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Abstract
Rationale: Passenger lymphocyte syndrome (PLS) may complicate minor ABO mismatched lung transplantation (LuTX) via donor-derived red cell antibody-induced hemolysis.
Objectives: To ascertain the incidence and specificity of PLS-relevant antibodies among the study population as well as the dynamics of hemolysis parameters and the transfusion requirement of patients with or without PLS.
Methods: In this cohort study, 1,011 patients who received LuTX between January 2010 and June 2019 were studied retrospectively. Prospectively, 87 LuTX (July 2019 to June 2021) were analyzed. Postoperative ABO antibody and hemolytic marker determinations, transfusion requirement, and duration of postoperative hospital care were analyzed. Retrospectively, blood group A recipients of O grafts with PLS were compared with those without.
Measurements and Main Results: PLS affected 18.18% (retrospective) and 30.77% (prospective) of A recipients receiving O grafts, 5.13% of B recipients of O grafts, and 20% of AB patients receiving O transplants. Anti-A and anti-A1 were the predominant PLS-inducing antibodies, followed by anti-B and anti-A,B. Significantly lower hemoglobin values (median, 7.4 vs. 8.3 g/dl; P = 0.0063) and an approximately twice as high percentage of patients requiring blood transfusions were seen in PLS. No significant differences in other laboratory markers, duration of hospital stay, or other complications after LuTX were registered.
Conclusions: Minor ABO incompatible LuTX recipients are at considerable risk of developing clinically significant PLS. Post-transplant monitoring combining red cell serology and hemolysis marker determination appears advisable so as not to overlook hemolytic episodes that necessitate antigen-negative transfusion therapy.
Passenger lymphocyte syndrome is a poorly studied and largely underrecognized graft-versus-host phenomenon with the potential to complicate the postoperative course of ABO minor incompatible lung recipients.
A high incidence of passenger lymphocyte syndrome was determined, associated with clinically relevant anemia and increased transfusion requirement. Novel insights into causative antibody specificities and diagnostic approaches are provided.
The number of patients listed for organ transplants by far exceeds the number of available organs (1). Lung transplantation (LuTX) is preferably performed using ABO blood group identical donors (2). However, blood groups are not distributed equally, with a more pronounced organ shortage in less frequent phenotypes (1, 3). A way to alleviate this problem is to transplant across ABO blood group barriers with a nonidentical but compatible (“minor incompatible”) match (1, 4). In minor ABO incompatibility, the donor has antibodies against the recipient’s red blood cell (RBC) antigens (5), as is the case for donors of blood group O and recipients of any non-O graft (A, B, or AB) (4). Blood groups A and AB can be differentiated into A1/A2 and A1B/A2B. A1 RBCs express A and A1 antigens, whereas A2 RBCs only carry A antigens (6). Anti-A and anti-B are generally present in individuals lacking the corresponding antigen, whereas anti-A1 occurs in O, B, and a minority of A2 and A2B individuals (7). Consequently, only in the presence of donor-derived anti-A1, transplants from A2 to A1 or A2B to A1B are ABO minor incompatible.
Passenger lymphocyte syndrome (PLS) is a graft-versus-host disease occurring after minor incompatible solid organ or stem cell transplantation (4, 8). Along with the graft, donor B lymphocytes are transferred to the recipient that, for the duration of their lifespan, may produce antibodies against recipient RBCs capable of inducing hemolysis (4, 6). Many patients with PLS require blood transfusion. Rarely, severe courses can lead to acute renal failure, arterial hypotension, disseminated intravascular coagulation, multiorgan failure, and death (4, 9, 10).
To date, mainly case reports of PLS after LuTX have been published (8, 11–13). This large cohort study of a high-volume LuTX center aimed to determine the incidence of PLS in LuTX, to identify pathogenic antibody specificities, and to explore the clinical PLS consequences.
The investigation was a cohort study and was approved by the local ethics committee (EK-No. 1463/2019). For the retrospective study, all LuTX performed at the Department of Thoracic Surgery at the Medical University of Vienna between January 2010 and June 2019 were included. Prospectively, all patients receiving ABO minor incompatible or potentially incompatible (A to A, AB to AB) LuTX between July 2019 and June 2021 were investigated. Further inclusion/exclusion criteria are visualized in Figures 1A and 1B. All patients received a triple immunosuppressive regimen consisting of tacrolimus, prednisolone, and mycophenolate mofetil. From 2012, alemtuzumab induction was introduced as standard, and mycophenolate mofetil was added 1 year post-transplant in these cases.
Figure 1. (A) Patient inclusion/exclusion flowchart for the retrospective cohort. The process of patient inclusion/exclusion for the retrospective study. (B) Patient inclusion/exclusion flow chart for the prospective cohort. The process of patient inclusion/exclusion for the prospective study. Don = donor; Np = number of prospective patients; Nr = number of retrospective patients; PLS = passenger lymphocyte syndrome; POD = postoperative day; Rec = recipient.
[More] [Minimize]Hemoglobin (HGB), haptoglobin, total bilirubin, lactate dehydrogenase (LDH) values, and immunohematologic results of the first 52 postoperative days (PODs) were collected. This time frame was based on described antibody appearance and persistence in previous publications (8, 11, 13–15). All patients underwent daily routine laboratory investigations in the ICU setting (including HGB, total bilirubin, LDH) and as needed on the general ward. The average number of laboratory assessments for retrospective patients with PLS and all prospective patients was 28 and 24, respectively, in the first 52 PODs. The duration of the ICU and primary hospital stay, transfusion requirement, and common post-transplant complications were evaluated. The median follow-up times for postoperative complications of PLS and control patients (group A patients receiving O grafts) were 7.5 and 7.3 years, respectively.
For all blood group serological investigations, reagents, test RBC preparations (routine screening test RBC panels and A1, A2, B, and O RBCs), and gel centrifugation cards from Bio-Rad were used. For the diagnosis of PLS, results of direct antiglobulin test (DAT), indirect antiglobulin test (IAT) of patient plasma, and antibody specification of RBC eluates by IAT were compiled to identify donor-derived ABO antibodies against recipient RBCs.
Statistical analysis was performed under pseudonymization. Mann-Whitney U tests were used for group comparison. Graphs showing proportions include the SEM. A GNU/Linux system running Debian Bullseye and using neovim version 0.4.4 as an integrated development environment as well as Nvim-R/nvimcom to interact with GNU R was used, with the following GNU R packages: ‘ggpubr,’ ‘tidyverse,’ and ‘tableone’ (16–19). This was an exploratory study. P values were not corrected for multiple testing and must be interpreted as purely descriptive.
From January 2010 to June 2019, a total of 1,035 LuTX were performed. After application of the exclusion criteria, 1,011 transplants were analyzed. Among the 136 ABO-nonidentical LuTX recipients, 15 (11.03%) presented with irregular ABO antibodies indicative of PLS, which was also true for 1 of 401 A patients with an A donor. Three-fourths of all PLS cases occurred in A recipients receiving O grafts, representing 18.18% (12 of 66) of the recipients with this blood group constellation. In B and AB recipients receiving O organs, 5.13% (2 of 39) and 20% (1 of 5) showed evidence for PLS, respectively (Table 1).
| ABO Don>Rec | PLS Cases/Transplants in Total | Proportion (%) |
|---|---|---|
| O>A* | 12/66 | 18.18% |
| O>B | 2/39 | 5.13% |
| O>AB | 1/5 | 20.00% |
| A>AB | 0/15 | — |
| B>AB | 0/11 | — |
| A>A | 1/401 | 0.25% |
| AB>AB | 0/51 | — |
| B>B | 0/114 | — |
| O>O | 0/309 | — |
The PLS cases of the retrospective cohort including immunohematologic results are detailed in Table E1 in the online supplement. The plasma IAT of 13 (81.25%) of the 16 cases suggested irregular anti-A1 antibodies. In three cases (R14, R15, and R16), anti-A (possibly including anti-A1) was detected, as evidenced by reactivity of RBC eluates with both A1 and A2 test cells. Anti-A1 was confirmed via eluate testing in three cases (R3, R12, and R13). Irregular anti-B was determined twice (R4 and R7). Patient R2 showed a positive postoperative DAT, combined with positive serologic cross-matching for a group A RBC unit in the absence of non-ABO antibodies, arguing for irregular anti-A or anti-A1.
In the retrospective cohort, DAT and IAT were only performed when RBC transfusions were required or when immune-mediated hemolysis was suspected, likely missing subclinical PLS cases. Eluate testing was not performed routinely. The first antibody detections of individual patients took place between PODs 7 and 37 (median, 16.5).
To study a population as homogeneous as possible, solely blood group A recipients receiving O grafts were investigated for comparison of clinical courses between patients with PLS and control patients. Baseline characteristics of both cohorts, such as age, sex, underlying pulmonary disease, Lung Allocation Score, and transplant type and size, were very similar (Table 2). Importantly, both cohorts exhibited almost identical preoperative HGB levels and perioperative (until POD 3) RBC transfusion requirements. In contrast, a statistically significant difference in lowest postoperative HGB values was seen: The median lowest HGB value of the PLS cohort was 7.4 g/dl compared with 8.3 g/dl in control subjects (P = 0.0063; Mann-Whitney U test) (Figure 2).
| Variable | PLS | Control |
|---|---|---|
| Number of patients per cohort | 11 | 35 |
| Sex (%) | ||
| Male | 4 (36.4) | 19 (54.3) |
| Female | 7 (63.6) | 16 (45.7) |
| Age, yr, median [IQR] | 49.00 [26.00, 59.50] | 55.00 [35.00, 61.00] |
| LAS, median [IQR] | 62.44 [33.75, 83.00] | 41.79 [35.88, 81.35] |
| ECMO, n (%) | ||
| Intraoperative HLM, postoperative ECMO | 1 (9.1) | 0 (0.0) |
| Intraoperative | 7 (63.6) | 22 (62.9) |
| Intra- and postoperative | 0 (0.0) | 6 (17.1) |
| Pre- and intraoperative | 0 (0.0) | 4 (11.4) |
| Pre-, intra-, and postoperative | 3 (27.3) | 2 (5.7) |
| None | 0 (0.0) | 1 (2.9) |
| Diagnosis (%) | ||
| Chronic obstructive lung disease | 3 (27.3) | 6 (17.1) |
| Interstitial lung disease | 3 (27.3) | 15 (42.9) |
| Idiopathic pulmonal hypertension | 0 (0.0) | 4 (11.4) |
| Cystic fibrosis | 4 (36.4) | 4 (11.4) |
| Other | 1 (9.1) | 6 (17.1) |
| Single/double transplant (%) | ||
| Single | 1 (9.1) | 3 (8.6) |
| Double | 10 (90.9) | 32 (91.4) |
| Transplant size (%) | ||
| Normal | 7 (63.6) | 14 (40.0) |
| Size reduced | 4 (36.4) | 14 (40.0) |
| Lobar | 0 (0.0) | 7 (20.0) |
| Initial hemoglobin, g/dl, median [IQR] | 11.30 [9.25, 12.70] | 11.50 [9.60, 12.75] |
Figure 2. Comparison of hemoglobin levels of passenger lymphocyte syndrome (PLS) and control patients. Preoperative and lowest postoperative hemoglobin values between postoperative days 3 and 52 in retrospectively studied patients with PLS and control patients of blood group A receiving lung transplants of O donors.
[More] [Minimize]Comparison of highest postoperative LDH and total bilirubin, as well as the duration of the ICU and hospital stay, did not show significant differences. Furthermore, there were no significant differences with respect to conventional complications after LuTX, such as cellular or humoral rejection, chronic lung allograft dysfunction, and survival at 3 months (Table E2). Likewise, mortality at 1, 3, and 5 years post-transplant showed no significant differences between the PLS group and control subjects.
Transfusion dependency was measured in RBC units (300 ml each). The postoperative period was divided into seven intervals of 7 days each, starting on POD 3. Mirroring lowest measured HGB values, the proportion of patients with a postoperative transfusion requirement was higher in the PLS cohort in each interval (Figure 3). Especially intervals 1 and 2 showed a significant difference, with a strikingly higher proportion of RBC transfusion in the PLS cohort (72.73% of patients with PLS in both intervals 1 and 2 as opposed to 31.43% and 40% in control subjects). Investigating the proportion of patients requiring more than two units per interval also showed a higher transfusion demand in patients with PLS in intervals 1 and 2 (27.27% of patients with PLS in both intervals 1 and 2 vs. 8.57% and 0% in control subjects; data not shown).
Figure 3. Comparison of transfusion requirements of patients with passenger lymphocyte syndrome (PLS) and control patients. Proportions including SEM of the retrospectively studied blood group A patients receiving lung transplants of O donors with and without PLS receiving red cell transfusions in different postoperative intervals are shown. Interval 1 = postoperative day (POD) 3–9; interval 2 = POD 10–16; interval 3 = POD 17–23; interval 4 = POD 24–30; interval 5 = POD 31–37; interval 6 = POD 38–44; interval 7 = POD 45–51.
[More] [Minimize]From July 2019 to June 2021, a total of 98 (possibly) ABO minor incompatible LuTX were performed. After applying the exclusion criteria, 93 transplantations remained for analysis, of which 87 patients were screened for PLS-defining antibodies postoperatively. Four (16%) of the 25 ABO-nonidentical LuTX recipients had PLS, all among group A patients receiving O grafts; thus, definitive PLS was encountered in 30.77% of patients with this blood group constellation (4 of 13) (Table 3).
| ABO Don>Rec | PLS Cases/Transplants in Total | Proportion (%) |
|---|---|---|
| O>A* | 4/13 | 30.77% |
| O>B | 0/5 | — |
| O>AB | 0/1 | — |
| A>AB | 0/4 | — |
| B>AB | 0/2 | — |
| A>A | 0/58 | — |
| AB>AB | 0/4 | — |
The confirmed PLS cases (P1–P4) of the prospective cohort are described further in Table E3. Although patients with PLS and control subjects were comparable regarding their baseline characteristics, hemorrhage in half of the prospective patients with PLS precluded further statistical comparison with control subjects.
In all four cases, IAT indicated the presence of anti-A1 in plasma. On the basis of eluate testing against A1, A2, B, and O RBCs, anti-A1 was identified in patient P2, anti-A in patient P3, and combined anti-A/anti-A,B reactivity in patients P1 and P4. The anti-A,B was demonstrated by reactivity of the eluate from A patient cells with B RBCs. First antibody detection occurred between PODs 12 and 14.
All four patients with PLS presented with an HGB decrease (three of four with rapid drop, one with slow decline) concurrent with circulating PLS-inducing antibodies. Patients P1 and P3 presented further laboratory signs of hemolysis, such as elevated total bilirubin and LDH, combined with low haptoglobin. Patients P1, P3, and P4 required multiple RBC transfusions, and patient P2 received erythropoietin. Patient P3 underwent revision for diffuse pleural bleeding at POD 17, which might have influenced HGB levels. Patient P4 experienced hemodynamically relevant gastrointestinal bleeding postoperatively.
In addition to the four confirmed PLS cases, six further patients (P5–P10) presented with positive DAT in the postoperative study period, but without available eluate. In these patients, all PLS-relevant antibodies may have bound to recipient RBCs, escaping detection in plasma IAT. In conjunction with signs of hemolysis (drop in HGB of at least 2 g/dl or the administration of a minimum of two RBC units within 1 wk of positive DAT), these cases were qualified as possible PLS (6.9% of prospectively screened cases) (Table E3). Anti-A1 derived from A2 or A2B donors could possibly have been involved in some of these patients (P5, P8–P10).
This study represents the largest analysis of PLS after LuTX, with a total observation period of 11.5 years and over 1,000 included patients. Blood group A patients receiving O grafts were particularly likely to develop PLS. The overall PLS rate in the retrospective cohort (15.83 per 1,000 recipients) is in line with previous data (20). However, considering the actually more relevant ABO-nonidentical subgroups, up to 20% of patients showed PLS, depending on the respective donor/recipient ABO constellation. Strikingly, in the prospective arm of the study, PLS occurred in more than 30% of A recipients of O grafts (4 of 13). This high proportion is presumably the consequence of active immunohematologic surveillance uncovering PLS-mediating antibodies; however, for interpretation of the results, the cohort size must be taken into consideration.
Because most of the data are observational, there are some limitations regarding results interpretation. In a retrospective cohort, there is always the issue of potential confounding leading to biased results. A causal inference approach (see the online supplement) allows the argument that the presence of confounders is highly unlikely, whereas the possibility of colliders is resolved by the stratified data analysis approach. In addition, the data from a prospective cohort were analyzed to validate the results of the observational study, largely showing agreement.
Earlier reports have documented the clinical relevance of PLS (4, 9), which was also evident in the present study. We found significantly lower postoperative HGB values in patients with PLS, with PLS-induced hemolysis likely having contributed to the anemia in this patient cohort. PLS-driven hemolysis is likely an additional risk factor besides thrombosis, infection, and other post-transplant complications that may worsen both clinical course and graft function (21). Our results do not argue against ABO minor incompatible lung allocation, despite the high PLS incidence in this setting. However, awareness about all potential factors affecting a patient’s postoperative state, including PLS, appears crucial for optimal postoperative care.
The association of higher initial postoperative HGB levels and lower 1-year mortality has been established in LuTX patients (22). Especially postoperative intervals 1 and 2 showed significantly higher transfusion dependency of patients with PLS than in control subjects. Higher transfusion requirement not only puts patients with PLS at higher risk for transfusion reactions but also may, at large amounts, contribute to severe primary graft dysfunction (23, 24).
Extended immunohematological studies including RBC eluate analysis provided novel insights into PLS etiology. The combined use of DAT, plasma IAT, and eluate IAT yielded the full spectrum of antibody specificities leading to PLS, as opposed to only plasma IAT that frequently suggested anti-A1 as the sole donor-derived specificity. Because of the higher A antigen expression of A1 as opposed to A2 RBCs (6), plasma IAT frequently showed false-negative results for A2 despite anti-A or anti-A,B being present. This may have implications for transfusion safety during ongoing PLS: For blood group A patients with PLS with only anti-A1 in plasma, A2 RBC units will be serologically compatible, whereas in cases without eluate studies being at risk to overlook further ABO specificities, blood group O RBC units should be preferred. In this study, the rare instance of anti-A,B (recognizing an epitope common to A and B carbohydrates) was demonstrated in two patients with PLS with O grafts. Of note, in all cases in which eluate testing indicated anti-A or anti-A,B, anti-A1 could have been present as well.
Donor ABO antibodies not directed against the recipient but against transfused RBCs is a phenomenon already described previously (25). In patient P2 (blood group A2, O graft), the anti-A1 formed in the course of LuTX may likely have reacted to transfused A1 RBCs rather than the recipient’s own RBCs. Generally, serologic pretransfusion RBC crossmatching for patients at risk for PLS may support the diagnosis when circulating PLS-relevant antibodies cause unexpected positive results and necessitate a tailored RBC unit selection.
In conclusion, PLS is common after ABO minor incompatible LuTX, especially in blood group A patients receiving O grafts, with the potential of complicating the patient’s postoperative clinical course. The causative specificities for PLS encompassed the full spectrum of ABO antibodies (anti-A1, anti-A, anti-A,B and anti-B), calling for appropriately matched antigen-negative RBC units. On the basis of observed lower postoperative HGB levels, higher transfusion requirements and evidence for hemolysis of patients with PLS, this entity appeared to be of clinical relevance. No specific risk factors for PLS development were identified, owing to the limited sample size. For all patients with ABO-nonidentical grafts, post-transplant laboratory and immunohematologic monitoring (DAT and IAT and, if required, eluate testing and serologic crossmatch) is recommended to achieve timely PLS diagnosis.
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* These authors contributed equally to this work.
This study was funded by the Medical University of Vienna, Austria.
Part of the data of this study were collected in the course of the diploma thesis elaboration of M.M.K. at the Medical University of Vienna, Austria.
Author Contributions: M.M.K., S.S., and G.F.K. conceived and designed the study. S.S., P.J., G.M., M.K., M.S., K.H., and G.F.K. provided donor and recipient data. M.M.K., A.T., and F.F. performed the statistical analysis and interpreted the data. M.M.K., S.S., and G.F.K. wrote the manuscript. P.J., K.H., and F.F. contributed important conceptual content. All authors revised the manuscript with significant intellectual contributions and gave their final approval for publication.
Data availability statement: Data used for this study are available upon reasonable request by contacting the corresponding author.
This article has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org.
Originally Published in Press as DOI: 10.1164/rccm.202306-1107OC on December 11, 2023
Author disclosures are available with the text of this article at www.atsjournals.org.
