By Philip R. Fischer, MD, DTM&H
Professor of Pediatrics, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN; Department of Pediatrics, Sheikh Shakhbout Medical City, Abu Dhabi, United Arab Emirates
SYNOPSIS: A large study of children hospitalized with influenza clearly shows that oseltamivir given at or near the time of admission is effective in reducing the duration of hospitalization, reducing the requirement for intensive care, and reducing subsequent readmissions within the week after discharge.
SOURCE: Walsh PS, Schnadower D, Zhang Y, et al. Association of early oseltamivir with improved outcomes in hospitalized children with influenza, 2007-2020. JAMA Pediatr 2022; Sep 19;e223261. doi:10.1001/jamapediatrics.2022.3261. [Online ahead of print].
Oseltamivir has been approved for use in the United States since 1999. Both the Infectious Diseases Society of America and the American Academy of Pediatrics recommend that oseltamivir be used in the treatment of all children hospitalized with influenza. These recommendations are based mostly on outpatient data showing significantly more rapid alleviation of symptoms in treated vs. non-treated children. As to inpatient use of oseltamivir, debate continues as to whether treatment actually improves inpatient outcomes. Even in the 2009 H1N1 outbreak, the use of oseltamivir reduced mortality in hospitalized adults but not in pediatric inpatients.
Thus, collaborators from two Midwestern U.S. institutions used a large multicenter database to see if outcomes are improved by the use of oseltamivir in pediatric inpatients. The data set included patients from 13 successive influenza seasons.
The study included all inpatients younger than 18 years of age with primary or secondary diagnoses of influenza from 36 hospitals in the Pediatric Health Information System that had full data for the entire 2007-2020 study period. Patients transferred to other facilities were excluded from data analysis because of uncertain post-transfer information. Patients with multiple admissions during the same influenza season had only one admission included in the data analysis.
Patients were categorized as having (or not having) received early oseltamivir treatment, with “early” indicating during the initial or next day of the hospitalization. Outcomes included length-of-stay, seven-day readmission, transfer to intensive care, and death.
The database included information on 70,926 encounters. Because of discharge from the hospital during the initial two days of hospitalization, 13,355 encounters were excluded from analysis. After excluding other patients, specifically those meeting the exclusion criteria mentioned earlier, a total of 55,799 patients were included in the analysis, with 33,207 (60%) having received early treatment with oseltamivir. The mean age of the children was 3.6 years, and 56% were male.
The median length of stay was three days; 3.7% of children admitted to a general ward required transfer for intensive care, 1.4% died, and 1.1% were subsequently readmitted.
Early treatment was associated with shorter median length-of-stay (three days vs. four days), fewer intensive care admissions, fewer readmissions, and less death. Propensity score weighted analysis yielded similar results.
The authors pointed out that the clear advantages associated with early oseltamivir use were consistent, even across high-risk subgroups. The new findings are consistent with smaller, less-controlled inpatient studies and with outpatient studies.
The authors went on to say that despite credible recommendations to use oseltamivir in all hospitalized children with influenza, 33% of the patients in this study received no oseltamivir, and 7% only received treatment late during their hospitalization. They rightly claimed that these new data support recommendations for early oseltamivir use for children hospitalized with influenza.
COMMENTARY
The article summarized here was part of a pair of papers from the same group using the same data set. The other article evaluated patient and time factors associated with oseltamivir use in hospitalized children with influenza.1 Children were more likely to receive oseltamivir if they had complex chronic conditions, a history of asthma, or early severe symptoms.1 Use of oseltamivir varied between hospitals (43% to 80%) and over time (20% in 2007-2008 and 78% in 2017-2018).1 Perhaps the new data from these studies will help practitioners make the shift to more standardized use of oseltamivir in children hospitalized with influenza.
After becoming available in the 1990s, oseltamivir quickly gained popularity, and initial studies supported its efficacy in treating influenza. However, significant concerns were raised about publication bias and the integrity of the data that supported the widespread use of this medication.2 Subsequent meta-analyses based on more complete data confirmed the value of oseltamivir in treating outpatient adults but left pediatric use open to uncertainty.3 The new data summarized here add strength to the recommendation to give oseltamivir to all hospitalized children with influenza.
There are data suggesting that oseltamivir is most effective in reducing symptoms if given within the initial 48 hours following symptom onset.4 Some of the clinicians whose patients were included in Walsh’s studies might have withheld treatment since symptoms already had been present for days by the time of hospital admission. Walsh’s new data suggest that withholding oseltamivir treatment is not appropriate in hospitalized children, even days after the onset of symptoms of influenza illness.
The articles from Walsh and colleagues are timely — not merely to remind us of the value of oseltamivir in hospitalized children with influenza, but also to remind us that influenza season has begun. We should encourage vaccination for our colleagues and for our pediatric patients.
REFERENCES
- Walsh PS, Schnadower D, Zhang Y, et al. Assessment of temporal patterns and patient factors associated with oseltamivir administration in children hospitalized with influenza, 2007-2020. JAMA Network Open 2022;5:e2233027.
- Goldacre B. Trying to get trial data from drug companies: The story of Tamiflu. In: Bad Pharma: How Drug Companies Mislead Doctors and Harm Partients. Fourth Estate;2012:82-91.
- Jefferson T, Jones M, Doshi P, et al. Oseltamivir for influenza in adults and children: Systematic review of clinical study reports and summary of regulatory comments. BMJ 2014;348:g2545.
- Fry AM, Goswami D, Nahar K, et al. Efficacy of oseltamivir treatment started within 5 days of symptom onset to reduce influenza illness duration and virus shedding in an urban setting in Bangladesh: A randomised placebo-controlled trial. Lancet Infect Dis 2014;14:109-118.
