Sections

Treatment

Approach Considerations

As with other diseases, prevention of influenza is the most effective strategy. The Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC) publishes recommendations for high-risk groups.

Selected patients may benefit from the use of antiviral agents. The ACIP also publishes recommendations on the use of antiviral agents for prevention and treatment of influenza.^[2]Early antiviral therapy must be considered among hospitalized children diagnosed with or suspected to have influenza, especially if they have risk factors such as asthma, cardiac problems, or other conditions, to prevent severe complications and prolonged hospitalization. Influenza vaccination also must be encouraged to prevent the infection.^[47]

One study analyzed the clinical data of adult patients with pandemic H1N1 2009 infection admitted to the ICU. Most of the 18 patients analyzed were obese and presented with severe respiratory distress and hypoxia in the summer months. A higher dose of oseltamivir (150 mg twice daily) and nonconventional modes of ventilation may have improved the outcome in these patients. The rapid influenza detection test (RIDT) had a 76% false-negative result; however, the infection was later confirmed with real-time reverse transcriptase polymerase chain reaction (rRT-PCR). These results suggest that early and aggressive treatment action should be taken in patients with a high clinical suspicion of severe influenza infection.^[48]

Supportive Care

Influenza symptoms may last longer than 1 week. Caregivers can relieve and soothe children's aches and pains with basic supportive care. Acetaminophen may be administered for fever and relief of other symptomatology. (Caution: In children < 16 y who have symptoms of influenza infection or colds, aspirin is not recommended because of an association with Reye syndrome.)

Use cough suppressants and expectorants to treat the cough. Steam inhalations may also be useful. If dehydration occurs, administration of oral or intravenous fluids is indicated.

Antiviral Therapy

Antiviral agents available for influenza treatment and/or prevention include neuraminidase inhibitors (oseltamivir, peramivir, zanamivir) and the cap-dependent endonuclease inhibitor (baloxavir marboxil).^{[8, 49, 50, 51]}The use of adamantanes, such as amantadine, has not been recommended since the 2005-2006 influenza season owing to resistance among influenza A viruses.^[52] The use of adamantanes, such as amantadine, has not been recommended since the 2005-2006 influenza season owing to resistance among influenza A viruses.

The Infectious Disease Society of America (IDSA) Guidelines for Antiviral Therapy

IDSA latest guidelines for antiviral therapy are as follows:^[53]

High risk individuals

Clinicians should initiate antivirals as soon as possible for adults and children with documented or suspected influenza, irrespective of influenza vaccination history, with the following:

Hospitalized with influenza, regardless of illness duration before hospitalization
Outpatients with severe or progressive illness, regardless of illness duration
Children younger than 2 years and adults aged 65 years or older
Women who are pregnant or within 2 weeks postpartum

Individuals not at high risk

Clinicians may consider antivirals for individuals with documented or suspected influenza, irrespective of influenza vaccination history, who are:

Outpatients with illness onset 2 days or less
Symptomatic outpatients with household contacts at high risk
Symptomatic healthcare providers who care for patients at high risk, particularly those who are severely immunocompromised

Baloxavir marboxil

Baloxavir marboxil was approved by the FDA in October 2018 for use in adults and adolescents aged 12 years or older as a single weight-based oral dose for use within 48 hours of symptom onset. It is a prodrug which inhibits cap-dependent endonuclease, an enzyme specific to influenza, resulting in inhibition of viral replication. In clinical trials, single-dose baloxavir is safe and effective in treating patients with uncomplicated influenza. It is active against influenza A and B including strains resistant to neuraminidase inhibitors.

Initial approval of baloxavir marboxil was based on the CAPSTONE-1 trial (N=1436). Patients aged 12 to 64 years were randomized to receive baloxavir, oseltamivir, or placebo. Of the 1064 patients included in the intention-to-treat infected population, the median time to alleviation of symptoms was 53.7 hours in the baloxavir group compared with 80.2 hours for placebo (P< .001). Similar results were observed shown with oseltamivir compared with placebo. Additionally, the baloxavir group had a significant decrease in viral load after 1 day of treatment compared with both placebo (P< .05) and oseltamivir (P< .05) groups.^[51]It is undetermined whether the rapid drop in viral load decreases the risk of virus transmission.

In August 2022, the indication for treatment and post-exposure prophylaxis was extended to include otherwise healthy children aged 5 years and older. The phase 3 miniStone-2 trial compared incidence and severity of adverse effects of baloxavir marboxil with oral oseltamivir in children. Single-dose baloxavir marboxil had a similar incidence of adverse effects compared with oseltamivir (46.1% vs 53.4%). The most common adverse effects in each group were vomiting and/or diarrhea. No serious adverse effects were observed.^[54]

The indication for post-exposure prophylaxis showed a significant prophylactic efficacy compared with placebo. A total of 752 household contacts of 545 index patients were randomly assigned to receive baloxavir or placebo. Among the index patients, 95.6% had influenza A virus infection, 73.6% were younger than 12 years of age, and 52.7% received baloxavir. Among the participants who could be evaluated (374 in the baloxavir group and 375 in the placebo group), the percentage in whom clinical influenza developed was significantly lower in the baloxavir group than in the placebo group (1.9% vs 13.6%; P< .001).^[55]

Oseltamivir and zanamivir

Inhibitors of influenza virus neuraminidase, an enzyme that releases viral particles from the plasma membrane of infected cells, reduce release of the virus and its spread. Oseltamivir (Tamiflu) is approved by the US Food and Drug Administration (FDA) for treatment and prophylaxis of influenza types A and B and is effective in treating avian influenza.^[50]Oseltamivir resistance has been rarely reported in pandemic H1N1 influenza virus and avian influenza A/H5N1 virus.^{[12, 56]}

Oseltamivir resistance emerged in the United States during the 2008-2009 influenza season. Because of this, zanamivir (Relenza) was recommended as the initial choice for antiviral prophylaxis or treatment when influenza A infection or exposure was suspected. However, as of March 2011, all US seasonal influenza viruses tested for resistance by the CDC were susceptible to neuraminidase inhibitors.^[56]

Zanamivir and oseltamivir are approved by the FDA for both prophylaxis and treatment of influenza A and B. When used for treatment, these agents can reduce the duration and severity of illness. They should be started as soon as possible after the onset of symptoms, but no later than 2 days after onset.

In an analysis of medical record data from 784 children hospitalized in intensive care units with laboratory-confirmed influenza during the 2009 H1N1 pandemic and postpandemic periods, early treatment with neuraminidase inhibitors (NAIs) (≤48 h of illness) improved survival. NAIs were administered to 90% of patients during the pandemic period and 63% of patients during the postpandemic period.^{[57, 58]}

Of the 653 children who received NAI treatment, 38 (6%) died, relative to 11 (8%) of the 131 children who did not receive NAIs. In multivariate analyses adjusted for variables (eg, comorbid conditions, pneumonia, need for mechanical ventilation), investigators observed a reduced estimated risk for death among those who received NAIs; in addition, when patients received NAIs within 48 hours of becoming ill, they were significantly more likely to survive.^{[57, 58]}

Peramivir

Peramivir is indicated for treatment of acute uncomplicated influenza in patients aged 6 months and older who have been symptomatic for no more than 2 days. It is administered as a one-time IV infusion. Pediatric approval was based on the interim analysis of an ongoing pediatric clinical study (Study 305), a randomized, active-controlled trial of adolescent and pediatric patients with acute uncomplicated influenza who received open-label treatment with a single dose of peramivir (n=84) or 5 days of treatment with oseltamivir administered within 48 hours of onset of symptoms of influenza. Median time to alleviation of combined influenza symptoms was 79 hours for peramivir compared with 107 hours for oseltamivir. Median time to recovery to normal temperature (ie, < 37°C) was 40 hours and 28 hours patients receiving peramivir and oseltamivir, respectively.^[59]

Treatment of avian influenza

Hospitalization is required in patients with avian influenza if respiratory distress results in subsequent ventilatory support. Oseltamivir is the primary drug of choice.^[45]Longer therapy may be needed to treat highly pathogenic (HP) avian influenza than seasonal influenza.

The WHO recommendations for HP avian influenza A/H5N1 are as follows^[3]:

Patients with confirmed or suspected H5N1 infection should be treated with oseltamivir as soon as possible
Zanamivir might also be considered as an alternative if the patient is capable of using an inhalers
If neuraminidase inhibitors are available, amantadine and rimantadine should not be used as first-line therapies because of potential resistance
If neuraminidase inhibitors are not available, amantadine can be used as a first-line therapy, provided the virus is susceptible
If neuraminidase inhibitors are not available, rimantadine can be used if the virus is known to be susceptible because it has fewer side effects than amantadine
If neuraminidase inhibitors are available, and if the virus is susceptible, then a combination of neuraminidase inhibitors and M2 inhibitors can be used in confirmed cases of H5N1 infection
For prophylaxis in high-risk and moderate-risk exposures, give oseltamivir for 7-10 days from the day of exposure
Prophylaxis is not recommended for low risk groups

For more information, see the World Health Organization Updated Guidelines for Avian Influenza Virus Management.

A combination of antiviral therapy (eg, oseltamivir and adamantanes if susceptibility is expected) and antibiotics is recommended if pneumonia and rapid progression is noted. If septic shock is present, corticosteroids and vasopressors may play a role.

Acute respiratory distress syndrome (ARDS) should be managed according to guidelines.

If the patient is hospitalized, an isolation room is required, with airborne precautions or a negative-pressure room. A particulate mask, such as N95, and goggles are recommended.

Diet and Activity

No special diet is indicated for influenza.

Adequate rest is recommended.

General Influenza Prevention

Handwashing with soap and water is the most appropriate way to prevent infection by an influenza virus. Other preventive measures are to avoid touching of eyes or nose before washing hands, and to avoid sharing personal items with another person during an influenza outbreak.

Patients with influenza who are clinically stable and are able to convalesce at home are instructed to stay at home to avoid spread in the community.

Vaccination in the Pediatric Population

Influenza vaccination in targeted high-risk populations is the best means of preventing severe disease caused by influenza virus. Guidelines regarding the prevention and control of influenza have been established by the ACIP, and are regularly updated.^{[60, 61]}

Vaccines made using inactivated influenza virus provide 60-90% protection against influenza when the vaccine matches the epidemic strain. The antigenic composition is reviewed annually so that the current vaccine contains the most recently circulating strains, usually one or more subtypes of influenza A virus and a subtype of influenza B virus.

A study by Flannery et al that assessed the effectiveness of the influenza vaccine in reducing the risk of influenza-associated death in children and adolescents found that in the 291 of 358 pediatric influenza deaths reported between 2010-2014 where vaccination status was determined, only 26% had received the vaccine before the start of the illness and 31% among children with high-risk conditions. Overall vaccination effectiveness against death was 65%, and 51% in children with high-risk conditions.^{[62, 63]}

As the administration of two separate vaccines for seasonal and pandemic influenza was needed in 2009, Frey et al conducted a randomized trial of monovalent 2009 H1N1 influenza vaccine (2009 H1N1 vaccine) and seasonal trivalent inactivated influenza vaccine (TIV; split virion) given sequentially or concurrently in 531 children who had been previously vaccinated. Generally, one dose of 2009 H1N1 vaccine and one dose of TIV, regardless of the sequence or concurrency of administration, was immunogenic in children 10 years of age and up, while children less than 10 years of age required two doses of 2009 H1N1 vaccine. The vaccines were well tolerated.^[64]

Live attenuated influenza vaccine (LAIV)

ACIP recommends return of intranasal flu vaccine in the United States for 2018-2019 season

The Advisory Committee on Immunization Practices (ACIP) recommends return of intranasal flu vaccine in the United States for 2018-2019 season. The recommendation was based on positive results from a US study in children between the ages of 2 to < 4 years evaluating the shedding and antibody responses of the H1N1 strain in the live attenuated influenza vaccine (LAIV). The study showed that the new 2017-2018 H1N1 LAIV post-pandemic strain (A/Slovenia) performed significantly better than the 2015-2016 H1N1 LAIV postpandemic strain (A/Bolivia), which was associated with lower effectiveness and not recommended during last 2 seasons.^[65]

LAIV4 was not recommended during the 2017-2018 or 2016-2017 influenza seasons because it was poorly effective against circulating strains of influenza in the United States.^{[66, 67]}

Quadrivalent vaccines

The US Food and Drug Administration (FDA) approved quadrivalent forms of the vaccine in 2012. Like the already approved trivalent, the quadrivalent vaccines contain weakened forms of the virus strains. This formulation includes a second B strain, which increases the likelihood of adequate protection against circulating influenza B strains. Starting in the 2022-2023 influenza season, all influenza vaccines distributed in the United States are expected to be quadrivalent vaccines.

Indications for influenza vaccine in the pediatric population include the following:

Annual vaccination of all children aged 6 months to 18 years^[68]
Annual vaccination of children and teenagers (6 mo to 18 y) with long-term use of aspirin or other conditions that place them at increased risk for complications from influenza^{[69, 70]}
Patients with chronic pulmonary (eg, asthma) or cardiac disorders (except hypertension)
Patients with chronic metabolic disease (eg, diabetes), renal dysfunction, hemoglobinopathies, or immunosuppression (eg, human immunodeficiency virus [HIV])
Persons who have any condition (eg, cognitive dysfunction, spinal cord injuries, seizure disorders, or other neuromuscular disorders) that may compromise respiratory function or the handling of respiratory secretions or that can increase the risk for aspiration
Pregnant women who will be in their second or third trimester during influenza season
Household members (eg, children aged < 5 y) of persons at high risk
Providers of essential community services (eg, police, fire)
International travelers
Students and dormitory residents
Anyone wishing to reduce risk of influenza

The CDC recommends that the following pediatric groups receive priority for inactivated influenza vaccine:

Residents of long-term care facilities
Persons aged 2-64 years with comorbid conditions
Children aged 6 months to 4 years (59 mo)^{[69, 70]}
Women who will be pregnant during the influenza season
Household contacts and out-of-home caregivers of children younger than 6 months

Recommendations regarding administration of influenza vaccine include the following:

For adults and older children, the recommended site of vaccination is the deltoid muscle
The preferred site for infants and young children is the anterolateral aspect of the thigh
Influenza vaccine should be administered during the autumn season in the Northern Hemisphere

Children requiring 2 doses

Because of the antigenic novelty of the 2009 (H1N1) pandemic virus children who aged 6 months through 8 years who have not been exposed to this antigen require 2 doses.^[70] If a child requires 2 doses, administer each dose at least 4 weeks apart. Administer 2 influenza doses (separated by at least 4 weeks) to children who are receiving influenza vaccine for the first time or who have not previously received 2 or more doses of trivalent or quadrivalent influenza vaccine in a previous season. Children aged 9 years or older may be immunized with a single dose.

Annual immunization is recommended because of declining immunity during the year after immunization and because, in most years, at least one of the antigens is changed in the vaccine to increase the antigenic similarity between the vaccine and circulating strains. The optimal time for influenza vaccination is usually between October and November.

A 2017 practice guideline from the Influenza Vaccine and Egg Allergy Practice Parameter Workgroup commissioned by Joint Task Force on Practice Parameters recommended that influenza vaccines should be administered to individuals with egg allergy of any severity, just as they would be to individuals without egg allergy.^[71]

Maternal immunization during pregnancy has been associated with a lower proportion of infants who were small for gestational age and an increase in mean birth weight.^[72]

The CDC recommends influenza vaccine be administered during pregnancy (all trimesters); vaccination during pregnancy has been shown to decrease the risk of illness in the mother, as well as the risk of influenza and influenza hospitalization in their infants during the first 6 months of life.^[73]

The CDC recommends influenza vaccine be administered during pregnancy (all trimesters); vaccination during pregnancy has been shown to decrease risk of illness in the mother, as well as the risk of influenza and influenza hospitalization, in their infants during the first 6 months of life.^[74]

Avian Influenza Prevention

To curtail a potential pandemic situation, the major goals are early identification of sources of HP avian influenza virus A/H5N1 infection and limiting spread of the virus. Both the WHO and the CDC recommend a high degree of surveillance worldwide to identify outbreaks in poultry and death of migratory birds.^[75]Rapid containment processes, such as culling of infected birds, vaccinating nearby at-risk poultry, and vigilance for respiratory illness among personnel in contact with the affected poultry, are also needed.

Simple measures (eg, strict hand hygiene; standard, contact, droplet, and airborne precautions for 21 d) might reduce the spread of the virus.

Pneumococcal vaccination has been suggested as a prophylaxis option, to prevent secondary pneumonia from this pathogen. However, deaths due to avian influenza have been reported even without secondary bacterial infection.

An alert system has been developed for avian influenza depending on the incidence of human cases due to HP avian influenza virus A/H5N1. It ranges from level I-VI.^[75]Currently, the alert is set at level III because of a few cases of human-to-human transmission.

The United States and several other countries have developed a preparedness plan for a potential influenza pandemic.^[11]The US Secretary of Health and Human Services has developed a multiagency National Influenza Pandemic Preparedness and Response Task Group. This initiative jointly involves the CDC and several other agencies (international, national, state, local, and private) in preparing for a potential pandemic.^[76]

Travel recommendations

No recommendations have advocated carrying oseltamivir or zanamivir when traveling to countries where human avian influenza has been reported. However, consulting a local physician if illness develops has been recommended.^[76]

Sick or dying poultry should not be consumed because doing so increases the risk of acquiring the virus. Avoiding undercooked poultry and areas where the poultry is sold in the market is prudent. Also avoid raw or undercooked eggs. After exposure to poultry or eggs, wash hands, utensils, and exposed surfaces with soap and water.

If an illness develops with fever, cough, sore throat, or respiratory distress after exposure to poultry in areas where avian influenza has been identified, individuals must contact medical personnel. The history of travel and exposure to poultry must be disclosed prior to contact with the physician.

Avian influenza vaccination

The FDA approved the first vaccine for highly pathogenic (HP) avian influenza H5N1 (ie, avian or bird flu) in April 2007. The approval was based on one multicenter, randomized, double-blind, placebo-controlled, dose-ranging study in healthy adults aged 18-64 years.^[77]The trial investigated the safety and immunogenicity of the vaccine. In the study, 45% of 103 healthy adults who received two 90-mcg intramuscular doses of the vaccine 28 days apart had an improved immune response and produced antibody levels expected to reduce the risk of disease. In a subsequent study, a booster given 12 months after the second dose significantly boosted immune responses.^[78]

The H5N1 vaccine is not commercially available; it is stockpiled by the federal government to be distributed when necessary.^[77]

A vaccine against another avian influenza strain, H9N2, has also been developed. A study of live-attenuated H9N2 vaccine given intranasally to 50 adults (41 were seronegative) showed immunogenicity after 2 doses.^[79]

The Society of Hospital Epidemiology of America has published a document recommending universal vaccination of health care workers as a preparedness plan.^[80]By enhancing the vaccination rate, viral shedding and transmission can be reduced. This eventually decreases the risk of reassortment.

The challenges faced include manufacturing vaccines in a timely manner, finding appropriate substrates from which to isolate the virus, product safety, efficacy, and acceptance by the approving agency and the public. The HP avian influenza A virus vaccine poses a challenge because the contemporary method of growing the vaccine in the egg may not work because the HP avian influenza A virus can kill the embryonated egg.

Once an outbreak occurs, both the infected individual and contacts require neuraminidase inhibitors. This may necessitate mobilization of neuraminidase inhibitors from nations with stockpiles to regions where an avian outbreak is detected. Although this may not completely inhibit the transmission, the inhibitors may slow it down by decreasing viral shedding.

An effort should be made to enhance seasonal influenza immunization rates.

Consultations

Avian influenza should prompt consultations with the following specialists:

Infectious diseases specialist
Pulmonologist
Critical care specialist
Infection control specialist

Complications

According to a prospective cohort study, as many as 1 in 3 children seeking treatment in the ED for influenza-like illnesses (ILI) at the peak of flu season are at high risk of suffering severe complications. Children with neurologic or neuromuscular conditions, like cerebral palsy or muscular dystrophy, are at even greater risk. Of the 241 children (< 19 years) involved in the study, 85 suffered severe complications with 63 experiencing pneumonia, 12 suffering respiratory failure, and 14 suffering seizures. These findings support the use of antiviral therapy.^[81]

Medication

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Media Gallery

Swine influenza virus. Colorized transmission electron micrograph (37,800X) of the A/New Jersey/76 (Hsw1N1) virus under plate magnification. Image taken during the virus' first developmental passage through a chicken egg. Courtesy of the CDC/Dr. E. Palmer; R.E. Bates.
Colorized transmission electron micrograph shows avian influenza A/H5N1 viruses (gold) grown in Madin-Darby canine kidney (MDCK) cells (green). Image courtesy of Centers for Disease Control and Prevention.
Transmission electron micrograph (original magnification X 150,000) shows ultrastructural details of an avian influenza A/H5N1 virion, a subtype of avian influenza A. Note the stippled appearance of the roughened surface of the proteinaceous coat encasing the virion. Image courtesy of Centers for Disease Control and Prevention.