In attempt to determine if DTAC/OPTN guidance document criteria would have identified donors with CNS infection at risk for transmitting to recipients, these criteria were applied to the 12 donors with proven or probable CNS infection. To provide context, donor records were examined for potentially confounding diagnoses at the time of donation that would have allowed them to be considered at low risk for transmission of a pathogen associated with CNS infection transmission. Confounding diagnoses or conditions were identified in six of the 12 donors (50%), and three of these donors transmitted infection to a recipient. Of the six that had no confounding diagnosis, three transmitted infection to recipients. Of these three donors, one had two, one had three, and the other had four of the seven criteria outlined in the guidance document. In two cases, the impression of the local radiologist included “encephalitis”, and in both of these cases, multiple other criteria for encephalitis were present.
Donors with proven CNS infection represented less than 4% of all PDDTE reported to the PSS and 0.05% of all deceased donors recovered during the reporting period of January 2008 through September 2010. Among donors with CNS infection and proven transmission to recipients, many had clinical findings consistent with a confounding diagnosis that would not generally be considered to be associated with a high risk of transmitting a DDI. Six donors with CNS infection did not transmit infection to recipients, likely a result of small inoculum, lack of organism in the transplanted organ, pre-existing immunity, and in one case use of antibiotics in the recipient that likely prevented transmission. Nonetheless, three donors with multiple signs suspicious for CNS infection of unknown etiology and no confounding diagnosis subsequently transmitted CNS infection to recipients. This finding emphasizes the need for those making procurement and organ evaluation and acceptance decisions to maintain a high index of suspicion with heightened awareness and vigilance to minimize the use of organs from donors with likely CNS infection of unknown etiology.
Previous published reports of other cases highlight the high risk to recipients posed by CNS pathogens that do not have reliably effective treatments, as well as the difficulty and challenges (in some cases) identifying donors with CNS infections (1, 4, 6). In the two clusters of lymphocytic choriomeningitis virus reported in 2006, seven of eight recipients died. The first donor was a 51-year-old man found unresponsive; neuroimaging demonstrated a subdural hematoma. He did not have fever or any other specific signs or symptoms suggesting CNS infection. Similarly, the second donor was a 45-year-old woman with a history of hypertension presenting with headache and left-sided weakness and diagnosed with a cerebral infarction. She was afebrile and developed CNS bleeding after receiving tissue plasminogen activator (4). In another report, all four recipients of a donor with rabies died. The donor had signs and symptoms concerning for CNS infection (fever, difficulty swallowing, confusion), but a positive toxicology screen for cocaine and imaging consistent with intracerebral hemorrhage confounded the diagnosis. After rabies was diagnosed in the recipients, questioning of a friend revealed a recent bat bite (6). A report from 2005 of donor-derived WNV infection described neuroinvasive disease in two of the four recipients. The donor suffered a traumatic head injury with epidural hematoma; his wife described that he felt febrile and had mosquito exposure before the bleed (1).
As both our results and the above cases illustrate, the organ donation and transplant community is faced with the difficult task of distinguishing between potentially transmissible CNS infection of unknown cause and other much more common causes of donor death with potentially overlapping or ambiguous and nonspecific clinical findings. The vast majority of donors have anoxia, head trauma, or cerebrovascular accident as a listed cause of death. To assist in identifying donors at high risk for transmissible CNS infection, the DTAC created a guidance document (9) that identifies a number of questions to consider before offering or accepting organs (Table 3). These “warning signs” should be considered in the context of all clinical information available to determine the risk of transmissible CNS infection. In circumstances where CNS infection with a transmissible agent has not been reasonably excluded, additional testing (e.g., lumbar puncture with cerebrospinal fluid [CSF] analysis) or consultation with a neurologist or transplant infectious disease physician may be indicated. In some circumstances (e.g., the potential donor with bacterial meningitis on treatment), it is well established that if prophylaxis is provided to the recipient, these organs can be safely transplanted.
One limitation of a clinical risk factor–based approach to identifying donors with CNS infection is that certain pathogens associated with infection of the CNS (e.g., WNV) are more frequently associated with asymptomatic infection or generalized symptoms without CNS involvement, thus their presence and the potential for transmission is less easily appreciated. Whether a more universal laboratory-based screening approach will ultimately be beneficial is unknown. For example, screening all donors to identify those with asymptomatic WNV may result in significant numbers of false-positive test results that may unnecessarily limit the donor pool. Difficulties of implementing this type of testing include determining the appropriate test to use, the population to target, timely availability of such tests, logistics of sample transport, as well as the cost effectiveness of this approach. In addition, because deceased organ donors often received multiple blood products, in rare cases blood transfusions received by the donor may be the source of donor-derived infection, and in these cases clinical findings in the donor would likely be absent.
Our study has a number of limitations. The OPTN PSS used by DTAC is a required but passive reporting system that collects information only when posttransplant donor or recipient findings are recognized as suggestive of donor-derived disease. Furthermore, DTAC files do not contain all of the available information on donor or recipient; it is possible that additional clinical clues may have been present in donors with and without transmission events. In addition, the clinical criteria identified in the guidance document as suggestive of undiagnosed CNS infection have not been validated and are based on expert opinion. Given the small number of donor-derived CNS infections, validation of such criteria would be very difficult.
Donor-derived disease with pathogens that cause CNS infections remain rare. Nonetheless, transmission of many of these pathogens (e.g., rabies, Balamuthia mandrillaris, WNV, lymphocytic choriomeningitis virus) is associated with significant recipient morbidity and mortality. As with any assessment of donor suitability, a careful balance must be struck between preventing rare events and an excess of caution limiting the number of life-saving organs available. Although risk of transmission of CNS infection cannot be entirely eliminated, a careful assessment of donors for characteristics suspicious for CNS infection (e.g., young donor with fever and lymphocytic pleocytosis in the CSF) and exercising extreme caution in using such donors is critical to minimize the risk of donor-derived infection.
MATERIALS AND METHODS
All PDTTE that were reported to the PSS from January 2008 to September 2010 were reviewed to determine the presence of CNS infection in the donor or recipient. The policy requirements for reporting such PDDTE to the PSS and the limitations on the data available to the DTAC have been described elsewhere (8). Reports were assessed to determine if specific concerns related to potential CNS infection were noted in the report to DTAC (e.g., meningitis or encephalitis in the recipient or donor). Furthermore, all PDDTE involving an organism with a recognized potential to cause CNS infection (e.g., tuberculosis, WNV) were also reviewed.
Cases that met the above criteria were then examined to determine if there was specific evidence of CNS infection in the donor or recipient. This included a review of the donor and recipient records that were available to DTAC, including the clinical presentation, any CSF, results, and laboratory (including microbiology results) and radiographic imaging reports. In many cases, the information (e.g., autopsy findings) was not available at the time of donation but became available at a later time. Proven or probable CNS infection in the donor or recipient, or both, was defined by otherwise unexplained CSF pleocytosis, biopsy of affected tissue, autopsy findings, and testing indicating the presence of infection with organisms associated with encephalitis or meningitis (e.g., Balamuthia species). Determination of DDI in recipients was based on previous categorization by DTAC using the standard classifications: proven, probable, possible, unlikely, intervention without documented transmission (IWDT), and excluded (8). Recipient outcomes were reviewed for those cases determined to be proven, probable, and IWDT cases.
Information related to the donor cause of death as initially reported to the OPTN by the host OPO was reviewed. For cases with documented CNS infection in the donor, we applied criteria abstracted from the DTAC guidance document “Guidance for Recognizing Central Nervous System Infections in Potential Deceased Donors: What to Consider During Donor Evaluation and Organ Offers” to determine if application of these criteria would have identified these donors pre-procurement (9). Criteria included the following: absence of cerebrovascular accident risk factors, recent history of fever or fever within 24 hr of presentation, acute mental status changes or seizure at presentation, radiological studies suggestive of CNS infection (e.g., based on local radiologist reading), CSF pleocytosis, donor immunosuppression, and environmental exposures to pathogens likely to cause meningoencephalitis. These criteria were based on expert opinion and experience, but were not derived from the cohort studied in this paper. To provide further context as to the assessment of the risk of using these donors, records available to DTAC were reviewed to determine if an alternate diagnosis was made that was a plausible explanation for the donor’s neurological symptomatology. For example, a donor with a history of hypertension and stroke admitted with new findings suggestive of cerebrovascular accident on neuroimaging but later found to have WNV would be considered to have a viable alternative diagnosis that might confound the diagnosis of CNS infection. Alternatively, a previously healthy child admitted with fever and mental status changes with no definitive diagnosis would not have an alternative explanation for death and would be considered to be at higher risk for harboring and potentially transmitting CNS infection to the recipients. Donors were thus characterized as having or not having a confounding noninfectious diagnosis. To determine the frequency of any CNS events as cause of death among the larger donor population, the OPTN database was queried as to the cause of death among all deceased donors from 2006 to 2010.
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Keywords:© 2014 by Lippincott Williams & Wilkins
Infectious diseases; Encephalitis; Donor evaluation; Donor-to-host transmission