Keeping an eye on H7N9, and learning from the past

Ann Griswold, PhD

June 2013—What began as a trickle of reports in China earlier this year swelled into a flood of patients with grave flu-like symptoms. Each time, PCR assays returned the same result: unsubtypable influenza A. Amid a rising mortality rate, viral samples were sent to China’s national laboratories for sequencing analyses. On March 31, Chinese officials posted the results to an open-access database and alerted the World Health Organization to a public health emergency of international concern: The H7N9 epidemic had begun.

Working quickly, the CDC developed an H7-specific real-time RT-PCR assay using the 19 viral sequences posted by the Chinese researchers to the Global Initiative on Sharing All Influenza Data (GISAID) database. In a rare move, the FDA approved test kits, each capable of testing about 1,000 specimens, under an emergency use authorization. This allowed distribution of the test kits to health departments in 50 states and the District of Columbia, as well as U.S. Department of Defense labs, private diagnostic test manufacturers, and WHO-recognized National Influenza Centers worldwide. Public health labs that have been certified by the CDC can order the H7N9 reagents from the Influenza Reagent Resource, and test protocols can be downloaded from the CDC’s Laboratory Support of Influenza Surveillance Web site.

With testing capabilities in place, clinicians have been advised to obtain samples from any patient with acute respiratory symptoms and a recent history of travel to an affected region. Hospital laboratories are encouraged to send samples that yield “unsubtypable” results on the seasonal flu test to their state health departments, where the CDC’s seasonal Flu rRT-PCR Dx panel will rule out other forms of influenza before the new test is used to confirm H7N9.

Though private manufacturers are modifying existing assays to detect H7N9, those assays will have to embark on a lengthy FDA approval process. Meanwhile, the test kit empowers state labs to detect H7N9, preventing a backlog of samples at the CDC. Until the FDA approves those tests, all H7N9 cases in the U.S. must be confirmed by public health laboratories following CDC-approved protocols.

In recent weeks, the lull in H7N9 cases has many wondering whether the storm has passed or whether China is merely rotating in the storm’s eye. “It’s really hard to forecast flu,” says Daniel Jernigan, MD, MPH, deputy director of the Influenza Division in the CDC’s National Center for Immunization and Respiratory Diseases. The trouble, he says, is that occurrences of human infection with avian influenza viruses normally decline in number during the spring and summer months, so the lull in H7N9 cases is to be expected.

“If you look at the epidemiology of H5 infections, in China and elsewhere, almost all of the bird and human cases occur between January and March. It’s possible we’ll see the human cases drop off. But the virus is likely to keep moving through bird markets throughout China and some of the adjacent countries, and may start to take off again when the cooler temperatures come back this fall and winter.”

And that’s if the viral sequence remains the same. If H7N9 evolves, all bets are off. “If in the course of its circulation, this new H7N9 virus has the opportunity to move back and forth between mammals and poultry, then there’s a chance it will gain adaptations that would make it more likely to spread from person to person. But there’s a fair amount of work that will need to happen before that occurs,” Dr. Jernigan says.

Soon after the H7N9 epidemic was announced, the number of cases swept into the hundreds and public health officials realized the H7N9 virus was targeting a peculiar population: older men. “The people who are getting sick are an interesting lot,” says Dr. Jernigan. By mid-May more than 130 people had been infected and about a quarter of the patients had died, many from multiorgan failure or respiratory failure. Of these, 71 percent were men and most were older than age 50. “That’s a fascinating epidemiologic finding,” Dr. Jernigan says. “It’s not what we would expect.”

Explaining the link between H7N9 and older men has proved challenging. For one thing, epidemiologists aren’t sure whether the numbers reflect exposures that are unique to older men, biological differences related to sex or age, or simply a surveillance bias. It’s possible that younger people and women are infected at similar rates as older men but less likely to develop severe illness. Indeed, one asymptomatic child in China has tested positive for H7N9. Amid the possible mechanisms, one theory has emerged as particularly plausible: “We’ve learned that in older men the prevalence of smoking is very high, and in older women it’s not very high at all,” Dr. Jernigan says. In fact, 76 percent of the cases so far have had at least one underlying condition such as lung disease.

Of these common threads in the patient medical histories, the most predictable is recent contact with live poultry. The first wave of patients included a butcher, a farmer, and a number of people who had visited live bird markets. “For a city as large as Shanghai, live bird markets require quite a lot of chickens coming in and out every day,” Dr. Jernigan says. The constant flux of feathers and fowl offers ample opportunity for avian influenza viruses to evolve. In 2006, steam spewing from the centrifuge-like defeathering machines used at live bird markets was found to transmit H5N1 influenza to bystanders, but a definitive link has not yet been established for H7N9. Epidemiologists have, however, noted a marked reduction in cases since officials closed live bird markets in China and Taiwan in early April.

China’s government has been praised for its efficient efforts to curb the epidemic. As of May 31, the H7N9 outbreak has been restricted to eight provinces and two municipalities, with just one confirmed case in a Taiwanese businessman who had traveled recently to mainland China. Still, it remains unclear whether additional infections are going undetected. “There are probably a lot of animal infections still occurring in the rural areas, and probably some human infections there too, but the surveillance systems are not in place to pick up those cases,” Dr. Jernigan notes.

In parsing the pandemic potential of H7N9, Dr. Jernigan explains, two factors are particularly worrisome. The first is the severity of the reported infections. “About 25 percent of the identified cases have died and about 30 percent have been discharged from the hospital,” he says. “So it’s still pretty dynamic. We don’t know what the outcomes will be, but we think many of the patients will probably die or have significant illness for a while.”

The second concern is the virus’ ability to move silently within the poultry population. “If birds are dying, you know where the virus is,” Dr. Jernigan points out. “You can be careful about how you handle them, and you can test people who have had contact with the infected birds.” But less than one percent of the chickens, ducks, and pigeons tested have been infected with H7N9 and in the absence of symptoms it’s impossible to know which birds are putting humans at risk.

“Together, these things indicate that H7N9 is a virus we need to watch closely,” Dr. Jernigan says. The CDC has ranked H7N9 fairly high on the Influenza Risk Assessment Tool’s “potential for emergence” and “severity of disease” scales, placing the pandemic potential of H7N9 between that of H1N1 and H5N1.

At this point, investigators have found no evidence of efficient and sustained H7N9 transmission between humans. But that could change. The H7N9 virus seems uniquely positioned to infect humans, possessing features in the hemagglutinin gene that may enhance the virus’ ability to attach to cell-surface receptors in the respiratory tracts of humans and other mammals. “That means the virus is one step closer to becoming capable of transmitting from human to human,” Dr. Jernigan warns. “Has it taken off? No, it hasn’t. Does it have the potential? Yes. But it will take some additional adaptations before that can occur.”