During influenza season, which children need an antiviral and which one should I prescribe? Do I need to verify that they have influenza first?

The pandemic of H1N1 influenza A virus (pH1N1) brought new attention to the use of antiviral drugs for influenza treatment. The ion-channel blocker amantidine is limited by frequent resistance (including for pH1N1) and, thus, has been largely replaced by neuraminidase inhibitors (NIs) for the treatment of influenza in children and adults (1). Both currently licensed NIs are active against influenza A and B. Oseltamivir is available as a suspension or capsule and is indicated for children older than one year of age, while zanamivir is delivered by dry powder inhalation and is indicated for children older than seven years of age. Time to resolution of symptoms is the primary outcome for most influenza treatment trials. A recent systematic review and meta-analysis published in the British Medical Journal updated a 2007 Cochrane review (2) and identified two randomized controlled trials each for osteltamivir (3,4) and zanamivir (5,6) for the treatment of children younger than 12 years of age in a community with clinically suspected or confirmed influenza infection (7). In the four trials, a total of 1766 out-patients with clinically suspected influenza (1243 laboratory confirmed) were treated within 48 h of symptom onset (Table 1). Overall, the study quality was ‘moderate’. Because of trial heterogeneity and poor data reporting, the data could not be pooled into a meta-analysis. The review concluded that treatment with oseltamivir or zanamivir resulted in median reductions in the time to resolution of symptoms of between 0.5 and 1.5 days (2), although in only two of the trials (3,6) was this reduction statistically significant. Randomized controlled trials of neuraminidase inhibitors for the treatment of influenza in children Reference 2. NR Not reported; NS Not significant Randomized controlled trials of neuraminidase inhibitors for the treatment of influenza in children Reference 2. NR Not reported; NS Not significant Two trials found a significant reduction (1.3 days) in the duration of cough and the duration of fever (0.5 to one day) (3,5). Only one (3) of three trials (3,4,6) that recorded the incidence of acute otitis media showed a significant reduction (16%) with oseltamivir, and only for the subset of children one to five years of age. After five days of oseltamivir treatment in asthmatic children with influenza, the forced expiratory volume in 1 s significantly improved compared with placebo (10.4% versus 4.7%); however, peak expiratory flows did not (4). Treatment with oseltamivir also significantly reduced viral titres from nose and throat swabs compared with placebo (3). The primary side effect of oseltamivir reported in two randomized controlled trials (3,4) was vomiting. Concerns regarding cases of adverse neuropsychiatric reactions were dispelled in three retrospective cohort studies (8–10). Early animal studies (11,12) showed central nervous system toxicity in young rats when given extremely high doses of oseltamivir; thus, the drug was contraindicated in children younger than one year of age. However, because toxicity occurred only with massive doses in very young rats and there were no alternative agents for use in small children, the drug has been used. Two retrospective studies (13,14) in infants younger than one year of age did not find an association between the use of oseltamivir and neurological events. Zanamivir has few side effects. Postmarketing surveillance in adults showed that bronchospasm may occur in patients with underlying respiratory disease who have been treated with zanamivir (15). When zanamivir was compared with a placebo diskhaler, there was no difference in adverse events in either paediatric trial (5,6); subgroup analysis on asthmatic children was not performed. In the year preceding the pandemic, only 8% of children admitted to Canadian paediatric hospitals with influenza received an antiviral (16). This changed dramatically in 2009/2010, during which many children with influenza-like illnesses (ILI) were prescribed oseltamivir in both inpatient and outpatient settings as a result of the pandemic, published treatment guidelines and increased availability of antiviral drugs (17,18). There is little evidence to support the widespread treatment of paediatric influenza with NIs, and recent guidelines have largely been based on expert opinion. There have been only four outpatient studies (3–6), of which only two showed a decrease in duration of symptoms. The only ‘high-risk’ population studied was asthmatics, with an underpowered study showing minimal benefit (4). While there is no evidence supporting the benefit of treating children more than 48 h after symptom onset, children at risk for severe complications or hospitalized children, there are some data to support the possible effectiveness of oseltamivir in hospitalized adults with severe influenza for which complications, mortality and length of stay were significantly reduced if oseltamivir was given within 48 h of illness onset (19). If the drug is given more than 48 h after illness onset, there may be some benefit with respect to reducing viral load (20). Two Canadian groups have provided recommendations for paediatric influenza treatment. The Public Health Agency of Canada suggests antiviral treatment for certain children with proven influenza or ILI (sudden onset of cough and fever, sore throat, coryza, fatigue/malaise/prostration, myalgias/arthralgias, headache, decreased appetite, or gastrointestinal symptoms such as nausea, vomiting and diarrhea). Those include children hospitalized because of influenza, moderately ill outpatients younger than two years of age, outpatients two to five years of age with underlying conditions (asthma and other chronic respiratory diseases, diabetes and other metabolic disorders, cardiac disease, chronic hepatic or renal disease, immunocompromised, immunosuppressed, blood disorders [including anemia and sickle cell anemia], neurological and neurodevelopmental disorders [that affect swallowing and breathing] and morbid obesity [body mass index greater than 35 kg/m2 (21)]). The Canadian Paediatric Society suggests treatment only for children hospitalized due to influenza and for moderately ill outpatients with underlying conditions (pregnancy, chronic heart, lung, renal disease, metabolic disease or diabetes, immunosuppression, anemia or hemoglobinopathy, chronic acetylsalicylic acid use and residing in a chronic care facility [22]). Current epidemiological data have shown that pH1N1 infections have a similar degree of severity to seasonal influenza strains (23,24). It is likely that pH1N1 will cocirculate with other seasonal strains this fall. Therefore, we suggest antiviral treatment for the following groups of children with proven influenza or ILI: children hospitalized because of influenza; moderately ill outpatients who are younger than two years of age and outpatients with underlying conditions (pregnancy, chronic heart disease, chronic lung disease [including those on daily therapy for asthma], chronic renal disease, metabolic disease or diabetes, immunosuppression, anemia or hemoglobinopathy, chronic acetylsalicylic acid use, residing in a chronic care facility and morbid obesity [body mass index greater than 35 kg/m2]). Treatment should also be considered for children with ILI or those with confirmed influenza residing in remote areas, or children of First Nations, Inuit or Métis backgrounds. Most treatment decisions must be made when the child presents with ILI and before laboratory confirmation. It is not practical to wait for the results of viral culture or viral nucleic acid testing because treatment of influenza should be initiated within the first 48 h of illness for maximal benefit. Rapid influenza diagnostic tests (also known as point of care tests) are limited by low sensitivities (62% to 83%), especially for pH1N1, and for their inability to differentiate between subtypes of influenza, which may have different antiviral susceptibilities (25). When the predominant circulating respiratory virus is influenza, as was the case in the 2009 pandemic, the clinical sensitivity and specificity for diagnosing influenza substantially increases. However, in a more typical influenza season, when other viruses are cocirculating, it can be difficult to differentiate which virus is the causative agent based on symptoms alone, especially in young children who harbour many febrile respiratory viral illnesses (26). If a decision is made to treat a child, knowledge of local resistance patterns is important. For example, seasonal pH1N1 strains that were initially susceptible to oseltamivir showed 100% resistance over one influenza season (27,28). As of January 2010, only a small percentage of pH1N1 isolates were resistant to oseltamivir, but all remained susceptible to zanamivir (29,30). Regarding other factors in choosing an NI, cost is comparable for both at approximately $50 for an adult treatment course. Zanamivir dry powder inhaler is approved for treating children seven years and older; however, administration may be difficult for a sick child of any age (21). Oseltamivir is available as 75 mg capsules and small capsules (30 mg and 45 mg), and as a commercial powder for suspension (12 mg/mL) (31). There is potential for medication dosing errors with the suspension when the enclosed syringe is used (32). Intravenous NIs (zanamivir and peramivir) are obtained through special access in Canada, and may be used when resistance to oseltamivir is suspected or nonparenteral administration is not practical (33). The evidence shows that NIs may cause a modest reduction in the duration of symptoms and the incidence of acute otitis media, especially if initiated early. Given this minimal benefit, it seems logical to limit therapy to children with underlying risk factors for severe infection and complications. If a decision is made to treat with NIs, treatment should be initiated before confirmation of the diagnosis. Antiviral susceptibilities of influenza strains can change quickly; thus, the Public Health Agency of Canada website should be consulted to determine the drug of choice in a given influenza season. More studies are needed to confirm the efficacy, pharmacokinetics and side effect profile of NIs in children younger than one year of age, those in intensive care and those with underlying health conditions. Studies examining the reduction in influenza-related complications for previously well children treated with NIs are also required.

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