Phenomenon of reduced blood oxygen saturation in COVID-19 patients after the use of monoclonal antibodies

Monoclonal antibodies IL-6 inhibitors (olokizumab) and IL-6 receptor inhibitors (tocylisumab, levilimab) are most widely used for proactive anti-inflammatory therapy in patients with COVID-19. A decrease in blood oxygen saturation after 12–72 hours of anticytokine therapy has been recently observed in some patients treated with MAB. Unfortunately, little attention is paid to this problem. As a rule, the deterioration of the patient’s condition is attributed to the natural course of the disease. The purpose of the study is to identify predictors of reduced blood oxygen saturation against the administration of IL-6 inhibitors and its receptors in patients with new coronavirus infection (COVID-19). Material and methods. The study included 54 patients with COVID-19 who were treated permanently between 2020 and 2021 and were given IL-6 inhibitors or receptors (tocilizumab, olokizumab or levililmab). The results of clinical examination, laboratory and instrumental research were evaluated. Results and conclusions. Clinical-laboratory parameters reliably correlated with decreased blood oxygen saturation against the administration of IL-6 inhibitors and its receptors are as follows: administration of MAB after 2 days of inpatient treatment (OR = 3.52; 95% CI 1.026–12.073; p = 0.04), the presence of hypertonic disease in combination with ischemic heart disease or obesity (OR = 4.0; 95% CI 1.0–16.925; p = 0.049 and OR = 7.353; 95% CI 1.429–37.848; p = 0.009 respectively), increase in the number of monocytes greater than 0.6 × 109/l (OR = 4.929; 95% CI 1.327–18.307; p = 0.014), the decrease of albumin less than 35.1 g/l (OR = 30.0; 95% CI 1.410–638.186; p = 0.033), glucose of venous blood 5.9 mmol/l and above (OR = 11.556; 95% CI 1.223–109.19; p = 0.018). Based on the data obtained in this study, it is recommended to evaluate the predictors listed above before conducting targeted anti-inflammatory therapy, and, if they are available, to dynamically monitor patients for reduced blood oxygen saturation.

1. Weekly epidemiological update on COVID-19 — 22 February 2022. WHO. 2022. [Electronic resource]. URL: https://www.who.int/publications/m/item/weekly-epidemiological-update-on-covid-19---22-february-2022 (date of access: 25.02.2022 г.)

2. Под редакцией Д.В. Тришкина. Стандарт диагностики и лечения новой коронавирусной инфекции (COVID-19) у военнослужащих Вооруженных Сил Российской Федерации. Версия 3 от 08.10.2021. Методические рекомендации. Москва, ГВМУ. 2021:64. [Edition by D.V. Trishkin. Standard of diagnosis and treatment of new coronavirus infection (COVID-19) in the Armed Forces of the Russian Federation. Version 3 08.10.2021. Guidelines. Moscow, GVMU. 2021:64 (In Russian)]

3. Временные методические рекомендации. Профилактика, диагностика и лечение новой коронавирусной инфекции (COVID-19). Версия-15 (22.02.2022). Москва, Министерство здравоохранения Российской Федерации. 2022:245. [Temporary methodological recommendations. Prevention, diagnosis and treatment of a new coronavirus infection (COVID-19). Version-15 (22.02.2022). Moscow, Ministry of Health of the Russian Federation. 2022:245. (In Russian)]

4. Diamanti A.P., Rosado M.M., Pioli C., Sesti G., Laganà B. Cytokine Release Syndrome in COVID-19 Patients, A New Scenario for an Old Concern: The Fragile Balance between Infections and Autoimmunity. Int. J. Mol Sci. 2020;21(9):1–18. DOI: 10.3390/ijms21093330

5. Zhou Z., Price C.C. Overview on the use of IL-6 agents in the treat ment of patients with cytokine release syndrome (CRS) and pneumonitis related to COVID-19 disease. Expert Opinion on Investigational Drugs. 2020;20(12):1407–1412. DOI: 10.1080/13543784.2020.1840549

6. Majidpoor J., Mortezaee K. Interleukin-6 in SARS-CoV-2 induced dis ease: Interactions and therapeutic applications. Biomedicine & Pharmacotherapy. 2022;145(112419):1–12. DOI: 10.1016/j.biopha.2021.112419

7. Choy E., Rose-John S. Interleukin-6 as a Multifunctional Regulator: Inflammation, Immune Response, and Fibrosis. Journal of Scleroderma and Related Disorders. 2017;2(2):1–5. DOI: 10.5301/jsrd.5000265

8. Shankar-Hari M., Vale C.L., Godolphin P.J., Fisher D., Higgins J.P.T., Spiga F., Savovic J., Tierney J., Baron G., Benbenishty J.S., Berry L.R., Broman N., Cavalcanti A.B., Colman R., De Buyser S.L., Derde L.P.G., Domingo P., Omar S.F., Fernandez-Cruz A., Feuth T., Garcia F., Garcia-Vicuna R., Gonzalez-Alvaro I., Gordon A.C., Haynes R., Hermine O., Horby P.W., Horick N.K., Kumar K., Lambrecht B.N., Landray M.J., Leal L., Lederer D.J., Lorenzi E., Mariette X., Merchante N., Misnan N.A., Mohan S.V., Nivens M.C., Oksi J., Perez-Molina J.A., Pizov R., Porcher R., Postma S., Rajasuriar R., Ramanan A.V., Ravaud P., Reid P.D., Rutgers A., Sancho-Lopez A., Seto T.B., Sivapalasingam S., Soin A.S., Staplin N., Stone J.H., Strohbehn G.W., Sunden-Cullberg J., Torre-Cisneros J., Tsai L.W., Hoogstraten H., Meerten T., Veiga V.C., Westerweel P.E., Murthy S., Diaz J.V., Marshall J.C., Sterne J.A.C. Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19: A Meta-analysis. JAMA. 2021;326(6):499–518. DOI: 10.1001/jama.2021.11330

9. Lomakin N.V., Bakirov B.A., Protsenko D.N., Mazurov V.I., Musaev G.H., Moiseeva O.M., Pasechnik E.S., Popov V.V., Smolyarchuk E.A., Gordeev I.G., Gilyarov M.Yu., Fomina D.S., SeleznevA.I., Linkova Y.N., Dokukina E.A., Eremeeva A.V., Pukhtinskaia P.S., Morozova M.A., Zinkina-Orikhan A.V., Lutckii A.A. The efficacy and safety of levilimab in severely ill COVID-19 patients not requiring mechanical ventilation: results of a multicenter randomized double-blind placebo-controlled phase III CORONA clinical study. Inflammation Research. 2021;70:1233–1246.DOI: 10.1007/s00011-021-01507-5

10. Антонов В.Н., Игнатова Г.Л., Прибыткова О.В., Слепцова С.С., Стребкова Е.А., Худякова Е.А., Симакова А.И., Рабец С.Ю., Тихонова Е.П., Курмаева Д.Ю., Петрушин М.А., Машков А.С., Гаязова Е.В., Яшева И.В., Андреев М.А., Хиновкер В.В., Карпунин А.Ю., Бережанский Б.В. Опыт применения олокизумаба у больных COVID-19. Терапевтический архив. 2020;92(12):148–154. [Antonov V.N., Ignatova G.L., Pribytkova O.V., Slepcova S.S., Strebkova E.A., Hudjakova E.A., Simakova A.I., Rabec S.Ju., Tihonova E.P., Kurmaeva D.Ju., Petrushin M.A., Mashkov A.S., Gajazova E.V., Jasheva I.V., Andreev M.A., Hinovker V.V., Karpunin A.Ju., Berezhanskij B.V. Experience of olokizumab use in COVID-19 patients. Therapeutic archive. 2020;92(12):148–154. (In Russian)]. DOI: 10.26442/00403660.2020.12.200522

11. Лекарственная терапия при COVID-19: Вариативные рекомендации. 24 сентября 2022. ВОЗ. 2022. [Therapeutics and COVID-19: Living guideline. September 24, 2022. WHO. 2022. (In Russian)]. [Electronic resource]. URL: https://https://apps.who.int/iris/bitstream/handle/10665/345356/WHO-2019-nCoV-therapeutics-2021.3-rus.pdf (date of access: 20.02.2022 г.)

12. Salvarani C., Dolci G., Massari M., Merlo D.F., Cavuto S., Savoldi L., Bruzzi P., Boni F., Braglia L., Turrà C., Ballerini P.F., Sciascia R., Zammarchi L., Para O., Inojosa W.O., Ravagnani V., Salerno N.D., Sainaghi P.P., Brignone A., Codeluppi M., Teopompi E., Milesi M., Bertomoro P., Claudio N., Salio M., Falcone M., Cenderello G., Donghi L., Bono V.D., Colombelli P.L., Angheben A., Passaro A., Secondo G., Pascale R., Piazza I., Facciolongo N., Costantini M. Effect of Tocilizumab vs Standard Care on Clinical Worsening in Patients Hospitalized With COVID-19 Pneumonia. JAMA Intern. Med. 2021;181(1):24–31. DOI: 10.1001/jamainternmed.2020.6615

13. Okoh A.K., Bishburg E., Grinberg S., Nagarakanti S. Tocilizumab use in COVID‐19‐associated pneumonia. J. Med. Virol. 2021;93(2):1023–1028. DOI: 10.1002/jmv.26471

14. Knorr J.P., Colomy V., Mauriello C.M., Ha S. Tocilizumab in patients with severe COVID-19: A single-center observational analysis. J. Med. Virol. 2020;92(11):2813–2820. DOI: 10.1002/jmv.26191

15. Шперлинг М.И., Ковалев А.В., Сукачев В.С., Власов А.А., Поляков А.С., Носков Я.А., Морозов А.Д., Мерзляков В.С.,Звягин цев Д.П., Козлов К.В., Жданов К.В. Моноцитоз у больных коронавирусной пневмонией на фоне лечения глюкокортикоидами. Вестник Российской Военно-медицинской академии. 2021;23(4):105–112. [Shperling M.I., Kovalev A.V., Sukachev V.S., Vlasov A.A., Poljakov A.S., Noskov Ja.A., Morozov A.D., Merzljakov V.S., Zvjagincev D.P., Kozlov K.V., Zhdanov K.V. Monocytosis in patients with coronavirus pneumonia after treatment with glucocorticoids. Vestnik Rossijskoj Voenno-medicinskoj akademii.2021;23(4):105–112 (In Russian)]. [Electronic resource]. URL: https: https://elibrary.ru/item.asp?id=47813439 (date of access: 25.02.2022 г.)

16. Тополянская С.В. Роль интерлейкина 6 при старении и возрастассоциированных заболеваниях. Клиницист. 2020;14(3–4):14–21. DOI: 10.17650/1818-8338-2020-14-3-4-К633. [Topolyanskaya S.V. Interleukin 6 in aging and age-related diseases. The Clinician. 2020;14(3–4):14–21. (In Russian)]

17. Swamy S., Koch C.A., Hannah-Shmouni F., Schiffrin E.L., KluboGwiezdzinska J., Gubbie S. Hypertension and COVID-19: Updates from the era of vaccines and variants. J. Clin. Transl Endocrinol.2022;27(100285):1–7. DOI: 10.1016/j.jcte.2021.100285

18. Targher G., Mantovani A., Wang X.B., Yan H.D., Sun Q.F., Pan K.H., Byrne C.D., Zheng K.I., Chen Y.P., Eslam M., George J., Zhengg M.H. Patients with diabetes are at higher risk for severe illness from COVID-19. Diabetes Metab. 2020;46(4):335–337. DOI: 10.1016/j.diabet.2020.05.001

19. Marfella R., Paolisso P., Sardu C., Bergamaschi L., D’Angelo E.C., Barbieri M., Rizzo M.R., Messina V., Maggi P., Coppola N., Pizzi C., Biffi M., Viale P., Galié N., Paolisso G. Negative impact of hyperglycaemia on tocilizumab therapy in COVID-19 patients. Diabetes Metab. 2020;46(5):403–405. DOI: 10.1016/j.diabet.2020.05.005

20. Козлов К.В., Ратникова А.К., Гриневич В.Б., Кравчук Ю.А., Миклуш П.И. Микробиота и кишечная проницаемость как драйверы гастроэнтерологических проявлений новой коронавирусной инфекции (COVID-19). Журнал инфектологии. 2021;13(4):57–

21. [Kozlov K.V., Ratnikova A.K., Grinevich V.B., Kravchuk Yu.A., Miklush P.I. Microbiota and intestinal permeability as drivers of gastroenterological manifestations of new coronavirus infection(COVID-19). Journal Infectology. 2021;13(4):57–65 (In Russian)]. DOI: 10.22625/2072-6732-2021-13-4-57-65