Korean J Transplant 2022; 36(3): 212-220
Published online September 30, 2022
© The Korean Society for Transplantation
1 Division of Infectious Diseases, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
2 Division of Infectious Diseases, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
3 Department of Internal Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Incheon, Korea
4Department of Pediatrics, Severance Children's Hospital, Yonsei University College of Medicine, Seoul, Korea
5Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
6 Division of Infectious Diseases, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
7Department of Surgery, College of Medicine, Kyung Hee University, Seoul, Korea
8 Division of Nephrology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
9 Division of Infectious Disease, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
10Department of Surgery, Hanyang University College of Medicine, Seoul, Korea
11Department of Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
12 Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
Correspondence to: Sang-Oh Lee
Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Background: Infections are a major cause of morbidity, graft failure, and mortality in solid organ transplant recipients. Preventive measures have greatly reduced the burden of posttransplant infections. However, little is known about the practice patterns of infection prevention in South Korea.
Methods: A questionnaire-based cross-sectional survey was conducted. The questionnaire was developed by a multidisciplinary discussion. From the Korean Network for Organ Sharing data, a list of hospitals that performed kidney, liver, heart, and lung transplantations in 2019 was selected. We invited participants to respond to the questionnaire via email from January to March 2022.
Results: The response rates for each organ were as follows; 41% (31/76 hospitals) for kidney, 49% (25/51) for liver, 40% (8/20) for heart, and 89% (8/9) for lung transplantations. The median duration of antibacterial prophylaxis after transplant ranged from 5 to 7 days. Prophylaxis was commonly applied in cytomegalovirus (CMV) D+/R– recipients. For non-lung CMV R+ recipients, a preemptive strategy was the most common method. The duration of viral load monitoring for preemptive or hybrid strategies varied. All lung transplant programs used mold-active antifungal agents for a median of 6 months. An interferon-gamma release assay was most commonly used to screen for latent tuberculosis infections.
Conclusions: The infection prevention protocols in most transplant programs in Korea were generally in accordance with the guidelines. However, some variability was observed regarding antibacterial prophylaxis and CMV prevention. Our results provide useful insights into practice patterns and will assist in the development of national guidelines.
Keywords: Transplantation, Prevention and control, Opportunistic infections, Surveys and questionnaires
In patients with terminal dysfunction of an organ, solid organ transplantation (SOT) is the final treatment modality. In South Korea (hereafter, Korea), after the first kidney transplant was successful in 1969, liver transplantation was successful in 1988, pancreas transplantation and heart transplantation in 1992, and lung transplantation in 1996. Various SOTs are now common in Korea, and according to data from the Korean Network for Organ Sharing (KONOS), about 4,200 SOTs were performed in 2019 . The development of immunosuppressants to reduce rejection has greatly contributed to the improvement of the long-term survival rate after SOT. However, at the same time, the occurrence of various infectious diseases remains a problem to be overcome.
Transplant centers around the world are using various prevention protocols to reduce the incidence of infectious diseases after SOT. In the meantime, there have been some national or international surveys on these protocols [2-10]. The international guidelines for post-SOT infection prevention have recently been updated [11-19]. In Korea, there has not yet been a nationwide survey on these protocols, and national guidelines have not been established. Therefore, the Korean Society for Transplantation formed the Transplant Infection Control Committee and conducted this nationwide survey on post-SOT infection prevention protocols.
Ethics approval and written consent were not applicable to this study because it did not report on or involve the use of any animal or human data or tissue.
This questionnaire-based cross-sectional study was conducted on behalf of the Transplant Infection Control Committee of the Korean Society for Transplantation. The questionnaire (Supplementary Material 1) was peer-reviewed and a pilot version was trialed by the committee members. It was prepared for kidney, liver, heart, and lung transplantations, respectively. These included (1) the respondent’s medical department and e-mail address; (2) the prophylactic antibacterial agents and duration of use; (3) cytomegalovirus (CMV) prevention in donor-seropositive/recipient-seronegative (D+/R–) and recipient-seropositive (R+) settings: universal prophylaxis, preemptive strategy, and hybrid (prophylaxis and preemptive) method; (4) herpes zoster prevention; (5) Epstein-Barr virus (EBV) monitoring for the prevention of posttransplant lymphoproliferative disease; (6) BK virus (BKV) monitoring in kidney transplantation; (7)
From the KONOS data, a list of hospitals that performed kidney, liver, heart, and lung transplantations in 2019 was selected. We sent an e-mail to the person in charge of the transplant center in each hospital to explain the purpose of the project, and asked them to specify who would respond to the survey for each organ. Respondents were asked to complete the survey based on their routine management for post-SOT infection prevention. We received replies from January 21 to March 11, 2022. If the answer was insufficient, a personal email was sent to the respondent to request a supplementary answer.
According to KONOS data, 2,293 kidney transplantations at 76 hospitals, 1,579 liver transplantations at 51 hospitals, 194 heart transplantations at 20 hospitals, and 157 lung transplantations at 9 hospitals were performed in 2019 . The response rates for each organ were as follows: 41% (31/76 hospitals) for kidney, 49% (25/51) for liver, 40% (8/20) for heart, and 89% (8/9) for lung transplantations. Of the total number of transplantation procedures, the proportions of transplantations for each organ performed by the respondents’ hospitals were as follows: 70% (1,611/2,293) for kidney, 83% (1,307/1,579) for liver, 76% (148/194) for heart, and 99% (155/157) for lung transplantations.
The respondents answered that third-generation (39%, 12/31) and first-generation (32%, 10/31) cephalosporins were often used as prophylactic antimicrobial agents in kidney transplantation (Table 1). Cefotaxime plus ampicillin/sulbactam (24%, 6/25) was most commonly used in liver transplantation. Characteristically, ampicillin containing regimens (56%, 14/25) were commonly used in liver transplantation. The median durations of prophylactic antimicrobial agents were 5 days for kidney, 5 days for liver, 7 days for heart, and 6 days for lung transplantations (Supplementary Fig. 1).
Table 2 shows CMV prevention protocols for CMV D+/R– transplant recipients. In kidney transplantation, a hybrid method (39%, 12/31) was most commonly used. Universal prophylaxis was applied for a median of 3 months, and then a preemptive strategy was applied up to a median of 8 months after kidney transplantation in the hybrid method (Supplementary Fig. 2A-C). A preemptive strategy (36%, 9/25) was most commonly used for a median of 3 months after liver transplantation. Universal prophylaxis (63%, 5/8) was the most common method for heart transplantation, and the hybrid method (63% 5/8) was the most common method for lung transplantation. Table 3 and Supplementary Fig. 2D show CMV prevention in CMV R+ transplant recipients. Preemptive strategies were most commonly used for kidney (65%, 20/31), liver (64%, 16/25), and heart (75%, 6/8) transplantations. For lung transplantation, the hybrid method (63%, 5/8) was used the most often in the CMV R+ setting. As a prophylactic antiviral drug, valacyclovir was used at some kidney transplant centers, but most of the other centers used valganciclovir.
Most often, no method was used to prevent herpes zoster in kidney (77%, 24/31) and liver (72%, 18/25) transplantations (Table 4). Acyclovir prophylaxis (75%, 6/8) was most commonly used in heart transplantation. In lung transplantation, valganciclovir prophylaxis (88%, 7/8) for CMV prevention also prevented herpes zoster. Although most hospitals did not use any method to monitor EBV, it was monitored in situations such as EBV D+/R– or pretransplant quantitative polymerase chain reaction positivity. BKV was monitored at most hospitals (90%, 28/31) up to a median of 12 months after kidney transplantation.
Most often, no method was used to prevent fungal infections in kidney transplantation (58%, 18/31) (Table 5). Antifungal prophylaxis was applied at 76% (19/25) of hospitals after liver transplantation and at 63% (5/8) after heart transplantation. In lung transplantation, all hospitals used mold-active antifungal prophylaxis for a median of 6 months, and 50% (4/8) of hospitals monitored serum galactomannan for a median of 12 months. The most common method used to screen for LTBI was an interferon-gamma release assay (Table 6).
This study is the first survey on infection prevention after SOTs in Korea. While the centers that responded to our survey comprised 40%–50% of all transplant centers in Korea, the respondents conducted ≥70% of transplants in the country.
The most remarkable finding about antibacterial prophylaxis was its duration. The median duration of postoperative antibacterial prophylaxis was 5 days for the kidney and the liver, and longer for the heart and the lung. This practice pattern is not in accordance with the latest American Society of Transplantation (AST) guidelines , where the general recommendation is 24 (kidney) to 48 (liver and heart) hours, except for lung transplantation (≤72 hours) and high-risk conditions (≤14 days). A recent Eurotransplant survey (n=65) also reported that the majority of centers used a single dose (45%) or ≤72 hours (22%) of prophylaxis . Regarding the choice of antibiotics, 39% of kidney transplant centers used third-generation cephalosporins while the guidelines recommend first-generation cephalosporins. This suggests room for potential improvement, considering that kidney transplantation is usually performed as a non-emergent clean surgery and the surgical site infection rate is low. Based on the results of this study, it is hoped that multi-center research led by the Korean Society for Transplantation will be conducted to reduce the duration of antibacterial prophylaxis.
Most centers employed prophylaxis or a hybrid strategy for the prevention of CMV disease in CMV D+/R– recipients. Three months of valganciclovir was the most commonly used regimen for prophylaxis alone; however, the duration of prophylaxis and subsequent monitoring was not consistent for the hybrid strategy. One interesting finding is the use of acyclovir in three centers. Oral acyclovir for prevention was reported to be effective in a 1989 study, but a high dose was used and the study size was small (n=104) . A small randomized controlled study on liver transplant recipients showed the lack of effectiveness of oral acyclovir . As acyclovir is not recommended for CMV prophylaxis and oral valganciclovir is covered by the National Health Insurance Service (NHIS) in Korea, there seems to be no reason to use acyclovir in CMV D+/R– recipients.
For the more common setting of CMV R+ recipients, most centers used a preemptive strategy except for lung transplant programs. There is no clear evidence that either prophylaxis or a preemptive strategy is superior in low-risk settings (e.g., CMV R+ kidney, liver, and heart recipients). Prophylaxis is supported by more data from large clinical trials and is logistically convenient; however, higher drug costs and the potential side effect of cytopenia are of concern. There seems to be a regional difference in the selection of CMV prevention strategies. Centers in the United States more commonly used prophylaxis, while those in Europe employed either prophylaxis or hybrid strategies . Asian centers have favored preemptive strategies. This regional variability might arise from differences in the seroprevalence of CMV. The geographical environment may also affect the choice of strategy, as a preemptive strategy requires more frequent monitoring with blood tests. In Korea, the reimbursement from the NHIS must be another strong factor in the decision, as valganciclovir is currently not covered by the NHIS for preventive use in CMV R+ recipients.
Most centers used a preemptive strategy for CMV R+ recipients. A notable exception was lung transplant programs, 63% of which used a hybrid strategy. The duration of prophylaxis in a hybrid strategy varied from 0.5 to 6 months, as did the duration of post-prophylaxis monitoring. However, most centers discontinued monitoring within 12 months after the end of prophylaxis. Preemptive monitoring for CMV mostly lasted for 6–12 months in kidney transplant programs and for 1–6 months in liver and heart transplants. The optimal duration of prophylaxis is yet unclear. A randomized clinical trial demonstrated the superiority of 200 days of prophylaxis compared to 100 days in CMV D+/R– kidney transplant recipients . However, there have been no similar comparative studies in liver and heart transplant recipients, while 12 months of valganciclovir was shown to reduce the risk for CMV disease compared to 3 months of prophylaxis in CMV D+/R– and D+/R+ lung recipients . The duration of prophylaxis in our survey was generally in line with the AST guidelines . However, post-prophylaxis monitoring was considerably longer than suggested, with most centers continuing monitoring for 3–12 months. Three months of monitoring for preemptive treatment is generally suggested, albeit without firm evidence . Interestingly, 26% of kidney transplant programs continued CMV monitoring up to 12 months posttransplant. However, it is unknown how often CMV monitoring was performed and whether patients were tested weekly for this prolonged duration.
Quantitative nucleic acid amplification was used for monitoring in most programs. The most commonly used viral load thresholds for antiviral treatment were either 1,000 or 10,000 copies or IU/mL. There is no universal viral load threshold to guide preemptive therapy, and programs are recommended to establish site- and assay-specific thresholds [17,25].
This survey did not examine whether the selection of CMV prevention methods differs by the use of lymphocyte-depleting agents. A report suggested that maintaining a preemptive strategy might be a viable option among patients who experience acute rejection within 6 months after kidney transplantation . Furthermore, we could not collect credible responses on the conditions for the discontinuation of preemptive antiviral therapy. The AST guidelines suggest two consecutive weekly tests using a less sensitive assay and a single negative result from a highly-sensitive assay as a discontinuation threshold . However, a report from a single transplant center suggested the safety of discontinuation after one negative test .
Screening and treatment for LTBI are widely implemented at most centers. However, 28% of liver transplant programs reported that they did not screen or treat for LTBI. This is probably due to the potential for hepatotoxicity of anti-tuberculosis drugs and the high prevalence of LTBI in Korea. An interferon-gamma release assay was the most common diagnostic method for screening, although a tuberculin skin test was used in combination with an interferon-gamma release assay at a minority of centers.
Our study has some strengths. First, this is the first nationwide survey on the prevention of opportunistic infections in solid organ recipients in Korea. The respondents in this survey performed the majority of transplants in Korea. Thus, our results provide useful insights into the current practice in most active transplant programs. Second, we developed our questionnaire through a discussion with a multidisciplinary team including infectious disease physicians, transplant surgeons, and internists.
However, there are some limitations. There were some transplant centers, mostly mid-size, which did not respond to our survey. Our results may not reflect practices at those centers with a relatively small volume of transplantation procedures. Some important issues regarding prevention strategies were either absent or insufficiently detailed to collect meaningful information. Future studies are warranted to fill the gaps in this survey.
The Transplant Infection Control Committee of the Korean Society of Transplantation conducted a nationwide survey on the infection prevention protocols in SOT programs in Korea. The protocols in most programs were in accordance with widely accepted guidelines, but some variability was observed regarding postoperative antibacterial prophylaxis and the prevention of CMV disease. Our results will assist in the development of national guidelines for the prevention of infectious complications in SOT recipients.
Conflict of Interest
Jong Man Kim is an editorial board member of the journal but was not involve in the peer reviewer selection, evaluation, or decision process of this article. No other potential conflict of interest relevant to this article was reported.
This study was supported by The Korean Society for Transplantation (2022-00-01005-012).
Conceptualization: SIK, SOL, JMK (Ji-Man Kang), JMK (Jong Man Kim), HJA. Data curation: KH, SJJ, YJK. Formal analysis: KH, SOL. Funding acquisition: SIK, OJK, MSK. Methodology: SOL, WBP, JY. Writing–original draft: KH, SOL. Writing–review & editing: all authors.
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