by FEV₁; 5 patients (33%) had stabilization, and 8 (53%) had continued decline in function. Because the natural history of the condition is variable, it is unclear whether the antilymphocyte preparation actually had any effect or not. Iacono and colleagues [17] discussed 9 patients with histologically active OB and deteriorating pulmonary function refractory to conventional immunosuppression who were given aerosolized cyclosporine. Compared with historical controls, the treatment group had stabilization of pulmonary function without nephrotoxicity, hepatotoxicity, or increased incidence of infection.

The third potential strategy for treating OBS, reversal of the disease with improvement in airflow and resolution of the intraluminal fibrovascular proliferation, has not been consistently demonstrated with any form of pharmacologic treatment.

In our series, patients were give MMF, an antimetabolite immunosuppressive agent that inhibits the de novo pathway for purine synthesis. Evidence suggests that MMF suppresses lymphocyte function but has minimal effects on neutrophils, erythrocytes, and other rapidly dividing cell lines [6, 8]. Therefore, MMF may have a selective advantage over other antimetabolite drugs in preventing or reversing allograft rejection. The drug has been used to treat acute rejection of heart, liver, and kidney allografts, and there is evidence that it may be useful in the prevention of chronic vascular rejection in animal models [7–10].

Our data indicate a stabilization of pulmonary function in the majority of patients receiving MMF. Administration of the drug was discontinued in 2 patients, and 64% of the others had stabilization of pulmonary function test results. Although we did not have a control group, the natural history of OB is a progressive decline in pulmonary function test results. Our data suggest that patients who receive MMF are less likely to demonstrate such progressive decline, ie, that MMF therapy is associated with slowing or stopping the progression of OB.

In addition to the desired outcome of stabilization of pulmonary function, there were surprisingly few major side effects of MMF. As with other antimetabolite drugs, such as azathioprine, the common side effects of MMF include myelosuppression and gastrointestinal side effects, such as vomiting and diarrhea [18]. Although 7 of the 13 patients had some gastrointestinal side effects, they were severe enough to warrant discontinuation of the drug in only 1 patient. Leukopenia occurred in only 1 patient and did not lead to discontinuation of the drug. Sepsis reportedly occurs in up to 20% of patients receiving MMF and generally involves CMV viremia [19]. This complication occurred in 1 patient in our series, and we saw no cases of CMV infection. Other opportunistic infections were also uncommon; only 1 patient had fungal colonization of the lung allograft.

In conclusion, this preliminary experience with MMF in the treatment of OB after lung transplantation suggests that the drug is well tolerated and is associated with stabilization of pulmonary function. As there is currently no effective treatment of OB after lung transplantation, a prospective, controlled study of this drug is necessary.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
Presented at the Poster Session of the Thirty-third Annual Meeting of The Society of Thoracic Surgeons, San Diego, CA, Feb 3–5, 1997.

Address reprint requests to Dr Whyte, Department of Cardiothoracic Surgery, Stanford University Medical Center, 300 Pasteur Dr, Stanford, CA 94305.

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 

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3. Cooper JD, Billingham M, Egan T, et al. A working formulation for the standardization of nomenclature and clinical staging of chronic dysfunction in lung allografts. J Heart Lung Transplant 1993;12:713–6.[Medline]
4. Reichenspurner H, Girgis RE, Robbins RC, et al. Obliterative bronchiolitis after lung and heart-lung transplantation. Ann Thorac Surg 1995;60:1845–53.[Abstract/Free Full Text]
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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Richard I. Whyte Michael S. Mulligan Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Whyte, R. I. Articles by Lynch, J. P. Search for Related Content PubMed PubMed Citation Articles by Whyte, R. I. Articles by Lynch, J. P., III