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—An acute viral disease of the respiratory tract
characterized by fever, headache, myalgia, prostration, coryza, sore throatand cough. Cough is often severe and protracted; other manifestations areself-limited in most patients, with recovery in 2–7 days. Recognition iscommonly by epidemiological characteristics (current quick tests lacksensitivity); only laboratory procedures can reliably identify sporadiccases. Influenza may be clinically indistinguishable from disease caused byother respiratory viruses, such as common cold, croup, bronchiolitis, viralpneumonia and undifferentiated acute respiratory disease. GI tract mani-festations (nausea, vomiting, diarrhea) are uncommon, but may accom-pany the respiratory phase in children, and have been reported in up to25% of children in school outbreaks of influenza B and A (H1N1).
Influenza derives its importance from the rapidity with which epidemics
evolve, the widespread morbidity and the seriousness of complications,notably viral and bacterial pneumonias. In addition, emergence amonghumans of influenza viruses with new surface proteins can cause pandem-ics ranking as global health emergencies (e.g. 1918, 1957, 1968) withmillions of deaths (c40 million in 1918). Severe illness and death duringannual influenza epidemics occur primarily among the elderly and thosedebilitated by chronic cardiac, pulmonary, renal or metabolic disease,anemia or immunosuppression. The proportion of total deaths associatedwith pneumonia and influenza in excess of that expected for the time ofyear (excess mortality) varies and depends on the prevalent virus type.
The annual global death toll is estimated to reach up to 1 million. In mostepidemics, 80%–90% of deaths occur in persons over 65; in the 1918pandemic, young adults showed the highest mortality rates. Reye syn-drome, involving the CNS and liver, is a rare complication following virusinfections in children who have ingested salicylates.
While the epidemiology of influenza is well understood in industrialized
countries, information on influenza in developing countries is minimal.
During the early febrile stage, laboratory confirmation is through
isolation of influenza viruses from pharyngeal or nasal secretions orwashings on cell culture or in embryonated eggs; direct identification ofviral antigens in nasopharyngeal cells and fluids (FA test or ELISA); rapiddiagnostic tests (these differ in the influenza viruses they detect); or viralRNA amplification. Demonstration of a specific serological responsebetween acute and convalescent sera may also confirm infection.
2. Infectious agents
—Three types of influenza virus are recognized:
A, B and C. Type A includes 15 subtypes of which only 2 (H1and H3) areassociated with widespread epidemics; type B is infrequently associatedwith regional or widespread epidemics; type C with sporadic cases andminor localized outbreaks. The antigenic properties of the 2 relativelystable internal structural proteins, the nucleoprotein and the matrixprotein, determine virus type.
Influenza A subtypes are classified by the antigenic properties of surface
glycoproteins, hemagglutinin (H) and neuraminidase (N). Frequent muta-tion of the genes encoding surface glycoproteins of influenza A andinfluenza B viruses results in emergence of variants that are described bygeographic site of isolation, year of isolation and culture number. Exam-ples are A/New Caledonia/20/99(H1N1), A/Moscow/10/99(H3N2)-likevirus, B/Hong Kong/330/2001.
Emergence of completely new subtypes—at irregular intervals and only
for type A viruses—results from antigenic shift in HA gene or unpredict-able recombination of human and mammalian or avian antigens, and leadsto pandemics. The relatively minor antigenic changes (antigenic drift) of Aand B viruses responsible for frequent epidemics and regional outbreaksoccur constantly and require annual reformulation of influenza vaccine.
—As pandemics (rare), epidemics (almost annual),
localized outbreaks and sporadic cases. Clinical attack rates during epi-demics range from 10% to 20% in the general community to more than50% in closed populations (e.g. nursing homes, schools). During the initialphase of epidemics in industrialized countries, infection and illness appearpredominantly in school-age children, with a sharp rise in school ab-sences, physician visits, and pediatric hospital admissions. Schoolchildreninfect family members, other children and adults. During a subsequentphase, infection and illness occur in adults, with industrial absenteeism,adult hospital admissions, and an increase in mortality from influenza-related pneumonia. Epidemics generally last 3– 6 weeks, although the virusis present in the community for a variable number of weeks before andafter the epidemic. The highest attack rates during type A epidemics occuramong children aged 5–9, although the rate is also high in preschoolchildren and adults.
Epidemics of influenza occur almost every year, caused primarily by
type A viruses, occasionally influenza B viruses or both. In temperatezones, epidemics tend to occur in winter; in the tropics, they often occurin the rainy season, but outbreaks or sporadic cases may occur in anymonth.
Influenza viral infections with different antigenic subtypes also occur
naturally in swine, horses, mink and seals, and in many other domesticspecies in many parts of the world. Aquatic birds are a natural reservoirand carrier for all influenza virus subtypes. Interspecies transmission(mainly transitory) and reassortment of influenza A viruses have beenreported among swine, humans and some wild and domestic fowl.
Since 1997 influenza avian infections of the A(H N ) type have been
identified in isolated human groups, with high fatality. Transmissiongradually increased among poultry; in the first half of 2004, poultryoutbreaks of influenza A(H N ) were occurring in several Asian countries,
with transmission to humans in Thailand and Viet Nam. The cases fatalitywas high in human infections; there are no records of person-to-persontransmission.
—Humans are the primary reservoir for human infec-
tions; birds and mammalian reservoirs such as swine are likely sources ofnew human subtypes thought to emerge through genetic reassortment.
5. Mode of transmission
—Airborne spread predominates among
crowded populations in enclosed spaces; the influenza virus may persistfor hours, particularly in the cold and in low humidity, and transmissionmay also occur through direct contact. New subtypes may be transmittedglobally within 3– 6 months.
6. Incubation period
—Short, usually 1–3 days.
7. Period of communicability
—Probably 3–5 days from clinical
onset in adults; up to 7 days in young children.
—Size and relative impact of epidemics and pandem-
ics depend upon level of protective immunity in the population, strainvirulence, extent of antigenic variation of new viruses and number ofprevious infections. Infection produces immunity to the specific antigenicvariant of the infecting virus; duration and breadth of immunity depend onthe degree of antigenic similarity between viruses causing immunity.
Pandemics (emergence of a new subtype): Total population immuno-
logically naive; children and adults equally susceptible, except for thosewho have lived through earlier pandemics caused by the same or anantigenically similar subtype.
Epidemics: Population partially protected because of earlier infections.
Vaccines produce serological responses specific for the subtype virusesincluded and elicit booster responses to related strains with which theindividual had prior experience.
Age-specific attack rates during an epidemic reflect persisting immunity
from past experience with strains related to the epidemic subtype, so thatincidence of infection is often highest in school-age children.
9. Methods of control
—Detailed recommendations for the preven-
tion and control of influenza are issued annually by national healthagencies and WHO.
A. Preventive measures:
1) Educate the public and health care personnel in basic
personal hygiene, especially transmission via unprotectedcoughs and sneezes, and from hand to mucous membrane.
2) Immunization with available inactivated and live virus vac-
cines may provide 70%– 80% protection against infection inhealthy young adults when the vaccine antigen closelymatches the circulating strains of virus. Live vaccines, usedin the Russian Federation for many years, have recentlybeen licensed in the USA: registered for intranasal applica-tion in healthy individuals aged 5– 49. In the elderly,
although immunization may be less effective in preventingillness, inactivated vaccines may reduce severity of diseaseand incidence of complications by 50%– 60% and deaths byapproximately 80%. Influenza immunization should prefer-ably be coupled with immunization against pneumococcalpneumonia (see Pneumonia).
A single dose suffices for those with recent exposure to
influenza A and B viruses; 2 doses more than 1 month apartare essential for children under 9. Routine immunizationprograms should be directed primarily towards those atgreatest risk of serious complications or death (see Identi-fication) and those who might spread infection (health carepersonnel and household contacts of high-risk persons).
Immunization of children on long-term aspirin treatment isalso recommended to prevent development of Reye syn-drome after influenza infection.
The vaccine should be given each year before influenza is
expected in the community; timing of immunization shouldbe based on the seasonal patterns of influenza in differentparts of the world (April to September in the southernhemisphere and rainy season in the tropics). Biannualrecommendations for vaccine components are based on theviral strains currently circulating, as determined by WHOthrough global surveillance.
Contraindications: Allergic hypersensitivity to egg pro-
tein or other vaccine components is a contraindication.
During the swine influenza vaccine program in 1976, theUSA reported an increased risk of developing Guillain-Barre
syndrome within 6 weeks after vaccination. Subsequentvaccines produced from other virus strains have not beenclearly associated with an increased risk of Guillain-Barre
3) Amantadine hydrochloride or rimantadine hydrochloride is
effective in the chemoprophylaxis of influenza A, but notinfluenza type B. The CNS side-effects associated withamantadine in 5%–10% of recipients may be more severe inthe elderly or those with impaired kidney function—thelatter should receive reduced dosages that reflect the degreeof renal impairment. Rimantadine is reported to cause fewerCNS side-effects. The use of these drugs should be consid-ered in nonimmunized persons or groups at high risk ofcomplications, such as residents of institutions or nursinghomes for the elderly, when an appropriate vaccine is notavailable or as a supplement to vaccine when immediatemaximal protection is desired against influenza A infection.
The drug will not interfere with the response to influenzavaccine and should be continued throughout the epidemic.
Inhibitors of influenza neuraminidase (oseltamivir) have
been shown to be safe and effective for both prophylaxisand treatment of influenza A and B, although not yetapproved in many countries for this use.
B. Control of patient, contacts and the immediate environment:
1) Report to local health authority: Reporting outbreaks or
laboratory-confirmed cases assists disease surveillance. Re-port identity of the infectious agent as determined bylaboratory examination if possible, Class 1 (see Reporting).
2) Isolation: Impractical under most circumstances because of
the delay in diagnosis, unless rapid tests are available. Inepidemics, because of increased patient load, it would bedesirable to isolate patients (especially infants and youngchildren) believed to have influenza by placing them in thesame room (cohorting) during the initial 5–7 days of illness.
3) Concurrent disinfection: Not applicable.
4) Quarantine: Not applicable.
5) Protection of contacts: A specific role has been shown for
antiviral chemoprophylaxis with amantadine or rimantadineagainst type A strains (see 9A3). Neuraminidase inhibitorsmay also be considered for influenza A and B.
6) Investigation of contacts and source of infection: Of no
7) Specific treatment: Amantadine or rimantadine started
within 48 hours of onset of influenza A illness and given forapproximately 3–5 days reduces symptoms and virus titresin respiratory secretions. Dosages are 5 mg/kg/day in 2divided doses for ages 1–9, 100 mg twice a day above 9years (if weight less than 45 kg, 5 mg/kg/day in 2 doses) for2–5 days. Doses should be reduced for those over 65 orwith decreased hepatic or renal function. Neuraminidaseinhibitors may also be considered for the treatment ofinfluenza A and B.
During treatment with either drug, drug-resistant viruses
may emerge late in the course of treatment and be trans-mitted to others; cohorting people on antiviral therapyshould be considered, especially in closed populations withmany high-risk individuals. Patients should be watched forbacterial complications and only then should antibiotics beadministered. Because of the association with Reye syn-drome, avoid salicylates in children.
C. Epidemic measures:
1) The severe and often disruptive effects of epidemic influ-
enza on community activities may be reduced in part byeffective health planning and education, particularly locally
organized immunization programs for high-risk patients andtheir care providers. Surveillance by health authorities ofthe extent and progress of outbreaks and reporting offindings to the community are important.
The response to influenza pandemic must be planned at
2) Closure of individual schools has not proven to be an
effective control measure; it is generally applied too late andonly because of high staff and students absenteeism.
3) Hospital administrators must anticipate the increased de-
mand for medical care during epidemic periods and possi-ble absenteeism of health care personnel as a result ofinfluenza. To prevent this, health care personnel should beimmunized annually.
4) Maintaining adequate supplies of antiviral drugs would be
desirable to treat high-risk patients and essential personnelin the event of the emergence of a new pandemic strain forwhich no suitable vaccine is available in time for the initialwave.
D. Disaster implications:
Aggregations of people in emergency
shelters will favor outbreaks of disease if the virus is introduced.
E. International measures:
A disease under surveillance by
1) Regularly report on epidemiological situation within a coun-
try to WHO (http://www.who.int/flunet).
2) Identify the causative virus in reports, and submit prototype
strains to one of the WHO Centres for Reference andResearch on Influenza in Atlanta, London, Melbourne andTokyo (http://www.who.int/influenza). Throat secretionspecimens, nasopharyngeal aspirates and paired blood sam-ples may be sent to any WHO-recognized national influenzacenter.
3) Conduct epidemiological studies and promptly identify
viruses to the national health agencies.
4) Ensure sufficient commercial and/or governmental facilities
to provide rapid production of adequate quantities ofvaccine and antiviral drugs; maintain programs for vaccineand antiviral drug administration to high-risk persons andessential personnel.
Further information also on http://www.oms.b3e.jussieu.
EC staff consolidated version as of 16 September 2009, IFRIC Interpretation 6 Liabilities arising from Participating in a Specific Market—Waste Electrical and Electronic Equipment References Accounting Policies, Changes in Accounting Estimates and Errors Provisions, Contingent Liabilities and Contingent Assets Background Paragraph 17 of IAS 37 specifies that an obligating
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