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Introduction: COVID-19 vaccination substantially reduces morbidity and mortality associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and severe illness. However, despite effective COVID-19 vaccines many questions remain about the efficacy of vaccines and the durability and robustness of immune responses, especially in immunocompromised persons. The NCI-funded Serological Sciences Network (SeroNet) is a coordinated effort including 11 sites to advance research on the immune response to SARS-CoV-2 infection and COVID-19 vaccination among diverse and vulnerable populations. The goals of the Pooling Project are: (1) to conduct real-world data (RWD) analyses using electronic medical records (EMR) data from four health care systems (Kaiser Permanente Northern California, Northwell Health, Veterans Affairs-Case Western, and Cedars-Sinai) to determine vaccine effectiveness in (a) cancer patients;(b) autoimmune diseases and (c) solid organ transplant recipients (SOTR);(2) to conduct meta-analyses of prospective cohort studies from eight SeroNet institutions (Cedars-Sinai, Johns Hopkins, Northwell Health, Emory University, University of Minnesota, Mount Sinai, Yale University) to determine post-vaccine immune responses in (a) lung cancer patients;(b) hematologic cancers/hematopoietic stem cell transplant (HSCT) recipients;(c) SOTR;(d) lupus. Method(s): For our RWD analyses, data is extracted from EMR using standardized algorithms using ICD-10 codes to identify immunocompromised persons (hematologic and solid organ malignancy;SOTR;autoimmune disease, including inflammatory bowel disease, rheumatoid arthritis, and SLE). We use common case definitions to extract data on demographic, laboratory values, clinical co morbidity, COVID-19 vaccination, SARS-CoV-2 infection and severe COVID-19, and diseasespecific variables. In addition, we pool individual-level data from prospective cohorts enrolling patients with cancer and other immunosuppressed conditions from across network. Surveys and biospecimens from serology and immune profiling are collected at pre-specified timepoints across longitudinal cohorts. Result(s): Currently, we have EMR data extracted from 4 health systems including >715,000 cancer patients, >9,500 SOTR and >180,000 with autoimmune conditions. Prospective cohorts across the network have longitudinal data on >450 patients with lung cancer, >1,200 patients with hematologic malignancies, >400 SOTR and >400 patients with lupus. We will report results examining vaccine effectiveness for prevention of SARS-CoV-2 infection, severe COVID-19 and post-acute sequelae of COVID-19 (PAS-C or long COVID) in cancer patients compared to other immunocompromised conditions. Conclusion(s): Our goal is to inform public health guidelines on COVID-19 vaccine and boosters to reduce SARS-CoV-2 infection and severe illness in immunocompromised populations.
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The goal of this research proposal is to provide better treatments for Fanconi Anemia (FA), an inherited bone marrow failure disorder that affects approximately 1 in 100,000 children. The combination of hematopoietic stress and inherent genomic instability leads to cancer and accumulation of genetic defects is likely the cause of AML progression. We proposed to study primary human cell defective in the FA pathway to delineate pathways of leukemia progression and eventually prevent progression to bone marrow failure or progression to leukemia. Our two aims are to 1)identify molecular vulnerabilities and genetic changes promoting oncogenesis in FA deficient CD34+ cells in vitro and to 2) determine molecular changes at the root of disease progression in primary human FA bone marrow and test potential therapeutic approaches in vivo in MISTRG-kitMUT mice. To achieve this goal we have to i) obtain primary FA patient cells and ii) generate human FANC gene KO CD34+ cells. Note that the COVID pandemic has significantly impaired our progress since 3/15/2020. We have focused our efforts on generating FA defective cells via two mechanisms: a) shRNA mediated knockdown and b) via CRISPR/Cas9 mediated deletion. We have encountered 2 difficulties which we are still addressing: inefficiency of deleting FA genes and selection against deleted cells;silencing of rescue lentiviral vectors in primary hematopoietic cells. With COVID all work had to halt and mouse work was minimal we are expanding colonies and actively transplanting primary FA samples with goal to further optimize engineering of FA samples and transplantation in MISTRG mice.
ABSTRACT
TOPIC: Chest Infections TYPE: Medical Student/Resident Case Reports INTRODUCTION: Increasing evidence suggests that COVID-19 is associated with hyperinflammatory status and various autoimmune disorders. There have been a few case reports of COVID-19 associated warm autoimmune hemolytic anemia (WAIHA). These cases were brought into clinicians' attention with anemia and positive direct antiglobulin test (DAT). Here we report a case of WAIHA in a patient who just recovered from COVID-19 with initial negative DAT but positive elution test. CASE PRESENTATION: 85-year-old man with history of coronary artery disease presented with several days of progressive shortness of breath. Three weeks ago, he had a mild course of COVID-19, which had completely resolved for two weeks. His vital sign was stable upon presentation. Physical exam was pertinent for pale conjunctiva. Lab revealed Hemoglobin (Hgb) 5.7 g/dL (baseline 13 g/dL), MCV 108 fL, reticulocyte percentage > 18%, total bilirubin 2.8 mg/dL, direct bilirubin 0.4 md/dL, lactate dehydrogenase (LDH) 461 U/L, haptoglobin <10 mg/dL. Peripheral blood smear showed reticulocytosis and increased microspherocytes. DAT was negative. Elution test identified warm IgG autoantibody. A diagnosis of WAIHA was made. He received 1U of RBC transfusion and was started on prednisone with a gradually taper course. Folic acid supplement and prophylaxis for pneumocystis pneumonia with atovaquone were also provided. His symptoms significantly improved throughout his 4-day hospitalization. 8 weeks after discharge, his Hgb was stable at 12.2 g/dL. DISCUSSION: WAIHA is a rare and serious complication associated with COVID-19. Similar to our case, two previously reported cases developed WAIHA about 2 weeks after the onset of COVID-19. Anemic symptoms from severe warm AIHA can be falsely attributed to respiratory failure. Typical lab finding of warm AIHA is low Hgb, increased reticulocyte count, elevated LDH, low haptoglobin, indirect bilirubinemia, and spherocytosis/microspherocytosis. It is important to recognize the possibility of DAT-negative warm AIHA to avoid treatment delay. If the clinical suspicion remains high for warm AIHA like our case, the clinician can utilize the elute test or "super-Coombs" test (enhanced DAT) to detect erythrocyte antibodies. In our case and other reported cases, corticosteroids are effective in treating COVID-19 associated WAIHA. CONCLUSIONS: WAIHA should be suspected in patients with recent COVID-19 history and typical hemolytic lab finding. Recognizing DAT-negative WAIHA with further testing such as enhanced DAT is crucial to avoid delays in treatment and unnecessary evaluations. Steroids treatment often leads to optimal response in these cases. REFERENCE #1: Lopez C, Kim J, Pandey A, Huang T, DeLoughery TG. Simultaneous onset of COVID-19 and autoimmune haemolytic anaemia. Br J Haematol. 2020;190(1):31-32. doi:10.1111/bjh.16786 REFERENCE #2: Go RS, Winters JL, Kay NE. How I treat autoimmune hemolytic anemia. Blood. 2017 Jun 1;129(22):2971-2979. doi: 10.1182/blood-2016-11-693689 REFERENCE #3: Hsieh TC, Sostin O. Severe warm autoimmune hemolytic anemia in COVID-19 managed with least incompatible RBC product and glucocorticoids. Ann Hematol. 2021 Feb 18:1–2. doi: 10.1007/s00277-021-04457-4 DISCLOSURES: No relevant relationships by Stephanie Halene, source=Web Response No relevant relationships by Tien-Chan Hsieh, source=Web Response No relevant relationships by Russell Lewis, source=Web Response