We identified 4917 articles (fig 1), and two authors independently reviewed 35 full text articles to identify those that met inclusion criteria. One further unpublished trial was found from the GlaxoSmithKline registry.w1 Seven randomised controlled trials met our inclusion criteria; four of these were studies of treatment of influenzaw1-w4 and three of postexposure prophylaxis of influenza contacts in households.w5-w7 Six of the seven trials used clinical criteria for enrolment,w2-w7 with virological tests performed at a later date to produce a post hoc group of confirmed cases; one used near patient testing for influenza at enrolment.w1 One trial confirmed the presence of influenza with near patient testing only in those participants who had received influenza vaccination in the current season.w2
Fig 1 Flowchart of search results
Two of the treatment trials tested inhaled zanamivirw1 w2
and two tested oral oseltamivirw3 w4
in a total of 1766 children, of whom 1243 had confirmed influenza (table 1). Three trials recruited otherwise healthy children,w1-w3
while one specifically recruited children with asthma.w4
In the three treatment trials that reported influenza type, 55-69% of participants had influenza A.w2-w4
The treatment trials reported the primary outcome measure of time to resolution of influenza in two ways: median time to resolution of illness, which was a composite outcome comprising resolution or alleviation of symptoms and resolution of fever and return to school or normal activityw3 w4
; and/or median time to resolution or alleviation of symptoms of influenza (including cough, fever, muscle and joint aches, sore throat, headache, and fever).w1-w4
Two trialsw3 w4
used the Canadian acute respiratory infection and flu scale (CARIFS).14
Table 1 Characteristics of the trials of zanamivir and oseltamivir for treatment of influenza*
For postexposure prophylaxis, we identified two trials of zanamivirw5 w6 and one trial of oseltamivir,w7 which involved a total of 863 paediatric contacts (427 intervention, 436 control) (table 2). All three trials randomised households as units to receive the same treatment. The drug given to the index case varied in all trials. In the oseltamivir trial all index cases received the active drugw7; in one of the zanamivir trials the index cases were given the same treatment as the household (zanamivir or placebo)w5; and in the other zanamivir trial the index case did not receive any study drug.w6 The primary outcome measured in these trials was the attack rate of symptomatic influenza in children during the period of prophylaxis.
Table 2 Characteristics of trials of zanamivir and oseltamivir for postexposure prophylaxis of influenza*
Assessment of quality of trials
Only one treatment trial reported sufficient detail of the methods to be judged as high quality.w2 The three others did not report sufficient details to determine whether allocation concealment and blinding were adequate (table 3).w1 w3 w4 The three trials of postexposure prophylaxis were of moderate quality.w5-w7 Two had insufficient details about allocation concealmentw5 w6 and one was open labelled (not blinded).w7 The baseline comparison data for paediatric contacts (all trials) was not available, but no differences were apparent in the data for all ages.
Table 3 Assessment of methodological quality
Effect of treatment on time to resolution of symptoms, resolution of illness, and return to school or normal activity
Treatment with zanamivir and oseltamivir provided a median reduction in time to resolution of symptoms of between 0.5 and 1.5 days (table 4). In children with confirmed influenza, one trial with zanamivirw2 and one with oseltamivirw3 showed significant reductions in the median time to resolution of influenza symptoms from 5.25 to 4.0 days (difference 1.25 days, 95% confidence interval 0.5 to 2.0 days, P<0.001) and from 4.2 to 2.6 days (difference 1.5 days, 0.25 to 2.5 days, P<0.001), respectively. A further trial of oseltamivir reported a similar but non-significant reduction in median time to resolution of influenza symptoms from 4.8 to 3.8 days (difference 1.1 days, confidence interval not reported, P=0.12).w4 One trial of zanamivir reported a smaller reduction in median time to resolution of symptoms from 5.5 to 5.0 days but did not report either a confidence interval or P value.w1 Only one trial reported the median time to resolution of symptoms in children with clinical influenza and found a significant reduction from 5.0 to 4.5 days (difference 0.5 days, 0.0 to 1.5 days, P=0.01).w2
Table 4 Effects of treatment on resolution of influenza symptoms, resolution of illness, and return to school or normal activities
The two oseltamivir trials reported a reduction of between 0.4 and 1.5 days in the median time to resolution of illness, defined as resolution of all symptoms and resolution of fever and return to school or normal activities (table 4). In children with confirmed influenza, oseltamivir provided a significant reduction in median time to resolution of illness from 5.7 to 4.2 days (difference 1.5 days, 0.3 to 2.5 days, P<0.001) in onew3 trial and a non-significant reduction from 5.6 to 5.2 days (difference 0.4 days, confidence interval not reported, P=0.54) in the second trial.w4 In children with clinical influenza, one oseltamivir trial reported a reduction in time to resolution of illness from 5.3 to 4.4 days (difference 0.9 days, 0.2 to 1.9 days, P<0.001).w3
Three treatment trials reported the effects of treatment on return to school or normal activity (table 4).w1 w2 w4 One trial found that children given zanamivir returned to school or normal activity one day sooner in those with confirmed influenza (P=0.019), as well as in those with clinical influenza (P=0.022).w2 The other zanamivir trial reported that, by day five, 36% (62/172) of children given zanamivir and 28% (25/89) of controls had returned to school or normal activity (risk difference 0.08, −0.04 to 0.20, P=0.19).w1 The one oseltamivir trial that reported this outcome found a non-significant reduction in median time to return to school from 4.8 to 4.2 days (difference 0.6, confidence interval not reported, P=0.46) in children with confirmed influenza.w4
Two trials provided data on the natural course of confirmed influenza in children.w2 w3 Resolution of illness occurred in 75% of children within 8.7 days (90% within 14.2 days).w2 Alleviation of all symptoms occurred in 75% of children within 7.3 days (90% within 13 days).w1
Effect of treatment on reduction in cough or fever
Two of the threew1-w3 trials that reported effects of treatment on cough showed significant effects: oseltamivir reduced the median duration of cough by 1.3 days in children with confirmed influenza in one trial (P<0.001),w3 and zanamivir reduced the incidence of “moderate or severe cough” at day five in children with confirmed influenza in a second trial (P=0.001),w2 but no magnitude of effect was reported. Of the two trials that reported the median duration of fever,w1 w3 there was a significant reduction of one day in the one trial of oseltamivir (P<0.001)w3 and a reduction of 0.5 days (significance not reported) in one trial of zanamivir.w1
Effect of treatment on change in asthma severity
One trial of oseltamivir specifically recruited children with asthma.w4 Treatment did not reduce the number of asthma exacerbations in children with confirmed influenza (risk difference −0.05, −0.15 to 0.05, P=0.34) or improve median change in peak flow between study entry and day six (P=0.35) compared with controls. The trial did, however, identify a small improvement in the forced expiratory volume in one second (FEV1) between study entry and day six (median improvement 10.8% v 4.7%, P=0.01). One trial of 471 children with clinical influenza (of whom 36 (8%) had unspecified concurrent chronic respiratory conditions requiring regular medication) showed no significant difference in asthma exacerbations between zanamivir and control (−0.01, −0.03 to 0.01, P=0.30).w2 Combining the results with a random effects model showed no significant change in asthma exacerbations with neuraminidase inhibitor treatment (−0.02, −0.05 to 0.02, P=0.27, I2=16%).
Effect of treatment on antibiotic use
Two trials reported the effect of treatment on overall use of antibiotics. In one, treatment with oseltamivir was associated with a 10% reduction in overall antibiotic use in children with confirmed influenza (risk difference −0.10, −0.19 to −0.01, P=0.03).w3 In contrast, treatment with zanamivir did not reduce overall antibiotic use in children with confirmed influenza (−0.03, −0.10 to 0.04, P=0.37).w2 Combining these results with a random effects model showed a non-significant reduction in antibiotic use (fig 2) (−0.06, −0.13 to 0.01, P=0.08, I2=34%).
Fig 2 Incidence of antibiotic use in children with confirmed influenza
Effect of treatment on otitis media
Treatment had no effect on the incidence of otitis media (risk difference −0.01, −0.04 to 0.02; P=0.92, I2=0%) in two trials of children aged 5-12 (who had an overall incidence of otitis media of 6%).w1 w4 In a third trial,w3 as reported in a separate abstract,w8 in children with confirmed influenza treatment with oseltamivir had no effect on the development of otitis media (confirmed with tympanometry) at day 10 in children aged 6-12 (−0.02, −0.11 to 0.06, P=0.57) but did reduce the incidence of otitis media from 31% to 15% in children aged 1-5 (−0.16, −0.29 to −0.04, P=0.009).
Effect of postexposure prophylaxis
A 10 day course of prophylaxis with either zanamivirw5 w6 or oseltamivirw7 was associated with an 8% reduction (risk difference −0.08, −0.12 to −0.05, P<0.001, I2=0%) in the risk of developing confirmed symptomatic influenza after the introduction of an index case of clinical influenza into the household. This equates to a number needed to treat of 13 (9 to 20) to prevent one additional household case of symptomatic influenza (fig 3).
Fig 3 Incidence of confirmed symptomatic influenza in paediatric contacts of index cases with clinical influenza
Safety and tolerability of oseltamivir and zanamivir
The four treatment trials reported on tolerability and adverse events.w1-w4 Overall reported adherence was high; 97% of participants took more than eight of the 10 doses of zanamivir,w2 and 90% took all 10 doses of oseltamivir.w3 There was no significant difference in the number of withdrawals because of adverse events between either zanamivir or oseltamivir and placebo.
All four treatment studies reported on the incidence of nausea, vomiting, and diarrhoea. Combination of data from all four trials that reported vomiting showed significant heterogeneity (I2=75%). Subgroup analysis of the two trials of zanamivir showed no significant increase in vomiting (risk difference 0.00, −0.02 to 0.02, P=0.82, I2=0%),w1 w2 whereas the two trials of oseltamivir showed an additional one in 20 children treated would have vomiting (0.05, 0.02 to 0.09, P=0.007, I2=0%).w3 w4 Overall, vomiting occurred in 6.7% (57/852) of untreated children with clinical influenza.w1-w4 In addition, there was a low incidence of nausea (3.4%, 29/852) and diarrhoea (6.6%, 56/852). Neither was affected by treatment with neuraminidase inhibitors (−0.01, −0.03 to 0.00, P=0.06, I2=0%, and −0.01, −0.03 to 0.00, P=0.16, I2=0%, respectively).
The two trials of zanamivir for prophylaxis stated that the incidence of adverse events was similar between treatment and control groups but did not provide quantitative data on the paediatric subgroups.w5 w6 No deaths were reported.