Compiled by Dr N K Singh, Admin – CME INDIA.

CME INDIA Discussion:

Dr Somnath, Intensivist & Internist, Hyderabad:

Asymptomatic Covid 19 positive. But IL 6 more than 125 (normal upto 7). PCT normal. Can tocilizumab be given.

Scenario (1)

Asymptomatic but HIV positive and Covid 19 positive.

Scenario (2)

Pregnant and Covid 19 positive. Can we give tocilizumab? All patients are asymptomatic.

Dr Prashant Waichal, Akola: How much is CD4?

Dr Sandeep: Can’t be given in pregnancy/HIV.

Dr N K Singh: How many days now?

Dr Somnath, Hyderabad: Pregnant women 5th day. HIV positive 6th day.

Dr N K Singh:

I have no experience…In serious cases data supports in linked article, 14th august publication says…

In a post-hoc analysis, a reduction in mortality was seen in patients who received tocilizumab who had concentrations of C-reactive protein of 15 mg/dL or higher. Therefore, tocilizumab seems to be among the first potentially successful treatments for patients with severe COVID-19 requiring ICU support, pending confirmation by an ongoing randomised trial”

Also, well known that:

Results from the COVACTA trial were released in July 2020, announcing that the trial did not meet its primary endpoint of improved clinical status in patients with COVID-19–associated pneumonia or the secondary endpoint of reduced patient mortality. The trial did show a positive trend in time to hospital discharge among patients who received tocilizumab. “

As I know, patients were treated with a standardized algorithm that included tocilizumab to treat cytokine release syndrome. Not in asymptomatic. Tocilizumab has been approved by DCGI on compassionate ground in view of ongoing pandemic. However, it is an experimental therapy, has a limited role, and should be used only in patients with cytokine syndrome after ruling out active infections as per AIIMS-Delhi e webinar broadcast (Updated). Tocilizumab and remdesivir may be effective for treatment of severe COVID-19 in pregnancy, but additional data are needed to guide risk–benefit considerations

Dr V.P.: Tocilizumab is a trial drug but can be used for moderate to severe covid 19 if the patient oxygen requirement increases inspite of oxygen,steroids and remedesevir. Based on IL-6 value alone in asymptomatic individuals, it is not indicated …you can repeat the inflammatory markers after 48-72 hrs depending on the clinical assessment.

NIH Updated 27th August 2020 Guidelines says about Interleukin-6 Inhibitors

Preliminary, unpublished data from randomized controlled trials have not demonstrated the efficacy of sarilumab or tocilizumab in patients with COVID-19. The data on the efficacy of siltuximab in patients• The Panel recommends against the use of anti-IL-6 receptor monoclonal antibodies (e.g., sarilumab, tocilizumab) or an anti-IL-6 monoclonal antibody (siltuximab) for the treatment of COVID-19, except in a clinical trial (BI).

Dr Ambrish Bhattacharya, Kolkata: After COVACTA trial, many of us have stopped prescribing Tocilizumab.

Some Very Important Dilemmas

[1] Role of Favipiravir

  • Studies have used Favipiravir mainly in mild or asymptomatic COVID, and claimed  to prevent progression, whereas majority of this cohort recover with just supportive care and monitoring and usually require no specific therapy.
  • Evidence is weak for the use of Favipiravir
  • It is currently not recommended in national guidelines.

[2] How to use Steroids

NIH(UK) updated guidelines, updated 1st September:

  • It recommends using dexamethasone 6 mg per day for up to 10 days or until hospital discharge, whichever comes first, for the treatment of COVID-19 in hospitalized patients who are mechanically ventilated and in hospitalized patients who require supplemental oxygen but who are not mechanically ventilated.
  • The Panel recommends against using dexamethasone for the treatment of COVID-19 in patients who do not require supplemental oxygen .
  • If dexamethasone is not available, the Panel recommends using alternative glucocorticoids such as prednisonemethylprednisolone, or hydrocortisone 
  • Coadministration of remdesivir and dexamethasone has not been formally studied, but a clinically significant pharmacokinetic interaction is not predicted.
  • Dexamethasone should be continued for up to 10 days or until hospital discharge, whichever comes first.
  • Whether use of other corticosteroids (e.g., prednisone, methylprednisolone, hydrocortisone) for the treatment of COVID-19 provides the same benefit as dexamethasone is unclear. The total daily dose equivalencies for these drugs to dexamethasone 6 mg (oral or intravenous [IV]) are:
    • Prednisone 40 mg
    • Methylprednisolone 32 mg
    • Hydrocortisone 160 mg
    • Long-acting corticosteroid: dexamethasone; half-life: 36 to 72 hours, administer once daily.
    • Intermediate-acting corticosteroids: prednisone and methylprednisolone; half-life: 12 to 36 hours, administer once daily or in two divided doses daily.
    • Short-acting corticosteroid: hydrocortisone; half-life: 8 to 12 hours, administer in two to four divided doses daily.
  • Inhaled corticosteroids that are used daily for patients with asthma and chronic obstructive pulmonary disease for control of airway inflammation should not be discontinued in patients with COVID-19. No studies to date have investigated the relationship between inhaled corticosteroids in these settings and virus acquisition, severity of illness, or viral transmission.
  • Short course of betamethasone and dexamethasone, which are corticosteroids known to cross the placenta, is routinely used to hasten fetal lung maturity and decrease the risk of neonatal respiratory distress syndrome in the premature infant with threatened delivery.
  • Given the potential benefit of decrease in maternal mortality and the low risk of fetal adverse effects for this short course of therapy, the Panel recommends using dexamethasone in pregnant women with COVID-19 who are mechanically ventilated or who require supplemental oxygen but who are not mechanically ventilated.
  • A short course of betamethasone and dexamethasone, which are known to cross the placenta, is routinely used to decrease neonatal complications of prematurity in women with threatened preterm delivery.
  • Indian Experience: Methyl prednisolone vs dexamethasone Corticosteroids are currently indicated in moderate to severe COVID-19 patients. Both IV dexamethasone or methyl prednisolone may be used based on the availability.

[3] What is current status of Remdesivir?

NIH recommends prioritizing remdesivir for use in hospitalized patients with COVID-19 who require supplemental oxygen but who do not require oxygen delivery through a high-flow device, non-invasive ventilation, invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).

There are insufficient data for the Panel to recommend either for or against the use of remdesivir in patients with mild or moderate COVID-19.

Recommendations for Patients with COVID-19 Who Require Supplemental Oxygen

For Patients Who Do Not Require Oxygen Delivery Through a High-Flow Device, Noninvasive Ventilation, Invasive Mechanical Ventilation, or ECMO

The Panel recommends using remdesivir for 5 days or until hospital discharge, whichever comes first.

  • If a patient who is on supplemental oxygen while receiving remdesivir progresses to requiring delivery of oxygen through a high-flow device, noninvasive ventilation, or invasive mechanical ventilation, or ECMO, the course of remdesivir should be completed.

For Patients Who Require Oxygen Delivery Through a High-Flow Device, Noninvasive Ventilation, Invasive Mechanical Ventilation, or ECMO

  • Because there is uncertainty regarding whether starting remdesivir confers clinical benefit in these groups of patients, the Panel cannot make a recommendation either for or against starting remdesivir.
  • Duration of Therapy for Patients Who Have Not Shown Clinical Improvement After 5 Days of Therapy: There are insufficient data on the optimal duration of remdesivir therapy for patients with COVID-19 who have not shown clinical improvement after 5 days of therapy. In this group, some experts extend the total remdesivir treatment duration to up to 10 days.

[4] Use of convalescent plasma for the treatment of COVID-19.

Based on the available evidence, the NIH Panel has determined the following:

  • There are insufficient data to recommend either for or against the use of convalescent plasma for the treatment of COVID-19.
  • Available data suggest that serious adverse reactions following the administration of COVID-19 convalescent plasma are infrequent and consistent with the risks associated with plasma infusions for other indications. The long-term risks of treatment with COVID-19 convalescent plasma and whether its use attenuates the immune response to SARS-CoV-2, making patients more susceptible to reinfection, have not been evaluated.
  • Convalescent plasma should not be considered standard of care for the treatment of patients with COVID-19.
  • Prospective, well-controlled, adequately powered randomized trials are needed to determine whether convalescent plasma is effective and safe for the treatment of COVID-19. Members of the public and health care providers are encouraged to participate in these prospective clinical trials.
  • Indian Experience: Convalescent plasma collected from ABO matched donors with high neutralizing titers can be given to patients at risk of developing severe COVID in early stages of the disease. It should also be considered an experimental therapy and should be used with caution.

[5] Dilemma of Post discharge Anticoagulation

AIIMS-Delhi version appears best suited to our scenario-

“Should we continue using anticoagulation post discharge? In our experience, there have been no delayed post-COVID thrombotic complications. Since the prothrombotic state parallels the viremic and inflammatory phase, once the patient has been discharged, the thrombotic risk also decreases. So, we don’t recommend anti-coagulation at discharge in routine COVID patients unless indicated for other reasons like DVT, prosthetic valve etc.”

[6] Can Ivermectin be used for COVID patients?

“Ivermectin has been found to be a potent inhibitor of SARS CoV2 replication in vitro, but the doses required to achieve this effect in vivo far exceeds the usual dose. It is currently not recommended in the national guidelines but can be used in patients in whom HCQ is contraindicated.” [Take Home Message form AIIMS]

NIH cautions its use in updated guideline of 1st September 2020

Proposed Mechanism of Action and Rationale for Use in Patients With COVID-19

Ivermectin acts by inhibiting the host importin alpha/beta-1 nuclear transport proteins, which are part of a key intracellular transport process that viruses hijack to enhance infection by suppressing the host antiviral response.

Ivermectin is therefore a host-directed agent, which is likely the basis for its broad spectrum activity in vitro against the viruses that cause dengue, Zika, HIV, and yellow fever.

Not Recommended

  • The COVID-19 Treatment Guidelines Panel recommends against the use of ivermectin for the treatment of COVID-19, except in a clinical trial.

Why NIH is against Ivermectin?

  • As Ivermectin has been shown to inhibit the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in cell cultures. However, pharmacokinetic and pharmacodynamic studies suggest that achieving the plasma concentrations necessary for the antiviral efficacy detected in vitro would require administration of doses up to 100-fold higher than those approved for use in humans.
  • Even though ivermectin appears to accumulate in the lung tissue, predicted systemic plasma and lung tissue concentrations are much lower than 2 µM, the half-maximal inhibitory concentration (IC50) against SARS-CoV-2 in vitro.
  • Ivermectin is not approved for the treatment of any viral infection, including SARS-CoV-2 infection.
  • Clinical Data in Patients With COVID-19 The available clinical data on the use of ivermectin to treat COVID-19 are limited.

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