Ongoing outbreaks of H5N1 avian influenza in migratory waterfowl, domestic poultry, and humans in Asia during the summer of 2005 present a continuing, protean pandemic threat. We review the zoonotic source of highly pathogenic H5N1 viruses and their genesis from their natural reservoirs. The acquisition of novel traits, including lethality to waterfowl, ferrets, felids, and humans, indicates an expanding host range. The natural selection of nonpathogenic viruses from heterogeneous subpopulations cocirculating in ducks contributes to the spread of H5N1 in Asia. Transmission of highly pathogenic H5N1 from domestic poultry back to migratory waterfowl in western China has increased the geographic spread. The spread of H5N1 and its likely reintroduction to domestic poultry increase the need for good agricultural vaccines. In fact, the root cause of the continuing H5N1 pandemic threat may be the way the pathogenicity of H5N1 viruses is masked by cocirculating influenza viruses or bad agricultural vaccines.

Three worldwide (pandemic) outbreaks of influenza occurred in the 20th century: in 1918, 1957, and 1968. The latter 2 were in the era of modern virology and most thoroughly characterized. All 3 have been informally identified by their presumed sites of origin as Spanish, Asian, and Hong Kong influenza, respectively. They are now known to represent 3 different antigenic subtypes of influenza A virus: H1N1, H2N2, and H3N2, respectively. Not classified as true pandemics are 3 notable epidemics: a pseudopandemic in 1947 with low death rates, an epidemic in 1977 that was a pandemic in children, and an abortive epidemic of swine influenza in 1976 that was feared to have pandemic potential. Major influenza epidemics show no predictable periodicity or pattern, and all differ from one another. Evidence suggests that true pandemics with changes in hemagglutinin subtypes arise from genetic reassortment with animal influenza A viruses.

The "Spanish" influenza pandemic of 1918–1919, which caused ≈50 million deaths worldwide, remains an ominous warning to public health. Many questions about its origins, its unusual epidemiologic features, and the basis of its pathogenicity remain unanswered. The public health implications of the pandemic therefore remain in doubt even as we now grapple with the feared emergence of a pandemic caused by H5N1 or other virus. However, new information about the 1918 virus is emerging, for example, sequencing of the entire genome from archival autopsy tissues. But, the viral genome alone is unlikely to provide answers to some critical questions. Understanding the 1918 pandemic and its implications for future pandemics requires careful experimentation and in-depth historical analysis.

In early 1976, the novel A/New Jersey/76 (Hsw1N1) influenza virus caused severe respiratory illness in 13 soldiers with 1 death at Fort Dix, New Jersey. Since A/New Jersey was similar to the 1918–1919 pandemic virus, rapid outbreak assessment and enhanced surveillance were initiated. A/New Jersey virus was detected only from January 19 to February 9 and did not spread beyond Fort Dix. A/Victoria/75 (H3N2) spread simultaneously, also caused illness, and persisted until March. Up to 230 soldiers were infected with the A/New Jersey virus. Rapid recognition of A/New Jersey, swift outbreak assessment, and enhanced surveillance resulted from excellent collaboration between Fort Dix, New Jersey Department of Health, Walter Reed Army Institute of Research, and Center for Disease Control personnel. Despite efforts to define the events at Fort Dix, many questions remain unanswered, including the following: Where did A/New Jersey come from? Why did transmission stop?

In 1976, 2 recruits at Fort Dix, New Jersey, had an influenzalike illness. Isolates of virus taken from them included A/New Jersey/76 (Hsw1n1), a strain similar to the virus believed at the time to be the cause of the 1918 pandemic, commonly known as swine flu. Serologic studies at Fort Dix suggested that >200 soldiers had been infected and that person-to-person transmission had occurred. We review the process by which these events led to the public health decision to mass-vaccinate the American public against the virus and the subsequent events that led to the program's cancellation. Observations of policy and implementation success and failures are presented that could help guide decisions regarding avian influenza.

Influenza pandemic risk assessment is an uncertain art. The theory that influenza A virus pandemics occur every 10 to 11 years and seroarcheologic evidence of virus recycling set the stage in early 1976 for risk assessment and risk management of the Fort Dix, New Jersey, swine influenza outbreak. Additional data and passage of time proved the theory untenable. Much has been learned about influenza A virus and its natural history since 1976, but the exact conditions that lead to the emergence of a pandemic strain are still unknown. Current avian influenza events parallel those of swine influenza in 1976 but on a larger and more complex scale. Pre- and postpandemic risk assessment and risk management are continuous but separate public health functions.

The 1918 influenza pandemic has shaped research and public health for nearly a century. In 1976, the specter of 1918 loomed large when a pandemic threatened the country again. Public health officials initiated a mass vaccination campaign, but the anticipated pandemic failed to occur. An examination of the available data in 1976 and the decision to vaccinate, as well as lessons learned from the HIV/AIDS epidemic in the early 1980s, may help shape an appropriate public health response to future threats from avian influenza or other infectious diseases.

The outcome of viral infections depends on a complex set of interactions between the viruses and their hosts. Particularly, viral infection triggers specific signaling programs within the infected cells that results in substantial changes in host gene expression. While some of these changes might be beneficial for viral replication, others represent the induction of a host antiviral response. In this respect, viruses have evolved genes that counteract this initial innate antiviral response. These viral-host interactions shape the subsequent phases of the disease and influence the adaptive immune response. In influenza viruses, the nonstructural protein 1 inhibits the interferon-mediated antiviral response. The regulatory activities of this viral protein play a major role in the pathogenicity of influenza virus and appear partially responsible for the ability of influenza viruses to infect multiple animal species, which likely contributes to the generation of new pandemic viruses in humans.

Current vaccine strategies against influenza focus on generating robust antibody responses. Because of the high degree of antigenic drift among circulating influenza strains over the course of a year, vaccine strains must be reformulated specifically for each influenza season. The time delay from isolating the pandemic strain to large-scale vaccine production would be detrimental in a pandemic situation. A vaccine approach based on cell-mediated immunity that avoids some of these drawbacks is discussed here. Specifically, cell-mediated responses typically focus on peptides from internal influenza proteins, which are far less susceptible to antigenic variation. We review the literature on the role of CD4+ and CD8+ T cell–mediated immunity in influenza infection and the available data on the role of these responses in protection from highly pathogenic influenza infection. We discuss the advantages of developing a vaccine based on cell-mediated immune responses toward highly pathogenic influenza virus and potential problems arising from immune pressure.

While measures such as closing schools and social distancing may slow the effects of pandemic influenza, only vaccines and antiviral drugs are clearly efficacious in preventing infection or treating illness. Unless the pandemic strain closely resembles one already recognized, vaccine will not be available early. However, studies can be conducted beforehand to address questions concerning vaccine dose, frequency of inoculation, and need for adjuvants. In contrast, antiviral drugs, particularly the neuraminidase inhibitors, will be effective for treatment and available if stockpiling takes place. Special questions need to be answered if a highly lethal virus, such as influenza A (H5N1), produces the pandemic. Both vaccines and antiviral drugs will be required for a coordinated strategy.

Killed and live influenza virus vaccines are effective in preventing and curbing the spread of disease, but new technologies such as reverse genetics could be used to improve them and to shorten the lengthy process of preparing vaccine seed viruses. By taking advantage of these new technologies, we could develop live vaccines that would be safe, cross-protective against variant strains, and require less virus per dose than conventional vaccines. Furthermore, pandemic vaccines against highly virulent strains such as the H5N1 virus can only be generated by reverse genetics techniques. Other technologic breakthroughs should result in effective adjuvants for use with killed and live vaccines, increasing the number of available doses. Finally, universal influenza virus vaccines seem to be within reach. These new strategies will be successful if they are supported by regulatory agencies and if a robust market for influenza virus vaccines against interpandemic and pandemic threats is made and sustained.

Recent outbreaks of highly pathogenic avian influenza in Asia and associated human infections have led to a heightened level of awareness and preparation for a possible influenza pandemic. Vaccination is the best option by which spread of a pandemic virus could be prevented and severity of disease reduced. Production of live attenuated and inactivated vaccine seed viruses against avian influenza viruses, which have the potential to cause pandemics, and their testing in preclinical studies and clinical trials will establish the principles and ensure manufacturing experience that will be critical in the event of the emergence of such a virus into the human population. Studies of such vaccines will also add to our understanding of the biology of avian influenza viruses and their behavior in mammalian hosts.

The threat of a human influenza pandemic has greatly increased over the past several years with the emergence of highly virulent avian influenza viruses, notably H5N1 viruses, which have infected humans in several Asian and European countries. Previous influenza pandemics have arrived with little or no warning, but the current widespread circulation of H5N1 viruses among avian populations and their potential for increased transmission to humans and other mammalian species may afford us an unprecedented opportunity to prepare for the next pandemic threat. The US Department of Health and Human Services is coordinating a national strategy to respond to an influenza pandemic that involves multiple agencies, including the Centers for Disease Control and Prevention, the Food and Drug Administration, and the National Institutes of Health (NIH). Within NIH, the National Institute of Allergy and Infectious Diseases (NIAID) conducts basic and clinical research to develop new vaccine technologies and antiviral drugs against influenza viruses. We describe recent research progress in preparing for pandemic influenza.

We compared strategies for stockpiling neuraminidase inhibitors to treat and prevent influenza in Singapore. Cost-benefit and cost-effectiveness analyses, with Monte Carlo simulations, were used to determine economic outcomes. A pandemic in a population of 4.2 million would result in an estimated 525–1,775 deaths, 10,700–38,600 hospitalization days, and economic costs of $0.7 to $2.2 billion Singapore dollars. The treatment-only strategy had optimal economic benefits: stockpiles of antiviral agents for 40% of the population would save an estimated 418 lives and $414 million, at a cost of $52.6 million per shelf-life cycle of the stockpile. Prophylaxis was economically beneficial in high-risk subpopulations, which account for 78% of deaths, and in pandemics in which the death rate was >0.6%. Prophylaxis for pandemics with a 5% case-fatality rate would save 50,000 lives and $81 billion. These models can help policymakers weigh the options for pandemic planning.

Although influenza causes more hospitalizations and deaths among American children than any other vaccine-preventable disease, deriving accurate population-based estimates of disease impact is challenging. Using 2 independent surveillance systems, we performed a capture-recapture analysis to estimate influenza-associated hospitalizations in children in Davidson County, Tennessee, during the 2003–2004 influenza season. The New Vaccine Surveillance Network (NVSN) enrolled children hospitalized with respiratory symptoms or fever and tested them for influenza. The Tennessee Emerging Infections Program (EIP) identified inpatients with positive influenza diagnostic test results through review of laboratory and infection control logs. The hospitalization rate estimated from the capture-recapture analysis in children <5 years of age was 2.4 per 1,000 (95% confidence interval 1.8–3.8). When NVSN estimates were compared with capture-recapture estimates, NVSN found 84% of community-acquired cases, EIP found 64% of cases in which an influenza rapid test was performed, and the overall sensitivity of NVSN and EIP for influenza hospitalizations was 73% and 38%, respectively.

We propose a Bayesian statistical framework for estimating the reproduction number R early in an epidemic. This method allows for the yet-unrecorded secondary cases if the estimate is obtained before the epidemic has ended. We applied our approach to the severe acute respiratory syndrome (SARS) epidemic that started in February 2003 in Hong Kong. Temporal patterns of R estimated after 5, 10, and 20 days were similar. Ninety-five percent credible intervals narrowed when more data were available but stabilized after 10 days. Using simulation studies of SARS-like outbreaks, we have shown that the method may be used for early monitoring of the effect of control measures.

We used a regression model to examine the impact of influenza on death rates in tropical Singapore for the period 1996–2003. Influenza A (H3N2) was the predominant circulating influenza virus subtype, with consistently significant and robust effect on mortality rates. Influenza was associated with an annual death rate from all causes, from underlying pneumonia and influenza, and from underlying circulatory and respiratory conditions of 14.8 (95% confidence interval 9.8–19.8), 2.9 (1.0–5.0), and 11.9 (8.3–15.7) per 100,000 person-years, respectively. These results are comparable with observations in the United States and subtropical Hong Kong. An estimated 6.5% of underlying pneumonia and influenza deaths were attributable to influenza. The proportion of influenza-associated deaths was 11.3 times higher in persons age >65 years than in the general population. Our findings support the need for influenza surveillance and annual influenza vaccination for at-risk populations in tropical countries.

We used a single equation with discrete phases to fit the daily cumulative case data from the 2003 severe acute respiratory syndrome outbreak in Toronto. This model enabled us to estimate turning points and case numbers during the 2 phases of this outbreak. The 3 estimated turning points are March 25, April 27, and May 24. The estimated case number during the first phase of the outbreak between February 23 and April 26 is 140.53 (95% confidence interval [CI] 115.88–165.17) if we use the data from February 23 to April 4; and 249 (95% CI: 246.67–251.25) at the end of the second phase on June 12 if we use the data from April 28 to June 4. The second phase can be detected by using case data just 3 days past the beginning of the phase, while the first and third turning points can be identified only ≈10 days afterwards. Our modeling procedure provides insights into ongoing outbreaks that may facilitate real-time public health responses.

Given the potential for laboratory-associated severe acute respiratory syndrome–associated coronavirus (SARS-CoV) infections, we must know which cell lines are susceptible to the virus. We investigated 21 cell lines routinely used for virus isolation or research. After infection with SARS-CoV, cells were observed for cytopathic effects, and quantitative real-time polymerase chain reaction was used to measure ongoing viral replication. An indirect immunofluorescence assay was also used as a confirmatory test. The study identified 10 new cell lines capable of supporting the replication of SARS-CoV and confirmed the susceptibility of 4 cell lines previously reported. This study shows that SARS-CoV can be isolated in several cell lines commonly used for diagnostic or research purposes. It also shows that SARS-CoV can achieve high titers in several cell lines, sometimes in the absence of specific cytopathic effects.

Since global availability of vaccine and antiviral agents against influenza caused by novel human subtypes is insufficient, the World Health Organization (WHO) recommends nonpharmaceutical public health interventions to contain infection, delay spread, and reduce the impact of pandemic disease. Virus transmission characteristics will not be completely known in advance, but difficulties in influenza control typically include peak infectivity early in illness, a short interval between cases, and to a lesser extent, transmission from persons with incubating or asymptomatic infection. Screening and quarantining entering travelers at international borders did not substantially delay virus introduction in past pandemics, except in some island countries, and will likely be even less effective in the modern era. Instead, WHO recommends providing information to international travelers and possibly screening travelers departing countries with transmissible human infection. The principal focus of interventions against pandemic influenza spread should be at national and community levels rather than international borders.

The World Health Organization's recommended pandemic influenza interventions, based on limited data, vary by transmission pattern, pandemic phase, and illness severity and extent. In the pandemic alert period, recommendations include isolation of patients and quarantine of contacts, accompanied by antiviral therapy. During the pandemic period, the focus shifts to delaying spread and reducing effects through population-based measures. Ill persons should remain home when they first become symptomatic, but forced isolation and quarantine are ineffective and impractical. If the pandemic is severe, social distancing measures such as school closures should be considered. Nonessential domestic travel to affected areas should be deferred. Hand and respiratory hygiene should be routine; mask use should be based on setting and risk, and contaminated household surfaces should be disinfected. Additional research and field assessments during pandemics are essential to update recommendations. Legal authority and procedures for implementing interventions should be understood in advance and should respect cultural differences and human rights.

We report a case of ocular vaccinia infection in an unvaccinated laboratory worker. The patient was infected by a unique strain used in an experiment performed partly outside a biosafety cabinet. Vaccination should continue to be recommended, but laboratories with unvaccinated workers should also implement more stringent biosafety practices.

We report, for the first time, serologic evidence of Rickettsia felis and R. aeschlimannii infections acquired in Tunisia from 1998 to 2003. We found that most patients with antibodies against both R. conorii and R. typhi had serologic evidence of R. felis infection.

Sapovirus was detected in 7 of 95 stool specimens from children with gastroenteritis of unknown etiology in Sydney, Australia, from August 2001 to August 2002 and from February 2004 to August 2004, by using reverse transcription–polymerase chain reaction. Sequence analysis of the N-terminal capsid region showed all human sapovirus genogroups.

Prospective surveillance for influenza was performed during the 2002 Salt Lake City Winter Olympics. Oseltamivir was administered to patients with influenzalike illness and confirmed influenza, while their close contacts were given oseltamivir prophylactically. Influenza A/B was diagnosed in 36 of 188 patients, including 13 athletes. Prompt management limited the spread of this outbreak.

In a pediatric surveillance network, 287 (5.1%) of 5,580 specimens from patients with acute respiratory infections tested positive for human metapneumovirus (HMPV). Phylogenetic analysis of N- and F-gene sequences of identified HMPV showed that 30% belonged to a novel phylogenetic cluster.

We report a novel parvovirus (PARV4) and related variants in pooled human plasma used in the manufacture of plasma-derived medical products. Viral DNA was detected by using highly selective polymerase chain reaction assays; 5% of pools tested positive, and amounts of DNA ranged from <500 copies/mL to >10⁶ copies/mL plasma.

Two Canadian urban areas received travelers with severe acute respiratory syndrome (SARS) before the World Health Organization issued its alert. By July 2003, Vancouver had identified 5 cases (4 imported); Toronto reported 247 cases (3 imported) and 43 deaths. Baseline preparedness for pandemic threats may account for the absence of sustained transmission and fewer cases of SARS in Vancouver.

We developed a model of pathogen dissemination in the outpatient clinic that incorporates key kinetic aspects of the transmission process, as well as uncertainty regarding whether or not each incident patient is contagious. Assigning appointments late in the day to patients suspected of being infectious should decrease pathogen dissemination.

We report a cluster of 4 cases of acute histoplasmosis (1 culture proven and 3 with positive serology, of which 2 were symptomatic) associated with exposure to soil during a golf course renovation. Patients in western Canada with compatible symptoms should be tested for histoplasmosis, regardless of their travel or exposure history.

We evaluated titers of homotypic and heterotypic neutralizing antibodies (NAbs) to Andes and Sin Nombre hantaviruses in plasma samples from 20 patients from Chile and the United States. All but 1 patient had high titers of NAb. None of the plasma samples showed high titers against the heterologous virus.