C reactive protein utilisation, a biomarker for early COVID-19 treatment, improves lenzilumab efficacy: results from the randomised phase 3 'LIVE-AIR' trial.

OBJECTIVE: COVID-19 severity is correlated with granulocyte macrophage colony-stimulating factor (GM-CSF) and C reactive protein (CRP) levels. In the phase three LIVE-AIR trial, lenzilumab an anti-GM-CSF monoclonal antibody, improved the likelihood of survival without ventilation (SWOV) in COVID-19, with the greatest effect in participants having baseline CRP below a median of 79 mg/L. Herein, the utility of baseline CRP to guide lenzilumab treatment was assessed. DESIGN: A subanalysis of the randomised, blinded, controlled, LIVE-AIR trial in which lenzilumab or placebo was administered on day 0 and participants were followed through Day 28. PARTICIPANTS: Hospitalised COVID-19 participants (N=520) with SpO2 ≤94% on room air or requiring supplemental oxygen but not invasive mechanical ventilation. INTERVENTIONS: Lenzilumab (1800 mg; three divided doses, q8h, within 24 hours) or placebo infusion alongside corticosteroid and remdesivir treatments. MAIN OUTCOME MEASURES: The primary endpoint was the time-to-event analysis difference in SWOV through day 28 between lenzilumab and placebo treatments, stratified by baseline CRP. RESULTS: SWOV was achieved in 152 (90%; 95% CI 85 to 94) lenzilumab and 144 (79%; 72 to 84) placebo-treated participants with baseline CRP <150 mg/L (HR: 2.54; 95% CI 1.46 to 4.41; p=0.0009) but not with CRP ≥150 mg/L (HR: 1.04; 95% CI 0.51 to 2.14; p=0.9058). A statistically significant interaction between CRP and lenzilumab treatment was observed (p=0.044). Grade ≥3 adverse events with lenzilumab were comparable to placebo in both CRP strata. No treatment-emergent serious adverse events were attributed to lenzilumab. CONCLUSION: Hospitalised hypoxemic patients with COVID-19 with baseline CRP <150 mg/L derived the greatest clinical benefit from treatment with lenzilumab. TRIAL REGISTRATION NUMBER: NCT04351152; ClinicalTrials.gov.

Functional humoral and cellular response of monovalent COVID-19-vaccines against Omicron BA.2 variant of SARS-CoV-2 in patients with chronic lymphocytic leukemia.

We designed a prospective study to evaluate the humoral (using a surrogate virus neutralization test) and cellular (using an IFN-γ ELISpot) immune response among patients with chronic lymphocytic leukemia (CLL) against Wuhan-Hu-1 and Omicron BA.2 strains of SARS-CoV-2, after mRNA-based vaccination. The proportion of patients with a functional humoral response was higher among untreated CLL patients compared to treated CLL patients against both Wuhan-Hu-1 and Omicron BA.2 after the second and the third dose of vaccination, and at 12 months after the first dose. The proportion of positive cellular response against the peptide pool covering the full-length Wuhan-Hu-1 spike protein was similar between untreated and treated CLL patients at all three timepoints. The cellular response to the mutated regions of BA.2 spike protein was lower than the response to the corresponding regions in the ancestral spike after the second dose, but this difference was eliminated after the third dose.

Lenzilumab in hospitalised patients with COVID-19 pneumonia (LIVE-AIR): a phase 3, randomised, placebo-controlled trial.

BACKGROUND: The pathophysiology of COVID-19 includes immune-mediated hyperinflammation, which could potentially lead to respiratory failure and death. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is among cytokines that contribute to the inflammatory processes. Lenzilumab, a GM-CSF neutralising monoclonal antibody, was investigated in the LIVE-AIR trial to assess its efficacy and safety in treating COVID-19 beyond available treatments. METHODS: In LIVE-AIR, a phase 3, randomised, double-blind, placebo-controlled trial, hospitalised adult patients with COVID-19 pneumonia not requiring invasive mechanical ventilation were recruited from 29 sites in the USA and Brazil and were randomly assigned (1:1) to receive three intravenous doses of lenzilumab (600 mg per dose) or placebo delivered 8 h apart. All patients received standard supportive care, including the use of remdesivir and corticosteroids. Patients were stratified at randomisation by age and disease severity. The primary endpoint was survival without invasive mechanical ventilation to day 28 in the modified intention-to-treat population (mITT), comprising all randomised participants who received at least one dose of study drug under the documented supervision of the principal investigator or sub-investigator. Adverse events were assessed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT04351152, and is completed. FINDINGS: Patients were enrolled from May 5, 2020, until Jan 27, 2021. 528 patients were screened, of whom 520 were randomly assigned and included in the intention-to-treat population. 479 of these patients (n=236, lenzilumab; n=243, placebo) were included in the mITT analysis for the primary outcome. Baseline demographics were similar between groups. 311 (65%) participants were males, mean age was 61 (SD 14) years at baseline, and median C-reactive protein concentration was 79 (IQR 41-137) mg/L. Steroids were administered to 449 (94%) patients and remdesivir to 347 (72%) patients; 331 (69%) patients received both treatments. Survival without invasive mechanical ventilation to day 28 was achieved in 198 (84%; 95% CI 79-89) participants in the lenzilumab group and in 190 (78%; 72-83) patients in the placebo group, and the likelihood of survival was greater with lenzilumab than placebo (hazard ratio 1·54; 95% CI 1·02-2·32; p=0·040). 68 (27%) of 255 patients in the lenzilumab group and 84 (33%) of 257 patients in the placebo group experienced at least one adverse event that was at least grade 3 in severity based on CTCAE criteria. The most common treatment-emergent adverse events of grade 3 or higher were related to respiratory disorders (26%) and cardiac disorders (6%) and none led to death. INTERPRETATION: Lenzilumab significantly improved survival without invasive mechanical ventilation in hospitalised patients with COVID-19, with a safety profile similar to that of placebo. The added value of lenzilumab beyond other immunomodulators used to treat COVID-19 alongside steroids remains unknown. FUNDING: Humanigen.

LENZILUMAB IN HOSPITALIZED BLACK/AFRICAN-AMERICAN COVID-19 PATIENTS: LIVE-AIR PHASE 3 STUDY RESULTS

The likelihood of SWOV was significantly improved by lenzilumab across races and ethnicities compared with placebo (HR: 1.54;95% CI: 1.02, 2.32;p=0.0403;N=479) and in patients with baseline CRP< 150 mg/L, < 85 years of age (HR 3.04;1.68, 5.51;p=0.0003;n=337). The hyperinflammatory cytokine storm accompanying SARS-CoV-2 infection is mediated by GM-CSF releasing downstream inflammatory chemokines, cytokines, and inflammatory markers including C-reactive protein (CRP), predictive of clinical worsening. B Background: b Black/African Americans (B/AA) are twice as likely as Whites to develop COVID-19, possibly due to disparities in healthcare access and genetics. [Extracted from the article] Copyright of Critical Care Medicine is the property of Lippincott Williams & Wilkins and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

Point-of-care program in HIV, tuberculosis, and associated conditions: A virtual global technical assistance platform to strengthen HIV and tuberculosis workforce capacity.

A global multi-disciplinary faculty was established to work collaboratively and provide virtual technical assistance, using a point-of-care continuing education model, to clinicians across the world engaged in the care of patients with either HIV infection or tuberculosis. Ancillary offerings included live or virtual lectures, case-based conferences, and courses. In spite of the considerable disruption of the program due to the COVID-19 pandemic, we engaged and assisted a substantial number of clinicians across the world and provided meaningful contributions to their continuous professional development and patient care. In light of the ongoing pandemic, virtual technical assistance models such as this should be scaled to continue essential high-quality HIV/TB services.

Outcomes of COVID-19 With the Mayo Clinic Model of Care and Research.

OBJECTIVE: To report the Mayo Clinic experience with coronavirus disease 2019 (COVID-19) related to patient outcomes. METHODS: We conducted a retrospective chart review of patients with COVID-19 diagnosed between March 1, 2020, and July 31, 2020, at any of the Mayo Clinic sites. We abstracted pertinent comorbid conditions such as age, sex, body mass index, Charlson Comorbidity Index variables, and treatments received. Factors associated with hospitalization and mortality were assessed in univariate and multivariate models. RESULTS: A total of 7891 patients with confirmed COVID-19 infection with research authorization on file received care across the Mayo Clinic sites during the study period. Of these, 7217 patients were adults 18 years or older who were analyzed further. A total of 897 (11.4%) patients required hospitalization, and 354 (4.9%) received care in the intensive care unit (ICU). All hospitalized patients were reviewed by a COVID-19 Treatment Review Panel, and 77.5% (695 of 897) of inpatients received a COVID-19-directed therapy. Overall mortality was 1.2% (94 of 7891), with 7.1% (64 of 897) mortality in hospitalized patients and 11.3% (40 of 354) in patients requiring ICU care. CONCLUSION: Mayo Clinic outcomes of patients with COVID-19 infection in the ICU, hospital, and community compare favorably with those reported nationally. This likely reflects the impact of interprofessional multidisciplinary team evaluation, effective leveraging of clinical trials and available treatments, deployment of remote monitoring tools, and maintenance of adequate operating capacity to not require surge adjustments. These best practices can help guide other health care systems with the continuing response to the COVID-19 pandemic.

Impact of Corticosteroids in Coronavirus Disease 2019 Outcomes: Systematic Review and Meta-analysis.

BACKGROUND: Since its appearance in late 2019, infections caused by severe acute respiratory syndrome coronavirus 2 have created unprecedented challenges for health systems worldwide. Multiple therapeutic options have been explored, including corticosteroids. Preliminary results of corticosteroids in coronavirus disease 2019 (COVID-19) are encouraging; however, the role of corticosteroids remains controversial. RESEARCH QUESTION: What is the impact of corticosteroids in mortality, ICU admission, mechanical ventilation, and viral shedding in COVID-19 patients? STUDY DESIGN AND METHODS: We conducted a systematic review of literature on corticosteroids and COVID-19 in major databases (PubMed, MEDLINE, and EMBASE) of published literature through July 22, 2020, that report outcomes of interest in COVID-19 patients receiving corticosteroids with a comparative group. RESULTS: A total of 73 studies with 21,350 COVID-19 patients were identified. Corticosteroid use was reported widely in mechanically ventilated patients (35.3%), ICU patients (51.3%), and severe COVID-19 patients (40%). Corticosteroids showed mortality benefit in severelly ill COVID-19 patients (OR, 0.65; 95% CI, 0.51-0.83; P = .0006); however, no beneficial or harmful effects were noted among high-dose or low-dose corticosteroid regimens. Emerging evidence shows that low-dose corticosteroids do not have a significant impact in the duration of SARS-CoV-2 viral shedding. The analysis was limited by highly heterogeneous literature for high-dose and low-dose corticosteroids regimens. INTERPRETATION: Our results showed evidence of mortality benefit in severely ill COVID-19 patients treated with corticosteroids. Corticosteroids are used widely in COVID-19 patients worldwide, and a rapidly developing global pandemic warrants further high-quality clinical trials to define the most beneficial timing and dosing for corticosteroids.

GM-CSF Neutralization With Lenzilumab in Severe COVID-19 Pneumonia: A Case-Cohort Study.

OBJECTIVE: To assess the efficacy and safety of lenzilumab in patients with severe coronavirus disease 2019 (COVID-19) pneumonia. METHODS: Hospitalized patients with COVID-19 pneumonia and risk factors for poor outcomes were treated with lenzilumab 600 mg intravenously for three doses through an emergency single-use investigational new drug application. Patient characteristics, clinical and laboratory outcomes, and adverse events were recorded. We also identified a cohort of patients matched to the lenzilumab patients for age, sex, and disease severity. Study dates were March 13, 2020, to June 18, 2020. All patients were followed through hospital discharge or death. RESULTS: Twelve patients were treated with lenzilumab; 27 patients comprised the matched control cohort (untreated). Clinical improvement, defined as improvement of at least 2 points on the 8-point ordinal clinical endpoints scale, was observed in 11 of 12 (91.7%) patients treated with lenzilumab and 22 of 27 (81.5%) untreated patients. The time to clinical improvement was significantly shorter for the lenzilumab-treated group compared with the untreated cohort with a median of 5 days versus 11 days (P=.006). Similarly, the proportion of patients with acute respiratory distress syndrome (oxygen saturation/fraction of inspired oxygen<315 mm Hg) was significantly reduced over time when treated with lenzilumab compared with untreated (P<.001). Significant improvement in inflammatory markers (C-reactive protein and interleukin 6) and markers of disease severity (absolute lymphocyte count) were observed in patients who received lenzilumab, but not in untreated patients. Cytokine analysis showed a reduction in inflammatory myeloid cells 2 days after lenzilumab treatment. There were no treatment-emergent adverse events attributable to lenzilumab. CONCLUSION: In high-risk COVID-19 patients with severe pneumonia, granulocyte-macrophage colony-stimulating factor neutralization with lenzilumab was safe and associated with faster improvement in clinical outcomes, including oxygenation, and greater reductions in inflammatory markers compared with a matched control cohort of patients hospitalized with severe COVID-19 pneumonia. A randomized, placebo-controlled clinical trial to validate these findings is ongoing (NCT04351152).

Augmented curation of clinical notes from a massive EHR system reveals symptoms of impending COVID-19 diagnosis.

Understanding temporal dynamics of COVID-19 symptoms could provide fine-grained resolution to guide clinical decision-making. Here, we use deep neural networks over an institution-wide platform for the augmented curation of clinical notes from 77,167 patients subjected to COVID-19 PCR testing. By contrasting Electronic Health Record (EHR)-derived symptoms of COVID-19-positive (COVIDpos; n = 2,317) versus COVID-19-negative (COVIDneg; n = 74,850) patients for the week preceding the PCR testing date, we identify anosmia/dysgeusia (27.1-fold), fever/chills (2.6-fold), respiratory difficulty (2.2-fold), cough (2.2-fold), myalgia/arthralgia (2-fold), and diarrhea (1.4-fold) as significantly amplified in COVIDpos over COVIDneg patients. The combination of cough and fever/chills has 4.2-fold amplification in COVIDpos patients during the week prior to PCR testing, in addition to anosmia/dysgeusia, constitutes the earliest EHR-derived signature of COVID-19. This study introduces an Augmented Intelligence platform for the real-time synthesis of institutional biomedical knowledge. The platform holds tremendous potential for scaling up curation throughput, thus enabling EHR-powered early disease diagnosis.