3
Toward Preparedness: Opportunities and Obstacles

OVERVIEW

The odds of detecting, controlling, and perhaps preventing the spread of an influenza virus with pandemic potential have improved dramatically since 1918, and they continue to increase with expanding knowledge of influenza viruses and the threat they present to human and animal health. Today, international programs permit the characterization of thousands of viral isolates each year and support worldwide surveillance and communications networks. These efforts are informed by research on viral molecular biology and evolution, and bolstered by simultaneous preparations against the threat of bioterrorism.

Yet major challenges to pandemic preparedness remain to be overcome. The world’s growing—and increasingly urbanized—population and the speed and volume of international travel create abundant opportunities for widespread viral transmission. Some countries will respond to a pandemic with abundant resources and expertise, but many others remain essentially defenseless. Even populations wealthy enough to obtain vaccine are unlikely to get enough to prevent significant morbidity and mortality from pandemic influenza unless more rapid vaccine production methods or novel prophylactic vaccines can be introduced before the next pandemic strikes. The circumstances surrounding 2 consecutive years of interpandemic flu vaccine shortages in the United States clearly illustrate this vulnerability. The 2003–2004 shortage, discussed by Glen Nowak in Chapter 6, resulted from increased demand for vaccine during an early and intense flu season, while the 2004–2005 shortage resulted from contamination that rendered



The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement



Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.

OCR for page 141
The Threat of Pandemic Influenza: Are We Ready? - Workshop Summary 3 Toward Preparedness: Opportunities and Obstacles OVERVIEW The odds of detecting, controlling, and perhaps preventing the spread of an influenza virus with pandemic potential have improved dramatically since 1918, and they continue to increase with expanding knowledge of influenza viruses and the threat they present to human and animal health. Today, international programs permit the characterization of thousands of viral isolates each year and support worldwide surveillance and communications networks. These efforts are informed by research on viral molecular biology and evolution, and bolstered by simultaneous preparations against the threat of bioterrorism. Yet major challenges to pandemic preparedness remain to be overcome. The world’s growing—and increasingly urbanized—population and the speed and volume of international travel create abundant opportunities for widespread viral transmission. Some countries will respond to a pandemic with abundant resources and expertise, but many others remain essentially defenseless. Even populations wealthy enough to obtain vaccine are unlikely to get enough to prevent significant morbidity and mortality from pandemic influenza unless more rapid vaccine production methods or novel prophylactic vaccines can be introduced before the next pandemic strikes. The circumstances surrounding 2 consecutive years of interpandemic flu vaccine shortages in the United States clearly illustrate this vulnerability. The 2003–2004 shortage, discussed by Glen Nowak in Chapter 6, resulted from increased demand for vaccine during an early and intense flu season, while the 2004–2005 shortage resulted from contamination that rendered

OCR for page 141
The Threat of Pandemic Influenza: Are We Ready? - Workshop Summary half of the U.S. vaccine supply—the product of a single manufacturer, Chiron, Inc.—unusable. This chapter discusses challenges to pandemic preparedness at international, national, and state levels. It begins with the executive summary of a technical consultation convened by the World Health Organization (WHO) in March 2004 in response to the threat posed by H5N1 avian influenza, and in particular to the evidence that this virus had been transmitted to humans in Vietnam and Thailand, with deadly results. More than 100 experts from 33 countries discussed a broad range of measures that could be introduced by WHO and national authorities to forestall emerging pandemics, slow their spread, and reduce their potential toll of morbidity, mortality, and social disruption. The executive summary presents the recommendations and conclusions of four working groups (surveillance, public health interventions, antivirals, and vaccines) regarding key issues in pandemic preparedness. In the United States, the Department of Health and Human Services released a draft Pandemic Preparedness and Response Plan for a 60-day period of public comment on August 26, 2004. This chapter includes an executive summary and a synopsis of this plan, which describes coordination and decision making at the national level; provides an overview of key issues; and outlines steps that should be taken at the national, state, and local levels before and during a pandemic. It is followed by two contributions that further discuss pandemic planning from the perspective of state and local public health officials, who will be largely responsible for implementing pandemic prevention and control actions in the United States. The first essay discusses pandemic planning as a collaborative process that involves officials at all levels of government and that is guided by federal priorities. The second essay highlights the importance of strengthening influenza surveillance at the state and local levels, both as a means to early detection of an emerging pandemic and to inform the public health response to interpandemic influenza. The chapter continues with a consideration of pharmaceutical defenses against pandemic influenza. Vaccines significantly reduce morbidity and mortality during annual (interpandemic) flu seasons, but as this chapter demonstrates, considerable obstacles currently hinder the production of a vaccine against a pandemic strain of influenza. The critical role of vaccine manufacturers in addressing a pandemic is described, accompanied by a review of methods and logistics for the development and production of a pandemic vaccine. Demand for vaccine during a pandemic will likely far exceed supply. These considerations are subsequently explored first in a discussion of the challenges to equitable and effective vaccine distribution, and then in a description of the potential use of antiviral drugs to fill unmet need for

OCR for page 141
The Threat of Pandemic Influenza: Are We Ready? - Workshop Summary vaccine, particularly during the initial phase of a pandemic. David Fedson advises that efforts toward pandemic vaccine development should initially focus on producing the largest possible supply of pandemic vaccine as quickly as possible. Europeans will most likely pursue this goal by developing a low-dose adjuvant pandemic vaccine, which differs from the strategy that will be undertaken by the National Institute of Allergy and Infectious Diseases in the United States. He also describes the potential advantages of engineering viral seed strains with reverse genetics and urges a quick resolution to the ongoing dispute regarding ownership of intellectual property for this technology. Given these obstacles to the timely production of pandemic vaccine, it is also imperative to develop near-term strategies to address a pandemic threat without recourse to vaccination. Dr. Fedson recounts recent findings suggesting that prophylaxis with statins or other commonly available therapeutic agents, which have recently been found to reduce serum concentrations of several inflammatory mediators, might mitigate the clinical course of human influenza. He suggests next steps in pursuing this idea, but it is not without risk or controversy. For example, a recent case study describes a patient undergoing therapy with two statins (cerivastatin and bezafibrate) who developed acute renal failure due to rhabdomyolysis only after being administered an influenza vaccine; similar cases had occurred in several patients receiving this combined therapy who had contracted influenza (Plotkin et al., 2000). Researchers have also reported that the in-vitro treatment of macrophages with another statin (lovastatin) did not decrease tumor necrotic factor (TNF) production, as would be expected to occur with lovastatin-induced immunosuppression, but instead resulted in increased production of TNF (Monick et al., 2003). The apparent contradiction between this observation and the reports cited by Dr. Fedson may be explained by tolerance induced in vivo subsequent to lovastatin-induced TNF production, or perhaps by differences between the long-term and acute effects of lovastatin. A second, more widely accepted strategy for coping with pandemic influenza in absence of vaccine is described in the subsequent review by Frederick Hayden, which focuses on the potential role of currently available antiviral drugs in such a pandemic response. However, as this review makes clear, a variety of supply and distribution problems must be solved before this promising strategy could be implemented. Although the American health care system is overwhelmingly privatized, little attention has yet been paid to private medicine’s potential role in preparing for pandemic influenza. This chapter concludes with a description of the status of pandemic planning within the private health care system, and suggestions for ways that private health care organizations could contribute to pandemic preparedness at all levels of government.

OCR for page 141
The Threat of Pandemic Influenza: Are We Ready? - Workshop Summary WHO CONSULTATION ON PRIORITY PUBLIC HEALTH INTERVENTIONS BEFORE AND DURING INFLUENZA PANDEMIC EXECUTIVE SUMMARY World Health Organization1 Reprinted with permission from the World Health Organization, Copyright World Health Organization, 2004, All Rights Reserved Background In January 2004, health authorities in Viet Nam and Thailand reported their first human cases of infection with avian influenza, caused by an H5N1 strain. The cases in humans are directly linked to outbreaks of highly pathogenic H5N1 avian influenza in poultry initially reported in the Republic of Korea in mid-December 2003 and subsequently confirmed in an additional seven Asian countries (Viet Nam, Japan, Thailand, Cambodia, China, Laos, and Indonesia). As at end-March 2004, no countries other than Viet Nam and Thailand had reported human cases. The number of human cases has remained small to date, but treatment has been largely ineffective and case fatality rates have been high. Moreover, the situation has several disturbing features, including the historically unprecedented scale of the outbreak in poultry. Of foremost concern is the risk that conditions present in parts of Asia could give rise to an influenza pandemic. Pandemics, which recur at unpredictable intervals, invariably cause high morbidity and mortality and great social disruption and economic losses. Conservative estimates based on mathematical modelling suggest that the next pandemic could cause from 2 million to 7.4 million deaths. Conditions favourable to the start of a pandemic are now much better understood than in the previous century, which witnessed three pandemics. Influenza research was greatly stimulated in 1997, when the world’s first known cases of human infection with the H5N1 strain of avian influenza virus were documented in Hong Kong Special Administrative Region of China. Investigations launched by that outbreak, including studies in molecular biology and epidemiology, helped elucidate the mechanisms by which pandemic viruses could emerge and further clarified the conditions that favour such an event. These studies also demonstrated, for the first 1   Editor’s note: During the production of this report, the WHO Executive Board released additional recommendations. For more information, see the following (1) Influenza Pandemic Preparedness and Response, available at: http://www.who.int/gb/ebwha/pdf_files/EB115/B115_44-en.pdf and (2) Strengthening Pandemic Influenza Preparedness and Response, available at: http://www.who.int/gb/ebwha/pdf_files/EB115/B115_R16-en.pdf.

OCR for page 141
The Threat of Pandemic Influenza: Are We Ready? - Workshop Summary time, that the H5N1 strain can infect humans directly without prior adaptation in a mammalian host. On that occasion, the culling within three days of Hong Kong’s poultry population, estimated at 1.5 million birds, is thought to have possibly averted a pandemic. Some experts believe that this improved understanding, when combined with efficient surveillance and immediate and aggressive action, might make it possible to detect events with pandemic potential and delay—or even prevent—their escalation and global spread. Research has identified three essential prerequisites for the start of a pandemic. First, a novel influenza subtype must be transmitted to humans. Second, the new virus must be able to replicate in humans and cause disease. Third, the new virus must be efficiently transmitted from one human to another; efficient human-to-human transmission is expressed as sustained chains of transmission causing community-wide outbreaks. Since 1997, the first two prerequisites have been met on four occasions: Hong Kong in 1997 (H5N1), Hong Kong in 2003 (H5N1), the Netherlands in 2003 (H7N7), and Viet Nam and Thailand in 2004 (H5N1). Of these outbreaks, those caused by H5N1 are of particular concern because of their association with severe illness and a high case fatality. Of even greater concern is the uniqueness of the present H5N1 situation in Asia. Never before has an avian influenza virus with a documented ability to infect humans caused such widespread outbreaks in birds in so many countries. This unprecedented situation has significantly increased the risk for the emergence of an influenza pandemic. A pandemic virus capable of efficient human-to-human transmission could arise via two mechanisms: virus reassortment (the swapping of genetic material between viruses) when humans or pigs are co-infected with H5N1 and a human influenza virus, and adaptive mutation during human infection. The risk that either event will occur remains so long as H5N1 is present in an animal reservoir, thus allowing continuing opportunities for human exposure and infection. The level of risk is determined most directly by the prevalence of the virus in poultry and the frequency of its transmission to humans. The risk also depends on the co-circulation of human and avian influenza viruses and the inherent propensity of these viruses to reassort. Most experts agree that control of the present outbreaks in poultry will take several months or even years; some believe that the virus may have already established endemicity in domestic poultry. The recent detection of highly pathogenic avian influenza in wild birds adds another layer of complexity to control. The world may therefore remain on the verge of a pandemic for some time to come. At the same time, the unpredictability of influenza viruses and the speed with which transmissibility can improve mean that the time for preparedness planning is right now. Such a task takes on added urgency because of the prospects opened by recent research: good planning and preparedness might mitigate the enormous consequences of a pandemic, and this opportunity must not be missed.

OCR for page 141
The Threat of Pandemic Influenza: Are We Ready? - Workshop Summary The Consultation In response to these concerns, WHO convened a technical consultation on preparedness for an influenza pandemic from 16 to 18 March 2004. The consultation, attended by more than 100 experts from 33 countries, considered a wide range of measures that could be introduced, by WHO and national authorities, both before and during a pandemic. Three main objectives were identified: to forestall potential pandemics as they emerge, to slow national and international spread, and to reduce the usually high levels of morbidity, mortality, and social disruption. Participants agreed that the effectiveness of specific interventions would change over time in line with distinct phases, defined by epidemiological criteria, during the progression from an incipient pandemic situation to the declaration of a pandemic. Interventions were therefore discussed in terms of their objectives and likely impact at different phases as well as their feasibility in different resource settings. Epidemiological triggers for shifting objectives and adapting the recommended mix of measures were also identified. The consultation fully recognized that the best opportunity for mitigating the consequences of a pandemic would occur early on, and that planning and preparedness, at both national and global levels, would be needed to take full advantage of this opportunity. Many key characteristics of a new pandemic virus—its pathogenicity, attack rate in different age groups, susceptibility to antivirals, and response to other treatments—would guide the selection of control measures, but could not be known with certainty in advance. In addition, many characteristics of normal human influenza, such as the role of asymptomatic transmission and the effectiveness of non-medical control measures, are poorly understood. During the chaos of a pandemic, health authorities would almost certainly need to make decisions, often with major social and economic consequences, in an atmosphere of considerable scientific uncertainty. To reduce some of this uncertainty, participants based their recommendations on relevant lessons from the recent SARS outbreak, knowledge about the epidemiology of previous influenza pandemics, and clinical data from outbreaks of H5N1 infection in Hong Kong in 1997 and Viet Nam and Thailand in 2004. Modelling of various scenarios for the emergence of a pandemic strain provided an especially useful planning tool. Against this background, three main questions were addressed: what reporting and monitoring systems are needed to detect the start of a pandemic at the earliest possible stage and track its evolution, which interventions will be both feasible and effective at different phases and in different resource settings, and what policy options might best cope with the inevitable shortage of vaccines and antivirals. These questions were considered by four working groups focused on surveillance, public health interven-

OCR for page 141
The Threat of Pandemic Influenza: Are We Ready? - Workshop Summary tions, antivirals, and vaccines. A more complete account of the deliberations and conclusions of each working group is provided in the main body of this report. Some discussion centered on the question of whether—with better scientific knowledge, better control tools, and the international solidarity shown during the SARS response—something might be done to prevent the present situation from evolving towards a pandemic. In this regard, good surveillance in all countries experiencing outbreaks of highly pathogenic avian influenza in poultry was considered to be a fundamental prerequisite. Guarding against the start of a pandemic would also depend on rapid detection, prompt laboratory confirmation, and accurate reporting of human cases, and the transparent sharing of all relevant information with WHO. Participants readily agreed that vaccines—the first line of defence for reducing morbidity and mortality—would not be available at the start of a pandemic and would remain in short supply throughout the first wave of international spread. For this reason, efforts to prevent or delay initial spread would have paramount importance. All countries would need to prioritize vaccine distribution and consider difficult ethical and practical questions of eligibility. Developing countries would face the most acute shortages, as manufacturing capacity is concentrated in Europe and North America, and countries can be expected to reserve scarce supplies for their own populations. In the absence of vaccines, antivirals would initially assume greater importance as a prophylactic and treatment tool for reducing morbidity and mortality. In practice, however, this potential role could be undermined by several problems, including high costs, uncertain efficacy, propensity to develop resistance, and extremely limited supplies, further constrained by the absence of any surge capacity for production. With the first line of defence not a viable option at the start of a pandemic, participants looked at interventions that could forestall or delay national and international spread pending antiviral availability, the augmentation of vaccine supplies, and the implementation of mass vaccination strategies. This strategy of “buying time” was linked to assumptions, partially based on modelling, that the first chains of human-to-human transmission might not reach the efficiency needed to initiate and sustain pandemic spread. In such a scenario, the first evidence of limited human-to-human transmission, most likely expressed as clusters of cases, would be the epidemiological trigger for intense international efforts aimed at interrupting further transmission or at least delaying further national and international spread. For this reason, surveillance systems in countries with outbreaks in animals caused by H5N1 or other influenza viruses of known human pathogenicity should be oriented towards early detection, reporting, and investigation of clusters of human cases, followed by aggressive con-

OCR for page 141
The Threat of Pandemic Influenza: Are We Ready? - Workshop Summary tainment measures, including tracing and management of contacts, targeted prophylactic use of antivirals, and travel-related measures. Participants recommended consideration of whether an international stockpile of antivirals should be established for use exclusively during this critical window of opportunity. Should early containment fail, the consultation concluded that, once a certain level of efficient transmission was reached, no interventions could halt further spread, and priorities would need to shift to the reduction of morbidity and mortality. It was also recognized that a reassortment event could result in a virus fully equipped for efficient human-to-human transmission, thus immediately curtailing opportunities to “buy time” through measures aimed at preventing geographical spread. Should early surveillance fail, the detection of transmission would likely take place only after efficient transmission was established, again curtailing opportunities to intervene. However, in these cases as well, advance planning had much to offer. As the consequences of a pandemic became apparent, public health authorities would face great public and political pressure to maintain or introduce often drastic, costly, and disruptive protective measures (travel restrictions, screening measures at borders, contacting tracing, isolation and quarantine) which, though useful at earlier stages, might have little or no impact once efficient transmission was established. By including provisions for stopping or adjusting measures in line with clear epidemiological criteria, preparedness plans would help public health authorities withstand this pressure and thus conserve resources for the next objectives: constraining transmission, preventing severe disease, and reducing case fatality. When objectives shift, clear and frank public information and good communications systems would be essential in helping lower expectations and discouraging the continuation of personal protective measures no longer considered effective. Participants agreed that, once a pandemic begins, its overall management would move outside the public health sector and take on great political and economic significance. Good public information might also protect governments from accusations that extraordinary measures introduced at earlier phases—causing great economic costs and social disruption—failed and were therefore inappropriate. In addition, populations would need to be prepared for the even greater social disruption, linked to high morbidity and mortality that could be expected as the pandemic progressed. Conclusions Some General Conclusions During the deliberations of the working groups and discussions in plenary session, the picture that emerged was one of a world inadequately

OCR for page 141
The Threat of Pandemic Influenza: Are We Ready? - Workshop Summary prepared to respond to an influenza pandemic. Response capacity was considered insufficient at levels ranging from vaccine manufacturing to the sensitivity of surveillance systems, the number of hospital beds, the affordability of diagnostic tests, and the supply of respirators and face masks. A recurring theme was the need to engage government departments beyond the health sector. At the same time, the urgency of the present situation was fully appreciated, and participants made a number of suggestions for improving capacity now. For example, better use of vaccines and antivirals during the inter-pandemic period would improve manufacturing capacity while also helping to reduce the estimated 250,000 to 500,000 deaths caused by seasonal influenza epidemics each year. The burden of influenza in developing countries, including its contribution to overall morbidity and mortality and economic impact, was virtually unknown in most cases. Studies of this burden would give national authorities a better foundation for making influenza a priority and bargaining for a share of resources. Establishment of vaccine manufacturing capacity in developing countries could be expected to improve access while reducing costs. Moreover, most participants agreed that, under the pressures of an eminent or unfolding pandemic, innovative solutions to some problems would be found. For example, manufacturing capacity for vaccines might be augmented by decreasing the antigen quantity per dose or using adjuvants. Research on antivirals could determine whether reduced drug dose or shortened treatment course might still have a prophylactic or therapeutic effect, and whether administration later in the course of infection might influence transmission dynamics by reducing virus shedding. As in all public health emergencies caused by an infectious agent, international mechanisms for alert and response can go only a certain way towards mitigating the consequences of an influenza pandemic. In the final analysis, each national health system will bear the burden of protecting populations and managing the emergency. The consultation concluded that international solidarity would have the greatest role to play at the start of human-to-human transmission, when an all-out effort would have the best chance of halting or at least delaying further national and international spread. Should that effort fail, inequities in capacity and the distribution of resources mean that the consequences of a pandemic would almost certainly be most severe in the developing world. Participants stressed the importance of addressing these inequalities now—before a pandemic makes the ethical implications of failing to do so both blatantly apparent and irrevocable.

OCR for page 141
The Threat of Pandemic Influenza: Are We Ready? - Workshop Summary Conclusions from the Working Groups Working Group One: Surveillance for pandemic preparedness One of the most important functions of surveillance is to ensure the detection of unusual clusters of cases and of the occurrence of human-to-human transmission at the earliest possible stage, when public health interventions have the greatest chance to prevent or delay further national and international spread. Once a pandemic is fully under way, no interventions are likely to halt further international spread during the first wave of infection. Influenza pandemics are, by their very nature, matters of global concern. Prompt and transparent reporting of early cases and results from the investigation of clusters related to novel influenza viruses is essential for the protection of international public health. The use of limited supplies of vaccines and antivirals will depend on the national situation and should consider the protection of essential community functions and the treatment of groups at highest risk of severe disease. Data from a national risk assessment and internationally coordinated epidemiological investigations will assist in the development of policies for vaccine and antiviral utilization. Data to inform policy decisions need to be produced as quickly and cost-effectively as possible. As the origins of pandemic influenza viruses have historically involved animal species, surveillance activities surrounding the emergence of a potentially pandemic virus require intersectoral collaboration with veterinarians as well as with clinicians, virologists, epidemiologists, and public health professionals. Given resource constraints in many countries, strengthening existing systems to include a capacity to detect and investigate clusters of acute febrile respiratory disease may be the best value for money. The objectives, methods, and attributes of an influenza surveillance system will vary according to different phases in the pre-pandemic and pandemic periods. To assist in preparedness planning, the group set out recommended objectives for influenza surveillance and identified the corresponding methods and activities appropriate at different inter-pandemic, pre-pandemic, and pandemic phases. These recommendations appear as a table in the working group’s report. Working Group Two: Public health interventions An influenza pandemic is a public health emergency that rapidly takes on significant political, social, and economic dimensions. A broad

OCR for page 141
The Threat of Pandemic Influenza: Are We Ready? - Workshop Summary range of government departments apart from public health should be engaged in pandemic preparedness planning and will need to be involved in decisions regarding interventions having potentially broad impact outside the health sector. Emergency decisions will need to be made in an atmosphere of scientific uncertainty. Health authorities may need to change recommended measures as data about the causative agent become available and the epidemiological situation evolves, and as interventions either succeed in containing transmission or lose their effectiveness. The basis for all interventions should be carefully explained to the public and professionals, as well as the fact that changes can be expected. Non-medical interventions will be the principal control measures pending the availability of adequate supplies of an effective vaccine. Many will have their greatest potential impact in pre-pandemic phases while others will have a role after a pandemic has begun. In some resource-poor settings, non-medical interventions will be the only control measures available throughout the course of a pandemic. Non-medical interventions considered by the consultation include public risk communication, isolation of cases, tracing and appropriate management of contacts, measures to “increase social distance” (such as cancellation of mass gatherings and closure of schools), limiting the spread of infection by domestic and international travel, and the targeted use of antiviral drugs. Certain measures are recommended for consideration based on a public health perspective, although it is recognized that other factors (such as availability of health resources, political, economic and social considerations) and a country’s special circumstances will legitimately influence national decisions regarding prioritization and implementation of the various options. In general, providing information to domestic and international travellers (risks to avoid, symptoms to look for, when to seek care) is a better use of health resources than formal screening. Entry screening of travellers at international borders will incur considerable expense with a disproportionately small impact on international spread, although exit screening should be considered in some situations. Emerging virus strains with pandemic potential require urgent and aggressive investigation to provide a stronger scientific basis for control recommendations and the strategic use of resources. Confirmation of early episodes of human-to-human transmission is especially important. Biological specimens as well as epidemiological and clinical data must be obtained and shared with extreme urgency, under the leadership of WHO. Advance planning is needed to take advantage of this narrow window of opportunity to contain or slow transmission, which will close quickly once a pandemic begins.

OCR for page 141
The Threat of Pandemic Influenza: Are We Ready? - Workshop Summary TABLE 3-7 Projected Economic Impact of Neuraminidase Inhibitor Treatment on Selected Outcomes During Pandemic Influenza   Out-patient Visits Saved per 1000 Ill Hospitalizations Saved per 1000 Ill Out-patient-related Days Off Work Saved per 1000 Ill Mean 95% CI Mean 95% CI Mean 95% CI 0-19 Years 162 152-171 2.2 0.8-3.5 800 754-847 20-64 Years 296 284-307 4.0 1.8-6.0 585 320-844 65+ Years 227 223-229 14.4 11.3-17.6 745 735-755 NOTE: The days off work saved only refer to out-patient illnesses and do not consider the effect of hospitalization. Paediatric illnesses were assumed to cause days off work for care givers (Meltzer et al. 1999). These outcomes are derived from the use of a previously described mathematical model (Meltzer et al. 1999) and the following assumptions regarding the effects of early antiviral treatment derived from studies with oseltamivir: neuraminidase inhibitor treatment reduces the days of illness by 1.5 days, the number of out-patient visits by 20% (0-19 years), 50% (20-64 years) and 30% (> 65 years) and hospitalizations by 50% compared with no treatment. CI, confidence interval.) SOURCE: M. I. Meltzer and F. G. Hayden, unpublished observations, .et al.

OCR for page 141
The Threat of Pandemic Influenza: Are We Ready? - Workshop Summary children would reduce out-patient visits and work/school days lost. By assigning direct and indirect dollar valuations to the health outcomes averted, it was estimated that the treatment of high-risk persons aged 65 years and older and non-high-risk persons aged 20–64 years would generate the largest and comparable savings per 1000 ill. If it were possible to extend early treatment to those who would not seek medical care, considerable savings in indirect costs due to days off work/school could be achieved across all age groups. However, the actual implementation of that strategy would require the development and validation of new treatment paradigms, such as telephone triage by non-physician health care providers or self-diagnosis through symptom checklists and then rapid access to antiviral drugs for patient-initiated therapy. Such assessments need to be undertaken during the interpandemic influenza period so that they might be acceptable for use during the next pandemic. In general, the results of such economic analyses depend on the nature of the pandemic and its associated age-related morbidity and mortality rates, the projected costs of outcomes and the assumed effectiveness of the intervention. Future research will need to include estimates of the cost of delivering treatments to various age and risk groups and examine other drug treatments and strategies including prophylaxis. However, such economic models can help guide decisions about the potential benefits of antiviral treatment or prophylaxis in different populations groups. PARTNERING WITH THE PRIVATE MEDICAL SYSTEM Gordon W. Grundy, MD, MBA Aetna, Inc. Health plans and managed care organizations (MCOs) operate at the center of the private medical system. Over 200 million American citizens are privately insured by more than 1,300 health care organizations. Aetna is among the largest with more than 13 million members. By virtue of financing, facilitating, and coordinating the delivery of health services, health plans have fiduciary and contractual relationships with a variety of constituents. These include individual citizens (health plan members), employers (payers of private health insurance), physicians, hospitals, and other ancillary providers (e.g., home health care agencies, skilled nursing facilities, and urgent care centers). In planning for pandemic influenza, the role of the private medical system as mediated through health plans and MCOs can be framed by addressing four key questions:

OCR for page 141
The Threat of Pandemic Influenza: Are We Ready? - Workshop Summary What capabilities can private health plans bring to influenza pandemic planning? How and why should health plans and MCOs interface with the planning process? How can health plans and MCOs facilitate the delivery of medical services during an influenza pandemic? How might a public–private partnership to address pandemic influenza be achieved? Capabilities of Private Health Plans Health plans and MCOs can contribute a broad range of resources to the pandemic planning process. They are experienced at increasing health awareness through educational initiatives and promoting preventive care with timely reminders to insured members. In addition, health plans often provide performance feedback to the physicians and hospitals with which they have contractual relationships. These activities reach significant numbers of constituents. For example, a single large health plan such as Aetna can communicate nationwide with more than 13 million individuals, 350,000 physicians, and 3,500 hospitals. Because MCO databases contain information on members, physicians’ practice locations, and hospital contacts, they are well positioned to conduct outreach in the event of a public health crisis. Education Most health plans have developed educational components within their wellness programs as well as in case and disease management functional areas. With some modification, these resources could be adapted to inform the public during an influenza pandemic. Health plans generally find that individual members attend to the topics that are discussed in mailings and in telephone campaigns. Given the proven capability of health plans and MCOs in outreach and education activities, public health agencies should consider them as potential partners in communicating with citizens during an influenza pandemic threat. Immunization Campaigns Aetna is one of many health plans that have experience in conducting preventive immunization campaigns and our ability to do so has been measured and accredited. In support of these efforts, we have established alternative sites for providing immunizations, such as retail establishments and pharmacies, and we have developed a variety of ways to get people to

OCR for page 141
The Threat of Pandemic Influenza: Are We Ready? - Workshop Summary sites where they can be appropriately immunized. Aetna’s extensive database enables us to target high-risk individuals and to build predictive modeling tools, including risk stratification. This allows us to identify those individuals within our health plan who would be at high risk for complications from influenza, whether due to age or a chronic condition. In December 2003, for example, when the influenza season got off to an early and severe start and the potential for a vaccine shortage became apparent, Aetna conducted an outreach campaign within its southeast region to urge health plan members at high risk for flu complications due to a chronic medical condition to be immunized. Over a period of 4 days, Aetna placed more than 134,000 telephone calls to insured members and ultimately contacted more than 100,000 people—many of whom received as many as 4 calls. Information was disseminated rapidly and thoroughly, reaching about 80 percent of our at-risk regional members. This success at sending public health messages quickly and broadly is an asset, and one that we and other health care plans can contribute in addressing pandemic influenza. Incentives for Physicians and Insured Members Through contractual relationships with physicians, health plans and MCOs can encourage them to improve annual influenza immunization rates. Physicians can receive feedback on their vaccination rates for members, especially those at high risk for flu complications. In addition, financial incentives might be established for outstanding performance in this area. Members can also be rewarded for taking appropriate preventive health measures by enhancing their plan benefits. Research and Demonstration Projects An Institute of Medicine workshop in 1998 noted a potential role for MCOs in research and demonstration projects related to emerging infections. In the past, however, there has been little incentive for health plans to participate in these projects. With the looming threat of an influenza pandemic, this worthwhile concept might well be revisited and meaningful incentives considered. The Planning Process How then should health plans and MCOs interface effectively with the planning process for pandemic influenza? First and foremost, they need to be part of the planning process. In addition to offering the previously described capabilities, health plan representatives need to be at the table because they understand how specific medical systems in individual com-

OCR for page 141
The Threat of Pandemic Influenza: Are We Ready? - Workshop Summary munities actually work. Their unique viewpoint can complement the knowledge of local public health departments. Health plan managers are familiar with each hospital’s issues, capacities, referral patterns, and nearby lower level care providers. In the course of health plan work, every effort is made to ensure that members who are hospitalized in acute care facilities are transitioned into lower levels of care as appropriate. Based on that experience, health plans may be able to assist in addressing the expected strain on hospital surge capacity resulting from pandemic influenza, particularly in intensive care units. For example, MCOs may be able to help transition or move hospitalized individuals into alternative sites of care in order to make optimal use of acute care resources. Health plans also need clear policies, directives, and recommendations from the CDC and other governmental agencies in order to ensure our effective participation in the response to pandemic influenza. In this, as in all medical circumstances, we rely on authoritative sources in the public health field and evidence-based literature to frame and craft our policies. Although health plans recognize the considerable uncertainties inherent in predicting the pandemic course and outcome, the clearer the statements we (and the public) receive, the more support we can provide. For example, if health plans are to encourage and incentivize immunization during a pandemic, we will need to know which populations to target. Will the focus be on people with chronic conditions in order to reduce morbidity and mortality? Alternatively, will the priority be working adults and children in order to reduce the economic impact of lost productivity by ensuring the health of caregivers? Or will we have a universal immunization program to decrease the overall burden of illness? Health plans can most effectively assist in implementing the strategy when it is clearly stated and understood. Finally, the planning process should recognize the full financial ramifications of an influenza pandemic. This goes beyond calculating the percentage increase in utilization of services and estimates of the aggregate dollar amounts that will be spent as a result. Cost estimates need to reach a more granular level, one that acknowledges that health care is delivered by individuals who get paid for their services. A considerable portion of the health services delivered in a pandemic will be provided by private practitioners who will expect reimbursement. Although certain expenses may be waived, the basic financial support system for the private medical system is carried by employers and needs to stay afloat. This issue requires further study and understanding before positing any recommendations. Facilitating Delivery of Medical Services In many circumstances, health plans can most effectively facilitate the delivery of medical services during an influenza pandemic by removing obstacles. More specifically, in the event of a pandemic, health plans will

OCR for page 141
The Threat of Pandemic Influenza: Are We Ready? - Workshop Summary need to temporarily remove or waive many of the policies and procedures that have been established to manage costs but could hinder the response to a public health crisis. This is exactly what many health plans did following the events of September 11, 2001, as well as after several recent natural disasters and the blackout that affected much of the northeastern United States during the summer of 2003. Most plans in the affected areas issued time-limited waivers of prior approval, referral, and formulary requirements, enabling their members to access care wherever they found it. Aetna even went a step further in September 2001 by bringing counseling teams to worksites in the metropolitan New York area to provide ready access to behavioral health services for plan members. This precedent to respond quickly and productively in emergency situations will no doubt be replicated during an influenza pandemic. Whether educating their members, promoting immunization, waiving procedures, enhancing surge capacity, or ensuring access to antiviral medications, health plans will play an important role in the day-to-day management of the pandemic. The challenge and responsibility for the private medical system will be to develop a coordinated response that can be launched at the direction of public health officials. Achieving Public–Private Partnership To comprehensively address the threat of pandemic influenza, a public–private partnership would most effectively leverage the strengths of health plans and MCOs. Many health plans—potentially every plan—would need to be involved in such an effort. A leading organization that could establish such broad representation is the trade association known as America’s Health Insurance Plans (AHIP). Composed of 1,300 health plans that insure more than 200 million citizens, AHIP is engaged in several activities that have public health dimensions. It has had a Disease Prevention and Public Health Work Group in place since 1996 and currently partners with the CDC to work on vaccine surveillance and safety assessment research. In addition, AHIP focuses on emergency preparedness related to bioterrorism and periodically issues public health updates for its member plans. Another possible partner is the Council for Affordable Quality Health Care (CAQH). Including 22 of the largest national and regional health plans, its member organizations insure more than 100 million Americans. Although less than 5 years old, CAQH is establishing a track record of public awareness initiatives, the most notable of which is a joint effort with the CDC to promote the appropriate use of antibiotics. The strengths of these national organizations could also be complemented by a series of partnerships with state-based health plan associations

OCR for page 141
The Threat of Pandemic Influenza: Are We Ready? - Workshop Summary that are closer to local public health agencies and often emphasize preventive care and quality. Should a public–private partnership in pandemic planning be pursued? The advantages are persuasive. Collaboration between public and private entities will bring different techniques and skill sets to bear on public health challenges while fostering innovation. Such partnerships seem likely to increase the chance for success in planning for and managing a future influenza pandemic. REFERENCES Almog Y, Shefer A, Novack V, Maimon N, Barski L, Eizinger M, Friger M, Zeller L, Danon A. 2004. Prior statin therapy is associated with a decreased rate of severe sepsis. Circulation 110:880–885. Barnett JM, Cadman A, Gor D, Dempsey M, Walters M, Candlin A, Tisdale M, Morley PJ, Owens IJ, Fenton RJ, Lewis AP, Claas EC, Rimmelzwaan GF, De Groot R, Osterhaus AD. 2000. Zanamivir susceptibility monitoring and characterization of influenza virus clinical isolates obtained during phase II clinical efficacy studies. Antimicrob Agents Chemother 44:78–87. Bean WJ, Thelkeld SC, Webster RG. 1989. Biologic potential of amantadine-resistant influenza A virus in an avian model. J Infect Dis 159:1050–1056. Boivin G, Goyette N, Hardy I, Aoki FY, Wagner A, Trottier S. 2000. Rapid antiviral effect of inhaled zanamivir in the treatment of naturally occurring influenza in otherwise healthy adults. J Infect Dis 181:1471–1474. Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, Joyal SV, Hill KA, Pfeffer MA, Skene AM; Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators. 2004. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 350:1495–1504. Carr J, Herlocher L, Elias S, Harrison S, Gibson V, Clark L, Roberts N, Ives J, Monto AS. 2001. Influenza virus carrying an R292K mutation in the neuraminidase gene is not transmitted in ferrets. Antiviral Res 50:A85. Cheung CY, Poon LL, Lau AS, Luk W, Lau YL, Shortridge KF, Gordon S, Guan Y, Peiris JS. 2002. Induction of proinflammatory cytokines in human macrophages by influenza A (H5N1) viruses: A mechanism for the unusual severity of human disease? Lancet 360:1831–1837. Chiron Corporation. 2004. Chiron to Produce Further Pandemic-Like Influenza Vaccines for National Institutes of Health Clinical Studies. [Online]. Available: http://phx.corporate-ir.net/phoenix.zhtml?c=105850&p=irol-newsArticle&ID=604514&highlight= [accessed November 10, 2004]. CPMP (Committee for Proprietary Medicinal Products). 1997. Note for Guidance on Harmonization of Requirements for Influenza Vaccines. CPMP/BWP/214/96 Circular No. 96-0666, pp. 1–2. [Online]. Available: http://www.emea.eu.int/pdfs/human/bwp/021496en.pdf [accessed December 17, 2004]. CPMP. 2004a. Guideline on Dossier Structure and Content for Pandemic Influenza Vaccine Marketing Authorisation Applications. [Online]. Available: http://www.emea.eu.int/pdfs/human/veg/4710703en.pdf [accessed December 17, 2004].

OCR for page 141
The Threat of Pandemic Influenza: Are We Ready? - Workshop Summary CPMP. 2004b. Guideline on Submission of Marketing Authorisation Applications for Pandemic Influenza Vaccine Through the Centralized Procedure. [Online]. Available: http://www.emea.eu.int/pdfs/human/veg/498603en.pdf [accessed December 17, 2004]. Diggory P, Fernandez C, Humphrey A, Jones V, Murphy M. 2001. Comparison of elderly people’s technique in using two dry powder inhalers to deliver zanamivir: Randomised controlled trial. BMJ 322:1–4. Doyle WJ, Skoner D, Alper CM, Allen G, Moody SA, Seroky J, Hayden FG. 1998. Effect of rimantadine treatment on clinical manifestations and otologic complications in adults experimentally infected with influenza A (H1N1) virus. J Infect Dis 177:1260–1265. Englund JA, Champlin RE, Wyde PR, Kantarjian H, Atmar RL, Tarrand J, Yousuf H, Regnery H, Klimov AI, Cox NJ, Whimbey E. 1998. Common emergence of amantadine and rimantadine resistant influenza A viruses in symptomatic immunocompromised adults. Clin Infect Dis 26:1418–1424. Fedson DS. 2003a. Pandemic influenza and the global vaccine supply. Clin Infec Dis 36: 1552–1561. Fedson DS. 2003b. Pandemic flu vaccine trials and reverse genetics: Foundation for effective response to next pandemic. Ensuring an adequate global supply of influenza vaccine. Infect Dis News 4:13. Ferguson NM, Mallett S. 2001. An epidemiological model of influenza to investigate the potential transmission of drug resistant virus during community use of antiviral treatment of influenza. Antiviral Res 50:A85. Fidler DP. 2004. Germs, governance, and global health in the wake of SARS. J Clin Invest 113:799–804. Fodor E, Devenish L, Engelhardt OG, Palese P, Brownlee GG, Garcia-Sastre A. 1999. Rescue of influenza A virus from recombinant DNA. J Virol 73:9679–9682. Galbraith AW, Oxford JS, Schild GC, Watson GI. 1969. Study of L-adamantanamine hydrochloride used prophylactically during the Hong Kong influenza epidemic in the family environment. Bull WHO 41:677–682. Galbraith AW, Oxford JS, Schild GC, Potter CW, Watson GI. 1971. Therapeutic effect of L-adamantanamine hydrochloride in naturally occurring influenza A 2-Hong Kong infection. A controlled double-blind study. Lancet 2:113–115. Gravenstein S, Drinka P, Osterweil D, Schilling M, McElhaney JE, Elliott M, Hammond J, Keene O, Krause P, Flack N. 2000. A multicenter prospective double-blind randomized controlled trial comparing the relative safety and efficacy of zanamivir to rimantadine for nursing home influenza outbreak control. In: Abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology. P. 270. Gubareva LV, Matrosovich MN, Brenner MK, Bethell R, Webster RG. 1998. Evidence for zanamivir resistance in an immunocompromised child infected with influenza B virus. J Infect Dis 178:1257–1262. Gubareva LV, Kaiser L, Hayden FG. 2000. Influenza virus neuraminidase inhibitors. Lancet 355:827–835. Hall CB, Dolin R, Gala CL, Markovitz DM, Zhang YQ, Madore PH, Disney FA, Talpey WB, Green JL, Francis AB, et al. 1987. Children with influenza A infection: Treatment with rimantadine. Pediatrics 80:275–282. Hay AJ. 1996. Amantadine and rimantadine-mechanisms. In: Richman DD, ed. Antiviral Drug Resistance. Chichester, United Kingdom: John Wiley & Sons Ltd. Pp. 43–58. Hayden FG. 1996. Amantadine and rimantadine-clinical aspects. In: Richman DD, ed. Antiviral Drug Resistance. Chichester, United Kingdom: John Wiley & Sons Ltd. Pp. 59–77. Hayden FG. 1997. Antivirals for pandemic influenza. J Infect Dis 176(Suppl I):S56–S61. Hayden FG. 2001. Perspectives on antiviral use during pandemic influenza. Philos Trans R Soc Lond B Biol Sci. 356(1416):1877–1884.

OCR for page 141
The Threat of Pandemic Influenza: Are We Ready? - Workshop Summary Hayden FG, Aoki FY. 1999. Amantadine, rimantadine, and related agents. In: Yu VL, Merigan TC, Barriere SL, eds. Antimicrobial Therapy and Vaccines. Baltimore, MD: Williams and Wilkins. Pp. 1344–1365. Hayden FG, Belshe RB, Clover RD, Hay AJ, Oakes MG, Soo W. 1989. Emergence and apparent transmission of rimantadine-resistant influenza A virus in families. N Engl J Med 321:1696–1702. Hayden FG, Treanor JJ, Fritz RS, Lobo M, Betts RF, Miller M, Kinnersley N, Mills RG, Ward P, Straus SE. 1999. Use of the oral neuraminidase inhibitor oseltamivir in experimental influenza: Randomized controlled trials for prevention and treatment. JAMA 282:1240–1246. Hayden FG, Gubareva LV, Monto AS, Klein TC, Elliot MJ, Hammond JM, Sharp SJ, Ossi MJ. 2000. Inhaled zanamivir for prevention of influenza in families. Zanamivir Family Study Group. N Eng J Med 343:1282–1289. Hehme N, Engelmann H, Kunzel W, Neumeier E, Sanger R. 2002. Pandemic preparedness: Lessons learnt from H2N2 and H9N2 candidate vaccines. Med Microbiol Immunol (Berl) 191:203–208. Hehme N, Engelmann H, Kuenzel W, Neumeier E, Saenger R. 2004. Immunogenicity of a monovalent, aluminum-adjuvanted influenza whole virus vaccine for pandemic use. Virus Res 103:163–171. Hollis A. 2002. The link between publicly funded health care and compulsory licensing. CMAJ 167:765–766. Iwahashi J, Tsuji K, Ishibashi T, Kajiwara J, Imamura Y, Mori R, Hara K, Kashiwagi T, Ohtsu Y, Hamada N, Maeda H, Toyoda M, Toyoda T. 2001. Isolation of amantadine resistant influenza A viruses (H3N2) from patients following administration of amantadine in Japan. J Clin Microbiol 39:1652–1653. Julkunen I, Sareneva T, Pirohonen J, Ronni T, Melen K, Matikainen S. 2001. Molecular pathogenesis of influenza A virus infection and virus-induced regulation of cytokine gene expression. Cytokine Growth Factor Rev 12:171–180. Kaiser L, Keene ON, Hammond J, Elliott M, Hayden FG. 2000. Impact of zanamivir on antibiotics use for respiratory events following acute influenza in adolescents and adults. Arch Intern Med 160:3234–3240. Keyser LA, Karl M, Nafziger AN, Bertino JS Jr. 2000. Comparison of central nervous system adverse effects of amantadine and rimantadine used as sequential prophylaxis of influenza A in elderly nursing home patients. Arch Intern Med 160:1485–1488. Knight V, Fedson D, Baldini J, Douglas RG, Couch RB. 1970. Amantadine therapy of epidemic influenza A2-Hong Kong. Infect Immun 1:200–204. Madjid M, Naghavi M, Litovsky S, Casscells SW. 2003. Influenza and cardiovascular disease. A new opportunity for prevention and the need for further studies. Circulation 108:2730–2736. McCullers JA, Rehg JE. 2002. Lethal synergism between influenza virus and Streptococcus pneumoniae: Characterizations of a mouse model and the role of platelet-activating factor receptor. J Infect Dis 186:341–350. McKimm-Breschkin JL. 2000. Resistance of influenza viruses to neuraminidase inhibitors—a review. Antiviral Res 47:1–17. Meltzer MI, Cox NJ, Fukuda K. 1999. The economic impact of pandemic influenza in the United States: Priorities for intervention. EID 5:659–671. Merx MW, Liehn EA, Janssens U, Lutticken R, Schrader J, Hanrath P, Weber C. 2004. HMG-CoA reductase inhibitor simvastatin profoundly improves survival in a murine model of sepsis. Circulation 109:2560–2565. Monick M, Powers L, Butler S, Hunninghake GW. 2003. Inhibition of Rho family GTPases results in increased TNF-alpha production after lipopolysaccharide exposure. J Immunol 171:2625–2630.

OCR for page 141
The Threat of Pandemic Influenza: Are We Ready? - Workshop Summary Monto AS, Gunn RA, Bandyk MG, King CL. 1979. Prevention of Russian influenza by amantadine. JAMA 241:1003–1007. Monto AS, Robinson DP, Herlocher ML, Hinson JM Jr, Elliott MJ, Crisp A. 1999a. Zanamivir in the prevention of influenza among healthy adults: A randomized controlled trial. JAMA 282:31–35. Monto AS, Webster A, Keene O. 1999b. Randomized, placebo-controlled studies of inhaled zanamivir in the treatment of influenza A and B: Pooled efficacy analysis. J Antimicrob Chemother 44(Suppl B):23–29. Murphy K, Eivindson A, Pauksens K, Stein WJ, Tellier G, Watts R, Leophonte P, Sharp SJ, Loeschel E. 2000. Efficacy and safety of inhaled zanamivir for the treatment of influenza in patients with asthma or chronic obstructive pulmonary disease. Clin Drug Invest 20:337–349. Nafta I, Turcanu AG, Braun I, Companetz W, Simionescu A, Birt E, Florea V. 1970. Administration of amantadine for the prevention of Hong Kong influenza. Bull WHO 42:423–427. NIAID (National Institute of Allergy and Infectious Diseases). 2004. NIAID Taps Chiron to Develop Vaccine Against H9N2 Avian Influenza. Award Part of NIAID Pandemic Influenza Preparedness Program. [Online]. Available: http://www2.niaid.nih.gov/newsroom/releases/h9n2.htm [accessed November 10, 2004]. Nichol KL, Nordin J, Mullooly J, Lask R, Fillbrandt K, Iwane M. 2003. Influenza vaccination and reduction in hospitalizations for cardiac disease and stroke among the elderly. N Engl J Med 348:1322–1332. Node K, Fujita M, Kitakaze M, Hori M, Liao JK. 2003. Short-term statin therapy improves cardiac function and symptoms in patients with idiopathic dilated cardiomyopathy. Circulation 108:839–843. Novak K. 2003. The WTO’s balancing act. J Clin Invest 112:1269–1273. Official Journal of the European Community. 1995. Article 7b, Regulation 541/95. European Union: Publications Office of the European Union. Official Journal of the European Community. 2003. Article 8, Regulation 1085/2003. European Union: Publications Office of the European Union. Oker-Blom N, Hovi T, Leinikki P, Palosuo T, Pettersson R, Suni J. 1970. Protection of man from natural infection with influenza A2 Hong Kong virus by amantadine: A controlled field trial. BMJ 3:676–678. Patriarca PA, Cox NJ. 1997. Influenza pandemic preparedness plan for the United States. J Infect Dis 176(Suppl 1):S4–S7. Peiris JS, Yu WC, Leung CW, Cheung CY, Ng WF, Nicholls JM, Ng TK, Chan KH, Lai ST, Lim WL, Yuen KY, Guan Y. 2004. Re-emergence of fatal human influenza A subtype H5N1 disease. Lancet 363:617–619. Peters PH, Gravenstein S, Norwood P, DeBock V, Van Cauter A, Gibbens M, van Planta T-A, Ward P. 2001. Long term use of oseltamivir for the prophylaxis of influenza in a vaccinated frail older population. J Am Geriatric Soc 49:1–7. Pettersson RF, Hellstrom PE, Penttinen K, Pyhala R, Tokola O, Vartio T, Visakorpi R. 1980. Evaluation of amantadine in the prophylaxis of influenza A (H1N1) virus infection: A controlled field trial among young adults and high-risk patients. J Infect Dis 142:377–383. Plotkin E, Bernheim J, Ben-Chetrit S, Mor A, Korzets Z. 2000. Influenza vaccine—a possible trigger of rhabdomyolysis induced acute renal failure due to the combined use of cerivastatin and bezafibrate. Nephrol Dial Transplant 15:740–741. Quarles JM, Couch RB, Cate TR, Goswick CB. 1981. Comparison of amantadine and rimantadine for prevention of type A (Russian) influenza. Antiviral Res 1:149–155.

OCR for page 141
The Threat of Pandemic Influenza: Are We Ready? - Workshop Summary Reichert TA, Simonsen L, Sharma A, Pardo SA, Fedson DS, Miller MA. 2004. Influenza and the winter increase in mortality in the United States, 1959–1999. Am J Epidemiol 160:492–502. Sacks FM. 2004. High-intensity statin treatment for coronary heart disease. JAMA 291:1132–1134. Schoch-Spana M. 2000. Implications of pandemic influenza for bioterrorism response. Clinical Infectious Diseases 31:1409–1413. [Online]. Available: http://www.wipo.int. Smorodintsev AA, Karpuhin GI, Zlydnikov DM, Malyseva AM, Svecova EG, Burov SA, Hramcova LM, Romanov JA, Taros LJ, Ivannikov JG, Novoselov SD. 1970. The prophylactic effectiveness of amantadine hydrochloride in an epidemic of Hong Kong influenza in Leningrad in 1969. Bull WHO 42:865–872. Stilianakis NI, Perelson AS, Hayden FG. 1998. Emergence of drug resistance during an influenza epidemic: Insights from a mathematical model. J Infect Dis 177:863–873. Subbarao K, Chen H, Swayne D, Mingay L, Fodor E, Brownlee G, Xu X, Lu X, Katz J, Cox N, Matsuoka Y. 2003. Evaluation of a genetically modified reassortant H5N1 influenza A virus vaccine candidate generated by plasmid-based reverse genetics. Virology 305:192–200. Tisdale M. 2000. Monitoring of viral susceptibility: New challenges with the development of influenza NA inhibitors. Rev Med Virol 10:45–55. Topol EJ. 2004. Intensive statin therapy—a sea change in cardiovascular prevention. N Engl J Med 350:1562–1564. Treanor JJ, Hayden FG, Vrooman PS, Barbarash R, Bettis R, Riff D, Singh S, Kinnersley N, Ward P, Mills RG. 2000. Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: A randomized controlled trial. U.S. Oral Neuraminidase Study Group. JAMA 283:1016–1024. VanVoris LP, Betts RF, Hayden FG, Christmas WA, Douglas RGJ. 1981. Successful treatment of naturally occurring influenza A/USSR/77 HIN1. JAMA 245:1128–1131. Walker JB, Hussey EK, Treanor JJ, Montalvo A, Hayden FG. 1997. Effects of the neuraminidase inhibitor zanamivir on otologic manifestations of experimental human influenza. J Infect Dis 176:1417–1422. Webby RJ, Perez DR, Coleman JS, Guan Y, Knight JH, Govorkova EA, McClain-Moss LR, Peiris JS, Rehg JE, Tuomanen EI, Webster RG. 2004. Responsiveness to a pandemic alert: Use of reverse genetics for rapid development of influenza vaccines. Lancet 363:1099–1103. Welliver R, Manto AS, Carewicz O, Schatteman E, Hassman M, Hedrick J, Huson L, Ward P, Oxford JS. 2001. Effectiveness of oseltamivir in preventing influenza in household contacts. JAMA 285:748–754. Whitley RJ, Hayden FG, Reisinger K, Young N, Dutkowski R, Ipe D, Mills RG, Ward P. 2001. Oral oseltamivir treatment of influenza in children. Pediatr Infect Dis J 20:127–133. WHO (World Health Organization). 2004 (April 27). WHO Consultation on Priority Public Health Interventions Before and During an Influenza Pandemic. [Online]. Available: http://www.who.int/csr/disease/avian_influenza/guidelines/pandemicconsultation/en/ [accessed December 17, 2004]. Wood JM. 2001. Developing vaccines against pandemic influenza. Philos Trans R Soc Lond B Biol Sci 356:1953–1960. Wood JM, Lewandowski RA. 2003. The influenza vaccine licensing process. Vaccine 21:1786–1788. Ziegler T, Hemphill ML, Ziegler ML, Perez-Oronoz G, Klimov AI, Hampson AW, Regnery HL, Cox NJ. 1999. Low incidence of rimantadine resistance in field isolates of influenza A viruses. J Infect Dis 180:935–939.