Influenza A is frequently a big culprit of respiratory illness during the winter months. Inevitably, the question often arrives from consultants, attendings, or colleagues at sign-out, “Did they get Tamiflu?” This is often met with a variety of responses and debates regarding its efficacy at times. However, what does the literature actually say regarding the use of Tamiflu?
The Basics:
Influenza seasonal incidence is approximately 8% annually (2010-2016) in the US. Per the CDC, there were an estimated 380,000 hospitalizations and 28,000 deaths in 2018-2019. Higher risk populations for severe disease and complications are those at extremes of age; pregnant and postpartum patients; patients with neurologic disorders; immunocompromised individuals; and patients living with chronic pulmonary, cardiac, or metabolic diseases (1).
Oseltamivir, otherwise known as Tamiflu, is one of several options for treatment. It is a neuraminidase inhibitor that serves to prevent the replication of the influenza virus in the body. It is effective against influenza A and B and should be initiated within 48hrs of symptom onset. It may be used for prophylaxis following exposure, as well (this use is outside the scope of this review). It is typically well tolerated, with the most common side effects being nausea and vomiting (~10%) and headache (~8%). There are rare reports of neuropsychiatric events, such as confusion, delirium, hallucinations, and suicidal ideation. Rarely, SJS and other dermatologic reactions may occur.
The Data:
Unfortunately, there are a myriad of conflicting studies with no consistently demonstrated outcomes on the efficacy of oseltamivir in preventing complications and hospitalizations. The data do consistently suggest that, when oseltamivir is promptly initiated, the duration of influenza symptoms is reduced. Hospitalized and vulnerable populations also likely benefit most. Below are several summaries of studies regarding oseltamivir’s clinical utility in various patient populations.
The positive in adults:
One study out of Australia (a systematic review and meta analysis) that specifically studied outcomes in high-risk populations (defined as any individual with a chronic lung or cardiac disease) who was diagnosed with influenza found that patients who received oseltamivir had a significant reduction in hospitalizations, respiratory tract complications, and time to alleviation of symptoms. The majority of patients were administered oseltamivir within 48hrs of onset of illness (2).
A retrospective cohort study with a total of 9090 adult patients who had diabetes and who were diagnosed with influenza demonstrated a decrease in the number of all-cause hospitalizations and respiratory illnesses. However, the study did not demonstrate any improvement in the rates of developing complications such as acute otitis media, pneumonia, or hospitalizations specifically for pneumonia (3).
Another retrospective cohort study in healthy adults and adolescents demonstrated a reduction in rates of acute otitis media, lower respiratory tract infections, and hospitalizations (4). A meta-analysis also showed similar reductions in these complications, in duration of illness, and in hospitalizations in adults (5).
The negative in adults:
A large systematic review and meta-analysis in JAMA from 2023 conducted on outpatients diagnosed with influenza saw no decrease in hospitalizations, including in the elderly and those at reported increased risk. There was an association with increased GI adverse events (6).
Two other systematic reviews demonstrated a reduction in time to alleviation of symptoms, though no reduction in hospitalizations or other complications (7,8).
What about pediatrics?
Generally, the same can be applied to pediatrics as adults when considering oseltamivir. Data most frequently point to the maximum gain in high-risk populations early in the course of the disease. One study by Piedra showed reduction in acute otitis media, respiratory illness, and all-cause hospitalizations in children with chronic medical conditions, neurologic diseases, or neuromuscular diseases who were hospitalized with influenza (9). Another study demonstrated improved outcomes (including length of stay, ICU days, time on ventilator) for critically ill pediatric patients hospitalized with influenza (10).
Conclusion
The data are not consistent regarding oseltamivir’s efficacy. There are many confounding factors and biases in the studies highlighted above, further muddying the results. Such confounders include poor documentation of patient’s vaccination status. Additionally, each influenza season varies in severity for wide number of reasons, leading to further confounding among studies done across several years.
Overall, patients who are hospitalized with influenza and those at greatest risk for developing severe illness (co-morbid conditions, extremes of age, pregnancy, immunocompromised) who receive initiation of oseltamivir treatment within 48 hours of illness onset will likely have maximum benefit from treatment. The data most strongly support oseltamivir’s use in reduction the duration of illness, though it may also possibly reduce hospitalizations and complications. As always, it should be a shared decision based on a discussion of risks and benefits with patients.
Additional guidelines and recommendations are provided below by the Infectious Disease Society of America in 2018 (11).
Which patients with suspected or confirmed influenza should be treated with antivirals?
Clinicians should start antiviral treatment as soon as possible for adults and children with documented or suspected influenza, irrespective of influenza vaccination history, who meet the following criteria:
Persons of any age who are hospitalized with influenza, regardless of illness duration prior to hospitalization (A-II).
Outpatients of any age with severe or progressive illness, regardless of illness duration (A-III).
Outpatients who are at high risk of complications from influenza, including those with chronic medical conditions and immunocompromised patients (A-II).
Children younger than 2 years and adults ≥65 years (A-III).
Pregnant women and those within 2 weeks postpartum (A-III).
Clinicians can consider antiviral treatment for adults and children who are not at high risk of influenza complications, with documented or suspected influenza, irrespective of influenza vaccination history, who are either:
Outpatients with illness onset ≤2 days before presentation (C-I).
Symptomatic outpatients who are household contacts of persons who are at high risk of developing complications from influenza, particularly those who are severely immunocompromised (C-III).
Symptomatic healthcare providers who care for patients who are at high risk of developing complications from influenza, particularly those who are severely immunocompromised (C-III).
For patients who are recommended to receive antiviral treatment for suspected or confirmed influenza, which antiviral should be prescribed, at what dosing, and for what duration?
Clinicians should start antiviral treatment as soon as possible with a single neuraminidase inhibitor (NAI) (either oral oseltamivir, inhaled zanamivir, or intravenous peramivir) and not use a combination of NAIs (A-1).
Clinicians should not routinely use higher doses of US Food and Drug Administration-approved NAI drugs for the treatment of seasonal influenza (A-II).
Clinicians should treat uncomplicated influenza in otherwise healthy ambulatory patients for 5 days with oral oseltamivir or inhaled zanamivir, or a single dose of intravenous peramivir (A-1).
Clinicians can consider longer duration of antiviral treatment for patients with a documented or suspected immunocompromising condition or patients requiring hospitalization for severe lower respiratory tract disease (especially pneumonia or acute respiratory distress syndrome [ARDS]), as influenza viral replication is often protracted (C-III).
Authored by Kathryn McGregor, MD and Eric Leser, MD.
References:
Tokars JI, Olsen SJ, Reed C. Seasonal incidence of symptomatic influenza in the United States. Clin Infect Dis 2018; 66:1511–18.
Shim SJ, Chan M, Owens L, Jaffe A, Prentice B, Homaira N. Rate of use and effectiveness of oseltamivir in the treatment of influenza illness in high-risk populations: A systematic review and meta-analysis. Health Sci Rep. 2021 Feb 10;4(1):e241. doi: 10.1002/hsr2.241. PMID: 33614979; PMCID: PMC7875571.
Orzeck EA, Shi N, Blumentals WA. Oseltamivir and the risk of influenza-related complications and hospitalizations in patients with diabetes. Clin Ther. 2007 Oct;29(10):2246-55. doi: 10.1016/j.clinthera.2007.10.001. PMID: 18042482.
Blumentals WA, Schulman KL. Impact of oseltamivir on the incidence of secondary complications of influenza in adolescent and adult patients: results from a retrospective population-based study. Curr Med Res Opin. 2007 Dec;23(12):2961-70. doi: 10.1185/030079907X242520. PMID: 17939881.
Joanna Dobson MSc, Richard J Whitley Prof, Stuart Pocock Prof and Arnold S Monto Prof. Oseltamivir treatment for influenza in adults: a meta-analysis of randomised controlled trials, Lancet, The, 2015-05-02, Volume 385, Issue 9979, Pages 1729-1737, Copyright © 2015 Elsevier Ltd.
Hanula R, Bortolussi-Courval É, Mendel A, Ward BJ, Lee TC, McDonald EG. Evaluation of Oseltamivir Used to Prevent Hospitalization in Outpatients With Influenza: A Systematic Review and Meta-Analysis. JAMA Intern Med. 2024;184(1):18–27. doi:10.1001/jamainternmed.2023.0699
Smieja M. ACP Journal Club. Review: oseltamivir relieves symptoms but does not reduce hospitalizations in influenza. Ann Intern Med. 2012 Sep 18;157(6):JC3-5. doi: 10.7326/0003-4819-157-6-201209180-02005. PMID: 22986397.
Patel, Deepa M.Hargraves, Joshua et al. Should Neuraminidase Inhibitors Be Prescribed for Patients With Influenza? Annals of Emergency Medicine, Volume 63, Issue 1, 54 - 55
Piedra PA, Schulman KL, Blumentals WA. Effects of oseltamivir on influenza-related complications in children with chronic medical conditions. Pediatrics. 2009 Jul;124(1):170-8. doi: 10.1542/peds.2008-0977. PMID: 19564297.
Coffin SE, Leckerman K, Keren R, Hall M, Localio R, Zaoutis TE. Oseltamivir shortens hospital stays of critically ill children hospitalized with seasonal influenza: a retrospective cohort study. Pediatr Infect Dis J. 2011 Nov;30(11):962-6. doi: 10.1097/INF.0b013e318232ede9. PMID: 21997661; PMCID: PMC3426912.
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