Causes of Lymphopenia in Patients Died from COVID-19

Introduction : Lymphopenia is one of the main laboratory signs of severe COVID-19 and a poor prognosis. The purpose of this study was to evaluate the content of lymphocyte subpopulations in lung tissue and spleen in patients who died from COVID-19.

Materials and methods . A study was conducted on autopsy material obtained from 17 patients who died from COVID-19. The control group consisted of 11 patients who died from other, non-infectious causes. The quantities of CD3+ lymphocytes and CD4+, CD8+, and CD20+ lymphocyte subpopulations were determined in lung tissue and spleen.

Results . An increase in the number of CD3+, CD4+, and CD8+ positive cells was found in the lungs of patients who died from COVID-19. CD4+ and CD8+ positive cells showed the most pronounced increase, with mean values 561 and 174 times higher than the control group, respectively. In the spleen of patients with COVID-19, a two-fold decrease in the number of CD3+ positive cells was observed compared to the control group. The most pronounced reduction was seen in CD8+ positive cells, whose mean value in COVID-19 patients was 2.8 times lower than in the control group. The median area of the splenic white pulp in patients with COVID-19 was 1.6 times smaller than in the control group.

Conclusion . Patients who died from severe forms of COVID-19 exhibit an accumulation in lung tissue and a depletion in the spleen. The identified reduction in the area of the splenic white pulp in COVID-19 patients indicates the development of immunosuppression.

1. Marik PE, Iglesias J, Varon J, Kory P. A scoping review of the pathophysiology of COVID-19. International Journal of Immunopathology and Pharmacology . 2021;35:1–16. DOI: https://doi.org/10.1177/20587384211048026.

2. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The Lancet . 2020;395(10223):497–506. DOI: https://doi.org/10.1016/s01406736(20)30183-5.

3. Yang X, Yu Y, Xu J, Shu H, Liu H, Wu Y, et al. Clinical course and outcomes of critically ill patients with SARS‐CoV‐2 pneumonia in Wuhan, China: A single‐centered, retrospective, observational study. The Lancet Respiratory Medicine . 2020;8(5):475–481. DOI: https://doi.org/10.1016/s2213-2600(20)30079-5.

4. Cizmecioglu A, Akay Cizmecioglu H, Goktepe MH, Emsen A, Korknaz C, Esenkaya Tasbent F, et al. T-cell lymphopenia is related to COVID-19 severity. Journal of Medical Virology . 2021;93(5):2867–2874. DOI: https://doi.org/10.1002/jmv.26742.

5. Virchows Archiv . Bösmüller H, Matter M, Fend F, Tzankov A. The pulmonary pathology of COVID-19. 2021;478:137–150. DOI: https://doi.org/10.1007/s00428-021-03053-1.

6. Zayratiants OV, Malyavin AG, Samsonova MV, Chernyaev AL, Mishnev OD, Mikhaleva LM, et al. Pathomorphological changes in the lungs during COVID-19: Clinical and therapeutic parallels. Therapy . 2020;5:3546. (In Russ.). DOI: https://dx.doi.org/10.18565/therapy.2020.5.35-46.

7. Hu Ch-AA, Murphy I, Klimaj S, Reece J, Chand HS. SARS-CoV-2, inflammatory apoptosis, and cytokine storm syndrome. The Open COVID Journal . 2021;1:22–31. DOI: https://doi.org/10.2174/2666958702101010022.

8. Xu X, Chang XN, Pan HX, Su H, Huang B, Yang M, et al. Pathological changes of the spleen in ten patients with coronavirus disease 2019 (COVID-19) by postmortem needle autopsy. Zhonghua Bing Li Xue Za Zhi . 2020;49(6):576–582. DOI: https://doi.org/10.3760/cma.j.cn112151-20200401-00278.

9. Zaitsev VB, Fedorovskaya NS, Diakonov DA, Fedorovskiy AM, Dorokh LB, Koledayeva YV, et al. Morpho-functional characteristics of human spleen (an immunohistochemical study). Morphology . 2013;143(3):27–31. (In Russ.). DOI: https://doi.org/10.17816/morph.398615.

10. Khaertynov KhS, Anokhin VA, Burganova GR, Pevnev GO, Mavlikeev MO, Kiyasov AP, et al. Intestinal mucosal lymphocytes in neonatal sepsis. Russian Bulletin of Perinatology and Pediatrics . 2019;64:(4):52–59 (in Russ.). DOI: https://doi.org/10.21508/1027-4065-2019-64-4-52-59.

11. Khaertynov KhS, Anokhin VA, Burganova GR, Pevnev GO, Mavlikeev MO, Kiyasov AP, et al. Adaptive immunity in the mucous membrane of the duodenum in neonatal sepsis. Kazan Medical Journal . 2020;101(1):31–39. (In Russ.). DOI: https://doi.org/10.17816/KMJ2020–31.

12. Zhao Q, Meng M, Kumar R, Wu Y, Huang J, Deng Y, et al. Lymphopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: A systemic review and meta-analysis. International Journal of Infectious Diseases . 2020;96:131–135. DOI: https://doi.org/10.1016/j.ijid.2020.03.017.

13. Alon R, Sportiello M, Kozlovski S, Kumar A, Reilly EC, Zarbock A, et al. Leukocyte trafficking to the lungs and beyond: Lessons from influenza for COVID-19. Nature Reviews Immunology . 2021;21:49–64. DOI: https://doi.org/10.1038/s41577-020-00470-2.

14. Boechat JL, Chora I, Morais A, Delgado L. The immune response to SARS-CoV-2 and COVID-19 immunopathology. Current perspectives. Pulmonology . 2021;27(5):423–437. DOI: https://doi.org/10.1016/j.pulmoe.2021.03.008.

15. Frisoni P, Neri M, D’Errico S, Alfieri L, Bonuccelli D, Cingolani M, et al. Cytokine storm and histopathological findings in 60 cases of COVID-19-related death: From viral load research to immunohistochemical quantification of major players IL-1β, IL-6, IL-15 and TNF-α. Forensic Science, Medicine and Pathology . 2022;18(1):4–19. DOI: https://doi.org/10.1007/s12024-021-00414-9.

16. Poloni TE, Moretti M, Medici V, Turturici E, Belli G, Cavriani E, et al. COVID-19 Pathology in the lung, kidney, heart and brain: The different roles of T-Cells, macrophages, and microthrombosis. Cells . 2022;11(19):3124. DOI: https://doi.org/10.3390/cells11193124.

17. Menezes RG, Rizwan T, Saad Ali S, Hassan W, Khetpal A, Aqil M, et al. Postmortem findings in COVID-19 fatalities: A systematic review of current evidence. Legal Medicine . 2022;54:102001. DOI: https://doi.org/10.1016/j.legalmed.2021.102001.

18. Sette A, Crotty S. Adaptive immunity to SARS-CoV-2 and COVID-19. Cell . 2021;184(4):861–880. DOI: https://doi.org/10.1016/j.cell.2021.01.007.

19. Vabret N, Britton GJ, Gruber C, Hegde S, Kim J, Kuksin M, et al. Immunology of COVID-19: Current state of the science. Immunity . 2020;52(6):910–941. DOI: https://doi.org/10.1016/j.immuni.2020.05.002.

20. Bergamaschi L, Mescia F, Turner L, Hanson AL, Kotagiri P, Dunmore BJ, et al. Longitudinal analysis reveals that delayed bystander CD8+ T cell activation and early immune pathology distinguish severe COVID-19 from mild disease. Immunity . 2021;54(6):1257–1275.e8. DOI: https://doi.org/10.1016/j.immuni.2021.05.010.

21. Evdokimova AE, Khaertynov KhS, Anokhin VA, Raginov IS. Immune dysregulation in coronavirus infection COVID-19. Journal Infectology . 2025;17(3):24–32. (In Russ.). DOI: https://doi.org/10.22625/20726732-2025-17-3-24-32.

22. Xiang Q, Feng Z, Diao B, Tu C, Qiao Q, Yang H, et al. SARS-CoV-2 induces lymphocytopenia by promoting inflammation and decimates secondary lymphoid organs. Frontiers in Immunoogyl . 2021;12:661052. DOI: https://doi.org/10.3389/fimmu.2021.661052.

23. Guo Z, Zhang Z, Prajapati M, Li Y. Lymphopenia caused by virus infections and the mechanisms beyond. Viruses . 2021;13:1876. DOI: https://doi.org/10.3390/v13091876.

24. Ovseenko TE, Kaplunova OA, Sokolov VV. Structural organization of the spleen in the age aspect. Medical Herald of the South of Russia . 2011;4:39–43. (In Russ.). EDN: https://e-library.ru/OOKMTZ.

25. Kurra N, Woodard PI, Gandrakota N, Gandhi H, Polisetty SR, Ang SP, et al. Opportunistic Infections in COVID-19: A systematic review and meta-analysis. Cureus . 2022;14(3):e23687. DOI: https://doi.org/10.7759/cureus.23687.

26. Cococcia S, Lenti MV, Santacroce G, Achilli G, Borrelli de Andreis F, Di Sabatino A. Liver-spleen axis dysfunction in COVID-19. World Journal of Gastroenterology . 2021;27(35):5919–5931. DOI: https://doi.org/10.3748/wjg.v27.i35.5919.