Human T-Cell Lymphotrophic Virus Infection in Organ Donors: A Need to Reassess Policy?
Human T-cell lymphotrophic virus (HTLV)-I/II infection has been considered a contra-indication to organ donation due to the risk of transmission of infection and the subsequent development of either adult T-cell leukemia or HTLV-I-associated myelopathy. However, neither the incidence of HTLV-I/II infection in organ donors nor the risk of transmission of HTLV-I/II by solid organ transplantation has been defined. Further, it is not known if HTLV infection contributes to significant morbidity in solid organ recipients. The purpose of this study was to evaluate the incidence of HTLV-I/II infection in organ donors in USA and to determine if transplanting these organs resulted in HTLV-related morbidity or mortality. We utilized the UNOS database to: (i) identify organ donors that were positive for HTLV-I or II infection between 1988 and 2000, and (ii) evaluate outcomes in the recipients of these organs. There were 25 HTLV-I/II-positive organ donors reported to UNOS between 1988 and 2000. Based on organ donors with a known HTLV-I/II status, the prevalence of HTLV-I infection in organ donors is 0.027% and the prevalence of HTLV-II is 0.064%. Twenty-two organs were transplanted from these HTLV-positive donors. There have been no reports of HTLV-I/II-related disease in the recipients with a median follow-up of 11.9 months. At our center, over the last 1.5 years there have been four multiorgan donors with false-positive HTLV-I/II screening assays, which resulted in the decision not to use organs from these donors. Based on the minimal chance of HTLV-related disease following transplantation of HTLV-I/II organs in this series, we recommend that careful consideration be given to transplanting organs from HTLV-I/II-positive organ donors.
Human T-cell lymphotrophic virus (HTLV)-I was first isolated in 1980 from a patient with a cutaneous T-cell lymphoma (1). Two years later, a related virus (HTLV-II) was found in a patient with hairy cell leukemia (2). HTLV-I infection has subsequently been linked to both adult T-cell leukemia/lymphoma (ATL) (3) and HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM) (4). Adult T-cell leukemia/lymphoma typically develops after a long incubation, with an estimated lifetime risk of 3–5% in patients infected with HTLV-I prior to age 20 (5–7). Perinatal infection appears to be more important in the pathogenesis of ATL than infection acquired later in life (8). The lifetime risk of HAM in HTLV-I carriers is estimated to be less then 2%, although the incubation period is shorter than that for ATL (9). Additionally, HTLV-I has been associated with a spectrum of less severe syndromes, including polymyositis, arthropathy, infective dermatitis in children, and uveitis (10). However, in the majority of cases infection with HTLV-I does not cause disease. Human T-cell lymphotrophic virus-II, despite its isolation from a leukemia patient, has not been clearly associated with disease (11).
Human T-cell lymphotrophic virus-I infection is endemic in the Caribbean, areas of Africa, south-western Japan, and Italy (12). Seroprevalance in these endemic areas increases with age and can be as high as 30% in the elderly (12). In nonendemic areas of the world, seroprevalance rates are significantly lower. Serology studies in United States blood donors report a 0.035% to 0.046% (approximately 1 person per 2500) prevalence of HTLV-I and II (13). However, in specific areas, such as central Brooklyn and south Florida, HTLV infection may be endemic with prevalence as high as 4% (14–16). HTLV-II is about 3 times more prevalent in the American population than HTLV-I, most likely secondary to an association with intravenous drug use (13,17). Further, there is an increased incidence (6%) of HTLV-I/II infection among hemodialysis patients, potentially related to multiple transfusions in this population (18). Transmission of HTLV occurs via breast-feeding, blood transfusions, shared needles among drug abusers, and sexual contact. Based on look-back studies, transfusion of cellular components infected with HTLV results in a 27% to 77% seroconversion rate in the recipient (19–21). It has not been proven that HTLV-I/II infection can be transferred via organ transplant, although there has been one case report (22).
Whether a potentially infected organ should be used in transplantation depends on the prevalence of infection among organ donors, the transmission rate, and morbidity of infection (23). The incidence of HTLV-I/II infection in organ donors is unknown. Further, the significance of HTLV-I infection in transplant and other immunosuppressed patients is unclear. Although there has been speculation, it is not obvious that immunosuppression is associated with an increased incidence of HTLV-related disease. We reviewed data from the United Network for Organ Sharing (UNOS) and the University of Wisconsin Organ Procurement Organization (OPO) concerning the HTLV-I/II status of organ donors. Further, we analyzed the results in patients reported to have received organs from HTLV-positive donors. Based on this analysis, we recommend HTLV-I/II-positive donor organs be utilized with discretion. Further, long-term results of these patients should be closely followed for evidence of HTLV-related disease.
Materials and Methods
Data from UNOS regarding seropositive HTLV-I/II organ donors was available from 1988 to 2000. However, complete information on the HTLV-I/II status of the majority of donors was only available from 1994 to 2000. The HTLV-I/II status of donors was reported to UNOS as positive, negative, indeterminate, or unknown. It is not known if confirmatory tests were performed on donors who had a positive screening test. Recipients of any solid organs from HTLV-I/II-positive donors were identified. Results of transplantation and post-transplant complications such as malignancy are reported in the recipients of these organs.
Data from the last 146 organ donors (January 2000 to July 2001) at the University of Wisconsin OPO concerning HTLV status were reviewed. All donors were screened for HTLV infection with the human T-lymphotrophic virus types I and II Abbott HTLV-I/HTLV-II EIA (Abbott Laboratories, Abbott Park, IL, USA). This assay uses a combination of HTLV-I and HTLV-II antigens to detect antibodies to the whole HTLV group. This assay is reported by the manufacturer to have a sensitivity of 100% and a specificity of 99.6%. Confirmatory testing was done by Western blot assay (Genelabs Diagnostics) at an outside reference laboratory.
All data are reported as mean ±standard deviation.
Incidence of HTLV-I/II in organ donors
From January 1994 to December 2000, UNOS reports that there were 38 977 organ donors. The HTLV-I status was reported for 36 765 (94.3%) of the donors. In total, 10 donors over this time period tested positive for HTLV-I, giving an incidence of 0.027%. Seven donors were reported as indeterminate (Table 1). Prior to 1994, two donors were reported as positive for HTLV-I. However, the HTLV status of the majority (99.9%) of donors is unknown for that time period, and they were therefore not included in this analysis of incidence of HTLV-I. Thirteen donors were positive for HTLV-II, and 24 were reported as indeterminate from January 1994 to December 2000. However, the HTLV-II status of a significantly greater number of donors was unknown (48.3% vs. 5.7%)(Table 2). No donors were reported positive for HTLV-II prior to 1994. The average HTLV-I/II-positive donor was 37 ± 17 years old, with a range from 12 to 71 years. Fifty-two per cent of the positive donors were men and 48% women. The positive donors were all United States citizens. Fifty-five per cent were white, 28% were African-American, and 17% were Hispanic. No history of i.v. drug use was reported in any of the donors; however, this information was lacking for 67% of the HTLV-positive donors. Serologies for hepatitis B, hepatitis C, and HIV were negative in the HTLV-positive donors. One important qualification regarding these data: it is not known what type of test (a screening assay such as an EIA or a confirmatory test such as a Western blot) was utilized to determine the donor HTLV status.
Table 1. : Incidence of HTLV-I organ donors 1994–2000
|1994|| 5100|| 1||0|| 3975||1124|
|1995|| 5361|| 1||0|| 5224|| 136|
|1996|| 5421|| 1||0|| 5248|| 172|
|1997|| 5485|| 0||3|| 5288|| 194|
|1998|| 5800|| 2||2|| 5663|| 133|
|1999|| 5825|| 2||0|| 5589|| 234|
|2000|| 5985|| 3||2|| 5761|| 219|
|Total||38 977||10||7||36 748||2212|
|% Total |
|% Tested||36 765||0.027%||0.019%||99.95%|| |
Table 2. : Incidence of HTLV-II in organ donors 1994–2000
|1994|| 5100|| 0||10|| 1250||3840|
|1995|| 5361|| 1|| 9|| 1275||4076|
|1996|| 5421|| 1|| 0|| 1022||4398|
|1997|| 5485|| 1|| 1|| 1160||4323|
|1998|| 5800|| 1|| 2|| 4309||1488|
|1999|| 5825|| 4|| 0|| 5341||480|
|2000|| 5985|| 5|| 2|| 5760||218|
|Total||38 977||13||24||20 117||18 823|
|% Total |
|% Tested||20 154||0.064%||0.12%||99.82%|| |
Results of transplantation of HTLV I/II-positive organs
From 25 HTLV-I/II seropositive donors (1988–2000), 22 organs were transplanted. Seven organs were from HTLV-I-positive donors and 15 from HTLV-II-positive donors (four donors were positive for both HTLV-I and II). Nine livers, 6 kidneys, 5 hearts, and 2 lungs were transplanted. The average recipient age was 50.2 ± 2.5 years, with a range from 25 to 67 years. The average follow-up was 23.1 ± 37.4 months (range: 2 days−11.8 years) with a median follow-up of 11.9 months post transplant. Length of follow-up was not reported on one patient (Table 3). Seventy-seven per cent (17/22) of the recipients were alive at last follow-up. Only one post-transplant malignancy has been reported in this group of patients (patient no. 15). She received an HTLV-II-positive liver for hepatocellular carcinoma and developed recurrence of this malignancy in both her liver and lung 4 years post-transplant. This is most likely not related to HTLV infection. There are no reports of post-transplant lymphoproliferative disorder, lymphomas, HAM, or other neurologic syndromes in recipients of HTLV-I/II-positive organs.
Table 3. : Results of organ transplantation using HTLV I and II positive donors
| 1||–||+||Liver||Hep C||67|| 344||Alive||Functioning||No|
| 2||–||+||Lung||Unknown||56|| 2||Died||Failed||No|
| 3||–||+||Kidney||Unknown||42|| 731||Alive||Functioning||No|
| 4||–||+||Liver||Hep C||48||Unknown||Alive||Unknown||No|
| 6||–||+||Liver||Hep C||45|| 363||Alive||Functioning||No|
| 7||–||+||Kidney||Unknown||37|| 358||Alive||Functioning||No|
| 8||–||+||Liver||PSC||48|| 425||Alive||Functioning||No|
| 9||–||+||Kidney||Unknown||28|| 371||Alive||Functioning||No|
|22||+||+||Liver||Hep C||65|| 364||Alive||Functioning||No|
The University of Wisconsin experience with HTLV-positive donors
The HTLV status of the last 146 potential donors (January 2000–July 2001) from the University of Wisconsin OPO was available. Four donors out of 146 (2.7%) tested positive for HTLV-I/II infection by a screening assay that detects antibodies to both HTLV-I and HTLV-II. All four (100%) were found to be false-positives when confirmatory Western blots were performed. However, 14 potential organs were discarded from these four donors because of the positive HTLV I/II screening assay.
The gap between supply and demand for donor organs is increasing. Each year, about 3000 patients die in USA while waiting for an organ transplant. Approximately 10% of organs procured are discarded, usually secondary to problems with the donor, including age, quality, size and weight of the organ, and positive serologic tests (24). In an attempt to increase utilization of potential donors, we set out to study the incidence of HTLV-I/II infection in organ donors and to investigate the potential morbidity of transplanting these organs. Based on UNOS data, we report an incidence of 0.027% for HTLV-I and 0.046% for HTLV-II in organ donors. This is similar to the incidence of HTLV-I/II infection in voluntary blood donors in USA (13). Further, we found a 2-fold higher incidence of HTLV-II infection over HTLV-I in organ donors. Again, this is similar to what has been reported in the blood donor population (13). At the Wisconsin OPO there have been four false-positive donors and no true-positive donors for HTLV-I/II over the last 1.5 years. The higher incidence seen in Wisconsin when compared to UNOS is most likely due to the Wisconsin OPO reporting all potential donors who had a positive screening test for HTLV-I/II. The UNOS data include only donors whose organs were transplanted and were positive for HTLV-I/II. The reported incidence of HTLV-I/II in French organ donors is 0.47–0.67/1000, significantly lower than the result we report (25,26). A study from Spain reported a 0% incidence of HTLV infection in organ donors (27). The reason for this discrepancy may be related to the higher incidence of HTLV-II in the United States (17). Unfortunately, we do not know how many organs are discarded each year due to a positive HTLV screening assay. Twenty-two patients have received HTLV-I/II-positive organs and none have developed, to our knowledge, HTLV-related illness including ATL. However, the failure to report a disease in a registry may not be associated with a true lack of disease. Median follow-up is only 1 year, and longer follow-up is clearly needed. However, one patient has been followed for almost 12 years after receiving a heart from an HTLV-I-positive donor without developing any HTLV-related complications.
One significant problem with these data is the HTLV testing methodology. It is not known which donors in the UNOS data underwent confirmatory testing. We assumed that all donors reported to UNOS as HTLV-I/II positive are true-positives; however, these donors may only have had a screening assay done. Due to the high false-positive rate of the screening test, we may be over-reporting the true incidence of HTLV-positive organ donors. All donors are required per UNOS policy to undergo an FDA-licensed screening test for HTLV-I antibody. Abbott Laboratories report that the HTLV-I/II assay utilized by our laboratory has 100% sensitivity and 99.6% specificity. When a very sensitive screening test is used to detect the presence of a disease with a low prevalence, the positive predictive value of the test tends to be poor. For this reason, it is recommended that all positive screening tests for HTLV-I/II be followed by a confirmatory test such as a Western blot. Unfortunately, confirmatory testing cannot be performed in a time-frame that would allow use of organs from false-negative donors. A survey of infectious disease testing by OPOs in USA revealed that only 60% routinely perform confirmatory testing for HTLV infection, as it is difficult to obtain confirmatory testing emergently (28). As we have found in our OPO, a false-positive screening test may result in unnecessary loss of transplantable organs.
An important concern with transplantation of HTLV-positive organs is whether immunosuppression alters the course of HTLV infection. There have been four case reports of ATL occurring in HTLV-I-infected individuals who received kidney transplants (29–32). All four case reports state that these patients were most likely carriers of HTLV-I prior to transplantation and did not become infected secondary to organ transplantation. An analysis of post-transplantation lymphoproliferative disorders in Japan revealed five cases of ATL. ATL was responsible for only 20% of reported post-transplant lymphoproliferative disorders in Japan, where HTLV-I/II infection is endemic (33). These case reports of ATL in transplant recipients have led to the assumption that immunosuppression shortens the latent period of HTLV infection. In fact, retrospective studies from Japan suggest that the incidence of HTLV-related disease is not altered by transplant immunosuppression. Two series examined HTLV-I carriers who received kidney allografts and standard immunosuppression. No cases of ATL or HAM were reported in 31 patients with an average follow-up of 8–10 years. Both sets of authors conclude that immunosuppression does not seem to further the progression of ATL (34,35). Further support for this idea comes from in vitro data demonstrating that cyclosporine and FK506 suppressed the proliferation of HTLV-I infected T cells (36). In fact, it has been suggested that cyclosporine be used as a therapeutic agent in HAM (37).
Human T-cell lymphotrophic virus-I-associated myelopathy/tropical spastic paraparesis occurs at a much lower frequency than ATL in HTLV-I infected patients, with a 2% lifetime risk (9). However, the incubation period from infection to onset of myelopathic symptoms is believed to range from months to years, a much shorter incubation period than for ATL. Due to the shorter latency period of HAM and the high incidence of HTLV-I/II infection in dialysis patients (18), one might expect to see a significant incidence of HAM in renal transplant patients. In fact, there are only two case reports in the literature, to our knowledge, of HAM occurring after renal transplantation (38,39). There is a single case report of transfusion-related transfer of HTLV-I to a cardiac transplant patient in France and the subsequent rapid (14 weeks) development of HAM (40). This case has led to the supposition that transfusion-related transfer of HTLV-I combined with immunosuppression shortens the latent period of infection. Interestingly, another heart transplant recipient received a unit of the same contaminated blood that led to the index case cited above. He remains HTLV antibody negative and clinically unaffected 16 months after receiving the donor's blood (41).
There has been one case report of suspected transmission of HTLV-I by solid organ transplantation (22). This occurred in Argentina following a living donor kidney transplant. The recipient developed HTLV-I antibodies after receiving a live donor kidney allograft from her mother. Her mother was documented to be HTLV-I positive, and the patient had been seronegative prior to transplant. The recipient received multiple blood transfusions prior to transplantation, all of which were nonreactive for HTLV-I. No genetic analysis of the virus was done to fully confirm that transfer of HTLV-I infection had occurred from mother to daughter. She remains free of HTLV-related disease 4 years after transplant. There have been no further reports, to our knowledge, documenting transfer of HTLV by organ transplant. Serology data are not available regarding the status of patients who received HTLV-positive organs reported in this study.
Our recommendation at this time would be to begin carefully utilizing HTLV-I/II-seropositive organ donors from nonendemic areas. Although we believe the risk to be minimal, we do feel that informed consent must be obtained from the recipient of any HTLV-positive organs. Until HTLV-positive organ donors are utilized routinely and the recipients followed prospectively for a period of time without evidence of HTLV-related disease, we feel informed consent is warranted. It has been suggested that informed consent be obtained from recipients of other extended donor pool organs (42,43). A rapid confirmatory test needs to be designed or a Western blot needs to be obtained emergently to confirm the HTLV status of the donor and avoid wasting viable organ transplants. If the confirmatory test is negative for HTLV-I/II, the organs should be considered for all potential candidates. We suggest that HTLV-positive organs be transplanted into patients who have a life-threatening illness and are in urgent need of transplant. Further, these organs may be used in older patients with a shorter life expectancy and who therefore are less likely to develop HTLV-related disease, particularly ATL. Patients who are HTLV positive pretransplant would also be a suggested population for utilizing these organs. We would not recommend transplant of HTLV-positive organs into children, as they may have a small but significant incidence of ATL over a longer lifetime. All patients who receive HTLV-positive organs, as well as any patients who are HTLV positive pretransplant, should be followed closely for any evidence of HTLV-related disease. Further, patients should be screened pretransplant for HTLV antibodies and followed for seroconversion post-transplant. As we begin to utilize HTLV-positive organs, these criteria may be expanded.