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Passenger Leucocyte Syndrome

Ahrens, Norbert MD; Hutchinson, James A. MD, PhD

doi: 10.1097/TP.0000000000001430
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1 Department of Surgery, University Hospital Regensburg, Regensburg, Germany.

2 Institute for Clinical Chemistry and Laboratory Medicine, Transfusion Medicine, University Hospital Regensburg, Regensburg, Germany.

Received July 10, 2016.

Accepted July 14, 2016.

N.A. has no conflicts of interest to declare. J.A.H. serves as Scientific Advisor to Trizell Holdings SA, which holds all rights to commercialisation of the Mreg_UKR cell product.

Correspondence: Norbert Ahrens, MD, Institute for Clinical Chemistry and Laboratory Medicine, Transfusion Medicine, University Hospital Regensburg, DE-93053 Regensburg, Germany. (norbert.ahrens@ukr.de); James A. Hutchinson, MD, PhD, Department of Surgery, University Hospital Regensburg, DE-93053 Regensburg, Germany. (james.hutchinson@ukr.de).

Passenger leucocyte syndrome (PLS) is an infrequent, but potentially serious complication of solid organ transplantation that results in delayed haemolytic anemia and its sequelae. Hemolysis is caused by donor-derived, graft-resident B cells or plasma cells that begin to produce donor-reactive isoagglutinins after transplantation.1 Disease is usually self-limiting, but can extend to life-threatening reactions and multiorgan failure; therefore, an awareness of the aetiology, presentation and management of PLS is important for transplant physicians and transfusion specialists. This article collates online resources with relevance to the readership of Transplantation that provide guidance on the diagnosis and treatment of PLS.

Link Library

[A] http://www.uptodate.com/contents/red-blood-cell-antigens-and-antibodies#H1

[B] http://www.ncbi.nlm.nih.gov/projects/gv/mhc/xslcgi.cgi?cmd=bgmut/home

[C] https://learn.transfusion.com.au/

[D] https://learn.transfusion.com.au/course/view.php?id=370

[E] http://kdigo.org/home/guidelines/care-of-the-kidney-transplant-recipient/

[F] http://www.pathlabtalk.com/forum/index.php?/topic/4821-abo-incompatibility-and-stem-cell-transplantation/#comment-29840

[G] https://itunes.apple.com/us/app/rbcx-calculation-tool/id1023483387?mt=8

[H] https://play.google.com/store/apps/details?id=com.terumo.RBCXCalculationTool

The general incidence of PLS in solid organ transplantation is less than 1%, but approaches 20% in donor-recipient combinations with minor ABO incompatibility.2,3 Although minor ABO-incompatible transplantation is relatively uncommon because O-type organs are preferentially allocated to O-type recipients, this is not always the case in old-for-old programs. In most cases, PLS is related to anti-A or anti-B antibodies4; however, antibodies to Rh,5 Jka, Fya, and other blood group antigens have also been reported to cause PLS.6 An easily digestible overview of red cell antigens and antibodies is available through uptodate.com [A]. National Center for Biotechnology Information hosts dbRBC, which comprises the Blood Group Antigen Gene Mutation Database and related online tools [B]. Antibodies responsible for PLS, which can be IgG or IgM isotype, are secreted by donor-derived B cells or plasma cells transferred with transplanted organs. Accordingly, PLS is more common after lung or liver transplantation, when lymphoid tissue is transferred with the graft, than in renal transplantation.1 Nevertheless, it is now recognized that antibody-secreting donor cells are not entirely restricted to lymphoid tissues and may be carried over to the recipient as graft-infiltrating cells. It is currently unknown how donor B cells and plasma cells evade rejection by innate or adaptive mechanisms, but HLA compatibility, absence of NK cell determinants, and immunosuppression are probably important aetiological factors.7 The website of the Australian Red Cross offers an impressive portfolio of open-access transfusion-related resources, including mobile apps, podcasts, and educational materials [C]. The webcast by Dr. Chris Hogan on “Transfusion Support and Issues Associated with Transplantation” is highly recommended [D].

There is growing appreciation for the many, complex roles of passenger B cells and T cells in determining transplant outcome, both in terms of promoting and preventing graft injury. At one end of the spectrum, passenger leucocytes are essential for inducing allograft tolerance8 and may contribute to clearance of viral infections9; at the other end, passenger leucocytes can cause recipient bone marrow aplasia10 or drive the production of autoantibodies that cause transplant vasculopathy.11 The clinical manifestation of PLS reflects the restricted graft-versus-recipient reaction against red cell antigens only, but this picture may extend to lethal graft-versus-host disease if sufficient donor T cells also happen to be transferred.12 Passenger leucocyte syndrome typically presents with mild hemolytic anemia of sudden onset between 3 and 24 days after transplantation. The clinical course is usually self-limiting even if long-term mixed chimerism is detectable13; however, PLS antibodies may persist at detectable levels for 12 to 851 days after transplantation.3

A diagnosis of PLS is made in cases of posttransplant hemolysis with new antibodies against recipient red cell antigens. The differential diagnosis of transplantation-associated anaemia is la long list,14 but only infection- and IVIg-related hemolytic reactions typically present with such acute onset [E]. Because timely treatment of PLS can prevent its most severe consequences, it may be valuable to perform antibody screening when hemolysis is first suspected,15 although this suggestion has not been widely adopted into transplant guidelines. The PathLabTalk forum hosts an interesting thread on diagnosis of PLS [F].

Management of PLS depends upon the severity of anemia. Most cases are mild and self-limiting, but some patients require escalation of corticosteroid treatment and red blood cell transfusion. Occasionally, red blood cell exchange may be necessary to stop hemolysis, which is more likely after hematopoietic stem cell transplantation than solid organ transplantation. Required red cell exchange volumes can be conveniently calculated using cellular phone apps [G&H]. In very rare circumstances, additional measures may be needed, such as depletion of B cells and plasma cells with Rituximab.

In summary, passenger leucocyte syndrome remains a relatively infrequent, albeit potentially serious complication of solid organ transplantation. With several recent high-profile publications in the field, the roles of passenger leucocytes in transplant pathology is reemerging as a hot topic.

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