Risk assessment and management of cases of human infection with avian influenza A(H7N9) virus in China

April 18, 2013

National Institute of Infectious Diseases

Background

The following risk assessment is based upon currently available data and information and will be updated as new information becomes available. We expect to regularly update our risk assessment every one to two weeks until the situation becomes stable.

Epidemiological Information

The cluster of cases in China is the first worldwide instance of reported human infection with avian influenza A(H7N9) virus. 

• Case fatality rate is 21% as of April 18th, 2013 (17 fatal cases out of 82 reported cases).
• The clinical onset of the earliest case was on February 19th, followed by sporadic cases reported until the middle of March. The case count has been increasing steadily since late March.
• Geographically, the first case was reported from the City of Shanghai, followed by a case report from Zhejiang on March 7th, from Anhui and Jiangsu in mid-March, and in Henan and in the City of Beijing in April, respectively. Currently, there are cases reported in two cities and four provinces of China. Intensified active surveillance may reveal new cases from other areas in China.
• Demographic data show that male cases are dominant (male to female ratio: 2.7 to 1), and that the age of patients ranges from 4 to 87 years old (median: 64 years old).
• Among the limited cases for which there is sufficient information, about 60% had a history of contact with poultry, but with no source of infection specified.
• Clinical manifestations of the first reported- three fatal cases included pneumonia accompanied by systemic symptoms. Neuraminidase inhibitors were administered on the 7th or 8th day of illness, which implies a possible association between delayed treatment and disease severity.
• Mild and asymptomatic cases have also been reported. We expect to accumulate new information including clinical manifestations, natural history, immune response, and response to treatment.
• The source and route of infections to date are unknown so far.
• Potential limited human-to-human infection may have occurred in a cluster of cases among family members in late March. However contact tracing of confirmed cases has not yet found any sustained human-to-human infection.

Virological Information

• The outbreak virus appeared as a reassortant of three different avian influenza viruses.
• Molecular phylogenetics demonstrated a strong similarity of four isolates from human cases (A/Shanghai/1/2013, A/Shanghai/2/2013, A/Anhui/1/2013, and A/Hangzhou/1/2013). However, one strain (A/Shanghai/1/2013) had a nucleotide sequence distinguishable from the other three strains. This finding suggested that close but different viruses derived from the common ancestor were circulating simultaneously.
• Three strains isolated from pigeons, chickens, and the environment in Shanghai marketplaces (A/pigeon/Shanghai/S1069/2013, A/chicken/Shanghai/S1053/2013, and A/environment/Shanghai/S1088/2013) were phylogenetically similar to the three strains from the human isolates (A/Shanghai/2/2013, A/Anhui/1/2013, and A/Hangzhou/1/2013). Since there were distinct differences in some nucleotide sequences between human and avian isolates, it is not plausible that avian virus directly infected the human cases.
• HA genes of all the four human isolates had a substitution enhancing the affinity to human receptors. PB2 genes of all human cases had a substitution that was known to lower the optimal temperature of RNA polymerase from 41°C in birds to 34°C in the mammal upper respiratory tract. These strains are thought to infect and proliferate in the upper respiratory tract more efficiently in humans.
• Three birds and environmental isolates were associated with HA gene with a higher affinity to human-type receptors. However, we did not find mutations lowering the optimal temperature of RNA polymerase.
• Genetic analysis of four human isolates, two avian isolates and one environmental isolate revealed that these viruses were low-pathogenic in birds, thus leaving the infected birds asymptomatic. H7 influenza virus is generally asymptomatic in swine. Collectively, it is possible that these viruses are being transmitted among mammals, and may be the source of infection for humans.
• Nucleotide sequencing of NA gene suggested one strain of the human cases (A/Shanghai/1/2013) reduced its sensitivity to antiviral drugs oseltamivir and zanamivir (neuraminidase inhibitors). However, current enzyme activity testing indicates viruses are sensitive to oseltamivir and zanamivir.
• All the viruses tested have been found to be resistant to amantadine and rimantadine based on the M gene analysis.
• Detailed virological analyses are still preliminary with the initial limited cases. We expect further analysis and information to be forthcoming.

Risk assessment and follow-up management

• We need to collaborate with the ongoing field and laboratory investigations underway in China, since the source and route of infection are not specified and no domestic cases have appeared in Japan to date.
• We continue to collect information, assess risks, and prepare for responding to the possibility of imported cases caused by avian influenza A (H7N9) virus appearing in Japan from China.
• The target population for domestic surveillance is still unknown. We currently encourage clinicians to proactively suspect avian influenza A(H7N9) virus infection in febrile pneumonia cases who have traveled to China, and to conduct confirmatory lab testing. As of now the local public health laboratories are getting ready to perform PCR testing for H7 confirmation.
• Given the possibility of limited human-to-human transmission in a few Chinese cases, it is important to consider the potential risk of secondary human cases of infection among close contacts, such as family members.

• Upon diagnosis of the first domestic case of avian influenza A(H7N9) virus infection in Japan, steps should be immediately taken (1) to implement infection control management procedures when transporting infected patients as well as in medical facilities receiving infected patients, (2) to conduct risk assessment of cases, and (3) to begin active surveillance to inform the clinical community and the public.
• Expert consultations should be made available for the treatment of avian influenza A (H7N9) virus infection cases. We expect that severe cases can be minimized with early diagnosis and early treatment, since the avian influenza A (H7N9) virus currently appears to be sensitive to neuraminidase inhibitors.
• Although sustained human-to-human infection has not yet been confirmed, it is evident that isolated viruses from birds have shown their increased affinity for human hosts. We will strengthen our pandemic preparedness efforts through timely risk assessment.