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Introduction

The orthomyxoviruses (influenza viruses) constitute the genus Orthomyxovirus, which consists of three types (species): A, B, and C These viruses cause influenza, an acute respiratory disease with prominent systemic symptoms !neumonia may develop as a complication and may "e fatal, particularly in elderly persons with underlying chronic disease Type A viruses cause periodic worldwide epidemics (pandemics)# "oth types A and B cause recurring regional and local epidemics $nfluenza epidemics have "een recorded throughout history $n temperate climates, the epidemics typically occur in the winter and cause considera"le mor"idity in all age groups An epidemic with associated mortality has occurred in most of the past %&& years The worst of these was the %'%( pandemic, which caused a"out )& million deaths worldwide and a"out *&&,&&& deaths in the +nited ,tates

Clinical Manifestation
The classic influenza syndrome is a fe"rile illness of sudden onset, characterized "y tracheitis and mar-ed myalgias .eadache, chills, fever, malaise, myalgias, anorexia, and sore throat appear suddenly The fever rapidly clim"s to %&% to %&/01 (2( 2 to /& &0C), and respiratory symptoms ensue A nonproductive cough is characteristic ,neezing, rhinorrhea, and nasal o"struction are common !atients may also report photopho"ia, hoarseness, nausea, vomiting, diarrhea, and a"dominal pain They appear acutely ill and are usually coughing 3inimal to moderate nasal o"struction, nasal discharge, and pharyngeal inflammation may "e present 4ung examination is usually negative A case of acute uncomplicated influenza in a healthy %(5year5old college student 3ost adults ill with an influenza virus infection do not display the classic syndrome descri"ed a"ove 3oreover, the influenza syndrome is uncommon in children and is not seen in infants A given patient may exhi"it symptoms including predominantly sneezing, nasal o"struction, and nasal discharge (common cold), nasal o"struction, discharge, and sore throat (upper respiratory illness)# sore throat with erythema (pharyngitis)# hoarseness (laryngitis)# or cough (tracheo"ronchitis) 1ever may "e a"sent The respiratory and systemic symptoms of influenza generally last % to * days Complications of influenza are many, "ut an influenza pneumonia, which can "e extensive, and secondary "acterial pneumonia are the most common

Structure
$nfluenza viruses are spherical and (& to %)& nm in diameter, although filamentous forms may also occur The antisense 67A genome occurs in eight separate segments containing %& genes The segments are complexed with nucleoprotein to form a nucleocapsid with helical symmetry The nucleocapsid is enclosed in an envelope consisting of a lipid "ilayer and two surface glycoproteins, a hemagglutinin and a neuraminidase Because influenza viruses are enveloped, they are readily inactivated "y nonpolar solvents and "y surface5active agents The influenza C virus is less well studied, "ut is -nown to contain only seven 67A segments and a single surface glycoprotein 8iagrammatic representation of a segment of the influenza virus particle .emagglutinin and neuraminidase proteins protrude from the surface of the virus The orientation of the nucleoprotein967A complex in the virion has not "een fully elucidated

Classification and Antigenic Types


Three influenza virus antigens9the nucleoprotein, the hemagglutinin, and the neuraminidase9are used in classification The nucleoprotein antigen is sta"le and is used to differentiate the three influenza virus types The nucleoprotein antigens of influenza viruses A, B, and C exhi"it no serologic cross reactivity

The hemagglutinin and neuraminidase antigens, on the other hand, are varia"le Anti"ody directed against these two surface antigens is responsi"le for immunity to infection

Multiplication
:rthomyxovirus replication ta-es a"out ; hours and -ills the host cell The viruses attach to permissive cells via the hemagglutinin su"unit, which "inds to cell mem"rane glycolipids or glycoproteins containing 75acetylneuraminic acid, the receptor for virus adsorption The virus is then engulfed "y pinocytosis into endosomes The acid environment of the endosome causes the virus envelope to fuse with the plasma mem"rane of the endosome, uncoating the nucleocapsid and releasing it into the cytoplasm A transmem"rane protein derived from the matrix gene (3)) forms an ion channel for protons to enter the virion and desta"ilize protein "inding allowing the nucleocapsid to "e transported to the nucleus, where the genome is transcri"ed "y viral enzymes to yield viral m67A +nli-e replication of other 67A viruses, orthomyxovirus replication depends on the presence of active host cell 87A The virus scavenges cap se<uences from the nascent m67A generated in the nucleus "y transcription of the host 87A and attaches them to its own m67A These cap se<uences allow the viral m67A to "e transported to the cytoplasm, where it is translated "y host ri"osomes The nucleocapsid is assem"led in the nucleus =irions ac<uire an envelope and undergo maturation as they "ud through the host cell mem"rane 8uring "udding, the viral envelope hemagglutinin is su">ected to proteolytic cleavage "y host enzymes This process is necessary for the released particles to "e infectious 7ewly synthesized virions have surface glycoproteins that contain 7 acetylneuraminic acid as a part of their car"ohydrate structure, and thus are vulnera"le to self5agglutination "y the hemagglutinin A ma>or function of the viral neuraminidase is to remove these residues

Gene Reassortment
Because the influenza virus genome is segmented, genetic reassortment can occur when a host cell is infected simultaneously with viruses of two different parent strains $f a cell is infected with two strains of type A virus, for example, some of the progeny virions will contain a mixture of genome segments from the two strains This process of genetic reassortment pro"a"ly accounts for the periodic appearance of the novel type A strains that cause influenza pandemics

Pathogenesis
$nfluenza virus is transmitted from person to person primarily in droplets released "y sneezing and coughing ,ome of the inhaled virus lands in the lower respiratory tract, and the primary site of disease is the tracheo"ronchial tree, although the nasopharynx is also involved The neuraminidase of the viral envelope may act on the 75acetylneuraminic acid residues in mucus to produce li<uefaction $n concert with mucociliary transport, this li<uified mucus may help spread the virus through the respiratory tract $nfection of mucosal cells results in cellular destruction and des<uamation of the superficial mucosa The resulting edema and mononuclear cell infiltration of the involved areas are accompanied "y such symptoms as nonproductive cough, sore throat, and nasal discharge Although the cough may "e stri-ing, the most prominent symptoms of influenza are systemic: fever, muscle aches, and general prostration =iremia is rare, so these systemic symptoms are not caused directly "y the virus Circulating interferon is a possi"le cause: administration of therapeutic interferon causes systemic symptoms resem"ling those of influenza !athogenesis of influenza

Current evidence indicates that the extent of virus5induced cellular destruction is the prime factor determining the occurrence, severity, and duration of clinical illness $n an uncomplicated case, virus can "e recovered from respiratory secretions for 2 to ( days !ea- <uantities of %& / to %&? infectious units@ml are detected at the time of maximal illness After % to / days of pea- shedding, the titer "egins to drop, in concert with the progressive a"atement of disease :ccasionally9particularly in patients with underlying heart or lung disease9the infection may extensively involve the alveoli, resulting in interstitial pneumonia, sometimes with mar-ed accumulation of lung hemorrhage and edema !ure viral pneumonia of this type is a severe illness with a high mortality =irus titers in secretions are high, and viral shedding is prolonged $n most cases, however, pneumonia associated with influenza is caused "y "acteria, principally pneumococci, staphylococci, and Aram5 negative "acteria These "acteria can invade and cause disease "ecause the preceding viral infection damages the normal defenses of the lung

Host Defenses
The immune mechanisms responsi"le for recovery from influenza have not "een clearly delineated ,everal mechanisms pro"a"ly act in concert $nterferon appears in respiratory secretions shortly after viral titers reach their pea- level, and may play a role in the su"se<uent reduction in viral shedding Anti"ody usually is not detected in serum or secretions until later in recovery or during convalescence# nevertheless, local anti"ody appears responsi"le for the final clearing of virus from secretions T cells and anti"ody5dependent cell5mediated cytotoxicity also participate in clearing the infection Anti"ody is the primary defense in immunity to reinfection $gA anti"ody, which predominates in lower respiratory secretions, appears to "e the most important The $gA in these secretions is derived from the serum, which accounts for the close correlation "etween serum anti"ody titer and resistance to influenza $gA anti"ody, which predominates in upper respiratory secretions, is less persistent than $gA "ut also contri"utes to immunity :nly anti"ody directed against the hemagglutinin is a"le to prevent infection A sufficient titer of anti5 hemagglutinin anti"ody will prevent infection 4ower titers of anti5hemagglutinin anti"ody lessen the severity of infection Anti5hemagglutinin anti"ody administered after an infection is under way reduces the num"er of infectious units released from infected cells, presuma"ly "ecause the divalent anti"ody aggregates many virions into a single infectious unit Anti"ody directed against the neuraminidase also reduces the num"er of infectious units (and thus the intensity of disease), presuma"ly "y impairing the action of neuraminidase against 75acetylneuraminic acid residues in the virion envelope and thus promoting virus aggregation Anti"ody directed against nucleoprotein has no effect on virus infectivity or on the course of disease $mmunity to an influenza virus strain lasts for many years 6ecurrent cases of influenza are caused primarily "y antigenically different strains

Epidemiology
A community experiences an influenza epidemic every year $n the initial phases of an epidemic, infection and illness appear predominantly in school5aged children, as indicated "y a sharp rise in school a"sences, physician visits, and pediatric hospital admissions These children "ring the virus into the home, where preschool children and adults ac<uire infection $nfection and illness in adults are reflected in industrial a"senteeism, adult hospital admissions, and an increase in mortality from influenza5related pneumonia The epidemic generally lasts 2 to ; wee-s, although the virus is present in the community for a varia"le num"er of wee-s "efore and after the epidemic The highest attac- rates during type A epidemics are in children * to ' years old, although the rate is also high in preschool children and adults

$nfluenza B epidemics exhi"it a similar pattern, except that the attac- rates in preschool children and adults usually are lower and the epidemic may not cause an increase in mortality over the expected num"er of deaths (Bexcess mortalityC) Correlation of nonvirologic indices of epidemic influenza with the num"er of isolates of influenza A@=ictoria virus according to wee- in .ouston during %'?; ($ndustrial a"senteeism is indicated "y the percentage with respiratory complaints ) Although influenza virus types A and B (and pro"a"ly C) cause illness every winter, an epidemic is usually caused "y only one variant The constellation of factors that precipitate an epidemic are not fully understood, "ut the most important is a population suscepti"le to the circulating strains $nfluenza can recur despite the development of immunity "ecause type A and B viruses are proficient at altering their surface antigens and thus at generating strains that evade the existing immunity $nfluenza strains are constantly appearing to which part or all of the human population is suscepti"le $nfluenza epidemics are of two types Dearly epidemics are caused "y "oth type A and type B viruses The rare, severe influenza pandemics are always caused "y type A virus Two different mechanisms of antigenic change are responsi"le for producing the strains that cause these two types of epidemic A ma>or change in one or "oth of the surface antigens9a change that yields an antigen showing no serologic relationship with the antigen of the strains prevailing at the time9is called antigenic shift Changes of this magnitude have "een demonstrated in type A virus only and produce the strains responsi"le for influenza pandemics 6epeated minor antigenic changes, on the other hand, which generate strains that retain a degree of serologic relationship with the currently prevailing strain, are called antigenic drift Antigenic drift occurs in "oth type A and type B influenza viruses and is responsi"le for the strains that cause yearly influenza epidemics Ehen persons are reinfected with drift viruses, the serum anti"ody responses to the surface antigens that are shared with earlier strains to which the person has "een exposed are fre<uently stronger and of greater avidity than are the responses to the new antigens This phenomenon, which has "een called Boriginal antigenic sin,C is sometimes useful in serologic diagnosis Antigenic drift represents selection for naturally occurring variants under the pressure of population immunity The completely novel antigens that appear during antigenic shift, in contrast, are ac<uired "y gene reassortment The donor of the new antigens is pro"a"ly an animal influenza virus Type A viruses have "een identified in pigs, horses, and "irds, and animal influenza viruses possessing antigens closely related to those of human viruses have "een descri"ed 1ourteen distinct hemagglutinin and nine neuraminidase antigens are -nown ,ince continued surveillance of animal influenza viruses in recent years has failed to discover new antigens, these may represent the full variety of ma>or influenza virus surface antigens (su"types) ,ince the initial isolation of influenza viruses from swine in %'2% and from humans in %'22, the emergence and prevalence of human antigenic strains have "een monitored 7ew su"types that arise spread around the world along transportation routes A new virus can seed a population during the Boff seasonC and may cause localized out"rea-s, "ut epidemics generally do not "egin until after school opens in the fall or during the succeeding winter

Diagnosis
A diagnosis of influenza is suggested "y the clinical picture of sudden onset of fever, malaise, headache, mar-ed muscle aches, sore throat, nonproductive cough, and coryza Ehen a syndrome resem"ling influenza occurs in the winter in an adult (the etiologies of illnesses of this type are more complex in children), an influenza virus is a li-ely cause $f an epidemic of fe"rile respiratory disease is -nown to "e under way in the community, the diagnosis is yet more li-ely 8efinitive diagnosis, however, relies on

detecting either the virus or a significant rise in anti"ody titer "etween acute phase and convalescent5 phase sera A rapid specific diagnosis of influenza may "e o"tained "y demonstrating viral antigens in cells o"tained from the nasopharynx in immunostaining tests such as immunofluorescence or in enzyme immunoassays (F4$,A) employing respiratory secretions $nfluenza virus is usually isolated from respiratory secretions "y "eing grown in tissue cultures or chic- em"ryos =irus growth in tissue cultures is detected "y testing for hemadsorption: red cells are added to the culture and adhere to virus "udding from infected cells $f the culture tests positive, serologic tests with specific antisera may "e used to identify the virus $n the chicem"ryo culture method, fluid from the amniotic or allantoic cavity of chic- em"ryos is tested for the presence of newly formed viral hemagglutinin# the virus in positive fluids is then identified "y hemagglutination inhi"ition tests with specific antisera 1inally, a rise in serum anti"ody titer "etween acute5phase and convalescent5phase sera can "e identified "y various tests, of which complement fixation, hemagglutination inhi"ition, and immunodiffusion (using specific viral antigens) are the most common 7one of these techni<ues will identify all infections

Control
Pre ention
$nactivated influenza virus vaccines have "een used for a"out /& years to prevent influenza The viruses for the vaccine are grown in chic- em"ryos, inactivated "y formalin, purified to some extent, and ad>usted to a dosage -nown to elicit an anti"ody response in most individuals A given vaccine contains the strains of types A and B viruses that are >udged most li-ely to produce epidemics during the following winter The vaccine is administered parenterally in the fall# one or two doses are re<uired, depending on the immune experience of the population with related antigens !rotection against illness has varied from *& to '& percent in civilian populations and from ?& to '& percent in military populations 4ocal and systemic reactions to the vaccine are minor and occur in the first day or two after vaccination 8uring the national swine flu immunization of %'?; in the +nited ,tates, an increased ris- of developing Auillain5Barre syndrome accompanied vaccination# however, this correlation has not "een detected since Annual use of inactivated influenza virus vaccine is currently recommended in the +nited ,tates for persons at ris- of developing pneumonia from the disease and for their close associates 4ive attenuated vaccines are "eing developed as alternatives to inactivated vaccine The synthetic drugs amantadine and rimantadine hydrochloride effectively prevent infection and illness caused "y type A, "ut not "y type B, viruses The drugs interfere with virus uncoating and transport "y "loc-ing the transmem"rane 3) ion channel (see multiplication) 8rugs prevent a"out *& percent of infections and a"out ;? percent of illnesses under natural conditions Ehen administered for %& days to household contacts of a person with influenza, drugs protect up to (& percent of the persons from illness ,ide effects are greater for amantadine and limited primarily to the central nervous system

Treatment
Amantadine and rimantadine are the only specific antiviral treatments availa"le for influenza As in the case of prophylaxis, they are effective only against type A virus Ehen administration is started early in the course of illness, drugs hasten the disappearance of fever and other symptoms Fmergence of viral resistance can occur during treatment