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Recent Data on Influenza

Avian Influenza

Beigel JH, Farrar J, Han AM, et al; Writing Committee of the World Health Organization (WHO) Consultation on Human Influenza A/H5. Avian influenza A (H5N1) infection in humans. N Engl J Med. 2005;353:1374-1385. The Writing Committee of the World Health Organization (WHO) Consultation on Human Influenza A/H5 has provided the following review of this virus.

Incidence: Table 1 is a summary of cases of avian influenza A (H5N1), which reflects data through May 2005. An updated version through December 1 is provided by the reviewer. Cases in humans reflect outbreaks of avian epidemics in 2004 and 2005; this region of avian cases (poultry) has subsequently expanded to Kazakhstan, Mongolia, Russia, Turkey, and Greece, but there have been no human cases in these more recent countries.

Transmission: Human influenza is transmitted by infectious droplets and droplet nuclei and by direct contact. With bird-human transmission, the defined risks are exposure to ill poultry and butchering of birds or other close contact with birds in at least 80% of cases. Most important is the issue of human-human transmission, which has been suggested in several household clusters, but in only 1 well-verified case report,^[1] and there are no cases of transmission by small-particle aerosol. Serologic testing of approximately 550 healthcare workers who are responsible for the care of patients with avian influenza and household contacts of these cases showed positive results in 15.

Clinical features: A summary is provided for 59 cases. The typical case is a previously healthy child or young adult who has exposure to sick poultry, develops the onset of flulike illness at a median incubation period of 4 days, develops typical symptoms of influenza but with a relatively high frequency of diarrhea and infrequent pharyngitis, quickly develops acute respiratory distress syndrome (ARDS), and dies on illness day 8. Specifics are given in Table 2 .

Diagnosis: The diagnosis is confirmed by viral isolation, detection of H5-specific RNA with pharyngeal specimens (throat swabs), or serology.

Management: Most of the patients required ventilatory support within 48 hours of admission and care in the intensive care unit for multiorgan failure. Routine treatment included broad-spectrum antibiotics, antiviral agents, and often corticosteroids. The mortality rate was 76% among 25 patients who were given oseltamivir and 75% in 12 patients who did not receive this drug. It is noted that the virus could generally not be cultivated within 2-3 days of oseltamivir, but there was clinical progression anyway. There was no evidence of response to corticosteroids.

Pathogenesis: Studies of the initial clinical isolates of H5N1 in Hong Kong, China, in 1997 showed that this strain has a substitution in the polymerase basic protein 2, which enhances replication, and a substitution in nonstructural protein 1, which increases resistance to inhibition by interferons and tumor necrosis factor (TNF) plus increased production of cytokines, including TNF. These strains have enhanced pathogenicity in mice and ferrets. Further mutations have occurred since these earlier studies that have altered receptor binding. The high frequency of diarrhea suggests that the virus may replicate in the gastrointestinal tract, and 1 autopsy study confirms this finding.^[2] Further, the virus has been found in the blood, cerebrospinal fluid, and stool of 1 patient.^[3] Patients who expire have elevated levels of inflammatory mediators, including interleukin (IL)-6, IL-8, and IL-1B. There are limited autopsy studies, but these show bindings that are consistent with previous reports of lethal influenza: alveolar spaces filled with fibrinous exudate, red cells, hyaline-membrane formation, and lymphocytic infiltrate.

Management recommendations:

Table 3 summarizes methods to prevent avian influenza transmission in a nonpandemic setting.

Conclusion: This is an excellent review of this timely topic. Of particular interest are the recommendations for therapy and for prevention that represent the state of the art from the World Health Organization (WHO). The obvious concern with oseltamivir is the fact that it has rarely been given sufficiently early to evaluate response. As noted, there is a sharp drop in cultivable virus when given after pneumonitis. It is quite possible that the "cytokine storm" is the issue that needs to be addressed at this stage. Zanamivir is advocated for oseltamivir-resistant strains. This may work for prevention, but a concern with its use after established disease is the inference that H5N1 replicates in the gastrointestinal tract. Zanamivir is found essentially only in the lungs.

Le QM, Kiso M, Someya K, et al. Avian flu: isolation of drug-resistant H5N1 virus. Nature. 2005;437:1108. This is a case report of a 14-year-old girl from Vietnam with influenza involving a strain of H5N1 that is resistant to oseltamivir.

The patient had cared for her 21-year-old brother who had documented infection with H5N1. She was given a prophylactic dose of oseltamivir (75 mg/day) from February 24 to 27, and then a therapeutic dose for 7 days beginning February 27. A viral isolate obtained on February 28 showed that the strain was highly resistant to oseltamivir with an IC50 exceeding 763 nM. One of the clones proved identical to the brother's strain. This strain, in the patient, showed reduced viral titers compared with oseltamivir-susceptible strains when given to ferrets (P = .0001). This strain was also sensitive to zanamivir in vitro and in vivo in ferrets. The girl was hospitalized, and both she and her brother were discharged, apparently having recovered.

Conclusion: The study authors stress the importance of their observations in terms of the need to monitor drug resistance in H5N1 isolates and the possible need to stockpile zanamivir as well as oseltamivir.

Comment: There are several observations of interest:

Taubenberger JK, Reid AH, Lourens RM, Wang R, Jin G, Fanning TG. Characterization of the 1918 influenza virus polymerase genes. Nature. 2005;437:889-893. The study authors present an analysis of influenza virus A polymerase from the 1918-1919 strain that was responsible for Spanish influenza. This polymerase functions as a heterotrimer formed by PB2, PB1, and PA proteins thought to be important in viral replication and host interaction, specifically in host specificity. The analysis of the 1918 polymerase genes suggests that this was an avian strain that mutated for mammalian adaptation. This is in contrast to the pandemic strains of 1957 and 1968, which appear to be reassortment viruses. These conclusions are based on 10 amino acid positions out of a total of 2232 codons that consistently distinguish the 1918 strain from subsequent human polymerase proteins at this heterotrimer. The PB2 protein shows 5 changes that distinguish human and avian sequences. H5N1 and H7N7 (the epidemic strain in The Netherlands) are among the few avian strains that showed some of these 5 changes. The study authors concluded that the epidemic strain for the 1957 and 1968 pandemics was avian/human resortants, presumably representing an avian PB1 by reassortment. By contrast, the 1918 strain was an avian virus that adapted to humans. The observation that amino acid changes of the 1918 strain in the heterotrimeric polymerase complex are also found in H5N1 and H7N7 -- both avian viruses that have been fatal to humans -- is an obvious concern.

Influenza Vaccines

Influenza vaccine 2005-2006. The Medical Letter. 2005;47:85. This summarizes the essentials of the influenza vaccine for 2005-2006.

Vaccine formulations: Two formulations in the United States include the inactivated intramuscular vaccine and the live attenuated intranasal vaccine (FluMist). Table 4 provides information on the vaccines that are available in the United States.

Composition: The new component of the 2005-2006 vaccine is the influenza A H3N2 vaccine strain. This component is different for the inactivated and live attenuated vaccines, but is considered equivalent. The specific content is summarized.

The following outlines the vaccine composition:

Recommendations: The optimal time to vaccinate is October or November. When there is a delay (as in this year and last year), the available supply should be used according to the following priority.

Efficacy: Vaccine efficacy for inactivated vaccine for preventing influenza is about 80%; it is less in elderly and varies by year depending on the match between the vaccine strains and the epidemic strain. Protection begins about 2 weeks after the inactivated vaccine and generally persists for 6 months, but only about 4 months in elderly persons. Protection with live vaccine appears to be similar and probably superior for new variants of influenza A H1N1 and for influenza B.

Adverse effects: The relationship between inactivated influenza vaccine and Guillain-Barré syndrome is controversial. live attenuated intranasal vaccine is generally well tolerated, but there may be mild symptoms of an upper respiratory infection. There is 1 unpublished report of transmission of the live virus vaccine strain. Both live and inactivated vaccines are grown in eggs, so egg hypersensitivity represents a contraindication to either.

Reduced dose: Intradermal administration will presumably reduce the dose to extend the supply.^[5] Studies with 20% of the standard dose have been found effective.^[6] The reduced dose may be less effective in elderly persons. These studies show immunogenicity, but have not been tested for clinical efficacy.

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