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Pathogenesis, Clinical Features and Diagnosis

During an influenza illness, the primary causes of disease are related to infection and replication of the virus in the respiratory epithelium. These cellular “factories” for virus production ultimately lead to lysis of the epithelial cell and desquamation of the respiratory lining. At the same time, sensors of viral replication stimulate the production of proinflammatory cytokines, including IL-1, IL-6 and TNF-α, which circulate in the body and are responsible for the systemic symptoms associated with influenza illness, such as fever, muscle aches and malaise.

Generally, flu is a self-limiting respiratory infection. The common circulating strains of influenza virus normally remain restricted to the respiratory tract and escape only under exceptional circumstances. As a result, the virus is rarely found circulating in the blood or in other organs. The main reason is that the protease required for cleavage of the viral HA is restricted to the epithelium of the airways and lungs (see Chapter 2). Host factors such as interferons and other components of the immune response may also be important for preventing the spread of the virus outside of the respiratory tract.

When a new influenza A subtype is introduced into the human population, the situation is different. The severity of disease may be considerably increased because of the complete lack of immunity in infected individuals under these conditions. Additional alterations in viral proteins may have contributed to the extremely high pathogenicity of the H1N1 Spanish flu pandemic virus of 1918 and that of the more recent avian H5N1 virus, which, in ongoing outbreaks thus far (March 1, 2006), has infected 179 people with a very high case fatality rate. 1 x Y Guan, LL Poon, CY Cheung, et al.. H5N1 influenza: a protean pandemic threat. Proc Natl Acad Sci USA 101 (2004) (8156 - 8161) Crossref. A hallmark of virulence of highly pathogenic avian influenza viruses, such as the H5 subtype viruses, is the presence of the multibasic cleavage site in the HA molecule, as discussed in Chapter 2. Yet, the 1918 HA does not have the multibasic cleavage site, indicating that other factors contributed to the extreme virulence of the Spanish flu virus. Recent studies, using virus reconstructed from genetic material obtained from victims of the 1918 pandemic, suggest a role for the NS1 protein. It appears that this viral protein adapted to antagonize the production of antiviral cytokines that suppress viral replication and are thus important during the early phase of infection. This type of adaptation of the NS1 gene may also be responsible for the enhanced proinflammatory cytokine response to H5N1 infection and the increased lethality of these highly pathogenic viral strains. 2, x JK Taubenberger. The virulence of the 1918 pandemic influenza virus: unraveling the enigma. Arch Virol Suppl 19 (2005) (101 - 115) Crossref. 3 x A Garcia-Sastre. Antiviral response in pandemic influenza viruses. Emerg Infect Dis 12 (2006) (44 - 47) Crossref.

Key Messages

  • Influenza spreads by aerosols or droplets – it can persist in the air and on hands or fomites for significant periods of time.
  • The pathogenesis of influenza is based on mucosal inflammation and lysis of respiratory epithelial cells.
  • Influenza virus does not normally spread beyond the respiratory tract due to the limited tissue distribution of proteases involved in activation of HA.
  • Systemic symptoms of influenza are mainly due to circulation of the inflammatory cytokines produced in response to infection.
  • Age, co-morbid illness and vaccination status affect the presentation of illness and are key determinants of illness severity.
  • Considering that older people may lose 2–3% of muscle power per day of bed rest, significant disability may result from influenza illness.
  • Pandemic influenza and the recent – often fatal – cases of human infection with the avian H5N1 virus underscore the high pathogenicity of influenza in immunologically naive individuals.
  • Physician awareness is the single most important factor in the diagnostic accuracy of influenza. It is essential therefore that primary care physicians be well informed about local influenza surveillance data.
  • Proper and rapid diagnosis is essential to control influenza infections by antiviral treatment and to avoid the inappropriate use of antibiotics.

Influenza is a common illness during the winter months, but the overlap of symptoms with other respiratory illnesses and the practitioner's knowledge of whether influenza is circulating in the community is key to the diagnosis. The severity of illness depends on the age of the patient (the very old and the very young are most susceptible to serious illness), whether or not high-risk conditions (chronic heart, lung and kidney diseases, diabetes or immunosuppressive conditions) are present, and whether or not the person has been vaccinated. Thus, physician knowledge about influenza in the community combined with an understanding of the individual risk of complications of influenza is required for clinical decision-making with respect to vaccination and prescription of antiviral drugs for prevention or treatment of influenza. 4 x KG Nicholson, JM Wood, M Zambon. Influenza. Lancet 362 (2003) (1733 - 1745) Crossref.

References

Label Authors Title Source Year
1

References in context

  • Additional alterations in viral proteins may have contributed to the extremely high pathogenicity of the H1N1 Spanish flu pandemic virus of 1918 and that of the more recent avian H5N1 virus, which, in ongoing outbreaks thus far (March 1, 2006), has infected 179 people with a very high case fatality rate.1 A hallmark of virulence of highly pathogenic avian influenza viruses, such as the H5 subtype viruses, is the presence of the multibasic cleavage site in the HA molecule, as discussed in Chapter 2.
    Go to context

Y Guan, LL Poon, CY Cheung, et al.. H5N1 influenza: a protean pandemic threat. Crossref. Proc Natl Acad Sci USA 101 (2004) (8156 - 8161) 2004
2

References in context

  • When a new influenza A subtype is introduced into the human population, the situation is different.
    Go to context

  • Extensive sequence analyses of the 1918 virus genome, using RNA material rescued from bodies of victims of the pandemic, as well as reconstruction of viruses containing elements of the 1918 virus, have indicated that adaptation of the NS1 protein may have contributed to the extreme pathogenicity of the virus.
    Go to context

  • Extensive sequence analyses of the 1918 virus genome, using RNA material rescued from bodies of victims of the pandemic, as well as reconstruction of viruses containing elements of the 1918 virus, have indicated that adaptation of the NS1 protein may have contributed to the extreme pathogenicity of the virus.
    Go to context

JK Taubenberger. The virulence of the 1918 pandemic influenza virus: unraveling the enigma. Crossref. Arch Virol Suppl 19 (2005) (101 - 115) 2005
3

References in context

  • When a new influenza A subtype is introduced into the human population, the situation is different.
    Go to context

  • Extensive sequence analyses of the 1918 virus genome, using RNA material rescued from bodies of victims of the pandemic, as well as reconstruction of viruses containing elements of the 1918 virus, have indicated that adaptation of the NS1 protein may have contributed to the extreme pathogenicity of the virus.
    Go to context

  • Extensive sequence analyses of the 1918 virus genome, using RNA material rescued from bodies of victims of the pandemic, as well as reconstruction of viruses containing elements of the 1918 virus, have indicated that adaptation of the NS1 protein may have contributed to the extreme pathogenicity of the virus.
    Go to context

A Garcia-Sastre. Antiviral response in pandemic influenza viruses. Crossref. Emerg Infect Dis 12 (2006) (44 - 47) 2006
4

References in context

  • Influenza is a common illness during the winter months, but the overlap of symptoms with other respiratory illnesses and the practitioner's knowledge of whether influenza is circulating in the community is key to the diagnosis.
    Go to context

  • With viral pneumonia, there is an interstitial pneumonitis with a predominantly mononuclear leucocyte infiltration. The alveolar walls become denuded of epithelium, hyaline membranes form, the intra-alveolar space becomes filled with exudate and haemorrhage from the surrounding capillaries, which significantly impairs the diffusion of gases.
    Go to context

KG Nicholson, JM Wood, M Zambon. Influenza. Crossref. Lancet 362 (2003) (1733 - 1745) 2003

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