Severe acute respiratory syndrome coronavirus 2 infection: Role of interleukin-6 and the inflammatory cascade

Table 1 Drugs with anti-interleukin-6 activity and their side effects with examples of clinical trials in coronavirus disease 2019

Ref.	SARS-CoV-2 clinical trials on Clinicaltrial.gov	Side effects	Examples	Category
[93]	NCT04661527, NCT04315298, NCT04357808, NCT04386239, NCT04341870, NCT04359901, NCT04380519	Cytopenia, intestinal perforation, Hypersensitivity, immunosuppression, and the possibility of infections, impairment of liver enzymes	Sarilumab	The anti-receptor of IL-6
[94,95]	NCT04445272, NCT04331795, NCT04346355, NCT04320615, NCT04356937, NCT04403685, NCT04339712	Intestinal perforation, Hypersensitivity, immunosuppression, and the possibility of infections, acute liver dysfunction, demyelination, cardiac injury, and hepatitis	Tocilizumab
[96]	NCT04322188, NCT04329650, NCT04330638	Hypersensitivity disorders, intestinal perforation, risk of infections	Siltuximab	Anti-IL-6
[97]	-	Preclinical; in a phase 2 trial of IBD, it showed effectiveness. Patients in this study who were treated with the drug had hypersensitivity skin reactions and respiratory infections. In animal studies, it did not show serious immunosuppression	Olamkicept	Specific gp130fc
[98]	NCT04358614, NCT04401579, NCT04640168, NCT04381936 (RECOVERY Trial), NCT04320277	Increased risk of infections including reactivation of latent infections, lymphoproliferative disorder, cytopenia, liver enzymes disturbances, clot formation, intestinal perforations	Baricitinib	JAK inhibitors
[99]	NCT04348071, NCT04377620, NCT04362137, NCT04366232	Skin malignancy, exacerbation with drug discontinuation, cytopenia, and immunosuppression, increased risk of infection	Ruxolitinib

SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; IL: Interleukin; IBD: Inflammatory bowel disease; JAK: Janus kinase.

Table 2 List of recent clinical trials and observational studies regarding interleukin-6 blocker monoclonal antibodies in severe acute respiratory syndrome coronavirus 2

Study design	Inclusion criteria		Interventions	Number of patients	Results		Ref.
Observational retrospective	Severe SARS-CoV-2 positive ICU admitted patients, with or without respiratory failure		Single 400 mg TCZ dose, without antimicrobialprophylaxis	55 severe patients were treated,Compared with 41 untreated (non-severe) patients	Lower mortality rate among treated patients against more disease severity, with no serious side effects and no significantly different increased infection rates		[53]
Quasi-experimental	SARS-CoV-2 positive patients with respiratory failure or a need for supplemental oxygen, with clinical or laboratory signs of acute inflammation		Comparing CSs, and TCZ (8 mg/kg up to 800 mg/dose up to 3 doses)	33 patients in the TCZ group and 60 in the CS group.	These drugs both reduced the need for supplemental oxygen and ICU stay to the same level, but in the CS group the survival rate was higher, use of TCZ was safe		[100]
Cohort	COVID-19 patients with respiratory failure and acute inflammatory laboratory findings, such as an elevated CRP level		Anakinra: 5 mg/kg BD until clinical improvement; TCZ: 400 mg single dose, repeated according to the clinical condition; Sarilumab: 400 mg single dose	62 patients received IL-1 blocker and 55 IL-6 blocker (26 sarilumab and 29 TCZ) (severe patients); 275 without IL blockade (standard of care only)	IL-6 blockade had only limited effectiveness in individuals with high concentrations of CRP, but IL-1 blockade reduced the mortality rate in all patients		[50]
Retrospective observational	Severe patients		Tocilizumab use was compared with standard of care in ICU patients	78 severe patients received tocilizumab and were compared with 112 severe patients who received standard of care	Patients on tocilizumab had a longer hospital and ICU stay and more costs with no reduction in the mortality rate		[101]
Retrospective observational	Severe SARS-CoV-2 patients with respiratory failure		TCZ 8 mg/kg	30 severe patients with respiratory failure who received TCZ were evaluated for inflammatory markers and clinical condition after treatment	Patients had better oxygenation and inflammatory markers decreased after treatment with TCZ		[102]
Randomized, double-blindclinical trial	Hospitalized patients without respiratory failure and mechanical ventilation, but with decreased SpO2 in room air		8 mg/kg up to 800 mg, TCZ; One-two doses	249 TCZ; 128 SOC	Likelihood ratio of; serious adverse outcomes were significantly lower in the treatment group; But no reduction in all-cause mortality rate		[8]
Clinical trial	Moderate and severe patients according to the clinical status, with higher IL-6 levels, neither ICU admitted nor on mechanical ventilation		TCZ 400 mg; Single-dose	29 patients were treated with TCZ and 32 received standard of care only	TCZ was safe but did not show any significant difference in clinical improvement		[103]
Cross-sectional, observational	Severe patients with high levels of inflammatory markers		TCZ 4 mg/kg	54 patients were treated with TCZ	Significant reduction in neutrophil count and CRP		[104]
Clinical trial	Patients with hyper-inflammatory state and acute respiratory failure		TCZ 8 mg/kg (up to 800 mg); After 12 h: second dosage	66 severe patients received TCZ and were compared with 60 patients who received standard of care	Not effective in decreasing the risk of disease deterioration		[105]
Open-label clinical trial	Proven SARS-CoV-2 infection, with the need for respiratory support and recent worsening in the clinical condition		TCZ 8 mg/kg	46 moderate and severe patients were treated with TCZ	Treatment improved respiratory function		[48]
Clinical trial	High levels of IL-6Moderate and severe disease severity		TCZ 400 mg (second dosage after 24h)	34 patients were treated and 31 were not	Treatment with TCZ improved respiratory condition without reducing the mortality rate		[106]
Clinical trial	Severe and critical patients		Sarilumab 400 mg	Total = 416 (Sarilumab 400 mg, n = 173; Placebo, n = 84; Sarilumab 200 mg, n = 159); Primary analysis between 194 severely ill patients who needed respiratory support	Did not meet the primary and secondary endpoints in improving disease progression and the study stopped further recruitment		NCT04315298 [107,108]
Randomized, double-blindclinical trial	Severe patients with decreased SpO2 without supplemental oxygen		TCZ 8 mg/kg up to 800 mg	2:1 Placebo+ Standard of care (151); TCZ+ SOC (301)	No significant benefits on mortality rate or clinical improvement, but a positive effect on hospitalization duration was observed with no significant side effects compared with the control group		NCT04320615 [109]
Retrospective cohort	SARS-CoV-2 positive patients with severe pneumonia		TCZ one to two doses, 400–800 mg every 12 h	n = 62 treated, n = 86 untreated	Treated patients showed significantly lower leukocytosis compared to the control group after 14 d. D-dimer and ferritin initially increased and then decreased in the treated group. The mortality rate at 28 d was statistically lower in the TCZ group. A longer hospital stay was shown in these patients although this was not statistically significant. Ten patients developed an infection during hospitalization		[62]
Retrospective cohort	Moderate to severe SARS-CoV-2 patients		One to two doses of TCZ 8 mg/kg	170 treated; 655 untreated	Clinical improvement was significantly better in the treatment group compared with the control group. A significant reduction in the mortality rate at 21 and 28 d was found in patients with respiratory failure and patients with IL-6 levels above 100 pg/mL		[110]
Randomized clinical trial	Critical patients with respiratory failure who were admitted to the ICU		TCZ one to two doses (8 mg/kg); Sarilumab (a single dose of 400 mg); Other interventions: Anakinra and interferon beta-1a	350 on TCZ; 45 on sarilumab; 1136 on another immunomodulator; 397 on no immunomodulation	IL-6 blocking agents were effective in reducing the mortality rate. When added to corticosteroids, this effect was stronger compared with IL-6 blockade alone		NCT02735707 [74]
Randomized, controlled, open-label clinical trial	COVID-19 patients with worsening clinical status or with high CRP levels after 21 d of the first randomization to dexamethasone, lopinavir–ritonavir, hydroxychloroquine, azithromycin, or colchicine or convalescent plasma or a combination of two anti-SARS-CoV-2 spike protein antibodies (REGN-COV2) or aspirin		A single dose of TCZ according to the patient’s weight	2022 received TCZ; 2094 received standard of care	TCZ group had a significantly lower mortality rate, need for mechanical ventilation, and higher chance of hospital discharge at day 28. This effect was similar in patients randomized less than or more than two days from hospitalization. In patients who were on mechanical ventilation at the time of drug administration, this drug had no significant effect on improving prognosis		[67]
Randomized, double-blindclinical trial	Severe COVID-19 patients	Sarilumab 200 or 400 mg, single dose		n = 153 sarilumab 400 mg, n = 141 sarilumab 200 mg, n = 75 placebo		No significant effectiveness was found in the treatment groups compared with the control group	[111]
Randomized, double-Blind, placebo-controlled trial	Patients with COVID-19 in a hyper-inflammatory state	TCZ 8 mg/kg up to 800 mg		TCZ (n = 161); Placebo (n = 81) + standard of care		No significant benefits from early TCZ administration in COVID-19 were observed	[112]

SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; ICU: Intensive care unit; TCZ: Tocilizumab; CSs: Corticosteroids; COVID-19: Coronavirus disease 2019.