Cytokine release syndrome (CRS) is an acute systemic inflammatory syndrome characterized by fever and multiple organ dysfunction. It is a well-known complication associated with chimeric antigen receptor T-cell therapy, certain therapeutic antibodies, and haploidentical allogeneic transplantation. CRS has now been recognized as a not-uncommon complication of COVID-19, with onset ranging from early in the course of the disease to several weeks after COVID-19 symptoms have resolved. 

CRS represents an intense, abnormal immune response that activates T-cells and/or other immune effector cells. The systemic reaction is associated with increased levels of inflammatory cytokines and activation of T-lymphocytes, macrophages, and endothelial cells. The onset and duration of CRS are variable and depend on the cause 

Some recent medical literature suggests that the multiorgan system dysfunction syndrome encountered with COVID-19 may not be caused by inflammatory cytokines but emphasize that the information is preliminary and larger studies are needed.

The required diagnostic criteria are:

• Fever greater than 100.4 °F (38.0 °C), and 
• Evidence of severe systemic inflammation elevated C-reactive protein level and inflammatory cytokines like interferon-gamma and interleukin-6.

Clinical findings range widely in severity, from mild, such as fatigue, headache, rash, diarrhea, arthralgia, myalgia, tachypnea, and tachycardia, to severe, characterized by hypotension, hypoxemia, uncontrolled severe SIRS, circulatory collapse, pulmonary edema, respiratory failure, renal failure, cardiac dysfunction, and multi-organ system failure.

The severity of CRS is classified by grade:

• Grade 1—no hypotension, hypoxia, or organ dysfunction; malaise, myalgias, arthralgias; supportive care only
• Grade 2—some signs of organ dysfunction (e.g., hypotension that does not require vasopressors and/or hypoxemia requiring supplemental oxygen at 6 L/min (44%) or less 
• Grade 3—acute organ dysfunction; hypotension treated with intravenous fluids (defined as multiple fluid boluses for blood pressure support) or low-dose vasopressors, coagulopathy requiring fresh frozen plasma or cryoprecipitate or fibrinogen concentrate, and hypoxemia requiring more than 6 L/min supplemental oxygen 
• Grade 4—life-threatening complications; shock requiring high-dose vasopressors; severe hypoxemia requiring ventilatory
• Grade 5—death due solely to CRS

Management involves supportive care, treatment of complications and, if severe, monoclonal antibodies.

ICD-10-CM codes for CRS are based on the grades (see Table). Grades 3, 4, and 5 are classified as comorbidities/complications (CCs) impacting diagnosis-related group (DRG) assignment and severity of illness. 

In summary, CRS may be associated with COVID-19 and certain immunotherapy. It is classified as grades 1-5 which should always be documented in the medical record for accurate data reporting and to avoid the inevitable documentation query request.