Rapid and sustained decline in CXCL-10 (IP-10) annotates clinical outcomes following TNFα-antagonist therapy in hospitalized patients with severe and critical COVID-19 respiratory failure

Hilal Hachem, Amandeep Godara, Courtney Schroeder, Daniel Fein, Hashim Mann, Christian Lawlor, Jill Marshall, Andreas Klein, Debra Poutsiaka, Janis L Breeze, Raghav Joshi, Paul Mathew, Hilal Hachem, Amandeep Godara, Courtney Schroeder, Daniel Fein, Hashim Mann, Christian Lawlor, Jill Marshall, Andreas Klein, Debra Poutsiaka, Janis L Breeze, Raghav Joshi, Paul Mathew

Abstract

Background: A feedforward pathological signaling loop generated by TNFα and IFN-γ synergy in the inflamed lung, driving CXCL-10 (IP-10) and CXCL-9 chemokine-mediated activated T-cell and monocyte/macrophage tissue recruitment, may define 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 5 mg/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 h. Secondary endpoints included 28-day mortality, dynamic cytokine profiles, 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 years, range 31-80), race-ethnic minorities (13/18, 72%), lymphopenic (13/18, 72%), steroid-treated (17/18, 94%), with a median ferritin of 1953 ng/ml. Sixteen patients (89%) met the primary endpoint within a median of 4 days; 14/18 (78%) were discharged in a median of 8 days and were alive at 28-day follow-up. Three deaths were attributed to secondary lung infection. Mean plasma IP-10 levels declined sharply from 9183 to 483 pg/ml at Day 3 and 146 pg/ml at Day 14/discharge. Significant Day 3 declines in IFN-, TNFα, IL-27, CRP, and ferritin occurred. 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: Infliximab-abda may rapidly abrogate pathological inflammatory signaling to facilitate clinical recovery in severe and critical COVID-19.

Keywords: COVID-19; CXCL-10; IP-10; TNFα; infliximababda; respiratory failure.

Conflict of interest statement

The authors have no conflicts of interest to declare.

© The Association for Clinical and Translational Science 2021.

Figures

Fig. 1.
Fig. 1.
Consort diagram. Hospitalized patients with SARS-COV2 infection and pneumonia were referred to the infliximab-abda study team for evaluation.
Fig. 2.
Fig. 2.
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 the last follow-up (discharged, alive, or dead) is indicated. ECMO, extracorporeal membrane oxygenation.
Fig. 3.
Fig. 3.
Decline in key cytokines and inflammatory markers following infliximab-abda 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.
Fig. 4.
Fig. 4.
Concept map of a feed-forward signaling loop implicating TNFα in the pathogenesis of COVID-19 respiratory failure.

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