Seasonal influenza in children: Management

INTRODUCTION — Influenza is an acute respiratory illness caused by influenza A or B viruses, and rarely influenza C viruses. It occurs in outbreaks worldwide every year, mainly during the winter seasons in temperate climates.

Influenza generally is an acute, self-limited, and uncomplicated disease in healthy children, but it can be associated with severe morbidity and mortality. Certain groups of children are at increased risk of severe or complicated influenza infection (table 1).

Immunization is the most important public health measure for the prevention of influenza infection. However, not all children receive influenza immunization, and children may develop influenza despite influenza immunization. Antiviral drugs are an important treatment option for patients who develop influenza.

The treatment of seasonal influenza in children will be presented here. The clinical features and diagnosis of influenza in children, influenza vaccination in children, the use of antiviral drugs for the prevention of influenza in children, the treatment of influenza in in adults, and the pharmacology of antiviral drugs used for influenza are discussed separately.

●(See "Seasonal influenza in children: Clinical features and diagnosis".)

●(See "Seasonal influenza in children: Prevention with vaccines".)

●(See "Seasonal influenza in children: Prevention with antiviral drugs".)

●(See "Seasonal influenza in adults: Role of antiviral prophylaxis for prevention" and "Seasonal influenza in nonpregnant adults: Treatment".)

●(See "Antiviral drugs for influenza: Pharmacology and resistance".)

GENERAL MEASURES

Symptom management — Influenza-related discomfort due to fever, headache, pharyngitis, and/or myalgia can be treated with acetaminophen or nonsteroidal anti-inflammatory drugs (eg, ibuprofen). 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'.)

Symptomatic management of cough and rhinitis is the same as that for the common cold. It is discussed separately. (See "The common cold in children: Management and prevention", section on 'Symptomatic therapy'.)

Over-the-counter combination cold medications have no proven benefit and have been associated with fatal overdose in children. They are not recommended. (See "The common cold in children: Management and prevention", section on 'Over-the-counter medications'.)

Indications for hospitalization — The decision to hospitalize a child with influenza is individualized. Potential indications for hospitalization include:

●Significant dyspnea at rest

●Change in mental status

●Progressive illness or clinical deterioration, especially if associated with hypoxemia

●Dehydration or inability to maintain hydration orally

●Worsening of chronic medical conditions

●Development of serious complications (eg, myocarditis, encephalitis, lower respiratory tract complications such as secondary bacterial pneumonia, severe myositis) (see "Seasonal influenza in children: Clinical features and diagnosis", section on 'Complications')

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 [1]. (See "Infection control measures for prevention of seasonal influenza", section on 'Isolation precautions'.)

Unless children require evaluation for influenza-like illness (eg, high-risk group (table 1), evidence of lower respiratory tract infection, severe illness, or rapid clinical deterioration), children with an influenza-like illness should avoid health care settings and contact with high-risk individuals until at least seven days after onset of symptoms or 24 hours after resolution of fever, whichever is longer [2,3]. Viral shedding, even with treatment, may exceed 10 days [4].

The Centers for Disease Control and Prevention recommends that children with an influenza-like illness stay home from school or day care until 24 hours after their fever (temperature >100.4°F [38°C]) has resolved without antipyretics [2]. 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).

ANTIVIRAL THERAPY — Antiviral drugs are an important treatment option for patients with influenza infection. Our recommendations for antiviral therapy are largely consistent with those of professional groups, including the Centers for Disease Control and Prevention [5,6], the American Academy of Pediatrics [1,7], and the Infectious Diseases Society of America [8]. (See 'Society guideline links' below.)

Licensed antiviral agents — The pharmacology of antiviral agents is discussed in detail separately. (See "Antiviral drugs for influenza: Pharmacology and resistance".)

The availability of licensed antiviral agents varies locally, particularly for peramivir and baloxavir.

●Neuraminidase inhibitors – Neuraminidase inhibitors prevent the release of virions from the host cell [9]. Neuraminidase inhibitors are active against influenza A viruses and influenza B viruses [5]. However, clinical trials of peramivir included a limited number of subjects with influenza B virus [10].

Neuraminidase inhibitors include:

•Oseltamivir – Oseltamivir is administered orally. In the United States, oseltamivir is licensed for the treatment of influenza in individuals ≥2 weeks of age [5], but it may be used in neonates when indicated [11]. (See 'Indications and preferred regimens' below.)

•Zanamivir – Dry powder zanamivir is administered by oral inhalation. In the United States, dry powder zanamivir is licensed for the treatment of influenza in individuals ≥7 years of age [12]. Use of a dry powder inhaler requires high enough inspiratory flow to mobilize and aerosolize the medication. It is prudent to ask the child to demonstrate proper technique before prescribing zanamivir.

An intravenous (IV) form of zanamivir has been evaluated in clinical trials [13,14]. The IV form is licensed in the United Kingdom and Europe but not in the United States [15,16].

•Peramivir – Peramivir is administered intravenously in a single dose. In the United States, peramivir is licensed for the treatment of influenza in patients ≥6 months who have been ill for ≤2 days [10].

•Laninamivir – Laninamivir is a long-acting inhaled neuraminidase inhibitor that is licensed for the treatment of influenza in Japan.

●Baloxavir – Baloxavir is administered orally in a single dose. It blocks influenza proliferation by inhibiting initiation of mRNA synthesis [17]. It has activity against influenza A and influenza B viruses.

In the United States, baloxavir is licensed for the treatment of uncomplicated influenza in children ≥5 to <12 years of age who are not at high risk for severe or complicated influenza (table 1) and in people ≥12 years of age whether or not they are at high risk for severe or complicated influenza [18].

In Japan, it is licensed for the treatment of influenza in people ≥12 years and children <12 years who weigh at least 10 kg.

●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.

Circulating strains of influenza A virus have been widely resistant to adamantane drugs since 2009 and they are not recommended for treatment of influenza [5,6,19]. (See "Antiviral drugs for influenza: Pharmacology and resistance".)

Efficacy

Neuraminidase inhibitors

●Duration of symptoms – Neuraminidase inhibitors reduce the duration of influenza symptoms by approximately one day compared with placebo if started within 48 hours of symptom onset.

Among the neuraminidase inhibitors, oseltamivir is the best studied in children, but data in high-risk children are limited. A 2014 systematic review of regulatory information (including published and unpublished data) identified three randomized trials evaluating oseltamivir in children [20]. In the single trial that enrolled healthy children (n = 669), oseltamivir shortened the mean duration of influenza symptoms by approximately 29 hours (95% CI 12-47 hours). A subsequent randomized trial supported these findings [21]. In the systematic review, two trials enrolled children with asthma (n = 660), and the duration of symptoms was similar in oseltamivir-treated and placebo-treated children (mean difference 5 hours, 95% CI -11 to 31 hours) [20].

In a similar meta-analysis of two pediatric trials evaluating zanamivir in children (n = 723), there was a nonsignificant trend towards reduced duration of symptoms with zanamivir treatment (mean difference 26 hours, 95% CI -56 to 3.6 hours) [22]. The difference in symptom duration was statistically significant in the meta-analysis of adult trials and the test for subgroup difference between adult and pediatric trials suggested that the effect was likely similar in both populations. When the adult and pediatric data were pooled together, zanamivir reduced the duration of symptoms by approximately 16 hours (95% CI 11-21 hours) [22].

A single randomized trial directly comparing oseltamivir and baloxavir found that the two agents have similar efficacy in reducing clinical illness in pediatric patients who lack risk factors for severe influenza (table 1) [23].

Clinical trials directly comparing different neuraminidase inhibitors with each other are lacking. Indirect comparisons using data from placebo-controlled trials (ie, network meta-analysis) suggest that zanamivir may be more effective than other antiviral agents in reducing clinical symptoms [24]. However, only 4 of the 26 trials included in the network meta-analysis were performed in hospitalized patients and only 5 trials were limited to pediatric patients.

Adult clinical trial data are discussed in greater detail separately. (See "Seasonal influenza in nonpregnant adults: Treatment".)

●Hospitalization and complications – Neuraminidase inhibitors may reduce the risk lower respiratory tract complications, hospitalization, severe illness, or death compared with placebo or no treatment.

Meta-analyses of randomized trials performed by different groups with different inclusion criteria have come to differing conclusions about the effect of neuraminidase inhibitors on hospitalization, lower respiratory tract complications, and other complications in adults; data in children are limited [20,22,25-27]. Adult clinical trial data are discussed in greater detail separately. (See "Seasonal influenza in nonpregnant adults: Treatment".)

Meta-analyses of observational studies suggest that oseltamivir treatment may decrease lower respiratory tract complications requiring antibiotics, hospital admissions in adults, and mortality among hospitalized high-risk patients [28,29]. 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 [30]. However, there was no apparent decrease in duration of intensive care unit days, rates of readmission within seven days, or mortality. Subsequent observational studies in children support an association between neuraminidase inhibitor treatment and reduced complications, including death [31-33].

●Viral shedding – Neuraminidase inhibitors appear to reduce the amount of viral shedding [21], but not the duration of shedding [21,34-36]. Whether they reduce household transmission is uncertain [37].

Baloxavir

●Baloxavir reduces the duration of influenza symptoms by approximately one day compared with placebo and may be more effective than oseltamivir for patients with influenza B virus.

Baloxavir has been evaluated in comparison to placebo and oseltamivir in two large multicenter clinical trials (CAPSTONE-1 and CAPSTONE-2) [38,39]. Though these trials included patients as young as 12 years old, most enrolled patients were adults (ie, only 58 of the 1163 patients in CAPSTONE-2 were ≤19 years old). The trials demonstrated that patients treated with baloxavir or oseltamivir had shorter duration of influenza symptoms compared with placebo (by approximately one day). However, in the subgroup of high-risk patients with influenza B virus, symptom duration was shorter in the baloxavir arm compared with oseltamivir (again, by approximately one day). These trials are discussed in greater detail separately. (See "Seasonal influenza in nonpregnant adults: Treatment".)

In a separate randomized trial that enrolled patients <12 years old (miniSTONE-2), baloxavir and oseltamivir had similar efficacy in reducing clinical illness in pediatric patients who lack risk factors for severe influenza. The median time to alleviation of signs and symptoms for baloxavir was 138.1 hours (95% CI 116.6-163.2 hours) and for oseltamivir was 150.0 hours (95% CI 115.0-165.7) (table 1) [23].

Clinical trial data directly comparing baloxavir with antiviral agents other than oseltamivir are lacking. However, in a network meta-analysis that estimated the relative efficacy of different antiviral agents (oseltamivir, zanamivir, peramivir, and baloxavir) based upon indirect comparisons from 26 placebo-controlled and oseltamivir-controlled trials (most involved adult patients and only 4 were performed in hospitalized patients), baloxavir therapy was associated with the lowest risk of complications [24]. As discussed above, zanamivir was associated with the shortest duration of symptoms. (See 'Neuraminidase inhibitors' below.)

Baloxavir appears to reduce the amount and duration of viral shedding [38,40].

Indications and preferred regimens — Antiviral therapy for influenza in children is summarized in the table (table 2). The availability of licensed antiviral agents varies locally, particularly for peramivir and baloxavir.

Severe illness — For children with confirmed or suspected influenza infection and severe illness (eg, those who are hospitalized, have serious complications [eg, lower respiratory tract complications, myocarditis, encephalitis], or have progressive clinical deterioration), we recommend antiviral therapy. Although prelicensure randomized trials of the licensed antiviral agents were generally conducted in healthy outpatients with uncomplicated illness, there is some evidence from observational studies that neuraminidase inhibitor treatment may be associated with reduced risk of complications or death [28,29,33,41-44]. (See 'Efficacy' above.)

We prefer oral oseltamivir (table 3A-B) to other antiviral agents for treatment of severe illness [5]. Clinical experience in hospitalized children is greater with oseltamivir than with other antiviral agents, and oseltamivir has been associated with reduced duration of stay in critically ill children with influenza [30]. A single dose of IV peramivir is an alternative for children who cannot take oral medications, although studies demonstrating the benefits of peramivir for the treatment of severe influenza are lacking [45]. Zanamivir and baloxavir have not been studied in children with severe influenza [5]. (See 'Antiviral agent administration' below.)

Nonsevere illness

●Indications

•High-risk children – For children in the outpatient setting with nonsevere confirmed or suspected influenza who are at high risk for severe or complicated illness (table 1), we suggest antiviral therapy. Limited evidence indicates that antiviral therapy may shorten hospitalization or prevent death, complications, or hospitalization [28,46]. (See 'Efficacy' above.)

•Children with high-risk contacts – For children in the outpatient setting with nonsevere confirmed or suspected influenza who have a household contact who is <6 months of age or is at high risk for complications (table 1), we suggest antiviral therapy. Treatment may reduce the amount or duration of viral shedding, lessening the risk of transmission to the high-risk contact. (See 'Efficacy' above.)

•Other children – For children with influenza who are not in one of the groups listed above and have had symptoms for <48 hours, we offer antiviral therapy on a case-by-case basis in shared decision-making with the caregivers, considering the potential benefits and risks of antiviral treatment. (See 'Efficacy' above and 'Adverse effects' below.)

For most previously healthy children, influenza is a mild and self-limiting infection [47-49]. Although indiscriminate use of antivirals is infrequent, it may contribute to the development of resistance [6]. (See 'Antiviral resistance' below.)

In addition, during influenza pandemics, unnecessary treatment of previously healthy children has the potential to diminish the supply of drugs for patients at risk of severe illness (table 1).

●Preferred antiviral regimens

•Age <5 years – For children <5 years of age who are treated in the outpatient setting for nonsevere confirmed or suspected influenza, we prefer oral oseltamivir (table 3A-B). A single dose of IV peramivir is an alternative for children who cannot take oral medications [5].

(See 'Antiviral agent administration' below.)

•Age ≥5 years – For children ≥5 years of age who are treated in the outpatient setting for nonsevere confirmed or suspected influenza, options for antiviral treatment include oral oseltamivir, inhaled zanamivir, oral baloxavir, and IV peramivir (table 3A-B).

The choice is determined by age, clinical features (eg, ability to tolerate oral or inhaled medications, contraindications, risk for severe or complicated influenza), and patient/caregiver preference (eg, single- versus multiple-dose therapy) (table 2) [50-52].

Timing — When clinically indicated, antiviral therapy with neuraminidase inhibitors or baloxavir should be started as soon as possible after symptom onset, ideally within 48 hours [5,8].

Treatment should be initiated whether or not the patient received the seasonal influenza vaccine and should not be delayed awaiting the results of viral testing to confirm influenza or to exclude severe acute respiratory coronavirus 2 (SARS-CoV-2), particularly when influenza is known to be circulating in the community based on local or regional surveillance. A negative rapid diagnostic test for influenza does not exclude influenza [5]. A positive test for influenza does not preclude coinfection with SARS-CoV-2, nor does a positive test for SARS-CoV-2 preclude coinfection with influenza virus. (See "Seasonal influenza in children: Clinical features and diagnosis", section on 'Whom to test' and "COVID-19: Clinical manifestations and diagnosis in children", section on 'Laboratory tests for SARS-CoV-2'.)

Earlier treatment is associated with improved outcomes [33,41,53-57]. 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) [33]. If oseltamivir therapy is administered within 12 to 24 hours of symptom onset, symptom duration may be reduced by as many as three days, particularly in young children [53-55].

Although earlier treatment is associated with improved outcomes, neuraminidase inhibitor therapy may be administered more than 48 hours after symptom onset, particularly in hospitalized children, those with serious complications or progressive disease, and those at high risk of complications [7].

Information about the effectiveness of baloxavir therapy initiated >48 hours after onset of symptoms is lacking [50].

Antiviral agent administration

●Oseltamivir – Oseltamivir is administered orally. Limited data suggest that it may be administered by orogastric or nasogastric tube [58,59], but the pharmacokinetics with enteric tube administration may be different than with oral administration, resulting in decreased concentrations of the active metabolite [60,61].

Oseltamivir is usually administered for five days. Patients in whom influenza treatment is initiated should receive a full course of therapy unless an alternative diagnosis is established, recognizing the potential for coinfection with other pathogens, including bacteria and SARS-CoV-2, particularly in patients with severe illness [5,6]. The treatment course may be extended in children who remain severely ill after five days of treatment and immunocompromised patients [5,8,62]. These patients may have prolonged viral replication [4]. Although the optimal duration of the extended course has not been established, it can be guided by virologic testing of lower respiratory tract specimens with polymerase chain reaction (PCR) [5].

The recommended dose of oseltamivir varies according to age and, for premature infants younger than nine months, postmenstrual age (table 3A-B) [7].

•Full-term infants <1 year – Weight-based dosing of oseltamivir is recommended for infants <1 year of age (table 3A) [6,62,63]:

-Age 0 through 8 months – 3 mg/kg per dose twice daily

-Age 9 through 11 months – 3.5 mg/kg per dose twice daily

If the infant's weight is not known, dosing by age may be necessary [64]:

-Age 0 through 3 months – 12 mg twice daily

-Age 4 through 5 months – 17 mg twice daily

-Age 6 through 11 months – 24 mg twice daily

•Preterm infants <9 months of age – Dosing for premature infants <9 months of age is based upon postmenstrual age (gestational age plus chronologic age) as follows [7,62,65,66]:

-<28 weeks postmenstrual age – Consultation with a specialist in pediatric infectious diseases is recommended

-28 through 37 weeks, six days postmenstrual age – 1 mg/kg per dose twice daily

-38 through 40 weeks postmenstrual age – 1.5 mg/kg per dose twice daily

->40 weeks postmenstrual age through 8 months chronologic age – 3 mg/kg per dose twice daily

•Age 1 through 12 years

-Weight ≤15 kg – 30 mg twice daily

-Weight >15 to 23 kg – 45 mg twice daily

-Weight >23 to 40 kg – 60 mg twice daily

-Weight >40 kg – 75 mg twice daily

•Age ≥13 years – 75 mg orally twice daily

●Zanamivir — Zanamivir (for children ≥7 years of age) dry powder is administered via inhalation. It should be avoided in children with a history of wheezing or underlying chronic respiratory disease (eg, asthma) or allergy to lactose or milk protein [12]. Zanamivir should not be reconstituted in any liquid and is not recommended for use in nebulizers or mechanical ventilators [67].

The dose is 10 mg (two inhalations) twice per day.

Zanamivir is usually administered for five days. Patients in whom influenza treatment is initiated should receive a full course of therapy unless an alternative diagnosis is established, recognizing the potential for coinfection with other pathogens, including bacteria and SARS-CoV-2, particularly in patients with severe illness [5,6]. The treatment course may be extended in children who remain severely ill after five days of treatment and immunocompromised patients [5,8,62]. These patients may have prolonged viral replication [4]. Although the optimal duration of the extended course has not been established, it can be guided by virologic testing of lower respiratory tract specimens with PCR [5].

●Peramivir — Peramivir is administered intravenously. Dosing for peramivir varies according to age:

•6 months through 12 years – 12 mg/kg IV in a single dose (maximum dose 600 mg)

•≥13 years – 600 mg IV in a single dose

●Baloxavir — Baloxavir (for otherwise healthy children ≥5 years of age or children ≥12 years of age who are otherwise healthy or at high risk for severe or complicated influenza) is administered orally as a single dose, which varies according to weight [18]:

•Weight <20 kg (oral suspension) – 2 mg/kg orally as a single dose

•Weight 20 to <80 kg (oral suspension or tablet) – 40 mg orally as a single dose

•Weight ≥80 kg (oral suspension or tablet) – 80 mg orally as a single dose

Baloxavir monotherapy should be avoided in severely immunocompromised children, given the lack of efficacy, safety, and resistance data and the concern for emergence of resistance during treatment [5].

Coadministration of baloxavir with dairy products, calcium-fortified beverages, polyvalent cation-containing laxatives, antacids, or oral supplements (eg, calcium, iron, magnesium, selenium, zinc) may decrease plasma concentrations of baloxavir and should be avoided [18].

Adverse effects

Neuraminidase inhibitors — Neuraminidase inhibitors are generally well tolerated in children of all ages with few adverse effects [10,18,68-70]. Serious adverse effects have been reported but are rare, and causality has not been established.

In prelicensure studies the most common adverse effects included:

●Oseltamivir – Nausea (8 to 10 percent), vomiting (8 to 16 percent), diarrhea (7 percent), and headache (2 to 17 percent) [11]

●Zanamivir – Sinusitis (<3 percent) and dizziness (<3 percent) [12]

●Peramivir – Diarrhea (8 percent) and vomiting (3 percent) [10]

Neurologic adverse effects have been reported in < 5 percent of patients treated with oseltamivir [71]. Although it is difficult to distinguish neurologic adverse effects from neurologic symptoms associated with influenza infection itself, adverse effects tend to be more frequently reported in younger children, be less severe and related to behavior (eg, irritability, hyperactivity), and to resolve upon discontinuation of treatment.

Postmarketing reports identified rare serious adverse events in <1 percent of patients with influenza treated with oseltamivir, including [11,72,73]:

●Neuropsychiatric effects (eg, delirium, hallucinations, confusion, abnormal behavior, encephalitis, self-injury), typically with abrupt onset and rapid resolution [74]; most of these reports involved oseltamivir and occurred in children in Japan, where use of neuraminidase inhibitors is widespread

Causality has not been established [75-79]. Some of the neuropsychiatric adverse events may have been related to influenza infection rather than treatment [80-84]. (See "Seasonal influenza in children: Clinical features and diagnosis", section on 'Complications'.)

●Severe skin reactions (eg, toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme) in adults and children

Adverse events suspected to be related to neuraminidase inhibitors should be reported to the US Food and Drug Administration MedWatch.

Baloxavir — Baloxavir appears to be well tolerated [85]. In a phase III trials, adverse events that were considered to be related to baloxavir were uncommon (eg, diarrhea in 2 percent of adolescents and adults and 5 percent of children; vomiting in 6 percent of children) [23,38]. In postmarketing surveillance, hypersensitivity reactions (eg, anaphylaxis, urticaria, angioedema, erythema multiforme) have been reported [18].

The development of escape mutants (ie, virus with mutations with decreased susceptibility to baloxavir) is discussed below. (See 'Antiviral resistance' below.)

MANAGEMENT OF COINFECTION — In children with influenza, antibiotics should be reserved for proven or strongly suspected bacterial complications (eg, bacterial pneumonia, acute otitis media, sinusitis).

Antibiotic choice may be guided by examination and culture of appropriate specimens. However, if the etiology of the bacterial complication remains uncertain, empiric antibiotics generally should be directed at the most common bacterial pathogens following influenza: Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes (group A Streptococcus), Haemophilus influenzae type b, and nontypeable H. influenzae. (See "Pneumonia in children: Inpatient treatment", section on 'Empiric therapy' and "Acute otitis media in children: Epidemiology, microbiology, and complications", section on 'Bacterial pathogens' and "Acute bacterial rhinosinusitis in children: Microbiology and management", section on 'Empiric antibiotics'.)

●Lower respiratory tract coinfection with S. pneumoniae or S. aureus – Lower respiratory tract coinfection with S. pneumoniae or S. aureus may occur in children without high-risk conditions and can be particularly severe and rapidly fatal. (See "Seasonal influenza in children: Clinical features and diagnosis", section on 'S. pneumoniae or S. aureus coinfection'.)

For children with life-threatening pneumonia complicating influenza infection, we provide broad empiric therapy (eg, combination therapy with vancomycin plus a second antibiotic [clindamycin, ceftaroline, or linezolid]) in addition to antiviral therapy [86]. (See "Staphylococcus aureus in children: Overview of treatment of invasive infections", section on 'Choice of therapy'.)

TREATMENT FAILURE — Evaluation and management of patients who worsen or fail to respond to antiviral treatment should be individualized [8]. Although some patients with severe influenza illness fail to improve with adequate antiviral therapy, other potential causes must be considered, including:

●Infection with an antiviral-resistant virus, particularly in immunocompromised patients (see 'Antiviral resistance' below)

Testing influenza isolates for antiviral resistance is not available in clinical settings, and clinical features do not distinguish resistant from susceptible viruses [6]. 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 Centers for Disease Control and Prevention. Certain laboratory tests can distinguish between influenza A and B viruses and between influenza subtypes (table 4) [6]. (See "Seasonal influenza in children: Clinical features and diagnosis", section on 'Approach to testing'.)

Consultation with an expert in infectious diseases is suggested. Treatment options for patients with suspected oseltamivir-resistant influenza include inhaled zanamivir if the patient is not hospitalized (no cross resistance has been documented) or intravenous (IV) peramivir [5]. Whether baloxavir is efficacious in patients with oseltamivir-resistant influenza is uncertain. For children with suspected baloxavir-resistant influenza, treatment options include inhaled zanamivir or IV peramivir, which have different mechanisms of action, and investigational therapies (eg, laninamivir, combination baloxavir and neuraminidase inhibitors).

●Development of a complication (eg, myocarditis; encephalitis; bacterial, viral, or fungal coinfection) (see "Seasonal influenza in children: Clinical features and diagnosis", section on 'Complications')

ANTIVIRAL RESISTANCE — Most circulating influenza virus strains are susceptible to neuraminidase inhibitors and baloxavir [87-89]. Information regarding antiviral resistance that emerges during the influenza season in the United States is available through the Centers for Disease Control and Prevention (CDC). (See "Antiviral drugs for influenza: Pharmacology and resistance".)

●Neuraminidase inhibitors – Minimal resistance to oseltamivir, zanamivir, or peramivir was identified in influenza viruses tested by the CDC during the 2019-2020 influenza season (the most recent season for which susceptibility information is available) [89].

However, oseltamivir resistance has been reported among children and immunocompromised patients during treatment with oseltamivir, predominantly among immunocompromised patients with influenza A(H1N1)pdm09 virus infection [90-93].

●Baloxavir – Baloxavir has been associated with treatment-emergent resistance, particularly when influenza A(H3N2) viruses were circulating [94]. In clinical trials, escape mutants (virus with mutations with decreased susceptibility to baloxavir) were detected in 5 to 10 percent of baloxavir recipients age 12 to 64 years and 14 to 19 percent of those age 1 to 12 years, often associated with increased viral titers [23,38,39]. Influenza viruses with reduced susceptibility to baloxavir have been detected in patients without baloxavir exposure, suggesting possible circulation of influenza virus with acquired baloxavir resistance and highlighting the need for ongoing surveillance of baloxavir susceptibility [95-97].

The United States and other countries established surveillance for baloxavir resistance after its licensure in 2018 [87,98,99].

Baloxavir resistance may prolong viral shedding and clinical illness [100,101].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Treatment and prevention of seasonal influenza with antivirals".)

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 5^th to 6^th 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 10^th to 12^th 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 email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword[s] of interest.)

●Basics topic (see "Patient education: Flu (The Basics)")

●Beyond the Basics topics (see "Patient education: Influenza prevention (Beyond the Basics)" and "Patient education: Influenza symptoms and treatment (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●General measures – Influenza-related discomfort due to fever, headache, pharyngitis, and/or myalgia can be treated with acetaminophen or nonsteroidal anti-inflammatory drugs (eg, ibuprofen). Salicylates should be avoided. Symptomatic management of cough and rhinitis is the same as that for the common cold and is discussed separately. (See 'Symptom management' above and "The common cold in children: Management and prevention", section on 'Symptomatic therapy'.)

Indications for hospitalization include difficulty breathing, change in mental status, progressive illness, clinical deterioration, dehydration or inability to maintain hydration orally, worsening of chronic medical conditions, or development of serious complications (eg, myocarditis, encephalitis, lower respiratory tract complications). (See 'Indications for hospitalization' above.)

●Potential benefits of antiviral therapy – Antiviral therapy shortens the duration of influenza symptoms by approximately one day if initiated within 48 hours of illness onset. Limited evidence suggests that it also may reduce lower respiratory tract complications, hospitalization, severe illness, and death. (See 'Efficacy' above.)

●Indications for antiviral therapy and preferred regimens – Indications for antiviral therapy for children with confirmed or suspected influenza should be made independent of seasonal influenza vaccine status and without waiting for results of viral testing (if viral testing is performed):

•Severe illness – For children with confirmed or suspected influenza and severe illness (eg, those who are hospitalized, have serious complications [eg, myocarditis, encephalitis], or have progressive clinical deterioration), we recommend antiviral therapy (Grade 1C). We suggest oseltamivir rather than other antiviral agents (Grade 2C). Intravenous peramivir is an alternative for patients who cannot tolerate oral therapy. Dosing for oseltamivir and peramivir is summarized in the tables (table 3A-B). (See 'Severe illness' above.)

•Nonsevere illness – For children in the outpatient setting with confirmed or suspected influenza and nonsevere illness who (see 'Nonsevere illness' above):

-Are at high risk for severe or complicated illness (table 1), we suggest antiviral therapy (Grade 2C).

-Have a household contact who is <6 months of age or is at high risk for severe or complicated influenza (table 1), we suggest antiviral therapy (Grade 2C).

-Are not in one of the groups listed above and have had symptoms for <48 hours, we offer antiviral therapy on a case-by-case basis in shared decision-making with the caregivers, considering the potential benefits and risks of antiviral treatment; we do not provide antiviral therapy to children with nonsevere influenza who have had symptoms for ≥48 hours.

For children with nonsevere influenza, options for antiviral therapy include oseltamivir (for those ≥2 weeks of age), zanamivir (for those ≥7 years of age), baloxavir (for those ≥5 years of age), or peramivir (for those ≥6 months of age). The choice is determined by age, clinical features, and patient/caregiver preference (table 2).

●Timing of antiviral therapy – Antiviral therapy should be administered as early as possible, ideally <48 hours of symptom onset. Although earlier treatment is associated with improved outcomes, neuraminidase inhibitor therapy may be administered ≥48 hours after symptom onset, particularly in children with severe illness or at high risk of complications. (See 'Timing' above.)

●Treatment failure – Evaluation and management of patients who worsen or fail to respond to antiviral treatment should be individualized. Potential causes of treatment failure include infection with an antiviral-resistant virus and development of a complication (eg, myocarditis, encephalitis, coinfection). (See 'Treatment failure' above.)