Cytokines: Friend or foe?

May 11th, 2020 / By Cheryl Manchenton, RN

I hope this blog finds you and your loved ones safe and well. One of the most frustrating aspects of the COVID-19 pandemic is dealing with the unknown. Our understanding of COVID-19 and its sequelae/manifestations is continually evolving. There is one “manifestation” of COVID-19 that is of interest for experimental treatment: cytokine release or storm.

First, let’s define cytokines. During an infection, the immune system increases the release of molecules called cytokines.  These molecules circulate in the blood stream like messengers calling upon immune cells to fight the offender (whether an infectious process or a misguided attack on the body). In some patients, for largely inexplicable reasons, this release continues even after the invading pathogen or body system is being destroyed by antibiotics, antivirals and/or our immune system. This uncontrolled response causes collateral damage to tissues, especially lung tissue. Several studies that analyzed cytokines (published prior to this pandemic) have described a “cytokine storm” that releases specific types of cytokines: interleukins (IL) to be exact, including IL-6, IL-1, IL-12, and IL-18, along with tumor necrosis factor alpha (TNFα) and other inflammatory mediators. The sustained, excessive cytokine release—or storm—is found in a variety of infectious diseases, including influenza, COVID-19, Ebola and sepsis, and is often a cause of (or contributor to) mortality.

Once cytokines have started this hyperactive response to a perceived threat, what happens next? The cytokines and TNF directly attack tissues and organs.  When a cytokine storm due to an infectious process occurs, the body receives a double insult: the direct attack of the infectious agent, as well as an immune system attack. This attack presents as a systemic inflammatory response syndrome (SIRS) with resultant end-organ damage.

In considering COVID-19, what documentation options are available to represent the cytokine release syndrome/storm? Per recent Coding Clinic advice (1st Q 2020, page 37), no unique code assignment is available for cytokine release syndrome (CRS). Also note that cytokine storm is not listed in the ICD-10-CM Alphabetic Index. I am hopeful that a unique code for this condition will be available one day. In the interim, what are our options for documentation, coding and reporting? 

  • Codes for the resultant manifestation(s), such as ARDS, tachycardia and neutropenia may be reported according to the official coding guidelines since there is not a unique code currently available for the syndrome.
  • SIRS cannot be coded since COVID-19 is an infectious condition. It would not be appropriate to query for or code SIRS due to non-infectious condition.
  • A code for sepsis may be assigned when documented by a provider. (Please refer to your facility guidelines for sepsis criteria)
  • A code for secondary hemophagocytic lymphohistiocytosis (sHLH) may be assigned when documented by a provider. HLH is a life-threatening syndrome of excessive immune activation. It can be either a primary HLH due to a genetic mutation or secondary (such as due to an infectious cause). Note there is only one code for HLH (D76.1). Viral infection has been reported as a common trigger in adults. sHLH criteria is similar to SIRS with additional findings of:
    • Cytopenia
    • Hepatosplenomegaly
    • Neurologic symptoms
    • Pulmonary involvement
    • High serum ferritin

When reviewing recent COVID-19 cases, it appears to me that sHLH is a better fit than sepsis. However, because the diagnostic waters are quite muddy, I recommend discussing this with an infectious disease physician in order to differentiate between SIRS with sepsis versus sHLH.

Treatment of COVID-19 patients is directed toward:

  • Organ system support
  • Anti-viral therapy such as remdesivir
  • Immune response modifiers, including interleukin-6 inhibiting medications such as sarilumab and tocilizumab (normally used in treatment of auto-immune diseases)

It will be interesting to see which treatment(s) is effective in combating not only the virus directly, but in reducing the cytokine effects without rendering the immune system helpless. I encourage organizations to discuss the various diagnosis options with your providers so that documentation fully represents the effects of the cytokine release. In this way, we can ensure an accurate reflection of the severity of illness and risk of mortality of our hospitalized COVID-19 patients. 

Stay safe and wash your hands!

Cheryl Manchenton is a senior inpatient consultant and project manager for 3M Health Information Systems.

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During a pandemic, healthcare information is gathered, studied, and published rapidly by scientists, epidemiologists and public health experts without the usual processes of review. Our understanding is rapidly evolving and what we understand today will change over time. Definitive studies will be published long after the fact. 3M Inside Angle bloggers share our thoughts and expertise based on currently available information.