Original Article

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

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


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.

1. Wu, Z. and J.M. McGoogan, Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72314 Cases From the Chinese Center for Disease Control and Prevention. JAMA, 2020. 323(13): p. 1239-1242.
2. Mortaz, E., et al., Increased serum levels of soluble TNF-α receptor is associated with mortality of ICU COVID-19 patients Front. Immunol, 2021. 12: p. 1-8.
3. Dezfuli, N., et al., Update on Immunology of COVID-19 Disease and Potential Strategy for Controlling Tanaffos 2020. 19(4): p. 274-290
4. Mortaz, E., et al., Serum cytokine levels of COVID-19 patients after 7 days of treatment with Favipiravir or Kaletra. Int Immunopharmacol, 2021. 93: p. 107407.
5. Hashemian, S.M., et al., Plasmapheresis reduces cytokine and immune cell levels in COVID-19 patients with acute respiratory distress syndrome (ARDS). Pulmonology, 2020: p. 1-7.
6. Alipoor, S.D., et al., COVID-19: Molecular and Cellular Response. Front Cell Infect Microbiol, 2021. 11: p. 563085.
7. Peng, X., et al., Sharing CD4+ T Cell Loss: When COVID-19 and HIV Collide on Immune System. Front Immunol, 2020. 11: p. 596631.
8. Alipoor, S.D., et al., Immunopathogenesis of Pneumonia in COVID-19. Tanaffos, 2020. 19(2): p. 79-82.
9. Mortaz, E., et al., The Immune Response and Immunopathology of COVID-19. Front Immunol, 2020. 11: p. 2037.
10. Rezaei, M., et al., Dynamic Changes of Lymphocyte Subsets in the Course of COVID-19. Int Arch Allergy Immunol, 2021. 182(3): p. 254-262.
11. Chen, Z. and E. John Wherry, T cell responses in patients with COVID-19. Nat Rev Immunol, 2020. 20(9): p. 529-536.
12. Mortaz, E., et al., Programmed cell death protein 1 (PD-1) molecule in Coronavirus disease 2019 (COVID)-19? Tanaffos, 2021. 20(1): p. 1-2.
13. Liu, L., L. Xu, and C. Lin, T cell response in patients with COVID-19. Blood Science, 2020. 2(3): p. 76-78.
14. World Health, O., Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected. Interim guidance. Pediatria i Medycyna Rodzinna, 2020. 16(1): p. 9-26.
15. Diao, B., et al., Reduction and Functional Exhaustion of T Cells in Patients With Coronavirus Disease 2019 (COVID-19). Front Immunol, 2020. 11: p. 827.
16. Fathi, N. and N. Rezaei, Lymphopenia in COVID-19: Therapeutic opportunities. Cell Biol Int, 2020. 44(9): p. 1792-1797.
17. De Biasi, S., et al., Marked T cell activation, senescence, exhaustion and skewing towards TH17 in patients with COVID-19 pneumonia. Nat Commun, 2020. 11(1): p. 3434.
18. Kong, Y., et al., Storm of soluble immune checkpoints associated with disease severity of COVID-19. Signal Transduct Target Ther, 2020. 5(1): p. 192.
19. Aghbash, P.S., et al., SARS-CoV-2 infection: The role of PD-1/PD-L1 and CTLA-4 axis. Life Sci, 2021. 270: p. 119124.
20. Rha, M.-S., et al., PD-1-Expressing SARS-CoV-2-Specific CD8+ T Cells Are Not Exhausted, but Functional in Patients with COVID-19. Immunity, 2021. 54(1): p. 44-52.e3.
21. Chen, J., et al., Regulation of PD-L1: a novel role of pro-survival signalling in cancer. Ann Oncol, 2016. 27(3): p. 409-16.
22. Guo, C., et al., Single-cell analysis of two severe COVID-19 patients reveals a monocyte-associated and tocilizumab-responding cytokine storm. Nat Commun, 2020. 11(1): p. 3924.
23. Pezeshki, P.S. and N. Rezaei, Immune checkpoint inhibition in COVID-19: risks and benefits. Expert Opin Biol Ther, 2021: p. 1-7.
24. Luo, J., et al., Impact of PD-1 Blockade on Severity of COVID-19 in Patients with Lung Cancers. Cancer Discovery, 2020. 10(8): p. 1121-1128.
25. Hung, I.F., et al., Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial. Lancet, 2020. 395(10238): p. 1695-1704.
26. Yamamura, H., et al., Effect of favipiravir and an anti-inflammatory strategy for COVID-19. Crit Care, 2020. 24(1): p. 413.
27. Group, R.C., et al., Dexamethasone in Hospitalized Patients with Covid-19 - Preliminary Report. N Engl J Med, 2020: p. 1-11.
28. Sharun, K., et al., Dexamethasone to combat cytokine storm in COVID-19: Clinical trials and preliminary evidence. Int J Surg, 2020. 82: p. 179-181.
29. Li, Y.N. and Y. Su, Remdesivir attenuates high fat diet (HFD)-induced NAFLD by regulating hepatocyte dyslipidemia and inflammation via the suppression of STING. Biochem Biophys Res Commun, 2020. 526(2): p. 381-388.
30. Wang, M., et al., Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res, 2020. 30(3): p. 269-271.
31. Grein, J., et al., Compassionate Use of Remdesivir for Patients with Severe Covid-19. N Engl J Med, 2020. 382(24): p. 2327-2336.
32. Gholamhoseini, M., et al., Safety and Efficacy of Remdesivir for the Treatment of COVID-19: A Systematic Review and Meta-Analysis. J Pharm Pharm Sci, 2021. 24: p. 237-245.
33. Lee, T.C., et al., Remdesivir and systemic corticosteroids for the treatment of COVID-19: A Bayesian re-analysis. Int J Infect Dis, 2021. 104: p. 671-676.
34. Vetter, P., et al., Dexamethasone and remdesivir: finding method in the COVID-19 madness. The Lancet Microbe, 2020. 1(8): p. e309-e310.
IssueVol 22 No 1 (2023) QRcode
SectionOriginal Article(s)
DOI https://doi.org/10.18502/ijaai.v22i1.12012
COVID-19 PD-1 CTLA-4 T cells cytokine storm Anti-viral therapy

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How to Cite
Mortaz E, Jamaati H, K.Dezfuli N, Sheikhzade H, Hashemian S, Roofchayee N, Dastan F, Tabarsi P, Folkerts G, Garssen J, Mumby S, Adcock I. 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. Iran J Allergy Asthma Immunol. 2023;22(1):99-109.