Treatment Recommendations for Influenza After 48 Hours of Symptom Onset

The Advisory Committee on Immunization Practices (ACIP) recommends that all patients aged 6 months and older be vaccinated against influenza, unless contraindicated.¹Annual influenza vaccination is the first and best way to prevent infection; vaccinations can be given well before an influenza virus exposure occurs and can provide safe and effective immunity throughout the influenza season.

Despite ACIP recommendations, however, the fact remains that less than 50% of the general US population received the flu vaccine during the 2014- 2015 influenza season.¹That being said, having received a flu vaccine does not rule out the possibility of infection in an ill patient with clinical signs and symptoms compatible with influenza.²Seasonal influenza is an acute respiratory illness caused by influenza A or B viruses and is generally characterized by a rapid onset of fever/chills, cough, sore throat, runny or stuffy nose, muscle/body aches, headaches and fatigue.^3,4It is usually a self-limited infection but can be associated with increased morbidity and mortality in certain high-risk populations.⁴

Rates of serious illness and death are highest among persons older than 65 years, children younger than 2 years, and those who have medical conditions that place them at an increased risk for complications. Medical conditions that increase the risk for complications from influenza include chronic pulmonary conditions; cardiovascular, renal, hepatic, hematologic, and metabolic disorders; neurological and neurodevelopment conditions; immunosuppression; morbid obesity (body mass index of 40 or greater); and pregnant or postpartum (within 2 weeks after delivery) women. Populations at risk of complications due to influenza include persons aged 18 years or younger on long-term aspirin therapy, American Indians/Alaska Natives, and residents of nursing homes and other chronic-care facilities.^4-7

Although the recommendations discussed herein focus primarily on outpatient treatment of individual influenza cases, we must note the potential for an influenza pandemic. Due to widespread illness at times of an influenza pandemic, antiviral demand may exceed availability, necessitating changes in treatment recommendations. This includes conservation of antiviral supplies and prioritizing use for those individuals at the highest risk for complications.⁷During the 2009-2010 H1N1 influenza A pandemic, antiviral treatment with oseltamivir was recommended as first-line therapy. Due to increased demands, however, the FDA also authorized the emergency use of peramivir, an investigational neuraminidase inhibitor that is administered intravenously.⁸During the H1N1 pandemic, it was advised that antiviral treatment be reserved for individuals with suspected or confirmed influenza, with severe illness, or at risk for complications.

Diagnostic Testing

Convenient care and office settings often use rapid influenza diagnostic tests (RIDTs) to identify the presence of influenza A and B viruses because these tests yield results in less than 15 minutes. It is important to note that false-negative results are common, especially when influenza activity is high. Tests such as real-time polymerase chain reaction and viral culture have increased accuracy and sensitivity, but time and availability constraints limit the use of these methods.⁹Clinicians use RIDTs as a frequent diagnostic tool during flu season, but they should not replace professional knowledge. It is important that providers continue to exercise clinical judgment and not withhold antiviral treatment for patients with symptoms of influenza due to a negative test, particularly in highrisk populations.^4,5,7

In addition to not withholding treatment based solely on RIDT results, providers must also be mindful of clinical situations when antiviral treatment is not indicated.⁹Testing and treatment are not required for adults who are younger than 65 years who have mild illness and do not have high-risk conditions. Antiviral treatment may be considered in these patients if they present within the first 48 hours of illness; those who present more than 48 hours after illness onset are unlikely to benefit from antivirals and should not be treated with them.⁴In either case, do not delay or withhold treatment while awaiting diagnostic test results for high-risk individuals and those requiring hospitalization who present more than 48 hours after symptom onset.⁴

Antiviral Therapies

There are currently 2 classes of antiviral medications available for the treatment and prevention of influenza: neuraminidase inhibitors (oseltamivir, zanamivir and peramivir) and adamantanes (amantadine and rimantadine). Oseltamivir (Tamiflu), zanamivir (Relenza), and peramivir (Rapivab) can be used to treat both A and B strains of the influenza virus, while amantadine and rimantadine are only effective against influenza A. Due to the high rates of resistance among the influenza A viruses, only neuraminidase inhibitors are recommended for use in the 2015-2016 influenza season.^4,7,10,11

Neuraminidase inhibitor antiviral therapy has the greatest benefit when given within the first 24 to 30 hours and in patients who present with fever, and can shorten the duration of influenza symptoms by approximately one-half day to 3 days.”⁴Currently, the ACIP recommends treatment with antivirals as early as possible for any patient with confirmed or suspected illness who is hospitalized; has severe, complicated, or progressive illness; or is at higher risk for influenza complications, even those with mild illness not requiring hospitalization.^2,4,7,12According to the Centers for Disease Control and Prevention (CDC), “Antiviral treatment might have some benefits in patients with severe, complicated or progressive illness, and in hospitalized patients when started after 48 hours of illness onset.”^2,7

Some studies suggest that antiviral treatment might still be beneficial in hospitalized patients when started up to 4 or 5 days after illness onset. Adequate hydration, ventilation, and prevention of secondary bacterial infection also prove to be critical for the care of severely ill patients with influenza.⁹In the treatment of pregnant women (of any trimester) with influenza A (2009 H1N1) virus infection, antiviral treatment has been shown to be most beneficial in preventing respiratory failure and death when started within less than 3 days of illness onset, but still provided benefit when started 3 to 4 days after onset compared with 5 or more days.²

Concerns regarding trends of increased resistance in both antiviral medications should be considered when deciding which patients to treat.4 During the 2008-2009 influenza season, there were high rates of oseltamivir- resistant strains of the H1N1 virus. Current data also show high rates of resistance among circulating influenza A strains to the adamantane class.^4,7,10,11According to the CDC, “During the 2013-2014 season, 98.2% of the 2009 H1N1 viruses tested for surveillance were susceptible to oseltamivir and 100% of the 2009 H1N1 viruses tested were susceptible to zanamivir.”¹⁰Ongoing surveillance for oseltamivir resistance among influenza viruses is essential for public health since this is the most widely used antiviral medication.

Treatment of influenza with oseltamivir is recommended for 5 days with twice-daily dosing in people 2 weeks of age and older and should be considered first-line treatment during pregnancy.^2,4Oseltamivir has been demonstrated to shorten the duration of influenza symptoms by approximately 1 day and reduce the duration of viral shedding.⁴Zanamivir administration is recommended for 5 days with twice-daily dosing in acute uncomplicated influenza for people aged 7 years and older and should not be used in people with underlying respiratory disease (ie, asthma and chronic obstructive pulmonary disease).^2,7,4It has been shown to shorten the duration of influenza symptoms by 1 to 3 days.⁴

As providers, it is imperative to treat each patient individually, as they will not all present in a “textbook” manner. Treatment plans should be based on a total assessment of the patient to ensure that high-quality, evidence-based care is rendered. Timing from onset of symptoms to presentation for treatment, medical history, and risk/benefit ratio should be considered when deciding whether or not to initiate influenza antiviral treatment. It is important to monitor weekly surveillance of local influenza activity and for circulating strains that may be resistant to current treatment recommendations.

Summary

In summary, the CDC and the ACIP recommend that antiviral treatment be reserved for patients with confirmed or suspected influenza who require hospitalization and/or who have progressive, severe, or complicated illness regardless of previous health or vaccination status. Observational studies have found benefit in early initiation of antiviral treatment (less than 48 hours from symptom onset), as well as when treatment is started up to 5 days after symptom onset, the greatest benefit being with earlier treatment. Empiric antiviral treatment is often warranted and should not be delayed while awaiting diagnostic test results.

Heidi Pantoja, MSN, FNP-C, is a family nurse practitioner for Target Clinic in Davie, Florida. She received her BSN from Barry University and her MSN from Florida Atlantic University. She has been practicing in the retail health setting for 5 years and is currently a market resource and trainer for her colleagues, as well as new providers.Brittany Baker, MSN, FNP-C, is a family nurse practitioner at Target Clinic in Charlotte, North Carolina. She received her BSN from Bowie State University and her MSN from Duke University. Upon graduating from Duke in May 2012, Brittany pursued a career in retail health with Target Clinics. She initially worked as a float nurse practitioner (NP) for Target Clinic, where she focused not only on building her skill set as a new NP but also frequently trained fellow colleagues new to the practice.

References

1. Centers for Disease Control and Prevention. Antiviral drug resistance among influenza viruses. www.cdc.gov/flu/professionals/antivirals/antiviral-drug-resistance.htm. Updated February 25, 2015. Accessed November 11, 2015.
2. Centers for Disease Control and Prevention. Flu symptoms and severity. www.cdc.gov/flu/consumer/symptoms.htm. Updated September 16, 2015. Accessed November 11, 2015.
3. Centers for Disease Control and Prevention. Guidance for clinicians on the use of rapid influenza diagnostic tests. www.cdc.gov/flu/professionals/diagnosis/clinician_guidance_ridt.htm. Updated October 13, 2015. Accessed November 11, 2015.
4. Centers for Disease Control and Prevention. Influenza antiviral drug resistance. www.cdc.gov/flu/about/qa/antiviralresistance.htm. Updated September 16, 2015. Accessed November 11, 2015.
5. Centers for Disease Control and Prevention. Influenza antiviral medications: summary for clinicians. www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm. Updated November 3, 2015. Accessed November 11, 2015.
6. Centers for Disease Control and Prevention. People at high risk of developing flu-related complications. www.cdc.gov/flu/about/disease/high_risk.htm. Updated January 8, 2015. Accessed November 11, 2015.
7. Centers for Disease Control and Prevention. What you should know about flu antiviral drugs. www.cdc.gov/flu/antivirals/whatyoushould.htm. Updated September 16, 2015. Accessed November 11, 2015.
8. Fiore AE, Fry A, Shay D, Gubareva L, Bresee JS, Uyeki TM; Centers for Disease Control and Prevention. Antiviral agents for the treatment and chemoprophylaxis of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Report. 2011;60(1):1-24.
9. Harper SA, Bradley JS, Englund JA, et al; Expert Panel of the Infectious Diseases Society of America. Seasonal influenza in adults and children—diagnosis, treatment, chemoprophylaxis, and institutional outbreak management: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis. 2009;48(8): 1003-1032. doi: 10.1086/598513.
10. Thorner AR. Treatment and prevention of pandemic H1N1 influenza (“swine influenza”). UpToDate website. www.uptodate.com/contents/treatment-and-prevention-of-pandemic-h1n1-influenza-swine-influenza. Updated November 25, 2014. Accessed November 11, 2015.
11. Wappes J. CDC: Flu vaccine coverage up a bit in 2014-15. Center for Infectious Disease Research and Policy website. www.cidrap.umn.edu/news-perspective/2015/09/cdc-flu-vaccine-coverage-bit-2014-15. Published September 17, 2015. Accessed November 11, 2015.
12. Zachary KC. Treatment of seasonal influenza in adults. UpToDate website. www.uptodate.com/contents/treatment-of-seasonal-influenza-in-adults. Updated August 31, 2015. Accessed November 11, 2015.