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Workshop Overview
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From page 1...
... health care facilities to implement emergency operations plans, the 2009 H1N1 influenza pandemic in the United States constitutes a national emergency." 1 The Forum's role was limited to planning the workshop, and this workshop summary has been prepared by the workshop rapporteurs as a factual summary of what occurred at the workshop. 2 While this pandemic H1N1 strain of influenza A virus has gone by many, many names -- ­including "swine flu" -- since it was first recognized and characterized in April 2009, for the purposes of this document we refer to it using the nomenclature found in the Report to the President on the U.S.
From page 2...
... The arrival of an influenza pandemic in 2009 was both anticipated and unexpected. That a novel, readily transmissible, influenza virus would spread widely and rapidly along with its globe-trotting hosts seemed inevitable; that this pandemic strain emerged in the Americas, rather than Asia, surprised many infectious disease experts.
From page 3...
... What Is Influenza? The influenza viruses are members of the family Orthomyxoviridae and include influenza virus types A, B, and C (see Box WO-1)
From page 4...
... . The scientific and public health response to the 2009-H1N1 influenza A pandemic was both informed and influenced by observations of past ­pandemics and seasonal influenza epidemics, by the response to an abortive pandemic threat from H1N1 swine influenza in 1976, and from ongoing efforts to address the pandemic threat posed by the highly pathogenic H5N1 avian influenza, following its emergence in humans in 1997.
From page 5...
... That fall, a second wave of severe disease (and in many places, a subsequent wave in early 1919) produced significantly higher rates of mortality among people between the ages of 20 and 34, and particularly among pregnant women, than is typical of seasonal influenza epidemics (Simonsen et al., 2005)
From page 6...
... Influenza infection and replication is a multistep process: the virus must first bind to and enter the cell, then deliver its genome to a site where it can produce new copies of viral proteins and RNA, as semble these components into new viral particles, and finally exit the host cell. Influenza viruses infect epithelial cells of the respiratory tract by attaching to sialic acid receptors.
From page 7...
... Drugs that inhibit neuraminidase, such as oseltamivir, therefore prevent the release of new infectious viruses and halt viral replication. After the release of new influenza viruses, the host cell dies (Figure WO-1)
From page 8...
... and H1N1 ("swine flu" outbreak) 12.4 1977-1978 H3N2 (drift)
From page 9...
... The dashed red arrow indicates a period without circulation. Solid red arrows indicate the evolutionary paths of human influenza virus lineages; solid blue Figure arrows, of swine influenza virus lineages; andWO-2 the blue-to-red arrow, of a swine-origin R01627 human influenza virus.
From page 10...
... (2009) note several similarities in epidemiologic behavior between the 1957 H2N2 pandemic and the 2009 H1N1 pandemic: both arose early in the year and spread widely during the spring, both abated over the early summer months in the Northern Hemisphere while major epidemics developed in the Southern Hemisphere (as is also typical of seasonal influenza)
From page 11...
... • October 1: First swine flu shots given. • November 12: Case of Guillain-Barré Syndrome in Minnesota vaccinee.
From page 12...
... of the U.S. Public Health Service, which concluded that the new virus had pandemic potential and that an immunization program should be launched in order to reduce the morbidity and mortality associated with a possible influenza pandemic.
From page 13...
... . Following the poultry eradication campaign in Hong Kong, the H5N1 influenza virus did not reappear until the end of 2003 (WHO, 2005b)
From page 14...
... 7 The current H5N1 virus tends to bind deep inside mammalian lung tissues, as compared with seasonal influenza viruses, which attach to nasal and pharyngeal tissues, and from which they are more easily spread by coughs and sneezes (Shinya et al., 2006; van Riel et al., 2006)
From page 15...
... In a world poised to prevent a devastating H5N1 avian influenza pandemic originating out of Asia, the appearance of an influenza pandemic in the form of a relatively mild (to date) swine-origin virus originating (apparently)
From page 16...
... Having documented Figure a rapid increase in the phylogenetic WO-3 diversity of circulating swine and antigenic influenza strains in the United States, Webby and coauthors (2004) presciently R01627 warned that "the growing complexity of influenza at this animal–human interface uneditable and the presence of viruses bitmapped with a seemingly image high affinity for reassortment makes the United States swine population an increasingly important reservoir of viruses with human pandemic potential" (Webby et al., 2004)
From page 17...
... "It's something that wouldn't have been possible 15 years ago," he added, "so we've come a long way." Many speakers and discussants also noted that this relatively mild pandemic, identified prior to its global spread by researchers poised to respond to the potential threat from the highly pathogenic H5N1 avian influenza virus, presents significant opportunities to improve influenza surveillance and monitoring, refine epidemiologic models, and enhance pandemic preparations in anticipation of the next "killer flu." Situation Assessment and Future Challenges In late June 2009, President Obama requested that his Council of Advisors on Science and Technology (PCAST) undertake an evaluation of the 2009-H1N1 influenza A pandemic and the nation's response to a probable recurrence in the fall of 2009.
From page 18...
... • It is a product of reassortment between European swine and North Ameri can swine lineage triple reassortant influenza A viruses, which likely occurred through a process of two or more steps. • No genetic markers for severe disease were detected.
From page 19...
... • It is resistant to amantadine and rimantadine; sporadic cases of resistance to oseltamivir have also been detected globally, mostly in association with pre-exposure prophylaxis. Origins of the 2009-H1N1 Influenza A Genome Viral isolates from index cases of 2009-H1N1 influenza A were characterized as "swine-origin" influenza on the basis of genomic analysis, which revealed their similarity to previously characterized swine influenza viruses (CDC, 2009e)
From page 20...
... Reassortment events Figure WO-4 not involved with the emergence of humanand A14-1 disease are omitted. Fort Dix refers to the R01627 last major outbreak of S-OIV in humans.
From page 21...
... . As a result of this dynamic, each person carries millions of variant influenza viruses, and many are infected with completely different viral strains and even different influenza types (A and B)
From page 22...
... starts to compete in the Northern and Southern hemispheres with the seasonal strains that co-circulate." When asked how more representative collections of influenza strains might be obtained, Holmes recommended two complementary approaches. One is to choose a few locations and study them in detail, as he has done with the counties around New York City.
From page 23...
... Viral load, as visualized with antigen-based immunohisto chemistry, was strikingly high in fatal cases of 2009-H1N1 influenza A compared with seasonal influenza. In addition, 2009-H1N1 influenza A viruses were pres ent in peripheral lung tissues as seen in H5N1 avian influenza but not typically with seasonal influenza viruses, which target the upper respiratory tract.
From page 24...
... FIGURE WO-6  Spherical viral particles typical of seasonal H1N1 influenza, and the filamentous 2009-H1N1 influenza A SOURCE: Adapted from Neumann et al.
From page 25...
... "The ability of CA04 to replicate in the lungs of mice, ferrets and nonhuman primates, and to cause appreciable pathology in this organ, is reminiscent of infections with highly pathogenic H5N1 influenza viruses," Kawaoka and coworkers observed (Itoh et al., 2009)
From page 26...
... Representative findings are shown to depict the distributionuneditable bitmapped of lesions in the image sections (shown as cross-sections placed next with to illustrations of each lung lobe) , withtext replaced or without viral antigen, as follows: brown, severe lung lesion containing moderate to many viral-antigen-positive cells; pink, mild lung lesions containing a few viral-antigen-positive cells; blue, lung lesions with alveolar wall thickening, with remaining air spaces unaffected.
From page 27...
... . Figure WO-9 and A5-3 R01627 uneditable bitmapped image
From page 28...
... They concluded that cross-reactive cell-mediated immunity18 to pandemic (H1N1) 2009 virus through conserved MHC class I-restricted epitopes19 may exist in persons previously immunized against, or exposed to, seasonal influenza.
From page 29...
... Because the 2009-H1N1 influenza A virus emerged just before the onset of the influenza season in the Southern Hemisphere, attention was focused on that region to see how the pandemic, and the virus itself, might evolve. Cox reported that, in general, the epidemiological characteristics of 2009-H1N1 influenza A noted in the initial disease wave in Central and North America -- for example, attack rates, risk groups for infection, and disease severity -- remained stable through the Southern Hemisphere's influenza season (see Box WO-3)
From page 30...
... . Figure WO-10 and A5-2 R01627 bitmapped image with type replaced
From page 31...
... FIGURE WO-11  2009-H1N1 influenza A pandemic laboratory-confirmed cases and cumulative number of deaths as reported to WHO as of March 7, 2010. SOURCE: Reprinted from WHO (2009e)
From page 32...
... and H5N1 avian influenza virus) had been detected in any of the 2009-H1N1 influenza A virus isolates.
From page 33...
... The follow­ing discussion highlights information that contrasted with general trends as described in Box WO-3, or which provided novel clinical insights on the 2009-H1N1 influenza A virus. The United States and Mexico As is typical for the Northern Hemisphere, overall influenza activity declined over the summer in the United States.
From page 34...
... . Southern Hemisphere influenza season: Several countries experienced multiple viral epidemics that included RSV, parainfluenza, and seasonal influenza (both H3N2 and H1N1)
From page 35...
... and the left y-axis shows the absolute number of specimens reported positive for influenza viruses (influenza A subtypes, pandemic H1N1, and influenza B)
From page 36...
... and the left y-axis shows the absolute number of specimens reported positive for influenza viruses (influenza A subtypes, pandemic H1N1, and influenza B)
From page 37...
... 700 6 600 5 500 4 400 3 300 ILI activity level 2 200 1 100 Number of specimens positive for influenza 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 Week number, 2009 A(H1)
From page 38...
... 38 BOX WO-4 Continued 900 6 800 5 700 600 4 500 3 400 influenza ILI activity level 300 2 200 Number of specimens positive for 1 100 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 Week number, 2009 A(H1)
From page 39...
... A(H5) Other subtypes ILI activity level FIGURE WO-16  Number of specimens positive for influenza by subtype, Hong Kong.
From page 40...
... 40 BOX WO-4 Continued 35 6 30 5 25 4 20 3 15 ILI activity level 2 10 1 5 Number of specimens positive for influenza 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 Week number, 2009 A(H1)
From page 41...
... 120 6 100 5 80 4 60 3 influenza ILI activity level 40 2 Number of specimens positive for 20 1 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 Week number, 2009 A(H1)
From page 42...
... . fixed bitmapped image with type replaced
From page 43...
... with permission from the Institute of Environmental Science and Research Limited. Figure WO-20 R01627 43 uneditable bitmapped image
From page 44...
... 44 IMPACTS OF THE 2009-H1N1 INFLUENZA A PANDEMIC schools resume session in late July, experienced an unusual late summer increase in ILI that has been attributed to 2009-H1N1 influenza A, Cox reported. This pattern was repeated throughout the country with the opening of most schools in early September, as shown in Figure WO-21, and the cases continue to mount.
From page 45...
... vector editable Ruiz-Palacios also reported several findings on the topic of viral shedding in 2009-H1N1 influenza A cases, a significant factor in disease transmission, as may be seen in Figure WO-23. In general, he observed, higher viral titers are present early in the course of 2009-H1N1 influenza A infection.
From page 46...
... The public health response to the 2009-H1N1 influenza A pandemic in Peru was based on, and supported by, the country's pandemic influenza plan, which had been established five years earlier, he added. However, as the 2009-H1N1 influenza A pandemic unfolded, Gotuzzo and his colleagues quickly found that the plan "had to be continuously reviewed and updated."
From page 47...
... WORKSHOP OVERVIEW 47 Confirmed Influenza A (HIN1) Cases in Peru - 2009 •06 Conglomerates •23 Confirmed imported cases •37 Confirmed cases associated with conglomerates of imported cases •19 Community/Community contact 6 Community outbreak - Huánuco Family after contact in the 5 Airport?
From page 48...
... There, in a population of 130,000, only one confirmed death due to 2009-H1N1 influenza A occurred. Asia and Australasia: Implications of Co-Infections The example of Argentina illustrates that while the epidemiological profile of 2009-H1N1 influenza A pandemic remained stable through the Southern Hemisphere's influenza season, its impact varied widely within and between countries.
From page 49...
... In both northern and southern China, H3N2 continues to represent about half of all isolated influenza viruses according to Cox of the CDC. "We're watching H3N2 circulation very carefully," said Cox.
From page 50...
... The pig was tested at the Minnesota State Fair as part of a University of Iowa and University of Minnesota ­cooperative agreement research project, funded by the CDC, which documents influenza viruses where humans and pigs interact (USDA, 2009)
From page 51...
... Both pregnant and non-pregnant HIV-positive individuals died at considerably higher rates from 2009-H1N1 influenza A infection than HIV-negative individuals, he reported. The Scientific Response Several workshop presentations and considerable discussion focused on the rapid, multipronged scientific response to the emergence of 2009-H1N1 influenza A, which was primed by global anticipation of an H5N1 avian influenza pandemic and strengthened by increased -- though still inadequate -- scrutiny of emerging zoonotic diseases, as several workshop participants observed.
From page 52...
... cases of 2009-H1N1 influenza A were quickly diagnosed, and the viral genome was sequenced and published online, according to Cox, thanks to recent surveillance initiatives to detect and investigate swine influenza cases in humans. "Novel influenza of humans has been a notifiable disease in the United States for a number of years," she stated, "and there have been increasing efforts ongoing at state health departments, at [the]
From page 53...
... "We expect that seasonal influenza viruses will co-circulate with [2009-H1N1 influenza A] ," Cox stated, "but the timing, spread, and severity of the 2009-2010 influenza season are unpredictable."
From page 54...
... Among 81 confirmed cases of 2009-H1N1 influenza A among healthcare personnel in 25 states, Bell and coworkers found that about 40 percent were community infections, and that more than half of infections that workers might have acquired from patients occurred in outpatient settings. Most disturbing of the study's findings was "a tremendous lack of adherence to even basic infection control recommendations," Bell observed (these recommendations are discussed in a subsequent section entitled "The Public Health Response")
From page 55...
... . Focusing on the International Society for Infectious Diseases' Program for Monitoring Emerging Diseases, known as ProMED-mail, and its performance during the 2009-H1N1 influenza A pandemic, Madoff (who has served as a ProMED-mail editor since 2002)
From page 56...
... org/geosentinel/main.html (accessed November 5, 2009)
From page 57...
... Rather, he observed, the "traditional public health system actually worked quite well in this outbreak," particularly systems put in place in anticipation of an H5N1 avian influenza pandemic. Today, he added, informal sources play an important role in monitoring the pandemic's progress.
From page 58...
... The results could be used to target surveillance efforts, making them more costeffective, or "smarter." In the case of H5N1 avian influenza, Daszak's group considered whether the disease was likeliest to reach the United States through the poultry trade, through wild bird migrations, or through wild birds imported by the pet trade. First, they determined the pathways by which H5N1 had spread through Asia, Europe, and North Africa (Kilpatrick et al., 2006a)
From page 59...
... events, when corrected for geography and timing of discovery, Daszak said, revealed "hot spots" for infectious disease emergence in places where the animal–human interface is particularly active. As it turns out, the area in Mexico where 2009-H1N1 influenza A appears to have emerged occupies one of these hot spots, he added (Figure WO-26)
From page 60...
... . As the 2009-H1N1 influenza A pandemic unfolded, Lipsitch and coworkers created models to estimate parameters of infection and to inform the public health response -- an experience, he said, that highlights inherent assumptions and uncertainties and also suggests ways to increase both the accuracy and timeliness of impact estimates (see Lipsitch in Appendix A7)
From page 61...
... WORKSHOP OVERVIEW 61 FIGURE WO-27  The pandemic severity scale developed by the U.S. government for planning and response.
From page 62...
... . This distinction from seasonal influenza -- in which approximately 90 percent of the deaths are in people over 65, mainly due to complications rather than to the direct effect of influenza infection -- makes comparisons between the potential impact of 2009-H1N1 influenza A infections with that of seasonal influenza challenging.
From page 63...
... TABLE WO-2  Age-Specific Severity Estimates sCHR: Ratio of Hospitalizations to sCIR: ratio of ICU Admissions to sCFR: Ratio of Deaths to Symptomatic Cases Symptomatic Cases Symptomatic Cases Self-reported 0-4 yr 0.33% (0.21-0.63)
From page 64...
... . Despite the dire predictions of many about the mortality associated with the 2009-H1N1 influenza A pandemic, it is proving to be the mildest influenza pandemic on record (Presanis et al., 2009)
From page 65...
... Shortridge, at the conclusion of his presentation on the epidemiology of 2009-H1N1 influenza A in Asia, defined four sets of pressing scientific questions raised by the pandemic. First, he said, what we know about the virus so far should lead us to further investigate the H1 subtype, the swine "mixing vessel" hypothesis, and the question as to whether 2009-H1N1 influenza A can act as a "third-party" virus to carry important genes to prevailing seasonal influenza viruses.
From page 66...
... "We're entering into a period where the issues are now becoming much more complex and difficult to deal with." Infection Control Infection control practices are focused on hospitals, which tend to be amplification centers for infectious diseases, noted Bell of the CDC. Consider emerg 33 Also known as Thiazolidinediones, a class of antidiabetes drugs that promote cell sensitivity to insulin and increase glucose uptake by cells (San Francisco AIDS Foundation, 2009)
From page 67...
... are substantially different from what we've seen in the past," he acknowledged. It remains to be determined where the pandemic strain of the 2009-H1N1 influenza A and other influenza viruses lie along the transmission continuum between droplet and airborne, and this has a bearing on infection precautions,
From page 68...
... . He noted that some researchers, using personal samplers for particulates, have detected airborne influenza viruses in clinical settings, but the viability of the viruses was not tested, nor were samples taken "in the community, in the parking lot, or anywhere else," for comparison.
From page 69...
... cities during the influenza pandemic of 1918-1919 (Markel et al., 2007)
From page 70...
... 34 Communicating the strategies and goals -- and the uncertainties -- of pandemic mitigation practices and guidance to the public is a challenging task, as Cetron and many other workshop participants noted, and doubly so for nonpharmaceutical interventions. "There is clearly a preference for ‘magic bullet' interventions over these traditional public health ones," the toughest being for adults and children to stay home when they are ill.
From page 71...
... . Viral RNA was uncommonly detected in the upper respiratory tract in these patients following antiviral treatment.
From page 72...
... In seasonal influenza, three retrospective studies found significant reductions in all-cause mortality in hospitalized patients treated with oseltamivir within about 96 hours after symptom onset (Hanshaoworakul et al., 2009; Lee et al., 2008; McGeer et al., 2007)
From page 73...
... . Intravenous zanamivir has been used as salvage therapy35 in several severely ill patients with proven or suspected oseltamivir resistance (Englund et al., 2009; Kidd et al., 2009)
From page 74...
... Several studies undertaken by the CDC and other agencies determined that seasonal influenza vaccine provides no protection against 2009-H1N1 influenza A However, Cox added, people who received the 1976 swine influenza vaccine did develop a robust antibody response to the 2009-H1N1 influenza A viruses, as determined by in vitro studies of stored serum.
From page 75...
... . Studies in the United States also showed that, within 14 days of a single dose, subjects generated antibody titers comparable to those achieved with seasonal influenza vaccine, he added.
From page 76...
... More important, she noted that the CDC plans to conduct enhanced surveillance for GBS as well as for other adverse events associated with the 2009-H1N1 influenza A vaccine. "We certainly don't want to focus exclusively on GBS," Cox emphasized, "but we want to be able to capture adverse events [and]
From page 77...
... that could derive from viruses collected within its borders. Indonesia criticized the WHO's practice of distributing influenza viruses it received for surveillance to pharmaceutical companies, which would make patented vaccines from such samples -- ­vaccines that were often too costly for developing countries to purchase.
From page 78...
... . First among these are the skeptical views of such a framework that arise among foreign policy makers who wonder why -- given global disparities in just about every other kind of health resources including clean water and adequate food -- influenza vaccines and antiviral drugs should receive greater priority in terms of global equity, solidarity, and justice.
From page 79...
... ; and • clear "triggers" for pandemic alert levels. The best model for constructing this framework is to use the IHR, which were recently revised to address emerging infectious diseases, Fidler said.
From page 80...
... "Before you get to any legal framework, you have to have the political interests lined up," Fidler responded. "The deal here obviously is the continued flow of information in return for response capacities, whether that is vaccines themselves or whether it is technology." In the case of the H5N1 negotiations, such a deal has yet to be made for lack of political incentives, he concluded, which demonstrates the difficulties of constructing the broader global framework for access to influenza vaccines envisioned by Fukuda.
From page 81...
... This rationale is used in emergency departments (EDs) , but it means resources will be used on patients with poor ­prognoses; when applied to immunization, 2009-H1N1 influenza A vaccines would go first to pregnant women and infants; for antiviral medications, post exposure prophylaxis for people with compromised immunity and/or living in residential settings.
From page 82...
... "I think that if we see even a 20 percent increase in severe cases in many of our communities, we may outstrip our intensive care capabilities and allocation of critical medical equipment and supplies will be necessary," he predicted. "I don't think people yet get that because 2009-H1N1 influenza A infection isn't a severe disease for most of the population." With hospitals operating at near-full capacity, a shortage in ventilators during a severe influenza pandemic is a likely scenario, Lo agreed.
From page 83...
... • Public messaging was a daunting challenge that will only become more difficult with the arrival of the 2009-H1N1 influenza A vaccine. Duchin provided a detailed description of public health under siege, due to the near-simultaneous arrival of pandemic influenza and economic recession (see Duchin in Appendix A3)
From page 84...
... Based on his experience during the spring wave of the H1N1 influenza pandemic Duchin called for more vigorous efforts to get antivirals to high-risk individuals. "With the sudden rise and the rapid transmission you can't expect patients to get to their physicians, get diagnosed, get to the pharmacy, and get their drug in the time frame that you really want that to happen," he asserted.
From page 85...
... virus ­after vaccination with seasonal influenza vaccine. Morbidity and Mortality Weekly Report 58(19)
From page 86...
... 2009. Pandemic influenza, http:// www.cidrap.umn.edu/cidrap/content/influenza/panflu/biofacts/panflu.html (accessed November 3, 2009)
From page 87...
... Emerging Infectious Diseases 4(3)
From page 88...
... 2009. In vitro and in vivo characterization of new swine-origin H1N1 influenza viruses.
From page 89...
... Clini cal Infectious Diseases 45(12)
From page 90...
... 2009. Emergence and pandemic potential of swine-origin H1N1 influenza virus.
From page 91...
... Emerging Infectious Diseases 12(1)
From page 92...
... 2009a. Avian influenza frequently asked questions, http://www.who.int/csr/disease/avian_ ­influenza/avian_faqs/en/index.html#isthere (accessed November 3, 2009)
From page 93...
... 2009. The emerging influenza pandemic: estimating the case fatality ratio.


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