Influenza (Seasonal)

Flu

Clinical Description

Identification

An acute viral disease of the respiratory tract characterized by fever, cough (usually dry), headache, myalgia, prostration, coryza, and sore throat. Cough is often severe and can last 2 or more weeks; fever and other symptoms generally resolve in 5–7 days. In temperate climates, recognition is commonly based on clinical presentation during winter months with a syndrome consistent with influenza. Diagnosis improves when influenza surveillance information is available to indicate influenza viruses are in circulation. Influenza may be clinically indistinguishable from disease caused by other respiratory viruses, such as rhinovirus, RSV, parainfluenza, adenovirus and other pathogens. Syndromes consistent with influenza include acute upper respiratory illness, croup, bronchiolitis, febrile seizures, and pneumonia. In children, GI tract manifestations (nausea, vomiting, diarrhea) may accompany the respiratory phase, and have been reported in up to 25% of children in school outbreaks of influenza B and A (H1N1). GI manifestations are uncommon in adults. Infants may present with a sepsis-like syndrome. Older adults with influenza can present with worsening of underlying conditions such as congestive heart failure, and may not have an elevated temperature.

Point-of-care rapid testing is increasingly available to assist with diagnosis. Such tests are useful especially in rapidly establishing influenza as the basis for out-of-season outbreaks or outbreaks in remote areas where specimen transportation takes time. Such information can enable timely implementation of control measures. Commercially available point-of-care tests are generally 70% or less sensitive, but approximately 95% specific. Thus, particularly in the setting of a known influenza epidemic, negative results from patients with symptoms consistent with influenza must be interpreted cautiously. If excluding a false-negative result is important, then more sensitive testing should be considered, including viral culture and RT-PCR testing.

Yearly seasonal influenza epidemics impose a substantial health burden on all age groups, but the highest risk of complications occur among children less than 2 years, adults older than 64 years, and persons of any age with certain medical conditions, including chronic cardiovascular, pulmonary, renal, hepatic, hematologic or metabolic disorders (e.g. diabetes); immunosuppression; pregnancy; and neurologic/neuromuscular conditions that can compromise respiratory function or handling of respiratory secretions. Secondary complications of influenza include bacterial pneumonia, including co-infection with MRSA and S. pneumonia; viral pneumonia; worsening of underlying conditions; sinusitis; otitis media; febrile seizures; encephalitis/encephalopathy; myositis; and Reye syndrome in association with use of salicylates. Although seasonal influenza deaths can occur in any age group, over 90% of influenza deaths occur among those aged 65 years and older. Annual epidemics of influenza can be explosive and overwhelm health care services.

Most studies of the epidemiology of influenza have been conducted in developed countries in temperate climates, but more information is now being obtained from developing and tropical countries that have found higher risk of influenza complications and death among children less than 5 years, the elderly, and those with chronic diseases. Reports of influenza outbreak investigations in Africa and Indonesia suggest malnutrition and poor access to health care are likely to contribute to higher rates of complications and death.

Infectious Agents

Three types of seasonal influenza virus are recognized: A, B and C. The antigenic properties of the two relatively stable internal structural proteins, the nucleoprotein and the matrix protein, determine virus type. Influenza A viruses are further divided into subtypes based on two viral surface glycoproteins: the hemagglutinin (H) and the neuraminidase (N). There are 16 different hemagglutinin subtypes and 9 different neuraminidase subtypes. The current subtypes of influenza A viruses circulating widely among humans are A (H1N1) and A (H3N2). Aquatic birds are the primary reservoir for influenza A viruses and all subtypes of influenza A have been found among birds. Influenza A viruses also circulate among other animals, including pigs, horses, seals, and other animals. Influenza B viruses are not divided into subtypes, but two antigenically distinct lineages of B viruses currently circulate among humans. Humans are the primary reservoir for influenza B. Both influenza A and B viruses can be further classified into strains, and can cause seasonal outbreaks of influenza. Only the emergence and spread of influenza A viruses bearing an H or H/N combination to which most persons have never been exposed are known to cause pandemics. Type C influenza is associated with sporadic cases and minor localized outbreaks and imposes much less of a disease burden than influenza A and B. Only influenza A and influenza B viruses are included in seasonal influenza vaccines.

Levels of antibody against the hemagglutinin are the most important predictor of protection against infection by human influenza viruses. Antibody against the neuraminidase can reduce the severity of illness. Genes encoding these surface glycoproteins are constantly changing through mutations, a process termed “drift” that occurs during virus replication. The constant emergence of new influenza strains through drift requires the annual review and periodic replacement of vaccine strains. Usually, one or more strains are replaced in each year's vaccine. The constant emergence of new strains is the virologic basis for yearly epidemics of seasonal influenza and one of the main reasons why multiple influenza infections can occur in an individual over their lifetime. Influenza virus strains are named based on their type, geographic site of isolation, laboratory number, year of isolation, and subtype (for A viruses only). Examples are A/New Caledonia/20/99(H1N1); A/Brisbane/10/2007 (H3N2); and B/Malaysia/2506/2004.


Diagnosis

Laboratory confirmation of influenza infection can be done by isolation of viruses from throat, nasal, and nasopharyngeal secretions or tracheal aspirate or washings using cell culture or in embryonated eggs; direct identification of viral antigens in nasopharyngeal cells and fluids (FA test or ELISA); rapid diagnostic tests; or viral RNA amplification. Demonstration of a 4-fold or greater rise in specific antibody titer between acute and convalescent sera can also be used to confirm acute infection. Single serological specimens cannot be used to diagnose an acute infection. Ideally, respiratory specimens should be collected as early in the illness as possible. Virus shedding starts to wane by the 3rd day of symptoms, and in most cases virus is not detected after 5 days in adults, though virus shedding can occur longer in children.


Epidemiology

Mode of Transmission

The relative contribution of large droplet, droplet nuclei (i.e. airborne spread), and contact transmission (direct and indirect) in the spread of seasonal influenza is unknown, although large droplet spread is believed to be the primary means of transmission, through coughing and sneezing by infected persons. Human influenza virus may persist for hours on solid surfaces, particularly in lower temperatures and lower humidity.

Incubation Period

Average 2 days (range 1–4) for seasonal influenza.

Period of Communicability

In adults, viral shedding and probable communicability is greatest in the first 3–5 days of illness. In young children, virus shedding can occur for longer, 7–10 days, and may be even longer in severely immunocompromised persons.

Reservoir

Humans are normally infected by human influenza viruses (H3N2, H1N1 and B), and form the primary reservoir for these human viruses. With some notable exceptions, seasonal influenza usually is not a zoonotic disease.

Susceptibility

The size and relative impact of epidemics and pandemics depend upon several factors, including natural or vaccine-induced levels of protective immunity in the population, the age and condition of the population, strain virulence, and the extent of antigenic variation of new viruses. Infection induces immunity to the infecting virus and antigenically similar viruses. The duration and breadth of immunity depend, in part, upon the degree of antigenic similarity between viruses causing immunity and those causing disease. During seasonal epidemics, much of the population has partial protection, because of earlier infections from related viruses. Vaccines produce serological responses specific for the influenza vaccine virus strains, but can also provide cross-protection against related strains.

Age-specific attack rates during seasonal influenza epidemics reflect persisting immunity from past experience with variant viruses related to the epidemic subtype, so that the incidence of infection is often highest in children who have fewer prior influenza infections and less pre-existing antibody.

Occurrence

Seasonal influenza results in yearly epidemics of varying severity, with sporadic cases or outbreaks of human disease occurring outside of typical seasonal patterns, and, rarely, as a pandemic. Clinical attack rates during annual epidemics can range from 5% to 20% in the general community to more than 50% in closed populations (e.g. nursing homes, schools). During yearly epidemics in industrialized countries, influenza illness often appears earliest among school-age children. The highest illness rates generally occur in children, with accompanying increases in school absences, physician visits, and pediatric hospital admissions. Influenza illness among adults is associated with increases in workplace absenteeism, adult hospital admissions, and mortality, especially among the elderly. In North America, epidemics generally last from 8–10 weeks. One or more strains, subtypes and/or types of influenza can circulate within a single influenza season in the same area. In temperate zones, epidemics tend to occur in winter months. In some tropical countries, influenza can occur year-round with 2 peaks per year consistent with peak activity in Northern and Southern Hemisphere temperate zones, and/or peaks during the rainy season.


Prevention and Control

1)    Preventive measures

a)    Educate the public and health care personnel in basic personal hygiene, including hand hygiene and cough etiquette, and especially transmission via unprotected coughs and sneezes, and from hand to mucous membranes.


b)    Immunization with available inactivated influenza vaccines (IIV) and live virus vaccines may provide 70%–90% protection against infection in healthy young adults when the vaccine antigen closely matches the circulating strains of virus. Live attenuated influenza vaccines (LAIV), used in Russia for many years, are now also licensed in other industrialized countries for intranasal application in healthy individuals aged 2–49. In the elderly, although immunization may be less effective in preventing illness, inactivated vaccines may reduce severity of disease and incidence of complications by 50%–60%, and deaths by approximately 80%. Influenza immunization should preferably be coupled with immunization against pneumococcal pneumonia for groups recommended to receive both vaccines.

A single dose suffices for those with prior exposures to influenza A and B viruses; 2 doses at least 4 weeks apart are essential for children less than 9 years old who have not previously been vaccinated against influenza. Routine immunization programs should focus efforts on vaccinating those at greatest risk of serious complications or death from influenza (see Identification, above) and those who might spread influenza (health care personnel and household contacts of high-risk persons) to high-risk persons. Immunization of children on long-term aspirin treatment is also recommended to prevent development of Reye syndrome after influenza infection.

The vaccine should be given each year before influenza is expected in the community; the timing of immunization should be based on a country's seasonal patterns of influenza circulation (i.e. winter months in temperate zones, often rainy season in tropical regions). Biannual recommendations for vaccine strain are based on the viral strains currently circulating, as determined by WHO through global surveillance.

Contraindications: Allergic hypersensitivity to egg protein or other vaccine components is a contraindication. During the swine influenza vaccine program in 1976, the USA reported an increased risk of developing Guillain-Barré syndrome (GBS) within 6 weeks after vaccination. Subsequent vaccines produced from other virus strains in other years have not been clearly associated with an increased risk of GBS. However, prior GBS is a contraindication for receiving an LAIV. The development of GBS within the 6 weeks following a dose of IIV is considered a precaution for future IIV use.

c)    There are two classes of antiviral agents that are available for prophylaxis and treatment of influenza infections. Antiviral agents are supplemental to vaccine when immediate maximal protection is desired. The use of antiviral agents should be considered in persons at high risk for complications due to influenza, persons hospitalized with influenza, and during facility outbreaks. Antiviral agents are effective at reducing inter-facility transmission during outbreaks, such as among residents of nursing homes for the elderly. The drugs will not interfere with the response to inactivated influenza vaccine, and should ideally be continued throughout the period of likely exposure to influenza. However, antivirals ideally should not be administered for 2 weeks after receipt of LAIV, and should be stopped for 2 days prior to LAIV vaccination. Treatment with antiviral agents within 48 hours of influenza symptom onset reduces the duration and severity of symptoms, and may reduce complications and deaths associated with influenza infections.

Inhibitors of influenza neuraminidase (oseltamivir and zanamivir) have been shown to be safe and effective for both prophylaxis and treatment of influenza A and B. Oseltamivir is an orally administered medicine; zanamivir is a powder administered via an inhaler. Oseltamivir may be used for persons 1 year and zanamivir is approved for treatment of persons 7 years and for prophylaxis for persons 5 years. Dosing is twice a day for 5 days for treatment and once a day for prophylaxis, with dosing for oseltamivir adjusted by body weight for children. Post-exposure prophylaxis should be continued for 7–10 days after a known exposure to influenza; however, prophylaxis used to prevent exposures throughout an influenza season would extend through the season. Few data, however, are available on the use of antiviral prophylaxis for more than 6 weeks. Reports of resistance to neuraminidase inhibitors have been rare until recently. In 2008, a significant increase in the number of oseltamivir-resistant influenza A (H1N1) viruses was detected in many countries. The proportion of viruses resistant to oseltamivir was variable among countries, and studies to characterize transmission and illness due to these viruses are underway. Resistance to zanamivir is rare. Serious cases of bronchospasm have been reported with zanamivir use in patients with and without underlying airways disease. Zanamivir use should be avoided in patients with underlying lung disease or reactive airway disease.

The adamantanes, amantadine and rimantadine, are effective for prophylaxis and treatment of influenza type A infection, but not influenza type B. Both adamantane agents may be used in persons 1 year of age. During treatment, 15–30% of patients develop resistance to adamantanes and resistant viruses are fully transmissible. Globally, adamantane resistance among influenza type A viruses is high. Therefore, routine use of adamantanes is not recommended. CNS side-effects are reported in 5%–10% of recipients of amantadine, and may be more severe in the elderly or those with impaired kidney function—the latter should receive reduced dosages that reflect the degree of renal impairment. Fewer CNS side effects have been reported with rimantadine use compared with amantadine.


2)    Control of patient, contacts and the immediate environment:

a)    Report to local health authority: Reporting outbreaks or laboratory-confirmed cases assists disease surveillance. Report identity of the infectious agent as determined by laboratory testing if possible, Class 1. Untypable or new subtypes of influenza infections should be further tested by qualified laboratories, and public health authorities should be rapidly notified.

b)    Isolation: Ideally, all persons admitted to a hospital with a respiratory illness, including suspected influenza, should be placed in single patient rooms or, if this is not possible, placed in a room with patients with similar illness (cohorting). When cohorting is used, adequate spacing between beds should be provided for droplet precautions. For influenza, isolation should continue for the initial 5–7 days of illness, and possibly longer for patients who are severely immunocompromised who may be infectious for longer periods. Both standard and droplet precautions are recommended.

c)    Concurrent disinfection: Not applicable for seasonal influenza.

d)    Quarantine: Not applicable for seasonal influenza.

e)    Protection of contacts: A specific role has been shown for antiviral chemoprophylaxis. Clinicians should take local antiviral susceptibility information into account when prescribing antivirals.

f)    Investigation of contacts and source of infection: Of no practical value during annual seasonal influenza epidemics.

g)    Specific treatment: Antiviral agents begun within 48 hours of symptom onset reduce illness duration and may reduce complications associated with influenza.

Patients should be watched for bacterial complications, including co-infection with MRSA, and antibiotics prescribed accordingly. Because of the association with Reye syndrome, avoid salicylates in children with suspected influenza infection.

3)    Epidemic measures:

a)    The severe and often disruptive effects of epidemic seasonal influenza on community activities may be reduced in part by effective health planning and education, particularly locally organized immunization programs for high-risk patients, their close contacts, and health care providers. Community surveillance for influenza, use of outbreak control measures, adherence to infection control recommendations, and reporting of surveillance and outbreak findings to the community are all important.

b)    Closure of individual schools has not been proven to be an effective measure to reduce the impact of seasonal influenza in a community, possibly because such measures are generally applied late in the course of an epidemic, due to high staff and student absenteeism rather than as an outbreak control measure.

c)    Hospital administrators should anticipate increased demand for medical care during epidemic periods and possible absenteeism of health care personnel as a result of influenza. Health care personnel should be immunized annually to minimize absenteeism and transmission of seasonal influenza from health care personnel to patients.

d)    Maintaining adequate supplies of appropriate antiviral drugs would be desirable to treat high-risk patients, persons hospitalized with influenza, and essential personnel in the event of the emergence of a new pandemic strain for which no suitable vaccine is available in time for the initial wave.

4)    Disaster implications:

Aggregations of people in emergency shelters will favor outbreaks of influenza if the virus is introduced.

5)    International measures:

A disease under surveillance by WHO. The following are recommended:

a)    Report regularly on epidemiological situations within each given country to WHO/GISN (http://www.who.int/flunet).

b)    Respiratory specimens, throat and nasal swabs, nasopharyngeal swabs or aspirates, and paired blood samples may be sent to any WHO-recognized National Influenza Center (http://www.who.int/csr/disease/influenza/centres/en/index.html). Identify the causative virus in reports, and submit prototype strains to one of the WHO Centers for Reference and Research on Influenza in Atlanta, London, Melbourne or Tokyo (http://www.who.int/influenza).

c)    Conduct epidemiological studies; promptly identify and report viruses to national and international health agencies.

d)    Ensure sufficient commercial and/or governmental facilities to provide rapid production of adequate quantities of vaccine and antiviral drugs, and maintain programs for vaccine and antiviral drug administration to high-risk persons and essential personnel.

Source: Heymann (Ed.). (2008). Control of Communicable Diseases Manual, 19th edition. Washington, DC: American Public Health Association.


Available Vaccines

WHO-Prequalified seasonal influenza vaccines

 

Common Disease Taxonomy: