Donor Derived Infections in Transplant Recipients

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Expected Transmissions

Expected transmissions are those, such as Epstein-Barr virus (EBV), cytomegalovirus (CMV), hepatitis B virus (HBV), hepatitis C virus (HCV), and toxoplasmosis in which routine screening tests detect the latent infection of the donor (1). These expected infections are transmitted regularly by transplanted organs. Transmission of expected donor-derived infections has been documented, but their impact is either minimal on the overall course (i.e. the use of an HCV+ donor in an HCV+ recipient for certain organ types) (3, 14) or can be modified with preventative strategies (i.e. HBIG plus HBV antivirals to prevent transmission of HBV or the use of preemptive monitoring or prophylaxis to minimize the impact of CMV on the recipient) (10, 11, 16, 28, 31). It is important to recognize that despite plans to minimize the impact of these donor-derived infections on the recipient, clinically significant disease does rarely occur (28).

Unexpected transmissions

Unexpected transmissions occur from a pathogen that was either unrecognized or not screened for in the donor, for example Chagas, HIV, HCV, lymphocytic choriomeningitis virus (LCVM), Mycobacterium tuberculosis, rabies, and West Nile Virus (WNV) (2, 4, 7, 8, 9, 13, 15, 19, 26, 27, 29, 30, 33). In some of these transmission events, clinical disease in the donor was not recognized at the time that they died (4, 15, 27, 20, 30, 33) while in others, screening, while available, was not performed for the pathogen of interest (4, 8, 9). Many of the unexpected transmissions have resulted in clinically significant morbidity and mortality.

Regulatory Framework for Screening and Reporting of Donor-Derived Infections in the United States

All regulations about donor-derived infections are based on the National Organ Transplant Act of 1984 which directs the Organ Procurement and Transplantation Network (OPTN) to “adopt … standards for preventing the acquisition of organs that are infected with the etiologic agent for acquired immune deficiency syndrome” (32). The Final Rule was published on October 20, 1999 and directed the development of policies and screening procedures by the Organ Procurement and Transplantation Network and organ procurement organizations (OPO) respectively “to prevent the acquisition of organs that are infected with the etiologic agent for acquired immune deficiency syndrome” and to “to prevent the spread of infectious diseases” (23).

To address these issues, the OPTN has developed policy 2.2 and policy 4 (24, 25).

Policy 2.2 requires the host Organ procurement organization to obtain appropriate information and perform appropriate tests to screen the donor for any potentially transmissible disease. Specifically, the policy requires testing for (24):

Human Immunodeficiency Virus (HIV)
Hepatitis B
Hepatitis C
Syphilis
CMV
EBV
Blood and Urine cultures

Policy 4 provides guidance on requirements for (25):

Screening donors and recipients for HIV
Communicating information about:
HIV status
Use of donors who have previously received human pituitary-derived growth factor

Screening for and reporting of transmissible disease or medical conditions in the donor, including, but not limited to:

Unknown infection of central nervous system (encephalitis, meningitis)
Suspected encephalitis
Hepatitis C
Herpes simplex encephalitis or other encephalitis
History of JC virus infection (causes progressive multifocal leukoencephalopathy)
West Nile virus infection
Cryptococcal infection of any site
Rabies
Creutzfeldt-Jacob disease
Other fungal or viral encephalitis
Bacterial meningitis
Infection with HIV (serologic or molecular)
Active viremia: herpes, acute EBV (mononucleosis)
Serologic (with molecular confirmation) evidence of HTLV-I/II
Active hepatitis A or B
Infection by: Trypanosoma cruzi, Leishmania, Strongyloides, Toxoplasmosis
Active Tuberculosis
SARS
Pneumonia
Bacterial or fungal sepsis (e.g. candidemia)
Syphilis
Multi-system organ failure due to overwhelming sepsis, such as gangrenous bowel
Malignancies-other active malignant neoplasms,
Melanoma, Merkel cell, including Kaposi’s
Hodgkins’ disease and non-Hodgkin’s lymphoma
Multiple myeloma
Leukemia
Aplastic anemia agranulocytosis
Miscellaneous carcinomas
Any new conditions identified by the CDC as being a potentially communicable disease

Technically, donors with all of these conditions can be used at the discretion of the individual transplant center. In general, patients with encephalitis or non-bacterial meningitis should be avoided as donors (patients with bacterial meningitis can be used as long as they have documented bacterial meningitis and have received appropriate therapy with clinical response; most will treat the recipient with a course of antibiotics to cover the documented pathogen. Further, there is growing evidence to suggest that donors who died of Naeglaria fowleri encephalitis can be safely used as donors, although it should be recognized that if the parasite is transmitted there is no proven therapy for this infection). Patients with proven prion disease should be avoided as donors because of the risk of disease transmission. In all cases in which a transmissible disease is recognized in the donor, the accepting team should discuss the finding with their local experts (i.e. Transplant Infectious Diseases or Oncology experts) and consult these physicians post-transplant to ensure that they are monitored and treated as indicated (17).

Until recently, screening for human T-lymphotrophic virus (HTLV)-1/2 was required for all donors. On careful review of the available data, it appears that most US donors with positive serology either do not have confirmed infection or are infected with HTLV-2 for which there is no clear link with disease in humans. Because of the poor specificity of the available tests, donors with positive serology should have confirmatory testing to determine the likelihood of HTLV-1 infection. Further, the exact risk of disease transmission appears to be low in these individuals. There are no clear guidelines on optimal monitoring or management of recipients of HTLV-1/2 positive donors other than watchful waiting as most appear to do well post-transplant (20).

Reporting of potential or confirmed transmission of disease or medical conditions.

Communication information and obtaining special consents when transplanting organs from “high risk” donors (5, 25). The designation of “high risk” donors is based on the “1994 Guidelines for the Prevention of Transmission of HIV Through Organ and Tissue Transplantation” and includes the following (5):
Behavior/History Criteria
1. Men who have had sex with another man in the preceding 5 years.
2. Persons who report nonmedical intravenous, intramuscular, or subcutaneous injection of drugs in the preceding 5 years
3. Persons with hemophilia or related clotting disorders who have received human-derived clotting factor concentrates
4. Men and women who have engaged in sex in exchange for money or drugs in the preceding 5 years
5. Persons who have had sex in the preceding 12 months with any person described in items 1–4 above or with a person known or suspected to have HIV infection
6. Persons who have been exposed in the preceding 12 months to known or suspected HIV-infected blood through percutaneous inoculation or through contact with an open wound, non-intact skin, or mucous membrane
7. Inmates of correctional systems
Specific Criteria for Pediatric Donors
1. Children meeting any of the criteria listed above for adults
2. Children born to mothers with HIV infection or mothers who meet the behavioral or laboratory criteria for adult donors (regardless of their HIV status) should not be accepted as donors unless HIV infection can be definitely excluded in the child as follows:
  Children >18 months of age who are born to mothers with or at risk for HIV infection, who have not been breast fed within the last 12 months, and whose HIV antibody tests, physical examination, and review of medical records do not indicate evidence of HIV infection can be accepted as donors
3. Children ≤18 months of age who are born to mothers with or at risk for HIV infection or who have been breast fed within the past 12 months should not be accepted as donors regardless of their HIV test results
Laboratory and Other Medical Criteria

Persons who cannot be tested for HIV infection because of refusal, inadequate blood samples (e.g., hemodilution that could result in false-negative tests), or any other reasons
Persons with a repeatedly reactive screening assay for HIV-1 or HIV-2 antibody regardless of the results of supplemental assays.
Persons whose history, physical examination, medical records, or autopsy reports reveal other evidence of HIV infection or high-risk behavior, such as a diagnosis of AIDS, unexplained weight loss, night sweats, blue or purple spots on the skin or mucous membranes typical of Kaposi’s sarcoma, unexplained lymphadenopathy lasting >1 month, unexplained temperature >100.5 F (38.6 C) for >10 days, unexplained persistent cough and shortness of breath, opportunistic infections, unexplained persistent diarrhea, male-to-male sexual contact, sexually transmitted diseases, or needle tracks or other signs of parenteral drug abuse.

Epidemiology of Donor-Derived Infections

Currently, the epidemiology of donor-derived infections is derived from reports made in the medical literature, to the Centers for Disease Control and Prevention, and to the OPTN. Based on reports to the OPTN, the following data are available based on data from 2005-2008 (Table 1) (17, 18):

Based on available data, unexpected donor-derived infectious disease transmissions are rare and appear to occur in less than 1% of all transplant procedures (17, 18). This is only a rough estimate because of the following limitations:

Significant under-recognition and under-reporting of donor-derived disease transmission events

Incomplete communications networks and lack of a national, mandatory transplantation adverse event sentinel network
Incomplete follow-up and testing of recipients for potential disease transmission

Further, when they do occur, unexpected donor-derived infectious diseases transmissions cause significant morbidity and mortality.

Donor Screening Methods

Several methods are currently utilized to minimize the risk of disease transmission:

Collection of a medical-social history on the donor
The medical and social history may identify factors, such as sexual practices and drug use, that may place the potential donor at higher risk of contracting blood-borne pathogens (5). This is not obtained in a standardized way and the validity of the information is never confirmed.
Physical examination of the donor, by both the OPO and the procurement surgeons
Serologic screening of the donor o Serologic tests are required to screen for HIV, HBV, HCV, CMV, EBV, and syphilis. Some OPOs do additional serologic screening for such pathogens as toxoplasmosis and Trypanasoma cruzii
These serologic tests assess the donor’s response to an infection and therefore will not detect an infection that is newly acquired – they actually detect the presence of an antibody (in the case of HIV, HBcAb, HCV, CMV, and EBV) or the antigen of the infectious agent (in the case of HBsAg).
The period of time between infection and the ability to detect antibodies to a pathogen is referred to as the window period. The window period for key blood-borne viruses is (12):
- HIV: 22 days
- HBV: 35-38 days
- HCV: 70 days
If the interval between initial infection (as measured by the exposure to the risk factor recognized in the history) and procurement is less than the window period, the serologic tests may be negative despite active infection in the donor
Infusion of large volumes of fluids or blood products may result in hemodilution (6).
With hemodilution, the concentration of the antibodies are diluted to a concentration below the limit of detection of the assay
Screening Using Nucleic Acid Testing Methods
To increase the sensitivity and reduce the window period, nucleic acid tests (NAT), which detect and amplify the DNA or RNA of the virus, have been used by some OPO’s
NAT is commonly referred to as PCR
However, there are currently no standardized approaches to NAT
Although the risk is reduced by using NAT, there is a period of residual risk, also referred to as the NAT Window Period, which is:
- HIV: 7 days
- HBV: 13 days
- HCV: 7 days
Although the greatest safety benefit would be obtained by screening all donors by NAT, non-reproducibly positive (or false positive) samples which may result in unnecessarily discarding organs
NAT may not detect all infected donors and rare transmissions may still occur (7, 26).
NAT has been used to screen for HIV, HBV, HCV, and West Nile Virus
Screening for West Nile Virus may not detect all infected donors; one documented case of donor-derived WNV transmission was from a donor who was NAT negative (7).
Routine screening of all donors by WNV NAT will result in more organs lost than diseases transmitted, based on one analysis (21).

Identification of Donor-Derived Infections

Although donor-derived infections are rare, it is critical to consider the donor as the source of any post-transplant infection. Failure to consider that an infection is potentially donor-derived will undoubtedly result in missed recognition. Typically, donor-derived disease transmissions result in multiple recipients of organs from the same donor developed a similar clinical syndrome. Challenges to recognition of a donor-derived disease transmission event include:

Recipients may be cared for by different teams within the same hospital

Organs may have been transplanted in a number of different hospitals which will (13).

Delay in transmission of positive culture data from hospitals to OPOs and on to transplant centers

Inadequate communications structures such that appropriate decision makers are not provided with key information (i.e. positive culture results) and there is resultant delay as the information passes from individuals at an OPO or Transplant Center until it reaches the appropriate clinician who recognizes the importance and need to intervene.

Delay in reporting to the OPO that a single organ recipient presents with an atypical course or that there is concern for an infection that may have been of donor origin

Lack of communications infrastructure at the OPO and Transplant Centers to rapidly assess the status of all other recipients of organs, tissues or vessels from the same donor

Presentation of patients in a non-synchronous way such that patients were initially well when concern of transmission was raised. In several well documented transmissions, some patients were initially well when initially evaluated and later became sick (2, 7, 19, 22, 30).

Lack of systems at transplant centers and OPO’s to flag recipients where concern for a donor-derived disease transmission or positive culture exists. Such a system could facilitate evaluation and management of the patient if they do become ill.

If a patient becomes ill or has an atypical course – consider a donor-derived infection and ask the OPO how other recipients are doing. Further, you should personally review all donor cultures and ask for follow-up of any cultures that are still pending or in the lab.

Prevention of Donor-Derived Infections

It is currently impossible to prevent all cases of donor-derived infections; most cases of unexpected infectious disease transmission are the result of infections for which no proven screening method has been identified or for which the prevalence is expected to be so low that screening would result in loss of far more organs from the donor pool than infections prevented (7, 21, 26).

Expected transmissions, such as toxoplasmosis, CMV, EBV, HCV, and HBV typically are managed by either preemptive monitoring or universal prophylaxis. These are discussed elsewhere in this document.

It is currently recommended that recipients of organs from OPTN-defined “high risk” donors undergo routine screening post-transplant to ensure that a blood-borne virus (HIV, HBV, or HCV) has not been transmitted. Since many recipients who have acquired infection do not seroconvert, the use of serology PLUS nucleic acid testing methods are recommended. Unless prior infection or protection for HIV, HBV, or HCV has been documented post-transplant, all recipients of OPTN-defined “high risk” donors should undergo serology and PCR-based testing for HIV, HBV, and HCV at 1, 3 and 12 months post-transplant. Testing of recipients of organs not deemed to be “high risk” of harboring a blood-borne pathogen should be screened based on your local protocol.

REFERENCES

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2. Ahn J, Cohen SM. Transmission of human immunodeficiency virus and hepatitis C virus through liver transplantation. Liver Transpl 2008;14(11):1603-8. [PubMed]

3. Ali MK, Light JA, Barhyte DY, et al. Donor hepatitis C virus status does not adversely affect short-term outcomes in HCV+ recipients in renal transplantation. Transplantation 1998;66(12):1694-7. [PubMed]

4. Centers for Disease Control. Transplantation-transmitted tuberculosis--Oklahoma and Texas, 2007. MMWR Morb Mortal Wkly Rep 2008 Apr 4;57(13):333-6. [PubMed]

5. Centers for Disease Control. Guidelines for preventing transmission of human immunodeficiency virus through transplantation of human tissue and organs. MMWR Morb Mortal Wkly Rep 1994;43(RR-8):1-17. [PubMed]

6. Centers for Disease Control. Human immunodeficiency virus infection transmitted from an organ donor screened for HIV antibody--North Carolina. MMWR Morb Mortal Wkly Rep 1987;36(20):306-8. [PubMed]

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13. Fischer SA, Graham MB, Kuehnert MJ, et al. Transmission of lymphocytic choriomeningitis virus by organ transplantation. N Engl J Med 2006;354(21):2235-49. [PubMed]

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19. Iwamoto M, Jernigan DB, Guasch A, et al. Transmission of West Nile Virus from an Organ Donor to Four Transplant Recipients. N Engl J Med 2003;348(22):2196-203. [PubMed]

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23. OPTN Final Rule. 42 CFR, part 121 et seq. [PubMed]

24. OPTN Policy 2.2. [PubMed]

25. OPTN Policy 4.0. [PubMed]

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Table 1. Potential Donor-Derived Infectious Diseases Transmissions Reported to OPTN 2005-2008 (26, 29)

Disease	# of Donor Reports	# of Recipients with Confirmed Transmission	# of DDD-Attributable Recipient Deaths
Bacteria*	21	8	4
Fungus°	12	4	1
M. tuberculosis and non-TB Mycobacteria	16	1	0
Parasitic†	15	8	2
Syphilis	4	1	0
Viral∞	54	14	6
Expected Transmissions§	14	—	—

°Acinetobacter, Enterococcus (including VRE), Ehrlichia spp, Gram Positive Bacteria, Klebsiella, Legionella, Listeria, Lyme Disease, Pseudomonas, Rocky Mountain Spotted Fever, Serratia, S. aureus, Veillonella; bacterial meningitis and bacterial emboli

° Aspergillus spp, Candida spp, histoplasmosis, zygomyces

†Babesia, Chagas, schistosomiasis, strongyloides

∞This includes 4 patients with both HIV and HCV transmission. All but three reports represent non-reproducible NAT results except for 1 report of HCV with 3 transmissions, 1 report of HCV/HIV with 4 transmissions and 1 death, and 1 patient with HIV infection acquired post-transplant

§14 Expected Transmissions: CMV, toxoplasmosis and EBV