Spatial and temporal clusters of avian influenza a (H7N9) virus in humans across five epidemics in mainland China: an epidemiological study of laboratory-confirmed cases

From 2013 up to now, the avian influenza A (H7N9) virus infections in humans in mainland China are unprecedented both in terms of mortality and morbidity [1‐3], with the risk of continuous emerge and spread for the virological and molecular characteristics of the virus [4‐8]. The A (H7N9) virus has the highest risk score among the 12 novel influence A virus assessed by the Influenza Risk Assessment Tool [9]. The risk assessment of A H7N9 is crucial for pandemic preparedness of public health, especially in the neglected locations [10].

Many researches have descripted the characteristics of the epidemics. Clinical features of human infections in China reported during the five epidemics were similar [1], and the spatial and temporal characteristics were not [11]. According to the research of the fourth epidemic, the area which had never been reported with cases before announced confirmed cases during the fourth epidemic [8]. At the same time, the start time differed across the epidemics, shifting gradually from February–April to December–March [7].

Surprisingly, although five epidemics have occurred in China, the evidence of spatial and temporal features have been gained through description methods without statistical inference [12]. Moreover, the inherent bias may be present due to the cases centralized at the prefecture or province level. Continuous epidemiological investigations should be crucial to outline the epidemic trajectory and inform public health for pandemic preparedness [13‐16]. In comparison of the epidemic description on the province level, the present study aimed to assess spatial and temporal variation across five epidemics through appropriate statistical inference methods. The result can help the public understand epidemic regulations better and enhance the emergency capacity of public health in China.

Our study presented the temporal and spatial features of avian influenza A (H7N9) virus in humans across the five epidemic in mainland China through the statistical inferences of the clusters. We demonstrated there were aggregation distributions in the east of China initially, followed by the inner and west of China presented cluster in the fourth and fifth epidemics. Moreover, the peak periods shifted gradually from the first until the fifth epidemic. The results were similar with Dong’s description results [20].

The Yangtze River Delta region and the Pearl River Delta region were higher intensity regions, especially the Yangtze River Delta region. The fourth epidemic has begun to expand to the central China, and the fifth epidemic has expanded to the northern and western regions. There was contest that geographical expansion of A (H7N9) virus implied the human-human epidemic trajectory. However, the evidence was not sufficient. The Yangtze River Delta region is well recognized as the original source for H7N9 outbreaks with the Pearl River Delta region as an additional region across the first three waves [21]. The H7N9 virus may spread silently due to most of them belonging to Low pathogenic avian influenza (LPAI), and then break human-animal interface without disease in poultry [22, 23]. The low pathogenic phenotype in poultry, the strains circulating in local farms and Live poultry markets (LPMs), converted into the high pathogenic phenotype with the four amino acids inserting into the HA cleavage site during the fifth wave [24, 25]. Local density of LPMs was the most important predictor of H7N9 infection risk [22, 26, 27]. LPMs, keeping the avian in crowded conditions which may facilitate avian influenza virus genetic reassortment, have been considered as the reservoir and amplifier for avian influenza viruses [28]. Higher density of markets may exacerbate the risk and explain the strong spatial correlation with H7N9 infection [29]. For the persistent circulation of H7N9 viruses in poultry, poultry trading and movements may contribute to the geographic expansion of the virus [21]. In accordance with the researches, exposure to LPMs was the major epidemic trajectory. Although spatial clusters virtually existed, there has been no evidence of sustained human-to-human transmission so far. To a certain extent, LPM closures were effective in the control of human risk of avian influenza A (H7N9) virus infection [30, 31], which was only a temporary measure for eliminating the source of the infection [30].

The peak incidence was concentrated in February and March, March in first epidemic and February in the following epidemics respectively. The result wasn’t consistent with prior reports. Lei [2] and et al. indicated that the fifth epidemic began earlier and increased rapidly through the description of the epidemics. However, the peak period was not earlier than before via statistical inference in our study. Li [32] and et al. found temperature and rainfall played important roles in the risk of human H7N9 infection, the same as research of Hu [33] and et al. The seasonality of A (H7N9) virus favoring the temperature ranged from approximately 9 °C to 19°Cwas related with the meteorological condition, and the at-risk period may shift gradually across China [33, 34]. For the climate condition, the peak incidence may not shifted significantly.

In response to the epidemic situation, a series of measures and interventions have already been implemented by the national and local authorities. Inter-departmental alliances and effective implementation of evidence-based disease management were crucial to form One Health in China [35]. It is necessary to facilitate the capacity to rapidly detect and contain public health threats at their source via risk communication [36].

Our study had the limitation. Our study analysed only laboratory-confirmed human infections with A (H7N9) virus and excluded the clinically mild cases without confirmed test. Dennis [37] and Yang [38] confirmed there was “clinical iceberg” phenomenon in influenza A (H7N9) in humans through the serological study. Therefore, the full spectrum of human infection may be different from the confirmed cases.

This analysis provided the statistical inference of spatial and temporal cluster of A (H7N9) epidemic in humans, and presented the aggregation distribution and peak periods. Yangtze River Delta region and the Pearl River Delta region had the spatial cluster and the peak period was from January to April. The spatial scope has begun to expand since the fourth epidemic and temporal heterogeneity varied slightly. With the evaluation, it is necessary to improve the comprehensive collaboration of inter-departmental alliances to monitor continuously, assess risk regularly and communicate epidemic risk.