Lenzilumab Treatment in COVID-19 Pneumonia Reduces Circulating Cytokines and Markers of Systemic Inflammation

Background. Coronavirus disease 2019 (COVID-19) results from SARS-CoV-2-induced hyperinflammatory immune response, orchestrated by granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF increases interleukin-6 (IL-6) levels, ultimately leading to increased C-reactive protein (CRP). The LIVE-AIR trial demonstrated that lenzilumab, the GM-CSF neutralizing antibody, improved the likelihood of survival without invasive mechanical ventilation (IMV) in hospitalized COVID-19 patients requiring supplemental oxygen but not IMV. This sub-analysis correlated levels of cytokines before and after lenzilumab treatment. Methods. LIVE-AIR was a phase 3, randomized, double-blind, placebocontrolled trial (NCT04351152). Patients hospitalized with COVID-19 pneumonia, requiring only supplemental oxygen, were randomized to receive lenzilumab (1800 mg in three equally divided doses of 600 mg, q8h) or placebo IV infusion, in addition to standard of care which included remdesivir and corticosteroids. Blood taken at baseline (BL) and subsequent to treatment through day 10 (D10) were obtained and analyzed by high sensitivity enzyme immunoassay for GM-CSF, IL-6, and CRP. Results. Baseline IL-6 levels (Loge-transformed for all cytokines and biomarkers) were linearly correlated with higher baseline GM-CSF levels (slope=0.60, p< 0.001). Baseline CRP levels were linearly correlated with higher baseline IL-6 levels (slope=0.29, p < 0.001). GM-CSF levels decreased with lenzilumab treatment on day 1 (D1) which persisted through D10 (Table). In contrast, GM-CSF increased with placebo treatment. IL-6 levels decreased only with lenzilumab treatment. CRP following lenzilumab or placebo treatment decreased on D1 to similar levels and further decreased on D10 only with lenzilumab treatment. Cytokine Levels Associated with Lenzilumab Treatment Conclusion. Lenzilumab decreased GM-CSF as well as downstream cytokines and systemic biomarkers of inflammation during the hyperinflammatory immune response of COVD-19.

Lenzilumab Efficacy and Safety in Newly Hospitalized COVID-19 Subjects: Results from a Phase 3 Randomized Double-Blind Placebo-Controlled Trial

Background. Severe coronavirus disease 2019 (COVID-19) often results from the immune-mediated cytokine storm, triggered by granulocyte macrophage-colony stimulating factor (GM-CSF), potentially leading to respiratory failure and death. Lenzilumab, a novel anti-human GM-CSF monoclonal antibody, neutralizes GM-CSF and demonstrated potential to improve clinical outcomes in a matched case-cohort study of patients with severe COVID-19 pneumonia. This Phase 3 randomized, double-blind, placebo-controlled trial investigated the efficacy and safety of lenzilumab to improve the likelihood of survival without invasive mechanical ventilation (SWOV), beyond available treatments. Methods. Hypoxic patients, hospitalized with COVID-19 (n=520), requiring supplemental oxygen, but not invasive mechanical ventilation, were randomized on Day 0 to receive lenzilumab (1800mg, n=261) or placebo (n=259), and available treatments, including remdesivir and/or corticosteroids;and were followed through Day 28. Results. Baseline demographics were comparable between groups: male, 64.7%;mean age, 60.5 years;median CRP, 79.0 mg/L. Patients across both groups received steroids (93.7%), remdesivir (72.4%), or both (69.1%). Lenzilumab improved the primary endpoint, likelihood of SWOV in the mITT population, by 1.54-fold (HR: 1.54;95%CI: 1.02-2.32, p=0.0403). Lenzilumab improved SWOV by 1.91-fold (nominal p=0.0073) and 1.92-fold (nominal p=0.0067) in patients receiving remdesivir or remdesivir and corticosteroids, respectively. A key secondary endpoint of incidence of IMV, ECMO or death was also improved in patients receiving remdesivir (p=0.020) or remdesivir and corticosteroids (p=0.0180). Treatment-emergent serious adverse events were similar across both groups. Conclusion. Lenzilumab significantly improved SWOV in hypoxic COVID-19 patients upon hospitalization, with the greatest benefit observed in patients receiving treatment with remdesivir and corticosteroids. NCT04351152.

Outcomes and Antibiotic Use in Patients with COVID-19 Admitted to an Intensive Care Unit

Background. Studies have shown the proportion of critically ill patients with COVID-19 receiving empiric antibiotics (ABX) greatly exceeds those with culture-proven bacterial co-infections. However, the benefits of continuing ABX in culture-negative (CxN) cases is unknown;this practice may increase the risks associated with ABX overuse. The purpose of this study was to evaluate outcomes and antibiotic use (AU) in intensive care unit (ICU) patients with COVID-19 based on culture results. Methods. This was a multicenter, retrospective cohort study evaluating adults in an ICU for the first episode of ABX initiated following a confirmed COVID-19 diagnosis between September to December 2020. Blood and/or respiratory cultures must have been obtained within 24 hours (h) of ABX initiation. Patients were categorized into three groups: 1) CxN, ABX discontinued ≤ 72 h, 2) CxN, ABX continued > 72 h, or 3) Culturepositive (CxP). Data on AU was obtained from electronic medication administration records. The primary outcome was clinical success, defined as being discharged alive or > 2-point decrease in the World Health Organization Clinical Progression Scale score from day of ABX initiation to day 30. Results. A total of 65 patients were included with 35.4% being CxP. ABX were discontinued ≤ 72 h in 23.8% of CxN patients. Methicillin-susceptible Staphylococcus aureus was the most common organism in 52.2% of CxP patients (66.7% respiratory;16.7% blood;16.7% both). Anti-methicillin-resistant Staphylococcus aureus and anti-pseudomonal antibiotics were the most prescribed for the initial regimen (Table 1). ABX de-escalation occurred in 58.5% of patients. Initial ABX duration was significantly longer in the CxP group (P < 0.01). No significant difference in clinical success was observed (Table 2). Although not significantly different, the highest rate of adverse events occurred in the CxN and ABX continued > 72 h group (40.6%). Conclusion. In ICU patients with COVID-19, empiric broad-spectrum ABX are often overutilized with an inertia to de-escalate despite negative culture results, potentially increasing the risk of adverse events. This remains an important area for focused antimicrobial stewardship efforts to mitigate the development of multidrug resistance.

Cholecystitis as a Possible Immunologic Consequence of COVID-19;Case Series from a Large Healthcare System

Background. Gastrointestinal manifestations are commonly seen in COVID-19 disease with up to 50% of patients reporting nausea or diarrhea. Cholecystitis has been described in rare cases related to COVID-19, possibly in consequence of immune activation, but biliary disease from SARS-CoV-2 infection is not well described. We examined a case series of patients with both COVID-19 and cholecystitis at our institution. Methods. We performed a retrospective chart review of all patients with a diagnosis of cholecystitis within 3 months of SARS-CoV-2 infection;looking at clinical, laboratory, and radiographic characteristics of this population. Results. 30 individuals were identified with a diagnosis of cholecystitis within 3 months of diagnosis of SARS-CoV-2 infection. Most patients presenting with cholecystitis were female and obese (see Table 1). 14 individuals were diagnosed with SARSCoV-2 infection during the same presentation as their cholecystitis diagnosis, usually as part of pre-operative screening. Of 16 individuals diagnosed with SARS-CoV-2 prior to their cholecystitis presentation, a mean of 24 and 17 days elapsed between SARS-CoV-2 infection and cholecystitis symptom onset and radiographic diagnosis, respectively (see Figure 1). Most of these patients had mild respiratory disease, with only 9 developing an oxygen requirement, and only 3 requiring mechanical ventilation. While 17 patients were treated surgically for their cholecystitis, this did not appear to impact symptom resolution. Conclusion. Cholecystitis may be an uncommon complication of COVID-19 disease. Cholecystitis may manifest most often 2-4 weeks following SARS-CoV-2 infection. This timing is similar to that in Multisystem Inflammatory Syndrome following SARS-CoV-2 infection and given similarities in timing to we hypothesize that cholecystitis in our patients could be driven by immune activation.

Bamlanivimab and Casirivimab/Imdevimab Treatment Outcomes: Results from a Large Healthcare System's Structured Implementation Experience

Background. Neutralizing antibody therapies targeting SARS-CoV-2 have been released for emergency use authorization by the FDA. Little is published on their real-world experience. In this retrospective study we share the results of our early experience on patient outcomes from use of these neutralizing antibodies within a large healthcare system. Methods. We retrospectively analyzed results of a healthcare system wide program to pro-actively identify and treat COVID-19 patients with neutralizing antibody therapy. Results. The 449 patients identified for SARS-CoV-2 neutralizing antibody therapy during the study period were retrospectively classified as falling in one of the three groups: untreated (199), bamlanivimab (87) and casirivimab/indevimab (125) treated patients (Table 1). Reasons identified patients were not treated most commonly were patient declined (n=74), unable to be contacted (n=36), out of treatment window (n=23), asymptomatic and feeling better (n=21) or did not have transportation (n=9). Bamlanivimab infusion did not reduce emergency room (ER) visits or hospitalization compared to untreated patient within 30-days of follow up (Table 2), and among all patients treated with antibody therapy only treatment with bamlanivimab and non-white race were predictors of need for hospitalization (Table 3). Casirivimab/ indevimab did reduce subsequent ER visits or hospitalization within 30 days post-infusion when compared to the untreated group. However, patients treated with either antibody therapy had lower acuity of COVID-19 disease as reflected in need for intensive care unit (ICU) stay, mechanical ventilation or death (Table 2). Conclusion. Either neutralizing antibody therapy appears to markedly reduce acuity of COVID-19 disease even if patients do progress to requiring hospitalization. However, casirivimab/indevimab therapy also decreased ER visits and hospitalization suggesting better efficacy in our experience.

C-reactive protein as a biomarker for improved efficacy of lenzilumab in Covid-19 patients: results from the LIVE-AIR trial

BackgroundThe hyperinflammatory cytokine storm (CS) of COVID-19 is mediated by GM-CSF leading to release of downstream inflammatory chemokines, cytokines, and markers of systemic inflammation (C-reactive protein, CRP). The LIVE-AIR study demonstrated that lenzilumab, an anti-GM-CSF monoclonal antibody in patients hospitalized with COVID-19, safely improved the likelihood of achieving the primary endpoint, survival without ventilation (SWOV) by 1.54-fold (HR: 1.54;95%CI: 1.02–2.32, p=0.0403) compared with placebo. An exploratory analysis in patients with CRP<150 mg/L and age<85 years was conducted to determine lenzilumab efficacy when administered prior to advanced inflammation.MethodsLIVE-AIR was a phase 3 randomized, double-blind, placebo-controlled trial. Patients with COVID-19 (n=520), >18 years, and ≤94% oxygen saturation on room air and/or requiring supplemental oxygen, but not invasive mechanical ventilation (IMV), were randomized to receive lenzilumab (600 mg, n=261) or placebo (n=259) via three intravenous infusions administered 8 hours apart. Participants were followed through Day 28 following treatment.ResultsOverall, baseline demographics were comparable between treatment groups: male, 64.7%;mean age, 60.5 years;mean BMI, 32.5 kg/m2;median CRP, 79 mg/L;CRP was <150 mg/L in 78% of participants. Participants received steroids (93.7%), remdesivir (72.4%), or both (69.1%). Lenzilumab (n=159) improved the likelihood of SWOV by 3.04-fold in participants with CRP<150 mg/L and age<85 years (3.04;1.68–5.51, nominal p=0.0003) compared with placebo (n=178). Response to lenzilumab was observed in the first through third quartiles of baseline CRP (<41 mg/L, HR:8.33;41<79 mg/L, HR:1.60;79<137 mg/L, HR: 2.12;>137 mg/L, HR: 1.17). The incidence of IMV, ECMO, or death was reduced (OR: 0.31;95%CI: 0.15–0.63, p=0.002) and mortality was improved by 2.22-fold (OR: 2.22;95%CI: 1.07–4.67, p=0.034). In these participants, lenzilumab decreased CRP as early as Day 2 following treatment, compared with placebo which was further decreased by 38% on Day 28 compared with placebo (24.4±3.4 mg/L vs 39.1±4.9 mg/L).ConclusionLenzilumab significantly improved SWOV in hospitalized, hypoxic participants with COVID-19 pneumonia with the greatest benefits in SWOV and survival in patients with CRP<150 mg/L and age <85 years. Inhibition of GM-CSF, an orchestrator of CS, early in the hyperinflammatory response improved outcomes in COVID-19. NCT04351152