Benefit of Interleukin-6 Testing for COVID-19 Patients

December 2020 - Vol.9 No. 11 - Page #16


The COVID-19 pandemic has thrust clinical laboratories into the media with a spotlight on testing strategies and any shortcomings in those strategies. Much of this attention has been focused on the use of molecular diagnostics that can detect the presence of current (molecular or antigen testing) or past (serologic testing) COVID-19 infection. While understandable, this intense focus on detection has largely ignored the importance of expanding prognostic testing that can allow for improved care and management of COVID-19 patients. This testing is especially important given the wide range of clinical presentations seen in COVID-19.

Thus far, the vast majority of COVID-19 cases are believed to be mild or asymptomatic and require limited health care resources. Unfortunately, a minority of patients suffer a severe course and require extensive medical intervention. In a study of hospitalized patients in New York, 14% of patients required admission to the intensive care unit (ICU) with 3% needing mechanical ventilation and 21% of those patients dying.1

Furthermore, there is a growing need for prognostic markers that can help ensure a utilitarian allocation of resources in the management of COVID-19 patients. Some of this is due to the advance of new and effective therapeutics. While showing benefit in treating COVID-19 patients, these therapeutics remain in limited supply and thus require strategies for determining which patients will benefit the most, and in what order. Unfortunately, the need for prognostic markers is also due in part to the continuing rise of COVID-19 cases. In these situations, having objective measures to determine patients most in need of higher levels of care can be tremendously helpful. At Norton Healthcare in Louisville, Kentucky, we were able to improve prognostic testing in COVID-19 patients in part due to the critical role of interleukin-6 (IL-6) testing.

Pathophysiology of IL-6 in COVID-19

The chemical IL-6 plays a critical role in the body’s response to viral infections, but in patients with COVID-19, its overexpression can have severe negative consequences. IL-6 is a soluble cytokine produced in response to infection as well as tissue injury. Its primary role is to serve as an early warning signal for the body by activating and amplifying the host immune response through a variety of mechanisms. IL-6 will induce expression of acute phase reactants such as C-reactive protein, serum amyloid A, and others in the liver. IL-6 also contributes to T-cell differentiation and B-cell differentiation and proliferation, ultimately leading to a more robust antibody response in the case of infection. Furthermore, IL-6 will induce expression of vascular endothelial growth factor (VEGF), leading to increased vascular permeability.

While these functions help ensure a robust host response and improved survival in the face of infection, they require a tightly regulated process whereby IL-6 levels rise rapidly and are then quickly downregulated. This process is key, as uncontrolled expression of IL-6 can lead to a hyper inflammatory state, which is associated with severe negative outcomes. Excess IL-6 levels in COVID-19 patients can create a procoagulant state that leads to disseminated intravascular coagulation (DIC). It has been observed that COVID-19 patients with elevated IL-6 levels are at increased risk of respiratory failure and death.2 These observations have been found repeatedly with the data clearly indicating that uncontrolled elevations in IL-6 confer a poor prognosis.

Prioritizing IL-6 Testing in the Clinical Laboratory

Few clinical laboratories in the United States currently offer IL-6 testing even though the availability of assays and the need for testing have both increased. That said, at the beginning of the pandemic, there were no FDA-approved IL-6 assays on the market. This meant that laboratories were required to implement these assays as laboratory developed tests (LDTs). Initially, few laboratories were motivated to validate an IL-6 LDT assay, especially in consideration of the demand for this testing. The indications for IL-6 testing pre-pandemic were far more limited and specialized. This meant that few hospitals had a volume of IL-6 orders that made the work effort of developing an LDT worthwhile. Today, COVID-19 has changed much of this thinking.

There are now two commercially available IL-6 assays that have been granted emergency use authorizations (EUA) by the FDA and validation of these assays does not require the same work effort as implementation of an LDT. Further, these assays are available on random-access platforms that likely already exist in a number of clinical laboratories across the US. In addition to the availability of EUA IL-6 assays, there is substantially increased demand for IL-6 testing given its utility in the treatment of patients with COVID-19. However, the recognition of this demand requires close communication with providers in your health system. Often, clinical laboratories monitor for increased demand of an assay by reviewing send-out volumes. But the turnaround time delays encountered with send-out testing for IL-6 levels would render the results of little value in the management of COVID-19 patients, specifically. Thus, send-out volumes for this test for COVID-19 management might not increase even though the demand has increased.

For laboratories that are interested in implementing IL-6 testing, one potential challenge may be a lack of harmonization amongst methods used for a given patient. This can be problematic from both the validation phase standpoint, as well as when trying to trend any patients who have been tested with another method. Assay-to-assay agreement for IL-6 assays is erratic, as our own validation study showed excellent agreement with another laboratory using the same platform, but poor agreement with a reference laboratory using an alternative platform. Correlation studies should, if possible, be done with another laboratory using the same method. If this is not possible, acceptable correlation data should be based on a rank-order approach. Ideally, the samples used for validation should also have additional inflammatory markers (eg, CRP, ferritin, etc) measured to augment the assessment.

Utility of IL-6 Monitoring in COVID-19 Patients

Among its benefits, in-house IL-6 testing can assist with upfront assessment of COVID-19 patients, as well as longitudinal monitoring for worsening conditions or recovery. At our institution, IL-6 is included in both the suspected COVID-19 patient order set and the daily labs for confirmed COVID-19 patients. As assessing IL-6 levels at presentation can help with initial patient triage, this upfront testing has been especially important when results from COVID-19 diagnostic tests have been substantially delayed (particularly at the onset of the pandemic). The finding of elevated IL-6 levels has been a helpful data point in our initial patient assessments and the relatively rapid TAT of our in-house testing, 24/7, has enabled these findings.

When we began utilizing IL-6 testing for patients with confirmed COVID-19, those patients’ levels were monitored on a daily basis. But over the course of the pandemic thus far, the monitoring interval has increased to every twelve hours. We found that for our patients with COVID-19, IL-6 levels would respond rapidly and that more frequent monitoring (every 12 hours instead of every 24) would enable better decision making on escalation or de-escalation of care. Overall, the implementation of IL-6 testing has allowed our laboratory to provide our clinicians with highly useful prognostic markers in the management of COVID-19 patients.


Since the beginning of the COVID-19 pandemic, clinical laboratories and the FDA have rushed to bring new COVID-19 diagnostic tests to patients. Thousands of clinical laboratories have brought in one or more of the dozens of FDA-approved molecular, antigen, and serologic tests in this effort. Unfortunately, a similar explosion in prognostic tests like IL-6 has not occurred as yet, but hopefully this will change and continue to evolve.

We have found IL-6 to be an effective, readily implementable test that can help provide substantial insight into proper patient management. As we continue to wrestle with the COVID-19 pandemic, clinical laboratorians should strive to ensure they are doing everything they can to help their health systems address the needs of this dynamic patient population. One method is to look beyond the microbiology laboratory and COVID-19 diagnostic tests, and into prognostic markers such as IL-6.


  1. Richardson S, Hirsch JS, Narasimhan M, et al. Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area. JAMA. 2020;323(20):2052–2059.
  2. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395: 497–506.

Joshua Hayden, PhD, DABCC, FAACC, is the chief of chemistry at Norton Healthcare in Louisville, Kentucky. Prior to joining Norton, he was an assistant professor of pathology at Weill Cornell Medical College and director of the toxicology and therapeutic drug monitoring laboratory at New York Presbyterian Weill Cornell Medical Center.

Alan Elliott, MT(ASCP), is the central laboratory director for Norton Children’s Hospitals and Norton Women’s and Children’s Hospital. With 25 years of experience as a lab director, he has overseen microbiology, flow cytometry, and histocompatibility, among other clinical disciplines. He received his medical technology certification from the University of Louisville.


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