Clinical, Immunological, and Molecular Variability of RAG Deficiency: A Retrospective Analysis of 22 RAG Patients

Purpose We described clinical, immunological, and molecular characterization within a cohort of 22 RAG patients focused on the possible correlation between clinical and genetic data. Methods Immunological and genetic features were investigated by multiparametric flow cytometry and by Sanger or next generation sequencing (NGS) as appropriate. Results Patients represented a broad spectrum of RAG deficiencies: SCID, OS, LS/AS, and CID. Three novel mutations in RAG1 gene and one in RAG2 were reported. The primary symptom at presentation was infections (81.8%). Infections and autoimmunity occurred together in the majority of cases (63.6%). Fifteen out of 22 (68.2%) patients presented autoimmune or inflammatory manifestations. Five patients experienced severe autoimmune cytopenia refractory to different lines of therapy. Total lymphocytes count was reduced or almost lacking in SCID group and higher in OS patients. B lymphocytes were variably detected in LS/AS and CID groups. Eighteen patients underwent HSCT permitting definitive control of autoimmune/hyperinflammatory manifestations in twelve of them (80%). Conclusion We reinforce the notion that different clinical phenotype can be found in patients with identical mutations even within the same family. Infections may influence genotype–phenotype correlation and function as trigger for immune dysregulation or autoimmune manifestations. Severe and early autoimmune refractory cytopenia is frequent and could be the first symptom of onset. Prompt recognition of RAG deficiency in patients with early onset of autoimmune/hyperinflammatory manifestations could contribute to the choice of a timely and specific treatment preventing the onset of other complications.

Serum Soluble Cytotoxic T-Lymphocyte-Associated Antigen 4 in Children and Adolescents with Autoimmune Cytopenia

Background Autoimmune cytopenias are characterized by the production of autoantibodies against differentiated hematopoietic cells because of defects in central and/or peripheral tolerance. It includes autoimmune hemolytic anemia (AIHA), immune thrombocytopenic purpura (ITP), autoimmune proliferative syndrome (ALPS) and Evans syndrome (EV). Aim of the Work to compare levels of sCTLA-4 in different types of immune cytopenias and their control. Patients and Methods Forty seven children and adolescents who have autoimmune cytopenias were recruited and assessed for eligibility in Pediatric Hematology Clinic, Ain Shams University Children’s Hospital and forming a patients group with age range 8 – 204 months old. An age and sex matched healthy control group were recruited including forty seven healthy participants with age range 6 – 156 months old. Results On initial examination in our study, the prevalence of hepatosplenomegaly and lymphadenopathy among the patients group was 27.7% and 2.1% respectively. Autoimmune cytopenic patients group have statistically significant higher serum sCTLA-4 levels (range 1 – 82 ng/ml) than control group (range 0 – 9 ng/ml) (where P < 0.01 HS). On the other hand, there was no significant difference when comparing levels of sCTLA-4 between sera of ITP, AIHA and ALPS patients (P > 0.05). Serum sCTLA-4 was inversely related to the age at diagnosis and positively related to disease duration. Our results demonstrated the presence of correlations between the levels of sCTLA4 and the severity of autoimmune cytopenias (negative correlation with Hemoglobin (R= -0.315; P = 0.031), mean Hemoglobin (last year) (R= -0.471; P = 0.001) and platelet (R= -0.324; P < 0.05)) and (positive correlation between levels of sCTLA-4 and Reticulocyte count (R = 0.413; P = 0.004), Indirect Bilirubin (R = 0.427; P = 0.003) and Lactate dehydrogenase (R = 0.357; P = 0.014)). There was a significant differences in the prevalence of hepatosplenomegaly among ITP, AIHA and ALPS patients (P < 0.05) with higher prevalence among ALPS patients. Conclusion Soluble form of CTLA4 (sCTLA4) presents in elevated levels in the sera of children and adolescents who have autoimmune cytopenia including AIHA/Evans, ITP and ALPS compared to healthy control group that suggests sCTLA4 could play a role in the pathogenesis of immune cytopenias.

Daratumumab, an original approach for treating multi-refractory autoimmune cytopenia

Not available.

Evan’s in a Case of Acute Myeloid Leukemia Post COVID-19 Infection

The Spectrum of Manifestations of COVID-19, A Pandemic Caused By Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), although emerged as a respiratory tract infection, is now regarded as a multi- system disease including hematological manifestations such as lymphopenia, thrombocytopenia, disseminated intravascular coagulopathy, COVID-19 associated coagulopathy and autoimmune cytopenia. It has been proposed that proinflammatory state induced by COVID-19 can lead to immune dysregulation and hence autoimmune cytopenia. Various case series have reported autoimmune hemolytic anemia (AIHA) post COVID-19 infection. We are reporting an unusual presentation of evan’s syndrome (Cold Autoimmune Hemolytic Anemia (CAIHA) with immune thrombocytopenia) secondary to COVID-19 in a case of Acute Myeloid Leukemia (AML) on consolidation chemotherapy with high dose cytarabine at our institute. As steroid did not seem to have any major response in our case, it is imperative to have a better understanding to guide the use of immunosuppression in autoimmune complications of SARS-CoV-2. We emphasize that one needs to be vigilant to look for these rare autoimmune manifestations, particularly in patients with underlying immune aberrancies due to their primary disease.

SARS-CoV-2 and Autoimmune Cytopenia

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with a variety of clinical manifestations related to viral tissue damage, as well as a virally induced immune response. Hyperstimulation of the immune system can serve as a trigger for autoimmunity. Several immune-mediated manifestations have been described in the course of SARS-CoV-2 infection. Immune thrombocytopenic purpura (ITP) and autoimmune hemolytic anemia (AIHA) are the most common hematologic autoimmune disorders seen in the course of SARS-CoV-2 infection. Vaccine-induced thrombocytopenia is a unique autoimmune hematologic cytopenia associated with SARS-CoV-2 vaccination. This paper will review the current literature on the association of SARS-CoV-2 infection and vaccination with autoimmune cytopenias and the clinical course of autoimmune cytopenias in patients with COVID-19.

Clinical, Immunological and Molecular Variability of RAG Deficiency: a Retrospective Analysis of 22 RAG Patients

Purpose RAG deficiency is associated with a variety of clinical phenotypes. We described clinical, immunological and molecular characterization within a cohort of 22 RAG patients focused on the possible correlation between clinical and genetic data. Methods Immunological and genetic features were investigated by Multiparametric Flow Cytometry and by Sanger or Next generation sequencing (NGS) respectively. Results Patients represented a broad spectrum of RAG deficiencies: SCID n=8, OS n=6, LS/AS n=4 and CID n=4. Four novel mutation in RAG1 gene and one in RAG2 were reported. The primary symptom at presentation were infections (81.8%). Infections and autoimmunity occurred together in the majority of cases (63.6%). Fifteen out of 22 (68.2%) patients presented autoimmune/hyperinflammatory manifestations. Four patients experienced severe autoimmune cytopenia refractory to different lines of therapy. Total lymphocytes count was reduced or almost lacking in SCID group. CD4 cells count was higher in OS patients. B lymphocytes were variably detected in AS and CID groups. Eighteen patients underwent HSCT permitting definitive control of autoimmune/hyperinflammatory manifestations in twelve of them (80%). Conclusion RAG deficiency still represents a challenge in the tracing of effective management and follow-up, notably considering the inability to predict the disease course in atypical cases. Immune dysregulation manifestations are common features often refractory to conventional medical management. Severe and early autoimmune refractory cytopenia is frequent and could be the first symptom of onset. Prompt recognition of RAG deficiency in patients with early onset of autoimmune/hyperinflammatory manifestations could contribute to the choice of a timely and specific treatment preventing the onset of other complications.

Autoimmune and Rheumatic Manifestations Associated With COVID-19 in Adults: An Updated Systematic Review

Background: Numerous cases of the coronavirus disease 2019 (COVID-19) with autoimmune and rheumatic manifestations have been reported. Despite the available reviews that summarized its autoimmune/rheumatic manifestations, a systematic approach is still lacking. Therefore, we conducted a comprehensive systematic review in order to give an overview upon these rare but clinically significant manifestations.Methods: We performed a literature search of PubMed and EMBASE as of October 9, 2020. All articles relevant to either systemic or organ-specific autoimmune and rheumatic manifestations potentially associated with COVID-19 were collected. The reviewed literature were limited to adults ≥18 years.Results: Although most of the existing evidence was based on case reports or case series without a long-term follow-up, a variety of autoimmune/rheumatic manifestations were associated with COVID-19. The manifestations that have a consistent association with COVID-19 include autoimmune cytopenia, cutaneous vasculitis, encephalitis, and Guillain-Barre syndrome. Such association is conflicting as regards to antiphospholipid syndrome, hemophagocytic lymphohistiocytosis, and myasthenia gravis.Conclusion: Our systematic review indicated the potential of the COVID-19 virus to trigger a myriad of autoimmune and rheumatic manifestations, which should be considered amid global efforts to combat COVID-19.