Passenger Lymphocyte Syndrome Following Solid Organ Transplantation: Graft Source, Incidence, Specificity, Duration, and Severity Of Hemolysis
Authors: Marton Ashley , Pendergrast Jacob M , Keshavjee Shaf , Singer Lianne , Hawes Janice , Cserti-Gazdewich Christine 
Published: October 2019

Abstract

Background
Passenger Lymphocyte Syndrome (PLS) is a rare complication of solid organ transplantation (SOT) and is marked by production of donor-derived antibodies towards host red blood cell (RBC) antigens. At Canada's largest SOT program, >400 transplants are conducted annually. The affiliated Transfusion Laboratory detects possible cases of PLS when previously seronegative hosts develop (delayed, non-transfusion-attributable) post-transplant antibodies (Ab) bearing unexpected, autoreactive (rather than alloreactive) RBC specificities. Donor attributability is established by discovery of the same specificity (on serologic lookback) and/or by the antithetical (seroconversion risk) phenotype. The incidence, duration, and severity of PLS remain unknown due to the infrequency of reported cases and the general absence of active surveillance.

Method
Between 1/10/2006 – 30/06/2013, PLS cases were discovered by the Blood Bank through pre-transfusion specimens. The specificities, phase (direct or indirect), correlative markers of hemolysis, and temporal profile of the Ab were subsequently followed according to patient and clinician interest. The severity of hemolysis (grade 0 to 5) at the time of nadir hemoglobin was judged according to the tiers defined by the Canadian Blood Services/IVIG Hemolysis Pharmacovigilance Group (CL#2011-34). Implicated organ and donor review (for relevant serology, and outcomes in any parallel organ distributions) were also attempted.

Results
Over 88 months, 2772 transplants occurred (992 kidney, 187 pancreas [with/after kidney in 113/74 respectively], 909 liver, 529 lung [437 double, 83 single, 9 +heart], 151 heart, 4 bowel). PLS was found in 14 or 0.5% (sex: 5F: 9M; mean age 56 years), with the implicated organ being lung or liver (9 [2%] and 5 [0.6%] respectively). All had a negative pre-transplant DAT with a pre-sensitized donor. PLS Ab specificities included ABO (8: 5A, 3B), RH (5 with ≥1 target [C:3, D:5, E:2, V:1]), and others (KIDD: Jka in 2; MNS: N in 1; unidentified in 1). Multiple Ab occurred in 5 (36%), usually within the same system (3 RH cases: C,D,E in 2; C,D,V in 1), but otherwise towards ABO + ≥1 target (B,Jka,N; B, unidentified). The time to the first detectable expression of an Ab (as signaled by a +DAT and/or screen) was 4-120 days (mean 24, median 15, n=14). Clinically significant hemolysis occurred in 11 (79%), with six grade 3 and five grade 4; the duration of hemolysis was 0-776 days (mean 148, median 38, n=11). The duration of Ab detectability (or the point of “last positivity”) was 12-851 days (mean 196, median 78, n=10), while the point of disappearance (“subsequent sustained negativity”) occurred between day 12-1288 (mean 298, median 45, n=10). Lookbacks were feasible with 5 implicated donors, and in only 1 case (of a contralateral lung's transplantation) was PLS detected in another recipient. PLS did not account directly for any deaths in the cohort, although hemolytic morbidity required treatment in 2 cases. Transfusion support with antigen-negative blood was provided to 11 patients for anemia that may have been due to hemolysis and/or other causes while the Ab was still evident. In one case, severe hemolysis provoked rate-uncontrolled atrial fibrillation with a supply and demand ischemia which culminated in irreversible congestive heart failure and cardiac death 2 months after PLS resolution.

Discussion/Conclusions
This is the largest series of PLS reported to date. Clinician-driven submissions of blood for transfusion compatibility testing, and the discovery of discrepant serologies, represented an unforced but prospective means by which to identify PLS in roughly 1 in 200 transplants. Several cases transcended the limits of previously described temporal profiles (with the most delayed onset at 120 days, and the most prolonged duration at 2.3 years). The duration of hemolysis was consistently shorter than the duration of seropositivity, and was rarely life-threatening, while the most severe grades associated with RH rather than ABO or other targets. The surveillance achieved in this cohort revealed a longer-than-previously-appreciated duration of Ab productivity, and raised the question of whether or not such prolongation is a function of observation bias or the current-day armamentarium of anti-rejection therapeutics, which may be more permissive to donor-derived chimerism.

Disclosures:
No relevant conflicts of interest to declare.