Medicine / Special Report

Vol. 5, NO. 1 / April 2020

Cytokine Storms

Tyler Hampton

Letters to the Editors

In response to “Cytokine Storms”

A cytokine storm is “the systemic expression of a vast array of inflammatory mediators that impact the body as a whole.”1 Extremely serious, cytokine storms may be fatal, and can occur as a result of many different triggers. A growing body of literature suggests a connection between SARS-CoV-2 infection and the induction of cytokine storms. The following collection of research briefs serves as a guide to relevant literature concerning cytokine storms in connection with COVID-19.

  • Exuberant Elevation of IP-10, MCP-3 and IL-1ra during SARS-CoV-2 Infection Is Associated with Disease Severity and Fatal Outcome (Preprint)

    Yang Yang et al. / March 6, 2020

    Studying 48 cytokines in plasma samples of 53 patients, Yang et al. found elevated levels of 14 proteins. Three were significantly higher in patients with severe symptoms: IP-10 (interferon γ-induced protein 10), MCP-3 (monocyte chemotactic protein-3), and IL-1ra (interleukin-1ra). Increased levels of these cytokines were highly correlated with lung-function deterioration. There was only a weak correlation between these cytokines and viral load. “These results suggested,” the authors write, “that the production of specific cytokines while not the viral burden might play central in the pathogenesis of COVID-19.”

    Yang Yang et al., “Exuberant Elevation of IP-10, MCP-3 and IL-1ra during SARS-CoV-2 Infection Is Associated with Disease Severity and Fatal Outcome,” medRxiv (2020), doi:10.1101/2020.03.02.20029975.

  • The Cytokine Release Syndrome (CRS) of Severe COVID-19 and Interleukin-6 Receptor (IL-6R) Antagonist Tocilizumab May Be the Key to Reduce the Mortality

    Chi Zhang et al. / March 29, 2020

    Levels of the cytokine protein interleukin-6 (IL-6) increase during COVID-19 infections. IL-6 can initiate a signal transduction event triggering an increase in B-cell and T-cell lymphocytes. The antibody tocilizumab binds to the same receptor protein as IL-6, but does not initiate a signal transduction event. Zhang et al. recommend its use in patients with elevated IL-6 levels and severe respiratory symptoms.

    Chi Zhang et al., “The Cytokine Release Syndrome (CRS) of Severe COVID-19 and Interleukin-6 Receptor (IL-6R) Antagonist Tocilizumab May Be the Key to Reduce the Mortality,” International Journal of Antimicrobial Agents (2020), doi:10.1016/j.ijantimicag.2020.105954.

  • COVID-19: Consider Cytokine Storm Syndromes and Immunosuppression

    Puja Mehta et al. / March 28, 2020

    Patients with severe COVID-19 present cytokine profiles suggestive of secondary hemophagocytic lymphohistiocytosis. Retrospective studies have found that increased levels of ferritin and the cytokine IL-6 are good predictors of mortality. Suppressing these cytokines means suppressing the immune system itself. This may be dangerous during a viral infection, but as Mehta et al. note, it may be still more dangerous to let the immune system become overactive. Considering several therapeutic options, they note that anakinra and tocilizumab block receptor proteins for certain cytokines, while steroids and Janus kinase (JAK) act as cytokine inhibitors.

    Puja Mehta et al., “COVID-19: Consider Cytokine Storm Syndromes and Immunosuppression,” The Lancet (2020), doi:10.1016/S0140-6736(20)30628-0.

  • Immunosuppression for Hyperinflammation in COVID-19: A Double-Edged Sword?

    Andrew Ritchie and Aran Singanayagam / March 24, 2020

    Ritchie and Singanayagam argue that while Mehta et al. are correct in noting a correlation between the cytokine storm syndrome and COVID-19 mortality rates, causation remains unclear. If cytokine storms are the immediate cause of organ failure and death, they should be stopped at all costs. If, on the other hand, uncontrolled viral replication is at fault, treatment should be directed toward reducing viral load rather than hyper-inflammation. Ritchie and Singanayagam note that some of the therapeutic options mentioned by Mehta et al. are designed to suppress the immune system at a time when it is needed most.

    Andrew Ritchie and Aran Singanayagam, “Immunosuppression for Hyperinflammation in COVID-19: A Double-Edged Sword?” The Lancet (2020), doi:10.1016/S0140-6736(20)30691⁠-⁠7.

  • The Use of Anti-Inflammatory Drugs in the Treatment of People with Severe Coronavirus Disease 2019 (COVID-19): The Perspectives of Clinical Immunologists from China

    Wen Zhang et al. / March 25, 2020

    Twenty percent of patients afflicted with SARS-CoV-2 become severely ill, and roughly 4% die. Critically ill patients share common features, including elevated pro-inflammatory cytokine levels, reduced lymphocyte counts, and atrophy of spleen and lymph nodes. Zhang et al. argue that even though cytokine storms are common in patients with advanced symptoms, they are not directly inculpated in reduced lymphocyte levels. Uncertainty surrounds treatment options. Several anti-inflammatory drugs are available to treat the hyper-inflammation characteristic of cytokine storms: “non steroidal anti-inflammatory drugs, glucocorticoids, chloroquine/hydroxychloroquine, immunosuppressants, inflammatory cytokines antagonists…” As already noted, there are real risks in these treatments. Zhang et al. review the data on four treatment options: glucocorticoids, tocilizumab, JAK inhibitors, and chloroquine and hydroxychloroquine. Some, such as tocilizumab, might regulate the production of the pro-inflammatory cytokine IL-6; others, such as hydroxychloroquine, may help regulate the immune system. “The efficacy and safety of [hydroxychloroquine] in the treatment of COVID-19,” the authors write, “need to be confirmed in further preclinical and clinical trials.”

    Wen Zhang et al., “The Use of Anti-Inflammatory Drugs in the Treatment of People with Severe Coronavirus Disease 2019 (COVID-19): The Perspectives of Clinical Immunologists from China,” Clinical Immunology 214 (2020), doi:10.1016/j.clim.2020.108393.

  • COVID-19: Melatonin as a Potential Adjuvant Treatment

    Rui Zhang et al. / March 23, 2020

    Patients with COVID-19 typically have elevated levels of interleukin -1β and interferon γ, decreased levels of lymphocytes and CD8+ T cells, and elevated inflammation. An amplified inflammatory response leads to widespread cell death of virally infected or compromised cells. Cell death leads to a further amplification of the inflammatory response, one independent of viral loads. Zhang et al. speculate that melatonin may be of use in managing the host immune response. Melatonin controls inflammation through its interactions with the proteins sirtuin-1 and NF-κB and could theoretically help control cytokine levels while encouraging the proliferation of T and B lymphocytes.

    Rui Zhang et al., “COVID-19: Melatonin as a Potential Adjuvant Treatment,” Life Sciences 250 (2020), doi:10.1016/j.lfs.2020.117583.

  • Cytokine Release Syndrome

    Alexander Shimabukuro-Vornhagen et al. / April 20, 2018

    Shimabukuro-Vornhagen et al. review aspects of cytokine release syndrome in patients after the administration of chimeric antigen receptor T-cell therapy and other T-cell engaging immunotherapies. Some patients, they speculate, may harbor genetic variation that predisposes them to potentially lethal cytokine storms, perhaps via genes controlling the cytotoxic activity of T cells and natural killer cells.

    Alexander Shimabukuro-Vornhagen et al., “Cytokine Release Syndrome,” Journal for Immunotherapy of Cancer 6, no. 1 (2018): 56, doi:10.1186/s40425-018-0343-9.

  • Cytokine Storms in Infectious Diseases

    John Teijaro / July 3, 2017

    This short paper functions as an introduction to an issue of the journal Seminars in Immunopathology dedicated to cytokine storms in infectious diseases. Teijaro notes that as of 2017, “no effective therapeutic treatments [were available] … to quell the pathology associated with cytokine storm.” Further discussions are addressed to the connection between cytokines and sepsis, and to cytokine storms arising in the context of the broad family of coronaviruses, Ebola virus infection, and severe dengue infection.

    John Teijaro, “Cytokine Storms in Infectious Diseases,” Seminars in Immunopathology 39 (2017), 501–503, doi:10.1007/s00281-017-0640-2.

  • Into the Eye of the Cytokine Storm

    Jennifer Tisoncik et al. / March 2012

    Knowledge of the molecular mechanisms underlying cytokine inflammations is incomplete. Tisoncik et al. discuss the signaling pathways initiated by various cytokine classes: interferons, interleukins, chemokines, colony-stimulating factors, and tumor necrosis factor. Studies in mice and macaques indicate that transcriptional changes in cytokines induced by various forms of the influenza virus lead to overproduction of cytokines that “hit hard and hit early.” Under certain conditions, toll-like receptors can become hyper-responsive, the genes in their signaling pathway overexpressed. Current immunotherapies include corticosteroids, aspirin, monoclonal antibodies, and other anti-cytokine agents, but few have proven effective. Treatment is context- and time-dependent. “In simple terms,” the authors write, “it is likely that during a severe acute infection, certain elements of the immune response need enhancing at times and need suppressing at other times.”

    Jennifer Tisoncik et al., “Into the Eye of the Cytokine Storm,” Microbiology and Molecular Biology Reviews 76, no. 1 (2012): 16–32, doi:10.1128/MMBR.05015-11.

  • TH17 Responses in Cytokine Storm of COVID-19: An Emerging Target of JAK2 Inhibitor Fedratinib

    Dandan Wu and Xuexian Yang / March 11, 2020

    Wu and Yang ask whether already available drugs such as fedratinib might be adapted to the treatment of COVID-19 infection. There is good reason to suppose that a TH17 response involving IL-17 is at work in severe cases of COVID-19. Suppression of TH17 offers a possible therapeutic route toward dampening the ensuing cytokine storm. This can be done by inhibiting Janus kinase 2 (JAK2), which is a critical protein en route to the activation and production of TH17 cells, and by extension, all of the cytokines produced by TH17 cells. Experiments in mice support the hypothesis. Advantages are considerable: reversible JAK2 inhibition has little adverse impact on critical B-cell function.

    Dandan Wu and Xuexian Yang, “TH17 Responses in Cytokine Storm of COVID-19: An Emerging Target of JAK2 Inhibitor Fedratinib,” Journal of Microbiology, Immunology and Infection (2020), doi:10.1016/j.jmii.2020.03.005.

  • Rheumatologists’ Perspective on Coronavirus Disease 19 (COVID-19) and Potential Therapeutic Targets

    Durga Prasanna Misra et al. / April 10, 2020

    Misra et al. note that COVID-19 can mimic certain rheumatic diseases, such as systemic lupus erythematosus, making diagnosis in some situations difficult. Common symptoms include pneumonia, lymphopenia, and thrombocytopenia. Rheumatic diseases also present with inhibited natural killer cell function and cytokine storms, “possibly due to secondary hemophagocytic lymphohistiocytosis.” Misra et al. consider the usefulness of chloroquine and hydroxychloroquine in dealing with cytokine storms. Chloroquine may suppress cytokine release, and increase levels of anti-inflammatory substances. Early, small trials with chloroquine and hydroxychloroquine showed promise, but various considerations “potentially undermine the quality” of these trials. The drug baricitinib may limit viral entry and control inflammation, and the drugs tocilizumab, anakinra, and sarilumab may be key in dampening those pathways activated by the cytokines IL-6 and IL-1. “Arguably,” the researchers note, “there is little evidence base for most of the potential drug therapies in COVID-19.”

    Durga Prasanna Misra et al., “Rheumatologists’ Perspective on Coronavirus Disease 19 (COVID-19) and Potential Therapeutic Targets,” Clinical Rheumatology (2020): 1–8, doi:10.1007/s10067-020-05073-9.

  • Dysregulation of Immune Response in Patients with COVID-19 in Wuhan, China

    Chuan Qin et al. / March 12, 2020

    Qin et al. found that COVID-19 patients consistently have elevated levels of inflammatory cytokines, such as tumor necrosis factor α, IL-2R, and IL-6, as well as other biomarkers indicating presence of infection, such as serum ferritin. In severe cases, certain cytokines, including IL-6 and IL-8, were elevated above the corresponding level found in milder COVID-19 infections. Severe cases tended to have abnormal immune-system profiles. This included a higher than normal ratio of neutrophils to lymphocytes, indicative of inflammation and infection, and lower lymphocyte and monocyte percentages. Helper T cells were abnormally low. “SARS-CoV-2 might mainly act on lymphocytes,” Qin et al. remark, “especially T lymphocytes, induce a cytokine storm in the body, and generate a series of immune responses to damage the corresponding organs.”

    Chuan Qin et al., “Dysregulation of Immune Response in Patients with COVID-19 in Wuhan, China,” Clinical Infectious Diseases, ciaa248 (2020), doi:10.1093/cid/ciaa248.

  • Trials of Anti-Tumour Necrosis Factor Therapy for COVID-19 Are Urgently Needed

    Marc Feldman et al. / April 9, 2020

    Tumor necrosis factor (TNF) is known to amplify an inflammatory response to infection. Feldman et al. suggest that anti-TNF monoclonal antibodies may damp down an inflammatory response, thus preventing the onset of a cytokine storm. The anti-TNF antibodies infliximab or adalimumab have been well studied and “have a well established safety profile.” Studies in mice using other respiratory viruses suggest that anti-TNF therapy may be effective in calming an immune response and increasing survival likelihood. It is a therapy that if it acts to the patient’s benefit, must also act to the benefit of the virus. It is not clear who profits the most from this arms race. Experiments in mice suggest that it is possible to use anti-TNF therapy to limit inflammation without completely impairing the immune system.

    Marc Feldman et al., “Trials of Anti-Tumour Necrosis Factor Therapy for COVID-19 Are Urgently Needed,” The Lancet (2020) doi:10.1016/S0140-6736(20)30858-8.

  • Regulation of Interferon Production as a Potential Strategy for COVID-19 Treatment (Preprint)

    Xiaobing Deng, Xiaoyu Yu, and Jianfeng Pei / March 2, 2020

    The type I interferon (IFN-I) cytokine influences many aspects of immune response. Since the immune and inflammatory response is not well regulated in severe COVID-19 patients, this may reflect the unusually vigorous activity of IFN-I. Deng, Yu, and Pei suggest checking or dampening the path to IFN-I as a therapeutic option. The proteins cGAS and STING control the transcription of IFN-I; if inhibited, an over-active inflammatory response might be halted. Sorafenib, anaplastic lymphoma kinase, and suramin block or inhibit the STING-cGAS pathway.

    Deng Xiaobing, Xiaoyu Yu, and Jianfeng Pei, “Regulation of Interferon Production as a Potential Strategy for COVID-19 Treatment,” arXiv (2020), arXiv:2003.00751.

  • Transplantation of ACE2– Mesenchymal Stem Cells Improves the Outcome of Patients with COVID-19 Pneumonia

    Zikuan Leng et al. / March 9, 2020

    Leng et al. administered mesenchymal stem cells (MSCs) to a group of seven patients with COVID-19. Symptoms ranged from mild to critically severe. MCSs are known to modulate immune function through secretion of cytokines and other means. The experiment proved promising, patients showing marked improvement in symptoms two to four days after treatment. Lymphocyte cell composition began to return to normal, and the proportion of inflammatory cytokines, such as TNF-α, decreased, while levels of anti-inflammatory cytokines, such as IL-10, increased. The anti-inflammatory protein factors TGF-β and HGF also helped ease the cytokine storm. MSCs do not themselves contain the receptor to which SARS-CoV-2 binds, and are thus immune to the virus.

    Zikuan Leng et al., “Transplantation of ACE2– Mesenchymal Stem Cells Improves the Outcome of Patients with COVID-19 Pneumonia,” Aging and Disease 11, no. 2 (2020): 216–28, doi:10.14336/AD.2020.0228.

  • Virology, Epidemiology, Pathogenesis, and Control of COVID-19

    Yuefei Jin et al. / March 27, 2020

    This piece is a broad summary of the biology of SARS-CoV-2 and COVID-19. Addressing the issue of cytokine storms, Jin et al. consider a variety of possible causes, ranging from rapid initial viral replication to the reduction in expression of ACE2. Differential susceptibility to cytokine over-expression may depend on antibody-dependent enhancement.

    Yuefei Jin et al., “Virology, Epidemiology, Pathogenesis, and Control of COVID-19,” Viruses 12, no. 4 (2020): 372, doi:10.3390/v12040372.

  • Is COVID-19 Receiving ADE from Other Coronaviruses?

    Jason Tetro / March 2020

    Tetro conjectures that differential susceptibility to SARS-CoV-2 depends on ADE, or antibody-dependent enhancement. Infection generally proceeds by a classic scenario involving an individual, a virus, and the antibodies it provokes. With the infection under control, antibodies remain to patrol the body. Under some circumstances, they may bind to a new virus, but fail to destroy it, the new antibody-virus complex binding to immune cell receptors and gaining entry into the immune cell itself. The result is a cytokine storm. Differential susceptibility to COVID-19 may reflect an antecedent encounter with genetically similar viruses.

    Jason Tetro, “Is COVID-19 Receiving ADE from Other Coronaviruses?” Microbes and Infection 22, no. 2 (2020): 72–73, doi:10.1016/j.micinf.2020.02.006.

  • Understanding SARS-CoV-2-Mediated Inflammatory Responses: From Mechanisms to Potential Therapeutic Tools

    Yajing Fu, Yuanxiong Cheng, and Yuntao Wu / March 3, 2020

    The rapid early proliferation of SARS-CoV-2 in alveolar epithelial cells and vascular endothelial cells leads to cell death, provoking an immune response. In addition, the viral spike (S) protein interacts with the receptor protein ACE2 in target host cells in a way that reduces transcription levels of ACE2. This can lead to a malfunctioning renin-angiotensin system as well as diminished lung function and increased inflammation. Experiments in macaques suggest that antibodies to neutralize the S protein may inadvertently lead to increased inflammation and lung damage. Human patients who develop an antibody for the S protein very early on in the course of infection are much more likely to have life-threatening symptoms, perhaps because the antibody that neutralizes the S protein may bind to the viral spike, and then bind to the macrophage receptor Fc, causing the release of cytokines.

    Yajing Fu, Yuanxiong Cheng, and Yuntao Wu, “Understanding SARS-CoV-2-Mediated Inflammatory Responses: From Mechanisms to Potential Therapeutic Tools,” Virologica Sinica (2020): 1–6, doi:10.1007/s12250-020-00207-4.

  • Vitamin D Supplementation Could Prevent and Treat Influenza, Coronavirus, and Pneumonia Infections (Preprint)

    William Grant et al. / March 30, 2020

    Vitamin-D deficient countries tend to have higher COVID-19 mortality rates. Vitamin D is known to modulate the immune system and regulate levels of inflammatory cytokines. Grant et al. argue that both very young and very old patients are at risk for developing cytokine storms, but that the pristine innate immune response for younger patients typically prevents complications, while in elderly patients, a weaker innate immune response requires an enhanced adaptive immune response. Inasmuch as vitamin D may affect both innate and adaptive immune responses, there could be a 15% reduction in the number of severe COVID-19 cases in populations enjoying an ideal vitamin D level.

    William Grant et al., “Vitamin D Supplementation Could Prevent and Treat Influenza, Coronavirus, and Pneumonia Infections,” Nutrients 12, no. 988 (2020), doi:10.20944/preprints202003.0235.v1.

  • The Potential of Low Molecular Weight Heparin to Mitigate Cytokine Storm in Severe COVID-19 Patients: A Retrospective Clinical Study (Preprint)

    Chen Shi et al. / April 15, 2020

    Shi et al. offer a retrospective study of low-molecular-weight heparin in the treatment COVID-19. After treatment with low-molecular-weight heparin, patients in the experimental group had an increased percentage of lymphocytes as well as reduced levels of cytokine IL-6.

    Chen Shi et al., “The Potential of Low Molecular Weight Heparin to Mitigate Cytokine Storm in Severe COVID-19 Patients: A Retrospective Clinical Study,” medRxiv (2020), doi:10.1101/2020.03.28.20046144.

  • Targeting the Catecholamine-Cytokine Axis to Prevent SARS-CoV-2 Cytokine Storm Syndrome (Preprint)

    Maximilian Konig et al. / April 18, 2020

    In patients receiving chimeric antigen receptor T-cell therapy, catecholamine levels rise rapidly, altering IL-6 levels by interacting with the receptor protein α1-AR. Konig et al. examined medical data from over 12,000 patients presenting acute respiratory distress syndrome, of whom roughly 1,000 had been given α1-AR antagonists the previous year. Their results suggested that patients receiving α1-AR antagonists had statistically improved mortality rates and were less likely to need mechanical ventilation, suggesting, in turn, that α1-AR antagonists, such as prazosin, may be of prophylactic use.

    Maximilian F. Konig et al., “Targeting the Catecholamine-Cytokine Axis to Prevent SARS-CoV-2 Cytokine Storm Syndrome,” medRxiv (2020), doi:10.1101/2020.04.02.20051565.

  • Potential Effect of Blood Purification Therapy in Reducing Cytokine Storm as a Late Complication of Critically Ill COVID-19

    Jie Ma et al. / April 1, 2020

    Patients given blood purification therapy seem to show symptomatic improvement in markers indicating a cytokine storm: “Expeditious control of the cytokine storm in early phase,” Ma et al. write, “might be beneficial to selective patients, and blood purification therapy is effective in our limited experiences. … Although randomized trial data is lacking, we propose that multi-disciplinary efforts should be made to maximize the availability of blood purification therapy to proper patients.”

    Jie Ma et al., “Potential Effect of Blood Purification Therapy in Reducing Cytokine Storm as a Late Complication of Critically Ill COVID-19,” Clinical Immunology 214 (2020), doi:10.1016/j.clim.2020.108408.

  • Tocilizumab Treatment in COVID-19: A Single Center Experience

    Pan Luo et al. / April 6, 2020

    Medical records from 15 patients were studied to determine the effectiveness of tocilizumab in treating cytokine storm symptoms. Several biological parameters were monitored before and after administration of tocilizumab, most notably levels of C-reactive protein and IL-6. Tocilizumab decreased both inflammation and IL-6 levels.

    Pan Luo et al., “Tocilizumab Treatment in COVID-19: A Single Center Experience,” Journal of Medical Virology (2020), doi:10.1002/jmv.25801.

  • Study of the Lymphocyte Change between COVID-19 and Non-COVID-19 Pneumonia Cases Suggesting Other Factors Besides Uncontrolled Inflammation Contributed to Multi-Organ Injury (Preprint)

    Yishan Zheng et al. / March 27, 2020

    Zheng et al. argue that toxic viral replication is a more important factor than cytokine storms with respect to morbidity and mortality in COVID-19 infections. They recommend the use of immune-boosting rather than immune-suppressing medications in view of the negative correlation between lymphocytopenia and organ failure.

    Yishan Zheng et al., “Study of the Lymphocyte Change between COVID-19 and Non-COVID-19 Pneumonia Cases Suggesting Other Factors Besides Uncontrolled Inflammation Contributed to Multi-Organ Injury,” medRxiv (2020), doi:10.1101/2020.02.19.20024885.

  • Cytokine Storm Syndrome

    Randy Cron and Edward Behrens / 2019

    A comprehensive anthology addressing pertinent aspects of cytokine storm syndrome.

    Randy Cron and Edward Behrens, eds., Cytokine Storm Syndrome (Cham, Switzerland: Springer Nature, 2019).

Endmark
  1. Randy Cron and Edward Behrens, eds., Cytokine Storm Syndrome (Cham, Switzerland: Springer Nature, 2019), xiii.

Tyler Hampton is an independent researcher in Pineville, Kentucky.

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