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

Mild to Moderate COVID-19 Disease

• Main goal of treatment is to prevent progression to severe disease, hospitalization or death
  • Other goals include accelerating symptom recovery and viral clearance
• 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

Severe COVID-19 Disease

• 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% 
  • Severely ill patients needing supplemental oxygen or non-invasive ventilation may be placed in an awake prone position
• 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

Antivirals

Remdesivir

• A monophosphate prodrug that binds to viral RNA-dependent RNA polymerase and inhibits viral replication through premature termination of RNA transcription
• First 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) 
• Recommended by the WHO Guideline Development Group (GDG) as a treatment option for patients with non-severe illness at highest risk of hospitalization and severe COVID-19 but not for patients with critical COVID-19

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

Molnupiravir

• An oral potent ribonucleoside analog authorized by United Kingdom Medicines and Healthcare products Regulatory Agency (MHRA) and granted by the US FDA with EUA for use in patients with mild to moderate COVID-19 and at least 1 risk factor for developing severe illness, such as obesity, older age (>60 years old), diabetes mellitus, and heart disease
• Given conditional recommendation by the WHO for patients with non-severe COVID-19 at highest risk of hospitalization, except for children, pregnant and breastfeeding women
• Recommended as an alternative therapy to Ritonavir-boosted Nirmatrelvir or Remdesivir
• Can be administered as soon as possible following a positive COVID-19 test and within 5 days of symptom onset
• It is not authorized in patients <18 years old due to its effect on bone and cartilage growth

Nirmatrelvir/Ritonavir

• Nirmatrelvir inhibits the SARS-CoV-2 protein that helps with cessation of viral replication while Ritonavir slows down Nirmatrelvir's breakdown for it to remain in the body for longer period at higher concentrations
  • Nirmatrelvir must be co-administered with Ritonavir
• Recommended by the WHO in patients with non-severe COVID-19 at highest risk of hospitalization
• Approved by the US FDA for the treatment of mild to moderate COVID-19 in adults who have positive SARS-CoV-2 test results and who are at risk of progressing to severe COVID-19, including hospitalization or death
  • Use of Nirmatrelvir/Ritonavir as a therapy option that was granted EUA for the treatment of mild to moderate COVID-19 in children age ≥12 years old with positive SARS-CoV-2 test results and at risk of progressing to severe disease, hospitalization, or death will continue to be available in the US
• Recommended to initiate oral therapy as soon as the diagnosis of COVID-19 is obtained and within 5 days of symptom onset
  • 3 tablets (2 tablets of Nirmatrelvir and 1 tablet of Ritonavir) are taken together twice a day for a maximum of 5 days

Corticosteroids

• Inhibit multiple inflammatory cytokines resulting in decreased edema, capillary leakage, and migration of inflammatory cells, thereby globally suppressing the inflammatory response
• Recommended by WHO for patients with severe or critical COVID-19
• Dexamethasone is recommended as primary immunomodulator in all patients that are requiring high-flow cannula oxygen, noninvasive ventilation, mechanical ventilation, or ECMO
• Inhaled steroids are not recommended for the treatment of COVID-19 pending the results of ongoing studies
• Oral, inhaled or intravenous (IV) steroids are not recommended for prophylaxis or prevention of COVID-19

Disease-Modifying Anti-rheumatic Drugs

Baricitinib

• A Janus kinase inhibitor that was recently granted EUA by the US FDA that it 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
• Recommended by WHO for patients with severe or critical COVID-19 in combination with corticosteroids as an alternative to IL-6 receptor blockers
• When Baricitinib is not available or not feasible to be used, it is recommended to use Tofacitinib

Monoclonal Antibodies

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
• Granted by the US FDA with EUA
• WHO has recommended Tocilizumab or Sarilumab in combination with corticosteroids for patients with severe or critical COVID-19
• 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
• When IV Tocilizumab is not available or not feasible to use, it is recommended to use IV Sarilumab

Vilobelimab 

• An anti-C5a monoclonal antibody, it targets C5a, which is a product of complement activation, and preserves membrane attack complex function
• Has been issued an EUA for the treatment of hospitalized adults with COVID-19 when it is given within 48 hours of mechanical ventilation or ECMO

Anticoagulants

• It is recommended that all patients that have been hospitalized should 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 (SC) or IV 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
• Interferons are for clinical trial use only

• 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

• 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 first-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

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 atelectrauma, 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