Volume 72, Issue 7 p. 1059-1063
Notes From the Field
Free Access

On the Alert for Cytokine Storm: Immunopathology in COVID-19

Lauren A. Henderson

Corresponding Author

Lauren A. Henderson

Boston Children’s Hospital and Harvard Medical School, Boston, Massachusetts

Address correspondence to Lauren A. Henderson, MD, MMsc, 1 Blackfan Circle, Karp Family Research Building, Tenth Floor, Boston, MA 02115. E-mail: [email protected].Search for more papers by this author
Scott W. Canna

Scott W. Canna

UPMC Children’s Hospital of Pittsburgh and University of Pittsburgh, Pittsburgh, Pennsylvania

Search for more papers by this author
Grant S. Schulert

Grant S. Schulert

Cincinnati Children’s Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, Ohio

Search for more papers by this author
Stefano Volpi

Stefano Volpi

Center for Autoinflammatory Diseases and Immunodeficiency, IRCCS Istituto Giannina Gaslini, and Università degli Studi di Genova, Genoa, Italy

Search for more papers by this author
Pui Y. Lee

Pui Y. Lee

Boston Children’s Hospital and Harvard Medical School, Boston, Massachusetts

Search for more papers by this author
Kate F. Kernan

Kate F. Kernan

UPMC Children’s Hospital of Pittsburgh and University of Pittsburgh, Pittsburgh, Pennsylvania

Search for more papers by this author
Roberto Caricchio

Roberto Caricchio

Temple University Hospital and Lewis Katz School of Medicine, Philadelphia, Pennsylvania

Search for more papers by this author
Shawn Mahmud

Shawn Mahmud

University of Minnesota Medical Center and University of Minnesota School of Medicine, Minneapolis

Search for more papers by this author
Melissa M. Hazen

Melissa M. Hazen

Boston Children’s Hospital and Harvard Medical School, Boston, Massachusetts

Search for more papers by this author
Olha Halyabar

Olha Halyabar

Boston Children’s Hospital and Harvard Medical School, Boston, Massachusetts

Search for more papers by this author
Kacie J. Hoyt

Kacie J. Hoyt

Boston Children’s Hospital and Harvard Medical School, Boston, Massachusetts

Search for more papers by this author
Joseph Han

Joseph Han

Icahn School of Medicine at Mount Sinai, New York, New York

Search for more papers by this author
Alexei A. Grom

Alexei A. Grom

Cincinnati Children’s Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, Ohio

Search for more papers by this author
Marco Gattorno

Marco Gattorno

Center for Autoinflammatory Diseases and Immunodeficiency, IRCCS Istituto Giannina Gaslini, and Università degli Studi di Genova, Genoa, Italy

Search for more papers by this author
Angelo Ravelli

Angelo Ravelli

Clinica Pediatrica e Reumatologia, IRCCS Istituto Giannina Gaslini, and Università degli Studi di Genova, Genoa, Italy

Search for more papers by this author
Fabrizio De Benedetti

Fabrizio De Benedetti

Ospedale Pediatrico Bambino Gesù, Rome, Italy

Search for more papers by this author
Edward M. Behrens

Edward M. Behrens

Children’s Hospital of Philadelphia and the University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania

Search for more papers by this author
Randy Q. Cron

Randy Q. Cron

Children’s of Alabama, University of Alabama at Birmingham, Birmingham

Search for more papers by this author
Peter A. Nigrovic

Peter A. Nigrovic

Boston Children’s Hospital, Brigham and Women’s Hospital, and Harvard Medical School, Boston, Massachusetts

Search for more papers by this author
First published: 15 April 2020
Citations: 472
Dr. Henderson's work was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH (grants K08-AR-073339 and P30-AR-070253) and the Investigator Award of the Rheumatology Research Foundation. Dr. Canna's work was supported by the National Institute of Child Health and Human Development, NIH (grant R01-HD-098428), the National Institute of General Medical Sciences, NIH (grant 2R01-GM-108618), and the RK Mellon Institute for Pediatric Research. Dr. Caricchio’s work was supported in part by a grant from the Lupus Research Alliance. Dr. Mahmud's work was supported in part by a University of Minnesota Medical School Academic Investment Education Program grant. Dr. Nigrovic's work was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH (awards 2R01-AR-065538, R01-AR-075906, R01-AR-073201, P30-AR-070253, and R21-AR-076630), the National Heart, Lung, and Blood Institute, NIH (award R21-HL-150575), the Fundación Bechara, and the Arbuckle Family Fund for Arthritis Research.
1Lauren A. Henderson, MD, MMSc, Pui Y. Lee, MD, PhD, Melissa M. Hazen, MD, Olha Halyabar, MD, Kacie J. Hoyt, MS: Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts; 2Scott W. Canna, MD, Kate F. Kernan, MD: UPMC Children's Hospital of Pittsburgh and University of Pittsburgh, Pittsburgh, Pennsylvania; 3Grant S. Schulert, MD, PhD, Alexei A. Grom, MD: Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, Ohio; 4Stefano Volpi, MD, PhD, Marco Gattorno, MD: Center for Autoinflammatory Diseases and Immunodeficiency, IRCCS Istituto Giannina Gaslini, and Università degli Studi di Genova, Genoa, Italy; 5Roberto Caricchio, MD: Temple University Hospital and Lewis Katz School of Medicine, Philadelphia, Pennsylvania; 6Shawn Mahmud, MD, PhD: University of Minnesota Medical Center and University of Minnesota School of Medicine, Minneapolis; 7Joseph Han, BS: Icahn School of Medicine at Mount Sinai, New York, New York; 8Angelo Ravelli, MD: Clinica Pediatrica e Reumatologia, IRCCS Istituto Giannina Gaslini, and Università degli Studi di Genova, Genoa, Italy; 9Fabrizio De Benedetti, MD: Ospedale Pediatrico Bambino Gesù, Rome, Italy; 10Edward M. Behrens, MD: Children's Hospital of Philadelphia and the University of Pennsylvania Perelman School of Medicine; 11Randy Q. Cron, MD, PhD: Children's of Alabama, University of Alabama at Birmingham; 12Peter A. Nigrovic, MD: Boston Children's Hospital, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts.
Drs. Henderson and Canna contributed equally to this work.
Dr. Henderson has received salary support from the Childhood Arthritis and Rheumatology Alliance and consulting fees from Sobi (less than $10,000). Dr. Canna has received research support from AB2 Bio related to a clinical trial. Dr. Schulert has received consulting fees from Sobi and Novartis (less than $10,000 each). Dr. Caricchio has received consulting fees from GlaxoSmithKline, Aurinia Pharmaceuticals, and Janssen (less than $10,000 each) and investigator-initiated research support from Janssen. Dr. Grom has received consulting fees from Novartis, AB2 Bio, and Sobi (less than $10,000 each) and research support from those companies. Dr. Gattorno has received consulting fees, speaking fees, and/or honoraria from Novartis and Sobi (less than $10,000 each) and research support from the Eurofever Project. Dr. Ravelli has received consulting fees, speaking fees, and/or honoraria from AbbVie, Bristol-Myers Squibb, Pfizer, Hoffmann-LaRoche, Novartis, Centocor, Angelini Holding, and Reckitt Benckiser (less than $10,000 each). Dr. De Benedetti has received research support paid to his institution from AbbVie, Hoffmann-La Roche, Pfizer, NovImmune, Novartis, Sobi, and Sanofi. Dr. Behrens has received research support from AB2 Bio to run a clinical trial. Dr. Cron has received consulting fees from Sobi, Novartis, and Pfizer (less than $10,000 each) and is a co–Principal Investigator of an investigator-initiated clinical trial to study anakinra in secondary hemophagocytic lymphohistiocytosis funded by Sobi. Dr. Nigrovic has received salary support from the Childhood Arthritis and Rheumatology Research Alliance, consulting fees from Sobi, Pfizer, Quench Bio, XBiotech, and Bristol-Myers Squibb (less than $10,000 each) and from Simcere and Miach Orthopedics (more than $10,000 each), royalties from UpToDate Inc. and the American Academy of Pediatrics, and research support from Novartis, Sobi, Pfizer, and Bristol-Myers Squibb. No other disclosures relevant to this article were reported.

Abstract

Poor outcomes in COVID-19 correlate with clinical and laboratory features of cytokine storm syndrome. Broad screening for cytokine storm and early, targeted antiinflammatory therapy may prevent immunopathology and could help conserve limited health care resources. While studies are ongoing, extrapolating from clinical experience in cytokine storm syndromes may benefit the multidisciplinary teams caring for patients with severe COVID-19.

COVID-19 (coronavirus disease 2019) is sweeping across the globe. Most patients have mild-to-moderate symptoms, but a subgroup will become severely ill. Sepsis, respiratory failure, and acute respiratory distress syndrome (ARDS) are common complications of the disease 1. Factors associated with admission to the intensive care unit and death include older age, comorbid conditions, elevated body mass index, lymphopenia, and elevated blood levels of transaminases, lactate dehydrogenase (LDH), d-dimer, ferritin, and soluble interleukin-2 receptor (sIL-2R) 1-4.

This constellation of features is reminiscent of a family of syndromes broadly gathered under the umbrella of cytokine storm syndrome, in which hyperinflammation and multiorgan disease arise through excessive cytokine release from uncontrolled immune activation (Figure 1). Rheumatologists face this foe regularly in systemic juvenile idiopathic arthritis (JIA), adult-onset Still's disease, and systemic lupus erythematosus, among other diseases. Macrophage activation syndrome (MAS), one form of cytokine storm syndrome, develops in at least 10% of patients with systemic JIA. Compared to systemic JIA patients without MAS, those with this complication are more likely to carry heterozygous variants in genes mediating the release of cytotoxic granules from natural killer (NK) cells and CD8+ T cells; biallelic mutations of these genes cause an inherited form of cytokine storm syndrome termed familial hemophagocytic lymphohistiocytosis (HLH). Reduced cytotoxicity impairs clearance of infected cells and elimination of activated macrophages, leading to massive release of proinflammatory mediators. One of these mediators, IL-6, further impairs NK cell function. Patients present with rapid onset of fever, cytopenias, coagulopathy, elevated transaminase levels, hyperferritinemia, and multiorgan dysfunction. Historically, the cornerstones of treatment were glucocorticoids, intravenous immunoglobulin (IVIG), and cyclosporine. Despite these interventions, mortality was as high as 20%. Identification of key mediators driving MAS—including IL-1β, IL-6, IL-18, and interferon-γ (IFNγ)—have inaugurated a new era of cytokine neutralization, potentially enabling a marked reduction in mortality 5, 6.

Details are in the caption following the image
The family of conditions characterized by cytokine storm. Malig. = malignancy; Assoc. = associations; SJIA = systemic juvenile idiopathic arthritis; MAS = macrophage activation syndrome; CRS = cytokine release syndrome; ARDS = acute respiratory distress syndrome; EBV = Epstein-Barr virus; HLH = hemophagocytic lymphohistiocytosis.

Herpes family viruses (e.g., Epstein-Barr virus) and influenza are major triggers of cytokine storm, both in systemic JIA and in patients without a preexisting immunologic diagnosis. As in systemic JIA–related MAS, the inflammatory cytokines IFNγ and IL-18 are key mediators of hyperinflammation in a murine model of repeated Toll-like receptor 9 stimulation, which mimics severe viral infection 6. In one study of patients without underlying rheumatic disease who died of H1N1 influenza, 81% displayed features of cytokine storm, and 36% carried pathologic variants in the cytolytic pathway 7. Treatments effective in systemic JIA–related MAS can benefit patients with cytokine storm triggered by infections 8, 9. Post hoc analysis of a phase III randomized controlled trial of anakinra (recombinant IL-1 receptor antagonist) in sepsis showed that patients with coagulopathy and elevated transaminase levels exhibited better survival with IL-1 blockade than with standard of care (65% versus 35%; hazard ratio for death 0.28, P = 0.007) 10. Similarly, IL-6 blockade is effective in treating the related cytokine release syndrome from chimeric antigen receptor T cell (CAR-T) therapy 11.

Hyperinflammation in COVID-19 is not MAS, and it may even be distinct from other forms of viral-induced cytokine storm, in that ferritin elevation is modest and severe end-organ disease is focused on the lung. Some patients with COVID-19 may simply have “garden-variety” ARDS associated with the tropism of the virus for the lung. However, critically ill patients with COVID-19 often demonstrate features suggestive of cytokine storm, including fever, characteristic changes in laboratory study findings, and ARDS. Lung tissue from patients with severe acute respiratory syndrome (SARS), the etiology of which has been attributed to a related coronavirus, showed hemophagocytosis—a central pathologic feature of cytokine storm—in 2 of 6 patients who succumbed to the disease 12. Patients with SARS also exhibited high levels of IFNγ and IL-18, which are particularly important in cytokine storm syndrome 13. Thus, the host's immune response and development of tissue-focused inflammation in the lung likely plays an important role in COVID-19.

These considerations suggest that, beyond antiviral therapy and supportive care, it will be important to monitor hospitalized patients with COVID-19 for evidence of cytokine storm. Impending hyperinflammation can manifest as cytopenias (thrombocytopenia and lymphopenia), coagulopathy (low platelet and fibrinogen levels, and elevated d-dimer levels), tissue damage/hepatitis (elevated LDH, aspartate aminotransferase, and alanine aminotransferase levels), and macrophage/hepatocyte activation (elevated ferritin levels) (Table 1 and Supplementary Table 1, available on the Arthritis & Rheumatology web site at http://onlin​elibr​ary.wiley.com/doi/10.1002/art.41285/​abstract). Cytokine measurement is a theoretically appealing approach, but IFNγ and IL-1β are not easily assessed in the peripheral blood and IL-6 levels have not yet been proven consistently predictive of poor outcomes. CXCL9, a stable chemokine, is a useful surrogate for IFNγ activity in MAS, as is adenosine deaminase 2 (ADA-2); however, real-time measurement of CXCL9 is not commonly available and ADA-2 testing remains available largely on a research basis. Experience suggests that trends in laboratory test findings, rather than threshold values, will be most informative. In a patient with COVID-19 who develops lymphopenia, worsening coagulopathy, hepatitis, and rising ferritin levels, it may make sense to target immune hyperactivity before end-organ manifestations, such as ARDS, ensue.

Table 1. Biomarkers of cytokine storm syndrome (CSS)a
Biomarker Biology Status in hyperinflammation Status in COVID-19 Test availability
CRP Hepatic release in response to IL-6 Nonspecific, useful for monitoring, blunted by IL-6 blockade Associated with severity, ARDS A
Complete blood cell count Multifactorial cytopenias May be indicative of CSS (especially thrombocytopenia) Associated with severity, ARDS A
d-dimer, ↓ fibrinogen Fibrin degradation product, reflective of DIC May be indicative of active CSS Associated with severity, ARDS A
LDH, AST, ALT Tissue injury, hepatitis May be indicative of active CSS Associated with severity, ARDS A
Ferritin Macrophage/hepatocyte activation Integral part of CSS diagnosis, predictive of sepsis mortality Associated with severity, ARDS A
Ferritin:ESR ratio ESR falls with fibrinogen consumption Higher specificity than ferritin alone Not assessed A
Procalcitonin Adipokine Nonspecific, useful for monitoring Variably associated with severity, ARDS A, S
IL-2Ra (CD25) Cleaved from T cells by inflammatory proteases Part of HLH diagnostic criteria, useful for monitoring Associated with severity S
IL-6 Pleiotropic inflammatory cytokine Elevated, nonspecific Associated with severity S
Neopterin Metabolite of GTP induced by IFNγ Elevated in blood and CSF Not assessed S
IFNγ Classic type 1/Th1 cytokine Elevated, but poor dynamic range Elevated compared with healthy control S, R
CXCL9 Chemokine induced by IFNγ Elevated in most CSS, useful for monitoring Not assessed S
IL-1β Inflammasome-activated Elevated, but poor dynamic range Variably elevated with severity S, R
IL-18 Inflammasome-activated, IFNγ inducing Very high levels may indicate MAS, not useful for monitoring Not assessed S
ADA-2 Released by IFNγ-activated monocytes Elevated in most CSS, useful for monitoring Not assessed S, R
S100 proteins Neutrophil/monocyte activation Elevated in active systemic JIA and MAS, and in some ARDS Not assessed S, R
CD163 Cleaved from tissue macrophages Elevated in active systemic JIA and MAS, and in ARDS Not assessed S, R
  • a Relevant citations are provided in Supplementary Table 1 (available on the Arthritis & Rheumatology web site at http://onlin​elibr​ary.wiley.com/doi/10.1002/art.41285/​abstract). COVID-19 = coronavirus disease 2019; CRP = C-reactive protein; IL-6 = interleukin-6; ARDS = acute respiratory distress syndrome; A = widely available; DIC = disseminated intravascular coagulation; LDH = lactate dehydrogenase; AST = aspartate aminotransferase; ALT = alanine aminotransferase; ESR = erythrocyte sedimentation rate; S = typically send-out; IL-2Ra = IL-2 receptor antagonist; HLH = hemophagocytic lymphohistiocytosis; IFNγ = interferon-γ; CSF = cerebrospinal fluid; R = may be available only on a research basis; MAS = macrophage activation syndrome; ADA-2 = adenosine deaminase 2; JIA = juvenile idiopathic arthritis.

The US Centers for Disease Control and Prevention provided an unqualified recommendation against the use of glucocorticoids for the treatment of COVID-19, based on prior experience with influenza, SARS, and coronavirus-induced Middle East respiratory syndrome (MERS) 14. However, a Cochrane review of glucocorticoids as adjunctive therapy in influenza found that the evidence was of low quality, largely because of confounding by indication 15. The literature with regard to glucocorticoids in patients with MERS and SARS has reported similar findings, although some data suggest that glucocorticoids could delay viral clearance 16. Importantly, these data reflect treatment of “all comers” with influenza, MERS, or SARS, rather than therapy targeted to patients with evidence of hyperinflammation. Of note, in one COVID-19 case series, the mortality rate was lower in patients with ARDS who were treated with methylprednisolone compared with those who did not receive glucocorticoids (46% versus 62%; hazard ratio for death 0.38, P = 0.003), although, again, the possibility of confounding by indication is difficult to exclude 2.

Experience from hyperinflammation in HLH, MAS, and cytokine release syndrome suggests that early intervention is essential to avoiding life-threatening tissue damage. In patients with COVID-19 who exhibit evidence of cytokine storm, treatment with glucocorticoids, IVIG, and/or anticytokine therapies should be considered, with the aim of reverting hyperinflammation before ARDS occurs (Table 2 and Supplementary Table 2, available on the Arthritis & Rheumatology web site at http://onlinelibrary.wiley.com/doi/10.1002/art.41285/abstract) 8, 17. Glucocorticoids remain a key first-line option, and clinical trials are urgently needed to test their efficacy and to identify optimal dosing, especially given the clear advantage of glucocorticoids in worldwide availability and cost. IL-1 blockade has shown particular promise as a treatment for cytokine storm syndrome, and high-dose regimens are safe even in the context of overt sepsis 5, 10. Tocilizumab (anti–IL-6 receptor) is effective in cytokine release syndrome associated with CAR-T therapy, a syndrome notably reminiscent of COVID-19 in that many patients develop ARDS 11. Emapalumab (anti-IFNγ) is approved by the US Food and Drug Administration for the treatment of HLH and may be effective in MAS. JAK inhibition appears promising; however, the safety of these medications in severe viral infection remains unknown.

Table 2. Treatments for cytokine storm syndrome of potential utility in severe COVID-19a
Intervention Biology Experience in hyperinflammation Experience in COVID-19 Potential likelihood of impairing viral suppression/clearanceb Concerns
Glucocorticoids (<2 mg/kg/day)c Transcriptional regulation via glucocorticoid receptor Mainstay of treatment May improve outcomes in ARDS (ChiCTR2000029386)d ++ Hypertension, immunosuppression, metabolic changes, mood alterations
Glucocorticoids (>250 mg/day)c Transcriptional regulation via glucocorticoid receptor Commonly used during initiation May improve outcomes in ARDS (ChiCTR2000029386)d ++ Hypertension, immunosuppression, metabolic changes, mood alterations
Cyclosporine, tacrolimus Inhibit calcineurin-mediated lymphocyte activation Case reports/small series in MAS, part of HLH treatment protocol Theoretical ++ Hypertension, renal failure, immunosuppression
Anakinra Block IL-1 signaling Re-analysis of sepsis trials, large series in MAS and HLH (NCT02780583) NCT04324021 + Rare transaminitis, neutropenia, eosinophilia
Sarilumab, tocilizumab Block IL-6 signaling CAR-T cytokine release syndrome, case reports, ongoing clinical trialse NCT04322773, NCT04317092, NCT04320615, NCT04306705, NCT04324073, NCT04315298 + Cytopenias, immunosuppression
Emapalumab Neutralize IFNγ Refractory familial HLH, other case reports, ongoing trialse NCT04324021 + Immunosuppression
JAK inhibitors Inhibit JAK/STAT pathway cytokines Case reports, ongoing clinical trials NCT04320277, NCT04321993 +++ Cytopenias, immunosuppression
Cytokine adsorption Remove from circulation Case reports NCT04324528 Minimal Central line access
IVIG Unclear mechanism Case reports Theoretical Minimal Hypertension, hemolysis
Therapeutic plasma exchange Remove cytokines/chemokines/DAMPs, replace factors Case reports Theoretical Minimal Central line access
  • a Relevant citations are provided in Supplementary Table 2 (available on the Arthritis & Rheumatology web site at http://onlin​elibr​ary.wiley.com/doi/10.1002/art.41285/​abstract). COVID-19 = coronavirus disease 2019; ARDS = acute respiratory distress syndrome; MAS = macrophage activation syndrome; HLH = hemophagocytic lymphohistiocytosis; IL-1 = interleukin-1; CAR-T = chimeric antigen receptor T cell therapy; IFNγ = interferon-γ; IVIG = intravenous immunoglobulin; DAMPs = damage-associated molecular patterns.
  • b +, ++, and +++ indicate low, moderate, and high likelihood of impairment.
  • c In methylprednisolone equivalent doses.
  • d Dosage unclear.
  • e Approved by the US Food and Drug Administration.

Clinical trials are currently enrolling patients with COVID-19 to study the safety and efficacy of glucocorticoids and cytokine blockade strategies utilizing neutralization of IL-1, IL-6, and IFNγ (Table 2). Absent the opportunity to enroll patients in one of these studies, we would consider immunosuppression in patients with COVID-19 who have incipient cytokine storm. Ideally, treatment decisions will be undertaken with the help of a multidisciplinary team familiar with the triggers, manifestations, and treatments of cytokine storm 17. Glucocorticoids will likely be useful. Cytokine blockers may play an important role as well, while we must remain cognizant of the ongoing need for these medications in patients with chronic rheumatologic conditions. Unfortunately, many patients with COVID-19 will become critically ill before high-quality evidence of treatment efficacy is available, leaving us to extrapolate as best we can from the available evidence and from current clinical experience in cytokine storm syndromes.

AUTHOR CONTRIBUTIONS

All authors drafted the article, revised it critically for important intellectual content, and approved the final version to be published.