Epidemiologic characterization of 30 confirmed cases of human infection with avian influenza A(H7N9) virus in Hangzhou, China

China reported the first events of human infection with H7N9 avian influenza A(H7N9) virus in March 2013. The virus has been proved to be a novel strain, the first of its kind ever found to infect humans, which was previously found only in wild bird populations. Avian influenza has caused frequent epidemics in humans and animals in recent years, the H5N1 avian influenza in 2005 and the novel H7N9 human influenza epidemic in 2013 in particular, which draws global attention. The avian influenza viruses isolated from domestic fowl and wild birds in many Asian, African and European countries not only cause devastating damage to the avian industries but pose a severe threat to public health of humanity [1–5]. Studies have revealed such viral strains as H7N1, H7N2, H7N3, H7N4, and H7N7 to cause outbreaks of avian influenza, which led to mass culling of over 75 million domestic birds [1]. Over the last few decades, researchers have realized that avian influenza viruses may be linked with human infections, primarily transmitted from domestic birds to humans directly [3, 6–9]. Infections and deaths attributed to the H9N2 [6], H7N3 [10], H7N2 [11], H7N7 [12], and H5N1 strains [7] have been reported globally. In March 2013 cases of human infection with avian influenza A(H7N9) virus were first reported in Shanghai and Anhui province of China, followed by cases in the surrounding cities and provinces. Most of the cases were severe with high fatality. By 17:00 May 1, 2013 China had reported a total of 129 confirmed cases, including 31 deaths, 42 recoveries, and 56 patients currently treated at designated facilities. By far the cases have been sporadic except for the household clusters found in Shanghai and Beijing. Of the 46 confirmed cases in Zhejiang province, 30 were found in Hangzhou city, including one pregnant woman and three deaths. In characterizing the cases to support future prevention and control, we report the clinical and epidemiologic characteristics of the 30 Hangzhou cases and their environmental test findings.

Field epidemiologic surveys were launched to attain the patients’ clinical and epidemiologic data, including their demographic information, disease onset, medical management, clinical presentations, dwelling environments and exposures, domestic fowl keeping, living habits and customs, past histories, possible sources of infection, transmission routes, and exposure factors. Close contacts of the patients were placed on medical observation. Informed consent to participate in the study was obtained from all the involved individuals. The current work was approved by the Hangzhou Center for Disease Control Ethics Committee (approval number: 47011685-X).

The epidemiologic surveys were carried out by epidemiologists from Hangzhou city and the local districts and counties, following the Prevention and Control Protocol for Human Infections with Avian Influenza A(H7N9) (1^st Edition) [13] issued by the National Health and Family Planning Commission (NHFPC). Throat swabs were collected from the patients and close contacts, which were packed and shipped, following the appropriate national bio-safety regulations, to the Influenza Monitoring Network laboratory for etiologic studies within 24 hours. All of the throat swabs were collected during standard medical care.

A total of 30 confirmed cases of human inflection with avian influenza A(H7N9) virus were reported in Hangzhou between April 1 and May 1, 2013, including 12 moderate and four severe cases. The clinical characteristics were consistent with the other cases reported in China [17–19]. The time series of disease progression indicate rapid progressive aggravation of severe pneumonia. The results of the current study are in alignment with the median duration before hospitalization reported by QIAN Fang, where the patients also experienced rapid progression [20].

As a newly emerging infectious disease, human infection with H7N9 avian influenza virus has drawn high attention in the professional and international communities. Timely detection is of grave importance for prevention and control measures. The 30 cases of human inflection with avian influenza A(H7N9) virus in Hangzhou were found by medical facilities through surveillance and screening of pneumonia of unknown cause and reported via the Online Direct Reporting System.

In further understanding the possible sources of infection and assessing risks of human infection, environmental specimens were collected from the live poultry markets that the patients and their family had visited as well as from poultry workers, close contacts of patients, and flu-like cases for etiologic studies. Pearson χ ² test results indicate a statistically significant difference (χ ²  = 16.563, p < 0.05) between the case-related environmental specimens and the non-case specimens in terms of H7N9 viral nucleic acid positive rate. None of the close contacts manifested progressively aggravating flu-like or pneumonic symptoms. This suggests that virus activity may exist in absence of an animal outbreak in the live poultry markets. Information on the virus-bearing animals, contaminated environments, pathogenic homology and the exposure history of population makes possible a general portrait of the chain of transmission. Testing and medical observation of close contacts have so far yielded no evidence of human-to-human transmission. Etiologic monitoring of outpatients with flu-like symptoms has documented no mild cases of H7N9 infection. However, as the monitoring employed throat swabbing, the results might be less sensitive compared with serologic testing and further evidence, serologic test results for example, may be needed.

Exposure mode investigation indicates that most patients were retired elderlies, who visited live poultry markets on a daily basis to purchase food ingredients, including live poultry products. It is a common practice in China that live poultry is slaughtered on site of purchase in the market to ensure freshness, which is believed to keep the food tasty. As a result, it was likely that the patients were repeatedly exposed in the less hygienic markets for significant periods of time, who were in immediate contact with live fowl and freshly slaughtered poultry products without appropriate nose and hand protections. Sustained exposures in the live poultry markets makes calculation of incubation period difficult. Fifteen of the Hangzhou cases had continual exposures between disease onset and hospitalization, where the exact valid exposure time points could not be determined to calculate the incubation periods. However, definitive time points of exposure to live poultry and/or the environments of live poultry markets before disease onset were available for 12 cases, including nine cases with single exposure time points, based on which the incubation period was calculated to be 1–14 days (median: 7 days), which is longer than that of avian influenza H5N1 in China. A study by HUAI Y indicates that based on the exposure and onset data of 24 confirmed H5N1 cases, the median incubation period of H5N1 avian influenza in China is calculated to be 5 days (range: 2–9.5 days) [21]. A more accurate incubation period of H7N9 may be determined by investigating the 127 confirmed cases countrywide in China.

At the moment, H7N9 cases are sporadic and scattered events except for the household clusters found in Shanghai and Beijing, and the main source of infection remains unclear [22]. The current work may not have covered all possible sources of infection. Despite a thorough infection source investigation carried out by a joint survey team, the sources of three confirmed cases remain undetermined. A similar situation was seen in an H5N1 study in Guangdong province, China [23].

The H7N9 PCR positive rate was the highest in the environmental specimens from Yuhang District, where only two cases were confirmed. In contrast, the other districts saw more cases despite lower environmental detection rates, Shangcheng District for instance, where eight cases were found while the environmental positive rate was lower. Yuhang is the largest district of Hangzhou city, where two major designated markets supply more than half of the live poultry for the rest of the city. Compared with Yuhang District, the population in the other districts is less dense. Additionally, the live poultry vendors are mixed with other food stalls, which the people in the other district visit on a daily basis. This might explain the higher environmental detection rate with fewer cases in Yuhang District.

According to the existing data, the main route of transmission is believed to be avian-to-human. The sources of infection could be exposures to live poultry markets. The mode of infection remains unclear. Humans generally lack immunity to the novel infectious disease and effective immunization is currently unavailable. Therefore, cutting of the chain of transmission and effective environment disinfection and isolation measures seem particularly important.

Most of the infected were retired individuals aged 60 years or older. Men made the majority. The cases are sporadic at present, with no evidence of human-to-human transmission. Exposures to poultry and live poultry markets may be important sources of infection.