BACKGROUND. Patients with coronavirus disease 2019 (COVID-19) develop pneumonia generally associated with lymphopenia and a severe inflammatory response due to uncontrolled cytokine release. These mediators are transcriptionally regulated by the JAK/STAT signaling pathways, which can be disabled by small molecules.METHODS. We treated a group of patients (n = 20) with baricitinib according to an off-label use of the drug. The study was designed as an observational, longitudinal trial and approved by the local ethics committee. The patients were treated with 4 mg baricitinib twice daily for 2 days, followed by 4 mg per day for the remaining 7 days. Changes in the immune phenotype and expression of phosphorylated STAT3 (p-STAT3) in blood cells were evaluated and correlated with serum-derived cytokine levels and antibodies against severe acute respiratory syndrome-coronavirus 2 (anti-SARS-CoV-2). In a single treated patient, we also evaluated the alteration of myeloid cell functional activity.RESULTS. We provide evidence that patients treated with baricitinib had a marked reduction in serum levels of IL-6, IL-1 beta, and TNF-alpha, a rapid recovery of circulating T and B cell frequencies, and increased antibody production against the SARS-CoV-2 spike protein, all of which were clinically associated with a reduction in the need for oxygen therapy and a progressive increase in the P/F (PaO2, oxygen partial pressure/FiO(2), fraction of inspired oxygen) ratio.CONCLUSION. These data suggest that baricitinib prevented the progression to a severe, extreme form of the viral disease by modulating the patients' immune landscape and that these changes were associated with a safer, more favorable clinical outcome for patients with COVID-19 pneumonia.

Baricitinib restrains the immune dysregulation in patients with severe COVID-19 / V. Bronte, S. Ugel, E. Tinazzi, A. Vella, F. De Sanctis, S. Canè, V. Batani, R. Trovato, A. Fiore, V. Petrova, F. Hofer, R.M. Barouni, C. Musiu, S. Caligola, L. Pinton, L. Torroni, E. Polati, K. Donadello, S. Friso, F. Pizzolo, M. Iezzi, F. Facciotti, P.G. Pelicci, D. Righetti, P. Bazzoni, M. Rampudda, A. Comel, W. Mosaner, C. Lunardi, O. Olivieri. - In: THE JOURNAL OF CLINICAL INVESTIGATION. - ISSN 1558-8238. - 130:12(2020 Dec 01), pp. 6409-6416. [10.1172/JCI141772]

Baricitinib restrains the immune dysregulation in patients with severe COVID-19

P.G. Pelicci;
2020

Abstract

BACKGROUND. Patients with coronavirus disease 2019 (COVID-19) develop pneumonia generally associated with lymphopenia and a severe inflammatory response due to uncontrolled cytokine release. These mediators are transcriptionally regulated by the JAK/STAT signaling pathways, which can be disabled by small molecules.METHODS. We treated a group of patients (n = 20) with baricitinib according to an off-label use of the drug. The study was designed as an observational, longitudinal trial and approved by the local ethics committee. The patients were treated with 4 mg baricitinib twice daily for 2 days, followed by 4 mg per day for the remaining 7 days. Changes in the immune phenotype and expression of phosphorylated STAT3 (p-STAT3) in blood cells were evaluated and correlated with serum-derived cytokine levels and antibodies against severe acute respiratory syndrome-coronavirus 2 (anti-SARS-CoV-2). In a single treated patient, we also evaluated the alteration of myeloid cell functional activity.RESULTS. We provide evidence that patients treated with baricitinib had a marked reduction in serum levels of IL-6, IL-1 beta, and TNF-alpha, a rapid recovery of circulating T and B cell frequencies, and increased antibody production against the SARS-CoV-2 spike protein, all of which were clinically associated with a reduction in the need for oxygen therapy and a progressive increase in the P/F (PaO2, oxygen partial pressure/FiO(2), fraction of inspired oxygen) ratio.CONCLUSION. These data suggest that baricitinib prevented the progression to a severe, extreme form of the viral disease by modulating the patients' immune landscape and that these changes were associated with a safer, more favorable clinical outcome for patients with COVID-19 pneumonia.
COVID-19; Immunology; Innate immunity; Aged; Aged, 80 and over; Azetidines; B-Lymphocytes; Cytokines; Female; Humans; Longitudinal Studies; Male; Middle Aged; Purines; Pyrazoles; Severity of Illness Index; Sulfonamides; T-Lymphocytes; COVID-19; Off-Label Use; SARS-CoV-2;
Settore MED/04 - Patologia Generale
1-dic-2020
Article (author)
File in questo prodotto:
File Dimensione Formato  
141772.3-20210401134110-covered-e0fd13ba177f913fd3156f593ead4cfd.pdf

accesso riservato

Tipologia: Publisher's version/PDF
Dimensione 1.54 MB
Formato Adobe PDF
1.54 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
Pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/930004
Citazioni
  • ???jsp.display-item.citation.pmc??? 152
  • Scopus 185
  • ???jsp.display-item.citation.isi??? 181
social impact