Use of immune-modulating agents to regulate hyperinflammation in severe COVID-19; the assessment of tocilizumab use in combination with steroids

doi:10.21203/rs.3.rs-3891806/v1

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Use of immune-modulating agents to regulate hyperinflammation in severe COVID-19; the assessment of tocilizumab use in combination with steroids

https://doi.org/10.21203/rs.3.rs-3891806/v1

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Introduction

COVID-19 infection might lead to hyperinflammatory state in severe cases leading to devastating outcomes. Immune modulation using steroids or other immune modulators can regulate the intensity of inflammatory response; however, this theory has not been adequately assessed in practice. The current study aims to investigate the use of corticosteroids alone or in combination with tocilizumab for the treatment of patients with severe COVID-19.

Methods

The current retrospective cross-sectional study has been conducted on 168 patients with severe COVID-19 infection who were categorized into three treatment groups of A: primary treatment with high-dose methylprednisolone (> 1 mg/kg) continued with tocilizumab; B: primary treatment with low-dose methylprednisolone (< 1 mg/kg) continued with tocilizumab and C: treatment with high-dose methylprednisolone (> 1 mg/kg) only. The parameters including clinical outcome, laboratory parameters, length of hospitalization, intensive care unit (ICU) admission requirement and drug-related adverse events were compared between the groups.

Results

The outcomes were significantly better in group B considering the shorter length of ICU stay, lower CRP, LDH, and higher oxygen saturation and platelet count in group B than the other groups (P-value < 0.05). Logistic regression assessment in crude and adjusted models revealed increased risks of mortality, the incidence of nosocomial infection and the incidence of adverse effects, including hepatic dysfunction, renal dysfunction and GIB in both groups A and C compared with group B (P-value < 0.05).

Conclusion

Based on the findings of this study, low-dose steroid continued with tocilizumab was superior over high-dose steroid alone or in combination with tocilizumab in terms of all evaluated parameters.

COVID-19

Tocilizumab

Steroids

COVID-19 infection emerged in Wuhan, China, in late days of December 2019. Soon, the world faced a remarkable pandemic to the extent that millions of individuals were involved with the infection found to be caused by a novel coronavirus named as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)(1).

Although most of the infected patients experienced asymptomatic to mild course of the disease limited to malaise, fever, cough and flu-like syndrome, up to 10% of them required hospitalization due to the incidence of acute respiratory distress syndrome (ARDS), multiorgan failure and intensive care unit (ICU) admission(2–4). The primary approach to the severe disease was restricted to supportive care including fluid management, oxygen therapy, and mechanical ventilation. However, as the time passed, the healthcare systems explored more potent and efficient treatments(5).

Given the hyperinflammatory state caused by COVID-19 infection, many authors focused on the immunomodulatory approaches including steroids and other immunomodulatory agents to regulate the intensity of inflammatory response(6, 7). However, the experience with SARS and MERS, the Infectious Diseases Society of America (IDSA) and the World Health Organization (WHO) cautioned against the use of systemic corticosteroids due to risk of worsening clinical status, delayed viral clearance, and adverse events(8, 9). Nevertheless, trials on the systemic glucocorticoids represented promising outcomes on the patients with severe COVID-19 or critically ill subjects leading to more inclination toward these agents(2, 10–13).

Moreover, some real life experiences in COVID-19 patients showed that the use of immunomodulatory agents might be beneficial. Given that, considering the presence of inflammatory cytokine storm in severe COVID-19, particularly interleukine-6 (IL-6), it has been proposed that tocilizumab, a monoclonal antibody binding to IL-6 receptor, might be beneficial for those with severe COVID-19(14). This agent was historically applied to mediate IL-6 associated inflammatory response in rheumatologic c disorders and cytokine-release syndrome associated with Chimeric Antigen Receptor T-cell (CAR-T) administration(15). The use of this agent in COVID-19 was accompanied by inconclusive, but promising outcomes(16–19). However, limited studies have evaluated its utility in combination with steroids or the best dosage of the medication. Accordingly, the current study aims to investigate the use of corticosteroids alone or in combination with tocilizumab for the treatment of patients with severe COVID-19.

Study population

The current retrospective cross-sectional study has been conducted on 168 patients with severe COVID-19 infection hospitalized at Al-Zahra Hospital affiliated with Isfahan University of medical Sciences from April 2021 to March 2022.

The study protocol was designed according to the tenets of Helsinki Declaration and proposed to the Ethics Committee of Isfahan University of Medical Sciences where approved it. The patients or their legal guardians were informed about the probable use of their medical data in scientific research, they were reassured regarding the confidentiality of their personal information and written informed consent was obtained by all the patients.

Over 18-year-old patients with documented COVID-19 infection based on the positivity of polymerase chain reaction (PCR) test who were categorized as severe COVID-19 infection or critically ill patient who did not respond to low-dose corticosteroid treatment were included. Severe COVID-19 infection was defined as on-admission oxygen saturation < 94%, PaO2/FiO2 < 300, respiratory rate > 30/min and lung infiltration of > 50%(20). Moreovor, critically ill patient was determined as acute respiratory distress syndrome (ARDS) and septic shock requiring intensive care unit (ICU) admission(21).

Pregnancy, serum platelet levels below 50000 per microliter, immunocompromised and absolute neutrophil count below 500 per microliter were defined as the unmet criteria. The patients whose length of hospital stay was less than 5 days and those with more than 20% defect in their medical data were excluded.

The studied population was selected through convenience sampling among all the patients who met the study criteria.

Patients subgrouping

The data of the studied patients whose infection was compatible with the severe form of COVID-19 infection or critically ill patient were recruited from the archives of Hospital Information System (HIS). All the included patients have been treated based on the latest national guidelines for COVID-19 infection treatment(22).

Then, the subjects were categorized into three subgroups of A: primary treatment with high-dose methylprednisolone (> 1 mg/kg) continued with tocilizumab; B: primary treatment with low-dose methylprednisolone (< 1 mg/kg) continued with tocilizumab and C: treatment with high-dose methylprednisolone (> 1 mg/kg) only(23).

Data collection

Afterward, the patients’ information including the demographic (age and gender), medical, clinical and laboratory data were gathered.

The recruited medical history of patients included Diabetes mellitus (DM), hypertension (HTN), ischemic heart disease (IHD), atrial fibrillation (AF), active malignancy, respiratory disease, hypothyroidism, congestive heart failure (CHF), Parkinson disease, dyslipidemia (DLP), history of coronary bypass grafting (CABG), chronic kidney disease (CKD), end-stage renal disease (ESRD), lichen planus, dementia, cerebrovascular accident (CVA), seizure and history of pulmonary thromboembolism (PTE).

Furthermore, the patients’ clinical data including on-admission and at discharge oxygen saturation and respiratory rate, the outcomes of hospitalization (death/ discharge), the length of hospital stay, the requirement for intensive care unit (ICU) admission and the length of ICU stay and the requirement for orotracheal intubation were collected.

Laboratory parameters C-reactive protein (CRP), lactate dehydrogenase (LDH), ferritin and platelet count were measured on-admission and within the fifth day of hospitalization.

Further investigations included drug-related adverse effects including the incidence of nosocomial infection, gastrointestinal bleeding (GIB), renal and hepatic failure.

Statistical analysis

The obtained data were entered into the Statistical Package for Social Sciences (SPSS Inc., Chicago, IL, USA) version 23. The qualitative data were presented as absolute numbers and percentages and the quantitative ones as mean and standard deviation. The normality of data distribution was assessed using the Smirnov-Kolmogorov test. The categorical data were compared using the Chi-square test. The continuous data were compared using ANOVA; in case of statistical significance, post-hoc tests were applied. Logistic regression analysis was performed in crude and adjusted models. P-value of less than 0.05 was determined as the level of significance.

In the current study, data of 168 patients in three groups of A (high-dose methylprednisolone (> 1 mg/kg) continued with tocilizumab), B (low-dose methylprednisolone (< 1 mg/kg) continued with tocilizumab) and C (high-dose methylprednisolone (> 1 mg/kg) only) were recruited. Given that, the patients were similar in terms of demographic, medical history, on-admission clinical and laboratory data (P-value > 0.05) except for their mean age (P-value = 0.04) and on-admission platelet count (P-value = 0.017). Detailed information is demonstrated in Table 1.

Table 1

Baseline data of the studied population
	Group A	Group B	Group C	P-value
Demographic information
Age (years), mean ± standard deviation	57.76 ± 13.14	55.28 ± 13.82	61.92 ± 14.64	0.04^#
Gender (male), n (%)	22 (39.3)	22 (39.3)	25 (44.6)	0.801^*
Medical history, n (%)
Diabetes mellitus	13 (23.2)	15 (26.8)	17 (30.4)	0.69^*
Hypertension	17 (30.4)	19 (33.9)	24 (42.9)	0.36^*
Ischemic heart disease	5 (8.9)	10 (17.9)	5 (8.9)	0.24^*
Atrial fibrillation	0 (0)	1 (1.8)	2 (3.6)	0.36^*
Active malignancy	0 (0)	1 (1.8)	0 (0)	0.36^*
Respiratory disease	3 (5.4)	3 (5.4)	2 (3.6)	0.87^*
Hypothyroidism	3 (5.4)	9 (16.1)	6 (10.7)	0.18^*
Congestive heart failure	0 (0)	1 (1.8)	2 (3.6)	0.36^*
Parkinson disease	0 (0)	0 (0)	2 (3.6)	0.13^*
Dyslipidemia	5 (8.9)	9 (16.1)	10 (17.9)	0.36^*
Coronary artery bypass grafting	0 (0)	5 (8.9)	1 (1.8)	0.027^*
Chronic kidney disease	1 (1.8)	1 (1.8)	3 (5.4)	0.43^*
End stage renal disease	0 (0)	0 (0)	0 (0)	-
Lichen planus	0 (0)	2 (3.6)	0 (0)	0.13^*
Dementia	0 (0)	1 (1.8)	0 (0)	0.36^*
Cerebrovascular accident	0 (0)	1 (1.8)	2 (3.6)	0.36^*
Seizure	2 (3.6)	1 (1.8)	1 (1.8)	0.77^*
Pulmonary thromboembolism	0 (0)	0 (0)	0 (0)	-
Clinical data
Interval between symptoms initiation and admission (days), mean ± standard deviation	8.87 ± 2.54	9.64 ± 3.45	9.28 ± 3.98	0.485^#
On-admission respiratory rate (per minute), mean ± standard deviation	27.82 ± 5.53	26.73 ± 5.07	26.98 ± 5.39	0.529^#
On-admission oxygen saturation (%), mean ± standard deviation	82.32 ± 10.21	84.71 ± 4.06	84.46 ± 4.96	0.139^#
On-admission C-reactive protein (mg/dl), mean ± standard deviation	89.85 ± 13.84	93.76 ± 10.58	88.76 ± 14.04	0.102^#
On-admission lactate dehydrogenase (U/Lit), mean ± standard deviation	11.81.08 ± 370.81	1193.58 ± 252.45	1206.55 ± 406.30	0.928^#
On-admission platelet count (per microliter), mean ± standard deviation	160539 ± 53488	169214 ± 54919	191982 ± 68259	0.017^#
On-admission ferritin (ng/ml), mean ± standard deviation	1624 ± 396	1619 ± 373	1553 ± 440	0.583^#
^#ANOVA ^*Chi-square test

The main scope of the study was to evaluate the efficacy of each therapeutic approach on the outcomes of the patients. Accordingly, the outcomes were categorized as the length of hospital and ICU stay, the incidence of adverse events and the effects of each approach on the clinical and laboratory parameters revealing remarkable difference between the groups in terms of the length of ICU stay (P-value = 0.004), orotracheal intubation requirement (P-value < 0.001), ICU admission requirement (P-value < 0.001), the incidence of renal dysfunction (P-value = 0.001), nosocomial infection (P-value < 0.001) and mortality rate (P-value < 0.001). The measured parameters including respiratory rate (P-value < 0.001), oxygen saturation (P-value < 0.001), CRP (P-value < 0.001), LDH (P-value < 0.001) and platelet count (P-value < 0.001) were significantly different among the groups (Table 2).

Table 2

The clinical outcomes of medications on the study population
	Group A	Group B	Group C	P-value
Length of hospital stay (days), mean ± standard deviation	14.80 ± 7.76	12.14 ± 6.97	12.92 ± 7.75	0.16^#
Length of ICU stay (days), mean ± standard deviation	7.27 ± 7.90	2.73 ± 5.04	5.89 ± 8.56	0.004^#
Adverse events, n (%)
Intubation	42 (75)	8 (14.3)	30 (53.6)	< 0.001^*
ICU admission requirement	38 (67.9)	17 (30.4)	33 (58.9)	< 0.001^*
Hepatic dysfunction	31 (55.4)	29 (51.8)	28 (50)	0.84^*
Renal dysfunction	25 (44.6)	10 (17.9)	29 (51.8)	0.001^*
Gastrointestinal bleeding	5 (8.9)	2 (3.6)	7 (12.5)	0.228^*
Nosocomial infection	41 (73.2)	5 (8.9)	26 (46.4)	< 0.001^*
Mortality	39 (69.6)	4 (7.1)	30 (53.6)	< 0.001^*
Fifth day laboratory parameters
Respiratory rate (per minute), mean ± standard deviation	29.67 ± 10.56	16.92 ± 5.66	26.41 ± 10.78	< 0.001^#
Oxygen saturation (%), mean ± standard deviation	75.94 ± 10.94	89.37 ± 5.11	81.37 ± 9.85	< 0.001^#
C-reactive protein (mg/dl), mean ± standard deviation	50.50 ± 36.08	17.17 ± 20.24	44.35 ± 35.39	< 0.001^#
Lactate dehydrogenase (U/Lit), mean ± standard deviation	1565 ± 751	872 ± 331	1394 ± 722	< 0.001^#
Platelet count (per microliter), mean ± standard deviation	165125 ± 83016	234785 ± 75048	206589 ± 103524	< 0.001^#
Ferritin (ng/ml), mean ± standard deviation	1653 ± 518	1018 ± 352	1815 ± 125	0.367^#
^#ANOVA ^*Chi-square test

Post-hoc test showed significantly shorter length of ICU stay, lower CRP, LDH, and higher oxygen saturation and platelet count in group B than the other groups (P-value < 0.05).

Logistic regression assessment in two crude and adjusted models revealed increased risks of mortality, the incidence of nosocomial infection and the incidence of adverse effects, including hepatic dysfunction, renal dysfunction and GIB in both groups A and C compared with group B (P-value < 0.05). Detailed information is depicted in Table 3.

Table 3

Logistic regression assessment
	Crude model				Adjusted model
Variables	Odds ratio	95% confidence interval		P-value	Odds ratio	95% confidence interval		P-value
Variables	Odds ratio	Minimum	Maximum	P-value	Odds ratio	Minimum	Maximum	P-value
Death^*
Group A	29.82	9.29	95.67	< 0.001	30.97	9.06	105.87	< 0.001
Group C	15	4.77	47.11	< 0.001	16.03	4.78	53.78	< 0.001
Constant (Group B)	1	-	-	-	1	-	-	-
Nosocomial infection^**
Group A	27.88	9.35	83.12	< 0.001	25.95	8.41	80.03	< 0.001
Group C	8.84	3.06	25.46	< 0.001	7.95	2.66	23.74	< 0.001
Constant (Group B)	1	-	-	-	1	-	-	-
Adverse effects^#
Group A	3.71	1.56	8.79	0.003	3.35	1.36	8.22	0.008
Group C	2.01	0.921	4.41	0.079	1.96	0.86	4.45	0.106
Constant (Group B)	1	-	-	-	1	-	-	-
^Adjusted for on-admission respiratory rate, CRP and oxygen saturation ^*Adjusted for the history ischemic heart disease, on-admission ^#Adjusted for gender distribution, hypothyroidism and lickenplanus

Despite all the progresses achieved in the management of COVID-19 infection by the emergence of various vaccines and therapeutic approaches, SARS-CoV-2 remained a health matter that might return to a significant challenge within days and months again. Moreover, although COVID-19 management in outpatient setting has turned to a negligible disease, the management of severe forms particularly critically ill patients is still a debating issue(24). Given that, we tried to investigate the utility of three regimens including high-dose corticosteroid only, low-dose or high-dose corticosteroid in combination with tocilizumab among these subjects. Our investigation revealed that low-dose corticosteroid combined with tocilizumab was superior over the other two approaches in terms of lower incidence of adverse events and mortality, lower rate and length of ICU stay as well as better laboratory parameters measured within the fifth day of interventions. Moreover, logistic regression assessment represented significant increased risk of adverse events, nosocomial infection and mortality among those treated with high-dose corticosteroids only or in combination with tocilizumab compared with low-dose steroids plus tocilizumab.

One of the lethal events following severe COVID-19 infection is cytokine storm in which IL-6 plays a critical role, a condition leading to theories regarding the use of immunomodulatory agents targeting cytokines. Accordingly, it has been proposed that tocilizumab, a selective IL-6 receptor blocker, might be beneficial for critically ill patients(16). Given that, the primary studies in the literature reported inconclusive outcomes; however, they administered tocilizumab alone (17, 19, 25, 26).

In the next step, the researchers applied this monoclonal antibody in combination with steroids where the major body of evidence represented outcomes in agreement with ours using tocilizumab in combination with steroid, either concurrently or within a short interval after the steroid (48 hours). In this regard, a large cohort study of Ruiz-Antora´n et al. investigated the use of steroid alone, tocilizumab alone or their combination on severe COVID-19 culminating in the superiority of combination therapy regarding the less probability of adverse events and mortality(27). Similarly, Mikulska and colleagues represented favorable outcomes regarding the use of methylprednisolone-tocilizumab therapy to reduce adverse events and mortality among patients with severe COVID-19 infection; however, they did not compare it with other regimens. Finally, they concluded that tocilizumab alone, steroids alone or their combination led to considerable favored outcomes over the standard care(14). The other consistent outcomes were presented in the study of Van den Eynde et al. assessing tocilizumab in combination with steroid versus steroid alone reporting that both approaches could efficiently reduce the mortality rate; however, those receiving the combination therapy had 25% less mortality than the latter group(16). Contrarily, despite the significant reduction in mortality rate and intubation requirement among the patients treated with dexamethasone alone or in combination with tocilizumab, none of the approaches was superior over the other; particularly considering the negligible difference between the groups in terms of adverse events(28).

Although our results are in line with the majority of data regarding the benefits of combination therapy over steroid alone, we have no logics for the superiority of low-dose steroid with tocilizumab compared with high-dose steroid plus tocilizumab.

Surfing the literature shows that high-dose steroids, dexamethasone or methylprednisolone, could effectively lead to reduced risk of intubation requirement and mortality if applied appropriately(24). Accordingly, they represented that steroids are most beneficial for those with severe COVID-19 as used in the current study. Therefore, its application in those with more moderate COVID-19 or in early stages can potentially lead to increased viral load due to more viral shedding which in turn lead to more inflammation and delayed viral clearance as suggested by several researchers(29). The studies continued that, steroids in low-dose might not be appropriate as they cannot affect the inflammatory storm as strongly as required (14, 30). Accordingly, we want to propose this hypothesis that the combination therapy of tocilizumab and low-dose steroids can efficiently regulate immune response in order to prevent from cytokine storm but do not suppress the immune system entirely as well as minimizing the adversities of corticosteroids. Further investigations are strongly recommended to generalize our theory.

The cross-sectional design of the study is the most significant limitation of the current report as randomized-trial or cohort design could lead to more reliable conclusive outcomes.

Based on the findings of the current study, low-dose steroid continued with tocilizumab was superior over high-dose steroid alone or in combination with tocilizumab in terms of all evaluated parameters including rate and length of ICU stay, the incidence of nosocomial infection and adverse events and mortality. Further investigations are strongly recommended.

Author Contribution

S S was contributed in literature search, clinical studies, experimental studies, data acquisition, data analysis, statistical analysis, manuscript preparation, manuscript editing, and manuscript reviewZ N was contributed in literature search, clinical studies, experimental studies, data acquisition, data analysis, statistical analysis, manuscript preparation, manuscript editing, and manuscript reviewM S was contributed in literature search, clinical studies, experimental studies, data acquisition, data analysis, statistical analysis, manuscript preparation, manuscript editing, and manuscript reviewF T was contributed in literature search, clinical studies, experimental studies, data acquisition, data analysis, statistical analysis, manuscript preparation, manuscript editing, and manuscript reviewN A was contributed in literature search, clinical studies, experimental studies, data acquisition, data analysis, statistical analysis, manuscript preparation, manuscript editing, and manuscript review

Availability of Data and Materials

All raw data are provided as a supplementary file in the submission profile.

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No competing interests reported.

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Use of immune-modulating agents to regulate hyperinflammation in severe COVID-19; the assessment of tocilizumab use in combination with steroids

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Introduction

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Study population

Patients subgrouping

Data collection

Statistical analysis

Results

Discussion

Limitations

Conclusion

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Author Contribution

Availability of Data and Materials

References

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