Seasonal inuenza in children: Prevention and treatment with antiviral drugs

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Official reprint from UpToDate www.uptodate.com 2014 UpToDate

Seasonal influenza in children: Prevention and treatment with antiviral drugs Author Flor M Munoz, MD, MSc Disclosures All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Mar 2014. | This topic last updated: Feb 26, 2014. INTRODUCTION Influenza is an acute respiratory illness caused by influenza A or B viruses, which occurs in outbreaks worldwide every year, mainly during the winter seasons in temperate climates. Certain groups of children are at increased risk of acquiring severe or complicated illness from influenza (table 1). Among healthy children, influenza generally is an acute, self-limited, and uncomplicated disease [1-3]. However, it can be associated with severe morbidity and mortality. Influenza causes an appreciable disease burden (eg, school and work absence, increased frequency of outpatient medical visits), and children are important vectors for the spread of disease. (See "Seasonal influenza in children: Clinical features and diagnosis", section on 'Epidemiology'.) Immunization is the major public health measure for the prevention of influenza infection [4-6]. However, antiviral drugs also may be used for prevention in high-risk patients who have not been immunized or who may have a suboptimal response to vaccine, in patients in whom influenza vaccine is contraindicated, and for anyone who wants to reduce their risk of acquiring influenza in seasons when the vaccine is a poor match for circulating influenza. Antiviral drugs are an important treatment option for patients who develop influenza infection despite immunization. Families of infants and children who are susceptible to severe disease from influenza should be reminded that these children may develop influenza infection despite immunization. If so, they should be seen by their health care provider as soon as possible after symptom onset because treatment is most beneficial when started early in the course of influenza. The use of antiviral drugs in the prevention and treatment of influenza in children will be presented here. Influenza vaccination in children and the use of antiviral drugs in adults are discussed separately. (See "Seasonal influenza vaccination in children" and "Prevention of seasonal influenza in adults" and "Treatment of seasonal influenza in adults".) INFLUENZA ACTIVITY The Centers for Disease Control and Prevention (CDC), in collaboration with the World Health Organization (WHO) and its reporting network, tracks influenza virus isolates throughout the world to monitor disease activity and to predict the appropriate components for the annual influenza vaccine. CDC and WHO surveillance between September 29 and December 7, 2013 found that approximately 90 percent of isolates were influenza A viruses, and among influenza A isolates, 90 percent were 2009 pandemic H1N1 influenza (pH1N1) viruses, which caused disproportionately severe illness among children and young adults during the 2009 pandemic [7,8]. It is not possible to predict whether this pattern will continue through the remainder of the 2013-2014 influenza season. Surveillance information, which is updated weekly during influenza season, is available via the CDC. In addition, FluNet, a database for global influenza virus surveillance, is available via the WHO. Local hospital or clinic laboratories may also collect information to monitor influenza activity in a specific geographic area. Section Editors George B Mallory, MD Morven S Edwards, MD Deputy Editor Mary M Torchia, MD

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Since July 2011, H3N2 influenza A variant viruses caused by reassortment of swine-origin H3N2 influenza A viruses and pandemic H1N1 influenza A viruses have been increasingly reported in the United States [9-11]. These viruses are susceptible to oseltamivir and zanamivir, but resistant to amantadine and rimantadine. Additional unexpected reassortment combinations may occur; updated information is available from the CDC. (See "Epidemiology of influenza", section on 'H3N2 variant influenza'.) ANTIVIRAL DRUGS Two classes of antiviral drugs are available for the prevention and treatment of influenza in children: neuraminidase inhibitors and adamantanes (M2 inhibitors) [1,12]. Neuraminidase inhibitors and adamantanes should not be used to treat illnesses caused by other respiratory viruses. The pharmacology of these drugs is discussed separately. (See "Pharmacology of antiviral drugs for influenza".) Since September 2009, >99 percent of circulating influenza virus strains have been susceptible to neuraminidase inhibitors [13-18]. However, high levels of resistance to adamantanes exist in the currently circulating strains and they should not be used for treatment of influenza. Information regarding antiviral resistance that emerges during the influenza season is available through the Centers for Disease Control and Prevention (CDC). Neuraminidase inhibitors Oseltamivir, zanamivir, laninamivir, and peramivir are neuraminidase inhibitors, which prevent the release of virions from the host cell [19]. Neuraminidase inhibitors are active against influenza A viruses (including the pandemic 2009-2010 H1N1 strain) and influenza B viruses [12]. Oseltamivir and zanamivir are available in the United States. Laninamivir and peramivir are available in Japan, but not yet licensed in the United States. " Oseltamivir Oseltamivir is active against both influenza A and B viruses. (See 'Antiviral resistance' below.) Oseltamivir is approved in the United States for treatment of influenza A and B viruses in individuals !2 weeks of age and the prophylaxis of influenza A and B viruses in individuals !1 year of age [12,20]. However, it may be used for the treatment and prophylaxis of influenza infection in younger children when indicated [12,20]. Oseltamivir is administered orally. It is available as a capsule or as a powder for liquid suspension. The dose and duration of oseltamivir vary according to weight and indication (eg, prophylaxis or treatment) (table 2 and table 3) [12]. (See 'Prophylaxis dosing' below and 'Treatment dosing' below.) " Zanamivir Zanamivir is active against both influenza A and B viruses. Zanamivir is approved in the United States for the prophylaxis of influenza in individuals !5 years and the treatment of influenza in individuals !7 years of age [12]. Zanamivir is a dry powder administered by oral inhalation; the dose and duration vary according to the indication (table 2 and table 3). Zanamivir inhalation powder should not be reconstituted in any liquid formulation and is not recommended for use in nebulizers or mechanical ventilators [21]. Zanamivir is not recommended for patients with a history of wheezing or underlying chronic respiratory disease [12]. These patients are at increased risk of developing bronchospasm and occasionally may have some decline in their respiratory function after administration of zanamivir. Intravenous zanamivir is available for investigational use and may be warranted for severely ill patients with oseltamivir-resistant 2009 H1N1 influenza infection, and patients who cannot tolerate or absorb oral oseltamivir because of suspected or known gastric stasis, malabsorption, or gastrointestinal bleeding [22]. Additional information about investigational use of intravenous zanamivir in the United States is available from the CDC. " Laninamivir Laninamivir is a long-acting neuraminidase inhibitor that is administered in a single inhalation [23,24]. In in vitro studies and clinical trials, it has shown activity against oseltamivir-resistant influenza viruses [23,25,26]. In randomized trials, the efficacy and safety of laninamivir in children with influenza infection were similar to those of oseltamivir and zanamivir [23,24]. " Peramivir Peramivir is an intravenously administered neuraminidase inhibitor that is available in some countries
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(eg, Japan, Korea), but no longer in the United States [27-29]. Adverse events In prelicensure studies, oseltamivir was well tolerated, with few adverse effects [30]. Gastrointestinal complaints were most frequent, occurring in 14 percent of oseltamivir recipients, compared with 8.5 percent of placebo recipients. In postmarketing reports, gastrointestinal symptoms continue to predominate [31-33]. During a school outbreak of 2009 pandemic influenza A (H1N1), 14 percent of students and 20 percent of staff who were prescribed oseltamivir prophylaxis discontinued it because of adverse effects (predominantly nausea, vomiting, and rash) [31]. In retrospective reviews, the use of oseltamivir for the treatment of influenza among infants younger than 12 months of age was not associated with increased risk of adverse neurologic events or mortality [34,35]. Zanamivir also is generally well tolerated [12]. In clinical trials, the frequencies of adverse events were similar for persons receiving inhaled zanamivir and placebo [12,36]. The most common adverse events (reported in fewer than 5 percent of recipients) include diarrhea; nausea; sinusitis; nasal signs and symptoms; bronchitis; cough; headache; dizziness; and ear, nose, and throat infections [37]. Rare adverse effects Postmarketing reports have identified rare but serious adverse events in patients with influenza who are taking neuraminidase inhibitors [38-41]. These events include neuropsychiatric effects (delirium, hallucinations, confusion, abnormal behavior, convulsions, and encephalitis), death, and severe skin reactions (including toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme) [20]. Most of the reports of neuropsychiatric events involved oseltamivir and occurred in children in Japan, where the use of neuraminidase inhibitors is widespread [42]. The events often had an abrupt onset and rapid resolution [40]. Severe skin reactions also have been reported in adults and non-Japanese children. A causal association between neuraminidase inhibitors and these events has not been established [43-47]. Some of the adverse events may have been related to influenza infection rather than treatment [48-52]. (See "Seasonal influenza in children: Clinical features and diagnosis", section on 'Complications'.) Adverse events related to neuraminidase inhibitors should be reported to the US Food and Drug Administration (FDA) MedWatch. Adamantane drugs Amantadine and rimantadine are adamantanes (also called M2 inhibitors). Adamantanes target the M2 protein of influenza A, which forms a protein channel in the viral membrane that is essential for efficient viral replication. Adamantanes are not active against influenza B viruses or against currently circulating strains of influenza A virus [16,36]. They are not recommended for the treatment or prophylaxis of influenza during the 2013-2014 season. However, they may have a role (in combination with a neuraminidase inhibitor) if an increase of oseltamivir resistance occurs [53]. Adamantanes are approved for prophylaxis against infection from influenza A viruses in children !1 year of age. Amantadine is also approved for the treatment of influenza A viral infections in children !1 year of age. Although rimantadine is not licensed by the FDA for the treatment of influenza in children younger than 13 years, published data suggest that it is safe and effective in children !1 year of age [54,55]. The pharmacology of adamantanes is discussed in greater detail separately. (See "Pharmacology of antiviral drugs for influenza".) Ribavirin Ribavirin is a nucleoside analog that has in vitro activity against both influenza A and B viruses. Reports have suggested clinical benefits when ribavirin was administered by aerosol to treat influenza A or B infections [56,57]. When administered orally, ribavirin is poorly absorbed and thus has not been shown to be effective against influenza. Ribavirin is not approved by the FDA for the treatment or prevention of influenza. ANTIVIRAL RESISTANCE Approximately 98 percent of influenza viruses tested by the Centers for Disease Control and Prevention (CDC) between October 1 and December 7, 2013 were sensitive to oseltamivir and all were susceptible
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to zanamivir [7]. Information regarding antiviral resistance that emerges during the influenza season is available through the CDC. (See "Antiviral drug resistance among seasonal influenza viruses".) Testing influenza isolates for antiviral resistance is not available in clinical settings, and clinical features do not distinguish oseltamivir-resistant from oseltamivir-susceptible viruses [36]. Clinicians should review local surveillance data to know which types and subtypes of influenza viruses are circulating in their communities. Local surveillance data may be obtained through the CDC. Certain laboratory tests can distinguish between influenza A and B viruses, and between influenza subtypes (table 4) [36]. (See "Seasonal influenza in children: Clinical features and diagnosis", section on 'Approach to testing'.) CHEMOPROPHYLAXIS Immunization is the major means of prevention of influenza infection, and chemoprophylaxis should not be substituted for vaccination in high-risk individuals (table 1) [4,6]. Chemoprophylaxis can be used to prevent influenza infection in high-risk children who have not been fully immunized. Chemoprophylaxis can be administered simultaneously with the inactivated influenza vaccine (given as an intramuscular injection) to provide protection until an immune response develops. Individuals immunized with the live-attenuated influenza vaccine (given intranasally) should not receive chemoprophylaxis for 14 days after receipt of the vaccine because the vaccine strains are susceptible to antiviral drugs [58]. Other preventive measures are integral to the management of all children, and particularly those who are high-risk. These measures include general infection control procedures, avoidance of ill contacts, administration of influenza vaccine unless specifically contraindicated, and immunization of household contacts and out-of-home caregivers. (See 'Infection control' below and "Seasonal influenza vaccination in children", section on 'Indications'.) Target groups Decisions regarding the use of influenza chemoprophylaxis should be made on a case-by-case basis. Factors to consider in making this decision include the potential for severe or complicated infection occurring in the child or the child's contacts, the potential for adverse side effects, the possibility of development of antiviral resistance, the likelihood of completion of therapy (failure to complete therapy may contribute to the development of resistance), and the supply of chemoprophylactic drugs (which are the same agents used for influenza treatment) [36]. Pre-exposure prophylaxis To limit emergence of anti-viral resistant viruses, the Centers for Disease Control and Prevention (CDC) and American Academy of Pediatrics (AAP) recommend that pre-exposure chemoprophylaxis be reserved for persons who are at high risk for influenza-related complications who cannot otherwise be protected during times when they are at high risk for exposure to influenza [5,12]. Indiscriminant use of chemoprophylaxis may promote resistance to antiviral medications and reduce availability of antiviral medications for the treatment of individuals who are severely ill or at high risk of influenza complications. When an outbreak of seasonal influenza is present in the community, potential target groups for pre-exposure chemoprophylaxis may include [5,12]: " Children at high risk for severe or complicated influenza (table 1) for whom influenza vaccine is contraindicated " Children at high risk for severe or complicated influenza during the two weeks after influenza immunization " Family members or healthcare providers who are unimmunized and are likely to have ongoing, close exposure to children younger than 24 months and unimmunized children who are at high risk for severe or complicated influenza " Unimmunized staff and children (to control influenza outbreaks in a closed institutional setting with pediatric residents at high risk for severe or complicated influenza) " High-risk children who may not respond to influenza vaccine, including those who are immunocompromised (as a

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supplement to influenza immunization) " Children at high risk and their family members/close contacts and healthcare providers when circulating strains of influenza virus are not matched with seasonal influenza vaccine strains (based on data from the CDC and local health departments) [12,36] (see 'Influenza activity' above) Post-exposure prophylaxis Post-exposure prophylaxis may be warranted for children who have had close contact with a confirmed or suspected case of influenza during the infectious period (ie, one day before the onset of symptoms until 24 hours after the fever ends) and who are at high risk for complications of influenza (table 1) [12]. Postexposure prophylaxis should be used only when antivirals can be started within 48 hours of the most recent exposure. Postexposure prophylaxis is not indicated [12]: " If more than 48 hours have elapsed since the last contact " When contact did not occur during the ill person's infectious period (one day before until 24 hours after the fever ends) Early treatment of exposed individuals is an alternative to postexposure prophylaxis [12]. (See 'Antiviral therapy' below.) Efficacy Oseltamivir and zanamivir chemoprophylaxis significantly diminishes influenza illness among household and hospital contacts of patients with laboratory-confirmed influenza [12,59,60]. Nonetheless, patients should be informed that chemoprophylaxis lowers, but does not eliminate, the risk of influenza, that susceptibility to influenza returns once the antiviral medication is stopped, and that immunization remains the primary means of protection [5]. High-risk individuals should seek medical evaluation if they develop a febrile respiratory illness or moderate to severe illness despite chemoprophylaxis. (See "Clinical manifestations and diagnosis of pandemic H1N1 influenza ('swine influenza')" and "Seasonal influenza in children: Clinical features and diagnosis", section on 'Clinical features'.) " Neuraminidase inhibitors A systematic review of seven randomized controlled trials found that prophylactic use of neuraminidase inhibitors reduced the risk of developing seasonal influenza by 70 to 90 percent [61]. The highest rates of protection are from studies examining the prevention of febrile laboratory-confirmed influenza infection (efficacy of oseltamivir: 82 percent; efficacy of zanamivir: 84 percent) [61]. " Adamantanes Amantadine and rimantadine are not active against influenza B viruses. When used prophylactically, amantadine and rimantadine have been reported to be 70 to 90 percent effective in preventing clinical illness with seasonal influenza A when circulating strains of influenza A are susceptible to adamantanes [61-64]. This level of effectiveness is similar to that afforded by immunization. The currently circulating influenza A viruses are not susceptible to adamantanes [13-15]. Choice of drug The choice of agent for prophylaxis is influenced by the age of the child and the susceptibility patterns of circulating strains (if known) (table 2) [5,12]. Neuraminidase inhibitors are recommended for the 2013-2014 influenza season based on viral surveillance and resistance data indicating that >99 percent of currently circulating influenza viruses are susceptible to neuraminidase inhibitors [7,18]. The CDC will provide updated recommendations for chemoprophylaxis as indicated throughout the 2013-2014 influenza season. Prophylaxis dosing The doses of the neuraminidase inhibitors used for influenza prophylaxis for children !1 year of age are listed in the table (table 2) [65]. Oseltamivir dosing for full-term infants <1 year of age depends upon the weight of the infant [36]: " Age <3 months Not recommended, except in critical situations " Age 3 through 11 months 3 mg/kg per dose once daily If weight is not known, dosing should be determined by age as follows [66]:

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" Age four to five months 17 mg once daily " Age 6 to 11 months 24 mg once daily The dosing regimens recommended above are not intended for premature infants, who may have slower clearance of oseltamivir due to immature renal function; doses recommended for full-term infants may lead to very high drug concentrations in premature infants younger than one year [36]. Limited data from cohorts of premature infants who received treatment with oseltamivir are discussed below. (See 'Treatment dosing' below.) When dispensing the oral suspension of oseltamivir to children <1 year of age, providers and pharmacists must take care to provide a dosing device that matches the units of measure on the prescription [67,68]. Healthcare providers should write doses in milligrams (mg) if the dosing dispenser with the drug is in mg [68]. As an alternative, the oral dosing dispenser that is provided in the package (which has markings for 30 mg, 45 mg, and 60 mg) can be removed, and pharmacists or healthcare personnel should provide an oral syringe that can accurately measure the prescribed milliliter (mL) dose [67]. The caregiver should also be counseled regarding proper administration. Oral suspension not available If the commercial preparation of oral suspension of oseltamivir is not available (ie, during a shortage), oseltamivir capsules may be opened and mixed with sweetened liquids (eg, chocolate syrup, corn syrup, etc) [20]. If the appropriate strength capsule is not available, retail pharmacies can compound an oral suspension (6 mg/mL) from oseltamivir 75 mg capsule by following instructions contained in the prescribing information [20]. Duration The duration for pre-exposure prophylaxis depends upon the indication. For individuals receiving chemoprophylaxis while awaiting the development of an immune response to the vaccine, the duration is usually two weeks [12]. Otherwise, pre-exposure chemoprophylaxis should be administered every day for the duration of potential exposure to a person with influenza. Zanamivir regimens as long as 28 days and oseltamivir regimens as long as 42 days have been well tolerated, but currently no published data for regimens longer than 42 days are available [69]. Post-exposure chemoprophylaxis should be administered for seven days after the last known exposure [12]. For control of outbreaks in long-term care facilities and hospitals, chemoprophylaxis should be administered for a minimum of two weeks, and up to one week after the last known case was identified. ANTIVIRAL THERAPY Treatment indications Decisions regarding treatment of influenza in children must consider underlying conditions, disease severity, and duration of symptoms [5,12]. The Centers for Disease Control and Prevention (CDC) and American Academy of Pediatrics (AAP) provide the following indications for antiviral treatment [12,70]: " Any child hospitalized with presumed influenza " Children with confirmed or suspected influenza who have severe, complicated, or progressive illness " Influenza infection of any severity in children at high risk for complications (table 1), regardless of influenzaimmunization status " Any otherwise-healthy child with influenza infection for whom a decrease in duration of clinical symptoms is felt to be warranted by his or her provider (particularly if treatment can be initiated within 48 hours of illness onset) For most previously healthy children, influenza is a mild and self-limiting infection [1-3]. Unnecessary treatment of such children, even when they present early in the course of illness, has the potential effect of resulting in a diminished supply of drugs for patients at risk for severe illness. In addition, indiscriminate treatment may contribute to the development of antiviral resistance. (See 'Antiviral resistance' above.) Timing of treatment When clinically indicated, antiviral therapy should be started as soon as possible after symptom onset, ideally within 48 hours [12]. Antiviral therapy may be administered after 48 hours of symptoms, particularly in
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hospitalized children, those with severe or progressive disease, and those at high risk of complications. However, earlier treatment is associated with improved outcome. In a case-control study, earlier initiation of neuraminidase inhibitor therapy among children (<18 years) with influenza requiring intensive care therapy was associated with decreased mortality (3.5 percent at 0 to 48 hours versus 5.3 percent at days 3 to 7 and 13.4 percent at !8 days) [71]. Treatment should be initiated whether or not the patient received seasonal influenza vaccine. Laboratory confirmation with viral culture or polymerase chain reaction (PCR) tests should not delay the initiation of antiviral therapy [12]. Negative rapid diagnostic tests do not exclude influenza. (See "Seasonal influenza in children: Clinical features and diagnosis", section on 'Laboratory diagnosis'.) Efficacy/effectiveness Clinical illness In randomized trials and meta-analyses, antiviral treatment of children and otherwise-healthy individuals within two days of seasonal influenza illness onset shortens the duration of illness by approximately one day and hastens the return to normal activity compared with placebo [59,72-74]. If antiviral therapy is administered within 12 hours of symptom onset, the reduction of duration may be increased by as many as three days [75,76]. The benefits may be increased in young children. In a randomized trial, initiation of oseltamivir within 24 hours of the onset of symptoms shortened the median time to resolution of illness by 3.5 days (3 versus 6.5 days) in children one to three years of age [32]. In a large randomized trial in children, treatment with oseltamivir shortened influenza-like illness by approximately one day [30]. Among 695 children with influenza symptoms (fever, cough, coryza), approximately two-thirds had laboratoryconfirmed influenza. Compared with children with influenza-like illness who were treated with placebo, those treated with oseltamivir had significant reduction in: " The duration of illness (101 versus 137 hours, 95% CI 89-118 hours versus 125 to 150 hours) " The incidence of otitis media (12 versus 21 percent) " The incidence of clinician-prescribed antibiotics (31 versus 41 percent) Antiviral treatment also may be effective if administered within five days of symptom onset. In a randomized trial in 1190 individuals (median age five years), initiation of oseltamivir within five days of symptom onset reduced duration of symptoms by one day (three versus four days) [77]. Data regarding the efficacy of antiviral treatment in high-risk children are limited. In a meta-analysis, treatment of highrisk individuals with neuraminidase inhibitors did not have a significant effect on the duration of symptoms [78]. Complications Limited data from some randomized trials and observational studies suggest that antiviral treatment can reduce the risk of complications, severe illness, or death [59,71,79-88]. In a retrospective study, treatment with neuraminidase inhibitors within 24 hours of hospital admission was associated with decreased duration of hospitalization among critically ill children with seasonal influenza [89]. However, no decrease in duration of intensive care unit days, rates of readmission within seven days, or mortality were observed. The role of oseltamivir in the prevention of lower respiratory tract infection complications in adolescents and adults is controversial. A meta-analysis of 10 trials, 8 of which were not published (all 10 of which were funded by the maker of oseltamivir) and pooled analysis of 2 published trials came to differing conclusions about prevention of lower respiratory tract complications [90,91]. An independent meta-analysis of the same ten trials and a subsequent randomized trial concluded that oseltamivir reduces the risk of lower respiratory tract infections in patients with influenza by 28 percent (95% CI 11 to 42 percent), but the diminished risk is limited to lower respiratory tract complications that are treated with antibiotics [92]. A subsequent meta-analysis of observational studies evaluated the effectiveness of oseltamivir versus no treatment in

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the prevention of influenza hospitalization and mortality [87]. Only observational studies that adjusted for potential confounding factors were included. In pooled analysis of four studies, oseltamivir appeared to reduce hospitalization among outpatients (odds ratio [OR] 0.75, 95% CI 0.66-0.89) and in pooled analysis of three studies, oseltamivir appeared to reduce mortality among hospitalized high-risk patients (OR 0.23, 95% CI 0.13-0.43). However, given the inherent limitations of observational studies, the overall quality of this evidence is low to very low. Viral shedding Although treatment of children with neuraminidase inhibitors reduces the amount of viral shedding, it does not appear to shorten the duration of shedding or household transmission. In a randomized trial in 1190 outpatients (median age five years), initiation of oseltamivir within five days of symptom onset reduced viral shedding (by polymerase chain reaction) by 12 to 50 percent during the week after initiation [77]. Other studies of children hospitalized with seasonal influenza suggest that viral shedding (by antigen detection) continues for approximately four to seven days, independent of treatment with neuraminidase inhibitors [80,93,94]. In a study of children hospitalized with pandemic 2009 H1N1 influenza virus who were treated with oseltamivir, viral shedding persisted for a median of nine days after the onset of symptoms [95]. In an outpatient study of 384 patients with positive rapid tests for influenza, oseltamivir treatment within 24 hours of symptom onset did not reduce or household transmission of influenza [96]. Choice of agent The choice of agent for treatment of influenza is influenced by the age of the child, the susceptibility patterns of circulating strains (if known), and the results of influenza testing (if testing is done) (table 3) [12]. Neuraminidase inhibitors are recommended for treatment during the 2013-2014 influenza season based on viral surveillance and resistance data indicating that >99 percent of currently circulating influenza viruses are susceptible to neuraminidase inhibitors [7,18]. The CDC will provide updated treatment recommendations as indicated throughout the 2013-2014 influenza season. (See 'Antiviral resistance' above.) Treatment dosing The doses of the neuraminidase inhibiting agents used for influenza treatment for children !1 year of age are listed in the table (table 3) [5]. Weight-based dosing of oseltamivir is recommended for infants <1 year of age [20,36]. The CDC recommends oseltamivir 3 mg/kg per dose twice daily for full-term infants <1 year of age [20,36]. In a pharmacokinetic study, infants #8 months of age who received a dose of 3 mg/kg twice daily achieved the target exposure (an area under the curve selected to maximize effectiveness and minimize development of resistance) [97]. However, a dose of 3.5 mg/kg twice daily was necessary to reliably achieve the target exposure in infants 9 through 11 months of age. Although the authors of the study suggest that the appropriate dose of oseltamivir for infants 9 through 11 months of age is 3.5 mg/kg twice daily, the CDC has not revised its recommendations for this age group. If the infants weight is not known, dosing by age may be necessary [66]: " Age zero to three months 12 mg twice daily for five days " Age four to five months 17 mg twice daily for five days " Age 6 to 11 months 24 mg twice daily for five days The dosing regimens recommended above are not intended for premature infants, who may have slower clearance of oseltamivir due to immature renal function; doses recommended for full-term infants may lead to very high drug concentrations in premature infants younger than one year [36]. Limited data from a cohort of 32 premature infants who were inadvertently exposed to 2009 pandemic H1N1 influenza by a healthcare worker suggest that 1.0 mg/kg twice daily produces drug concentrations similar to those in older children receiving 3 mg/kg twice daily [98]. Additional limited data support a dose of 1 mg/kg twice daily for premature infants <38 weeks postmenstrual age [99]. When dispensing the oral suspension of oseltamivir to children <1 year of age, providers and pharmacists must take

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care to provide a dosing device that matches the units of measure on the prescription [67,68]. Healthcare providers should write doses in mg if the dosing dispenser with the drug is in mg [68]. As an alternative, the oral dosing dispenser that is provided in the package (which has markings for 30 mg, 45 mg, and 60 mg) can be removed, and pharmacists or healthcare personnel should provide an oral syringe that can accurately measure the prescribed milliliter (mL) dose [67]. The caregiver should also be counseled regarding proper administration. Doubling the standard age- or weight-based dose of oseltamivir has been suggested for some severely ill patients with H5N1 avian influenza and was also suggested for certain severely ill patients (eg, immunocompromised hosts) during the H1N1 influenza pandemic [100,101]. However, in a randomized trial of 326 patients with severe influenza (75 percent of whom were children) admitted to hospital between 2007 and 2010 in Indonesia, Singapore, Thailand, or Vietnam, doubling the dose of oseltamivir did not affect the rate of clearance of virus on day five of treatment (approximately 70 percent); mortality (7.3 versus 5.6 percent); median days of supplemental oxygen, intensive care, or mechanical ventilation; or tolerability [102]. Viral clearance was not related to virus type/subtype, age, or duration of illness before enrollment. Oral suspension not available If the commercial preparation of oral suspension of oseltamivir is not available (ie, during a shortage), oseltamivir capsules may be opened and mixed with sweetened liquids (eg, chocolate syrup, corn syrup, etc) [20]. If the appropriate strength capsule is not available, retail pharmacies can compound an oral suspension (6 mg/mL) from oseltamivir 75 mg capsule by following instructions contained in the prescribing information [20]. Treatment duration The usual duration of antiviral therapy for influenza is five days. Patients in whom influenza treatment is initiated should receive a full course of therapy unless an alternative diagnosis is established [36]. Hospitalized patients with severe illness may require an extended course of therapy. Treatment failure Patients receiving neuraminidase inhibitors who do not respond to treatment may have an infection with an antiviral resistant virus. Oseltamivir resistance has been reported among children and immunocompromised during treatment with oseltamivir, predominantly among immunocompromised patients with 2009 H1N1 virus infection [103-106]. Treatment options for patients with suspected oseltamivir-resistant influenza may include inhaled zanamivir (no cross resistance has been documented) or investigational parenteral neuraminidase inhibiting agents (eg, peramivir and zanamivir) available through clinical trials or single patient emergency Investigational New Drug protocols [36]. OTHER THERAPIES Supportive care Other measures for the treatment of influenza include symptomatic therapy for fever, headache, and myalgia with acetaminophen. The use of salicylates should be avoided in children younger than 18 years of age because of the association with Reye syndrome. (See "Acute toxic-metabolic encephalopathy in children", section on 'Reye syndrome'.) Over-the-counter cold medications have no proven benefit and have been associated with fatal overdose in young children. They are not recommended. (See "The common cold in children: Treatment and prevention", section on 'Treatment'.) Antibiotics Antibiotics should be reserved for proven or strongly suspected bacterial complications of acute influenza, such as bacterial pneumonia, otitis media, and sinusitis. The choice of antibiotics may be aided by examination and culture of appropriate specimens. However, if the etiology of the bacterial complication is not clear from the examination of such specimens, empiric antibiotics generally should be directed at the most common bacterial pathogens following influenza: primarily Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus, Haemophilus influenzae type b, and nontypeable H. influenzae. (See "Acute otitis media in children: Epidemiology, microbiology, clinical manifestations, and complications", section on 'Bacteria' and "Pneumonia in children: Inpatient treatment", section on 'Empiric therapy' and "Acute bacterial rhinosinusitis in children: Microbiology and treatment", section on 'Empiric antibiotic therapy'.)
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INFECTION CONTROL When children are hospitalized with influenza or an influenza-like illness, standard precautions and droplet precautions are recommended for the duration of illness [58]. (See "Infection control measures to prevent seasonal influenza in healthcare settings", section on 'Isolation precautions'.) Unless children require evaluation for influenza-like illness (eg, high-risk group, evidence of lower respiratory tract infection, severe illness, or rapid clinical deterioration), children with an influenza-like illness should stay away from healthcare settings and high-risk individuals until at least seven days after onset of symptoms or 24 hours after resolution of fever, whichever is longer [107]. Viral shedding, even with treatment, may exceed 10 days [70,95]. The Centers for Disease Control and Prevention (CDC) recommends that children with an influenza-like illness stay home from school or day care until 24 hours after their fever (temperature >100F (37.8C)) has resolved without antipyretics [107]. This recommendation applies whether or not the child received antiviral therapy. It also applies to other settings in which the majority of people are not at increased risk of complications from influenza (eg, camp, stores, community gatherings). More stringent guidelines and longer exclusion periods may be made at the community level [107]. INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) " Basics topics (see "Patient information: Flu (The Basics)") " Beyond the Basics topics (see "Patient information: Influenza prevention (Beyond the Basics)" and "Patient information: Influenza symptoms and treatment (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Resistance " Influenza viruses circulating during the 2013-2014 season are susceptible to neuraminidase inhibitors (oseltamivir and zanamivir), but the current strains exhibit high levels of resistance to adamantanes (amantadine and rimantadine). (See 'Antiviral resistance' above.) Prophylaxis " Immunization is the major means of prevention of influenza infection. Chemoprophylaxis should not replace vaccination for individuals who are at high risk for severe or complicated influenza infection (table 1). (See 'Chemoprophylaxis' above and "Seasonal influenza vaccination in children", section on 'Indications'.) " Decisions regarding the use of chemoprophylaxis for influenza should be made on a case-by-case basis. Factors to be considered in the benefit-to-risk calculation include the potential for severe or complicated infection in the child or the child's contacts, the potential for adverse side effects, the possibility of development of antiviral resistance, the likelihood of completion of therapy, and the supply of chemoprophylactic drugs (which are the same agents used for influenza treatment). (See 'Target groups' above.)

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" When chemoprophylaxis is necessary during the 2013-2014 influenza season, neuraminidase inhibitors (oseltamivir or zanamivir) are recommended. The choice of agent depends upon the age of the child (table 2). (See 'Choice of drug' above.) " The duration of pre-exposure chemoprophylaxis varies depending upon the indication. Post-exposure prophylaxis should be continued for seven days after the last known exposure. For control of outbreaks in long-term care facilities and hospitals, chemoprophylaxis should be administered for a minimum of two weeks, and up to one week after the last known case was identified. (See 'Duration' above.) Treatment " Among individuals without risk factors for severe or complicated influenza (table 1), treatment of influenza with antiviral therapy shortens the duration of illness by approximately one day if initiated within 48 hours of illness onset. (See 'Efficacy/effectiveness' above.) " Antiviral treatment of high-risk patients has not been shown to reduce the duration of illness, but may decrease the risk of complications or need for hospitalization. (See 'Efficacy/effectiveness' above.) " Treatment, when indicated, should be administered as early in the course of illness as possible, ideally within 48 hours of symptom onset. Laboratory confirmation should not delay the initiation of antiviral therapy in individuals in whom treatment is indicated. Negative rapid diagnostic tests do not exclude influenza. (See 'Efficacy/effectiveness' above and "Seasonal influenza in children: Clinical features and diagnosis", section on 'Laboratory diagnosis'.) " In accord with the Centers for Disease Control and Prevention and the American Academy of Pediatrics, we recommend antiviral therapy for (Grade 1A) (see 'Treatment indications' above): Children hospitalized with confirmed or suspected influenza Children with an influenza-like illness who are at increased risk of severe or complicated influenza (table 1) Otherwise-healthy children with influenza infection for whom a decrease in duration of clinical symptoms is felt to be warranted by his or her provider " Neuraminidase inhibitors (oseltamivir or zanamivir) are recommended for the treatment of influenza virus during the 2013-2014 influenza season. The choice of agent depends upon the age of the child (table 3). (See 'Choice of agent' above.) " Dosing for oseltamivir treatment varies according to the child's weight (table 3). The dose for zanamivir treatment is 10 mg (two inhalations) twice per day. (See 'Treatment dosing' above.) " We recommend NOT using salicylates for symptomatic therapy in children with influenza who are younger than 18 years of age (Grade 1C). (See 'Supportive care' above.) Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Guidance on the use of zanamivir, oseltamivir and amantadine for the treatment of influenza. Technology Appraisal No. 58. National Institute for Clinical Excellence London, 2003. www.nice.org.uk (Accessed on September 07, 2008). 2. Kumar S, Havens PL, Chusid MJ, et al. Clinical and epidemiologic characteristics of children hospitalized with 2009 pandemic H1N1 influenza A infection. Pediatr Infect Dis J 2010; 29:591.

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3. Poehling KA, Edwards KM, Weinberg GA, et al. The underrecognized burden of influenza in young children. N Engl J Med 2006; 355:31. 4. Guidance on the use of oseltamivir and amantadine for the prophylaxis of influenza. Technology Appraisal No. 67. National Institute for Clinical Excellence London, 2003 www.nice.org.uk (Accessed on August 07, 2008). 5. Committee on infectious diseases. Recommendations for prevention and control of influenza in children, 20132014. Pediatrics 2013; 132:e1089. 6. Centers for Disease Control and Prevention (CDC). Prevention and control of seasonal influenza with vaccines. Recommendations of the Advisory Committee on Immunization Practices--United States, 2013-2014. MMWR Recomm Rep 2013; 62:1. 7. Centers for Disease Control and Prevention (CDC). Update: influenza activity - United States, September 29December 7, 2013. MMWR Morb Mortal Wkly Rep 2013; 62:1032. 8. CDC Health Advisory. Notice to clinicians: Early reports of pH1N1-associated illnesses for the 2013-14 influenza season. http://www.bt.cdc.gov/HAN/han00359.asp (Accessed on January 13, 2014). 9. Centers for Disease Control and Prevention (CDC). Update: Influenza A (H3N2)v transmission and guidelines five states, 2011. MMWR Morb Mortal Wkly Rep 2012; 60:1741. 10. Centers for Disease Control and Prevention (CDC). Notes from the field: Outbreak of influenza A (H3N2) virus among persons and swine at a county fair--Indiana, July 2012. MMWR Morb Mortal Wkly Rep 2012; 61:561. 11. Centers for Disease Control and Prevention. CDC Health Advisory. Variant influenza virus (H3N2v) infections. http://emergency.cdc.gov/HAN/han00351.asp (Accessed on July 17, 2013). 12. Centers for Disease Control and Prevention. Influenza antiviral medications: Summary for clinicians. http://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm (Accessed on September 23, 2013). 13. Centers for Disease Control and Prevention (CDC). Update: influenza activity --- United States, October 3December 11, 2010. MMWR Morb Mortal Wkly Rep 2010; 59:1651. 14. Centers for Disease Control and Prevention (CDC). Update: influenza activity - United States, 2009-10 season. MMWR Morb Mortal Wkly Rep 2010; 59:901. 15. Centers for Disease Control and Prevention (CDC). Update: influenza activity--United States, October 3, 2010February 5, 2011. MMWR Morb Mortal Wkly Rep 2011; 60:175. 16. Centers for Disease Control and Prevention (CDC). Update: influenza activity - United States, 2011-12 season and composition of the 2012-13 influenza vaccine. MMWR Morb Mortal Wkly Rep 2012; 61:414. 17. Centers for Disease Control and Prevention (CDC). Influenza activity--United States, 2012-13 season and composition of the 2013-14 influenza vaccine. MMWR Morb Mortal Wkly Rep 2013; 62:473. 18. Centers for Disease Control and Prevention. Update: influenza activity--United States and worldwide, May 19September 28, 2013. MMWR Morb Mortal Wkly Rep 2013; 62:838. 19. Couch RB. Prevention and treatment of influenza. N Engl J Med 2000; 343:1778. 20. Tamiflu (oseltamivir phosphate) prescribing information. www.gene.com/download/pdf/tamiflu_prescribing.pdf (Accessed on January 02, 2013). 21. US Food and Drug Administration. MedWatch Safety Alert. Relenza (zanamivir) inhalation powder www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm186081.htm (Accessed on September 06, 2011). 22. Centers for Disease Control and Prevention. Intravenous influenza antiviral medications and CDC considerations related to investigational use of intravenous zanamivir for 2013-2014i nfluenza season. www.cdc.gov/flu/professionals/antivirals/intravenous-antivirals.htm (Accessed on February 11, 2014). 23. Sugaya N, Ohashi Y. Long-acting neuraminidase inhibitor laninamivir octanoate (CS-8958) versus oseltamivir as treatment for children with influenza virus infection. Antimicrob Agents Chemother 2010; 54:2575. 24. Katsumi Y, Otabe O, Matsui F, et al. Effect of a single inhalation of laninamivir octanoate in children with influenza. Pediatrics 2012; 129:e1431. 25. Watanabe A, Chang SC, Kim MJ, et al. Long-acting neuraminidase inhibitor laninamivir octanoate versus oseltamivir for treatment of influenza: A double-blind, randomized, noninferiority clinical trial. Clin Infect Dis 2010;
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51:1167. 26. Gubareva LV, Trujillo AA, Okomo-Adhiambo M, et al. Comprehensive assessment of 2009 pandemic influenza A (H1N1) virus drug susceptibility in vitro. Antivir Ther 2010; 15:1151. 27. Centers for Disease Control and Prevention. Termination of the emergency use authorization (EUA) of medical products and devices. Available at http://www.cdc.gov/h1n1flu/eua/. 28. Sorbello A, Jones SC, Carter W, et al. Emergency use authorization for intravenous peramivir: evaluation of safety in the treatment of hospitalized patients infected with 2009 H1N1 influenza A virus. Clin Infect Dis 2012; 55:1. 29. Yu Y, Garg S, Yu PA, et al. Peramivir use for treatment of hospitalized patients with influenza A(H1N1)pdm09 under emergency use authorization, October 2009-June 2010. Clin Infect Dis 2012; 55:8. 30. Whitley RJ, Hayden FG, Reisinger KS, et al. Oral oseltamivir treatment of influenza in children. Pediatr Infect Dis J 2001; 20:127. 31. Strong M, Burrows J, Stedman E, Redgrave P. Adverse drug effects following oseltamivir mass treatment and prophylaxis in a school outbreak of 2009 pandemic influenza A(H1N1) in June 2009, Sheffield, United Kingdom. Euro Surveill 2010; 15:pii/19565. 32. Heinonen S, Silvennoinen H, Lehtinen P, et al. Early oseltamivir treatment of influenza in children 1-3 years of age: a randomized controlled trial. Clin Infect Dis 2010; 51:887. 33. Siedler K, Skopnik H. Oseltamivir for treatment of influenza in infants less than one year: a retrospective analysis. Pediatr Infect Dis J 2010; 29:495. 34. Kimberlin DW, Shalabi M, Abzug MJ, et al. Safety of oseltamivir compared with the adamantanes in children less than 12 months of age. Pediatr Infect Dis J 2010; 29:195. 35. Okamoto S, Kamiya I, Kishida K, et al. Experience with oseltamivir for infants younger than 1 year old in Japan. Pediatr Infect Dis J 2005; 24:575. 36. Fiore AE, Fry A, Shay D, et al. Antiviral agents for the treatment and chemoprophylaxis of influenza --recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2011; 60:1. 37. Relenza (zanamivir) [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2008. 38. U.S. Food and Drug Administration. Tamiflu pediatric adverse events: Questions and answers www.fda.gov/cder/drug/infopage/tamiflu/QA20051117.htm (Accessed on September 06, 2011). 39. U.S. Food and Drug Administration. 2008 Safety alerts for drugs, biologics, medical devices, and dietary supplements. Tamiflu (oseltamivir phosphate). http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm095044.htm (Accessed on September 06, 2011). 40. U.S. Food and Drug Administration. 2008 Safety alerts for drugs, biologics, medical devices, and dietary supplements. Relenza (zanamivir). http://www.fda.gov/Safety/MedWatch/Safetyinformation/SafetyAlertsforHumanMedicalProducts/ucm094982.htm (Accessed on September 06, 2011). 41. Hoffman KB, Demakas A, Erdman CB, et al. Neuropsychiatric adverse effects of oseltamivir in the FDA Adverse Event Reporting System, 1999-2012. BMJ 2013; 347:f4656. 42. Pollack A. Childhood deaths in Japan bring new look at flu drug. New York Times, November 18, 2005. 43. Casscells SW, Granger E, Kress AM, Linton A. The association between oseltamivir use and adverse neuropsychiatric outcomes among TRICARE beneficiaries, ages 1 through 21 years diagnosed with influenza. Int J Adolesc Med Health 2009; 21:79. 44. Lindemann L, Jacobsen H, Schuhbauer D, et al. In vitro pharmacological selectivity profile of oseltamivir prodrug (Tamiflu) and active metabolite. Eur J Pharmacol 2010; 628:6. 45. Hoffmann G, Funk C, Fowler S, et al. Nonclinical pharmacokinetics of oseltamivir and oseltamivir carboxylate in the central nervous system. Antimicrob Agents Chemother 2009; 53:4753. 46. Smith JR, Sacks S. Incidence of neuropsychiatric adverse events in influenza patients treated with oseltamivir or no antiviral treatment. Int J Clin Pract 2009; 63:596.
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47. Toovey S, Rayner C, Prinssen E, et al. Assessment of neuropsychiatric adverse events in influenza patients treated with oseltamivir: a comprehensive review. Drug Saf 2008; 31:1097. 48. Terada K, Kawai Y, Monju A, et al. Adolescent jump case in Japan associated with influenza but not oseltamivir. Pediatr Infect Dis J 2008; 27:88. 49. Hara K, Tanabe T, Nakano R, et al. Clinical characteristics of children with abnormal behaviors associated with influenza infection. J Jpn Pediatr Soc 2007; 111:38. 50. Wang YH, Huang YC, Chang LY, et al. Clinical characteristics of children with influenza A virus infection requiring hospitalization. J Microbiol Immunol Infect 2003; 36:111. 51. Huang YC, Li WC, Tsao KC, et al. Influenza-associated central nervous system dysfunction in Taiwanese children: clinical characteristics and outcomes with and without administration of oseltamivir. Pediatr Infect Dis J 2009; 28:647. 52. Tanabe T, Hara K, Nakajima M, et al. Oseltamivir treatment for children showing abnormal behavior during influenza virus infection. Brain Dev 2010; 32:440. 53. CDC issues interim recommendations for the use of influenza antiviral medications in the setting of oseltamivir resistance among circulating influenza A (H1N1) viruses, 2008-09 influenza season. http://emergency.cdc.gov/HAN/han00279.asp (Accessed on September 06, 2011). 54. Hall CB, Dolin R, Gala CL, et al. Children with influenza A infection: treatment with rimantadine. Pediatrics 1987; 80:275. 55. Harper SA, Bradley JS, Englund JA, et al. 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; 48:1003. 56. Gilbert BE, Wilson SZ, Knight V, et al. Ribavirin small-particle aerosol treatment of infections caused by influenza virus strains A/Victoria/7/83 (H1N1) and B/Texas/1/84. Antimicrob Agents Chemother 1985; 27:309. 57. Chan-Tack KM, Murray JS, Birnkrant DB. Use of ribavirin to treat influenza. N Engl J Med 2009; 361:1713. 58. American Academy of Pediatrics. Influenza. In: Red Book: 2012 Report of the Committee on Infectious Diseases, 29th, Pickering LK. (Ed), American Academy of Pediatrics, Elk Grove Village, IL 2012. p.439. 59. Wang K, Shun-Shin M, Gill P, et al. Neuraminidase inhibitors for preventing and treating influenza in children. Cochrane Database Syst Rev 2012; 1:CD002744. 60. Shinjoh M, Takano Y, Takahashi T, et al. Postexposure prophylaxis for influenza in pediatric wards oseltamivir or zanamivir after rapid antigen detection. Pediatr Infect Dis J 2012; 31:1119. 61. Jackson RJ, Cooper KL, Tappenden P, et al. Oseltamivir, zanamivir and amantadine in the prevention of influenza: a systematic review. J Infect 2011; 62:14. 62. Crawford SA, Clover RD, Abell TD, et al. Rimantadine prophylaxis in children: a follow-up study. Pediatr Infect Dis J 1988; 7:379. 63. Glezen WP. Modifying clinical practices to manage influenza in children effectively. Pediatr Infect Dis J 2008; 27:738. 64. Clover RD, Crawford SA, Abell TD, et al. Effectiveness of rimantadine prophylaxis of children within families. Am J Dis Child 1986; 140:706. 65. American Academy of Pediatrics Committee on Infectious Diseases. Antiviral therapy and prophylaxis for influenza in children. Pediatrics 2007; 119:852. 66. American Academy of Pediatrics Committee on Infectious Diseases. Recommendations for prevention and control of influenza in children, 2011-2012. Pediatrics 2011; 128:813. 67. Tamiflu (oseltamivir) for oral suspension: potential medication errors. www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm183714.htm (Accessed on September 06, 2011). 68. FDA Public Health Alert: Potential medication errors with Tamiflu for oral suspension. www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm183649.htm (Accessed on September 06, 2011). 69. Khazeni N, Bravata DM, Holty JE, et al. Systematic review: safety and efficacy of extended-duration antiviral
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chemoprophylaxis against pandemic and seasonal influenza. Ann Intern Med 2009; 151:464. 70. De Serres G. 49th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) San Francisco, September 2009. 71. Louie JK, Yang S, Samuel MC, et al. Neuraminidase inhibitors for critically ill children with influenza. Pediatrics 2013; 132:e1539. 72. Smieja M. ACP Journal Club. Review: oseltamivir relieves symptoms but does not reduce hospitalizations in influenza. Ann Intern Med 2012; 157:JC3. 73. Jefferson T, Jones MA, Doshi P, et al. Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. Cochrane Database Syst Rev 2012; 1:CD008965. 74. Alves Galvao MG, Rocha Crispino Santos MA, Alves da Cunha AJ. Amantadine and rimantadine to prevent and treat influenza A in children and the elderly. http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD002745.pub3/abstract. 75. Aoki FY, Macleod MD, Paggiaro P, et al. Early administration of oral oseltamivir increases the benefits of influenza treatment. J Antimicrob Chemother 2003; 51:123. 76. Kawai N, Ikematsu H, Iwaki N, et al. Factors influencing the effectiveness of oseltamivir and amantadine for the treatment of influenza: a multicenter study from Japan of the 2002-2003 influenza season. Clin Infect Dis 2005; 40:1309. 77. Fry AM, Goswami D, Nahar K, et al. Efficacy of oseltamivir treatment started within 5 days of symptom onset to reduce influenza illness duration and virus shedding in an urban setting in Bangladesh: a randomised placebocontrolled trial. Lancet Infect Dis 2014; 14:109. 78. Cooper NJ, Sutton AJ, Abrams KR, et al. Effectiveness of neuraminidase inhibitors in treatment and prevention of influenza A and B: systematic review and meta-analyses of randomised controlled trials. BMJ 2003; 326:1235. 79. Piedra PA, Schulman KL, Blumentals WA. Effects of oseltamivir on influenza-related complications in children with chronic medical conditions. Pediatrics 2009; 124:170. 80. Yu H, Liao Q, Yuan Y, et al. Effectiveness of oseltamivir on disease progression and viral RNA shedding in patients with mild pandemic 2009 influenza A H1N1: opportunistic retrospective study of medical charts in China. BMJ 2010; 341:c4779. 81. Jain S, Kamimoto L, Bramley AM, et al. Hospitalized patients with 2009 H1N1 influenza in the United States, AprilJune 2009. N Engl J Med 2009; 361:1935. 82. Lee EH, Wu C, Lee EU, et al. Fatalities associated with the 2009 H1N1 influenza A virus in New York city. Clin Infect Dis 2010; 50:1498. 83. Farias JA, Fernndez A, Monteverde E, et al. Critically ill infants and children with influenza A (H1N1) in pediatric intensive care units in Argentina. Intensive Care Med 2010; 36:1015. 84. Domnguez-Cherit G, Lapinsky SE, Macias AE, et al. Critically Ill patients with 2009 influenza A(H1N1) in Mexico. JAMA 2009; 302:1880. 85. Creanga AA, Johnson TF, Graitcer SB, et al. Severity of 2009 pandemic influenza A (H1N1) virus infection in pregnant women. Obstet Gynecol 2010; 115:717. 86. Louie JK, Acosta M, Jamieson DJ, et al. Severe 2009 H1N1 influenza in pregnant and postpartum women in California. N Engl J Med 2010; 362:27. 87. Hsu J, Santesso N, Mustafa R, et al. Antivirals for treatment of influenza: a systematic review and meta-analysis of observational studies. Ann Intern Med 2012; 156:512. 88. Falagas ME, Koletsi PK, Vouloumanou EK, et al. Effectiveness and safety of neuraminidase inhibitors in reducing influenza complications: a meta-analysis of randomized controlled trials. J Antimicrob Chemother 2010; 65:1330. 89. Coffin SE, Leckerman K, Keren R, et al. Oseltamivir shortens hospital stays of critically ill children hospitalized with seasonal influenza: a retrospective cohort study. Pediatr Infect Dis J 2011; 30:962. 90. Kaiser L, Wat C, Mills T, et al. Impact of oseltamivir treatment on influenza-related lower respiratory tract complications and hospitalizations. Arch Intern Med 2003; 163:1667. 91. Jefferson T, Jones M, Doshi P, Del Mar C. Neuraminidase inhibitors for preventing and treating influenza in healthy
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adults: systematic review and meta-analysis. BMJ 2009; 339:b5106. 92. Hernn MA, Lipsitch M. Oseltamivir and risk of lower respiratory tract complications in patients with flu symptoms: a meta-analysis of eleven randomized clinical trials. Clin Infect Dis 2011; 53:277. 93. Sato M, Hosoya M, Kato K, Suzuki H. Viral shedding in children with influenza virus infections treated with neuraminidase inhibitors. Pediatr Infect Dis J 2005; 24:931. 94. Sugaya N, Tamura D, Yamazaki M, et al. Comparison of the clinical effectiveness of oseltamivir and zanamivir against influenza virus infection in children. Clin Infect Dis 2008; 47:339. 95. Li CC, Wang L, Eng HL, et al. Correlation of pandemic (H1N1) 2009 viral load with disease severity and prolonged viral shedding in children. Emerg Infect Dis 2010; 16:1265. 96. Ng S, Cowling BJ, Fang VJ, et al. Effects of oseltamivir treatment on duration of clinical illness and viral shedding and household transmission of influenza virus. Clin Infect Dis 2010; 50:707. 97. Kimberlin DW, Acosta EP, Prichard MN, et al. Oseltamivir pharmacokinetics, dosing, and resistance among children aged <2 years with influenza. J Infect Dis 2013; 207:709. 98. Acosta EP, Jester P, Gal P, et al. Oseltamivir dosing for influenza infection in premature neonates. J Infect Dis 2010; 202:563. 99. McPherson C, Warner B, Hunstad DA, et al. Oseltamivir dosing in premature infants. J Infect Dis 2012; 206:847. 100. Kumar D, Morris MI, Kotton CN, et al. Guidance on novel influenza A/H1N1 in solid organ transplant recipients. Am J Transplant 2010; 10:18. 101. WHO. Clinical management of human infection with avian influenza A (H5N1) virus http://www.who.int/influenza/resources/documents/clinical_management_h5n1_15_08_2007/en/index.html (Accessed on October 18, 2011). 102. South East Asia Infectious Disease Clinical Research Network. Effect of double dose oseltamivir on clinical and virological outcomes in children and adults admitted to hospital with severe influenza: double blind randomised controlled trial. BMJ 2013; 346:f3039. 103. Valinotto LE, Diez RA, Barrero PR, et al. Emergence of intratreatment resistance to oseltamivir in pandemic influenza A H1N1 2009 virus. Antivir Ther 2010; 15:923. 104. Suhaila M, Tang JW, Lee HK, et al. Mixtures of oseltamivir-sensitive and -resistant pandemic influenza A/H1N1/2009 viruses in immunocompromised hospitalized children. Pediatr Infect Dis J 2011; 30:625. 105. Nguyen HT, Fry AM, Loveless PA, et al. Recovery of a multidrug-resistant strain of pandemic influenza A 2009 (H1N1) virus carrying a dual H275Y/I223R mutation from a child after prolonged treatment with oseltamivir. Clin Infect Dis 2010; 51:983. 106. Whitley RJ, Boucher CA, Lina B, et al. Global assessment of resistance to neuraminidase inhibitors, 2008-2011: the Influenza Resistance Information Study (IRIS). Clin Infect Dis 2013; 56:1197. 107. CDC Recommendations for the amount of time persons with influenza-like illness should be away from others www.cdc.gov/h1n1flu/guidance/exclusion.htm (Accessed on September 06, 2011). Topic 5985 Version 30.0

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GRAPHICS Groups at high risk for influenza complications

Children <2 years* Adults !65 years of age Persons with chronic pulmonary (including asthma), cardiovascular (except hypertension), renal, hepatic, hematologic (including sickle cell disease), metabolic (including diabetes mellitus), neurologic, neuromuscular, and neurodevelopmental disorders (including disorders of the brain, spinal cord, peripheral nerve and muscle such as cerebral palsy, epilepsy, stroke, intellectual disability [mental retardation], moderate to severe developmental delay, muscular dystrophy, or spinal cord injury) Immunosuppression (including immunosuppression caused by medications or by human immunodeficiency virus) Women who are pregnant or postpartum (within 2 weeks after delivery) Children <19 years of age and receiving long-term aspirin therapy Native Americans and Alaskan Natives Morbidly obese (body mass index [BMI] !40 for adults or BMI >2.33 standard deviations above the mean for children) Residents of nursing homes and other chronic care facilities * Although all children <5 years of age are considered to be at higher risk for complications of influenza, the highest risk is for those <2 years of age, with the highest hospitalization and death rates among infants <6 months of age. Adapted from: Influenza Division, National Center for Immunization and Respiratory Diseases, CDC. Prevention and control of seasonal influenza with vaccines. MMWR Recomm Rep 2013; 62:1. Graphic 72029 Version 11.0

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Dosing recommendations for neuraminidase inhibiting agents for prevention of influenza in children and adolescents*
Drug/formulation
Oseltamivir (Tamiflu) # 30 mg capsule 45 mg capsule 75 mg capsule 6 mg/mL suspension $ Zanamivir (Relenza) 5 mg per inhalation (Diskhaler) * The choice of agent for prophylaxis depends upon the age of the patient and the susceptibility patterns of circulating strains (see text for details). The duration of prophylaxis depends upon the clinical circumstances of the individual case. Please see text for details. ! # Dose adjustment is necessary for patients with renal insufficiency. Oseltamivir doses for infants younger than one year of age are provided in the text. $ When dispensing the oral suspension of oseltamivir, providers and pharmacists must take care to provide a dosing device that matches the units of measure on the prescription. ! Zanamivir inhalation powder should not be reconstituted in any liquid formulation and is not recommended for use in nebulizers or mechanical ventilators. Data from: 1. American Academy of Pediatrics. Antiviral drugs. In: Red Book: 2012 Report of the Committee on Infectious Diseases, 29th ed, Pickering LK (Ed), American Academy of Pediatrics, Elk Grove Village, IL, 2012. p.841. 2. US Food and Drug Administration. Safety Alerts for Human Medical Products. Tamiflu (oseltamivir) for Oral Suspension. Available at: www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm18371 4.htm (Accessed on September 23, 2013). 3. US Food and Drug Administration. Safety Alerts for Human Medical Products. Relenza (zanamivir) Inhalation Powder. Available at: www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm18608 1.htm (Accessed on September 23, 2013). Graphic 61888 Version 13.0 Children !5 years and adults 2 inhalations (10 mg total per dose)

Dosing recommendations for prophylaxis

1 through 12 years "15 kg 30 mg once daily >15-23 kg 45 mg once daily >23-40 kg 60 mg once daily >40 kg 75 mg once daily !13 years 75 mg once daily

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Dosing recommendations for neuraminidase inhibiting agents for treatment of influenza in children and adolescents*
Drug/formulation
Oseltamivir (Tamiflu) 30 mg capsule 45 mg capsule 75 mg capsule 6 mg/mL suspension # 1 through 12 years "15 kg 60 mg/day divided into 2 doses for 5 days >15-23 kg 90 mg/day divided into 2 doses for 5 days >23-40 kg 120 mg/day divided into 2 doses for 5 days >40 kg 150 mg/day divided into 2 doses for 5 days

Dosing recommendations
!13 years 150 mg/day divided into 2 doses for 5 days

Children !12 months should receive ~4 mg/kg per day divided into 2 doses for a 5-day treatment course Children !7 years and adults 2 inhalations (10 mg total per dose), twice daily for 5 days

Zanamivir $ (Relenza) 5 mg per inhalation (Diskhaler)

* The choice of agent for treatment depends upon the age of the patient and the susceptibility patterns of circulating strains (see text for details). Dose adjustment is necessary for patients with renal insufficiency. Oseltamivir doses for infants younger than one year of age are provided in the text. ! # When dispensing the oral suspension of oseltamivir, providers and pharmacists must take care to provide a dosing device that matches the units of measure on the prescription. $ Zanamivir inhalation powder should not be reconstituted in any liquid formulation and is not recommended for use in nebulizers or mechanical ventilators. ! Two doses should be administered on day one, provided the doses can be spaced at least two hours apart. Data from: 1. American Academy of Pediatrics. Antiviral drugs. In: Red Book: 2012 Report of the Committee on Infectious Diseases, 29th ed, Pickering LK (Ed), American Academy of Pediatrics, Elk Grove Village, IL, 2012. p.841. 2. US Food and Drug Administration. Safety Alerts for Human Medical Products. Tamiflu (oseltamivir) for Oral Suspension. Available at: www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm18371 4.htm (Accessed on September 23, 2013). 3. US Food and Drug Administration. Safety Alerts for Human Medical Products. Relenza (zanamivir) Inhalation Powder. Available at: www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm18608 1.htm (Accessed on September 23, 2013). Graphic 70571 Version 10.0

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Influenza testing methods

Time Test
RT-PCR (conventional gel-based PCR, realtime RT-PCR, and multiplex PCR)

to results
2h

Acceptable specimens
NP swab, NP or bronchial washing, nasal or endotracheal aspirate, sputum, throat swab* NP swab or washing, bronchial washing, nasal or endotracheal aspirate

Comments
High sensitivity and very high specificity; highly recommended; can differentiate between influenza types (A or B) and subtypes (including pandemic H1N1 influenza and avian H5N1 influenza) Moderately high sensitivity and high specificity; recommended

Immunofluorescence

Direct fluorescent antibody staining Indirect fluorescent antibody staining

2-4 h

...

Detects and distinguishes between influenza A and B and between A/B and other respiratory viruses Detects and distinguishes between influenza A and B and between A/B and other respiratory viruses

2-4 h

...

Rapid influenza diagnostic tests #

NP swab, nasal washing, nasal aspirate, throat swab*

Low to moderate sensitivity and high specificity; recommended; during periods of peak influenza activity, negative rapid antigen tests do not reliably exclude influenza
Depending on which EIA test is used, will either detect influenza A only, will detect and distinguish between influenza A and B, or will detect but not distinguish between influenza A and B Detects but does not distinguish between influenza A and B

Antigen detection (EIA)

10-20 min

...

Neuraminidase detection assay

20-30 min

...

Viral culture

NP swab, NP or bronchial washing, nasal or endotracheal aspirate, sputum, throat swab*

48-72 h 3-10 days ... ...

Moderately high sensitivity and highest specificity; this test is important for confirming screening test results and for public health surveillance, but it is not useful for timely clinical management
... ...

Shell viral culture Isolation in cell culture

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Serologic tests (hemagglutinin inhibition, ELISA, complement-fixation, and neutralization) $

Serum

Available only in reference laboratories; not useful for timely clinical management; recommended only for retrospective diagnosis, surveillance, or research purposes

RT-PCR: reverse-transcriptase polymerase chain reaction; NP: nasopharyngeal; EIA: enzyme immunoassay; ELISA: enzyme-linked immunosorbent assay. * Throat swabs are inferior to NP specimens for the detection of influenza viruses, but may be used if NP specimens cannot be obtained. Requires fluorescence microscope. # Includes moderately complex and Clinical Laboratory Improvement Amendments (CLIA)-waived tests. $ Requires paired acute- and convalescent-phase serum samples. Adapted with permission from: 1. Harper SA, Bradley JS, Englund JA, et al. Seasonal Influenza in Adults and Children--Diagnosis, Treatment, Chemoprophylaxis and Institutional Outbreak Management: Clinical Practice Guidelines of the Infectious Diseases Society of America for Seasonal Influenza in Adults and Children. Clin Infect Dis 2009; 48:1003. Copyright 2009 University of Chicago Press. 2. US Centers for Disease Control and Prevention. Guidance for clinicians on the use of rapid influenza diagnostic tests. Available at: www.cdc.gov/flu/professionals/diagnosis/clinician_guidance_ridt.htm. Accessed on June 28, 2012.

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