Background
Influenza virus infection, one of the most common infectious diseases, is a highly contagious airborne disease that causes an acute febrile illness and results in variable degrees of systemic symptoms, ranging from mild fatigue to respiratory failure and death. These symptoms contribute to significant loss of workdays, human suffering, mortality, and significant morbidity.
Although the usual strains of influenza 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 (although 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.
In addition to humans, influenza also infects a variety of animal species. Some of these influenza strains are species specific, but new strains of influenza may spread from other animal species to humans (see Pathophysiology). The term avian influenza used 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. For more information on the 2009 influenza pandemic, a recombinant influenza consisting of a mix of swine, avian, and human gene segments, see the article H1N1 Influenza (Swine Flu).
The signs and symptoms of influenza overlap with those of many other viral upper respiratory tract infections (URTIs). Viruses including 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. (See Differentials.)
The criterion standard for diagnosing influenza A and B is a viral culture of nasopharyngeal samples and/or throat samples. However, the process may require 3-7 days, long after the patient has left the clinic, office, or emergency department and well past the time when drug therapy could be efficacious. Recently, nucleic acid polymerase chain reaction (PCR) types of laboratory tests have become available, with turnaround times of less than 24 hours and good sensitivity. In September 2011 the FDA approved a new CDC-developed test to diagnose influenza infections, including avian influenza. The Human Influenza Virus Real-Time RT-PCR Detection and Characterization Panel (rRT-PCR Flu Panel) is an in vitro laboratory diagnostic test 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 and will be given at no cost to qualified international public health laboratories. Other older bedsiderapiddiagnostic tests are available, but because of cost, availability, and sensitivity issues, most physicians diagnose influenza based on clinical criteria alone. (See Workup.)
The avian influenza (H5N1) virus is best identified by conducting an H5N1-specific reverse-transcriptase polymerase chain reaction. This assay can be performed at all state and many local public health laboratories. Viral culture of H5N1 should be performed only in a biosafety level 3 laboratory. (See Workup.)
As with other diseases, 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 good protection against immunized strains, becoming effective 10-14 days after administration. Pregnant women and infants who get influenza are at increased risk for severe illness. Even in these patients, a single dose of a nonadjuvanted influenza A (H1N1) vaccine with 15 mcg of hemagglutinin is safe and triggers a strong immune response and a high rate of neonatal seroprotection.[1]
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.)
Also see Pediatric Influenza.
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 spread of the infection.[2]
Major typing of influenza A occurs through identification of both N and H. Sixteen N and 9 H types have ben identified. All hemagglutinins and neuraminidases infect wild waterfowl, and the various combinations of H and N results in 144 combinations and potential subtypes of influenza. The most common subtypes of human influenza virus identified to date contain only hemagglutinins 1, 2, and 3 and neuraminidases 1 and 2. These variants result in much of the species specificity due to differences in the receptor usage (specifically sialic acid, which binds to hemagglutinin and which is cleaved by neuraminidase when the virus exits the cell).
The variants are used to identify influenza A virus subtypes. For example, influenza A subtype H3N2 expresses hemagglutinin 3 and neuraminidase 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.
The viral RNA polymerase lacks error-checking mechanisms and, as such, the antigenic drift from year to year is sufficient to ensure a significant susceptible host population. However, the segmented genome also has the potential to allow re-assortment of genome segments from different strains of influenza in a co-infected 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, rarely, in pigs.
Some of these influenza strains are species specific. 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 virus 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.[3] Changes in its major functional and antigenic proteins occur by means of 2 well-described mechanisms: antigenic drift and 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 as 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 co-infection 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 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 re-assortment of an avian strain with a mammalian strain may produce a chimeric virus that is transmissible between mammals; such mutation products may contain hemagglutinin and/or neuraminidase 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 such influenza pandemics have occurred in recorded history: the 1918 Spanish influenza (H1N1) pandemic and the pandemics of 1957 (H2N2) and 1968 (H3N2). Smaller outbreaks occurred in 1947, 1976, and 1977.
Avian influenza
Hemagglutinin type H5 attaches well to avian respiratory cells and thus spreads easily among avian species. However, attachment to human cells and resultant infection is more difficult. The reasons why humans can be infected with H5 are poorly understood. Some of the earliest cases of human infection with H5N1 were observed during an outbreak of severe respiratory disease in Hong Kong in 1997. The outbreak was successfully contained with the slaughter of the entire local chicken population (around 1.5 million birds). However, only 18 human cases were reported, 6 of them fatal.[4]
Note the image below.
Colorized transmission electron micrograph shows avian influenza A H5N1 viruses (gold) grown in MDCK cells (green). Image courtesy of Centers for Disease Control and Prevention. Since then, H5N1 has been found in chickens, ducks, and migratory fowl throughout Asia and is now spreading west through Europe and North Africa. Human cases are following the route of the avian spread, but H5N1 has also been found in dead birds in several countries without any reported human cases (eg, the United Kingdom, Germany; see image below).
Global map of countries where avian influenza (bird and human infections) has been reported. Image courtesy of PandemicFlu.gov. As of fall 2008, more than 390 human cases had been documented and more than 246 persons had died following H5N1 outbreaks among poultry and resulting bird-to-human transmission.[5] Most human deaths due to bird flu have occurred in Indonesia. Sporadic outbreaks among humans have continued elsewhere, including China, Egypt, Thailand, and Cambodia.
To date, avian influenza remains a zoonosis, with no sustained human-to-human transmission. Family clusters have been reported but appear to be almost always related to common exposures; however, limited human-to-human spread through close proximity could not be officially ruled out. In September 2004, one case in Thailand probably involved daughter-to-mother transmission; the mother died.[6]
At present, the poor transmissibility of the virus from human to human limits the extent of disease due to avian H5N1 influenza. The virus is continuing to undergo genetic changes, however, and experts are concerned that additional point mutations could convert H5N1 to a strain that is easily transferred from human to human.[7] Such a strain has the potential to spread rapidly and precipitate a catastrophic worldwide pandemic.
The pathophysiology of avian influenza differs from that of normal influenza. Avian influenza is still primarily a respiratory infection but involves more of the lower airways than human influenza typically does. This is likely due to differences in the hemagglutinin protein and the types of sialic acid residues to which the protein binds.
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.[8] One group has reported that ex vivo cultures of human tonsillar, adenoidal, and nasopharyngeal tissues can support replication of H5N1 avian influenza.[9]
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. Many are concerned that subtle mutation of the hemagglutinin protein through antigenic drift will result in a virus capable of binding to upper and lower respiratory epithelium, creating the potential for pandemic spread.
Differences in the PA, NP, M1, NS1, and PB2 genes tend to correlate with human strains of influenza, including human infections with avian influenza.[10] The functional role of these genetic markers has yet to be determined but likely involves replication enhancement and immune suppression.
In contrast to human influenza, most deaths associated with avian influenza have been due to primary viral pneumonia, with no evidence of secondary bacterial infection.
Reservoirs for avian influenza A
Waterfowl, including ducks and geese, are considered to be the natural reservoirs for avian influenza A. Most infections in these birds are believed to be asymptomatic.[11] However, because these viruses can also infect and cause disease in domestic poultry and because of the potential economic implications, substantial attention has been given to avian influenza.
Most strains that infect poultry cause only minor illness. These strains are collectively called low pathogenic avian influenza virus (LPAIV). However, after infecting domestic poultry, some strains of LPAIV have become highly virulent and caused death in nearly all infected chickens. These emergent strains are referred to as highly pathogenic avian influenza virus (HPAIV), where highly pathogenic refers to the nature of the disease in birds.
To date, HPAIV strains have occurred in only the H5 and H7 subtypes. Such HPAIV outbreaks required aggressive quarantining and culling measures to prevent major setbacks to poultry farming. The current H5N1 strain of HPAIV is unique and alarming in that it is the only HPAIV known to cause clinically significant disease in humans.[12] In theory, HPAIV genes could find their way into the common human influenza types H1N1, H2N2, and H3N2.
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.[12]
Influenza viruses spread from human to human via aerosols created by coughs or sneezes of infected individuals. Influenza virus infection occurs after inhalation of the aerosol by a person who is immunologically susceptible. If not neutralized by secretory antibodies, the virus invades airway and respiratory tract cells.
Once within host cells, cellular dysfunction and degeneration occur, along with viral replication and release of viral progeny. Systemic symptoms result from inflammatory mediators, similar to other viruses. The incubation period of influenza ranges from 18-72 hours.
Viral shedding
Viral shedding occurs at the onset of symptoms or just before the onset of illness (0-24 h). Shedding continues for 5-10 days. Young children may shed virus longer, placing others at risk for contracting infection with the virus. Shedding may persist for weeks to months in highly immunocompromised persons.[13]
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.[14] In the United States, during the 2010-2011 influenza season, both influenza A and B viruses circulated, with the predominant virus type varying over time and by region.[15] Influenza viruses are classified within the family Orthomyxoviridae.
The primary risk factor for human infection with avian H5N1 influenza virus is direct contact with diseased or deceased birds infected with it. 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.
During the 2006-2007 influenza season, almost 180,000 respiratory specimens tested positive for influenza, as reported by the World Health Organization and National Respiratory and Enteric Virus Surveillance System.[16] However, millions of people may develop infection during a given year. The pandemics of 1918-1919 and 1957, which resulted in higher infection rates and profound morbidity and mortality rates, demonstrate the impact of the disease.
In the United States in 2006, influenza caused 849 deaths, 608 of them in persons aged 75 years and older[16] ; in 2007, influenza caused 411 deaths—79 of them in persons aged 75-84 years and 139 of them in persons aged 85 years and older.[17] The combined category of influenza and pneumonia yields significantly higher mortality, with 36,000 deaths annually in the United States.[18]
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 US in the spring of 2009, followed by a second, larger wave in the fall and winter; activity peaked in October and then declined quickly to below baseline levels by January, but small numbers of cases were reported through the spring and summer of 2010.[19]
In addition, the effect of H1N1 influenza across the lifespan differed from typical influenza. Disease was more severe among people younger than 65 years of age than in non-pandemic influenza seasons, with significantly higher pediatric mortality, and higher rates of hospitalizations in children and young adults.[19]
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 can be found on the Centers for Disease Control and Prevention online resources Avian Influenza Web page. Two case reports describe humans infected with another avian influenza virus, H7N2, in Virginia (in 2002) and in New York (in 2003); the patients had no symptoms but positive serologic results and mild respiratory symptoms, respectively.
Avian influenza statistics
As of March 14, 2011, 532 cases of avian influenza had been reported worldwide, with 315 deaths.[5] Most cases have been in eastern Asia; some cases have been reported in Eastern Europe and North Africa. 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. From 2010 to early 2011, cases were reported in Egypt, Indonesia, Vietnam, Cambodia, and China.
Although the risk remains largely theoretical, the ease of global travel emphasizes the possibility of international spread. The risks have been highlighted recently with the rapid spread of the low-pathogenicity H1N1 swine-origin influenza in 2009. The risk of a successful recombination event occurring between swine-origin H1N1 and avian H5N1 cannot be easily assessed.
The images below depict the countries where avian influenza has been reported and statistics by the World Health Organization (WHO).
Global map of countries where avian influenza (bird and human infections) has been reported. Image courtesy of PandemicFlu.gov. 
Avian H5N1 influenza in humans, annual case counts from the World Health Organization. Cases of avian influenza have been reported in all age groups (range, 3 mo to 75 y), with a median age of 20 years. Most cases and the highest mortality rate (79%) have been observed in individuals aged 10-19 years.[20] The age range affected resembles the epidemiologic age distribution of the 1918 influenza epidemic more than that of seasonal human influenza.
Avian influenza has the highest case-fatality rate among persons aged 10-39 years. Unlike seasonal influenza, which disproportionately affects very young and very old individuals, young adults make up a large proportion of the avian influenza cases. Half of reported cases have been in people younger than 20 years, and 40% involve persons aged 20-40 years.
In Egypt, avian influenza has been associated with a relatively low mortality rate, which seems to be associated with a high rate of infection in young children (< 10 y); as of May 2009, the mortality rate in this subpopulation has been zero. The significance and reproducibility of these findings remains to be seen.[21]
Race appears to be a factor in avian influenza only to the extent that geographic differences in the rate of HPAI among birds and the degree of bird-to-human contact are significant.
In Egypt, 90% of fatalities due to avian influenza have involved women, a pattern that has not been readily apparent elsewhere.[21] Among WHO-confirmed cases to date, the male-to-female ratio is 0.9.
Age-related differences in incidence
For more information on influenza in children, see Pediatric Influenza.
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.
The prognosis in patients with avian influenza is related to the degree and duration of hypoxemia. The cases to date have exhibited a 60% mortality rate. The risk of mortality depends on the degree of respiratory disease rather than the bacterial complications (pneumonia). Little evidence regarding the long-term effects of disease among survivors is available. The mortality rate among those cared for in the most developed nations is significantly lower.
The CDC estimates that seasonal influenza is responsible for an average of more than 20,000 deaths annually. Mortality rates are highest in infants and the elderly.
The following facts are offered for comparison:
- The 1918 H1N1 influenza pandemic caused 500,000-700,000 deaths in the United States—almost 200,000 of them in October 1918 alone—and an estimated 30-40 million deaths worldwide, mostly among people 15-35 years of age
- 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
Patient Education
For patient education information, see Colds, Flu in Adults, and Flu in Children.
Tsatsaris V, Capitant C, Schmitz T, Chazallon C, Bulifon S, Riethmuller D, et al. Maternal Immune Response and Neonatal Seroprotection From a Single Dose of a Monovalent Nonadjuvanted 2009 Influenza A(H1N1) Vaccine: A Single-Group Trial. Ann Intern Med. Dec 6 2011;155(11):733-741. [Medline].
Gubareva LV, Kaiser L, Hayden FG. Influenza virus neuraminidase inhibitors. Lancet. Mar 4 2000;355(9206):827-35. [Medline].
Drake JW. Rates of spontaneous mutation among RNA viruses. Proc Natl Acad Sci U S A. May 1 1993;90(9):4171-5. [Medline]. [Full Text].
World Health Organization. H5N1 avian influenza: Timeline of major events. World Health Organization. Available at http://www.who.int/csr/disease/avian_influenza/Timeline_2007_03_20.pdf. Accessed March 15, 2011.
World Health Organization. Cumulative Number of Confirmed Human Cases of Avian Influenza A/(H5N1) Reported to WHO. World Health Organization. Available at http://www.who.int/csr/disease/avian_influenza/country/cases_table_2011_03_14/en/index.html. Accessed March 14, 2011.
Ungchusak K, Auewarakul P, Dowell SF, Kitphati R, Auwanit W, Puthavathana P, et al. Probable person-to-person transmission of avian influenza A (H5N1). N Engl J Med. Jan 27 2005;352(4):333-40. [Medline].
Gambotto A, Barratt-Boyes SM, de Jong MD, Neumann G, Kawaoka Y. Human infection with highly pathogenic H5N1 influenza virus. Lancet. Apr 26 2008;371(9622):1464-75. [Medline].
Auewarakul P, Suptawiwat O, Kongchanagul A, Sangma C, Suzuki Y, Ungchusak K, et al. An avian influenza H5N1 virus that binds to a human-type receptor. J Virol. Sep 2007;81(18):9950-5. [Medline]. [Full Text].
Nicholls JM, Chan MC, Chan WY, Wong HK, Cheung CY, Kwong DL, et al. Tropism of avian influenza A (H5N1) in the upper and lower respiratory tract. Nat Med. Feb 2007;13(2):147-9. [Medline].
Chen GW, Chang SC, Mok CK, Lo YL, Kung YN, Huang JH, et al. Genomic signatures of human versus avian influenza A viruses. Emerg Infect Dis. Sep 2006;12(9):1353-60. [Medline].
Hulse-Post DJ, Sturm-Ramirez KM, Humberd J, Seiler P, Govorkova EA, Krauss S, et al. Role of domestic ducks in the propagation and biological evolution of highly pathogenic H5N1 influenza viruses in Asia. Proc Natl Acad Sci U S A. Jul 26 2005;102(30):10682-7. [Medline]. [Full Text].
Avian influenza ("bird flu"): fact sheet. World Health Organization. Available at http://www.who.int/mediacentre/factsheets/avian_influenza/en/print.html. Accessed February 2006.
Bell DM, World Health Organization Writing Group. Nonpharmaceutical interventions for pandemic influenza, international measures. Emerg Infect Dis. Jan 2006;12(1):81-7.7. [Full Text].
Matsuzaki Y, Abiko C, Mizuta K, Sugawara K, Takashita E, Muraki Y, et al. A nationwide epidemic of influenza C virus infection in Japan in 2004. J Clin Microbiol. Mar 2007;45(3):783-8. [Medline]. [Full Text].
Update: Influenza Activity --- United States, October 3, 2010--February 5, 2011. MMWR Morb Mortal Wkly Rep. Feb 18 2011;60(6):175-81. [Medline].
Heron M, Hoyert D, Murphy SL, Xu J, Kochanek KD, Tejada-Vera B. Division of Vital Statistics. Deaths: Final Data for 2006. National Vital Statistics Reports. National Center for Health Statistics. Available at http://www.cdc.gov/nchs/data/nvsr/nvsr57/nvsr57_14.pdf.
Xu J, Kochanek KD, Murphy SL, Tejada-Vera B. Division of Vital Statistics. Deaths: Final Data for 2007. National Vital Statistics Reports. National Center for Health Statistics. Available at http://www.cdc.gov/NCHS/data/nvsr/nvsr58/nvsr58_19.pdf.
Centers for Disease Control and Prevention. Key Facts About Seasonal Influenza (Flu). Centers for Disease Control and Prevention. Available at http://www.cdc.gov/flu/keyfacts.htm. Accessed October 2007.
Centers for Disease Control and Prevention. Seasonal Influenza: 2009-2010 Influenza (Flu) Season. Available at http://www.cdc.gov/flu/about/season/current-season.htm. Accessed March 14, 2011.
Epidemiology of WHO-confirmed human cases of avian influenza A(H5N1) infection. Wkly Epidemiol Rec. Jun 30 2006;81(26):249-57. [Medline].
Dudley JP. Age-specific infection and death rates for human A(H5N1) avian influenza in Egypt. Euro Surveill. May 7 2009;14(18):[Medline].
Steininger C, Popow-Kraupp T, Laferl H, Seiser A, Gödl I, Djamshidian S, et al. Acute encephalopathy associated with influenza A virus infection. Clin Infect Dis. Mar 1 2003;36(5):567-74. [Medline].
Beigel JH, Farrar J, Han AM, Hayden FG, Hyer R, de Jong MD, et al. Avian influenza A (H5N1) infection in humans. N Engl J Med. Sep 29 2005;353(13):1374-85. [Medline].
Apisarnthanarak A, Erb S, Stephenson I, Katz JM, Chittaganpitch M, Sangkitporn S, et al. Seroprevalence of anti-H5 antibody among Thai health care workers after exposure to avian influenza (H5N1) in a tertiary care center. Clin Infect Dis. Jan 15 2005;40(2):e16-8. [Medline].
Chotpitayasunondh T, Ungchusak K, Hanshaoworakul W, Chunsuthiwat S, Sawanpanyalert P, Kijphati R, et al. Human disease from influenza A (H5N1), Thailand, 2004. Emerg Infect Dis. Feb 2005;11(2):201-9. [Medline].
Clinical management of human infection with avian influenzaA (H5N1) virus. World Health Organization. World Health Organization. Available at http://www.who.int/csr/disease/avian_influenza/guidelines/ClinicalManagement07.pdf. Accessed March 15, 2011.
Tasher D, Stein M, Simões EA, Shohat T, Bromberg M, Somekh E. Invasive bacterial infections in relation to influenza outbreaks, 2006-2010. Clin Infect Dis. Dec 2011;53(12):1199-207. [Medline].
Updated Interim Guidance for Laboratory Testing of Persons with Suspected Infection with Highly Pathogenic Avian Influenza A (H5N1) Virus in the United States. Center for Disease Control and Prevention. Available at http://www.cdc.gov/flu/avian/professional/guidance-labtesting.htm. Accessed February 2009.
U.S. Food and Drug Administration. Performance and Cautions in Using Rapid Influenza Virus Diagnostic Tests. Available at http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/TipsandArticlesonDeviceSafety/ucm109432.htm%20. Accessed March 15, 2011.
Oner AF, Bay A, Arslan S, Akdeniz H, Sahin HA, Cesur Y, et al. Avian influenza A (H5N1) infection in eastern Turkey in 2006. N Engl J Med. Nov 23 2006;355(21):2179-85. [Medline].
FDA Clears Rapid Test for Avian Influenza A Virus in Humans. Center for Disease Control and Prevention. Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm149557.htm. Accessed April 7, 2009.
Lee VJ, Yap J, Cook AR, Chen MI, Tay JK, Barr I, et al. Effectiveness of public health measures in mitigating pandemic influenza spread: a prospective sero-epidemiological cohort study. J Infect Dis. Nov 1 2010;202(9):1319-26. [Medline].
Treanor J, Falsey A. Respiratory viral infections in the elderly. Antiviral Res. Dec 15 1999;44(2):79-102. [Medline].
Centers for Disease Control and Prevention. Antiviral Agents for the Treatment and Chemoprophylaxis of Influenza. Recommendations of the Advisory Committee on Immunization Practices (ACIP). Available at http://www.cdc.gov/mmwr/preview/mmwrhtml/rr6001a1.htm?s_cid=rr6001a1_e. Accessed March 15, 2011.
Adisasmito W, Chan PK, Lee N, Oner AF, Gasimov V, Aghayev F, et al. Effectiveness of antiviral treatment in human influenza A(H5N1) infections: analysis of a Global Patient Registry. J Infect Dis. Oct 15 2010;202(8):1154-60. [Medline].
Randomised trial of efficacy and safety of inhaled zanamivir in treatment of influenza A and B virus infections. The MIST (Management of Influenza in the Southern Hemisphere Trialists) Study Group. Lancet. Dec 12 1998;352(9144):1877-81. [Medline].
Treanor JJ, Hayden FG, Vrooman PS, Barbarash R, Bettis R, Riff D, et al. Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: a randomized controlled trial. US Oral Neuraminidase Study Group. JAMA. Feb 23 2000;283(8):1016-24. [Medline].
Hayden FG, Gubareva LV, Monto AS, Klein TC, Elliot MJ, Hammond JM, et al. Inhaled zanamivir for the prevention of influenza in families. Zanamivir Family Study Group. N Engl J Med. Nov 2 2000;343(18):1282-9. [Medline].
Hayden FG, Treanor JJ, Fritz RS, Lobo M, Betts RF, Miller M, et al. Use of the oral neuraminidase inhibitor oseltamivir in experimental human influenza: randomized controlled trials for prevention and treatment. JAMA. Oct 6 1999;282(13):1240-6. [Medline].
Hayden FG, Atmar RL, Schilling M, Johnson C, Poretz D, Paar D, et al. Use of the selective oral neuraminidase inhibitor oseltamivir to prevent influenza. N Engl J Med. Oct 28 1999;341(18):1336-43. [Medline].
Heinonen S, Silvennoinen H, Lehtinen P, Vainionpää R, Vahlberg T, Ziegler T, et al. Early oseltamivir treatment of influenza in children 1-3 years of age: a randomized controlled trial. Clin Infect Dis. Oct 15 2010;51(8):887-94. [Medline].
Maternal and Infant Outcomes Among Severely Ill Pregnant and Postpartum Women with 2009 Pandemic Influenza A (H1N1) --- United States, April 2009--August 2010. MMWR Morb Mortal Wkly Rep. Sep 9 2011;60:1193-6. [Medline]. [Full Text].
Lam J, Nikhanj J, Ngab T, et al. Severe Cases of Pandemic H1N1 Pneumonia and Respiratory Failure Requiring Intensive Care. J Intensive Care Med. 5;26:318-25.
Hill G, Cihlar T, Oo C, Ho ES, Prior K, Wiltshire H, et al. The anti-influenza drug oseltamivir exhibits low potential to induce pharmacokinetic drug interactions via renal secretion-correlation of in vivo and in vitro studies. Drug Metab Dispos. Jan 2002;30(1):13-9. [Medline].
Watanabe A, Chang SC, Kim MJ, Chu DW, Ohashi Y. Long-acting neuraminidase inhibitor laninamivir octanoate versus oseltamivir for treatment of influenza: A double-blind, randomized, noninferiority clinical trial. Clin Infect Dis. Nov 15 2010;51(10):1167-75. [Medline].
Kohno S, Kida H, Mizuguchi M, Shimada J. Efficacy and safety of intravenous peramivir for treatment of seasonal influenza virus infection. Antimicrob Agents Chemother. Nov 2010;54(11):4568-74. [Medline]. [Full Text].
Clinical management of human infection with avian influenza A (H5N1) virus. World Health Organization. Available at http://www.who.int/csr/disease/avian_influenza/guidelines/ClinicalManagement07.pdf.
US Food and Drug Administration (FDA). Influenza Virus Vaccine for the 2011 - 2012 Season. US Department of Health and Human Services. Available at http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Post-MarketActivities/LotReleases/ucm262681.htm. Accessed July 18, 2011.
Benowitz I, Esposito DB, Gracey KD, Shapiro ED, Vázquez M. Influenza vaccine given to pregnant women reduces hospitalization due to influenza in their infants. Clin Infect Dis. Dec 15 2010;51(12):1355-61. [Medline].
Carr S, Allison KJ, Van De Velde LA, Zhang K, English EY, Iverson A, et al. Safety and immunogenicity of live attenuated and inactivated influenza vaccines in children with cancer. J Infect Dis. Nov 2011;204(10):1475-82. [Medline].
Han K, Ma H, An X, Su Y, Chen J, Lian Z, et al. Early Use of Glucocorticoids Was a Risk Factor for Critical Disease and Death From pH1N1 Infection. Clin Infect Dis. Aug 2011;53(4):326-33. [Medline].
[Best Evidence] Falsey AR, Treanor JJ, Tornieporth N, Capellan J, Gorse GJ. Randomized, double-blind controlled phase 3 trial comparing the immunogenicity of high-dose and standard-dose influenza vaccine in adults 65 years of age and older. J Infect Dis. Jul 15 2009;200(2):172-80. [Medline].
Hung IF, Leung AY, Chu DW, Leung D, Cheung T, Chan CK, et al. Prevention of acute myocardial infarction and stroke among elderly persons by dual pneumococcal and influenza vaccination: a prospective cohort study. Clin Infect Dis. Nov 1 2010;51(9):1007-16. [Medline].
Christenson B, Pauksen K, Sylvan SP. Effect of influenza and pneumococcal vaccines in elderly persons in years of low influenza activity. Virol J. Apr 28 2008;5:52. [Medline]. [Full Text].
[Best Evidence] Woods JA, Keylock KT, Lowder T, Vieira VJ, Zelkovich W, Dumich S, et al. Cardiovascular exercise training extends influenza vaccine seroprotection in sedentary older adults: the immune function intervention trial. J Am Geriatr Soc. Dec 2009;57(12):2183-91. [Medline].
FDA Approves First U.S. Vaccine for Humans Against the Avian Influenza Virus H5N1. Center for Disease Control and Prevention. Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm108892.htm. Accessed April 17, 2007.
US Food and Drug Administration. H5N1 Inf luenza Virus Vaccine. US Food and Drug Administration. Available at http://www.fda.gov/cber/products/h5n1san041707qa.htm. Accessed October 2007.
Belshe RB, Frey SE, Graham I, Mulligan MJ, Edupuganti S, Jackson LA, et al. Safety and immunogenicity of influenza A H5 subunit vaccines: effect of vaccine schedule and antigenic variant. J Infect Dis. Mar 2011;203(5):666-73. [Medline].
Availability of a new recombinant H5N1 vaccine virus. World Health Organization. Available at http://www.who.int/csr/disease/avian_influenza/H5N1virus26May/en/index.html. Accessed May 26, 2009.
Gensheimer KF, Meltzer MI, Postema AS, Strikas RA. Influenza pandemic preparedness. Emerg Infect Dis. Dec 2003;9(12):1645-8. [Medline]. [Full Text].
[Guideline] Fiore AE, Uyeki TM, Broder K, Finelli L, Euler GL, Singleton JA, et al. Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2010. MMWR Recomm Rep. Aug 6 2010;59:1-62. [Medline]. [Full Text].
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