Modifying clinical practices to manage influenza in children effectively

Children less than 5 years of age are at increased risk of morbidity from influenza infection compared with older children and adults aged 18-54 years. Although much of the disease burden can be prevented by annual vaccination, the misperception that influenza does not result in serious illness in children, including schoolchildren, contributes to ongoing low vaccination rates. In conjunction with community surveillance of influenza activity, rapid diagnostic tests can help identify influenza patients who may benefit from initiation of antiviral therapy. Antiviral therapy is most effective when started within at least 48 hours of the onset of symptoms, the earlier the better. The neuraminidase inhibitors oseltamivir and zanamivir are safe and effective as first-line treatments and prophylaxis for influenza in children. These agents have been shown to decrease symptoms and shorten the duration of illness, as well as to curb the spread of influenza infection. The neuraminidase inhibitors also have shown efficacy against influenza B infection and exhibit less viral resistance than the older adamantane antiviral class.     

Antiviral therapy of influenza

The prevention of influenza virus infections by the use of vaccines remains the most cost-effective and practical method of influenza virus control, but the use of antiviral prophylaxis and treatment in certain populations or high-risk individuals is also possible. Four antiviral drugs are currently licensed in the United States for the treatment and/or prevention of influenza virus infection in children. The M2 blockers, (amantadine and rimantadine) have been licensed for the prophylaxis and treatment of influenza in diverse high-risk populations, including children, for years. Advantages of these agents include the low cost, high oral bioavailability, and relative tolerability of one of these agents (rimantadine) in children. Disadvantages include efficacy against influenza A viruses only (not type B), the relative rapid development of resistance, and adverse effects associated with amantadine in particular (especially in the elderly and those with decreased renal function). Two agents in a new antiviral class, the neuraminidase inhibitors, have been licensed recently for the treatment and prophylaxis of influenza in the United States. Oseltamivir is licensed for the treatment of influenza in children older than 1 year and for the prophylaxis in children older than 13 years. This drug is safe and well-tolerated, and is available in capsules or a liquid suspension. Another neuraminidase inhibitor, zanamivir, is administered as an inhaled powder via a special inhaler device and is licensed for the treatment of influenza in children older than 7 years. Both neuraminidase inhibitors appear to be similarly effective and are not associated with the development of antiviral resistance. No direct comparisons of any of these antiviral agents has been performed; all result in clinical improvement approximately 1 to 2 days earlier in otherwise healthy children when therapy is initiated within 48 hours of onset of symptoms.     

Antiviral therapy: respiratory infections, chronic hepatitis

This review focuses on the activity, clinical pharmacology, and clinical indications of antiviral agents used in the management of influenza, respiratory syncytial virus infections, and chronic hepatitis B and C. Two neuraminidase inhibitors, a new class of antiviral agents, were recently approved for the treatment of influenza A and B in children.     

Seasonal and pandemic influenza: an overview with pediatric focus

Influenza is an important cause of respiratory illness in children, who have the highest attack rates during the annual influenza outbreaks [60]. Clinical infection ranges from subclinical illness to complicated disease that affects multiple organs. Annual vaccination remains the most effective strategy for the prevention and control of influenza [2]. Recently developed antiviral drugs offer new approaches to the prevention and treatment of influenza.     

Antiviral therapy and prophylaxis for influenza in children

Antiviral agents are available that are safe and effective for the treatment and prophylaxis of influenza virus infections in children. The neuraminidase inhibitors (oseltamivir [Tamiflu] and zanamivir [Relenza]) are preferred agents because of current widespread resistance to the adamantanes (amantadine [Symmetrel] and rimantadine [Flumadine]). Therapy should be provided to children with influenza infection who are at high risk of severe infection and to children with moderate-to-severe influenza infection who may benefit from a decrease in the duration of symptoms. Prophylaxis should be provided (1) to high-risk children who have not yet received immunization and during the 2 weeks after immunization, (2) to unimmunized family members and health care professionals with close contact with high-risk unimmunized children or infants who are younger than 6 months, and (3) for control of influenza outbreaks in unimmunized staff and children in an institutional setting. Testing of current H5N1 avian influenza virus isolates, the potential agents of pandemic influenza, suggests susceptibility to oseltamivir and zanamivir. Because no prospective data exist on the efficacy of these agents in humans for H5N1 strains, the dosage and duration of therapy in adults and children may differ from those documented to be effective for epidemic influenza strains.     

Natural history of pandemic H1N1 2009 influenza infection in healthy pediatric outpatients

ObjectiveThe pandemic influenza H1N1 2009 (pH1N1) virus is expected to remain a prominent circulating strain in the current and subsequent influenza seasons. The objective of this study was to compare the clinical course of infection with laboratory-confirmed pH1N1 and seasonal influenza A and B in a cohort of previously healthy children managed in the outpatient setting without antiviral therapy.MethodsPreviously healthy children 17 years of age or younger were prospectively enrolled during the first wave of the 2009 pandemic (May–July 2009) and the 2 preceding influenza seasons from a single primary care physician office and a tertiary children’s hospital emergency department. Inclusion criteria were: age ≤17 years; laboratory-confirmed influenza; and not receiving antiviral agents. Follow-up telephone interviews were conducted approximately 2 days and 14 days after presentation to assess symptom duration.ResultsA total of 251 patients (101 with pH1N1, 90 with seasonal influenza A, 60 with seasonal influenza B) were included. Presenting symptoms and duration of symptoms associated with pH1N1 were similar to those with seasonal influenza. Median fever duration in pH1N1 was 3 days and had resolved within 8 days in 95% of patients. Among patients with pH1N1, abnormalities on chest auscultation (10 of 101), the hospitalization rate (2 of 101), the proportion of children receiving intravenous fluid therapy (1 of 101) or supplemental oxygen (1 of 101) were not significantly different from patients with seasonal influenza.ConclusionsIn most children without underlying risk factors for severe influenza, pH1N1 virus causes an uncomplicated respiratory tract illness, no more severe than seasonal influenza.     

Severe respiratory syncytial virus infection in older children

Serious respiratory syncytial virus (RSV) disease requiring hospitalization occurs primarily in infants younger than 12 months. The incidence, risk factors, and clinical features in older children have not been studied extensively. Of 282 children hospitalized at our institution with severe RSV disease during a 3-year period, 62 (22%) were older than 12 months. These 62 older children were matched for sex, onset of illness, and hospital location with 62 hospitalized children younger than 12 months with proved RSV infection. Older children had underlying chronic disease more commonly than younger children (47 of 62 vs 24 of 62). Chronic illnesses in older children included bronchopulmonary dysplasia and/or reactive airway disease (34 of 47), congenital heart disease (9 of 47), gastrointestinal disease (7 of 47), and genetic disorders (7 of 47). Three of the four deaths from RSV infection occurred in older children; all four had underlying disease (three with congenital heart disease and one with biliary atresia). We conclude that children older than 12 months with underlying disease are at increased risk for serious or fatal RSV infection and are not always protected by previous RSV disease. Such older children should be considered candidates for passive or active immunoprophylaxis against RSV infection as such agents become available.     

The burden of seasonal and pandemic influenza in infants and children

The burden of influenza is unevenly distributed, with more severe outcomes in children aged <5 years than older children and adults. In spite of this, immunisation policies for young children are far from universal. This article provides an overview of the published evidence on the burden of influenza in children worldwide, with a particular interest in the impact of pandemic influenza in 2009–2010 (caused by the H1N1pdm09 virus). In an average season, up to 9.8 % of 0- to 14-year olds present with influenza, but incidence rates can be markedly higher in younger children. Children aged <5 years have greater rates of hospitalisation and complications than their older counterparts, particularly if the children have co-existing illnesses; historically, this age group have had higher mortality rates from the disease than other children, although during the 2009–2010 pandemic the median age of those who died of influenza was higher than in previous seasons. Admissions to hospital and emergency departments appear to have been more frequent in children with H1N1pdm09 infections than during previous seasonal epidemics, with pneumonia continuing to be a common complication in this setting. Outcomes in children hospitalised with severe disease also seem to have been worse for those infected with H1N1pdm09 viruses compared with seasonal viruses. Studies in children confirm that vaccination reduces the incidence of seasonal influenza and the associated burden, underlining the importance of targeting this group in national immunisation policies. Conclusions: Children aged <5 years are especially vulnerable to influenza, particularly that caused by seasonal viruses, and vaccination in this group can be an effective strategy for reducing disease burden.     

The use of antiviral drugs for influenza: Guidance for practitioners, 2012/2013; Paediatric summary

This practice point summarizes the use of antiviral drugs to manage influenza illness in children and youth for the 2012/2013 season. It excerpts a recently published, full-length update of Canadian recommendations for clinicians on the use of antiviral drugs for the prevention and treatment of influenza, with a focus on paediatric antiviral therapy. Detailed information on the selective use of chemoprophylaxis can be found in the source document, which also highlights the importance of secondary bacterial infections (Streptococcus pneumoniae, methicillin-sensitive Staphylococcus aureus and methicillin-resistant S aureus) in cases of severe influenza illness.     

Influenza B infections in children: A review

Influenza B (IFB) virus belongs to the Orthomyxoviridae family and has two antigenically and genetically distinct lineages; B/Victoria/2/87-like (Victoria lineage) and B/Yamagata/16/88-like (Yamagata lineage). The illness caused by IFB differs from that caused by influenza A. Outbreaks of IFB occur worldwide and young children exposed to IFB are likely to have a higher disease severity compared with adults. IFB mostly causes mild to moderate respiratory illness in healthy children. However, the involvement of other systems, a severe disease especially in children with chronic medical conditions and immunosuppression, and rarely mortality, has been reported. Treatment with oseltamivir or zanamivir decreases the severity of illness and hospitalization. Due to the enormous health and economic impact of IFB, these strains are included in vaccines. IFB illness is less studied in children although its impact is substantial. In this review, the epidemiology, clinical manifestations, treatment, prognosis, and prevention of IFB illness in children are discussed.     

Comparison of clinical characteristics of influenza and respiratory syncytial virus infection in hospitalised children and adolescents

While significant morbidity due to respiratory syncytial virus (RSV) infection in the paediatric population has been well acknowledged, little is known about the burden of influenza in primarily healthy children in Europe. In our institution, a University Childrens Hospital in Switzerland, medical staff were encouraged to take nasopharyngeal specimens for multiplex polymerase chain reaction assays for influenza A and B, RSV and several other pathogens from patients hospitalised with respiratory symptoms. We took advantage of this strategy and performed a retrospective study to compare specific characteristics of influenza virus infections with those of RSV during two consecutive winter seasons. Overall, 126 patients were positive for RSV and 60 patients were positive for influenza (type A: 45; type B: 15). The median age of children with RSV, influenza A, and influenza B infection was 4 months; 2 years and 4 months; and 6 years and 2 months, respectively (P<0.001). Fever and cough predominated in children with influenza infection whereas cough, rhinorrhoea, feeding difficulties and dyspnoea were the major symptoms in children with RSV infection. Of patients with influenza, 41% suffered from lower respiratory tract infection compared to 91% of those with RSV infection (P<0.001). Of 60 patients hospitalised with influenza, 12 (20%) experienced febrile convulsions. None of the patients with influenza had been immunised in the respective winter season, although 27% of them had at least one underlying medical condition that would have counted as an indication for immunisation in Switzerland. Conclusion: influenza virus infections, like respiratory syncytial virus infections, are a major cause of hospitalisation in children with respiratory illness during the winter season. Since it is impossible to make an aetiological diagnosis on clinical grounds, it is important to apply specific diagnostic tools in children hospitalised with respiratory illness in order to better characterise the relative burden of disease caused by the respective agents.Abbreviations LRTI lower respiratory tract infection - NPS nasopharyngeal specimens - RAT rapid antigen test - RSV respiratory syncytial virusThis work forms the medical thesis of Susanne Meury at the Medical Faculty, University of Basel, Switzerland.     

Vaccines and therapeutics against influenza virus infections

BACKGROUND: Vaccination prior to epidemic season is the best measure to control influenza virus infection; however, there are several issues to be considered regarding influenza vaccines in Japan. In the present review, current issues regarding influenza vaccine in Japan are described, as well as the future prospects of vaccine development. As well as vaccination, anti-influenza agents such as amantadine are now available in Japan. Furthermore, neuraminidase inhibitors are expected to appear in the market in near future. These anti-influenza agents represent new options for influenza control. CONCLUSIONS: Vaccination and antiviral agents are a major armamentarium against influenza infections. Thus, exploratory studies on novel forms of vaccine and anti-influenza drugs should help to prepare against pandemics that must emerge in near future.     

Clinical features of children infected with different strains of influenza B in southern Taiwan

BACKGROUND: This study was designed to determine the clinical characteristics of children infected with different strains of influenza B viruses isolated in southern Taiwan. The clinical features were compared with influenza A infection occurring in the same period. METHODS: All children enrolled in the study had laboratory-confirmed infection with influenza A or B viruses. Influenza B speciation was performed by RNA extraction, cDNA synthesis, and amplification by polymerase chain reaction and sequencing. Demographic data, clinical findings, diagnoses, and outcomes were obtained. RESULTS: During the study period, 163 strains of influenza A and 118 strains of influenza B were isolated. The Yamagata-like strains were most prevalent in 2001. New reassortant strains were identified since 2002 and became predominant in 2005 and 2006. Children with influenza B were more likely than those with influenza A to be diagnosed as upper respiratory tract infection, myositis, and gastroenteritis (P < 0.05). Children infected with Yamagata-like strains were more likely to develop lower respiratory tract infection (P < 0.05) and accounted for all cases of invasive disease. Children infected with the Victoria-like group had the longest hospital stays associated with severe bacterial superinfection. CONCLUSIONS: Currently new reassortant influenza B viruses are the predominant strains circulating in southern Taiwan. There is considerable similarity of clinical features between influenza A and B in children. The Yamagata-like strains were associated with more invasive infections. Continuous influenza virus surveillance is essential particularly in Taiwan where pandemic strains tend to appear earlier than in other countries.     

Influenza in Children

In children, influenza is one among the commonest causes of acute respiratory illness and loss of school days. Influenza A, B, and C are 3 types of viruses responsible for illness. Type A virus has many subtypes based on antigens but Type B and Type C viruses have no known subtypes. Currently, influenza A/H1N1, A/H3N2, and influenza type B viruses are circulating in humans. Transmission of influenza occurs through droplets from infected person or through direct contact with person or fomites. Clinically, influenza is characterized by acute onset fever, chills, running nose, cough, sore throat, headache and myalgia. Mostly, febrile illness lasts for 3–4 d with resolution of disease in 7–10 d. Confirmation of influenza can be done either by virus culture, RT-PCR or specific neutralizing antibodies in blood. Basic principles of management include prompt institution of infection control measures, early identification of children at higher risk, supportive care and antiviral drugs. Vaccine and chemoprophylaxis are two commonly used methods for prevention of influenza. Currently, inactivated influenza vaccine (IIV) and live attenuated influenza vaccine (LAIV) are available for use with good efficacy. Cough etiquette, use of face masks and hand hygiene are the most important measures to reduce the risk of infection transmission from person to person.     

Impact of influenza on morbidity in children with cystic fibrosis

Recommendations concerning annual influenza vaccination in children suffering from cystic fibrosis (CF) are not uniform. Previous studies have shown that influenza causes a small proportion of episodes of acute respiratory deterioration in CF patients. During the 1989 Australian winter, we studied the association between serologically proven influenza infection and acute respiratory morbidity in 20 children with CF. Six children were shown to have influenza infection, four with type A and two with type B. Four of five children requiring hospital admission were shown to have influenza, but only 2 of 15 did not need admission (P less than or equal to 0.025). As well, influenza was diagnosed in 6 of 12 children who suffered acute respiratory illness leading to school absenteeism (including hospitalization), but diagnosed in no children without this degree of illness (P less than or equal to 0.025). Influenza significantly increases the incidence of hospitalization and of less serious respiratory illness in children with CF, a finding which suggests that influenza vaccine efficacy studies are necessary in this group.     

The burden of influenza in children under 5 years admitted to the Children's Hospital at Westmead in the winter of 2006

Objective: Active surveillance to determine influenza disease burden in children admitted to hospital with influenza‐like illness (ILI). Methods: A prospective hospital‐based cohort study conducted June–October 2006 in children <5 years hospitalised at The Children's Hospital at Westmead with ILI (fever and respiratory symptoms). Influenza and other viral infections were diagnosed either by antigen detection using immunofluorescence or nucleic acid amplification testing of nasopharyngeal aspirates. Data were collected using researcher‐administered questionnaires. Main outcome measures include proportion of hospitalisations with influenza, vaccination and treatment, risk factors for influenza and associated medical and social burdens. Results: Data on 275 children with ILI aged <5 years were analysed. Thirty‐one (11%) children with ILI had influenza (22 had influenza A and 9 had influenza B). Thirty‐five percent were under 6 months of age and 61% under 1 year. Twenty‐nine percent of children with influenza A were born prematurely. The mean duration of hospital stay for influenza was 2.8 days (95% confidence interval 2.1–3.4) and 26% had a lumbar puncture. Although 68% received intravenous antibiotics, only 3% (one case) was given an antiviral. Eighty‐four percent had visited their local doctor before admission and all came through the emergency department. On average, in one‐third (32%) of families of children with influenza a parent developed, ILI during admission or soon after hospital discharge resulted in an average of 3.2 days of work absenteeism. Only 3.5% (7/199) of children older than 6 months with ILI received any influenza vaccination. Conclusions: Both the burden of influenza in childhood morbidity and its social impact are substantial. There is considerable room for improvement in both the prevention and early recognition (trigger treatment with antivirals) of influenza. Our data will inform decisions regarding the value of a universal influenza vaccine programme.     

Uncomplicated pneumonia in healthy Canadian children and youth: Practice points for management

Although immunization has decreased the incidence of bacterial pneumonia in vaccinated children, pneumonia remains common in healthy children. Symptoms of bacterial pneumonia frequently overlap those present with viral infections or reactive airway disease. Optimally, the diagnosis of bacterial pneumonia should be supported by a chest radiograph before starting antimicrobials. Factors such as age, vital signs and other measures of illness severity are critical when deciding whether to admit a patient to hospital. Because Streptococcus pneumoniae continues to be the most common cause of bacterial pneumonia in children, prescribing amoxicillin or ampicillin for seven to 10 days remains the mainstay of empirical therapy for nonsevere pneumonia. If improvement does not occur, consideration should be given to searching for complications (empyema or lung abscess). Routine chest radiographs at the end of therapy are not recommended unless clinically indicated.     

An update on the prevention of influenza in children and adolescents

Influenza virus types A and B cause yearly outbreaks of respiratory tract infections in all age groups including children and adolescents. Complications, such as high fever, febrile convulsions, secondary bacterial infections and myositis frequently lead to hospitalisation. Safe and effective split, subunit and virosome vaccines are available from 6 months of age onwards. Most European countries do have guidelines for the use of influenza vaccines and current strategies primarily aim at decreasing the burden of influenza disease in certain, heterogeneously defined high risk groups. Conclusion:unfortunately, compliance of many physicians and patients with immunisation recommendations is rather poor and several barriers to immunisation have been identified. These deserve our specific attention in the future. Recently, neuraminidase inhibitors with curative and preventive efficacy against influenza virus types A and B have become available. They serve as second line weapons for influenza prophylaxis under specific circumstances.Abbreviations CAIV-T cold-adapted trivalent influenza vaccine - HA haemagglutinin - NA neuraminidase - NI neuraminidase inhibitor - RSV respiratory syncytial virus The author has temporarily served on the Data Monitoring Safety Board for an intranasal influenza vaccine (Nasalflu) of Berna Biotech Ltd, Bern, Switzerland and has actively participated as an investigator in pre-licensure studies of influenza vaccines produced by Berna Biotech and Wyeth.     

Technical report: Reduction of the influenza burden in children

Epidemiologic studies have shown that children of all ages with certain chronic conditions, such as asthma, and otherwise healthy children younger than 24 months (6 through 23 months) are hospitalized for influenza and its complications at high rates similar to those experienced by the elderly. Annual influenza immunization is already recommended for all children 6 months and older with high-risk conditions. By contrast, influenza immunization has not been recommended for healthy young children. To protect children against the complications of influenza, increased efforts are needed to identify and recall high-risk children. In addition, immunization of children between 6 through 23 months of age and their close contacts is now encouraged to the extent feasible. Children younger than 6 months may be protected by immunization of their household contacts and out-of-home caregivers. The ultimate goal is universal immunization of children 6 to 24 months of age. Issues that need to be addressed before institution of routine immunization of healthy young children include education of physicians and parents about the morbidity caused by influenza, adequate vaccine supply, and appropriate reimbursement of practitioners for influenza immunization. This report contains a summary of the influenza virus, protective immunity, disease burden in children, diagnosis, vaccines, and antiviral agents.