key: cord-0046252-30ihtibn authors: Cantini, Fabrizio; Niccoli, Laura; Nannini, Carlotta; Matarrese, Daniela; Natale, Massimo Edoardo Di; Lotti, Pamela; Aquilini, Donatella; Landini, Giancarlo; Cimolato, Barbara; Pietro, Massimo Antonio Di; Trezzi, Michele; Stobbione, Paolo; Frausini, Gabriele; Navarra, Assunta; Nicastri, Emanuele; Sotgiu, Giovanni; Goletti, Delia title: Retrospective, multicenter study on the impact of baricitinib in COVID-19 moderate pneumonia date: 2020-06-24 journal: J Infect DOI: 10.1016/j.jinf.2020.06.052 sha: 40ea0e6a24a4689827c6c0e3f811cf863860982a doc_id: 46252 cord_uid: 30ihtibn • Baricitinib, an anti-JAK1/JAK2, reduces cytokine release and SARS-Co-V2 entry; • In a retrospective multicenter study baricitinib reduces COVID-19 mortality rate; • Baricitinib reduces Intensive Care Unit admissions of COVID-19 pneumonia; • Baricitinb reduces SARS-CoV-2 viral burden detected by nasopharyngeal swab; • Baricitinib used for 2 weeks was not associated with serious adverse events.  Baricitinib, an anti-JAK1/JAK2, reduces cytokine release and SARS-Co-V2 entry  In a retrospective multicenter study baricitinib reduces COVID-19 mortality rate  Baricitinib reduces Intensive Care Unit admissions of COVID-19 pneumonia  Baricitinb reduces SARS-CoV-2 viral burden detected by nasopharyngeal swab  Baricitinib used for 2 weeks was not associated with serious adverse events As recently discussed in the Journal [1] , baricitinib was safe and improved the clinical conditions in 12 patients with mild-moderate Coronavirus Disease 2019 (COVID-19) pneumonia. It is known that severe symptoms of COVID-19 may develop after a median of 8-days from illness-onset, with a median time to Intensive Care Unit (ICU) admission of 5 days from the dyspnea occurrence [2] . Currently, no antiviral therapies or vaccines are available. An uncontrolled immune response [3] is observed and is likely involved in tissues injury [4] . Baricitinib is an anti-Janus kinase inhibitor-1 and -2, and has a dual action on COVID-19 therapy including the inhibition of cytokine release and SARS-CoV-2 endocytosis [5] . Based on this evidence, we conducted an observational, retrospective, longitudinal multicenter-study in consecutive-hospitalized patients with COVID-19 moderate pneumonia to evaluate the 2-week effectiveness and safety of baricitinib combined with antivirals (lopinavir/ritonavir) compared with the standard of care therapy which was hydroxychloroquine and lopinavir/ritonavir. Primary aim was to evaluate the mortality rate; secondary aims were to evaluate the rate of ICU transfer, hospital discharge, improvement of respiratory parameters, adverse events (AEs) occurrence. Moreover, associations between therapy and modification of respiratory parameters and C-Reactive Protein (CRP), interleukin-6 (IL-6), lymphocyte percentage were evaluated. Baricitinib-treated arm included consecutive-hospitalized patients,18 years-older, SARS-CoV-2 naso-pharingeal swab-positive, with a moderate pneumonia characterized by typical symptoms, radiological findings of pneumonia, SpO2 >92% on room air,and PaO2/FiO2 100-300 mmHg, admitted between March 15 th -May 5 th , 2020. Baricitinib 4mg/day was provided orally associated with lopinavir/ritonavir tablets 250 mg/bid for 2 weeks. Control-arm included all consecutive-hospitalized patients from February 20 th -March 15 th , 2020 with moderate COVID-19 pneumonia, 18 years-older, treated with hydroxychloroquine (HCLR) and lopinavir/ritonavir. Exclusion criteria were: history of thrombophlebitis, latent tuberculosis infection [6, 7] , HBV or HCV infection, current varicella zoster or bacterial infection, pregnancy, lactation, contraceptive pills intake, previous (last 5 years) or current malignancy, neutrophil count<1.0x10 9 /L, lymphocyte count<0.2 x10 9 /L, platelets count<50 x10 9 /L, transaminases values 4fold higher than the upper normal limit. Prophylactic anti-thrombotic therapy with low-weight molecular heparin was administered. Patients had supportive therapy (O 2 supply, rehydration, diuretics, anti-hypertensive, antibiotics) if needed. Corticosteroids were not allowed. If patients were discharged earlier than 2 weeks, they were requested to continue the ongoing therapy until the scheduled 14-days. Temperature, respiratory and pulse rate, arterial blood gas analysis, blood pressure, blood cell count, liver and kidney tests function were daily assessed. IL-6 serum levels of (RayBio® Human IL-6 ELISA Kit, RayBiotech Co.,USA) were tested at baseline, week 1 and 2. Since low lymphocyte percentage can predict a poor prognosis [6] , patients were stratified at baseline as: lymphocytes >20%, >5% to <20%, and <5%. Patients provided a written-informed consent. The off-label use of baricitinib was approved by the Hospital-Committee and Ethical-Committee of Toscana-Region (Code: BARIC-off; 17261; approval date: May 5 th 2020). Mann-Whitney U test was used to compare quantitative variables; Wilcoxon test for paired data; Chi-squared or Fisher's exact test for categorical variables. A two-tailed p-value <0.05 was considered significant. At baseline, 113 patients were in the baricitinib-arm, and 78 in the control-arm ( Table 1 Seven AEs, not requiring the therapy discontinuation, were recorded in the baricitinib-arm, including transaminase increase in 4 (3.5%) patients, epistaxis due to heparin overdose in 1 patient, urinary infection in 1 patient, and oral candidiasis in 1 patient. The results of the present observational, retrospective, longitudinal, multicenter-study in 113 consecutive-hospitalized patients with moderate pneumonia confirm the effectiveness and safety of baricitinib in patients with moderate COVID-19 pneumonia previously reported [1] . Baricitinibtherapy was started in the early phase of COVID-19 disease (median: 7-days from symptoms onset), and the early treatment and the rapid action of the drug may explain the low number of ICU admissions and deaths. The importance of early starting COVID-19 therapies is highlighted in trials of tociluzimab showing a higher efficacy to reduce ICU admission if administered during the initial phase of pneumonia [8, 9] . Interestingly, a significant reduction of positive naso-pharingeal swabs was observed in the baricitinib-arm at discharge, with only 12.5% positive-swabs compared to 40% in the controlgroup, confirming the anti-inflammatory and anti-viral effects of the baricitinib recently described in 4 patients [10] . The short-term administration of the drug compared to the long-term treatment in rheumatoid arthritis, may probably explain the absence of serious AEs. In conclusion, baricitinib is a promising and safe therapy in patients with moderate COVID-19 pneumonia. A randomized clinical trial is needed to confirm our findings. Disclosure of potential conflict of interests All Authors have nothing to disclose. This work was not supported by any funding. Baricitinib therapy in COVID-19: A pilot study on safety and clinical impact Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China Cytokine storm intervention in the early stages of COVID-19 pneumonia Clinicopathological and immunohistochemical findings from autopsy of patient with COVID-19 COVID-19: combining antiviral and anti-inflammatory treatments Update on tuberculosis biomarkers: From correlates of risk, to correlates of active disease and of cure from disease Tocilizumab treatment in COVID-19: a single center experience Effective treatment of severe COVID -19 patients with tocilizumab Mechanism of baricitinib supports artificial intelligence-predicted testing in COVID-19 patients We are grateful to engineers Alessandra Cantini and Marco Bicchi for their assistance in data imputing in the electronic database, and in the statistical analysis.The authors are grateful to all the patients, nurses and physicians who helped to perform this study.References.