A potentially fatal disorder known as Cytokine Release Syndrome, also known as CRS or Cytokine Storm, is characterized by an unchecked systemic inflammatory response that can be brought on by medications or infections like COVID-19 infection.

The development of cytokine release syndrome involves a number of chemical mediators and cytokines. Notably, Interleukin 6 has a significant impact. In patients with cytokine release syndrome, especially in those who have more severe symptoms, IL-6 has consistently been reported to be high.

Cardiomyopathy, neurotoxicity, macrophage activation syndrome/hemophagocytic lymphohistiocytosis (HLH)-like presentation, endothelial dysfunction (detected by elevated von Willebrand factor and Ang 2 levels), and cardiomyopathy are among conditions made worse by IL-6 in patients with CRS.

What are the symptoms and signs of cytokine release syndrome?

Patients can present with fever, lethargy, malaise, headache, nausea, rash, body aches, and flu-like symptoms [Ref]. Tachypnea may be the only symptom of mild cases, which may also include coughing.

These individuals may experience bilateral chest infiltrates, which could develop into acute respiratory distress syndrome quickly (ARDS). In severe cases, there is pulmonary capillary leakage and patients may develop peripheral and pulmonary edema.

Patients may have other symptoms that might suggest an underlying diagnosis or differential diagnoses such as diarrhea, productive cough, and dysuria.

As a result of the excessive release of cytokines, patients may progress to a toxic state manifesting as difficulty in breathing, low blood pressure, multi-organ failure, DIC (disseminated intravascular coagulation), shock (refractory to fluids), and death.

Laboratory features of Cytokine Release Storm:

Since cytokine release storm is characterized by the overshooting of the inflammatory cascade, laboratory features are suggestive of raised inflammatory markers. Important laboratory markers of cytokine release syndrome include:

• Raised Interleukin 6 (IL-6) levels.
• Elevated CRP (C-reactive protein).
• Raised serum Ferritin levels.
• Cytopenias (thrombocytopenia and neutropenia)
• Deranged coagulation profile manifesting as raised aPTT, D-dimers, and low fibrinogen.

Patients may develop features that resemble hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome. These patients have raised ferritin levels, hypertriglyceridemia, and very a high-grade fever.

Severe cases of CRS may develop organ failure, DIC, and refractory shock. These patients may develop cardiac dysfunction with a low ejection fraction, renal failure, and neurotoxicity.

Patients who develop neurotoxicity may not be able to protect their airways and may need intubation and mechanical ventilation.

Cytokine Release Syndrome Severity Grading:

The American Society for Transplantation and Cellular Therapy (ASTCT) has created a severity grading system based on three crucial clinical characteristics of CRS.

1. Fever (greater than 38 C, however, fever is not included if the patient is receiving corticosteroids or anti-Interleukin 6 such as Tocilizumab).
2. Hypoxia
3. Hypotension.

It is important to note that the grading is guided by the most severe feature. Low flow and High flow oxygen is an oxygen requirement of less than or more than 6 liters/minute. The grading system is as follows:

• Grade 1:

  • Fever without hypoxia or hypotension

• Grade 2:

  • Fever

  • Hypoxia that requires the use of low-flow oxygen via a nasal cannula or blow-by oxygen therapy

  • Hypotension that does not require vasopressors support

• Grade 3:

  • Fever

  • Hypoxia requiring high-flow oxygen

  • Hypotension requiring a vasopressor with or without vasopressin

• Grade 4:

  • Hypotension requiring a combination of vasopressors excluding vasopressin

  • Hypoxia requiring positive pressure ventilation 

  • Fever

How to treat Cytokine Release Syndrome?

Based on the harshness of the CRS, the therapy is individualized.

Treatment of Mild CRS:

Mild CRS is defined as Grade 1 or 2 based on the severity assessment defined above. Most patients with mild CRS require supportive treatment such as antipyretics, fluid resuscitation, antihistamines, and low flow oxygen.

Most medical professionals believe that corticosteroids should be used as the first line of treatment for patients with Grade 2 and some Grade 3 CRS.

Treatment of Severe CRS:

Severe CRS is defined as Grade 3 or 4 based on the severity assessment defined above. Patients with severe CRS may require intensive care support and mechanical ventilation.

Most patients with life-threatening CRS require interleukin-6 inhibitor therapy, tocilizumab, in conjunction with corticosteroids. Other supportive therapies must also include the use of broad-spectrum antibiotics, vasopressors, mechanical ventilation, and the underlying condition's therapy.

Tocilizumab does not pass the blood-brain barrier and does not prevent the cerebral interleukin 6-driven cascade of CRS, which is important to keep in mind.

Such cases may benefit most from a combination of high-dose glucocorticoids and Tocilizumab. Other treatment modalities that are being investigated in the treatment of CRS include alemtuzumab, siltuximab, and other immune modulators [Ref].

Siltuximab, like Tocilizumab, inhibits Interleukin 6, however it inhibits endogenous IL-6 only. It does not inhibit IL-6 induced by viruses and may not be used in the treatment of COVID-19 infection-triggered CRS, theoretically.

Tocilizumab dosage in Cytokine Release Syndrome induced by COVID-19 infection:

Tocilizumab Dosage is discussed in detail here Actemra (Tocilizumab). A single Intravenous dose of Actemra (Tocilizumab) is recommended. Two additional doses may be administered in patients with persistent hypotension and cytopenias.

• Patients weighing less than 30 kgs:

  • 12 mg/kg

• Patients weighing more than 30 kgs:

  • 8 mg/kg

• The maximum dose is 800 mg per dose