Impact of donor infections on outcome of orthotopic liver transplantation

REVIEW

Impact of Donor Infections on Outcome of Orthotopic Liver Transplantation Michael Angelis, Jeffrey T. Cooper, and Richard B. Freeman Infection occurs when microbial agents enter the host, either through airborne transmission or by direct contact of a substance carrying the infectious agent with the host. Human body fluids, solid organs, or other tissues often are ideal vectors to support microbial agents and can transmit infections efficiently from donor to recipient. In the case of blood transfusion and tissue transplantation, the main consequence of such a transmission is infection of the recipient. However, in the case of solid-organ transplantation, and particularly for liver transplantation, donor infections are not only transmitted to the recipient, the donor infection also may affect the donated liver’s preservability and subsequent function in the recipient irrespective of the systemic consequences of the infection. In addition, solid organ recipients of infected organs are less able to respond to the infectious agent because of their immunosuppressive treatment. Thus, transmission of infections from organ donor to liver recipient represents serious potential risks that must be weighed against a candidate’s mortality risk without the transplant. However, the ever-increasing gap between the number of donors and those waiting for liver grafts makes consideration of every potential donor, regardless of the infection status, essential to minimize waiting list mortality. In this review, we will focus on assessing the risk of transmission of bacterial, fungal, viral, and parasitic infectious agents from cadaveric liver donors to recipients and the effect such a transmission has on liver function, morbidity, and mortality. We will also discuss risk-benefit deliberations for using organs from infected donors for certain types of recipients. These issues are critically important to maximize the use of donated organs but also minimize recipient morbidity and graft dysfunction. (Liver Transpl 2003; 9:451-462.)

Donors With Bacterial Infections Systemic bacterial infection has been regarded a contraindication to cadaveric organ donation for transplantation because of the fear of transmitting pathogenic organisms to the immunosuppressed recipient. There are many reports documenting isolated instances of transmission of infectious agents from donors to recipients.1-6 Although there is a case report documenting poor function of a liver allograft procured from a bacteremic donor,7 other larger series have not documented poorer graft and patient outcomes.8-10 In a study from the New England Organ Bank,10 there were 95 (5.1%) bacteremic donors from 1990 to 1996. Fifty-four liver trans-

plants were performed from these bacteremic donors. These recipients had no difference in 30-day graft and patient survival when compared with recipients of livers from donors without bacteremia. Another study of bacteremic donors from the Louisiana Organ Procurement Agency found only 3 (8%) of 36 organ recipients had infections caused by organisms found in contaminated donor organs, and only one of nine liver transplant recipients had the same organism isolated from the blood as that recovered from the donor.11 Bacterial meningitis does not appear to be a contraindication to organ donation provided that the donor and recipients have been adequately treated with antibiotic therapy. Several studies have addressed the use of livers from donors with bacterial meningitis.8,12,13 None of the recipients of organs recovered from these donors developed infectious complications attributable to the donors, and long-term allograft function was good. In most of the larger series, recipients of organs from bacteremic donors were treated more aggressively with antibacterial prophylaxis, usually longer than 48 hours after transplant. There is no controlled trial indicating the optimal duration of antibacterial treatment for recipients of organs from bacteremic donors but 5 to 7 days of appropriate therapy seems to be the most frequently cited regime. Even though donor bacterial infection is relatively common, these data suggest that livers procured from bacteremic donors are likely to function well and pose little if any increased risk to the recipient, provided that the recipient is treated with antibacterial agents active against the donor bacterial isolate.

From the Division of Transplantation, Tufts-New England Medical Center, Boston, MA. Address reprint requests to Richard B. Freeman, MD, Division of Transplantation, Tufts-New England Medical Center, Box 40, 750 Washington St, Boston, MA 02111. Telephone: 617-636-5592; FAX: 617-636-8228; E-mail: [email protected] Copyright © 2003 by the American Association for the Study of Liver Diseases 1527-6465/03/0905-0001$30.00/0 doi:10.1053/jlts.2003.50094

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Donors With Fungal Infections One case report documents transmission of candida infection from donor to naive liver recipient. The recipient required antifungal treatment but went on to survive in the long term.14 The recipients of the two kidneys from this donor developed mycotic infections of the vascular anastamoses, and both lost their renal grafts. Other larger series of donors with fungal infections have not documented infection or graft sequellae in recipients of these livers.10,11 Aspergillus transmission from a liver recipient who became a cadaveric kidney and heart donor has been reported. Both renal recipients lost their grafts to infection, and the heart recipient developed fungal endocarditis, opthalmitits, and dermatitis but survived.15 One case of transmission of histoplasmosis from a renal donor to renal recipient has been reported in which the graft functioned well,16 but there are no other reports of fungal transmission from donor to liver recipients. The lack of consistent evidence for significant consequences from the use of livers from donors infected with fungal organisms suggests that the risk of transmission is low and morbidity also is minimal. Livers from donors with isolated fungal infections should be routinely used, especially for candidates with urgent or emergent indications for transplantation.

Donors With Viral Disease Hepatitis B Virus Active hepatitis B virus (HBV) infection usually is diagnosed by the presence of hepatitis B surface antigen (HBsAg) in the serum. Donors testing positive for HBsAg usually transmit HBV infection to the recipients17,18 but the long-term effects of this infection may not be deleterious,19,20 especially for candidates with high waiting list mortality risk and for whom lamivudine is appropriate therapy. In the absence of HBsAg, an isolated serologic finding of anti– hepatitis B core antibody (HBcAb) alone, or accompanied by anti-hepatitis B surface antibody (HBsAb), has been considered indicative of resolved HBV infection. For this reason, blood donors positive for HBcAb are thought to have a low risk of transmitting HBV to blood recipients, with only a few documented cases reported in the literature.21,22 In the case of solid-organ donors positive for HBcAb, the risk of transmitting HBV infection appears dependent on the organ being transplanted, with the highest rate of transmission to liver recipients and exceedingly rare transmission to kidney or heart recipients.23,24

De novo HBV infection has been documented in 25% to 95% of recipients of livers from HbsAg-negative, HbcAb-positive donors, compared with less than 1% of recipients of HBcAb-negative livers.23-28 When HBsAb is present with HBcAb in a liver donor, it has not shown a consistently protective effect against the transmission of HBV to the naive liver recipient.23-25 Although an HBcAb-positive donor liver implies a high rate of HBV transmission, the broad range of HBV transmission reported in these studies may be related to the HBcAb assays with false positive rates ranging from 10% to 75%.29,30 This variation in transmission rates also may be influenced by variations in immunosuppressive regimens because corticosteroids can facilitate HBV replication caused by the steroid-sensitive transcriptional enhancer component present in the HBV genome.28 The natural history of HBV infection in naive recipients of HBcAb-positive donors has not been well studied, but reports of frequent hepatitis and fibrosis25-28 have generally convinced practioners to prophylax these recipients with lamivudine.27,31,32,34,35 The use of hepatitis B immune globulin (HBIg) alone or in combination with lamivudine to prevent HBV liver disease in recipients of HBcAb-positive livers appears to be more effective but also much more expensive.28,32,35,36 A recent study has suggested that lamivudine monophrophylaxis may be adequate for prevention of HBV transmission from HBcAb-positive donor to naive recipient.34 Long-term treatment with lamivudine may lead to antiviral-resistant HBV mutant strains in liver transplantation. Until more experience is gained, the best treatment for these resistant strains may be with HBIg and other newer antiviral drugs such as adefovir and tenofovir.36-39 HBcAb-positive recipients of livers from HBcAbpositive donors apparently have low frequencies (0% to 13%) of HBV reactivation.27-29,31-33 It is controversial whether the presence of HBsAb in liver recipients of HBcAb-positive livers has a protective effect for HBV reactivation. Three series have shown no HBV reactivation24,28,29 in this setting, but in one series, one of three HBsAb-positive recipients of HBcAb-positive livers developed reactivation of HBV.25 The long-term survival for recipients of HBcAb-positive donor livers has not been well defined. In one study of recipients of HBcAb-positive livers, 4-year patient survival was 68% compared with 76% for recipients of HBcAb-negative grafts, but this difference did not reach statistical significance.29 Better tools are needed to predict the probability of HBV reactivation in recipients of livers from HBcAbpositive donors. Given the time constraints involved in

Impact of Donor Infections on OLT

organ procurements, evaluating donor-recipient HBVDNA status is impractical except for a few centers.32 Despite this, retrospective analyses of HBV-DNA in stored serum and liver tissue have suggested that the absence of circulating HBV-DNA in donors positive for HBcAb does not preclude transmission of HBV to liver recipients.24,25,28,33 The United Network for Organ Sharing collects serologic data on donors from whom at least one organ has been procured. From 1995 to 2002, 1595 livers were recovered from donors testing positive for HbcAb, of which 1316 actually were transplanted for an overall usage rate of 82.5% compared with 34,198 livers recovered from HBcAb-negative donors, of which 30,799 (90.1%) underwent transplantation. Over these 8 years, 4.7% of donors from whom a liver was recovered tested positive for HbcAb, and the usage of these organs was slightly less than for livers recovered from HBcAbnegative donors. There are no data available for donors testing positive for HBcAb from whom no organs were recovered. Use of kidneys from HBcAb-positive donors (75.6%) is slightly lower than livers and is similarly reduced compared with kidneys from HBcAb-negative donors (87.5%), with 5.2% of all renal donors testing positive for HBcAb. Any liver donor positive for HBsAg or HBcAb has a high likelihood of transmitting HBV infection to the naive recipient. At the present time, these organs are ideally used for candidates already exposed to HBV. The recipients should be treated with postoperative prophylaxis; however, the ideal regimen is yet to be defined. More controversial is the use of such organs for the HBV naive recipient. Current data suggest that these recipients may not fare as well as those receiving organs from HBV-negative donors. However, aggressive prophylaxis against HBV reactivation may achieve acceptable results, especially with the newer agents now available. Because there is effective preventive treatment for HBV infection, HBcAb-positive donor livers may be considered appropriate for HBV-negative candidates who are at extremely high risk of dying without transplant. Hepatitis C Virus Hepatitis C virus (HCV) infection is a major cause of chronic liver disease; 4 million Americans and 170 million people worldwide are infected with HCV.40 In the United States, HCV is the most common indication for liver transplantation.41 The availability of second-generation antibody testing for HCV and, more recently the advent of polymerase chain reaction (PCR) amplification of viral RNA,42 have greatly improved the accu-

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rate diagnosis of HCV infection. With these more precise tests, it has become evident that HCV recurrence after liver transplantation is nearly universal and may lead to graft failure.43-46 Transplantation of hepatic allografts from antiHCV–positive donors to recipients with HCV-related liver disease has not resulted in differences in graft and patient survival, compared with HCV recipients of grafts from HCV-negative donors.47-49 A study from the University of California Los Angeles (UCLA) reported that patient and graft survival rates are not reduced for HCV-positive liver recipients who are given HCV-positive donor livers or in whom HCV recurs histologicaly.48 However, HCV-positive recipients of HCV-positive donor livers had a significantly reduced median time to recurrence of 22.9 months, compared with 35.7 months for HCV-positive recipients receiving grafts from HCV-negative donors. Another study using the UNOS registry examined 190 HCV-positive grafts transplanted into HCV-positive recipients.49 At 3 years, the graft survival rate for livers from HCV-negative donors was 69% compared with 73% for grafts from HCV-positive donors. A small number of cases (n ⫽ 29) also were reported to UNOS, in which HCV-positive grafts were transplanted to HCV-negative recipients, with these patients having similar patient survival rates compared with the HCV-positive recipients. Authors of this study, using a multivariate analysis, found that recipient but not donor HCV status was an independent predictor of reduced graft survival after transplantation (5-year survival for HCV-negative recipients 70.1% versus 62.2% for HCV-positive recipients). This contrasts with other studies reporting comparable overall patient and graft survival rates for HCV-positive recipients compared with other indications for liver transplantation.43,48,50-53 UNOS data for donors from which at least one organ has been recovered documents that 556 (71.5%) livers were transplanted from the 778 livers that were recovered from HCV-positive donors over the 1995 to 2002 time period. Over the same time period, 32,861 (90.2%) livers were transplanted from 36,441 livers recovered from HCV-negative donors. Overall, 2.1% of these donors tested positive for HCV. For renal donors, 65.6% of kidneys from HCV-positive donors were used compared with 87.6% of kidneys from HCV-negative donors from 1995 to 2002. In this cohort of donors, 2.9% of all renal donors from whom at least one organ was recovered tested positive for HCV. A more detailed analysis has shown that when the donor and recipient HCV genotypes were unmatched,

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only one viral strain prevails. Subtype 1b and type 1 always became the predominant strain regardless of the donor of recipient origin.54 These data suggest that the virulence of the HCV strain, regardless of its source, may be more important for predicting recipient recurrent HCV disease than donor or recipient HCV status. The weight of evidence suggests that donor HCV is routinely transmitted to recipients. HCV-negative recipients of HCV-positive organs may have reduced patient and graft survival rates. In the absence of effective prophylactic regimens, livers from HCV-positive donors are best used for recipients with HCV infection. Long-term results will be necessary to determine final risk benefit calculations, but at the present time, there does not appear to be any short-term detriment to using these organs for HCV-positive recipients. Important in these considerations is the activity of the HCV in the donor liver. Donor liver biopsies can be helpful in this regard because livers with active hepatitis or fibrosis are likely to have poorer results. Avoiding the use of particularly virulent donor HCV strains will not be possible until more rapid genotyping can be conducted within the time constraints of organ procurement procedures. Cytomegalovirus Cytomegalovirus (CMV) infection is the single most frequent infectious complication in transplant recipients, and occurs more frequently in liver transplant recipients than in transplantation of any other organ type.55 CMV infection may be limited to viremia or vuruia without overt symptoms, or it may present as a viral syndrome with fever malaise, leucopoenia, or signs and symptoms of tissue invasion. Recipients at highest risk for CMV infection are usually naive recipients of organs from CMV infected donors.56,57 Before the era of routine prophylaxis against CMV transmission, CMV infection had been reported in 30% to 50% of liver transplant recipients, with half of these recipients developing CMV disease.58-62 Transmission of donor CMV to recipients has become less of a concern with the development of effective oral prophylactic regimens. Many prophylactic approaches have been proposed to reduce CMV infection after liver transplantation. One approach selectively targets recipients who are at high risk for CMV to receive preemptive antiviral therapy with ganciclovir.63 A second alternative involves prophylaxis with antiviral agents for the entire transplant population.64 More recently, Kim et al62 have shown that monitoring recipients for viral replication in blood and treating only when signs of viral replication appear, can also be an effective preventative approach. This has been shown to be cost effec-

tive even for the high-risk group of recipients, again making the consequences of donor to recipient transmission less significant for this virus. For the high-risk CMV-naive recipient of a liver from a CMV-positive donor, ganciclovir has been proven to be a superior prophylactic agent when compared with acyclovir for the prevention of CMV infection.62,64 Preliminary data has shown that valganciclovir, a more bioavalible derivative of ganciclovir, is as effective as ganciclovir for preventing CMV disease in these high-risk liver recipients.65 More recently, the use of oral ganciclovir prophylaxis to prevent CMV disease transmitted from donor to recipient also has improved recipient rejection rates and graft and patient survival rates.66 Thus, transmission of CMV from donor to recipient represents a relatively low-risk infection when effective prophylaxis is used. In most cases, the benefit of liver transplantation far outweighs the risks associated with transmission of CMV disease because of these improvements. Epstein-Barr Virus Epstein-Barr virus (EBV) infects approximately 95% of the world’s adult population. In the immunocompetent host, it leads to a persistent, latent infection of B cells. Primary infection will occur in the EBV-naive transplant recipient who receives a solid-organ transplant from a previously infected donor.67 Multiple groups have shown these phenomena.68,69 B cell infection by EBV may lead to uncontrolled proliferation and the development of posttransplant lymphoproliferative disorder (PTLD). The risk of developing PTLD clearly is influenced by the type of organ received, with the highest rates occurring in recipients of lung allografts.70 In addition, the risk of developing PTLD is associated with the intensity of the immunosuppressive treatment. PTLD has been linked to the use of cyclosporine, tacrolimus, and, especially, antilymphocyte therapy.71 Given the greater incidence of EBV-naive recipients in the pediatric transplant population, concern has been raised regarding the greater risk of EBV transmission. However, fears about the increased risk of developing PTLD in this population must be balanced by the reduced availability of suitable organs for this age group, especially when the incidence of PTLD in younger recipients is only about 12%.72,73 Interest has grown in the prophylactic use of acyclovir and ganciclovir in seronegative recipients to prevent the development of PTLD.74 Other groups have tried to tailor antiviral use to those recipients who show elevated viral load in peripheral blood.75 Efforts to prevent the development of PTLD remain important, because

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the mortality rate remains as high as 70%.76 The primary therapeutic maneuver for recipients developing PTLD remains reduction of the dose and intensity of immunosuppression, followed by chemotherapy and radiation, as well as anti–B cell therapy.76-78 Adoptive immunotherapy with human leukocyte antigenmatched, donor-derived cytotoxic T lymphocytes also has shown promise for treating PTLD.78,79 At the present time, liver recipients without previous EBV exposure should be monitored closely for the development of PTLD, especially if they have received an organ from an EBV-positive donor. However, because the probability of developing PTLD after transplant remains low, even for the unexposed recipient, allowing transmission of EBV infection remains acceptable. It is to be hoped that with newer antiviral therapies this primarily pediatric problem can be prevented. Human Immunodeficiency Virus Before the advent of uniform screening for the human immunodeficiency virus (HIV) type 1 (HIV-1) in 1985, sporadic cases of transmission of the virus to solid organ recipients were reported.80-83 Even with uniform screening, there have been isolated case reports of virus transmission from screened donors. In one report, all four recipients of solid organs from a single donor, as well as three recipients of unprocessed fresh-frozen bone from the same donor, became infected with the HIV-1 virus.84 The donor was seronegative; however, he received fresh frozen plasma just before donation, which was later shown to be contaminated with HIV. Thirty-four recipients of other processed tissue, including corneas, lyophilized soft tissue, and ethanol-treated bone, did not acquire the virus. Of the four solid organ recipients, two died of aquired immune deficiency syndrome (AIDS)-related causes. None of the 4 patients survived longer than 32 months. Additional cases of transmission have occurred, but usually in the setting of trauma resuscitations for the donors in which the HIV serologic test may be unreliable because of dilution.85 Currently, about 900,00 people are alive in the United States with HIV: between 0.01% to 0.25 % of all military recruits test positive for HIV-1 or HIV-2.86 There are no national data regarding the number of potential solid organ donors that are not pursued because of positive HIV serologies. At the New England Organ Bank (NEOB), for the year 2001, there were 215 donors from whom organs were retrieved. An additional 6 potential donors were referred to the NEOB but were ruled out on the basis of a positive HIV antibody (personal communication, K. O’Connor, NEOB, November 2002).

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The UNOS/Organ Procurement and Transplantation Network minimum procurement standards include Food and Drug Administration (FDA) licensed HIV-1/HIV-2 enzyme immunosorbent assay (EIA) testing.87 Listed sensitivity is 100%, with a specificity of 99.73%. Organs from donors with a positive EIA cannot undergo transplantation unless subsequent testing, namely Western blot analysis, indicates that the original test was a false positive. In addition, UNOS guidelines stipulate that the host organ procurement organization (OPO) must obtain a history on each donor to determine whether the donor is in a high-risk group as defined by the Centers for Disease Control (CDC) (http://www.optn.org). Such a history must be communicated to all institutions receiving organs from the particular donor. For those donors that receive transfusions after pretransfusion serology results are negative for the antibody, additional testing does not need to take place if the transfused blood has also tested negative. Organs from a donor who has not been tested for HIV can be used if, in the medical judgment of the host OPO and recipient institution, both feel there is an extreme emergency to warrant waiving the tests. In such a situation, informed consent must be obtained from the transplant recipient. HIV transmission from donor to recipient has been rare because of the regulations cited above. The recipient deaths reported for HIV transmission occurred before the advent of the effective antiretroviral therapy that is available today. In addition, immunosuppressive expertise has improved dramatically. Considering that 40% of HIV-infected individuals also have HCV, it is likely that there will be increased demand for liver transplantation from an HIV-infected candidate pool. The transplant community may have to reconsider use of HIV-infected organs, at least for the HIV-infected candidates. Otherwise, although there is very limited data on the outcome of HIV transmission to liver recipients, the risks outweigh the benefits for using these donors for most liver recipients. Human T Cell Lymphotrophic Virus Human T cell lymphotrophic virus (HTLV)-I/II infection has been considered a contraindication to organ donation because of the risk of transmission of infection and the subsequent development of either adult T cell leukemia or myelopathy.88-90 The majority of HTLV-I infections do not cause disease in immunocompetent hosts,91 and, despite the isolation of HTLV-II in a patient with leukemia, there has not been a clear association with the HTLV-II variant with human disease.92 There is one case report of a transmission of

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HTLV-I from living kidney donor to the recipient.93 The recipient remains free of HTLV-related disease 4 years after from transplantation. Serologic studies of volunteer blood donors in the United States estimate that the prevalence of HTLVI/II is 0.035% to 0.046% or one case per 2500 blood donors.94 But there are endemic areas in the Caribbean, Africa, southwestern Japan, and Italy where the seroprevalance increases with age and can be as high as 30% in the elderly.95 Despite a very sensitive and specific screening test for HTLV-I/II, there will be false positives in low prevalence areas. Unfortunately confirmatory tests such as Western blot cannot be performed in a time frame that would allow the use of organs from false-negative donors.96 There were 25 HTLV-I/II positive organ donors reported to UNOS between 1994 and 2000. The prevalence for HTLV-I infection in organ donors was 0.027%, and the prevalence for HTLV-II was 0.064%.97 Twenty-two cadaveric organs (nine livers) were transplanted from these donors. There are no reports of HTLV-I/II related disease in any of these recipients, with a median follow up of 11.9 months. Based on the minimal chance of developing HTLVrelated disease after transplantation of HTLV-I/II organs, consideration should be given in transplanting these organs in recipients who have an urgent need of transplant, older recipients, and patients who are HTLV-positive before transplantation.

frequent among older individuals and the immunosuppressed. Currently, there is no approved screening test for blood or organ donors for WNV infection. Moreover, it is not known whether WNV can be transmitted by organ or blood donation in the absence of active viral replication. In addition, past outbreaks of other flavivirus infections have been episodic. For example, very few recent cases of St. Louis encephalitis have been reported since the epidemic in the 1970s. If, in fact, WNV is transmitted only when there is viral replication in the donor, screening tests will have to be nucleic acid based and may not be feasible in the organ donation decisionmaking window of time. At the present time, organ procurement organizations must continue their thorough history taking, paying special attention to recent history of CNS symptoms, especially in areas in which WNV is endemic. Unfortunately, the donor’s clinical history is not likely to discriminate WNV-infected individuals well. Transplant professionals will have to keep abreast of developments in this field to accurately assess the prevalence of WNV in the donor population and the outcomes for WNV infected organ recipients. Development of good screening technologies and practices for the blood donor pool may significantly reduce the risk of WNV transmission from organ donors to recipients because the case reported above has been traced to a WNV tainted unit of blood given to the donor immediately before the donation procedure.

West Nile Virus A recent case of West Nile virus (WNV) infection transmitted to four transplant recipients from a single donor has resulted in one death.98,99 The other three recipients showed clinical symptoms, laboratory test results consistent with WNV infection, or both. WNV infection in organ transplant or blood transfusion recipients has not been previously reported, and the risk of acquiring the disease from these sources is not known. WNV is primarily an infection of birds and culicine mosquitoes, with humans and horses serving as incidental hosts. WNV, and the closely related St. Louis encephalitis virus, are members of the flavivirus group and appear to have a similar ecology and epidemiology. The virus has spread throughout most of the United States and has been identified in Canada and the Cayman Islands. Among humans, the disease peaks in late summer and early fall. One in five humans infected with WNV develops mild febrile illness lasting 3 to 6 days. Meningitis or encephalitis develops in approximately 1 of 150 infected individuals.99 Meningoencephalitis is rare among young persons, but is more

Donors with Parasitic Diseases Chagas Disease Infection with Trypanosoma cruzi is limited to Central and South America and Mexico, where an estimated 16 to 18 million persons are afflicted.100 An estimated 25,000 to 100,000 Latin American immigrants living in the United States are infected with T. cruzi.101 The disease caused by this organism, Chagas disease, has a fatality rate in nonimmunocompromized patients of about 5% in the acute phase; the fatality rate in the chronic state is difficult to assess.101 Life-threatening myocarditis or meningeoencephalatis can occur during the acute phase. After years to decades of subclinical infection, 10% to 30% of infected individuals develop chronic Chagas disease, which is characterized by potentially lethal cardiomyopathy, megasyndromes (megaesophagus/megacolon), or both.102 Diagnosis involves detection of circulating organisms by microscopic examination, blood culture in the acute phase, and by serologic testing thereafter. Even persons testing

Impact of Donor Infections on OLT

positive, who remain asymptomatic, probably are infectious for life, with low levels of parasite in blood and other tissues. This raises the possibility of transmission of this disease with blood or organs from asymptomatic individuals to their recipients. Transmission of T. cruzi infection by kidneys from donors infected with the parasite has been reported in Latin America,103-106 where serologic screening of organ donors and recipients for antibody to T. cruzi is standard practice. In the United States, three cases of T. cruzi recipient infection (simultaneous kidney/pancreas, kidney alone, and liver transplant) by transmission of the disease by organs from the same donor resulted in one death, caused by Chagasic myocarditis.107 The donor was an immigrant from Central America and presumably was infected by T. cruzi, although no predonation testing was performed. The three recipients presented initially with febrile illness, and T. cruzi trypomastigotes were identified in the peripheral blood. Blood cultures from all three recipients also grew T. cruzi. The kidney recipient was treated with nifurtimox for 4 months and survived; the liver recipient died of sepsis unrelated to T. cruzi infection. Currently, in the United States, there are no approved screening tests for T. cruzi infection. An accurate history for travel to or residence in areas in which T. cruzi is endemic is important for screening potentially infected donors. Unfortunately, in areas in which there are large populations of Latin Americans, this may not be too helpful. At this time, it is difficult to assess the risk of transmission of T. cruzi from liver donor to recipient. Effective treatment can be obtained through the CDC for infected persons who should be treated as early in the course of infection as possible.107 Benznidole is another potentially effective agent, but it is not available in the United States. Toxoplasmosis Toxoplasmosis, caused by the obligate intracellular parasite Toxoplasma gondii, does not usually cause severe disease in adult immunocompetent hosts. However, in immunocompromized individuals, Toxoplasmosis can cause encephalitis, myocarditis, pneumonitis, and disseminated lymphadenopathy. The prevalence varies within and outside of the United States, and as many as 90% of some populations can test positive serologically.108 Because the organism can persist as latent infection in the myocardium of infected individuals, T. gondii has been most often transmitted from infected donors to naive heart recipients.109-111 At least two cases of transmission of toxoplasmosis from donor to liver recipient have been reported.112,113 Because of these

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reports of high transmissibility, some have argued that serologic donor screening for T. gondii should be routine, especially in areas with higher prevalence rates,114 but the efficacy and widespread use of trimethoprim/ sulfamethoxazole prophylaxis after liver transplantation have led others to suggest that donor screening is not necessary.115 Currently, serologic testing of donors for exposure to T. gondii is not required by UNOS policy.116 Centers considering donors from endemic areas should be aware of the risk of transmission of toxoplasmosis should hold donor and recipient serum for retrospective testing in cases in which transmission or reactivation is suspected and should routinely use trimethoprim/sulfamethoxazole in nonallergic recipients. At the present time, the efficacy of trimethoprim/ sulfamethoxazole for the prevention of toxoplasmosis transmission makes the risk to recipients of organs from infected donors quite low. Malaria As migration of populations around the world increases, the prevalence of individuals infected with organisms usually confined to specific geographic areas also increases. As in the case of Chagas disease, individuals infected with malaria are increasingly more likely to be encountered as potential donors anywhere in the world. Recently, transmission of malaria tertiana from an organ donor to a liver recipient was reported in Germany.117 The donor recently had migrated from Africa to Germany with no signs of active malaria. The liver and one renal recipient developed positive blood smears for Plasmodium vivax 5 to 6 weeks after transplantation. Both the liver and renal recipient responded to antimalarial treatment, but the liver recipient developed progressive cholestasis as a side effect of the treatment and died 5 months after transplantation. Although it may be possible to control the malarial infection transmitted from infected donors to recipients, the toxicity (renal, hematologic, and hepatic) of the treatments increases the risk of poor outcome in such cases. For these reasons, use of organs from donors infected with Plasmodium spp. carries risks that are not balanced by the waiting list mortality risk of most liver recipients. Donors recently emigrating from endemic areas should be suspected and careful history should be obtained when possible.

Conclusions Donor infections clearly are transmissible to recipients. The result of such a transmission has varying results that can be altered in some types of infections with effective

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Table 1. Use of Liver Transplant Grafts From Infected Donors Donor Infection

Acceptable Recipient

Preventive Measures

Bacterial

Any*

IV Antibiotics 5–7 days

Fungal

Any*

IV anti-fungals unknown duration

HBV ⫹, HBsAb ⫹, MELD ⬎ 30, Status 1

Lamivudine ⫾ HBIG

Unknown early interferon

CMV

HCV ⫹ Unknown high risk HVC⫺ All

EBV

All

HIV HTLV

Unknown HIV ⫹ Unknown HTLV ⫹, Unknown MELD ⬎ 30, Status 1 Unknown

Viral HBV

HCV

WNV Parasitic Chagas Toxoplasmosis Malaria

Unknown T. cruzi ⫹ T. gondii ⫹, Unknown any* Unknown

Expected Outcome Extremely low transmission rates, no reduction in patient or graft survival Only one documented case of transmission with liver transplantation Rare cases of HBV resistance to lamivudine. Long-term outcome equal to HBV negative donors. Equal to HCV negative donors. More virulent strain prevails

Anti-viral prophylaxis for high risk cases Consider prophylaxis for PTLD high risk cases (children). HAART for HIV ⫹ recipient Unknown

Equal to CMV negative donors if effective prophylaxis is used EBV negative donor is rare, outcomes equal Unknown long-term effects No malignancies documented to date

Unknown

Significant morbidity and 1 mortality in 4 cases

Nifurtimox or benznidole Trimethoprim/sulfamethoxazole

Chaga’s myocarditis and death in one case Effective prophylaxis makes risks low

Quinine/quinidine, primaquine or chloroquine

Recipients eradicate infection with treatment but drug toxicity increase risk of poor outcome

Abbreviations: MELD, model for end stage liver disease; IV, intravenous; HBV, hepatitis B virus; HCV, hepatitis C virus; HBsAb, HBV surface antibody; HIV, human immunodeficiency virus; HTLV, human T cell lymphotrophic virus; HBIG, hepatitis B immune globulin; HAART, highly active antiretroviral therapy; CMV, cytomegalovirus. *Candidates with increased waiting list mortality risk are likely to have more favorable risk/benefit ratios for use of these donors.

treatment (Table 1). These treatable donor-to-recipient infections pose the least risk to recipients, although they are not risk-free. Specifically, livers from bacteremic donors or those infected by CMV or EBV function well after transplant. The infections transmitted to unexposed recipients generally are well controlled by agents shown to be effective for the causative organism or reducing the immunosuppressive load. Further work needs to be performed to clarify the optimal length of antimicrobial treatment for these types of infections and the optimal immunosuppressive regimen to limit their morbidity and mortality. Transmission of HCV from donor to recipient does not appear to have significant short-term sequelae at this time. However, the natural history of hepatitis C infection is longer than the published follow-up of patients receiving grafts from HCV-infected donors. Also, there is evidence that suggests HCV may recur

earlier in HCV-positive recipients of HCV-positive livers, which may pose a significant problem for long-term graft survival. Whereas there does not appear to be any short-term diminution in patient or graft survival for naive recipients of livers from HCV-positive donors, clinical judgment would dictate using these grafts preferentially for recipients already infected with HCV. Similarly, HBV-infected donors can provide excellent liver grafts. Donors positive for HBsAg or HBcAb are likely to transmit HBV infection to their recipients. Available evidence suggests that effective prophylaxis is necessary for the prevention of HBV disease in the recipients of these organs. The best and most costeffective prophylactic regimen has not yet been established, but lamivudine alone, or in combination with HBIg, has been used effectively. However, these inconclusive results must be balanced with the clearly poor survival rates for the more severely ill candidates who

Impact of Donor Infections on OLT

may not receive a timely transplant for fear of transmission of an infection. Although the infection rates documented in the donor pool by UNOS are quite low, it is possible that a significant number of donors are never pursued because of positive serologies. Better understanding of the risks and benefits of transplanting livers from HCV- or HBV-infected donors may increase the usage rates and make clinicians more willing to consider these organs. Assessing risks verses benefit for using livers from HIV-, HTLV-, WNV-, or T. cruzi–infected donors is much more difficult because of an extreme lack of data. The scant available data suggest that transmission of HIV and HTLV to liver recipients may not cause severe disease in some cases. With the advent of intensive antiretroviral therapies and a high prevalence of HCV infection in HIV infected individuals, liver transplantation has become a consideration for HIV-infected patients with cirrhosis. HIV-infected donors may be an important source of donor organs for this population. The lack of accurate, rapidly available screening tests for WNV and T. cruzi make assessing the prevalence of these infections in the donor population extremely difficult. This void also makes assessment of risk of transmission to recipients impossible. In this review, we have tried to emphasize a riskbenefit approach to usage of organs from infected donors. Paramount in any risk-benefit analysis is informing the patient of these risks and benefits. Use of these organs, in cases in which an infection is knowingly transmitted, must be allowed only in the setting of informed consent of the recipient. For those infections about which there is adequate data, such an informed consent process should be conducted before the actual transplant event. Candidates can be informed that the possibility of transmission of an infection exists well before a donor organ is offered so that they have the opportunity to consider this possibility. However, for infection for which there is little data and the possibility that an infection might be unknowingly transmitted because of false-negative donor testing results, or the lack of a screening test altogether, candidates still must be informed in general terms that transmission of infectious diseases (and other diseases like malignancies) is possible with transplantation. These risks are small but not well quantified and are not likely to ever become zero.

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