By Richard R. Watkins, MD, MS, FACP, FIDSA, FISAC
Synopsis: A multicenter observational study on adults hospitalized with influenza found that initiation of oseltamivir on the day of admission reduced the risk of disease progression, including pulmonary and extra-pulmonary organ failure and death.
Source: Lewis NM, Harker EJ, Grant LB, et al. Benefit of early oseltamivir therapy for adults hospitalized with influenza A: An observational study. Clin Infect Dis 2024; Nov 28:ciae584. [Online ahead of print].
The current Infectious Diseases Society of America (IDSA) guidelines for the treatment of patients hospitalized with influenza A recommend starting oseltamivir as soon as possible, regardless of symptom duration.1 However, there continues to be variability in the clinical use and timing of oseltamivir therapy. There also is a concern that the variation in yearly influenza strains may affect the effectiveness of oseltamivir. Lewis and colleagues aimed to evaluate the benefits of following the guidelines for treating adults hospitalized with influenza A with oseltamivir as early as possible (i.e., on the day of hospital admission), compared to later or no treatment.
The study was conducted at 24 hospitals in 19 states that were part of a surveillance program funded by the Centers for Disease Control and Prevention (CDC). Patients were included who were at least 18 years of age, were hospitalized for a respiratory illness, and had a positive molecular or antigen test for influenza. Patients were excluded from the analysis who tested positive for SARS-CoV-2 or respiratory syncytial virus (RSV), including co-infections with influenza viruses, received anti-influenza medications other than oseltamivir not indicated for hospitalized patients, or who were discharged on the day of admission (i.e., no follow-up for outcome assessment).
The patients who were treated with oseltamivir on the day of admission were designated as the early treatment (ET) group. Patients who were not treated with oseltamivir on the day of hospital admission, including those who started taking oseltamivir later during their hospitalization and those who never received oseltamivir, were designated as the late treatment/no treatment (LTNT) group. The primary end point was patient outcomes in the ET group vs. the LTNT group. The major outcome was the peak pulmonary disease severity level the patient experienced during hospitalization. For secondary outcomes, patients who were never treated with oseltamivir were excluded, and those who received oseltamivir on the day of hospital admission were compared to patients who received the drug later in the hospitalization. These outcomes included hospital length of stay (LOS), intensive care unit (ICU) admission, initiation of extra-pulmonary organ support with vasopressors or new kidney replacement therapy, and in-hospital mortality.
There were 840 patients included in the study, of whom 415 (49%) were in the ET group and 425 (51%) were in the LTNT group. There were more patients aged ≥ 75 years in the ET group compared to the LTNT group (27% vs. 19%, respectively). Patients in the ET group had higher baseline pulmonary disease severity (P < 0.001) along with a lower proportion of those not treated with any oxygen support on hospital day 1 (34% vs. 56%). Furthermore, compared to the LTNT group, those in the ET group were less likely to have disease progression after the day of hospital admission, as measured by an escalation of pulmonary disease severity (11% vs. 21%, respectively; P < 0.001). The time from admission to peak disease severity was comparable between the ET and LTNT groups.
Regarding the secondary outcomes, patients in the ET group had a shorter hospital LOS (median, 4 days [range, 2-7 days] vs. 4 days [range, 3-8 days], adjusted hazard ratio [HR] for discharge, 1.19; 95% confidence interval [CI], 1.05-1.36), and lower odds of ICU admission (adjusted odds ratio [aOR], 0.25; 95% CI, 0.13- 0.49), acute vasopressor use or new kidney replacement therapy (aOR, 0.40; 95% CI, 0.22-0.67), and in-hospital death (aOR, 0.36; 95% CI, 0.19-0.69). Of the 14 patients who died in the hospital, four were in the ET group (1.0% of the total population), seven were in the late treatment group (2.3%), and three were in the no treatment group (2.4%). While the timing of ICU admission was similar between ET and LTNT patients, acute kidney replacement or vasopressor use and death tended to happen earlier during the hospitalization for the LTNT patients.
Commentary
This study provides further empirical evidence for the early use of oseltamivir in patients hospitalized with influenza, thus supporting the current IDSA guideline recommendations. It was surprising that more than half of the patients were not treated early, given that the guidelines were published in 2018. This clearly demonstrates that many physicians need further education about the optimal management of influenza. The authors hypothesized that there may be confusion among physicians about the 48-hour treatment window for outpatients with influenza also applying to inpatients.
There were a few limitations to the study. First, because of the observational design, unmeasured confounding variables may have affected the results. For example, these could have included outpatient antiviral treatment before hospital admission or other treatments, such as macrolides, statins, corticosteroids, or immunomodulators, before or during hospitalization. Second, the study was conducted during the 2022-2023 influenza season in which the influenza A (H3N2) strain was predominant, so the results may not be generalizable when the circulating strain of influenza is different. Third, the size of the untreated group was too small to conduct a separate analysis comparing no treatment to early or late treatment. Finally, there were several clinical metrics that the authors did not collect that would have been useful, such as virologic replication measures, antiviral resistance, oseltamivir adverse events, and influenza season dynamics.
Although this was an observational study, the conclusion that patients hospitalized with influenza should receive oseltamivir on the day of admission seems both valid and axiomatic. There is no objective reason for delaying oseltamivir, and doing so likely increases the risk for bad outcomes. One hopes the study can inculcate hospital physicians that when managing influenza, earlier treatment is better.
Richard Watkins, MD, is Professor of Medicine, Division of Infectious Diseases, Northeast Ohio Medical University, Rootstown, OH.
Reference
1. Uyeki TM, Bernstein HH, Bradley JS, et al. Clinical Practice Guidelines for the Diagnosis, Treatment, Chemoprophylaxis, and Institutional Outbreak Management of Seasonal Influenza: 2018 Update by IDSA. Clin Inf Dis 2019;68:e1-e47.
A multicenter observational study on adults hospitalized with influenza found that initiation of oseltamivir on the day of admission reduced the risk of disease progression, including pulmonary and extra-pulmonary organ failure and death.
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