A 2-year-old male came to clinic with a 24 hour history of fever to 102-103°, rhinorrhea, cough and what his parents believe were muscle aches. There was no nausea, emesis or rash. He was drinking but not eating solid foods and was urinating well. He had received acetaminophen for his fever and discomfort with symptomatic relief. He had received a seasonal influenza vaccine 3 months prior to the visit. Influenza was circulating in the community and he had a known exposure to influenza at his daycare. Additionally there was a 2-month old sibling at home. The past medical history was positive for 3 otitis media episodes in the past.
The pertinent physical exam showed a tired, sick appearing male. His temperature was 38.5°C. His respiratory rate was 36 without increased work of breathing. His oxygen saturation was 95% on room air. The rest of his vital signs were normal with growth parameters in the 75-95%. He had copious clear rhinorrhea and tearing with some mild conjunctival injection. His mouth and ears were normal. His lungs were clear. There were no rashes. He complained of muscle aches with palpation of his arms and legs but did not appear to have any joint involvement. The rest of his examination was normal. The diagnosis of presumed influenza was made. He was started on oseltamivir for treatment. His parents had also received a seasonal influenza vaccine and they contacted their own physicians and received prophylactic oseltamivir. At followup for a health maintenance visit for the sibling the following week, the mother said that the infant did not develop influenza.
Oseltamivir (Tamiflu®) is an oral neuraminidase inhibitor of influenza viruses types A and B. It first came on the market in Switzerland in 1999 and currently is used around the world along with other neuraminidase inhibitors to treat seasonal and pandemic influenza.
Oseltamivir is easily absorbed from the gastrointestinal tract, and circulates to the liver where it is converted to its active metabolite oseltamivir carboxylate (OC). In adults approximately 75% of the oral medication is converted and it then travels to the upper and lower respiratory tracts. Unchanged oseltamivir is eliminated in the urine. OC “inhibits the conserved active site of the neuraminidase enzymes that are present as major surface antigens on all types of influenza viruses. As neuraminidase is essential for the release of progency virions from infected cells, inhibiting this enzyme limits the duration and severity of the infection.” OC half-life is about 1-2 hours and the maximal concentrations occur ~ 3-4 hours after administration. Children < 12 years of age clear OC faster than teenagers and adults resulting in a lower drug exposure.
Oseltamivir is approved for use for treatment of uncomplicated influenza especially for those at increased risk such as infants, pregnant women and those with chronic cardiac, respiratory or metabolic problems, for severe or progressive influenza, and for those that are immunosuppressed. It can also be used for post-exposure prophylaxis. Oseltamivir can be used more than once during the season and has been used for seasonal prophylaxis particularly in institutional settings such as nursing homes. If resistance to oseltamivir is known (such as the H275Y mutation in season H1N1 viral strains) then other neuraminidase inhibitors such as zanamivir are recommended.
The most common side effects in children are nausea and vomiting. Neuropsychiatric symptoms that have been reported with use of oseltamivir include mental status changes, agitation, anxiety, confusion, delusions, hallucinations and nightmares. It is not clear why these symptoms may occur as oseltamivir does not cross the blood-brain barrier to any appreciable extent.
One study estimated the cost-effectiveness of different treatment strategies using oseltamivir for uncomplicated seasonal influenza in unimmunized patients 1-17 years. Empirically treatment was more cost effective than testing and then treating. Both empiric treatment or testing and then treating were more cost effective than no treatment. However, the cost effectiveness was very sensitive to the prevalence of oseltamivir-resistant strains that are circulating.
Of course, oseltamivir is not a substitution for receiving the seasonal influenza vaccine. Treatment recommendations or prophylaxis are always changing because of the changes in the influenza virus and its epidemiology. Health professionals should follow current recommendations from public health authorities.
The burden of influenza is often not apparent to many individuals. In the United States, up to 20% of the population develop influenza each year, deaths occur in 36,000-49,000 people, and ~250,000 require hospitalizations for complications such as pneumonia. Some strains have higher morbidity and mortality. For example, children and young adults had higher morbidity and mortality during the 2009-2010 H1N1 pandemic. The Avian H5N1 strain are more virulent than seasonal strains and have mortality rates >50%.
A 2014 Cochrane Review of the effectiveness of oseltamivir treatment included 107 clinical studies and 73 trials and found:
For treatment of symptomatic patients, time to first symptom alleviation was reduced by 16.8 hours or from 7 to 6.3 days. In children the reduction was 29 hours. There was no change for asthmatic children. In children there was no significant effect on hospitalizations. There also were no significant reduction in serious complications or in hospitalizations, but there are problems with the data because of lack of diagnostic definitions. Oseltamivir did reduce the risk of symptomatic influenza for individuals or households for those who used it for prophylaxis.
Questions for Further Discussion
1. What is the cost of oseltamivir in your local area?
2. What other neuraminidase inhibitors do you have available in your local area?
3. What is the rate of season influenza vaccination in your own practice?
- Disease: Influenza
- Age: Toddler
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Smith JR, Rayner CR, Donner B, et. al. Oseltamivir in seasonal, pandemic, and avian influenza: a comprehensive review of 10-years clinical experience. Adv Ther. 2011 Nov;28(11):927-59.
Lavelle TA, Uyeki TM, Prosser LA. Cost-effectiveness of oseltamivir treatment for children with uncomplicated seasonal influenza. J Pediatr. 2012 Jan;160(1):67-73.e6.
Jefferson T, Jones MA, Doshi P, et. al. Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. Cochrane Database Syst Rev. 2014 Apr 10;4:CD008965.
Centers for Disease Control. Estimating Seasonal Influenza-Associated Deaths in the United States: CDC Study Confirms Variability of Flu.
Available from the Internet at http://www.cdc.gov/flu/about/disease/us_flu-related_deaths.htm (rev. 3/18/16, cited 5/24/16).
Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa Children’s Hospital