Passenger lymphocyte syndrome (PLS) is an immune response that occurs as a result of graft-versus-host interaction. This results in immune-mediated hemolysis. It usually occurs in minor ABO and Rh mismatched transplants. It was initially reported in patients who received minor-mismatched kidney grafts. Passenger lymphocyte syndrome is an important cause of immune hemolysis after organ transplantation. It occurs when viable B-lymphocytes are passively transferred to the recipient, and antibodies are formed, resulting in red blood cell destruction.
How Does Passenger Lymphocyte Syndrome Occur?
In recent times there has been an increased demand for organ transplantation with a shortage in organ supply. Passenger lymphocyte syndrome occurs mainly after an organ transplant, hematopoietic stem cell or administration of B cell-rich cellular infusion. It is mostly seen in minor ABO mismatches; for example, the donor group is O-type, and the recipient group is A-type. If the ABO or Rh is mismatched in the transplant, it causes this condition. Viable donor B-lymphocyte and/or plasma cells are transferred with the transplanted organ. They continue or are stimulated to produce antibodies against the recipient's red blood cell antigen.
The donor passenger lymphocyte causes antibody production against the recipients' red blood cell antigens, which leads to complement-mediated hemolysis. It has been observed after lung, kidney, liver, pancreas, heart-lung, pancreas-spleen, and hematopoietic cell transplantation. The transported B-lymphocyte produces antibodies against recipient red blood cells, which results in hemolysis (destruction of RBCs). The donor lymphocytes are believed to travel from the graft to the recipient's blood and thereafter to bone marrow or lymphoid tissues, including lymph nodes and thymus. More the volume of the transplanted tissue, the more the incidence of hemolysis. It can also occur in other blood group systems like Rh, K, Fy, and Kidd, where the donor lacks the recipient's antigens. In some cases, immunosuppressive therapies which target T-lymphocytes can give way to PLS development by permitting the proliferation of B-lymphocytes and, thereby, antibody production.
How Does Passenger Lymphocyte Syndrome Progress?
Passenger lymphocyte syndrome is commonly associated with a minor ABO mismatch between the donor and recipient. Since the HLA system is inherited independently of the ABO system, the mismatch is quite common. However, out of these, only 10-15% result in immune hemolysis due to the antibodies produced by the passenger lymphocytes. PLS occurs 5-15 days after transplantation. Although the majority of the PLS results from anti-A or anti-B production due to ABO mismatch, a small number of cases have been reported to occur due to non-ABO antibodies. The risk of hemolysis increases with the mass of lymphocytes transplanted with the graft. The higher the lymphocyte count, the higher the risk. It is more frequent in lung-heart transplants, followed by liver and kidney transplants. When the donor lymphocytes proliferate, they cause an immune response, and hemolysis may start 5 to 15 days after the transplant. In most cases, hemolysis is self-limiting. Most cases do not continue beyond 170 days. Hemolysis stops as antibody production declines. This occurs if B-lymphocytes fail to renew or the graft tissue develops a tolerance to the recipient antigen. In rare cases, B-lymphocytes, when transferred and stimulated, have been found to be capable of sustained antibody production. In these cases, hemolysis can continue even beyond 170 days.
What Are the Types of ABO-Mismatches?
There may be major, minor, or bi-directional mismatches in transplantation.
1. Major ABO-Mismatches: Occur when recipient A or B antibodies are directed against the ABO antigens on the graft. For example, an A-type donor graft is transplanted into an O-type recipient.
2. Minor Mismatches: Occur when the recipient expresses an ABO antigen that is not present in the donor graft. For example, an O-type donor into an A-type recipient. It can also occur if an A-type or B-type donor is transplanted into an AB-type recipient. This occurs when there is a limited supply of organs and an increased need for transplantation. This type can cause delayed hemolysis after PLS.
3. Bi-directional Mismatches: Occur when, for example, an A-type donor is transplanted into a B-type recipient. This is a combination of major and minor mismatch, and the recipient is at risk of both host-vs-graft and graft-vs-host reactions.
A bidirectional incompatibility occurs when simultaneously both major and minor incompatibilities are present:
If a group B recipient receives from a group-A donor, it is a major incompatibility.
It is a minor incompatibility if the anti-B in donor plasma reacts with the antigen B of the recipient.
What Are the Risk Factors of Passenger Lymphocyte Syndrome?
Some of the reported risk factors for PLS include:
Previous red blood cell sensitization, such as pregnancy and blood transfusions.
O-type donor to A or B-type recipient.
Infection immediately after transplantation.
What Are the Clinical Features of Passenger Lymphocyte Syndrome?
Independent of the type of graft, PLS develops 1-3 weeks after the transplant.
It is usually self-limiting but rarely can cause death if associated with the following:
How Is Passenger Lymphocyte Syndrome Diagnosed?
Physicians should watch out for jaundice or anemia within three weeks of the transplant. Confirmation is done by biochemical tests such as the direct antiglobulin test (DAT). It can help identify antibodies derived from the donor.
How Is Passenger Lymphocyte Syndrome Treated?
Passenger lymphocyte syndrome is usually a self-limiting condition. If it requires treatment, it can be successfully treated with blood transfusions. The important step in this is that the transfused blood should be identical to that of the donor if PLS is suspected. Using the donor's ABO type replaces the red blood cells that are susceptible to hemolysis.
Some studies recommend waiting until the specific antibodies have been developed to confirm the diagnosis.
Rituximab has been used in some studies, while the use of corticosteroids has differing and conflicting opinions. Rituximab targets B-lymphocytes.
If an ABO mismatched organ is received by a patient, the physician should be monitoring for PLS. If the patient develops jaundice and anemia, PLS can be suspected. The hemolysis can lead to the destruction of red blood cells, which results in anemia and increased bilirubin which causes jaundice. If suspected, the patient can be tested for autoantibodies, and once the diagnosis is confirmed, a blood transfusion may be done.
Other treatment modalities include immunosuppressive therapy, corticosteroids, and immunomodulation.
Passenger lymphocyte syndrome is cell-mediated hemolysis (destruction of red blood cells) that most commonly occurs after a minor ABO mismatched organ or bone marrow transplant. Viable B-lymphocytes are transferred along with the organ, which produces antibodies against the red blood cells of the recipient, causing hemolysis. It is usually rare and self-limiting. A physician can monitor a patient who has received a mismatched organ. If the patient develops jaundice or anemia, PLS can be suspected. If the disease is not self-limiting, a blood transfusion can be done after confirming the diagnosis.