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August 25, 2008 14:00 GMT
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Article Summaries ...
Regional Reporting and Surveillance
Lagos Warns On Bird Flu
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Regional Reporting and Surveillance
Thailand: Vaccination scheme to be expanded
8/25/08 Bangkok Post--Thailand plans to extend the influenza vaccination programme to protect those in the high-risk group and prevent a possible outbreak of human flu pandemic in a bid to reduce the huge flu treatment costs involved annually.
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Cameroon: FCFA 163 Million to Re-Launch Poultry Sector
8/25/08 All Africa--The government of Cameroon has provided FCFA 163 million to re-launch the poultry sector in the country. The fund came in the wake of the bird flu scare that was reported in Cameroon notably around Doualare in Maroua and Malape in Garoua in March 2006. The scare led to dwindling consumption of chicken and poultry products as well as the massive destruction of eggs and day-old chicks across the country.
Regional Reporting and Surveillance
Japan: Ministry to seek 59.8 bil. yen to fight possible new flu pandemic
8/23/08 Japan Today--Japan?s health ministry will seek 59.8 billion yen in the budget for fiscal 2009 to prevent a possible outbreak of a new human flu pandemic, especially one linked to bird flu, ministry sources said Friday.
Regional Reporting and Surveillance
Vietnam?s bird flu vaccine successful in first human test phase
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UAE takes strict precautionary measures against bird flu
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Regional Reporting and Surveillance
Science and Technology
Predominant Role of Bacterial Pneumonia as a Cause of Death in Pandemic Influenza: Implications for Pandemic Influenza Preparedness
8/24/08 Journal of Infectious Diseases--Background. Despite the availability of published data on 4 pandemics that have occurred over the past 120 years, there is little modern information on the causes of death associated with influenza pandemics.
AI Research
Planning for an Influenza Pandemic: Thinking beyond the Virus
8/24/08 Journal of Infectious Diseases--R. Théophile H. Laennec was the first to describe the pathology of pandemic influenza. The inventor of the stethoscope and of the technique of auscultation, Laennec published in the early 19th century a series of observations on diseases of the chest which remain relevant reading today. Among his many contributions to science was his recognition while practicing in Paris during the 1803 pandemic that pneumonia was a frequent, fatal complication of influenza [1]. He described an increase in expectoration of yellow to greenish-tinged sputum, an increased frequency of ?double? pneumonia, and noted that in most fatal cases, the lungs were at the early pneumonic stage of ?engorgement? when examined by autopsy.
AI Research
IHI Unit to Design Pandemic Flu Vaccine Plant for UMN
8/22/08 Jiji Press--A fully owned subsidiary of heavy equipment maker IHI Corp. <7013> has signed a contract with UMN Pharma Inc. to design a facility to produce a pandemic flu vaccine being developed by the biotechnology firm, IHI said Friday.
Vaccines
Full Text of Articles follow ...
AI Research
Predominant Role of Bacterial Pneumonia as a Cause of Death in Pandemic Influenza: Implications for Pandemic Influenza Preparedness
8/24/08 Journal of Infectious Diseases--Background. Despite the availability of published data on 4 pandemics that have occurred over the past 120 years, there is little modern information on the causes of death associated with influenza pandemics.
Methods. We examined relevant information from the most recent influenza pandemic that occurred during the era prior to the use of antibiotics, the 1918?1919 ?Spanish flu? pandemic. We examined lung tissue sections obtained during 58 autopsies and reviewed pathologic and bacteriologic data from 109 published autopsy series that described 8398 individual autopsy investigations.
Results. The postmortem samples we examined from people who died of influenza during 1918?1919 uniformly exhibited severe changes indicative of bacterial pneumonia. Bacteriologic and histopathologic results from published autopsy series clearly and consistently implicated secondary bacterial pneumonia caused by common upper respiratory?tract bacteria in most influenza fatalities.
Conclusions. The majority of deaths in the 1918?1919 influenza pandemic likely resulted directly from secondary bacterial pneumonia caused by common upper respiratory?tract bacteria. Less substantial data from the subsequent 1957 and 1968 pandemics are consistent with these findings. If severe pandemic influenza is largely a problem of viral-bacterial copathogenesis, pandemic planning needs to go beyond addressing the viral cause alone (e.g., influenza vaccines and antiviral drugs). Prevention, diagnosis, prophylaxis, and treatment of secondary bacterial pneumonia, as well as stockpiling of antibiotics and bacterial vaccines, should also be high priorities for pandemic planning.
Received 13 June 2008; accepted 8 July 2008; electronically published 18 August 2008.
*
(See the editorial commentary by McCullers, on pages XXX?XXX.)
Reprints or correspondence: David M. Morens, MD, Bldg. 31, Room 7A-10, 31 Center Dr., MSC 2520, National Institute of Allergy and Inectious Diseases, National Institutes of Health, Bethesda, MD 20892?2520 (dmorens@niaid.nih.gov).
?If grippe condemns, the secondary infections execute? [1, p. 448].
??Louis Cruveilhier, 1919
Influenza pandemic preparedness strategies in the United States [2] assume 3 levels of potential severity corresponding to the 20th century pandemics of H1N1 ?Spanish flu? (1918?1919), H2N2 ?Asian flu? (1957?1958), and H3N2 ?Hong Kong flu? (1968?1969), which were responsible for an estimated 675,000 [3], 86,000 [4], and 56,300 [5] excess deaths in the United States, respectively. Extrapolation from 1918?1919 pandemic data to the current population and age profile has led United States government officials to plan for more than 1.9 million excess deaths during a severe pandemic [2].
An important question related to pandemic preparedness remains unanswered: what killed people during the 1918?1919 pandemic and subsequent influenza pandemics? In the present study, we have examined recut tissue specimens obtained during autopsy from 58 influenza victims in 1918?1919, and have reviewed epidemiologic, pathologic, and microbiologic data from published reports for 8398 postmortem examinations bearing on this question. We have also reviewed relevant information, accumulated over 9 decades, related to the circulation of descendants of the 1918 virus. With the recent reconstruction of the 1918 pandemic influenza virus, investigators have begun to examine why it was so highly fatal [6, 7]. Based on contemporary and modern evidence, we conclude here that influenza A virus infection in conjunction with bacterial infection led to most of the deaths during the 1918?1919 pandemic.
Methods
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Examination of tissue specimens from 1918?1919 influenza fatalities. We reviewed hematoxylin and eosin?stained slides recut from blocks of lung tissue obtained during autopsy from 58 influenza fatalities in 1918?1919. These materials, sent during the pandemic from various United States military bases to the National Tissue Repository of the Armed Forces Institute of Pathology [8?10], represent all known influenza cases from this collection for which lung tissue is available.
Pathology and bacteriology research records from the 1918?1919 influenza pandemic. We reviewed the late 19th- and early 20th-century literature on gross and microscopic influenza pathology and bacteriology, including evidence from 1918?1919 autopsy series with postmortem cultures of lung tissue, blood samples (usually heart blood), pleural fluid, and samples from other compartments. In an effort to obtain all publications possibly reporting influenza pathology and/or bacteriology in 1918?1919, we searched major bibliographic sources [e.g., 11?17] for papers in all languages and tables of contents of major journals in English, German, and French; in addition, we searched all of the papers we identified for additional citations. From more than 2000 such publications, we carefully examined the 1539 reports that contained human pathologic and/or bacteriologic findings (the full bibliographic list available at http://www3.niaid.nih.gov/topics/Flu/1918/bibliography.htm), 109 of which provided useful bacteriologic information derived from 173 autopsy series. These series reported 8398 individual autopsy investigations undertaken in 15 countries, which can be characterized as follows: 96 postmortem lung tissue culture series, 42 blood culture series, and 35 pleural fluid culture series. When they were published as parts of an autopsy series, we included in our analyses antemortem cultures of blood and pleural fluid samples, which were mostly obtained during the terminal stages of illness. A priori, we stratified data by military and civilian populations (see Discussion), and by the quality of lung tissue culture results, considering to be of ?higher quality? the 68 autopsy series with lung tissue culture results that reported, for all autopsies, both the presence and absence of negative culture results and the bacterial components of mixed culture results.
Results
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Background epidemiologic data on influenza mortality rates in 1918?1919. Although death certificates listing cardiac and other chronic causes of death increased in number during the time frame of the 1918?1919 pandemic [18], for all age groups death was predominantly associated with pneumonia and related pulmonary complications [13, 14, 18?20]. The pandemic caused a ?W-shaped? age-specific mortality curve, which exhibited peaks in infancy, between about 20?40 years of age, and in elderly individuals [3, 21]. In all age groups younger than 65 years, the influenza mortality rate was elevated beyond what would have been expected on the basis of data from the previous pandemic of ?Russian influenza? (1889?1893) [3, 22, 23]. The increased fatality rate in the 3 high-risk age groups was predominantly due to the increased frequency of bronchopneumonia, not to increased incidence of influenza or an increased bronchopneumonia case-fatality rate [19]. Because few autopsy reports and, to our knowledge, no autopsy series addressed conditions other than predominantly pulmonary complications, nonpulmonary causes of death are not considered here.
Histologic examination of lung tissue from 1918 victims. The examination of recut lung tissue sections from 1918?1919 influenza case material revealed, in virtually all cases, compelling histologic evidence of severe acute bacterial pneumonia, either as the predominant pathology or in conjunction with underlying pathologic features now believed to be associated with influenza virus infection [10, 24] (figure 1). The latter include necrosis and desquamation of the respiratory epithelium of the tracheobronchial and bronchiolar tree, dilation of alveolar ducts, hyaline membranes, and evidence of bronchial and/or bronchiolar epithelial repair [25, 26]. The majority of the cases examined demonstrated asynchronous histopathological changes, in which the various stages of development of the infectious process, from early bronchiolar changes to severe bacterial parenchymal destruction, were noted in focal areas. The histologic spectrum observed in the cases corresponded to the characteristic pathology of bacterial pneumonia, including bronchopneumonia [10,24?33]: lobar consolidation with pulmonary infiltration by neutrophils in pneumococcal pneumonia; a bronchopneumonic pattern, edema, and pleural effusions in streptococcal and sometimes in pneumococcal pneumonia; and in staphylococcal pneumonia, multiple small abscesses with a marked neutrophilic infiltration in airways and alveoli [27]. Bacteria were commonly observed in the sections, often in massive numbers.
Figure thumbnailFigure 1. (197 KB)
Figure 1. Examples of hematoxylin and eosin?stained postmortem lung sections from 4 victims of the 1918?1919 influenza pandemic (see text). A, Typical picture of severe, widespread bacterial bronchopneumonia with transmural infiltration of neutrophils in a bronchiole and with neutrophils filling the airspaces of surrounding alveoli (original magnification, 40×). B, Massive infiltration of neutrophils in the airspaces of alveoli associated with bacterial bronchopneumonia as in A (original magnification, 200×). C, Bronchopneumonia with intra-alveolar edema and hemorrhage. Numerous bacteria are visible both in the edema fluid and in the cytoplasm of macrophages (original magnification, 400×). D, Bronchopneumonia with evidence of pulmonary repair. The alveolar epithelium is hyperplastic; interstitial fibrosis is seen between alveoli (original magnification, 200×).
Published pathologic and/or bacteriologic findings from the 1918?1919 influenza pandemic. Although the cause of influenza was disputed in 1918, there was almost universal agreement among experts [e.g., 20, 27?33] that deaths were virtually never caused by the unidentified etiologic agent itself, but resulted directly from severe secondary pneumonia caused by well-known bacterial ?pneumopathogens? that colonized the upper respiratory tract (predominantly pneumococci, streptococci, and staphylococci). Without this secondary bacterial pneumonia, experts generally believed that most patients would have recovered [20]. In type, pattern, and case-fatality rate, influenza-associated bacterial pneumonia was typical of pneumonia that was endemic during periods when influenza was not prevalent [25, 28, 33, 34]. As described above, in cases for which a single lung pathogen was recovered from culture, the anatomical-pathological type of the pneumonia usually corresponded to what was expected. Bacteria were commonly observed in cases of pneumonia caused by each of these pathogens. Such findings reflect the characteristic pathology of bacterial pneumonia [10, 25, 27].
Surprising aspects of 1918?1919 influenza-associated pneumonia fatalities included the following: (1) the high incidence of secondary pneumonia associated with standard bacterial pneumopathogens; (2) the frequency of pneumonia caused by both mixed pneumopathogens (particularly pneumococci and streptococci) and by other mixed upper respiratory?tract bacteria; (3) the aggressiveness of bacterial invasion of the lung, often resulting in ?phenomenal? [30] numbers of bacteria and polymorphonuclear neutrophils, as well as extensive necrosis, vasculitis, and hemorrhage [20, 32, 33]; and (4) the predominance of bronchopneumonia and lobular pneumonia, as opposed to lobar pneumonia, consistent with diffuse predisposing bronchiolar damage [27?33].
Contemporary views of the natural history of severe influenza during the 1918?1919 influenza pandemic. By examining influenza autopsy materials from a range of patients in different stages of disease, pathologists in 1918?1919 identified the primary lesion in early severe influenza-associated pneumonia as desquamative tracheobronchitis and bronchiolitis extending diffusely over all or much of the pulmonary tree to the alveolar ducts and alveoli, associated with sloughing of bronchiolar epithelial cells to the basal layer, hyaline membrane formation in alveolar ducts and alveoli, and ductal dilation [20, 24, 27, 29?33].
Primary ?panbronchitis? [35] was thought to reflect rapidly spreading epithelial cytolytic infection of the entire bronchial tree [32, 35, 36]; this was thought to have led to the secondary spread of enormous numbers of bacteria along the denuded bronchial epithelium to every part of the bronchial tree, following which focal bronchiolar infections broke through into the lung parenchyma. Secondary bacterial invasion and zones of vasculitis, capillary thrombosis, and necrosis surrounding areas of bronchiolar damage were seen in severe cases. As was true for the 58 autopsy cases we reviewed (see above), published autopsies for victims of the 1918?1919 pandemic generally showed histopathological asynchrony [20]. Repair, represented by early epithelial regeneration, capillary repair, and occasionally by fibrosis, was commonly seen in tissues sections from even the most fulminant fatal cases [20, 27, 32]. Among the 60% of individuals who survived such severe pneumonia, severe chronic pulmonary damage was apparently uncommon [37, 38].
Bacteriologic studies in autopsy series during the 1918?1919 influenza pandemic. Negative lung culture results were uncommon in the 96 identified military and civilian autopsy series, which examined 5266 subjects (4.2% of results overall) (table 1; full bibliographic list available at http://www3.niaid.nih.gov/topics/Flu/1918/bibliography.htm). In the 68 higher-quality autopsy series, in which the possibility of unreported negative cultures could be excluded, 92.7% of autopsy lung cultures were positive for 1 bacterium (table 1). Of these 96 series, 82 reported pneumopathogens in 50% of lungs examined, either alone or in mixed culture results that included other bacteria (table 1). Outbreaks of meningococcal pneumonia complicating influenza also were documented [39]. Despite higher military case-fatality rates, the differences in the frequency with which specific bacteria were isolated from lung tissue cultures (table 1) and from culture of blood and pleural or empyema fluids (data not shown) were minimal. Many of the series were methodologically rigorous: in one study of approximately 9000 subjects who were followed from clinical presentation with influenza to resolution or autopsy [40], researchers obtained, with sterile technique, cultures of either pneumococci or streptococci from 164 of 167 lung tissue samples. There were 89 pure cultures of pneumococci; 19 cultures from which only streptococci were recovered; 34 that yielded mixtures of pneumococci and/or streptococci; 22 that yielded a mixture of pneumococci, streptococci, and other organisms (prominently pneumococci and nonhemolytic streptococci); and 3 that yielded nonhemolytic streptococci alone. There were no negative lung culture results.
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Table 1. Bacterial culture results in autopsy series involving 96 postmortem cultures of lung tissue from victims of the 1918?1919 influenza pandemic.
In the 14 of 96 autopsy series that did not report the predominance of lung pneumopathogens [29, 36, 41?53], pneumopathogens accounted collectively for 37.4% of pneumonia deaths. The rest of the deaths were associated collectively with either culture of nonpneumopathogenic ?other bacteria,? such as nonhemolytic and viridans streptococci, ?green-producing streptococci? [54], probably largely corresponding to ?-hemolytic streptococci, uncharacterized diplostreptococci, Micrococcus (Moraxella) catarrhalis, Bacillus (Escherichia) coli, Klebsiella species, and complex mixed bacteria (36.1% of cultures). Cultures also yielded Bacillus influenzae (18.8%) and no bacterial growth (7.7%). These findings reflect rates of bacterial isolation similar to those of the series that reported the predominance of pneumopathogens (above and table 1), but with higher isolation rates for ?other bacteria? offsetting the lower isolation rates for pneumococci, streptococci and staphylococci. It is noteworthy that pneumococcal typing antisera were unavailable in 11 of these 14 studies, and that many of the cultured ?other? bacteria were reported as ?gram-positive diplococci,? ?streptococci,? or ?diplostreptococci? (data not shown), consistent with the possibility that in this early era of bacterial typing, some of the unidentified organisms in the culture may have been pneumopathogens.
The predominant coinfecting microorganism in lung tissue cultures containing 1 pneumopathogen was Bacillus influenzae (largely corresponding to the modern Hemophilus influenzae), an upper respiratory?tract organism not commonly found in pure culture of samples from any anatomical compartment [20, 36, 55]. Bacillus influenzae tended to appear early in symptomatic influenza in association with diffuse bronchitis and/or bronchiolitis, sometimes infiltrating the bronchiolar submucosa [35]; it caused seroconversion [56] and was then typically replaced by other secondary organisms.
Cultures of blood samples in 30 military and 12 civilian series, which examined a total of 1887 subjects (table 2), had positive results in 70.3% of cases and typically contained either pneumococci or streptococci in pure culture. Cultures of pleural or empyema fluid, reported in 23 military and 12 civilian series examining a total of 1245 subjects (table 2), revealed either streptococci or pneumococci as the most commonly recovered organism in all but 7 series: in 4 series mixed pneumopathogens predominated, and in 3 series Staphylococcus aureus predominated. Most subjects with positive culture results in the blood and pleural or empyema fluid series also had 1 pneumopathogen cultured in samples from the lungs (data not shown).
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Table 2. Bacterial culture results in autopsy series involving culture of blood and pleural fluid or empyema fluid from victims of the 1918?1919 influenza epidemic.
Of 2007 pneumococcal isolates, 874 (43.5%) were serotyped by agglutination. Type I was isolated from 124 (14.2%) of 874 subjects; type II from 163 (18.6%); type IIa from 26 (3.0%); type III from 184 (21.1%); and type IV, a category containing diverse and, at the time, untypeable organisms, from 377 (43.1%).
Pathologic and bacteriologic information obtained from later pandemic and seasonal influenza cases. The viruses that caused the 1957 and 1968 pandemics were descendants of the 1918 virus in which 3 (the 1957 virus) or 2 (the 1968 virus) new avian gene segments had been acquired by reassortment [21]. Although lower pathogenicity resulted in far fewer deaths, hence fewer autopsies, most 1957?1958 deaths were attributable to secondary bacterial pneumonia, as had been the case in 1918. Staphylococcus aureus, a relatively minor cause of the 1918 fatalities, was predominant in the culture results from 1957?1958 [21, 57?61], and negative lung tissue cultures were more common, possibly as a result of the widespread administration of antibiotics [57, 58, 61]. The few relevant data from the 1968?1969 pandemic (see below) are consistent with information from the earlier 20th-century pandemics.
Human tracheobronchial biopsy studies performed since the 1957-1958 epidemic characterized the natural history of influenza virus infection as featuring rapid (within 24 h) development of bronchial epithelial necrosis, preservation of the basal layer, limited inflammatory response, and evidence of prompt repair [62], consistent with the observations of pathologists in 1918?1919.
Discussion
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In the most recent influenza pandemic that did not involve the use of antibiotics to suppress bacteria (the 1918?1919 pandemic), histological and bacteriologic evidence suggests that the vast majority of influenza deaths resulted from secondary bacterial pneumonia. Compelling evidence for this conclusion includes the examination of 58 recut and restained autopsy specimens that showed changes fully consistent with classical descriptions of extensive bacterial pneumonia [25], culture results from numerous international autopsy series, and consistent epidemiologic and clinical findings (table 3).
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Table 3. Summary of evidence from the 1918?1919 influenza pandemic consistent with the conclusion that bacterial pneumonia, rather than primary viral pneumonia, was the cause of most deaths.
Between 1890 and 1950, most observers believed fatal influenza to be a polymicrobial infection in which an inciting agent of low pathogenicity (either a bacterium such as Bacillus influenzae or a ?filter passing agent??most of which have now been identified as viruses) acted synergistically with known pneumopathogenic bacteria [13, 14, 20, 33, 64?66]. This view was dramatically supported in 1917?1918 by the measles epidemics in US Army training camps, in which most deaths resulted from streptococcal pneumonia or, less commonly, pneumococcal pneumonia [20, 30, 32]. The pneumonia deaths during the influenza pandemic in 1918 proved so highly similar, pathologically, to the then-recent pneumonia deaths from the measles epidemics that noted experts considered them to be the result of one newly emerging disease: epidemic bacterial pneumonia precipitated by prevalent respiratory tract agents [20, 33, 63].
The question of whether the pathogenesis of severe influenza-associated pneumonia was primarily viral (i.e., assumed to be an unknown etiologic agent in 1918) or a combination of viral and bacterial agents was carefully considered by pathologists in 1918?1919, without definitive resolution [26, 33]. The issue was addressed anew in the early 1930s when Shope published a series of experimental studies that involved the just-discovered swine influenza A virus: severe disease in an animal model resulted only when the virus and Hemophilus influenzae suis were administered together [67]. In 1935, Brightman studied combined human influenza and streptococcal infection in a ferret intranasal inoculation model. Even though neither agent was pathogenic when administered alone, they were highly fatal in combination [68]. In rhesus monkeys, human influenza viruses given intranasally were not pathogenic, but could be made so by nasopharyngeal instillation of otherwise nonpathogenic bacteria [69]. During the 1940s, additional studies in ferrets, mice, and rats established that the influenza virus in combination with any of several pneumopathic bacteria acted synergistically to produce either a higher incidence of disease, a higher death rate, or a shortened time to death [70?73]; these effects could be mitigated or eliminated if antibiotics were given shortly after establishment of combined infection [73]. More recent data suggest that influenza vaccination may prevent bacterial disease [74].
As reviewed recently by McCullers [75], a body of experimental research during the last 3 decades has identified possible mechanisms by which coinfection with the influenza virus and bacteria might affect pathogenicity. These include viral neuraminidase (NA)?induced exposure of bacterial adherence receptors; bacterial NA-induced upregulation of influenza infection; interleukin 10?induced susceptibility to pneumococci and possibly staphylococci [76]; interferon type 1 effects [77]; viral PB1-F2 effects, the proaptotic and mitochondriopathic effects of which are correlated with enhanced bacterial infection [78]; and virus-induced desensitization to bacterial Toll-like receptor ligands [79].
We believe that the weight of 90 years of evidence (table 3), including the exceptional but largely forgotten work of an earlier generation of pathologists, indicates that the vast majority of pulmonary deaths from pandemic influenza viruses have resulted from poorly understood interactions between the infecting virus and secondary infections due to bacteria that colonize the upper respiratory tract. The data are consistent with a natural history in which the virus, highly cytopathic to bronchial and bronchiolar epithelial cells, extends rapidly and diffusely down the respiratory tree, damages the epithelium sufficiently to break down the mucociliary barrier to bacterial spread, and if able to gain access to the distal respiratory tree?perhaps on the basis of receptor affinity [80]?creates both a direct pathway for secondary bacterial spread and an environment (cell necrosis and proteinaceous edema fluid) favorable to bacterial growth. It remains unresolved whether cocolonizing, nonpneumopathic upper respiratory?tract organisms such as Bacillus (Hemophilus) influenzae play an ancillary role, or are merely innocent bystanders. It is uncertain why Hemophilus influenzae was much less prominent in 1957?1958 and thereafter, but this phenomenon may relate to antibiotic use and conceivably, in recent years, to Hemophilus influenzae b vaccination of children.
The extraordinary severity of the 1918 pandemic remains unexplained. That the causes of death included so many different bacteria, alone or in complex combinations, argues against specific virulent bacterial clones. The pathologic and bacteriologic data appear consistent with copathogenic properties of the virus itself, perhaps related to viral growth, facility of cell-to-cell spread, cell tropism, or interference with or induction of immune responses. Certain observers believed that cotransmission of the influenza agent and of pneumopathogenic bacteria was responsible for many severe and fatal cases, especially during the October?November 1918 peak of mortality and case-fatality rates [81]. We speculate that any influenza virus with an enhanced capacity to spread to and damage bronchial and/or bronchiolar epithelial cells, even in the presence of an intact rapid reparative response, could precipitate the appearance of severe and potentially fatal bacterial pneumonia due to prevalent upper respiratory?tract bacteria.
In the modern era, the widespread use of antibiotics and the establishment of life-prolonging intensive care unit treatment make it more difficult than it was in 1918 to document the importance of bacterial lung infection for influenza-related mortality. Influenza-associated pneumonia patterns may now be influenced by the administration of pneumococcus, Hemophilus influenzae b, and meningococcus vaccine, and cases have tended to occur in elderly individuals, who rarely undergo autopsy. The 1968 influenza pandemic was mild, and autopsy studies were uncommon [21]. Fatal cases of influenza-associated viral pneumonia that are considered to be ?primary? (i.e., with little or no bacterial growth) continue to be identified [82, 83]; however, their incidence appears to be low, even in pandemic peaks. The issue of the pathogenesis of fatal influenza-associated pneumonia remains important; the fact that even severe, virus-induced tissue damage is normally followed by rapid and extensive repair [20, 26] suggests that early and aggressive treatment, including antibiotics and intensive care, could save most patients [84, 85] and also underscores the importance of prevention and prophylaxis.
The 1918 pandemic and subsequent pandemics differed with respect to the spectrum and extent of secondary bacterial pneumonia (e.g., the switch in prevalence during the antibiotic era to predominantly staphylococcal secondary pneumonia, as opposed to streptococcal, pneumococcal, and mixed secondary pneumonia; and the greatly decreased involvement of Bacillus [Hemophilus] influenzae), suggesting that additional factors affect the level of influenza morbidity and mortality. These might include the use of antibiotics and antiviral agents, the rate of influenza vaccination and bacterial vaccination, and demographic and social factors. The aging population in the United States, the increasing number of persons living in nursing home facilities, and the number of persons who are immunosuppressed or affected by cardiac disease, renal disease, and/or diabetes mellitus all represent potential factors that might change the profile of morbidity and mortality during a future pandemic. For example, elderly persons in nursing homes are at risk for pneumonia caused by enteric organisms and sometimes by drug-resistant nosocomial organisms. The spread of bacteria such as methicillin-resistant Staphylococcus aureus and highly pathogenic clones of Streptococcus pyogenes pose more general risks [86].
The viral etiology of and timing of the next influenza pandemic cannot be predicted [87]. If, as some fear, a future pandemic is caused by a derivative of the current highly pathogenic avian H5N1 virus, lessons from previous pandemics may not be strictly applicable. Although histopathologic information concerning current human H5N1 infections is sparse [10], its pathogenic mechanisms may be atypical because the virus is poorly adapted to humans [88] and because, in certain experimental animal models [e.g., 89], some strains have induced severe pathology that differs from the findings associated with circulating human influenza viruses (which, in these models, cause disease resembling self-limited seasonal influenza in humans [90]). However, if an H5N1 virus were to fully adapt to humans, the clinicopathologic spectrum of associated disease could become more like that of previous pandemics.
If the next pandemic is caused by a human-adapted virus similar to those recognized since 1918, we believe the infection is likely to behave as it has in past pandemics, precipitating severe disease associated with prevalent colonizing bacteria. Recent reviews have discussed the importance of new and improved influenza antiviral drugs and influenza vaccines in controlling a pandemic [84, 91, 92]. The present work leads us to conclude that in addition to these critical efforts, prevention, diagnosis, prophylaxis, and treatment of bacterial pneumonia, as well as the stockpiling of antibiotics and bacterial vaccines [84, 85, 93], should be among the highest priorities in pandemic planning. We are encouraged that such considerations are already being discussed and implemented by the agencies and individuals responsible for such plans [94, 95].
Acknowledgments
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We thank Betty Murgolo and the staff of the National Institutes of Health (NIH) Library, for extensive research efforts in locating publications, and the staff of the History of Medicine Division, National Library of Medicine, NIH, for additional library research support. We also thank Cristina Cassetti, PhD, and Andrea Scollard, DDS, PhD for translation of Italian language and Portuguese language papers, respectively; Hillery A. Harvey, PhD, for scientific assistance; and Gregory K. Folkers, MS, MPH, for helpful discussion and editorial assistance. John J. McGowan, PhD, and the staff of the National Institute of Allergy and Infectious Diseases (NIAID) Pandemic Influenza Digital Archives project provided substantial assistance in organizing and indexing historical manuscripts.
References
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AI Research
Planning for an Influenza Pandemic: Thinking beyond the Virus
8/24/08 Journal of Infectious Diseases--R. Théophile H. Laennec was the first to describe the pathology of pandemic influenza. The inventor of the stethoscope and of the technique of auscultation, Laennec published in the early 19th century a series of observations on diseases of the chest which remain relevant reading today. Among his many contributions to science was his recognition while practicing in Paris during the 1803 pandemic that pneumonia was a frequent, fatal complication of influenza [1]. He described an increase in expectoration of yellow to greenish-tinged sputum, an increased frequency of ?double? pneumonia, and noted that in most fatal cases, the lungs were at the early pneumonic stage of ?engorgement? when examined by autopsy.
This general pattern of increased incidence, increased mortality, and typical pathologic findings of bacterial pneumonia was repeated in virtually all of the generally recognized epidemics and pandemics through the modern era, when rigorous pathologic examination of fatal pneumonia cases fell out of use as a diagnostic modality. Indeed, Edwin O. Jordan, in his comprehensive survey of all literature relevant to the 1918 pandemic, argued that the general clinical and epidemiologic character of the pandemics of 1889?1890 and 1918?1919 were indistinguishable, including the disproportionately high attack rate in young adults which has been regarded to be pathognomonic of the 1918 pandemic [2]. This contention runs counter to the prevailing view espoused in both the scientific and lay media that the 1918 pandemic strain was uniquely virulent, and that factors intrinsic to the behavior of the virus and the pathogenesis of the viral infection must account for the strikingly high worldwide mortality associated with this pandemic.
In this issue of the Journal, Morens et al. review 109 published autopsy series from the 1918 pandemic and add new data for an additional 58 autopsies from which lung sections had been preserved [3]. Their findings are striking in the context of modern conceptions of the 1918 pandemic; the great majority of deaths could be attributed to secondary bacterial pneumonia caused by common respiratory pathogens, particularly pneumococci, group A streptococci, and staphylococci, and not to the virus itself. In fact, although evidence of severe viral bronchiolitis was found, often the primary viral insult appeared to be resolving at the time of the secondary infection responsible for the fatality. Their conclusions are strengthened by the remarkable consistency in theme, if not details, displayed across the many studies reviewed and the inclusion in their review of not only gross pathologic findings but blood and lung tissue culture data. In only 4% of the more than 8000 cases reviewed was no bacterial superinfection documented.
One insight offered by the authors is that this information is not new?we have simply lost this perspective over the last 50?60 years during the shift in modern medicine towards sophisticated imaging studies and molecular diagnostics and away from gross pathology. In similar fashion, the design of the current study is itself not new; a reexamination of pathology from a past pandemic was undertaken by a German scientist during the 1918 pandemic [4], much as has been done by Morens et al. [3]. Otto Lubarsch compared preserved autopsy specimens from the 1889?1890 pandemic to fresh autopsy samples from 1918?1919 and concluded the pathologic processes were nearly identical. This homogeneity in findings reinforces the idea that the end result, death from bacterial pneumonia, is a common feature of all pandemics in the preantibiotic era. If this supposition is correct, the virulence of the virus itself may not be the key predictor of mortality; the ability to interact with bacteria may be the more important factor [5]. In this light, the study of virulence factors that increase the incidence or enhance the case fatality rate of secondary bacterial infections is as important as understanding the basic biology of influenza viruses with pandemic potential.
Current interest in the pathogenesis of deaths during the 1918 pandemic must be put into the context of concern over, and preparation for, the next pandemic?an occurrence that history tells us is inevitable, although unpredictable. An intense global effort to prepare for this potentiality has been ongoing for approximately 5 years, following the reemergence in 2003 of highly pathogenic avian influenza viruses of the H5N1 subtype [6]. The majority of pandemic preparation has centered around prevention or treatment of the virus itself by developing vaccines against pandemic candidates and stockpiling antiviral drugs [7]. Little to no attention has been paid to prevention and treatment of potential bacterial superinfections, which, as Morens et al. remind us [3], have historically caused the great majority of deaths during pandemics. Part of this failure can be traced to our collective amnesia regarding the 1918 pandemic, as discussed above, and part can be attributed to assumptions about the clinical features of a theoretical H5N1 pandemic.
The clinicopathologic syndrome suffered by persons infected with avian influenza viruses of the H5N1 subtype over the last 10 years does not closely resemble that reported during previous pandemics in the preantibiotic era. Instead, illness manifests as severe, progressive pneumonia that rapidly acquires characteristics of acute respiratory distress syndrome, leading in most cases to death [8]. Rather than wound healing and regeneration, proceeding to resolution of viral disease with superimposed bacterial infection [3], the few pathologic examinations done after H5N1 infection show diffuse alveolar damage, necrosis, squamous metaplasia, and hemorrhage [8, 9]. Bacterial infections have been shown to complicate H5N1 infections in a minority of cases, but they have not been a prominent cause of death, likely due to modern intensive care and provision of broad-spectrum antimicrobial agents.
More important in the context of pandemic planning, however, is the difficulty inherent in extrapolating data from a limited series of zoonotic infections to the broader range of possibilities inherent in a full pandemic. Currently circulating influenza viruses of the H5N1 subtype are not fully adapted to humans; they lack the capacity to easily be transmitted from person to person. Because acquisition of this trait will require adaptation or reassortment with human influenza viruses, the pathogenesis of these theoretical pandemic strains cannot be predicted with any assurance. In addition, there is no guarantee that the next pandemic will be caused by viruses of the H5N1 subtype, and there is an equally compelling argument to be made for several other candidates [8]. The assumption implicit in some pandemic plans, that the disease course during the next pandemic will be similar to that seen in the limited clinical experience with H5N1 viruses in Eurasia, may be entirely wrong. Deaths due to the next pandemic strain, even if it is an adapted H5N1, may follow precisely the pattern evident from history, and bacterial superinfections may be the predominant fatal events. Even if a clinical course similar to our recent H5N1 experience occurs in the next pandemic, our ability to provide modern intensive care and administer broad-spectrum antibiotics will certainly be compromised if clinical attack rates approach the 25%?30% range seen in previous pandemics. In this scenario, bacterial infections are likely to emerge as a major complication in survivors of the primary influenzal disease.
What is to be done? At this point pandemic planners have started to recognize the issue but have not yet begun to deal with it. A shift in focus is required. Pandemic planning must take into account the possibility that secondary bacterial pneumonia will be a frequent complication of pandemic influenza. Basic research into the interactions between influenza viruses and bacteria is needed. Modeling studies extrapolating the breadth of potential risk should be undertaken. Planning for prevention of disease must include pneumococcal vaccines as well as influenza vaccines [10]. A comprehensive survey of the sources, supply, and surge capacity of important antibiotics should be undertaken. This should include analysis of distribution patterns, as has been done for influenza vaccines [11]; it is likely that many of the countries in the developing world, where complications of pandemic influenza are likely to be worst, will have little to no access to appropriate antimicrobials in this scenario. Planners should consider strengthening and diversifying these pipelines?in the United States alone in the last 3 years, there have been shortages of more than a dozen antibiotics [12]. Included among these is vancomycin, an important drug used in the treatment of antibiotic-resistant infections due to Streptococcus pneumoniae and Staphylococcus aureus, the 2 most common secondary pathogens in the infections that follow influenza. If these shortages are occurring in times of constant demand, it seems likely that worse will occur when there is a surge in demand.
Since the 1997 H5N1 outbreak in Hong Kong, a tremendous amount of work has been done to understand influenza viruses and prepare for the next pandemic. As Morens et al. have reminded us, however, the virus is only half of the story, and the bacterial superinfections may be the more deadly half [3]. Harry S. Truman may have summed it up best, ?The only thing new in the world is the history you don't know? [13]. This timely reminder of our past should act as an impetus to help prevent the history of the 1918 pandemic from repeating itself.
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Regional Reporting and Surveillance
Lagos Warns On Bird Flu
8/22/08 The PM News--The State Chairman, Public Enlightenment Committee on Avian Influenza Control, Mr. Tunde Awobiyi, has reiterated that, up till now, there has not been any known cure for bird flu. He quickly added, however, that, if a victim of the disease cries out early, its menace could still be managed.
Mr. Awobiyi, who led a delegation of Government Officials drawn from the Lagos State Ministry of Information and Strategy on an advocacy visit to the Olu of Agege, Oba Lateef Adams, and his Council of Chiefs, to solicit co-operation, stated further that since the threat of Avian Influenza (Bird flu) is real, they have come to the Kabiyesi as part of a public awareness campaign to prevent a reoccurrence and possible infection of human-beings in the State.
In a release by the Committee?s Spokesman, Musbau Razak, the Chairman explained that Avian influenza comes in three dimensions; bird to bird, bird to person, and person to person, cushioning that ?the best medicine is cleanliness as prevention is better that cure.
He stated that, though the disease appeared to have subsided in the State, Government would intensify the Campaign and Promotion of Safe Health Practices.
The State Avian Influenza Communication Desk Officer further stated that the disease has not reached a pandemic level in the country, adding that should this occur, it could end up claiming millions of lives globally, especially in developing countries.
In his reaction, the host, Oba Lateef Adam, said; we have continued to tell our people that cleanliness is the best method of prevention and that they should take care of their homes and places of work. The Olu of Agege stressed that; the palace will take up the campaign just as he did with propagation of vaccine against polio.
Oba Lateef Adam, in demonstration of his commitment to the campaign, charged his Council of Chiefs, the Leader of Market men and Leaders of Muslims and Christians in attendance to begin the campaign immediately in their in their respective domain.
Regional Reporting and Surveillance
Thailand: Vaccination scheme to be expanded
8/25/08 Bangkok Post--Thailand plans to extend the influenza vaccination programme to protect those in the high-risk group and prevent a possible outbreak of human flu pandemic in a bid to reduce the huge flu treatment costs involved annually.
Research on the economic evaluation of a seasonal influenza vaccine is currently being undertaken among 2,000 elderly people considered the most vulnerable group in Phitsanulok and Udon Thani to study if the vaccine programme could help cut the cost of treatment in the coming years.
The one-year study, scheduled for completion in August next year, is expected to identify the age group that should be prioritised for the national influenza vaccination scheme, enhance the prevention programme and financially help lighten the state's health-care and treatment burden, said Jongkol Lertiendumrong, a researcher attached to the International Health Policy Programme.
Out-patient treatment seekers for influenza and other acute respiratory illnesses exceed 900,000 cases each year. Up to 75,000 of the victims need hospitalisation due to severe complications, costing the state around two billion baht in treatment costs, according to a Public Health Ministry report.
An estimated 26 million Thais would contract the deadly virus and hundreds of thousands would die in the event of an outbreak, bringing the national economy to its knees.
More than 90% of influenza deaths have occurred in people aged 65 years or older, according to the World Health Organisation.
In Thailand, this group accounts for six million of the population.
However, health authorities are finding it difficult to provide free vaccine services due to an inadequate budget.
Only 100,000 of the elderly suffering from problems like asthma, bronchitis, cancer, diabetes, heart diseases, kidney failure are annually shortlisted for the anti-flu vaccines.
The other 300,000 doses are reserved for doctors and health professionals.
Dr Jongkol said the study's findings would enable health authorities to effectively expand the vaccination programme for a larger number of the population as part of preventive measures and preparations to deal with the worst case scenario - a flu pandemic.
"The current anti-flu measures and the vaccine stocks will not be enough if there really is an outbreak of a pandemic," warned virologist Prasert Thongcharoen.
He said the H5N1 strain of the flu virus could mutate into a more deadlier form that could enable it to jump from human to human, unlike today when it can only cause animal to human infections.
Scientific research and development of vaccines for local use was a must during the pre-pandemic phase along with the stockpiling of the anti-viral medicine oseltamivir so that the country would be in a position to cope with the severest outbreak, he added.
An industrial-scale vaccine manufacturing plant, under construction in Saraburi's Kaeng Khoi district, expected to be completed in three to five years, will have the capacity to produce enough doses for the entire population.
Regional Reporting and Surveillance
Cameroon: FCFA 163 Million to Re-Launch Poultry Sector
8/25/08 All Africa--The government of Cameroon has provided FCFA 163 million to re-launch the poultry sector in the country. The fund came in the wake of the bird flu scare that was reported in Cameroon notably around Doualare in Maroua and Malape in Garoua in March 2006. The scare led to dwindling consumption of chicken and poultry products as well as the massive destruction of eggs and day-old chicks across the country.
As a result, poultry farmers incurred enormous losses.The money was provided to poultry farmers recently in Yaounde through the Cameroon Inter-Professional Poultry Association known by its French acronym as IPAVIC. The signing of two conventions of collaboration between the government and promoters of micro poultry farming projects marked the occasion.
The Deputy Secretary General in the Prime Minister's Office, Emmanuel Nganou Ndjoumessi, signed on behalf of the President of the Inter-Ministerial Adhoc Committee for the prevention and fight against bird flu while the Secretary General for IPAVIC, François Djonou, signed for the poultry farmers.
Prior to the August 12 ceremony, the Coordinator of the Inter Ministerial Committee, Dr. Jermias Inrombe, had, at a press briefing on August 11, revealed that in addition to money to re-launch the poultry sector, materials from donors are also available for the field staff of the ministries involved in the fight against bird flu.
In a statement at the occasion, the UNDP Resident Representative, Mrs. Ekoue Dede, said the material donor agencies gave to government is just part of the support compared to the numerous field activities and technical support being given to the integrated national plan for the prevention and fight against bird flu.
Meanwhile, the IPAVIC SG noted that poultry farmers suffered great losses following the outbreak of the bird flu amounting to some FCFA 3.131 billion. He said the fight against the disease did not foresee any support to such a situation.
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Information from the Inter-Ministerial Committee indicates that some 15 common initiative groups from each of the ten provinces would benefit from the FCFA 163 million. The groups are expected to eventually give back some of their products to other farmers in a revolving manner.
Regional Reporting and Surveillance
Japan: Ministry to seek 59.8 bil. yen to fight possible new flu pandemic
8/23/08 Japan Today--Japan?s health ministry will seek 59.8 billion yen in the budget for fiscal 2009 to prevent a possible outbreak of a new human flu pandemic, especially one linked to bird flu, ministry sources said Friday.
The sum, which is much larger than the 6.3 billion yen allocated in the budget for the current fiscal year, will be included in the ministry?s budgetary requests for fiscal 2009 starting April 1.
Regional Reporting and Surveillance
Vietnam?s bird flu vaccine successful in first human test phase
8/24/08 Xinhua--The first phase of the H5N1 Fluvax vaccine?s first human trials have proved the drug?s safety, announced the Ministry of Health and other agencies at a meeting in Hanoi Thursday.
The working session was held by the ministry?s Bureau of Science of Training to review the Fluvax trials implemented by the National Institute of Hygiene and Epidemiology and the Military Medical Academy in Hanoi.
?To date, after more than three months since the last injection shot, volunteers have seen no serious side effects, proving the safety of the vaccine,? said Doan Huy Hau, head of the academy?s epidemiology unit.
The trial began in late March on more than 30 volunteers aged 20-40, including seven scientists in the research group.
Subjects were administered two injections of the bird flu vaccine 28 days apart.
Hau said blood samples taken at different times showed protective antibodies in the volunteers.
Relevant agencies are drafting a report on the trial to be submitted to the Ministry of Health, according to a spokesperson from the institute?s Company for Vaccine and Biological Production No. 1, which produced the vaccine.
If the ministry certifies the effectiveness and safety of the vaccine, the second phase of testing would be implemented in five months on more volunteers, said company spokesperson Nguyen Tuyet Nga.
If the second phase were to be successful, the flu vaccine would be registered for production and circulation on the market, said Nga.
The company could produce several million doses of the vaccine annually with each does expected to cost VND40,000 (US$2.4), she added.
The research on Fluvax began in 2004.
Since 2003, Vietnam has seen 106 infection cases of the bird flu virus in 36 localities nationwide, said head of the National Institute of Hygiene and Epidemiology Nguyen Tran Hien at another meeting on Thursday.
Of those infected, 52 have died in Vietnam.
All five infection cases this year have been fatal, said Hien.
There have been at least 241 human deaths globally from the virus and some 380 confirmed cases of infection since 2003, according to World Health Organization data.
Regional Reporting and Surveillance
UAE takes strict precautionary measures against bird flu
8/24/08 Xinhua--The United Arab Emirates (UAE) is gearing up for a battle against bird flu as the season of birds' migration approaches with strict precautionary measures to prevent an outbreak of the disease in the country, local newspaper Khaleej Times reported on Sunday.
Technical teams of the UAE National Committee for Emergency Response to the Bird Flu will intensify field surveys on the UAE coastlines, islands and other locations to monitor birds, and take random samples for testing from the beginning of September, according to the report.
The measures will coincide with the beginning of the season of birds' migration from the North to the South. Migratory birds often arrive in different parts of the UAE during September every year.
The program for observing and watching the wild and migratory birds will be conducted through special devices, which cover 25 square km along the country's coast.
The committee has also intensified surveillance at the border check-points, airports and sea beaches to ensure that birds entering the country are not infected with the deadly H5N1 virus.
Any birds and poultry products to be imported into the UAE will be examined by the Environment Agency and the Food Control Authority to ensure they are safe, free of any contagious diseases, and fit for human consumption.
Vaccines
IHI Unit to Design Pandemic Flu Vaccine Plant for UMN
8/22/08 Jiji Press--A fully owned subsidiary of heavy equipment maker IHI Corp. <7013> has signed a contract with UMN Pharma Inc. to design a facility to produce a pandemic flu vaccine being developed by the biotechnology firm, IHI said Friday.
To proceed with the project and strengthen ties with UMN, IHI Plant Engineering Corp. has acquired a 1.93 pct equity stake in the Akita-based firm for some 200 million yen.
The vaccine, UMN-0501, developed by cell culture using recombinant protein, can be produced in about eight weeks. It is subjected to Phase I and II clinical trials.
A pandemic flu is feared to occur when a new influenza virus, to which human beings have no immunity, emerges through the mutation of a deadly bird flu virus.
