PandemieGrippaleV1, Istex, Corpus, bibRecord, 001A75

The Risk of Seasonal and Pandemic Influenza: Prospects for Control

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The Risk of Seasonal and Pandemic Influenza: Prospects for Control

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Clinical Infectious Diseases [ 1058-4838 ] ; 2009.

RBID : ISTEX:7908B91BE9B706CECD5EBC1D6F6DCF79874445E0

Abstract

Seasonal influenza is an underappreciated cause of morbidity and mortality in the United States. Seasonal vaccination of individuals in groups at high risk of complications has long been recommended. However, there has been a gradual expansion of the recommended groups for annual influenza immunization in order to reduce the incidence of uncomplicated infection, to alleviate the impact of seasonal influenza on health care, and to simplify the application of recommendations. The threat of an influenza pandemic, heightened by recent cases of highly pathogenic avian influenza in humans, requires continued efforts in preparedness. Strategies for the control of pandemic influenza must include vaccines, antiviral drugs, and nonpharmaceutical interventions like school closure and voluntary quarantine around cases. The prophylactic efficacy of neuraminidase inhibitors, previously observed in household studies, suggests that they will be a useful adjunct to voluntary quarantine. Stockpiles of antiviral drugs are being established for therapeutic and perhaps preventive use for pandemic influenza.

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DOI: 10.1086/591853

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ISTEX:7908B91BE9B706CECD5EBC1D6F6DCF79874445E0

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<front><div type="abstract">Seasonal influenza is an underappreciated cause of morbidity and mortality in the United States. Seasonal vaccination of individuals in groups at high risk of complications has long been recommended. However, there has been a gradual expansion of the recommended groups for annual influenza immunization in order to reduce the incidence of uncomplicated infection, to alleviate the impact of seasonal influenza on health care, and to simplify the application of recommendations. The threat of an influenza pandemic, heightened by recent cases of highly pathogenic avian influenza in humans, requires continued efforts in preparedness. Strategies for the control of pandemic influenza must include vaccines, antiviral drugs, and nonpharmaceutical interventions like school closure and voluntary quarantine around cases. The prophylactic efficacy of neuraminidase inhibitors, previously observed in household studies, suggests that they will be a useful adjunct to voluntary quarantine. Stockpiles of antiviral drugs are being established for therapeutic and perhaps preventive use for pandemic influenza.</div>
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<profileDesc><abstract><p>Seasonal influenza is an underappreciated cause of morbidity and mortality in the United States. Seasonal vaccination of individuals in groups at high risk of complications has long been recommended. However, there has been a gradual expansion of the recommended groups for annual influenza immunization in order to reduce the incidence of uncomplicated infection, to alleviate the impact of seasonal influenza on health care, and to simplify the application of recommendations. The threat of an influenza pandemic, heightened by recent cases of highly pathogenic avian influenza in humans, requires continued efforts in preparedness. Strategies for the control of pandemic influenza must include vaccines, antiviral drugs, and nonpharmaceutical interventions like school closure and voluntary quarantine around cases. The prophylactic efficacy of neuraminidase inhibitors, previously observed in household studies, suggests that they will be a useful adjunct to voluntary quarantine. Stockpiles of antiviral drugs are being established for therapeutic and perhaps preventive use for pandemic influenza.</p>
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<corresp id="cor1">Reprints or correspondence: Dr. Arnold S. Monto, University of Michigan School of Public Health, 109 Observatory St., Ann Arbor, MI 48109-2029 (<email>asmonto@umich.edu</email>
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<abstract>

<p>Seasonal influenza is an underappreciated cause of morbidity and mortality in the United States. Seasonal vaccination of individuals in groups at high risk of complications has long been recommended. However, there has been a gradual expansion of the recommended groups for annual influenza immunization in order to reduce the incidence of uncomplicated infection, to alleviate the impact of seasonal influenza on health care, and to simplify the application of recommendations. The threat of an influenza pandemic, heightened by recent cases of highly pathogenic avian influenza in humans, requires continued efforts in preparedness. Strategies for the control of pandemic influenza must include vaccines, antiviral drugs, and nonpharmaceutical interventions like school closure and voluntary quarantine around cases. The prophylactic efficacy of neuraminidase inhibitors, previously observed in household studies, suggests that they will be a useful adjunct to voluntary quarantine. Stockpiles of antiviral drugs are being established for therapeutic and perhaps preventive use for pandemic influenza.</p>

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<sec id="sec1">

<title>Risk Factors for Complications of Seasonal Influenza</title>

<p>Seasonal influenza is an underappreciated cause of morbidity and mortality in the United States. Seasonal influenza is estimated to result in >200,000 hospitalizations and 36,000 deaths annually [<xref ref-type="bibr" rid="ref1">1</xref>
]. Although primary and secondary cases of pneumonia are commonly regarded as the most typical complications of seasonal influenza that require hospitalization, a landmark analysis performed by Thompson et al. [<xref ref-type="bibr" rid="ref1">1</xref>
] demonstrated that the most common discharge diagnoses after hospitalization for influenza were vascular and respiratory complications other than pneumonia. Included in these diagnoses are the <italic>International Classification of Diseases</italic>
 codes corresponding to chronic obstructive pulmonary disease and ischemic heart disease. Over the 22 influenza seasons reviewed by Thompson et al. [<xref ref-type="bibr" rid="ref1">1</xref>
], diagnoses of vascular disease and other respiratory disease were, on average, ∼7 times more common than diagnoses of pneumonia and influenza. The failure to understand the true extent of influenza-related complications and deaths has permitted, in part, this vaccine-preventable disease to have a more extensive impact on individuals and the health care system than otherwise would be the case.</p>

<p>Elderly persons, very young persons, and others with underlying conditions, whatever their age, as well as pregnant women are among the groups at increased risk of complications from influenza virus infection. It is not a surprise that rates of hospitalization due to influenza-related cardiorespiratory complications increase with age (<xref ref-type="fig" rid="fig1">figure 1</xref>
). What is a bit of a surprise is the number of hospitalizations of younger individuals. Among individuals aged <65 years, hospitalization rates vary from ∼20% to ∼50% of the rate among individuals aged 65–69 years [<xref ref-type="bibr" rid="ref2">2</xref>
]. This is especially the case among young children. On the other hand, death from seasonal influenza in younger age groups is rare in the United States (<xref ref-type="fig" rid="fig2">figure 2</xref>
) [<xref ref-type="bibr" rid="ref2">2</xref>
].</p>

<p>Currently, there is debate about how well influenza vaccination works in elderly persons [<xref ref-type="bibr" rid="ref3">3</xref>
]. Vaccine efficacy is never 100%, even among otherwise-healthy adults aged <65 years [<xref ref-type="bibr" rid="ref4">4</xref>
]. Studies conducted before influenza vaccine had become a Medicare-covered benefit suggest that age is a surrogate for immune senescence. In an evaluation of influenza vaccine effectiveness in the prevention of influenza-like illness among nursing home residents in lower Michigan in 1989–1990, vaccination was 44% effective in the prevention of influenza-like illness among residents aged 65–84 years and 35% effective in the prevention of influenza-like illness among residents aged >85 years; the latter figure was not statistically significantly different from 0 [<xref ref-type="bibr" rid="ref5">5</xref>
]. In the United States, the mean age of nursing home residents is ∼85 years, and, even in facilities with a well-vaccinated population, outbreaks of influenza A(H3N2) virus infection continue to occur. Influenza A(H3N2) virus infection is associated with higher rates of mortality than is infection with either A(H1N1) or B strains. Nevertheless, numerous studies have shown that seasonal vaccination reduces rates of hospitalization and death among nursing home residents, even if it does not always prevent milder infection [<xref ref-type="bibr" rid="ref5">5</xref>
–<xref ref-type="bibr" rid="ref7">7</xref>
]. In the future, more-effective seasonal vaccines may become available as an outgrowth of the development of new platforms and approaches to vaccines against pandemic influenza.</p>

<p>Children aged <6 months are a particularly vulnerable population and, at present, cannot be vaccinated. Since these children cannot be vaccinated, the US Advisory Committee on Immunization Practices (ACIP) recommends vaccination of family members in order to indirectly protect these children [<xref ref-type="bibr" rid="ref4">4</xref>
]. Although pediatric deaths from influenza are rare in developed nations (except during pandemics), this may not be the case in developing nations. During the 2006–2007 influenza season in the United States, the overall rate of deaths was lower than expected; however, coinfection with <italic>Staphylococcus aureus</italic>
 and influenza virus resulted in 21 pediatric deaths, a significant increase over the 2 preceding seasons [<xref ref-type="bibr" rid="ref8">8</xref>
].</p>

<p>In recent years, pregnant women have been included among the recommended groups for influenza vaccination. This recommendation now includes pregnant women who are not otherwise at risk for influenza-related complications owing to some other medical condition. Data from the Tennessee Medicaid program showed that pregnant women aged 15–44 years who were at low risk for influenza-related complications experience high rates of influenza-related acute cardiopulmonary events (<xref ref-type="fig" rid="fig3">figure 3</xref>
) [<xref ref-type="bibr" rid="ref9">9</xref>
]. Influenza virus infection during pregnancy during a pandemic is associated with many other complications. During the 1918 influenza pandemic, higher rates of spontaneous abortion and fetal abnormalities, among other complications, were recorded [<xref ref-type="bibr" rid="ref10">10</xref>
]. Pregnant women may be vaccinated at any time during pregnancy [<xref ref-type="bibr" rid="ref4">4</xref>
, <xref ref-type="bibr" rid="ref11">11</xref>
]. Some intriguing data from Bangladesh suggest that maternal influenza immunization may offer protection to newborns for the first 6 months of life or even longer, via passive transfer of influenza virus antibodies [<xref ref-type="bibr" rid="ref12">12</xref>
]. Since young infants cannot be vaccinated against influenza, this provides another excellent reason to vaccinate pregnant women.</p>

</sec>

<sec id="sec2">

<title>Changes in Seasonal Influenza Vaccination Policies and Trends in Vaccination Rates</title>

<p>In the past, the policies adopted by the ACIP were weighted toward the prevention of influenza virus infection in individuals at high risk of complications. Current sentiment favors the prevention of illness in the community. The ACIP now suggests that annual vaccination for all persons, including school-aged children, who want to reduce the risk of becoming ill with influenza is appropriate. However, the ACIP prioritizes vaccination of those who can transmit infection to others who are at high risk of serious outcomes [<xref ref-type="bibr" rid="ref4">4</xref>
]. At one time, Japan required vaccination of school-aged children but stopped because of parental concerns about possible adverse effects and various medicolegal issues. While this policy was in place, it may have translated into a decline in the incidence of deaths in the older adult population, which surged again when the policy changed [<xref ref-type="bibr" rid="ref13">13</xref>
]. The United States and several other countries now are considering adopting a policy of vaccination of school-aged children. Some data also support this strategy for reducing the incidence of illness among household contacts [<xref ref-type="bibr" rid="ref4">4</xref>
, <xref ref-type="bibr" rid="ref14">14</xref>
]. This does not mean that we should stop vaccinating elderly persons while moving to vaccination of younger individuals. In the last influenza pandemic (1968–1969), studies done in Michigan communities found that about half of influenza virus isolates came from people aged >40 years, even though ∼85% of school-aged children had been vaccinated [<xref ref-type="bibr" rid="ref15">15</xref>
]. Globally, the supply of seasonal influenza vaccine is increasing each year; thus, the concern that there will not be enough vaccine to supply US residents included in the expanded recommendations is diminished. The Canadian province of Ontario recently instituted universal influenza vaccination [<xref ref-type="bibr" rid="ref16">16</xref>
]. Seasonal influenza vaccination rates have increased among the general public, individuals with at least 1 chronic health condition (i.e., “high-risk persons”), and health care workers since this policy was instituted in 2000. In 2006, immunization rates varied from 21% of adults aged 18–24 years to 73% of adults aged >75 years. For hospital staff, median immunization coverage in 2006 was 57%. Policy makers in Canada and the United States eagerly await the epidemiological outcomes of this policy.</p>

<p>Vaccination rates currently are higher among adults aged >65 years than in any other group. A US survey of 5944 individuals in this age group, conducted in 2005, found that 59.6% had been vaccinated [<xref ref-type="bibr" rid="ref4">4</xref>
]. On the other hand, this same survey found that only 18.0% of 2576 adults aged 18–49 years who fell into one of the high-risk categories had been vaccinated and that healthy adults aged 18–49 years had the lowest vaccination rates of all groups surveyed, at just 9.5% [<xref ref-type="bibr" rid="ref4">4</xref>
]. Trivalent inactivated vaccine (TIV) is more effective than live-attenuated influenza vaccine (LAIV) in older individuals [<xref ref-type="bibr" rid="ref17">17</xref>
], whereas the reverse is true in young children [<xref ref-type="bibr" rid="ref18">18</xref>
]. In healthy adults, TIV efficacy is probably similar to the efficacy of LAIV but may vary from year to year [<xref ref-type="bibr" rid="ref5">5</xref>
].</p>

<p>The increased emphasis on influenza vaccination for children aged <5 years stems mainly from hospitalization data but also from community clusters of influenza-related deaths occurring among children that were observed during the 2003–2004 influenza season. In that season, 153 deaths were reported among children aged <18 years, with the median age being 3 years [<xref ref-type="bibr" rid="ref19">19</xref>
]. Of these deaths, 96 (63%) were of children aged <5 years, and 43 (28%) were of children aged 6–23 months. Distressingly, 47% of the children who died had been healthy previously; 20% had some underlying condition, although not a condition recognized at that time as placing them in a high-risk category in accordance with the ACIP guidelines for that season. Likewise, a retrospective study of pediatric intensive care unit admissions in the state of California for the years 2003–2005 found that a significant proportion of admitted patients did not belong to any of the groups for which seasonal influenza vaccination was routinely recommended [<xref ref-type="bibr" rid="ref20">20</xref>
]. This study also found that half of all fatalities (6 of 12) occurred among children with secondary bacterial infections. As indicated above, LAIV is more effective than TIV in young children, including those lacking prior immunity [<xref ref-type="bibr" rid="ref18">18</xref>
, <xref ref-type="bibr" rid="ref21">21</xref>
, <xref ref-type="bibr" rid="ref22">22</xref>
]. In 2007, approval for an inhalable LAIV was expanded to include children aged 2–5 years. As of 2005, only 33.4% of children aged <2 years had been vaccinated [<xref ref-type="bibr" rid="ref4">4</xref>
].</p>

<p>Vaccination of health care workers may prevent influenza transmission to the most vulnerable institutionalized and hospitalized populations who may not mount a good immune response. Current vaccination rates among health care workers are low. A survey of 2135 US health care workers conducted in 2005 found that only 33.5% had been vaccinated [<xref ref-type="bibr" rid="ref4">4</xref>
]. In an audience survey of infectious disease specialists and related health care workers, conducted at a satellite symposium held in conjunction with the 45th Annual Meeting of the Infectious Diseases Society of America (IDSA), only 55% of respondents stated that their institution has a mandatory vaccination policy for all health care workers, whereas 39% had such a policy for all staff working in critical care areas (International Medical Press, unpublished data). The IDSA mandates influenza vaccination of health care workers [<xref ref-type="bibr" rid="ref23">23</xref>
].</p>

</sec>

<sec id="sec3">

<title>Prevention and Treatment of Pandemic Influenza</title>

<p>A concomitant benefit of the expansion of groups for whom seasonal influenza vaccination is recommended is the recognition that ensuring sufficient vaccine for a pandemic requires that sufficient production for seasonal influenza vaccination already exists and provides an economically sustainable market for these vaccines. The United States and other countries regard vaccines as one part of a layered containment strategy for pandemic influenza. Antiviral medications and nonpharmaceutical interventions (NPIs) are the other 2 key parts. A pandemic is an unpredictable event in terms of both cause and timing, but the short period of time between the evolution of a pandemic virus and an outbreak implies that the rapid development of a new vaccine, possibly the prepandemic stockpiling of vaccine, and the prepandemic stockpiling of antiviral drugs will all be needed.</p>

<p>Pandemics differ in the degree and pattern of their morbidity and mortality (<xref ref-type="fig" rid="fig4">figure 4</xref>
) [<xref ref-type="bibr" rid="ref24">24</xref>
]. During the 1957 pandemic, the greatest mortality was among traditionally high-risk groups. In contrast, during the 1918 pandemic, the greatest mortality was among younger, healthy adults. After careful analysis, recent data confirm that older individuals were relatively spared (<xref ref-type="fig" rid="fig5">figure 5</xref>
) [<xref ref-type="bibr" rid="ref25">25</xref>
]. The first-quarter wave was similar to a seasonal outbreak and had the typical mortality pattern in terms of age distribution. The major pandemic wave occurred mainly in the fourth quarter, when the mortality pattern showed a disproportionately greater impact on children and adults aged <40 years [<xref ref-type="bibr" rid="ref25">25</xref>
]. These different mortality patterns clearly pose a challenge for determining vaccine recommendations, if the risk groups themselves may vary so greatly.</p>

<p>Some of the current research being done on vaccines against H5 strains of influenza A virus may lead to seasonal vaccines with improved efficacy. In trying to produce a vaccine against H5 strains, some manufacturers have used adjuvant technology originally designed to produce better efficacy in elderly persons. Accordingly, the adjuvanted vaccines now in development for influenza A(H5N1) virus will need to be evaluated carefully to see whether they promote better immunity in older individuals, compared with similar, nonadjuvanted vaccines.</p>

<p>The Centers for Disease Control and Prevention, together with a number of other federal agencies, issued new pandemic planning guidance for community mitigation in February 2007 [<xref ref-type="bibr" rid="ref26">26</xref>
]. This report categorizes the severity of pandemics and the response to each category (<xref ref-type="fig" rid="fig6">figure 6</xref>
 and <xref ref-type="fig" rid="tab1">table 1</xref>
). Under these classifications, pandemics such as those of 1957 and 1968–1969 would fall into category 2, whereas the 1918 pandemic would be between categories 4 and 5 (<xref ref-type="fig" rid="fig6">figure 6</xref>
) [<xref ref-type="bibr" rid="ref26">26</xref>
].</p>

<p>NPIs include such strategies as school closure, public gathering bans, isolation or quarantine, masks, hand-washing precautions, and so on. School closures and public gathering bans also are referred to as social distancing measures. In a severe pandemic, the recommendations call for social distancing and postexposure antiviral prophylaxis targeted to close contacts of case patients (<xref ref-type="fig" rid="tab1">table 1</xref>
) [<xref ref-type="bibr" rid="ref26">26</xref>
]. The efficacy and timing of NPIs, relative to the time at which a pandemic is recognized in a particular location, are not well established. Markel et al. [<xref ref-type="bibr" rid="ref27">27</xref>
] examined weekly death rates versus the type and duration of NPIs used in 4 US cities (St. Louis, New York, Denver, and Pittsburgh) during the 1918 pandemic and found that death rates appeared to be reduced the most by prompt school closure and, to a lesser degree, by public gathering bans. In univariate analyses, reductions in peak death rates began within 3–4 days following the institution of school closure in the 3 cities that adopted this strategy (all but New York), whereas reductions began 3–8 days following public gathering bans in the same cities. Contrary to expectation, isolation or quarantine of case patients did not appear to have as much impact as school closure and public gathering bans, and the value of all other NPIs was uncertain. Reduced death rates were not observed until isolation or quarantine measures had been imposed for a week or longer [<xref ref-type="bibr" rid="ref27">27</xref>
]. To date, few controlled clinical trials to assess the efficacy of specific NPIs have been undertaken. Currently, at least 3 trials are planned or ongoing to determine whether face masks, hand sanitizers, and behavioral interventions are useful in preventing the transmission of seasonal influenza [<xref ref-type="bibr" rid="ref28">28</xref>
–<xref ref-type="bibr" rid="ref30">30</xref>
].</p>

<p>In the current interim guidelines, postexposure prophylaxis was recommended as an adjunct to voluntary quarantine. Postexposure prophylaxis was developed on the basis of experience with prophylaxis among family members given zanamivir (Relenza; GlaxoSmithKline) or oseltamivir (Tamiflu; Roche Laboratories) during an outbreak of seasonal influenza. These studies showed that prophylactic treatment of household members with either agent reduced secondary transmission by 79%–89%, even when the index case patient did not receive treatment [<xref ref-type="bibr" rid="ref31">31</xref>
–<xref ref-type="bibr" rid="ref34">34</xref>
]. Antiviral drugs are one cornerstone in the management of pandemic influenza, since they may be the only specific treatments available during the early stages of a pandemic. National and state stockpiles of antiviral drugs are being established, with an eventual goal of 81 million courses of treatment available within the United States [<xref ref-type="bibr" rid="ref35">35</xref>
]. Most of the stockpiled drugs are planned for use in treating ill persons, and additional drugs would need to be procured if wide-scale postexposure prophylaxis was to be used. As of July 2007, the US Department of Health and Human Services had reached 72% of its antiviral stockpile goal, but the states had met only 38.7% of their collective goal [<xref ref-type="bibr" rid="ref35">35</xref>
].</p>

</sec>

<sec id="sec4">

<title>Future Trends in Influenza-Management Policies</title>

<p>Public health policy for both seasonal and pandemic influenza prevention and management is likely to evolve almost as rapidly as the virus itself. The 3 cornerstones of pandemic influenza management—vaccination, antiviral therapy, and NPIs—are each undergoing significant, evidence-driven revisions. Recognition of the true burden of disease imposed by influenza has promoted greater emphasis on preventing uncomplicated seasonal disease through broadened vaccination guidelines. Ongoing research efforts toward the rapid development of candidate pandemic vaccines may have the concomitant benefit of permitting more-rapid production of seasonal vaccines, should changes in prevalent strains occur late. Another benefit of ongoing vaccine-research efforts is likely to be the development of vaccines with greater efficacy in elderly persons. Generous grants by the US Department of Health and Human Services also are funding the development of new antiviral drugs for influenza. Much remains to be learned about the most effective NPIs for reducing influenza transmission. There currently is a paucity of evidence to support such practices as the use of disposable masks, hand sanitizers, and social distancing measures, but a number of clinical trials are being conducted to answer these questions. As new data become available, there is no doubt that they will be incorporated into the appropriate guidelines, to reduce the impact of both seasonal and pandemic influenza.</p>

</sec>

</body>

<back>

<ack>

<title>Acknowledgments</title>

<p><italic><bold>Financial support</bold>
</italic>
. BioCryst Pharmaceuticals, Inc., provided educational grant support to develop this article and the symposium on which it is based, “Antiviral Therapy for Influenza: Challenging the Status Quo” (San Diego), 4 October 2007.</p>

<p><italic><bold>Supplement sponsorship</bold>
</italic>
. This article was published as part of a supplement entitled “Antiviral Therapy for Influenza: Challenging the Status Quo,” jointly sponsored by the Institute for Medical and Nursing Education and International Medical Press and supported by an educational grant from BioCryst Pharmaceuticals, Inc.</p>

<p><italic><bold>Manuscript preparation</bold>
</italic>
. Margery Tamas of International Medical Press (Atlanta) provided assistance in preparing and editing the manuscript.</p>

<p><italic><bold>Potential conflicts of interest</bold>
</italic>
. A.S.M. has served as a formal advisor for Roche, GlaxoSmithKline, Solvay, and Novartis and has participated in research activities supported by Sanofi Pasteur.</p>

</ack>

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<p>Community intervention strategies, by pandemic influenza severity.</p>

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<mods version="3.6"><titleInfo><title>The Risk of Seasonal and Pandemic Influenza: Prospects for Control</title>
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<titleInfo type="alternative" contentType="CDATA"><title>The Risk of Seasonal and Pandemic Influenza: Prospects for Control</title>
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<name type="personal"><namePart type="given">Arnold S.</namePart>
<namePart type="family">Monto</namePart>
<affiliation>Department of Epidemiology, School of Public Health, and the University of Michigan Bioterrorism Preparedness Initiative, University of Michigan, Ann Arbor</affiliation>
<affiliation>E-mail: asmonto@umich.edu</affiliation>
</name>
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<originInfo><publisher>The University of Chicago Press</publisher>
<dateIssued encoding="w3cdtf">2009-01-01</dateIssued>
<copyrightDate encoding="w3cdtf">2008</copyrightDate>
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<abstract>Seasonal influenza is an underappreciated cause of morbidity and mortality in the United States. Seasonal vaccination of individuals in groups at high risk of complications has long been recommended. However, there has been a gradual expansion of the recommended groups for annual influenza immunization in order to reduce the incidence of uncomplicated infection, to alleviate the impact of seasonal influenza on health care, and to simplify the application of recommendations. The threat of an influenza pandemic, heightened by recent cases of highly pathogenic avian influenza in humans, requires continued efforts in preparedness. Strategies for the control of pandemic influenza must include vaccines, antiviral drugs, and nonpharmaceutical interventions like school closure and voluntary quarantine around cases. The prophylactic efficacy of neuraminidase inhibitors, previously observed in household studies, suggests that they will be a useful adjunct to voluntary quarantine. Stockpiles of antiviral drugs are being established for therapeutic and perhaps preventive use for pandemic influenza.</abstract>
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The Risk of Seasonal and Pandemic Influenza: Prospects for Control

The Risk of Seasonal and Pandemic Influenza: Prospects for Control

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