Cytomegalovirus (CMV)

Summary

NAC statement regarding appropriateness of use of Cytomegalovirus (CMV) sero negative versus CMV safe product (February 14, 2017)

Recommendation #1

The National Advisory Committee recommends that CMV safe (leukoreduced) and CMV IgG seronegative products be considered equivalent except for Intrauterine transfusion.

Recommendation #2

The National Advisory Committee recommends that Canadian Blood Services stop their current process for testing and provision of CMV seronegative units issued to hospital facilities and develop a new process to maintain a small inventory of CMV seronegative blood components for the sole purpose of Intrauterine transfusion.

Recommendation #3

The National Advisory Committee recommends that Canadian Blood Services explores the feasibility of providing a small boutique inventory of dually tested (seronegative and NAT) CMV negative blood components for the sole purpose of  Intrauterine transfusion.

CMV References

Additional Resources

NAC Education Document: Transfusion and Cytomegalovirus In The Canadian Blood System

Transfusion-transmitted CMV:  Can you  confidently abandon CMV seronegative products in the modern era of pre-storage leukoreduction?  Author:  Jeannie Callum, BA, MD, FRCPC 

PowerPoint Presentation from July 2017

Videos by Dr. Callum.

Powerpoint with audio:  https://youtu.be/rcwYqdwzplc

Video:  https://youtu.be/Cw746m78X3U

Credits
Prepared by
Susan Nahirniak, MD
Lani Liebermann, MD
Jutta Preiksaitis, MD
Donna Wall, MD
Provincial Ministry Representative
Judy Hoff (Saskatchewan)
Date of Original Release
Publication Date

Table of Contents

CMV

Cytomegalovirus (CMV) is a herpes virus demonstrating seroprevalence ranges of 40- 80% in the general population with variability due to age, geographic location and socioeconomic status.1,2,3 CMV is transmitted by direct contact with bodily secretions (blood, saliva, urine or breast milk) or tissues. In everyone previously exposed to CMV infection, CMV persists indefinitely in a latent state in mononuclear cells and perhaps other tissues but healthy individuals are generally asymptomatic. In immunocompromised individuals, CMV infections can manifest as serious complications including interstitial pneumonia, hepatitis, retinitis and encephalitis.

The pathogenesis of transfusion-transmitted CMV is uncertain. Although there has been a focus on the possible infectivity of seroconverting blood donors, reactivation of CMV in seropositive subjects has been described as part of normal aging. In addition, later CMV reactivation in a transfused recipient after transfusion of only latently infected cells is also a possible mechanism of CMV transmission. Unlike other transfusion transmissible viruses, the testing performed by blood suppliers is reliant on serologic tests that measure evidence of previous exposure to CMV. Current nucleic acid testing methods are designed as diagnostic tests to detect active CMV infection and are not licensed for screening, as they lack the sensitivity to detect the low levels of CMV DNA in seroconverting blood donors. Moreover, the CMV DNA documented in these individuals may represent non-infectious cell free CMV DNA rather than infectious virions.4,5 Currently, the components provided when clinicians request CMV negative units in Canada are those where the donor does not have detectable IgG or IgM antibodies. Red blood cell and platelet components that have been prestorage leukoreduced are considered CMV safe components.

Historically, there have been cases of transfusion transmitted CMV infections (TT-CMV) demonstrating transmission rates as high as 60% with fresh warm whole blood7 but with current prestorage leukoreduction techniques the rate of transfusion transmission has dramatically reduced and is estimated to be 1 in 13,575,000.8 In 2016, Mainou and colleagues performed a systematic review and meta-analysis evaluating component leukoreduction with or without donor serology testing in risk reduction of transfusion transmitted CMV. Despite some concerns with respect to quality of some studies, in the 11 studies evaluated, there was no signal of increased risk, demonstrated by clinical and/or laboratory evidence of CMV infection, when comparing leukoreduction to CMV untested units (n=5); leukoreduction to CMV seronegative units (n=3) or leukoreduction alone versus leukoreduction plus CMV seronegativity (n=2).9

In 2012, the National Advisory Committee was tasked at evaluating the evidence behind TTCMV and risk benefit of changing the approach to CMV testing to help Canadian hospital transfusion services and Canadian Blood Services address a) the complexity of marked variability in clinical practice of CMV seronegative requests, b) the limited availability of CMV seronegative components (particularly HLA matched platelet products) often delaying clinically required transfusions and c) the difficulties with managing dual inventory. Due to ongoing improvements in the leukoreduction process and practice pattern evidence from jurisdictions, both within Canada and internationally where CMV seronegative blood components are not being used even for patients considered high risk, it was evident to members on the NAC CMV Working group that eliminating the utilization for CMV seronegative components would reduce component wastage rates, improve the ability of the blood supplier to meet demand, and reduce the cost per unit without compromising patient safety.

As of February 2017, the National Advisory Committee endorsed the following recommendations:

Recommendation #1

The National Advisory Committee recommends that CMV safe (leukoreduced) and CMV IgG seronegative products be considered equivalent except for Intrauterine transfusion.

Recommendation #2

The National Advisory Committee recommends that Canadian Blood Services stop their current process for testing and provision of CMV seronegative units issued to hospital facilities, and develop a new process to maintain a small inventory of CMV seronegative blood components for the sole purpose of intrauterine transfusion.

Recommendation #3

The National Advisory Committee recommends that Canadian Blood Services explores the feasibility of providing a small boutique inventory of dually tested (seronegative and NAT) CMV negative blood components for the sole purpose of intrauterine transfusion.

The provision of CMV seronegative components for intrauterine transfusion (IUT) balanced the risk to this specific population with the capacity of the blood supplier to meet the clinical needs. Intrauterine transfusions in Canada are comparatively infrequent, are performed at highly specialized sites, typically are scheduled in advance, and already require special red cell or platelet component phenotypes and modifications. Therefore, it is within the capacity of Canadian Blood Services to provide CMV seronegative tested units for this high risk population.

The NAC working group members are aware that there is no current method for CMV nucleic acid testing approved as high throughput screening; however, in the future, it may be possible with the limited inventory required for IUT support to add CMV nucleic acid testing if deemed beneficial to reduce the window period risk in fetuses.

There are many routes by which congenital CMV infection can occur including a) primary infection of a seronegative pregnant woman, b) reinfection of a seropositive woman or c) reactivation of CMV in a seropositive woman, with TT-CMV potentially implicated in (a) and (b). Moreover, fetal transfusion is one of the few clinical settings in which extremely prolonged survival of donor leukocytes have been described, increasing the possibility of CMV reactivation after transfusion of latently infected cells. Of fetuses that become congenitally infected, 10% will demonstrate microcephaly, growth restriction, hepatosplenomegaly, cytopenias, chorioretinitis, CNS impairment and sensorineural hearing loss at birth and have exhibited a death rate as high as 29%. In addition, of those asymptomatic at birth an additional 10-15% will develop symptoms, most commonly sensorineural hearing loss.10 The clinical significance and burden of these infections, difficulty of monitoring fetal infection and lack of effective in utero therapy has prompted the recommendations above.

The same recommendation has NOT been made for low birth weight neonatal transfusion. The primary rationale is that CMV is excreted in breast milk and breast milk transmission is of significantly higher risk than transfusion transmission. A prospective study involving 462 mothers of 539 infants with a birth weight less than or equal to 1500g demonstrated a maternal seroprevalence rate of 76.2%. Twenty seven of the 539 infants developed postnatal CMV infection secondary to CMV positive breast milk at 12 weeks, with 5 exhibiting symptomatic disease and 3 progressing to death .11 In addition, the risk benefit ratio is also altered with the fact that screening for CMV disease could be performed using either urine, saliva or dried blood spot analysis in most facilities that would care for low birth weight neonates. This would allow for treatment of CMV infection in the postnatal period with ganciclovir and other antiviral agents regardless of the method of infection. 10 There are also some that advocate for the protective nature of passive transfer of CMV antibodies in seroconverted donors in prevention of CMV infection in these breast fed infants. In addition, there has been no evidence of increased neonatal CMV disease in two Canadian facilities, the Hospital for Sick Kids and the Stollery Children’s Hospital, who have abandoned CMV seronegative component transfusion for low birth weight infants for more than 10 years.

References

1. Lancini DV, Faddy HM, Ismay S, Chesnau S, Hogan C, Flower RL. Cytomegalovirus in Australian blood donors: seroepidemiology and seronegative red blood cell component inventories. Transfusion 2016; 56 (6 Pt2): 1616-21

2. Roback JD. CMV and blood transfusions. Reviews in medical virology Jul-Aug 2002 12(4): 211-219

3. Furui Y, Satake M, Hoshi Y, Uchida S, Suzuki, K and Tadokora, K. Cytomegalovirus (CMV) seroprevalence in Japanese blood donors and high detection frequency of CMV DNA in elderly donors. Transfusion Complications. 2013 Volume 53, 2190-2197).

4. Preiksaitis JK. Prevention of transfusion-acquired CMV infection: is there a role for NAT? Transfusion. 2003 Mar;43(3):302-5.

5. Ziemann M, Krueger S, Maier AB, Unmack A, Goerg S, Henning H. High prevalence of cytomegalovirus DNA in plasma samples of blood donors in connection with seroconversion. Transfusion 2007 47(11):1972-83).

6. Drew WL, Tegtmeier GE, Alter HJ, Laycock ME, Miner RC, Busch MP. Frequency and duration of plasma CMV viremia in seroconverting blood donors and recipients. Transfusion 2003 43:309-13

7. Allain JP, Stramer SL, Carneiro-Prioetti AB, et al Transfusion Transmitted Infectious Diseases. Biologicals April 2009 37(2):71-77

8. Seed CR, Wong J, Polizzotto MN, Faddy H, Keller AJ, Pink J. The residual risk of transfusion transmitted cytomegalovirus infection associated with leucodepleted blood components. Vox Sang 2015 109:11-17.

9. Mainou M, Alahdab F, Tobian AA, Asi N, Mohammed K, Murad MH, Grossman BJ Reducing the risk of transfusion transmitted cytomegalovirus infection: a systematic review and meta-analysis. Transfusion 2016; 56(6 Pt2): 1569-80.

10. Nyholm JL, Schleiss MR. Prevention of maternal cytomegalovirus infection: current status and future prospects. Intl J Wom Health 2010; 2:23-35.

11. Josephson CD, Caliendo AM, Easley KA, Knezevic A, Shenvi N, Hinkes MT, Patel RM, Hilyer CD, Roback JD. Blood Transfusion and Breast Milk Transmission of Cytomegalovirus in Very Low-Birth-Weight Infants A Prospective Cohort Study. JAMA Pediatr. 2014 168(11): 1054-1062.

Appendices

ADDITIONAL RESOURCES CONSIDERED WHEN GENERATING RECOMMENDATIONS:

Neonatal Transfusion

Delaney M, Mayock D, Knezevic A, Norby-Slycord C, Kleine E, Patel R, Easley K, Josephson C. Postnatal cytomegalovirus infection: a pilot comparative effectiveness study of transfusion safety using leukoreduced only transfusion strategy. Transfusion 2016 Aug; 56(8):1945-50.

Hematopoietic Stem Cell Transplants

Hall S, Danby R, Osman H, Peniket A, Rocha V, Craddock C, Murphy M, Chaganti S. Transfusion in CMV seronegative T-depleted allogeneic stem cell transplant recipients with CMV-unselected blood components results in zero CMV transmissions in the era of universal leukocyte reduction: a UK dual centre experience. Transfusion Medicine. 2015; 25(6):418-23.

Kekre N, Tokessy M, Mallick R, McDiarmid S, Huebsch L, Bredeson C, Allan D, Tay J, Tinmouth A, Sheppard D. Is cytomegalovirus testing of blood products still needed for hematopoietic stem cell transplant recipients in the era of universal leukoreduction? Biol Blood Marrow Transplant. 2013;19(12):1719-24.

Nash T, Hoffmann S, Butch S, Davenport R, Cooling L. Safety of leukoreduced, cytomegalovirus (CMV)-untested components in CMV-negative allogeneic human progenitor cell transplant recipients. Transfusion. 2012 Oct;52(10):2270-2.

Thiele T, Kruger W, Zimmerman K, Itterman T, Wessel A, Steinmetz I, Dolken G, Greinacher A. Transmission of cytomegalovirus (CMV) infection by leukoreduced blood products not tested for CMV antibodies: a single-center prospective study in high-risk patients undergoing allogeneic hematopoietic stem cell transplantation. Transfusion. 2011;51(12):2620-6

Boeckh M, Nichols WG, Papanicolaou G, Rubin R, Wingard JR, Zaia J. Cytomegalovirus in hematopoietic stem cell transplant recipients: Current status, known challenges, and future strategies. Biol Blood Marrow Transplant. 2003 Sep;9(9):543-58.

Solid Organ Transplantation Preiksaitis JK, Sandhu J, Strautman M. The risk of transfusion-acquired CMV infection in seronegative solid-organ transplant recipients receiving non-WBC-reduced blood components not screened for CMV antibody (1984 to 1996): experience at a single Canadian center. Transfusion. 2002 Apr;42(4):396-402.

Preiksaitis J, Nahirniak S, Mabilangan C, Fearon M, O’Brien S. Residual risk of transfusionacquired cytomegalovirus (CMV) infection in CMV seronegative solid organ transplant recipients receiving CMV seronegative organs and leukodepleted blood products. 2015. Poster Presentation, Canadian Society of Transplantation.

International Practice

Heddle NM, Boeckh M, Grossman B, Jacobson J, Kleinman S, Tobian AA, Webert K, Wong EC, Roback JD. AABB Committee Report: Reducing Transfusion Transmitted Cytomegalovirus Infections. Transfusion. 2016 Jun; 56(6 Pt 2):1581-7.

Lieberman L, Devine DV, Reesink HW, Panzer S, Wong J, Raison T, Benson S, Pink J, Leitner GC, Horvath M, Compernolle V, Prado Scuracchio PS, Wendel S, Delage G, Nahirniak S, Dongfu X, Krusius T, Juvonen E, Sainio S, Cazenave JP, Guntz P, Kientz D, Andreu G, Morel P, Seifried E, Hourfar K, Lin CK, O'Riordan J, Raspollini E, Villa S, Rebulla P, Flanagan P, Teo D, Lam S, Ang AL, Lozano M, Sauleda S, Cid J, Pereira A, Ekermo B, Niederhauser C, Waldvogel S, Fontana S, Desborough MJ, Pawson R, Li M, Kamel H, Busch M, Qu L, Triulzi D. Prevention of transfusion transmitted cytomegalovirus (CMV) infection: Standards of care.Vox Sang. 2014 Oct;107(3):276-311.

Advisory Committee on the Safety of Blood, Tissues and Organs (SaBTO). Cytomegalovirus Tested Blood Components Position Statement. March 2012. Available online: http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/Publicat… dance/DH_132965. Accessed April 26th, 2016.

Smith D, Lu Q, YuanS, Goldfinger D, Fernando LP, Ziman A. A Survey of current practice for prevention of transfusion transmitted cytomegalovirus in the United States: Leucoreduction versus cytomegalovirus seronegative. Vox Sang Jan 2010; 98(1): 29-36.