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Editorial
June 30, 2020

Is a “Cytokine Storm” Relevant to COVID-19?

Author Affiliations
  • 1Division of Pulmonary, Department of Medicine, Critical Care, Allergy and Sleep Medicine; University of California, San Francisco
  • 2Department of Anesthesia; University of California, San Francisco
  • 3Cardiovascular Research Institute; University of California, San Francisco
JAMA Intern Med. 2020;180(9):1152-1154. doi:10.1001/jamainternmed.2020.3313

In its most severe form, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19), leads to a life-threatening pneumonia and acute respiratory distress syndrome (ARDS). The mortality rate from COVID-19 ARDS can approach 40% to 50%.1,2 Although the mechanisms of COVID-19–induced lung injury are still being elucidated, the term cytokine storm has become synonymous with its pathophysiology, both in scientific publications and the media. Absent convincing data of their effectiveness in COVID-19, drugs such as tocilizumab and sarilumab, which are monoclonal antibodies targeting interleukin (IL)-6 activity, are being used to treat patients; trials of these agents typically cite the cytokine storm as their rationale (NCT04306705, NCT04322773). A critical evaluation of the term cytokine storm and its relevance to COVID-19 is warranted.

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    8 Comments for this article
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    PICs not CRS relevant to CoVID19
    Camilo Colaco, PhD | ImmunoBiology Ltd
    The article suggests that "the more intriguing question to ask is why are clinical outcomes in COVID-19 so unfavorable despite relatively low levels of circulating IL-6?" and point outs that a recent postmortem report of patients with COVID-19 ARDS identified severe vascular injury, including alveolar microthrombi that were 9 times more prevalent than found in postmortem studies of patients with influenza.

    The editorial concludes correctly that the linkage of cytokine storm to COVID-19 maybe nothing more than a tempest in a teapot, but fails to offer an alternative explanation. I would like to point out that there is
    an alternative hypothesis that explains much more of the 'unusual' features observed with CoVID19, that the primary pathogenic feature is a virally induced coagulopathy (1,2). This includes the microthrombi reported in the post mortems of CoVID deaths but also a number of other 'thrombolytic complications' (2) which include the characteristic CT scans and the low O2 saturation in the absence of breathing difficulty seen in some CoVID patients (2). Moreover, given the variable IL6 levels noted in the editorial, elevated levels of d-dimer (consistent with coagulopathy) has been widely reported as an early marker of CoVID19 infection and very high levels correlated with mortality (2,3).
    Most importantly, the early use of LMW heparin in CoVID19 patients has changed mortality outcomes in hospitalized patients (2) and may also be beneficial in reducing cytokine storms (3) and needs to be more widely appreciated than simply in clinical practice.

    1. McGonagle D, O’Donnell JS, Sharif K, Emery P, Bridgewood C. Immune mechanisms of pulmonary intravascular coagulopathy in COVID-19 pneumonia. Lancet Rheumatology Published online May 7, 2020. https://doi.org/10.1016/S2665-9913(20)30121-1 .
    2.Oudkerk M et.al. Diagnosis, Prevention, and Treatment of Thromboembolic Complications in COVID-19: Report of the National Institute for Public Health of the Netherlands. Radiology Published Online Apr 23 2020. https://doi.org/10.1148/radiol.2020201629
    3. Chen S et.al. The potential of low molecular weight heparin to mitigate cytokine storm in severe COVID-19 patients: a retrospective clinical study. medRxiv 2020.03.28.20046144; https://doi.org/10.1101/2020.03.28.20046144.
    CONFLICT OF INTEREST: None Reported
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    Chaos theory helps in the understanding of a cytokine storm
    Richard Schmidt, BPharm, PhD | [Retired pharmacist]
    The National Cancer Institute definition of a cytokine storm is "a severe immune reaction in which the body releases too many cytokines into the blood too quickly."[1] The term is considered synonymous with hypercytokinemia. In the context of COVID-19, the term is seemingly being used in a sensational sense – "an inflammatory response flaring out of control", as discussed in [2] – to describe the severe inflammatory reaction in the lungs that is a widely recognised feature of the coronavirus infection. As occurs with other inflammatory pathologies, there is a lesser or greater degree of spill-over of inflammatory cytokines into the blood. When the cytokine IL-6 escapes from a local site of inflammation into the blood and then reaches the liver, it triggers the secretion of C-reactive protein, a well-known and widely used marker of inflammation. A raised IL-6 level is a feature of inflammatory pathologies, but it is only one of many pro- and anti-inflammatory cytokines that are released when inflammation occurs. It is just one member of an orchestra in which IL-6, TNF-α , and perhaps granulocyte-macrophage colony-stimulating factor (GM-CSF) may function as conductors. The tune that this orchestra plays is determined by the principles espoused by "chaos theory" (now also called complexity theory), which in practical terms means that you can't predict exactly what that tune will be – as discussed in [3]. In chaos theory parlance, the tune will be "critically dependant on initial conditions" – otherwise described as "the butterfly effect". And the tune will settle to "a strange attractor" or "emergent phenomenon", that will be slightly different in each individual patient. This will be as predictable as, but no more predictable than, the weather. The actual composition of the cytokine storm at any point in time will show patient-to-patient variation and will be dependent not only on whatever the coronavirus is doing / has done to set off the inflammatory process, but also on the ability of each cell / tissue / organ / whole body to maintain redox homeostasis in the face of a pro-inflammatory insult that generates oxidative stress, as discussed in [4]. And this, in turn, will be dependent upon any background pathology and/or medication that may already have shifted the redox state of any particular cell / tissue / organ towards the cliff-edge that leads to inflammation and indeed a cytokine storm. Further, this will be dependent upon dietary availability of vitamin C and vitamin E and other factors / nutrients that play a part in maintaining redox homeostasis. So, it probably doesn't matter that a high level of IL-6 cannot be detected in a COVID-19 patient. The cytokine storm can still be raging. And rather than targeting the first violins or indeed the conductor of the cytokine storm, the best way to control it might be to provide a new score through an intervention that helps restores the reducing environment of the cell / tissue / organ, an intervention such as N-acetylcysteine,[5] which has long been used to quench the cytokine storm that is produced in the liver[6] and lungs[7,8] in those who overdose on acetaminophen / paracetamol.

    [1] https://www.cancer.gov/publications/dictionaries/cancer-terms/def/cytokine-storm
    [2] https://doi.org/10.1128/MMBR.05015-11
    [3] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3202497/
    [4] https://doi.org/10.3390/v10080392
    [5] https://doi.org/10.1016/j.rmcr.2020.101063
    [6] https://bit.ly/2QqZmvl
    [7] https://doi.org/10.1289/ehp.94102s963
    [8] https://doi.org/10.1164/rccm.200409-1269OC
    CONFLICT OF INTEREST: None Reported
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    COVID-19: a riddle wrapped in a mystery inside an enigma
    Antonio Aceti, Professor | Sapienza University AOU Sant'Andrea, Rome, Itaky
    In COVID-19 front-line white blood cells release inflammatory molecules called cytokines, which in turn summon more immune cells that target and kill virus-infected cells, leaving a stew of fluid and dead cells behind. This is the underlying pathology of pneumonia, with its corresponding symptoms: coughing; fever; and rapid, shallow respiration. But others deteriorate, often quite suddenly, developing a condition called acute respiratory distress syndrome (ARDS). Oxygen levels in their blood plummet and they struggle ever harder to breathe. Their lungs are riddled with white opacities where black space—air—should be. Commonly, these patients end up on ventilators. Many die. Autopsies show their alveoli became stuffed with fluid, white blood cells, mucus, and the detritus of destroyed lung cells. In serious cases, SARS-CoV-2 lands in the lungs and can do deep damage there. But the virus, or the body’s response to it, can injure many other organs. We really don’t understand who is vulnerable, why some people are affected so severely, why it comes on so rapidly and why it is so hard [for some] to recover.
    In COVID-19 patients the organism is all involved (1). COVID-19 is a viral sepsis.
    Sepsis is one of the oldest and most elusive syndromes in medicine.
    In 1992, an international consensus panel defined sepsis as a systemic inflammatory response to infection, noting that sepsis could arise in response to multiple infectious causes. Thus, it was suggested that it was the host, not the germ, that drove the pathogenesis of sepsis(2). The sepsis syndrome may be considered a constellation of signs and symptoms that represent the host’s response to infection, whereby the effects of cytokines (or substances triggered by cytokines) are responsible for most of the clinical manifestations.
    According to the third international consensus definitions for sepsis and septic shock (sepsis-3), sepsis should be defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Acute organ dysfunction most commonly affects the respiratory and cardiovascular systems3. Respiratory compromise is classically manifested as the acute respiratory distress syndrome (ARDS), which is defined as hypoxemia with bilateral infiltrates of noncardiac origin.
    This is the case of COVID-19.
    COVID-19 can attack almost anything in the body with devastating consequences.
    Understanding the rampage could help the doctors on the front lines treat the fraction of infected people who become desperately and sometimes mysteriously ill.
    Taking a systems approach may be beneficial as we start thinking about therapies.
    What follows is a snapshot of the fast-evolving understanding of how the virus attacks cells around the body, especially in the roughly 5% of patients who become critically ill. A clear picture is elusive, as the virus acts like no microbe humanity has ever seen. We need to keep a very open mind as this phenomenon goes forward.
    At this time, COVID-19 is a riddle wrapped in a mystery inside an enigma (Winston Churchill).
    1. Zhou M, Zhang X, Qu J. Coronavirus disease 2019 (COVID-19): a clinical update [published online ahead of print, 2020 Apr 2]. Front Med. 2020;10.1007/s11684-020-0767-8. doi:10.1007/s11684-020-0767-8.
    2. Bone RC, Sibbald WJ, Sprung CL. TheACCP-SCCM Consensus Conference on
    sepsis and organ failure. Chest 1992;101:1481-1483.
    3. Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801–810. doi:10.1001/jama.2016.0287
    CONFLICT OF INTEREST: None Reported
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    Microthrombi are not unexpected
    Richard Schmidt, BPharm PhD | [Retired pharmacist]
    In response to the comment from Camilo Colaco above, I would point out that those who are immersed in the literature on oxidative stress / redox homeostasis will not be surprised by the finding that microthrombus formation is a feature of COVID-19 pathology, and indeed the pathology of ageing, type 2 diabetes, COPD, etc, (see, for example, [1], [2], [3], & [4]), all being conditions that predispose patients to serious outcomes upon infection with the coronavirus. The picture that is emerging from the literature is that the COVID-19 virus (SARS-CoV-2) is somehow causing a shift in pro-oxidant / antioxidant status that particular cells / tissues / organs are unable adequately to control through normal redox homeostatic processes, perhaps at the level of the mitochondria. Although this process may start locally at the point of initial entry of the virus, it evidently spreads systemically. This would explain the various other COVID-19-associated conditions that are being reported such as a Kawasaki-like syndrome[5] and other inflammatory skin conditions[6] seen in dermatology where a particular cell type / tissue / organ that is suitably predisposed is seemingly tipped into a state where endogenous antioxidant processes fail to maintain the proper pro-oxidant / antioxidant state. Microthombi have been seen in "COVID toes".[7] Fortunately, such reactions in the skin are not life-threatening ...

    [1] https://doi.org/10.1016/j.freeradbiomed.2009.11.020
    [2] https://doi.org/10.1111/j.1538-7836.2010.03910.x
    [3] https://doi.org/10.1016/j.exger.2017.04.006
    [4] https://doi.org/10.1136/thx.2009.130260
    [5] https://doi.org/10.1016/S0140-6736(20)31129-6
    [6] https://doi.org/10.1111/jdv.16474
    [7] https://doi.org/10.1016/j.jaad.2020.05.145
    CONFLICT OF INTEREST: None Reported
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    Hyperinflammation is like a tropical cyclone with its three evolutionary stages
    Anselmo Abdo, MD, PhD | Centro de Investigaciones Médico Quirurgicas. Universidad de Ciencias Médicas de La Habana
    Tropical cyclones are classified into three types according to the speed of their maximum winds; the first is called a tropical depression, when its winds are less than 63 km/h; the second is a tropical storm, which includes winds between 63 km/h and 118 km/h and the third category is that of a hurricane, as it presents winds with a speed greater than 118 km/h.

    If we evaluate the levels of cytokines (and the inflammatory response) that characterizes hemophagocytic lymphohistiocytosis, we would classify it from the meteorological point of view as a hurricane or a tropical storm, perhaps that
    is where the term cytokine storm comes from.

    It is true that the levels described in COVID-19 are not the magnitude of a storm or hurricane, but neither are they slight elevations. If we use the meteorological classification we could name it as a tropical depression.

    As the authors of the Editorial [1] suggest, perhaps the methodology used for the quantification of IL-6, in the studies shown in the table: Plasma Levels of Interleukin-6 Reported in COVID-19 Compared With Levels Previously Reported in ARDS, no it is comparable to the studies used for comparison (related to ARDS).

    Saavedra et al [2], in a series of cases of Cuban patients diagnosed with COVID-19 (rtPCR positive to SARS-CoV-2) report that the mean serum IL-6 was 337.4 pg/mL for critically ill patients; 95.65 pg/mL, for severely ill and 26.27 pg/mL for moderately ill patients.

    The use of Itolizumab reduced IL-6 in critically and severely ill patients and stabilizes its levels in moderately ill patients [2]. A study pending publication shows improvement in a group of clinical variables related to oxygenation and radiological imaging.

    Itolizumab is a humanized recombinant anti-CD6 monoclonal antibody (MAb) of immunoglobulin G1 (IgG1) isotype which binds to domain 1 of human CD6, and modulates T-lymphocytes activation and proliferation induced by CD6-costimulation This MAb was developed at the Center of Molecular Immunology (CIM, Havana, Cuba).

    Cuba until June 25, 2020 reported 2325 SARS-CoV-2 positive patients, with 86 deaths (all adults and more than 80 % with comorbidities), for a case fatality rate of 3.6 %.

    In the author's opinion, the results achieved were related to: hygienic-epidemiological measures (eg isolation of patients and contacts) designed in close relationship between the health authority and the government [3], combined antiviral strategy (including Interferon), antithrombotic prophylaxis and treatment of hyperinflammation (Itolizumab, CIGB 258).

    Cytokine increase (storm or tropical depression as in meteorology) must be modulated.


    [1] Sinha P, et al. Is a “Cytokine Storm” Relevant to COVID-19? JAMA Intern Med. doi:10.1001/jamainternmed.2020.3313
    [2] Saavedra D, et al. An Anti-CD6 Monoclonal Antibody (Itolizumab) Reduces Circulating IL-6 in Severe Covid-19 Elderly Patients. Research Square pre print. DOI: doi.org/10.21203/rs.3.rs-32335/v1
    [3] Díaz-Canel M, et al. Government management and Cuban science in the confrontation with COVID-19. Anales de la Academia de Ciencias de Cuba.
    CONFLICT OF INTEREST: None Reported
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    Hypercytokinemia and Pulmonary/Non-pulmonary Organ Damage—Causation or Association?
    mohamad abdelsalam, Master of Medicine | Suez General Hospital, Critical Care Department, Suez, Egypt
    Causation: It may be that hypercytokinenemia is causally related to ARDS and multi-organ failure without necessarily being able to differentiate the cause (predictor) from the effect (outcome). On the one hand, pulmonary and non-pulmonary organ damage may result from direct viral cytopathy, ventilation-induced lung injury, biotrauma or tissue hypoxia, and ultimately leads to hypercytokinenemia that may further exacerbate ARDS and multi-organ failure. However, on the other hand, hypercytokinenemia due to dysregulated immune response or cytokine storm syndrome can lead to pulmonary and non-pulmonary organ damage that may result in further cytokine release.
    Association: It may be that hypercytokinenemia is
    associated with (not causally related to) ARDS and multi-organ failure, and that hypercytokinenemia and pulmonary/non-pulmonary organ failure both result from direct viral cytopathy.
    Causation or Association: In order to establish the nature of the relationship between hypercytokinenemia and pulmonary/non-pulmonary organ damage (causation vs association), we would need: 1) Clinical trial to determine how anti-cytokine therapy would affect the clinical outcome of COVID-19. 2) Comprehensive post-mortem study to look for evidence of multi-organ viral infection, which is required to prove that extra-pulmonary complications such as cardiac injury, liver dysfunction and acute kidney injury are disease specific (resulting from direct viral cytopathy) and are not due to non-specific (dysregulated) immune response.
    CONFLICT OF INTEREST: None Reported
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    VALID BIOMARKERS OF CYTOKINE STORM OF COVID-19
    Kenny Jialal, IJ-MD,PH.D ,SD-PH.D | I Jialal and S Devaraj
    In a recent article, we presented a working diagnosis of the CSS of COVID-19 from the vantage point of the clinical laboratory.2 We suggested 4 biomarkers that clinicians should consider in entertaining a diagnosis of CSS at the nascent stage : C-reactive protein (CRP)> 50mg/L, Ferritin >700ug/L, D-dimer >0.5 mg/L and Interleukin-6(IL-6) levels greater than the reference range of the only FDA approved assay (>7.0pg/ml). These criteria should be used in conjunction with the clinical presentation and lymphopenia. Sinha et al were rather dismissive of the role of CSS in the sequalae of COVID-19. The authors of the editorial  appear to base their conclusion on one biomarker, IL-6.
    As we point out in our commentary, standardized assays for cytokines such as IL-6 are not available in clinical laboratories for informing clinical care. They are offered by reference laboratories for research use only and values can vary depending on the type of assay used. There is only one assay approved by the FDA , the Roche IL-6 assay. We are in agreement that there are major issues with reporting cytokines/chemokines etc. in the clinical laboratory since standardization is a major issue and most studies reporting IL-6 levels did not detail their assay configuration and characteristics. Hence in support of Cron3 and England4 we believe that 2 well standardized assays for clinical care, CRP and Ferritin are better biomarkers. Both are well established downstream proteins of the inflammatory cascade 2. In the published literature both have been shown to increase with ICU admission, ARDS severity and death in patients with COVID-19.2, 4 In addition, given the nexus between inflammation and thrombosis, another established clinical assay that is elevated with the above sequalae is D-dimer.
    Hence, we posit based on the preponderance of published studies that CSS presages the sequelae of COVID-19 including ARDS, multi- organ failure and death. This was underscored in a recent study in 100 patients showing clinical improvement in >75% of patients with a concomitant reduction in both CRP and ferritin with Tocilizumab therapy in an uncontrolled study under desperate circumstances (IL-6 levels are not helpful with receptor blockers)5.
    We believe that it is premature at this early stage to discount CSS in the pathogenesis of COVID-19 with its high mortality until further studies show otherwise.

    References
    1- Sinha P, Matthay MA and Calfee CS .Is a “Cytokine Storm” relevant to COVID-19 ?JAMA Intern Med .doi:10.1001/jamainternmed.2020.3313

    2- Jialal I and Devaraj S Defining the Cytokine Storm Syndrome of COVID-19: Role of the Clinical Laboratory. Annals of Clinical Laboratory Sciences 2020(in press)


    3- England JT, Abdulla A, Biggs CM, Lee AYY, Hay KA, Hoiland RL, Wellington CL, Sekhon M, Jamal S, Shojania K, Chen LYC. Weathering the COVID-19 storm: Lessons from hematologic cytokine syndromes [published online ahead of print, 2020 May 15]. Blood Rev. 2020; 100707. doi:10.1016/j.blre.2020.100707

    4- Cron R Q and Chatham WW. The Rheumatologist’s role in COVID-19.The Journal of Rheumatology 2020; 47:639-642. doi:10.3899/jrheum.200334

    5-Toniati P, Piva S, Cattalini M, et al. Tocilizumab for the treatment of severe COVID-19 pneumonia with hyperinflammatory syndrome and acute respiratory failure: A single center study of 100 patients in Brescia, Italy. Autoimmun Rev. 2020;19(7):102568. doi:10.1016/j.autrev.2020.102568
    CONFLICT OF INTEREST: None Reported
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    The Roche IL-6 assay is not FDA approved
    Roma Levy, MS, molecular biology | Siemens Healthineers
    I will  look forward to reading the study in press by Drs. Jialal and Devaraj. I would like to point out, however, that the Roche assay is technically not FDA approved. At this time, it has received an Emergency Use Authorization (EUA) only for use during the COVID pandemic, and specifically for the purpose of assessing the risk the need for intubation with mechanical ventilation in patients hospitalized with severe COVID-19. Furthermore, this EUA is based on a single study on an initial evaluation cohort of 40 patients and a validation cohort of 49 patients. I do believe it is a useful assay for this purpose, and it is clear from this and several other studies already cited by others that IL-6 is a useful analyte for assessing risk of COVID-19 severity.

    1. Herold T, Jurinovic V, Arnreich C, et al. JACI. 2020;146(1):128-36, e4. DOI: 10.1016/j.jaci.2020.05.008.
    CONFLICT OF INTEREST: Medical writer for Siemens Healthineers
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