Survey on Transfusion-Transmitted Cytomegalovirus and Cytomegalovirus Disease Mitigation

A supplemental survey was added to the CAP Transfusion Medicine (Comprehensive) Participant Survey in 2015. The supplemental survey (see supplemental digital content at www.archivesofpathology.org in the December 2017 table of contents) posed questions regarding the practices used for TT-CMV mitigation and CMV disease prevention. Respondents were asked to answer questions on the following topics: (1) adult and/or pediatric special services that their institutions provide among the choices of solid organ transplant, hematopoietic progenitor cell (HPC) transplant, maternal-fetal medicine (MFM) specialists managing high-risk pregnancies, and/or neonatal intensive care units (NICUs); (2) use of leukoreduced and/or CMV-seronegative products for high-risk patient populations; and (3) use of CMV monitoring and prophylaxis in high-risk populations.

All respondents were indexed according to the types of services their institutions provide and their responses were analyzed by using descriptive statistics (Microsoft Excel 2003, Redmond, Washington).

The supplemental questionnaire on practices to mitigate TT-CMV and CMV disease was sent to 3560 institutions, and 86% (3072 of 3560) of institutions responded. All CAP member institutions that use the proficiency survey were also asked to respond to the supplemental questionnaire. Among the individuals who completed the questionnaire, 4% (135 of 3072) were medical directors, 59% (1819 of 3072) were chief technologists, 32% (983 of 3072) were laboratory technologists, and 4% (135 of 3072) indicated “other.” Among responding institutions, 9% (291 of 3072) and 4% (128 of 3072) provide adult and pediatric solid organ transplant programs, respectively; 8% (250 of 3072) and 5% (153 of 3072) provide adult and pediatric HPC transplant programs, respectively; 25% (754 of 3072) provide MFM services; and 36% (1095 of 3072) have NICUs.

From the survey results, institutions were categorized into 3 mutually exclusive groups according to the type of services they provide to at-risk patients. The 3 categories included (1) NICU/MFM—centers providing NICU and/or MFM services but no transplant services, 27% (836 of 3072); (2) transplant—all centers providing HPC and/or solid organ transplant with or without NICU and MFM, 13% (394 of 3072); and (3) no high-risk services—centers that did not indicate any of the listed specialized services, 60% (1842 of 3072) (Figure 1, A).

Institutions were asked if the transfusion service provides universal leukoreduced red blood cell and platelet products and 99% (3032 of 3072) replied either “yes” or “no.” Ninety percent (2712 of 3032) of the responding institutions provided universal leukoreduced products (Figure 1, B). The proportion of institutions reporting universal leukoreduction was slightly lower among those institutions providing specialized services to patients at high risk for CMV disease: 87% (724 of 827) for institutions providing NICU/MFM, and 84% (330 of 392) for institutions providing transplant services versus no specialized services (91% [1658 of 1813]) (Table 1). Ninety-two percent (295 of 320) of institutions without universal leukoreduction provided leukoreduced products on the basis of clinical criteria. The clinical criteria used for selecting patients to receive leukoreduced products reflected the specialized services provided by the institutions (Table 1).

The survey also asked if the transfusion service provides CMV-seronegative products, and 98% (3004 of 3072) replied either “yes” or “no.” Among responding institutions, 83% (2481 of 3004) reported providing CMV-seronegative products and 97% (2399 of 2470) reported that CMV-seronegative products are also leukoreduced. Institutions that reported providing CMV-seronegative products were asked what patient populations receive these units per institutional policy. The most common indications for issuing CMV-seronegative products were neonates younger than 4 months (49%, 1228 of 2481), intrauterine transfusion (23%, 583 of 2481), and HPC or solid organ transplant with CMV-seronegative donor and recipient (14% [345 of 2481] and 13% [316 of 2481], respectively) (Table 2). In addition, 40% (999 of 2481) of respondents chose “other” as indication for CMV-seronegative products. Among institutions that selected “other” as an indication, 65% (647 of 999) specified “physician request,” and a wide range of indications based on the patient population (eg, elderly, immunocompromised, exchange transfusion, cardiac surgery, and oncology).

Institutions that provide NICU/MFM and transplant services reported similar availability of CMV-seronegative products, compared to institutions with no high-risk services; however, a greater proportion of institutions with no high-risk services indicated “physician request” as the indication for providing CMV-seronegative products (Figure 2, A). Institutions with no high-risk services reported low rates of policies to provide CMV-seronegative blood to high-risk patient groups (Figure 2, B). Institutions with NICU/MFM services reported the highest rate of policies to give CMV-seronegative products to neonates (82%, 602 of 734; Figure 2, C). Transplant centers reported the highest rate of providing CMV-seronegative blood in cases of CMV-negative donor/recipient pairs: 29% (80 of 278) for solid organ and 38% (107 of 278) for HPC transplant patients (Figure 2, D).

High-risk patients may be managed with CMV prophylaxis and monitoring. The percentage of institutions providing prophylaxis and monitoring for CMV reported was as follows: for CMV-negative HPC transplant recipients, 4% (125 of 3072) used ganciclovir or valganciclovir prophylaxis, and 4% (132 of 3072) used weekly to monthly CMV polymerase chain reaction (PCR) monitoring (1 facility performed CMV antigen testing); for low-birth-weight infants, 2% (61 of 3072) used ganciclovir or valganciclovir prophylaxis, and 1% (40 of 3072) used weekly to monthly CMV PCR monitoring; for CMV-negative pregnant women, 1% (42 of 3072) used ganciclovir or valganciclovir prophylaxis, and 1% (29 of 3072) used weekly to monthly CMV PCR monitoring; and for CMV-negative solid organ transplant recipients, 4% (135 of 3072) used ganciclovir or valganciclovir prophylaxis, and 3% (88 of 3072) used weekly to monthly CMV PCR monitoring. Institutions with NICU/MFM and transplant services reported uniformly low rates of CMV monitoring and prophylaxis for low-birth-weight infants and CMV-negative pregnant women; however, institutions that provide transplant services reported higher rates in using CMV prophylaxis and monitoring for HPC and solid organ transplant recipients (Figure 3, A through D).

Ninety percent of institutions reported providing leukoreduced products universally as the primary method of TT-CMV mitigation. Among those facilities not providing universal leukoreduction, there is a lack of consensus regarding which, if any, at-risk populations should receive leukoreduced and/or CMV-seronegative products. This practice puts the burden on clinicians to have a heightened awareness of the type of products available, recognition of high-risk patients, and knowledge of what the risk, resulting in CMV disease, might be for a given patient population. Given the lack of high-quality data to inform use of CMV-seronegative and leukoreduced blood products, high-quality studies are needed to create evidence-based practices.

Cytomegalovirus disease is a potentially life-threatening complication for immunosuppressed patients. Latent CMV infection affects a large proportion of the blood donor pool and is transmitted predominately by virus within donor leukocytes. Provision of standard—nonleukoreduced, non–CMV-tested—blood products to at-risk patients was associated with high rates of CMV infection and disease.^16,17  In the early to mid 1980s, provision of CMV-seronegative blood products was found to markedly reduce CMV infection rates in solid organ and bone marrow transplant patients and infants born to CMV-seronegative mothers.^18,19  In the late 1980s blood filters capable of 3-log₁₀ leukocyte reduction of platelet and red blood cell products were introduced and were shown to also prevent TT-CMV.^17,20  In 1995 one prospective randomized study²¹  compared the 2 methods for TT-CMV mitigation in bone marrow transplant patients and showed no significant difference in CMV infection or disease in those receiving CMV-seronegative compared to leukoreduced blood products. Based on this study and subsequent retrospective and observational studies, leukoreduction has been deemed equivalent to CMV-seronegative products for TT-CMV mitigation in susceptible patient populations.^21–24  Although many institutions have adopted universal leukoreduction policies, the question of providing leukoreduced blood products that are also CMV seronegative for specific at-risk patient populations has remained unanswered.

There have been few large-scale prospective randomized clinical trials comparing the efficacy of products that are leukoreduced or CMV seronegative alone to products that are both leukoreduced and CMV seronegative in mitigating TT-CMV.²⁵  Small studies in select patient populations have suggested that additional provision of CMV seronegativity may be unnecessary.^22–24  Fewer studies^7,26  support the contrasting view that CMV seronegativity may be required to minimize TT-CMV risk from leukoreduced blood. All of these studies involve specific high-risk populations (HPC transplant recipients) and have difficulty confirming TT-CMV because the source of CMV infection can be from multiple routes.²⁵  Further, these studies often fail to address the role of prophylactic treatment or viremic monitoring in prevention of CMV disease.

Most institutions responding to this survey (1842 of 3072, 60%) did not report having specialized services for CMV at-risk patients, which reflects the expected hospital demographics. According to the American Hospital Association Annual Survey of Hospitals, in 2013 there were 5686 hospitals in the United States, of which 3609 (63%) were smaller hospitals with fewer than 200 beds.²⁷  Although large multispecialty and academic medical centers make up a small proportion of total hospitals, they proportionally treat a larger number of high-risk patients.²⁸  Thus, the survey data were analyzed both in aggregate and with the institutions categorized into mutually exclusive groups according to the type of specialized services they provide.

The patient population most commonly designated to receive CMV-seronegative products at institutions providing CMV-seronegative blood was neonates younger than 4 months at 1228 of 2481 institutions (49%). Institutions providing NICU and/or MFM services reported the highest rate of CMV-seronegative blood availability (734 of 828 responding centers, 89%), and 602 of 734 institutions (82%) with CMV-seronegative blood available reported providing it to all neonates younger than 4 months. Most respondents (2399 of 2470, 97%) reported that their CMV-seronegative blood products were also leukoreduced. This practice is likely due to concern for the lifelong neurodevelopmental consequences of CMV disease in neonates. A recent study by Josephson et al²⁹  demonstrated that use of leukoreduced products that were also CMV seronegative effectively prevented TT-CMV in neonates, but it did not investigate, and no study has yet to investigate, CMV transmission to neonates from products that are leukoreduced or CMV seronegative alone. Importantly, in this study all cases of neonatal CMV were secondary to breast milk rather than transfusion.^25,29 

Transplant patients are also at high risk for CMV disease; however, most institutions surveyed indicated no established policy to provide CMV-seronegative products to transplant patients. That these facilities do not specify a requirement for the provision of CMV-seronegative products reflects the available evidence-based literature, which indicates equivalence of leukoreduced compared to CMV-seronegative products for prevention of TT-CMV in HPC transplant recipients.^21,23,24  Accordingly, 330 of 392 transplant centers (84%) reported providing universal leukoreduction, and, among the 62 centers without universal leukoreduction, 49 (79%) and 52 (84%) provide selective leukoreduction for solid organ and HPC transplant patients, respectively. Among 394 transplant centers, 59 (15%) and 99 (25%) reported policies for CMV PCR monitoring for CMV-negative solid organ and HPC transplant patients, respectively. Additionally, 97 (25%) and 80 (20%) of the transplant centers reported policies for CMV prophylaxis for solid organ and HPC transplant patients, respectively. Thus, transplant centers predominately use leukoreduction to mitigate the risk of CMV disease in transplant recipients.

Lack of national policies or guidelines causes variation in clinical practice. Forty percent of institutions indicated “other” or physician discretion as the second most common indication for the use of CMV-seronegative products, with this category including diverse comments and indications. The results of a small survey (n = 126 with 45% response rate) of Ontario hospital laboratories recently showed a similar lack of consensus regarding use of CMV-untested, leukoreduced versus CMV-seronegative, leukoreduced blood products.³⁰  This indicates a lack of institutional policy or guidelines, potentially due to the lack of evidence-based guidelines from national organizations. Additional data will be required to create such guidelines, ideally from prospective randomized clinical trials comparing the effectiveness of leukoreduced-only products versus CMV-seronegative and leukoreduced products in the prevention of CMV disease among high-risk patients.

To understand appropriate use of CMV-safe products, it is important to understand the use of CMV monitoring and prophylaxis practices for high-risk patient populations. The institutions reported low rates of monitoring and prophylaxis, providing it only for transplant recipients. Accordingly, there are no evidence-based practice guidelines currently recommending universal CMV prophylaxis or monitoring for pregnant women or low-birth-weight infants. Testing and treatment for CMV in these patients is based on clinical suspicion.^31–33  In contrast, for prevention of CMV disease in solid organ and HPC transplant patients, evidence-based guidelines support using either CMV prophylaxis or a preemptive approach using CMV antigenemia or PCR monitoring with immediate treatment for evidence of viral replication.^34–36  The use of CMV prophylaxis and monitoring at transplant centers may, in fact, be higher than what was reported in this survey because survey respondents were predominantly blood bank supervisors or laboratory technologists, who are often removed from direct patient care.

Our survey offers a current view of strategies used by institutions primarily in the United States to reduce CMV disease secondary to transfusion. However, our study has some limitations. The study respondents were largely technologists working at nontertiary medical institutions. The technologists may not be aware of strategies in place regarding mitigation of CMV disease. While our response rate was high, there is always the possibility for question misinterpretation. Finally, the use of alternative technologies, such as pathogen reduction, nucleic acid testing, and other methodologies for TT-CMV mitigation, was not included in the survey. Notably, the survey was distributed before US Food and Drug Administration (FDA) approval of pathogen reduction technologies or use of CMV nucleic acid testing for blood components.

Among all centers surveyed, leukoreduction is the primary TT-CMV mitigation strategy. Dependence on universal leukoreduction as the primary TT-CMV mitigation strategy can leave institutions vulnerable to leukoreduction filter failure. For example, in June 2016 the FDA issued a large-scale leukoreduction filter recall during which time the supply of leukoreduced blood and CMV-seronegative blood was temporarily limited.³⁷  Thus, institutions should maintain policies delineating which patients should receive CMV-safe blood when universal leukoreduction is not possible.

In addition, most centers with NICU/MFM services provide leukoreduced blood that is also CMV seronegative to neonates younger than 4 months, and this dual-prevention strategy is variably used for other immunosuppressed patient groups despite being of questionable clinical benefit. High-quality clinical studies should be performed to determine if CMV seronegativity is required to further reduce CMV transmission from leukoreduced blood products. These studies should be carefully designed to discriminate between cases of TT-CMV and those resulting from the multiple other routes of CMV transmission, particularly breast milk. Studies are also ongoing to identify CMV monitoring and prophylaxis strategies that prevent CMV disease and its neurodevelopmental sequelae in neonates.^29,38  Evidence-based guidelines derived from high-quality clinical studies are needed to better standardize practices for CMV mitigation across community and multispecialty institutions.

The survey was reviewed by the Transfusion Medicine Resource Committee, College of American Pathologists. The committee also reviewed the survey results and related publications.