ABSTRACT
A cytokine storm induces acute respiratory distress syndrome, the main cause of death in coronavirus disease 2019 (COVID-19) patients. However, the detailed mechanisms of cytokine induction due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain unclear. To examine the cytokine production in COVID-19, we mimicked the disease in SARS-CoV-2-infected alveoli by adding the lysate of SARS-CoV-2-infected cells to cultured macrophages or induced pluripotent stem cell-derived myeloid cells. The cells secreted interleukin (IL)-6 after the addition of SARS-CoV-2-infected cell lysate. Screening of 25 SARS-CoV-2 protein-expressing plasmids revealed that the N protein-coding plasmid alone induced IL-6 production. The addition of anti-N antibody further enhanced IL-6 production, but the F(ab’)2 fragment did not. Sera from COVID-19 patients also enhanced IL-6 production, and sera from patients with severer disease induced higher levels of IL-6. These results suggest that anti-N antibody promotes IL-6 production in SARS-CoV-2-infected alveoli, leading to the cytokine storm of COVID-19. (150 words)
Subject(s)
COVID-19ABSTRACT
Condition:
COVID-19 infections diseaseIntervention:
JH509 or placebo is administered by inhalation for 15 minutes using a disposable nebulizer, twice daily (morning and evening) for 7 days. If symptoms consistently exist, the drug administration course can be extended up to 10 days. Adverse events will be observed up to 28 days after starting drug administration.Primary outcome:
Time to clinical improvement by two points on a 7-point ordinal scaleCriteria:
Inclusion criteria: 1.Written informed consent has been obtained from the participants with the age of over 20 years at the time of signing the informed consent.2.SARS-CoV-2 infection is diagnosed by RT-PCR within 72 hours before starting drug administration.
3.Less than 6 days from onset of COVID-19 symptoms to starting the administration of the investigational drug. The symptoms are defined as one or more of the following: fever (37.5 or higher), respiratory symptoms (cough, shortness of breath, chest pain, sore throat, running nose, nasal congestion, etc.), headache, malaise, abdominal pain, diarrhea, nausea, vomiting, loss of smell, loss of taste, or other COVID-19 symptoms defined by investigators or physicians.
4.Have at least one of the following findings.
Oxygen saturation (SpO2) measured by pulse oximeter is less than 96% but more than 93%.
Chest X-ray or CT scan shows pneumonia findings suggestive of COVID-19 infection
Exclusion criteria: 1.History of hypersensitivity to interferon or Novaferon or any excipients of interferon or Novaferon.
2.Having received other antiviral treatments (Favipiravir, Remdesivir, interferon, etc.)
3.CTCAE Grade 3 or higher liver dysfunction (ALT / AST> 5ULN) or renal dysfunction (eGFR <30 mL / min / 1.73 m2)
4.Active infections or other medical conditions that contraindicate inhalation therapy
ABSTRACT
We administered tocilizumab into 13 severe-to-critically ill patients with coronavirus disease 2019 (COVID-19) for compassionate use in combination with potential anti-viral agents in those who required an oxygen supply and showed increased laboratory inflammatory markers such as C-reactive protein (CRP) and ferritin. One injection of tocilizumab led to rapid improvements in clinical features, inflammatory findings, and oxygen supply in seven patients with severe COVID-19 and substantial amelioration in two patients who were critically ill, whereas four patients, who exhibited rapidly worsened respiratory function, required artificial ventilatory support even after tocilizumab treatment. Three of these four patients ultimately recovered from deterioration after methylprednisolone treatment. Administration of tocilizumab did not affect viral elimination nor IgG production specific for the virus. Compared with well-responding patients, rapidly-worsened patients showed a significantly higher ratio of ferritin vs. CRP. These findings suggest that tocilizumab has beneficial effects in severe-to-critically ill patients with COVID-19; however, in some cases, addition of methylprednisolone is required for disease rescue.