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China?WHO Joint Mission on Human Infection with Avian Influenza A(H7N9)Virus - 18 ? 24April 2013, Mission Report (WHO, May 18 2013)
[Source: World Health Organization, full PDF document: (LINK). Edited.]
China?WHO Joint Mission on Human Infection with Avian Influenza A(H7N9)Virus - 18 ? 24April 2013, Mission Report
Executive Summary
Introduction
On 31 March 2013, in accordance with the International Health Regulations(2005)[IHR], the Government of China reported the detection of three cases of human infection with a novel influenza A(H7N9) virus (hereafter,H7N9) in Shanghai and the province of Anhui. At the same time,the Chinese Center for Disease Control and Prevention (China CDC) posted full genome sequences of viruses isolated from the first three cases in a publicly accessible database. Overt he next two weeks additional cases were confirmed in the municipalities of Shanghai and Beijing, and in the provinces of Anhui, Jiangsu and Zhejiang. Most cases were marked by severe pneumonia and a substantial number of deaths followed. Investigations identified live bird markets as a possible source of human infection.
In response to this situation and at the invitation of the National Health and Family Planning Commission of China, a China─WHO Joint Mission on Human Infection with Avian Influenza A(H7N9) Virus was formed to assess the outbreak and provide guidance on its management (see terms of reference in Annex 3. The Joint Mission was composed of experts from China and WHO and four from Australia, Europe, Hong Kong, Special Administrative Region of China, and the United States of America. The team visited Beijing and Shanghai over 6 days, 19 ? 24 April 2013, meeting with senior officials and many experts from the human and animal health sectors involved in the continuing outbreak investigation, following an agreed method of work (see Agenda in Annex 6).
Although the team was unable to visit other affected areas because of time constraints, outcomes of the extensive investigations already undertaken in China were openly shared and vigorously discussed. The team?s findings, assessment and recommendations were formed on the basis of the data available, site visits and discussions. These are presented in this report.
Main Findings
Epidemiology
As of 22 April 2013, 104 confirmed cases, including 21 deaths, have been reported in Zhejiang (40 cases), Jiangsu (24),Henan (3), Anhui (3) provinces, Shanghai (33), and Beijing (1). Patients are predominantly older (median 62 years) and male (69%). Of 77 cases reported nationally for which data are available, 18 (23%)reported no identified contact with poultry; 56 (72%) reported some recent contact with live poultry and live poultry markets.
An additional case in an asymptomatic four‐year‐old boy was detected by Beijing CDC during enhanced case finding that followed the identification of the first case in Beijing.
Almost all cases have been sporadic but three family clusters have been identified. Evidence thus far is not sufficient to conclude that person‐to‐person transmission has occurred. Of more than 3000 close contacts, 19 developed respiratory symptoms. None of these symptomatic patients tested positive for H7N9 by reverse‐transcriptase polymerase chain reaction (RT‐PCR) testing. Results of serology testing are pending.
On 1 April, enhanced surveillance was introduced throughout the country for pneumonia of unknown origin and in sentinel influenza‐like illness(ILI) surveillance sites; molecular diagnostic kits were also distributed. Since then, an increase has been observed in the number of ILI consultations in ILI sites. This increase isomer likely to be related to concerns among the population than to an increase inH7N9 cases. Enhanced ILI surveillance has identified one ILI case that tested positive for H7N9 by RT‐PCR.
Although it is too early to confirm the effectiveness of the closure of live bird markets in Shanghai, which took place on 6 April, no new cases have been reported there with dates of onset later than 13 April.
Areas of major uncertainty
Some important uncertainties remain, including the following:
Clinical features and management
The most common presenting signs and symptoms were those characteristic of influenza. Encephalopathy and conjunctivitis were uncommon, and nasal congestion and rhinorrhea were not reported as initial presentations. Common laboratory findings included normal white cell count, leukocytopenia, lymphocytopenia, thrombocytopenia, and mildly elevated liver enzymes. Most cases were severe, and a number of these rapidly deteriorated within 1 to 2 days of hospitalization to acute respiratory failure, leading to refractory hypoxemia and multiple organ failure, the major cause of death. A few mild cases were reported, especially in children.
Neuraminidase inhibitors (NAIs) were given to almost all patients but only after a median of 6 days after disease onset.
NHFPC developed a risk‐based management protocol for areas where confirmed cases are reported so that NAIs could be given earlier to symptomatic cases, even before the confirmatory result of laboratory tests for H7N9 virus.
Infection prevention and control measures in fever clinics and designated hospitals complied with national and WHO guidance.
Characteristics of avian influenza A(H7N9) viruses
The novel viruses are reassortants, comprising H7HA, N9NA and the six internal genes of H9N2 influenza A viruses. This combination of influenza genes has not previously been identified among viruses obtained from birds, humans or any other species, although individual genes are related to those of recent avian influenza viruses circulating in East Asia.
H7N9 viruses obtained from human cases, poultry and environmental samples are closely related and contain a number of genetic signatures previously associated with low pathogenicity in poultry, enhanced capacity for mammalian infection and resistance to the adamantane class of antiviral drugs. Several human H7N9 viruses were shown to be sensitive to the NAIs oseltamivir and zanamivir in vitro. It is important to note that one mammalian adaptation (E627K in the PB2 gene) occurred in many of the human H7N9 viruses but did not occur in any of the non‐human viruses. Continuing analyses are essential to improve understanding of these viruses and to detect any future changes affecting their transmissibility between humans and their pathogenicity in birds.
Preliminary analyses suggest that many people lack antibodies to this virus and that production of an effective vaccine will require the selection of a new candidate H7 vaccine virus.
Animal health
The detection ofH7N9 virus in live poultry markets in the vicinity of human cases in Shanghai, the contact history with live poultry or live poultry markets in a substantial number of cases, and the apparent reduction in human cases after the closure of live poultry markets in Shanghai, suggest exposure to live poultry as a key risk factor for human H7N9 infection. Although the H7N9 virus has not been detected in poultry farms so far, it is likely that they provide the source of infection, with subsequent amplification within live poultry markets leading to human infections.
Although data are limited at this early stage of the investigation, it may be that the H7N9 virus is currently sustained through intra‐ and inter‐provincial trading of live poultry. If infection in poultry is not controlled the H7N9 virus may spread to additional provinces in China, leading to an even greater zoonotic threat, and thus increasing its pandemic potential. It may also facilitate the emergence of a virus that is highly pathogenic in poultry. The human and poultry viruses genetically sequenced thus far show that this H7N9 virus has adaptations that allow it to infect humans, although virological information is limited as the animal A(H7N9) test and the test strategy in China remain to be validated.
Response strategies and measures
A joint multi‐sectorial prevention and control mechanism(JPCM) has been established at national and local levels to lead and coordinate the emergency response to H7N9 virus. The national JPCM, led by the National Health and Family Planning Commission, consists of 13 governmental ministries and commissions, including the Ministry of Agriculture, the State Forestry Administration, and the Ministry of Science and Technology. An inter‐regional JPCM has also been established to support sharing of information and coordinated response among the affected provinces and municipalities, including Anhui, Jiangsu, Shanghai, and Zhejiang. Significant efforts are being made to ensure that the emergency response to the newly detected H7N9 virus is based on laws and regulations, the principle of transparency, prioritization and international collaboration. An approach based on risk assessment and evidence is being applied to inform coordinated, balanced public health interventions.
Coordinated but tailored response strategies and guidance have been provided to the different provinces based on the epidemiological situation and local needs. Early detection, early reporting, early diagnosis and early treatment ("the Four Earlys") have been the general guiding principles for the operational response.
Response measures include close collaboration between public health and animal health sectors, enhanced surveillance in humans and animals, case investigation, field investigation, risk assessment, clinical management, hospital infection prevention and control, public health interventions, risk communication, and research. Reagents for PCR detection ofH7N9 viruses in humans have been distributed to more than 400 laboratories throughout China. Several national guidelines have been issued for surveillance and epidemiological investigation, including contact tracing, laboratory testing and patient isolation and treatment.
The priority response measures have been focused on the following:
International collaboration
Any novel influenza A virus that causes human infections is of global interest and, if disease is severe, is a cause for serious concern. After it first identified the H7N9 virus, China recognized its vital role in contributing to global public health through open channels of communication with global influenza partners and the international community.
On 31 March 2013 the China National IHR Focal Point notified WHO of the first three cases of human infection with H7N9 virus and has since made regular reports to WHO and its Member States. Regular situation updates and transparent sharing of information have demonstrated the openness of Chinese Government authorities. In addition, China CDC has shared genetic sequence data, diagnostic test protocols and viruses with the global public health and research communities. The National Avian Influenza Reference Laboratory, Harbin, has also shared genome sequences of H7N9 viruses. These actions have contributed greatly to the global risk assessment and response, including the selection and development of candidate human H7N9 vaccine viruses and vaccine potency and diagnostic reagents, as well as a better understanding of antigenicity, pathogenicity and transmissibility of the virus.
The National Health and Family Planning Commission has maintained close technical collaboration with WHO staff through China CDC. As a newly designated WHO Collaborating Centre for Reference and Research on Influenza, the National Influenza Centre in China has maintained regular communication and technical discussions with other WHO Collaborating Centres for influenza. As a member of the Global Outbreak Alert and Response Network (GOARN), China CDC provided a situation update to GOARN partners.
In summary, China?s transparent and timely sharing of technical information, data and viruses is greatly appreciated and has contributed immensely to current global understanding of the H7N9 virus, risk assessment and actions required to manage the shared risk.
Assessment
In March 2013, China identified three human infections by an avian influenza A(H7N9) virus.
This virus had never been known to infect people before. China responded quickly including by establishing a joint multi‐sectorial coordination mechanism, initiating several investigations, notifying WHO under the International Health Regulations 2005), posting sequences of the virus, sharing viruses with the WHO Influenza Collaborating Centers and other laboratories and mounting effective countermeasures such as closure of live poultry markets in some locations. The response has demonstrated that health authorities were well prepared and acted quickly, effectively and professionally.
Since then, this virus has caused over 100 human infections. Most of these infections have led to severe disease, including more than 20 deaths.
Currently, evidence so far is not strong enough to conclude there is person‐to‐person transmission. The limited available information suggests that many infections caused by this virus may be related to exposure to infected poultry in live poultry markets or to environments contaminated by this virus.
However, future studies can strengthen the evidence.
The risk to people posed by the emergence of the H7N9 virus must be considered unusually serious, for several reasons. First, this virus has caused serious disease, including death, in some people. Second,this virus does not appear to cause disease in poultry (although it could change in the future to become highly pathogenic) and therefore could spread silently. Third, this virus has caused more human infections and disease in a shorter period of time than any other known avian influenza virus.
Fourth, some H7N9 viruses show genetic changes that suggest they are partially adapted to infect humans more easily than other avian influenza viruses. Taken together,these findings suggest that the possibility of this virus becoming transmissible among people is higher than for any other known avian influenza virus and therefore it must not be ignored.
On the basis of this assessment, the Joint Mission has made seven high‐level recommendations to the Government of China, as below.
Recommendations
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China?WHO Joint Mission on Human Infection with Avian Influenza A(H7N9)Virus - 18 ? 24April 2013, Mission Report
Executive Summary
Introduction
On 31 March 2013, in accordance with the International Health Regulations(2005)[IHR], the Government of China reported the detection of three cases of human infection with a novel influenza A(H7N9) virus (hereafter,H7N9) in Shanghai and the province of Anhui. At the same time,the Chinese Center for Disease Control and Prevention (China CDC) posted full genome sequences of viruses isolated from the first three cases in a publicly accessible database. Overt he next two weeks additional cases were confirmed in the municipalities of Shanghai and Beijing, and in the provinces of Anhui, Jiangsu and Zhejiang. Most cases were marked by severe pneumonia and a substantial number of deaths followed. Investigations identified live bird markets as a possible source of human infection.
In response to this situation and at the invitation of the National Health and Family Planning Commission of China, a China─WHO Joint Mission on Human Infection with Avian Influenza A(H7N9) Virus was formed to assess the outbreak and provide guidance on its management (see terms of reference in Annex 3. The Joint Mission was composed of experts from China and WHO and four from Australia, Europe, Hong Kong, Special Administrative Region of China, and the United States of America. The team visited Beijing and Shanghai over 6 days, 19 ? 24 April 2013, meeting with senior officials and many experts from the human and animal health sectors involved in the continuing outbreak investigation, following an agreed method of work (see Agenda in Annex 6).
Although the team was unable to visit other affected areas because of time constraints, outcomes of the extensive investigations already undertaken in China were openly shared and vigorously discussed. The team?s findings, assessment and recommendations were formed on the basis of the data available, site visits and discussions. These are presented in this report.
Main Findings
Epidemiology
As of 22 April 2013, 104 confirmed cases, including 21 deaths, have been reported in Zhejiang (40 cases), Jiangsu (24),Henan (3), Anhui (3) provinces, Shanghai (33), and Beijing (1). Patients are predominantly older (median 62 years) and male (69%). Of 77 cases reported nationally for which data are available, 18 (23%)reported no identified contact with poultry; 56 (72%) reported some recent contact with live poultry and live poultry markets.
An additional case in an asymptomatic four‐year‐old boy was detected by Beijing CDC during enhanced case finding that followed the identification of the first case in Beijing.
Almost all cases have been sporadic but three family clusters have been identified. Evidence thus far is not sufficient to conclude that person‐to‐person transmission has occurred. Of more than 3000 close contacts, 19 developed respiratory symptoms. None of these symptomatic patients tested positive for H7N9 by reverse‐transcriptase polymerase chain reaction (RT‐PCR) testing. Results of serology testing are pending.
On 1 April, enhanced surveillance was introduced throughout the country for pneumonia of unknown origin and in sentinel influenza‐like illness(ILI) surveillance sites; molecular diagnostic kits were also distributed. Since then, an increase has been observed in the number of ILI consultations in ILI sites. This increase isomer likely to be related to concerns among the population than to an increase inH7N9 cases. Enhanced ILI surveillance has identified one ILI case that tested positive for H7N9 by RT‐PCR.
Although it is too early to confirm the effectiveness of the closure of live bird markets in Shanghai, which took place on 6 April, no new cases have been reported there with dates of onset later than 13 April.
Areas of major uncertainty
Some important uncertainties remain, including the following:
- (1) It is unclear why severe disease has been found predominantly in older male urban residents. This pattern could be associated with behavioral factors or, as for seasonal influenza, H7N9 could be causing a larger number of mild and symptomatic infections that have gone undetected to date;
- (2) Although surveillance for pneumonia of unknown origin is routine, it is impossible to exclude the possibility that these infections have been occurring for some time;
- (3) Currently, evidence so far is not strong enough to conclude there is person‐to‐person transmission;
- (4) The extent of occurrence of unrecognized mild / asymptomatic infections is unclear and may affect estimates of case‐fatality. Persons who have mild or asymptomatic illness may not have been tested in any of the testing algorithms outlined.
Clinical features and management
The most common presenting signs and symptoms were those characteristic of influenza. Encephalopathy and conjunctivitis were uncommon, and nasal congestion and rhinorrhea were not reported as initial presentations. Common laboratory findings included normal white cell count, leukocytopenia, lymphocytopenia, thrombocytopenia, and mildly elevated liver enzymes. Most cases were severe, and a number of these rapidly deteriorated within 1 to 2 days of hospitalization to acute respiratory failure, leading to refractory hypoxemia and multiple organ failure, the major cause of death. A few mild cases were reported, especially in children.
Neuraminidase inhibitors (NAIs) were given to almost all patients but only after a median of 6 days after disease onset.
NHFPC developed a risk‐based management protocol for areas where confirmed cases are reported so that NAIs could be given earlier to symptomatic cases, even before the confirmatory result of laboratory tests for H7N9 virus.
Infection prevention and control measures in fever clinics and designated hospitals complied with national and WHO guidance.
Characteristics of avian influenza A(H7N9) viruses
The novel viruses are reassortants, comprising H7HA, N9NA and the six internal genes of H9N2 influenza A viruses. This combination of influenza genes has not previously been identified among viruses obtained from birds, humans or any other species, although individual genes are related to those of recent avian influenza viruses circulating in East Asia.
H7N9 viruses obtained from human cases, poultry and environmental samples are closely related and contain a number of genetic signatures previously associated with low pathogenicity in poultry, enhanced capacity for mammalian infection and resistance to the adamantane class of antiviral drugs. Several human H7N9 viruses were shown to be sensitive to the NAIs oseltamivir and zanamivir in vitro. It is important to note that one mammalian adaptation (E627K in the PB2 gene) occurred in many of the human H7N9 viruses but did not occur in any of the non‐human viruses. Continuing analyses are essential to improve understanding of these viruses and to detect any future changes affecting their transmissibility between humans and their pathogenicity in birds.
Preliminary analyses suggest that many people lack antibodies to this virus and that production of an effective vaccine will require the selection of a new candidate H7 vaccine virus.
Animal health
The detection ofH7N9 virus in live poultry markets in the vicinity of human cases in Shanghai, the contact history with live poultry or live poultry markets in a substantial number of cases, and the apparent reduction in human cases after the closure of live poultry markets in Shanghai, suggest exposure to live poultry as a key risk factor for human H7N9 infection. Although the H7N9 virus has not been detected in poultry farms so far, it is likely that they provide the source of infection, with subsequent amplification within live poultry markets leading to human infections.
Although data are limited at this early stage of the investigation, it may be that the H7N9 virus is currently sustained through intra‐ and inter‐provincial trading of live poultry. If infection in poultry is not controlled the H7N9 virus may spread to additional provinces in China, leading to an even greater zoonotic threat, and thus increasing its pandemic potential. It may also facilitate the emergence of a virus that is highly pathogenic in poultry. The human and poultry viruses genetically sequenced thus far show that this H7N9 virus has adaptations that allow it to infect humans, although virological information is limited as the animal A(H7N9) test and the test strategy in China remain to be validated.
Response strategies and measures
A joint multi‐sectorial prevention and control mechanism(JPCM) has been established at national and local levels to lead and coordinate the emergency response to H7N9 virus. The national JPCM, led by the National Health and Family Planning Commission, consists of 13 governmental ministries and commissions, including the Ministry of Agriculture, the State Forestry Administration, and the Ministry of Science and Technology. An inter‐regional JPCM has also been established to support sharing of information and coordinated response among the affected provinces and municipalities, including Anhui, Jiangsu, Shanghai, and Zhejiang. Significant efforts are being made to ensure that the emergency response to the newly detected H7N9 virus is based on laws and regulations, the principle of transparency, prioritization and international collaboration. An approach based on risk assessment and evidence is being applied to inform coordinated, balanced public health interventions.
Coordinated but tailored response strategies and guidance have been provided to the different provinces based on the epidemiological situation and local needs. Early detection, early reporting, early diagnosis and early treatment ("the Four Earlys") have been the general guiding principles for the operational response.
Response measures include close collaboration between public health and animal health sectors, enhanced surveillance in humans and animals, case investigation, field investigation, risk assessment, clinical management, hospital infection prevention and control, public health interventions, risk communication, and research. Reagents for PCR detection ofH7N9 viruses in humans have been distributed to more than 400 laboratories throughout China. Several national guidelines have been issued for surveillance and epidemiological investigation, including contact tracing, laboratory testing and patient isolation and treatment.
The priority response measures have been focused on the following:
- Field investigations, including source of infection
- Enhanced surveillance in humans and animals
- Clinical management, infection prevention and control
- Risk communication
- Scientific research.
International collaboration
Any novel influenza A virus that causes human infections is of global interest and, if disease is severe, is a cause for serious concern. After it first identified the H7N9 virus, China recognized its vital role in contributing to global public health through open channels of communication with global influenza partners and the international community.
On 31 March 2013 the China National IHR Focal Point notified WHO of the first three cases of human infection with H7N9 virus and has since made regular reports to WHO and its Member States. Regular situation updates and transparent sharing of information have demonstrated the openness of Chinese Government authorities. In addition, China CDC has shared genetic sequence data, diagnostic test protocols and viruses with the global public health and research communities. The National Avian Influenza Reference Laboratory, Harbin, has also shared genome sequences of H7N9 viruses. These actions have contributed greatly to the global risk assessment and response, including the selection and development of candidate human H7N9 vaccine viruses and vaccine potency and diagnostic reagents, as well as a better understanding of antigenicity, pathogenicity and transmissibility of the virus.
The National Health and Family Planning Commission has maintained close technical collaboration with WHO staff through China CDC. As a newly designated WHO Collaborating Centre for Reference and Research on Influenza, the National Influenza Centre in China has maintained regular communication and technical discussions with other WHO Collaborating Centres for influenza. As a member of the Global Outbreak Alert and Response Network (GOARN), China CDC provided a situation update to GOARN partners.
In summary, China?s transparent and timely sharing of technical information, data and viruses is greatly appreciated and has contributed immensely to current global understanding of the H7N9 virus, risk assessment and actions required to manage the shared risk.
Assessment
In March 2013, China identified three human infections by an avian influenza A(H7N9) virus.
This virus had never been known to infect people before. China responded quickly including by establishing a joint multi‐sectorial coordination mechanism, initiating several investigations, notifying WHO under the International Health Regulations 2005), posting sequences of the virus, sharing viruses with the WHO Influenza Collaborating Centers and other laboratories and mounting effective countermeasures such as closure of live poultry markets in some locations. The response has demonstrated that health authorities were well prepared and acted quickly, effectively and professionally.
Since then, this virus has caused over 100 human infections. Most of these infections have led to severe disease, including more than 20 deaths.
Currently, evidence so far is not strong enough to conclude there is person‐to‐person transmission. The limited available information suggests that many infections caused by this virus may be related to exposure to infected poultry in live poultry markets or to environments contaminated by this virus.
However, future studies can strengthen the evidence.
The risk to people posed by the emergence of the H7N9 virus must be considered unusually serious, for several reasons. First, this virus has caused serious disease, including death, in some people. Second,this virus does not appear to cause disease in poultry (although it could change in the future to become highly pathogenic) and therefore could spread silently. Third, this virus has caused more human infections and disease in a shorter period of time than any other known avian influenza virus.
Fourth, some H7N9 viruses show genetic changes that suggest they are partially adapted to infect humans more easily than other avian influenza viruses. Taken together,these findings suggest that the possibility of this virus becoming transmissible among people is higher than for any other known avian influenza virus and therefore it must not be ignored.
On the basis of this assessment, the Joint Mission has made seven high‐level recommendations to the Government of China, as below.
Recommendations
- Undertake intense and focused investigations to determine the source(s) of human H7N9 infections. Identification of the source will enable urgent action to prevent continuing virus spread, with its potentially severe consequences for human and animal health.
- Maintain a high level of alert, preparedness and response even though human cases might drop in the summer (ast hey do for many other avian influenza viruses) because of the seriousness of the risk posed by this virus and because much basic information remains unknown.
- Continue to conduct and strengthen both epidemiological and laboratory‐based surveillance in human and animals in all provinces of China to identify changes that might indicate the virus is spreading geographically and gaining the ability to infect people more easily or transmit efficiently from person to person.
- Ensure frequent mutual sharing of information, close and timely communication and, when appropriate, coordinated or joint investigations and research among ministries of health, agriculture and forestry because this threat requires the combined efforts of all these sectors.
- Continue high‐level scientific collaboration, communication and sharing of sequence data and viruses with WHO and international partners because the threat of H7N9 is also an international shared risk and concern.
- Encourage and foster the scientific and epidemiological studies and research needed to close major gaps in critical knowledge and understanding.
- Continue preparedness planning and other IHR core capacity strengthening work because such investments make a major difference in readiness to address health security risks and emergencies, including H7N9.
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