Compassionate Use of REGEN-COV ® in Patients with COVID-19 and Immunodeficiency-Associated Antibody Disorders

Background Patients with immunodeficiency-associated antibody disorders are at a higher risk of prolonged/persistent COVID-19 infection, having no viable treatment options. Methods A retrospective analysis of patients with primary and/or secondary immunodeficiency-associated antibody disorders who received casirivimab and imdevimab (REGEN-COV ®) under emergency compassionate use. Objectives describe safety and response to REGEN-COV, focusing on the subset of patients who had COVID-19 duration ≥21 days before treatment. Results Quantitative (change in oxygenation status and/or viral load) and/or qualitative (physician-reported clinical status) patient outcomes data are reported from 64 patients who received REGEN-COV. Improvement in ≥1 outcome was observed in 90.6% of the overall patient group. Thirty-seven of these had COVID-19 duration ≥21 days before treatment; median time from diagnosis to REGEN-COV was 60.5 days. Of the 29 patients with COVID-19 duration ≥21 days before treatment and available outcome data, 96.6% showed improvement in ≥1 outcome. In the 14 patients with post-treatment RT-PCR results available, 11 (78.6%) reported a negative RT-PCR following treatment, with 5 (45.5%) reporting a negative RT-PCR within 5 days and 8 (72.7%) within 21 days of treatment. Ten of 85 patients (11.8%) experienced serious adverse events, only one was an infusion-related reaction, possibly related to REGEN-COV. Two deaths were reported, neither were attributed to REGEN-COV. Conclusions In this retrospective analysis of immunodeficient patients granted REGEN-COV under the compassionate use program, REGEN-COV treatment was associated with rapid viral clearance and clinical improvement in patients with long-standing COVID-19. Adverse events were consistent with COVID-19 and its associated complications, and due to patients’ concurrent medical conditions.

Safety and Efficacy of Repurposed Siddha Medicines in Mild, Moderate, and Severe COVID-19 Patients Admitted To a Government Tertiary Hospital Near Chennai, Tamil Nadu– An Open-Labeled, Randomized, Controlled Trial.

BackgroundCOVID-19 resulted in loss of human lives owing to respiratory failure caused by dysregulated immune system. Though many treatments are evaluated, the most appropriate is yet to be established. We hypothesized accelerated recovery and reduced mortality in mild, moderate and severe COVID-19 with Siddha regimen consisting of natural products.MethodsIn a randomized, controlled open-label trial conducted on 200 hospitalized COVID-19 patients, they were allocated equally to be treated with add-on Siddha regimen with Standard care or only standard care. The primary and secondary end points were accelerated recovery (≤ 7 days) and mortality comparison between the groups respectively. Patients were followed through 90 days.ResultsIn this study the accelerated recovery was 59.0% and 27.0% in treatment and control group (ITT analyses) (p < 0.001) respectively and Odds for it were four times higher in the treatment group (OR: 3.9; 95% CI: 1.9, 8.0). The estimated median time for recovery in the treatment group was 7 days (95% CI: 6.0, 8.0; p=0.003) and 10 days (95% CI: 8.7, 11.3) in control. Hazard ratio for death in control was 2.3 times that of treatment group. No adverse reactions or alarming laboratory values were observed in response to intervention. In severe treatment group (n=80), mortality was 15.0% and 39.5% in control (n=81). The COVID stage progression was 65% less in treatment group.ConclusionSiddha regimen demonstrated that they can synergistically improve oxygenation status, enhance the recovery rate and reduce the mortality better as compared to only Standard of Care.

Quantitative susceptibility mapping as a measure of cerebral oxygenation in neonatal piglets

Prominence of cerebral veins using susceptibility weighted magnetic resonance imaging (SWI) has been used as a qualitative indicator of cerebral venous oxygenation (CvO2). Quantitative susceptibility mapping (QSM) adds more precision to the assessment of CvO2, but has not been applied to neonatal hypoxic ischemic injury (HII). We proposed to study QSM measures of venous susceptibility and their correlation with direct measures of brain oxygenation and cerebral blood flow (CBF) in the neonatal piglet. The association of QSM intravascular cerebral venous susceptibility, with brain tissue O2 tension, CBF, cortical tissue oxyhemoglobin saturation, and the partial pressure of oxygen in arterial blood measurement during various oxygenation states was determined by linear regression. Compared to normoxia, venous susceptibility in the straight sinus increased 56.8 ± 25.4% during hypoxia, while decreasing during hyperoxia (23.5 ± 32.9%) and hypercapnia (23.3 ± 73.1%), which was highly correlated to all other measures of oxygenation (p < 0.0001) but did not correlate to CBF (p = 0.82). These findings demonstrate a strong relationship between venous susceptibility and brain tissue O2 tension. Our results suggest that QSM-derived venous susceptibility is sensitive to cerebral oxygenation status across various oxygenation states.

CBIO-01. INHIBITION OF EXTRACELLULAR CARBONIC ANHYDRASES INHIBITS GLIOBLASTOMA CELL INVASION

BACKGROUND Malignant gliomas metabolize glucose preferably by glycolysis which is in accordance with the Warburg effect. This induces a high demand of glucose combined with a significant lactic acid load. The hypoxia-inducible carbonic anhydrase (CA) IX has been shown to moderate the extrusion of hydrogen ions into the extracellular space. Since the acidification of the extracellular environment contributes to host tissue invasion due to activation of proteolytic enzymes, we hypothesized that CA IX plays an important role in malignant glioma Recently, specific small molecule inhibitors of this enzyme have been developed and may provide an innovative strategy for anti – invasive treatment. METHODS Two established and 4 primary GBM cell lines (2 with mesenchymal and 2 with proneural transcriptional profile) were exposed to the CAIX inhibitor U104 under normoxic and hypoxic conditions. Cell toxicity was measured by ATP and crystal violet assay. For invasion assessment, a matrigel invasion chamber system with 8 µm pore size polycarbonate filter was used. CAIX expression was analyzed by quantitative RTPCR and Western Blot. RESULTS Hypoxia significantly induced CAIX expression in all cell lines. Invasiveness increased significantly under hypoxic conditions in the mesenchymal cells (p &lt; 0.01). Regardless of oxygenation status, the mesenchymal group displayed significantly higher invasiveness compared to the proneural group (p = 0.006). Looking at all cell lines, invasion is significantly inhibited by U104, both under normoxic and hypoxic conditions (p &lt; 0.01). However, while the mesenchymal group showed the highest susceptibility to CAIX inhibition followed by the proneurally differentiated group, the established cell lines were entirely refractory to CAIX inhibition. CONCLUSION Our data demonstrate that CAIX inhibition can effectively inhibit invasion in malignant glioma cells independent from oxygenation status, however the effects are significantly influenced by cell type specific biological features.

539. Impact of Corticosteroids when Combined with Tocilizumab or Remdesivir for the Treatment of Severe SARS-CoV-2

Background Tocilizumab (TCZ) and remdesivir (RDV) have both shown benefit for patients with SARS-CoV-2. However, there have been no head to head studies comparing the efficacy of the two therapies. The purpose of this study is to compare clinical outcomes of patients who have received corticosteroids (CS) along with TCZ or RDV. Methods This is an IRB approved retrospective observational study completed in a three hospital health system in New Jersey. Patients were included if age was ≥ 18, admitted with SARS-CoV2 infection requiring oxygen. Patients were stratified into two treatment arms; CS + TCZ and CS + RDV. The primary objective was to compare all-cause inpatient mortality (ACIM) based on oxygenation status; nasal cannula (NC), high-flow nasal cannula (HFNC), and invasive mechanical intubation (IMV). Secondary objectives was a snapshot analysis with a focus on clinical improvement (CI) defined as improvement in clinical ordinal scale by 2 or more at end of stay. Additional endpoint included progression to IMV after therapy initiation. Results There were total of 1053 patients included (123 in the CS+TCZ arm, 930 in the CS+RDV arm). Oxygen requirements were as follows: In the CS+TCZ arm (NC n=57, HFNC n=26, IMV n=40), and the RD+CS arm (NC n=669, HFN n=159, and IMV n=102). Results from the primary endpoints can be found in Table 1. No statistically significant differences were observed between the two treatment arms. For the secondary objective there were 214 patients included (70 in the CS+TCZ arm and 105 in the CS+RDV arm). For patients receiving NC, no difference seen in CI between two treatment arms (81.4% CS+RDV vs. 81.5% CS+TCZ). In HFNC group more patients in the CS+TCZ group observed CI compared to CS+RDV (68.8% vs. 40%). Less patients requiring HFNC progressed to IMV in CS+TCZ group (25%) compared to CS+RDV (40%). Conclusion No statistical difference in ACIM was detected between the two treatment arms regardless of baseline oxygenation requirements. There was a trend towards lower ACIM for IMV patients in the CS+TCZ arm compared to the CS+RDV arm. More patients experienced CI in CS+TCZ group compared to CS+RDV in HFNC group. Less HFNC patients also required new IMV in the CS+TCZ arm. Larger studies need to be performed to evaluate a true statistical difference between the two treatment arms. Disclosures All Authors: No reported disclosures

Exogenous ketosis increases blood and muscle oxygenation but not performance during exercise in hypoxia

Available evidence indicates that elevated blood ketones are associated with improved hypoxic tolerance in rodents. From this perspective, we hypothesized that exogenous ketosis by oral intake of the ketone ester (R)-3-hydroxybutyl (R)-3-hydroxybutyrate (KE) may induce beneficial physiological effects during prolonged exercise in acute hypoxia. As we recently demonstrated KE to deplete blood bicarbonate, which per se may alter the physiological response to hypoxia, we evaluated the effect of KE both in the presence and absence of bicarbonate intake (BIC). Fourteen highly trained male cyclists performed a simulated cycling race (RACE) consisting of 3h intermittent cycling (IMT180') followed by a 15-min time-trial (TT15') and an all-out sprint at 175% of lactate threshold (SPRINT). During RACE, fraction of inspired oxygen (FiO2) was gradually decreased from 18.6 to 14.5%. Before and during RACE, participants received either i) 75g ketone ester (KE), ii) 300 mg/kg body mass bicarbonate (BIC), iii) KE+BIC or iv) a control drink in addition to 60g carbohydrates per h in a randomized, crossover design. KE counteracted the hypoxia-induced drop in blood (SpO2) and muscle oxygenation by ~3%. In contrast, BIC decreased SpO2 by ~2% without impacting muscle oxygenation. Performance during TT15' and SPRINT were similar between all conditions. In conclusion, KE slightly elevated the degree of blood and muscle oxygenation during prolonged exercise in moderate hypoxia without impacting exercise performance. Our data warrant to further investigate the potential of exogenous ketosis to improve muscular and cerebral oxygenation status, and exercise tolerance in extreme hypoxia.

Re-expansion pulmonary edema following a pneumothorax drainage in a patient with COVID-19

Background Re-expansion pulmonary edema is an uncommon complication following drainage of a pneumothorax or pleural effusion. While pneumothorax is noted to complicate COVID-19 patients, no case of COVID-19 developing re-expansion pulmonary edema has been reported. Case representation A man in his early 40 s without a smoking history and underlying pulmonary diseases suddenly complained of left chest pain with dyspnea 1 day after being diagnosed with COVID-19. Chest X-ray revealed pneumothorax in the left lung field, and a chest tube was inserted into the intrathoracic space without negative pressure 9 h after the onset of chest pain, resulting in the disappearance of respiratory symptoms; however, 2 h thereafter, dyspnea recurred with lower oxygenation status. Chest X-ray revealed improvement of collapse but extensive infiltration in the expanded lung. Therefore, the patient was diagnosed with re-expansion pulmonary edema, and his dyspnea and oxygenation status gradually improved without any intervention, such as steroid administration. Abnormal lung images also gradually improved within several days. Conclusions This case highlights the rare presentation of re-expansion pulmonary edema following pneumothorax drainage in a patient with COVID-19, which recovered without requiring treatment for viral pneumonia. Differentiating re-expansion pulmonary edema from viral pneumonia is crucial to prevent unnecessary medication for COVID-19 pneumonia and pneumothorax.

P13.14 Inhibition of extracellular carbonic anhydrases reduces glioblastoma cell invasion

BACKGROUND Malignant gliomas metabolize glucose preferably by glycolysis which is in accordance with the Warburg effect. This induces a high demand of glucose combined with a significant lactic acid load. The hypoxia-inducible carbonic anhydrase (CA) IX has been shown to moderate the extrusion of hydrogen ions into the extracellular space. Since the acidification of the extracellular environment contributes to host tissue invasion due to activation of proteolytic enzymes, we hypothesized that CA IX plays an important role in malignant glioma Recently, specific small molecule inhibitors of this enzyme have been developed and may provide an innovative strategy for anti - invasive treatment. MATERIAL AND METHODS Two established and 4 primary GBM cell lines (2 with mesenchymal and 2 with proneural transcriptional profile) were exposed to the CAIX inhibitor U104 under normoxic and hypoxic conditions. Cell toxicity was measured by ATP and crystal violet assay. For invasion assessment, a matrigel invasion chamber system with 8 µm pore size polycarbonate filter was used. CAIX expression was analyzed by quantitative RTPCR and Western Blot. RESULTS Hypoxia significantly induced CAIX expression in all cell lines. Invasiveness increased significantly under hypoxic conditions in the mesenchymal cells (p &lt; 0.01). Regardless of oxygenation status, the mesenchymal group displayed significantly higher invasiveness compared to the proneural group (p = 0.006). Looking at all cell lines, invasion is significantly inhibited by U104, both under normoxic and hypoxic conditions (p &lt; 0.01). However, while the mesenchymal group showed the highest susceptibility to CAIX inhibition followed by the proneurally differentiated group, the established cell lines were entirely refractory to CAIX inhibition. CONCLUSION Our data demonstrate that CAIX inhibition can effectively inhibit invasion in malignant glioma cells independent from oxygenation status, however the effects are significantly influenced by cell type specific biological features.

Investigating spectroscopic measurement of sublingual veins and tissue to estimate central venous oxygen saturation

BACKGROUND: Venous oxygen saturation reflects venous oxygenation status and can be used to assess treatment and prognosis in critically ill patients. A novel method that can measure central venous oxygen saturation (ScvO2) non-invasively may be beneficial and has the potential to change the management routine of critically ill patients. OBJECTIVE: The study aims to evaluate the potential of sublingual venous oxygen saturation (SsvO2) to be used in the estimation of ScvO2. METHODS: We have developed two different approaches to calculate SsvO2. In the first one, near-infrared spectroscopy (NIRS) measurements were performed directly on the sublingual veins. In the second approach, NIRS spectra were acquired from the sublingual tissue apart from the sublingual veins, and arterial oxygen saturation was measured using a pulse oximeter on the fingertip. RESULTS: Twenty-six healthy subjects were included in the study. In the first and second approaches, average SsvO2 values were 75.0% ± 1.8 and 75.8% ± 2.1, respectively. The results of the two different approaches were close to each other and similar to ScvO2 of healthy persons (> 70%). CONCLUSION: Oxygen saturation of sublingual veins has the potential to be used in intensive care units, non-invasively and in real-time, to estimate ScvO2.