When inflammation goes overboad

Insights into the life-threatening cytokine storm

Defining the cytokine storm

Cytokines—small, cell-signaling proteins—are integral in the immune system’s armamentarium, regulating immune and inflammatory responses at the site of injury or infection.1 But in many critical-care patients, a dysregulated cytokine response can cause hyperinflammation, known as a cytokine storm, and this can lead to tragic outcomes unless stopped in time.

The genesis of the cytokine storm

Inflammatory cytokines respond to injury or infection by increasing local blood flow and temperature and mobilizing immune cells to the site.1,2 Neutrophils and monocytes—leukocytes (white blood cells) that are integral to the inflammatory process—produce cytokines and are also recruited to an injured or infected site.3,4

In a normal immune response, neutrophils are the first immune cells to arrive at the site and are key to the entire immune response through a variety of functions, including the production of neutrophil extracellular traps (NETs) that kill pathogens.3-6 Because neutrophils and monocytes have heterogenic properties, they are also integral to tissue remodeling and repair.7

In a dysregulated immune response, overactive monocytes and NETs lead to the overproduction of cytokines,4,7,8 and neutrophil apoptosis may be delayed.3 Additionally, feedback mechanisms that regulate the immune system are altered, so negative feedback is all but absent while positive feedback is left unchecked, with cytokines continually recruiting immune cells.9 This results in damaging hyperinflammation at the site, but it doesn’t stop there.

The destructive path of the cytokine storm

In the cytokine storm, local hyperinflammation spreads uncontrollably through the systemic circulation to other parts of the body, leading to endothelial dysfunction and consequent organ damage.1 Without effective treatment, patients can suffer from catastrophic organ failure and lose their lives.

Pathogenic and mechanical triggers of a cytokine storm

Through organ crosstalk, damaged organs can cause further destruction to other organs (as illustrated by arrows). Note: These are not all the possible morbidities associated with the cytokine storm.

Pathogenic and mechanical triggers of a cytokine storm

viral infection

VIRAL INFECTION

Examples:
SARS-CoV-2, influenza A, dengue virus

bacterial infection

BACTERIAL INFECTION

Examples:
Staphylococcus aureus, Escherichia coli, Francisella tularensis

trauma

TRAUMA

Examples:
Acute lung injury, acute kidney injury, hemorrhagic shock

surgery

SURGERY

Examples:
Surgical AKI, invasive surgery, tissue injury, septic shock

The cytokine storm can exert its lethal effect by damaging multiple organs, including 10-17:

Through organ crosstalk, damaged organs can cause further destruction to other organs (as illustrated by arrows). Note: These are not all the possible morbidities associated with the cytokine storm.

Impact of Cytokines on the Kidneys and Lungs

The COVID-19 pandemic has raised understanding of the connection between the lungs and the kidneys. Loss of normal function in either organ can induce direct and indirect dysregulation of the other, as seen with COVID-19 patients.

There are two phases of COVID-19: the viral replicative phase and the hyperinflammatory phase. The latter is the most severe phase of the disease, manifesting as extra-pulmonary systemic hyperinflammation syndrome.18 Coupled with the disease’s inhibition of the adaptive immune response—including a reduction in helper, suppressor, and regulatory T cell counts—the cytokine storm can make COVID-19 deadly.12,18

COVID-19-associated AKI and ARDS are prevalent and deadly:

In studies of hospitalized COVID-19 patients:

46% developed AKI,
with a 50% mortality rate19

Among hospitalized COVID-19 patients with AKI, 19% required dialysis.19

33% developed ARDS,
with a 45% mortality rate20

Approximately 75% of COVID-19 patients in the ICU had ARDS.20

AKI

ARDS

In critically ill patients, stopping the cytokine storm can be crucial to improve outcomes.

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