Robert L. Gottlieb M.D. Ph.D.

Jamil, A. K., A. Alam, R. M. Youssef, J. Felius, J. S. van Zyl and R. L. Gottlieb (2021). “Pneumothorax and Pneumomediastinum in COVID-19 Suggest a Pneumocystic Pathology.” Mayo Clin Proc Innov Qual Outcomes 5(5): 827-834.

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OBJECTIVE: To determine whether the apparent excess incidence of pneumothorax and pneumomediastinum in patients with coronavirus disease 2019 (COVID-19) is explained adequately by iatrogenic causes vs reflecting sequelae of severe acute respiratory syndrome coronavirus 2 infection. PATIENTS AND METHODS: We retrospectively reviewed patients within our health care system from March 15, 2020, through May 31, 2020, who had a diagnosis of pneumothorax or pneumomediastinum during hospitalization for confirmed COVID-19 infection with attention to timing of pneumothorax and pneumomediastinum; presence, laterality, and placement, or attempts at central lines; and presence of mechanical ventilation before the event. RESULTS: We report clinical data and outcomes from 9 hospitalized patients with COVID-19 who developed pneumothorax and/or pneumomediastinum among more than 1200 hospitalized patients admitted within our hospital system early in the pandemic. Many events were inexplicable by iatrogenic needle injury, including 1 spontaneous case without central line access or mechanical ventilation. One occurred before central line placement, 2 in patients with only a peripherally inserted central line, and 1 contralateral to a classic central line. Three of these 9 patients died of complications of COVID-19 during their hospital stay. CONCLUSION: With COVID-19 affecting the peripheral lung pneumocytes, patients are vulnerable to develop pneumothorax or pneumomediastinum irrespective of their central line access site. We hypothesize that COVID-19 hyperinflammation, coupled with the viral tropism that includes avid involvement of peripheral lung pneumocytes, induces a predisposition to peripheral bronchoalveolar communication and consequent viral hyperinflammatory-triggered pneumothorax and pneumomediastinum.

van Zyl, J.S., Felius, J., Alam, A., Hall, S.A., Jamil, A.K., Spak, C.W. and Gottlieb, R.L. (2021). “Dynamic albumin values as clinical surrogate for COVID-19 therapeutics.” J Investig Med May 28;jim-2021-001895. [Epub ahead of print].

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We studied patients admitted for management of COVID-19. Thus, dynamic changes clearly reflect COVID-19 disease. We posited that albumin levels fall dynamically due to the hyperinflammatory pathophysiology of COVID-19, with attendant capillary leak.2 We are delighted that the author of the above letter shares our burning question: does the dynamic fall of serum albumin track the hyperinflammatory markers of C-reactive protein, ferritin, and interleukin 6 (IL-6), and do immunomodulators such as glucocorticoids or anti-IL-6 receptor or anti-IL-6 cytokine monoclonal antibody therapies reverse this? This is an important avenue for future investigation. As IL-6 values are not routinely measured, that question can only be addressed prospectively.[No abstract; excerpt from article].

Taylor, P.C., Adams, A.C., Hufford, M.M., de la Torre, I., Winthrop, K. and Gottlieb, R.L. (2021). “Neutralizing monoclonal antibodies for treatment of COVID-19.” Nat Rev Immunol 21(6): 382-393.

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Several neutralizing monoclonal antibodies (mAbs) to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been developed and are now under evaluation in clinical trials. With the US Food and Drug Administration recently granting emergency use authorizations for neutralizing mAbs in non-hospitalized patients with mild-to-moderate COVID-19, there is an urgent need to discuss the broader potential of these novel therapies and to develop strategies to deploy them effectively in clinical practice, given limited initial availability. Here, we review the precedent for passive immunization and lessons learned from using antibody therapies for viral infections such as respiratory syncytial virus, Ebola virus and SARS-CoV infections. We then focus on the deployment of convalescent plasma and neutralizing mAbs for treatment of SARS-CoV-2. We review specific clinical questions, including the rationale for stratification of patients, potential biomarkers, known risk factors and temporal considerations for optimal clinical use. To answer these questions, there is a need to understand factors such as the kinetics of viral load and its correlation with clinical outcomes, endogenous antibody responses, pharmacokinetic properties of neutralizing mAbs and the potential benefit of combining antibodies to defend against emerging viral variants.

Taylor, P.C., Adams, A.C., Hufford, M.M., de la Torre, I., Winthrop, K. and Gottlieb, R.L. (2021). “Neutralizing monoclonal antibodies for treatment of COVID-19.” Nat Rev Immunol: 1-12.

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Several neutralizing monoclonal antibodies (mAbs) to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been developed and are now under evaluation in clinical trials. With the US Food and Drug Administration recently granting emergency use authorizations for neutralizing mAbs in non-hospitalized patients with mild-to-moderate COVID-19, there is an urgent need to discuss the broader potential of these novel therapies and to develop strategies to deploy them effectively in clinical practice, given limited initial availability. Here, we review the precedent for passive immunization and lessons learned from using antibody therapies for viral infections such as respiratory syncytial virus, Ebola virus and SARS-CoV infections. We then focus on the deployment of convalescent plasma and neutralizing mAbs for treatment of SARS-CoV-2. We review specific clinical questions, including the rationale for stratification of patients, potential biomarkers, known risk factors and temporal considerations for optimal clinical use. To answer these questions, there is a need to understand factors such as the kinetics of viral load and its correlation with clinical outcomes, endogenous antibody responses, pharmacokinetic properties of neutralizing mAbs and the potential benefit of combining antibodies to defend against emerging viral variants.

Gottlieb, R.L., Nirula, A., Chen, P., Boscia, J., Heller, B., Morris, J., Huhn, G., Cardona, J., Mocherla, B., Stosor, V., Shawa, I., Kumar, P., Adams, A.C., Van Naarden, J., Custer, K.L., Durante, M., Oakley, G., Schade, A.E., Holzer, T.R., Ebert, P.J., Higgs, R.E., Kallewaard, N.L., Sabo, J., Patel, D.R., Klekotka, P., Shen, L. and Skovronsky, D.M. (2021). “Effect of Bamlanivimab as Monotherapy or in Combination With Etesevimab on Viral Load in Patients With Mild to Moderate COVID-19: A Randomized Clinical Trial.” Jama 325(7): 632-644.

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IMPORTANCE: Coronavirus disease 2019 (COVID-19) continues to spread rapidly worldwide. Neutralizing antibodies are a potential treatment for COVID-19. OBJECTIVE: To determine the effect of bamlanivimab monotherapy and combination therapy with bamlanivimab and etesevimab on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load in mild to moderate COVID-19. DESIGN, SETTING, AND PARTICIPANTS: The BLAZE-1 study is a randomized phase 2/3 trial at 49 US centers including ambulatory patients (N = 613) who tested positive for SARS-CoV-2 infection and had 1 or more mild to moderate symptoms. Patients who received bamlanivimab monotherapy or placebo were enrolled first (June 17-August 21, 2020) followed by patients who received bamlanivimab and etesevimab or placebo (August 22-September 3). These are the final analyses and represent findings through October 6, 2020. INTERVENTIONS: Patients were randomized to receive a single infusion of bamlanivimab (700 mg [n = 101], 2800 mg [n = 107], or 7000 mg [n = 101]), the combination treatment (2800 mg of bamlanivimab and 2800 mg of etesevimab [n = 112]), or placebo (n = 156). MAIN OUTCOMES AND MEASURES: The primary end point was change in SARS-CoV-2 log viral load at day 11 (±4 days). Nine prespecified secondary outcome measures were evaluated with comparisons between each treatment group and placebo, and included 3 other measures of viral load, 5 on symptoms, and 1 measure of clinical outcome (the proportion of patients with a COVID-19-related hospitalization, an emergency department [ED] visit, or death at day 29). RESULTS: Among the 577 patients who were randomized and received an infusion (mean age, 44.7 [SD, 15.7] years; 315 [54.6%] women), 533 (92.4%) completed the efficacy evaluation period (day 29). The change in log viral load from baseline at day 11 was -3.72 for 700 mg, -4.08 for 2800 mg, -3.49 for 7000 mg, -4.37 for combination treatment, and -3.80 for placebo. Compared with placebo, the differences in the change in log viral load at day 11 were 0.09 (95% CI, -0.35 to 0.52; P = .69) for 700 mg, -0.27 (95% CI, -0.71 to 0.16; P = .21) for 2800 mg, 0.31 (95% CI, -0.13 to 0.76; P = .16) for 7000 mg, and -0.57 (95% CI, -1.00 to -0.14; P = .01) for combination treatment. Among the secondary outcome measures, differences between each treatment group vs the placebo group were statistically significant for 10 of 84 end points. The proportion of patients with COVID-19-related hospitalizations or ED visits was 5.8% (9 events) for placebo, 1.0% (1 event) for 700 mg, 1.9% (2 events) for 2800 mg, 2.0% (2 events) for 7000 mg, and 0.9% (1 event) for combination treatment. Immediate hypersensitivity reactions were reported in 9 patients (6 bamlanivimab, 2 combination treatment, and 1 placebo). No deaths occurred during the study treatment. CONCLUSIONS AND RELEVANCE: Among nonhospitalized patients with mild to moderate COVID-19 illness, treatment with bamlanivimab and etesevimab, compared with placebo, was associated with a statistically significant reduction in SARS-CoV-2 viral load at day 11; no significant difference in viral load reduction was observed for bamlanivimab monotherapy. Further ongoing clinical trials will focus on assessing the clinical benefit of antispike neutralizing antibodies in patients with COVID-19 as a primary end point. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04427501.