Casirivimab-imdevimab neutralizing SARS-CoV-2: post-infusion clinical events and their risk factors

Background Casirivimab-imdevimab has been developed to neutralize SARS-CoV-2. The global clinical trials in outpatients documented several adverse effects (AE), which mandate caution in Japan where part of patients return home. To investigate post-infusion clinical events and their risk factors, we attempted a retrospective study. Main body Subjects were a consecutive series of inpatients with COVID-19 undergoing an infusion of casirivimab-imdevimab in our institute. The criteria for administration were in accordance with previous clinical trials, e.g., exclusion of patients necessitating oxygen supply. In Japan, however, SARS-CoV-2 vaccinees were eligible. Methods were review of background factors of status, imaging, and laboratory findings for the outcome of post-infusion events such as temperature increase (Temp+), pulse oximetry below 94%, and other events. Also, we documented the drug efficacy. Of a total of 96 patients with a median follow-up of 54 days, one (1.0%) died who alone was an exception demanding oxygen supply. Other 95 patients (99.0%) recovered from fever and hypoxia by Day 4 and later had no worsening of COVID-19. Median increase of body temperature was 1.0 degrees Celsius, which was used for computation of Temp+. Multivariate analysis showed that for Temp+ (n = 47), white blood cell counts more than 4.3 × 103/microliter (Odds Ratio [OR] 2.593, 95% Confidence Interval [CI] 1.060–6.338, P = 0.037) was at risk, whereas 2-time vaccination for SARS-CoV-2 (OR 0.128, 95% CI 0.026–0.636, P = 0.012) was a preventing factor. Likewise for lowered oximetry (n = 21), CT showing bilateral ground glass attenuation (OR 5.544, CI 1.599–19.228, P = 0.007) was a significant risk factor. Two patients (2.1%) showed bradycardia (asymptomatic, intervention not indicated) on Day 3 and recovery on Day 5. Limitations for this study included the difficulty distinguishing AE from worsening of COVID-19, thus we documented as clinical events. Conclusions For 24 h after infusion of casirivimab-imdevimab, COVID-19 patients with increased white blood cell counts may be predisposed to temperature elevation more than 1.0 degrees centigrade, as may bilateral ground glass opacity to lowered oximetry. Thus, patients with leukocytosis and bilateral ground glass attenuation may need precaution for transient fever and hypoxia, respectively.

Study of serum bilirubin as a diagnostic method to predict acute perforated appendicitis

Background: Acute appendicitis is the commonest cause of ‘acute surgical abdomen’. Appendicectomy is the most frequently performed urgent abdominal operation and is often the first major procedure performed by a surgeon in training. The aim of the study was to whether hyperbilirubinemia might be used as a diagnostic tool to predict perforated appendicitis.Methods: This study comprised patients who presented with the condition of appendicitis and abnormal liver function tests on admission and had a laparoscopic or open appendectomy. The age information, duration of symptoms, temperature, white blood cell counts, bilirubin levels, and histology data were gathered. Peritoneal fluid was cultured and examined for sensitivity.Results: The average bilirubin level of all participating patients was 0.92 mg/dl (range, 0.1-4.3 mg/dl). The mean bilirubin levels were higher for patients with simple appendicitis compared to those with a non-inflamed appendix (0.7 mg/dl and 0.4 mg/dl, p<0.001). Hyperbilirubinaemia was reported to have a specificity of 89% and a positive predictive value of 90.02% for acute appendicitis. Patients with appendiceal perforation, however, had a mean bilirubin level of 1.7 mg/dl and were more likely to have hyperbilirubinaemia (p<0.001). The specificity of hyperbilirubinaemia for perforation or gangrene was 73%.Conclusions: Patients with hyperbilirubinemia with appendicitis condition should be screened for a greater risk of appendiceal perforation than those with normal bilirubin levels.

Prerenal Transplant Education and Evaluation Positively Impacts Outcomes

Introduction: An outstanding question in kidney transplantation is how to prepare candidates and their social supports for optimal posttransplant outcomes. Project Aims: This program evaluation assessed whether a pretransplant quality improvement clinic improved clinical outcomes in the year posttransplant compared to recipients receiving standard of care. Design: The Countdown to Transplant Clinic was implemented with kidney transplant candidates expected to receive a transplant within the next few months. The clinic included an enhanced education session on posttransplant lifestyle management, confirmation of support (≥2 adults), and evaluations by transplant social work, psychology, and nephrology. Results: Seventy-five patients participated in the clinic and underwent a transplant. A retrospective chart review of posttransplant laboratory values, rehospitalizations (within 3-months posttransplant), biopsy-confirmed graft failure, and mortality (within 1-year posttransplant) were collected from both groups. Univariate and multivariate propensity score-weighted linear or logistic regression models were used to evaluate the association between clinic participation and outcomes. In models adjusting for relevant covariates, participation in The Countdown to Transplant Clinic (vs standard care) was associated with a lower coefficient of variation of serum tacrolimus (all values collected 3-12 months posttransplant), 30-day posttransplant white blood cell counts (but not 90-day), 90-day posttransplant potassium, and 30 and 31 to 90 days rehospitalizations. Clinic participation did not predict serum glucose levels at 30- or 90-days posttransplant. Due to low rates of rejection and mortality, meaningful comparisons were not possible. Conclusion: Participation in a pretransplant, multicomponent clinic may improve certain outcomes of interest posttransplantation. Pilot testing for feasibility for randomized controlled trials is a necessary next step.

Predicting risk factors for thromboembolic complications in patients with sickle cell anaemia – lessons learned for prophylaxis

Objective To assess the clinical and laboratory predictors of venous thromboembolism (VTE) in patients with sickle cell anaemia (SCA) and its relationship to morbidity and mortality. Methods This retrospective case–control study analysed data from patients with SCA that experienced VTE compared with matched control patients with SCA but no VTE (2:1 ratio). Results A total of 102 patients with SCA were enrolled (68 cases with VTE and 34 controls). Amongst the 68 cases (median age, 29.5 years), 26 (38.2%) presented with isolated pulmonary embolism (PE). A higher prevalence of splenectomy (73.5% versus 35.3%) was observed in the cases compared with the controls. A significantly higher prevalence of central venous catheter (CVC) insertion (42.6% versus 8.8%) was observed in the cases compared with the controls. High white blood cell counts, serum lactic dehydrogenase (LDH), bilirubin and C-reactive protein (CRP) and low haemoglobin (Hb) and HbF were significant risk factors for VTE. Forty-two cases (61.8%) developed acute chest syndrome, 10 (14.7%) had a stroke and seven (10.3%) died. Conclusions VTE in patients with SCA has a high impact on morbidity and mortality. PE was the leading presentation of VTE, with CVC insertion, high LDH, bilirubin, CRP and white blood cell counts along with low Hb and HbF constituting other significant risk factors.

Transient hypertriglyceridemia: a common finding during Epstein-Barr virus-induced infectious mononucleosis

Background Hypertriglyceridemia can occur in lymphoproliferative disorders. Infectious mononucleosis is a self-limiting, benign lymphoproliferative disorder. This study aimed to investigate the serum triglyceride concentrations and their change over time in patients with infectious mononucleosis. Methods We evaluated an adult patient with severe hypertriglyceridemia (>1000 mg/dL) during infectious mononucleosis and reviewed the records of 360 patients admitted to our hospital because of infectious mononucleosis (median age, 19 years; range, 15-87 years; 51.4% male). We compared the serum triglyceride concentrations with those of a control sample from the general population (n=75). A second triglyceride measurement, obtained during convalescence (median of 30 days after the initial determination), was available for 160 patients. Results The triglyceride concentrations in the acute phase (median: 156 mg/dL) were significantly higher than those of the controls (median, 76 mg/dL; P<0.001). A total of 194 (53.9%) patients presented with hypertriglyceridemia (>150 mg/dL), which was more common in the patients older than 30 years than in the younger patients (78.6% vs. 50.6%; P<0.001). A significant correlation (P<0.005) was observed between the triglyceride levels and white blood cell counts, total cholesterol levels, and liver damage markers. The triglyceride concentrations decreased during convalescence (P<0.001) and were lower than the initial measurement in 83.7% of the cases. Conversely, the total cholesterol concentrations during the acute phase were lower than those of the controls and increased during convalescence (P<0.001). Conclusions Patients with severe infectious mononucleosis frequently show mild, transient hypertriglyceridemia. Further studies are needed to elucidate the mechanisms underlying this finding.

Lymphocyte Counts and Multiple Sclerosis Therapeutics: Between Mechanisms of Action and Treatment-Limiting Side Effects

Although the detailed pathogenesis of multiple sclerosis (MS) is not completely understood, a broad range of disease-modifying therapies (DMTs) are available. A common side effect of nearly every MS therapeutic agent is lymphopenia, which can be both beneficial and, in some cases, treatment-limiting. A sound knowledge of the underlying mechanism of action of the selected agent is required in order to understand treatment-associated changes in white blood cell counts, as well as monitoring consequences. This review is a comprehensive summary of the currently available DMTs with regard to their effects on lymphocyte count. In the first part, we describe important general information about the role of lymphocytes in the course of MS and the essentials of lymphopenic states. In the second part, we introduce the different DMTs according to their underlying mechanism of action, summarizing recommendations for lymphocyte monitoring and definitions of lymphocyte thresholds for different therapeutic regimens.

Characteristics and Prognosis of Antibody Non-Responders with COVID-19

Background：The coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been spreading globally. The information regarding the characteristics and prognosis of antibody non-responders with COVID-19 is scarce.Method: In this retrospective, single-center study, we included all the patients with confirmed COVID-19 using real-time reverse transcriptase-polymerase chain reaction (RT-PCR) admitted to the Fire God Mountain hospital from February 3, 2020, to April 14, 2020. A total of 1921 patients were divided into the antibody-negative group (n=94) and antibody-positive group (n=1827), and the 1:1 propensity score matching (PSM) was used to match two groups.Results: In the antibody negative group, 40 patients (42.6%) were male, 54 patients (57.4%) were female, and 49 patients (52.1%) were older than 65 years old. Cough was the most common symptoms in the antibody negative group. White blood cell counts (WBC) 6.6×109/L [5.0, 9.1], Neutrophils 4.3×109/L [3.1, 6.6], C-reactive protein 7.3 mg/L [1.3, 49.0], Procalcitonin (PCT) 0.1 ng/mL [0.0, 0.2], Interleukin-6 (IL-6) 64.2 [1.5, 28.7], Lactate dehydrogenase (LDH) 193.8 U/L [154.9,260.6], Creatine kinase 60.5 U/L [40.5, 103.7], Creatine kinase isoenzyme 10.3 ng/mL [8.2, 14.5], Urea nitrogen 5.3 mmol/L [4.0, 8.7] and Creatinine 77.7 μmol/L [60.6, 98.7] were significantly higher in antibody negative patients than in antibody positive group (P<0.005). The days of nucleic acid negative conversion in the antibody negative group was shorter than that in the antibody positive group (P < 0.001). Meanwhile, the hospitalization time of antibody negative patients was shorter than that of antibody positive patients (8.0 [6.0, 10.0] VS 13.0 [8.2, 23.0], P < 0.001).Conclusion: Some COVID-19 patients without specific antibodies had mild symptoms, but the inflammatory reaction caused by innate clinical immunity was more intense than those with antibodies, and the virus was cleared faster. The production of specific antibodies was unnecessary for SARS-CoV-2 clearance, and non-specific immune responses played an essential role in virus clearance.

Genetically Determined Obesity and Adipose Distribution Impact Human Blood Trait Variation across Cell Lineages

Introduction Genome wide association studies (GWAS) have catalogued thousands of loci that influence blood traits, but genetic mechanisms and impacted cell types are often unknown. While some regulatory factors are blood cell-autonomous, other extrinsic regulatory factors respond to systemic physiology. Epidemiologic studies have correlated generalized obesity (increased body mass index, BMI) and high cholesterol with anemia, but cell types and mechanisms that mediate these effects are incompletely understood, and these studies do not provide evidence for causality. Thus, we wanted to use genetic effects of BMI and cholesterol on hemoglobin level (HGB) and other blood traits to infer causal relationships, identify relevant cell types, and propose genetic mechanisms. Methods Mendelian randomization (MR), akin to a "genetic randomized controlled trial", uses variants linked to an exposure trait to estimate causal effects of that exposure on a given outcome. 1 Random variant allele allocation at meiosis enables this approach to address confounding and reverse causality that can otherwise preclude causal inference from epidemiologic and cohort studies. Further, effects of multiple factors can be parsed using multivariable MR and causal mediation analyses to help explain genetic associations. 2 Our study used gender- and age-adjusted GWAS summary statistics from European individuals. Results We hypothesized that increased genetically determined BMI would decrease HGB. Using a MR framework, we found that a 5 kg/m 2 (1 standard deviation unit) increase in BMI decreased hemoglobin by 0.06±0.01 g/dL (p=1x10 -5, Fig). Increased BMI also decreased erythrocyte count, and unexpectedly also decreased platelet and white blood cell counts (all with p&lt;5x10 -3). These data showed that obesity-related mechanisms extended beyond the erythroid lineage, perhaps impacting multipotent hematopoietic progenitor cells (HPCs). Similar to BMI, a 1 SD unit increase in total cholesterol decreased HGB (0.10±0.03 g/dL, p=2x10 -3, Fig). However, genetic effects of cholesterol were restricted to erythroid traits (HGB and hematocrit). Multivariable and mediation analyses confirmed that effects of BMI and cholesterol functioned through distinct genetic mechanisms. We speculated that multilineage effects from BMI could reflect a genetic predisposition to accumulate bone marrow adipose tissue, which can impact HPCs and hematopoiesis. 3 A tendency for 'central' adiposity increases one's waist-hip ratio (WHR), and increases cardiovascular disease risk concordant with BMI. Unexpectedly, we found that increased WHR, in contrast to BMI, increased HGB (0.08±0.02 g/dL, p=9x10 -6) as well as erythrocyte, platelet, and white blood cell counts (all with p&lt;4x10 -3, Fig). In multivariable experiments, the effects of WHR were exacerbated after accounting for BMI at the individual or population level. Thus, obesity impacts blood traits through genetically determined adipose distribution. Conclusions Our results confirm that BMI and cholesterol negatively impact HGB at a genetic level, consistent with clinical observations. The unexpected multilineage effects of genetically determined BMI most likely reflects a tendency to accumulate bone marrow adipose tissue, which in turn impacts HPCs and downstream blood cell production. Our findings suggest that adjustment for BMI and adiposity traits may be considered in blood trait GWAS analyses and illuminate opportunities to functionally dissect related genes and molecular pathways. References 1. Hemani, G. et al. Elife 7, (2018). PMID: 29846171. 2. Sanderson, E. et al. Int. J. Epidemiol. 48, 713-727 (2019). PMID: 30535378. 3. Wang, H. et al. Front. Endocrinol.. 9, 694 (2018). PMID: 30546345. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.