Multiple autoimmune disorders refractory to glucocorticoids after allogeneic hematopoietic stem cell transplantation: a case report and review of the literature.

We report here the case of a 50-year-old man who was first diagnosed with myelodysplastic syndrome with excess blasts-2 (MDS-EB-2) and underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) in 2019, resulting in complete remission. However, he was diagnosed in 2021 with several autoimmune disorders, including autoimmune hepatitis (AIH), Hashimoto's thyroiditis (HT), and autoimmune hemolytic anemia (AIHA). This is referred as multiple autoimmune syndrome (MAS), which is a rare occurrence after allo-HSCT, as previously noted in the literature. Despite being treated with glucocorticoids, cyclosporine A, and other medications, the patient did not fully recover. To address the glucocorticoid-refractory MAS, a four-week course of rituximab (RTX) at a weekly dose of 100mg was administered, which significantly improved the patient's condition. Thus, this case report underscores the importance of implementing alternative treatments in patients with post-transplant autoimmune diseases, who are glucocorticoid-refractory or glucocorticoid-dependent, and highlights the effectiveness of RTX as second-line therapy.

IgA plasma cell myeloma presenting as cold agglutinin-induced haemolytic transfusion reaction.

Cold agglutinins produced in the setting of B cell neoplasms, such as lymphoplasmacytic lymphoma and plasma cell myeloma, can mediate autoimmune haemolytic anemia. Transfusion of these patients can exacerbate cold agglutinin-mediated haemolysis. Moreover, the workup for these reactions represents a diagnostic challenge due in part to false negative direct antiglobulin tests (DATs). Here, we report an anaemic patient who after a red blood cell (RBC) transfusion performed without blood warming, experienced a DAT-negative haemolytic transfusion reaction, and was later diagnosed with IgA-multiple myeloma, which showed an uncommon granular pattern by CD138 immunohistochemistry. Extensive workup excluded other diagnostic possibilities, including the presence of Donath-Landsteiner antibodies and cryoglobulins. Successful treatment with CyBorD (cyclophosphamide, bortezomib and dexamethasone) achieved complete remission, and additional RBC transfusions using warmers were completed uneventfully.

RH genotypes and red cell alloimmunization rates in chronically transfused patients with sickle cell disease: A multisite study in the USA.

BACKGROUND: Red cell alloimmunization remains a challenge for individuals with sickle cell disease (SCD) and contributes to increased risk of hemolytic transfusion reactions and associated comorbidities. Despite prophylactic serological matching for ABO, Rh, and K, red cell alloimmunization persists, in part, due to a high frequency of variant RH alleles in patients with SCD and Black blood donors. STUDY DESIGN AND METHODS: We compared RH genotypes and rates of alloimmunization in 342 pediatric and young adult patients with SCD on chronic transfusion therapy exposed to >90,000 red cell units at five sites across the USA. Genotyping was performed with RHD and RHCE BeadChip arrays and targeted assays. RESULTS: Prevalence of overall and Rh-specific alloimmunization varied among institutions, ranging from 5% to 41% (p = .0035) and 5%-33% (p = .0002), respectively. RH genotyping demonstrated that 33% RHD and 57% RHCE alleles were variant in this cohort. Patients with RHCE alleles encoding partial e antigens had higher rates of anti-e identified than those encoding at least one conventional e antigen (p = .0007). There was no difference in anti-D, anti-C, or anti-E formation among patients with predicted partial or altered antigen expression compared to those with conventional antigens, suggesting that variant Rh on donor cells may also stimulate alloimmunization to these antigens. DISCUSSION: These results highlight variability in alloimmunization rates and suggest that a molecular approach to Rh antigen matching may be necessary for optimal prevention of alloimmunization given the high prevalence of variant RH alleles among both patients and Black donors.

Autoimmune Cytopenias Are Highly Associated with Inborn Errors of Immunity and They May Be the Initial Presentations in Cases without Severe Infections.

INTRODUCTION: Inborn errors of immunity (IEIs) are inherited disorders that present with increased susceptibility to infections as well as noninfectious complications. Due to the aberrant immune functions of patients with IEI, autoimmune cytopenia (AIC) may be the initial finding, which makes diagnosis a challenge. We aimed to evaluate the clinical course, laboratory findings, and treatment response of AIC in children with IEI. METHODS: Data of children with autoimmune hemolytic anemia (AIHA) and/or immune thrombocytopenic purpura (ITP) were obtained from a retrospective chart review of IEI patients diagnosed and followed in our center. Demographic and clinical features and therapeutic outcomes were evaluated. Immunologic findings were compared between patients with AIHA, ITP, and Evans syndrome (ES). The patients were also divided into two subgroups based on the presence or absence of immune dysregulation diseases (IDDs), and all data were compared between these two groups. RESULTS: Out of 562 patients with IEI, 6% (n: 34) had AIC which were ITP (23.5%), AIHA (35.5%), and ES (41.2%). AIC was the initial finding in 50% of these 34 patients. Patients with ES had a higher mean percentage of CD8+ T lymphocytes than ITP patients (40.77 ± 20.21% vs. 22.33 ± 12.48%, p = 0.011). Patients with IDDs were more likely to develop ES (p = 0.004), lymphoproliferation (p = 0.005), and resistance to first-line therapy (p = 0.021) than other IEI groups. CONCLUSION: This study shows that AIC may be the initial finding of IEI, particularly when lymphoproliferation and resistance to first-line therapy co-occur. Therefore, detailed investigation should be offered to all patients to avoid diagnostic delay.

[Multiple microthromboses with autoimmune hemolytic anemia after BNT162b2 mRNA vaccination].

A 68-year-old man was referred to our hospital with dizziness and mild fever one week after receiving the second dose of the COVID-19 mRNA vaccine (BNT162b2). Laboratory tests showed hemolytic anemia and a positive direct Coombs test, and he was diagnosed with autoimmune hemolytic anemia (AIHA). On admission, the patient had impaired consciousness with auditory hallucinations, and a head MRI scan showed multiple high-signal areas on diffusion-weighted imaging, suggesting multiple recent infarctions. Echocardiography also showed decreased wall motion in the inferior and posterior walls. A skin biopsy to investigate the cause revealed many platelets and fibrin thrombi in the capillaries and small veins, which was considered the cause of the organ damage. After starting prednisolone (1 mg/kg) for AIHA, hemolytic anemia as well as impaired consciousness, and decreased wall motion rapidly improved. Microthrombosis after BNT162b2 mRNA vaccination is rare, and autoimmune abnormalities appeared to contribute to onset in this case.

Sutimlimab suppresses SARS-CoV-2 mRNA vaccine-induced hemolytic crisis in a patient with cold agglutinin disease.

Cold agglutinin disease (CAD) is a rare form of acquired autoimmune hemolytic anemia driven mainly by antibodies that activate the classical complement pathway. Several patients with CAD experience its development or exacerbation of hemolysis after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or after receiving the SARS-CoV-2 mRNA vaccine. Therefore, these patients cannot receive an additional SARS-CoV-2 mRNA vaccination and have a higher risk of severe SARS-CoV-2 infection. Sutimlimab is a monoclonal antibody that inhibits the classical complement pathway of the C1s protein and shows rapid and sustained inhibition of hemolysis in patients with CAD. However, whether sutimlimab could also inhibit hemolysis caused by SARS-CoV-2 mRNA vaccination is uncertain. Here, we present the case of a 70-year-old man with CAD who repeatedly experienced a hemolytic crisis after receiving SARS-CoV-2 mRNA vaccines. The patient eventually underwent SARS-CoV-2 mRNA vaccination safely, without hemolytic attack, under classical pathway inhibition therapy with sutimlimab. This report suggests that appropriate sutimlimab administration can suppress SARS-CoV-2 mRNA vaccination-induced CAD exacerbation, and that it could be a preventive strategy to minimize hemolytic attacks in susceptible populations.

[Autoimmune hemolytic anemia following the third dose of the COVID-19 vaccine].

The development and exacerbation of autoimmune diseases following coronavirus disease 2019 (COVID-19) vaccination have been reported; however, there are few reports of autoimmune hemolytic anemia (AIHA). A 75-year-old woman was admitted to the emergency department 46 days after receiving her third dose of the mRNA-1273 COVID-19 vaccine because of fatigue and general weakness. Initial laboratory analyses revealed severe hemolytic anemia with positive direct and indirect Coombs test and elevation of serum indirect bilirubin and lactate dehydrogenase. The patient had no underlying disease after a close examination and was diagnosed with warm AIHA, which was thought to be associated with COVID-19 vaccination. The anemia improved daily after the administration of prednisolone. Clinicians should be aware of the possibility of AIHA being caused by COVID-19 vaccination, and monotherapy with prednisolone should be considered in cases of severe anemia.

Relapse of Evans syndrome following BNT162b2 (Pfizer-BioNTech) COVID-19 vaccine: case report and literature review.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) vaccines are considered to be safe. Only few cases of vaccine-induced immune thrombocytopenia or immune hemolysis have been reported so far. Evans syndrome (ES) is a very rare syndrome characterized mainly by warm autoimmune hemolytic anemia (wAIHA) and immune thrombocytopenia (ITP). CASE PRESENTATION: We present a case of a 47-year-old male with a history of wAIHA, diagnosed in 1995 and successfully treated with glucocorticoids, with sustained remission. ITP was diagnosed in May 2016. Due to refractoriness to glucocorticoids, intravenous immunoglobulins (IVIGs), azathioprine and vinblastine, he was splenectomised in April 2017, resulting in complete remission. In May 2021, eight days after the second dose of BNT162b2 (Pfizer-BioNTech) COVID-19 vaccine, he experienced mucocutaneous bleeding. Blood tests showed platelet count (PC) of 8×109/L, while his hemoglobin (Hb) was normal (153 g/L). He was treated with prednisone and azathioprine, without response. On day 28 after vaccine administration, weakness, jaundice and dark brown urine occurred. His laboratory tests: PC 27×109/L, Hb 45 g/L, reticulocytes 10.4%, total bilirubin 106.6 µmol/L, direct bilirubin 19.8 µmol/L, lactate dehydrogenase 633 U/L, haptoglobin ˂0.08 g/L, and positive Coombs test were consistent with ES relapse. After treatment with glucocorticoids, azathioprine and IVIGs, his blood count finally improved (PC 490×109/L, Hb 109 g/L) and remained stable on day 40 of hospitalization. CONCLUSIONS: Although it is unclear whether the relationship between COVID-19 vaccination and relapse of ES in our patient is coincidental or causal, it highlights the need for monitoring of serious outcomes following vaccination.

Possible role of IL-23 inhibitor in autoimmune hemolytic anemia.

Rituximab and prednisone are commonly used treatments for autoimmune hemolytic anemia (AIHA), where the body's immune system attacks and destroys its red blood cells. However, some AIHA patients may become refractory to rituximab treatment, and this can result in continued hemolysis and persistent anemia, making it challenging for affected individuals to manage their symptoms. The underlying causes of rituximab refractoriness in AIHA patients can be complex and vary from patient to patient. Herein, we present a case of newly diagnosed warm and cold AIHA that remained in remission with an interleukin-23 inhibitor.

Ultrastructural analysis of nucleated erythrocyte in patients with autoimmune hemolytic anemia (AIHA).

Autoimmune hemolytic anemia (AIHA) is a group of diseases characterized by immune-mediated lysis of mature red blood cells (RBCs). It is mainly classified into primary and secondary types based on etiology and mechanisms underlying autoantibody production. AIHA is diagnosed using morphological observation of bone marrow smears under a light microscope and monospecific direct antiglobulin test to detect hemolysis. Here, we retrospectively studied ultrastructural abnormalities of nucleated erythroid cells in bone marrows from 10 patients with AIHA using transmission electron microscopy. Our results revealed severe damage and injury to nucleated erythroid cells, including morphological irregularity, pyknosis, karyolysis, expansion of perinuclear cisternae and cytoplasmic lysis. These results indicate that aberrant immunity attacks not only mature RBCs but also nucleated erythroid cells, and ineffective hematopoiesis is partly involved in the pathogenesis of AIHA.

The Histopathology of Cold Agglutinin Disease-Associated B-Cell Lymphoproliferative Disease.

OBJECTIVES: Primary cold agglutinin disease is a type of autoimmune hemolytic anemia caused by circulating antibodies against I antigen, a carbohydrate expressed on most cells, including red blood cells. The underlying disease has been characterized in recent years as a distinct B-cell lymphoproliferative disease of the bone marrow, occurring mostly in the elderly. The disease has been now been included as a separate entity in the most recent classifications of mature B-cell neoplasms. METHODS: A review of the characteristics of cold agglutinin disease is provided, with an emphasis on the pathology features. RESULTS: A detailed description of the histopathology, immunophenotype, and genetics of cold agglutinin disease is provided and compared to other B-cell lymphoproliferative diseases in the bone marrow with similar features. CONCLUSIONS: Recognition of the pathology features of cold agglutinin disease allows to distinguish it from other diseases, especially lymphoplasmacytic lymphoma and marginal zone lymphoma.

Abatacept as salvage therapy for life-threatening refractory autoimmune hemolytic anemia: a case report.

Autoimmune hemolytic anemia (AIHA) can be life-threatening, if hemoglobin (Hb) levels continue to decline after established treatments with glucocorticoids, rituximab, intravenous immunoglobulins, and plasmapheresis. Impaired regulatory T cells (Treg) are proposed to alleviate AIHA development through decreased binding of CTLA-4 to antigen-presenting cells. Abatacept is a fusion protein with a CTLA-4 domain and is approved for use in rheumatoid arthritis. It mimics the immunosuppressive CTLA-4 effect of Treg. Thus, application of abatacept in refractory AIHA might be reasonable. A 54-year-old woman with known AIHA was admitted to our clinic due to therapy-refractory hemoglobin decrease to 4.0 g/dl. Previously, multiple courses of glucocorticoids, rituximab, azathioprine, mycophenolate mofetil, cyclophosphamide, bortezomib, and a splenectomy failed to stop or stabilize hemoglobin levels and hemolysis. A new immunosuppressive therapy with cyclosporine was initiated and erythropoiesis was stimulated with darbepoetin alfa. Again, therapy failed even though we tried to support immunosuppressive therapy by reducing the amount of pathogenic antibody through plasmapheresis. We stopped the treatment with cyclosporine and applied abatacept instead. After seven days hemoglobin stabilized at 4.3 g/dl and no further red blood cells transfusions were necessary. About one month later hemolysis aggravated again and azathioprine was added to the ongoing abatacept treatment. Finally, the combination of abatacept and azathioprine led to a long-lasting increase of the Hb level above 11 g/dl six months later. Abatacept can be applied to overcome therapy refractory autoimmune hemolytic anemia but should be combined with an additional immunosuppressive medication such as azathioprine.

Development of the Cold Agglutinin Disease Symptoms and Impact Questionnaire (CAD-SIQ).

OBJECTIVES: Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia. This study aimed to identify disease-related symptoms and impacts important to patients with CAD, and to develop a novel CAD-specific patient-reported outcome measure. METHODS: Adults with CAD were randomly selected from a United States patient panel to participate in concept elicitation (CE) interviews to identify important symptoms and impacts or cognitive debriefing (CD) interviews to assess the comprehension and relevance of the draft item set. RESULTS: Overall, 37 adults were included (mean [range] age 67.2 [35-87] years). In CE interviews (n = 16), the most frequently reported CAD-related symptoms were reactions to cold environments and fatigue (both 93.8%). CAD had negative impacts on enjoyable activities (81.3%) and daily activities (75.0%). Following CE, standard survey methodological principles were used to develop a draft item pool of 14 concepts. Items were refined through three iterative rounds of CD interviews (n = 21), yielding 11 final items: fatigue; cold sensitivity; dyspnea; wearing extra clothing; limited physical, social, and enjoyable activities; difficulty with usual activities; mood; frustration; and anxiety/stress. CONCLUSIONS: The novel 11-item CAD-Symptoms and Impact Questionnaire provides a measure of the symptoms and impacts of CAD that are important to patients.

Cold antibody autoimmune hemolytic anemia following varicella infection.

Introduction: Autoimmune hemolytic anemia (AIHA) is a rare complication of chicken pox. In adults, such AIHA is due to warm antibodies. We report a case of cold antibody AIHA following chicken pox in a young female. Case Report: A 24-year-old female presented with clinical and laboratory features consistent with hemolytic anemia 5 days after the onset of chicken pox. Her hemoglobin levels dropped rapidly during the course of admission from 7.9 to 3.8 g/dL with evidence of ongoing haemolysis in the form of rising total and indirect bilirubin. Peripheral smear revealed red cell agglutinates and erythrophagocytosis. Direct Coomb's test (DCT) was positive for C3d suggesting a cold antibody AIHA. Since test for Donath Landsteiner antibody was negative, and all other tests for common causes of hemolytic anemia were noncontributory, it was presumed to be due to chicken pox. The fulminant course necessitated a short course of oral steroids to which she responded with rise in hemoglobin and no further hemolysis. Two weeks later, her peripheral smear was normal and DCT negative. Conclusion: In patients presenting with acute onset anemia following chicken pox, possibility of cold antibody AIHA must be considered and appropriate testing pursued. Despite lack of empiric evidence, short course of steroids may be beneficial if drop in hemoglobin is rapid with evidence of fulminant hemolysis, showing no abatement after first week.

Warm autoimmune hemolytic anemia with anti-Jka specificity following babesiosis masquerading as a delayed hemolytic transfusion reaction.

BACKGROUND: Warm autoimmune hemolytic anemia (WAIHA) is characterized by the development of autoantibodies that react with red blood cells (RBCs) optimally at physiologic temperature, classically resulting in a positive direct antiglobulin test (DAT) for IgG and a panreactive eluate. Babesiosis has been described as a potentiator of WAIHA, and all cases have shown classic blood bank findings. Only rare reports have described autoantibodies, both secondary to babesiosis and overall, with specificity for Kidd antigens. METHODS: Antibody detection and identification were performed using IgG-specific column agglutination technology. Jka antigen phenotyping was assessed using monoclonal reagents and genotypic analysis was performed at an immunohematology reference laboratory. DATs were performed via standard tube methods. The elution was performed using the ELUclear glycine acid red cell elution kit. RESULTS: We report a case of WAIHA induced by Babesia microti infection with an autoantibody with Jka specificity, originally believed to be a delayed hemolytic transfusion reaction, given the detection of an RBC antibody in close proximity to numerous RBC transfusions. Determination of autoantibody status with anti-Jka -like reactivity was only confirmed after Kidd antigen genotyping predicted expression of the Jka antigen. DISCUSSION: Healthcare providers should be cognizant of the potential for babesiosis-induced WAIHA, particularly in individuals who continue to hemolyze despite undetectable parasitemia. Furthermore, this case highlights the possibility for warm autoantibodies to demonstrate Kidd antigen specificity. Though Kidd antigen variants are rare, antigen genotyping may be beneficial, particularly in the context of recent RBC transfusions, which typically preclude accurate serological phenotypic assessment.

Clinical and epidemiological features of paroxysmal cold hemoglobinuria: a systematic review.

Paroxysmal cold hemoglobinuria (PCH) is a rare autoimmune hemolytic anemia often overlooked as a potential etiology of hemolysis and is challenging to diagnose because of the complicated testing methods required. We performed a systematic review of all reported cases to better assess the clinical, immunohematologic, and therapeutic characteristics of PCH. We systematically analyzed PubMed, Medline, and EMBASE to identify all cases of PCH confirmed by Donath-Landsteiner (DL) testing. Three authors independently screened articles for inclusion, and systematically extracted epidemiologic, clinical, laboratory, treatment, and outcomes data. Discrepancies were adjudicated by a fourth author. We identified 230 cases, with median presentation hemoglobin of 6.5 g/dL and nadir of 5.5 g/dL. The most common direct antiglobulin test (DAT) result was the presence of complement and absence of immunoglobulin G (IgG) bound to red blood cells, although other findings were observed in one-third of cases. DL antibody class and specificity were reported for 71 patients, of which 83.1% were IgG anti-P. The use of corticosteroids is common, although we found no significant difference in the length of hospitalization for patients with and without steroid therapy. Recent reports have highlighted the use of complement inhibitors. Among patients with follow-up, 99% (213 of 216) were alive at the time of reporting. To our knowledge, this represents the largest compilation of PCH cases to date. We discovered that contemporary PCH most commonly occurs in children with a preceding viral infection, corticosteroid use is frequent (but potentially ineffective), and DAT results are more disparate than traditionally reported.