Etiology

Influenza viruses are members of the family Orthomyxoviridae. They are large, single-stranded RNA viruses with a segmented genome encased in a lipid-containing envelope. The 2 major surface proteins that determine the serotype of influenza, hemagglutinin (HA) and neuraminidase (NA), project as spikes through the envelope. Influenza viruses are divided into three types: A, B, and C. Influenza virus types A and B are the primary human pathogens and cause epidemic disease. Influenza virus type C is a sporadic cause of predominantly upper respiratory tract disease. Influenza virus types A and B are further divided into serotypically distinct strains that circulate on a yearly basis through the population.

Epidemiology

Influenza A viruses have a complex epidemiology involving avian and mammalian hosts that serve as reservoirs for diverse strains with the potential for infecting the human population. The segmented nature of the influenza genome allows reassortment to occur between an animal virus and a human virus when co-infection occurs. Thus, potentially any of 15 HAs and 9 NAs residing in animal reservoirs may be introduced into humans; these influenza A viruses behave epidemiologically as though they were immunologically distinct serotypes without apparent cross-protection. Minor changes within a serotype are termed antigenic drift; major changes in serotype are termed antigenic shift. Migratory birds can spread disease, as illustrated by H5N1 avian influenza. The introduction of novel HA strains has occurred in the Far East with H5N1 and H9N2 viruses, in the Netherlands with H7N7 virus, and in Mexico with the 2009 novel swine-origin H1N1 virus.

The highly virulent avian H5N1 influenza virus remains a potential threat to spread more broadly in the human population. By mid 2009, >400 cases had been documented. It has demonstrated major virulence, with mortality consistently >50% in humans in direct contact with infected poultry, although it has not yet acquired the ability to spread readily from person to person.

The novel H1N1 virus emerged in Mexico in the spring of 2009 and circulated widely enough that by June of 2009 it was declared a global pandemic. In the fall of 2009 it circulated throughout the USA, generally producing mild disease but occasionally resulting in death, especially in pregnant women and in patients with underlying disease. Influenza B virus has much less capacity for major antigenic change and no identified animal reservoir.

The worldwide epidemiology of influenza viruses demonstrates annual spread between the Northern and Southern hemispheres, with the origins of new strains often traced to Asia. When a virus identified by a novel and serologically distinct HA or NA enters the population, there is potential for a pandemic of influenza with excess morbidity and mortality on a global scale in a largely nonimmune population. The most dramatic pandemic in recorded history occurred in 1918, when influenza was estimated to have killed >20 million people. More common is the almost yearly variation in the antigenic composition of the surface proteins, conferring a selective advantage to a new strain and resulting in localized epidemics of disease with hospitalization and mortality greatest in infants, the elderly, and patients with underlying cardiopulmonary disease. Each year’s strain is novel for infants, because they have no pre-existing antibody except for maternally transferred antibody in the first few months of life.

The attack rate and frequency of isolation of influenza are highest in young children. In a typical year as many as 30-50% of children have serologic evidence of infection. Influenza is marked by increased school absenteeism and a yearly peak in sick visits to the pediatrician. Children undergoing primary exposure to an influenza strain have higher levels and more prolonged shedding of the virus than adults, making the former extremely effective transmitters of infection. Influenza is a disease of the colder months of the year in temperate climates. Spread of influenza appears to occur by small-particle aerosol, and transmission through a community is rapid, with the highest incidence of illness occurring within 2-3 wk of introduction. Influenza has been implicated in hospital spread of infection and may complicate the original illness that required hospitalization.

On a country or global basis, 1 or 2 predominant strains spread to create the annual epidemic. Until 2009, influenza type A strains with the H1N1 and H3N2 serotypes and type B strains were co-circulating, and either type could predominate in a given year, making predictions about the serotype and severity of the upcoming influenza season difficult. It is not clear whether the novel H1N1 strain will alter this pattern.

Strain variants are identified by their HA and NA serotypes, by the geographic area from which they were originally isolated, by their isolate number, and by year of isolation. Thus, the seasonal influenza vaccine for 2009-2010 was trivalent, containing A/Brisbane/59/2007 (H1N1)–like, A/Brisbane/10/2007 (H3N2)–like, and B/Brisbane 60/2008–like antigens.

Pathogenesis

Influenza virus attaches to sialic acid residues on cells via the HA and, by endocytosis, makes its way into vacuoles, where with progressive acidification there is fusion to the endosomal membrane and release of the viral RNA into the cytoplasm. The RNA is transported to the nucleus and transcribed. Newly synthesized RNA is returned to the cytoplasm and translated into proteins, which are transported to the cell membrane. Subsequently, viral assembly and budding through the cell membrane take place. In a manner that is not well understood, the packaging usually incorporates the appropriate 10 segments of the genome. A host cell–mediated proteolytic cleavage of the HA occurs at some point in the assembly or release of the virus, which is essential for successful fusion and release from the endosome and amplification of virus titer. In humans, the influenza virus replicative cycle is confined to the respiratory epithelium. With primary infection, virus replication continues for 10-14 days.

Influenza virus causes a lytic infection of the respiratory epithelium with loss of ciliary function, decreased mucus production, and desquamation of the epithelial layer. These changes permit secondary bacterial invasion, either directly through the epithelium or, in the case of the middle ear space, through obstruction of the normal drainage through the eustachian tube. Influenza types A and B have been reported to cause myocarditis, and influenza type B can cause myositis. Reye syndrome can result with the use of salicylates during influenza type B infection (Chapter 353).

The exact immune mechanisms involved in termination of primary infection and protection against re-infection are not well understood but may correspond to the induction of cytokines that inhibit viral replication, such as interferon and tumor necrosis factor. The incubation period of influenza can be as short as 48-72 hr. The extremely short incubation period of influenza and the growth of influenza virus on the mucosal surface pose particular problems for invoking an adaptive immune response. Antigen presentation occurs primarily at mucosal sites acting through the bronchial tract–associated lymphoid tract. The most easily detected humoral response is directed against the HA. High serum antibody levels inhibiting HA activity are generated by inactivated vaccine and correlate with protection. Mucosally produced immunoglobulin A (IgA) antibodies are thought to be the most effective and immediate protective response generated during influenza infection. Unfortunately, detectable IgA antibodies against influenza virus persist for a relatively short period. Because of the short duration of appreciable IgA as well as strain variation, symptomatic re-infection with influenza virus can be seen at intervals of 3-4 yr. Although heterotypic immunity can be demonstrated in the mouse through cell-mediated immune mechanisms directed toward common internal proteins, heterotypic immunity has been more difficult to show in humans.

Clinical Manifestations

Influenza types A and B cause predominantly respiratory illness. The onset of illness is abrupt and is dominated by fever, myalgias, chills, headache, malaise, and anorexia; coryza, pharyngitis, and dry cough are associated features overshadowed by the other systemic signs (Table 250-1). The predominant symptoms may localize anywhere in the respiratory tract, producing an isolated upper respiratory tract illness, croup, bronchiolitis, or pneumonia. More than any other respiratory virus, influenza virus causes systemic signs such as high temperature, myalgia, malaise, and headache. Many of these signs and symptoms may be mediated through cytokine production by the respiratory tract epithelium, because there is no systemic spread of the virus. The typical duration of the febrile illness is 2-4 days. Cough may persist for longer periods, and evidence of small airway dysfunction is often found weeks later.

Table 250-1 RELATIVE FREQUENCY OF SYMPTOMS AND SIGNS DURING CLASSIC INFLUENZA IN OLDER CHILDREN AND ADOLESCENTS

++++, 76-100%; +++, 51-75%; ++, 26-50%; +, 1-25%.

Owing to the high transmissibility of influenza, other family members or close contacts of an infected person often experience a similar illness. Influenza is a less distinct illness in younger children and infants. The infected young infant or child may be highly febrile and toxic in appearance, prompting a full diagnostic work-up. Despite some distinctive features of influenza, the illness it causes is often indistinguishable from that caused by other respiratory viruses, such as respiratory syncytial virus, parainfluenza virus, and adenovirus.

Laboratory Findings

The clinical laboratory abnormalities associated with influenza are nonspecific. Relative leukopenia is frequently seen. Chest radiographs show evidence of atelectasis or infiltrate in about 10% of children.

Diagnosis and Differential Diagnosis

The diagnosis of influenza depends on epidemiologic, clinical, and laboratory considerations. In the context of an epidemic, the clinical diagnosis of influenza in a young child who has fever without a focus, malaise, and respiratory symptoms can be made with some certainty. The laboratory confirmation of influenza can be made in the following 4 ways:

Treatment

Two classes of antiviral drugs may be effective in the treatment of influenza. Guidelines for the use of the neuraminidase inhibitors zanamivir and oseltamivir against the novel H1N1 virus include use for children from the ages of 7 yr and 1 yr, respectively (Table 250-2). These drugs are given either as an inhalation (zanamivir) or orally (oseltamivir). Their effectiveness can be strain specific, as exemplified by the current seasonal H1N1 virus, which is resistant to oseltamivir but sensitive to zanamivir. Oseltamivir is not approved for use in children younger than 1 yr. Limited safety data on oseltamivir treatment of seasonal influenza in children younger than 1 yr suggest that severe adverse events are rare. Oseltamivir is authorized for emergency use in children younger than 1 yr by the U.S. Food and Drug Administration (Table 250-3).

Table 250-2 ANTIVIRAL MEDICATION DOSING RECOMMENDATIONS FOR TREATMENT OR CHEMOPROPHYLAXIS OF 2009 H1N1 INFECTION*

* Published as Updated interim recommendations for the use of antiviral medications in the treatment and prevention of influenza for the 2009-2010 season October 16, 2009; available at www.cdc.gov/h1n1flu/recommendations.htm. For current details, consult annually updated recommendations from the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention, at www.cdc.gov/flu/.

Table 250-3 OSELTAMIVIR DOSING RECOMMENDATIONS FOR ANTIVIRAL TREATMENT OR CHEMOPROPHYLAXIS IN CHILDREN <1 YR*

* Published as Updated interim recommendations for the use of antiviral medications in the treatment and prevention of influenza for the 2009-2010 season October 16, 2009; available at www.cdc.gov/h1n1flu/recommendations.htm. For current details, consult annually updated recommendations from the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention, at www.cdc.gov/flu/.

The 2nd class of drugs includes amantadine and rimantadine, which can be used in influenza type A outbreaks. These 2 antivirals are not effective against influenza type B strains and are not approved for use in children <1 yr of age. The H5 avian influenza virus is often resistant to amantadine and rimantadine. The novel H1N1 strain and the current seasonal H3N2 viruses are also resistant. It is important to review annual recommendations and updates published by the Centers for Disease Control and Prevention (CDC) before prescribing influenza antivirals.

Each class of drug must be given within the 1st 48 hr of symptoms to decrease the severity and duration of influenza. Confusion and inability to concentrate or sleep are seen in some patients given amantadine. Drug resistance can develop fairly quickly during a course of amantadine or rimantadine therapy. All of these drugs are only an adjunct to a strong vaccination program. The family setting and schoolroom may be appropriate places to try to prevent secondary illness by drug treatment, particularly when exposed individuals have underlying conditions that predispose them to severe or complicated influenza infection.

Supportive Care

Adequate fluid intake and rest are important components in the management of influenza. Acetaminophen or ibuprofen (but not salicylates because of the risk for Reye syndrome; Chapter 353) should be used as antipyretics to control fever. The most difficult question for parents is the appropriate timing of consultation with a health care provider. Bacterial superinfections are relatively common, and when they occur, antibiotic therapy should be administered. Bacterial superinfections should be suspected with recrudescence of fever, prolonged fever, or deterioration in clinical status. With uncomplicated influenza, children should feel better after the 1st 48-72 hr of symptoms.

Complications

Otitis media and pneumonia are common complications of influenza in young children. Acute otitis media may be seen in up to 25% of cases of documented influenza. Pneumonia accompanying influenza may be a primary viral process. An acute hemorrhagic pneumonia may be seen in the most severe cases, as was frequent with the highly virulent strain seen in 1918 and as has been seen in patients with the current H5 avian influenza. The more common cause of pneumonia is probably secondary bacterial infection through the damaged epithelial layer. Unusual clinical manifestations of influenza include acute myositis seen with influenza type B, which follows the acute respiratory illness by 5-7 days and is marked by muscle weakness and pain, particularly in the calf muscles, and myoglobinuria. Myocarditis also follows influenza, and toxic shock syndrome can be associated with toxin-producing staphylococcal colonization. Influenza is particularly severe in children with underlying cardiopulmonary disease, including congenital and acquired valvular disease, cardiomyopathy, bronchopulmonary dysplasia, asthma, cystic fibrosis, and neuromuscular diseases affecting the accessory muscles of breathing. Pregnant women are at special risk for severe influenza. Virus is shed for longer periods in children receiving cancer chemotherapy and children with immunodeficiency.

Prognosis

The prognosis for recovery from influenza is excellent, although full return to normal levels of activity and freedom from cough usually require weeks rather than days.

Prevention

Influenza vaccination of targeted populations is the best means of preventing severe disease due to influenza. Recommendations for use of influenza vaccine have become progressively broader as the impact of influenza is appreciated in such groups as pregnant women and young children. Chemoprophylaxis with the drugs discussed in the treatment section is a secondary means of prevention.

Chemoprophylaxis

Amantadine, oseltamivir, and zanamivir are licensed for prophylaxis of influenza A infections (see Table 250-2). These agents are recommended as a 10-day course for prophylaxis for vaccinated and unvaccinated high-risk patients and their unvaccinated health care providers during influenza A outbreaks in closed settings, for unvaccinated persons and health care providers during community influenza A outbreaks, and for immunodeficient persons and those for whom the influenza vaccine is contraindicated during the period of peak influenza A activity.