COMMENTARY

Infectious Diseases: February 15, 2004

John Bartlett, MD

Disclosures

February 17, 2004

In This Article

Influenza

The following represents a synthesis of information from multiple sources, but the primary sources are Basic Information About Avian Influenza (Bird Flu) from the CDC[28] and the WHO fact sheet on Avian influenza.[29]

History: In 1997, the Hong Kong Health Department reported an outbreak of influenza A (H5N1) in both chickens and humans. This was the first time that Avian influenza virus had ever been found to be transmitted directly from birds to humans. In this outbreak, there were 18 patients hospitalized with this infection, and 6 died. The decision was made to eliminate the chicken source of infection. Serologic studies at that time showed relatively high rates of positive tests among persons with high levels of exposure to infected poultry and those who worked in the laboratory with this virus. There was no evidence of human-human transmission on the basis of serologic studies in healthcare workers and family members.[30] The decision to eliminate the poultry source of this infection came at the end of 1997 and, within 3 days, the entire poultry population of Hong Kong (estimated at about 1.5 million birds) was destroyed. Many authorities now feel that this intervention may have averted a major influenza pandemic.

H5N1 update: There were no further confirmed cases of infection in humans involving this strain of influenza until 2003, when 2 cases were reported in persons who traveled from China to Hong Kong, including 1 who died. Large outbreaks of influenza involving this strain have been reported in chickens in 2003 in Vietnam, South Korea, and Japan. Of these, the only country with human cases is Vietnam, which has 3 confirmed cases and 11 others where the investigation is pending. Of these 14, there have been 12 deaths, 11 of which were in children.

Potential for influenza pandemic: The major limitation of the avian strain of influenza to cause a major epidemic is its inability to be transmitted from human-human. Thus, the risk appears to be primarily from fecal-oral transmission directly from the poultry source. However, influenza viruses are genetically labile, and they tend to undergo frequent antigenic changes, which accounts for the need for global influenza monitoring for new vaccine production each season. H5N1 mutates frequently and has a documented tendency to acquire genes from viruses infecting other animal species. Genetic analysis to date has shown only avian genes, but increasing infection in humans multiplies the likelihood of production of a novel subtype with human genes that would permit person-to-person transmission. Because these viruses have had such a limited role in human disease, the human population would have little antigenic protection, thus promoting the pandemic potential.

Other avian influenza infections: There are 15 avian influenza virus H subtypes and 9 neuraminidase subtypes. H7N7 avian influenza was reported from The Netherlands in February 2003; this was responsible for at least 1 death in a veterinarian and many cases of conjunctivitis.

H9N2: This strain appears to cause a mild infection in humans, and there have been a modest number of cases in mainland China and Hong Kong. There does not appear to be human-human transmission of H9N2 according to serologic studies in healthcare workers and family members.[31]

Pandemics: There were 3 major pandemics in the 20th century, as shown in Table 13 .

"Avian" influenza A symptoms: The symptoms of avian influenza are generally similar to those seen with other forms of influenza, including fever, cough, sore throat, and myalgias. A unique feature of H5N1 is the severity of the illness, which may include the acute respiratory distress syndrome or viral pneumonia. H7N7 usually causes conjunctivitis, but may also cause typical influenza symptoms.

Antiviral agents: These drugs appear to be effective and have been advocated as prophylaxis in workers assigned to culling poultry sources.

Flu mystified: hospitals are in a fog of live viral vaccine issues. Hosp Infect Control. 2004;31:1. Several facets of influenza and influenza vaccine are discussed, including an interview with Dr. Julie Gerberding, director of the CDC. Some of the points worth emphasizing are the following:

  • One of the reasons that the Fujian strain is not included in the vaccine for this season is due to difficulty in growing it in eggs. To include it would have delayed availability of the vaccine.

  • There appears to be an ample supply of FluMist for healthy persons of 5-49 years.

  • The estimated risk of transmission of the virus in the live virus FluMist vaccine to close contacts is 0.6% to 2.4%.

  • Some hospitals apparently are concerned with the use of FluMist in healthcare workers due to potential transmission. According to an interview with Dennis Maki, some hospitals have established policies that require healthcare workers to take a 21-day unpaid vacation.

  • Regarding early reports of 6 deaths in children 21 months to 15 years of age in Colorado, there is unconfirmed speculation that some may have had complicating bacterial infections; community-acquired methicillin-resistant Staphylococcus aureus (MRSA) is also a specific suspicion. (This number has subsequently increased to 93 pediatric deaths[32]; the role of bacterial superinfection in many of these cases remains unclear.)

CDC. Preliminary assessment of the effectiveness of the 2003-04 inactivated influenza vaccine—Colorado, December 2003. MMWR. 2004;53:8. The authors report an analysis of the effectiveness of this season's influenza vaccine vs the predominant influenza strain, A/Fujian/411/2002. The analysis was based on a questionnaire that was completed by 1886 employees of Children's Hospital in Denver. Of these, 1424 (78%) were vaccinated, 289 (16%) reported a lower respiratory infection, 28 had tests for influenza, and 13 of these tested positive. Two methods were used to estimate vaccine efficacy: (1) categorical analysis was based on the attack rate for vaccinated/unvaccinated; (2) the person-time analysis was incidence rates for lower respiratory tract infections for vaccinated vs unvaccinated person-times. These studies showed little or no evidence of effectiveness of the vaccine against lower respiratory tract infections as summarized below:

Attack rate
Ratio - Vaccinated:Unvaccinated   0.87
Vaccine efficacy   14%

Incidence rate
Ratio - vaccinated:unvaccinated   1.07
Vaccine efficacy   -10%

The authors conclude there are several limitations to the conclusions of this study, including the fact that the data are inadequate for any assessment of the effectiveness of the vaccine against laboratory-confirmed influenza and its complications.

Comment: These preliminary data suggest little or no benefit for this season's vaccine in protecting against lower respiratory tract infections that predominate this season. The limitations of the study are profound -- only 13 had confirmed influenza.

CDC. Weekly report: influenza summary update. This is the CDC report for antigenic characterization for 518 influenza virus strains collected in US laboratories from October 1, 2003 through January 10, 2004. These results are summarized in Table 14 , which shows that the "Fujian strain" accounts for 80% of the isolates.

Comment: Efficacy of influenza vaccine is obviously dependent on the match between the vaccine strain and the circulating and the predominant circulating virus, which varies for each season. A review of the experience indicates that the match has been good in virtually all seasons for the last 15 years, with 2 possible exceptions. One was the surprise appearance of the Sydney strain in the 1997-98 season, where antigenic cross-protection was partial, and this may be the Fujian strain for this season. Data on the cross-protection issue are incomplete, but the preliminary data from an inconclusive report suggest virtually no protection against lower respiratory tract infections.[33] This strain was not necessarily unanticipated. The problem was developing a vaccine in a timely fashion. This virus kills the embryonated eggs, which is the standard cultivation method requiring alternative methods for vaccine development. The time required would have delayed availability.

CDC. National centers for infectious diseases, travelers' health. WHO has reported 3 cases of avian influenza A (H5N1) in Vietnam as confirmed by the Hong Kong National Influenza Center. These include 2 children and 1 adult from a recent experience with 14 cases of severe respiratory illnesses that resulted in 12 deaths, including 11 deaths in children. It is not known whether all cases involve this strain; SARS has been ruled out. The report states that there is no definitive evidence of human-human transmission, and no H5N1 infections have been documented in healthcare workers. The CDC and WHO have not issued any travel alerts or advisories for Vietnam, but travelers to this area are advised to avoid contact with animals in live food markets and any places that appear to be contaminated with feces from poultry or other animals.

CDC. Update: influenza-associated deaths reported among children aged <18 years—United States, 2003-04 influenza season. MMWR. 2004;52:1286. The authors review 93 influenza-associated deaths in children younger than 18 years of age during the 2003-04 influenza season through January 6. All patients had influenza established by laboratory tests. Of the 93 deaths, 15 cases (16%) were reported to have had an invasive bacterial coinfection, 35 (38%) were reported to have had an underlying medical condition, 15 (27%) died at home, and 55 (59%) were under the age of 5 years. The vaccine status was known in 45 cases: 33 (73%) were not vaccinated and 6(13%) had received 1 of 2 doses.

Comment: The authors note that influenza deaths among children are not reportable, so this experience cannot be compared with those from prior years. Although the emphasis on the report is pediatric mortality, 19 (20%) of the deaths were in children aged 12-17 years.

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