The turning point for people with COVID-19 typically comes in the second week of symptoms. As most people begin to recover, a few others find it increasingly difficult to breathe and wind up in the hospital.
It has been theorized that those whose lungs begin to fail are victims of their own overactive immune systems.
A new study from Washington University School of Medicine in St. Louis and St. Jude Children’s Research Hospital in Memphis, Tenn., however, suggests that an out-of-control immune response is not the main problem for the vast majority of hospitalized COVID-19 patients.
Only 4% of patients in the study had the sky-high levels of immune molecules that signify a so-called “cytokine storm.” The rest had inflammation, but not a remarkably high amount for people fighting infection. If anything, the COVID-19 patients had less inflammation than a comparable group of influenza patients.
The findings, published Nov. 13 in Science Advances, help explain why anti-inflammatory medications such as dexamethasone benefit only a fraction of people with severe COVID-19, and suggest that more research is needed to identify the causes of respiratory failure in COVID-19 patients.
“One of the very first papers published on COVID-19 patients in China reported high levels of cytokines in people in intensive care, what we might call a cytokine storm,” said co-senior author Philip Mudd, MD, Ph.D., an assistant professor of emergency medicine who sees patients at Barnes-Jewish Hospital.
“We wanted to have a better idea of what this cytokine storm looked like, so we began looking for it in our patients, and we were very surprised when we didn’t find it.
We found that cytokine storm does happen, but it’s relatively rare, even in the COVID-19 patients that go on to have respiratory failure and require a ventilator.
But now this idea has gotten established that respiratory failure in COVID-19 is driven by cytokine storm, and lots of unproven anti-inflammatory treatments are being given to critically ill COVID-19 patients in an attempt to suppress the cytokine storm. That worries me because such treatments are unlikely to help most people with COVID-19.”
Before the pandemic, Mudd started investigating the immune response to influenza infection, using blood samples obtained, with consent, from flu patients who seek care in the Barnes-Jewish Hospital emergency department.
In late March, as COVID-19 patients began filling the emergency department, Mudd and co-senior author Ali Ellebedy, Ph.D., an assistant professor of pathology and immunology and a fellow influenza expert, realized they could use the same approach to investigate how the immune response goes awry in severe cases of COVID-19.
The researchers analyzed immune cells and molecules in blood samples from 168 COVID-19 patients, 26 influenza patients and 16 healthy people. The samples were drawn from influenza patients in 2019 or 2020, and from COVID-19 patients and healthy controls this year.
They also collected information about how each patient fared – whether a patient ended up needing intensive care or mechanical ventilation—and whether he or she survived. Along with Mudd and Ellebedy, the research team included co-senior author Paul Thomas, Ph.D., and co-first author Jeremy Crawford, Ph.D., both of St. Jude, among others.
The numbers of inflammatory cells in the blood of COVID-19 and influenza patients were about the same. Seven of the COVID-19 patients (4%) showed signs of a cytokine storm, with extremely high levels of cytokines even when compared to other severely ill patients.
The majority of the COVID-19 patients with acute respiratory failure not only did not have a cytokine storm, they had less inflammation than influenza patients who were equally ill.
A few clinical trials have shown that some severely ill COVID-19 patients improve on steroid drugs such as dexamethasone that suppress inflammation. A meta-analysis published in September placed the percentage who benefit between 2% and 9%.
Those results jibe with the findings of this study, Mudd said.
“It could be that the 4% of people who have cytokine storm are the ones who benefit from steroids in those clinical trials,” Mudd said. “I think our work helps explain why steroids help some people.
But from our data, it doesn’t look like most COVID-19 patients have a deficiency of steroids. If you’re giving steroids to someone who already has a lot of steroids in their body, that might not be good for them.”
The key will be to find a way to identify the people at high risk for a cytokine storm when they first arrive at the hospital, so that steroid treatment can be appropriately targeted to the ones most likely to benefit and least likely to be harmed.
The researchers ran a panel of routine lab tests – blood cell counts, measurements of common inflammatory markers – but could not find a signature of an impending cytokine storm. They are pursuing more in-depth analyses to find a way to predict who will develop a cytokine storm.
“The subjects in the cohort with the ‘true’ cytokine storm phenotype are such outliers immunologically compared to the others, it seems likely that there are significant differences in multiple immune pathways driving this phenotype,” Thomas said.
“If we can identify features of those pathways that can be assessed quickly in a clinical setting, it could be useful for patient stratification.”
With cytokine storm largely ruled out, the cause of most cases of respiratory failure in COVID-19 patients remains unknown, Mudd said.
“In the population we studied, 24% died but only 4% had a cytokine storm,” Mudd said. “Most people who died of COVID-19 died without a cytokine storm. Severe flu is more inflammatory than severe COVID-19. So what’s causing their lungs to fail?
We still don’t know. We’re trying to find out.”
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.
Cytokine storm has no definition. Broadly speaking, it denotes a hyperactive immune response characterized by the release of interferons, interleukins, tumor-necrosis factors, chemokines, and several other mediators. These mediators are part of a well-conserved innate immune response necessary for efficient clearance of infectious agents.
Cytokine storm implies that the levels of released cytokines are injurious to host cells. Distinguishing an appropriate from a dysregulated inflammatory response in the pathophysiology of critical illness, however, has been a major challenge. To add further complexity, most mediators implicated in cytokine storm demonstrate pleotropic downstream effects and are frequently interdependent in their biological activity.
The interactions of these mediators and the pathways they inform are neither linear nor uniform. Further, although their quantified levels may suggest severity of responses, they do not necessarily imply pathogenesis. This complex interplay illustrates the limitations of interfering in the acute inflammatory response based on single mediators and at indiscriminate time points.
Why has the “cytokine storm” been so closely associated with COVID-19? During the SARS epidemic caused by SARS-CoV-1, the term cytokine storm was described as a feature and associated with adverse outcomes.3 Several early case series in COVID-19 reported levels of some plasma cytokines elevated above the normal range. In most cases, however, they are lower than plasma levels in previous cohorts of patients with ARDS.
Interleukin-6, a proinflammatory cytokine, is a key mediator in the acute inflammatory response and the purported cytokine storm.
The Table summarizes reported IL-6 levels in 5 cohorts of patients with COVID-19,1,2,4-6 each with more than 100 patients, and 3 cohorts of patients with ARDS.7-9 Although the median values are above the normal range in many (but not all) cases, they are lower than the median values typically reported in ARDS.
The median values in randomized clinical trials conducted by the National Heart, Lung and Blood Institute’s ARDS Network are approximately 10- to 40-fold higher, even when only patients with severe COVID-19 are considered.7-9
The hyperinflammatory phenotype of ARDS is characterized by elevated proinflammatory cytokines, an increased incidence of shock, and adverse clinical outcomes.7-9
The characteristics of this phenotype could be considered as most consistent with those expected with the cytokine storm. However, median IL-6 levels in patients with the hyperinflammatory phenotype of ARDS are 10- to 200-fold higher than levels in patients with severe COVID-19 (Table).
Table. Plasma Levels of Interleukin-6 Reported in COVID-19 Compared With Levels Previously Reported in ARDSa
Putting the unsubstantiated theory of the cytokine storm aside, the more intriguing question to ask is why are clinical outcomes in COVID-19 so unfavorable despite relatively low levels of circulating IL-6?
One hypothesis is that severe viral pneumonia from COVID-19 produces primarily severe lung injury, without the same magnitude of systemic responses in most patients with COVID-19 as reported in prior studies of the hyperinflammatory phenotype in ARDS.7-9
For example, 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 ARDS.10 Ongoing research may identify more specific mechanisms of COVID-19–mediated lung injury.
There are some limitations to these observations. Almost all the COVID-19 IL-6 data are from clinical laboratory tests. In most studies, details of the exact methods used are not available; calibration issues could lead to underestimating IL-6 levels compared with measurements based on enzyme-linked immunosorbent assay used in prior ARDS studies.7-9
Furthermore, plasma levels of cytokines may not be representative of lung inflammation. Given the number of COVID-19 cases worldwide, the data on IL-6 levels are from a very small fraction of patients.
Nevertheless, the theory of the cytokine storm is based on these data, and the case for its presence in COVID-19 seems weak.
A more appropriate conclusion would be that in comparison to other causes of ARDS, COVID-19 is characterized by lower levels of circulating cytokine responses. Perhaps the most valid conclusion, however, is that the current data are insufficient to ascertain the precise role and scope of dysregulated cytokine responses in COVID-19.
Widespread acceptance of the term cytokine storm in COVID-19 has motivated the use of potent immunomodulatory therapies both in the setting of clinical trials and on a compassionate basis. These drugs, such as IL-6 inhibitors and high-dose corticosteroids, block pathways critical to host immune responses.
Many monoclonal antibody drugs are being repurposed from treating patients with chronic inflammatory conditions where optimal pharmacokinetics demand prolonged half-lives. Long-lasting and indiscriminate suppression of inflammation in the acute critical care setting raises concerns about impaired clearance of SARS-CoV-2 and increased risk for secondary infections.
Enthusiasm for the use of immunomodulatory approaches in COVID-19 seems to derive in large part from clinical experience with cytokine release syndrome (CRS), a term frequently interchanged with cytokine storm. In the 2016 study of CRS by Maude and colleagues, patients who developed CRS following treatment with chimeric antigen receptor T cells were effectively treated with tocilizumab.11
Notably, the peak plasma IL-6 level in patients who developed CRS was approximately 10 000 pg/mL—almost 1000-fold higher than that reported in severe COVID-19.
Conceivably, these therapies could be effective in COVID-19, but the likelihood for success would be enhanced by selecting the right patients with predictive enrichment and the right timing for intervention.7
Given reports that dexamethasone may improve survival for patients with COVID-19 and ARDS, it should be determined whether these effects differ between ARDS phenotypes and if they occur despite the absence of a circulating hyperinflammatory cytokine response.
If so, the additional information about dexamethasone would further substantiate the importance of studying local inflammatory responses to COVID-19 in the lungs.
For these reasons, the term cytokine storm may be misleading in COVID-19 ARDS. Incorporating a poorly defined pathophysiological entity lacking a firm biological diagnosis may only further increase uncertainty about how best to manage this heterogeneous population of patients.
The manifestations of elevated circulating mediators in the purported cytokine storm are likely to be endothelial dysfunction and systemic inflammation leading to fever, tachycardia, tachypnea, and hypotension.
This constellation of symptoms already has a long history in critical care, known as systemic inflammatory response syndrome, and was used to define sepsis for decades. Interventions targeting single cytokines in sepsis, unfortunately, also have a long history of failure.
Although the term cytokine storm conjures up dramatic imagery and has captured the attention of the mainstream and scientific media, the current data do not support its use.
Until new data establish otherwise, the linkage of cytokine storm to COVID-19 may be nothing more than a tempest in a teapot.
- Wu C, Chen X, Cai Y, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med. Published online March 13, 2020. doi:10.1001/jamainternmed.2020.0994
- Qin C, Zhou L, Hu Z, et al. Dysregulation of immune response in patients with COVID-19 in Wuhan, China. Clin Infect Dis. Published online March 12, 2020;ciaa248. doi:10.1093/cid/ciaa248PubMedGoogle Scholar
- Huang KJ, Su IJ, Theron M, et al. An interferon-gamma-related cytokine storm in SARS patients. J Med Virol. 2005;75(2):185-194. doi:10.1002/jmv.20255PubMedGoogle ScholarCrossref
- Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054-1062. doi:10.1016/S0140-6736(20)30566-3PubMedGoogle ScholarCrossref
- Mo P, Xing Y, Xiao Y, et al. Clinical characteristics of refractory COVID-19 pneumonia in Wuhan, China. Clin Infect Dis. Published online March 16, 2020;ciaa270. doi:10.1093/cid/ciaa270PubMedGoogle Scholar
- Cummings MJ, Baldwin MR, Abrams D, et al. Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: a prospective cohort study. Lancet. 2020;395(10239):1763-1770. doi:10.1016/S0140-6736(20)31189-2PubMedGoogle ScholarCrossref
- Calfee CS, Delucchi K, Parsons PE, Thompson BT, Ware LB, Matthay MA; NHLBI ARDS Network. Subphenotypes in acute respiratory distress syndrome: latent class analysis of data from two randomised controlled trials. Lancet Respir Med. 2014;2(8):611-620. doi:10.1016/S2213-2600(14)70097-9PubMedGoogle ScholarCrossref
- Famous KR, Delucchi K, Ware LB, et al; ARDS Network. Acute respiratory distress syndrome subphenotypes respond differently to randomized fluid management strategy. Am J Respir Crit Care Med. 2017;195(3):331-338. doi:10.1164/rccm.201603-0645OCPubMedGoogle ScholarCrossref
- Sinha P, Delucchi KL, Thompson BT, McAuley DF, Matthay MA, Calfee CS; NHLBI ARDS Network. Latent class analysis of ARDS subphenotypes: a secondary analysis of the statins for acutely injured lungs from sepsis (SAILS) study. Intensive Care Med. 2018;44(11):1859-1869. doi:10.1007/s00134-018-5378-3PubMedGoogle ScholarCrossref
- Ackermann M, Verleden SE, Kuehnel M, et al. Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19. N Engl J Med. Published online May 21, 2020. doi:10.1056/NEJMoa2015432PubMedGoogle Scholar11.Maude S, Barrett DM. Current status of chimeric antigen receptor therapy for haematological malignancies. Br J Haematol. 2016;172(1):11-22. doi:10.1111/bjh.13792PubMedGoogle ScholarCrossref
More information: Distinct inflammatory profiles distinguish COVID-19 from influenza with limited contributions from cytokine storm, Science Advances (2020). DOI: 10.1126/sciadv.abe3024 , advances.sciencemag.org/conten … adv.abe3024.abstract