The Epidemiological Characteristics Of Human Infections With Avian Influenza A H5N1,H7N9 And H5N6

Background:Human infections with avian influenza virus is a global public health problem,with four influenza pandemics since 1900 have been closely related with avian influenza viruses.The epidemic of avian influenza not only will inflict heavy losses on poultry farming,but also will lead to mass morbidity and death in human.Among all avian influenza A viruses,H5N1 and H7N9 are the two subtypes causing the most infections in humans.The first reported case of human illness caused by H5N1 infection occurred in 1997 in Hong Kong,China,and it is also the first reported case caused by highly pathogenic avian influenza(HPAI)virus.Human infection with H5N1 virus has high mortality,and the geographic range of affected countries has expanded.However,there is a lack of comprehensive analysis for global epidemiological of human H5N1 cases.Moreover,avian influenza A(H7N9)virus has caused human infections in China since 2013,and the number of H7N9 cases is more than the total number of cases caused by all other subtypes.Compared to previous epidemic waves of H7N9 infection in humans,the fifth epidemic wave occurred earlier and spread to more areas with more cases.However,studies are needed to assess the changing epidemiology and clinical severity of H7N9 infections in the last five epidemic waves since 2013.Avian influenza virus A(H5N6)is one of the HPAI viruses,however,there is also a lack of studies to investigate the epidemiologic characteristics of laboratory-confirmed H5N6 human cases,as well as the difference comparing to H5N1 and H7N9 human infections.Objective:To define the global magnitude and distribution of human H5N1 cases by investigating the characteristics,seasonal and geographical patterns,and high risk factors of death;to understand the epidemiological features and clinical severity of H7N9 infection by comparing the fifth epidemic wave with previous waves;to enunciate the epidemiologic characteristics of human infection with H5N6 cases by assessing the epidemiological difference between H5N6 cases and H5N1 and H7N9 infections.Methods:1.For H5N1,we collected data of all individual human cases from a variety of sources by systematic review and searching in publicly available datasets.Descriptive analyses were conducted to present the epidemiological characteristics in different regions,and heatmaps were plotted to exhibit the peak season.We mapped the global geographical distribution of human cases.The distribution of time intervals from onset of symptoms to hospital admission was presented and smoothed using kernel density estimation.2.We systematically collected information of H7N9 and H5N6 cases from the Chinese national surveillance system of notifiable infectious diseases and relevant publications.The bootstrap method and survival analysis were conducted to estimate clinical severity.Logistic regression models were used to assess potential factors associated with the risk of death among hospitalized patients.selected appropriate parametric(Weibull,Gamma and lognormal distribution)to estimate incubation period,the time from illness onset to hospital admission,the time from illness onset to hospital admission or discharge/death,the time from illness onset to initiation of antiviral treatment.We also plotted the geographical distribution and heatmaps to present the magnitude and seasonal characteristics by waves and regions.Results:1.A total of 926 human H5N1 cases were reported globally during the 20-year period from May 1,1997 through December 31,2017.The number of affected countries has risen between 2003 and 2008,with expansion from East Asia to Southeast Asia,then West Asia,North Africa and other regions,and 90%cases occurred in China,Vietnam,Cambodia,Indonesia and Egypt.66.6%cases occurred from December to March,and the overall case fatality risk was 53.5%(483/903),which varied across geographical regions.95.9%cases reported a history of poultry exposure,and 84.9%reported a history of sick/dead exposure.The cases with≥3 days from onset of illness to hospitalization were more likely to be fatal than those admitted within 3 days of onset(OR:3.6;95%Cl:2.5,5.1).Although the incidence in Egypt has increased dramatically since November 2014,compared to the cases beforehand there were no significant differences in the fatality risk,history of exposure to poultry,history of human case contact,and time from onset to hospitalization in the recent cases.The death risk was the highest(OR:11.5;95%CI:7.5,17.8)in Indonesian with a fatality risk of 84.7%.2.A total of 1,522 laboratory-confirmed human infections with A(H7N9)virus has been reported between 19 February 2013 and 30 September 2017 in mainland China.The fifth epidemic wave(1 October 2016-30 September 2017)began earlier,spread to more counties in affected provinces and had more confirmed cases than previous epidemic waves.The proportion of cases in middle-aged adults increased steadily from 41.0%to 56.9%from the first wave to the fifth wave.Proportions of cases in semi-urban and rural residents in the fifth wave were higher than those in the first four waves.The clinical severity of hospitalized cases in the fifth wave was comparable to the previous waves.Case-patients with underlying medical conditions or that received antiviral treatment>48 hours after symptom onset consistently had higher risks of death,although the adjusted odds ratios(aORs)were not statistically significant.3.A total of 19 human H5N6 cases have been reported globally as of 31 December 2017,with 13 deaths.All cases were reported in China,and mainly in the south and southwest of China.Among them,53.6%cases were having underlying medical condition.All cases received antibiotics treatment and reported recent exposure to poultry.There has been no evidence of sustained human-to-human A(H5N6)virus transmission to date.H5N6 cases were older than H5N1 but younger than H7N9 cases.H5N1 and H7N9 cases occurred more sporadically across a broader part of the country.Epidemiological time-to-event distributions were similar in the three viruses,and a wide range of duration from hospital admission to death was observed in confirmed infections of the three viruses.The time from illness onset to the initiation of antiviral treatment was shorter for H5N6 cases compared to H7N9 and H5N1 cases.Similar epidemiologic characteristics and severity were observed between H5N6 and H5N1 virus infections,while H7N9 virus infections had lower severity.Conclusions:1.The geographic distribution of human infection with H5N1 cases has been expanding,with variations in outcome,demography,seasonality and the clade or subclade of viruses across the regions.2.The age distribution and case sources have changed gradually across H7N9 epidemic waves,while the changes of clinical severity were not statistically significant.3.Similar epidemiologic characteristics and severity were observed between H5N6 and H5N1 virus infections,but H5N6 cases had higher severity than H7N9 cases.4.In view of the persistent threats to human beings by avian influenza A virus,there is a need for sustained efforts and close collaboration between countries,and conducting sustained surveillance and early clinical management for avian influenza virus infection in humans.Continued surveillances for the dynamics of avian influenza A viruses in human,poultry and wide birds are also needed as an essential component of influenza pandemic preparedness.