Living-donor lobar lung transplantation from a hepatitis B surface antigen-positive donor to a negative recipient

Abstract

A man in his 40s was diagnosed with interstitial pneumonia at another hospital. He was referred to our hospital for lung transplantation. His lung function was rapidly declining, necessitating semiurgent living-donor lobar lung transplantation (LDLLT). Although he was negative for hepatitis B surface antigen (HBsAg) and hepatitis B surface antibody (HBsAb), one of the candidate donors was proven HBsAg-positive. The risk of hepatitis B virus (HBV) infection at transplantation was considered high; however, after careful discussion about the safety of the recipient and donor, it was decided to conduct LDLLT. For prophylaxis, human anti-HBV surface immunoglobulin and entecavir were administered to the recipient. HBsAg and HBsAb were continuously monitored postoperatively and consistently negative, suggesting no signs of reactivation in the recipient, even after corticosteroid pulse treatment for acute cellular rejection. More than 6 months after LDLLT, there were no signs of HBV reactivation in either the recipient or donor.

Background

For patients with severe respiratory disease, lung transplantation is often the only radical therapeutic option. Although cadaveric lung transplantation (CLT) is the standard option, there is a severe donor shortage; thus, living-donor lobar lung transplantation (LDLLT) is an optional treatment for urgent cases.

The use of hepatitis B surface antigen (HBsAg)-positive organs remains controversial because chronic immunosuppression after organ transplantation may cause transmission of hepatitis B virus (HBV) and result in severe liver injury without prophylaxis. In lung transplantation, limited numbers of cases involving the use of HBsAg-positive cadaveric donors have been reported with successful prevention of viral transmission or reactivation in recipients by appropriate prophylaxis, suggesting the possibility of expanding the donor pool.¹

We here report a case of LDLLT from an HBsAg-positive donor to a negative recipient. We successfully maintained the negative HBsAg and HBV-DNA status in the recipient after LDLLT by administering entecavir and human anti-HBV surface immunoglobulin (HBIG) to the recipient.

Case presentation

A man in his 40s presented to our hospital for evaluation for lung transplantation. He had been diagnosed with idiopathic interstitial pneumonia at another hospital and treated with corticosteroids. His lung function was gradually declining, and his forced vital capacity was 0.8 L on admission. He had a smoking history of 11 pack-years and had quit smoking 15 years previously. He had no family history of pulmonary disease.

The patient’s percutaneous oxygen saturation (SpO₂) level was 98% while receiving supplemental oxygen (7 L/min). Peripheral blood and serum tests revealed slightly elevated levels of C reactive protein and alanine aminotransferase; no other liver enzymes were elevated. Abdominal CT images and the hepatitis virus status of the recipient were normal. He was seropositive for both cytomegalovirus and Epstein-Barr virus without evidence of antigenaemia. We attributed his elevated liver enzymes to medications such as trimethoprim-sulfamethoxazole, cyclosporine and vonoprazan fumarate. Chest CT showed diffuse bilateral fibrosis and peripheral consolidation (figure 1). Because the patient’s respiratory condition was so severe that he was unlikely to survive until CLT, we decided to perform LDLLT. However, in the process of testing the recipient and his donors, his brother, one of the candidate donors, was found to be an HBV carrier with HBsAg and HBV-DNA levels of 1541 IU/mL and 2.8 Log IU/mL, respectively. The recipient had no history of hepatitis virus infection, and he was negative for HBsAg and hepatitis B surface antibody (HBsAb). Lung transplantation from an HBsAg-positive donor to an HBsAb-negative recipient was thought to be associated with a high risk of postoperative HBV reactivation. Although the calculated donor/recipient lung sizes indicated that bilateral lung transplantation was necessary for LDLLT, the recipient had no potential donor candidates other than his sister and the HBsAg-positive brother. After a thorough discussion on the risk of HBV reactivation in the recipient and donor safety along with acquisition of informed consent, we concluded that the benefits of LDLLT outweighed the risks.

Figure 1.

Chest CT at admission showed diffuse bilateral fibrosis and peripheral consolidation.

Treatment

Because the recipient had donor-specific antibody to B52 of his sister (the left lung donor) with a high mean fluorescence intensity value of 4353, plasma exchange was performed twice preoperatively to reduce the donor-specific antibody level following the desensitisation protocol of our institution (2–4 times of plasma exchange with or without intravenous immunoglobulin before lung transplantation). LDLLT was performed the day after the last plasma exchange. The operation time was 9 hours 15 min, and the bleeding volume was 2250 mL. The recipient’s and two donors’ operations were conducted in parallel. The donors underwent posterolateral thoracotomy, followed by procurement of the lower lobes without the need for additional bronchovascular plasty. The recipient underwent a clamshell incision followed by right pneumonectomy and transplantation of his brother’s right lower lobe; the anastomosis was conducted in the order of bronchus, pulmonary artery and pulmonary vein (the donor’s lower pulmonary vein anastomosed to the recipient’s upper pulmonary vein). The left-side transplantation was conducted in the same manner. During pneumonectomy and anastomosis, the patient was supported by central venoarterial extracorporeal membrane oxygenation, which was removed after completing the left-side anastomosis. During the surgery, 10 000 units of HBIG were administered immediately before reperfusion of the right lung. After the surgery, 5000 units of HBIG and the first dose of entecavir were administered in the intensive care unit (figure 2).

Figure 2.

Course of treatments and levels of liver enzymes and HBsAb of the recipient described in the present case report. ALT, alanine transaminase; AST, aspartate transaminase; HBIG, human anti-hepatitis B virus surface immunoglobulin; HBsAb, hepatitis B surface antibody; Ope, operation; POD, postoperative day.

Outcome and follow-up

Treatment with entecavir (0.5 mg daily) was continued after the surgery. Taking the balance between the recipient’s DSA-positive status and high risk of HBV reactivation, the immunosuppression regimen with triple therapy (tacrolimus, mycophenolate mofetil and steroid) was not changed with the regular target trough levels of tacrolimus (11–14 ng/mL). HBsAg and HBsAb were measured daily for 1 week postoperatively. Blood tests on postoperative day (POD) 1 revealed positivity for HBsAb derived from HBIG and negativity for HBsAg. Although the liver enzymes were slightly elevated, there were no signs of HBV transmission (figure 2). Because the HBsAb titre had decreased to <1000 mIU/mL, an additional 5000 units of HBIG were administered on POD 7. The patient’s respiratory condition was good, and he was extubated on POD 7. Because of his stable general condition, he was transferred to the general ward on POD 14. Thereafter, HBsAb was measured every 2 days, and HBIG was not administered because the HBsAb titre remained above 1,000 mIU/mL (figure 2). On POD 22, The patient’s SpO₂ level decreased. Chest CT showed diffuse ground-glass opacity shadows in the right lung and bilateral pleural effusion. He was diagnosed with acute cellular rejection, and corticosteroid pulse therapy was introduced. His SpO₂ level improved, and the dose of methylprednisolone was gradually reduced. The patient was discharged on POD 54. More than 6 months after lung transplantation, the patient remained negative for HBsAg and HBV-DNA despite intensive immunosuppressive therapy. At the time of this writing, he was still taking entecavir daily, which will be continued lifelong. His brother, the right lung donor, was also being followed up on an outpatient basis with no treatment, and no HBV reactivation had been observed at the time of this report (figure 3). One year after transplantation, the follow-up at our hospital as a living donor will be completed but he will be continuously followed up locally for his HBV status.

Figure 3.

Levels of ALT and HBV-DNA of the right lung donor described in the present case report. ALT, alanine aminotransferase; HBV, hepatitis B virus; POD, postoperative day.

Discussion

CLT is the standard technique of lung transplantation; LDLLT is a limited option that should be considered only when the respiratory condition of the recipient is too severe to wait for the emergence of cadaveric donors because of ethical concerns. We encountered a patient with severe idiopathic interstitial pneumonia without HBV immunity, and LDLLT from an HBsAg-positive donor was the only option to save the patient’s life. Although there are ethical and technical concerns in the conductance of LDLLT, successful LDLLT was performed without evidence of HBV transmission to the recipient using prophylactic administration of HBIG and entecavir.

Organ transplantation from HBsAg-positive donors must be carefully considered because of the potential risk of viral transmission to the recipient, especially in the context of post-transplant immunosuppression. A previous study showed no differences in graft or patient survival between HBsAg-positive and HBsAg-negative donors in kidney transplantation for HBsAb-positive recipients.² In that study, 20 (53.5%) recipients from HBsAg-positive donors received 100 mg of lamivudine daily for 12 months, and 2 (4.7%) recipients were given a single dose of 5000 units of HBIG in addition to lamivudine. Another report also showed no new HBV infections in 35 recipients with HBV immunity who underwent kidney transplantation from HBsAg-positive donors.³ In that report, recipients whose HBsAb titre was <10 mIU/mL were vaccinated, and no patients received any prophylaxis, such as HBIG and lamivudine. These studies suggest that effective prophylaxis and pretransplant vaccination can prevent HBV transmission from HBsAg-positive donors in kidney transplantation.^{2 3} For these reasons, the British Transplantation Society recommends HBV vaccination in solid-organ transplant recipients who are HBV-naïve.⁴ Although our recipient was similarly HBV-naïve, we decided to prioritise lung transplantation without vaccination because of his rapidly progressing respiratory failure.

The use of organs from HBsAg-positive donors for HBsAb-negative recipients is very rare. In a recent retrospective single-centre study from China, 20 HBsAb-negative recipients received kidney transplantation from HBsAg-positive donors.⁵ In this study, 2 (10%) recipients became HBsAg-positive and one died of acute liver failure. The recipient who died had received a single dose of 2000 IU HBIG immediately before transplantation and lamivudine for 2 months, and the other recipient received lamivudine alone for 1.5 months. Both recipients became HBsAg-positive after completion of prophylaxis, suggesting that the relatively short duration of treatment may have affected the outcome.

The use of HBsAg-positive organs in thoracic organ recipients is also very rare. A previous study from Taiwan reported successful heart transplantation from HBsAg-positive donors.⁶ Three patients who were HBsAb-negative before transplantation were treated with HBIG perioperatively and received HBsAg-positive organs. Although one patient became HBsAg-positive, the patient was successfully treated with lamivudine. In addition, a previous study using data from the Organ Procurement and Transplantation Network reported nine cases of HBsAg-positive-to-negative lung transplantation with comparable long-term recipient survival between HBsAg-positive and HBsAg-negative donors.¹

The most appropriate prophylaxis for HBsAb-negative recipients has not been established. In one study of kidney transplantation from HBsAg-positive donors to HBsAb-positive recipients, HBIG and lamivudine prophylaxis contributed to good graft and patient survival rates.² Such prophylaxis may be equally effective in HBsAb-negative recipients, and the British Transplantation Society also recommends combination therapy with HBIG and/or a potent nucleotide analogue as prophylaxis against post-transplant HBV recurrence.⁴ There is no evidence supporting the appropriate duration of prophylaxis, and lifelong administration of a nucleotide analogue is recommended.⁷

In a reported case of lung transplantation from an HBsAg-positive donor, the HBsAb-negative recipient received HBIG before and after CLT daily for 7 days and was initiated on entecavir immediately postoperatively; both HBsAg and HBV-DNA remained negative.¹ In our case, HBIG was administered during and after lung transplantation, and entecavir was also administered according to the above-mentioned report.¹ Furthermore, HBsAg and HBV-DNA were continuously monitored, and HBIG was additionally administered when the HBsAb level decreased. The recipient has been treated with entecavir and has shown no signs of HBV transmission as of the time of this writing. Although this treatment strategy may be suitable, few data are available, including information regarding the most appropriate prophylaxis methods and duration. Further studies of HBV prophylaxis are needed.

In LDLLT, the risk of the donor must also be thoroughly evaluated. One study showed that host factors associated with HBV reactivation were older age, male sex, cirrhosis and underlying diseases such as lymphoma, solid tumours and rheumatoid arthritis.⁸ Immunosuppressive agents and chemotherapy were also reported as the major risk factors of HBV reactivation.⁹ However, to our knowledge, no reports have indicated that lung surgery itself is a risk factor for HBV reactivation. Therefore, in our case, the risk of HBV reactivation was not considered to be increased by lobectomy. Conversely, with respect to virological factors, detectable HBV-DNA and HBsAg are considered risk factors for HBV reactivation.¹⁰ In our case, the donor showed relatively high levels of HBsAg and HBV-DNA, suggesting possible reactivation in the near future with or without donation of his lung. However, there was no time to introduce antiviral treatment because of the recipient’s progressive respiratory dysfunction. Thus, although we considered that the risk of donating his lung was acceptable, reactivation of HBV needs to be carefully monitored.

In conclusion, LDLLT from an HBsAg-positive donor to a negative recipient was successfully conducted. Whether CLT or LDLLT is performed, lung transplantation from HBsAg-positive donors is likely to be performed safely with appropriate prophylaxis for HBV-immune recipients. Although this strategy has a potential to expand the donor pool, especially for urgent cases, further accumulation of experience is needed and acquisition of appropriate informed consent is mandatory.

Learning points.

• Lung transplantation from a living donor with positive hepatitis B surface antigen (HBsAg) to an HBsAg-negative recipient is feasible.

• If urgent lung transplantation is needed, the use of an HBsAg-positive organ should be considered.

• Prophylaxis with human anti-hepatitis B virus (HBV) surface immunoglobulin and entecavir should be initiated immediately if a recipient has no HBV immunity.

• When performing living-donor lobar lung transplantation from an HBsAg-positive donor, great attention should also be paid to avoid HBV reactivation in the donor.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).