VOLUME 18, NUMBER 4                                                           JULY / AUGUST 2005

Review Article
Infections transmitted from donors to recipients following organ transplantation
YANNAM GOVARDHANA RAO, D. F. MIRZA

ABSTRACT
There is an ever-increasing gap between the number of donors and those waiting for organ grafts, resulting in increased waiting times and mortality on transplant waiting lists. Consequently, every potential donor must be considered for possible transplantation even if they are outside the conventional donor criteria. To address this imbalance, organs are currently transplanted from living donors, older donors, haemodynamically unstable and non-heart-beating donors, and donors with prior infections. There is a potential to transmit infections and, to a lesser extent, malignancy from the donor organ to the immunosuppressed recipient, and this may also have an effect on subsequent organ function in the recipient. Thus, transmission of infections from organ donors to recipients represents low but serious potential risks that must be weighed against a candidate’s risk of dying before a transplant becomes available.
Natl Med J India 2005;18:189–94

INTRODUCTION
The risk of infection being transmitted through transplanted organs is well recognized.1 However, the shortage of donors and the ever-increasing list of potential recipients has prompted a re-evaluation of the risks of transplantation of organs from donors with various infections. Transmission of infections from an organ donor to a recipient must be weighed against the chances of recipient mortality during the waiting period. In addition, certain infections adversely affect the overall outcome after transplantation.1 This review discusses various infections transmitted by donors to transplant recipients as well as current prophylactic treatments.

VIRAL INFECTIONS
Hepatitis B virus (HBV)
HBV can be transmitted by all solid organ transplants. The transmission rate depends on the stage of HBV infection in the donor, the presence or absence of viraemia, replication status of the virus in the liver, the anti-HBs immune status of the patient and the transplanted allograft.2 Several markers, which reflect the stage and course of HBV infection, permit definition of the risk of transmission and suitability of transplantation of the organ. Following acute infection, hepatitis B surface antigen (HBsAg) appears in the blood in about 6 weeks to 3 months and then disappears. If it persists, it indicates either chronic infection or a carrier state. IgM anti-hepatitis B core antibodies (anti-HBc) are the earliest antibodies to be detected, usually 6 weeks after HBV infection. IgG anti-HBc persists throughout life in previously infected patients. The antibody to HBsAg (anti-HBs) appears subsequently and may take up to 6 months. A window period of isolated anti-HBc positivity occurs after an acute infection during which HBsAg has cleared from the serum but anti-HBs has not yet appeared. Donors are screened for the presence of HBsAg, anti-HBs and anti-HBc. Donors may present with either isolated HBsAg positivity, anti-HBs positivity, or anti-HBc positivity, or with both anti-HBs and anti-HBc positivity. The presence of isolated anti-HBs positivity is possible after vaccination with hepatitis B vaccine, after administration of hepatitis B immunoglobulin (HBIG), after transfusion of blood products from an immunized donor or after previous HBV infection.3
  Hepatitis B surface antigen positive. HBV transmission has been documented to occur after transplantation from HBsAg-positive donors.4,5 Although HBsAg-positive allografts have been transplanted successfully to critically ill HBsAg-negative recipients in life-threatening conditions,6 a satisfactory clinical course depends on whether the recipient has been previously immunized against HBV.7 Since almost all recipients acquire HBV infection, hepatitis B-positive donors are used only for life-threatened heart transplant recipients.
Isolated anti-HBs positive. A donor with isolated anti-HBs positivity is unlikely to transmit HBV infection because there is no evidence of active viral replication. However, some of these donors with anti-HBs may be HBV DNA positive in blood and liver biopsy specimens.8 HBV DNA viraemia can be detected by PCR in the serum and liver more than a decade after apparent recovery from HBV infection. Experience with these donors has shown that they could transmit infection to recipients.8 Fortunately, the risk is minimal (<1%), and if one encounters such a scenario, additional donor details regarding vaccination and administration of HBIG must be obtained.
  HBsAg negative, and anti-HBs and anti-HBc positive. A donor serological profile of both hepatitis B surface and core antigens confers donors with immunity to HBV. However, when these donor organs are transplanted, there is a risk of HBV transmission as the liver continues to harbour HBV, which replicates in an immunosuppressed environment.
  Isolated anti-HBc positive. Isolated anti-HBc positivity is of particular concern. Liang et al. using PCR detected HBV viraemia in 30% of healthy blood donors who were IgG anti-HBc positive and anti-HBs negative, and in 8% of donors with IgG anti-HBc and high titres of anti-HBs.9 The prevalence of anti-HBc in organ and blood donors reflects the frequency of HBV in the general population, and organ donors have nearly two-fold higher anti-HBc prevalence than blood donors.9
  The risk of de novo HBV infection from anti-HBc positive donors varies with the immune status of the recipient. Recipients who are anti-HBs positive have the lowest risk of developing de novo HBV infection with a liver allograft from an anti-HBc donor. Recipients who are positive only for anti-HBc have a significantly higher risk (13%) and recipients who are naïve (anti-HBs negative and anti-HBc negative) have the highest risk (72%) of de novo HBV infection.10 Although anti-HBc-positive donors accounted for 3.8% of the transplanted livers, 86% of post-transplantation de novo hepatitis B infection could be attributed to these donors.11
  The risk of HBV infection also varies with the type of allograft transplanted. It is now well established that HBV has been transmitted to liver allograft recipients from cadaver donors who are only anti-HBc positive. The risk is minimal with kidney and heart allograft when compared to liver allograft recipients. In the University of California, San Francisco study, only 1 in 42 kidney and 0 of 7 heart allograft recipients became HBsAg positive following transplantation from isolated anti-HBc-positive donors, whereas 3 of 6 liver transplant recipients became HBsAg positive from similar donors.12 In another study by Kadian et al. using anti-HBc-positive donors, 4 of 12 liver transplant recipients and none of 19 kidney and 12 heart transplant recipients became de novo HBsAg positive.13
Experience with de novo HBV infection transmitted from organ donors suggests that the clinical course is benign, with no liver failure or adverse effect on graft and patient survival.14 Thus, if livers from anti-HBc-positive donors are to be used for transplantation, long term antiviral therapy should be considered. The use of HBIG prophylaxis to delay or inhibit HBV reinfection has been well documented.15 Lamivudine therapy has been successful but there is a risk of emergence of resistant mutants.16,17 Encouraging results have also been reported with a combination of HBIG and lamivudine or other newer antiviral drugs such as adefovir and tenofovir.18,19

Hepatitis C virus (HCV)
HCV infection is a major cause of chronic liver disease. Approximately 170 million people worldwide are infected with HCV.20 It is estimated that approximately 5% of all organ donors are anti-HCV positive.21 Most organ procurement organizations have made it a policy to screen all donors for anti-HCV, which appears in the blood sample within 2 months after exposure. Unfortunately, the presence of antibody in the blood does not confer immunity22 and, surprisingly, it does not predict transmission either.21 Transmissibility of HCV to the recipient is better assessed by testing HCV antigen (RNA) in the blood by PCR. All PCR-positive donors will transmit HCV to organ recipients. Usually only 50% of anti-HCV positive patients are positive for HCV antigen by second-generation PCR. Though the test is 98% specific, the positive predictive value of PCR is low in the donor population with a low prevalence for HCV (55%) and it is not feasible for testing cadaver donors.21 Additionally, the risk of HCV transmission from an anti-HCV positive, PCR-negative donor is not known. Thus, exclusion of all anti-HCV positive donors, while eliminating the possibility of transmission, would unnecessarily discard some organs which are not infected with HCV.
  HCV-negative recipients of HCV-positive donors have reduced patient and graft survival rates. It is evident that transplantation of hepatic allografts from HCV-positive donors to recipients with HCV-related liver disease has not resulted in differences in graft and patient survival, compared to HCV-positive recipients from HCV-negative donors.23–25 However, the recurrence rate is faster in HCV-positive recipients who receive organs from donors positive for HCV.24 Subsequent analysis has shown that when genotype mismatch occurs between donor and recipient types, only one viral genotype prevails. Subtype 1b and type 1 always become predominant strains.26 Data show that the virulence of the HCV strain, regardless of its source, may be more important in predicting recurrent HCV disease in the recipient than the HCV status of the donor or recipient.
  HCV infection usually takes a chronic, indolent and slowly progressive course, with cirrhosis or liver cancer not developing till 5–20 years after infection. However, the consequences of transplantation-acquired HCV infection have not been fully evaluated and depend on different viral and/or host factors.27
  Treatment of HCV infection in immunocompromised recipients is not successful. Interferon,28 ribavirin29 and immunoglobulins30 have been tried with variable results. Bizollon et al. used a combination of interferon–ribavirin therapy in 44 patients with recurrent hepatitis C after liver transplant. In 93% of patients a sustained virological response was noted for at least 3 years after cessation of therapy.31
  The present data suggest that there is no short term deterrent to using HCV-positive donors for HCV-positive recipients. Donor liver biopsies may be of help in this regard, because livers with active hepatitis are more likely to yield poor results. Avoiding the use of particularly virulent donor HCV strains will not be possible until more rapid genotyping techniques are available.

Cytomegalovirus (CMV)
CMV has been shown to be transmitted by all solid organ transplants from seropositive donors. The vast majority of sero-negative recipients will acquire CMV infection from liver allografts and are at high risk of developing CMV disease within the first few months after transplantation. Both donors and recipients should be tested for CMV status (antibody to CMV) as it has implications for subsequent therapy. Transplantation of organs from a CMV-positive donor to a CMV-negative recipient poses a 40%–73% risk of primary infection.32 Recipients who are CMV positive are at moderate risk (6%–38%), while CMV-negative recipients who receive a transplant from a CMV-negative donor are at the lowest risk (<1%).32 The immunosuppressed status of the recipient provides an ideal environment for virus activation and replication. In addition, there is a risk of superinfection by different strains from the donor.
  The occurrence of CMV disease has been associated with increased morbidity and decreased survival in solid organ transplantation. CMV infection may be limited to viraemia or viruria without overt symptoms, or it may present as a viral syndrome with fever, malaise or signs and symptoms of tissue invasion. Indirect evidence identifies CMV as a risk factor for acute graft rejection, which is correlated with poor long term graft survival. As a consequence of its effects on the immune system, CMV also increases the risk of fungal and other superinfections in transplant recipients.33 In liver transplants, there is an increased risk of hepatic artery thrombosis, vanishing bile duct syndrome and biliary complications.34
  However, transplantation of organs from CMV-seropositive donors has not been considered a contraindication because the high prevalence of the virus among the general population makes it impractical to rule out such donors. Recent evidence suggests that even such mismatches between CMV-positive donors and CMV-negative recipients can be successfully overcome by prophylaxis against CMV. Treatment with valacyclovir after renal transplantation has reduced the incidence or delayed the onset of CMV disease in both seronegative and seropositive patients.35 In another study, the prophylactic use of oral valacyclovir was found to be as effective as oral ganciclovir in reducing CMV infection and disease after kidney transplantation.36 More recently, the use of oral ganciclovir prophylaxis to prevent transmission of CMV disease from donor to recipient has also improved graft and recipient survival rates.37

Epstein–Barr virus (EBV)
Serological testing for this virus is not performed routinely because more than 95% of donors are positive for the IgG antibody. However, the risk is higher in EBV-negative patients receiving organs from an EBV-positive donor. The critical effect of EBV is its role in post-transplant lymphoproliferative disease (PTLD). The risk of developing PTLD is associated with the type and intensity of the immunosuppressive regimen. PTLD has been linked to the use of immunosuppressants such as cyclosporin, tacrolimus and, more importantly, antilymphocytic therapy.38 The risk of developing PTLD is influenced by the type of allograft received, with the highest incidence in recipients of lung allografts.39
  Currently, there is no effective way of preventing PTLD other than reducing or completely stopping all immunosuppressive medication. Encouraging results have been obtained with the prophylactic use of acyclovir and ganciclovir in preventing PTLD in seronegative recipients.40 Some other groups have measured the viral load in peripheral blood and tailored antiviral drug usage to those recipients who showed an elevated viral load.41

Human immunodeficiency virus (HIV)
Among the most detrimental infections transmitted from the donor to the recipient is HIV type-1. The transmission rate is high irrespective of the transplanted organ. Screening of donors with a highly sensitive assay for HIV antibodies is routine in all centres. Organs from donors with a positive ELISA test cannot be used for transplantation unless subsequent testing with western blot analysis indicates that the original test was indeed false-positive. Several instances of HIV transmission from individuals who were not yet seroconverted and were negative for antibody have been reported. Therefore, screening for HIV-1 p24 antigen has been proposed but the diagnostic window that can be shortened by p24 testing is only about 6 days. If PCR is employed, it further shortens this window by another 5 days.42 However, with time constraints imposed by cadaver donation, PCR testing is not practical. The utility of p24 antigen testing was evident in a retrospective analysis by Simonds.43 He reported transmission of HIV to 7 recipients from seronegative donors, which presumably could have been avoided if the donor had been tested for the p24 antigen. However, these tests have false-positive results and this should be taken into consideration as such organs would be wasted. The Centers for Disease Control (CDC) has developed guidelines for the prevention of transmission of HIV infection to organ and tissue recipients. It recommends obtaining a social history of the donor before considering organ donation, and the potential risk of donor HIV infection has to be informed to recipients even though the risk is presumed by behavioural social history.44 In contrast, there is no such time constraint for testing in live donors. All donors are advised voluntary testing for HIV 2–3 months prior to organ donation. The potential donor is advised to avoid high-risk behaviour which may lead to HIV infection and HIV testing should be repeated immediately prior to donation.

Human T cell leukaemia virus-1 (HTLV-1)
Although reports of transmission of HTLV-1 through blood transfusion are available in the literature, the risk through organ donation is not known. A patient infected with HTLV-1 by blood transfusion is at risk of developing either adult T-cell leukaemia or neurological disorders.45 There is a case report of transmission of HTLV-1 from a living kidney donor to the recipient.46 Thus, a positive donor screening test for this virus is an absolute contra-indication for organ donation.

Human herpes virus-8 (HHV-8)
HHV-8 infection is associated with Kaposi sarcoma. In 220 renal transplant recipients, the presence of antibodies to HHV-8 on serum samples was tested on the day of transplantation and after 1 year. Seroconversion was detected in 25 patients and Kaposi sarcoma developed in 2 of them within the first year following transplantation. None of the controls who were seronegative at the time of transplantation and had received allografts from HHV-8 negative donors had seroconversion during the same period.47 Milliancourt et al. studied 287 patients who were HHV-8 seronegative before renal transplantation and were tested for HHV-8 antibodies by an immunofluorescence assay 12 months after transplantation. Six patients (2.1%) had seroconverted after renal transplantation.48 These results show that HHV-8 seroconversion can be observed even in a low HHV-8 prevalence area and confirms the need to perform systematic screening for HHV-8 antibodies in renal graft donors and recipients. Routine screening of cadaver donors for this virus is not warranted due to the rarity of Kaposi sarcoma in transplant recipients.

Other viruses
Reports of transmission of rabies and Creutzfeldt–Jakob disease from tissue donors are available in the literature. A positive history of these diseases is a contraindication for organ donation.49 Although successful transplantation of organs from patients who died with Reye syndrome has been reported, many transplant centres do not consider organs from donors who had died with undiagnosed viral infections.50 A recent case of West Nile virus (WNV) transmitted through organ transplantation in the USA has been reported.51 At present, there are no approved screening tests for organ donors for West Nile virus infection. In endemic areas, donor procurement organizations should consider this risk and take necessary precautions.

BACTERIAL INFECTIONS
Bacterial transmission from donated organs may occur from contamination at the time of retrieval, or from environmental contamination of the organ during transport and storage. Recent review articles describe the transmission of bacterial infections following transplantation resulting in vascular anastomotic infections, graft infections and bacteraemia.1,52–54 Organisms such as Staphylococcus aureus,52 Bacteroides spp.,53 Klebsiella, Enterobacter,54 E. coli54 and Pseudomonas aeruginosa55 have been transmitted to allograft recipients resulting in mycotic aneurysms and disruption of vascular anastomoses. However, critical analysis of the published literature fails to provide clear evidence that there is transmission of bacterial infection to the recipients.
  Donors with bacterial meningitis have been successfully transplanted without increased risk of complications and with no difference in graft and recipient survival. In a study by Satoi et al., liver grafts from 33 donors with bacterial meningitis were transplanted into 34 recipients. There was no difference in recipient and graft survival rates between the study group and the recipient-matched groups, with a mean post-transplant follow up of 37 months.56 In another study by Lopez-Navidad et al. using organs from donors with meningitis, none of the recipients developed infectious complications caused by meningeal pathogens57 and in a subsequent study they reported a successful outcome in 11 recipients.58 Haemophilus influenzae, Streptococcus pneumoniae, Neisseria meningitides and E. coli are the most common bacterial pathogens and these can be controlled by treating the donor and recipient with broad-spectrum antibiotics.59 Many bacterial organisms including N. meningitidis, S. pneumoniae and H. influenzae are extremely susceptible to unfavourable environmental changes, including low temperatures attained during perfusion and storage at 4 ºC prior to transplantation. This may be responsible for the favourable outcome even when the donor has a bacterial infection.
  Experience with organ transplantation from donors with documented bacteraemia has also been encouraging. Freeman et al. reported their experience with 95 bacteraemic donors from whom 212 recipients received organs. Forty-six donors (48%) had pathogens in their blood and the remaining 49 donors had either Staphylococcus epidermidis or other unlikely pathogens recovered from the blood. In none of them was there documented evidence of infection, and graft and recipient survival was not significantly different from that of recipients of organs from that of non-bacteraemic donors.60 Lammermeier et al. reported their experience of 14 infected donors (7 with documented bacteraemia and 7 with pneumonia with positive sputum cultures) with no infectious complications in the recipients.61 Little et al. reported a successful outcome in 6 orthotopic liver transplants, 11 renal transplants, 1 combined heart–lung transplant and 1 simultaneous kidney and pancreas transplant with organs from 8 donors in whom bacterial meningitis (n=7) and acute bacterial epiglottitis (n=1) were the antecedent causes of death.62 Successful transplantation of organs from a donor with endocarditis has also been reported.63
  The available data do not provide enough evidence to answer many of the questions surrounding the transmission of bacterial infections from infected donors. In most of the larger series, recipients of organs from bacteraemic donors were treated more aggressively with antibiotic prophylaxis, usually longer than 48 hours after transplant. There is also no consensus on the timing and duration of antibiotic prophylaxis both before and after transplantation. Even though donor bacterial infections are relatively common, these data suggest that organs procured from these donors are likely to function well and pose little, if any, risk to the recipient, provided that the recipient is treated with suitable antibacterial agents.

Tuberculosis
The transmission of tuberculosis by donor organs has been reported in recipients of kidney, lung and liver allografts.64,65 A recent review by Singh and Paterson reported that donor transmission was the proposed source of tuberculosis in 4% of transplant recipients with tuberculosis.64 In addition, extrapulmonary tuberculosis transmitted from the donated kidney and liver has been reported. Both isolates from separate recipients were indistinguishable using IS6110 typing.

Syphilis
Iatrogenic transmission of syphilis is rare, particularly with advances in blood transfusion practices. There has been no documented case of syphilitic transmission by organ transplantation to date. However, the risk of syphilitic transmission is not insignificant and has been estimated to be about 0.15%. Fortunately, the risk of transmission is further lowered by the frequent use of penicillin in perfusion solutions and the low temperature at which organs are perfused and stored. There is no contraindication to organ procurement from donors with a positive serology for syphilis. Additionally, a standard course of antibiotic treatment with either penicillin or doxycyclin/erythromycin in those allergic to penicillin would provide sufficient coverage to prevent syphilitic complications in the recipient. There are at least 3 reports of successful organ transplantation from donors with positive serological tests for syphilis.66–68

PARASITIC INFECTIONS
Toxoplasmosis
Toxoplasma gondii can be transmitted by solid organ transplants to seronegative recipients resulting in serious infections. In immunocompromised individuals it can cause encephalitis, myocarditis, pneumonitis and generalized lymphadenopathy. Due to its propensity to persist in its encysted form in muscle tissue, recipients of heart transplants are particularly prone to toxoplasmosis.69,70 Fatal outcomes have also been observed in renal71 and liver transplant recipients.72 It has been estimated that without prophylaxis, approximately 50% of seronegative heart recipients, 20% of liver recipients and <1% of kidney recipients acquire toxoplasmosis. Fortunately, a combination of trimethoprim– sulphamethoxazole used for prophylaxis against Pneumocystis carinii in transplant recipients is also effective against T. gondii. This reduces the risk to recipients of organs from infected donors.73 Seropositivity with T. gondii is not a contraindication per se for organ donation.

Other parasites
As migration of populations around the world increases, the number of individuals infected with organisms usually confined to specific geographic areas also increases. Recent reports of Trypanosoma cruzi74,75 and malaria76 being transmitted from donors leading to an adverse outcome have been described in the literature. Although the routine screening of donors for these infections may not be required, these infections must be considered in the differential diagnoses, particularly if the donor belongs to an endemic area. Antimicrobial therapy for these infections is usually successful, though drug toxicity may result in a poor outcome.

FUNGAL INFECTIONS
Patients with fungaemia may not be suitable for transplantation due to lack of adequate treatment and paucity of data in this regard. Reports of transmission of Candida albicans,77 Cryptococcus,77 and Histoplasma capsulatum53 from donors causing mycotic aneurysms and anastomotic disruption are available in the literature. Keating et al. reported transmission of invasive aspergillosis from a subclinically infected donor to 3 different organ transplant recipients with dismal results.78 Candida infection remains a major complication in patients with intra-abdominal solid organ transplantations in which the bowel is surgically manipulated. Aspergillus infection remains the main fungal complication in lung transplantation recipients. Suppression of Candida growth at the time of surgical manipulation of the bowel is the best way to prevent this infection in intra-abdominal organ transplantation. To prevent Candida infection in recipients of pancreas transplants, many centres prophylactically administer amphotericin B through the nasogastric tube during organ procurement.79

CONCLUSION
Donor infections are transmissible to recipients. The results of such transmission have a variable effect, depending upon the type of organism and the presence of prophylactic and curative treatment. On the other hand, failure to perform an organ transplant may result in an additional risk of complications to the recipient while awaiting transplant, and a poorer outcome post-transplant. A risk–benefit assessment must be done when transplanting such organs and the risk should be clearly explained to the prospective recipient.

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