DIAGNOSIS
Passenger Lymphocyte Syndrome
DISCUSSION
What is passenger lymphocyte syndrome:
Passenger lymphocyte syndrome (PLS) is a specific type of graft-versus-host disease resulting in an immune-mediated hemolysis in the post-transplant patient. Initially reported in the 1980s in patient's receiving minor-mismatched renal allografts, PLS occurs when viable donor B-lymphocytes are passively transferred to the recipient within the allograft and form antibodies that result in complement-mediated red blood cell destruction.
Types of ABO-mismatches in transplantation:
Major ABO-mismatches occur when preformed recipient A/B antibodies are directed against donor ABO antigens present on the allograft. An example of this type of mismatch would be an A-type donor allograft being transplanted into an O-type recipient.
Minor mismatches occur when a recipient expresses an ABO antigen not present in the donor allograft. An example of this type of mismatch include: O-type donor allograft into an A-type recipient or an A/B-type donor allograft into an AB recipient. These types of transplants are occurring more frequently in response to the limited supply of organs to meet the increasing demands for transplantation. However, this type of mismatch transplant put the recipient at risk of developing delayed hemolysis secondary to PLS.
Bi-direction mismatches are a combination of major and minor mismatches. An example of this type of mismatch would be an A-type donor allograft being transplanted into a B-type recipient. This places the recipient at risk for both host-vs-graft and graft-vs-host disease.
What is the pathogenesis of PLS:
In the setting of a minor-ABO mismatched allograft, stimulated donor B-lymphocytes produce antibodies against antigen present on the recipient's red blood cells shortly after transplantation. Hemolysis occurs via complement-mediated red blood cell destruction. It is postulated that donor lymphocytes migrate from the allograft into the recipient's blood and then to the bone marrow or secondary lymphoid tissue including spleen, thymus, and lymph nodes. The volume of lymphoid tissue transplanted with the allograft appears to play an influence on the incidence of antibodies and hemolysis when comparing various types of allograft. Heart and lung transplants have the highest incidence of PLS, followed by liver transplant, and then kidney transplants. Immunosuppressive therapies targeting T-lymphocytes following allograft transplantation can provide a permissive effect on the development of PLS by permitting the rapid proliferation of spared donor B-lymphocytes and antibody production. Better HLA-matching will result in less effective clearing of donor B-lymphocytes from the recipient, increasing the risk of PLS. Rare cases of PLS involving antigens outside the ABO-group have been reported. The majority of cases involve anti-D, but individual cases have been seen with anti-c, anti-e, anti-Kell, anti-Jka, anti-Fya. The risk of developing PLS in these cases is higher when the donor has been sensitized to other RBC antigens via a previous transfusion or pregnancy which primes lymphocytes to produce an amnestic response in the recipient.
Clinical manifestations and laboratory diagnosis:
PLS typically presents 1-3 weeks post-transplant, with a time course independent of the type of allograft transplanted. The clinical syndrome is typically mild and self-limiting. However, rare significant morbidity and mortality can occur with acute renal failure, disseminated intravascular hemolysis, hypotension, and multiorgan system failure. Severity is influenced by a combination of the quantity of lymphoid tissue transplanted, donor titer of isoagglutinins, and the rise in antibody titer in the recipient after transplant.
Confirmation of the syndrome includes biochemical identifiers of hemolysis: low haptoglobin, high transaminases, and unconjugated bilirubin. Positivity of the direct antiglobulin test (DAT) typically coincides with the development of donor-derived antibodies. These antibodies are most frequently IgG, although IgM can develop. The antibodies are fairly short-lived, lasting a median of 5 weeks in renal transplants and 2-3 weeks in liver transplants. The identification of donor attributed anti-recipient antibody in the recipients sera is the final piece of diagnostic evidence. PLS generally resolves within 3 months.
Treatment of Passenger Lymphocyte Syndrome:
Most cases of PLS are treated by transfusion of blood products. Red blood cell products should be of the donor's ABO-type. Using the donor's ABO-type replaces susceptible red cells with cells that will not be hemolyzed. Plasma products should be of the recipient's ABO-type. In our particular case, the donor was type-B and the recipient was type-AB. Transfusion with either B or O-type blood would be indicated if necessary.
Using the recipient's ABO-type will reduce the risk of hemolysis by providing soluble ABO-antigen capable of neutralizing donor-derived antibodies.
In cases of severe hemolysis, plasmapheresis and red-cell exchange with donor ABO-type red cells. However, there is a lack of data proving the efficacy of these treatments. Utilizing B-lymphocyte targeted therapy such as Rituximab has been used with reported success. Other treatment modalities include increasing the patient's immunosuppressive therapy, immunomodulation with IVIG, and corticosteroids. However, there are a limited number of studies regarding the efficacy of these therapies.
Other causes of Post-transplant anemia:
There are several causes of post-transplant anemia. A useful way to understand classify the various etiologies is by when the anemia develops in relation to the time of transplant.
Several diagnostic studies can be used to determine the etiology of the anemia. Blood cultures, CMV antigens, Parvovirus IgM, and B19 DNA can be used to rule out infectious causes. Haptoglobin, LDH, unconjugated bilirubin, and direct antibody tests can rule out hemolytic causes. Bone marrow biopsy can be utilized for aplastic anemia and PTLD. Autoimmune hemolytic anemia typically occurs after many months to years and is an uncommon cause of post-transplant hemolytic anemia. During drug mediated hemolysis, the offending drug acts as a hapten and generated immune complexes on the red blood cell. This leads to a positive DAT without detectable autoantibodies. It is important to note that a significant number of patients will not have an identifiable cause of their anemia.
REFERENCES
Contributed by Bryan Stevens, MD and Alesia Kaplan, MD
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