Cochrane Review: Neuraminidase inhibitors for preventing and treating influenza in children (published trials only)
Authors: Wang Kay , Shun‐Shin Matthew , Gill Peter , Perera Rafael , Harnden Anthony 
Published: September 2012

Background

During epidemics, influenza attack rates in children may exceed 40%. Options for prevention and treatment currently include the neuraminidase inhibitors zanamivir and oseltamivir. Laninamivir octanoate, the prodrug of laninamivir, is currently being developed.

Objectives

To assess the efficacy, safety and tolerability of neuraminidase inhibitors in the treatment and prevention of influenza in children.

Search methods

For this update we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 1) which includes the Acute Respiratory Infections Group's Specialised Register, MEDLINE (1966 to January week 2, 2011) and EMBASE (January 2010 to January 2011).

Selection criteria

Double‐blind, randomised controlled trials (RCTs) comparing neuraminidase inhibitors with placebo or other antiviral drugs in children aged up to and including 12 years. We also included safety and tolerability data from other types of studies.

Data collection and analysis

Four review authors selected studies, assessed study quality and extracted data for the current and previous versions of this review. We analysed data separately for oseltamivir versus placebo, zanamivir versus placebo and laninamivir octanoate versus oseltamivir.

Main results

Six treatment trials involving 1906 children with clinical influenza and 450 children with influenza diagnosed on rapid near‐patient influenza testing were included. Of these 2356 children, 1255 had laboratory‐confirmed influenza. Three prophylaxis trials involving 863 children exposed to influenza were also included. In children with laboratory‐confirmed influenza oseltamivir reduced median duration of illness by 36 hours (26%, P < 0.001). One trial of oseltamivir in children with asthma who had laboratory‐confirmed influenza showed only a small reduction in illness duration (10.4 hours, 8%), which was not statistically significant (P = 0.542). Laninamivir octanoate 20 mg reduced symptom duration by 2.8 days (60%, P < 0.001) in children with oseltamivir‐resistant influenza A/H1N1. Zanamivir reduced median duration of illness by 1.3 days (24%, P < 0.001). Oseltamivir significantly reduced acute otitis media in children aged one to five years with laboratory‐confirmed influenza (risk difference (RD) ‐0.14, 95% confidence interval (CI) ‐0.24 to ‐0.04). Prophylaxis with either zanamivir or oseltamivir was associated with an 8% absolute reduction in developing influenza after the introduction of a case into a household (RD ‐0.08, 95% CI ‐0.12 to ‐0.05, P < 0.001). The adverse event profile of zanamivir was no worse than placebo but vomiting was more commonly associated with oseltamivir (number needed to harm = 17, 95% CI 10 to 34). The adverse event profiles of laninamivir octanoate and oseltamivir were similar.

Authors' conclusions

Oseltamivir and zanamivir appear to have modest benefit in reducing duration of illness in children with influenza. However, our analysis was limited by small sample sizes and an inability to pool data from different studies. In addition, the inclusion of data from published trials only may have resulted in significant publication bias. Based on published trial data, oseltamivir reduces the incidence of acute otitis media in children aged one to five years but is associated with a significantly increased risk of vomiting. One study demonstrated that laninamivir octanoate was more effective than oseltamivir in shortening duration of illness in children with oseltamivir‐resistant influenza A/H1N1. The benefit of oseltamivir and zanamivir in preventing the transmission of influenza in households is modest and based on weak evidence. However, the clinical efficacy of neuraminidase inhibitors in 'at risk' children is still uncertain. Larger high‐quality trials are needed with sufficient power to determine the efficacy of neuraminidase inhibitors in preventing serious complications of influenza (such as pneumonia or hospital admission), particularly in 'at risk' groups.

Plain Language Summary

Neuraminidase inhibitors for preventing and treating influenza in children

Influenza (true 'flu) is an infection of the airways caused by the Influenza group of viruses. Influenza occurs most commonly during winter months and can result in symptoms such as fever, cough, sore throat, headache, muscle aches and fatigue. These are usually self limiting but may persist for one to two weeks. The most common complications of influenza are secondary bacterial infections including otitis media (ear infections) and pneumonia. Influenza infection is also highly contagious and is spread from person‐to‐person by droplets produced when an infected individual coughs or sneezes.

This update reviews the randomised controlled trial evidence of a class of drugs called the neuraminidase inhibitors in treating and preventing influenza in children. Neuraminidase inhibitors work against influenza by preventing viruses from being released from infected cells and subsequently infecting further cells. Oseltamivir (Tamiflu), an oral medication, and zanamivir (Relenza), an inhaled medication, are currently licensed, whilst laninamivir is undergoing Phase III clinical trials. Neuraminidase inhibitors are usually prescribed to patients presenting with flu‐like symptoms during epidemic periods to reduce symptoms or prevent spread of the virus.

We included six treatment trials involving 1906 children with clinically suspected influenza and 450 children with influenza diagnosed on rapid influenza testing. Of these 2356 children, 1255 had proven influenza infection confirmed on laboratory testing. We also included three trials of neuraminidase inhibitors for the prevention of influenza, which involved 863 children who had been exposed to influenza.

This review found that treatment with neuraminidase inhibitors was only associated with modest clinical benefit in children with proven influenza. Treatment with oseltamivir or zanamivir shortened the duration of illness in healthy children by about one day. One trial demonstrated that the new neuraminidase inhibitor drug laninamivir reduces duration of illness by almost three days in children with oseltamivir‐resistant influenza. The effect of neuraminidase inhibitors in preventing transmission of influenza was also modest; 13 children would need to be treated to prevent one additional case. Neuraminidase inhibitors are generally well tolerated but there will be one extra case of vomiting for every 17 children treated with oseltamivir. Other side effects such as diarrhoea and nausea were no more common in children treated with neuraminidase inhibitors compared to placebo. There is currently no high‐quality evidence to support targeted treatment of 'at risk' children (with underlying chronic medical conditions) with neuraminidase inhibitors.