Anti-inflammatory therapy for COVID-19: effectiveness and predictors of response

Abstract

BACKGROUND: According to the international guidelines and expert opinions, medicines for the treatment of COVID-19 are prescribed off-label; however, the final decision is made by a physician based on an assessment of the risk/benefit ratio for each patient. Global studies of the efficacy and safety of the use of baricitinib, tocilizumab, olokizumab, dexamethasone in the treatment of COVID-19 are ongoing. There is no information about comparative efficacy of these drugs and on the prognosis of their use in COVID-19.

AIM: To compare the effects of pre-emptive anti-inflammatory therapy (PAT) with tocilizumab, olokizumab, baricitinib, dexamethasone in patients with COVID-19 to identify response predictors and the choice of the most effective treatment.

MATERIALS AND METHODS: A retrospective analysis of 229 cases of severe and moderate course of COVID-19 requiring various types of UPT at the Hospital for War Veterans has been carried out.

RESULTS: In the study of 229 clinical cases of severe COVID-19, it was found that the most significant predictors of the effects of anticytokine therapy include C-reactive protein (CRP), body mass index (BMI), body temperature, saturation level and the need for a certain type of oxygen support at the start of a therapy, platelet count, hematocrit, neutrophil count, and duration of the disease from its onset to development of signs of a cytokine storm. The probability of recovery in the patients with early appointment of UPT increases by 13%; the need for additional oxygen support increases the risk of mortality by 5.3 times as it increases with the transition to each subsequent level; an increase in the level of CRP by 1% increases the unfavorable prognosis; an increase in D-dimer worsens the prognosis by 16%.

CONCLUSION: Based on the statistical data obtained by the method of stepwise regression analysis, was proposed method for predicting the effectiveness of proactive anti-inflammatory therapy in novel coronavirus infections.

Keywords

COVID-19 / community-acquired pneumonia / tocilizumab / baricitinib / dexamethasone / olokizumab / anti-inflammatory therapy / cytokine storm / anti-cytokine therapy / efficacy prediction

References

[1] International register “Dynamics analysis of comorbidities in SARS-CoV-2 survivors” (AKTIV SARS-CoV-2): analysis of predictors of short-term adverse outcomes in COVID-19. Russian Journal of Cardiology. 2021;26(4):116–131. DOI: 10.15829/1560-4071-2021-4470

[2] Международный регистр «Анализ динамики Коморбидных заболеваний у пациентов, перенесших инфицирование SARS-CoV-2» (АКТИВ SARS-CoV-2): анализ предикторов неблагоприятных исходов острой стадии новой коронавирусной инфекции // Российский кардиологический журнал. 2021. Vol. 26, No. 4. P. 116–131. DOI: 10.15829/1560-4071-2021-4470

[3] Materialy po koronavirusu dlya terapevtov [Internet]. Ofitsial'nyy sayt Evraziyskoy Assotsiatsii Terapevtov. Available from: https://euat.ru/covid-19/publications. Accessed: Sept 25, 2021. (In Russ.)

[4] Материалы по коронавирусу для терапевтов [Электронный ресурс] // Официальный сайт Евразийской Ассоциации Терапевтов. Режим доступа: https://euat.ru/covid-19/publications. Дата обращения: 25.09.2021.

[5] Shimabukuro-Vornhagen A, Gödel P, Subklewe M, et al. Cytokine release syndrome. J Immunother Cancer. 2018;6(1):56. DOI: 10.1186/s40425- 018-0343-9

[6] Shimabukuro-Vornhagen A., Gödel P., Subklewe M. et al. Cytokine release syndrome // J. Immunother. Cancer. 2018. Vol. 6, No. 1. P. 56. DOI: 10.1186/s40425- 018-0343-9

[7] Zhang C, Wu Z, Li J-W, et al. Cytokine release syndrome in severe COVID-19: interleukin-6 receptor antagonist tocilizumab may be the key to reduce mortality. Int J Antimicrob Agents. 2020;55(5):105954. DOI: 10.1016/j.ijantimicag.2020.105954

[8] Zhang C., Wu Z., Li J.-W. et al. Cytokine release syndrome in severe COVID-19: interleukin-6 receptor antagonist tocilizumab may be the key to reduce mortality // Int. J. Antimicrob. Agents. 2020. Vol. 55, No. 5. P. 105954. DOI: 10.1016/j.ijantimicag.2020.105954

[9] Vremennye metodicheskie rekomendatsii. Profilaktika, diagnostika i lechenie novoy koronavirusnoy infektsii (COVID-19). Versiya 12 ot 21.09.2021 [Internet]. Available from: http://nasci.ru/?id=50819. Accessed: Sept 15, 2021. (In Russ.)

[10] Временные методические рекомендации. Профилактика, диагностика и лечение новой коронавирусной инфекции (COVID-19). Версия 12 от 21.09.2021. [Электронный ресурс]. Режим доступа: http://nasci.ru/?id=50819. Дата обращения: 15.09.2021.

[11] Liu Y, Wang Z, Ren J, et al. A COVID-19 Risk assessment decision support system for general practitioners: design and development study. J Med Internet Res. 2020;22:(6):e19786. DOI: 10.2196/19786

[12] Liu Y., Wang Z., Ren J. et al. A COVID-19 Risk assessment decision support system for general practitioners: design and development study // J. Med. Internet Res. 2020. Vol. 22, No. 6. P. e19786. DOI: 10.2196/19786

[13] Patent RU2751410C1/13.07.2021. Shkurnikov MYu, Nersisyan SA, Tonevickij AG. Method for assessing the risk of development of severe COVID-19. (In Russ.)

[14] Патент RU2751410C1/13.07.2021. Шкурников М.Ю., Нерсисян С.А., Тоневицкий А.Г. Способ оценки риска развития тяжелой формы COVID-19.

[15] Patent RU2736341C1/16.11.2020. Stepanova YuA, Kirillova MS, Kurochkina AI. Sposob prognozirovaniya techeniya pnevmonii pri COVID-19 na osnovanii sopostavleniya rezul’tatov UZI i MSKT legkikh. (In Russ.)

[16] Патент RU2736341C1/16.11.2020. Степанова Ю.А., Кириллова М.С., Курочкина А.И. Способ прогнозирования течения пневмонии при COVID-19 на основании сопоставления результатов УЗИ и МСКТ легких.

[17] WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, Sterne JAC, Murthy S, et al. Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: a meta-analysis. JAMA. 2020;324:1330–1341. DOI: 10.1001/jama.2020.17023

[18] WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, Sterne JAC, Murthy S, et al. Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: a meta-analysis // JAMA. 2020. Vol. 324. P. 1330–1341. DOI: 10.1001/jama.2020.17023

[19] Veiga VC, Prats JAGG, Farias DLC, et al. Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randomised controlled trial. BMJ. 2021;372:n84. DOI: 10.1136/bmj.n84

[20] Veiga V.C., Prats J.A.G.G., Farias D.L.C. et al. Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randomised controlled trial // BMJ. 2021. Vol. 372. P. n84. DOI: 10.1136/bmj.n84

[21] Fomina DS, Poteshkina NG, Beloglazova IP, et al. Comparative analysis of tocilizumab in severe COVID-19-associated pneumonia in patients of different age groups. Pulmonologiya. 2020;30(2):164–172. (In Russ.). DOI: 10.18093/0869-0189-2020-30-2-164-172

[22] Фомина Д.С., Потешкина Н.Г., Белоглазова И.П. и др. Сравнительный анализ применения тоцилизумаба при тяжелых COVID-19-ассоциированных пневмониях у пациентов разных возрастных групп // Пульмонология. 2020. Т. 30, № 2. С. 164–172. DOI: 10.18093/0869-0189-2020-30-2-164-172

[23] Fomina DS, Lysenko MA, Beloglazova IP, et al. Temporal clinical and laboratory response to Interleukin-6 receptor blockade with Tocilizumab in 89 hospitalized patients with COVID-19 pneumonia. Pathog Immun. 2020;5(1):327–341. DOI: 10.20411/pai.v5i1.392

[24] Fomina D.S., Lysenko M.A., Beloglazova I.P. et al. Temporal clinical and laboratory response to Interleukin-6 receptor blockade with Tocilizumab in 89 hospitalized patients with COVID-19 pneumonia // Pathog. Immun. 2020. Vol. 5, No. 1. P. 327–341. DOI: 10.20411/pai.v5i1.392

[25] Tocilizumab in COVID-19 Pneumonia (TOCIVID-19) ClinicalTrials.gov NCT04317092.

[26] Ganyukova NG, Likstanov MI, Kosinova MV, et al. Efficiency of IL-6 inhibitor (olokizumab) in suppressing inflammation in patients with moderate COVID-19 pneumonia. Fundamental and Clinical Medicine. 2020;5(4):8–13. (In Russ.). DOI: 10.23946/2500-0764-2020-5-4-8-13

[27] Ганюкова Н.Г., Ликстанов М.И., Косинова М.В. и др. Эффективность таргетной терапии ингибитором ил-6 (олокизумаб) в купировании гипервоспаления при среднетяжелой пневмонии, обусловленной вирусом Sars-Cov-2 // Фундаментальная и клиническая медицина. 2020. Т. 5, № 4. С. 8–13. DOI: 10.23946/2500-0764-2020-5-4-8-13

[28] Cantini F, Niccoli L, Nannini C, et al. Beneficial impact of Baricitinib in COVID-19 moderate pneumonia; multicentre study. J Infect. 2020;81(4):647–679. DOI: 10.1016/j.jinf.2020.06.052

[29] Cantini F., Niccoli L., Nannini C. et al. Beneficial impact of Baricitinib in COVID-19 moderate pneumonia; multicentre study // J. Infect. 2020. Vol. 81, No. 4. P. 647–679. DOI: 10.1016/j.jinf.2020.06.052

[30] Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395:1054–1062. DOI: 10.1016/S0140-6736(20)30566-3

[31] Zhou F., Yu T., Du R. et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study // Lancet. 2020. Vol. 395. P. 1054–1062. DOI: 10.1016/S0140-6736(20)30566-3

[32] Sayganov SA, Mazurov VI, Bakulin IG, et al. Current, effectiveness of therapy and outcomes of new coronavirus infection: preliminary analysis. Herald of North-Western State Medical University named after I.I. Mechnikov. 2020;12(2):27–38. (In Russ.). DOI: 10.17816/mechnikov34932

[33] Сайганов С.А., Мазуров В.И., Бакулин И.Г. и др. Клиническое течение, эффективность терапии и исходы новой коронавирусной инфекции: предварительный анализ // Вестник Северо-Западного государственного медицинского университета им. И.И. Мечникова. 2020. Т. 12, № 2. С. 27–38. DOI: 10.17816/mechnikov202012227-38

[34] Hermine O, Mariette X, Tharaux P-L, et al. Effect of tocilizumab vs usual care in adults hospitalized with COVID-19 and moderate or severe pneumonia: a randomized clinical trial. JAMA Intern Med. 2021;181(1):32–40. DOI: 10.1001/jamainternmed.2020.6820

[35] Hermine O., Mariette X., Tharaux P.-L. et al. Effect of tocilizumab vs usual care in adults hospitalized with COVID-19 and moderate or severe pneumonia: a randomized clinical trial // JAMA Intern. Med. 2021. Vol. 181, No. 1. P. 32–40. DOI: 10.1001/jamainternmed.2020.6820

[36] Drapkina OM, Mayev IV, Bakulin IG, et al. Provisional guidelines: “Diseases of the digestive organs in conditions of a pandemic new coronavirus infection (COVID-19)”. Version 2. Profilakticheskaya Meditsina. 2021;24(5–2):4–41. (In Russ.). DOI: 10.17116/profmed2021240524

[37] Драпкина О.М., Маев И.В., Бакулин И.Г. и др. Временные методические рекомендации: «Болезни органов пищеварения в условиях пандемии новой коронавирусной инфекции (COVID-19)». Версия 2 // Профилактическая медицина. 2021. Т. 24, № 5–2. С. 4–41. DOI: 10.17116/profmed2021240524

[38] ClinicalTrials.gov: Идентификатор EudraCT : 2020-001386-37 [Internet]. Accessed: Sept 15, 2021.

[39] ClinicalTrials.gov: Идентификатор EudraCT : 2020-001386-37 [Электронный ресурс]. Дата обращения: 15.09.2021.

[40] Sciascia S, Aprà F, Baffa A, et al. Pilot prospective open, single-arm multicentre study on off-label use of tocilizumab in patients with severe COVID-19. Сlin Exp Rheumatol. 2020;38(3):529–532.

[41] Sciascia S., Aprà F., Baffa A. et al. Pilot prospective open, single-arm multicentre study on off-label use of tocilizumab in patients with severe COVID-19 // Сlin. Exp. Rheumatol. 2020. Vol. 38, No. 3. P. 529–532.

[42] Truhacheva NV. Medicinskaya statistika: uchebnoe posobie. Rostov-na-Donu: Feniks, 2017. (In Russ.)

[43] Трухачева Н.В. Медицинская статистика: учебное пособие. Ростов-на-Дону: Феникс, 2017.

[44] Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579(7798):270–273. DOI: 10.1038/s41586-020-2012-7

[45] Zhou P., Yang X.L., Wang X.G. et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin // Nature. 2020. Vol. 579, No. 7798. P. 270–273. DOI: 10.1038/s41586-020-2012-7

[46] Wang X, Fang X, Cai Z, et al. Comorbid chronic diseases and acute organ injuries are strongly correlated with disease severity and mortality among covid-19 patients: a systemic review and meta-analysis. Research (Wash DC). 2020;2020:2402961. DOI: 10.34133/2020/2402961

[47] Wang X., Fang X., Cai Z. et al. Comorbid chronic diseases and acute organ injuries are strongly correlated with disease severity and mortality among covid-19 patients: a systemic review and meta-analysis // Research (Wash DC). 2020. Vol. 2020. P. 2402961. DOI: 10.34133/2020/2402961

[48] Bonafe M, Prattichizzo F, Giuliani A, et al. Inflamm-ag-ing: Why older men are the most susceptible to SARS-CoV-2 complicated outcomes. Cytokine Growth Factor Rev. 2020;53:33–37. DOI: 10.1016/j.cytog-fr.2020.04.005

[49] Bonafe M., Prattichizzo F., Giuliani A. et al. Inflamm-ag-ing: Why older men are the most susceptible to SARS-CoV-2 complicated outcomes // Cytokine Growth Factor Rev. 2020. Vol. 53. P. 33–37. DOI: 10.1016/j.cytog-fr.2020.04.005

[50] Martin-Rodriguez F, Lopez-Izquierdo R, Del Pozo Vegas C, et al. Can the prehospital National Early Warning Score 2 identify patients at risk of in-hospital early mortality? A prospective, multicenter cohort study. Heart Lung. 2020;49(5):585–591. DOI: 10.1016/j.hrtlng.2020.02.047

[51] Martin-Rodriguez F., Lopez-Izquierdo R., Del Pozo Vegas C. et al. Can the prehospital National Early Warning Score 2 identify patients at risk of in-hospital early mortality? A prospective, multicenter cohort study // Heart Lung. 2020. Vol. 49, No. 5. P. 585–591. DOI: 10.1016/j.hrtlng.2020.02.047

[52] Luk AOY, Ng SSS, Holt RIG. Impact of diabetes on COVID-19 and other infection: Report from the 22nd Hong Kong Diabetes and Cardiovascular Risk Factors – East Meets West Symposium. Diabet Med. 2021;38(5):e14547. DOI: 10.1111/dme.14547

[53] Luk A.O.Y., Ng S.S.S., Holt R.I.G. Impact of diabetes on COVID-19 and other infection: Report from the 22nd Hong Kong Diabetes and Cardiovascular Risk Factors – East Meets West Symposium // Diabet Med. 2021. Vol. 38, No. 5. P. e14547. DOI: 10.1111/dme.14547

RIGHTS & PERMISSIONS

Sukhomlinova I.M., Bakulin I.G., Kabanov M.Y.