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COVID-19 is a disease with a very wide spectrum. The clinical symptoms range from asymptomatic to uncomplicated upper respiratory tract infection to pneumonia, acute respiratory distress syndrome (ARDS), sepsis and septic shock with multi organ failure. Diagnosis of COVID-19 is made based on a positive PCR (Polymerase Chain Reaction) involving different gene targets. Since COVID-19 is caused by a novel virus, SARS-COV-2, there is a very limited evidence to support effective treatments. The different guidelines outline currently available information. Information is changing rapidly, so there is a need for updating regularly.

Inputs, true as on 25th March 2020, pertaining to treatment of COVID-19 patients, have been collected from, Antimicrobial Stewardship Program (ASP) at Michigan Medicine (University of Michigan); Brigham and Women’s Hospital, Boston, associated with Harvard Medical School; Vanderbilt University Medical Center and from CommonSpirit Health. Based on these inputs, Outpatient and Inpatient treatments for COVID-19 patients have been compiled here.

Disclaimer: The recommendations given below are meant to serve as treatment guidelines. If you are an individual experiencing an emergent medical condition, call emergency immediately. These guidelines should not replace a provider’s professional medical advice based on clinical judgment, or be used in lieu of an Infectious Diseases consultation when necessary. As a result of ongoing research, practice guidelines may change with time. The author of this guidelines has made all attempts to ensure the accuracy based on current information, however, due to ongoing research, users of these guidelines are strongly encouraged to confirm the information contained within them through an independent source.

Outpatient Treatment options for COVID-19

At present there is no current evidence from RCT (Randomized Controlled Trials) to recommend any specific anti-COVID-19 treatment for patients with suspected or confirmed infection. Antiviral treatment is to be considered only for patients with high risk for morbidity and mortality, such as elderly and immunocompromised patients. Supportive Care is actually the main stay of treatment for non-hospitalized patients. Certain Institutions like Vanderbilt University Medical Center (VUMC) do not recommend administering antivirals like Hydroxychloroquine to outpatients.

Hydroxychloroquine:

Treating Clinicians may choose to administer Hydroxychloroquine as a medication for COVID-19 based on emerging early observations. The current opinion regarding the dosage is:

Adverse events of Hydroxychloroquine

Retinopathy rash, nausea, diarrhea, and glucose fluctuations. GI symptoms can be mitigated by taking with food.

• Use with caution in diabetic patients. Patient should be educated to monitor for signs of hypoglycemia, and glucose levels should be frequently monitored
• Use with caution in patient at risk for QT prolongation
• Recommend to avoid taking hydroxychloroquine with antacids. Stagger administration by at least 4 hours.
• Recommended to obtain G6PD test even though post marketing studies suggest that risk of hemolysis is very low. It is reasonable to start hydroxychloroquine in most patients while awaiting G6PD testing.
• It is contraindicated in patients of Porphyria.

Pregnant and Nursing Mothers

Hydroxychloroquine has been associated with fetal ocular toxicity in animal studies. Additionally, hydroxychloroquine is excreted into breast milk. Thorough evaluation of the risk:benefit should be discussed with the patient prior to starting therapy

Inpatient Treatment options for COVID-19

Consideration for Inpatient Treatment of a Coronavirus infected patient varies between treating institutions to some extent. The various options of treatment are as under:

Hydroxychloroquine

As per the protocols at CommonSpirit Health and Michigan Medicine, Inpatient treatment with Hydroxychloroquine should be considered if following risk factors are present and patient is not clinically improving:

• Age ≥ 65
• Significant history of heart, lung and kidney disease
• Immunosuppression
• Radiographic evidence of moderate to severe pneumonia
• Lower Respiratory Tract infection requiring supplemental oxygen.
• ALT or AST > 5 times the upper limit of normal
• Creatinine Clearance < 50 ml/min
• Non pregnant adult patients on mechanical ventilation

The dosage of Hydroxychloroquine recommended at Michigan Health is:

Note: There is no requirement to adjust the dose for renal or liver dysfunction.

Duration of Treatment:

5 days

Adverse events of Hydroxychloroquine:

Discussed above in the outpatient treatment options.

Tocilizumab

Tocilizumab may be added to Antiviral therapy for COVID-19 positive patients meeting the following criterion:

• Rapidly worsening respiratory gas exchange
• Radiographic infiltrates by imaging (Chest X-ray, CT Scan etc.)
• Clinical assessment (evidence of rales/crackles on physical examination) and SpO2 ≤ 93% on room air or greater than 6 L/min O2
• Patients at high risk for developing Cytokine Storm (1 or more of the following)
  • Serum IL-6 ≥ 3 times upper limit of the normal
  • Ferritin > 300 µg/L with doubling within 24 hours
  • Ferritin > 600 µg/L at presentation and LDH > 250 U/L
  • Elevated D-dimer (> 1 mg/L)
• High risk for severe disease, i.e.,
  • age > 65 years
  • Chronic cardiovascular, pulmonary, hepatic, renal, hematologic or neurologic conditions
  • Immunocompromised

Duration of treatment:

1 dose

Adverse events of Tocilizumab

• Gastrointestinal perforation
• Anemia
• Hepatitis
• Infusion Reaction

Pregnant and Nursing Mothers

• Avoid in pregnancy
• Tocilizumab may be harmful to newborns, so mothers should stop breast feeding if receiving this medicine.

Remdesivir

Remdesivir is a preferred therapy for children and pregnant women who are hospitalized due to COVID-19 and on mechanical ventilation. As per Michigan Medicine, at present, Remdesivir is available only through Gilead with approved investigational new drug (IND) application for children and pregnant women.

Since Remdesivir is in a stage of clinical trials, the inclusion & exclusion criterion and the dosing vary from trial to trial and institution to institution. The criterion laid down by Michigan Medicine for one of the trials is as under:

Inclusion Criterion

• Hospitalization
• SARS-CoV-2 by PCR
• Mechanical Ventilation

Exclusion Criterion

• Multi organ failure
• Vasopressor requirement
• ALT > 5 times upper limit of normal
• Creatinine Clearance < 30 ml/min, dialysis, or CVVH (Continuous Veno-Venous Hemofiltration)
• Concomitant use of other experimental antiviral agents (e.g., Lopinavir-Ritonavir)

Duration of treatment

As per protocol of the trial

Lopinavir-Ritonavir (Kaletra)

Lopinavir-Ritonavir (Kaletra) is to be administered as an alternative therapy if remdesivir and hydroxychloroquine are unavailable or if the patient has contraindications or adverse effects of these drugs. Before administering Lopinavir-Ritonavir (Kaletra) HIV antigen / antibody has to be checked prior to first dose. Since this drug is a major substrate and inhibitor of Cytochrome P450, and can cause severe drug-drug interactions, thorough evaluation of a patient’s medication profile should be done before starting therapy.

Duration of Treatment

5 days

Adverse events of Lopinavir-Ritonavir

• Hepatotoxicity
• Pancreatitis
• Diabetes
• QT prolongation
• Lipid Elevations
• Fat redistribution

Pregnancy

It is safe to use during pregnancy

Nitazoxanide

Some in vitro studies have demonstrated potency against SARS-CoV-2, though clinical use against other coronaviruses has not demonstrated benefit. It has a poorly tolerated formulation but the safety profile is relatively benign.

Duration of Treatment

5 days

Adverse events of Nitazoxanide

• Headache, nausea, abdominal pain, urine discoloration

Pregnant and Nursing Mothers

• Use is safe in pregnancy after the first trimester
• There is no data on excretion into breast milk.

Azithromycin

The preliminary data evaluating combination of hydroxychloroquine and azithromycin for COVID-19 patients (Gautret et al) is available on International Journal of Antimicrobial agents. This study concluded that there is a greater viral load reduction when combining azithromycin with hydroxychloroquine compared to monotherapy with hydroxychloroquine. As this study evaluated only six patients in the combination group, it is considered as a weak evidence against the routine use of azithromycin by many, at this time.

According to Michigan Medicine, University of Michigan, azithromycin should not be given unless providing community acquired bacterial pneumonia treatment. However the treatment guidelines established by CommonSpirit Health, combination of azithromycin and hydroxychloroquine may be used for inpatient treatment under the following conditions:

• Patients with lower respiratory tract infection requiring supplemental oxygen and not improving clinically, with rapidly increasing oxygen demands.
• Patients with lower respiratory tract infection requiring mechanical ventilation or BiPAP.

Dosing

500 mg IV q 24 hour x 5 days, or

500 mg PO x 1 day, followed by 250 mg daily for 4 days (may convert from IV to PO as appropriate)

Adverse events of Azithromycin & Hydroxychloroquine

This combination can increase the risk of Torsades de Pointes (TdP). Appropriate patient selection and monitoring is recommended.

Adjunctive Therapy in COVID-19

Corticosteroids

These should be avoided, if possible, for COVID-19, because of the potential for prolonging viral replication as observed in MERS-CoV patients. This does not preclude use of steroids for other indications such as COPD, refractory septic shock, etc.

NSAIDs

As per FDA there is not enough scientific evidence to link the use of NSAIDs to worsening of symptoms of COVID-19. However, until further information is available, use Acetaminophen (Paracetamol) as a first line for fever, if no contraindications are present.

ACE inhibitors/ARBS

The HFSA (Heart Failure Society of America), ACC (American College of Cardiology) and AHA (American Heart Association) recommend continuation of RAAS (renin-angiotensin –aldosterone system) antagonists for those patients who are currently prescribed such agents. Currently there are no experimental or clinical data demonstrating beneficial or adverse outcomes with background use of ACE inhibitors, ARBs or other RAAS antagonists in COVID-19 patients.

References

1. Gilead
2. Gautret P, Lagier J, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open label non-randomized clinical trial
3. COVID-19 (novel coronavirus) information, Michigan University
4. Brigham and Women’s Hospital COVID-19 Critical Care Clinical Guidelines
5. Vanderbilt University Medical Center Clinical Recommendations for treatment of COVID-19 adult patients
6. https://www.cdc.gov/coronavirus/2019-ncov/hcp/faq.html
7. FDA advises patients on use of non-steroidal anti-inflammatory drugs (NSAIDs) for COVID-19
8. CommonSpirit Health COVID-19 inpatient adult treatment guidelines updated on 03/24/2020.