EFFECTS OF TOCILIZUMAB AND SYSTEMIC CORTICOSTEROIDS IN PATIENTS WITH CARDIOVASCULAR DISEASE ON CLINICAL OUTCOMES IN COVID-19

Zudi Osmani1image, Belma Paralija2image, *Rusmir Baljić3image

1Institute for public health, Mehmeda Spahe 1, 72270 Travnik, Bosnia and Herzegovina.

2Clinic of Lung Diseases and Tuberculosis, Clinical Centre University of Sarajevo, Bardakcije 90, 71000 Sarajevo.

3Clinic of Infectious Diseases, Clinical Center University of Sarajevo, Bolnicka 25, 71000 Sarajevo, Bosnia and Herzegovina.

 

 

Abstract

 

Background: COVID-19 is a respiratory disease caused by a novel coronavirus, with a high mortality, especially in patients with underlying diseases. Patients with COVID-19 pneumonia may express an immune response such as cytokine storm or macrophage activation syndrome, which can lead to organ failure and death.Some studies suggest that corticosteroid and tocilizumab can improve the respiratory status and clinical outcome of patients with COVID-19 pneumonia. 

Aim: The aim of the study was to determine the potential effect of the use of tocilizumab and corticosteroids in patients with concomitant cardiovascular diseases on the clinical course and outcome during COVID-19 infection.

Methods: We performed an observational retrospective study of adult patients admitted to “Travnik” and “Jajce” Hospital, Bosnia and Herzegovina, between 01.03.2020 and 01.12.2022 with confirmed COVID-19 and underlying cardiovascular disease (CVD).

Results: The majority of patients (110 or 60.4%) had previously reported cardiomyopathy, and other cardiovascular disease included earlier myocardial infarction, stroke, cardiac arrhythmias, cardiac surgery, compensated cardial disease, and acute myocardial infarction. Total of 159 (87.4%) patients received corticosteroids during treatment. Tocilizumab has been used in 16 patients; nine survived and seven died. 

Conclusion: Even some studies proved that it might improve clinical presentation and prevent lethal outcomes; in our study there were no significant results to confirm this thesis.

Keywords: COVID-19, corticosteroids, respiratory disease, tocilizumab.

INTRODUCTION

 

COVID-19 is a respiratory disease caused by a novel coronavirus, with high mortality, especially in patients with underlying diseas1. Most people with COVID-19 will have a mild form of disease, but older patients, males and those with comorbidity have a higher risk for an unfavourable outcome2. Patients with COVID-19 pneumonia can express immune response such as cytokine storm or macrophage activation syndrome, which can lead to organ failure and death3. Previous studies reported a strong association between underlying cardiovascular diseases and bad prognosis for COVID-19 patients4. Tocilizumab is a monoclonal antibody against interleukin-6, and it is used for the therapy of some inflammatory disease5. Some studies suggest that Tocilizumab can improve the respiratory status and clinical outcome of patients with COVID-19 pneumonia6. Corticosteroids are widely in use for the treatment of COVID-19 patients; even their role in the therapy is still controversial. In some studies there was no significant decrease in mortality after use of high dose of dexamethasone7.

The aim of the present study was to determine the potential impact of tocilizumab and corticosteroid use in patients with concomitant cardiovascular disease on the clinical course and outcome during COVID-19 infection.

 

SUBJECTS AND METHODS

 

We conducted an observational retrospective study of patients admitted to “Travnik” and “Jajce” Hospital, Bosnia and Herzegovina, between 1 March 2020 to 1 December 2920. Inclusion criteria were PCR confirmed diagnosis of COVID-19, age of patients 18 years and above, medical record of previously diagnosed of underlying cardiovascular disease (CVD). Data necessary for the study were retrieved from the patient's history: age, sex, duration of symptoms before hospitalisation, need for oxygen support with facial mask, corticosteroids and tocilizumab use, developed complication, requirement for invasive ventilation, and the outcome of disease. Among 355 hospitalised patients, 182 of them had one or more CVD. We collected clinical and demographic data including cardiovascular comorbidities, use of tocilizumab and systemic corticosteroids, complications, and outcomes of the disease.  The statistical analysis of data was done by SPSS version 24 statistical program and Microsoft Excel version 11.  Level of p<0.05 considered  as statistically significant. After statistical analysis, results were presented by tables and graphicons. The research was approved by the Ethics Committee of the both medical centres.

 

RESULTS

 

Among 355 analysed histories of admitted patients with COVID 19, 182 met inclusion criteria. Infection with SARS-COV-2 virus was confirmed with PCR analysis. All patients had COVID-19 pneumonia, verified by chest X-ray of CT scan. There were 113 (62%) male and 69 (39%) female patients (Figure 1).  The median age of the patients was 67.5, ranged 33 – 90 years. Median prehospital time was 7 days, in the range of 3-14 days. The majority of patients (110 or 60.4%) had a previously registered cardiomyopathy, and other CVD included earlier myocardial infarction, stroke, arrhythmias, cardiac surgery, compensated cardial disease, and acute myocardial infarct.

Values of CRP range from 3 mg/dl to 403 g/dl, with a median of 153 g/dl. Median value of peripheral oxygen saturation  at admission was 82.1% (range 44-99%),  and 40 (22%) of them required oxygen support with a facial mask.

Total of 159 (87.4%) patients received corticosteroids during treatment, 155 (85.2%) Dexamethason in a dose of 6 mg per day for 10 days and 4 (2.2%) patients Metilprednizolon, in a dose of 80 mg per day, total 8 days. Tocilizumab in a dose of 600mg twice daily was given to 16 (8.8%) patients, while 166 (91.2%) did not receive it (Table 1). During treatment, 88 (48.4%) of patients developed one of the possible life-threatening complications: acute respiratory distress syndrome or pulmonary embolism (Table 2). Corticosteroids were used in total 159 (87.4%) patients, and 78 (48.4%) of them developed complications, while 81 (51.6%) did not (Table 3). Chi-square test did not find any difference between these groups.

Tocilizumab was used in total 16 (8.8%) patients, and 11 (6%) of them developed complications, while 5 (2.7%) did not (Table 3). Chi-square test did not find any difference between these groups. Among patients who used corticosteroids 94 (51.7%) of them survived, and 65 (35.7%) died (Table 4).   Nine  patients who received tocilizumab survived and seven died (Table 4). Chi-sqare test found no difference in outcome regarding use of corticosteroids and tocilizumab, p>0.05. We used univariate binary regression to determine possible influence of multiple factors (prehospital time, age, sex, presented complications, CRP values, use of tocilizumab and corticosteroids) to outcome of the disease. The statistically significant individual influence (p<0.05) according to Wald coefficients were: complications (Wald=19.19; OR= 0.09), age (Wald=6.76:=OR=1.07), and values of CRP (Wald=6.34; OR=1.006). 

Other variables were not of significant influence.  The values of Cox and Snell R2=0.356 and Nagelkerke R2=0.483 show that the set of variables explain 35.6% to 48.3% of the variance. Hosmer and Lemeshow test support the claim that the model is good: Chi-sqare =12.312, p=0.138.

 

DISCUSSION

 

The use of corticosteroids in the treatment of bacterial or viral infection is always controversial. Corticosteroids affect the innate and adaptive immune systems and can improve conditions in many infectious states, but also in some cases no improvement is achieved8.  In some syndromes, like SARS, MERS or severe influenza, corticosteroids have been widely used, but without strong evidence of efficacy. On the other hand, some studies of corticosteroid use in SARS or MERS concluded that this therapy can also be harmful9. The recovery trial proved efficacy of using dexamethason (6 mg/day/10 days) but only in patients who required respiratory support. In these patients, corticosteroid therapy reduced 28-day overall mortality10. Cytokine storm is a usual manifestation of the severe form of COVID-19.  The main characteristics are systemic inflammatory response and elevated levels of cytokines, including CRP, ferritin, interleukin-6. which usually lead to mutiple organ dysfunction11,12.  Acute respiratory distress syndrome (ARDS) has been described in almost half of the COVID-19 patients who developed severe forms of the disease.

Use of corticosteroids in such patients can improve clinical status and shorten the requirement for mechanical ventilation, with a reduction in mortality13. The use of corticosteroids in patients with moderate to severe ARDS is also recommended by The Society of Critical Care Medicine and European Society of Intensive Care Medicine14.  So far, almost all studies conducted during COVID-19 pandemic suggest that corticosteroid therapy in COVID-19 must be titrated and tampered after clinical improvement. Also prolonged treatment or high dosage of corticosteroids should be avoided15. In our study almost 88% of the patients received corticosteroidal therapy. Despite that, 81 developed clinical presentation with complications, and 65 died, which is almost 41%. Acute respiratory distress syndrome was a complication presented in 84 (46.2%) cases which is similar to previously published studies16.  Unfortunately, most of the patients arrived after 7 days of presented symptoms and treatment as outpatients, already with severe clinical presentation at admission, which in most cases progressed to non-invasive or invasive ventilation. Use of tocilizumab had different results in patients with Covid-19, which depended of disease severity, type of care and protocol used17. In most cases, the reason for use of tolicizumab was increase in CRP values, ferritin or dramatic deterioration of clinical state. Protocols for tolicizumab changed over the time, while in the beginning two doses of a maximum of 800 mg per dose were recommended, but after conducted studies the dose was set to one, and second dose only as optional18.

 

CONCLUSIONS

 

The use of corticosteroids and tocilizumab in the treatment of COVID-19 patients with pneumonia remains controversial. Some studies have even shown that it may improve clinical presentation and prevent fatal outcomes; in most cases, there have been no significant results to confirm this hypothesis. Our results in patients with comorbid heart disease and COVID-19 pneumonia did not demonstrate that corticosteroids and tocilizumab can be effective in preventing complications or fatal outcomes.

Limitation of the study

We were not able to follow values of C-reactive protein or Interleukin-6 during the treatment with corticosteroids and tocilizumab, since during the COVID-19 pandemic laboratories were under high pressure and could not receive and process so many requests for additional test. In that situation it is difficult to distinct influence of COVID itself, and concomitant cardivascular diseases for the clinical course. Nevertheless, out results are similar to the form previous studies: use of corticosteroids and tocilizumab are not “game-changers”, especially in the patients with concomitant cardiovascular diseases.

 

ACKNOWLEDGEMENT

 

Authors are thankful for Clinical Center University of Sarajevo, Bosnia and Herzegovina to provide necessary facilities required for this work. 

 

AUTHOR’S CONTRIBUTIONS

 

Osmani Z: methodology, investigation. Paralija B: critical review, data processing. Baljić R: review and editing, formal analysis. All authors reviewed and approved the final version of the article.

 

CONFLICT OF INTEREST 

 

None to declare. 

 

REFERENCES

 

  1. Huang C, Wang Y, Li X, Ren L, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020 Feb 15; 395(10223):497-506. https://doi.org/10.1016/S0140-6736(20)30183-5
  2. Wu J, Liu J, Zhao X, et al. Clinical characteristics of imported cases of coronavirus disease 2019 (COVID-19) in Jiangsu province: A multicenter descriptive study. Clin Infect Dis 2020; 71(15):706-712.https://doi.org/10.1093/cid/ciaa199
  1. Leisman DE, Ronner L, Pinotti R, et al. Cytokine elevation in severe and critical COVID-19: A rapid systematic review, meta-analysis, and comparison with other inflammatory syndromes. Lancet Respir Med 2020; 8:1233–1244.https://doi.org/10.1016/S2213-2600(20)30404-5
  1. Aggarwal G, Cheruiyot I, Aggarwal S, et al. Association of Cardiovascular Disease With Coronavirus Disease 2019 (COVID-19) Severity: A meta-analysis. Curr Probl Cardiol 2020 Aug; 45(8):100617.https://doi.org/10.1016/j.cpcardiol.2020.100617
  1. Rubbert-Roth A, Furst DE, Nebesky JM, Jin A, Berber E. A review of recent advances using tocilizumab in the treatment of rheumatic diseases. Rheumatol Ther 2018; 5:21-42. https://doi.org/10.1007/s40744-018-0102-x
  2. Petrelli F, Cherri S, Ghidini M, Perego G, Ghidini A, Zaniboni A. Tocilizumab as treatment for COVID-19: A systematic review and meta-analysis. World J Methodol. 2021 May 20;11(3):95-109.https://doi.org/10.5662/wjm.v11.i3.95
  1. Jamaati H, Hashemian SM, Farzanegan B, et al. No clinical benefit of high dose corticosteroid administration in patients with COVID-19: A preliminary report of a randomized clinical trial. Eur J Pharmacol 2021; 897:173947. https://doi.org/10.1016/j.ejphar.2021.173947
  2. Ni YN, Chen G, Sun J, Liang BM, Liang ZA. The effect of corticosteroids on mortality of patients with influenza pneumonia: A systematic review and meta-analysis. Crit Care 2019; 23:99.https://doi.org/10.1186/s13054-019-2395-8
  1. Arabi YM, Mandourah   Y, Al-Hameed   F, et al.  Saudi Critical Care Trial Group. Corticosteroid therapy for critically ill patients with Middle East respiratory syndrome. Am J Respir Crit Care Med 2018;197(6):757-767. https://doi.org/10.1164/rccm.201706-1172OC
  2. Recovery Collaborative Group. Dexamethasone in Hospitalized Patients with Covid-19. N Engl J Med 2021 Feb 25; 384(8):693-704.https://doi.org/10.1056/NEJMoa2021436
  1. Moore JB, June CH. Cytokine release syndrome in severe COVID-19. Science 2020; 368:473-474.https://doi.org/10.1126/science.abb8925
  1. Fajgenbaum DC, June CH. Cytokine Storm. N Engl J Med 2020;383:2255–73.https://doi.org/10.1056/NEJMra2026131
  1. van Paassen J, Vos JS, Hoekstra EM, et al. Corticosteroid use in COVID-19 patients: a systematic review and meta-analysis on clinical outcomes. Crit Care 2020 Dec 14;24(1):696.https://doi.org/10.1186/s13054-020-03400-9
  1. Annane D, Pastores SM, Rochwerg B, et al. Guidelines for the diagnosis and management of Critical Illness-Related Corticosteroid Insufficiency (CIRCI) in Critically Ill Patients (Part I): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017. Crit Care Med 2017;45:2078–88. https://doi.org/10.1097/CCM.0000000000002737
  2. Villar J, Ferrando C, Martínez D, et al. Dexamethasone in ARDS network. Dexamethasone treatment for the acute respiratory distress syndrome: A multicentre, randomised controlled trial. Lancet Respir Med 2020;8:267–76. https://doi.org/10.1016/S2213-2600(19)30417-5
  3. Piluso M, Ferrari C, Pagani, et al. COVID-19 Acute respiratory distress syndrome: Treatment with helmet CPAP in respiratory intermediate care unit by pulmonologists in the three Italian Pandemic Waves. Adv Respir Med 2023 Sep 20; 91(5):383-396.https://doi.org/10.3390/arm91050030
  1. Salama C, Han J, Yau L, et al. Tocilizumab in patients hospitalized with Covid-19 Pneumonia. N Engl J Med 2021; 384:20-30. https://doi.org/10.1056/NEJMoa2030340
  1. Hasanin A, Mostafa M. Tocilizumab in patients with COVID-19: which patient, time, and dose? J Anesth 2021 Dec; 35(6):896-902.https://doi.org/10.1007/s00540-021-02974-0
  1. REMAP-CAP. Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19. N Engl J Med 2021 Apr 22; 384(16):1491-1502.https://doi.org/10.1056/NEJMoa2100433
  1. Soin AS, Kumar K, Choudhary NS, et al. Tocilizumab plus standard care versus standard care in patients in India with moderate to severe COVID-19-associated cytokine release syndrome (COVINTOC): An open-label, multicentre, randomised, controlled, phase 3 trials. Lancet Respir Med 2021 May; 9(5):511-521.https://doi.org/10.1016/S2213-2600(21)00081-3
  1. Veiga VC, Prats JAGG, Farias DLC, Rosa RG, 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 Jan 20;372:n84.https://doi.org/10.1136/bmj.n84
  2. Salvarani C, Dolci G, Massari M, et al. Effect of tocilizumab vs standard care on clinical worsening in patients hospitalized with COVID-19 pneumonia: A randomized clinical trial. JAMA Intern Med 2021 Jan 1;181(1):24-31. https://doi.org/10.1001/jamainternmed.2020.6615