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Impact of tocilizumab on clinical outcomes in severe covid-19 patients and risk of secondary infection: A case-control study

Year 2021, Volume: 34 Issue: 2, 112 - 119, 31.05.2021
https://doi.org/10.5472/marumj.942700

Abstract

Objective: This study aimed to identify the effect of tocilizumab (TCZ) on clinical outcomes in severe COVID-19 patients.
Material and Methods: We included hospitalized COVID-19 patients with an initial WHO scale ≥4. We matched the patients with
baseline characteristics by using propensity scores. Then, we selected patients with C-reactive protein levels above 30 and showing
an upward trend. We assessed the effect of TCZ in patients on clinical outcomes by using Mann – Whitney U and Chi-square tests.
Results: Of 200 patients who had an initial WHO scale ≥ 4, 42 (21%) were given TCZ in addition to standard of care (SOC). Twentyfive
patients (50%) needed mechanical ventilation (MV) in the TCZ group, compared with 35 (21%) of 158 patients with SOC
(p<0.01). Nineteen (45%) and 37 (23%) patients died in 30 days in these groups, respectively (p <0.01). The secondary infection rate
was significantly higher in the TCZ group (p=0.004). However, no difference was observed in all these parameters in the propensity
score-matched cohort (14 patients in TCZ and 14 in the SOC group) (p=0.45, 0.45, 1.0 respectively).
Conclusions: Tocilizumab does not provide a beneficial effect on MV requirement and mortality in severe COVID-19, and it does not
increase the risk of secondary bacterial infection.

References

  • World Health Organization. Coronavirus Disease 2019 (COVID-19) – Situation Report. Available at: <https:// www.who.int/publications/m/item/weekly-epidemiologicalupdate—- 29-december-2020>. Accessed: 05.01.2021
  • Moore JB, June CH. Cytokine release syndrome in severe COVID-19. Science 2020;368:473-4. doi: 10.1126/science. abb8925
  • Hirano T, Murakami M. COVID-19: A new virus, but a familiar receptor and cytokine release syndrome. Immunity 2020;52:731-3. doi: 10.1016/j.immuni.2020.04.003
  • 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;395:1054-62. doi:https://doi.org/10.1016/S0140-6736(20)30566-3
  • Mehta P, McAuley DF, Brown M, et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 2020;395:1033-4. doi:https://doi.org/10.1016/S0140- 6736(20)30628-0
  • Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395:497-506. doi:https://doi.org/10.1016/S0140- 6736(20)30183-5
  • Zhang C, Wu Z, Li JW, 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;55:105954. doi: 10.1016/j.ijantimicag.2020.105954
  • Navarro G, Taroumian S, Barroso N, et al. Tocilizumab in rheumatoid arthritis: a meta-analysis of efficacy and selected clinical conundrums. Semin Arthritis Rheum 2014;43:458-69. doi: 10.1016/j.semarthrit.2013.08.001
  • Yokota S, Miyamae T, Imagawa T, et al. Therapeutic efficacy of humanized recombinant anti-interleukin-6 receptor antibody in children with systemic-onset juvenile idiopathic arthritis. Arthritis Rheum2005;52:818-25. doi: 10.1002/art.20944
  • Navarro-Millan I, Singh JA, Curtis JR. Systematic review of tocilizumab for rheumatoid arthritis: a new biologic agent targeting the interleukin-6 receptor. Clin Ther 2012;34:788- 802 e3. doi: 10.1016/j.clinthera.2012.02.014
  • Luo P, Liu Y, Qiu L, et al. Tocilizumab treatment in COVID-19: A single center experience. J Med Virol 2020;92:814-8. doi: 10.1002/jmv.25801
  • Sciascia S, Apra F, Baffa A, et al. Pilot prospective open, single-arm multicentre study on off-label use of tocilizumab in patients with severe COVID-19. Clin Exp Rheumatol 2020;38:529-32.
  • Xu X, Han M, Li T, et al. Effective treatment of severe COVID-19 patients with tocilizumab. Proc Natl Acad Sci U S A 2020;117:10970-5. doi: 10.1073/pnas.200.561.5117
  • Klopfenstein T, Zayet S, Lohse A, et al. Tocilizumab therapy reduced intensive care unit admissions and/or mortality in COVID-19 patients. Med Mal Infect 2020;50:397-400. doi: 10.1016/j.medmal.2020.05.001
  • Rossotti R, Travi G, Ughi N, et al. Safety and efficacy of antiil6- receptor tocilizumab use in severe and critical patients affected by coronavirus disease 2019: A comparative analysis. J Infect 2020;81:e11-e7. doi: 10.1016/j.jinf.2020.07.008
  • Guaraldi G, Meschiari M, Cozzi-Lepri A, et al. Tocilizumab in patients with severe COVID-19: a retrospective cohort study. Lancet Rheumatol2020;2:e474-e84. doi: 10.1016/S2665- 9913(20)30173-9
  • Capra R, De Rossi N, Mattioli F, et al. Impact of low dose tocilizumab on mortality rate in patients with COVID-19 related pneumonia. Eur J Intern Med 2020;76:31-5. doi: 10.1016/j.ejim.2020.05.009
  • Hill JA, Menon MP, Dhanireddy S, et al. Tocilizumab in hospitalized patients with COVID-19: Clinical outcomes, inflammatory marker kinetics, and safety. J Med Virol 2020. doi: 10.1002/jmv.26674
  • Patel K, Gooley TA, Bailey N, et al. Use of the IL-6R antagonist tocilizumab in hospitalized COVID-19 patients. J Intern Med 2020. doi: 10.1111/joim.13163
  • Somers EC, Eschenauer GA, Troost JP, et al. Tocilizumab for treatment of mechanically ventilated patients with COVID-19. Clin Infect Dis 2020;ciaa954. doi: 10.1093/cid/ciaa954
  • World Health Organisation (WHO). COVID-19 Therapeutic Trial Synopsis. Available at: <https://www.who.int/ publications/i/item/covid-19-therapeutic-trial-synopsis>. Accessed: 20.07.2020
  • National Institutes of Health (NIH). Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. Clinical Spectrum of SARS-CoV-2 Infection. Available at: <https://www. covid19treatmentguidelines.nih.gov/overview/clinicalspectrum/>. Accessed: 27.07.2020
  • Austin PC. An introduction to propensity score methods for reducing the effects of confounding in observational studies. Multivariate Behav Res 2011;46:399-424. doi: 10.1080/00273.171.2011.568786
  • Henderson AR. Testing experimental data for univariate normality. Clin Chim Acta 2006;366:112-29. doi: 10.1016/j. cca.2005.11.007
  • Huang I, Pranata R, Lim MA, et al. C-reactive protein, procalcitonin, D-dimer, and ferritin in severe coronavirus disease-2019: a meta-analysis. Ther Adv Respir Dis 2020;14:175.346.6620937175. doi: 10.1177/175.346.6620937175
  • Zhou B SJ, Wang Y, Ma X. Utility of ferritin, procalcitonin, and C-reactive protein in severe patients with 2019 novel coronavirus disease. Research Square 2020. doi:10.21203/ rs.3.rs-18079/v1
  • Yang K, Sheng Y, Huang C, et al. Clinical characteristics, outcomes, and risk factors for mortality in patients with cancer and COVID-19 in Hubei, China: a multicentre, retrospective, cohort study. Lancet Oncol 2020;21:904-13. doi: 10.1016/ S1470-2045(20)30310-7
  • Huang I, Pranata R. Lymphopenia in severe coronavirus disease-2019 (COVID-19): systematic review and meta-analysis. J Intensive Care 2020;8:36. doi:10.1186/ s40560.020.00453-4
  • Liu J, Li S, Liu J, et al. Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients. EBioMedicine 2020;55:102763. doi: 10.1016/j.ebiom.2020.102763
  • Stone JH, Frigault MJ, Serling-Boyd NJ, et al. Efficacy of Tocilizumab in Patients Hospitalized with Covid-19. N Engl J Med 2020;383:2333-44. doi: 10.1056/NEJMoa2028836
  • Rossi B, Nguyen LS, Zimmermann P, et al. Effect of tocilizumab in hospitalized patients with severe covid-19 pneumonia: A case-control cohort study. Pharmaceuticals (Basel) 2020;13 :317. doi :10.3390/ph13100317
  • Campochiaro C, Della-Torre E, Cavalli G, et al. Efficacy and safety of tocilizumab in severe COVID-19 patients: a single-centre retrospective cohort study. Eur J Intern Med 2020;76:43-9. doi: 10.1016/j.ejim.2020.05.021
  • Rojas-Marte G, Khalid M, Mukhtar O, et al. Outcomes in patients with severe COVID-19 disease treated with tocilizumab: a case-controlled study. QJM 2020;113:546-50. doi: 10.1093/qjmed/hcaa206
  • Allenbach Y, Saadoun D, Maalouf G, et al. Development of multivariable prediction model of intensive care unit transfer or death: A French prospective cohort study of COVID-19 patients. PLoS ONE 2020;15:e0240711. doi: doi.org/10.1371/ journal.pone.0240711
  • RECOVERY Collaborative Group HP, Horby P, Lim WS, Emberson JR, et al. Dexamethasone in hospitalized patients with Covid-19. N Engl J Med 2021; 384:693-704. doi: 10.1056/ NEJMoa2021436
  • Nelson BC, Laracy J, Shoucri S, et al. Clinical Outcomes Associated with Methylprednisolone in Mechanically Ventilated Patients with COVID-19. Clin Infect Dis 2021;72:e367-372.. doi: 10.1093/cid/ciaa1163
  • Fernandez-Ruiz M, Lopez-Medrano F, Perez-Jacoiste Asin MA, et al. , . Combination therapy with tocilizumab and corticosteroids for aged patients with severe COVID-19 pneumonia: A single-center retrospective study. J Med Virol 2021;93:831-42 doi. 10.1002/jmv.26308
  • Langford BJ, So M, Raybardhan S, et al. Bacterial co-infection and secondary infection in patients with COVID-19: a living rapid review and meta-analysis. Clin Microbiol Infect 2020;26:1622-9. doi:10.1016/j.cmi.2020.07.016
Year 2021, Volume: 34 Issue: 2, 112 - 119, 31.05.2021
https://doi.org/10.5472/marumj.942700

Abstract

References

  • World Health Organization. Coronavirus Disease 2019 (COVID-19) – Situation Report. Available at: <https:// www.who.int/publications/m/item/weekly-epidemiologicalupdate—- 29-december-2020>. Accessed: 05.01.2021
  • Moore JB, June CH. Cytokine release syndrome in severe COVID-19. Science 2020;368:473-4. doi: 10.1126/science. abb8925
  • Hirano T, Murakami M. COVID-19: A new virus, but a familiar receptor and cytokine release syndrome. Immunity 2020;52:731-3. doi: 10.1016/j.immuni.2020.04.003
  • 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;395:1054-62. doi:https://doi.org/10.1016/S0140-6736(20)30566-3
  • Mehta P, McAuley DF, Brown M, et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 2020;395:1033-4. doi:https://doi.org/10.1016/S0140- 6736(20)30628-0
  • Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395:497-506. doi:https://doi.org/10.1016/S0140- 6736(20)30183-5
  • Zhang C, Wu Z, Li JW, 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;55:105954. doi: 10.1016/j.ijantimicag.2020.105954
  • Navarro G, Taroumian S, Barroso N, et al. Tocilizumab in rheumatoid arthritis: a meta-analysis of efficacy and selected clinical conundrums. Semin Arthritis Rheum 2014;43:458-69. doi: 10.1016/j.semarthrit.2013.08.001
  • Yokota S, Miyamae T, Imagawa T, et al. Therapeutic efficacy of humanized recombinant anti-interleukin-6 receptor antibody in children with systemic-onset juvenile idiopathic arthritis. Arthritis Rheum2005;52:818-25. doi: 10.1002/art.20944
  • Navarro-Millan I, Singh JA, Curtis JR. Systematic review of tocilizumab for rheumatoid arthritis: a new biologic agent targeting the interleukin-6 receptor. Clin Ther 2012;34:788- 802 e3. doi: 10.1016/j.clinthera.2012.02.014
  • Luo P, Liu Y, Qiu L, et al. Tocilizumab treatment in COVID-19: A single center experience. J Med Virol 2020;92:814-8. doi: 10.1002/jmv.25801
  • Sciascia S, Apra F, Baffa A, et al. Pilot prospective open, single-arm multicentre study on off-label use of tocilizumab in patients with severe COVID-19. Clin Exp Rheumatol 2020;38:529-32.
  • Xu X, Han M, Li T, et al. Effective treatment of severe COVID-19 patients with tocilizumab. Proc Natl Acad Sci U S A 2020;117:10970-5. doi: 10.1073/pnas.200.561.5117
  • Klopfenstein T, Zayet S, Lohse A, et al. Tocilizumab therapy reduced intensive care unit admissions and/or mortality in COVID-19 patients. Med Mal Infect 2020;50:397-400. doi: 10.1016/j.medmal.2020.05.001
  • Rossotti R, Travi G, Ughi N, et al. Safety and efficacy of antiil6- receptor tocilizumab use in severe and critical patients affected by coronavirus disease 2019: A comparative analysis. J Infect 2020;81:e11-e7. doi: 10.1016/j.jinf.2020.07.008
  • Guaraldi G, Meschiari M, Cozzi-Lepri A, et al. Tocilizumab in patients with severe COVID-19: a retrospective cohort study. Lancet Rheumatol2020;2:e474-e84. doi: 10.1016/S2665- 9913(20)30173-9
  • Capra R, De Rossi N, Mattioli F, et al. Impact of low dose tocilizumab on mortality rate in patients with COVID-19 related pneumonia. Eur J Intern Med 2020;76:31-5. doi: 10.1016/j.ejim.2020.05.009
  • Hill JA, Menon MP, Dhanireddy S, et al. Tocilizumab in hospitalized patients with COVID-19: Clinical outcomes, inflammatory marker kinetics, and safety. J Med Virol 2020. doi: 10.1002/jmv.26674
  • Patel K, Gooley TA, Bailey N, et al. Use of the IL-6R antagonist tocilizumab in hospitalized COVID-19 patients. J Intern Med 2020. doi: 10.1111/joim.13163
  • Somers EC, Eschenauer GA, Troost JP, et al. Tocilizumab for treatment of mechanically ventilated patients with COVID-19. Clin Infect Dis 2020;ciaa954. doi: 10.1093/cid/ciaa954
  • World Health Organisation (WHO). COVID-19 Therapeutic Trial Synopsis. Available at: <https://www.who.int/ publications/i/item/covid-19-therapeutic-trial-synopsis>. Accessed: 20.07.2020
  • National Institutes of Health (NIH). Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. Clinical Spectrum of SARS-CoV-2 Infection. Available at: <https://www. covid19treatmentguidelines.nih.gov/overview/clinicalspectrum/>. Accessed: 27.07.2020
  • Austin PC. An introduction to propensity score methods for reducing the effects of confounding in observational studies. Multivariate Behav Res 2011;46:399-424. doi: 10.1080/00273.171.2011.568786
  • Henderson AR. Testing experimental data for univariate normality. Clin Chim Acta 2006;366:112-29. doi: 10.1016/j. cca.2005.11.007
  • Huang I, Pranata R, Lim MA, et al. C-reactive protein, procalcitonin, D-dimer, and ferritin in severe coronavirus disease-2019: a meta-analysis. Ther Adv Respir Dis 2020;14:175.346.6620937175. doi: 10.1177/175.346.6620937175
  • Zhou B SJ, Wang Y, Ma X. Utility of ferritin, procalcitonin, and C-reactive protein in severe patients with 2019 novel coronavirus disease. Research Square 2020. doi:10.21203/ rs.3.rs-18079/v1
  • Yang K, Sheng Y, Huang C, et al. Clinical characteristics, outcomes, and risk factors for mortality in patients with cancer and COVID-19 in Hubei, China: a multicentre, retrospective, cohort study. Lancet Oncol 2020;21:904-13. doi: 10.1016/ S1470-2045(20)30310-7
  • Huang I, Pranata R. Lymphopenia in severe coronavirus disease-2019 (COVID-19): systematic review and meta-analysis. J Intensive Care 2020;8:36. doi:10.1186/ s40560.020.00453-4
  • Liu J, Li S, Liu J, et al. Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients. EBioMedicine 2020;55:102763. doi: 10.1016/j.ebiom.2020.102763
  • Stone JH, Frigault MJ, Serling-Boyd NJ, et al. Efficacy of Tocilizumab in Patients Hospitalized with Covid-19. N Engl J Med 2020;383:2333-44. doi: 10.1056/NEJMoa2028836
  • Rossi B, Nguyen LS, Zimmermann P, et al. Effect of tocilizumab in hospitalized patients with severe covid-19 pneumonia: A case-control cohort study. Pharmaceuticals (Basel) 2020;13 :317. doi :10.3390/ph13100317
  • Campochiaro C, Della-Torre E, Cavalli G, et al. Efficacy and safety of tocilizumab in severe COVID-19 patients: a single-centre retrospective cohort study. Eur J Intern Med 2020;76:43-9. doi: 10.1016/j.ejim.2020.05.021
  • Rojas-Marte G, Khalid M, Mukhtar O, et al. Outcomes in patients with severe COVID-19 disease treated with tocilizumab: a case-controlled study. QJM 2020;113:546-50. doi: 10.1093/qjmed/hcaa206
  • Allenbach Y, Saadoun D, Maalouf G, et al. Development of multivariable prediction model of intensive care unit transfer or death: A French prospective cohort study of COVID-19 patients. PLoS ONE 2020;15:e0240711. doi: doi.org/10.1371/ journal.pone.0240711
  • RECOVERY Collaborative Group HP, Horby P, Lim WS, Emberson JR, et al. Dexamethasone in hospitalized patients with Covid-19. N Engl J Med 2021; 384:693-704. doi: 10.1056/ NEJMoa2021436
  • Nelson BC, Laracy J, Shoucri S, et al. Clinical Outcomes Associated with Methylprednisolone in Mechanically Ventilated Patients with COVID-19. Clin Infect Dis 2021;72:e367-372.. doi: 10.1093/cid/ciaa1163
  • Fernandez-Ruiz M, Lopez-Medrano F, Perez-Jacoiste Asin MA, et al. , . Combination therapy with tocilizumab and corticosteroids for aged patients with severe COVID-19 pneumonia: A single-center retrospective study. J Med Virol 2021;93:831-42 doi. 10.1002/jmv.26308
  • Langford BJ, So M, Raybardhan S, et al. Bacterial co-infection and secondary infection in patients with COVID-19: a living rapid review and meta-analysis. Clin Microbiol Infect 2020;26:1622-9. doi:10.1016/j.cmi.2020.07.016
There are 38 citations in total.

Details

Primary Language English
Subjects Clinical Sciences
Journal Section Original Articles
Authors

Buket Erturk Sengel This is me 0000-0003-2182-4693

Serra Ozel This is me 0000-0003-2111-1183

Fethi Gul This is me 0000-0002-6426-6436

Can Ilgın This is me 0000-0003-1751-8546

Elif Tukenmez Tıgen This is me 0000-0003-2027-4116

Luftiye Nilsun Altunal This is me 0000-0003-4794-9283

Feyyaz Kabadayı This is me 0000-0003-1177-7360

Uluhan Sılı This is me 0000-0002-9939-9298

Mehtap Aydın This is me 0000-0003-4044-9366

Zekaver Odabası This is me 0000-0001-8091-6999

Ismail Cınel This is me 0000-0002-7595-1295

Volkan Korten This is me 0000-0002-9991-814X

Publication Date May 31, 2021
Published in Issue Year 2021 Volume: 34 Issue: 2

Cite

APA Erturk Sengel, B., Ozel, S., Gul, F., Ilgın, C., et al. (2021). Impact of tocilizumab on clinical outcomes in severe covid-19 patients and risk of secondary infection: A case-control study. Marmara Medical Journal, 34(2), 112-119. https://doi.org/10.5472/marumj.942700
AMA Erturk Sengel B, Ozel S, Gul F, Ilgın C, Tukenmez Tıgen E, Altunal LN, Kabadayı F, Sılı U, Aydın M, Odabası Z, Cınel I, Korten V. Impact of tocilizumab on clinical outcomes in severe covid-19 patients and risk of secondary infection: A case-control study. Marmara Med J. May 2021;34(2):112-119. doi:10.5472/marumj.942700
Chicago Erturk Sengel, Buket, Serra Ozel, Fethi Gul, Can Ilgın, Elif Tukenmez Tıgen, Luftiye Nilsun Altunal, Feyyaz Kabadayı, Uluhan Sılı, Mehtap Aydın, Zekaver Odabası, Ismail Cınel, and Volkan Korten. “Impact of Tocilizumab on Clinical Outcomes in Severe Covid-19 Patients and Risk of Secondary Infection: A Case-Control Study”. Marmara Medical Journal 34, no. 2 (May 2021): 112-19. https://doi.org/10.5472/marumj.942700.
EndNote Erturk Sengel B, Ozel S, Gul F, Ilgın C, Tukenmez Tıgen E, Altunal LN, Kabadayı F, Sılı U, Aydın M, Odabası Z, Cınel I, Korten V (May 1, 2021) Impact of tocilizumab on clinical outcomes in severe covid-19 patients and risk of secondary infection: A case-control study. Marmara Medical Journal 34 2 112–119.
IEEE B. Erturk Sengel, “Impact of tocilizumab on clinical outcomes in severe covid-19 patients and risk of secondary infection: A case-control study”, Marmara Med J, vol. 34, no. 2, pp. 112–119, 2021, doi: 10.5472/marumj.942700.
ISNAD Erturk Sengel, Buket et al. “Impact of Tocilizumab on Clinical Outcomes in Severe Covid-19 Patients and Risk of Secondary Infection: A Case-Control Study”. Marmara Medical Journal 34/2 (May 2021), 112-119. https://doi.org/10.5472/marumj.942700.
JAMA Erturk Sengel B, Ozel S, Gul F, Ilgın C, Tukenmez Tıgen E, Altunal LN, Kabadayı F, Sılı U, Aydın M, Odabası Z, Cınel I, Korten V. Impact of tocilizumab on clinical outcomes in severe covid-19 patients and risk of secondary infection: A case-control study. Marmara Med J. 2021;34:112–119.
MLA Erturk Sengel, Buket et al. “Impact of Tocilizumab on Clinical Outcomes in Severe Covid-19 Patients and Risk of Secondary Infection: A Case-Control Study”. Marmara Medical Journal, vol. 34, no. 2, 2021, pp. 112-9, doi:10.5472/marumj.942700.
Vancouver Erturk Sengel B, Ozel S, Gul F, Ilgın C, Tukenmez Tıgen E, Altunal LN, Kabadayı F, Sılı U, Aydın M, Odabası Z, Cınel I, Korten V. Impact of tocilizumab on clinical outcomes in severe covid-19 patients and risk of secondary infection: A case-control study. Marmara Med J. 2021;34(2):112-9.