INTRODUCTION SUPPLEMENT ARTICLE

Seasonal and Pandemic Influenza Preparedness: A Global Threat Downloaded from https://academic.oup.com/jid/article/194/Supplement_2/S65/851306 by guest on 01 October 2021 Richard J. Whitley1 and Arnold S. Monto2 1Departments of Pediatrics, Microbiology, Medicine, and Neurosurgery and Center for Biodefense and Emerging Infections, University of Alabama at Birmingham, Birmingham; 2Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor

The increase in the incidence of avian influenza worldwide in both poultry and humans introduces the potential for another influenza A pandemic that could pose a significant threat to both human health and the global economy. The impact of the next influenza pandemic will be influenced, in part, by how well the medical, government, business, and lay communities are prepared. Despite the additional tools and resources that have become available since prior epidemics, there are limits to the quantity of antiviral drugs that can be manufactured and concerns over the current vaccine production systems. Despite these challenges, there is an opportunity to take action before the emergence of a pandemic influenza strain and, possibly, to prevent its spread or at least mitigate its impact on the world. In February 2006, a group of representatives from federal, state, and local governments; professional bodies; academia; and the pharmaceutical industry met to review the current state of preparedness in the United States for a potential influenza pandemic and its relationship to seasonal influenza. The goal of the meeting was to examine the recently revised US Department of Health and Human Services plan for preparedness and response to an influenza pandemic and to make recommendations to actualize this plan at the state and local levels.

The worldwide increase in the incidence cant threats to human health, national and tion and marked pulmonary damage, in of influenza caused by avian influenza global economies, and, potentially, socie- part resulting from activation of a vigor- A(H5N1) virus, manifested in poultry out- ties. With the emergence of the H5N1 vi- ous proinflammatory cytokine cascade breaks and sporadic human infections, rus, the threat of a pandemic is higher now that may have contributed to acute respi- highlights the concern that another influ- than it has been since the last influenza A ratory distress syndrome [6]. Since the enza A pandemic is likely to occur soon. pandemic, in 1968. Three pandemics oc- 1918 pandemic, the population of the Should this happen, there will be signifi- curred during the past century. Of these, world has grown 3-fold; therefore, if a new the 1918 H1N1 influenza pandemic was influenza A virus is as lethal as the 1918

Presented in part: Seasonal and Pandemic Influenza 2006: by far the worst, resulting in 50–100 mil- virus, as many as 180–360 million people At the Crossroads, a Global Opportunity, Washington, DC, 1–2 lion deaths [1]. The H1N1 virus that caused could die [7]. Such a pandemic would February 2006 (for a list of sponsors and funding, see the the pandemic originated from an avian overwhelm the health care systems of the Acknowledgments). The authors were co-chairs of the independent committee that planned and coordinated the influenza virus, which adapted to humans world and have a devastating socioeco- conference. by mutation [2]. Unlike seasonal influ- nomic impact. The 1957 H2N2 and 1968 Potential conflicts of interest: A.S.M. has received grant support from Roche and Sanofi Pasteur and the National enza, which causes most of its estimated H3N2 pandemics also involved new influ- Institutes of Health (grant U01 AI057853) and has served as an 36,000 annual US deaths among the el- enza viruses generated by reassortment ad hoc consultant to Roche, MedImmune, and Chiron. R.J.W. 1 is on the Scientific Advisory Board for Gilead Sciences and is derly [3], 90% of the deaths caused by events, and, although they were less vir- a member of the GlaxoSmithKline and Novartis Speakers pandemic influenza have occurred in ulent than the 1918 H1N1 virus, they still Bureaus. ! Financial support: supplement sponsorship is detailed in healthy people 65 years of age [4]. This caused significant morbidity and mortality. the Acknowledgments. H1N1 virus was particularly virulent and Recently, several avian influenza A virus Reprints or correspondence: Dr. Richard J. Whitley, University showed extraordinarily high levels of rep- subtypes, including H5N1, H9N2, H7N3, of Alabama at Birmingham, CHB 303, 1600 7th Ave. S, Birmingham, AL 35233-1711 ([email protected]). lication in the lungs of experimentally in- and H7N7, have been shown to cross the The Journal of Infectious Diseases 2006;194:S65–9 fected animals [5]. Indeed, a conventional species barrier from poultry or wild mi- 2006 by the Infectious Diseases Society of America. All rights reserved. human virus containing only the 1918 gratory birds to infect humans. The H7N7 0022-1899/2006/19409S2-0001$15.00 hemagglutinin caused high viral replica- and H9N2 viruses largely resulted in mild

Seasonal and Pandemic Influenza: Introduction • JID 2006:194 (Suppl 2) • S65 self-limiting disease or asymptomatic in- transmission efficient. Although genotype whelmed state and local public health in- fection, although 1 lethal infection asso- Z appears to be dominant in most parts frastructures in Louisiana and Mississippi, ciated with a mutated H7N7 virus was rec- of Asia, there are 2 major clades circulat- required an unprecedented federal re- ognized in a Dutch veterinarian [8]. In ing, as well as a diversity of genotypes in sponse, and led to international offers of addition, since the emergence of H5N1 parts of southern China, with observations assistance. Although this response was in Hong Kong in 1997, clinically doc- indicating that the virus continues to successful in some areas, several important umented H5N1 infections have been as- evolve. Because different viruses may have weaknesses were identified [18]. The most sociated with a high mortality rate in altered antigenicity, it would be unwise to concerning, in terms of a potential re- humans [9–11]. Since 2003, 241 labora- rely on a single target virus for vaccine sponse to pandemic influenza, was the tory-confirmed cases have been reported development [16]. Indeed, in the United poor coordination of federal assets, within in 10 countries (Azerbaijan, Cambodia, States, the Department of Health and Hu- and across agencies, resulting from a frag- Downloaded from https://academic.oup.com/jid/article/194/Supplement_2/S65/851306 by guest on 01 October 2021 China, Egypt, Indonesia, Iraq, Thailand, man Services (HHS) has recently an- mented command and response structure. Turkey, Vietnam, and Djibouti); as of 23 nounced its intention to proceed with de- This caused substantial delays in the de- August 2006, 141 (59%) of these cases velopment of a candidate vaccine based ployment of federal assets in critical areas. have resulted in death [11]. Typically, on clade 2 H5N1 virus [17]. In other cases, assets were deployed in- death after infection with the H5N1 virus The impact of the next influenza pan- appropriately and were subsequently un- occurred, on average, 9–10 days after the demic on the world’s populations will be derutilized. In addition, communication onset of illness and was usually the result influenced, in part, by how well the med- to the public was poorly coordinated of progressive respiratory failure [12]. The ical, government, business, and lay com- among federal, state, and local agencies, high mortality rates may be an overesti- munities are prepared. Additional tools which resulted in contradictory and con- mate, because limited surveillance studies and resources are available, such as anti- fusing messages being issued [18]. in Vietnam have reported that several con- viral drugs, diagnostics, and vaccines, that Background. In February 2006, a tacts of patients may have developed mild did not exist during prior pandemics. group of representatives from federal, or asymptomatic infection with H5N1 However, there are limits to the quantity state, and local governments; professional [13]. However, recent serologic studies of antiviral drugs that can be manufac- bodies; academia; and the pharmaceutical in Southeast Asia have found infrequent tured and effectively deployed, as well as industry met to review the current state H5N1 antibody positivity in apparently uncertainties regarding vaccine effective- of preparedness in the United States for a healthy contacts, indicating that most in- ness and concerns regarding the current potential influenza pandemic and its re- lationship to seasonal influenza. The goal fections are clinically manifest. By any vaccine production systems. In addition, of the meeting was to examine the recently standard, H5N1 infection is highly viru- new challenges exist, such as rapid inter- revised HHS plan for preparedness and lent in humans. continental transportation and a larger response to an influenza pandemic [17] The final step required for a pandemic global population. Despite these chal- and to make recommendations to actu- is efficient human-to-human transmission lenges, there is an opportunity to take ac- alize this plan at the state and local levels. of the virus. The H5N1 virus is now en- tion before the emergence of a pandemic In addition, the group identified areas for demic in poultry in Asia and parts of Af- influenza strain and, possibly, to prevent further research and consideration. rica and is spreading globally despite active or delay its spread or at least mitigate its The revised HHS plan was designed to control measures. The greatest current impact on the world. In part, this can be provide guidance to national, state, and concern is that the H5N1 virus may be- achieved by improving the current infra- local policy makers and health depart- come more transmissible in humans, ei- structure for managing seasonal influenza, ments, to enable them to prepare for the ther through mutation or through genet- an action that would have the additional management of an influenza pandemic. It ic reassortment with a human influenza benefit of reducing morbidity and mor- has 2 key components: strain. Fortunately, to date, human-to-hu- tality regardless of the emergence of a man transmission of the virus appears to pandemic. For example, increased vaccine • Strategic plan. This section outlines be inefficient, and only a few instances production can be used to control seasonal public health care and medical sup- have been documented [13, 14]. However, disease and ensure more capability to pro- port strategies required to prepare the H5N1 virus has undergone multiple duce vaccine for a pandemic. for and respond to an influenza pan- genetic reassortment events with avian vi- Important lessons can be learned from demic. In addition to outlining plan- ruses since its emergence in 1997, resulting our ability to respond to natural disasters, ning assumptions, it also assigns the in a dominant genotype (Z) present in which can help us to prepare more effec- roles and responsibilities of HHS. chickens and ducks [15], and could po- tively for pandemic influenza. The recent • Public health guidance to state and tentially mutate further, becoming more experience of Hurricane Katrina over- local partners. This section provides

S66 • JID 2006:194 (Suppl 2) • Seasonal and Pandemic Influenza: Introduction guidance to state, local, and tribal a response to the issues highlighted. At the with regard to planning and funding for governments in 11 areas of prepar- end of the meeting, the recommendations a national response was addressed by Jay edness: surveillance, laboratory di- of each group were presented for further Levi, George Washington University, who agnostics, health care planning, in- discussion. The proceedings of these ses- also highlighted some of the challenges fection control, clinical guidelines, sions and the recommendations are de- facing the public and private sectors in vaccine distribution and use, anti- tailed in the final article in this supple- pandemic preparedness. viral drug distribution and use, ment [19]. Subsequent presentations addressed les- community disease control and pre- The meeting was opened by presenta- sons learned from past influenza pandem- vention, management of travel-re- tions from Anthony Fauci, NIAID, and ics. Harvey Fineberg, Institute of Medi- lated risks of disease, public health Julie Gerberding, CDC, on seasonal and cine, reviewed the experience of the 1976

communication, and work force pandemic influenza preparedness, high- swine flu episode, sharing 5 key lessons: Downloaded from https://academic.oup.com/jid/article/194/Supplement_2/S65/851306 by guest on 01 October 2021 support. lighting the existing burden of seasonal the importance of (1) building a base for influenza and reviewing the current US decision making; (2) thinking hard about The Seasonal and Pandemic Influenza national plans for pandemic influenza pre- doing; (3) consideration for the media; (4) 2006 meeting was sponsored by the In- paredness. Dr. Fauci highlighted the major maintaining long-term credibility; (5) and fectious Diseases Society of America limitations of the current vaccine produc- thinking twice about medical knowledge. (IDSA), the Society for Healthcare Epi- tion system in the United States and the Arnold Monto, University of Michigan, demiology of America (SHEA), the Na- challenges that need to be overcome in reviewed the lessons from the 1918, 1957, tional Institute of Allergy and Infectious developing a vaccine for the H5N1 influ- and 1968 pandemics, highlighting the dif- Diseases (NIAID), and the Centers for enza virus. Dr. Gerberding presented the ferent aspects of each and the potential Disease Control and Prevention (CDC). CDC’s pandemic influenza plan, which is impact of future pandemics. Adolfo Gar- Funding for the meeting was supplied aimed at preventing or delaying the entry cı´a-Sastre, Mount Sinai School of Medi- through an unrestricted educational grant and spread of a pandemic influenza virus cine, presented what was learned from the from Gilead Sciences, GlaxoSmithKline, in the United States, thus allowing time reconstruction of the 1918 H1N1 virus Roche Laboratories, MedImmune, Sano- to develop an effective vaccine. and the insights that it provided regarding fi Pasteur, Biota Holdings, and BioCryst The next session reviewed the epide- the pandemic potential of other influenza Pharmaceuticals. The content of the meet- miological profile, surveillance, diagnos- viruses and potential targets for therapeu- ing was planned and coordinated by an tics, and treatment of seasonal influenza. independent planning committee consist- tic and prophylactic interventions. Bill Thompson, CDC, opened the session ing of 6 US infectious diseases experts. The current status of H5N1 infections, Meeting overview. The meeting was by giving an overview of models used to the spread of the virus from Asia to Eu- structured to provide a series of overviews assess influenza-associated morbidity and rope, and the outcome of the resultant of current knowledge about seasonal and mortality, highlighting the challenges as- human infections were presented by Tim pandemic influenza and the state of pre- sociated with determining the true impact Uyeki, CDC. John Treanor, University of paredness for an influenza pandemic in of seasonal influenza. Kristin Nichol, Uni- Rochester Medical Center, reviewed op- the United States. Summaries of these pre- versity of Minnesota, reviewed vaccination tions for producing pandemic vaccines sentations are provided in the accompa- and prevention strategies for seasonal in- comparing live vaccines, inactivated vac- nying articles in this supplement. In ad- fluenza, emphasizing the underuse of cur- cines, and experimental approaches. Fred dition, panel discussions explored issues rent vaccines, and Andy Pavia, University Hayden, University of Virginia School of relating to state epidemiology, local health of Utah, gave an overview of antiviral ther- Medicine, tackled the issue of eliminating care systems, and professional education. apies currently available for treatment of a pandemic at its source through the use The meeting attendees were assigned to and prophylaxis against seasonal influ- of antiviral therapy. He also reviewed the groups to evaluate specific components of enza. Lastly, the management of children, potential impact of antiviral therapy on the current HHS guidelines (vaccine de- immunocompromised hosts, pregnant mortality during a pandemic. Andrea velopment and production; education and women, and nursing home residents was Morgan, US Department of Agriculture communication; surveillance and diag- reviewed by Richard Whitley, University (USDA), outlined the role of USDA in the nostics; distribution of vaccines, antiviral of Alabama at Birmingham. prevention, surveillance, and response to medications, and medical supplies; con- The next session focused on planning an outbreak of avian influenza. tainment procedures; and surge capacity initiatives for pandemic influenza and was The second day of the meeting started for patient care). Each group addressed opened with a review of the recently re- with a presentation by Nancy Cox, CDC, questions posed by a moderator, and a vised US national plan and progress with regarding the role of the World Health discussant led each group in constructing planning at the state level. Progress made Organization in the prevention and man-

Seasonal and Pandemic Influenza: Introduction • JID 2006:194 (Suppl 2) • S67 agement of an influenza pandemic. This Henry Masur, IDSA and NIAID, re- the Centers for Disease Control and Prevention. Funding for the conference was supplied through was followed by a session addressing the viewed the professional educational pro- an unrestricted educational grant from Gilead state and local perspectives on pandemic grams for pandemic influenza, presenting Sciences, GlaxoSmithKline, Roche Laboratories, planning, which was chaired by Michael the efforts of organizations such as IDSA, MedImmune, Sanofi Pasteur, Biota Holdings, and Osterholm, University of Minnesota. The highlighting some of the lessons learned BioCryst Pharmaceuticals. Supplement sponsorship. This article was session was opened by Kathleen Genshei- from the response to Hurricane Katrina, published as part of a supplement entitled “Sea- mer, State Epidemiologist, Maine Depart- and raising the issue of how professional sonal and Pandemic Influenza: At the Cross- ment of Health and Human Services, who society resources could be more effectively roads, a Global Opportunity,” sponsored by the gave her perspective regarding planning utilized by federal, state, and local au- Infectious Diseases Society of America, the So- ciety for Healthcare Epidemiology of America, for an influenza pandemic. A subsequent thorities in the event of a pandemic. the National Institute of Allergy and Infectious panel discussion highlighted the chal- The final session of the meeting con- Diseases, and the Centers for Disease Control Downloaded from https://academic.oup.com/jid/article/194/Supplement_2/S65/851306 by guest on 01 October 2021 lenges faced at state and local levels. These sisted of a review of the recommendations and Prevention. include distribution of vaccines and an- generated at each of the break-out ses- tiviral drugs, coordination of a second sions. After presentations made by each of dose of vaccine, and identifying when and the groups, the meeting participants were References for how long it is appropriate to close invited to make further suggestions or re- 1. Johnson NP,Meuller J. Updating the accounts: down schools and businesses. There was finements. After the meeting, these rec- global mortality of the 1918–1920 “Spanish” some concern that responsibility for too ommendations were reviewed and further influenza pandemic. Bull Hist Med 2002; 76: 105–15. refined by the Planning Committee. The many decisions was being left to local of- 2. Taubenberger JK, Reid AH, Lurens RM, Wang ficials, and a desire was expressed for fur- full details of these recommendations are R, Jin G, Fanning TG. 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Pandemic versus tion of these recommendations is beyond focused further on local health care issues, epidemic influenza mortality: a pattern of with perspectives presented by Isaac Weis- the ability of any individual organization changing age distribution. J Infect Dis 1998; fuse, New York City Department of Health and will require fostering collaborationbe- 178:53–60. 5. Tumpey TM, Garcı´a-Sastre A, Taubenberger and Mental Hygiene; Lawrence Deyton, tween government agencies, international bodies, academic bodies, professional so- JK, et al. Pathogenicity of influenza viruses Department of Veterans Affairs; Dan Han- with genes from the 1918 pandemic virus: cieties, and the business world. In addi- fling, Inova Health System; and Trish Perl, functional roles of alveolar macrophages and tion, ongoing review and development of Johns Hopkins University. A number of neutrophils in limiting virus replication and these plans and recommendations are mortality in mice. J Virol 2005; 79:14933–44. areas of concern were identified during mandatory to ensure that plans are refined 6. Kobasa D, Takada A, Shinya K. Enhanced vir- these presentations and in the subsequent ulence of influenza A viruses with the hae- in the event of new developments. The period of discussion, including (1) the un- magglutinin of the 1918 pandemic virus. Na- authors acknowledge that this initial set intended consequences of actions such as ture 2004; 431:703–7. of recommendations is focused on the 7. Osterholm MT. Preparing for the next pan- school closures, which would leave a large United States. However, there is an inten- demic. N Engl J Med 2005; 352:1839–42. number of children without nutrition; (2) 8. Kemink SA, Fouchier RA, Rozandaal FW, et tion to broaden the scope of this docu- the lack of surge capacity in the health care al. A fatal infection due to avian influenza-A ment in the future, to include additional system, which would result in hospitals (H7N7) virus and adjustment of the preven- recommendations for an international tative measures. Ned Tijdschr Geneeskd 2004; and laboratories being overwhelmed; (3) audience. 148:2190–4. the lack of spare mechanical ventilators 9. Yuen KY, Chan PK, Peiris M, et al. Clinical that would be required to support criti- features of rapid viral diagnosis of human dis- cally ill patients; (4) the impact on health ease associated with avian influenza A H5N1 Acknowledgments virus. Lancet 1998; 351:467–71. care workers and the need for significant We thank John Fry for his assistance in writing 10. Nicholson KG, Wood JM, Zambon M. Influ- numbers of additional staff; (5) the impact this manuscript. The “Seasonal and Pandemic In- enza. Lancet 2003; 362:1733–45. of individuals who are infected but are not fluenza 2006: At the Crossroads, a Global Oppor- 11. World Health Organization. Confirmed hu- aware of it; and (6) the lack of rapid sen- tunity” conference was sponsored by the Infectious man cases of avian influenza A (H5N1). Avail- Diseases Society of America, the Society for able at: http://www.who.int/csr/disease/avian sitive diagnostic tests for use in local Healthcare Epidemiology of America, the National _influenza/country/en/. Accessed 12 April facilities. Institute of Allergy and Infectious Diseases, and 2006.

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Seasonal and Pandemic Influenza: Introduction • JID 2006:194 (Suppl 2) • S69