Article

Autopsy series of 68 cases dying before and during the 1918 influenza pandemic peak

Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 09/2011; 108(39):16416-21. DOI: 10.1073/pnas.1111179108
Source: PubMed

ABSTRACT

The 1918 to 1919 "Spanish" influenza pandemic virus killed up to 50 million people. We report here clinical, pathological, bacteriological, and virological findings in 68 fatal American influenza/pneumonia military patients dying between May and October of 1918, a period that includes ~4 mo before the 1918 pandemic was recognized, and 2 mo (September-October 1918) during which it appeared and peaked. The lung tissues of 37 of these cases were positive for influenza viral antigens or viral RNA, including four from the prepandemic period (May-August). The prepandemic and pandemic peak cases were indistinguishable clinically and pathologically. All 68 cases had histological evidence of bacterial pneumonia, and 94% showed abundant bacteria on Gram stain. Sequence analysis of the viral hemagglutinin receptor-binding domain performed on RNA from 13 cases suggested a trend from a more "avian-like" viral receptor specificity with G222 in prepandemic cases to a more "human-like" specificity associated with D222 in pandemic peak cases. Viral antigen distribution in the respiratory tree, however, was not apparently different between prepandemic and pandemic peak cases, or between infections with viruses bearing different receptor-binding polymorphisms. The 1918 pandemic virus was circulating for at least 4 mo in the United States before it was recognized epidemiologically in September 1918. The causes of the unusually high mortality in the 1918 pandemic were not explained by the pathological and virological parameters examined. These findings have important implications for understanding the origins and evolution of pandemic influenza viruses.

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    • "The first wave also affected countries more distant from the European theatre of war, such as India, Australia , New Zealand, and the western islands of the Dutch Indies (Hill, 2011; Patterson and Pyle, 1991). In the United States, the first wave was detected in 37 army training camps across the country (Barry et al., 2008; Crosby, 2003; Sheng et al., 2011) and among civilians in Detroit (Crosby, 1989) and New York City (Olson et al., 2005). It was present in Mexico between February and May of 1918 (Chowell et al., 2010) and in Newfoundland in July 1918 (Sattenspiel, 2011). "
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    ABSTRACT: Objectives This article evaluates the evidence for the presence of the first, mild wave of the 1918 influenza pandemic among soldiers in the Canadian Expeditionary Force (CEF).Methods Death records for soldiers in the CEF who died in Canada in 1917 and 1918 were extracted from the Commonwealth War Graves Commission and record-linked to the Canada War Graves Registers, Circumstances of Casualty database. Monthly mortality rates from pneumonia and influenza (P&I) were compared with mortality rates from all other causes for 1917 and 1918, and by region for 1918.ResultsThe herald wave of influenza was present among CEF soldiers in 1918. P&I mortality was significantly higher in March and April 1918 than during the same period in 1917. P&I mortality rates varied across the country and were significantly higher among soldiers who died in the Maritime region of Canada. In March, Maritime P&I mortality was significantly higher than its counterpart in the West; in April it was significantly higher than P&I mortality in both the Central and Western regions.Conclusions The CEF findings suggest that local, geographic heterogeneity characterized the first wave of the 1918 influenza pandemic in Canada and illustrate the ways in which well-established, historical patterns of cross-border social contact with the United States, coupled with the special conditions created by warfare, disproportionately funnelled influenza into particular regions. Identification of the mild first wave among soldiers in the CEF calls for more research on the civilian experience of both waves of influenza in Canada. Am. J. Hum. Biol., 2015. © 2015 Wiley Periodicals, Inc.
    Full-text · Article · Mar 2015 · American Journal of Human Biology
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    • "The first wave also affected countries more distant from the European theatre of war, such as India, Australia , New Zealand, and the western islands of the Dutch Indies (Hill, 2011; Patterson and Pyle, 1991). In the United States, the first wave was detected in 37 army training camps across the country (Barry et al., 2008; Crosby, 2003; Sheng et al., 2011) and among civilians in Detroit (Crosby, 1989) and New York City (Olson et al., 2005). It was present in Mexico between February and May of 1918 (Chowell et al., 2010) and in Newfoundland in July 1918 (Sattenspiel, 2011). "
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    ABSTRACT: Objectives: This paper evaluates the evidence for the presence of the first, mild wave of the 1918 influenza pandemic among soldiers in the Canadian Expeditionary Force (CEF). Methods: Death records for soldiers in the Canadian Expeditionary Force (CEF) who died in Canada in 1917 and 1918 were extracted from the Commonwealth War Graves Commission and record-linked to the Canada War Graves Registers Circumstances of Casualty database. Monthly mortality rates from pneumonia and influenza (P/I) were compared to mortality rates from all other causes for 1917 and 1918, and by region for 1918. Results: The spring herald wave of influenza was present among CEF soldiers in 1918. P&I mortality was significantly higher in March and April 1918 than during the same period in 1917. P&I mortality rates varied across the country and were significantly higher among soldiers who died in the Maritime region of Canada. In March, Maritime P&I mortality was significantly higher than its counterpart in the West; in April, it was significantly higher than P&I mortality in the Central and Western Regions. Conclusions: The CEF findings suggest that local, geographic heterogeneity characterized the first wave of the 1918 influenza pandemic in Canada and illustrate the ways in which well established, historical patterns of cross-border social contact with the U.S., coupled with the special conditions created by warfare, disproportionately funnelled influenza into particular regions. Identification of the mild first wave among soldiers in the CEF complicates our understanding of the deadly second wave in the fall of 1918 and calls for more research on the civilian experience of both waves of influenza in Canada.
    Full-text · Article · Mar 2015 · American Journal of Human Biology
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    • "An overwhelming infection of large airways, coupled with a robust T cell response, would likely result in considerable morbidity (as in the 1957 influenza pandemic), and significant susceptibility to secondary bacterial pneumonia (resulting from multiple potential mechanisms currently under investigation [3]–[7]). In contrast, the significant mortality attributed to infection with avian strains (such as H5N1 [8]) and likely to extraordinary mortality observed in the 1918 pandemic (characterized by an unusual mortality distribution, and descriptions from the period, which include instances of very short intervals between first symptoms and death [9]) are likely attributable to multiple factors, including highly efficient replication [10], as well as viral tropism for the distal airways, i.e. the alveolar epithelium [10], [11]. Significant injury to alveolar epithelial cells may have an enormous impact on respiratory gas exchange, which is often incompatible with host survival [12]. "
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    ABSTRACT: Virus infection triggers a CD8+ T cell response that aids in virus clearance, but also expresses effector functions that may result in tissue injury. CD8+ T cells express a variety of activating and inhibiting ligands, though regulation of the expression of inhibitory receptors is not well understood. The ligand for the inhibitory receptor, NKG2A, is the non-classical MHC-I molecule Qa1b, which may also serve as a putative restricting element for the T cell receptors of purported regulatory CD8+ T cells. We have previously shown that Qa1b-null mice suffer considerably enhanced immunopathologic lung injury in the context of CD8+ T cell-mediated clearance of influenza infection, as well as evidence in a non-viral system that failure to ligate NKG2A on CD8+ effector T cells may represent an important component of this process. In this report, we examine the requirements for induction of NKG2A expression, and show that NKG2A expression by CD8+ T cells occurs as a result of migration from the MLN to the inflammatory lung environment, irrespective of peripheral antigen recognition. Further, we confirmed that NKG2A is a mediator in limiting immunopathology in virus infection using mice with a targeted deletion of NKG2A, and infecting the mutants with two different viruses, influenza and adenovirus. In neither infection is virus clearance altered. In influenza infection, the enhanced lung injury was associated with increased chemoattractant production, increased infiltration of inflammatory cells, and significantly enhanced alveolar hemorrhage. The primary mechanism of enhanced injury was the loss of negative regulation of CD8+ T cell effector function. A similar effect was observed in the livers of mutant mice infected intravenously with adenovirus. These results demonstrate the immunoregulatory role of CD8+ NKG2A expression in virus infection, which negatively regulates T cell effector functions and contributes to protection of tissue integrity during virus clearance.
    Full-text · Article · Sep 2014 · PLoS ONE
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