Infectious Disease

Rosas, I. O., G. Diaz, R. L. Gottlieb, S. M. Lobo, P. Robinson, B. D. Hunter, A. W. Cavalcante, J. S. Overcash, N. A. Hanania, A. Skarbnik, J. Garcia-Diaz, I. Gordeev, J. Carratalà, O. Gordon, E. Graham, N. Lewin-Koh, L. Tsai, K. Tuckwell, H. Cao, D. Brainard and J. K. Olsson (2021). “Tocilizumab and remdesivir in hospitalized patients with severe COVID-19 pneumonia: a randomized clinical trial.” Intensive Care Med 47(11): 1258-1270.

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PURPOSE: Trials of tocilizumab in patients with severe COVID-19 pneumonia have demonstrated mixed results, and the role of tocilizumab in combination with other treatments is uncertain. Here we evaluated whether tocilizumab plus remdesivir provides greater benefit than remdesivir alone in patients with severe COVID-19 pneumonia. METHODS: This randomized, double-blind, placebo-controlled, multicenter trial included patients hospitalized with severe COVID-19 pneumonia requiring > 6 L/min supplemental oxygen. Patients were randomly assigned (2:1 ratio) to receive tocilizumab 8 mg/kg or placebo intravenously plus ≤ 10 days of remdesivir. The primary outcome was time from randomization to hospital discharge or “ready for discharge” (defined as category 1, assessed by the investigator on a 7-category ordinal scale of clinical status) to day 28. Patients were followed for 60 days. RESULTS: Among 649 enrolled patients, 434 were randomly assigned to tocilizumab plus remdesivir and 215 to placebo plus remdesivir. 566 patients (88.2%) received corticosteroids during the trial to day 28. Median time from randomization to hospital discharge or “ready for discharge” was 14 (95% CI 12-15) days with tocilizumab plus remdesivir and 14 (95% CI 11-16) days with placebo plus remdesivir [log-rank P = 0.74; Cox proportional hazards ratio 0.97 (95% CI 0.78-1.19)]. Serious adverse events occurred in 128 (29.8%) tocilizumab plus remdesivir and 72 (33.8%) placebo plus remdesivir patients; 78 (18.2%) and 42 (19.7%) patients, respectively, died by day 28. CONCLUSIONS: Tocilizumab plus remdesivir did not shorten time to hospital discharge or “ready for discharge” to day 28 compared with placebo plus remdesivir in patients with severe COVID-19 pneumonia.

Dougan, M., A. Nirula, M. Azizad, B. Mocherla, R. L. Gottlieb, P. Chen, C. Hebert, R. Perry, J. Boscia, B. Heller, J. Morris, C. Crystal, A. Igbinadolor, G. Huhn, J. Cardona, I. Shawa, P. Kumar, A. C. Adams, J. Van Naarden, K. L. Custer, M. Durante, G. Oakley, A. E. Schade, T. R. Holzer, P. J. Ebert, R. E. Higgs, N. L. Kallewaard, J. Sabo, D. R. Patel, M. C. Dabora, P. Klekotka, L. Shen and D. M. Skovronsky (2021). “Bamlanivimab plus Etesevimab in Mild or Moderate Covid-19.” N Engl J Med 385(15): 1382-1392.

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BACKGROUND: Patients with underlying medical conditions are at increased risk for severe coronavirus disease 2019 (Covid-19). Whereas vaccine-derived immunity develops over time, neutralizing monoclonal-antibody treatment provides immediate, passive immunity and may limit disease progression and complications. METHODS: In this phase 3 trial, we randomly assigned, in a 1:1 ratio, a cohort of ambulatory patients with mild or moderate Covid-19 who were at high risk for progression to severe disease to receive a single intravenous infusion of either a neutralizing monoclonal-antibody combination agent (2800 mg of bamlanivimab and 2800 mg of etesevimab, administered together) or placebo within 3 days after a laboratory diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The primary outcome was the overall clinical status of the patients, defined as Covid-19-related hospitalization or death from any cause by day 29. RESULTS: A total of 1035 patients underwent randomization and received an infusion of bamlanivimab-etesevimab or placebo. The mean (±SD) age of the patients was 53.8±16.8 years, and 52.0% were adolescent girls or women. By day 29, a total of 11 of 518 patients (2.1%) in the bamlanivimab-etesevimab group had a Covid-19-related hospitalization or death from any cause, as compared with 36 of 517 patients (7.0%) in the placebo group (absolute risk difference, -4.8 percentage points; 95% confidence interval [CI], -7.4 to -2.3; relative risk difference, 70%; P<0.001). No deaths occurred in the bamlanivimab-etesevimab group; in the placebo group, 10 deaths occurred, 9 of which were designated by the trial investigators as Covid-19-related. At day 7, a greater reduction from baseline in the log viral load was observed among patients who received bamlanivimab plus etesevimab than among those who received placebo (difference from placebo in the change from baseline, -1.20; 95% CI, -1.46 to -0.94; P<0.001). CONCLUSIONS: Among high-risk ambulatory patients, bamlanivimab plus etesevimab led to a lower incidence of Covid-19-related hospitalization and death than did placebo and accelerated the decline in the SARS-CoV-2 viral load. (Funded by Eli Lilly; BLAZE-1 ClinicalTrials.gov number, NCT04427501.).

Dougan, M., M. Azizad, B. Mocherla, R. L. Gottlieb, P. Chen, C. Hebert, R. Perry, J. Boscia, B. Heller, J. Morris, C. Crystal, A. Igbinadolor, G. Huhn, J. Cardona, I. Shawa, P. Kumar, A. Blomkalns, A. C. Adams, J. Van Naarden, K. L. Custer, J. Knorr, G. Oakley, A. E. Schade, T. R. Holzer, P. J. Ebert, R. E. Higgs, J. Sabo, D. R. Patel, M. C. Dabora, M. Williams, P. Klekotka, L. Shen, D. M. Skovronsky and A. Nirula (2021). “A randomized, placebo-controlled clinical trial of bamlanivimab and etesevimab together in high-risk ambulatory patients with COVID-19 and validation of the prognostic value of persistently high viral load.” Clin Infect Dis Oct 28; ciab912. [Epub ahead of print].

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BACKGROUND: Based on interim analyses and modelling data, lower doses of bamlanivimab and etesevimab together (700mg/1400mg) were investigated to determine optimal dose and expand availability of treatment. METHODS: This Phase 3 portion of the BLAZE-1 trial characterized the effect of bamlanivimab with etesevimab on overall patient clinical status and virologic outcomes in ambulatory patients ≥12 years old, with mild-to-moderate COVID-19, and ≥1 risk factor for progressing to severe COVID-19 and/or hospitalization. Bamlanivimab and etesevimab together (700mg/1400mg) or placebo were infused intravenously within 3 days of patients’ first positive COVID-19 test. RESULTS: 769 patients were infused (median age [range]; 56.0 years [12, 93], 30.3% of patients ≥65 years of age and median duration of symptoms; 4 days). By day 29, 4/511 patients (0.8%) in the antibody treatment group had a COVID-19-related hospitalization or any-cause death, as compared with 15/258 patients (5.8%) in the placebo group (Δ[95% CI]=-5.0 [-8.0, -2.1], p<0.001). No deaths occurred in the bamlanivimab and etesevimab group compared with 4 deaths (all COVID-19-related) in the placebo group. Patients receiving antibody treatment had a greater mean reduction in viral load from baseline to Day 7 (Δ[95% CI]=-0.99 [-1.33, -0.66], p<0.0001) compared with those receiving placebo. Persistently high viral load at Day 7 correlated with COVID-19-related hospitalization or any-cause death by Day 29 in all BLAZE-1 cohorts investigated. CONCLUSIONS: These data support the use of bamlanivimab and etesevimab (700mg/1400mg) for ambulatory patients at high risk for severe COVID-19. Evolution of SARS-CoV-2 variants will require continued monitoring to determine the applicability of this treatment.

Tenforde, M. W., A. P. Campbell, M. G. Michaels, C. J. Harrison, E. J. Klein, J. A. Englund, R. Selvarangan, N. B. Halasa, L. S. Stewart, G. A. Weinberg, J. V. Williams, P. G. Szilagyi, M. A. Staat, J. A. Boom, L. C. Sahni, M. N. Singer, P. H. Azimi, R. K. Zimmerman, M. M. McNeal, H. K. Talbot, A. S. Monto, E. T. Martin, M. Gaglani, F. P. Silveira, D. B. Middleton, J. M. Ferdinands and M. A. Rolfes (2021). “Clinical Influenza Testing Practices in Hospitalized Children at United States Medical Centers, 2015-2018.” J Pediatric Infect Dis Soc Oct 13;piab096. [Epub ahead of print].

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At nine US hospitals that enrolled children hospitalized with acute respiratory illness (ARI) during 2015-2016 through 2017-2018 influenza seasons, 50% of children with ARI received clinician-initiated testing for influenza and 35% of cases went undiagnosed due to lack of clinician-initiated testing. Marked heterogeneity in testing practice was observed across sites.

Tenforde, M. W., W. H. Self, K. Adams, M. Gaglani, A. A. Ginde, T. McNeal, S. Ghamande, D. J. Douin, H. K. Talbot, J. D. Casey, N. M. Mohr, A. Zepeski, N. I. Shapiro, K. W. Gibbs, D. C. Files, D. N. Hager, A. Shehu, M. E. Prekker, H. L. Erickson, M. C. Exline, M. N. Gong, A. Mohamed, D. J. Henning, J. S. Steingrub, I. D. Peltan, S. M. Brown, E. T. Martin, A. S. Monto, A. Khan, C. L. Hough, L. W. Busse, C. C. Ten Lohuis, A. Duggal, J. G. Wilson, A. J. Gordon, N. Qadir, S. Y. Chang, C. Mallow, C. Rivas, H. M. Babcock, J. H. Kwon, N. Halasa, J. D. Chappell, A. S. Lauring, C. G. Grijalva, T. W. Rice, I. D. Jones, W. B. Stubblefield, A. Baughman, K. N. Womack, J. P. Rhoads, C. J. Lindsell, K. W. Hart, Y. Zhu, S. M. Olson, M. Kobayashi, J. R. Verani and M. M. Patel (2021). “Association Between mRNA Vaccination and COVID-19 Hospitalization and Disease Severity.” Jama Nov 4. [Epub ahead of print].

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IMPORTANCE: A comprehensive understanding of the benefits of COVID-19 vaccination requires consideration of disease attenuation, determined as whether people who develop COVID-19 despite vaccination have lower disease severity than unvaccinated people. OBJECTIVE: To evaluate the association between vaccination with mRNA COVID-19 vaccines-mRNA-1273 (Moderna) and BNT162b2 (Pfizer-BioNTech)-and COVID-19 hospitalization, and, among patients hospitalized with COVID-19, the association with progression to critical disease. DESIGN, SETTING, AND PARTICIPANTS: A US 21-site case-control analysis of 4513 adults hospitalized between March 11 and August 15, 2021, with 28-day outcome data on death and mechanical ventilation available for patients enrolled through July 14, 2021. Date of final follow-up was August 8, 2021. EXPOSURES: COVID-19 vaccination. MAIN OUTCOMES AND MEASURES: Associations were evaluated between prior vaccination and (1) hospitalization for COVID-19, in which case patients were those hospitalized for COVID-19 and control patients were those hospitalized for an alternative diagnosis; and (2) disease progression among patients hospitalized for COVID-19, in which cases and controls were COVID-19 patients with and without progression to death or mechanical ventilation, respectively. Associations were measured with multivariable logistic regression. RESULTS: Among 4513 patients (median age, 59 years [IQR, 45-69]; 2202 [48.8%] women; 23.0% non-Hispanic Black individuals, 15.9% Hispanic individuals, and 20.1% with an immunocompromising condition), 1983 were case patients with COVID-19 and 2530 were controls without COVID-19. Unvaccinated patients accounted for 84.2% (1669/1983) of COVID-19 hospitalizations. Hospitalization for COVID-19 was significantly associated with decreased likelihood of vaccination (cases, 15.8%; controls, 54.8%; adjusted OR, 0.15; 95% CI, 0.13-0.18), including for sequenced SARS-CoV-2 Alpha (8.7% vs 51.7%; aOR, 0.10; 95% CI, 0.06-0.16) and Delta variants (21.9% vs 61.8%; aOR, 0.14; 95% CI, 0.10-0.21). This association was stronger for immunocompetent patients (11.2% vs 53.5%; aOR, 0.10; 95% CI, 0.09-0.13) than immunocompromised patients (40.1% vs 58.8%; aOR, 0.49; 95% CI, 0.35-0.69) (P < .001) and weaker at more than 120 days since vaccination with BNT162b2 (5.8% vs 11.5%; aOR, 0.36; 95% CI, 0.27-0.49) than with mRNA-1273 (1.9% vs 8.3%; aOR, 0.15; 95% CI, 0.09-0.23) (P < .001). Among 1197 patients hospitalized with COVID-19, death or invasive mechanical ventilation by day 28 was associated with decreased likelihood of vaccination (12.0% vs 24.7%; aOR, 0.33; 95% CI, 0.19-0.58). CONCLUSIONS AND RELEVANCE: Vaccination with an mRNA COVID-19 vaccine was significantly less likely among patients with COVID-19 hospitalization and disease progression to death or mechanical ventilation. These findings are consistent with risk reduction among vaccine breakthrough infections compared with absence of vaccination.