SIGNIFICANCE OF ELEVATED SARS-CoV-2 ANTIGEN LEVELS DURING EARLY HOSPITALIZATION

Background: Patients hospitalized with COVID-19 randomized to standard of care (SoC) plus placebo or SoC plus monoclonal antibody (mAb)[bamlanivimab, sotrovimab, amburvimab-romlusevimab, or tixagevimab-cilgagavimab] as separate arms of TICO/ACTIV-3 did not show differences in the time to sustained recovery through day 90. Combining these cohorts, we assessed if early changes in plasma nucleocapsid antigen(pNA) were associated with clinical outcomes. Method(s): TICO/ACTIV-3 enrolled 2,254 patients between 8/5/2020 to 9/30/2021. We used the Quanterix assay to measure pNA of stored samples. We selected those with pNA in the top quartile at baseline through day 5 and examined the association with baseline factors and clinical outcomes through day 90 using regression methods (proportional odds logistic, Cox proportional hazard, and Fine-Gray competing risk models as appropriate). Result(s): Of the 2,149 patients with a baseline value and at least one measurement of pNA on Days 1-5, we found a median age 57 (IQR 46-68), 58% male, 64.9% with one or more co-morbidities, 82.1% unvaccinated, 37.6% with delta variant, median symptom duration 8 days (IQR 6-10), and 9.2% on high flow nasal oxygen (HFNO) or non-invasive ventilation (NIV). Participants with pNA in the top quartile (>4693.5 ng/L at baseline and >29.9 ng/L at day 5) occurred more commonly among those with baseline renal impairment [OR 4.1 (95% CI 2.8 to 5.9)], and pulmonary severity of illness requiring oxygen of < 4 L/min [OR 2.2 (95 %CI: 1.5 to 3.4)], >4 L/min [OR 4.9(95% CI: 3.3, to 7.4)], and HFNO/NIV [OR 5.3 (95% CI: 3.1 to 9.0)] compared to those not using supplemental oxygen at study entry. Patients with positive anti-spike antibody at baseline had lower odds of persistently high pNA [OR 0.15 (95%CI: 0.10 to 0.20)]. Participants with pNA levels in the top quartile through day 5 were associated with increased risk of all-cause day 90 mortality [HR 4.4 (95% CI: 3.2, 5.9)], and reduced incidence of sustained recovery through day 90 [RRR 0.40 (95% CI: 0.35 to 0.45)]. Conclusion(s): PNA levels in the top quartile over the first 5 days were associated with elevated risk for death and reduced recovery. This group includes those with renal impairment, use of oxygen for COVID-19, and negative for anti-spike antibody. Top quartile pNA in early infection identified subjects on lower level of oxygen that were high risk for poor outcomes potentially identifying those that would benefit from additional treatment. (Figure Presented).

COVID-19 Hospitalizations in North Texas: Impact of Insurance Status

Background. Texas has one of the highest rates of uninsured populations in the US (Fig1). We hypothesized that those without insurance were more likely to be hospitalized for COVID-19 but were at higher risk for severe disease and mortality due to uncontrolled medical illness prior to hospitalization. Methods. We conducted a retrospective analysis of patients hospitalized in 81 hospitals in Dallas- Ft. Worth (DFW) area. All inpatients and outpatients with COVID-19 from 3/1/2020 to 4/1/2021 were included to examine risk for hospitalization. Subset analysis included those hospitalized with COVID-19. Data presented is comparison between Medicaid and uninsured population as they were similar in age distribution (Fig 2). Results. 198, 174 COVID-19 unique individuals were identified;7.5% had Medicaid and 25.1% were uninsured. Among Medicaid, 29.6% were hospitalized vs. 25.8% of Medicaid vs. uninsured (adjusted odds ratio (aOR) 1.26 (1.20, 1.33). Among the 71,778 (~36%) hospitalized for COVID-19, comparing Medicaid vs. uninsured: 44.9 vs. 56.3% had ICU care;51.4% vs. 80.2% had pneumonia, 41.1% vs. 67.5% had respiratory failure with higher odds of developing these outcomes in uninsured (see Table 1). Median duration of hospital stay was longer in uninsured than Medicaid ( see Table 2a) and mortality in the hospital was 7.4% vs. 7.9% among Medicaid vs. uninsured (p< 0.0001). Thirty-day readmission rates were lower for Medicaid vs. uninsured (Table 3). In the year prior to the COVID-19 hospitalizations, use of health care among the uninsured was lower compared to Medicaid patients for outpatient, inpatient, and ER visits (p< 0.0001 for all comparisons;see Table 2b). Conclusion. Uninsured in North Texas had lower odds of hospitalization vs. Medicaid patients, likely due to younger age, but once hospitalized had higher risk for COVID pneumonia, ICU care, and respiratory failure. Median number of days was higher among uninsured but in-hospital mortality was higher among Medicaid population. Prior contact with healthcare system was lower among uninsured and 30-day readmissions were also lower, suggesting barriers accessing health care. Poorer outcomes among uninsured once hospitalized may be due to untreated comorbidities (Fig 3). Expansion of Medicaid has the potential of ameliorating these disparities.

COVID-19 Hospitalization Impact of Age, Race and Ethnicity Among Medicaid and Uninsured

Background. Texas has one of the highest rates of uninsured patients in the US and is one of the few states that has not expanded Medicaid (Fig 1). We sought to examine if there were differences by age, race, and ethnicity in the risk COVID-19 outcomes among those with Medicaid coverage vs. the uninsured population. (Table Presented) Methods. We conducted a retrospective analysis of all patients hospitalized in 81 hospitals in Dallas-Fort Worth area. All inpatients with COVID-19 from 3/1/2020 to 9/30/2021 were included in the analysis. We examined the following COVID-19 outcomes: ICU care, pneumonia, and respiratory failure stratified (separate logistic models for each outcome) by race, ethnicity, and age adjusted for a multitude of sociodemographic, clinical, and co-morbid characteristics (Fig 2). Results. 71,778 individuals diagnosed with COVID-19 were hospitalized: 12.9% had Medicaid and 23% were uninsured. For all COVID-19 study outcomes (ICU care, pneumonia, and respiratory failure), White Medicaid patients had lower odds ratios vs. their White uninsured counterparts indicating worse outcomes compared to Black Medicaid patients vs. Black uninsured counterparts (Table 1). Similarly, for all outcomes, Hispanic Medicaid patients had lower (worse) odds ratios vs. Hispanic uninsured counterparts compared to the same model with non-Hispanic patients. Finally, for all three outcomes, the youngest Medicaid age cohort (18-44 years) were less likely to require ICU care, have pneumonia or respiratory failure vs. the youngest uninsured patients;while conversely there was trend (not always statistically significant) that middle aged or older Medicaid cohorts were more likely compared to their same age uninsured counterparts to experience these outcomes. Adjusted odds ratio of COVID-19 outcomes by insurance status stratified by race, ethnicity, and age group. Conclusion. We found that age modified the risk for ICU care with younger Medicaid recipients at lower odds vs. uninsured than older cohorts. For race and Hispanic ethnicity, all Medicaid groups had lower likelihood of poor COVID-19 outcomes compared to their uninsured counterparts. However, the effect was more pronounced among Whites vs. Blacks and Hispanics vs. non-Hispanics (Fig 3). Providing health insurance such as Medicaid to uninsured younger patients could significantly improve health outcomes, especially among Whites, Hispanics, and younger patients.

TOCILIZUMAB (BIOSIMILAR) USE in CYTOKINE STORM of SEVERE COVID-19 PNEUMONIA

Background: Tocilizumab is an IgG1 class humanized monoclonal antibody targeting IL-6 receptor (IL-6R). IL-6 is a key cytokine involved in cytokine storm of severe COVID-19. Tocilizumab down-regulates IL-6 preventing fatal and permanent damage to vital organs, significantly preventing COVID-19 related mortality and morbidity. Therefore, this study aimed to compare the efficacy and safety of Tocilizumab (biosimilar) developed by Hetero Biopharma Ltd, India vs reference medicinal product (RMP)-Tocilizumab manufactured by Roche in cytokine storm of severe COVID-19 pneumonia. Methods: This multicenter, randomized, double-blind, active-controlled study enrolled patients aged 18 to 65 years, with laboratory-confirmed, hospitalized, severe COVID-19 disease with elevated inflammatory markers not on mechanical ventilation. Patients were randomized (3:1 ratio) to receive either Test-Tocilizumab (Test) 8 mg/kg or RMP-Tocilizumab 8mg/kg, maximum 800mg, administered once on day 1. The primary endpoint was the cumulative proportion of patients requiring mechanical ventilation by Day 14. Secondary endpoints included 28 day mortality rate, proportion of patients with a 2-point decrease in WHO ordinal scale, time to clinical failure (death or required mechanical ventilation or withdrawn), change in inflammatory markers (CRP, IL-6, Ferritin and D-dimer) and duration of hospital stay in days. Safety endpoints included the incidence of adverse events;the proportion of patients discontinued the study due to adverse events and the incidence of any post-treatment bacterial and/or fungal infection. Results: Out of 211 patients screened, 172 patients were randomized (131 to Test and 41 to RMP) to receive Tocilizumab 8mg/kg. Patients were similar in both groups at baseline in terms of age, gender, weight etc. Fourteen (10.69%) patients in Test and 5 (12.20%) patients in RMP progressed to mechanical ventilation by Day 14 (p=0.7789). Overall, 9 (7.83%) patients died in Test vs 5 (13.16%) in RMP during 28 days follow up (p=0.3382). Clinical improvement was seen 62.60% and 77.10% vs 53.66% and 73.17% in Test vs RMP at day 14 and 28 respectively. The time to clinical failure was 6 vs 5 days and time to clinical improvement was 11 vs 11.5 days. Hospitalization duration was 12.9 versus 13.8 days in the Test and RMP. ARDS, Insomnia and Pain were most commonly reported adverse events. Conclusion: Tocilizumab biosimilar is comparable with RMP-Tocilizumab in preventing mechanical ventilation in severe COVID19 pneumonia patients.

Atovaquone for Treatment of COVID-19 (Ataq COVID-19) Trial

Background. Our group performed an in-silico screen to identify FDA approved drugs that inhibit SARS-C0V-2 main protease (Mpro), followed by in vitro viral replication assays, and in vivo pharmacokinetic studies in mice. These studies identified atovaquone as a promising candidate for inhibiting viral replication. Methods. Enrolled patients were randomized in a 2:1 fashion to atovaquone 1500 mg twice daily versus matched placebo. Patients received standard of care treatment including remdesivir, dexamethasone, or convalescent plasma as deemed necessary by the treating team. Patients agreed to allow collection of saliva at baseline and twice a day while hospitalized or up to 10 days. Saliva was collected and RNA extracted for viral load (VL) measurement by Real-time PCR. Our primary outcome was to examine the between group differences in log transformed VL(copies/mL) using generalized linear mixed-effect models of repeated measures from all samples. Additional analysis of Atovquone plasma concentrations were examined and correlated with viral load and body mass index (BMI). Results. Of the 61 patients enrolled;41 were received atovaquone and 19 placebo. Overall the population was predominately male Hispanic with a mean age of 51 years. The two groups were balanced (Table 1) with regard to age, gender, race, co-morbidities, days from onset of symptoms, baseline oxygen requirements, and receipt of COVID-19 specific standard of care treatment. A higher proportion with diabetes was noted in the Atovaquone arm. The log10 VL was 5.25 copies/mL vs. 4.79 copies/mL at baseline in the atovaquone vs. placebo group. Although there was a decrease in VL over time, there was no differences between the atovaquone plus standard of care arm versus the standard of care arm (Figure 1). Additional analysis of atovaquone plasma concentration demonstrated a wide variation in atovaquone levels, inverse association between atovaquone levels and BMI (rho -0.44, p=0.03), and Day 5 concentrations and VL (rho -0.54, p=0.005). Conclusion. Although atovaquone showed promising in vitro antiviral properties for COVID-19, in this pilot study we did not detect a change in VL in patients who received atovaquone compared to placebo, possibly due to failure of patients achieve adequate drug levels.

Multisystem inflammatory syndrome in children;a rare case found in Covid-19 pandemic

Introduction In April 2020, a group of children with hyperinflammatory shock were reported in England. Now many cases have been reported from across the world. We here report a case of Multisystem Inflammatory Syndrome in Children (MIS-C) detected in the Odisha state of India. © 2021, Sri Lanka Journal of Child Health. All Rights Reserved.

Multisystem Inflammatory Syndrome in Children Associated with COVID-19: An Interim Review

The pediatric population is relatively less affected by novel coronavirus disease 2019 (COVID-19) compared with adults, both in numbers and severity. However, evolution of a new entity, named multisystem inflammatory syndrome in children (MIS-C), has led to significant number of children being admitted to hospital, especially to intensive care units. Case definitions of MIS-C have been defined by the World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC) separately. Autoantibodies and antibody-dependent enhancement (ADE) are the key factors proposed in pathogenesis, leading to immune dysregulation, and cytokine storm. Three distinct clinical types are observed as follows: (1) fever and elevated inflammatory markers with no end-organ damage;(2) shock with severe myocardial dysfunction similar to toxic shock syndrome (155);and (3) with mucocutaneous features like Kawasaki's disease (KD). Cardiovascular and gastrointestinal symptoms are the predominant presentations. Inflammatory markers like C-reactive protein (CRP), ferritin, and interleukin (IL)-6 are raised along with high D-dimer and lactate dehydrogenase (LDH). Echocardiography may demonstrate low left ventricular ejection fraction (<50%) and/or coronary aneurysms. Reverse-transcription polymerase chain reaction (RT-PCR) for severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) is usually negative, with most having antibodies against the virus. KD, KD shock syndrome (KDSS), and toxic shock syndrome (TSS) are the important differential diagnoses to be considered. Immunomodulatory therapy is the cornerstone of the management. Intravenous immunoglobulin (IVIg) is preferred, the next option being steroids. Supportive care, antiplatelet, and anticoagulation medications, when indicated, are also vital aspects of treatment plan. The prognosis is favorable with low mortality but meticulous cardiac monitoring and follow-up by a multidisciplinary team is very important. Being an evolving disease, future research may reveal different manifestations, newer diagnostic modalities, and better treatment options.