Epidemiology of avian influenza A H7N9 virus in human beings across five epidemics in mainland China, 2013–17: an epidemiological study of laboratory-confirmed case series

doi:10.1016/S1473-3099(17)30323-7

The Lancet Infectious Diseases

Volume 17, Issue 8, August 2017, Pages 822-832

https://doi.org/10.1016/S1473-3099(17)30323-7 Get rights and content

Summary

Background

The avian influenza A H7N9 virus has caused infections in human beings in China since 2013. A large epidemic in 2016–17 prompted concerns that the epidemiology of the virus might have changed, increasing the threat of a pandemic. We aimed to describe the epidemiological characteristics, clinical severity, and time-to-event distributions of patients infected with A H7N9 in the 2016–17 epidemic compared with previous epidemics.

Methods

In this epidemiological study, we obtained information about all laboratory-confirmed human cases of A H7N9 virus infection reported in mainland China as of Feb 23, 2017, from an integrated electronic database managed by the China Center for Disease Control and Prevention (CDC) and provincial CDCs. Every identified human case of A H7N9 virus infection was required to be reported to China CDC within 24 h via a national surveillance system for notifiable infectious diseases. We described the epidemiological characteristics across epidemics, and estimated the risk of death, mechanical ventilation, and admission to the intensive care unit for patients admitted to hospital for routine clinical practice rather than for isolation purpose. We estimated the incubation periods, and time delays from illness onset to hospital admission, illness onset to initiation of antiviral treatment, and hospital admission to death or discharge using survival analysis techniques.

Findings

Between Feb 19, 2013, and Feb 23, 2017, 1220 laboratory-confirmed human infections with A H7N9 virus were reported in mainland China, with 134 cases reported in the spring of 2013, 306 in 2013–14, 219 in 2014–15, 114 in 2015–16, and 447 in 2016–17. The 2016–17 A H7N9 epidemic began earlier, spread to more districts and counties in affected provinces, and had more confirmed cases than previous epidemics. The proportion of cases in middle-aged adults increased steadily from 41% (55 of 134) to 57% (254 of 447) from the first epidemic to the 2016–17 epidemic. Proportions of cases in semi-urban and rural residents in the 2015–16 and 2016–17 epidemics (63% [72 of 114] and 61% [274 of 447], respectively) were higher than those in the first three epidemics (39% [52 of 134], 55% [169 of 306], and 56% [122 of 219], respectively). The clinical severity of individuals admitted to hospital in the 2016–17 epidemic was similar to that in the previous epidemics.

Interpretation

Age distribution and case sources have changed gradually across epidemics since 2013, while clinical severity has not changed substantially. Continued vigilance and sustained intensive control efforts are needed to minimise the risk of human infection with A H7N9 virus.

Funding

The National Science Fund for Distinguished Young Scholars.

Introduction

The emergence in 2013 of novel avian influenza A H7N9 virus poses a pandemic threat to human beings, and necessitates close monitoring of the virus and continuing assessment of pandemic risk.¹ Human cases of A H7N9 virus infection have occurred during annual winter-spring epidemics in mainland China since 2013.¹ After peaking in 2013–14, the number of cases identified in subsequent epidemics was generally lower, until a surge in A H7N9 cases was recorded in December, 2016, in the fifth epidemic in human beings.² The fifth epidemic that started on Oct 1, 2016, has included 447 laboratory-confirmed cases in mainland China (as of Feb 23, 2017), and is the largest epidemic wave so far. The earlier start and larger epidemic size in the fifth A H7N9 epidemic have prompted concerns about whether the epidemiology has changed to suggest an increasing pandemic threat.2, 3

Before the 2016–17 epidemic, the avian influenza A H7N9 viruses circulating among poultry in China had been classified as low pathogenic avian influenza (LPAI), and infected poultry had been asymptomatic. Experimental studies have reported that some A H7N9 virus strains have acquired tropism to bind to receptors that are present in the human upper respiratory tract, which could facilitate increased transmissibility among human beings.4, 5 On Feb 19, 2017, the Chinese Center for Disease Control and Prevention (China CDC) reported that the A H7N9 virus with a four basic aminoacid insertion in a host protease cleavage site in the haemagglutinin protein was identified in two patients with A H7N9 virus infection in Guangdong province.⁶ Moreover, such A H7N9 virus strains have evolved to become highly pathogenic in poultry.

Research in context

Evidence before this study

Avian influenza A H7N9 virus emerged in 2013, posing a pandemic threat to human beings. Human cases of avian influenza A H7N9 virus infection have occurred during annual winter-spring epidemics in mainland China since 2013. A sudden increase in human infections with avian influenza A H7N9 virus was recorded in December, 2016, in mainland China, prompting concerns of whether the epidemiology had changed to suggest an increasing pandemic threat. On March 13, 2017, we searched PubMed with the terms “H7N9” and “epidemiolog*” in title or abstract, restricting the publication date after Oct 1, 2016. We identified 12 English language publications, but none described the fifth A H7N9 epidemic after reviewing the title and abstract. We have been continuously tracking the publications of A H7N9 epidemiological characteristics and clinical assessment since Oct 1, 2016. We knew of an article published in the Western Pacific Surveillance Response Journal that described the epidemic curve of human infections with A H7N9 virus up to December, 2016, in China. However, human infections had not reached the peak when that paper was published. We also knew of a recent article published in the Morbidity and Mortality Weekly Report reporting human cases infected with A H7N9 virus until February, 2017, but no epidemiological characteristics were reported. No study assessing the clinical severity of A H7N9 virus infection for the fifth epidemic was identified.

Added value of this study

Our study presented the temporal pattern and spatial dissemination of five A H7N9 epidemics in mainland China. The fifth epidemic started earlier, spread to more districts and counties in affected provinces and infected more people compared with previous epidemics. Detailed epidemiological data for the laboratory-confirmed human cases of A H7N9 virus infection in the fifth epidemic were provided and compared with previous epidemics. Residence of patients infected with A H7N9 shifted gradually from urban to semi-urban and rural areas from the first to the fifth epidemic, although the situation varied by province. The poultry exposure risk has not changed substantially. The clinical severity of human infections with A H7N9 virus among hospitalised cases remained similar to previous three epidemics.

Implications of all the available evidence

To our knowledge, this is the first study that provides detailed epidemiological characteristics and assesses the clinical severity for hospitalised cases of human infections with A H7N9 virus in the fifth epidemic. Regular closure of live poultry market before annual winter A H7N9 epidemics and expansion of areas with permanent closure of live poultry markets are recommended. Continued vigilance and sustained intensive control efforts are needed to minimise the risk of human infection with the A H7N9 virus.

The A H7N9 virus has the highest risk score among the 12 novel influenza A viruses assessed by the Influenza Risk Assessment Tool up to date, and is characterised as posing moderate to high potential pandemic risk by the US Centers for Disease Control and Prevention.³ In addition to the ongoing monitoring of virological and molecular characteristics of A H7N9 viruses recovered from infected poultry and human beings, continuous epidemiological investigations and clinical severity assessments of patients infected with A H7N9 are crucial to inform public health for pandemic preparedness.7, 8, 9, 10, 11, 12 The present study aims to assess changes in basic epidemiology, clinical severity, and key epidemiological parameters of time-to-event distributions of patients infected with A H7N9 in the fifth epidemic compared with previous epidemics in mainland China.

Section snippets

Data

We collected individual records of all laboratory-confirmed human cases of avian influenza A H7N9 virus infection in mainland China from an integrated electronic database managed by China CDC and provincial CDCs. Every identified human case of A H7N9 virus infection was required to be reported to China CDC within 24 h via a national surveillance system for notifiable infectious diseases. Staff from the local CDCs were responsible for field investigations to collect data using a standardised

Results

The first epidemic of human infections with A H7N9 virus occurred in the spring of 2013 in mainland China, followed by four successive winter-spring epidemics in 2013–14, 2014–15, 2015–16, and 2016–17, with laboratory-confirmed cases of 134, 306, 219, 114 and 447, respectively (table 1, figure 1). The number of A H7N9 cases identified in the fifth epidemic was the highest of all epidemics and is still ongoing (figure 1). The heat map of epidemic-specific weekly proportion of

Discussion

Our study presents the temporal pattern and spatial dissemination of A H7N9 epidemics in China, provides a comprehensive description of the epidemiology of laboratory-confirmed cases of A H7N9 virus infection, and assesses the clinical severity of patients infected with A H7N9 during the fifth epidemic. The fifth epidemic occurred earlier, spread to more districts or counties in affected provinces, and infected more people than did previous epidemics. Although there was only one additional

References (27)

D van Riel et al.
Novel avian-origin influenza A (H7N9) virus attaches to epithelium in both upper and lower respiratory tract of humans
Am J Pathol
(2013)
MC Chan et al.
Tropism and innate host responses of a novel avian influenza A H7N9 virus: an analysis of ex-vivo and in-vitro cultures of the human respiratory tract
Lancet Respir Med
(2013)
H Yu et al.
Human infection with avian influenza A H7N9 virus: an assessment of clinical severity
Lancet
(2013)
BJ Cowling et al.
Comparative epidemiology of human infections with avian influenza A H7N9 and H5N1 viruses in China: a population-based study of laboratory-confirmed cases
Lancet
(2013)
JS Peiris et al.
Interventions to reduce zoonotic and pandemic risks from avian influenza in Asia
Lancet Infect Dis
(2016)
H Yu et al.
Effect of closure of live poultry markets on poultry-to-person transmission of avian influenza A H7N9 virus: an ecological study
Lancet
(2014)
R Gao et al.
Human infection with a novel avian-origin influenza A (H7N9) virus
N Engl J Med
(2013)
L Zhou et al.
Sudden increase in human infection with avian influenza AH7N9 virus in China, September-December 2016
Western Pac Surveill Response J
(2017)
AD Iuliano et al.
Increase in human infections with avian influenza AH7N9 virus during the fifth epidemic—China, October 2016–February 2017
MMWR Morb Mortal Wkly Rep
(2017)
Mutations on H7N9 virus have been identified in H7N9 patients in China

L Feng et al.

Clinical severity of human infections with avian influenza AH7N9 virus, China, 2013/14

Euro Surveill

(2014)

P Wu et al.

Human infection with influenza AH7N9 virus during 3 major epidemic waves, China, 2013–2015

Emerg Infect Dis

(2016)

Q Li et al.

Epidemiology of human infections with avian influenza AH7N9 virus in China

N Engl J Med

(2014)

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^*: Contributed equally to this work

^†: Joint senior authors

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ArticlesEpidemiology of avian influenza A H7N9 virus in human beings across five epidemics in mainland China, 2013–17: an epidemiological study of laboratory-confirmed case series

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Data

Results

Discussion

Am J Pathol

Lancet Respir Med

Lancet

Lancet

Lancet Infect Dis

Lancet

Human infection with a novel avian-origin influenza A (H7N9) virus

N Engl J Med

Sudden increase in human infection with avian influenza AH7N9 virus in China, September-December 2016

Western Pac Surveill Response J

Increase in human infections with avian influenza AH7N9 virus during the fifth epidemic—China, October 2016–February 2017

MMWR Morb Mortal Wkly Rep

Mutations on H7N9 virus have been identified in H7N9 patients in China

Clinical severity of human infections with avian influenza AH7N9 virus, China, 2013/14

Euro Surveill

Human infection with influenza AH7N9 virus during 3 major epidemic waves, China, 2013–2015

Emerg Infect Dis

Epidemiology of human infections with avian influenza AH7N9 virus in China

N Engl J Med

Articles
Epidemiology of avian influenza A H7N9 virus in human beings across five epidemics in mainland China, 2013–17: an epidemiological study of laboratory-confirmed case series