An outbreak of human infections with a novel avian influenza A(H7N9) virus began in February 2013 and as of December 1 had resulted in 139 confirmed cases identified in 10 provinces and 2 municipalities, primarily in eastern China. Although persons in a wide age spectrum were affected (age range, 2 to 91 years), the majority of patients with confirmed H7N9 virus infection were older (median age, 61 years), male (71%), and urban residents (73%), and most were considered to be at increased risk for complications from influenza owing to age (<5 years or ≥65 years) or the prevalence of certain underlying medical conditions. Most patients were hospitalized with severe lower respiratory tract illness,10 with a case fatality proportion of 34% to date. Except for four case clusters among family members, most patients with confirmed H7N9 virus infection were epidemiologically unrelated. Two additional cases in critically ill patients were not included in our analyses; one patient had traveled from eastern China to Taiwan, where illness onset occurred and H7N9 virus infection was confirmed,11 and one had traveled from southern China to the Hong Kong Special Administrative Region (HKSAR), where illness onset occurred and H7N9 virus infection was confirmed in early December. Since December 1, other confirmed cases of H7N9 virus infection have been identified in China, HKSAR, and Taiwan.

Human infections with avian influenza A (H7) viruses have been reported sporadically and are usually associated with exposures to poultry.12-14 Previous cases of H7 virus infection in humans have been characterized by mild illness (conjunctivitis or uncomplicated influenza) or by moderate illness (lower respiratory tract disease) that results in hospitalization.12,13,15,16 Only one fatal case of H7 virus infection has been reported previously; that case occurred in an adult with a highly pathogenic avian influenza A (H7N7) virus infection.17 Many of the confirmed H7N9 case patients had critical and fatal illness, suggesting that the H7N9 virus is more virulent in humans than are other H7 viruses. The age distribution among H7N9 case patients is older and wider than that among H5N1 case patients in China (Fig. S1 in the Supplementary Appendix), whereas the case fatality proportion and the risk of death to date are lower than those for reported cases of H5N1 virus infection in China and worldwide.18,19

Early surveillance for H7N9 cases was focused on case finding for severe lower respiratory tract illness, and since April 3, expanded testing of outpatients with influenza-like illness has identified some mild cases of illness with H7N9 virus infection.20-22 Enhanced surveillance for less severe illness with H7N9 virus infection can help to determine the clinical spectrum of the illness and the total number of cases of H7N9 symptomatic illness and to inform an understanding of the true case fatality proportion. Since this H7N9 virus appears to have emerged recently to infect humans, population immunity is expected to be low, and persons of any age may be susceptible to infection. Owing to limitations of surveillance and testing, the number of patients with confirmed cases of H7N9 virus infection is likely to be an underestimate of all symptomatic cases that have occurred. One modeling study estimated that 27,000 cases of symptomatic H7N9 virus infection (95% confidence interval, 9530 to 65,000) had occurred in China as of May 28.23 Very limited data are available from small seroprevalence studies.24,25 Larger seroepidemiologic studies among different exposed groups can help define the true denominator of H7N9 virus infections.

The median time from the onset of illness to hospitalization among the 133 of 137 patients with confirmed H7N9 virus infection for whom data on hospitalization were available was 4 days, and the median time from the onset of illness to the development of ARDS among the 48 case patients with ARDS (of 83 patients for whom data on ARDS were available) was 7 days; the corresponding median times among patients with H5N1 virus infection were 7 days and 7.5 days.18,26 The median duration from the onset of illness to death among the 47 persons with confirmed cases who died was 21 days, which is much longer than the corresponding median of 11 days among 30 persons with fatal H5N1 cases in China.

Patients with confirmed H7N9 infection received oseltamivir antiviral treatment a median of 6 days after the onset of illness (the median before April 3 was 9 days), probably owing to delays in seeking medical help and consequent delays in the identification of suspected influenza. Retrospective observational studies of influenza A(H1N1)pdm09 and H5N1 virus infections suggest that early oseltamivir treatment has the greatest clinical benefit but that starting treatment up to 5 days after the onset of illness may still reduce the risk of critical illness and death.27-30 Reports suggest that the H7N9 viruses isolated from humans and analyzed to date are resistant to adamantane antiviral agents and are susceptible to neuraminidase inhibitors.3,31,32 Early clinical suspicion of H7N9 virus infection and early administration of oseltamivir may help to reduce the severity of the disease. However, emergence of the R292K mutation in viral neuraminidase, which confers in vitro resistance to neuraminidase inhibitors, has been documented in H7N9 viruses during or after oseltamivir treatment in some critically ill patients.3,33 Therefore, to inform clinical management, clinical trials are needed to define efficacious therapy for H7N9 virus infection, including investigational agents and combination antiviral treatment.

Although the source of H7N9 virus infection in patients with confirmed cases who had exposure to animals cannot be verified without extensive H7N9 testing of animals, we suspect that it is likely to be infected poultry. H7N9 virus is a low pathogenic avian influenza A virus and does not cause identifiable illness or death in poultry; therefore, only laboratory testing can identify poultry infections. Among cases for which data are available, 82% occurred in patients who had exposure to live animals such as poultry or swine, including during visits to live animal markets. This raises the possibility of zoonotic H7N9 virus transmission from healthy-appearing poultry or swine to humans through direct or close contact or through exposure to environments that are contaminated with infected poultry or swine. For example, visiting a live poultry market, where avian influenza A viruses can be maintained and amplified, has been identified as a risk factor for H5N1 virus infection in Hong Kong34 and urban China.35,36 H7N9 virus has been isolated from poultry or environmental specimens collected at live poultry markets that were visited by some patients with confirmed cases before the onset of illness, and genetic sequencing results revealed the same H7N9 virus strain in viruses isolated from humans and from poultry or environmental samples from live poultry markets.37-40 Nine cases of H7N9 virus infection (6.5%) occurred in poultry workers, including seven workers in live poultry markets.

Further evidence implicating live poultry markets in urban areas as the source of zoonotic H7N9 virus transmission is derived from case–control studies and the observed reduction in confirmed H7N9 cases after closure of live poultry markets. One case–control study identified direct contact with poultry or birds in the 2 weeks before the onset of illness, chronic medical conditions excluding hypertension, and exposure to an environment with poultry, including visiting a live poultry market, as risk factors associated with H7N9 virus infection.41 A larger study identified visiting live poultry markets as a risk factor, and contact with poultry as an independent risk factor, for H7N9 virus infection (unpublished data from the China CDC). One ecologic modeling study estimated that closure of live poultry markets reduced the mean daily number of H7N9 virus infections in the four most affected cities by 97 to 99%.42

To date, follow-up prospective investigations of close contacts of patients with confirmed H7N9 virus infection have not conclusively established human-to-human H7N9 virus transmission. However, in four family clusters, limited, nonsustained human-to-human transmission of H7N9 virus after close, prolonged, unprotected contact with a symptomatic patient with H7N9 virus infection remains a possibility. Confirmed cases in three of the four clusters were identified in blood-related family members. Similar family clusters of H5N1 cases that occurred after common exposures to poultry or limited human-to-human transmission have been identified.8,43,44 Paired serum samples were obtained during the acute and convalescent stages of illness from contacts of case patients for further assessment of the potential for secondary human-to-human H7N9 virus transmission, including the potential identification of asymptomatic infections when testing is completed. Several studies have shown that H7N9 virus can bind to receptors in both the upper and lower airway in humans and can be transmitted variably from experimentally infected ferrets to susceptible ferrets by means of droplets.31,37,45-49 These studies support the observation that limited, nonsustained human-to-human transmission of H7N9 virus might occur.

Although the risk of human-to-human H7N9 virus transmission appears to be low, Chinese national guidelines recommend implementing control measures, such as prompt isolation of H7N9 patients; implementation of standard, contact, and droplet precautions by health care personnel in hospitals; and active monitoring of close contacts for illness. In addition, national guidelines recommend that antiviral treatment with oseltamivir should be administered as soon as possible in patients with suspected or confirmed cases of H7N9 virus infection.

Our study had several limitations. First, we were not able to collect detailed information from all patients on exposures, such as the times, frequency, intensity, and duration of exposures. Information on exposures is useful for estimating the incubation period after possible exposure to animals or live-animal markets and for evaluating risk factors for H7N9 virus infection. Second, we may not have identified all the close contacts of case patients. Third, we did not have a standard protocol and questionnaire to collect information from all contacts of the 139 patients with confirmed cases. However, the China CDC issued a guideline and protocol for field investigations of case patients and close contacts and since April 1 has provided training for personnel at all 31 provincial CDCs. A structured Internet-based reporting system was used to collect information on confirmed cases. This has helped to standardize data collection. Fourth, specimens were not available for H7N9 testing from some patients with suspected cases. It is also possible that by obtaining a single throat swab to test for the presence of the H7N9 virus, as compared with obtaining multiple specimens from different respiratory sites on different days, we could have missed detection of the virus in symptomatic contacts. Paired serum samples have not been obtained from some of the contacts because they have declined to have serum collected. Fifth, in-hospital mortality may be an underestimate of H7N9-associated mortality; one patient with a confirmed case was hospitalized, recovered, was discharged, and later died of an underlying medical condition but was not included as one of the 47 deaths among hospitalized patients with confirmed cases. Owing to surveillance limitations, some H7N9 virus infections have probably been missed.23 Finally, since the outbreak is ongoing, we were unable to include in our analyses data from the patients with confirmed H7N9 cases that have been identified since December 1, 2013, or from their close contacts.

In summary, a novel avian influenza A(H7N9) virus has caused severe and fatal lower respiratory tract illness in persons in 12 different areas of China. Some clinically mild cases have been identified since the surveillance was widened, suggesting that there is a wide clinical spectrum of H7N9 virus infection. The epidemiologic findings suggest that most confirmed H7N9 cases were epidemiologically unrelated. On the basis of data from various studies to date, most case patients were probably exposed to H7N9 virus and infected during visits to live poultry markets, and the decline in cases during May followed the closure of live poultry markets in Shanghai municipality and nine provinces. Follow-up investigations of contacts of patients with confirmed H7N9 virus infection suggest that the risk of secondary transmission of H7N9 virus, including to health care personnel, is low at this time. However, in four family clusters, limited, nonsustained human-to-human transmission of H7N9 virus could not be ruled out and may have occurred.

On the basis of the experience with increased circulation of H5N1 virus among poultry during periods of cooler temperatures, the spread of H7N9 virus among poultry is likely to increase during the winter and spring months, with the potential for increased transmission to exposed persons. Therefore, enhanced surveillance for H7N9 virus among poultry and people, investigations of contacts of confirmed cases, and virologic analyses to assess genetic changes that might suggest increased transmissibility among humans are all critical to informing prevention and control efforts and assessing the pandemic potential of this H7N9 virus. Prompt closure of live poultry markets is indicated in areas where new human cases of H7N9 virus infection are detected.

Editor's note: As of January 21, 2014, more than 200 confirmed cases of H7N9 had been identified since February 2013, including more than 65 since December 1, 2013, in this ongoing outbreak.