SARS-CoV-2 Causes a Different Cytokine Response Compared to Other Cytokine Storm-Causing Respiratory Viruses in Severely Ill Patients

Abstract

Hyper-induction of pro-inflammatory cytokines, also known as a cytokine storm or cytokine release syndrome (CRS), is one of the key aspects of the currently ongoing SARS-CoV-2 pandemic. This process occurs when a large number of innate and adaptive immune cells activate and start producing pro-inflammatory cytokines, establishing an exacerbated feedback loop of inflammation. It is one of the factors contributing to the mortality observed with coronavirus 2019 (COVID-19) for a subgroup of patients. CRS is not unique to the SARS-CoV-2 infection; it was prevalent in most of the major human coronavirus and influenza A subtype outbreaks of the past two decades (H5N1, SARS-CoV, MERS-CoV, and H7N9). With a comprehensive literature search, we collected changing the cytokine levels from patients upon infection with the viral pathogens mentioned above. We analyzed published patient data to highlight the conserved and unique cytokine responses caused by these viruses. Our curation indicates that the cytokine response induced by SARS-CoV-2 is different compared to other CRS-causing respiratory viruses, as SARS-CoV-2 does not always induce specific cytokines like other coronaviruses or influenza do, such as IL-2, IL-10, IL-4, or IL-5. Comparing the collated cytokine responses caused by the analyzed viruses highlights a SARS-CoV-2-specific dysregulation of the type-I interferon (IFN) response and its downstream cytokine signatures. The map of responses gathered in this study could help specialists identify interventions that alleviate CRS in different diseases and evaluate whether they could be used in the COVID-19 cases.

Keywords: MERS- and SARS-CoV; SARS-CoV-2; cytokine response; influenza A; literature analysis; systematic review.

Figure 1

The literature curation workflow applied in this study. Publications were considered valid for the inclusion into our data collection if (i) they contained patient-derived data (model organisms and cell lines were excluded), (ii) the study data were collected from cohorts of at least 10 participants per group and (iii) it included a directional change in cytokine levels. Total hits to queries in bioRxiv, medRxiv, and PubTator are shown separately in the second box from the top. In the end, 55 publications were selected that matched our curation criteria listed above.

Figure 2

Number of cytokines measured in the studies for each of the five CRS-causing viruses. Each stacked bar indicates how many cytokines were found at increased levels (yellow) in the blood/solid tissue of the patients, not changed (blue) or both increased and not changed across different studies of the same virus (green). The n number shown at the bottom of the bar charts corresponds to the number of articles citing cytokine changes during infection.

Figure 3

Influenza viruses, SARS-CoV and MERS-CoV and SARS-CoV-2 form separated clusters (I–VIII) based on their cytokine response. Hierarchical clustering is based on Jaccard distance and complete linkage.

Figure 4

Type-I IFN response upon infection with the different CRS-causing viruses. The measured cytokines in the influenza virus infected patients are increased. In the case of the coronaviruses, the responses are mixed, and not all of the anti-inflammatory cytokines are elevated. Only a fraction of the cytokines is depicted for clarity: yellow for increase in that virus, green for mixed results and blue for no change.