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Fatal Flu

IntroductionHuman influenza pandemics over the last 100 years have been caused by H1, H2, and H3 subtypes ofinfluenza A viruses.

More recently, avian influenza virus subtypes (that is, H5, H7) have been found to directly infect humans fromtheir avian hosts. The recent emergence, host expansion, and spread of a highly pathogenic avian influenza(HPAI) H5N1 subtype in Asia have heightened concerns globally, in regards to mortality from HPAI H5N1infection in humans[1].

Swine influenza A subtypes H1N1,H1N2,H2N3,H3N1, andH3N2 in pigs are the most common strainsworldwide. In theUnited States, the H1N1 subtype was exclusively prevalent among swine populations before1998.

Influenza A virusesInfluenza A, B and C are the most important genera of the Orthomyxoviridae family, causing both

pandemic and seasonal disease in humans. Influenza A viruses are enveloped, single-stranded RNA viruseswith a segmented genome (Table 1) [2]. They are classified into subtypes on the basis of the antigenicproperties of the hemagglutinin (HA) and neuraminidase (NA) glycoproteins expressed on the surface of thevirus. Influenza A viruses are characterized by their pathogenicity, with highly pathogenic avian influenza(HPAI) causing severe disease or death in domestic poultry. Molecular changes in the RNA genome occurthrough two main mechanisms: point mutation (antigenic drift) and RNA segment reassortment (antigenic shift)Point mutations cause minor changes in the antigenic character of viruses.Vaccination for influenza A is given yearly. Reassortment occurs when a host cell is infected with two or moreinfluenza A viruses, leading to the creation of a novel subtype. The influenza subtypes of the 1957 (H2N2) and1968 (H3N2) pandemics occurred through reassortment, while the origins of the 1918 (H1N1) pandemic areunclear.

The HA glycoprotein mediates attachment and entry of the virus by binding to sialic acid receptors on thecell surface. The binding affinity of the HA to the host sialic acid allows for the host specificity of influenza A.Avian influenza subtypes prefer to bind to sialic acid linked to galactose by -2,3 linkages, which are found inavian intestinal and respiratory epithelium (Table 2)[3]. Human virus subtypes bind to -2,6 linkages found inhuman respiratory epithelium. Swine contain both -2,3 and -2,6 linkages in their respiratory epithelium,allowing for easy co-infection with both human and avian subtypes (thus acting as a mixing vessel for newstrains). Humans have been found to contain both -2,3 and -2,6 linkages in their lower respiratory tract andconjunctivae, which allows for human infections by avian subtypes. The HA glycoprotein is the main target forimmunity by neutralizing antibodies [3].

The NA glycoprotein allows the spread of the virus by cleaving the glycosidic linkages to sialic acid on hostcells and the surface of the virus. The virus is then spread in secretions or other bodily fluids. The NAglycoprotein is not the major target site for neutralization of the virus by antibodies [4].

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Host range of influenza A viruses

Influenza A viruses infect a wide range of hosts, including many avian species, and various mammalianspecies, such as swine, ferrets, felids, mink, whales, horses, seals, dogs, civets, and humans.

Wild birds (ducks, geese, swans, and shorebirds) are important natural reservoirs of these viruses, and all ofthe known 16 HA and 9 NA subtypes have been found in these birds. In most cases, these subtypes are foundwithin the gastrointestinal tract of the birds, are shed in their feces, and rarely cause disease. Since 2002,

however, HPAI H5N1 viruses originating in Asia have been reported from approximately 960 wild bird species,causing disease in some instances and asymptomatic shedding in others [5].

Epidemiology and pathogenicity in humansAvian influenza

The incidence of avian influenza infections in humans has increased over the past decade. In December of2003, HPAI H5N1 surfaced in poultry in Korea and China, and from 2003 to 2006 the outbreak stretchedworldwide in the largest outbreak in poultry history. Human cases of HPAI H5N1 followed the poultry outbreak,with a total of 256 cases and 151 fatalities thus far. Other limited outbreaks have occurred, causing variablehuman disease (Table 3).

However, HPAI H5N1 remains the largest and most significant poultry and human avian influenza outbreak.Epidemiological investigations of human cases of avian influenza show that the virus was acquired by direct

contact with infected birds. Influenza A is transmitted through the fecal-oral and respiratory routes among wildbirds and poultry. Human interaction with these infected secretions and birds was the major mode of

transmission, with contact including consumption of undercooked or raw poultry products, handling of sick ordead birds without protection, or food processing at bird cleaning sites. All birds were domesticated (chicken,duck, goose) and no transmission from birds in the wild (migrating) or contaminated waterways has beendocumented. In a few cases, limited human to human transmission has been reported among health careworkers and family members (Table 4) [6]. In each of these cases, no personal protective equipment was used,which is the major factor in transmission between humans.

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Swine influenza

Transmission of influenza from swine to humans who work with swine was documented in a smallsurveillance study performed in 2004 at the University of Iowa. This study among others forms the basis of arecommendation that people whose jobs involve handling poultry and swine be the focus of increased publichealth surveillance. Other professions at particular risk of infection are veterinarians and meat processingworkers, although the risk of infection for both of these groups is lower than that of farm workers [7].

Interaction with avian H5N1 in pigs

Pigs are unusual as they can be infected with influenza strains that usually infect three different species: pigs,birds and humans. This makes pigs a host where influenza viruses might exchange genes, producing new and

dangerous strains. In August 2004, researchers in China found H5N1 in pigs [8].

Clinical manifestations in humansAvian influenza

The clinical manifestations of avian influenza in humans has ranged from mild conjunctivitis to severepneumonia with multi-organ system failure . The median age of patients was 16 years in the 2003 to 2006HPAI H5N1 outbreak in Southeast Asian cases (range 2 months to 90 years). The incubation period ranged

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from two to eight days from contact with sick or dead birds to symptom onset. The predominant clinical findingsappear to vary with each influenza A subtype; for example, in 2003 during the Netherlands outbreak (H7N7)92% (82 of 89) of patients presented with conjunctivitis and a minority with respiratory symptoms. Ryesyndrome, pulmonary hemorrhage, and predominant nausea, vomiting, and diarrhea complicate these cases.Laboratory findings include both thrombocytopenia and lymphopenia . Chest radiographic findings includeinterstitial infiltrates, lobar consolidation, and air bronchograms. The clinical course of patients with HPAI H5N1is rapid, with 68% percent of patients developing ARDS and multiorgan failure within 6 days of disease onset.

The case fatality rate ranges form 67% to 80%, depending on the case series [9]. Once the patients reachedthe critical care unit, however, the mortality rate was 90%.The average time of death from disease onset wasnine to ten days.

Avian influenza A infections in humans differ from seasonal influenza in several ways. The presence ofconjunctivitis is more common with avian influenza A infections than with seasonal influenza. Gastrointestinalsymptoms, as seen with HPAI H5N1, and reports of primary influenza pneumonia and development of ARDSare also more common with avian influenza A infections . Finally, the rapid progression to multi-organ failureand eventually death occurs at a much higher rate with avian influenza A infections [10].

Swine influenzaAccording to the Centers for Disease Control and Prevention (CDC), in humans the symptoms of the 2009"swine flu" H1N1 virus are similar to those ofinfluenza and ofinfluenza-like illness in general. Symptomsinclude fever, cough, sore throat, body aches, headache, chills and fatigue. The 2009 outbreak has shown anincreased percentage of patients reporting diarrhea and vomiting. Because these symptoms are not specific toswine flu, a differential diagnosis ofprobable swine flu requires not only symptoms but also a high likelihood ofswine flu due to the person's recent history [11].

The most common cause of death is respiratory failure. Other causes of death are pneumonia (leading tosepsis)[12], high fever (leading to neurological problems), dehydration (from excessive vomiting and diarrhea)and electrolyte imbalance. Fatalities are more likely in young children and the elderly.

Diagnosis

The clinical diagnosis ofavian influenza infection in humans is difficult and relies on theepidemiological link to endemic areas, contact with sick or dead poultry, or contact with aconfirmed case of avian influenza. Since many infectious diseases present with similar

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symptoms, the only feature significant to the clinician may be contact in an endemic area,through travel or infected poultry, and the clinician should always elicit a detailed patient history.The definitive diagnosis is made from isolation of the virus in culture from clinical specimens. Thismethod not only provides the definitive diagnosis, but the viral isolate is now available for furthertesting, including pathogenicity, antiviral resistance, and DNA sequencing and analysis.Alternatively, antibody testing can be performed, with a standard four-fold titer increase to thespecific subtype of avian influenza virus. Neutralizing antibody titer assays for H5, H7 and H9 are

performed by the micorneutralization technique. Westernblot analysis with recombinant H5 is the confirmatory test for any positive microneutralizationassay. More recently, rapid diagnosis can be performed with reverse transcription-PCR on clinicalsamples with primers specific for the viral subtype. This test should be performed only onpatients meeting the case definition of possible avian influenza A infection [13].

Diagnosis ofH1N1

Clinicians should consider the possibility of H1N1 influenza virus infections in patients whopresent with febrile respiratory illness.

If H1N1 flu is suspected, the clinician should obtain a respiratory swab for H1N1 influenza testingand place it in a refrigerator (not a freezer). Once collected, the clinician should contact his or herstate or local health department to facilitate transport and timely diagnosis at a state publichealth laboratory.

A number of diagnostic tests are available to detect the presence of influenza viruses inrespiratory specimens. These tests differ in their sensitivity and specificity for detecting influenzaviruses, commercial availability, processing time, approved clinical setting, and ability todistinguish between different influenza virus types (A versus B) and influenza A subtypes (e.g.,2009 H1N1 versus seasonal H1N1 versus seasonal H3N2 viruses)[14].

Rapid influenza diagnostic tests (RIDTs) are widely available, advantages are that the test isrelatively easy to perform and results can be obtained as early as 30 minutes. Disadvantages areits low sensitivity (10% to 70%) and inability to determine the subtype of influenza A. Alsonegative result does not rule out H1N1 swine influenza infection.

Like RIDTs, direct immunofluorescence assays (DFAs) are widely available, have variablesensitivity (range 47 93%) for 2009 H1N1 influenza virus, and a high specificity (96%7). DFAsdetect and distinguish between influenza A and B viruses but do not distinguish among differentinfluenza A subtypes.

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When influenza viruses are circulating in a community, the positive predictive value of the RIDTand DFA tests are generally high and a positive test result indicates that influenza virus infectionis likely. However, as stated above, a negative test does not rule out influenza virus infection.

Nucleic acid amplification tests, including rRT-PCR, are the most sensitive and specific influenzadiagnostic tests, but they may not be readily available, obtaining test results may take one toseveral days, and test performance depends on the individual rRT-PCR assay. As with any assay,

false negatives can occur. Not all nucleic acid amplification assays can specifically differentiate2009 H1N1 influenza virus from other influenza A viruses. If specific testing for 2009 H1N1influenza virus is required, testing with an rRT-PCR assay specific for 2009 H1N1 influenza or viralculture should be performed [15].

Treatment

Treatment of avian influenza infections in humans

It includes antiviral therapy and supportive care. Controlled clinical trials on the efficacy ofantivirals (NA inhibitors), supportive therapy, or adjuvant care have never been performed, socurrent recommendations stem from the experiences of past avian influenza outbreaks andanimal models.

The adamantanes (rimantadine and amantadine) and NA inhibitors (oseltamivir and zanamivir)are the antivirals used for treatment and prophylaxis of influenza infections in humans. In avianinfluenza virus infections, adamantanes have no role due to widespread resistance through a M2protein alteration. In addition, over 90% of isolates of H1 and H3 human subtypes duringseasonal influenza have had resistance to the adamantanes. Their role has now been limited toprophylaxis in the community when the circulation strain is know to be susceptible to theadamantanes[16]. NA inhibitors (oseltamivir and zanamivir) have been studied for bothtreatment and prophylaxis with the human influenza A subtypes H1, H2, and H3 as well asinfluenza B. In animal models with HPAI H5N1, their efficacy has been well documented, withimproved survival rates seen after infection. Oseltamivir has been used in avian influenzaoutbreaks involving HPAI H5N1, and therapy with oseltamivir has been shown to decrease the

viral load in nasal secretions in patients infected with HPAI H5N1. Resistance to oseltamivir hasbeen documented in a HPAI H5N1 subtype in a Vietnamese girl treated with 75 mg daily for 4days as post-exposure prophylaxis. In one study, the viral count of HPAI H5N1 in nasal secretionsdid not decrease with the administration of oseltamivir when the H5N1 isolate carried thisresistance mutation. However, resistance produced by this change may be overcome with higherdoses of oseltamivir in vitro, and this change has not been documented to confer resistance tozanamivir[17].

The timing of treatment with NA inhibitors is paramount, as early therapy is directly related toimproved survival. The greatest level of protection was seen if the NA inhibitors were startedwithin 48 hours of infection, and protection rapidly dropped after 60 hours. These initial studies,

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however, were performed with seasonal human influenza A and B, where the period of viralshedding is approximately 48 to 72 hours. In HPAI H5N1 cases from Southeast Asia, survivalappeared to be improved in patients who received oseltamavir earlier (4.5 days versus 9 daysafter onset of symptoms). Both of these time periods are much longer than documented inanimal models, so the window of optimal therapy is still unknown, particularly if viral sheddingexceeds the average 48 to 72 hour period seen in seasonal influenza A and B infections.Combination therapy with influenza A viruses has not been studied. Ribavirin by inhalation has

been evaluated invitro with some avian influenza A subtypes. Further animal model studies areindicated to determine if there is a role for ribavirin or combination therapy with avian influenza Aviruses. Supportive care with intravenous rehydration, mechanical ventilation, vasopressortherapy, and renal replacement therapy are required if multiorgan failure and ARDS are a featureof disease. Due to the progression of pneumonia to ARDS, non-invasive ventilation is notrecommended, and early intubation may be beneficial before overt respiratory failure ensues.Corticosteroids have been used in some patients with HPAI H5N1, but no definitive role forsteroids has been determined. Other immunomodulatory therapy has not been reported [18].

Treatment of H1N1 in humans

Treatment is largely supportive and consists of bedrest, increased fluid consumption, coughsuppressants, and antipyretics and analgesics (eg, acetaminophen, nonsteroidal anti-inflammatory drugs) for fever and myalgias. Severe cases may require intravenous hydration andother supportive measures. Antiviral agents may also be considered for treatment or prophylaxis(see Medications).Patients should be encouraged to stay home if they become ill, to avoid close contact with peoplewho are sick, to wash their hands often, and to avoid touching their eyes, nose, and mouth. TheCDC recommends the following actions when human infection with H1N1 influenza (swine flu) isconfirmed in a community [19]:

Home isolationPatients who develop flulike illness (ie, fever with either cough or sore throat) should be stronglyencouraged to self-isolate in their home for 7 days after the onset of illness or at least 24 hoursafter symptoms have resolved, whichever is longer.To seek medical care, patient should contact their health care providers to report illness (bytelephone or other remote means) before seeking care at a clinic, physician's office, or hospital.

Patients who have difficulty breathing or shortness of breath or who are believed to be severelyill should seek immediate medical attention.If the patient must go into the community (eg, to seek medical care), he or she should wear aface mask to reduce the risk of spreading the virus in the community when coughing, sneezing,talking, or breathing. If a face mask is unavailable, ill persons who need to go into the communityshould use tissues to cover their mouth and nose while coughing.While in home isolation, patients and other household members should be given infection controlinstructions, including frequent hand washing with soap and water. Use alcohol-based hand gels(containing at least 60% alcohol) when soap and water are not available and hands are notvisibly dirty. Patients with H1N1 influenza should wear a face mask when within 6 feet of othersat home.

Household contacts who are not illRemain home at the earliest sign of illness.

Minimize contact in the community to the extent possible.Designate a single household family member as caregiver for the patient to minimizeinteractions with asymptomatic persons.

School dismissal and childcare facility closureStrong consideration should be given to close schools upon a confirmed case of H1N1 flu or asuspected case epidemiologically linked to a confirmed case.Decisions regarding broader school dismissal within these communities should be left to localauthorities, taking into account the extent of influenzalike illness within the community.Cancelation of all school or childcare related gatherings should also be announced.

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Encourage parents and students to avoid congregating outside of the school if school is canceled.Duration of schools and childcare facilities closings should be evaluated on an ongoing basisdepending on epidemiological findings.Consultation with local or state health departments is essential for guidance concerning when toreopen schools. If no additional confirmed or suspected cases are identified among students (orschool-based personnel) for a period of 7 days, schools may consider reopening.Schools and childcare facilities in unaffected areas should begin preparation for possible school

closure.

Social distancingLarge gatherings linked to settings or institutions with laboratory-confirmed cases should becanceled (eg, sporting events or concerts linked to a school with cases); other large gatherings inthe community may not need to be canceled at this time.Additional social distancing measures are currently not recommended.Persons with underlying medical conditions who are at high risk for complications of influenzashould consider avoiding large gatherings.

WHO guidelines for H1N1

WHO guidelines recommend treating serious cases immediately [20].The guidelines represent aninternational panel of experts who reviewed all available studies regarding antiviral agents (withemphasis on oseltamivir and zanamivir). Evidence indicates that oseltamivir, when properlyprescribed, significantly decreases risk of pneumonia (a leading cause of death for bothpandemic and seasonal influenza) and the need for hospitalization.

For patients who initially present with severe illness or whose condition begins to deteriorate,initiate oseltamivir as soon as possible. For patients with severe or deteriorating illness,treatment should be provided even if started later. Where oseltamivir is unavailable or cannot beused for any reason, zanamivir may be given. This recommendation applies to all patient groups,including pregnant women, and all age groups, including young children and infants.

For patients with underlying medical conditions that increase the risk of more severe disease,WHO recommends treatment with either oseltamivir or zanamivir. These patients should alsoreceive treatment as soon as possible after symptom onset, without waiting for the results of

laboratory tests. Pregnant women are included among groups at increased risk, and WHOrecommends that pregnant women receive antiviral treatment as soon as possible after symptomonset.

At the same time, the presence of underlying medical conditions will not reliably predict all oreven most cases of severe illness. Worldwide, around 40% of severe cases are now occurring inpreviously healthy children and adults, usually younger than 50 years. Some of these patientsexperience a sudden and very rapid deterioration in their clinical condition, usually on day 5 or 6following the onset of symptoms.Clinical deterioration is characterized by primary viral pneumonia, which destroys the lung tissueand does not respond to antibiotics, and the failure of multiple organs, including the heart,kidneys, and liver. These patients require management in intensive care units using therapies inaddition to antivirals .

Initiate antiviral agents within 48 hours

Prompt initiation of antiviral agents within 48 hours of symptom onset is imperative for providingtreatment efficacy against influenza virus. In studies of seasonal influenza, evidence for benefitsof treatment is strongest when treatment is started within 48 hours of illness onset. However,some studies of treatment of seasonal influenza have indicated benefit, including reductions inmortality or duration of hospitalization, even in patients in whom treatment was started morethan 48 hours after illness onset. The recommended duration of treatment is 5 days.*Prophylaxis with antiviral agents should also be considered in the following individuals (pre-exposure or postexposure):

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-Close household contacts of a confirmed or suspected case who are at high risk forcomplications (eg, chronic medical conditions, persons >65 y or 65 y, pregnant women)

Pediatric considerations

Aspirin or aspirin-containing products (eg, bismuth subsalicylate [Pepto Bismol]) should not beincluded in the treatment of confirmed or suspected viral infection in persons aged 18 years oryounger because of the risk of Reye syndrome. For relief of fever, other antipyretic medications(eg, acetaminophen, nonsteroidal anti-inflammatory drugs) are recommended.

Pregnant women

Oseltamivir and zanamivir are "Pregnancy Category C" medications, indicating that no clinicalstudies have been conducted to assess the safety of these medications in pregnant women.

Because of the unknown effects of influenza antiviral drugs on pregnant women and theirfetuses, oseltamivir or zanamivir should be used during pregnancy only if the potential benefitjustifies the potential risk to the embryo or fetus; the manufacturers' package inserts should beconsulted. However, no adverse effects have been reported among women who receivedoseltamivir or zanamivir during pregnancy or among infants born to women who have receivedoseltamivir or zanamivir.

Pregnancy should not be considered a contraindication to oseltamivir or zanamivir use. Because

zanamivir is an inhaled medication and has less systemic absorption, some experts preferzanamivir over oseltamivir for use in pregnant women, when feasible [21] .Others recommendthat, because pregnant women may have a decreased ability to inhale zanamivir, they should begiven oseltamivir.

Antiviral Agents [21]

Drugs indicated for treatment of H1N1 influenza A virus include neuraminidase inhibitors (ie,oseltamivir and zanamivir).

Antivirals reduce the length of illness by an average of 1.5 days. (In a subgroup of high-riskpatients, illness was reduced by 2.5 d.) In addition, the severity of symptoms is also reduced.

On October 23, 2009, the FDA announced emergency-use authorization of the investigational

intravenous neuraminidase inhibitor, peramivir.

Oseltamivir (Tamiflu)

Inhibits neuraminidase, which is a glycoprotein on the surface of influenza virus that destroys aninfected cell's receptor for viral hemagglutinin. By inhibiting viral neuraminidase, decreasesrelease of viruses from infected cells and thus viral spread. Effective to treat influenza A or BStart within 40 h of symptom onset. Available as 30-mg, 45-mg, and 75-mg oral capsules and asa powder for suspension that contains 12 mg/mL after reconstitution. Precautions in renalimpairment, chronic cardiac or respiratory disease, and breastfeeding; (preclinical trials have

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demonstrated death in young animals, possibly related to immature blood brain barriers);postmarketing reports (mostly from Japan) of self-injury and delirium in patients with influenza(reports primarily among children), unknown if oseltamivir directly contributes to this behavior(monitor for abnormal behavior throughout treatment period.

Pediatric dosing:

Treatmentfor acute illness and age

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Peramivir IV in certain patients The dose not to exceed 600 mg IV qd for 5-10 days, dilutewith 0.45% or 0.9% NaCl and infuse IV over 60 min.

Emergency-use authorization issued by US FDA for use of peramivir inhospitalized adult and pediatric patients with suspected or laboratory-confirmed2009 H1N1 influenza unresponsive to oseltamivir or zanamivir, unable to take PO or

inhaled drugs (or delivery route not dependable or feasible), or other circumstancesdetermined by clinician .

*Do not use Peramivir IV for the treatment of seasonal influenza A or Bvirus infections, for outpatients with acute uncomplicated 2009 H1N1virus infection or for pre- or post-exposure chemoprophylaxis(prevention) of influenza.[22]

Vaccination

Vaccines of H5N1

Human vaccination for avian influenza viruses has not been widely used, although multiplevaccination trials are underway. Prior avian vaccines in humans have been poorly immunogenicand thus have limited use. An inactivated H5N3 has been tested and was tolerated but withlimited immunogenicity. Other H5 vaccines have resulted in the development of neutralizingantibodies, but to a limited degree. Recently, a large randomized trial looked at an H5N1attenuated vaccine from the Vietnam strain [23].Only a modest immune response was seen, with microneutralization antibodies being developedat 12 times the dose used in the seasonal influenza vaccine. The side effects were minimal. Anumber of other industry trials with adjuvant vaccines are currently ongoing. Although promising,human vaccination against avian influenza viruses is still under development. Underscoring thisdevelopment is the uncertainty of a pandemic strain, which may have vastly different antigenicproperties from any developed H5 vaccine [1].

Vaccines of H1N1[24]

Four manufacturers are supplying the H1N1 vaccine. The vaccine is available as an Intramuscularinjection and as an intranasal product.

Influenza A virus vaccine (H1N1)

Available as monovalent, inactivated influenza A virus vaccine (H1N1) for IM injection. Indicatedfor active immunization against influenza caused by pandemic (H1N1) 2009 virus. Stimulatesactive immunity to influenza virus infection by inducing production of specific antibodies.AdultIM injection: 0.5 mL IM in deltoid muscle of upper arm (1 dose)PediatricIM injection (Sanofi Pasteur vaccine)6-35 months: 0.25 mL IM; administer 2 injections approximately 4 wk apart

3-9 years: 0.5 mL IM; administer 2 injections approximately 4 wk apart10-17 years: Administer as in adults

IM injection (Novartis vaccine)4-9 years: 0.5 mL IM; administer 2 injections approximately 4 wk apart10-17 years: Administer as in adults

Administer IM injection in anterolateral aspect of thigh for infants, and administer in deltoidmuscle of upper arm in toddlers and children.Avoid gluteal region or areas with major nerve trunk,

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PrecautionsGuillain-Barr syndrome has occurred within 6 wk of previous influenza vaccination;immunocompromised persons may have a diminished immune response to vaccine; commoninjection site adverse effects (10%) include tenderness, pain, redness, and swelling; commonsystemic adverse effects (10%) include headache, malaise, and myalgia; multidose vialcontains thimerosal, a mercury derivative.

*Trivalent seasonal influenza immunization is recommended for all children aged 6months through 18 years. Healthy children aged 2 through 18 years can receive either

TIV or LAIV [25].Also the combination of A (H1N1) vaccine with trivalent seasonal vaccine would havesignificant regulatory implications. [26]

Influenza A virus vaccine (H1N1), intranasal

Available as monovalent live virus vaccine for intranasal administration. Indicated for activeimmunization against influenza caused by pandemic (H1N1) 2009 virus. Stimulates activeimmunity to influenza virus infection by inducing production of specific antibodies.

Dose:AdultIntranasal (10-49 years): 0.2 mL/dose (0.1 mL per nostril) intranasally (1 dose)

PediatricIntranasal (MedImmune vaccine)

2-9 years: 0.2 mL/dose (0.1 mL per nostril) intranasally; administer 2 doses approximately 4 wkapart>9 years: Administer as in adults

PrecautionsGuillain-Barr syndrome has occurred within 6 wk of previous influenza vaccination; adverseeffects include rhinitis, nasal congestion, fever >100F in children aged 2-6 y, and sore throat inadults; administer intranasal vaccine with caution to individuals with asthma or recurrentwheezing; intranasal vaccine has potential for viral transmission to immunocompromisedhousehold contacts.

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1-Christian Sandrock, Terra KellyCritical Care 2007, 11:209 (doi:10.1186/cc5675).

2. World Health Organization Expert Committee: A revision of thesystem of nomenclature for influenza viruses: a WHO Memorandum.Bull WHO 1980, 58:585-591.

3-Couceiro JN, Paulson JC, Baum LG: Influenza virus strainsselectively recognize sialyloligosaccharides on human respiratoryepithelium: the role of the host cell in selection ofhemagglutinin receptor specificity. Virus Res 1993, 29:155-165

4-Matrosovich MN, Matrosovich TY, Gray T, Roberts NA, Klenk HD:Human and avian influenza (AI) viruses target different celltypes in cultures of human airway epithelium. Proc Natl AcadSci USA 2004, 101:4620-4624

5-Webster RG, Bean WJ, Gorman OT, Chambers TM, Kawaoka Y:Evolution and ecology of influenza A viruses. Microbiol Rev1992, 56:152-179.

6-Buxton Bridges C, Katz JM, Seto WH, Chan PK, Tsang D, Ho W,Mak KH, Lim W, Tam JS, Clarke M, et al.: Risk of influenza A(H5N1) infection among health care workers exposed topatients with influenza A (H5N1), Hong Kong.J Infect Dis2000, 181:344-348

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22-Peramivir EUA, Fact Sheet for HCP Authorized by FDA on October 23, 2009

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24- www.pediatrics.org/cgi/doi/10.1542/peds.2009-1806 Policy Statement

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26-Recommendations of the Strategic Advisory Group of Experts(SAGE) on Influenza A (H1N1) vaccines .19 May 2009