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

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.

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.
Files
IssueVol 22 No 1 (2023) QRcode
SectionOriginal Article(s)
DOI https://doi.org/10.18502/ijaai.v22i1.12012
Keywords
COVID-19 PD-1 CTLA-4 T cells cytokine storm Anti-viral therapy
Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
How to Cite
1.
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.