Lung transplantation for bronchiolitis obliterans syndrome after allogenic hematopoietic stem cell transplantation

Abstract

Bronchiolitis obliterans syndrome (BOS) after hematopoietic stem cell transplantation (HSCT) is a major cause of morbidity and mortality with limited treatment options. Lung transplantation (LTX) has been rarely reported as a treatment option for selected HSCT recipients with this problem. In the present study, we reported six patients who underwent LTX due to BOS after HSCT (two females, four males) from January 2012 to December 2014 in our center. The median time from HSCT to diagnosis of BOS was 2.5 years (ranging from 1 to 5 years). At a median time of 4 years (ranging from 2 to 5 years) after diagnosis of BOS, four patients received bilateral sequential LTX, and two patients received single LTX. One of the recipients suffered from mild acute rejection after LTX, another suffered from primary lung graft dysfunction on post-operation day 2, and three experienced fungal infections. The median time for follow-up after LTX was 19.5 months (ranging from 12 to 39 months). At present, all patients are alive with good functional capacity and no relapse of BOS and hematologic malignancy conditions. Patients who received bilateral LTX have better pulmonary functions than patients who received single LTX.

Keywords

bronchiolitis obliterans syndrome (BOS) / hematopoietic stem cell transplantation (HSCT) / lung transplantation (LTX)

Introduction

Hematopoietic stem cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood. It has been used as a life-saving procedure for many malignant hematologic, immunologic, and inherited metabolic diseases. Late-onset non-infectious pulmonary complications (LONIPCs) are an important cause of post-transplantation mortality and morbidity in allogeneic HSCT recipients [¹]. Among these complications, bronchiolitis obliterans syndrome (BOS), which is characterized clinically by persistent progressive airflow obstruction unresponsive to bronchodilator therapy, is predominant. Up to 14% of patients with chronic graft-versus-host disease (GVHD) suffered from BOS [²–⁴]. If the patient does not respond to conventional immunosuppressive treatment within three to six months, the prognosis is poor [⁵]. Lung transplantation (LTX) is an alternative therapeutic option for BOS in some selected patients; however, it has been rarely reported as a treatment option for selected HSCT recipients with this disease. We reported six cases of LTX for BOS after HSCT and described the clinical features and outcomes of these patients.

Case presentation

Since the first BOS patient was referred to us in 2012, six patients had undertaken LTX for BOS after HSCT in our institution, representing 1.6% of our indications for this treatment option. Clinical data and pulmonary function tests (PFTs) were obtained from the patients’ charts. Special attention was paid to patients’ characteristics, age at LTX, time from HSCT to the diagnosis of BOS, time from the diagnosis of BOS to LTX, the type of LTX, the immunosuppression regimens after LTX, complications after LTX, and follow-up of PFTs.

Patients’ characteristics

Patients’ characteristics are shown in Table 1. Six patients (male, n = 4; female, n = 2) with a median age of 24.5 years underwent HSCT for their hematologic diseases. Two patients received allogenic bone marrow transplant from their human leukocyte antigen (HLA) semi-identical parents, two received peripheral blood stem cells (PBSC) from a matched unrelated donor, one received PBSC from his HLA-matched sister, and one received PBSC plus bone marrow from her HLA semi-identical parent. All patients had normal lung functioning tests after three months of HSCT. The median time from HSCT to diagnosis of BOS was 2.5 years (range from 1 to 5 years). Immunosuppressive therapies were used in all patients for at least 12 months with corticosteroids (all patients), cyclosporine (n=3), mycophenolate mofetil (MMF) (n=3), and tacrolimus (n=1). However, the pulmonary function decreased irreversibly. Supplemental oxygen was required for 24 h, and the patients became totally bedridden. When these patients were referred to our center, five patients could not tolerate PFTs. The only patient who received PFT showed severe airflow obstruction with an FEV₁ of 18.8%. None of the patients could tolerate 6MWT. Most of the patients had higher PCO₂ (n = 5), and arterial oxygen saturation was low in five patients. CT scans showed diminution of peripheral vascularity, segmental bronchial dilatation, pulmonary emphysema, and pneumatocele (Fig. 1A and 1C).

Lung transplantation

At a median time of 4 years (ranging from 2 to 5 years) after the diagnosis of BOS, four patients received bilateral sequential LTX, and two patients received single LTX (patients 3 and 5, both of them had right LTX). Due to patients’ low BMI and flat thorax, size-matched lungs were not available. Size reduction of the donor lungs was achieved by peripheral segmental resection, and no major thoracic surgical complications related to size mismatch were observed. Lung pathology showed massive infiltration of immune cells, severe disruption of the small airway epithelium, and thickening of the underlying smooth muscle and stroma (Fig. 2). In all patients, no induction therapy was given, and the initial immunosuppressive therapy consisted of tacrolimus, MMF, and steroids. Two received suspended MMF due to granulocytopenia.

Complications after lung transplantation

After the surgery, one of the patients experienced primary lung graft dysfunction in post-operation day 2 (POD2), which was treated with lung protective ventilation strategy. Another patient experienced acute rejection in POD9 and was treated with bolus steroids, which showed good response. Three patients experienced aspergillus infections, one with invasive pulmonary fungal disease and the others with bronchial anastomotic infections that led to anastomotic stenosis. The invasive pulmonary fungal disease was treated with voriconazole, inhalation of amphotericin B, and reduction of immunosuppression with good response after treatment. As the anastomotic infections showed poor response to voriconazole, the two patients were treated successfully with posaconazole and inhalation of amphotericin B. The anastomotic stenoses were treated with interventional bronchoscopy, including cryotherapy (patients 4 and 5) and bronchoscopic balloon dilatation (patient 5).

Follow-up of PFT

So far, all the six patients were followed up at a median time of 19.5 months (12 to 39 months) after the LTX and at a median time of 8.5 years (5 to 12.25 years) after the HSCT. At present, all patients are alive and leading normal lives. PFTs after LTX have shown improvement of all parameters in all patients (Fig. 3). Patient 5 needed non-invasive ventilatory support temporarily, and the rest of the patients were leading an active and normal life.

Discussion

HSCT has been successfully performed for decades in thousands of patients, leading to long-term survival. However, these patients are at risk of morbidity and mortality secondary to pulmonary complications. BOS has received considerable attention as a major course of obstructive lung disease along with active chronic GVHD after HSCT. The incidence of BOS after HSCT varies from 2.7% to 7.6% according to the published studies [⁶,⁷]. The disease can be diagnosed by lung function tests that demonstrate irreversible airway obstruction. The management of such patients includes immunosuppressive therapy, bronchodilators, antibiotics, and immunoglobulins. Despite the improvement in immunosuppressive treatment, the prognosis of the disease tends to be poor; 87% of patients who did not respond to the medical treatment died within 5 years after diagnosis [⁷]. Hence, LTX was used as a potential therapeutic option for HSCT patients who developed BOS.

The six patients had a median onset of BOS at 2.5 years after allogeneic HSCT. They received classic management of BOS with immunosuppressive agents, such as corticosteroids, CsA, FK506, MMF, and bronchodilators. Despite all these immunosuppressive treatments for at least one year, our patients experienced severe worsening of pulmonary functioning tests. At present, BOS occurring after HSCT is not a usual condition for LTX. Only a few medical reports describe LTX for BOS after HSCT [⁵,⁸,⁹].

The only concern for LTX is that it may lead to a relapse of the malignant condition that was treated with HSCT. Currently, the International Society for Heart and Lung Transplantation recommends that LTX should not be performed in the first two years of malignant condition [¹⁰]. In our patients, LTX was performed at 6.5 years after HSCT (ranging from 4 to 11 years), and no relapse was observed. This is in accordance with the observations reported previously. In 2014, Soubani et al. [¹¹] reviewed 84 patients who received LTX due to BOS after HSCT. Only two patients (2.4%) had relapse of the underlying hematologic malignancy during the follow-up period. The reported relapse rate following allogeneic HSCT in general was 34%–41% [¹²]. Another concern for the patients was that they were underweight. Although active nutritional supports were given to all patients before LTX, their body mass index was far below 19, which was the relative contradiction of LTX [¹⁰]. Due to their small and flat chests, size-matched lungs were not available. Size reduction of the donor lungs was achieved by peripheral segmental resection, and no major thoracic surgical complications related to size mismatch were observed.

Induction therapy is an intensive immunosuppressant therapy given perioperatively to reduce the risk of acute rejection and to delay initiation of maintenance immunosuppression. Some retrospective studies proposed that there is lower incidence for acute allograft rejection and bronchiolitis obliterans syndrome (BOS) with induction [¹³–¹⁵]. However, when the International Society of Heart and Lung Transplantation Registry data were reviewed, only 57% of the newly transplanted patients received some form of induction therapy. In our study, none of the patients received induction therapy. A total of 16.7% of patients suffered from one episode of acute cellular rejection, and no signs of BOS appeared during the follow-up period. Hartert et al. found that 33.9% of lung transplant recipients developed an acute rejection within the first two years after transplantation, whereas the incidence of BOS was 9.5% and 39.7% after lung transplantation for one and five years, respectively [¹⁶]. Our observations do not present any conclusive results but showed that the incidence of acute and chronic rejection was not higher than that of other recipients even without intensive immunosuppressant therapy.

Another concern about lung transplantation due to BOS after HSCT is the increased risk of fungal infections. Although fungal infections are less common than bacterial or viral infections in lung transplant recipients, they are associated with higher morbidity and mortality [¹⁷–¹⁹]. Approximately 15%–35% of patients developed fungal infections post-LTX, with an overall mortality of nearly 60% [¹⁹]. In our study, 50% of patients suffered from aspergillus infections, one with invasive pulmonary fungal infection and the other two with bronchial anastomotic infections, which led to anastomotic stenosis. The increased risk of infection is probably related to interruption of mucosal barriers associated with GVHD, hypogammaglobulinemia, prolonged immunosuppressive therapy, and colonization of Aspergillus. A more intensive antifungal prophylaxis after LTX for patients with several treatment lines of immunosuppressants should be discussed.

Given the increasing rate of HSCT and numbers of long-term survivors, LONIPCs especially BOS will be an increasing problem. This study indicated that LTX may be an effective therapy in terms of lung function and survival for patients with respiratory failure secondary to the development of BOS after HSCT. Further studies are needed to determine the appropriate timing and outcome of this approach.

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