Active 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 the fact that no pediatric patients were included and high mortality rates in both control and intervention groups. 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 critically ill children age 2 to < 9 years old and in older patients in whom baricitinib is contraindicated if all of the following criteria are met and the ID and inpatient/ICU team agree that therapy is indicated. However, treatment with tocilizumab should be pursued with caution, as ARDS or cardiovascular failure related to acute COVID-19 hyperinflammation are less common in young children. Further, data from adult trials is less generalizable to this population.

Tocilizumab should be administered in combination with dexamethasone unless there is a contraindication to dexamethasone. Clinicians should consider a time-limited (e.g., up to 12-24 hours) trial of dexamethasone and supportive care with observation for clinical improvement prior to administration of tocilizumab.

  • Age 2 to < 9 years old1 or age ≥ 9 years with contraindication to baricitinib and
  • SARS-CoV-2 PCR or antigen test positive, and
  • Symptoms attributable to SARS-CoV-2 infection, and
  • Therapy can be initiated promptly (e.g., within approximately 24 hours of ICU admission or onset of respiratory deterioration), and
  • Lab evidence of hyperinflammation (e.g., elevated CRP2), and
  • At least one of the following:
    • New significant non-invasive mechanical ventilation requirement (e.g., high flow nasal canula, CPAP/BiPap support) or need for 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
  1. For children age 2 to < 9 years old with acute COVID-19 who otherwise meet the criteria above, use of a second immunomodulator (i.e., in addition to dexamethasone) could be considered on a case-by-case basis with caution. The rationale for increased caution in this younger age group is that ARDS or cardiovascular failure related to acute COVID-19 are less common in children under 9 years old vs. older children and adolescents. Because there are limited data evaluating baricitinib dosing in young children and because this drug has not been studied for treatment of COVID-19 in pediatric populations, we suggest that tocilizumab be used instead of baricitinib in younger patients
  2. No specific cut-point for CRP is established.

Instructions for Ordering Providers

After the ID and inpatient/ICU teams agree that treatment with tocilizumab is indicated, the following steps should be completed:

  1. Provide the child/family:
  2. Obtain Informed Consent – link to consent form is also included in the order
  3. Order tocilizumab using the COVID-19 inpatient orderset
  4. Report all medication errors and adverse events (death, serious adverse events3) considered potentially related to tocilizumab within 7 days of the event to FDA MedWatch
  1. Serious adverse events include any of the following occurring while receiving tocilizumab: death, life-threatening event, event resulting in hospitalization or prolongation of existing hospitalization, persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, a congenital anomaly/birth defect, a medical or surgical intervention to prevent death, a life-threatening event, hospitalization, disability, or congenital anomaly.
Tocilizumab Dosing and Administration
Weight Dose
< 30 kg 12 mg/kg IV as a single dose
≥ 30 kg 8 mg/kg IV as a single dose

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 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.