Safety and Efficacy of Dupilumab for the Treatment of Hospitalized Patients with Moderate to Severe COVID 19: A Phase IIa Trial

BackgroundA profound need remains to develop further therapeutics for treatment of those hospitalized with COVID-19. Based on data implicating the type 2 cytokine interleukin (IL)-13 as a significant factor leading to critical COVID-19, this trial was designed to assess dupilumab, a monoclonal antibody that blocks IL-13 and IL-4 signaling, for treatment of inpatients with COVID-19. MethodsWe conducted a phase IIa randomized double-blind placebo-controlled trial to assess the safety and efficacy of dupilumab plus standard of care versus placebo plus standard of care in mitigating respiratory failure and death in those hospitalized with COVID-19. Subjects were followed prospectively for 60 days. The primary endpoint was the proportion of patients alive and free of invasive mechanical ventilation at 28 days. FindingsForty eligible subjects were enrolled from June to November of 2021. There was no difference in adverse events nor in ventilator free survival at day 28 between study arms. However, for the secondary endpoint of mortality at day 60, subjects randomized to dupilumab had a higher survival rate compared to the placebo group (89.5% vs 76.2%, adjusted HR 0.05, 95% CI: 0.0-0.72, p=0.03). There were fewer subjects admitted to the ICU in the dupilumab group compared to placebo (33.3% vs 66.7%; adjusted HR 0.44, 95% CI: 0.09-2.09, p=0.30). Lastly, we saw downstream evidence of IL-4 and IL-13 signaling blockade in the dupilumab group through analysis of immune biomarkers over time. InterpretationDupilumab was well tolerated and improved 60-day survival in patients hospitalized with moderate to severe COVID-19. Trial RegistrationThis trial is registered with ClinicalTrials.gov, NCT04920916. FundingVirginia Biosciences Health Research Corporation, PBM C19, Henske Family Foundation, National Institutes of Health, National Cancer Institute

Convalescent plasma for preventing critical illness in COVID-19: A phase 2 trial and immune profile

RationaleThe COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an unprecedented event requiring rapid adaptation to changing clinical circumstances. Convalescent immune plasma (CIP) is a promising treatment that can be mobilized rapidly in a pandemic setting. ObjectivesWe tested whether administration of SARS-CoV-2 CIP at hospital admission could reduce the rate of ICU transfer or 28 day mortality. MethodsIn a single-arm phase II study, patients >18 years-old with respiratory symptoms documented with COVID-19 infection who were admitted to a non-ICU bed were administered two units of CIP within 72 hours of admission. Detection of respiratory tract SARS-CoV-2 by polymerase chain reaction and circulating anti-SARS-CoV-2 antibody titers were measured before and at time points after CIP transfusion. Measurements and Main ResultsTwenty-nine patients were transfused CIP and forty-eight contemporaneous controls were identified with comparable baseline characteristics. Levels of anti-SARS-CoV-2 IgG, IgM, and IgA anti-spike, anti-receptor-binding domain, and anti-nucleocapsid significantly increased from baseline to post-transfusion for all proteins tested. In patients transfused with CIP, the rate of ICU transfer was 13.8% compared to 27.1% for controls with a hazard ratio 0.506 (95% CI 0.165-1.554), and 28-day mortality was 6.9% compared to 10.4% for controls, hazard ratio 0.640 (95% CI 0.124-3.298). ConclusionsTransfusion of high-titer CIP to patients early after admission with COVID-19 respiratory disease was associated with reduced ICU transfer and 28-day mortality but was not statistically significant. Follow up randomized trials may inform the use of CIP for COVID-19 or future coronavirus pandemics.

IgG Antibodies against SARS-CoV-2 Correlate with Days from Symptom Onset, Viral Load and IL-10

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in a pandemic of the respiratory disease coronavirus disease 2019 (COVID-19). Antibody testing is essential to identify persons exposed to the virus and potentially in predicting disease immunity. 183 COVID-19 patients (68 of whom required mechanical ventilation) and 41 controls were tested for plasma IgG, IgA and IgM against the SARS-CoV-2 S1, S2, receptor binding domain (RBD) and N proteins using the MILLIPLEX(R) SARS-CoV-2 Antigen Panel. Plasma cytokines were concurrently measured using the MILLIPLEX(R) MAP Human Cytokine/Chemokine/Growth Factor Panel A. As expected the 183 COVID-19 positive patients had high levels of IgG, IgA and IgM anti-SARS-CoV-2 antibodies against each of the viral proteins. Sensitivity of anti-S1 IgG increased from 60% to 93% one week after symptom onset. S1-IgG and S1-IgA had specificities of 98% compared to the 41 COVID-19 negative patients. The 68 ventilated COVID-19 positive patients had higher antibody levels than the 115 COVID-19 positive patients who were not ventilated. IgG antibody levels against S1 protein had the strongest positive correlation to days from symptom onset. There were no statistically significant differences in IgG, IgA and IgM antibodies against S1 based on age. We found that patients with the highest levels of anti-SARS-CoV-2 antibodies had the lowest viral load in the nasopharynx. Finally there was a correlation of high plasma IL-10 with low anti-SARS-CoV-2 antibodies. Anti-SARS-CoV-2 antibody levels, as measured by a novel antigen panel, increased within days after symptom onset, achieving > 90% sensitivity and specificity within one week, and were highest in patients who required mechanical ventilation. Antibody levels were inversely associated with viral load but did not differ as a function of age. The correlation of high IL-10 with low antibody response suggests a potentially suppressive role of this cytokine in the humoral immune response in COVID-19.

Development of wastewater pooled surveillance of SARS-CoV-2 from congregate living settings

Wastewater-based monitoring for SARS-CoV-2 holds promise as tool to inform public health-decision making. Testing at individual building-level could be an efficient, passive means of preventing early detection of new cases in congregate living settings, but this approach has not been validated. Sample collection protocols were developed and refined during preliminary sampling from a hospital and a local municipal wastewater treatment plant. Molecular diagnostic methods were compared side-by-side to assess feasibility, performance and sensitivity. Optimized sample collection and processing protocols were then used to monitor two occupied dormitory complexes (n=105 and 66) over eight weeks. Wastewater results were validated using known case counts from external clinical testing of building occupants. Results confirm that ultracentrifugation from a 24 hour composite collection had a sensitivity of 95% and a specificity of 100%. However, if the detection of convalescent shedding is considered a false positive then the sensitivity would be 95.2% but the specificity would drop to 52%. We determined a highly sensitive method for detecting SARS-CoV-2 shedding in building wastewater however our methods could not distinguish new infectious cases from persistent convalescent shedding of SARS-CoV-2 RNA. Future work must focus on methods to distinguish new infections from convalescent shedding to widely deploy this promising wastewater surveillance tool.

IL-13 Predicts the Need for Mechanical Ventilation in COVID-19 Patients

Immune dysregulation is characteristic of the more severe stages of SARS-CoV-2 infection. Understanding the mechanisms by which the immune system contributes to COVID-19 severity may open new avenues to treatment. Here we report that elevated interleukin-13 (IL-13) was associated with the need for mechanical ventilation in two independent patient cohorts. In addition, patients who acquired COVID-19 while prescribed Dupilumab had less severe disease. In SARS-CoV-2 infected mice, IL-13 neutralization reduced death and disease severity without affecting viral load, demonstrating an immunopathogenic role for this cytokine. Following anti-IL-13 treatment in infected mice, in the lung, hyaluronan synthase 1 (Has1) was the most downregulated gene and hyaluronan accumulation was decreased. Blockade of the hyaluronan receptor, CD44, reduced mortality in infected mice, supporting the importance of hyaluronan as a pathogenic mediator, and indicating a new role for IL-13 in lung disease. Understanding the role of IL-13 and hyaluronan has important implications for therapy of COVID-19 and potentially other pulmonary diseases. SummaryL-13 levels are elevated in patients with severe COVID-19. In a mouse model of disease, IL-13 neutralization results in reduced disease and lung hyaluronan deposition. Similarly, blockade of hyaluronans receptor, CD44, reduces disease, highlighting a novel mechanism for IL-13-mediated pathology.