coronavirus%20disease%202019%20(covid-19)
CORONAVIRUS DISEASE 2019 (COVID-19)
Treatment Guideline Chart

It is a viral infection of the respiratory tract caused by a newly emergent coronavirus, SARS-CoV-2, that was recognized in Wuhan, China in December 2019.

Mode of transmission is through contact and droplet via direct indirect, or close contact with infected individuals through secretions ie saliva and respiratory secretions.

Generally after exposure to the virus, the mean time to develop symptoms is 4-6 days, with a range of between 1 and 14 days.

Coronavirus%20disease%202019%20(covid-19) Treatment

Principles of Therapy

Mild to Moderate COVID-19

  • Symptomatic treatment is recommended such as antipyretics for fever and pain, adequate nutrition and appropriate rehydration by oral fluids and isolation at home or in temporary treatment and monitoring facilities
  • Patient should be informed of the signs and symptoms of severe disease or complications and should be advised to seek immediate care once observed
  • Antibiotic therapy or prophylaxis is not recommended
  • Studies done in Hong Kong and Toronto have shown that early treatment with Interferon beta-1b or Peginterferon lambda may help reduce duration of viral shedding and hospital stay thus early treatment of high-risk patients (eg >65 years of age, with comorbidities like hypertension, diabetes mellitus, asthma, COPD) is essential and associated with better outcomes

Severe COVID-19 

  • Site of treatment should have the following: 
    • Pulse oximeter
    • Functioning oxygen systems 
    • Disposable, single-use, oxygen-delivering interfaces (nasal cannula, Venturi mask, mask with reservoir bag)
  • Supplemental oxygen therapy should be immediately administered to those with emergency signs (eg obstructed or absent breathing, severe respiratory distress, central cyanosis, shock, coma and/or contusions) or to those without emergency signs but with SpO2 <90% 
  • Fluid management should be used cautiously in patients without tissue hypoperfusion and fluid responsiveness 
  • Use of nebulizers is not recommended
  • Antivirals (eg Remdesivir) can be given in hospitalized patients with severe disease

Pharmacotherapy

Antivirals

Remdesivir

  • A monophosphate prodrug that binds to viral RNA-dependent RNA polymerase and inhibits viral replication through premature termination of RNA transcription
  • 1st US FDA-approved COVID-19 treatment for adult and children ≥12 years old and weighing at least 40 kg requiring hospitalization
    • Should only be administered in the hospital or in a healthcare facility capable of providing acute care 
  • Recommended in hospitalized patients with severe COVID-19 
    • Remdesivir treatment for 5 days is suggested for patients on supplemental oxygen but not on mechanical ventilation, high-flow device, non-invasive ventilation or extracorporeal membrane oxygenation (ECMO) 
  • For patients with mild to moderate COVID-19, there are insufficient data to recommend either for or against the use of  Remdesivir 

Remdesivir with Baricitinib

  • Recommended by the US FDA with emergency use authorization (EUA) for treatment of suspected or laboratory-confirmed COVID-19 in hospitalized adults and pediatric patients ≥2 years of age requiring supplemental oxygen, invasive mechanical ventilation, or ECMO

Corticosteroids

  • Inhibit multiple inflammatory cytokines resulting in decreased edema, capillary leakage, and migration of inflammatory cells, thereby globally suppressing the inflammatory response
  • Low-dose  Dexamethasone is suggested in hospitalized COVID-19 patients who are receiving supplemental oxygen or have non-critical disease
  • Dexamethasone is recommended in hospitalized COVID-19 patients with critical disease
  • There is moderate quality evidence to recommend the use of corticosteroids particularly Dexamethasone as adjunctive treatment for patients with COVID-19
  • Inhaled steroids are not recommended for the treatment of COVID-19 pending the results of ongoing studies
  • Oral, inhaled or IV steroids are not recommended for prophylaxis or prevention of COVID-19
Disease-Modifying Antirheumatic Drugs
Baricitinib
  • A janus kinase inhibitor that was recently given US FDA EUA that can be given alone even without Remdesivir
  • It is indicated for treatment of adults and pediatric patients ≥2 years of age hospitalized with COVID-19 disease requiring supplemental oxygen, non-invasive or invasive mechanical ventilation, or ECMO

Monoclonal Antibodies

Casirivimab/Imdevimab and Sotrovimab

  • Recombinant human monoclonal antibodies that bind to non-overlapping epitopes of the spike protein receptor binding domain of SARS-CoV-2
  • Recommended by the US FDA with EUA
  • Criteria for initiation of treatment: 
    • With mild to moderate COVID-19
    • Adults and pediatric patients ≥12 years old or weighing at least 40 kg
    • Presence of at least one of the below criteria for high-risk patients: 
      • BMI ≥35
      • Chronic kidney disease
      • Immunosuppressive disease
      • Currently receiving immunosuppressive therapy
      • Age ≥65 years old
      • Age ≥55 years old with cardiovascular disease, hypertension or chronic obstructive pulmonary disease
      • Age 12-17 years old with BMI ≥85 or sickle cell disease or heart disease or neurodevelopmental disorders, medical-related technological dependence, asthma 
  • Should not be given to the following COVID-19 patients:
    • Hospitalized
    • Requiring oxygen therapy
    • Need increase in baseline oxygen flow rate on chronic oxygen therapy due to underlying comorbidities
  • Casirivimab/Imdevimab can be used as post-exposure (ie within 7 days of high-risk exposure) prophylaxis for selected individuals
Regdanvimab
  • Recombinant human IgG1 monoclonal antibody that binds to the receptor-binding domain of the spikes protein of SARS-CoV-2
  • It is currently under rolling review by the European Medicines Agency (EMA) and is given EUA by Indonesia's National Agency of Drug and Food Control
  • Can be used for the treatment of adult patients with confirmed COVID-19 who do not require supplemental oxygen therapy and who are at high risk of progressing to severe COVID-19
  • It is given by infusion (drip) into a vein

Tocilizumab 

  • A recombinant humanized anti-human IL-6 receptor monoclonal antibody that specifically binds sIL-6R and mIL-6R and inhibits signal transduction
  • Recommended by the US FDA with EUA
  • It is recommended in some countries to be used in patients admitted within 24 hours in ICU and who require high-flow oxygen or more intensive respiratory support
  • In some countries, it is recommended to be used in combination with Dexamethasone in certain hospitalized patients who are in rapid respiratory decompensation due to COVID-19
  • Avoid use in patients who are significantly immunocompromised or outpatient treatment
  • There is still insufficient evidence to recommend the routine use of Tocilizumab or other IL-6 inhibitors for severe COVID-19 patients suspected to be in cytokine storm except in the context of a clinical trial or for compassionate use

Anticoagulants

  • It is suggested that all patients with severe disease receive standard prophylactic anticoagulation with low-molecular-weight Heparin if without contraindications (eg active bleeding or severe thrombocytopenia)

Interferons

  • In vitro it has been shown that Interferon beta inhibits SARS-CoV-2 replication
  • Large multinational trial using subcutaneous or intravenous Interferon beta has shown no difference in the 28-day mortality compared with standard care in patients hospitalized with COVID-19
  • An open-label, randomized trial was done in Hong Kong in adult patients with confirmed SARS-CoV-2 with mild to moderate disease where they were given Interferon beta-1b in the early onset of symptoms together with the combination of Lopinavir/Ritonavir and Ribavirin and treatment showed clinical improvement of symptoms, shortening of viral shedding and faster time to hospital discharge
    • Future studies are warranted for a double antiviral therapy with Interferon beta-1b as the backbone
  • A double-blind, placebo-controlled randomized trial was done in Toronto wherein confirmed patients with SARS-CoV-2 with mild to moderate disease were given in their early days of COVID-19 infection Peginterferon lambda and trial showed increased viral decline and increased proportion of patients with viral clearance at day 7 of treatment showing that Peginterferon lambda has potential to prevent clinical deterioration

Acute Respiratory Distress Syndrome (ARDS)

  • New or worsening respiratory symptoms with onset within a week of known pneumonia
  • A lung injury that is acute, diffuse and inflammatory which is due to a variety of etiologies
  • Chest imaging shows:
    • Bilateral opacities, not fully explained by volume overload
    • Lobar or lung collapse or nodules

Classification Based on Impairment in Oxygenation in Adults

  • Mild ARDS: 200 mmHg <PaO2/FiO2 ≤300 mmHg [with positive end-expiratory pressure (PEEP) or continuous positive airway pressure (CPAP) ≥5 cmH2O, or non-ventilated]
  • Moderate ARDS: 100 mmHg <PaO2/FiO2 ≤200 mmHg (with PEEP ≥5 cmH2O, or non-ventilated)
  • Severe ARDS: PaO2/FiO2 ≤100 mmHg (with PEEP ≥5 cmH2O, or non-ventilated)

Management

  • Airborne precautions
  • Admission in ICU
  • Conservative fluid management for ARDS patients without tissue hypoperfusion and fluid responsiveness
  • Empiric antimicrobials following the guidelines of pneumonia management
  • Consideration of neuromuscular blockade in intubated patients 
  • Anticoagulation therapy
  • Dexamethasone 6 mg/day for 10 days
    • Titrate upwards and consider use of Methylprednisolone when dealing with cytokine storm
  • Observe ARDS protocol for mechanical ventilation
    • Initiation of recruitment maneuvers and lung protection strategies eg PEEP titration 
      • PEEP titration requires consideration of benefits (reducing atelectrauma and improving alveolar recruitment) versus risks (end-inspiratory overdistension leading to lung injury and higher pulmonary vascular resistance) 

Sepsis/Septic Shock

Sepsis

  • Organ dysfunction that is acute and life-threatening due to dysregulated host response to suspected or proven infection
  • Signs of organ dysfunction include: Altered mental status, difficult or fast breathing, low oxygen saturation, reduced urine output, fast heart rate, weak pulse, cold extremities or low blood pressure, skin mottling, laboratory evidence of coagulopathy, thrombocytopenia, acidosis, high serum lactate level, or hyperbilirubinemia 

Septic Shock

  • There is persistent hypotension despite volume resuscitation that requires vasopressors to maintain mean arterial pressure (MAP) ≥65 mmHg and serum lactate level >2 mmol/L
  • It is important to recognize early the signs of septic shock 
  • The following should be done within 1 hour of recognition: 
    • Administer antimicrobial therapy
    • Initiate fluid bolus and vasopressors for hypotension
      • The use of central venous and arterial catheters should be based on resource availability and individual patient needs
  • Give 250-500 mL crystalloid fluid (includes normal saline and Ringer’s lactate) as rapid bolus in first 15-30 minutes of resuscitation
    • Fluid administration should be reduced or discontinued if there is no response to fluid loading or signs of volume overload appear (eg jugular venous distension, crackles on lung auscultation, pulmonary edema on imaging, or hepatomegaly) 
  • When shock persists during or after fluid resuscitation, administer vasopressors 
    • Initial blood pressure target is MAP ≥65 mmHg in adults and improvement of markers of perfusion
    • Norepinephrine is considered the 1st-line treatment in adult patients; Epinephrine or Vasopressin can be added to achieve the MAP target
      • Because of the risk of tachyarrhythmia, reserve Dopamine for selected patients with low risk of tachyarrhythmia or those with bradycardia

Other Therapies

Oxygenation and Ventilation 

  • It is recommended to closely monitor patients receiving supplemental oxygen for worsening respiratory status and that intubation should be done by an experienced practitioner in a controlled setting
  • In patients with acute hypoxemic respiratory failure despite conventional oxygen therapy, it is recommended to give high-flow nasal cannula (HFNC) oxygen over noninvasive positive pressure ventilation (NIPPV)
  • If there is no indication for endotracheal intubation, it is recommended to monitor trial of NIPPV for adults with COVID-19 and acute hypoxemic respiratory failure if HFNC is not available
  • For patients with persistent hypoxemia after increasing supplemental oxygen and endotracheal intubation is not otherwise indicated, it is recommended to consider a trial of awake prone positioning to improve oxygenation
  • It is not recommended using awake prone positioning as a rescue therapy for refractory hypoxemia to avoid intubation in patients who otherwise require intubation and mechanical ventilation
  • For mechanically-ventilated COVID-19 patients with ARDS: 
    • It is recommended to use low tidal volume (VT 4-8 mL/kg of predicted body weight) ventilation over higher tidal volumes (VT >8 mL/kg) 
    • The recommended target plateau pressure is <30 cmH2O
    • It is recommended to use a conservative fluid strategy over a liberal fluid strategy
    • Routine use of inhaled nitric oxide is not recommended
  • For mechanically-ventilated COVID-19 patients with moderate-severe ARDS: 
    • It is recommended to use higher PEEP strategy over a lower PEEP strategy 
      • PEEP is beneficial in patients with ARDS because it prevents alveolar collapse, improves oxygenation, and minimizes atelectotrauma, a source of ventilator-induced lung injury
    • For those who have refractory hypoxemia despite optimized ventilation, it is recommended to use prone ventilation for 12-16 hours per day over no prone ventilation
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