Taubenberger
Jeffery K Taubenberger (Volver a Personas. Cronología. Fuentes.)
Autor en 2008 junto con Johan V Hultin y David M Morens de: Discovery and characterization of the 1918 pandemic influenza virus in historical context.
National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA *Corresponding author: Tel: +1 301 443 5960; Fax: +1 301 480 5722; E-mail: taubenbergerj@niaid.nih.gov
Trata tres temas:
1) alleged discovery of a bacterial cause of influenza during the 1889–1893 pandemic,
2) the controversial detection of ‘filter-passing agents’ during the 1918–1919 pandemic,
3) and subsequent breakthroughs in the 1930s that led to isolation of human and swine influenza viruses
En el artículo sobre las 68 autopsias de 2011 aparece él como diseñador del proyecto y solo aparece su e-mail:
Proc Natl Acad Sci U S A. 2011 Sep 27; 108(39): 16416–16421. Published online 2011 Sep 19. doi: 10.1073/pnas.1111179108 PMCID: PMC3182717 Microbiology
Autopsy series of 68 cases dying before and during the 1918 influenza pandemic peak
Zong-Mei Sheng,a Daniel S. Chertow,a Xavier Ambroggio,b Sherman McCall,c Ronald M. Przygodzki,d Robert E. Cunningham,e Olga A. Maximova,f John C. Kash,a David M. Morens,g and Jeffery K. Taubenberger a,1
aViral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases,
bBioinformatics and Computational Biosciences Branch,
fOffice of the Chief, Laboratory of Infectious Diseases, and
gOffice of the Director, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
cClinical Pathology Laboratory, US Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD 21702;
dDepartment of Veterans Affairs, Washington, DC 20420; and
eDepartment of Biophysics, Armed Forces Institute of Pathology, Rockville, MD 20850
1To whom correspondence should be addressed. E-mail: taubenbergerj@niaid.nih.gov
Edited* by Robert G. Webster, St. Jude Children's Research Hospital, Memphis, TN, and approved August 16, 2011 (received for review July 11, 2011) Author contributions: J.K.T. designed research; Z.-M.S., D.S.C., X.A., S.M., R.M.P., R.E.C., O.A.M., J.C.K., and J.K.T. performed research; X.A. and O.A.M. contributed new reagents/analytic tools; Z.-M.S., D.S.C., X.A., J.C.K., D.M.M., and J.K.T. analyzed data; and J.K.T. wrote the paper.
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.
Keywords: archaevirology, postmortem, immunohistochemistry The 1918 “Spanish” influenza pandemic killed ∼50 million people (1). Archaevirological sequence determination (2–8) and viral reconstruction make it possible to study structure and in vivo pathogenicity of the 1918 pandemic virus (9–21). The origin of the 1918 virus, how and where it evolved before global pandemic spread, and the mechanisms by which this virus caused extraordinarily high mortality have not been fully elucidated. We report here clinical, pathological, bacteriological, and virological features in a case series of 68 influenza/pneumonia fatalities with available autopsy material from the National Tissue Repository of the Armed Forces Institute of Pathology (AFIP) (22, 23) obtained during the period March 1, 1918 to February 28, 1919, a period that includes ∼4 mo before the pandemic was recognized, and 2 mo (September and October 1918) during which it appeared and peaked. This study is unique in demonstrating that the 1918 influenza pandemic virus was circulating and causing fatalities at least 4 mo prior to the pandemic being detected and recognized.
Go to: RESULTS Study Patients. All postmortem examinations with available formalin-fixed, paraffin-embedded (FFPE) lung-tissue blocks were examined (Table S1). The 68 soldiers were all men stationed in US Army training camps, located in the continental US. Medical records indicating date and location of death were available for 59 of 68 cases (87%). The 68 deaths occurred between May 11, 1918 and October 24, 1918 (Fig. 1). Nine of these deaths occurred between May 11 and August 8, 1918, a prepandemic time period with little reported influenza activity in the United States (24). The remaining 59 deaths occurred during the pandemic peak (25), between September 14 and October 24, 1918. Exact date of death was not recorded for 9 of these 59 cases, but their accession numbers indicate that death occurred between September 22 and October 24, 1918 (Table S1).
Fig. 1. Fig. 1. Troop strength, monthly admissions for, and deaths from, influenza or pneumonia of nonindicated cause at seven United States military training camps, October 1917 to March 1919. The camps include Camp Dodge, Johnston, IA; Camp Funston, Manhattan, KS;
Influenza virus RNA was detected by RT-PCR in a subset of 13 of 21 (61%) cases tested (Table S1) (see Materials and Methods). Partial HA1 domain sequences encoding the principal amino acids of the viral receptor-binding domain (RBD) (31, 34) were determined in 11 of these cases (Table S3), providing additional data for comparison with viral sequences previously reported (2, 3, 35). Three of four HA1 domain sequences from the prepandemic cases shared the RBD sequence configuration of viruses from two previously reported cases (2, 3, 35), having a mixed α2-3 SA (“avian-like:) and α2-6 SA (“human-like”) glycan binding specificity (Table S3). Seven of nine sequences from pandemic peak cases, and two of three sequences from postpeak cases [as published previously (2, 3, 35)] had the RBD sequence configuration associated with α2-6 SA glycan binding. All sixteen available 1918 virus HA1 sequences possess an 187D change from the avian influenza A virus HA consensus, associated with a switch to α2-6 SA glycan binding in HAs of the H1 subtype. As noted, there were no apparent differences in histopathology or viral antigen distribution between cases with the G222 (mixed α2-3 SA/α2-6 SA) or D222 (α2-6 SA) polymorphism, or between prepandemic peak and pandemic peak cases.
DISCUSSION The place and time of origin of the 1918 influenza pandemic virus is unknown, with no evidence of excess respiratory disease or of excess mortality detected in United States military camps from May through September 1918 (36) (Fig. 1). As would be expected based on the explosive United States pandemic outbreak later in the fall, the pandemic influenza virus must nevertheless have been circulating silently—and causing occasional fatalities—at least 4 mo before the pandemic was first detected in the United States. The lack of detectable disease and mortality in the prepandemic months is consistent with a virus, perhaps imported from abroad (37), needing time to spread from one individual case to another and thereby gradually reach a threshold of epidemiological detection. With a speculative serial generation time of 4.5 d (38), basic reproductive rate of 1.8 (39), and case-fatality ratio probably no higher than 1% to 2% in the summer months, it would clearly take weeks, even under favorable circumstances, for an imported “founding virus” to produce enough cases for a small outbreak to occur or for fatalities to be detected statistically.
For unknown reasons, summer (Northern Hemisphere) spread of newly introduced pandemic influenza viruses has historically (e.g., 1580, 1782) and more recently (e.g., 1957, 1968, and 2009) been indolent (40). In this respect, it is noteworthy that mortality peaks associated with respiratory disease had occurred in a few Northern European countries in July to August 1918 (37). This finding is consistent with the possibility that the pandemic virus had relative difficulty gaining a foothold in Europe during the unfavorable summer months, assuming that—as long believed—elevated temperature and humidity may hinder pandemic influenza virus transmission in all but the coolest, driest climates (41, 42). Moreover, independent of transmission, summer influenza mortality and case-fatality are usually lower than in the winter (40), when primary and secondary bacterial pneumonias are more highly incident (43).
In summary, the 1918 pandemic influenza virus circulated silently in the United States for at least 4 mo before the pandemic was first detected in late September to October 1918. Based on a small number of HA1 receptor-binding domain sequences, early prepandemic circulation may have been associated with viral variants bearing a G222 RBD configuration, often described as “avian-like” on the basis of in vitro binding studies. The significance of this finding, if any, is unknown. Prepandemic, pandemic peak, and postpandemic viruses all caused fatalities associated with the same apparent clinical and pathological features of pan-bronchitis, bronchiolitis, and diffuse alveolar damage associated with early focal repair, but complicated by severe secondary bacterial pneumonia. This pathology is indistinguishable from that of influenza deaths in subsequent pandemics, including the 2009 H1N1 pandemic, and in seasonal influenza deaths (28, 29, 33), and may suggest a common pathway to severe and fatal outcomes associated with many or most human-adapted influenza viruses. The high number of influenza deaths in 1918 has led in recent years to the widespread speculation about unusual viral virulence properties, supported by experimental animal studies (12, 13), but in its disease course and clinicopathologic features the 1918 pandemic was different in degree, but not in kind, from previous and subsequent pandemics (25). Despite the extraordinary number of global deaths, the vast majority of influenza cases in 1918 (>97% in industrialized nations) were self-limited and essentially indistinguishable from influenza cases today (36). Additionally, influenza severity and death in 1918 to 1919 correlated with the frequency of well-understood secondary bacterial pneumonias caused by common pneumopathogens (43). The cause of extraordinarily high mortality in the 1918 pandemic appears not to be exclusively a factor of viral virulence, and thus remains to be more fully elucidated (13, 14).
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