On may 15, 1997, a previously healthy 3-year-old boy in Hong Kong was admitted to hospital with a six-day history of fever, sore throat, and cough. He died nine days later of respiratory failure due to viral pneumonia in the intensive care unit of Victoria Hospital. Culture of a tracheal aspirate had yielded influenza virus, but typing of the virus with standard reagents was unsuccessful. Subsequent investigations identified the virus as influenza A(H5N1), a strain previously identified as circulating in poultry in Hong Kong since March 1997, but never before detected in humans. The New York Times reported that this child’s pre-school had its own petting zoo with five chickens and eight ducks.
As of December 23, 1997, an additional eight cases, described in this CDC report, have been confirmed. The age of the patients ranges from 2 years to 54 years; five of the nine patients are male. Patient 9 is the sister of patient 7 and cousin of patient 6. Patients 1 through 6, however, lived in different areas of Hong Kong, had had no contact with each other, and had no common exposures. At least three patients have died.
To date, no definitive human-to-human transmission has been identified. Some medical and nursing personnel have had influenza-like illness, but none have been confirmed as due to H5N1.
COMMENT BY STAN DERESINSKI, MD, FACP
Influenza A(H5N1) was first recovered in South Africa from terns in 1961. Outbreaks of infection with this strain were first observed in Hong Kong poultry farms in the spring of 1997 and led to the demise of thousands of chickens. The cases described above are the first documented human infections with avian influenza virus.
Influenza is an RNA virus whose genome is segmented into eight single stranded portions of unequal size, with each segment coding for a specific polypeptide(s). Thus, RNA segments 1-3 code for polypeptides PB1, PB2, and PA, which possess polymerase activity. Segment 4 codes for the hemagglutinins, HA1 and HA2, while RNA segment 5 codes for NP (nucleocapsid subunit polypeptide). RNA segment 6 codes for the neuraminidase (NA), segment 7 for the matrix protein (MP), and segment 8 for nonstructural proteins (NS1 and NS2). The capability of these RNA segments for rearrangement provides the virus with the capability of dramatic antigenic changes.
The genome segments appear to be randomly incorporated during virion assembly, an inefficient method for producing infectious virus, but one that creates great genetic plasticity. This plasticity also allows a potentially high frequency of reassortment of RNA segments between two virions which may occur when a cell is simultaneously infected with two different influenza viruses.
The resultant antigenic variation is of two typesdrift and shift. Antigenic drift refers to relatively minor changes that occur every year or every several years within an influenza subtype, which are designated by their hemagglutinins and neuraminidases. Until the Hong Kong experience, only three of the former (H1, H2, and H3) and two of the latter (N1 and N2) had been identified in virus recovered from humans. Strains within subtypes are further designated by the site and year of initial isolation. Thus, the strains of influenza A expected that had been predicted to circulate in the United States during the 1997-1998 season, and which are included in the current vaccine along with B/Harbin, are A/Johannesburg/96/H1N1 and A/Nanchang/95/H3N2. Antigenic drift is the result of mutations in the RNA segment coding for hemagglutinin or, less commonly, neuraminidase, which results in changes of one or a few amino acids leading to minor changes in antigenicity. Viruses with these minor antigenic changes are selected for in human populations incompletely immune to the viral strain.
In contrast, major antigenic shifts are the result of reassortment between strains that produce new subtypes of influenza virus. When a new hemagglutinin or neuraminidase is introduced, the human population lacks immunity, and a pandemic may result. These shifts are the result of genetic reassortment.
Human and swine influenza viruses appear to have a common ancestor in avian influenza A. Prior to the Hong Kong experience, there had been no evidence of transmission of relevant virus between birds and humans, but there is evidence of transmission between swine and humans, as well as between swine and avian species. The devastating 1918 "Spanish" influenza pandemic that killed at least 20 million people was caused by a novel H1N1 virus belonging to a subgroup of strains that infect humans and swine, but not avian species (Taubenberger JK, et al. Science 1997;27:1793-1796). Swine may serve as a "mixing vessel" for genomic reassortment between diverse influenza A viruses. In the current Hong Kong episode, the "mixing vessel" has been entirely bypassed, and avian influenza A virus has been directly introduced into humans.
China has been the source of at least three previous pandemics of influenza A infectionthose of 1957, 1968, and 1977. It is believed that China is favored as the source of new subtypes of influenza A because the virus circulates there throughout the year and because of the frequent proximity of humans, swine, and birds.
Thus, the Hong Kong influenza A/H5N1 may have the potential to cause a new pandemic. As of January 3, 1997, a total of 16 confirmed cases with four deaths had occurred, according to senior Hong Kong health officials. However, to date there has been no definitive evidence of human-to-human transmission, and there has, in fact, been no increase in acute respiratory illness in the Hong Kong population. Thus, it can be hoped that this virus will remain confined.
Table
Initial cases of human infection with avian influenza virus
Patient Onset Age Sex Comorbidity Outcome
1 5/9/97 3 yrs male none died
congenital
2 11/8/97 2 yrs male heart dis. recovered
3 11/20/97 13 yrs female none on ventilator
4 11/24/97 54 yrs male ? died
5 12/7/97 24 yrs female ? on ventilator
6 12/7/97 5 yrs female ? improved
7 12/12/97 2 yrs male ? ?
8• 11/24/97 37 yrs male none recovered
9• 12/13/97 3 yrs female ? ?
•Listed as possible cases by CDC, as confirmed by WHO as of 12/23/97.
In the meantime, however, extensive surveillance activity is being instituted and laboratory investigation has been initiated to identify a candidate vaccine strain. Industrial production of an H5N1 vaccine may prove difficult since the virus kills chicken eggs, the usual vehicle for influenza vaccine growth. Fortunately, influenza A(H5N1) is susceptible to both amantadine and rimantadine and, therfore, these drugs may prove efficacious both prophylactically and therapeutically.
On December 23, 1997, the WHO stated that, "In the absence of any sign of human-to-human transmission of the H5N1 influenza virus, no new measures, such as travel restrictions or quarantine, are warranted." Since then, however, a slaughter of Hong Kong chickens has taken place. If the virus is present, as seems likely, in migratory bird populations, the slaughter may have been in vain.
Which of the following is correct?
a. Avian influenza viruses are capable of infecting swine.
b. Avian influenza viruses have repeatedly been shown to infect humans.
c. The 1918 pandemic of "Spanish flu" was caused by the transmission of an avian influenza virus to humans.
d. Birds, particularly fowl, appear to serve as a "mixing vessel" in which swine and human influenza virus commonly undergo reassortment.
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