A TIME'S MEMORY

Saudi Arabia lift the state of emergency after discovery of a NCoV suspected case in Riyadh (AMEinfo.com, May 19 2013, edited)

2013-05-19T19:05:00.001+02:00

[Source: AME Info, full text in Arabic: (LINK). Automatic translation. h / t Helen Branswell.]

Saudi Arabia lift the state of emergency after discovery of a NCoV suspected case in Riyadh

Qatar: Sunday, May 19, 2013 - 11:32

Increased health devices in the Saudi capital Riyadh maximum state of emergency after suspected infecting patient with Corona, was taken to King Saud Medical Complex, where the results of the analysis takes for the suspected case takes anywhere from three to four days at the latest, according to Saudi newspaper today published.

On the other hand, the eagerness of the Minister of Health Dr. Abdullah Al-Rabiah to be a visit to the province of Hasa surprise and bear the stamp of secrecy to follow developments disease Coruna, where it took the visit an hour and a half ago and began the visit of Minister of Health to a private hospital and then went to King Fahd Hospital Balhvov and then met in a closed meeting with the medical staff and administrative Department of Health.

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Hong Kong, Update on number of suspected human cases of avian influenza A (H7) notified (May 19 2013)

2013-05-19T17:47:00.001+02:00

[Source: Centre for Health Protection, Hong Kong PRC SAR, full text: (LINK).]

Update on number of suspected human cases of avian influenza A (H7) notified

The Centre for Health Protection (CHP) of the Department of Health (DH) today (May 19) provided an update on the latest number of suspected human cases of avian influenza A(H7) notified to the CHP, including cases fulfilling reporting criteria and remaining ones not fulfilling reporting criteria.

From noon yesterday (May 18) to noon today, the CHP received no notification of cases which fulfilled reporting criteria, but two cases which did not fulfil reporting criteria. (…)

The total number of notifications received by the CHP since March 31 of cases fulfilling reporting criteria of suspected human cases of avian influenza A(H7) hence remains at 25, while the total number of notifications not fulfilling reporting criteria is now 101.

A DH spokesman urged travellers not to visit wet markets with live poultry in the affected areas, and to avoid direct contact with poultry, birds or their droppings. If contact has been made, they should thoroughly wash hands with soap and water.

"Influenza A(H7) is a statutorily notifiable infectious disease in Hong Kong.’’

‘’Locally, no confirmed human cases of avian influenza A(H7N9) have been recorded so far," the spokesman stressed.

The spokesman reminded doctors to report to the CHP any suspected case of influenza A(H7). The Public Health Laboratory Services Branch of the CHP is ready to receive and test specimens whenever necessary.

The public may visit the CHP's avian influenza page (www.chp.gov.hk/en/view_content/24244.html) for further information.

Ends/Sunday, May 19, 2013
Issued at HKT 16:26
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Hong Kong, No new human case of avian influenza A (H7N9) in the Mainland (May 19 2013)

2013-05-19T17:45:00.001+02:00

[Source: Centre for Health Protection, Hong Kong PRC SAR, full text: (LINK).]

No new human case of avian influenza A (H7N9) in the Mainland

The Centre for Health Protection (CHP) of the Department of Health (DH) verified with the National Health and Family Planning Commission (NHFPC) no new human case of avian influenza (H7N9) in the Mainland today (May 19).

As of 9pm today, a total of 130 cases have been laboratory confirmed with avian influenza (H7N9) in the Mainland, which included:

Zhejiang (46 cases),

Shanghai (33 cases),

Jiangsu (27 cases),

Jiangxi (six cases),

Fujian (five cases),

Anhui (four cases),

Henan (four cases),

Shandong (two cases),

Hunan (two cases) and

Beijing (one case).

A spokesman for the DH stressed that the CHP is closely monitoring the situation and will continue to maintain close liaison with the Mainland health authorities for more case information, as well as keep a close eye on the latest advice from the World Health Organization.

The spokesman also reminded travellers, especially those returning from Shanghai, Jiangsu, Zhejiang, Anhui, Henan, Beijing, Shandong, Jiangxi, Fujian, Hunan and Guangdong, with fever or respiratory symptoms to wear facial masks immediately, seek medical attention, and reveal their travel history to doctors. Health-care professionals should also pay special attention to those who might have had contact with birds, poultry or their droppings in the affected areas.

"No human case of avian influenza A (H7N9) has been identified so far in Hong Kong," the spokesman reiterated.

"We would like to reassure the public that the Government will be as transparent as possible in the dissemination of information on human cases of avian influenza A (H7N9). Whenever there is a suspected case, the CHP will release information to the public as soon as possible," the spokesman added.

The spokesman urged travellers not to visit wet markets with live poultry in the affected areas and to avoid direct contact with poultry, birds or their droppings. If contacts have been made, they should thoroughly wash hands with soap and water.

Members of the public should remain vigilant and are reminded to take heed of the following preventive advice against avian influenza:

Poultry and eggs should be thoroughly cooked before eating;

Wash hands frequently with soap, especially before touching the mouth, nose or eyes, handling food or eating; after going to the toilet or touching public installations or equipment such as escalator handrails, elevator control panels or door knobs; or when hands are dirtied by respiratory secretions after coughing or sneezing;

Cover the nose and mouth while sneezing or coughing, and hold the spit with tissue and put it into a covered dustbin;

Avoid crowded places and contact with fever patients; and

Wear a mask when respiratory symptoms develop or you need to take care of fever patients.

The public may visit the Avian Influenza page of the CHP (www.chp.gov.hk/en/view_content/24244.html) for further information.

Ends/Sunday, May 19, 2013
Issued at HKT 21:31
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Hong Kong, Additional overseas case of Severe Respiratory Disease associated with Novel Coronavirus closely monitored by DH (May 19 2013)

2013-05-19T09:00:00.001+02:00

[Source: Department of Health, Hong Kong PRC SAR, full text: (LINK).]

Additional overseas case of Severe Respiratory Disease associated with Novel Coronavirus closely monitored by DH

The Department of Health (DH) is today (May 19) closely monitoring an additional case of Severe Respiratory Disease associated with Novel Coronavirus reported to the World Health Organization (WHO) by the Kingdom of Saudi Arabia (KSA).

According to the WHO, the patient is an 81-year-old woman with multiple coexisting medical conditions. She became ill on April 28.

The patient was identified as part of the ongoing investigation into an outbreak that began in a health-care facility since the beginning of April. She was in the same health-care facility previously identified as the focus of this outbreak, from April 8 to 28. To date, a total of 22 patients including nine deaths, have been reported from this outbreak in the Eastern KSA. The KSA government is conducting ongoing investigation into the outbreak.

This brings the latest global number of confirmed cases of Severe Respiratory Disease associated with Novel Coronavirus to 41, including 20 deaths.

"The Centre for Health Protection (CHP) of the DH will seek more information on the case from the WHO and the relevant health authority. The CHP will stay vigilant and continue to work closely with the WHO and overseas health authorities to monitor the latest developments of this novel infectious disease," a DH spokesman said.

Locally, the CHP will continue its surveillance mechanism with public and private hospitals, practising doctors and the airport for any suspected case of severe respiratory disease associated with novel coronavirus.

"No human infection with this virus has been identified so far in Hong Kong," the spokesman stressed.

"We would like to reassure the public that the Government will be as transparent as possible in the dissemination of information on cases of Severe Respiratory Disease associated with Novel Coronavirus. Whenever there is a suspected case, particularly involving patients with travel history to the Middle East and the affected areas, the CHP will release information to the public as soon as possible," the spokesman said.

Health-care providers are advised to be vigilant among recent travellers returning from novel coronavirus-affected areas who develop severe acute respiratory infections and are reminded to adhere to strict infection control measures while handling suspected cases. Patients' lower respiratory tract specimens should also be obtained for diagnosis when possible. Doctors are reminded that novel coronavirus infection should be considered even with atypical signs and symptoms in patients who are significantly immunocompromised.

Travellers returning from novel coronavirus-affected areas with respiratory symptoms are advised to wear face masks, seek medical attention and reveal their travel history to doctors.

The spokesman reminded members of the public to take heed of personal hygiene:

Wash hands before touching the eyes, nose and mouth;
Wash hands before eating or handling food;
Wash hands after using the toilet;
Wash hands after sneezing or coughing and cleaning the nose; and
Avoid direct contact with animals, birds or poultry.

Members of the public may visit the CHP's website for more information on Severe Respiratory Disease associated with Novel Coronavirus (www.chp.gov.hk/en/view_content/26511.html) or personal hygiene (www.chp.gov.hk/en/content/9/460/19899.html).

Ends/Sunday, May 19, 2013
Issued at HKT 13:11
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Novel coronavirus infection–update (WHO, May 18 2013, edited)

2013-05-18T21:06:00.001+02:00

[Source: World Health Organization, full page: (LINK). Edited.]

Novel coronavirus infection – update

18/05/2013

The Ministry of Health in Saudi Arabia has informed WHO of an additional laboratory-confirmed case of infection with the novel coronavirus (nCoV).

The patient is an 81-year-old woman with multiple coexisting medical conditions. She became ill on 28 April 2013 and is currently in critical but stable condition.

The patient was identified as part of the ongoing investigation into an outbreak that began in a health care facility since the beginning of April 2013. She was in the same health care facility previously identified as the focus of this outbreak, from 8 to 28 April 2013. To date, a total of 22 patients including nine deaths, have been reported from this outbreak in the Eastern part of Saudi Arabia. The government is conducting ongoing investigation into the outbreak.

From September 2012 to date, WHO has been informed of a global total of 41 laboratory-confirmed cases of infection with nCoV, including 20 deaths.

Several countries in the Middle East have been affected, including Jordan, Qatar, Saudi Arabia, and the United Arab Emirates (UAE).

Cases have also been reported by three countries in Europe: France, Germany, and the United Kingdom.

All of the European cases have had a direct or indirect connection to the Middle East, including two cases with recent travel history from the UAE.

In France and the United Kingdom, there has been limited local transmission among close contacts who had not been to the Middle East but had been in contact with a traveler who recently returned from the Middle East.

Based on the current situation and available information, WHO encourages all Member States to continue their surveillance for severe acute respiratory infections (SARI) and to carefully review any unusual patterns.

Health care providers are advised to be vigilant among recent travelers returning from areas affected by the virus who develop severe SARI. Specimens from patients’ lower respiratory tracts should be obtained for diagnosis where possible. Clinicians are reminded that nCoV infection should be considered even with atypical signs and symptoms, such as diarrhoea, particularly in patients who are immunocompromised.

Health care facilities that provide care for patients with suspected nCoV infection should take appropriate measures to decrease the risk of transmission of the virus to other patients, health care workers and visitors. Health care facilities are reminded of the importance of systematic implementation of infection prevention and control (IPC).

All Member States are reminded to promptly assess and notify WHO of any new case of infection with nCoV, along with information about potential exposures that may have resulted in infection and a description of the clinical course. Investigation into the source of exposure should promptly be initiated to identify the mode of exposure, so that further transmission of the virus can be prevented.

WHO does not advise special screening at points of entry with regard to this event nor does it currently recommend the application of any travel or trade restrictions.

WHO continues to closely monitor the situation.

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Hong Kong, Update on number of suspected human cases of avian influenza A(H7) notified (May 18 2013)

2013-05-18T19:24:00.001+02:00

[Source: Centre for Health Protection, Hong Kong PRC SAR, full text: (LINK).]

Update on number of suspected human cases of avian influenza A(H7) notified

The Centre for Health Protection (CHP) of the Department of Health (DH) today (May 18) provided an update on the latest number of suspected human cases of avian influenza A(H7) notified to the CHP, including cases fulfilling reporting criteria and remaining ones not fulfilling reporting criteria.

From noon yesterday (May 17) to noon today, the CHP received no notification of cases which fulfilled reporting criteria, but one case which did not fulfil reporting criteria. (...)

The total number of notifications received by the CHP since March 31 of cases fulfilling reporting criteria of suspected human cases of avian influenza A(H7) hence remains at 25, while the total number of notifications not fulfilling reporting criteria is now 99.

A DH spokesman urged travellers not to visit wet markets with live poultry in the affected areas, and to avoid direct contact with poultry, birds or their droppings. If contact has been made, they should thoroughly wash hands with soap and water.

"Influenza A(H7) is a statutorily notifiable infectious disease in Hong Kong.’’

‘’Locally, no confirmed human cases of avian influenza A(H7N9) have been recorded so far," the spokesman stressed.

The spokesman reminded doctors to report to the CHP any suspected case of influenza A(H7). The Public Health Laboratory Services Branch of the CHP is ready to receive and test specimens whenever necessary.

The public may visit the CHP's avian influenza page (www.chp.gov.hk/en/view_content/24244.html) for further information.

Ends/Saturday, May 18, 2013
Issued at HKT 17:31
NNNN

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Hong Kong, No new human case of avian influenza A (H7N9) in the Mainland (May 18 2013)

2013-05-18T19:22:00.001+02:00

[Source: Centre for Health Protection, Hong Kong PRC SAR, full text: (LINK).]

No new human case of avian influenza A (H7N9) in the Mainland

The Centre for Health Protection (CHP) of the Department of Health (DH) verified with the National Health and Family Planning Commission (NHFPC) no new human case of avian influenza A (H7N9) in the Mainland today (May 18).

As of 9pm today, a total of 130 cases have been laboratory confirmed with avian influenza A (H7N9) in the Mainland, which included:

Zhejiang (46 cases),

Shanghai (33 cases),

Jiangsu (27 cases),

Jiangxi (six cases),

Fujian (five cases),

Anhui (four cases),

Henan (four cases),

Shandong (two cases),

Hunan (two cases) and

Beijing (one case).

A spokesman for the DH stressed that the CHP is closely monitoring the situation and will continue to maintain close liaison with the Mainland health authorities for more case information, as well as keep a close eye on the latest advice from the World Health Organization.

The spokesman also reminded travellers, especially those returning from Shanghai, Jiangsu, Zhejiang, Anhui, Henan, Beijing, Shandong, Jiangxi, Fujian, Hunan and Guangdong, with fever or respiratory symptoms, to wear facial masks immediately, seek medical attention, and reveal their travel history to doctors. Healthcare professionals should also pay special attention to those who might have had contact with birds, poultry or their droppings in the affected areas.

"No human case of avian influenza A (H7N9) has been identified so far in Hong Kong," the spokesman reiterated.

"We would like to reassure the public that the Government will be as transparent as possible in the dissemination of information on human cases of avian influenza A (H7N9). Whenever there is a suspected case, the CHP will release information to the public as soon as possible," the spokesman added.

The spokesman urged travellers not to visit wet markets with live poultry in the affected areas and to avoid direct contact with poultry, birds or their droppings. If contacts have been made, they should thoroughly wash hands with soap and water.

Members of the public should remain vigilant and are reminded to take heed of the following preventive advice against avian influenza:

Poultry and eggs should be thoroughly cooked before eating;

Wash hands frequently with soap, especially before touching the mouth, nose or eyes, handling food or eating; after going to the toilet or touching public installations or equipment such as escalator handrails, elevator control panels or door knobs; or when hands are dirtied by respiratory secretions after coughing or sneezing;

Cover the nose and mouth while sneezing or coughing, and hold the spit with tissue and put it into a covered dustbin;

Avoid crowded places and contact with fever patients; and

Wear a mask when respiratory symptoms develop or you need to take care of fever patients.

The public may visit the Avian Influenza page of the CHP (www.chp.gov.hk/en/view_content/24244.html) for further information.

Ends/Saturday, May 18, 2013
Issued at HKT 21:59
NNNN

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Interim surveillance recommendations for human infection with novel coronavirus. As of 18 May 2013–Update (WHO, edited)

2013-05-18T19:05:00.001+02:00

[Source: World Health Organization, full PDF document: (LINK). Edited.]

Interim surveillance recommendations for human infection with novel coronavirus. As of 18 May 2013 – Update

WHO is updating its guidance for surveillance for novel coronavirus (nCoV) on the basis of additional information received since the original recommendations were published in October 2012. WHO will continue to update these recommendations as information becomes available.

This document has been revised to emphasize WHO recommendations, rather than to summarize current case reports, which are found on the main WHO novel coronavirus page (http://www.who.int/csr/disease/coronavirus_infections/en/ ). It is important to note that these recommendations need to be implemented in different countries with varying resources and epidemiological patterns.

Key clinical points in this update:

It is now evident that non-sustained human-to-human transmission has occurred.
Co-infection of novel coronavirus with influenza A has also been reported. However, a number of unanswered questions remain, including what the virus reservoir is, how seemingly sporadic infections are being acquired, the mode of transmission between infected persons, the clinical spectrum of infection, and the incubation period.

This document offers guidance on:

Individuals who should be tested for novel coronavirus
Advice on reporting suspected or confirmed cases to WHO
Recommendations for research to offer insight into critical clinical and epidemiological features of the virus.

Background

Human-to-human transmission of nCoV has now been documented in several clusters of cases, including among family members and in health care facilities. Two health care workers have been infected following contact with confirmed cases in hospital. So far, there has been no evidence of sustained transmission beyond the immediate clusters. The mode of transmission has not been determined either for sporadic cases or for human-to-human transmission, nor has a source of the virus been identified.

All confirmed cases have had respiratory disease and most have had pneumonia. However, one immunocompromised patient presented initially with fever and diarrhea and was only incidentally found to have pneumonia on a radiograph. Half of all confirmed cases have died. Complications during the course of illness have included severe pneumonia with respiratory failure requiring mechanical ventilation, acute respiratory distress syndrome (ARDS) with multi-organ failure, renal failure requiring dialysis, consumptive coagulopathy and pericarditis. A number of cases have also had gastrointestinal symptoms including diarrhea during the course of their illness.

Limited evidence suggests that nasopharyngeal swabs may not be as sensitive as lower respiratory specimens for detecting nCoV infections. Lower respiratory specimens such as sputum, endotracheal aspirate or bronchoalveolar lavage should be used when possible in addition to nasopharyngeal swab until more information is available. If initial testing of a nasopharyngeal swab is negative in a patient strongly suspected to have nCoV infection, consideration should be given to retesting using a lower respiratory specimen.

All cases have had some link to the Middle East, although local transmission from recent travelers has been observed in France and the United Kingdom.

Objectives of surveillance

The primary objectives of the enhancements described in this document are to:

1. Detect early, sustained human-to-human transmission.
2. Determine the geographic risk area for infection with the virus.

Additional clinical and epidemiological investigations (see table below) are needed to:

1. Determination of key clinical characteristics of the illness, such as incubation period, spectrum of disease, and the natural history of the disease.
2. Determination of key epidemiological characteristics of the virus, such as exposures that result in infection, risk factors, secondary attack rates, and mode of transmission.

The following people should be investigated and tested for novel coronavirus:

1. A person with an acute respiratory infection, which may include history of fever and cough and indications of pulmonary parenchymal disease (e.g. pneumonia or ARDS), based on clinical or radiological evidence of consolidation, who requires admission to hospital. In addition, clinicians should be alert to the possibility of atypical presentations in patients who are immunocompromised.

AND any of the following:

The disease is in a cluster1 that occurs within a 10-day period, without regard to place of residence or history of travel, unless another aetiology has been identified.
The disease occurs in a health care worker who has been working in an environment where patients with severe acute respiratory infections are being cared for, particularly patients requiring intensive care, without regard to place of residence or history of travel, unless another aetiology has been identified. 3
The person has history of travel to the Middle East2 within 10 days before onset of illness, unless another aetiology has been identified.3
The person develops an unusual or unexpected clinical course, especially sudden deterioration despite appropriate treatment, without regard to place of residence or history of travel, even if another aetiology has been identified, if that alternate aetiology does not fully explain the presentation or clinical course of the patient.

2. Individuals with acute respiratory illness of any degree of severity who, within 10 days before onset of illness, were in close physical contact4 with a confirmed or probable case of novel coronavirus infection, while that patient was ill.
3. For countries in the Middle East, the minimum standard for surveillance should be testing of patients with severe respiratory disease requiring mechanical ventilation. The minimum standard should also include investigation of all those in three categories listed above—patients with unexplained pneumonia or ARDS occurring in clusters; health care workers requiring admission for respiratory disease and patients with unusual presentation or clinical course. However, countries in the Middle East are also strongly encouraged to consider adding testing for nCoV to current testing algorithms as part of routine sentinel respiratory disease surveillance and, if local capacity can support it, some testing of patients with milder, unexplained, community-acquired pneumonia requiring admission to hospital.

WHO does not advise special screening at points of entry with regard to this event nor does it recommend that any trade or travel restrictions be applied.

Reporting

WHO requests that probable and confirmed cases be reported within 24 hours of classification, through the Regional Contact Point for International Health Regulations at the appropriate WHO Regional Office. See current definitions for probable and confirmed cases at: http://www.who.int/csr/disease/coronavirus_infections/case_definition/en/index.html.

Investigations around cases of novel coronavirus infection

Many of the critical questions regarding the clinical manifestation and epidemiological characteristics of novel coronavirus infection will be answered only by careful, detailed investigations around cases. The following provides some guidance on the types of studies that should be considered. WHO is currently working with technical partners to develop standard protocols and data collection instruments for this purpose, which will be posted when they are finalized. For technical support, contact WHO on the email address outbreak@who.int with “NCV epi surv recs” in the subject line.

Investigations around confirmed cases of novel coronavirus infection

[Investigation – Purpose]

Complete data collection on clinical history, presentation, occurrence of complications, important laboratory and X-ray findings, and course of illness.

Describe the clinical presentation and natural history of infection.

Investigation of potential exposures in the last 10 days before onset of illness. Include travel history, exposures to animals (type of animals and type of contact), exposures to other patients with acute respiratory infections, including exposures in health care settings, and consumption of raw foods and unprocessed beverages, Collect detailed information on time, duration, and intensity of exposure and type of contact.

Determine the source of infection and type of exposure.

Contact tracing, including contacts in household, workplace, school and social settings. Careful history should be taken with regard to the timing of contact with sick individuals and the onset of illness. Contacts should be tested with polymerase chain reaction (PCR) and acute and convalescent serology. Information on the severity and course of illness should be collected from even mildly symptomatic contacts who are tested for virus.

Detect evidence of human-to-human transmission; estimate secondary attack rates, duration of infectivity, and incubation period. Describe spectrum of disease, especially milder cases.

Survey of health care workers working in the environment where cases are cared for. Survey should include those not directly involved in care but working in the same ward or unit as well as those who provide intermittent care, such as radiologists, respiratory and physical therapists, etc. Include information on timing, duration, and intensity of contact, type of interaction, use of personal protective equipment (PPE), and other potential exposures outside of health care setting (e.g. animals in the home environment).

Detect evidence of human-to-human transmission, effectiveness of PPE.

Investigations for recent increases in respiratory disease activity in the community. This would include review of local hospital admission records and outpatient records of selected general practitioners in the community where infection is thought to have been acquired.

Detect signals of background transmission of novel virus.

Retrospective testing of stored specimens from patients with respiratory disease.

Detect the pre-existence of virus in the community.

Retrospective testing of stored animal specimens for presence of nCoV or antibodies.

Determine the animal reservoir and origin of the virus.

Serological surveys of potentially exposed groups of individuals such as animal workers, market workers, health care workers, and office workers (as a comparison group). Detailed information should be collected from each participant on the type and degree of exposure.

Identify types of exposure that result in infection.

_______

For questions about this document: Email outbreak@who.int. Please put “NCV epi surv recs” in the subject line.

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Research Articles Abstracts–May 18 2013 Issue

2013-05-18T18:54:00.001+02:00

[Source: AMEDEO, homepage: (LINK).]

Research Articles Abstracts–May 18 2013 Issue

This Week’s Abstracts:

________

Arch Virol

KIM SH , Kim HJ, Jin YH, Yeoul JJ, et al

Isolation of influenza A(H3N2)v virus from pigs and characterization of its biological properties in pigs and mice.

Arch Virol. 2013.

PubMed
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ZHANG K , Xu W, Zhang Z, Wang T, et al

Experimental infection of non-human primates with avian influenza virus (H9N2).

Arch Virol. 2013.

PubMed
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Epidemiol Infect

EDELSTEIN M , Pebody R

Can we achieve high uptakes of influenza vaccination of healthcare workers in hospitals? A cross-sectional survey of acute NHS trusts in England.

Epidemiol Infect. 2013.

PubMed
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J Gen Virol

ANDREJEVA J , Norsted H, Habjan M, Thiel V, et al

ISG56/IFIT1 is primarily responsible for interferon-induced changes to patterns of parainfluenza virus type 5 transcription and protein synthesis.

J Gen Virol. 2013;94.

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J Immunol

BEDOYA F , Cheng GS, Leibow A, Zakhary N, et al

Viral Antigen Induces Differentiation of Foxp3+ Natural Regulatory T Cells in Influenza Virus-Infected Mice.

J Immunol. 2013.

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KNUSCHKE T , Sokolova V, Rotan O, Wadwa M, et al

Immunization with Biodegradable Nanoparticles Efficiently Induces Cellular Immunity and Protects against Influenza Virus Infection.

J Immunol. 2013.

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J Virol

KITAGAWA Y , Yamaguchi M, Zhou M, Nishio M, et al

Human Parainfluenza Virus Type 2 V Protein Inhibits TRAF6-mediated Ubiquitination of IRF7 to Prevent Toll-like Receptor 7 (TLR7)- and TLR9-Dependent Interferon Induction.

J Virol. 2013.

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SAIRA K , Lin X, Depasse JV, Halpin R, et al

Sequence analysis of in vivo defective-interfering (DI)-like RNA of influenza A H1N1 pandemic virus.

J Virol. 2013.

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WANG W , Lu J, Cotter CR, Wen K, et al

Identification of critical residues in the hemagglutinin (HA) and neuraminidase (NA) of H1N1pdm for vaccine virus replication in embryonated chicken eggs.

J Virol. 2013.

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Lancet

HONIGSBAUM M

"An inexpressible dread": psychoses of influenza at fin-de-siecle.

Lancet. 2013;381:988-9.

XU J , Lu S, Wang H, Chen C, et al

Reducing exposure to avian influenza H7N9.

Lancet. 2013 May 9. pii: S0140-6736(13)60950.

LEE SS , Wong NS, Leung CC

Exposure to avian influenza H7N9 in farms and wet markets.

Lancet. 2013 May 9. pii: S0140-6736(13)60949.

PLoS One

WIE SH , So BH, Song JY, Cheong HJ, et al

A Comparison of the Clinical and Epidemiological Characteristics of Adult Patients with Laboratory-Confirmed Influenza A or B during the 2011-2012 Influenza Season in Korea: A Multi-Center Study.

PLoS One. 2013;8:e62685.

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SEVILLA-REYES EE , Chavaro-Perez DA, Piten-Isidro E, Gutierrez-Gonzalez LH, et al

Protein Clustering and RNA Phylogenetic Reconstruction of the Influenza a Virus NS1 Protein Allow an Update in Classification and Identification of Motif Conservation.

PLoS One. 2013;8:e63098.

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VANDERSTOCKEN G , Van de Paar E, Robaye B, di Pietrantonio L, et al

Protective role of P2Y2 receptor against lung infection induced by pneumonia virus of mice.

PLoS One. 2012;7:e50385.

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TURNER C , Turner P, Cararra V, Eh Lwe N, et al

A high burden of respiratory syncytial virus associated pneumonia in children less than two years of age in a South East Asian refugee population.

PLoS One. 2012;7:e50100.

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Vaccine

Proceedings of the Fourth ESWI Influenza Conference, September 11-14, 2011, Malta.

Vaccine. 2012;30:7343-438.

Will there be another flu pandemic? Should we be prepared?

Vaccine. 2012;30:7429-31.

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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, edited)

2013-05-18T18:42:00.001+02:00

[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:

(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.

The current response at national and local levels seen by the Team has been excellent and appears to be effective. The risk assessment and evidence‐based response to H7N9 virus could serve as a model of emergency response to similar events.

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.

Annexes

Annex 1 –Detailed Findings

Epidemiology

Data as of 23 April 2013

The first cases of infection with novel avian influenza A(H7N9) were a father and son pair in Minhang District, Shanghai. They both had disease onset dates of 19 February 2013, initially presenting with influenza‐like illness, which rapidly progressed to pneumonia. A second son had previously been hospitalised with pneumonia. Concerned by these three cases, clinicians immediately alerted public health authorities. Four more patients with similar symptoms were admitted to the same hospital in Shanghai in late February and early March.

Specimens from the father and an unrelated case with onset date of 27 February 2013 were positive for influenza A but unsubtypable: hence, specimens were referred to the WHO Influenza Collaborating Centre at the Chinese CDC (see timeline). A third similar influenza A unsubtypable case was reported to the Chinese CDC from neighbouring Anhui Province. The isolates from all three were very similar novel reassortant avian influenza viruses. Therefore, on 31 March the Chinese authorities notified them to WHO under the IHR.

Diagnostic test kits were distributed to laboratories across the country beginning 1 April. As of 22 April 104 confirmed cases have been reported in five adjoining Chinese Provinces, plus Beijing, with 54 counties/district involved. The affected areas include Zhejiang (40 cases), Shanghai (33), Jiangsu (24), Henan (3), Anhui (3) and Beijing (1). An additional case in an asymptomatic 4‐year‐old boy was also detected by Beijing CDC during enhanced surveillance for those who had the same exposure to potentially infected poultry and the environment.

As of 22 April the virus has not been detected in the other 25 provinces in China despite ongoing routine sentinel ILI surveillance, increasing numbers of persons seeking testing and enhanced surveillance for pneumonia with unknown aetiology. Eighty‐three per cent of cases were reported to be urban residents.

Of reported cases, three have been mild, 21 cases(20%) are known to have died and 13 cases are known to have been discharged from hospital. There were more than twice as many males as females( 69% vs. 31%), with a median age of 62 (range 2‐89 years).

Generally, the age pattern was considerably older and far more male dominated than was observed in China for A(H5N1) (Figure 1). Child cases discovered were either mild or asymptomatic. Many more H7N9 cases had been confirmed over four weeks than had been confirmed and reported for A(H5N1) in China over ten years (Figure 1), Examination of risk factors showed the prevalence of chronic ill health that would be expected in such an older population. An association with contact with animals and in particular live poultry was observed.

Of 77 cases reported nationally for which data were available, only 18 cases (23%) reported no contact with animals and 56 (72%) reported some recent contact with live poultry. In the 33 Shanghai cases, after detailed questioning only 2 cases reported no exposure of any kind to poultry.

However, an unknown factor is the frequency of such exposure in an older population living in urban areas where visits to live bird markets (so‐called wet markets) are common. The incubation period is estimated to be approximately 7 days by calculating the median number of days from exposure to poultry or live poultry markets to illness onset, both for confirmed cases with clear multiple exposures and for those with a single exposure.

The cases occurred mainly as sporadic incidents, with only three small clusters of two and three cases. Intensive case finding among 3000 contacts found 19 persons with respiratory symptoms, including 14 health care workers but none of these were positive for H7N9 by the new specific PCR test. Currently, evidence so far is not strong enough to conclude there is person‐to‐person transmission. The occurrence of asymptomatic and milder cases could not be excluded as serological testing is awaited.

Results of interventions

After declaration of the outbreak by national authorities on 31 March, alerting of populations to seek care and intensified surveillance by a number of regions, sentinel sites for ILI reported a significant rise in the number of consultations.

However, virtually no new H7N9 cases were detected at these sites. For example, in Shanghai Municipality, although some influenza A(H1N1) cases were detected, no new unsubtypable influenza A infections were seen.

Because of the association with exposure to poultry and, in particular, live bird markets, three provinces with the largest number of cases closed large live bird markets in some cities. Closure was followed by a substantial drop in the numbers of new cases reported to authorities, though two incubation periods have yet to be passed (Figure 3).

Areas of major uncertainty

At this time a number of important uncertainties remain. These include the following:

Why severe disease occurs predominantly in older male urban residents is not clear. It could be that behavioural factors and exposure to live birds in wet markets increased the risk of infection. Alternatively, it could be that they represent only a proportion of a much larger number of mild and symptomatic infections and disease progression is mainly observed in the most vulnerable population, as is the case for seasonal influenza (Figure 4). However, a problem with this hypothesis how to explain the gender imbalance.
Similarly, it remains to be determined whether the predominance of exposure to live poultry in the cases is in fact a risk factor or simply the norm in the older male urban populations where these infections occur.
Although active surveillance for pneumonia of unknown aetiology is routine, the possibility cannot be excluded that these infections have been occurring for some time.

(...)

Clinical features and management

Clinical features

As of 16 April, a total of 77 confirmed cases were reported in six provinces and municipalities, among whom 67 had sufficient clinical data to analyse. The outcomes of these patients as of 22 April were 14 deaths and 9 discharges; the remaining 44 patients were still hospitalized. In some cases hospitalization was for infection control considerations rather than active treatment.

The median age of the patients was 63 years (range 4 to 87), and two‐thirds were male.

Comorbidities would be expected in this age and gender group; about 60% of the patients had comorbidities such as coronary heart disease, diabetes, hypertension, and chronic obstructive pulmonary disease.

Presenting symptoms

These included fever, cough,shortness of breath, fatigue,muscle aches, hemoptysis, and gastrointestinal symptoms(Figure 5). Signs such as encephalopathy (n = 2) and conjunctivitis (n = 1) were uncommon.

Nasal congestion and rhinorrhoea were not reported as initial symptoms.

Mild cases were described, all in children and often manifested as fever only. In comparison, some adult patients had rapid progression to bilateral pulmonary infiltrates, often leading to severe hypoxemia within 1 to 2 days.

Laboratory findings

These included normal white cell count, leukocytopenia, lymphocytopenia, thrombocytopenia, and mildly elevated liver enzymes.

Initial treatment

A National Practice Guideline for Clinical Management of Avian Influenza A(H7N9) Infection was issued by the NHFPC on 2 April, and revised on 10 April. In most cases, initial treatment complied with the recommendations of these guidelines.

Specifically, NAIs were given to almost all patients but only after a median of 6 days (range 0 to 23) after disease onset.

Medical complications and their treatment

About two‐thirds of cases developed severe pneumonia and required ventilatory support in intensive care units.

Other complications included shock, acute renal failure, and barotrauma. Some patients with severe hypoxemia responded poorly to conventional mechanical ventilation, which necessitated advanced supportive therapy, such as high‐frequency oscillation ventilation (HFOV) and ECMO. Refractory hypoxemia and multiple organ failure were the leading causes of death. Lymphocytopenia and organ failure, rather than age,sex, or comorbidities, appeared to be risk factors for mortality in hospital.

Patients treated with NAIs within three days appeared to have had better clinical outcomes than other patients. More than 60% of patients received intravenous corticosteroids in an initial daily dose equivalent to 100mg hydrocortisone (range 25 to 300mg).

Patient handling and infection control

A risk‐based protocol was developed in national practice guidelines to support early antiviral therapy in suspected cases (Table). In addition, training materials for epidemiology, clinical manifestation, diagnostic specimen collection, and diagnosis and treatment were distributed to all hospitals in affected areas. The planned referral system in these areas was such that, for every suspected case, respiratory specimen testing using PCR would be completed at the local Center for Disease Control and Prevention within 6 to 8 hours. All confirmed cases, except those whose severe condition did not permit transportation, were then transferred to designated hospitals. Close contacts were closely monitored under medical observation, with NAIs prescribed only after onset of clinical symptoms. Among the 2033 close contacts, no confirmed cases were reported as of 22 April.

In general, infection prevention and control measures in fever clinics and designated hospitals complied with national and WHO guidance. Apart from hand hygiene, different types of personal protective equipment (PPE) were reported to have been used during the care of suspected and confirmed cases. Intense surveillance was undertaken in healthcare workers exposed to cases, and there were no reported infections among healthcare workers.

Table. Indications for early antiviral therapy*

Confirmed case with avian influenza A(H7N9) infection
ILI case testing positive by influenza A rapid antigen test
ILI case testing negative by influenza A rapid antigen test or without access to influenza A antigen test, who meets any of the following criteria:
- Close contact (including healthcare workers)
- One of the cluster cases
- Recent exposure to poultry (within one week)
- Significant comorbidities, such as chronic cardiopulmonary diseases, advanced age, or pregnancy
- Rapid progression that merits antiviral therapy as judged by treating physician
- Pneumonia of unknown cause

* From National Practice Guidelines on Clinical Management of Avian Influenza A(H7N9) Infection. ILI, influenza‐like illness

Conclusions

Severe cases deteriorated rapidly, within 1 to 2 days, leading to refractory hypoxemia and multiple organ failure, which were the major causes of death.

Mild cases were reported,though there were few

NHFPC developed a diagnostic and treatment protocol for human infection with avian influenza A(H7N9) virus for areas where confirmed cases were reported such that NAIs could be given earlier, even before confirmation by laboratory testing for H7N9 virus.

(...)

Characteristics of the avian influenza A(H7N9) viruses

The preliminary analysis of the first cases by the Shanghai Public Health Clinical Center and the Shanghai CDC, followed by the isolation and full genome sequencing of three viruses (A/Shanghai/1/2013, A/Shanghai/2/2013 and A/Anhui/1/2013) by China CDC, were critically important steps in the management of the outbreak. Immediate posting of the sequences in the publicly accessible GISAID database and rapid sharing of viruses by China CDC have enabled Chinese and international scientists to begin analyzing the viruses at the earliest possible stage.

Analyses of the first three isolates showed that the viruses were reassortants comprising H7 HA, N9NA and the six internal genes of H9N2 influenza A viruses. This gene constellation had not been identified previously among viruses obtained from birds, humans or any other species. While all three viruses were closely related, A/Shanghai/2/2013 and A/Anhui/1/2013 were more similar to each other across all 8 gene segments than to A/Shanghai/1/2013, which was distinct at multiple sites. Comparisons with other influenza A virus sequences in public databases showed that the most closely related viruses were recent low‐pathogenic Eurasian H7N3 viruses (e.g., A/duck/Zhejiang/12/2011(H7N3)), Eurasian H7N9 (egg, A/wild bird/Korea/A14/2011(H7N9)) and H9N2 viruses (e.g., A/brambling/Beijing/16/2012(H9N2)).

The first three isolates contained a number of genetic signatures previously associated in other subtypes with low pathogenicity in poultry, enhanced capacity for mammalian infection, resistance to the adamantane class of antiviral drugs and sensitivity to the neuraminidase inhibitors oseltamivir and zanamivir. These signatures include the following:

A single arginine at the HA cleavage site, consistent with low pathogenicity in poultry;
Deletion of five amino acids in the NA stalk, associated with adaptation to poultry;
Q226L substitution in the HA, associated with enhanced binding to the α‐2,6‐linked sialylated receptors found in the mammalian respiratory tract;
E627K in the PB2 protein, associated with viral replication at the lower temperature of the mammalian respiratory tract;
S31N in the M2 protein, conferring resistance to adamantanes;
Absence of the H275Y substitution in the NA, associated with resistance to the oseltamivir in H1N1 viruses;
R292K in one virus (A/Shanghai/1/2013), associated with markedly reduced sensitivity to oseltamivir and modestly reduced sensitivity to zanamivir.

In vitro analyses confirmed that all three viruses bound both α ‐2,3‐ and α ‐2,6 linked sialic acids, suggesting an ability to bind to both avian and mammalian cells. In functional assays, all three isolates were sensitive to both NAIs. In the case of A/Shanghai/1/2013, this result appears to reflect the presence of a mixture of viruses with R or K at position 292 of the NA.

All three viruses could be propagated readily in embryonated hen’s eggs and human, canine and porcine cell lines. Pathogenicity studies in birds or animals have not yet been performed but these and comprehensive antigenic analyses will begin soon.

It is expected that production of an effective vaccine against the new H7N9 viruses will require the development of a new candidate vaccine virus.

Further isolates and full or partial genome sequences have since been obtained by several laboratories. These isolates were from other human cases and from poultry and environmental samples taken from live poultry markets or other locations in Shanghai, Jiangsu, Zhejiang and Beijing, including many samples analysed by the National Avian Influenza Reference Laboratory, Harbin. Some of these sequences have been posted in the GISAID database. These viruses have provided important additional information on the diversity of H7N9 viruses currently circulating in eastern China. For example:

Viruses isolated from humans, avian species and environmental samples are closely related;
All lack a multi‐basic amino acid cleavage site in the HA;
Most but not all human isolates have 226L in the HA;
Only some human isolates have 627K in PB2; all tested avian and environmental isolates have 627E in PB2;
All apart from A/Shanghai/1/2013 have R292 in the NA;
All those tested to date are susceptible to oseltamivir and zanamivir in vitro.

Development and availability of human diagnostic and serological assays

Between 2 and 13 April (see timeline), real‐time PCR primers and probes based on the sequences of the first three virus isolates were distributed by China CDC to more than 400 surveillance and other diagnostic laboratories throughout China.

Protocols, along with primer and probe sequences, were posted on the WHO website. All PCR‐confirmed human cases have been diagnosed using these reagents.

Preliminary human serological assays have been undertaken using antigens from A/Anhui/1/2013, with early data indicating that sera from children, adults and the elderly lack antibodies to this virus before and after immunization with 2012–2013 seasonal influenza vaccine. This assay was used to detect antibodies in convalescent serum from two patients. Assays of avian serum samples to date have used A(H7N2) antigens and antisera (see section on animal health). Full development of H7N9‐specific serological assays for human and animal use awaits the availability of specific post‐infection antisera raised against H7N9 viruses in ferrets or chickens.

Animal health

In response to the detection of H7N9 human infections, agricultural authorities have as of 22 April sampled 2582 live bird markets, 8798 poultry farms, 337 poultry slaughter houses, 341 wild bird habitats, 227 pig slaughter houses and 633 environmental sites. A total of 218,344 samples from22 provinces have been tested. These samples were collected from three surveillance zones. The first zone comprises the four Chinese Provinces Zhejiang, Jiangsu, Henan, and Anhui, plus the municipalities of Shanghai and Beijing, from which 122,344 samples have been tested; the second comprises those provinces adjacent to the affected provinces from which 38,759 samples have been tested; and the third comprises the other provinces, from which 57,039 samples have been tested.

The swab samples (both oro‐pharyngeal and cloacal) were tested in provincial laboratories by real‐time PCR using H7 Eurasian lineage HA primers; positives were confirmed by virus isolation at the National Avian Influenza Reference Laboratory,Harbin. Blood samples were tested using a low pathogenic H7N2 virus antigen and a corresponding positive control antiserum provided by the National Avian Influenza Reference Laboratory, Harbin.

Preliminary data suggest that this antigen will detect antibody raised against the recent H7N9 virus. Of these, 39 positive swab samples from live bird markets were identified by virus isolation: 20 in Shanghai, 12 in Jiangsu,six in Zhejiang and one in Anhui.

One additional specimen from a wild pigeon in Nanjing,Jiangsu Province, was also positive.

No positive serum samples were detected.

As a result of targeted investigation of the source of infection for the first confirmed H7N9 case and suspected family cluster in Shanghai, environmental samples from a poultry market frequented by these family members tested positive for H7N9 by PCR. Further, poultry in four other live poultry markets within 1.5 km of the residence of the infected cases were found to be infected with H7N9.

Following the H7N9 outbreak,surveillance in wild birds was also enhanced nationally but no H7N9‐positive samples from wild birds or their environments have been detected thus far.

Initial conclusions

H7N9 viruses were detected in live bird markets in 3 provinces (Anhui,Jiangsu and Zhejiang) and one municipality (Shanghai).

Environmental samples collected from a poultry market frequented by the members of the family cluster in Shanghai had evidence of extensive contamination byH7 virus RNA.

It appears that the closure of live poultry markets in Shanghai was associated with a reduction in the number of new human cases, although a causal relationship should not be inferred and a definitive conclusion cannot be drawn at this time (see Epidemiology section and Figure 3).

Taken together with contact history with live poultry/live poultry markets in a substantial number of cases,these findings support a key role for exposure to live poultry as a risk factor for humanH7N9 infection.

Viruses have not been detected in poultry farms thus far. For example, in Shanghai, viruses have not been detected in the local farms that supply Shanghai live bird markets.However, 75% of the Shanghai poultry supply comes from adjacent provinces where the virus source has not been identified (as of 21 April). AlthoughH7N9 viruses have not been detected in poultry farms, it is well recognized that avian influenza is amplified and maintained in live poultry markets. It is possible therefore that a small number of infected farms could explain the level of infection in live bird markets.Given the number and severity ofH7N9 human infections it is critical to identify the source(s) ofH7N9‐infected poultry so that appropriate interventions can take place. The extensive surveillance in farms so far is still likely to be insufficient to detect small numbers of farms that may be infected withH7N9 virus at low prevalence rates.

Eleven human virus isolates and 39 poultry/environmental isolates have been genetically sequenced thus far at the China CDC and the National Avian Influenza Reference Laboratory, Harbin,respectively. The majority of the sequenced isolates from both humans and poultry/environment have the amino acid 226L in the haemagglutinin gene, which is known to confer enhanced binding to the α 2‐6‐ linked sialic acid receptors found in human upper airways. It is notable that none of the 39 viruses isolated from poultry have the mammalian adaptation marker PB2 627K while over half of the human virus isolates do. Adaptation within infected humans may explain this observation; however, other possibilities cannot be excluded at this time.

Although data at this early stage of the investigation are limited, it appearsthattheH7N9 virus is currently sustained through intra‐ and inter‐provincial trading of live poultry. If infection in poultry is not controlled,the virus may spread to additional provinces in China.

Such a situation would lead to an even greater zoonotic threat, and thus increase its pandemic potential. Continued circulation of a low pathogenicH7 virus in poultry also poses the risk of the emergence of a virus that is highly pathogenic in poultry.

Initial conclusions based on combined epidemiological, clinical, virological and animal health information

The data are most consistent with an avian influenza virus that is considerably more transmissible to humans than any earlier avian influenza virus known to date. This H7N9 influenza virus is also the first reported low pathogenic A(H7) avian influenz
virus of any subtype that has caused severe disease in humans.

Evidence so far is not sufficient conclude there is person‐to‐person transmission.

Moreover, no sustained person‐to‐person transmission has been found.

The reasons for the unusual age and gender distribution of the human cases are unknown and demand deeper investigation. This would include seroepidemiological studies to determine whether there have been larger numbers of mild and asymptomatic infections than have thus far been recognized.

The virological adaptations to mammalian hosts are particularly concerning but they need to be studied in combination with clinical and epidemiological data rather than in isolation.

Response strategies and measures

Leadership, command and coordination

In line with the national and local pandemic influenza preparedness and response plans, 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 theH7N9 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, including Anhui,Jiangsu, Shanghai, and Zhejiang.

Response principles

Significant efforts are being made to ensure that the emergency response to the newly detectedH7N9 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.

Different 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

Response measures include close collaboration between public health and animal health sectors, enhanced surveillance in humans and animals, field investigation,risk assessment, clinical management, hospital infection prevention and control, public health interventions, risk communication, and research. Several technical guidance documents 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
- Field investigations on all confirmed cases, including contact tracing, have been conducted by local CDCs with the support from China CDC. The National Influenza Centre at China CDC, which is also a WHO Collaborating Centre of the Global Influenza Surveillance and Response System(GISRS), isolated and sequenced the full genomes of the firstthreeH7N9 viruses from humans and shared, at the earliest possible moment,the gene sequences through the publicly accessible database GISAID.Genome sequences of three A(H7N9) viruses from birds and environment were also uploaded to GISAID by China Avian Influenza Reference Laboratory in Harbin, China.
- Based on the preliminary findings that the virus was an avian virus,the Ministry of Agriculture classified A(H7N9) as first class at interim for animal surveillance and notification, and with other ministries enhanced joint surveillance in poultry farms and live bird markets(so‐called wet markets). In some cities where human cases were occurring live bird markets were closed temporarily.
- In Shanghai,studies have been developed through collaboration between the Shanghai CDC, Shanghai Animal Institute)the Shanghai Bureau of Industry and Commence and the Forestry Commission under the Joint Investigation Structure to find the source of human infection.
Enhanced surveillance in humans and animals
- The national surveillance network was alerted and surveillance was enhanced. In addition to the routine IL surveillance, emphasis was placed on enhancing surveillance for pneumonia of unknown origin and severe acute respiratory infections. Surveillance data are being reported in a timely manner to provincial authorities and to China CDC for risk assessment and response. As part of the global WHOGISRS,the CNIC, in addition to uploading sequences of the whole genome of the first three novelH7N9 viruses, has contributed significantly to global alert and surveillance activities. These contributions include the PCR protocol for virus detection and virus isolates to enable WHO Collaborating Centers and Essential Regulatory Laboratories to select and develop vaccine viruses, vaccine reagents and diagnostic reagent kits, and to conduct further characterization of the virus, e.g. pathogenicity and transmissibility. China CDC published its findings in the New England Journal of Medicine within 15 days.
- Diagnostic kits were developed by the CNIC based on PCR technology. Reagent kits were distributed to all provincial CDCs, and to all prefecture/city CDC in affected provinces within 48 hours. Reagent kits have been sent to all CDC laboratories at provincial, prefecture and city levels, and military and border‐control laboratories in China.
- Surveillance forH7N9 has been initiated in animals, including poultry, pigeons, and ducks by virus or antibody detection. WhereH7N9 viruses were detected in markets, backward source tracing was undertaken to determine the source farms of the poultry, and additional specimens were collected from the source(s)for analysis.
Clinical management, infection prevention and control
- Fever clinics were activated in health care facilities for screening of patients and to ensure appropriate infection prevention and control and clinical management.National guidance onH7N9 case management was issued.Hospitals, with infection control recommendations strictly implemented, were designated specifically tomanageH7N9 cases. In Shanghai the Municipal Public Health Clinical Centre, which has 500 beds and hosts high‐level expertise in clinical management, has hospitalized and managed suspected cases, and accumulated report Page 30 valuable experience in managing and treating patients with a disease associated with a new virus. The Chinese government is providing free clinical care for allH7N9 patients.
- At national level, expertise was absorbed into groups for case management, in particular for severe cases, and information was dispatched nationwide whenever there was a need. The Chinese regulatory agency,the China Food and Drug Administration (CFDA), accelerated the regulatory process and has approved Peramivir, an injectable NAI, for treatment. National stockpiles of Oseltamivir and Zanamivir were also reviewed and renewed. Medical supplies have also been ensured.
Risk communication
- Epidemiological and virological findings were shared in a timely and transparent manner with WHO,the Food and Agriculture Organisation of the United Nations(FAO) and the World Organization for Animal Health (OIE). Continuous information was supplied through the International Health Regulations(IHR)system and was posted on the WHO website; formal notifications were made of outbreaks in poultry through the OIE system.
- Updates on surveillance and risk assessment were shared with the public in a timely manner in collaboration with media at national and local levels.
- Regular press releases were made to the public by local and national governments, especially by the health authorities,to provide timely updates on theH7N9 situation and to address public concerns.
- Health education activities are being implemented to advise about health risks ofH7N9 and to promote good hygiene practices, including hand washing, cough etiquette and safe handling of food.
Scientific research
- Under the overall coordination of JPCM, a research programme has been developed with the Ministry of Science and Technology as the lead agency to better understand the virus and disease, including the source of infection, antigenicity, pathogenicity and transmissibility ofH7N9, and to develop and evaluate interventions, including pharmaceutical and non‐pharmaceutical measures.
Conclusions
- Response at national and local levels has been excellent and appears to be effective.
- The risk assessment and evidence‐based response toH7N9 virus could serve as a model of emergency response to similar events.
International collaboration
- Any human infection with a new subtype of influenza virus, especially one causing severe disease, is of global interest and serious concern. After it first identified theH7N9 virus, China, in addition to fulfilling its obligations in timely notification under the IHR, has recognized its vital role in contributing to global public health work through open channels of communication with global influenza partners and the international community. Event reporting and information sharing with the international community The China National IHR Focal Point notified WHO of the first three cases of human infection withH7N9 on 31 March 2013. The outbreak is considered an event that may constitute a potential Public Health Emergency of International Concern. Since then,regular reporting has been made to WHO through the WHOIHR Contact Point for the Western Pacific Region, and updated information has been shared with all WHO Member States through the Event Information Site, which is open to all the National IHR Focal Points.
- Other channels of communication include regular updates on the NHFPC website, as well as on WHO websites at Country, Regional, and Headquarters level, including through Disease Outbreak News(DON).
- Given strong interest from the public and the media, and to address concerns about this new virus, joint NHFPC‐WHO press briefings were convened, including the first such press conference with WHO Country Office on 8 April 2013,to supplement individual press contacts with both offices. These situation updates and transparent sharing of information demonstrated Chinese collaboration with WHO and the openness of Government authorities, and was widely disseminated by more than 75media representatives.
Sharing of virus and information
- The whole genome sequences of the first three human cases were uploaded by the National Influenza Centre, which is also a WHOCC for Reference and Research on Influenza,to the GISAID as quickly as possible for public access.Genome sequences ofthreeH7N9 viruses from birds and the environment were also uploaded to GISAID by the national avian influenza reference laboratory in Harbin in China. This has contributed significantly to global risk assessment and risk response, and promoted the spirit of the Pandemic Influenza Preparedness(PIP) Framework. AstheH7N9 viruses are defined as PIP Biological Materials under the PIP Framework,their distribution is covered by the principle of sharing of benefits arising from their use according to public health risk and need.
- The WHOCC in Beijing has undertaken timely sharing of virus isolates with other WHOCCs for influenza and WHO Essential Regulatory Laboratories of GISRS. Thus far, all six WHOCCs and four WHO Essential Regulatory Laboratories of GISRS have receivedH7N9 virus isolates from the WHOCC in Beijing. In addition,the virus has been shared with laboratories in Taiwan and Hong Kong SAR, WHOH5 Reference Laboratories, and other requesters. As of 22 April, 15 shipments have been made to 13 recipients, including GISRS laboratories and other entities such as vaccine manufacturers. This is a significant contribution to the global risk response and will lead to the selection and development ofH7N9 candidate vaccine viruses, potency reagents, PCR reagent kits and diagnostic protocols, as well as better understanding of antigenicity, pathogenicity and transmissibility ofH7N9.
Technical collaboration
- The NHFPC,through the Chinese CDC, quickly established and has maintained very close technical collaboration with WHO staff, with daily discussions at country level, and frequentconsultation involving all three levels of WHO: Country Office, Western Pacific Regional Office and WHO Headquarters. As a newly designated WHO Collaborating Center for Reference and Research on Influenza,the National Influenza Center in China has maintained close and regular communication and technical consultation with other WHOCollaborating Centers for Reference and Research on Influenza. The Chinese CDC, as as member of the Global Alert and Response Network (GOARN), also provided a situation update to the GOARN Steering Committee members. Bi‐lateral collaboration is also ongoing, including sharing of information and technical collaboration with US CDC, Canada Public Health Agency, ECDC,NIID and Korean CDC In the second week of April,the NHFPC formally invited WHO to identify technical experts to join a China‐WHO joing mission on human infection with avian influenza A(H7N9) virus. The on‐site mission was conducted in Beijing and Shanghai 19‐24 April o understand the nature of the outbreak, investigate the prevention and control measures already taken by the Chinese Government, assess the outbreak situation and public health risks, and to provide recommendations on future prevention and control measures, and priority areas for specific research,resulting in this report.
Conclusions
- International collaborative efforts, especially transparent and timely sharing of information and viruses, as well as technical level discussions and consultations convened by China in the response toH7N9 are highly appreciated and well recognized by the international community.
- The collective efforts by China and the international community in line with the IHR and other international and regional frameworks have greatly contributed to our current understanding about the nature oftheH7N9 virus, public health risk assessments and actions required to manage the shared risk.

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Epidemiologic Characteristics of Cases for Influenza A(H7N9) Virus Infections in China (Clin Infect Dis., extract, edited)

2013-05-18T10:31:00.001+02:00

[Source: Clinical Infectious Diseases, full text: (LINK). Extract, edited.]

Epidemiologic Characteristics of Cases for Influenza A(H7N9) Virus Infections in China

Wenyi Zhang 1,a, Liya Wang 1,a, Wenbiao Hu 2,a, Fan Ding 3,a, Hailong Sun 1, Shenlong Li 1, Liuyu Huang 1, and Chengyi Li 1

Author Affiliations: ¹Institute of Disease Control and Prevention, Academy of Military Medical Sciences, Beijing, China ²School of Population Health, Infectious Disease Epidemiology Unit, University of Queensland, Brisbane, Australia ³Chinese Center for Disease Control and Prevention, Beijing, China

Correspondence: Chengyi Li, Institute of Disease Control and Prevention, 20 Dong-Da Street, Fengtai District, Beijing 100071, People's Republic of China (licy_60@163.com).

To the Editor —

China's National Health and Family Planning Commission announced 3 deaths caused by avian-origin influenza A(H7N9) virus in March, which was the first time that the H7N9 strain has been found in humans [1]. This is of major public health significance and raises urgent questions and global concerns [2, 3]. To explore epidemic characteristics of human infections with H7N9 virus, data on individual cases from 19 February 2013 (onset date of first case) to 14 April 2013 were collected from the China Information System for Disease Control and Prevention, which included information about sex; age; occupation; residential address; and day of symptom onset, diagnosis, and outcome for each case. The definition of an unconfirmed probable H7N9 case is a patient with epidemiologic evidence of contact …

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Malondialdehyde–deoxyguanosine and bulky DNA adducts in schoolchildren resident in the proximity of the Sarroch industrial estate on Sardinia Island, Italy (Mutagen., abstract, edited)

2013-05-18T10:19:00.001+02:00

[Source: Mutagenesis, full text: (LINK). Abstract, edited. h / t dr Giuseppe Lixia.]

Malondialdehyde–deoxyguanosine and bulky DNA adducts in schoolchildren resident in the proximity of the Sarroch industrial estate on Sardinia Island, Italy

Marco Peluso*, Armelle Munnia, Marcello Ceppi 1, Roger W. Giese 2, Dolores Catelan 3,4, Franca Rusconi 5, Roger W. L. Godschalk 6 and Annibale Biggeri 3,4

Author Affiliations: Cancer Risk Factor Branch, Cancer Prevention and Research Institute, Via il Vecchio 2, 50139 Florence, Italy,1 Epidemiology and Biostatistic Unit, IRCCS San Martino Hospital–IST National Cancer Research Institute, tower B, plan 1, L. go Benzi 10, 16132 Genova, Italy, 2 Department of Pharmaceutical Sciences in the Bouve College of Health Sciences, Barnett Institute, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA, 3 Department of Statistics ‘G. Parenti’, University of Florence, Viale Margagni 59, 50134 Florence, Italy, 4 Biostatistics Unit, Cancer Prevention and Research Institute, Via delle Oblate 2, 50141 Florence, Italy, 5 Epidemiology Unit, Anna Meyer Children’s University Hospital, Viale Pieraccini 24, 50139 Florence, Italy and 6 Department of Toxicology, Research Institute NUTRIM, Maastricht University, Universiteitssingel 50, PO Box 616, 6200 Maastricht, The Netherlands

*To whom correspondence should be addressed. Tel: +39 05532697867; Fax: +39 05532697879; Email: m.peluso@ispo.toscana.it

Abstract

Air quality is a primary environmental concern in highly industrialised areas, with potential health effects in children residing nearby. The Sarroch industrial estate in Cagliari province, Sardinia Island, Italy, hosts the world’s largest power plant and the second largest European oil refinery and petrochemical park. This industrial estate produces a complex mixture of air pollutants, including benzene, heavy metals and polycyclic aromatic hydrocarbons. Thus, we conducted a cross-sectional study to evaluate the prevalence of malondialdehyde–deoxyguanosine adducts in the nasal epithelium of 75 representative children, aged 6–14 years, attending primary and secondary schools in Sarroch in comparison with 73 rural controls. Additionally, the levels of bulky DNA adducts were analysed in a subset of 62 study children. DNA damage was measured by 32P-postlabelling methodologies. The air concentrations of benzene and ethyl benzene were measured in the school gardens of Sarroch and a rural village by diffusive samplers. Outdoor measurements were also performed in other Sarroch areas and in the proximity of the industrial estate. The outdoor levels of benzene and ethyl benzene were significantly higher in the school gardens of Sarroch than in the rural village. Higher concentrations were also found in other Sarroch areas and in the vicinity of the industrial park. The mean levels of malondialdehyde–deoxyguanosine adducts per 108 normal nucleotides ± standard error (SE) were 74.6±9.1 and 34.1±4.4 in the children from Sarroch and the rural village, respectively. The mean ratio was 2.53, 95% confidence interval (CI): 1.71–2.89, P < 0.001, versus rural controls. Similarly, the levels of bulky DNA adducts per 108 normal nucleotides ± SE were 2.9±0.4 and 1.6±0.2 in the schoolchildren from Sarroch and the rural village, respectively. The means ratio was 1.90, 95% CI: 1.25–2.89, P = 0.003 versus rural controls. Our study indicates that children residing near the industrial estate have a significant increment of DNA damage.

© The Author 2013. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

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MERS-CoV, Saudi Arabia: One new confirmed case in Eastern Region (Health Min., May 17 2013, edited)

2013-05-17T22:16:00.001+02:00

[Source: Saudi Arabia Ministry of Health, full text in Arabic: (LINK). Automatic translation.]

MERS-CoV, Saudi Arabia: One new confirmed case in Eastern Region

May 17 2013

Within the framework of continuous monitoring and epidemiological investigation of the new Corona virus, one new confirmed case has been recorded in the eastern region, where he receives treatment and is subject to medical care. This brings the total of confirmed infected cases 31 cases.

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China's H7N9 outbreak slows but experts remain wary (The Lancet Respiratory Medicine, extract, edited)

2013-05-17T21:58:00.001+02:00

[Source: The Lancet Respiratory Medicine, full text: (LINK). Extract, edited.]

The Lancet Respiratory Medicine, Early Online Publication, 17 May 2013

doi:10.1016/S2213-2600(13)70092-4

China's H7N9 outbreak slows but experts remain wary

Original Text

Ted Alcorn

The novel strain of H7N9 avian influenza that appeared in China in February, 2013, is waning nearly as rapidly as it had emerged. The upward march of new cases—which climbed by more than 120 during April—slowed to a crawl in May, with just five reported as of May 14. After 3 weeks with no new cases in Shanghai, officials declared an end to the emergency response they activated on April 2, although hospitals will continue to monitor influenza-like illnesses and live poultry markets remain shuttered.

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Novel Inhibitors of SARS-CoV Entry acting by Three Distinct Mechanisms. (J Virol., abstract, edited)

2013-05-17T21:18:00.001+02:00

[Source: US National Library of Medicine, full text: (LINK). Abstract, edited.]

J Virol. 2013 May 15. [Epub ahead of print]

Novel Inhibitors of SARS-CoV Entry acting by Three Distinct Mechanisms.

Adedeji AO, Severson W, Jonsson C, Singh K, Weiss SR, Sarafianos SG.

Source: Christopher S. Bond Life Sciences Center, Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, Missouri, 65211.

Abstract

Severe acute respiratory syndrome (SARS) is an infectious and highly contagious disease that is caused by SARS coronavirus, (SARS-CoV) and for which there are currently no approved treatments. We report the discovery and characterization of small molecule inhibitors of SARS-CoV replication that block viral entry by three different mechanisms. The compounds were discovered by screening a chemical library of compounds for blocking entry of HIV-1 pseudotyped with SARS-CoV surface glycoprotein S (SARS-S), but not with Vesicular Stomatitis Virus surface glycoprotein G (VSV-G). Studies on their mechanisms of action revealed that they act by three distinct mechanisms: a) SSAA09E2 (N-[[4-(4-methylpiperazin-1-yl)phenyl]methyl]-1,2-oxazole-5-carboxamide) acts through a novel mechanism of action, by blocking early interactions of SARS-S with the receptor for SARS-CoV, Angiotensin Converting Enzyme-2 (ACE2); b) SSAA09E1 ([(Z)-1-thiophen-2-ylethylideneamino]thiourea), which acts later by blocking cathepsin L, a host protease required for processing of SARS-S during viral entry and c) SSAA09E3 (N-(9,10-dioxo-9,10-dihydroanthracen-2-yl)benzamide)), which also acts later and does not affect interactions of SARS-S with ACE2 or the enzymatic functions of cathepsin L, but prevents fusion of the viral membrane with the host cellular membrane. Our work demonstrates that there are at least three independent strategies to block SARS-CoV entry, validates these mechanisms of inhibition, and introduces promising leads for the development of SARS therapeutics.

PMID: 23678171 [PubMed - as supplied by publisher]

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Human infection with avian influenza A(H7N9) virus – update (WHO, May 17 2013)

2013-05-17T19:32:00.001+02:00

[Source: World Health Organization, full page: (LINK). Edited.]

Human infection with avian influenza A(H7N9) virus – update

17 May 2013

Since 8 May 2013, no new laboratory-confirmed cases of human infection with avian influenza A(H7N9) have been reported to WHO by the National Health and Family Planning Commission, China. However, four additional deaths have been reported from previously laboratory-confirmed cases.

To date, WHO has been informed of a total of 131 laboratory-confirmed cases, including 36 deaths.

Authorities in affected locations continue to maintain enhanced surveillance, epidemiological investigations, close contact tracing, clinical management, laboratory testing and sharing of samples as well as prevention and control measures.

In the past week, the Shanghai and Zhejiang provincial governments have started to normalize their emergency operations into their routine surveillance and response activities. WHO offices in country, regional and headquarters continue to work closely to ensure timely information updates.

Until the source of infection has been identified and controlled, it is expected that there will be further cases of human infection with the virus.

So far, there is no evidence of sustained human-to-human transmission.

WHO does not advise special screening at points of entry with regard to this event, nor does it currently recommend any travel or trade restrictions.

WHO continues to work with Member States and international partners. WHO will provide updates as the situation evolves.

Several documents have been published on the WHO web site:

WHO Risk Assessment as of 10 May 2013 pdf, 137kb

Interim WHO surveillance recommendations for human infection with avian influenza A(H7N9) virus pdf, 118kb

Update of WHO biosafety risk assessment and guidelines for the production and quality control of human influenza vaccines against avian influenza A(H7N9) virus pdf, 615kb

Laboratory biorisk management for laboratories handling human specimens suspected or confirmed to contain avian influenza A(H7N9) causing human disease – interim recommendations pdf, 75kb

Candidate vaccine viruses for avian influenza A(H7N9)

WHO WPRO Human Infection with Avian Influenza A(H7N9) Situation update

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Population-level antibody estimates to novel influenza A/H7N9 (J Infect Dis., abstract, edited)

2013-05-17T19:03:00.001+02:00

[Source: The Journal of Infectious Diseases, full free text: (LINK). Abstract, edited.]

Population-level antibody estimates to novel influenza A/H7N9

Maciej F Boni 1,2, Nguyen Van Vinh Chau 3, Nguyen Dong 4, Stacy Todd 1,5, Nguyen Thi Duy Nhat 1, Erwin de Bruin 6, Janko van Beek 6,7, Nguyen Tran Hien 8, Cameron P Simmons 1,2,9, Jeremy Farrar 1,2 and Marion Koopmans 6,7

Author Affiliations: ¹Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, Ho Chi Minh City, Vietnam ²Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK ³The Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam ⁴Khanh Hoa Provincial Hospital, Nha Trang, Vietnam ⁵Liverpool School of Tropical Medicine, Liverpool, UK ⁶National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands ⁷Department of Virology, Erasmus Medical Center, Rotterdam, The Netherlands ⁸National Institute for Hygiene and Epidemiology, Hanoi, Vietnam ⁹Nossal Institute for Global Health, University of Melbourne, Victoria, Australia

Correspondence: Maciej F Boni, Oxford University Clinical Research Unit, Hospital for Tropical Diseases, 764 Vo Van Kiet Street, District 5, Ho Chi Minh City, Vietnam, Email: mboni@oucru.org, Tel +84 83 923 7954, Fax +84 83 923 8904

Abstract

There are no contemporary data available describing human immunity to novel influenza A/H7N9. Using 1723 prospectively collected serum samples in southern Vietnam, we tested for antibodies to five avian influenza antigens using a protein microarray. General-population antibody titers against subtype H7 virus are higher than antibody titers against subtype H5, and lower than titers against H9. The highest titers were observed for human influenza subtypes. Titers to avian influenza antigens increased with age and with geometric mean antibody titer to human influenza antigens. There were no titer differences between the urban and the rural location in our study.

Received April 15, 2013. Revision received May 8, 2013. Accepted May 14, 2013.

© The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.

This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/3.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work properly cited. For commercial re-use, please contact journals.permissions@oup.com

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France, Coronavirus : les deux patients dans un état stable mais «très préoccupant» (Libération, May 17 2013)

2013-05-17T19:00:00.001+02:00

[Source: Libération, full text: (LINK). Extract.]

Coronavirus : les deux patients dans un état stable mais «très préoccupant»

17 mai 2013 à 16:51 - Par AFP, Libération

Les deux malades atteints du nouveau coronavirus hospitalisés en réanimation à Lille sont «dans un état stable qui reste très préoccupant», a indiqué vendredi à la presse, près de Tours, la ministre des Affaires sociales et de la Santé, Marisol Touraine.

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Hong Kong, Update on number of suspected human cases of avian influenza A(H7) notified (May 17 2013)

2013-05-17T18:14:00.001+02:00

[Source: Centre for Health Protection, Hong Kong PRC SAR, full text: (LINK).]

Update on number of suspected human cases of avian influenza A(H7) notified

The Centre for Health Protection (CHP) of the Department of Health (DH) today (May 17) provided an update on the latest number of suspected human cases of avian influenza A(H7) notified to the CHP, including cases fulfilling reporting criteria and remaining ones not fulfilling reporting criteria.

From noon yesterday (May 16) to noon today, the CHP received no notification of cases which fulfilled reporting criteria, but four cases which did not fulfil reporting criteria.

The total number of notifications received by the CHP since March 31 of cases fulfilling reporting criteria of suspected human cases of avian influenza A(H7) hence remains at 25, while the total number of notifications not fulfilling reporting criteria is now 98.

A DH spokesman urged travellers not to visit wet markets with live poultry in the affected areas, and to avoid direct contact with poultry, birds or their droppings. If contact has been made, they should thoroughly wash hands with soap and water.

"Influenza A(H7) is a statutorily notifiable infectious disease in Hong Kong.’’

‘’Locally, no confirmed human cases of avian influenza A(H7N9) have been recorded so far," the spokesman stressed.

The spokesman reminded doctors to report to CHP any suspected case of influenza A(H7). The Public Health Laboratory Services Branch of CHP is ready to receive and test specimens whenever necessary.

The public may visit CHP's avian influenza page (www.chp.gov.hk/en/view_content/24244.html) for further information.

Ends/Friday, May 17, 2013
Issued at HKT 17:37
NNNN

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Hong Kong, No new human case of avian influenza A (H7N9) in the Mainland (May 17 2013)

2013-05-17T18:09:00.001+02:00

[Source: Centre for Health Protection, Hong Kong PRC SAR, full text: (LINK).]

No new human case of avian influenza A (H7N9) in the Mainland

The Centre for Health Protection (CHP) of the Department of Health (DH) verified with the National Health and Family Planning Commission (NHFPC) no new human case of avian influenza A (H7N9) in the Mainland today (May 17).

As of 9pm today, a total of 130 cases have been laboratory confirmed with avian influenza A (H7N9) in the Mainland, which included:

Zhejiang (46 cases),

Shanghai (33 cases),

Jiangsu (27 cases),

Jiangxi (six cases),

Fujian (five cases),

Anhui (four cases),

Henan (four cases),

Shandong (two cases),

Hunan (two cases) and

Beijing (one case).

A spokesman for the DH stressed that the CHP is closely monitoring the situation and will continue to maintain close liaison with the Mainland health authorities for more case information, as well as keep a close eye on the latest advice from the World Health Organization.

The spokesman also reminded travellers, especially those returning from Shanghai, Jiangsu, Zhejiang, Anhui, Henan, Beijing, Shandong, Jiangxi, Fujian, Hunan and Guangdong, with fever or respiratory symptoms to wear facial masks immediately, seek medical attention, and reveal their travel history to doctors. Health-care professionals should also pay special attention to those who might have had contact with birds, poultry or their droppings in the affected areas.

"No human case of avian influenza A (H7N9) has been identified so far in Hong Kong," the spokesman reiterated.

"We would like to reassure the public that the Government will be as transparent as possible in the dissemination of information on human cases of avian influenza A (H7N9). Whenever there is a suspected case, the CHP will release information to the public as soon as possible," the spokesman added.

The spokesman urged travellers not to visit wet markets with live poultry in the affected areas and to avoid direct contact with poultry, birds or their droppings. If contacts have been made, they should thoroughly wash hands with soap and water.

Members of the public should remain vigilant and are reminded to take heed of the following preventive advice against avian influenza:

Poultry and eggs should be thoroughly cooked before eating;

Wash hands frequently with soap, especially before touching the mouth, nose or eyes, handling food or eating; after going to the toilet or touching public installations or equipment such as escalator handrails, elevator control panels or door knobs; or when hands are dirtied by respiratory secretions after coughing or sneezing;

Cover the nose and mouth while sneezing or coughing, and hold the spit with tissue and put it into a covered dustbin;

Avoid crowded places and contact with fever patients; and

Wear a mask when respiratory symptoms develop or you need to take care of fever patients.

The public may visit the Avian Influenza page of the CHP (www.chp.gov.hk/en/view_content/24244.html) for further information.

Ends/Friday, May 17, 2013
Issued at HKT 21:45
NNNN

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H7N9, Taiwan: Avian influenza virus isolated from first patient possibly partially resistant to oseltamivir (Ifeng, May 17 2013, edited)

2013-05-17T17:52:00.001+02:00

[Source: Ifeng, full text: (LINK). Automatic translation from Chinese.]

H7N9, Taiwan: Avian influenza virus isolated from first patient possibly partially resistant to oseltamivir

2013 05 17, 2007 17:15 Source: China Taiwan network

China Taiwan Network May 17, according to Taiwan's "Central News Agency" reports, Taiwan's first case of H7N9 infection has transferred to the general ward, National Taiwan University Hospital inspection found that infected individuals with the deposit resistant and non-resistant strain of the virus, treatment difficult, but fortunately the ability of the virus of human-to-human transmission is limited.

National Taiwan University Hospital, director of the Pediatric Infectious Diseases, Li-Min Huang explained that the H7N9 virus may invade the body does not have the resistance to the invasion natural evolution of H7N9 Tamiflu resistant, co-existence and non-drug-resistant strains of the virus, due to the patient's condition is serious, National Taiwan University The hospital medical team for another antiviral injections.

Li-Min Huang said, The sick Taiwanese with both viruses at the same time makes the medical staff not easy to judge whether the ineffective treatment for drug resistance.

H7N9 Tamiflu resistant is not common, other viral drugs still effective, and H7N9 caused lung disease, but not infection of the upper respiratory tract, the patient does not appear runny nose, sneezing and other symptoms, so the virus will not be from the nose The pharyngeal opening secretion droplets.

Sick Taiwanese go from March 28 to April 9, Suzhou City, Jiangsu Province , returned to Taiwan via Shanghai on April 9, the onset of the 12th. 20 turn into National Taiwan University Hospital, ECMO about 9-10 days to maintain heart and lung function, has dropped before ECMO, endotracheal intubation, turn into the general ward from the intensive care unit. (China Taiwan Network Shuai)

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Case-control study to assess potential risk factors related to human illness caused by novel coronavirus (WHO, May 17 2013, edited)

2013-05-17T17:31:00.001+02:00

[Source: World Health Organization, full PDF document: (LINK). Edited.]

Case-control study to assess potential risk factors related to human illness caused by novel coronavirus

Date: 17 May 2013

Contact: Dr Anthony Mounts, mountsa@who.int

Acknowledgement

This document was adapted from a protocol developed by the Consortium for the Standardization for Influenza Seroepidemiology (CONSISE), a global partnership aiming to develop influenza investigation protocols and standardize seroepidemiology to inform public health policy for pandemic, zoonotic and seasonal influenza. This international partnership was created out of a need, identified during the 2009 H1N1 pandemic, for better (standardized, validated) seroepidemiological data to estimate infection attack rates and severity of the pandemic virus and to inform policy decisions. More information on the CONSISE network can be found on their website: www.CONSISE.tghn.org.

PROTOCOL SUMMARY

This investigation will provide data to evaluate exposures and risk factors for human cases of novel coronavirus infection to determine those that are related to infection. This protocol outlines a case-control study and the epidemiological methods to guide data collection to assess risk factors for illness caused by nCoV infection. Health care personnel and the evaluation of other contacts are addressed in a separate protocol.

Comments for the user’s consideration are provided in purple text throughout the document as the user may need to modify methods slightly because of the local context in which this study will be carried out.

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1.0 SCIENTIFIC BACKGROUND AND RATIONNALE

The novel coronavirus, sometimes referred to as the Middle Eastern Respiratory Syndrome coronavirus (MERS-CoV) was first detected in a patient living in Saudi Arabia in September of 2012. Since that time, it has returned in both sporadic cases, in small clusters, and in large outbreaks. While the source of the virus is currently unknown, it is thought to originate in animals. Human-to-human transmission has also been documented on multiple occasions. Although finding the putative animal reservoir is an important step in controlling spread of the virus, a more immediate need is to understand the route and mode of transmission to humans, and the types of exposures that result in infection. Several possibilities exist, including direct contact with an infected animal, which could be either the reservoir species or an intermediate host species; contact with or consumption of unprocessed animal products; contact with the environment where an infected animal has recently been; or consumption of a food or beverage which has been contaminated by animal excreta. All of these have been implicated in other zoonotic infections. Learning the mode of transmission to humans will allow measures to be taken to interrupt transmission. This investigation will provide data to evaluate risk factors for infection by reviewing exposures of known cases and comparing them to rates of exposure in similar uninfected individuals in the general population.

Current information on the novel coronavirus and cases can be found on the WHO website: http://www.who.int/csr/disease/coronavirus_infections/en/index.html.

A separate protocol is available specifically for assessment of exposed Health Care Personnel and contacts of cases (see http://consise.tghn.org/articles/novel-coronavirus-ncov/ ).

1.1 OBJECTIVES

The data collected from this study will be used to refine/update recommendations for surveillance and case definitions, to characterize the key epidemiological transmission features of nCoV virus, help understand spread, severity, spectrum of disease, impact on the community and to inform operational models for implementation of countermeasures such as case isolation, contact tracing and quarantine.

The primary objective of this study is to:

Identify modifiable non-human exposures that lead to human nCoV infection.

2.0 STUDY PROCEDURES

2.1 METHODOLOGY

The study uses a case-control design that examines the differences in types of exposures between symptomatic individuals with laboratory confirmed nCoV infection and healthy controls in order to determine the risk associated with that exposure. A standard questionnaire has been provided in this protocol (appendix A), however, the study must begin with less structured interviews of confirmed cases (or their proxies if unable to respond due to critical illness or death) in order to develop hypotheses about the possible exposures. Once these hypotheses have been developed, they can be tested through this case control study. For example, many of the cases might report that they ate a fruit such as dates in the week before they became ill. However, many people in the region eat dates frequently. The purpose of the case control study is to determine if a case was more likely to have eaten dates in the 10 days before he became ill than a similar uninfected person in the community.

Ideally, this study should be done prospectively, enrolling new cases as they are identified and selection controls at the same time. However, it will be necessary to do the study retrospectively for many of the cases as they occurred some time ago. For retrospective cases the period of interest is still the 10 days before the onset of their illness however as the controls have not been sick, either the same 10 day period can be used if the elapsed time is short enough to allow sufficient recall or the 10 day period before the questionnaire is administered. Controls should be chosen at random from the area of residence of the cases and of the same age and sex as the cases.

2.2 STUDY POPULATION

Study subjects will include only cases who are known to have been infected with nCoV through laboratory confirmation (see section 2.4.2 below). If the case is part of a cluster, only the case which is thought to be the “index case” or first person infected in the cluster will be included. This will exclude cases for whom the transmission may have occurred from exposure to the index case (i.e. human-to-human transmission). While there are many questions about the mode of transmission and risk factors for human-to-human transmission, the primary purpose of this study is to determine the non-human source of infection, such as exposures to animals or contaminated food products. Probable cases should be excluded from this study because the current probable case definition requires exposure to a known nCoV case in order to be classified as probable.

2.2.1 CASE DEFINITIONS

Case definitions for reporting are provided by WHO and are subject to change as more information becomes available.1

CONFIRMED CASE

A confirmed case of nCoV is a person with laboratory confirmation of infection with nCoV, either through direct detection of the virus (by viral isolation) or viral RNA (by molecular methods such as RT-PCR) in clinical specimens.
Currently, serological testing has not been used as a confirmatory test as assays are still in development. However, in the future the confirmed case definition may change. Investigators are encouraged to refer to the WHO website for current recommendations and case definitions.

2.3 SUBJECT RECRUITMENT

2.3.1 SUBJECT RECUITMENT AND DATA COLLECTION

RECRUITMENT OF CASES

Primary study subjects are laboratory confirmed cases of nCoV infection. If cases are part of a cluster, only the index case – that is, the case with the earliest date of onset of illness – should be included in the analysis. (note, it may be useful to collect the same data from all of the cases in the cluster as there are a number of other questions that may be studied but for the purposes of this study, only the index case will be included.)

As stated above, probable cases should generally not be included in the analysis as they by definition are cases with exposure to known cases and as such are part of a cluster in which nCoV transmission may have occurred from person to person. The one exception may be if during an interview with a confirmed case, it is discovered that a contact, such as another family member, would meet the definition for probable case AND that the probable case occurred earlier, making him or her the likely index case.

COMMENT: In some clusters, more than one index case may appear simultaneously (co-primary/co-index cases) and it is possible to tease out the transmission dynamics and identify the index case; another option for preliminary analysis is to exclude these clusters.

RECRUITMENT OF CONTROLS

To understand how rates of exposures to potential sources of infection differ between cases and uninfected individuals, it is necessary to recruit age and sex matched control subjects who live in approximately the same neighborhood as the case. Controls should be randomly selected as described below and asked for their consent to participate in the study.

To maximize the power to show differences in exposures, it may be desirable to recruit as many as four controls for each case.

Controls should be of the same sex as their respective case and from the same general area where the case lives.

Age matching can be done within a range that depends on the age of the case for which the control is being selected, as outlined below:

[Age of case - Age range of control]

< 5 y.o.- Within ±1 year of age
5 to 18 y.o. - Within ± 3 years of age
≥18 y.o. - Within ± 5 years of age

COMMENT: Currently, circulation of this virus in the community is thought to be nonexistent or minimal at most and the numbers of infections low. For that reason, prospective controls who have not had recent respiratory illness can be enrolled without laboratory confirmation of the absence of nCoV infection. However, if the situation changes in the future, it will be necessary to exclude controls from the study who are determined to have had nCoV infection through serological testing.

RANDOM SELECTION OF CONTROLS

Controls will be selected randomly. There are several ways to do this, the simplest is the most direct – to go to the area where the case lives and select them directly through a random selection process on site. Once arriving at the home of the case, select the closest dwelling to the case home. If a decision is needed about the closest dwelling, for example if there are two dwellings on either side equal distance from the case home, decide the direction by a coin toss. When arriving at the home, inquire about the members of the household to determine if any residents would meet the requirements for a control in terms of matching the case in age and sex. If multiple members of the household would qualify, choose by a coin toss (if only two) or drawing numbers at random. Only use one member of a given household for a control. Continue on until four controls are selected for each case. If the residence is a multi-family dwelling such as an apartment building, choose the floor to start on by random number drawing. Choose the direction to proceed on the selected floor by a coin toss. Choose the first apartment on the floor, if there are multiple, by random number drawing. If no suitable control is found in the first apartment, continue through consecutive apartments on the floor after choosing the direction from the first apartment by coin toss. Alternatively, a simple random sample of families in the neighborhood can be selected using random numbers and a list of households, if available.

INFORMED CONSENT

During the visit to both cases and controls, the purpose of the study will be explained to all eligible subjects and their consent obtained by a trained member of the investigation team. Consent for children under the age of 18 years old will be obtained from their parents or guardians. Verbal assent will also be obtained for children under 17 years old.

COMMENT: The age of consent may vary by country. Check with local IRB requirements.

MINIMUM DATA COLLECTION

After enrollment and informed consent is obtained, a standardized minimum data set will be collected. A template of the study questionnaire for the use of all cases and contacts can be found in Appendix A. These include some identifying information, demographic information, and date of onset.

RISK FACTORS FOR HUMAN INFECTION

In addition to the minimum dataset, detailed questions to evaluate risk factors for human infection with nCoV will be asked in a questionnaire (Appendix A). These are included in the data collection form in under the section for “exposures”. These questions are more specific and include aspects of timing of, frequency and duration of exposure(s).

2.3.2 PREVENTION OF NCOV TRANSMISSION IN FRONT-LINE STAFF

Prior to study implementation, front-line staff including all study personnel will be trained in infection control procedures (standard, contact, droplet or airborne precautions) including proper hand hygiene and the correct use of surgical or respiratory face masks, if necessary, not only to minimize their own risk of infection when in close contact with patients during home visits and elsewhere, but also to minimize the risk of the personnel acting as a vector of nCoV transmission between subjects members or between households. If N-95 respirators are to be used, they should be fit tested in advance.

2.4 SPECIMEN COLLECTION AND LABORATORY TESTING

2.4.1 SPECIMEN COLLECTION, TRANSPORTATION

Laboratory testing is necessary to prospectively identify cases and, if needed, to eliminate individuals who have been infected from the control group. Please refer to the current WHO laboratory guidance for appropriate collection, storage, shipment, and testing procedures. Current WHO lab guidance is available at: http://www.who.int/csr/disease/coronavirus_infections/LaboratoryTestingNovelCoronavirus_21Dec12.pdf.

Additional records should be kept for each biological sample, including the time of collection, the conditions for transportation and the time of arrival at the study laboratory.

2.4.2 LABORATORY PROCEDURES

VIROLOGIC TESTING

COMMENT: Limited available data suggests that lower respiratory specimens such as sputum, endotracheal aspirates, or brochoaveolar lavage, will have a higher yield for testing than upper respiratory specimens such as nasopharyngeal swabs. Ideally, multiple respiratory specimens should be collected from different respiratory sites on multiple days to maximize detection of nCoV. A person suspected to have nCoV infection but who has a nasopharyngeal swab collected that tested negative for nCoV should have repeat testing on subsequent days if strongly suspected to have nCoV infection. nCoV has also been found in stool of infected patients, which may provide an additional of confirmation.

To consider a case as laboratory-confirmed, one of the following conditions must be met:

positive RT-PCR or other validated molecular assays for at least two different specific targets on the nCoV genome

one positive RT-PCR assay for a specific target on the nCoV genome and an additional different PCR product sequenced, confirming identity to known sequences of the new virus.

A positive RT-PCR assay for a single specific target without further testing is considered presumptive evidence of nCoV infection. Final classification of cases will depend on clinical and epidemiological information combined with laboratory data. Case definitions can be found at: http://www.who.int/csr/disease/coronavirus_infections/case_definition/en/index.html

Member States are requested to immediately notify WHO.

See full details for virologic laboratory testing of nCoV can be found here: http://www.who.int/csr/disease/coronavirus_infections/LaboratoryTestingNovelCoronavirus_21Dec12.pdf.

COMMENT: there is currently no provision for case confirmation using a serological assay, however, this may become available in the near future. Investigators should refer to current WHO case definitions for determining case classification.

SEROLOGIC METHODS

The methods described in this section may be useful if it becomes necessary to exclude infected individuals from the control group.

COMMENT: Validated serologic assays for nCoV are currently limited but are being pursued by a small number of laboratories across the globe. Here we provide details of the only published serologic testing available for nCoV.1,2

COMMENT: Only a limited number of laboratories have the facilities for nCoV serologic testing and therefore collaboration between countries without current capacity and designated reference laboratories is possible. Collaboration is up to the discretion of member states carrying out the research, but WHO/EMRO strongly support such collaboration and would willingly facilitate collaboration and possible shipment elsewhere for testing.

The following laboratory assay results are currently available for defining a case as nCoV antibody positive and full details can be found in1,2.

Screening for antibodies reactive to nCoV by indirect immunofluoresence assay (IFA) described by 1,2
It is strongly recommended that confirmatory serologic testing should be done using microneutralization or ELISA-based assays using appropriately timed sera (ideally paired acute and convalescent sera)1,2

2.5 ETHICAL CONSIDERATIONS

Ethical approval will be sought in accordance with local, regional and national authorities.
Comment: It is strongly recommended that ethical approval is obtained in advance from relevant ethical or institutional review boards (e.g., national Ministries of Health, Agriculture, etc.) using a generic protocol such as this one prior to an outbreak. Once an outbreak occurs, the study design, questionnaires, sampling and consent forms can be modified rapidly to the actual situation. This may still have to be resubmitted for ethical approval, but as the generic protocol including this final step has already been approved, this could be a very rapid process, without substantial delay to the start of the investigations.

3.0 STUDY ENDPOINTS & STATISTICAL ANALYSES

The following section discusses the endpoints – that is, what will be measured and calculated using the data that are collected in this study – for the primary objectives, including statistical advice.

3.1 STUDY OUTCOME MEASURES

3.1.1 PRIMARY OUTCOME

The following will be assessed as study endpoint corresponding to the study’s primary objective:

The ratio of the odds of exposure vs. odds of no exposure to a variety of potential sources of infection in cases vs. controls.
The exposure or combination of exposures that best explain the resulting infection based on a regression model of all exposures.

3.2 STATISTICAL ANALYSES

3.2.1 FOR PRIMARY OBJECTIVE

RISK FACTORS FOR HUMAN INFECTION

The reported practices among cases and matched controls should be compared using appropriate statistical tests, e.g., Bivariate associations between risk factors and infection will be determined by chi-square statistics or 2-sided Fisher’s exact test and expressed as odds ratios with 95% confidence intervals. Multivariable logistic regression will be used to further analyze the associations to determine which best explains the resulting infection.

COMMENT: Univariate statistical analysis by use of logistic regression for a case‐control study could be used to test the significance of each predictor on the outcome of infection. Multivariable logistic regression can be used to identify a combination of risk factors associated with the odds of infection.

COMMENT: Alternatively, Mantel-Haenszel matched-pair analysis (McNemar test) can be used to estimate the strength and statistical significance of associations between exposures and infection.3

4.0 REPORTING OF FINDINGS

Any deviations of the study methodologies should be reported along with the results to aid in the interpretation of findings and to assist others in improving future versions of the protocol.

5.0 OTHER STUDIES

Although not described as part of this investigation, we recommended that in conjunction with this case control study , full epidemiological and virological outbreak investigations around new cases, including (1) further investigations of close familial, social and health care worker contacts, (2) environmental sampling including testing of areas around the infected household, farms, markets and potential contaminated water sources and (3) retrospective animal mortality investigations should supplement these activities in collaboration with relevant parties, in particular if the objective would include identifying a zoonotic source of infection among index and/or contacts of the index.

REFERENCES

Papers related to nCoV:

Buchholz U, Müller MA, Nitsche A, et al. Contact investigation of a case of human novel coronavirus infection treated in a German hospital, October-November 2012. Euro Surveill. 2013;18(8):pii=20406. Available online: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20406.
WHO. Novel coronavirus infection in the United Kingdom, 23 September 2012; Available at: http://www.who.int/csr/don/2012_09_23/en/index.html.
Albarrak AM, Stephens GM, Hewson R, et al. Recovery from severe novel coronavirus infection. Saudi Med J 2012;33(12):1265-9.
Corman VM, Müller MA, Costabel U, et al. Assays for laboratory confirmation of novel human coronavirus (hCoV-EMC) infections. Euro Surveill. 2012;17(49):pii=20334. Available from: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20334.

Risk factor investigations of other novel viruses:

Dinh P, Long H, Tien N, et al. Risk factors for human infection with avian influenza A H5N1, Vietnam, 2004. Emerg Infect Dis 2006;12(12):1841-7.
Reynolds MG, Anh BH, Thu VH, et al. Factors associated with nosocomial SARS-CoV transmission among healthcare workers in Hanoi, Vietnam, 2003. BMC Public Health 2006;6(207):207 doi:10.1186/1471-2458-6-207.
Zhou L, Liao Q, Dong L, et al. Risk Factors for Human Illness with Avian Influenza
A (H5N1) Virus Infection in China. JID 2009:199 (15 June): 1726-34.
Areechokchai D, Jiraphongsa C, Laosiritaworn Y, et al. Investigation of Avian Influenza (H5N1) Outbreak in Humans — Thailand, 2004. MMWR vol. 5 suppl. April 28 2006.
Mounts A, Kwong H, Izurieta HS, et al. Case-Control Study of Risk Factors for Avian Influenza A (H5N1) Disease, Hong Kong, 1997. JID 1999;180:505-8.

APPENDIX A DATA COLLECTION FORM

Questionnaire for case-control study to assess risk factors related to human illness caused by novel coronavirus

The following questionnaire should be used for all cases and controls included in the investigation. The time frame for the questions to cases is the 10 day period before the onset of their illness. For cases that happened in the past, it is useful to use memory prompts such as birthdays, holidays, or other memorable events that occurred around the same time to help the interviewee recall the specific time frame of interest. For controls, ideally the same time frame would be asked about as for the cases, however for retrospective cases in the remote past, this is not generally feasible. In that situation, the 10 day period just before the interview can be used as a reference. For cases that are enrolled prospectively when they are diagnosed, controls should be chosen at that time and the time frame of reference for the questions should be the same as for the case.

If the case has died or is otherwise unable to answer questions, a proxy such as a close relative who knows the person well can answer the questions for him or her.

Each subject should be allocated a unique identification number.

COMMENT: Once questionnaire is finalized, full instructions and skip patterns should be added. Comments throughout the questionnaire are highlighted with purple text.

COMMENT: Note that adding multiple choice answers will allow for easier data analysis.

(…)

_________
(1) WHO Case Definition for nCoV: http://www.who.int/csr/disease/coronavirus_infections/case_definition/en/index.html

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Novel coronavirus summary and literature update – as of 17 May 2013 (WHO, edited)

2013-05-17T17:14:00.001+02:00

[Source: World Health Organization, full page: (LINK). Edited.]

Novel coronavirus summary and literature update – as of 17 May 2013

Since April 2012, there have been 40 laboratory-confirmed cases of human infection with novel coronavirus (nCoV). Several countries in the Middle East have been affected, including Jordan, Saudi Arabia, the United Arab Emirates (UAE), and Qatar.

Cases have also been reported by three countries in Europe: France, Germany, and the United Kingdom. All of the European cases have had a direct or indirect connection to the Middle East. However, in France and the United Kingdom, there has been limited local transmission among close contacts who had not been to the Middle East but had been in contact with a traveler recently returned from the Middle East.

The most recent case reported had onset on 10 May 2013.

Most patients are male (79%; 31 of 39 cases with sex reported), and range in age from 24 to 94 years (median 56 years). All of the laboratory confirmed cases had respiratory disease as part of the illness, and most had severe acute respiratory disease requiring hospitalization. Reported clinical features include acute respiratory distress syndrome (ARDS), renal failure requiring hemodialysis, consumptive coagulopathy, and pericarditis.

Many patients have also had gastrointestinal symptoms including diarrhea during the course of their illness. One patient, who was immunocompromised, presented with fever, diarrhea and abdominal pain, but had no respiratory symptoms initially; pneumonia was identified incidentally on a radiograph. 20 of the 40 patients have died.

Since 6 April 2013, 21 cases of infection have been confirmed and reported in the region of Al-Ahsa in the Eastern Province of Saudi Arabia (16 males and 5 females, median age 56 years). Nine of these have died, and six remain critically ill. Most patients were reported to have at least one comorbidity. The majority of the initial cases were associated with a single health care facility in Al-Ahsa. Additional cases have subsequently been identified who were not patients at the facility. Three family members of cases linked to the facility and two health care workers not associated with the Al-Ahsa facility but who had contact with laboratory confirmed cases have become infected. Two additional cases have been identified in the community that did not have any links with other cases from the Al-Ahsa healthcare facility. Although investigations are still ongoing into the source of this outbreak, early information indicated that only a small minority of these cases had contact with animals in the time leading up to their illness.

Since 8 May 2013, two cases have been reported by France. The first case became ill after a 9 day vacation to Dubai, UAE. The second case, reported on 12 May, is a patient who shared a room at a health care facility with the first case. Investigations to look for additional cases among fellow travelers of the first case and close contacts of both cases are currently underway, but no further cases have been identified. Of note, the patient’s initial nasopharyngeal swab was negative, but a bronchoalveolar lavage was found to be positive for nCoV.

All clusters reported to date have occurred among family contacts or in a health care setting. Human-to-human transmission occurred in at least some of these clusters, however, the exact mode of transmission is unknown. So far, no evidence of sustained transmission beyond the clusters into the community has been observed.

Recent peer-reviewed papers published since the last update

The Coronavirus Study Group of the International Committee on Taxonomy of Viruses has published a proposed new designation for the novel coronavirus, the Middle East Respiratory Syndrome Coronavirus (MERS-CoV). Reference: De Groot RJ, et al. Middle East Respiratory Syndrome Coronavirus (MERS-CoV): Announcement of the Coronavirus Study Group. J Virol. Published ahead of print 15 May 2013. doi:10.1128/JVI.01244-13.

Summary assessment

The nCoV is thought to be of animal origin and to be sporadically transmitted to humans through an as yet unknown route. However, it is clear that the virus can also be transmitted between humans. So far, human-to-human transmission has only been observed in health care facilities and close family contacts and sustained transmission in the community has not been observed.

The continued appearance of cases that are not part of larger clusters, and who do not have a history of animal contact, increases concerns about possible community transmission. This possibility is being investigated by authorities in Saudi Arabia.

The infection of two health care workers who had contact with infected patients and other examples of nosocomial transmission re-emphasize the need for meticulous adherence to appropriate infection control measures when nCoV is suspected, beginning with initial patient triage. Current infection control recommendations can be found at: http://www.who.int/csr/disease/coronavirus_infections/en/.

The large number of cases with reported co-morbidities suggests that increased susceptibility from underlying medical conditions may play a role in transmission. In addition, it has now been demonstrated that nCoV infection may present atypically, and initially without respiratory symptoms, in immunocompromised individuals.

Limited evidence suggests that the use of nasopharyngeal swabs for diagnosis may not be as sensitive as the use of lower respiratory specimens. Lower respiratory specimens should be used for diagnosis in addition to nasopharyngeal swabs when they are available. If an nasopharyngeal swab tests negative, consider retesting using lower respiratory specimens such as sputum, endotracheal aspirate, or bronchoalveolar lavage. Clinicians should take care to follow strict infection prevention and control guidelines when collecting respiratory specimens of any kind.

The recent increase in cases may in part be related to increased awareness among the medical community, however the demonstrated ability of this virus to transmit between humans and to cause large outbreaks, has increased concerns about the possibility of sustained transmission. Countries in the Middle East in particular should maintain a high level of vigilance and a low threshold for testing of suspect cases. Current surveillance recommendations can be found at:
http://www.who.int/csr/disease/coronavirus_infections/en/.

WHO expects that more cases will be identified. Control of the disease will require urgent multisectoral investigations aimed at identifying the source of the virus and the exposures that result in infection. It is critical for member states to report these cases and related information urgently to WHO, as required by the International Health Regulations, to inform effective international alertness, preparedness and response.

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Severe respiratory disease associated with Middle East respiratory syndrome coronavirus (MERS-CoV) (ECDC, May 17 2013, edited)

2013-05-17T17:01:00.001+02:00

[Source: European Centre for Disease Prevention and Control (ECDC), full PDF documento: (LINK). Edited.]

UPDATED RAPID RISK ASSESSMENT

Severe respiratory disease associated with Middle East respiratory syndrome coronavirus (MERS-CoV)

17 May 2013

Summary

As of 14 May 2013, 38 cases of Middle East respiratory syndrome coronavirus (MERS-CoV) have been reported worldwide, including 20 deaths. All cases remain associated (including indirect association following secondary person-to-person transmission in the UK and France) with transmission in the Arabian Peninsula and Jordan. The age of cases ranges from 24 to 94 years (N=34 cases), with a mean of 55.5 years and a male/female ratio of 1:0.2.
The report of 19 new infections in Saudi Arabia in the past two weeks – including one infection with the novel coronavirus acquired in the United Arab Emirates and later imported to Europe – indicate that there is an ongoing source of infection and risk of transmission to humans in the Arabian Peninsula and Jordan.
The most recent imported case, which resulted in a nosocomial transmission, originated in the United Arab Emirates and then moved to France. Both patients had underlying conditions and a degree of immunosuppression. One of the transmissions in the UK also affected an immunosuppressed person. These underlying conditions may be increasing vulnerability and the risk of transmission.
The first French case raises the possibility that presentations may not include respiratory symptoms initially, especially in those with immunosuppression or underlying chronic conditions. This needs also to be taken into account when revising case-finding strategies.
The confirmed infection in France of a patient who shared a hospital room with a patient returning from the United Arab Emirates indicates the risk of nosocomial transmission. This is the second nosocomial transmission in Europe. The first one took place when an imported case in the UK visited a relative in the hospital in February 2013.
These conclusions should be seen in the light of the many uncertainties that still continue with the investigation of cases in the Arabian Peninsula and Jordan. It is unusual to have such a degree of uncertainty at this stage in an outbreak.

Recommendations

Healthcare workers in the EU should be vigilant in identifying patients that may require further investigation; they should also follow ECDC and national guidance for case finding. Patients developing severe respiratory infections and who have been in the Arabian Peninsula or neighbouring countries in the preceding 10 days should be investigated rapidly. Special attention should be given to medical evacuated patients from the Arabian Peninsula and neighbouring countries.
Patients with chronic underlying conditions who develop severe infections (not just respiratory infections) should also be investigated rapidly for novel coronavirus if they have been in the Arabian Peninsula or neighbouring countries in the preceding 10 days.
Since routine microbiological sampling (nasopharyngeal swabs) may give misleading negative results in persons later shown to be infected with the coronavirus, tests should be repeated with deeper respiratory sampling if a person fits into a category that requires investigation, especially if their condition is worsening.
As demonstrated by a case with dual influenza and novel coronavirus infections, there is a possibility of co-infection and this should be considered by healthcare personnel. Identification of one causative agent should not exclude testing for novel coronavirus where indicated.
Mapping of international routes of medical evacuation or emergency medical care from the Arabian Peninsula and neighbouring countries to the EU could be considered in order to determine the most vulnerable centres in the EU where these cases might arrive.
Companies undertaking medical evacuations from affected areas should be reminded of the risk of transferring infections across borders and of their obligations to protect staff engaged in the transfer; the same holds true for the staff of institutions which receive patients.
Healthcare workers caring for patients under investigation for MERS-CoV should exercise standard infection control measures following national or international guidance.
Close contacts of confirmed cases must be monitored for symptoms for 10 days after the last exposure, and should be tested, and should be informed what to do should they become ill. This should be carried out according to guidance, such as that developed by Public Health England UK (See ‘Sources of additional information’ below).
Healthcare workers caring for confirmed cases should be monitored for early symptoms of infection and advised to seek testing and thereafter self-isolate if they become unwell.
Clusters of severe acute respiratory infections in the community or in healthcare settings, either among patients or healthcare workers, should always be reported rapidly and investigated for a range of pathogens, regardless of where in the world these infections occur.
ECDC does not currently consider a need for testing individual patients with unexplained pneumonias or other respiratory symptoms unless they fall under one of the above categories.
Any probable or confirmed case being diagnosed in the EU/EEA should be reported to national authorities through the Early Warning and Response System (EWRS) and to WHO under the International Health Regulations (2005). Reporting through EWRS qualifies as IHR notification and avoids double reporting. Patients still under investigation do not need to be reported internationally before confirmation, but information on outcome of such testing exercises should be shared with ECDC.
ECDC supports the WHO travel advice which imposes no travel or trade restrictions in relation to novel coronaviruses. However, EU citizens travelling to the Arabian Peninsula and neighbouring countries need to be aware of the presence of MERS-CoV in this geographical area and of the small risk of infection. Member States may consider active information efforts for travellers to areas most at risk.
Although the reservoir of infection in the Middle East is unknown, other novel coronaviruses are zoonoses and have come from animal sources. Travellers should therefore follow standard good hygiene practise and avoid contact with animals or their waste products.

Source and date of request

ECDC internal decision, 6 May 2013.

Public health issue

This fourth update of the rapid risk assessment of severe respiratory disease associated with a novel coronavirus (MERS-CoV) was produced in relation to 22 additional cases of laboratory-confirmed infections reported in the last two months. The aim of this updated risk assessment is to review changes since the February update and assess the implications of change on ECDC’s recommendations for EU/EEA countries.

ECDC internal response team

Paloma Carrillo-Santisteve, Denis Coulombier, Alastair Donachie, Assimoula Economopoulou, Kaja Kaasik Aaslav, Angus Nicoll, Lara Payne, Marc Struelens, Hervé Zeller (in alphabetical order).

Consulted experts

ECDC acknowledges the valuable contributions from the members of the ECDC Advisory Forum (all have submitted Declarations of Interest). It should be noted that opinions expressed by individual experts do not necessarily represent the opinion of their institutions.

Background information

On 19 February 2013, the date of the last ECDC rapid risk assessment, 12 cases of MERS-CoV had been confirmed worldwide.

The first confirmed case was reported in a 60-year-old male who lived in Saudi Arabia. He died from severe pneumonia complicated by renal failure in Jeddah on 24 June 2012. The genome of the new coronavirus was isolated from this case, sequenced and the genetic code put in the public domain [1]. In September 2012, a 49-year-old male living in Qatar presented with symptoms similar to the first case. He was transferred to Europe for further care [2]. A virus was isolated from this case, sequenced and the genetic code put in the public domain by the UK authorities. It was found to be almost identical to the virus from the case in Saudi Arabia. The emergence of a novel coronavirus causing severe respiratory disease in two separate parts of the Arabian Peninsula led to notifications through the International Health Regulations (IHR) and the EU Early Warning and Response System (EWRS) on 22 September 2012.

In November 2012, four additional cases with similar symptomatology were diagnosed in Saudi Arabia, including a family cluster of three confirmed cases, one probable case [3] and a second imported case to Europe (from Qatar to Germany) reported on 23 November.

Two fatal cases were confirmed retrospectively in Jordan. Both cases came from a cluster of 11 people with severe lower respiratory infections associated with a hospital in April 2012. Although the other nine persons also matched the WHO definition for probable novel coronavirus infections, the cases were less severe than the two confirmed cases. It has not yet been possible to undertake confirmatory virological or serological testing for these probable cases.

Three additional cases were diagnosed in February 2013 in the UK in a family cluster associated with an index case who has a travel history to Saudi Arabia and Pakistan. These cases included the first two transmissions in Europe [4]. These cases resulted in a total of four cases identified and reported by the UK to date.

Recent developments

Between 13 February, when the last ECDC risk assessment was published, and 12 May 2013, 26 additional confirmed cases of MERS-CoV were reported worldwide, including 12 deaths:

Single case imported into Germany:

one case was diagnosed and reported by Germany on 25 March. The person arrived from the United Arab Emirates to receive medical care in Germany. It was the second imported case to be reported by this EU Member State. The patient, a 73-year-old male with underlying clinical conditions, had been hospitalised in United Arab Emirates and was transferred to a hospital in Germany for specific clinical care where the diagnosis of MERS-CoV infection was confirmed. Despite intensive-care treatment the patient died on 26 March [5].

Twenty-three cases from Saudi Arabia:

23 cases were detected and reported by Saudi Arabia in the last two weeks; WHO started reporting these case on 2 May 2013. Nineteen of these cases seem to be part of a recently detected cluster in Al-Hasa in the Eastern Province of Saudi Arabia, which may be linked to the same healthcare facility. Onset dates are from 6 April to1 May 2013 [6]. Although investigations are stated to be ongoing by the Saudi Arabian authorities, no additional information or analyses have been made available to ECDC as of 14 May 2013.

Single case imported into France:

This first case reported by France on 7 May 2013 was in a French resident with a history of travel to Dubai, United Arab Emirates, in the two weeks prior to onset of illness in France (9–17 April). The 65-year-old man had a history of renal impairment and had sought medical care in France for fever, diarrhoea and lumbar pain on 23 April. Though he did not initially present with respiratory symptoms, pneumonia was subsequently diagnosed and laboratory tests were undertaken for novel coronavirus infection, as recommended by national and ECDC guidance. A naso-pharyngeal specimen was negative for MERS-CoV on 3 May. A bronchoalveolar lavage (BAL) specimen taken on 26 April arrived at the Reference Laboratory on 7 May and tested positive for MERS-CoV. The patient is on mechanical ventilation [communication by France, EWRS message, 7 May 2013] and investigations are underway concerning the possible exposure in Dubai [7].

Single nosocomial transmission in France:

On 12 May, France informed ECDC of an additional laboratory-confirmed case. The case is an immunosuppressed male in his fifties who, from 27 to 29 April 2013, shared a hospital room with the first laboratory-confirmed patient in France. This patient was identified as part of the epidemiological investigation initiated by the French authorities, following laboratory confirmation of the first case on 7 May 2013. The patient is currently hospitalised. An epidemiological investigation and contact identification is ongoing.

Epidemiological summary

As of 14 May, 38 cases have been reported worldwide, including 20 deaths. An epicurve of the month of onset of reported cases by clinical outcome and probable place of infection is shown in Figure 1.

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All 38 cases worldwide remain associated (including indirect association following secondary person-to-person transmission in the UK and France) with transmission in the Arabian Peninsula; the majority of cases are from Saudi Arabia.

Eight cases were initially diagnosed in three European countries: three came to Europe as a result of medical transfers, two developed illness after returning from the Middle East, and three were the result of limited non-sustained person-to-person transmission in Europe (two of them were nosocomial infections).

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Virological information

MERS-CoV is distinct from the coronavirus which caused the SARS outbreaks in 2003, and distinct from the endemic human coronaviruses (HCoV) OC43, 229E, HKU1, and NL63. The International Committee on Taxonomy of Viruses (ICTV) has recognised four genera within the Coronavirinae subfamily: Alphacoronavirus, Betacoronavirus, Gammacoronavirus, and Deltacoronavirus.

HCoV-229E and HCoV-NL63 are viruses belonging to the genus Alphacoronavirus, while HCoV-OC43, HCoV-HKU1, SARS-CoV, and MERS-CoV belong to the genus Betacoronavirus [8]. Within the genus Betacoronavirus, four monophyletic lineages, A through D, are commonly recognised. Lineage A includes HCoV-OC43 and HCoVHKU1, and lineage B the SARS-CoV, all of which belong to different species.

Lineages C and D include viruses detected only in bats, for example:

In China: Rousettus bat coronavirus HKU9 (BtCoV-HKU9) (lineage D), Tylonycteris bat coronavirus HKU4 (BtCoV-HKU4), and Pipistrellus bat coronavirus HKU5 (BtCoV-HKU5) (both lineage C).
In Europe: Pipistrellus bat coronaviruses 8-691 from Romania, UKR-G17 from Ukraine, or VM314 from the Netherlands [8].

MERS-CoV belongs to lineage C, and is thus the first Betacoronavirus lineage C member isolated from humans. It appears most closely related to several European bat coronaviruses [8].

No animal reservoir or mode of zoonotic transmission has yet been identified for MERS-CoV although the similarities to bat coronaviruses make bats a likely source, specifically insectivorous species such as Pipistrellus. However, experience with SARS indicates that the exposure may not be directly from bats but can result from environmental contamination or via intermediary animal hosts [9].

Analysis of virus tropism indicates that these viruses can infect a variety of cell lines, including human cells via surface receptors distinct from SARS coronavirus receptors [10]. Novel coronavirus seems to be fully able to penetrate human bronchial epithelia cultures. At the same time, like SARS-CoV, it appears to be sensitive to treatment with interferons (types I and III) [11]. Cyclosporin A has been shown as an inhibitor of MERS-CoV replication in cell culture and MERS-CoV was found to be 50 to 100 times more sensitive to interferon-alpha (IFN-α) treatment than SARS-CoV [12].

Interim laboratory testing guidance for screening and confirmation of MERS-CoV infection was issued by WHO in December 2012. A survey by ECDC and the WHO Regional Office for Europe ascertained the availability of national reference laboratory testing as of November 2012. Screening by controlled upE-RT-PCR assay was available in 19 of 30 EU/EEA countries [13]. Confirmation of positive-screened samples by either ORF1b – RT-PCR, or other target RT-PCR assays with sequence analysis or whole-genome sequence analysis, was available in 18 of 30 EU/EEA countries [13]. However, this does not imply the capacity for large-scale or rapid testing with such non-commercial technically demanding tests in these 18 countries. Additional molecular assays for sensitive and specific-case confirmation have been described [14]. More information about diagnostic procedures can be found in other articles [13-16] and on the University of Bonn website.

Since routine microbiological sampling through nasopharyngeal swabs may give initial negative results in persons later shown to be infected with the coronavirus, tests should be repeated on deeper respiratory samples if a person meets the criteria for investigation, especially if their condition is worsening.

Serological tools for the detection of specific MERS-CoV IgM and IgG antibodies based on protein microarray technology have been recently developed and validated with a limited number of specimens [17]. These assays, presently in the hands of some specialised laboratories, can be used to aid diagnosis in individual patients, for confirmatory testing of positive tests and for (large-scale) contact studies. These tests will need to be validated for use in the Arabian Peninsula and Jordan [18].

Following the identification and analysis of the viruses obtained from the first identified cases, the flow of viruses to specialised laboratories, especially from the Middle East cases, has slowed down, limiting the possibility to determine the full virological picture and making it difficult to assess whether the viruses are evolving.

Epidemiological surveillance

On 16 January 2013, WHO re-published its earlier case-definition for the novel coronavirus in humans, along with its interim surveillance recommendations for human infection of December 2012 [19]. This publication also includes a category for ‘patient under investigation’. A confirmed case is a case in which novel coronavirus has been identified in a biological sample from the patient. Interim laboratory testing guidance for screening and confirmation of infection was issued by WHO in December 2012.

The initial case-finding strategy was based on two approaches:

Firstly, looking for the virus in people with severe lower respiratory tract infection, especially in those with no other microbiological diagnosis. WHO recommends that special attention should be paid to persons who report onset of symptoms ten days (or less) after arriving from the Arabian Peninsula and Jordan.
Secondly, contact tracing should be performed among all close contacts1 of confirmed cases, both for control purposes and to assess whether human-to-human transmission occurred. If numbers increase and it becomes apparent that more are presenting with milder symptoms, a more selective approach will be needed.

The first French case raises the possibility that presentations may not initially include respiratory symptoms, especially in those with immunosuppression or other underlying chronic conditions and, as a result, delay the detection and implementation of measures.

The number of cases with immunosuppression or other underlying conditions, and the transmission to and from them, as in the two French cases, suggest that such persons may be at increased risk of acquiring or transmitting infections.

Protocols on the standardisation of influenza seroepidemiology have already been published [18, 20]. Drawing on these and in-country protocols, the UK has published a protocol specifically for the purpose of investigating cases of MERS-CoV infections.

This protocol is suitable for use in other EU countries [21]. Most recently, the CONSISE group has published specific coronavirus protocols [20]. Seroepidemiological studies of close contacts are being undertaken in France, similar to studies already performed in Germany [27].

The epidemiological pattern of the infections is unusual, with an excess of male cases and of cases presenting with co-morbidities, as well as an underrepresentation of children [22]. This is different from SARS, where there was a small female excess, co-morbidities were less marked, and cases were younger.

Applied epidemiological and laboratory studies will be of assistance here, and opportunistic and retrospective case-finding will be invaluable, focusing on severe cases for which there are suitable samples as defined by the WHO laboratory guidance of 12 December 2012. Particular emphasis should be on capturing the results of case finding operations, negative as well as positive. The ECDC-WHO laboratory survey could serve as an example, as it helped to inform about the true geographical extent of these infections [13, 18].

Possible sources and routes of transmission

The retrospective finding of two cases in Jordan raised the issue of whether this is a new infection in humans or one that has been occurring for some time. Since similar animal coronaviruses can be found in bats in all regions of the world [8-9, 23-26], it is possible that these infections are to be found sporadically in many countries. This makes a strong case for further studies of animal coronaviruses and prospective and retrospective searches for cases in other regions – as was already pointed out in ECDC’s risk assessment in February 2013. The testing of people with respiratory tract infections among those coming to Europe between September and November 2012 did not reveal any additional infections to the three already mentioned [2, 13, 27].

No reservoir or source of infection for MERS-CoV has been identified so far in Saudi Arabia, the country reporting most indigenous cases to date. The same is true for other cases and clusters in the other reporting countries of the Arabian Peninsula and Jordan. For a number of cases, contact with animals, in particular camels in herds or in camel markets has been mentioned. However, this information is not available for many of the primary cases.

The routes of transmission to humans have not yet been determined. This is a common issue with emerging zoonoses where there are often simultaneous possibilities, including environmental, animal and human exposures. There is very little information in the public domain, which contrasts with the situation during the SARS outbreak ten years ago [28-31].

In Germany and the UK, a follow-up of nearly 200 personal contacts and healthcare workers who were exposed to the first two imported confirmed cases has been completed and did not find evidence of human-to-human transmission. Although some contacts in Germany and the UK developed mild respiratory infections, virological and serological investigations did not link these infections to MERS-CoV [2, 26]. In France, the epidemiological investigation and contact tracing are ongoing.

There have been at least three instances in Europe where person-to-person transmission is certain to have taken place. Two of these transmissions were in a small family cluster of three cases in the UK. One transmission took place from an imported case to a healthy relative paying a hospital visit [4]. Person-to-person transmission also took place in the most recent French cases.

Threat assessment for the EU

Information on many of the basic epidemiological indicators required for determining effective control measures is still missing for most cases that occurred in the Middle East, e.g. the reservoir of infection, risk groups, incubation period, period of infectivity, settings where infection has occurred – despite the requirements formulated in Article 6.2 of the 2005 International Health Regulations [18]. In particular, information from the earlier clusters in private homes, from hospitals in the Arabian Peninsula, and from the recent cases in Saudi Arabia is insufficient, which makes it difficult to comment on the routes of transmission or the underlying pattern of infection and disease. Consequently, it is not possible to estimate the disease risk. As a result, ECDC has to consider a number of underlying scenarios that are compatible with the information available. At this stage, it is not possible to exclude a SARS-like scenario, especially in the light of the hospital-related outbreaks in Jordan and Al-Hasa, Saudi Arabia.

The additional coronavirus cases reported by the Saudi Arabian authorities in the past two weeks and the recent imported cases reported by Germany (related to medical evacuation) and France (travel related) indicate that an ongoing source of human infections remains present in the Arabian Peninsula and Jordan and that more cases may be identified in the EU in the immediate future.

Medical evacuations represent a potent introduction of cases in the European Member States. Numbers of transfers may increase as concerns arise among clinicians and the public in the Middle East that there is a risk of MERS-CoV infection associated with in hospitals in the area.

The three person-to-person transmissions that have been documented in Europe, two of which are nosocomial, indicate that the risk of onward transmissions in Europe is significant, in particular in healthcare settings.

In those cases from the Middle East in which more detailed information is available, the majority have a history of underlying disease and/or immunosuppression. However, given a median age of 55.5 years, this may be normal for these age groups [22]. Hence, it needs to be investigated whether the elderly may be at increased risk of acquiring MERS-CoV infection and/or transmitting it.

The reason for the strong male predominance among the cases is unexplained. This is different from SARS, and it needs to be investigated whether this represents a difference in care-seeking behaviour or care receiving in the Middle East [22].

Despite extensive contact tracing amongst previous contacts, only one secondary case with mild symptoms has been detected to date in the EU. It is, however, a reason for concern that milder cases could be present in exposed populations in the Arabian Peninsula and Jordan.

Further work to document the spectrum of illness and the route of transmission is still needed. A seroepidemiological approach might be useful once the available tests are validated in the Middle East [18].

Conclusions

As of 14 May 2013, 38 cases of MERS-CoV have been reported worldwide, including 20 deaths. All cases remain associated (including indirect association following secondary person-to-person transmission in the UK and France) with transmission in the Arabian Peninsula and Jordan. The age of cases ranges from 24 to 94 years (N=34 cases), with a mean of 55.5 years and a male/female ratio of 1:0.2.
The report of 19 new infections in Saudi Arabia in the past two weeks – including one infection with MERS-CoV acquired in the United Arab Emirates and later imported to Europe – indicate that there is an ongoing source of infection and risk of transmission to humans in the Arabian Peninsula and Jordan.
The most recent imported case, which resulted in a nosocomial transmission, originated in the United Arab Emirates and then moved to France. Both patients had underlying conditions and a degree of immunosuppression. One of the transmissions in the UK also affected an immunosuppressed person. These underlying conditions may be increasing vulnerability and the risk of transmission.
The first French case raises the possibility that presentations may not include respiratory symptoms initially, especially in those with immunosuppression or underlying chronic conditions. This needs also to be taken into account when revising case-finding strategies.
The confirmed infection in France of a patient who shared a hospital room with a patient returning from the United Arab Emirates indicates the risk of nosocomial transmission. This is the second nosocomial transmission in Europe. The first one took place when an imported case in the UK visited a relative in the hospital in February 2013.
These conclusions should be seen in the light of the many uncertainties that still continue with the investigation of cases in the Arabian Peninsula and Jordan. It is unusual to have such a degree of uncertainty at this stage in an outbreak.

Recommendations

Healthcare workers in the EU should be vigilant in identifying patients that may require further investigation; they should also follow ECDC and national guidance for case finding. Patients developing severe respiratory infections and who have been in the Arabian Peninsula or neighbouring countries in the preceding 10 days should be investigated rapidly. Special attention should be given to medical evacuated patients from the Arabian Peninsula and neighbouring countries.
Patients with chronic underlying conditions who develop severe infections (not just respiratory infections) should also be investigated rapidly for MERS-CoV if they have been in the Arabian Peninsula or neighbouring countries in the preceding 10 days.
Since routine microbiological sampling (nasopharyngeal swabs) may give misleading negative results in persons later shown to be infected with the coronavirus, tests should be repeated with deeper respiratory sampling if a person fits into a category that requires investigation, especially if their condition is worsening.
As demonstrated by a case with dual influenza and MERS-CoV infections, there is a possibility of co-infection and this should be considered by healthcare personnel. Identification of one causative agent should not exclude testing for MERS-CoV where indicated.
Mapping of international routes of medical evacuation or emergency medical care from the Arabian Peninsula and neighbouring countries to the EU could be considered in order to determine the most vulnerable centres in the EU where these cases might arrive.
Companies undertaking medical evacuations from affected areas should be reminded of the risk of transferring infections across borders and of their obligations to protect staff engaged in the transfer; the same holds true for the staff of institutions which receive patients.
Healthcare workers caring for patients under investigation or confirmed for MERS-CoV should exercise infection control measures following national and international guidance [32].
Close contacts of confirmed cases must be monitored for symptoms for 10 days after the last exposure, and should be tested, and should be informed what to do should they become ill. This should be carried out according to guidance, such as that developed by Public Health England UK (See ‘Sources of additional information’ below).
Healthcare workers caring for confirmed cases should be monitored for early symptoms of infection and advised to seek testing and thereafter self-isolate if they become unwell.
Clusters of severe acute respiratory infections in the community or in healthcare settings, both among patients or healthcare workers, should always be reported rapidly and investigated for a range of pathogens, regardless of where in the world these infections occur.
ECDC does not currently consider a need for testing individual patients with unexplained pneumonias or other respiratory symptoms unless they fall under one of the above categories.
Any probable or confirmed case being diagnosed in the EU/EEA should be reported to national authorities through the Early Warning and Response System (EWRS) and to WHO under the International Health Regulations (2005). Reporting through EWRS qualifies as IHR notification and avoids double reporting. Patients still under investigation do not need to be reported internationally before confirmation, but information on outcome of such testing exercises should be shared with ECDC.
ECDC supports the WHO position of no travel or trade restrictions in relation to MERS-CoV. However, EU citizens travelling to the Arabian Peninsula and neighbouring countries need to be aware of the presence of MERS-CoV in this geographical area and of the small risk of infection. Member States may consider active information efforts for travellers to areas most at risk.
Although the reservoir of infection in the Middle East is unknown, other novel coronaviruses are zoonoses and have come from animal sources. Travellers should therefore follow standard good hygiene practise and avoid contact with animals or their waste products.

References

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[10] Müller M, Raj V, Muth D, et al. Human Coronavirus EMC Does Not Require the SARS-Coronavirus Receptor and Maintains Broad Replicative Capability in Mammalian Cell Lines. America Society for Microbiology. 11 December 2012 doi:10.1128/mBio.00508-12
[11] Kindler E, Jónsdóttira HR, Muthb D, Hammingc OJ, Hartmannc R, Rodriguez R et al. Efficient replication of the novel human betacoronavirus EMC on primary Human Epithelium Highlights Its Zoonotic Potential mBio doi: 10.1128/mBio.00611-12 19 February 2013 mBio vol. 4 no. 1 e00611-12.
[12] de Wilde AH, Ray VS, Oudshoorn D, Bestebroer TM, van Nieuwkoop S, Limpens RW, Posthuma CC, van der Meer Y, Bárcena M, Haagmans BL, Snijder EJ, van den Hoogen BG.Human coronavirus-EMC replication induces severe in vitro cytopathology and is strongly inhibited by cyclosporin A or interferon-alpha treatment. J Gen Virol. 2013 Apr 25. [Epub ahead of print]
[13] Palm D, Pereyaslov D, Vaz J, Broberg E, Zeller H, Gross D et al on behalf of the Joint ECDC-WHO Regional Office for Europe Novel Coronavirus Laboratory Survey participants; ECDC National Microbiology Focal Points, WHO European Region EuroFlu Network and European Network for Diagnostics of "Imported" Viral Diseases (ENIVD). Laboratory capability for molecular detection and confirmation of novel coronavirus in Europe, November 2012. Euro Surveill. 2012;17(49):pii=20335. Available at: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20335
[14] Corman VM, Müller MA, Costabel U, Timm J, Binger T, Meyer B et al. Assays for laboratory confirmation of novel human coronavirus (hCoV-EMC) infections. Euro Surveill. 2012;17(49):pii=20334. Available at: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20334
[15] Corman VM, Eckerle I, Bleicker T, Zaki A, Landt O, Eschbach-Bludau M et al. Detection of a novel human coronavirus by real-time reverse-transcription polymerase chain reaction. Euro Surveill. 2012;17(39):pii=20285. Available at: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20285
[16] Bermingham A, Chand MA, Brown CS, Aarons E, Tong C, Langrish C et al. Severe respiratory illness caused by a novel coronavirus, in a patient transferred to the United Kingdom from the Middle East, September 2012. Euro Surveill. 2012;17(40):pii=20290. Available at: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20290
[17] Reusken C, Mou H, Godeke GJ, van der Hoek L, Meyer B, Müller MA, Haagmans B, de Sousa R, Schuurman N, Dittmer U, Rottier P, Osterhaus A, Drosten C, Bosch BJ, Koopmans M. Specific serology for emerging human coronaviruses by protein microarray. Euro Surveill. 2013;18(14):pii=20441. Available online: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20441
[18] Nicoll A. Public health investigations required for protecting the population against novel coronaviruses. Eastern Mediterranean Health Journal 2013 (in press).
[19] Danielsson N, on behalf of the ECDC Internal Response Team, Catchpole M. Novel coronavirus associated with severe respiratory disease: Case definition and public health measures. Euro Surveill. 2012;17(39):pii=20282. at: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20282
[20] Van Kerkhove M, Broberg E, Engelhardt OG, Wood J, Nicoll A on behalf of the CONSISE steering committee. The consortium for the standardization of influenza seroepidemiology (CONSISE): a global partnership to standardize influenza seroepidemiology and develop influenza investigation protocols to inform public health policy Influenza and Other Respiratory Viruses DOI: 10.1111/irv.12068. Available at: http://onlinelibrary.wiley.com/doi/10.1111/irv.12068/full
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[23] Drexler JF, Gloza-Rausch F, Glende J, Corman VM, Muth D, Goettsche M, et al. Genomic characterization of severe acute respiratory syndrome-related coronavirus in European bats and classification of coronaviruses based on partial RNA-dependent RNA polymerase gene sequences J Virol. 2010;84(21):11336–49. Available at: http://jvi.asm.org/content/84/21/11336.abstract
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[27] Buchholz U, Nitsche A, Sanewski A, Bauer-Balci T, Bonin F et al Contact investigation of a case of human coronavirus infection treated in a German hospital, October-November 2012. Euro Surveill. 2013;18(8):pii=20406. Available online: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20406
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[30] Anderson RM, Fraser C, Ghani A, Donnelly C, Riley S, Ferguson NM et al Epidemiology, transmission dynamics and control of SARS: the 2002-2003 epidemic Philos Trans R Soc Lond B Biol Sci. 2004 July 29; 359(1447): 1091–1105. doi: 10.1098/rstb.2004.1490. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1693389/
[31] WHO Press Statement Related to the Novel Coronavirus Situation May 12 2013. http://www.who.int/mediacentre/news/statements/2013/Novel_Coronavirus_12052013/en/index.html
[32] WHO Infection prevention and control during health care for probable or confirmed cases of novel coronavirus (nCoV) infection Interim guidance.6 May 2013. Available at: http://www.who.int/csr/disease/coronavirus_infections/IPCnCoVguidance_06May13.pdf

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________

(1) A standard definition for ‘close contact’ is available online at http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20427

Aeroplane setting:

the aircraft passengers in the same row and the two rows in front and behind a symptomatic case.

Household setting:

any person who had prolonged (>15 minutes) face-to-face contact with the confirmed case(s) any time during the illness in a household setting.

Healthcare setting:

either (i)

a worker who provided direct clinical or personal care to or examined a symptomatic confirmed case or was within close vicinity of an aerosol-generating procedure
AND
who was not wearing full personal protective equipment (PPE) at the time;
or
(ii) a visitor to the hospital who was not wearing PPE at the bedside of a confirmed case; full PPE was defined as correctly fitted high filtration mask (FFP3), gown, gloves and eye protection.

Other setting:

any person who had prolonged (>15 minutes) face-to-face contact with a confirmed symptomatic case in any other enclosed setting.

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Thailand, Fears of disease as dead pigs found dumped in creek (Bangkok Post, May 17 2013)

2013-05-17T10:50:00.001+02:00

[Source: Bangkok Post, full page: (LINK). Extract.]

Dead pigs dumped in creek

Published: 17 May 2013 at 14.25

ROI ET – Six stinking bags containing dead pigs have been found dumped in a small creek near a village in tambon Khon Kaen of Muang district, sparking fears the animals may have died of a contagious disease. Pol Lt Col Reungsak Suwansri,case specialist at Muang district, said local people reported that the foul smelling bags had been left under a bridge of Lam Huay Nua creek, between Tab Tao and Nong Hung villages.

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