H7N9 gene study links patient and poultry-market viruses

Apr 25, 2013 (CIDRAP News) – A genetic comparison of an H7N9 virus from a critically ill Chinese patient with a chicken H7N9 isolate from one of the markets he likely visited showed close similarity, providing the strongest evidence yet that market poultry are a source of the virus, a Chinese research team reported today.

The report also detailed the clinical course and follow-up investigations of the patient's infection, plus three others, yielding new clues that could help guide medical management and assess the transmissibility of the disease.

The research team from Zhejiang province, an area near the center of the outbreak, reported its findings in an early online edition of The Lancet.

After the province detected its first case in the outbreak, in a 39-year-old man who worked as a chef, researchers conducted retrospective tests on nearly 500 patients who had been admitted to three hospitals for respiratory infections in the province between Mar 7 and Apr 8. They found three more H7N9 cases, which they described in today's report along with the first case. The other patients are two men, ages 64 and 68, and a 51-year-old woman. Two died, and two were still recovering at the time of publication.

All four had been exposed to poultry through their work or from visiting poultry markets, and the patients got sick from 3 to 8 days after poultry exposure. All four had underlying medical conditions, which ranged from chronic bronchitis to chronic rheumatic heart disease. Three of the patients were smokers.

To assess whether the virus was passing from poultry to humans, the researchers targeted six poultry markets that the patients had probably visited and took cloacal swabs from 20 chickens, 4 quail, 5 pigeons, and 57 ducks. They detected the virus in only 4 chickens and 2 pigeons.

Phylogenetic analysis of the gene sequence of the 64-year-old man's H7N9 isolate showed that it clustered with that of a wet-market chicken H7N9 isolate. The H7 hemagglutinin of both isolates clustered with H7N3 in Zhejiang ducks, and the N9 neuraminidase of both clustered with that from H7N9 of wild birds in Korea. The internal genes were closest to poultry H9N2 viruses in China.

Genetic analysis of the isolates revealed mutations for human receptor binding only in the human isolate, which the team said suggests the virus gained that ability when it jumped from poultry to humans.

The findings suggest sporadic poultry-to-human transmission, the group wrote. They noted that the human infections occurred at a time when migratory birds were heading north along the Yangtze River delta.

Clinically, the infections resembled H5N1 infections, with the hallmarks of fever, severe lower respiratory infection, breathing difficulty, and multiorgan involvement, the team observed. However, they said gastrointestinal problems were documented in only one patient, a pattern that appears to differ from H5N1 and 2009 H1N1 cases.

Lab studies on the patients found markers for cytokine storm, similar to H5N1 infection, at levels that seemed to correspond to illness severity. Immune modulators may be helpful for treating severe H7N9 infections, the group wrote. Three of the patients received oseltamivir, but it was relatively late in the illness course, because of late presentation and the delay in H7N9 diagnosis.

The group's follow-up of the patients' contacts found 303, including 82 healthcare workers who had unprotected contact with the H7N9 patients. During the 14-day surveillance period none of the contacts had any respiratory symptoms, suggesting that the virus isn't currently able to transmit between humans.

The World Health Organization (WHO) has reported at least three family clusters that Chinese authorities have been investigating, and a Chinese team from Shanghai included a description of two of the clusters yesterday in a New England Journal of Medicine report. Both clusters involved blood relatives.

Limited transmission isn't surprising, and so far investigations and studies have found no evidence of sustained human-to-human transmission.

In an editorial on the study in the same issue of The Lancet, two virologists from the Netherlands' National Institute for Public Health and the Environment wrote that the detailed clinical and genetic profiles of some of the outbreak's first cases are crucial for understanding the emerging disease. The authors are Marion Koopmans, DVM, PhD, and Menno de Jong, MD, PhD.

One of the study's notable findings is that viral RNA shedding can be prolonged, which could signal lack of previous immunity, comorbidity, or both, the two wrote. Another is that the virus may not be found in upper-respiratory samples, which signals the importance of obtaining lower respiratory samples, if possible. They also observed that cytokine and chemokine concentrations and viral loads were higher in a patient who died than in one who has survived so far.

The group's genetic comparison of the human and animal isolates shows that they are closely related, but when considered alongside other recent findings, enough diversity exists to suggest that the virus has been circulating a while, most likely in animals, Koopmans and de Jong wrote.

The presence in the study's human isolate, and in other H7N9 human isolates, of amino acid substitutions linked to human adaptation is worrying, they wrote. "The absence of these changes in epidemiologically linked viruses isolated from poultry suggests that these changes arose during human infection."

Though person-to-person transmission appears negligible so far, health authorities need to remain vigilant, "as just a few mutations could change this behavior," the authors said.

Chen Y, Liang W, Yang S, et al. Human infections with the emerging avian influenza A H7N9 virus from wet market poultry: clinical analysis and characterization of viral genome. Lancet 2013 Apr 25 [Abstract]

Koopmans M, de Jong M. Avian influenza A H7N9 in Zhejiang, China. (Editorial) Lancet 2013 Apr 25 [Extract]

See also:

Apr 24 CIDRAP News story "Report: Most H7N9 patients had underlying conditions, animal exposure"

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