By Richard R. Watkins, MD, MS, FACP, FIDSA, FISAC

Professor of Internal Medicine, Northeast Ohio Medical University; Division of Infectious Diseases, Cleveland Clinic Akron General, Akron, OH

Dr. Watkins reports no financial relationships relevant to this field of study.

SYNOPSIS: A meta-analysis that included more than 18,000 patients from 70 clinical centers in 36 countries found that neuraminidase inhibitors started at the beginning of hospitalization in patients with clinically suspected or laboratory-confirmed influenza A reduced the length of hospitalization by 19%.

SOURCE: Venkatesan S, Myles PR, Bolton KJ, et al. Neuraminidase inhibitors and hospital length of stay: A meta-analysis of individual participant data to determine treatment effectiveness among patients hospitalized with nonfatal 2009 pandemic influenza A(H1N1) virus infection. J Infect Dis 2020;22:356-366.

There is ample evidence that neuraminidase inhibitors (NAIs) reduce illness duration, complications, and mortality in patients with influenza. Venkatesan and colleagues sought to determine whether early administration of NAIs (i.e., at the beginning of hospitalization) would reduce hospital length of stay (LOS) in patients with clinically suspected or laboratory-confirmed influenza A. Reducing LOS is an important goal for lowering healthcare costs and managing hospital bed surges.

The study was a meta-analysis conducted with data from patients hospitalized during the 2009-2010 influenza pandemic. The specific pandemic virus was influenza A (H1N1), hereafter referred to as influenza A. The primary outcome was the LOS in whole days. Patients were excluded if they received NAI therapy before admission, continued NAI therapy after discharge, had an LOS less than one day, had nosocomial influenza, or died. The study center was used as a random intercept in the mixed-effects negative binomial regression model to account for clustering. A comparator group was designated as patients with influenza who did not receive NAI therapy. Adjusted incidence rate ratios (aIRRs) were used to determine the difference in LOS in days between a treated patient and an untreated patient with similar characteristics.

There were 18,309 patients with influenza A included in the analysis who were admitted to one of the 70 study centers from 36 countries between Jan. 2, 2009 and March 14, 2011. Of these, 81.1% were laboratory confirmed and 18.9% were clinically diagnosed. Most patients (57.3%) were hospitalized for more than 48 hours from the onset of influenza symptoms. For those who received NAIs on admission, researchers observed a 19% overall reduction in LOS (aIRR, 0.81; 95% confidence interval [CI], 0.78-0.85; median decrease, 1.19 days) compared to no therapy or if therapy was started later. The association remained significant across all subgroups. Paradoxically, early NAI therapy was associated with a 28% increase in LOS in patients with chest radiograph-confirmed influenza pneumonia (aIRR, 1.28; 95% CI, 1.11-1.48). There was no difference in LOS when patients had received the influenza vaccine previously (P = 0.68) or in-hospital antibiotic therapy (P = 0.20). There was a slight increase in LOS when corticosteroids were prescribed with NAIs (aIRR, 1.17 days; 95% CI, 1.00-1.36). Early NAI therapy decreased LOS by 39% in pregnant women (aIRR, 0.61; 95% CI, 0.52-0.70) and by 27% in obese patients (aIRR, 0.73; 95% CI, 0.65-0.83).

COMMENTARY

The primary finding of the study, that initiation of NAI therapy at admission reduced LOS by 19%, supports the so-called “treat-at-the-door” strategy for managing patients suspected or confirmed to have seasonal influenza. The study also highlights prior evidence that NAI therapy still is beneficial when given > 48 hours after symptoms start, albeit with some reduction in effectiveness.1 Notably, 57.3% of patients included in the study were hospitalized > 48 hours after symptom onset. It often is difficult for clinicians to ascertain when patients became symptomatic, so treating all hospitalized patients with suspected or confirmed influenza with NAIs is a pragmatic approach. Indeed, the latest Infectious Diseases Society of America guidelines on the management of influenza recommend that “persons of any age who are hospitalized with influenza, regardless of illness duration prior to hospitalization, be started on antiviral treatment as soon as possible.”2 Nausea and vomiting are not uncommon with NAIs, especially in children, although these symptoms are manageable and usually do not require discontinuation of therapy.

The researchers did not observe a reduction in LOS in children in the present study. The authors rationalized this finding by noting the study might have been underpowered in children, as well as the fact that LOS typically is shorter in children compared to adults. Furthermore, influenza often is a milder illness in children, and serious outcomes (e.g., intensive care unit admission or death) are less common than in adults.

This was a large study, especially compared to previous ones that examined outcomes in hospitalized patients with influenza. Nonetheless, there are some limitations to consider. First, by excluding patients who died, the investigators could not determine the impact of NAI therapy on the relationship between LOS and in-hospital mortality. Indeed, by removing nonsurviving patients, the investigators altered the aggregate presenting patient characteristics. Second, the attempt to ascertain early benefit vs. late benefit of NAIs was subject to time-dependent bias. Third, other influenza pandemics have been associated with longer LOS than the median LOS of five days observed in the present study. Finally, the prevalence of pregnancy (23%) was comparably high.

The findings from the study by Venkatesan and colleagues support current guideline recommendations and, if followed widely, may lead to reduced LOS for patients hospitalized with influenza. This would result in a significant decrease in healthcare expenses and better management of bed surge that commonly occurs during influenza season.

REFERENCES

  1. Muthuri SG, Venkatesan S, Myles PR, et al. Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: A meta-analysis of individual participant data. Lancet Respir Med 2014;2:395-404.
  2. Uyeki TM, Bernstein HH, Bradley JS, et al. Clinical Practice Guidelines by the Infectious Diseases Society of America: 2018 Update on diagnosis, treatment, chemoprophylaxis, and institutional outbreak management of seasonal influenza A. Clin Infect Dis 2019;68:895-902.