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: A feed-forward pathological signaling loop generated by TNFα and IFN-γ in inflamed lung tissue, driving CXCL-10 (IP-10) and CXCL-9 chemokine-mediated activated T-cell and monocyte/macrophage tissue recruitment, may define, sustain and amplify the inflammatory biology of lethal COVID-19 respiratory failure. 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, Eve Technologies), secondary infections, duration of supplemental oxygen support and hospitalization. Findings: 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 > 65yrs age with pre-existing lung disease or multiple comorbidities were attributed to secondary lung infection. Mean plasma IP-10 levels declined sharply from 9183 pg/ml to 483 pg/ml at Day 3 and further to 146 pg/ml at Day 14/discharge. Significant declines in IFN-γ, TNFα, IL-27, CRP and ferritin were specifically observed at Day 3 whereas other cytokines were unmodified. IL-6 levels declined sharply among patients with baseline levels >10 pg/ml. 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). Interpretation: Consistent with a pathophysiological 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 required to formally assess mortality outcomes. Funding: National Center for Advancing Translational Sciences

Spatial transcriptomic characterization of COVID-19 pneumonitis identifies immune circuits related to tissue injury

“…It is known that BAFF can promote CD4 + T cell IFN production and CD8 + T cell cytotoxicity in chronic obstructive pulmonary disease (COPD) (42), supporting the concept that it may be part of a positive feedback loop that sustains non-specific cytotoxic lymphocyte activation in COVID-19. It is also likely that elevated levels of IL-1, IL-6 and TNF may contribute to dysregulation of CD8 T cells, NK cells and macrophages as part of the so-called 'cytokine storm' (26,43).…”

Inflammatory pathways in COVID‐19: Mechanism and therapeutic interventions

“…A clinical study (NCT04425538) reported results that infliximab treatment improved oxygenation and eliminated pathological inflammatory signals. 361 Most of these are still being evaluated for their clinical effectiveness. Adalimumab is registered in two clinical trials (NCT04705844 and ChiCTR2000030089), and infliximab is also in four clinical trials (NCT04922827, NCT04734678, NCT05220280, and NCT04593940).…”

“…The current use of inhibitors against TNF‐α for the treatment of COVID‐19 mainly includes monoclonal antibodies, such as adalimumab, golimumab, infliximab, certulizumab, and the TNF‐α receptor fusion protein etanercept. A clinical study (NCT04425538) reported results that infliximab treatment improved oxygenation and eliminated pathological inflammatory signals 361 . Most of these are still being evaluated for their clinical effectiveness.…”

Biological and Exploitable Crossroads for the Immune Response in Cancer and COVID-19

“…As far as TNFα inhibitors exclusively meant for an anti-COVID-19 treatment are concerned, a clinical trial evaluating adalimumab has been reported in China (ChiCTR2000030089). Furthermore, a completed phase II clinical trial showed that infliximab may extinguish the pathological inflammatory signaling providing clinical recovery in severe COVID-19 [ 181 ]. Indeed, the results of further clinical trials are necessary, to better elucidate the role and the timing of TNF inhibitors in COVID-19 treatment.…”