We found that critically ill children treated with oseltamivir had a shorter duration of total hospital stay when compared with matched patients who did not receive antiviral treatment within 24 hours of hospital admission. The duration of hospital stay was approximately 18% shorter for critically ill children treated with oseltamivir within 24 hours of hospitalization as compared with those whom were either untreated or received oseltamivir more than 24 hours after hospital admission. This is the first study to demonstrate a benefit of oseltamivir in critically ill children hospitalized with influenza.
Prior studies have demonstrated improved outcomes for non-hospitalized patients who received antiviral therapy. Oseltamivir treatment has been associated with reduced duration of illness, rates of influenza-related complications, and subsequent hospitalization among previously healthy, influenza-infected children8
and adults.17, 34
Using health insurance claims data, Piedra and colleagues35
recently demonstrated that oseltamivir therapy improved the outcomes of influenza-infected children with chronic medical conditions. Chronically ill outpatients who received oseltamivir within 1 day of influenza diagnosis had lower rates of respiratory complications, otitis media, and all-cause hospitalizations as compared to untreated children. Recently published data suggest initiation of antiviral therapy within 48 hrs of symptom onset, as compared with either delayed or no antiviral therapy, was associated with better clinical outcomes among adults hospitalized 2009 H1N1 influenza.18
Although children treated with oseltamivir had a shorter total length of hospital stay, we did not find a difference in the secondary outcomes examined such as duration of ICU stay, mortality, or readmission within 7 days. We did not power the study detect a difference in mortality, as the mortality rate among children hospitalized with influenza has historically been relatively low.5
Because the median duration of ICU stay was 4 days for both treated and untreated patients and ICU stay was measured in days, we suspect we were also underpowered to detect modest differences in this outcome. Because oseltamivir prevents viral replication we hypothesize that the drug may have minimal effect in altering the course of acute inflammatory reaction associated with severe influenza. Oseltamivir may hasten the time to resolution of other symptoms and thereby shortening the duration of non-ICU hospital stay. It is unclear why there was no difference between treated and untreated patients in the readmission rate.
Our study had several limitations. First, the use of administrative data might have led to misclassification of the principal exposure of interest (oseltamivir treatment) and important covariates (such as severity of illness measures), however we believe this bias would be non-differential. We recognize that we might not have fully adjusted for all differences in severity of illness. However, any residual confounding by indication would have biased our findings toward oseltamivir having less effect on the outcome of interest; thus, we believe that the difference in length of stay would be even greater in favor of the oseltamivir treated group. Selection bias (e.g. the use of ICD-9 codes for identifying influenza infected patients) might have led to under-ascertainment of influenza-infected patients; however this bias would have also led to a reduction in the difference in the duration of hospital stay among treated and untreated patients. Finally, we were unable to determine whether the time interval between symptom onset and initiation of oseltamivir influenced the impact of antiviral therapy on patient outcomes. Prior reports have suggested that antiviral medications may have negligible effect if begun greater than 48 hours after symptom onset.36
However, it is unlikely that all patients had symptoms for only 24 hours and therefore the effect size is likely to have been greater had treatment been initiated prior to hospital admission.
In summary, oseltamivir treatment reduced the duration of hospital stay among critically ill children with influenza infection when begun within 24 hours of hospital admission. This finding can assist clinical decision making to improve patient outcomes. In the event of critical shortages, our results suggest that severely ill children should be given priority to receive antiviral treatment. Future studies are needed to assess the effectiveness of antiviral medications upon specific populations of critically ill patients and less seriously ill hospitalized children.