William Check, PhD
Immunosuppression after organ transplantation acts as a two-edged sword: It increases the likelihood of successful engraftment but also the chance that the patient will contract an infection that can jeopardize the transplant it was intended to save. Transplantation itself is a two-edged sword: While a transplanted organ or tissue is often lifesaving, in some cases it acts like a Trojan horse, bringing with it an infectious agent. To guard against this danger, all donors of organs and tissues are screened for common communicable diseases.
At a symposium at the 2012 meeting of the American Society for Microbiology, symposium organizer Moon H. Nahm, MD, professor of pathology at the University of Alabama at Birmingham, succinctly expressed the two-faced nature of organ transplants. “Transplants save lives,” Dr. Nahm said, and then he added: “Transplantation is a very easy way to spread infections. It offers direct inoculation from donor to recipient.”
Dr. Nahm’s talk focused on the challenge that pre-implantation testing poses for clinical laboratories. They are “the most recent addition to transplantation stakeholders,” he said of clinical labs. They’re critical to preventing transmission of infectious diseases yet they are faced with burdens and complexities.
“As a practicing pathologist in charge of clinical immunology,” he told CAP TODAY, “I see that transplantation testing is becoming a bigger problem every year. We have to do testing for transplantation in a manner acceptable to FDA, which sends inspectors to pathology laboratories quite often. They spend sometimes several days and go over all documents and other details. Yet if you look at the literature, the policies for organ transplantation are not developed by pathologists. Mainly they are done by public health people or surgeons or internal medicine subspecialties. When I look at it as a pathologist, we don’t have any voice in shaping policies.”
A second issue in pre-transplant testing for infectious diseases is how to make the testing more effective. As part of his talk, Matthew J. Kuehnert, MD, director of blood, organ, and other tissue safety at the Centers for Disease Control and Prevention, showed a slide of 17 “notable organ transplant-transmitted infections investigated by public health authorities” between 1985 and 2011. One striking aspect: Most of the organisms involved are not on the list of agents that must be screened for according to Organ Procurement and Transplantation Network (OPTN) policy. They included West Nile virus, babesiosis, rabies, zygomycosis, and the amoeba Balamuthia mandrillaris. Nonetheless, Dr. Kuehnert suggested, it would have been possible to prevent some of these transmissions.
As always, communication is critical, Dr. Kuehnert told CAP TODAY. Some deaths from transplant-transmitted infections resulted from communicating wrong information, passing on information too late, or simply not telling the transplant team a critical fact, he says.
Speaking about infections transmitted by tissue transplantation and how to prevent them, Scott A. Brubaker, CTBS, chief policy officer of the American Association of Tissue Banks, too, highlighted the need for effective communication. “With available technology for improved testing, along with extensive donor screening steps, transfusion and tissue transplantation are safe,” Brubaker said in an interview. “However, rare events do occur. Typically they are related to some type of human error.”
Oversight for organ transplants is separate from oversight for blood and tissue. For organs, regulation originates in HRSA (Health Resources and Services Administration), which contracts with UNOS (United Network for Organ Sharing). UNOS operates OPTN to set policy. “Tissues are regulated under a different system,” Dr. Kuehnert said. “This is confusing for people, even though the bugs don’t care who regulates what.” The FDA establishes regulations for tissue banks.
Infections possibly derived from blood or tissue are reported to the FDA, while responsibility for reporting organ-related infections settles on OPTN members to report to UNOS. The FDA makes it mandatory for tissue banks to report a recipient adverse reaction when there is a reasonable possibility the tissue allograft caused the response. However, clinician reporting to tissue banks is voluntary. The CDC has authority to investigate infections possibly related to organ or tissue transplants, when state and local health departments ask for assistance. Ultimately, recognition of all transplant-related infections—whether from organs or tissue—depends on voluntary reporting by clinicians.
“There is no public health surveillance system for these adverse events,” Dr. Kuehnert told CAP TODAY. “We depend on astute clinicians to make the diagnosis of an infection possibly related to a transplant and to ask whether there are other recipients who could be affected. That’s how most investigations are triggered for organ or tissue transplants.”
Voluntary reporting systems are known to be inefficient in capturing events. To estimate the actual number of transplant-related infections relative to those reported, Dr. Kuehnert points to HIV transmission through blood transfusions. “Based on testing relative to what we actually recognize, it’s about 30 times,” he said. “For organs, the estimated risk of suspected unintended disease transmission is as much as one percent of recipients.”
The notion of an “unintended” transmission of infectious disease may sound odd, implying as it does that some infections are intended. This terminology derives from the scarcity of solid organs. “Many more organs are needed than are available, so the choices are very different than with blood and tissue,” Dr. Kuehnert noted. A liver known to carry hepatitis B or C virus may still be transplanted, because solid organs are needed so badly that the risk of a patient becoming infected is accepted for the benefit of getting an organ. In such situations, transplant recipients are treated “expectantly” for a donor’s infection.
Thus, an unintended transmission is one in which the organ donor is not known to be infected. The rather high one percent rate partly results from another difference between organs and tissue: Except for risk for HIV, behavioral screening or personal history does not exclude the organ donor, as the decision to accept an offer of an organ from a recovery organization is up to the transplant team, with the informed consent of the patient.
Among the 17 instances of infectious disease transmission investigated by the CDC, some raise questions about current transplantation policies and where to draw the line on which organ donors are acceptable in terms of risk. For instance, an outbreak in which four transplant recipients died of rabies transmitted from a common donor provoked a July 10, 2005 article in the New York Times headlined, “Will any organ do?”
Five incidents in which recipients contracted donor-derived meningoencephalitis from West Nile virus, M. tuberculosis, lymphocytic choriomeningitis virus, coccidiomycosis, and Balamuthia “[highlight] the lack of a national policy on whether to bar people with poorly defined neurological disorders as donors,” according to a Dec. 28, 2009 New York Times article Dr. Kuehnert shared.
Over the last decade, he noted, dozens of organ recipients with encephalitis-related illnesses (the majority fatal) have been recognized, and likely there were more unrecognized. Some donors had no evidence of an infectious cause of death, for example, while others had meningoencephalitis of unknown cause, including documentation of abnormal lumbar puncture. Therefore, among these events, the risk of using organ donors with meningoencephalitis was recognized in some cases and unrecognized in others.
Dr. Kuehnert cited a list of possible steps to decrease the number of such cases. One is to determine the appropriate workup of donors with encephalitis of unknown etiology. Another option is a special registry of donors with encephalitis, with special informed consent, testing, and prospective collection of outcome measures. “Another idea,” Dr. Kuehnert told CAP TODAY, “derives from the fact that many times information comes to light after donation in meningoencephalitis. What we found very helpful is when there was an autopsy of the donor, particularly when the cause of the transmission cluster is unknown. You have so much more potential information with an autopsy than if you have no donor specimens to work with in this sort of investigation. This is very important for pathologists working to find the cause.”
Because organs and many types of tissue can be obtained from the same donor, when that donor is infected, the number of infected recipients can be high. In one case eight people were infected with hepatitis C virus from a single donor through organ and tissue implants over almost a two-year period before the source was recognized and further use of that donor’s tissues was stopped (Tugwell BD, et al. Ann Intern Med. 2005;143:648–654).
A more recent incident in which recipients of both solid organs and a tissue implant were infected with HCV from a single donor illustrates the potential danger of multi-recipient transmission of infectious disease, but it also demonstrates a number of other important points. One is the difference between risk factor screening between organ procurement organizations and tissue banks; another is the difference between the sensitivity of serological assays and nucleic acid testing. A third concerns communication. “Transplant surgeons diagnosed both organ recipients as having hepatitis C, but they didn’t realize it could have come from the donor until both teams talked to each other,” Dr. Kuehnert told CAP TODAY.
He cites several recommendations derived from investigation of this incident:
- HCV nucleic acid testing for organ donor screening regardless of risk status.
- Immediate notification of potential donor-derived disease in transplant recipients.
- Implementation of a real-time tracking and notification system for organs and tissues.
Another factor contributing to these transmitted infections was that the tissue bank used a nucleic acid test for HCV (the organ procurement organization used only a serological assay) but a procedural error led to a false-negative result. Thus this recommendation: algorithms or other procedures to ensure accurate reading of test results.
To address the need to update recommendations on organ donor screening and other transplant issues, a guideline called “PHS Guideline for Preventing Transmission of HIV, HBV, and HCV Through Solid Organ Transplantation” is now in the draft stage. Dr. Kuehnert estimates it will be released by the end of the year. One section identifies when nucleic acid testing should be used. In fact, this type of testing is already prevalent: According to a recent unpublished survey, the vast majority of organ procurement organizations routinely use HIV and HCV NAT, compared with about 50 percent in 2008 (Kucirka LM, et al. Am J Transplant. 2009;9:1197–1204).
Dr. Kuehnert’s emphasis on poor communication is supported by an incident in which multi-drug resistant (MDR) E. coli was transmitted to two kidney recipients (MMWR. 2010;59:1642–1646). The urine culture collected by the procurement team showed MDR E. coli. The organ procurement organization notified the transplant centers by phone, but there was no record; information was uploaded to DonorNet more than two weeks later. Another chance to treat this infection properly occurred when kidney perfusate was cultured by the organ procurement organization and found to be positive for MDR E coli; results were communicated to the transplant center 26 days later. As a result, when recipients developed a fever, they were treated empirically, because the transplant team was not aware of the MDR organism. Many recommendations to prevent these types of incidents arose from this analysis, most of them involving improved communication. One change: Try to eliminate fax and phone communication in favor of structured electronic communication with a paper trail.
A number of articles on the problem of transplant transmission of bacteria and potential solutions were published in the June 2012 issue of Transplant Infectious Disease.
Use of tissue transplants is much broader than organ transplantation. Musculoskeletal, cardiac, skin, and soft tissue transplants are common. Tissue allograft distribution surpassed 2 million grafts in 2007, Brubaker said, reporting the results of a 2007 American Association of Tissue Banks survey. He cited a CDC estimate that the incidence of infections from tissue allografts is 0.0004 percent (Proceedings from the HHS workshop on preventing organ and tissue allograft-transmitted infection: priorities for public health intervention. June 2–3, 2005; Atlanta. Page 7).
One reason for this low incidence could be that tissue banks are required to perform nucleic acid testing for HIV and HCV. Another possible reason is that tissue donor behavioral risk screening is required and is more restrictive when determining eligibility. Probably the largest reason for the safety record of tissue transplants is that the vast majority of tissue handled is highly processed, Brubaker said. “Processing mitigates the chance for error to cause transmission,” he explains. “A small set of tissue grafts is lightly processed, so those are the few types that can pose some risk.”
The American Association of Tissue Banks issued the results of a 2007 survey of various practices of tissue banks regarding donor referral/consent/authorization, tissue recovery, donor screening for infectious diseases (testing for HIV-1 and -2, HBV, HCV, and syphilis are required), and processing. “This was the first time we reached out to both AATB-accredited tissue banks and those who perform recovery of donor tissues who are not accredited by AATB,” Brubaker said. One important finding from the survey: “Most tissue banks used an effective, validated method of processing.” Processing is essentially a series of controlled steps that can include a combination of gamma radiation, antibiotic soaks, and often a proprietary method of treatment using chemicals and mechanical agitation.
For the infectious disease testing protocols to work to full potential, Brubaker said, five factors must be met: the qualification of the blood sample was evaluated without error; sample handling requirements were met; the best test kit was used; the test was performed in accordance with the manufacturer’s instructions; and the technician performing the testing made no errors when testing or reporting. In a few well-documented instances of organ or tissue transplant-related disease transmission, one or more of these requirements was not met.
As the population becomes more diverse, and with veterans returning from the Middle East with infections not seen before, there is a larger menu of organisms to look for, says Geoffrey Talmon, MD, associate professor in the Departments of Pathology and Microbiology at the University of Nebraska Medical Center. (He was not a presenter at the ASM session.) As an example of diversity, Dr. Talmon cites Nebraska’s large Sudanese population.
While Dr. Talmon is not involved in formal pre-transplantation screening, he does sometimes identify fungal infections by morphology in livers intended for transplantation. “We do frozen sections on all donor livers looking to evaluate for preexisting liver disease. In donor organs, it is not uncommon to see necrotizing granulomatous inflammation. If it is not sarcoidosis, which is rare in our patient population, it is most likely to be fungal infection.” In Dr. Talmon’s part of the country, such fungal infections are most likely to be histoplasmosis. “An immunocompetent person can contract histoplasmosis through inhalation of aerosolized organisms, but have no clinical symptoms,” he says. These organs are transplanted. However, since an immunosuppressed patient can get disseminated histoplasmosis, the recipient may need to be treated.
In one exceptional case, a recipient contracted schistosomiasis from an organ donated by a Sudanese person. “It blindsided us,” Dr. Talmon says.
Speaking with CAP TODAY, Dr. Nahm discussed what can be done to improve the situation from the laboratory’s viewpoint. One important step would be for industry productivity metrics to recognize the costly nature of performing complex tests in an unscheduled manner. Without that recognition, the laboratory will be understaffed and underfunded. Second, there are few FDA-approved kits for this type of testing. “There are a lot of tests for normal human serum, but sometimes we are dealing with cadaver serum and few assays are approved for cadaver serum,” he says. The route to FDA approval for donor screening assays differs from that for diagnostic assays.
Dr. Nahm cites assays for HIV as an example of where testing can be approved. “Sometimes we get donors in the process of acquiring HIV infection,” he says. “Those samples test negative in the serological assay we use for transplantation screening. So far FDA only recommends serological assays for early detection of HIV. DNA may be useful, but that guideline has not been established.” In addition, he says, the CDC recommends testing of the living donors right before their organ donation, “and the recommendation gives us a very narrow time window for performing the tests.”
Developing more assays is one part of the solution, in Dr. Nahm’s view. “I think pathologists have to actively participate in the decisionmaking process at the level of professional organizations or government,” he says. “This problem is only going to get bigger.”
William Check is a medical writer in Ft. Lauderdale, Fla.