499. Rapid and Sustained Decline in CXCL-10 (IP-10) Annotates Clinical Outcomes Following TNF-α Antagonist Therapy in Hospitalized Patients with Severe and Critical COVID-19 Respiratory Failure

Abstract Background TNFα and IFN-γ may synergize to induce cytokine-driven lethal hyperinflammation and immune exhaustion in COVID-19 illness. Methods To assess TNFα-antagonist therapy, 18 hospitalized adults with hypoxic respiratory failure and COVID-19 pneumonia received single-dose infliximab-abda therapy 5mg/kg intravenously between April and December 2020. The primary endpoint was time to increase in oxygen saturation to fraction of inspired oxygen ratio (SpO2/FiO2) by ≥ 50 compared to baseline and sustained for 48 hours. Secondary endpoints included 28-day mortality, dynamic cytokine profiles (Human Cytokine 48-Plex Discovery Assay), secondary infections, duration of supplemental oxygen support and hospitalization. Consort diagram Hospitalized patients with SARS-COV2 infection and pneumonia that were referred to the infliximab-abda study team for evaluation. Results Patients were predominantly in critical respiratory failure (15/18, 83%), male (14/18, 78%), above 60 years (median 63 yrs, range 31-80), race-ethnic minorities (13/18, 72%), lymphopenic (13/18, 72%), steroid-treated (17/18, 94%), with a median ferritin of 1953ng/ml. Sixteen patients (89%) met the primary endpoint within a median of 4 days, 15/18 (83%) recovered from respiratory failure, and 14/18 (78%) were discharged in a median of 8 days and were alive at 28-day follow-up. Deaths among three patients ≥ 65 years age with pre-existing lung disease or multiple comorbidities were attributed to secondary lung infections. Mean plasma IP-10 levels declined sharply from 9183 pg/ml to 483 pg/ml at Day 3 and 146 pg/ml at Day 14/discharge. Significant declines in IFN-γ, TNFα, IL-27, IL-6 (baseline above 10pg/ml), CRP and ferritin were specifically observed at Day 3 whereas other cytokines were unaffected. Among 13 lymphopenic patients, six (46%) had resolution of lymphopenia by day 3, and 11 by day 14. CXCR3-ligand (IP-10 and CXCL-9) declines were strongly correlated among patients with lymphopenia reversal (Day 3, Pearson r: 0.98, p-value: 0.0006). Demographics and clinical characteristics Demographics, comorbidities, clinical features, inflammatory markers, and outcomes of 18 patients with COVID-19 respiratory failure treated with infliximab-abda between April and December 2020. Changes in oxygen support status following infliximab-abda treatment Colored bars indicate the maximal level of oxygen support for each individual following treatment with infliximab-abda. The status of the patient at last follow-up (discharged, alive or dead) is indicated. ECMO: extracorporeal membrane oxygenation Control of inflammatory markers and cytokines following infliximab therapy Values from individuals are connected with solid lines, with deceased individuals indicated in red. Statistics: n=18, paired ratio t-test compared to baseline; *: P<0.05, **: P<0.01, ***: P<0.001, ****: P<0.0001, n.s.: not significant. Conclusion Consistent with a central role of TNFα, the clinical and cytokine data indicate that infliximab-abda may rapidly abrogate pathological inflammatory signaling to facilitate clinical recovery in severe and critical COVID-19. Randomized studies are formally evaluating infliximab therapy in this context. Funding: National Center for Advancing Translational Sciences Disclosures All Authors: No reported disclosures

Methods. To assess TNFα-antagonist therapy, 18 hospitalized adults with hypoxic respiratory failure and COVID-19 pneumonia received single-dose infliximab-abda therapy 5mg/kg intravenously between April and December 2020. The primary endpoint was time to increase in oxygen saturation to fraction of inspired oxygen ratio (SpO2/FiO2) by ≥ 50 compared to baseline and sustained for 48 hours. Secondary endpoints included 28-day mortality, dynamic cytokine profiles (Human Cytokine 48-Plex Discovery Assay), secondary infections, duration of supplemental oxygen support and hospitalization.
Consort diagram Hospitalized patients with SARS-COV2 infection and pneumonia that were referred to the infliximab-abda study team for evaluation.
Demographics and clinical characteristics Demographics, comorbidities, clinical features, inflammatory markers, and outcomes of 18 patients with COVID-19 respiratory failure treated with infliximab-abda between April and December 2020.
Changes in oxygen support status following infliximab-abda treatment S352 • OFID 2021:8 (Suppl 1) • Abstracts Colored bars indicate the maximal level of oxygen support for each individual following treatment with infliximab-abda. The status of the patient at last follow-up (discharged, alive or dead) is indicated. ECMO: extracorporeal membrane oxygenation Control of inflammatory markers and cytokines following infliximab therapy Values from individuals are connected with solid lines, with deceased individuals indicated in red. Statistics: n=18, paired ratio t-test compared to baseline; *: P<0.05, **: P<0.01, ***: P<0.001, ****: P<0.0001, n.s.: not significant.
Conclusion. Consistent with a central role of TNFα, the clinical and cytokine data indicate that infliximab-abda may rapidly abrogate pathological inflammatory signaling to facilitate clinical recovery in severe and critical COVID-19. Randomized studies are formally evaluating infliximab therapy in this context. Funding: National Center for Advancing Translational Sciences Disclosures. All Authors: No reported disclosures

Session: P-24. COVID-19 Treatment
Background. Anti-spike monoclonal antibodies (mAb) including Bamlanivimab (BAM) and Bamlanivimab-Etesevimab (BAM/E) have shown reduced hospitalization rates for non-severe coronavirus disease 2019 (COVID-19) in clinical trials. Recent studies provided real-world hospitalization rates for BAM. But, similar data on those who received BAM/E are lacking. In spring 2021, Michigan experienced a surge of COVID-19 with more cases per capita than any other state. We sought to quantify the impact of BAM monotherapy versus BAM/E combination on hospitalization and mortality among a real-world high-risk cohort of outpatients with COVID-19.
Methods. This retrospective cohort study evaluated outpatients ≥18 years with laboratory-confirmed mild/moderate COVID-19 who received mAb in a Detroit health system based on emergency use authorization criteria. Inclusion began on December 3 rd 2020 with BAM monotherapy, changed to BAM/E combination on March 27, 2021, and included patients until April 19 th 2021 ( Figure 1). Demographics, comorbidities, and clinical characteristics were compared between patients who received BAM verses BAM/E using Chi-square and Mann-Whitney U test. Primary outcome was 30-day COVID-19 related hospitalization. Secondary outcomes were 30-day mortality and length of stay (LOS).
Inclusion began on December 3rd 2020 with BAM monotherapy, changed to BAM/E combination on March 27, 2021, andincluded patients until April 19th 2021. In spring 2021, Michigan experienced a surge of COVID-19 with more cases per capita than any other state resulting in a large sample of real-world patients for analysis.
Results. 643 patients received mAb (294 in BAM group and 349 in BAM/E group). Patients in the BAM/E cohort were younger and more obese with lower rates of diabetes, myocardial infarction, and cancer. Other characteristics were similar (Table  1). BAM/E patients had longer time from symptom onset to infusion (6 vs 4 days, p< 0.001). COVID-19 related 30-day hospitalization rates did not differ between groups (7.8 vs 7.2%, p=0.751). LOS and 30-day mortality (1% vs 0.3%, p=0.238) were also similar ( Table 2).
Patients in the BAM/E cohort were younger and more obese with lower rates of diabetes, myocardial infarction, and cancer. Other characteristics were similar BAM/E patients had longer time from symptom onset to infusion (6 vs 4 days, p<0.001). COVID-19 related 30-day hospitalization rates did not differ between groups. Length of stay and 30-day mortality were also similar.
Conclusion. Rates of hospitalization in our study were higher than in clinical trials of mAB and may reflect differences in study populations (Table 3). Compared to other real-world studies, our cohort of young, obese, and Black patients, had similar hospitalization rates of 7.5%. The lack of difference in outcomes noted among the mAB formulations in our study may be related to longer time from symptom onset to infusion in the BAM/E combination group.