Cytokine release syndrome

The sequencing of codes for cytokine release syndrome and causative conditions is complicated.


Cytokine release syndrome (CRS), also known as cytokine storm, is an acute systemic inflammatory syndrome characterized by fever and multiple organ dysfunction. It is often fatal. It is a well-known complication associated with chimeric antigen receptor T-cell therapy, certain therapeutic antibodies, and haploidentical allogeneic transplantation.

Image by Getty Images
Image by Getty Images

CRS is an exaggerated response to immune therapy 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 required diagnostic criteria are fever greater than 100.4 °F (38.0 °C), which may rise to 105 °F (40.5 °C) or higher, and evidence of systemic inflammation like systemic inflammatory response syndrome (SIRS) criteria or elevations in C-reactive protein level and/or 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 onset and duration of CRS are variable and depend on the cause. It typically begins within one to 14 days after chimeric antigen receptor T-cell therapy or within one to three days after haploidentical allogeneic transplantation. It may occur within minutes to hours after infusion of certain antibodies. CRS is now 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.

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 hypoxia requiring supplemental oxygen at 6 L/min [44%] or less)
  • Grade 3—acute organ dysfunction; hypotension treated with IV fluids (defined as multiple fluid boluses for blood pressure support) or low-dose vasopressors; coagulopathy requiring fresh frozen plasma or cryoprecipitate or fibrinogen concentrate; hypoxia requiring more than 6 L/min supplemental oxygen
  • Grade 4—life-threatening complications; shock requiring high-dose vasopressors; severe hypoxia requiring ventilator support
  • Grade 5—death due solely to CRS

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 classification.

The sequencing of CRS codes and the codes for causative conditions gets a little complicated. In almost all situations, the cause is sequenced first, followed by the CRS code. However, even though CRS is sequenced as a secondary diagnosis when caused by infusion of T-cell therapy or certain therapeutic antibodies or by allogeneic transplantation, an immunity disorder DRG (814-816) will be assigned based on CRS rather than the principal diagnosis. When CRS is due to COVID-19, the latter is sequenced as the principal diagnosis, resulting in a respiratory infection DRG.

For example, CRS grade 3 due to chimeric antigen receptor T-cell therapy is coded with principal diagnosis code T80.89XA (Other complications following infusion, transfusion and therapeutic injection, initial encounter) with code D89.833 (CRS stage 3) as a secondary diagnosis. The DRG will be 816 (Immunity disorders without major CC). If CRS grade 3 is due to COVID-19 pneumonia, the following code sequence is assigned: U07.1 (COVID-19) first, followed by J12.89 (Other viral pneumonia) and D89.833 (CRS stage 3). The DRG will be 177 (Respiratory infections with major CC).