Research Spotlight

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].

Full text of this article.

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.

Doyle, D. J., A. Goyal, P. Bansal and E. H. Garmon (2021). American Society of Anesthesiologists Classification. StatPearls. Treasure Island (FL), StatPearls Publishing.

Full text of this article.

The American Society of Anesthesiologists (ASA) physical status classification system was developed to offer clinicians a simple categorization of a patient’s physiological status to help predict operative risk. The ASAPS originated in 1941 and has seen some revisions since that time.

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].

Full text of this article.

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].

Full text of this article.

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.

Lewis, K., R. Dummer, A. S. Farberg, A. Guminski, N. Squittieri and M. Migden (2021). “Effects of Sonidegib Following Dose Reduction and Treatment Interruption in Patients with Advanced Basal Cell Carcinoma During 42-Month BOLT Trial.” Dermatol Ther (Heidelb) Oct 20. [Epub ahead of print].

Full text of this article.

INTRODUCTION: Sonidegib is a Hedgehog pathway inhibitor approved to treat locally advanced basal cell carcinoma and, depending on regulatory approval, metastatic basal cell carcinoma. Results from the BOLT study demonstrated robust efficacy and continued tolerability through 42 months. This analysis evaluated the impact of sonidegib dose reductions and interruptions in patients with advanced basal cell carcinoma through 42 months. METHODS: BOLT was a randomized, double-blind, multicenter, phase 2 study. Adults with no previous Hedgehog pathway inhibitor therapy were randomized 1:2 to sonidegib 200 or 800 mg once daily. Primary endpoint was objective response rate. Dose modifications were permitted in patients unable to tolerate the dosing schedule or if a treatment-related adverse event was suspected. RESULTS: The incidence of dose interruptions was similar between the 200- and 800-mg groups (68.4% vs 65.3%, respectively). Dose reductions occurred more frequently in patients receiving sonidegib 800 mg (36.7%) than 200 mg (16.5%). Overall response rate for all patients receiving sonidegib 200 mg daily was 48.1% and was similar to those of patients without dose reduction or interruption (48.5%) and patients with at least one dose reduction or interruption (46.2%). CONCLUSION: Dose reductions and interruptions were practical and did not impact the efficacy of sonidegib. In patients with advanced basal cell carcinoma who necessitate long-term treatment, dose interruptions may be beneficial for continued treatment and disease control. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01327053.