Living Donor Liver transplantation in an alloimmunised patient: Immunological challenges and Management in Indian Settings.

Liver transplantation (LT) is often associated with hematological abnormalities with immune or non-immune etiologies and require timely diagnosis and interventions. We report a case of a patient suffering from non-alcoholic steato-hepatitis (NASH) related end stage liver disease (ESLD) with multiple red cell antibodies who underwent LT surgery. In postoperative phase, she developed immune hemolysis as well as acute antibody mediated rejection (AMR) which was managed with therapeutic plasma exchange and IVIG. The case highlights the need to develop an algorithm for red cell and HLA antibody screening in high-risk patients for timely detection and management.

Tocilizumab for treatment of chronic active antibody-mediated rejection in kidney transplant recipients.

BACKGROUND: The optimal treatment for chronic active antibody-mediated rejection (ca-AMR) remains unclear. Tocilizumab (TCZ), a monoclonal antibody against IL-6, has been proposed as a therapeutic option. We reported our experience treating ca-AMR with TCZ either as the first line option or as a rescue therapy. METHODS: We studied 11 adult kidney transplant recipients with biopsy-proven ca-AMR and preserved kidney function (eGFR 57 ± 18) who were treated with TCZ (8 mg/kg IV monthly). All biopsies were prompted by abnormal surveillance biomarker testing with DSA and/or dd-cfDNA. Clinical monitoring included dd-cfDNA and DSA testing every 3 months during the treatment with TCZ. RESULTS: In this cohort, ca-AMR was diagnosed at a median of 90 months (range 14-224) post-transplant, and 4 of 11 patients had DSA negative ca-AMR. Patients received a minimum of 3 months of TCZ, with 6 patients receiving at least 12 months of TCZ. Dd-cfDNA was elevated in all patients, with a median 2.24% at the start of TCZ treatment. After 6 months of TCZ treatment, 8/11 patients had dd- cfDNA <1%, and 3/11 had values <0.5%. Among those who completed at least 12 months of TCZ, dd-cfDNA decreased by 29% at 6 months (p = .05) and 47% by 12 months (p = .04). DSA also stabilized and, by 12 months, was reduced by 29% (p = .047). Graft function remained stable with no graft loss during treatment. There was a nonsignificant trend towards proteinuria reduction. During the course of treatment with tocilizumab, two patients experienced moderate to severe infections. CONCLUSIONS: In our early short-term experience, TCZ appears to reduce graft injury as measured by dd-cfDNA and modulate the immune response as evident by a modest reduction in immunodominant DSA MFI. Allograft function and proteinuria also stabilized.

COVID-19 infection and vaccination rarely impact HLA antibody profile in waitlisted renal transplant candidates- a multicenter cohort.

Although rare, infection and vaccination can result in antibodies to human leukocyte antigens (HLA). We analyzed the effect of SARS-CoV-2 infection or vaccination on HLA antibodies in waitlisted renal transplant candidates. Specificities were collected and adjudicated if the calculated panel reactive antibodies (cPRA) changed after exposure. Of 409 patients, 285 (69.7 %) had an initial cPRA of 0 %, and 56 (13.7 %) had an initial cPRA > 80 %. The cPRA changed in 26 patients (6.4 %), 16 (3.9 %) increased, and 10 (2.4 %) decreased. Based on cPRA adjudication, cPRA differences generally resulted from a small number of specificities with subtle fluctuations around the borderline of the participating centers' cutoff for unacceptable antigen listing. All five COVID recovered patients with an increased cPRA were female (p = 0.02). In summary, exposure to this virus or vaccine does not increase HLA antibody specificities and their MFI in approximately 99 % of cases and 97 % of sensitized patients. These results have implications for virtual crossmatching at the time of organ offer after SARS-CoV-2 infection or vaccination, and these events of unclear clinical significance should not influence vaccination programs.

Clazakizumab for the treatment of chronic active antibody-mediated rejection (AMR) in kidney transplant recipients: Phase 3 IMAGINE study rationale and design.

BACKGROUND: Chronic active antibody-mediated rejection (AMR) is a major cause of graft loss with no approved drugs for its treatment. Currently, off-label regimens are used, reflecting the high unmet need for effective therapies based on well-controlled trials. Clazakizumab is a high-affinity, humanized monoclonal antibody that binds interleukin-6 and decreases donor-specific antibody (DSA) production and inflammation. Phase 2 pilot studies of clazakizumab in kidney transplant recipients with chronic active AMR suggest modulation of DSA, stabilization of glomerular filtration rate (GFR), and a manageable safety profile. We report the design of the Phase 3 IMAGINE study (NCT03744910) to evaluate the safety and efficacy of clazakizumab for the treatment of chronic active AMR. METHODS: IMAGINE is a multicenter, double-blind trial of approximately 350 kidney transplant recipients with chronic active AMR (Banff chronic glomerulopathy [cg] >0 with concurrent positive human leukocyte antigen DSA) randomized 1:1 to receive clazakizumab or placebo (12.5 mg subcutaneous once every 4 weeks). The event-driven trial design will follow patients until 221 occurrences of all-cause graft loss are observed, defined as return to dialysis, graft nephrectomy, re-transplantation, estimated GFR (eGFR) <15 mL/min/1.73m2, or death from any cause. A surrogate for graft loss (eGFR slope) will be assessed at 1 year based on prior modeling validation. Secondary endpoints will include measures of pharmacokinetics/pharmacodynamics. Recruitment is ongoing across North America, Europe, Asia, and Australia. DISCUSSION: IMAGINE represents the first Phase 3 clinical trial investigating the safety and efficacy of clazakizumab in kidney transplant recipients with chronic active AMR, and the largest placebo-controlled trial in this patient population. This trial includes prognostic biomarker enrichment and uniquely utilizes the eGFR slope at 1 year as a surrogate endpoint for graft loss, which may accelerate the approval of a novel therapy for patients at risk of graft loss. The findings of this study will be fundamental in helping to address the unmet need for novel therapies for chronic active AMR. TRIAL REGISTRATION: ClinicalTrials.gov NCT03744910 . Registered on November 19, 2018.

On a Long and Winding Road: Alloantibodies in Organ Transplantation.

Today we know that both the humoral and the cellular arm of the immune system are engaged in severe immunological challenges. A close interaction between B and T cells can be observed in most "natural" challenges, including infections, malignancies, and autoimmune diseases. The importance and power of humoral immunity are impressively demonstrated by the current coronavirus disease 2019 pandemic. Organ transplant rejection is a normal immune response to a completely "artificial" challenge. It took a long time before the multifaceted action of different immunological forces was recognized and a unified, generally accepted opinion could be formed. Here, we address prominent paradigms and paradigm shifts in the field of transplantation immunology. We identify several instances in which the transplant community missed a timely paradigm shift because essential, available knowledge was ignored. Moreover, we discuss key findings that critically contributed to our understanding of transplant immunology but sometimes developed with delay and in a roundabout way, as was the case with antibody-mediated rejection-a main focus of this article. These include the discovery of the molecular principles of histocompatibility, the recognition of the microcirculation as a key interface of immune damage, the refinement of alloantibody detection, the description of C4d as a footmark of endothelium-bound antibody, and last but not least, the developments in biopsy-based diagnostics beyond conventional morphology, which only now give us a glimpse of the enormous complexity and pathogenetic diversity of rejection.

Evaluating patients with autoimmune hemolytic anemia in the transfusion service and immunohematology reference laboratory: pretransfusion testing challenges and best transfusion-management strategies.

The serologic evaluation of autoimmune hemolytic anemia (AIHA) confirms the clinical diagnosis, helps distinguish the type of AIHA, and identifies whether any underlying alloantibodies are present that might complicate the selection of the safest blood for any needed transfusion. The spectrum of testing is generally dependent on the amount and class (immunoglobulin G or M) of autoantibody as well as the resources and methodologies where testing is performed. The approach may range from routine pretransfusion testing, including the direct antiglobulin test, to advanced techniques such as adsorptions, elution, and red cell genotyping. When transfusion is needed, the selection of the optimal unit of red blood cells is based on urgency and whether time allows for the completion of sophisticated serologic and molecular testing methods. From the start of when AIHA is suspected until the completion of testing, communication among the clinical team and medical laboratory scientists in the transfusion service and immunohematology reference laboratory is critical as testing can take several hours and the need for transfusion may be urgent. The frequent exchange of information including the patient's transfusion history and clinical status, the progress of testing, and any available results is invaluable for timely diagnosis, ongoing management of the patient, and the safety of transfusion if required before testing is complete.

Do Blood Phenotypes of Feline AB Blood Group System Affect the SARS-CoV-2 Antibody Serostatus in Cats?

Cats are susceptible to coronavirus infections, including infection by human severe acute respiratory syndrome coronavirus (SARS-CoV). In human ABO system blood groups, alloantibodies can play a direct role in resistance to infectious diseases. Individuals with the AB blood type were over-represented in the SARS-CoV-2 infection group. Blood type AB individuals lack both anti-A and anti-B antibodies, and therefore lack the protective effect against SARS-CoV-2 infection given by these antibodies. Starting from this knowledge, this pilot preliminary study evaluated a possible association between feline blood phenotypes A, B, and AB and serostatus for SARS-CoV-2 antibodies in cats. We also investigated selected risk or protective factors associated with seropositivity for this coronavirus. A feline population of 215 cats was analysed for AB group system blood phenotypes and antibodies against the nucleocapsid (N-protein) SARS-CoV-2 antigen using a double antigen ELISA. SARS-CoV-2 seropositive samples were confirmed using a surrogate virus neutralization test (sVNT). Origin (stray colony/shelter/owned cat), breed (DSH/non DSH), gender (male/female), reproductive status (neutered/intact), age class (kitten/young adult/mature adult/senior), retroviruses status (seropositive/seronegative), and blood phenotype (A, B, and AB) were evaluated as protective or risk factors for SARS-CoV-2 seropositivity. Seropositivity for antibodies against the SARS-CoV-2 N-protein was recorded in eight cats, but only four of these tested positive with sVNT. Of these four SARS-CoV-2 seropositive cats, three were blood phenotype A and one was phenotype AB. Young adult age (1-6 years), FeLV seropositivity and blood type AB were significantly associated with SARS-CoV-2 seropositivity according to a univariate analysis, but only blood type AB (p = 0.0344, OR = 15.4, 95%CI: 1.22-194.39) and FeLV seropositivity (p = 0.0444, OR = 13.2, 95%CI: 1.06-163.63) were significant associated risk factors according to a logistic regression. Blood phenotype AB might be associated with seropositivity for SARS-CoV-2 antibodies. This could be due, as in people, to the protective effect of naturally occurring alloantibodies to blood type antigens which are lacking in type AB cats. The results of this pilot study should be considered very preliminary, and we suggest the need for further research to assess this potential relationship.

Development of donor specific antibodies after SARS-CoV-2 vaccination in kidney and heart transplant recipients.

This study examined the development of new or changes in donor specific antibodies (DSA) mean-fluorescence intensity (MFI) after SARS-CoV-2 vaccination in 100 kidney and 50 heart transplant recipients. The study was performed when the Center for Disease Control and Prevention (CDC) recommended two doses of Pfizer/BioNTech [BNT162b2] and Moderna [mRNA-1273 SARS-CoV-2] vaccine or 1 dose Johnson & Johnson/Janssen [Ad26.COV2·S] vaccines for full vaccination in transplant recipients. A novel assay bead-based platform for detecting antibodies against 4 domains of the SARS-CoV-2 spike protein to determine vaccine response (SA) and one nucleocapsid protein (NC) to determine prior SARS-CoV-2 infection was utilized. These assays were performed on the multiplex, bead-based platform utilized to assay DSA levels. 61/150 patients (40.7%) had successful vaccination. 18 patients had confirmed SARS-CoV-2 infection based on positive NC assay or previous Covid-19 oropharyngeal swab. 138 patients had no DSA prior to vaccination but 3 heart recipients developed new DSA's. Among 12 patients with known DSA prior to vaccination, 4 developed new DSA's or increased MFI. All 7 patients with new or increased DSA had stable graft function without rejection and had no changes in immunosuppression. All 8 patients with stable post vaccine DSA had stable graft function and immunosuppression was not changed. The presence of DSA before vaccination was associated with subsequent development of increased MFI or new DSA's (p = 0.001). There was no association between pre-vaccine DSA and positive vaccine response (NS). There was no association with successful vaccination or prior SARS-CoV-2 infection and DSA changes (NS).

COVID-19 in orthotopic heart transplant recipients and association with donor specific antibodies.

De novo donor-specific antibodies (DSAs) are associated with increased risk of antibody-mediated rejection and worse clinical outcomes after orthotopic heart transplant (OHT). No study has reported the production of DSAs after infection by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in an OHT population. In this retrospective study, we described coronavirus disease 2019 (COVID-19) incidence and clinical course in a large, contemporary OHT cohort. We showed that the case-fatality rate has significantly decreased since the early days of the pandemic, although remains higher than that of the general population. In addition, we found that 10% of OHT recipients developed de novo DSAs or experienced an increase in pre-existing DSAs after COVID-19, with the majority occurring in unvaccinated patients (15% vs 2%). Further studies are necessary to substantiate our findings in an external cohort.

Association between SARS-CoV-2 infection and de novo HLA donor specific antibody production in lung transplant recipients: Single-center study.

The COVID-19 pandemic has led to significant morbidity and mortality in lung transplant recipients. Respiratory viral infections may be associated with de-novo HLA donor-specific antibody production and impact lung transplant outcome. Since one of the immunomodulation strategies post-SARS-CoV-2 infection in lung transplant recipients include decreasing or holding anti-metabolites, concerns have been raised for higher incidence of de-novo HLA donor specific antibody production in lung transplant recipients. We performed a retrospective chart review of 24 consecutive lung transplant recipients diagnosed with COVID-19 to investigate this concern. We observed no significant differences in the CPRA or MFI levels of HLA class I and II antibodies pre- COVID-19 compared to 1 and 6 months post-COVID-19 diagnosis in 11/24 (45.8 %) LTR (p = 0.98 and p = 0.63 respectively). HLA class I and II DSA were detected in 5/24 LTR pre-COVID-19 diagnosis and persisted with no significant differences in the median MFI levels at 1 and 6 months post-COVID-19 diagnosis (p = 0.89). De-novo HLA class I and II DSA were detected in 1/24 (4.2 %) LTR at one month post-COVID-19 diagnosis and persisted with no significant differences in the median MFI levels at 1 and 6 months post-COVID-19 diagnosis (p = 0.54). Our results suggest that there was no significant association between SARS-CoV-2 infection and immunomodulation on pre-existing or de novo HLA donor specific antibodies.

Hyperhemolysis in a patient with sickle cell disease and recent SARS-CoV-2 infection, with complex auto- and alloantibody work-up, successfully treated with tocilizumab.

BACKGROUND: Hyperhemolysis syndrome (HHS) is a severe delayed hemolytic transfusion reaction seen in sickle cell disease (SCD) patients, characterized by destruction of donor and recipient RBCs. It results in a drop in hemoglobin to below pretransfusion levels and frequently reticulocytopenia. CASE REPORT: We report a case of a man in his thirties with SCD with a recent hospitalization 2 weeks prior for COVID-19. His red cell antibody history included anti-Fy(a) and warm autoantibody. At that time, he was given 2 units of RBC and discharged with a hemoglobin of 10.2 g/dl. He returned to the hospital approximately 1.5 weeks later with hemoglobin 6.0 g/dl and symptoms concerning for acute chest syndrome. Pretransfusion testing now showed 4+ pan-agglutinin in both gel-based and tube-based testing. Alloadsorption identified an anti-N and a strong cold agglutinin. Three least incompatible units were transfused to this patient over several days, with evidence of hemolysis. Further reference lab work revealed anti-Fya , anti-Fyb , anti-Lea , anti-Leb , and an anti-KN system antibody. The patient's hemoglobin nadired at 4.4 g/dl. The patient was treated with a single dose of tocilizumab, his hemoglobin stabilized, and he was discharged. DISCUSSION: We present a case of HHS proximate to recent SARS-CoV-2 infection with multiple allo and autoantibodies identified. Information on the relationship between SARS-CoV-2 infection and HHS is limited; however, it is possible that inflammation related to COVID-19 could predispose to HHS. Tocilizumab is an approved treatment for COVID-19. Additionally, tocilizumab appears to be a promising treatment option for patients with HHS.

Non-Invasive Monitoring for Rejection in Kidney Transplant Recipients After SARS-CoV-2 mRNA Vaccination.

Introduction: Studies have shown reduced antiviral responses in kidney transplant recipients (KTRs) following SARS-CoV-2 mRNA vaccination, but data on post-vaccination alloimmune responses and antiviral responses against the Delta (B.1.617.2) variant are limited. Materials and methods: To address this issue, we conducted a prospective, multi-center study of 58 adult KTRs receiving mRNA-BNT162b2 or mRNA-1273 vaccines. We used multiple complementary non-invasive biomarkers for rejection monitoring including serum creatinine, proteinuria, donor-derived cell-free DNA, peripheral blood gene expression profile (PBGEP), urinary CXCL9 mRNA and de novo donor-specific antibodies (DSA). Secondary outcomes included development of anti-viral immune responses against the wild-type and Delta variant of SARS-CoV-2. Results: At a median of 85 days, no KTRs developed de novo DSAs and only one patient developed acute rejection following recent conversion to belatacept, which was associated with increased creatinine and urinary CXCL9 levels. During follow-up, there were no significant changes in proteinuria, donor-derived cell-free DNA levels or PBGEP. 36% of KTRs in our cohort developed anti-wild-type spike antibodies, 75% and 55% of whom had neutralizing responses against wild-type and Delta variants respectively. A cellular response against wild-type S1, measured by interferon-γ-ELISpot assay, developed in 38% of KTRs. Cellular responses did not differ in KTRs with or without antibody responses. Conclusions: SARS-CoV-2 mRNA vaccination in KTRs did not elicit a significant alloimmune response. About half of KTRs who develop anti-wild-type spike antibodies after two mRNA vaccine doses have neutralizing responses against the Delta variant. There was no association between anti-viral humoral and cellular responses.

SARS Cov-2 vaccination induces de novo donor-specific HLA antibodies in a renal transplant patient on waiting list: A case report.

The ability of COVID-19 vaccination to induce anti-HLA antibodies (Abs) formation in renal transplant candidates is not well studied. A 42-year-old man on a renal transplant waitlist, with no sensitization history, was tested for DSA before and after COVID-19 vaccination. Patient has consistently tested negative for COVID-19 virus. Eighteen days after receiving first dose of mRNA-based vaccine, flow cytometry crossmatch (FCXM) was strongly positive with de novo donor-specific Ab (dnDSA) against B57 and de novo non-DSA against B58. Before vaccination, preliminary FCXM was negative with no anti-HLA Abs. This event prompted the transplant team to cancel the surgery. COVID-19 vaccination could be associated with anti-HLA Abs formation in renal patients on waitlists that could affect future transplantability.

A Randomized Clinical Trial of Anti-IL-6 Antibody Clazakizumab in Late Antibody-Mediated Kidney Transplant Rejection.

BACKGROUND: Late antibody-mediated rejection (ABMR) is a leading cause of transplant failure. Blocking IL-6 has been proposed as a promising therapeutic strategy. METHODS: We performed a phase 2 randomized pilot trial to evaluate the safety (primary endpoint) and efficacy (secondary endpoint analysis) of the anti-IL-6 antibody clazakizumab in late ABMR. The trial included 20 kidney transplant recipients with donor-specific, antibody-positive ABMR ≥365 days post-transplantation. Patients were randomized 1:1 to receive 25 mg clazakizumab or placebo (4-weekly subcutaneous injections) for 12 weeks (part A), followed by a 40-week open-label extension (part B), during which time all participants received clazakizumab. RESULTS: Five (25%) patients under active treatment developed serious infectious events, and two (10%) developed diverticular disease complications, leading to trial withdrawal. Those receiving clazakizumab displayed significantly decreased donor-specific antibodies and, on prolonged treatment, modulated rejection-related gene-expression patterns. In 18 patients, allograft biopsies after 51 weeks revealed a negative molecular ABMR score in seven (38.9%), disappearance of capillary C4d deposits in five (27.8%), and resolution of morphologic ABMR activity in four (22.2%). Although proteinuria remained stable, the mean eGFR decline during part A was slower with clazakizumab compared with placebo (-0.96; 95% confidence interval [95% CI], -1.96 to 0.03 versus -2.43; 95% CI, -3.40 to -1.46 ml/min per 1.73 m2 per month, respectively, P=0.04). During part B, the slope of eGFR decline for patients who were switched from placebo to clazakizumab improved and no longer differed significantly from patients initially allocated to clazakizumab. CONCLUSIONS: Although safety data indicate the need for careful patient selection and monitoring, our preliminary efficacy results suggest a potentially beneficial effect of clazakizumab on ABMR activity and progression.

Positive flow cytometry crossmatch with discrepant antibody testing results following COVID-19 vaccination.

The impact of COVID-19 vaccination on the alloimmunity of transplant candidates is unknown. We report a case of positive B cell flow cytometry crossmatch in a patient waiting for second kidney transplantation, 37 days after receiving the COVID-19 vaccine. The preliminary crossmatch, using sample collected before COVID-19 vaccination, was negative. The antibodies to mismatched donor HLA-DR7 were detected only with multi-antigen beads but not with single-antigen beads, excluding possible prozone effects in solid-phase antibody assays. The crossmatches were positive with HLA-DR7-positive surrogates (n = 2) while negative with HLA-DR7-negative surrogates (n = 3), which confirms the HLA-DR7 alloreactivity. The antigen configurations on B lymphocytes are similar to that on the multi-antigen beads while distinct from the single-antigen beads. HLA-DR7 was the repeating mismatched antigen with the failing first kidney allograft. The newly emerged antibody to HLA-DR7 probably is the consequence of bystander activation of memory response by the COVID-19 vaccination. This case highlights the importance of verifying allo-sensitization history and utilizing multiple assays, including cell-based crossmatch and solid-phase assays with multi-antigens. COVID-19 immunization may deserve special attention when assessing the immunological risk before and after organ transplantation.

Ubiquitous convalescent plasma: An artificial universal plasma for COVID-19 patients.

OBJECTIVES AND BACKGROUND: In December 2019, the first case of COVID-19 was reported in Wuhan, China. Its causative virus, is a novel strain of RNA viruses with high mortality rate. There is no definitive treatment, but among available approaches the use of recovered patients' plasma containing specific antibodies can enhance the immune response against coronavirus. However, the dearth of eligible donors and also ABO incompatibility in plasma transfusion, have limited this therapeutic method. Therefore, it is highly desirable to introduce a simple procedure that allows efficient reduction or even removal of natural ABO antibodies. Accordingly, we aimed to evaluate a RBC-mediated adsorption technique that reduces the titer of the mentioned antibodies in plasma. METHODS/MATERIALS: This experimental study was conducted in Kerman University of Medical Sciences, Kerman, Iran. The pre- and post-incubation antibody titers of 168 plasma samples were determined. For incubation, each plasma sample was exposed (60 min) to different percentages of RBCs at room temperature or 4 °C. RESULTS: The results evidenced that both the concentration of RBCs and temperature had significant decreasing effects on antibody titer (P < 0.001) and all concentrations significantly reduced titer. Compared to RT, 4 °C further reduced the antibody titer. Overall, the best incubation condition for reducing antibody titer in all blood groups was 4 °C and 2% RBCs concentration. CONCLUSION: The presented adsorption procedure is able to produce universal plasma (we call it Ubiquitous Convalescent Plasma) with a non-immunogenic level of ABO mismatch antibodies which can be used for COVID-19 patients with any type of blood group with desirable simplicity, feasibility, and efficacy.

COVID-19 does not impact HLA antibody profile in a series of waitlisted renal transplant candidates.

HLA antibodies are typically produced after exposure to transplanted tissue, pregnancy, and blood products. Sensitization delays access to transplantation and preclude utilization of donor organs. Infections and vaccinations have also been reported to result in HLA antibody formation. It is not known if patients develop HLA antibodies after infection with SARS-CoV-2. Here we analyzed a series of eighteen patients waiting for kidney transplantation who had symptomatic COVID-19 disease and recovered. None of the patients in this initial series developed de novo HLA antibodies. Notably, there was no increase in preexisting HLA antibodies in four highly sensitized patients with a CPRA > 80%. These preliminary data suggest that there may not be a need to repeat HLA antibody testing or perform a physical crossmatch on admission serum before kidney transplant for COVID-19 recovered patients. Data from a large number of patients with different demographics needed.

ABO Blood Types and COVID-19: Spurious, Anecdotal, or Truly Important Relationships? A Reasoned Review of Available Data.

Since the emergence of COVID-19, many publications have reported associations with ABO blood types. Despite between-study discrepancies, an overall consensus has emerged whereby blood group O appears associated with a lower risk of COVID-19, while non-O blood types appear detrimental. Two major hypotheses may explain these findings: First, natural anti-A and anti-B antibodies could be partially protective against SARS-CoV-2 virions carrying blood group antigens originating from non-O individuals. Second, O individuals are less prone to thrombosis and vascular dysfunction than non-O individuals and therefore could be at a lesser risk in case of severe lung dysfunction. Here, we review the literature on the topic in light of these hypotheses. We find that between-study variation may be explained by differences in study settings and that both mechanisms are likely at play. Moreover, as frequencies of ABO phenotypes are highly variable between populations or geographical areas, the ABO coefficient of variation, rather than the frequency of each individual phenotype is expected to determine impact of the ABO system on virus transmission. Accordingly, the ABO coefficient of variation correlates with COVID-19 prevalence. Overall, despite modest apparent risk differences between ABO subtypes, the ABO blood group system might play a major role in the COVID-19 pandemic when considered at the population level.