Passenger lymphocyte syndrome with severe haemolysis misdiagnosed/treated as cold agglutinin syndrome: Analysis of case and diagnostic error

Abstract

Dear Editor, Passenger lymphocyte syndrome (PLS) may occur following a minor ABO-incompatible solid organ transplant when donor lymphocytes within the transplanted graft produce antibodies against recipient red blood cell (RBC) antigens. A 69-year-old male with a history of cirrhosis and hepatocellular carcinoma underwent minor ABO-incompatible orthotopic liver transplantation, requiring no blood products perior post-operatively. Early immunosuppression with tacrolimus and mycophenolate was transitioned to cyclosporine and prednisone. Five days following discharge (12 days post-transplant), the patient was readmitted for exertional dyspnea, hypotension, anaemia (haemoglobin 4.8 g/dL; reference: 14.0–18.1 g/dL), and mildly elevated total bilirubin (1.8 mg/dL; reference: 0.2–1.2 mg/dL). The anaemia was suspected to be secondary to acute blood loss compounded by suppression of erythropoiesis secondary to immunosuppressive medications. Type and screen and red blood cells (RBCs) were ordered, but the blood bank was not notified of the minor ABO-incompatible status of the transplant. Historical medical records included AB RhD-positive blood type and negative antibody screen prior to transplant. Upon ABO typing, the patient s RBCs demonstrated possible spontaneous agglutination that dispersed when washed with phosphate-buffered saline. This was interpreted as rouleaux, and the ABO type was reported as AB RhD-positive with a negative antibody screen. Three units of AB RBCs were transfused. Post-transfusion labs were significant for a haemoglobin of 7.0 g/dL, elevated lactate dehydrogenase (LDH) (365 U/L; reference: 125–220 U/L), and deceased haptoglobin (<8 mg/dL; reference: 40–273 mg/dL). Over the next 3 days, the patient remained anaemic despite transfusion of five additional units of AB RBCs. LDH continued to rise to 403 U/L and haptoglobin remained <8 mg/dL. Peripheral blood showed reticulocytosis (17.0%; reference: 0.5–1.8%), polychromasia, and microand macro-spherocytes. Direct antiglobulin testing (DAT) was performed and showed C3 (1+ reactivity), but no IgG (0 reactivity) bound to RBCs. Cold agglutinin (CA) titres at 4 C were not detected. A full CA screen was not ordered; however, the patient was diagnosed with cold agglutinin syndrome (CAS) by the haematology clinical team. A second ABO type and screen demonstrated ABO discrepancy: a forward type consistent with type AB, but agglutination on reverse typing when patient plasma was tested against A1 reagent RBCs. This discrepancy was presumably secondary to CAs given the initial diagnosis of CAS. Haematology and transplant services were reluctant to increase immunosuppression, believing CAS was secondary to underlying active infection; therefore, plasma exchange (PLEX) with type AB plasma was performed for 5 days for transfusion-refractory anaemia, during which 10 additional units of AB RBCs were administered. Extensive evaluation for infectious organisms was ultimately negative. Following PLEX, the patient s haemoglobin stabilised, and haptoglobin and LDH normalised. The patient remained above the transfusion threshold for 5 days before requiring three additional units of AB RBCs over the following 2 days. During transfusion of the third unit of RBCs, administered immediately following the second unit, he experienced a sudden onset of chills, dyspnea, hypotension, tachycardia, and tachypnea, and a transfusion reaction evaluation was performed. A chest radiograph showed no significant interval change. The preand post-transfusion samples demonstrated an ABO discrepancy with agglutination on reverse typing with A1 reagent RBCs. DAT performed on the post-transfusion sample was negative for IgG and C3. However, laboratory values were significant for LDH of 526 U/L (215 U/L prior to transfusion), haptoglobin <8 mg/dL (45 mg/dL the day prior), and total bilirubin 17.4 mg/dL (4.0 mg/dL before transfusion). It was then discovered the patient had received a minor ABOincompatible transplanted liver from a blood type B donor. This had never been communicated to the blood bank. An anti-A1 titre was significant for a titre of 8. Testing of the patient s RBCs with anti-A1 Dolichos bifloris lectin did not result in RBC agglutination; however, patient plasma agglutinated both A1 RBCs (3+ reactivity) and A2 RBCs (1+ reactivity), indicating the original agglutination seen in the reverse type with A1 reagent RBCs was due to anti-A, and not specifically anti-A1. These findings suggested PLS resulting from a type B liver allograft containing lymphocytes producing anti-A. Therefore, the patient was switched to type O RBCs and immunosuppression was increased. The patient stabilised, haemolysis biomarkers began to normalise, and he was discharged 3 days later. PLS is a documented but under-recognised aetiology of anaemia following organ transplantation, most frequently associated with ABO-mismatched transplants. In rare cases, PLS may occur in patients who receive ABO-identical organs due to minor RBC antigen mismatches between donor and recipient. PLS occurs when B Received: 8 January 2021 Revised: 10 March 2021 Accepted: 24 March 2021