Interleukin-6, Serum

Serum

1 mL

1 mL

Red-top tube or gel-barrier tube

Elecsys IL-6 immunoassay is an in-vitro diagnostic test for the quantitative determination of IL-6 (interleukin-6) in human serum and plasma.^1,2 This assay is used to assist in identifying severe inflammatory response in patients with confirmed COVID-19 illness to aid in determining the risk of intubation with mechanical ventilation, in conjunction with clinical findings and the results of other laboratory testing.

FDA-authorized Fact sheets for health care providers² and patients³ can be accessed at the following links:

• Fact Sheet for Health Care Providers: Elecsys IL-6–Roche Diagnostics

• Fact Sheet for Patients: Elecsys IL-6–Roche Diagnostics

This test has not been FDA cleared or approved. This test has been authorized by FDA under and EUA for use by authorized laboratories.^1,2 This test has been authorized only to assist in identifying severe inflammatory response, when used as an aid in determining the risk of intubation with mechanical ventilation in confirmed COVID-19 patients.^1,2 This test is only authorized for the duration of the declaration that circumstances exist justifying the authorization of emergency use of medical devices under Section 564(b)(1) of the Act, 21 U.S.C. & 360bbb-3(b),¹ unless the authorization is terminated or revoked sooner.^1,2

Further limitations include^1,2:

• For diagnostic purposes, the results should always be assessed in conjunction with the patient's medical history, clinical examination and other findings.

• Individual IL-6 levels need to be considered in combination with other clinical findings to mitigate the possible risks of false positive or false negative IL-6 results.

• In the event of a false positive result, risk to patients could include additional unnecessary intensive care admission, intubation with mechanical ventilation, and other unnecessary supportive therapy.

• Low IL-6 levels indicate that it is less likely that the patient suffers from a cytokine release syndrome and the risk for respiratory support is reduced. However, low levels if IL-6 do not preclude disease progression and future development of severe inflammatory response.

• A false negative result may occur if the test reports lower values than actual levels of IL-6 that are in the sample. When diagnostic testing is negative, the possibility of a false negative result should be considered in the context of a patient's clinical presentation and the presence of clinical signs and symptoms consistent with severe inflammatory response.

• Risk to a patient of a false negative result include: delayed or lack of supportive respiratory treatment, or other unintended adverse events.

• In rare cases, interference due to extremely high titers of antibodies to analyte-specific antibodies, streptavidin or ruthenium can occur. These effects are minimized by suitable test design.

Electrochemiluminescence Immunoassay (ECLIA)

Interleukein-6 (IL-6) is a pleiotropic cytokine that acts as both a pro-inflammatory and anti-inflammatory mediator that plays an important role in the proliferation and differentiation of cells in humans.^4-7 IL-6 is involved in many physiological responses, including acute phase response, fever induction, angiogenesis, B and T cell differentiation as well as in lipid and iron metabolism.⁸ IL-6 is produced locally at the site of infectious or injured lesions and is delivered to the whole body via the blood stream, promptly activating the host defense system to perform diverse functions.⁶ This essential cytokine stimulates acute phase reactions, immune responses, hematopoiesis and various internal organs to prepare for host defense.⁶ IL-6 is an important mediator of fever and the acute phase response that enhances the innate immune system to protect against tissue damage.⁷

In severe cases, IL-6 levels measured can trigger excessive defense signaling and threaten survival.⁹ Sustained and excessive production of IL-6 can occur in a variety of inflammatory diseases.^4-7,10 Historically. the first disease to be associated with markedly elevated IL-6 was cardiac myxoma, a benign heart tumor, where increased IL-6 levels cause extensive inflammatory symptoms.^11,12 Markedly elevated IL-6 levels are also found in Castleman's disease, a condition where patients suffer from severe inflammatory symptoms related to massive infiltration of mature plasma cells into lymph nodes.¹³ IL-6 is involved in pathogenesis of rheumatoid arthritis^14,15 and other autoimmune conditions.⁵ Elevated levels of IL-6 in patients with community acquired pneumonia are associated with increased all-cause and cause-specific mortality during admission and over one-year post-admission, despite resolution of clinical signs of an acute infection.^16-18 Increased amounts of IL-6 in serum were associated with pulmonary inflammation and extensive lung in SARS coronavirus patients.^19,20

Secondary haemophagocytic lymphohistiocytosis (sHLH) is a hyperinflammatory syndrome characterized by a massive and often fatal increase in cytokine levels (including IL-6) with multi-organ failure that is most commonly triggered by viral infections.^21-22 A cytokine release syndrome (CRS), similar to sHLH, with markedly increased levels of a number of cytokines including IL-6 has been reported in patients with severe COVID-19 infections.^15,23-32 IL-6 levels have been found to be more elevated patients with severe COVID-19 as compared to non-severe cases²⁶ and IL-6 has been reported to be a clinical predictor of mortality in these patients.^25,28

Many patients with confirmed COVID-19 have developed fever and/or symptoms of severe inflammatory responses, sometimes referred to as "cytokine release syndrome"(CRS) or "cytokine storm."² Severe symptoms may occur in >20% of COVID-19 patients. Symptoms of severe inflammatory response in COVID-19 may include, but are not limited to, fever, hypotension. dyspnea, organ dysfunction, and organ failure.² Among the different cytokines that may contribute to systemic inflammation, measurement of IL-6 can be indicative of the severity of such inflammation because IL-6 is known to have a central role in inflammation.²

Measurement of IL-6 in COVID-19 confirmed patients is used to identify patients with severe inflammatory response who may be at risk of intubation with mechanical ventilation.² Healthcare professionals may use the IL-6 measurement together with other laboratory and clinical findings. Elevated IL-6 levels may be an important indicator of severe inflammatory response.^1,2 In an external study using Elecsys IL-6 on samples from 817 apparently healthy individuals, the upper limit of the reference range for IL-6 was 7 pg/mL (95th percentile).^1-2

The following clinical data are from Munich, Germany, from polymerase chain reaction (PCR) confirmed symptomatic COVID patients presenting in the Emergency Department (ED). In the validation data set of 49 hospitalized patients, 19 patients required intubation for respiratory support subsequent to ED presentation.^1,32 The Elecsys IL-6 assay, using a cutoff of 35 pg/mL, correctly identified 16 of the 19 patients that required intubation — positive predictive value: 59% (95% Cl = 47% to 71%); negative predictive value: 86% (95% Cl = 68% to 95%); prevalence of mechanical ventilation in COVID-19 confirmed, hospitalized patients: 39% (95% Cl = 25% to 54%).³ The cutoff was established on retrospectively collected samples (n=37) and validated with prospectively collected samples (n=49) based on the need for mechanical ventilation during the hospitalization. The receiver operator curve was calculated for the first assessment value of Elecsys IL-6 at presentation to the ED. Sensitivity and specificity is shown for patients who subsequently underwent or did not undergo intubation with mechanical ventilation.