CDC warns that pandemic flu strain still could emerge from Hong Kong

Mutation could occur between avian, human strains

Warning that there is still a threat of an emerging influenza pandemic, the Centers for Disease Control and Prevention is advising clinicians in the United States to be alert for incoming cases of avian influenza A (H5N1) linked to Hong Kong. The primary concern is that the avian strain could genetically reassort with a circulating human influenza strain, creating a highly transmissible virus for which there would be neither available vaccine nor existing human immunity.

The H5N1 strain has not been found in humans outside of Hong Kong. Data from the ongoing investigation indicate "the virus probably is not being efficiently transmitted among humans," the CDC reports.1,2 As Hospital Infection Control went to press, CDC and Hong Kong health officials had confirmed 18 cases of H5N1, including six people who died. The first known case of human infection with H5N1 occurred in a three-year-old boy who died in May 1997. The most recent case had onset of illness on Dec. 28, 1997, raising hopes that the threat is subsiding. However, the CDC is warning that the normal influenza season in Hong Kong peaks in the months of March and April, creating a situation where genetic reassortment between human influenza type A (H3N2), for example, and the H5N1 avian strain could occur. Likewise, the World Health Organization has advised Hong Kong health officials to stay alert for new cases through July of this year.

Though it is not known why the avian virus is now infecting humans, no viral mutation appears to be occurring in those infected so far, explains Brian Mahy, ScD, PhD, director of the CDC division of viral and rickettsial diseases.

"These [H5N1] viruses are genetically indistinguishable from viruses that we are recovering from chickens in the same area," he says. "They don’t appear to have adapted to the humans — mutated or reassorted in any way. That could happen in the future, of course. The concern is that will occur, and an H3 will reassort with an H5 that is in a human. Then you would have a virus with an enormous potential for spread."

Indeed, the situation has raised questions about U.S. pandemic preparedness and rapid vaccine development, with public health officials conceding neither may have been adequate had the H5N1 strain rapidly reassorted and emerged as a highly transmissible strain. (See related story, p. 37.)

"I think it would have been extremely difficult because there are basically no antibodies to H5 in the population of the world," Mahy says. "A virus with an H5 has an enormous advantage. If it can replicate well in a human, it will spread very rapidly. The time taken to produce vaccines by the conventional licensed means is four to six months. We are still at the stage of developing a candidate."

To hone hospital surveillance and avoid unnecessary culturing of normal flu strains circulating in the United States, the CDC looked at the cases in Hong Kong and issued its advisory based on symptoms and recent travel history. The cases there were not detected in outpatient settings, but in hospitalized patients with severe symptoms, says Stephen Ostroff, MD, associate director for epidemiologic science in the CDC’s national center for infectious diseases.

"All of them were severely ill and were initially hospitalized with a viral pneumonia," he says. "So the recommendation that we made to the states [was to] concentrate on severely ill individuals who are hospitalized with a viral pneumonia and who have had a history of travel to Asia within the preceding 10 days to two weeks."

The matter is not as simple as confining surveillance to major ports of entry because additional travel must be assumed, Ostroff adds.

"They could just as easily be in Kansas City as they could in San Francisco," he says. "So we have sent out this recommendation for consideration to all of the state health departments."

‘It is still out there somewhere’

Though it appears control measures like the poultry slaughter in Hong Kong may have effectively eliminated the viral reservoir there, the CDC remains concerned because the second case in the outbreak did not occur until some six months after the first.

"I don’t think we can let our guard down that there won’t be additional cases next week or three months from now," Ostroff says. "Secondly, this virus came from somewhere. We haven’t identified ultimately where it came from and got into Hong Kong. So it is still out there somewhere. We can’t rest on our laurels and think that this is the last time we will see this bug."

The CDC left it to the discretion of individual state health departments whether to distribute the advisory to their respective hospitals. For example, those in New York have been alerted. (See recommendations, p. 35.)

"They did send out an alert which we will be sending to all of our medical staff," says George Allen, MS, CIC, director of infection control at University Hospital of Brooklyn. "They seem to have contained it in Hong Kong, but if it happened there it certainly could happen here."

Current flu control methods called ‘adequate’

At press time, the CDC had not issued any special infection control measures should such cases arise. The prevailing opinion was that current influenza isolation measures and droplet precautions — including wearing masks within three feet of the patient — would prevent nosocomial transmission.3,4 (See highlights, p. 36.) In addition, the avian strain is susceptible to amantadine and rimantadine, antivirals that have proven potent when used as prophylaxis during influenza A outbreaks.

"Basically, we feel the current CDC recommendations in the isolation guideline and in the personnel health guideline are going to be perfectly adequate for control of either the Asian flu they are dealing with now or any other flu," says William Jarvis, MD, acting director of the CDC hospital infections program.

Though serological findings suggest some human-to-human transmission may have occurred in Hong Kong, including a possible nosocomial case involving a pediatrician, all 18 confirmed cases involve severe disease and appear to have been acquired directly from handling or working around chickens, Mahy adds.

"We have one health care worker around the first case that appeared to have seroconverted by our tests," he tells Hospital Infection Control. "We do have some difficulty interpreting these [tests] because we don’t know when they were infected. But this particular health care worker did claim that she had examined the conjunctivitis in the first case — the three-year-old — without wearing gloves and had close contact with the child. The assumption has been that may be how she seroconverted, but there hasn’t been much evidence of illness."

Indeed, the health care worker was one of four secondary contacts of the first case that showed serologic evidence of infection (elevated neutralization antibody titers) but reported few symptoms. The CDC is still analyzing tests for hundreds of contacts around the other 17 confirmed cases. A number of other health care worker contacts have actually reported symptoms, but all have been found to have another influenza strain or some other viral infection, he adds.

With all signs pointing to inefficient transmission between humans, the prime concern remains genetic reassortment. Mutable influenza strains are known to occasionally reassort genetically, resulting in antigenic "drifts" or more dramatic "shifts" that may elude the current batch of vaccine and result in increased pathogenicity. In two of the worst pandemics of this century — 1957 and 1968 — genetic reassortment occurred between human influenza viruses and avian genes from ducks. According to the Institute of Medicine (IOM) in Washington, DC, the 1957 and 1968 pandemics killed a combined total of 90,000 people in the United States alone and cost billions of dollars in medical care and total economic burden.5

The IOM notes that the infamous 1918 Spanish flu pandemic remains the single most devastating flu outbreak in human history, claiming many otherwise healthy people in a death toll that hit 20 million worldwide in less than a year. In the United States, approximately one in four people were infected and 500,000 died. The virus was never isolated, though researchers may be getting close. (See story on Arctic expedition to recover fragments of the original 1918 virus, p. 38.) The IOM concluded that though genetic reassortments that create pandemic strains are rare, "many scientists believe it is simply a matter of time before one occurs again." Indeed, at a national influenza pandemic conference in 1995, it was noted the "the ancestral viruses that caused the Spanish influenza and the viruses that provided gene segments for the Asian/57 and Hong Kong/68 pandemics are still circulating in wild birds, with few or no mutational changes."6

Pigs are often thought to be the "mixing vessel" for such reassortments because swine can carry both avian and human strains. The H5N1 strain under study in Hong Kong appears to have bypassed the intermediate pig host, directly infecting humans in an unprecedented fashion, explains Arnold Monto, MD, a lecturer at the pandemic conference and a consultant to the CDC on emerging infections.

"The curious thing about this type of influenza is, how is it getting in [to humans]?" asks Monto, professor of epidemiology at the University of Michigan School of Public Health in Ann Arbor. "There don’t seem to be receptors in humans for this kind of influenza. Nobody really knows the answer to that. In theory, this should not have happened."

Though the data are still coming in on the current Hong Kong situation, flu in general has been much underestimated as an emerging pathogen with global consequences, Monto notes.

"To me, if nothing else, this is a wake-up call because we have become totally complacent about influenza." he says. "In terms of emerging and re-emerging infections, many of the ones that are capturing a lot of attention cause far fewer deaths and illnesses on an annual basis than flu does, with 20,000 excess deaths in an ordinary year."

References

1. Centers for Disease Control and Prevention. Update: Isolation of avian influenza A (H5N1) viruses from humans — Hong Kong 1997-1998. MMWR 1998; 46:1,245-1,247.

2. Centers for Disease Control and Prevention. Isolation of avian influenza A (H5N1) from humans — Hong Kong, May-December 1997. MMWR 1997; 46:1,204-1,207.

3. Centers for Disease Control and Prevention. Draft guideline for infection control in health care personnel, 1997; notice. 62 Fed Reg 47,276-47,327 (Sept. 8, 1997).

4. Garner JS, Hospital Infection Control Practices Advisory Committee. Guideline for isolation precautions in hospitals. Infect Control Hosp Epidemiol 1996; 17:53-80.

5. Lederberg J, Shope RE, Oaks SC, eds. Emerging Infections: Microbial Threats to Health in the United States. Washington, DC: National Academy Press; 1992.

6. Webster RG. Predictions for future human influenza pandemics. J Infect Dis 1997; 176:(suppl 1)S14-S19.