Pediatric Influenza 

Updated: Apr 23, 2019
Author: Itzhak Brook, MD, MSc; Chief Editor: Russell W Steele, MD 

Overview

Practice Essentials

Influenza is one of the most significant causes of acute upper respiratory tract infections worldwide. Influenza viruses are highly contagious and can cause seasonal epidemics, manifesting as an acute febrile illness with variable degrees of severity, ranging from mild fatigue to respiratory failure and death. See the image below.

Swine influenza virus. Colorized transmission elec Swine influenza virus. Colorized transmission electron micrograph (37,800X) of the A/New Jersey/76 (Hsw1N1) virus under plate magnification. Image taken during the virus' first developmental passage through a chicken egg. Courtesy of the CDC/Dr. E. Palmer; R.E. Bates.

Signs and symptoms

Signs and symptoms of pediatric seasonal influenza include the following:

  • High fever

  • Chills

  • Myalgia

  • Headache

  • Fatigue

  • Sore throat/pharyngitis

  • Nasal congestion

  • Rhinitis

  • Nonproductive cough

  • Cervical lymphadenopathy

  • Conjunctivitis

Conjunctivitis, rhinitis, and gastrointestinal symptoms are more common in infants and young children than in adults.

Avian influenza

Symptoms of avian influenza include the following:

  • Fever: More than 90% of the time

  • Cough

  • Sore throat

  • Respiratory distress

  • Myalgia

  • Conjunctivitis

  • Vomiting

  • Diarrhea

  • Pleurisy

  • Abdominal pain

  • Rhinorrhea

  • Lymphadenitis

  • Nasal and gingival bleeding

  • Signs and/or symptoms of encephalitis: Occasionally noted on presentation

See Clinical Presentation for more detailed information on the signs and symptoms of pediatric influenza.

Diagnosis

The diagnosis and evaluation of influenza A or B can involve the following:

  • Viral culture of nasopharyngeal and/or throat samples

  • Hemagglutination inhibition techniques

  • Immunofluorescence assay

  • Enzyme-linked immunosorbent assay (ELISA)

  • Rapid influenza diagnostic tests (RIDTs)[1]

Avian influenza

Tests for avian influenza include the following:

  • Blood culture

  • Complete blood count with differential

  • Electrolyte level measurement

  • Liver enzyme assay

  • Blood urea nitrogen and creatinine level measurement

  • RIDTs

Histologic findings may include pulmonary changes with alveolar damage similar to seasonal influenza.

See Clinical Presentation and Workup for more detailed information on the diagnosis of pediatric influenza.

Management

Supportive care for pediatric influenza can include the following:

  • Acetaminophen for fever

  • Cough suppressants and expectorants

  • Steam inhalation

  • Oral or intravenous fluids if dehydration occurs

  • Antiviral therapy for selected patients[2]

Avian influenza

World Health Organization (WHO) recommendations for the management of avian influenza are as follows[3] :

  • Patients with confirmed or suspected H5N1 infection should be treated with oseltamivir as soon as possible

  • Zanamivir may be considered as an alternative if the patient is capable of using an inhaler

  • If neuraminidase inhibitors are available, amantadine and rimantadine should not be used as first-line therapies, because of potential resistance

  • If neuraminidase inhibitors are available and if the virus is susceptible, a combination of neuraminidase inhibitors and M2 inhibitors can be used in confirmed cases of H5N1 infection

  • If neuraminidase inhibitors are not available, amantadine can be used as a first-line therapy, provided the virus is susceptible

  • If neuraminidase inhibitors are not available, rimantadine can be used if the virus is known to be susceptible, because it has fewer side effects than amantadine

  • For prophylaxis in high-risk and moderate-risk exposures, give oseltamivir for 7-10 days from the day of exposure

  • Prophylaxis is not recommended for low-risk groups

See Treatment and Medication for more detailed information on the management of pediatric influenza.

Background

Influenza is the one of the most significant acute upper respiratory tract infections. Influenza viruses cause a broad array of respiratory illnesses responsible for significant morbidity and mortality in children. Influenza viruses cause epidemic disease (influenza virus types A and B) and sporadic disease (type C) in humans. Seasonal human influenza causes about 36,000 deaths and 226,000 hospitalizations in the United States annually.[4, 5]

The word influenza may have been derived from the Latin word influo, which means "to flow in," indicating airborne transmission, or from the Italian word influence, which indicates influence of weather or an astrological influence.[6]

In addition to humans, influenza also infects a variety of animal species. Some of these influenza strains are species specific, but new strains of influenza may spread from other animal species to humans (see Pathophysiology). The term avian influenza used in this context refers to zoonotic human infection with an influenza strain that primarily affects birds.

Swine influenza refers to infections from strains derived from pigs. For more information on the 2009 influenza pandemic, a recombinant influenza consisting of a mix of swine, avian, and human gene segments, see the article H1N1 Influenza (Swine Flu).

Typical symptoms of influenza begin 2-3 days after exposure to the virus. Influenza produces an acute febrile respiratory illness with cough, headache, and myalgia for 3-4 days, with symptoms that may persist for as long as 2 weeks (see Clinical). Accurately diagnosing influenza A or B infection based solely on clinical criteria is difficult because of the overlapping symptoms caused by the various viruses associated with upper respiratory tract infection (see Differentials).

As with other diseases, prevention of influenza is the most effective strategy. Each year in the United States, a vaccine that contains antigens from the strains most likely to cause infection during the winter flu season is produced. The vaccine provides good protection against immunized strains, becoming effective 10-14 days after administration. Antiviral agents are also available that can prevent some cases of influenza; when given soon after the development of influenza, they can reduce the duration and severity of illness. (See Treatment.)

For discussion of influenza in adults, see Influenza.

Pathophysiology

Influenza viruses are negative-sense, single-strand RNA viruses that belong to the family Orthomyxoviridae.[7] Human influenza viruses are divided into 3 major types: A, B, and C.

Influenza type A viruses cause disease in humans and many animal species. Waterfowl (eg, ducks, geese) are the natural reservoir for type A. In addition, in freshwater lakes, influenza A virus can stay alive for 4 days at 22o C and for more than a month at 0o C.

Influenza type B viruses primarily cause disease in humans, particularly children. Infections with influenza type C viruses are rare.

Influenza viral RNA has 8 genetic elements. The RNA has a lipid envelope with 2 major antigenic components on its surface, hemagglutinin (H) and neuraminidase (N). These components enable the replication and subsequent release of the virus, leading to its spread. Influenza type A viruses also have ionic channel proteins, termed M2 proteins.[7]

The H antigen is the major virulence determinant because these antigens help viral attachment to the cell. H proteins are divided into 16 types, whereas N proteins are divided into 9 types. N act on the sialic acid component of the cell, which enables viral detachment.[8, 9]

Different subtypes of influenza viruses are identified based on the combinations of these antigenic structures, with 144 combinations possible. For example, influenza A subtype H3N2 expresses hemagglutinin 3 and neuraminidase 2. Influenza A subtype H5N1, or avian influenza, has been found in chickens, ducks, and migratory fowl throughout Asia and is now spreading west through Europe and North Africa. It is highly virulent in humans but is poorly transmissible between humans.

Currently, influenza A/H1N1, A/H3N2, and influenza type B viruses are the circulating influenza strains that cause seasonal human infections. The influenza vaccine components for the current year are intended to provide protection from these strains.[10] In contrast with the typical course of disease caused by seasonal influenza, a higher viral load and prolonged viral replication are observed in infections caused by avian influenza virus A/H5N1.[11, 12]

Current research is focusing on broadly neutralizing antibodies against influenza viruses for potential treatments and vaccines. One group recently reported isolating and characterizing human monoclonal antibody CR8020 with broad neutralizing activity against most group 2 viruses, including H3N2 and H7N7,[13] and another group isolated a neutralizing monoclonal antibody that recognized the hemagglutinin glycoprotein of all 16 subtypes and neutralized both group 1 and group 2 influenza A viruses.[14]

Antigenic drift and shift

Influenza virus type A is readily prone to mutations, which can lead to minor antigenic changes (antigenic drift) or major antigenic changes (antigenic shift). These changes can result in viral strains capable of causing either an epidemic or a pandemic, because overall immunity in the population is lower or nonexistent.[15]

With antigenic drift, the surface hemagglutinin or neuraminidase proteins are slightly altered by accumulated point mutations and nucleotide substitutions, insertions, or deletions. Because the antigens are only slightly altered, an infected person’s immune system still recognizes the virus to some extent, and the infection is usually less severe.

Antigenic shift refers to a major change in the viral RNA caused by gene reassortment. This results in replacement of the surface hemagglutinin or neuraminidase proteins, and these new proteins may be unrecognizable by an infected person’s immune system. The newly reasserted viral strain may cause a pandemic in an immunologically naïve population.

Because avian influenza viruses attach to receptors specific to birds, whereas human influenza viruses attach to receptors specific to humans, transmission of influenza from birds to humans is rare. However, an intermediate host that has receptors used by both viruses (eg, pigs) can become co-infected with both avian and human influenza viruses; this permits reassortment that may produce major changes in the genetic component of surface proteins. The resulting viral strain may be more capable of transmission to humans.

Infection

Influenza is an acute infection of the respiratory tract that involves the nose, throat, and, sometimes, the lungs. Following respiratory transmission, the virus attaches to and penetrates respiratory epithelial cells in the trachea and bronchi. Viral replication occurs, which results in the destruction of the host cell. Viremia does not occur. The virus is shed in respiratory secretions for 5-10 days.

Influenza occurs as sporadic illness, epidemics, or pandemics. Epidemic disease occurs annually, especially in the winter months. Global pandemics occur in part because of the high degree of transmissibility and the emergence of an influenza virus with a major antigenic shift (major antigenic variations on the hemagglutinin surface protein) in a nonimmune population.

The most recent pandemics included the 1889 pandemic, the 1918-1919 pandemic (influenza virus subtype H1), the 1957 pandemic (subtype H2N2), the 1968-1969 pandemic (Hong Kong subtype H3N2), and, to a lesser extent, the mild pediatric pandemic in 1977 (subtype H1N1). Approximately 21 million persons died worldwide in the 1918-1919 influenza pandemic, with 549,000 deaths in the United States.

Geographic eponyms for these pandemics (eg, Spanish flu for the 1918-1919 pandemic, Russian flu for the 1977 pandemic) typically reflect areas strongly affected, rather than sites of origin.[16]

Avian influenza

An enormous release of cytokines is probably responsible for the severity of avian influenza in humans, resulting in rapid progression.[17] The major entry site seems to be conjunctiva and oropharynx.

Hyperinduction of cytokine storm with elevated interferon in serum samples is observed.[10, 18] Increased cytokines and chemokines with high levels of tumor necrosis factor alpha, interleukin 6, and interferon gamma lead to tissue destruction.[10] Pulmonary and intestinal involvement with isolation of viral messenger RNA (mRNA) in these tissues is reported.

Prolonged viral RNA detection in the respiratory tracts results in systemic dissemination in fatal cases of avian influenza.[10] Lung changes include diffuse alveolar damage, interstitial pneumonia, bronchiolitis, and hemorrhages. The type II pneumocytes showed reactive hyperplasia without cytopathic changes. Predominant macrophage infiltrates in the lung are reported.

Superimposed opportunistic infection by fungus and aspergillosis has been reported. Histiocytic hyperplasias have been noted in the spleen, bone marrow, and lymph nodes. Hemophagocytic syndrome with multisystem involvement is also reported.[19] Minimal fatty changes in liver with portal infiltrates with lymphocytes were reported. Edema and focal areas of necrosis in the brain have been reported. The intestines, heart, kidneys, and other organs are unremarkable.

Autopsy studies of cases of avian influenza A/H5N1 infection in pregnancy reveal that, unlike human influenza, A/H5N1 causes viremia and disseminates across the placenta. It infects cytotrophoblasts and macrophages similar to cytomegalovirus. The avian influenza A/H5N1 virus genomic sequence has been identified in fetal lung tissue without severe lung injury compared with severe adult lung injury. This could be due to the poor immune status and low cytokine storm.[20]

The images below show the avian influenza A/H5N1 virus as viewed on electron micrographs.

Colorized transmission electron micrograph shows a Colorized transmission electron micrograph shows avian influenza A/H5N1 viruses (gold) grown in Madin-Darby canine kidney (MDCK) cells (green). Image courtesy of Centers for Disease Control and Prevention.
Transmission electron micrograph (original magnifi Transmission electron micrograph (original magnification X 150,000) shows ultrastructural details of an avian influenza A/H5N1 virion, a subtype of avian influenza A. Note the stippled appearance of the roughened surface of the proteinaceous coat encasing the virion. Image courtesy of Centers for Disease Control and Prevention.

Etiology

Influenza is an acute infection caused by any of 3 types of influenza viruses (A, B, C). Types A and B cause epidemic disease, and type C causes sporadic disease. Type A is the most common.

Influenza is highly contagious. The virus is spread when an individual inhales contaminated airborne droplets (following coughing or sneezing by an infected person) or comes in direct contact with an infected person's secretions (eg, kissing, sharing of handkerchiefs and other items, sharing of objects such as spoons and forks). Viruses may also be transmitted via touching of smooth surfaces, such as doorknobs, handles, and telephones.

Certain populations are at higher risk for influenza. Risk factors include the following:

  • Advanced age

  • Chronic respiratory disease

  • Chronic cardiac disease

  • Chronic renal failure

  • Diabetes mellitus

  • Immunosuppression

  • Residence in residential care homes and long-stay facilities

Avian influenza

The main reservoir for influenza A viruses are migratory birds, especially waterfowl. Birds with low-pathogenic influenza A virus infection can be asymptomatic and can be a source of infection for domestic poultry. The influenza A viruses are shed in oral secretions and feces.

Domesticated birds are infected via secretions and excretions and via contaminated utensils. Highly pathogenic (HP) avian influenza A viruses can kill domesticated birds in 48 hours. HP avian influenza H5N1 viruses have crossed the species barrier in Asia, resulting in several human cases.[21] This poses a potential pandemic threat.

Most H5N1 cases have been in eastern Asia; some cases have been reported in Eastern Europe and North Africa. Infection has been associated with exposure to infected poultry and poultry products. No cases of infection with the H5N1 avian influenza virus have been reported in North America.

Epidemiology

In tropical areas, influenza occurs throughout the year. In temperate areas, the influenza season typically starts in early fall, peaks in mid-February, and ends in the late spring of the following year. Approximately 250,000-500,000 cases of seasonal influenza occur each year in the United States, with about 200,000 hospitalizations.

By convention, mortality statistics for influenza are combined with those for pneumonia. For the population as a whole, influenza and pneumonia result in 20,000 deaths each year in the United States. Pediatric mortality from influenza is typically highest in the first year of life. For example, in the United States in 2007, death rates from influenza and pneumonia were 5.2 deaths per 100,000 population for infants younger than 1 year, compared with 0.7 and 0.3 for children aged 1-4 years and 5-14 years, respectively.[22]

H1N1 influenza statistics

The 2009-2010 influenza season was affected by the H1N1 (“swine flu”) global pandemic, the first wave of which hit the United States in the spring of 2009, followed by a second, larger wave in the fall and winter; activity peaked in October and then declined quickly to below baseline levels by January, but small numbers of cases were reported through the spring and summer of 2010.[23, 24, 25] For more information, see the article H1N1 Influenza (Swine Flu).

The H1N1 pandemic in 2009 in Argentina was associated with pediatric death rates that were 10 times the rates for seasonal influenza in previous years; the overall rate of death was 1.1 per 100,000 children, compared with 0.1 per 100,000 children for seasonal influenza in 2007.[26] In the United States, from August 30, 2009 to March 27, 2010, at least 81%% of deaths associated with influenza were due to H1N1 disease.[27]

An analysis of data from a statewide public health surveillance in California, including 345 children (< 18 y), noted that more than 25% of children hospitalized for 2009 novel influenza A (H1N1) required intensive care (27%) and/or died (3%).[28] This study documents the severe nature of H1N1 infection in children.

Avian influenza statistics

A potential influenza pandemic could have a major impact economically and in health care. In the United States, a medium-level pandemic could lead to approximately 89,000-207,000 deaths, 314,000-734,000 hospitalizations, 20-47 million people with infection, and probably 18-42 million outpatient visits.[29]

Previous pandemics have occurred in waves, with new waves occurring in intervals of 3-7 months. Approximately 15-35% of the US population may be involved by an influenza pandemic, and the economic loss could be $71.3-166.5 billion.[29]

In 1997, the first report of human cases infected with HP avian influenza A/H5N1 documented 6 deaths among 18 hospitalized patients in Hong Kong.[30] In 1999, HP avian influenza A/H9N2 infection was reported in 2 girls with fever and rhinorrhea; they recovered and no human-to-human transmission was noted.[31]

Between January-March of 2004, 34 human cases of HP avian influenza A/H5N1 virus infections were confirmed from Vietnam and Thailand. Significant respiratory illness that required hospitalization resulted in a 68% fatality rate. In Vietnam, 15 deaths were reported among 22 cases; in Thailand, 8 deaths were reported among 12 cases.[31] Children and young adults were predominantly involved, and all human cases were associated with outbreaks of HP avian influenza A/H5N1 among domestic poultry in the back yard and in the farms. More than 100 million domestic poultry have been culled.[32]

Migratory birds are presumed to be responsible for the recent spread of HP avian influenza virus A/H5N1 from Southeast Asia, where the poultry outbreak has been reported, to other regions across the globe. The HP avian influenza virus A/H5N1 was confirmed in ducks, chicken, turkey, and geese in Russia and Kazakhstan in July 2005, resulting in an implementation of restrictions on importation of birds from these areas.[15] In January 2006, 2 cases of HP avian influenza virus A/H5N1 infection were reported in humans in Turkey.

By August 2007, a total of 12 cases and 4 deaths were reported.[33] Iraq, the seventh country to have reported human cases, has reported 3 HP avian influenza A/H5N1–related human cases. Laboratory confirmation is performed by the US Naval Medical Research Unit, located in Cairo, Egypt.[34] In Egypt, from 2006-2007, 38 human cases were reported, with 15 deaths due to severe respiratory illness.[33] Although poultry deaths are noted, HP avian influenza A/H5N1 viruses have not been isolated from poultry in these areas.

Globally, as of March 2011, 532 cases of avian influenza A/H5N1 had been reported worldwide, with 315 deaths.[35]

During the 2003-2004 influenza season, one case of avian influenza virus A/H7N3 was reported in New York; the patient had respiratory symptoms and required hospitalization but recovered, although the source of infection was unknown.[31] In March 2004, 2 poultry workers were involved in the culling of poultry during an avian influenza outbreak in British Columbia, Canada; one worker reportedly had conjunctivitis and headache, whereas the other had nasal drainage. Both workers recovered without hospitalization.[31]

The avian influenza A/H5N1 outbreak noted in Manipur, India was unique and was unrelated to the 2006 virus.[36]

Sexual and racial differences in incidence

No difference based on sex has been identified. No difference based on race has been identified. Race appears to be a factor in avian influenza only to the extent that geographic differences in the rate of avian influenza A/H5N1 among birds and the degree of bird-to-human contact are significant.

Age-related differences in incidence

The infection rate of influenza viruses is high in all age groups. The infection rate and the frequency of isolation of influenza viruses are highest in young children. The infection rate in healthy children is 10-30% annually.

Prognosis

Generally, the prognosis for recovery from seasonal influenza is excellent, although full return to normal levels of activity and freedom from cough usually requires weeks rather than days. However, a Centers for Disease Control and Prevention (CDC) review of data on 794 pediatric influenza-related deaths that occurred between October 2004 and September 2012 revealed that 341 children (43%) had no high-risk medical conditions such as neurologic disorders, asthma, or diseases of the heart, kidney, liver, or immune system.[37, 38] Median age of death was 7 years. Otherwise healthy children were more likely to die before hospital admission than children with other high-risk conditions (relative risk, 1.9; 95% confidence interval [CI], 1.6 - 2.4) and were 1.6 times more likely to die within 3 days of the onset of symptoms (95% CI, 1.3 - 2.0).[37, 38]

In contrast, the prognosis for patients with avian influenza is poor. Through August 2007, overall mortality from avian influenza A/H5N1 was 60%[34] ; the case-fatality rate in children younger than 15 years was approximately 89%.[17] The average duration from onset of illness to death varied from 1-3 weeks.[34] Poor prognostic features include a high viral load, leukopenia, lymphopenia, longer duration of illness prior to treatment, and old age.[18]

Children with neurological and neurodevelopmental conditions are at increased risk for severe outcomes from influenza, including death. This was evident in April 2011 during an outbreak of influenza at an Ohio residential facility for 130 such children. Ten were hospitalized and 7 died. A high index of suspicion and low threshold to empirically test for influenza and initiate empiric antiviral therapy during influenza season should be considered if there is worsening respiratory status among these patients.[39]

Patient Education

Education regarding covering the mouth when coughing and strict handwashing is helpful. Household contacts of patients should be instructed to monitor fever, cough, and respiratory distress symptoms. These household contacts should be given prophylactic antiviral therapy with oseltamivir. If they are symptomatic, they must be tested for the virus. Avoiding close contact with the patient is recommended.

For patient education information, see Colds, Flu in Adults, and Flu in Children.

For information on avian influenza, follow the travel advisories recommended by the CDC and the World Health Organization. For example, people traveling to certain countries should avoid poultry farms and markets or other places where live poultry are present.

 

Presentation

History

Typical symptoms of influenza begin 2-3 days after exposure to the virus. Influenza produces an acute febrile respiratory illness with cough, headache, and myalgia for 3-4 days, with symptoms that may persist for as long as 2 weeks. Similar symptoms can be seen in close contacts or family members.

Patients may present with sudden onset of the following:

  • High fever

  • Chills

  • Myalgia

  • Headache

  • Fatigue

Subsequent respiratory symptoms include the following:

  • Sore throat/pharyngitis

  • Nasal congestion

  • Rhinitis

  • Nonproductive cough

  • Cervical lymphadenopathy

  • Conjunctivitis

Conjunctivitis, rhinitis, and GI tract symptoms are more common in infants and young children than in adults.

In young infants, influenza may produce a sepsislike picture with shock; occasionally, influenza viruses can cause croup or pneumonia.

Avian influenza

Determine if the patient has a history of recent travel to countries where epidemics of avian influenza A/H5N1are reported.[34] If so, determine if the patient has a history of exposure to poultry from a region with an outbreak of highly pathogenic avian influenza A virus. They may be health care workers with exposure to infected patients. Poultry cullers with this infection have been reported. The incubation period of HP avian influenza A virus is typically 2-5 days but can be as long as 8-17 days.[21]

Avian influenza manifests with cough, respiratory distress, myalgia, conjunctivitis, diarrhea, and vomiting. Diarrhea can precede respiratory symptoms and is watery, without any inflammatory features. Occasionally, signs and/or symptoms of encephalitis may be noted upon presentation.

Physical Examination

Manifestations of influenza range from mild to severe. Fever, respiratory symptoms, and myalgia are typical.[40]

Patients with avian influenza A/H5N1 virus infection predominantly present with community-acquired pneumonia, conjunctivitis, and fever. Compared with patients who have seasonal influenza, patients avian influenza A virus tend to have fever more than 90% of the time, vomiting, pleurisy, abdominal pain, myalgia, sore throat, rhinorrhea, lymphadenitis, and nasal and gingival bleeding.

Patients with avian influenza can develop dyspnea within approximately 5 days from onset of illness. The sputum is occasionally bloody.

Complications

The following complications of seasonal influenza are noted:

  • Primary influenza viral pneumonia

  • Secondary bacterial pneumonia

  • Croup

  • Exacerbation of chronic pulmonary disease

  • Myositis

  • Myocarditis

  • Toxic shock syndrome

  • Guillain-Barré syndrome

  • Reye syndrome

Potential complications of avian influenza include the following:

  • Pneumonia

  • Respiratory failure

  • Congestive heart failure

  • Multiorgan failure

  • Acute respiratory distress syndrome (ARDS)

  • Pulmonary hemorrhage

  • Cardiac arrhythmia

  • Death

Respiratory failure due to an ARDS-like picture reportedly occurs 4-13 days after onset of illness.

 

DDx

Diagnostic Considerations

Accurately diagnosing influenza A or B infection based solely on clinical criteria is difficult because of the overlapping symptoms caused by the various viruses associated with upper respiratory tract infection (URTI). In addition, several serious viruses, including adenoviruses, enteroviruses, and paramyxoviruses, may initially cause influenzalike symptoms.

Differential Diagnoses

 

Workup

Approach Considerations

The criterion standard for diagnosing influenza A and B is a viral culture of nasopharyngeal samples and/or throat samples.

Laboratory Studies

Isolation of influenza viruses or detection of viral antigens in respiratory secretions (eg, throat swabs, nasopharyngeal washes, sputum) can be performed during acute influenza infection. Specimens for culture should be obtained within 3 days of onset of illness.

The type of influenza virus (A or B) may be determined by immunofluorescence or hemagglutination inhibition (HAI) techniques, and the hemagglutinin subtypes of influenza A virus (H1, H2, H3) may be identified using HAI with subtype-specific antisera.

Complement-fixation (CF) and hemagglutination inhibition (HI) tests are the most common methods used to compare sera in persons with acute and convalescent infection, although these tests have low sensitivity and specificity. Rises in immunoglobulin (Ig) titer of at least fourfold are considered diagnostic of infection. Significant rises as measured by enzyme-linked immunosorbent assay (ELISA) are diagnostic of acute infection.

Viral antigens in respiratory secretions can be detected by immunofluorescence (IF) assay, time-resolved immunofluorescence assay (TRIFA), radioenzyme immunoassay, and ELISA. ELISA results can be obtained within 1 hour.

Rapid Diagnostic Tests

The US Food and Drug Administration (FDA) has waived federal Clinical Laboratories Improvement Act (CLIA) requirements and cleared for marketing 7 rapid influenza diagnostic tests that directly detect influenza A or B virus–associated antigens or enzyme in throat swabs, nasal swabs, or nasal washes and can produce results within 30 minutes.[1] The following 3 of these tests are considered low complexity and may be used in physicians’ offices:

  • QuickVue Influenza A+B test (Quidel)

  • ZstatFlu (ZymeTx)

  • QuickVue Influenza test (Quidel)

The QuickVue tests provide results in 10 minutes or less; the ZstatFlu test provides results in 20 minutes. Because of cost, availability, and sensitivity issues, most physicians diagnose influenza based on clinical criteria alone.

A study from the Centers for Disease Control and Prevention (CDC) of 11 rapid influenza diagnostic tests (RIDTs) that were given clearance by the FDA found variations in the tests’ ability to detect flu virus. The researchers determined the following[41, 42] :

  • Most RIDTs detected viral antigens in samples with higher viral concentrations

  • Tests had fewer positive results with lower viral concentrations

  • The tests differed in their ability to detect A and B influenza viruses

Testing for avian influenza

In September 2011 the FDA approved a new kit developed by the CDC for diagnosing human infections with seasonal influenza viruses and novel influenza A viruses with pandemic potential.

The Human Influenza Virus Real-Time RT-PCR Detection and Characterization Panel (rRT-PCR Flu Panel) is an in vitro laboratory diagnostic test that can provide results within 4 hours. It is the only in vitro diagnostic test for influenza that is cleared by the FDA for use with lower respiratory tract specimens and will be given at no cost to qualified international public health laboratories.

Consisting of 3 modules, the kit can:

  • Identify and distinguish between influenza A and B viruses,

  • Classify influenza A viruses by subtype, and

  • Detect highly pathogenic avian influenza A (H5N1) virus infection in human respiratory tract specimens.

Other FDA-approved assays for diagnosing avian influenza include the Influenza A/H5 (Asian Lineage) Virus Real-Time Reverse Transcription–Polymerase Chain Reaction (RT-PCR) Primer and Probe Set and inactivated virus as a positive RNA control for the in vitro detection of highly pathogenic influenza virus A/H5 (Asian lineage).[43]

The CDC recommendation is to test for highly pathogenic (HP) avian influenza A/H5N1 if a patient has severe respiratory symptoms and a risk for exposure (eg, direct contact with ill, dead, or infected poultry in a country with known poultry outbreaks of HP avian influenza A/H5N1), with specific criteria included. Testing must be performed under biosafety level 3.[44, 45] Viral culture of human and animal specimens should not be performed in the same laboratory.[45]

Positive laboratory test findings must be confirmed by the CDC, which is the World Health Organization (WHO) H5 reference laboratory.

If other test findings are negative, paired avian influenza virus serologies can be performed at the CDC. However, reagents may not be widely available, and acute and convalescent serum analysis requires time to allow a 4-fold increase in antibody.

Other laboratory tests include the following:

  • Blood culture

  • Complete blood count (CBC) with differential

  • Electrolyte level measurement

  • Liver enzyme assay

  • Blood urea nitrogen (BUN) and creatinine level measurement

Lumbar puncture is indicated in selected patients. Very rarely, central nervous system involvement is documented by viral isolation from cerebrospinal fluid (CSF) and blood in patients who present with seizure and coma.[46]

Radiography

Chest radiography may be necessary to exclude the diagnosis of pneumonia. In avian influenza, chest radiography, both posteroanterior and lateral views, may reveal patchy or diffuse infiltrates, an interstitial pattern, and lobar consolidation revealing air bronchogram or an acute respiratory distress syndrome (ARDS)–like picture.

Histologic Findings in Avian Influenza

Histologic findings may include pulmonary changes with alveolar damage similar to seasonal influenza. Fibrinous exudate membrane formation and lymphocyte infiltrates are noted in postmortem analysis of patients who had avian influenza.

Necrosis is noted in organs such as the liver and kidney. The spleen may be depleted of lymphoid cells. Bone marrow demonstrates hemophagocytosis.[17]

 

Treatment

Approach Considerations

As with other diseases, prevention of influenza is the most effective strategy. The Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC) publishes recommendations for high-risk groups.

Selected patients may benefit from the use of antiviral agents. The ACIP also publishes recommendations on the use of antiviral agents for prevention and treatment of influenza.[2] Early antiviral therapy must be considered among hospitalized children diagnosed with or suspected to have influenza, especially if they have risk factors such as asthma, cardiac problems, or other conditions, to prevent severe complications and prolonged hospitalization. Influenza vaccination also must be encouraged to prevent the infection.[47]

One study analyzed the clinical data of adult patients with pandemic H1N1 2009 infection admitted to the ICU. Most of the 18 patients analyzed were obese and presented with severe respiratory distress and hypoxia in the summer months. A higher dose of oseltamivir (150 mg twice daily) and nonconventional modes of ventilation may have improved the outcome in these patients. The rapid influenza detection test (RIDT) had a 76% false-negative result; however, the infection was later confirmed with real-time reverse transcriptase polymerase chain reaction (rRT-PCR). These results suggest that early and aggressive treatment action should be taken in patients with a high clinical suspicion of severe influenza infection.[48]

Supportive Care

Influenza symptoms may last longer than 1 week. Caregivers can relieve and soothe children's aches and pains with basic supportive care. Acetaminophen may be administered for fever and relief of other symptomatology. (Caution: In children < 16 y who have symptoms of influenza infection or colds, aspirin is not recommended because of an association with Reye syndrome.)

Use cough suppressants and expectorants to treat the cough. Steam inhalations may also be useful. If dehydration occurs, administration of oral or intravenous fluids is indicated.

Antiviral Therapy

Antiviral agents available for influenza treatment and/or prevention include neuraminidase inhibitors (oseltamivir, peramivir, zanamivir) and the cap-dependent endonuclease inhibitor (baloxavir marboxil).[8, 49, 50, 51] The use of adamantanes, such as amantadine, has not been recommended since the 2005-2006 influenza season owing to resistance among influenza A viruses.[52]  The use of adamantanes, such as amantadine, has not been recommended since the 2005-2006 influenza season owing to resistance among influenza A viruses.

The Infectious Disease Society of America (IDSA) Guidelines for Antiviral Therapy

IDSA latest guidelines for antiviral therapy are as follows:[53]

High risk individuals

Clinicians should initiate antivirals as soon as possible for adults and children with documented or suspected influenza, irrespective of influenza vaccination history, with the following:

  • Hospitalized with influenza, regardless of illness duration before hospitalization
  • Outpatients with severe or progressive illness, regardless of illness duration
  • Children younger than 2 years and adults aged 65 years or older
  • Women who are pregnant or within 2 weeks postpartum

Individuals not at high risk

Clinicians may consider antivirals for individuals with documented or suspected influenza, irrespective of influenza vaccination history, who are:

  • Outpatients with illness onset 2 days or less
  • Symptomatic outpatients with household contacts at high risk
  • Symptomatic healthcare providers who care for patients at high risk, particularly those who are severely immunocompromised

Baloxavir marboxil was approved by the FDA in October 2018 for use in adults and adolescents aged 12 years or older as a single weight-based oral dose for use within 48 hours of symptom onset. It is a prodrug which inhibits cap-dependent endonuclease, an enzyme specific to influenza, resulting in inhibition of viral replication. In clinical trials, single-dose baloxavir is safe and effective in treating patients with uncomplicated influenza. It is active against influenza A and B including strains resistant to neuraminidase inhibitors.

Approval of baloxavir marboxil was based on the CAPSTONE-1 trial (N=1436). Patients aged 12 to 64 years were randomized to receive baloxavir, oseltamivir, or placebo. Of the 1064 patients included in the intention-to-treat infected population, the median time to alleviation of symptoms was 53.7 hours in the baloxavir group compared with 80.2 hours for placebo (P < 0.001). Similar results were observed shown with oseltamivir compared with placebo.  Additionally, the baloxavir group had a significant decrease in viral load after 1 day of treatment compared with both placebo (P < 0.05) and oseltamivir (P < 0.05) groups.[51] It is undetermined whether the rapid drop in viral load decreases the risk of virus transmission.

Inhibitors of influenza virus neuraminidase, an enzyme that releases viral particles from the plasma membrane of infected cells, reduce release of the virus and its spread. Oseltamivir (Tamiflu) is approved by the U.S. Food and Drug Administration (FDA) for treatment and prophylaxis of influenza types A and B and is effective in treating avian influenza.[50] Oseltamivir resistance has been rarely reported in pandemic H1N1 influenza virus and avian influenza A/H5N1 virus.[12, 54]

Oseltamivir resistance emerged in the United States during the 2008-2009 influenza season. Because of this, zanamivir (Relenza) was recommended as the initial choice for antiviral prophylaxis or treatment when influenza A infection or exposure was suspected. However, as of March 2011, all US seasonal influenza viruses tested for resistance by the CDC were susceptible to neuraminidase inhibitors.[54]

Zanamivir and oseltamivir are approved by the FDA for both prophylaxis and treatment of influenza A and B. When used for treatment, these agents can reduce the duration and severity of illness. They should be started as soon as possible after the onset of symptoms, but no later than 2 days after onset.

In an analysis of medical record data from 784 children hospitalized in intensive care units with laboratory-confirmed influenza during the 2009 H1N1 pandemic and postpandemic periods, early treatment with neuraminidase inhibitors (NAIs) (≤48 h of illness) improved survival. NAIs were administered to 90% of patients during the pandemic period and 63% of patients during the postpandemic period.[55, 56]

Of the 653 children who received NAI treatment, 38 (6%) died, relative to 11 (8%) of the 131 children who did not receive NAIs. In multivariate analyses adjusted for variables (eg, comorbid conditions, pneumonia, need for mechanical ventilation), investigators observed a reduced estimated risk for death among those who received NAIs; in addition, when patients received NAIs within 48 hours of becoming ill, they were significantly more likely to survive.[55, 56]

Peramivir is indicated for treatment of acute uncomplicated influenza in patients aged 2 years or older who have been symptomatic for no more than 2 days. It is administered as a one-time IV infusion. Pediatric approval was based on the interim analysis of an ongoing pediatric clinical study (Study 305), a randomized, active-controlled trial of adolescent and pediatric patients with acute uncomplicated influenza who received open-label treatment with a single dose of peramivir (n=84) or 5 days of treatment with oseltamivir administered within 48 hours of onset of symptoms of influenza. Median time to alleviation of combined influenza symptoms was 79 hours for peramivir compared with 107 hours for oseltamivir. Median time to recovery to normal temperature (ie, < 37°C) was 40 hours and 28 hours patients receiving peramivir and oseltamivir, respectively.[57]

Treatment of avian influenza

Hospitalization is required in patients with avian influenza if respiratory distress results in subsequent ventilatory support. Oseltamivir is the primary drug of choice.[45] Longer therapy may be needed to treat highly pathogenic (HP) avian influenza than seasonal influenza.

The WHO recommendations for HP avian influenza A/H5N1 are as follows[3] :

  • Patients with confirmed or suspected H5N1 infection should be treated with oseltamivir as soon as possible

  • Zanamivir might also be considered as an alternative if the patient is capable of using an inhalers

  • If neuraminidase inhibitors are available, amantadine and rimantadine should not be used as first-line therapies because of potential resistance

  • If neuraminidase inhibitors are not available, amantadine can be used as a first-line therapy, provided the virus is susceptible

  • If neuraminidase inhibitors are not available, rimantadine can be used if the virus is known to be susceptible because it has fewer side effects than amantadine

  • If neuraminidase inhibitors are available, and if the virus is susceptible, then a combination of neuraminidase inhibitors and M2 inhibitors can be used in confirmed cases of H5N1 infection

  • For prophylaxis in high-risk and moderate-risk exposures, give oseltamivir for 7-10 days from the day of exposure

  • Prophylaxis is not recommended for low risk groups

For more information, see the World Health Organization Updated Guidelines for Avian Influenza Virus Management.

A combination of antiviral therapy (eg, oseltamivir and adamantanes if susceptibility is expected) and antibiotics is recommended if pneumonia and rapid progression is noted. If septic shock is present, corticosteroids and vasopressors may play a role.

Acute respiratory distress syndrome (ARDS) should be managed according to guidelines.

If the patient is hospitalized, an isolation room is required, with airborne precautions or a negative-pressure room. A particulate mask, such as N95, and goggles are recommended.

Diet and Activity

No special diet is indicated for influenza.

Adequate rest is recommended.

General Influenza Prevention

Handwashing with soap and water is the most appropriate way to prevent infection by an influenza virus. Other preventive measures are to avoid touching of eyes or nose before washing hands, and to avoid sharing personal items with another person during an influenza outbreak.

Patients with influenza who are clinically stable and are able to convalesce at home are instructed to stay at home to avoid spread in the community.

Vaccination in the Pediatric Population

Influenza vaccination in targeted high-risk populations is the best means of preventing severe disease caused by influenza virus. Guidelines regarding the prevention and control of influenza have been established by the ACIP, and are regularly updated.[58, 59]

Vaccines made using inactivated influenza virus provide 60-90% protection against influenza when the vaccine matches the epidemic strain. The antigenic composition is reviewed annually so that the current vaccine contains the most recently circulating strains, usually one or more subtypes of influenza A virus and a subtype of influenza B virus.

A study by Flannery et al that assessed the effectiveness of the influenza vaccine in reducing the risk of influenza-associated death in children and adolescents found that in the 291 of 358 pediatric influenza deaths reported between 2010-2014 where vaccination status was determined, only 26% had received the vaccine before the start of the illness and 31% among children with high-risk conditions. Overall vaccination effectiveness against death was 65%, and 51% in children with high-risk conditions.[60, 61]

As the administration of two separate vaccines for seasonal and pandemic influenza was needed in 2009, Frey et al conducted a randomized trial of monovalent 2009 H1N1 influenza vaccine (2009 H1N1 vaccine) and seasonal trivalent inactivated influenza vaccine (TIV; split virion) given sequentially or concurrently in 531 children who had been previously vaccinated. Generally, one dose of 2009 H1N1 vaccine and one dose of TIV, regardless of the sequence or concurrency of administration, was immunogenic in children 10 years of age and up, while children less than 10 years of age required two doses of 2009 H1N1 vaccine. The vaccines were well tolerated.[62]

Live attenuated influenza vaccine (LAIV)

ACIP recommends return of intranasal flu vaccine in the U.S. for 2018-2019 season

The Advisory Committee on Immunization Practices (ACIP) recommends return of intranasal flu vaccine in the U.S. for 2018-2019 season. The recommendation was based on positive results from a U.S. study in children between the ages of 2 to < 4 years evaluating the shedding and antibody responses of the H1N1 strain in the live attenuated influenza vaccine (LAIV). The study showed that the new 2017-2018 H1N1 LAIV post-pandemic strain (A/Slovenia) performed significantly better than the 2015-2016 H1N1 LAIV postpandemic strain (A/Bolivia), which was associated with lower effectiveness and not recommended during last 2 seasons.[63]

LAIV4 was not recommended during the 2017-2018 or 2016-2017 influenza seasons because it was poorly effective against circulating strains of influenza in the United States.[64, 65]

Quadrivalent vaccines

The US Food and Drug Administration (FDA) approved quadrivalent forms of the vaccine in 2012. Like the already approved trivalent, the quadrivalent vaccines contain weakened forms of the virus strains. This formulation includes a second B strain, which increases the likelihood of adequate protection against circulating influenza B strains.

Indications for influenza vaccine in the pediatric population include the following:

  • Annual vaccination of all children aged 6 months to 18 years[66]

  • Annual vaccination of children and teenagers (6 mo to 18 y) with long-term use of aspirin or other conditions that place them at increased risk for complications from influenza[67, 68]

  • Patients with chronic pulmonary (eg, asthma) or cardiac disorders (except hypertension)

  • Patients with chronic metabolic disease (eg, diabetes), renal dysfunction, hemoglobinopathies, or immunosuppression (eg, human immunodeficiency virus [HIV])

  • Persons who have any condition (eg, cognitive dysfunction, spinal cord injuries, seizure disorders, or other neuromuscular disorders) that may compromise respiratory function or the handling of respiratory secretions or that can increase the risk for aspiration

  • Pregnant women who will be in their second or third trimester during influenza season

  • Household members (eg, children aged < 5 y) of persons at high risk

  • Providers of essential community services (eg, police, fire)

  • International travelers

  • Students and dormitory residents

  • Anyone wishing to reduce risk of influenza

The CDC recommends that the following pediatric groups receive priority for inactivated influenza vaccine:

  • Residents of long-term care facilities

  • Persons aged 2-64 years with comorbid conditions

  • Children aged 6 months to 4 years (59 mo)[67, 68]

  • Women who will be pregnant during the influenza season

  • Household contacts and out-of-home caregivers of children younger than 6 months

Recommendations regarding administration of influenza vaccine include the following:

  • For adults and older children, the recommended site of vaccination is the deltoid muscle

  • The preferred site for infants and young children is the anterolateral aspect of the thigh

  • Influenza vaccine should be administered during the autumn season in the Northern Hemisphere

Children requiring 2 doses

Because of the antigenic novelty of the 2009 (H1N1) pandemic virus children who aged 6 months through 8 years who have not been exposed to this antigen require 2 doses.[68]  If a child requires 2 doses, administer each dose at least 4 weeks apart. Administer 2 influenza doses (separated by at least 4 weeks) to children who are receiving influenza vaccine for the first time or who have not previously received 2 or more doses of trivalent or quadrivalent influenza vaccine in a previous season. Children aged 9 years or older may be immunized with a single dose.

Annual immunization is recommended because of declining immunity during the year after immunization and because, in most years, at least one of the antigens is changed in the vaccine to increase the antigenic similarity between the vaccine and circulating strains. The optimal time for influenza vaccination is usually between October and November.

A 2017 practice guideline from the Influenza Vaccine and Egg Allergy Practice Parameter Workgroup commissioned by Joint Task Force on Practice Parameters recommended that influenza vaccines should be administered to individuals with egg allergy of any severity, just as they would be to individuals without egg allergy.[69]

Maternal immunization during pregnancy has been associated with a lower proportion of infants who were small for gestational age and an increase in mean birth weight.[70]

The CDC recommends influenza vaccine be administered during pregnancy (all trimesters); vaccination during pregnancy has been shown to decrease the risk of illness in the mother, as well as the risk of influenza and influenza hospitalization in their infants during the first 6 months of life.[71]

The CDC recommends influenza vaccine be administered during pregnancy (all trimesters); vaccination during pregnancy has been shown to decrease risk of illness in the mother, as well as the risk of influenza and influenza hospitalization, in their infants during the first 6 months of life.[72]

Avian Influenza Prevention

To curtail a potential pandemic situation, the major goals are early identification of sources of HP avian influenza virus A/H5N1 infection and limiting spread of the virus. Both the WHO and the CDC recommend a high degree of surveillance worldwide to identify outbreaks in poultry and death of migratory birds.[73] Rapid containment processes, such as culling of infected birds, vaccinating nearby at-risk poultry, and vigilance for respiratory illness among personnel in contact with the affected poultry, are also needed.

Simple measures (eg, strict hand hygiene; standard, contact, droplet, and airborne precautions for 21 d) might reduce the spread of the virus.

Pneumococcal vaccination has been suggested as a prophylaxis option, to prevent secondary pneumonia from this pathogen. However, deaths due to avian influenza have been reported even without secondary bacterial infection.

An alert system has been developed for avian influenza depending on the incidence of human cases due to HP avian influenza virus A/H5N1. It ranges from level I-VI.[73] Currently, the alert is set at level III because of a few cases of human-to-human transmission.

The United States and several other countries have developed a preparedness plan for a potential influenza pandemic.[11] The US Secretary of Health and Human Services has developed a multiagency National Influenza Pandemic Preparedness and Response Task Group. This initiative jointly involves the CDC and several other agencies (international, national, state, local, and private) in preparing for a potential pandemic.[74]

Travel recommendations

No recommendations have advocated carrying oseltamivir or zanamivir when traveling to countries where human avian influenza has been reported. However, consulting a local physician if illness develops has been recommended.[74]

Sick or dying poultry should not be consumed because doing so increases the risk of acquiring the virus. Avoiding undercooked poultry and areas where the poultry is sold in the market is prudent. Also avoid raw or undercooked eggs. After exposure to poultry or eggs, wash hands, utensils, and exposed surfaces with soap and water.

If an illness develops with fever, cough, sore throat, or respiratory distress after exposure to poultry in areas where avian influenza has been identified, individuals must contact medical personnel. The history of travel and exposure to poultry must be disclosed prior to contact with the physician.

Avian influenza vaccination

The FDA approved the first vaccine for highly pathogenic (HP) avian influenza H5N1 (ie, avian or bird flu) in April 2007. The approval was based on one multicenter, randomized, double-blind, placebo-controlled, dose-ranging study in healthy adults aged 18-64 years.[75] The trial investigated the safety and immunogenicity of the vaccine. In the study, 45% of 103 healthy adults who received two 90-mcg intramuscular doses of the vaccine 28 days apart had an improved immune response and produced antibody levels expected to reduce the risk of disease. In a subsequent study, a booster given 12 months after the second dose significantly boosted immune responses.[76]

The H5N1 vaccine is not commercially available; it is stockpiled by the federal government to be distributed when necessary.[75]

A vaccine against another avian influenza strain, H9N2, has also been developed. A study of live-attenuated H9N2 vaccine given intranasally to 50 adults (41 were seronegative) showed immunogenicity after 2 doses.[77]

The Society of Hospital Epidemiology of America has published a document recommending universal vaccination of health care workers as a preparedness plan.[78] By enhancing the vaccination rate, viral shedding and transmission can be reduced. This eventually decreases the risk of reassortment.

The challenges faced include manufacturing vaccines in a timely manner, finding appropriate substrates from which to isolate the virus, product safety, efficacy, and acceptance by the approving agency and the public. The HP avian influenza A virus vaccine poses a challenge because the contemporary method of growing the vaccine in the egg may not work because the HP avian influenza A virus can kill the embryonated egg.

Once an outbreak occurs, both the infected individual and contacts require neuraminidase inhibitors. This may necessitate mobilization of neuraminidase inhibitors from nations with stockpiles to regions where an avian outbreak is detected. Although this may not completely inhibit the transmission, the inhibitors may slow it down by decreasing viral shedding.

An effort should be made to enhance seasonal influenza immunization rates.

Consultations

Avian influenza should prompt consultations with the following specialists:

  • Infectious diseases specialist

  • Pulmonologist

  • Critical care specialist

  • Infection control specialist

Complications

According to a prospective cohort study, as many as 1 in 3 children seeking treatment in the ED for influenza-like illnesses (ILI) at the peak of flu season are at high risk of suffering severe complications. Children with neurologic or neuromuscular conditions, like cerebral palsy or muscular dystrophy, are at even greater risk. Of the 241 children (< 19 years) involved in the study, 85 suffered severe complications with 63 experiencing pneumonia, 12 suffering respiratory failure, and 14 suffering seizures. These findings support the use of antiviral therapy.[79]

 

Medication

Medication Summary

Baloxavir marboxil is an oral antiviral which inhibits cap-dependent endonuclease, an enzyme specific to influenza, resulting in inhibition of viral replication. It is indicated for the treatment of influenza in adolescents and adults and adolescents aged 12 years or older. It has shown activity against influenza A and B as well as strains resistant to neuraminidase inhibitors and is dosed in a convenient single PO weight-based dose. Oseltamivir and zanamivir are antiviral neuraminidase inhibitors that are used for chemoprophylaxis and treatment of influenza A and B infection. Oseltamivir is an oral antiviral that is approved for children aged 2 weeks or older for treatment and aged 1 year or older for prophylaxis. Zanamivir is an oral powder that is inhaled. It is approved for children aged 7 years or older for treatment and aged 5 years or older for prophylaxis. It is not recommended for use in children with underlying conditions who may be unable to adequately inhale the drug (eg, asthma, muscular dystrophy). Peramivir is a neuraminidase inhibitor that is administered IV as a single dose in children aged 2 years or older for treatment. Amantadine and rimantadine are older antiviral agents that are no longer recommended by the CDC because of resistance.

Vaccines against seasonal influenza are reformulated annually in order to contain the most recently circulating strains. For the trivalent formulation influenza vaccines, two strains of influenza A and one of influenza B are included. The quadrivalent vaccines contain an additional influenza B strain. The vaccine viruses recommended by the World Health Organization and the CDC for the 2019-2020 Northern Hemisphere influenza season differs from the previous season.[80]

The trivalent 2019-2020 Northern Hemisphere vaccine season, contains the following components:

  • A/Brisbane/02/2018 (H1N1)pdm09-like virus (New for 2019-2020)

  • A/Kansas/14/2017 (H3N2)-like virus (New for 2019-2020) 

  • B/Colorado/06/2017-like virus (B/Victoria/2/87 lineage) (no change from last season)

The quadrivalent influenza vaccines contain the following additional B strain in addition to the 3 viral strains listed above:

  • B/Phuket/3073/2013-like virus (B/Yamagata lineage) (no change from last year)

Antiviral agents

Class Summary

Use of influenza-specific antiviral drugs for chemoprophylaxis or treatment of influenza is an important adjunct to vaccination, particularly for controlling outbreaks in closed populations.

Baloxavir marboxil, a cap-dependent endonuclease inhibitor, is the most recent antiviral approved in the U.S. for treatment of influenza. It has shown activity against influenza A and B as well as strains resistant to neuraminidase inhibitors and is dosed as a single PO weight-based dose.

Zanamivir and oseltamivir are members of a class of drugs termed neuraminidase inhibitors and are active against both influenza virus type A and type B. They are approved for both prophylaxis and treatment of influenza. When used for treatment, these agents should be started as soon as possible after the onset of symptoms, but no later than 2 days after onset.

Oseltamivir (Tamiflu) resistance emerged in the United States during the 2008-2009 influenza season, and the CDC issued revised interim recommendations for antiviral treatment and prophylaxis of influenza. Similarly, during the 2009-2010 novel influenza A H1N1 pandemic, preliminary data from a limited number of states indicated a high prevalence of virus strains resistant to oseltamivir. Because of this, zanamivir was recommended as the initial choice for antiviral prophylaxis or treatment when influenza A infection or exposure was suspected.

A second-line alternative is a combination of oseltamivir plus rimantadine, rather than oseltamivir alone. Local influenza surveillance data and laboratory testing can assist the physician regarding antiviral agent choice.

The neuraminidase inhibitor peramivir, is approved for children aged 2 years or older for treatment of acute uncomplicated influenza. It is administered as a single IV dose infused over 15-30 minutes.

Amantadine and rimantadine are effective against type A influenza virus only. They are approved by the US Food and Drug Administration (FDA) for prophylaxis of influenza type A in patients older than 1 year. Amantadine is also FDA-approved for treatment in children.

Since the 2005-2006 influenza season, amantadine and rimantadine are no longer recommended by the Centers for Disease Control and Prevention (CDC) because circulating strains of influenza virus have proved resistant.

Baloxavir marboxil (Xofluza)

Baloxavir marboxil is a prodrug that is metabolized to baloxavir. It inhibits cap-dependent endonuclease, an enzyme specific to influenza, resulting in inhibition of viral replication. It is indicated as a single, oral, weight-based dose for treatment of acute uncomplicated influenza in adults and adolescents aged 12 years or older who have been symptomatic for less than 48 hours.

Oseltamivir (Tamiflu)

Oseltamivir is an inhibitor of neuraminidase, which is a glycoprotein on the surface of the influenza virus that destroys the infected cell's receptor for viral hemagglutinin. By inhibiting viral neuraminidase, release of viruses from infected cells and viral spread are decreased. Oseltamivir is effective against influenza virus types A and B.

Oseltamivir is approved for use in children older than 1 year, for prevention of influenza following exposure. It is approved for treatment of influenza A or B in children aged 2 weeks or older who have been symptomatic for no more than 2 days. It is available as capsules and as an oral suspension. During the 2009-2010 novel influenza A (H1N1) pandemic, the CDC issued an emergency use authorization for oseltamivir prophylaxis in patients younger than 1 year.

As resistance to oseltamivir may occur, physicians should maintain awareness of current CDC recommendations for antiviral treatment and prophylaxis of influenza. In addition, local influenza surveillance data and laboratory testing can assist the physician regarding antiviral agent choice. A second-line alternative is a combination of oseltamivir plus rimantadine, rather than oseltamivir alone.

Zanamivir (Relenza)

Zanamivir is an inhibitor of neuraminidase, which is a glycoprotein on the surface of the influenza virus that destroys the infected cell's receptor for viral hemagglutinin. By inhibiting viral neuraminidase, release of viruses from infected cells and viral spread are decreased. Zanamivir is effective against both influenza types A and B.

Zanamivir is approved for the treatment of uncomplicated acute influenza A or B in persons aged 7 years and older who have been symptomatic for no more than 2 days, and for prophylaxis of influenza in adults and pediatric patients aged 5 years and older. This agent is inhaled through a Diskhaler PO inhalation device. Circular foil disks containing 5-mg blisters of drug are inserted into a supplied inhalation device.

Peramivir (Rapivab)

Inhibitor of influenza virus neuraminidase, an enzyme that releases viral particles from the plasma membrane of infected cells. Indicated for treatment of acute uncomplicated influenza in patients aged 2 years or older who have been symptomatic for <2 days.

Vaccines

Class Summary

These agents elicit active immunization to increase resistance to infection. Vaccines consist of microorganisms or cellular components, which act as antigens. Administration of the vaccine stimulates the production of antibodies with specific protective properties.

Current seasonal influenza vaccines provide no protection against human infection with highly pathogenic avian influenza type A viruses, including H5N1. However, reducing seasonal influenza risk through influenza vaccination of persons who might be exposed to nonhuman influenza viruses (eg, H5N1 viruses) might reduce the theoretical risk for recombination of an avian influenza type A virus and human influenza type A virus by preventing seasonal influenza virus infection within a human host. The CDC has recommended that persons who are charged with responding to avian influenza outbreaks among poultry receive seasonal influenza vaccination.

Influenza virus vaccine trivalent (Fluzone, Afluria, Fluarix, Fluvirin)

Influenza vaccine is indicated for active immunization to prevent infection from influenza A and B viruses. The vaccine induces antibodies specific to virus strains contained in the vaccine. The US Public Health Service determines influenza vaccine contents annually. Typically, 3 live attenuated virus strains, which antigenically represent the influenza strains likely to circulate the next flu season, are included in the formulation each year. Fluzone is approved for children as young as 6 months, Fluarix for children aged 3 years or older, Fluvirin for children aged 4 years or older, and Afluria for children aged 5 years or older.

Influenza virus vaccine quadrivalent (Afluria Quadrivalent, Fluarix Quadrivalent, Fluzone Quadrivalent, FluLaval Quadrivalent)

Quadrivalent vaccines contain two strains of influenza A and two of influenza B. The vaccine induces antibodies specific to virus strains contained in vaccine. Each year, the US Public Health Service determines which viral strains will be included in the seasonal influenza vaccine that will antigenically represent the viral strains most likely to circulate in the next flu season. It is administered as an IM injection. Afluria, Fluzone, FluLaval, and Fluarix Quadrivalent vaccines are approved for children aged 6 months or older. Flucelvax Quadrivalent is approved for children aged 4 y or older.

Influenza virus vaccine quadrivalent, intranasal (FluMist Quadrivalent)

The Advisory Committee on Immunization Practices (ACIP) recommends return of intranasal flu vaccine in the U.S. for 2018-2019 season. The recommendation was based on positive results from a U.S. study in children between the ages of 2 to <4 years evaluating the shedding and antibody responses of the H1N1 strain in the live attenuated influenza vaccine (LAIV).

Influenza virus vaccine (H5N1)

The H5N1 inactivated virus vaccine induces antibodies against viral hemagglutinin, thereby blocking viral attachment to human respiratory tract epithelial cells. The vaccine is estimated to reduce the risk of contracting avian influenza by 45%. This vaccine is indicated for active immunization of adults at increased risk of exposure to the H5N1 influenza virus subtype.