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.
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.
CRITERIA FOR LUTX
All patients fulfilled the following criteria by the ISHLT guidelines and the American Thoracic Society (36).
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).
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.
MATERIALS AND METHODS
Between 1996 and 2012, seven patients experiencing severe therapy-refractory BO after allogeneic HCT received a LuTX at our institution.
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.
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).
The authors thank Anita Felber for updating the patient data base regularly.
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Keywords:© 2013 Lippincott Williams & Wilkins, Inc.
Hematopoietic stem cell transplantation; Lung transplantation; Bronchiolitis obliterans