Endogenous IFNβ expression predicts outcome in critical patients with COVID-19

Abstract

Although the subject of intensive preclinical and clinical research, controversy on the protective versus deleterious effects of endogenous and therapeutic IFN on COVID-19 remains. Some apparently conflicting results are most likely due to the intricacy of IFN subtypes (ie, type I: interferon alfa and interferon beta, type III: interferon lambda), timing and mode of administration (ie, nebulised or subcutaneous), and clinical groups that are targeted (ie, patients with asymptomatic, mild, moderate, or severe or critical COVID-19). A phase 2 clinical trial reporting the use of peginterferon lambda achieved its primary clinical outcome (ie, change in clinical condition on the WHO Ordinal Scale for Clinical Improvement) in patients with COVID-19 who were admitted to hospital.1Feld JJ Kandel C Biondi MJ et al.Peginterferon lambda for the treatment of outpatients with COVID-19: a phase 2, placebo-controlled randomised trial.Lancet Respir Med. 2021; (published online Feb 5.)https://doi.org/10.1016/S2213-2600(20)30566-XSummary Full Text Full Text PDF PubMed Scopus (95) Google Scholar Another phase 2 clinical trial reporting the use of interferon beta-1a achieved its virological outcome (ie, proportion of patients who were negative for SARS-CoV-2 RNA on day 7 after the injection) in ambulatory patients with COVID-19.2Monk PD Marsden RJ Tear VJ et al.Safety and efficacy of inhaled nebulised interferon beta-1a (SNG001) for treatment of SARS-CoV-2 infection: a randomised, double-blind, placebo-controlled, phase 2 trial.Lancet Respir Med. 2021; 9: 196-206Summary Full Text Full Text PDF PubMed Scopus (244) Google Scholar As set forth previously,3Park A Iwasaki A Type I and type III interferons – induction, signaling, evasion, and application to combat COVID-19.Cell Host Microbe. 2020; 27: 870-878Summary Full Text Full Text PDF PubMed Scopus (457) Google Scholar understanding the different kinetics of endogenous IFN production in patients with mild and severe COVID-19, relative to viral replication, will help to identify the therapeutic window. Thus, endogenous IFNs add complexity to the COVID-19 IFN conundrum but have been understudied in patients who are of critical status in intensive care units (ICUs). Within a prospective COVID-19 clinical trial (NCT04327570), we quantified type I (IFNA2 and IFNB1) and type III IFN (IFNL2 and IFNL3) transcripts in nasal mucosa of 57 patients with critical COVID-19, by use of digital transcriptomics technology (nCounter) that was previously validated in a large cohort of patients with acute respiratory infection.4Fukutani KF Nascimento-Carvalho CM Bouzas ML et al.In situ immune signatures and microbial load at the nasopharyngeal interface in children with acute respiratory infection.Front Microbiol. 2018; 92475Crossref PubMed Scopus (6) Google Scholar All patients in ICUs received standard-of-care treatment (ie, corticosteroids, anticoagulants, vasopressors, antibiotics, or a combination, in addition to ventilation or extracorporeal membrane oxygenation) but none received IFN treatment. IFNB1 transcript expression, but not IFNA2, IFNL2, or IFNL3 transcript expression nor viral load (not shown), predicted the length of ICU stay (figure A–C). Multivariate regression suggests IFNB1 expression (β=0·45 [95% CI 0·24–0·67]; p=0·0002) and Acute Physiology and Chronic Health Evaluation II score (β=1·06 [0·49–1·65]; p=0·0009) as independent predictors, whereas viral load, age, gender, body-mass index, or Charlson Comorbidity Index were not. Moreover, IFNB1 expression also predicted worse clinical outcome measured by maximal WHO ordinal scale (Mann-Whitney, p=0·027) or maximal oxygen support (Mann-Whitney, p=0·0068) and a composite score (ie, discharge to rehabilitation centre, hospital stay >60 days, or death; Mann-Whitney p=0·040). Notably, 45% (5 of 11) of patients who were positive for IFNB1 required extracorporeal membrane oxygenation versus 9% (4 of 46) of patients who were negative for IFNB1. Total days on extracorporeal membrane oxygenation was also higher in patients who were positive for IFNB1 (median 24·0 days vs 10·5 days; Mann-Whitney p=0·016). IFNB1 expression also predicted multiorgan involvement, another hallmark of critical COVID-19 (median Sequential Organ Failure Assessment score 7 for patients who were negative for IFNB1 vs 12 for patients who were positive for IFNB1; Mann-Whitney p=0·0072). Surprisingly, IFNB1 expression was not correlated to viral load (figure D), in contrast to IFNA2 (r=0·45; p=0·0007) and IFNL2 and IFNL3 (r=0·47; p=0·0003). In conclusion, endogenous IFNβ production in the nasal mucosa predicts clinical outcome, independent of viral replication or Acute Physiology and Chronic Health Evaluation II score, and should be considered as a prognostic tool in a precision medicine approach of IFN therapy in clinical management of COVID-19. We declare no competing interests. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication. The funder of the study had no role in study, design, data collection, data analysis, data interpretation, or writing the report. Peginterferon lambda for the treatment of outpatients with COVID-19: a phase 2, placebo-controlled randomised trialPeginterferon lambda accelerated viral decline in outpatients with COVID-19, increasing the proportion of patients with viral clearance by day 7, particularly in those with high baseline viral load. Peginterferon lambda has potential to prevent clinical deterioration and shorten duration of viral shedding. Full-Text PDF