Interleukin-6: obstacles to targeting a complex cytokine in critical illness

McElvaney, Oliver J; Curley, Gerard F.; Rose–John, Stefan; McElvaney, Noel G.

doi:10.1016/s2213-2600(21)00103-x

Cited by 164 publications

(111 citation statements)

References 146 publications

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“…The functional impact of pleotropic cytokines, including IL-6, may not be reflected in the absolute level of the cytokine measured in serum ( 35 ). Further understanding of the impact of soluble mediators in the context of their diverse immune and nonimmune functions remains a challenge.…”

Section: Discussionmentioning

confidence: 99%

Defining Potential Therapeutic Targets in Coronavirus Disease 2019: A Cross-Sectional Analysis of a Single-Center Cohort

Arulkumaran

Snow

Kulkarni

et al. 2021

Critical Care Explorations

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Multiple mechanisms have been proposed to explain disease severity in coronavirus disease 2019. Therapeutic approaches need to be underpinned by sound biological rationale. We evaluated whether serum levels of a range of proposed coronavirus disease 2019 therapeutic targets discriminated between patients with mild or severe disease.Design: A search of ClinicalTrials.gov identified coronavirus disease 2019 immunological drug targets. We subsequently conducted a retrospective observational cohort study investigating the association of serum biomarkers within the first 5 days of hospital admission relating to putative therapeutic biomarkers with illness severity and outcome.Setting: University College London, a tertiary academic medical center in the United Kingdom.Patients: Patients admitted to hospital with a diagnosis of coronavirus disease 2019. Interventions: None. Measurements and Main Results:Eighty-six patients were recruited, 44 (51%) with mild disease and 42 (49%) with severe disease. We measured levels of 10 cytokines/signaling proteins related to the most common therapeutic targets (granulocyte-macrophage colony-stimulating factor, interferon-α2a, interferon-β, interferon-γ, interleukin-1β, interleukin-1 receptor antagonist, interleukin-6, interleukin-7, interleukin-8, tumor necrosis factor-α), immunoglobulin G antibodies directed against either coronavirus disease 2019 spike protein or nucleocapsid protein, and neutralization titers of antibodies. Four-hundred seventy-seven randomized trials, including 168 different therapies against 83 different pathways, were identified. Six of the 10 markers (interleukin-6, interleukin-7, interleukin-8, interferon-α2a, interferon-β, interleukin-1 receptor antagonist) discriminated between patients with mild and severe disease, although most were similar or only modestly raised above that seen in healthy volunteers. A similar proportion of patients with mild or severe disease had detectable spike protein or nucleocapsid protein immunoglobulin G antibodies with equivalent levels between groups. Neutralization titers were higher among patients with severe disease.Conclusions: Some therapeutic and prognostic biomarkers may be useful in identifying coronavirus disease 2019 patients who may benefit from specific immunomodulatory therapies, particularly interleukin-6. However, biomarker absolute values often did not discriminate between patients with mild and severe disease or death, implying that these immunomodulatory treatments may be of limited benefit.

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Section: Discussionmentioning

confidence: 99%

Defining Potential Therapeutic Targets in Coronavirus Disease 2019: A Cross-Sectional Analysis of a Single-Center Cohort

Arulkumaran

Snow

Kulkarni

et al. 2021

Critical Care Explorations

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“…(2) cardiovascular system support (defined as receipt of vasopressors) or death by 28 days in patients not receiving cardiovascular system support at randomization; (3) secondary infections by 28 days (this is the most important safety outcome); (4) in-hospital mortality; (5) kidney replacement therapy (KRT) or death by 28 days in patients not receiving KRT at randomization (excluding patients with underlying dialysis dependence or ≥stage III chronic kidney disease); (6) discharged alive from the hospital by 28 days; (7) mortality by 90 days; (8) duration of IMV up to 28 days (in those receiving IMV at randomization, with duration coded as 28 days for patients who died); and ( 9) secondary infections by 90 days. Data on serious adverse events or serious adverse reactions (as defined in each trial) were collected; however, no meta-analysis was planned because diverse definitions were used by different trials.…”

Section: Outcomes and Comparisonsmentioning

confidence: 99%

Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19

Domingo

Mur

Mateo

et al. 2021

JAMA

556

387

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The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group IMPORTANCE Clinical trials assessing the efficacy of IL-6 antagonists in patients hospitalized for COVID-19 have variously reported benefit, no effect, and harm.OBJECTIVE To estimate the association between administration of IL-6 antagonists compared with usual care or placebo and 28-day all-cause mortality and other outcomes.DATA SOURCES Trials were identified through systematic searches of electronic databases between October 2020 and January 2021. Searches were not restricted by trial status or language. Additional trials were identified through contact with experts.STUDY SELECTION Eligible trials randomly assigned patients hospitalized for COVID-19 to a group in whom IL-6 antagonists were administered and to a group in whom neither IL-6 antagonists nor any other immunomodulators except corticosteroids were administered. Among 72 potentially eligible trials, 27 (37.5%) met study selection criteria. DATA EXTRACTION AND SYNTHESISIn this prospective meta-analysis, risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I 2 statistic. The primary analysis was an inverse variance-weighted fixed-effects meta-analysis of odds ratios (ORs) for 28-day all-cause mortality. MAIN OUTCOMES AND MEASURESThe primary outcome measure was all-cause mortality at 28 days after randomization. There were 9 secondary outcomes including progression to invasive mechanical ventilation or death and risk of secondary infection by 28 days.RESULTS A total of 10 930 patients (median age, 61 years [range of medians, 52-68 years]; 3560 [33%] were women) participating in 27 trials were included. By 28 days, there were 1407 deaths among 6449 patients randomized to IL-6 antagonists and 1158 deaths among 4481 patients randomized to usual care or placebo (summary OR, 0.86 [95% CI, 0.79-0.95]; P = .003 based on a fixed-effects meta-analysis). This corresponds to an absolute mortality risk of 22% for IL-6 antagonists compared with an assumed mortality risk of 25% for usual care or placebo. The corresponding summary ORs were 0.83 (95% CI, 0.74-0.92; P < .001) for tocilizumab and 1.08 (95% CI, 0.86-1.36; P = .52) for sarilumab. The summary ORs for the association with mortality compared with usual care or placebo in those receiving corticosteroids were 0.77 (95% CI, 0.68-0.87) for tocilizumab and 0.92 (95% CI, 0.61-1.38) for sarilumab. The ORs for the association with progression to invasive mechanical ventilation or death, compared with usual care or placebo, were 0.77 (95% CI, 0.70-0.85) for all IL-6 antagonists, 0.74 (95% CI, 0.66-0.82) for tocilizumab, and 1.00 (95% CI, 0.74-1.34) for sarilumab. Secondary infections by 28 days occurred in 21.9% of patients treated with IL-6 antagonists vs 17.6% of patients treated with usual care or placebo (OR accounting for trial sample sizes, 0.99; 95% CI, 0.85-1.16). CONCLUSIONS AND RELEVANCEIn this prospective meta-analysis of clinical trials of patients hosp...

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“…In addition, inflammatory cytokines can potentially induce cardiac sympathetic hyperactivation via hypothalamus-mediated and peripheral pathways [ 52 ]. Specific cytokines, such as interleukin (IL)-6, derived from T cells and macrophages, have been implicated in the inflammatory response and will be further elaborated [ 53 , 54 ].…”

Section: Pathophysiology Of Covid-19-associated Cardiovascular Complicationsmentioning

confidence: 99%

COVID-19-Associated Cardiovascular Complications

et al. 2021

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Coronavirus disease 2019 (COVID-19) has been reported to cause cardiovascular complications such as myocardial injury, thromboembolic events, arrhythmia, and heart failure. Multiple mechanisms—some overlapping, notably the role of inflammation and IL-6—potentially underlie these complications. The reported cardiac injury may be a result of direct viral invasion of cardiomyocytes with consequent unopposed effects of angiotensin II, increased metabolic demand, immune activation, or microvascular dysfunction. Thromboembolic events have been widely reported in both the venous and arterial systems that have attracted intense interest in the underlying mechanisms. These could potentially be due to endothelial dysfunction secondary to direct viral invasion or inflammation. Additionally, thromboembolic events may also be a consequence of an attempt by the immune system to contain the infection through immunothrombosis and neutrophil extracellular traps. Cardiac arrhythmias have also been reported with a wide range of implicated contributory factors, ranging from direct viral myocardial injury, as well as other factors, including at-risk individuals with underlying inherited arrhythmia syndromes. Heart failure may also occur as a progression from cardiac injury, precipitation secondary to the initiation or withdrawal of certain drugs, or the accumulation of des-Arg9-bradykinin (DABK) with excessive induction of pro-inflammatory G protein coupled receptor B1 (BK1). The presenting cardiovascular symptoms include chest pain, dyspnoea, and palpitations. There is currently intense interest in vaccine-induced thrombosis and in the treatment of Long COVID since many patients who have survived COVID-19 describe persisting health problems. This review will summarise the proposed physiological mechanisms of COVID-19-associated cardiovascular complications.

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Interleukin-6: obstacles to targeting a complex cytokine in critical illness

Cited by 164 publications

References 146 publications

Defining Potential Therapeutic Targets in Coronavirus Disease 2019: A Cross-Sectional Analysis of a Single-Center Cohort

Defining Potential Therapeutic Targets in Coronavirus Disease 2019: A Cross-Sectional Analysis of a Single-Center Cohort

Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19

COVID-19-Associated Cardiovascular Complications

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