Risk of secondary bacterial infections during treatment with anti-inflammatory genetically engineered biological drugs in COVID-19 patients

The aim of the work was to identify the presence and strength of association between the use of anti-inflammatory genetically engineered biological drugs and the development of secondary bacterial infections in COVID-19 patients.

Materials and methods. We used 1 296 medical records of patients hospitalized in the infectious diseases hospital of the Volgograd region with a diagnosis of COVID-19 in September 2020, March and September 2021, March, September and November 2022, have been analyzed. A matched case-control study was performed with 275 pairs identical in gender, age (±2 years), the severity of the lung damage according to computed tomography / chest X-ray, a COVID-19 outcome, concomitant carbohydrate metabolism disorders. Patients with the signs of the secondary bacterial infection (leukocytes ≥12×109/l, procalcitonin ≥0.5 ng/ml and/or viral-bacterial pneumonia according to the autopsy data) were presented as a case. The “control” group included patients without signs of any bacterial infection (leukocytes <11×109/l, procalcitonin <0.5 ng/ml, no description of clinical signs of the bacterial infection in the medical record during the hospitalization). The prescription of 6 anti-inflammatory genetically engineered biological drugs (tocilizumab, sarilumab, olokizumab, levilimab, netakimab, secukinumab) has been studied for these groups.

Results. The use of any anti-inflammatory genetically engineered biological drug was associated with the development of the secondary bacterial infection signs (OR=2.41; 95% CI: from 1.54 to 3.77; p <0.001): for levilimab, the OR was 3.44 (95% CI: from 1.64 to 7.23; p <0.001), for tocilizumab – OR=1.75 (95% CI: from 0.73 to 4.17; p=0.201), for olokizumab – OR=1.28 (95% CI: from 0.81 to 2.03; p=0.292).

Conclusion. Among the three drugs (tocilizumab, olokizumab, levilimab), the Russian biosimilar olokizumab, a monoclonal antibody to circulating interleukin-6, has shown itself as the safest drug in terms of preventing the secondary bacterial infection signs. Further studies of developing bacterial complications risk in COVID-19 patients receiving anti-inflammatory genetically engineered biological drugs are required.

1. Egorov AYu. The problem of bacterial complications in respiratory viral infections. Microbiology Independent Research journal. 2018;5(1);1–11. DOI: 10.18527/2500-2236-2018-5-1-1-11

2. Morens DM, Taubenberger JK, Fauci AS. Predominant role of bacterial pneumonia as a cause of death in pandemic influenza: implications for pandemic influenza preparedness. J Infect Dis. 2008;198(7);962–70. DOI: 10.1086/591708

3. Farrell JM, Zhao CY, Tarquinio KM, Brown SP. Causes and Consequences of COVID-19-Associated Bacterial Infections. Front Microbiol. 2021;12;682571. DOI: 10.3389/fmicb.2021.682571

4. Chieng Yeo C, Teo J, Clarke SC, Morris DE, Cleary DW. Secondary bacterial infections associated with influenza pandemics. Front Microbiol. 2012;8;1041. DOI: 10.3389/fmicb.2017.01041

5. Mirzaei R, Goodarzi P, Asadi M, Soltani A, Aljanabi HAA, Jeda AS, Dashtbin S, Jalalifar S, Mohammadzadeh R, Teimoori A, Tari K, Salari M, Ghiasvand S, Kazemi S, Yousefimashouf R, Keyvani H, Karampoor S. Bacterial co-infections with SARS-CoV-2. IUBMB Life. 2020;72(10);2097–111. DOI: 10.1002/iub.2356.

6. Langford BJ, So M, Raybardhan S, Leung V, Westwood D, MacFadden DR, Soucy JR, Daneman N. Bacterial co-infection and secondary infection in patients with COVID-19: a living rapid review and meta-analysis. Clin Microbiol Infect. 2020;26(12);1622–9. DOI: 10.1016/j.cmi.2020.07.016

7. Chong WH, Saha BK, Ananthakrishnan Ramani, Chopra A. State-of-the-art review of secondary pulmonary infections in patients with COVID-19 pneumonia. Infection. 2021;49(4);591–605. DOI: 10.1007/s15010-021-01602-z

8. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, Guan L, Wei Y, Li H, Wu X, Xu J, Tu S, Zhang Y, Chen H, Cao B. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229);1054–62. DOI: 10.1016/S0140-6736(20)30566-3

9. Wang L, He W, Yu X, Hu D, Bao M, Liu H, Zhou J, Jiang H. Coronavirus disease 2019 in elderly patients: Characteristics and prognostic factors based on 4-week follow-up. J Infect. 2020;80(6);639–45. DOI: 10.1016/j.jinf.2020.03.019

10. Ferrando C, Mellado-Artigas R, Gea A, Arruti E, Aldecoa C, Bordell A, Adalia R, Zattera L, Ramasco F, Monedero P, Maseda E, Martínez A, Tamayo G, Mercadal J, Muñoz G, Jacas A, Ángeles G, Castro P, Hernández-Tejero M, Fernandez J, Gómez-Rojo M, Candela Á, Ripollés J, Nieto A, Bassas E, Deiros C, Margarit A, Redondo FJ, Martín A, García N, Casas P, Morcillo C, Hernández-Sanz ML; de la Red de UCI Española para COVID-19. Patient characteristics, clinical course and factors associated to ICU mortality in critically ill patients infected with SARS-CoV-2 in Spain: A prospective, cohort, multicentre study. Rev Esp Anestesiol Reanim (Engl Ed). 2020;67(8);425–37. English, Spanish. DOI: 10.1016/j.redar.2020.07.003

11. Dejager L, Vandevyver S, Ballegeer M, Van Wonterghem E, An LL, Riggs J, Kolbeck R, Libert C. Pharmacological inhibition of type I interferon signaling protects mice against lethal sepsis. J Infect Dis. 2014;209(6);960–70. DOI: 10.1093/infdis/jit600

12. Li W, Moltedo B, Moran TM. Type I interferon induction during influenza virus infection increases susceptibility to secondary Streptococcus pneumoniae infection by negative regulation of gammadelta T cells. J Virol. 2012;86(22);12304-12. DOI:10.1128/JVI.01269-12.

13. Shahangian A, Chow EK, Tian X, Kang JR, Ghaffari A, Liu SY, Belperio JA, Cheng G, Deng JC. Type I IFNs mediate development of postinfluenza bacterial pneumonia in mic. J ClinInvest. 2009;119(7);1910–20. DOI: 10.1172/JCI35412

14. Petrov VI, Ryazanova AY, Nekrasov DA, Svinukhov VI, Privaltseva NS. Safety of Therapy with Tocilizumab and Other Interleukin Inhibitors. Safety and Risk of Pharmacotherapy. 2022;10(1);34–47. DOI: 10.30895/2312-7821-2022-10-1-34-47

15. Schiff MH, Kremer JM, Jahreis A, Vernon E, Isaacs JD, van Vollenhoven RF. Integrated safety in tocilizumab clinical trials. Arthritis Res Ther. 2011;13(5);R141. DOI: 10.1186/ar3455

16. Saki A, Rajaei E, Rahim F. Safety and efficacy of tocilizumab for rheumatoid arthritis: a systematic review and metaanalysis of clinical trial studies. Reumatologia/Rheumatology. 2021;59(3);169-179. DOI:10.5114/reum.2021.107026.

17. Choy E, Freemantle N, Proudfoot C, Chen CI, Pollissard L, Kuznik A, Van Hoogstraten H, Mangan E, Carita P, Huynh TM. Evaluation of the efficacy and safety of sarilumab combination therapy in patients with rheumatoid arthritis with inadequate response to conventional disease-modifying antirheumatic drugs or tumour necrosis factor α inhibitors: systematic literature review and network meta-analyses. RMD Open. 2019;5:e000798. DOI: 10.1136/rmdopen-2018-000798

18. Rutherford AI, Subesinghe S, Hyrich KL, Galloway JB. Serious infection across biologic-treated patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis. Ann Rheum Dis. 2018;77(6);905–10. DOI: 10.1136/annrheumdis-2017-212825

19. Grzhibovsky AM, Ivanov SV, Gorbatova MA. Case-control studies in healthcare. Science and health care. 2015;4;5–17. Russian

20. Rossotti R, Travi G, Ughi N, Corradin M, Baiguera C, Fumagalli R, Bottiroli M, Mondino M, Merli M, Bellone A, Basile A, Ruggeri R, Colombo F, Moreno M, Pastori S, Perno CF, Tarsia P, Epis OM, Puoti M; Niguarda COVID-19 Working Group. Safety and efficacy of anti-il6-receptor tocilizumab use in severe and critical patients affected by coronavirus disease 2019: A comparative analysis. J Infect. 2020;81(4):e11-e17. DOI: 10.1016/j.jinf.2020.07.008.

21. Minihan B, McAuliffe E, Powell J, Wong SL, Wilkie K, Murphy C, Maher A, Power L, O’Connell NH, Dunne CP. Association between tocilizumab treatment of hyperinflammatory patients with COVID-19 in a critical care setting and elevated incidence of hospital-acquired bacterial and invasive fungal infections. J Hosp Infect. 2022;126;29–36. DOI: 10.1016/j.jhin.2022.04.007

22. Moreno-Torres V, de Mendoza C, de la Fuente S, Sánchez E, Martínez-Urbistondo M, Herráiz J, Gutiérrez A, Gutiérrez Á, Hernández C, Callejas A, Maínez C, Royuela A, Cuervas-Mons V; Puerta de Hierro COVID-19 working group. Bacterial infections in patients hospitalized with COVID-19. Intern Emerg Med. 2022;17(2);431–8. DOI:10.1007/s11739-021-02824-7

23. Moore JL, Stroever SJ, Rondain PE, Scatena RN. Incidence of Secondary Bacterial Infections Following Utilization of Tocilizumab for the Treatment of COVID-19 – A Matched Retrospective Cohort Study. J Glob Infect Dis. 2021;13(2);67–71. DOI: 10.4103/jgid.jgid_358_20

24. Agarwal A, Hunt B, Stegemann M, Rochwerg B, Lamontagne F, Siemieniuk RA, Agoritsas T, Askie L, Lytvyn L, Leo YS, Macdonald H, Zeng L, Alhadyan A, Muna A, Amin W, da Silva ARA, Aryal D, Barragan FAJ, Bausch FJ, Burhan E, Calfee CS, Cecconi M, Chacko B, Chanda D, Dat VQ, De Sutter A, Du B, Freedman S, Geduld H, Gee P, Haider M, Gotte M, Harley N, Hashimi M, Hui D, Ismail M, Jehan F, Kabra SK, Kanda S, Kim YJ, Kissoon N, Krishna S, Kuppalli K, Kwizera A, Lado Castro-Rial M, Lisboa T, Lodha R, Mahaka I, Manai H, Mendelson M, Migliori GB, Mino G, Nsutebu E, Peter J, Preller J, Pshenichnaya N, Qadir N, Ranganathan SS, Relan P, Rylance J, Sabzwari S, Sarin R, Shankar-Hari M, Sharland M, Shen Y, Souza JP, Swanstrom R, Tshokey T, Ugarte S, Uyeki T, Evangelina VC, Venkatapuram S, Vuyiseka D, Wijewickrama A, Tran L, Zeraatkar D, Bartoszko JJ, Ge L, Brignardello-Petersen R, Owen A, Guyatt G, Diaz J, Kawano-Dourado L, Jacobs M, Vandvik PO. A living WHO guideline on drugs for covid-19. BMJ. 2022;377:o1045. DOI: 10.1136/bmj.o1045

25. Kooistra EJ, van Berkel M, van Kempen NF, van Latum CRM, Bruse N, Frenzel T, van den Berg MJW, Schouten JA, Kox M, Pickkers P. Dexamethasone and tocilizumab treatment considerably reduces the value of C-reactive protein and procalcitonin to detect secondary bacterial infections in COVID-19 patients. Crit Care. 2021;25(1);281. DOI: 10.1186/s13054-021-03717-z