Guidelines for early empiric antiviral treatment in persons with suspected influenza

[H1N1]),” the guidelines authors write. “Among people who become infected with 2009 H1N1, certain groups appear to be at increased risk of complications and may benefit most from early treatment with antiviral medications. Based on currently available data, approximately 70% of persons hospitalized with 2009 H1N1 influenza have had a recognized high risk condition.”

High-risk groups include children younger than 2 years, adults 65 years or older, and pregnant women and those up to 2 weeks after delivery or miscarriage. In addition, persons at high-risk include those with immunosuppression; disorders compromising respiratory tract function or handling of respiratory secretions or increasing risk for aspiration; or chronic pulmonary (including asthma), cardiovascular (except hypertension), renal, hepatic, hematologic (including sickle cell disease), or metabolic diseases (including diabetes mellitus).

Updated Guidelines

Updates since the September 22, 2009, guidelines include the following:

• The guidelines authors elucidate considerations for treatment and chemoprophylaxis in persons vaccinated with the 2009 H1N1 and seasonal influenza vaccines.
• In addition to pregnant women, those up to 2 weeks postpartum or after a miscarriage are now included as being at increased risk for complications from 2009 H1N1 influenza.
• For children younger than 1 year, additional oseltamivir dosing instructions are given.
• Adverse events and contraindications associated with use of oseltamivir and zanamivir are reviewed.

The guidelines note that antiviral medications can decrease the severity and duration of influenza illness and can lower the risk for severe illness, mortality, and other complications. Treatment or prophylaxis with antiviral medications is not necessary for most healthy individuals with an illness consistent with uncomplicated influenza or for those who appear to be recovering from influenza. Severe symptoms, including evidence of lower respiratory tract infection or clinical deterioration, in persons of any age or previous health status presenting with suspected influenza should mandate prompt empiric antiviral therapy.

All persons hospitalized for suspected or confirmed influenza should be treated with oseltamivir or zanamivir. Persons with suspected or confirmed influenza who are at higher risk for complications should be considered for early empiric treatment with oseltamivir or zanamivir.

Compared with older children and adults, children aged 2 to 4 years are more likely to need hospitalization or urgent medical evaluation for influenza. However, the risk is still much lower vs children younger than 2 years, and antiviral treatment is not necessarily needed for children aged 2 to 4 years with mild illness and without high-risk conditions.

When antiviral treatment is indicated, it should be started as soon as possible because maximal benefits ensue when patients begin treatment within the first 2 days of illness, although some studies of patients hospitalized for seasonal and 2009 H1N1 influenza have shown possible benefit of antiviral therapy started later than 48 hours after symptom onset.

Measures to minimize delays in starting treatment may include educating individuals who are at higher risk for influenza complications of the signs and symptoms of influenza and the need for early treatment as soon as possible after onset of influenza symptoms such as fever or respiratory tract symptoms. In addition, these patients and those who report severe illness should have rapid access to telephone consultation and clinical evaluation. Empiric treatment based on telephone contact may be considered for patients at higher risk for influenza complications, if hospitalization is not needed, and if this will result in markedly less delay before treatment is started.

Because a negative rapid test result for influenza does not rule out influenza, treatment should not be delayed pending laboratory confirmation of influenza. Sensitivity of rapid tests ranges from 10% to 70% for detection of 2009 H1N1.

In accordance with guidelines from local and state health departments, real-time reverse transcriptase-polymerase chain reaction testing for 2009 H1N1 influenza infection should be prioritized for individuals with suspected or confirmed influenza requiring hospitalization.

Consideration for antiviral chemoprophylaxis should usually be limited to individuals at greater risk for influenza-related complications who have been exposed to someone likely to have been infected with influenza. After a suspected exposure, however, early treatment may be an option preferred vs chemoprophylaxis.

Those persons at high risk who are household or close contacts of confirmed or suspected influenza cases can be educated regarding the early signs and symptoms, and if these develop, they can be instructed to contact their healthcare provider immediately for evaluation and possible early treatment. When vaccinated persons have a suspected exposure, early recognition of illness and treatment when indicated are preferred vs chemoprophylaxis.

Circulating Viruses

In the 2009-2010 influenza season, the most common influenza viruses among those circulating are likely to be 2009 H1N1 influenza viruses, especially in younger age groups, but circulation of seasonal influenza viruses is also anticipated. These predictions are based on global experience to date, but the timing and intensity of seasonal influenza virus vs 2009 H1N1 circulation may not be accurately predicted in advance.

The 2009 H1N1 viruses now circulating are susceptible to oseltamivir and zanamivir but are resistant to amantadine and rimantadine. Based on new antiviral resistance or viral surveillance data, however, recommended antiviral treatment regimens may change accordingly. The updated guidelines contain information on the dose and dosing schedule for oseltamivir and zanamivir. The emergency use of oseltamivir in children younger than 1 year is reviewed in an  Emergency Use Authorization.

Clinical Context

The CDC guidelines issued October 16, which update those from September 22, 2009, aim to help clinicians prioritize use of antiviral medications for hospitalized patients and those at higher risk for influenza complications during the 2009 to 2010 season. As of October 3, a total of 99% of circulating influenza viruses in the United States were 2009 H1N1 influenza.

Updates since the September 22, 2009, guidelines include the following:

• Expanded considerations for treatment and chemoprophylaxis in persons vaccinated with the 2009 H1N1 and seasonal influenza vaccines.

• A new recommendation that women up to 2 weeks postpartum or after a miscarriage should be considered to be at increased risk for complications from 2009 H1N1 influenza.

• Additional oseltamivir dosing instructions for children younger than 1 year.

• A review of adverse events and contraindications associated with use of oseltamivir and zanamivir.

Study Highlights

•           Dosing recommendations for antiviral treatment or chemoprophylaxis with oseltamivir for children younger than 1 year are as follows:

o          Recommended treatment dose for infants younger than 3 months is 12 mg twice daily for 5 days.

o          Because of limited data on use of oseltamivir in infants younger than 3 months, prophylaxis is not recommended unless the situation is judged to be critical.

o          For infants aged 3 to 5 months, recommended treatment dose is 20 mg twice daily for 5 days, and recommended prophylaxis dose is 20 mg once daily for 10 days.

o          At ages 6 to 11 months, recommended treatment dose is 25 mg twice daily for 5 days, and recommended prophylaxis dose is 25 mg once daily for 10 days.

o          Prescribers should specify the concentration (eg, oral suspension 12 mg/mL) if prescribing in milliliters or teaspoons, or to prescribe the dose in milligrams.

•           Oseltamivir and zanamivir are generally well tolerated.

•           Compared with placebo, oseltamivir is more often associated with reports of nausea and vomiting in adults (nausea without vomiting, approximately 10% vs 6%; vomiting, approximately 9% vs 3%).

•           In children, 14% of those treated with oseltamivir had vomiting vs 8.5% of placebo recipients.

•           Sorbitol contained in oseltamivir suspension may cause diarrhea and abdominal pain in fructose-intolerant patients.

•           Zanamivir is an inhaled formulation that may induce bronchospasm, and it is therefore not recommended in patients with underlying pulmonary disease.

•           Zanamivir should be used only as directed, with use of the Diskhaler device provided with the drug product.

•           Commercially available zanamivir (Relenza Inhalation Powder; GlaxoSmithKline) uses a lactose drug carrier and should not be used in any nebulizer or mechanical ventilator because the lactose sugar may obstruct proper functioning of mechanical ventilator equipment.

•           Both oseltamivir and zanamivir have been associated with allergic reactions (rash, face or tongue swelling, or anaphylaxis).

•           Transient neuropsychiatric events (self-injury or delirium) with oseltamivir and zanamivir have rarely been reported in postmarketing surveillance, mostly in children and adolescents living in Japan.

•           However, influenza itself may cause neurologic and behavioral symptoms, so any causal role of the neuraminidase inhibitors in these symptoms is unclear.

•           Retrospective analyses to date have not shown an increased risk for neuropsychiatric events after oseltamivir use.

•           The FDA recommends that persons receiving neuraminidase inhibitors be monitored for abnormal behavior until additional data are available.

•           Healthcare professionals should promptly report all serious adverse events seen after use of antiviral medication to Ministry of Health.

Clinical Implications

•           The new CDC guidelines contain dosing recommendations for antiviral treatment (for 5 days) or chemoprophylaxis (for 10 days) with oseltamivir for children younger than 1 year. Because of limited data on use of oseltamivir in infants younger than 3 months, prophylaxis is not recommended in this age group unless the situation is judged to be critical.

•           Oseltamivir and zanamivir are generally well tolerated. Oseltamivir use may be associated with nausea and vomiting. Zanamivir is an inhaled formulation that may induce bronchospasm, and it is not recommended in patients with underlying pulmonary disease. Both drugs have been associated with allergic reactions.