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Official reprint from UpToDate www.uptodate.com ©2014 UpToDate

AuthorFlor M Munoz, MD, MSc

Section EditorsGeorge B Mallory, MDMorven S Edwards, MD

Deputy EditorMary M Torchia, MD

Seasonal influenza in children: Prevention and treatment with antiviral drugs

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 inoutbreaks 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 canbe associated with severe morbidity and mortality. Influenza causes an appreciable disease burden (eg, school and workabsence, 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 drugsalso may be used for prevention in high-risk patients who have not been immunized or who may have a suboptimalresponse to vaccine, in patients in whom influenza vaccine is contraindicated, and for anyone who wants to reduce theirrisk 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 thesechildren may develop influenza infection despite immunization. If so, they should be seen by their health care provider assoon as possible after symptom onset because treatment is most beneficial when started early in the course ofinfluenza.

The use of antiviral drugs in the prevention and treatment of influenza in children will be presented here. Influenzavaccination in children and the use of antiviral drugs in adults are discussed separately. (See "Seasonal influenzavaccination 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 WorldHealth Organization (WHO) and its reporting network, tracks influenza virus isolates throughout the world to monitordisease activity and to predict the appropriate components for the annual influenza vaccine. CDC and WHO surveillancebetween 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 causeddisproportionately severe illness among children and young adults during the 2009 pandemic [7,8]. It is not possible topredict whether this pattern will continue through the remainder of the 2013-2014 influenza season. Surveillanceinformation, which is updated weekly during influenza season, is available via the CDC. In addition, FluNet, a databasefor global influenza virus surveillance, is available via the WHO. Local hospital or clinic laboratories may also collectinformation to monitor influenza activity in a specific geographic area.

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Since July 2011, H3N2 influenza A variant viruses caused by reassortment of swine-origin H3N2 influenza A viruses andpandemic H1N1 influenza A viruses have been increasingly reported in the United States [9-11]. These viruses aresusceptible to oseltamivir and zanamivir, but resistant to amantadine and rimantadine. Additional unexpectedreassortment 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 inchildren: neuraminidase inhibitors and adamantanes (M2 inhibitors) [1,12]. Neuraminidase inhibitors and adamantanesshould not be used to treat illnesses caused by other respiratory viruses. The pharmacology of these drugs is discussedseparately. (See "Pharmacology of antiviral drugs for influenza".)

Since September 2009, >99 percent of circulating influenza virus strains have been susceptible to neuraminidaseinhibitors [13-18]. However, high levels of resistance to adamantanes exist in the currently circulating strains and theyshould not be used for treatment of influenza. Information regarding antiviral resistance that emerges during theinfluenza season is available through the Centers for Disease Control and Prevention (CDC).

Neuraminidase inhibitors — Oseltamivir, zanamivir, laninamivir, and peramivir are neuraminidase inhibitors, whichprevent 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 inthe 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 ofage and the prophylaxis of influenza A and B viruses in individuals ≥1 year of age [12,20]. However, it may be usedfor 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 andduration 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 Statesfor 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 theindication (table 2 and table 3). Zanamivir inhalation powder should not be reconstituted in any liquid formulationand is not recommended for use in nebulizers or mechanical ventilators [21]. Zanamivir is not recommended forpatients with a history of wheezing or underlying chronic respiratory disease [12]. These patients are at increasedrisk of developing bronchospasm and occasionally may have some decline in their respiratory function afteradministration of zanamivir.

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Intravenous zanamivir is available for investigational use and may be warranted for severely ill patients withoseltamivir-resistant 2009 H1N1 influenza infection, and patients who cannot tolerate or absorb oral oseltamivirbecause of suspected or known gastric stasis, malabsorption, or gastrointestinal bleeding [22]. Additionalinformation 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 thoseof oseltamivir and zanamivir [23,24].

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Peramivir – Peramivir is an intravenously administered neuraminidase inhibitor that is available in some countries●

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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 8.5percent 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 wereprescribed oseltamivir prophylaxis discontinued it because of adverse effects (predominantly nausea, vomiting, andrash) [31]. In retrospective reviews, the use of oseltamivir for the treatment of influenza among infants younger than 12months 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 forpersons receiving inhaled zanamivir and placebo [12,36]. The most common adverse events (reported in fewer than 5percent 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 withinfluenza 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 (includingtoxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme) [20]. Most of the reports ofneuropsychiatric events involved oseltamivir and occurred in children in Japan, where the use of neuraminidaseinhibitors is widespread [42]. The events often had an abrupt onset and rapid resolution [40]. Severe skin reactions alsohave been reported in adults and non-Japanese children. A causal association between neuraminidase inhibitors andthese events has not been established [43-47]. Some of the adverse events may have been related to influenza infectionrather 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 targetthe M2 protein of influenza A, which forms a protein channel in the viral membrane that is essential for efficient viralreplication. Adamantanes are not active against influenza B viruses or against currently circulating strains of influenza Avirus [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 resistanceoccurs [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. Althoughrimantadine is not licensed by the FDA for the treatment of influenza in children younger than 13 years, published datasuggest 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 forinfluenza".)

Ribavirin — Ribavirin is a nucleoside analog that has in vitro activity against both influenza A and B viruses. Reportshave 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 Controland Prevention (CDC) between October 1 and December 7, 2013 were sensitive to oseltamivir and all were susceptible

(eg, Japan, Korea), but no longer in the United States [27-29].

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to zanamivir [7]. Information regarding antiviral resistance that emerges during the influenza season is available throughthe 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 notdistinguish oseltamivir-resistant from oseltamivir-susceptible viruses [36]. Clinicians should review local surveillance datato know which types and subtypes of influenza viruses are circulating in their communities. Local surveillance data maybe obtained through the CDC. Certain laboratory tests can distinguish between influenza A and B viruses, and betweeninfluenza 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 chemoprophylaxisshould 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 intramuscularinjection) to provide protection until an immune response develops. Individuals immunized with the live-attenuatedinfluenza vaccine (given intranasally) should not receive chemoprophylaxis for 14 days after receipt of the vaccinebecause 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 influenzavaccine 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 childor the child's contacts, the potential for adverse side effects, the possibility of development of antiviral resistance, thelikelihood of completion of therapy (failure to complete therapy may contribute to the development of resistance), and thesupply 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 andPrevention (CDC) and American Academy of Pediatrics (AAP) recommend that pre-exposure chemoprophylaxis bereserved for persons who are at high risk for influenza-related complications who cannot otherwise be protected duringtimes when they are at high risk for exposure to influenza [5,12]. Indiscriminant use of chemoprophylaxis may promoteresistance to antiviral medications and reduce availability of antiviral medications for the treatment of individuals who areseverely ill or at high risk of influenza complications.

When an outbreak of seasonal influenza is present in the community, potential target groups for pre-exposurechemoprophylaxis 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 tochildren younger than 24 months and unimmunized children who are at high risk for severe or complicatedinfluenza

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Unimmunized staff and children (to control influenza outbreaks in a closed institutional setting with pediatricresidents at high risk for severe or complicated influenza)

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High-risk children who may not respond to influenza vaccine, including those who are immunocompromised (as a●

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Post-exposure prophylaxis — Post-exposure prophylaxis may be warranted for children who have had closecontact with a confirmed or suspected case of influenza during the infectious period (ie, one day before the onset ofsymptoms until 24 hours after the fever ends) and who are at high risk for complications of influenza (table 1) [12]. Post-exposure prophylaxis should be used only when antivirals can be started within 48 hours of the most recent exposure.

Postexposure prophylaxis is not indicated [12]:

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 andhospital contacts of patients with laboratory-confirmed influenza [12,59,60]. Nonetheless, patients should be informedthat chemoprophylaxis lowers, but does not eliminate, the risk of influenza, that susceptibility to influenza returns oncethe antiviral medication is stopped, and that immunization remains the primary means of protection [5]. High-riskindividuals should seek medical evaluation if they develop a febrile respiratory illness or moderate to severe illnessdespite 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'.)

Choice of drug — The choice of agent for prophylaxis is influenced by the age of the child and the susceptibilitypatterns of circulating strains (if known) (table 2) [5,12]. Neuraminidase inhibitors are recommended for the 2013-2014influenza season based on viral surveillance and resistance data indicating that >99 percent of currently circulatinginfluenza viruses are susceptible to neuraminidase inhibitors [7,18]. The CDC will provide updated recommendations forchemoprophylaxis as indicated throughout the 2013-2014 influenza season.

Prophylaxis dosing — The doses of the neuraminidase inhibitors used for influenza prophylaxis for children ≥1 year ofage are listed in the table (table 2) [65]. Oseltamivir dosing for full-term infants <1 year of age depends upon the weightof the infant [36]:

If weight is not known, dosing should be determined by age as follows [66]:

supplement to influenza immunization)

Children at high risk and their family members/close contacts and healthcare providers when circulating strains ofinfluenza virus are not matched with seasonal influenza vaccine strains (based on data from the CDC and localhealth departments) [12,36] (see 'Influenza activity' above)

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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 feverends)

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Neuraminidase inhibitors – A systematic review of seven randomized controlled trials found that prophylactic use ofneuraminidase inhibitors reduced the risk of developing seasonal influenza by 70 to 90 percent [61]. The highestrates 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].

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Adamantanes – Amantadine and rimantadine are not active against influenza B viruses. When usedprophylactically, amantadine and rimantadine have been reported to be 70 to 90 percent effective in preventingclinical 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 Aviruses are not susceptible to adamantanes [13-15].

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Age <3 months – Not recommended, except in critical situations●Age 3 through 11 months – 3 mg/kg per dose once daily●

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The dosing regimens recommended above are not intended for premature infants, who may have slower clearance ofoseltamivir due to immature renal function; doses recommended for full-term infants may lead to very high drugconcentrations in premature infants younger than one year [36]. Limited data from cohorts of premature infants whoreceived 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 takecare to provide a dosing device that matches the units of measure on the prescription [67,68]. Healthcare providersshould write doses in milligrams (mg) if the dosing dispenser with the drug is in mg [68]. As an alternative, the oraldosing 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 prescribedmilliliter (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, cornsyrup, 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 receivingchemoprophylaxis while awaiting the development of an immune response to the vaccine, the duration is usually twoweeks [12]. Otherwise, pre-exposure chemoprophylaxis should be administered every day for the duration of potentialexposure to a person with influenza. Zanamivir regimens as long as 28 days and oseltamivir regimens as long as 42days 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 controlof outbreaks in long-term care facilities and hospitals, chemoprophylaxis should be administered for a minimum of twoweeks, 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) andAmerican Academy of Pediatrics (AAP) provide the following indications for antiviral treatment [12,70]:

For most previously healthy children, influenza is a mild and self-limiting infection [1-3]. Unnecessary treatment of suchchildren, even when they present early in the course of illness, has the potential effect of resulting in a diminished supplyof drugs for patients at risk for severe illness. In addition, indiscriminate treatment may contribute to the development ofantiviral resistance. (See 'Antiviral resistance' above.)

Timing of treatment — When clinically indicated, antiviral therapy should be started as soon as possible after symptomonset, ideally within 48 hours [12]. Antiviral therapy may be administered after 48 hours of symptoms, particularly in

Age four to five months – 17 mg once daily●Age 6 to 11 months – 24 mg once daily●

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 influenza-immunization status

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Any otherwise-healthy child with influenza infection for whom a decrease in duration of clinical symptoms is felt tobe warranted by his or her provider (particularly if treatment can be initiated within 48 hours of illness onset)

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hospitalized children, those with severe or progressive disease, and those at high risk of complications. However, earliertreatment is associated with improved outcome. In a case-control study, earlier initiation of neuraminidase inhibitortherapy among children (<18 years) with influenza requiring intensive care therapy was associated with decreasedmortality (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 confirmationwith 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 anddiagnosis", section on 'Laboratory diagnosis'.)

Efficacy/effectiveness

Clinical illness — In randomized trials and meta-analyses, antiviral treatment of children and otherwise-healthyindividuals within two days of seasonal influenza illness onset shortens the duration of illness by approximately one dayand hastens the return to normal activity compared with placebo [59,72-74]. If antiviral therapy is administered within 12hours of symptom onset, the reduction of duration may be increased by as many as three days [75,76]. The benefitsmay be increased in young children. In a randomized trial, initiation of oseltamivir within 24 hours of the onset ofsymptoms shortened the median time to resolution of illness by 3.5 days (3 versus 6.5 days) in children one to threeyears of age [32].

In a large randomized trial in children, treatment with oseltamivir shortened influenza-like illness by approximately oneday [30]. Among 695 children with influenza symptoms (fever, cough, coryza), approximately two-thirds had laboratory-confirmed influenza. Compared with children with influenza-like illness who were treated with placebo, those treated withoseltamivir had significant reduction in:

Antiviral treatment also may be effective if administered within five days of symptom onset. In a randomized trial in 1190individuals (median age five years), initiation of oseltamivir within five days of symptom onset reduced duration ofsymptoms 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 high-risk 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 antiviraltreatment can reduce the risk of complications, severe illness, or death [59,71,79-88]. In a retrospective study, treatmentwith neuraminidase inhibitors within 24 hours of hospital admission was associated with decreased duration ofhospitalization among critically ill children with seasonal influenza [89]. However, no decrease in duration of intensivecare 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 iscontroversial. A meta-analysis of 10 trials, 8 of which were not published (all 10 of which were funded by the maker ofoseltamivir) and pooled analysis of 2 published trials came to differing conclusions about prevention of lower respiratorytract complications [90,91]. An independent meta-analysis of the same ten trials and a subsequent randomized trialconcluded 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 withantibiotics [92].

A subsequent meta-analysis of observational studies evaluated the effectiveness of oseltamivir versus no treatment 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)●

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the prevention of influenza hospitalization and mortality [87]. Only observational studies that adjusted for potentialconfounding factors were included. In pooled analysis of four studies, oseltamivir appeared to reduce hospitalizationamong outpatients (odds ratio [OR] 0.75, 95% CI 0.66-0.89) and in pooled analysis of three studies, oseltamivirappeared to reduce mortality among hospitalized high-risk patients (OR 0.23, 95% CI 0.13-0.43). However, given theinherent 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 viralshedding, 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 symptomonset 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 astudy of children hospitalized with pandemic 2009 H1N1 influenza virus who were treated with oseltamivir, viral sheddingpersisted for a median of nine days after the onset of symptoms [95]. In an outpatient study of 384 patients with positiverapid tests for influenza, oseltamivir treatment within 24 hours of symptom onset did not reduce or householdtransmission of influenza [96].

Choice of agent — The choice of agent for treatment of influenza is influenced by the age of the child, the susceptibilitypatterns 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 viralsurveillance and resistance data indicating that >99 percent of currently circulating influenza viruses are susceptible toneuraminidase inhibitors [7,18]. The CDC will provide updated treatment recommendations as indicated throughout the2013-2014 influenza season. (See 'Antiviral resistance' above.)

Treatment dosing — The doses of the neuraminidase inhibiting agents used for influenza treatment for children ≥1 yearof 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 recommendsoseltamivir 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 curveselected to maximize effectiveness and minimize development of resistance) [97]. However, a dose of 3.5 mg/kg twicedaily was necessary to reliably achieve the target exposure in infants 9 through 11 months of age. Although the authorsof the study suggest that the appropriate dose of oseltamivir for infants 9 through 11 months of age is 3.5 mg/kg twicedaily, the CDC has not revised its recommendations for this age group.

If the infant’s weight is not known, dosing by age may be necessary [66]:

The dosing regimens recommended above are not intended for premature infants, who may have slower clearance ofoseltamivir due to immature renal function; doses recommended for full-term infants may lead to very high drugconcentrations in premature infants younger than one year [36]. Limited data from a cohort of 32 premature infants whowere inadvertently exposed to 2009 pandemic H1N1 influenza by a healthcare worker suggest that 1.0 mg/kg twice dailyproduces drug concentrations similar to those in older children receiving 3 mg/kg twice daily [98]. Additional limited datasupport 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

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●

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care to provide a dosing device that matches the units of measure on the prescription [67,68]. Healthcare providersshould write doses in mg if the dosing dispenser with the drug is in mg [68]. As an alternative, the oral dosing dispenserthat is provided in the package (which has markings for 30 mg, 45 mg, and 60 mg) can be removed, and pharmacists orhealthcare 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 withH5N1 avian influenza and was also suggested for certain severely ill patients (eg, immunocompromised hosts) duringthe H1N1 influenza pandemic [100,101]. However, in a randomized trial of 326 patients with severe influenza (75 percentof 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 70percent); mortality (7.3 versus 5.6 percent); median days of supplemental oxygen, intensive care, or mechanicalventilation; or tolerability [102]. Viral clearance was not related to virus type/subtype, age, or duration of illness beforeenrollment.

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, cornsyrup, 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 influenzatreatment 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 infectionwith an antiviral resistant virus. Oseltamivir resistance has been reported among children and immunocompromisedduring 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, peramivirand 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, andmyalgia with acetaminophen. The use of salicylates should be avoided in children younger than 18 years of age becauseof the association with Reye syndrome. (See "Acute toxic-metabolic encephalopathy in children", section on 'Reyesyndrome'.)

Over-the-counter cold medications have no proven benefit and have been associated with fatal overdose in youngchildren. 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 acuteinfluenza, such as bacterial pneumonia, otitis media, and sinusitis. The choice of antibiotics may be aided byexamination and culture of appropriate specimens. However, if the etiology of the bacterial complication is not clear fromthe examination of such specimens, empiric antibiotics generally should be directed at the most common bacterialpathogens 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: Inpatienttreatment", 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, standardprecautions and droplet precautions are recommended for the duration of illness [58]. (See "Infection control measuresto 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 tractinfection, severe illness, or rapid clinical deterioration), children with an influenza-like illness should stay away fromhealthcare settings and high-risk individuals until at least seven days after onset of symptoms or 24 hours afterresolution 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 stayhome from school or day care until 24 hours after their fever (temperature >100ºF (37.8ºC)) has resolved withoutantipyretics [107]. This recommendation applies whether or not the child received antiviral therapy. It also applies toother 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 “Beyondthe Basics.” The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, andthey answer the four or five key questions a patient might have about a given condition. These articles are best forpatients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient educationpieces are longer, more sophisticated, and more detailed. These articles are written at the 10 to 12 grade readinglevel 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 toyour patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” andthe keyword(s) of interest.)

SUMMARY AND RECOMMENDATIONS

Resistance

Prophylaxis

th th

th th

Basics topics (see "Patient information: Flu (The Basics)")●

Beyond the Basics topics (see "Patient information: Influenza prevention (Beyond the Basics)" and "Patientinformation: Influenza symptoms and treatment (Beyond the Basics)")

●

Influenza viruses circulating during the 2013-2014 season are susceptible to neuraminidase inhibitors (oseltamivirand zanamivir), but the current strains exhibit high levels of resistance to adamantanes (amantadine andrimantadine). (See 'Antiviral resistance' above.)

●

Immunization is the major means of prevention of influenza infection. Chemoprophylaxis should not replacevaccination 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. Factorsto be considered in the benefit-to-risk calculation include the potential for severe or complicated infection in thechild or the child's contacts, the potential for adverse side effects, the possibility of development of antiviralresistance, the likelihood of completion of therapy, and the supply of chemoprophylactic drugs (which are the sameagents used for influenza treatment). (See 'Target groups' above.)

●

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Treatment

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REFERENCES

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2. Kumar S, Havens PL, Chusid MJ, et al. Clinical and epidemiologic characteristics of children hospitalized with2009 pandemic H1N1 influenza A infection. Pediatr Infect Dis J 2010; 29:591.

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 prophylaxisshould be continued for seven days after the last known exposure. For control of outbreaks in long-term carefacilities and hospitals, chemoprophylaxis should be administered for a minimum of two weeks, and up to one weekafter the last known case was identified. (See 'Duration' above.)

●

Among individuals without risk factors for severe or complicated influenza (table 1), treatment of influenza withantiviral therapy shortens the duration of illness by approximately one day if initiated within 48 hours of illnessonset. (See 'Efficacy/effectiveness' above.)

●

Antiviral treatment of high-risk patients has not been shown to reduce the duration of illness, but may decrease therisk 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 48hours of symptom onset. Laboratory confirmation should not delay the initiation of antiviral therapy in individuals inwhom 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, werecommend 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 isfelt to be warranted by his or her provider

•

Neuraminidase inhibitors (oseltamivir or zanamivir) are recommended for the treatment of influenza virus duringthe 2013-2014 influenza season. The choice of agent depends upon the age of the child (table 3). (See 'Choice ofagent' above.)

●

Dosing for oseltamivir treatment varies according to the child's weight (table 3). The dose for zanamivir treatment is10 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 18years of age (Grade 1C). (See 'Supportive care' above.)

●

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104. Suhaila M, Tang JW, Lee HK, et al. Mixtures of oseltamivir-sensitive and -resistant pandemic influenzaA/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. ClinInfect 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 otherswww.cdc.gov/h1n1flu/guidance/exclusion.htm (Accessed on September 06, 2011).

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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, spinalcord, peripheral nerve and muscle such as cerebral palsy, epilepsy, stroke, intellectual disability[mental retardation], moderate to severe developmental delay, muscular dystrophy, or spinal cordinjury)

Immunosuppression (including immunosuppression caused by medications or by humanimmunodeficiency 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 themean 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.

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Dosing recommendations for neuraminidase inhibiting agents forprevention of influenza in children and adolescents*

Drug/formulation Dosing recommendations for prophylaxis

Oseltamivir(Tamiflu)

30 mg capsule

45 mg capsule

75 mg capsule

6 mg/mL suspension

1 through 12 years ≥13 years

≤15 kg >15-23 kg >23-40 kg >40 kg 75 mg oncedaily30 mg once

daily45 mg oncedaily

60 mg oncedaily

75 mg oncedaily

Zanamivir (Relenza)

5 mg per inhalation(Diskhaler)

Children ≥5 years and adults

2 inhalations (10 mg total per dose)

* The choice of agent for prophylaxis depends upon the age of the patient and the susceptibility patterns ofcirculating strains (see text for details).• The duration of prophylaxis depends upon the clinical circumstances of the individual case. Please seetext for details. Δ Dose adjustment is necessary for patients with renal insufficiency. Oseltamivir doses for infants youngerthan one year of age are provided in the text.◊ When dispensing the oral suspension of oseltamivir, providers and pharmacists must take care to providea dosing device that matches the units of measure on the prescription. § Zanamivir inhalation powder should not be reconstituted in any liquid formulation and is notrecommended 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/ucm183714.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/ucm186081.htm (Accessed on September 23, 2013).

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Dosing recommendations for neuraminidase inhibiting agents fortreatment of influenza in children and adolescents*

Drug/formulation Dosing recommendations

Oseltamivir(Tamiflu)

30 mg capsule

45 mg capsule

75 mg capsule

6 mg/mL suspension

1 through 12 years ≥13 years

≤15 kg >15-23 kg >23-40 kg >40 kg 150 mg/daydivided into2 doses for 5days

60 mg/daydivided into2 doses for5 days

90 mg/daydivided into2 doses for5 days

120 mg/daydivided into2 doses for 5days

150 mg/daydivided into2 doses for 5days

Children ≥12 months should receive ~4 mg/kg per daydivided into 2 doses for a 5-day treatment course

Zanamivir(Relenza)

5 mg per inhalation(Diskhaler)

Children ≥7 years and adults

2 inhalations (10 mg total per dose), twice daily for 5 days

* The choice of agent for treatment depends upon the age of the patient and the susceptibility patterns ofcirculating strains (see text for details).• Dose adjustment is necessary for patients with renal insufficiency. Oseltamivir doses for infants youngerthan one year of age are provided in the text. Δ When dispensing the oral suspension of oseltamivir, providers and pharmacists must take care to providea dosing device that matches the units of measure on the prescription.◊ Zanamivir inhalation powder should not be reconstituted in any liquid formulation and is notrecommended for use in nebulizers or mechanical ventilators. § Two doses should be administered on day one, provided the doses can be spaced at least two hoursapart.

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/ucm183714.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/ucm186081.htm (Accessed on September 23, 2013).

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Influenza testing methods

TestTime

toresults

Acceptablespecimens

Comments

RT-PCR (conventionalgel-based PCR, real-time RT-PCR, andmultiplex PCR)

2 h NP swab, NP orbronchial washing,nasal orendotrachealaspirate, sputum,throat swab*

High sensitivity and very high specificity;highly recommended; can differentiatebetween influenza types (A or B) andsubtypes (including pandemic H1N1influenza and avian H5N1 influenza)

Immunofluorescence NP swab orwashing, bronchialwashing, nasal orendotrachealaspirate

Moderately high sensitivity and highspecificity; recommended

Direct fluorescentantibody staining

2-4 h ... Detects and distinguishes between influenza Aand B and between A/B and other respiratoryviruses

Indirect fluorescentantibody staining

2-4 h ... Detects and distinguishes between influenza Aand B and between A/B and other respiratoryviruses

Rapid influenzadiagnostic tests

NP swab, nasalwashing, nasalaspirate, throatswab*

Low to moderate sensitivity and highspecificity; recommended; during periods ofpeak influenza activity, negative rapidantigen tests do not reliably excludeinfluenza

Antigen detection(EIA)

10-20 min ... Depending on which EIA test is used, will eitherdetect influenza A only, will detect anddistinguish between influenza A and B, or willdetect but not distinguish between influenza Aand B

Neuraminidasedetection assay

20-30 min ... Detects but does not distinguish betweeninfluenza A and B

Viral culture NP swab, NP orbronchial washing,nasal orendotrachealaspirate, sputum,throat swab*

Moderately high sensitivity and highestspecificity; this test is important forconfirming screening test results and forpublic health surveillance, but it is notuseful for timely clinical management

Shell viral culture 48-72 h ... ...

Isolation in cellculture

3-10 days ... ...

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Serologic tests(hemagglutinininhibition, ELISA,complement-fixation,and neutralization)

Serum Available only in reference laboratories; notuseful for timely clinical management;recommended only for retrospectivediagnosis, surveillance, or researchpurposes

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 NPspecimens cannot be obtained.• Requires fluorescence microscope.Δ 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 theInfectious 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 influenzadiagnostic tests. Available at: www.cdc.gov/flu/professionals/diagnosis/clinician_guidance_ridt.htm.Accessed on June 28, 2012.

http://www.journals.uchicago.edu/

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