A dysregulated immune response, a cytokine storm and cytokine release syndrome1,2 are some of the terms used to describe the overexuberant response of defense that is thought to contribute to the severity of illness in certain people who become seriously ill with COVID-19. However, an accurate definition of this type of immune disorder function remains indispensable. Sign in Nature, Lucas and others.3 fill in some gaps in our knowledge.
A holy grail of COVID-19 research is the ability to assess a person’s immune response, to identify those individuals who have mild symptoms but who are on course to develop the intensive response of defense that ‘. t is associated with serious illness. This is important because there is a broad spectrum of clinical disease in people infected with SARS-CoV-2, the coronavirus that causes COVID-19: some infected individuals may be asymptomatic, while others are at risk of dying. and require hospitalization in an intensive care unit and use of a ventilator for breathing4,5. Identifying those whose dysregulated signature of immune response predicts the development of serious disease could be monitored more intensively to minimize disease progression.
Lucas and colleagues conducted extensive analyzes of immune responses (longitudinal studies) in 113 people hospitalized with COVID-19 who had a moderate or severe illness, and assessed a similar number of SARS-CoV-2-free healthy people as controls. The authors analyzed molecules in blood plasma (Fig. 1) and monitored peripheral blood mononuclear cells – white blood cells of the immune system such as CD4 T cells, CD8 T cells and B cells. The longitudinal nature of this study leads to conclusions that would not be possible by analyzing research studies that individuals do not follow over time.
Figure 1 | Immune responses to COVID-19 infection. Lucas and others.3 analyzed blood samples taken over time from persons admitted to hospital with moderate or severe COVID-19. Such information is useful for efforts to try to predict individuals that are at risk of developing a severe form of the disease, which is often accompanied by an intense immune response. in, The authors identified a subset of immune-signaling molecules called cytokines that are expressed in people with moderate to severe disease; IFN-α is one such ‘nuclear’ cytokine. b, The expression level of certain other cytokines, such as IFN-λ, changed especially as the disease progressed. c, The level of some inflammation-promoting cytokines, such as TNF-α, correlated with viral load in the nasal passages. d, Viral load decreased over time in people with a moderate COVID-19, but not in those with severe disease. e, Some cytokines that are not associated with antiviral responses, such as IL-5, which helps defend against parasitic worms and is released during allergic reactions, were, surprisingly, regulated because humans develop severe disease. f, The levels of CD4 and CD8 T cells, which are important immune cells involved in viral clearance, were lower in people with moderate or severe disease than in healthy individuals not infected with SARS-CoV-2, the virus that causes COVID-19. (Graphs based on data from ref. 3.)
The authors found that levels of various inflammation-promoting molecules – immunomodulatory molecules called cytokines, including IL-1α, IL-1β, IFN-α, IL-17A and IL-12 p70 – were higher in all people taking COVID – 19 then in the healthy controls, providing a ‘core’ COVID-19 signature. Other cytokines, such as IFN-λ, thrombopoietin (which is associated with blood clotting abnormalities), IL-21, IL-23 and IL-33, were upregulated to a greater extent in people with severe COVID-19 than in those with moderate disease. Several of the molecules regulated in the nuclear COVID-19 signature, such as those seen in severe disease, have been previously identified as positively correlated with COVID-19 pregnancy6,7. Severe disease was characterized by a prolonged increase in many of these molecules, while the levels of most of them were present in people with moderate disease. In addition, individuals with severe disease showed elevated levels of cytokines associated with activation of a protein complex called the inflammasome, a component of the immune response that is a driver of inflammation. Also, elevated levels of IL-1Ra, a protein that normally inhibits excessive inflammatory function, provided a rare example of an upregulated molecule that attenuates the immune response in severe disease.
Levels molecules associated with a defensive response to viral infection – released by a type of activated CD4 T cell called a TH1 cell – were higher in people with severe disease than in those with moderate COVID-19. This occurred although blood levels of CD4 T cells and CD8 T cells, which are commonly associated with expression of these molecules, were similarly reduced (a condition called lymphopenia) in people with moderate or severe disease. More noteworthy is that cytokines are associated with immune responses to fungi (cytokines released by a type of CD4 T cell called a TH17 cells) were increased and remained so in people with severe disease. The same was true for cytokines associated with immune responses to parasites, including worms, as well as with allergic reactions (cytokines such as IL-5, released by a type of CD4 T cell called a TH2 sel). The discovery that parts of the immune system that are not related to viral control would be triggered by a viral infection was unexpected. Less surprising was the finding that levels of inflammatory cytokines in the blood, particularly the proteins IFN-α, IFN-γ, TNF-α and TRAIL, correlated with viral RNA levels in the nasal passage, independent of disease severity.
From their analysis of proteins in human peripheral mononuclear cells, the authors divided individuals into three groups based on their next clinical course and disease severity. In general, at early stages after infection, those who continued with moderate illness had low levels of inflammatory markers and an increase in the level of proteins associated with tissue repair. In contrast, people who continued to develop severe or very ill disease had an increased expression of IFN-α, IL-1Ra and proteins associated with TH1-, TH2- and TH17-cell responses, even at early times (10-15 days after onset of symptoms). These results were validated using data for the entire patient population, over all time points, so that it was shown that these characteristic expression patterns persist over time in people with each type of disease.
What have we learned from this report, and what remains to be done? It is clear from these and other studies that the immune response in patients with hospitalization with serious COVID-19 is characterized by lymphopenia and the expression of molecules associated with persistent inflammation8, while these same molecules are expressed at a lower level in people with mild to moderate disease. Differences in immune responses between the different categories of disease severity are even more pronounced when people with a very mild or subclinical disease are included in the analyzes4.
A next step will be to analyze samples from people with extremely early signs of COVID-19, and compare longitudinal data in those who do and those who do not require hospitalization. Some people who develop serious illness initially appear to have a suboptimal immune response, which allows for uncontrolled viral replication9. Such high replication could in turn contribute to serious illness.
Further analyzes should identify molecules that are useful in predicting which individuals will later be hospitalized and require intensive care. It will also be important to understand how severe disease results in an upregulation of cytokines that are normally linked to the immune response to parasites and allergic reactions, and whether this apparent dysregulation of the immune response to viral infection is unique to COVID. 19. It will also be worthwhile to determine if these changes in the expression of inflammatory molecules in the blood also occur in cells at the site of infection – the airways and lungs. Lucas and others. analyzed blood samples, because obtaining cells from an infected lung is much more difficult and results in the production of aerosols that may contain SARS-CoV-2.
For results to be clinically useful, it will be necessary to define a limited number of biomarkers that can be both easily measured and used to predict disease outcomes. This can be difficult because many of the changes in cytokine expression observed in studies such as those of Lucas and colleagues are useful for population-level analyzes, but less so for predicting outcomes in individual patients. Levels of specific cytokines differ substantially between humans, making it difficult to benchmark a level of cytokine expression that is a sign of abnormality. Therefore, groups of cytokines, each with varying degrees of inter-individual variability, must be measured to identify beneficial changes.
The identification of infected people on course to develop serious COVID-19 will be an important step forward in patient care. For example, it would increase the ability to correctly select individuals most in need of targeted treatment, as in therapies that directly impede viral replication. Progress has been made in identifying such treatments, and the continuous development of antiviral drugs that have increased their effectiveness and specificity will be crucial in reducing the disease and reducing the cause of death associated with the COVID-19 pandemic. Ideally, such medications should be administered orally, reducing the need for hospitalization. Continued progress in unraveling the immune response to SARS-CoV-2 infection will help to improve clinical treatments for COVID-19.
