Changes in PD-1- and CTLA-4-bearing Blood Lymphocytes in ICU COVID-19 Patients Treated with Favipiravir/Kaletra or Dexamethasone/Remdesivir:  A Pilot Study

Esmaeil Mortaz; Hamidreza Jamaati; Neda K. Dezfuli; Hakime Sheikhzade; Seyed MohammadReza Hashemian; Neda Dalil Roofchayee; Frazaneh Dastan; Payam Tabarsi; Gert Folkerts; Johan Garssen; Sharon Mumby; Ian M Adcock

doi:10.18502/ijaai.v22i1.12012

Esmaeil Mortaz Clinical Tuberculosis and Epidemiology Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
Hamidreza Jamaati Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
Neda K. Dezfuli Center for Vaccine Development, University of Maryland, School of Medicine, Baltimore, MD, United States
Hakime Sheikhzade Clinical Tuberculosis and Epidemiology Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
Seyed MohammadReza Hashemian Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
Neda Dalil Roofchayee Clinical Tuberculosis and Epidemiology Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
Frazaneh Dastan Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
Payam Tabarsi Clinical Tuberculosis and Epidemiology Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
Gert Folkerts Division of Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands
Johan Garssen Division of Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands
Sharon Mumby National Heart and Lung Institute, Imperial College London, London, United Kingdom
Ian M Adcock National Heart and Lung Institute, Imperial College London, London, United Kingdom

DOI: https://doi.org/10.18502/ijaai.v22i1.12012

Keywords: Antiviral therapy; COVID-19; Cytotoxic T-lymphocyte–associated protein 4; Cytokine storm; Program cell death 1; T cells

Abstract

COVID-19, caused by SARS-CoV-2, requires new approaches to control the disease. Programmed cell death protein (PD-1) and cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) play important roles in T-cell exhaustion in severe COVID-19. This study evaluated the frequency of whole blood lymphocytes expressing PD-1 and CTLA-4 in COVID-19 patients upon admission to the intensive care unit (ICU) (i.e., severe) or infection ward (i.e., moderate) and after 7 days of antiviral therapy.

COVID-19 patients were treated with either favipiravir or Kaletra (FK group, 11 severe and 11 moderate) or dexamethasone plus remdesivir (DR group, 7 severe and 10 moderate) for 7 days in a pilot study. Eight healthy control subjects were also enrolled. The frequency of PD-1⁺ and CTLA-4⁺ lymphocytes in whole blood was evaluated by flow cytometry.

Patients on DR therapy had shorter hospital stays than those on FK therapy. The frequency of PD-1⁺ lymphocytes in the FK group at baseline differed between COVID-19 patients and healthy controls, while the frequency of both PD-1⁺ and CTLA-4⁺ cells increased significantly 7 days of FK therapy. The response was similar in both moderate and severe patients. In contrast,the frequency of PD-1⁺ and CTLA-4⁺ lymphocytes varied significantly between patients and healthy controls before DR treatment. DR therapy enhanced PD-1⁺ but not the CTLA-4⁺ frequency of these cells after 7 days.

We show that the frequency of PD-1 and CTAL-4-bearing lymphocytes during hospitalization was increased in Iranian ICU COVID-19 patients who received FK treatment, but that the frequency of CTLA-4⁺ cells was higher at baseline and did not increase in patients who received DR. The effectiveness of DR treatment may reflect differences in T-cell activation or exhaustion status, particularly in CTLA-4-expressing cells.