ПРИЧИНЫ ГИПОКСЕМИИ ПРИ COVID-19
PDF

Ключевые слова

коронавирусная инфекция (SARS-CoV-2)
цитокиновый шторм
гипоксемия
острая дыхательная недостаточность

Как цитировать

Донина, Ж. А. (2021). ПРИЧИНЫ ГИПОКСЕМИИ ПРИ COVID-19. Российский физиологический журнал им. И. М. Сеченова, 108(1), 3–12. https://doi.org/10.31857/S0869813922010058

Аннотация

Пандемия нового коронавирусного заболевания (COVID-19) поставила перед специалистами здравоохранения всего мира задачи, связанные с диагностикой, интенсивным изучением эпидемиологических и клинических особенностей протекания коронавирусной инфекции, разработкой профилактики, терапевтических подходов к методам лечения и реабилитационным мероприятиям. Но несмотря на достигнутые успехи в изучении патогенеза COVID-19, многие аспекты, усугубляющие тяжесть протекания заболевания и высокую смертность пациентов, остаются неясными.

Основным клиническим проявлением нового варианта вирусной инфекции SARS-CoV-2 является пневмония с массивным паренхиматозным поражением легочной ткани, диффузным повреждением альвеол, тромботическими проявлениями, нарушением вентиляционно-перфузионных отношений и др. Однако симптомы у пациентов, госпитализированных с COVID-пневмонией, имеют значительные различия: у большинства заболевание протекает с минимальными проявлениями, у других развивается тяжелая дыхательная недостаточность, осложненная развитием острого респираторного дистресс-синдрома (ОРДС) с быстро прогрессирующей гипоксемией, приводящей к высокой смертности. Многочисленные публикации клиницистов сообщают, что у части пациентов с COVID-пневмонией без субъективных признаков тяжелой дыхательной недостаточности (одышка, воздушный «голод») был зарегистрирован чрезвычайно (экстремально) низкий уровень сатурации. В результате возникает ситуация, получившая названия «тихая гипоксия», «молчаливая гипоксия», «счастливая гипоксия», противоречащая основам физиологии – тяжелая гипоксемия, несовместимая с жизнью и отсутствие при этом ощущений дыхательного дискомфорта. Все это вызывает многочисленные вопросы у врачей, что привело к широкой дискуссии в научных публикациях, освещающих вопросы патогенеза COVID-19. Дыхательная недостаточность – сложная клиническая проблема, многие аспекты которой остаются спорными. Однако, по мнению большинства авторов, одним из объективных показателей клинического признака дыхательной недостаточности, прежде всего, являются изменения внешнего дыхания, связанные с гипоксемией. В данном обзоре рассматриваются некоторые возможные причины возникновения гипоксемии при COVID-19.

https://doi.org/10.31857/S0869813922010058
PDF

Литература

Cao Y, Hiyoshi A, Montgomery S (2020) COVID-19 case-fatality rate and demographic and socioeconomic influencers: worldwide spatial regression analysis based on country-level. Data BMJ Open 10(11):е043560. s://doi.org/10.1136/bmjopen-2020-043560

Franks TJ, Chong PY, Chui P, Galvin JR, Lourens RM, Reid AH, Selbs E, Mcevoy PL, Hayden DL, Fukuoka J, Taubenberger JK, Travis WD (2003) Lung pathology of severe acute respiratory syndrome (SARS): a study of 8 autopsy cases from Singapore. Hum Pathol 34:743–748. s://doi.org/10.1016/S0046-8177(03)00367-8

Gilbert JA (2018) Advancing towards precision medicine in ARDS. Lancet Respir Med 6:494–495. s://doi.org/10.1016/S2213-2600(18)30156-5

Li S, Fu B, Meshram CD (2019) Innate immune and inflammatory responses to respiratory viruses. Mediators Inflamm 1–2. s://doi.org/10.1155/2019/3146065

Azkur AK, Akdis M, Azkur D, Sokolowska M, Van De Veen W, Bruggen MC, O’Mahony L, Gao Y, Nadeau K, Akdis AC (2020) Immune response to SARS-CoV-2 and mechanisms of immunopathological changes in COVID-19. Allergy 75:1564–1581. https://doi.org/10.1111/all.14364

Behrens EM, Koretzky GA (2017) Review: Cytokine storm syndrome: Looking toward the precision medicine era. Arthritis & Rheumatology 69(6):1135–1143. https://doi.org/10.1002/art.40071

Liu W, Hualan L (2020) COVID-19: Attacks the 1-Beta chain of hemoglobin and captures the porphyrin to inhibit human heme metabolism. ChemRxiv Epub ahead of print. https://doi.org/10.26434/chemrxiv.11938173.v9

Sun X, Wang T, Cai D, Hu Z, Chen J, Liao H, Zhi L, Wei H, Zhang Z, Qiu Y, Wang J, Wang A (2020) Cytokine storm intervention in the early stages of COVID-19 pneumonia. Cytokine Growth Factor Rev 53:38–42. s://doi.org/10.1016/j.cytogfr.2020.04.002

Zhang H, Penninger JM, Li Y, Zhong N, Slutsky AS (2020) Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Med 46(4):586–590. s://doi.org/10.1007/s00134-020-05985-9

Abdin SM, Elgendy SM, Alyammahi SK, Alhamad DW, Omar HA (2020) Tackling the cytokine storm in COVID-19, challenges and hopes. Life Siences 257:118054. https://doi.org/10.1016/j.lfs.2020.118054

Xie J, Covassin N, Fan Z, Singh P, Gao W, Li G, Kara T, Somers VK (2020) Association between hypoxemia and mortality in patients with COVID-19. Mayo Clin Proc 95:1138–1147. https://doi.org/10.1016/j.mayocp.2020.04.006

Shang J, Wan Y, Luo C, Ye G, Geng Q, Auerbach A. Li F (2020) Cell entry mechanisms of SARS-CoV-2. Proc Natl Acad Sci U S A 117(21):11727–11734. https://doi.org/10.1073/pnas.2003138117

Letko M., Marzi A., Munster V. (2020) Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses. Nat Microbiol 5:562–569. https://doi.org/10.1038/s41564-020-0688-y

Wan Y, Shang J, Graham R, Baric RS, Li F (2020) Receptor recognition by the novel coronavirus from Wuhan: An analysis based on decade-long structural studies of SARS coronavirus. J Virol 94:00127-20. s://doi.org/10.1128/JVI.00127-20

Чучалин АГ (2004) Тяжелый острый респираторный синдром. Терапевт архив 79(3):5–11. [Chuchalin AG (2004) Severe acute respiratory syndrome. Therapeutic Archiv 79(3):5–11. (In Russ)].

Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B, Huan Y, Yang P, Zhang Y, Deng W, Bao L, Zhang B, Liu G, Wang Zh, Chappell M, Liu Y, Zheng D, Leibbrandt A, Wada T, Slutsky AS, Liu D, Qin C, Jiang C, Penninger JM (2005) A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med 11(8):875–879. https://doi.org/10.1038/nm1267

Cameron MJ, Bermejo-Martin JF, Danesh A, Muller MP, Kelvin DJ (2008) Human immunopathogenesis of severe acute respiratory syndrome (SARS). Virus Res 133(1):13–19. https://doi.org/10.1016/j.virusres.2007.02.014

Jiang Y, Xu J, Zhou C (2005) Characterization of cytokine/chemokine profiles of severe acute respiratory syndrome. Am J Respir Crit Care Med 171(8):850–857. https://doi.org/10.1164/rccm.200407-857OC

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 (2020) Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395:497–506. s://doi.org/10.1016/S0140-6736(20)30183-5

Varga Z, Flammer AJ, Steiger P, Haberecker M, Anermatt R, Zinkernagel A, Mehra MR, Schuepbach RA, Ruschitzka F (2020) Endothelial cell infection and endotheliitis in COVID-19. Lancet 395:1417–1418. s://doi.org/10.1016/S0140-6736(20)30937-5

Bhattacharya S, Agarwal S, Shrimali N, Guchhai P (2021) Interplay between hypoxia and inflammation contributes to the progression and severity of respiratory viral diseases. Mol Aspects Med 19:101000. s://doi.org/10.1016/j.mam.2021.101000

Tobin MJ (2020) Basing respiratory management of coronavirus on physiological principles. Am J Respir Crit Care Med 201(11):1319–1320. s://doi.org/10.1164/rccm.202004-1076ED

Dhont S, Eric Derom E, Braeckel EV, Depuydt P, Lambrecht BN (2020) The pathophysiology of «happy» hypoxemia in COVID-19. Respirat Res 21:198. https://doi.org/10.1016/j.mam.2021.101000

Bein T, Grasso S, Moerer O, Quintel M, Guerin C, Deja M, Brondani M, Mehta S (2016) The standard of care of patients with ARDS: ventilatory settings and rescue therapies for refractory hypoxemia. Intensive Care Med 42:699–711. s://doi.org/10.1007/s00134-016-4325-4

Wilkerson RG, Adler JD, Shah NG, Brown R (2020) Silent hypoxia: a harbinger of clinical deterioration in patients with COVID-19. Am J Emerg Med 38(10):2243. https://doi.org/10.1016/j.ajem.2020.05.044

Levitan R (2020) The infection that’s silently killing coronavirus patients. The New York Times Apr 20.

Philip K, Bennett B, Fuller S, Lonergan B, McFadyen C, Burns J, Tidswell R, Vlachou A (2020) Working accuracy of pulse oximetry in COVID-19 patients stepping down from intensive care: a clinical evaluation. BMJ Open Respir Res 7(1):000778. s://doi.org/10.1136/bmjresp-2020-000778

Roe PG, Jones JG (1993) Analysis of factors which affect the relationship between inspired oxygen partial pressure and arterial oxygen saturation. Br J Anaesth 71:488–494. https://doi.org/10.1093/bja/71.4.488

Hamilton C, Steinlechner B, Gruber E, Simon P, Wollenek G (2004) The oxygen dissociation curve: quantifying the shift. Perfusion 19:141–144. https://doi.org/10.1191/0267659104pf734oa

Woyke S, Rauch S, Strohle M, Gatterer H (2021) Modulation of Hb-O2 affinity to improve hypoxemia in COVID-19 patients. Clin Nutr 40:38–39. s://doi.org/10.1016/j.clnu.2020.04.036

Ottestad W, Seim M, Mæhlen JO (2020) COVID-19 with silent hypoxemia. Tidsskr Den Nor Laegeforening 140. s://doi.org/10.4045/tidsskr.20.0299

Couzin-Frankel J (2020) The mystery of the pandemic’s «happy hypoxia». Science 368(6490):455–456. s://doi.org/10.1126/science.368.6490.455

Gattinoni L, Chiumello D, Rossi S (2020) COVID-19 pneumonia: ARDS or not? Crit Care 24:154–154. s://doi.org/10.1186/s13054-020-02880-z

Simonson S, Baker T, Banzett R, Bishop T, Dempsey J, Feldman JL, Guyenet PG, Hodson EJ, Mitchell GS, Moya EA, Nokes BT, Orr JE, Owens RL, Poulin M, Rawling JM, Schmickl CN, Watters JJ, Younes M, Malhotra A (2021) Silent hypoxaemia in COVID-19 patients. J Physiol 599(4):1057–1065. s://doi.org/10.1113/JP280769

Bhatia P, Mohammed S (2020) Severe Hypoxemia in Early COVID-19 Pneumonia. Am J Respir Crit Care Med 202(4):621–622. s://doi.org/10.1164/rccm.202004-1313LE

Nicholls JM, Poon LL, Lee KC (2003) Lung pathology of fatal severe acute respiratory syndrome. Lancet 361:1773–1778. s://doi.org/10.1016/S0140-6736(03)13413-7

Tang N, Li D, Wang X, Sun Z (2020) Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost 18:844–847. s://doi.org/10.1111/jth.14768

Liu X, He L, Stensaas L, Dinger B, Fidone S (2009) Adaptation to chronic hypoxia involves immune cell invasion and increased expression of inflammatory cytokines in rat carotid body. Am J Physiol Lung Cell Mol Physiol 296:158–166. s://doi.org/10.1152/ajplung.90597.2008

Fung ML (2015) Expressions of angiotensin and cytokine receptors in the paracrine signaling of the carotid body in hypoxia and sleep apnea. Respir Physiol Neurobiol 209:6–12. https://doi.org/10.1016/j.resp.2014.09.014

Hoffmann M, Kleine-Weber H, Schroeder S, Kruger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A, Muller MA, Drosten C & Pohlmann S (2020) SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 181:271–280. s://doi.org/10.1016/j.cell.2020.02.052

Liu B, Li M, Zhou Z, Guan X, Xiang Y (2020) Can we use interleukin-6 (IL-6) blockade for coronavirus disease 2019 (COVID-19)-induced cytokine release syndrome (CRS)? J Autoimmun 111:102452. s://doi.org/10.1016/j.jaut.2020.102452

Manganelli F, Vargas M, Iovino A, Iacovazzo C, Santoro L & Servillo G (2020). Brainstem involvement and respiratory failure in COVID-19. Neurol Sci 41:1663–1665. https://doi.org/10.1007/s10072-020-04487-2

Schultz HD (2011). Angiotensin and carotid body chemo-reception in heart failure. Curr Opin Pharmacol 11:144–149. s://doi.org/10.1016/j.coph.2010.12.004

Hariri LP, North CM, Shih AR, Israel RA, Maley JH, Villalba JA, Vinarsky V, Rubin J, Okin DA, Sclafani A, Alladina JW, Griffith JW, Gillette MA, Raz Y, Richards CJ, Wong AK, Ly A, Hung YP, Chivukula RR, Petri CR, Calhoun TF, Brenner LN, Hibbert KA, Medoff BD, Hardin CC, Stone JR, Mino-Kenudson M (2021) Lung histopathology in COVID-19 as compared to SARS and H1N1 influenza: a systematic review. Chest 159:73–84. https://doi.org/10.1016/j.chest.2020.09.259

Mao L, Jin H, Wang M, Hu Y, Chen S, He Q, Chang J, Hong C, Zhou Y, Wang D, Miao X, Li Y, Hu B (2020) Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol 77:683–690. s://doi.org/10.1001/jamaneurol.2020.1127

Moriguchi T, Harii N, Goto J, Harada D, Sugawara H, Takamino J, Ueno M, Sakata H, Kondo K, Myose N, Nakao A, Takeda M, Haro H, Inoue O, Suzuki-Inoue K, Kubokawa K, Ogihara S, Sasaki T, Kinouchi H, Kojin H, Ito M, Onishi H, Shimizu T, Sasaki Y, Enomoto N, Ishihara H, Furuya S, Yamamoto T, Shimada S (2020) A first case of meningitis/encephalitis associated with SARS-Coronavirus-2. Int J Infect Dis 94:55–58. https://doi.org/10.1016/j.ijid.2020.03.062

Paniz-Mondolfi A, Bryce C, Grimes Z, Gordon RE, Reidy J, Lednicky J, Sordillo EM, Fowkes M (2020) Central nervous system involvement by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). J Med Virol 92: 699–702. s://doi.org/10.1002/jmv.25915

McCray PB Jr, Pewe L, Wohlford-Lenane C, Hickey M, Manzel L, Shi L, Netland J, Jia HP, Halabi C, Sigmund CD, Meyerholz DK, Kirby P, Look DC, Perlman S (2007) Lethal infection of K18-hACE2 mice infected with severe acute respiratory syndrome coronavirus. J Virol 81(2):813–821. s://doi.org/10.1128/JVI.02012-06

Netland J, Meyerholz DK, Moore S, Cassell M, Perlman S (2008). Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2. J Virol 82:15:7264–7275. s://doi.org/10.1128/JVI.00737-08

Li K, Wohlford-Lenane C, Perlman S, Zhao J, Jewell AK, Reznikov LR, Gibson-Corley KN, Meyerholz DK, McCray PB Jr (2016) Middle east respiratory syndrome coronavirus causes multiple organ damage and lethal disease in mice transgenic for human dipeptidyl peptidase 4. J Infect Dis 213(5):712–722. s://doi.org/10.1093/infdis/jiv499

Talbot PJ, Ekandé S, Cashman NR, Mounir S, Stewart JN (1993) Neurotropism of human coronavirus 229E. Adv Exp Med Biol 342:339–346. s://doi.org/10.1007/978-1-4615-2996-5_52

Glass WG, Subbarao K, Murphy B, Murphy PM (2004) Mechanisms of host defense following severe acute respiratory syndrome‐coronavirus (SARS‐CoV) pulmonary infection of mice. J Immunol 173:4030–4039. s://doi.org/10.4049/jimmunol.173.6.4030

Li YC, Bai WZ, Hirano N, Hayashida T, Hashikawa T (2012) Coronavirus infection of rat dorsal root ganglia: ultrastructural characterization of viral replication, transfer, and the early response of satellite cells. Virus Res 163(2):628–635. https://doi.org/10.1016/j.virusres.2011.12.021

Jia HP, Look DC, Shi L, Hickey M, Pewe L, Netland J, Farzan M, Wohlford-Lenane C, Perlman S, McCray PB Jr (2005) ACE2 receptor expression and severe acute respiratory syndrome coronavirus infection depend on differentiation of human airway epithelia. J Virol 79(23):14614–14621. s://doi.org/10.1128/JVI.79.23.14614-14621.2005

Klok FA, Kruip MJHA, van der Meer NJM, Arbous MS, Gommers DAMPJ, Kant KM, Kaptein FHJ, Paassen J, Stals MAM, Huisman MV, Endeman H (2020) Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res 191:145–147. https://doi.org/10.1016/j.thromres.2020.04.013

Wichmann D, Sperhake J-P, Lütgehetmann M, Steurer S, Edler C, Heinemann A, Heinrich F, Mushumba H, Kniep I, Schröder AN, Burdelski C, Heer G, Nierhaus A, Frings D, Pfefferle S, Becker H, Bredereke-Wiedling H, Weerth A, Paschen HR, Sheikhzadeh-Eggers S, Stang A, Schmiedel S, Bokemeyer C, Addo MM, Aepfelbacher M, Püschel K, Kluge S, Less S (2020) Autopsy findings and venous thromboembolism in patients with COVID-19: a prospective cohort study. Ann Intern Med 173(4):268–277. s://doi.org/10.7326/M20-2003

Eriksson O, Hultström M, Persson B, Lipcsey M, Ekdahl KN, Nilsson B, Frithiof R (2020) Mannose-binding lectin is associated with thrombosis and coagulopathy in critically ill COVID-19 patients. Thrombosis and Haemostasis 120(12):1720–1724. s://doi.org/10.1055/s-0040-1715835

Lee KY (2017) Pneumonia, acute respiratory distress syndrome, and early immune-modulator therapy. Int J Mol Sci 18:388. s://doi.org/10.3390/ijms18020388

Sarkar M, Niranjan N, Banyal PK (2017) Mechanisms of hypoxemia. Lung India 34(1):2–15. s://doi.org/10.4103/0970-2113.197116

Khomich OA, Kochetkov SN, Bartosch B, Ivanov AV (2018) Redox biology of respiratory viral infections. Viruses 10(8):392. s://doi.org/10.3390/v10080392

Ackermann M, Verleden SE, Kuehnel M, Haverich A, Welte T, Laenger F, Vanstapel A, Werlein C, Stark H, Tzankov A, Li WW, Li VW, Mentzer SJ, Jonigk D (2020). Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19. N Engl J Med 383(2):120–128. s://doi.org/10.1056/NEJMoa2015432

Cloonan SM, Choi AM (2016) Mitochondria in lung disease. J Clin Invest 126(3):809–820. s://doi.org/10.1172/JCI81113

Wenzhong L, Hualan L (2020) COVID-19 Disease: ORF8 and surface glycoprotein inhibit heme metabolism by binding to porphyrin. ChemRxiv Preprint. https://doi.org/10.26434/chemrxiv.11938173

Cavezzi A, Troiani E, Corrao S (2020) COVID-19: hemoglobin, iron, and hypoxia beyond inflammation. A narrative review. Clin Pract 10(2):1271. s://doi.org/10.4081/cp.2020.1271

Cloonan SM, Choi AM (2016) Mitochondria in lung disease. J Clin Invest 126(3):809–820. s://doi.org/10.1172/JCI81113

Dassios T, Curley A, Morley C, Ross-Russell R (2015) Using measurements of shunt and ventilation-to-perfusion ratio to quantify the severity of bronchopulmonary dysplasia. Neonatology 107(4):283–288. s://doi.org/10.1159/000376567

D’Alonzo GE, Dantzker DR (1983) Respiratory failure, mechanisms of abnormal gas exchange, and oxygen delivery. Med Clin North Am 67:557–571. s://doi.org/10.1016/S0025-7125(16)31189-0

West JB (2008) Respiratory physiology – the essentials. 9th ed. Baltimore: Lippincott Williams&Wilkins.

Ackermann M, Verleden SE, Kuehnel M, Haverich A, Welte T, Laenger F, Vanstapel A, Werlein C, Stark H, Tzankov A, Li WW, Li VW, Mentzer SJ, Jonigk D (2020) Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N Engl J Med 383:120–128. https://doi.org/10.1056 / NEJMoa2015432

Nouri-Vaskeh M, Sharifi A, Khalili N, Zand R, Sharifi A (2020) Dyspneic and non-dyspneic (silent) hypoxemia in COVID-19: possible neurological mechanism. Clin Neurol Neurosurg 198:106217. s://doi.org/10.1016/j.clineuro.2020

Wichmann D, Sperhake J-P, Lütgehetmann M, Steurer S, Edler C, Heinemann A, Heinrich F, Mushumba H, Kniep I, Schröder AN, Burdelski C, Heer G, Nierhaus A, Frings D, Pfefferle S, Becker H, Bredereke-Wiedling H, Weerth A, Paschen HR, Sheikhzadeh-Eggers S, Stang A, Schmiedel S, Bokemeyer C, Addo MM, Aepfelbacher M, Püschel K, Kluge S, Less S. (2020) Autopsy findings and venous thromboembolism in patients with COVID-19: a prospective cohort study. Ann Intern Med 173 (4):268–277. s://doi.org/10.7326/M20-2003

Mahjoub Y, Rodenstein DO, Jounieaux V (2020) Severe Covid-19 disease: rather AVDS than ARDS? Crit Care 24:327. s://doi.org/10.1186/s13054-020-02972-w