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

van Zyl, J.S., Alam, A., Felius, J., Youssef, R.M., Bhakta, D., Jack, C., Jamil, A.K., Hall, S.A., Klintmalm, G.B., Spak, C.W. and Gottlieb, R.L. (2021). “ALLY in fighting COVID-19: magnitude of albumin decline and lymphopenia (ALLY) predict progression to critical disease.” J Investig Med Jan 11;jim-2020-001525. [Epub ahead of print].

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The global severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic leading to coronavirus disease 2019 (COVID-19) is straining hospitals. Judicious resource allocation is paramount but difficult due to the unpredictable disease course. Once hospitalized, discerning which patients may progress to critical disease would be valuable for resource planning. Medical records were reviewed for consecutive hospitalized patients with COVID-19 in a large healthcare system in Texas. The main outcome was progression to critical disease within 10 days from admission. Albumin trends from admission to 7 days were analyzed using mixed-effects models, and progression to critical disease was modeled by multivariable logistic regression of laboratory results. Risk models were evaluated in an independent group. Of 153 non-critical patients, 28 (18%) progressed to critical disease. The rate of decrease in mean baseline-corrected (Δ) albumin was -0.08 g/dL/day (95% CI -0.11 to -0.04; p<0.001) or four times faster, in those who progressed compared with those who did not progress. A model of Δ albumin combined with lymphocyte percentage predicting progression to critical disease was validated in 60 separate patients (sensitivity, 0.70; specificity, 0.74). ALLY (delta albumin and lymphocyte percentage) is a simple tool to identify patients with COVID-19 at higher risk of disease progression when: (1) a 0.9 g/dL or greater albumin drop from baseline within 5 days of admission or (2) baseline lymphocyte of ≤10% is observed. The ALLY tool identified >70% of hospitalized cases that progressed to critical COVID-19 disease. We recommend prospectively tracking albumin. This is a globally applicable tool for all healthcare systems.

Gottlieb, R.L. and Spak, C.W. (2021). “The Olympiad of SARS-CoV-2 vaccinology: Fundamentals to Complement Technical Frontiers.” Clin Infect Dis Jan 30;ciab088. [Epub ahead of print].

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SARS-CoV-2 is a consequential and devastating virus, yet it is unlikely to be a particularly “fit,” having limited genomic size and a constrained sequence space to sample for escape mutations. If spike mutations happen to decrease efficacy of spike-specific vaccine strategies, the world may require comparative efficacy data from multiple workarounds. Chimeric derivatives of mRNA or vectored vaccines encoding various different spike variant cassettes may suffice, but inactivated vaccines offer a back-up of alternative epitopes just in case. Like saline for cholera, or like a goal in sports, vaccinology does not need to be fancy… it just needs to work. The world eagerly awaits the next steps – objective data from phase 3 trials of this, and similar, inactivated SARS-CoV-2 vaccines. [No abstract; excerpt from article].

Naik, C.A., Mathai, S.K., Sandkovsky, U.S., Ausloos, K.A., Guileyardo, J.M., Schwartz, G., Mason, D.P., Gottlieb, R. and Grazia, T.J. (2021). “Acute myocardial infarction secondary to mucormycosis after lung transplantation.” IDCases 23: e01019.

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We present a case of a 57-year-old man who underwent bilateral lung transplantation for idiopathic pulmonary fibrosis. His immediately post-operative course was complicated by fever and cardiac arrest. Despite supportive care and broad-spectrum antibiotics, he experienced continued clinical decline. Autopsy results indicated angioinvasive mucormycosis and coronary arteritis resulting in acute myocardial infarction as the cause of death.

Lundgren, J.D., Grund, B., Barkauskas, C.E., Holland, T.L., Gottlieb, R.L., Sandkovsky, U., Brown, S.M., Knowlton, K.U., Self, W.H., Files, D.C., Jain, M.K., Benfield, T., Bowdish, M.E., Leshnower, B.G., Baker, J.V., Jensen, J.U., Gardner, E.M., Ginde, A.A., Harris, E.S., Johansen, I.S., Markowitz, N., Matthay, M.A., Østergaard, L., Chang, C.C., Davey, V.J., Goodman, A., Higgs, E.S., Murray, D.D., Murray, T.A., Paredes, R., Parmar, M.K.B., Phillips, A.N., Reilly, C., Sharma, S., Dewar, R.L., Teitelbaum, M., Wentworth, D., Cao, H., Klekotka, P., Babiker, A.G., Gelijns, A.C., Kan, V.L., Polizzotto, M.N., Thompson, B.T., Lane, H.C. and Neaton, J.D. (2020). “A Neutralizing Monoclonal Antibody for Hospitalized Patients with Covid-19.” N Engl J Med Dec 22;NEJMoa2033130. [Epub ahead of print].

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BACKGROUND: LY-CoV555, a neutralizing monoclonal antibody, has been associated with a decrease in viral load and the frequency of hospitalizations or emergency department visits among outpatients with coronavirus disease 2019 (Covid-19). Data are needed on the effect of this antibody in patients who are hospitalized with Covid-19. METHODS: In this platform trial of therapeutic agents, we randomly assigned hospitalized patients who had Covid-19 without end-organ failure in a 1:1 ratio to receive either LY-CoV555 or matching placebo. In addition, all the patients received high-quality supportive care as background therapy, including the antiviral drug remdesivir and, when indicated, supplemental oxygen and glucocorticoids. LY-CoV555 (at a dose of 7000 mg) or placebo was administered as a single intravenous infusion over a 1-hour period. The primary outcome was a sustained recovery during a 90-day period, as assessed in a time-to-event analysis. An interim futility assessment was performed on the basis of a seven-category ordinal scale for pulmonary function on day 5. RESULTS: On October 26, 2020, the data and safety monitoring board recommended stopping enrollment for futility after 314 patients (163 in the LY-CoV555 group and 151 in the placebo group) had undergone randomization and infusion. The median interval since the onset of symptoms was 7 days (interquartile range, 5 to 9). At day 5, a total of 81 patients (50%) in the LY-CoV555 group and 81 (54%) in the placebo group were in one of the two most favorable categories of the pulmonary outcome. Across the seven categories, the odds ratio of being in a more favorable category in the LY-CoV555 group than in the placebo group was 0.85 (95% confidence interval [CI], 0.56 to 1.29; P = 0.45). The percentage of patients with the primary safety outcome (a composite of death, serious adverse events, or clinical grade 3 or 4 adverse events through day 5) was similar in the LY-CoV555 group and the placebo group (19% and 14%, respectively; odds ratio, 1.56; 95% CI, 0.78 to 3.10; P = 0.20). The rate ratio for a sustained recovery was 1.06 (95% CI, 0.77 to 1.47). CONCLUSIONS: Monoclonal antibody LY-CoV555, when coadministered with remdesivir, did not demonstrate efficacy among hospitalized patients who had Covid-19 without end-organ failure. (Funded by Operation Warp Speed and others; TICO ClinicalTrials.gov number, NCT04501978.).

Chen, P., Nirula, A., Heller, B., Gottlieb, R.L., Boscia, J., Morris, J., Huhn, G., Cardona, J., Mocherla, B., Stosor, V., Shawa, I., Adams, A.C., Van Naarden, J., Custer, K.L., Shen, L., Durante, M., Oakley, G., Schade, A.E., Sabo, J., Patel, D.R., Klekotka, P. and Skovronsky, D.M. (2020). “SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19.” N Engl J Med Oct 28;NEJMoa2029849. [Epub ahead of print].

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BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (Covid-19), which is most frequently mild yet can be severe and life-threatening. Virus-neutralizing monoclonal antibodies are predicted to reduce viral load, ameliorate symptoms, and prevent hospitalization. METHODS: In this ongoing phase 2 trial involving outpatients with recently diagnosed mild or moderate Covid-19, we randomly assigned 452 patients to receive a single intravenous infusion of neutralizing antibody LY-CoV555 in one of three doses (700 mg, 2800 mg, or 7000 mg) or placebo and evaluated the quantitative virologic end points and clinical outcomes. The primary outcome was the change from baseline in the viral load at day 11. The results of a preplanned interim analysis as of September 5, 2020, are reported here. RESULTS: At the time of the interim analysis, the observed mean decrease from baseline in the log viral load for the entire population was -3.81, for an elimination of more than 99.97% of viral RNA. For patients who received the 2800-mg dose of LY-CoV555, the difference from placebo in the decrease from baseline was -0.53 (95% confidence interval [CI], -0.98 to -0.08; P = 0.02), for a viral load that was lower by a factor of 3.4. Smaller differences from placebo in the change from baseline were observed among the patients who received the 700-mg dose (-0.20; 95% CI, -0.66 to 0.25; P = 0.38) or the 7000-mg dose (0.09; 95% CI, -0.37 to 0.55; P = 0.70). On days 2 to 6, the patients who received LY-CoV555 had a slightly lower severity of symptoms than those who received placebo. The percentage of patients who had a Covid-19-related hospitalization or visit to an emergency department was 1.6% in the LY-CoV555 group and 6.3% in the placebo group. CONCLUSIONS: In this interim analysis of a phase 2 trial, one of three doses of neutralizing antibody LY-CoV555 appeared to accelerate the natural decline in viral load over time, whereas the other doses had not by day 11.