Acute COVID-19, Clinical Pathway — All Settings

Tocilizumab

Background

Tocilizumab is a monoclonal anti-IL-6 receptor blocking antibody which has been used extensively in the treatment of rheumatologic conditions and for cytokine release syndrome associated with CAR-T therapy. A large randomized trial (REMAP-CAP  ) demonstrated a greater number of organ-failure-free days as well as a reduction in mortality among adults hospitalized in the ICU and requiring invasive or non-invasive mechanical ventilation or vasopressors. The largest trial to date (RECOVERY  ) included hospitalized adults and demonstrated reductions in 28-day mortality with tocilizumab therapy. The majority of patients in both trials received dexamethasone, and in both trials, most patients received tocilizumab within 2 days of admission. Several smaller randomized trials conducted in non-critically ill patients did not demonstrate improvements in clinical outcomes with tocilizumab. Important limitations to these data include no pediatric patients included and high mortality rates in both control and intervention groups (~30%). Despite these limitations, tocilizumab may have a role in the treatment of critically ill patients early in their hospital course.

Indications

Use of tocilizumab (in addition to dexamethasone) can be considered on a case-by-case basis in children hospitalized in the ICU who meet all of the following criteria AND in whom the ID and ICU attending agree that therapy is appropriate:

  • SARS-CoV-2 PCR positive within 72 hours, AND
  • Symptoms attributable to acute COVID-19, AND
  • Within 24 hours of ICU admission or onset of respiratory failure, AND
  • Evidence of hyperinflammation (e.g., CRP>7.5 mg/dL OR IL-6 >25 pg/ml) AND
  • At least one of the following:
    • New significant non-invasive mechanical ventilation requirement (e.g., BiPap support with >40% FiO2) or invasive ventilation
    • Rapidly escalating respiratory support needs not yet meeting this requirement
    • Significant increase in baseline mechanical ventilation support
    • Hemodynamic instability despite fluid resuscitation with a vasopressor or extracorporeal support requirement attributable to COVID-19 hyperinflammation

Dose

Tocilizumab: IV infusion over 1 hour dosed by total body weight:

  • Patient weight < 30 kg: 12 mg/kg IV
  • Patient weight > 30 kg: 8 mg/kg IV (max 800 mg)

If no improvement with 1st dose of tocilizumab within 12-18 hours, consider a 2nd dose of tocilizumab using the same dose above.

Empiric treatment for Strongyloides

Patients from regions where Strongyloides stercoralis is endemic (e.g., low/middle income countries with tropical climates) should be treated empirically with ivermectin if receiving tocilizumab and dexamethasone in discussion with ID, as there are reports of disseminated Strongyloides in patients with COVID-19 treated with immunomodulators. Of note, ivermectin has no activity against COVID-19 and is being used exclusively for Strongyloides in high-risk patients.

Dosing for children > 15 kg and adults
Ivermectin 200 mcg/kg/dose PO daily x 2 days

Vaccines and Tocilizumab

Patients should generally not receive tocilizumab if they received a live, attenuated vaccine within the two weeks prior to therapy due to the concern for vaccine strain infection and/or decreased effectiveness of the vaccine. Current guidance from CDC for vaccine administration in patients with altered immunocompetence also recommends live vaccines should be withheld for 3 months following discontinuation of immunosuppressive therapy. The risk versus benefit of administering a live vaccine sooner than 3 months following discontinuation of tocilizumab therapy should be evaluated on a case-by-case basis.

Definition of high dose vasoactive medications
Vasoactive Dose for ≥ 3 hours
Norepinephrine monotherapy ≥ 0.1 mcg/kg/min
Dopamine monotherapy ≥ 10 mcg/kg/min
Phenylephrine monotherapy ≥ 10 mcg/kg/min
Epinephrine monotherapy ≥ 0.1 mcg/kg/min
If on vasopressin Any dose of vasopressin for the indication of shock
If on combination vasopressors (not vasopressin) Norepinephrine equivalent of ≥ 0.1 mcg/kg/min