Bacterial Pathogens and Death during the 1918 Influenza Pandemic

Chien, Yu Wen; Klugman, Keith P.; Morens, David M.

doi:10.1056/nejmc0908216

Cited by 116 publications

(94 citation statements)

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“…Therefore, it remains unclear if the identified mechanisms generally apply to strains of different pneumococcal serotypes. Importantly, blood cultures from living cases of the 1918 IAV pandemic revealed a higher prevalence of less invasive serotypes in secondary pneumococcal infections than the common pathogenic serotypes found at that time (2,26). This observation implicates a preference for otherwise colonizing strains to cause severe infections in IAV-infected individuals and strongly supports the hypothesis that a preexisting IAV infection influences the pathogenic effect of these strains.…”

supporting

confidence: 65%

mentioning

confidence: 99%

“…This lethal synergism has been recognized as early as during the 1918-1919 IAV pandemic with an estimated global death toll of 50 to 100 million (1,2). Retrospective studies disclosed that 71% of the fatal cases during this pandemic were positive for Streptococcus pneumoniae (also called pneumococcus), providing the first epidemiological evidence for viral-bacterial coinfections (2). A clear predisposition to bacterial disease was also evident in all of the succeeding influenza pandemics, including the more recent 2009 H1N1 outbreak, which had a 10 to 55% higher incidence of hospitalizations and mortality due to bacterial pneumonia (3).…”

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confidence: 99%

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Influenza A Virus Infection Predisposes Hosts to Secondary Infection with Different Streptococcus pneumoniae Serotypes with Similar Outcome but Serotype-Specific Manifestation

et al. 2016

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e Influenza A virus (IAV) and Streptococcus pneumoniae are major causes of respiratory tract infections, particularly during coinfection. The synergism between these two pathogens is characterized by a complex network of dysregulated immune responses, some of which last until recovery following IAV infection. Despite the high serotype diversity of S. pneumoniae and the serotype replacement observed since the introduction of conjugate vaccines, little is known about pneumococcal strain dependency in the enhanced susceptibility to severe secondary S. pneumoniae infection following IAV infection. Thus, we studied how preinfection with IAV alters host susceptibility to different S. pneumoniae strains with various degrees of invasiveness using a highly invasive serotype 4 strain, an invasive serotype 7F strain, and a carrier serotype 19F strain. A murine model of pneumococcal coinfection during the acute phase of IAV infection showed a significantly increased degree of pneumonia and mortality for all tested pneumococcal strains at otherwise sublethal doses. The incidence and kinetics of systemic dissemination, however, remained bacterial strain dependent. Furthermore, we observed strain-specific alterations in the pulmonary levels of alveolar macrophages, neutrophils, and inflammatory mediators ultimately affecting immunopathology. During the recovery phase following IAV infection, bacterial growth in the lungs and systemic dissemination were enhanced in a strain-dependent manner. Altogether, this study shows that acute IAV infection predisposes the host to lethal S. pneumoniae infection irrespective of the pneumococcal serotype, while the long-lasting synergism between IAV and S. pneumoniae is bacterial strain dependent. These results hold implications for developing tailored therapeutic treatment regimens for dual infections during future IAV outbreaks. Infection with secondary bacterial pathogens is attributed to be the major cause of excessive mortality during influenza A virus (IAV) outbreaks. This lethal synergism has been recognized as early as during the 1918-1919 IAV pandemic with an estimated global death toll of 50 to 100 million (1, 2). Retrospective studies disclosed that 71% of the fatal cases during this pandemic were positive for Streptococcus pneumoniae (also called pneumococcus), providing the first epidemiological evidence for viral-bacterial coinfections (2). A clear predisposition to bacterial disease was also evident in all of the succeeding influenza pandemics, including the more recent 2009 H1N1 outbreak, which had a 10 to 55% higher incidence of hospitalizations and mortality due to bacterial pneumonia (3). Pneumococcal colonization is transient and asymptomatic in immunocompetent individuals and most commonly occurs in early childhood (4). At the same time, however, pneumococci are able to cause a variety of diseases ranging from mild sinusitis and otitis media to more-severe infections like sepsis and meningitis. Even though the introduction of the polyvalent pneumococcal conjugate vaccines...

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confidence: 65%

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confidence: 99%

mentioning

confidence: 99%

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Influenza A Virus Infection Predisposes Hosts to Secondary Infection with Different Streptococcus pneumoniae Serotypes with Similar Outcome but Serotype-Specific Manifestation

et al. 2016

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“…A re-analysis of the lung autopsy specimens from 58 patients who succumbed to pneumonia during the 1918 influenza pandemic revealed the evidence of bacterial infection in all the specimens [58], and likewise, an analysis of the blood, lung and pleural fluid cultures obtained during life from influenza patients who developed pneumonia, reveals a predominance of bacterial infections, particularly by pneumococci, followed by haemolytic streptococci [59]. Finally, although the effectiveness of whole cell bacterial vaccines directed against the pneumococcus has not been established, there is evidence from the 1918 pandemic that these types of vaccines may have contributed to a reduction in influenza-associated pneumonia and mortality [60].…”

Section: Role Of the Pneumococcus In Influenza-associated Pneumonia Hmentioning

confidence: 99%

Contribution of vaccines to our understanding of pneumococcal disease

Klugman

2011

Phil. Trans. R. Soc. B

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Pneumonia is the leading cause of mortality in children in developing countries and is also the leading infectious cause of death in adults. The most important cause of pneumonia is the Gram-positive bacterial pathogen, Streptococcus pneumoniae, also known as the pneumococcus. It has thus become the leading vaccine-preventable cause of death and is a successful and diverse human pathogen. The development of conjugate pneumococcal vaccines has made possible the prevention of pneumococcal disease in infants, but has also elucidated aspects of pneumococcal biology in a number of ways. Use of the vaccine as a probe has increased our understanding of the burden of pneumococcal disease in children globally. Vaccination has also elucidated the clinical spectrum of vaccine-preventable pneumococcal infections; the identification of a biological niche for multiple pneumococcal serotypes in carriage and the differential invasiveness of pneumococcal serotypes; the impact of pneumococcal transmission among children on disease burden in adults; the role of carriage as a precursor to pneumonia; the plasticity of a naturally transformable pathogen to respond to selective pressure through capsular switching and the accumulation of antibioticresistance determinants; and the role of pneumococcal infections in hospitalization and mortality associated with respiratory viral infections, including both seasonal and pandemic influenza. Finally, there has been a recent demonstration that pneumococcal pneumonia in children may be an important cause of hospitalization for those with underlying tuberculosis.

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“…Streptococcus pneumoniae is one of the pathogens that commonly cause the coinfection (2). Pneumococcus is also the major pathogen associated with mortality in both the 1918 Spanish influenza pandemic (3)(4)(5) and the 2009 H1N1 pandemic (6,7). Given this clinical importance, it is imperative that we understand how the host immune response can be modulated after the coinfection.…”

mentioning

confidence: 99%

Lethal Coinfection of Influenza Virus and Streptococcus pneumoniae Lowers Antibody Response to Influenza Virus in Lung and Reduces Numbers of Germinal Center B Cells, T Follicular Helper Cells, and Plasma Cells in Mediastinal Lymph Node

Lam

et al. 2015

J Virol

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Secondary Streptococcus pneumoniae infection after influenza is a significant clinical complication resulting in morbidity and sometimes mortality. Prior influenza virus infection has been demonstrated to impair the macrophage and neutrophil response to the subsequent pneumococcal infection. In contrast, how a secondary pneumococcal infection after influenza can affect the adaptive immune response to the initial influenza virus infection is less well understood. Therefore, this study focuses on how secondary pneumococcal infection after influenza may impact the humoral immune response to the initial influenza virus infection in a lethal coinfection mouse model. Compared to mice infected with influenza virus alone, mice coinfected with influenza virus followed by pneumococcus had significant body weight loss and 100% mortality. S econdary bacterial infection of the respiratory tract following influenza is a severe complication that often increases morbidity (1). Streptococcus pneumoniae is one of the pathogens that commonly cause the coinfection (2). Pneumococcus is also the major pathogen associated with mortality in both the 1918 Spanish influenza pandemic (3-5) and the 2009 H1N1 pandemic (6, 7). Given this clinical importance, it is imperative that we understand how the host immune response can be modulated after the coinfection.Prior influenza virus infection has been demonstrated to impair the immune defense against subsequent pneumococcal growth and infection (8, 9). For example, influenza virus can desensitize epithelial cells and alveolar macrophages to Toll-like receptor (TLR) signals for defense against bacteria (10). Gamma interferon (IFN-␥) induced by influenza virus can inhibit the phagocytosis of pneumococcus by macrophages (11). The type I IFN induced by influenza virus can impair neutrophils (12) and macrophages (13) in the defense against pneumococcus. Influenza virus can decrease tumor necrosis factor alpha (TNF-␣) production from natural killer cells in the lung, which allows an increase bacterial growth (14).In contrast, how secondary pneumococcal infection after influenza can influence the immune response to the initial influenza virus is relatively less well understood. The host adaptive immune response is largely responsible for controlling the influenza virus infection. It has been reported that coinfection could dysregulate Th17 (15) and gamma/delta T cells (16). However, whether the B cell response would be modulated during the coinfection is still not clear. It is reported that vaccine-induced immunity to influenza virus

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Bacterial Pathogens and Death during the 1918 Influenza Pandemic

Cited by 116 publications

References 4 publications

Influenza A Virus Infection Predisposes Hosts to Secondary Infection with Different Streptococcus pneumoniae Serotypes with Similar Outcome but Serotype-Specific Manifestation

Influenza A Virus Infection Predisposes Hosts to Secondary Infection with Different Streptococcus pneumoniae Serotypes with Similar Outcome but Serotype-Specific Manifestation

Contribution of vaccines to our understanding of pneumococcal disease

Lethal Coinfection of Influenza Virus and Streptococcus pneumoniae Lowers Antibody Response to Influenza Virus in Lung and Reduces Numbers of Germinal Center B Cells, T Follicular Helper Cells, and Plasma Cells in Mediastinal Lymph Node

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