Wednesday, January 19, 2011

CMV, Serologic Testing, and Leukoreduction

For years, blood bankers and physicians have debated the relative merits of preventing CMV infection through the exclusive use of blood from donors who do not have demonstrable anti-CMV antibodies vs. blood that is leukocyte reduced. The data is mixed, and the two methods seem to be nearly equivalent (and imperfect). Why both fail at roughly the same low rate (about 1-4%) has never been particularly clear to me, until recently.

Background: Cytomegalovirus (CMV) is a human herpes virus that is extremely common in the United States (and elsewhere). At least 50% of blood donors have been infected at one point or another, but in healthy people, that is no big deal. In people that have compromised immune systems, however, such as CMV-negative solid-organ and progenitor cell transplant recipients and premature neonates, CMV can be absolutely devastating. Potential consequences include overwhelming hepatitis, retinitis, and pneumonitis, and if transmitted to a fetus by an infected mother, can result in mental retardation, blindness, deafness, and death.

Given the above, it is clearly incumbent on blood banks to provide blood that has as little risk as possible to those most susceptible to CMV's effects. As above, this includes those with substantially compromised immune systems, as well as those expected to have significant compromise soon (chemotherapy patients and those about to start preparation for a progenitor cell transplant, to name a couple).

Traditionally, in these settings, clinicians would simply order "CMV-negative" blood, and that is what blood banks would try to provide. "CMV-negative" (or "CMV-seronegative") simply means that the donor has been tested and is negative for the presence of anti-CMV antibodies. This process is not enormously difficult, but it can be difficult to find blood for a particular patient that has the appropriate testing sometimes. As a result, the blood bank industry looked for an option, and when a major study was published in 1995 in Blood (Bowden, et al), we thought we had nailed it! That study compared the use of CMV-negative blood products with blood that was leukocyte-reduced, with near equivalent results (the logic behind this is explained in an FAQ on the bbguy site).

Since the Bowden study came out, there has been much debate and much back and forth on this issue, with the discussion between the blood bank and clinicians usually going something like this:

  • Clinician: "I'd like CMV-negative blood for my patient, please"
  • Blood Banker: "You know, leukoreduced blood has the same risk as CMV-negative blood"
  • Clinician: "I'd like CMV-negative blood for my patient, please"
  • Blood Banker: "The AABB considers them equivalent"
  • Clinician: "I'd like CMV-negative blood for my patient, please"
  • Blood Banker: "I'll have to try and find some; I stopped testing last year"
  • Clinician: "I'd REALLY like CMV-negative blood for my patient, please"
You get the idea. Blood bankers like the leukocyte reduced idea, while clinicians tend to favor the seronegative option. As I mentioned above, however, it is important to recognize that both methods fail, and at about the same rate (1-4% or so). I recently read a discussion of this issue in a new edition of a book from AABB Press called Transfusion Therapy: Clinical Principles and Practices (3rd ed) that shed new light on this issue for me. I am indebted to that book for the rest of this discussion.

Let's take a second to understand how each method works, and describe the weakness of each test.
  • CMV serology testing: A fairly sensitive and specific enzyme immunoassay or hemagglutination assay is used to detect antibodies against CMV. Either test is good and reliable, but our main problem is with acutely infected donors that have not seroconverted yet ("window period" donors). Main method vulnerability: Window period infections.
  • Leukocyte reduction (LR): LR is thought to work for CMV prevention because in established CMV infections, the virus is limited to a small number of monocytes (1 to 25 CMV-infected cells per million white cells) and isn't floating around free in plasma. LR is so efficient at removing all WBCs (99.99% or more using currently available technology) including monocytes means that the load is reduced below infectious levels. If, however, CMV was free in plasma, LR would have essentially NO preventive effect. Main method vulnerability: CMV in plasma.
As it turns out, there is significant overlap between these two vulnerabilities, and that overlap is obvious when we analyze the acute stage of CMV infection. During the first 6-8 weeks after infection, no antibody is detectable because the body has not yet responded (the window period). In addition, during those 6-8 weeks, CMV actually does circulate in plasma ("viremic stage") in substantial numbers. As a result, it seems clear that the acutely infected, window period, viremic donor has an infection that could elude either method, potentially leading to CMV disease in a susceptible recipient. In other words, the most likely donors to give failures of either method are from exactly the same group! As a result, several authors have suggested that the "safest" blood may actually be from those donors that are CMV-positive (indicating an established infection and avoiding the window period) AND leukocyte reduced (removing the small numbers of infected cells). I don't think that strategy is popular at this point, however!

Bottom line: Both methods are good for CMV transmission prevention, and the methods are probably equivalent in non-acutely infected donors. Chances are good that the failures would be failures no matter the method used, according to the discussion above. I believe that individual facilities must have the discussion about how they will handle this, however, and stick to that policy (whichever method is favored). My personal belief is that the two methods are interchangeable, and that is usually my advice to inquiring blood bankers and clinicians.