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In this issue, Ahm and Cohen1 report on a 66-year-old liver transplant recipient who received a liver transplant in January 2007. The donor was a 39-year-old male, deceased after a head trauma, with a history of sex with men. His hepatitis C virus (HCV) and human immunodeficiency virus (HIV) serology before and after blood transfusion were negative. The donor heart and kidneys were accepted by other medical centers in the Chicago area. In November 2007, the hospital was notified by the local Organ Procurement Organization (OPO) that the donor was found to be both HIV-positive and HCV-positive. Apparently, the other recipients of the same donor at the other institutions were tested positive by nucleic acid amplification test (NAT) for HIV and HCV. At that point the liver transplant recipient was retested and was found to be positive for both of these viruses. The patient was placed on antiretroviral medications but later on developed urosepsis, cytomegalovirus viremia, and renal failure, and expired at the end of January 2008. This report is alarming because it brings up the question of organ transplantation safety.

Donor-transmitted infections have been reported in the literature before, including bacterial, fungal, viral, and protozoal infections. Gottesdiener2 reviewed these infections in detail in 1989 and among the viral infections transmitted by transplantation, he also described HIV in solid organ and bone marrow transplantation, rabies in corneal transplantation, and Creutzfeldt-Jakob Disease in dural matter and cornea transplant recipients. The eligibility criteria for deceased donor organ donation was defined and approved by the Association of Organ Procurement Organizations.3 Over the last decade, severe and unexpected life-threatening donor-transmitted viral infections after solid organ transplantation have been reported, as follows.

WEST NILE VIRUS

  1. Top of page
  2. WEST NILE VIRUS
  3. RABIES
  4. LYMPHOCYTIC CHORIOMENINGITIS VIRUS
  5. HUMAN T-CELL LEUKEMIA VIRUS TYPE I
  6. REFERENCES

In August 2002, an organ donor in Georgia transmitted West Nile virus (WNV) infection through kidney, heart, and liver transplantation to 4 transplant recipients, of which 3 developed WNV encephalitis (1 fatally) and the last of the 4 recipients developed a febrile illness.4–6 The organ donor had a negative titer for WNV. He had received multiple blood products prior to donation, and 1 unit of plasma from 1 of the blood donors was positive by polymerase chain reaction (PCR), which was demonstrated later on seroconversion. The blood donor recalled a “viral illness” a few weeks prior to plasma donation. Retrospectively, serum and plasma samples at organ recovery yielded WNV nucleic acid. In June 2003, the blood collection agencies implemented WNV screening by NAT,5 which is the most efficient test to detect WNV viremia. The original screening of 1 million donations at the beginning of August 2003 demonstrated 0.03% positivity by this method. In August 2005, a second incidence of transmission occurred from a common donor to 4 recipients including 2 kidney recipients, 1 liver recipient, and 1 lung recipient. The donor was hospitalized in New York City with a head trauma injury. The liver and the lung recipients developed WNV encephalitis and became comatose, the 2 kidney recipients did well.7 The donor acquired WNV infection through a mosquito bite and a blood test done 1 day prior to organ donation was negative by PCR but positive by serology for immunoglobulin (Ig)M and IgG antibodies.

Screening of all organ donors by WNV NAT, as is the practice in blood donation, is currently not done because of logistics and validation issues. The Health Resources Services Administration had published some recommendations8 in January 2004 regarding NAT testing. They called for consideration of the diagnosis of WNV in the right setting and to withhold transplantation for 28 days in the case of living donors with positive NAT. In the case of deceased donors they advised to proceed with transplantation only if the recipient's condition is life-threatening and after the patient is fully aware of the risks involved.

RABIES

  1. Top of page
  2. WEST NILE VIRUS
  3. RABIES
  4. LYMPHOCYTIC CHORIOMENINGITIS VIRUS
  5. HUMAN T-CELL LEUKEMIA VIRUS TYPE I
  6. REFERENCES

In May 2004, rabies encephalitis was diagnosed in a hospital in Texas. The patients were recipients of a liver and 2 kidneys and a vascular graft implanted in another liver transplant recipient, all from a common donor with undiagnosed rabies.9 All 4 patients died after developing agitation, confusion, delirium, and tremors. A fifth patient, a recipient of a lung transplant, died of surgical complications. The donor was a 20-year-old man who developed confusion, agitation, and body ballistic movements. Misleading factors in the diagnosis were the presence of marijuana and cocaine in toxicology tests and development of subarachnoid hemorrhage and the absence of a history of rabies exposure. Only after the diagnosis was made was it learned from friends of the donor that he had a history of a bat bite. The virus was found to be a bat variant. In late December 2004, there was a similar occurrence in Germany.10, 11 A 26-year-old woman was a donor for 6 transplant recipients including kidney, simultaneous kidney-pancreas, liver, lung, and corneas. She had developed fever, headaches, and aggressive behavior. Three patients died with rabies after developing progressive neurological symptoms (kidney, kidney-pancreas, and lung recipients). The implanted corneas were removed and the patients survived, and the liver recipient had received rabies vaccine years prior to transplantation and had detectable antibodies after transplantation and survived. It was learned that the donor visited India in October 2004, and most likely acquired rabies there.

In both incidents of rabies transmission by organ transplantation, the diagnosis was not suspected prior to death of the recipients and there was no history of rabies exposure at time of donor screening. Canine rabies was eradicated from the United States and Canada via vaccination of animals, and the bat variant has become the predominant type to cause rabies.12 The teeth of the bat are so delicate that many times the bite is completely unrecognized. Of 56 cases of rabies transmitted by a bat, almost 50% had no history of direct contact and a third did not recall any exposure whatsoever.

LYMPHOCYTIC CHORIOMENINGITIS VIRUS

  1. Top of page
  2. WEST NILE VIRUS
  3. RABIES
  4. LYMPHOCYTIC CHORIOMENINGITIS VIRUS
  5. HUMAN T-CELL LEUKEMIA VIRUS TYPE I
  6. REFERENCES

In 2003, a 51-year-old man in Wisconsin, after head trauma, was a donor for transplantation, including liver, kidneys, lung, musculoskeletal tissues, and vascular tissues.13 The 4 organ transplant recipients presented with febrile illness and multiple other signs and symptoms after transplantation and all died. Tissues from recipients demonstrated Old World arenavirus by electron microscopy and viral cultures. The virus recovered from the 2 kidney recipients were identical and were different from previous lymphocytic choriomeningitis virus (LCMV) strains. The donor tissues were negative for virus and his serology titer for LCMV was also negative. There was no known exposure to rodents. In April 2005, a transplantation was performed that included a liver, lungs, kidneys, corneas, and skin.13, 14 The 4 recipients of the liver, lungs, and kidneys developed a febrile illness, abdominal pain, and various other symptoms and 3 of them died (the liver, lungs, and kidney recipients). LCMV, a rodent-borne Old World arenavirus infection, was the cause of death. Diagnosis was done by immunohistochemical stains, reverse-transcriptase PCR, viral cultures, and serology testing. One kidney transplant recipient was treated with ribavirin and survived. The donor in these transplantations was a 45-year-old woman from Rhode Island with hypertension who presented with intracranial and subarachnoid hemorrhages. Investigation revealed that a pet hamster was acquired and cared for by a family member in the donor's household. No virus was detected in the donor and serology titer for LCMV was also negative. The molecular analysis showed that the recipients' and the hamster's virus from the 2005 report were identical but different from the viral isolate in the 2003 report. In February 2008, a report from Australia15 described a 57-year-old male with cerebral hemorrhage donating to 3 organ recipients (liver and kidneys) who all died of febrile illness between 4 and 6 weeks after transplantation. Immunohistochemical analysis of tissue from the recipients demonstrated arenavirus antigen. New arenavirus related to LCMV was demonstrated by molecular techniques in the recipients' tissue. The donor and 1 of the recipients showed serum IgM and IgG virus-specific antibodies. There was no history of exposure to rodents but the donor did have a recent travel history to rural areas in the former Yugoslavia.

Common to these reports was the fact that the virus was not found in the donors and in the first 2 incidents (Wisconsin and Rhode Island) no serological evidence of LCMV infection was detected, but somehow the virus was transmitted to the recipients. One could postulate that transmission may have occurred via colonizing virus or at the window period before serological conversion. The Centers for Disease Control and Prevention (CDC) has discussed ways to minimize risk of LCMV infection from rodents.16, 17 Pet rodents (mice, guinea pigs, and hamsters) usually get infected with LCMV after contact with wild house mice (in pet stores, breeding places, and the home) and may then transmit LCMV to their owners. Infection in normal hosts usually presents as a viral-like illness but aseptic meningitis may occur. In immunosuppressed hosts and pregnant women it may cause severe and life threatening illness. Therefore, purchasing rodent pets for the immunocompromised is discouraged and contact with rodents should be avoided.16, 17

HUMAN T-CELL LEUKEMIA VIRUS TYPE I

  1. Top of page
  2. WEST NILE VIRUS
  3. RABIES
  4. LYMPHOCYTIC CHORIOMENINGITIS VIRUS
  5. HUMAN T-CELL LEUKEMIA VIRUS TYPE I
  6. REFERENCES

In October 1998, a young healthy man in Spain became a donor after head injury of 2 kidneys, liver, and 2 corneas.18 Less than 2 years after transplantation the 3 solid organ recipients presented with severe spastic paraparesis and were diagnosed with human T-cell leukemia virus (HTLV) type I (HTLV-I) myelopathy. Retrospectively, the donor and his mother were seropositive for HTLV-I and the organ recipients were originally seronegative but seroconverted to positivity at time of presentation with paraparesis. HTLV-I DNA sequencing demonstrated that the mother's and the recipients' virus were identical. The donor's mother was from Venezuela and had moved to Spain after she married a local Spaniard.

The virus was most likely transmitted from mother to son via breast feeding and then transmitted to the organ recipients. The virus is endemic in parts of Japan, Africa, the Caribbean basin, and Melanesia.19 Transmission by blood products is well known and the seroprevalence rate in blood donors in the United States is 0.016%. Blood in the United States has been routinely screened since 1988. Donor HTLV serology positivity is an indication for nonusage of organs for fear of virus transmission. Based on the United Network for Organ Sharing (UNOS) database the donor prevalence between 1988 and 2000 for HTLV-I was 0.027% and for HTLV-II it was 0.064.20

Common to all these reports including the one by Ahm and Cohen1 is a multiorgan donor who transmitted severe and life-threatening viral infection to organ recipients. These infections are rare but can happen in every transplant center unless special precautions are put in place. According to the Organ Procurement and Transplantation Network (OPTN) there are currently 16,908 candidates on the liver transplantation waiting list, while 6493 liver transplantations were performed in the United States in 2007.21 Because of the high discrepancy between donor availability and the number of candidates, marginal donors and high-risk-lifestyle donors have been used by many centers.22 The CDC had defined high-risk behavior and recommended excluding these donors unless the risk of not performing the transplantation was higher than the risk of HIV transmission.23 The behavior risk exclusion criteria include men who have sex with men, drug addictions (intravenous, intramuscular, and subcutaneous injection), persons with hemophilia who had received clotting factors, people engaged in prostitution, people who have sexual activity with individuals who belong in the other categories, those exposed to known or suspected HIV-positive blood, and inmates of correctional systems. In December 2007, the OPTN/UNOS Executive Committee adopted new requirements regarding risky donors.24 If the donor is found to belong to the “high risk” group, the host OPO has to communicate this information to all the institutions that receive organs from this donor. In addition, the transplant center must inform the recipient of this risk, consent must be signed by the recipient or other delegates, and the documentation must be kept for the record.

Even though these donor-transmitted infections are rare, it is important to develop a strategy of prevention. It is important to learn from previous cases of documented donor-transmitted infections to understand whether these infections could have been prevented and what can be done in the future. Accurate history-taking regarding social and medical events is important: the donor's recent and remote exposures are a crucial part in the assessment of donor eligibility. As can be learned from previous cases, questions have to be focused, not general, and experience from previous cases can be used as a guide in construction of the interrogation (eg, “Was there any contact with a bat or stray dogs? Any contact with pet rodents like a hamster or guinea pig?”). An example is the United States rabies infection:9 post factum it was learned that the donor previously had a bat bite. This assessment is a difficult task because medical personnel have to approach the grieving family with questions and expect informative answers. Special attention should be given to unusual neurological presentations even if toxicology testing shows the presence of drugs. It has been recommended not to use organs from donors with viral encephalitis or meningitis and those with unexplained neurologic syndromes3 The 2 donors who transmitted rabies to their recipients (United States and Germany) were both in their twenties, presented with combative behavior, and were both found to have cocaine in the toxicology tests.9, 10

With an ongoing shortage in donors and the subsequent demise of patients on the waiting list, it is important to reach a consensus on how to screen donors for potential donor-transmitted life-threatening infections while at the same time not wasting organs that could be the single opportunity for survival for those patients on the waiting list. The laboratory plays a very important role in the screening process of each potential donor. Positive results may need confirmation by other tests, but at times organs are discarded because the risk for infection may be real and there is no time to wait for confirmation.25 An example is screening for HTLV-I/II. Organs from 4 donors were found to be seropositive for HTLV-I/II by a screening test in 2000 and 2001 at the University of Wisconsin and therefore were not used. Later confirmatory testing by Western blot demonstrated the false positivity of all 4 donors.20

Recent virus exposures can be missed by serological testing, especially when the testing occurs before reactive antibodies are produced (the window period). Significant progress was made in the prevention of viruses in blood products by the introduction of the NAT test to medical practice. Examples include WNV, HCV, and HIV. In the United States, routine blood donation testing for HCV and HIV-1 was introduced in 1999. During the following 3 years, 12 donations (1 per 3.1 million) and 170 donations (1 per 230,000) were found to be negative by antibody test but positive by nucleic acid amplification for HIV-1 and HCV, respectively.26 In 1 transplant center between November 2001 and February 2004, 1445 organs from deceased donors were screened for anti-HCV antibodies.27 In 6 (0.9%) of 663 seronegative samples HCV RNA was detected with a viral load 3 to 4 log lower than samples from seropositive donors. In the most recent Guidance for Industry,28 the U.S. Food and Drug Administration recommends both NAT screening and anti-HCV screening test to determine eligibility of donors of human cells, tissues, and cellular-based and tissue-based products.

Finally, collaboration between transplant centers and between the various OPOs is important for the future. Confirmatory tests should be done and results shared for 2 main reasons. First, even if organs are not used, as in the case of HTLV-I/II positivity by initial screening, confirmatory information is necessary so we can all improve assessment in the future. Second, if the organs were used, the confirmatory information may be life-saving. One of the kidney transplant recipients with LCMV survived after diagnosis was made and treatment with ribavirin was initiated. Also, in the rabies report from Germany, the 2 implanted corneas were removed and the patients survived. The liver transplant recipient had previously received rabies vaccine and also survived; such treatment (rabies Ig and vaccine) could be given prospectively after confirmatory analysis. Development of donor assessment strategies may improve safety and at the same time increase the donor pool eligibility.

REFERENCES

  1. Top of page
  2. WEST NILE VIRUS
  3. RABIES
  4. LYMPHOCYTIC CHORIOMENINGITIS VIRUS
  5. HUMAN T-CELL LEUKEMIA VIRUS TYPE I
  6. REFERENCES
  • 1
    Ahn J, Cohen S. Transmission of human immunodeficiency virus and hepatitis C virus through liver transplantation. Liver Transpl 2008; 14: 16031608.
  • 2
    Gottesdiener KM. Transplanted infections: donor-to-host. Ann Intern Med 1989; 110: 10011016.
  • 3
    Wilck M, Fishman JA. The challenges of infection in transplantation: donor-derived infections. Curr Opin Organ Transplant 2005; 10: 301306.
  • 4
    Centers for Disease Control and Prevention. West Nile virus infection in organ donor and transplant recipients—Georgia and Florida, 2002. MMWR 2002; Public Health Dispatch September 6, 2002.
  • 5
    Centers for Disease Control and Prevention. Detection of West Nile virus in blood donations—United States, 2003. MMWR Surveill Summ 2003; 52: 769772.
  • 6
    Iwamoto M, Jernigan DB, Guasch A, Trepka MJ, Blackmore CG, Hellinger WC, et al. , Transmission of West Nile virus from an organ donor to four transplant recipients. N Engl J Med 2003; 348: 21962203.
  • 7
    Centers for Disease Control and Prevention. West Nile virus infection in organ transplant recipients—New York and Pennsylvania, August–September, 2005. MMWR Surveill Summ 2005; 54 (dispatch): 13.
  • 8
    Health Resources and Services Administration. A special announcement from HRSA regarding West Nile Virus. Available at: http://www.unos.org/news. Accessed June 2008.
  • 9
    Srinivasan A, Burton EC, Kuehnert MJ, Rupprecht C, Sutker WL, Ksiazek TG, et al. , Transmission of rabies virus from an organ donor to four transplant recipients. N Engl J Med 2005; 352: 11031111.
  • 10
    Rabies in patients who received organ transplants in Germany. CDR Wkly (Online) 2005;15:News.
  • 11
    Bronnert J, Wilde H, Tepsumethanon V, Lumlertdacha B, Hemachudha T. Review article: organ transplantation and rabies transmission. J Travel Med 2007; 14: 177180.
  • 12
    De Serres G, Dallaire F, Cote M, Skowronski DM. Bat rabies in the United States and Canada from 1950 through 2007: human cases with and without bat contact. Clin Infect Dis 2008; 46: 13291337.
  • 13
    Fischer SA, Graham MB, Kuehnert MJ, Kotton CN, Srinivasan A, Marty FM, et al. , Transmission of lymphocytic choriomeningitis virus by organ transplantation. N Engl J Med 2006; 354: 22352249.
  • 14
    Centers for Disease Control and Prevention. Lymphocytic choriomeningitis virus infection in organ transplant recipients—Massachusetts, Rhode Island, 2005. MMWR Surveill Summ 2005; 54: 537539.
  • 15
    Palacios G, Druce J, Du L, Tran T, Birch C, Briese T, et al. A new arenavirus in a cluster of fatal transplant-associated disease. N Engl J Med 2008; 358: 991998.
  • 16
    Centers for Disease Control and Prevention. Interim guidance for minimizing risk for human lymphocytic choriomeningitis virus infection associated with pet rodents. interim guidance. MMWR Surveill Summ 2005; 54: 747749.
  • 17
    Centers for Disease Control and Prevention. Update: interim guidance for minimizing risk for human lymphocytic choriomeningitis virus infection associated with pet rodents. MMWR Surveill Summ 2005; 54: 799801.
  • 18
    Gonzalez-Perez MP, Munoz-Juarez L, Cardenas F, Imirizaldu JJZ, Carraceja JC, Garcia-Saiz A. Human T-cell leukemia virus type I infection in various recipients of transplant from the same donor. Transplantation 2003; 75: 10061011.
  • 19
    Centers for Disease Control and Prevention. Recommendations for counseling persons infected with human T-lymphotrophic virus, type I and II. MMWR Recomm Rep 1993; 42(RR-9): 113.
  • 20
    Shames BD, D'Alessandro AM, Sollinger HW. Human T-cell lymphotrophic virus infection in organ donors: a need to reassess policy? Am J Transplant 2002; 2: 658663.
  • 21
    OPTN: Organ Procurement and Transplantation Network. Available at: http://www.optn.org/latestData/rptData.asp. Accessed May 2008.
  • 22
    Attia M, Silva MA, Mirza DF. Review: the marginal liver donor—an update. Transpl Int 2008; 21: 713724.
  • 23
    Centers for Disease Control and Prevention. Guidelines for preventing transmission of human Immunodeficiency Virus through transplantation of human tissue and organs. MMWR Recomm Rep 1994; 43( RR-8): 117.
  • 24
    United Network for Organ Sharing. Summary of actions taken at the OPTN/UNOS Executive Committee Meeting—December 18, 2007. Available at: http://www.unos.org. Accessed August 2008.
  • 25
    Molmenti EP, Smith DM, Molmenti H, Fasola CG, Aguanno JJ, Savino AC, et al. Unusually high incidence of positive HTLVI/II results among young female organ donors in the peripartum period. Dig Dis Sci 2002; 47: 23832385.
  • 26
    Stramer SL, Glynn SA, Kleinman SH, Strong DM, Caglioti S, Wright DJ, et al. Detection of HIV-1 and HCV infections among antibody-negative blood donors by nucleic acid amplification testing. N Engl J Med 2004; 351: 760768.
  • 27
    Aswad S, Khan NS, Comanor L, Chinchilla C, Corado L, Mone T, et al. Role of nucleic acid testing in cadaver organ donor screening: detection of hepatitis C virus RNA in seropositive and seronegative donors. J Viral Hepat 2005; 12: 627634.
  • 28
    U.S. Food and Drug Administration. Guidance for Industry. Eligibility determination for donors of human cells, tissues, and cellular and tissue-based products (HCT/Ps)). August 2007. Available at: http://www.fda.gov/cber/gdlns/tissdonor.pdf. Accessed June 2008.