Targeted Therapies for Influenza in Children: Current Evidence and Future Directions

1. Introduction

Seasonal influenza is a leading cause of acute respiratory illness in childhood and contributes substantially to outpatient visits, school absence, hospital admission, and family disruption. A global modelling analysis estimated that, in 2018, children younger than 5 years experienced 109.5 million influenza episodes, 10.1 million influenza-associated acute lower respiratory infections, and approximately 870,000 related hospital admissions [1]. Earlier analyses likewise identified influenza as an important contributor to pediatric respiratory hospitalizations, with substantial variation by age and geography [2]. A systematic review of risk factors found particularly increased odds of admission in children with neurologic disorders, prematurity, sickle cell disease, immunosuppression, diabetes, and age younger than 2 years [3]. Influenza-associated mortality is concentrated in settings with limited access to healthcare, although severe and fatal illness also occurs in high-income countries [1,4].

Annual vaccination remains the principal preventive intervention. Antiviral drugs are an adjunct for treatment and, in selected circumstances, post-exposure prophylaxis. Current recommendations emphasize early treatment of children who are hospitalized, have severe, complicated, or progressive disease, or are at increased risk of complications; in these groups, treatment should not be delayed while awaiting test results [5,6,7,8]. Recommendations for otherwise healthy outpatients with uncomplicated influenza vary somewhat among jurisdictions and depend on timing, age, risk, availability, and shared decision-making. The World Health Organization (WHO) guideline also distinguishes non-severe from severe disease and grades several antiviral recommendations as conditional because certainty about the magnitude of benefit is limited [6,7].

The term “targeted therapy” in this review refers primarily to drugs acting on viral proteins or replication processes. The currently used agents target viral neuraminidase or the cap-dependent endonuclease of the polymerase complex. Other compounds in clinical development target viral polymerase functions or host pathways that influenza viruses depend on [9,10]. The challenge is to translate antiviral activity and reductions in viral load into measurable pediatric benefits, while accounting for age-dependent pharmacology, resistance, route of administration, and the distinction between uncomplicated outpatient disease and severe lower respiratory tract infection.

This narrative review summarizes the current evidence for antiviral therapies in children, highlights limitations in the evidence base, and discusses priorities for future pediatric studies. Adult trials are included when they inform mechanism or drug development, but are identified as indirect evidence and are not assumed to establish pediatric efficacy or safety.

2. Methods

2.1. Review Design and Scope

We conducted a narrative review of evidence on targeted therapies for influenza in children. The review focused on seasonal influenza A and B in patients younger than 18 years and addressed currently available antiviral drugs, therapies under investigation, efficacy and safety, antiviral resistance, and gaps in the pediatric evidence base. Prevention and supportive care were considered only where relevant to the context or interpretation of antiviral treatment.

2.2. Search Strategy and Information Sources

Focused, web-based searches were conducted on 29 October 2026. Searches targeted PubMed-indexed records and guidance published by the World Health Organization (WHO), the American Academy of Pediatrics (AAP), and the US Centers for Disease Control and Prevention (CDC). Search terms were combined using Boolean operators and included: influenza AND (child OR children OR pediatric OR paediatric); influenza AND (antiviral OR treatment OR therapy); influenza AND (oseltamivir OR zanamivir OR peramivir OR baloxavir); influenza AND (antiviral resistance OR resistance); influenza AND (severe OR hospitalized OR hospitalised) AND (child OR pediatric); influenza AND (investigational OR novel antiviral OR host-directed therapy). Searches were also directed at pediatric clinical trials, current treatment recommendations, and reports describing emerging antiviral agents or resistance. The search was limited to English-language sources.

2.3. Eligibility and Source Selection

Sources were considered relevant if they addressed influenza treatment in children or adolescents, including clinical trials, observational studies, systematic reviews, and clinical practice guidelines. We prioritized studies reporting pediatric data on clinical outcomes, virologic outcomes, safety, dosing, or resistance. Guidance documents were included to summarize current recommendations and age-specific treatment considerations.

Adult studies were considered when they provided relevant information on antiviral mechanisms or investigational approaches for which pediatric evidence was limited. These findings were treated as indirect evidence and were not assumed to establish efficacy or safety in children. Studies focused exclusively on influenza prevention, vaccine effectiveness, or non-influenza respiratory infections were outside the review’s scope unless they provided context relevant to treatment.

2.4. Data Collection and Synthesis

For each selected source, we considered the study design, population and age range, influenza type, antiviral agent, treatment timing, comparator, and reported clinical, virologic, and safety outcomes. We also noted limitations relevant to interpreting the findings in children, including small sample sizes, restricted age ranges, and limited evidence in hospitalized patients or those with severe disease.

Findings were synthesized narratively and organized by therapeutic class and clinical evidence. We distinguished evidence from pediatric studies from adult or mechanistic evidence and compared it with recommendations in current guidance documents. Because this was a narrative review based on focused searches, we did not conduct a formal systematic-review screening process, meta-analysis, or PRISMA assessment.

3. Virology and Therapeutic Targets

Influenza A and B viruses are enveloped, segmented, negative-sense RNA viruses. Their replication cycle offers several potential therapeutic targets. Hemagglutinin mediates attachment and membrane fusion; the M2 ion channel facilitates viral uncoating; the nuclear polymerase complex transcribes and replicates the viral genome; and neuraminidase cleaves sialic acid residues to release newly formed virions [9]. Influenza A polymerase “cap-snatches” short capped fragments of host RNA to prime viral messenger RNA synthesis. The PA subunit contains the cap-dependent endonuclease targeted by baloxavir, while PB2 cap binding and RNA synthesis are targets for other investigational inhibitors [9,10].

The distinction between direct-acting and host-directed treatment is clinically relevant. Direct-acting antivirals aim to inhibit viral replication with limited disruption of normal host function, although resistance can arise through viral mutation. Host-directed agents aim to modify host processes that support replication or contribute to tissue injury. Their potential advantage is a higher barrier to viral escape; their central risk is interfering with protective immune responses or causing toxicity in a developing child. At present, approved pediatric treatment is based on direct-acting antivirals, and host-directed strategies have no established routine role [10].

Older M2 ion-channel blockers, amantadine and rimantadine, were active against influenza A but not influenza B. Widespread resistance among circulating influenza A viruses led to recommendations against their routine use [11]. They are not considered current standard therapy. The modern clinical toolkit instead relies on neuraminidase inhibitors (NAIs) and baloxavir, with susceptibility patterns and regulatory indications changing over time and varying by region [5,8,12].

4. Current Antiviral Agents

4.1. Oseltamivir

Oseltamivir is an oral prodrug converted to its active carboxylate, which inhibits influenza A and B neuraminidase. It is administered twice daily for a five-day treatment course in uncomplicated disease; weight-based dosing is used in most children, with age-specific dosing in infants and dose adjustment in selected clinical circumstances. The oral suspension is particularly useful in younger children. Guidance differs in how it handles infants younger than the age included in local product labeling, so clinicians should follow current national recommendations and dosing references [5,8,13].

Oseltamivir is generally preferred for children who require treatment because it can be administered orally or enterically, has extensive pediatric experience, and is recommended for hospitalized patients by major North American guidance [5,8,12]. Treatment should begin as soon as possible in high-risk or severely ill children, including when symptom onset was more than 48 hours earlier. In otherwise healthy outpatients, expected benefit is greatest when treatment starts early, ideally within 48 hours [5,8,12]. The 48-hour interval is not a reason to withhold treatment from a child with severe or progressive illness or a high-risk condition. For children seen early with uncomplicated disease, the decision is more preference-sensitive: expected symptom benefit is modest, treatment must begin promptly, and the family should weigh this benefit against vomiting, dosing burden, and the child’s baseline risk. A positive molecular test strengthens the rationale for treatment, but a negative rapid antigen test does not reliably exclude influenza when community activity is high. In priority groups, treatment should begin on clinical suspicion while testing proceeds; antiviral therapy can be reconsidered if subsequent testing and the clinical course point to another diagnosis [5,8,12].

The landmark placebo-controlled pediatric trial found that among laboratory-confirmed influenza cases, oseltamivir reduced median illness duration by about 36 hours and reduced new diagnoses of otitis media, but increased vomiting [14]. A subsequent trial in children aged 1–3 years found a substantial reduction in illness duration among children with influenza A when treatment began within 24 hours; the study did not demonstrate efficacy for influenza B, although the number of influenza B cases was small [15]. A systematic review and individual-patient-data meta-analysis of randomized trials found a reduction in illness duration in infected children and lower otitis media risk, alongside a higher risk of vomiting; results varied by asthma status and other trial characteristics [16]. A Cochrane review similarly concluded that clinical benefit in children with confirmed influenza is modest and that trial sample sizes and heterogeneity limit conclusions about serious complications [17].

Evidence regarding later initiation is more nuanced than a simple 48-hour cutoff. In a randomized trial conducted in Bangladesh that included many children, oseltamivir modestly shortened symptoms overall and reduced viral isolation even when treatment began at least 48 hours after onset, but the results were not uniformly strong across subgroups and should not be interpreted as proof of equal clinical benefit from late therapy [18]. The trial supports biologic activity after 48 hours, while guidelines prioritize treatment of severe and high-risk patients regardless of delay [5,6,8].

For hospitalized children, randomized evidence is limited. Observational studies suggest that early treatment is associated with shorter length of stay and improved outcomes, but confounding by indication, timing, severity, and diagnostic ascertainment complicates causal interpretation. In one surveillance cohort, antiviral treatment initiated within two days was associated with shorter hospitalization in children with high-risk conditions or intensive care admission [19]. A large multicenter study of 55,799 pediatric hospitalizations found that early oseltamivir use was associated with shorter length of stay and lower odds of readmission, late ICU transfer, and the composite of death or extracorporeal membrane oxygenation [20]. These findings support guideline recommendations but do not replace a randomized trial; the rare outcomes and nonrandom treatment assignment remain important limitations.

Oseltamivir’s most common adverse effects are nausea, vomiting, and headache. Vomiting may affect adherence, particularly in young children, and can be mitigated in some cases by administration with food. Post-marketing reports describe neuropsychiatric events, but a causal relationship has not been established consistently; influenza itself can produce delirium, seizures, and behavioral changes. Families should receive clear instructions about expected adverse effects and when to seek reassessment. Antiviral therapy does not treat bacterial coinfection, and deterioration or persistent fever requires clinical reassessment rather than automatic extension or escalation of antiviral dosing [5,8].

4.2. Zanamivir

Zanamivir is an inhaled NAI that inhibits influenza A and B neuraminidase. Inhaled administration avoids dependence on gastrointestinal absorption, but requires the child to use a dry-powder inhaler correctly. The age threshold varies by jurisdiction; in the United States, treatment is approved from age 7 years. It is not recommended for children with asthma or other underlying airway disease because bronchospasm can occur, and administration may be impractical for children who are too young or too ill to use the device reliably [5,8].

In a randomized trial of children aged 5–12 years, inhaled zanamivir was generally well tolerated and produced evidence of benefit in children with laboratory-confirmed influenza, although the overall effect depended on the analysis population and symptom endpoints [21]. Adult and mixed-age trials establish antiviral activity but offer only indirect evidence for younger children and severe pediatric disease [22]. Zanamivir may be considered for selected children when oral oseltamivir is unsuitable and the inhaled route can be used safely and effectively. It is not a preferred treatment for hospitalized children with lower respiratory tract disease, and inhaled delivery should not be assumed to achieve adequate drug exposure in the lower respiratory tract. The distinction between trial eligibility and current labeling matters: the pivotal pediatric study included children from age 5 years, whereas US treatment authorization begins at age 7 years. In practice, the ability to operate the device and the risk of bronchospasm may be more decisive than the child’s chronological age alone. Zanamivir should also not be confused with nebulized formulations; the dry powder formulation is device-specific and is not intended for nebulizers or ventilator circuits [5,8,21].

4.3. Peramivir

Peramivir is an intravenous NAI given as a single dose for acute uncomplicated influenza in ambulatory patients in the United States, including children aged 6 months and older. It can be useful when oral or enteric treatment cannot be delivered, but it requires intravenous access and infusion. Pediatric registration data include limited numbers of children, and the evidence does not establish a routine advantage over oral oseltamivir [23,24]. A single dose can be convenient, but convenience alone does not demonstrate better clinical outcomes [8,23,24].

Evidence for peramivir in hospitalized children with severe influenza is limited. Intravenous administration may be considered in selected patients who cannot absorb or tolerate enteric oseltamivir, in consultation with local guidance and infectious-disease expertise. Current guidance does not support routine substitution of peramivir for oseltamivir in all hospitalized children, and the optimal duration or role of repeated dosing in severe disease remains uncertain [8,12,23,24].

4.4. Baloxavir Marboxil

Baloxavir marboxil is a prodrug of a selective cap-dependent endonuclease inhibitor. By targeting the PA subunit of the viral polymerase, it blocks cap-snatching and viral messenger RNA synthesis. Its main practical distinction from NAIs is single-dose oral administration and rapid reduction of infectious viral titers. Age indications differ among regulatory authorities and have changed over time; local product labeling should be checked, particularly for younger children and children with high-risk conditions [5,8,25].

In CAPSTONE-1, a randomized trial in otherwise healthy adults and adolescents with uncomplicated influenza, baloxavir shortened time to symptom alleviation compared with placebo and had symptom outcomes similar to oseltamivir, while reducing viral titers more rapidly [26]. In CAPSTONE-2, which enrolled high-risk adolescents and adults, baloxavir shortened time to improvement compared with placebo and had a similar overall clinical effect to oseltamivir; the trial included participants aged 12 years and older and therefore does not independently establish efficacy in younger children [27]. These adult and adolescent studies provide context but should not be generalized to infants or children with severe disease.

The pediatric miniSTONE-2 trial compared single-dose baloxavir with five days of oseltamivir in otherwise healthy children aged 1 to younger than 12 years. The primary objective was safety; symptom alleviation was similar between treatment groups, but the study was not designed to establish superiority for clinical outcomes or to evaluate high-risk and hospitalized children [28]. Japanese pediatric studies report rapid viral-load decline and clinical recovery, but observed treatment-emergent PA substitutions and symptom or fever recurrence in some subgroups warrant careful interpretation [29]. The evidence supports baloxavir as a useful option for eligible children with uncomplicated influenza under local guidance, not as an established therapy for severe or hospitalized pediatric influenza. Current US authorization includes children aged 5 years and older, whereas study populations, product formulations, and age thresholds differ across countries. Baloxavir should be given as a single dose as soon as possible and within 48 hours for uncomplicated illness; coadministration with polyvalent cations, including calcium, iron, magnesium, and zinc, can reduce drug exposure. These practical details are important in children who use supplements or antacids. Evidence remains particularly limited for children with substantial comorbidity, immunocompromise, or illness requiring admission [5,8,25].

Baloxavir is also approved for post-exposure prophylaxis in some jurisdictions. In a household-contact trial, a single dose reduced laboratory-confirmed clinical influenza compared with placebo, including in pediatric subgroups, although the main outcome was prevention rather than treatment [30]. Prophylaxis decisions should account for age, exposure timing, risk of complications, vaccination status, local recommendations, and the possibility of selecting reduced-susceptibility variants. The treatment and prophylaxis evidence should not be conflated.

The main differences among currently available agents—including target, route, pediatric role, and practical limitations—are summarized in Table 1.

5. Antiviral Resistance

Resistance is an evolutionary property of influenza viruses and must be considered alongside drug activity. Resistance can emerge during treatment, especially in young children with prolonged viral replication, in immunocompromised patients, or when antiviral exposure is suboptimal. Current surveillance generally finds low population-level resistance to recommended agents, but the frequency varies by season, subtype, treatment pressure, and region [8,31].

For oseltamivir, substitutions in neuraminidase can reduce drug susceptibility. The H275Y substitution in A(H1N1)pdm09 is a well-characterized marker associated with reduced oseltamivir susceptibility. Early pediatric studies documented emergence of resistant viruses during treatment [32,33], and a clinical study found reduced effectiveness of oseltamivir against resistant H1N1 viruses in children, with a larger effect in younger age groups [34]. These studies occurred in specific epidemiologic contexts and do not imply that resistance is common in every current season. They support ongoing surveillance and consideration of resistance testing when a high-risk or immunocompromised child remains ill with persistent viral replication despite treatment [8,31].

Baloxavir resistance is associated most often with substitutions at PA residue I38, including I38T, I38M, or I38F. Such variants have emerged in clinical trials and are observed more frequently in children younger than 12 years than in adults [25,26,28,29,35]. In children under 5 years, the current prescribing information notes higher frequencies of treatment-emergent substitutions than in older children and adults; this has influenced age-specific regulatory restrictions [25]. These mutations can be associated with rebound in viral titers and prolonged shedding, although clinical consequences vary. Transmission of variants with reduced susceptibility has been reported, but sustained community spread has not been established as a dominant pattern [30,36].

Resistance findings need to be interpreted in relation to the clinical setting and sampling strategy. A variant detected after treatment does not necessarily imply treatment failure, and a genotype alone may not predict the duration or severity of illness. Conversely, prolonged viral replication in an immunocompromised child can allow continued selection and shedding of resistant virus, creating potential risk for household and healthcare contacts. When feasible, serial sampling can distinguish persistent detection from ongoing replication; sequencing and phenotypic susceptibility testing can help guide expert consultation in complex cases. Routine resistance testing is not required for every child who remains symptomatic, since cough and fatigue can persist after viral replication has declined.

The history of adamantane resistance provides a broader lesson. A rapid global increase in amantadine-resistant influenza A viruses made that drug class unsuitable for routine seasonal treatment [11]. A new antiviral should therefore be evaluated not only for short-term efficacy but also for resistance barrier, transmission fitness, and the effect of treatment on within-host viral evolution. Combination therapy could theoretically raise the resistance barrier, but it should not be adopted without evidence of improved patient-important outcomes and acceptable safety.

The principal resistance pathways, pediatric evidence, and practical implications for surveillance are summarized in Table 2.

6. Antivirals for Severe or Hospitalized Pediatric Influenza

Children hospitalized with influenza form a high-priority group, yet one of the least well studied populations in randomized trials. Severe disease may involve viral pneumonia, hypoxemia, respiratory failure, neurologic complications, bacterial coinfection, or decompensation of chronic disease. In these settings, antiviral treatment is only one part of care; supportive management, assessment for coinfection, and treatment of complications remain essential. Current pediatric guidance recommends oseltamivir as soon as possible in hospitalized children and in those with severe, complicated, or progressive illness, without requiring a positive test before treatment when influenza is circulating and clinical suspicion is high [5,8].

The evidence supporting treatment in hospitalized children is largely observational. Retrospective cohorts have associated earlier NAI treatment with shorter length of stay and, in some studies, improved survival or fewer complications. However, treatment assignment may be influenced by severity, clinician judgment, access, or time from onset. Studies can also misclassify influenza based on diagnostic codes or include mixed antiviral regimens. Large administrative-data studies improve precision but cannot eliminate residual confounding [19,20]. Thus, guidelines reasonably favor treatment given the potential severity and biologic plausibility, while the magnitude of pediatric inpatient benefit remains uncertain.

Evidence does not support routine high-dose oseltamivir. Standard dosing is generally used, with decisions about duration individualized for severe lower respiratory tract disease, prolonged viral replication, or immunocompromise in consultation with specialists [8]. Inhaled zanamivir may be unsuitable in patients with airway disease or respiratory support needs. Intravenous peramivir is a possible alternative when enteric absorption is not feasible, although data in severe influenza are limited. Baloxavir has not been established as monotherapy for hospitalized pediatric disease. These limitations underscore why uncomplicated outpatient trials cannot be used as a direct proxy for severe disease.

Table 3. maps the clinical evidence by population and setting, highlighting where pediatric findings are direct and where they rely on observational or adult data.

7. Investigational Antivirals and Future Therapeutic Strategies

7.1. Polymerase Inhibitors

The influenza polymerase complex contains several druggable functions beyond the PA endonuclease. Pimodivir inhibits the PB2 cap-binding domain and has shown antiviral activity in experimental infection and earlier clinical studies [10,37]. However, two phase 3 studies of pimodivir plus standard of care in high-risk adolescents and adults were terminated early after futility in the hospitalized study. Published results found no additional clinical benefit in hospitalized patients; the outpatient study suggested faster symptom resolution in some analyses [38]. These were not pediatric efficacy trials, and the results illustrate the gap between a promising mechanism, virologic effects, and consistent clinical benefit.

Favipiravir is a nucleoside analogue that inhibits viral RNA-dependent RNA polymerase after intracellular activation. It has been studied in adults, including in phase 3 trials with mixed clinical efficacy, and its use is constrained by safety, reproductive toxicity concerns, regulatory status, and uncertainty about its role in routine seasonal influenza [39]. It is not an established pediatric treatment. Any future pediatric evaluation would require dedicated pharmacokinetic, safety, and dose-ranging studies rather than simple extrapolation from adult dosing.

Other polymerase inhibitors and molecules directed at viral entry, assembly, or release are in preclinical or clinical development [9,10,40]. For children, the development pipeline should prioritize drugs that can be delivered reliably across age groups, have a high barrier to resistance, retain activity against circulating subtypes, and can be used in severe disease. Formulation is not a minor issue: a tablet, suspension, inhaled formulation, or intravenous preparation may have different feasibility and adherence across infancy, early childhood, and adolescence.

7.2. Combination Therapy

Combining drugs with different mechanisms could theoretically reduce viral replication more rapidly and limit resistance. However, a combination may also add toxicity, drug interactions, cost, and complexity. In the FLAGSTONE randomized trial of hospitalized patients aged 12 years and older, adding baloxavir to standard-of-care NAI therapy did not improve the primary clinical outcome compared with NAI therapy alone [41]. The pimodivir phase 3 program likewise did not demonstrate a clear added benefit in hospitalized patients [38]. Neither trial establishes pediatric effectiveness. Combination therapy should therefore remain a research question, especially for immunocompromised children with prolonged replication, rather than routine practice.

7.3. Host-Directed and Immunomodulatory Approaches

Severe influenza can reflect both viral replication and dysregulated host inflammation. Candidate host-directed strategies include modulation of inflammatory signaling, cell entry factors, or pathways needed for viral replication [10]. The therapeutic window may be narrow: suppressing damaging inflammation could also impair viral clearance or increase secondary infection risk. Pediatric development requires age-specific evaluation of immune maturation and long-term safety.

Corticosteroids are sometimes administered for other indications, such as asthma exacerbation or refractory shock, but they are not recommended as routine adjunctive therapy for influenza itself. Observational studies and meta-analyses have associated corticosteroid use in influenza with harm, though confounding by indication is substantial because the sickest patients are more likely to receive steroids [42]. The WHO guideline conditionally recommends against corticosteroids and several other adjunctive immunomodulators in severe influenza in the absence of another clear indication [7]. This is an example of why mechanistic rationale alone is insufficient to justify adjunctive therapy.

Passive immune approaches, including convalescent plasma and monoclonal antibodies, have theoretical appeal for high-risk patients and novel influenza strains. Their development faces challenges from antigenic diversity, escape mutations, timing, delivery, and the need to demonstrate benefit beyond antivirals and supportive care. Current WHO guidance does not support routine passive immune therapy for severe seasonal influenza outside trials or specific indications [7]. Future work may identify broadly neutralizing antibodies or long-acting agents useful in prophylaxis for profoundly immunocompromised children, but this remains an area for investigation rather than standard treatment [9,10,40].

8. Clinical Evidence Gaps and Research Priorities

The pediatric evidence base has several recurring limitations. First, many randomized trials recruit otherwise healthy outpatients with uncomplicated influenza and exclude children with chronic disease, immunocompromise, severe illness, or recent antiviral use. Those are precisely the groups for whom clinicians most need robust outcome data. Second, trials frequently use symptom duration or viral shedding as endpoints, while families and health systems care about hospitalization, return to school, complications, antibiotic exposure, intensive care, and mortality. Serious outcomes are uncommon enough that trials need large, pragmatic, multicenter designs to detect meaningful differences.

Third, children are not a homogeneous pharmacologic group. Drug disposition, renal function, body size, immune response, and ability to use a delivery device change from infancy through adolescence. Development plans should include preterm and term infants, age-appropriate formulations, and dose selection based on pharmacokinetic and pharmacodynamic targets. Studies should also address feeding tubes, vomiting, renal impairment, obesity, and prolonged shedding in immunocompromised children. Current dose recommendations are based on available evidence and guidance, but data remain thinner in the youngest infants and in children with complex comorbidity [5,8,13].

Fourth, timing and diagnosis influence apparent treatment effectiveness. Many trials enroll within 48 hours, while high-risk patients may present later. Rapid molecular testing can help direct therapy, but empiric treatment should not be delayed in priority groups. Future trials could compare pragmatic testing-and-treatment pathways, measure time from symptom onset to first dose, and distinguish influenza A subtypes and influenza B lineages where sample size permits. Data on coinfections and bacterial complications are also needed, because an antiviral cannot replace appropriate evaluation of a child whose clinical course worsens.

Fifth, resistance surveillance must be integrated into trials and routine care. Studies should collect serial specimens from children with prolonged illness, immunocompromise, or treatment failure and report both genotypic markers and phenotypic susceptibility where feasible. Baloxavir trials should report resistance stratified by age and subtype, including the transmission and clinical consequences of selected variants. NAI resistance monitoring should remain linked to global surveillance because local prevalence may shift rapidly [8,31,36].

Finally, equity and feasibility matter. The global burden of severe influenza in young children is concentrated in low- and middle-income settings [1,2]. A single-dose agent may improve adherence but may also be more expensive or unavailable. Oral suspension stability, supply, diagnostic access, and the capacity to recognize severe illness shape whether a therapy can meaningfully reduce burden. Trials should include diverse geographic settings and report costs, access, and practical feasibility alongside efficacy.

A useful pediatric evidence program would coordinate randomized trials with prospective surveillance rather than rely on isolated small studies. Core outcome sets could include time to sustained symptom resolution, return to normal activity, complications requiring a change in care, hospitalization, and serious adverse events, alongside viral kinetics and resistance. Stratification by age, influenza type or subtype, vaccination status, baseline risk, and time to treatment would improve interpretability. For hospitalized children, pragmatic platform designs may permit comparison of standard-dose oseltamivir with clinically plausible alternatives without delaying standard care. Embedded pharmacokinetic studies can address infants and children receiving enteral feeds, while follow-up after treatment can assess prolonged shedding and emergence of resistance. Such designs would generate findings that can change practice rather than simply confirm antiviral activity.

Table 4. translates the evidence gaps into study priorities, populations, and outcomes that could make future pediatric trials more useful for clinical decisions.

9. Conclusions

Targeted antivirals have an established role in pediatric influenza, but the strength of evidence differs markedly by drug, age, and clinical setting. Oseltamivir remains the best-established option for children who are hospitalized, severely ill, or at increased risk of complications, with early treatment generally preferred. Zanamivir and peramivir are alternatives for selected circumstances but have route-specific and evidence limitations. Baloxavir adds a convenient single-dose mechanism and has supportive evidence for uncomplicated disease in eligible children, while age-related resistance concerns and limited severe-disease data require careful patient selection.

The next phase of progress will depend less on adding agents with antiviral activity alone and more on proving age-appropriate clinical benefit. Pediatric trials should enroll high-risk and hospitalized children, evaluate outcomes that matter to patients and families, characterize pharmacology and resistance, and include the settings where influenza causes the greatest burden. Until those data are available, clinical decisions should follow current local guidance, distinguish pediatric evidence from adult extrapolation, and integrate antiviral treatment with vaccination, timely diagnosis, and careful supportive care.