Prolonged Low-Dose Methylprednisolone in Patients With Severe COVID-19 Pneumonia

Francesco Salton; Paola Confalonieri; G Umberto Meduri; Pierachille Santus; Sergio Harari; Raffaele Scala; Simone Lanini; Valentina Vertui; Tiberio Oggionni; Antonella Caminati; Vincenzo Patruno; Mario Tamburrini; Alessandro Scartabellati; Mara Parati; Massimiliano Villani; Dejan Radovanovic; Sara Tomassetti; Claudia Ravaglia; Venerino Poletti; Andrea Vianello; Anna Talia Gaccione; Luca Guidelli; Rita Raccanelli; Paolo Lucernoni; Donato Lacedonia; Maria Pia Foschino Barbaro; Stefano Centanni; Michele Mondoni; Matteo Davì; Alberto Fantin; Xueyuan Cao; Lucio Torelli; Antonella Zucchetto; Marcella Montico; Annalisa Casarin; Micaela Romagnoli; Stefano Gasparini; Martina Bonifazi; Pierlanfranco D'Agaro; Alessandro Marcello; Danilo Licastro; Barbara Ruaro; Maria Concetta Volpe; Reba Umberger; Marco Confalonieri

doi:10.1093/ofid/ofaa421

Prolonged Low-Dose Methylprednisolone in Patients With Severe COVID-19 Pneumonia

Open Forum Infect Dis. 2020 Sep 12;7(10):ofaa421. doi: 10.1093/ofid/ofaa421. eCollection 2020 Oct.

Authors

Francesco Salton¹, Paola Confalonieri¹, G Umberto Meduri², Pierachille Santus³, Sergio Harari⁴, Raffaele Scala⁵, Simone Lanini⁶, Valentina Vertui⁷, Tiberio Oggionni⁷, Antonella Caminati⁸, Vincenzo Patruno⁹, Mario Tamburrini¹⁰, Alessandro Scartabellati¹¹, Mara Parati¹¹, Massimiliano Villani¹¹, Dejan Radovanovic³, Sara Tomassetti¹², Claudia Ravaglia¹³, Venerino Poletti¹³, Andrea Vianello¹⁴, Anna Talia Gaccione¹⁵, Luca Guidelli⁵, Rita Raccanelli⁸, Paolo Lucernoni¹⁵, Donato Lacedonia¹⁶, Maria Pia Foschino Barbaro¹⁶, Stefano Centanni¹⁷, Michele Mondoni¹⁷, Matteo Davì¹⁷, Alberto Fantin⁹, Xueyuan Cao¹⁸, Lucio Torelli¹⁹, Antonella Zucchetto²⁰, Marcella Montico²⁰, Annalisa Casarin²¹, Micaela Romagnoli²², Stefano Gasparini²³, Martina Bonifazi²³, Pierlanfranco D'Agaro²⁴, Alessandro Marcello²⁵, Danilo Licastro²⁶, Barbara Ruaro¹, Maria Concetta Volpe²⁷, Reba Umberger¹⁸, Marco Confalonieri^{1

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Affiliations

¹ Department of Pulmonology, University Hospital of Cattinara, Trieste, Italy.
² Pulmonary, Critical Care, and Sleep Medicine Service and Research Service, Memphis VA Medical Center and Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
³ Department of Biomedical and Clinical Sciences (DIBIC), Università degli Studi di Milano, "L. Sacco" University Hospital, ASST-Fatebenefratelli-Sacco, Milano, Italy.
⁴ Department of Medical Sciences, San Giuseppe Hospital MultiMedica IRCCS, and Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy.
⁵ Pulmonology and Respiratory Intensive Care Unit, S. Donato Hospital, Arezzo, Italy.
⁶ National Institute for the Infectious Diseases "L. Spallanzani," Rome, Italy.
⁷ Pulmonology Unit, Policlinico San Matteo IRCCS, Pavia, Italy.
⁸ Division of Pulmonary and Critical Care Medicine, San Giuseppe Hospital MultiMedica IRCCS, Milan, Italy.
⁹ Pulmonology Department, S. Maria della Misericordia University Hospital, Udine, Italy.
¹⁰ S.C. Pneumologia, Azienda Ospedaliera Friuli Occidentale, Pordenone, Italy.
¹¹ Department of Pulmonology and Respiratory High-Dependency Unit, Ospedale Maggiore, Crema, Italy.
¹² Department of Experimental and Clinical Medicine, Careggi University Hospital, Florence, Italy.
¹³ Department of Respiratory and Thorax Diseases, GB Morgagni Hospital, Forlì, Italy.
¹⁴ Division of Respiratory Pathophysiology and Intensive Care, University-City Hospital, Padova, Italy.
¹⁵ Pulmonology Department, Vittorio Veneto Hospital, Vittorio Veneto, Italy.
¹⁶ Department of Medical and Surgical Science-University of Foggia, Policlinico Riuniti, Italy.
¹⁷ Pulmonology Department, S. Paolo Hospital, Milan, Italy.
¹⁸ Department of Acute and Tertiary Care, College of Nursing, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
¹⁹ Department of Clinical, Surgery and Health Sciences, University of Trieste, Trieste, Italy.
²⁰ Scientific Directorate, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy.
²¹ Centre for Health Services and Clinical Research, University of Hertfordshire, Hatfield, UK.
²² Pulmonary Unit, Treviso Hospital, Treviso, Italy.
²³ Department of Biomedical Sciences and Public Health, Polytechnic University of Marche Region-Azienda Ospedali Riuniti, Ancona, Italy.
²⁴ Laboratorio di Riferimento per SARS-CoV-2, Regione Friuli-Venezia Giulia, Azienda Sanitaria Universitaria Integrata Giuliano Isontina (ASUGI), University of Trieste, Trieste, Italy.
²⁵ Laboratory of Molecular Virology, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy.
²⁶ ARGO Open Lab Platform for Genome Sequencing, Area Science Park, Trieste, Italy.
²⁷ University of Trieste, Trieste, Italy.

Abstract

Background: In hospitalized patients with coronavirus disease 2019 (COVID-19) pneumonia, progression to acute respiratory failure requiring invasive mechanical ventilation (MV) is associated with significant morbidity and mortality. Severe dysregulated systemic inflammation is the putative mechanism. We hypothesize that early prolonged methylprednisolone (MP) treatment could accelerate disease resolution, decreasing the need for intensive care unit (ICU) admission and mortality.

Methods: We conducted a multicenter observational study to explore the association between exposure to prolonged, low-dose MP treatment and need for ICU referral, intubation, or death within 28 days (composite primary end point) in patients with severe COVID-19 pneumonia admitted to Italian respiratory high-dependency units. Secondary outcomes were invasive MV-free days and changes in C-reactive protein (CRP) levels.

Results: Findings are reported as MP (n = 83) vs control (n = 90). The composite primary end point was met by 19 vs 40 (adjusted hazard ratio [aHR], 0.41; 95% CI, 0.24-0.72). Transfer to ICU and invasive MV were necessary in 15 vs 27 (P = .07) and 14 vs 26 (P = .10), respectively. By day 28, the MP group had fewer deaths (6 vs 21; aHR, 0.29; 95% CI, 0.12-0.73) and more days off invasive MV (24.0 ± 9.0 vs 17.5 ± 12.8; P = .001). Study treatment was associated with rapid improvement in PaO₂:FiO₂ and CRP levels. The complication rate was similar for the 2 groups (P = .84).

Conclusion: In patients with severe COVID-19 pneumonia, early administration of prolonged MP treatment was associated with a significantly lower hazard of death (71%) and decreased ventilator dependence. Treatment was safe and did not impact viral clearance. A large randomized controlled trial (RECOVERY trial) has been performed that validates these findings. Clinical trial registration. ClinicalTrials.gov NCT04323592.

Keywords: ARDS; COVID-19; SARS-CoV-2; methylprednisolone; pneumonia.

Associated data

ClinicalTrials.gov/NCT04323592