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Pathogenesis, Clinical Features and Diagnosis

Pathogenesis of influenza

The different types of influenza are of variable clinical importance in people. The influenza A H3N2 subtype is usually associated with greater mortality than the H1N1 subtype and the influenza B virus. Influenza C causes clinically unimportant illness. The effects of influenza on the naive immune system are evident in the high-risk population of children under the age of 2 years, with some protection mediated by maternal antibodies in infants less than 6 months old. 5 x WP Glezen, LH Taber, AL Frank, WC Gruber, PA Piedra. Influenza virus infections in infants. Pediatr Infect Dis J 16 (1997) (1065 - 1068) Crossref. Elderly people are particularly at risk for influenza illness, because of ageing effects on the immune system and the greater incidence of underlying medical conditions. The more co-morbid conditions, the greater the risk. People in residential care are particularly susceptible because they are generally older, have a high rate of chronic ill health, live in close proximity to each other (facilitating transmission) and respond less well to vaccination. Interestingly, the current cohort of older people appears to be less susceptible compared to young adults and children when H1N1 strains circulate in the community. 6 x AM McBean, PL Hebert. New estimates of influenza-related pneumonia and influenza hospitalizations among the elderly. Int J Infect Dis 8 (2004) (227 - 235) Crossref. This protection of older adults against H1N1-mediated illness has been attributed to priming with H1N1 strains that circulated during their childhood and may have generated protective immunological memory.

Mode of transmission

The primary mode of influenza transmission is by aerosol or droplets. The virus may remain suspended in the air for long periods of time and can be dispersed by air currents. Transmission may also occur by contact with virus-contaminated hands or fomites. Inhaled virus may be trapped in mucus produced by airway epithelial cells and then transported by the cilia to the posterior pharynx, where it is swallowed or expectorated (“tracheal toilet”). This mechanism may be impaired in cases of chronic obstructive lung disease or asthma, or in debilitated people.

Lysis of respiratory epithelial cells

The influenza virus causes a lytic infection of respiratory epithelial cells (see Chapter 2). As a consequence, mucosal cells become vacuolated and oedematous, and desquamate, leaving only the basal cells and the basement membrane of the respiratory epithelium. The resulting exudative process with increased mucus production causes a runny nose, cough and nasal congestion. In uncomplicated influenza, acute diffuse mucosal inflammation and oedema of the upper airway and bronchi are observed. In older people, cough is the most common presenting feature of influenza illness, often in the absence of other more classic symptoms such as fever and myalgia, but these symptoms do not distinguish influenza from other viral respiratory illnesses. 7 x M Loeb, A McGeer, M McArthur, RW Peeling, M Petric, AE Simor. Surveillance for outbreaks of respiratory tract infect-ions in nursing homes. Can Med Assoc J 162 (2000) (1133 - 1137)

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. Progressive hypoxia occurs as the alveolar space is obliterated. In pandemic influenza, where the immune system has no immunological memory for the infecting virus strain, this may be a common scenario even in healthy young people. 4 x KG Nicholson, JM Wood, M Zambon. Influenza. Lancet 362 (2003) (1733 - 1745) Crossref.

Immunopathogenesis

The immune response to influenza has been presented in the previous chapter. This section discusses the immunopathogenesis of influenza – how the body's response to the virus contributes to the symptoms of influenza. Inflammatory cytokines, including tumour necrosis factor-alpha (TNF-α) and type I interferons (IFN-α/β), have been associated with the pathogenesis of influenza infection. Although they are critical components in the down-regulation of intracellular protein synthesis, thus limiting new virus production, these cytokines, along with interleukins (IL-1β, IL-6) produced by the adaptive immune response, are largely responsible for the systemic symptoms of influenza illness, including fever and myalgia. Importantly, influenza virus is limited to the lungs except in rare circumstances where infections of muscles and the central nervous system have been documented. Local symptoms such as cough and sore throat may be a combination of desquamation of the epithelial lining of the airways and the resulting inflammatory response to necrosis of the cells in the process of viral replication. In particular, plasma IL-6 levels correspond to the severity of respiratory symptoms and fever in community-acquired influenza A illness, although serum levels of a number of other cytokines are elevated as well. 8 x L Kaiser, RS Fritz, SE Straus, L Gubareva, FG Hayden. Symptom pathogenesis during acute influenza: interleukin-6 and other cytokine responses. J Med Virol 64 (2001) (262 - 268) Crossref. Paradoxically, older people often do not mount a fever with influenza infection, even though IL-6 levels increase with age. In children, influenza-mediated upper respiratory illness is an important cause of acute otitis media. 9 x S Vesa, M Kleemola, S Blomqvist, A Takala, T Kilpi, T Hovi. Epidemiology of documented viral respiratory infections and acute otitis media in a cohort of children followed from two to twenty-four months of age. Pediatr Infect Dis J 20 (2001) (574 - 581) Crossref.

“There was clear evidence of … shortage of breath and the appearance of mahogany spots around the mouth which would extend and coalesce into a violaceous heliotrope cyanosis until ‘a white man could not be distinguished from a coloured’. A peculiar stench emanated from many patients. With increasing cyanosis, patients begin to gasp for breath; bloodstained fluid would froth from the mouth; patients would become delirious, and death would follow from suffocation. With rigor mortis, bloody fluid would gush from the mouth and nostrils. The time from hospital admission to death could be a few hours to 2–3 days.”Textbook of Influenza ( Ref. 33 x CW Potter. Chronicle of influenza pandemics. KG Nicholson, RG Webster, AJ Hay (Eds.) Textbook of Influenza (Blackwell Science, Oxford, 1998) (3 - 18) )

Pathogenesis of pandemic influenza

In pandemic influenza, a novel virus subtype is introduced into the human population, to which, at that point, no immunity exists (see Chapter 3). Factors contributing to the increased severity of illness under these conditions relate to the induction of a primary viral pneumonia and a profound inflammatory response. Especially in immunologically naive individuals, non-specific destruction of cells by both viral and immunologic mechanisms, and the delay in the activation of the adaptive immune response, are involved in the pathogenesis of the disease. Destruction of respiratory epithelium due to viral replication and the inflammatory exudates produced may lead to profound hypoxia and death within days from the onset of illness, as illustrated in the text box above, describing the typical disease picture caused by the Spanish flu virus.

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. The innate immune response to the influenza includes sensors in the host cell that recognize viral RNA and stimulate the synthesis of type I interferons (IFN-α/β). It appears that in the case of the 1918 pandemic virus, the NS1 gene has adapted to efficiently suppress the IFN-α/β system. Because of the role of type 1 interferons in suppressing viral replication, the inhibitory effect of the 1918 NS1 may have considerably enhanced the pathogenicity of the virus. 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. It is likely that other properties of the 1918 virus have contributed to its extreme pathogenicity as well, but these are still not completely understood. 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. 10, x AH Reid, JK Taubenberger. The 1918 flu and other influenza pandemics: “over there” and back again. Lab Invest 79 (1999) (95 - 101) 11 x RG Webster. 1918 Spanish influenza: the secrets remain elusive. Proc Natl Acad Sci USA 96 (1999) (1164 - 1166) Crossref.

As shown in Figure 20 , death was age-related during interpandemic years preceding the Spanish flu outbreak, with high mortality rates in the under 5-year-olds and the elderly. During the 1918 pandemic, the mortality curve was W-shaped, reflecting the higher attack rates that are generally seen in healthy young adults (25–49-year-olds) but with a higher mortality rate in this population during the pandemic compared to interpandemic years. The highest incidence of infection was in 5–14-year-olds, but they had the lowest mortality. Death was frequently due to primary viral pneumonia (usually uncommon) or secondary bacterial pneumonia (antibiotic treatment was not yet available).

Figure 20 Influenza and pneumonia mortality by age in the USA. Influenza- and pneumonia-specific mortality by age, including the pandemic year 1918 and the average of the interpandemic years 1911–15, is shown. Specific death rate is per 100,000 of the population for each age division. Purple line, 1918 pandemic; orange line, average of interpandemic years 1911–15. source: Adapted from Potter CW, editor. Influenza (Perspectives in Medical Virology), 2003 with permission from Elsevier.

f05-20-9780723434337

References in context

  • As shown in Figure 20, death was age-related during interpandemic years preceding the Spanish flu outbreak, with high mortality rates in the under 5-year-olds and the elderly.
    Go to context

Attack rates of Asian flu (1957–58) varied in different communities around the world. Groups with the highest infection rates included school children aged 5–14 years (>50%), the institutionalized and those living in crowded conditions. Overall, mortality was only 10% of that seen with the Spanish flu, but despite this, it translated into 33,000 excess deaths during the second wave in the UK, and 39,000 and 20,000 excess deaths during the first and second waves respectively in the USA. Many factors have been postulated to explain differences in attack rates, but these have yet to be determined (reviewed in Ref. 4).

 
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Figure 20 Influenza and pneumonia mortality by age in the USA. Influenza- and pneumonia-specific mortality by age, including the pandemic year 1918 and the average of the interpandemic years 1911–15, is shown. Specific death rate is per 100,000 of the population for each age division. Purple line, 1918 pandemic; orange line, average of interpandemic years 1911–15. source: Adapted from Potter CW, editor. Influenza (Perspectives in Medical Virology), 2003 with permission from Elsevier.

f05-20-9780723434337

References in context

  • As shown in Figure 20, death was age-related during interpandemic years preceding the Spanish flu outbreak, with high mortality rates in the under 5-year-olds and the elderly.
    Go to context

References

Label Authors Title Source Year
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
5

References in context

  • The effects of influenza on the naive immune system are evident in the high-risk population of children under the age of 2 years, with some protection mediated by maternal antibodies in infants less than 6 months old.5 Elderly people are particularly at risk for influenza illness, because of ageing effects on the immune system and the greater incidence of underlying medical conditions.
    Go to context

WP Glezen, LH Taber, AL Frank, WC Gruber, PA Piedra. Influenza virus infections in infants. Crossref. Pediatr Infect Dis J 16 (1997) (1065 - 1068) 1997
6

References in context

  • Interestingly, the current cohort of older people appears to be less susceptible compared to young adults and children when H1N1 strains circulate in the community.6 This protection of older adults against H1N1-mediated illness has been attributed to priming with H1N1 strains that circulated during their childhood and may have generated protective immunological memory.
    Go to context

AM McBean, PL Hebert. New estimates of influenza-related pneumonia and influenza hospitalizations among the elderly. Crossref. Int J Infect Dis 8 (2004) (227 - 235) 2004
7

References in context

  • The influenza virus causes a lytic infection of respiratory epithelial cells (see Chapter 2).
    Go to context

M Loeb, A McGeer, M McArthur, RW Peeling, M Petric, AE Simor. Surveillance for outbreaks of respiratory tract infect-ions in nursing homes. Can Med Assoc J 162 (2000) (1133 - 1137) 2000
8

References in context

  • In particular, plasma IL-6 levels correspond to the severity of respiratory symptoms and fever in community-acquired influenza A illness, although serum levels of a number of other cytokines are elevated as well.8 Paradoxically, older people often do not mount a fever with influenza infection, even though IL-6 levels increase with age.
    Go to context

L Kaiser, RS Fritz, SE Straus, L Gubareva, FG Hayden. Symptom pathogenesis during acute influenza: interleukin-6 and other cytokine responses. Crossref. J Med Virol 64 (2001) (262 - 268) 2001
9

References in context

  • The immune response to influenza has been presented in the previous chapter.
    Go to context

S Vesa, M Kleemola, S Blomqvist, A Takala, T Kilpi, T Hovi. Epidemiology of documented viral respiratory infections and acute otitis media in a cohort of children followed from two to twenty-four months of age. Crossref. Pediatr Infect Dis J 20 (2001) (574 - 581) 2001
10

References in 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

AH Reid, JK Taubenberger. The 1918 flu and other influenza pandemics: “over there” and back again. Lab Invest 79 (1999) (95 - 101) 1999
11

References in 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

RG Webster. 1918 Spanish influenza: the secrets remain elusive. Crossref. Proc Natl Acad Sci USA 96 (1999) (1164 - 1166) 1999
33

References in context

CW Potter. Chronicle of influenza pandemics. KG Nicholson, RG Webster, AJ Hay (Eds.) Textbook of Influenza (Blackwell Science, Oxford, 1998) (3 - 18) 1998

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