Influenza
(influenza vaccination)

Clinical

• Influenza A or B
• Classically: abrupt onset of fever, headache, myalgia, and malaise; respiratory tract illness, such as cough, sore throat, and rhinitis.
• PE: Fever (≥38.9ºC is most frequent), incr RR, conjunctival erythema, nasal injection, edema, and discharge, cervical lympadenopathy.
• Oropharyngeal abnormalities, other than slight to moderate hyperemia are uncommon, even with complaints of sore throat.
• Young children also have less experience with influenza viruses and therefore less immunity. They tend to have higher fevers, febrile seizures, and more gastrointestinal complaints (eg, nausea, vomiting, poor appetite) initially. Respiratory symptoms may be less prominent at the onset of illness than in older children and adults
• usually improve gradually over two to five days
• may last for more than a week, particularly in young children.
• continued presence of cough for longer periods is common.
• Persistence of symptoms of weakness and easy fatiguability, referred to as postinfluenza asthenia, may last for several weeks in older children.
• Outbreaks caused by influenza B viruses are generally less extensive and are associated with less severe disease than those caused by influenza A viruses, although differentiation between influenza A and B infections in individual cases is not possible on clinical grounds alone

Complications

• #1 otitis media complicates the course of influenza in 10 to 50 percent of children
• lower respiratory tract involvement
• interstitial pneumonia, laryngotracheitis (croup), bronchitis, and occasionally bronchiolitis
• exacerbations of chronic underlying conditions, especially asthma
• laryngotracheobronchitis and laryngotracheitis are more frequently associated with influenza than with RSV and may be particularly severe (although parainfluenza viruses are the most common cause of laryngotracheobronchitis,)
• croup associated with influenza infection is complicated by bacterial superinfection (bacterial tracheitis).
• pneumonia:
• The median age of children with pneumonia was 2.2 years and 25 percent had an underlying illness (eg, neurologic disease, asthma)
• Bacterial pneumonia, most commonly due to Streptococcus pneumoniae and S. aureus, may arise as a secondary infection in normal children with influenza
• Neurologic — aseptic meningitis, acute cerebellar ataxia, transverse myelitis, Guillain-Barré syndrome, acute necrotizing and postinfectious encephalitis (also known as acute disseminated encephalomyelitis), encephalopathy, febrile seizures, and acute mental status changes. Reye syndrome is rarely observed with the diminished use of aspirin
• Myositis and rhabdomyolysis — reported most frequently among children .
• myalgias are a prominent feature of most cases of influenza
• true myositis is uncommon.
• more frequent with influenza B vs A.
• extreme tenderness of the affected muscles, most commonly in the legs.
• In the most severe cases, swelling and bogginess of the muscles may be noted.
• markedly elevated serum creatine phosphokinase (CK) \
• myoglobinuria with associated renal failure has been reported
• myocarditis, pericarditis
• toxic shock syndrome (associated with Staphylococcus aureus infection and acute influenza)

Time Course

• Influenza A outbreaks typically begin abruptly, peak over a two to three week period, and last for two to three months
• It is estimated that 15 to 42 percent of preschool and school-age children become infected with influenza each year
• Most outbreaks have attack rates of 10 to 20 percent in the general population, but rates can exceed 50 percent in pandemics

Diagnosis

Viral culture — Viral isolation is frequently successful within 48 to 72 hours of inoculation, especially in children, who generally have higher viral titers and a longer period of viral shedding than do adults.Rapid diagnostic testing — Rapid viral diagnostic tests involving immunoassays or detection of viral neuraminidase are commercially available for influenza A and/or B viruses and widely available for rapid in-office based testing. The sensitivity and specificity, however, are variable (ranging from 45 to 96 percent for sensitivity and 52 to 100 percent for specificity).
The PCR assay for detection of influenza RNA appears to offer the highest sensitivity and specificity but often is not readily enough available for clinical use
Rapid screening tests are recommended for use only during periods when influenza is prevalent in the community. For patients in whom a diagnosis is necessary (eg, those in whom antiviral therapy for influenza is being considered), negative rapid diagnostic tests should be confirmed with viral culture or other means.

Treatment

ANTIVIRAL DRUGS 

• neuraminidase inhibitors (oseltamivir and zanamivir) and adamantanes (M2 inhibitors)
• start within 48 hours of the onset of symptoms
• Antiviral guidance from CDC: http://www.cdc.gov/flu/professionals/antivirals/index.htm
• Chemoprophylaxis can be administered simultaneously with the inactive influenza vaccine to provide protection until an immune response develops. Simultaneous administration of antiviral agents and the live-attenuated influenza vaccine has not been studied. However, it is not recommended because administration of antiviral agents may interfere with the desired replication of vaccine virus. (Approximately two weeks is generally required to mount an immune response after influenza vaccination)
• Also consider a combination of oseltamivir and an adamantane

Neuraminidase inhibitors

• reduces the risk of developing influenza by 70 to 90 percent
• Tx x 5 days. (for ppx see following section)
• Oseltamivir
• Approved for age >= 1 yo
• Oral drug
• they prevent the release of virions from the host cell
• active against both influenza A and influenza B
• mean inhibitory concentration for most type B viruses is higher (vs A)
• less likely to promote the development of viral resistance than the adamantanes , but oseltamivir resistance among influenza A (H1N1) isolates is increasing
• well tolerated with few adverse effects. GI complaints most frequent, in 14 percent of oseltamivir recipients compared vs 8.5 percent of placebo recipients.
• Zanamivir
• against both influenza A and B viruses
• approved in the United States for the prophylaxis of influenza in individuals ≥5 years and the treatment of influenza in individuals ≥7 years of age; who are without chronic cardiopulmonary conditions and are capable of inhaling the medication
• dry powder administered by oral inhalation
• not recommended for patients with underlying chronic respiratory disease; can cause bronchospasm and a decline in respiratory function in such patients.
• Well tolerated; most common adverse events (reported in fewer than 5 percent of recipients) include diarrhea; nausea; sinusitis; nasal signs and symptoms; bronchitis; cough; headache; dizziness; and ear, nose, and throat infections
• rare, but serious adverse events (causal association between neuraminidase inhibitors and these events has not been established; may have been related to influenza infection rather than tx)
• neuropsychiatric (delirium, hallucinations, confusion, abnormal behavior, convulsions, and encephalitis); mostly with oseltamivir; mostly in in Japan (widespread use of neuramid inhib);abrupt onset and rapid resolution.
• death
• severe skin reactions.

Adamantanes (aka M2 inhibitors)

• amantadine and rimantidine
• 70 to 90 percent effective in preventing clinical illness with influenza A when circulating strains of influenza A are susceptible to adamantanes (protection is similar to vaccination)
• emergence of antiviral resistance appears to be more frequent with adamantanes vs neuraminidase inhibitors
• target the M2 protein of influenza A, which forms a protein channel in the viral membrane that is essential for efficient viral replication.
• not active against influenza B viruses.
• because of high levels of resistance to adamantanes among influenza A isolates during the 2005-2006 influenza season, the United States Centers for Disease Control and Prevention (CDC) recommended that these drugs should not be used for the chemoprophylaxis or treatment of influenza in the United States, unless the predominant circulating virus is known to be susceptible
• However, d/t incr. rate of oseltamivir resistance among influenza A (H1N1) isolates, adamantanes (either alone or in combination with oseltamivir) provide an alternative for children who require chemoprophylaxis or treatment of influenza and are unable to take zanamivir (because of age, contraindications, or difficulty with oral inhalation)
• Tx (amantadine): treat for 24-48 hours after the disappearance of signs and symptoms.

Ribavirin — Ribavirin is a nucleoside analog that has in vitro activity against both influenza A and B viruses. Reports have suggested clinical benefits when ribavirin was administered by aerosol to treat influenza A or B infections. When administered orally, ribavirin is poorly absorbed and thus has not been shown to be effective against influenza. Ribavirin is not approved by the FDA for the treatment or prevention of influenza.
Duration of prophylaxis

• For high-risk children with contraindications to immunization or in whom a poor response to immunization is expected, or in years when the circulating strains differ from those included in the vaccine, chemoprophylaxis should be administered daily during the duration of influenza activity in the community (seasonal prophylaxis)
• For high-risk children who are immunized less than two weeks before, or after the onset of circulation of influenza in the community, the duration of prophylaxis depends upon the number of influenza doses required:
• For children who require two doses, continue for at least six weeks after the first dose, or two weeks after the second dose (whichever is longer)
• For children who require only one dose, chemoprophylaxis should continue for two weeks after immunization.
• For control of outbreaks in institutions, chemoprophylaxis should continue for a minimum of two weeks; if new cases continue to occur, chemoprophylaxis should continue until approximately one week after the end of the outbreak (post-exposure prophylaxis).
• For close contacts of an individual infected with influenza, chemoprophylaxis should begin within two days after exposure and continue for 7 to 10 days (post-exposure prophylaxis) [52].

Table: Children and adolescents at increased risk for severe or complicated influenza

TIV: trivalent inactivated influenza vaccine; LAIV: live-attenuated influenza vaccine.
* LAIV may be administered to individuals who are healthy, nonpregnant, and between 2 and 49 years of age.
Epidemiology

• Influenza A viruses, in particular, have a remarkable ability to undergo periodic changes in the antigenic characteristics of their envelope glycoproteins, the hemagglutinin and the neuraminidase.
• Influenza hemagglutinin is a surface glycoprotein that binds to sialic acid residues on respiratory epithelial cell surface glycoproteins. This interaction is necessary for the initiation of infection. After viral replication, progeny virions are also bound to the host cell.
• Neuraminidase cleaves these links and liberates the new virions; it also counteracts hemagglutinin-mediated self-aggregation entrapment in respiratory secretions
• Major changes in these glycoproteins are referred to as antigenic shifts and minor changes are called antigenic drifts. Antigenic shifts are associated with epidemics and pandemics of influenza A, while antigenic drifts are associated with more localized outbreaks of varying extent.
• Antigenic drifts are believed to result from point mutations in the RNA gene segments that code for the hemagglutinin or the neuraminidase; they are thought to occur sequentially as the virus spreads through a susceptible population [6]. Changes in the hemagglutinin which result in antigenic shifts are of such great magnitude that they cannot be accounted for by point mutations; thus, the origin of pandemic strains is unknown. Influenza viruses have a segmented genome, which can result in high rates of reassortment among viruses that coinfect the same cell. It has been suggested that pandemic strains may arise by reassortment of genes between human and animal influenza viruses that simultaneously infect a human host
• Among influenza A viruses that infect humans, three major subtypes of hemagglutinins (H1, H2, and H3) and two subtypes of neuraminidases (N1 and N2) have been described.
• Influenza B viruses have a lesser propensity for antigenic changes, and only antigenic drifts in the hemagglutinin have been described.
• Influenza monitoring: www.cdc.gov/ncidod/diseases/flu/weekly.htm.

Seasonality

• Outbreaks of influenza occur almost exclusively during the winter months in the northern and southern hemispheres (which occur at different times of the year). It is highly unusual to detect influenza A viruses at other times, although individual infections and even outbreaks have been reported during the warm weather months.
• How influenza A virus persists between outbreaks remains poorly understood; they may be imported by travel, as influenza occurs throughout the year in the tropics

Transmission

• person to person, primarily through respiratory secretions
• Large amounts of virus are present in respiratory secretions of infected persons, which can be transmitted through sneezing, coughing, talking, and by self-inoculation of secretions containing fomites.
• Viral shedding peaks at 24 to 48 hours of illness and then rapidly declines; little or no viral replication is usually detectable in the respiratory tract after 5 to 10 days [6,7]. Due to the relative lack of immunity, longer periods of shedding can occur in young children, especially those with primary infection or in immunocompromised hosts [3,8,9]. Although systemic symptoms are common, viral replication only occurs in the respiratory tract.

Health Care Burden

• Outpatient visits — The number of outpatient visits among children related to influenza virus infection each year in the United States has ranged from 6 to 29 per 100 children, and varies according to age and year
• The ratio of the estimated rate of outpatient visits to hospitalizations for confirmed influenza was approximately 10:1 for infants 0 to 5 months of age, 100:1 for those 6 to 23 months of age, and 250:1 for those 24 to 59 months.
• In Adults: Using weekly national vital statistics from 1972 through 1992, influenza epidemics accounted for 426,000 deaths in the United States. Because of the high attack rates, the morbidity caused by influenza in the general population is substantial. Increased rates of morbidity and mortality are associated with age, underlying comorbidities, and vaccination status. Mortality associated with influenza disproportionately affects elderly persons. Factors that contribute to more severe influenza infections in elderly patients include decreased lung compliance, decreased respiratory muscle strength, declining cellular immunity, and decreased B cell responses to new antigens
• Fatal infections in children are less common than in adults. CDC surveillance data on mortality during the 2003-2004 influenza season:
• nearly one-half of deaths occurred in previously healthy children.
• highest mortality occurred among infants <6 months of age
• Among 111 children with known vaccination status, 18 children (16 percent) had received at least one dose of vaccine, and only 8 had documentation of full influenza vaccination for the 2003-2004 season
• importance of influenza vaccination in children with high-risk conditions, including neuromuscular conditions, and in household contacts of infants 0 to 6 months of age.

Vaccination

The

injectable influenza vaccine protects between 70 and 90 percent of healthy children from developing laboratory-confirmed influenza infection. The nasal spray vaccine protects about 87 percent of children between ages 5 and 7 years.

From UpToDate (last updated Spring 2009)

Epidemiology of influenza Author Raphael Dolin, MD Section Editor Martin S Hirsch, MD Deputy Editor Anna R Thorner, MD Last literature review version 16.3: October 2008  |  This topic last updated: June 24, 2008
Clinical features and diagnosis of influenza in children
Author Caroline Breese Hall, MD	Section Editor Morven S Edwards, MD	Deputy Editor Mary M Torchia, MD

Last literature review version 16.3: October 2008  |  This topic last updated: September 29, 2008  

Antiviral drugs for the prevention and treatment of influenza in children
Author Caroline Breese Hall, MD	Section Editors Morven S Edwards, MD Dan K Seilheimer, MD	Deputy Editor Mary M Torchia, MD

Last literature review version 16.3: October 2008  |  This topic last updated: January 2, 2009