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
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Abstract
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
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SciScore for 10.1101/2021.05.29.21258010: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics Consent: Patients (Figure 1): Eligible subjects were at least 18 years old, could provide informed consent, had pneumonia evidenced by chest X-ray or computerized tomography, and laboratory (reverse transcriptase-polymerase chain reaction) confirmed infection for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with at least one of the following: respiratory frequency ≥30/min, blood oxygen saturation ≤93% on room air, partial pressure of arterial oxygen to fraction of inspired oxygen ratio (PaO2/FiO2) <300, worsening of lung involvement defined as an increase in number and/or extension of pulmonary areas of consolidation, need for increased FiO2 to maintain stable oxygen … SciScore for 10.1101/2021.05.29.21258010: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics Consent: Patients (Figure 1): Eligible subjects were at least 18 years old, could provide informed consent, had pneumonia evidenced by chest X-ray or computerized tomography, and laboratory (reverse transcriptase-polymerase chain reaction) confirmed infection for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with at least one of the following: respiratory frequency ≥30/min, blood oxygen saturation ≤93% on room air, partial pressure of arterial oxygen to fraction of inspired oxygen ratio (PaO2/FiO2) <300, worsening of lung involvement defined as an increase in number and/or extension of pulmonary areas of consolidation, need for increased FiO2 to maintain stable oxygen saturation, or worsening oxygen saturation of >3% with stable FiO2.
IRB: Study approval: The study was approved by the institutional review board and written informed consent was received from participants or designees prior to inclusion.Sex as a biological variable not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Table 2: Resources
Software and Algorithms Sentences Resources 11 Statistics: Mean ferritin, CRP, and cytokine levels on Day 1 and the mean dynamic change on Day 3 and Day 14 were compared using pairwise ratio t-tests (GraphPad Prism). GraphPadsuggested: (GraphPad Prism, RRID:SCR_002798)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04425538 Completed A Phase 2 Trial of Infliximab in Coronavirus Disease 2019 (C… NCT04593940 Recruiting Immune Modulators for Treating COVID-19 Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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