Highlights of the Infectious Diseases Society of America 43rd Annual Meeting

October 6-9, 2005; San Francisco, California

John G. Bartlett, MD

Disclosures

November 21, 2005

In This Article

Avian Influenza

Avian influenza was the top story at the time of the Infectious Diseases Society of America (IDSA) 43rd Annual Meeting; October 6-9, 2005; San Francisco, California, both inside and outside the Moscone Center, where the conference took place.

Klaus Stohr, PhD, from the World Health Organization (WHO), Geneva, Switzerland, gave the opening address, which was devoted to this topic and the current state of preparedness.[1] He not only reviewed the substantial morbidity and mortality of "ordinary flu," but also emphasized the unique experience with pandemic influenza in 1918-1919. This pandemic resulted in 30-50 million deaths, and in retrospect it appears that organism was an avian strain similar to the H5N1 avian influenza strain that is now circulating throughout Asia and beyond. Much of the talk dealt with preparedness with respect to both vaccines and antivirals. The conclusion is that there is not enough of either vaccines and antivirals -- the world currently lacks production capacity to make enough of either and countries in Africa are most vulnerable because of a virtual absence of any production capacity.

This year's IDSA conference brought constant reminders of possible parallels between the avian influenza virus of 1918 and contemporary avian influenza, some of which are shown in Table 1 , which reflects the current status of H5N1.

The 1918 Influenza Virus

The October 6, 2005 issue of Nature included a report by Taubenberger and coworkers[2] from the Armed Forces Institute of Pathology in Rockville, Maryland. Their research characterized polymerase genes from the 1918 pandemic influenza strain. This showed that the strain was "avian-like," and similarities with H5N1 were noted. This study shows the dynamic nature of influenza in terms of transmission and evolution in humans and animals. Another study in Science by Tumpey and colleagues,[3] from the US Centers for Disease Control and Prevention (CDC), reported successful recreation of the 1918 influenza strain and showed sequences that were found only in birds that confer virulence; some, but not all, of these sequences are found in H5N1. In total, these studies show the potentially serious consequences of avian influenza in terms of virulence properties similar to the 1918 strain, as highlighted by Garcia-Sastre[4] in a presentation at the IDSA conference.

Avian Influenza Now

The first reports of human cases of avian influenza were from Hong Kong in 1997, when there were 18 cases with 6 fatalities.[5] This was the first reported direct transmission of influenza virus from poultry to humans. The high fatality rate was worrisome, but serologic surveys showed limited human-human transmission. Nevertheless, the decision was made to cull chickens and the outbreak abruptly stopped.

The next chapter was the large epidemic of H5N1 in poultry in 8 Asian countries. More importantly, there have been human cases in 4 of these countries and a case-fatality rate approximating 50%. Data at the time of the IDSA conference are shown in Table 2 .[6]

Transmission

Human influenza virus is usually transmitted by inhalation of droplet nuclei. Avian influenza appears to be transmitted primarily by direct contact with poultry. Most studies show that healthcare workers with patient contact do not have serologic or clinical evidence of infection, but there is one well-documented exception with a family contact. The limitation of the epidemic appears to be the failure of any sustained human-to-human spread and total absence of any human-to-human transmission by aerosol. Despite these generally negative studies, there is concern that efficient person-to-person transmission could evolve dramatically with mixtures of seasonal influenza and avian influenza viruses in the same host or with spontaneous mutations.[4]

Clinical Features of Avian Influenza in Humans

The incubation period in humans is generally 2-5 days.[5,6] A review of 59 cases in 4 countries showed median ages of 10-20 years, and 70% to 100% of infected humans had contact with ill poultry. The most frequent findings were fever, cough, and x-ray evidence of pneumonia; about one third had diarrhea and/or vomiting, suggesting a wider systemic distribution than is usually found with influenza. Of the 59 cases, 41 (70%) had acute respiratory distress syndrome (ARDS). The overall mortality rate was 38 of 59 (64%) and 80% for those younger than 15 years of age.

Antivirals to Treat Avian Influenza

Frederick Hayden, MD,[5] of the University of Virginia Health Science Center, Charlottesville, Virginia, reviewed the current status of antivirals that may be useful against avian influenza. Amantadine and rimantadine are not viable options due to resistance. The efficacy of oseltamivir against "ordinary" epidemic influenza in the United States is shown in Table 3 .

Clinical experience with using antivirals to treat H5N1 is limited. The cumulative experience of cases treated with oseltamivir is shown in Table 4 .[6]

The experience-to-date is considered inconclusive because the drug was given too late and the numbers are small.

Influenza Strains: Resistance to Antivirals

The frequency of oseltamivir resistance with endemic influenza has been relatively rare, according to Dr. Hayden.[5] The rate reported was 3 of 1180 strains (.3%). This rate increases with extensive use, especially in children -- up to 16%. Nevertheless, Japan has the highest use of oseltamivir with 16 million courses/year, but resistance rates continue to be low. The mechanism of resistance is point mutations in the influenza genome, which varies with different drugs and different influenza subtypes. For example, E119V confers resistance to oseltamivir but not to zanamivir or peramivir (an experimental neuraminidase inhibitor). The most common mutation is at codon 274, which causes high-level resistance but also substantially reduces viral fitness.

Vaccines

The developments were exciting but the timeline was depressing. The standard method is killed split-virus vaccines, which have been produced by US-based companies licensed for this (GlaxoSmithKline, Chiron Corporation, and Sanofi Pasteur). New methods for improved engineering of influenza vaccines include reverse genetics and cell culture.[7] In addition, the use of adjuvants, such as alum, to "boost" the immune response, is particularly promising.[7] The problem is the time required for developing new technology, production capacity, and addressing regulatory issues. The regulatory issue is the concern that the US Food and Drug Administration (FDA) considers split-virus vaccine a tested process so that the product produced receives an expedited review. However, new methods are viewed by the FDA as a new product requiring a full review, which generally means > 1 year. The influenza pandemic of 1918-1919 traversed the world in 8-10 months.

Stockpile: Antiviral Supplies round the World

Dr. Stohr[1] of the WHO painted a bleak picture based on substantial geographic differences in commitment based on orders for antivirals and an inadequacy of supplies even for current orders. It was estimated that the current supply of oseltamivir is adequate for only 2% of the global population. If the existing production system proceeded at maximum capacity, then there would be a sufficient supply for 20% in 10 years.[1,5] Despite anticipated shortages, several countries (the United Kingdom, France, Finland, Norway, Switzerland, and New Zealand) have orders to cover 20% to 40% of their population. The WHO has ordered 3 million courses for areas of need. The largest gap is African countries, which have essentially no capacity for containing an influenza epidemic. An attractive option for developing countries is technology transfer. However, it was estimated that this would require 2-5 years. The United States had a relatively meager response with orders for 2.3 million courses. However, during the IDSA meeting, it was reported that the United States was moving on a bill to address avian influenza that included $3 billion to stockpile antivirals. The oseltamivir regimens for treatment and prophylaxis are shown in Table 5 .

The US Plan

How to plan for an influenza pandemic is a rapidly moving issue, and each day of the IDSA meeting was accompanied by new plans for avian influenza that would scale up the response. A recent publication[8] used computational modeling to examine methods to control an epidemic of avian flu by 3 methods: (1) social distancing (close schools and businesses and quarantine), (2) a reduction of infectiousness (antivirals and isolation of patients), and (3) a reduction of susceptibility (vaccine or prophylactic antivirals). After 10,000 analyses with multiple variables, the study authors concluded that, based on the 1918 influenza epidemic, the best results for containment were "ring antivirals" (prophylaxis to all contacts of cases) combined with social distancing. Containing the epidemic would require (1) a rapidly lethal infection (to recognize it), (2) reduced transmission (reproductive ratio [R0] < 1.8, meaning each patient would transmit to 1.8 persons or fewer), (3) a health system that could respond, and (4) an antiviral that was effective. Dr. Hayden reviewed this plan and concluded that it had scientific credibility but many contingencies that were impossible to predict.[5] The consensus of others is that a stockpile of oseltamivir that would be adequate for 40% to 50% of the US population is needed, an amount that far exceeds production capacity.[1,5,9] A vaccine is obviously very attractive, but the best candidates will be considered to be in the "new products" category by the FDA and will require 8-12 months to establish safety and efficacy.

Recent US Developments. As noted previously, avian influenza was the major topic of interest and concern at the Moscone Center in San Francisco, where the IDSA meeting was held. It was also a major issue outside the Moscone Center with several developments in Washington, DC. During the meeting, the Senate moved to appropriate $3 billion to the purchase of oseltamivir. Democrats called for an "Influenza Czar" in the White House; Senator Bill Frist, MD, called for an Influenza "Manhattan Project"; and several bills were introduced to address other issues of avian influenza preparedness. US Health and Human Services (HHS) Secretary Michael Leavitt announced that the risk for pandemic influenza was very high and announced that HHS plans to purchase sufficient vaccine for 20 million people, as well as antivirals for 20 million people. There was also increased pressure for generic versions of oseltamivir. Roche reported that sales of the Roche brand oseltamivir (Tamiflu), for the first half of 2005, were $450 million. They also noted production had doubled in 2004 and would double again in 2005. On the influenza virus front, avian influenza cases in birds were confirmed in Turkey, Bulgaria, Siberia, Greece, Romania, Russia, and the United Kingdom. Cases in humans were still restricted to Southeast Asia.

Summary: Avian Influenza

  • Influenza of 1918-1919 had a mortality rate of 2% in those infected and resulted in 40-50 million deaths in the world.
     

  • Avian influenza (influenza A H5N1) has genetic similarities with the agent of the 1918-1919 pandemic. Major differences are a 50% mortality rate and lack of sustained human-human transmission by influenza A H5N1.
     

  • Most deaths in the 1918-1919 pandemic and with avian flu have been in children or previously healthy young adults. By contrast, "seasonal flu" usually causes death only in people with major comorbidities or the "elderly elderly." The mechanism of death with H5N1 is probably immune-mediated.
     

  • Oseltamivir and zanamivir are active in vitro vs nearly all strains of H5N1. Clinical data show no efficacy for treatment, but the data are anecdotal and most were treated late in the course.
     

  • Strains of seasonal flu that are resistant to oseltamivir often show a mutation of codon 274, which attenuates virulence in animals and retains sensitivity to zanamivir.
     

  • The main limitation with antivirals is the short supply compared with global needs.
     

  • The main limitations with a vaccine are(1) the need for rapid production of vaccines that protect against strains that mutate frequently and (2) a limited global production capacity.
     

  • Major methods of control are(1) social distancing (close schools, businesses, and quarantine); (2) infected people are treated with antivirals and isolated; and (3) contacts are vaccinated, given antivirals ("ring antivirals"), and isolated.

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