Despite prevailing assumptions in the literature, cytokine storm syndrome is relatively rare among patients with moderate and severe coronavirus disease 2019 (COVID-19), according to a study published in Science Advances. Rather, the study revealed that the majority of COVID-19 patients exhibited suppressed immune profiles relative to the patterns observed among influenza-infected patients.
To understand the relationship between inflammatory host responses and the respiratory failure observed in COVID-19 patients, Philip A Mudd, Washington University School of Medicine, Saint Louis, Missouri, and colleagues undertook a comparative investigation of inflammatory responses in a cohort of 79 COVID-19 patients, 26 influenza A or B patients and 16 healthy controls. Both the COVID-19 and influenza cohorts included patients with moderate disease, defined by individuals with symptomatic illness requiring evaluation in the hospital, and severe disease, defined by individuals requiring mechanical ventilation for acute respiratory failure or who ultimately died due to their illness.
Among the COVID-19 patients, 3 exhibited obviously distinct cytokine profiles in principal component analysis. They were characterized by cytokine levels > 2 standard deviations from the mean for more than 17 of the 35 cytokines measured (range: 49%-89%), encompassing broad and unfocused immune responses characteristic of classic cytokine storm. After controlling for key confounding factors such as age and sample time point, the researchers found that COVID-19 patients exhibited lower cytokine levels than influenza patients. Among the statistically significant reduced cytokines exhibited by COVID-19 patients compared to influenza patients were IFN-γ, MIG, IL-1RA, IL-2R, GCSF, IL-17a, IL-9, and MIP-1α.
In order to validate the cytokine patterns, the researchers analysed cytokine data from a follow-up cohort that consisted of another 89 COVID-19 patients. Among the patients in the validation cohort, 4 patients exhibited marked variation in their cytokine profiles whereby the samples were characterized by cytokine levels > 2 standard deviations from the mean for more than 9 of the 35 cytokines measured (range: 26%-49%).
“Overall, these data validated our observation in the primary cohort that many cytokines are down-regulated in COVID-19 patients compared to influenza-infected patients, suggesting that overall higher inflammation is foremost predictive of influenza infection and that a defining feature of COVID-19 disease is generally reduced inflammation compared to influenza; aside from the 4% of patients with extreme cytokine dysregulation (ie, cytokine storm syndrome), COVID-19 subjects were not characterized by overall high levels of cytokines, but rather exhibited a selective pattern of inflammation in which only a subset of inflammatory cytokines were up-regulated and most were down-regulated when compared with seasonal influenza patients,” the researchers reported.
In addition, the researchers said that COVID-19 and influenza patients exhibited trends of decreased B cells and significant reductions in both T cell subsets, which generally constitute the majority of circulating peripheral blood mononuclear cells (PBMCs) in healthy controls. Circulating activated CD4+ and CD8+ cells were equivalent across all groups. However, when compared with either influenza patients or controls, COVID-19 patients exhibited significantly reduced numbers of circulating monocytes, including all three common classifications of human monocytes (classical, intermediate, and non-classical).
Further, COVID-19 patients were observed to have reduced abundances of HLA-DR on the surface of intermediate monocytes when compared with influenza patients or controls after controlling for covariate effects. Additionally, COVID-19 patients exhibited significantly less surface HLA-DR on CD8+ T cells than influenza patients, and trends toward less HLA-DR on CD4+ T cells in comparison to both influenza patients and healthy controls. The researchers also found that, compared to moderately ill patients, the severest patients exhibited substantially less HLA-DR on intermediate and non-classical monocytes.
Meanwhile, single-cell transcriptional profiling was noted to be concordant with profound suppression in interferon signaling among COVID-19 patients.
“Multiple forms of COVID-19 immune dysregulation were observed: a cytokine storm phenotype in 3-4% of patients across primary and validation cohorts (7 of 168), a Th22 phenotype in 3% of the validation cohort patients (3 of 89), and a far more common phenotype characterized by targeted immunosuppression relative to influenza-infected patients,” the authors wrote. “The signatures of this common COVID-19 phenotype compared to influenza were equivalent levels of IL-6 and IL-8, paired with lower levels of cytokines in many other pathways and essentially the absence of any Type I or Type II IFN response.”
“While lymphocyte numbers (except for plasmablasts) were reduced in both infected groups compared to healthy controls, several lymphocyte subsets had functional signatures of suppression in COVID-19 patients compared to influenza patients, including type I and II IFN signaling,” the authors added. “IFN-γ production is critical for effector type I responses, and its absence may limit antiviral activity. “