Treatments for COVID-19

Co-authored with Julie Grishaw, ACNP

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For more information, please refer to the body of World Health Organization articles about COVID-19 to date.

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.

COVID-19 has been associated with profound cytokine storm leading to a hyperinflammatory state. A component of immune dysregulation is also suspected, and the virus may have a potential for attacking specifically 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.

This post will focus on treatments for COVID-19. 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.

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 may be less likely to require intubation as compared to those managed with traditional oxygen therapy. The SCCM reports data is lacking for the concern that HFNC increases the risk for aerosolization of COVID-19. The SCCM further recommends 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.

In contrast to viral pneumonia, which is often complicated by superimposed bacterial pneumonia, some severely ill patients are progressing directly to acute respiratory distress syndrome (ARDS). 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 if patients experience hypoxia despite optimizing mechanical ventilation. They recommend against the utilization of staircase recruitment maneuvers. The SCCM guidelines recommend proning strategies in patients with moderate to severe ARDS with neuromuscular blockage for up to 28 hours.

While the routine use of nitric oxide is not recommended, a trial of an inhaled pulmonary vasodilator can be used per the SCCM guidelines in those patients with severe ARDS. If no improvement is seen, it should be tapered off.

While there are no clinical trials that have reported data on the outcomes of venovenous 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.

Management of Shock:

The SCCM Guidelines recommends for adults with COVID-19 and shock, that 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, vasopressin or 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 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.

Steroids:

The SCCM guidelines do not recommend steroids for treatment of mechanically ventilated patients without ARDS. They do recommend systemic corticosteroids in patients with COVID-19 and ARDS, though issued a statement that this is a weak recommendation with low quality evidence and not all board members agreed, that some wished not to issue a recommendation without further evidence. The IDSA and NIH guidelines are in agreement with the above recommendations.

Antimicrobial Therapy:

The SCCM guidelines recommend empiric antimicrobial therapy for mechanically ventilated patients with COVID-19 with daily reassessment of need and potential for de-escalation.

Antipyretics:

The SCCM guidelines recommend the use of acetaminophen for fever control, noting that it may increase patient comfort and does not increase the rate of mortality. fThey note that enough evidence is not available to recommend the use of non-steroidal anti-inflammatory drugs. There is no evidence that NSAIDS worsen the course or outcome of COVID-19.

The SCCM guidelines recommends against routine use of lopinavir/ritonavir for management of patients with COVID-19 and says there is insufficient evidence to provide a recommendation on any other antivirals for treatment of patients with COVID-19 at this time. 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.

Antithrombotic Therapy:

According to the NIH guidelines, there is no data to support 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.

More specific recommendations are available in the NIH guidelines regarding post-discharge VTE prophylaxis:

Routine post-discharge VTE prophylaxis is not recommended for patients with COVID-19 (AIII). However, the benefits of post-discharge prophylaxis for certain high-risk patients without COVID-19 led to the Food and Drug Administration approval of two regimens: rivaroxaban 10 mg daily for 31 to 39 days, and betrixaban 160 mg on Day 1, followed by betrixaban 80 mg once daily for 35 to 42 days.

Inclusion criteria for the trials that studied these regimens included:

 

  • Modified IMPROVE-VTE score ≥4; or
  • Modified IMPROVE-VTE score ≥2 and D-dimer level >2 times the upper limit of normal;16 or • Age ≥75 years; or
  • Age >60 years and D-dimer level >2 times the upper limit of normal; or
  • Age 40 to 60 years, D-dimer level >2 times the upper limit of normal, and previous VTE event or cancer.
  • Any decision to use post-discharge VTE prophylaxis should consider the individual patient’s risk factors, including reduced mobility, bleeding risks, and feasibility.

 

Antiviral Therapy & Other Investigational Therapies:

Remdesivir is an antiviral, reported to have in-vitro activity against SARS-CoV-2. Based on preliminary clinical trial data, the NIH guidelines recommend remdesivir for the treatment of COVID-19 in hospitalized patients with severe disease, defined as SpO2 ≤94% on room air, requiring supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation (BI). Remdesivir is not approved by the Food and Drug Administration (FDA); however, it is available through an FDA emergency use authorization for the treatment of hospitalized adults and children with COVID-19. Remdesivir is also being investigated in clinical trials, and it is available through an emergency access program for children and pregnant patients.  The Panel does not recommend remdesivir for the treatment of mild or moderate COVID-19 outside the setting of a clinical trial. For information on specific clinical trials underway for treatment of patients with COVID-19, see clinicaltrials.gov, and www.chictr.org.

Tocilizumab (anti-IL 6) is a humanized immunoglobulin that blocks receptor binding to IL-6. Randomized controlled trials are underway exploring the use of in efforts to suppress the hyperinflammatory syndrome associated with COVID-19. Secondary hemophagocytic lymphohistiocytosis (sHLH) has been seen to develop in this patient population and is characterized by fulminant and fatal hypercytokinaemia with multiorgan failure. This mechanism is also an important component by which patients are developing fulminant myocarditis, an often fatal consequence of COVID-19 in very severe cases. SCCM guidelines state that there is insufficient data to issue a recommendation for or against use of tocilizumab (anti-IL 6) in the treatment of COVID-19 in critically ill adults. The IDSA states that tocilizumab should be used for treatment of COVID-19 only in the setting of a clinical trial. Updated as of May 12, the NIH reports there is insufficient data to determine if tocilizumab should be used for treatment of COVID-19.

The IDSA recommends that lopinavir/ritonavir be used in the treatment of COVID-19 only in the context of a clinical trial.  The NIH is in agreement with this recommendation.

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). The SCCM guidelines state that there is insufficient data to issue a recommendation for or against use of interferon in the treatment of COVID-19 in critically ill adults.

The SCCM guidelines and NIH guidelines report there is insufficient evidence for or against using chloroquine or hydroxychloroquine for the treatment of COVID-19.  The NIH guidelines recommends against using high-dose chloroquine (600 mg twice daily for 10 days) for the treatment of COVID-19, because the high dose carries a higher risk of toxicities than the lower dose. The FDA IDSA guidelines cautions against using either drug outside of a clinical trial for treatment of COVID-19. 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. High-dose chloroquine (600 mg twice daily for 10 days) has been associated with more severe toxicities than lower-dose chloroquine (450 mg twice daily for 1 day, followed by 450 mg once daily for 4 days).

ACE-I and Angiotensin-II receptor antagonists (ARBs) have been tried. The primary route of virus entry into cells seems to be ACE2 receptors which are blocked by ARBsHowever, ARBs upregulate the ACE2 receptor. There is no data suggesting that ARBS or ACE-I worsen outcomes in COVID-19. These medications are not mentioned in the SCCM guidelines. It is not recommended that patients stop their ACE-I and ARBs.  See European Society of Cardiology statement here. The American Heart Association, American College of Cardiology and Heart Failure Society of America also recommend against stopping ACE-I and ARBs. https://www.hfsa.org/patients-...

Convalescent plasma: The IDSA recommends this treatment be used only in the setting of a clinical trial. The NIH guidelines indicate there is not enough data for or against use of convalescent plasma in treatment of COVID-19.  In their guidelines, they note that 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  National COVID-19 Convalescent Plasma Project website provides more information.

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Gautret et al. (2020) Hydroxychloroquine and azithromycin as a treatment of COVID‐19: results of an open‐label non‐randomized clinical trial. International Journal of Antimicrobial Agents – In Press 17 March 2020 – DOI : 10.1016/j.ijantimicag.2020.105949

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