American Journal of Transplantation 2015; 15: 547–554 Wiley Periodicals Inc.
C
Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons doi: 10.1111/ajt.13006
Brief Communication
Transfusion Transmitted Infections in Solid Organ Transplantation A. K. Mezochow1, R. Henry1, E. A. Blumberg2 and C. N. Kotton3,* 1
U.S. Department of Health and Human Services, Office of the Assistant Secretary for Health, Division of Blood and Tissue Safety and Availability, Washington, DC 2 Department of Medicine, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA 3 Division of Infectious Disease, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA Corresponding author: Camille Kotton, [email protected]
While the risk of infectious disease transmission through blood transfusion has been greatly reduced as a result of improved screening methods, transfusion-transmissible infections remain a concern for transplant recipients, especially those receiving multiple transfusions. Although transfusion and transplant recipients are at risk for similar infections, the current reporting requirements for infections transmitted by transfusions and organ transplantation vary greatly and remain distinctly separate with no communication between reporting systems. This article reviews 23 past reports of transfusion-transmitted infections in organ recipients acquired through transfusions. While cytomegalovirus was a major focus of such reports in the 1980s, more recent reports have focused on West Nile virus transmission. Additionally, this article highlights challenges in determining transfusion-transmitted infection risk in transplant recipients related to the current reporting systems. Abbreviations: CDC, U.S. Centers for Disease Control and Prevention; CMV, cytomegalovirus; FDA, U.S. Food and Drug Administration; FFP, fresh frozen plasma; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; MMWR, Morbidity and Mortality Weekly Report; NAT, nucleic acid test; NHSN, National Healthcare Safety Network; OPTN, Organ Procurement Transplantation Network; PLT, platelets; RBC, red blood cell; SOT, solid organ transplantation; TTI, transfusion-transmitted infection; WB, whole blood; WNV, West Nile virus Received 08 May 2014, revised 13 August 2014 and accepted for publication 28 August 2014
Introduction Since the introduction of blood product screening for transfusion-transmitted infections (TTIs) in the mid-1980s, the risk of acquiring an infection from a transfusion has significantly decreased as a result of antibody and nucleic acid testing (NAT) (1). Approximately 20,933,000 red blood cell (RBC) and non-RBC units (i.e. plasma, platelets and cryoprecipitate) were transfused in the U.S. in 2011, resulting in 36 reported posttransfusion viral infection transmissions, or approximately one for every 585,726 units transfused (2). From 2009 through 2013, 10% (19/ 190) of transfusion related fatalities were caused by microbial infections (3). Modeling has estimated the risk of acquiring human immunodeficiency virus (HIV) through a transfusion as 1 per 1,467,000 units transfused, while the risk of acquiring hepatitis C virus (HCV) and hepatitis B virus (HBV) are estimated at 1 per 1,149,000 and 1 per 765,000– 1,006,000 units transfused, respectively (1,4,5). Nonetheless, TTIs remain a concern for individuals receiving multiple transfusions, particularly for those who are also immunosuppressed, including solid organ transplant (SOT) recipients. Currently, the frequency with which transplant patients develop transfusion related infectious diseases is unknown (6). These events are likely under reported due to both the failure to recognize the transfusion as the infection source, particularly in cases of infections with long incubation periods (such as hepatitis), as well as the lack of required comprehensive reporting. Similar infections can be transmitted through transfusion and transplantation. However, current reporting systems for TTIs and organ donor derived infections exist as separate systems, increasing the difficulty in identifying the rates of such infections (6). Despite the Organ Procurement Transplantation Network’s (OPTN) requirements for all donor derived infectious diseases to be reported, mandatory reporting is not uniformly required for TTIs (7). Due to this lack of mandatory reporting for TTIs, there is currently no system for aggregating data on the rate of TTIs in transfusion recipients in the U.S. Additionally, while there is comparable donor screening for these infections involving screening questionnaires and laboratory tests, some key differences remain (Table 1).
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Mezochow et al Table 1: Blood and SOT donor infection screening: exclusionary criteria1
Bacterial Syphilis4 Parasitic Babesiosis Chagas disease Leishmaniasis Malaria Prion VCJD Viral CMV Dengue HBV HCV HTLV HIV WNV
Blood donor deferral, questionnaire
Blood donor deferral, test2
SOT donor screening3, questionnaire
SOT donor screening3, test
Yes
Treponema pallidum antibodies
Yes
Treponema pallidum antibodies
Yes Yes No Yes
No T. cruzi antibodies No No
No Yes No Yes
No No No No
Yes
No
Yes
No
No No Yes Yes No Yes No
Anti-CMV only upon request No HBsAg, Anti-HBc, HBV DNA Anti-HCV, HCV RNA Anti-HTLV I/II Anti-HIV 1/2, HIV RNA WNV RNA
No No Yes Yes No Yes Yes
Anti-CMV No HBsAg, anti-HBc, anti-HBs Anti-HCV No Anti-HIV 1/2 No
Data from the Full-Length Blood Donor History Questionnaire (39), Donor Risk Assessment Interview (Donor >12 yrs old) (40), OPTN Minimum Procurement Standards for an Organ Procurement Organization Policy 2.2.4 (7) and A Compendium of Transfusion Practice Guidelines (41). 2 Blood units are pooled for initial screening. If a pool tests positive, individual units are then tested and, if confirmed positive, discarded. 3 In the case of SOT donors, a positive for a deferral question or test does not necessarily indicate that a donor will not be used, but instead falls to the discretion of the recipient(s) and their transplant physicians. 4 Organ donors are not deferred for syphilis. 1
This report aims to explore previous case reports of infections in transplant patients acquired through transfusion and to elucidate areas in which further study is needed.
from each manuscript. Any information not included in the event report was listed as unspecified within the tables.
Results Methods A systematic search of the PubMed database was conducted on February 18, 2014 for studies relating to transfusion transmitted infectious disease acquired during or related to transplantation. The Morbidity and Mortality Weekly Report (MMWR), which functions as the primary publication vehicle for the U.S. Centers for Disease Control and Prevention (CDC) to report on investigations relating to infection transmissions, was also searched. Manuscripts were eligible for inclusion if the transfusiontransmission event and transplantation occurred in the United States. In order for a manuscript to be included, the authors had to determine either directly (through the testing of a blood donor or donation) or indirectly (through ruling out infection in the allograft donor) that the infection was a result of transfusion. No articles were excluded based on their date of publication or language. The database search utilized the terms ‘‘(organ) and (transplant) and (transfusion) and ((transmission) or (acquired))’’. A title search was performed for manuscripts to assess their relevancy with all unrelated articles excluded. Following the title review, abstracts of relevant titles were evaluated to assess whether articles fit the search criteria. A title search of footnotes was also performed for those seeming to meet the inclusion criteria to recover articles that may have been missed by the initial search. Full text copies were then retained and reviewed for all relevant manuscripts. Details surrounding the transplant (e.g. organ), transfusion (e.g. units transfused, infected component, other recipients), transmission (e.g. infectious agent, incubation) and recipient outcome were all extracted
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Two hundred and thirty nine titles were found during the initial title search of PubMed, 93 from the MMWR and 79 from the footnote search. The abstracts were then reviewed and 22 manuscripts were identified as meeting inclusion criteria and are detailed in Tables 2 and 3. Excluding cases of cytomegalovirus (CMV), there were 11 reported cases of TTIs related to transplants ranging from 1992 to 2008 (Table 2) (8–18). Six of these reports were cases of West Nile virus (WNV), which resulted in nine transmissions to SOT recipients (8,10–14). The other five reports included two cases of malaria, two cases of babesiosis and one case of HIV (9,15–18). Of the recipients who developed infections, six had received kidneys, four had received hearts and three received livers. The range of the total blood products received by infected recipients was 2 to 174 units. Plasma, RBCs, whole blood and platelets were all shown to be potential sources of infection, with the infectious unit type, as identified in the reports, being nearly evenly split between red blood cells (4/11), frozen plasma (3/11) and platelets (3/11). In recipients who were infected with WNV, the incubation period averaged 13 days and was American Journal of Transplantation 2015; 15: 547–554
Transfusion Infections in Organ Transplants Table 2: Reported cases of transfusion related infections in transplant recipients Total blood Infectious
Organ
product units
Infected blood
Timing of
Year
agent
transplanted
received
component1
transfusion
2008
WNV
Heart
10 (organ donor)
FFP
2 days before donor declared brain dead
8 days
Lived, but could not walk without assistance
CDC (9)
2008
HIV
Kidney
Unspecified
FFP
Unspecified
N/A3
Started on anti-retroviral therapy
CDC (10)
2006
WNV
Kidney
2
RBC
4 days posttransplant
17 days
Recovered
CDC (11)
2002
WNV
Liver
24
PLT
6 days posttransplant
13 days
Recovered
Pealer et al (12) 4 Murtagh et al (13)
2002 2002
WNV WNV
Kidney Heart
RBC PLT & WB
Unspecified During ‘‘perioperative period’’5
10 days 2 weeks
Died Lived, but developed severe neurologic impairment.
Iwamoto et al (14) 2
2002
WNV
Kidney (1)
FFP
Day and day before donor declared brain dead
16 days
Recovered
Kidney (2) Heart Liver Heart
19 days 12 days 9 days 35 days
Died Recovered Recovered Recovered
Reference CDC (8)
2
Lux et al (15)
2000
B. microti
Talabiska et al (16)
1995
Barat et al (17)
1993
Malaria, P. ovale Malaria, P. ovale
Perdrizet et al (18)
1992
B. microti
Unspecified 174
53 (organ donor)
Incubation
Recipient
Other recipient
status
outcomes
65
RBC
5 days post-transplant
Liver
Unspecified
PLT
5 weeks6
Recovered
Liver
110
Unspecified, prior to transplant Unspecified, during hospitalization for transplant
1 month7
Recovered
1 day post-transplant
10 days
Recovered
Kidney
2
Unspecified
RBC
Patient who received RBC from donor was asymptomatic, but had WNV antibodies Second patient received RBC from donor, but died shortly thereafter Patient who received donor’s FFP had received transplant 5 years prior and was on immunosuppressants. Patient developed WNV-associated myelitis Patient who received donor’s RBC developed WNV fever and was WNV IgM antibody positive. Unspecified RBC recipient (from WB donor) was well and negative for WNV antibodies. Other nine donors who received PLT from PLT donor were asymptomatic for WNV No other patients received components from this donor
No other patients received components from this donor Unspecified Patient who received RBC from donor was asymptomatic, but had antibodies to P. ovale Unspecified
1
RBC denotes red blood cells, FFP denotes fresh frozen plasma, PLT denotes platelets, WB denotes whole blood. Organ donor received infectious blood unit in hospitalization immediately before becoming an organ donor (death unrelated to infectious blood unit). Infection was passed from donor onto organ recipients. 3 Infection was discovered through look-back investigation 5 months posttransplant. Recipient was asymptomatic at time of infection discovery. 4 Report also includes case of liver recipient described above (CDC. MMWR. 2002; 51(39): 879). This case is not duplicated in this row. 5 This term is per author designation as used in their manuscript. 6 Onset of illness was 5 weeks posttransplant. Patient had a history of prior transfusion (date unspecified), which her infection was traced to. 7 Patient was diagnosed with malaria one month following transplant. Time to onset of illness was unspecified. 2
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550 Multi-city (46 transplant centers)
Stanford, CA
Pittsburgh, PA
Portland, OR
1976–1978 1980–1981
1984–1985
Chou et al (26)
Cleveland, OH
Pittsburgh, PA
1984–1986
Gorensek et al (25)
Cleveland, OH
1981–1983
1984–1987
Gorensek et al (30)
Omaha, NE
Dummer et al (29) J Infect Dis 1985; 152(6): 1182–91. Preiksaitis (30)
1985–1989
Stratta et al (23,24)
Rochester, MN
Unspecified
1988–1990
Paya et al (22)
Boston, MA
Rubin et al (28)
1987–1990
Falagas et al (21)
Pittsburgh, PA
1984–1985
1990
~ez et al (20) Man
Location
Singh et al (27)
Year
Reference
Table 3: Reported cases of CMV in transplant recipients
No (1976–78) Yes (1980–81)
No
No
No
Most patients received almost exclusively leukocyte-poor blood screened for CMV. Some components irradiated
No
No
No
No
No
Leukoreduced or screened blood
Of those receiving renal transplants from deceased donors, only one recipient (1/32) became seropositive for CMV following transfusion with two units of leukocytes and all of the recipients receiving one unit remained CMV seronegative. This study found 46% of blood donors to be CMV seropositive and estimated that 89% of those receiving one unit and 99% of those receiving two units would have been exposed to a CMV seropositive donation In this cohort of liver transplant recipients, one of 12 (8%) CMV seronegative recipients receiving a liver from a seronegative donor developed CMV infection This study found that of CMV seronegative patients receiving CMV negative allografts, 17% receiving conventional immunosuppression and 24% with an antilymphocyte preparation seroconverted (approximately 20% overall). Of the patients who did not receive a transfusion and were CMV negative and received CMV negative allografts, none seroconverted Nine of 14 patients either receiving a heart or heart-lung transplant who were CMV seronegative prior to transplant and had a seronegative organ donor developed infection following transplantation Of the patients receiving unscreened blood (1976–78) who were initially negative for anti-CMV and received a seronegative heart, 20% (1/5) became CMV positive. All of the patients receiving pre-screened, CMV negative blood (1980–81) who were also initially CMV seronegative and received a CMV negative organ remained CMV seronegative (0/8)
Two individuals (13%) who were part of a cohort study and received CMV negative organs developed CMV infection as a result of transplant related transfusions. Only one of those two individuals went on to develop symptomatic CMV In this cohort, found 20% (9/44) of newly acquired CMV infection in liver recipients to be as a result of transplant related transfusions Two of 15 CMV seronegative transplant patients receiving livers from seronegative donors developed CMV infection post-transplant as a result of blood transfusions received within the month prior to transplant In cohort of liver transplant patients, found 22% incidence of CMV transfusion transmission resulting in disease in cases where both donor and recipient were CMV negative Four of 14 (28%) liver recipients initially CMV seronegative who received organs from similarly seronegative donors developed CMV infection. Two of these recipients then also went on to develop symptomatic CMV Of 11 CMV seronegative heart recipients who received a seronegative organ, five developed CMV infection
Notes
Mezochow et al
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slightly over one month for those infected with Plasmodium ovale (8,10–14,16–17). All of the donations where a time of year was specified for the WNV transmissions occurred in either July (1/5), August (2/5) or September (2/5) and the transfusions took place in Louisiana, South Dakota, Michigan, Texas and Georgia (8,10–14). The blood donations resulting in the two cases of babesiosis were obtained during the summer from donors in New York and Connecticut (15,18). In both instances of malaria transmissions, the blood donors had previously traveled to an area endemic for malaria (16–17). The four reports discussing WNV transmission during 2002 occurred prior to the licensing and requiring of WNV NAT assays in 2005 (11–14,19). In two of the eleven reports, the organ donor (instead of the recipient) was the one to receive the infectious unit just prior to transplantation, with subsequent transmission to the organ recipients (8,14). In one of these cases, the donor gave organs to four different recipients, all of whom developed WNV infection (14). In the case of a liver recipient described by Talabiska et al, the Plasmodium ovale infection was discovered post-transplant, but was likely related to a pretransplant platelet transfusion administered to the recipient (16). All recipients outlined in the eleven reports developed symptomatic disease, with the exception of the HIV transmission. All nine of the individuals who were infected with WNV developed severe neurologic complications and at least five of these recipients required mechanical ventilation during their hospital stay (8,14). Ultimately, two of the WNV patients died and at least two developed lasting neurologic complications (8,12–14). Additionally, all of the other recipients who had received the WNVcontaminated blood products either remained asymptomatic or only developed mild infection. The one exception to this was a patient who was immunosuppressed as a result of a kidney transplant five years prior and then developed WNV-associated myelitis after receiving a transfusion with WNV infected plasma during a spinal surgery (10). In addition to the eleven cases outlined in Table 2, there were eleven reports (from twelve manuscripts) that discussed CMV transmission resulting from transfusions related to transplantation (Table 3) (20–31). All twelve of these manuscripts report on the outcomes of transplant recipient cohorts where a portion of the cohort was CMV negative at the time of transplant and received an organ from a seronegative donor, but then developed CMV infection following a transfusion. While all twelve articles illustrate cases of transfusion transmission, only two of these manuscripts explicitly examined the effects of transfusion on CMV (20,26). The reports are from the years 1976–1990, prior to the uniform use of leukoreduced or CMV seronegative blood in SOT recipients. Reported rates of CMV in initially CMV negative transplant recipients American Journal of Transplantation 2015; 15: 547–554
receiving seronegative organs varied among those receiving untreated blood units with a median infection rate of 20%. Transfused blood was only consistently screened for CMV antibodies in one of these ten cohorts and one other study irradiated some of the blood used prior to transfusion (26,30). When blood products were pre-screened for CMV by serology, none of the recipients developed CMV infection (30).
Discussion While there are relatively few reports of TTIs in SOT recipients, these transmissions are likely underestimated due to a lack of knowledge about the risks, as well as the absence of robust reporting systems for TTIs. Despite their relative infrequency, these events are notable for the resultant consistently poor patient outcomes. While CMV was found to be the most commonly reported TTI, reports of CMV in organ donors as a result of transfusions dropped off in the 1990s likely due to the use of leukoreduced and CMV screened blood for CMV negative organ recipients. Despite the prevalence of CMV remaining largely consistent in the general population (32), there is now the option for adopting strategies in immunocompromised patients to prevent CMV transmission. In the early 1990s, it was determined that providing leukocyte reduced or CMV seronegative blood products to immunosuppressed individuals was highly effective in preventing CMV transmission in patients who were CMV negative and this has now become common practice for CMV seronegative recipients (33). The majority of more recent reports involve WNV. This is likely due both to epidemics of WNV in recent years and enhanced clinician awareness of the possibility of transfusion associated WNV transmission due to the large amount of publicity it has received since it was initially discovered to be transmissible in 2002 (34–36). Additionally, the onset of WNV symptoms typically occurs within weeks following the transfusion when transplant patients are still being closely monitored. The other two infections in which multiple cases were reported, babesiosis and malaria, are also infections that have relatively short incubation periods, making them easier to associate with the transfusion. In contrast, the reported HIV case was only identified upon tracing back a blood donor’s past donations when it was later discovered that the blood donor was positive for HIV. HIV, HBV and HCV all have incubation periods that can last years, making them significantly more difficult to trace back to their original source or associate them with transfusion. These cases highlight the importance of seasonality and geography in considering possible transfusion transmissions as well as the importance of insect vectors in TTIs. Of the 11 non-CMV TTIs identified in this review, 10 were vector borne infections: 6 WNV, 2 malaria and 2 babesiosis. 551
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Both cases of babesiosis occurred in high prevalence areas during summer months. While the locations where WNV transmissions occurred were more geographically varied, these all originated in areas with reported WNV activity and also clustered around summer months as is consistent with the seasonality of WNV. Although these reports illustrate the decline in transfusion-transmitted WNV cases since the implementation of blood donor screening, transmissions do continue to occur. Additionally, there is currently no blood donor screening test in use for malaria or babesiosis. These cases underscore the need for physicians to consider the possibility of TTIs in SOT recipients who received blood, especially in cases involving a vector borne infection and where an infection does not seem demographically appropriate (e.g. a babesiosis infection where neither the SOT donor nor recipient spent time in an endemic area). Transplant physicians should also be aware of the ability to trace back a blood donation to the original donor, which is important not only for determining the source of infection, but also for identifying other potentially infectious units or infected patients. While these eleven reports illustrate the need for physicians to consider the possibility of TTIs related to transfusions just before, during, and immediately following transplantation, they also demonstrate the potential importance of recent transfusions that occur in the organ donor (8,14). The report by Iwamoto et al also showed the potential for TTIs in organ donors to be particularly challenging, both related to lack of suspicion for these events and the efficiency of transmission to multiple recipients (14). Such cases also illustrate the potential for multiple recipients receiving organs from the transfused donor to be infected. This review has multiple limitations, primarily due to the limited reports on which it is based and the likely underreporting of TTIs. Given the absence of a required reporting system for nonfatal TTIs, there are likely more TTIs occurring than are reported in the literature and thus included in this review, making it difficult to understand the true risk of TTIs for transplant recipients. A more robust reporting system would be required; additionally, events with longer incubation periods would need to be investigated for the potential of TTI. The absence of any established mechanisms for communication between the transplant and transfusion communities increases the likelihood that TTIs may fall through the gaps. While the OPTN requires reporting of any unexpected transmission of infection from organ donor to recipient allowing for active surveillance, there is no equivalent requirement for TTIs (7). At present, there is no mandatory reporting regulation for adverse reactions resulting from transfusions, with two exceptions that require reporting to the U.S. Food and Drug Administration (FDA): when an adverse reaction leads to death or when a manufacturing error occurs that may impact the ‘‘safety, purity or potency’’ 552
of the blood product (37). The FDA also runs the voluntary FDA Adverse Events Reporting System (FAERS), which allows healthcare professionals and consumers to report any adverse reactions relating to blood products directly to the FDA. Additionally, the CDC hosts their own surveillance program for infections acquired through transfusion. Due to HIV’s status as a nationally notifiable disease, all newly diagnosed infections, including those acquired via transfusion, must be reported to the CDC. However, a case is only investigated as a TTI if a transfusion is reported and no other risk factors are present (38). For HCV and HBV, the CDC primarily conducts only passive surveillance, without mandatory reporting. In 2010, the CDC also launched the Hemovigilance module within the National Healthcare Safety Network (NHSN) to allow for hospital level reporting of adverse events associated with transfusions. NHSN reporting is voluntary, plagued by a low participation rate (of approximately 4,600 transfusing facilities, fewer than 200 are enrolled and less than half contribute data regularly), and likely to only capture acute infections (38). Although NAT has greatly reduced the risk of TTIs, instances of transmission do occur. As a result of their rarity, physicians assessing a patient posttransplant may be less likely to consider this risk. Creating a mechanism for combining surveillance or allowing for communication across the transplant and transfusion systems would potentially facilitate the determination of whether an infection is derived from a transfusion, organ donor or other factor. Such communication is imperative in enhancing safety for other organ and blood product recipients at risk for such infections from the same donor. Further challenges in determining whether an infection is transfusion acquired result from the many blood products that may be given around the time of transplant. As was seen in the case reported by Perdrizet et al the cause of infection may be difficult to distinguish from other events such as acute organ rejection or donor derived or hospital acquired infections, ultimately delaying diagnosis and treatment (18). Additionally, due to immunosuppression, infections in transplant recipients may be associated with uncommon manifestations that make them more difficult to recognize. Presently, data relating to transfusions are often fragmented and separated into the different silos of blood and transfusion centers, with the possibility of a single recipient’s transfused blood components originating from multiple blood collection centers. While there are systems for hospitals to communicate with blood centers, it can be very difficult to trace back an infection to one of the many donors from whom a patient received blood, especially if a blood sample is no longer on file at the blood collection centers. Transplant programs should consider the risk of TTIs when investigating the cause of an infection in organ recipients, American Journal of Transplantation 2015; 15: 547–554
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especially in the case of vector borne infections. Creating an integrated surveillance system and facilitating communication across the transfusion and transplant networks could help in establishing TTI risk. Such a system could aid in increasing the reporting of TTIs related to organ transplantation, allowing for a better understanding of the true TTI risk, ultimately leading to greater awareness, faster diagnosis of infections and enhanced safety in organ transplant recipients.
Disclaimer The findings and conclusions of this report are those of the authors and do not necessarily represent the official position of the U.S. Department of Health and Human Services.
Disclosure The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.
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new-test-finds-west-nile-in-donated-blood.html. Accessed July 20, 2014. Altman LK, Testing Finds, Blood Donors, Are Carrying, Nile Virus. The New York Times. 2003 Sept 19. Available at: http://www. nytimes.com/2003/09/19/us/testing-finds-blood-donors-are-carrying-nile-virus.html. Accessed July 20, 2014. Food and Drug Administration Center for Biologics Evaluation and Research. Guidance for industry: Biological product deviation reporting for blood and plasma establishments. Rockville, MD: Food and Drug Administration, 2006. Glynn S, Establishing A. U.S. donor transfusion-transmissible infection monitoring system—next steps. Presented at the Advisory Committee on Blood and Tissue Safety and Availability. Rockville, MD, December 5, 2013. AABB. Full-length donor history questionnaire. 2008; Available at: https://www.aabb.org/resources/donation/questionnaires/Documents/dhq/v1-3/Full-LengthDonorHistoryQuestionnairev1.3.pdf. Accessed April 30, 2014. American Association of Tissue Banks. Donor risk assessment interview (donor >12 yrs old). 2012. Available at: http://www.aatb. org/Donor-Risk-Assessment-Interview-DRAI. Accessed April 30, 2014. Vassallo R, Bachowski G, Benjamin RJ, et al. A compendium of transfusion practice guidelines, 2nd ed. Washington, DC: American Red Cross, 2013.
American Journal of Transplantation 2015; 15: 547–554
C
Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons doi: 10.1111/ajt.13006
Brief Communication
Transfusion Transmitted Infections in Solid Organ Transplantation A. K. Mezochow1, R. Henry1, E. A. Blumberg2 and C. N. Kotton3,* 1
U.S. Department of Health and Human Services, Office of the Assistant Secretary for Health, Division of Blood and Tissue Safety and Availability, Washington, DC 2 Department of Medicine, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA 3 Division of Infectious Disease, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA Corresponding author: Camille Kotton, [email protected]
While the risk of infectious disease transmission through blood transfusion has been greatly reduced as a result of improved screening methods, transfusion-transmissible infections remain a concern for transplant recipients, especially those receiving multiple transfusions. Although transfusion and transplant recipients are at risk for similar infections, the current reporting requirements for infections transmitted by transfusions and organ transplantation vary greatly and remain distinctly separate with no communication between reporting systems. This article reviews 23 past reports of transfusion-transmitted infections in organ recipients acquired through transfusions. While cytomegalovirus was a major focus of such reports in the 1980s, more recent reports have focused on West Nile virus transmission. Additionally, this article highlights challenges in determining transfusion-transmitted infection risk in transplant recipients related to the current reporting systems. Abbreviations: CDC, U.S. Centers for Disease Control and Prevention; CMV, cytomegalovirus; FDA, U.S. Food and Drug Administration; FFP, fresh frozen plasma; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; MMWR, Morbidity and Mortality Weekly Report; NAT, nucleic acid test; NHSN, National Healthcare Safety Network; OPTN, Organ Procurement Transplantation Network; PLT, platelets; RBC, red blood cell; SOT, solid organ transplantation; TTI, transfusion-transmitted infection; WB, whole blood; WNV, West Nile virus Received 08 May 2014, revised 13 August 2014 and accepted for publication 28 August 2014
Introduction Since the introduction of blood product screening for transfusion-transmitted infections (TTIs) in the mid-1980s, the risk of acquiring an infection from a transfusion has significantly decreased as a result of antibody and nucleic acid testing (NAT) (1). Approximately 20,933,000 red blood cell (RBC) and non-RBC units (i.e. plasma, platelets and cryoprecipitate) were transfused in the U.S. in 2011, resulting in 36 reported posttransfusion viral infection transmissions, or approximately one for every 585,726 units transfused (2). From 2009 through 2013, 10% (19/ 190) of transfusion related fatalities were caused by microbial infections (3). Modeling has estimated the risk of acquiring human immunodeficiency virus (HIV) through a transfusion as 1 per 1,467,000 units transfused, while the risk of acquiring hepatitis C virus (HCV) and hepatitis B virus (HBV) are estimated at 1 per 1,149,000 and 1 per 765,000– 1,006,000 units transfused, respectively (1,4,5). Nonetheless, TTIs remain a concern for individuals receiving multiple transfusions, particularly for those who are also immunosuppressed, including solid organ transplant (SOT) recipients. Currently, the frequency with which transplant patients develop transfusion related infectious diseases is unknown (6). These events are likely under reported due to both the failure to recognize the transfusion as the infection source, particularly in cases of infections with long incubation periods (such as hepatitis), as well as the lack of required comprehensive reporting. Similar infections can be transmitted through transfusion and transplantation. However, current reporting systems for TTIs and organ donor derived infections exist as separate systems, increasing the difficulty in identifying the rates of such infections (6). Despite the Organ Procurement Transplantation Network’s (OPTN) requirements for all donor derived infectious diseases to be reported, mandatory reporting is not uniformly required for TTIs (7). Due to this lack of mandatory reporting for TTIs, there is currently no system for aggregating data on the rate of TTIs in transfusion recipients in the U.S. Additionally, while there is comparable donor screening for these infections involving screening questionnaires and laboratory tests, some key differences remain (Table 1).
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Mezochow et al Table 1: Blood and SOT donor infection screening: exclusionary criteria1
Bacterial Syphilis4 Parasitic Babesiosis Chagas disease Leishmaniasis Malaria Prion VCJD Viral CMV Dengue HBV HCV HTLV HIV WNV
Blood donor deferral, questionnaire
Blood donor deferral, test2
SOT donor screening3, questionnaire
SOT donor screening3, test
Yes
Treponema pallidum antibodies
Yes
Treponema pallidum antibodies
Yes Yes No Yes
No T. cruzi antibodies No No
No Yes No Yes
No No No No
Yes
No
Yes
No
No No Yes Yes No Yes No
Anti-CMV only upon request No HBsAg, Anti-HBc, HBV DNA Anti-HCV, HCV RNA Anti-HTLV I/II Anti-HIV 1/2, HIV RNA WNV RNA
No No Yes Yes No Yes Yes
Anti-CMV No HBsAg, anti-HBc, anti-HBs Anti-HCV No Anti-HIV 1/2 No
Data from the Full-Length Blood Donor History Questionnaire (39), Donor Risk Assessment Interview (Donor >12 yrs old) (40), OPTN Minimum Procurement Standards for an Organ Procurement Organization Policy 2.2.4 (7) and A Compendium of Transfusion Practice Guidelines (41). 2 Blood units are pooled for initial screening. If a pool tests positive, individual units are then tested and, if confirmed positive, discarded. 3 In the case of SOT donors, a positive for a deferral question or test does not necessarily indicate that a donor will not be used, but instead falls to the discretion of the recipient(s) and their transplant physicians. 4 Organ donors are not deferred for syphilis. 1
This report aims to explore previous case reports of infections in transplant patients acquired through transfusion and to elucidate areas in which further study is needed.
from each manuscript. Any information not included in the event report was listed as unspecified within the tables.
Results Methods A systematic search of the PubMed database was conducted on February 18, 2014 for studies relating to transfusion transmitted infectious disease acquired during or related to transplantation. The Morbidity and Mortality Weekly Report (MMWR), which functions as the primary publication vehicle for the U.S. Centers for Disease Control and Prevention (CDC) to report on investigations relating to infection transmissions, was also searched. Manuscripts were eligible for inclusion if the transfusiontransmission event and transplantation occurred in the United States. In order for a manuscript to be included, the authors had to determine either directly (through the testing of a blood donor or donation) or indirectly (through ruling out infection in the allograft donor) that the infection was a result of transfusion. No articles were excluded based on their date of publication or language. The database search utilized the terms ‘‘(organ) and (transplant) and (transfusion) and ((transmission) or (acquired))’’. A title search was performed for manuscripts to assess their relevancy with all unrelated articles excluded. Following the title review, abstracts of relevant titles were evaluated to assess whether articles fit the search criteria. A title search of footnotes was also performed for those seeming to meet the inclusion criteria to recover articles that may have been missed by the initial search. Full text copies were then retained and reviewed for all relevant manuscripts. Details surrounding the transplant (e.g. organ), transfusion (e.g. units transfused, infected component, other recipients), transmission (e.g. infectious agent, incubation) and recipient outcome were all extracted
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Two hundred and thirty nine titles were found during the initial title search of PubMed, 93 from the MMWR and 79 from the footnote search. The abstracts were then reviewed and 22 manuscripts were identified as meeting inclusion criteria and are detailed in Tables 2 and 3. Excluding cases of cytomegalovirus (CMV), there were 11 reported cases of TTIs related to transplants ranging from 1992 to 2008 (Table 2) (8–18). Six of these reports were cases of West Nile virus (WNV), which resulted in nine transmissions to SOT recipients (8,10–14). The other five reports included two cases of malaria, two cases of babesiosis and one case of HIV (9,15–18). Of the recipients who developed infections, six had received kidneys, four had received hearts and three received livers. The range of the total blood products received by infected recipients was 2 to 174 units. Plasma, RBCs, whole blood and platelets were all shown to be potential sources of infection, with the infectious unit type, as identified in the reports, being nearly evenly split between red blood cells (4/11), frozen plasma (3/11) and platelets (3/11). In recipients who were infected with WNV, the incubation period averaged 13 days and was American Journal of Transplantation 2015; 15: 547–554
Transfusion Infections in Organ Transplants Table 2: Reported cases of transfusion related infections in transplant recipients Total blood Infectious
Organ
product units
Infected blood
Timing of
Year
agent
transplanted
received
component1
transfusion
2008
WNV
Heart
10 (organ donor)
FFP
2 days before donor declared brain dead
8 days
Lived, but could not walk without assistance
CDC (9)
2008
HIV
Kidney
Unspecified
FFP
Unspecified
N/A3
Started on anti-retroviral therapy
CDC (10)
2006
WNV
Kidney
2
RBC
4 days posttransplant
17 days
Recovered
CDC (11)
2002
WNV
Liver
24
PLT
6 days posttransplant
13 days
Recovered
Pealer et al (12) 4 Murtagh et al (13)
2002 2002
WNV WNV
Kidney Heart
RBC PLT & WB
Unspecified During ‘‘perioperative period’’5
10 days 2 weeks
Died Lived, but developed severe neurologic impairment.
Iwamoto et al (14) 2
2002
WNV
Kidney (1)
FFP
Day and day before donor declared brain dead
16 days
Recovered
Kidney (2) Heart Liver Heart
19 days 12 days 9 days 35 days
Died Recovered Recovered Recovered
Reference CDC (8)
2
Lux et al (15)
2000
B. microti
Talabiska et al (16)
1995
Barat et al (17)
1993
Malaria, P. ovale Malaria, P. ovale
Perdrizet et al (18)
1992
B. microti
Unspecified 174
53 (organ donor)
Incubation
Recipient
Other recipient
status
outcomes
65
RBC
5 days post-transplant
Liver
Unspecified
PLT
5 weeks6
Recovered
Liver
110
Unspecified, prior to transplant Unspecified, during hospitalization for transplant
1 month7
Recovered
1 day post-transplant
10 days
Recovered
Kidney
2
Unspecified
RBC
Patient who received RBC from donor was asymptomatic, but had WNV antibodies Second patient received RBC from donor, but died shortly thereafter Patient who received donor’s FFP had received transplant 5 years prior and was on immunosuppressants. Patient developed WNV-associated myelitis Patient who received donor’s RBC developed WNV fever and was WNV IgM antibody positive. Unspecified RBC recipient (from WB donor) was well and negative for WNV antibodies. Other nine donors who received PLT from PLT donor were asymptomatic for WNV No other patients received components from this donor
No other patients received components from this donor Unspecified Patient who received RBC from donor was asymptomatic, but had antibodies to P. ovale Unspecified
1
RBC denotes red blood cells, FFP denotes fresh frozen plasma, PLT denotes platelets, WB denotes whole blood. Organ donor received infectious blood unit in hospitalization immediately before becoming an organ donor (death unrelated to infectious blood unit). Infection was passed from donor onto organ recipients. 3 Infection was discovered through look-back investigation 5 months posttransplant. Recipient was asymptomatic at time of infection discovery. 4 Report also includes case of liver recipient described above (CDC. MMWR. 2002; 51(39): 879). This case is not duplicated in this row. 5 This term is per author designation as used in their manuscript. 6 Onset of illness was 5 weeks posttransplant. Patient had a history of prior transfusion (date unspecified), which her infection was traced to. 7 Patient was diagnosed with malaria one month following transplant. Time to onset of illness was unspecified. 2
American Journal of Transplantation 2015; 15: 547–554
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550 Multi-city (46 transplant centers)
Stanford, CA
Pittsburgh, PA
Portland, OR
1976–1978 1980–1981
1984–1985
Chou et al (26)
Cleveland, OH
Pittsburgh, PA
1984–1986
Gorensek et al (25)
Cleveland, OH
1981–1983
1984–1987
Gorensek et al (30)
Omaha, NE
Dummer et al (29) J Infect Dis 1985; 152(6): 1182–91. Preiksaitis (30)
1985–1989
Stratta et al (23,24)
Rochester, MN
Unspecified
1988–1990
Paya et al (22)
Boston, MA
Rubin et al (28)
1987–1990
Falagas et al (21)
Pittsburgh, PA
1984–1985
1990
~ez et al (20) Man
Location
Singh et al (27)
Year
Reference
Table 3: Reported cases of CMV in transplant recipients
No (1976–78) Yes (1980–81)
No
No
No
Most patients received almost exclusively leukocyte-poor blood screened for CMV. Some components irradiated
No
No
No
No
No
Leukoreduced or screened blood
Of those receiving renal transplants from deceased donors, only one recipient (1/32) became seropositive for CMV following transfusion with two units of leukocytes and all of the recipients receiving one unit remained CMV seronegative. This study found 46% of blood donors to be CMV seropositive and estimated that 89% of those receiving one unit and 99% of those receiving two units would have been exposed to a CMV seropositive donation In this cohort of liver transplant recipients, one of 12 (8%) CMV seronegative recipients receiving a liver from a seronegative donor developed CMV infection This study found that of CMV seronegative patients receiving CMV negative allografts, 17% receiving conventional immunosuppression and 24% with an antilymphocyte preparation seroconverted (approximately 20% overall). Of the patients who did not receive a transfusion and were CMV negative and received CMV negative allografts, none seroconverted Nine of 14 patients either receiving a heart or heart-lung transplant who were CMV seronegative prior to transplant and had a seronegative organ donor developed infection following transplantation Of the patients receiving unscreened blood (1976–78) who were initially negative for anti-CMV and received a seronegative heart, 20% (1/5) became CMV positive. All of the patients receiving pre-screened, CMV negative blood (1980–81) who were also initially CMV seronegative and received a CMV negative organ remained CMV seronegative (0/8)
Two individuals (13%) who were part of a cohort study and received CMV negative organs developed CMV infection as a result of transplant related transfusions. Only one of those two individuals went on to develop symptomatic CMV In this cohort, found 20% (9/44) of newly acquired CMV infection in liver recipients to be as a result of transplant related transfusions Two of 15 CMV seronegative transplant patients receiving livers from seronegative donors developed CMV infection post-transplant as a result of blood transfusions received within the month prior to transplant In cohort of liver transplant patients, found 22% incidence of CMV transfusion transmission resulting in disease in cases where both donor and recipient were CMV negative Four of 14 (28%) liver recipients initially CMV seronegative who received organs from similarly seronegative donors developed CMV infection. Two of these recipients then also went on to develop symptomatic CMV Of 11 CMV seronegative heart recipients who received a seronegative organ, five developed CMV infection
Notes
Mezochow et al
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slightly over one month for those infected with Plasmodium ovale (8,10–14,16–17). All of the donations where a time of year was specified for the WNV transmissions occurred in either July (1/5), August (2/5) or September (2/5) and the transfusions took place in Louisiana, South Dakota, Michigan, Texas and Georgia (8,10–14). The blood donations resulting in the two cases of babesiosis were obtained during the summer from donors in New York and Connecticut (15,18). In both instances of malaria transmissions, the blood donors had previously traveled to an area endemic for malaria (16–17). The four reports discussing WNV transmission during 2002 occurred prior to the licensing and requiring of WNV NAT assays in 2005 (11–14,19). In two of the eleven reports, the organ donor (instead of the recipient) was the one to receive the infectious unit just prior to transplantation, with subsequent transmission to the organ recipients (8,14). In one of these cases, the donor gave organs to four different recipients, all of whom developed WNV infection (14). In the case of a liver recipient described by Talabiska et al, the Plasmodium ovale infection was discovered post-transplant, but was likely related to a pretransplant platelet transfusion administered to the recipient (16). All recipients outlined in the eleven reports developed symptomatic disease, with the exception of the HIV transmission. All nine of the individuals who were infected with WNV developed severe neurologic complications and at least five of these recipients required mechanical ventilation during their hospital stay (8,14). Ultimately, two of the WNV patients died and at least two developed lasting neurologic complications (8,12–14). Additionally, all of the other recipients who had received the WNVcontaminated blood products either remained asymptomatic or only developed mild infection. The one exception to this was a patient who was immunosuppressed as a result of a kidney transplant five years prior and then developed WNV-associated myelitis after receiving a transfusion with WNV infected plasma during a spinal surgery (10). In addition to the eleven cases outlined in Table 2, there were eleven reports (from twelve manuscripts) that discussed CMV transmission resulting from transfusions related to transplantation (Table 3) (20–31). All twelve of these manuscripts report on the outcomes of transplant recipient cohorts where a portion of the cohort was CMV negative at the time of transplant and received an organ from a seronegative donor, but then developed CMV infection following a transfusion. While all twelve articles illustrate cases of transfusion transmission, only two of these manuscripts explicitly examined the effects of transfusion on CMV (20,26). The reports are from the years 1976–1990, prior to the uniform use of leukoreduced or CMV seronegative blood in SOT recipients. Reported rates of CMV in initially CMV negative transplant recipients American Journal of Transplantation 2015; 15: 547–554
receiving seronegative organs varied among those receiving untreated blood units with a median infection rate of 20%. Transfused blood was only consistently screened for CMV antibodies in one of these ten cohorts and one other study irradiated some of the blood used prior to transfusion (26,30). When blood products were pre-screened for CMV by serology, none of the recipients developed CMV infection (30).
Discussion While there are relatively few reports of TTIs in SOT recipients, these transmissions are likely underestimated due to a lack of knowledge about the risks, as well as the absence of robust reporting systems for TTIs. Despite their relative infrequency, these events are notable for the resultant consistently poor patient outcomes. While CMV was found to be the most commonly reported TTI, reports of CMV in organ donors as a result of transfusions dropped off in the 1990s likely due to the use of leukoreduced and CMV screened blood for CMV negative organ recipients. Despite the prevalence of CMV remaining largely consistent in the general population (32), there is now the option for adopting strategies in immunocompromised patients to prevent CMV transmission. In the early 1990s, it was determined that providing leukocyte reduced or CMV seronegative blood products to immunosuppressed individuals was highly effective in preventing CMV transmission in patients who were CMV negative and this has now become common practice for CMV seronegative recipients (33). The majority of more recent reports involve WNV. This is likely due both to epidemics of WNV in recent years and enhanced clinician awareness of the possibility of transfusion associated WNV transmission due to the large amount of publicity it has received since it was initially discovered to be transmissible in 2002 (34–36). Additionally, the onset of WNV symptoms typically occurs within weeks following the transfusion when transplant patients are still being closely monitored. The other two infections in which multiple cases were reported, babesiosis and malaria, are also infections that have relatively short incubation periods, making them easier to associate with the transfusion. In contrast, the reported HIV case was only identified upon tracing back a blood donor’s past donations when it was later discovered that the blood donor was positive for HIV. HIV, HBV and HCV all have incubation periods that can last years, making them significantly more difficult to trace back to their original source or associate them with transfusion. These cases highlight the importance of seasonality and geography in considering possible transfusion transmissions as well as the importance of insect vectors in TTIs. Of the 11 non-CMV TTIs identified in this review, 10 were vector borne infections: 6 WNV, 2 malaria and 2 babesiosis. 551
Mezochow et al
Both cases of babesiosis occurred in high prevalence areas during summer months. While the locations where WNV transmissions occurred were more geographically varied, these all originated in areas with reported WNV activity and also clustered around summer months as is consistent with the seasonality of WNV. Although these reports illustrate the decline in transfusion-transmitted WNV cases since the implementation of blood donor screening, transmissions do continue to occur. Additionally, there is currently no blood donor screening test in use for malaria or babesiosis. These cases underscore the need for physicians to consider the possibility of TTIs in SOT recipients who received blood, especially in cases involving a vector borne infection and where an infection does not seem demographically appropriate (e.g. a babesiosis infection where neither the SOT donor nor recipient spent time in an endemic area). Transplant physicians should also be aware of the ability to trace back a blood donation to the original donor, which is important not only for determining the source of infection, but also for identifying other potentially infectious units or infected patients. While these eleven reports illustrate the need for physicians to consider the possibility of TTIs related to transfusions just before, during, and immediately following transplantation, they also demonstrate the potential importance of recent transfusions that occur in the organ donor (8,14). The report by Iwamoto et al also showed the potential for TTIs in organ donors to be particularly challenging, both related to lack of suspicion for these events and the efficiency of transmission to multiple recipients (14). Such cases also illustrate the potential for multiple recipients receiving organs from the transfused donor to be infected. This review has multiple limitations, primarily due to the limited reports on which it is based and the likely underreporting of TTIs. Given the absence of a required reporting system for nonfatal TTIs, there are likely more TTIs occurring than are reported in the literature and thus included in this review, making it difficult to understand the true risk of TTIs for transplant recipients. A more robust reporting system would be required; additionally, events with longer incubation periods would need to be investigated for the potential of TTI. The absence of any established mechanisms for communication between the transplant and transfusion communities increases the likelihood that TTIs may fall through the gaps. While the OPTN requires reporting of any unexpected transmission of infection from organ donor to recipient allowing for active surveillance, there is no equivalent requirement for TTIs (7). At present, there is no mandatory reporting regulation for adverse reactions resulting from transfusions, with two exceptions that require reporting to the U.S. Food and Drug Administration (FDA): when an adverse reaction leads to death or when a manufacturing error occurs that may impact the ‘‘safety, purity or potency’’ 552
of the blood product (37). The FDA also runs the voluntary FDA Adverse Events Reporting System (FAERS), which allows healthcare professionals and consumers to report any adverse reactions relating to blood products directly to the FDA. Additionally, the CDC hosts their own surveillance program for infections acquired through transfusion. Due to HIV’s status as a nationally notifiable disease, all newly diagnosed infections, including those acquired via transfusion, must be reported to the CDC. However, a case is only investigated as a TTI if a transfusion is reported and no other risk factors are present (38). For HCV and HBV, the CDC primarily conducts only passive surveillance, without mandatory reporting. In 2010, the CDC also launched the Hemovigilance module within the National Healthcare Safety Network (NHSN) to allow for hospital level reporting of adverse events associated with transfusions. NHSN reporting is voluntary, plagued by a low participation rate (of approximately 4,600 transfusing facilities, fewer than 200 are enrolled and less than half contribute data regularly), and likely to only capture acute infections (38). Although NAT has greatly reduced the risk of TTIs, instances of transmission do occur. As a result of their rarity, physicians assessing a patient posttransplant may be less likely to consider this risk. Creating a mechanism for combining surveillance or allowing for communication across the transplant and transfusion systems would potentially facilitate the determination of whether an infection is derived from a transfusion, organ donor or other factor. Such communication is imperative in enhancing safety for other organ and blood product recipients at risk for such infections from the same donor. Further challenges in determining whether an infection is transfusion acquired result from the many blood products that may be given around the time of transplant. As was seen in the case reported by Perdrizet et al the cause of infection may be difficult to distinguish from other events such as acute organ rejection or donor derived or hospital acquired infections, ultimately delaying diagnosis and treatment (18). Additionally, due to immunosuppression, infections in transplant recipients may be associated with uncommon manifestations that make them more difficult to recognize. Presently, data relating to transfusions are often fragmented and separated into the different silos of blood and transfusion centers, with the possibility of a single recipient’s transfused blood components originating from multiple blood collection centers. While there are systems for hospitals to communicate with blood centers, it can be very difficult to trace back an infection to one of the many donors from whom a patient received blood, especially if a blood sample is no longer on file at the blood collection centers. Transplant programs should consider the risk of TTIs when investigating the cause of an infection in organ recipients, American Journal of Transplantation 2015; 15: 547–554
Transfusion Infections in Organ Transplants
especially in the case of vector borne infections. Creating an integrated surveillance system and facilitating communication across the transfusion and transplant networks could help in establishing TTI risk. Such a system could aid in increasing the reporting of TTIs related to organ transplantation, allowing for a better understanding of the true TTI risk, ultimately leading to greater awareness, faster diagnosis of infections and enhanced safety in organ transplant recipients.
Disclaimer The findings and conclusions of this report are those of the authors and do not necessarily represent the official position of the U.S. Department of Health and Human Services.
Disclosure The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.
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