COVID-19: Treatment

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Patients with COVID-19 who demonstrate very mild illness may not require hospitalization (refer here for criteria on which patients should be screened for COVID-19). Determining which patients may be screened and treated as outpatients as opposed to which patients should present for in-person screening is individualized, but those who are elderly or have chronic, underlying lung disease are part of a higher risk population group.

Our understanding of the pathogenesis of COVID-19 has been an a rapidly changing landscape.  The most current literature suggests that the early course of the disease is characterized by rapid viral replication.  The later course is then characterized by an exaggerated immune response/cytokine storm leading to a hyperinflammatory state. A component of immune dysregulation is also suspected, and the virus may have a potential for specifically attacking T lymphocytes. In the most severe cases, this can progress to fulminant ARDS, multisystem organ failure, and fatal dysrhythmias. While much is to be learned about this disease, interleukin-6 (IL6) is at least one of the mediators of cytokine storm-related organ dysfunction. Additional clinical manifestations of this cytokine storm syndrome include capillary leak syndrome, hypotension, renal disease, myocarditis with heart failure, and renal failure. A markedly elevated serum ferritin is an early marker of cytokine storm. Cytokine storm related myocarditis and heart failure is the cause of at least some COVID-19 related mortality.

Understanding this complex pathogenesis is directing clinical trials and targeting treatments.  It is hypothesized that antiviral treatments have the greatest impact early in the course of disease when viral replication is the highest and anti-inflammatory therapies are most beneficial in the later stages of the disease.

This post will focus on treatments for COVID-19. Please note that pediatric and pregnancy specific considerations are addressed in other posts.  The treatments for COVID-19 are largely supportive and include management complications such as hypoxia and shock.

The Society of Critical Care Medicine COVID-19 Guidelines, Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19, and the National Institutes of Health COVID-19 Treatment Guidelines are covered in this post.

Supportive Therapies

Optimizing Oxygenation:

The SCCM guidelines recommend that high flow nasal cannula (HFNC) be used over conventional oxygen therapy for management of hypoxia in patients with COVID-19. Some data suggests that patients on high flow oxygen may be less likely to require intubation as compared to those managed with traditional oxygen therapy. The SCCM reports data is lacking as to whether HFNC increases the risk for aerosolization of COVID-19. The SCCM and NIH further recommend that HFNC be used over non-invasive positive pressure ventilation (NIPPV) for the management of hypoxic respiratory failure in patients with COVID-19 as NIPPV is showing a high failure rate in COVID-19 and also a much higher risk of transmitting the virus to health-care providers due to aerosolization of particles. The SCCM guidelines note certain situations in which NIPPV may be beneficial, and also note that patients on either HFNC or NIPPV should be monitored carefully as they are at risk for very rapid decline and early intubation should be considered.

The NIH now recommends against awake proning as rescue therapy in management of refractory hypoxia.  Proning is effective at increasing oxygenation but should not be considered as a salvage treatment to prevent intubation.  For those patients that require intubation, the SCCM guidelines recommend ARDS volume ventilation strategies, with low tidal volume, high PEEP, lung protective ventilation with target plateau pressures of <30 cm H20. They also recommend recruitment maneuvers (a short-term increase in PEEP in attempts to “recruit” alveoli that are not currently participating in gas exchange) if patients experience hypoxia despite optimizing mechanical ventilation. They recommend against the utilization of staircase recruitment maneuvers. The graded increase in PEEP with a target of 40 cm H20 then backing off and repeating (“staircase recruitment”) increases mortality in ARDS. The SCCM guidelines recommend proning strategies in intubated patients with moderate to severe ARDS with neuromuscular blockade for up to 48 hours.  The NIH does not recommend the routine use of inhaled nitric oxide.

While there are no clinical trials that have reported data on the outcomes of veno-venous ECMO in patients with COVID-19, the SCCM guidelines do recommend this as a rescue therapy for patients who experience refractory hypoxia despite proning, paralysis and maximum optimization via mechanical ventilation.  The NIH states that there is not enough data to issue a recommendation for or against ECMO in this patient population as a rescue therapy.

Management of Shock:

The SCCM Guidelines recommends that for the treatment of adults with COVID-19 and shock, crystalloids be used as fluid resuscitation of choice. They recommend that norepinephrine be the first line pressor, with vasopressin be added as the second line vasopressor. If norepinephrine is not available, epinephrine should be used as the first line vasopressor agent to target a MAP goal of 60-65 mm Hg. The SCCM recommends that dobutamine be added if there is evidence of continued cardiac dysfunction with hypoperfusion despite adequate fluid resuscitation despite norepinephrine.  The NIH and SCCM guidelines specifically recommend against albumin for resuscitation due to lack of benefit.

For patients with refractory shock, the SCCM guidelines recommend low-dose corticosteroid therapy as opposed to high-dose corticosteroid therapy (200mg hydrocortisone/day) typically utilized in septic shock used to combat acute, secondary adrenal insufficiency.

Renal failure: As in the management of septic shock, the NIH guidelines recommend the use of CRRT when indicated for patients with renal failure in the setting of shock.

ECMO: According to the NIH guidelines insufficient data exists to recommend either for or against the use of extracorporeal membrane oxygenation in patients with COVID-19 and refractory hypoxemia.  Many institutions are utilizing this as rescue therapy early in the course of refractory hypoxemia associated with COVID-19 and studies are ongoing.

Antimicrobial Therapy:

The NIH guidelines note that there is not enough data to issue a recommendation for or against empiric antimicrobial therapy for mechanically ventilated patients with COVID-19.  They do note that daily reassessment of need and potential for de-escalation is required if antimicrobial therapy is initiated.

Antipyretics:

There was initial concern that NSAIDs increase the expression of ACE2 and inhibit antibody production, thereby worsening COVID-19.  However, there is no clinical evidence that NSAIDS actually worsen the course or outcome of COVID-19.  The NIH guidelines recommend that patients taking NSAIDs for a comorbid condition continue to do so as prescribed and that there be no difference in the use of antipyretic strategies (e.g., with acetaminophen or NSAIDs) between patients with or without COVID-19.  However, NSAIDs should be avoided if possible in those with renal disease, cardiac disease, a high risk of bleeding, etc.

Therapeutic Management:

Antiviral Therapies:

Remdesivir is the only antiviral that is FDA approved for the management of hospitalized adult and pediatric patients (aged ≥12 years and weighing ≥40 kg) with COVID-19.  Remdesivir is not recommended for patients with eGFR <30ml/min.  The NIH reports there is not enough evidence to recommend for or against use of remdesivir in hospitalized patients that do not require supplemental oxygen, but that it may be reasonable to begin therapy in patients with a high risk of disease progression.  They recommend remdesivir for those who require minimal supplemental oxygen, and remdesivir plus dexamethasone in those with increasing oxygen requirements.  Of note, remdesivir has not shown benefit in those who require mechanical ventilation and is not recommended in this subgroup.

Of note, on 11/19/20, the FDA issued an emergency use authorization (EUA) for the use of baricitinib in combination with remdesivir in hospitalized adults and children aged ≥2 years with COVID-19 who require supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). This medication is discussed further under the section on JAK inhibitors.

Chloroquine and hydroxychloroquine, with and without azithromycin, have been studied for the treatment of COVID-19.  The NIH guidelines recommends against these therapies for the treatment of COVID-19, unless as part of a clinical trial.  Chloroquine and hydroxychloroquine have been associated with serious dysrhythmias in patients with COVID-19, often in combination with azithromycin and other medicines that prolong the QTc interval.  Studies found that hydroxychloroquine did not decrease mortality when compared to the usual standard of care in hospitalized patients and may increase length of stay and increase risk of death in some patient subgroups.

The NIH recommends against the use of ivermectin outside of a clinical trial for the treatment of COVID-19.  Studies suggest that it would require administration of 100x the normal dose approved for humans to achieve the dose necessary to eradicate the COVID-19 virus.  Ivermectin is not currently FDA approved for treatment of any viral illness.

The SCCM guidelines recommends against routine use of lopinavir/ritonavir for management of patients with COVID-19.  The NIH also recommends against use of this drug combination for the treatment of COVID-19 outside of a clinical trial. Lopinavir/Ritonavir has been shown to be ineffective in the treatment of COVID-19 in a 199-person randomized trial.  All patients were hospitalized and had a PO2 of <94%. There was no difference in time to clinical improvement. There was no difference in 28-day mortality (19.2% vs. 25.0%; difference, −5.8 percentage points; 95% CI, −17.3 to 5.7) or detectable viral RNA. (NEJM. https://www.nejm.org/doi/full/...) DOI: 10.1056/NEJMoa2001282.

Immune-Based Therapies:

The FDA has provided guidance for the use of COVID-19 convalescent plasma under an Emergency Investigational New Drug Application. The FDA has also approved a national expanded access program for the use of convalescent plasma for the treatment of patients with COVID-19. The NIH guidelines indicate in their update as of October 2, 2020, that insufficient data exists to recommend for or against use of convalescent plasma for treatment of COVID-19.  The IDSA guidelines recommend against the use of convalescent plasma outside the setting of a clinical trial for the treatment of COVID-19. Most of the data for convalescent plasma is negative, including a recent article published from the NEJM on November 24th, 2020.

The NIH guidelines state there is insufficient evidence to recommend either for or against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunoglobulins for the treatment of COVID-19.

Non-SARS-CoV-2-specific intravenous immunoglobulins (IVIG) is not recommended by the NIH guidelines for the treatment of COVID-19 in the absence of a clinical trial.  The panel notes that this does not preclude the use of IVIG when otherwise indicated for treatment of routine complications of COVID-19.

Mesenchymal stem cells are not currently approved by the FDA for treatment of COVID-19.  The NIH recommends against using this therapy for treatment of COVID-19 outside of a clinical trial.  Hypothetically, mesenchymal stem cells could reduce lung injury and inhibit the cell-mediated inflammatory response induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).  However, this data has not been sufficiently studied or proven.

Immunomodulators:

While corticosteroids were not initially recommended for treatment of hypoxia associated with COVID, additional data found that dexamethasone improved survival in hospitalized patients with COVID who require supplemental oxygen.  This benefit has been observed to have the greatest impact on those patients who require mechanical ventilation. The NIH guidelines strongly recommend dexamethasone therapy for hospitalized patients with COVID who require supplemental oxygen.

The NIH guidelines recommend against the use of interferons for patients with severe or critical COVID-19, unless part of a clinical trial.  Insufficient data exists to recommend for or against use of interferon beta for the treatment of patients with early mild-moderate COVID-19. Interferon beta-1a showed no benefit in a well done randomized, controlled trial of ARDS (not specific to COVID-19) (JAMA. 2020;323(8):725-733. doi:10.1001/jama.2019.22525). There are concerns that due to the pharmacokinetic properties of this drug combination, that it may be unable to achieve concentrations high enough to inhibit the SARS-CoV-2 proteases.

Anakinra is a recombinant human IL-1 receptor antagonist used in some case series to treat COVID-19.  The rationale is that endogenous IL-1 is elevated in patients with COVID-19.  The NIH guidelines state that there is currently insufficient evidence to recommend for or against the use of Anakinra for the treatment of COVID-19. Please visit this link to view the clinical trials currently ongoing to study Anakinra for treatment of COVID-19.

The IDSA amended their guidelines on February 16, 2021 to include a recommendation for use of tocilizumab, an IL-6 inhibitor. The NIH guidelines recommend tocilizumab for hospitalized adults with progressive severe or critical COVID-19 who have elevated markers of systemic inflammation.  In these cases, the IDSA guidelines recommend  tocilizumab in addition to steroids rather than steroids alone.  The NIH guidelines state that there is not enough data to recommend for or against the use of tocilizumab oustide of a clinical trial.  They do state that if tocilizumab is used, it should be used as a single dose for patients who are within 24 hours of admission to the ICU and who require invasive or
noninvasive mechanical ventilation or high-flow oxygen (>0.4 FiO2
/30 L/min of oxygen flow).  Other IL-6 inhibitors (sarilumab or siltuximab) are not currently recommended due to insufficient testing.  

Baricitinib is an oral Janus kinase (JAK) inhibitor that is selective for JAK1 and JAK2 that was recently issued an EUA for  use in combination with remdesivir in hospitalized adults and children aged ≥2 years with COVID-19 who require supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). It is hypothesized that baricitinib may prevent cellular immune activation and inflammation, thereby proving an effective treatment for COVID-19.  After examining the currently available data, the NIH panel has determined that insufficient data exists to recommend for or against the use of baricitinib in combination with remdesivir for the treatment of COVID-19 in hospitalized patients in cases where corticosteroids can be used instead.  In unusual circumstances where corticosteroids cannot be used, the guidelines recommend using baricitinib in combination with remdesivir for the treatment of COVID-19 in hospitalized, non-intubated patients who require oxygen supplementation.  They also recommend against the use of baricitinib in the absence of remdesivir outside of clinical trial.

The NIH guidelines recommend against using Bruton’s tyrosine kinase (BTK) inhibitors, such as acalabrutinib, ibrutinib, and zanubrutinib; and Janus kinase (JAK) inhibitors, with the exception of baricitinib for the treatment of COVID-19.

Recombinant Human Monoclonal Antibodies

Casirivimab and imdevimab are two recombinant human monoclonal antibodies. The casirivimab plus imdevimab combination blocks the binding of the receptor-binding domain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to the host cell and is being evaluated for the treatment of COVID-19. On November 21, 2020, the Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) to make the casirivimab plus imdevimab combination available for the treatment of non-hospitalized patients with mild to moderate COVID-19 who are at high risk for progressing to severe disease and/or hospitalization. The FDA has also issued an EUA for bamlanivimab, another SARS-CoV-2 neutralizing antibody, for the same patient population.

On February 23, the NIH guidelines were updated to say that bamlanivimab plus etesevimab should be used for the treatment of patients with mild to moderate COVID who are at high risk of clinical progression.  Treatment should be started as soon as possible after a positive test and within 10 days of symptom onset. This is not recommended for hospitalized due to COVID.

The NIH guidelines indicate that insufficient data exists to recommend for or against use of casirivimab plus imdevimab for the treatment of outpatients with mild to moderate COVID-19. They recommend that, due to possible limited supply of the drug, patients at highest risk for COVID-19 progression should be prioritized for use of the combination drug through the EUA.  They recommend against use of this combination in hospitalized patients outside of a clinical trial.

Antithrombotic Therapy:

According to the NIH guidelines, there is no data to support full dose anticoagulation in non-hospitalized patients with COVID-19, unless there are other indications.  The guidelines recommend VTE prophylaxis for all hospitalized patients with COVID-19. The guidelines note that there is insufficient evidence to recommend for or against full-dose anticoagulation in patients without signs and symptoms of VTE despite the status of their coagulation biomarkers. Further, there are currently insufficient data to recommend for or against routine deep vein thrombosis screening in COVID-19 patients without signs or symptoms of VTE, regardless of the status of their coagulation markers.

Vitamin C/Vitamin D: The NIH guidelines report that there is insufficient evidence to support for or against the use of vitamin C or Vitamin D in treatment of either the critically ill or non-critically ill patient population with COVID-19.

Zinc: The NIH guidelines report that there is insufficient evidence to support for or against the use of zinc in treatment of either the critically ill or non-critically ill patient population with COVID-19.  The guidelines recommend against using zinc supplementation above the recommended dietary allowance for the prevention of COVID-19 (11 mg daily for men and 8 mg for nonpregnant women), except in a clinical trial.

ACE Inhibitors (ACEIs) and Angiotensin Receptor Blockers (ARBs):

The NIH guidelines, American Heart Association, the Heart Failure Society of America, and the American College of Cardiology recommend that patients with COVID-19 who are prescribed ACEIs and ARBs for other comorbid conditions continue these medications, but that they should not be used for treatment of COVID-19 outside of a clinical trial. 

Statins: The NIH guidelines recommend that patients with COVID-19 who are prescribed statins for other comorbid conditions continue these medications, but that statins should not be used for treatment of COVID-19 outside of a clinical trial.

 

References:

Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19 Published by IDSA on 4/11/2020. Last updated, 12/2/2020. Accessed 12/24/2020: https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/

NIH COVID Treatment Guidelines: Accessed 12/20/2020: https://www.covid19treatmentguidelines.nih.gov/

Surviving Sepsis Campaign: guidelines on the management of critically ill adults with Coronavirus Disease 2019 (COVID-19): https://link.springer.com/article/10.1007/s00134-020-06022-5. Accessed 12/24/2020

Simonovich, VA et al, A Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia. New England Journal of Medicine; November 24, 2020 DOI: 10.1056/NEJMoa2031304

Julie Grishaw, ACNP

Senior Editor, McGraw-Hill Education

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