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Cited by 576Influenza Virus Research StudiesPneumonia and Respiratory InfectionsRespiratory viral infections research

Secondary bacterial infections associated with influenza pandemics

Open access
Morris, Denise E., Cleary, David W., Clarke, Stuart C.·2017·Frontiers in Microbiology
DOI 10.3389/fmicb.2017.01041PMC PMC5481322
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Abstract

Lower and upper respiratory infections are the fourth highest cause of global mortality (Lozano et al., 2012). Epidemic and pandemic outbreaks of respiratory infection are a major medical concern, often causing considerable disease and a high death toll, typically over a relatively short period of time. Influenza is a major cause of epidemic and pandemic infection. Bacterial co/secondary infection further increases morbidity and mortality of influenza infection, with Streptococcus pneumoniae, Haemophilus influenzae and Staphylococcus aureus reported as the most common causes. With increased antibiotic resistance and vaccine evasion it is important to monitor the epidemiology of pathogens in circulation to inform clinical treatment and development, particularly in the setting of an influenza epidemic/pandemic.

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Written from the paper’s full text.

TL;DR

This narrative review concludes that bacterial co/secondary infections, most commonly Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus, substantially increased morbidity and mortality during influenza pandemics since the late 1800s. It synthesizes historical and contemporary evidence on mechanisms, epidemiology, and pandemic-specific bacterial complications.

Key findings

  • Bacterial co/secondary infection is frequent and severe: up to 75% of influenza patients who acquire pneumonia have confirmed bacterial co-infection; up to 65% of laboratory-confirmed influenza cases showed bacterial co/secondary infection, although a cited meta-analysis found most estimates between 11% and 35%.
  • The most commonly reported bacteria in influenza pandemics since the late 1800s are S. pneumoniae, H. influenzae, and S. aureus; S. pneumoniae is described as the most common bacterial cause in viral secondary infections.
  • Historical pandemic burden: 1918 A(H1N1) infected 50% of the world’s population and caused 40–50 million deaths, with bacterial pneumonia estimated in up to 95% of deaths; 1957 A(H2N2) caused 1.5–4 million global deaths and 69,800 US deaths, with bacterial infection in up to 80% of severe/fatal cases; 1968 A(H3N2) caused 1–2 million global deaths and 33,800 US deaths; 2009 A(H1N1) caused about 284,000 deaths worldwide, with secondary bacterial pneumonia identified in 29–55% of mortalities.
  • Mechanisms include influenza-induced epithelial damage, increased bacterial adhesion/colonization, impaired immune clearance, and in some cases bacterial proteases cleaving influenza HA; timing matters, as H. influenzae co-infection showed high lethality when introduced 3–4 days apart but not simultaneously or 7+ days later.

Methods

  • Design: narrative review of influenza pandemics since the late 1800s and associated bacterial co/secondary infections.
  • Data: published laboratory, clinical, epidemiological, and historical literature, including a table of significant pandemics (1889, 1918, 1957–1958, 1968–1969, 1977–1978, 2009) and cited animal and human studies.
  • Analysis: qualitative synthesis of evidence on pathogens, mechanisms, pandemic-specific bacterial complications, and factors affecting severity; no systematic search or meta-analysis described.

Limitations

  • The paper states uncertainty about whether Moraxella catarrhalis was truly absent or rare in early pandemics or was missed because it was not considered pathogenic before the 1980s and because pre-1983 culture methods were less sensitive than PCR.
  • The paper states it is unclear whether increased viral load during bacterial co-infection reflects bacterial–viral cooperation or simply bacterial burden on the host immune system, requiring further research.
  • Evident from the text: as a narrative review, it does not report a systematic search strategy, inclusion/exclusion criteria, or formal quality assessment, and many cited estimates come from heterogeneous historical, autopsy, animal, and clinical studies.

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Integrity signals

Registry

Crossref · 10.3389/fmicb.2017.01041

Cites

210 of 210 references verified0 citation errors · 0 not checkable

Statistics

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Claims the paper makes

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  • Premisecitation

    Bacterial co/secondary infection increases the morbidity and mortality of influenza and other viral respiratory infections.

    “Bacterial co/secondary infection further increases morbidity and mortality of influenza infection, with Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus reported as the most common causes.”
    • Also stated in: § Introduction · boosted
      “bacterial co/secondary infection is known lead to increased morbidity (Smith and McCullers, 2014).”
    • Also stated in: § Bacterial Co-Infection and Secondary Infections · boosted
      “Laboratory, clinical and epidemiological research has made it abundantly clear that bacterial co/secondary infection can significantly increase the morbidity and mortality of viral infections (Gupta et al., 2008).”
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    A range of bacteria including Legionella pneumophila, Streptococcus pyogenes, Neisseria meningitidis, Moraxella catarrhalis, S. pneumoniae, H. influenzae, S. aureus, Pseudomonas aeruginosa, and other Streptococcus and Staphylococcus spp. have been associated with co-infection of influenza.

    “Legionella pneumophila (Rizzo et al., 2010), Streptococcus pyogenes (Chertow and Memoli, 2013), Neisseria meningitidis, Moraxella catarrhalis, S. pneumoniae, H. influenzae, S. aureus (Dela Cruz and Wunderink, 2017), Pseudomonas aeruginosa as well as a number of other Streptococcus and Staphylococcus spp. (Yang et al., 2016a) have all been associated with co-infection of influenza.”
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    Influenza infection facilitates the acquisition, colonization, and development of disease from S. pneumoniae in people of all ages.

    “Many studies have shown that influenza infection facilitates the acquisition, colonization and development of disease from S. pneumoniae in people of all ages (Shrestha et al., 2013; Grijalva et al., 2014; Siegel et al., 2014).”
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    Co-infection may assist in the spreading of S. pneumoniae infection to the lower respiratory tract.

    “These findings are reflected in several other studies, with some even showing that co-infection may assist in the spreading of S. pneumoniae infection to the lower respiratory tract (Takase et al., 1999; Seki et al., 2004).”
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    Viral respiratory infections including influenza, respiratory syncytial virus, parainfluenza virus, and human metapneumovirus can be complicated by co/secondary bacterial infection by a variety of bacteria including S. pneumoniae, H. influenzae, and S. aureus.

    “A number of viral infections (including infection from influenza virus, respiratory syncytial virus, parainfluenza virus and human metapneumovirus) can be complicated by co/secondary infection by a variety of bacteria including Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus.”
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    Premisecitation

    In squirrel monkeys, co-infection with influenza A and S. pneumoniae resulted in severe morbidity with a 75% death rate within 40 hours, whereas individual infections caused minor illness with 100% survival.

    “Co-infection of influenza A with S. pneumoniae resulted in severe morbidity with a 75% death rate within 40 h, clear evidence of the consequences of co/secondary bacterial infection (Berendt et al., 1975).”
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    Co-infection of a virus and a bacterium can occur either from mixed viral-bacterial infection or from a viral infection sequentially followed by a bacterial infection; sequential bacterial infection normally occurs within 7 days of the viral infection.

    “Wu et al. (2011), showed that co-infection of a virus and a bacterium can either occur from mixed viral bacterial infection, or from a viral infection being sequentially followed by a bacterial infection. Sequential bacterial infection normally occurs within a 7-day period of the viral infection.”
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    In laboratory-confirmed influenza, bacterial co/secondary infection has been reported in up to 65% of cases, although a meta-analysis found that in most included studies the figure ranged between 11 and 35%.

    “Studies have shown that up to 65% of laboratory confirmed cases of influenza infection exhibited bacterial co/secondary infection, although Klein et al. (2016) state that in the majority of the research included in their meta-analysis this figure ranged between 11 and 35%.”
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    S. pneumoniae is the most common bacterium found in viral secondary bacterial infections and is particularly associated with high mortality and morbidity during influenza epidemics and pandemics.

    “Streptococcus pneumoniae is the most common bacteria found in viral secondary bacterial infections, and is particularly associated with causing high mortality and morbidity during influenza epidemics and pandemics (Brundage, 2006; Joseph et al., 2013).”
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    Influenza neuraminidase releases sialic acid from host cells and mucus, which S. pneumoniae can catabolise; influenza also increases mucus production, further increasing the metabolite available for S. pneumoniae.

    “This is partly due to S. pneumoniae’s ability to catabolise sialic acid which is released from host cells and mucus by influenza’s NA. Influenza infection also results in increased mucus production, further increasing the amount of metabolite available for S. pneumoniae.”
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    Immunosuppression is associated with more severe morbidity and a higher risk of mortality from co/secondary bacterial infection.

    “Immunosuppression is associated with more severe morbidity and a much higher risk of mortality from co/secondary bacterial infection (Rice et al., 2012).”
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    Infection with some influenza subtypes, such as H1N1 and H5N1, typically results in lymphopenia, which has been associated with higher viral load.

    “Furthermore infection with some influenza subtypes, for instance H1N1 and H5N1, typically result in lymphopenia, a state of abnormally low levels of lymphocytes, which has been associated with higher viral load.”
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    H. influenzae serotype B was a major cause of invasive disease.

    “H. influenzae serotype B was a major cause of invasive disease (Wenger, 1998; Murphy, 2003; Chin et al., 2005; Brouwer et al., 2010)”
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    Where lymphopenia occurs, studies have shown a corresponding increase in macrophages, supported by increases in IP-10, IL-8, IL-6, and MCP-1.

    “Where lymphopenia occurs, studies have shown a corresponding increase in macrophages.”
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    In a mouse model, highly invasive pneumococcal serotype 4 caused pneumonia in 58% and bacteraemia in 21% in single infection; co-infection with influenza increased these to 100% and 90%, respectively, and mortality increased from 0% to 79%.

    “The highly invasive pneumococcal serotype 4 caused pneumonia in 58% of mice and bacteraemia in 21% in a single infection model. When co-infecting with influenza these figures increased to 100 and 90% for pneumonia and bacteraemia, respectively. Mortality rates increased from 0% for individual infection to 79% during co-infection.”
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    Studies have shown a 90% reduction of alveolar macrophages in mice within a week of influenza infection, with evidence of necrosis in the remaining macrophages.

    “Studies have shown a 90% reduction of alveolar macrophages in mice within a week of influenza infection, and evidence of necrosis in the remaining macrophages (Robinson et al., 2015).”
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    Co-infection with influenza and H. influenzae caused bronchial necrosis, bronchial inflammation and bronchitis within the same time period or less, and led to epithelial erosion.

    “Conversely, co-infection caused bronchial necrosis, bronchial inflammation and bronchitis within the same time period or less, and led to further complication such as epithelial erosion (Lee L.N. et al., 2010).”
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    In Shope's study, co-infection with influenza and H. influenzae resulted in severe disease or death, whereas individual infections caused only mild infection or disease.

    “Shope found that co-infection resulted in severe disease or death when on their own H. influenzae and influenza only caused mild infection or disease (Shope, 1931).”
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    In rats, prior influenza infection reduced the dose of H. influenzae required to cause meningitis by 100-fold, while about 50% acquired meningitis in both groups.

    “In both groups ∼50% of the rats acquired meningitis, however, the naïve rats required a 100-fold larger dose of H. influenzae (Michaels et al., 1977).”
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    Widespread implementation of the Hib vaccine has significantly reduced the burden of H. influenzae serotype B disease.

    “although widespread implementation of the Hib vaccine has significantly reduced the burden of disease (Rosenstein and Perkins, 2000).”
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    In a mouse model, carrier strain serotype 19F caused pneumonia in 91% and bacteraemia in 0% in single infection; co-infection with influenza increased these to 100% and 33%, and mortality rose from 0% to 63%.

    “In comparison, individual infection with a carrier strain (of lower invasive potential) of serotype 19F, caused pneumonia in 91% of cases and bacteraemia in 0%. When co-infecting with influenza and 19F these figures increased to 100 and 33%. Mortality rose from 0% during individual infection to 63% during co-infection (Sharma-Chawla et al., 2016).”
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    Non-typeable H. influenzae remains a significant cause of bacterial meningitis, otitis media and exacerbations of chronic lung disease such as COPD worldwide.

    “Those H. influenzae that lack a capsule, denoted non-typeable H. influenzae (NTHi), remain a significant cause of bacterial meningitis, otitis media and exacerbations of chronic lung disease such as COPD worldwide (Langereis and de Jonge, 2015).”
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    de Jong et al. (2006) found that influenza infection caused lower levels of cytotoxic T cell lymphocytes, which would negatively affect acquired immunity.

    “de Jong et al. (2006) found influenza infection caused lower levels of cytotoxic T cell lymphocytes, which would therefore negatively affect acquired immunity (de Jong et al., 2006; Cunha et al., 2009).”
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    Influenza infection causes decreased mucociliary activity, dysfunction of immune cells, and reduced phagocytosis, which reduces clearance of the virus from host airways and the host's ability to fight the virus.

    “Virally induced decreased mucociliary activity, the dysfunction of immune cells and the reduction of phagocytosis reduces clearance of the virus from the host airways and the host’s ability to fight the virus (Brundage, 2006; Wu et al., 2011; Cauley and Vella, 2015).”
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    The 1918 influenza pandemic was caused by influenza strain A(H1N1).

    “The 1918 influenza pandemic was a result of influenza strain A (H1N1).”
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    S. aureus is transiently carried in the nose of 30% of the population, and 20% have persistent nasal colonization.

    “S. aureus is transiently carried in the nose of 30% of the population, whilst 20% of the population have persistent nasal colonization (Wertheim et al., 2005).”
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    In mice, low doses of influenza, low doses of S. aureus, and high doses of S. aureus were survivable.

    “Lee M.H. et al. (2010) showed that mice infected with low doses of influenza, low doses of S. aureus and high doses of S. aureus were able to survive.”
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    India alone suffered 7 million deaths during the 1918 pandemic.

    “India alone suffered 7 million deaths (Potter, 2001; Hilleman, 2002; Brundage, 2006; Michaelis et al., 2009).”
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    The main groups affected by the 1918 pandemic were those aged 20-40, infants, and those over 65.

    “The main groups of individuals affected by this pandemic were those aged 20–40 years old, in addition to infants and those over 65.”
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    S. aureus is an opportunistic pathogen and a major cause of bacteraemia.

    “Like H. influenzae and S. pneumoniae, S. aureus is an opportunistic pathogen and a major cause of bacteraemia (Wertheim et al., 2005; Tong et al., 2015).”
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    The 1918 pandemic infected 50% of the world's population and resulted in approximately 40-50 million deaths worldwide.

    “It is considered the most devastating influenza pandemic ever recorded, infecting 50% of the world’s population and resulting in approximately 40–50 million deaths worldwide.”
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    In mouse models, pre-infection with influenza before S. aureus exposure increases lung damage and bacterial density.

    “Increased lung damage and bacterial density has also been shown (DeLeo and Musser, 2010; Lee M.H. et al., 2010; Iverson et al., 2011).”
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    S. aureus is a common cause of pneumonia.

    “It is also a common cause of pneumonia (Kollef et al., 2005);”
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    Nasopharyngeal and sputum samples from 158 pneumonia cases at Camp Fremont found S. pneumoniae in 41%, H. influenzae in 38%, and other Streptococcus spp. in 29%.

    “Nasopharyngeal and sputum samples from 158 pneumonia cases found S. pneumoniae in 41% of cases, H. influenzae in 38%, and other Streptococcus spp. in 29% (Brem et al., 1918).”
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    At Camp Jackson, 17% of influenza cases progressed to pneumonia, and 31% of pneumonia cases were fatal.

    “At Camp Jackson, 17% of influenza cases progressed to pneumonia with a further 31% of pneumonia cases proving fatal.”
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    At Camp Jackson, autopsies found S. pneumoniae to be the bacterial co-infection most associated with pneumonia, and 155 of 312 lung cultures were positive for S. aureus.

    “Autopsies found S. pneumoniae to be the bacterial co-infection most associated with pneumonia, however, 155 of 312 lung cultures were positive for S. aureus (Michael, 1942; Brundage, 2006).”
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    In 1919 re-examination of lung tissue from 1918 fatalities, S. pyogenes longus was found in 36%, S. pneumoniae in 29%, and H. influenzae in 25%.

    “Further lung tissue from fatalities of this pandemic were re-examined in 1919; S. pyogenes longus was found in 36% of cases, S. pneumoniae in 29% of cases and H. influenzae in 25% (Abrahams et al., 1919; Brundage, 2006).”
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    Camp Fremont experienced 2418 hospitalizations, 17% had pneumonia, of which 36% were fatal.

    “Camp Fremont experienced 2418 hospitalizations, 17% had pneumonia of which 36% were fatal.”
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    Out of 20 tested sputum specimens from a British army camp in north France, 90% presented with H. influenzae, 65% with S. pneumoniae, 25% with other Streptococcus spp., and 15% with Staphylococcus spp.

    “Out of 20 tested sputum specimens from a British army camp based in north France, 90% presented with H. influenzae, 65% presented with S. pneumoniae, 25% with other Streptococcus spp. and 15% with Staphylococcus spp.”
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    At Camp Devens, of those infected with influenza, 17% developed pneumonia, of which 35% were fatal.

    “Of those infected, 17% developed pneumonia, of which 35% of cases were fatal.”
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    At Camp Logan, 2,487 influenza-associated hospitalizations were recorded, 17% acquired pneumonia, and 4% of pneumonia cases were fatal.

    “Here 2,487 influenza-associated hospitalizations were recorded, 17% acquired pneumonia with 4% of these cases being fatal.”
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    At Camp Custer, 21% of influenza cases progressed to pneumonia, of which 28% died.

    “At Camp Custer, 21% of influenza cases progressed to pneumonia, of which 28% died.”
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    At Camp Devens, blood culture revealed 65% had S. pneumoniae, 2.5% had H. influenzae, and 1.3% had S. aureus.

    “Blood culture revealed 65% had S. pneumoniae, 2.5% had H. influenzae and 1.3% had S. aureus (Spooner et al., 1919; Brundage, 2006).”
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    At Camp Custer, sputum cultures proved presence of S. pneumoniae in 26% of cases, and 28% of lung and blood cultures were positive for S. pneumoniae.

    “Sputum cultures proved the presence of S. pneumoniae in 26% of cases. Further investigation found 28% of lung and blood cultures were positive for S. pneumoniae, again acting as supporting evidence of the invasive potential of such co-infections (Blanton and Irons, 1918; Brundage, 2006).”
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    Among specimens positive for H. influenzae, many exhibited simultaneous H. influenzae and S. pneumoniae co-infection, with H. influenzae identified as the primary bacterial infector.

    “Out of the specimens positive for H. influenzae, many exhibited simultaneous H. influenzae and S. pneumoniae co-infection; with H. influenzae identified as the primary bacterial infector.”
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    At the Mayo Clinic in Minnesota, of 129 adults diagnosed with pandemic influenza, pneumonia was established in 16%, of which 40% (6% of all 129) were fatal.

    “Of 129 adults diagnosed with pandemic influenza, pneumonia was established in 16%, of which 40% of these cases (6% of all 129 influenza cases) were fatal.”
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    In the United States, review of 77 deaths during May-August 2009 found bacterial co-infection in almost 30% of cases; 46% were with S. pneumoniae, 9% with S. aureus, and 1% with H. influenzae.

    “Further studies in the United States have reviewed 77 deaths during the period of May–August 2009 and found bacterial co-infection in almost 30% of cases; 46% of which were with S. pneumoniae, 9% with S. aureus and 1% with H. influenzae (Centers for Disease Control and Prevention, 2009).”
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    • cites Centers for Disease Control and Prevention, 2009

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Within 4 weeks, the 2009 influenza A(H1N1) outbreak spread to 41 countries, resulting in 11,034 confirmed cases and 85 deaths.

    “Within 4 weeks this outbreak of influenza A(H1N1) had spread to 41 countries resulting in 11,034 confirmed cases and 85 deaths (Michaelis et al., 2009; Wang and Palese, 2009).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Michaelis et al., 2009 source

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    • cites Wang and Palese, 2009

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Overall 33,800 people died in the United States during the 1968-1969 pandemic, and the pandemic cost 3.9 billion dollars.

    “Overall 33,800 people died in the United States (Klimov et al., 1999) and the pandemic cost 3.9 billion dollars (Hilleman, 2002).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Klimov et al., 1999 source

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    • cites Hilleman, 2002 source

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  • May combine two claims.

    Premisecitation

    Out of 79 cases of fatal influenza with pneumonia complications during the 1968-1969 pandemic, 16% had bacterial co-infection, with S. pneumoniae (6%), S. pyogenes (5%), and S. aureus (1%) as main causes; more than one bacterium was present in 4% of cases.

    “out of 79 cases of fatal influenza with pneumonia complications, 16% had bacterial co-infection with S. pneumoniae (6%), S. pyogenes (5%), and S. aureus (1%) being the main causes. More than one of these bacteria were present in 4% of cases (Schwarzmann et al., 1971; Metersky et al., 2012).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Schwarzmann et al., 1971 source

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    • cites Metersky et al., 2012 source

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  • May combine two claims.

    Premisecitation

    Of 148 fully examined deaths presumed to be from the 1957 Asian pandemic in the Netherlands, 75% presented with bacterial pneumonia, 15% were positive for S. pneumoniae, and 59% were positive for S. aureus.

    “of the 148 deaths presumed to be from the Asian pandemic influenza strain that were examined fully, 75% presented with bacterial pneumonia of which 15% were positive for S. pneumoniae and 59% were positive for S. aureus (Hers et al., 1958).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Hers et al., 1958 source

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  • May combine two claims.

    Premisecitation

    At the Mayo Clinic, S. aureus or P. aeruginosa bacterial infection was present in 75% of all fatal cases, indicating bacterial co/secondary infection was a major determinant of severe disease and death.

    “S. aureus or P. aeruginosa bacterial infection was present in 75% of all fatal cases, indicating bacterial co/secondary infection was a major determinant of severe disease and death (Lindsay et al., 1970).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Lindsay et al., 1970 source

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  • May combine two claims.

    Premisecitation

    In Argentina, among almost 200 cases of pandemic influenza, H. influenzae was found in 52%, S. pneumoniae in 31%, and S. aureus in 18% of nasopharyngeal swab samples.

    “Palacios et al. (2009) examined nasopharyngeal swab samples from almost 200 cases of pandemic influenza. H. influenzae was found in 52%, S. pneumoniae was found in 31% and S. aureus in 18% of samples.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Palacios et al., 2009 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The 1957 Asian influenza pandemic affected 40-50% of people worldwide and was caused by influenza strain A(H2N2).

    “This pandemic affected 40–50% of people worldwide. The cause was influenza strain A (H2N2) (Potter, 2001).”
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    • cites Potter, 2001 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The death toll in the United States during the 1957 pandemic was 69,800.

    “the death toll in the United States is accurately reported to have been 69, 800 (Klimov et al., 1999; Hilleman, 2002).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Klimov et al., 1999 source

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    • cites Hilleman, 2002 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    There is a positive association between colonization of H. influenzae and S. pneumoniae, and colonization is a prerequisite for disease.

    “Of course it is known that there is a positive association between the colonization of H. influenzae and S. pneumoniae, and colonization is a prerequisite for disease, so the presence of such co-infection fits with current knowledge (Jacoby et al., 2007; Abdullahi et al., 2008).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Jacoby et al., 2007 source

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    • cites Abdullahi et al., 2008 source

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  • May combine two claims.

    Premisecitation

    Bacteraemia was observed in 5% of admissions in the pediatric ICU study, for which S. aureus was the main cause.

    “Bacteraemia was observed in 5% of admissions, for which S. aureus was the main cause (Randolph et al., 2011).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Randolph et al., 2011 source

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  • May combine two claims.

    Premisecitation

    A hospital in Atlanta suffered a threefold increase in cases of Staphylococcal pneumonia during the 1968-1969 pandemic, and Staphylococcal infection caused 26% of pneumonia cases.

    “A hospital in Atlanta suffered a threefold increase in cases of Staphylococcal pneumonia during this pandemic. Staphylococcal infection caused 26% of pneumonia cases during this period, and a high correlation was recognized between influenza infection and bacterial pneumonia (Schwarzmann et al., 1971).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Schwarzmann et al., 1971 source

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  • May combine two claims.

    Premisecitation

    In 1969, England and Wales saw a 55% increase in respiratory deaths, of which co/secondary bacterial infection was a major contributor.

    “In 1969, England and Wales saw a 55% increase in respiratory deaths, of which co/secondary bacterial infection was shown to be a major contributor (Tillett et al., 1983).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Tillett et al., 1983 source

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  • May combine two claims.

    Premisecitation

    During the 1957 pandemic, the United States and many other countries experienced an increase in hospitalization rates, with a majority due to pneumonia predominantly caused by S. pneumoniae, H. influenzae, and S. aureus.

    “During this pandemic the United States, and many other countries, experienced an increase in hospitalization rates. A majority were due to pneumonia, predominantly caused by S. pneumoniae, H. influenzae, and S. aureus infection (Petersdorf et al., 1959).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Petersdorf et al., 1959 source

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  • May combine two claims.

    Premisecitation

    In 838 critically ill children infected with pandemic influenza in US pediatric intensive care units, within 72 h of admission 33% exhibited bacterial co-infection; in 26% of these cases S. aureus was identified (48% MRSA), 5.5% were positive for S. pneumoniae, and 5% for H. influenzae.

    “investigated 838 critically ill children who were infected with pandemic influenza. Within 72 h of admission to the intensive care unit 33% exhibited bacterial co-infection; in 26% of these cases S. aureus was identified as the cause (48% of which were MRSA), 5.5% were positive for S. pneumoniae and 5% were positive for H. influenzae.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Randolph et al., 2011 source

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  • May combine two claims.

    Premisecitation

    In 140 people hospitalized with pneumonia at Sheffield City General Hospital in 1957, a majority showed evidence of influenza A infection; 27% had co/secondary S. aureus infection (47% death rate), 15% S. pneumoniae, and 4% H. influenzae.

    “A majority showed evidence of influenza A infection; 27% of those had co/secondary infection of S. aureus (which had a 47% death rate), 15% S. pneumoniae and 4% H. influenzae, although this is likely to be an underestimation as many patients had already started taking antibiotics (Robertson et al., 1958).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Robertson et al., 1958 source

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  • May combine two claims.

    Premisecitation

    In the United Kingdom, of 457 fatalities in the 2009 pandemic, 68 were autopsied; 41% had complications associated with secondary bacterial infection, most commonly (25% of cases) due to S. pneumoniae.

    “In the United Kingdom, of the 457 fatalities 68 were autopsied. Of these, 41% were shown to have complications associated with secondary bacterial infection, most commonly (25% of cases) due to S. pneumoniae (Lucas, 2010).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Lucas, 2010 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    By the end of the 2009 pandemic, there were 284,000 deaths worldwide, with Mexico and the United States most severely affected.

    “By the end of the pandemic it is thought that there were 284,000 deaths worldwide, with Mexico and the United States being most severely affected (Chertow and Memoli, 2013).”
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    • cites Chertow and Memoli, 2013

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Worldwide 1-2 million people died during the 1968-1969 Hong Kong influenza pandemic, which was caused by influenza strain A(H3N2).

    “Worldwide 1–2 million people died during this pandemic which was caused by the influenza strain A(H3N2) (Michaelis et al., 2009).”
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    • cites Michaelis et al., 2009 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Global death toll estimates for the 1957 pandemic vary between 1.5 million and 2-4 million.

    “Although global death toll estimates vary [between 1.5 million (Gatherer, 2009) and 2–4 million (Michaelis et al., 2009)]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Gatherer, 2009 source

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    • cites Michaelis et al., 2009 source

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  • May combine two claims.

    Premisecitation

    During the 2009 Swine Flu Pandemic, almost 30% of the first 47 deaths in New York City showed invasive bacterial disease, with S. pneumoniae the most common causative agent.

    “Surveillance by the New York City Department of Health and Mental Hygiene has shown that during the 2009 Swine Flu Pandemic almost 30% of the first 47 deaths showed invasive bacterial disease. S. pneumoniae was the most common causative agent identified (followed by S. pyogenes) (Lee E.H. et al., 2010).”
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    • cites Lee E.H. et al., 2010

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  • May combine two claims.

    Premisecitation

    In early influenza pandemics such as the 1918 Spanish pandemic, M. catarrhalis rarely appears to be a noted cause of co-infection, whereas in the 2009 pandemic it is seen in up to 18% of cases.

    “In early influenza pandemics such as the 1918 Spanish pandemic, M. catarrhalis rarely appears to be a noted cause of co-infection. However, in the 2009 pandemic it is seen in up to 18% of cases (Nguyen et al., 2012).”
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    • cites Nguyen et al., 2012 source

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  • May combine two claims.

    Premisecitation

    Non-pathogenic and mammalian influenza HA undergoes cleavage outside of the host cell, whereas highly pathogenic strains are cleaved inside host cells.

    “Interestingly non-pathogenic and mammalian influenza HA undergoes cleavage outside of the host cell where as highly pathogenic strains are cleaved inside host cells (Steinhauer, 1999).”
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    • cites Steinhauer, 1999 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Neuraminidase enables release of newly formed progeny virions by hydrolysing sialic acid and detaching it from HA.

    “Neuraminidase enables the release of newly formed progeny virions; by hydrolysing the sialic acid and detaching it from the HA the virion becomes liberated from the host cell (Zambon, 2001).”
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    • cites Zambon, 2001 source

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  • May combine two claims.

    Premisecitation

    Influenza, as well as other upper respiratory tract viral infections, leads to a greater risk of infection from bacterial pathobionts and an increased likelihood of colonization with bacteria such as S. pneumoniae, H. influenzae, and S. aureus.

    “It has become clear that influenza, as well as other upper respiratory tract viral infections, leads not only to a greater risk of infection from bacterial pathobionts but also an increased likelihood that an individual may become colonized with bacteria such as S. pneumoniae, H. influenzae and S. aureus (Hament et al., 1999; Hilleman, 2002).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Hament et al., 1999 source

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    • cites Hilleman, 2002 source

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  • May combine two claims.

    Premisecitation

    In a retrospective study of 50 patients infected during pandemic influenza, 28% showed co/secondary bacterial infection; Mycoplasma pneumoniae was found in 10%, S. aureus in 6%, K. pneumoniae and S. pneumoniae in 4%, and M. catarrhalis, P. aeruginosa, S. pyogenes, and Streptococcus agalactiae in 2%.

    “In a retrospective study of 50 patients who were infected during pandemic influenza, 28% showed co/secondary bacterial infection (Dhanoa et al., 2011). Mycoplasma pneumoniae was found in 10%, making it the most common co/secondary infecting bacteria. This was followed by S. aureus found in 6%, K. pneumoniae and S. pneumoniae found in 4% and M. catarrhalis, P. aeruginosa, S. pyogenes, and Streptoc”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Dhanoa et al., 2011 source

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  • May combine two claims.

    Premisecitation

    Influenza A is the type most commonly associated with co/secondary bacterial infection, and subtypes with NA2 traditionally result in more severe infection.

    “Research shows that influenza A is the type most commonly associated with co/secondary bacterial infection and subtypes with NA2 traditionally result in more severe infection (Peltola et al., 2005).”
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    • cites Peltola et al., 2005 source

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  • May combine two claims.

    Premisecitation

    Poor disease outcome has been linked to lost lung repair function and loss of basal epithelial cells, including alveolar epithelial cells, which is associated with increased bacterial attachment and apoptosis.

    “Furthermore, poor disease outcome has been linked to lost lung repair function and loss of basal epithelial cells, including alveolar epithelial cells; which is associated with increased bacterial attachment and apoptosis (Kash et al., 2011).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Kash et al., 2011 source

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  • May combine two claims.

    Premisecitation

    In another US pediatric intensive care unit study, 51% of children with influenza infection had bacterial co/secondary infection; of these 35% had S. aureus, 18% P. aeruginosa, 18% M. catarrhalis, 9% NTHI, 6% S. pneumoniae, and 6% Group A Streptococcus.

    “In another study of vulnerable and critically ill children in a pediatric intensive care unit in the United States, 51% of those with influenza infection had bacterial co/secondary infection. Of these 35% presented with S. aureus, 18% P. aeruginosa, 18% M. catarrhalis, 9% NTHI, 6% S. pneumoniae and 6% Group A Streptococcus.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Nguyen et al., 2012 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    M. catarrhalis is now acknowledged as the third most common cause of otitis media after S. pneumoniae and H. influenzae, and the second most common cause of exacerbations in COPD, accounting for up to 4 million exacerbations per year in the United States alone.

    “Moraxella catarrhalis is a bacteria of increasing importance being now acknowledged as the third most common cause of otitis media (OM), after S. pneumoniae and H. influenzae (Bluestone, 1986; Faden et al., 1994; Kilpi et al., 2001; Dupont et al., 2010) and the second most common cause of exacerbations in COPD, accounting for up to 4 million exacerbations per year in the United States alone (Mur”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Bluestone, 1986 source

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    • cites Faden et al., 1994 source

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    • cites Kilpi et al., 2001 source

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  • May combine two claims.

    Premisecitation

    Seasonal influenza A virus binds to α2-6 sialylated glycans on cells in the upper respiratory tract, whereas highly pathogenic avian H5N1 binds to α2-3 sialylated glycans on type 2 pneumocytes lining lung alveoli.

    “traditionally seasonal influenza A virus binds to α2-6 sialylated glycans on cells in the upper respiratory tract whereas the highly pathogenic avian H5N1 strain binds to α2-3 sialylated glycans on type 2 pneumocytes lining lung alveoli (Shinya et al., 2006).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Shinya et al., 2006 source

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  • May combine two claims.

    Premisecitation

    In autopsies from the 1918 pandemic, S. pneumoniae was the most common co-infector, followed by S hemolytic, S. aureus, and H. influenzae; M. catarrhalis was grouped within 'Other bacteria'.

    “For example, autopsies from the 1918 pandemic were reviewed and it was found that S. pneumoniae was the most common co-infector, followed by S hemolytic, S. aureus, and H. influenzae. ‘Other bacteria’ were also highlighted within which M. catarrhalis was grouped (Morens et al., 2008).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Morens et al., 2008 source

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  • May combine two claims.

    Premisecitation

    The low pH in the endosome causes a conformational change to HA allowing it to be cleaved, an important step in penetrating into the host cell; HA and availability of appropriate host proteases are determinants of infectivity.

    “The low pH in the endosome causes a conformational change to the HA allowing it to be cleaved, an important step in penetrating into the host cell. Therefore HA and the availability of appropriate host proteases are determinants of infectivity (Steinhauer, 1999; Samji, 2009).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Steinhauer, 1999 source

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    • cites Samji, 2009

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  • May combine two claims.

    Premisecitation

    In that pediatric ICU study, those with S. aureus showed more severe morbidity and were more likely to develop disseminated intravascular coagulation.

    “Those with S. aureus showed more severe morbidity and were more likely to develop disseminated intravascular coagulation which leads to a compromised blood flow within body tissue and therefore tissue damage (Nguyen et al., 2012).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Nguyen et al., 2012 source

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  • May combine two claims.

    Premisereasoning

    Various factors are known to impact the severity of viral infection, which in turn increases the likelihood of bacterial co/secondary infections; these include the type of HA and NA surface antigen.

    “Various factors are known to impact the severity of viral infection, which in turn increases the likelihood of bacterial co/secondary infections; these include the type of HA and NA surface antigen.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    M. catarrhalis is a cause of pneumonia and invasive disease such as bacteraemia and meningitis, with bacteraemia being a common complication of pneumonia, particularly in adults.

    “M. catarrhalis is a cause of pneumonia (Berg and Bartley, 1987; Hager et al., 1987; Marchant, 1990; Verduin et al., 2002) and invasive disease such as bacteraemia (Ioannidis et al., 1995) and meningitis (Newing and Christie, 1947), with bacteraemia being a common complication of pneumonia, particularly in adults (Collazos et al., 1992; Ioannidis et al., 1995).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Berg and Bartley, 1987

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    • cites Hager et al., 1987 source

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    • cites Marchant, 1990 source

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  • May combine two claims.

    Premisecitation

    Impaired neutrophils correlate with secondary bacterial infection in chinchillas, due to the importance of phagocytosis during innate immunity.

    “Impaired neutrophils have been shown to correlate with secondary bacterial infection in Chinchillas, due to the importance of phagocytosis during innate immunity (Abramson et al., 1981).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Abramson et al., 1981 source

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  • May combine two claims.

    Premisecitation

    Influenza infection appears to prime host airways for bacterial infection and modifies and impairs immune responses in a number of ways.

    “Influenza infection appears to prime the host airways for bacterial infection, whilst modifying and impairing immune responses in a number of ways (Joseph et al., 2013).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Joseph et al., 2013 source

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  • May combine two claims.

    Premisecitation

    During influenza infection, impaired immunologic cells can suppress host immune responses and immune cell dysfunction can reduce the host's ability to fight bacteria.

    “host immune responses can be suppressed when immunologic cells are impaired during influenza infection and immune cell dysfunction can reduce the host’s ability to fight bacteria”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Peltola and McCullers, 2004

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    • cites Brundage, 2006 source

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    • cites Wu et al., 2011

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  • May combine two claims.

    Premisecitation

    Pulmonary IFNγ pro-inflammatory cytokines are produced by natural killer (NK) cells as part of innate immunity and by CD4 and CD8 NK T cells as part of adaptive immunity.

    “pulmonary IFNγ pro-inflammatory cytokines are produced by natural killer (NK) cells as part of innate immunity and by CD4 and CD8 NK T cells as part of adaptive immunity (Schoenborn and Wilson, 2007).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Schoenborn and Wilson, 2007

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  • May combine two claims.

    Premisecitation

    Type I IFN-mediated inhibition of Th17 immunity reduces CD4+ T cells and gamma delta T cells, leading to reduced production of IL-17 and IL-22 and preventing clearance of bacteria.

    “and therefore there is a reduction in the levels of CD4+ T cells and gamma delta T cells and hence a reduction in the production of IL-17 and IL-22, preventing the clearance of bacteria (Shahangian et al., 2009; Kudva et al., 2011; Mulcahy and McLoughlin, 2016).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Shahangian et al., 2009 source

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    • cites Kudva et al., 2011 source

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    • cites Mulcahy and McLoughlin, 2016

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  • May combine two claims.

    Interpretationcitation

    The reduction in alveolar macrophages during S. pneumoniae and influenza co-infection likely hinders bacterial clearance, leading to increased bacterial load and prolonged inflammatory response increasing morbidity.

    “This reduction is likely to hinder bacterial clearance, hence the increased bacterial load found during co-infection during this study, and results in prolonged inflammatory response increasing morbidity.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Sharma-Chawla et al., 2016 source

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  • May combine two claims.

    Premisecitation

    Influenza A virus can produce viral cytotoxin PB1-F2, which increases inflammation, host cell damage, bacterial adherence, mortality and morbidity.

    “Influenza A virus can produce a viral cytotoxin PB1-F2 (Conenello and Palese, 2007; Iverson et al., 2011) which plays a role in increasing inflammation and therefore host cell damage and bacterial adherence, increasing mortality and morbidity (Lee et al., 2016).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Conenello and Palese, 2007

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    • cites Iverson et al., 2011 source

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    • cites Lee et al., 2016 source

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  • May combine two claims.

    Interpretationcitation

    IL-1β plays a role in Th17 polarization, so decreased IL-1β further hinders Th17 immunity.

    “IL-1β has been shown to play a role in Th17 polarization, therefore further hindering this pathway of immunity (Robinson et al., 2013).”
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    • cites Robinson et al., 2013 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Inflammation causes tissue damage, revealing more attachment sites for increased/developed bacterial infection.

    “Inflammation causes tissue damage, revealing more attachment sites for increased/developed bacterial infection.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Distress signals such as ATP and norepinephrine produced by damaged influenza instigate biofilm dispersal, helping spread of S. aureus into the lungs and assisting development of pneumonia and invasive disease.

    “Distress signals, such as ATP and norepinephrine, produced by damaged influenza also have several effects on S. aureus; namely the instigation of biofilm dispersal which helps the spread of S. aureus into the lungs, assisting in the development of pneumonia and invasive disease (Mulcahy and McLoughlin, 2016).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Mulcahy and McLoughlin, 2016

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  • May combine two claims.

    Interpretationreasoning

    Viral infection aids bacterial infection by unveiling/providing more sites for adhesion, impairing immune responses, and causing cell and tissue destruction allowing spread of bacteria and development of invasive infection.

    “Viral infection aids bacterial infection in a number of ways, including unveiling/providing more sites for adhesion, impairing immune responses and causing cell and tissue destruction allowing for the spread of bacteria and development of invasive infection.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisereasoning

    When S. pneumoniae successively co-infects with influenza, it leads to severe clinical complications, partly due to increased apoptosis of dendritic cells, reducing T cell priming and impairing adaptive immunity.

    “In addition, when S. pneumoniae successively co-infects with influenza it leads to severe clinical complications; partly due to an increase in apoptosis of dendritic cells, which therefore reduces T cell priming impairing the development of adaptive immunity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    IP-10 attracts various immune cells including activated T cells, monocytes and macrophages, causing inflammation.

    “IP-10 attracts various immune cells including activated T cells, monocytes and macrophages, therefore causing inflammation (Dufour et al., 2002; Hoffmann et al., 2016).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Dufour et al., 2002 source

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    • cites Hoffmann et al., 2016 source

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    Premisecitation

    IL-22 is involved in controlling production of antimicrobial peptides and staphylococcal ligand expression.

    “IL-22 in involved in controlling the production of antimicrobial peptides as well as staphylococcal ligand expression (Robinson et al., 2014; Mulcahy et al., 2016).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Robinson et al., 2014 source

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    • cites Mulcahy et al., 2016

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  • May combine two claims.

    Premisecitation

    IP-10 is increased during H. influenzae and S. aureus co-infection and correlates with pneumonia etiology.

    “IP-10 is increased during H. influenzae and S. aureus co-infection as well, and like with S. pneumoniae, correlates with/highlights pneumonia etiology (Hoffmann et al., 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Hoffmann et al., 2016 source

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92 of 92

  • The paper relies on this without support.

    Antibiotic resistance is increasing.

    “With increased antibiotic resistance and vaccine evasion it is important to monitor the epidemiology of pathogens in circulation to inform clinical treatment and development, particularly in the setting of an influenza epidemic/pandemic.”
    “increasing levels of antibiotic resistance”

  • The paper relies on this without support.

    Vaccine evasion occurs.

    “With increased antibiotic resistance and vaccine evasion it is important to monitor the epidemiology of pathogens in circulation to inform clinical treatment and development, particularly in the setting of an influenza epidemic/pandemic.”

  • The paper relies on this without support.

    Vaccine implementation is lower in low and middle income countries.

    “lower levels of vaccine implementation in low and middle income countries”

  • The paper relies on this without support.

    Pneumococcal vaccines have fractional serotype coverage.

    “fractional serotype coverage”

  • The paper relies on this without support.

    Antibiotic resistance is at an all-time high.

    “with antibiotic resistance at an all-time high”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • One of the most feared consequences of influenza infection is secondary bacterial infection and resulting ARDS, due to the substantial increase in morbidity and mortality.

    “One of the most feared consequences of influenza infection is secondary bacterial infection (this is bacterial infection that occurs during or after an infection from another pathogen; commonly viruses) (Morris et al., 2017) and resulting ARDS, due to the substantial increase in morbidity and mortality.”

    From Viral Infections, the Microbiome, and Probiotics (2021) · cites this paper as Morris et al., 2017

Cites

Flagged first, then by citations

Research works printed but not linked: 5

  1. Johnson, 2016, The Spanish Flu Pandemic of 1918.
  2. Opie, 1921, The pneumonias and other infections of the respiratory tract accompanying influenza and measles. St. Louis: CV Mosby, Epidemic Respiratory Disease, 107
  3. Racaniello, 2009, The A, B, and C of Influenza Virus.
  4. 2016, Influenza (Seasonal) Factsheet.
  5. 2017, Smallpox.

Cited by

Sorted by citations

Related

Authors
Morris, D. E., Cleary, D. W., & Clarke, S. C.
Affiliations
University Hospital Southampton NHS Foundation Trust (GB)
Corresponding author
  • Morris, Denise E.
  • Clarke, Stuart C.
ORCID
Venue
Frontiers in Microbiology
Publisher
Frontiers Media SA
Published
2017-06-23
Volume
8
Pages
1041-1041
ISSN
1664-302X (ISSN-L)
DOI
10.3389/fmicb.2017.01041
PMC
PMC5481322
OpenAlex
W2718738457
Semantic Scholar
d292c61e7f79b50cb0c488b3d362ea9e6aa10310
Cited by
576
References
210
Citations by year
2026: 28 · 2025: 45 · 2024: 77 · 2023: 95 · 2022: 90 · 2021: 109 · 2020: 76 · 2019: 25 · 2018: 17 · 2017: 1
FWCI
4.31
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Frontiers in Microbiology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • ePrints Soton (University of Southampton) (acceptedVersion)
  • National University of Singapore (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
Topics
  • Health Sciences › Medicine › Epidemiology › Influenza Virus Research Studies
  • Health Sciences › Medicine › Epidemiology › Pneumonia and Respiratory Infections
  • Health Sciences › Medicine › Epidemiology › Respiratory viral infections research
Keywords
secondary bacterial infection, pandemic influenza, Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, bacterial co-infection, respiratory infections, antibiotic resistance, vaccine evasion, pathogen epidemiology

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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