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Lung Transplantation for Bronchiolitis Obliterans After Allogeneic Hematopoietic Stem Cell Transplantation: A Single-Center Experience

Vogl, Ursula M.1; Nagayama, Kazuhiro2,6; Bojic, Marija1; Hoda, Mir Ali Reza2; Klepetko, Walter2; Jaksch, Peter2; Dekan, Sabine3; Siersch, Viktoria1; Mitterbauer, Margit1; Schellongowski, Peter4; Greinix, Hildegard T.1; Petkov, Ventzislav5; Schulenburg, Axel1; Kalhs, Peter1; Rabitsch, Werner1,7

doi: 10.1097/TP.0b013e318277e29e
Clinical and Translational Research
Free

Background Bronchiolitis obliterans (BO) is a detrimental late pulmonary complication after allogeneic hematopoietic stem cell transplantation (HCT) associated with chronic graft-versus-host disease (cGvHD). When systemic immunosuppressive treatment fails to improve, severe BO patients should be considered for lung transplantation (LuTX). We present seven patients undergoing LuTX for severe refractory BO after HCT.

Methods Seven patients with hematologic malignancies developed severe cGvHD with lung involvement presenting as BO after allogeneic HCT. Evaluation for LuTX was initiated after failure of a median of 4 immunosuppressive regimens.

Results Between 1996 and 2012, seven patients with severe refractory BO were evaluated for LuTX. The median time from HCT to diagnosis of chronic lung GvHD was 8.2 months (range, 3.7–16.6). At a median time of 18.1 months (range, 6–120) after diagnosis of BO, six patients received a bilateral sequential LuTX, and one patient received a single LuTX. Six postoperative courses were uneventful; the patient with single LuTX died from septic multiorgan failure. Three LuTX recipients had a mild acute rejection after one to three months after LuTX, and one patient experienced fatal chronic rejection and hemolytic uremic syndrome. At present, three (43%) LuTX recipients remain alive at a median observation time of 26 months (range, 1 month–16 years) after LuTX. The median overall survival from LuTX was 24 months (95% CI, 0.5–78); the median overall survival time after allogeneic HCT is 98 months (95% CI, 46–198).

Conclusion This case series illustrates that LuTX is a possible therapeutic option for selected patients with severe treatment-refractory BO.

1 Department of Internal Medicine I, Bone Marrow Transplantation, Medical University Vienna, Vienna, Austria.

2 Department of Thoracic Surgery, Medical University Vienna, Vienna, Austria.

3 Department of Pathology, Medical University Vienna, Vienna, Austria.

4 Intensive Care Unit, University Clinic of Medicine I, Medical University Vienna, Vienna, Austria.

5 Department of Pulmonology, University Clinic of Medicine II, Medical University Vienna, Vienna, Austria.

6 Department of Thoracic Surgery, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.

7 Address correspondence to: Werner Rabitsch, M.D., Department of Medicine I, Bone Marrow Transplantation Unit, Medical University Vienna, Währinger Gürtel 18-20 A-1090 Vienna, Austria.

The authors declare no funding or conflicts of interest.

E-mail: werner.rabitsch@meduniwien.ac.at

U.M.V. and K.N. contributed equally. U.M.V., K.N., W.K., P.J., M.M., H.T.G., P.K., and W.R. participated in the research design; writing of the paper: U.M.V., K.N., M.H., P.J., H.T.G., P.K., and W.R. participated in writing the paper; U.M.V., K.N., V.S., V.P., and W.R. participated in performing the research; U.M.V., K.N., M.B., P.J., S.D., P.S., A.S., and W.R. participated in data analysis.

Received 6 August 2012. Revision requested 24 August 2012.

Accepted 5 October 2012.

Allogeneic HCT is a well-established curative therapy for selected patients with hematologic and oncologic diseases (1). The risk of development of cGvHD is around 60% in 6 years (2). There is a marked reduction in overall survival in patients with severe cGvHD, and the quality of life is reduced (3–5). The incidence of cGvHD has been rising with the use of unrelated donor or mismatched donor grafts, peripheral blood (PBSC) as stem cell source, and increasing patient and donor age (6).

Lung involvement by cGVHD is defined as bronchiolitis obliterans (BO) occurring in up to 20% of patients with severe cGvHD (7, 8). Nakaseko et al. (9) published a series of 2,087 patients after allogeneic HCT with a cumulative incidence for BO of 2.8%.

The National Institutes of Health (NIH) development project on cGvHD defined lung involvement by cGvHD as decrease of forced expiratory volume in one second (FEV1) less than 75% in lung function tests, signs of air trapping in high-resolution (HR) computed tomography (CT) scan of the lungs, absence of active respiratory tract infection, and at least one other diagnostic or distinctive manifestation of cGvHD when histologic confirmation of BO is missing (10).

Treatment of BO consists of systemic corticosteroids as soon as lung involvement by cGVHD is diagnosed. The response rates are limited with an improvement of lung function tests in about 20% of patients (11, 12). The results of salvage immunosuppressive therapies like calcineurin inhibitors, mycophenolate mofetil (MMF), or sirolimus are disappointing, and no clinical trials have investigated their efficacy so far, leading to a level C-2 recommendation by the German/Austrian/Swiss consensus conference recently published by Hildebrandt and colleagues (12). Extracorporeal photopheresis (ECP) has shown to be beneficial in patients with lung involvement by cGVHD as reported by several investigators (13–15), but experience is still limited. Other immunosuppressive strategies, such as administration of tumor necrosis factor (TNF)-alpha blockers, rituximab or imatinib, have been used in small patient numbers and, thus, have to be considered experimental (16–20).

So far, the prognosis of patients with moderate or severe BO is dismal (9). In severe therapy-refractory BO, LuTX can be a therapeutic option for selected patients (21, 22).

We report a case series of seven patients who underwent LuTX after failure of systemic immunosuppressive therapy for BO after allogeneic HCT.

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RESULTS

Patient characteristics are shown in Table 1. Seven patients (male: n=5, female: n=2) with a median age of 24 years underwent allogeneic HCT for their hematologic disease. Four patients received peripheral blood stem cells (PBSC) from a HLA-identical sibling donor, one patient had a matched unrelated donor, and two patients received PBSC from a 1-allele mismatched unrelated donor. Absolute neutrophil counts greater than 0.5×109/L and platelet counts greater than 20×109/L without further transfusion requirements were achieved at median day 20 and median day 14, respectively, after grafting. The early posttransplant course was unremarkable with no signs of acute GvHD in the patient with CML. The other five patients showed acute GvHD of the skin and gastrointestinal tract stages II to IV. The initial treatment consisted of corticosteroids in addition to CsA. One patient needed salvage therapy and received extracorporeal photopheresis treatment.

TABLE 1

TABLE 1

All patients had normal lung functioning tests after 3 months of HCT. The median onset of first signs of chronic lung GvHD presenting as dyspnea was 8.2 months (range, 3.7–16.6). Pulmonary function tests showed severe airflow obstruction and hypoxemia with an FEV1 of 27% to 31% of normal, meaning severe obstruction. No signs of restriction were found in the lung functioning test of all patients. Arterial oxygen saturation was also lowered in all seven patients (85%–92% SO2).

All seven patients fulfilled the criteria of BO as described in the “Methods” section (23, 24). Despite immunosuppressive therapy (median treatment lines: 4, range 2–5) for at least 6 months with corticosteroids (all patients), CsA (all patients), ECP (n=5), mycophenolate mofetil (MMF) (n=4), rituximab (n=1), tacrolimus (n=2), and thalidomide (n=2), pulmonary function tests worsened. At this time, patients were immobilized, oxygen dependent, and in severe respiratory distress.

At a median time of 18.1 months after HCT (range, 6–120 months) for all seven patients, the lungs of a blood-group identical donor became available. A bilateral sequential LuTX was performed in six patients; one patient received a single LuTX.

The postoperative course was uneventful in the six patient who received bilateral LuTx with a median hospitalization of 17.5 days (range, 14–23 days) after LuTx. One patient with single LuTX died from septic multiorgan failure. The explanted lungs were histologically analyzed and confirmed the diagnosis of BO in all seven patients.

At present, all seven patients were followed at a median time of 26 months (range, 1 month–16 years) after LuTX for BO and at a median time of 8 years (range, 2.3–17 years) after allogeneic HCT for their hematologic disease.

Three (43%) of seven patients are still alive and have a good quality of life. One patient (male) died shortly after LuTX during the ICU stay because of respiratory failure, one patient (female) died of respiratory failure of unknown cause and thrombotic thrombocytopenic purpura (TTP)/hemolytic uremic syndrome (HUS) 86 days after LuTX, another male patient died because of a secondary malignancy (myxofibrosarcoma) 24 months after LuTX, and the fourth patient (female) died after development of chronic rejection of the lung and recurring infections 63 months after LuTX and 92 months after HSCT.

The median overall survival time after LuTX was 24 months (95% CI, 0.5–78 months) (Fig. 1); the median overall survival time after allogeneic HCT is 98 months (46–198 months) (Fig. 2).

FIGURE 1

FIGURE 1

FIGURE 2

FIGURE 2

All patients who are still alive are in complete hematologic and cytogenetic remission from their original hematologic disease.

Four histologically proven acute rejections episodes (ISHLT grade A2 or higher) within 8 months after LuTX were noted in three patients. These patients were treated with high-dose methylprednisolone for 3 days and responded with resolution of rejection. Concerning infectious complications, two patients experienced CMV infections, one patient experienced Pneumocystis jirovecii pneumonia, and another patient experienced pulmonary fungal infections (Aspergillus, Candida). One patient was diagnosed with acute heart failure because of ischemic heart disease 5 months after LuTX.

Pulmonary function tests after LuTX have shown improvement of all parameters in 6 patients between three and six months. Only one patient who experienced acute rejection, CMV, parvovirus infection, and TTP HUS developed BOS 51 months after LuTX, required long-term oxygen therapy and died because of respiratory insufficiency.

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DISCUSSION

Bronchiolitis obliterans after allogeneic HCT is a serious noninfectious pulmonary complication, which occurs in up to 20% of patients with cGvHD. Histologically, BO is characterized by obstruction or obliteration of small airways leading to luminal occlusion by inflammation and fibrous tissue of the respiratory bronchioles. The cause is multifactorial, most likely are donor cytotoxic T-lymphocytes interacting with host’s cells (24).

The incidence of BO depends on different risk factors like acute and chronic GvHD, mismatched HLA-donor, abnormal pre-HCT lung functioning tests, respiratory viral infections within the first 100 days after transplantation, high-dose conditioning or the use of PBSC as a donor source (8, 11, 12, 25, 26). All seven patients of our series had multiple of these risk factors for the development of BO.

Our seven patients had a median onset of BO at 8.2 months after allogeneic HCT. They received classic management of BO with immunosuppressive agents, such as corticosteroids, CsA, ECP, azathioprine, MMF, bronchodilators, and immunoglobulin replacement and even experimental treatment with thalidomide or rituximab. The recent guidelines on diagnosis and treatment of chronic pulmonary GvHD recommend systemic corticosteroids as level A recommendation and evidence II, topical steroids as level B evidence IIII-1, and all other treatments mentioned above as level C1 or C2 recommendation with evidence levels III-1 to III-3 or even experimental (12). Despite all these immunosuppressive treatments for at least 6 months, our patients experienced severe worsening of pulmonary functioning tests and fulfilled the criteria for being listed for bilateral LuTX. Therefore, the development of modern effective immunosuppressive drugs is needed in the future.

There are only a few medical reports on LuTX for BO after allogeneic HCT (22, 27). Because of the guidelines, LuTX is considered the ultima ratio for severely affected therapy-refractory patients. The severe limitations in quality of life with oxygen dependence, recurring infections with hospitalization, and side effects of systemic immunosuppressants have to be compared with the risks and complications associated with bilateral LuTX, for example, life-long immunosuppression with the risk of secondary malignancies, infections, and the risk of relapse of the primary hematologic disease. Bunin et al. (28) reported a recent case series of solid organ transplants performed in children including two with LuTX, with all two of them being alive with no further complications. Another recent publication on LuTX in children and adults was published by Koenecke et al. (22), with 12 patients receiving either an unrelated deceased organ (n=11) or a lobe from a living related donor (n=1). Eight of 12 patients are alive and have normal graft function.

So far, there are no larger reports of LuTX in adult patients after allogeneic HCT, only some single patient case reports (21, 27, 29–32).

As reported in these case studies, primary graft dysfunction, infection, and late graft failure account for the majority of deaths in the first year after LuTX. Chronic allograft rejection or BO syndrome develops in the majority of patients by 5 years. In our patient series, one patient developed chronic BO 51 months after LuTX, was oxygen dependent, and died because of respiratory insufficiency; one other patient was observed for more than 10 years after LuTX for BO. This patient has no signs of BO syndrome so far, and he is the only patient with no further infectious complications. This might be due to the fact that he had no acute GvHD, only three immunosuppressants for chronic GvHD, a longer time from HCT to onset of lung GvHD, and he waited only 5 months until he received a LuTX. However, because of the small patient sample, all these risk factors cannot be statistically validated.

Our patients have a median overall survival time from LuTX of 24 months. One patient received a single LuTX and died in the postoperative course because of respiratory failure, probably because of the single graft. The second patient died because of respiratory failure and TTP HUS. However, her post-LuTX period was marked by several fungal respiratory infections (Aspergillus and Candida). For that reason, one could discuss to enhance the antifungal prophylaxis after LuTX in patients who are heavily immunosuppressed before LuTX because of chronic GvHD.

The most common reasons for lung transplantation in the general population are emphysema, COPD (chronic obstructive pulmonary disease), or cystic fibrosis. In the literature, the reported 5-year survival rate post-LuTX for this general population of lung transplant recipients is 49% (33). Therefore, all the reports published in the literature for LuTX after allogeneic HCT, including our patient data, have at least the same survival rate as in patients given LuTX for other indications.

In summary, the early detection and therapy of BO by regular lung function tests after allogeneic HCT should be considered as standard in the routine follow-up because of NIH consensus guidelines (34). Routine pulmonary function tests give the opportunity to start early treatment. However, it cannot prevent therapy-refractory BO. A more intensive antifungal prophylaxis after LuTX for patients with several treatment lines of immunosuppressants should be discussed, and a complete cardiac check-up for older patients (over 50 years) with risk factors for ischemic heart disease should be considered before LuTX.

To the best of our knowledge, our case series is one of the largest uniform series of adult BO patients, who received a single or bilateral LuTX after allogeneic HCT. The outcome and overall survival of LuTX patients after allogeneic HCT seems to be at least similar to patients whose underlying disease is other than chronic lung GvHD; therefore, LuTX could be considered as a possible therapeutic option for carefully selected patients with severe therapy-refractory BO.

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CRITERIA FOR LUTX

All patients fulfilled the following criteria by the ISHLT guidelines and the American Thoracic Society (36).

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Bilateral LuTX

Blood group compatibility as a prerequisite, donor/recipient matching was based on size with the predicted total donor lung capacity compared with the recipient’s predicted and real total lung capacity as the primary method. Harvesting of the cadaveric donor lungs was standardized for all patients as previously described (36). The surgical approach was either two separate anterolateral thoracotomies in the fourth or fifth intercostals space or bilateral trans-sternal anterior thoracotomy (Clamshell incision). After standard pneumonectomy and preparation of the hilum, the first step of the implantation was the bronchial anastomosis, which was performed in an end-to-end technique using a single running suture technique with 4/0 or 5/0 polydioxanone suture (PDS; Ethicon Inc., Somerville, NJ). Thereafter, the atrial anastomosis was sutured using 4/0 prolene (Ethicon Inc.) and the arterial anastomosis with 5/0 prolene. After retrograde and antegrade flushing, controlled reperfusion was performed. If intraoperative and/or postoperative cardiopulmonary support was required, extracorporeal membrane oxygenation was routinely used (36).

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Postoperative Management

All patients received a triple immunosuppressive therapy including corticosteroids and MMF with either tacrolimus or CsA. All patients routinely received antibiotic prophylaxis according to pretransplant resistance testing. Antifungal medication was started in case of positive fungal cultures whenever indicated. All patients received a 3-month inhalation therapy with amphotericin B. All patients basically received valgancyclovir 900 mg/day for 3 months. Patients who had the high risk of CMV infection received a combined prophylaxis with intravenous gancyclovir for two weeks and four doses of CMV hyperimmunoglobulin and were treated with valgancyclovir for 12 months (37).

Surveillance bronchoscopies with transbronchial biopsy were performed at 2 weeks and 1, 2, 3, 6, and 12 months after LuTX, or additionally as clinically indicated. All diagnoses of acute rejection were confirmed with biopsy specimens, and standard histologic criteria and grading schemes were used. Pulmonary function tests were performed at regular intervals, and BOS was diagnosed using the guidelines of ISHLT.

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MATERIALS AND METHODS

Patients

Between 1996 and 2012, seven patients experiencing severe therapy-refractory BO after allogeneic HCT received a LuTX at our institution.

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Allogeneic HCT

Patients had routine assessment of organ function before conditioning. This included electrocardiogram and echocardiogram, pulmonary function tests, blood tests (hepatic function, renal function, blood count, coagulation, viral tests, etc.), a recent CT scan or positron emission tomography–CT, sinus x-ray with ear-nose-and throat -check-up, teeth check-up, and gynecology and urology consolidations.

All patients received myeloablative conditioning (Table 1). After individual conditioning, therapy (PBSC) was infused. GvHD prophylaxis consisted of cyclosporine (CsA), starting 1 day before stem cell infusion, and a short course of methotrexate (MTX). For cytomegalovirus (CMV) prophylaxis, the patient received 500 mg/m2 acyclovir three times a day starting with conditioning until day 30. CMV polymerase chain reaction (PCR) screening was performed in all patients after HCT from day 30 onward weekly.

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Diagnosis of Lung Involvement by cGvHD

Diagnosis of BO was established by obstructive lung function tests (FEV1, <75% of predicted), signs of air trapping in a high-resolution CT or pathologic finding of BO; absence of active respiratory tract infection by negative tests for bacterial, viral (including CMV, Epstein-Barr virus [EBV], respiratory syncytial virus [RSV], and herpes simplex virus [HSV]), or mycobacterial (Aspergillus, Candida) infections with bronchoalveolar lavage by fiberoptic bronchoscopy and negative chest X-rays; and one other diagnostic manifestation of cGvHD (12). Biopsies of the lung were performed in all seven patients. Until 2005, only patients with dyspnea had pulmonary function tests performed. In case of decrease of FEV1, high-resolution CT scans were performed, and respiratory tract infections were excluded. Since 2005, starting on day 100 after allogeneic HCT, all patients routinely have pulmonary function tests every 3 months for 2 years. In case of obstructive changes, all patients undergo high-resolution CT scans of the lungs and bronchoalveolar lavage (BAL) with transbronchial lung biopsies (TBLB).

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ACKNOWLEDGMENT

The authors thank Anita Felber for updating the patient data base regularly.

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Keywords:

Hematopoietic stem cell transplantation; Lung transplantation; Bronchiolitis obliterans

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