Kazan medical journalKazan medical journalКазанский медицинский журнал0368-48142587-9359Eco-Vector63325710.17816/KMJ633257Theoretical and clinical medicineТеоретическая и клиническая медицинаResearch ArticleLymphocyte apoptosis in patients with coronavirus infection COVID-19Апоптоз лимфоцитов у пациентов с коронавирусной инфекцией COVID-19https://orcid.org/0000-0002-9013-44026504772063G-9088-20177602-2918KhaertynovKhalit S.ХаертыновХалит Саубанович
Russian Federation

MD, Dr. Sci. (Med.), Assoc. Prof., Depart. of Children's Infections

д-р мед. наук, доц., каф. детских инфекций

khalit65@yandex.ruhttps://orcid.org/0000-0003-2415-10846506322420R-2839-20168058-6246BoichukSergey V.БойчукСергей Васильевич
Russian Federation

MD, Dr. Sci. (Med.), Prof., Head of Depart., Depart. of General Pathology

д-р мед. наук, проф., зав. каф., каф. общей патологии

boichuksergei@mail.ruhttps://orcid.org/0000-0003-1050-90817005644258А-5230-20195291-7172AnokhinVladimir A.АнохинВладимир Алексеевич
Russian Federation

MD, Dr. Sci. (Med.), Prof., Head of Depart., Depart. of Children's Infections

д-р мед. наук, проф., зав. каф., каф. детских инфекций

anokhin56@mail.ruhttps://orcid.org/0000-0002-0293-297456529709300Y-8761-20199985-9062GalembikovaAigul R.ГалембиковаАйгуль Рафиковна
Russian Federation

Assistant, Depart. of General Pathology

асс., каф. общей патологии

ailuk000@mail.ruhttps://orcid.org/0000-0001-9851-23868011-3837EvdokimovaArina E.ЕвдокимоваАрина Эдуардовна
Russian Federation

Graduate Student, Depart. of Children's Infections

асп., каф. детских инфекций

tilai.ar@yandex.ruKazan State Medical UniversityКазанский государственный медицинский университет2711202410569269350606202427082024Copyright ©; 2024, Eco-VectorCopyright ©; 2024, Эко-Вектор2024Eco-VectorЭко-Векторhttp://creativecommons.org/licenses/by-nc-sa/4.0https://kazanmedjournal.ru/kazanmedj/article/view/633257

BACKGROUND: Lymphopenia in patients with coronavirus infection COVID-19 is associated with the risk of developing severe forms and unfavorable outcome. One of the reasons for the development of lymphopenia is apoptosis.

AIM: Evaluation of the severity of peripheral blood lymphocytes' apoptosis in patients with moderate and severe COVID-19.

MATERIAL AND METHODS: A total of 42 patients with COVID-19 aged 37 to 90 years were examined. They were hospitalized at the Republican Clinical Infectious Diseases Hospital named after Professor A.F. Agafonov, Kazan, from October 24, 2021 to March 1, 2022. In 13 patients, the lung lesion volume ranged from 10 to 25% (CT-1), in 20 — from 25 to 50% (CT-2), in 9 — from 50 to 75% (CT-3). Ribonucleic acid of the SARS-CoV-2 virus was isolated from the nasopharynx in 35 (83%) patients. COVID-19 was moderate in 14 patients, and severe in 28 patients. The control group consisted of 10 conditionally healthy people of the same age. Lymphocyte apoptosis was assessed by quantifying hypodiploid cells by changing the intensity of their staining with propidium iodide using flow cytometry. To determine the reliability of differences in indicators between the compared groups, the Mann–Whitney U-test was used, and when comparing percentages, the χ2 criterion was used. The reliability of differences was established at p <0.05.

RESULTS: It was found that patients with COVID-19 had significantly higher lymphocyte apoptosis activity compared to the control group. The median of the studied indicator in patients with COVID-19 was 39.3%, while in the control group it was 15.1% (p <0.001). The severity of lymphocyte apoptosis correlated with the severity of the disease: the highest rates were recorded in patients with severe COVID-19 (p=0.02). Moreover, lymphocyte apoptosis >55% was associated with the risk of death (p=0.03). A moderate correlation was established between lymphocyte apoptosis rates and blood ferritin levels (Spearman coefficient p=0.39, p <0.05).

CONCLUSION: Coronavirus infection COVID-19 was accompanied by an increase in the activity of peripheral blood lymphocyte apoptosis; the highest apoptosis rates were recorded in patients with severe COVID-19.

Актуальность. Лимфопения у пациентов с коронавирусной инфекцией COVID-19 ассоциируются с риском развития тяжёлых форм и неблагоприятного исхода. Одна из причин развития лимфопении — апоптоз.

Цель. Оценка выраженности апоптоза лимфоцитов периферической крови у пациентов со среднетяжёлым и тяжёлым течением COVID-19.

Материал и методы. Обследованы 42 пациента с COVID-19 в возрасте от 37 до 90 лет, госпитализированных в ГАУЗ «Республиканская клиническая инфекционная больница имени профессора А.Ф. Агафонова», г. Казань, в период с 24 октября 2021 г. по 1 марта 2022 г. У 13 пациентов объём поражения лёгких составил от 10 до 25% (КТ-1), у 20 — от 25 до 50% (КТ-2), у 9 — от 50 до 75% (КТ-3). Рибонуклеиновая кислота вируса SARS-CoV-2 из носоглотки была выделена у 35 (83%) пациентов. У 14 больных было среднетяжёлое течение COVID-19, у 28 — тяжёлое. Контрольную группу составили 10 условно здоровых людей аналогичного возраста. Оценку апоптоза лимфоцитов осуществляли на основании количественного определения гиподиплоидных клеток по изменению интенсивности их окраски пропидия йодидом с помощью проточной цитометрии. Для определения достоверности различий показателей между сравниваемыми группами применяли U-критерий Манна–Уитни, при сравнении процентных долей — критерий χ2. Достоверность различий устанавливали при р <0,05.

Результаты. Выявлено, что у пациентов с COVID-19 достоверно более высокая активность апоптоза лимфоцитов по сравнению с контрольной группой. Медиана изучаемого показателя у больных COVID-19 составила 39,3%, тогда как в контрольной группе — 15,1% (р <0,001). Выраженность апоптоза лимфоцитов коррелировала с тяжестью заболевания: наиболее высокие показатели зарегистрированы у пациентов с тяжёлым течением COVID-19 (р=0,02). При этом апоптоз лимфоцитов >55% ассоциировался с риском летального исхода (р=0,03). Была установлена умеренно выраженная корреляционная связь между показателями апоптоза лимфоцитов и уровнем в крови ферритина (коэффициент Спирмена р=0,39, p <0,05).

Вывод. Коронавирусная инфекция COVID-19 сопровождается повышением активности апоптоза лимфоцитов периферической крови; наиболее высокие показатели апоптоза зарегистрированы у пациентов с тяжёлым течением COVID-19.

coronavirus infection COVID-19lymphocytesapoptosisкоронавирусная инфекция COVID-19лимфоцитыапоптозMarik PE, Iglesias J, Varon J, Kory P. A scoping review of the pathophysiology of COVID-19. Int J Immunopathol Pharmacol. 2021;35:1–16. doi: 10.1177/20587384211048026Marik P.E., Iglesias J., Varon J., et al. A scoping review of the pathophysiology of COVID-19 // Int J Immunopathol Pharmacol. 2021. Vol. 35. P. 1–16. doi: 10.1177/20587384211048026Castelli V, Cimini A, Ferri C. Cytokine storm in COVID-19: “When you come out of the storm, you won’t be the same person who walked in”. Front Immunol. 2020;11:2132. doi: 10.3389/fimmu.2020.02132Castelli V., Cimini A., Ferri C. Cytokine storm in COVID-19: “When you come out of the storm, you won’t be the same person who walked in” // Front Immunol. 2020. Vol. 11. P. 2132. doi: 10.3389/fimmu.2020.02132Cizmecioglu A, Akay Cizmecioglu H, Goktepe MH, Emsen A, Korkmaz C, Esenkaya Tasbent F, Colkesen F, Artac H. T-cell lymphopenia is related to COVID-19 severity. J Medical Virol. 2021;93(5):2867–2874. doi: 10.1002/jmv.2674211Cizmecioglu A., Akay Cizmecioglu H., Goktepe M.H., et al. T-cell lymphopenia is related to COVID-19 severity // J Medical Virol. 2021. Vol. 93, N. 5. P. 2867–2874. doi: 10.1002/jmv.2674211Guo Z, Zhang Z, Prajapati M, Li Y. Lymphopeniacaused by virus infections and the mechanisms beyond. Viruses. 2021;13:1876. doi: 10.3390/v130918764.Guo Z., Zhang Z., Prajapati M., et al. Lymphopenia caused by virus infections and the mechanisms beyond // Viruses. 2021. Vol. 13. P. 1876. doi: 10.3390/v13091876Prevention, diagnostics and treatment of new coronavirus infection. Temporary methodical recommendations. Version 10 (08.02.2021). Available from: https://static-0.minzdrav.gov.ru/system/attachments/attaches/000/054/662/original/Временные_МР_COVID-19_%28v.10%29.pdf Accessed: Feb 8, 2021.Профилактика, диагностика и лечение новой коронавирусной инфекции (COVID-19). Временные методические рекомендации. Версия 10 (08.02.2021). Режим доступа: https://static-0.minzdrav.gov.ru/system/attachments/attaches/000/054/662/original/Временные_МР_COVID-19_%28v.10%29.pdf Дата обращения: 08.02.2021.Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, Wang J, Cao B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Nature. 2020;395(10223):497–506. doi: 10.1016/S0140-6736(20)30183-5Huang C., Wang Y., Li X., et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China // Nature. 2020. Vol. 395, N. 10223. P. 497–506. doi: 10.1016/S0140-6736(20)30183-5Chu H, Zhou J, Wong BH, Li C, Chan JF, Cheng ZS, Yang D, Wang D, Lee AC, Li C, Yeung ML, Cai JP, Chan IH, Ho WK, To KK, Zheng BJ, Yao Y, Qin C, Yuen KY. Middle east respiratory syndrome coronavirus efficiently infects human primary T lymphocytes and activates the extrinsic and intrinsic apoptosis pathways. J Infect Dis. 2016;213(6):904–914. doi: 10.1093/infdis/jiv380Chu H., Zhou J., Wong B.H., et al. Middle east respiratory syndrome coronavirus efficiently infects human primary T lymphocytes and activates the extrinsic and intrinsic apoptosis pathways // J Infect Dis. 2016. Vol. 213, N. 6. P. 904–914. doi: 10.1093/infdis/jiv380Ren X, Wen W, Fan X, Hou W, Su B, Cai P, Li J, Liu Y, Tang F, Zhang F, Yang Y, He J, Ma W, He J, Wang P, Cao Q, Chen F, Chen Y, Cheng X, Deng G, Deng X, Ding W, Feng Y, Gan R, Guo C, Guo W, He S, Jiang C, Liang J, Li YM, Lin J, Ling Y, Liu H, Liu J, Liu N, Liu SQ, Luo M, Ma Q, Song Q, Sun W, Wang G, Wang F, Wang Y, Wen X, Wu Q, Xu G, Xie X, Xiong X, Xing X, Xu H, Yin C, Yu D, Yu K, Yuan J, Zhang B, Zhang P, Zhang T, Zhao J, Zhao P, Zhou J, Zhou W, Zhong S, Zhong X, Zhang S, Zhu L, Zhu P, Zou B, Zou J, Zuo Z, Bai F, Huang X, Zhou P, Jiang Q, Huang Z, Bei JX, Wei L, Bian XW, Liu X, Cheng T, Li X, Zhao P, Wang FS, Wang H, Su B, Zhang Z, Qu K, Wang X, Chen J, Jin R, Zhang Z. COVID-19 immune features revealed by a large-scale single-cell transcriptome atlas. Cell. 2021;184(7):1895–1913. doi: 10.1016/j.cell.2021.01.053Ren X., Wen W., Fan X., et al. COVID-19 immune features revealed by a large-scale single-cell transcriptome atlas // Cell. 2021. Vol. 184, N. 7. P. 1895–1913. doi: 10.1016/j.cell.2021.01.053.Jackson CB, Farzan M, Chen B, Choe H. Mechanisms of SARS-CoV-2 entry into cells. Nat Rev Mol Cell Biol. 2022;23(1):3–20. doi: 10.1038/s41580-021-00418-xJackson C.B., Farzan M., Chen B., et al. Mechanisms of SARS-CoV-2 entry into cells // Nat Rev Mol Cell Biol. 2022. Vol. 23, N. 1. P. 3–20. doi: 10.1038/s41580-021-00418-xShen XR, Geng R, Li Q, Chen Y, Li SF, Wang Q, Min J, Yang Y, Li B, Jiang RD, Wang X, Zheng XS, Zhu Y, Jia JK, Yang XL, Liu MQ, Gong QC, Zhang YL, Guan ZQ, Li HL, Zheng ZH, Shi ZL, Zhang HL, Peng K, Zhou P. ACE2-independent infection of T lymphocytes by SARS-CoV-2. Signal Transduct Target Ther. 2022;7:83. doi: 10.1038/s41392-022-00919-xShen X.R., Geng R., Li Q., et al. ACE2-independent infection of T lymphocytes by SARS-CoV-2 // Signal Transduct Target Ther. 2022. Vol. 7. P. 83. doi: 10.1038/s41392-022-00919-xWang K, Chen W, Zhang Z, Deng Y, Lian JQ, Du P, Wei D, Zhang Y, Sun XX, Gong L, Yang X, He L, Zhang L, Yang Z, Geng JJ, Chen R, Zhang H, Wang B, Zhu YM, Nan G, Jiang JL, Li L, Wu J, Lin P, Huang W, Xie L, Zheng ZH, Zhang K, Miao JL, Cui HY, Huang M, Zhang J, Fu L, Yang XM, Zhao Z, Sun S, Gu H, Wang Z, Wang CF, Lu Y, Liu YY, Wang QY, Bian H, Zhu P, Chen ZN. CD147-spike protein is a novel route for SARS-CoV-2 infection to host cells. Signal Transduct Target Ther. 2020;5(1):283. doi: 10.1038/s41392-020-00426-xWang K., Chen W., Zhang Z., et al. CD147-spike protein is a novel route for SARS-CoV-2 infection to host cells // Signal Transduct Target Ther. 2020. Vol. 5, N. 1. P. 283. doi: 10.1038/s41392-020-00426-xTaghiloo S, Aliyali M, Abedi S, Mehravaran H, Sharifpour A, Zaboli E, Eslami-Jouybari M, Ghasemian R, Vahedi-Larijani L, Hossein-Nattaj H, Amjadi O, Rezazadeh H, Ajami A, Asgarian-Omran H. Apoptosis and immunophenotyping of peripheral blood lymphocytes in Iranian COVID-19 patients: Clinical and laboratory characteristics. J Med Virol. 2021;93(3):1589–1598. doi: 10.1002/jmv.26505Taghiloo S., Aliyali M., Abedi S., et al. Apoptosis and immunophenotyping of peripheral blood lymphocytes in Iranian COVID-19 patients: Clinical and laboratory characteristics // J Med Virol. 2021. Vol. 93, N. 3. P. 1589–1598. doi: 10.1002/jmv.26505Kvasnikov AM, Borovkova NV, Petrikov SS, Godkov MA, Andreev YuV, Storozheva MV, Poluektova VB, Kasholkina EA, Lebedev DA, Popugaev KA. Regulation of lymphocyte apoptosis in intensive care patients with COVID-19. Russian Journal of Anesthesiology and Reanimathology. 2023;1:49–55. (In Russ.) doi: 10.17116/anaesthesiology202301149Квасников А.М., Боровкова Н.В., Петриков С.С., и др. Регуляция апоптоза лимфоцитов у реанимационных больных с COVID-19 // Анестезиология и реаниматология. 2023. № 1. C. 49–55. doi: 10.17116/anaesthesiology202301149Elmore S. Apoptosis: A review of programmed cell death. Toxicol Pathol. 2007;35(4):495–516. doi: 10.1080/01926230701320337Elmore S. Apoptosis: A review of programmed cell death // Toxicol Pathol. 2007. Vol. 35, N. 4. P. 495–516. doi: 10.1080/01926230701320337André S, Picard M, Cezar R, Roux-Dalvai F, Alleaume-Butaux A, Soundaramourty C, Cruz AS, Mendes-Frias A, Gotti C, Leclercq M, Nicolas A, Tauzin A, Carvalho A, Capela C, Pedrosa J, Castro AG, Kundura L, Loubet P, Sotto A, Muller L, Lefrant JY, Roger C, Claret PG, Duvnjak S, Tran TA, Racine G, Zghidi-Abouzid O, Nioche P, Silvestre R, Droit A, Mammano F, Corbeau P, Estaquier J. T cell apoptosis characterizes severe COVID-19 disease. Cell Death Differ. 2022;29(8):1486–1499. doi: 10.1038/s41418-022-00936-xAndré S., Picard M., Cezar R., et al. T cell apoptosis characterizes severe COVID-19 disease // Cell Death Differ. 2022. Vol. 29, N. 8. P. 1486–1499. doi: 10.1038/s41418-022-00936-xHotchkiss RS, Coopersmith CM, Karl IE. Prevention of lymphocyte apoptosis — a potential treatment of sepsis? Clin Inf Diseases. 2005;41(7):465–469. doi: 10.1086/431998Hotchkiss R.S., Coopersmith C.M., Karl I.E. Prevention of lymphocyte apoptosis — a potential treatment of sepsis? // Clin Inf Diseases. 2005. Vol. 41, N. 7. P. 465–469. doi: 10.1086/431998Ren Y, Shu T, Wu D, Mu J, Wang C, Huang M, Han Y, Zhang XY, Zhou W, Qiu Y, Zhou X.The ORF3a protein of SARS-CoV-2 induces apoptosis in cells. Cell Mol Immunol. 2020;17:881–883. doi: 10.1038/s41423-020-0485-9Ren Y., Shu T., Wu D., et al. The ORF3a protein of SARS-CoV-2 induces apoptosis in cells // Cell Mol Immunol. 2020. Vol. 17. P. 881–883. doi: 10.1038/s41423-020-0485-9Kogan EA, Berezovsky YuS, Protsenko DD, Bagdasaryan TR, Gretsov EM, Demura SA, Demyashkin GA, Kalinin DV, Kukleva AD, Kurilina EV, Nekrasova TP, Paramonova NB, Ponomarev AB, Radenska-Lopovok SG, Semyonova LA, Tertychny AS. Pathological anatomy of infection caused by SARS-CoV-2. Russian Journal of Forensic Medicine. 2020;6(2):8–30. (In Russ.) doi: 10.19048/2411-8729-2020-6-2-8-30Коган Е.А., Березовский Ю.С., Проценко Д.Д., и др. Патологическая анатомия инфекции, вызванной SARS-CoV-2 // Судебная медицина. 2020. T. 6, № 2. С. 8–30. doi: 10.19048/2411-8729-2020-6-2-8-30Xiang Q, Feng Z, Diao B, Tu C, Qiao Q, Yang H, Zhang Y, Wang G, Wang H, Wang C, Liu L, Wang C, Liu L, Chen R, Wu Y, Chen Y. SARS-CoV-2 induces lymphocytopenia by promoting inflammation and decimates secondary lymphoid organs. Front. Immunol. 2021;12:661052. doi: 10.3389/fimmu.2021.661052Xiang Q., Feng Z., Diao B., et al. SARS-CoV-2 induces lymphocytopenia by promoting inflammation and decimates secondary lymphoid organs // Front Immunol. 2021. Vol. 12. P. 661052. doi: 10.3389/fimmu.2021.661052Hu Ch-AA, Murphy I, Klimaj S, Reece J, Chand HS. SARS-CoV-2, inflammatory apoptosis, and cytokine storm syndrome. Open COVID Journal. 2021;1:22–31. doi: 10.2174/2666958702101010022Hu Ch.-A.A., Murphy I., Klimaj S., et al. SARS-CoV-2, inflammatory apoptosis, and cytokine storm syndrome // Open COVID Journal. 2021. Vol. 1. P. 22–31. doi: 10.2174/2666958702101010022Gupta S. Tumor necrosis factor-alpha-induced apoptosis in T cells from aged humans: A role of TNFR-I and downstream signaling molecules. Exp Gerontol. 2002;37(2–3):293–299. doi: 10.1016/s0531-5565(01)00195-4Gupta S. Tumor necrosis factor-alpha-induced apoptosis in T cells from aged humans: A role of TNFR-I and downstream signaling molecules // Exp Gerontol. 2002. Vol. 37, N. 2–3. P. 293–299. doi: 10.1016/s0531-5565(01)00195-4Choi C, Park JY, Lee J, Lim JH, Shin EC, Ahn YS, Kim CH, Kim SJ, Kim JD, Choi IS, Choi IH. Fas ligand and Fas are expressed constitutively in human astrocytes and the expression increases with IL-1, IL-6, TNF-alpha, or IFN-gamma. J Immunol. 1999;162:1889–1895. doi: 10.4049/jimmunol.162.4.1889Choi C., Park J.Y., Lee J., et al. Fas ligand and Fas are expressed constitutively in human astrocytes and the expression increases with IL-1, IL-6, TNF-alpha, or IFN-gamma // J Immunol. 1999. Vol. 162. P. 1889–1895. doi: 10.4049/jimmunol.162.4.1889Giamarellos-Bourboulis EJ, Netea MG, Rovina N, Akinosoglou K, Antoniadou A, Antonakos N, Damoraki G, Gkavogianni T, Adami ME, Katsaounou P, Ntaganou M, Kyriakopoulou M, Dimopoulos G, Koutsodimitropoulos I, Velissaris D, Koufargyris P, Karageorgos A, Katrini K, Lekakis V, Lupse M, Kotsaki A, Renieris G, Theodoulou D, Panou V, Koukaki E, Koulouris N, Gogos C, Koutsoukou A. Complex immune dysregulation in COVID-19 patients with severe respiratory failure. Cell Host Microbe. 2020;27:992–1000. doi: 10.1016/j.chom.2020.04.009Giamarellos-Bourboulis E.J., Netea M.G., Rovina N., et al. Complex immune dysregulation in COVID-19 patients with severe respiratory failure // Cell Host Microbe. 2020. Vol. 27. P. 992–1000. doi: 10.1016/j.chom.2020.04.009Kushner I, Rzewnicki DL. The acute phase response: general aspects. Baillieres Clin Rheumatol. 1994;8(3):513–530. doi: 10.1016/s0950-3579(05)80113-xKushner I., Rzewnicki D.L. The acute phase response: general aspects // Baillieres Clin Rheumatol. 1994. Vol. 8, N. 3. P. 513–530. doi: 10.1016/s0950-3579(05)80113-xHuang I, Pranata R, Lim MA, Oehadian A, Alisjahbana B. C-reactive protein, procalcitonin, D-dimer, and ferritin in severe coronavirus disease-2019: A meta-analysis. Ther Adv Respir Dis. 2020;14:1–14. doi: 10.1177/175346662093717Huang I., Pranata R., Lim M.A., et al. C-reactive protein, procalcitonin, D-dimer, and ferritin in severe coronavirus disease-2019: A meta-analysis // Ther Adv Respir Dis. 2020. Vol. 14. P. 1–14. doi: 10.1177/175346662093717Zhang C, Wu Z, Li JW, Zhao H, Wang GQ. The cytokine release syndrome (CRS) of severe COVID-19 and interleukin-6 receptor (IL-6R) antagonist Tocilizumab may be the key to reduce the mortality. Inter J Antimicrob Agents. 2020;55(5):105954. doi: 10.1016/j.ijantimicag.2020.105954Zhang C., Wu Z., Li J.W., et al. The cytokine release syndrome (CRS) of severe COVID-19 and interleukin-6 receptor (IL-6R) antagonist Tocilizumab may be the key to reduce the mortality // Inter J Antimicrob Agents. 2020. Vol. 55, N. 5. P. 105954. doi: 10.1016/j.ijantimicag.2020.105954Liu Y, Garron TM, Chang Q, Su Z, Zhou C, Qiu Y, Gong EC, Zheng J, Yin YW, Ksiazek T, Brasel T, Jin Y, Boor P, Comer JE, Gong B. Cell-type apoptosis in lung during SARS-CoV-2 infection. Pathogens. 2021;10:509. doi: 10.3390/ pathogens10050509Liu Y., Garron T.M., Chang Q., et al. Cell-type apoptosis in lung during SARS-CoV-2 infection // Pathogens. 2021. Vol. 10. P. 509. doi: 10.3390/ pathogens10050509Tong X, Ping H, Gong X, Zhang K, Chen Z, Cai C, Lu Z, Yang R, Gao S, Wang Y, Wang X, Liu L, Ke H. Pyroptosis in the lung and spleen of patients died from COVID-19. European Journal of Inflammation. 2022; 20:1–12. doi: 10.1177/1721727X221140661Tong X., Ping H., Gong X., et al. Pyroptosis in the lung and spleen of patients died from COVID-19 // European Journal of Inflammation. 2022. Vol. 20. P. 1–12. doi: 10.1177/1721727X221140661