Coronavirus Disease 2019 (COVID-19) Management

Evaluation

Mild to Moderate COVID-19 (Non-severe COVID-19 or Clinical Stage 1 to 3)

Mild disease is characterized by the absence of pneumonia or hypoxia and abnormal chest imaging findings. It includes the presence of acute onset of fever or cough with ≥3 of the following: Fever, cough, coryza, sore throat, diarrhea, anorexia or nausea or vomiting, loss of sense of smell or taste, general weakness or body malaise or fatigue, headache, and myalgia.

Moderate disease features evidence of lower respiratory disease clinically or in imaging with oxygen saturation (SpO₂) of ≥94% on room air at sea level and respiratory rate of <30 breaths/minute. 

Severe COVID-19 (Clinical Stage 4)

Patients with severe disease exhibit severe pneumonia clinically and in diagnostic exams. Dyspnea, hypoxia, and/or >50% lung involvement on imaging are present and oxygen saturation is <90% on room air.

Patients with severe COVID-19 disease have signs of severe respiratory distress and present as follows:

• Adult: Use of accessory muscle, unable to complete full sentences, respiratory rate of >30 breaths/minute
• Children: Very severe chest wall in-drawing, grunting, central cyanosis, unable to breastfeed or drink, lethargy, convulsions, or reduced level of consciousness

Critical COVID-19 (Clinical Stage 5)

Patients with critical COVID-19 disease have pneumonia and impending respiratory failure that requires high-flow oxygen, non-invasive or invasive ventilation, acute respiratory distress syndrome, sepsis or shock, deteriorating sensorium, or multi-organ failure.

Comorbidities

There is an increased risk for severe COVID-19 illness in adult patients of any age with certain underlying conditions. There is currently limited data and information on the effects of many comorbidities on the risk for severe COVID-19 illness. It is essential that those people at increased risk of severe illness of COVID-19 and those who live with them protect themselves from getting COVID-19.

Asthma 

Systematic reviews have shown that people with asthma are not at increased risk of acquiring COVID-19. However, there is an increased risk of COVID-19 deaths in asthmatic patients who recently needed treatment with oral corticosteroids. 

It is recommended that patients with severe asthma continue to take biologic therapy or oral corticosteroids if prescribed. When asthma worsens, it is recommended to increase controller and reliever medications. If appropriate, a short course of oral corticosteroids can be taken for patients with severe asthma exacerbations. Nebulizers should be avoided, where possible, in order to avoid the spread of the virus. It is preferred to use a pressurized metered-dose inhaler via a spacer except for life-threatening exacerbations. In patients with confirmed or suspected COVID-19, spirometry should be avoided.

Cardiovascular Disease*

COVID-19 patients with cardiovascular comorbidities are common and they have a higher risk of morbidity and mortality. Thus, cardiovascular disease prevention strategies are essential, especially strategies that bring a wide spectrum of possible beneficial effects.

SARS-CoV-2 counteracts the effects of angiotensin II in conditions with excessive activation of the renin-angiotensin system. More than 25% of critical cases of COVID-19 exhibit myocardial injury and present as acute myocardial injury and dysfunction on presentation and myocardial injury develops as illness severity intensifies. It can be caused by direct myocardial injury associated with upregulation of ACE2 in the heart and coronary vessels, or it can be secondary to molecular mimicry following the activation of adaptive autoimmune-type mechanisms or be exacerbated by hypoxia in the context of respiratory failure.

It is recommended to continue clinically indicated ACE inhibitor and angiotensin receptor blocker (ARB) medications at this time.

Case series data have shown that there is a massive inappropriate activation of the coagulation cascade that occurs in COVID-19 patients. Low-molecular-weight Heparin or Fondaparinux has been recommended in hospitalized COVID-19 patients.

*Please see Cardiovascular Disease Prevention disease management chart for further information.

Hypertension*

Hypertension is the most frequent comorbidity in COVID-19 patients. It is believed that the use of ACE inhibitors contributes to the entry of SARS-CoV-2 in the cells but present data show no association between COVID-19 and hypertension. No clinical data showed beneficial or adverse outcomes in those who used ACE inhibitors, ARBs, or other renin-angiotensin-aldosterone system antagonists in COVID-19.

It is recommended to continue clinically indicated ACE inhibitor and ARB medications at this time, and until further information becomes available, it is recommended to treat hypertensive patients based on current clinical practice guidelines.

*Please see Hypertension disease management chart for further information.

Diabetes Mellitus

Individuals with diabetes with poor glycemic control have a high risk of severe illness or poor prognosis from COVID-19. Mechanisms that can increase the ability of COVID-19 to impact patients with diabetes include decreased viral clearance, diminished function of T-cells, increased susceptibility to hyperinflammation and cytokine storm, and the presence of cardiovascular disease.

The poorer prognosis of patients with diabetes might be caused by the syndromic nature of the disease and the presence of hyperglycemia, older age, and comorbidities (in particular hypertension, obesity, and cardiovascular disease) that increase the risk.

For patients with mild COVID-19, glucose-lowering therapies should be continued, and blood glucose monitoring should be performed. In hospitalized patients with severe COVID-19, there might be a need to modify their diabetes therapy including withdrawing ongoing treatments and initiating insulin therapy depending on the severity of the COVID-19 disease.

Insulin and dipeptidyl peptidase-4 (DPP-4) inhibitor therapy may be continued in patients with COVID-19. Antiviral drugs such as Lopinavir and Ritonavir may lead to hyperglycemia and may worsen glycemic control. Glucocorticoid use may cause worsening of insulin resistance or glycemic control, sustaining gluconeogenesis, and marked hyperglycemia.

Dyslipidemia

Generally, all individuals on lipid-lowering therapy should continue medications even during the pandemic or in patients with an increased risk of COVID-19 infection. In patients with confirmed COVID-19, lipid-lowering therapy may still continue with care on the avoidance of drug interaction between lipid-lowering medications and drugs that are being used for the treatment of COVID-19, especially in patients with abnormal liver function tests.

Statin therapy initiation may be considered in high-risk patients during severe manifestations of COVID-19 to prevent some of the life-threatening cardiovascular complications. Some studies have shown that statin therapy helps in plaque stabilization, cholesterol reduction, cardiovascular risk prevention, and inflammation reduction. They also have potential antiviral properties.

Obesity

Obesity has been associated with more severe illness of COVID-19 and death. Abdominal fat has a detrimental ventilatory effect as there is a need for more mechanical ventilation for those with a body mass index (BMI) of >35 kg/m² than those with a BMI of <25 kg/m².

Intravascular disseminated coagulation may develop causing impaired lung perfusion in patients with severe COVID-19. Obesity is associated with immune dysregulation and chronic inflammation that could cause organ failure in patients with COVID-19.

SARS-COV-2 Reinfection and Breakthrough Infection

Reinfection

Repeat testing for evaluation of reinfection should be considered only for those patients who have fully recovered from the initial SARS-CoV-2 infection but present with symptoms compatible with COVID-19 with no obvious alternative etiology.

Reinfection often occurs in those with weak immune response during the initial infection, as is usually reported in those with mild illness. It may also occur as initial immune responses wane over time. The majority of cases occurred in individuals who were unvaccinated and there were a few patients who were symptomatic during reinfection than during the initial infection. Treatment of reinfection is the same as that for initial infection.

Breakthrough Infection

Breakthrough infection is the infection that occurs in patients who completed the primary vaccine series and is less likely to lead to severe illness than in infection in unvaccinated individuals. The treatment is the same as that for an initial infection. 

Principles of Therapy

Mild to Moderate COVID-19 

The main goal of treatment in mild to moderate COVID-19 disease 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.

The 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 among these patients.

Severe COVID-19

In patients with severe COVID-19 disease, the site of treatment should have a pulse oximeter, functioning oxygen systems, and 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 an SpO₂ of <90%.

Fluid management should be used cautiously in patients without tissue hypoperfusion and fluid responsiveness. The use of nebulizers is not recommended. Antivirals, immune-modulation therapies, including corticosteroids, may be indicated for severe COVID-19 and can be given to hospitalized patients with severe COVID-19.

Nonpharmacological

Isolation

Isolation is the separation of infected COVID-19 patients from those who are not infected. Isolation should be determined on the basis of clinical symptoms. Isolate individuals with COVID-19 symptoms who can recover at home.  Asymptomatic COVID-19-positive patients are not required to isolate but should consider isolation as testing positive is a marker of contagiousness. Patients who did not undergo isolation are advised to wear a mask in public for 5 days after testing positive for SARS-CoV-2.

During isolation, the patient should monitor symptoms and if there are warning signs, seek emergency care. Warning signs include difficulty breathing, persistent or new-onset fever, RR >25, persistent pressure or pain in the chest, new confusion, inability to wake or keep awake, and bluish lips or face.

If possible, stay in a separate room from other members of the household and use separate bathrooms during isolation. Avoid contact with other members of the household and pets and do not share personal household items (eg cups, towels, utensils). Advise patients to wear a mask if around other people.

Criteria for Releasing COVID-19 Patients from Isolation

Symptomatic patients may be released from isolation after fever resolution for at least 24 hours without fever-reducing medications and if there is improvement of other symptoms. Prevention strategies (eg masking , distancing, enhancing hygiene practices) are encouraged for 5 days after isolation. 

Severely ill and immunocompromised patients may be released from isolation at least 10 days up to 20 days after symptom onset as they may produce replication-competent virus beyond 10 days or may need additional testing and infectious disease expert consultation for an appropriate duration of isolation and precautions. 

Other Therapy

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 oxygen over noninvasive positive pressure ventilation (NIPPV). If there is no indication for endotracheal intubation, it is recommended to monitor the trial of NIPPV for adults with COVID-19 and acute hypoxemic respiratory failure if a high-flow nasal cannula 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 to use 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 acute respiratory distress syndrome, it is recommended to use low tidal volume (VT 4 to 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. The routine use of inhaled nitric oxide is not recommended.

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Pharmacological therapy

Antivirals

Remdesivir

Remdesivir is a monophosphate prodrug that binds to viral RNA-dependent RNA polymerase and inhibits viral replication through premature termination of RNA transcription. It is the first United States Food and Drug Administration (US FDA)-approved COVID-19 treatment for adults and children. It may also be given to term neonates from birth to <28 days old weighing at least 1.5 kilograms. It should only be administered in the hospital or in a healthcare facility capable of providing acute care. 

It is 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 devices, non-invasive ventilation, or extracorporeal membrane oxygenation.

It is recommended by the WHO Guideline Development Group (GDG) as a treatment option for patients with non-severe illness at the highest risk of hospitalization and severe COVID-19 but not for patients with critical COVID-19.

Remdesivir with Baricitinib

Remdesivir with Baricitinib is 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 extracorporeal membrane oxygenation.

Molnupiravir

Molnupiravir is an oral potent ribonucleoside analog authorized by the 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 one risk factor for developing severe illness, such as obesity, older age (>60 years old), diabetes mellitus, and heart disease.

It is given conditional recommendation by the WHO for patients with non-severe COVID-19 who are at the highest risk of hospitalization, except for children, pregnant, and breastfeeding women. It is also recommended as an alternative therapy to Ritonavir-boosted Nirmatrelvir or Remdesivir. It 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 the cessation of viral replication while Ritonavir slows down Nirmatrelvir's breakdown for it to remain in the body for longer periods at higher concentrations. Nirmatrelvir must be co-administered with Ritonavir.

This combination is recommended by the WHO in patients with non-severe COVID-19 at the highest risk of hospitalization. It is 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. The use of Nirmatrelvir/Ritonavir as a therapy option that was granted EUA for the treatment of mild to moderate COVID-19 in children aged ≥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.

It is recommended to initiate oral therapy as soon as the diagnosis of COVID-19 is obtained and within 5 days of symptom onset. Three tablets (2 tablets of Nirmatrelvir and 1 tablet of Ritonavir) are taken together twice a day for a maximum of 5 days.

Corticosteroids

Corticosteroids inhibit multiple inflammatory cytokines resulting in decreased edema, capillary leakage, and migration of inflammatory cells, thereby globally suppressing the inflammatory response. It is recommended by WHO for patients with severe or critical COVID-19.

Dexamethasone is recommended as the primary immunomodulator in all patients who require high-flow cannula oxygen, noninvasive ventilation, mechanical ventilation, or extracorporeal membrane oxygenation. 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.

Cytotoxic T-Lymphocyte-Associated Antigen 4 (CTLA-4) Agonists

Abatacept

Abatacept is a CTLA-4 protein receptor that is expressed by activated T cells. It modulates the excessive T cell stimulation and proliferation that is believed to propagate the pathogenesis of COVID-19. In clinical trials, it has been evaluated for the treatment of hospitalized patients with moderate to severe COVID-19. It is currently not approved by US FDA for this indication.  

Disease-Modifying Anti-rheumatic Drugs

Baricitinib

Baricitinib is a US-FDA-approved Janus kinase inhibitor that was recently granted EUA by the US FDA that can be given alone even without Remdesivir. It is indicated for the 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 extracorporeal membrane oxygenation.

It is recommended by WHO for patients with severe or critical COVID-19 in combination with corticosteroids as an alternative to interleukin (IL)-6 receptor blockers. When Baricitinib is not available or not feasible to be used, it is recommended to use Tofacitinib.

Monoclonal Antibodies

Regdanvimab

Regdanvimab is a recombinant human IgG1 monoclonal antibody that binds to the receptor-binding domain of the spike proteins of SARS-CoV-2. It is given EUA by Indonesia's National Agency of Drug and Food Control. It 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

Tocilizumab is a US-FDA-approved recombinant humanized anti-human IL-6 receptor monoclonal antibody that specifically binds sIL-6R and mIL-6R and inhibits signal transduction. It is 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 the intensive care unit (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 its use in patients who are significantly immunocompromised or for 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 intravenous Tocilizumab is not available or not feasible to use, it is recommended to use IV Sarilumab.

Vilobelimab

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

Tumor Necrosis Factor (TNF) -Alpha Inhibitor

Infliximab

Infliximab is a TNF-alpha inhibitor that is a pleiotropic proinflammatory cytokine that is mainly activated by macrophages, lymphocytes and natural killer cells. It has been hypothesized that if the action of TNF-alpha has been modulated, it will reduce the duration or severity of COVID-19. Infliximab was evaluated for treatment of patients that have been hospitalized with moderate to severe COVID-19. It is currently not approved by US FDA for this indication.

Anticoagulants

It is recommended that all patients who 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. A 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 the 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 the trial showed increased viral decline and an 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. 

Prevention

Hand Hygiene

The most effective action to be taken to reduce the spread of pathogens and prevent infections is hand hygiene. It is recommended to avoid touching eyes, nose, and mouth with unwashed hands and to wash hands with soap and water whenever possible, especially after coughing or sneezing; when caring for the sick; before, during, and after preparing food; before eating; after toilet use; when hands are visibly dirty; and after handling animals or animal waste. Additionally, frequently touched objects and surfaces should be cleansed and disinfected. 

Hand sanitizers are used if handwashing is not possible and should contain at least 60% alcohol. They should be applied properly by rubbing the gel over all surfaces of the hands and fingers until the hands are dry.  

It has been shown in the evidence from both the severe acute respiratory syndrome (SARS) and COVID-19 epidemics that hand hygiene is very important to protect healthcare workers from getting infected. Plain soap is effective at inactivating enveloped viruses such as the COVID-19 virus due to the oily surface membrane that is dissolved by soap thus killing the virus. The duration of alcohol-based hand rubbing is 20 to 30 seconds while handwashing with soap and water should be 40 to 60 seconds. 

Face Masks

It is recommended that a face mask be worn in public settings, like in public and mass transportation, at events and gatherings, and anywhere that the person will be around other people. It is important to cover cough or sneeze with a tissue, then throw the used tissue in the trash. It is used for either protection of healthy persons or to prevent onward transmission.  

A medical face mask is recommended for healthcare workers in clinical settings, any person who is feeling unwell including those with mild symptoms (ie muscle aches, slight cough, sore throat, or fatigue), COVID-19-positive individuals or those awaiting the result of COVID-19 test, those caring for suspected or confirmed COVID-19 patients outside of health facilities, those aged ≥60 years old, and those at any age who have underlying conditions including chronic respiratory disease, cardiovascular disease, cancer, obesity, immunocompromised status, and diabetes mellitus.  

Non-medical fabric masks are recommended for the general public under the age of 60 and who do not have underlying health conditions.  

A fabric mask should have a good filtration rate, cover the nose and mouth completely, snugly fit against the side of the face without gaps, and have ≥2 layers of washable, breathable fabric. The inner layer should be an absorbent material, such as cotton; the middle layer should be a non-woven non-absorbent material, such as polypropylene; and the outer layer should be a non-absorbent material, such as polyester or polyester blend.  

Medical or surgical masks should consist of three layers of synthetic non-woven materials, be configured to have filtration layers sandwiched in the middle, be available in different thicknesses, and have various levels of fluid resistance and filtration.    

Respirators (also known as filtering facepiece [FFP] respirators) are available at different performance levels ie FFP2, FFP3, N95, and N99. They are used to protect healthcare workers who provide care to COVID-19 patients in settings and areas where aerosol-generating procedures are undertaken. Before using the respirator, healthcare workers should be fit tested to ensure that they wear the correct size.  

Medical masks and respirator masks have similar protection values. The hands should be washed before putting on a mask and the mask should not be touched while wearing it. In taking off the mask, handle only by the ear loops or ties then fold the outside corners together and dispose properly. In washing the mask, regular laundry detergent and the warmest appropriate water setting for the cloth used to make the mask should be used then it is left in the dryer until completely dry. Masks or respirators with exhalation valves are not recommended.

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• N95 respirator (or equivalent or higher-level respirator) or facemask (if a respirator is not available) should be worn before entry into the patient’s room; should be removed and disposed of properly upon exiting the patient’s room and hand hygiene should be done
• Eye protection using goggles or a face shield that covers the front and sides of the face should be worn before entering the patient’s room; it should be compatible with the respirator
• Gloves that are clean and non-sterile should be worn before entry into the patient’s room; should be removed and disposed of properly upon exiting the patient’s room and hand hygiene should be done; double gloving is not recommended
• An isolation gown that is clean should be worn before entry into the patient’s room; and should be removed and disposed of properly upon exiting the patient’s room and hand hygiene should be done; wearing >1 gown at a time is not recommended

Antiviral

Ensitrelvir  

Ensitrelvir inhibits the SARS-CoV-2 main protease and is approved by the US FDA for post-exposure prophylaxis against COVID-19 in adults and adolescents 12 years of age and older following contact with an infected individual. In a randomized, double-blind, placebo-controlled multinational trial in asymptomatic adults and pediatric patients 12 years and older who were household contacts of an individual with COVID-19, administration of the drug reduced the risk of confirmed symptomatic COVID-19 through day 10 by 67% compared with placebo.

COVID-19 Vaccines

From 2020 up to April 2025, a total of 13.64 billion vaccine doses has been administered worldwide as per WHO data. WHO initially had four types of COVID-19 vaccines (ie inactivated, mRNA, protein subunit, viral vector), currently, only the mRNA and protein subunit COVID-19 vaccines are updated to Omicron-adapted formulations.

Coronavirus Disease 2019 (COVID-19)_Management