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Abstract

  1. Top of page
  2. Abstract
  3. TRENDS IN ORGAN AVAILABILITY
  4. RISK MITIGATION THROUGH DONOR SCREENING
  5. TRANSMISSION OF DONOR-DERIVED INFECTIOUS DISEASES AND LIVER TRANSPLANTATION
  6. CONCLUSION
  7. REFERENCES

Advances in surgical techniques, immunosuppressive medications, and robust infectious disease prophylaxis have resulted in liver transplantation becoming the treatment of choice for patients with end-stage liver disease and unresectable hepatocellular carcinoma. Nonetheless, organ transplantation is not without risk. Unexpected donor-derived disease transmission is a newly recognized risk that complicates approximately 0.2% of all organ transplants. We review the epidemiology of donor-derived infectious diseases and methods of risk mitigation with a focus on liver transplantation. Liver Transpl 19:575–585, 2013. © 2013 AASLD.

Abbreviations
EBV

Epstein-Barr virus

HBV

hepatitis B virus

HCV

hepatitis C virus

HEV

hepatitis E virus

HIV

human immunodeficiency virus

IgG

immunoglobulin G

IgM

immunoglobulin M

NAT

nucleic acid amplification testing

OPTN

Organ Procurement and Transplantation Network

WNV

West Nile virus

Advances in surgical techniques, immunosuppressive medications, and robust infectious disease prophylaxis have resulted in liver transplantation becoming the treatment of choice for patients with end-stage liver disease and unresectable hepatocellular carcinoma. Nonetheless, organ transplantation is not without risk. Unexpected donor-derived disease transmission is a newly recognized risk that complicates approximately 0.2% of all organ transplants. We review the epidemiology of donor-derived infectious diseases and methods of risk mitigation with a focus on liver transplantation.

TRENDS IN ORGAN AVAILABILITY

  1. Top of page
  2. Abstract
  3. TRENDS IN ORGAN AVAILABILITY
  4. RISK MITIGATION THROUGH DONOR SCREENING
  5. TRANSMISSION OF DONOR-DERIVED INFECTIOUS DISEASES AND LIVER TRANSPLANTATION
  6. CONCLUSION
  7. REFERENCES

The demand for liver transplantation continues to expand and outstrip the number of organs available for transplantation. In 2011, 6342 patients underwent transplantation the United States, but unfortunately, during the same year, 1596 patients who were listed for liver transplantation died on the wait list; still more died waiting for transplantation but were delisted before death. Furthermore, there are currently 16,097 patients listed for transplantation.[1] Unfortunately, the decline in the number of living liver organ donors and the nonrecovery of livers from deceased donors (21% in 2010) remain significant.[2, 3] As a result, there is increasing use of livers from donors with a wide range of risks, including deceased after cardiac death donors and donors with an increased risk of infectious disease transmission. One risk of using a broader array of donors is that there are rare (approximately 0.2%) transmissions of infections, malignancies, and other diseases from the donors to the recipients.

RISK MITIGATION THROUGH DONOR SCREENING

  1. Top of page
  2. Abstract
  3. TRENDS IN ORGAN AVAILABILITY
  4. RISK MITIGATION THROUGH DONOR SCREENING
  5. TRANSMISSION OF DONOR-DERIVED INFECTIOUS DISEASES AND LIVER TRANSPLANTATION
  6. CONCLUSION
  7. REFERENCES

To reduce the risk of disease transmission through liver transplantation, donors are generally screened with the following:

  1. A careful review of the donor's medical and social history to identify evidence of preexisting transmissible conditions or risk factors for transmissible infections. Such risk factors for donors at increased risk of infectious disease transmission are defined by the Organ Procurement and Transplantation Network (OPTN) in agreement with US Public Health Service guidelines, which are currently undergoing revision[4, 5] (see Table 1).
  2. A physical examination of the patient by the organ procurement organization and of the organ by the transplanting surgical team.[5]
  3. An assessment of preexisting or latent infections through serological and nucleic acid tests of the donor's blood[5] (see Table 2 [4, 6-10] for required and recommended screening assays).
Table 1. Behavioral Risk Factors Placing a Donor at Increased Risk of Transmitting HIV, HBV, and HCV
  1. NOTE: This table has been adapted from proposed guidelines still under development.

High-risk sexual contacts
• Persons who have had sex with someone known or suspected to have an HIV, HBV, or HCV infection in the preceding 12 months
• Men who have had sex with another man in the preceding 12 months
• Women who have had sex with a man with a history of men-who-have-sex-with-men behavior in the preceding 12 months
• Persons who have had sex in exchange for money or drugs in the preceding 12 months
• Persons who have had sex with a person who injected drugs by an intravenous, intramuscular, or subcutaneous route for nonmedical reasons in the preceding 12 months
Persons born to a mother infected with HIV, HBV, or HCV (for infant donors 2 years old or younger)
Persons who have injected drugs by an intravenous, intramuscular, or subcutaneous route for nonmedical reasons in the preceding 12 months
Inmates of a correctional facility (eg, jail, prison, or juvenile detention) for >3 days in the preceding 12 months
Persons who have or have been treated for syphilis, gonorrhea, chlamydia, or genital ulcers in the preceding 12 months
Persons who have been on hemodialysis in the preceding 12 months
Table 2. Required and Recommended Donor Screening Testing
  1. NOTE: This table is based on Centers for Disease Control and Prevention,[4] Fischer and Avery,[6] Singh et al.,[7] Morris et al.,[8] Chin-Hong et al.,[9] and OPTN.[10]

  2. a

    Only testing licensed for screening before organ donation is acceptable; diagnostic testing is not acceptable.

  3. b

    Food and Drug Administration–approved diagnostic tests are acceptable.

OPTN-required screening tests for deceased liver donors
• Food and Drug Administration–licensed anti-HIV I/IIa
• Hepatitis screen serological testing
○ HBV surface antigen
○ HBV core antibody
○ HCV antibody
• Venereal Disease Research Laboratory test or rapid plasma reaginb
• Anti-cytomegalovirus
• EBV serological testing
• Blood and urine cultures
• Chest X-ray
Screening tests recommended in guidelines but not required by OPTN policy
• Coccidioides serology (for donors from endemic areas)
• HIV, HCV, and/or HBV NAT
• Human T cell lymphotropic virus I/II antibody
• Herpes simplex virus IgG antibody
• Hepatitis B surface antibody
• Strongyloides serology (for donors from endemic areas)
• Toxoplasma antibody (usually only for heart donors)
• T. cruzi serology (for donors from endemic areas)
• Varicella zoster virus antibody
• WNV NAT
Screening tests recommended for living donors
• Purified protein derivative or interferon-γ release assay for latent tuberculosis infection
• Repeat testing for HIV, HBV, and HCV within 30 days (but optimally within 14 days) of the organ donation procedure

In general, screening for viral infections in donors can detect infections by serology or nucleic acid amplification testing (NAT).[11] Serology detects the host's immune response to an infection and can take anywhere from 3 to 12 weeks to develop; the time between infection and detection is termed the window period.[11] With NAT, the window period for detection is reduced for human immunodeficiency virus (HIV) from 22 to 9 days, for hepatitis B virus (HBV) from 44 to 22 days, and for hepatitis C virus (HCV) from 66 to 7 days. Although NAT reduces the window period significantly, it is important to recognize that transmission can still occur despite negative test results.[11] This is especially true of hepatitis virus infections, in which local replication in the liver may predate systemic detectable viremia. For instance, the covalently closed circular DNA of HBV may be present in the donor liver without evidence of ongoing replication; typically, the donor is serologically positive for the core antibody.[12, 13] In this setting, posttransplant replication can occur even if the donor was not viremic at the time of procurement.

Recent reports of the unexpected transmission of HIV and HCV through transplantation have focused attention on optimizing donor screening.[5, 14] Areas of particular attention include OPTN-defined increased-risk donors, who are used disproportionately in liver transplantation, and screening modalities for further mitigating the risk of infectious disease transmission.[15, 16] Although the use of donors with known HBV and HCV infections is an accepted practice at many liver transplant centers, unexpected transmissions have occurred. Most of these unexpected disease transmissions appear to result because of testing during the window period, donors with significant hemodilution, or the inadvertent use of HCV-infected organs or vessels in a previously uninfected recipient.[11, 17-19]

NAT is increasingly employed to shorten this window period. Experts have cautioned against the widespread use of NAT for donor screening because of its cost, its unclear yield in identifying additional infections, and the risk of false-positive results.[11] Residual rates of HIV and HCV have been estimated despite serological and NAT screening. Such data can be used to determine which donors necessitate expanded screening and testing and the provision of informed consent to the recipient (see Table 3 21,22). To date, there are few studies that have directly measured the rate of the residual risk of infection despite screening.

Table 3. Residual Risk of Undiagnosed HIV and HCV Infections per 10,000 Donors at Increased Risk of Infection
Risk FactorHIVHCV
Serology AloneSerology and NATSerology AloneSerology and NAT
  1. NOTE: This table is based on Kucirka et al.[20, 21]

Men who have sex with men8.33.436.03.8
Nonmedical intravenous, intramuscular, or subcutaneous drug use12.95.3350.037.8
Hemophilia0.050.020.460.05
Sex in exchange for money or drugs2.91.2107.811.5
Partnering with someone with any of the above risk factors2.71.1126.213.5
Exposure to blood or blood products from someone with HIV or HCV1.30.522.02.3
Incarceration1.50.668.67.3

TRANSMISSION OF DONOR-DERIVED INFECTIOUS DISEASES AND LIVER TRANSPLANTATION

  1. Top of page
  2. Abstract
  3. TRENDS IN ORGAN AVAILABILITY
  4. RISK MITIGATION THROUGH DONOR SCREENING
  5. TRANSMISSION OF DONOR-DERIVED INFECTIOUS DISEASES AND LIVER TRANSPLANTATION
  6. CONCLUSION
  7. REFERENCES

Most donor-derived disease transmissions are expected.[5] Such expected transmissions, including transmissions of cytomegalovirus and HBV, result with the knowledge that the transmissions will occur. The donor is known to be infected with a pathogen, and virological monitoring and preemptive treatment and/or universal prophylaxis are used to minimize the impact of the disease transmissions. Unexpected transmissions of diseases such as Chagas disease, HIV, HCV, lymphocytic choriomeningitis virus, Mycobacterium tuberculosis, rabies, and West Nile virus (WNV) can occur despite current screening strategies and are not suspected in the donor at the time of organ placement.[14, 22-30] In some transmission events, clinical disease in the donor was not recognized at the time of the donor's death,[27, 31] whereas in other cases, screening, although available, was not performed for the pathogen of interest.[28-30] Although most disease transmissions have involved deceased donors, recent transmissions of HIV and HCV have shown that recipients of living donors may also be at risk.[19, 32]

There are currently few robust systems for assessing the epidemiology of donor-derived infectious disease transmissions. Currently, systems are well established in France (Agence de la Biomédecine) and the United States (OPTN's Ad Hoc Disease Transmission Advisory Committee), and there is a more recently established system in Italy (Donor Risk of Infection). Additionally, there was a research infrastructure that tracked disease transmission for a finite period in Spain (Spanish Network for Research on Infection in Transplantation).[24, 33] The French, Italian, and US systems require recognition that the disease in the recipient is potentially of donor origin, and then the disease must be reported to the national registry. As such, underrecognition and underreporting of cases are likely and limit current data.[5]

Despite these limitations, it is possible to draw several generalizations. It appears that donor-derived infectious diseases complicate approximately 0.2% of deceased organ donor transplants[5, 31] (details from OPTN data are presented in Table 4); it should be noted that a slightly higher rate (1.7%) was noted during the Spanish Network for Research on Infection in Transplantation study period, although these data were collected as part of a study and may have captured transmissions missed by other more passive systems.[24, 33] When an infection is transmitted, it is typically associated with significant morbidity and mortality; cases that are associated with less severe disease (eg, transient bacteremia that responds quickly to therapy) are likely underrecognized and, therefore, underreported.[5] Furthermore, there are variable rates of transmission likely related to the inoculum of the pathogen, the organ transplanted, and the type of immunosuppression used (eg, lymphocyte depletion). Lastly, existing data do not provide significant enough detail to define which infections may be more frequently transmitted to liver recipients versus recipients of other transplant types, except as highlighted next.

Table 4. Summary of Potential Donor-Derived Infectious Disease Transmissions Reported to the US OPTN (2005-2011)
Infection TypeDonor Reports (n)Recipients With Confirmed Transmission (n)Recipient Deaths Attributable to Donor-Derived Infections (n)
  1. NOTE: This table is based on Ison and Nalesnik[5] and Ison et al.[31]

  2. a

    Adenovirus, HBV, HCV, HEV, HIV, human T cell lymphotropic virus, herpes simplex, influenza, lymphocytic choriomeningitis virus, parainfluenza 3, parvovirus B19, rabies, and WNV.

  3. b

    Acinetobacter, Brucella, Enterococcus (including vancomycin-resistant Enterococcus), Ehrlichia species, Escherichia coli, gram-positive bacteria, Klebsiella, Legionella, Listeria, Lyme disease, Nocardia, Pseudomonas, Rocky Mountain spotted fever, Serratia, S. aureus (methicillin-resistant S. aureus), Streptococcus species, syphilis, Veillonella, bacterial meningitis, and bacterial emboli.

  4. c

    Aspergillus species, Candida species, C. immitis, Cryptococcus neoformans, Histoplasma capsulatum, Scopulariopsis, and Zygomyces.

  5. d

    Tuberculosis and nontuberculosis mycobacteria. Although reported, no transmissions of nontuberculosis mycobacteria have been confirmed. All confirmed transmissions have exclusively involved tuberculosis mycobacteria.

  6. e

    Babesia, Balamuthia mandrillaris, Chagas disease (T. cruzi), N. fowleri, schistosomiasis, and Strongyloides.

Virusesa1664816
Bacteriab118349
Fungic753110
Mycobacteriad53103
Parasitese35227

Viral Infectious Disease Transmission

The risk of transmission of a blood-borne virus through organ transplantation is related to the prevalence of the virus in the donor population, the viral load in the donor, the organ allograft transplanted, and the efficiency of virus transmission after contact with blood and tissues.[5] Because many viruses are recognized to replicate in the liver, liver transplantation has been associated with the transmission of viruses that classically cause hepatitis as well as blood-borne viruses without hepatitis as a predominant manifestation. Although donors may have risk factors for infection (eg, donors are at increased risk for blood-borne pathogens), most viral transmission events typically involve donors without recognized risk factors. Although a number of viral infections have been transmitted through organ transplantation (see Table 4), further details will be discussed about HBV, HCV, hepatitis E virus (HEV), WNV, and Epstein-Barr virus (EBV).

It is important to note that encephalitis (particularly with fever) without a documented source is particularly associated with viral infectious disease transmission.[34] Because there is no registry of donors with encephalitis, the true risk of transmission is unknown. In many instances of transmission, encephalitis is not initially suspected in the donor. Therefore, most experts believe that donors with clinical encephalitis without a proven cause should likely be avoided.[35]

Hepatitis B Virus

Occult transmission of HBV remains rare and most often occurs in core antibody–positive donors. The persistence of viral DNA in donor hepatocytes is the likely source.[36-41] In the absence of prophylaxis, surface antibody–negative recipients are more likely to subsequently develop allograft hepatitis. Recipient anti-HBV surface antibodies may control viral replication,[42] but the transmission of viral hepatitis can be mitigated with the use of antiviral prophylaxis such as lamivudine or entecavir with or without supplemental hepatitis B immune globulin.[43-47] Outcomes with HBV core antibody–positive donors are linked to the recipients' viral profiles. In these instances, recipient HCV infections as well as recipient coinfections with HCV and HBV are linked to poorer outcomes, including HCV recurrence and the loss of grafts.[48, 49] Experiences with HBV core antibody–positive donors for HIV-monoinfected patients and for HIV-coinfected patients with HBV (with or without HCV) have not been well described in the literature to date.

Hepatitis C Virus

The use of HCV antibody–positive grafts in recipients with HCV is a common practice and is generally considered safe.[50-52] The transplantation of HCV-infected donor livers into HCV recipients has not been associated with greater disease progression or graft loss.[53] Superinfection with a donor genotype distinct from the recipient genotype may occur with all genotypes. As such, candidates infected with subtypes other than type 1 before transplantation are at risk of acquiring a type 1 infection through the use of donor organs of that genotype. For candidates with non–type 1 infections, HCV-positive donors (whose genotype may not be known at the time of procurement) are often avoided out of concern over the reduced ability to clear the more difficult to treat type 1 genotype should a superinfection occur. Although triple therapy may change the recommendation, its safety and efficacy in liver transplant recipients with HCV are still being studied. As for the treatment of HCV genotype 1 recurrence after liver transplantation, early studies are promising.[54, 55]

The use of HCV antibody–positive grafts in recipients with HIV and HCV coinfections has been associated with poorer graft and patient survival.[56-58] Optimal strategies for donor and recipient selection have not been fully delineated in this population to date.

Lastly, stored blood vessels used as conduits in organ transplantation from HCV- and HBV-infected donors were recently documented to be associated with transmission of infection from donor to the uninfected recipients.[19] The transmission of HCV through the use of infected vessels in uninfected recipients was confirmed. As a result, OPTN policy was amended to preclude the storage of vessels from donors infected with HBV or HCV for use in recipients other than the recipients of the corresponding organs.[59]

Hepatitis E Virus

HEV, previously felt to be limited to acute hepatitis, is increasingly recognized as an agent of chronic hepatitis in liver transplant recipients.[60-63] HEV may present from transplantation, from de novo acquisition, or as reactivation.[61, 64, 65] Recently, HEV transmission via a liver donor who was negative for HEV according to serology and NAT before transplantation was documented.[66] Retrospectively, however, HEV RNA was identified in high concentrations in the liver tissue of the donor. Animal studies in a reservoir population (wild boars) support this notion with the identification of HEV RNA exclusively in bile.[67] Thus, a proportion of previously described de novo post–liver transplant HEV cases may have been donor-derived because donor liver tissue was not analyzed for HEV RNA.[68] Larger phylogenetic studies including examinations of donor tissue are necessary to fully define the epidemiology of donor-derived HEV.

West Nile Virus

WNV emerged predominantly in the United States as a significant problem in 1999.24 The detection of serum immunoglobulin M (IgM) occurs approximately 4 days after viremia, and seroconversion to immunoglobulin G (IgG) occurs at approximately 8 days.[68] Nonetheless, WNV serum IgM may persist up to 500 days after acute infection. Thus, neither the presence of WNV serum IgM nor its absence is sufficient to exclude active infection; donor screening requires the use of NAT to identify acutely infected donors.[69] Furthermore, a cross-reaction with other related viruses (eg, the dengue virus) could give false-positive serology results. NAT may rarely fail to detect viremia in donors who transmit WNV.[69, 70] Asymptomatic infections are common, so the screening of potential donors in high-prevalence areas during periods of ongoing local transmission has been advocated by some.[69] It should be noted, however, that the use of NAT in low-prevalence settings is more likely to yield false-positive results than true-positive results.[71] Transmission from infected donors to transplant recipients has not occurred in every instance, and preexisting immunity in recipients may limit transmission. No intervention has been prospectively studied to prevent the transmission of WNV if an infection is discovered after organ implantation.[69] Once an infection occurs, symptomatic disease is more common among immunocompromised patients, and significant persistent neurological morbidity or mortality may ensue. There are no proven treatments for WNV at this time.

In contrast, NAT has been reported to be 55% sensitive for neuroinvasive disease, and the diagnosis of an acute infection is otherwise dependent on enzyme-linked immunosorbent assay testing of cerebrospinal fluid.[72] WNV cerebrospinal fluid IgM is most often the basis for a diagnosis, but it may also persist for up to 199 days, and the significance of this finding is unknown.[73] WNV cerebrospinal fluid IgG cannot be trusted because it is able to cross the blood-brain barrier and thus may not necessarily be representative of central nervous system disease. Furthermore, cross-reactivity of WNV IgG is induced by other flaviviruses.[74] Ultimately, in cases of encephalitis, it may be prudent to avoid the use of these donors, as described earlier; the use of donors with known WNV infections of the central nervous system is not advised because of the risk of recipient transmission.[69, 70, 75-77]

Epstein-Barr Virus

EBV is of particular concern because of its association with posttransplant lymphoproliferative disorder, especially in the pediatric population. Donor and recipient screening should be performed, and there should be consideration of preemptive monitoring in high risk situations (i.e. D+/R−). A concomitant reduction in immunosuppression is a mainstay of treatment. Early graft dysfunction should prompt an evaluation for hepatic involvement of posttransplant lymphoproliferative disorder; later presentations of posttransplant lymphoproliferative disorder are more likely to present with disseminated disease and particularly colonic involvement.[78, 79]

Bacterial Infectious Disease Transmission

Donor bacterial infections (particularly bacteremias) likely represent the most common risk of donor-derived disease transmission. Bacterial contamination of the organ during recovery, packaging, and transport also poses a risk for transmission. Fortunately, the transmission of bacterial infections is frequently mitigated by the common use of perioperative antibiotics. Furthermore, much has been learned about the risk of bacterial infections in donors: donors with select bacterial infections can be safely used as long as appropriate therapy is provided to both the donor before procurement and the recipient after transplantation.

Donors With Diagnosed and Actively Treated Bacterial Infections

Not infrequently, an individual with a proven bacterial infection may become eligible to become an organ donor. Several studies and case series suggest that in general, organs from these individuals can be used with a low risk of disease transmission. Nonetheless, a careful review of the available culture data, the involvement of the local transplant infectious disease team, and the informed consent of the recipient are essential.

Available information suggests that organs from a donor with a bacteremia who has received active antibacterial treatment for at least 48 hours can be safely used as long as the same effective antibiotic therapy is continued in the recipients.[80-85] Generally, it should be known that the bacterial isolate is susceptible to the antibiotic being used, and there should be some evidence of a clinical response to the infection, such as defervescence, normalization of markers of ongoing infection (eg, total white blood cell counts and pressor requirements), and, optimally, negative blood cultures in bacteremic donors. The donor should be assessed for disseminated foci of infection because this may represent a higher risk of transmission of infection, and the risk is especially high if the organ to be used has evidence of involvement. The strongest data come from donors with documented bacterial meningitis who received effective antimicrobial therapy for at least 24 to 48 hours: the risk of transmission was exceptionally low with the active treatment of the donor and the recipient. Infection at site not involving the liver or biliary tree (eg, sputum and urine) without demonstration of disseminated infections do not typically require treatment of recipients.[6] Recipients who have continued active antibiotic treatment against causative microorganisms have generally had excellent outcomes without documented transmission.[86-89]

Published case series suggest that with specific antimicrobial treatments, the transmission of donor-derived bacterial infections to recipients is rare, and serious complications are infrequent. Although the ideal duration of antimicrobial therapy in the recipient has not been prospectively studied, most experts recommend treating the recipient with active therapy directed against the cultured bacteria for at least 14 days.[85]

With Staphylococcus aureus and Pseudomonas aeruginosa in particular, there is concern in the transplant community about the use of donors with infections known to have a propensity for endovascular infection. In one series, 14% of donors were bacteremic at the time of procurement: S. aureus accounted for 15% of these, and P. aeruginosa accounted for 3.1%.[90] Posttransplant sepsis and mycotic aneurysms have previously been described, but generally as rare occurences.[91-93] When there is potential transmission of particularly virulent organisms, guidelines recommend that the recipient receive 2 to 4 weeks of active therapy.[6] Although poorly studied, the risk of transmission would be expected to be higher with evidence of dissemination (eg, embolic infections) or with active endocarditis.

Many of the proven transmission events have involved multidrug-resistant bacteria. Organs from donors infected with highly resistant Acinetobacter baumannii, carbapenemase-producing Klebsiella pneumoniae, and vancomycin-resistant Enterococcus have rarely been used safely.[94, 95] The use of organs from donors with highly resistant bacteria, however, should be used with extreme caution, and this should be managed in collaboration with an experienced infectious diseases physician. When infections are transmitted, morbidity (particularly graft loss) and mortality rates are often high.[96]

Donors With Positive Syphilis Serology

Although the transmission of syphilis from an infected donor has been rarely reported, the prophylactic treatment of recipients who receive organs from donors with positive syphilis serology generally prevents transmission.[97, 98] Typically, recipients are treated for late latent syphilis [ie, 3 doses of intramuscular penicillin G benzathine (2.4 million units)].[6] Donors with a positive nontreponemal syphilis serology (ie, rapid plasma reagin or Venereal Disease Research Laboratory test) should have confirmatory testing performed even if these results become available after transplantation because the rate of false positivity among organ donors is high.[99] Confirmed positive syphilis serologies are considered a marker for risk behaviors that place the donor at an increased risk for HIV, HBV, and HCV by US Public Health Service guidelines.[4]

Fungal Infectious Disease Transmission

The fungal infections most commonly transmitted from donors to recipients include Candida species, endemic mycoses (particularly Coccidioides immitis), and Cryptococcus.[5] When transmitted, these mycoses are associated with significant morbidity in addition to frequent graft and/or recipient loss.

The presence of Candida in donor cultures (particularly donor blood) appears to be a risk factor for donor-derived Candida infections.[7] Contamination of the organ during procurement and preservation appears to occur more commonly than transmissions of infection.[100-102] Cultures of preservation fluid, when they are positive for Candida species, should prompt consideration for treatment. Because azole antifungals potentially interact with calcineurin inhibitors and mammalian target of rapamycin inhibitors, appropriate dose adjustments and close monitoring of drug levels when azoles are started and stopped should be considered.[7] Patients typically present early after transplantation with donor-derived Candida infections and may have a catastrophic event (eg, the rupture of a mycotic aneurysm) as their presenting sign.[103]

Although all endemic mycoses have been documented to be transmitted from donors to recipients, there is controversy about the optimal role of donor screening and treatment with the exception of C. immitis.[7] Donors from Coccidioides-endemic regions should be screened for infection by serology, and recipients of organs from seropositive donors should be treated with an active azole antifungal.[7] Donor-derived coccidioidomycosis typically presents within 2 months of transplantation with fever and pneumonia.[7]

Although the true incidence of donor-derived cryptococcal disease has not been completely defined, several recent studies have suggested that a donor origin should be considered, particularly when disease develops early after transplantation.[7, 104-106] Donors often have a history of unexplained neurological illness, immunosuppression, or high-dose steroid treatment as part of donor maintenance (although the last factor is common to many donors currently). It is critical to note that asymptomatic cryptococcemia has also been described in patients with advanced liver disease, which complicates the determination of the origin of early posttransplant cryptococcal disease.[7, 107] Donor-derived disease should be especially considered when there is nonpulmonary or surgical site involvement.[108, 109]

Mycobacterial Infectious Disease Transmission

Donor-derived M. tuberculosis transmission has been well described in transplantation.[30, 110-116] Nontuberculosis mycobacteria, even when cultured from the donor, has not resulted in a documented transmission event to date (see Table 4); the risk to liver recipients is likely exceptionally low.[5, 31] The risk of transmission may be related to the incidence of tuberculous infection in the general population because a higher proportion of donors may have a dormant infection. In general, donors with evidence of active tuberculosis should not be used as organ donors; if donors with untreated latent tuberculosis infections are used, the treatment of the recipients should be considered according to recent international guidelines.[8] Although presumed donor-derived tuberculosis cases have been diagnosed up to 30 months after transplantation, most proven donor-derived tuberculosis infections have become symptomatic less than 3 months after transplantation.[30, 110, 114, 115, 117, 118] It is important to note that symptoms, particularly in liver recipients, may be atypical and include fever, sepsis, and elevated liver enzymes.

Parasitic Infectious Disease Transmission

Wide ranges of parasitic infections have been transmitted from donors to transplant recipients. Although acute infections in donors are rarely implicated (typically in donors with rapidly progressive encephalitis), most transmissions occur as the result of latent infections in donors. Strongyloides stercoralis and Trypanosoma cruzi are among the more commonly recognized and reported parasitic infections and are discussed further.[119] In general, risk factors for transmissible parasitic disease in a donor include living in or traveling to an endemic region and eosinophilia in an infected donor. Most transmissible parasites remain latent and relatively asymptomatic in humans for an extended period of time, so their presence may be missed without specific testing.[119] Testing for many of the parasitic infections is not widely available, and available tests often lack specificity. Serological test results do not differentiate between acute and remote infections or give information about parasitemia.

Although most parasitic infections present early after organ transplantation, this may be modulated by such factors as the parasitic load in the transplanted organ, the degree and type of immune suppression used, and the presence of preexisting immunity. Presentation is variable and is highly dependent on the parasite transmitted, although fever, rash, and mental status changes are commonly seen with many of the transmitted infections.[119]

Strongyloides is a parasitic infection that can remain asymptomatic in donors but can be transmitted to transplant recipients. The increased use of high doses of steroids as part of maintenance strategies for donors may result in a hyperacute infection facilitating transmission through organ donation.[119, 120] Donors from endemic regions (the tropics and subtropics and temperate areas of southern and eastern Europe, the Caucasus, Belgium, and the Appalachian Mountain region of the United States) should be screened by serology for infection. If a donor is seropositive, the donor and/or recipient may be treated with ivermectin (200 μg/kg), typically with 2 doses. Transmission should be considered when the recipient presents with polymicrobial sepsis or polymicrobial meningitis.[119, 120]

Chagas disease is caused by the parasite T. cruzi, which can remain asymptomatic for a prolonged period of time after infection. The screening of donors from endemic regions of Central America and northern South America by serology can identify donors at risk of infection transmission.[9, 121, 122] Unfortunately, serology lacks specificity, and confirmation with a secondary assay is required, with results typically coming after organs have been allocated. Although transmission occurs in most cases for heart recipients, transmission for other organ types appears to be much lower.[9] As such, livers from donors who are seropositive for T. cruzi can be considered for transplantation. Recipients whose donors have proven T. cruzi seropositivity should be screened regularly for parasitemia after transplantation and treated as soon as parasitemia is documented.[9] Transmission should be considered in patients presenting with fever, which is frequently accompanied by a painful, erythematous rash that mimics bacterial cellulitis.[9, 122]

There is 1 parasitic infection that may cause donor death, but is associated with a low risk of transmission to recipients: Naegleria fowleri. Existing data suggest that donors with proven Naegleria meningoencephalitis, even if it is the cause of death, can be safely used with a low risk of transmission as long as the recipients are informed of the risk and monitored closely.[123, 124]

CONCLUSION

  1. Top of page
  2. Abstract
  3. TRENDS IN ORGAN AVAILABILITY
  4. RISK MITIGATION THROUGH DONOR SCREENING
  5. TRANSMISSION OF DONOR-DERIVED INFECTIOUS DISEASES AND LIVER TRANSPLANTATION
  6. CONCLUSION
  7. REFERENCES

The available organ pool is declining, but the demand for liver transplantation is not. To address this gap, transplantation centers are more frequently using donors with risk factors for transmitting a range of infectious diseases. Among the inherent risks of organ transplantation, the risk of the unexpected transmission of infectious diseases from donors to recipients remains exceedingly low (approximately 0.2%). Nonetheless, the transplant provider should remain vigilant to the possibility of donor-derived infectious disease transmission. In agreement with policies and regulations in the United States, the European Union, and elsewhere, any such potential donor-derived infectious disease transmissions should be reported immediately to the local organ procurement organization. Because early reporting may allow intervention in other recipients, reporting should occur quickly and should not wait for confirmation of the donor origin of the infection.

REFERENCES

  1. Top of page
  2. Abstract
  3. TRENDS IN ORGAN AVAILABILITY
  4. RISK MITIGATION THROUGH DONOR SCREENING
  5. TRANSMISSION OF DONOR-DERIVED INFECTIOUS DISEASES AND LIVER TRANSPLANTATION
  6. CONCLUSION
  7. REFERENCES