CDC airs H7N9 worries as report profiles early victims

Apr 11, 2013 (CIDRAP News) – US health officials voiced concern about the emerging H7N9 influenza virus in China today as a report in the New England Journal of Medicine (NEJM) described the severe illnesses that killed three of the first patients identified.

The NEJM article offered a sobering list of complications in the three patients, including respiratory failure, septic shock, multiple organ failure, and several more. All three patients had preexisting medical conditions, and two of them had been exposed to poultry.

In an accompanying perspective article and at a press conference, flu experts with the US Centers for Disease Control and Prevention (CDC) showed their concern about the severity of illness and the virus's epidemiologic characteristics. They also revealed that a few US travelers returning from China have been tested for H7N9, with negative results.

In the perspective piece, two CDC experts suggested that developing a vaccine for H7N9 may be a tough challenge, because vaccines previously developed for H7 subtype viruses as part of pandemic preparedness efforts induced poor immune responses in humans.

At the press conference, Nancy Cox, PhD, director of the CDC's Influenza Division, cited several other reasons for concern. First, she said the virus "causes quite severe illness in people who have been infected. However, once we learn more about possible mild cases, we'll be able to determine the true severity of illness."

In response to questions, she said the CDC is aware of eight mild cases, out of the 38 cases that have been identified in China thus far. (The World Health Organization, in an update today, listed nine mild cases.)

"Our information is incomplete, but out understanding is that at least one patient has recovered and been discharged, and the good news is that it appears that from the illness onset data provided, our Chinese colleagues are identifying cases earlier and getting them treated earlier," she added.

Another worry is that genetic sequences of the viruses show they may have adapted to infect mammals more easily than other avian flu viruses can, Cox said. Third, she said, "This virus doesn't cause notable illness among birds and poultry, which increases the potential for wide geographic spread in bird populations."

The NEJM report, written by a large Chinese team, describes fatal illnesses in an 87-year-old Shanghai man, a 27-year-old Shanghai man, and a 35-year-old woman from Anhui province. All of them fell ill with fever, cough, and dyspnea; they died after illnesses lasting from about 12 to 27 days.

The older man had a history of chronic obstructive pulmonary disease, while the young man, a butcher, had a history of hepatitis B infection and the woman had a history of depression, hepatitis B, and obesity. The two younger patients had had some recent exposure to poultry, but the older man had not.

The report says the three patients did not receive antiviral treatment until the seventh or eighth day of illness, which is well beyond the 2-day window that's recommended for best results with oseltamivir (Tamiflu) or zanamivir (Relenza).

In their commentary, the CDC authors, Cox and Timothy Uyeki, MD, MPH, write, "The clinical features described in the three patients with H7N9 infection, including fulminant pneumonia, respiratory failure, acute respiratory distress syndrome (ARDS), septic shock, multiorgan failure, rhabdomyolysis, and encephalopathy, are very troubling.

At the press conference, Uyeki, also with the CDC's Influenza Division, commented, "What is worrisome is the constellation of findings, suggesting rapidly progressive viral pneumonia with acute respiratory distress syndrome." He said all of the complications cited in the three patients have been seen in seasonal and pandemic flu cases, but they are rare.

Genetic analysis showed that one of the two Shanghai viruses was phylogenetically distinct from the other one and the Anhui isolate, which suggests that "there have been at least two introductions into humans," the NEJM report says. Health officials repeated today that they have not yet seen evidence of human-to-human transmission.

Both of the NEJM pieces say that one mutation found in H7N9, called Q226L, has been shown to be associated with spread of H5N1 virus by respiratory droplets in ferrets—one of the findings in two controversial studies published last year that described lab-modified H5N1 strains.

The Chinese authors cite two other mutations that, on the basis of findings in animals, "may contribute to the human infections and severe disease": a deletion of five amino acids in the viral neuraminidase stalk and substitution E627K in the PB2 gene.

As for vaccine development, Cox said at the press conference that some previous H7 viruses, including H7N3 and H7N7 strains, had been suggested to have pandemic potential, which triggered development of vaccines. Clinical trial lots of vaccine were made for some strains.

"In all cases where these were trialed, it was found the vaccines were poorly immunogenic, and this is a signal that we might be facing challenges in producing an immunogenic vaccine using this virus," Cox said.

In the commentary, she and Uyeki suggested that vaccine development could be slow. "Even if new vaccine manufacturing technologies, such as tissue-cell-culture–derived vaccine antigens, are utilized, the process from vaccine development to availability will probably take many months," they wrote.

CDC officials said today that they have received an H7N9 isolate from China. They said last week that isolates would be used to develop diagnostic test kits, help make a vaccine, and test for antiviral susceptibility.

In response to questions, Cox revealed that "a few" illnesses in travelers returning from China have been investigated by states and/or the CDC. "All of them are negative," she said.

When reporters pressed CDC officials to compare their levels of concern over H7N9 and H5N1, Cox said, "I'd have to say that it's very similar to the level of concern for H5N1 in many respects."

H5N1 viruses have a very wide geographic spread, while that's not known to be the case with H7N9, she said. "But on the other hand, , the fact that we're hearing about an additional two to maybe five cases per day in China sort of raises the level of concern in the opposite direction in favor of H7N9. They're difficult situations to compare, so it's hard to say one is worse than the other."

Later, she mentioned the more than 300 cases of variant swine-origin H3N2 viruses found in the United States last summer and fall, mostly mild and mostly in children. "Each different emergence of novel influenza A virus in human is a story of its own. We're very early on," she said. "We have to watch very carefully and see how the H7N9 story unfolds."

See also:

Apr 11 NEJM report

Apr 11 NEJM commentary

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