Synergy Between NK Cells and Monocytes in Potentiating Cardiovascular Disease Risk in Severe COVID-19.

BACKGROUND: Evidence suggests that COVID-19 predisposes to cardiovascular diseases (CVDs). While monocytes/macrophages play a central role in the immunopathogenesis of atherosclerosis, less is known about their immunopathogenic mechanisms that lead to CVDs during COVID-19. Natural killer (NK) cells, which play an intermediary role during pathologies like atherosclerosis, are dysregulated during COVID-19. Here, we sought to investigate altered immune cells and their associations with CVD risk during severe COVID-19. METHODS: We measured plasma biomarkers of CVDs and determined phenotypes of circulating immune subsets using spectral flow cytometry. We compared these between patients with severe COVID-19 (severe, n=31), those who recovered from severe COVID-19 (recovered, n=29), and SARS-CoV-2-uninfected controls (controls, n=17). In vivo observations were supported using in vitro assays to highlight possible mechanistic links between dysregulated immune subsets and biomarkers during and after COVID-19. We performed multidimensional analyses of published single-cell transcriptome data of monocytes and NK cells during severe COVID-19 to substantiate in vivo findings. RESULTS: During severe COVID-19, we observed alterations in cardiometabolic biomarkers including oxidized-low-density lipoprotein, which showed decreased levels in severe and recovered groups. Severe patients exhibited dysregulated monocyte subsets, including increased frequencies of proinflammatory intermediate monocytes (also observed in the recovered) and decreased nonclassical monocytes. All identified NK-cell subsets in the severe COVID-19 group displayed increased expression of activation and tissue-resident markers, such as CD69. We observed significant correlations between altered immune subsets and plasma oxidized-low-density lipoprotein levels. In vitro assays revealed increased uptake of oxidized-low-density lipoprotein into monocyte-derived macrophages in the presence of NK cells activated by plasma of patients with severe COVID-19. Transcriptome analyses confirmed enriched proinflammatory responses and lipid dysregulation associated with epigenetic modifications in monocytes and NK cells during severe COVID-19. CONCLUSIONS: Our study provides new insights into the involvement of monocytes and NK cells in the increased CVD risk observed during and after COVID-19.

Synergistic Role of NK Cells and Monocytes in Promoting Atherogenesis in Severe COVID-19 Patients.

Clinical data demonstrate an increased predisposition to cardiovascular disease (CVD) following severe COVID-19 infection. This may be driven by a dysregulated immune response associated with severe disease. Monocytes and vascular tissue resident macrophages play a critical role in atherosclerosis, the main pathology leading to ischemic CVD. Natural killer (NK) cells are a heterogenous group of cells that are critical during viral pathogenesis and are known to be dysregulated during severe COVID-19 infection. Their role in atherosclerotic cardiovascular disease has recently been described. However, the contribution of their altered phenotypes to atherogenesis following severe COVID-19 infection is unknown. We demonstrate for the first time that during and after severe COVID-19, circulating proinflammatory monocytes and activated NK cells act synergistically to increase uptake of oxidized low-density lipoprotein (Ox-LDL) into vascular tissue with subsequent foam cell generation leading to atherogenesis despite recovery from acute infection. Our data provide new insights, revealing the roles of monocytes/macrophages, and NK cells in COVID-19-related atherogenesis.

Evaluation of Red Blood Cell Transfusion Practice and Knowledge Among Cancer Surgeons.

BACKGROUND: Transfusion of blood products has a negative impact on surgical and cancer outcomes. The objective of the current study was to evaluate surgeons' practice and knowledge of red blood cell transfusion for surgical patients. METHODS: A survey of residents, fellows, and faculty surgeons at the Ohio State University Wexner Medical Center and surgeons who identified as taking care of cancer patients nationally was conducted. Four domains were addressed including perceived preoperative assessment and management of anemia, perceived use of transfusion alternatives, perceived use of and factors influencing packed red blood cell administration, and transfusion practice knowledge. RESULTS: Among 158 respondents, 87 (64.5%) were surgeons on faculty at an academic medical center, 26 (19%) were surgeons in private practice, and 24 (15.2%) were surgical residents or fellows. The majority of respondents were surgical oncologists or hepatobiliary surgeons (N = 83, 62.0%) and had been in practice > 10 years (> 10-15 N = 28, 20.6%) and > 15 years N = 59, 43.4%). Only thirteen (N = 13, 8.2%) surgeons reported that they routinely complete a preoperative anemia workup. The majority of providers reported that they rarely or never use alternatives to transfusion such as erythropoietin (N = 135, 91.8%), tranexamic acid (N = 140, 94.6%), autologous blood transfusion (N = 141, 95.3%), or cell saver for benign (N = 107, 72.3%) or malignant cases (N = 133, 90.4%). Provider transfusion knowledge was variable. CONCLUSIONS: Surgeons varied widely in their transfusion practice and knowledge. Further education of surgeons regarding transfusion medicine and practice, as well as use of transfusion alternatives, could lead to improved patient outcomes. Patient blood management programs may help inform individual surgeon practices.

Clinical and cost outcomes of pre-emptive plerixafor administration in patients with multiple myeloma undergoing stem cell mobilization.

PURPOSE: The stem cell mobilization agent plerixafor significantly improves CD34+ stem cell procurement in patients with multiple myeloma undergoing autologous stem cell transplant. We compared mobilization success rates and costs of two regimens of plerixafor administration: pre-emptive (P-PL, initiated the evening prior to the first day of stem cell collection) and standard (S-PL, initiated the evening prior to the second day of stem cell collection in the event of inadequate collection on the first day). METHODS: Patients with multiple myeloma undergoing mobilization were categorized as either P-PL or S-PL. Stem cell collection success was evaluated using logistic regression models. Associated costs were aggregated in terms of average collections per patient in each mobilization option (patient level), and escalated to a panel of 5000 patients (population level). RESULTS: 299 patients were evaluable; 241 received P-PL and 58 received S-PL. Patients receiving P-PL had higher median CD34+ count pre-collection and higher median total CD34+ cell harvest on the first collection (6.75 × 106/kg for P-PL, 1.96 × 106/kg for S-PL; P<0.01). In multivariable analyses, P-PL remained significantly associated with the ability to collect ≥2 × 106/kg CD34+ on the first day (OR = 4.05, 95% CI, 1.19-13.83, P = 0.03) and ≥5 × 106/kg CD34+ in total (OR = 3.09, 95% CI, 1.04-9.23, P = 0.04). P-PL saved $11,248 (46%) per patient compared with S-PL. CONCLUSION: P-PL significantly enhanced collection efficiency, with most patients completing collection in 1 day, resulting in substantial cost savings.

Perioperative use of blood products is associated with risk of morbidity and mortality after surgery.

BACKGROUND: Administration of blood products may be associated with increased morbidity and perioperative mortality in surgical patients. METHODS: Patients aged 18 + who underwent gastrointestinal surgery at the Ohio State University Wexner Medical Center 9/10/2015-5/9/2018 were identified. Multivariable logistic regression models were used to evaluate impact of blood product use on survival and complications, as well as to identify factors associated with receipt of transfusions. RESULTS: Among 10,756 patients, 35,517 units of blood products were transfused. Preoperative nadir hemoglobin was associated with receipt of blood product transfusion (OR 0.55, 95% CI 0.53, 0.68). After adjusting for patient and procedural characteristics, patients undergoing transfusion of blood products had an increased risk of perioperative mortality (OR 7.80, 95% CI 6.02, 10.10). CONCLUSIONS: The use of blood products was associated with increased risk of complication and death. Patient blood management programs should be implemented to provide rational criteria and guidance for the transfusion of blood products.

Anti-M Alloimmunization: Management and Outcome at a Single Institution.

Objective The objective of this study was to review the management strategies and outcomes in gravidas with anti-M alloimmunization over 15 years. Study Design Data collected from 195 pregnant patients with anti-M antibodies from July 2000 through June 2016 were reviewed retrospectively. We analyzed indirect antiglobulin test titer results, paternal or fetal/neonatal M antigen status, antepartum course, and perinatal outcomes. Results Anti-M antibodies were found in 146 women and 195pregnancies. Among those with positive indirect antiglobulin tests, 193 pregnancies had titers at or below 1:4. Only one patient with an initial low titer experienced a more than twofold increase to a titer 1:64. Two women underwent an amniocentesis and cordocentesis. Ninety-five (73.6%) of the 129 infants tested were positive for the M antigen. Nine infants required phototherapy. There were no cases of hemolytic disease of the fetus or newborn, mild or severe. Conclusion The incidence of severe hemolytic disease of the newborn due to anti-M is extremely low. We found no cases in our review of 195 pregnancies, despite several cases of severe hemolytic disease of the newborn reported in the literature. We have created an algorithm for the management of anti-M antibodies in pregnancy based on our data and extensive literature review.

Acute Hemolytic Transfusion Reaction Caused by a Red Cell Antibody That Was Missed by Pretransfusion Testing Using Tube Method.

Pretransfusion testing is very important to prevent transfusion of incompatible red cells, which might result in a hemolytic transfusion reaction. This includes the detection of antibodies in recipients' serum and compatibility testing between donor cells and recipient serum. The most commonly used methods include gel and tube techniques. We present a case in which an anti-E alloantibody was detected by gel method but not by tube testing. As a result, red cells that were retrospectively phenotyped as positive for E antigen were inadvertently selected and transfused after crossmatch using the same tube method. After transfusion, the patient developed signs of hemolytic transfusion reaction. This case highlights the potential risk of transfusion of incompatible red cells when alloantibody detection is solely relied on tube testing.

TRALI following fresh frozen plasma resuscitation from burn shock.

INTRODUCTION: Resuscitation from burn shock using fresh frozen plasma (FFP) has been described. Critics of FFP resuscitation cite the development of transfusion related acute lung injury (TRALI) as a deterrent to its use. This study examines the occurrence of TRALI with FFP resuscitation of critically ill burned patients. METHODS: A retrospective chart review was conducted of severely burned patients who received FFP resuscitation. Data points included age, TBSA, TBSA full thickness, presence of alternate etiologies of acute lung injury, total FFP administered, and signs and symptoms of TRALI as defined per the Canadian Blood Services Consensus Conference. RESULTS: Eighty-three patients met the definition of severe burn and received FFP resuscitation. Of those, 65 met exclusion criteria. Eighteen patients were left for analysis with only one found to have signs and symptoms of TRALI. That patient suffered a 53.5% TBSA burn, received a total of 6228ml FFP, had no competing etiologies of ALI, and was diagnosed with TRALI within 6h of completing the FFP transfusion. CONCLUSION: The possible occurrence of TRALI in burn patients receiving FFP resuscitation should be weighed against the reported benefits of such a resuscitation strategy.

The tipping point: The critical role of therapeutic apheresis in a case of refractory acquired hemophilia.

Acquired hemophilia A (AHA) is a rare autoimmune disorder that leads to factor VIII (FVIII) deficiency via autoantibody formation. Standard treatment options include FVIII bypassing factors and immunosuppression. However, the role of therapeutic plasma exchange (TPE) is not clear in the treatment of AHA. We present a case of idiopathic AHA in a 66 year old female with severe bleeding and a FVIII inhibitor of 17.6 Bethesda units (BU). She failed to respond to standard treatment including maximum dose of recombinant FVIIa (rFVIIa), rituximab, and other immunosuppressive agents. Her FVIII inhibitor rapidly increased to 140 BU and FVIII was below 5%. TPE was initiated 3 weeks after admission and her bleeding stabilized after the first treatment and completely stopped after three treatments. Repeat testing revealed increased FVIII to 15% and FVIII inhibitor decreased to 2.0 BU. After an additional TPE treatment, her FVIII increased to 27% and FVIII inhibitor decreased to 0.6 BU and she was discharged without bleeding 40 days after admission. In this case, TPE played a critical role in reducing FVIII inhibitor, which resulted in a recovery of FVIII activity and hemostasis. Therefore, TPE should be initiated early in AHA patients with bleeding and high titer of FVIII inhibitor.

Warm Autoimmune Hemolytic Anemia and Direct Antiglobulin Testing With a False-Negative Result in a 53-Year-Old Man: The DAT Will Set You Free.

Warm autoimmune hemolytic anemia (WAIHA), the most common of the relatively uncommon autoimmune-mediated hemolytic anemias (AIHAs), is mediated by polyclonal immunoglobulin (Ig)G autoantibodies in most cases. Herein, we present a case of WAIHA involving a direct antiglobulin test (DAT) with an initially negative result. Using a modified DAT protocol, repeat testing of the same specimen material from a previously healthy 53-year-old man yielded positive results. This case demonstrates that investigation of an apparently negative DAT result plays a critical role in the differential diagnosis of patients with rapidly progressing hemolytic anemia and the reversal of that decline.

Hemolytic Disease of the Fetus and Newborn due to Intravenous Drug Use.

Objectives The objective is to present a pregnancy complication associated with intravenous drug use, namely, that of red blood cell alloimmunization and hemolytic disease of the fetus and newborn. Methods An observational case series is presented including women with red blood cell alloimmunization most likely secondary to intravenous drug abuse Results Five pregnancies were identified that were complicated by red blood cell alloimmunization and significant hemolytic disease of the fetus and newborn, necessitating intrauterine transfusion, an indicated preterm birth, or neonatal therapy. Conclusions As opioid abuse continues to increase in the United States, clinicians should be aware of the potential for alloimmunization to red blood cell antibodies as yet another negative outcome from intravenous drug abuse.

Atorvastatin for the Prophylaxis of Acute Graft-versus-Host Disease in Patients Undergoing HLA-Matched Related Donor Allogeneic Hematopoietic Stem Cell Transplantation (allo-HCT).

Statins possess potent immunomodulatory effects that may play a role in preventing acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic cell transplantation (allo-HCT). We performed a phase II study of atorvastatin for aGVHD prophylaxis when given to allo-HCT recipients and their HLA-matched sibling donors. Atorvastatin (40 mg/day) was administered to sibling donors, beginning 14 days before the anticipated start of stem cell collection. Allo-HCT recipients (n = 40) received atorvastatin (40 mg/day) in addition to standard aGVHD prophylaxis. The primary endpoint was cumulative incidence of grades II to IV aGVHD at day 100. Atorvastatin was well tolerated, with no attributable grades III to IV toxicities in donors or their recipients. Day 100 and 180 cumulative incidences of grades II to IV aGVHD were 30% (95% confidence interval [CI], 17% to 45%) and 40% (95% CI, 25% to 55%), respectively. One-year cumulative incidence of chronic GVHD was 43% (95% CI, 32% to 69%). One-year nonrelapse mortality and relapse incidences were 5.5% (95% CI, .9% to 16.5%) and 38% (95% CI, 18% to 47%), respectively. One-year progression-free and overall survival rates were 54% (95% CI, 38% to 71%) and 82% (95% CI, 69% to 94%). One-year GVHD-free, relapse-free survival was 27% (95% CI, 16% to 47%). These results did not differ from our historical control subjects (n = 96). Although safe and tolerable, the addition of atorvastatin did not appear to provide any benefit to standard GVHD prophylaxis alone.