An association between a positive direct antiglobulin test and HLA-DR12 in COVID-19.

SARS-CoV-2 infection has been reported to be associated with a positive direct antiglobulin test (DAT). In this study, an analysis of 40 consecutive coronavirus disease 2019 (COVID-19) cases from December 2020 to September 2021 in Japan revealed that patients of 70 years and over were predisposed to a positive DAT. DAT positivity was related to a decrease in the hemoglobin level. Anemia in DAT-positive COVID-19 patients was attributed to hemolysis, which was corroborated by high reticulocyte counts and an increase in the red blood cell distribution width. Human leukocyte antigen (HLA)-DRB1*12:01 and DRB1*12:02 were exclusively found in DAT-positive COVID-19 patients. In silico assays for the Spike protein of SARS-CoV-2 predicted several common core peptides that met the criteria for a B cell epitope and strong binding to both HLA-DRB1*12:01 and DRB1*12:02. Among these peptides, the amino acids sequence TSNFR, which is found within the S1 subunit of SARS-CoV-2 Spike protein, is shared by human blood group antigen Rhesus (Rh) CE polypeptides. In vitro analysis showed that the expression of HLA-DR in CD4+ T cells and CD8+ T cells from a DAT-positive patient was increased after pulsation with TSNFR-sequence-containing peptides. In summary, positive DAT is related to enhanced anemia and to HLA-DR12 in the Japanese population. A peptide sequence within SARS-CoV-2 Spike protein may act as an epitope for IgG binding to RBCs in DAT-positive COVID-19 patients.

Updates in the Management of Warm Autoimmune Hemolytic Anemia.

Warm autoimmune hemolytic anemia (wAIHA) is an uncommon and heterogeneous disorder caused by autoantibodies to RBC antigens. Initial evaluation should involve the DAT, with wAIHA typically IgG positive with or without C3 positivity, and a search for underlying conditions associated with secondary wAIHA, which comprise 50% of cases. First-line therapy involves glucocorticoids, increasingly with rituximab, though a chronic relapsing course is typical. While splenectomy and a number of immunosuppressive therapies have been used in the setting of relapsed and refractory disease, the optimal choice and sequence of therapies is unknown, and clinical trials should be offered when available. Newer investigational targets include spleen tyrosine kinase inhibitors, monoclonal antibodies targeting CD38, Bruton's tyrosine kinase inhibitors, complement inhibitors, and antibodies against neonatal Fc receptors.

Autoimmune hemolytic anemia: causes and consequences.

INTRODUCTION: Autoimmune hemolytic anemia (AIHA) is classified according to the direct antiglobulin test (DAT) and thermal characteristics of the autoantibody into warm and cold forms, and in primary versus secondary depending on the presence of associated conditions. AREAS COVERED: AIHA displays a multifactorial pathogenesis, including genetic (association with congenital conditions and certain mutations), environmental (drugs, infections, including SARS-CoV-2, pollution, etc.), and miscellaneous factors (solid/hematologic neoplasms, systemic autoimmune diseases, etc.) contributing to tolerance breakdown. Several mechanisms, such as autoantibody production, complement activation, monocyte/macrophage phagocytosis, and bone marrow compensation are implicated in extra-/intravascular hemolysis. Treatment should be differentiated and sequenced according to AIHA type (i.e. steroids followed by rituximab for warm, rituximab alone or in association with bendamustine or fludarabine for cold forms). Several new drugs targeting B-cells/plasma cells, complement, and phagocytosis are in clinical trials. Finally, thrombosis and infections may complicate disease course burdening quality of life and increasing mortality. EXPERT OPINION: Beyond warm and cold AIHA, a gray-zone still exists including mixed and DAT negative forms representing an unmet need. AIHA management is rapidly changing through an increasing knowledge of the pathogenic mechanisms, the refinement of diagnostic tools, and the development of novel targeted and combination therapies.

Cytomegalovirus-Induced Coombs-Positive Hemolysis or Drug-Induced Hemolysis in an Immunocompetent Young Adult.

Coombs-positive hemolytic anemia induced by cytomegalovirus (CMV) infection is a rare phenomenon, often not life-threatening in immunocompetent young adults. To date, the pathogenesis of CMV-induced severe hemolysis is still unknown. Here, we discuss a case of a 22-year-old male without significant past medical history who presented with severe hemolytic anemia that required four units of packed red blood cells. Urinalysis showed microscopic hematuria but urine culture and drug screen reported normal findings. Hemoccult result at the bedside was negative. Abdominal ultrasound and computed tomography (CT) imaging all resulted in normal findings except for splenomegaly measured 18 cm. Hematology was consulted which showed a positive direct Coombs antibody test with 3+ IgG and 3+ complement. Peripheral blood smear showed no evidence of schistocytes or occasional teardrop cells but showed toxic granulations and neutrophils indicating an underlying infection. The patient had a bone marrow biopsy which showed erythroid hyperplasia with a slight increase in sideroblast cells; but revealed no evidence of lymphoma, leukemia, or dysplasia. Infectious workup reported negative findings for HIV and hepatitis panel. However, Epstein-Barr virus (EBV) IgM antibodies to viral capsid antigen (VCA) was reported with a value of greater than 160 U/mL. Polymerase chain reaction (PCR) testing for cytomegalovirus (CMV) DNA detected high titers with 481269 IU/mL. The patient initially received intravenous immunoglobulin (IVIG) therapy for five days, antiviral medication for seven days, and high dose therapeutic corticosteroids resulting in stabilization of his blood hemoglobin (Hb) level. Infections commonly underlie secondary autoimmune hemolytic anemia (AIHA), or it can also be a result of therapy that further exacerbates the course of AIHA. Possible CMV manifestations inducing severe hemolytic anemia in immunocompetent individuals have received inadequate attention. CMV serology studies are not collected regularly in patients with hemolysis, so the incidence of this disorder might be under-reported. Thus, clinicians should take initiative to consider an underlying infection in the differential diagnosis of hemolytic anemia before opting for invasive procedures such as bone marrow biopsy. Randomized control trials are needed for a conclusive treatment specific to hemolytic anemia induced by CMV.

COVID-19-associated Evans syndrome: A case report and review of the literature.

Evans syndrome is a rare condition characterized by simultaneous or sequential development of autoimmune hemolytic anemia and immune thrombocytopenia (and/or immune neutropenia). Coronavirus disease 2019 (COVID-19) may cause various hematologic conditions, such as coagulation abnormalities (e.g., bleeding or thrombosis) or cell count alterations (e.g., lymphopenia and neutrophilia). COVID-19 may also induce Evans syndrome via immune mechanisms. Here, we describe the case of a patient developing Evans syndrome shortly after COVID-19 infection. Immune thrombocytopenia and warm-type autoimmune hemolytic anemia developed simultaneously, and intravenous immunoglobulin and methylprednisolone were initially administered. Additionally, we intend to review all COVID-19-induced Evans syndrome cases currently present in the literature and emphasize the differences as well as the similarities regarding patient characteristics, relationship to COVID-19 infection, and treatment approach. Since autoimmune cytopenias are frequent in COVID-19 patients, clinicians should pay particular attention to profound and abrupt-onset cytopenias. In these circumstances, hemolysis markers such as lactate dehydrogenase, haptoglobulin, Coombs tests, etc. should be investigated, and the possibility of Evans syndrome should always be considered to ensure prompt and appropriate treatment. These factors are essential to ensure hematologic recovery and prevent complications such as thrombosis.

Severe autoimmune hemolytic anemia following receipt of SARS-CoV-2 mRNA vaccine.

BACKGROUND: Large clinical trials have demonstrated the overall safety of vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, reports have emerged of autoimmune phenomena, including vaccine-associated myocarditis, immune thrombocytopenia, and immune thrombotic thrombocytopenia. CASE PRESENTATION: Here we present a novel case of a young woman who developed life-threatening autoimmune hemolytic anemia (AIHA) after her first dose of a SARS-CoV-2 mRNA vaccine. Notably, initial direct antiglobulin testing was negative using standard anti-IgG reagents, which are "blind" to certain immunoglobulin (IgG) isotypes. Further testing using an antiglobulin reagent that detects all IgG isotypes was strongly positive and confirmed the diagnosis of AIHA. The patient required transfusion with 13 units of red blood cells, as well as treatment with corticosteroids, rituximab, mycophenolate mofetil, and immune globulin. CONCLUSION: As efforts to administer SARS-CoV-2 vaccines continue globally, clinicians must be aware of potential autoimmune sequelae of these therapies.

Positive direct antiglobulin test in COVID-19 patients: Decision-making process.

In this unprecedented crisis of severe acute respiratory syndrome coronavirus 2 and its associated coronavirus disease 2019 (COVID-19), polymerase chain reaction and then serological testing platforms have been massively developed to face the important screening demand. Polymerase chain reaction and serological testing platforms are not the only actors impacted by the crisis, transfusion services are facing important difficulties. A positive direct antiglobulin test is frequently observed for patients encountering COVID-19. Patients with severe symptoms may develop anaemia and become good candidates for blood transfusions. The interpretation of a positive direct antiglobulin test for patients recently transfused and suffering from COVID-19 is complex. The differentiation between COVID-19 induced antibodies and possible associated transfusion alloantibodies is therefore crucial. In this context, the elution technique incorporated in an appropriate decision-making process plays its full role. This intricate topic is presented through a case report followed by literature review and finally decision-making process for COVID-19 patients necessitating red blood cells administration.