CLINICAL
AND
TRANSLATIONAL RESEARCH
Solid Organ Transplant Donors With Central Nervous System Infection Daniel R. Kaul,1,8 Shandie Covington,2 Sarah Taranto,2 Michael Green,3 G. Marshall Lyon,4 Shimon Kusne,5 Rachel A. Miller,6 and Emily A. Blumberg7 Background. While donor-derived infections (DDI) remain uncommon, multiple reports describe DDI with pathogens that cause central nervous system (CNS) infection resulting in significant recipient disease. The Ad Hoc Disease Transmission Advisory Committee (DTAC) reviewed the records of potential donor-derived disease transmission events (PDDTE) to describe donor characteristics and outcomes associated with DDI from CNS pathogens. Methods. All PDDTE reported from January 2008 to September 2010 were reviewed for characteristics suggesting CNS infection in the donor or the recipient. Identified cases were further examined to determine if donor CNS infection resulted in recipient infection. Results. Ninety-one PDDTE cases in which there was concern for CNS infection in the donor or recipient were identified. Further review confirmed CNS infection in 12 donors, six of whom transmitted infection to 10 of 15 exposed recipients with five recipient deaths. Pathogens included Balamuthia mandrillaris, Cryptococcus neoformans, lymphocytic choriomeningitis virus, and West Nile virus. Listed cause of death at procurement for these donors included stroke, anoxia, acute disseminated encephalomyelitis, and meningoencephalitis. Confounding diagnoses were present in 6 of 12 donors that would have allowed them to be considered at low risk of transmitting a CNS pathogen. Of the six donors with no confounding conditions, three exhibited at least two suspicious ‘‘DTAC warning criteria’’ for CNS infection. Conclusion. Careful clinical assessment of donors combined with a high index of suspicion for ambiguous or misleading findings associated with CNS infection can reduce, but not eliminate, DDI with CNS pathogens. Keywords: Infectious diseases, Encephalitis, Donor evaluation, Donor-to-host transmission. (Transplantation 2014;98: 666Y670)
ecent reports suggest that donors with central nervous system (CNS) infection are an uncommon but important and sometimes deadly source of donor-derived infection (DDI)
R
S.C. and S.T. are employees of OPTN/UNOS. The authors declare no funding or conflicts of interest. 1 Department of Internal Medicine, Division of Infectious Diseases, University of Michigan Medical School, Ann Arbor, MI. 2 United Network for Organ Sharing, Richmond, VA. 3 Department of Pediatrics and Surgery, Division of Pediatric Infectious Diseases, University of Pittsburgh Medical School, Pittsburgh, PA. 4 Department of Internal Medicine, Division of Infectious Diseases, Emory University School of Medicine, Atlanta, GA. 5 Division of Infectious Diseases, Mayo Clinic in Arizona, Phoenix, AZ. 6 Department of Internal Medicine, Division of Infectious Diseases, University of Iowa Carver College of Medicine, Iowa City, IA. 7 Department of Medicine, Division of Infectious Disease, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA. 8 Address correspondence to: Daniel R. Kaul, M.D., Division of Infectious Diseases, University of Michigan Medical Center, 3120 Taubman Center, 1500 E. Medical Center Dr., SPC 5378, Ann Arbor, MI E-mail: [email protected] D.K., S.K., M.L., M.G., R.M., and E.B. participated in designing and performing the research, analyzing the data, and writing the article. S.C. and S.T. participated in designing and performing the research. Some of the data in this manuscript was presented at the American Transplant Congress, Philadelphia, PA 2011. Abstract#572. Received 6 December 2013. Revision requested 30 December 2013. Accepted 5 February 2014. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0041-1337/14/9806-666 DOI: 10.1097/TP.0000000000000117
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in solid organ transplant recipients (1Y6). Recognition of potentially transmissible pathogens associated with CNS infection in patients being evaluated for organ donation may be challenging as confounding circumstances that suggest a non-transmissible source of illness may be present (e.g., presumed stroke in a patient with amoebic encephalitis, cocaine use in a patient with intracerebral hemorrhage who has unrecognized rabies) (6, 7). Thus, unexpected transmission and subsequent morbidity and even mortality may occur. Currently, the Organ Procurement and Transplantation Network (OPTN) policy requires Organ Procurement Organizations (OPOs) and organ transplant hospitals to report any recognized potential donor-derived disease transmission events (PDDTE) to the OPTN Patient Safety System (PSS). The ad hoc Disease Transmission Advisory Committee (DTAC), an OPTN committee, reviews all potential PDDTE and categorizes each as to the likelihood of disease transmission (8). We conducted a review of all PDDTE reported to DTAC during a 33-month period to determine and describe donor characteristics and outcomes associated with unexpected transmission of pathogens associated with CNS infections in donors.
RESULTS From January 2008 to September 2010, 386 PDDTE were reported to DTAC. During this same period of time, a total of 66,723 organs were procured and transplanted from Transplantation
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Kaul et al.
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TABLE 1.
667
Listed diagnosis for reviewed cases
Bacterial Syphilis (5) Ehrlichia spp. (2) Meningococcus (1) Listeria (1) Lyme disease (1) Nocardia spp. (1)
Fungal
Viral
Mycobacterial
Parasitic
Coccidiomycosis (8) Cryptococcosis (8) Histoplasmosis (5) Blastomycosis (1) Dimorphic fungi (1)
West Nile virus (8) Herpes simplex (1) Rabies (1) LCM virus (1)
Tuberculosis (21)
Amoebic encephalitis (3) Toxoplasmosis (4) Chagas disease (4) Amoeba (2) Babesia spp. (2)
LCM, lymphocytic choriomeningitis virus. Other diagnoses: encephalitis (4), Creutzfeldt-Jacob disease (3), tuberculosis or histo (1), meningitis (1), fever of unknown origin (1).
21,998 deceased donors. Based upon screening criteria defined in methods section, 91 cases (23.3%) were selected for review. These included donors who were ultimately found to have CNS infection and those infected with potential CNS pathogens regardless of site of infection. The mean donor age was 35 years and 34.5% were female. The ultimate diagnoses (made after review of all information available to DTAC) of these 91 cases are listed in Table 1. Tuberculosis, endemic fungi, cryptococcosis, and West Nile virus (WNV) were the most common diagnoses. At the time of procurement, the recorded cause of death in the vast majority of these donors was not infection. Most of these PDDTE were reported to the PSS because of information obtained postmortem including donor tests with results received after transplantation, donor autopsy findings, or a recipient infection that triggered an investigation ultimately identifying donor infection as the source. Identified causes of donor death at the time of procurement included head trauma (22), stroke (18), gunshot wound to the head (12), anoxia (10), intracerebral hemorrhage (8), meningoencephalitis (7), subarachnoid hemorrhage (4), overdose (3), subdural (2), asphyxiation (1), Balamuthia (1), ruptured aneurysm (1), seizure (1), and unknown (1). Twelve of the 91 (13%) donors screened for CNS infection were ultimately determined to have CNS infection. There
TABLE 2.
was no significant difference in age or gender between the 12 donors with CNS infection and the 79 without CNS infection (27.3 years, 25% female vs. 36.2 years, 37.9% female). Table 2 lists the pathogen or disease process and recorded cause of death (at the time of procurement) of the 12 donors with CNS infection. For six of these 12 donors (50%), no transmission to recipients occurred. In one of these cases, the donor had Pneumococcal meningitis, and all recipients received prophylactic antibiotics and none developed disease. The remaining six donors had proven or probable transmission of infection to 10 of 15 (67%) recipients of organs from these donors. Of the 10 recipients with proven donor-derived infection, eight (80%) developed CNS infection. For the other two recipients, one developed disseminated infection with the transmitted organisms (Cryptococcus neoformans) that did not include CNS infection and the other recipient developed serologic evidence of WNV infection but without known disease. Five of the ten recipients with proven or probable donor-derived infection died (50% mortality rate). The flow from initial PDDTE to recipient outcome is illustrated in Figure 1. 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
Characteristics of donors with proven or probable meningoencephalitis
Pathogen/disease
Listed cause of death
Confounding diagnosis
Donors with CNS infection but no donor-derived infection in recipient (6)
Donors with CNS infection resulting in recipient transmission (6)
Amoebic encephalitis Viral encephalitis (3)a Probable CNS tuberculosisb Pneumococcal meninigitisc Meningoencephalitis (2) Encephalitis (1) Meningitis (1) Stroke (1) Anoxia (1) Bacterial meningitis AMI with anoxia Hemorrhagic stroke with history of CNS AVM
Balamuthia mandrillaris (2) Cryptococcus neoformans (2) West Nile virus LCM virus Stroke (2) Anoxia (2) ADEM Meningoencephalitis Stroke; history of cocaine use Stroke; history of stroke MRSA bacteremia
a
Two donors diagnosed by autopsy, one with unexplained lymphocytic pleocytosis. Granulomatous hemorrhagic lesions in brain with possible pulmonary tuberculosis. c Recipient received prophylactic antibiotics. CNS, central nervous system; AVM, arterial-venous malformation; ADEM, acute demyelinating encephalomyelitis; AMI, acute myocardial infarction. b
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FIGURE 1. Flowchart illustrating identification of donorderived central nervous system infections.
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.
DISCUSSION 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
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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
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Kaul et al.
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TABLE 3.
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Characteristics to consider when screening potential donors for CNS infection
Donor characteristic Cerebrovascular accident diagnosis in a patient without risk factors Fever at presentation of illness/admission without clear explanation Altered mental status/seizure at presentation illness/admission CNS imaging characteristics Cerebrospinal fluid abnormalities Immunosuppressed host Environmental exposures
Comments Higher risk potential donors would include young adults or pediatric patients without risk factors with stroke as listed cause of death Early fever with mental status changes would be higher risk; fevers after hospitalization are common and nonspecific in critically ill patients Higher risk would include potential donors with new and otherwise unexplained seizures or mental status changes May be significant overlap with noninfectious causes of CNS disease Higher risk findings include unexplained CSF pleocytosis, low glucose, and elevated protein Examples include treated autoimmune disease, cirrhosis (risk factor for Cryptococcosis), previous transplant Examples include exposures to bat or other potentially rabid animals, heavy mosquito exposure
CNS, central nervous system.
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 factorYbased 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 donorderived 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
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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.
REFERENCES 1.
Centers for Disease Control and Prevention. West Nile virus infections in organ transplant recipientsVNew York and Pennsylvania, AugustY September, 2005. MMWR Morb Mortal Wkly Rep 2005; 54: 1021.
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2. 3. 4. 5.
6. 7. 8. 9.
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Centers for Disease Control and Prevention. Balamuthia mandrillaris Transmitted Through Organ TransplantationVMississippi, 2009. MMWR Morb Mortal Wkly Rep 2010; 59: 1165. Centers for Disease Control and Prevention. Notes From the Field: Transplant-Transmitted Balamuthia mandrillarisVArizona, 2010. MMWR Morb Mortal Wkly Rep 2010; 59: 1182. Fischer SA, Graham MB, Kuehnert MJ, et al. Transmission of lymphocytic choriomeningitis virus by organ transplantation. N Engl J Med 2006; 354: 2235. Rhee C, Eaton EF, Concepcion W, et al. West Nile virus encephalitis acquired via liver transplantation and clinical response to intravenous immunoglobulin: case report and review of the literature. Transpl Infect Dis 2011; 13: 312. Srinivasan A, Burton EC, Kuehnert MJ, et al. Transmission of rabies virus from an organ donor to four transplant recipients. N Engl J Med 2005; 352: 1103. Notes From the Field: Transplant-Transmitted Hepatitis B VirusV United States, 2010. MMWR Morb Mortal Wkly Rep 2011; 60: 1087. Ison MG, Nalesnik MA. An update on donor-derived disease transmission in organ transplantation. Am J Transplant 2011; 11: 1123. Guidance for Recognizing Central Nervous System Infections in Potential Deceased Organ Donors: What to Consider During Donor Evaluation and Organ Offers, http://optn.transplant.hrsa.gov/Content Documents/Guidance_DTAC_CNS_Infections_07-2012.pdf. Accessed November 3, 2013.
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AND
TRANSLATIONAL RESEARCH
Solid Organ Transplant Donors With Central Nervous System Infection Daniel R. Kaul,1,8 Shandie Covington,2 Sarah Taranto,2 Michael Green,3 G. Marshall Lyon,4 Shimon Kusne,5 Rachel A. Miller,6 and Emily A. Blumberg7 Background. While donor-derived infections (DDI) remain uncommon, multiple reports describe DDI with pathogens that cause central nervous system (CNS) infection resulting in significant recipient disease. The Ad Hoc Disease Transmission Advisory Committee (DTAC) reviewed the records of potential donor-derived disease transmission events (PDDTE) to describe donor characteristics and outcomes associated with DDI from CNS pathogens. Methods. All PDDTE reported from January 2008 to September 2010 were reviewed for characteristics suggesting CNS infection in the donor or the recipient. Identified cases were further examined to determine if donor CNS infection resulted in recipient infection. Results. Ninety-one PDDTE cases in which there was concern for CNS infection in the donor or recipient were identified. Further review confirmed CNS infection in 12 donors, six of whom transmitted infection to 10 of 15 exposed recipients with five recipient deaths. Pathogens included Balamuthia mandrillaris, Cryptococcus neoformans, lymphocytic choriomeningitis virus, and West Nile virus. Listed cause of death at procurement for these donors included stroke, anoxia, acute disseminated encephalomyelitis, and meningoencephalitis. Confounding diagnoses were present in 6 of 12 donors that would have allowed them to be considered at low risk of transmitting a CNS pathogen. Of the six donors with no confounding conditions, three exhibited at least two suspicious ‘‘DTAC warning criteria’’ for CNS infection. Conclusion. Careful clinical assessment of donors combined with a high index of suspicion for ambiguous or misleading findings associated with CNS infection can reduce, but not eliminate, DDI with CNS pathogens. Keywords: Infectious diseases, Encephalitis, Donor evaluation, Donor-to-host transmission. (Transplantation 2014;98: 666Y670)
ecent reports suggest that donors with central nervous system (CNS) infection are an uncommon but important and sometimes deadly source of donor-derived infection (DDI)
R
S.C. and S.T. are employees of OPTN/UNOS. The authors declare no funding or conflicts of interest. 1 Department of Internal Medicine, Division of Infectious Diseases, University of Michigan Medical School, Ann Arbor, MI. 2 United Network for Organ Sharing, Richmond, VA. 3 Department of Pediatrics and Surgery, Division of Pediatric Infectious Diseases, University of Pittsburgh Medical School, Pittsburgh, PA. 4 Department of Internal Medicine, Division of Infectious Diseases, Emory University School of Medicine, Atlanta, GA. 5 Division of Infectious Diseases, Mayo Clinic in Arizona, Phoenix, AZ. 6 Department of Internal Medicine, Division of Infectious Diseases, University of Iowa Carver College of Medicine, Iowa City, IA. 7 Department of Medicine, Division of Infectious Disease, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA. 8 Address correspondence to: Daniel R. Kaul, M.D., Division of Infectious Diseases, University of Michigan Medical Center, 3120 Taubman Center, 1500 E. Medical Center Dr., SPC 5378, Ann Arbor, MI E-mail: [email protected] D.K., S.K., M.L., M.G., R.M., and E.B. participated in designing and performing the research, analyzing the data, and writing the article. S.C. and S.T. participated in designing and performing the research. Some of the data in this manuscript was presented at the American Transplant Congress, Philadelphia, PA 2011. Abstract#572. Received 6 December 2013. Revision requested 30 December 2013. Accepted 5 February 2014. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0041-1337/14/9806-666 DOI: 10.1097/TP.0000000000000117
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in solid organ transplant recipients (1Y6). Recognition of potentially transmissible pathogens associated with CNS infection in patients being evaluated for organ donation may be challenging as confounding circumstances that suggest a non-transmissible source of illness may be present (e.g., presumed stroke in a patient with amoebic encephalitis, cocaine use in a patient with intracerebral hemorrhage who has unrecognized rabies) (6, 7). Thus, unexpected transmission and subsequent morbidity and even mortality may occur. Currently, the Organ Procurement and Transplantation Network (OPTN) policy requires Organ Procurement Organizations (OPOs) and organ transplant hospitals to report any recognized potential donor-derived disease transmission events (PDDTE) to the OPTN Patient Safety System (PSS). The ad hoc Disease Transmission Advisory Committee (DTAC), an OPTN committee, reviews all potential PDDTE and categorizes each as to the likelihood of disease transmission (8). We conducted a review of all PDDTE reported to DTAC during a 33-month period to determine and describe donor characteristics and outcomes associated with unexpected transmission of pathogens associated with CNS infections in donors.
RESULTS From January 2008 to September 2010, 386 PDDTE were reported to DTAC. During this same period of time, a total of 66,723 organs were procured and transplanted from Transplantation
& Volume 98, Number 6, September 27, 2014
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Kaul et al.
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TABLE 1.
667
Listed diagnosis for reviewed cases
Bacterial Syphilis (5) Ehrlichia spp. (2) Meningococcus (1) Listeria (1) Lyme disease (1) Nocardia spp. (1)
Fungal
Viral
Mycobacterial
Parasitic
Coccidiomycosis (8) Cryptococcosis (8) Histoplasmosis (5) Blastomycosis (1) Dimorphic fungi (1)
West Nile virus (8) Herpes simplex (1) Rabies (1) LCM virus (1)
Tuberculosis (21)
Amoebic encephalitis (3) Toxoplasmosis (4) Chagas disease (4) Amoeba (2) Babesia spp. (2)
LCM, lymphocytic choriomeningitis virus. Other diagnoses: encephalitis (4), Creutzfeldt-Jacob disease (3), tuberculosis or histo (1), meningitis (1), fever of unknown origin (1).
21,998 deceased donors. Based upon screening criteria defined in methods section, 91 cases (23.3%) were selected for review. These included donors who were ultimately found to have CNS infection and those infected with potential CNS pathogens regardless of site of infection. The mean donor age was 35 years and 34.5% were female. The ultimate diagnoses (made after review of all information available to DTAC) of these 91 cases are listed in Table 1. Tuberculosis, endemic fungi, cryptococcosis, and West Nile virus (WNV) were the most common diagnoses. At the time of procurement, the recorded cause of death in the vast majority of these donors was not infection. Most of these PDDTE were reported to the PSS because of information obtained postmortem including donor tests with results received after transplantation, donor autopsy findings, or a recipient infection that triggered an investigation ultimately identifying donor infection as the source. Identified causes of donor death at the time of procurement included head trauma (22), stroke (18), gunshot wound to the head (12), anoxia (10), intracerebral hemorrhage (8), meningoencephalitis (7), subarachnoid hemorrhage (4), overdose (3), subdural (2), asphyxiation (1), Balamuthia (1), ruptured aneurysm (1), seizure (1), and unknown (1). Twelve of the 91 (13%) donors screened for CNS infection were ultimately determined to have CNS infection. There
TABLE 2.
was no significant difference in age or gender between the 12 donors with CNS infection and the 79 without CNS infection (27.3 years, 25% female vs. 36.2 years, 37.9% female). Table 2 lists the pathogen or disease process and recorded cause of death (at the time of procurement) of the 12 donors with CNS infection. For six of these 12 donors (50%), no transmission to recipients occurred. In one of these cases, the donor had Pneumococcal meningitis, and all recipients received prophylactic antibiotics and none developed disease. The remaining six donors had proven or probable transmission of infection to 10 of 15 (67%) recipients of organs from these donors. Of the 10 recipients with proven donor-derived infection, eight (80%) developed CNS infection. For the other two recipients, one developed disseminated infection with the transmitted organisms (Cryptococcus neoformans) that did not include CNS infection and the other recipient developed serologic evidence of WNV infection but without known disease. Five of the ten recipients with proven or probable donor-derived infection died (50% mortality rate). The flow from initial PDDTE to recipient outcome is illustrated in Figure 1. 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
Characteristics of donors with proven or probable meningoencephalitis
Pathogen/disease
Listed cause of death
Confounding diagnosis
Donors with CNS infection but no donor-derived infection in recipient (6)
Donors with CNS infection resulting in recipient transmission (6)
Amoebic encephalitis Viral encephalitis (3)a Probable CNS tuberculosisb Pneumococcal meninigitisc Meningoencephalitis (2) Encephalitis (1) Meningitis (1) Stroke (1) Anoxia (1) Bacterial meningitis AMI with anoxia Hemorrhagic stroke with history of CNS AVM
Balamuthia mandrillaris (2) Cryptococcus neoformans (2) West Nile virus LCM virus Stroke (2) Anoxia (2) ADEM Meningoencephalitis Stroke; history of cocaine use Stroke; history of stroke MRSA bacteremia
a
Two donors diagnosed by autopsy, one with unexplained lymphocytic pleocytosis. Granulomatous hemorrhagic lesions in brain with possible pulmonary tuberculosis. c Recipient received prophylactic antibiotics. CNS, central nervous system; AVM, arterial-venous malformation; ADEM, acute demyelinating encephalomyelitis; AMI, acute myocardial infarction. b
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FIGURE 1. Flowchart illustrating identification of donorderived central nervous system infections.
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.
DISCUSSION 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
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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
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Kaul et al.
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TABLE 3.
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Characteristics to consider when screening potential donors for CNS infection
Donor characteristic Cerebrovascular accident diagnosis in a patient without risk factors Fever at presentation of illness/admission without clear explanation Altered mental status/seizure at presentation illness/admission CNS imaging characteristics Cerebrospinal fluid abnormalities Immunosuppressed host Environmental exposures
Comments Higher risk potential donors would include young adults or pediatric patients without risk factors with stroke as listed cause of death Early fever with mental status changes would be higher risk; fevers after hospitalization are common and nonspecific in critically ill patients Higher risk would include potential donors with new and otherwise unexplained seizures or mental status changes May be significant overlap with noninfectious causes of CNS disease Higher risk findings include unexplained CSF pleocytosis, low glucose, and elevated protein Examples include treated autoimmune disease, cirrhosis (risk factor for Cryptococcosis), previous transplant Examples include exposures to bat or other potentially rabid animals, heavy mosquito exposure
CNS, central nervous system.
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 factorYbased 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 donorderived 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
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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.
REFERENCES 1.
Centers for Disease Control and Prevention. West Nile virus infections in organ transplant recipientsVNew York and Pennsylvania, AugustY September, 2005. MMWR Morb Mortal Wkly Rep 2005; 54: 1021.
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Centers for Disease Control and Prevention. Balamuthia mandrillaris Transmitted Through Organ TransplantationVMississippi, 2009. MMWR Morb Mortal Wkly Rep 2010; 59: 1165. Centers for Disease Control and Prevention. Notes From the Field: Transplant-Transmitted Balamuthia mandrillarisVArizona, 2010. MMWR Morb Mortal Wkly Rep 2010; 59: 1182. Fischer SA, Graham MB, Kuehnert MJ, et al. Transmission of lymphocytic choriomeningitis virus by organ transplantation. N Engl J Med 2006; 354: 2235. Rhee C, Eaton EF, Concepcion W, et al. West Nile virus encephalitis acquired via liver transplantation and clinical response to intravenous immunoglobulin: case report and review of the literature. Transpl Infect Dis 2011; 13: 312. Srinivasan A, Burton EC, Kuehnert MJ, et al. Transmission of rabies virus from an organ donor to four transplant recipients. N Engl J Med 2005; 352: 1103. Notes From the Field: Transplant-Transmitted Hepatitis B VirusV United States, 2010. MMWR Morb Mortal Wkly Rep 2011; 60: 1087. Ison MG, Nalesnik MA. An update on donor-derived disease transmission in organ transplantation. Am J Transplant 2011; 11: 1123. Guidance for Recognizing Central Nervous System Infections in Potential Deceased Organ Donors: What to Consider During Donor Evaluation and Organ Offers, http://optn.transplant.hrsa.gov/Content Documents/Guidance_DTAC_CNS_Infections_07-2012.pdf. Accessed November 3, 2013.
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