Influenza

Paul G. Auwaerter, M.D.

PATHOGENS

Influenza viruses are enveloped, negative-sense, single-stranded RNA viruses in the Orthomyxoviridae family with segmented genomes.
- Influenza A infects humans and numerous animal species and is classified by its surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA).
  - The principal seasonal human subtypes currently are A(H1N1)pdm09 and A(H3N2).
  - It circulates in animal reservoirs (birds, mammals), and its segmented genome permits reassortment (antigenic shift), conferring pandemic potential for influenza A.
  - The gradual accumulation of mutations (antigenic drift) drives seasonal epidemics and necessitates periodic updates to vaccine strains.
- Influenza B predominantly infects humans and causes seasonal epidemics but not pandemics.
  - Unlike influenza A, it is not divided into H/N subtypes. Rather, lineages are described, e.g., B/Victoria.
  - B/Victoria is currently circulating; naturally occurring B/Yamagata has not been detected since 2020.
- Influenza C infects humans and usually causes mild, sporadic upper-respiratory illness, particularly in children.
  - It is not an important cause of seasonal influenza epidemics, and is not included in routine influenza vaccines
  - It is not detected by standard clinical influenza A/B assays.
Seasonal influenza A and B are among the most common respiratory viruses afflicting infants, children, and adults, along with SARS-CoV-2 and RSV.
- 2025-2026 respiratory season, May 2026 estimates from the CDC, a season characterized as an usually rapid mid-winter surge driven by antigenically drifted influenza A (H3N2) known as subclade K.
  - Influenza cases in the U.S.: 32 million
    - Hospitalizations: 390,000
    - Influenza-associated deaths: ~24,000 with 191 reported pediatric deaths (Aug 2026 estimate)
    - Peak intensity for outpatient visits occurred just after the holidays, with influenza-like illness doctor visits peaking in December 2025.
See the Avian Influenza module for details regarding these influenza viruses.

CLINICAL

Transmission occurs primarily through infectious respiratory particles generated during breathing, speaking, coughing, or sneezing; contact transmission can also occur.
- In healthcare, use recommended source-control/PPE measures; use a fit-tested N95 or higher respirator for aerosol-generating procedures
Typically uncomplicated influenza symptoms: abrupt-onset fever with dry cough and systemic symptoms. Patients may say something like "I was hit by a truck," reflecting the rapidity of feeling ill.
- Myalgia, headache, malaise, sore throat, and rhinitis.
  - GI effects may occur or precede, including nausea, vomiting, and abdominal pain.
- Children have more otitis media and nausea/vomiting.
- Severe disease will cause cough, shortness of breath, and potentially confusion/altered mental status.
- Most vulnerable (seasonal flu): infants (< 2 yrs), elderly, hospitalized, immunocompromised hosts, pregnancy, and those with comorbidities -- especially preexisting heart and lung disease.
DDx includes other respiratory viral infections: COVID-19 and RSV.
- Difficult to discern clinically; testing needed.
  - Leading explanations include SARS-CoV-2 and RSV.
    - May also consider rhinovirus/enterovirus and hMPV (see upper respiratory tract infection module for details).
Common complications: bacterial sinusitis, otitis media, exacerbations of chronic bronchitis, bacterial pneumonia (CAP), asthma, cardiac decompensation, and worsening of diabetic or other chronic disease.
- Bacterial superinfections (CAP, pneumonia): S. pneumoniae, S. aureus (including MRSA, which may present with necrotizing/cavitary pneumonia). Group A Streptococcus
Prevention: Basics include covering sneezes, practicing good hand hygiene, and staying home when ill.
- For healthcare: Use Standard + Droplet Precautions.
  - Healthcare personnel should wear a facemask when entering the room.
  - Use a fit-tested N95 or equivalent for aerosol-generating procedures.
Infectivity: mostly due to shedding.
- Most adults can transmit influenza from ~1 day before illness onset through 5–7 days after. Children and immunocompromised patients may shed the virus for longer.

DIAGNOSIS

Signs and symptoms of influenza, RSV, and COVID-19 may overlap.
- Consider viral co-infection, such as influenza and SARS-CoV-2.
- Testing is especially recommended for hospitalized patients and when results affect management/
  - Treatment in those with severe illness or in high-risk groups should not wait for results.
- Specimens used include upper and lower respiratory tract secretions obtained by swabs, washes, or aspirates.
Molecular NAAT/RT-PCR is preferred for clinical diagnosis due to its high sensitivity (90-100%) and potential for rapid turnaround time. Specificity rests at 95-100%.
- Availability, cost, and turnaround vary by setting.
- Often part of a multiplex panel.
- Some assays are point-of-care and have turnaround times of 15-30 minutes.
- Extremely low risk of false negatives.
Rapid influenza diagnostic tests (RIDTs): antigen-based tests offer rapid, inexpensive point-of-care testing but are relatively insensitive (sensitivity of 50-70%; automated readers improve this to 75-80%) and remain highly specific (95-99%), so positive results are informative.
- Negative tests do not rule out the disease.
- Check the kit directions for allowable sample types for testing.
Viral culture: mainly useful for public health and virologic characterization, not used for clinical care.
Influenza, COVID-19, and RSV cannot reliably be distinguished by symptoms alone.
- During influenza circulation, uncomplicated influenza is often diagnosed clinically in an outpatient setting based on the presence of fever and cough.
- Molecular testing is particularly useful for hospitalized or high-risk patients, and when results will alter management, such as prescribing antivirals.
- Primary competing diagnoses: SARS-CoV-2, parainfluenza, RSV, adenovirus, metapneumovirus, rhinovirus, human coronavirus.

Table 1. Influenza Lab Tests (stand-alone or antigen/molecular may be part of a multiplex panel)
Test	Time to report	Sensitivity	Samples
Rapid Testing, antigen (RIDTs)	< 15 minutes	50-70%, depending on test kit components and circulating strains. Relatively insensitive but specific and least expensive. Can trust positive results when influenza is circulating; false positives are more likely when prevalence is low. Some kits are CLIA-waived or available for home use. Some use an analyzer reader to standardize results, resulting in better sensitivity (75-80%). Can distinguish between influenza A and B.	NP swab, aspirate or wash, nasal swab, aspirate or wash, throat swab
Rapid Molecular Assay (viral RNA or NAAT)	15-30 minutes	High sensitivity: performance is assay-dependent, and some rapid NAATs approach laboratory RT-PCR. Some platforms are CLIA-waived. Sensitivity 90-95%.	NP swab, nasal swab
PCR, RT-PCR	1-8 hrs, depending on the assay	Very high: reference standard, both sensitive and specific. Preferred tests are now often part of multiplex panels (film arrays). They are usually done in hospital settings and may be part of a multiplex panel. Now, platforms offer POC testing within 15 to 30 minutes. Can distinguish between Influenza A and B.	NP swab, throat swab, NP or bronchial wash, nasal or endotracheal aspirate, sputum
Culture	1-3 days (rapid shell vial culture); 3-10 days (conventional culture)	Moderately high sensitivity, now rarely performed except as part of public health lab surveillance that will yield isolates for strain and resistance testing.	NP swab, throat swab, NP or bronchial wash, nasal or endotracheal aspirate, sputum; (specimens need to be in viral transport media)
Serology	Days-weeks	Not clinically useful. Best for epidemiology or surveillance purposes.	Blood

TREATMENT

Antivirals

Supportive care for healthy patients with uncomplicated influenza +/- antiviral therapy.
Treatment of persons with uncomplicated influenza (suspected or proven) if symptoms < 48 hours may be considered, lessening the duration of illness to ~1 day.
- RCTs have suggested a 1-day reduction in illness among ambulatory patients when administered within the first 48 hours of symptom onset.
CDC recommendations: as of March 2026.
- Clinicians should not wait for influenza, SARS-CoV-2, or multiplex molecular assay results to initiate empiric antiviral treatment for influenza in priority groups.
The treatment is recommended for persons likely to have a serious outcome and/or for those with a high risk of serious infection/ (risk factors or hospitalized patients), even if> 48 hrs
- Antiviral treatment is recommended as early as possible for any patient with confirmed or suspected influenza, including those who are suspected but do not require laboratory confirmation.
  - A negative RIDT should not prompt discontinuation of therapy when clinical suspicion is high.
  - In severe/hospitalized disease, consider repeat or lower-respiratory molecular testing when appropriate.
  - High risk includes age <5 years (especially <2), ≥65 years, pregnancy/postpartum (up to 2 weeks post-delivery), immunocompromised status, long-term care residence, BMI ≥40, and significant chronic pulmonary, cardiac, renal, hepatic, neurologic, hematologic, or metabolic disease.
See CDC for the most up-to-date recommendations based on circulating strains and resistance profiles: http://www.cdc.gov/flu/professionals/antivirals/index.htm.
- Nearly all circulating viruses remain susceptible to neuraminidase inhibitors and baloxavir; reduced susceptibility to oseltamivir remains uncommon. Adamantane resistance remains widespread, so amantadine and rimantadine are not recommended.
  - In 2025–26, 31/4,609 viruses showed reduced/highly reduced oseltamivir inhibition, and none of the 4,491 showed decreased baloxavir susceptibility.
  - Oseltamivir: an original influenza antiviral that has the most data. In healthy outpatients, it may reduce symptoms if started within 48 h, with mild side effects (N/V) that should be weighed against the benefit of saving a single day of minor illness. For those at severe risk of influenza or hospitalized, there is a potential to reduce complications, respiratory failure, or death, which far outweigh any ill effects.
    - No sufficiently powered placebo-controlled RCT has established the benefit of neuraminidase-inhibitor monotherapy in hospitalized influenza; recommendations rely on observational evidence and limited randomized data.
  - Zanamivir: resistance is rare, but inhalation delivery is often difficult for patients, so the drug is rarely used.
  - Baloxivir: CDC surveillance includes antiviral susceptibility testing; treatment-emergent PA/I38 substitutions occur particularly in children.
    - Several reports have suggested that shed virus after baloxivir has varying percentages of baloxivir-resistant mutations, especially in children. The clinical impact remains to be determined and is seen most in Japan, where this drug has the highest usage.
    - Early antiviral therapy with baloxavir reduces household transmission, with an RCT showing fewer lab-confirmed cases, though symptomatic transmission was not reduced.[14]
Antiviral Options:
- Hospitalized: Use oseltamivir PO or NGT for confirmed or suspected influenza, starting as soon as possible.
  - Peramivir (off-label) would be used only if oral medications cannot be administered.
- Outpatients with complicated or progressive influenza: oseltamivir PO
- Outpatients with uncomplicated influenza: oseltamivir PO, zanamivir inhaled, peramivir IV (though rarely used for this indication), or baloxivir PO
Dosing:
- CDC-recommended agents
  - Neuraminidase inhibitors:
    - Oseltamivir
      - Adult: 75 mg PO twice daily
      - Pediatric: approved for use at age ≥ 14 days.
        Premature infants require postmenstrual-age dosing rather than the usual 3 mg/kg twice-daily infant regimen
        Age < 1 yr: 3 mg/kg PO dosed twice daily
        AAP permits 3.5 mg/kg/dose twice daily at 9–11 months.
        FDA treatment indication begins at 14 days, but CDC/AAP recommend treatment at any age.
        ≥ 1 year and ≤ 15 kg: 30 mg PO twice daily
        15 - 23 kg: 45 mg PO twice daily
        23.1 - 40 kg: 60 mg twice daily
        > 40 kg: use adult dosing
      - Duration: 5 days
    - Zanamivir is approved for use in ages ≥ 7 years
      - 10 mg (2 puffs) twice daily
      - Duration: 5 days
    - Peramivir: FDA-approved for uncomplicated influenza < 48 h; may be considered when enteric oseltamivir cannot be administered or reliably absorbed.
      - Age ≥ 6 mos- 12 yrs: 12 mg/kg IV as a single dose, 600 mg max.
      - Age ≥ 13 yrs: 600 mg IV single dose (uncomplicated influenza)
      - Infuse for a minimum of 15 minutes.
      - Not routinely recommended for hospitalized influenza because efficacy data are lacking.
  - Baloxavir: cap-dependent endonuclease inhibitor with weight-based dosing; it is administered as a single dose due to its long half-life. Little data are available on its use in hospitalized patients; therefore, it is not currently recommended for this setting. FDA-approved for ages ≥ 5 yrs.
    - ≥ 80 kg: 80 mg PO x 1 dose
    - 20-80 kg: 40 mg PO x 1 dose
    - .<20 kg: 2 mg/kg x 1 dose
    - Note: oral suspension is unavailable in the US.
- Other agents used internationally:
  - Favipiravir (available in some countries, not FDA-approved or available in the US)
    - Day 1: 1600 mg PO twice daily
    - Day 2-5: 600 mg PO twice daily
    - Total duration: 5 days
    - Notes: An oral antiviral used in some countries for influenza, particularly when other agents are unsuitable or during outbreaks involving resistant viruses.
      - Not FDA-approved in the U.S. Clinical efficacy data for seasonal influenza are less robust than for neuraminidase inhibitors or baloxavir.
      - Avoid during pregnancy because of embryotoxic/teratogenic risk.
The amantadine class is not recommended for seasonal influenza because widespread resistance persists.
- No activity against influenza B.

Symptomatic treatment

Supportive care: fluids/rest and acetaminophen or an NSAID for fever/aches.
- Avoid salicylates in children and adolescents due to the risk of Reye’s syndrome.
- Use bronchodilators only for bronchospasm/wheezing.
- Routine cough/cold combinations have limited benefit and carry age-specific safety restrictions.

Complications

General
- Influenza may exacerbate underlying chronic health conditions, e.g., asthma, chronic obstructive lung disease, congestive heart failure, etc.
Sinusitis and otitis media
Bacterial pneumonia may complicate or follow influenza infection.
- Patient groups who are more likely to have bacterial pneumonia:
  - Age
    - < 5 years
    - > 65 years
  - Nursing home residents
  - Chronic cardiovascular or pulmonary disease
  - Smokers
  - Immunocompromised
- Major pathogens: S. aureus, S. pneumoniae, and Group A Streptococcus.
  - Two patterns:
    - Concurrent infection: Viral influenza pneumonia with bacterial coinfection may be present from the outset.
    - Influenza resolving and bacterial superinfection: Secondary bacterial pneumonia often presents after initial clinical improvement, typically several days after influenza onset ("double-sickening").
      - MRSA is a significant concern and can have a rapid onset and high morbidity/mortality.
        Clues: young adult, seriously ill, hemorrhagic or necrotizing pneumonia, leukopenia or erythroderma.
      - Broaden empiric coverage for MRSA or P. aeruginosa when validated risk factors are present (e.g., prior respiratory isolation or recent hospitalization with parenteral antibiotics), guided by illness severity and local epidemiology.
        For severe post-influenza pneumonia with MRSA risk,
ARDS:
- Severe influenza may cause ARDS
  - Pregnancy and obesity are risk factors.
- Critically ill influenza patients, or those who are immunosuppressed, may develop mold infections, particularly Aspergillus.
  - Have a high index of suspicion for patients in the ICU with ARDS presentation, unexplained worsening of disease, or immunosuppression.
    - Invasive pulmonary aspergillosis infection (IAPA) appears more commonly in influenza than in SARS-CoV-2.
      - Those with a history of solid organ transplantation, hematogenous malignancy, immunocompromised status, or use of prolonged steroids were at higher risk for IAPA.
      - Consider checking serum and BAL galactomannan, and begin antifungal therapy (e.g., voriconazole) if disease is probable or proven, or if clinical suspicion is sufficiently high.
- ECMO may be considered for those failing mechanical ventilatory support.
Rhabdomyolysis: uncommon but may be striking and precipitate acute kidney injury.
CNS: encephalitis
Multi-organ system failure

Prevention

May co-administer the COVID-19 vaccine with other vaccines, including influenza, in separate limbs if possible.
- See the influenza vaccine module for details regarding multiple formulations and indications.
U.S. influenza vaccine policy has been affected by recent administrative changes and ongoing litigation; however, due to judicial stays, the current CDC guidance remains the 2025 ACIP/CDC influenza-vaccination framework.
- Continue to follow the standing 2025 CDC/ACIP influenza vaccination recommendations/schedule:
  - Annual influenza vaccination for everyone aged ≥6 months without a contraindication, using an age- and health-appropriate vaccine and the usual timing recommendations.
  - Optimal timing is September or October in the Northern Hemisphere, but it should be given at any time throughout the influenza season if later.
What’s emphasized this season:
- All three components were updated by the FDA for 2026–27, including the H3N2 component to address the subclade K lineage.
- U.S. vaccines remain trivalent.

Influenza Chemoprophylaxis

Consider antiviral prophylaxis following close contact with influenza exposure < 48 hours of known or suspected influenza, especially for high-risk patients who are not immunized or cannot mount an immune response.
- Post-exposure prophylaxis with oseltamivir, zanamivir, or baloxavir reduces the risk of secondary influenza when administered promptly, depending on age, contraindications, and exposure settings.
See the influenza immunization and chemoprophylaxis module for details on the patient and drug selection.

Selected Drug Comments

Drug	Recommendation
Amantadine Rimantadine	Not currently recommended for seasonal influenza due to widespread resistance among circulating influenza A; also, neither has activity against influenza B.
Baloxivir	Single-dose oral treatment and post-exposure prophylaxis for persons ≥5 y. Symptom benefit is similar in magnitude to oseltamivir when started ≤48 h. CENTERSTONE showed reduced laboratory-confirmed household transmission. Treatment-emergent PA substitutions can reduce susceptibility, especially in children. Avoid coadministration with polyvalent cations. Insufficient data for use in patients hospitalized with influenza, pregnancy, breastfeeding, or severe immunocompromise.
Oseltamivir	Preferred for hospitalized, severe/progressive, pregnant, and other high-risk patients; start promptly and do not delay for testing. Early treatment of uncomplicated influenza modestly shortens the duration of symptoms by ~1 day. The main adverse effects are nausea/vomiting. Doses should be adjusted for renal impairment.
Zanamivir	Inhaled neuraminidase inhibitor that requires the use of a tricky gadget that requires manual dexterity. The significant side effect is bronchospasm, primarily in asthmatics. It is FDA-approved for treatment (age > 7 years) and prophylaxis (age > 5 years). It is effective against most oseltamivir-resistant strains. It should not be used in patients with asthma or chronic obstructive pulmonary disease (COPD). It is uncommonly used due to the delivery system.
Peramivir	The FDA approved the first injectable neuraminidase inhibitor in 2014 for uncomplicated influenza < 48 hours. Probably considered off-label for patients hospitalized with severe flu who cannot receive or adequately absorb oral oseltamivir.

OTHER INFORMATION

Seasonal influenza is a significant cause of serious disease in persons >65 years, nursing home residents, and persons with chronic diseases - lung, heart, liver/renal failure, diabetes, etc.
- Influenza can precipitate acute cardiovascular events and cause decompensation of underlying cardiopulmonary disease.
- It is essential to know whether your community has a high circulating influenza rate to inform decision-making.
Oseltamivir and baloxavir are the most commonly employed anti-influenza drugs.
- Treat as soon as possible all patients who are hospitalized, have severe/progressive influenza, or are at increased risk for complications.
  - Do not wait for laboratory confirmation.
  - Oral or enteric oseltamivir is preferred for hospitalized influenza.
  - CDC recommends treatment of hospitalized patients even when >48 h after onset, with observational studies suggesting benefit may persist with later initiation.
- For otherwise healthy outpatients, treatment may be considered when it can be started within 48 hours of illness onset.
CDC weekly influenza updates: https://www.cdc.gov/fluview/index.html
Federal vaccine policy, including that regarding influenza, remains under litigation.
- A March 16, 2026, preliminary federal court order stayed ACIP votes taken at the June, September, and December 2025 meetings, as well as the January 2026 CDC childhood-schedule revision.
- The CDC therefore currently identifies the July 2, 2025 schedule as its operative child/adolescent schedule. Until superseding CDC/ACIP guidance is lawfully adopted, continue the standing 2025 influenza vaccination framework: annual vaccination for everyone aged ≥6 months without contraindications, using an age- and health-appropriate vaccine.
  - The Administration has appealed. White House executive orders in May and August 2026 directed reconsideration of the federal childhood schedule; the August order categorized pediatric influenza vaccination as shared clinical decision-making and instructed agencies to advance that framework “to the fullest extent allowable by law.” These executive directives should therefore be distinguished from published ACIP recommendations, current CDC scheduling under the injunction, and recommendations of independent professional societies.

Pathogen Specific Therapy

Basis for recommendation

Uyeki TM, Bernstein HH, Bradley JS, et al. Clinical Practice Guidelines by the Infectious Diseases Society of America: 2018 Update on Diagnosis, Treatment, Chemoprophylaxis, and Institutional Outbreak Management of Seasonal Influenzaa. Clin Infect Dis. 2019;68(6):895-902. [PMID:30834445]
Comment: Updated guideline that emphasizes the use of molecular diagnostics if lab testing is pursued in patients with influenza, as well as infection control, chemoprophylaxis, and antiviral treatment recommendations.
CDC. Influenza Antiviral Medications: Summary for Clinicians (accessed 9/8/2026, last updated 3/10/26) https://www.cdc.gov/flu/hcp/antivirals/summary-clinicians.html
Comment: The page is typically up to date and includes excerpts from the IDSA Influenza guideline.

References

Maloney P, Reeves EL, Wielgosz K, et al. Interim Estimates of 2025-26 Seasonal Influenza Vaccine Effectiveness - United States, September 2025-February 2026. MMWR Morb Mortal Wkly Rep. 2026;75(9):116-123. [PMID:41818161]
Comment: Interim U.S. 2025–26 vaccine-effectiveness (VE) estimates from their three surveillance networks. VE was 38–41% against outpatient influenza and 41% against hospitalization in children and adolescents, with 22–34% against outpatient illness and 30% against hospitalization in adults. Despite substantial H3N2 antigenic drift, immunization still provided meaningful protection.
Monto AS, Kuhlbusch K, Bernasconi C, et al. Efficacy of Baloxavir Treatment in Preventing Transmission of Influenza. N Engl J Med. 2025;392(16):1582-1593. [PMID:40267424]
Comment: A large randomized household-transmission trial demonstrated that treatment of the index patient with a single dose of baloxavir reduced lab-confirmed secondary influenza among household contacts. The reduction in symptomatic transmission was not statistically significant. Supports a transmission-reduction effect without implying complete prevention, but for vulnerable patients in a household, it may provide some basis for reducing the risk of acquiring infection.
Bai AD, Srivastava S, Al Baluki T, et al. Oseltamivir Treatment vs Supportive Care for Seasonal Influenza Requiring Hospitalization. JAMA Netw Open. 2025;8(6):e2514508. [PMID:40493366]
Comment: A large contemporary cohort of 11,073 adults hospitalized with influenza showed that oseltamivir started within the first 2 hospital days was associated with lower in-hospital mortality (adjusted absolute risk reduction 1.8%), earlier discharge, and fewer 30-day readmissions. Supports current inpatient-treatment recommendations, although confounding remains because treatment was not randomized.
Gao Y, Zhao Y, Liu M, et al. Antiviral Medications for Treatment of Nonsevere Influenza: A Systematic Review and Network Meta-Analysis. JAMA Intern Med. 2025;185(3):293-301. [PMID:39804622]
Comment: Meta-analysis of 73 randomized trials involving 34,332 participants with nonsevere influenza, which highlights the modest effect of antivirals on symptom duration and limited evidence for preventing major outcomes. More convincing evidence suggests that baloxavir may reduce hospitalizations in high-risk outpatients, but there is potential for selecting for treatment-emergent resistance.
Lu LY, Lee HM, Burke A, et al. Prevalence, Risk Factors, Clinical Features, and Outcome of Influenza-Associated Pulmonary Aspergillosis in Critically Ill Patients: A Systematic Review and Meta-Analysis. Chest. 2024;165(3):540-558. [PMID:37742914]
Comment: In their analysis of 10 studies, patients with a history of solid organ transplantation, hematogenous malignancy, immunocompromised or use of prolonged steroids were at higher risk for IAPA.
Zhao Y, Gao Y, Guyatt G, et al. Antivirals for post-exposure prophylaxis of influenza: a systematic review and network meta-analysis. Lancet. 2024;404(10454):764-772. [PMID:39181596]
Comment: For those at high risk, any approved antivirals for influenza appear to reduce risk if used appropriately and in a timely manner. Zanamivir, oseltamivir and baloxavir probably achieve important reductions in symptomatic influenza in individuals at high risk of severe disease (zanamivir: risk ratio 0·35, 95% CI 0·25-0·50; oseltamivir: 0·40, 0·26-0·62; baloxavir: 0·43, 0·23-0·79; moderate certainty) when given promptly (e.g., within 48 h) after exposure
Gao Y, Guyatt G, Uyeki TM, et al. Antivirals for treatment of severe influenza: a systematic review and network meta-analysis of randomised controlled trials. Lancet. 2024;404(10454):753-763. [PMID:39181595]
Comment: Among 8 trials with 1424 patients hospitalized with severe influenza, those who received antiviral with oseltamivir found that the LOS was 1.63 days less, and there was little to no difference in time to alleviation of symptoms. Levels of certainty were low as there were no RCTs available.
Hayden FG, Lenk RP, Stonis L, et al. Favipiravir Treatment of Uncomplicated Influenza in Adults: Results of Two Phase 3, Randomized, Double-Blind, Placebo-Controlled Trials. J Infect Dis. 2022;226(10):1790-1799. [PMID:35639525]
Comment: Though not licensed in the US, this drug is used in other countries. In an uncomplicated influenza trial in healthy adults, the drug reduced illness duration by 14.4 hours (median, 84.2 vs. 98.6 hours; P = .004) in one trial but not the other (median, 77.8 vs. 83.9 hours). Given the inconsistency, authors venture that more studies using higher doses or in combination are warranted.
Kumar D, Ison MG, Mira JP, et al. Combining baloxavir marboxil with standard-of-care neuraminidase inhibitor in patients hospitalised with severe influenza (FLAGSTONE): a randomised, parallel-group, double-blind, placebo-controlled, superiority trial. Lancet Infect Dis. 2022;22(5):718-730. [PMID:35085510]
Comment: Combining an NAI and an endcap endonuclease inhibitor (baloxivir) did not affect the primary outcome, time to clinical improvement, in this RCT among hospitalized patients aged 12 and older. One caveat is that treatment was initiated within 48 hours of symptom onset in only 39% of patients (enrollment up to 96 hours was allowed).
Ison MG, Portsmouth S, Yoshida Y, et al. Early treatment with baloxavir marboxil in high-risk adolescent and adult outpatients with uncomplicated influenza (CAPSTONE-2): a randomised, placebo-controlled, phase 3 trial. Lancet Infect Dis. 2020;20(10):1204-1214. [PMID:32526195]
Comment: This trial served as the basis for an expanded FDA indication for this drug in patients at high risk for complications of influenza when seen in the outpatient setting. Also intriguing is that baloxavir performed better than oseltamivir in influenza B-infected patients. The trial was conducted during an exceptionally large year for influenza B.
Baker J, Block SL, Matharu B, et al. Baloxavir Marboxil Single-dose Treatment in Influenza-infected Children: A Randomized, Double-blind, Active Controlled Phase 3 Safety and Efficacy Trial (miniSTONE-2). Pediatr Infect Dis J. 2020;39(8):700-705. [PMID:32516282]
Comment: Randomized controlled pediatric trial comparing baloxavir with oseltamivir in children aged 1 to <12 years. Baloxavir demonstrated similar clinical efficacy and an acceptable safety profile, supporting its use in pediatric patients.
Ikematsu H, Hayden FG, Kawaguchi K, et al. Baloxavir Marboxil for Prophylaxis against Influenza in Household Contacts. N Engl J Med. 2020;383(4):309-320. [PMID:32640124]
Comment: RCT with 374 in the single-dose baloxavir group and 375 in the placebo group, influenza developed less in the baloxavir group than in the placebo group (1.9% vs. 13.6%) (adjusted risk ratio, 0.14; 95% confidence interval [CI], 0.06 to 0.30; P< 0.001). This is similar to oseltamivir.
Butler CC, van der Velden AW, Bongard E, et al. Oseltamivir plus usual care versus usual care for influenza-like illness in primary care: an open-label, pragmatic, randomised controlled trial. Lancet. 2020;395(10217):42-52. [PMID:31839279]
Comment: This large trial confirmed an approximately 1-day improvement with oseltamivir for ILI in outpatients. Elderly patients and those with comorbidities improved 2-3 days faster.
Uehara T, Hayden FG, Kawaguchi K, et al. Treatment-Emergent Influenza Variant Viruses With Reduced Baloxavir Susceptibility: Impact on Clinical and Virologic Outcomes in Uncomplicated Influenza. J Infect Dis. 2020;221(3):346-355. [PMID:31309975]
Comment: Some patients who developed baloxavir resistance experienced delayed symptom alleviation or even infection rebound. Viruses containing PA/I38X substitutions were identified 3-9 days after baloxavir treatment in 9.7% (36/370) of patients, of whom 85.3% had transient virus titer rises. The median time to sustained cessation of infectious virus detection was 192, 48, and 96 hours in baloxavir recipients with PA/I38X-substituted viruses, baloxavir recipients without PA/I38X-substituted viruses, and placebo recipients, respectively. The median times for alleviating symptoms were 63.1, 51.0, and 80.2 hours, respectively. After day 5, symptom increases occurred in 11.5%, 8.0%, and 13.0% of patients, respectively, and in 8.9% of oseltamivir recipients.
Hayden FG, Sugaya N, Hirotsu N, et al. Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents. N Engl J Med. 2018;379(10):913-923. [PMID:30184455]
Comment: Pivotal phase 2/3 baloxavir study in uncomplicated influenza. Single-dose baloxavir shortened symptoms versus placebo and had clinical efficacy similar to 5 days of oseltamivir, with a more rapid reduction in viral load. Reduced-susceptibility variants were observed in some following therapy.
Ramirez J, Peyrani P, Wiemken T, et al. A Randomized Study Evaluating the Effectiveness of Oseltamivir Initiated at the Time of Hospital Admission in Adults Hospitalized With Influenza-Associated Lower Respiratory Tract Infections. Clin Infect Dis. 2018;67(5):736-742. [PMID:29659754]
Comment: An RCT examining whether giving oseltamivir benefits hospitalized patients with influenza is currently a CDC recommendation. In this report, there appeared to be no effect if the drug was given 5 days or more after symptom onset.
Markel H, Lipman HB, Navarro JA, et al. Nonpharmaceutical interventions implemented by US cities during the 1918-1919 influenza pandemic. JAMA. 2007;298(6):644-54. [PMID:17684187]
Comment: A review of the 1918-19 pandemic of influenza showed that "social distancing," by closing schools and limiting mass gatherings, reduced peak flu cases, pneumonia cases, and excess deaths.
Nicholson KG, Aoki FY, Osterhaus AD, et al. Efficacy and safety of oseltamivir in treatment of acute influenza: a randomised controlled trial. Neuraminidase Inhibitor Flu Treatment Investigator Group. Lancet. 2000;355(9218):1845-50. [PMID:10866439]
Comment: This multicenter study in 51 centers of 475 patients with influenza symptoms for less than or equal to 36 hrs. randomized to 2 doses of oseltamivir x 5 days or placebo. OSELTAMIVIR REDUCED THE DURATION OF FLU SYMPTOMS BY A MEDIAN OF 29 HRS. Better results were found with earlier treatment. GI side effects were noted in 15-20%.
Treanor JJ, Hayden FG, Vrooman PS, et al. Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: a randomized controlled trial. US Oral Neuraminidase Study Group. JAMA. 2000;283(8):1016-24. [PMID:10697061]
Comment: A randomized oseltamivir trial vs. placebo for influenza in 629 persons aged 16-65 years. Oseltamivir REDUCED THE AVERAGE DURATION OF FLU SYMPTOMS FROM 103 to 72 HOURS.
Sukhal S, Sethi J, Ganesh M, et al. Extracorporeal membrane oxygenation in severe influenza infection with respiratory failure: A systematic review and meta-analysis. Ann Card Anaesth. 2017;20(1):14-21. [PMID:28074789]
Comment: Systematic review of ECMO in severe influenza-associated respiratory failure. These observational data suggested that delayed initiation may be associated with worse outcomes; however, the evidence base is limited and heterogeneous.
American Academy of Pediatrics. Committee on Infectious Diseases: Recommendations for Prevention and Control of Influenza in Children, 2026–2027: Policy Statement. https://doi.org/10.1542/peds.2026-078778 [accessed 9/8/2026]
Comment: Current AAP pediatric influenza policy. Recommends annual influenza vaccination for all children aged ≥6 months without contraindications and prompt antiviral treatment for hospitalized, severe/progressive, or high-risk children. These evidence-based recommendations are useful independent professional-society guidance during current federal policy uncertainties.
CDC. Influenza (flu). ACIP Recommendations Summary. https://www.cdc.gov/flu/hcp/vax-summary/acip-recommendations.html [last updated 6/10/26, accessed 9/8/2026].
Comment: Current CDC clinician-facing influenza vaccination guidance. Continues the standing recommendation for annual influenza vaccination of everyone aged ≥6 months without contraindications and links clinicians to current vaccine administration and product guidance.
CDC; FluView -- https://www.cdc.gov/fluview/index.html; last accessed 9/8/2026
Comment: Website for updates concerning seasonal and pandemic influenza, with an influenza-like illness (ILI) map of the US and positive influenza testing rates in clinical labs and US public health labs.

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