Date: July 6, 2023 Reference: Hanula R et al. Evaluation of oseltamivir used to prevent hospitalization in outpatients with influenza: a systematic review and meta-analysis. JAMA Int Med 2023. Guest Skeptic: Dr. Anand Swaminathan is an Assistant Professor of Emergency Medicine at Staten Island University Hospital. Managing editor of EM:RAP and Associate Editor at REBEL EM. Case: A 57-year-old woman with hypertension, hyperlipidemia and type-2 diabetes mellitus presents to the emergency department (ED) with fever, cough, myalgias, headache and congestion. It’s flu season and you’ve already seen 15 people with the same symptoms. Her vitals look good: Temperature 38.5C, heart rate 102 beats/minute, blood pressure 143/88 and oxygen saturation of 99% on room air.  She is breathing comfortably without any increased work of breathing. You send off COVID and flu swabs and the results come back as positive for influenza. She looks well enough to go home but asks if she should be prescribed oseltamivir (Tamiflu) because some of her friends have been given it recently by their doctors. Background: Oseltamivir was approved by the FDA in 1999 based on evidence from trials funded by the maker of the drug, Roche. Safety issues popped up soon after widespread use of the drug including neuropsychiatric effects as well as the more common adverse effects of nausea and vomiting. The Cochrane collaboration published analyses of the available data in 1999, 2003 and 2006. In 2009, the Cochrane group questioned Roche about the completeness of the data and after four years of requests, finally got access to all the data in 2013 and updated their review in 2014. We covered this SRMA on SGEM#98. The 2014 Cochrane review found an improvement in time to first alleviation of symptoms in adults by about 17 hours coupled with several side effects including nausea, vomiting, headaches, and neuropsychiatric effects. Despite these findings, the World Health Organization (WHO), Infection Disease Society of America (IDSA) and the Center for Disease Control and Prevention (CDC) all continue to recommend use of oseltamivir, particularly in patients at increased risk of hospitalization and bad outcomes. There was a large unblinded RCT of over 3,000 patients published in the Lancet in 2020. It looked at patients presenting to their primary care physician with influenza. The results were those treated with oseltamivir recovered about one day earlier than the control group but experienced more nausea and vomiting. This was critically appraised on SGEM#312. A subgroup analysis of the Lancet RCT showed that older, sicker patients with comorbidities and longer previous symptom duration recovered 2–3 days sooner. While this is interesting it should be considered hypothesis generating. Wallach et al JAMA Intern Med 2017, previously reported that subgroup claims are often not corroborated by subsequent studies and rarely confirmed. Also, Yusuf et al JAMA 1991 stated: “the overall trial result is usually a better guide to the direction of effect in subgroups than the apparent effect observed within a subgroup.” When it comes to children suspected of influenza and ill enough to be admitted to hospital there was an observational study looking at the impact of oseltamivir (JAMA Ped 2022). SGEM Peds expert Dr. Dennis Ren did a structed critical appraisal of that study on SGEM#397. The bottom line from that episode was we do not have high-quality evidence to support the routine use of oseltamivir in the treatment of children admitted to hospital with suspected influenza. Clinical Question: Is oseltamivir effective in preventing hospitalization from influenza in adults and adolescent outpatients? Reference: Hanula R et al. Evaluation of oseltamivir used to prevent hospitalization in outpatients with influenza: a systematic review and meta-analysis. JAMA Int Med 2023. Population: RCTs of outpatients 12 years and older diagnosed with natural infl...