Hospitalized SARS-CoV-2 RNA Positive with Cytokine Storm Management Guidelines for Clinicians

Updated January 10, 2021

Originally published April 4, 2020

This management guideline is to aid clinicians in diagnosing and managing cytokine storm syndrome in COVID-19 patients infected with SARS-CoV-2.

Every patient who is confirmed to be COVID-19 positive should undergo serological evaluation for possible cytokine storm syndrome. However, clinicians should understand that a positive COVID-19 diagnosis does not indicate that a patient will necessarily deteriorate due to cytokine storm syndrome, and clinicians should continuously monitor possible alternative etiologies of a patient’s deterioration throughout each patient’s course of hospitalization. Cytokine storm syndrome is extremely silent, progresses exponentially and the consequences of not treating it effectively are dire. Nevertheless, this autoimmune reaction may be the underlying cause of other complications associated with COVID-19 including but not limited to: renal failure, stroke, Guillain-Barré syndrome or myocarditis; however, this warrants further investigation.

In addition to normal laboratory evaluation at initial presentation in the emergency room and the outpatient setting, clinicians should obtain serum ferritin, CRP, and D-dimer levels. The ferritin and CRP levels are of paramount significance, as they may alert clinicians to the presence of intense inflammation and possible progression to cytokine storm syndrome, which may lead to acute respiratory failure and possible multi-system organ failure. Based on the initial level of ferritin, clinicians should consider serial testing of each inflammatory marker throughout the patient’s hospitalization course.

Because the care of patients suspected to have cytokine storm syndrome is very complex, the team of physicians managing this syndrome should include a pulmonary and critical care physician and an infectious disease physician. We strongly recommend that the team also include a rheumatologist who may be more familiar with the use of the immunosuppressive medications described below.

Hallmark to the diagnosis and treatment of cytokine storm syndrome is the knowledge that diagnosis and treatment is not one-size-fits-all. Therefore, clinicians should evaluate each patient individually and tailor therapies accordingly.

All patients should be continuously monitored for other causes of clinical deterioration. These include but are not limited to:

·         Secondary infection

·         Cardiac disease such as congestive heart failure or acute myocardial infarction with pulmonary edema

·         Asthma or COPD exacerbation

·         Pulmonary embolus, which is often a silent disease, and this case, D-dimer may not be useful, as it is commonly elevated in patients with cytokine storm syndrome. Clinicians should evaluate the patient and utilize radiological imaging to diagnose pulmonary embolus.

Ferritin Level Less Than 400 ng/mL

Assuming clinicians have ruled out iron deficiency with or without anemia, these patients are at low likelihood to develop cytokine storm syndrome. They should undergo repeat serum ferritin, CRP, and D-dimer levels at 48 hours intervals. If the patient’s CRP levels becomes elevated and the patient’s clinical status deteriorates, clinicians should consider initiation of immunosuppressive therapy with an IL-6 inhibitor and follow the below management guideline.

Ferritin Level Greater Than 400 ng/mL

Assuming clinicians have ruled out alternative etiologies for elevated ferritin, these patients should be considered high risk to develop cytokine storm syndrome with possible progression and should have their CRP levels evaluated every 24-48 hours. For the patient that presents with elevated CRP levels and is clinically unstable, clinicians should strongly consider initiation of therapy with an IL-6 inhibitor and follow the management guideline below. If the patient has elevated CRP levels upon presentation but is clinically stable, the patient may be considered for expedited initiation of an IL-6 inhibitor or be closely monitored with daily CRP levels at the discretion of the clinician. If the patient clinically deteriorates with progressive hypoxemia, the clinician should strongly consider initiation of therapy with an IL-6 inhibitor and follow the below management guidelines.

NOTE: There is a subset of patients who initially present with low ferritin levels, and these patients should not immediately be ruled low risk for development of cytokine storm syndrome, as they should be evaluated for iron deficiency with or without anemia.  This is commonly seen in patients with intravenous drug abuse. Conversely, the presence of a high ferritin level does not necessarily confirm cytokine storm syndrome in COVID-19 patients. Clinicians should evaluate for other etiologies such as a secondary infection, Hepatitis B, Hepatitis C, hemochromatosis or other liver diseases.

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Once a patient has been deemed high risk for developing cytokine storm syndrome based on their clinical status and inflammatory markers, clinicians should consider several components of cytokine storm syndrome: anticoagulation, oxygen requirement and immunosuppression.

Anticoagulation

Patients deemed high risk for developing cytokine storm syndrome that have been placed on DVT prophylaxis should be evaluated for an increase in anticoagulation therapy. If a patient is found to have an elevated D-dimer (>1.5-2 ug/mL FEU) or have increasing oxygen requirements, clinicians should consider obtaining doppler ultrasound to rule out possible DVT and should be evaluated for increase in anticoagulation from prophylactic dosage.

Oxygen Requirement

Patients deemed high risk for developing cytokine storm syndrome that require oxygen supplementation at any flow rate should be initiated on prone ventilation for 16 hours per day.

If the patient’s oxygen requirement increases to 3-4 liters per minute, clinicians should suspect an active cytokine storm. At this time, clinicians should consider obtaining patient consent for initiation of IL-6 inhibitor and continuously monitor the patient and rule out alternate etiologies for patient decompensation.

If the patient’s oxygen requirement increases beyond 5-6 liters per minute and the patient becomes tachypneic, clinicians should suspect worsening of active cytokine storm. At this time, clinicians should strongly consider treatment with IL-6 inhibitor. Clinicians should continue to closely monitor these patients, as well as continuously rule out alternate etiologies for patient decompensation.

If the patient is on mechanical ventilation and the clinician has ruled out alternative etiologies for the patient’s mechanical ventilation, clinicians should suspect an active, advanced cytokine storm syndrome as the possible etiology of mechanical ventilation. At this time, clinicians should obtain the appropriate consent to initiate therapy with immunosuppressive agents.

Immunosuppression

Current guidelines regarding corticosteroid use in hospitalized COVID-19 patients requiring any liter flow of supplemental oxygen is as follows: Dexamethasone 6 mg IV x 10 days. Patients may be transitioned to oral dexamethasone at the discretion of the treating clinician.

Once the patient consent has been obtained for the initiation of immunosuppressive therapy and prior to initiation of therapy, patients should undergo laboratory evaluation to evaluate for active tuberculosis disease, invasive fungal disease or other opportunistic infections. This can be performed with serum Quantiferon TB Gold, as well as 1,3 Beta-D- Glucan upon admission.  However, clinicians should strongly consider expedited initiation of therapy if the patient is clinically deteriorating.

Timely initiation of treatment is of the utmost importance in treating COVID-19 patients with cytokine storm syndrome, as early and aggressive treatment may prevent progressive deterioration.

The use of tocilizumab is currently the preferred choice in IL-6 inhibition. If the patient’s oxygen requirement is below 50% high flow oxygen, the initial dose of the tocilizumab should be given at 4 mg/kg IV over one hour. If the patient’s oxygen requirement is greater than 50% high flow oxygen, the initial dose of tocilizumab should be given at 8 mg/kg IV over one hour.

Once initiated on an IL-6 inhibitor, if the patient’s oxygen saturation and clinical status does not improve within the next 8-12 hours, clinicians should strongly consider evaluating the patient for another dose of an IL-6 inhibitor. If the patient’s oxygen saturation and clinical status does not improve within the next 8-12 hours, clinicians should strongly consider a third dose of tocilizumab if maximum dose has not been reached per institution guidelines. If within 24-48 hours, the patient’s oxygen saturation and clinical status do not improve despite maximum dose of tocilizumab, clinicians should strongly consider increase in corticosteroids of dexamethasone to 10 mg IV every 6 hours if the patient’s FiO2 is greater than 70% or 10 mg every 8-12 hours if the patient’s FiO2 is below 70%, with tapering over 3-5 days.

Clinicians should also be advised that upon initiation of an IL-6 inhibitor, CRP levels alone are no longer useful to track the patient’s clinical status, and each patient must be individually evaluated. Patients should also be evaluated for empiric antibiotic therapy, especially if the patient has received full-dose IL-6 inhibition and concomitant increased corticosteroid administration. Clinicians should also continuously monitor the patient’s laboratory values of white blood cell count, procalcitonin, and lactic acid every 1-2 days to monitor any possible development of nosocomial infection.

The adverse effects of IL-6 inhibitor include, but are not limited to, the following:

·         Myelosuppression

·         Worsening or unmasking of infection which may be severe (particularly tuberculosis, invasive fungal infections, and other opportunistic infections)

·         Gastrointestinal perforation

·         Hypertension

·         Headache

·         Injection site reactions

·         LFT abnormalities

The management guideline above is based on best practices existing as of the date of this report, and the best practices with respect to the treatment of COVID-19 cytokine storm syndrome are rapidly changing.  Importantly, the standard of care in the future will be determined by ongoing controlled randomized clinical trials.  

Below is a tabulated guideline for inclusion and exclusion criteria for the use of tocilizumab in hospitalized severe COVID-19 patients with cytokine storm.