key: cord-0817863-onz6vfre
authors: Titanji, Boghuma K; Farley, Monica M; Mehta, Ashish; Connor-Schuler, Randi; Moanna, Abeer; Cribbs, Sushma K; O’Shea, Jesse; DeSilva, Kathryn; Chan, Bonnie; Edwards, Alex; Gavegnano, Christina; Schinazi, Raymond F; Marconi, Vincent C
title: Use of Baricitinib in Patients with Moderate and Severe COVID-19
date: 2020-06-29
journal: Clin Infect Dis
DOI: 10.1093/cid/ciaa879
sha: 5ae230357f1612677eaefdf9a2639f5808eb6e9b
doc_id: 817863
cord_uid: onz6vfre

Cytokine storm and hyperinflammation are associated with increased mortality in COVID-19. In this small uncontrolled cohort of patients with moderate-severe COVID-19, treatment with baricitinib plus hydroxychloroquine was associated with recovery in 11 of 15 patients. Baricitinib for the treatment of COVID-19 should be further investigated in randomized controlled clinical trials.

Coronavirus Infectious Disease-19 (COVID-19), caused by Severe Acute Respiratory Virus Syndrome Coronavirus-2 (SARS-CoV-2) has led to over 8 million confirmed infections worldwide with an estimated global mortality of 5.6% as of June 17 th 2020 1 . Virus-driven hyperinflammation and cytokine storm syndrome are important features of severe COVID-19 2 . A multi-center, retrospective study of 150 patients with severe COVID-19 showed a strong association between elevated ferritin and interleukin (IL)-6 levels and adverse clinical outcomes 3 . Recognizing and treating cytokine storm may present a viable approach to reducing the mortality from COVID-19. The Janus kinase (JAK) 1/2 inhibitor, baricitinib, is an attractive candidate due to its properties as a potent anti-inflammatory agent and its hypothesized off-target antiviral effects against SARS-CoV-2 4, 5 . In this brief report of 15 patients, we present the clinical use of baricitinib for the treatment of patients with moderatesevere COVID-19.

This study was conducted at the Atlanta Veterans Affairs Medical Center (VAMC) with approvals from the Emory University Institutional Review Board and Atlanta VAMC Office of Research and Development. Data were abstracted from the electronic health records between March 1, 2020 and April 18, 2020.

Patients had laboratory confirmed COVID-19, diagnosed by quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) testing of oropharyngeal, nasopharyngeal or tracheal aspirate samples and were treated at the discretion of the medical team with a combination of hydroxychloroquine and baricitinib if they fulfilled at least one of the following criteria: 1) evidence of pneumonia on lung imaging and requiring supplemental oxygen on admission or development of a new oxygen requirement during the course of their hospitalization 2) moderate disease requiring hospitalization (e.g., severe diarrhea requiring volume resuscitation, encephalopathy, evidence of end-A c c e p t e d M a n u s c r i p t organ damage); 3) elevated or rising inflammatory markers during hospitalization. Statistical analyses were performed using GraphPad and R software.

Moderate COVID-19 patients met any of the following criteria: fever, confusion, severe diarrhea, dyspnea, evidence of pneumonia on lung imaging, requiring hospitalization for ongoing medical care but not ICU-level care. Severe COVID-19 patients met any of the following criteria; respiratory rate (RR) >30 times/min, oxygen saturation by pulse oximetry 93% at rest or PaO2/FiO2<300 mmHg. However, 20% of patients progress to moderate-severe disease and require hospitalization and peak viral loads occur approximately one week after the initial onset of symptoms 2 . Disease severity is marked by hyperinflammation and cytokine storm syndromes with increased levels of type II (gamma) which drives IL-6 expression through the JAK-STAT pathway 2 .

In animal models of SARS and MERS, the initial (Type 1) interferon response has beneficial effects in the early phases of disease, but may become damaging in the latter phases (Type II) 8 . This suggests that patients most likely to benefit from treatment with JAK1/2 inhibitors are those with evidence of disease progression and hyperinflammation characterized by rising levels of inflammatory markers, progressive pulmonary disease, and overall clinical deterioration. In addition, at a 2-4 mg daily dosage, baricitinib primarily inhibits Type II interferon and less likely Type I interferon A c c e p t e d M a n u s c r i p t responses. Baricitinib is FDA approved for the treatment of RA 10 . Long-term use has been associated with increased risk for infections and thrombo-embolic events 11 . These adverse events are less likely to occur with a limited course of therapy as received by patients in this cohort. However, it is unclear whether the thrombotic events noted in 3 of the 15 patients were related to baricitinib therapy, were general nosocomial complications, or occurred as part of the pathogenesis of COVID-19 disease.

This study has several limitations. It is a small non-randomized cohort and does not include controls.

Thus, it is unclear if these patients would have improved without baricitinib treatment. All patients were concomitantly treated with hydroxychloroquine, which has in-vitro antiviral activity against SARS-CoV-2 as well as anti-inflammatory properties 12 

World Health Organization. Coronavirus Disease 2019 -Situation report number 148

COVID-19: consider cytokine storm syndromes and immunosuppression

Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China

Baricitinib as potential treatment for 2019-nCoV acute respiratory disease

COVID-19: combining antiviral and anti-inflammatory treatments

Baricitinib therapy in COVID-19: A pilot study on safety and clinical impact

Mechanism of baricitinib supports artificial intelligence-predicted testing in COVID-19 patients

IFN-I response timing relative to virus replication determines MERS coronavirus infection outcomes

Estimates of the severity of coronavirus disease 2019: a model-based analysis

Baricitinib for the treatment of rheumatoid arthritis and systemic lupus erythematosus: a 2019 update

THU0211 Meta-analysis of serious infections with baricitinib, tofacitinib and biologic dmards in rheumatoid arthritis

In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)

Vincent Marconi and Raymond F Schinazi are partially funded by -Emory University Center for AIDS Research (AI050409). Raymond F Schinazi and Christina Gavegnano are funded in part by NIH grant 5-R01-MH116695.

Dr. Vincent C. Marconi has consulted or received research support from ViiV, Gilead, Lilly and Bayer. Dr. Raymond Schinazi served as an unpaid consultant for Eli Lilly whose drugs are being evaluated in the research described in this paper. In addition, Dr. Schinazi owns shares in Eli Lilly and Gilead, and has been issued patents 20190134039, 10022378, and 9662332. The terms of this arrangement have been reviewed and approved by Emory University in accordance with its conflict of interest policies. All other authors do not have any conflicts to declare.

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