Overlapping but Disparate Inflammatory and Immunosuppressive Responses to SARS-CoV-2 and Bacterial Sepsis: An Immunological Time Course Analysis

Abstract

Both severe SARS-CoV-2 infections and bacterial sepsis exhibit an immunological dyscrasia and propensity for secondary infections. The nature of the immunological dyscrasias for these differing etiologies and their time course remain unclear. In this study, thirty hospitalized patients with SARS-CoV-2 infection were compared with ten critically ill patients with bacterial sepsis over 21 days, as well as ten healthy control subjects. Blood was sampled between days 1 and 21 after admission for targeted plasma biomarker analysis, cellular phenotyping, and leukocyte functional analysis via enzyme-linked immunospot assay. We found that circulating inflammatory markers were significantly higher early after bacterial sepsis compared with SARS-CoV-2. Both cohorts exhibited profound immune suppression through 21 days (suppressed HLA-DR expression, reduced mononuclear cell IFN-gamma production), and expanded numbers of myeloid-derived suppressor cells (MDSCs). In addition, MDSC expansion and ex vivo production of IFN-gamma and TNF-alpha were resolving over time in bacterial sepsis, whereas in SARS-CoV-2, immunosuppression and inflammation were accelerating. Despite less severe initial physiologic derangement, SARS-CoV-2 patients had similar incidence of secondary infections (23% vs 30%) as bacterial sepsis patients. Finally, COVID patients who developed secondary bacterial infections exhibited profound immunosuppression evident by elevated sPD-L1 and depressed HLA-DR. Although both bacterial sepsis and SARS-CoV-2 are associated with inflammation and immune suppression, their immune dyscrasia temporal patterns and clinical outcomes are different. SARS-CoV-2 patients had less severe early inflammation and organ dysfunction but had persistent inflammation and immunosuppression and suffered worse clinical outcomes, especially when SARS-CoV-2 infection was followed by secondary bacterial infection.

Cytomegalovirus blood reactivation in COVID-19 critically ill patients: risk factors and impact on mortality

“…Interestingly, the incidence of CMV reactivation in COVID-19 appears to be lower than that reported in no-COVID-19 immunocompetent critically ill patients with sepsis, in whom it ranges between 30 and 60% depending on the time of screening, specimen and methods used [ 11 , 33 ]. Several factors may theoretically explain this difference, but the severity scores of COVID-19 patients and the impact of SARS-CoV-2 infections on the immune response are usually less severe in the first 15 days than those in patients with sepsis from bacterial infections admitted to ICU [ 34 ]. These aspects, combined with younger age, fewer pre-existing comorbidities and the shorter duration of ICU stay, may justify the reduced occurrence of CMV reactivation in COVID-19 patients compared to the septic ICU population [ 13 ].…”

SARS-CoV-2 Brain Regional Detection, Histopathology, Gene Expression, and Immunomodulatory Changes in Decedents with COVID-19

“…There are considerable interindividual differences in the COVID-19 circulating immune profile, as well as changes during the clinical course, with some evidence of an early immunosuppressive or maladapted immune response ( 233–236 , 240 , 246 ). Early lymphopenia, including decreases in circulating CD4 and CD8 cells, is relatively common.…”

“…For example, elevations in IL-6 have been identified not only in acute COVID-19 but also in other critical illnesses such as sepsis and acute respiratory distress syndrome, and while the pro-inflammatory effects of IL-6 are well known, it may also play an anti-inflammatory role. Complicating such scenarios is the likelihood that the circulating cytokine profile evolves differently between subjects and day-to-day in the initial days and weeks of the acute illness ( 246 , 247 ). Generally, however, the immune response triggered by COVID-19 infection results in an increase of serum cytokines including IL-1, IL-6, IL-10, and TNF-α ( 248 , 249 ) and this is paralleled to some extent in our finding of elevations of 4 cytokines, IL12p80, GRO, VEGF, MIP-1a, and MMP-9, in postmortem COVID-19 blood serum.…”

Epigenetics at the Intersection of COVID-19 Risk and Environmental Chemical Exposures

“…SARS-CoV-2 can lead to dysregulation of the innate (non-specific) and adaptive (specific) arms of the immune systems, subverting natural defense mechanisms and resulting in severe disease [ 12 ••, 13 ••]. A complex inflammatory response is a hallmark of COVID-19 hospitalization and death [ 14 – 16 ]. Although immunopathology is not the focus of this article, a basic summary of the relevant immune pathways involved in COVID-19 is critical to understand how environmental chemical exposures and epigenetic perturbations may contribute.…”

“…Cells of the innate immune system include granulocytes, monocytes, macrophages, and natural killer cells, among others, whereas cells of the adaptive immune system include B and T lymphocytes [ 25 ]. In severe cases of COVID-19, increased neutrophil and decreased lymphocyte counts are often observed, suggesting disruption of the immune cell milieu as an additional contributor to critical symptoms and death [ 14 – 16 , 26 – 28 ].…”