ABSTRACT
A central paradigm of immunity is that interferon (IFN) mediated antiviral responses precede the pro-inflammatory ones, optimizing host protection and minimizing collateral damage. Here, we report that for COVID-19 this does not apply. By investigating temporal IFN and inflammatory cytokine patterns in 32 COVID-19 patients hospitalized for pneumonia and longitudinally followed for the development of respiratory failure and death, we reveal that IFN-{lambda} and type I IFN production is both diminished and delayed, induced only in a fraction of patients as they become critically ill. On the contrary, pro-inflammatory cytokines such as TNF, IL-6 and IL-8 are produced before IFNs, in all patients, and persist for a prolonged time. By comparison, in 16 flu patients hospitalized for pneumonia with similar clinicopathological characteristics to COVID-19 and 24 milder non-hospitalized flu patients IFN-{lambda} and type I IFN are robustly induced, earlier, at higher levels and independently of disease severity, while pro-inflammatory cytokines are only acutely and transiently produced. Notably, higher IFN-{lambda} levels in COVID-19 patients correlate with lower viral load in bronchial aspirates and faster viral clearance, and a higher IFN-{lambda}:type I IFN ratio with improved outcome of critically ill patients. Moreover, altered cytokine patterns in COVID-19 patients correlate with longer hospitalization time and higher incidence of critical disease and mortality compared to flu. These data point to an untuned antiviral response in COVID-19 contributing to persistent viral presence, hyperinflammation and respiratory failure.
Subject(s)
Pneumonia , Critical Illness , Death , COVID-19 , Respiratory InsufficiencyABSTRACT
Background: As novel coronavirus disease (COVID-19) cases continue to steeply rise globally within an unprecedented short period of time, solid evidence from large randomised controlled trials is still lacking. Currently, numerous trials testing potential treatment and preventative options are undertaken globally. Objectives: We summarised all currently registered clinical trials examining treatment and prevention options for COVID-19 pneumonia. Additionally, we evaluated the quality of the retrieved interventional studies. Data sources: The ClinicalTrials.gov, the Chinese Clinical Trial Registry and the European Union Clinical Trials Register were systematically searched. Study eligibility criteria: Registered clinical trials examining treatment and/or prevention options for COVID-19 were included. No language, country or study design restrictions were applied. Withdrawn, cancelled studies and trials not reporting therapeutic or preventative strategies for COVID-19 were excluded. Participants and interventions: No restrictions in terms of participants' age and medical background or type of intervention were enforced. Methods: The registries were searched using the term "coronavirus" or "COVID-19" from their inception until 26th March 2020. Additional manual search of the registries was also performed. Eligible studies were summarised and tabulated. Interventional trials were methodologically analysed, excluding expanded access studies and trials testing Traditional Chinese Medicine. Results: In total, 309 trials evaluating therapeutic management options, 23 studies assessing preventive strategies and 3 studies examining both were retrieved. Interventional treatment studies were mostly randomised (n=150, 76%) and open-label (n=73, 37%) with a median number of planned inclusions of 90 (IQR 40-200). Major categories of interventions that are currently being investigated are discussed. Conclusion: Numerous clinical trials have been registered since the onset of the COVID-19 pandemic. Summarised data on these trials will assist physicians and researchers to promote patient care and guide future research efforts for COVID-19 pandemic containment. However, up to the end of March, 2020, significant information concerning reported trials was lacking.