Clinical Guidance for Outpatients With Acute Respiratory Illness at Higher Risk of Severe COVID-19 and/or Influenza

Purpose

  • This page provides guidance for patients with acute respiratory illness seen in an outpatient clinic or emergency department who do not require hospital admission.
  • This guidance is based upon local public health surveillance data and testing at local healthcare facilities.

Background

SARS-CoV-2, the virus that causes COVID-19, and influenza viruses as well as other respiratory viruses usually co-circulate during the fall and winter months in most of the United States. Both viruses can cause acute respiratory illnesses with similar signs and symptoms such as fever, chills, cough, malaise, sore throat, and headache. Therefore, the decision to start empiric antiviral treatment can be challenging. Co-infections with SARS CoV-2 and influenza can occur but are not common.

Clinicians should consider several factors when evaluating patients with acute respiratory illness, particularly when influenza and COVID-19 are suspected, to facilitate early antiviral treatment. A thorough medical history to understand recent exposures and risk factors can provide valuable information to direct treatment. A positive test result is not required to initiate antiviral treatment for COVID-19 or influenza, but testing can guide appropriate treatment. Additionally, it is important for clinicians to be aware of the current activity levels of these respiratory pathogens in their local jurisdictions to inform clinical decision making. CDC has developed a respiratory illness data channel to provide real-time data on respiratory virus activity across the United States. These factors can inform clinical suspicion of influenza and COVID-19 and help clinicians diagnose and treat patients appropriately.

Risk for severe disease

Clinicians should especially consider treatment among patients who are at higher risk of severe disease such as hospitalization and death. Age is the most important factor in assessing risk for severe disease for both influenza and COVID-19. Risk for severe disease increases as age increases; persons 65 years and older are at highest risk of hospitalization and death due to influenza or COVID-19. Risk factors for severe influenza include children aged <2 years, adults aged ≥65 years, pregnant persons, and people with certain medical conditions such as chronic lung disease, neurologic and neurodevelopmental conditions, blood disorders, endocrine disorders, heart disease, liver disorders, kidney disease, extreme obesity, and immunocompromising conditions. Certain medical conditions also increase the risk for severe COVID-19 and many are the same as those that increase risk for severe influenza and other respiratory diseases such as respiratory syncytial virus. Studies have shown that risk for severe COVID-19 increases substantially with the presence of multiple medical conditions which commonly occurs in older individuals. Additionally, residents of nursing homes are at increased risk of severe respiratory disease due to influenza and COVID-19. Some racial and ethnic minority groups are at higher risk of severe disease due to multiple barriers accessing health care including lack of insurance, transportation, child-care, or ability to take time off from work.

Clinical judgment is needed to accurately assess a person's risk on a case-by-case basis and determine whether treatment is indicated.

Specimen collection

For specimen collection, it is important to implement recommended infection prevention and control measures and collect respiratory specimens as indicated for influenza and SARS-CoV-2 testing. Two different specimens may need to be collected if multiplex testing for influenza viruses and SARS-CoV-2 is unavailable on-site.

Testing

Testing can support diagnosis and guide appropriate treatment. For patients who are at risk for severe disease, molecular assays, such as nucleic acid detection assays are preferred, however, antigen detection assays can be used if nucleic acid detection assays are not available. Antigen testing may be used to help with diagnostic and treatment decisions for patients in outpatient clinical settings, such as whether to prescribe antiviral medications.

Several types of tests are available for influenza, including rapid molecular assays which have high sensitivity and specificity, and rapid influenza diagnostic tests. Rapid influenza diagnostic tests are antigen detection assays with moderate sensitivity and high specificity. Due to the limited sensitivities, negative results of rapid influenza diagnostic tests do not exclude influenza virus infection in patients with signs and symptoms suggestive of influenza. Therefore, clinicians should consider confirming negative test results with molecular assays, especially during periods of peak community influenza activity.

Comprehensive information about types of SARS CoV-2 tests can be accessed here. Because SARS CoV-2 antigen detection assays have lower sensitivity than SARS CoV-2 nucleic acid detection assays, a negative antigen detection assay result does not necessarily exclude SARS CoV-2 infection. This should be confirmed by a nucleic acid detection assay (preferred) or repeat antigen testing, per , especially during SARS CoV-2 surges.

Because SARS-CoV-2 and influenza virus co-infection can occur, and may result in severe disease, a positive influenza test result without SARS-CoV-2 testing does not exclude COVID-19, and a positive SARS-CoV-2 test result without influenza testing does not exclude influenza when SARS COV-2 and influenza are co-circulating.Multiplex nucleic acid detection assays are ideal to test for both SARS CoV-2 and influenza to guide antiviral treatment decisions.

If tests are negative for both influenza and SARS CoV-2, consider other respiratory pathogens such as respiratory syncytial virus.

Antiviral therapy

Early initiation of antiviral therapy after symptom onset for COVID-19 can reduce progression to severe disease among persons at higher risk for severe disease. Early initiation of antiviral treatment after symptom onset for influenza can reduce the risk of some complications and the duration of illness. In a person who is at higher risk for severe disease with clinical suspicion of influenza or COVID-19, empiric therapy is recommended. Treatment can be initiated for either or both influenza and COVID-19 based on clinical judgment. Antiviral treatment should be started as soon as possible among eligible patients with suspected influenza or COVID-19. A positive test result is not necessary to initiate treatment for influenza or COVID-19 in symptomatic patients. If the patient tests negative by antigen detection assays, further testing by molecular or nucleic acid detection assays may be indicated to refine management.

Treatment of influenza

Keep Reading: Influenza Antiviral Medications: Summary for Clinicians

Antiviral treatment of influenza provides the greatest clinical benefit when treatment is initiated shortly after symptom onset and ideally within 2 days of symptom onset in outpatients. However, for persons with influenza who are at increased risk of severe influenza complications, or those with progressive disease not requiring hospitalization, initiation of antiviral treatment is recommended even when >2 days after symptom onset.

For outpatients with suspected or confirmed uncomplicated influenza, oral oseltamivir, inhaled zanamivir, intravenous peramivir, or oral baloxavir may be used for treatment, depending upon approved age groups and contraindications (see Table 1). For outpatients with complications or progressive disease and suspected or confirmed influenza (e.g., pneumonia, or exacerbation of underlying chronic medical conditions), initiation of antiviral treatment with oral oseltamivir is recommended as soon as possible.

Clinicians may also wish to consult the Infectious Disease Society of America ( and American Thoracic Society ( for further information.

Table 1. Antiviral treatment for outpatients at increased risk for influenza complications.
Influenza Antiviral Treatment Who Route Frequency and Duration Time from Illness Onset Specific Issues
Oseltamivir Persons aged <2 years or ≥65 years, or of any age with high-risk conditions. Oral Twice daily for 5 days As soon as possible, ideally within 2 days Adjust dosing by weight for children. Dosage adjustment needed for reduced creatinine clearance
Baloxavir Otherwise healthy persons aged ≥5 years or ≥12 years with high-risk conditions Oral Single dose As soon as possible, ideally within 2 days Not recommended for pregnant people.
Recommended to use if above medications cannot be used or are unavailable. 
Influenza Antiviral Treatment Who Route Frequency and Duration Time from Illness Onset Specific Issues
Zanamivir Persons aged ≥7 years with high-risk conditions Inhaled Twice daily for 5 days As soon as possible, ideally within 2 days Requires using a disk inhaler device that may be difficult for children and older adults. Not recommended for persons with underlying airways disease.
Peramivir Persons aged ≥6 months to <2 years or ≥2 years with high-risk conditions Intravenous Single IV infusion As soon as possible, ideally within 2 days Dosage adjustment needed for reduced creatinine clearance

Treatment of COVID-19

Keep Reading: COVID-19 Treatment Clinical Care for Outpatients

Antiviral treatment for mild to moderate COVID-19 should be started within 5-7 days of symptom onset among persons at high risk of severe disease, regardless of history of prior infection or vaccination status. among eligible adult outpatients: nirmatrelvir/ritonavir, and remdesivir are preferred options and molnupiravir for whom the preferred options are not accessible or appropriate (see Table 2.). A positive SARS CoV-2 test is not required prior to initiation of treatment. Clinicians should start treatment as soon as possible and not delay initiation for results of testing, especially during surges of SARS CoV-2 activity.

Clinicians may want to consult the for further recommendations for outpatient treatment.

Table 2. COVID-19 antiviral treatment options for outpatients who are at higher risk of progression to severe disease.
COVID-19 Antiviral Treatment Who Route Duration Time from Illness Onset Specific Issues
Adults; children aged 12 years and older and at least 40kg Oral 5 days ≤5 days Adjust dosing in some cases; ; severe kidney and liver contraindications
Adults; children aged 28 days and older and at least 3kg Intravenous 3 days ≤7 days Infusion over 30-120 minutes; infusion over 3 consecutive days; Need to check liver function and prothrombin time before initiation
Recommended to use if above medications cannot be used or are unavailable. 
COVID-19 Antiviral Treatment Who Route Duration Time from Illness Onset Specific Issues
Adults Oral 5 days ≤5 days Women who are able to become pregnant and their partners should use birth control; avoid in pregnant women
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Content Source:
National Center for Immunization and Respiratory Diseases (NCIRD)
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