INFLUENZA Practice Essentials The US Centers for Disease Control and Prevention (CDC) estimates that seasonal influenza

is responsible for an average of more than 20,000 deaths annually.[1] Mortality is highest in infants and the elderly. The 2012-2013 season was notable for widespread disease and a higher death rate than was reported in previous years. In addition, the predominant influenza virus subtype was an H3N2, in contrast to dominance by H1N1 subtypes in recent past years.[2] Essential update: Diabetes increases risk of severe flu-related illness In a recent cohort study of 166,715 individuals in Manitoba, Canada, Lau and colleagues found that adults with diabetes, compared with those without diabetes, are at significantly greater risk for serious illness related to influenza, justifying guideline recommendations for influenza vaccination in this population. After controlling for age, sex, socioeconomic status, location of residence, comorbidities, and vaccination, adults with diabetes had a significant 6% increase in all-cause hospitalizations associated with influenza (P = .044). Only 16% of the diabetic patients in the cohort and 7% of the nondiabetic patients had been vaccinated.[3, 4] Signs and symptoms The presentation of influenza virus infection varies, but it usually includes many of the following signs and symptoms: Fever Sore throat Myalgias Frontal or retro-orbital headache Nasal discharge Weakness and severe fatigue Cough and other respiratory symptoms Tachycardia Red, watery eyes The incubation period of influenza is 2 days long on average but may range from 1 to 4 days in length. Aerosol transmission may occur 1 day before the onset of symptoms[5] ; thus, it may be possible for transmission to occur via asymptomatic persons or persons with subclinical disease, who may be unaware that they have been exposed to the disease.[6, 7] See Presentation for more detail. Diagnosis Influenza has traditionally been diagnosed on the basis of clinical criteria, but rapid diagnostic tests, which have a high degree of specificity but only moderate sensitivity, are becoming more widely used. The criterion standard for diagnosing influenza A and B is a viral culture of nasopharyngeal samples or throat samples. In elderly or high-risk patients with pulmonary symptoms, chest radiography should be performed to exclude pneumonia. Avian influenza

Avian influenza (H5N1) is rare in humans in developed countries. Unless advised by the CDC or regional health departments, clinicians do not routinely need to test for avian influenza. See Workup for more detail. Management Prevention Prevention of influenza is the most effective management strategy. Influenza A and B vaccine is administered each year before flu season. The CDC analyzes the vaccine subtypes each year and makes any necessary changes on the basis of worldwide trends. Traditionally, the vaccine is trivalent (ie, designed to provide protection against 3 viral subtypes, generally an A-H1, an A-H3, and a B). The first quadrivalent vaccines, which also provide coverage against a second influenza B subtype, were approved in 2012 and were made available for the 2013-2014 flu season.[8, 9] The FDA has approved a vaccine for H5N1 influenza. It is available only to government agencies and for stockpiles.[10] In addition to vaccination, other public health measures are also effective in limiting influenza transmission in closed environments. Enhanced surveillance with daily temperature taking and prompt reporting with isolation through home medical leave and segregation of smaller subgroups decrease the spread of influenza.[11] Treatment In the United States, the following prescription antiviral drugs have been approved for treatment and chemoprophylaxis of influenza and are active against recently circulating subtypes of influenza: Oseltamivir Zanamivir See Treatment and Medication for more detail. Image library

Chest radiograph of severe lung disease in a patient with avian influenza.

Background Influenza, one of the most common infectious diseases, is a highly contagious airborne disease that occurs in seasonal epidemics and manifests as an acute febrile illness with variable degrees of systemic symptoms, ranging from mild fatigue to respiratory failure and death. Influenza causes significant loss of workdays, human suffering, and mortality. Although the seasonal strains of influenza virus that circulate in the annual influenza cycle constitute a substantial public health concern, far more lethal influenza strains than these have emerged periodically. These deadly strains produced 3 global pandemics in the last century, the worst of which occurred in 1918. Called the Spanish flu (though cases appeared earlier in the United States and elsewhere in Europe), this pandemic killed an estimated 20-50 million persons, with 549,000 deaths in the United States alone.[12] Besides humans, influenza also infects a variety of animal species. Some of these influenza strains are species-specific, but new strains may spread from other animals to humans (see Pathophysiology). The term avian influenza, in this context, refers to zoonotic human infection with an influenza strain that primarily affects birds. Swine influenza refers to infections from strains derived from pigs. The 2009 influenza pandemic was a recombinant influenza involving a mix of swine, avian, and human gene segments (see H1N1 Influenza [Swine Flu]). The signs and symptoms of influenza overlap with those of many other viral upper respiratory tract infections (URIs). A number of viruses, including human parainfluenza virus, adenoviruses, enteroviruses, and paramyxoviruses, may initially cause influenzalike illness. The early presentation of mild or moderate cases of flavivirus infections (eg, dengue) may initially mimic influenza. For example, some cases of West Nile fever acquired in New York in 1999 were clinically misdiagnosed as influenza.[6] (See DDx.) When influenza viruses are circulating in the community, clinicians can often diagnose influenza on the basis of clinical criteria alone (see Presentation). Rapid diagnostic tests for influenza that can provide results within 30 minutes and can help confirm the diagnosis. It should be kept in mind, however, that these rapid tests have limited sensitivities and predictive values; false-negative results are common, especially when influenza activity is high, and false-positive results can also occur, especially when influenza activity is low.[13] Nevertheless, influenza virus testing may be considered if the results will change the clinical care of the patient (especially if the patient is hospitalized or has a high-risk condition) or influence the care of other patients.[13] The criterion standard for confirming influenza virus infection is reverse transcription-polymerase chain reaction (RT-PCR) testing or viral culture of nasopharyngeal or throat secretions. However, culture may require 3-7 days, yielding results long after the patient has left the clinic, office, or emergency department and well past the time when drug therapy could be efficacious. Prevention of influenza is the most effective strategy. Each year in the United States, a vaccine that contains antigens from the strains most likely to cause infection during

the winter flu season is produced. The vaccine provides reasonable protection against immunized strains, becoming effective 10-14 days after administration. Antiviral agents are also available that can prevent some cases of influenza; when given after the development of influenza, they can reduce the duration and severity of illness. (See Treatment.) For information on influenza in children, see Pediatric Influenza. For patient education information, see Colds, Flu in Adults, and Flu in Children. Pathophysiology Influenza viruses are encapsulated, negative-sense, single-stranded RNA viruses of the family Orthomyxoviridae. The core nucleoproteins are used to distinguish the 3 types of influenza viruses: A, B, and C. Influenza A viruses cause most human and all avian influenza infections. The RNA core consists of 8 gene segments surrounded by a coat of 10 (influenza A) or 11 (influenza B) proteins. Immunologically, the most significant surface proteins include hemagglutinin (H) and neuraminidase (N). Hemagglutinin and neuraminidase are critical for virulence, and they are major targets for the neutralizing antibodies of acquired immunity to influenza. Hemagglutinin binds to respiratory epithelial cells, allowing cellular infection. Neuraminidase cleaves the bond that holds newly replicated virions to the cell surface, permitting the infection to spread.[14] Major typing of influenza A occurs through identification of both H and N proteins. Nine H and 16 N types have been identified. All hemagglutinins and neuraminidases infect wild waterfowl, and the various combinations of H and N yield 144 potential subtypes of influenza. The hemagglutinin and neuraminidase variants are used to identify influenza A virus subtypes. For example, influenza A subtype H3N2 expresses hemagglutinin 3 and neuraminidase 2. The most common subtypes of human influenza virus identified to date contain only hemagglutinins 1, 2, and 3 and neuraminidases 1 and 2. H3N2 and H1N1 are the most common prevailing influenza A subtypes that infect humans. Each year, the trivalent vaccine used worldwide contains influenza A strains from H1N1 and H3N2, along with an influenza B strain. Because the viral RNA polymerase lacks error-checking mechanisms, the year-toyear antigenic drift is sufficient to ensure that there is a significant susceptible host population each year. However, the segmented genome also has the potential to allow reassortment of genome segments from different strains of influenza in a coinfected host. Interspecies spread In addition to humans, influenza also infects a variety of animal species. More than 100 types of influenza A infect most species of birds, pigs, horses, dogs, and seals. Influenza B has also been reported in seals, and influenza C has been reported, though rarely, in pigs. Some of these influenza strains are species-specific. The species specificity of

influenza strains is partly due to the ability of a given hemagglutinin to bind to different sialic acid receptors on respiratory tract epithelial cells. Avian influenza viruses generally bind to alpha-2,3-sialic acid receptors, whereas human influenza viruses bind to alpha-2,6-sialic acid receptors. In this context, the term avian influenza (or bird flu) refers to zoonotic human infection with an influenza strain that primarily affects birds. Swine influenza refers to infections from strains derived from pigs. New strains of influenza may spread from other animal species to humans, however. Alternatively, an existing human strain may pick up new genes from a strain that usually infects birds or pigs. Antigenic drift and shift Influenza A is a genetically labile virus, with mutation rates as high as 300 times that of other microbes.[15] Changes in its major functional and antigenic proteins occur by means of 2 well-described mechanisms: antigenic drift and antigenic shift. Antigenic drift is the process by which inaccurate viral RNA polymerase frequently produces point mutations in certain error-prone regions in the genes. These mutations are ongoing and are responsible for the ability of the virus to evade annually acquired immunity in humans. Drift can also alter the virulence of the strain. Drift occurs within a set subtype (eg, H2N2). For example, AH2N2 Singapore 225/99 may reappear with a slightly altered antigen coat as AH2N2 New Delhi 033/01. Antigenic shift is less frequent than antigenic drift. In a shift event, influenza genes between 2 strains are reassorted, presumably during coinfection of a single host. Segmentation of the viral genome, which consists of 10 genes on 8 RNA molecules, facilitates genetic reassortment. Because pigs have been susceptible to both human and avian influenza strains, many experts believe that combined swine and duck farms in some parts of Asia may have facilitated antigenic shifts and the evolution of previous pandemic influenza strains. The reassortment of an avian strain with a mammalian strain may produce a chimeric virus that is transmissible between mammals; such mutation products may contain H or N proteins that are unrecognizable to the immune systems of mammals. This antigenic shift results in a much greater population of susceptible individuals in whom more severe disease is possible. Such an antigenic shift can result in a virulent strain of influenza that possesses the triad of infectivity, lethality, and transmissibility and can cause a pandemic. Three major influenza pandemics have been recorded: The Spanish influenza pandemic of 1918 (H1N1) The pandemic of 1957 (H2N2) The pandemic of 1968 (H3N2) Smaller outbreaks occurred in 1947, 1976, 1977, and 2009. Transmission and infection Transmission of influenza from poultry or pigs to humans appears to occur predominantly as a result of direct contact with infected animals. The risk is

especially high during slaughter and preparation for consumption; eating properly cooked meat poses no risk. Avian influenza can also be spread through exposure to water and surfaces contaminated by bird droppings.[16] Influenza viruses spread from human to human via aerosols created when an infected individual coughs or sneezes. Infection occurs after an immunologically susceptible person inhales the aerosol. If not neutralized by secretory antibodies, the virus invades airway and respiratory tract cells. Once the virus is within host cells, cellular dysfunction and degeneration occur, along with viral replication and release of viral progeny. As in other viral infections, systemic symptoms result from release of inflammatory mediators. The incubation period of influenza ranges from 1 to 4 days. Aerosol transmission may occur 1 day before the onset of symptoms[5] ; thus, it may be possible for transmission to occur via asymptomatic persons or persons with subclinical disease, who may be unaware that they have been exposed to the disease.[6, 17, 7] Viral shedding Viral shedding occurs at the onset of symptoms or just before the onset of illness (024 hours). Shedding continues for 5-10 days. Young children may shed virus longer, placing others at risk for contracting infection. In highly immunocompromised persons, shedding may persist for weeks to months.[17] H5N1 avian influenza To date, avian influenza (H5) remains a zoonosis. The vast majority of cases of avian influenza have been acquired from direct contact with live poultry, with no sustained human-to-human transmission. Hemagglutinin type 5 attaches well to avian respiratory cells and thus spreads easily among avian species. However, attachment to human cells and resultant infection is more difficult. Avian viruses tend to prefer sialic acid alpha(2-3) galactose, which, in humans, is found in the terminal bronchi and alveoli. Conversely, human viruses prefer sialic acid alpha(2-6) galactose, which is found on epithelial cells in the upper respiratory tract.[18] Although this results in a more severe respiratory infection, it probably explains why few, if any, definite human-to-human transmissions of avian influenza have been reported: infection of the upper airways is probably required for efficient spread via coughing and sneezing. Most human deaths from bird flu have occurred in Indonesia. Sporadic outbreaks among humans have continued elsewhere, including China, Egypt, Thailand, and Cambodia.[19] In theory, however, mutation of the hemagglutinin protein through antigenic drift could result in a virus capable of binding to upper and lower respiratory epithelium, creating a strain that is easily transferred from human to human and thus could cause a worldwide pandemic. Etiology

Influenza results from infection with 1 of 3 basic types of influenza virus: A, B, or C. Influenza A is generally more pathogenic than influenza B. Epidemics of influenza C have been reported, especially in young children.[20] In the United States, during the 2011-2012 influenza season, H3N2 viruses predominated overall, but H1N1 and influenza B viruses also circulated widely.[21] Influenza viruses are classified within the family Orthomyxoviridae. Avian influenza (ie, human infection with avian H5N1 influenza virus) is transmitted primarily through direct contact with diseased or deceased birds infected with the virus. Contact with excrement from infected birds or contaminated surfaces or water are also considered mechanisms of infection. Close and prolonged contact of a caregiver with an infected person is believed to have resulted in at least 1 case. Other specific risk factors are not apparent, given the few cases to date. Epidemiology In tropical areas, influenza occurs throughout the year. In the Northern Hemisphere, the influenza season typically starts in early fall, peaks in mid-February, and ends in the late spring of the following year. The duration and severity of influenza epidemics vary, however, depending on the virus subtype involved. The World Health Organization estimates that worldwide, annual influenza epidemics result in about 3-5 million cases of severe illness and about 250,000 to 500,000 deaths.[22] In the United States, individual cases of seasonal flu and flu-related deaths in adults are not reportable illnesses; consequently, mortality is estimated by using statistical models.[1] The US Centers for Disease Control and Prevention (CDC) estimates that fluassociated deaths in the US ranged from about 3000 to 49,000 annually between 1976 and 2006. The CDC notes that the often-cited figure of 36,000 annual flu-related deaths was derived from years when the predominant virus subtype was H3N2, which tends to be more lethal than H1N1.[1] Unlike adult flu-related deaths, pediatric flu-related deaths are reportable in the United States. (See Pediatric Influenza.) For the 2011-2012 influenza season, which was mild in comparison with preceding years, 26 laboratory-confirmed influenzaassociated pediatric deaths were reported.[21] The 2012-2013 season, in which the predominant virus subtype was an H3N2, was notable for widespread disease and a higher mortality than the previous years. By March 3, 2013, a total of 87 influenzaassociated pediatric deaths had been reported.[23] The following statistics are offered for comparison: The 1918 H1N1 influenza pandemic caused 500,000-700,000 deaths in the United Statesalmost 200,000 of them in October 1918 aloneand an estimated 3040 million deaths worldwide, mostly among people aged 15-35 years The 1957 H2N2 influenza pandemic (Asian flu) caused an estimated 70,000 deaths in the United States and 1-2 million fatalities worldwide The 1968 H3N2 influenza pandemic (Hong Kong flu) caused an estimated 34,000 deaths in the United States and 700,000 to 1 million fatalities worldwide In contrast to typical influenza seasons, the 2009-2010 influenza season was affected

by the H1N1 (swine flu) influenza epidemic, the first wave of which hit the United States in the spring of 2009, followed by a second, larger wave in the fall and winter; activity peaked in October and then quickly declined to below baseline levels by January, but small numbers of cases were reported through the spring and summer of 2010.[24] In addition, the effect of H1N1 influenza across the lifespan differed from that of typical influenza. Disease was more severe among people younger than 65 years than in nonpandemic influenza seasons, with significantly higher pediatric mortality and higher rates of hospitalizations in children and young adults. Of the 477 reported H1N1-associated deaths from April to August 2009, 36 were in children younger than 18 years; 67% of those children had 1 or more high-risk medical conditions.[24] No cases of the highly pathogenic H5N1 influenza have been reported in humans or birds in the United States. Frequently updated information on H5N1 avian influenza cases and pandemic flu preparedness is available from the CDC.[25] Two case reports describe humans infected with another avian influenza virus, H7N2, one in Virginia in 2002 and the other in New York in 2003. The patients had no characteristic symptoms, but the first had positive serologic results and the second had mild respiratory symptoms. As of June 2013, 630 cases of avian influenza had been reported by the World Health Organization (WHO) worldwide, with 375 deaths.[19] Currently, reporting from areas with poor access to health care may be limited to clinically severe cases; illness that does not fulfill WHO diagnostic criteria is not reported.[26] Most cases have been in eastern Asia; some cases have been reported in Eastern Europe and North Africa (see the image below). Underreporting has been a concern, particularly in China, but the prevailing attitude about the need to suspect, test, and report cases of avian influenza is growing. In 2013, cases were reported in Cambodia, Vietnam, China, Egypt, and Bangladesh.

Countries where avian influenza has been reported. Image courtesy of the World Health Organization. Prognosis In patients without comorbid disease who contract seasonal influenza, the prognosis is very good. However, some patients have a prolonged recovery time and remain weak and fatigued for weeks. Mortality from seasonal influenza is highest in infants and the elderly.

The prognosis for patients with avian influenza is related to the degree and duration of hypoxemia. Cases to date have exhibited a 60% mortality; however, Wang et al suggest that this may be an overestimate stemming from the underreporting of mild cases.[26] The risk of mortality from avian influenza depends on the degree of respiratory disease rather than on the bacterial complications (pneumonia). Mortality is significantly lower among patients cared for in more-developed nations. Little evidence is available regarding the long-term effects of disease among survivors. 2013-2014 season In December 2013, the CDC issued a health advisory based on reports of severe respiratory illness among young and middle-aged adults, including a number who were infected with influenza A (H1N1) pdm09 (pH1N1) virus, the strain responsible for the 2009 influenza pandemic. Concerns have been raised that if the virus continues to circulate widely during the 2013-14 flu season, young and middle-aged adults will be disproportionately affected.[27, 28] According to the CDC, evidence from previous flu seasons, including from the 2009 pandemic, indicates that antiviral medications initiated as early as possible after the onset of illness reduce severe influenza outcomes. History The presentation of influenza virus infection varies; however, it usually includes many of the symptoms described below. Patients with influenza who have preexisting immunity or who have received vaccine may have milder symptoms. Onset of illness can occur suddenly over the course of a day, or it can progress more slowly over the course of several days. Typical signs and symptoms include the following (not necessarily in order of prevalence): Cough and other respiratory symptoms Fever Sore throat Myalgias Headache Nasal discharge Weakness and severe fatigue Tachycardia Red, watery eyes Cough and other respiratory symptoms may be initially minimal but frequently progress as the infection evolves. Patients may report nonproductive cough, coughrelated pleuritic chest pain, and dyspnea. In children, diarrhea may be a feature. Fever may vary widely among patients, with some having low fevers (in the 100F range) and others developing fevers as high as 104F. Some patients report feeling feverish and feeling chills. Sore throat may be severe and may last 3-5 days. The sore throat may be a significant reason why patients seek medical attention. Myalgias are common and range from mild to severe. Frontal or retro-orbital

headache is common and is usually severe. Ocular symptoms develop in some patients with influenza and include photophobia, burning sensations, or pain upon motion. Some patients with influenza develop rhinitis of varying severity, but it is generally not the chief symptom. Weakness and severe fatigue may prevent patients from performing their normal activities or work. Patients report needing additional sleep. In some cases, patients with influenza may be bedridden. The incubation period of influenza averages 2 days but may range from 1 to 4 days in length. Because of aerosol transmission, and the possibility (albeit less likely) of transmission by asymptomatic persons and contaminated surfaces, the patient may be unaware of exposure to the disease.[17] 2009-2010 H1N1 influenza pandemic In the 2009-2010 H1N1 influenza pandemic, initial symptoms included the following: High fever Myalgias Rhinorrhea Sore throat Nausea and vomiting Diarrhea For more information, see the article H1N1 Influenza (Swine Flu) Physical Examination The general appearance varies among patients who present with influenza. Some patients appear acutely ill, with some weakness and respiratory findings, whereas others appear only mildly ill. Upon examination, patients may have some or all of the following findings: Fever of 100-104F; fever is generally lower in elderly patients than in young adults Tachycardia, which most likely results from hypoxia, fever, or both Pharyngitis - Even in patients who report a severely sore throat, findings may range from minimal infection to more severe inflammation Eyes may be red and watery Skin may be warm to hot, depending on core temperature status; patients who have been febrile with poor fluid intake may show signs of mild volume depletion with dry skin Pulmonary findings may include dry cough with clear lungs or rhonchi, as well as focal wheezing Nasal discharge is absent in most patients Fatigued appearance Acute encephalopathy has been associated with influenza A virus infection. In a case series of 21 patients, Steininger et al described clinical, cerebrospinal fluid (CSF), magnetic resonance imaging (MRI), and electroencephalographic (EEG) findings.[29] Clinical features included altered mental status, coma, seizures, and ataxia. Of patients who underwent further testing, most had abnormal CSF, MRI, and EEG

findings. Complications Primary influenza pneumonia is characterized by progressive cough, dyspnea, and cyanosis following the initial presentation. Chest radiographs show bilateral diffuse infiltrative patterns, without consolidation, which can progress to a presentation similar to acute respiratory distress syndrome (ARDS). Risks for viral pneumonia involve complex host immune responses and viral virulence. Women in the third trimester of pregnancy are at higher risk, as they are for other complications of influenza A and B. The elderly, especially nursing home patients, and those with cardiovascular disease are usually the groups at highest risk; however, particular influenza strains may target younger persons. For example, in the 1918-1919 epidemic, many young adults died of a pneumonia that some experts believe was caused directly by the virus.[12] Secondary bacterial pneumonia can occur from numerous pathogens (eg, Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae). The most dreaded complication is staphylococcal pneumonia, which develops 2-3 days after the initial presentation of viral pneumonia. Patients appear severely ill, with productive bloody cough, hypoxemia, an elevated white blood cell (WBC) count, and multiple cavitary infiltrates on chest radiography.[30] A study from Israel found an increase in S pneumoniae bacteremia during regular influenza seasons; in addition, during the 2009-2010 H1N1 influenza pandemic, there were higher rates of Spneumoniae bacteremia among children (but not among adults) and higher rates of S aureus and Streptococcus pyogenes infections in all age groups.[31] Methicillin-susceptible S aureus( MSSA) and methicillin-resistant S aureus (MRSA) pneumonias have occurred after influenza pneumonia. MRSA pneumonia may be severe and difficult to treat, and deaths have occurred within 24 hours of presentation of pneumonia symptoms. S pneumoniae or H influenzae pneumonia, if occurring as a complication, usually develops 2-3 weeks after the initial symptoms of influenza. These cases can be managed as a community-acquired pneumonia, in accordance with standard antibiotic and admission-discharge guidelines. Myositis is a rare complication. This group of patients may develop frank rhabdomyolysis, with elevated creatine kinase levels and myoglobinuria. Myocarditis and pericarditis have been associated with influenza infections.[32] A review of avian influenza cases in 4 countries found that the clinical course progressed to ARDS and respiratory failure in 70-100% of patients.[33] The mean time to the development of ARDS was 6 days. Lymphopenia at presentation is a significant predictor of the progression to ARDS and death.[34]

Severe cases of avian influenza may progress to multiorgan failure. In a study of 12 hospitalized patients with confirmed H5N1 influenza, 75% had respiratory failure, 42% had cardiac failure, and 33% had renal failure.[33] Diagnostic Considerations Accurately diagnosing influenza A or B infection solely on the basis of clinical criteria is difficult because of the overlapping symptoms caused by the various viruses associated with upper respiratory tract infection (URI). Viruses that may initially cause influenzalike symptoms include adenoviruses, enteroviruses, and paramyxoviruses. The early presentation of mild or moderate cases of flavivirus infections (eg, dengue) may initially mimic influenza. For example, some cases of West Nile fever acquired in New York in 1999 were clinically misdiagnosed as influenza.[6] Like influenza, URIs from these viruses are more common in the winter. As a result, during the winter, clinics and emergency department waiting rooms fill with patients who have influenza or other URIs. Influenza pneumonia must be differentiated from other forms of viral pneumonia, bacterial pneumonia, and noninfectious causes of respiratory distress, such as heart failure, chronic obstructive pulmonary disease, pulmonary edema, and aspiration pneumonitis. H5N1 avian influenza Risk factors or features that should raise the index of suspicion of H5N1 avian influenza include the following[35] : Recent (within the preceding 2 weeks) travel to or location in a country with known avian influenza cases in animals or humans Unusual comorbidities such as encephalopathy or diarrhea History of exposure to birds, especially living in close proximity to birds, contact with sick or dying birds, or consumption of incompletely cooked bird meat History of exposure to individuals with known avian influenza, especially family, or to sick people in a country with known human cases of avian influenza The situation can be complicated during outbreaks of severe respiratory disease other than avian influenza. The first case of laboratory-confirmed avian influenza infection was documented during the severe acute respiratory syndrome (SARS) outbreak of 2002-2003 and was mistakenly misdiagnosed as SARS.[36] Cases of avian influenza in which respiratory disease was limited or not apparent (with even normal chest radiography findings) have been described, though they account for only a small percentage of cases overall.[35] The primary presenting illness has been encephalitis or diarrhea. Differential Diagnoses Acute Respiratory Distress Syndrome Adenoviruses Arenaviruses

 Cytomegalovirus Dengue Fever Echoviruses Hantavirus Pulmonary Syndrome HIV Disease Legionnaires Disease Parainfluenza Virus Approach Considerations The criterion standard for confirming influenza virus infection is reverse transcription-polymerase chain reaction (RT-PCR) or viral culture of nasopharyngeal or throat secretions. Rapid diagnostic tests for influenza are available and are becoming more widely used. These tests have high specificity but only moderate sensitivity. Findings of standard laboratory studies, such as a complete blood count (CBC) and electrolyte levels, are nonspecific but helpful in the workup of influenza. Leukopenia and relative lymphopenia are typical findings. Thrombocytopenia may be present. In severe cases of influenza, the patient is likely to have hypoxemia, and the alveolararterial (A-a) gradient may be increased (>35 mm Hg). Patients with physical examination findings compatible with meningitis should undergo lumbar puncture. Rapid Diagnostic Tests The US Food and Drug Administration (FDA) has waived federal Clinical Laboratories Improvement Act (CLIA) requirements and cleared for marketing 7 rapid influenza diagnostic tests that directly detect influenza A or B virus associated antigens or enzyme in throat swabs, nasal swabs, or nasal washes. These tests can produce results within 30 minutes.[37] A meta-analysis examining the accuracy of rapid influenza diagnostic tests found a pooled sensitivity of 62% and specificity of 98%.[38] The tests tended to be more sensitive in children (67%) than in adults (54%) and better at detecting influenza A (65%) than influenza B (52%). The accuracy of these tests depends in part on the collection technique and skill of the person performing the test. Nasal swabs must be deeply inserted and then swirled to attach the influenza virus. The following 3 rapid diagnostic tests are considered of low complexity and may be used in physicians offices: QuickVue Influenza A+B test (Quidel) ZstatFlu (ZymeTx) QuickVue Influenza test (Quidel) The QuickVue tests provide results in 10 minutes or less; the ZstatFlu test provides results in 20 minutes. Genetic and antigenic changes in the virus can adversely affect diagnostic test performance; thus, these tests should be monitored annually.[39]

Viral Culture and Polymerase Chain Reaction Testing RT-PCR testing or viral culture of nasopharyngeal or throat secretions is the criterion standard for confirming influenza virus infection. Culture may require 3-7 days, yielding results long after the patient has left the clinic, office, or emergency department and well past the time when drug therapy could be efficacious. Viral culture For viral culture, nasopharyngeal samples are obtained with Dacron swabs and sent in appropriate viral transport media (eg, multimicrobe [M4] transport media) to the laboratory to be cultured in several lines of cells. A laboratory diagnosis of influenza is established once specific cytopathic effect is observed or hemadsorption testing findings are positive. For example, staining the infected cultured cell lines with fluorescent antibody confirms the diagnosis. Polymerase chain reaction tests Most laboratories and hospitals now offer nucleic acid (PCR)-based studies. A nasal swab is submitted in special transport media to the laboratory, and results can be available within 24 hours. Sensitivity for influenza is greater than 90%. These tests may be offered as respiratory panels that provide information on the presence of other viruses, such as respiratory syncytial virus (RSV) and adenovirus. The FDA has approved an influenza RT-PCR test developed by the US Centers for Disease Control and Prevention (CDC) that can provide results within 4 hours. It is the only in vitro diagnostic test for influenza that is cleared by the FDA for use with lower respiratory tract specimens.[13] Consisting of 3 modules, the kit can do the following: Identify and distinguish between influenza A and B viruses Classify influenza A viruses by subtype Detect highly pathogenic avian influenza A (H5N1) virus infection in human respiratory tract specimens Direct Immunofluorescent Tests and Serologic Testing Some laboratories offer direct immunofluorescent tests on fresh specimens, but these tests are labor- and personnel-intensive and are less sensitive than culture methods. In order to overcome the expensive and time-consuming obstacle of culturing, several serologic tests have become available. In reality, many of these are not bedside tests; generally, 30-60 minutes are required to perform the tests multiple steps. Test sensitivities generally range from 60-70%. A study by Haran et al suggests that cytokine markers may help distinguish influenza from bacterial pneumonia or other viral respiratory infections. In this study, differences were observed between the bacterial pneumonia group, on one hand, and all other viral infections grouped together, on the other, with regard to interleukin (IL)-4, IL-5, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon gamma levels. However, IL-10 concentrations were uniquely elevated in patients with influenza (88.69 pg/mL) as compared with all other groups combined (39.19 pg/mL; P = .003).[40]

Testing for Avian Influenza The standard commercially available rapid influenza A tests do not detect H5N1 avian influenza.[41] A rapid test from nasopharyngeal swab specific to H5N1 influenza (Arbor Vita Corporation) was approved by the FDA in 2009.[42] A CBC may be more clinically useful in avian influenza than in seasonal influenza. Leukopenia (WBC count 454-4900/L), especially lymphopenia, is common and is observed in 50-80% of patients.[43] In at least one study, lymphopenia at presentation (absolute lymphocyte count < 1500/L) was a significant predictor of the progression to acute respiratory distress syndrome.[44] More than half of patients will have mildto-moderate thrombocytopenia. In addition to thrombocytopenia, some patients with severe disease will develop disseminated intravascular coagulation (DIC), as shown in coagulation studies.[16] Liver function tests (LFTs) may be useful in differentiating avian influenza from other febrile tropical diseases. Aminotransferase levels are elevated in more than half of all patients with H5N1 infection.[16] A basic metabolic panel is generally required in the care of all seriously or critically ill patients. Abnormalities in renal function may herald the progression to organ failure. According to CDC recommendations,[34] clinicians should attempt to specifically identify avian H5N1 influenza in patients with all of the following characteristics: Severe illness that necessitates hospitalization or is fatal Documented temperature of 38C (100.4F) or higher in the past 24 hours or a history of feverishness during that time Radiographically confirmed pneumonia, acute respiratory distress syndrome (ARDS), or other severe respiratory illness for which an alternative diagnosis has not been established At least 1 potential exposure within 7 days of symptom onset Testing may be considered in discussion with public health authorities in patients who have only some of these characteristics; all testing should be discussed with local public health departments. The CDC defines potential exposure as follows: History of travel to a country where highly pathogenic avian influenza (HPAI) H5N1 virus has been documented in poultry, wild birds, or humans, with potential exposure to the virus during the visit Close contact (approach within ~6 ft) with an ill person who was under investigation for possible HPAI H5N1 virus infection Working with live HPAI H5N1 virus in a laboratory If avian influenza is suspected, cultures should not be ordered without guidance from a public health laboratory. Many laboratories are not equipped to deal with the isolation needed to safely contain avian influenza (biosafety category 3+ containment, which is higher than that used for HIV). If a sample is accidentally handled, the laboratory may have to be shut down for decontamination.

Samples from patients with suspected avian influenza should be sent to a dedicated central reference laboratory, such as that at the CDC. The CDC laboratory can perform antiviral sensitivity testing, as well as subtyping of the virus. The best specimens are material collected with oropharyngeal swabs, material from bronchoalveolar washes, or tracheal aspirates. Specimens from nasopharyngeal swabs are acceptable, but they may contain a low quantity of the virus. The CDC recommends obtaining multiple respiratory specimens from different sites on at least 2 consecutive days, as soon as possible after illness onsetideally, within the first 7 days.[34] Pneumatic tubing is not recommended for transport; hand transport using a leakproof specimen bag is preferred. The specimen should be clearly labeled as suspected AI, and the person who transports the specimen should use appropriate protective equipment.[34] Testing for H7N9 In a June 7, 2013 Health Update, the CDC recommended that only patients who meet specific exposure criteria and have respiratory illness severe enough to require hospitalization should be tested for avian influenza A (H7N9). The recommendations include the following[45, 46] : Clinicians should consider H7N9 testing by reverse-transcription polymerase chain reaction (RT-PCR) assay for patients who meet both clinical criteria (new onset of acute respiratory infection that is severe enough to require hospitalization, and lack of identification of an alternative infectious etiology) and exposure criteria (travel within 10 days of symptom onset to areas with known human cases of H7N9 infection or to areas where H7N9 viruses are circulating in animals, or close contact with confirmed human cases of H7N9 infection) In cases in which human H7N9 infection is suspected on the basis of current screening recommendations, respiratory specimens should be collected using infection precautions for novel virulent influenza viruses; the swab or aspirate should be placed in viral transport medium, and the state or local health department should be contacted to arrange transport to the appropriate health department for testing (viral culture should not be performed in these cases) Rapid influenza diagnostic tests may not identify H7N9 in respiratory specimens, and a negative test result does not exclude H7N9 infection; in addition, a positive test result for influenza A is unable to distinguish between influenza A virus subtypes, so it cannot confirm avian influenza virus infection; respiratory specimens should be obtained and sent for RT-PCR assay at a state public health laboratory when rapid influenza diagnostic tests are positive for influenza in patients suspected of having novel influenza A virus infection Chest Radiography In elderly or high-risk patients with pulmonary symptoms, chest radiography is indicated to exclude pneumonia. Early radiographic findings include no or minimal bilateral symmetrical interstitial infiltrates. Later, bilateral symmetrical patch infiltrates become visible. Focal infiltrates indicate superimposed bacterial pneumonia.

With avian influenza, pulmonary infiltrates are seen in almost all patients. The widely varied radiographic characteristics range from diffuse or patchy infiltrates to lobar multilobar consolidation. Effusions and lymphadenopathy are also observed, as well as cystic changes (see the image below).

Chest radiograph of severe lung disease in a patient with avian influenza. In avian influenza, the severity of radiologically apparent disease is a good predictor of mortality, including findings consistent with ARDS, such as a diffuse, bilateral ground-glass appearance. Approach Considerations Prevention is the most effective management strategy for influenza. To prevent seasonal flu, the Advisory Committee on Immunization Practices (ACIP) of the US Centers for Disease Control and Prevention (CDC) recommends routine annual influenza vaccination for all persons aged 6 months or older, preferably before the onset of influenza activity in the community.[47] The ACIP also publishes recommendations on the use of antiviral agents for prevention and treatment of influenza.[48] The ACIP's 2014 Adult Immunization Schedule for influenza vaccine includes information about the recombinant influenza vaccine and addresses the use of this vaccine and the inactivated influenza vaccine in patients with egg allergy. Additional changes have been made for Td/Tdap vaccine, varicella vaccine, human papillomavirus vaccine, zoster vaccine, 13-valent pneumococcal conjugate and 23valent pneumococcal polysaccharide vaccines, meningococcal vaccine, and Haemophilus influenzae type B vaccine.[49] In a statement issued in September 2013, the American Academy of Pediatrics (AAP) recommended that all children aged 6 months or older receive an influenza vaccination as soon as trivalent or quadrivalent vaccine became available.[50, 51] Public health measures are effective in limiting influenza transmission in closed environments.[11] Enhanced surveillance with daily temperature taking and prompt reporting with isolation through home medical leave and segregation of smaller subgroups decrease the spread of influenza. In one study, symptomatic illness attributable to influenza decreased from 12% to about 4% with the use of these measures.[11] Patients with influenza generally benefit from bed rest. Most patients with influenza recover in 3 days; however, malaise may persist for weeks.

Patients most often require hospitalization when influenza exacerbates underlying chronic diseases. Some patients, especially elderly individuals, may be too weak to care for themselves alone at home. On occasion, the direct pathologic effects of influenza may necessitate hospitalization. Most commonly, this is influenza pneumonia. Prevention Influenza vaccine provides reasonable protection against immunized strains. The vaccination becomes effective 10-14 days after administration. Specific recommendations for individuals who should be immunized can be obtained from the CDC, which publishes regular updates of this information (see Seasonal Influenza Vaccination Resources for Health Professionals). Historically, influenza vaccine has had 50-60% efficacy against infection with influenza A viruses and 70% efficacy against influenza B viruses. For the 2012-2013 season, overall efficacy against influenza A and B virus infections associated with medically attended acute respiratory illness was 56%; the vaccine had 47% efficacy against the predominant influenza A H3N2 subtype and 67% efficacy against influenza B virus infections.[2] Seasonal influenza vaccines Each year in the United States, a vaccine that contains antigens from the strains most likely to cause infection during the winter flu season is produced; 2 strains of influenza A and 1 of influenza B are included for trivalent vaccinees.[52] The quadrivalent flu vaccines have an additional B virus. The 2013-2014 Northern Hemisphere components for the trivalent influenza vaccine include A/California/7/2009 (H1N1) pdm09-like (same as 2012-2013), A/Texas/50/2012 (H3N2; antigenically similar to the 2012-2013 strain), and B/Massachusetts/2/2012-like virus (B/Yamagata lineage, similar to 2012-2013 but not the same ). The quadrivalent flu vaccine includes an additional B virus, B/Brisbane/60/2008-like (B/Victoria lineage). The AAP expressed no preference regarding trivalent versus quadrivalent vaccine for 2013-2014 vaccinations. Injectable vaccine, which contains inactivated virus, is available in a variety of dosage forms. The intramuscular (IM) form contains 45 g of influenza hemagglutinin per 0.5 mL. A microinjection system for intradermal delivery (Fluzone Intradermal) is available in the United States and features an ultrafine needle that is 90% shorter than the typical 1- to 1.5-in. needle used for IM injections. The intradermal dosage form contains 27 g of influenza hemagglutinin per 0.1 mL. Influenza vaccine is also available as a nasal spray (FluMist) that contains live, attenuated influenza virus (LAIV). LAIV is not appropriate for all patients; it is indicated only for healthy people aged 2-49 years who are not pregnant. Clinical trials are limited in scope regarding the protective effects of live vaccine. A comparison study in children with cancer found that although the live vaccine was well tolerated, serum antibody responses against influenza A strains were greater with the standard inactivated viral vaccine.[53]

In February 2012, the US Food and Drug Administration (FDA) approved a quadrivalent form of the nasal spray vaccine (FluMist Quadrivalent) that includes a second B strain, thereby increasing the likelihood of adequate protection against circulating influenza B strains.[9] In December 2012, the FDA approved an intramuscular quadrivalent influenza vaccine (Fluarix Quadrivalent) for use in adults and children aged 3 years or older.[8] Because the influenza vaccine was traditionally produced by using fertilized chicken eggs, it was contraindicated in persons who have had severe allergic reactions to eggs. In November 2012, however, the FDA approved an influenza vaccine produced by using cultured animal cells of mammalian origin (Flucelvax) for prevention of seasonal influenza in people ages 18 years and older.[54] In January 2013, the FDA approved Flublok (Protein Sciences), a trivalent seasonal influenza vaccine produced by means of a technique that may allow faster vaccine manufacture in influenza pandemics.[55, 56] The manufacturing process for Flublok, which is indicated for adults aged 18-49 years, uses recombinant DNA technology and an insect virus expression system rather than the traditional embryonated chicken egg technique, and it does not utilize influenza viruses. The ACIP recommends FluBlok for vaccination of persons aged 18 through 49 years with egg allergy of any severity.[57] Prevention in pregnant women A CDC analysis stressed the importance of vaccinating pregnant women regardless of trimester and prompt treatment with a neuraminidase inhibitor (ie, within 2 days of symptom onset) if influenza occurs during pregnancy.[58] Vaccination of high-risk pregnant patients also provides some protective immunity for newborns and reduces subsequent hospitalizations in the infants.[59] A case-control study by Thompson et al supported previous evidence that seasonal trivalent inactivated influenza vaccine reduces the risk of acute respiratory illness (ARI) by more than half in pregnant women with laboratory-confirmed influenza infection. In the study, which was conducted over 2 flu seasons (2010-2011 and 20112012), 42 pregnant women with influenza who had been vaccinated during flu season were compared with over 110 vaccinated controls with ARI but no influenza infection and 126 matched, vaccinated controls with no ARI.[60, 61] Prevention in elderly persons Vaccination may provide less protection against influenza in patients older than 65 years.[2] In an effort to improve the immunogenicity of influenza virus vaccine in elderly adults, a high-dose trivalent inactivated influenza vaccine has been developed. In a multicenter, randomized, double-blind controlled trial involving elderly adults (65 years), those who received the high-dose vaccine exhibited a statistically significantly higher seroconversion rate than those who received the standard-dose vaccine.[62] The high-dose vaccine met superiority criteria for both strains of influenza A, and noninferiority criteria were met for influenza B strains.[62] Seroprotection rates were higher for the high-dose vaccine than for the standard-dose vaccine. The authors suggest that the high-dose vaccine may provide improved immunity for elderly adults.

Dual vaccination with pneumococcal and influenza vaccine is effective in protecting elderly persons with chronic illness from developing complications due to respiratory, cardiovascular, and cerebrovascular diseases, thereby reducing hospitalization, coronary care unit (CCU) or intensive care unit (ICU) admissions, and death.[63, 64] Woods et al found that in sedentary elderly adults, cardiovascular exercise extends influenza vaccine seroprotection. A randomized controlled trial in 144 sedentary but healthy elderly adults showed that peak (3- and 6-week) postvaccine anti-influenza hemagglutination inhibition titers were similar in those who underwent cardiovascular exercise or flexibility and balance training, but those in the cardiovascular exercise group were significantly more likely to have seroprotective titers at 24 weeks, a period that could cover the entire influenza season.[65] Prevention in poultry and swine workers Some data from animal studies suggest that the standard inactivated influenza vaccine may confer partial immunity toward avian influenza.[66] Accordingly, it has been recommended that poultry workers receive annual influenza vaccinations to prevent illness and to prevent viral reassortment through simultaneous infection with the 2 types of influenza.[67] Similarly, vaccination of swine workers against seasonal influenza may help prevent cross-species sharing of influenza viruses and the origination of novel reassortant viruses.[68] Prevention of H5N1 avian influenza No avian influenza vaccine is currently available to the public, though various products are in clinical trials and appear immunogenic. One complication is that the highly pathogenic viruses cannot be easily grown by means of the traditional embryonated chicken egg method, because the embryos often die during incubation. An H5N1 monovalent killed-virus vaccine produced by sanofi-Pasteur has been approved by the FDA in the United States but is available only to government agencies and for stockpiles.[10] It is derived from the influenza A/Vietnam/1203/2004 strain isolated from humans. A second H5N1 influenza vaccine was approved by the FDA in November 2013 that contains a different viral strain, A/Indonesia/05/2005. This new H5N1 vaccine also contains the ASO3 adjuvant that allows a smaller amount of antigen to simulate an immune response. The first H5N1 vaccine was approved on the basis of a limited safety and immunogenicity study of 500 adults aged 18-64 years.[10] Fewer than half of those receiving the highest dose of vaccine responded and achieved antibody titers expected to be fully effective (ie, hemagglutination inhibition antibody titers >1:40) on the basis of experience with seasonal influenza. The vaccine contains thimerosal (unlike many other seasonal influenza vaccines) because of the need for multidose vials.[69] In a study of vaccination against Vietnamese- and Indonesian-origin H5N1 strains using a prime-boost strategy, which included 491 subjects, optimal antibody titers required at least a 14-day interval between doses. Results were no better at 28 days.[70] A newer recombinant H5N1 vaccine is also available from the World Health Organization (WHO).[71] The CDC provides additional information about Avian

Influenza Vaccines. Adjuvanted vaccine In November 2013, the FDA approved the first adjuvanted vaccine for the prevention of H5N1 avian influenza. Influenza A (H5N1) Virus Monovalent Vaccine, Adjuvanted (ID Biomedical Corporation), is meant for use in people aged 18 years or older with a relatively greater risk of H5N1 exposure. It is not intended for commercial use but has instead been purchased by the US Department of Health and Human Services for addition to the Strategic National Stockpile (of drugs and medical supplies) and, if warranted, subsequent distribution by public health officials.[72, 73] Approval of the vaccine was based on a multicenter study in which investigators evaluated the immune response of about 2000 vaccinated adults, determining that 91% of persons aged 18-64 years and 74% of those aged 65 years or older achieved an antibody level that would be expected to reduce their risk of developing avian influenza.[72, 73] Avian influenza and travelers Because avian influenza is rare in humans, the CDC does not currently recommend against travel to any country affected by H5N1. (See Avian Flu Travel Information.) Prophylactic antivirals are not indicated for patients who plan to travel to areas where avian influenza has been reported. Travelers who plan to travel to areas of the world affected by avian influenza outbreaks in birds or humans are advised to avoid close contact with poultry, especially diseased or dead birds, and to consume only adequately cooked meat. If contact with birds in enclosed spaces is unavoidable, an N-95 respirator mask (or equivalent), gloves, and goggles should be used to minimize contact with droplets or particulates. Containing pandemic influenza Preparedness for pandemic influenza is widely considered to be grossly inadequate. The following 5 areas are important for managing a surge in severe illness[74] : Surveillance and diagnostic services Information sharing and dissemination Community support Hospital and physician capacity Supply and delivery of vaccines and drugs Even in the absence of a pandemic illness, the lack of capacity in US emergency departments has been described as a crisis by the Institute of Medicine. (See the WHO Global Influenza Preparedness Plan.) Prehospital Care Prehospital care is predominantly supportive. Supplemental oxygenation to manage respiratory symptoms or objective hypoxia may be needed. Ventilatory support with a bag-valve-mask device or with field intubation may be required if the patient is in respiratory failure. Intravenous access should be obtained, and a bolus of a crystalloid

can be administered to support hemodynamic stability. Attention should be given to the appropriate use of personal protective equipment (PPE) by the prehospital providers, and advance notification should be given to the hospital regarding the potential need for patient respiratory isolation. General guidelines in low-risk areas are that patients with fever and respiratory complaints should wear a standard mask, if tolerated, to decrease airborne droplets.[75] Antiviral Pharmacologic Therapy In the United States, the following 4 prescription antiviral drugs are approved for chemoprophylaxis and treatment of influenza: Oseltamivir Zanamivir Amantadine Rimantadine The neuraminidase inhibitors (oseltamivir and zanamivir) have activity against influenza A and B viruses (including H1N1), whereas the adamantanes (amantadine and rimantadine) have activity against influenza A viruses only. Since 2006, only the neuraminidase inhibitors have been recommended, because of widespread resistance to the adamantanes among influenza A (H3N2) virus strains. Oseltamivir resistance emerged in the United States during the 2008-2009 influenza season. Oseltamivir and zanamivir work by inhibiting influenza virus neuraminidase, a glycoprotein spike that protrudes from the virus envelope; this spike is needed for successful cellular release of virus and transmission within the body. To be effective as treatment, these agents must be administered within 48 hours of symptom onset. For critically ill patients with H5N1 infection, evidence suggests that initiation of oseltamivir therapy up to 6-8 days from onset of symptoms may reduce mortality.[76] Studies also demonstrate the efficacy of these agents in preventing influenza A and B. For acute treatment, these agents are given twice daily for 5 days. For prevention, they are given once daily for 10 days. Prompt use of antiviral drugs during the 2009 H1N1 influenza pandemic improved survival among severely ill pregnant women. A CDC study of 347 pregnant women (including 272 who required ICU admission but survived and 75 who died) and 15 severely ill postpartum women (9 of whom died) found that 94.8% of survivors received antiviral treatment with oseltamivir or zanamivir, compared with 86.1% of those who died, a statistically significant difference.[58] Time from symptom onset to initiation of treatment was significantly longer for women who died than for those who survived. Only 7% of those who died received an antiviral within 2 days of symptom onset, compared with 41% of survivors. This analysis reaffirms the importance of prevention (ie, vaccination of pregnant women regardless of trimester) and prompt treatment with a neuraminidase inhibitor (ie, within 2 days of symptom onset) if influenza occurs during pregnancy.[58] A meta-analysis of outcome in patients hospitalized with H1N1 influenza during the 2009-2010 pandemic found that early treatment with neuraminidase inhibitors (ie,

within 48 hours of symptom onset) reduced the death rate by 63%. Although neuraminidase treatment (early or late) during hospitalization did not produce a statistically significant reduction in severe outcomes (eg, critical care unit admission), preadmission use did.[77] Lam et al suggested that cases of suspected severe influenza infection should be treated early and aggressively, even before diagnostic tests can be confirmed.[78] In their study, a higher dose of oseltamivir and nonconventional methods of ventilation improved outcome in patients with pandemic H1N1 2009 infection. Advantages and disadvantages of neuraminidase inhibitors Whether to prescribe one of the newer neuraminidase inhibitors should depend on the patient, the probable type of influenza involved (A or B), and the potential benefit. The advantages of prescribing these agents include significantly reducing illness severity and duration. In elderly and high-risk patients who receive these agents, the secondary complications of influenza are also decreased.[79] The disadvantages include potential adverse effects and higher costs. Adverse effects include potential bronchospasm with inhaled zanamivir and nausea, vomiting, and headache from oseltamivir. The bronchospasm associated with zanamivir has received attention from national media. Until more data are available, physicians should not prescribe zanamivir to patients prone to bronchospasm. Oseltamivir research Hayden et al documented the prophylactic efficacy of oseltamivir.[80] In this study, 1559 healthy, nonimmunized patients were treated with either placebo or oseltamivir for 6 weeks; at the end of the period, 4.8% of the placebo group had laboratoryconfirmed influenza, compared with only 1.2% of the oseltamivir group. Although oseltamivir is approved for use up to 48 hours after the onset of symptoms, one study found that earlier initiation increased the therapeutic effects of the drug: Initiation of therapy within the first 12 hours after fever onset reduced the total median illness duration by 74.6 hours (41%) more than intervention at 48 hours.[81] Probenecid, a uricosuric agent, approximately doubles the effective dose of oseltamivir by disrupting renal excretion of the drug. It may have a role to play in a pandemic or in severe infections[82] ; however, no studies have yet been performed to confirm the appropriate dosing regimen in this situation. A novel study documented the prophylactic and therapeutic effects of oseltamivir in experimentally induced influenza in humans.[83] In a controlled laboratory environment, volunteers were inoculated intranasally with influenza A/Texas/36/91 (H1N1). In the prophylaxis arm of the study, subjects received either oseltamivir or placebo 26 hours before virus inoculation; in the treatment arm, subjects received oseltamivir or placebo 28 hours after inoculation. In the prophylactic group, 38% of patients developed influenza, compared with 67% of patients in the placebo group.[83] In the treatment group, oseltamivir reduced the duration of illness from 95 to 53 hours and reduced the severity by 50%, compared with placebo.

A placebo-controlled study of oseltamivir by Treanor et al demonstrated the ability of this agent to decrease the duration and severity of influenza.[84] The analysis included patients with laboratory-based diagnoses of influenza and those with clinical diagnoses based on symptoms. Compared with placebo, both standard-dose and highdose oseltamivir reduced the mean illness duration from 103 to 70 hours and reduced symptom severity by 40%. In a randomized, double-blind, placebo-controlled trial of children aged 1-3 years with influenza A or B, Heinonen et al found that oseltamivir decreased the incidence of acute otitis media (a common bacterial complication of influenza) by 85% when treatment began within 12 hours of symptom onset.[85] When treatment began within 24 hours of symptom onset, no significant reduction in the incidence of acute otitis media was observed. Heinonen et al also found that when oseltamivir treatment was started within 24 hours for children with influenza A, the median time to resolution of illness was decreased by 3.5 days in all children and parental work absenteeism was reduced by 3 days.[85] Efficacy was not demonstrated against influenza B infections. A meta-analysis of available data by Jefferson et al cited a substantial risk of publication bias with oseltamivir trials, noting that 60% of patient data from phase III treatment trials of oseltamivir have never been published and that reporting bias has been documented in the published trials.[86] This meta-analysis concluded that alleviation of influenzalike symptoms began about 21 hours sooner in patients treated with oseltamivir compared with placebo; however, oseltamivir treatment appeared to have no effect on hospitalization.[86] Zanamivir research In a study of 837 relatives of family members infected with influenza, 20% of those treated with placebo became ill, compared with only 4% of those who received prophylactic zanamivir.[87] In addition, this study provided treatment to the index case family member, resulting in a 2.5-day reduction in illness as compared with placebo. Recombinant DNA viral sequences were performed in this study, and no resistant influenza strains developed. In a placebo-controlled study of 445 patients by the Management of Influenza in the Southern Hemisphere Trialists (MIST) group 1, zanamivir reduced the duration and severity of illness.[88] Zanamivir was administered within 36 hours of symptom onset. The duration of influenza was reduced by 1.5 days in normal-risk groups and 2.5 days in high-risk groups. A significant decrease in the severity of illness in patients treated with zanamivir allowed them to resume normal activities much sooner. Antiviral drug recommendations The CDC has made the following recommendations regarding the use of antiviral drugs in influenza[48] : Antiviral treatment is recommended as soon as possible for patients with confirmed or suspected influenza who have severe, complicated, or progressive illness or who require hospitalization

 Antiviral treatment is recommended as soon as possible for outpatients with confirmed or suspected influenza who are at higher risk for influenza complications on the basis of their age or underlying medical conditions; clinical judgment should be an important component of outpatient treatment decisions Currently recommended antiviral medications include oseltamivir and zanamivir Oseltamivir may be used for treatment or chemoprophylaxis of influenza among infants younger than 1 year, when indicated Antiviral treatment also may be considered on the basis of clinical judgment for any outpatient with confirmed or suspected influenza who does not have known risk factors for severe illness, if treatment can be initiated within 48 hours of illness onset Because antiviral resistance patterns can change over time, clinicians should monitor local antiviral resistance surveillance data Investigational antiviral agents Investigational antiviral agents for influenza include laninamivir octanoate and peramivir. Although these agents are not yet available in the United States, they have been approved in Japan.[89] In a double-blind, randomized controlled trial, the median time to illness alleviation with a 40-mg dose of laninamivir octanoate was similar to that with oseltamivir.[90] A single inhalation of laninamivir octanoate proved effective for the treatment of seasonal influenza, including cases caused by oseltamivir-resistant virus, in adults. A single intravenous dose of peramivir, a sialic acid analogue and a selective inhibitor of neuraminidases produced by influenza A and B viruses, is effective and well tolerated in subjects with uncomplicated seasonal influenza virus infection. At both 300 mg and 600 mg, peramivir significantly reduced the time to alleviation of symptoms in comparison with placebo.[91] Consultations Consultation with an infectious disease specialist is prudent in some cases of seasonal influenza. For management of severe disease, intensive care specialists must be involved. In suspected H5N1 influenza, a pulmonary specialist, a critical care specialist, an infectious disease specialist, and the staff of the local public health department may all be consulted. Clinical laboratory personnel should be informed before potential H5N1 isolates are sent to them. In addition, hospital infection-control officers should be involved early in the care of any patient who might have avian flu. Ultimately, the WHO, the CDC, or both should be contacted; the CDC can safely perform serotyping for suspected avian influenza strains. Early involvement of the local public health department and the hospital infection control service is necessary to contain any outbreaks. Long-Term Monitoring Most patients with influenza recover in 3 days; however, malaise may persist for

weeks. Patients who do not improve should return for further evaluation. Patients diagnosed with influenza should be educated about potential complications and encouraged to return for evaluation if concerned. This is especially true of patients with underlying chronic disease or those who are immunocompromised. Medication Summary The goals of pharmacotherapy are to reduce morbidity and to prevent complications. Agents include vaccines and antiviral drugs. The uricosuric agent probenecid may be used as an adjunct to antiviral treatment. Antivirals, Influenza Class Summary The antiviral drugs indicated for the treatment and chemoprophylaxis of influenza are the neuraminidase inhibitors (ie, oseltamivir and zanamivir). Neuraminidase inhibitors act directly on the viral proteins, decreasing the virulence of infection. Adamantanes (amantadine and rimantadine) were used in the past, but resistance against these agents has become widespread, and they are no longer recommended. View full drug information Oseltamivir (Tamiflu) Oseltamivir inhibits neuraminidase, an enzyme that breaks the bond between newly produced virions and the host cell membrane. Specifically, neuraminidasea glycoprotein located on the surface of the influenza viruscleaves the attachment between hemagglutinin on the viral surface and the sialic acid receptor on the host cell membrane, thereby facilitating the release of the virion from the cell. Inhibition of neuraminidase thus decreases viral spread. Oseltamivir is effective for the treatment of influenza A or B. It must be administered within 48 hours of symptom onset. The sooner it is taken after symptom onset, the better the effect. Oseltamivir reduces the length of illness by an average of 1.5 days. (In a subgroup of high-risk patients, illness was reduced by 2.5 days.) It also reduces the severity of symptoms. This agent is available as capsules (75, 45, and 30 mg) and as an oral suspension. Oseltamivir resistance emerged in the United States during the 2008-2009 influenza season. Accordingly, zanamivir is now recommended as the initial choice for antiviral prophylaxis or treatment when influenza A infection or exposure is suspected. A second-line alternative is to use a combination of oseltamivir and rimantadine rather than oseltamivir alone. Local influenza surveillance data and laboratory testing can assist the physician regarding antiviral agent choice. The efficacy of oseltamivir against avian influenza is not well established. View full drug information Zanamivir (Relenza)

Zanamivir is an inhibitor of neuraminidase, an enzyme that breaks the bond between newly produced virions and the host cell membrane. Specifically, neuraminidasea glycoprotein located on the surface of the influenza viruscleaves the attachment between hemagglutinin on the viral surface and the sialic acid receptor on the host cell membrane, thereby facilitating the release of the virion from the cell. Inhibition of neuraminidase thus decreases viral spread. This agent is effective against both influenza A and B; its efficacy against avian influenza is not well established. Severe and even fatal bronchospasm has been reported during treatment with zanamivir; consequently, this agent is not recommended for treatment or prophylaxis of influenza in individuals with underlying airway diseases (eg, asthma and chronic obstructive pulmonary disease). Zanamivir is inhaled through a Diskhaler oral inhalation device. Circular foil disks that contain 5-mg blisters of drug are inserted into the supplied inhalation device. Vaccines, Inactivated, Viral Class Summary Influenza vaccine is administered each year before flu season. Typically, 3 virus strains (2 influenza A and 1 influenza B), which antigenically represent the influenza strains likely to circulate the next flu season, are included in the formulation each year. Quadrivalent vaccines that included 2 influenza A strains and 2 influenza B strains became available during the 2013/2014 flu season. The US Food and Drug Administration (FDA) makes the final decision about vaccine strains for influenza vaccines to be sold in the United States, based on year-round surveillance conducted by the US Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO).[52] In April 2007, the FDA approved the first vaccine for H5N1 influenza (ie, avian influenza or bird flu). A second H5N1 influenza vaccine was approved by the FDA in November 2013. It contains the ASO3 adjuvant that allows a smaller amount of antigen to simulate an immune response. Each of these vaccines provides different viral strains; A/Vietnam/1203/2004 and A/Indonesia/05/2005 for the original and adjuvanted vaccines, respectively. H5N1 vaccines are available only to government agencies and for stockpiles. View full drug information Influenza virus vaccine trivalent (Afluria, FluLaval, Fluarix, Fluvirin, Fluzone, Fluzone High-Dose, Fluzone Intradermal) Influenza vaccine is indicated for active immunization to prevent infection from influenza A and B viruses. The vaccine induces antibodies specific to virus strains contained in the vaccine. The FDA determines influenza vaccine contents annually. Fluzone is approved for children as young as 6 months, whereas Fluvirin is approved for children aged 4 years or older. View full drug information Influenza virus vaccine trivalent, recombinant (Flublok)

This vaccine is made from recombinant HA proteins that are not derived from egg or chick embryo. The CDC's Advisory Committee on Immunization Practices (ACIP) recommends FluBlok for vaccination of persons aged 18 through 49 years with egg allergy of any severity. Influenza vaccine is indicated for active immunization to prevent infection from influenza A and B viruses. The vaccine induces antibodies specific to virus strains contained in the vaccine. The US Public Health Service determines influenza vaccine contents annually. Typically, 3 live attenuated virus strains, which antigenically represent the influenza strains likely to circulate the next flu season, are included in the formulation each year. It is administered as an IM injection and approved for adults aged 18 through 49 years. View full drug information Influenza virus vaccine quadrivalent Quadrivalent, FluLaval Quadrivalent) (Fluarix Quadrivalent, Fluzone

Quadrivalent vaccines contain two strains of influenza A and two of influenza B. The vaccine induces antibodies specific to virus strains contained in vaccine. Each year, the US Public Health Service determines which viral strains will be included in the seasonal influenza vaccine that will antigenically represent the viral strains most likely to circulate in the next flu season. It is administered as an IM injection. Influenza virus vaccine (H5N1) The H5N1 inactivated virus vaccine induces antibodies against viral hemagglutinin, thereby blocking viral attachment to human respiratory tract epithelial cells. The vaccine is estimated to reduce the risk of contracting avian influenza by 45%. This vaccine is indicated for active immunization of adults at increased risk for exposure to the H5N1 influenza virus subtype A/Vietnam/1203/2004.[10] Influenza virus vaccine (H5N1), adjuvanted This vaccine contains the AS03 adjuvant. In clinical studies, the adjuvanted vaccine formulation stimulated the required immune response while using a smaller amount of antigen as compared to a formulation without adjuvant. It is indicated for active immunization for the prevention of disease caused by the influenza A virus H5N1 subtype A/Indonesia/05/2005. Vaccines, Live, Viral Class Summary Influenza vaccine is administered each year before flu season. The FDA makes the final decision about vaccine strains for influenza vaccines to be sold in the United States, based on year-round surveillance conducted by the CDC and the WHO.[52] View full drug information Influenza virus vaccine quadrivalent, intranasal (Flumist Quadrivalent)

Intranasal influenza vaccine is indicated for active immunization to prevent influenza A and B viruses in healthy children, adolescents, and adults aged 2 to 49 years. In February 2012 the FDA approved a quadrivalent form of the intranasal vaccine (FluMist Quadrivalent). Like the already approved FluMist (a trivalent formulation), the quadrivalent vaccine contains weakened forms of the virus strains and is administered as a spray into the nose. However, this new formulation includes a second B strain, which increases the likelihood of adequate protection against circulating influenza B strains. The trivalent intranasal vaccine is no longer available in the United States. Uricosuric Agents Class Summary Agents that inhibit the tubular secretion of the active metabolite of oseltamivir may be used as adjunctive therapy with this antiviral drug. View full drug information Probenecid Probenecid inhibits tubular secretion of the active metabolite of oseltamivir, reducing its clearance by approximately 50% and approximately doubling systemic exposure to oseltamivir. The appropriate dosing for combination therapy with probenecid and oseltamivir in the treatment of avian influenza has not been established.